3-(4-PIPERIDINE-1YLMETHYL-PHENYL)-PROPION ACID-PHENYLAMIDE-DERIVATIVES AND RELATED COMPOUNDS USED IN THE FORM OF MCH ANTAGONISTS (MELANINE CONCENTRATING HORMONE) FOR TREATING EATING DISORDERS

DERIVES D'ACIDE 3-(4-PIPERIDINE-1YLMETHYL-PHENYL) PROPIONIQUE-PHENYLAMIDE ET COMPOSES APPARENTES, UTILISES COMME ANTAGONISTES MCH (HORMONE DE CONCENTRATION EN MELANINE) POUR LE TRAITEMENT DE TROUBLES DUS A L'ALIMENTATION

English Abstract

The invention relates to amid compounds of general formula (I), wherein groups
and residuals A, B, b, W, X, Y, Z, R1, R2 and R3 have significances given in a
claim 1. In addition, said invention relates to drugs containing at least one
type of inventive amid. Because of the antagonist activity of an MCH-receptor,
the inventive drugs are suitable for treating metabolic disturbances and/or
eating disorders, in particular adiposity, bulimia, anorexia, hyperphagia and
diabetes.

French Abstract

L'invention concerne des composés amides, de formule générale (I), dans laquelle les groupes et les restes A, B, b, W, X, Y, Z, R1, R2 et R3 ont les significations données dans la revendication 1. En outre, l'invention concerne des médicaments renfermant au moins un amide selon l'invention. En raison de l'activité antagoniste du récepteur de MCH, les médicaments selon l'invention conviennent pour le traitement de troubles métaboliques et/ou de troubles dus à l'alimentation, en particulier, adipositas, boulimie, anorexie, hyperphagie et diabètes.

Claims

342
Claims
1. Amide compounds of general formula I
<IMG>
wherein
R1, R2 independently of one another denote H, a C1-8-alkyl or C3-7-cycloalkyl
group optionally mono- or polysubstituted by the group R11, while a
-CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group
may be replaced by -O-, -S- or -NR13-, or a phenyl or pyridinyl group
optionally mono- or polysubstituted by the group R12 and/or
monosubstituted by nitro, or
R1 and R2 form a C2-8-alkylene bridge, wherein
- one or two -CH2- groups independently of one another may be
replaced by -CH=N- or -CH=CH- and/or
- one or two -CH2 groups independently of one another may be
replaced by -O-, -S-, -SO-, -(SO2)-, -C=N-O-R18-, -CO-, -C(=CH2)- or
-NR13- in such a way that heteroatoms are not directly joined
together, and that a group -C=N-O-R18 or -CO- is not directly linked to
the group R1R2N-,
while in the alkylene bridge defined hereinbefore one or more H atoms
may be replaced by R14, and
the alkylene bridge defined hereinbefore may be substituted by one or
two identical or different carbo- or heterocyclic groups Cy such that the
bond between the alkylene bridge and the group Cy is made
- via a single or double bond,
- via a common C atom forming a spirocyclic ring system,

343
- via two common adjacent C and/or N atoms forming a fused bicyclic
ring system or
- via three or more C and/or N atoms forming a bridged ring system,
R3 denotes H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl or
phenyl-
C1-3-alkyl,
X denotes a single bond or a C1-8-alkylene bridge, wherein
- a -CH2- group which is not directly linked to the group R1R2N- may
be replaced by -CH=CH- or -C.ident.C- and/or
- one or two non-adjacent -CH2- groups, which are not directly linked to
the group R1R2N-, may be replaced independently of one another by
-O-, -S-, -(SO)-, -(SO2), -CO- or -NR4- in such a way that in each case
two O, S or N atoms or an O and an S atom are not directly joined
together,
while the bridge X may be connected to R1 including the N atom linked
to R1 and X, forming a heterocyclic group, while the bridge X may
additionally also be connected to R2 including the N atom connected to
R2 and X, forming a heterocyclic group, and
while two C atoms or a C and an N atom of the alkylene bridge may be
joined together by an additional C1-4-alkylene bridge, and
a C atom may be substituted with R10 and/or one or two C atoms may
be substituted in each case by one or two identical or different
substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-
cycloalkenyl-C1-3-alkyl, while two alkyl and/or alkenyl substituents may
be joined together, forming a carbocyclic ring system, and
W denotes a single bond, while

344
Z denotes -C.ident. C-C(=O)-, -CR7a=CR7c-C(=O)- or -CR7aR7b-CR7cR7d-C(=O)-
, or
W denotes -C(=O)-C.ident. C-, while
Z denotes a single bond; and
Y has one of the meanings given for Cy,
while X may be connected to Y, forming a carbo- or heterocyclic group
fused to Y, and/ or
optionally R1 may be connected to Y, including the group X and the N
atom connected to R1 and X, forming a heterocyclic group fused to Y,
and
A has one of the meanings given for Cy, while if the index b has the value
0, the group Cy does not have an amino group as substituent in the
ortho position to the bridge W;
B has one of the meanings given for Cy,
b denotes the value 0 or 1,
Cy denotes a carbo- or heterocyclic group selected from one of the
following meanings
- a saturated 3- to 7-membered carbocyclic group,
- a unsaturated 4- to 7-membered carbocyclic group,
- a phenyl group,
- a saturated 4- to 7-membered or unsaturated 5- to 7-membered
heterocyclic group with an N, O or S atom as heteroatom,
- a saturated or unsaturated 5- to 7-membered heterocyclic group with
two or more N atoms or with one or two N atoms and one O or S
atom as heteroatoms,

345
- an aromatic heterocyclic 5- or 6-membered group with one or more
identical or different heteroatoms selected from N, O and/or S,
while the above-mentioned 4, 5-, 6- or 7-membered groups may be
fused to a phenyl or pyridine ring via two common adjacent C atoms,
and
in the above-mentioned 5-, 6- or 7-membered groups one or two non-
adjacent -CH2- groups may independently of one another be replaced by
a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and
the above-mentioned saturated 6- or 7-membered groups may also
occur as bridged ring systems with an imino, N-(C1-4-alkyl)-imino,
methylene, C1-4-alkyl-methylene or di-(C1-4-alkyl)-methylene bridge, and
the above-mentioned cyclic groups may be mono- or polysubstituted by
R20 at one or more C atoms, in the case of a phenyl group may also
additionally be monosubstituted by nitro, and/or one or more NH groups
may be substituted by R21,
R4 has one of the meanings given for R17 or denotes C2-6-alkenyl or C3-6-
alkynyl,
R7a, R7c denote H, F, Cl, C1-4-alkyl or CF3,
R7b, R7d denote H, F, C1-4-alkyl, while R7b and R7d representing alkyl may be
joined together to form a cyclopropyl group;
R10 denotes hydroxy, hydroxy-C1-3-alkyl, C1-4-alkoxy, C1-4-alkoxy-C1-3-alkyl,
carboxy, C1-4-alkoxycarbonyl, amino, C1-4-alkyl-amino, di-(C1-4-alkyl)-
amino, cyclo-C3-6-alkyleneimino, amino-C1-3-alkyl, C1-4-alkyl-amino-C1-3-
alkyl, di-(C1-4-alkyl)-amino-C1-3-alkyl, cyclo-C3-6-alkyleneimino-C1-3-alkyl,
amino-C1-3-alkoxy, C1-4-alkyl-amino-C1-3-alkoxy, di-(C1-4-alkyl)-amino-C1-
3-alkoxy, cyclo-C3-6-alkyleneimino-C1-3-alkoxy, aminocarbonyl, C1-4-alkyl-

346
aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or cyclo-C3-6-
alkyleneimino-carbonyl,
R11 denotes C2-6-alkenyl, C2-6-alkynyl, R15-O-, R15-O-C1-3-alkyl, R15-O-CO-,
R15-CO-O-, R16R17N, cyano, R18R19N-CO- or Cy,
R12 has one of the meanings given for R20,
R13 has one of the meanings given for R17, with the exception of carboxy,
R14 denotes halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-O, R15-O-CO,
R15-CO, R15-CO-O, R16R17N, R18R19N-CO-, R15-O-C1-3-alkyl, R15-O-CO-
C1-3-alkyl, R15-O-CO-NH, R15-SO2-NH, R15-O-CO-NH-C1-3-alkyl, R15-
SO2-NH-C1-3-alkyl, R15-CO-C1-3-alkyl, R15-CO-O-C1-3-alkyl, R16R17N-C1-
3-alkyl, R18R19N-CO-C1-3-alkyl or Cy-C1-3-alkyl,
R15 denotes H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl,
phenyl,
phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl,
R16 denotes H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-
cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, hydroxy-C2-3-alkyl, C1-4-alkoxy-
C2-3-alkyl, amino-C2-6-alkyl, C1-4-alkyl-amino-C2-6-alkyl, di-(C1-4-alkyl)-
amino-C2-6-alkyl or cyclo-C3-6-alkyleneimino-C2-6-alkyl,
R17 has one of the meanings given for R16 or denotes
phenyl, phenyl-C1-3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C1-
4-alkylcarbonyl, carboxy, hydroxycarbonyl-C1-3-alkyl,
C1-4-alkoxycarbonyl, C1-4-alkoxycarbonyl-C1-3-alkyl, C1-
4-alkylcarbonylamino-C2-3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-
amino-C2-3-alkyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonylamino-C2-3-alkyl
or N-(C1-4-alkylsulphonyl)-N(C1-4-alkyl)-amino-C2-3-alkyl

347
R18, R19 independently of one another denote H or C1-6-alkyl,
R20 denotes halogen, hydroxy, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-4-alkyl, R2-C1-4-
alkyl or has one of the meanings given for R22,
R21 denotes C1-4-alkyl, hydroxy-C2-3-alkyl, C1-4-alkoxy-C2-6-alkyl, C1-4-alkyl-
amino-C2-6-alkyl, di-(C1-4-alkyl)-amino-C2-6-alkyl, cyclo-C3-6-
alkyleneimino-C1-6-alkyl, phenyl-C1-3-alkyl, C1-4-alkyl-carbonyl,
C1-4-alkoxy-carbonyl or C1-4-alkylsulphonyl,
R22 denotes phenyl-C1-3-alkoxy, cyclo-C3-6-alkyleneimino-C2-4-alkoxy, OHC-,
HO-N=HC-, C1-4-alkoxy-N=HC-, C1-4-alkoxy, C1-4-alkylthio, carboxy,
C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylamino-
carbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyclo-C3-6-alkyl-amino-carbonyl,
cyclo-C3-6-alkyleneimino-carbonyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl-
aminocarbonyl, phenyl-amino-carbonyl, C1-4-alkyl-sulphonyl, C1-4-alkyl-
sulphinyl, C1-4-alkyl-sulphonylamino, amino, C1-4-alkylamino, di-(C1-4-
alkyl)-amino, C1-4-alkyl-carbonyl-amino, cyclo-C3-6-alkyleneimino, phe-
nyl-C1-3-alkylamino, N-(C1-4-alkyl)-phenyl-C1-3-alkylamino, acetylamino,
propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino,
hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-
carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-
methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or
alkylaminocarbonylamino-,
while in the above-mentioned groups and radicals, particularly in A, B, W, X,
Y, Z, R1
to R4, R7a, R7b, R7c, R7d, R10 to R22, in each case one or more C atoms may
additionally be mono- or polysubstituted by F and/or in each case one or two C
atoms
independently of one another may additionally be monosubstituted by Cl or Br
and/or
in each case one or more phenyl rings may independently of one another
additionally
comprise one, two or three substituents selected from the group F, Cl, Br, I,
C1-4-
alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-
alkylamino, di-
(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy,

348
trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl and di-(C1-3-
alkyl)-amino-
C1-3-alkyl and/or may be monosubstituted by nitro, and
the H atom of a carboxy group present or an H atom bound to an N atom in each
case may be replaced by a group which can be cleaved in vivo,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and
the salts
thereof,
while the following compounds according to provisos (M1) to (M14) are not
included:
(M1) N-[4-[[(methylamino)sulphonyl]methyl]phenyl]-3-[2-(dimethylamino)-ethyl]-
1-
H-indole-5-propanamide oxalate,
(M2) 3-[2-[3-[3.6-dihydro-4-(2-naphthyl)-1 (2H)-pyridinyl]-2-
hydroxypropoxy]phenyl]-
N-methyl-N-phenyl-2-propenamide,
(M3) 3-[2-[2-hydroxy-3-[4-(1-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-
N-
phenyl-2-propenamide,
(M4) 3-[2-[2-hydroxy-3-[4-(2-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-
N-
phenyl-2-propenamide,
(M5) 3-[2-[2-hydroxy-3-[4-(2-naphthalyl)-1-piperidinyl]propoxy]phenyl]-N-
phenyl-2-
propenamide,
(M6) N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-phenyl-2-propinamide,
(M7) 2'-[[3-(dimethylamino)propyl]thio]-3-phenyl-propiolanilide,
(M8) 2-(methylthio)-5-[[3-[4-(octadecylamino)phenyl]-1-oxopropyl]amino]-
benzoic
acid, including the trifluoroacetate salt,
(M9) 4-amino-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide,

349
(M10) 4-(dimethylamino)-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide,
(M11) .beta.-methyl-4-[[3-[2-[(2-methylphenyl)amino]-6-benzoxazolyl]-1-
oxopropylamino]-benzenepropanoic acid,
(M12) 4-[3-[[1-oxo-3-[2-(phenylamino)-6-benzoxazolyl]- propyl]amino]phenoxy]-
butanoic acid,
(M13) 2-chloro-5-[[1-oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-
benzoic
acid,
(M14) methyl2-chloro-5-[[1-oxo-3-[4-[(5-
phenylpentyl)amino]phenyl]propyl]amino]-
benzoate.
2. Amide compounds according to claim 1 characterised by formulae Ia or Ib
<IMG>
wherein R1, R2, R3, X, Y, A, B and b have the meanings given in claim 1.
3. Amide compounds according to claim 1, characterised by formulae Ic or Id
<IMG>

350
<IMG>
wherein R1, R2, R3, R7a, R7b, R7c, R7d, X, Y, A, B and b have the meanings
given in claim 1.
4. Amide compounds according to one or more of the preceding claims,
characterised in that R1, R2 independently of one another denote C1-6-alkyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C2-4-alkyl, NC-C2-4-
alkyl,
C1-4-alkoxy-C2-4-alkyl, C1-4-alkoxy-carbonyl-C1-4-alkyl, carboxyl-C1-4-alkyl,
amino-C2-4-alkyl, C1-4-alkyl-amino-C2-4-alkyl, di-(C1-4-alkyl)-amino-C2-4-
alkyl,
cyclo-C3-6-alkyleneimino-C2-4-alkyl, pyrrolidin-3-yl, while the NH group may
be substituted by R13, pyrrolidinyl-C1-3-alkyl, while the NH group may be
substituted by R13, piperidin-3-yl or -4-yl, while the NH group may be
substituted by R13, piperidinyl-C1-3-alkyl, while the NH group may be
substituted by R13, tetrahydropyran-3-yl or -4-yl, tetrahydropyranyl-C1-3-
alkyl,
tetrahydrofuran-3-yl, tetrahydrofuranyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl,
pyridyl or pyridyl-C1-3-alkyl,
while in the above-mentioned groups and radicals one or more C atoms may
be mono- or polysubstituted by F and/or one or two C atoms, particularly one
C atom may independently of one another be monosubstituted by Cl or Br,
and
the phenyl or pyridyl group may be mono- or polysubstituted by the group R12
defined hereinbefore and/or may be monosubstituted by nitro, and
cycloalkyl rings may be mono- or polysubstituted by substituents selected
from hydroxy, hydroxy-C1-3-alkyl, C1-3-alkyl or C1-3-alkyloxy, and
C2-4-alkyl bridges contained in hydroxy-C2-4-alkyl- and C1-4-alkoxy-C2-4-alkyl-
may additionally be monosubstituted by hydroxy, hydroxy-C1-3-alkyl, C1-3-alkyl

351
or C1-3-alkyloxy, and
one of the groups R1, R2 may also represent H, and
R13 is defined as in claim 1.
5. Amide compounds according to one or more of claims 1 to 3, characterised in
that R1 and R2 form an alkylene bridge according to claim 1 such that R1R2N-
denotes a group selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-
dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-
azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, wherein the free imine
function is substituted by R13, piperidin-4-one-oxime, piperidin-4-one-O-C1-4-
alkyl-oxime, morpholine and thiomorpholine,
while according to claim 1 one or more H atoms may be replaced by R14, and/
or may be substituted by one or two identical or different carbo- or
heterocyclic groups Cy in the manner specified in claim 1,
while R13, R14 and Cy have the meaning given in claim 1.
6. Amide compounds according to one or more of the preceding claims,
characterised in that
the group <IMG>
is defined according to one of the following partial formulae
<IMG>

352
<IMG>

353
<IMG>

354
<IMG>
while in the heterocycle formed by the group R1R2N- one or more H atoms may be
replaced by R14 and/or a H atom may be substituted by Cy defined as C3-7-
cycloalkyl,
which may be mono- or polysubstituted by R20, and the ring connected to the
heterocycle formed by the group R1R2N- may be mono- or polysubstituted at one
or
more C atoms by R20, and in the case of a phenyl ring may also additionally be
monosubstituted by nitro, and
X', X" independently of one another denote a single bond or C1-3-alkylene and
in the event that the group Y is linked to X' or X" via a C atom, may also
denote -C1-3-alkylene-O-, -C1-3-alkylene-NH- or -C1-3-alkylene-N(C1-3-alkyl)-,
and
X" additionally also denotes -O-C1-3-alkylene-, -NH-C1-3-alkylene- or
-N(C1-3-alkyl)-C1-3-alkylene- and
in the event that the group Y is linked to X" via a C atom, also denotes
-NH-, -N(C1-3-alkyl)- or -O-,
while in the meanings given for X', X" hereinbefore in each case a C atom
may be substituted by R10, preferably by a hydroxy, w-hydroxy-C1-3-alkyl,

355
.omega.-(C1-4-alkoxy)-C1-3-alkyl and/or C1-4-alkoxy group, and/or one or two C
atoms in each case may be substituted by one or two identical or different
substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-
cycloalkenyl-C1-3-alkyl, while two alkyl and/or alkenyl substituents may be
joined together, forming a carbocyclic ring system, and
in X', X" independently of one another in each case one or more C atoms
may be mono- or polysubstituted by F and/or in each case one or two C
atoms independently of one another may be monosubstituted by Cl or Br
and
wherein R2, R10, R13, R14, R20, R21 and X have the meanings given in claim 1.
7. Amide compounds according to one or more of the preceding claims,
characterised in that X denotes an unbranched C1-4-alkylene bridge and
in the event that the group Y is linked to X via a C atom, it also denotes a
single bond,
-CH2-CH=CH-, -CH2-C.ident.C-, C2-4-alkylenoxy or C2-4-alkylene-NR4,
while the bridge X may be connected to R1, including the N atom connected to
R1 and
X, forming a heterocyclic group, and
in X a C atom may be substituted by R10 and/or one or two C atoms may each be
substituted by one or two identical or different substituents selected from C1-
6-alkyl,
C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-
cycloalkenyl
and C4-7-cycloalkenyl-C1-3-alkyl, while two alkyl and/or alkenyl substituents
may be
joined together, forming a carbocyclic ring system, and
in the above-mentioned groups and radicals one or more C atoms may be mono- or
polysubstituted by F and/or one or two C atoms independently of one another
may be
monosubstituted by Cl or Br and

356
R1, R4 and R10 are defined as in claim 1.
8. Amide compounds according to claim 7, characterised in that X denotes
-CH2-, -CH2-CH2- or -CH2-CH2-CH2- and
in the event that the group Y is linked to X via a C atom, it also denotes
a single bond, -CH2-CH=CH-, -CH2-C.ident.C-, -CH2-CH2-O-, -CH2-CH2-CH2-O-,
-CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-,
while the bridge X may be connected to R1, including the N atom linked to R1
and X, forming a heterocyclic group, and
in X a C atom may be substituted by R10, preferably a hydroxy,
hydroxy-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl and/or C1-4-alkoxy group, and/or
one
or two C atoms in each case may be substituted by one or two identical or
different substituents selected from C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,
C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl and C4-7-
cycloalkenyl-
C1-3-alkyl, while two alkyl and/or alkenyl substituents may be joined
together,
forming a carbocyclic ring system, and
in each case one or more C atoms may be mono- or polysubstituted by F
and/or in each case one or two C atoms independently of one another may be
monosubstituted by Cl or Br and
wherein R1, R4 and R10 have one of the meanings given in claim 1.
9. Amide compounds according to one or more of the preceding claims,
characterised in that the group Y is selected from among the bivalent cyclic
groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl,
dihydroindolyl,
quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl,
dihydroisoquinolinyl, tetrahydro-isoquinolinyl and benzoxazolinyl,
while the above-mentioned cyclic groups may be mono- or polysubstituted by

357
R20 at one or more C atoms, in the case of a phenyl group may also
additionally be monosubstituted by nitro, and/or may be substituted by R21 at
one or more N atoms,
while X may be connected to Y as in claim 1, and
X, R20 and R21 have the meanings given in claim 1.
10. Amide compounds according to one or more of the preceding claims,
characterised in that the group Y is selected from among the bivalent cyclic
groups
<IMG>
while the above-mentioned cyclic groups may be mono- or polysubstituted by
R20at one or more C atoms, in the case of a phenyl group may also

358
additionally be monosubstituted by nitro, and/or one or more NH groups may
be substituted by R21, wherein R20 and R21 are defined as in claim 1.
11. Amide compounds according to one or more of the preceding claims,
characterised in that the group Y is linked to the group X forming a
carbocyclic group fused to Y, while the carbocyclic group -X-Y- formed is
selected from
<IMG>
while in the above-mentioned bicyclic groups the phenyl ring may be mono-
or polysubstituted by R20 or may also additionally be monosubstituted by
nitro,
and the saturated carbocyclic ring may be mono- or disubstituted by C1-3-
alkyl.
12. Amide compounds according to one or more of the preceding claims,
characterised in that the group A denotes phenyl, pyridyl or naphthyl,
while the above-mentioned cyclic groups may be mono- or polysubstituted by
R20 at one or more C atoms, and in the case of a phenyl ring may also
additionally be monosubstituted by nitro, and/or one or more NH groups may
be substituted by R21, while if the index b has the value 0, the group A does
not have an amino group as substituent in the ortho position to the bridge W,
and
R20 and R21 have the meanings given in claim 1.

359
13. Amide compounds according to one or more of the preceding claims,
characterised in that b has the value 0.
14. Amide compounds according to one or more of the preceding claims,
characterised in that b has the value 1 and B has a meaning selected from
the group consisting of phenyl, furanyl, thienyl and pyridyl,
while the above-mentioned cyclic groups may be mono- or polysubstituted by
R20 at one or more C atoms, and in the case of a phenyl ring may also
additionally be monosubstituted by nitro, and
R20 has the meaning given in claim 1.
15. Amide compounds according to one or more of the preceding claims,
characterised in that
Y is defined according to claim 9 or 10 and 11,
A is defined according to claim 12,
B is defined according to claim 14 and
b denotes the value 0 or 1.
16. Amide compounds according to claim 15, characterised in that
R1, R2 are defined as in claim 4 and 5 or 4 and 6,
X is defined as in claim 7 or 8,

360
W and Z are defined as in claim 2 or 3.
17. Amide compounds according to one or more of the preceding claims,
characterised in that
R20 denotes F, Cl, Br, I, OH, cyano, C1-4alkyl, C1-4-alkoxy,
difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy,
amino, C1-3-alkyl-amino, di-C1-3-alkyl-amino, carboxy or C1-4-
alkoxy-carbonyl, while substituents R20 occurring more than once
may have the same or different meanings and in the case of a
phenyl ring this may also additionally be monosubstituted by nitro.
18. Physiologically acceptable salts of the amide compounds according to one
or
more of claims 1 to 17.
19. Composition containing at least one amide compound according to one or
more of claims 1 to 17 and/ or a salt according to claim 18 optionally
together
with one or more physiologically acceptable excipients.
20. Pharmaceutical compositions, containing at least one amide compound
according to one or more of claims 1 to 17 and/ or a salt according to claim
18
optionally together with one or more inert carriers and/or diluents.
21. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for influencing the eating
behaviour of a mammal.
22. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by

361
provisos (M1) to (M14) according to claim 1, for reducing the body weight
and/ or for preventing an increase in the body weight of a mammal.
23. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition with an MCH-receptor-antagonistic activity.
24. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition, which is suitable for preventing and/or treating symptoms and/or
diseases which are caused by MCH or are otherwise causally connected with
MCH.
25. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition, which is suitable for preventing and/or treating metabolic
disorders and/or eating disorders, particularly obesity, bulimia, bulimia
nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.
26. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition, which is suitable for preventing and/or treating diseases and/or
disorders associated with obesity, particularly diabetes, especially type II
diabetes, complications of diabetes including diabetic retinopathy, diabetic
neuropathy, diabetic nephropathy, insulin resistance, pathological glucose
tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases,
particularly arteriosclerosis and high blood pressure, arthritis and gonitis.

362
27. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition which is suitable for preventing and/or treating hyperlipidaemia,
cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis,
emotional disorders, affective disorders, depression, anxiety, sleep
disorders,
reproductive disorders, sexual disorders, memory disorders, epilepsy, forms
of dementia and hormonal disorders.
28. Use of at least one amide compound according to one or more of claims 1 to
17 and/ or a salt according to claim 18, including the compounds excluded by
provisos (M1) to (M14) according to claim 1, for preparing a pharmaceutical
composition which is suitable for preventing and/or treating micturition
disorders, such as for example urinary incontinence, hyperactive urinary
bladder, urgency, nycturia and enuresis.
29. Process for preparing a composition or a pharmaceutical composition
according to one or more of claims 19 to 28, characterised in that at least
one
amide compound according to one or more of claims 1 to 17 and/ or a salt
according to claim 18 is incorporated in one or more inert carriers and/or
diluents by a non-chemical method.
30. Pharmaceutical compositions, containing
a first active substance selected from the amide compounds according to one
or more of claims 1 to 17 and/ or a salt according to claim 18, including the
compounds excluded by provisos (M1) to (M14) according to claim 1, and
a second active substance selected from the group consisting of active
substances for the treatment of diabetes, active substances for the treatment
of diabetic complications, active substances for the treatment of obesity,
preferably other than MCH antagonists, active substances for the treatment of
high blood pressure, active substances for the treatment of hyperlipidaemia,
including arteriosclerosis, active substances for the treatment of arthritis,
active

363
substances for the treatment of anxiety states and active substances for the
treatment of depression,
optionally together with one or more inert carriers and/or diluents.

Description

CA 02550649 2006-06-20
WO 2005/063239 1 PCT/EP2004/014378
85967pct.214
New amide-compounds with MCH antagonistic activity and medicaments
comprising these compounds
The present invention relates to new amide compounds, the physiologically
acceptable salts thereof as well as their use as MCH antagonists and their use
in
preparing a pharmaceutical preparation which is suitable for the prevention
and/or
treatment of symptoms and/or diseases caused by MCH or causally connected with
MCH in some other way. The invention further relates to the use of a compound
according to the invention for influencing eating behaviour and for reducing
body
weight and/or for preventing an increase in the body weight of a mammal. The
invention also relates to compositions and medicaments containing a compound
according to the invention, and processes for preparing them. Further objects
of this
invention relate to processes for preparing the compounds according to the
invention.
Background to the Invention
The intake of food and its conversion in the body is an essential part of life
for all
living creatures. Therefore, deviations in the intake and conversion of food
generally
lead to problems and also illness. The changes in the lifestyle and nutrition
of
humans, particularly in industrialised countries, have promoted morbid
overweight
(also known as corpulence or obesity) in recent decades. In affected people,
obesity
leads directly to restricted mobility and a reduction in the quality of life.
There is the
additional factor that obesity often leads to other diseases such as, for
example,
diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary
heart
disease. Moreover, high body weight alone puts an increased strain on the
support
and mobility apparatus, which can lead to chronic pain and diseases such as
arthritis
or osteoarthritis. Thus, obesity is a serious health problem for society.
The term obesity means an excess of adipose tissue in the body. In this
connection,
obesity is fundamentally to be seen as the increased level of fatness which
leads to a
health risk. There is no sharp distinction between normal individuals and
those
suffering from obesity, but the health risk accompanying obesity is presumed
to rise
continuously as the level of fatness increases. For simplicity's sake, in the
present

CA 02550649 2006-06-20
WO 2005/063239 2 PCT/EP2004/014378
invention, individuals with a Body Mass Index (BMI), which is defined as the
body
weight measured in kilograms divided by the height (in metres) squared, above
a
value of 25 and more particularly above 30, are preferably regarded as
suffering from
obesity.
Apart from physical activity and a change in nutrition, there is currently no
convincing
treatment option for effectively reducing body weight. However, as obesity is
a major
risk factor in the development of serious and even life-threatening diseases,
it is all
the more important to have access to pharmaceutical active substances for the
prevention and/or treatment of obesity. One approach which has been proposed
very
recently is the therapeutic use of MCH antagonists (cf. inter alia WO 01
/21577, WO
01 /82925).
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19
amino acids. It is synthesised predominantly in the hypothalamus in mammals
and
from there travels to other parts of the brain by the projections of
hypothalamic
neurones. Its biological activity is mediated in humans through two different
glycoprotein-coupled receptors (GPCRs) from the family of rhodopsin-related
GPCRs,
namely the MCH receptors 1 and 2 (MCH-1 R, MCH-2R).
Investigations into the function of MCH in animal models have provided good
indications for a role of the peptide in regulating the energy balance, i.e.
changing
metabolic activity and food intake [1.2]. For example, after intraventricular
administration of MCH in rats, food intake was increased compared with control
animals. Additionally, transgenic rats which produce more MCH than control
animals,
when given a high-fat diet, responded by gaining significantly more weight
than
animals without an experimentally altered MCH level. It was also found that
there is a
positive correlation between phases of increased desire for food and the
quantity of
MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock-out
mice are particularly important in showing the function of MCH. Loss of the
neuropeptide results in lean animals with a reduced fat mass, which take in
significantly less food than control animals.

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WO 2005/063239 3 PCT/EP2004/014378
The anorectic effects of MCH are presumably mediated in rodents through the G-
Galpha i-coupled MCH-1 R [3-6], as, unlike primates, ferrets and dogs, no
second
MCH receptor subtype has hitherto been found in rodents. After losing the MCH-
1 R,
knock-out mice have a lower fat mass, an increased energy conversion and, when
fed
on a high fat diet, do not put on weight, compared with control animals.
Another
indication of the importance of the MCH system in regulating the energy
balance
results from experiments with a receptor antagonist (SNAP-7941 ) [3]. In long
term
trials the animals treated with the antagonist lose significant amounts of
weight.
In addition to its anorectic effect, the MCH-1 R antagonist SNAP-7941 also
achieves
additional anxiolytic and antidepressant effects in behavioural experiments on
rats [3].
Thus, there are clear indications that the MCH-MCH-1 R system is involved not
only in
regulating the energy balance but also in affectivity.
Literature:
1. Qu, D., et al., A role for melanin-concentrating hormone in the central
regulation
of feeding behaviour. Nature, 1996. 380(6571 ): p. 243-7.
2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are
hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.
3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a
melanin-concentrating hormone-1 receptor antagonist. Nat Med, 2002. 8(8): p.
825-30.
4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone
receptor-1 results in hyperphagia and resistance to diet-induced obesity.
Endocrinology, 2002. 143(7): p. 2469-77.
5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient
mice are
lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl
Acad Sci U S A, 2002. 99(5): p. 3240-5.
6. Takekawa, S., et al., T 226296: A novel, orally active and selective
melanin-
concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p.
129-35.
In the patent literature certain amine compounds are proposed as MCH
antagonists.
Thus, WO 01/21577 (Takeda) describes compounds of formula

CA 02550649 2006-06-20
WO 2005/063239 4 PCT/EP2004/014378
1
Ar'-X-Ar-Y-N~ R
R2
wherein Ar1 denotes a cyclic group , X denotes a spacer, Y denotes a bond or a
spacer, Ar denotes an aromatic ring which may be fused with a non-aromatic
ring, R1
and R2 independently of one another denote H or a hydrocarbon group, while R1
and
R2 together with the adjacent N atom may form an N-containing hetero ring and
R2
with Ar may also form a spirocyclic ring, R together with the adjacent N atom
and Y
may form an N-containing hetero ring, as MCH antagonists for the treatment of
obesity, inter alia.
Moreover WO 01/82925 (Takeda) also describes compounds of formula
1
Ar'-X-Ar-Y-N~ R
R2
wherein Ar1 denotes a cyclic group , X and Y represent spacer groups, Ar
denotes an
optionally substituted fused polycyclic aromatic ring, R1 and R2 independently
of one
another represent H or a hydrocarbon group, while R1 and RZ together with the
adjacent N atom may form an N-containing heterocyclic ring and RZ together
with the
adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists
for
the treatment of obesity.
EP 0 237 678 A1 describes indole derivatives for the treatment of migraine.
Example
4 mentions the compound N-[4-[[(methylamino)sulphonyl]methyl]phenyl]-3-[2-
(dimethylamino)-ethyl]-1-H-indole-5-propanamide oxalate.
JP 2000086603 describes propenamide derivatives which have a 2-hydroxypropoxy
group, used as 5-HT1A receptor antagonists.
WO 99/29674 describes N-imidazolyl- and N-triazolylalkyl-phenyl-acetamide
derivatives as inhibitors of the retinoid metabolism. The substance N-[4-[1-(1
H-
imidazol-1-yl)-2-methylpropyl]phenyl]-3-phenyl-2-propinamide is mentioned as
compound number 198.

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WO 2005/063239 5 PCT/EP2004/014378
J. Krapcho et al. mention in J. Med. Chem. (1969), 12(1 ), 164-6 entitled
"Immunosuppressive activity of 2'-(3-dimethylaminopropylthio)cinnamanilide
(cinanserin) and related compounds" inter alia the compound 2'-[[3-
(dimethylamino)propyl]thio]-3-phenyl-propiolanilide.
WO 2001002344 describes aminobenzoic acid derivatives as VEGF receptor
antagonists and mentions, among others, the compound 2-(methylthio)-5-[[3-[4-
(octadecylamino)phenyl]-1-oxopropyl]amino]-benzoic acid.
JP 04054118 proposes 4-(acylamino)phenols as 5-lipoxygenase inhibitors and
mentions among others the compounds 4-amino-N-(4-hydroxy-3, 5-dimethylphenyl)-
benzenepropanamide as well as 4-(dimethylamino)-N-(4-hydroxy-3, 5-
dimethylphenyl)-benzenepropanamide.
The preparation of [[(benzoxyzolylalkanoyl)amino]phenyl]alkanoates and their
suitability as integrin receptor ligands are described in WO 2000049005.
Mention is
made inter alia of the compound [i-methyl-4-[[3-[2-[(2-methylphenyl)amino]-6-
benzoxazolyl]-1-oxopropylamino]-benzenepropanoic acid.
WO 2000005223 describes benzoxazole derivatives as inhibitors of the
interaction
between VCAM-1 and/or fibronectin and the integrin receptor VLA-4. Mention is
made
inter alia of the compound 4-[3-[[1-oxo-3-[2-(phenylamino)-6-
benzoxazolyl]propyl]amino]phenoxy]-butanoic acid.
The preparation of carboxylic acid derivatives as EDG-1 receptor agonists is
described in WO 2002092068. Mention is made interalia of 2-chloro-5-[[1-oxo-3-
[4-
[(5-phenylpentyl)amino]phenyl]propyl]amino]-benzoic acid and the corresponding
methyl ester.
Published International Application WO 2004/072018 proposes amine derivatives
as
antagonists of the MCH receptor. As well as compounds covered by general
formula

CA 02550649 2006-06-20
WO 2005/063239 6 PCT/EP2004/014378
1 O Ray Ra3 ~R~
Ar-C-N-C-C Ar-Y-N
z
R Ra2 Ra4 R , a number of different individual compounds
are also published.
Aim of the invention
The aim of the present invention is to provide new amide compounds,
particularly
those which are effective as MCH antagonists.
The invention also sets out to provide new amide compounds which can be used
to
influence the eating habits of mammals and achieve a reduction in body weight,
particularly in mammals, and/or prevent an increase in body weight.
The present invention further sets out to provide new pharmaceutical
compositions
which are suitable for the prevention and/or treatment of symptoms and/or
diseases
caused by MCH or otherwise causally connected to MCH. In particular, the aim
of this
invention is to provide pharmaceutical compositions for the treatment of
metabolic
disorders such as obesity and/or diabetes as well as diseases and/or disorders
which
are associated with obesity and diabetes. Other objectives of the present
invention
are concerned with demonstrating advantageous uses of the compounds according
to
the invention. The invention also sets out to provide a process for preparing
the amide
compounds according to the invention. Other aims of the present invention will
be
immediately apparent to the skilled man from the foregoing remarks and those
that
follow.
Object of the invention
In a first aspect the present invention relates to amide compounds of general
formula
R'
N X Y Z N W A~B,b
R Rs

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WO 2005/063239 7 PCT/EP2004/014378
wherein
R', R2 independently of one another denote H, a C~_$-alkyl or C3_~-cycloalkyl
group optionally mono- or polysubstituted by the group R", while a
-CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group
may be replaced by -O-, -S-, -NR'3-, or a phenyl or pyridinyl group
optionally mono- or polysubstituted by the group R'2 and/or
monosubstituted by nitro, or
R' and R2 form a C2_8-alkylene bridge, wherein
- one or two -CH2- groups independently of one another may be
replaced by -CH=N- or -CH=CH- and/or
- one or two -CH2- groups independently of one another may be
replaced by -O-, -S-, -SO-, -(S02)-, -C=N-O-R'$, -CO-, -C(=CH2)- or
-NR'3- in such a way that heteroatoms are not directly joined
together, and that a group -C=N-O-R'$ or -CO- is not directly linked to
the group R' R2N-,
while in the alkylene bridge defined hereinbefore one or more H atoms
may be replaced by R'4, and
the alkylene bridge defined hereinbefore may be substituted by one or
two identical or different carbo- or heterocyclic groups Cy such that the
bond between the alkylene bridge and the group Cy is made
- via a single or double bond,
- via a common C atom forming a spirocyclic ring system,
- via two common adjacent C and/or N atoms forming a fused bicyclic
ring system or
- via three or more C and/or N atoms forming a bridged ring system,
R3 denotes H, C~_6-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~~-alkyl or phenyl-
C~_3-alkyl,
X denotes a single bond or a C~_8-alkylene bridge, wherein

CA 02550649 2006-06-20
WO 2005/063239 $ PCT/EP2004/014378
- a -CH2- group which is not directly linked to the group R'R2N- may
be replaced by -CH=CH- or -C---C- and/or
- one or two non-adjacent -CH2- groups, which are not directly linked to
the group R'RZN-, may be replaced independently of one another by
-O-, -S-, -(SO)-, -(S02)-, -CO- or -NR4- in such a way that in each
case two O, S or N atoms or an O and an S atom are not directly
joined together,
while the bridge X may be connected to R' including the N atom linked
to R' and X, forming a heterocyclic group, while the bridge X may
additionally also be connected to R2 including the N atom connected to
R2 and X, forming a heterocyclic group, and
while two C atoms or a C and an N atom of the alkylene bridge may be
joined together by an additional C~_4-alkylene bridge, and
a C atom may be substituted with R'° and/or one or two C atoms may
be substituted in each case by one or two identical or different
substituents selected from C~_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_~-
cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, C4_~-cycloalkenyl and C4_~-
cycloalkenyl-C~_3-alkyl, while two alkyl and/or alkenyl substituents may
be joined together, forming a carbocyclic ring system, and
W denotes a single bond, while
Z denotes -C= C-C(=O)-, -CR'a=CR'°-C(=O)- or -CR'aR'b-
CR'°R'd-C(=O)-
or
W denotes -C(=O)-C= C-, while
Z denotes a single bond; and
Y has one of the meanings given for Cy,
while X may be connected to Y, forming a carbo- or heterocyclic group
fused to Y, and/ or

CA 02550649 2006-06-20
WO 2005/063239 g PCT/EP2004/014378
optionally R' may be connected to Y, including the group X and the N
atom connected to R' and X, forming a heterocyclic group fused to Y,
and
A has one of the meanings given for Cy, while if the index b has the value
0, the group Cy does not have an amino group as substituent in the
ortho position to the bridge W;
B has one of the meanings given for Cy,
b denotes the value 0 or 1,
Cy denotes a carbo- or heterocyclic group selected from one of the
following meanings
- a saturated 3- to 7-membered carbocyclic group,
- a unsaturated 4- to 7-membered carbocyclic group,
- a phenyl group,
- a saturated 4- to 7-membered or unsaturated 5- to 7-membered
heterocyclic group with an N, O or S atom as heteroatom,
- a saturated or unsaturated 5- to 7-membered heterocyclic group with
two or more N atoms or with one or two N atoms and one O or S
atom as heteroatoms,
- an aromatic heterocyclic 5- or 6-membered group with one or more
identical or different heteroatoms selected from N, O and/or S,
while the above-mentioned 4, 5-, 6- or 7-membered groups may be
fused to a phenyl or pyridine ring via two common adjacent C atoms,
and
in the above-mentioned 5-, 6- or 7-membered groups one or two non-
adjacent -CH2- groups may independently of one another be replaced by
a -CO-, -C(=CH2)-, -(SO)- or -(S02)- group, and

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the above-mentioned saturated 6- or 7-membered groups may also
occur as bridged ring systems with an imino, N-(C~~-alkyl)-imino,
methylene, C~~-alkyl-methylene or di-(C~_4-alkyl)-methylene bridge, and
the above-mentioned cyclic groups may be mono- or polysubstituted by
RZ° at one or more C atoms, in the case of a phenyl group may also
additionally be monosubstituted by nitro, and/or one or more NH groups
may be substituted by R2',
R4 has one of the meanings given for R" or denotes C2_s-alkenyl or C3_s-
alkynyl,
R'a, R'° denote H, F, CI, C~~,-alkyl or CF3,
R'b, R'd denote H, F, C~~-alkyl, while R'b and R'd representing alkyl may be
joined together to form a cyclopropyl group;
R'° denotes hydroxy, hydroxy-C~_3-alkyl, C~~,-alkoxy, C~~-alkoxy-C~_3-
alkyl,
carboxy, C~_4-alkoxycarbonyl, amino, C~_4-alkyl-amino, di-(C~~-alkyl)-
amino, cyclo-C3_s-alkyleneimino, amino-C~_3-alkyl, C~_4-alkyl-amino-C~_3-
alkyl, di-(C~~-alkyl)-amino-C~_3-alkyl, cyclo-C3_s-alkyleneimino-C~_3-alkyl,
amino-C~_3-alkoxy, C~~-alkyl-amino-C~_3-alkoxy, di-(C~~-alkyl)-amino-C~_
3-alkoxy, cyclo-C3_s-alkyleneimino-C~_3-alkoxy, aminocarbonyl, C~~-alkyl-
aminocarbonyl, di-(C~_4-alkyl)-aminocarbonyl or cyclo-C3_s-
alkyleneimino-carbonyl,
R" denotes CZ_s-alkenyl, C2_s-alkynyl, R'5-O-, R'S-O-C~_3-alkyl, R'S-O-CO-,
R'S-CO-O-, R'sR'~N-, cyano, R'8R'9N-CO- or Cy,
R'2 has one of the meanings given for R2°,
R'3 has one of the meanings given for R", with the exception of carboxy,

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R'4 denotes halogen, C~_s-alkyl, C2_s-alkenyl, CZ_s-alkynyl, R'S-O-, R'S-O-CO-
R~5-CO-, R~5-CO-O-, R~sR1'N, R~aRisN-CO, R~5-O-C~_3-alkyl , R'S-O-
CO-C~_3-alkyl, R'S-O-CO-NH-, R'S-SOz-NH, R'S-O-CO-NH-C~_3-alkyl,
R'S-S02-NH-C~_3-alkyl, R'S-CO-C~_3-alkyl, R'S-CO-O-C~_3-alkyl, R'sR"N-
C~_3-alkyl, R'$R'9N-CO-C~_3-alkyl or Cy-C~_3-alkyl,
R'S denotes H, C~_4-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl,
phenyl,
phenyl-C~_3-alkyl, pyridinyl or pyridinyl-C~_3-alkyl,
R's denotes H, C~_s-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, C4_~-
cycloalkenyl, C4_~-cycloalkenyl-C~_3-alkyl, hydroxy-C2_3-alkyl, C»-alkoxy-
C2_3-alkyl, amino-C2_s-alkyl, C~_4-alkyl-amino-C2_s-alkyl, di-(C~_4-alkyl)-
amino-CZ_s-alkyl or cyclo-C3_s-alkyleneimino-CZ_s-alkyl,
R" has one of the meanings given for R's or denotes
phenyl, phenyl-C~_3-alkyl, pyridinyl, dioxolan-2-yl, -CHO, C~_
4-alkylcarbonyi, carboxy, hydroxycarbonyl-C~_3-alkyl,
C~_4-alkoxycarbonyl, C~_4-alkoxycarbonyl-C~_3-alkyl, C1_
4-alkylcarbonylamino-C2_3-alkyl, N-(C~_4-alkylcarbonyl)-N-(C~~-alkyl)-
amino-CZ_3-alkyl, C~~-alkylsulphonyl, C~~-alkylsulphonylamino-C2_3-alkyl
or N-(C~_4-alkylsulphonyl)-N(C~_4-alkyl)-amino-C2_3-alkyl
R'$, R'9 independently of one another denote H or C~_s-alkyl,
R2° denotes halogen, hydroxy, cyano, C~_s-alkyl, C2_s-alkenyl, C2_s-
alkynyl,
C3_~-cycloalkyl, C3_~-cycloaikyl-C~_3-alkyl, hydroxy-C~_4-alkyl, R22-C~-s-
alkyl or has one of the meanings given for R22,
R2' denotes C~~-alkyl, hydroxy-CZ_3-alkyl, C~_4-alkoxy-C2_s-alkyl, C~~-alkyl-
amino-C2_s-alkyl, di-(C~~-alkyl)-amino-C2_s-alkyl, cyclo-C3_s-
alkyleneimino-C2_s-alkyl, phenyl-C~_3-alkyl, C~_4-alkyl-carbonyl,
C~~-alkoxy-carbonyl or C~~-alkylsulphonyl,

CA 02550649 2006-06-20
WO 2005/063239 12 PCT/EP2004/014378
R22 denotes phenyl-C~_3-alkoxy, cyclo-C3_6-alkyleneimino-C2.~-alkoxy, OHC,
HO-N=HC, C,_4-alkoxy-N=HC, C~_4-alkoxy, C~~-alkylthio, carboxy,
C»-alkylcarbonyl, C~~-alkoxycarbonyl, aminocarbonyl, C~~-alkylamino-
carbonyl, di-(C»-alkyl)-aminocarbonyl, cyclo-C3_6-alkyl-amino-carbonyl,
cyclo-C3_6-alkyleneimino-carbonyl, cyclo-C3_6-alkyleneimino-C2_4-alkyl-
aminocarbonyl, phenyl-amino-carbonyl, C~_4-alkyl-sulphonyl, C~_4-alkyl-
sulphinyl, C~_4-alkyl-sulphonylamino, amino, C~_4-alkylamino, di-(C~_a-
alkyl)-amino, C~~-alkyl-carbonyl-amino, cyclo-C3_6-alkyleneimino, phe-
nyl-C~_3-alkylamino, N-(C~_4-alkyl)-phenyl-C~_3-alkylamino, acetylamino,
propionylamino, phenylcarbonylamino, phenylcarbonylmethylamino,
hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-
carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-
methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or
alkylaminocarbonylamino-,
while in the above-mentioned groups and radicals, particularly in A, B, W, X,
Y, Z, R'
to R4, R'a, R'b, R'°, R'd, R'° to R22, in each case one or more
C atoms may
additionally be mono- or polysubstituted by F and/or in each case one or two C
atoms
independently of one another may additionally be monosubstituted by CI or Br
and/or
in each case one or more phenyl rings may independently of one another
additionally
comprise one, two or three substituents selected from the group F, CI, Br, I,
C~_4-
alkyl, C~~-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C~_3-
alkylamino, di-
(C~_3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy,
trifluoromethoxy, amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl and di-(C~_3-
alkyl)-amino-
C~_3-alkyl and/or may be monosubstituted by nitro, and
the H atom of a carboxy group present or an H atom bound to an N atom in each
case may be replaced by a group which can be cleaved in vivo,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and
the salts
thereof,
while the following compounds according to provisos (M1) to (M14) are not
included:

CA 02550649 2006-06-20
WO 2005/063239 13 PCT/EP2004/014378
(M1) N-[4-[[(methylamino)sulphonyl]methyl]phenyl]-3-[2-(dimethylamino)-ethyl]-
1-
H-indole-5-propanamide oxalate,
(M2) 3-[2-[3-[3.6-dihydro-4-(2-naphthyl)-1 (2H)-pyridinyl]-2-
hydroxypropoxy]phenyl]-
N-methyl-N-phenyl-2-propenamide,
(M3) 3-[2-[2-hydroxy-3-[4-(1-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-
N-
phenyl-2-propenamide,
(M4) 3-[2-[2-hydroxy-3-[4-(2-naphthyl)-1-piperidinyl]propoxy]phenyl]-N-methyl-
N-
phenyl-2-propenamide,
(M5) 3-[2-[2-hydroxy-3-[4-(2-naphthalyl)-1-piperidinyl]propoxy]phenyl]-N-
phenyl-2-
propenamide,
(M6) N-[4-[1-(1 H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-phenyl-2-
propinamide,
(M7) 2'-[[3-(dimethylamino)propyl]thio]-3-phenyl-propiolanilide,
(M8) 2-(methylthio)-5-[[3-[4-(octadecylamino)phenyl]-1-oxopropyl]amino]-
benzoic
acid, including the trifluoroacetate salt,
(M9) 4-amino-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide,
(M10) 4-(dimethylamino)-N-(4-hydroxy-3,5-dimethylphenyl)-benzenepropanamide,
(M11) [i-methyl-4-[[3-[2-[(2-methylphenyl)amino]-6-benzoxazolyl]-1-
oxopropylamino]-benzenepropanoic acid,
(M12) 4-[3-[[1-oxo-3-[2-(phenylamino)-6-benzoxazolyl]- propyl]amino]phenoxy]-
butanoic acid,
(M13) 2-chloro-5-[[1-oxo-3-[4-[(5-phenylpentyl)amino]phenyl]propyl]amino]-
benzoic
acid,

CA 02550649 2006-06-20
WO 2005/063239 14 PCT/EP2004/014378
(M14) methyl2-chloro-5-[[1-oxo-3-[4-[(5-
phenylpentyl)amino]phenyl]propyl]amino]-
benzoate.
In view of the individual compounds disclosed in WO 2004/072018 the following
compounds are preferably not included either according to the invention:
N-(4-pentyl-phenyl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide,
N-(4-bromo-phenyl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide,
N-(4'-chloro-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide,
N-(4-bromo-phenyl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylamide,
N-(4'-chloro-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylamide,
N-(4-bromo-2-fluoro-phenyl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide,
N-(4'-chloro-3-fluoro-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-
propionamide.
The compounds according to the present invention, including the
physiologically
acceptable salts, are especially effective as antagonists of the MCH receptor,
particularly the MCH-1 receptor, and exhibit very good affinity in MCH
receptor
binding studies. In addition, the compounds according to the invention have a
high to
very high selectivity with regard to the MCH receptor. Generally the compounds
according to the invention have low toxicity, they are well absorbed by oral
route and
have good intracerebral transitivity, particularly brain accessibility.
The invention also relates to the compounds in the form of the individual
optical
isomers, mixtures of the individual diastereomers, enantiomers or racemates,
in the
form of the tautomers and in the form of the free bases or the corresponding
acid
addition salts with pharmacologically safe acids. The subject of the invention
also
includes the compounds according to the invention, including their salts,
wherein one
or more hydrogen atoms are replaced by deuterium.
This invention also includes the physiologically acceptable salts of the amide
compounds according to the invention as described above and hereinafter.

CA 02550649 2006-06-20
WO 2005/063239 15 PCT/EP2004/014378
Also covered by this invention are compositions containing at least one amide
compound according to the invention and/ or a salt according to the invention
optionally together with one or more physiologically acceptable excipients.
Also covered by this invention are pharmaceutical compositions containing at
least
one amide compound according to the invention and/ or a salt according to the
invention optionally together with one or more inert carriers and/or diluents.
The invention also relates to the use of at least one amide compound according
to the
invention and/ or a salt according to the invention, including the compounds
excluded
by provisos (M1) to (M14), for influencing the eating behaviour of a mammal.
The invention also relates to the use of at least one amide compound according
to the
invention and/ or a salt according to the invention, including the compounds
excluded
by provisos (M1) to (M14), for reducing the body weight and/or for preventing
an
increase in the body weight of a mammal.
The invention also relates to the use of at least one amide compound according
to the
invention and/ or a salt according to the invention, including the compounds
excluded
by provisos (M1) to (M14), for preparing a pharmaceutical composition with an
MCH-
receptor-antagonistic activity, particularly with an MCH-1-receptor-
antagonistic
activity.
Moreover, the invention relates to the use of at least one amide compound
according
to the invention and/ or a salt according to the invention, including the
compounds
excluded by provisos (M1) to (M14), for preparing a pharmaceutical composition
which is suitable for the prevention and/or treatment of symptoms and/or
diseases
which are caused by MCH or are otherwise causally connected with MCH.
The invention also relates to the use of at least one amide compound according
to the
invention and/ or a salt according to the invention, including the compounds
excluded
by provisos (M1) to (M14), for preparing a pharmaceutical composition which is
suitable for the prevention and/or treatment of metabolic disorders and/or
eating

CA 02550649 2006-06-20
WO 2005/063239 1 g PCT/EP2004/014378
disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia,
anorexia
nervosa and hyperphagia.
This invention also relates to the use of at least one amide compound
according to
the invention and/ or a salt according to the invention, including the
compounds
excluded by provisos (M1) to (M14), for preparing a pharmaceutical composition
which is suitable for the prevention and/or treatment of diseases and/or
disorders
associated with obesity, particularly diabetes, especially type II diabetes,
complications of diabetes including diabetic retinopathy, diabetic neuropathy,
diabetic
nephropathy, insulin resistance, pathological glucose tolerance,
encephalorrhagia,
cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis
and high
blood pressure, arthritis and gonitis.
Moreover, the invention relates to the use of at least one amide compound
according
to the invention and/ or a salt according to the invention, including the
compounds
excluded by provisos (M1) to (M14), for preparing a pharmaceutical composition
which is suitable for the prevention and/or treatment of hyperlipidaemia,
cellulitis, fat
accumulation, malignant mastocytosis, systemic mastocytosis, emotional
disorders,
affective disorders, depression, anxiety, sleep disorders, reproductive
disorders,
sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal
disorders.
Another object of the invention is the use of at least one amide compound
according
to the invention and/ or a salt according to the invention, including the
compounds
excluded by provisos (M1) to (M14), for preparing a pharmaceutical composition
which is suitable for the prevention and/or treatment of micturition
disorders, such as
for example urinary incontinence, hyperactive urinary bladder, urgency,
nycturia and
enuresis.
Furthermore the invention relates to processes for preparing a pharmaceutical
composition according to the invention, characterised in that at least one
amide
compound according to the invention and/ or a salt according to the invention
is
incorporated in one or more inert carriers and/or diluents by a non-chemical
method.

