Note: Descriptions are shown in the official language in which they were submitted.
CA 02554138 2006-07-20
A.S ORIGINALLY FILL'D
Aryl-substituted heterocycles, method for production and thereof as
medicaments
The invention relates to aryl-substituted heterocycles and to the
physiologically tolerated
salts and physiologically functional derivatives thereof.
~ o Compounds similar in their overall structure to the heterocycles described
herein and
having a pharmacological effect have been described in the prior art. Thus,
for example,
WO 03/097047 describes aryl-substituted oxadiazoles for the treatment of
obesity and
diabetes.
Compounds with MCH-antagonistic activity for treatment of obesity are
disclosed in the
~ 5 prior art (examples: W02001021577, W02003035624, W02002089729,
W02002006245,
W02002002744, W02002057233, W02003045313, W02003097047, W02002010146,
W02003087044).
The invention was based on the object of providing compounds which bring about
a weight
2o reduction in mammals and are suitable for the prevention and treatment of
obesity and
diabetes.
Surprisingly, a series of compounds which modulate the activity of MCH
receptors has
been found. In particular, the compounds are distinguished by MCHIR
antagonism.
25 The invention therefore relates to compounds of the formula I,
R7 R6 R3
A-B NR R
R11 ~K~E~X-Het---~~ ~~N ~ 1 2
G-D R4
m
R9 R8 R5 I
in which the meanings are
CA 02554138 2006-07-20
2
Ri, R2 independently of one another H, (C,-CH)-alkyl, -(CR13R14)o-R12, (C~-Ca)-
alkoxy-(C,-C~)-alkyl, (C~-Cs)-alkenyl, (C~-Cs)-alkynyl, CO-(C,-Cg)-alkyl, -
CO-(CH~)~ R 12, CO(C(R 15)(R 16)),~N(R17)(R18),
CO(C(R 19)(R20))50(R2 I ); or R 1 and R2 form together with the nitrogen
S atom to which they are bonded a 4 to 10-membered mono-, bi- or
spirocyclic ring which, apart from the nitrogen atom, may include 0 to 4
additional heteroatorns selected from the group of oxygen, nitrogen and
sulfur, where the heterocyclic ring system may additionally be substituted
by F, Cl, Br, CFA, NO~, CN, (C,-C~)-alkyl, O-(C,-Cs)-alkyl, (C,-C4)-alkoxy-
W (C,-Ca)-alkyl, hydroxy-(C,-C4)-alkyl, (Co-C~)-alkylene-aryl, oxo, CO(R22),
CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C~-C6)-alkyl,
N(R27)(R28) or SOZCH3;
0 0, I , 2, 3, 4, 5, 6;
~5
q, s independently of one another 0, l, 2, 3, 4;
R 15, R 16, R 17, R 18, R 19, R20, R21, R22, R23, R24, R25, R26, R27, R28
independently of one another H, (C1-C6)-alkyl;
2o
R 17 and R 18, R23 and R24, R27 and R28
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
'S (Cl-C6)-alkyl, oxygen and sulfur;
R12 OH, O-(C,-C6)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33), 3-12
membered mono-, bi- or spirocyclic ring which may comprise one or more
heteroatoms from the group of N, O and S, and the 3-12 membered ring may
30 comprise further substituents such as F, Cl, Br, I, OH, CF3, N02, CN, OCF3,
oxo, O-(CI-C6)-alkyl, (C~-C4)-alkoxy-(C,-C4)-alkyl, S-(C~-C6)-alkyl, (C~-
C6)-alkyl, (CZ-C6)-alkenyl, (C3-Cg)-cycloalkyl, (C~-C6)-alkynyl, O-(Co-Cg)-
CA 02554138 2006-07-20
3
alkylene-aryl, (C«-CH)-alkylene-aryl, N(R34)(R35), CO(C,-C6)-alkyl,
COO(R36) and S(O)" (R37);
a 0, l, 2;
R34, R35
independently of one another H, (C,-CH)-alkyl;
R34 and R35
m optionally together with the nitrogen atom to which they are bonded a 5-6
membered ring which, apart from the nitrogen atom, may also include 0-1
further heteroatoms from the group of NH, N-(C1-C6)-alkyl, oxygen and
sulfur, and optionally be substituted by 1-2 ~oxo groups;
~ 5 R36, R37 H, (C,-CR)-alkyl;
R13, R14 independently of one another H, (C,-Cs)-alkyl, hydroxy-(C~-C4)-alkyl,
OH,
(C, -C4)-alkoxy-(C, -Ca)-alkyl;
2o R29, R30, R31
independently of one another H, (C~-Cg)-alkyl, (C~-C6)-alkenyl, (Co-Cg)-
alkylene-aryl;
R32, R33 independently of one another H, (C~-C6)-alkyl
ZS or
R32 and R33
optionally together with the nitrogen atom to which they are bonded a 5-6
membered ring which, apart from the nitrogen atom, may also include 0-1
further heteroatoms from the group of NH, N-(C,-C6)-alkyl, oxygen and
3o sulfur and optionally be substituted by 1-2 oxo groups;
R3 H, (C,-C6)-alkyl;
CA 02554138 2006-07-20
4
R4, RS independently of one another H, (C,-C~,)-alkyl, OH, O-(C,-C6)-alkyl, O-
CO(C,-C~)-alkyl, S-(C,-C6)-alkyl;
R6, R7, R8, R9
independently of one another H, (C,-C~)-alkyl,
or
R6 and R7, R8 and R9
independently of one another optionally oxo;
I o n, m independently of one another 0, 1, 2;
A, B, D, G independently of one another N, C(R38);
R38 H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C,-C6)-alkyl, O-(C,-C4)-
Is alkoxy-(C,-C4)-alkyl, S-(C,-C~)-alkyl, (C1-C6)-alkyl, (CZ-C6)-alkenyl, (C3-
CR)-cycloalkyl, O-(C3-CA)-cycloalkyl, (C3-Cg)-cycloalkenyl, O-(C3-Cg)
cycloalkenyl, (Cz-C6)-alkynyl, (C~-Cg)-alkylene-aryl, O-(Co-C8)-alkylene
aryl, S-aryl, N(R39)(R40), S02-CH3, COOH, COO-(C,-C6)-alkyl,
CON(R41)(R42), N(R43)CO(R44), N(R45)SOZ(R46), CO(R47),
20 (CR48R49)X-O(R50);
R39, R40, R41, R42, R43, R45
independently of one another H, (C,-Cg)-alkyl;
or
25 R39 and R40, R41 and R42
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(C~-C6)-alkyl, oxygen and sulfur;
R44, R46, R47
independently of one another H, (C,-Cg)-alkyl, aryl;
CA 02554138 2006-07-20
S
R4H, R49 independently of one another H, (C,-CH)-alkyl;
R50 H, (C,-C~,)-alkyl;
x I , 2, 3, 4;
Het five-membered aromatic heterocycle
X a bond, a group of the formula -(CR51R52)y- in which one or more
o (CR51 R52)- groups may be replaced by Y to result in a chemically
reasonable radical, C=C, C=C;
Y O, S, N(R53), CO, SO, SO2;
~5 RSI, R52 independently of one another H, (C,-C4)-alkyl, where R51 and R52
in the y
groups may in each case have the same or different meanings;
y l , 2, 3, 4, 5, 6;
2o R53 H, (C,-Cg)-alkyl;
E 3-14 membered bivalent carbo- or heterocyclic ring structure having 0-4
heteroatoms from the group of N, O and S, which may optionally have
substituents from the group of H, F, Cl, Br, I, OH, CF3, NO~, CN, OCF3,
25 oxo, O-(C,-C6)-alkyl, O-(C1-C4)-alkoxy-(C,-C4)-alkyl, S-(C~-C6)-alkyl, (C1-
C6)-alkyl, (CZ-C6)-alkenyl, (C3-Cg)-cycloalkyl, O-(C3-Cg)-cycloalkyl, (C2-
C6)-alkynyl, (Co-Cs)-alkylene-aryl, O-(Co-Cg)-alkylene-aryl, S-aryl,
N(R54)(R55), SOZ-CH3, COOH, COO-(C,-C6)-alkyl, CON(R56)(R57),
N(R58)CO(R59), N(R60)SOZ(R61), CO(R62) and be mono- or bicyclic;
R54, R55, R56, R57, R58, R60
independently of one another H, (C1-Cg)-alkyl;
CA 02554138 2006-07-20
6
R54 and R55, R56 and R57
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membercd ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N
(C,-C~)-alkyl, oxygen and sulfur;
R59, R61, R62
independently of one another H, (C,-CA)-alkyl, aryl;
to K a bond, a group of the formula -(CR63R64)Z in which one or more -
(CR63R64)- groups may be replaced by Z to result in a chemically
reasonable radical, C=C, C=C;
Z O, S, N(R65), CO, SO, S02;
R63, R64 independently of one another H, (C,-Cg)-alkyl, hydroxy, (C,-C6)-
alkoxy,
where R63 and R64 in the z groups may in each case have the same or
different meanings;
2o z 1, 2, 3, 4, 5, 6; preferably 2, 3, 4, 5, 6;
R65 H, (C,-Cg)-alkyl;
Rll H, (C,-Cg)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, (C~-Cg)-alkenyl, (C3-Cg)-
alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may
include 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the ring system may additionally be substituted by F, Cl, Br,
CF3, NO2, CN, (C1-C6)-alkyl, O-(C~-C8)-alkyl, (CI-C4)-alkoxy-(C~-C4)-
alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy,
hydroxy-(CI-C4)-alkyl, COO(R69), N(R70)CO(C~-C6)-alkyl, N(R71)(R72)
or SOZCH3;
CA 02554138 2006-07-20
7
R66, R67, R68, R69, R70, R71, R72
independently of one another H, (C,-CH)-alkyl;
or
R67 and R68, R71 and R72
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(CI-C~)-alkyl, oxygen and sulfur; or
I o the N-oxides thereof and the physiologically tolerated salts thereof.
