COMPOSES DE CETOAMIDES BETA A ACTION ANTAGONISTE ET MEDICAMENTS COMPRENANT LEDIT COMPOSE

BETA-KETOAMIDE COMPOUNDS HAVING AN MCH-ANTAGONISTIC EFFECT AND MEDICAMENTS CONTAINING SAID COMPOUNDS

Abrégé français

L'invention concerne des composés de cétoamides B de formule (I), dans laquelle les groupes et les restes A, B, b, X, Y, Z, R?1¿, R?2¿, R?3¿, R?5a¿ et R?5b¿ sont spécifiés dans la revendication 1. L'invention concerne, de plus, des médicaments comprenant au moins un amide de l'invention. Les médicaments de l'invention conviennent pour le traitement de troubles du métabolisme et/ou des troubles de l'appétit, en particulier l'adiposité, la boulimie, l'anorexie, l'hyperphagie et le diabète, grâce à l'activité antagoniste du récepteur de MCH.

Abrégé anglais

The invention relates to .beta.-ketoamide compounds of general formula (I)
wherein the groups and radicals A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b have
the designations cited in patent claim 1. The invention also relates to
medicaments containing at least one inventive amide. As a result of the MCH
receptor antagonistic activity, the inventive medicaments are suitable for
treating metabolic disorders and/or eating disorders, especially adipositas,
bulimia, anorexia, hyperphagia and diabetes.

Revendications

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Claims
1. .beta.-Ketoamide 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-, -NR13-, or a phenyl or pyridinyl group
optionally mono- or polysubstituted by the group R20 and/or
monosubstituted by vitro, 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(=CH2)- or -NR13- in such a
way that heteroatoms are not directly joined together, and that a
group -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,

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- 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 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 not directly connected to a heteroatom may be substituted by
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
Z denotes a single bond or -CR7a R7b-CR7c R7d-,

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Y has one of the meanings given for Cy,
while 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/or
X may be connected to Y forming a carbo- or heterocyclic group fused to Y, and
A has one of the meanings given for Cy,
B has one of the meanings given for Cy,
b has 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,
- an 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 be replaced independently of one another by a -CO-, -C(=CH2)-, -
(SO)-
or -(SO2)- group, and
the above-mentioned saturated 6- or 7-membered groups may also be present 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

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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 C3-6-alkenyl or C3-6-
alkynyl,
R5a, R5b independently of one another denote H, C1-3-alkyl, C3-7-cycloalkyl,
C3-7-cycloalkyl-
C1-3-alkyl, CF3, F or Cl, while R5a and R5b representing alkyl may be joined
together such that a C3-7-cycloalkyl group is formed together with the C atom
to
which R5a and R5b are linked,
R7a, R7c independently of one another denote H, F, Cl, C1-4-alkyl or CF3,
R7b, R7d independently of one another denote H, F, C1-4-alkyl, C3-7-
cycloalkyl, C3-7-
cycloalkyl-C1-3-alkyl or CF3,
while R7a and R7b representing alkyl may be joined together such that a C3-7-
cycloalkyl group is formed together with the C atom to which R7a and R7b are
linked, and/or
R7c and R7d representing alkyl may be joined together such that a C3-7-
cycloalkyl
group is formed together with the C atom to which R7c and R7d are linked, or
R7b and R7d representing alkyl may be joined together such that a C3-7-
cycloalkyl
group is formed together with the two C atoms to which R7b and R7d are linked;
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-aminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl or
cyclo-C3-6-
alkyleneimino-carbonyl,
R11 denotes C1-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-O-, R15-O-C1-3-alkyl-,
R15-O-CO-,
R15-CO-O, cyano, R16R17N-, R18R19N-CO- or Cy,
R13 has one of the meanings given for R17,

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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, C1-4-alkylcarbonyl,
hydroxy-
carbonyl-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-,
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, R22-C1-3-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-C2-6-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, C1-4-
alkoxy, C1-4-
alkylthio, carboxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl,
C1-4-alkylaminocarbonyl, 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-

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carbonyl-amino, cyclo-C3-6-alkyleneimino, phenyl-C1-3-alkylamino, N-(C1-4-
alkyl)-
phenyl-C1-3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino,
phenylcarbonylmethylamino, hydroxy-C1-3-alkylaminocarbonyl, (4-morpholinyl)-
carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)-carbonyl, (hexahydro-1-
azepinyl)-
carbonyl, (4-methyl-1-piperazinyl)-carbonyl, aminocarbonylamino or C1-4-
alkylamino-
carbonyl-amino,
while in the above-mentioned groups and radicals, particularly in X, R1 to R4,
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, 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.
2. .beta.-Ketoamide compounds according to claim 1, characterised in that R1,
R2
independently of one another denote H, C1-6-alkyl, C3-5-alkenyl, C3-5-alkynyl,
C3-7-
cycloalkyl, hydroxy-C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, (hydroxy-C3-7-
cycloalkyl)-C1-3-alkyl, hydroxy-C2-4-alkyl, NC-C2-3-alkyl, C1-4-alkoxy-C2-4-
alkyl,
hydroxy-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, N-(C1-4-alkyl)-pyrrolidinyl,
pyrrolidinyl-
C1-3-alkyl, N-(C1-4-alkyl)-pyrrolidinyl-C1-3-alkyl, piperidin-3-yl or -4-yl, N-
(C1-4-alkyl)-
piperidin-3-yl or -4-yl, piperidinyl-C1-3-alkyl, N-(C1-4-alkyl)-piperidinyl-C1-
3-alkyl,
tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyranyl-C1-3-alkyl,
tetrahydrofuran-3-yl, tetrahydrofuranyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl,
pyridyl or

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pyridyl-C1-3-alkyl, while in the above-mentioned groups and residues one or
more C
atoms may be mono- or polysubstituted by F and/or one or two C atoms,
particularly
one C atom, may be monosubstituted independently of one another with Cl or Br,
and the phenyl or pyridyl group may be mono- or polysubstituted by the group
R20
as defined in claim 1 and/or monosubstituted by nitro.
3. .beta.-Ketoamide compounds according to claim 1, characterised in that R1
and R2 form
an alkylene bridge according to claim 1 such that R1R2N- forms a group
selected
from among 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, morpholine and thiomorpholine,
while according to claim 1 one or more H atoms may be replaced by R14, and/ or
the
alkylene bridge may be substituted in the manner recited in claim 1 with one
or two
identical or different carbo- or heterocyclic groups Cy,
while R13, R14 and Cy are defined as recited in claim 1.
4. .beta.-Ketoamide 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>

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<IMG>

-118-
<IMG>

-119-
<IMG>
wherein one or more H atoms of the heterocycle formed by the group R1R2N- may
be replaced by R14 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, .omega.-hydroxy-C1-3-
alkyl,
.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

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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.
5. .beta.-Ketoamide 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
-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
the bridge X may additionally be connected to R2, including the N atom
connected to R2 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 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
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
R1, R2, R4 and R10 are defined as in claim 1.

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6. .beta.-Ketoamide compounds according to claim 5, characterised in that X
denotes -CH2-,
-CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH=CH-CH2- and
in the event that the group Y is linked to X via a C atom, X also denotes
-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 connected to
R1 and X, forming a heterocyclic group, and
in X a C atom may be substituted by R10, preferably a hydroxy,
w-hydroxy-C1-3-alkyl, .omega.-(C1-4-alkoxy)-C1-3-alkyl and/or C1-4-alkoxy
group, and/or
one or two C atoms independently of one another may each be substituted by
one or two identical or different C1-4-alkyl groups, while two alkyl groups
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 may independently of one another be
monosubstituted
by Cl or Br and
R1, R4 and R10 may have one of the meanings given in claim 1.
7. .beta.-Ketoamide 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 at
one or more C atoms by R20, 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 R21,

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R1 may be connected to Y and/or X may be connected to Y as specified in
claim 1, and
X, R1, R20 and R21 have the meanings given in claim 1.
8. .beta.-Ketoamide compounds according to claim 7, characterised in that the
group Y is
selected from among the bivalent cyclic groups
<IMG>

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while the above-mentioned cyclic groups may be mono- or polysubstituted at one
or
more C atoms by R20, and 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,
wherein R20 and R21 are defined as in claim 1.
9. .beta.-Ketoamide 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 at one
or
more C atoms by R20, and in the case of a phenyl ring may also additionally be
monosubstituted by nitro, and
R20 and R21 may have the meanings given in claim 1.
10. .beta.-Ketoamide compounds according to one or more of the preceding
claims,
characterised in that b has the value 0.
11. .beta.-Ketoamide 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
among
phenyl, furanyl, thienyl and pyridyl,
white the above-mentioned cyclic groups 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
R20 has the meaning given in claim 1.
12. .beta.-Ketoamide compounds according to one or more of the preceding
claims,
characterised in that Z denotes a single bond or -CH2-CH2-.
13. .beta.-Ketoamide compounds according to one or more of the preceding
claims,
characterised in that R3 denotes H or methyl.

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14. .beta.-Ketoamide compounds according to one or more of the preceding
claims,
characterised in that
<IMG>
B denotes phenyl,
while the cyclic groups mentioned hereinbefore in relation to Y, A and B
may independently of one another be mono- or polysubstituted at one or
more C atoms by identical or different R20, and in the case of a phenyl
group may also additionally be monosubstituted by nitro, and
b has the value 0 or 1.
15. .beta.-Ketoamide compounds according to claim 14, characterised in that
R1, R2 are defined as in claim 2 or 3,
X is defined as in claim 5.

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16. .beta.-Ketoamide compounds according to one or more of the preceding
claims,
characterised in that
R20 denotes halogen, hydroxy, cyano, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-4-alkyl, R22-C1-3-
alkyl or has one of the meanings given for R22, and
R22 denotes C1-4-alkoxy, C1-4-alkylthio, carboxy, C1-4-alkylcarbonyl,
C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl,
di-(C1-4-alkyl)-aminocarbonyl, 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, hydroxy-C1-3-alkylaminocarbonyl,
aminocarbonylamino or C1-4-alkylaminocarbonyl-amino,
while in the definitions provided for R20 and 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.
17. Physiologically acceptable salts of the .beta.-ketoamide compounds
according to
one or more of claims 1 to 16.
18. Composition containing at least one .beta.-ketoamide compound according to
one
or more of claims 1 to 16 and/ or a salt according to claim 17 optionally
together with one or more physiologically acceptable excipients.
19. Pharmaceutical compositions, containing at least one .beta.-ketoamide
compound
according to one or more of claims 1 to 16 and/ or a salt according to claim
17 optionally together with one or more inert carriers and/or diluents.
20. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 for influencing the eating
behaviour of a mammal.

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21. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 for reducing the body weight and/
or for preventing an increase in the body weight of a mammal.
22. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 for preparing a pharmaceutical
composition with an MCH-receptor-antagonistic activity.
23. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 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.
24. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 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.
25. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 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.

-127-
26. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 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.
27. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 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.
28. Use of at least one .beta.-ketoamide compound according to one or more of
claims
1 to 16 and/ or a salt according to claim 17 for preparing a pharmaceutical
composition which is suitable for preventing and/or treating dependencies
and/or withdrawal symptoms.
29. Process for preparing a composition or a pharmaceutical composition
according to one or more of claims 18 to 28, characterised in that at least
one
.beta.-ketoamide compound according to one or more of claims 1 to 16 and/ or a
salt according to claim 17 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 .beta.-ketoamide compounds
according to
one or more of claims 1 to 16 and/ or a salt according to claim 17 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

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high blood pressure, active substances for the treatment of dyslipidaemia or
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.
31. Process for preparing .beta.-ketoamide compounds of formula I
<IMG>
where A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b are defined as in claim 1,
wherein an amine compound of formula A1
<IMG>
where X, Y, Z, R1, R2 and R3 are as hereinbefore defined,
is reacted with a carboxylic acid compound or a carboxylic acid derivative of
formula A2
<IMG>
wherein A, B, b, R5a and R5b are as hereinbefore defined,
and the group M denotes OH, Cl, C1-6-alkoxy, C1-6-alkylthio or C1-6-alkyl-COO-
,

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in the presence of at least one base in a solvent or mixture of solvents.
32. Process for preparing .beta.-ketoamide compounds of formula I
<IMG>
where A, B, b, X, Y, Z, R1, R2 and R3 are defined as in claim 1,
wherein a propynoic acid amide compound of formula B1
<IMG>
where A, B, b, X, Y, Z, R1, R2 and R3 are as hereinbefore defined,
is hydrolysed by the addition of an acid or base in a solvent or mixture of
solvents
and optionally in the presence of an activating nucleophile.

Description

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WO 2005/085221 _ 1 - PCT/EP2005/002132
86568pct
BETA-KETOAMIDE COMPOUNDS HAVING AN MCH-ANTAGONISTIC EFFECT AND
MEDICAMENTS CONTAINING SAID COMPOUNDS
The present invention relates to new ~i-ketoamide 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 excess
weight
(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

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WO 2005/085221 _ 2 - PCT/EP2005/002132
continuously as the level of fatness increases. For simplicity's sake, in the
present
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/$2925).
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
G-protein-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 2005/085221 - 3 - PCT/EP2005/002132
The anorectic effects of MCH are presumably mediated in rodents through the
Gas coupled MCH-1 R [3-6], as, unlike primates, ferrets and dogs, no second
MCH
receptor subtype has hitherto been found in rodents. Loss of the MCH-1 R in
knock-
out mice leads to a lower fat mass, an increased energy conversion and, when
fed
on a high fat diet, no increase in 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
1
Ar'-X-Ar-Y-N~ R
R2

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WO 2005/085221 - 4 - PCT/EP2005/002132
wherein Ar' 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, R~
and R2 independently of one another denote H or a hydrocarbon group, while R~
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
R~
Ar1 X-Ar-Y-N
R
wherein Ar' denotes a cyclic group , X and Y represent spacer groups, Ar
denotes an
optionally substituted fused polycyclic aromatic ring, R' and R2 independently
of one
another represent H or a hydrocarbon group, while R' and R2 together with the
adjacent N atom may form an N-containing heterocyclic ring and R2 together
with the
adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists
for the treatment of obesity.
Aim of the invention
The aim of the present invention is to provide new ~i-ketoamide compounds,
particularly those which are effective as MCH antagonists.
The invention also sets out to provide new ~i-ketoamide 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

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WO 2005/085221 _ 5 _ PCT/EP2005/002132
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.
Subject of the invention
The invention relates firstly to ~i-ketoamide compounds of general formula I
R\ O O
R2~N X Y Z ~N A--~B ]n
R3 R5a R5b
wherein
R', R2 independently of one another denote H, a C~_$-alkyl or C3_~-cycloalkyl
group optionally mono- or polysubstituted by the group R~~, while a
-CH2 group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group
may be replaced by -O, -S, -NR'3-, or a phenyl or pyridinyl group
optionally mono- or polysubstituted by the group R2° and/or
monosubstituted by nitro, or
R~ and R2 form a C2_$-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(=CH2)- or -NR~3- in such a
way that heteroatoms are not directly joined together, and that a
group -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