CA 02550649 2006-06-20
WO 2005/063239 17 PCT/EP2004/014378
The invention further relates to a pharmaceutical composition containing a
first active
substance selected from the amide compounds according to the invention and/ or
the
corresponding salts, including the compounds excluded by provisos (M1) to
(M14),
as well as a second active substance selected from the group consisting of
active
substances for the treatment of diabetes, active substances for the treatment
of
diabetic complications, active substances for the treatment of obesity,
preferably other
than MCH antagonists, active substances for the treatment of high blood
pressure,
active substances for the treatment of hyperlipidaemia, including
arteriosclerosis,
active substances for the treatment of arthritis, active substances for the
treatment of
anxiety states and active substances for the treatment of depression,
optionally
together with one or more inert carriers and/or diluents.
Detailed Description of the invention
Unless otherwise specified, the groups, residues and substituents,
particularly A, B,
W, X, Y, Z, R~ to R4, R'a, R'b, R'°, R'a, R'° to R22, and the
index b have the meanings
given hereinbefore.
If groups, residues and/or substituents occur more than once in a compound,
they
may have the same or different meanings in each case.
Preferred embodiments of this invention comprise compounds which may in each
case be described by the following formulae la, Ib, Ic and Id:
R\N-X-Y- N-o-C-C-A Bl la
2/ ~ 3 ~ Jb
R R
R\N-X-Y-C-C-OC-N -A B Ib
2/ ~ ~ Jb
R R
Rya Roc
Ic
R\N-X-Y- C-C-CI-N-A Bl
2/ ~ Jb
R Rib Rya Rs

CA 02550649 2006-06-20
WO 2005/063239 1$ PCT/EP2004/014378
R'~ O
R\N X C C CI N l Id
2/ ~ Jb
R
R7a R
wherein R', R2, R3, R'a, R'b, R'°, R'd, X, Y, A, B and b have the
meanings given
above and hereinafter, particularly the meanings stated as being preferred.
Particularly preferred definitions of the groups R'a, R'b, R'°, R'd are
H or methyl,
particularly H.
The preferred definitions of the individual groups and substituents given
below refer to
compounds of formula I according to the invention, particularly in each case
to the
four embodiments described by formulae la, Ib, Ic and Id.
Preferred meanings of the substituent R3 are H, C»-alkyl, C3_s-cycloalkyl or
C3_s-
cycloalkyl-C~_3-alkyl; particularly H or C~_3-alkyl. R3 particularly
preferably denotes H
or methyl, particularly H.
The substituents R' and R2 may have the meanings given above and hereinafter
as
separate groups or may be connected to one another as a bridge. For
simplicity's
sake, the preferred meanings of R' and R2 as separate groups will be described
first
of all and then the preferred meanings of the groups R' and R2 connected to
one
another to form a bridge. Preferred compounds according to the invention
therefore
have one of the preferred meanings of R' and R2 described below, as separate
groups combined with one of the preferred meanings of R' and R2 described
hereinafter as groups connected to one another to form a bridge.
If R' and R2 are not joined together via an alkylene bridge, R' and RZ
independently
of one another preferably denote a C~_$-alkyl or C3_~-cycloalkyl group
optionally
mono- or polysubstituted by the group R", while a -CH2- group in position 3 or
4 of a
5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR'3-,
or a

CA 02550649 2006-06-20
WO 2005/063239 1 g PCT/EP2004/014378
phenyl or pyridinyl group optionally mono- or polysubstituted by the group R'2
and/or
monosubstituted by nitro, while one of the groups R' and R2 may also represent
H.
Preferably the groups R', R2 independently of one another represent C~_6-
alkyl, C3_~-
cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, hydroxy-CZ_4-alkyl, NC-C2_4-alkyl,
C~_4-alkoxy-
CZ_4-alkyl, C~~-alkoxy-carbonyl-C~~-alkyl, carboxyl-C~~-alkyl, amino-CZ~-
alkyl, C~_a-
alkyl-amino-C2~-alkyl, di-(C~~-alkyl)-amino-C2~-alkyl, cyclo-C3_6-
alkyleneimino-C2~-
alkyl, pyrrolidin-3-yl, while the NH group may be substituted by R'3,
pyrrolidinyl-C~_3-
alkyl, while the NH group may be substituted by R'3, piperidin-3-yl or -4-yl,
while the
NH group may be substituted by R'3, piperidinyl-C~_3-alkyl, while the NH group
may
be substituted by R'3, tetrahydropyran-3-yl or -4-yl, tetrahydropyranyl-C~_3-
alkyl,
tetrahydrofuran-3-yl, tetrahydrofuranyl-C~_3-alkyl, phenyl, phenyl-C~_3-alkyl,
pyridyl or
pyridyl-C~_3-alkyl, while in the above-mentioned groups and radicals one or
more C
atoms may be mono- or polysubstituted by F and/or one or two C atoms,
particularly
one C atom may independently of one another be monosubstituted with CI or Br,
and
the phenyl or pyridyl group may be mono- or polysubstituted by the group R'2
defined
hereinbefore and/or may be monosubstituted by nitro, and one of the groups R',
R2
may also represent H. Preferably the above-mentioned cycloalkyl rings may be
mono-
or polysubstituted by substituents selected from hydroxy, hydroxy-C~_3-alkyl,
C~_3-alkyl
or C~_3-alkyloxy, particularly hydroxy, hydroxymethyl, methyl and methoxy.
Also
preferably the CZ~-alkyl bridges contained in hydroxy-CZ~-alkyl and C~~-alkoxy-
CZ~-alkyl may additionally be monosubstituted by hydroxy, hydroxy-C~_3-alkyl,
C~_3-
alkyl or C~_3-alkyloxy, particularly hydroxy, hydroxymethyl, methyl or
methoxy.
Preferred substituents R'2 of the above-mentioned phenyl or pyridyl groups are
selected from among F, CI, Br, I, cyano, C~_4-alkyl, C~_4-alkoxy,
difluoromethyl,
trifluoromethyl, hydroxy, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino,
acetylamino,
aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C~_3-alkyl, C~_3-
alkylamino-
C~_3-alkyl and di-(C~_3-alkyl)-amino-C~_3-alkyl, while a phenyl group may also
be
monosubstituted by nitro.
Particularly preferred definitions of the groups R' and/or R2 are selected
from the
group consisting of C,_6-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl,
tetrahydropyran-3 or -4-yl, tetrahydropyranyl-C~_3-alkyl, piperidin-3 or -4-
yl, while the
NH group may be substituted by R'3, piperidinyl-C~_3-alkyl, while the NH group
may

CA 02550649 2006-06-20
WO 2005/063239 2p PCT/EP2004/014378
be substituted by R'3, phenyl, pyridyl, phenyl-C~_3-alkyl, pyridyl-C~_3-alkyl,
hydroxy-C2~-alkyl, C~~-alkoxy-C2~-alkyl, amino-C2~-alkyl, C~_4-alkyl-amino-
C2_4-alkyl-
and di-(C~~-alkyl)-amino-C2~-alkyl, while cycloalkyl rings may be mono-, di-
or
trisubstituted by substituents selected from hydroxy, hydroxy-C~_3-alkyl, C~_3-
alkyl or
C~_3-alkyloxy, particularly hydroxy, hydroxymethyl, methyl and methoxy, and
C2~-alkyl
bridges contained in hydroxy-C2_4-alkyl- and C~_4-alkoxy-C2_4-alkyl- may
additionally be
monosubstituted by hydroxy, hydroxy-C~_3-alkyl, C~_3-alkyl or C~_3-alkyloxy,
particularly
hydroxy, hydroxymethyl, methyl or methoxy, and alkyl groups may be mono- or
polysubstituted by F and/or monosubstituted by CI, and one of the groups R'
and R2
may also represent H.
R'3 preferably denotes H, C~_6-alkyl, C~~-alkylcarbonyl or C»-
alkyloxycarbonyl.
Particularly preferably R'3 denotes H or C~~-alkyl, particularly H, methyl,
ethyl or
propyl.
Most particularly preferred definitions of the groups R' and/or R2 are
selected from
the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
cyclopropyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl,
cyclohexylmethyl,
phenyl, pyridyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl,
tetrahydropyran-4-
yl-methyl, piperidin-4-yl, which may be substituted by R'3 at the N atom, or
piperidin-
4-yl-methyl, which may be substituted by R'3 at the N atom, while the ethyl,
propyl
and butyl groups mentioned may be monosubstituted by amino, methylamino or
dimethylamino or mono- or disubstituted by hydroxy, methoxy or ethoxy, and the
above-mentioned cycloalkyl rings may be mono- or disubstituted by hydroxy,
hydroxymethyl or methyl, and methyl groups may be mono- or polysubstituted by
fluorine, and one of the groups R' and R2 may also represent H.
Examples of most particularly preferred definitions of the groups R' and/or R2
are
methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl, 2-hydroxy-propyl, 3-
hydroxypropyl, 2-
hydroxy-2-methyl-propyl, 2-methoxyethyl, 3-amino-propyl, cyclopropyl,
cyclopentyl,
cyclohexyl, cyclopropylmethyl, (1-hydroxycyclopropyl)methyl, phenyl, pyridyl,
phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methyl-piperidin-4-yl, N-
(methylcarbonyl)-piperidin-4-yl and N-(tert.butyloxycarbonyl)-piperidin-4-yl,
while

CA 02550649 2006-06-20
WO 2005/063239 21 PCT/EP2004/014378
hydroxyalkyl groups may additionally be substituted by hydroxy, and one of the
groups R', R2 may also represent H.
If the substituent R' has one of the meanings stated above as being preferred,
but not
H, the substituent RZ most particularly preferably denotes H, methyl, ethyl, n-
propyl, i-
propyl, 2-hydroxyethyl or 2-methoxyethyl.
Compounds according to the invention, particularly those which may be
described by
formula Ic or Id, are also preferred wherein one or both groups R', R2
represent one
or more groups selected from 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, 2-
methoxyethyl, 3-amino-propyl, cyclopropyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, (1-hydroxycyclopropyl)methyl, phenyl, pyridyl,
phenylmethyl,
pyridylmethyl, tetrahydropyran-4-yl, N-methyl-piperidin-4-yl, N-
(methylcarbonyl)-
piperidin-4-yl and N-(tert.butyloxycarbonyl)-piperidin-4-yl, particularly 2-
hydroxyethyl,
2-hydroxy-2-methyl-propyl, 2-methoxyethyl, tetrahydropyran-4-yl,
cyclopropylmethyl
and (1-hydroxycyclopropyl)methyl, while hydroxyalkyl groups may additionally
be
substituted by hydroxy.
Particularly preferably at least one of the groups R', R2, most particularly
preferably
both groups, have a meaning other than H.
If R' and R2 form an alkylene bridge, this is preferably a C3_~-alkylene
bridge, wherein
- a -CH2- group not adjacent to the N atom of the R'R2N group may be replaced
by
-CH=CH- and/or
- a -CH2- group which is preferably not adjacent to the N atom of the R'R2N-
group
may be replaced by -O-, -S-, -C(=N-O-R'$)-, -CO-, -C(=CH2)- or -NR'3-,
particularly preferably by -O-, -S- or -NR'3-, in such a way that heteroatoms
are
not directly joined together and a group -C=N-O-R'$ or -CO- is not directly
linked
to the group R'R2N-,
while in the alkylene bridge defined hereinbefore one or more H atoms may be
replaced by R'4, and
the alkylene bridge defined hereinbefore may be substituted by a carbo- or

CA 02550649 2006-06-20
WO 2005/063239 22 PCT/EP2004/014378
heterocyclic group Cy in such a way that the bond between the alkylene bridge
and
the group Cy is made
- via a single or double bond,
- via a common C atom forming a spirocyclic ring system,
- via two common adjacent C and/or N atoms forming a fused bicyclic ring
system
or
- via three or more C and/or N atoms forming a bridged ring system.
R'3 preferably denotes H, C~_s-alkyl, C~~-alkylcarbonyl or C~_4-
alkyloxycarbonyl.
Particularly preferably R'3 denotes H or C~_~-alkyl, particularly H, methyl,
ethyl or
propyl.
Also preferably R' and R2 form an alkylene bridge in such a way that R'R2N-
denotes
a group selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-
1 H-
pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-
tetrahydro-
1 H-azepine, piperazine wherein the free imine function is substituted by R'3,
piperidin-4-one, piperidin-4-one-oxime, piperidin-4-one-O-C~_4-alkyl-oxime,
morpholine and thiomorpholine,
particularly a group selected from pyrrolidine, piperidine, 2,5-dihydro-1 H-
pyrrole,
morpholine, thiomorpholine and piperazine, wherein the free imine function is
substituted by R'3,
while according to the general definition of R' and R2 one or more H atoms may
be
replaced by R'4, and/ or the above-mentioned groups may be substituted by one
or
two identical or different carbo- or heterocyclic groups Cy in a manner
specified
according to the general definition of R' and R2. Particularly preferred
groups Cy for
this are phenyl, C3_~-cycloalkyl, aza-C4_~-cycloalkyl, particularly phenyl,
C3_6-cycloalkyl,
cyclo-C3_5-alkyleneimino, as well as N-C~~-alkyl-(aza-C4_6-cycloalkyl), while
the cyclic
groups Cy may be substituted as specified.
The alkylene bridge formed by R' and R2, wherein -CH2- groups may be replaced
as
specified, may be substituted, as described, by one or two identical or
different carbo-
or heterocyclic groups Cy.

CA 02550649 2006-06-20
WO 2005/063239 23 PCT/EP2004/014378
In the event that the alkylene bridge is linked to a group Cy via a single
bond, Cy is
preferably selected from the group consisting of C3_~-cycloalkyl, cyclo-C3_s-
alkyleneimino, piperazinyl, 1 H-imidazole, thienyl and phenyl, particularly
C3_s-
cycloalkyl, pyrrolidinyl, piperidinyl and piperazinyl, which may be
substituted as
specified, and particularly the N atoms may be substituted by C~~-alkyl in
each case.
In the event that the alkylene bridge is linked to a group Cy via a common C
atom
forming a spirocyclic ring system, Cy is preferably selected from the group
consisting
of C3_~-cycloalkyl, aza-C4_$-cycloalkyl, oxa-C4_$-cycloalkyl, 2,3-dihydro-1 H-
quinazolin-
4-one, particularly cyclopentyl and cyclohexyl, which may be substituted as
specified,
and particularly the N atoms may be substituted by C~~-alkyl in each case.
In the event that the alkylene bridge is linked to a group Cy via two common
adjacent
C and/or N atoms forming a fused bicyclic ring system, Cy is preferably
selected from
the group consisting of C4_~-cycloalkyl, aza-C4_~-cycloalkyl, phenyl, thienyl,
particularly
phenyl and pyrrolidinyl, which may be substituted as specified, and
particularly the N
atoms may be substituted by C~~-alkyl in each case.
In the event that the alkylene bridge is linked to a group Cy via three or
more C and/or
N atoms forming a bridged ring system, Cy preferably denotes C4_8-cycloalkane
or
aza-C4_8-cycloalkane, particularly cylopentane, cyciohexane, pyrrolidine or
piperidine,
while the N atoms may be substituted by C~~-alkyl in each case.
R' NiX~',
Particularly preferably the group
R2
is defined according to one of the following partial formulae
N-X~ ~N-X~ N X

CA 02550649 2006-06-20
WO 2005/063239 24 PCT/EP2004/014378
\
\ ; ( 'N-X-; ~ N-X-
N-X-~ ~ '
R N N-X-
I N-X~ ~ ~ N-X
N-X ~ ~ N N-X
U
18
N N-X-, R -O,N- N-X
~N
O N-X-; ~ ~ N-X~ ~ ~ N-X
Rz ~
N
S N-X
,
v
N-X
Rz~ N \N-X-~ N-X
Rz~iN
_ ~ \ \
N N-X~ N N-X
R2? N
, N
v , ' ,
N-X N-X
' N
v , ' ,
N-X~ N-X

CA 02550649 2006-06-20
WO 2005/063239 25 PCT/EP2004/014378
v ~ v
N-X ; N-X
, , , ,
N N w>
Rz1
v
\ N N-X-;
N-XJ
R21
N Rzi N N-X
"
N-X
R21
\ N N \N-X
' Rz1 i ~ ' ,
N-X
N-X~ R2'-N N-X
,
N X~ ~ ~ I N X ~ , / I N-X~ ,
S~ '
v , . ,
N-X~ N-X~, N-X~,
N N-X~, \
N ~; ,
R13~N

CA 02550649 2006-06-20
WO 2005/063239 26 PCT/EP2004/014378
RZ N~X" ; R? N R? N
X"
X'-''
R2 N R? N
X"
X'
_ ~N
I
' N~ ~~. ~ N~ ~
N X~~j' X~ X
while in the heterocycle formed by the group R'R2N- one or more H atoms may be
replaced by R'4 and/or a H atom may be substituted by Cy defined as C3_~-
cycloalkyl,
which may be mono- or polysubstituted by R2°, particularly by F,
hydroxy, C~_3-alkyl,
CF3, C~_3-alkyloxy, OCF3 or hydroxy-C~_3-alkyl, and the ring connected to the
heterocycle formed by the group R' RZN- may be mono- or polysubstituted at one
or
more C atoms by R2°, and in the case of a phenyl ring may also
additionally be
monosubstituted by vitro and
X', X" independently of one another denote a single bond or C~_3-alkylene and
in the event that the group Y is linked to X' or X" via a C atom, may also
denote -Ci_3-alkylene-O-, -C~_3-alkylene-NH- or -C~_3-alkylene-N(C~_3-alkyl)-,
and
X" additionally also denotes -O-C~_3-alkylene, -NH-C~_3-alkylene or
-N(C~_3-alkyl)-C~_3-alkylene and
in the event that the group Y is linked to X" via a C atom, also denotes
-NH-, -N(C~_3-alkyl)- or -O-,
while in the meanings given for X', X" hereinbefore in each case a C atom

CA 02550649 2006-06-20
WO 2005/063239 27 PCT/EP2004/014378
may be substituted by R'°, preferably by a hydroxy, ~-hydroxy-C~_3-
alkyl,
w-(C~_4-alkoxy)-C~_3-alkyl and/or C~_4-alkoxy group, and/or one or two C
atoms in each case may be substituted by one or two identical or different
substituents selected from C~_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_~-
cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, C4_~-cycloalkenyl and C4_~-
cycloalkenyl-C~_3-alkyl, while two alkyl and/or alkenyl substituents may be
joined together, forming a carbocyclic ring system, and
in X', X" independently of one another in each case one or more C atoms
may be mono- or polysubstituted by F and/or in each case one or two C
atoms independently of one another may be monosubstituted by CI or Br
and
wherein R2, R'°, R13, Rya, R'a, R2o, R2' and X have the meanings given
above and
hereinafter.
Preferably X', X" independently of one another represent a single bond or C~_3-
alkylene and in the event that the group Y is linked to X' or X" via a C atom,
may also
denote -C~_3-alkylene-O, -C~_3-alkylene-NH or -C~_3-alkylene-N(C~_3-alkyl),
and X"
additionally also denotes -O-C~_3-alkylene, -NH-C~_3-alkylene or -N(C~_3-
alkyl)-C~_3-
alkylene and in the event that the group Y is linked to X" via a C atom, X "
also
denotes -NH, -N(C~_3-alkyl)- or -O-. Particularly preferably X', X"
independently of one
another represent a single bond or methylene and in the event that the group Y
is
linked to X' or X" via a C atom, also represent -CH2-O-, -CH2-NH- or -CH2-N(C~-
3-
alkyl)-, and in the event that the group Y is linked to X" via a C atom, X"
also denotes
-NH-, -N(C~_3-alkyl) or -O-.
In the preferred and particularly preferred meanings of R~R2N- listed above
the
following definitions of the substituent R'4 are preferred: F, CI, Br, C~_4-
alkyl, C2_4-
alkenyl, C2~-alkynyl, C3_~-cycloalkyl-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl,
C~_4-alkoxy, w-(C~~ -alkoxy)-C~_3-alkyl, C~_4-alkyl-carbonyl, carboxy, C»-
alkoxy-
carbonyl, hydroxy-carbonyl-C~_3-alkyl, C~~-alkoxycarbonyl-C~_3-alkyl, C~~-
alkoxy-
carbonylamino, C~_4-alkoxy-carbonylamino-C~_3-alkyl, amino, C~_4-alkyl-amino,
C3_~-
cycloalkyl-amino, N-(C3_~-cycloalkyl)-N-(C~~-alkyl)-amino, di-(C~_4-alkyl)-
amino,

CA 02550649 2006-06-20
WO 2005/063239 2$ PCT/EP2004/014378
amino-C~_3-alkyl, C~~-alkyl-amino-C~_3-alkyl, C3_~-cycloalkyl-amino-C~_3-
alkyl, N-(C3_~-
cycloalkyl)-N-(C~_4-alkyl)-amino-C~_3-alkyl, di-(C~~-alkyl)-amino-C~_3-alkyl,
cyclo-C3_s-
alkyleneimino-C~_3-alkyl, aminocarbonyl, C~_4-alkyl-amino-carbonyl, C3_~-
cycloalkyl-
amino-carbonyl, N-(C3_~-cycloalkyl)-N-(C~_4-alkyl)-amino-carbonyl, di-(C~~-
alkyl)-
amino-carbonyl, pyridinyl-oxy, pyridinyl-amino, pyridinyl-C~_3-alkyl-amino. In
the above
meanings of the group R'4 one or more C atoms may be mono- or polysubstituted
by
F and/or one or two C atoms independently of one another may be
monosubstituted
by CI or Br, and in particular alkyl groups may be mono- or polysubstituted by
fluorine.
Most particularly preferred meanings of the substituent R'4 are F, CI, C~_4-
alkyl, C3_s-
cycloalkyl-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~~-alkoxy, C~_4-alkoxy-
C~_3-alkyl,
amino-C~_3-alkyl, C~_4-alkyl-amino-C~_3-alkyl, C3_~-cycloalkyl-amino-C~_3-
alkyl, N-(C3_~-
cycloalkyl)-N-(C~~-alkyl)-amino-C~_3-alkyl, di-(C~_4-alkyl)-amino-C~_3-alkyl,
cyclo-C3_s-
alkyleneimino-C~_3-alkyl, aminocarbonyl and pyridylamino. In the above
meanings of
the group R'4 one or more C atoms, and particularly alkyl groups, may be mono-
or
polysubstituted by fluorine.
If in the heterocycle formed by the group R'R2N- an H atom is replaced by Cy
representing C3_~-cycloalkyl, which may be mono- or polysubstituted by
R2°, Cy
preferably denotes C3_s-cycloalkyl and R2° preferably denotes F,
hydroxy, C~_3-alkyl,
CF3, C~_3-alkyloxy, OCF3 or hydroxy-C~_3-alkyl, particularly F, hydroxy,
methyl,
methoxy, CF3, OCF3 or hydroxymethyl. Particularly preferred meanings of Cy are
C3_s-cycloalkyl and 1-hydroxy-C3_5-cycloalkyl.
R' N ~~
Most particularly preferably the group
R2
is defined according to one of the following partial formulae
v , ~ ,
N-r ~-
' N '

CA 02550649 2006-06-20
WO 2005/063239 2g PCT/EP2004/014378
,
N N
' ' N
,
N-'
\N~
O , R~s N N-T
,
U , , U ,
N-1 N N~- \
N '
' ' R~3~N~ w
while in the heterocycle formed by the group R'R2N- one or more H atoms may be
replaced by R'4 and/or an H atom may be replaced by Cy representing C3_s-
cycloalkyl, which may be mono- or polysubstituted by R2°, particularly
by F, hydroxy,
C~_3-alkyl, CF3, C~_3-alkyloxy, OCF3 or hydroxy-C~_3-alkyl, particularly
preferably by F,
hydroxy, methyl, methoxy, CF3, OCF3 or hydroxymethyl, and
the ring connected to the heterocycle formed by the group R'R2N- may be mono-
or
polysubstituted, preferably monosubstituted at one or more C atoms by
R2°, or in the
case of a phenyl ring may also additionally be monosubstituted by nitro and
R'4 in each case independently of one another denotes F, CI, C~_4-alkyl, C3_s-
cycloalkyl-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~~-alkyloxy, C~_4-alkoxy-
C~_3-alkyl, pyridylamino or aminocarbonyl, while in each case one or more C
atoms, particularly alkyl groups may additionally be mono- or polysubstituted
by F; most particularly preferably denotes methyl, ethyl, propyl,
trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-
hydroxy-1-methyl-ethyl, 1-hydroxycyclopropyl, methoxy, ethoxy,
methoxymethyl, pyridylamino or aminocarbonyl; and
R'3 is as hereinbefore defined, particularly denotes H or C~_3-alkyl.

CA 02550649 2006-06-20
WO 2005/063239 3Q PCT/EP2004/014378
Compounds according to the invention, particularly those which may be
described by
formula Ic or Id, are also preferred, wherein the group
R' N ~~
is defined according to one of the following partial formulae
R2
N N
' ' N
N-'
N ; R~s N N_-T
~ ,
N~ N N-=r \
' ~ N '
' R13~N
wherein H atoms may be replaced as specified hereinbefore and the ring
connected
to the heterocycle formed by the group R~R2N- may be mono- or polysubstituted,
preferably monosubstituted at one or more C atoms by R2°, in the case
of a phenyl
ring may also additionally be monosubstituted by vitro, or
R, N i',
wherein the group ,
Rz
is defined according to one of the following partial formulae
v , v
N---r -r
' N '
wherein at least one H atom of the heterocycle formed by the group R'R2N- is
substituted by a substituent selected from hydroxy, hydroxy-C~_3-alkyl, 1-
hydroxy-C3_5-

CA 02550649 2006-06-20
WO 2005/063239 31 PCT/EP2004/014378
cycloalkyl, C~~-alkyloxy and C~~-alkoxy-C~_3-alkyl, and wherein additionally
one or
more, preferably one or two H atoms of the heterocycle formed by the group
R'R2N-
may be replaced by the substituent R'4 defined hereinbefore and/or an H atom
of the
heterocycle formed by the group R'R2N- may be replaced by Cy representing C3_s-
cycloalkyl, which may be mono- or polysubstituted by RZ°, particularly
by F, hydroxy,
C~_3-alkyl, CF3, C~_3-alkyloxy, OCF3 or hydroxy-C~_3-alkyl, particularly
preferably by F,
hydroxy, methyl, methoxy, CF3, OCF3 or hydroxymethyl.
Preferably X denotes a C~_s-alkylene bridge, wherein
- a -CH2 group not adjacent to the N atom of the R'R2N- group may be replaced
by -CH=CH- or -C---C- and/or
- a -CH2- group not adjacent to the N atom of the R'R2N group may be replaced
by -O-, -S-, -CO- or -NR4-, particularly preferably by -O-, -S- or -NR4-, in
such a
way that in each case two O, S or N atoms or an O and an S atom are not
directly joined together,
while R4 may be attached to Y, forming a heterocyclic ring system with one
another,
while the bridge X may be connected to R' including the N atom linked to R'
and X,
forming a heterocyclic group, and
two C atoms or a C and an N atom of the alkylene bridge may be joined together
by
an additional C~~-alkylene bridge, and
a C atom may be substituted by R'° and/or one or two C atoms may each
be
substituted by one or two identical or different substituents selected from
C~_s-alkyl,
C2_s-alkenyl, C2_s-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, C4_~-
cycloalkenyl
and C4_~-cycloalkenyl-C~_3-alkyl, while two alkyl and/or alkenyl substituents
may be
joined together forming a carbocyclic ring system, particularly a cyclopropyl,
cyclobutyl or cyclopentyl group.
Preferably, in the group X a -CH2- group directly adjacent to the group R'R2N-
is not
replaced by -O-, -S-, -(SO)-, -(S02)-, -CO- or -NR4-.

CA 02550649 2006-06-20
WO 2005/063239 32 PCT/EP2004/014378
If in the group X one or two -CH2- groups independently of one another are
replaced
by -O-, -S-, -(SO)-, -(S02)-, -CO- or -NR4-, these groups are preferably
spaced from
the R'R2N- group by an alkylene bridge with at least 2 C atoms.
If in the group X two -CH2 groups independently of one another are replaced by
-O-,
-S-, -(SO)-, -(S02)-, -CO- or -NR4-, these groups are preferably separated
from one
another by an alkylene bridge with at least 2 C atoms.
If in the group X a -CH2- group of the alkylene bridge is replaced according
to the
invention, this -CH2- group is preferably not directly connected to a
heteroatom, a
double or triple bond.
Preferably the alkylene bridge X, X' or X" has no imino groups or at most only
one
imino group. The position of the imino group within the alkylene bridge X, X'
or X" is
preferably selected so that no aminal function is formed together with the
amino group
NR'R2 or another adjacent amino group, or two N atoms are not adjacent to one
another.
If in X, X' or X" a C atom is substituted, preferred substituents are selected
from
among the C~_4-alkyl, C2~-alkenyl, C2_4-alkynyl, C3_~-cycloalkyl, C3_~-
cycloalkyl-C~_3-
alkyl, hydroxy, w-hydroxy-C~_3-alkyl, w-(C~~-alkoxy)-C~_3-alkyl and C~_4-
alkoxy groups.
Moreover in X, X' or X" a C atom may be disubstituted and/or one or two C
atoms
may be mono- or disubstituted, while preferred substituents are selected from
among
C~~-alkyl, C2~-alkenyl, C2~-alkynyl, C3_~-cycloalkyl and C3_~-cycloalkyl-C~_3-
alkyl, and
two C~~-alkyl- and/or C2~-alkenyl substituents may also be joined together to
form a
saturated or monounsaturated carbocyclic ring.
Advantageously the group X representing C2~-alkylenoxy, particularly -CH2-CH2-
CH2-
O-, has no hydroxy substituent.
Most particularly preferred substituents of one or two C atoms in X, X' or X"
are
selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl,
cyclopropylmethyl, while

CA 02550649 2006-06-20
WO 2005/063239 33 PCT/EP2004/014378
two alkyl substituents on one C atom may also be joined together to form a
carbocyclic ring.
In the definitions of the substituents of the bridges X, X' and/or X" and the
definitions
of the bridges X, X' and/or X" themselves mentioned above and hereinafter, in
each
case one or more C atoms may additionally be mono- or polysubstituted by F
and/or
in each case one or two C atoms independently of one another may additionally
be
monosubstituted by CI or Br.
If in the group X, X' or X" one or more C atoms are substituted by a hydroxy
and/or
C~~-alkoxy group, the substituted C atom is preferably not immediately
adjacent to
another heteroatom.
Preferably X denotes an unbranched C~.~-alkylene bridge and
in the event that the group Y is finked to X via a C atom, it also denotes
-CHZ-CH=CH-, -CH2-C--__C-, C2_4-alkylenoxy or CZ_4-alkylene-NR4, particularly
C2~-
alkylenoxy or C2~-alkylene-NR4-,
while R4 may be connected to Y, forming a heterocyclic ring system,
while the bridge X may be connected to R', including the N atom connected to
R' and
X, forming a heterocyclic group, and
in X a C atom may be substituted by R'° and/or one or two C atoms may
be
substituted in each case by one or two identical or different substituents
selected from
C~_6-alkyl, CZ_s-alkenyl, C2_6-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-
alkyl, C4_~-
cycloalkenyl and C4_~-cycloalkenyl-C~_3-alkyl, particularly selected from C~_3-
alkyl,
while two alkyl and/or alkenyl substituents may be joined together, forming a
carbocyclic ring system, and
in the above-mentioned groups and radicals one or more C atoms may be mono- or
polysubstituted by F and/or one or two C atoms independently of one another
may be
monosubstituted by CI or Br and

CA 02550649 2006-06-20
WO 2005/063239 34 PCT/EP2004/014378
R', R4 and R'° are as hereinbefore defined.
The substituent R'° preferably denotes a hydroxy, hydroxy-C~_3-alkyl,
C~~-alkoxy-
C~_3-alkyl and/or C~~-alkoxy group, particularly hydroxy, hydroxymethyl or
methoxy.
Preferred meanings of the substituent R4 are H, C~_6-alkyl and C3_6-alkenyl.
Particularly preferably R4 denotes H or C~_3-alkyl. If R4 is connected to Y
forming a
heterocyclic ring system, particularly preferred meanings of R4 are CZ_6-alkyl
and C2_6-
alkenyl.
In the event that R4 is linked to Y forming a heterocyclic ring system, Y
preferably
denotes phenyl and R4 preferably denotes C2~-alkyl or C2_6-alkenyl. Preferred
heterocyclic ring systems are indole, dihydroindole, quinoline,
dihydroquinoline,
tetrahydroquinoline and benzoxazole.
Particularly preferably X denotes -CH2-, -CHZ-CH2- or -CH2-CH2-CH2- and
in the event that the group Y is linked to X via a C atom (of the group Y), it
may also
denote -CH2-CH=CH-, -CH2-C-_-C-, -CH2-CH2-O-, -CH2-CH2-CHZ-O- or
-CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, particularly -CH2-CH2-O-, -CHZ-CH2-CH2-O-,
-CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-,
while R4 may be connected to Y, forming a heterocyclic ring system,
while the bridge X may be connected to R', including the N atom linked to R'
and X,
forming a heterocyclic group, and
in X a C atom may be substituted by R'° and/or one or two C atoms
independently of
one another may each be substituted by one or two identical or different C~_4-
alkyl
groups, while two alkyl groups may be joined together, forming a carbocyclic
ring
system; preferably in X one or two C atoms may each be substituted
independently of
one another by one or two identical or different C~_3-alkyl groups, while two
alkyl
groups may be joined together to form a carbocyclic ring system, particularly
a

CA 02550649 2006-06-20
WO 2005/063239 35 PCT/EP2004/014378
cyclopropyl group, and
in each case one or more C atoms may be mono- or polysubstituted by F and/or
in
each case one or two C atoms independently of one another may be
monosubstituted
by CI or Br, preferably in each case one or more C atoms may be mono- or
polysubstituted by F.
Most particularly preferably, if the group Y is linked to X via a C atom (of
the group
Y), X denotes -CH2-, -CH2-CHZ-, -CHZ-CH2-CH2-, 1,1-cyclopropylene, -CH2-CH2-O-
,
-CH2-CHZ-CHZ-O-, -CH2-CH2-NR4- or -CH2-CH2-CHz-NR4-, while these groups are
unsubstituted or the alkylene bridge is substituted as specified, preferably
mono- or
disubstituted by methyl and/or fluorine.
The group R4 preferably only denotes vinyl if R4 is linked to Y forming a
heterocyclic
ring system.
The group X preferably does not comprise a carbonyl group.
If Y denotes a fused bicyclic ring system, a preferred definition of the group
X is a
single bond, -CH2-, -CH2-CH2- or -CH2-CH2-CH2- , particularly a single bond, -
CH2- or
-CH2-CH2-, most particularly preferably -CH2 or -CH2-CH2, which may be
substituted
as specified.
In the event that the index b has the value 1, X particularly preferably
denotes -CH2-
or 1,1-cyclopropylene. X representing -CH2- may be linked to Y forming a
bicyclic ring
system as specified, while for this purpose the -CHZ bridge is substituted by
C2_3-alkyl.
The -CH2- bridge may comprise one or two substituents independently of one
another
selected from the group comprising C~_3-alkyl, while two alkyl groups may be
joined
together, forming a carbocyclic ring system.
In the event that the index b has the value 0, X particularly preferably
denotes -CH2-
CH2-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-, while
the above-mentioned groups may comprise one or two substituents independently
of

CA 02550649 2006-06-20
WO 2005/063239 36 PCT/EP2004/014378
one another selected from the group comprising C~_3-alkyl, while two alkyl
groups may
be joined together, forming a ring system.
The bridge X may also represent a single bond. Preferably the bridge X only
forms a
single bond if Y denotes a bicyclic ring system. Also preferably, the bridge X
may
only represent a single bond if the compound according to the invention can be
described according to one of the partial formulae la, Ib or Id, particularly
according to
one of the partial formulae la or Ib, most particularly preferably the partial
formula Ib.
The group Y preferably has a meaning selected from among the bivalent cyclic
groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl,
dihydroindolyl,
quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl,
dihydroisoquinolinyl,
tetrahydro-isoquinolinyl or benzoxazolyl, while the above-mentioned cyclic
groups
may be mono- or polysubstituted at one or more C atoms by RZ°, in the
case of a
phenyl group may also additionally be monosubstituted by nitro, and/or at one
or
more N atoms may be substituted by R2'. R' may be connected to Y and/or X may
be
connected to Y as specified hereinbefore.
If the group Y denotes phenyl or pyridinyl, the bridges X and Z are preferably
connected to the group Y in the para position.
Particularly preferably the group Y has a meaning selected from among the
bivalent
cyclic groups
~ , , ,
-N ,
~ ,
' ~ ~ ' ' ~/ N ~ ~ '
,~ , ,
N
N

CA 02550649 2006-06-20
WO 2005/063239 37 PCT/EP2004/014378
,
,~ , ,
N ~ ~ ~ , ,
N
/ , ; /
/ , I /
~N O
and in particular Y has one of the following meanings
, , ' ,
, , ,~ ,
N
N ~ '~ /
, ,
' /
,
' O / , ~ I /
~N
,
,,~ , ,'~ ,
N ~ ~ ~ and N ;
while the above-mentioned cyclic groups may be mono- or polysubstituted by
R2° at
one or more C atoms, in the case of a phenyl group may also additionally be
monosubstituted by vitro, and/or one or more NH groups may be substituted by
R2'.
The group Y may be linked to the group X forming a carbo- or heterocyclic
group
fused to Y. Preferred definitions of the groups -X-Y- linked to another are
selected
from the list comprising

CA 02550649 2006-06-20
WO 2005/063239 3$ PCT/EP2004/014378
particularly ~ ~ ,
while in the above-mentioned bicyclic groups the phenyl ring may be mono- or
polysubstituted by R2° or may also additionally be monosubstituted by
nitro, and the
saturated carbocyclic ring may be mono- or disubstituted by C~_3-alkyl.
The group Y is preferably unsubstituted or mono- or disubstituted.
Particularly preferred substituents R2° of the group Y are selected
from the group
consisting of fluorine, chlorine, bromine, cyano, nitro, C»-alkyl, C2_6-
alkenyl, hydroxy,
hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-
alkynyl,
C~~-alkoxycarbonyl, C~_4-alkoxy-~_3-alkyl, C~_4-alkoxy-carbonylamino, amino,
C~_4-
alkyl-amino, di-(C»-alkyl)-amino, aminocarbonyl, C»-alkyl-amino-carbonyl, di-
(C~~-
alkyl)-amino-carbonyl, -CH=N-OH and -CH=N-O-C~~-alkyl.
Most particularly preferred substituents R2° of the group Y are
selected from the
group consisting of fluorine, chlorine, bromine, iodine, cyano, C~_3-alkyl,
C~_3-alkoxy,
C~_4-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, amino, or, in the case
of a
phenyl ring, additionally nitro.

CA 02550649 2006-06-20
WO 2005/063239 3g PCT/EP2004/014378
Most particularly preferably the group Y denotes substituted phenylene of the
partial
formula
L'
wherein L' has one of the meanings given hereinbefore for R2°,
preferably F, CI, Br, I,
CH3, CF3, OCH3, OCF3, methoxycarbonyl, ethoxycarbonyl, CN, amino or N02, or
denotes H.
A preferred meaning of the group A is aryl or heteroaryl.
Preferably the group A is selected from among the cyclic groups phenyl,
pyridinyl or
naphthyl, which may be mono- or polysubstituted at one or more C atoms by
R2°, and
in the case of a phenyl ring may also additionally be monosubstituted by
nitro, while
the group A does not contain an amino group as substituent in the ortho
position to
the bridge W.
Preferably the group A has no substituent selected from the group consisting
of C,_4-
alkyl-sulphonylamino, C~~-alkyl-carbonyl-amino, C~~-alkyl-sulphonylamino-C~_3-
alkyl,
C»-alkyl-carbonyl-amino-C~_3-alkyl and phenylcarbonylamino. Other non-
preferred
substituents are aminocarbonyl, C~_4-alkylaminocarbonyl, di-(C~_4-alkyl)-
aminocarbonyl, cyclo-C3_6-alkyl-amino-carbonyl, cyclo-C3_6-alkyleneimino-
carbonyl,
cyclo-C3_6-alkyleneimino-C2~-alkyl-aminocarbonyl, phenyl-amino-carbonyl,
aminocarbonyl-C~_3-alkyl, C~_4-alkylaminocarbonyl-C~_3-alkyl, di-(C~_
4-alkyl)-aminocarbonyl-C~_3-alkyl, cyclo-C3_6-alkyl-amino-carbonyl-C~_3-alkyl,
cyclo-C3_
6-alkyleneimino-carbonyl-C~_3-alkyl, cyclo-C3_6-alkyleneimino-CZ~-alkyl-
aminocarbonyl-
C~_3-alkyl and phenyl-amino-carbonyl-C~_3-alkyl.
Moreover, the group A preferably has no substituent selected from the group
consisting of nitro and tert-butyloxycarbonylamino in the ortho position to
the bridge W
in each case.

CA 02550649 2006-06-20
' WO 2005/063239 40 PCT/EP2004/014378
If b has the value 0, the group A is preferably mono-, di- or trisubstituted.
If b has the value 1, the group A is preferably unsubstituted or mono- or
disubstituted.
If b has the value 1 and the group A is monosubstituted, the substituent is
preferably
in the ortho position relative to the group W.
Most particularly preferably A is one of the following groups
,
B Jb , ~ ~ ~ B Jb
N
B Jb ,
,
while the groups listed may be mono- or polysubstituted by R2° as
specified, while if
the index b has the value 0, the group A does not have an amino group as
substituent
in the ortho position to the bridge W. The definitions phenyl and pyridyl
given for the
group A are preferred when b has the value 1.
Particularly preferred substituents R2° of the group A are selected
from among
fluorine, chlorine, bromine, cyano, C~~-alkyl, C2_6-alkenyl, -CHO, hydroxy,
hydroxy-C~_3-alkyl, C~~-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-
alkynyl, carboxy,
C~_4-alkoxycarbonyl, C~_4-alkoxy-C~_3-alkyl, C~_4-alkoxy-carbonylamino, amino,
C~_a-
alkyl-amino, di-(C~~-alkyl)-amino, cyclo-C3_6-alkyleneimino, aminocarbonyl,
C~_a-alkyl-
amino-carbonyl, di-(C~_4-alkyl)-amino-carbonyl, -CH=N-OH and -CH=N-O-C~_4-
alkyl.
Most particularly preferred substituents R2° of the group A are
selected from among
fluorine, chlorine, bromine, cyano, C~_4-alkyl, C~.~-alkoxy, trifluoromethyl,
trifluoromethoxy, carboxy, C~_4-alkoxycarbonyl, C~_4-alkyl-amino- and di-(C»-
alkyl)-
amino.
If b has the value 0, a particularly preferred meaning of the group A is
substituted
phenyl of the partial formula

CA 02550649 2006-06-20
' WO 2005/063239 41 PCT/EP2004/014378
~LZ~a
' 3
L
wherein
LZ has one of the meanings given for R2° or denotes H, preferably F,
CI, Br, I,
CH3, CF3, OCH3, OCF3, CN or N02; particularly preferably F, CI or Br;
L3 has one of the meanings given for R2° or denotes H, preferably F,
CI, Br, I,
CF3, OCF3, CN, NO2, C~_4-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl,
C»-alkoxy, C3_~-cycloalkyl-O, C3_~-cycloalkyl-C~_3-alkoxy, -COO-C~_4-alkyl
or -COOH; particularly preferably F, CI, Br, C~~-alkyl, CF3, methoxy, OCF3,
CN or N02; most particularly preferably CI, Br, CF3 or N02;
q has the value 0, 1 or 2.
with the proviso that the phenyl group may only be at most monosubstituted by
vitro.
Particularly preferably A is substituted phenyl according to the above partial
formula,
wherein q denotes 1 or 2 and/or at least one substituent L2 is in the meta
position to
the substituent L3.
Another preferred partial formula for A, particularly where b has the value 0,
is
L2
1
2 ~\ \
3
wherein the bond to the group W is effected via the C atom in position number
2 or 3
and LZ and L3 are as hereinbefore defined.
In the event that b has the value 1, a preferred meaning of the group B is
aryl or
heteroaryl, which may be substituted as specified.

CA 02550649 2006-06-20
WO 2005/063239 42 PCT/EP2004/014378
Preferred definitions of the group B are selected from the group consisting of
phenyl,
pyridyl, thienyl and furanyl. Particularly preferably, the group B denotes
phenyl. The
group B defined as specified may be mono- or polysubstituted by R2°, a
phenyl group
may additionally also be monosubstituted by vitro. Preferably the group B is
mono-,
di- or trisubstituted, particularly mono- or disubstituted. In the case of a
monosubstitution the substituent is preferably arranged in the ortho or para
position,
particularly in the para position to the group A.
Particularly preferred substituents R2° of the group B are selected
from the group
consisting of fluorine, chlorine, bromine, cyano, vitro, C~_4-alkyl, hydroxy,
hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-
alkynyl, carboxy,
C~_4-alkoxycarbonyl, C~~-alkoxy-C~_3-alkyl, C~~-alkoxy-carbonylamino, amino,
C~_4-
alkyl-amino, di-(C~_4-alkyl)-amino, cyclo-C3_s-alkyleneimino, aminocarbonyl,
C~~-alkyl-
amino-carbonyl and di-(C~~-alkyl)-amino-carbonyl.
Most particularly preferred substituents R2° of the group B are
selected from the
group consisting of fluorine, chlorine, bromine, cyano, CF3, C~_3-alkyl, C~~-
alkoxy and
trifluoromethoxy or vitro; particularly fluorine, chlorine, bromine, methoxy,
CF3 and
trifluoromethoxy.
Generally R4 has one of the meanings given for R", preferably one of the
meanings
given for R~s.
Particularly preferred meanings of the substituent R4 are H, C~_s-alkyl and
C3_s-
alkenyl. If R4 is linked to Y forming a heterocyclic ring system, particularly
preferred
meanings of R4 are C2_s-alkyl and CZ_s-alkenyl.
If R" is a C2_s-alkenyl or CZ_s-alkynyl group, the definitions -CH=CH2, -
CH=CH(CH3),
-CH=C(CH3)Z, C---CH and-C---C-CH3 are preferred.
The substituent R2° preferably has none of the following structural
elements:
a) -CO-aryl or -CO-heteroaryl, particularly -CO-phenyl, while heteroaryl, aryl
and
phenyl may be substituted,

CA 02550649 2006-06-20
WO 2005/063239 43 PCT/EP2004/014378
b) -C(=NH)-NH, wherein the H atoms may be substituted and/or
c) -NH-CO-NH, wherein the H atoms may be substituted.
Generally preferred definitions of the group Rz° are halogen, hydroxy,
cyano, C~_4-
alkyl, C3_~-cycloalkyl, C~~-alkoxy, C~~-alkoxycarbonyl or amino, while, as
hereinbefore
defined, in each case one or more C atoms may additionally be mono- or
polysubstituted by F and/or in each case one or two C atoms independently of
one
another may additionally be monosubstituted by CI or Br. Particularly
preferably R2°
denotes F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl,
ethyl, n-propyl,
iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, iso-
propoxy, methoxycarbonyl, ethoxycarbonyl or amino.
Preferred definitions of the group Rz' are C~_4-alkyl, C~_4-alkylcarbonyl, C»-
alkoxycarbonyl, C~~-alkylsulphonyl, -S02-NH2, -S02-NH-C~_3-alkyl, -S02-N(C~_3-
alkyl)2
and cyclo-C3_6-alkyleneimino-sulphonyl, while, as hereinbefore defined, in
each case
one or more C atoms may additionally be mono- or polysubstituted by F and/or
in
each case one or two C atoms independently of one another may additionally be
monosubstituted by CI or Br.
Most particularly preferred meanings of R2' are H, C»-alkyl, C~_4-
alkylcarbonyl, C»-
alkoxycarbonyl, particularly H and C~_3-alkyl.
Cy preferably denotes a C3_~-cycloalkyl, particularly a C5_~-cycloalkyl group,
a C5_~-
cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl,
aryl or heteroaryl, while aryl or heteroaryl preferably denotes a monocyclic
or fused
bicyclic ring system, and the above-mentioned cyclic groups may be mono- or
polysubstituted by R2° at one or more C atoms, and in the case of a
phenyl group may
also additionally be monosubstituted by vitro, and/or one or more NH groups
may be
substituted by R2'
Preferred compounds according to the invention are those wherein one or more
of
the groups, radicals, substituents and/or indices have one of the meanings
specified
above as being preferred.

CA 02550649 2006-06-20
WO 2005/063239 44 PCT/EP2004/014378
Particularly preferred compounds according to the invention are those wherein
the bridge X denotes -CH2, -CHZ-CHZ, -CHZ-CH2-CH2 or 1,1-cyclopropylene, and
if the group Y is linked to X via a C atom (of the group Y), may also denote -
CH2-
CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-NR4- or -CH2-CH2-CH2-NR4-,
while the groups mentioned for X are unsubstituted or wherein the alkylene
bridge
as specified is preferably mono- or disubstituted by methyl and/or fluorine,
while two
methyl groups may be joined together to form a cyclopropyl ring; and
the group Y has one of the following meanings
~ ,
,-
N
N ~ '~ /
/ ,
/ ~ I /
~N
,~~ , ~'~ ,
N ~ and N '
or the group Y is linked to the group X forming a carbo- or heterocyclic group
fused to
Y, while the group -X-Y- denotes
,

CA 02550649 2006-06-20
' WO 2005/063239 45 PCT/EP2004/014378
while the above-mentioned phenyl rings or the bicyclic groups containing
heteroatoms may be mono- or polysubstituted by R2° and phenyl rings may
also
additionally be monosubstituted by nitro, and the saturated carbocyclic ring
in the
indane skeleton may be mono- or disubstituted by C~_3-alkyl, and
the group A denotes one of the following partial formulae
B Jb , ~ ~ ~ B Jb ,
N
B Jb ,
,
which may be mono- or polysubstituted by R2°, while if the index b has
the value 0,
the group A does not have an amino group as substituent in the ortho position
to the
bridge W, and
the group B denotes phenyl, which is mono- or polysubstituted by RZ°,
and
b denotes the value 0 or 1.
Most particularly preferred according to the invention are those compounds
wherein
A, B, b, X, Y, Z, R', R2, R3 and W independently of one another have one or
more of
the above-mentioned preferred meanings.
Preferred groups of compounds according to this invention can be described by
the
following formulae, particularly preferably by the formulae 1a.1, la.2a,
la.2b, 1a.3, 1a.5,
1a.6, 1a.7, 1a.8, Ib.1, Ib.2, Ic.1 and Id.1

CA 02550649 2006-06-20
' WO 2005/063239 46 PCT/EP2004/014378
L R2~ r [ R2~, s
R \ N - C _ O 1a.1
Rz~ z \ ~ N C C-C
R3 Q
L RzJr [ R2~]s
R \ ~ la.2a
Rz~N CHz C z \ ~ N C C C \
R3 Q
L R2~r
R \ ~ la.2b
R z z \ / N-C-C-C \
z~N-CH -C '
R3 Q
C RZ~ r
R \ 4 ~ 1a.3
N-CH -CH -NR '
Rz, z z ~ ~ N-C-CSC \
R3 Q
C R2~r
R \ 4 ~ 1a.4
N-CH -CH -CH -N
Rzi z z z ~ ~ N-C-C-C \
R3 Q
RzJr
R ~ ~ 1a.5
N-CH -CH -O '
Rz, z z ~ ~ N-C-C-C \
R3 Q

CA 02550649 2006-06-20
WO 2005/063239 47 PCT/EP2004/014378
L ~1 ~p L R2Jr
R ~ O 1a.6
RZ~N-CH2 CH2-CH2-O ~ ~ ~ N3 C-C=C \
R Q
/ L~~~p LR2Jr
RAN O 1a.7
R2i ~N ~ ~ N C C C \
R3 Q
R'
N N L L~ ~p L R2Jr
R O 1a.8
N-C-C-C \ I /
R3 Q
L ~1 Jp L R2Jr L R2~]s
R N O 1a.9
R ~ ~ N3 C-C-C
R
L R2Jr L R2~~s
R ~ ~ Ib.1
2iN C 2 ~ ' ~ C=C-C-N \
R Rs Q
f , 1 L R2~ r L R2~, s
R N 0 Ib.2
R C C C N \
R3 Q

CA 02550649 2006-06-20
' WO 2005/063239 4$ PCT/EP2004/014378
L~ Jp ~ R2Jr [ R2°]s
R ~ ~ Ic.1
R2~N-C 2 ~ ~ ~ CH2 CH2-C-N
R3 Q
f , 1 [ R2~ r [ R2°] s
RAN ~ Ic.2
RZ/ CH2 CHZ C-N
R3 Q
L~ ~P ~ R2Jr [ R2°~s
R ~ ~ Id.1
2iN C Z ~ . ~ H-CH-C-N \
R Rs Q
f , 1 [ R2~r [ R2°]s
RAN ~ Id.2
R H CH
while the bridges X contained in formulae 1a.1 to 1a.8, Ib.1, Ic.1 and Id.1
representing
-CH2-, -CH2-CH2-, -CH2-CHZ-NR4-, -CHZ-CH2-CH2-NR4-, -CHZ-CH2-O- and
-CH2-CH2-CH2-O- may have one or two substituents selected independently of one
another from the group consisting of C~_3-alkyl and C3_5-cycloalkyl, while two
alkyl
substituents may be joined together to form a C3_6-cycloalkyl group;
particularly
preferably these bridges X, particularly representing -CH2-, may have one or
two
methyl substituents, while two methyl substituents may be joined together to
form a
cyclopropyl group; and
L', R', R2, R3, R4 and R2° have the meanings given above and
substituents occurring
more than once may have identical or different meanings; and particularly

CA 02550649 2006-06-20
WO 2005/063239 4g PCT/EP2004/014378
R', R2 independently of one another are selected from among C~_6-alkyl, C3_~
cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, tetrahydropyran-3 or -4-yl,
tetrahydropyranyl-C,_3-alkyl, piperidin-3 or -4-yl, wherein the NH group may
be substituted by R'3, piperidinyl-C~_3-alkyl, wherein the NH group may be
substituted by R'3, phenyl, pyridyl, phenyl-C~_3-alkyl, pyridyl-C~_3-alkyl,
hydroxy-C2~-alkyl, C~_4-alkoxy-C2~-alkyl, amino-C2~-alkyl, C~~-alkyl-amino-
CZ~-alkyl and di-(C~~-alkyl)-amino-CZ_4-alkyl, while cycloalkyl rings may be
mono-, di- or trisubstituted by substituents selected from hydroxy, hydroxy-
C~_3-alkyl, C~_3-alkyl or C~_3-alkyloxy, particularly hydroxy, hydroxymethyl,
methyl and methoxy, and C2~-alkyl bridges contained in hydroxy-C2~-alkyl-
and C~_4-alkoxy-C2_4-alkyl may additionally be monosubstituted by hydroxy,
hydroxy-C~_3-alkyl, C~_3-alkyl or C~_3-alkyloxy, particularly hydroxy,
hydroxymethyl, methyl or methoxy, and alkyl groups may be mono- or
polysubstituted by F and/or monosubstituted by CI, and one of the groups R'
and R2 may also represent H; or
R~, R2 are connected to each other in such a way that the
R'-N ~~
group ,
R2
is defined according to one of the following partial formulae
v ,
N--r -T
N '
N Nj
' ' N
N-'
' N ,
0 R~3 N N-T
' ~/ ~ ,

CA 02550649 2006-06-20
' WO 2005/063239 50 PCT/EP2004/014378
N-1 N N=r
R13,N' Y
while in the heterocycle formed by the group R'R2N- one or more H atoms
may be replaced by R'4 and/or a H atom may be replaced by Cy representing
C3_s-cycloalkyl, which is mono- or polysubstituted by RZ°, particularly
with F,
hydroxy, C~_3-alkyl, CF3, C~_3-alkyloxy, OCF3 or hydroxy-C~_3-alkyl,
particularly
preferably with F, hydroxy, methyl, methoxy, CF3, OCF3 or hydroxymethyl,
and
the ring attached to the heterocycle formed by the group R'R2N- may be
mono- or polysubstituted, preferably monosubstituted at one or more C atoms
by R2°, and in the case of a phenyl ring may also additionally be
monosubstituted by nitro and
R3 preferably denotes H or methyl,
R'4 in each case independently of one another denotes F, CI, C~_4-alkyl, C3_s-
cycloalkyl-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, C»-alkyloxy, C~_4-alkoxy-
C~_3-alkyl, pyridylamino or aminocarbonyl, while in each case one or more C
atoms may additionally be mono- or polysubstituted by F or in each case a C
atom may be monosubstituted by CI; most particularly preferably denotes
methyl, ethyl, propyl, trifluoromethyl, hydroxy, hydroxymethyl, 1-
hydroxyethyl,
2-hydroxyethyl, 1-hydroxy-1-methyl-ethyl, methoxy, ethoxy, methoxymethyl,
pyridylamino or aminocarbonyl; and
R'3 denotes H, C~_4-alkyl, C~_4-alkylcarbonyl or C~~-alkyloxycarbonyl;
particularly
preferably denotes H or C~_3-alkyl; and
Q denotes CH or N, while CH may be substituted by R2°,
L' preferably denotes fluorine, chlorine, bromine, cyano, C~_3-alkyl, C~_3-
alkoxy,
trifluoromethyl, trifluoromethoxy, C~~-alkoxycarbonyl, amino or nitro;

CA 02550649 2006-06-20
WO 2005/063239 51 PCT/EP2004/014378
particularly preferably denotes fluorine, chlorine, bromine, methyl, methoxy,
trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, cyano, amino or nitro;
p has the value 0 or 1,
Rz° in each case independently of one another preferably denotes
fluorine,
chlorine, bromine, cyano, nitro, C~~,-alkyl, Cz_6-alkenyl, hydroxy,
hydroxy-C~_3-alkyl, C~~-alkoxy, trifluoromethyl, trifluoromethoxy, Cz_4-
alkynyl,
carboxy, C»-alkoxycarbonyl, C~_4-alkoxy-C~_3-alkyl, C~_4-alkoxy-carbonyl-
amino, amino, C»-alkyl-amino, di-(C~~-alkyl)-amino, aminocarbonyl,
C~~-alkyl-amino-carbonyl, di-(C»-alkyl)-amino-carbonyl, while if the index b
has the value 0, the group Cy does not have an amino group as substituent in
the ortho position to the bridge W;
particularly preferably Rz° is selected from fluorine, chlorine,
bromine, cyano,
nitro, C,~-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~~-alkoxy, trifluoromethyl,
trifluoromethoxy, Cz~-alkynyl, carboxy, C~_4-alkoxycarbonyl- and C~~-alkoxy-
C~_3-alkyl;
most particularly preferably denotes fluorine, chlorine, bromine, cyano, CF3,
C~_3-alkyl, C~~-alkoxy and trifluoromethoxy or nitro;
r, s in each case independently of one another have the value 0, 1, 2 or 3,
preferably at least one index r or s does not denote the value 0, and
the compounds according to provisos (M1) to (M14) are not included.
The groups contained in formulae 1a.1 to Id.2
L R2~ r C R2~ r [ R2~] s
,, ,,
' ~I/ ~l/ .
Q and Q advantageously have the following

CA 02550649 2006-06-20
' WO 2005/063239 52 PCT/EP2004/014378
R2o R2o R2o
zo ', R2o
. ~ Q / R ' Q / \ /
substitution pattern . or ,
wherein R2° has one of the meanings given hereinbefore, including H,
and
substituents R2° occurring more than once may have the same or
different meanings,
and preferably at least one substituent R2° has a meaning other than H.
The compounds listed in the Examples and Tables, including the tautomers, the
diastereomers, the enantiomers, the mixtures thereof and the salts thereof,
are
preferred according to the invention. Particularly preferred compounds are
listed
below, while the relevant Example number is given in square brackets:
3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid-(4'-methoxy-biphenyl-4-yl)-
amide [1-
$l~
3-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-propynoic acid-(4'-
methoxy-
biphenyl-4-yl)-amide [1-11];
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-3-fluoro-biphenyl-
4-yl)-
amide [1.17];
3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-2'-
fluoro-
biphenyl-4-yl)-amide [1-18];
3-[4-((R)-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-3-
fluoro-biphenyl-4-yl)-amide [1-20];
3-[4-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-3-
fluoro-
biphenyl-4-yl)-amide [1-21];
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
methyl-
amide [1-23];
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide [1-
33];
3-{4-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-ylmethyl]-phenyls-propynoic
acid-(4'-
chloro-biphenyl-4-yl)-amide [1-34];
3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
amide [1-35];

CA 02550649 2006-06-20
WO 2005/063239 53 PCT/EP2004/014378
3-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
amide [1-36];
3-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-
biphenyl-4-yl)-amide [1-37];
3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide [1-
38];
3-{4-[(cyclohexyl-ethyl-amino)-methyl]-phenyl}-propynoic acid-(4'-chloro-
biphenyl-4-
yl)-amide [1-52];
3-{4-[cyclopentyl-methyl-amino)-methyl]-phenyl}-propynoic acid-(4'-chloro-
biphenyl-4-
yl)-amide [1-425];
3-(1-pyrrolidin-1-yl-indan-5-yl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide [2-3];
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-ylmethyl-phenyl)-
amide [3-6];
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-methoxy-piperidin-1-ylmethyl)-
phenyl]-
amide [3-13];
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-methyl-piperidin-1-ylmethyl)-
phenyl]-
amide [3-14J;
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-{4-[(cyclopropylmethyl-methyl-
amino)-
methyl]-phenyl~-amide [3-15];
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-hydroxy-4-trifluoromethyl-
piperidin-1-
ylmethyl)-phenyl]-amide [3-17];
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-hydroxy-I-piperidin-1-
ylmethyl)-
phenyl]-amide [3-18];
3-[5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid-(4-piperidin-1-ylmethyl-
phenyl)-
amide [3-25];
3-[5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid-[4-(3,5-dimethyl-piperidin-
1-
ylmethyl)-phenyl]-amide [3-29J;
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-diethylamino-
ethoxy)-
phenylJ-amide [3-38];
3-(2,4-dichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenylJ-
amide [4-1];
3-(2,4-dichloro-phenyl)-propynoic acid-[3-methoxy-4-(2-diethylamino-ethoxy)-
phenylJ-
amide-hydrochloride [4-7];
3-(4-chloro-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-
amide [4-
10];

CA 02550649 2006-06-20
WO 2005/063239 54 PCT/EP2004/014378
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-
ethyl)-1H-
indol-5-yl]-amide [4-11];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-bromo-4-(2-
diethylamino-
ethoxy)-phenyl]-amide [4-15];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-nitro-4-(2-
diethylamino-
ethoxy)-phenyl]-amide [4-17];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methoxy-4-(2-
diethylamino-
ethoxy)-phenyl]-amide-hydrochloride (4-20];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methyl-4-(2-
diethylamino-
ethoxy)-phenyl]-amide [4-21 ];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-diethylamino-
ethoxy)-3-
fluoro-phenyl]-amide [4-25];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-
1-yl)-ethylamino]-phenyl}-amide [4-27];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(3-chloro-4-(2-
diethylamino-
ethyl)-phenyl]-amide [4-31];
3-(4-bromo-2-chloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-amide [4-35];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-methoxy-4-[2-(4-methyl-
piperidin-1-yl)-ethoxy]-phenyl}-amide [4-270];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(3,5-dimethyl-
piperidin-1-yl)-
ethoxy]-3-methoxy-phenyl}-amide [4-271];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(2,6-dimethyl-
piperidin-1-yl)-
ethoxy]-3-methoxy-phenyl}-amide [4-277];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(cyclopropylmethyl-
methyl-
amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride [4-278];
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(cyclopropylmethyl-
propyl-
amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride [4-279];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-
acrylamide [5-2];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-
acrylamide [5-4];
1-{4-[(E)-2-(4'-chloro-biphenyl-4-ylcarbamoyl)-vinyl]-benzyl}-piperidine-4-
carboxylic
acid amide [5-6];

CA 02550649 2006-06-20
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(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-
methyl}-
phenyl)-acrylamide [5-7];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-hydroxymethyl-piperidin-1-ylmethyl)-
phenyl]-
acrylamide [5-8];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-((S)-3-hydroxy-pyrrolidin-1-ylmethyl)-
phenyl]-
acrylamide [5-9];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylamide
[5-13];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-cyclopropylaminomethyl-phenyl)-acrylamide
[5-
14];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclopropylmethyl-methyl-amino)-methyl]-
phenyl}-acrylamide [5-17];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclohexyl-methyl-amino)-methyl]-
phenyl}-
acrylamide [5-19];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclohexyl-methyl-amino)-methyl]-
phenyl}-
acrylamide [5-21 ];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(2,6-dimethyl-morpholin-4-ylmethyl)-
phenyl]-
acrylamide [5-23];
(E)-3-[4-(8-aza-spiro[4,5]dec-8-ylmethyl)-phenyl]-N-(4'-chloro-biphenyl-4-yl)-
acrylamide [5-25];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-{[(2-hydroxy-2-methyl-propyl)-(2-methoxy-
ethyl)-
amino]-methyl}-phenyl)-acrylamide [5-27];
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(3-piperidin-1-yl-pyrrolidin-1-ylmethyl)-
phenyl]-
acrylamide [5-28]
N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-
propionamide
[6-2];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-
propionamide [6-3];
N-(4'-chloro-biphenyl-4-yl)-3-(4-morpholin-4-ylmethyl-phenyl)-propionamide [6-
4];
1-{4-[2-(4'-chloro-biphenyl-4-ylcarbamoyl)-ethyl]-benzyl}-piperidine-4-
carboxylic acid
amide [6-5];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-hydroxymethyl-piperidin-1-ylmethyl)-
phenyl]-
propionamide [6-6];
N-(4'-chloro-biphenyl-4-yl)-3-[4-((S)-3-hydroxy-pyrrolidin-1-ylmethyl)-phenyl]-
propionamide [6-7];

CA 02550649 2006-06-20
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N-(4'-chloro-biphenyl-4-yl)-3-[4-((R)-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-
phenyl]-
propionamide [6-8];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-
phenyl]-
propionamide [6-9];
N-(4'-chloro-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide [6-
11];
N-(4'-chloro-biphenyl-4-yl)-3-(4-f [methyl-(tetrahydro-pyran-4-yl)-amino]-
methyl}-
phenyl)-propionamide [6-12];
N-(4'-chloro-biphenyl-4-yl)-3-(4-[(cyclopropylmethyl-methyl-amino)-methyl]-
phenyl}-
propionamide [6-13];
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[(2-hydroxy-2-methyl-propyl)-(2-methoxy-
ethyl)-
amino]-methyl}-phenyl)-propionamide [6-14];
N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclopropyl-methyl-amino)-methyl]-phenyl}-
propionamide [6-15];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-
phenyl]-
propionamide [6-16];
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-
phenyl)-
propionamide [6-17];
3-{4-[(benzyl-methyl-amino)-methyl]-phenyl)-N-(4'-chloro-biphenyl-4-yl)-
propionamide
[6-18];
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-
methyl}-phenyl)-propionamide [6-19];
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(2-phenoxy-ethyl)-amino]-methyl)-
phenyl)-
propionamide [6-20];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(2,6-dimethyl-morpholin-4-ylmethyl)-phenyl]-
propionamide [6-21 ];
N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}-
propionamide [6-22];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1 ]hept-2-
ylmethyl)-
phenyl]-propionamide [6-23];
N-(4'-chloro-biphenyl-4-yl)-3-[4-(3-piperidin-1-yl-pyrrolidin-1-ylmethyl)-
phenyl]-
propionamide [6-25];
N-(4'-chloro-biphenyl-4-yl)-3-[4-((3S.5R)-3,5-dimethyl-piperidin-1-ylmethyl)-
phenyl]-
propionamide [6-26];

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3-(4-f [(3-amino-propyl)-methyl-amino]-methyl}-phenyl)-N-(4'-chloro-biphenyl-4-
yl)-
propionamide [6-27];
3-[4-(8-aza-spiro[4.5]dec-8-ylmethyl)-phenyl]-N-(4'-chloro-biphenyl-4-yl)-
propionamide
[6-28];
N-(4'-chloro-biphenyl-4-yl)-3-[4-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-phenyl]-
propionamide [6-29];
N-(4'-chloro-biphenyl-4-yl)-3-{4-[(methyl-pyridin-3-ylmethyl-amino)-methyl]-
phenyl}-
propionamide [6-33];
N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclohexyl-ethyl-amino)-methyl]-phenyl}-
propionamide [6-35];
N-(4'-chloro-biphenyl-4-yl)-3-(4-cyclohexylaminomethyl-phenyl)-propionamide [6-
39];
N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclohexyl-isopropyll-amino)-methyl]-
phenyl}-
propionamide [6-40];
N-(4'-chloro-biphenyl-4-yl)-3-(4-cyclopentylaminomethyl-phenyl)-propionamide
[6-41];
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[ethyl-(2-hydroxy-2-methyl-propyl)-amino]-
methyl}-
phenyl)-propionamide [6-42];
including the tautomers, the diastereomers, the enantiomers, the mixtures
thereof and
the salts thereof.
Some expressions used hereinbefore and below to describe the compounds
according to the invention will now be defined more fully.
The term halogen denotes an atom selected from among F, CI, Br and I,
particularly
F, CI and Br.
The term C~_~-alkyl, where n has a value of 3 to 8, denotes a saturated,
branched or
unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups
include
methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-
pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc. Substituted alkyl
groups, such
as for example the CZ~-alkyl group in hydroxy-C2~-alkyl or C~_4-alkoxy-CZ~-
alkyl, may
also be branched or unbranched.