The invention relates to compounds of the formula I in the form of their
racemates,
enantiomer-enriched mixtures and pure enantiomers and to their diastereomers
and
I5 mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4,
R5, R6, R7, R8,
R9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19, R20, R21, R22,
R23, R24, R25,
R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40,
R41, R42,
2o R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57,
R58, R59,
R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74,
R75, R76,
R77, R78, R79, R80, R81, R82, R83 and R84 may be either straight-chain,
branched or
optionally halogenated.
25 In a further embodiment, the alkyl, alkenyl and alkynyl radicals in the
substituents R1, R2,
R3, R4, R5, R6, R7, R8, R9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R
18, R 19, R20,
R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35,
R36, R37,
R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52,
R53, R54,
R55, R56, R57, R58, R59, R60, R61, R62. R63, R64, R65, R66, R67, R68, R69,
R70, R71,
30 R72, R73, R74, R75, R76, R77, R78, R79. R80, R81, R82, R83 and R84 may be
both
straight-chain, branched and/or optionally substituted by substituents such as
aryl,
heteroaryl, alkoxy or halogen. This also applies if the alkyl, alkenyl and
alkynyl radicals
are part of another group, for example part of an alkoxy group (such as (C1-
C4)-alkoxy-
CA 02554138 2006-07-20
g
(C,-C4)-alkyl)). Suitable halogens are fluorine, chlorine, bromine and iodine,
preferably
fluorine, chlorine and bromine, particularly preferably fluorine.
Examples of alkyl groups are: methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl and octyl.
Included therein are both the n isomers of these radicals and branched isomers
such as
isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-
dimethylbutyl etc.
Unless described otherwise, the term alkyl additionally includes alkyl
radicals which are
unsubstituted or optionally substituted by one or more further radicals, for
example 1, 2, 3
or 4 identical or different radicals such as aryl, heteroaryl, alkoxy or
halogen. It is
moreover possible for the additional substituents to occur in any position of
the alkyl
radical.
Cycloalkyl means for the purposes of the present application cycloalkyl and
cycloalkyl-
alkyl(alkyl which is substituted in turn by cycloalkyl, e.g.
cyclopropylmethyl), where
~ 5 cycloalkyl has at least 3 carbon atoms. Examples of cycloalkyl radicals
are: cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and
cyclodecyl.
Optional possibilities are also polycyclic ring systems such as decalinyl,
norbornanyl,
bornanyl or adamantanyl. The cycloalkyl radicals may be unsubstituted or
optionally
substituted by one or more further radicals as listed above by way of example
for the alkyl
2o radicals.
Examples of alkenyl and alkynyl groups are: vinyl, 1-propenyl, 2-propenyl
(allyl),
2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, ethynyl, 1-propynyl, 2-
propynyl
(propargyl), 1-butynyl, 2-butynyl or 3-butynyl.
Cycloalkenyl means for the purposes of the present application cycloalkenyl
radicals and
cycloalkenyl-alkyl radicals (alkyl which is substituted by cycloalkenyl),
which comprise at
least three carbon atoms. Examples of cycloalkenyl are: cyclopentenyl,
cyclohexenyl,
cycloheptenyl and cyclooctenyl. The alkenyl radicals and cycloalkenyl radicals
may have
3o one to three conjugated or unconjugated double bonds (thus also alk-dienyl
and alk-trienyl
radicals), preferably one double bond in a straight or branched chain. The
same applies to
the triple bonds in alkynyl radicals. The alkenyl and alkynyl radicals may be
unsubstituted
or optionally substituted by one or more further radicals as listed above by
way of example
CA 02554138 2006-07-20
9
for the alkyl radicals.
Aryl refers in the present invention to radicals derived from monocyclic or
bicyclic
aromatic compounds comprising no ring heteroatoms. Where aryl refers to
systems which
are not monocyclic, the saturated form (perhydroform) or the partially
unsaturated form
(for example the dihydroform or tetrahydroform) is also possible, where the
respective
forms are known and stable, for the second ring. The term aryl also includes
in the present
invention for example bicyclic radicals in which both rings are aromatic and
bicyclic
radicals in which only one ring is aromatic. Examples of aryl are: phenyl,
naphthyl,
to indanyl, 1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or
1,2,3,4-tetrahydronaphthyl. Aryl is particularly preferably phenyl or
naphthyl. The term
"aryl" thus means in particular a phenyl or naphthyl group.
Heteroaryl radicals mean radicals derived from monocyclic or bicyclic aromatic
compounds comprising ring heteroatoms, preferably N, O or S. Otherwise, the
statements
made about aryl radicals apply to heteroaryl radicals.
The aryl and heteroaryl radicals may be unsubstituted or substituted by one or
more further
radicals. Suitable further radicals are listed by way of example above for the
alkyl radicals.
The compounds of the formula I may comprise one or more centers of asymmetry.
The
compounds of the formula I may therefore be in the form of their racemates,
enantiomer-
enriched mixtures, pure enantiomers, diastereomers and diastereomer mixtures.
The
present invention includes all these isomeric forms of the compounds of the
formula I.
These isomeric forms can be obtained by known methods even if not expressly
described
m some cases.
Mono-, bi- or spirocyclic rings may be saturated, partially saturated or
unsaturated and also
bridged.
C=C means a group of the formula R'C=CR" in which R' and R" are independently
of one
another H, (C,-Cg)-alkyl, preferably H.
CA 02554138 2006-07-20
l~
In the case where R1 and R2 together with the nitrogen atom to which they are
bonded
form a ring, this ring may be substituted by one or more of the substituents
mentioned.
Pharmaceutically acceptable salts are particularly suitable for medical
applications because
their solubility in water is higher than the initial or basic compounds. These
salts must have
a pharmaceutically acceptable anion or cation. Suitable pharmaceutically
acceptable acid
addition salts of the compounds according to the invention are salts of
inorganic acids such
as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric and
sulfuric
acids, and organic acids such as, for example, acetic acid, benzenesulfonic,
benzoic, citric,
~ o ethanesulfonic, fumaric, gluconic, glycolic, isethionie, lactic,
lactobionic, malefic, malic,
methanesulfonic, trifluoromethanesulfonic, succinic, p-toluenesulfonic,
tartaric and
trifluoroacetic acids. The chloride salt is particularly preferably used for
medical purposes.
Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali
metal salts
(such as sodium and potassium salts) and alkaline earth metal salts (such as
magnesium
~ 5 and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-
propanediol),
diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion likewise fall within the
scope of the
invention as useful intermediates for preparing or purifying pharmaceutically
acceptable
2o salts and/or for use in nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any
physiologically
tolerated derivative of a compound according to the invention of the formula
I, for example
an ester, which is able on administration to a mammal such as, for example, a
human to
25 form (directly or indirectly) a compound of the formula I or an active
metabolite thereof.
The physiologically functional derivatives also include prodrugs of the
compounds
according to the invention, as described, for example, in H. Okada et al.,
Chem. Pharm.
Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound
according
3o to the invention. These prodrugs may themselves be active or not.
The compounds according to the invention may also exist in various
polymorphous forms,
for example as amorphous and crystalline polymorphous forms. All polymorphous
forms
CA 02554138 2006-07-20
11
of the compounds according to the invention lie within the scope of the
invention and are a
further aspect of the invention.
All references hereinafter to "compound(s) of formula (I)" refer to compounds)
of the
formula (I) as described above, and the salts, solvates and physiologically
functional
derivatives thereof as described herein.
If radicals or substituents can occur more than once in the compounds of the
formula I,
they may all independently of one another have the stated meanings and be
identical or
0 different.