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WO 2005/085221 _ 6 - PCT/EP2005/002132
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 C~_$-alkylene bridge, wherein
- 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'R2N-, 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~~-alkylene bridge, and
a C atom not directly connected to a heteroatom 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~_s-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

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WO 2005/085221 _ 7 - PCT/EP2005/002132
alkenyl substituents may be joined together, forming a carbocyclic ring
system, and
Z denotes a single bond or -CR'aR'b-CR'~R'd,
Y has one of the meanings given for Cy,
while 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/or
X may be connected to Y forming a carbo- or heterocyclic group fused to Y, and
A has one of the meanings given for Cy,
B has one of the meanings given for Cy,
b has 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,
- an 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 -
CHZ
groups may be replaced independently of one another by a -CO-, -C(=CH2)-, -
(SO)
or -(S02)- group, and

CA 02552907 2006-07-06
WO 2005/085221 - $ - PCT/EP2005/002132
the above-mentioned saturated 6- or 7-membered groups may also be present as
bridged ring systems with an imino, N-(C,~-alkyl)-imino, methylene, C,~-alkyl-
methylene or di-(C~~-alkyl)-methylene bridge, and
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 nitro, and/or one or more NH groups may be substituted by
R2',
R4 has one of the meanings given for R" or denotes C3_6-alkenyl or C3~-
alkynyl,
Rsa, R5b independently of one another denote H, C~_3-alkyl, C3_~-cycloalkyl,
C3_~-cycloalkyl-
C~_3-alkyl, CF3, F or CI, while R5a and R5b representing alkyl may be joined
together such that a C3_,-cycloalkyl group is formed together with the C atom
to
which R5a and R5b are linked,
R'a, R'' independently of one another denote H, F, CI, C»-alkyl or CF3,
R'b, R'd independently of one another denote H, F, C~~,-alkyl, C3_~-
cycloalkyl, C3_T
cycloalkyl-C~_3-alkyl or CF3,
while R'a and R'b representing alkyl may be joined together such that a C3_~-
cycloalkyl group is formed together with the C atom to which R'a and R'b are
linked, and/or
R'' and R'd representing alkyl may be joined together such that a C3_~-
cycloalkyl
group is formed together with the C atom to which R'' and R'd are linked, or
R'b and R'd representing alkyl may be joined together such that a C3_~-
cycloalkyl
group is formed together with the two C atoms to which R'b and R'd are linked;
R'° denotes hydroxy, hydroxy-C~_3-alkyl, C~~-alkoxy, (C~_4-alkoxy)-C,_3-
alkyl, carboxy,
C~_4-alkoxycarbonyl, amino, C~~,-alkyl-amino, di-(C»-alkyl)-amino, cyclo-C3~-
alkyleneimino, amino-C~_3-alkyl, C~~,-alkyl-amino-C~_3-alkyl, di-(C~~-alkyl)-
amino-C~_3-
alkyl, cyclo-C3~-alkyleneimino-C~_3-alkyl, amino-C~_3-alkoxy, C»-alkyl-amino-
C~_3-
alkoxy, di-(C»-alkyl)-amino-C~_3-alkoxy, cyclo-C3~-alkyleneimino-C~_3-alkoxy,
aminocarbonyl, C~~-alkyl-aminocarbonyl, di-(C»-alkyl)-aminocarbonyl or cyclo-
C3~-

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WO 2005/085221 _ g _ PCT/EP2005/002132
alkyleneimino-carbonyl,
R" denotes C,_3-alkyl, CZ~-alkenyl, C2.~-alkynyi, R'5-O-, R'5-O-C,_3-alkyl-,
R'S-O-CO-,
R'5-CO-O-, cyano, R'6R"N-, R'8R'9N-CO- or Cy,
R'3 has one of the meanings given for R",
R'4 denotes halogen, C,~-alkyl, C2~-alkenyl, Cz.~-alkynyl, R'S-O-, R'5-O-CO-,
R'S-CO,
R'S-CO-O-, R'6R"N-, R'$R'9N-CO-, R'S-O-C,_3-alkyl , R'5-O-CO-C~_3-alkyl, R'S-O-
CO-NH-, R'S-S02-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'6R"N-C~_3-alkyl, R'8R'9N-CO-C~_3-alkyl or Cy-
C,_3-
alkyl-,
R'S denotes H, C,~-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, phenyl,
phenyl-C~_3-
alkyl, pyridinyl or pyridinyl-C~_3-alkyl,
R'6 denotes H, C~~-alkyl, C3_~-cycloalkyl, C3_,-cycloalkyl-C~_3-alkyl, Cue,-
cycloalkenyl, C~
-cycloalkenyl-C~_3-alkyl, hydroxy-Cz_3-alkyl, C,~-alkoxy-Cz_3-alkyl, amino-
C2.~-alkyl,
C»-alkyl-amino-C2~-alkyl, di-(C,~-alkyl)-amino-C2.~-alkyl or cyclo-C3~-
alkyleneimino-C2.~-alkyl,
R" has one of the meanings given for R'6 or denotes
phenyl, phenyl-C,_~-alkyl, pyridinyl, dioxolan-2-yl, C~_4-alkylcarbonyl,
hydroxy-
carbonyl-C,_3-alkyl, C»-alkoxycarbonyl, C~~-alkoxycarbonyl-C,_3-alkyl,
C,_4-alkylcarbonylamino-C2_3-alkyl, N-(C,~-alkylcarbonyl)-N-(C~~-alkyl)-amino-
C2_3-alkyl, C»-alkylsulphonyl, C~_4-alkylsulphonylamino-C2_3-alkyl or
N-(C»-alkylsulphonyl)-N-(C~_4-alkyl)-amino-CZ_3-alkyl-,
R'8, R'9 independently of one another denote H or C»-alkyl,
R2° denotes halogen, hydroxy, cyano, C~~-alkyl, C2~-alkenyl, C2~-
alkynyl, C~~-
cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, hydroxy-C»-alkyl, R22-C~_3-alkyl or
has one of
the meanings given for Rz2,
RZ' denotes C~~-alkyl, hydroxy-C2_3-alkyl, C,~-alkoxy-C2~-alkyl, C»-alkyl-
amino-C2~-
alkyl, di-(C,~-alkyl)-amino-C2~-alkyl, cyclo-C3~-alkyleneimino-C2~-alkyl,
phenyl-C~_3-

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WO 2005/085221 - 10 - PCT/EP2005/002132
alkyl, C,~-alkyl-carbonyl, C,~-alkoxy-carbonyl or C,_4-alkylsulphonyl,
R22 denotes phenyl-C~_3-alkoxy, cyclo-C3_6-alkyleneimino-C2~,-alkoxy, C~~,-
alkoxy, C»
alkylthio, carboxy, C~_4-alkylcarbonyl, C,~-alkoxycarbonyl, aminocarbonyl,
C~_4-alkylaminocarbonyl, di-(C,.~-alkyl)-aminocarbonyl, cyclo-C3.~-alkyl-amino-
carbonyl, cyclo-C3~-alkyleneimino-carbonyl, cyclo-C3.~-alkyleneimino-C2~,-
alkyl-
aminocarbonyl, phenyl-amino-carbonyl, C,~-alkyl-sulphonyl, C»-alkyl-sulphinyl,
C»-alkyl-sulphonylamino, amino, C»-alkylamino, di-(C~.~-alkyl)-amino, C»-alkyl-
carbonyl-amino, cyclo-C3~-alkyleneimino, phenyl-C~_3-alkylamino, N-(C~~,-
alkyl)-
phenyl-C,_3-alkylamino, acetylamino, propionylamino, phenylcarbonylamino,
phenylcarbonylmethylamino, hydroxy-C~_3-alkylaminocarbonyl, (4-morpholinyl)-
carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)-carbonyl, (hexahydro-1-
azepinyl)-
carbonyl, (4-methyl-1-piperazinyl)-carbonyl, aminocarbonylamino or C~~-
alkylamino-
carbonyl-amino,
while in the above-mentioned groups and radicals, particularly in X, R' to R4,
R'°, R",
R'3 to RZZ, 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»-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.
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

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WO 2005/085221 _ 11 _ PCT/EP2005/002132
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 ~i-
ketoamide
compounds according to the invention as described above and hereinafter.
Also covered by this invention are compositions containing at least one ~3-
ketoamide
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 ~i-ketoamide 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 ~-ketoamide compound
according to the invention and/ or a salt according to the invention for
influencing the
eating behaviour of a mammal.
The invention also relates to the use of at least one ~i-ketoamide compound
according to the invention and/ or a salt according to the invention 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 (3-ketoamide compound
according to the invention and/ or a salt according to the invention for
preparing a

CA 02552907 2006-07-06
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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 ~i-ketoamide
compound
according to the invention and/ or a salt according to the invention 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 ~i-ketoamide compound
according to the invention and/ or a salt according to the invention for
preparing a
pharmaceutical composition which is suitable for the prevention and/or
treatment of
metabolic disorders and/or eating disorders, particularly obesity, bulimia,
bulimia
nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.
This invention also relates to the use of at least one ~3-ketoamide compound
according to the invention and/ or a salt according to the invention 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 ~i-ketoamide
compound
according to the invention and/ or a salt according to the invention 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 ~i-ketoamide
compound
according to the invention and/ or a salt according to the invention far
preparing a

CA 02552907 2006-07-06
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pharmaceutical composition which is suitable for the prevention andlor
treatment of
micturition disorders, such as for example urinary incontinence, hyperactive
urinary
bladder, urgency, nycturia and enuresis.
The invention further relates to the use of at least one (3-ketoamide compound
according to the invention and/ or a salt according to the invention for
preparing a
pharmaceutical composition which is suitable for the prevention and/or
treatment of
dependencies and/or withdrawal symptoms.
Furthermore the invention relates to processes for preparing a pharmaceutical
composition according to the invention, characterised in that at least one (3-
ketoamide 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.
The invention further relates to a pharmaceutical composition containing a
first active
substance selected from the (3-ketoamide compounds according to the invention
and/
or the corresponding salts 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 dyslipidaemia
or
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.
The invention also relates to a process for preparing [3-ketoamide compounds
of formula I
R\ O O
R2~N X Y Z ~N A-~-B ]b
R3 R5a 'R5b

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WO 2005/085221 - 14 - PCT/EP2005/002132
wherein A, B, b, X, Y, Z, R', R2, R3, R5a and R5b have the meanings given
hereinbefore and
hereinafter,
wherein an amine compound of formula A1
R'
R2~N X Y Z ~ A1
IH
R3
where X, Y, Z, R', R2 and R3 have the meanings given hereinbefore and
hereinafter,
is reacted with a carboxylic acid compound or a carboxylic acid derivative of
formula A2
O O
M A--~B ~b p2
R5a R5b
where A, B, b, R5a and R5b are as hereinbefore defined,
and the group M denotes OH, CI, C»-alkoxy, C,_6-alkylthio or C~~-alkyl-COO-,
in the presence of at least one base, in a solvent or mixture of solvents.
This invention further relates to a process for preparing ~i-ketoamide
compounds of formula I
R\ O O
R2~N X Y Z ~N A-~-B ]b
I3
R
where A, B, b, X, Y, Z, R', R2 and R3 have the meanings given hereinbefore and
hereinafter,
wherein a propynoic acid amide compound of formula B1

CA 02552907 2006-07-06
WO 2005/085221 - 15 - PCT/EP2005/002132
R\ O
R2~N X Y Z ~N ~ A-f -B ~b B1
R3
where A, B, b, X, Y, Z, R', R2 and R3 are as hereinbefore defined,
is hydrolysed by the addition of an acid or base in a solvent or mixture of
solvents and
optionally in the presence of an activating nucleophile.
The starting materials and intermediate products used in the synthesis
according to the
invention, particularly the compounds of formula A1, A2 and B1, are also a
subject of this
invention.
Detailed description of the invention
Unless otherwise specified, the groups, residues and substituents,
particularly A, B, X,
Y, Z, R' to R4, RSa, R5b' R'a, R'b, R'°, R'a, R'o, R", R'3 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.
According to the invention the tautomers of the compounds of formula I,
particularly the enol
tautomers of the keto form represented by formula I, are also included.
In the event that R5b denotes a H atom, the following compounds are included
according to
the invention, while formula I (keto) indicates the keto form and formula I
(enol) indicates the
associated enol form:
R\ O O
R2~N-X-Y- Z ~N A~B 1b I(Keto)
R3 R5a ,H

CA 02552907 2006-07-06
WO 2005/085221 - 16 - PCT/EP2005/002132
R\ O OH
R2~N-X-Y- Z ~N ~ A--~B ]b I(Enol)
R3 R5a
In the embodiments and Examples described hereinafter, only the keto form is
explicitly
mentioned; the corresponding enol form which is readily obtainable by anyone
skilled in the
art is also included in every case, according to the invention.
Particularly preferred definitions of the groups RSa, Rsb are in each case
independently of one
another H, F, CI, CF3, methyl, ethyl, particularly H, F, methyl, ethyl,
particularly preferably H,
F, methyl. According to another preferred embodiment R5a and R5b representing
methyl are
joined together in such a way that a cyclopropyl group is formed together with
the C atom to
which R5a and R5b are linked.
Most particularly preferably RSa, Rsb denote H.
Preferred meanings of the substituent R3 are H, C~~-alkyl, C3~-cycloalkyl or
C3~-cycloalkyl-
C~_3-alkyl; particularly H or C,_3-alkyl. Particularly preferably R3 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 will be given. 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 R2
independently
of one another preferably denote a C~_8-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
phenyl or pyridinyl group optionally mono- or polysubstituted by the group
R2° and/or
monosubstituted by nitro, while one of the groups R' and R2 may also represent
H.