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The term C~_~-alkylene, where n may have a value of 1 to 8, denotes a
saturated,
branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of
such
groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene
(-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2-CH2-), n-prop-1,3-ylene (-CH2-
CH2-
CHZ-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop-1,3-ylene (-
CH2-
CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.
The term C2_n-alkenyl, where n has a value of 3 to 6, denotes a branched or
unbranched hydrocarbon group with 2 to n C atoms and at least one C=C-double
bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-
propenyl,
1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-
pentenyl, 2-
pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-
hexenyl,
4-hexenyl, 5-hexenyl etc.
The term C2_~-alkynyl, where n has a value of 3 to 6, denotes a branched or
unbranched hydrocarbon group with 2 to n C atoms and a C--__C triple bond.
Examples
of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-
butynyl, 2-
butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-
pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-
hexynyl
etc.
The term C~_~-alkoxy denotes a C~_~-alkyl-O- group, wherein C~_n-alkyl is
defined as
above. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-
propoxy, n-
butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-
pentoxy, tert-
pentoxy, n-hexoxy, iso-hexoxy etc.
The term C~_~-alkylthio denotes a C~_~-alkyl-S- group, wherein C~_~-alkyl is
defined as
above. Examples of such groups include methylthio, ethylthio, n-propylthio,
iso-
propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-
pentylthio, iso-
pentylthio, neo-pentylthio, tert-pentylthio, n-hexylthio, iso-hexylthio, etc.
The term C~_~-alkylcarbonyl denotes a C~_~-alkyl -C(=O)- group, wherein C~_~-
alkyl is
defined as above. Examples of such groups include methylcarbonyl,
ethylcarbonyl, n-
propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-

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butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-
pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
The term C3_n-cycloalkyl denotes a saturated mono-, bi-, tri- or
spirocarbocyclic,
preferably monocarbocyclic group with 3 to n C atoms. Examples of such groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl,
cyclononyl, cyclododecyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl,
norbonyl,
norcaryl, adamantyl, etc.
The term C5_~-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or
spirocarbocyclic group with 5 to n C atoms. Examples of such groups include
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.
The term C3_~-cycloalkylcarbonyl denotes a C3_~-cycloalkyl-C(=O) group,
wherein C3_n-
cycloalkyl is as hereinbefore defined.
The term aryl denotes a carbocyclic, aromatic ring system, such as for example
phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl,
pentalenyl,
azulenyl, biphenylenyl, etc. A particularly preferred meaning of "aryl" is
phenyl.
The term cyclo-C3_~-alkyleneimino denotes a 4- to 7-membered ring which
comprises
3 to 7 methylene units as well as an imino group, while the bond to the
residue of the
molecule is made via the imino group.
The term cyclo-C3_~-alkyleneimino-carbonyl denotes a cyclo-C3_~-alkyleneimino
ring as
hereinbefore defined which is linked to a carbonyl group via the imino group.
The term heteroaryl used in this application denotes a heterocyclic, aromatic
ring
system which comprises in addition to at least one C atom one or more
heteroatoms
selected from N, O and/or S. Examples of such groups are furanyl, thiophenyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-
triazolyl, 1,3,5-
triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-
triazinyl, 1,2,4-
triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-
thiadiazolyl,

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tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl
(thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl,
benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl,
isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl,
diazepinyl,
acridinyl, etc. The term heteroaryl also comprises the partially hydrogenated
heterocyclic, aromatic ring systems, particularly those listed above. Examples
of such
partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl,
pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
Particularly preferably
heteroaryl denotes a heteroaromatic mono- or bicyclic ring system.
Terms such as aryl-C~_~-alkyl, heteroaryl-C~_~-alkyl, etc. refer to C~_n-
alkyl, as defined
above, which is substituted with an aryl or heteroaryl group.
Many of the terms given above may be used repeatedly in the definition of a
formula
or group and in each case have one of the meanings given above, independently
of
one another.
The term "unsaturated", for example in "unsaturated carbocyclic group" or
"unsaturated heterocyclic group", as used particularly in the definition of
the group Cy,
comprises in addition to the mono- or polyunsaturated groups, the
corresponding,
totally unsaturated groups, but particularly the mono- and diunsaturated
groups.
The term "optionally substituted" used in this application indicates that the
group thus
designated is either unsubstituted or mono- or polysubstituted by the
substituents
specified. If the group in question is polysubstituted, the substituents may
be identical
or different.
The style used hereinbefore and hereinafter, according to which in a cyclic
group a
bond of a substituent is shown towards the centre of this cyclic group, unless
otherwise stated, indicates that this substituent may be bound to any free
position of
the cyclic group carrying an H atom.

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R2oJs
Thus in the example
the substituent R2° where s = 1 may be bound to any of the free
positions of the
phenyl ring; where s = 2 selected substituents R2° may differently from
one another
be bound to different free positions of the phenyl ring.
The H atom of any carboxy group present or an H atom bound to an N atom (imino
or
amino group) may in each case be replaced by a group which can be cleaved in
vivo.
By a group which can be cleaved in vivo from an N atom is meant, for example,
a
hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a
C~-~s-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl,
pentanoyl or
hexanoyl group, an allyloxycarbonyl group, a C~_~s-alkoxycarbonyl group such
as the
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,
octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,
dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C~_s-alkoxycarbonyl
group such as the benzyloxycarbonyl, phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a C~_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C~_3-
alkoxy-
C2~-alkoxy-CZ~-alkoxycarbonyl or ReCO-O-(RfCR9)-O-CO- group wherein
Re denotes a C~_$-alkyl, C5_~-cycloalkyl, phenyl or phenyl- C~_3-alkyl group,
Rf denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and
R9 denotes a hydrogen atom, a C~_3-alkyl or ReCO-O-(RfCR9)-O group wherein
Re to R9 are as hereinbefore defined,
while the phthalimido group is an additionally possibility for an amino group,
and the
above-mentioned ester groups may also be used as a group which can be
converted
in vivo into a carboxy group.

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The residues and substituents described above may be mono- or polysubstituted
by
fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl,
difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are
fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated
alkylsulphinyl and alkylsulphonyl groups are trifluoromethylsulphinyl and
trifluoromethylsulphonyl.
The compounds of general formula I according to the invention may have acid
groups, predominantly carboxyl groups, and/or basic groups such as e.g. amino
functions. Compounds of general formula I may therefore be present as internal
salts,
as salts with pharmaceutically useable inorganic acids such as hydrochloric
acid,
sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for
example
malefic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as
salts with
pharmaceutically useable bases such as alkali or alkaline earth metal
hydroxides or
carbonates, zinc or ammonium hydroxides or organic amines such as e.g.
diethylamine, triethylamine, triethanolamine inter alia.
The compounds according to the invention may be obtained using methods of
synthesis which are known in principle. Preferably the compounds are obtained
analogously to the methods of preparation explained more fully hereinafter,
which are
also an object of this invention. The abbreviations used hereinafter are
defined in the
introduction to the experimental section or are already familiar to those
skilled in the
art.
If the starting materials or intermediate products listed below contain groups
R', R2,
R3, X, Y, Z, A or B with amine functions, these are preferably used in
protected form,
for example with a Boc, Fmoc or Cbz protective group, and liberated at the end
of the
reactions using standard methods.

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Diagram 1:
R\N-X-Y-I + H-C-C OC-N -A B l
Rz/ - I3 ~ Jb
A1 A2 R
[Pd]
Cul, Base
R\N-X-Y-C-C OC-N -A B l
z/ - ~3 ~ Jb
R R
Ib
To obtain a compound of general formula Ib, a compound of general formula A1
is
reacted with a compound of general formula A2 in a Sonogashira coupling in the
presence of a catalyst such as for example palladium with or without ligands
and
copper iodide in a solvent such as for example dioxane, DMF, toluene,
acetonitrile or
THF or a mixture of solvents, using an amine base such as for example
triethylamine
or an inorganic base such as caesium carbonate at temperatures between -20
°C and
200 °C.

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Diagram 2:
\ Hal 'Pd' ~ \ R
/ .~ Y. R --~ 3 /
HR3N Base HR N
2 3
Hal: Br, I if R=Alkin, Y=H
if R=Aryl, Y= B(OH)Z
+ H-C-C- COOH
Base / 13
4 R
_ 'Pd',
Cul, Base
.Pd,, I
Cul, Base
Rz \ I HO ~ /
I
R»N ~ / 5 7
\ R
/
N
(3
R
R»N~RZ _
\ R
/
N
Is
R
In order to obtain compounds of formula 6, an aniline derivative of formula 1
is
reacted with a compound of formula 2. If the compound 2 is an arylboric acid
derivative, the reaction to the compound 3 is carried out in the presence of a
catalyst
such as for example palladium with or without ligands in a solvent or mixture
of
solvents comprising for example dioxane, DMF, toluene, THF or water using a
base
such as for example triethylamine or potassium carbonate at temperatures
between
ambient temperature and 200°C. Instead of the arylboric acid
derivatives it is also
possible to use organometallic aryl compounds such as for example tin or zinc
\ R
O
~N /
compounds. If the compound 2 is an alkyne derivative, the reaction to obtain
the

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compound 3 is carried out as a Sonogashira coupling in the presence of a
catalyst
such as for example palladium with or without ligands and copper iodide in a
solvent
or mixture of solvents comprising for example dioxane, DMF, toluene,
acetonitrile or
THF using a base such as for example triethylamine at temperatures between -
20°C
and 200 °C. A compound of formula 4 is obtained by reacting a compound
of formula
3 with propynecarboxylic acid in the presence of a base and activating
reagents such
as for example CDI, TBTU or DCC. Instead of the propynecarboxylic acid it is
also
possible to use propynecarboxylic acid chloride. Compounds of formula 4 may be
reacted to compounds of formula 6 by a Sonogashira coupling as hereinbefore
described. Alternatively a compound of formula 4 may be reacted with compound
7 in
a Sonogashira coupling as described. The resulting compound of formula 8 is
converted into the sulphonic acid derivative 9 by reacting with
methanesulphonic acid
chloride in the presence of a base such as triethylamine in an inert solvent
such as for
example dichloromethane at a temperature between 0°C and 50°C.
For the reaction
to a compound of formula 6 it is possible to use an analogous tosylate or a
corresponding halogen compound instead of the mesylate 9. A compound of
formula
9 is reacted with the corresponding amine in a solvent such as for example THF
at a
temperature between 0°C and 150 °C, producing a compound of
formula 6.
Diagram 3a:
O
~o~ O
A~B ]b A~B Jb
[Pd], Cul, Base
A3 A4
O
A~B Jb
HO
A5
In order to obtain a compound of general formula A4, a compound of general
formula
A3 is reacted with an ester of propynoic acid, preferably with ethyl
propynoate, in a
Sonogashira coupling in the presence of a catalyst such as for example
palladium
with or without ligands and copper iodide in a solvent such as for example
dioxane,
DMF, toluene, acetonitrile or THF or a solvent mixture, using an amine base
such as

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for example triethylamine or an inorganic base such as caesium carbonate, at
temperatures between -20°C and 200°C. The compound of general
formula A4 is
converted into a compound of general formula A5 in the course of an ester
splitting.
The ester splitting may take place in a solvent such as ethanol, dioxane or
THF with
or without the addition of water in the presence of an inorganic base such as
sodium
hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate at
temperatures from 0°C to 150°C. Ester splitting is also possible
in an organic solvent
such as THF or dioxane in the presence of acid, for example aqueous
hydrochloric
acid or sulphuric acid.
Diagram 3b:
Br
HO A~g ~ HO l
b Brz A~B Jb
O O~ \Br
A6 A7
O
A~B Jb
HO
A5
A compound of general formula A5 may also be prepared by reacting a compound
of
general formula A7 in an organic solvent such as for example dioxane, ethanol
or
THF with or without the addition of water with a base such as potassium tert.
butoxide, sodium hydroxide or sodium ethoxide at temperatures from 0°C
to 150°C.
However, it is also possible in this reaction to react a compound of general
formula A7
with pyridine or quinoline at temperatures from 0°C to 150°C. A
compound of general
formula A7 is obtained by brominating a compound of general formula A6 in a
solvent
such as for example carbon tetrachloride at temperatures between -20°C
to 100°C,
preferably at temperatures between 0°C and ambient temperature.

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Diagram 3c:
1 3
Rz N-X-Y-NCR + A L B Jb
R H HO
A8 A5
R\N-X-Y- N-OC C-C-A B l
RZ/ ~ ~ Jb
R
la
A compound of general formula la is obtained by reacting a compound of general
formula A8 with a compound of general formula A5 in an organic solvent such as
for
example DMF, THF, dioxane, acetonitrile or toluene in the presence of a base
such
as for example triethylamine and activating reagents such as for example CDI,
TBTU
or DCC. Instead of the compound A5 it is also possible to use carboxylic acid
chloride
or a mixed anhydride of the compound A5 .

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WO 2005/063239 6$ PCT/EP2004/014378
Diagram 4:
Rio O
R
\N-X-Y- C=C
Rzi
OH
A9 R
Hz
I
H
Rya R7c O '+' \N-A~B ]b
3~
R\N-X-Y- C-C R A11
Rz/ I ~ OH
A10 H H
R'° O
Rv I ~ ~
H' z~N-X-Y- C=C-C-N-A~B ]b
N-A~-B ] b R ~ 7a R3
Rs~ R
A11 A12
Hz
Rya Roc O
R~___~_~_~~__
Rz~N X Y i C C N A~B Jb
H H R3
Ic
A compound of general formula Ic is advantageously obtained by hydrogenation
of a
compound of general formula A12 in an organic solvent such as for example
methanol, ethanol, THF or dioxane in the presence of a catalyst such as Raney
nickel, palladium or platinum at temperatures between 0 °C and
150° C. The reaction
of the compound A12 to the compound Ic may however also take place in the
presence of other hydrogen-transferring reagents. A compound of general
formula
A12 is obtained by reacting a compound of general formula A9 with a compound
of
general formula A11 in an organic solvent such as for example DMF, THF,
dioxane,

CA 02550649 2006-06-20
WO 2005/063239 gg PCT/EP2004/014378
acetonitrile or toluene in the presence of a base such as for example
triethylamine
and activating reagents such as for example CDI, TBTU or DCC. Instead of the
compound A9 it is also possible to use the carboxylic acid chloride of the
compound
Ag. Compound Ic may also be obtained by reacting a compound of general formula
A10 with a compound of general formula A11 under conditions as described above
for
the reaction of A9 and A11 to A12. The compound of general formula A10 may be
obtained by reduction of a compound of general formula A9 analogously to the
reaction of A12 to Ic.

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WO 2005/063239 70 PCT/EP2004/014378
Diagram 5:
H~
0 0 + 3~N A L B ~b
R
off HC(OMe)3 I ~ \ off A11
o I ~ ~ ,o i
o NEt3, TBTU
H
A13 A14
0 0
I \ j3 A~B,b H+ o I / \ j3 A L B ~b
,p / R ~ R
A15 H A16
0
NaB(OZCCH3)sH _ w ~ N-A~B lb
HO I / R J3
A17
R'
' A19 0
I ~ N-A~B ~ ~ R' I ~ ~ nir-A B
w o RZ/N'H ~ Jb
N R
T / R3 b R2~
A18 A20
T= CI, MeS020-
O
Raney-Ni R~ ~ ~A~B ] b
H Rz ~ N I / R3
A21
A compound of general formula A21 may be obtained as follows. The cinnamic
acid
derivative A13 is converted by reaction with orthomethyl formate with or
without an
organic solvent such as for example methanol, THF or dioxane at temperatures
between ambient temperature and 200 °C into the protected cinnamic acid
derivative
A14. This is reacted in the course of an amide linking with the amine of
general

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WO 2005/063239 71 PCT/EP2004/014378
formula A11 in the presence of TBTU and triethylamine in an organic solvent
such as
for example DMF or THF at a temperature between 0 °C and ambient
temperature, to
obtain a compound of general formula A15. A compound of general formula A16 is
obtained by the action of acid such as for example trifluoroacetic acid on the
compound A15 in a solvent such as for example dichloromethane, chloroform or
water or combinations thereof at temperatures between 0 °C and 100
°C. Reduction
of the compound A16 by the action of a hydride transfer agent such as sodium
triacetoxyborohydride or sodium borohydride in an organic solvent such as for
example THF in the presence of an acid such as acetic acid at temperatures
between
0° C and 100° C yields a compound of general formula A17.
Reacting A17 with
methanesulphonic acid chloride in an organic solvent such as dichloromethane
in the
presence of a base such as triethylamine at temperatures between 0° C
and 100° C
yields a compound of general formula A18. To convert A17 into A18 it is also
possible
to react A17 with thionyl chloride. Compound A20 is obtained by reacting A18
with a
compound of general formula A19 in an organic solvent such as DMF,
acetonitrile or
THF at temperatures of 0°C and 100°C. A compound of general
formula A21 is
obtained by hydrogenation of a compound of general formula A20 in an organic
solvent such as for example methanol, ethanol, THF or dioxane in the presence
of a
catalyst such as Raney nickel, palladium or platinum at temperatures between
0°C
and 150°C. The reaction of compound A20 to compound A21 may however
also be
carried out in the presence of other hydrogen-transferring reagents.
The compounds according to the invention may advantageously also be obtained
by
the processes described in the Examples that follow, and these may also be
combined with processes known to the skilled man from the literature, for
example
from WO 04/024702, WO 04/039780 and WO 04/039764.
Stereoisomeric compounds of formula (I) may chiefly be separated by
conventional
methods. The diastereomers are separated on the basis of their different
physico-
chemical properties, e.g. by fractional crystallisation from suitable
solvents, by high
pressure liquid or column chromatography, using chiral or preferably non-
chiral
stationary phases.

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Racemates covered by general formula (I) may be separated for example by HPLC
on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD).
Racemates
which contain a basic or acidic function can also be separated via the
diastereomeric,
optically active salts which are produced on reacting with an optically active
acid, for
example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-
)-monomethyl
tartrate or (+)-camphorsulphonic acid, or an optically active base, for
example with
(R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine or (S)-brucine.
According to a conventional method of separating isomers, the racemate of a
compound of general formula (I) is reacted with one of the above-mentioned
optically
active acids or bases in equimolar amounts in a solvent and the resulting
crystalline,
diastereomeric, optically active salts thereof are separated using their
different
solubilities. This reaction may be carried out in any type of solvent provided
that it is
sufficiently different in terms of the solubility of the salts. Preferably,
methanol, ethanol
or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then
each of
the optically active salts is dissolved in water, carefully neutralised with a
base such
as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. with
dilute
hydrochloric acid or aqueous methanesulphonic acid and in this way the
corresponding free compound is obtained in the (+) or (-) form.
The (R) or (S) enantiomer alone or a mixture of two optically active
diastereomeric
compounds covered by general formula I may also be obtained by performing the
syntheses described above with a suitable reaction component in the (R) or (S)
configuration.
As already mentioned, the compounds of formula (I) may be converted into the
salts
thereof, particularly for pharmaceutical use into the physiologically and
pharmacologically acceptable salts thereof. These salts may be present on the
one
hand as physiologically and pharmacologically acceptable acid addition salts
of the
compounds of formula (I) with inorganic or organic acids. On the other hand,
in the
case of acidically bound hydrogen, the compound of formula (I) may also be
converted by reaction with inorganic bases into physiologically and
pharmacologically
acceptable salts with alkali or alkaline earth metal cations as counter-ion.
The acid
addition salts may be prepared, for example, using hydrochloric acid,
hydrobromic

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acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic
acid,
toluenesulphonic acid, benzenesulphonic acid, acetic acid, fumaric acid,
succinic
acid, lactic acid, citric acid, tartaric acid or malefic acid. Moreover,
mixtures of the
above mentioned acids may be used. To prepare the alkali and alkaline earth
metal
salts of the compound of formula (I) with acidically bound hydrogen the alkali
and
alkaline earth metal hydroxides and hydrides are preferably used, while the
hydroxides and hydrides of the alkali metals, particularly of sodium and
potassium,
are preferred and sodium and potassium hydroxide are most preferred.
The compounds according to the present invention, including the
physiologically
acceptable salts, are effective as antagonists of the MCH receptor,
particularly the
MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies.
Pharmacological test systems for MCH-antagonistic properties are described in
the
following experimental section.
As antagonists of the MCH receptor the compounds according to the invention
are
advantageously suitable as pharmaceutical active substances for the prevention
and/or treatment of symptoms and/or diseases caused by MCH or causally
connected
with MCH in some other way. Generally the compounds according to the invention
have low toxicity, they are well absorbed by oral route and have good
intracerebral
transitivity, particularly brain accessibility.
Therefore, MCH antagonists which contain at least one compound according to
the
invention are particularly suitable in mammals, such as for example rats,
mice, guinea
pigs, hares, dogs, cats, sheep, horses, pigs, cattle, monkeys and particularly
humans,
for the treatment and/or prevention of symptoms and/or diseases which are
caused
by MCH or are otherwise causally connected with MCH.
Diseases caused by MCH or otherwise causally connected with MCH are
particularly
metabolic disorders, such as for example obesity, and eating disorders, such
as for
example bulimia, including bulimia nervosa. The indication obesity includes in
particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity,
hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic
obesity, symptomatic obesity, infantile obesity, upper body obesity,
alimentary

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obesity, hypogonadal obesity, central obesity. This range of indications also
includes
cachexia, anorexia and hyperphagia.
Compounds according to the invention may be particularly suitable for reducing
hunger, reining in appetite, controlling eating behaviour and/or inducing a
feeling of
satiation.
In addition, the diseases caused by MCH or otherwise causally connected with
MCH
also include hyperlipidaemia, cellulitis, fatty accumulation, malignant
mastocytosis,
systemic mastocytosis, emotional disorders, affectivity disorders, depression,
anxiety
states, reproductive disorders, sexual disorders, memory disorders, epilepsy,
forms
of dementia and hormonal disorders.
Compounds according to the invention are also suitable as active substances
for the
prevention and/or treatment of other illnesses and/or disorders, particularly
those
which accompany obesity, such as for example diabetes, diabetes mellitus,
particularly type II diabetes, hyperglycaemia, particularly chronic
hyperglycaemia,
complications of diabetes including diabetic retinopathy, diabetic neuropathy,
diabetic
nephropathy, etc., insulin resistance, pathological glucose tolerance,
encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly
arteriosclerosis and high blood pressure, arthritis and gonitis.
MCH antagonists and formulations according to the invention may advantageously
be
used in combination with a dietary therapy, such as for example a dietary
diabetes
treatment, and exercise.
Another range of indications for which the compounds according to the
invention are
advantageously suitable is the prevention and/or treatment of micturition
disorders,
such as for example urinary incontinence, hyperactive bladder, nycturia,
enuresis,
while the hyperactive bladder and urinary incontinence may or may not be
connected
with benign prostatic hyperplasia.
The dosage required to achieve such an effect is conveniently, by intravenous
or sub-
cutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg
of

CA 02550649 2006-06-20
WO 2005/063239 75 PCT/EP2004/014378
body weight, and by oral or nasal route or by inhalation, 0.01 to 50 mg/kg of
body
weight, preferably 0.1 to 30 mg/kg of body weight, in each case 1 to 3 x
daily.
For this purpose, the compounds of formula I prepared according to the
invention may
be formulated, optionally together with other active substances as described
hereinafter, together with one or more physiologically acceptable excipients,
inert
conventional carriers and/or diluents, e.g. with corn starch, lactose,
glucose,
microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric
acid,
tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,
water/polyethylene
glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or
fatty
substances such as hard fat or suitable mixtures thereof, to produce
conventional
galenic preparations such as plain or coated tablets, capsules, powders,
granules,
solutions, emulsions, syrups, aerosols for inhalation, ointments or
suppositories.
In addition to pharmaceutical compositions the invention also includes
compositions
containing at least one amide compound according to the invention and/ or a
salt
according to the invention optionally together with one or more
physiologically
acceptable excipients. Such compositions may also be for example foodstuffs
which
may be solid or liquid, in which the compound according to the invention is
incorporated.
For the above mentioned combinations it is possible to use as additional
active
substances particularly those which for example potentiate the therapeutic
effect of an
MCH antagonist according to the invention in terms of one of the indications
mentioned above and/or which make it possible to reduce the dosage of an MCH
antagonist according to the invention. Preferably one or more additional
active
substances are selected from among
- active substances for the treatment of diabetes,
- active substances for the treatment of diabetic complications,
- active substances for the treatment of obesity, preferably other than MCH
antagonists,
- active substances for the treatment of high blood pressure,
- active substances for the treatment of hyperlipidaemia, including
arteriosclerosis,
- active substances for the treatment of arthritis,

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- active substances for the treatment of anxiety states,
- active substances for the treatment of depression.
The above mentioned categories of active substances will now be explained in
more
detail by means of examples.
Examples of active substances for the treatment of diabetes are insulin
sensitisers,
insulin secretion accelerators, biguanides, insulins, a-glucosidase
inhibitors, ~i3
adreno-receptor agonists.
Insulin sensitisers include pioglitazone and its salts (preferably
hydrochloride),
troglitazone, rosiglitazone and its salts (preferably maleate), JTT-501, GI-
262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702 and
GW-1929.
Insulin secretion accelerators include sulphonylureas, such as for example
tolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramide and
its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples
of
insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-
1229) and JTT-608.
Biguanides include metformin, buformin and phenformin.
Insulins include those obtained from animals, particularly cattle or pigs,
semisynthetic human insulins which are synthesised enzymatically from insulin
obtained from animals, human insulin obtained by genetic engineering, e.g.
from
Escherichi coli or yeasts. Moreover, the term insulin also includes insulin-
zinc
(containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc
obtainable from zinc chloride, protamine sulphate and insulin. Insulin may
also
be obtained from insulin fragments or derivatives (for example INS-1, etc.).
Insulin may also include different kinds, e.g. with regard to the onset time
and
duration of effect ("ultra immediate action type", "immediate action type",
"two

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WO 2005/063239 77 PCT/EP2004/014378
phase type", "intermediate type", "prolonged action type", etc.), which are
selected depending on the pathological condition of the patient.
a-Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
~i3 Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552,
AZ40140.
Active substances for the treatment of diabetes other than those mentioned
above include ergoset, pramlintide, leptin, BAY-27-9955 as well as glycogen
phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine
phosphatase 1 B inhibitors, dipeptidyl protease inhibitors, glipazide,
glyburide.
Active substances for the treatment of diabetic complications include for
example
aldose reductase inhibitors, glycation inhibitors and protein kinase C
inhibitors, DPPIV
blockers, GLP-1 or GLP-2 analogues and SGLT-2 inhibitors.
Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat,
zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.
An example of a glycation inhibitor is pimagedine.
Protein Kinase C inhibitors are for example NGF, LY-333531.
DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as
815541, 823093 and 825964 (all GIaxoSmithkline).
GLP-1 analogues are for example Liraglutide (NN2211) (NovoNordisk),
CJC1131 (Conjuchem), Exenatide (Amylin).
SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe,
Johnson&Johnson).

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Active substances other than those mentioned above for the treatment of
diabetic complications include alprostadil, thiapride hydrochloride,
cilostazol,
mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-
711 ).
Active substances for the treatment of obesity, preferably other than MCH
antagonists, include lipase inhibitors and anorectics.
A preferred example of a lipase inhibitor is orlistat.
Examples of preferred anorectics are phentermine, mazindol, fluoxetine,
sibutramine, baiamine, (S)-sibutramine, SR-141716, NGD-95-1.
Active substances other than those mentioned above for the treatment of
obesity include lipstatin.
Moreover for the purposes of this application the active substance group of
anti-
obesity active substances also includes the anorectics, of which the a3
agonists,
thyromimetic active substances and NPY antagonists should be emphasised.
The range of substances which may be considered as preferred anti-obesity or
anorectic active substances is indicated by the following additional list, by
way of
example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a
cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine
reuptake inhibitor (such as for example sibutramine), a sympathomimetic active
substance, a serotonergic active substance (such as for example
dexfenfluramine, fenfluramine or a 5-HT2C agonist such as BVT.933 or
APD356), a dopamine antagonist (such as for example bromocriptine or
pramipexol), a melanocyte-stimulating hormone receptor agonist or mimetic, an
analogue of melanocyte-stimulating hormone, a cannabinoid receptor antagonist
(Rimonabant, ACOMPLIA TM), an MCH antagonist, the OB protein (hereinafter
referred to as leptin), a leptin analogue, a leptin receptor agonist, a
galanine
antagonist, a GI lipase inhibitor or reducer (such as for example orlistat).
Other
anorectics include bombesin agonists, dehydroepiandrosterone or its analogues,
glucocorticoid receptor agonists and antagonists, orexin receptor antagonists,

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urocortin binding protein antagonists, agonists of the Glucagon-like Peptide-1
receptor, such as for example exendin and ciliary neurotrophic factors, such
as
for example axokines. In this context mention should also be made of the forms
of therapy which produce weight loss by increasing the fatty acid oxidation in
the
peripheral tissue, such as for example inhibitors of acetyl-CoA carboxylase.
Active substances for the treatment of high blood pressure include inhibitors
of
angiotensin converting enzyme, calcium antagonists, potassium channel openers
and
angiotensin II antagonists.
inhibitors of angiotensin converting enzyme include captopril, enalapril,
alacepril,
delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril,
temocapril,
trandolapril, manidipine (hydrochloride).
Examples of calcium antagonists are nifedipine, amlodipine, efonidipine,
nicardipine.
Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121.
Angiotensin II antagonists include telmisartan, losartan, candesartan
cilexetil,
valsartan, irbesartan, CS-866, E4177.
Active substances for the treatment of hyperlipidaemia, including
arteriosclerosis,
include HMG-CoA reductase inhibitors, fibrate compounds.
HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin,
atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and
their salts.
Fibrate compounds include bezafibrate, clinofibrate, clofibrate and
simfibrate.

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Active substances for the treatment of arthritis include NSAIDs (non-steroidal
antiinflammatory drugs), particularly COX2 inhibitors, such as for example
meloxicam
or ibuprofen.
Active substances for the treatment of anxiety states include
chlordiazepoxide,
diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam,
alprazoiam, fludiazepam.
Active substances for the treatment of depression include fluoxetine,
fluvoxamine,
imipramine, paroxetine, sertraline.
The dosage for these active substances is conveniently 1/5 of the lowest
normal
recommended dose up to 1/1 of the normal recommended dose.
In another embodiment the invention also relates to the use of at least one
alkyne
compound according to the invention and/ or a salt according to the invention
for
influencing the eating behaviour of a mammal. This use is particularly based
on the
fact that compounds according to the invention may be suitable for reducing
hunger,
restricting appetite, controlling eating behaviour and/or inducing a feeling
of satiety.
The eating behaviour is advantageously influenced so as to reduce food intake.
Therefore, compounds according to the invention are advantageously used for
reducing body weight. Another use according to the invention is the prevention
of
increases in body weight, for example in people who had previously taken steps
to
lose weight and are interested in maintaining their lower body weight.
According to
this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic
use
might be a cosmetic use, for example to alter the external appearance, or an
application to improve general health. The compounds according to the
invention are
preferably used non-therapeutically for mammals, particularly humans, not
suffering
from any diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes
and/or
no diagnosed micturition disorders, particularly urinary incontinence.
Preferably, the
compounds according to the invention are suitable for non-therapeutic use in
people
whose BMI (body mass index), defined as their body weight in kilograms divided
by
their height (in metres) squared, is below a level of 30, particularly below
25.

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The Examples that follow are intended to illustrate the invention:
Preliminary remarks:
As a rule, IR, 1 H-NMR and/or mass spectra have been obtained for the
compounds
prepared. Unless otherwise stated the Rf values were determined using ready-
made
silica gel 60 TLC plates F254 (E. Merck, Darmstadt, Item no. 1.05714) without
chamber saturation. The Rf values obtained under the heading Alox were
determined
using ready-made aluminium oxide 60 TLC plates F254 (E. Merck, Darmstadt, Item
no. 1.05713) without chamber saturation. The ratios specified for the eluants
are
based on units by volume of the solvents in question. The units by volume
specified
in the case of NH3 relate to a concentrated solution of NH3 in water. For
chromatographic purification, silica gel made by Messrs Millipore (MATREXTM,
35-70
my) is used. For chromatographic purification, Alox (E. Merck, Darmstadt,
standardised aluminium oxide 90, 63-200 Nm, Item no.: 1.01097.9050) is used.
The
HPLC data specified were measured under the parameters indicated below:
Analytical columns: Zorbax column (Agilent Technologies), SB (Stable Bond) -
C18;
3.5 Nm; 4.6 x 75 mm; column temperature: 30°C; flow: 0.8 mL / min;
injection volume:
5 NL; detection at 254 nm (methods A and B).
Symmetry 300 (Waters), 3.5 Nm; 4.6 x 75 mm; column temperature: 30°C;
flow: 0.8
mL / min; injection volume: 5 NL; detection at 254 nm (method C)
Method A: water:acetonitrile:formic acid 9:1:0.01 towards 1:9:0.01 over 9 min
Method B: water:acetonitrile:formic acid 9:1:0.01 towards 1:9:0.01 over 4 min,
then 6
min 1:9:0.01
method C: water:acetonitrile:formic acid 9:1:0.01 after 1:9:0.01 over 4 min,
then 6
min 1:9:0.01
Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) -
C18;
3.5 Nm; 30 x 100 mm; column temperature: ambient temperature; flow: 30 mL /
min;
detection at 254 nm.
In preparative HPLC purification, as a rule the same gradients are used which
were
used when obtaining the analytical HPLC data.
The products are collected under mass control, the fractions containing the
product
are combined and freeze-dried.

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If there is no specific information as to the configuration, it is not clear
whether there
are pure enantiomers or whether partial or even total racemisation has taken
place.
The following abbreviations are used above and hereinafter:
abs. absolute
Boc tert-butoxycarbonyl
Cbz benzyloxycarbonyl
CDI N,N'-carbonyldiimidazole
CDT 1,1'-carbonyldi(1,2,4-triazole)
DMF N,N-dimethylformamide
Et ethyl
ether diethyl ether
EtOAc ethyl acetate
EtOH ethanol
Fmoc 9-fluorenylmethoxycarbonyl
sat. saturated
semiconc. semi-concentrated
HCI hydrochloric acid
HOAc acetic acid
HOBt 1-hydroxybenzotriazole-hydrate
Hunig base N-ethyldiisopropylamine
HV high vacuum
i. vac. in vacuo (under vacuum)
KOH potassium hydroxide
conc. concentrated
Me methyl
MeOH methanol
MTBE methyl-tert-butylether
NaCI sodium chloride
NaOH sodium hydroxide
org. organic
Ph phenyl
RT ambient temperature (approx.
20C)

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TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-
tetrafluoroborate
TEBAC triethylbenzylammonium chloride
TFA trifluoroacetic acid
THF tetrahydrofuran
~* denotes the binding site of a group
In the structural formulae shown previously and hereinafter, as well as the H
atoms at
C atoms, the H atoms at O and N atoms, as in hydroxyl or amino groups, for
example,
are generally not specifically shown for reasons of clarity.

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Example 1.1:
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid- (4-prop-1-ynyl-phenyl)-
amide
~I
H
~N I /
1.1.a. 4-prop-1-ynyl-phenylamine
5.47 g (25 mmol) 4-iodoaniline, 0.878 g (1.25 mmol) bistriphenylphosphine
palladium
dichloride, 0.47 g (2.5 mmol) copper(I)iodide and 20 ml piperidine are placed
in a
pressure apparatus. Then 6.1 bar gaseous propyne are piped into the pressure
apparatus, while the temperature rises to 39°C. It is therefore cooled
with water. The
mixture is stirred for two hours at ambient temperature and the reaction
mixture is
then extracted with ethyl acetate and water. The organic phase is dried over
sodium
sulphate, evaporated down and the residue purified by column chromatography on
silica gel (eluant: cyclohexane/ ethyl acetate= 4:1 ).
Yield: 2.1 g (64 % of theoretical)
CgHgN (M= 131.17)
Calc.: Molecular ion peak (M+H)+: 132 Found: Molecular ion peak
(M+H)+: 132
1.1.b. propynoic acid- (4-prop-1-ynyl-phenyl)-amide
1.2 g (5.86 mmol) DCC are added to a solution of 375 mg (5.35 mmol) propynoic
acid
in 10 ml dichloromethane at 0°C and the mixture is stirred for 30
minutes. Then 0.7 g
(5.35 mmol) 4-prop-1-ynyl-phenylamine, dissolved in dichloromethane, are
slowly
added dropwise and the mixture is stirred for two hours again at 0°C.
The reaction
mixture is then filtered through Celite and the filtrate is evaporated down.
The
purification is carried out by column chromatography on silica gel (eluant:
dichloromethane/ethanol= 40:1).
Yield: 0.7 g (71.4 % of theoretical)
Cl2HgN0 (M= 183.21)

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Calc.: Molecular ion peak (M+H)+: 184 Found: Molecular ion peak
(M+H)+: 184
Rf value: 0.65 (silica gel, dichloromethane/ethanol/acetic acid 20:1 )
1.1.c. 1-(4-iodobenzyl)-pyrrolidine
A solution of 5 g (16.83 mmol) 4-iodobenzyl bromide, 1.41 ml (17 mmol)
pyrrolidine
and 4.8 ml (34.43 mmol) triethylamine in 50 ml dichloromethane are stirred for
14
hours at ambient temperature. The reaction mixture is combined with water, the
organic phase is separated off and dried over sodium sulphate.
Yield: 4 g (82.7 % of theoretical)
C11 H141N (M= 287.14)
Calc.: Molecular ion peak (M+H)+: 288 Found: Molecular ion peak
(M+H)+: 288
1.1.d. 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid- (4-prop-1-ynyl-
phenyl)-amide
10 ml acetonitrile are degassed and combined with 0.35 ml (2 mmol)
ethyldiisopropylamine and 0.2 g (0.69 mmol) 1-(4-iodobenzyl)-pyrrolidine. Then
the
mixture is again degassed and 13 mg copper(I)iodide, 34 mg
tetrakistriphenylphosphine palladium and 137 mg (0.75 mmol) propynoic acid- (4-
prop-1-ynyl-phenyl)-amide are then added in succession. The reaction mixture
is
stirred for 24 hours at ambient temperature and then combined with 60 mg
propynoic
acid- (4-prop-1-ynyl-phenyl)-amide. After 24 hours the mixture is evaporated
down.
The purification is carried out by column chromatography on silica gel
(dichloromethane/ methanol/ ammonia = 30:1:0.1 to 20:1:0.1 )
Yield: 24 mg (10 % of theoretical)
C23H22N2~ (M= 342.44)
Calc.: Molecular ion peak (M+H)+: 343 Found: Molecular ion peak
(M+H)+: 343
Rf value: 0.2 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1)
Example 1.2:
3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid- (4-prop-1-ynyl-phenyl)-amide

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_ \
H
~/
1.2.a. 3-(4-hydroxymethyl-phenyl)-propynoic acid-(4-prop-1-ynyl-phenyl)-amide
40 ml THF are degassed, combined with 2.62 g (8.03 mmol) caesium carbonate and
4-iodobenzylalcohol and again degassed. To this reaction mixture are added
successively 138 mg (0.12 mmol) tetrakistriphenylphosphine palladium, 53 mg
(0.28
mmol) copper(I)iodide and 0.7 g (3.2 mmol) propynoic acid- (4-prop-1-ynyl-
phenyl)-
amide. The mixture is stirred for 24 hours at ambient temperature and the
reaction
mixture is then evaporated down. The purification of the residues is carried
out by
column chromatography on silica gel (eluant: dichloromethane/ethanol= 60:1 ).
Yield: 0.5 g (57.8 % of theoretical)
C19H15N~2 (M= 289.33)
Calc.: Molecular ion peak (M+H)+: 290 Found: Molecular ion peak
(M+H)+: 290
Rf value: 0.21 (silica gel, dichloromethane/ ethanol = 50:1 )
1.2.b. -4-[(4-prop-1-ynyl-phenylcarbamoyl)-ethynyl]-benzyl methanesulphonate
0.14 ml (1.8 mmol) methanesulphonic acid chloride are slowly added dropwise at
ambient temperature to a solution of 0.5 g (1.72 mmol) 3-(4-hydroxymethyl-
phenyl)-
propynoic acid (4-prop-1-ynyl-phenyl)-amide and 0.49 ml (3.6 mmol)
triethylamine in
20 ml dichloromethane and the reaction mixture is stirred for two hours at
ambient
temperature. It is extracted three times with water and the organic phase is
dried over
sodium sulphate. The solvent is distilled off and the residue is stirred with
diisopropylether.
Yield: 0.48 g (75.6 % of theoretical)
C20H 17N04S (M= 367.42)
Calc.: Molecular ion peak (M+H)+: 368 Found: Molecular ion peak
(M+H)+: 368
Rf value: 0.48 (silica gel, dichloromethane/ ethanol = 20:1 )

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1.2.c. 3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid- (4-prop-1-ynyl-
phenyl)-amide
A reaction mixture of 0.5 mg (0.13 mmol) 4-[(4-prop-1-ynyl-phenylcarbamoyl)-
ethynyl]-benzyl methanesulphonate, 0.028 ml (0.28 mmol) piperidine in 5 ml THF
is
stirred for 14 hours at ambient temperature. The reaction mixture is
evaporated down.
The purification is carried out by column chromatography on silica gel
(eluant:
dichloromethane/ethanol= 25:1 to 15:1 ).
Yield: 13 mg (26.8 % of theoretical)
Melting point: 180-181 °C
C24H24N2~ (M= 356.47)
Calc.: Molecular ion peak (M+H)+: 357 Found: Molecular ion peak
(M+H)+: 357
Rf value: 0.21 (silica gel, dichloromethane/ ethanol = 20:1 )
The following compounds are prepared analogously to Example 1.2.c:
R'RZN~X
/
-N
H
ExampleR~RZN-X educt empirical mass mp Rf
formula spectrum [C] value
1.3 ~ 1.2.b C25HZ6N20 371 [M+H]+158- 0.21
N~ 159 (A)
1.4 0 1.2.b C25H26N202 387 [M+H]+176- 0.3
~N~ 177 (A)
1.5 " 1.2.b CZ9H28N40 449 [M+H]+141 0.18
N
~ N ~N~ A

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1.6 \ I o,H 1.2.b C3oH28N202 449 [M+H]+161.5 0.3
(A)
1.7 " 1.2.b C2~H3oNz02 415 [M+H]+120 0.1
0
(A)
Rf value: A= (silica gel, dichloromethane/ethanol/ 20:1)
Example 1.8:
3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid-(4'-methoxy-biphenyl-4-yl)-
amide
o~
i
0
N
1.8.a. propynoic acid-(4'-methoxy-biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.b from propynoic acid and 4'-methoxy-
biphenyl-
4-ylamine.
Yield: 1.3 g (17.2 % of theoretical)
C16H13N02 (M= 251.28)
Calc.: Molecular ion peak (M+H)+: 252 Found: Molecular ion peak
(M+H)+:252
Rf value: 0.6 (silica gel, dichloromethane/ ethanol = 20:1)
1.8.b. 3-(4-hydroxymethyl-phenyl)-propynoic acid-(4'-methoxy-biphenyl-4-yl)-
amide
Prepared analogously to Example 1.2.a from iodobenzylalcohol and propynoic
acid-
(4'-methoxy-biphenyl-4-yl)-amide.
Yield: 0.21 g (22.9 % of theoretical)
C23H1gN03 (M= 357.41)

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Calc.: Molecular ion peak (M+H)+: 358 Found: Molecular ion peak
(M+H)+: 358
Rf value: 0.35 (silica gel, dichloromethane/ ethanol = 20:1 )
1.8.c. 4-[(4'-methoxy-bipheny-4-ylcarbamoyl)-ethynyl]-benzyl methanesulphonate
Prepared analogously to Example 1.2.b from 3-(4-hydroxymethyl-phenyl)-
propynoic
acid-(4'-methoxy-biphenyl-4-yl)-amide and methanesulphonic acid chloride.
Yield: 0.18 g (70.3 % of theoretical)
C24H21 N05S (M= 435.50)
Rf value: 0.58 (silica gel, dichloromethane/ ethanol = 20:1 )
1.8.d. 3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid- (4'methoxy -phenyl)-
amide
Prepared analogously to Example 1.2.c from 4-[(4'-methoxy-bipheny-4-
ylcarbamoyl)-
ethynyl]-benzyl methanesulphonate and piperidine.
Yield: 5 mg (18.8 % of theoretical)
Melting point: 170°C
C28H28N202 (M= 424.54)
Calc.: Molecular ion peak (M+H)+: 425 Found: Molecular ion peak
(M+H)+:425
Rf value: 0.28 (silica gel, dichloromethane/ ethanol = 20:1 )
The following compounds are prepared analogously to Example 1.8.d:
/ I o~
o /
~N
H
R~RzN~X /
ExampleR~R2N-X educt empirical mass mp Rf
formula spectrum [C] value

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1.9 ~ 1.8.c C29H3oN20z 439 [M+H]+168- 0.2
N~ 169 (A)
1.10 0 1.8.c C29H3oN2O3 455 [M+H]+190.5 0.22
~N~:% (A)
1.11 " 1.8.c C33H32N4O2 517 [M+H]+196- 0.15
N
N ~N~ 197 (A)
1.12 \ I ,H 1.8.c C34H32N2O3 517 [M+H]+167.5 0.2
(A)
1.13 H 1.8.c CZ9H3oN2O3 455 [M+H]+156 0.35
'
o
1 ~- ( B>
1.14 " 1.8.c C3~H34N2~3 483 [M+H]+192- 0.45
0
193 (B)
N
1.15 ~ 1.8.c C32H35N3O2 494 [M+H]+181- 0.05
182 (B)
N
1.16 I ~ ~ 1.8.c C33H31N3~3 518 [M+H]+196-
1 N N
197
Rf value: A= (silica gel, dichloromethane/ethanol/ammonia 20:1)
B= (silica gel, dichloromethane/ethanol/ammonia 5:1)
Example 1.17:
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-3-fluoro-biphenyl-
4-yl)-
amide
ci
o i
H F
N

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1.17.a. 4'-chloro-3-fluoro-biphenyl-4-ylamine
1.95 g (12.47 mmol) 4-chlorophenylboric acid, dissolved in 10 ml of methanol,
and 3.9
g (36.79 mmol) sodium carbonate, dissolved in 10 ml of water, are added
successively to a reaction mixture of 2.28 g (12 mmol) 4-bromo-2-fluoroaniline
and
0.6 g (0.51 mmol) tetrakistriphenylphosphine palladium in 90 ml dioxane and
stirred
for 14 hours at 80°C. Then ethyl acetate is added and the reaction
mixture is filtered.
The filtrate is evaporated down and extracted with ethyl acetate and water.
The
organic phase is dried over sodium sulphate. The purification is carried out
by column
chromatography on silica gel (eluant: cyclohexane/ ethyl acetate= 3:1 ).
Yield: 2 g (75.2 % of theoretical)
Cl2HgFN (M= 221.66)
Calc.: Molecular ion peak (M+H)+: 222 Found: Molecular ion peak
(M+H)+: 222
Rf value: 0.41 (silica gel, cyclohexane/ethyl acetate 3:1 )
1.17.b. propynoic acid-(4'-chloro-3-fluoro-biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.b from 4'-chloro-3-fluoro-biphenyl-4-
ylamine
and propynoic acid.
Yield: 0.16 g (43.7 % of theoretical)
ClSHgCIFNO (M= 273.69)
Calc.: Molecular ion peak (M+H)+: 274/276 Found: Molecular ion
peak (M+H)+: 274/276
Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate 3:1 )
1.17.c. 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-3-fluoro-
biphenyl-
4-yl)-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-pyrrolidine and
propynoic acid-(4'-chloro-3-fluoro-biphenyl-4-yl)-amide.
Yield: 20 mg (13 % of theoretical)
Melting point: 136°C
C26H22CIFN20 (M= 432.92)

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Calc.: Molecular ion peak (M+H)+: 433/435/437 Found: Molecular ion
peak (M+H)+: 433/435/437
Rf value: 0.3 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1)
Example 1.18:
3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-2'-
fluoro-
biphenyl-4-yl)-amide
c~
0
i
_ w
H F
1.18.a. 3-(4-hydroxymethyl-phenyl)-propynoic acid-(4'-chloro-2'-fluoro-
biphenyl-4-yl)-
amide
Prepared analogously to Example 1.2.a from propynoic acid-(4'-chloro-3-fluoro-
biphenyl-4-yl)-amide and 4-iodobenzylalcohol.
Yield: 0.4 g (41 % of theoretical)
C22H15CIFN02 (M= 379.82)
Calc.: Molecular ion peak (M+H)+: 380/382 Found: Molecular ion
peak (M+H)+: 380/382
Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia=20:1:0.1 )
1.18.b. 4-[(4'-chloro-2'-fluoro-biphenyl-4-ylcarbamoyl)-ethynyl]-benzyl
methanesulphonate
Prepared analogously to Example 1.2.b from 3-(4-hydroxymethyl-phenyl)-
propynoic
acid-(4'-chloro-2'-fluoro-biphenyl-4-yl)-amide and methanesulphonic acid
chloride.
Yield: 0.23 g (50 % of theoretical)
C23H17CIFN202S (M= 457.91)
Calc.: Molecular ion peak (M+H)+: 456/458 Found: Molecular ion peak
(M+H)+: 456/458
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ ammonia = 20:1:0.1)

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1.18.c. 3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
2'-fluoro-
biphenyl-4-yl)-amide
Prepared analogously to Example 1.2.c from 4-[(4'-chloro-2'-fluoro-biphenyl-4-
ylcarbamoyl)-ethynyl]-benzyl methanesulphonate and 4-methylpiperidine.
Yield: 13 mg (21 % of theoretical)
Melting point: 149-150°C
C28H2gCIFN20 (M= 460.98)
Calc.: Molecular ion peak (M+H)+: 461/463 Found: Molecular ion peak
(M+H)+: 461 /463
Rf value: 0.3 (silica gel, dichloromethane/ methanol/ ammonia = 20:1:0.1)
The following compounds were prepared analogously to Example 1.2.c:
i I
o i
j ~N
H
R~RZN~X
ExampleR~R2N-X educt empirical mass mp Rf
formula spectrum [C] value
1.19 1.18.b C28H25CIFN302488/490 222- 0.1
N ~~ [M+H]+ 223 (A)
~
1.20 1.18.b CZ~H24CIFN202463/465 146- 0.25
N
[M+H]+ 148 (A)
o
1.21 ~ 1.18.b C2~H24CIFN202463/465 164- 0.3
N"' [M+H]+ 165 (B)
1.22 0~ 1.18.b C26H22CIFN202449/451 0.3
~N~
[M+H]+ (A)
Rf value: A= (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
B= (silica gel, dichloromethane/methanol/ammonia 10:1:0.1 )

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Example 1.23:
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
methyl-
amide
ci
\ I
o i
~N
~N
1.23.a. propynoic acid-(4'-chloro-biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.b from 4'-chloro-biphenyl-4-ylamine and
propynoic acid.
Yield: 0.4 g (29.2 % of theoretical)
C15H10CIN0 (M= 255.70)
Calc.: Molecular ion peak (M+H)+: 256/258 Found: Molecular ion
peak (M+H)+: 256/258
Rf value: 0.35 (silica gel, dichloromethane/ ethanol 20:1 )
1.23.b. propynoic acid-(4'-chloro-biphenyl-4-yl)-methyl-amide
75 mg (1.72 mmol) sodium hydride (55%) are added to a solution of 0.4 g (1.56
mmol) propynoic acid-(4'-chloro-biphenyl-4-yl)-amide in 10 ml THF at
0°C and stirred
for one hour at this temperature. Then 0.098 ml (1.56 mmol) methyl iodide are
added
dropwise and the mixture is stirred for 14 hours, while the reaction mixture
is allowed
to come up to ambient temperature. Then the reaction mixture is extracted with
water
and ethyl acetate and the organic phase is dried over sodium sulphate. The
purification is carried out by column chromatography on silica gel (eluant:
cyclohexane/ ethyl acetate= 3:1 ).
Yield: 0.15 g (35.6 % of theoretical)
C1gH12CIN0 (M= 269.73)
Calc.: Molecular ion peak (M+H)+: 270/272 Found: Molecular ion
peak (M+H)+: 270/272
Rf value: 0.61 (silica gel, cyclohexane/ ethyl acetate 1:1

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1.23.c. 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-
4-yl)-
methyl-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-pyrrolidine and
propynoic acid-(4'-chloro-biphenyl-4-yl)-methyl-amide.
Yield: 38 mg (25.4 % of theoretical)
Melting point: 161-164°C
C27H25CIN20 (M= 428.96)
Calc.: Molecular ion peak (M+H)+: 429/431 Found: Molecular ion
peak (M+H)+: 429/431
Rf value: 0.41 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1 )
Example 1.24:
3-[4-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-biphenyl-
4-yl)-methyl-amide-ditrifluoroacetate
C:~
1.24.a. 1-(4-iodobenzyl)-4-pyrrolidin-1-yl-piperidine
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-
pyrrolidin-1-
yl-piperidine.
Yield: 0.57 g (51 % of theoretical)
C16H231Nz (M= 370.28)
Calc.: Molecular ion peak (M+H)+: 371 Found: Molecular ion peak
(M+H)+:371
Rf value: 0.3 (silica gel, dichloromethane/ ethanol 20:1 )
1.24.b. 3-[4-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-
(4'-chloro-
biphenyl-4-yl)-methyl-amide-ditrifluoroacetate

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Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-4-pyrrolidin-1-yl-
piperidine and propynoic acid-(4'-chloro-biphenyl-4-yl)-methyl-amide.
Yield: 5 mg (4 % of theoretical)
Melting point: 161-164°C
C32H34CIN30 X 2 CF3C02H(M= 740.14)
Calc.: Molecular ion peak (M+H)+: 512/514 Found: Molecular ion
peak (M+H)+: 512/514
Rf value: 0.41 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1 )
Example 1.25:
3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
methyl-amide
c~
o i
~N
N
1.25.a. 3-(4-hydroxymethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
methyl-
amide
Prepared analogously to Example 1.2.a from 4-iodobenzylalcohol and propynoic
acid-
(4'-chloro-biphenyl-4-yl)-methyl-amide.
Yield: 0.52 g (90 % of theoretical)
C23H18CINOZ (M= 375.85)
Calc.: Molecular ion peak (M+H)+: 376/378 Found: Molecular ion
peak (M+H)+: 376/378
Rf value: 0.4 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1)
1.25. b. 4-{[(4'-chloro-biphenyl-4-yl)-methyl-carbamoyl]-ethynyl}-benzyl
methanesulphonate
Prepared analogously to Example 1.2.b from 3-(4-hydroxymethyl-phenyl)-
propynoic
acid-(4'-chloro-biphenyl-4-yl)-methyl-amide.
Yield: 0.54 g (100 % of theoretical)

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C24H2pCIN04S (M= 453.94)
Calc.: Molecular ion peak (M+H)+: 454/456 Found: Molecular ion
peak (M+H)+: 454/456
1.25.c. 3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-methyl-amide
Prepared analogously to Example 1.2.c from 4-~[(4'-chloro-biphenyl-4-yl)-
methyl-
carbamoyl]-ethynyl}-benzyl methanesulphonate and 4-methylpiperidine.
Yield: 8 mg (16 % of theoretical)
C2gH2gCIN20 (M= 457.02)
Calc.: Molecular ion peak (M+H)+: 457/459 Found: Molecular ion
peak (M+H)+: 457/459
Rf value: 0.41 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1 )
The following compounds are prepared analogously to Example 1.2.c:
/ cl
o /I
j N \
R~RzN~X /
Example R~R2N-X educt empirical mass mp Rf
formula spectrum [C] value
1.26 0 1.25.cC29H29CIN202 473/475 163.5
~N~ [M+H]+
1.27 ~ I 1.25.cC28H2~CIN20 443/445 131.5
N
[M+Hl+
1.28 N 1.25.cC29H29CIN202 473/475 147-
o [M+H]+ 148

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1.29 ~ 1.25.c C3pH33CIN2~3 505/507 134
[M+H]+
1.30 1.25.c C32HssCIN20 497/499 190
[M+H]+
1.31 1.25.c C3H3~CINZO 471/473 166
[M+Hl+
1.32 N 1.25.c C2~H25CIN20 429/431 148-
+
[M+H] 149
Rf value: A= (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)
Example 1.33:
3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide
ci
~I
o i
~I
H
~N I /
1.33.a. 1-(4-trimethylsilanylethynyl-benzyl)-pyrrolidine
A reaction mixture of 1 g (3.48 mmol) 1-(4-iodobenzyl)-pyrrolidine, 5 ml
piperidin, 105
mg (0.091 mmol) tetrakistriphenylphosphine palladium and 10 mg (0.053 mmol)
copper(I)iodide is cooled to 0°C. At this temperature 0.59 ml (4.18
mmol)
trimethylsilylacetylene is added dropwise and then the cooling bath is
removed. It is
stirred for three hours at ambient temperature, then combined with a saturated
aqueous ammonium chloride solution and extracted with dichloromethane. The
organic phase is dried over sodium sulphate. The purification is carried out
by column
chromatography on silica gel (eluant: cyclohexane/ ethyl acetate= 1:1 ).
Yield: 0.75 g (83.6 % of theoretical)
C16H23NSi (M= 257.45)