In a preferred embodiment, the meanings in the compounds of the formula I are
R1, R2independently of one another H, (Cl-CA)-alkyl, -(CR13R14)o-R12, (C,-C~)-
alkoxy-
(C1-C4)-alkyl, (C3-Cs)-alkenyl, (C3-Cs)-alkynyl, CO-(C,-Cg)-alkyl, -CO-
(CHZ)o -R12, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))SO(R21);
~ 5 or R 1 and R2 form together with the nitrogen atom to which they are
bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from
the nitrogen atom, may include 0 to 4 additional heteroatoms selected from
the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system
may additionally be substituted by F, Cl, Br, CF3, N02, CN, (C1-C6)-alkyl,
2o O-(C,-Cg)-alkyl, (C~-C4)-alkoxy-(C,-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (Co-
Cg)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy, COO(R25),
N(R26)CO(C,-C6)-alkyl or N(R27)(R28);
R12 OH, O-(C,-C6)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33), 3-12
25 membered mono-, bi- or spirocyclic ring which may comprise one or more
heteroatoms from the group of N, O and S, and the 3-12 membered ring may
comprise further substituents such as F, Cl, Br, I, OH, CF3, N02, CN, OCF~,
oxo, O-(C,-C6)-alkyl, (C1-C4)-alkoxy-(C~-C4)-alkyl, S-(C~-C6)-alkyl, (C,-
C6)-alkyl, (C~-C6)-alkenyl, (C3-C~)-cycloalkyl, (C2-C6)-alkynyl, O-(Co-Cg)-
3o alkylene-aryl, (Co-C~)-alkylene-aryl, N(R34)(R35), CO(C~-C6)-alkyl and
COO(R36);
and
CA 02554138 2006-07-20
12
R6, R7, R8, R9
independently of one another H, (C,-Cg)-alkyl;
where the further radicals and groups in the compounds of the formula I have
the meanings
mentioned hereinbefore and preferred meanings mentioned hereinafter.
In a further preferred embodiment, the present invention relates to compounds
of the
formula I
the meanings are:
io
Rl, R2 independently of one another H, (C,-Cs)-alkyl, -(CR13R14)o -R12, (C,-
Ca)-alkoxy-
(C,-C4)-alkyl, (C3-Cg)-alkenyl, CO-(Cl-C8)-alkyl, -CO-(CH2)o -R12,
CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))SO(R21); or R1 and R2
form together with the nitrogen atom to which they are bonded a 4 to 10-
~ 5 membered mono-, bi- or spirocyclic ring which, apart from the nitrogen
atom, may include 0 to 2 additional heteroatoms selected from the group of
oxygen, nitrogen and sulfur, where the heterocyclic ring system may
additionally be substituted by F, Cl, CF3, (C,-C6)-alkyl, O-(C,-C4)-alkyl,
(Ci-C4)-alkoxy-(C,-C4)-alkyl, hydroxy-(C~-C4)-alkyl, (Ca-CZ)-alkylene-aryl,
20 oxo, CO(R22), CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C,-C6)-
alkyl, N(R27)(R28) or SOZCH3;
preferably independently of one another H, (C1-C~)-alkyl,
-(CR13R14)o R12, (C~-C4)-alkoxy-(C,-C4)-alkyl, CO-(C1-Cg)-alkyl, -CO-
(CHZ)o R12, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))SO(R21);
25 or R1 and R2 form together with the nitrogen atom to which they are
bonded a 4 to 10-membered mono- or bicyclic ring which, apart from the
nitrogen atom, may include 0 to 2 additional heteroatoms selected from the
group of oxygen, nitrogen and sulfur, where the heterocyclic ring system
may additionally be substituted by F, Cl, CF3, (C,-C6)-alkyl, O-(C1-C4)-
3o alkyl, (C,-C4)-alkoxy-(Ca-C4)-alkyl, (Co-C~)-alkylene-aryl, oxo, CO(R22),
hydroxy, N(R27)(R28) or S02CH3;
particularly preferably independently of one another H, (C,-C~)-alkyl, -
(CR13R14)o R12, (C,-C4)-alkoxy-(C,-C4)-alkyl, CO-(C1-Cg)-alkyl, -CO-
CA 02554138 2006-07-20
13
(CH2)~ R12, CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form together
with the nitrogen atom to which they are bonded a 4 to 10-membered mono-
or bicyclic ring which, apart from the nitrogen atom, may include 0 to 2
additional heteroatoms selected from the group of oxygen and nitrogen,
where the heterocyclic ring system may additionally be substituted by F,
(Ci-C6)-alkyl, (C~-C4)-alkoxy-(C,-C~)-alkyl, oxo, CO(R22), hydroxy,
N(R27)(R28);
0 0, l, 2, 3, 4, 5, 6; preferably 0, l, 2, 3, 4; particularly preferably 0, l,
2, 3;
~o
q l, 2, 3; preferably 1 or 2;
s 0, l, 2, 3, 4; preferably 0, l, 2, 3; particularly preferably 0, 1, 2;
~ 5 R 15, R 16, R 17, R 18, R 19, R20, R21, R22, R23, R24, R25, R26, R27, R28
independently of one another H, (C1-C~)-alkyl;
or
R 17 and R 18, R23 and R24, R27 and R28
independently of one another optionally together with the nitrogen atom to
2o which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(C1-C6)-alkyl, oxygen and sulfur; the ring is preferably pyrrolidine,
piperidine, N-methylpiperazine, morpholine;
25 R12 OH, O-(C,-C6)-alkyl, CN, COO(R29), CON(R30)(R31), 3-12 membered
mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms
from the group of N, O and S, and the 3-12 membered ring may comprise
further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O-(C,-C6)-alkyl,
(C~-Cd)-alkoxy-(C,-C4)-alkyl, (C,-C6)-alkyl, O-(Co-Cg)-alkylene-aryl, (Co-
30 Cg)-alkylene-aryl, N(R34)(R35), CO(C1-C6)-alkyl, COO(R36), S(O)"(R37);
preferably OH, O-(Cl-C6)-alkyl, CN, 3-10 membered mono- or bicyclic ring
which may comprise 1-3 heteroatoms from the group of N, O and S, and the
3-10 membered ring may comprise further substituents such as F, Cl, Br,
CA 02554138 2006-07-20
14
OH, CF3, CN, oxo, O-(C,-C~)-alkyl, (C,-C4)-alkoxy-(Cl-C4)-alkyl, (C,-C~)-
alkyl, (Co-Cz)-alkylene-aryl, N(R34)(R35), CO(Cl-C6)-alkyl;
particularly preferably OH, O-(C,-C~)-alkyl, 3-10 membered mono- or
bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O
and S, and the 3-10 membered ring may comprise further substituents such
as F, OH, oxo, (C,-C~,)-alkyl, CO(C,-C~;)-alkyl;
a 0, 1, 2; preferably 0 or 2; particularly preferably 2;
i o R34, R35
independently of one another H, (C~-Cs)-alkyl;
or
R34 and R35
optionally together with the nitrogen atom to which they are bonded a 5-6
i5 membered ring which, apart from the nitrogen atom, may also include 0-1
further heteroatoms from the group of NH, N-(C,-C6)-alkyl, oxygen and
sulfur, and optionally be substituted by 1-2 oxo groups;
R36, R37 H, (C,-Cs)-alkyl;
R13, R14 independently of one another H, (C1-Cg)-alkyl, hydroxy-(C~-Cø)-alkyl,
OH,
(C, -C4)-alkoxy-(C 1-Ca)-alkyl;
R29, R30, R31
independently of one another H, (C1-C~)-alkyl;
R3 H, (Ci-C6)-alkyl; preferably H;
R4, RS independently of one another H, (CI-C6)-alkyl, OH, O-(CI-C6)-alkyl, O-
3o CO(CI-C6)-alkyl, S-(Cl-C6)-alkyl; preferably independently of one another
H, (C,-C6)-alkyl, OH, O-(C,-C~)-alkyl, O-CO(C~-C6)-alkyl; particularly
preferably independently of one another H, OH, O-(C~-C6)-alkyl, very
particularly preferably H;
CA 02554138 2006-07-20
R6, R7, R8, R9
H;
or
5 R6 and R7, R8 and R9
independently of one another optionally oxo;
R6, R7, R8, R9 are preferably H;
n 1
~o
m 1 or 2; preferably l;
A, B, D, G independently of one another N, C(R38);
or
~ 5 the groups A and B or D and G are in each case C(R38) and together form
an ortho-phenylene unit so that the overall result is a 1,4-bisubstituted
naphthalene system;
preferably A, B, G and D are independently of one another N, C(R38);
particularly preferably D and G are C(R38) and either A or B is N, with the
respective other group B or A being C(R38); very particularly preferably
B is N, C(R38); and A, D, G C(R38);
especially preferably
A, B, D, G are C(R38);
R38 H, F, Cl, Br, CF3, CN, O-(CI-C6)-alkyl, O-(CI-C~)-alkoxy-(Cl-C4)-alkyl, S-
(C~-C6)-alkyl, (C1-C6)-alkyl, (Co-Cg)-alkylene-aryl, O-(CQ-Cg)-alkylene-aryl,
N(R39)(R40), SOZ-CH3, CON(R41)(R42), N(R43)CO(R44), CO(R47), -
(CR48R49)X-O(R50);
preferably H, F, Cl, Br, CF3, CN, O-(C,-C6)-alkyl, (C~-C6)-alkyl, SOZ-CHI,
3o CON(R41)(R42), N(R43)CO(R44), CO(R47),
-(CR48R49)X-O(R50);
particularly preferably H, F, Cl, CF3, CN, (C,-Cb)-alkyl,
-(CR48R49)X-O(R50);
CA 02554138 2006-07-20
16
R39, R40, R41, R42, R43
independently of one another H, (C1-C8)-alkyl;
or
R39 and R40, R41 and R42
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(C,-C~)-alkyl, oxygen and sulfur;
fo
R44, R47
independently of one another H, (C,-Cg)-alkyl, aryl; preferably
independently of one another H, (C,-CA)-alkyl;
R48, R49 H;
~5
R50 H, (C,-C6)-alkyl;
x 1, 2; preferably l;
20 Het five-membered aromatic heterocycle, preferably
i~,~
_~t r~ J' __, i , f- , _ ~~,-W'
%,3 ~ !~'. ° ,- ~'x!