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In the groups R' and R2 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,
Br or CN.
Preferred meanings of the group R" are C~_3-alkyl, Cz~-alkenyl, C2~-alkynyl,
R'S-O-, cyano,
R'6R"N-, C3_~-cycloalkyl, cyclo-C3~-alkyleneimino, pyrrolidinyl, -N-(C~~,-
alkyl)-pyrrolidinyl,
piperidinyl, N-(C»-alkyl)-piperidinyl, phenyl and pyridyl, while in the above-
mentioned groups
and residues 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, Br or CN,
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 vitro,
and/or one or more NH groups may be substituted by R2'. If R" has one of the
meanings
R'S-O-, cyano, R'6R"N- or cyclo-C3~-alkyleneimino, the C atom of the alkyl or
cycloalkyl
group substituted by R" is preferably not directly connected to a heteroatom,
such as for
example the group -N-X.
Preferably the groups R', R2 independently of one another denote H, C~.~-
alkyl, C3_5-alkenyl,
C3_5-alkynyl, C3_,-cycloalkyl, hydroxy-C3_,-cycloalkyl, C3_~-cycloalkyl-C~_3-
alkyl, (hydroxy-C3_~-
cycloalkyl)-C~_3-alkyl, hydroxy-C2~-alkyl, NC-C2_3-alkyl, C~~-alkoxy-C2~-
alkyl, hydroxy-
C»-alkoxy-CZ_4-alkyl, C~_4-alkoxy-carbonyl-C~_4-alkyl, carboxyl-C»-alkyl,
amino-C2~-alkyl,
C,~-alkyl-amino-CZ~-alkyl, di-(C,~-alkyl)-amino-C2~-alkyl, cyclo-C3~-
alkyleneimino-C2.~-alkyl,
pyrrolidin-3-yl, N-(C»-alkyl)-pyrrolidinyl, pyrrolidinyl-C,_3-alkyl, N-(C»-
alkyl)-pyrrolidinyl-C,_3-
alkyl, piperidin-3-yl or -4-yl, N-(C»-alkyl)-piperidin-3-yl or -4-yl,
piperidinyl-C,_3-alkyl, N-(C,~-
alkyl)-piperidinyl-C,_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-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 residues one or
more C atoms
may be mono- or polysubstituted by F and/or one or two C atoms, particularly
one C atom,
may be monosubstituted independently of one another with CI or Br, and the
phenyl or
pyridyl group may be mono- or polysubstituted by the group R2° and/or
monosubstituted by
vitro. 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. Preferably also, the C2~,-alkyl
bridges in the
definitions hydroxy-C2~-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 of the above-mentioned phenyl or
pyridyl groups
are selected from among F, CI, Br, I, cyano, C»-alkyl, C~~-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

CA 02552907 2006-07-06
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and di-(C~_3-alkyl)-amino-C~_3-alkyl, while a phenyl group may also be
monosubstituted by
vitro.
Particularly preferred definitions of the groups R' and/or R2 are selected
from among H, C~~-
alkyl, C3_,-cycloalkyl, C3_,-cycloalkyl-C~_3-alkyl, tetrahydropyran-3 or-4-yl,
tetrahydropyranyl-
C~_3-alkyl, piperidin-3-yl or -4-yl, N-(C~_4-alkyl)-piperidin-3-yl or -4-yl,
piperidinyl-C~_3-alkyl,
N-(C~~-alkyl)-piperidinyl-C~_3-alkyl, phenyl, pyridyl, phenyl-C~_3-alkyl,
pyridyl-C~_3-alkyl,
hydroxy-C2~-alkyl, C,.~-alkoxy-C2_4-alkyl, amino-Cz.~-alkyl, C»-alkyl-amino-
CZ~-alkyl and di-
(C,~-alkyl)-amino-C2~,-alkyl, while cycloalkyl rings may be mono-, dl- 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 in the
definitions
hydroxy-C2~-alkyl and C»-alkoxy-C2~-alkyl may additionally be monosubstituted
by hydroxy,
hydroxy-C~_3-alkyl, C~_3-alkyl or Cy_3-alkyloxy, particularly hydroxy,
hydroxymethy(, methyl or
methoxy, and alkyl groups may be mono- or polysubstituted by F and/or
monosubstituted by
CI.
Particularly preferred definitions of the groups R' and/or R2 are also
selected from among H,
C,~-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_,-cycloalkyl, G3_~-cycloalkyl-C~_3-
alkyl, C»-alkoxy-
Cz_3-alkyl, pyridyl and benzyl, while the alkyl, cycloalkyl or cycloalkylalkyl
group may be
mono- or disubstituted by hydroxy, mono- or polysubstituted by F or
monosubstituted by Br,
CI or CN, and one of the groups R' and RZ may also represent H.
Most particularly preferred groups R' and/or R2 are selected from among H,
methyl, ethyl, n
propyl, i-propyl, n-butyl, i-butyl, propen-3-yl, propin-3-yl, cyclopropyl,
cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl,
phenylmethyl,
pyridylmethyl, tetrahydropyran-4-yl, tetrahydropyran-4-yl-methyl, piperidin-4-
yl, N-(C~~-
alkyl)-piperidin-4-yl, piperidin-4-yl-methyl, N-(C,_4-alkyl)-piperidin-4-yl-
methyl, while the
above-mentioned ethyl, propyl and butyl groups 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.
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, propen-3-yl, propin-3-yl,
cyclopropyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, (1-
hydroxycyclopropyl)methyl,
phenyl, pyrdiyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methyl-
piperidin-4-yl, N-

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(methylcarbonyl)-piperidin-4-yl and N-(tert.butyloxycarbonyl)-piperidin-4-yl,
while
hydroxyalkyl groups may additionally be substituted by hydroxy, and one of the
groups R', RZ
may also represent H.
if the substituent R' has one of the meanings stated above as being preferred,
but
not H, the substituent R2 most particularly preferably denotes H, methyl,
ethyl, n-
propyl, i-propyl, 2-hydroxyethyl or 2-methoxyethyl.
Particularly preferably at least one of the groups R', R2, and 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-, -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 -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 alkyiene bridge defined hereinbefore may be substituted by a carbo- or
heterocyclic group Cy in such a way that the bond between the alkyiene bridge
and
the group Cy is made
- via a single or double bond,
- via a common C atom forming a spirocyclic ring system,
- via firvo 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,.~-alkyl, C~~-alkylcarbonyl or C~~,-
alkyloxycarbonyl. R'3
particularly preferably denotes H or C,~-alkyl, particularly H, methyl, ethyl
or propyl.

CA 02552907 2006-07-06
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Preferably also R' and R2 form an alkylene bridge such 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.-on, morpholine
and thiomorpholine,
particularly selected from pyrrolidine, piperidine, piperidin-4-one, 2,5-
dihydro-1 H-pyrrole,
piperazine, wherein the free imine function is substituted by R'3, morpholine
and
thiomorpholine,
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_s-
cycloalkyl, cyclo-C3_5-alkyleneimino, as well as N-C~~-alkyl-(aza-C4_s-
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, which may be substituted as defined
hereinbefore.
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_8-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~_4-alkyl in each case.

CA 02552907 2006-07-06
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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~_4-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 C~$-
cycloalkyl
or aza-Cø$-cycloalkyl.
~X
Particularly preferably the group R N ~'
1 2
R
is defined according to one of the following partial formulae
'N-X~ , 'N-X-T , N-X
' N-X
N-X~ , I N-X-~ ,
N-X~ ' N-X~ ' R13 ~N-X-;
N-X . ~ ~ N N-X
N-X--~ , O N-X
N \
O N-X~ , ~ N-X-; , N-X
U

CA 02552907 2006-07-06
WO 2005/085221 _ 22 _ PCT/EP2005/002132
R2~N
S N-X
v
N-X--
R2' N N-X-~ N-X
. , ,
R2~iN
~ ,
N N-X-; , N N-X
R2' N I
N
v . v
N-X-~ N-X-
N N
v . v
N-X-; N-X-
v . v
N-X ~ , N-X
N N
R2'
~N N-X
N-X-.
R2~
R2' N N-X-
N
N X
R2~
\N , N N-X
R2~ i
N-X

CA 02552907 2006-07-06
WO 2005/085221 _ 23 - PCT/EP2005/002132
N-X-; , R2'-N N-X
\ . /
N X~ ' ~ I N X ' ' / I N-X-T ,
S
~ ~ ,
N-X~ N-X-,,, , N-X~,
N N-X~, \ ,
R~3~N N~X~,, ,
R? N~X" ~ , R? N , R2 N
X"-
X'-''
R? N, l , R2 N
X"~
X'
_ , ~N ,
N~X,~j., IN/ V~X,i~, N~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~R2N- 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

CA 02552907 2006-07-06
WO 2005/085221 - 24 - PCT/EP2005/002132
monosubstituted by nitro 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 (of the group
Y), 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 (of the group Y),
also denotes -NH-, -N(C~_3-alkyl)- or -O-,
while in the meanings given for X', X" hereinbefore in each case a C atom
may be substituted by R~°, preferably by a hydroxy, w-hydroxy-C~_3-
alkyl,
w-(C»-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 finro 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_7-
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, R14~ R~s, R2o, Rz~ 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"

CA 02552907 2006-07-06
WO 2005/085221 - 25 - PCT/EP2005/002132
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 -CHZ-
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,~-
alkyl, C2~-
alkenyl, C2.~-alkynyl, C3_,-cycloalkyl-C,_3-alkyl, hydroxy, hydroxy-C,_3-
alkyl, C,_4-alkoxy,
cu-(C,~,alkoxy)-C,_3-alkyl, C,~,-alkyl-carbonyl, carboxy, C,_4-alkoxycarbonyl,
hydroxy-carbonyl-
C,_3-alkyl, C,~-alkoxycarbonyl-C,_3-alkyl, C,_4-alkoxy-carbonylamino, C,~-
alkoxy-carbonyl-
amino-C,_3-alkyl, amino, C,_4-alkyl-amino, C3_~-cycloalkyl-amino, N-(C3_~-
cycloalkyl)-N-(C,~-
alkyl)-amino, di-(C,~-alkyl)-amino, amino-C,_3-alkyl, C,~-alkyl-amino-C,_3-
alkyl, C3_,-cyclo-
alkyl-amino-C,_3-alkyl, N-(C3_,-cycloalkyl)-N-(C,~-alkyl)-amino-C,_3-alkyl, di-
(C,~-alkyl)-amino-
C,_3-alkyl, cyclo-C3~-alkyleneimino-C,_3-alkyl, aminocarbonyl, C,~-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,~-
alkyl, C3~-
cycloalkyl-C,_3-alkyl, hydroxy, hydroxy-C,_3-alkyl, C,_4-alkoxy, C,~-alkoxy-
C,_3-alkyl, amino-
C,_3-alkyl, C,~-alkyl-amino-C,_3-alkyl, C3_,-cycloalkyl-amino-C,_3-alkyl, N-
(C3_~-cycloalkyl)-N-
(C,~-alkyl)-amino-C,_3-alkyl, di-(C,~-alkyl)-amino-C,_3-alkyl, cyclo-C3~-
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. Thus, preferred meanings of R'4 also include for example -CF3 and -
OCF3.
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_6-cycloalkyl and R2° preferably denotes F,
hydroxy, C,_3-alkyl,

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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.
%'~,
Most particularly preferably the group R
R2
is defined according to one of the following partial formulae
'
N--T N-r N
' ,
'
N ~ I -' O N-;
N ' , ,
'
N N-y
. ,
' N
N-'
O N ~ R'3 N~ N--
U ~ ~.
\ ' ~ ,
N~ , N N~ N
R13iN w
\ ' ~ '
N~ N
' , ,
while the group R'3 has the meanings given hereinbefore and hereinafter, and
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 RZ°, particularly
by F, hydroxy,

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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 vitro and
R'4 in each case independently of one another denotes F, Ci, C~.~-alkyl, C3~-
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.
Preferably X denotes a C~_6-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
a C atom not directly connected to a heteroatom 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~_6-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_~-
cycloalkyl, C3_~-

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cycloalkyl-C~_3-alkyl, C4_~-cycloalkenyl and C4_~-cycloalkenyl-C~_3-alkyl,
particularly
C»-alkyl, while two alkyl and/or alkenyl substituents may be joined together
forming
a carbocyclic ring system, particularly a cyclopropyl, cyclobutyl or
cyclopentyl group.
In the above-mentioned definition of the bridge X two C atoms or a C and an N
atom of the
alkylene bridge may be joined together by an additional C~.~-alkylene bridge.
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-.
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.
Preferably X denotes an unbranched C~_4-alkylene bridge and
in the event that the group Y is linked to X via a C atom (of the group Y), it
also
denotes -CH2-CH=CH-, -CH2-C---C-, C2_4-alkylenoxy or C2_4-alkylene-NR4,
particularly
C2~,-alkylenoxy or C2_4-alkylene-NR4-,
while R4 may be connected to Y, forming a heterocyclic ring system,

CA 02552907 2006-07-06
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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~~-alkyl, C2_6-alkenyl, C2_6-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-
C~_3-alkyl,
C~7-cycloalkenyl and C4_~-cycloalkenyl-C~_3-alkyl, particularly C~_4-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
R', R4 and R'° are as hereinbefore defined.
Particularly preferably X denotes -CHZ-, -CH2-CH2- or -CH2-CHZ-CH2- or -CHZ-
CH=CH-CHz-
and
in the event that the group Y is linked to X via a C atom (of the group Y), X
also denotes
-CH2-CH=CH-, -CH2-C--_C-, -CH2-CH2-O-, -CHZ-CH2-CHZ-O- or -CH2-CHZ-NRQ- or -
CHZ-CHz-
CHZ-NR4-, particularly -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CHZ-NR4- or -CH2-CHZ-
CH2-
N R4-,
while R4 may be connected to Y forming a heterocyclic ring system with one
another,
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'°, preferably a hydroxy,
c°-hydroxy-C~_3-alkyl,
cu-(C,~-alkoxy)-C,_3-alkyl and/or C,_4-alkoxy group, and/or one or two C atoms
independently
of one another may each be substituted by one or two identical or different
C~~-alkyl groups,
while two alkyl groups may be joined together, forming a carbocyclic ring
system, and

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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 may independently of one another be monosubstituted by
CI or Br.
Most particularly preferably, in the event that the group Y is linked to X via
a C atom (of the
group Y), X denotes -CH2-, -CH2-CH2-, -CHz-CHZ-CH2-, -CHZ-CHZ-O-, -CHZ-CH2-CH2-
O-, -
CHZ-CHZ-NR4- or -CH2-CH2-CHZ-NR4-, which may be unsubstituted or substituted
as
described.
R4 has one of the meanings given for R", preferably has one of the meanings
given for R's.
Particularly preferred meanings of the substituent R4 are H, C»-alkyl and C3~-
alkenyl. Most
particularly preferably R4 denotes H, methyl or ethyl. If R4 is joined to Y,
forming a
heterocyclic ring system, particularly preferred meanings of R4 are C2.~-alkyl
and C2~-alkenyl.
In the event that R4 is linked to Y forming a heterocyclic ring system with
one another, Y
preferably denotes phenyl and R4 preferably denotes C2~-alkyl or C2~-alkenyi.
The
heterocyclic ring systems preferably formed are indole, dihydroindole,
quinoline,
dihydroquinoline, tetrahydroquinoline and benzoxazole.
The group R4 preferably denotes vinyl only when R4 is linked to Y forming a
heterocyclic ring
system.
The substituent R'° preferably denotes hydroxy, c°-hydroxy-C,_3-
alkyl, C~.~-alkoxy or
cu-(C~~,-alkoxy)-C,_3-alkyl, particularly hydroxy, hydroxymethyl or methoxy.
The group X preferably does not comprise a carbonyl group.
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, cu-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_4-alkynyl, C3_~-cycloalkyl and C3_~-cycloalkyl-C~_3-
alkyl,
particularly C,~-alkyl, and two C~_4-alkyl and/or C2_4-alkenyl substituents
may also be
joined together to form a saturated or monounsaturated carbocyclic ring.