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Calc.: Molecular ion peak (M+H)+: 258 Found: Molecular ion peak
(M+H)+: 258
1.33.b. 1-(4-ethynyl-benzyl)-pyrrolidine
A solution of 0.75 g (2.91 mmol) 1-(4-trimethylsilanylethynyl-benzyl)-
pyrrolidine in 10
ml dichloromethane and 10 ml of methanol is combined with 2.4 ml of a 1 M
sodium
hydroxide solution and stirred for three hours at ambient temperature. The
reaction
mixture is evaporated down and the residue is extracted with water and ethyl
acetate.
The organic phase is stirred with activated charcoal, filtered and then dried
over
sodium sulphate.
Yield: 0.4 g (74.1 % of theoretical)
C13H15N (M= 185.27)
Calc.: Molecular ion peak (M+H)+: 186 Found: Molecular ion peak
(M+H)+: 186
1.33.c. (4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid
5.98 ml (14.85 mmol) of a 1.6 M butyllithium solution in n-hexane are added
dropwise
to a solution of 2.3 g (12.41 mmol) 1-(4-ethynyl-benzyl)-pyrrolidine in 50 ml
THF at
-78°C and stirred for one hour at this temperature. Then dry ice is
added to the
reaction mixture. Then the reaction mixture is allowed to come up to ambient
temperature and stirred for 14 hours. The reaction mixture is combined with
dilute
hydrochloric acid and extracted with dichloromethane. The organic phase is
separated off and dried over sodium sulphate. The sodium sulphate is separated
off
and the solvent is removed.
Yield: 0.3 g (10.5 % of theoretical)
C14H15N~2 (M= 229.28)
Calc.: Molecular ion peak (M+H)+: 230 Found: Molecular ion peak
(M+H)+: 230
Rf value: 0.15 (silica gel, dichloromethane/ methanol/ ammonia = 9:1:0.1 )
1.33.d. 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-
4-yl)-
amide

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A solution of 0.3 g (1.30 mmol) (4-pyrrolidin-1-ylmethyl-phenyl)-propynoic
acid, 0.27
g (1.32 mmol) 4'-chloro-biphenyl-4-ylamine, 0.42 g (1.32 mmol) TBTU and 0.18
ml
(1.32 mmol) triethylamine in 30 ml DMF is stirred for 14 hours at ambient
temperature. The reaction mixture is evaporated down and the residue is
extracted
with water and dichloromethane. The organic phase is dried over sodium
sulphate.
The purification is carried out by column chromatography on silica gel
(eluant:
dichloromethane/ethanol= 10:1 ).
Yield: 0.095 g (17.5 % of theoretical)
Melting point: from 180°C
C2gH23CIN20 (M= 414.93)
Calc.: Molecular ion peak (M+H)+: 415/417 Found: Molecular ion
peak (M+H)+: 415/417
Rf value: 0.3 (silica gel, dichloromethane/ ethanol = 5:1)
Example 1.34:
3-~4-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-ylmethyl]-phenyl}-propynoic
acid-(4'-
chloro-biphenyl-4-yl)-amide
0
O ~ ~N
i
N
1.34.a. 2-[1-(4-iodobenzyl)-piperidin-4-yl]-propan-2-of
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 2-
piperidin-4-
yl-propan-2-ol.
Yield: 1.01 g (67% of theoretical)
C15H221N0 (M= 359.25)
Calc.: Molecular ion peak (M+H)+: 360 Found: Molecular ion peak
(M+H)+: 360
Rf value: 0.4 (silica gel, dichloromethane/ ethanol 20:1 )
1.34.b. 3-{4-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-ylmethyl]-phenyl}-
propynoic
acid-(4'-chloro-biphenyl-4-yl)-amide

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WO 2005/063239 101 PCT/EP2004/014378
y T
Prepared analogously to Example 1.1.d from 2-[1-(4-iodobenzyl)-piperidin-4-yl]-
propan-2-of and propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 45 mg (30 % of theoretical)
Melting point: 194-195°C
C3pH31 CIN202 (M= 487.04)
Calc.: Molecular ion peak (M+H)+: 487/489 Found: Molecular ion
peak (M+H)+: 487/489
Rf value: 0.3 (silica gel, dichloromethane/ methanol/ ammonia = 10:1:0.1)
Example 1.35:
3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
amide
1.35.a. 1-(4-iodobenzyl)-4-methyl-piperidine
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methyl-
pipiridine.
Yield: 0.95 g (71.6% of theoretical)
C13H181N (M= 315.20)
Calc.: Molecular ion peak (M+H)+: 316 Found: Molecular ion peak
(M+H)+: 316
Rf value: 0.6 (silica gel, dichloromethane/ ethanol 20:1 )
1.35.b. 3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-4-methyl-
piperidine
and propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 50 mg (27 % of theoretical)
C28H27CIN20 (M= 442.99)

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r
Calc.: Molecular ion peak (M+H)+: 443/445 Found: Molecular ion
peak (M+H)+: 443/445
Rf value: 0.45 (silica gel, dichloromethane/ methanol = 10:1 )
Example 1.36:
3-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
amide
c~
~I
o i
I ~I
O / .N
\ H
N
1.36.a. 1-(4-iodobenzyl)-4-methoxy-piperidine
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methoxy-
piperidine.
Yield: 0.93 g (66.7% of theoretical)
C13H181N0 (M= 331.19)
Calc.: Molecular ion peak (M+H)+: 332 Found: Molecular ion peak
(M+H)+: 332
Rf value: 0.55 (silica gel, dichloromethane/ ethanol 20:1 )
1.36.b. 3-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-
biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-4-methoxy-
piperidine
and propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 25 mg (13 % of theoretical)
Melting point: 145-146 C
C28H27CIN202 (M= 458.99)
Calc.: Molecular ion peak (M+H)+: 459/461 Found: Molecular ion
peak (M+H)+: 459/461
Rf value: 0.4 (silica gel, dichloromethane/ methanol = 10:1)

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Example 1.37:
3-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-
biphenyl-4-yl)-amide
i
o I ~-
0
N
1.37.a. 1-(4-iodobenzyl)-4-methyl-piperidin-4-of
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and 4-methyl-
piperidin-4-ol.
Yield: 0.22 g (30% of theoretical)
C13H181N0 (M= 331.19)
Calc.: Molecular ion peak (M+H)+: 332 Found: Molecular ion peak
(M+H)+: 332
Rf value: 0.45 (silica gel, dichloromethane/ ethanol 20:1 )
1.37.b. 3-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-
(4'-
chloro-biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-4-methyl-piperidin-
4-of
and propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 25 mg (13 % of theoretical)
Melting point: 192-193 C
C28H27CIN202 (M= 458.99)
Calc.: Molecular ion peak (M+H)+: 459/461 Found: Molecular ion
peak (M+H)+: 459/461
Rf value: 0.2 (silica gel, dichloromethane/ methanol = 10:1 )
Example 1.38:
3-[4-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-(4'-
chloro-biphenyl-
4-yl)-amide

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, , WO 2005/063239 104 PCT/EP2004/014378
/ CI
\I
° /I
N ~ _N
I\ H
N /
1.38.a. 3-[4-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-propynoic acid-
(4'-chloro-
biphenyl-4-yl)-amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-4-pyrrolidin-1-yl-
piperidine and propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 15 mg (7 % of theoretical)
Melting point: 191-192 C
C31 H32CIN30 (M= 498.07)
Calc.: Molecular ion peak (M+H)+: 498/500 Found: Molecular ion
peak (M+H)+: 498/500
Rf value: 0.45 (silica gel, dichloromethane/ methanol/ammonia = 10:1:0.1)
Example 1.39:
3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide
/ cl
I
/ \
I
_ \
\ / H
N I/
1.39.a. 1-(4-iodobenzyl)-piperidine
Prepared analogously to Example 1.1.c from 4-iodobenzyl bromide and
pipiridine.
Yield: 0.85 g (67% of theoretical)
C12H161N (M= 301.17)
Calc.: Molecular ion peak (M+H)+: 322 Found: Molecular ion peak
(M+H)+: 302
Rf value: 0.55 (silica gel, dichloromethane/ ethanol 20:1 )

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1.39.b. 3-(4-piperidin-1-ylmethyl-phenyl)-propynoic acid-(4'-chloro-biphenyl-4-
yl)-
amide
Prepared analogously to Example 1.1.d from 1-(4-iodobenzyl)-piperidine and
propynoic acid-(4'-chloro-biphenyl-4-yl)-amide.
Yield: 6 mg (4 % of theoretical)
Melting point: 179.5 C
C27H25CIN20 (M= 428.96)
Calc.: Molecular ion peak (M+H)+: 429/431 Found: Molecular ion
peak (M+H)+: 429/431
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ammonia = 10:1:0.1)
Example 1.40:
3-{4-[cyclopropylmethyl-methyl-amino)-methyl]-phenyl}-propynoic acid-(4'-
chloro-
biphenyl-4-yl)-amide
ci
~N
1.40.a. propynoic acid-(4'chloro-biphenyl-4-yl)-amide
36 ml of a 1 molar DCC solution in dichloromethane are added dropwise at -
10°C to a
solution of 4.9 g (70 mmol) propynoic acid in 120 ml dichloromethane and the
mixture
is stirred for 30 min. Then 7 g (34.37 mmol) 4'-chloro-biphenyl-4-ylamine,
dissolved in
dichloromethane, are slowly added dropwise and the mixture is stirred for 2 h
at -8°C.
The reaction mixture is then filtered through Celite, washed again with
methanol and
the filtrate is evaporated down. The purification is carried out by column
chromatography on silica gel ( eluant: cyclohexane/ethyl acetate=6:1 to 2:1)
Yield: 7.6 g (95 % of theoretical)
C15H10CINO (M=255.70)
Calc.: Molecular ion peak (M+H)+: 256/8 (CI) Found: Molecular ion
peak (M+H)+: 256/8 (CI)
Rf value: 0.2 (silica gel, cyclohexane/ethyl acetate 1:1 )

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1.40.b 3-(4-hydroxymethyl-phenyl)-propynoic acid-4'-chloro-biphenyl-4-yl)-
amide
g (30.69 mmol) caesium carbonate and 2.4 g (10.26 mmol) 4-iodobenzylalcohol
are placed in 120 ml THF and cooled to -15°C in the ice/methanol bath,
rinsed with
5 argon and degassed. To this reaction mixture are added successively 660 mg
(0.57
mmol) tetrakistriphenylphosphine palladium and 240 mg (1.26 mmol)
copper(I)iodide
and the mixture is again degassed. 3.2 g (12.52 mmol) propynoic acid-(4'-
chloro-
biphenyl-4-yl)amide are finally added. The mixture is stirred for 24 hours at
ambient
temperature and the reaction mixture is then evaporated down. The residue is
10 extracted with water and ethyl acetate. The organic phase is dried over
sodium
sulphate, evaporated down and the residue is purified by column chromatography
on
silica gel (eluant: dichloromethane/methanol= 30:1).
Yield: 2 g (54 % of theoretical)
C22H16CIN02 (M= 361.82)
Calc.: Molecular ion peak (M+H)+: 362/4 (CI) Found: Molecular ion
peak (M+H)+: 362/4 (CI)
Rf value: 0.35 (silica gel, dichloromethane/ ethanol/ammonia 20:1:0.1 )
1.40.c. 3-(4-chloromethyl-phenyl)-propynoic acid-(4'chloro-biphenyl-4-yl)-
amide
0.45 ml (5.81 mmol) methanesulphonic acid chloride are slowly added dropwise
at
ambient temperature to a solution of 2 g (3.87 mmol) 3-(4-hydroxymethyl-
phenyl)-
propynoic acid-4'-chloro-biphenyl-4-yl)-amide and 1.56 ml (11.2 mmol)
triethylamine
in 100 ml dichloromethane and the reaction mixture is stirred for 24 hours at
ambient
temperature. It is extracted three times with water and the organic phase is
dried over
sodium sulphate. The solvent is distilled off and the residue is stirred with
diisopropylether and suction filtered.
Yield: 0.8 g (54 % of theoretical)
C22H15C12N0 (M= 380.27)
Calc.: Molecular ion peak (M+H)+: 380/2/4 (C12) Found: Molecular ion
peak (M+H)+: 380/2/4 (C12)
Rf value: 0.7 (silica gel, dichloromethane/ ethanol = 50:1 )

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1.40.d. 3-{4-[cyclopropylmethyl-methyl-amino)-methyl]-phenyls-propynoic acid-
(4'-
chloro-biphenyl-4-yl)-amide
A reaction mixture of 70 mg (0.18 mmol) 3-(4-chloromethyl-phenyl)-propynoic
acid-
(4'chloro-biphenyl-4-yl)-amide, 19 mg (0.19 mmol) cyclopropylmethyl-
methylamine
and 51 mg (0.37 mmol) potassium carbonate in 5 ml acetone is agitated for 24
hours
at reflux temperature. The reaction mixture is evaporated down. The residue is
extracted between water and ethyl acetate. The organic phase is dried over
sodium
sulphate, evaporated down and the residue is purified by column chromatography
on
silica gel (eluant: dichloromethane/methanol= 100:0 to 50:50).
Yield: 30 mg (38 % of theoretical)
Melting point: 181 °C
C27H25CIN20 (M= 428.95)
Calc.: Molecular ion peak (M+H)+: 429/31 (CI) Found: Molecular ion
peak (M+H)+: 429/31 (CI)
Rf value: 0.5 (silica gel, dichloromethane/ ethanol/ammonia = 20:1:0.1 )
The following compounds are prepared analogously to Example 1.40.d:
/ ci
o /I
~N
H
ExampleR~R2N-X educt empirical mass mp Rf
formula spectrum [C] value
1.41 ~ 1.40.cC28HZ~CIN202 459/61 196 0.35
(CI)
N
[M+Hl+ (A)
1.42 ~ 1.40.cC29H29CIN20 457/9 (CI)215 0.4
N
[M+Hl+ (A)

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WO 2005/063239 1 Q$ PCT/EP2004/014378
1.43 o I 1.40.c C29H29CIN2O2 473/5 (CI)181- 0.5
~~~
N M+H + 182 A
[ 1 ()
1.44 o Chirai 1.40.c C26H2sCIN202 431/3 (CI)175 0.15
~N~ [M+H1+ (A)
1.45 o Ci,irai 1.40.c C26HZSCIN202 431 /3 135- 0.15
(CI)
[M+H]+ 136 (A)
1.46 ~ 1.40.c CZ6H25CIN202 433/5 (CI)149 0.3
wo~N~ [M+H]+ (A)
1.47 1.40.c C3~ H2~CIN20 479/81 162- 0.3
(CI)
~ Chiral
[M+H]+ 164 (B)
i
1.48 1.40.c C3~HZ~CIN20 479/81 165- 0.3
(CI)
Chiral
[M+H]+ 166 (B)
1.49 ~ N 1.40.c C29H23CIN20 451/3 (CI)150- 0.2
i ~ [M+H]+ 154 (B)
1.50 ~ N~ 1.40.c C29H24CIN30 466/68 186 0.1
(CI)
I (B)
N~ ~
1.51 1.40.c C28HZ~CIN20 443/5 (CI)223,5-0.2
~
N 224 (B)
1.52 N 1.40.c C3oH3~CIN20 471/3 (CI)156- 0.2
~ 157 (B)
1.53 N~ 1.40.c C29H24CIN30 466/68 175-
(CI)
~
N 176
Rf value: A= (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1 )
B= (silica gel, dichloromethane/ethanol/ammonia 50:1:0.1)
Example 1.54:

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3-(4-{[(2-hydroxy-2-methyl-propyl)-(2-methoxy-ethyl)amino]-methyl-phenyl)-
propionic
acid-(4'-chloro-biphenyl-4-yl) amide trifluoroacetate
CI
0
~o
~N
H
N ( /
\v
\5
A reaction mixture of 70 mg (0.18 mmol) 3-(4-chloromethyl-phenyl)-propynoic
acid-
(4'chloro-biphenyl-4-yl)-amide, 19 mg (0.19 mmol) 1-(2-methoxy-ethylamino)-2-
methyl-propan-2-of and 51 mg (0.37 mmol) potassium carbonate in 5 ml acetone
is
agitated for 24 hours at reflux temperature. The reaction mixture is
evaporated down.
The residue is extracted between water and ethyl acetate. The organic phase is
dried
over sodium sulphate, evaporated down and the residue is purified by column
chromatography first of all on silica gel (eluant: dichloromethane/methanol=
100:0 to
50:50) and then on RP-18 (eluant: water + 0.1 % trifluoroacetic acid /
acetonitrile +
0.1 % trifluoroacetic acid=100:0 to 50:50).
Yield: 11 mg (11 % of theoretical)
C2gH31 CIN203*C2HF302 (M= 605.04)
Calc.: Molecular ion peak (M+H)+: 491/93 (CI) Found: Molecular ion peak
(M+H)+: 491/93 (CI)
The following compounds are prepared analogously to Example 1.54:
ci
R~RZN

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~ WO 2005/063239 110 PCT/EP2004/014378
ExampleR~RZN-X educt empirical mass mp
formula spectrum [C]
1.55 0 ~ 1.40.c C28H24CIF3N202513/15 70-78
N (CI)
F
F
F
1.56 ~ 1.40.c C28H29CIN202 461/63
(CI)
~N
O
1.57 N~ 1.40.c C25HZ~CIN20 401/3 (CI)224-
~
225
Example 1.58:
3-{4-[(methyl-pyridin-2-ylmethyl-amino)-methyl-phenyl}-propynoic acid-
(4'chloro-
biphenyl-4-yl)amide
CI
0
~N
~N I ~ H
\ I N
A reaction mixture of 55 mg (0.15 mmol) 3-(4-chloromethyl-phenyl)-propynoic
acid-
(4'chloro-biphenyl-4-yl)-amide, 18.3 mg (0.159 mmol) methyl-pyridin-2-ylmethyl-
amine and 51 mg (0.37 mmol) potassium carbonate in 5 ml acetone is agitated
for 24
hours at reflux temperature. The reaction mixture is evaporated down. The
residue is
triturated with water and diisopropylether and the product is suction filtered
and dried
in the air.
Yield: 20 mg (30 % of theoretical)
Melting point: 217-218 °C
C2gH24CIN30 (M= 465.97)
Calc.: Molecular ion peak (M+H)+: 466/468 (CI) Found: Molecular ion
peak (M+H)+: 466/468 (CI)

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WO 2005/063239 111 PCT/EP2004/014378
The following compound is prepared analogously to Example 1.58:
Ci
10
R~R2N~X
Example R~RZN-X educt empirical mass mp
formula spectrum [C]
1.59 N 1.40.c CZ~H25CIN20 429/31/33 195-
~
(CI) 196
The following compounds are prepared analogously to Example 1.2.c:
Lz
R~RzN
Example R~ R2N-X L~ L2
1.60 H CI
N
1.61 I H CI
~N
1.62 H CI
N

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WO 2005/063239 112 PCT/EP2004/014378
1.63 H CI
N
1.64 ~ H CI
N
1.65 H CI
N
O
1.66 ° H CI
N ~N
1.67 ~ H CI
N
1.68 ~ H CI
~N~
1.69 I H CI
°~N
1.70 ~ I I H CI
\ N
1.71 I H CI
~~N~
N
1.72 0~~ I H CI
N
1.73 ~ I I H CI
\ °~\/N\i!
1.74 I H CI
~N~
1.75 ~ H CI
~N~

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WO 2005/063239 113 PCT/EP2004/014378
R~RzN
/ Lz
O
\ / _N
H L~
~X /
Example R~ R2N-X L~ L2
1.76 I F CI
O~N
1.77 ~N F CI
1.78 I F CI
O~N
1.79 ~ F CI
°~N~
1.80 F CI
N
1.81 ~ F CI
N
1.82 I F CI
~N
1.83 F CI
N
1.84 F C I
N
1.85 ~ F CI
N
1.86 ° F CI
~N~
1.87 ~ F CI
~N~

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1.88 I F CI
~~/N\i~
1.89 ~ ~ I F CI
\ N
1.90 I F CI
~N~
ii
N
1.91 0~ I F CI
N
1.92 ~ I I F CI
\ ~N~
1.93 I F CI
~N~
1.94 ~ F CI
~N
R'RZN~X
/ Lz
O / a
j
L~
Example R~ R2N-X L~ L2
1.95 ~ H CI
N
1.96 H CI
N
1.97 ~ H CI
N
1.98 ° H CI
~N~

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1.99 H CI
N
O
1.100 H CI
N
N
~
\i~
1.101 ~ H CI
N~
1.102 ~ H CI
~N~
1.103 I H CI
~~/N\i~
1.104 ~ I I H CI
\ N
1.105 I H CI
~N~
/,
N
1.106 0~ I H CI
N
1.107 ~ I I H CI
\ ~N~
1.108 I H CI
~NV!
1.109 ~ H CI
~N
O /
j
L,
R,RzN~X /
Lz
Example R~R2N-X L~ Lz

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1.110 I F CI
O~N
1.111 ~N F CI
1.112 I F CI
O~N
1.113 ~ F CI
°~N~
1.114 F CI
N
1.115 ~ F CI
N
1.116 I F CI
~N
1.117 ~ F CI
N
1.118 F CI
N
1.119 F CI
N
1.120 ~ F CI
N
1.121 ° F CI
~N~
1.122 F CI
N
O
1.123 ° F CI
N ~1
1.124 ~ F CI
N

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1.125 ~ F CI
~N~
1.126 ~ F CI
N
1.127 I F CI
~~~\/N\i(
1.128 ~ I I F CI
\ N
1.129 I F CI
~N~
ii
N
1.130 0~~ I F CI
N
1.131 ~ I I F CI
\ ~~\/N\%
1.132 I F CI
~N~
1.133 ~ F CI
~N
/ L
\
O / y/
\ / _N
H L~
R~RZN~X ~ /
Example R~R2N-X L~ L2
1.134 o H CF3
~N~
1.135 ~N H CF3
1.136 N H C F3
o~ ~

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WO 2005/063239 11$ PCT/EP2004/014378
1.137 ~ H CF3
°~N~
1.138 H CF3
N
1.139 ~ H CF3
N
1.140 N H CF3
1.141 ~ H CF3
N
1.142 H CF3
N
1.143 H CF3
N
1.144 ~ H CF3
N
1.145 ° H CF3
~N~
1.146 H CF3
N
O
1.147 ° H CF3
N ~1
1.148 ~ H CF3
N
1.149 ~ H CF3
~N~
1.150 ~ H CF3
N
1.151 I H CF3
~°~N

CA 02550649 2006-06-20
WO 2005/063239 11 g PCT/EP2004/014378
1.152 ~ H CF3
N
1.153 I H CF3
~N~
ii
N
1.154 0~~ I H CF3
N
1.155 ~ I I H CF3
O~\/NWi!
1.156 I H CF3
~N~
1.157 ~ H CF3
~N
/ Lz
\
O / ~ a
\ / _N
H L,
R,RzN~X /
ExampleR~RZN-X L~ L2
1.158 I H Me
O~N
1.159 N H Me
~
1.160 I H Me
~N
rJ~'O
1.161 ~ H Me
~O~N~X
1.162 H Me
N

CA 02550649 2006-06-20
. WO 2005/063239 120 PCT/EP2004/014378
1.163 ~ H Me
N
1.164 I H Me
~N
1.165 ~ H Me
N
1.166 H Me
N
1.167 H Me
N
1.168 ~ H Me
N
1.169 ° H Me
~N~
1.170 H Me
N
O
1.171 ° H Me
N ~1
1.172 ~ H Me
N
1.173 ~ H Me
~N~
1.174 ~ H Me
N
1.175 I H Me
°~N\
1.176 ~ I I H Me
\ N
1.177 I H Me
~N~
ii
N
1.178 0~ I H Me
N

CA 02550649 2006-06-20
WO 2005/063239 121 PCT/EP2004/014378
1.179 ~ I I H Me
O~\/N
1.180 I H Me
~N~
1.181 ~ H Me
~N
/ Lz
O / ~ a
\ / -N
H L~
R~RzN~X /
ExampleR~RZN-X L~ L2
1.182 I H F
O~N
1.183 N H F
~
1.184 I H F
O~N
1.185 ~ H F
~O~NU!
1.186 H F
N
1.187 ~ H F
N
1.188 I H F
~N
1.189 ~ H F
N

CA 02550649 2006-06-20
WO 2005/063239 122 PCT/EP2004/014378
1.190 H F
N
1.191 H F
N
1.192 ~ H F
N
1.193 ° H F
~N~
1.194 H F
N
O
1.195 ° H F
N ~1
1.196 ~ H F
N
1.197 ~ H F
~N~
1.198 ~ H F
N
1.199 I H F
~o~N\
1.200 ~ I ~ H F
\ N
1.201 I H F
~N~
ii
N
1.202 0~ I H F
N
1.203 \ ~ N H F
\%'
1.204 I H F
~N~

CA 02550649 2006-06-20
WO 2005/063239 123 PCT/EP2004/014378
1.205 ~ H F
~N
/ L
O / ~ a
\ / _N
H L~
R~RZN~x /
Example R~ R2N-X L~ L2
1.206 o F CF3
~N~
1.207 ~ N F CF3
1.208 N F CF3
o~ ~
1.209 ~ F CF3
~o~N
1.210 F CF3
N
1.211 ~ F CF3
N
1.212 N F CF3
d
1.213 ~ F CF3
N
1.214 F CF3
N

CA 02550649 2006-06-20
WO 2005/063239 124 PCT/EP2004/014378
1.215 F CF3
N
1.216 ~ F CF3
N
1.217 ° F CF3
~N~
1.218 F CF3
N
O
1.219 ° F CF3
N ~N\~
1.220 ~ F CF3
N
1.221 ~ F CF3
~N~
1.222 ~ F CF3
N
1.223 \ ~N F CF3
0
1.224 ~ I ~ F CF3
\ N
1.225 N F CF3
N
1.226 0~ ~ F CF3
N
1.227 \ ~ N F CF3
o~ ~%'
1.228 N F CF3
1.229 ~ F CF3
~N

CA 02550649 2006-06-20
WO 2005/063239 125 PCT/EP2004/014378
R'RzN~X
/ Lz
O / ~ a
\ / _N
H L~
Example R~R2N-X L~ L2
1.230 I F Me
O~N
1.231 ~N F Me
1.232 I F Me
~N
~~'(O
1.233 ~ F Me
°~N~x
1.234 F Me
N
1.235 ~ F Me
N
1.236 I F Me
~N
1.237 ~ F Me
N
1.238 F Me
N
1.239 F Me
N
1.240 ~ F Me
N
1.241 ° F Me
~N~

CA 02550649 2006-06-20
WO 2005/063239 126 PCT/EP2004/014378
1.242 F Me
N
O
1.243 F Me
N
1
~
N
1.244 ~ F Me
N
1.245 ~ F Me
~N~
1.246 ~ F Me
N
1.247 I F Me
~O~/N\i!
1.248 ~ I I F Me
\ N
1.249 I F Me
~N~
/,
N
1.250 0~ I F Me
N
1.251 ~ I I F Me
\ ~N~
1.252 I F Me
~N~
1.253 ~ F Me
~N
R~RzN
Example ~ R~ RZN-X L~ L2

CA 02550649 2006-06-20
WO 2005/063239 127 PCT/EP2004/014378
1.254 I F F
O~N
1.255 ~N F F
1.256 I F F
O~N
1.257 ~ F F
~O~N~
1.258 F F
N
1.259 ~ F F
N
1.260 I F F
~N
1.261 ~ F F
N
1.262 F F
N
1.263 F F
N
1.264 ~ F F
N
1.265 ° F F
~N~
1.266 F F
N
O
1.267 ° F F
N ~N
1.268 ~ F F
N

CA 02550649 2006-06-20
WO 2005/063239 12$ PCT/EP2004/014378
1.269 ~ F F
~N~
1.270 ~ F F
N
1.271 I F F
~p~/N\i(
1.272 ~ I I F F
\ N
1.273 I F F
~N~
ii
N
1.274 0~ I F F
N
1.275 ~ I I F F
\ ~~/N\i!
1.276 I F F
~N~
1.277 ~ F F
~N~
/ Lz
O / ~ a
N
L
R~RzN~X /
Example R~RZN-X L~ L2
1.278 o H CF3
~N~
1.279 ~N H CF3
1.280 N H CF3
o~ ~

CA 02550649 2006-06-20
, WO 2005/063239 12g PCT/EP2004/014378
1.281 ~ H CF3
°~N~
1.282 H CF3
N
1.283 ~ H CF3
N
1.284 I H CF3
~N
1.285 ~ H CF3
N
1.286 H CF3
N
1.287 H CF3
N
1.288 ~ H CF3
N
1.289 ° H CF3
~N~
1.290 H CF3
N
O
1.291 ° H CF3
N ~N~
1.292 ~ H CF3
N
1.293 ~ H CF3
~N~
1.294 ~ H CF3
N
1.295 I H CF3
°~N

CA 02550649 2006-06-20
WO 2005/063239 130 PCT/EP2004/014378
1.296 \ I N H CF3
1.297 I H CF3
~N~
N
1.298 0~ I H CF3
N
1.299 ~ I I H CF3
O~/Nwi!
1.300 I H CF3
~N~
1.301 ~ H CF3
~N~
O
j
L~
R~ RZN~X
LZ
Example R~ R2N-X L~ LZ
1.302 I H Me
O~N
1.303 N H Me
~
1.304 I H Me
O~N
1.305 ~ H Me
~p~/N
1.306 H Me
N

CA 02550649 2006-06-20
WO 2005/063239 131 PCT/EP2004/014378
1.307 ~ H Me
N
1.308 I H Me
~N
1.309 ~ H Me
N
1.310 H Me
N
1.311 H Me
N
1.312 ~ H Me
N
1.313 ° H Me
~N~
1.314 H Me
N
O
1.315 ° H Me
N ~N~
1.316 ~ H Me
N
1.317 ~ H Me
~N~
1.318 ~ H Me
N
1.319 I H Me
~°~N
1.320 ~ I I H Me
\ N
1.321 I H Me
~N~
ii
N
1.322 ~~ I H Me
N

CA 02550649 2006-06-20
WO 2005/063239 132 PCT/EP2004/014378
1.323 ~ I I H Me
O~/N~i!
1.324 I H Me
~N~
1.325 ~ H Me
~N
O
j
L~
R~R2N~X
Lz
Example R~RZN-X L~ L2
1.326 I H F
O~N
1.327 N H F
~
1.328 I H F
O~N
1.329 ~ H F
~O~N~
1.330 H F
N
1.331 ~ H F
N
1.332 I H F
~N
1.333 ~ H F
N

CA 02550649 2006-06-20
WO 2005/063239 133 PCT/EP2004/014378
1.334 H F
N
1.335 H F
N
1.336 ~ H F
N
1.337 ° H F
~N~
1.338 H F
N
O
1.339 ° H F
N ~N~
1.340 ~ H F
N
1.341 ~ H F
~N~
1.342 ~ H F
N
1.343 I H F
~o~N
1.344 ~ ~ I H F
\ N
1.345 I H F
~N~
/,
N
1.346 0~ I H F
N
1.347 ~ ~ I H F
\ °~/N~i!
1.348 I H F
~N~

CA 02550649 2006-06-20
WO 2005/063239 134 PCT/EP2004/014378
1.349 ~ H F
~N
Lz
R' RzN ~X
Example R~ R2N-X L~ L2
1.350 I F CF3
O~N
1.351 ~N F CF3
1.352 I F CF3
O~N
1.353 ~ F CF3
~o~N~
1.354 F CF3
N
1.355 ~ F CF3
N
1.356 N F CF3
d
1.357 ~ F CF3
N
1.358 F CF3
N

CA 02550649 2006-06-20
WO 2005/063239 135 PCT/EP2004/014378
1.359 F CF3
N
1.360 ~ F CF3
N
1.361 ° F CF3
~N~
1.362 F C F3
N
O
1.363 ° F CF3
N ~N\:~
1.364 ~ F CF3
N
1.365 ~ F CF3
~N~
1.366 ~ F CF3
N
1.367 I F C F3
°~N\
1.368 ~ I I F CF3
\ N
1.369 N F CF3
N
1.370 0~ I F CF3
N
1.371 \ I N F CF3
o~
1.372 N F CF3
1.373 ~ F CF3
~N

CA 02550649 2006-06-20
WO 2005/063239 136 PCT/EP2004/014378
R'RZN~X
/ L
O /
/ N
/ I L
1
Example R~R2N-X ~ L~ L2
1.374 I F Me
O~N
1.375 ~N F Me
1.376 I F Me
O~N
1.377 ~ F Me
°~N~
1.378 F Me
N
1.379 ~ F Me
N
1.380 I F Me
~N
1.381 ~ F Me
N
1.382 F Me
N
1.383 F Me
N
1.384 ~ F Me
N
1.385 ° F Me
~N~

CA 02550649 2006-06-20
. WO 2005/063239 137 PCT/EP2004/014378
1.386 F Me
N
O
1.387 F Me
1.388 ~ F Me
N
1.389 ~ F Me
~N~
1.390 ~ F Me
N
1.391 I F Me
~O~/N\i(
1.392 ~ I I F Me
\ N
1.393 I F Me
~N~
ii
N
1.394 ~~ I F Me
N
1.395 ~ F Me
I
I
\ ~/N~i!
1.396 I F Me
~N~
1.397 ~ F Me
~N~
/ Lz
O / ~ ~/
N
L
R~RZN~X /

CA 02550649 2006-06-20
WO 2005/063239 13$ PCT/EP2004/014378
Example R~RZN-X L~ L2
1.398 I F F
O~N
1.399 n N F F
'~i~
1.400 I F F
O~Nwi!
1.401 ~ F F
°~N~
1.402 F F
N
1.403 ~ F F
N
1.404 I F F
~N~
1.405 ~ F F
N
1.406 F F
N
1.407 F F
N
1.408 ~ F F
N
1.409 ° F F
~N~
1.410 F F
N
O
1.411 ° F F
N ~1