~:
~' I
S f: 1
~J'S--- ~i ~yi,:_...~yJ~
o r ~ ___. ,
in which
A' is O, S, NR73,
X' , Y' and Z'
CA 02554138 2006-07-20
17
are independently of one another CR74 or N, and
R73, R74 are independently of one another H, (CI-Cg)-alkyl;
Het is particularly preferably selected from the group consisting of
oxadiazoles, thiadiazoles, thiazoles, oxazoles, triazoles, thiophenes, furans
and pyrroles; Het is very particularly preferably selected from oxadiazoles,
thiadiazoles, thiazoles and oxazoles;
X a bond, a group of the formula -(CR51R52)y- in which one or more -
o (CR51R52)- groups may be replaced by Y to result in a chemically
reasonable radical, C=C, C=C; preferably a bond, CHZ-CHZ, CH2Y, YCH2,
(R75)YCH2, CHZ-NCO(R75), CHZCON(R75); C(R76)(R77),
C(R78)(R79)O, N(R75), C=C, C-C; particularly preferably a bond, CHZ-
CHZ, C(R76)(R77), N(R75), CH2Y, CH2Y(R75), CH2-NCO(R75),
~ 5 CHZCON(R75); C=C; very particularly preferably a bond, CHI-CHz,
C(R76)(R77), C=C, (R75)YCH2, CHZ-NCO(R75);
Y O, S, N(R53), CO; preferably O, S, N(R53);
2o R53 H, (C~-Cg)-alkyl;
R75, R76, R77, R78, R79
independently of one another H, (C1-CA)-alkyl;
25 E 3-8 membered bivalent carbo- or heterocyclic ring structure having 0-4
heteroatoms from the group of N, O and 5, which may optionally have
substituents from the group of H, F, Cl, Br, OH, CF3, NO~, CN, OCF~, O-
(Cl-C6)-alkyl, O-(C,-C4)-alkoxy-(Cl-C4)-alkyl, S-(CI-C6)-alkyl, (Ct-C6)-
alkyl, (CZ-C6)-alkenyl, O-(C3-Cs)-cycloalkyl, (C2-C6)-alkynyl, (Co-Cg)-
3o alkylene-aryl, O-(Co-Cg)-alkylene-aryl, S-aryl, N(R54)(R55), S02-CH3,
N(R58)CO(R59), N(R60)S02(R61), CO(R62) and be mono- or bicyclic;
preferably 5-7 membered bivalent carbo- or heterocyclic ring structure
having 0-3 heteroatoms from the group of N, O and S, which may optionally
CA 02554138 2006-07-20
18
have substituents from the group of H, F, C1, Br, OH, CF3, NO~, CN, OCF3,
O-(C~-C6)-alkyl, S-(C1-C6)-alkyl, (CI-C6)-alkyl, (C2-C6)-alkenyl, O-(Co-Cg)-
alkylene-aryl, S-aryl, N(R54)(R55), SOZ-CH3, N(R58)CO(R59), CO(R62)
and be mono- or bicyclic;
s particularly preferably 5-7 membered bivalent carbo- or heterocyclic ring
structure having 0-2 heteroatoms from the group of N, O and S, which may
optionally have substituents from the group of H, F, Cl, Br, OH, CF3, N02,
OCF3, O-(C,-C6)-alkyl, (C,-C6)-alkyl, (C2-C6)-alkenyl, N(R54)(R55), SOZ-
CH3, CO(R62), and which is very particularly preferably monocyclic;
o e.g. E is benzene, pyridine, pyrimidine, piperidine, pyrrolidine,
cyclopentane, cyclohexane, piperazine, homopiperazine, thiazole, thiophene,
furan, pyrrole, pyrazole, 1,2,3,6-tetrahydropyridine, 4,5-dihydroisoxazole,
oxazole;
~ 5 R54, R55, R58, R60
independently of one another H, (C,-Cs)-alkyl;
R59, R61, R62
independently of one another H, (Ci-Cg)-alkyl, aryl; preferably
2o independently of one another H, (C1-Cg)-alkyl;
K O, a bond, CHZO, OCHZ, S, SO, SOZ, N(R80), N(R81)CO, CON(R82),
(C(R83)(R84))~, CO, C=C, C=C, SCH~, SOzCHz;
preferably O, a bond, CH~O, OCH2, N(R80), N(R81)CO, CON(R82),
25 (C(R83)(R84)),,, CO, C---C, SCH2; particularly preferably O, a bond, CH20,
OCH~, CON(R82), (C(R83)(R84))", CO, C=C;
v l, 2, 3, 4; preferably l, 2, 3; particularly preferably 1,2;
3o R80, R81, R82, R83, R84
independently of one another H, (C,-Cg)-alkyl;
CA 02554138 2006-07-20
19
R11 H, (C,-Cg)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, (C3-Cg)-alkenyl, (C3-Cs)-
alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may
include 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the ring system may additionally be substituted by F, Cl, Br,
CF3, CN, (C1-C6)-alkyl, O-(Ci-Cs)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl,
hydroxy-(C,-C4)-alkyl, (Co-Cs)-alkylene-aryl, oxo, CO(R66),
CON(R67)(R68), hydroxy, COO(R69), N(R70)CO(C~-C6)-alkyl,
N(R71 )(R72) or S02CH3;
preferably (C,-Cg)-alkyl, (C,-C4)-alkoxy-(C~-C4)-alkyl, a 3 to 10-membered
mono-, bi- or spirocyclic ring which may include 0 to 3 heteroatoms
selected from the group of oxygen, nitrogen and sulfur, where the ring
system may additionally be substituted by F, Cl, Br, CF3, CN, (C,-C6)-alkyl,
O-(C,-Cs)-alkyl, (C~-CZ)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68),
hydroxy, N(R70)CO(C~-C6)-alkyl, N(R71)(R72) or SOzCH3;
is particularly preferably (C,-C8)-alkyl, (C1-C4)-alkoxy-(C,-C4)-alkyl, a 3 to
10-membered mono- or bicyclic ring which may include 0 to 2 heteroatoms
selected from the group of oxygen, nitrogen and sulfur, where the ring
system may additionally be substituted by F, Cl, Br, CF3, CN, (C,-C6)-alkyl,
O-(C,-Cg)-alkyl, oxo, CO(R66), CON(R67)(R68), N(R70)CO(Ci-C6)-alkyl,
20 or SO~CH3;
R66, R67, R68, R69, R70, R71, R72
independently of one another H, (CI-Cg)-alkyl;
or
R67 and R68, R71 and R72
25 independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(C1-C6)-alkyl, oxygen and sulfur; or
3o the N-oxides thereof and the physiologically tolerated salts thereof.