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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.
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
two alkyl
substituents at a C atom may 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 as specified
hereinbefore,
particularly preferred meanings of X, X' and X" are selected from among
O '
y\'~0~,~ , ,
.~' , , O
, ~,
~, ,
, ,
OH
O
y\~ , ,, ,
O , ~, ,
, , ,
OH
/ ~.,
r , ~ / ,
, , , ,
/ ~ , ~., / , ,
,
, ,
, ,
,
~ , ,
, , N ',
/ , ~, ,
, , , ,
, , ~,
, / ,:~~N
, ,

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If Y denotes a fused bicyclic ring system, a preferred definition of the group
X is -CH2-, -CH2-
CHZ- and -CH2-CH2-CH2-, particularly -CHZ- or -CH2-CHZ-, which may be
substituted as
specified.
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, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-
onyl, thienyl,
benzothienyl, pyrimidinyl or benzofuranyl, while the above-mentioned cyclic
groups may
be mono- or polysubstituted at one or more C atoms by R2°, in the case
of a phenyl
ring may also additionally be monosubstituted by vitro, 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, while Y preferably denotes phenyl.
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

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WO 2005/085221 - 33 - PCT/EP2005/002132
.
,~N ~ ~ ' ' ~ ~ ~ '
' N \ '
/ \ , ,
' ;
~ ~ / O /
'N
\ ,
\ , ~ ,
' /
' S
O '
S
O
O
in particular Y has one of the following meanings
1
' N
-N
N \ ' ' '
/ I
O '
while 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 ring may also additionally be
monosubstituted by
nitro, and/or one or more NH groups may be substituted by R2'

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The group Y representing phenyl 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 one
another are selected from the list comprising
, ~ / , . ,
/ ' ~ / '
,
/ ~ ,
r
' o
while the above-mentioned cyclic groups may be mono- or polysubstituted by
RZ° at one or
more C atoms, and in the case of a phenyl ring may also additionally be
monosubstituted by
nitro.
The group Y is preferably unsubstituted or mono- or disubstituted.
Particularly preferred substituents RZ° of the group Y are selected
from among fluorine,
chlorine, bromine, cyano, vitro, C»-alkyl, CZ_6-alkenyl, hydroxy, hydroxy-C~_3-
alkyl,
C»-alkoxy, trifluoromethyl, trifluoromethoxy, Cz~-alkynyl, C,~,-
alkoxycarbonyl, C~.~-alkoxy-
C~_3-alkyl, C»-alkoxy-carbonylamino, amino, C»-alkyl-amino, di-(C»-alkyl)-
amino,
aminocarbonyl, C~_4-alkyl-amino-carbonyl and di-(C~_4-alkyl)-amino-carbonyl.
Most particularly preferred substituents Rz° of the group Y are
selected from among fluorine,
chlorine, bromine, cyano, C~_3-alkyl, C,_3-alkoxy, C,_4-alkoxycarbonyl,
trifluoromethyl,
trifluoromethoxy, amino, and in the case of a phenyl ring also vitro.
Most particularly preferably the group Y denotes substituted phenylene of the
partial formula
L'
' , wherein L' has one of the meanings given
, ~ / ,

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previously for RZ°, preferably F, CI, Br, I, CH3, CF3, OCH3, OCF3,
methoxycarbonyl,
ethoxycarbonyl, CN, amino or NO2, or denotes H. Particularly preferred
meanings of the
substituent L' are H, CI or methoxy.
The bridge Z denotes a single bond or -CR'aR'b-CR'°R'd, wherein R'a,
R'b, R'~, R'd
independently of one another preferably represent H, F, CH3 or CF3.
Other preferred definitions of the bridge Z are selected from:
~, , ', ,
. , , , , '
', ,
,
Particularly preferred definitions of the bridge Z are a single bond and -CH2-
CH2-. Most
particularly preferably Z is a single bond.
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 by R2° at one or more C
atoms, and in the
case of a phenyl ring may also additionally be monosubstituted by vitro.
If b 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 based on the ~3-ketoamide group.
Most particularly preferably A is one of the following groups

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,
N
while these groups may be mono- or polysubstituted by R2° as specified.
Particularly preferred substituents RZ° of the group A are selected
from among fluorine,
chlorine, bromine, cyano, C~_4-alkyl, C2~-alkenyl, hydroxy, hydroxy-C~_3-
alkyl, C»-alkoxy,
trifluoromethyl, trifluoromethoxy, CZ_4-alkynyl, carboxy, C,~-alkoxycarbonyl,
C~~-alkoxy-
C~_3-alkyl, C~~-alkoxy-carbonylamino, amino, C,~-alkyl-amino, di-(C»-alkyl)-
amino, cyclo-
C3~-alkyleneimino, aminocarbonyl, C,~-alkyl-amino-carbonyl and di-(C»-alkyl)-
amino-
carbonyl.
Most particularly preferred substituents R2° of the group A are
selected from among fluorine,
chlorine, bromine, cyano, C,~-alkyl, C,~-alkoxy, trifluoromethyl,
trifluoromethoxy, carboxy,
C~~-alkoxycarbonyl, C,~-alkyl-amino and di-(C,~-alkyl)-amino.
In the event that b has the value 0, a particularly preferred definition of
the group A is
substituted phenyl of the partial formula
(L )a
' 3
~~ ~ L
wherein
L2 has one of the meanings given for R2° or denotes H, preferably F,
CI, Br, I, CH3,
CF3, OCH3, OCF3, CN or NOZ,
L3 has one of the meanings given for R2° or denotes H, preferably F,
CI, Br, I, CF3,
OCF3, CN, N02, C,~-alkyl, C3_,-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, C»-
alkoxy,
C3_~-cycloalkyl-O, C3_,-cycloalkyl-C,_3-alkoxy, -COO-C~~,-alkyl or -COOH;
particularly preferably F, CI, Br, C,~-alkyl, CF3, methoxy, OCF3, CN or N02;
most
particularly preferably CI, Br, CF3 or N02;

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q has the value 0, 1 or 2.
with the proviso that the phenyl group can 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.
A particularly preferred definition of the substituent L2 is CI.
Particularly preferred meanings of the substituent L3 are CI, methoxy and CF3.
In the event that b = 1, the group A preferably denotes unsubstituted phenyl
or phenyl
substituted by L2, while L2 is preferably in the ortho position to the (3-
ketoamide group. L2 is
as hereinbefore defined.
In the event that b has the value 1, a preferred definition of the group B is
aryl or heteroaryl,
which may be substituted as specified.
Preferred definitions of the group B are selected from among 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 unsubstituted or mono-, di-
or
trisubstituted, particularly unsubstituted or mono- or disubstituted. In the
case of a
monosubstitution the substituent is preferably in the ortho or para position,
particularly in the
para position to the group A.
Preferred substituents RZ° of the group B are selected from among
fluorine, chlorine,
bromine, cyano, vitro, C,_4-alkyl, hydroxy, hydroxy-C,_3-alkyl, C»-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~.~-alkyl)-amino, cyclo-
C3.~-
alkyleneimino, aminocarbonyl, C,_4-alkyl-amino-carbonyl and di-(C~~-alkyl)-
amino-carbonyl.
Particularly preferred substituents RZ° of the group B are selected
from among fluorine,
chlorine, bromine, cyano, CF3, C,_3-alkyl, C,_4-alkoxy, trifluoromethoxy and
vitro; particularly
fluorine, chlorine, bromine, methoxy, CF3 and trifluoromethoxy.

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Most particularly preferred substituents RZ° of the group B are
selected from among chlorine
and methoxy.
The following are preferred definitions of other substituents according to the
invention:
Preferably the substituent R'3 has one of the meanings given for R'6.
Particularly preferably
R'3 denotes H, C,~-alkyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C,_3-alkyl, w-
hydroxy-C2_3-alkyl,
cu-(C,~-alkoxy)-C2_3-alkyl. Most particularly preferably R'3 denotes H or C,~-
alkyl. The alkyl
groups mentioned above may be monosubstituted by CI or mono- or
polysubstituted by F.
Preferred meanings of the substituent R'S are H, C,_4-alkyl, C3_~-cycloalkyl,
C3_~-cycloalkyl-
C~_3-alkyl, 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 R'S
denotes H, methyl, ethyl, propyl or butyl.
The substituent R'6 preferably denotes H, C,_4-alkyl, C3_,-cycloalkyl, C3_~-
cycloalkyl-C~_3-alkyl,
c~-hydroxy-C2_3-alkyl or w-(C,_4-alkoxy)-C2_3-alkyl, 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 R'6 denotes H, C,_3-alkyl, C3~-cycloalkyl or
C3~-cycloalkyl-C,_3-
alkyl.
Preferably the substituent R" has one of the meanings given for R'6 as
preferred meanings
or denotes phenyl, phenyl-C,_3-alkyl, pyridinyl or C,_4-alkylcarbonyl.
Particularly preferably R"
has one of the meanings given for R'6 as preferred meanings.
The substituent R2° preferably denotes halogen, hydroxy, cyano, C,~,-
alkyl, CZ~-alkenyl, C2~-
alkynyl, C3_,-cycloalkyl, C3_~-cycloalkyl- C,_3-alkyl, hydroxy-C,~-alkyl, R22-
C,_3-alkyl or has one
of the meanings given for R22 as preferred meanings, 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 preferred definitions of the group R2° are halogen,
hydroxy, cyano, C,~-alkyl,
C3_~-cycloalkyl and C,_4-alkoxy, 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

CA 02552907 2006-07-06
WO 2005/085221 _ 3g - PCT/EP2005/002132
atoms independently of one another may additionally be monosubstituted by CI
or Br. Most
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.
The substituent R22 preferably denotes C~_4-alkoxy, C»-alkylthio, carboxy, C»-
alkylcarbonyl,
C~_4-alkoxycarbonyl, aminocarbonyl, C,_4-alkylaminocarbonyl, di-(C1~-alkyl)-
aminocarbonyl,
C~~-alkyl-sulphonyl, C~_4-alkyl-sulphinyl, C,~,-alkyl-sulphonylamino, amino,
C~~-alkylamino,
di-(C»-alkyl)-amino, C,~-alkyl-carbonyl-amino, hydroxy-C~_3-
alkylaminocarbonyl,
aminocarbonylamino or C~~-alkylaminocarbonyl-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.
Preferred definitions of the group R2' are C,_4-alkyl, C~_4-alkylcarbonyl,
C~_4-alkylsulphonyl, -
S02-NH2, -SOZ-NH-C~_3-alkyl, -S02-N(C,_3-alkyl)2 and cyclo-C3.~-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 RZ' are H, C,_4-alkyl, C~~,-
alkylcarbonyl, C~_4-
alkoxycarbonyl, particularly H and C,_3-alkyl.
Cy preferably denotes a C3_,-cycloalkyl, particularly a C3.~-cycloalkyl group,
a C~~-
cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, a
phenyl ring to which a C5_~-cycloalkyl or aza-C4_~-cycloalkyl group is fused,
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
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'.
The term aryl preferably denotes phenyl or naphthyl, particularly phenyl.
The term heteroaryl preferably comprises pyridyl, indolyl, quinolinyl and
benzoxazolyl.

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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.
Particularly preferred compounds according to the invention are those wherein
Y has one of the following meanings
' ~ ~ . ,,~
' N
-N
N ~ '. ' ,
'
/ I ,
. /
O '
while 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 ring may also additionally be
monosubstituted by vitro, and/or
A denotes phenyl or pyridyl, which may be mono- or polysubstituted by
R2°, and may
also additionally be monosubstituted by vitro, and/or
B denotes phenyl which may be mono- or polysubstituted by R2°, and
may also
additionally be monosubstituted by vitro, and/or
b has the value 0 or 1.
Most particularly preferred are those compounds according to the invention
wherein A, B, b,
X, Y, Z, R', R2, R3, R5a and R5b independently of one another have one or more
of the
preferred meanings mentioned above.
Preferred groups of compounds according to this invention can be described by
the following
formulae, particularly La, I.b and I.c:

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L 1 J p ~ R2 J r [ R2~, s
I.a
R\ O O
R2/N C 2 ~ ~ Z i C % \ C
R3 R~ R5b
L1 Jp ~ R2Jr [ R2~]s
R\ O O Lb
R2/N CHZ C 2 ~ ~ Z i C / \ C \C
R3 R5a R5b
L1 .1p L R2Jr [ R2~]s
Lc
R\N-CH -CH - Z-N-O-C-O
z/
R 2 2 ~ 3 5a/ ~ 5b
R R R
L2 J r
Ld
R \N-C Z -N-O-C-O L3
2/ 2 I \
R R3 R5a R5b Q
L~ Jp ~ L2 Jr
O O Le
R
2 N-CH2-C 2 Z-N-C-C-C \~/ L3
R Ra RSa/ R5b Q
[ L~,p L L2Jr
Lf
R\ O O
2/N CH2 CH2 ~ ~ Z-N-C C C \ I ~ L3
R R3 R5a R5b Q

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L R2 J r [ RZ~, s
I.g
R O O
R2/N~N ~ I ~ Z i C ~ \ C
R3 R5a R5b
RAN N [ L1 ]p L R2Jr [ R2~]s
R2/ ~ O O I.h
Z -N-C-~ -C \ ~ '
3 5a ~ 5b
R R R
[L1]p LL2Jr
Li
R /N N Z-N- -C-~ Ls
R2 ~ 3 5a/ ~ 5b
R R R
RAN N [ L~,p ~ Lz Jr
R2/ ~ 0 ~ 3 1.j
O \ ' / Z-N-C-~ -C \ '~L
R3 R5a R5b QQ
while the bridges X appearing in formulae I.a to I.j representing -CH2-, -CH2-
CH2- and -CH2-
CH2-O- may have one or two substituents independently of one another selected
from
among C~_3-alkyl and C3_5-cycloalkyl, while two alkyl substituents may be
joined together,
forming a C3~-cycloalkyl group; particularly preferably, the above-mentioned
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', L2, L3, R', R2, R3, R5a, R5b and RZ° are as hereinbefore defined
and substituents occurring
several times may have the same or different meanings; particularly
R', R2 independently of one another denote H, C,~-alkyl, C3_~-cycloalkyl, C3_7-
cycloalkyl-
C~_3-alkyl, tetrahydropyran-3 or -4-yl, tetrahydropyranyl-C,_3-alkyl,
piperidin-3-yl or

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-4-yl, N-(C~~-alkyl)-piperidin-3-yl or -4-yl, piperidinyl-C~_3-alkyl, N-(C~~-
alkyl)-
piperidinyl-C,_3-alkyl, phenyl, pyridyl, phenyl-C~_3-alkyl, pyridyl-C~_3-
alkyl,
hydroxy-C2~,-alkyl, C,_4-alkoxy-Cz_4-alkyl, amino-C2_4-alkyl, C»-alkyl-amino-
C2~-
alkyl or 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
CZ_4-alkyl bridges in the definitions hydroxy-Cz~-alkyl and C~~-alkoxy-C2.~-
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; R',
RZ independently of one another denote methyl, ethyl, n-propyl, i-propyl, 2-
hydroxyethyl, 2-hydroxy-propyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 2-
methoxyethyl, 3-amino-propyl, propen-3-yl, propin-3-yl, cyclopropyl,
cyclopentyl,
cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, (1-
hydroxycyclopropyl)methyl,
phenyl, pyrdiyl, phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl, N-methyl-
piperidin-4-yl, N-(methylcarbonyl)-piperidin-4-yl or N-(tert.butyloxycarbonyl)-
piperidin-4-yl, while hydroxyalkyl groups may additionally be substituted by
hydroxy, and one of the groups R', RZ may also represent H; or
,,
R', R2 are joined together such that the group R1
R2
is defined according to one of the following partial formulae
\
v . ~ . N_
N-~- N-r
\ ,
( 'N-X-: O N
N-X-~ ' ' '
N N
' N
N-'