CA 02550649 2006-06-20
WO 2005/063239 13g PCT/EP2004/014378
1.412 ~ F F
N
1.413 ~ F F
~N~
1.414 ~ F F
N
1.415 I F F
~~~\/N\i~
1.416 ~ I I F F
\ N
1.417 I F F
~N~
ii
N
1.418 0~l F F
N
1.419 ~ I I F F
\ ~~N~
1.420 I F F
~N~
1.421 ~ F F
~N~
Example 1.422:
3-[4-(1-amino-cyclopropyl)-phenyl]-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide
trifluoroacetate
/ CI
O \ \
N /
N
1.422.a: tert-butyl1-(4-bromo-phenyl)-cyclopropyl]carbamate

CA 02550649 2006-06-20
WO 2005/063239 140 PCT/EP2004/014378
g (29.04 mmol) 1-(4-bromobenzene)1-cyclopropanecarboxylic acid and 6.07 ml
(43.55 mmol) triethylamine are dissolved in 63 ml tent butanol. At RT 9.68 ml
(43.55
mmol) diphenylphosphorylazide (DPPA) are added dropwise and refluxed for 15 h.
Then 14.69 g (65.27 mmol) di-tert. butyl pyrocarbonate are added and the
mixture is
5 refluxed for another 15 h. The solvent is distilled off and the residue is
taken up in
ethyl acetate, washed successively with 5% citric acid, saturated sodium
hydrogen
carbonate solution and saturated sodium chloride solution. The organic phase
is dried
with magnesium sulphate, filtered and the solvent is distilled off.
Yield: 6.00 g (66 % of theoretical)
10 C14H18BrN02 (M= 312.20)
Calc.: Molecular ion peak (M+H)+: 312/14 (Br) Found: Molecular ion peak
(M+H)+: 312/14 (Br)
Rf value: 0.8 (silica gel, dichloromethane/ ethanol = 20:1 )
1.422.b. tert-butyl [1-(4-iodo-phenyl)-cyclopropyl]carbamate
0.43 ml (4 mmol) N,N'-dimethylethylenediamine are added to a reaction mixture
of
0.4 g (2 mmol) copper(I)iodide, 6.2 g (19.86 mmol) tert-butyl [1-(4-bromo-
phenyl)-
cyclopropyl]carbamate and 6 g (40 mmol) sodium iodide in 15 ml 1,4-dioxane and
refluxed for 24 h under nitrogen. Then the cooled suspension is combined with
30%
ammonia solution, poured onto dist. water and extracted with dichloromethane.
The
organic phase is dried over sodium sulphate, filtered and the solvent is
distilled off.
Yield: 6.60 g (93 % of theoretical)
C14H181N02 (M= 359.20)
Calc.: Molecular ion peak (M+H)+: 360 Found: Molecular ion peak (M+H)+:
360
Rf value: 0.8 (silica gel, dichloromethane/ ethanol = 50:1 )
1.422.c. 3-[4-(1-tert-butoxycarbonyl-amino-cyclopropyl)-phenyl]-propynoic acid-
(4'-
chloro-biphenyl-4-yl)amide
1.4 g (4.2 mmol) caesium carbonate and 0.5 g (1.4 mmol) tert-butyl [1-(4-iodo-
phenyl)-cyclopropyl]carbamate are placed in 20 ml THF and cooled to -
15°C in the
ice/methanol bath, rinsed with argon and degassed. To this reaction mixture
are
added successively 160 mg (0.14 mmol) tetrakistriphenylphosphine palladium and
30

CA 02550649 2006-06-20
WO 2005/063239 141 PCT/EP2004/014378
mg (0.158 mmol) copper(I)iodide and the mixture is again degassed. 0.5 g (1.4
mmol)
propynoic acid-(4'-chloro-biphenyl-4-yl)amide are finally added. The mixture
is stirred
for 24 hours at ambient temperature and the reaction mixture is then
evaporated
down. The residue is triturated with water and ethyl acetate, suction
filtered, washed
with ethyl acetate and dried in the air.
Yield: 0.4 g (59 % of theoretical)
C29H27CIN203 (M= 486.99)
Calc.: Molecular ion peak (M+H)+: 487/89 (CI) Found: Molecular ion peak
(M+H)+: 487/89 (CI)
Rf value: 0.62 (silica gel, cyclohexane/ethyl acetate 1:1 )
1.422.d. 3-[4-(1-amino-cyclopropyl)phenyl]propynoic acid-(4'-chloro-biphenyl-4-
yl)-
amide trifluoroacetate
1 ml (12.92 mmol) trifluoroacetic acid are added to a solution of 0.24 g (0.49
mmol) 3-
[4-(1-tert-butoxycarbonyl-amino-cyclopropyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)amide in 20 ml dichloromethane and stirred for 24 h. Then the
solvent is
eliminated by rotary evaporation and the residue is combined with toluene and
again
subjected to rotary evaporation. This residue is then triturated with
dichloromethane,
suction filtered and dried in the air.
Yield: 0.22 g (89 % of theoretical)
C24H1gCIN20* C2HF302 (M=500.90)
Calc.: Molecular ion peak (M+H)+: 387 (CI) Found: Molecular ion
peak (M+H)+: 387 (CI)
mp=160-164 °C
Example 1.423:
3-[4-(1-methylamino-cyclopropyl)phenyl]propynoic acid-(4'-chloro-biphenyl-4-
yl)-
amide trifluoroacetate

CA 02550649 2006-06-20
WO 2005/063239 142 PCT/EP2004/014378
,N
CI
O
~N
\
1.423.a: tert-butyl [1-(4-iodo-phenyl)-cyclopropyl]methyl-carbamate
131 mg (3 mmol) sodium hydride (55%) are added at RT to a solution of 1 g
(2.78
mmol) tert-butyl [1-(4-iodo-phenyl)-cyclopropyl]carbamate in 20 ml DMF and the
mixture is stirred for 30 min at RT. Then 0.287 ml (4.4 mmol) methyl iodide
are added
dropwise and the mixture is stirred for 24 hours. The solvent is eliminated by
rotary
evaporation. The residue is extracted between water and ethyl acetate and the
organic phase is dried over sodium sulphate. The solvent is again eliminated
by
rotary evaporation.
Yield: 1 g (96 % of theoretical)
C15H201N02 (M= 373.23)
Calc.: Molecular ion peak (M+H)+: 374 Found: Molecular ion peak
(M+H)+: 374
Rf value: 0.68 (silica gel, cyclohexane/ ethyl acetate 3:1 )
1.423.b: 3-[4-(1-tert butoxycarbonyl-methyl-amino-cyclopropyl)-phenyl]-
propynoic
acid-(4'-chloro-biphenyl-4-yl)amide
2.28 g (7 mmol) caesium carbonate and 1 g (2.68 mmol) tert-butyl [1-(4-iodo-
phenyl)-
cyclopropyl]-methylcarbamate are placed in 20 ml THF and cooled to -
15°C in the
ice/methanol bath, rinsed with argon and degassed. To this reaction mixture
are
added successively 180 mg (0.16 mmol) tetrakistriphenylphosphine palladium and
50
mg (0.263 mmol) copper(I)iodide and the mixture is again degassed. 0.75 g (2.9
mmol) propynoic acid-(4'-chloro-biphenyl-4-yl)amide are finally added. The
mixture is
stirred for 24 hours at ambient temperature and the reaction mixture is then
evaporated down. The residue is extracted between water and ethyl acetate, the
organic phase is dried with sodium sulphate and the solvent is eliminated by
rotary
evaporation. The purification is carried out by column chromatography on
silica gel

CA 02550649 2006-06-20
WO 2005/063239 143 PCT/EP2004/014378
(eluant: cyclohexane/ethyl acetate 2:1 ).
Yield: 0.75 g (56 % of theoretical)
C3pH2gCIN203 (M= 501.02)
Calc.: Molecular ion peak (M+H)+: 501/3 (CI) Found: Molecular ion
peak (M+H)+: 501/3 (CI)
Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate 1:1 )
1.423.c: 3-[4-(1-methylamino-cyclopropyl)phenyl]propynoic acid-(4'-chloro-
biphenyl-4-
yl)-amide
Prepared analogously to Example 1.422.d from 3-[4-(1-tert butoxycarbonyl-
methyl-
amino-cyclopropyl)-phenyl]-propynoic acid-(4'-chloro-biphenyl-4-yl)amide
Yield: 0.43 g (56 % of theoretical)
C25H21CIN20* C2HF302 (M= 514.92)
Calc.: Molecular ion peak (M+H)+: 401/3 (CI) Found: Molecular ion
peak (M+H)+: 401/3 (CI)
mp=217.3 °C
Example 1.424:
3-{4-[1-(4-methyl-piperidin-1-yl)-cyclopropyl]-phenyl}-propynoic acid(4'-
chloro-
biphenyl-4-yl)amide
~N
ci
0
~N
1.424.a:1-(4-iodo-phenyl)-cyclopropylamine
3 ml (38.76 mmol) trifluoroacetic acid are added to a solution of 1 g (2.78
mmol) tert-
butyl [1-(4-iodo-phenyl)-cyclopropyl]carbamate in 40 ml dichloromethane and
stirred
for 24 h. Then the solvent is eliminated by rotary evaporation and the residue
is

CA 02550649 2006-06-20
. WO 2005/063239 144 PCT/EP2004/014378
combined with toluene and then again eliminated by rotary evaporation. This
residue
is then added to a solution of 0.39 g (2.8 mmol) potassium carbonate in 20 ml
of
water and stirred for 30 min at RT. The aqueous phase is extracted with
dichloromethane, the organic phase is dried with sodium sulphate and the
solvent is
eliminated by rotary evaporation.
Yield: 0.7 g (97 % of theoretical)
CgH101N (M= 259.09)
Calc.: Molecular ion peak (M+H)+: 260 Found: Molecular ion peak
(M+H)+: 260
1.424.b:1 [1-1-(4-iodo-phenyl)cyclopropyl]-4-methylpiperidine
0.55 g (4 mmol) potassium carbonate are added to a reaction mixture of 0.5 g
(1.93
mmol) 1-(4-iodo-phenyl)-cyclopropylamine and 0.89 g (2 mmol) of 1,5-dibromo-3-
methylpentane in 20 ml N,N-dimethylformamide and stirred at 80 °C for
24 h. Then
the solvent is evaporated down and the residue is extracted between ethyl
acetate
and water. The organic phase is dried over sodium sulphate. The purification
is
carried out by column chromatography (eluant: cyclohexane/ethyl acetate 3:1).
Yield: 0.065 g (10 % of theoretical)
C15H201N (M= 341.23)
Calc.: Molecular ion peak (M+H)+: 342 Found: Molecular ion peak
(M+H)+: 342
Rf value: 0.65 (silica gel, cyclohexane/ethyl acetate 3:1 )
1.424.c: 3-{4-[1-(4-methyl-piperidin-1-yl)-cyclopropyl]-phenyl}-propynoic
acid(4'-
chloro-biphenyl-4-yl)amide
Prepared analogously to Example 1.424.b from 1[1-1-(4-iodo-phenyl)cyclopropyl]-
4-
methylpiperidine and propynoic acid-(4'-chloro-biphenyl-4-yl)amide
Yield: 20 mg (24 % of theoretical)
C3pH2gCIN20 (M= 469.02)
Calc.: Molecular ion peak (M+H)+: 469/71 (CI) Found: Molecular ion peak
(M+H)+: 469/71 (CI)
Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate 3:1 )
mp=128-129 °C

CA 02550649 2006-06-20
WO 2005/063239 145 PCT/EP2004/014378
Example 1.425:
3-{4-[cyclopentyl-methyl-amino)-methyl]-phenyl}-propynoic acid-(4'-chloro-
biphenyl-4-
yl)-amide
i
Prepared analogously to Example 1.40 d from 3-(4-chloromethyl-phenyl)-
propynoic
acid-(4'chloro-biphenyl-4-yl)-amide and methyl-cyclopentylamine.
Yield: 10 mg (316 % of theoretical)
Melting point: 217-219°C
C28H27CIN20 (M= 442.98)
Calc.: Molecular ion peak (M+H)+: 443/45(CI) Found: Molecular ion peak
(M+H)+: 443/45(CI)
Example 2.1.:
3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-biphenyl-4-ylamide
G
0
H
2.1.a.2-(4-iodo-phenyl)-ethanol
0.474 g (2.48 mmol) copper(I)iodide, 5 g (24.86 mmol 2-(4-bromo-phenyl)-
ethanol
and 7.45 g (49.73 mmol) sodium iodide are successively added to a flask under
an

CA 02550649 2006-06-20
WO 2005/063239 146 PCT/EP2004/014378
argon atmosphere. Then 0.438 g (4.97 mmol) dimethylenediamine and 25 ml
dioxane
are added and the reaction mixture is refluxed for 14 hours. Then the reaction
mixture
is combined with 20 ml concentrated ammonia solution at ambient temperature,
with
100 ml of water diluted and extracted with dichloromethane. The organic phase
is
extracted three times with water and dried over sodium sulphate.
Yield: 5.4 g (87.5 % of theoretical)
C8Hgl0 (M= 248.06)
Calc.: Molecular ion peak (M)+: 248 Found: Molecular ion peak (M)+:
248
Rf value: 0.6 (silica gel, dichloromethane/ ethanol = 10:1 )
2.1.b. 2-(4-iodo-phenyl)-ethyl methanesulphonate
Prepared analogously to Example 1.2.b from 2-(4-iodo-phenyl)-ethanol and
methanesulphonic acid chloride.
Yield: 5.7 g (77.4 % of theoretical)
CgH11103S (M= 326.15)
Calc.: Molecular ion peak (M)+: 326 Found: Molecular ion peak (M)+:
326
2.1.c.1-[2-(4-iodo-phenyl)-ethyl]-pyrrolidine
1 ml (12.26 mmol) pyrrolidine are added to a solution of 2 g (6.13 mmol) 2-(4-
iodo-
phenyl)-ethyl methanesulphonate in 30 ml DMF and the reaction solution is
stirred for
six hours at 70°C. The reaction mixture is poured onto water and
extracted with ethyl
acetate. The organic phase is extracted three times with water and dried over
sodium
sulphate. The sodium sulphate is separated off and the solvent removed.
Yield: 1.28 g (69.3 % of theoretical)
C12H161N (M= 301.17)
Calc.: Molecular ion peak (M+H)+: 302 Found: Molecular ion peak
(M+H)+: 302
Rf value: 0.4 (silica gel, dichloromethane/ methanol = 10:1 )
2.1.d. propynoic acid-biphenyl-4-ylamide

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9.38 g (45.5 mmol) DCC are added batchwise to a solution of 2.89 g (41.36
mmol)
propynoic acid in 100 ml dichloromethane at -15°C and stirred for one
hour. Then a
solution of 7 g (41.36 mmol) biphenyl-4-ylamine -15°C is added dropwise
to 30 ml
dichloromethane and stirred for two hours. After this time the cooling bath is
removed
and the reaction mixture is allowed to come up to ambient temperature. 20 g
Celite
are added to the reaction mixture and it is then filtered. The filtrate is
evaporated
down in vacuo. The residue is combined with acetonitrile and stirred. The
suspension
is filtered, the filtrate is evaporated down and the residue is stirred with
petroleum
ether and pentane. The solid is isolated by filtration.
Yield: 5.5 g (60.1 % of theoretical)
C15H11N0 (M= 221.26)
Calc.: Molecular ion peak (M+H)+: 222 Found: Molecular ion peak
(M+H)+: 222
Rf value: 0.7 (silica gel, dichloromethane/ methanol = 10:1 )
2.1.e. 3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-biphenyl-4-
ylamide
ml THF are degassed and combined with 0.25 g (0.83 mmol) 1-[2-(4-iodo-phenyl)-
ethyl]-pyrrolidine, 0.81 g (2.49 mmol) caesium carbonate, 16 mg (0.083 mmol)
copper(I)iodide and 38 mg (0.033 mmol) tetrakistriphenylphosphine palladium.
Then
20 the mixture is again degassed, and 184 mg (0.83 mmol) propynoic acid-
biphenyl-4-
ylamide are added. The reaction mixture is stirred for 3 hours at ambient
temperature,
poured onto water and extracted with ethyl acetate. The organic phase is
extracted
three times with water and dried over sodium sulphate. The purification is
carried out
by column chromatography on silica gel (dichloromethane/ methanol/ ammonia =
25 10:1:0.1)
Yield: 90 mg (27.5 % of theoretical)
Melting point: 180-189°C
C27H2gN20 (M= 394.52)
Calc.: Molecular ion peak (M+H)+: 395 Found: Molecular ion peak
(M+H)+:395
Example 2.2.:
3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-4-chloro-phenylamide

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CI
O
_ \
\ / H
N
G
2.2.a. propynoic acid-(4-chloro-phenyl)-amide
Prepared analogously to Example 1.1.b from propynoic acid and 4-chloro-
aniline.
Yield: 0.56 g (31.2 % of theoretical)
CgHgCINO (M= 179.60)
Calc.: Molecular ion peak (M-H)-: 178/180 Found: Molecular ion
peak (M-H)-: 178/180
Rf value: 0.53 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
2.2.b. 3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-4-chloro-
phenylamide
Prepared analogously to Example 2.1.e from propynoic acid-(4-chloro-phenyl)-
amide
and 1-[2-(4-iodo-phenyl)-ethyl]-pyrrolidine.
Yield: 80 mg (34.1 % of theoretical)
Melting point: 153-154°C
C21 H21 CIN20 (M= 352.86)
Calc.: Molecular ion peak (M+H)+: 353/355 Found: Molecular ion
peak (M+H)+: 353/355
Example 2.3.:
3-(1-pyrrolidin-1-yl-indan-5-yl)-propynoic acid-(4'-chloro-biphenyl-4-yl)-
amide

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CI
U
2.3.a. 5-bromo-indan-1-of
0.987 g (23 mmol) sodium borohydride are added to a solution of 5 g (22.98
mmol) 5-
bromo-1-indanone in 100 ml isopropanol at ambient temperature and the reaction
mixture is stirred for five hours. Then an acidic pH is obtained by the
careful addition
of potassium hydrogen sulphate solution and the reaction mixture is extracted
with
tert.butylmethylether. The organic phase is extracted with saturated sodium
chloride
solution and then dried with magnesium sulphate. The filtrate is evaporated
down in
vacuo after removal of the magnesium sulphate. The residue is dissolved in
tert.butylmethylether and extracted successively with dilute sodium hydrogen
carbonate solution and water. Then it is dried over magnesium sulphate and
filtered
through activated charcoal. The filtrate is evaporated down in vacuo.
Yield: 3.6 g (73.5 % of theoretical)
CgHgBrO (M= 213.07)
Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate = 6:4)
2.3.b. 5-bromo-1-chloro-indane
3.09 ml (37.45 mmol) thionyl chloride, dissolved in cooled dichloromethane,
are
added dropwise at -10°C to a solution of 3.8 g (17.83 mmol) 5-bromo-
indan-1-of in
200 ml dichloromethane. The reaction mixture is allowed to come up slowly to
ambient temperature and stirred for 14 hours at ambient temperature. Then ice
and
100 ml of dilute sodium hydrogen carbonate solution are added successively.
The
organic phase is extracted twice with 50 ml of water. The combined organic
phases
are dried over magnesium sulphate, filtered and the solvent is distilled off.
Yield: 3.7 g (90 % of theoretical)
CgHBBrCI (M= 231.52)

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Rf value: 0.91 (silica gel, petroleum ether/ethyl acetate = 6:4)
2.3.c. 1-(5-bromo-indan-1-yl)-pyrrolid ine
7 ml (85.23 mmol) pyrrolidine are added at 0°C to a solution of 3.71 g
(16.92 mmol) 5-
bromo-1-chloro-indane in 250 ml dichloromethane. The reaction mixture is
allowed to
come up to ambient temperature and stirred for 24 hours. Then it is extracted
once
with water and the organic phase is extracted with potassium hydrogen sulphate
solution. The aqueous phase is extracted once with dichloromethane. Then the
aqueous phase is made basic with sodium carbonate solution, in order to
liberate the
product. This solution is extracted with dichloromethane, the organic phase is
extracted with water and dried over magnesium sulphate.
Yield: 1.81 g (42.4 % of theoretical)
C13H16BrN (M= 266.18)
Calc.: Molecular ion peak (M+H)+: 266/268 Found: Molecular ion
peak (M+H)+: 266/268
2.3.d. 1-(5-iodo-indan-1-yl)-pyrrolidine
Prepared analogously to Example 2.1.a from 1-(5-bromo-indan-1-yl)-pyrrolidine.
Yield: 1.42 g (83.5 % of theoretical)
C13H161N (M= 313.18)
Calc.: Molecular ion peak (M+H)+: 314 Found: Molecular ion peak
(M+H)+: 314
2.3.e. (1-pyrrolidin-1-yl-indan-5-yl)-propynoic acid
Under an argon atmosphere at 0°C, 0.5 g (1.59 mmol) 1-(5-iodo-indan-
1-yl)-
pyrrolidine and 123 microlitres (2 mmol) propynoic acid are dissolved in 25 ml
acetonitrile. 0.66 ml (4.79 mmol) triethylamine, 30 mg (0.16 mmol)
copper(I)iodide
and 80 mg (0.11 mmol) ditriphenylphosphine palladium dichloride are added to
this
solution and the mixture is stirred for two hours, while the solution is
allowed to come
up to ambient temperature. The purification is carried out by preparative HPLC
(eluant: dichloromethane/methanol/ammonia = 8:2:0.2)
Yield 0.1 g (24.5 % of theoretical)

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C16H17N02 (M= 255.31)
Calc.: Molecular ion peak (M+H)+: 256 Found: Molecular ion peak
(M+H)+: 256
2.3.f. 3-(1-pyrrolidin-1-yl-indan-5-yl)-propynoic acid-(4'-chloro-biphenyl-4-
yl)-amide
A solution of 0.1 g (0.39 mmol) (1-pyrrolidin-1-yl-indan-5-yl)-propynoic acid
and 47
microlitres (0.43 mmol) N-methylmorpholine in 5 ml absolute THF is combined
with 56
microlitres (0.43 mmol) isobutyl chloroformate at -15°C and stirred for
ten minutes.
Then 87 mg (0.43 mmol) 4'-chloro-biphenyl-4-ylamine are added at ambient
temperature and the reaction mixture is stirred for 14 hours. Then 3 ml of
dichloromethane are added to the reaction mixture and this is stirred for 48
hours.
Then the reaction mixture is filtered, the filtrate is evaporated down,
combined with
water and extracted with dichloromethane. The organic phase is evaporated
down.
The purification is carried out by preparative HPLC (eluant: dichloromethane /
methanol/ammonia = 8:2:0.2)
Yield: 9 mg (5.7 % of theoretical)
C28H25CIN20 (M= 440.97)
Calc.: Molecular ion peak (M+H)+: 441/443 Found: Molecular ion
peak (M+H)+: 441/443
Example 2.4.:
3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-(4'-chloro-biphenyl-4-
yl)-amide
ci
0
H
N
G
2.3.a. 3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-(4'-chloro-
biphenyl-4-yl)-
amide

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Prepared analogously to Example 2.1.e from propynoic acid-(4'-chloro-biphenyl-
4-yl)-
amide and 1-[2-(4-iodo-phenyl)-ethyl]-pyrrolidine.
Yield: 70 mg (32.8 % of theoretical)
Melting point: 217-218 C
C27H25CIN20 (M= 428.96)
Calc.: Molecular ion peak (M+H)+: 429/431 Found: Molecular ion
peak (M+H)+: 429/431
Rf value: 0.3 (silica gel, dichloromethane/ methanol=10:1 )
Example 2.5.:
3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-(4-prop-1-ynyl-phenyl)-
amide
G
H
2.4.a. 3-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-propynoic acid-(4-prop-1-ynyl-
phenyl)-
amide
Prepared analogously to Example 2.1.e from propynoic acid- (4-prop-1-ynyl-
phenyl)-
amide and 1-[2-(4-iodo-phenyl)-ethyl]-pyrrolidine.
Yield: 20 mg (11 % of theoretical)
Melting point: 198-199 C
C24H24N2~ (M= 356.47)
Rf value: 0.1 (silica gel, dichloromethane/ methanol=10:1)

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Example 3.1.:
3-phenyl-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-methyl-amide
/
\ N
N ~/\ / O
O
3.1.a. diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine
88.7 g (515.41 mmol) (2-chloro-ethyl)-diethyl-amine-hydrochloride are added at
ambient temperature to a suspension of 71.7 g (515.41 mmol) p-nitrophenol and
284.94 g (2.061 mol) potassium carbonate in 600 ml DMF and the reaction
mixture is
heated to 80°C for eight hours. The reaction mixture is evaporated down
and the
residue poured onto water and extracted with ethyl acetate. The organic phase
is
extracted three times with water and dried over sodium sulphate. The desiccant
is
filtered off and the filtrate is evaporated down.
Yield: 110.52 g (90 % of theoretical)
C12H18N2~3 (M= 238.28)
Rf value: 0.52 (silica gel, dichloromethane/ methanol = 10:1 )
3.1.b. 4-(2-diethylamino-ethoxy)-phenylamine
A reaction mixture of 110.52 g (0.464 mol) diethyl-[2-(4-nitro-phenoxy)-ethyl]-
amine
and 17 g Raney nickel in 700 ml of methanol is hydrogenated for 30 hours at
20°C
and 3 bar hydrogen. The catalyst is filtered off and the filtrate is
evaporated down.
Yield: 93 g (96.2 % of theoretical)
C12H20N2~ (M= 208.30)
Calc.: Molecular ion peak (M)+: 209 Found: Molecular ion peak (M)+:
209
3.1.c. methyl [4-(2-diethylamino-ethoxy)-phenyl]-carbamate
76.38 g (366.66 mmol) 4-(2-diethylamino-ethoxy)-phenylamine and 101.65 ml
(733.33
mmol) triethylamine are dissolved in 400 ml THF. A solution of 49.16 g (366.66
mmol) dimethylpyrocarbonate in 200 ml THF is added dropwise to this solution
within
45 minutes at 25°C and the mixture is stirred for two hours at ambient
temperature.

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The reaction mixture is evaporated down, the residue is added to water and
extracted
with ethyl acetate. The combined organic phases are extracted twice with
water. The
organic phase is evaporated down, during which time a precipitate forms, which
is
filtered off. The filtrate is evaporated down further. The purification is
carried out by
column chromatography on aluminium oxide (eluant: ethyl acetate/ petroleum
ether=
3:1 ).
Yield: 63.3 g (64.8 % of theoretical)
C14H22N203 (M= 266.34)
Calc.: Molecular ion peak (M+H)+: 267 Found: Molecular ion peak
(M+H)+:267
Rf value: 0.62 (aluminium oxide, ethyl acetate/ petroleum ether = 3:1 )
3.1.d. [4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine
30 g (112.63 mmol) methyl [4-(2-diethylamino-ethoxy)-phenyl]-carbamate,
dissolved
in 300 ml absolute THF, are slowly added dropwise to a suspension of 10.68 g
(281.59 mmol) lithium aluminium hydride in 600 ml absolute THF while cooling
with
ice under a nitrogen atmosphere. Then the mixture is stirred for 14 hours,
while the
reaction mixture is allowed to come up to ambient temperature. Then after the
reaction has been monitored 7 g lithium aluminium hydride are added and the
mixture
is stirred for 14 hours. The reaction is stopped by the addition of 60 ml 20%
sodium
hydroxide solution. The precipitate is filtered off and rinsed with
diisopropylether. The
filtrate is dried over sodium sulphate and the solvent is distilled off.
Yield: 24.7 g (98.6 % of theoretical)
C13H22N20 (M= 222.33)
Calc.: Molecular ion peak (M+H)+: 223 Found: Molecular ion peak
(M+H)+: 223
Rf value: 0.44 (silica gel, dichloromethane/ methanol/ammonia = 10:1)
3.1.e. 3-phenyl-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-methyl-amide
A solution of 0.29 g (2 mmol) phenyl-propynoic acid, 0.44 g (2 mmol) [4-(2-
diethylamino-ethoxy)-phenyl]-methyl-amine, 0.7 g (2.2 mmol) TBTU 0.29 g (2.2
mmol)
HOBT and 0.51 ml (3 mmol) Hunig base in 30 ml THF and 2 ml DMF is stirred for
14
hours at ambient temperature. The reaction mixture is evaporated down. The

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purification is carried out by column chromatography on silica gel
(dichloromethane/
methanol = 80:20)
Yield: 130 mg (18.5 % of theoretical)
C22H2gN202 (M= 350.46)
Calc.: Molecular ion peak (M+H)+: 351 Found: Molecular ion peak
(M+H)+: 351
Rf value: 0.39 (silica gel, dichloromethane/ methanol = 80:20)
Example 3.2.:
3-(4-methoxy-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-methyl-
amide
/ o
N
N~ / O
O
3.2.a. 3-(4-methoxy-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-
methyl-amide
Prepared analogously to Example 3.1.e from [4-(2-diethylamino-ethoxy)-phenyl]-
methyl-amine and (4-methoxy-phenyl)-propynoic acid in dichloromethane as
solvent.
Yield: 300 mg (46.3 % of theoretical)
C23H28N2~3 (M= 380.49)
Calc.: Molecular ion peak (M+H)+: 381 Found: Molecular ion peak
(M+H)+: 381
Rf value: 0.42 (silica gel, dichloromethane/ methanol = 80:20)
Example 3.3:
3-(4-chloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-methyl-
amide

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/ CI
N
N~ / O
O
3.3.a. 3-(4-chloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-
methyl-
amide
Prepared analogously to Example 3.1.e from [4-(2-diethylamino-ethoxy)-phenyl]-
methyl-amine and (4-chloro-phenyl)-propynoic acid in dichloromethane as
solvent.
Yield: 36 mg (5 % of theoretical)
C22H25CIN202 (M= 384.91)
Calc.: Molecular ion peak (M+H)+: 385/387 Found: Molecular ion
peak (M+H)+: 385/387
Rf value: 0.4 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
Example 3.4:
3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-
amide
H
I
N
N ~ /
~O
3.4.a. 2,3-dibromo-3-(2,4-dichloro-phenyl)-propanecarboxylic acid
9.45 g (59.14 mmol) bromine, dissolved in 20 ml carbon tetrachloride, are
added
dropwise at 0°C to a suspension of 11.67 g (53.76 mmol) 2,6-
dichlorocinnamic acid in
500 ml carbon tetrachloride and the mixture is stirred for three hours at
ambient
temperature. Then the solvent is distilled off and the residue is combined
with
petroleum ether. The solid is filtered off and dried in the circulating air
dryer at 50°C.
Yield: 19.22 g (94.9 % of theoretical)
Melting point: 184-185°C
CgHgBr2C1202 (M= 376.86)

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3.4.b. (2,4-dichloro-phenyl)-propynoic acid
A solution of 19.2 g (50.94 mmol) 2,3-dibromo-3-(2,4-dichloro-phenyl)-
propanecarboxylic acid in 130 ml tert-butanol is combined batchwise with a
total of
22.86 (203.78 mmol) potassium tert. butoxide, so that the temperature does not
exceed 40°C. Then the mixture is stirred for another 90 min at this
temperature. The
reaction mixture is poured into 2N hydrochloric acid and the precipitate is
taken up in
ethyl acetate. The organic phase is extracted three times with water and dried
over
sodium sulphate. The desiccant is filtered off and the solvent is distilled
off. The
residue is dried in the circulating air dryer at 80°C.
Yield: 9.73 g (88.8 % of theoretical)
Melting point: 168-171 °C
CgH4C1202 (M= 215.03)
Rf value: 0.5 (silica gel, dichloromethane/ ethanol/glacial acetic acid =
10:1:0.1)
3.4.c. 3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-
phenyl]-
amide
Prepared analogously to Example 2.3.f from 4-(2-diethylamino-ethoxy)-
phenylamine
and (2,4-dichloro-phenyl)-propynoic acid.
Yield: 0.62 g (85 % of theoretical)
Melting point: 107-109°C
C21 H22C12N2~2 (M= 405.32)
Calc.: Molecular ion peak (M+H)+: 405/407/409 Found: Molecular ion
peak (M+H)+: 405/407/409
Rf value: 0.6 (silica gel, dichloromethane/ methanol/ammonia = 5:1:0.1)
Example 3.5:
3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-propoxy)-phenyl]-
amide

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H
N
CI
NCO / O
CI
3.5.a. 3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-propoxy)-
phenyl]-
amide
Prepared analogously to Example 3.4.c from 4-(2-diethylamino-propoxy)-
phenylamine
and (2,4-dichloro-phenyl)-propynoic acid.
Yield: 0.41 g (65.2 % of theoretical)
Melting point: 70-72°C
C22H24C12N202 (M= 419.35)
Calc.: Molecular ion peak (M+H)+: 419/421/423 Found: Molecular ion
peak (M+H)+: 419/421/423
Rf value: 0.4 (silica gel, dichloromethane/ ethanol/ammonia = 5:1:0.01 )
Example 3.6:
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-ylmethyl-phenyl)-
amide
H
N
N ~ / O
3.6.a. ethyl (E)-3-(4'-chloro-biphenyl-4-yl)-acrylate
173 mg (0.15 mmol) tetrakistriphenylphosphine palladium and 4.4 ml (8.8 mmol)
of a
2M sodium carbonate solution are added at ambient temperature to a solution of
1.124 g (4.04 mmol) ethyl (E)-3-(4-bromo-phenyl)-acrylate in 50 ml dioxane.
0.689 g
(4.404 mmol) 4-chloro-phenylboric acid dissolved in 10 ml of methanol are
added to
this reaction mixture and refluxed for five hours. The reaction mixture is
evaporated
down, the residue is taken up in dichloromethane and extracted with water. The

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organic phase is dried over sodium sulphate. The purification is carried out
by column
chromatography on silica gel (eluant: petroleum ether/ ethyl acetate= 9:1 ).
Yield: 0.94 g (74.4 % of theoretical)
C17H15C102 (M= 286.76)
Calc.: Molecular ion peak (M+H)+: 287/289 Found: Molecular ion
peak (M+H)+: 287/289
Rf value: 0.44 (silica gel, petroleum ether/ ethyl acetate = 40:10)
3.6.b. [(E)-3-(4'-chloro-biphenyl-4-yl)-acrylic acid
6.27 ml of a 1 M sodium hydroxide solution are added to a solution of 0.9 g
(3.13
mmol) ethyl (E)-3-(4'-chloro-biphenyl-4-yl)-acrylate in 30 ml of ethanol and
stirred for
three hours at ambient temperature. The reaction is stopped by the addition of
6.27
ml of 1 N hydrochloric acid and the reaction mixture is stirred for two hours.
Then the
mixture is evaporated down, the residue is combined with water and the
precipitate is
filtered off. The precipitate is repeatedly rinsed with water and dried at
80°C in the
vacuum drying chamber.
Yield: 0.68 g (67 % of theoretical)
C 15H 110102 (M= 258.70)
Calc.: Molecular ion peak (M-H)-: 257/259 Found: Molecular ion
peak (M-H)-: 257/259
Rf value: 0.5 (silica gel, dichloromethane/methanol = 90:10)
3.6.c. (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-piperidin-1-ylmethyl-phenyl)-
acrylamide
Prepared analogously to Example 3.1.e from [(E)-3-(4'-chloro-biphenyl-4-yl)-
acrylic
acid and 4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.57 g (62.9 % of theoretical)
Melting point: 265-270°C
C27H27CIN20 (M= 430.98)
Calc.: Molecular ion peak (M+H)+: 431/433 Found: Molecular ion
peak (M+H)+: 431/433
Rf value: 0.31 (silica gel, dichloromethane/methanol = 90:10)

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3.6.d. 2,3-dibromo-3-(4'-chloro-biphenyl-4-yl)-N-(4-piperidin-1-ylmethyl-
phenyl)-
propionamide
A suspension of 150 mg (0.348 mmol) (E)-3-(4'-chloro-biphenyl-4-yl)-N-(4-
piperidin-1-
ylmethyl-phenyl)-acrylamide in 15 ml dichloromethane is combined with 0.02 ml
(0.383 mmol) bromine and stirred for three hours at ambient temperature. Then
the
reaction mixture is evaporated down, the residue is recrystallised from
petroleum
ether and dried at 70°C in the vacuum drying chamber.
Yield: 0.19 g (92.4 % of theoretical)
Melting point: 145-150°C
C27H27Br2CIN20 I(M= 590.79)
Calc.: Molecular ion peak (M+H)+: 589/591/593/595
Found: Molecular ion peak (M+H)+: 589/591/593/595
Rf value: 0.47 (silica gel, dichloromethane/methanol/ammonia = 90:10:1 )
3.6.e. 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-ylmethyl-
phenyl)-amide
Prepared analogously to Example 3.4.b from 2.3-dibromo-3-(4'-chloro-biphenyl-4-
yl)-
N-(4-piperidin-1-ylmethyl-phenyl)-propionamide.
Yield: 26 mg (23.9 % of theoretical)
C27H25CIN20 I(M= 428.96)
Calc.: Molecular ion peak (M+H)+: 429/431 Found: Molecular ion peak (M+H)+:
429/431
Rf value: 0.42 (silica gel, dichloromethane/methanol/ammonia = 90:10:1 )
Example 3.7: 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-
ylmethyl-
phenyl)-methyl-amide
~N / ~ O
\ i ~ ~ \
/ \
/
CI
3.7.a. 2,3 dibromo-3-(4'-chloro-biphenyl-4-yl) propynoic acid

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3.3 ml (64.22 mmol) bromine are added dropwise at ambient temperature to a
suspension of 15 g (58 mmol) 3-(4'-chloro-biphenyl-4-yl) acrylic acid in 370
ml carbon
tetrachloride and stirred for three hours at ambient temperature. The
precipitate
obtained is suction filtered, washed with petroleum ether and dried in the
circulating
air dryer at 70°C.
Yield: 24 g (99 % of theoretical)
Melting point: 230-234 °C
C15H11 Br2C102 (M= 418.51)
Rf value: 0. 2 (silica gel, dichloromethane/methanol= 90:10)
3.7.b. (4'-chloro-biphenyl-4-yl)-propynoic acid
A solution of 24 g (57.35 mmol) 2,3 dibromo-3-(4'-chloro-biphenyl-4-yl)
propynoic
acid in 270 ml THF is combined batchwise with 25.74 g (229.39 mmol) potassium
tert.
butoxide, so that the temperature does not exceed 40 °C. Then the
mixture is stirred
for another 3.5 hours at this temperature. The reaction mixture is poured onto
ice
water/conc. hydrochloric acid and the precipitate is taken up in ethyl
acetate. The
organic phase is washed with water and dried over sodium sulphate. The
desiccant is
filtered off and the solvent is distilled off. The residue is stirred with
petroleum ether
and suction filtered.
Yield: 14.2 g (97 % of theoretical)
ClSHg C102 (M= 256.68)
Rf value: 0. 45 (silica gel, dichloromethane/methanol/glacial acetic acid=
90:10:0.1 )
3.7.c. 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-ylmethyl-
phenyl)-
methyl-amide
A solution of 0.26 g (1 mmol) (4'-chloro-biphenyl-4-yl)-propynoic acid and
0.12 ml (1.1
mmol) N-methylmorpholine in 20 ml absolute THF is combined at -15°C
with 0.14 ml
(1.1 mmol) isobutyl chloroformate and stirred for ten minutes. Then 0.225 g
(1.1
mmol) methyl-(4-piperidin-1-ylmethyl-phenyl)-amine dissolved in 10 ml THF are
added and the reaction mixture is stirred for two hours until it reaches
ambient
temperature. The reaction mixture is evaporated down and the residue is
dissolved in
dichloromethane. The organic phase is washed twice with water and then dried
over
sodium sulphate. The desiccant is filtered off and the solvent is distilled
off. The

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residue is triturated with ether, suction filtered and dried at 80°C in
the vacuum drying
chamber.
Yield: 220 mg (50 % of theoretical)
Melting point: 237-239 °C
C28H27CIN20 (M= 442.98)
Calc.: Molecular ion peak (M+H)+: 443/445 (CI) Found: Molecular ion
peak (M+H)+: 443/445 (CI)
Rf value: 0. 5 (silica gel, dichloromethane/methanol = 90:10)
Example 3.8: 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-methyl-piperazin-
1-
ylmethyl)-phenyl]-amide
~N / ~ O
/NJ \ N % \
/ CI
A solution of 0.26 g (1 mmol) (4'-chloro-biphenyl-4- yl)-propynoic acid and
0.12 ml
(1.1 mmol) N-methylmorpholine in 20 ml absolute THF is combined at -
15°C with 0.14
ml (1.1 mmol) isobutyl chloroformate and stirred for ten minutes. Then 0.226 g
(1.1
mmol) 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine, dissolved in 7 ml THF are
added and the reaction mixture is stirred for two hours until ambient
temperature is
reached. The reaction mixture is evaporated down and the residue is dissolved
in
dichloromethane. The organic phase is washed twice with water and then dried
over
sodium sulphate. The desiccant is filtered off and the solvent is distilled
off. The
residue is triturated with ether and suction filtered. The purification is
carried out by
column chromatography on silica gel (dichloromethane/methanol/ammonia=
90/10/0.1 )
Yield: 60 mg (14 % of theoretical)
Melting point: 182-185 °C
C27H2gCIN30 (M= 443.97)
Calc.: Molecular ion peak (M+H)+: 444/446 (CI) Found: Molecular ion
peak (M+H)+: 444/446 (CI)
Rf value: 0. 4 (silica gel, dichloromethane/methanolic ammonia = 90:10:0.1 )

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Example 3.9. 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(2,6-dimethyl-
piperidin-1-
ylmethyl)-phenyl]-amide
~N ~ I o
N \~~ I \
cl
Prepared analogously to Example 3.8. from (4'-chloro-biphenyl-4-yl)-propynoic
acid
and 4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenylamine.
Yield: 100 mg (22 % of theoretical)
Melting point: 158-163 °C
C2gH2gCIN20 (M= 457.01)
Calc.: Molecular ion peak (M+H)+: 458/460 (CI) Found: Molecular ion
peak (M+H)+: 458/460 (CI)
Rf value: 0. 50 (silica gel, dichloromethane/methanolic ammonia = 90:10:0.1 )
Example 3.10: 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-{4-[(cyclohexyl-
methyl-
amino)-methyl]-phenyl}-amide
0
\
N
CI
Prepared analogously to Example 3.8. from (4'-chloro-biphenyl-4-yl)-propynoic
acid
and 4-[(cyclohexyl-methyl-amino)-methyl]-phenylamine hydrochloride
Yield: 60 mg (13 % of theoretical)
Melting point: 205-210 °C
C2gH2gCIN20 (M= 457.01 )
Calc.: Molecular ion peak (M+H)+: 457/459 (CI) Found: Molecular ion
peak (M+H)+: 457/459 (CI)

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Rf value: 0. 60 (silica gel, dichloromethane/methanol = 90:10)
Example 3.11: B100017862
3-(4'-chloro-biphenyl-4-yl)propynoic acid-(4-{[(2-methoxy-ethyl)-methyl-amino]-
methyl}-phenyl)-amide
/OWN / O
I
\ N ~ I \
/ \
I/
CI
Prepared analogously to Example 3.8. from (4'-chloro-biphenyl-4-yl)-propynoic
acid
and 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenylamine.
Yield: 150 mg (35 % of theoretical)
Melting point: 130-133 °C
C26H25CIN202 (M= 432.94)
Calc.: Molecular ion peak (M+H)+: 433/435 (CI) Found: Molecular ion
peak (M+H)+: 433/435 (CI)
Rf value: 0. 50 (silica gel, dichloromethane/methanol/ammonia = 90:10:1)
Example 3.12:
3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(3,5-dimethyl-piperidin-1-
ylmethyl)-
phenyl]-amide
N / I o
\ N ~ I \
/ \
I/
cl
A solution of 0.26 g (1 mmol) (4'-chloro-biphenyl-4-yl)-propynoic acid and
0.12 ml (1.1
mmol) N-methylmorpholine in 20 ml absolute THF is combined With 0.14 ml (1.1
mmol) isobutyl chloroformate at -15°C and stirred for ten minutes. Then
0.240 mg

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(1.1 mmol) 4-[(3,5-dimethyl-cyclohexylamino)-methyl]-phenylamine, dissolved in
7 ml
THF are added and the reaction mixture is stirred for 16 hours. The reaction
mixture
is evaporated down. The purification is carried out by column chromatography
on
silica gel (dichloromethane/methanol = 90/10).
Yield: 300 mg (66 % of theoretical)
Melting point: 209-214 °C
C2gH2gCIN20 (M= 457.01 )
Calc.: Molecular ion peak (M+H)+: 457/459 (CI) Found: Molecular ion
peak (M+H)+: 457/459 (CI)
Rf value: 0. 60 (silica gel, dichloromethane/methanol = 90:10)
The following compounds are prepared analogously to Example 3.12.:
R~R2N/X /
N
CI
Example R~RZN-X educt empirical formulamass mp R,
spectrum [C] value
3.13 0 3.7.b C28H2~CIN202 459/461 227- 0.6
(CI)
~N~ [M+H]+ 234 (B)
3.14 ~ 3.7.b C28H2~CIN20 443/445 263- 0.5
(CI)
N~ [M+HJ+ 268 (B)
3.15 I 3.7.b C2~H25CIN20 429/431 164- 0.5
(CI)
~
N [M+H]+ 167 (A)
3.16 N~, 3.7.b C26H2sCIN202 431/433 180- 0.4
(CI)
[M+H]+ 184 (B)
3.17 0 ~. 3.7.b C28H24C1 F3N202513/515 194- 0.5
N (CI)
[M+H]+ 200 B
F

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Rf value: A= (silica gel, dichloromethane/methanol/ammonia 90:10:0.1 )
B= (silica gel, dichloromethane/methanol 90:10)
Example 3.18: 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-[4-(4-hydroxy-
piperidin-1-
ylmethyl)-phenyl]-amide
0
i
N
CI
3.18.a 4-(4-nitro-benzyl)-piperidin-4-of
137 ml (0.983 mol)triethylamine are added to a solution of 41.5 g (0.410 mol )
4-
hydroxypiperidine in 500 ml dichloromethane. Then 56.28 g (0.328 mol ) 4-
nitrobenzylchloride are slowly added. The reaction mixture is boiled for 12
hours. The
solid formed is suction filtered, the filtrate is washed twice with water and
dried over
magnesium sulphate. The solvent is evaporated down.
Yield: 66.45 g (86 % of theoretical)
C12H16N2~3 (M= 236.27)
Calc.: Molecular ion peak (M+H)+: 237 Found: Molecular ion peak (M+H)+:
237
3.18.b.4-(4-amino-benzyl)-piperidin-4-of
6.6 g Raney nickel are added to a solution of 66.45 g (0.281 mol) 4-(4-nitro-
benzyl)-
piperidin-4-of in 660 ml of methanol. The reaction mixture is hydrogenated for
13
hours at ambient temperature and 3 bar hydrogen. The catalyst is filtered off
and the
filtrate is evaporated down.
Yield: 64.5 g (111 % of theoretical)
C12H18N20 (M= 206.28)
Calc.: Molecular ion peak (M+H)+: 207 Found: Molecular ion peak (M+H)+:
207

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3.18.c. 4-[4-(tent-butyl-dimethyl-silanyloxy)-piperidin-1-ylmethyl]-
phenylamine
3.3 g (22 mmol) tert. butyldimethylchlorosilane are added to a solution of
4.13 g ( 20
mmol) 4-(4-amino-benzyl)-piperidin-4-of and 3.4 g (50 mmol) imidazole in 30 ml
of
dimethylformamide. The reaction mixture is stirred for 16 hours at ambient
temperature . Then the solvent is evaporated down and extracted between ether
and
water. The organic phase is dried over sodium sulphate and evaporated down.
The
purification is carried out by column chromatography on aluminium oxide
(eluant:
petroleum ether/ethyl acetate 90:10).
Yield: 1.65 g (26 % of theoretical)
C18H32N20Si (M= 320.55)
Calc.: Molecular ion peak (M+H)+: 321 Found: Molecular ion peak (M+H)+:
321
Rf value: 0. 80 (aluminium oxide, petroleum ether/ethyl acetate = 1:1)
3.18.d. 3-(4'-chloro-biphenyl-4-yl)propynoic acid-{4-[(4-hydroxy-
cyclohexylamine)-
methyl]-phenyl}-amide
A solution of 0.26 g (1 mmol) (4'-chloro-biphenyl-4-yl)-propynoic acid and
0.12 ml (1.1
mmol) N-methylmorpholine in 20 ml absolute THF is combined with 0.14 ml (1.1
mmol) isobutyl chloroformate at -15°C and stirred for ten minutes. Then
0.350 g (1.1
mmol) 4-[4-(tent butyl-dimethyl-silanyloxy)-piperidin-1-ylmethyl]-phenylamine,
dissolved in 7 ml THF are added and the reaction mixture is stirred for four
hours. The
reaction mixture is evaporated down. The residue is dissolved in 30 ml of
tetrahydrofuran and combined with 0.95 g (3 mmol) tetrabutylammonium fluoride
hydrate. The reaction mixture is stirred for 16 h at ambient temperature. Then
another
0.5 g (1.5 mmol) tetrabutylammonium fluoride hydrate are added and the mixture
is
stirred for another 16 h at ambient temperature. The last step is repeated
twice more.
Then the solvent is evaporated down and the residue is extracted between
dichloromethane and water. The organic phase is dried over sodium sulphate ,
the
desiccant is filtered off and the filtrate is evaporated down. The
purification is carried
out by column chromatography on silica gel (dichloromethane/methanol = 90/10)
Yield: 100 mg (23 % of theoretical)
Melting point: 243-247 °C
C27H25CIN202 (M= 444.95)

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Calc.: Molecular ion peak (M+H)+: 445/447 (CI) Found: Molecular ion
peak (M+H)+: 445/447 (CI)
Rf value: 0. 40 (silica gel, dichloromethane/methanol/ammonia = 90:10:1)
Example 3.19: 3-(4'-chloro-biphenyl-4-yl)propynoic acid-[1-(2-pyrrolidin-1-yl-
ethyl)-
1 H-indol-5-yl]-amide
GN~N
O
\ N
\
/ \
/
CI
3.19.a. 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole
A reaction mixture of 16.22 g (0.1 mol) 5-nitroindole, 35 g (0.205 mol) 1-(2-
chloro-
ethyl)-pyrrolidine-hydrochloride and 51 g (0.369 mol) potassium carbonate in
500 ml
DMF is stirred for 48 hours at ambient temperature and then filtered. The
filtrate is
evaporated down, the residue dissolved in dichloromethane and dried over
sodium
sulphate. The desiccant is filtered off and the filtrate is evaporated down.
Yield: 25 g (96.3 % of theoretical)
C14H17N3~2 (M= 259.31)
Calc.: Molecular ion peak (M+H)+: 260 Found: Molecular ion peak
(M+H)+: 260
Rf value: 0.65 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
3.19. b. 5-amino-1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole
Prepared analogously to Example 3.1.b from 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-
1H-
indole in THF as solvent.
Yield: 0.83 g (93.9 % of theoretical)
C14H1gN3 (M= 229.32)
Calc.: Molecular ion peak (M+H)+: 230 Found: Molecular ion peak
(M+H)+: 230
Rf value: 0.37 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1 )

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3.19.c. 3-(4'-chloro-biphenyl-4-yl)propynoic acid-[1-(2-pyrrolidin-1-yl-ethyl)-
1H-indol-5-
yl]-amide
Prepared analogously to Example 3.7.c. from 5-amino-1-(2-pyrrolidin-1-yl-
ethyl)-1H-
indole and (4'-chloro-biphenyl-4-yl)-propynoic acid in THF as solvent.
Yield: 230 mg (49 % of theoretical)
C2gH2gCIN30 (M= 467.99)
Melting point: 224-227°C
Calc.: Molecular ion peak (M+H)+: 468/470 (CI) Found: Molecular ion
peak (M+H)+: 468/470 (CI)
Rf value: 0.4 (silica gel, dichloromethane/ methanol = 90:10)
Example 3.20: 3-(4'-chloro-biphenyl-4-yl)-propynoic acid-(3-chloro-4-piperidin-
1-
ylmethyl-phenyl)-amide
C~
~N
N
CI
3.20.a: (2-chloro-4-nitro-phenyl)-methanol
35.9 g (0.22 mol) 1,1'-carbonyldiimidazole are slowly added to a solution of
41.1 g
(0.2 mol) 2-chloro-4-nitrobenzoic acid in 400 ml of tetrahydrofuran. The
reaction
mixture is stirred for 1.5 h at 35 °C. Then the green reaction mixture
is cooled down
using ice and at max. 20 °C combined dropwise with a solution of 26.5 g
(0.7 mol)
sodium borohydride in 400 ml of water. After 1.5 hours stirring the reaction
mixture is
diluted with 200 ml of water and then neutralised with 250 ml semiconcentrated
hydrochloric acid. It is stirred for one hour, then extracted twice with ethyl
acetate and
the organic phase is dried over sodium sulphate. The desiccant is filtered off
and the
solvent is evaporated down. The residue is crystallised with petroleum ether,
suction '
filtered and dried at 50 °C in the drying chamber.
Yield: 37.66 g (100 % of theoretical)
Melting point: 62-64 °C
C7HgCIN03 (M= 187.58)

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Calc.: Molecular ion peak (M+H)+: 187/189 (CI) Found: Molecular ion
peak (M+H)+: 187/189 (CI)
Rf value: 0. 70 (silica gel, dichloromethane/methanol = 90:10)
3.20.b.2-chloro-1-chloromethyl-4-vitro-benzene
11.6 ml (160 mmol) thionyl chloride and 1 ml of dimethylformamide are added to
a
solution of 15 g (80 mmol) 2-chloro-4-vitro-phenyl)-methanol in 300 ml
dichloromethane and the whole lot is refluxed for 2 hours. Then the solvent is
evaporated down and the residue is dissolved in ethyl acetate and washed with
water.
The organic phase is dried over sodium sulphate, the desiccant is filtered off
and the
filtrate is evaporated down. Oily product.
Yield: 16.8 g (102 % of theoretical)
C7H5C12N02 (M= 206.03)
Calc.: Molecular ion peak (M+H)+: 205/7/9 (C12) Found: Molecular ion
peak (M+H)+: 205/7/9 (C12)
Rf value: 0. 90 (silica gel, dichloromethane/methanol = 90:10)
3.20.c. 1-(2-chloro-4-vitro-benzyl)-piperidine
2g (9.71 mmol) 2-chloro-1-chloromethyl-4-vitro-benzene are slowly added to 4
ml
(40.04 mmol) piperidine at ambient temperature. After 15 min the reaction
mixture is
combined with ethyl acetate and washed twice with water. The organic phase is
dried
over sodium sulphate, the desiccant is filtered off and the filtrate is
evaporated down.
Oily product.
Yield: 2.39 g (97 % of theoretical)
C12H15CIN202 (M= 254.71)
Rf value: 0. 30 (silica gel, petroleum ether/ ethyl acetate = 6:1 )
3.20.d 3-chloro-4-piperidin-1-ylmethyl-phenylamine
0.4 g Raney nickel are added to a solution of 2.37 g (9.31 mmol) 1-(2-chloro-4-
nitro-
benzyl)-piperidine in 100 ml of tetrahydrofuran and hydrogenated at ambient
temperature and 3 bar hydrogen. After hydrogen uptake has ended the catalyst
is
filtered off and the filtrate is evaporated down.
Yield: 1.88 g (90 % of theoretical)

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C12H17CIN2 (M= 224.73)
Calc.: Molecular ion peak (M+H)+: 255/7 (CI) Found: Molecular ion peak
(M+H)+: 255/7 (CI)
Rf value: 0. 20 (silica gel, dichloromethane/methanol = 90:10)
3.20.e 3-(4'-chloro-biphenyl-4-yl)-propynoic acid(3-chloro-4-piperidin-1-
ylmethyl-
phenyl)-amide
Prepared analogously to Example 3.7.c from (4'-chloro-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.1 g (22 % of theoretical)
Melting point: 277-281 °C
C27H24C12N2 O (M= 463.4)
Calc.: Molecular ion peak (M+H)+: 463/5/7 (C12) Found: Molecular ion
peak (M+H)+: 463/5/7 (C12)
Rf value: 0. 50 (silica gel, dichloromethane/methanol = 90:10)
The following compounds are prepared analogously to Example 3.20:
cl
R~R2N~X / ( O
\ N ~ ~ \
/ \
/
CI
Example R~R2N-X educt empirical mass mp R, value
formula spectrum [C]
3.21 3.7.b C29H28C12N20491/3/5 (C12)282- 0.5
1 [M+H]+ 286 (A)
N
3.22 ~ 3.7.b CZ~H24C12N202479/81/83 197- 0.5
(C12)
p
[M+H]+ 203 (B)
3.23 ~ 3.7.b C2~H24C12N202479/81/83 204- 0.45
(C12)
[M+H]+ 209 (B)

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Rf value: A= (silica gel, dichloromethane/methanol 90:10)
B= (silica gel, dichloromethane/methanol/ammonia 90:10:0.1)
Example 3.24: 3-(4'chloro-biphenyl-4-yl)-propynoic acid-[3-chloro-4-(2-
dimethylamino-ethoxy)-phenyl]-amide hydrochloride
CIH
CI
/~N~/O /
N
CI
Prepared analogously to Example 3.7.c from (4'-chloro-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine.
Yield: 0.28 g (58 % of theoretical)
Melting point: 226-233 °C
C27H2gC12N2 02 (M= 481.41)*HCI
Calc.: Molecular ion peak (M+H)+: 481/3/5 (C12) Found: Molecular ion
peak (M+H)+: 481/3/5 (C12)
Rf value: 0. 45 (silica gel, dichloromethane/methanol = 90:10)
Example 3.25:
3-[5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid-(4-piperidin-1-ylmethyl-
phenyl)-
amide
cl
N / O
3.25.a.5-bromo-2-trimethylsilanylethynyl-pyridine
1.15 g (1.63 mmol) tetrakistriphenylphosphine palladium, 0.311 g (1.63 mmol)
copper(I)iodide and 50 ml triethylamine are added to a solution of 20 g (81.89
mmol)
2,5-dibromopyridine in 250 ml absolute THF under an argon atmosphere. At 17
°C a
solution of 13 ml (90.14 mmol) trimethylsilylacetylene in 20 ml THF is
immediately

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added dropwise to this reaction mixture. After ten minutes the cooling is
removed.
After 20 minutes the temperature is 30° C. The mixture is then cooled
to 20°C and
briefly stirred. The reaction mixture is evaporated down, the residue is taken
up in
ethyl acetate and extracted twice with sodium hydrogen carbonate solution. The
combined organic phases are dried over magnesium sulphate. The purification is
carried out by column chromatography on silica gel (eluant: petroleum ether).
Yield: 20.4 g (98 % of theoretical)
C10H12grNSi (M= 254.20)
Calc.: Molecular ion peak (M+H)+: 254/256 Found: Molecular ion
peak (M+H)+: 254/256
Rf value: 0.72 (silica gel, petroleum ether)
3.25.b. 5-(4-chloro-phenyl)-2-trimethylsilanylethynyl-pyridine
In an argon atmosphere 6.93 g (6 mmol) tetrakistriphenylphosphine palladium
and 17
ml of a 2M sodium carbonate solution are added to a solution of 20.4 g (80.25
mmol)
5-bromo-2-trimethylsilanylethynyl-pyridine and 26.33 g (160 mml) 4-
chlorophenylboric
acid in 350 ml dioxane and the reaction mixture is stirred for five hours at
90 C, while
every 30 minutes 7 ml of 2M sodium carbonate solution are added. Then at
ambient
temperature 1000 ml of ethyl acetate are added, and the mixture is extracted
twice
with 400 ml sodium hydrogen carbonate solution. The organic phase is dried
over
magnesium sulphate. The purification is carried out by column chromatography
on
silica gel (eluant: petroleum ether to petroleum ether/ ethyl acetate= 9:1 ).
Yield: 7.9 g (34.4 % of theoretical)
C16H16CINSi (M= 285.85)
Calc.: Molecular ion peak (M-H)-: 286/288 Found: Molecular ion
peak (M-H)-: 286/288
Rf value: 0.6 (silica gel, petroleum ether/ ethyl acetate = 8:2)
3.25.c. 5-(4-chloro-phenyl)-2-ethynyl-pyridine
A reaction mixture of 7.4 g (25.88 mmol) 5-(4-chloro-phenyl)-2-
trimethylsilanylethynyl-
pyridine and 7.18 g (52 mmol) potassium carbonate in 80 ml of methanol is
stirred for
30 minutes at ambient temperature. 500 ml dichloromethane are added and the
reaction mixture is extracted with water and sodium hydrogen carbonate
solution. The
combined organic phases are dried over magnesium sulphate. The purification is

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carried out by column chromatography on silica gel (eluant: petroleum ether to
petroleum ether/ ethyl acetate= 8:2).
Yield: 2 g (36.2 % of theoretical)
C13H8CIN (M= 213.66)
Calc.: Molecular ion peak (M+H)+: 214/216 Found: Molecular ion
peak (M+H)+: 214/216
3.25.d. [5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid
1.6 ml (2.46 mmol) butyllithium solution (1.6M in hexane) are added dropwise
at -10 C
to a solution of 0.5 g (2.34 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine in
30 ml
absolute THF and the mixture is stirred for five minutes at -8°C
stirred. The reaction
mixture is combined with dry ice batchwise at -70° C, stirred for one
hour at ambient
temperature and evaporated down. The residue is suspended in 5 ml of water and
combined with 1.6 ml 1 N hydrochloric acid, whereupon a precipitate is formed.
Then
ethyl acetate is added and the suspension is filtered. The solid is dried in
the vacuum
drying chamber at 70 °C.
Yield: 0.25 g (41.5 % of theoretical)
Melting point: 210°C
C14H8CIN02 I(M= 257.67)
Calc.: Molecular ion peak (M+H)+: 258/260
Found: Molecular ion peak (M+H)+: 258/260
3.25.e. 3-[5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid-(4-piperidin-1-
ylmethyl-
phenyl)-amide
Prepared analogously to Example 2.3.f from [5-(4-chloro-phenyl)-pyridin-2-yl]-
propynoic acid and 4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.2 g (48 % of theoretical)
C26H24CIN30 I(M= 429.95)
Calc.: Molecular ion peak (M+H)+: 430/432 Found: Molecular ion
peak (M+H)+: 430/432
Rfvalue: 0.4 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1)
The following compounds are prepared analogously to Example 3.25:

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R~RzN.X / I O
\ N \
\
N / \
I/
CI
Example R~RZN-X educt empirical mass mp R, value
formula
spectrum [C]
3.26 I 3.24.d C2~H26CIN302460/462 (CI)155- 0.6
o
N~ [M+H]+ 159 (A)
3.27 ~ 3.24.d CZ~HZSCIN30 444/446 (CI)183- 0.7
[M+H]+ 185 (B)
3.28 ~I 3.24.d C26H2aCIN30 430/432 (CI)158- 0.6
~
N
[M+H]+ 161 (B)
3.29 3.24.d CZ$H28CIN30 458/460 (CI)195- 0.7
[M+H]+ 197 (B)
Rf value: A= (silica gel, dichloromethane/methanol 90:10)
B= (silica gel, dichloromethane/methanol/ammonia 90:10:0.1)
The following compounds are prepared analogously to Example 3.25:
cl
R1RzN/X / (
N
CI
Example R,R2N-X educt empirical formula mass mp Rf value

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spectrum [
C]
3.30 ~ 3.24.d C26H2sC12Ns0 464/66/68 150- 0.6
(C12)
[M+H]+ 153 (A)
3.31 3.24.d C28H2~CIZN30 492/94/96 180- 0.8
(C12)
[M+H]+ 185 (A)
Rf value: A= (silica gel, dichloromethane/methanol/ammonia 90:10:0.1 )
Example 3.32: 3-(3-chloro-biphenyl-4-yl)-propynoic acid-[3-chloro-4-(2-
diethylamino-
ethoxy)phenyl]-amide hydrochloride
ci
~N~o i
N
X HCI
3.32.a. trifluoro-methanesulphonic acid 3-chloro-biphenyl-4-yl ester
6.7 ml (40.32 mmol) trifluoromethanesulphonic acid anhydride, dissolved in 5
ml
dichloromethane, are added dropwise between -10 to -5°C to a solution
of 7.5 g
(36.65 mmol) 3-chloro-biphenyl-4-of and 6.1 ml (44 mmol) triethylamine in 100
ml
dichloromethane. Then the mixture is stirred for 30 minutes. The reaction
solution is
then extracted with water, the organic phase is separated off and filtered
through an
alox frit. The filtrate is concentrated by evaporation.
Yield: 12 g (97 % of theoretical)
C13H8CIF303 S (M= 336.72)
Calc.: Molecular ion peak (M+H)+: 336/338 (CI) Found: Molecular ion peak
(M+H)+: 336/338 (CI)
Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate = 5:1 )
3.32.b. tert-butyl-(3-chloro-biphenyl-4-ylethynyl)-dimethyl-silane
0.84 g (1.2 mmol) bis-(triphenylphosphine)-palladium(II)-chloride, 0.23 g (1.2
mmol)
copper(I)iodide and 6.28 ml (33.6 mmol) (tert-butyldimethylsilyl)acetylene are
added
under an argon atmosphere to a solution of 8.1 g (24 mmol) 3-chloro-biphenyl-4-
yl

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trifluoro-methanesulphonate in 50 ml absolute dimethylformamide and 13.31 ml
(96
mmol) triethylamine. At ambient temperature the reaction mixture is stirred
for 24
hours. Then the reaction mixture is evaporated down, the residue is taken up
in ethyl
acetate and extracted with water. The organic phase is dried. The purification
is
carried out by column chromatography on silica gel (eluant: petroleum
ether/ethyl
acetate 4:1 ).
Yield: 8.4 g (107 % of theoretical)
C20H23CISi (M= 326.94)
Calc.: Molecular ion peak (M+H)+: 327/329 (CI) Found: Molecular ion
peak (M+H)+: 327/329 (CI)
Rf value: 0.7 (silica gel, petroleum ether/toluene 9:1 )
3.32.c. 3-chloro-4-ethynyl-biphenyl
7.85 g (24 mmol) tert-butyl-(3-chloro-biphenyl-4-ylethynyl)-dimethyl-silane
are
dissolved in 150 ml absolute tetrahydrofuran and at 5°C combined
batchwise with
11.4 g (36 mmol) tetrabutylammonium fluoride*3H20. The reaction mixture
reaches
ambient temperature after 30 minutes. Then the solvent is evaporated down and
the
residue is extracted between ether and water. The organic phase is dried,
combined
with activated charcoal and filtered through Celite. The filtrate is
evaporated down.
The purification is carried out by column chromatography on silica gel
(eluant:
petroleum ether/ethyl acetate 20:1)
Yield: 4.7 g (92 % of theoretical)
Cl4HgCl (M= 212.67)
Rf value: 0.6 (silica gel, petroleum ether/toluene 5:1 )
3.32.d. (3-chloro-biphenyl-4-yl)-propynoic acid
13.8 ml (22.1 mmol) butyllithium solution (1.6M in hexane) are added dropwise
to a
solution of 4.7 g (22.1 mmol) 3-chloro-4-ethynyl-biphenyl in 100 ml absolute
tetrahydrofuran at -10 to -20°C and after five minutes cooled to -
60°C. At this
temperature dry ice is added batchwise to the reaction mixture and it is
slowly allowed
to come up to ambient temperature. Then the solvent is evaporated down and the
residue is extracted between ethyl acetate and 1 M hydrochloric acid. The
organic
phase is dried, the desiccant filtered off and the solvent concentrated by
evaporation.

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The residue is stirred with petroleum ether, suction filtered and dried at
80°C in the
circulating air dryer.
Yield: 4.8 g (85 % of theoretical)
ClSHgCl02 (M= 256.68)
Calc.: Molecular ion peak (M+H)+: 257/259 (CI) Found: Molecular ion
peak (M+H)+: 257/259 (CI)
Rf value: 0.2 (silica gel, dichloromethane/methanol/glacial acetic acid
90:10:0.1)
3.32.e. 3-(3-chloro-biphenyl-4-yl)-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)phenyl]-amide hydrochloride
Prepared analogously to Example 3.8.a from (3-chloro-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine.
Yield: 0.35 g (68 % of theoretical)
Melting point: 195-200 °C
C27H26C12N2 02*HCI (M= 517.87)
Calc.: Molecular ion peak (M+H)+: 481/3/5 (C12) Found: Molecular ion
peak (M+H)+: 481/3/5 (C12)
Rf value: 0. 6 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1 )
Example 3.33: 3-(3-chloro-biphenyl-4-yl)-propynoic acid-(4-piperidin-1-
ylmethyl-
phenyl)-amide hydrochloride
GN / , ~
\ N ~ CI
\
/ \
/
X HCI
Prepared analogously to Example 3.8. from (3-chloro-biphenyl-4-yl)-propynoic
acid
and 4-piperidin-1-ylmethyl-phenylamine.
Yield: 0.35 g (75 % of theoretical)
Melting point: 260-265 °C
C27H25CIN2 O*HCI (M= 465.41 )

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Calc.: Molecular ion peak (M+H)+: 429/31 (CI) Found: Molecular ion peak
(M+H)+: 429/31 (CI)
Rf value: 0. 6 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1)
Example 3.34:
3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethyl)-phenyl]-amide-
hydrochloride
cl
H
N X HCI
/~N I /
3.34.a. 3-(2,4-dichloro-phenyl)-propynoic acid-[4-(2-diethylamino-ethyl)-
phenyl]-
amide-hydrochloride
Prepared analogously to Example 2.3.f from 4-(2-diethylamino-ethyl)-
phenylamine
and (2,4-dichloro-phenyl)-propynoic acid.
Yield: 0.3 g (47 % of theoretical)
Melting point: 204-208°C
C21 H22C12N20 (M= 425.78)
Calc.: Molecular ion peak (M+H)+: 389/391/393 Found: Molecular ion
peak (M+H)+: 389/391/393
Rf value: 0.6 (silica gel, dichloromethane/ ethanol/ammonia = 5:1:0.01 )
Example 3.35.
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-diethylamino-ethyl)-
phenyl]-
amide

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~I
N
CI
/ 0
CF3
Prepared analogously to Example 2.3.f from 90 mg (0.44 mmol) 4-(2-diethylamino-
ethyl)-phenylamine and 99 mg (0.40 mmol) 2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid.
Yield: 71 mg (42 % of theory)
Melting point: 145-150 C
C22H22CIF3N20 (M= 422.88)
Calc.: Molecular ion peak (M+H)+: 423/425 Found: Molecular ion peak
(M+H)+:423/425
Rf value: 0.30 (silica gel, dichloromethane/methanol = 9:1 )
Example 3.36
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[N-(2-dimethylamino-
ethyl)-
methylamino]-phenyl}-amide-formate
/ CFs
~I
N
CI
/ O
Prepared analogously to Example 2.3.f. from 90 mg (0.44 mmol) 4-[N-(2-
dimethylamino-ethyl)-methylamino]-phenylamine (for preparation see
International
Patent Application WO 01/27081) and 99 mg (0.40 mmol) 2-chloro-4-
trifluoromethyl-
phenyl)-propynoic acid.
Yield: 64 mg (38 % of theory)
C21 H21 CIF3N30 x CH20 2 (M= 469.89)

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Calc.: Molecular ion peak (M+H)+: 424/426 Found: Molecular ion peak
(M+H)+: 424/426
Rfvalue: 0.35 (silica gel, dichloromethane/methanol = 9:1)
Example 3.37
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-diethylamino-
propoxy)-
phenyl]-amide
/ CF3
H ~I
N
CI
O / O
Prepared analogously to Example 2.3.f. from 67 mg (0.3 mmol) 4-(2-diethylamino-
propoxy)-phenylamine and 75 mg (0.3 mmol) (2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid.
Yield: 71 mg (52 % of theory)
Melting point: 172-176 C
C23H24CIF3N202 (M= 452.90)
Calc.: Molecular ion peak (M+H)+: 453/455 Found: Molecular ion peak
(M+H)+: 453/455
Rf value: 0.30 (silica gel, dichloromethane/methanol = 9:1 )
Example 3.38
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-diethylamino-
ethoxy)-
phenyl]-amide
~CF3
H
N
CI
O / O

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Prepared analogously to Example 2.3.f from 69 mg (0.33 mmol) 4-(2-diethylamino-
ethoxy)-phenylamine and 75 mg (0.30 mmol) (2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid.
Yield: 70 mg (53 % of theory)
Melting point: 194-197 °C
C22H22CIF3N202 (M= 438.88)
Calc.: Molecular ion peak (M+H)+: 439/441 Found: Molecular ion peak
(M+H)+: 439/441
Rfvalue: 0.35 (silica gel, dichloromethane/methanol = 9:1)
Example 3.39
3-(2-chloro-4-methyl-phenyl)-propynoic acid-[4-(2-diethylamino-ethoxy)-phenyl]-
methyl-amide
CF3
N
N~ I /
O
Prepared analogously to Example 2.3.f from [4-(2-diethylamino-ethoxy)-phenyl]-
methyl-amine and (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 60 mg (22 % of theory)
Melting point: 135-138 °C
C23H24CIF3N202 (M= 452.90)
Calc.: Molecular ion peak (M+H)+: 453/455 Found: Molecular ion peak
(M+H)+: 453/455
Rf value: 0.4 (silica gel, dichloromethane/methanol = 9:1)
Example 3.40
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(4-diethylaminomethyl-
phenyl)-
amide

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/ CFs
~I
N
CI
~N / O
Prepared analogously to Example 2.3.f from 4-diethylaminomethyl-phenylamine
and
(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 72 mg (59 % of theory)
C21 H20CIF3N20 (M= 408.85)
Calc.: Molecular ion peak (M+H)+: 409/411 Found: Molecular ion peak
(M+H)+: 409/411
Rfvalue: 0.35 (silica gel, dichloromethane/methanol = 9:1)
Example 3.41 3-(2-chloro-4-trifluoromethyl-phenyl)propynoic acid(4-piperidin-1-
ylmethyl-phenyl)-amide hydrochloride
~N~ O
CI
F
F F
x HCI
Prepared analogously to Example 2.3.f from 4-piperidin-1-ylmethyl-phenylamine
and
(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 170 mg (40 % of theory)
C22H20CIF3N20 (M= 420.86)
Melting point: 193-195 °C
Calc.: Molecular ion peak (M-H)-: 419/421 (CI) Found: Molecular ion peak (M-
H)-: 419/421 (CI)
Rf value: 0.5(silica gel, dichloromethane/methanol = 9:1 )

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Example 3.42
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-imidazol-1-yl-
ethoxy)-
phenyl]-amide
/ CFs
H
N' \ N
CI
O
Prepared analogously to Example 2.3.f from 4-(2-imidazol-1-yl-ethoxy)-
phenylamine
and (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 78 mg (60 % of theory)
Melting point: 182-186 °C
C21H15CIF3N302 (M=433.82)
Calc.: Molecular ion peak (M+H)+: 434/436 Found: Molecular ion peak
(M+H)+: 434/436
Rf value: 0.33 (silica gel, dichloromethane/methanol = 9:1)
Example 3.43
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-pyrazol-1-yl-
ethoxy)-
phenyl]-amide
/ c
~I
N
CI
~N
N ~O / O
F3
Prepared analogously to Example 2.3.f from 4-(2-pyrazol-1-yl-ethoxy)-
phenylamine
and (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 56 mg (43 % of theory)
Melting point: 120-125 °C
C21 H15CIF3N302 (M= 433.82)

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Calc.: Molecular ion peak (M+H)+: 434/436 Found: Molecular ion peak
(M+H)+: 434/436
Rf value: 0.6 (silica gel, dichloromethane/methanol = 9:1 )
Example 3.44
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(2-[1,2,4]triazol-4-yl-
ethoxy)-
phenyl]-amide
3
N
_I/
N~N~O /
Prepared analogously to Example 2.3.f from 4-(2-[1,2,4]triazol-4-yl-ethoxy)-
phenylamine and (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 51 mg (39.4 % of theory)
Melting point: 223-227 °C
C2pH 14CIF3N402 (M= 434.80)
Calc.: Molecular ion peak (M+H)+: 435/437 Found: Molecular ion peak
(M+H)+: 435/437
Rfvalue: 0.31 (silica gel, dichloromethane/methanol = 9:1)
Example 3.45 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid {4-[2-(4-
methyl-
piperidin-1-yl)-ethoxy]-phenyl}-amide hydrochloride
NCO ~ O
CI
N
F x HCI
F F
3.45.a. 4-methyl-1-[2-(4-nitro-phenoxy)-ethyl]-piperidine
200 mg (4.2 mmol) sodium hydride (55%) are added at 0°C to a solution
of 0.54 g
(3.83 mmol) 1-fluoro-4-nitrobenzene and 0.6 g (4.2 mmol) 2-(4-methyl-piperidin-
1-yl)-
ethanol in 10 ml of dimethylformamide under an argon atmosphere. The reaction

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mixture is stirred for two hours at 0°C and then stirred for a further
1.5 hours at
ambient temperature. The reaction mixture is evaporated down and the residue
is
extracted between water and ethyl acetate. The organic phase is dried, the
desiccant
is filtered off and the filtrate is evaporated down. The purification is
carried out by
column chromatography on silica gel (eluant: dichloromethane/methanol 9:1 )
Yield: 700 mg (69 % of theory)
C14H20N2~3 (M= 264.32)
Calc.: Molecular ion peak (M+H)+: 265 Found: Molecular ion peak (M+H)+:
265
Rf value: 0.7 (silica gel, dichloromethane/methanol = 9:1)
3.45.b. 4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylamine
A reaction mixture of 680 mg (2.57 mmol) 4-methyl-1-[2-(4-nitro-phenoxy)-
ethyl]-
piperidine and 80 mg palladium (10% on charcoal) in 10 ml of methanol is
hydrogenated at ambient temperature and 3 bar hydrogen for 4.5 hours. The
catalyst
is suction filtered and the filtrate is evaporated down.
Yield: 540 mg (90 % of theory)
C14H22N20 (M= 234.34)
Calc.: Molecular ion peak (M+H)+: 235 Found: Molecular ion peak (M+H)+:
235
Rf value: 0.33 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1 )
3.45.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid {4-[2-(4-methyl-
piperidin-
1-yl)-ethoxy]-phenyl}-amide hydrochloride
Prepared analogously to Example 3.7.c. from 4-[2-(4-methyl-piperidin-1-yl)-
ethoxy]-
phenylamine and (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid.
Yield: 230 mg (49 % of theoretical)
C24H24 CIF3N202 (M= 464.91)*HCI
Melting point: 240-245°C
Calc.: Molecular ion peak (M+H)+: 465/467 (CI) Found: Molecular ion
peak (M+H)+: 465/467 (CI)

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Rf value: 0.6 (silica gel, dichloromethane/methanol = 9:1)
The following compounds are prepared analogously to the Examples mentioned
above:
L~
R~RZN~X ~ \ O
H \ \
Q
Table 1
B
Exam le R~R2N-X L1 L2 B Q
3.52 ~ "3 -H -H , \ C H
HaCiN~
/ CI
3.53 H3~~ -H -H , \ CH
H3C~ IN~
/ CI
3. 54 -H -H \ C H
~N\i~ ,;
CI
3.55 ~ -H -H ,; \ CH
N~ I ~
CI
3.56 off -H -H - CH
N ' ,, I \
3.57 S~ -H -H ,; CH
~N~ I ,
CI
3.58 Ho -H -H CH
HsC'~~ .: I \
N
CI
3.59 -H -H ; CH
~N ' ~ I \
HO
CI

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3.60 Ho -H -H CH
HO . ~ I \
H3C
~N~ CI
,.
3.61 NHZ -H -H ; CH
. I \
/
~N~ CI
3.62 / -H -H ; \ CH
\ I N~ . I /
,.
CI
3.63 / H,c1 -H -H ,; CH
I \
~N~ /
CI
3.64 ~ -H -H ,; \ CH
N
/ CI
3.65 -H -H ; CH
/
~. CI
3.66 cH3 H -H -H ; \ CH
~ 'N~ '
H3C~ ~. /
CI
3.67 cH, -H -H ; CH
I\
CH3 ~CH3
/ CI
~N~
H3C t
3.68 H -H -H ,; CH
~N~x . I \
/ CI
3.69 cH, -H -H ; CH
I /
~N~ CI
3.70 -H -H CH
\
/~ I/
~N~ CI
,.
3.71 -H -H ; C H
- I \
/
~N~ CI
3.72 cH3 -CI -H ,; CH
. I \
HaCi ~ /
CI

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3.73 H3c1 -CI -H . ; CH
\
H3C~N
CI
3.74 -CI -H ; CH
~N~x . I \
CI
3.75 ~ -CI -H ,; \ CH
~N~x I ~
CI
3.76 °H -CI -H ; CH
\
N~ I ~
' CI
3.78 cH3 -CI -H ; CH
. I \
I ~ cl
N
H3C '.
3.79 cH3 -CI -H ; CH
1' - \
N~ I ~
CI
CH3
3.80 °~ -CI -H ,; CH
~N~ I ,
' CI
3.81 S~ -CI -H ,; CH
~N~ I
CI
3.82 nneo -C I -H ~ C H
~N ' . ~ I \
CI
3.83 Ho -CI -H ; CH
HaC.\~ .~ \
N~ I / CI
3.84 Ho -CI -H ; CH
H c ~~''
~N~ CI
'.
3.85 NHz -CI -H ; CH
- I \
~N~ CI
'.
3.86 ~ -CI -H ; CH
\ I N~ - I \
cl

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3.87 / H,c -CI -H ; \ CH
\ I ~~ I /
..
cl
3.88 Hac~N~ -CI -H ,; CH
~N~ I ,
CI
3.89 ~ -CI -H ,; \ CH
N~ I /
CI
3.90 -CI -H ; CH
/
CI
3.91 cH3 -CI -H CH
H !~ \
N
H3C /
CI
3.92 cH3 -CI -H ; CH
I \
CH3 ~CH3
~N~ CI
H3C / ~
3.93 H -CI -H ; CH
N . ! \
CI
3.94 ~ H, -CI -H ; CH
! \
N
/ CI
3.95 cH3 -CI -H ; CH
/
~N~ CI
3.96 -CI -H - CH
I/
~N~ CI
..
3.97 -CI -H ; CH
- I \
/ cl
N
3.98 ~ H3 -H -H ; N
N~ ! I \
H3C . /
CI
3.99 H,c1 -H -H r ; N
I\
H3C~N
., /
CI

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3.100 -H -H ; \ N
~N~ . I /
CI
3.101 ~ -H -H ,; \ N
~N~x
CI
3.102 off -H -H ,; \ N
N~ I /
~. CI
3.103 cH, -H -H - N
! \
N~ I /
cl
CH3
3.104 0~ -H -H ,; \ N
,
N\:~ I /
ci
3.105 S~ -H -H ,; \ N
~ INS I /
3.106 Ho -H -H ; N
H3C.~~ , \
IN ~ I /
ci
3.108 -H -H ; N
\
J~N~ ' I /
HO ~.
CI
3.109 Ho -H -H ; N
HO ! \
HsC ...., I /
~N~ CI
,.
3.110 NHZ -H -H ; N
- I \
~ /
~N~ CI
t
3.111 / -H -H ; N
I . \
C~~~N
CI
3.112 / H,c1 -H -H N
!; \
\ N~ I /
cl
3.113 H,cwN~ -H -H I - N
~N~ ~ I ~
3.114 ~ -H -H , ; N
N~ I \
/ CI

CA 02550649 2006-06-20
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3.115 -H -H ; N
1 ~ ,;
CI
3.116 cH3 -H -H - N
' !- I \
H'C ~ /
CI
3.117 cH, -H -H N
~ \
CH3 r 'CH3 . I /
~NI ~ CI
H3C/~ '.
3.118 H -H -H N
~N ' .: \
/ CI
3.119 cH3 -H -H ; N
I /
~N~ CI
''.
3.120 -H -H ; N
I /
~N~ CI
'.
3.121 -H -H ; N
. I \
/ cl
~N~
'.
3.122 ~ H, -CI -H N
\
N~
H3C ' /
CI
3.123 H3c1 -CI -H . ; N
I\
H3C~N~ /
' CI
3.124 -CI -H ; N
~N~x . I \
CI
3.125 ~ -CI -H I ; \ N
~N~x,
CI
3.126 off -CI -H ; N
N .' . I \
CI
3.127 H,c -CI -H ; N
\
\~N
'.
CI

CA 02550649 2006-06-20
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3.128 cH3 -CI -H ; N
- I \
I ~ cl
N
H3C '.
3.129 cH3 -CI -H ; N
- \
N~ I ~
cl
CH3
3.130 0~ -CI -H ,; \ N
~N~ I ,
CI
3.131 S~ -CI -H ,; \ N
'
N~ I ,
cl
3.132 nneo -CI -H ; N
\
'
\~N~ I ,
cl
3.133 H° -CI -H ; N
H3C'~~ . \
N~ I ~
' cl
3.134 Ho -CI -H ; N
~~N~ . I \
..
cl
3.135 -CI -H N
..; \
HO N
CI
3.136 Ho -CI -H N
H O~~.~, . : I \
~N~ CI
..
3.137 NHz -CI -H ; N
- I \
~N~ CI
'.
3.138 ~ -CI -H ; N
I , \
~~%~N ~ I ,
'.
CI
3.139 , H3c -CI -H ; N
\
~N~
'.
CI
3.140 H3C~N~ -CI -H ; N
~N~ I,
CI

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3.141 ~ -CI -H . - N
N~ ' I \
/ cl
3.142 -CI -H ; N
. \
Nix I /
CI
3.143 cH3 -CI -H ; N
N ~ ! \
H3c ~x, I /
CI
3.144 cH3 -CI -H ; N
I\
CH3 r 'CH3
~NI ~ CI
H3C /~
3.145 H -CI -H ; N
N . ! \
/ CI
3.146 i H3 -CI -H ,; \ N
~N
/ CI
3.147 cH3 -CI -H ; N
I /
~N~ CI
..
3.148 -CI -H ; N
/
~N~ CI
..
3.149 -CI -H ; N
- I \
/ cl
N
The following compounds are prepared analogously to Example 3.20:
cl
R~RZN~x / I O
\ N ~ I \
/ \
I/
CI
ExampleR,R2N-X educt empirical mass mp Rf value
formula spectrum [C]

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3.166 ~ 3.7.b C28H26C12N20477/79/81 160- 0.8
(C12)
"~' [M+H]+ 164 (B)
3.167 3.7.b C28Hz3C12F3N2547/49/51 128- 0.5
(C12)
~
F OZ [M+H]+ 132 (A)
F F N.h
Rf value: A= (silica gel, dichloromethane/methanol 90:10)
B= (silica gel, dichloromethane/methanol/ammonia 90:10:0.1)
Example 3.168:
3-[5-(4-chloro-phenyl)-pyridin-2-yl]-propynoic acid-[4-(4-hydroxy-piperidin-1-
ylmethyl)-
phenyl]-amide
J JN \
O
CI
Prepared analogously to Example 2.3.f from [5-(4-chloro-phenyl)-pyridin-2-yl]
propynoic acid and 4-[4-(tent-butyl-dimethyl-silanyloxy)-piperidin-1-ylmethyl]
phenylamine. The cleaving of the silyl group is carried out by adding
tetrabutylammonium fluoride to a solution of the silylether in THF.
Yield: 0.25 g (43 % of theoretical)
Melting point: 186-190 C
C26H24CIN302 (M= 445.94)
Calc.: Molecular ion peak (M+H)+: 446/448 Found: Molecular ion
peak (M+H)+: 446/448
Rf value: 0.6 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1 )

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Example 4.1:
3-(2,4-dichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-
amide
/ cl
~I
N
CI
~N~ / O
O
CI
4.1.a. [2-(2-chloro-4-vitro-phenoxy)-ethyl]-diethyl-amine
112 g (0.81 mol) potassium carbonate are added to a solution of 35 g (0.202
mol) 2-
chloro-4-vitro-phenol in 350 ml DMF. Then the reaction mixture is combined
with 35 g
(0.203 mol) (2-chloro-ethyl)-diethyl-amine hydrochloride and stirred for three
hours at
80° C and 14 hours at ambient temperature. The reaction mixture is
evaporated down
and the residue is poured onto 1000 ml of water and this mixture is extracted
three
times with ethyl acetate. The combined organic phases are dried over sodium
sulphate, the desiccant is filtered off and the filtrate is evaporated down.
Yield: 49.6 g (90 % of theoretical)
C12H17CIN203 (M= 272.73)
Calc.: Molecular ion peak (M+H)+: 273 Found: Molecular ion peak
(M+H)+: 273
Rf value: 0.36 (silica gel, dichloromethane/methanol = 90:10)
4.1.b. [2-(2-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine
Prepared analogously to Example 3.1.b from [2-(2-chloro-4-vitro-phenoxy)-
ethyl]-
diethyl-amine in methanol in a reaction time of 4.5 hours.
Yield: 36.12 g (81.8 % of theoretical)
C12H1gCIN20 (M= 242.75)
Calc.: Molecular ion peak (M+H)+: 243/245 Found: Molecular ion
peak (M+H)+: 243/245
Rf value: 0.36 (silica gel, dichloromethane/methanol = 90:10)
4.1.c. (2,4-dichloro-phenyl)-propynoic acid chloride

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A reaction mixture of 0.34 g (1.58 mmol) (2,4-dichloro-phenyl)-propynoic acid
and
0.14 ml (1.9 mmol) thionyl chloride in 15 ml absolute toluene is stirred for
three hours
at 70 °C and then evaporated down. The residue is taken up in absolute
toluene and
the solution is evaporated to dryness. This procedure is then repeated once
more and
the residue is further reacted in its crude state.
4.1.d. 3-(2,4-dichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)-
phenyl]-amide
0.37 g (1.58 mmol) (2,4-dichloro-phenyl)-propynoic acid chloride are dissolved
in 15
ml absolute toluene and while cooling with ice combined with 0.77 g (3.16
mmol) [2-
(2-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine, dissolved in 10 ml absolute
toluene,
and stirred for four hours at ambient temperature. Then the reaction mixture
is
extracted with ethyl acetate and dilute aqueous ammonia solution. The organic
phase
is extracted with water and dried over sodium sulphate. The purification is
carried out
by column chromatography on silica gel (eluant: dichloromethane/methanol= 9:1
).
The product obtained is recrystallised from petroleum ether and dried in the
vacuum
drying chamber at 50° C.
Yield: 0.21 g (30.2 % of theoretical)
Melting point: 98-100°C
C21 H21 C13N2~2 (M= 439.77)
Calc.: Molecular ion peak (M+H)+: 439/441/443 Found: Molecular ion
peak (M+H)+: 439/441/443
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ammonia = 9:1:0.1)
Example 4.2:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-
ethoxy)-phenyl]-amide

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F
H
I
\ N
~N~ / O
O
CI
4.2.a. (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid chloride
Prepared analogously to Example 4.1.c from (2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid. The compound is further reacted in its crude state.
4.2.b. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-ethoxy)-phenyl]-amide
Prepared analogously to Example 4.1.d from (2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid chloride and [2-(2-chloro-4-amino-phenoxy)-ethyl]-diethyl-
amine.
Yield: 0.26 g (27.5 % of theoretical)
C22H21 C12F3N2~2 (M= 473.32)
Calc.: Molecular ion peak (M+H)+: 473/475 Found: Molecular ion peak
(M+H)+: 473/475
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ammonia = 9:1:0.1 )
Example 4.3:
3-pyridin-2-yl-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-
amide-
hydrochloride
H
~N~
N X HCI
~/\ O / O
2~ CI
4.3.a. pyridin-2-yl-propynoic acid
6.3 ml n-butyllithium solution (1.6 M in hexane) are added dropwise at -
10°C to a
solution of 1 g (9.7 mmol) 2-ethynylpyridine in 30 ml absolute THF and stirred
for 30

CA 02550649 2006-06-20
WO 2005/063239 1 gg PCT/EP2004/014378
minutes. At -78 C dry ice is added batchwise and the reaction mixture is
allowed to
heat up to ambient temperature. After about one hour the reaction mixture is
evaporated down and the residue is taken up in 10 ml 1 N hydrochloric acid
while
cooling with ice. The precipitate is filtered off, rinsed with isopropanol and
diethyl
ether and dried in the vacuum drying chamber at 70°C.
Yield: 0.6 g (42 % of theoretical)
Melting point: 130°C
C8H5N02 (M= 147.13)
Calc.: Molecular ion peak (M+H)+: 148 Found: Molecular ion peak (M+H)+:
148
4.3.b. 3-pyridin-2-yl-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-
amide-hydrochloride
Prepared analogously to Example 2.3.f from pyridin-2-yl-propynoic acid and [2-
(2-
chloro-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.37 g (53.3 % of theoretical)
C2pH22CIN302 X HCI (M= 408.33)
Calc.: Molecular ion peak (M+H)+: 372/374 Found: Molecular ion peak
(M+H)+: 372/374
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ammonia = 9:1:0.1 )
Example 4.4:
3-biphenyl-4-yl-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-
amide
N~
O
4.4.a. 3-biphenyl-4-yl-2.3-dibromo-propanecarboxylic acid
Prepared analogously to Example 3.4.a from 3-biphenyl-4-yl-acrylic acid.

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Yield: 5 g (91.2 % of theoretical)
Melting point: 200-203°C
C15H12Br2~2 (M= 384.07)
Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid = 90:10:1)
4.4.b. biphenyl-4-yl-propynoic acid
Prepared analogously to Example 3.4.b from 3-biphenyl-4-yl-2.3-dibromo-
propanecarboxylic acid.
Yield: 2.8 g (96.8 % of theoretical)
C15H10~2 (M= 222.24)
Melting point: 170°C
Calc.: Molecular ion peak (M+H)+: 223 Found: Molecular ion peak
(M+H)+: 223
Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid = 90:10:1 )
4.4.c. biphenyl-4-yl-propynoic acid chloride
Prepared analogously to Example 4.1.c from biphenyl-4-yl-propynoic acid. The
compound is further reacted in its crude state.
4.4.d. 3-biphenyl-4-yl-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-
amide
Prepared analogously to Example 4.1.d from biphenyl-4-yl-propynoic acid
chloride
and [2-(2-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.28 g (31.3 % of theoretical)
Melting point: 105-108°C
C27H27CIN202 (M= 446.98)
Calc.: Molecular ion peak (M+H)+: 447/449 Found: Molecular ion
peak (M+H)+: 447/449
Rf value: 0.5 (silica gel, dichloromethane/ methanol/ammonia = 9:1:0.1 )

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Example 4.5:
3-(2,4,6-trichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-
amide-hydrochloride
cl , cl
H
N
CI
N~ / O X HCI
O
CI
4.5.a. triphenyl-(2,4,6-trichloro-phenylethynyl)-silane
In an argon atmosphere 9 g (34.6 mmol) 1-bromo-2,4,6-trichlorobenzene, 9.8 g
(34.45 mmol) triphenylsilylacetylene and 15 ml triethylamine are dissolved in
100 ml
absolute dioxane and at 90 °C combined with 0.2 g (1.04 mmol)
copper(I)iodide and
1.2 g (1.04 mmol) tetrakistriphenylphosphine palladium and stirred for 20
hours. The
reaction mixture is filtered through Celite and the filtrate is evaporated
down. The
residue is taken up in ethyl acetate and extracted with water. The organic
phase is
dried over sodium sulphate. The purification is carried out by column
chromatography
on silica gel (eluant: petroleum ether/ toluene= 5:1 ). The product is
recrystallised from
petroleum ether and dried in the vacuum drying chamber at 70 °C.
Yield: 6.9 g (43 % of theoretical)
Melting point: 115-120°C
C26H17C13Si (M= 463.87)
Calc.: Molecular ion peak (M+H)+: 463/465/467/469
Found: Molecular ion peak (M+H)+: 463/465/467/469
Rf value: 0.6 (silica gel, petroleum ether/ toluene= 4:1 )
4.5.b. 1,3,5-trichloro-2-ethynyl-benzene
A reaction mixture of 5 g (10.8 mmol) triphenyl-(2,4,6-trichloro-
phenylethynyl)-silane
and 4.2 g (16.2 mmol) tetrabutylammonium fluoride in 50 ml absolute THF is
stirred
for half an hour at ambient temperature and then evaporated down. The residue
is
taken up in diethyl ether and water and extracted. The organic phase is dried
over
sodium sulphate. The purification is carried out by column chromatography on
silica
gel (eluant: petroleum ether/ toluene= 9:1 ).

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Yield: 0.46 g (20.7 % of theoretical)
Rf value: 0.6 (silica gel, petroleum ether/ toluene= 9:1 )
4.5.c. (2,4,6-trichloro-phenyl)-propynoic acid
Prepared analogously to Example 4.3.a from triphenyl-(2,4,6-trichloro-
phenylethynyl)-
silane and dry ice.
Yield: 3.3 g (77.7 % of theoretical)
Melting point: 170-175°C
CgH3C1302 (M= 249.48)
Calc.: Molecular ion peak (M+H)+: 249/251/253 Found: Molecular ion
peak (M+H)+: 249/251/253
Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid = 50:10:1 )
4.5.d. 3-(2,4,6-trichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)-
phenyl]-amide-hydrochloride
Prepared analogously to Example 2.3.f from (2,4,6-trichloro-phenyl)-propynoic
acid
and [2-(2-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.72 g (82.9 % of theoretical)
Melting point: 188-191 °C
C21 H20C14N2~2 X HCI (M= 510.67)
Calc.: Molecular ion peak (M+H)+: 473/475/477/479/481
Found: Molecular ion peak (M+H)+: 473/475/477/479/481
Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia= 90:10:0.1 )
Example 4.6:
3-(2,4-dichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-propoxy)-
phenyl]-
amide-hydrochloride
/ cl
~I
N
CI X HCI
O / O
CI

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4.6.a. [2-(2-chloro-4-nitro-phenoxy)-propyl]-diethyl-amine
1.6 g (33 mmol) sodium hydride (50% in oil) are added at 0°C to a
solution of 5.3 g
(30 mmol) 3-chloro-4-fluoro-nitrobenzene and 4.3 g (33 mmol) 3-
diethylaminopropan-
1-0l in 50 ml DMF and stirred for two hours. Then the mixture is heated to
ambient
temperature and stirred for one hour. The reaction mixture is evaporated down,
combined with water and extracted with ethyl acetate. The organic phase is
dried over
sodium sulphate. The purification is carried out by column chromatography on
silica
gel (eluant: dichloromethane/methanol/ammonia= 9:1:0.1 ).
Yield: 8 g (93 % of theoretical)
C13H1gCIN203 (M= 286.76)
Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia = 90:10:0.1 )
4.6.b. [2-(2-chloro-4-amino-phenoxy)-propyl]-diethyl-amine
Prepared analogously to Example 3.1.b from [2-(2-chloro-4-nitro-phenoxy)-
propyl]-
diethyl-amine in methanol in a reaction time of 8 hours.
Yield: 6.7 g (93.5 % of theoretical)
C13H21CIN20 (M= 256.77)
Calc.: Molecular ion peak (M+H)+: 257/259 Found: Molecular ion
peak (M+H)+: 257/259
Rfvalue: 0.4 (silica gel, dichloromethane/methanol/ammonia = 50:10:0.1)
4.6.c. 3-(2,4-dichloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-
propoxy)-
phenyl]-amide-hydrochloride
Prepared analogously to Example 3.4.c from [2-(2-chloro-4-amino-phenoxy)-
propyl]-
diethyl-amine and (2,4-dichloro-phenyl)-propynoic acid
Yield: 0.62 g (84.3 % of theoretical)
Melting point: 180-185°C
C22H23C13N202 X HCI(M= 490.26)
Calc.: Molecular ion peak (M+H)+: 453/455/457/459
Found: Molecular ion peak (M+H)+: 453/455/457/459
Rf value: 0.7 (silica gel, dichloromethane/ methanol/ammonia = 50:10:0.1)

CA 02550649 2006-06-20
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Example 4.7:
3-(2,4-dichloro-phenyl)-propynoic acid-[3-methoxy-4-(2-diethylamino-ethoxy)-
phenylJ-
amide-hydrochloride
/ cl
H ~I
X HCI
CI
N~ / O
O
4.7.a. 3-(2,4-dichloro-phenyl)-propynoic acid-[3-methoxy-4-(2-diethylamino-
ethoxy)-
phenyl]-amide-hydrochloride
Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl)-propynoic
acid
chloride and [2-(2-methoxy-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.25 g (31.2 % of theoretical)
Melting point: 205-207°C
C22H24C12N2~3 X HCI (M= 471.81)
Calc.: Molecular ion peak (M+H)+: 435/437/439 Found: Molecular ion
peak (M+H)+: 435/437/439
Rf value: 0.6 (silica gel, dichloromethane/ methanol/ammonia = 50:10:0.1 )
Example 4.8:
3-(2,4-dichloro-phenyl)-propynoic acid-[2-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-
amide
/ cl
CI
N
CI X HCI
N~ / O
O
4.8.a. [2-(3-chloro-4-vitro-phenoxy)-ethyl]-diethyl-amine
Prepared analogously to Example 4.1.a from 3-chloro-4-vitro-phenol and (2-
chloro-
ethyl)-diethyl-amine hydrochloride.

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Yield: 1.25 g (79.5 % of theoretical)
C12H17CIN203 (M= 272.73)
Calc.: Molecular ion peak (M+H)+: 273/275 Found: Molecular ion
peak (M+H)+: 273/275
Rf value: 0.44 (silica gel, dichloromethane/methanol = 90:10)
4.8.b. [2-(3-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine
Prepared analogously to Example 3.1.b from [2-(3-chloro-4-nitro-phenoxy)-
ethyl]-
diethyl-amine in ethyl acetate.
Yield: 1.05 g (95.4 % of theoretical)
C12H1gCIN20 (M= 242.75)
Calc.: Molecular ion peak (M+H)+: 243/245 Found: Molecular ion
peak (M+H)+: 243/245
Rf value: 0.41 (silica gel, dichloromethane/methanol = 90:10)
4.8.c. 3-(2,4-dichloro-phenyl)-propynoic acid-[2-chloro-4-(2-diethylamino-
ethoxy)-
phenyl]-amide-hydrochloride
Prepared analogously to Example 2.3.f from (2,4-dichloro-phenyl)-propynoic
acid
chloride and [2-(3-chloro-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.53 g (65.5 % of theoretical)
Melting point: 128-130°C
C21 H21 C13N202 X HCI(M= 476.23)
Calc.: Molecular ion peak (M+H)+: 439/441/443 Found: Molecular ion
peak (M+H)+: 439/441/443
Rf value: 0.7 (silica gel, dichloromethane/ methanol/ammonia = 50:10:0.1)
Example 4.9:
3-(4-chloro-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-
amide

CA 02550649 2006-06-20
UVO 2005/063239 206 PCT/EP2004/014378
/ C
~I
N
N / O
N
4.9.a. 5-vitro-1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole
A reaction mixture of 16.22 g (0.1 mol) 5-nitroindole, 35 g (0.205 mol) 1-(2-
chloro-
ethyl)-pyrrolidine-hydrochloride and 51 g (0.369 mol) potassium carbonate in
500 ml
DMF is stirred for 48 hours at ambient temperature and then filtered. The
filtrate is
evaporated down, the residue dissolved in dichloromethane and dried over
sodium
sulphate. The desiccant is filtered off and the filtrate is evaporated down.
Yield: 25 g (96.3 % of theoretical)
C14H17N3~2 (M= 259.31)
Calc.: Molecular ion peak (M+H)+: 260 Found: Molecular ion peak
(M+H)+: 260
Rf value: 0.65 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
4.9.b.5-amino-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole
Prepared analogously to Example 3.1.b from 5-vitro-1-(2-pyrrolidin-1-yl-ethyl)-
1H-
indole in THF as solvent.
Yield: 0.83 g (93.9 % of theoretical)
C14H19N3 (M= 229.32)
Calc.: Molecular ion peak (M+H)+: 230 Found: Molecular ion peak
(M+H)+: 230
Rf value: 0.37 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1 )
4.9.c. 3-(4-chloro-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-ethyl)-1H-
indol-5-yl]-
amide
Prepared analogously to Example 3.1.e from 5-amino-1-(2-pyrrolidin-1-yl-ethyl)-
1H-
indole and (4-chloro-phenyl)-propynoic acid in THF as solvent.

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Yield: 186 mg (47.5 % of theoretical)
C23H22CIN30 (M= 391.90)
Melting point: 135-144°C
Calc.: Molecular ion peak (M+H)+: 393/394 Found: Molecular ion
peak (M+H)+: 393/394
Rf value: 0.4 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
Example 4.10:
3-(4-chloro-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-
amide
/ cl
H
N
CI
N / O
N
Prepared analogously to Example 3.1.e from 5-amino-1-(2-pyrrolidin-1-yl-ethyl)-
1H-
indole and (2,4-dichloro-phenyl)-propynoic acid in THF as solvent.
Yield: 133 mg (31.2 % of theoretical)
C23H21 C12N30 (M= 426.34)
Melting point: 127-129°C
Calc.: Molecular ion peak (M+H)+: 426/428/430 Found: Molecular ion
peak (M+H)+: 426/428/430
Rf value: 0.4 (silica gel, dichloromethane/ methanol/ammonia = 90:10:1)
Example 4.11:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[1-(2-pyrrolidin-1-yl-
ethyl)-1H-
indol-5-yl]-amide

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F I
/ w
~I
N
CI
N / O
N
F
4.11.a. ethyl (2-chloro-4-trifluoromethyl-phenyl)-propynoate
A reaction mixture of 0.556 ml (5.42 mmol) ethyl propynoate, 875 mg (2.8 mmol)
3
chloro-4-iodo-benzotrifluoride, 214 mg (0.3 mmol) bistriphenylphosphine
palladium
dichloride, 57.1 mg (0.3 mmol) copper(I)iodide and 1.17 g (3.6 mmol) caesium
carbonate in 50 ml THF is degassed and stirred for 24 hours at ambient
temperature
under an argon atmosphere. The reaction mixture is combined with a saturated
sodium hydrogen carbonate solution and twice extracted with ethyl acetate. The
combined organic phases are extracted with saturated sodium chloride solution
and
dried over sodium sulphate.
Yield: 0.65 g (43.3 % of theoretical)
C12H8CIF302 (M= 276.64)
Calc.: Molecular ion peak (M+H)+: 277/279 Found: Molecular ion
peak (M+H)+: 277/279
4.11.b. (2-chloro-4-trifluoromethyl-phenyl)-propynoic acid
0.65 g (1.175 mmol) ethyl (2-chloro-4-trifluoromethyl-phenyl)-propynoate are
dissolved in 20 ml of ethanol, combined with 2 ml 2M sodium hydroxide solution
and
stirred for three hours at ambient temperature. The reaction mixture is
evaporated
down, the residue is taken up in water and extracted with ethyl acetate. The
aqueous
phase is combined with 2 ml 1 M hydrochloric acid and stirred for one hour at
ambient
temperature. Then it is extracted three times with ethyl acetate. The combined
organic phases are dried over sodium sulphate.
Yield: 0.14 g (48 % of theoretical)
ClpH4CIF302 (M= 248.59)

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Calc.: Molecular ion peak (M-H)-: 247/249 Found: Molecular ion
peak (M-H)-: 247/249
Rf value: 0.09 (silica gel, petroleum ether/ethyl acetate= 4:1 )
4.11.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[1-(2-pyrrolidin-
1-yl-ethyl)-
1 H-indol-5-yl]-amide
Prepared analogously to Example 2.3.f from 5-amino-1-(2-pyrrolidin-1-yl-ethyl)-
1H-
indole and (2-chloro-4-trifluorophenyl)-propynoic acid.
Yield: 160 mg (66.5 % of theoretical)
C24H21 CIF3N30 (M= 459.90)
Melting point: 200-205°C
Calc.: Molecular ion peak (M+H)+: 460/462 Found: Molecular ion
peak (M+H)+: 460/462
Rf value: 0.45 (silica gel, dichloromethane/ methanol= 90:10:)
Example 4.12:
3-(2,4-dichloro-phenyl)-propynoic acid-[2-(2-pyrrolidin-1-yl-ethyl)-benzoxazol-
5-yl]-
amide
cl
~I
CN N ~N
/ CI
0 ~ o
4.12.a. 5-nitro-2-vinyl-benzoxazole
A reaction mixture of 1.54 g (10 mmol) 2-amino-4-nitrophenol, 1.36 g (10 mmol)
ethyl
3-chloropropionate and 20 g polyphosphoric acid is stirred for two hours at
170°C.
Then the mixture is neutralised by the addition of saturated sodium hydrogen
carbonate solution at ambient temperature. The aqueous phase is extracted with
dichloromethane. The organic phase is dried over sodium sulphate. The
purification is
carried out by column chromatography on silica gel (eluant:
dichloromethane/ethanol
= 20:1 ).
Yield: 0.3 g (15.8 % of theoretical)
CgHgN203 (M= 190.16)

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Calc.: Molecular ion peak (M+H)+: 191 Found: Molecular ion peak
(M+H)+: 191
Rf value: 0.8 (silica gel, dichloromethane/ethanol = 20:1 )
4.12.b.5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-benzoxazole
A solution of 1 g (5.25 mmol) 5-nitro-2-vinyl-benzoxazole and 0.66 ml (8 mmol)
pyrrolidine in 8 ml of ethanol is stirred for two hours at ambient
temperature. Then the
reaction solution is evaporated down. The purification is carried out by
column
chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia =
20:1:0.1 ).
Yield: 0.74 g (53.9 % of theoretical)
C13H15N3~3 (M= 261.28)
Calc.: Molecular ion peak (M+H)+: 262 Found: Molecular ion peak