In a preferred embodiment of the invention, the radicals R1, R2, R1 l, R38 and
groups X,
E, K have the following meanings:
CA 02554138 2006-07-20
Rl, R2 independently of one another H, (C,-CR)-alkyl, -(CR13R14)o R12, (C,-C4)-
alkoxy-(C,-C4)-alkyl, or Rl and R2 form together with the nitrogen atom to
which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring
5 which, apart from the nitrogen atom, may include 0 to 2 additional
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the heterocyclic ring system may additionally be substituted by (C,-C6)-
alkyl, O-(CI-C4)-alkyl, (Ci-C4)-alkoxy-(C,-C4)-alkyl, hydroxy-(C,-C4)-
alkyl, (Co-CZ)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy,
N(R27)(R28) or SO~CH3;
preferably independently of one another H, (C1-C$)-alkyl, -(CR13R14)o-,
R12, (Cl-C4)-alkoxy-(C,-C4)-alkyl, or Rl and R2 form together with the
nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or
spirocyclic ring which, apart from the nitrogen atom, may include 0 to 2
~ 5 additional heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the heterocyclic ring system may additionally be substituted
by (C,-C6)-alkyl, O-(C~-C4)-alkyl, (C,-C4)-alkoxy-(C~-C4)-alkyl, hydroxy-
(C~-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24),
hydroxy or N(R27)(R28);
2o very particularly preferably independently of one another H, (C,-Cg)-alkyl,
or R1 and R2 form together with the nitrogen atom to which they are
bonded a 5 to 6-membered monocyclic ring which, apart from the nitrogen
atom, may include 0 to 1 additional heteroatoms selected from the group of
oxygen, nitrogen and sulfur, where the heterocyclic ring system may
additionally be substituted by (Cl-C6)-alkyl;
especially preferably independently of one another H, (C1-Cg)-alkyl;
0 0, 1, 2, 3, 4;
3o R22, R23, R24, R27, R28
independently of one another H, (C,-C6)-alkyl;
or
R23 and R24, R27 and R28
CA 02554138 2006-07-20
21
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH, N-
(Cl-C~)-alkyl, oxygen and sulfur;
R12 OH, O-(C,-C~)-alkyl, CN, 3-12 membered mono-, bi- or spirocyclic ring
which may comprise 1 to 3 heteroatoms from the group of N, O and S, and
the 3-12 membered ring may comprise further substituents such as F, OH,
CF3, CN, oxo, (C1-C6)-alkyl, (C~-CZ)-alkylene-aryl, N(R34)(R35),
o COO(R36), CO(C,-C6)-alkyl;
R34, R35
independently of one another H, (C,-C4)-alkyl;
~5 R36 H, (C~-C6)-alkyl;
R13, R14 independently of one another H, (C,-Cs)-alkyl, hydroxy-(C,-C4)-alkyl,
OH,
(C, -C~)-alkoxy-(C I-C4)-alkyl;
20 R38 H, F, Cl, Br, CFA, CN, (C~-C6)-alkyl;
X a bond, CHZCH~, C(R76)(R77), N(R75), C=C, (R75)YCH2,
CHZ-NCO(R75), CHZCON(R75);
25 Y O, S, N(R53), CO
R75, R76, R77
independently of one another H, (CI-Cg)-alkyl;
3o R53 H, (C,-Cg)-alkyl;
E 5-7 membered bivalent carbo- or heterocyclic ring structure having 0-3
heteroatoms from the group of N, O and S, which may optionally have
CA 02554138 2006-07-20
22
substituents from the group of H, F, Cl, Br, CF3, OH, CN, OCF3, O-(C1-C~)-
alkyl, (C,-C6)-alkyl, SOZ-CH3, CO(R65);
R65 H, (C,-Cg)-alkyl;
K O, a bond, CH20, CH2, OCH2, S, SO2, N(R80), N(R81)CO, CON(R82),
(C(R83)(R84))", CO, C---C, SCH~, SOZCH2;
preferably O, a bond, CH20, CHZ, OCH2, N(R80), C---C;
io v l, 2, 3;
R80, R81, R82, R83, R84
independently of one another H, (C1-Cg)-alkyl;
~5 R11 (Cl-Cx)-alkyl, (C,-C4)-alkoxy-(C~-C4)-alkyl, a 3 to 10-membered mono-,
bi-
or spirocyclic ring which may include 0 to 4 heteroatoms selected from the
group of oxygen, nitrogen and sulfur, where the ring system may
additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C~-Cs)-
alkyl, oxo, CO(R66), hydroxy, N(R70)CO(C1-C6)-alkyl, or SOZCH3;
R66, R70
independently of one another H, (C~-Cg)-alkyl;
the N-oxides thereof and the physiologically tolerated salts thereof.
Particularly preferred compounds of the formula I are those in which
A, B, D, G are independently of one another N or C(R38), and the total number
of
nitrogen atoms in this ring is 0-2, preferably 0 or I , and in the case where
the total number of nitrogen atoms is l, particularly preferably A or B are N,
and very particularly preferably B is N.
CA 02554138 2006-07-20
23
Very particularly preferred compounds of the formula I are those in which
n is 1 and
m is 1 or 2.
S
Especially preferred compounds of the formula I are those in which
A, B, D, G are independently of one another N or C(R38), and the total number
of
nitrogen atoms in this ring is 0-2, preferably 0 or l, and in the case where
m the total number of nitrogen atoms is l, particularly preferably A or B are
N,
and very particularly preferably B is N.
n is l and
IS m is 1 or2.
The radical R38 has the aforementioned meanings.
Especially preferred compounds of the formula I are those in which
~o
Het is selected from the group consisting of oxadiazoles, thiadiazoles,
thiazoles,
oxazoles, triazoles, thiophenes, furans and pyrroles; Het is very particularly
preferably selected from oxadiazoles, thiadiazoles, thiazoles and oxazoles.
25 The further radicals may have the aforementioned meanings in the
aforementioned
preferred embodiments.
In a very particularly preferred embodiment, the present application relates
to compounds
of the formula IA
CA 02554138 2006-07-20
24
. . ~.i _- j~..i'';.1
,'
i-t . _ ~ = ' - -. ,~. - 3~ ~ ~ ,---- ~ ~ I ..
. . a .. ' '
in which the meanings are
i.~:
;_
,r
>>
Het ~~,;-..,,_ Or ,
in which
A' is O, S,
X' and Y'
I o are independently of one another CR74 or N, and
R74 are independently of one another H, (C1-Cs)-alkyl;
A, B are CH or CF, where in the case of CF only one of the two groups A or B
is
CF and the other group is CH;
Rl, R2 independently of one another H, (C,-Cg)-alkyl, -(CR13R14)o-R12, (C1-C4)-
alkoxy-(C,-C4)-alkyl, (C3-Cg)-alkenyl, (C3-Cg)-alkynyl, CO-(Cl-Cg)-alkyl,
-CO-(CHZ)o R12, CO(C(R15)(R16))qN(R17)(R18),
CO(C(R 19)(R20))50(R21 ); or R 1 and R2 form together with the nitrogen
2o atom to which they are bonded a 4 to 10-membered mono-, bi- or
spirocyclic ring which, apart from the nitrogen atom, may include 0 to 4
additional heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the heterocyclic ring system may additionally be substituted
by F, Cl, Br, CF3, NO2, CN, (C~-C6)-alkyl, O-(C~-Cs)-alkyl, (C~-C4)-alkoxy-
(CI-C4)-alkyl, hydroxy-(C~-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R22),
CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C1-C6)-alkyl,
N(R27)(R28) or SOZCH3;
CA 02554138 2006-07-20
particularly preferably independently of one another H, (C,-CA)-alkyl,
-(CR13R14)~-R12, (C,-C4)-alkoxy-(C,-C4)-alkyl, CO-(Cl-C$)-alkyl,
-CO-(CH~)a-R12; or RI and R2 form together with the nitrogen atom to
which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring
5 which, apart from the nitrogen atom, may include 0 to 4 additional
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the heterocyclic ring system may additionally be substituted by F, Cl, CF3,
(C,-C~)-alkyl, O-(C,-Cg)-alkyl, (C,-C~)-alkoxy-(C~-C4)-alkyl, hydroxy-(C~
C4)-alkyl, (C~-C~)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxyl,
o N(R26)CO(C,-C6)-alkyl, N(R27)(R28);
very particularly preferably independently of one another H, (CI-Cg)-alkyl, -
(CR13R14)o-R12, (C,-C4)-alkoxy-(C1-C4)-alkyl, -CO-(CHZ)o-R12; or R1
and R2 form together with the nitrogen atom to which they are bonded a 4 to
7-membered monocyclic ring which, apart from the nitrogen atom, may
~ 5 include 0 to 2 additional heteroatoms selected from the group of oxygen,
nitrogen and sulfur, where the heterocyclic ring system may additionally be
substituted by F, Cl, CF3, (C1-C6)-alkyl, O-(C,-C~)-alkyl, hydroxy-(C,-C4)-
alkyl, CO(R22), CON(R23)(R24), hydroxy, N(R26)CO(C,-C6)-alkyl,