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R~s N NN-T N
O N ' ,
~ . ,
N N~ \
' ' N
R 13i
N
' ~ '
N . N ,
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.~-
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'RzN- may be mono-
or polysubstituted, preferably monosubstituted by R2° at one or more C
atoms,
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 denote F, CI, C,~-alkyl, C~-
cycloalkyl-C,_3-alkyl, hydroxy, hydroxy-C,_3-alkyl, C,_4-alkyloxy, C,~,-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,_4-alkyloxycarbonyl;
particularly
preferably denotes H or C,_3-alkyl; and
Q denotes CH or N, particularly denotes CH, while CH may be substituted by
R2°,

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L', L2, L3 in each case independently of one another have one of the meanings
given
previously for RZ°, preferably denote fluorine, chlorine, bromine,
cyano, C~_3-alkyl,
C~_3-alkoxy, trifluoromethyl, trifluoromethoxy or nitro,
p has the value 0 or 1,
r, s in each case independently of one another have the value 0, 1, 2 or 3,
preferably
0, 1 or 2, particularly preferably 0 or 1, and
Z, RSa, Rsb and RZ° are as hereinbefore defined and substituents
occurring more than once
may have the same or different meanings, and in particular
Z denotes a single bond or -CHZ-CH2-, particularly preferably a single bond,
RSa, Rsb independently of one another denote H, F, CI, methyl or ethyl,
particularly
preferably H,
R2° in each case independently of one another preferably denote
fluorine, chlorine,
bromine, cyano, C,_4-alkyl, C2_6-alkenyl, hydroxy, hydroxy-C~_3-alkyl, C»-
alkoxy,
trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C~~-alkoxycarbonyl,
C~~-alkoxy-C,_3-alkyl, C~_4-alkoxy-carbonylamino, amino, C~~-alkyl-amino,
di-(C»-alkyl)-amino, cyclo-C3~-alkyleneimino, aminocarbonyl, C~.~-alkyl-amino-
carbonyl and di-(C,~-alkyl)-amino-carbonyl,
particularly preferably Rz° is selected from fluorine, chlorine,
bromine, cyano,
vitro, C~~-alkyl, hydroxy, w-hydroxy-C~_3-alkyl, C~_4-alkoxy, trifluoromethyl,
trifluoromethoxy, CZ_4-alkynyl, carboxy, C,~-alkoxycarbonyl and C~~-alkoxy-
C~_3-alkyl.
The compounds listed in the experimental section are preferred according to
the invention.
Some particularly preferred compounds are shown below:

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NJ
A.1
a
° i ~ o
' ~~
~i
H3C
A.2
rN
A.3
G
H3C~N~° ~ ~ O O G
A.4
,~~J \ N \
i
H3C:~~~° ~ ~ O O CI
H3C N ~ I A.5
A.6

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WO 2005/085221 _ q.7 _ PCT/EP2005/002132
~H
J~
H~c
A.7
c~
I
0 0
A.8
G'J'''
Hs~/N /
A.9
N
A.10

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WO 2005/085221 _ 4g _ PCT/EP2005/002132
a
A.11
A.12
A.13
A.14
0 0
/ N v \
/ \
A.15
/
N

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WO 2005/085221 _ qg - PCT/EP2005/002132
N~ A.16
H3C
~N
~CH3
A.17
A.18
/ \
a
/
N I ~ A.19
\
i
a
Fi3C~N~O / ~ O CI
H3cJ I \ A.20
/ F
F F
Some expressions used hereinbefore and below to describe the compounds
according to the invention will now be defined more fully.

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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.
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-CH2-), 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_~-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-
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~_~-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.

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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-
butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-
pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
The term C3_~-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_~ 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.

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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,
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 C3_rcycloalkyl-C,_~ alkyl, aryl-C~_~ alkyl, heteroaryl-C~_~
alkyl, etc. refer to
C~_~ alkyl, as defined above, which is substituted with a C3_~-cycloalkyl,
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 expression "optionally substituted" used in this application indicates
that the
group thus designated is either unsubstituted or mono- or polysubstituted by
the

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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.
R2ols
Thus in the example J 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~_~6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl,
pentanoyl or
hexanoyl group, an allyloxycarbonyl group, a C~_~6-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~_6-alkoxycarbonyl
group such as the benzyloxycarbonyl, phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a C~_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C~_3-
alkoxy-
C2~,-alkoxy-C2~-alkoxycarbonyl or ReCO-O-(RfCRg)-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

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R9 denotes a hydrogen atom, a C~_3-alkyl or ReCO-O-(RfCRg)-O- group wherein Re
to
R9 are as hereinbefore defined,
while the phthalimido group is an additional 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.
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,

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for example with a Boc, Fmoc or Cbz protective group, and liberated at the end
of the
reactions using standard methods.
~nthesis plan A:
R~ O O
R2~N X Y Z~NH + M A--~B,b
R3 R5a R5b
A1 i
R\ O O
R2~N X Y Z ~N A-~-B ~b
R3 R~ R5b
Compounds of formula I according to the invention are obtained according to
Synthesis plan
A by reacting an amine of formula A1 with a carboxylic acid or a carboxylic
acid derivative of
formula A2 using amide synthesis methods known in the art. In the carboxylic
acid derivative
A2 the group M preferably has a meaning selected from OH, CI, C»-alkoxy, C»-
alkylthio,
C~_6-alkyl-COO, etc.
Preferably the carboxylic acid compound of formula A2 (M = OH) is reacted with
at least one
peptide coupling reagent, such as for example TBTU, in a solvent or mixture of
solvents and
then the reaction mixture is further reacted with the amine compound of
formula A1, while the
minimum of one base is added to the reaction mixture before and/or after the
reaction of the
carboxylic acid compound with TBTU. The peptide coupling reagent, such as
TBTU, is
advantageously used in an equimolar amount or in an excess relative to the
carboxylic acid
A2, preferably from equimolar to a 50 mol% excess. Alternatively the reaction
may also be
carried out in the presence of an amount of HOBt which is equimolar to the
TBTU.
Advantageously the carboxylic acid of formula A2 is used with TBTU and then
this reaction
mixture is used with the amine compound of formula A1 in a molar ratio of the
carboxylic acid
compound of formula A2 : amine compound of formula A1 : TBTU : base of 1 ~
0.25 : 1 ~
0.25 : 1 t 0.25 : 1 to 4.

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Instead of a carboxylic acid it is also possible to use the corresponding
activated carboxylic
acid derivatives, such as for example esters, orthoesters, carboxylic acid
chlorides or
anhydrides.
Suitable bases are, in particular, tertiary amines such as triethylamine or
Hunig base as well
as alkali metal carbonates, for example potassium carbonate. The reactions
take place in a
suitable solvent or mixture of solvents, while DMF and/or THF is preferably
used. The
carboxylic acid or the carboxylic acid derivative (A2) and the amine (A1 ) are
preferably used
in a molar ratio of 1.5:1 to 1:1.S.The reaction is advantageously carried out
over a period of
from 1 to 24 hours in a temperature range from 0°C to 120 °C,
preferably 20°C to 80°C.
If activation of the carboxylic acid compound A2 (M = OH) is desired, this can
advantageously be done using a mixed anhydride. The mixed anhydride of the
carboxylic
acid A2 in question is preferably prepared by reacting the carboxylic acid
with an excess of
alkyl chloroformate, preferably isopropyl chloroformate, in a molar ratio of
1:1 to 1:1.2.
Suitable bases are preferably tertiary amines, for example N-
methylmorpholines, which are
used in an equimolar amount to the alkyl chloroformate in question.
The reaction is carried out in a suitable solvent such as THF of temperatures
between -20 °C
and 20 °C, particularly -15 to 0°C, and takes place over a
period of 10 to 2400 minutes.
The mixed anhydride thus obtained is preferably reacted with an amine compound
(A1 )
without further purification. The amine compound (A1 ) is used in an excess
relative to the
carboxylic acid derivative (A2) in question, preferably in a 5-10 mol% excess.
The reaction is
carried out for example at 0°C to 60°C over a period of 1 to 4
hours.

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Synthesis plan B1:
R~ O
2 N-X-Y- Z ~N%~A B B1
R ~ 3 ---E- Jb
R
R\ O O
2~N-X-Y- Z wN%~A B
R ~ 3 .--.~ J b
R
Alternatively compounds of formula I according to the invention may be
obtained according
to Synthesis plan B1 by hydrolysis of the triple bond of the propynoic acid
amides of formula
B1. The hydrolysis of the propynoic acid amides to form the corresponding ~i-
ketoamide is
carried out by the addition of an acid or base and optionally in the presence
of an activating
nucleophile. Suitable acids for this purpose are particularly strong inorganic
or organic acids,
such as for example hydrochloric acid, sulphuric acid, acetic acid, formic
acid, oxalic acid,
methanesulphonic acid or trifluoromethanesulphonic acid. Suitable bases are
particularly
alkali metal hydroxides, carbonates or acetates, such as for example potassium
hydroxide,
sodium hydroxide, lithium hydroxide, sodium acetate or potassium carbonate, or
aqueous
solutions of secondary or tertiary amines, such as for example triethylamine,
piperidine,
morpholine, diisopropylethylamine or diethylamine.
The acid or base is advantageously used in a molar excess compared with the
propynoic
acid amide.
Examples of suitable activating nucleophiles include in particular secondary
amines, such as
for example piperidine, morpholine or diethylamines or thiols, such as for
example
ethanethiol or thiophenol, or phosphines such as for example
triphenylphosphine or
tributylphosphine.
The reaction is advantageously carried out in a suitable solvent or mixture of
solvents,
possibly in alcohols, such as for example in ethanol, or in acetone,
dimethylformamide,
dimethylsulphoxide or acetonitrile, optionally in each case with the addition
of small amounts
of water, particularly less than or equal to 10 vol-% based on the volume of
solvent, at

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temperatures between 20 and 120°C, preferably in the region of the
boiling temperature of
the solvent. Suitable reaction times are usually in the range from 1 to 24
hours.
Synthesis plan B2:
1 3
R /N-X Y Z NvR + p'--~B ]b
R H HO
B2 B3
R\ O
R2/N 7C Y Z i 3 C C-C A-~"B Jb
R
B1
Compounds of formula B1 may be obtained by reacting an amine compound of
general
formula B2 with a propynoic acid compound of general formula B3 in an organic
solvent such
as for example DM, TH, 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 B3 it is also possible to use the carboxylic acid
chloride or a mixed
anhydride of compound B3. The amide linking process described in connection
with
Synthesis plan A may also be used here.

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Synthesis plan B3:
Br
HO / p~g Jb gr HO A~B Jb
z
O B4 O Br
B5
O
A~g Jb
HO
B3
A compound of general formula B3 may also be prepared by reacting a compound
of general
formula B5 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 for this
reaction to react a compound of general formula B5 with pyridine or quinolin
at temperatures
from 0°C to 150°C. A compound of general formula B5 is obtained
by brominating a
compound of general formula B4 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.
The compounds according to the invention may advantageously also be obtained
by the
methods described in the following Examples, which may also be combined with
methods
known to the skilled man from the literature, for example.
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.
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

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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
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

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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
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
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, curbing appetite, controlling eating behaviour and/or inducing a
feeling of
satiation.

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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 andlor treatment of other illnesses and/or disorders, particularly
those
which accompany obesity, such as for example diabetes, diabetes meNitus,
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, urgency,
nycturia,
enuresis, while the hyperactive bladder and urgency may or may not be
connected
with benign prostatic hyperplasia.
Generally speaking, the compounds according to the invention are potentially
suitable for
preventing and/or treating dependencies, such as for example alcohol and/or
nicotine
dependency, and/or withdrawal symptoms, such as for example weight gain in
smokers
coming off nicotine. By "dependency" it is generally meant here an
irresistible urge to take an
addictive substance and/or to perform certain actions, particularly in order
to either achieve
a feeling of wellbeing or to eliminate negative emotions. In particular, the
term "dependency"
is used here to denote a dependency on an addictive substance. By "withdrawal
symptoms"
are meant here, in general, symptoms which occur or may occur when addictive
substances
are withdrawn from patients dependent on one or more such substances. The
compounds

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according to the invention are potentially suitable particularly as active
substances for
reducing or ending tobacco consumption, for the treatment or prevention of a
nicotine
dependency and/or for the treatment or prevention of nicotine withdrawal
symptoms, for
reducing the craving for tobacco and/or nicotine and generally as an anti-
smoking agent. The
compounds according to the invention may also be useful for preventing or at
least reducing
the weight gain typically seen when smokers are coming off nicotine. The
substances may
also be suitable as active substances which prevent or at least reduce the
craving for andlor
relapse into a dependency on addictive substances. The term addictive
substances refers
particularly but not exclusively to substances with a psycho-motor activity,
such as narcotics
or drugs, particularly alcohol, nicotine, cocaine, amphetamine, opiates,
benzodiazepines
and barbiturates.
The dosage required to achieve such an effect is conveniently, by intravenous
or
subcutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5
mg/kg of
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 in conjunction with other active substances as
described hereinafter, together with one or more 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, lozenges, 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
maybe solid or liquid, in which the compound according to the invention is
incorporated.

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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 dyslipidaemia, including
arteriosclerosis,
- active substances for the treatment of arthritis,
- 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 glitazones, particularly 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.

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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
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.

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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).
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 ~3
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,

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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, 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 fatty acid synthase (FAS)
antagonist,
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, urocortin binding protein
antagonists,
agonists of the Glucagon-like Peptide-1 receptor, such as for example exendin,
AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors 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.