(M+H)+: 262
Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia = 20:1:0.1 )
4.12.c. 5-amino-2-(2-pyrrolidin-1-yl-ethyl)-benzoxazole
A reaction mixture of 0.74 g (2.83 mmol) 5-nitro-2-(2-pyrrolidin-1-yl-ethyl)-
benzoxazole and 0.1 g palladium (10% on activated charcoal) in 20 ml of
ethanol is
hydrogenated for three hours at 3 bar and 20°C. The catalyst is
filtered off and the
filtrate is evaporated down.
Yield: 0.6 g (91.6 % of theoretical)
C13H17N3~ (M= 231.30)
Calc.: Molecular ion peak (M+H)+: 232 Found: Molecular ion peak
(M+H)+:232
Rf value: 0.3 (silica gel, dichloromethane/ethanol/ammonia = 20:1:0.1 )
4.12.d. 3-(2,4-dichloro-phenyl)-propynoic acid-[2-(2-pyrrolidin-1-yl-ethyl)-
benzoxazol-
5-yl]-amide
Prepared analogously to Example 3.1.e from 5-amino-2-(2-pyrrolidin-1-yl-ethyl)-
benzoxazole
and (2,4-dichlorophenyl)-propynoic acid.
Yield: 43 mg (33.1 % of theoretical)

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C22H19C12N3~2 (M= 428.32)
Melting point: 130°C
Calc.: Molecular ion peak (M+H)+: 428/430/432 Found: Molecular ion
peak (M+H)+: 428/430/432
C13H17N30 (M= 231.30)
Calc.: Molecular ion peak (M+H)+: 232 Found: Molecular ion peak
(M+H)+: 232
Rf value: 0.21 (silica gel, dichloromethane/methanol/ammonia = 10:1:0.1 )
Example: 4.13 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(2-
pyrrolidin-1-
ylmethyl-benzoxazol-5-yl)-amide
CN
~= N
O
N
F
4.13.a 2-chloromethyl-5-nitro-benzoxazole
10.5 ml (77.87 mmol) 2-chloro-orthoacetic acid are added to a solution of 12 g
(77.86
mmol) 2-amino-4-nitrophenol in 110 ml of ethanol and the whole lot is heated
for 3 h
at 80 °C. Then the reaction mixture is poured onto water, the
precipitate formed is
suction filtered and washed several times with water. The product is dried at
80°C in
the circulating air dryer.
Yield: 14.2 g (86 % of theoretical)
C8H5CIN203 (M= 212.59)
Calc.: Molecular ion peak (M+H)+: 213/215 (CI) Found: Molecular ion
peak (M+H)+: 213/215 (CI)
4.13.b. 5-nitro-2-pyrrolidin-1-ylmethyl-benzoxazole
A reaction mixture of 3 g (14.11 mmol) 2-chloromethyl-5-nitro-benzoxazole, 1.5
ml
(17.97 mmol) pyrrolidine and 3.9 g (28.22 mmol) potassium carbonate in 30 ml
of
dimethylformamide is stirred for 4 h at 50 °C. Then the reaction
mixture is diluted with

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water and covered with diisopropylether. The precipitated yellow solid is
suction
filtered, washed again and dried in the circulating air dryer at 60 °C.
Yield: 1.8 g (52 % of theoretical)
C12H13N3~3 (M= 247.25)
Calc.: Molecular ion peak (M+H)+: 248 Found: Molecular ion peak (M+H)+:
248
Rf value: 0.4 (silica gel, dichloromethane/ethanol = 20:1 )
4.13.c. 2-pyrrolidin-1-ylmethyl-benzoxazol-5-ylamine
Prepared analogously to Example 4.12.c from 5-vitro-2-pyrrolidin-1-ylmethyl-
benzoxazole.
Yield: 1.1 g (70 % of theoretical)
C12H15N3~ (M= 217.27)
Calc.: Molecular ion peak (M+H)+: 218 Found: Molecular ion peak (M+H)+:
218
Rf value: 0.6 (aluminium oxide, dichloromethane/ethanol = 20:1 )
4.13.d. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid (2-pyrrolidin-1-
ylmethyl-
benzoxazol-5-yl)-amide
Prepared analogously to Example 2.3.f from 0.2 g (0.92 mmol) 2-pyrrolidin-1-
ylmethyl-benzoxazol-5-ylamine and 0.2 g (0.8 mmol) (2-chloro-4-trifluoromethyl-
phenyl)-propynoic acid.
Yield: 290 mg (81 % of theoretical)
C22H17 CIF3N302 (M= 447.84)
Melting point: 218-223 °C
Calc.: Molecular ion peak (M+H)+: 448/450 (CI) Found: Molecular ion
peak (M+H)+: 448/450 (CI)
Rf value: 0.33 (silica gel, dichloromethane/methanol = 19:1 )
Example 4.14
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-ethoxycarbonyl-4-(2-
diethylamino-ethoxy)-phenyl]-amide

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w
F
H
I
N
N
/ O
0 ~O
4.14.a. ethyl 2-(2-diethylamino-ethoxy)-5-nitro-benzoate
1.06 g (5.00 mmol) ethyl 2-fluoro-5-nitro-benzoate and 0.58 ml (5.00 mmol) 2-
diethylaminoethanol are dissolved in 20 ml of dimethylformamide and at 0
°C 0.36 g
(7.45 mmol) sodium hydride (50%) is added. The mixture is stirred for 45
minutes at
0°C, poured onto ice water and finally extracted three times with ethyl
acetate. The
organic phase is dried over sodium sulphate, the solvent is eliminated and the
residue
is purified through a silica gel column with petroleum ether/ethyl acetate 4.1
as eluant.
Yield: 0.30 g (19 % of theory)
C15H22N2~5 (M= 310.35)
Calc.: Molecular ion peak (M+H)+: 311 Found: Molecular ion peak
(M+H)+: 311
Rf value: 0.1 (silica gel, petroleum ether/ethyl acetate 4:1 )
4.14.b. ethyl5-amino-2-(2-diethylamino-ethoxy)-benzoate
Prepared analogously to Example 3.1.b. from 0.30 g ethyl 2-(2-diethylamino-
ethoxy)-
5-nitro-benzoate in ethyl acetate.
Yield: 0.27 g (100 % of theory)
C15H24N2~3 (M= 280.37)
Calc.: Molecular ion peak (M+H)+: 281 Found: Molecular ion peak
(M+H)+: 281
Rf value: 0.40 (silica gel, dichloromethane/methanol/ammonia = 39:1:0.1)
4.14.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-ethoxycarbonyl-
4-(2-
diethylamino-ethoxy)-phenyl]-amide

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Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 120 mg (0.44 mmol) ethyl 5-amino-2-
(2-
diethylamino-ethoxy)-benzoate.
Yield: 44 mg (22 % of theory)
C25H26CIF3N204 (M= 510.94)
Calc.: Molecular ion peak (M+H)+: 511/513 Found: Molecular ion peak
(M+H)+: 511 /513
Rf value: 0.35 (silica gel, dichloromethane/methanol = 9:1)
Example 4.15
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-bromo-4-(2-
diethylamino-
ethoxy)-phenyl]-amide
H
N
NCO ~ / O
Br
4.15.a. [2-(2-bromo-4-nitro-phenoxy)-ethyl]-diethyl-amine
Prepared analogously to method 4.13.a. starting from 0.66 g (2.00 mmol) 2-
bromo-1-
fluoro-4-nitro-benzene and 0.40 ml (3.00 mmol) 2-diethylamino-ethanol.
Yield: 0.95 g (100 % of theory)
C~2H~~BrN203 (M= 317.185)
Calc.: Molecular ion peak (M+H)+: 317/319 Found: Molecular ion peak
(M+H)+: 317/319
Rf value: 0.50 (silica gel, dichloromethane /methanol 9:1).
4.15.b.3-bromo-4-(2-diethylamino-ethoxy)-phenylamine
Prepared analogously to Example 3.1.b. from 1.10 g (3.47 mmol) [2-(2-bromo-4-
nitro-
phenoxy)-ethyl]-diethyl-amine in ethyl acetate.
Yield: 0.58 g (58 % of theory)

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C12H1gBrN20 (M= 287.202)
Calc.: Molecular ion peak (M+H)+: 287/289 Found: Molecular ion
peak (M+H)+: 287/289
Rf value: 0.30 (silica gel, dichloromethane /methanol 9:1).
4.15.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-bromo-4-(2-
diethylamino-ethoxy)-phenyl]-amide
Prepared analogously to Example 2.3.f. from 450 mg (1.80 mmol) (2-chloro-4
trifluoromethyl-phenyl)-propynoic acid and 550 mg (1.92 mmol) 3-bromo-4-(2
diethylamino-ethoxy)-phenylamine.
Yield: 370 mg (40 % of theory)
C22H21 BrCIF3N202 (M= 517.77)
Calc.: Molecular ion peak (M+H)+: 517/519/521 Found: Molecular ion
peak (M+H)+: 517/519/521
Rfvalue: 0.45 (silica gel, dichloromethane/methanol = 19:1)
Example 4.16 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-bromo-4-
(2-
morpholin-4-yl-ethoxy)-phenyl]-amide
Br
~o i o
N
CI
N
F
F F
4.16.a.4-[2-(2-bromo-4-nitro-phenoxy)-ethyl]-morpholine
92 mg (1.9 mmol) sodium hydride (55%) are added at 0°C to a solution of
0.3 g (1.27
mmol) 3-bromo-4-chloro-nitrobenzene and 0.15 ml (1.27 mmol) in 20 ml of
dimethylformamide under an argon atmosphere. The reaction mixture is stirred
for
two hours at 0°C and then poured onto ice water. The aqueous phase is
extracted
three times with ethyl acetate. The organic phase is dried, the desiccant is
filtered off
and the filtrate is evaporated down. The purification is carried out by column
chromatography on silica gel (eluant: dichloromethane/methanol 19:1)
Yield: 230 mg (55 % of theory)
C12H15BrN204 (M= 331.16)

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Calc.: Molecular ion peak (M+H)+: 331/333 (Br) Found: Molecular ion
peak (M+H)+: 331/333 (Br)
4.16.b. 3-bromo-4-(2-morpholin-4-yl-ethoxy)-phenylamine
A reaction mixture of 220 mg (0.66 mmol) 4-[2-(2-bromo-4-nitro-phenoxy)-ethyl]-
morpholine and 100 mg Raney nickel in 50 ml of ethyl acetate is hydrogenated
at
ambient temperature and 3 bar hydrogen. The catalyst is suction filtered and
the
filtrate is evaporated down. The purification is carried out by column
chromatography
on aluminium oxide (eluant: petroleum ether/ethyl acetate 1:1).
Yield: 100 mg (50 % of theory)
C12H17BrN2~2 (M= 301.18)
Calc.: Molecular ion peak (M+H)+: 301/303 (Br) Found: Molecular ion
peak (M+H)+: 301/303 (Br)
4.16.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-bromo-4-(2-
morpholin-
4-yl-ethoxy)-phenyl]-amide
Prepared analogously to Example 2.3.f from 100 mg ( 0.33 mmol) 3-bromo-4-(2-
morpholin-4-yl-ethoxy)-phenylamine and 75 mg (0.3 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid.
Yield: 130 mg (82 % of theoretical)
C22H1g BrCIF3N203 (M= 531.75)
Calc.: Molecular ion peak (M+H)+: 529/531/533 (Br, CI)
Found: Molecular ion peak (M+H)+: 529/531/533 (Br, CI)
Rf value: 0.33 (aluminium oxide, petroleum ether/ethyl acetate = 1:1 )
Example 4.17
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-nitro-4-(2-
diethylamino-
ethoxy)-phenyl]-amide

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F
H
N
NCO ~ / O
O_.N~~O
4.17.a. N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide
0.74 g (7.29 mmol) potassium nitrate are added batchwise at -10 °C to a
solution of
1.52 g (6.07 mmol) N-[4-(2-diethylamino-ethoxy)-phenyl]-acetamide in 25 mL
conc.
sulphuric acid and the mixture is stirred for 1 hour at -10 °C. The
reaction mixture is
poured onto a mixture of ice and concentrated aqueous ammonia and the aqueous
phase is exhaustively extracted with ethyl acetate. The combined organic
phases are
dried over sodium sulphate and evaporated down.
Yield: 1.8 g (100 % of theory)
C14H21 N3~4 (M= 295.34)
Calc.: Molecular ion peak (M+H)+: 296 Found: Molecular ion peak (M+H)+:
296
Rf value: 0.50 (Alox, dichloromethane/methanol 39:1).
4.17.b. 4-(2-diethylamino-ethoxy)-3-nitro-phenylamine
A solution of 1.85 g (6.26 mmol) N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-
acetamide in semiconcentrated aqueous hydrochloric acid is stirred for 2 hours
at
100°C, cooled to ambient temperature, made basic with ice and
concentrated
aqueous ammonia and the aqueous phase is exhaustively extracted with ethyl
acetate. The combined organic phases are washed with water and dried over
sodium
sulphate.
Yield: 1.38 g (87% of theory)
C~2H~9N303 (M= 253.30)
Calc.: Molecular ion peak (M+H)+: 254 Found: Molecular ion peak (M+H)+:
254
Rf value: 0.68 (Alox, dichloromethane/methanol 39:1 ).

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4.17.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-vitro-4-(2-
diethylamino-
ethoxy)-phenyl]-amide
Prepared analogously to Example 2.3.f. from 450 mg (1.80 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 500 mg (1.98 mmol) 4-(2-
diethylamino-
ethoxy)-3-vitro-phenylamine.
Yield: 590 mg (68 % of theory)
C22H21 CIF3N304 (M= 483.87)
Calc.: Molecular ion peak (M+H)+: 484/486 Found: Molecular ion peak
(M+H)+:484/486
Rfvalue: 0.40 (silica gel, dichloromethane/methanol = 9:1)
Example 4.18:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(3-
diethylamino-
propoxy)-phenyl]-amide-formate
F
H
N
/ O
N O
CI
Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 110 mg (0.44 mmol) [2-(2-chloro-4-
amino-
phenoxy)-propyl]-diethyl-amine.
Yield: 49 mg (25 % of theory)
Melting point: 112-116 °C
C23H22C12F3N202 x CH202 (M= 533.37)
Calc.: Molecular ion peak (M+H)+: 487/489/491 Found: Molecular ion
peak (M+H)+: 487/489/491
Rfvalue: 0.35 (silica gel, dichloromethane/methanol = 9:1)

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Example 4.19:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-
ethoxy)-phenyl]-methyl-amide
F
N
N~0 ~ /
4.19.a. tert. butyl [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-carbamate
Prepared analogously to Method 3.1.c. starting from 3.00 g (12.4 mmol) 3-
chloro-4-(2-
diethylamino-ethoxy)-phenylamine and 2.97 g (13.6 mmol) di-tert-butyl-
pyrocarbonate
in dichloromethane.
Yield: 2.85 g (67 % of theory)
C»HZ~CIN203 (M= 342.86)
Calc.: Molecular ion peak (M+H)+: 343/345 Found: Molecular ion peak
(M+H)+: 343/345
4.19.b. [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methylamine
Prepared analogously to Example 3.1.d. from 2.85 g (8.31 mmol) tert.butyl [3-
chloro-
4-(2-diethylamino-ethoxy)-phenyl]-carbamate with 10.63 ml (24.9 mmol) 10%
lithium
aluminium hydride solution in tetrahydrofuran.
Yield: 0.72 g (34 % of theory)
C13H21CIN20 (M= 256.77)
Calc.: Molecular ion peak (M+H)+: 257/259 Found: Molecular ion
peak (M+H)+: 257/259
Rf value: 0.80 (silica gel, ethyl acetate/methanol/ammonia 9:1:0.1 ).
4.19.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-ethoxy)-phenyl]-methylamide

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Prepared analogously to Example 2.3.f. from 99 mg (0.40 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 110 mg (0.44 mmol) [3-chloro-4-(2-
diethylamino-ethoxy)-phenyl]-methylamine.
Yield: 54 mg (28 % of theory)
Melting point: 97-100° C
C23H23C12F3N2~2 (M= 487.35)
Calc.: Molecular ion peak (M+H)+: 487/489/491 Found: Molecular ion
peak (M+H)+: 487/489/491
Rf value: 0.35 (silica gel, dichloromethane/methanol = 9:1)
Example 4.20:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methoxy-4-(2-
diethylamino-
ethoxy)-phenyl]-amide-hydrochloride
CF3
N~
O
/O
Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 79 mg (0.33 mmol) [2-(2-methoxy-4-
amino-
phenoxy)-ethyl]-diethyl-amine.
Yield: 14 mg (10 % of theory)
C23H24CIF3N203 (M= 468.90)
Calc.: Molecular ion peak (M+H)+: 469/471 Found: Molecular ion peak
(M+H)+: 469/471
Rf value: 0.35 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.21:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methyl-4-(2-
diethylamino-
ethoxy)-phenyl]-amide

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CF3
~N~
O
4.21.a. diethyl-[2-(2-methyl-4-vitro-phenoxy)-ethyl]-amine
0.92 g (19.2 mmol) sodium hydride (50% in oil) are added at 0 °C under
an argon
atmosphere to a solution of 2.70 g (17.4 mmol) 2-fluoro-5-vitro-toluene and
2.54 ml
(19.2 mmol) 2-diethylaminoethanol in 50 mL DMF and the mixture is stirred for
2
hours at 0 °C and for 1 hour at ambient temperature. The solvent is
removed, the
residue is taken up in ethyl acetate and extracted with water. The organic
phase is
dried over sodium sulphate and evaporated down i. vac. . Then it is purified
by silica
gel column chromatography with dichloromethane/methanol 9:1 as eluant.
Yield: 3.1 g (71 % of theory)
C~3H2oN203 (M= 252.31)
Calc.: Molecular ion peak (M+H)+: 253 Found: Molecular ion peak (M+H)+:
253
Rf value: 0.60 (silica gel, dichloromethane/methanol 9:1 )
4.21.b. 4-(2-diethylamino-ethoxy)-3-methyl-phenylamine
3.10 g (12.3 mmol) diethyl-[2-(2-methyl-4-vitro-phenoxy)-ethyl]-amine are
dissolved in
250 mL ethyl acetate, 0.55 g Raney nickel are added and the mixture is
hydrogenated
for 36 hours at 50 psi and ambient temperature. The catalyst is filtered off
and the
filtrate is evaporated down i. vac. .
Yield: 2.70 g (99% of theory)
C~3H22N20 (M= 222.33)
Calc.: Molecular ion peak (M+H)+: 223 Found: Molecular ion peak (M+H)+:
223
Rf value: 0.35 (silica gel, dichloromethane/methanol 9:1)
4.21.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methyl-4-(2-
diethylamino-ethoxy)-phenyl]-amide

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Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 73 mg (0.33 mmol) 4-(2-diethylamino-
ethoxy)-3-methyl-phenylamine.
Yield: 134 mg (99 % of theory)
C23H24CIF3N202 (M= 452.90)
Calc.: Molecular ion peak (M+H)+: 453/455 Found: Molecular ion peak
(M+H)+: 453/455
Rf value: 0.40 (silica gel, dichloromethane/methanol = 9:1)
Example 4.22
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-amino-4-(2-
diethylamino-
ethoxy)-phenyl]-amide
H
N
NCO ~ / O
NHZ
870 mg (10.3 mmol) sodium hydrogen carbonate and 1.17 g (5.17 mmol) tin-(II)-
chloride-dihydrate are added at ambient temperature to a solution of 250 mg
(0.52
mmol) 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-nitro-4-(2-
diethylamino-
ethoxy)-phenyl]-amide in 50 ml of ethyl acetate. The mixture is refluxed for
twelve
hours. After cooling water is added and the organic phase is separated off.
The
aqueous phase is extracted twice more with ethyl acetate. The combined organic
phases are dried over sodium sulphate and the solvent is eliminated. The
purification
of the residue is carried out by column chromatography on Alox (eluant:
dichloromethane/methanol = 39:1 ).
Yield: 100 mg (43 % of theory)
Melting point: 127-130 °C
C22H23CIF3N302 (M= 453.89)

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Calc.: Molecular ion peak (M+H)+: 454/456 Found: Molecular ion
peak (M+H)+: 454/456
Rf value: 0.60 (Alox, dichloromethane/methanol = 39:1)
Example 4.23:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-diethylamino-
ethoxy)-3-
methanesulphonylamino-phenyl]-amide
H
N
N~ I /
O
O
NHS
I O
0.019 ml (0.242 mmol) methanesulphonic acid chloride are added dropwise at
0° C to
a solution of 0.1 g (0.22 mmol) 3-(2-chloro-4-trifluoromethyl-phenyl)-
propynoic acid-[3-
amino-4-(2-diethylamino-ethoxy)-phenyl]-amide in 5 ml of pyridine. The
reaction
mixture is slowly heated to ambient temperature and stirred for three hours.
Then the
reaction mixture is poured into ice water and extracted three times with ethyl
acetate.
The combined organic phases are dried over sodium sulphate and the solvent is
distilled off. The residue is freeze-dried.
Yield: 101 mg (86.3 % of theory)
Melting point: 57-60 °C
C23H25CIF3N304S (M= 531.98)
Calc.: Molecular ion peak (M+H)+: 532/534 Found: Molecular ion peak
(M+H)+: 532/534
Rfvalue: 0.32 (silica gel, dichloromethane/methanol = 9:1)
Example 4.24:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-diethylamino-
ethoxy)-3-
methoxy-phenyl]-methyl-amide

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F
N
NCO ~ / O
/O
4.24.a. tert.butyl [4-(3-diethylamino-ethoxy)-3-methoxy-phenyl]-carbamate
Prepared analogously to 3.1.c from 4-(3-diethylamino-ethoxy)-3-methoxy-
phenylamine.
Yield: 0.26 g (91.6 % of theory)
C18H3pN204 (M= 338.45)
Calc.: Molecular ion peak (M+H)+: 339 Found: Molecular ion peak (M+H)+:
339
Rf value: 0.45 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )
4.24.b. [4-(3-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine
Prepared analogously to 3.1.d from tert.butyl [4-(3-diethylamino-propoxy)-3-
methoxy-
phenyl]-carbamate.
Yield: 0.08 g (44.7 % of theory)
C14H24N2~2 (M= 252.36)
Calc.: Molecular ion peak (M+H)+: 253 Found: Molecular ion peak (M+H)+:
253
4.24.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-
diethylamino-
ethoxy)-3-methoxy-phenyl]-methyl-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and [4-(3-diethylamino-propoxy)-3-methoxy-phenyl]-methyl-amine.
Yield: 33 mg (30 % of theory)
C24H26CIF3N203 (M= 482.93)
Calc.: Molecular ion peak (M+H)+: 483/485 Found: Molecular ion peak
(M+H)+: 483/485
Rf value: 0.43 (silica gel, dichloromethane/methanol = 9:1)

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Example 4.25:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-diethylamino-
ethoxy)-3-
fluoro-phenyl]-amide
H
I
N
NCO ~ /
F
F
4.25.a. [diethyl-[3-(2-fluoro-4-vitro-phenoxy)-ethyl]-amine
Prepared analogously to 4.6.a from 3,4-difluoro-nitrobenzene and 2-
diethylaminoethanol.
Yield: 6.94 g (87.4 % of theory)
C12H17FN203 (M= 256.27)
Calc.: Molecular ion peak (M+H)+: 257 Found: Molecular ion peak (M+H)+:
257
Rf value: 0.46 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )
4.25.b.4-(3-diethylamino-ethoxy)-3-fluoro-phenylamine
Prepared analogously to 3.1.b from [diethyl-[3-(2-fluoro-4-vitro-phenoxy)-
ethyl]-amine.
Yield: 5.93 g (97.1 % of theory)
C12H1gFN20 (M= 226.29)
Calc.: Molecular ion peak (M+H)+: 229 Found: Molecular ion peak (M+H)+:
227
Rf value: 0.33 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )
4.25.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[4-(3-
diethylamino-
ethoxy)-3-fluoro-phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 4-(3-diethylamino-ethoxy)-3-fluoro-phenylamine.
Yield: 0.14 g (33.5 % of theory)
Melting point: 85-88 C

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C22H21 CIF4N202 (M= 456.87)
Calc.: Molecular ion peak (M+H)+: 455/457 Found: Molecular ion peak
(M+H)+: 455/457
Rf value: 0.35 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.26:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-
1-yl)-ethoxy]-phenyl}-amide
F I
/ w
~I
N
I CI
NCO / O
F
4.26.a. 1-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-4-methyl-piperidine
A reaction mixture of 7.8 g (27.81 mmol) 1-(2-bromo-ethoxy)-2-chloro-4-nitro-
benzene
and 10.14 ml (84 mmol) 4-methylpiperidine in 100 ml dichloromethane is stirred
for
18 hours at ambient temperature. Then the solution is purified by column
chromatography on 400 g Alox act. II-III (eluant:
dichloromethane/methanol=49:1 ).
Yield: 6.9 g (83 % of theory)
C14H19CIN203 (M= 298.77)
Calc.: Molecular ion peak (M+H)+: 209/301 Found: Molecular ion peak
(M+H)+: 209/301
Rf value: 0.48 (Alox, petroleum ether/ethyl acetate = 3:1 )
4.26.b. 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylamine
Prepared analogously to 3.1.b from 1-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-4-
methyl-
piperidine.
Yield: 3.66 g (59 % of theory)
C14H21CIN20 (M= 268.78)
Calc.: Molecular ion peak (M+H)+: 269/271 Found: Molecular ion peak
(M+H)+: 269/271

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Rfvalue: 0.52 (silica gel, dichloromethane/methanol = 9:1)
4.26.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-
methyl-
piperidin-1-yl)-ethoxy]-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-
phenylamine.
Yield: 0.33 g (66 % of theory)
C24H23C12F3N2~2 (M= 499.36)
Calc.: Molecular ion peak (M+H)+: 499/501/503 Found: Molecular ion
peak (M+H)+: 499/501 /503
Rf value: 0.68 (Alox, dichloromethane/methanol = 49:1 )
Example 4.27:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-
1-yl)-ethylamino]-phenyl}-amide
F F
/ ~F
H
N
CI
NON / O
CI
4.27.a. (2-chloro-4-nitro-phenyl)-[2-(4-methyl-piperidin-1-yl)-ethyl]-amine
A solution of 12.02 g (32.45 mmol) 2-(4-methyl-piperidin-1-yl)-ethylamine in
100 ml
DMF is combined with 17.94 g (64.82 mmol) potassium carbonate and stirred for
15
minutes at ambient temperature . Then 5.81 g (32.45 mmol) 3-chloro-4-fluoro-
nitrobenzene are added and the reaction mixture is stirred for 18 hours. Then
the
reaction mixture is poured into ice water and the crystalline residue is
filtered off.
Yield: 8.85 g (91.6 % of theory)
C14H20CIIV302 (M= 297.78)
Calc.: Molecular ion peak (M+H)+: 298/300 Found: Molecular ion peak
(M+H)+: 298/300

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4.27.b. 2-chloro-N1-[2-(4-methyl-piperidin-1-yl)-ethyl]-benzene-1,4-diamine
Prepared analogously to 3.1.b from (2-chloro-4-nitro-phenyl)-[2-(4-methyl-
piperidin-1-
yl)-ethyl]-amine.
Yield: 7 g (89.3 % of theory)
C14H22CIN3 (M= 267.80)
Calc.: Molecular ion peak (M+H)+: 268/270 Found: Molecular ion peak
(M+H)+: 268/270
Rf value: 0.6 (Alox, dichloromethane/methanol = 49:1)
4.27.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-
methyl-
piperidin-1-yl)-ethylamino]-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 2-chloro-N1-[2-(4-methyl-piperidin-1-yl)-ethyl]-benzene-1,4-
diamine.
Yield: 0.35 g (70.2 % of theory)
C24H24C12F3N30 (M= 498.38)
Calc.: Molecular ion peak (M+H)+: 455/457 Found: Molecular ion peak
(M+H)+: 455/457
Example 4.28:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-
ethylamino)-phenyl]-amide-formate
H
I
N
~/N~N I /
CI
4.28.a. N'-(2-chloro-4-nitro-phenyl)-N,N-diethyl-ethane-1,2-diamine
Prepared analogously to 4.25.a from N1,N1-diethyl-ethane-1,2-diamine and 3-
chloro-
4-fluoro-nitrobenzene.
Yield: 9.2 g (99.1 % of theory)

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C12H18CIN302 (M= 271.74)
Calc.: Molecular ion peak (M+H)+: 272/274 Found: Molecular ion peak
(M+H)+: 272/274
Rf value: 0.72 (Alox, dichloromethane/methanol = 49:1 )
4.28.b. 2-chloro-N1-(2-diethylamino-ethyl)-benzene-1,4-diamine
Prepared analogously to 3.1.b from N'-(2-chloro-4-nitro-phenyl)-N,N-diethyl-
ethane-
1,2-diamine.
Yield: 6.15 g (78 % of theory)
C12H2pCIN3 (M= 241.76)
Calc.: Molecular ion peak (M+H)+: 242/244 Found: Molecular ion peak
(M+H)+: 242/244
Rf value: 0.62 (Alox, dichloromethane/methanol = 49:1 )
4.28.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-ethylamino)-phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 2-chloro-N1-(2-diethylamino-ethyl)-benzene-1,4-diamine.
Yield: 0.17 g (32.8 % of theory)
C22H22C12F3N30 x HCOOH (M= 518.36)
Calc.: Molecular ion peak (M+H)+: 472/474/476 Found: Molecular ion
peak (M+H)+: 472/474/476
Example 4.29:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(4-methyl-
piperidin-1-
ylmethyl)-phenyl]-amide
F F
/ ~F
~I
N
CI
N / O
CI

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4.29.a. 1-(2-chloro-4-nitro-benzyl)-4-methyl-piperidine
1 g (4.85 mmol) 2-chloro-4-nitrobenzylchloride is slowly added dropwise to 2
ml
(16.22 mmol) 4-methylpiperidine at ambient temperature and the mixture is
stirred for
15 minutes. The reaction mixture is diluted with ethyl acetate and extracted
twice with
water. The organic phase is dried over sodium sulphate and evaporated down.
Yield: 1.3 g (99.7 % of theory)
C13H17CIN202 (M= 268.74)
Calc.: Molecular ion peak (M+H)+: 269/271 Found: Molecular ion peak
(M+H)+: 269/271
Rf value: 0.4 (Alox, petroleum ether)
4.29.b. 3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenylamine
Prepared analogously to 3.1.b from 1-(2-chloro-4-nitro-benzyl)-4-methyl-
piperidine.
Yield: 0.93 g (80 % of theory)
C12H20CIN3 (M= 241.76)
Calc.: Molecular ion peak (M+H)+: 242/244 Found: Molecular ion peak
(M+H)+: 242/244
Rf value: 0.59 (Alox, petroleum ether/ethyl acetate = 3:1 )
4.29.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(4-
methyl-
piperidin-1-ylmethyl)-phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-chloro-4-(4-methyl-piperidin-1-ylmethyl)-phenylamine.
Yield: 25 mg (5.3 % of theory)
C23H21 C12F3N20 (M= 469.33)
Calc.: Molecular ion peak (M+H)+: 469/471/473 Found: Molecular ion
peak (M+H)+: 469/471/473
Rf value: 0.59 (Alox, petroleum ether/ethyl acetate = 3:1 )
Example 4.30: 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(3-chloro-4-
piperidin-1-ylmethyl-phenyl)amide

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CI
N ~~~~ O
N CI
F F
F
4.30.a. 1-(2-chloro-4-nitro-benzyl)-piperidin
Prepared analogously to Example 4.29.a. from 4 ml (40 mmol) piperidine and 2 g
(9.71 mmol) 2-chloro-4-nitrobenzylchloride.
Yield: 2.39 g (97 % of theory)
C12H15CIN202 (M= 254.71)
Calc.: Molecular ion peak (M+H)+: 255/257 (CI) Found: Molecular ion
peak (M+H)+: 255/257 (CI)
Rf value: 0.32 (silica gel, petroleum ether/ethyl acetate = 6:1 )
4.30.b. 3-chloro-4-piperidin-1-ylmethyl-phenylamine
Prepared analogously to Example 3.1.b from 1-(2-chloro-4-nitro-benzyl)-
piperidine.
Yield: 1.88 g (90 % of theory)
C12H17CIN2 (M= 224.73)
Calc.: Molecular ion peak (M+H)+: 225/227 (CI) Found: Molecular ion
peak (M+H)+: 225/227 (CI)
Rf value: 0.2 (silica gel, dichloromethane/methanol = 9:1)
4.30.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(3-chloro-4-
piperidin-1-
ylmethyl-phenyl)amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-chloro-4-piperidin-1-ylmethyl-phenylamine.
Yield: 200 mg (44 % of theory)
C22H1gC12F3N20 (M= 455.3) x HCI
Calc.: Molecular ion peak (M+H)+: 455/457/459 (CI) Found: Molecular ion peak
(M+H)+: 455/457/459 (CI)
Rfvalue: 0.49 (silica gel, dichloromethane/methanol = 9:1)

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Example 4.31:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-
ethyl)-phenyl]-amide
H
I
N
~N
J
F
4.31 .a. (2-chloro-4-nitro-phenyl)-acetic acid chloride
Prepared analogously to 4.1.c from (2-chloro-4-vitro-phenyl)-acetic acid. The
product
is used in other reactions without further purification.
Yield: 8.8 g (100 % of theory)
C8H5C12N03 (M= 234.04)
4.31. b. 2-(2-chloro-4-vitro-phenyl)-N, N-d iethyl-acetamide
Prepared analogously to 4.1.d from (2-chloro-4-vitro-phenyl)-acetic acid
chloride and
diethylamine in ethyl acetate.
Yield: 3.7 g (100 % of theory)
C12H15CIN203 (M= 270.71)
Calc.: Molecular ion peak (M+H)+: 271/273 Found: Molecular ion peak
(M+H)+: 271 /273
Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:1 )
4.31.c. [2-(2-chloro-4-vitro-phenyl)-ethyl]-diethyl-amine
65 ml (65 mmol) of a 1M borane-THF solution are added dropwise to a solution
of 3.7
g (13.67 mmol) 2-(2-chloro-4-vitro-phenyl)-N,N-diethyl-acetamide in 130 ml THF
at
ambient temperature and stirred for four hours. Then the reaction mixture is
evaporated down and the residue is combined with 15 ml of methanol and 15 ml
dilute hydrochloric acid. The mixture is then stirred for 15 minutes at 100
°C, cooled
and diluted with water. Then the mixture is made alkaline with sodium
carbonate

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solution and extracted twice with ethyl acetate. The combined organic phases
are
extracted twice with water and once with saturated saline solution and dried
over
sodium sulphate. The purification is carried out by column chromatography on
Alox,
neutral, act.ll-III (eluant: petroleum ether/ ethyl acetate= 4:1 ).
Yield: 2.1 g (59.8 % of theory)
C12H17CIN202 (M= 256.73)
Rf value: 0.63 (Alox, petroleum ether/ ethyl acetate= 3:1 )
4.31.d.3-chloro-4-(2-diethylamino-ethyl)-phenylamine
Prepared analogously to 3.1.b from [2-(2-chloro-4-nitro-phenyl)-ethyl]-diethyl-
amine.
Yield: 1.8 g (100 % of theory)
C12H1gCIN2 (M= 226.75)
Calc.: Molecular ion peak (M+H)+: 227/229 Found: Molecular ion peak
(M+H)+:227/229
Rf value: 0.63 (Alox, petroleum ether/ ethyl acetate= 1:1 )
4.31.e. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-chloro-4-(2-
diethylamino-ethyl)-phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and chloro-4-(2-diethylamino-ethyl)-phenylamine.
Yield: 0.21 g (46.8 % of theory)
C22H21 C12F3N20 (M= 457.32)
Calc.: Molecular ion peak (M+H)+: 457/459/461 Found: Molecular ion
peak (M+H)+: 457/459/461
Rf value: 0.63 (Alox, petroleum ether/ ethyl acetate= 1:1 )
Example 4.32:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-
1-yl)-ethyl]-phenyl}-amide

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F F
/ ~F
~I
N
CI
~N / O
CI
4.32.a. 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine
Prepared analogously to 4.28.a to c from (2-chloro-4-nitro-phenyl)-acetic acid
chloride.
Yield: 0.71 g (99.3 % of theory)
C14H21 CIN2 (M= 252.79)
Calc.: Molecular ion peak (M+H)+: 253/255 Found: Molecular ion peak
(M+H)+: 253/255
4.32.b. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-(4-
methyl-
piperidin-1-yl)-ethyl]-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine.
Yield: 0.21 g (45.3 % of theory)
C24H23C12F3N20 (M= 483.36)
Calc.: Molecular ion peak (M+H)+: 483/485/487 Found: Molecular ion
peak (M+H)+: 483/485/487
Rf value: 0.65 (Alox, petroleum ether/ ethyl acetate= 1:1 )
Example 4.33:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-
(cyclopropyl-
methyl-amino)-ethyl]-phenyl}-amide

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F F
/ ~F
~I
N
CI
N / O
I CI
4.33.a. [(E)-2-(2-chloro-4-vitro-phenyl)-vinyl]-dimethyl-amine
A reaction mixture of 8.49 g (48 mmol) 2-chloro-4-nitrotoluene and 15.03 ml
(72.8
mmol) tert.butoxybis(dimethylamino)methane in 200 ml THF is refluxed for eight
hours. The reaction solution is evaporated down and the residue is combined
with
petroleum ether. The precipitate is filtered off, rinsed with petroleum ether
and dried at
ambient temperature under a high vacuum. The product is used in other
reactions
without further purification.
Yield: 11 g
C 1 pH 11 CIN202 (M= 226.66)
Calc.: Molecular ion peak (M+H)+: 227/229 Found: Molecular ion peak
(M+H)+: 227/229
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 3:1 )
4.33.b. (2-chloro-4-vitro-phenyl)-acetaldehyde
50 ml 1 N hydrochloric acid are added dropwise to a solution of 10 g (30.88
mmol)
[(E)-2-(2-chloro-4-vitro-phenyl)-vinyl]-dimethyl-amine in 200 ml of ethanol
and the
reaction mixture is then refluxed for one hour. Then the reaction mixture is
evaporated
down, diluted with water and twice extracted with ethyl acetate. The combined
organic
phases are dried over sodium sulphate. The purification is carried out by
column
chromatography on silica gel (eluant: petroleum ether/ ethyl acetate= 3:1 ).
Yield: 4.5 g (73 % of theory)
CBHgCIN03 (M= 199.59)
Rf value: 0.62 (silica gel, petroleum ether/ethyl acetate = 1:1 )
4.33.c. [2-(2-chloro-4-vitro-phenyl)-ethyl]-cyclopropyl-methyl-amine
1.07 g (10 mmol) N-methyl-cyclopropylamine is added to a solution of 1 g (5.01
mmol)
(2-chloro-4-vitro-phenyl)-acetaldehyde in 50 ml THF and then 4.46 g (20 mmol)
sodiumtriacetoxyborohydride (95 %) are added. The reaction mixture is stirred
for 120

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WO 2005/063239 236 PCT/EP2004/014378
hours at ambient temperature and then poured into a saturated sodium hydrogen
carbonate solution and twice extracted with ethyl acetate. The combined
organic
phases are dried over sodium sulphate. The purification is carried out by
column
chromatography on Alox, neutral, act.ll-III (eluant: petroleum ether/ ethyl
acetate=
5:1).
Yield: 0.75 g (58.8 % of theory)
C12H15CIN202 (M= 254.71)
Calc.: Molecular ion peak (M+H)+: 255/257 Found: Molecular ion peak
(M+H)+: 255/257
Rf value: 0.61 (Alox, petroleum ether/ ethyl acetate= 5:1 )
4.33.d. 3-chloro-4-[2-(cyclopropyl-methyl-amino)-ethyl]-phenylamine
Prepared analogously to 3.1.b from [2-(2-chloro-4-nitro-phenyl)-ethyl]-
cyclopropyl-
methyl-amine.
Yield: 0.6 g (100 % of theory)
C12H17CIN2 (M= 224.73)
Calc.: Molecular ion peak (M+H)+: 225/227 Found: Molecular ion peak
(M+H)+: 225/227
Rf value: 0.57 (Alox, petroleum ether/ ethyl acetate= 1:1 )
4.33.e. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-chloro-4-[2-
(cyclopropyl-methyl-amino)-ethyl]-phenyl)-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-chloro-4-[2-(cyclopropyl-methyl-amino)-ethyl]-
phenylamine.
Yield: 15 mg (3.4 % of theory)
C22H1gC12F3N20 (M= 455.31)
Calc.: Molecular ion peak (M+H)+: 455/457/459 Found: Molecular ion
peak (M+H)+: 455/457/459
Rf value: 0.3 (Alox, petroleum ether/ ethyl acetate= 3:1 )

CA 02550649 2006-06-20
WO 2005/063239 237 PCT/EP2004/014378
Example 4.34:
3-(2-chloro-4-nitro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-amide
0
II+
/ N~
O
H
N
CI
~/N~O / O
CI
4.34.a. ethyl (2-chloro-4-nitro-phenyl)-propynoate
Prepared analogously to 4.11.a from 3-chloro-4-iodo-nitrobenzene and ethyl
propynoate
Yield: 1.6 g (46.5 % of theory)
C11 H8CIN04 (M= 253.64)
Calc.: Molecular ion peak (M+H)+: 254/256 Found: Molecular ion peak
(M+H)+: 254/256
Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate = 6:1 )
4.34.b. (2-chloro-4-nitro-phenyl)-propynoic acid
Prepared analogously to 4.11.b from ethyl (2-chloro-4-nitro-phenyl)-
propynoate.
Yield: 0.76 g (66.8 % of theory)
CgH4CIN04 (M= 225.59)
Calc.: Molecular ion peak (M+H)+: 225/227 Found: Molecular ion peak
(M+H)+: 225/227
4.34.c. 3-(2-chloro-4-nitro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)-
phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-nitro-phenyl)-
propynoic acid
and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine.
Yield: 0.49 g (54.4 % of theory)
C21 H21 C12N304 (M= 450.32)
Calc.: Molecular ion peak (M+H)+: 448/450/452 Found: Molecular ion
peak (M+H)+: 448/450/452

CA 02550649 2006-06-20
WO 2005/063239 23$ PCT/EP2004/014378
Rfvalue: 0.36 (silica gel, dichloromethane/methanol = 9:1)
Example 4.35:
3-(4-bromo-2-chloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-
phenyl]-amide
/ Br
~I
N
CI
~/N~O / O
CI
4.35.a. ethyl (4-bromo-2-chloro-phenyl)-propynoate
Prepared analogously to 4.11.a from 3-chloro-4-iodo-bromobenzene and ethyl
propynoate
Yield: 0.97 g (48.2 % of theory)
C11 HBBrCl02 (M= 287.54)
Calc.: Molecular ion peak (M+H)+: 287/289/291 Found: Molecular ion
peak (M+H)+: 287/289/291
Rf value: 0.62 (silica gel, petroleum ether/ethyl acetate = 6:1 )
4.35.b. (4-bromo-2-chloro-phenyl)-propynoic acid
Prepared analogously to 4.11.b from ethyl (4-bromo-2-chloro-phenyl)-
propynoate.
Yield: 0.8 g (93.4 % of theory)
CgH4BrCl02 (M= 259.48)
Calc.: Molecular ion peak (M+H)+: 258/260/262 Found: Molecular ion
peak (M+H)+: 258/260/262
4.35.c. 3-(4-bromo-2-chloro-phenyl)-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)-phenyl]-amide
Prepared analogously to Example 2.3.f. from (4-bromo-2-chloro-phenyl)-
propynoic
acid and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine.
Yield: 0.25 g (64.5 % of theory)
C21 H21 BrC12N202 (M= 484.22)

CA 02550649 2006-06-20
WO 2005/063239 23g PCT/EP2004/014378
Calc.: Molecular ion peak (M+H)+: 483/485/487/489
Found: Molecular ion peak (M+H)+: 483/485/487/489
Rf value: 0.86 (silica gel, dichloromethane/methanol = 49:1)
The following compounds are prepared analogously to the above-mentioned
Examples:
L~
R~RzN~X I \ O
/ Lz
H \ \
I/
L3
R~RZN-X L~ L2 L3
4.36 H3 1
H3C~N~0~ -Br -CI -CF3
4.37 H3w"~oX
-Br -CI -CF3
CH3
4.38 N~oX
=Br -CI -CF3
4.39 N~oX
~J -Br -CI -CF3
H C
3
4.40 H,c
-Br -CI -CF3
CH3
4.41 cH3
"~'o" -Br -CI -CF3
CH3
4.43
-Br -CI -CF3
NJ
H3C~
4.44
-Br -CI -CF3
Me0

CA 02550649 2006-06-20
WO 2005/063239 240 PCT/EP2004/014378
4.45 N~oX
-Br -CI -CF3
HO
4.46 N~oX
Ho~ -Br -CI -CF3
H3C
4.47 H0""
~x
N _gr -CI -CF3
"o,~
H3C
4.48 N~x
HzN -Br -CI -CF3
0
4.49 ~N~oX
-Br -CI -CF3
4.50 ~N~x
-Br -CI -CF3
4.51 off
N~x -Br -CI -CF3
4.52
N -Br -CI -CF3
4.53 0 ;
-Br -CI -CF3
H3C
4.54
B
- -CI -CF3
r
HN~ y
4.55
B
- -CI -CF3
r
N
i
4.56
B CI
- - -CF3
r
HaC/~N~O:C
4.57
N~ y -Br -CI -CF3
o
~

CA 02550649 2006-06-20
WO 2005/063239 241 PCT/EP2004/014378
4.58
-Br -CI -CFs
~N
~O~
4.59 c"3
"3c~ -Br -CI -CFs
HN~ y
O ~,
4.60 c"3
cH, ~cH, -Br -CI -CFs
H3C~N~0%c
4.61 H3C N/~NX
-Br -CI -CFs
CH3
4.62 N~NX
~J -Br -CI -CFs
H C-
3
4.63 N ;
H3C~N~ x -Br -CI -CFs
H3CJ
4.64 H3c1
H C N O ; -CHs -CI -CFs
4.65 H,c~ ~oX
" ~ -CHs -CI -CFs
CH3
4.66 N~oX
-CHs -CI -CFs
4.67 N~oX
~J -CHs -CI -CFs
HC
3
4.68 H3o N~oX
-CHs -CI -CFs
CH3
4.69 cH3
N~/OX
-CHs -CI -CFs
CH3
4.70
~N ' -CHs -CI -CFs
4.71 ~N~o~
-CHs -CI -CFs
NJ
H3C ~

CA 02550649 2006-06-20
WO 2005/063239 242 PCT/EP2004/014378
4.72 N~pX
-CHs -CI -CFs
Me0
4.73 N~ox
-CHs -CI -CFs
HO
4.74 N/~oX
Ho~ -CHs -CI -CFs
H3C
4.75 Ho",~,~ N~oX
"o,,...~ -CHs -CI -CFs
H3 ~ ~C
4.76 N~pX
HZN -CHs -CI -CFs
0
4.77 ~N~x
-CHs -CI -CFs
4.78 ~N~oX
-CHs -CI -CFs
4.79 off
N~~ -CHs -CI -CFs
4.8~ / N~pX
' -CHs -CI -CFs
4.81 ~ N~oX
-CHs -CI -CFs
H3C
4.82
CH CI
- - -CFs
s
HN~Oy
4.83
CH CI
s - -CFs
-
Me'N~O~
4.84
-CHs -CI -CFs
HaC/~N~OiC
4.85
~N~o~, -CHs -CI -CFs

CA 02550649 2006-06-20
WO 2005/063239 243 PCT/EP2004/014378
4.86
-CH3 -CI -CF3
~N~O:!
4.87 c"3
"3c~ -CH3 -CI -CF3
,
HN~ y
4.88 cH3
cH3 ~cH, -CH3 -CI -CF3
H3C~N~0%c
4.89 "3c N~NX
-CH3 -CI -CF3
CH3
4.90 H .
~N~NX -CH3 -CI -CF3
H3C
4.91 H .
H'c J ~Nx -CH3 -CI -CF3
H3C
4.92 H, 1
H C N O ; -H -CI -CF3
4.93 H3cwN~oX
-H -CI -CF3
CH3
4.94 N~oX
-H -CI -CF3
4.96 H3c N~oX
-H -CI -CF3
CH3
4.97 cH,
N~ox -H -CI -CF3
CH3
4.98 ~N~o,~ -H -CI -CF3
4.99 ~N~oX
-H -CI -CF3
NJ
H3C~
4.100 N~oX
-H -CI -CF3
Me0

CA 02550649 2006-06-20
WO 2005/063239 244 PCT/EP2004/014378
4.101 N~oX
-H -CI -CF3
HO
4.102 N~oX
Ho~ -H -CI -CF3
H3C
4.103 Ho""~,~ N~oX
Ho,",J ) -H -CI -CF3
H3 ~ ~C
4.104 N~oX
HzN -H -CI -CF3
0
4.105 ~N~oX
-H -CI -CF3
4.106 ~N~Ox
-H -CI -CF3
4.107 off
N~/OX -H -CI -CF3
4.108 , N~o
' -H -CI -CF3
4.109 , N~ox
-H -CI -CF3
H3C
4.110
H I
- -C -CF3
HN~ y
4.111
H C I
- - -C F3
Me'N~O~',
4.112
-H -CI -CF3
HaC /~ N ~O:C
4.113
~N~o~, -H -CI -CF3

CA 02550649 2006-06-20
WO 2005/063239 245 PCT/EP2004/014378
4.114
-H -CI -CF3
~N~
O
4.115 cH,
"3c~ -H -CI -CF3
,
HN~oj
,
4.116 c"3
cH, ~cH, -H -CI -CF3
H3C~N~0%c
4.117 H3C N/~NX
-H -CI -CF3
CH3
4.118 H .
~NX
~N -H -CI -CF3
H3C
4.119 "
"
c
~NX
' -H -CI -CF3
J
H3C
4.120 H, 1
H C N O ; -OCH3 -CI -CF3
3
4.121 H3c~
~oX
N -OCH3 -CI -CF3
c
"
3
4.122 N~oX
-OCH3 -CI -CF3
4.123 ~oX
~N
J -OCH3 -CI -CF3
N
H3C~
4.124 N~oX
~J -OCH3 -CI -CF3
HO v
4.125 N/~oX
"o~ -OCH3 -CI -CF3
H3C
4.126 Ho"" N~oX
"o,~ -OCH3 -CI -CF3
H3C
4.127 ~N~oX
=' OCH3 -CI -CF
3

CA 02550649 2006-06-20
WO 2005/063239 246 PCT/EP2004/014378
4.128 ~N~o ;'
-OCH3 -CI -CF3
4.129
-OCH3 -CI -CF3
H3C
4.130
-OCH3 -CI -CF3
HN~Oy
4.131
N~o~, -OCH3 -CI CF3
4.132
-OCH3 -CI -CF3
~N~O:r
4.133 c"a
"ac~ -OCH3 -CI -CF3
HN~ y
4.134 c"a
CHa ~CHa -OCH3 -CI -CF3
HaC/~N~O%C
4.135 "ac N~NX
-OCH3 -CI -CF3
CHa
4.136 "
~N~/NX
-OCH3 -CI -CF3
H3C
4.137 "
"ac~N~N?~ -OCH3 -CI -CF3
"aC J
4.138 H,c~ ~oX
" ~ -CI -CI -CF3
CHa
4.139 N~oX
-CI -CI -CF3
4.140 HaC N~CX
-CI -CI -CF3
CHa

CA 02550649 2006-06-20
WO 2005/063239 247 PCT/EP2004/014378
4.141 cH3
N~o" -CI -CI -CF3
CH3
4.142
' -CI -CI -CF3
4.143
~N ' -CI -CI -CF3
N
H3C ~
4.144 N~oX
-CI -CI -CF3
Me0
4.145 N~pX
~J -CI -CI -CF3
~
HO
4.146 N~oX
Ho~ -CI -CI -CF3
H3C
4.147 Ho",
~oX
N -CI -CI -CF3
"o,~
H3C
4.148 N~o
H2N -CI -CI -CF3
O
4.149 ~N~oX
=C I -CI -CF3
4.150 ~N~oX
-CI -CI -CF3
4.151 off
N~,< -CI -CI -CF3
4.152 ~ N~oX
-CI -CI -CF3
4.153 0 ;
''
-cl -cl -cF3
H3C
4.154
CI
- -CI -CF3
HN~ y
O ,

CA 02550649 2006-06-20
WO 2005/063239 24$ PCT/EP2004/014378
4.155
-CI -CI -CF3
Me~N~O~
4.156
-CI -CI -CF3
H3C~/N~O:~
4.157
N~o~, -CI -CI -CF3
4.158
-CI -CI -CF3
~N~ ;!
O
4.159 ~H3
"3~~ -CI -CI -CF3
,
HN~ y
O ~,
4.160 ~Ha
cH3 ~CH, -CI -CI -CF3
H3C~N~0~
4.161 H3C N/~NX
-CI -CI -CF3
CH3
4.162 H .
N~/NX
~ I -CI -CF3
=C
H3C
4.163 H
"
~
~Nx
' -CI -CI -CF3
J
H3C
L~
R~RzN~X \
N
H
L3

CA 02550649 2006-06-20
WO 2005/063239 24g PCT/EP2004/014378
R~R2N-X L~ L2 L3
4.164 ~N~o~
' -CI -CI -NH2
4.165 ~ ~o\ oII
N ' CI CI ~
?~
J - - N
H
4.166 ~N~o~ , ,
' -CI -CI
4.167 ~N~o~
' -CI -CI -OMe
4.168 ~N~o~
' -CI -CI -Me
4.169 N~o
' -CI -CI -Br
4.170 N~o
' -CI -CI -N02
4.171 N~o
' -CI -CI -NH2
4.172 0 ,, o
N~ ~ CI :~
~
~ - -CI N
~ 1
H
4.173 N~o~ ,
' -CI -CI
4.174 N~o
' -CI -CI -OMe
4.175 N~o
' -CI -CI -Me
4.176
~N -CI -CI -CF
'
~ 3
,
4.177
N~~ -CI -CI -CF3
N

CA 02550649 2006-06-20
WO 2005/063239 250 PCT/EP2004/014378
4.178
N~~
-CI -CI -CF3
,
\N
4.179
N~~ -CI -CI -CF3
O
4.180
N~~ -CI -CI -CF3
\O
4.181 0
~ -CI -CI -CF
-
N~ 3
,,
4.182
~ -CI -CI -CF
~
3
N~'
,
4.183 0
N -CI -CI -CF3
N ~'
4.184
' -CI -CI -CF
~N
~ 3
,
4.185 N
-CI -CI -CF3
N ~'
,.
4.186 ~Ni
-CI -CI -CF3
N ~'
,,
4.187 0
-CI -CI -CF3
N ~'
,
4.188 i
0
-CI -CI -CF3
N ~'

CA 02550649 2006-06-20
WO 2005/063239 251 PCT/EP2004/014378
4.189
-CI -CI -CF3
,,
4.190 N
-CI -CI -CF3
,,
4.191
N~
-CI -CI -CF3
,,
4.192
t -CI -CI -CF3
N ~'
,,
4.193
~N~' -CI -CI -CF3
,
4.194
~N~' -CI -CI -CF3
,
4.195
o~N~- -CI -CI -CF3
,
4.196
~N~~ -CI -CI -CF3
,
4.197
~N~' -CI -CI -CF3
,
4.198
~N~' -CI -CI -CF3
,
4.199 /~
~N~~ -CI -CI -CF3
,
4.200
~N~' -CI -CI -CF3
,
4.201 /~
~N~~ -CI -CI -CF3
4.202
~N~' -CI -CI -CF3

CA 02550649 2006-06-20
WO 2005/063239 252 PCT/EP2004/014378
4.203
-CI -CI -CF3
o ,
4.204
-C I -C I -C F
3
,
4.205
' -CI -CI -CF3
,
4.206
,,
-CI -CI -CF3
4.207
-Me -CI -CF3
4.208
-Me -CI -CF
,,
3
4.209
-Me -CI -CF
3
4.210
' M CI CF
- - -
e 3
4.211
' -Me -CI -CF3
4.212
-Me -CI -CF3
4.213
-Me -CI -CF
3
,,
4.214
-Me -CI -CF3
4.215
-Me -CI -CF3
4.216
' -Me -CI -CF3

CA 02550649 2006-06-20
WO 2005/063239 253 PCT/EP2004/014378
4.217
~N~. -Me -CI -CF3
4.218
~N~~ -Br -CI -CF3
4.219
,,
-Br -CI -CF3
4.220
\~ -Br -CI -CF3
,
N~
,,
4.221
~N -Br -CI -CF
'
~ 3
,
4.222 n
~N B -CI -CF
~ - 3
r
4.223
~Ny -Br -CI -CF3
4.224
~N~, -Br -CI -CF3
4.225
-Br -CI -CF3
~N~'
,,
4.226
~N~~ -Br -CI -CF3
,
4.227
~N~' -Br -CI -CF3
4.228
~Ny -Br -CI -CF3
4.229
~N~ -Br -CI -CF3
,
4.230
~N~~ -Br -CI -CF3
4.231
~Ny -OMe -CI -CF3

CA 02550649 2006-06-20
WO 2005/063239 254 PCT/EP2004/014378
4.232
~N~'
-OMe -CI -CF3
,
4.233
\~ -OMe -CI -CF3
.
N~
,,
4.234
~N -OMe -CI -CF
'
~ 3
4.235
~N OM -CI -CF
~
~ - 3
e
4.236
~Ny -OMe -CI -CF3
4.237
,,
-OMe -CI -CF3
4.238
-OMe -CI -CF3
~N~'
,,
4.239
~N~' -OMe -CI -CF3
4.240
~N~' -OMe -CI -CF3
4.241
-OMe -CI -CF3
4.242
-OMe -CI -CF3
4.243
~Ny -OMe -CI -CF3
o ,
4.244
~N~'
-CI -CI -CI
,
4.245
\~ -CI -CI -CI
-
N~

CA 02550649 2006-06-20
WO 2005/063239 255 PCT/EP2004/014378
4.246
~N -CI -CI -CI
'
~
,
4.247
,,
-CI -CI -Me
4.248
\~ -CI -CI -Me
.
N~
,
4.249
~N -CI -CI -Me
'
~
4.250
~N~
-CI -CI -OMe
,
4.251
\~ -CI -CI -OMe
.
N~
4.252
~N -CI -CI -OMe
'
~
4.253
~N~'
-CI -CI
,
4.254
\ ,
~N ~- -C I -C I
,
, '
,
4.255 ,
~N -CI -CI
'
~
,,
4.256
-CI -Br -CF3
4.257
\~ -CI -Br -CF
.
N~ 3
4.258
~N -CI -Br -CF
'
~ 3
4.259
~N~'
-CI -Me -CF3

CA 02550649 2006-06-20
WO 2005/063239 256 PCT/EP2004/014378
4.260
\~ -CI -Me -CF3
,
N~
4.261
~N -CI -Me -CF
'
~ 3
4.262
~N~'
-CI -OMe -CF3
,
4.263
\
~N~, -CI -OMe -CF3
,,
4.264
~N -CI -OMe -CF
'
~ 3
4.265
~N~, -CI -F -CF3
4.266
\
~N~, -CI -F -CF3
,,
4.267
~N -CI -F -CF
~ 3
4.268 ~ N
' -CI -CI -CF3
4.269 N~ N~'
-CI -CI -CF3
Example 4.270:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-~3-methoxy-4-[2-(4-methyl-
piperidin-1-yl)-ethoxy]-phenyl}-amide
H
N
N~
O
/O

CA 02550649 2006-06-20
WO 2005/063239 257 PCT/EP2004/014378
4.270.a. 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-4-methyl-piperidine
Prepared analogously to Method 1.1.c from 1-(2-bromo-ethoxy)-2-methoxy-4-nitro-
benzene and 4-methylpiperidine.
Yield: 0.7 g (88.2 % of theory)
C~5H22N204 (M= 294.35)
Calc.: Molecular ion peak (M+H)+: 295 Found: Molecular ion peak (M+H)+:
295
Rf value: 0.5 (silica gel, dichloromethane/methanol 9:1 ).
4.270.b.3-methoxy-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylamine
Prepared analogously to Example 3.1.b. from 1-[2-(2-methoxy-4-nitro-phenoxy)-
ethyl]-4-methyl-piperidine.
Yield: 0.51 g (81.1 % of theory)
C15H24N2~2 (M= 264.37)
Calc.: Molecular ion peak (M+H)+: 265 Found: Molecular ion peak
(M+H)+: 265
Rf value: 0.3 (silica gel, dichloromethane/methanol 9:1 ).
4.270.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{3-methoxy-4-[2-
(4-
methyl-piperidin-1-yl)-ethoxy]-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-methoxy-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-
phenylamine.
Yield: 70 mg (23.5 % of theory)
Melting point: 207-209 C
C25H26CIF3N203 (M= 494.94)
Calc.: Molecular ion peak (M+H)+: 495/497 Found: Molecular ion peak
(M+H)+: 495/497
Rfvalue: 0.45 (silica gel, dichloromethane/methanol = 9:1)
Example 4.271:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-f4-[2-(3,5-dimethyl-
piperidin-1-yl)-
ethoxy]-3-methoxy-phenyl}-amide

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F f
/ w
N
CI
/ O
O
/O
F
4.271.a. 1-[2-(2-methoxy-4-vitro-phenoxy)-ethyl]-3,5-dimethyl-piperidine
Prepared analogously to Method 1.1.c from 1-(2-bromo-ethoxy)-2-methoxy-4-nitro-
benzene and 3,5-dimethylpiperidine.
Yield: 0.4 g (48.1 % of theory)
C~sHzaN2~a (M= 308.38)
Calc.: Molecular ion peak (M+H)+: 309 Found: Molecular ion peak (M+H)+:
309
Rf value: 0.5 (silica gel, dichloromethane/methanol 9:1 ).
4.271.b. 4-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine
Prepared analogously to Example 3.1.b. from 1-[2-(2-methoxy-4-vitro-phenoxy)-
ethyl]-3,5-dimethyl-piperidine.
Yield: 0.35 g (96.9 % of theory)
C15H24N2~2 (M= 264.37)
Calc.: Molecular ion peak (M+H)+: 279 Found: Molecular ion peak
(M+H)+: 279
Rf value: 0.3 (silica gel, dichloromethane/methanol 9:1 ).
4.271.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(3,5-
dimethyl-
piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 4-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-
phenylamine.
Yield: 160 mg (52.1 % of theory)
Melting point: 196-201 C
C26H28CIF3N203 (M= 508.97)

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Calc.: Molecular ion peak (M+H)+: 509/511 Found: Molecular ion peak
(M+H)+: 509/511
Rf value: 0.5 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.272:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-((S)-2-
hydroxymethyl-
pyrrolidin-1-yl)-ethoxy]-3-methoxy-phenyl)-amide
O
H
N
N
~O
/O
F
4.272.a. {(S)-1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidin-2-yl}-
methanol
Prepared analogously to Method 1.1.c from 1-(2-bromo-ethoxy)-2-methoxy-4-nitro-
benzene and (S)-1-pyrrolidin-2-yl-methanol.
Yield: 0.2 g (25 % of theory)
C~4H2oN205 (M= 296.32)
Calc.: Molecular ion peak (M+H)+: 297 Found: Molecular ion peak (M+H)+:
297
Rfvalue: 0.55 (silica gel, dichloromethane/methanol 9:1).
4.272.b. ~(S)-1-[2-(4-amino-2-methoxy-phenoxy)-ethyl]-pyrrolidin-2-yl}-
methanol
Prepared analogously to Example 3.1.b. from {(S)-1-[2-(2-methoxy-4-nitro-
phenoxy)-
ethyl]-pyrrolidin-2-yl)-methanol.
Yield: 0.15 g (83.4 % of theory)
C14H22N2~3 (M= 266.34)
Calc.: Molecular ion peak (M+H)+: 267 Found: Molecular ion peak
(M+H)+: 267
Rf value: 0.15 (silica gel, dichloromethane/methanol 9:1 ).

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4.272.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-((S)-2-
hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-3-methoxy-phenyl}-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and {(S)-1-[2-(4-amino-2-methoxy-phenoxy)-ethyl]-pyrrolidin-2-
yl)-
methanol.
Yield: 140 mg (58.9 % of theory)
Melting point: decomposition at 300 °C
C24H24CIF3N204 (M= 496.91 )
Calc.: Molecular ion peak (M+H)+: 497/499 Found: Molecular ion peak
(M+H)+:497/499
Rf value: 0.2 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.273:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methoxy-4-(2-morpholin-
4-yl-
ethoxy)-phenyl]-amide
F
I~
~N~
O
/O
4.273.a. 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine
Prepared analogously to Method 1.1.c from 1-(2-bromo-ethoxy)-2-methoxy-4-nitro-
benzene and morpholine.
Yield: 0.3 g (39.4 % of theory)
0131-1181V2~5 (NI= 282.29)
Calc.: Molecular ion peak (M+H)+: 283 Found: Molecular ion peak (M+H)+:
283
Rfvalue: 0.6 (silica gel, dichloromethane/methanol 9:1).
4.273.b. 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine

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Prepared analogously to Example 3.1.b. from 4-[2-(2-methoxy-4-vitro-phenoxy)-
ethyl]-morpholine.
Yield: 0.23 g (85.8 % of theory)
C13H2pN203 (M= 252.31)
Calc.: Molecular ion peak (M+H)+: 253 Found: Molecular ion peak
(M+H)+: 253
Rf value: 0.5 (silica gel, dichloromethane/methanol 9:1 ).
4.273.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-[3-methoxy-4-(2-
morpholin-4-yl-ethoxy)-phenyl]-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine.
Yield: 20 mg (6.9 % of theory)
Melting point: 209-211 C
C23H22CIF3N204 (M= 482.89)
Calc.: Molecular ion peak (M+H)+: 483/485 Found: Molecular ion peak
(M+H)+: 483/485
Rf value: 0.5 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.274: 3-(2-chloro-4-trifluoromethyl-phenyl)propynoic acid-{3-methoxy-
4-[2-
(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}amide
o'
NCO ~ O
\ I CI
O N
F
F F
4.274.a. 4-methoxy-1-[2-(2-methoxy-4-vitro-phenoxy)-ethyl]-piperidine
Prepared analogously to Example 1.1.c from 1g (3.62 mmol) 1-(2-bromo-ethoxy)-2-
methoxy-4-vitro-benzene and 1.25 g (10.87 mmol) 4-methoxypiperidine.
Yield: 1 g (89 % of theory)
C~SHZZN2O5 (M= 310.35)

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Calc.: Molecular ion peak (M+H)+: 311 Found: Molecular ion peak (M+H)+:
311
Rfvalue: 0.5 (silica gel, dichloromethane/methanol 9:1).
4.274.b.3-methoxy-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenylamine
Prepared analogously to Example 3.1.b. from 1 g (3.22 mmol) 4-methoxy-1-[2-(2-
methoxy-4-vitro-phenoxy)-ethyl]-piperidine.
Yield: 0.85 g (94 % of theory)
C15H24N2~3 (M= 280.36)
Calc.: Molecular ion peak (M+H)+: 281 Found: Molecular ion peak
(M+H)+: 281
Rf value: 0.6 (silica gel, dichloromethane/methanol 9:1)
4.274.c. 3-(2-chloro-4-trifluoromethyl-phenyl)propynoic acid-{3-methoxy-4-[2-
(4-
methoxy-piperidin-1-yl)-ethoxy]-phenyl}amide
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 186 mg (0.66 mmol) 3-methoxy-4-[2-
(4-
methoxy-piperidin-1-yl)-ethoxy]-phenylamine.
Yield: 20 mg (7 % of theory)
Melting point: 195-197° C
C25H26CIF3N204 (M= 510.93)
Calc.: Molecular ion peak (M+H)+: 511/513 (CI) Found: Molecular ion peak
(M+H)+:
(M+H)+: 511/513 (CI)
Rf value: 0.3 (silica gel, dichloromethane/methanol = 9:1 )
Example 4.275: 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(3,4-
dihydro-1 H-isoquinolin-2-yl)-ethoxy]-3-methoxy-phenyl)-amide-formate
~o
~ I N~~ ~
N
F

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4.275.a. 2-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-1,2,3,4-tetrahydro-
isoquinoline
Prepared analogously to Example 1.1.c from 1 g (3.622 mmol) 1-(2-bromo-ethoxy)-
2-
methoxy-4-nitro-benzene and 1.36 ml (10.87 mmol) 1,2,3,4-tetrahydro-
isoquinoline.
Yield: 1.4 g (77 % of theory)
C~$H2oN204 (M= 328.36)
Calc.: Molecular ion peak (M+H)+: 329 Found: Molecular ion peak (M+H)+:
329
Rf value: 0.7 (silica gel, dichloromethane/methanol 9:1 ).
4.275.b. 4-[2-(3,4-dihydro-1 H-isoquinolin-2-yl)-ethoxy]-3-methoxy-phenylamine
Prepared analogously to Example 3.1.b. from 1.4 g (2.77 mmol) 2-[2-(2-methoxy-
4-
nitro-phenoxy)-ethyl]-1,2.3,4-tetrahydro-isoquinolin (65 %).
Yield: 1.2 g (94 % of theory)
C18H22N2~2 (M= 298.38)
Calc.: Molecular ion peak (M+H)+: 299 Found: Molecular ion peak
(M+H)+: 299
Rf value: 0.5 (silica gel, dichloromethane/methanol 9:1 )
4.275.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-~4-[2-(3,4-
dihydro-1 H-
isoquinolin-2-yl)-ethoxy]-3-methoxy-phenyl}-amide-formate
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 304 mg (0.66 mmol) 4-[2-(3,4-
dihydro-1 H-
isoquinolin-2-yl)-ethoxy]-3-methoxy-phenylamine (65 %).
Yield: 17 mg (5 % of theory)
Melting point: 92-95 C
C28H24CIF3N203 (M=528.96) *CH202
Calc.: Molecular ion peak (M+H)+: 529/531 (CI) Found: Molecular ion peak
(M+H)+:
529/531 (CI)
Rf value: 0.55 (silica gel, dichloromethane/methanol = 9:1)
Example 4.276: 1-(2-{4- [3-(2-chloro-4-trifluoromethyl-phenyl)-propynoylamino]-
2-
methoxy-phenoxy}-ethyl)-piperidine-4-carboxylic acid amide

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~O
NCO / ~ O
N ~ CI
N
O F
F
F
4.276.a. 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-piperidine-4-carboxylic acid
amide
Prepared analogously to Example 1.1.c from 1 g (3.622 mmol) 1-(2-bromo-ethoxy)-
2-
methoxy-4-nitro-benzene and 1.4 g (10.87 mmol) piperidine-4-carboxylic acid
amide.
Yield: 1.05 g (90 % of theory)
C~5HZ~N3O5 (M= 323.34)
Calc.: Molecular ion peak (M+H)+: 324 Found: Molecular ion peak (M+H)+:
324
Rfvalue: 0.4 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1).
4.276.b. 1-[2-(4-amino-2-methoxy-phenoxy)-ethyl]-piperidine-4-carboxylic acid
amide
Prepared analogously to Example 3.1.b. from 1 g (3.1 mmol) 1-[2-(2-methoxy-4-
nitro-
phenoxy)-ethyl]-piperidine-4-carboxylic acid amide.
Yield: 0.8 g (88 % of theory)
C15H23N3~3 (M= 298.38)
Calc.: Molecular ion peak (M+H)+: 294 Found: Molecular ion peak
(M+H)+: 294
Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
4.276.c. 3-(1-(2-f4- [3-(2-chloro-4-trifluoromethyl-phenyl)-propinoylamino]-2-
methoxy-
phenoxy}-ethyl)-piperidine-4-carboxylic acid amide
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 194 mg (0.66 mmol) 1-[2-(4-amino-2-
methoxy-phenoxy)-ethyl]-piperidine-4-carboxylic acid amide.
Yield: 310 mg (98 % of theory)
Melting point: 150 °C
C25H25CIF3N304 (M=523.93)
Calc.: Molecular ion peak (M+H)+: 524/526 (CI) Found: Molecular ion peak
(M+H)+: 524/526 (CI)

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Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1)
Example 4.277: 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(2,6-
dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-amide
\O
NCO /
N
F F
4.277.a. 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2,6-dimethyl-
piperidinePrepared
analogously to Example 1.1.c from 1 g (3.622 mmol) 1-(2-bromo-ethoxy)-2-
methoxy-
4-nitro-benzene and 1.5 ml (10.87 mmol) 2,6-dimethyl-piperidine.
Yield: 0.85 g (76 % of theory)
C~6H2aIV24a (M= 308.37)
Calc.: Molecular ion peak (M+H)+: 309 Found: Molecular ion peak (M+H)+:
309
Rf value: 0.55 (silica gel, dichloromethane/methanol 9:1 ).
4.277.b.4-[2-(2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine
Prepared analogously to Example 3.1.b. from 0.84 g (2.72 mmol) 1-[2-(2-methoxy-
4-
nitro-phenoxy)-ethyl]-2,6-dimethyl-piperidine.
Yield: 0.65 g (86 % of theory)
C16H26N2~2 (M= 278.39)
Calc.: Molecular ion peak (M+H)+: 279 Found: Molecular ion peak
(M+H)+: 279
Rf value: 0.1 (silica gel, dichloromethane/methanol 9:1 )
4.277.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-(2,6-
dimethyl-
piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-amide
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 185 mg (0.663 mmol) 4-[2-(2,6-
dimethyl-
piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine.

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Yield: 150 mg (49 % of theory)
Melting point: 225-227° C
C2gH28CIF3N203 (M=508.96)
Calc.: Molecular ion peak (M+H)+: 509/511 (CI) Found: Molecular ion peak
(M+H)+:
509/511 (CI)
Rf value: 0.2 (silica gel, dichloromethane/methanol 9:1 )
Example 4.278: 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-
(cyclopropylmethyl-methyl-amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride
~o
NCO / O
CI x HCI
N
F
F F 4.278.a.
cyclopropylmethyl-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-methyl-amine
Prepared analogously to Example 1.1.c from 1 g (3.62 mmol) 1-(2-bromo-ethoxy)-
2-
methoxy-4-nitro-benzene and 900 mg (10.57 mmol) cyclopropyl-methyl-amine.
Yield: 0.95 g (94 % of theory)
C~4HZONZ04 (M= 280.32)
Calc.: Molecular ion peak (M+H)+: 281 Found: Molecular ion peak (M+H)+:
281
Rfvalue: 0.4 (silica gel, dichloromethane/methanol 9:1).
4.278.b.4-[2-(cyclopropylmethyl-methyl-amine)-ethoxy]-3-methoxy-phenylamine
Prepared analogously to Example 3.1.b. from 950 mg (3.4 mmol)
cyclopropylmethyl-
[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-methyl-amine.
Yield: 0.68 g (80 % of theory)
C14H22N2~2 (M= 250.34)
Calc.: Molecular ion peak (M+H)+: 251 Found: Molecular ion peak
(M+H)+: 251
Rfvalue: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)

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4.278.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-
(cyclopropylmethyl-
methyl-amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 166 mg (0.66 mmol) 4-[2-
(cyclopropylmethyl-methyl-amine)-ethoxy]-3-methoxy-phenylamine.
Yield: 130 mg (45 % of theory)
Melting point: 173-176 C
C24H24CIF3N203 (M=480.91 ) *HCI
Calc.: Molecular ion peak (M+H)+: 481/483 (CI) Found: Molecular ion peak
(M+H)+:
481/483 (CI)
Rf value: 0.2 (silica gel, dichloromethane/methanol 9:1)
Example 4.279: 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-
(cyclopropylmethyl-propyl-amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride
~o
O
\ ~ CI
x HCI
F
F F 4.279.a.
cyclopropylmethyl-[2-(2-methoxy-4-vitro-phenoxy)-ethyl]-propyl-amine
Prepared analogously to Example 1.1.c from 1 g (3.62 mmol) 1-(2-bromo-ethoxy)-
2-
methoxy-4-vitro-benzene and 1.51 ml (10.57 mmol) cyclopropyl-methyl-propyl-
amine.
Yield: 0.95 g (85 % of theory)
C~sH2aN20a (M= 308.37)
Calc.: Molecular ion peak (M+H)+: 309 Found: Molecular ion peak (M+H)+:
309
Rf value: 0.4 (silica gel, dichloromethane/methanol 9:1 ).
4.279.b. 4-[2-(cyclopropylmethyl-propyl-amino)-ethoxy]-3-methoxy-phenylamine
Prepared analogously to Example 3.1.b. from 950 mg (3.1 mmol)
cyclopropylmethyl-
[2-(2-methoxy-4-vitro-phenoxy)-ethyl]-propyl-amine.
Yield: 0.74 g (86 % of theory)

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C16H26N202 (M= 278.39)
Calc.: Molecular ion peak (M+H)+: 279 Found: Molecular ion peak
(M+H)+: 279
Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
4.279.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-{4-[2-
(cyclopropylmethyl-
propyl-amino)-ethoxy]-3-methoxy-phenyl}-amide-hydrochloride
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) (2-chloro-4-
trifluoromethyl-phenyl)-propynoic acid and 185 mg (0.66 mmol) 4-[2-
(cyclopropylmethyl-propyl-amino)-ethoxy]-3-methoxy-phenylamine.
Yield: 180 mg (59 % of theory)
Melting point: 185-188° C
C2gH28CIF3N203 (M=508.96) '~HCI
Calc.: Molecular ion peak (M+H)+: 509/511 (CI) Found: Molecular ion peak
(M+H)+:
509/511 (CI)
Rf value: 0.35 (silica gel, dichloromethane/methanol 9:1)
Example 4.281:
3-(3-bromo-biphenyl-4-yl)-propynoic acid-f3-chloro-4-[2-(4-methyl-piperidin-1-
yl)-
ethyl]-phenyl}-amide
ci
N / I o
\ Br
N
/ \
/
4.281 a. 3-bromo-biphenyl-4-ylamine
8.7 ml (76.8 mmol) of a 48% hydrogen bromide solution are added dropwise to a
solution of 13.008 g (76.8 mmol) biphenyl-4-ylamine in 60 ml DMSO at ambient
temperature and the mixture is stirred for 14 hours. Then it is heated to 100
°C for one
hour, the mixture is then cooled and poured onto water. By the addition of
ammonia

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solution the reaction mixture is made alkaline and the precipitate formed is
filtered off
and washed with water. The purification is carried out by column
chromatography on
silica gel (eluant: dichloromethane).
Yield: 11.3 g (60 % of theory)
C12H10BrN0 (M= 248.19)
Calc.: Molecular ion peak (M+H)+: 248/250 (CI) Found: Molecular ion peak
(M+H)+: 248/250 (CI)
4.281 b. 3-iodo-biphenyl-4-ylamine
A solution of 7.3 g (29.4 mmol) 3-bromo-biphenyl-4-ylamine in 120 ml acetic
acid is
mixed with 6 ml concentrated hydrochloric acid at ambient temperature, cooled
to
15°C and stirred for 30 minutes. A solution of 2 g (28.9 mmol) sodium
nitrite in 7 ml of
water is slowly added dropwise to this reaction mixture at 15 °C and
stirred for 30
minutes. Then at 5°C a solution of 5.4 g (32.5 mmol) potassium iodide
in 28 ml of
water is slowly added dropwise and the mixture is stirred. After 30 minutes
2.95g
sodium thiosulphate are added and the mixture is stirred for a further 30
minutes.
Then the reaction mixture is evaporated down and combined with water/ethyl
acetate.
The aqueous phase is again extracted with ethyl acetate, the combined aqueous
phases are extracted once with water and dried over sodium sulphate. The
purification is carried out by column chromatography on silica gel (eluant:
petroleum
ether).
Yield: 6.6 g (85 % of theory)
C12H8Brl (M= 359.00)
Calc.: Molecular ion peak (M)+: 358/360 (Br) Found: Molecular ion peak (M)+:
358/360 (Br)
4.281 c. (3-bromo-biphenyl-4-ylethynyl)-tert-butyl-dimethyl-silane
Prepared analogously to 1.1.d from 3-iodo-biphenyl-4-ylamine and tent butyl-
ethynyl-
dimethyl-silane.
Yield: 0.52 g (72 % of theory)
C20H23BrSi (M= 371.38)
Calc.: Molecular ion peak (M+H)+: 371/373 (Br) Found: Molecular ion peak
(M+H)+: 371/373 (Br)

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4.281.d 3-bromo-4-ethynyl-biphenyl
1.99 ml (1.99 mmol) of a 1 M tetrabutylammonium fluoride solution in THF are
added
batchwise at 5 °C to a solution of 495 mg (1.33 mmol) (3-bromo-biphenyl-
4-ylethynyl)-
tert-butyl-dimethyl-silane in 8 ml anhydrous THF. The reaction mixture is
stirred for
another 30 minutes at ambient temperature and evaporated down. The residue is
combined with diethyl ether and water and the organic phase is dried over
sodium
sulphate.
Yield: 0.34 g (99 % of theory)
Cl4HgBr (M= 257.12)
Calc.: Molecular ion peak (M-H)-: 255/257 (Br) Found: Molecular ion peak (M-H)-
:
255/257 (Br)
4.281 e. (3-bromo-biphenyl-4-yl)-propynoic acid
Prepared analogously to 4.3.a from 3-bromo-4-ethynyl-biphenyl and carbon
dioxide.
Yield: 2.5 g (89% of theory)
ClSHgBr02 (M= 301.13)
Calc.: Molecular ion peak (M+H)+: 301/303 (Br) Found: Molecular ion peak
(M+H)+: 301/303 (Br)
Rf value: 0.3 (silica gel, dichloromethane/methanol 90:10)
4.281.f. 3-(3-bromo-biphenyl-4-yl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-1-
yl)-ethyl]-phenyls-amide
Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine.
Yield: 0.24 g (50% of theory)
C2gH28BrCIN20 (M= 535.90)
Calc.: Molecular ion peak (M+H)+: 535/37/39 Found: Molecular ion peak
(M+H)+: 535/37/39
Rf value: 0.48 (silica gel, dichloromethane/methanol 90:10)

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Example 4.282:
3-(3-bromo-biphenyl-4-yl)-propynoic acid-[3-chloro-4-(2-diethylamino-ethyl)-
phenyl]-
amide-hydrochloride
ci
~N / I o
\ Br
N
/ \
/
Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-(2-diethylamino-ethyl)-phenylamine.
Yield: 95 mg (23.8% of theory)
C27H26BrCIN20 * HCI(M= 546.32)
Calc.: Molecular ion peak (M+H)+: 509/11/13 Found: Molecular ion peak
(M+H)+: 509/11 /13
Rf value: 0.3 (silica gel, dichloromethane/methanol 90:10)
Example 4.283:
3-(3-bromo-biphenyl-4-yl)-propynoic acid-[3-chloro-4-(2-pyrrolidin-1-yl-ethyl)-
phenyl]-
amide
ci
N / I o
\ N \ Br
/ \
Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl)-propynoic
acid
and 3-chloro-4-(2-pyrrolidin-1-yl-ethyl)-phenylamine.
Yield: 140 mg (27.2% of theory)
C27H24BrCIN20 I(M= 507.84)
Calc.: Molecular ion peak (M+H)+: 507/09/11 Found: Molecular ion peak
(M+H)+: 507/09/11

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Example 4.284:
3-(3-bromo-biphenyl-4-yl)-propynoic acid-{3-chloro-4-[2-(4-hydroxy-4-
trifluoromethyl-
piperidin-1-yl)-ethyl]-phenyls-amide
0
F
F ~ l CI
F N / ~ O
Br
N
/ \
/
Prepared analogously to Example 2.3.f. from (3-bromo-biphenyl-4-yl)-propynoic
acid
and 1-[2-(4-amino-2-chloro-phenyl)-ethyl]-4-trifluoromethyl-piperidin-4-ol.
Yield: 36 mg (10.5% of theory)
C2gH25BrCIF3N202 (M= 605.87)
Calc.: Molecular ion peak (M+H)+: 605/07/09 Found: Molecular ion peak
(M+H)+: 605/07/09
Example 4.285:
3-pyridin-3-yl-propynoic acid-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-
amide
~N~° I \ o
J
N
Prepared analogously to Example 2.3.f from pyridin-3-yl-propynoic acid and [2-
(2-
chloro-4-amino-phenoxy)-ethyl]-diethyl-amine.
Yield: 0.42 g (66.4 % of theoretical)
Melting point: 118-120°C
C20H22CIN302 (M= 371.86)
Calc.: Molecular ion peak (M+H)+: 372/374 Found: Molecular ion peak
(M+H)+: 372/374
Rf value: 0.4 (silica gel, dichloromethane/ methanol/ammonia = 9:1:0.1)

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Example 5.1:
(E)-N-(4'-methoxy-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylamide
o~
I
o i
~\N
N I ~ H
5.1.a. ethyl (E)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylate
2 g (7.43 mmol) ethyl (E)-3-(4-bromomethyl-phenyl)-acrylate are added to a
suspension of 0.69 ml (8.2 mmol) pyrrolidine and 2.05 g (14.86 mmol) potassium
carbonate in 40 ml DMF and stirred for 18 hours at ambient temperature. The
reaction
mixture is evaporated down and the residue is extracted with water and ethyl
acetate.
The organic phase is dried over sodium sulphate, evaporated down and the
residue is
purified by column chromatography on silica gel (eluant:
dichloromethane/methanol/ammonia = 90:10:1).
Yield: 0.3 g (15.6 % of theoretical)
C16H21 N02 (M= 259.35)
Calc.: Molecular ion peak (M+H)+: 260 Found: Molecular ion peak
(M+H)+: 260
Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia 90:10:1 )
5.1.b. (E)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-acrylic acid
A reaction mixture of 0.3 g (1.15 mmol) ethyl (E)-3-(4-pyrrolidin-1-ylmethyl-
phenyl)-
acrylate and 0.4 g (9.53 mmol) lithium hydroxide-monohydrate in 20 ml of a 1:1
mixture of methanol, THF and water is stirred for 48 hours at ambient
temperature.
Then the reaction mixture is evaporated down, the residue is diluted with
water and
acidified with hydrochloric acid. The mixture is evaporated down, combined
with
methanol and dichloromethane, filtered and the filtrate is evaporated to
dryness.
Yield: 0.27 g
C14H17N~2 (M= 231.29)

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WO 2005/063239 274 PCT/EP2004/014378
Calc.: Molecular ion peak (M+H)+: 232 Found: Molecular ion peak
(M+H)+: 232
Rf value: Starting spot (silica gel, dichloromethane/methanol/ammonia 90:10:1
)
5.1.c. (E)-N-(4'-methoxy-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-
acrylamide
Prepared analogously to 3.1.e from (E)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-
acrylic acid
and 4'-methoxy-biphenyl-4-yl-amine.
Yield: 74 mg (15.4 % of theoretical)
Melting point: 199-200° C
C27H28N202 (M= 412.53)
Calc.: Molecular ion peak (M+H)+: 413 Found: Molecular ion peak
(M+H)+: 413
Rf value: 0.77 (silica gel, dichloromethane/ methanol/ ammonia = 80:20:1 )
Example 5.2:
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-
acrylamide
ci
o i
~ ~N
N ~ ~ H
5.2.a. (E)-3-(4-dimethoxymethyl-phenyl)-acrylic acid
38.81 ml (0.354 mmol) trimethylorthoformate are added to a suspension of 25 g
(0.141 mol) (E)-3-(4-formyl-phenyl)-acrylic acid in 350 ml of methanol and the
mixture
is refluxed for 48 hours. After cooling the reaction mixture is filtered and
the filtrate is
evaporated down. The residue is taken up in 500 ml dichloromethane and
filtered
through Celite . The filtrate is evaporated down to 150 ml and cooled to
0°C. The
precipitate formed is filtered off, washed with dichloromethane/petroleum
ether (1:1 )
and dried at 60 °C in the circulating air dryer.
Yield: 12.05 g (31.5 % of theoretical)
C12H14~a (M= 222.24)

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WO 2005/063239 275 PCT/EP2004/014378
Calc.: Molecular ion peak (M+H)+: 245 Found: Molecular ion peak
(M+H)+: 245
Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate = 1:1 )
5.2.b. (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-dimethoxymethyl-phenyl)-acrylamide
Prepared analogously to 3.1.e from (E)-3-(4-dimethoxymethyl-phenyl)-acrylic
acid and
4'-chloro-biphenyl-4-yl-amine.
Yield: 9.8 g
C24H22CIN03 (M= 407.90)
Calc.: Molecular ion peak (M+H)+: 408/410 Found: Molecular ion
peak (M+H)+: 408/410
Rf value:0.3 (silica gel, dichloromethane/ethanol 20:1 )
5.2.c. (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-formyl-phenyl)-acrylamide
70 ml of water and 21 ml trifluoroacetic acid are added to a suspension of 9.8
g
(24.02 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-dimethoxymethyl-phenyl)-
acrylamide in 280 ml chloroform and the reaction mixture is stirred for eight
hours at
ambient temperature. It is diluted with chloroform and water, the organic
phase is
separated off and extracted with water. The organic phase is dried, filtered
through
silica gel and the solvent is distilled off.
Yield: 5.5 g
C22H16CINOZ (M= 361.83)
Calc.: Molecular ion peak (M+H)+: 362/364 Found: Molecular ion
peak (M+H)+: 362/364
Rf value:0.6 (silica gel, cyclohexane/ethyl acetate 1:1 )
5.2.d. (E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methyl-piperidin-1-ylmethyl)-
phenyl]-
acrylamide
Prepared analogously to 4.30.c from (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
formyl-
phenyl)-acrylamide and 4-methyl-piperidine.
Yield: 80 mg (21.7 % of theoretical)
Melting point: 207-208 C
C28H2gCIN20 (M= 445.00)

CA 02550649 2006-06-20
WO 2005/063239 27g PCT/EP2004/014378
Calc.: Molecular ion peak (M+H)+: 445/447 Found: Molecular ion
peak (M+H)+: 445/447
Rf value: 0.76 (silica gel, dichloromethane/ methanol = 10:1 )
Example 5.3:
(E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(cis-3,5-dimethyl-piperidin-1-ylmethyl)-
phenyl]-
acrylamide
ci
o i
~ ~N
N ~ / H
5.3.a. (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-hydroxymethyl-phenyl)-acrylamide
A solution of 4.4 g (12.16 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-formyl-
phenyl)-
acrylamide in 200 ml THF is adjusted with glacial acetic acid to a pH of
three,
combined with 8.14 g (36.48 mmol) sodium triacetoxyborohydride and stirred for
18
hours at ambient temperature. Then the reaction mixture is poured into water
and the
precipitate is filtered off. The filtrate is extracted with ethyl acetate,
washed with water
and dried over sodium sulphate. The solvent is removed and the residue is
combined
with the solid which has been filtered off. The purification is carried out by
column
chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=
30:1:0.1).
Yield: 3.2 g (72.4 % of theoretical)
C22H18CIN02 (M= 363.84)
Calc.: Molecular ion peak (M+H)+: 364/366 Found: Molecular ion
peak (M+H)+: 364/366
Rf value: 0.2 (silica gel, dichloromethane/ethanol = 20:1 )
5.3.b. (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-chloromethyl-phenyl)-acrylamide
A suspension of 2.1 g (5.77 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
hydroxymethyl-
phenyl)-acrylamide in 100 ml dichloromethane is with 1.7 ml (12.19 mmol)
triethylamine and then combined with 0.46 ml (5.88 mmol) methanesulphonic acid
chloride. The reaction mixture is stirred for three hours at ambient
temperature,

CA 02550649 2006-06-20
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diluted with water and extracted several times with dichloromethane. The
combined
organic phases are dried over sodium sulphate, filtered through silica gel and
the
filtrate is evaporated down.
Yield: 0.4 g (18.1 % of theoretical)
C22H17C12N0 (M= 382.29)
Calc.: Molecular ion peak (M+H)+: 381/383/385 Found: Molecular ion
peak (M+H)+: 381/383/385
5.3.c. (E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-(cis-3,5-dimethyl-piperidin-1-
ylmethyl)-
phenyl]-acrylamide
Prepared analogously to 1.2.c from (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-
phenyl)-acrylamide and cis-3,5-dimethylpiperidine.
Yield: 30 mg (30 % of theoretical)
Melting point: 217-218 C
C2gH31 CIN20 (M= 459.03)
Calc.: Molecular ion peak (M+H)+: 459/461 Found: Molecular ion
peak (M+H)+: 459/461
The following compounds are prepared analogously to Example 5.3.c:
CI
0
N
I
R~R2N~x / H
Example R,R2N-X educt empirical mass mp Rf value
formula
spectrum [C]
5.4 0 5.3.b C28H29CINz02461/463 205- 0.4
[M+H]+ 206 (A)

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WO 2005/063239 27$ PCT/EP2004/014378
5.5 0~ 5.3.b C26H25CIN202 432/435 184- 0.6
~N~ [M+H]+ 185 (A)
5.6 5.3.b C28H28CIN302 474/476 254- 0.05
N ~N [M+H]+ 255 (A)
~
5.7 I 5.3.b C28H29CIN202 461/463 196- 0.2
o~N~ [M+H]+ 197 (A)
5.8 0~ 5.3.b C28H29CIN202 461/463 190- 0.1
N~ [M+H]+ 191 (A)
5.9 - 5.3.b C26H2sCIN202 433/435 178- 0.14
~N~ [M+H]+ 179 (A)
5.10 5.3.b C2~H2~CIN202 447/449 192- 0.2
-f [M+H]+ 193 (A)
N~
5.11 5.3.b C28HZ9CIN202 461/463 212 0.25
0
N~ [M+H]+ (B)
5.12 ~N~ 5.3.b C2~H28CIN30 446/448 216 0.2
~N~
[M+H] (B)
5.13 ~ 5.3.b C26H2sCIN20 417/419 219 0.25
N
[M+H]+ (B)
Rf value: A= (silica gel, dichloromethane/methanol (10:1 )
B= (silica gel, dichloromethane/methanol/ammonia (10:1:0.1 )
Example 5.14.
(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-cyclopropylaminomethyl-phenyl)-acrylamide
/ ci
I
o I w
N /
~O~/N I /

CA 02550649 2006-06-20
~.NO 2005/063239 27g PCT/EP2004/014378
A reaction mixture of 100 mg (0.26 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-phenyl)-acrylamide, 70 mg (0.77 mmol) 2-methoxy-ethylmethylamine
and 140 mg (1 mmol) potassium carbonate in 10 ml acetone is agitated for 24
hours
at reflux temperature. The reaction mixture is evaporated down. The residue is
purified by column chromatography on silica gel (eluant:
dichloromethane/ethanol/ammonia 20/1/0.1)
Yield: 92 mg (81 % of theoretical)
Melting point: 222-223°C
C2gH27CIN202 (M= 434.96)
Calc.: Molecular ion peak (M+H)+: 435/37(CI) Found: Molecular ion peak
(M+H)+: 435/37(CI)
Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia = 20:1:0.1)
The following compounds are prepared analogously to Example 5.14:
/ CI
0
N
I
R~RZN~X / H
ExampleR,RZN-X educt empirical mass mp Rf value
formula
spectrum [C]
5.15 5.3.b C28H28CIN30 458/460 206- 0.1
N
[M+H]+ 207 (B)
N
5.16 ~ 5.3.b C29H3oCIN30 472/474 223- 0.2
[M+H]+ 224 (A)
5.17 ~ 5.3.b C2~HZ~CIN20 431/433 246- 0.4
[M+H]+ 247 (B)
5.18 ~ 5.3.b C3oH2~CIN20 467/469 210- 0.6
I I
\ N
[M+H]+ 212 (A)

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WO 2005/063239 280 PCT/EP2004/014378
5.19 ~ 5.3.b CZ9H3~CIN202 475/477 181 0.35
~~
N ~,!
[M+H]+ (A)
5.20 ~ ~ ~ 5.3.b C3~H2gCIN2O2 497 188- 0.35
~N~i [M+H]+ 189 (A)
0
5.21 I 5.3.b C29H3~CIN20 459/461 262- 0.4
~N~ [M+H]+ 263 (A)
5.22 ~ 5.3.b C26H2sCIN20 417/419 238- 0.5
[M+H]+ 239 (B)
5.23 5.3.b C28H29CIN202 461/463 212- 0.45
[M+H]+ 213 (A)
~N~
5.24 5.3.b C26H25CIN203S481/83 264- 0.45
o' ~N [M+H]+ 266 (B)
5.25 5.3.b C3~H33CIN20 485/87 250 0.35
[M+Hl+ (B)
N
5.26 I 5.3.b CZ6H2aCIN30 430/32 160- 0.45
Ni~N''r [M+H]+ 161 (B)
5.27 ~ 5.3.b C29H33CIN203 493/95 125- 0.4
[M+H]+ 126 (A)
O~N
5.28 ~ 5.3.b C3~H34CIN30 500/02 209- 0.15
[M+H]+ 210 (A)
~N
Rf value: A= (silica gel, dichloromethane/ethanol/ammonia (20:1:0.1 )
B= (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)
Example 5.29: (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(4-methyl-
cyclohexyl)amino]-methyl}-phenyl)-acrylamide

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WO 2005/063239 2$1 PCT/EP2004/014378
Ct
0
I ~ ~N
N
5.29.a. 4-[(E)-2-(4'-chloro-biphenyl-4-ylcarbamoyl)-vinyl]-benzyl
methanesulphonate
A suspension of 2.3 g (6.3 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
hydroxymethyl-
phenyl)-acrylamide in 200 ml dichloromethane is combined with 1.94 ml (13.9
mmol)
triethylamine and then with 0.54 ml (6.92 mmol) methanesulphonic acid
chloride. The
reaction mixture is stirred for 18 hours at ambient temperature, diluted with
water and
extracted several times with dichloromethane. The combined organic phases are
dried over sodium sulphate, filtered through silica gel and the filtrate is
evaporated
down.
Yield: 1.85 g (67 % of theoretical)
C23H2pCIN04S (M= 441.93)
Calc.: Molecular ion peak (M+H)+: 442/444 (CI) Found: Molecular ion
peak (M+H)+: 442/444 (CI)
Rf value: 0.73 (silica gel, dichloromethane/methanol/ammonia = 90:10: 1 )
5.29.b. (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(4-methyl-
cyclohexyl)amino]-
methyl}-phenyl)-acrylamide
A reaction mixture of 100 mg (0.226 mmol) 4-[(E)-2-(4'-chloro-biphenyl-4-
ylcarbamoyl)-vinyl]-benzyl methanesulphonate, 37.34 mg (0.29 mmol) methyl-(4-
methyl-cyclohexyl)-amine and 0.1 ml triethylamine in 10 ml dichloromethane is
stirred
for 18 hours at ambient temperature. Then the reaction mixture is extracted
between
water and dichloromethane, the organic phase is separated off, dried and
evaporated
down. The residue is purified by column chromatography on silica gel (eluant:
dichloromethane/methanol/ammonia 90:10:1 ).
Yield: 52 mg (49 % of theoretical)
C30H33CIN20 (M= 473.05)
Melting point: 227-258°C
Calc.: Molecular ion peak (M+H)+: 473/475 (CI) Found: Molecular ion
peak (M+H)+: 473/475 (CI)

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~llO 2005/063239 2$2 PCT/EP2004/014378
Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia = 90:10:1 )
The following compounds are prepared analogously to Example 5.29.b:
CI
0
N
I
R~R2N~X / H
ExampleR~RZN-X educt empirical mass mp Rf
formula [C]
spectrum value
5.30 ~ 5.29.aC29H3~CIN202 475/477 225- 0.37
(CI)
265 A
0 [M+HJ+ (
)
5.31 ~ 529.a C29H3zCIN30 474/476 226- 0.6
(CI)
N~N~ [M+HJ+ 254 (A)
~
5.32 ~ 5.29.aC3oH33CIN20 473/475 205- 0.42
(CI)
N~ [M+HJ+ 210 (A)
Rf value: A= (silica gel, dichloromethane/methanol/ammonia (90:10:1)
Example 5.33:
(E)-N-(4'chloro-biphenyl-4-yl)-3-(4-cyclohexylaminomethyl-phenyl)-acrylamide
ci
0
i
~,. _ N
N

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WO 2005/063239 2$3 PCT/EP2004/014378
0.082 ml (0.72 mmol) cyclohexylamine are added to a suspension of 150 mg (0.39
mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-chloromethyl-phenyl)-acrylamide in
5 ml of
tetrahydrofuran and the mixture is refluxed for 18 h. Then the reaction
mixture is
poured onto water and the precipitate formed is suction filtered. Further
purification is
carried out by column chromatography on silica gel (eluant:
dichloromethane/methanol 95:5 - 50:50).
Yield: 70 mg (40 % of theoretical)
C28H2gCIN20 (M= 444.99)
Melting point: 247-248°C
Calc.: Molecular ion peak (M+H)+: 445/447 (CI) Found: Molecular ion
peak (M+H)+: 445/447 (CI)
Example 5.34: (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-~[(2-hydroxy-cyclohexyl)-
methyl-
amino]-methyl)-phenyl)-acrylamide
\ ci
o \ I /
p I / \ N I /
\I
Prepared analogously to Example 5.33. from (E)-N-(4'-chloro-biphenyl-4-yl)-3-
(4-
chloromethyl-phenyl)-acrylamide and 2-methylamino-cyclohexanol.
Yield: 90 mg (48 % of theoretical)
C2gH31 CIN202 (M= 475.02)
Melting point: 210-211 °C
Calc.: Molecular ion peak (M+H)+: 475/477 (CI) Found: Molecular ion
peak (M+H)+: 475/477 (CI)
Example 5.35: tent-butyl 4-({-[(E)-2-(4'-chloro-biphenyl-4-ylcarbamoyl)-vinyl]-
benzyl)-
methyl-amino)-piperidine-1-carboxylate

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WO 2005/063239 2$4 PCT/EP2004/014378
O
I ~ ~N
N
O N
O
0.5 g (2.34 mmol) tent butyl 4-methylamino-piperidine-1-carboxylate are added
to a
suspension of 300 mg (0.79 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-
phenyl)-acrylamide in 5 ml of dimethylformamide and the mixture is stirred for
18 h at
80 °C. Then the reaction mixture is poured onto water and the
precipitate formed is
suction filtered. Further purification is carried out by stirring out from a
little methanol.
Yield: 200 mg (45 % of theoretical)
C33H38CIN303 (M= 560.13)
Melting point: 168-169°C
Calc.: Molecular ion peak (M+H)+: 560/562 (CI) Found: Molecular ion
peak (M+H)+: 560/562 (CI)
Example 5.36: (E)-N-(4'chloro-biphenyl-4-yl)-3-{4[(methyl-piperidin-4-yl-
amino)-
methyl]-phenyl}-acrylamide x trifluoroacetic acid acetate
c~
o I
i
N X F3CCOOH
N
1 ml trifluoroacetic acid are added to a suspension of 170 mg (0.3 mmol) tent-
butyl 4-
({-[(E)-2-(4'-chloro-biphenyl-4-ylcarbamoyl)-vinyl]-benzyl}-methyl-amino)-
piperidine-1-
carboxylate (Example 5.35) in 25 ml dichloromethane and the mixture is stirred
for 18
h at ambient temperature. Then the solvent is evaporated down and the residue
is
crystallised from ethyl acetate/diisopropylether 1:1. The precipitated solid
is suction
filtered and dried at 60°C in the circulating air dryer.
Yield: 70 mg (40 % of theoretical)
C28H3pCIN30 (M= 460.02)* trifluoroacetic acid acetate
Melting point: 207-208°C

CA 02550649 2006-06-20
1~V0 2005/063239 2$5 PCT/EP2004/014378
Calc.: Molecular ion peak (M+H)+: 460/462 (CI) Found: Molecular ion
peak (M+H)+: 460/462 (CI)
Example 5.37:
(E)-3-(4-{[(1-acetyl-piperidin-4-yl)-methyl-amino]-methyl}-phenyl)-N-(4'-
chloro-
biphenyl-4-yl)-acrylamide
\ ci
\ I ~
o I
N i
N \
N
O
0.017 ml (0.18 mmol) acetic anhydride are added to a solution of 50 mg (0.087
mmol)
(E)-N-(4'chloro-biphenyl-4-yl)-3-{4[(methyl-piperidin-4-yl-amino)-methyl]-
phenyl}-
acrylamide x trifluoroacetic acid acetate in 4 ml acetic acid and the mixture
is stirred
for 18 hours at ambient temperature. Then the reaction mixture is poured onto
water
and made basic with ammonia. The precipitate formed is suction filtered and
washed
with water. The product is dried at 60 °C in the circulating air dryer.
Yield: 20 mg (46 % of theoretical)
C30H32CIN302 (M= 502.05)
Melting point: 225-226°G
Calc.: Molecular ion peak (M+H)+: 502/504 (CI) Found: Molecular ion
peak (M+H)+: 502/504 (CI)
Example 5.38:
(E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-{[cyclohexyl-(2-hydroxy-ethyl)-amino]-
methyl}-
phenyl)-acrylamide
ci
0 0
\ I
I v ~N
N \
0.24 g (1.7 mmol) 2-cyclohexylamino-ethanol are added to a suspension of 130
mg
(0.34 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-chloromethyl-phenyl)-
acrylamide in
70 ml of dimethylformamide and the mixture is stirred for 48 hours at 80
°C. Then the

CA 02550649 2006-06-20
WO 2005/063239 2$g PCT/EP2004/014378
reaction mixture is poured onto water and the precipitate formed is suction
filtered and
washed with water. The solid is dried in the circulating air dryer at
50°C .
Yield: 20 mg (10 % of theoretical)
C30H33CIN202 (M= 489.05)
Melting point: 178-179°C
Calc.: Molecular ion peak (M+H)+: 489/491 (CI) Found: Molecular ion
peak (M+H)+: 489/491 (CI)
Example 5.39:
(E)-N-(4'-chloro-biphenyl-4-yl)-3-{4-[(cyclopentyl-methyl-amino)-methyl]-
phenyl}-
acrylamide
\ ci
o \ I /
/ \ N I /
\I
A reaction mixture of 200 mg (0.523 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-phenyl)-acrylamide, 295 mg (1.56 mmol) cyclopentyl-methyl-amine
oxalic acid acetate and 0.44 ml (3.12 mmol) triethylamine in 5 m1 of
tetrahydrofuran is
refluxed for 18 hours. Then the reaction mixture is poured onto water and the
precipitate formed is suction filtered. Further purification is carried out by
column
chromatography on silica gel (eluant: dichloromethane/methanol 10:1).
Yield: 10 mg (4 % of theoretical)
C28H2gCIN20 (M= 445.0)
Melting point: 209-210°C
Calc.: Molecular ion peak (M+H)+: 445/447 (CI) Found: Molecular ion
peak (M+H)+: 445/447 (CI)
The following compounds are prepared analogously to Example 5.3.c:

CA 02550649 2006-06-20
WO 2005/063239 2$7 PCT/EP2004/014378
O ~ \
\
\ \u 'N
RRN~ ~ / H
2 X
Example R~ RZN-X L~ L2
5.40 ~ H CI
N
5.41 H CI
N
5.42 ~ H CI
~N~
O / \
\
\ \u 'N
RRN~ ~ / H
z X
Example R~RZN-X L~ L2
5.43 I F CI
O~N
5.44 n N F C I
5.45 I F CI
O~N
5.46 ~ F CI
~O~\/N~
5.47 F CI
N
L2
L2

CA 02550649 2006-06-20
WO 2005/063239 2$$ PCT/EP2004/014378
5.48 ~ F CI
N
5.49 I F CI
~N
5.50 ~ F CI
N
5.51 F CI
N
5.52 F CI
N
5.53 ~ F CI
N
5.54 ° F CI
~N~
5.55 F CI
N
O
5.56 ° F CI
N ~N~
5.57 0~ F CI
~N~
5.58 ~ F CI
~N~
5.59 ~ F CI
N
5.60 I F CI
~°~/N~
5.61 ~ F CI
wl
5.62 I F CI
~~N
N
5.63 0~~ I F CI
N

CA 02550649 2006-06-20
V'JO 2005/063239 2$9 PCT/EP2004/014378
5.64 ~ I I F CI
O~/N
5.65 I F CI
~N~
5.66 ~ F CI
~N~
O / \
\ \~ ~ N
I
RRN~ ~ / H
1 2 X 1
ExampleR~RzN-X L1 L2
5.67 I H CF3
O~N
5.68 n N H CF3
'~\~
5.69 I H CF3
O~N
5.70 ~ H CF3
~O~\/N Wig,'
5.71 H CF3
N
5.72 ~ H CF3
N
5.73 I H CF3
~N~
5.74 ~ H CF3
N
L2

CA 02550649 2006-06-20
WO 2005/063239 2gQ PCT/EP2004/014378
5.75 H CF3
N
5.76 H CF3
N
5.77 ~ H CF3
N
5.78 ° H CF3
~N~
5.79 H CF3
N
O
5.80 ° H CF3
N
5.81 ~ H CF3
N
5.82 ~ H CF3
~N~
5.83 ~ H CF3
N
5.84 I H CF3
°~N
5.85 ~ I H CF3
w I N
5.86 N H CF3
N
5.87 0~ I H C F3
N
5.88 ~ I I H CF3
°~/N~
5.89 N H CF3

CA 02550649 2006-06-20
WO 2005/063239 291 PCT/EP2004/014378
5.90 H CF3
o~
~N~
/
O / \
\
\ \~ ~ N
I
R~RzN~X ~ / H L~
L2
Example R~RZN-X
5.91 I H Me
O~N
5.92 ~N H Me
5.93 I H Me
°~N~
5.94 ° H Me
~o~N
5.95 H Me
N
5.96 ~ H Me
N
5.97 I H Me
~N~
5.98 ~ H Me
N
5.99 H Me
N
5.100 H Me
N

CA 02550649 2006-06-20
WO 2005/063239 2g2 PCT/EP2004/014378
5.101 ~ H Me
N
5.102 H Me
~N~
5.103 H Me
N
O
5.104 H Me
N
1
~
5.105 ~ H Me
N
5.106 ~ H Me
~N~
5.107 ~ H Me
N
5.108 I H Me
~~/N~
5.109 ~ H Me
\ I N
5.110 I H Me
,~N~
N
5.111 0~I H Me
N
5.112 ~ I I H Me
\ ~/N~
5.113 I H Me
~N~
5.114 ~ H Me
~N~

CA 02550649 2006-06-20
WO 2005/063239 2g3 PCT/EP2004/014378
L2
O
\ \u
R~R2N~X / H L~
Example R~RZN-X L~ L2
5.115 I H F
O~N
5.116 ~N H F
5.117 I H F
O~N
5.118 ~ H F
°~N
5.119 H F
N
5.120 ~ H F
N
5.121 I H F
~N
5.122 ~ H F
N
5.123 H F
N~%
5.124 H F
N
5.125 ~ H F
N
5.126 ° H F
~N~

CA 02550649 2006-06-20
.WO 2005/063239 2g4 PCT/EP2004/014378
5.127 H F
N
O
5.128 H F
N
~.N~.%r
5.129 ~ H F
N
5.130 ~ H F
~N~
5.131 ~ H F
N
5.132 I H F
~''~.'N\%!
5.133 ~ I I H F
\ N
5.134 I H F
/~N~
N
5.135 0~~ ~ H F
N
5.136 ~ ~ i H F
\ ~N~
5.137 I H F
~N
5.138 ~ H F
~N~
O
I
\N
R~ R2N ~X / H L~
L2
Example ~ R~ R2N-X L~ LZ

CA 02550649 2006-06-20
lfVO 2005/063239 295 PCT/EP2004/014378
5.139 I F CF3
O~N
5.140 ~N F CF3
5.141 I F CF3
O~N
5.142 ~ F CF3
~°~N
5.143 F CF3
N
5.144 ~ F CF3
N
5.145 I F CF3
~N
5.146 ~ F CF3
N
5.147 F CF3
N V%
5.148 F CF3
N
5.149 ~ F CF3
N
5.150 ° F C F3
~N~
5.151 F CF3
N
O
5.152 ° F CF3
N ~N~
5.153 ~ F CF3
N

CA 02550649 2006-06-20
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5.154 ~ F CF3
~N~
5.155 ~ F CF3
N
5.156 I F CF3
~O~/NWi!
5.157 ~ I I F CF3
\ N
5.158 I F CF3
~~N~r
N
5.159 0~~ I F CF3
N
5.160 ~ ~ I F CF3
\ O~/N\i!
5.161 I F CF3
~N~
5.162 ~ F CF3
~N~
Lz
O
R~RZN~X / H L~
ExampleR~ R2N-X L~ L2
5.163 I F Me
O~N
5.164 N F Me
~
5.165 I F Me
O~N

CA 02550649 2006-06-20
WO 2005/063239 297 PCT/EP2004/014378
5.166 ~ F Me
°~N
5.167 F Me
N
5.168 ~ F Me
N
5.169 I F Me
~N
5.170 ~ F Me
N
5.171 F Me
N~!
5.172 F Me
N
5.173 ~ F Me
N
5.174 ° F Me
~N~
5.175 F Me
N
O
5.176 ° F Me
N ~N~
5.177 ~ F Me
N
5.178 ~ F Me
~N~
5.179 ~ F Me
N
5.180 I F Me
~O~/N~

CA 02550649 2006-06-20
WO 2005/063239 2g$ PCT/EP2004/014378
5.181 ~ F Me
\ I N
5.182 I F Me
/~N~
N
5.183 0~~ I F Me
N
5.184 ~ i ~ F Me
\ O~/N\i~
5.185 I F Me
~N~
5.186 ~ F Me
~N~
/ Lz
O / ~ \.~
N
I
R~RZN~X / H L~
Example R~RZN-X L~ L2
5.187 I F F
O~N
5.188 ~N F F
5.189 I F F
O~N\
5.190 ~ F F
~O~/N~
5.191 F F
N

CA 02550649 2006-06-20
WO 2005/063239 2gg PCT/EP2004/014378
5.192 ~ F F
N
5.193 I F F
~N~
5.194 ~ F F
N
5.195 F F
N~%
5.196 F F
N
5.197 ~ F F
N
5.198 ° F F
~N~
5.199 F F
N
O
5.200 ° F F
5.201 ~ F F
N
5.202 ~ F F
~N~
5.203 ~ F F
N
5.204 I F F
°~N
5.205 ~ I I F F
\ N
5.206 I F F
~~N
N
5.207 0~ I F F
N

CA 02550649 2006-06-20
~/VO 2005/063239 300 PCT/EP2004/014378
5.208 ~ ~ I F F
~~/N~
5.209 I F F
~N~
5.210 ~ F F
~N~
Example 6.1:
N-(4'-methoxy-biphenyl-4-yl)-3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionamide
o~
0
N \
N ~ i
A reaction mixture of 60 mg (0.14 mmol) (E)-N-(4'-methoxy-biphenyl-4-yl)-3-(4-
pyrrolidin-1-ylmethyl-phenyl)-acrylamide and 10 mg Raney nickel in 30 ml of
methanol
is hydrogenated for four hours. The catalyst is filtered off and the filtrate
is evaporated
to dryness.
Yield: 56 mg (93.2% of theoretical)
Melting point: 185-188 °C
C27H3pN202 (M= 414.55)
Calc.: Molecular ion peak (M+H)+: 415 Found: Molecular ion peak
(M+H)+: 415
Rf value: 0.29 (silica gel, dichloromethane/methanol/ammonia = 90:10:1 )
Example 6.2:
N-(4'-chloro-biphenyl-4-yl)-3-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-
propionamide
~'"

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WO 2005/063239 301 PCT/EP2004/014378
A reaction mixture of 80 mg (0.18 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-[4-
(4-
methyl-piperidin-1-ylmethyl)-phenyl]-acrylamide and 20 mg Raney nickel in 15
ml of
ethyl acetate and 15 ml of methanol is hydrogenated for one hour at 50 psi and
ambient temperature. The catalyst is filtered off, the filtrate is evaporated
to dryness
and stirred with diisopropylether.
Yield: 40 mg (49.7 % of theoretical)
Melting point: 150-151 ° C
C28H31 CIN20 (M= 447.02)
Calc.: Molecular ion peak (M+H)+: 447/449 Found: Molecular ion
peak (M+H)+: 447/449
Rfvalue: 0.5 (silica gel, dichloromethane/methanol = 10:1)
The following compounds are prepared analogously to Example 6.2.:
c
0
N
R~R2N~x / H
Ex. R~R2N-X educt empirical mass mp Rf
formula spectrum [C] value
6.3 0 5.4 C28H3~CIN202463/465 143- 0.4
~N~ [M+H]+ 144 (A)
6.4 0~ 5.5 C26HZ~CIN202435/437 193-
~'N~ [M+H]+ 194
6.5 5.6 C28H3oCIN302476/478 240-
N
[M+H]+ 241
6.6 0'~ 5.8 CZ$H3~CIN202463/465 185- 0.1
I
~ [M+H]+ 186 (A)
NS
6.7 - 5.9 C26H2~CIN202435/437 171- 0.14
~N~ [M+H]+ 172 (A)

CA 02550649 2006-06-20
!NO 2005/063239 302 PCT/EP2004/014378
6.8 5.10 CZ~H29CINZ02 449/451 156- 0.2
[M+H]+ 157 (A)
6.9 5.11 CZ8H3~CIN202 463/465 192 0.25
0
[M+H]+ (B)
6.10 ~N~ 5.12 C2~H3oCIN30 448/450 172 0.2
[M+H]+ (g)
6.11 ~ 5.13 C26H2~CIN20 419 183- 0.25
[M+H]+ 184 (B)
Rf value: A, B as specified hereinbefore
C= (silica gel, dichloromethane/ethanol/ammonia 20/1/0.1)
Example 6.12:
N-(4'-chloro-biphenyl-4-yl)-3-(4-{[methyl-(tetrahydro-pyran-4-yl)-amino]-
methyl}-
phenyl)-propionamide
ci
N
O
A reaction mixture of 60 mg (0.13 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-
{[methyl-
(tetrahydro-pyran-4-yl)-amino]-methyl}-phenyl)-acrylamide and 20 mg Raney
nickel in
10 ml N,N-dimethylformamide is hydrogenated for three hours at 50 psi and
ambient
temperature. The catalyst is filtered off and the filtrate is evaporated to
dryness. The
purification is carried out by column chromatography on silica gel (eluant:
dichloromethane/methanol/ammonia 20/1/0.1)
Yield: 22 mg (29 % of theoretical)
Melting point: 167-173 C
C28H31 CIN202 (M= 463.01 )
Calc.: Molecular ion peak (M+H)+: 463/65 (CI) Found: Molecular ion peak
(M+H)+: 463/65 (CI)

CA 02550649 2006-06-20
WO 2005/063239 303 PCT/EP2004/014378
The following compounds are prepared analogously to Example 6.12.:
/ CI
o iI
N
I I
R~R2N~X / H
Example R~RZN-X educt empirical mass mp
formula spectrum [C]
6.13 I 5.17 Cz~H29CINZ0 433/35 156
(CI)
~
N
[M+H]+
6.14 ~ 5.27 C29H35CINZ03 495/97 108-
(CI)
[M+H]+ 109
~o~N~
6.15 N 5.22 C26H2~CINzO 418/20 191-
(CI)
+
[M+H] 192
6.16 ~ 5.16 C29H32CIN30 474/76 177
(CI)
N~:,- [M+H]+
6.17 I 5.14 C26H29CIN202 437/39 138
(CI)
~~~/N~
[M+Hl+
6.18 ~ I I 5.18 C3H29CIN20 469/71 174-
(CI)
w N~ [M+H]+ 175
6.19 0~~ I 5.19 C29H33CIN202 477/79 162-
(CI)
N~ [M+H]+ 163
6.20 ~ I I 5.20 C3~H3~CIN202 499/501 122-
o~'N~ (CI) 124
[M+H]+
6.21 ~ 5.23 C2gH3~CIN2O2 463/65 158.5-
(CI)
~N~
[M+H]+ 160.5
6.22 N 5.21 C29H33CIN20 461/63 201-
(CI)
[M+H]+ 204