N(R27)(R28);
2o especially preferably independently of one another H, (C1-Cs)-alkyl, or R1
and R2 form together with the nitrogen atom to which they are bonded a 5 to
6-membered monocyclic ring which, apart from the nitrogen atom, may
include 0 to 1 additional heteroatoms selected from the group of oxygen,
nitrogen and sulfur, where the heterocyclic ring system may additionally be
z5 substituted by (C,-C6)-alkyl;
further very particularly preferably independently of one another H,
(C,-Cg)-alkyl;
0 0, 1, 2, 3, 4, 5, 6; preferably 0, I, 2, 3, 4;
3o
q, s independently of one another 0, l, 2, 3, 4;
R 15, R I 6, R 17, R 18, R 19, R20, R21, R22, R23, R24, R25, R26, R27, R28
CA 02554138 2006-07-20
26
independently of one another H, (C,-Cf,)-alkyl;
R 17 and R 18, R23 and R24, R27 and R28
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of NH,
N-(C ~-C~,)-alkyl, oxygen and sulfur;
R12 OH, O-(C,-C~,)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33), 3-12
o membercd mono-, bi- or spirocyclic ring which may comprise one or more
heteroatoms from the group of N, O and S, and the 3-12 memhered ring may
comprise further substituents such as F, Cl, Br, l, OH, CFA, NO~, CN, OCF3,
oxo, O-(C~-C6)-alkyl, (C,-Ca)-alkoxy-(C,-C4)-alkyl, S-(C~-C6)-alkyl, (C,-
C6)-alkyl, (C~-C~)-alkenyl, (C3-CA)-cycloalkyl, (CZ-C6)-alkynyl, O-(C~-C~)-
~5 alkylene-aryl, (C~-Cs)-alkylene-aryl, N(R34)(R35), CO(Ci-C6)-alkyl,
COO(R36) and S(O)"(R37);
particularly preferably OH, O-(C,-C6)-alkyl, CN, CON(R30)(R31),
N(R32)(R33), 3-7 membered monocyclic ring which may comprise one or
more heteroatoms from the group of N, O and S, and the 3-7 membered ring
2o may comprise further substituents such as F, Cl, OH, CF3, CN, OCF3, oxo,
O-(C,-C6)-alkyl, (C~-C4)-alkoxy-(C~-C4)-alkyl, S-(C1-C6)-alkyl, (C1-C6)-
alkyl, (CZ-C6)-alkenyl, (C3-Cg)-cycloalkyl, (CZ-C6)-alkynyl, O-(Co-Cg)-
alkylene-aryl, (C~-C8)-alkylene-aryl, N(R34)(R35) and CO(C1-C6)-alkyl;
25 a 0, 1, 2;
R34, R35
independently of one another H, (C,-Cg)-alkyl;
30 R34 and R35
optionally together with the nitrogen atom to which they are bonded a 5-6
membered ring which, apart from the nitrogen atom, may also include 0-1
CA 02554138 2006-07-20
27
further heteroatoms from the group of NH, N-(C~-C~)-alkyl, oxygen and
sulfur and optionally be substituted by 1-2 oxo groups;
R36, R37 H, (C,-Cs)-alkyl;
S
R13, R14 independently of one another H, (Cl-Cs)-alkyl, hydroxy-(C,-C4)-alkyl,
OH,
(C, -C4)-alkoxy-(C ~ -C4)-alkyl;
R29, R30, R31
o independently of one another H, (C~-Cg)-alkyl, (CZ-C6)-alkenyl, (Co-Cg)-
alkylene-aryl;
R32, R33 independently of one another H, (C,-C6)-alkyl
or
~ 5 R32 and R33
optionally together with the nitrogen atom to which they are bonded a 5-6
membered ring, which, apart from the nitrogen atom, may also include 0-1
further heteroatoms from the group of NH, N-(C~-C6)-alkyl, oxygen and
sulfur and optionally be substituted by 1-2 oxo groups;
X a bond, a group of the formula -(CR51R52)y- in which one or more
-(CR51 R52)- groups may be replaced by Y to result in a chemically
reasonable radical, C=C, C---C; preferably a bond, CHZ-CH2, CH~Y, YCH2,
(R75)YCHZ, CHZ-NCO(R75), CHZCON(R75); C(R76)(R77),
C(R78)(R79)O, N(R75), C=C, C=C; particularly preferably a bond, CHZ-
CH2, C(R76)(R77), N(R75), CHZY, CH2Y(R75), CHZ-NCO(R75),
CH2CON(R75); C=C; very particularly preferably a bond, CHZ-CH2,
C(R76)(R77), C=C; (R75)YCH~, CH2-NCO(R75);
3o Y O, S, N(R53), CO, SO, SOZ; particularly preferably O, S, N(R53), CO; very
particularly preferably O, N (R53);
CA 02554138 2006-07-20
28
R51, R52 independently of one another H, (C,-C4)-alkyl, where R51 and R52 in
the y
groups in each case can have the same or different meanings;
y 1,2,3,4,5,6;
R53 H, (C,-Cs)-alkyl;
E 3-14 membered bivalent carbo- or heterocyclic ring structure having 0-4
heteroatoms from the group of N, O and S, which may optionally have
substituents from the group of H, F, Cl, Br, I, OH, CFA, NOZ, CN, OCF3,
oxo, O-(C,-C6)-alkyl, O-(C1-C4)-alkoxy-(C,-C4)-alkyl, S-(C1-C6)-alkyl,
(Cl-C6)-alkyl, (C~-C6)-alkenyl, (C3-C~)-cycloalkyl, O-(C3-C8)-cycloalkyl,
(CZ-C6)-alkynyl, (Co-C~)-alkylenc-aryl, O-(Co-C8)-alkylene-aryl, S-aryl,
N(R54)(R55), S02-CH3, COOH, COO-(C1-C6)-alkyl, CON(R56)(R57),
~5 N(R58)CO(R59), N(R60)SOZ(R61), CO(R62) and be mono- or bicyclic;
preferably 5-7 membered bivalent carbo- or heterocyclic ring structure
having 0-3 heteroatoms from the group of N, O and S, which may optionally
have substituents from the group of H, F, Cl, OH, CN, CF3, OCF3, O-(Cl-
C6)-alkyl, (C,-C6)-alkyl, (Co-Cg)-alkylene-aryl, O-(C3-Cg)-cycloalkyl,
2o N(R54)(R55), SOZ-CHI, CON(R56)(R57), N(R58)CO(R59),
N(R60)SOZ(R61), CO(R62) and be mono- or bicyclic; particularly
preferably 5-7 membered bivalent carbo- or heterocyclic ring structure
having 0-3 heteroatoms from the group of N, O and S, which may optionally
have substituents from the group of H, F, Cl, CF3, OCF3, O-(C,-C6)-alkyl,
25 (CI-C6)-alkyl, (Co-CZ)-alkylene-aryl, O-(C3-C6)-cycloalkyl, N(R54)(R55),
CON(R56)(R57), N(R58)CO(R59), CO(R62) and be mono- or bicyclic;
R54, R55, K56, R57, R58, R60
independently of one another H, (Ci-C8)-alkyl;
R54 and R55, R56 and R57
independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
CA 02554138 2006-07-20
29
atom, may also include 0-1 further heteroatoms from the group of NH,
N-(C,-C6)-alkyl, oxygen and sulfur;
R59, R61, R62
independently of one another H, (C,-Cg)-alkyl, aryl;
K a bond, a group of the formula -(CR63R64),-, in which one or more
-(CR63R64)- groups may be replaced by Z to result in a chemically
reasonable radical, C---C, C=C;
I o preferably O, a bond, CH~O, CH2, OCH2, S, SO2, N(R80), N(R81 )CO,
CON(R82), (C(R83)(R84))~, CO, C=C, SCHZ, SOZCH~;
Z O, S, N(R65), CO, SO, SO2;
I5 R63, R64 independently of one another H, (C,-Cg)-alkyl, hydroxy, (C~-C6)-
alkoxy,
where R63 and R64 in the z groups may in each case have the same or
different meanings;
z l, 2, 3, 4, 5, 6, preferably 2, 3, 4, 5, 6;
R65 H, (C~-Cs)-alkyl;
R11 H, (C1-Cg)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, (C3-C8)-alkenyl, (C3-Cg)-
alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may
include 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the ring system may additionally be substituted by F, Cl, Br,
CF3, NO2, CN, (C1-C6)-alkyl, O-(C,-Cs)-alkyl, (C1-C4)-alkoxy-(C1-C4)
alkyl, (Co-Cg)-alkylene-aryl, oxo, CO(Rb6), CON(R67)(R68), hydroxy,
hydroxy-(CI-C4)-alkyl, COO(R69), N(R70)CO(Cl-C6)-alkyl, N(R71)(R72)
3o or SO~CH3;
preferably H, (Ci-Cg)-alkyl, (C,-C4)-alkoxy-(C1-C4)-alkyl, a 5 to 6-
membered monocyclic ring which may include 0 to 3 heteroatoms selected
CA 02554138 2006-07-20
from the group of oxygen, nitrogen and sulfur, where the ring system may
additionally be substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O-
(Cz-Cg)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, CO(R66), CON(R67)(R68),
hydroxy, N(R70)CO(C,-C6)-alkyl, N(R71)(R72) or SO~CH3;
5 particularly preferably H, (C,-Cs)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, a 5
to
6-membered monocyclic ring which may include 0 to 2 heteroatoms
selected from the group of oxygen, nitrogen and sulfur, where the ring
system may additionally be substituted by F, Cl, Br, CFA, N02, CN, (C,-C6)-
alkyl or O-(C~-Cg)-alkyl;
io
R66, R67, R68, R69, R70, R71, R72
independently of one another H, (C,-Cs)-alkyl;
or
R67 and R68, R71 and R72
i 5 independently of one another optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0- I further heteroatoms from the group of NH,
N-(C,-C6)-alkyl, oxygen and sulfur; or
2o the N-oxides thereof and the physiologically tolerated salts thereof.