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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.
Active substances for the treatment of dyslipidaemia, including
arteriosclerosis,
include e.g. medicaments which raise the HDL level, such as e.g. nicotinic
acid and
derivatives and preparations thereof, such as e.g. niaspan, as well as
agonists of the
nicotinic acid receptor.
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,
alprazolam, 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
amide
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

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fact that compounds according to the invention may be suitable for reducing
hunger,
curbing appetite, controlling eating behaviour and/or inducing a feeling of
satiety. The
eating behaviour is advantageously influenced so as to reduce food intake.
Therefore, the 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.
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 pm, Item no.: 1.01097.9050) is used.
The following abbreviations for the eluant mixtures are used hereinafter when
giving the Rf
values:

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(A): silica gel, methylene chloride/methanol/ammonia (9:1:0.01 )
(B) silica gel, methylene chloride/methanol/ammonia (5:1:0.01 )
(C): silica gel, methylene chloride/methanol (9:1 )
(D): silica gel, methylene chloride/methanol/ammonia (9:1:0.1 )
(E): aluminium oxide, methylene chloride/methanol (30:1 )
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
Cbz benzyloxycarbonyl
DMF N,N-dimethylformamide
EII electron impact ionisation
ether diethyl ether
EtOAc ethyl acetate
EtOH ethanol
Fmoc 9-fluorenylmethoxycarbonyl
MeOH methanol
Ph phenyl
RT ambient temperature
TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-
tetrafluoroborate
THF tetrahydrofuran
Preparation of the starting compounds:
Example 1.1
Ethyl 3-biphenyl-4-yl-3-oxo-propionate
H3C~O
/ \
/

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14.7 g (75.0 mmol) of 4-acetyl-biphenyl are dissolved in 150 ml
diethylcarbonate. Under
protective gas a total of 6.50 g (150 mmol) sodium hydride in oil (55%) are
added batchwise
at 0°C. The mixture is kept for 5 minutes at 0°C, then stirred
for 2 hours at 80°C. After
cooling the mixture is poured onto water, extracted with methylene chloride,
the organic
phase is washed with water and finally dried over sodium sulphate. The solvent
is eliminated,
the residue is suspended in water and neutralised with 1 N hydrochloric acid.
The aqueous
phase is extracted with diethyl ether, the organic phase is dried over sodium
sulphate and
finally the solvent is eliminated. Lastly the residue is recrystallised from
petroleum ether and
the product is dried in vacuo at 50°C .
Yield: 15.3 g (76% of theory),
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 5:2)
M.p. 75-77 °C
C17H16~3
EII Mass spectrum: m/z = 269 [M+H]+
Example 11.1
Ethyl 3- 4'-chloro-biphenyl-4-yl)-3-oxo-propionate
/ \
CI
4.29 g (32.5 mmol) monoethyl malonate are dissolved in 100 ml of
tetrahydrofuran and 42.3
ml (67.7 mmol) butyllithium solution (1.6N in hexane) is added dropwise at -
60°C. The
temperature is allowed to come up to -15°C, then the mixture is cooled
again to -65°C and
3.40 g (13.5 mmol) of 4'-chloro-biphenyl-4-carboxylic acid chloride (for
preparation see Gazz.
Chim. Ital. 1949, 79, 453.) in 30 ml of tetrahydrofuran are added dropwise.
The mixture is
kept for 5 minutes at -65°C, then heated for 2 hours to ambient
temperature. The mixture is
poured onto 50 ml 1 N hydrochloric acid, extracted with 300 ml diethyl ether,
the organic
phase is washed with saturated sodium hydrogen carbonate solution and water
and finally
dried over sodium sulphate. The solvent is eliminated, the residue is
recrystallised from
petroleum ether and the product is dried in vacuo.
Yield: 3.10 g (76% of theory),
Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 5:2)
M.p. 45-50 °C
C17H15C1~3
EII mass spectrum: m/z = 303/305 [M+H]~

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The following compounds are also synthesised analogously to the method
described above:
(11.2) ethyl3-(3-chloro-biphenyl-4-yl)-3-oxo-propionate
(11.3) ethyl3-(4-methoxyphenyl)-3-oxo-propionate
Example 111.1
3-chloro-4-(2-(4-methyl-piperidi n-1-yl )-ethoxyl-phenylam ine
NHZ
111.1.a
~2-bromo-ethoxy)-3-chloro-nitrobenzene
36.6 ml (416 mmol) 1,2-dibromoethane are dissolved in 200 ml DMF and 11.5 g
(83.3 mmol)
of potassium carbonate are added. 7.20 g (41.6 mmol) 2-chloro-4-nitro-phenol
in 40 ml DMF
are slowly added dropwise to this mixture. The mixture is stirred for 3 hours
at ambient
temperature. The solvent is eliminated, the residue is taken up in ethyl
acetate and washed
with saturated saline solution. The organic phase is dried over sodium
sulphate. The solvent
is eliminated and the residue is purified through a silica gel column with a
gradient of
petroleum ether/ethyl acetate (4:1 to 9:1 ).
Yield: 7.9 g (68% of theory),
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 3:1 )
C$H~BrCIN03
111.1.b
3-chloro-4-f2-(4-methyl-piperidin-1-yl )-ethoxyl-nitrobenzene
7.80 g (27.8 mmol) 4-(2-bromo-ethoxy)-3-chloro-nitrobenzene (111.1.a) and 10.1
ml (84.0
mmol) 4-methyl-piperidin are dissolved in 100 ml methylene chloride and
stirred for 12 hours
at ambient temperature. Then the mixture is filtered through 400 g aluminium
oxide (activity
2-3) with methylene chloride/methanol 49:1 as eluant.
Yield: 6.9 g (83% of theory),
Rf value: 0.50 (aluminium oxide, petroleum ether/ethyl acetate = 3:1 )
C'r,41"I~gCIN2O3
EII mass spectrum: m/z = 299/301 [M+H]+

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111.1.c
3-chloro-4-f2-(4-methyl-piperidin-1-yl)-ethoxyl-phenylamine
6.90 g (23.1 mmol) 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-
nitrobenzene (111.1.b) are
dissolved in 100 ml of tetrahydrofuran and hydrogenated for 8 hours at ambient
temperature
at a pressure of 20 psi with hydrogen and 3.0 g Raney nickel as catalyst. Then
the catalyst is
filtered off, the solvent is eliminated and the residue is purified through a
silica gel column
with a gradient of methylene chloride/methanol (33:1 to 9:1 ) as eluant.
Yield: 3.66 g (59% of theory),
Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1 )
C~4HZ~CIN20
EII mass spectrum: m/z = 269/271 [M+H]+
The following compounds are also synthesised analogously to the method
described above:
(111.2) 4-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine
(111.3) 4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine
(111.4) 3-chloro-4-[2-(morpholin-4-yl)-ethoxy]-phenylamine
(111.5) 3-chloro-4-[2-(N-methyl-cyclopropylmethylamino)-ethoxy]-phenylamine
(111.6) 3-chloro-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenylamine
(111.7) 3-chloro-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine
(111.8) 3-chloro-4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenylamine
Example IV.1
3-chloro-4-(2-diethylamino-ethoxy)-phen~ilamine
H3
H3
CI
O I ~ NHz
IV.1.a
3-chloro-4-(2-diethylamino-ethoxy)-nitrobenzene
52.0 g (0.30 mol) 2-chloro-4-nitro-phenol are dissolved in 500 ml of DMF and
165 g (1.20
mol) potassium carbonate are added batchwise. The mixture is stirred for 30
minutes at
ambient temperature. Then 51.6 g (0.30 mol) 2-diethylamino-ethylchloride-
hydrochloride are
added and the mixture is stirred for 3 days at ambient temperature. After this
time the mixture
is filtered off, the solvent is eliminated, the residue is taken up in ethyl
acetate and washed
with water. The organic phase is filtered through aluminium oxide (activity 2-
3) and
concentrated by evaporation.

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Yield: 41.0 g (50% of theory),
Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.01)
C,ZH~~CIN203
IV.I.b
3-chloro-4-(2-diethylamino-ethoxy)-phe~rlamine
41.0 g (150 mmol) 3-chloro-4-(2-diethylamino-ethoxy)-nitrobenzene (IV.1.a) are
dissolved in
250 ml of methanol and hydrogenated for 5 hours at ambient temperature at a
pressure of 50
psi with hydrogen and 4.0 g Raney nickel as catalyst. Then the catalyst is
filtered off and the
solvent is eliminated. The residue is recrystallised from petroleum ether and
dried in vacuo.
Yield: 33.0 g (91 % of theory),
Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.01 )
C~2H~9GIN20
EII mass spectrum: m/z = 243/245 [M+H]+
The following compounds are also synthesised analogously to the method
described above:
(1V.2) 4-(2-diethylamino-ethoxy)-phenylamine
(1V.3) 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine
(1V.4) 4-(2-pyrrolidin-1-yl-ethoxy)-3-trifluoromethyl-phenylamine
(1V.5) 4-(3-diethylamino-propoxy)-phenylamine
Example V.1
3-methoxvcarbonyl-4-(2-pyrrolidin-1-yl-ethox~)-phenylamine
O-CH3
~O
O ~ ~ NHz
V.1.a
3-methoxycarbonyl-4-(2-pyrrolidin-1-yl-ethoxy)-nitrobenzene
3.43 g (29.8 mmol) 2-pyrrolidin-1-yl-ethanol are dissolved in 60 ml of toluene
and 575 mg
(25.0 mmol) sodium are added batchwise. The mixture is heated to 100°C
and then stirred
for a further 12 hours at 50°C. After cooling 5.00 g (22.5 mmol) methyl
2-chloro-5-nitro-
benzoate are added batchwise and the mixture is stirred for 1 day at ambient
temperature.
After this time the solvent is eliminated, the residue is taken up in
methylene chloride and
washed with water. The organic phase is dried over sodium sulphate and
concentrated by

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rotary evaporation. Finally the product is purified through a silica gel
column with a gradient
of methylene chloride/methanol/ammonia (8:2 to 8:2:0.1 ) as eluant.
Yield: 1.65 g (25% of theory),
Rf value: 0.45 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 )
CtqHt8N2~5
EII mass spectrum: m/z = 295 [M+H]+
V.1.b
3-methoxycarbonyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine
1.65 g (5.61 mmol) 3-methoxycarbonyl-4-(2-pyrrolidin-1-yl-ethoxy)-nitrobenzene
(V.1.a) are
dissolved in 100 ml of methanol and hydrogenated with hydrogen and 200 mg
Raney nickel
as catalyst until the reaction is complete. Then the catalyst is filtered off
and the solvent is
eliminated.
Yield: 1.43 g (97% of theory),
Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 )
C14H20N2~3
EII mass spectrum: m/z = 265 [M+H)+
Example VI.1
3-chloro-4-(2-diethylamino-ethyl)-phenylamine
CI
H3C_J ~ ~ NH
2
VI.1.a
L2-chloro-4-nitro-phenyl)-acetic acidchlorid
8.10 g (37.6 mmol) (2-chloro-4-nitro-phenyl)-acetic acid are suspended in 40
ml of thionyl
chloride and refluxed for 2 hours. The product is reacted further without any
more
purification.
Crude yield: 8.80 g (100% of theory)
C8H5CI2NO3
VI.1.b
2-(2-chloro-4-nitro-phenyl)-N,N-diethyl-acetamide
5.67 ml (54.0 mmol) diethylamine are dissolved in 50 ml of ethyl acetate and
3.20 g (13.7
mmol) (2-chloro-4-vitro-phenyl)-acetic acid chloride (VI.1.a) in 50 ml of
ethyl acetate are

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slowly added dropwise at 0°C. Then the mixture is stirred for another 2
hours at ambient
temperature. After this time some more ethyl acetate is added and the mixture
is washed
twice with water and twice with saturated saline solution. The organic phase
is dried over
sodium sulphate, the solvent is eliminated and the residue is dried in vacuo.
Yield: 3.70 g (100% of theory)
Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:1 )
C,2H,sCINz03
EII mass spectrum: m/z = 271/273 [M+H]+
VI.1.c
f2-(2-chloro-4-nitro-phenyl)-ethyll-diethyl-amine
65.0 ml (65.0 mmol) of a 1 M borane-THF solution are added dropwise at ambient
temperature to a solution of 3.70 g (13.7 mmol) 2-(2-chloro-4-nitro-phenyl)-
N,N-diethyl-
acetamide (VL1.b) in 130 ml THF and the mixture is stirred for 4 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
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,
activity II-III) with
petroleum ether/ethyl acetate (4:1 ) as eluant.
Yield: 2.10 g (60% of theory)
Rf value: 0.65 (Alox, petroleum ether/ethyl acetate = 3:1 )
C~2H~~CIN202
Vl.1.d
3-chloro-4-(2-diethylamino-ethyl)-phenylamine
2.00 g (7.79 mmol) (2-(2-chloro-4-vitro-phenyl)-ethyl]-diethyl-amine (VL1.c)
are dissolved in
50 ml THF and hydrogenated for 2.5 hours at ambient temperature at a pressure
of 25 psi
with hydrogen and 0.8 g Raney nickel as catalyst. Then the catalyst is
filtered off and the
solvent is eliminated.
Yield: 1.80 g (100% of theory)
Rf value: 0.45 (Alox, petroleum ether/ethyl acetate = 1:1 )
CizHisCIN2
EII mass spectrum: m/z = 227/229 [M+H]+

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The following compounds are also synthesised analogously to the method
described above:
(V1.2) 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethyl]-phenylamine
(V1.3) 3-chloro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenylamine
(V1.4) 3-chloro-4-[2-(N-methyl-isopropylamin)-ethyl]-phenylamine
(V1.5) 3-chloro-4-{2-[4-(morpholin-4-yl)-piperidin-1-yl]-ethyl}-phenylamine
(V1.6) 3-chloro-4-[2-(4-hydroxy-4-trifluoromethyl-piperidin-1-yl)-ethyl]-
phenylamine
(V1.7) 3-chloro-4-[2-(4-tert.butoxycarbonylamino-piperidin-1-yl)-ethyl]-
phenylamine
(V1.8) 3-chloro-4-[2-(N-ethyl-2-hydroxy-ethylamino)-ethyl]-phenylamine
(V1.9) 2-amino-5-(piperidin-1-yl-methyl)-pyridine
Example VI1.1
5-amino-1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole
N~/N I ~ Nli
V11.1.a
5-vitro-1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole
A reaction mixture of 16.2 g (100 mmol) 5-nitroiridole, 35.0 g (206 mmol) 1-(2-
chloro-ethyl)-
pyrrolidine-hydrochloride and 51.0 g (369 mmol) potassium carbonate in 500 ml
DMF is
stirred for 48 hours at ambient temperature and then filtered. The filtrate is
evaporated down,
the residue is dissolved in dichloromethane and dried over sodium sulphate.
The drying
agent is filtered off and the filtrate evaporated down.
Yield: 25 g (96% of theory)
R, value: 0.65 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )
C14H17N3O2
EII mass spectrum: m/z = 260 [M+H]'
VI1.1.b
5-amino-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole
Prepared analogously to Example VI.1.d from 27.0 g (104 mmol) 5-vitro-1-(2-
pyrrolidin-1-yl-
ethyl)-1H-indole (VIl.1.a) in THF as solvent.
Yield: 23.2 g (97% of theory)
Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )

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ClaHlsN3
EII mass spectrum: m/z = 230 [M+H]+
The following compounds are also synthesised analogously to the method
described above:
(V11.2) 5-amino-1-(2-piperidin-1-yl-ethyl)-1 H-indole
(V11.3) 5-amino-1-(2-azepan-1-yl-ethyl)-1H-indole
(V11.4) 5-amino-1-(2-diisoproylamino-ethyl)-1H indole
(V11.5) 5-amino-1-(2-[bis-(2-methoxyethyl)-amino]-ethyl}-1
H-indole
(V11.6) 5-amino-1-[2-(N-benzyl-ethylamino)-ethyl]-1
H indole
(V11.7) 5-amino-1-(2-diethylamino-ethyl)-1H-indole
Example VI11.1
2-(pyrrolidin-1-yl-mett~l)-benzoxazol-6-yl-amine
V111.1.a
2-chloromethyl-6-vitro-benzoxazole
A reaction mixture of 12.0 g (77.9 mmol) 2-amino-4-vitro-phenol and 10.5 ml
(77.9 mmol) 2-
chloro-1.1.1-trimethoxy-ethane in 110 ml of ethanol is stirred for 3 hours at
80°C. After this
time the mixture is poured onto water and the precipitate formed is filtered
off. The filtrate is
washed with water and dried at 80°C.
Yield: 14.2 g (86% of theory)
C8H5CIN203
EII mass spectrum: m/z = 213/215 [M+H]+
V111.1. b
6-vitro-2-(p~rrrolidin-1-YI-metal)-benzoxazole
A reaction mixture of 3.00 g (14.1 mmol) 2-chloromethyl-6-vitro-benzoxazole
(VI11.1.a), 1.50
ml (18.0 mmol) pyrrolidine and 3.90 g (28.2 mmol) potassium carbonate in 30 ml
DMF is
stirred for 12 hours at 50°C. After this time the mixture is diluted
with water and covered with
diethyl ether. The precipitate formed is filtered off and dried at
80°C.
Yield: 1.80 g (52% of theory)
C12H13N3O3

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EII mass spectrum: m/z = 248 [M+H]+
VI11.1.c
2-( pyrrolid in-1-yl-methyl )-benzoxazol-6-yl-amine
Prepared analogously to Example VI.1.d from 1.80 g (7.28 mmol) 6-vitro-2-
(pyrrolidin-1-yl-
methyl)-benzoxazole (V111.1.b) in methanol as solvent.
Yield: 1.10 g (70% of theory)
Rf value: 0.60 (aluminium oxide, dichloromethane/ethanol = 20:1 )
C,zH~sNs~
EII mass spectrum: m/z = 218 [M+H]+
Example IX.1
2-( 4-dimethvlaminomethvl-phenvlLethylamine
CH3
NHZ
IX.1.a
(4-dimethylaminomethyl-phenyl)-acetonitrile
A reaction mixture of 4.40 g (20.9 mmol) (4-bromomethyl)-acetonitrile (for
preparation
method see Magnet. Reson. Chem. 2000, 38, 129-134), 1.71 g (21.0 mmol)
dimethylamine-
hydrochloride and 9.12 g (66.0 mmol) potassium carbonate in 30 ml acetone is
stirred for 4
hours at ambient temperature. After this time the mixture is concentrated by
evaporation,
taken up in methylene chloride and washed with water. The organic phase is
dried over
sodium sulphate and then the solvent is eliminated.
Yield: 3.60 g (99% of theory)
C~iHi4Nz
EII mass spectrum: m/z = 175 [M+H]+
IX.1.b
2-(4-dimethylaminomethyl-phenyl)-ethylamine
3.60 g (20.7 mmol) (4-dimethylaminomethyl-phenyl)-acetonitrile (IX.1.a) are
dissolved in 50
ml of methanolic ammonia and hydrogenated for 5 hours at 50°C at a
pressure of 3 bar with
hydrogen and 0.45 g Raney nickel as catalyst. Then the catalyst is filtered
oft and the solvent
is eliminated.

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Yield: 3.60 g (98% of theory)
R, value: 0.20 (silica gel, methylene chloride/methanol = 9:1 )
C~iH~aNz
EII mass spectrum: m/z = 179 [M+H]+
The following compounds are also synthesised analogously to the method
described above:
(1X.2) 2-[4-(pyrrolidin-1-yl-methyl)-phenyl]-ethylamine
(1X.3) 2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethylamine
(1X.4) 2-[4-(4-hydroxy-4-phenyl-piperidin-1-yl-methyl)-phenyl]-ethylamine
(1X.5) ~1-[4-(2-amino-ethyl)-benzyl]-piperidin-4-yl}-pyridin-2-yl-amine
(1X.6) 2-methyl-2-[4-(pyrrolidin-1-yl-methyl)-phenyl]-propylamine
Example X
The following compounds are synthesised using methods already described in
international
Patent Application WO 01/27081 or may at least be prepared analogously to
methods
described therein:
(X.1 ) 4-(piperidin-1-yl-methyl)-phenylamine
(X.2) 4-(diethylaminomethyl)-phenylamine
(X.3) 4-(2-diethylamino-ethyl)-phenylamine
(X.4) 3-chloro-4-(piperidin-1-yl-methyl)-phenylamine
(X.5) 3-chloro-4-((cis-3,5-dimethyl-piperidin-1-yl)-methyl]-phenylamine
(X.6) 4-[(3.5-dimethyl-piperidin-1-yl)-methyl]-phenylamine
(X.7) 4-[(4-methoxy-piperidin-1-yl)-methyl]-phenylamine
(X.8) 4-[(4-methyl-piperidin-1-yl)-methyl]-phenylamine
(X.9) 4-[(4-methyl-piperazin-1-yl)-methyl]-phenylamine
(X.10) 4-[(N-methyl-cyclopropylmethylamino)-methyl]-phenylamine
(X.11) 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-phenylamine
(X.12) 4-(pyrrolidin-1-yl-methyl~phenylamine
(X.13) 4-(morpholin-4-yl-methyl)-phenylamine
(X.14) 4-[(4-hydroxy-piperidin-4-yl)-methyl]-phenylamine
Example X1.1
N-methyl-4-(2-diethylamino-ethoxy)-phenylamine

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H3C-
H
O
CH
3
Xl.1.a
N-methoxycarbonyl-4-(2-diethylamino-ethoxy)-phenylamine
76.4 g (0.367 mol) 4-(2-diethylamino-ethoxy)-phenylamine (compound IV.2) and
102 ml
(0.733 mol) triethylamine are dissolved in 400 ml THF and 49.2 g (0.367 mol)
dimethylpyrocarbonate in 200 ml THF are added over 45 minutes at ambient
temperature.
The mixture is stirred for a further 2 hours at ambient temperature. After
this time the solvent
is evaporated down, the residue is taken up in ethyl acetate and water and the
organic phase
is washed twice with water. The solvent is eliminated and the residue purified
through an
aluminium oxide column with petroleum ether/ethyl acetate (3:1 ) as eluant.
Yield: 63.3 g (65% of theory),
Rf value: 0.60 (aluminium oxide, petroleum ether/ethyl acetate = 1:3)
C~aHzzt~lzCs
EII mass spectrum: m/z = 267 [M+H]+
X1.1.b
N-methyl-4- 2-diethylamino-ethoxy)-phenylamine
10.7 g (280 mmol) lithium aluminium hydride are placed in 600 ml THF and 30.0
g (113
mmol) N-methoxycarbonyl-4-(2-diethylamino-ethoxy)-phenylamine (compound
XI.1.a) in 300
ml THF are carefully added dropwise at 0°C. The mixture is stirred for
12 hours at ambient
temperature. After this time a further 7.00 g (183 mmol) of lithium aluminium
hydride are
added and the mixture is stirred for a further 24 hours at ambient
temperature. After this time
it is carefully neutralised with sodium hydroxide solution. The mixture is
filtered, the filtrate is
dried over sodium sulphate and finally the solvent is eliminated.
Yield: 24.7 g (99% of theory),
R, value: 0.45 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 )
C~3Hz2N20
EII mass spectrum: m/z = 223 [M+H]'
The following compound is also synthesised analogously to the preparation
method
described above:
(X1.2) N-methyl-4-(piperidin-1-yl-methyl)-phenylamine

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Example X11.1
3-biphenyl-4-yl-propynoic acid-f3-chloro-4-(2-diethylamino-ethoxy)-phenyll-
amide
0.48 g (2.0 mmol) biphenyl-4-yl-propynoic acid chloride (for preparation
method see Bioorg.
Med. Chem. 1996, 4, 851 ) are dissolved in 15 ml of toluene and 0.58 g (2.4
mmol) [2-(2-
chloro-4-amino-phenoxy)-ethyl]-diethyl-amine (educt IV.1 ) in 10 ml of toluene
at ambient
temperature are added dropwise. The mixture is stirred for 8 hours at ambient
temperature,
the solvent is eliminated, the residue is taken up in ethyl acetate and washed
with water. The
organic phase is dried over sodium sulphate, the solvent is eliminated and the
residue is
purified through a silica gel column with dichloromethane/methanol/ammonia
(9:1:0.01 ) as
eluant.
Yield: 0.28 g (31 % of theory)
M.p.: 105-108°C
Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia = 9:1:0.1 )
C2~H2~CIN202
EII mass spectrum: m/z = 447/449 [M+H]+
The following compounds are also synthesised analogously to the method
described above:
(X11.2) 3-(2-chloro-4-trifluoromethyl-phenyl-)-propynoic acid-[3-chloro-4-(2-
diethylamino-ethoxy)-phenyl]-amide
(X11.3) 3-(3-bromo-biphenyl-4-yl)-propynoic acid-{3-chloro-4-[2-(4-methyl-
piperidin-1-
yl-)-ethyl]-phenyl)-amide

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Preparation of the end comaounds:
Example 1.0
3-biphenyl-4-yl-N-(3-chloro-4-f2-(4-methyl-piperidin-1 yl)-ethoxyl-phenyl)-3-
oxo-
propionamide
300 mg (1.00 mmol) ethyl 3-biphenyl-4-yl-3-oxo-propynoate (educt 1.1) and 269
mg (1.00
mmol) 3-chloro-4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylamine (educt 111.1
) are dissolved
in 5 ml of toluene and stirred for 8 hours at 120°C in the open test
tube, while ethanol is
distilled off. After cooling, petroleum ether is added, the precipitate formed
is suction filtered
and dried in vacuo at 80°C.
Yield: 300 mg (61 % of theory),
Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 )
M.p.135-139°C
C29H3~CIN203
EII mass spectrum: m/z = 491/493 [M+H]+
The following compounds of general formula I-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
RvNiX /
R2
H v ~~~ (I-1 )
/ B

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Exa mass M.p. R,-
R'R2NX L' LZ B Educts
mple spectrum[C] value*
1 499/501
I1 /
. 175- 0.50
1
1 LzN~p~. CI H ~ ~ / 03
. IV + 180 (A)
1
. [M+H]
431 140- 0.40
H _H /
EtZN~O
1.2 ~ _ ~ +
IV.2 [M+H] 142 (A)
461 108- 0.60
. pCH H /
Et2N~o
1.3 ~ - - ~ +
3
IV.3 [M+H] 110 (B)
499/501
11
2
. 108- 0.40
4 Et2N'~p~. -CI -CI ~ / 503
1
. 1 111 (C)
IV ,
. [M+H]
11.2 465/467108- 0.40
Et2N~o H CI ~
~ '/
1.5 ~; - - ~ +
IV.2 [M+H] 112 (A)
11.2 485/497157- 0.70
1 Et2N~'O -OCH -CI /
6
. ~; 3 ~ [M+Hl+ 160 (B)
IV.3
497 130- 0.45
1 C -CF -H /
7 N~-o
.
. , 3 ~ [M+H]+ 135 (D)
,;
IV.4
EtZN
1 1.1 ~5 152- 0.45
8 . H H
'~-o
. , +
IV.5 [M+H] 157 (D)
-COO- ,
1 1.1 487 131- 0.45
9 N~-o . H //
. r CH3 \ V.1 [M+H]+ 135 (D)
EtzN~' -CI _H / H
1 ,, 1.1 449/451118- 0.20
. , ~ [M+H]+ 122 (A)
VI.1
11 483/485/
2
. 132- 0.20
E~N '
H
1.11 ~' -CI -CI ~ 487
~ /
, VI 136 (A)
1 +
. [M+H]
1.1 413 157- 0.50
12 CN ='~~ -H H ~~
1 / H
. , ~ X.1 [M+H]+ 160 (A)

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401 126- 0.60
1 J
13 H H ,
I
. H , ~ +
c
3 X.2 [M+H] 130 (A)
11.2 447/44972- 0.50
1 GN ='~~ -H -CI '
14
. , v
X.1 [M+Hl 75 (A)
11.2 435/437155- 0.50
1 J ~'' -H -CI /
15
. H ~ +
c
3 X.2 LM+H] 160 (A)
1 CN =~~ -H _H / CI
16 ', 11.1 447/449202- 0.40
. , ~ X.1 [M+H]+ 204 (A)
1.1 415 144- 0.50
H
1.17Hsc~N -H -H '
v /
, X.3 [M+H] 148 (D)
H3c 1.1
1 v 501 224- 0.60
18 ~JN~~~~ OCH H / H
. 3 , ~ M+H 228 D
111.2 + (
C 1 )
~' 1.1 487 106- 0.60
1 H -OCH -H
19 c~ ,
. 3 3 111.3 IM+H] 110 (D)
1 CN~~ -CI -H / c1
20 , 11.1 482 175- 0.45
. , v X.4 [M+H]+ 177 (C)
H3C 11.1 509/511174- 0.80
1.21~N~'I -CI -H ' /
~ / c1 513
H3c , X.5 [M+H]+ 177 (C)
H3C I1.1 475/477
' 175- 0.45
.22 ~JN~' H H v / c1
, 178 D
X.6 [M+H]+ (
)
1 ~ -H -H / CI
23 N~' ' 11.1 477/479178- 0.50
. MeO , y
J
X.7 (M+H]+ 181 (C)
I1.1 461 168- 0.35
1 ~N ='s~ -H -H '' /463
24 / c1
. H3c , ~
X.8 [M+H] 170 (C)
1 ~N ='a~ _H -H / c1
25 ; 11.1 462/464176- 0.30
. H C. \
X.9 [M+H]+ 178 (D)

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D~N~' , CI
11.1 447/449167- 0.50
6 H H ~/
1
. H3c ~ X,10 [M+H]' 170 (C)
CH3 11.1 475/477168- 0.45
27 ~N :~' _H -H \ / c1
1 ,
. ' X.11 [M+H]+ 171 (C)
CH3
11.1 433/435187- 0.35
~ H H ~
N ='~~ / c1
1.28 , - ~
, X.12 [M+H]+ 189 (C)
H , 11.1 435/437175- 0.35
c~-, c1
,
1.29 3 -H H ,, ~ / 178 (C)
N~ +
H
cJ
3 X.2 ]
[M+H
_ ' CI 11.1 449/451188- 0.45
1 ~N '''~ -H H ~/
30
. ~ X.13 [M+H]+ 190 (C)
1 ~N''s' _H _H ~ / CI
31 , 11.1 463/465146- 0.30
. HO , X.14 [M+H]+ 149 (C)
_ 1.1 479/481120- 0.70
1 -CI -H ~
32 p N~-O / H
. ~ , ~ 111.4 [M+H] 126 (D)
'J '
477/479130- 0.40
~N'Lp ~
1.33 H ~ ,,; -CI -H , ~ /
11.5 M+H]+ 32 C)
34 MeO~N~~~ 1.1 507/509120- 0.40
1 -CI -H
. [M+H]' 125 (C)
111.6
~N-~p , H 1.1 492/494130- 0.30
1.35 HsC_NJ '' -CI -H '~, ~
/ [M+H]+ 135 (C)
111.7
1 ~N~-p _C) _H ~hi
36 1.1 493/495115- 0.30
. Hp [M+H1+ 118 (C)
111.8
Hsc , 1.1 475/477227- 0.44
37 ~ -CI -H ~
1 / H
. , ~ VI [M+Hl 232 (C)
2
y .
Me0 _ 1.1 491/493 0.53
1 ~ -CI -H ~H >130
38 /
. \ [M+H]+ (C)
y VI.3