CA 02550649 2006-06-20
WO 2005/063239 304 PCT/EP2004/014378
6.23 5.15 CZ$H3oCIN30 460/62 143-
(CI)
\N [M+H]+ 144
N
6.24 ~ 5.24 C26H2~CIN203S483/85 198-
(CI)
o ~N~;! [M+H]+ 201
6.25 ~ 5.28 C3~H36CIN30 502/04 168.8
(CI)
[M+H]+
6.26 5.3.c C29HssCIN20 461/63 164-
(CI)
[M+H]+ 169
N
6.27 ~ 5.26 C26H3oCIN30 436/38 165
(CI)
N~/N~ +
[M+H]
6.28 5.25 C3~H35CIN20 487/89 201.5
(CI)
[M+H]+
Example 6.29
N-(4'chloro-biphenyl-4-yl)-3-[4-(R)-3-hydroxy-pyrrolidin-1-ylmethyl)-phenyl]-
propionamide
/
0
0
N
N I /
A reaction mixture of 40 mg (0.09 mmol) 3-[4-((R)-3-hydroxy-pyrrolidin-1-
ylmethyl)-
phenyl]-propynoic acid(4'-chloro-biphenyl-4-yl)amide and 10 mg Raney nickel in
10
ml N,N-dimethylformamide is hydrogenated for three hours at 50 psi and ambient
temperature. The catalyst is filtered off and the filtrate is evaporated to
dryness. The