The compounds of the invention of the formula I and their precursors can be
prepared by
processes known to the skilled worker.
z5 The preparation of compounds of the invention of the formula I is described
below for the
example of the preparation of [1,3,4]-oxadiazoles (Ia), [1,3,4]-thiadiazoles
(Ib) and [1,2,4]-
oxadiazoles (Ic):
CA 02554138 2006-07-20
31
N H
O OR O OR O N~NH
2
\ NR1 R2 / I H2N-NH2 x H20 /
\ \
F N1 N1
NR1 R2 NR1 R2
(III) (IV)
in which
R is H, (C,-Cs)-alkyl, and
R 1 and R2 have the aforementioned meanings;
O
R11 ~K~E~X~OH ~ ~
(IV) _ X O ~ N\/ -NR1R2
CI PF6 ~K~E~ ~
+~ R11 N-N
~N ~ N~
U
(la)
0 or Burgess' reagent
CA 02554138 2006-07-20
32
O
H
O O N~N~X~E~K~R11
H
R11 ~K~E~X~OH
(V)
TOTU
i
N
NR1 R2 Lawesson's reagent
N~'NRiR2
x
~K~E~ ~ /
R11 N-N
(1b)
in which Rl, R2, Rl i and X, E and K have the aforementioned meanings.
CA 02554138 2006-07-20
33
. _ ..' ww
__- ~ ,, ,
.. w:,:y.
;../.i... ;= v
~ lIE.;S~i..l
~i
' . .
' '
~ ,
;i
;~v..~f~,i,j-.r
.. ; -
~~-~~ ,_ S~'y
'1a ~ .
~1 -,;~.-:- ~ ;~.'
_.. ,, ,
,~;,ir n
.w.;
in which R1, R2, R1 l and X, E and K have the aforementioned meanings.
s Use
This invention further relates to the use of compounds of the formula I and
their
pharmaceutical compositions as MCH receptor ligands. The MCH receptor ligands
of the
invention are particularly suitable as modulators of the activity of the
MCH1R.
t0
The role of MCH in regulating the energy balance has now been well documented
(Qu, D.
et al.; Nature 1996, 380, 243-7; Shimada, M. et al. Nature 1998, 396, 670-4;
Chen, Y. et al.
Endocrinology 2002, 143, 2469-77; Endocrinology 2003, 144, 4831-40; Review: G.
Hervieu, Expert Opin. Ther. Targets 2003, 7, 495-511 ).
There are also indications that MCH antagonists can have a beneficial
influence on
centrally related disorders such as, for example, depression (Borowsky, B. et
al.; Nature
CA 02554138 2006-07-20
34
Medicine 2002, 8, 825-30; Review: G. Hervieu, Expert Opin. Ther. Targets 2003,
7, 495-
511).
Compounds of this type are particularly suitable for the treatment and/or
prevention of
1. Obesity
2. Diabetes mellitus, especially type 2 diabetes, including the prevention of
the sequelae
associated therewith.
Particular aspects in this connection are
- hyperglycemia,
- improvement in insulin resistance,
- improvement in glucose tolerance,
- protection of the pancreatic 13 cells
~ 5 - prevention of macro- and microvascular disorders
3. Dyslipidemias and their sequelae such as, for example, atherosclerosis,
coronary heart
disease, cerebrovascular disorders etc., especially those (but not restricted
thereto)
which are characterized by one or more of the following factors:
20 - high plasma triglyceride concentrations, high postprandial plasma
triglyceride
concentrations,
- low HDL cholesterol concentration
4. Various other conditions which may be associated with the metabolic
syndrome, such
2S as:
- thromboses, hypercoagulable and prothrombotic stages (arterial and venous)
- high blood pressure
- heart failure such as, for example (but not restricted thereto), following
myocardial
infarction, hypertensive heart disease or cardiomyopathy
5. Psychiatric indications such as
- depression
- anxiety states
CA 02554138 2006-07-20
- disturbances of the circadian rhythm
- affection disorders
- schizophrenia
- addictive disorders
5
Formulations
The amount of a . compound of formula (I) which is necessary to achieve the
desired
biological effect depends on a number of factors, for example the specific
compound
~ o chosen, the intended use, the mode of administration and the clinical
condition of the
patient. In general, the daily dose is in the range from 0.001 mg to 100 mg,
preferably from
0.3 mg to 100 mg (typically from 0.01 mg to 50 mg, preferably from 3 mg to 50
mg) per
day per kilogram of body weight, for example 0.1-10 mg/kg/day, preferably 3-10
mg/kglday. An intravenous dose may be, for example, in the range from 0.001 mg
to 1.0
is mgfkg, preferably from 0.3 mg to 1.0 mglkg, which can most suitably be
administered as
infusion of from 10 ng to 100 ng per kilogram and per minute. Suitable
infusion solutions
for these purposes may contain, for example, from 0.1 ng to 10 mg, typically
from 1 ng to
10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10
g of the
active ingredient. Single doses may contain, for example, from 1 mg to 10 g of
the active
2o ingredient. It is thus possible for ampoules for injections to contain, for
example, from
1 mg to 100 mg, and for single-dose formulations which can be administered
orally, such
as, for example, tablets or capsules, to contain, for example, from 0.05 to
1000 mg,
typically from 0.5 to 600 mg, or in a further embodiment from 1.0 to 1000 mg,
typically
from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the
aforementioned
25 weight data are based on the weight of the salt of the underlying free
compound. For the
prophylaxis or therapy of the abovementioned conditions, the compounds of
formula (I)
can be used as the compound itself, but they are preferably in the form of a
pharmaceutical
composition with an acceptable carrier. The carrier must, of course, be
acceptable in the
sense that it is compatible with the other ingredients of the composition and
is not
3o hazardous for the patient's health. The carrier may be a solid or a liquid
or both and is
preferably formulated with the compound as a single dose, for example as a
tablet which
may contain from 0.05% to 95% by weight of the active ingredient. Further
pharmaceutically active substances may likewise be present, including other
compounds of
CA 02554138 2006-07-20
36
formula (I). The pharmaceutical compositions according to the invention can be
produced
by one of the known pharmaceutical methods which essentially consist of mixing
the
ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions according to the invention are those suitable for
oral, rectal,
topical, peroral (for example sublingual) and parenteral (for example
subcutaneous,
intramuscular, intradermal or intravenous) administration although the most
suitable mode
of administration in each individual case depends on the nature and severity
of the
condition to be treated and on the nature of the compound of formula (I) used
in each case.
o Coated formulations and coated slow-release formulations also lie within the
scope of the
invention. Formulations resistant to acid and gastric fluid are preferred.
Suitable coatings
resistant to gastric fluid comprise cellulose acetate phthalate, polyvinyl
acetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic
acid and
methyl methacrylate.
l5
Suitable pharmaceutical preparations for oral administration may be in the
form of separate
units such as, for example, capsules, cachets, suckable tablets or tablets,
each of which
contain a defined amount of the compound of formula (I); as powders or
granules; as
solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-
water or water-
2o in-oil emulsion. These compositions may, as already mentioned, be prepared
by any
suitable pharmaceutical method which includes a step in which the active
ingredient and
the carrier (which may consist of one or more additional ingredients) are
brought into
contact. In general, the compositions are produced by uniform and homogeneous
mixing of
the active ingredient with a liquid and/or finely divided solid carrier, after
which the
25 product is shaped if necessary. Thus, for example, a tablet can be produced
by compressing
or molding a powder or granules of the compound, where appropriate with one or
more
additional ingredients. Compressed tablets can be produced by tableting the
compound in
tree-flowing form, such as, for example, a powder or granules, where
appropriate mixed
with a binder, lubricant, inert diluent and/or a (plurality of) surface-
active/dispersing
30 agents) in a suitable machine. Molded tablets can be produced by molding
the compound
which is in powder form and is moistened with an inert liquid diluent in a
suitable
machine.
CA 02554138 2006-07-20
37
Pharmaceutical compositions suitable for peroral (sublingual) administration
comprise
suckable tablets which contain a compound of formula (I) with a flavoring,
normally
sucrose and gum arabic or tragacanth, and pastilles which comprise the
compound in an
inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration comprise
preferably
sterile aqueous preparations of a compound of formula (I), which are
preferably isotonic
with the blood of the intended recipient. These preparations are preferably
administered
intravenously, although administration may also take place by subcutaneous,
intramuscular
0 or intradermal injection. These preparations can preferably be produced by
mixing the
compound with water and making the resulting solution sterile and isotonic
with blood.
Injectable compositions according to the invention generally contain from 0.1
to 5% by
weight of the active compound.
I5 Suitable pharmaceutical compositions for rectal administration are
preferably in the form
of single-dose suppositories. These can be produced by mixing a compound of
formula (I)
with one or more conventional solid carriers, for example cocoa butter, and
shaping the
resulting mixture.