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1 H3CYN H3 CI H H 1.1 449/451 81- 0.32
39 '
,,
. H3o ~I _ _ / VL4 [M+Hl+ 85 (C)
,
\
O
~N -H - H I ~ 546/548 171-0.24
1 -CI ~ 1
40 /
. , \ tM+Hl 175 (C)
VI.S
Ho 1.1
1 -CI _H ~ H 545/547 187-0.38
41 3 ~~
F o /
. N ~ \ VL6 IM+H~+ 191 (C)
y
CN3
H
C
0
s , 1.1 576/578 157-0.42
1 T -CI -H
42 H3c HN o /
. +
V1.7 IM+H~ 159 (C)
1.1
1 HO'~N -CI -H
43
. V1.8
R
(11_1
The following compounds of general formula II-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
Exa mass M.p. R~
' ' z 3
2
R L L L Educts
R
NX
mple spectrum [C] value*
11.3 419/421 0.40
2 E~N~o CI H OCH 120
0 ' 122
. ~; - - - -
3
IV.1 IM+H]+ (A)
Example 2

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(iii-1 j
The following compounds of general formula III-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
Examp ~ 2 2 mass M.p. R,-
R R NX L B Educts
1e spectrum [C] value*
11.2 419/421 0.40
3 ~ CI '~ 120
0 H 122
. - ~ / -
~, , VI1.1 [M+H]+
1.1 0.50
1 ~ ' *
H
3. , -H ~ 452 [M+H]135-142
~ /
~ , VI1.1
- 1.1 0.50
3.2 ~ -H '~ 466 [M+H]+60-65
~ / H
~, , p
VI1.2
- 1.1 0.50
3.3 ~ -H ~ 480 [M+H]+127-129
~ / H
, VI1.3
H3 ~ch3 , H 1.1 0.65
3.4 H3~YN -H '~ + 139-144
~ ~ / 482 [M+H]
~
H3C , VI1.4
'''
OMe
1.1 0.60
3.5 ~N,~. -H ~ 514 [M+H]+83-86
~ / H
Meo , VI1.5
/ 1
1
~ , . 0.70
3.6 ~ -H / H 516 [M+H]+85-90
H3C'~N~. V11.6 O)
1.1 0.55
~ +
H
3.7 H3C~N -H ' 454 [M+H]99-104
~ /
, VI1.7
Example 3

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Example 4
The following compounds of general formula IV-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
Rz
R~
Examp~ 2 z mass M.p. R~
R R NX L B Educts
1e spectrum [C] value*
1~1 + 0.55
4.0 ~,N~~ -H '~ 440 [M+HJ135-138
~ /
, VI11.1 (D)
Example 5
The following compounds of general formula V-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
R:~.x /
Rz
Ryn H
/ B
Examp~ 2 ~a ~b mass M.p. R,-
R R NX R /R B Educts
1e spectrum [C] value*
-. , 1.1 120- 0.40
5 H -H ~' 401 (M+HJ+
0 J '''' / H
. H C , ~ IX.1 125 (D)
5.1 GN :~' -H - 1.1 121- 0.55
~ 427 [M+HJ'
~ / H
, IX.2 125 (D)
1.1 107- 0.40
5.2 ~N '''~ -H ~ 509 [M+HJ+
~ / H
, IX.3 111 (D)

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I 1
~'' 1
, . 0.40
5.3 ~N '~~ -H ~ ~ / 533 [M+H]+98-103
H
~
Ho IX.4 (D)
\ 'N -H -- H 1.1 533 M+H 109- 0.30
4 , +
/ ( ]
. ' ' ~
N N~ '1X.5 112 (D)
H~J
1.1 100- 0.40
5.5 ~,N ='~~ -CH3 ~, ~ / 455 (M+H]+
H
IX.6 106 (D)
Example 6
The following compounds of general formula VI-1 are prepared analogously to
Example 1.0,
5 the educts used being shown in the column headed "Educts":
RvNix
RZ \
I v ~ \ (VI-1 )
CH3
Exa R~R2NX L' L2 B Eductsmass M.p. R,-
mple spectrum (C] value*
1.1 0.50
6 Et2N~'~~;~ -H -H '~ 445 [M+H]+108-112
0 / H
. , ~ XI.1 (D)
1.1 0.70
6.1 CN ='~~ -H -H '~ 427 (M+H]+175
~ / H
, XL2 (A)
Example 7.0
3-biphenyl-4-yl-N-f3-chloro-4-(2-dieth rLmino-ethoxy phenyll-3-oxo-
propionamide

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0.16 g (0.36 mmol) 3-biphenyl-4-yl-propynoic acid-[3-chloro-4-(2-diethylamino-
ethoxy)-
phenyl]-amide (educt X/1.1 ) are dissolved in 10 ml aqueous ethanol and 0.10
ml (1.0 mmol)
piperidine are added. The mixture is stirred for 8 hours at reflux
temperature. After cooling
the solvent is eliminated, the residue is suspended in ether and filtered off.
The residue is
dried in vacuo at 50°C.
Yield: 75 mg (45% of theory),
Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.01 )
M.p. 148-151 °C
C2~HZ9CIN203
EII mass spectrum: m/z = 465/467 [M+H]+
The following compounds of general formula VII-1 are prepared analogously to
Example 7.0,
the educts used being shown in the column headed "Educts":
R~N~X
(VII-1)
Exa mass M.p. R~-
R'R2NX L' L2 L3 educt
mple spectrum [C] value*
491 /493/ 0.40
7 E~N~'Or -CI -CI -CF3 X/1.2 n.
1 b.
. [ M+H]+ (E)
495
~ 553/555/557139- 0.48
,~
/
-CI -Br , ~ X/1.3
7.2 ,~. [M+H]+ 144 (C)

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Example 8.0
5-(3-bj~henyl-4-yl-3-oxo-propionylamino)-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic
acid
O OH
O /
\ I N \
H I
/ \
I/
0.25 g (0.51 mmol) methyl 5-(3-biphenyl-4-yl-3-oxo-propionylamino)-2-(2-
pyrrolidin-1-yl-
ethoxy)-benzoate (compound 1.9) are dissolved in 20 ml of methanol, 2.0 ml 1 N
sodium
hydroxide solution are added and the mixture is stirred for 3 hours at
50°C and 12 hours at
ambient temperature. After this time another 1.0 ml of 1 N sodium hydroxide
solution are
added and the mixture is stirred for another 3 hours at 50°C. After
cooling 3.0 ml 1 N
hydrochloric acid are added and the mixture is stirred for 1 hour at ambient
temperature. The
solvent is evaporated down, the residue is taken up in a little methanol and
the precipitate
obtained is suction filtered and dried in vacuo at 80°C.
Yield: 240 mg (100% of theory),
Rf value: 0.20 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 )
M.p. 236-240°C
C2sH2sN205
EII mass spectrum: m/z = 473 [M+HJ+
Exam~~le 9.0
N ~4-f2-(4-amino-piperidin-1=yl)-ethyll-3-chloro-phenyl)-3-biphenyl-4-yl-3-oxo-
propionamide
0.19 g (0.33 mmol) N-{4-[2-(4-tert.butoxycarbonylamino-piperidin-1-yl)-ethyl]-
3-chloro-
phenyl)-3-biphenyl-4-yl-3-oxo-propionamide (compound 1.41 ) are dissolved in 7
ml

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_ WO 2005/085221 _ g3 _ PCT/EP2005/002132
methylene chloride, 500 ml trifluoroacetic acid are added and the mixture is
stirred for 12
hours at ambient temperature. After this time saturated sodium hydrogen
carbonate solution
is added and the precipitate formed is suction filtered. The residue is dried
in vacuo over
sodium hydroxide.
Yield: 160 mg (100% of theory),
Rf value: 0.10 (silica gel, methylene chloride/methanol = 9:1 )
M.p. above 144°C (decomposition)
C2aHsoCIN302
EII mass spectrum: m/z = 476/478 [M+H]+
Example 10
1
RvN~X ~ z
z ~I
R N_ 'N ~ (VIII-1)
H I
The following compounds of general formula VIII-1 are prepared analogously to
Example 1.0,
the educts used being shown in the column headed "Educts":
Exa ~ 2 ~ 2 3 mass M.p. R~
R R NX L L L Educts
mple spectrum [C] value*
1.1 0.40
10.0CN%'~~ -H -H '~ 414 [M+H]+178-182
~ / H
, VL9 (A)
The following compounds are prepared analogously to the foregoing Examples:
RAN
I.
R'
Example ~ R'R2NX ~ L' ~ LZ ~ B

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WO 2005/085221 _ g4 - PCT/EP2005/002132
11 -~N~-o,;, _C1 _H ., ~ / H
H3C
H3C
12 ~JN'~~~~ -CI -H y ~ / H
H3C
~, H
13 CHO~N~~'~~ -CI -H '~, ~ /
14 H2 ~N~'~~: -CI _H ,,, \ / H
15 ~N~-o~. _C1 _H \ / H
HO ,,
,
HO
16 ~N'~o -CI -H .,, \ / H
.
~
17 H -CI _H .,, ~ / H
~N~~''~
HO
CH3
18 ~N'~o~. _C1 -H \ / H
,,
CH3 ,
19 GNP-o,;' _C1 _H ,,, \ / H
NCO
20 ~ ''' -CI _H .,1 \ / H
HO
~N~O~;. ' H
21 ' -CI -H
y
HO
CH3
22 H3C~N~0 . -CI -H ~,
~ / H
H3C~CH3 ~ ,
H3C
23 ~N-~o -CI _H ,,, \ / H
,

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24 ~ -CI -. -H ,,
' \ / H
y ,
25 ~ -CI -H ',
\ / H
,
H3C
26 ~N~ -CI -H ', \ / H
H3C
27 Hz ~N~'' _C1 _H ,,' \ / H
28 H~~N'~- _CI _H ,,, \ / H
HO
29 ~N~ -CI -H '~, \ / H
30 ~N'~=,; _C1 _H ,,, \ / H
31 H ~_ ~N'~- _CI -H ,,, \ / H
3
32 Ho~N~ _C1 _H ,,, \ / H
CH3
33 ~N'~ -CI _H ,,1 \ / H
CH3
34 GN'~ -CI _H ,,, \ / H
N
35 ~ -CI -H '~, \ / H
HO
36 ~ -CI -H '~, \ / H
HO
~ H3
H
7 H3~ ~ ~ CI H ,
/
HsC CHs , \

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38 H3c\N~ -CI -H ., ~ / H
H3C,
39 ~N~ -CI -H
H
40 C,N'~ _C1 -H ,,, ' / H
41 GN'~ _C1 _H .,, \ / H
~ Hs
42 ~ '~:- -CI -H ,, ~ / H
H
C
s
CHs
43 H3 c~ ~'' -CI -H ., ~ / H
3 CH3
H3C~
44 HsC~ ~ _C1 _H ,,
\ / H
H3C '
~ Hs
45 H3C~ ~ -CI -H ., \ / H
H3C
46 ~ ~' -CI _H ., \ / H
OH
~
47 ~, -CI -CI -CF3
~
48 ~. -CI -CI -CF3
49 H c~N~; -CI -CI -CF3
3
H3C
N
50 ~ -CI -CI -CF3
~
H3C

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51 CHO~N~ -CI -CI -CF3
52 HZN~N~'' -CI -CI -CF3
O
53 Ho~N~ -CI -CI -CF3
HO
54 ~N'~ -CI -CI -CF3
55 ~N~=- -CI -CI -CF3
56 o_ ~ ~- -CI -CI -CF3
H
3
57 HHO~N~ -CI -CI -CF3
C H3
58 ~N~ -CI -CI -CF3
CH3
59 GNP -CI -CI -CF3
60 ~ -CI -CI -CF3
HO
61 -~ -CI -CI -CF3
HO
~ Hs
H
~
62 3 -CI -CI -CF3
N~=;-
C'~
H
3
CH3
H3C\
63 N~ -CI -CI -CF3

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H3C,
~
64 N~ -CI -CI -CF3
65 C,N~ -CI -CI -CF3
66 C,N~ -CI -CI -CF3
~ Hs
67 N~; -CI -CI -CF3
C.(
H
s
CHs
H3C~
68 H ~~ ~'' -CI -CI -CF3
3 CHs
H3C~
69 HaC~ ~' -CI -CI -CF3
H3C
~ Hs
70 H3C~ ~'' -CI -CI -CF3
H3C
HN
71 ~ -CI -CI -C F3
OH
72 N'V- -CI -H \ / H
H3C\
H3C
73 o~N~ -CI -H ,
~ / H
,
74 GN-CN~ _C1 _H ,,1 \ / H
HO,
75 H3C~N'4 -CI _H ,,1 ' / H
HO
HO
76 H3C ~~N'4 -CI _H ,,, ' / H
HO

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'~.:- H
H3c ,
77 N -CI _H ,, \ ~
H3C
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 pg/ml leupeptin and
1 NM
phosphoramidone) to a concentration of 5 to 15 Ng/ml.
200 microlitres of this membrane fraction (contains 1 to 3 Ng of protein) are
incubated
for 60 minutes at ambient temperature with 100 pM of '251-tyrosyl melanin
concentrating hormone ('251-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

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retained on the filter is then determined after the addition of scintillator
substance
(Packard Microscint 20) in a measuring device (TopCount of Packard).
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 X251-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 (1 M) (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)

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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
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% C02 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 FLIPR3~ 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.

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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) ~ EC50(MCH) -1 ) -IOg C(testsubstance)
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 10-6 M.
The following IC50 values were determined using the MCH-1 receptor binding
test
described above:
Compound
according to Structure ICSO value
Example no.
I\
5.1 ° ° 63.7 nM
I\
/ \
( /
a
/ o a
7.1 \ I 34.8 nM
I\
F
F F

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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
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 mg 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 NI

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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:
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
Propellant type metered dose aerosol containing 1 ma 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

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Nasal spray containing 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:
The active substance and the excipients are dissolved in water and transferred
into a
corresponding container.
Example F
Iniectable solution containing 5 mg 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.

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Example G
Injectable solution containing 100 ma 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
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 ma of active substance
Composition:
Active substance 10 mg
Mannitol 300 mg
human serum albumin 20 mg

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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 mg of active substance
Composition:
active substance 20 mg
lactose 120
mg
maize starch 40 mg
magnesium stearate 2 mg
Povidone K 25 18 mg
Preparation:
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.

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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 containing 50 mg of active substance
Composition:
active substance 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
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.

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Example L
Iniectable solution containinct 10 ma 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.

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