CA 02550649 2006-06-20
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purification is carried out by column chromatography on silica gel (eluant:
dichloromethane/methanol/ammonia 15/1/0.1)
Yield: 20 mg (50 % of theoretical)
Melting point: 169-170 C
C2gH27CIN202 (M= 434.96)
Calc.: Molecular ion peak (M+H)+: 435/37 (CI) Found: Molecular ion peak
(M+H)+: 435/37 (CI)
The following compounds are prepared analogously to Example 6.29.:
CI
0
N
I
R~RZN~X / H
ExampleR~RZN-X educt empirical mass mp
formula spectrum [C]
6.30 1.47 C3~H3~CINzO 483/85 137-
(CI)
1 ~ ~ [M+H]+ 138
6.31 1.48 C3~H3~CINzO 483/85 133-
(CI)
N~
I ~ ~ [M+H]+ 136
Example 6.32:
N-(4'-chloro-biphenyl-4-yl)-3-~4-[(methyl-pyridin-4-ylmethyl-amino)-methyl]-
phenyl}-
propionamide
/ CI
\
O
N, \ ~ /
~N
\ ~ N ~ /
6.32.a N-(4'-chloro-biphenyl-4-yl)-3-(4-cyano-phenyl)-propionamide

CA 02550649 2006-06-20
WO 2005/063239 306 PCT/EP2004/014378
6 ml (43.04 mmol) triethylamine and 13.73 g (42.75 mmol) TBTU are added to a
reaction mixture of 7.5 g (42.81 mmol) 4-cyano-phenylpropionic acid in 150 ml
N,N-
dimethylformamide and the mixture is stirred for 30 min at RT . Then a further
6 ml
(43.04 mmol) triethylamine and 8.72 g (42.83 mmol) 4'-chloro-biphenyl-4-
ylamine are
added and the mixture is stirred for 24 h at RT. The solution is mixed with
plenty of
water and the precipitated N-(4'-chloro-biphenyl-4-yl)-3-(4-cyano-phenyl)-
propionamide is suction filtered, washed with water and finally with
diisopropylether.
The yellow solid is dried for 6 h at 50°C and 20 mbar in the vacuum
drying chamber.
Yield: 14.22 g (92 % of theoretical)
C22H17CIN20 (M= 360.84)
Calc.: Molecular ion peak (M+H)+: 361/63 (CI) Found: Molecular ion peak
(M+H)+: 361/63 (CI)
Rf value: 0.5 (silica gel, dichloromethane/ethanol = 20:1 )
6.32.b N-(4'-chloro-biphenyl-4-yl)-3-(4-formyl-phenyl)-propionamide
100 ml formic acid are added to a reaction mixture of 3 g Raney nickel
moistened with
water and 14.22 g (39.41 mmol) N-(4'-chloro-biphenyl-4-yl)-3-(4-cyano-phenyl)-
propionamide and refluxed for 20 h. Then the catalyst is suction filtered and
the filtrate
is diluted with plenty of water. The precipitated N-(4'-chloro-biphenyl-4-yl)-
3-(4-formyl-
phenyl)-propionamide is suction filtered and dissolved in ethyl acetate. The
organic
phase is washed first of all with 2 molar sodium hydroxide solution, then with
water
and finally with saturated sodium chloride solution, dried over sodium
sulphate and
activated charcoal and freed from solvent by rotary evaporation.
Yield: 11.7 g (57 % of theoretical)
C22H18CIN02 (M= 363.84)
Calc.: Molecular ion peak (M+H)+: 364/66 (CI) Found: Molecular ion peak
(M+H)+: 364/66 (CI)
Rf value: 0.5 (silica gel, cyclohexane/ethyl acetate = 1:1 )
6.32.c N-(4'-chloro-biphenyl-4-yl)-3-(4-hydroxymethyl-phenyl)-propionamide
First of all 8 ml glacial acetic acid are added to a reaction solution of 11.7
g (22.51
mmol) N-(4'-chloro-biphenyl-4-yl)-3-(4-formyl-phenyl)-propionamide in 200 ml
of

CA 02550649 2006-06-20
WO 2005/063239 307 PCT/EP2004/014378
tetrahydrofuran and then 15.1 g ( 67.53 mmol) sodiumtriacetoxyborohydride are
added and the mixture is stirred for 20 h at RT. The reaction mixture is
poured onto
plenty of water and the precipitate formed is suction filtered. This is
purified by column
chromatography on silica gel. (eluant: dichloromethane/acetone 15/1 to 10/1 )
Yield: 5.46 g (66 % of theoretical)
C22H20CIN02 (M= 365.85)
Calc.: Molecular ion peak (M+H)+: 366/68 (CI) Found: Molecular ion peak
(M+H)+: 366/68 (CI)
Rf value: 0.35 (silica gel, dichloromethane/acetone = 10:1 )
6.32.d N-(4'-chloro-biphenyl-4-yl)-3-(4-chloromethyl-phenyl)-propionamide
0.43 ml (5.6 mmol) methanesulphonic acid chloride are slowly added dropwise at
ambient temperature to a solution of 2 g (5.47 mmol) N-(4'-chloro-biphenyl-4-
yl)-3-(4-
hydroxymethyl-phenyl)-propionamide and 1.56 ml (11.2 mmol) triethylamine in 50
ml
dichloromethane and the reaction mixture is stirred for 24 hours at ambient
temperature. It is extracted with water and the organic phase is dried over
sodium
sulphate. The solvent is distilled off and the residue is stirred with
diisopropylether
and suction filtered.
Yield: 1.45 g (69 % of theoretical)
C22H1gC12N0 (M= 384.3)
Calc.: Molecular ion peak (M+H)+: 384/86/88 (C12) Found: Molecular ion peak
(M+H)+: 384/86/88 (C12)
Rf value: 0.45 (silica gel, dichloromethane/ ethanol = 50:1 )
6.32.eN-(4'-chloro-biphenyl-4-yl)-3-{4-[(methyl-pyridin-4-ylmethyl-amino)-
methyl]-
phenyl)-propionamide
A reaction mixture of 70 mg (0.18 mmol) N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-phenyl)-propionamide, 18 mg (0.15 mmol) methylpyridin-4-
ylmethylamine and 41 mg (0.3 mmol) potassium carbonate in 5 ml acetone is
agitated
for 24 hours at reflux temperature. The reaction mixture is evaporated down.
The
residue is triturated with water and diisopropylether, suction filtered and
dried in the
air.
Yield: 52 mg (87 % of theoretical)

CA 02550649 2006-06-20
WO 2005/063239 3Q$ PCT/EP2004/014378
Melting point: 102°C
C2gH28CIN30 (M= 470.01 )
Calc.: Molecular ion peak (M+H)+: 470/72(CI) Found: Molecular ion peak
(M+H)+: 470/72(CI)
CI
0
N \
I
R~RZN~X / H
The following compounds are prepared analogously to Example 6.32.e:
ExampleR~RZN-X educt empirical mass mp
formula spectrum [C]
6.33 ~ Ni 6.32.d C29H28CIN30 470/72 168-
(CI)
I [M+H]+ 169
N
6.34 ~ Ni 6.32.d C29H28CIN30 470/72 144-
(CI)
I
1 [M+H]+ 145
~ N ,:
6.35 ~ 6.32.d C3H35CIN20 475/77 149-
(CI)
~
N [M+H]+ 150.5
6.36 0 ~, 6.32.d C28H28CIF3N202517/19 193
N (CI)
F [M+H]+
F
F
6.37 ~ 6.32.d C28H3~CIN20 447/49 182,5-
(CI)
~N [M+H]+ 184
Example 6.38.
3-[4-(benzylamino-methyl)-phenyl]-N-(4'-chloro-biphenyl-4-yl)-propionamide

CA 02550649 2006-06-20
WO 2005/063239 3Qg PCT/EP2004/014378
/ CI
O ~ \
N /
/ \
\ ~ N ~ /
A reaction mixture of 70 mg (0.18 mmol) N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-phenyl)-propionamide, 16 mg (0.15 mmol) benzylamine and 41 mg
(0.3
mmol) potassium carbonate in 5 ml acetone is agitated for 24 hours at reflux
temperature. The reaction mixture is evaporated down. The residue is
triturated with
water and diisopropylether, suction filtered and dried in the air. The residue
is purified
by column chromatography on silica gel (eluant:
dichloromethane/ethanol/ammonia
30/1 /0.1 )
Yield: 23 mg (40 % of theoretical)
Melting point: 176°C
C2gH27CIN20 (M= 454.99)
Calc.: Molecular ion peak (M+H)+: 455/57(CI) Found: Molecular ion peak
(M+H)+: 455/57(CI)
The following compounds are prepared analogously to Example 6.38:
ExampleR,R2N-X educt empirical mass mp Rf
formula
spectrum [C] value
6.39 6.32.d C28H3~CIN20 447/49 208
(CI)
[M+H]+
6.40 ~ 6.32.d C3~H3~CIN20 489/91 165
(CI)
[M+H]+
6.41 6.32.d C2~H29CIN20 432/34 196-
(CI)
[M+H]+ 197
6.42 ~ 6.32.d C28H33CIN202 465/67 135 0.3
(CI)
~Nwi! [M+H]+ (A)
o

CA 02550649 2006-06-20
WO 2005/063239 310 PCT/EP2004/014378
Rf value: A= (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
Example 6.43.
N-(4'-chloro-biphenyl-4-yl)-3-(4-cycloprpylaminomethyl-phenyl)-propionamide
trifluoroacetate
/
0
/
~N
N ~ /
d
A reaction mixture of 70 mg (0.18 mmol) N-(4'-chloro-biphenyl-4-yl)-3-(4-
chloromethyl-phenyl)-propionamide, 16 mg (0.15 mmol) cyclopropylamine and 41
mg
(0.3 mmol) potassium carbonate in 5 ml acetone is shaken for 24 hours at
reflux
temperature. The reaction mixture is evaporated down. The residue is
triturated with
water and diisopropylether, suction filtered and dried in the air. The residue
is purified
by column chromatography on silica gel (eluant:
dichloromethane/ethanol/ammonia
30/1/0.1 ) and then by column chromatography on RP-18 (eluant: water + 0.1
trifluoroacetic acid/acetonitrile + 0.1 % trifluoroacetic acid 100/0 to 50/50
)
Yield: 24 mg (36 % of theoretical)
Melting point: 208°C
C25H25CIN20* C2HF302 (M= 518.96)
Calc.: Molecular ion peak (M+H)+: 405/07(CI) Found: Molecular ion peak
(M+H)+:405/07(CI)
The following compound is prepared analogously to Example 6.43:
ExampleR~R2N-X educt empirical mass mp
formula
spectrum [C]
6.44 I 6.32.d C26H2sCIN30 432/34 148-
(CI)
~N
N' [M+H]+ 149
Example: 6.45

CA 02550649 2006-06-20
, WO 2005/063239 311 PCT/EP2004/014378
3-[4-(8-aza-spiro[4.5]dec-8-ylmethyl)-phenyl]-N-(4'-chloro-biphenyl-4-yl)-N-
methyl-
propionamide
CI
o ~ w
N
Prepared analogously to Example 6.29 from 3-[4-(8-aza-spiro[4.5]dec-8-
ylmethyl)-
phenyl]-propynoic acid(4'-chloro-biphenyl-4-yl)methyl-amide.
Yield: 43 mg (86 % of theoretical)
Melting point: 119°C
C32H37CIN20 (M= 501.10)
Calc.: Molecular ion peak (M+H)+: 501/07(CI) Found: Molecular ion peak
(M+H)+: 501/03(CI)
The following compounds are prepared analogously to Example 6.2:
Lz
O
a
R~ RZN ~X
Example R~ R2N-X L~
6.46 ~ H CI
N
6.47 H CI
N

CA 02550649 2006-06-20
WO 2005/063239 312 PCT/EP2004/014378
6.48 ~ H CI
~N~
O
I
\N
R~RZN~x / H L~
Lz
Example R~RZN-X L~ L2
6.49 I F CI
O~N
6.50 ~N F CI
6.51 I F CI
O~Nyir'
6.52 ~ F CI
~o~N
6.53 F CI
N
6.54 ~ F CI
N
6.55 I F CI
~N~
6.56 ~ F CI
N
6.57 F CI
N
6.58 F CI
N

CA 02550649 2006-06-20
. WO 2005/063239 313 PCT/EP2004/014378
6.59 ~ F CI
N
6.60 F CI
~N~
6.61 F CI
N
O
6.62 F CI
N
~N~
6.63 ~ F CI
N
6.64 1 F CI
~N~
6.65 ~ F CI
N
6.66 I F CI
~\
~
N~
,/
6.67 ~ ~ I F CI
\ N
6.68 I F CI
/~N~r
N
6.69 oI F CI
~
~
N~
6.70 ~ ~ I F CI
\ ~/N\i~
6.71 I F CI
~N~
6.72 ~ F CI
~N~

CA 02550649 2006-06-20
WO 2005/063239 314 PCT/EP2004/014378
/ Lz
O /
N
I
R~RZN~X / H L~
Example R~R2N-X L~ L2
6.73 I H CF3
O~N
6.74 ~N H CF3
6.75 I H CF3
O~N
6.76 ~ H CF3
°~N
6.77 H CF3
N
6.78 ~ H CF3
N
6.79 I H CF3
~N~
6.80 ~ H CF3
N
6.81 H CF3
N
6.82 H CF3
N
6.83 ~ H CF3
N
6.84 ° H CF3
~N~

CA 02550649 2006-06-20
~WO 2005/063239 315 PCT/EP2004/014378
6.85 H CF3
N
O
6.86 H CF3
N
~N~
6.87 ~ H CF3
N
6.88 ~ H CF3
~N~
6.89 ~ H CF3
N
6.90 I H CF3
~
~
i!
N
\
/
6.91 ~ H CF3
\ I N
6.92 I H CF3
/~N~
N
6.93 0~~ I H CF3
N
6.94 ~ I I H CF3
\ ~/N\i~
6.95 I H CF3
~N~
6.96 ~ H CF3
~N~
/
O / ~ a
N
R~RzN~X / H L~
Example R~R2N-X L~ L2

CA 02550649 2006-06-20
WO 2005/063239 316 PCT/EP2004/014378
6.97 I H Me
O~N
6.98 ~ N H Me
6.99 I H Me
O~N
6.100 ~ H Me
°~N
6.101 H Me
N
6.102 ~ H Me
N
6.103 I H Me
~N~
6.104 ~ H Me
N
6.105 H Me
N
6.106 H Me
N
6.107 ~ H Me
N
6.108 ° H Me
~N~
6.109 H Me
N
O
6.110 ° H Me
N
6.111 ~ H Me
N

CA 02550649 2006-06-20
1IV0 2005/063239 317 PCT/EP2004/014378
6.112 ~ H Me
~N~
6.113 ~ H Me
N
6.114 I H Me
~O~/NWi!
6.115 ~ I I H Me
\ N
6.116 I H Me
/~N~
N
6.117 0~~ I H Me
~N~
6.118 ~ I I H Me
\ O~/N\i~
6.119 I H Me
~N~
6.120 ~ H Me
~N~
O
J w ~ ,N
RiR2N~X / H L~
L2
ExampleR~R2N-X L~ L2
6.121 I H F
O~N\i~
6.122 N H F
~
6.123 I H F
O~N

CA 02550649 2006-06-20
WO 2005/063239 31$ PCT/EP2004/014378
6.124 ~ H F
~°~N
6.125 H F
N
6.126 ~ H F
N
6.127 I H F
~N
6.128 ~ H F
N
6.129 H F
N
6.130 H F
N
6.131 ~ H F
N
6.132 ° H F
~N~
6.133 H F
N
O
6.134 ° H F
N ~N~
6.135 ~ H F
N
6.136 ~ H F
~N~
6.137 ~ H F
N
6.138 I H F
~°~N

CA 02550649 2006-06-20
t/V0 2005/063239 319 PCT/EP2004/014378
6.139 ~ ~ I H F
\ N
6.140 I H F
/~N~
N
6.141 0~~ I H F
N
6.142 ~ I i H F
\ O~\/N
6.143 I H F
~N~
6.144 ~ H F
~N~
O ~ \
\I
\ ~ ,N
I
R~RzN~X / H L~
L2
ExampleR~RZN-X L~ L2
6.145 I F CF3
o\~
~lN~
6.146 n N F CF3
'~\~
6.147 I F CF3
O~N
6.148 ~ F CF3
~O~\/N~
6.149 F CF3
N

CA 02550649 2006-06-20
WO 2005/063239 320 PCT/EP2004/014378
6.150 ~ F CF3
N
6.151 I F CF3
~N
6.152 ~ F CF3
N
6.153 F CF3
N
6.154 F CF3
N
6.155 ~ F CF3
N
6.156 ° F CF3
~N~
6.157 F CF3
N
O
6.158 ° F CF3
N ~N~
6.159 ~ F CF3
N
6.160 ~ F CF3
~N~
6.161 ~ F CF3
N
6.162 I F CF3
°~N
6.163 ~ ~ I F CF3
\ N
6.164 I F CF3
~~N
N
6.165 0~ I F CF3
N

CA 02550649 2006-06-20
1N0 2005/063239 321 PCT/EP2004/014378
6.166 ~ I I F CF3
O~\/N
6.167 I F CF3
~N~
6.168 ~ F CF3
~N~
O / \
\
\ ~ ,N
I
R~R2N~X / H L~
Lz
ExampleR~RZN-X L~ L2
6.169 I F Me
O~N
6.170 ~ N F Me
6.171 I F Me
O~N
6.172 ~ F Me
~O~\/N~
6.173 F Me
N
6.174 ~ F Me
N
6.175 I F Me
~N~
6.176 ~ F Me
N

CA 02550649 2006-06-20
WO 2005/063239 322 PCT/EP2004/014378
6.177 F Me
N
6.178 F Me
N
6.179 ~ F Me
N
6.180 ° F Me
~N~
6.181 F Me
N
O
6.182 ° F Me
N
6.183 ~ F Me
N
6.184 ~ F Me
~N~
6.185 ~ F Me
N
6.186 I F Me
~°~N
6.187 ~ ~ I F Me
\ N
6.188 I F Me
~~N
N
6.189 0~ I F Me
N
6.190 ~ ~ I F Me
\ °~/N\i~
6.191 I F Me
~N~

CA 02550649 2006-06-20
WO 2005/063239 323 PCT/EP2004/014378
6.192 F Me
o~
~N~
/ Lz
O / ~ a
N
I
R~R2N~X / H L~
Example R~R2N-X L~
6.193 I F F
O~N
6.194 ~N F F
6.195 I F F
O~N
6.196 ~ F F
~o~N
6.197 F F
N
6.198 ~ F F
N
6.199 I F F
~N
6.200 ~ F F
N
6.201 F F
N~!
6.202 F F
N

CA 02550649 2006-06-20
WO 2005/063239 324 PCT/EP2004/014378
6.203 ~ F F
N
6.204 F F
~N~
6.205 F F
N
O
6.206 F F
N
~N~
6.207 ~ F F
N
6.208 ~ F F
~N~
6.209 ~ F F
N
6.210 I F F
~O~/N~
6.211 ~ F F
\ I N
6.212 I F F
~~N~r
N
6.213 0~~ I F F
N
6.214 ~ I I F F
\ O~/N\i~
6.215 I F F
~N~
6.216 ~ F F
~N~
Example 6.217:
2-(4-morpholin-4-ylmethyl-phenyl)-cyclopropanecarboxylic acid (4'-chloro-
biphenyl-4-
yl)-amide

CA 02550649 2006-06-20
WO 2005/063239 325 PCT/EP2004/014378
~N /
OJ \
N \
O I / \
I/
CI
Preparation of diazomethane: 0.15 g (1.48 mmol) N-nitroso-N-methylurea are
added
with manual shaking to 10 ml diethyl ether, over a lower layer of 3 ml of 40%
potassium hydroxide solution, at 5 to 0°C. The reaction mixture is left
to stand for ten
minutes and then the yellow ether solution is decanted off and dried over
potassium
hydroxide.
The yellow diazomethane solution prepared is slowly added dropwise at
0°C to a
suspension of 80 mg (0.19 mmol) (E)-N-(4'-chloro-biphenyl-4-yl)-3-(4-morpholin-
4-
ylmethyl-phenyl)-acrylamide (for preparation see 6.4) and 202 mg (0.001 mmol)
palladium(II)acetate in 20 ml diethyl ether. The dark reaction mixture is
stirred for 30
min. Then the reaction mixture is mixed twice with double the amount of a
diazomethane solution. After the reaction has ended 10 ml glacial acetic acid
are
added dropwise to the suspension and extracted several times with a sodium
hydrogen carbonate solution. The organic phase is dried over sodium sulphate,
the
desiccant is filtered off and the filtrate is evaporated down. Further
purification is
carried out by column chromatography on silica gel (eluant:
dichloromethane/ethanol/ammonia 30:1:0.1)
Yield: 32 mg (82.6 % of theoretical)
C27H27CIN202 (M= 446.97)
Melting point: 187-188°C
Calc.: Molecular ion peak (M+H)+: 447/449 (CI) Found: Molecular ion
peak (M+H)+: 447/449 (CI)
Rf value: 0.3 (silica gel, dichloromethane/ethanol/ammonia = 20:1:0.1 )

CA 02550649 2006-06-20
WO 2005/063239 326 PCT/EP2004/014378
Example 7.1:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(2-piperidin-1-yl-
quinolin-6-yl)-
amide
/ CF
N
CI
O
~N N
7.1.a.6-amino-2-piperidin-2-yl-quinoline
3
Prepared analogously to 3.1.b from 6-nitro-2-piperidin-2-yl-quinoline.
Yield: 0.79 g (59.6% of theory)
C~4H~7N3 (M= 227.31)
Calc.: Molecular ion peak (M+H)+: 228 Found: Molecular ion peak (M+H)+:
228
Rf value: 0.37 (silica gel, dichloromethane/methanol 19:1 )
7.1.b. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(2-piperidin-1-yl-
quinolin-6-
yl)-amide
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and 6-amino-2-piperidin-2-yl-quinoline.
Yield: 170 mg (37.1 % of theory)
Melting point: 176-179°C
C24H1gCIF3N30 (M=457.88)
Calc.: Molecular ion peak (M+H)+: 456/458 Found: Molecular ion peak
(M+H)+: 456/458
Rf value: 0.62 (silica gel, dichloromethane/methanol = 19:1)
Example 7.2:
3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(2-isopropylamino-
quinolin-6-yl)-
amide

CA 02550649 2006-06-20
'WO 2005/063239 327 PCT/EP2004/014378
N
CI
O
N N
H
7.2.a. isopropyl-(6-nitro-quinolin-2-yl)-amine
CF3
2.55 ml (29.96 mmol) isopropylamine are added to a solution of 1.25 g (5.99
mmol) 2-
chloro-6-nitro-quinoline in 50 ml of ethanol and the mixture is stirred for 18
hours at
ambient temperature. Then the reaction mixture is heated to 65°C in the
microwave
for two hours. The reaction mixture is then evaporated down, the residue is
taken up
in 20 ml DMF, combined with 2.55 ml (29.96 mmol) isopropylamine and stirred
for 18
hours at ambient temperature. The reaction mixture is evaporated down and the
residue is combined with ethyl acetate and water. The organic phase is
extracted
twice with water. The aqueous phases are extracted twice with ethyl acetate.
The
combined organic phases are dried over sodium sulphate and the solvent is then
removed.
Yield: 0.75 g (54.1 % of theory)
C~2H~3N3O2 (M= 221.25)
Calc.: Molecular ion peak (M+H)+: 232 Found: Molecular ion peak (M+H)+:
232
R, value: 0.48 (silica gel, petroleum ether/ethyl acetate 2:1 )
7.2.b. N2-isopropyl-quinoline-2,6-diamine
Prepared analogously to 3.1.b from isopropyl-(6-nitro-quinolin-2-yl)-amine.
Yield: 0.51 g (78.1 % of theory)
C~2H~5N3 (M= 201.27)
Calc.: Molecular ion peak (M+H)+: 202 Found: Molecular ion peak (M+H)+:
202
Rf value: 0.25 (silica gel, dichloromethane/methanol 19:1 )
7.2.c. 3-(2-chloro-4-trifluoromethyl-phenyl)-propynoic acid-(2-isopropylamino-
quinolin-
6-yl)-amide

CA 02550649 2006-06-20
WO 2005/063239 328 PCT/EP2004/014378
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethyl-
phenyl)-
propynoic acid and N2-isopropyl-quinoline-2,6-diamine.
Yield: 140 mg (46.3 % of theory)
Melting point: 57-60°C
C22H17CIF3N30 (M= 431.84)
Calc.: Molecular ion peak (M+H)+: 432/434 Found: Molecular ion peak
(M+H)+: 432/434
Rf value: 0.49 (silica gel, petroleum ether/ethyl acetate 2:1 )
The following compounds are prepared analogously to Example 7.1:
\ Lz
L3 H I /
\ \ N
R~R2N~X ~ N~ O
Example R~ R2N-X- L~ L2 L3
7.3
-CI -CF3 -H
7.4 Ny'
-CI -CF3 -H
7.5 ~Ny,
H
-CI -CF3 -
7.6
H2N -CI -CF3 -H
0
7.7 ;
-CI -CF3 -H
7.8 '' _CI -CF3 _H
GN
7.g off
-CI -CF3 -H

CA 02550649 2006-06-20
WO 2005/063239 329 PCT/EP2004/014378
7.10 ~ I N
-CI -CF3 -H
7.11
N~ -CI -CF3 -H
J
H3~
7.12 H
-CI -CF3
HN
..
7.13
-H
-CI -CF3
N ~'
H3C
7.14
-H
-CI -CF3
N
H C~
3
7.15
-H
N~ CI -CF3
7.16
-CI -CF3 -H
~NT
,
7.17 cH3
H,c~ _H
-CI -CF3
HN
7.18 Ni
-H
H2N -CI -CF3
0
7.19 Me1
HN
-CI -CF3 -H
7.20 Me
HN~ -CI -CF3 -H
7.21
-H
-CI -CF3
HN
7.22
-H
-CI -CF3
~ N .'
Me

CA 02550649 2006-06-20
WO 2005/063239 330 PCT/EP2004/014378
7.23
-CI -CF3
"J
7.24 ~Ny'
-CI -CF3 -Me
7.25 Ny'
-CI -CF3 -Me
7.26 ~
y
N
' -CI -CF3 -Me
7.27 N,;
HzN ' -CI -CF3 -Me
0
7.28 N' -CI -CF3
-Me
29 '' -CI -CF3 -Me
G".
7.30 off
N~; -CI -CF3 -Me
7.31
"~ -CI -CF3 -Me
7.32 ~ I N'~ -CI -CF3 -Me
~J
3
7.33
-Me
-CI -CF3
HN
..
7.34
-Me
-CI -CF3
N ,
H3C~ \.
7.35
-Me
-CI -CF3
HC~"~
3
7.36
-Me
-CI -CF3

CA 02550649 2006-06-20
WO 2005/063239 331 PCT/EP2004/014378
7.37
-Me
-CI -CF3
~N~
7.38 ~"3
-Me
"3~ -CI -CF3
HN
7.39 N
H -CI -CF3 -Me
N
Z
0
7.19 Me1
"N~ -CI -CF3 -Me
7.20 Me
"N~ -CI -CF3 -Me
7.21
-Me
-CI -CF3
HN
7.21
-Me
-CI -CF3
~ N ~'
Me
.
.
7.22 y
-CI -CF3 -Me

CA 02550649 2006-06-20
WO 2005/063239 332 PCT/EP2004/014378
Some test methods for determining an MCH-receptor antagonistic activity will
now be
described. In addition, other test methods known to the skilled man may be
used, e.g.
by inhibiting the MCH-receptor-mediated inhibition of CAMP production, as
described
by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are
expressed and functional in human skin", Biochem. Biophys. Res Commun. 296
(2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH
receptor in the presence of antagonistic substances by plasmon resonance, as
described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface
Reconstitution
of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance
Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing
antagonistic activity to MCH receptors are contained in the references and
patent
documents mentioned hereinbefore, and the description of the test methods used
is
hereby incorporated in this application.
MCH-1 receptor
binding test
Method: MCH binding to hMCH-1 R transfected cells
Species: Human
Test cell: hMCH-1 R stably transfected into CHO/Galpha16
cells
Results: IC50 values
Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1 R are
resuspended using a syringe (needle 0.6 x 25 mm) and diluted in test buffer
(50 mM
HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin
(protease-free), 0.021 % bacitracin, 1 Ng/ml aprotinin, 1 Ng/ml leupeptin and
1 pM
phosphoramidone) to a concentration of 5 to 15 pg/ml.
200 microlitres of this membrane fraction (contains 1 to 3 pg of protein) are
incubated
for 60 minutes at ambient temperature with 100 pM of X251-tyrosyl melanin
concentrating hormone 0251-MCH commercially obtainable from NEN) and
increasing
concentrations of the test compound in a final volume of 250 microlitres.
After the
incubation the reaction is filtered using a cell harvester through 0.5% PEI
treated
fibreglass filters (GF/B, Unifilter Packard). The membrane-bound radioactivity
retained
on the filter is then determined after the addition of scintillator substance
(Packard
Microscint 20) in a measuring device (TopCount of Packard).

CA 02550649 2006-06-20
WO 2005/063239 333 PCT/EP2004/014378
The non-specific binding is defined as bound radioactivity in the presence of
1
micromolar MCH during the incubation period.
The analysis of the concentration binding curve is carried out on the
assumption of
one receptor binding site.
Standard:
Non-labelled MCH competes with labelled '251-MCH for the receptor binding with
an
IC50 value of between 0.06 and 0.15 nM.
The KD value of the radioligand is 0.156 nM.
MCH-1 receptor-coupled Ca2+ mobilisation test
Method: Calcium mobilisation test with human MCH (FLIPR38a)
Species: Human
Test cells: CHO/ Galpha 16 cells stably transfected with hMCH-R1
Results: 1 st measurement:: % stimulation of the reference (MCH 10-6M)
2nd measurement: pKB value
Reagents: HBSS (10x) (GIBCO)
HEPES buffer (1M) (GIBCO)
Pluronic F-127 (Molecular Probes)
Fluo-4 (Molecular Probes)
Probenecid (Sigma)
MCH (Bachem)
bovine serum albumin (Serva)
(protease-free)
DMSO (Serva)
Ham's F12 (BioWhittaker)
FCS (BioWhittaker)
L-Glutamine (GIBCO)
Hygromycin B (GIBCO)
PENStrep (BioWhittaker)
Zeocin (Invitrogen)
Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cell culture
medium (with L-glutamine; BioWhittaker; Cat.No.: BE12-615F). This contains per
500

CA 02550649 2006-06-20
WO 2005/063239 334 PCT/EP2004/014378
ml 10% FCS, 1 % PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml
hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin (100 Ng/ml stock solution).
One
day before the experiment the cells are plated on a 384-well microtitre plate
(black-
walled with a transparent base, made by Costar) in a density of 2500 cells per
cavity
and cultivated in the above medium overnight at 37°C, 5% COZ and 95%
relative
humidity. On the day of the experiment the cells are incubated with cell
culture
medium to which 2 mM Fluo-4 and 4.6 mM Probenicid have been added, at
37°C for
45 minutes. After charging with fluorescent dye the cells are washed four
times with
Hanks buffer solution (1 x HBSS, 20 mM HEPES), which has been combined with
0.07% Probenicid. The test substances are diluted in Hanks buffer solution,
combined
with 2.5% DMSO. The background fluorescence of non-stimulated cells is
measured
in the presence of substance in the 384-well microtitre plate five minutes
after the last
washing step in the FLIPR384 apparatus (Molecular Devices; excitation
wavelength:
488 nm; emission wavelength: bandpass 510 to 570 nm). To stimulate the cells
MCH
is diluted in Hanks buffer with 0.1 % BSA, pipetted into the 384-well cell
culture plate
35 minutes after the last washing step and the MCH-stimulated fluorescence is
then
measured in the FLIPR384 apparatus.
Data analysis:
1 st measurement: The cellular Ca2+ mobilisation is measured as the peak of
the
relative fluorescence minus the background and is expressed as the percentage
of
the maximum signal of the reference (MCH 10-6M). This measurement serves to
identify any possible agonistic effect of a test substance.
2nd measurement: The cellular Ca2+ mobilisation is measured as the peak of the
relative fluorescence minus the background and is expressed as the percentage
of
the maximum signal of the reference (MCH 10-6M, signal is standardised to
100%).
The EC50 values of the MCH dosage activity curve with and without test
substance
(defined concentration) are determined graphically by the GraphPad Prism 2.01
curve
program. MCH antagonists cause the MCH stimulation curve to shift to the right
in the
graph plotted.
The inhibition is expressed as a pKB value:
pKB=IOg(ECSO(testsubstance+MCH) / EC5o(MCH) -1 ) -IOg C(testsubstance)

CA 02550649 2006-06-20
' WO 2005/063239 335 PCT/EP2004/014378
The compounds according to the invention, including their salts, exhibit an
MCH-
receptor antagonistic activity in the tests mentioned above. Using the MCH-1
receptor
binding test described above an antagonistic activity is obtained in a dosage
range
from about 10-'° to 10-5 M, particularly from 10-9 to 10-s M.
The following IC50 values were determined using the MCH-1 receptor binding
test
described above:
Compound
according to Structure IC50 value
Example no.
cl
(
1.23 0 / ( ~ 7.5 nM
\
-N
~N I /
O\
5.1 I I 20 nM
<~
4.8 / cl 50 nM
CI H \
\ N
I CI X HCI
~N\/~ / O
O
Some examples of formulations will be described hereinafter, wherein the term
"active substance" denotes one or more compounds according to the invention,
including their salts. In the case of one of the combinations with one or more
active
substances described, the term "active substance" also includes the additional
active
substances.
Example A

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Capsules for powder inhalation containing 1 ma active substance
Composition:
1 capsule for powder inhalation contains:
active substance 1.0 mg
lactose 20.0 mg
hard gelatine capsules 50.0 ma
71.0 mg
Method of preparation:
The active substance is ground to the particle size required for inhalation.
The
ground active substance is homogeneously mixed with the lactose. The mixture
is
packed into hard gelatine capsules.
Example B
Inhalable solution for Respimat~ containing 1 mgr active substance
Composition:
1 spray contains:
active substance 1.0 mg
benzalkonium chloride 0.002 mg
disodium edetate 0.0075 mg
purified water ad 15.0 pl
Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and
packed
into Respimat~ cartridges.
Example C
Inhalable solution for nebulisers containing 1 mg active substance
Composition:
1 vial contains:

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WO 2005/063239 337 PCT/EP2004/014378
active substance 0.1 g
sodium chloride 0.18 g
benzalkonium chloride 0.002 g
purified water ad 20.0 ml
Method of preparation:
The active substance, sodium chloride and benzalkonium chloride are dissolved
in
water.
Example D
Pr~~ellant type metered dose aerosol containing 1 mg active substance
Composition:
1 spray contains:
active substance 1.0 mg
lecithin 0.1
propellant gas ad 50.0 NI
Method of preparation:
The micronised active substance is homogeneously suspended in the mixture of
lecithin and propellant gas. The suspension is transferred into a pressurised
container
with a metering valve.
Example E
Nasal spray containinct 1 mg active substance
Composition:
active substance 1.0 mg
sodium chloride 0.9 mg
benzalkonium chloride 0.025 mg
disodium edetate 0.05 mg
purified water ad 0.1 ml
Method of preparation:

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WO 2005/063239 33$ PCT/EP2004/014378
The active substance and the excipients are dissolved in water and transferred
into a
corresponding container.
Example F
Injectable solution containing 5 ma of active substance per 5 ml
Composition:
active substance 5 mg
glucose 250 mg
human serum albumin 10 mg
glycofurol 250 mg
water for injections ad 5 ml
Preparation:
Glycofurol and glucose are dissolved in water for injections (Wfl); human
serum
albumin is added; active ingredient is dissolved with heating; made up to
specified
volume with Wfl; transferred into ampoules under nitrogen gas.
Example G
Injectable solution containing 100 mgi of active substance per 20 ml
Composition:
active substance 100 mg
monopotassium dihydrogen phosphate
= KH2P04 12 mg
disodium hydrogen phosphate
= Na2HP04~2H20 2 mg
sodium chloride 180 mg
human serum albumin 50 mg
Polysorbate 80 20 mg
water for injections ad 20 ml

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WO 2005/063239 339 PCT/EP2004/014378
Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and
disodium hydrogen phosphate are dissolved in water for injections (Wfl); human
serum albumin is added; active ingredient is dissolved with heating; made up
to
specified volume with Wfl; transferred into ampoules.
Example H
Lyophilisate containing 10 mg of active substance
Composition:
Active substance 10 mg
Mannitol 300 mg
human serum albumin 20 mg
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg
mannitol 200 mg
water for injections ad 10 ml
Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred
into ampoules.
Example I
Tablets containing 20 mgi of active substance
Composition:

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WO 2005/063239 340 PCT/EP2004/014378
active substance 20 mg
lactose 120 mg
maize starch 40 mg
magnesium stearate 2 mg
Povidone K 25 18 mg
Pre~~aration:
Active substance, lactose and maize starch are homogeneously mixed; granulated
with an aqueous solution of Povidone; mixed with magnesium stearate;
compressed
in a tablet press; weight of tablet 200 mg.
Example J
Capsules containing 20 mg active substance
Composition:
active substance 20 mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Preparation:
Active substance, maize starch and silica are homogeneously mixed; mixed with
magnesium stearate; the mixture is packed into size 3 hard gelatine capsules
in a
capsule filling machine.
Example K
Suppositories containingi 50 mgi of active substance
Composition:
active substance 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg

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WO 2005/063239 341 PCT/EP2004/014378
Preparation:
Hard fat is melted at about 38°C; ground active substance is
homogeneously
dispersed in the molten hard fat; after cooling to about 35°C it is
poured into chilled
moulds.
Example L
Iniectable solution containing 10 mg of active substance per 1 ml
Composition:
active substance 10 mg
mannitol 50 mg
human serum albumin 10 mg
water for injections ad 1 ml
Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is
added;
active ingredient is dissolved with heating; made up to specified volume with
Wfl;
transferred into ampoules under nitrogen gas.

Representative Drawing