2o Suitable pharmaceutical compositions for topical application to the skin
are preferably in
the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers
which can be used
are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of
two or more of
these substances. The active ingredient is generally present in a
concentration of from 0.1
to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical
compositions for
transdermal uses can be in the form of single plasters which are suitable for
long-term
close contact with the patient's epidermis. Such plasters suitably contain the
active
ingredient in an optionally buffered aqueous solution, dissolved and/or
dispersed in an
adhesive or dispersed in a polymer. A suitable active ingredient concentration
is about 1 %
to 35%, preferably about 3% to 15%. As a special possibility, the active
ingredient can be
released as described, for example, in Pharmaceutical Research, 2(6): 318 (
1986) by
electrotransport or iontophoresis.
CA 02554138 2006-07-20
38
The compounds of the formula I are distinguished by beneficial effects on
lipid
metabolism, and they are particularly suitable for weight reduction and for
maintaining a
reduced weight after weight reduction has taken place in mammals and as
anorectic agents.
The compounds are distinguished by their low toxicity and their few side
effects.
The compounds can be employed alone or in combination with other weight-
reducing or
anorectic active ingredients. Further anorectic active ingredients of this
type are mentioned,
for example, in the Rote Liste, chapter 01 under weight-reducing
agents/appetite
suppressants, and may also include active ingredients which increase the
energy turnover
t o of the organism and thus lead to weight reduction or else those which
influence the general
metabolism of the organism in such a way that an increased calorie intake does
not lead to
an enlargement of the fat depots and a normal calorie intake leads to a
reduction of the fat
depots of the organism. The compounds are suitable for the prophylaxis and, in
particular,
for the treatment of excessive weight or obesity. The compounds are further
suitable for the
t 5 prophylaxis and, in particular, for the treatment of type II diabetes, of
arteriosclerosis and
for normalizing lipid metabolism and for the treatment of high blood pressure.
Combinations with other medicaments
20 In a further aspect of the invention, the compounds of the formula I can be
administered in
combination with one or more other pharmacologically active substances which
have, for
example, favorable effects on metabolic disturbances or disorders frequently
associated
therewith. Examples of such medicaments are
1. medicaments which lower blood glucose, antidiabetics,
25 2. active ingredients for the treatment of dyslipidemias,
3. antiatherosclerotic medicaments,
4. antiobesity agents,
5. antiinflammatory active ingredients
6. active ingredients for the treatment of malignant tumors
30 7. antithrombotic active ingredients
8. active ingredients for the treatment of high blood pressure
9. active ingredients for the treatment of heart failure and
CA 02554138 2006-07-20
39
10. active ingredients for the treatment and/or prevention of complications
caused
by diabetes or associated with diabetes.
They can be combined with the compounds of the invention of the formula I in
particular
for a synergistic improvement in the effect. Administration of the active
ingredient
combination can take place either by separate administration of the active
ingredients to the
patient or in the form of combination products in which a plurality of active
ingredients are
present in one pharmaceutical preparation.
~ o Further pharmacologically active substances suitable in particular are:
Antidiabetics
All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be
combined
~ 5 with the compounds of the formula I of the invention in particular for a
synergistic
improvement of the effect. Administration of the active ingredient combination
may take
place either by separate administration of the active ingredients to the
patient or in the form
of combination products in which a plurality of active ingredients are present
in one
pharmaceutical preparation. Most of the active ingredients listed below are
disclosed in the
2o USP Dictionary of USAN and International Drug Names, US Pharmacopeia,
Rockville
2001.
Suitable antidiabetics include all insulins and insulin derivatives such as,
for example,
Lantus" or HMR 1964 or Apidra~, and other fast-acting insulins (see, e.g., US
6,221,633),
25 amylin, GLP-1 and GLP-2 derivatives such as described in WO 01/04146 or
else such as,
for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally
effective
hypoglycemic active ingredients.
The orally effective hypoglycemic active ingredients include, preferably,
sulfonylureas,
30 biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones,
glucosidase
inhibitors, glucagon receptor antagonists, GLP-1 agonists, DPP-IV inhibitors,
potassium
channel openers such as, for example, those disclosed in WO 97/26265 and WO
99/03861
of Novo Nordisk A/S, insulin sensitizers, activators of insulin receptor
kinase, inhibitors of
CA 02554138 2006-07-20
GSK3-beta, inhibitors of liver enzymes involved in the stimulation of
gluconeogenesis
and/or glycogenolysis, for example inhibitors of glycogen phosphorylase,
modulators of
glucose uptake and glucose excretion, compounds which alter lipid metabolism
and lead to
a change in the lipid composition of the blood, such as antihyperlipidemic
active
5 ingredients and antilipidemic active ingredients, e.g. HMGCoA reductase
inhibitors,
inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile
acid reabsorption
or inhibitors of microsomal triglyceride transfer protein (MTP), compounds
which reduce
food intake and/or food absorption, PPAR and RXR agonists and active
ingredients which
act on the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the present compounds are administered in
combination with insulin.
In one embodiment of the invention, the compounds of the formula I are
administered in
~ 5 combination with substances which influence hepatic glucose production
such as, for
example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO
03/084923, WO 03/084922, WO 03/104188).
In one embodiment, the compounds of the formula I are administered in
combination with
20 a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide
or glimepiride.
In one embodiment, the compounds of the formula I are administered in
combination with
an active ingredient which acts on the ATP-dependent potassium channel of the
beta cells,
such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with a biguanide such as, for example, metformin.
In a further embodiment, the compounds of the formula I are administered in
combination
3o with a meglitinide such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with
a thiazolidinedione such as, for example, troglitazone, ciglitazone,
pioglitazone,
rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's
Research
Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-
quinazolinylmethoxy]-
CA 02554138 2006-07-20
41
phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with
a DPPIV inhibitor as described, for example, in W098/19998, W099/61431,
W099/67278, W099/67279, WO01/72290, WO 02/38541, W003/040174, in particular P
93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,
LAF237 (1-
[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021
((2S, 4S)-
4-fluoro-1-[ [(2-hydroxy-1,1-dimethylethyl)amino] acetyl]pyrrolidine-2-
carbonitrile
monobenzenesulfonate).
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a PPARgamma agonist such as, for example, rosiglitazone,
pioglitazone.
In one embodiment, the compounds of the formula I are administered in
combination with
~ 5 compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed
directly or
indirectly for example in PCTBP03/06841, PCT/EP03/ 13454 and PCT/EP03/ 13455.
In one embodiment, the compounds of the formula I are administered in
combination with
an a-glucosidase inhibitor such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in
combination with
more than one of the aforementioned compounds, e.g. in combination with a
sulfonylurea
and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin
and a
sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and
lovastatin, etc.
Lipid modulators
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an HMGCoA reductase inhibitor such as lovastatin,
fluvastatin,
3o pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin,
rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a bile acid absorption inhibitor (see, for example, US
6,245,744, US
6,221,897, US 6,277,831, EP 0 683 773, EP 0 683 774).
CA 02554138 2006-07-20
42
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a polymeric bile acid adsorbent such as, for example,
cholestyramine,
colesevelam.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a cholesterol absorption inhibitor as described for example
in
WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are
administered in
o combination with an LDL receptor inducer (see, for example, US 6,342,512).
In one embodiment, the compounds of the formula I are administered in
combination with
bulking agents, preferably insoluble bulking agents (see, for example,
carob/Caromax~
(Zunft H J; et al., Carob pulp preparation for treatment of
hypercholesterolemia,
~ 5 ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6); Caromax is a carob
containing product from Nutrinova, Nutrition Specialties & Food Ingredients
GmbH,
Industriepark Hoechst, 65926 Frankfurt/Main). Combination with Caromax~ is
possible in
one preparation or by separate administration of compounds of the formula I
and
Caromax~. Caromax° can in this connection also be administered in the
form of food
2o products such as, for example, in bakery products or muesli bars.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a PPARalpha agonist.
25 In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a fibrate such as, for example, fenofibrate, gemfibrozil,
clofibrate,
bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in
3o combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a CETP inhibitor, e.g. CP- 529, 414 (torcetrapib).
35 In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ACAT inhibitor.
CA 02554138 2006-07-20
43
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an MTP inhibitor such as, for example, implitapide.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an antioxidant.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein lipase inhibitor.
to In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ATP citrate lyase inhibitor.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a squalene synthetase inhibitor.
~5
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein(a) antagonist.
Antiobesity agents
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipase inhibitor such as, for example, orlistat.
In one embodiment, the further active ingredient is fenfluramine or
dexfenfluramine.
In another embodiment, the further active ingredient is sibutramine.
In another embodiment, the further active ingredient is rimonabant.
In a further embodiment, the compounds of the formula I are administered in
combination
3o with CART modulators (see "Cocaine-amphetamine-regulated transcript
influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:
Hormone and
Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-
1-sulfonic
acid {4-[(4-aminoquinazolin-2-ylamino)methyl] cyclohexylmethyl}amide;
hydrochloride
(CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-
carboxylic
acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-
5-yl)-1-
(4-chlorophenyl)-2-oxoethyl]amide; (WO 01/91752)), orexin antagonists (e.g. I-
(2-
CA 02554138 2006-07-20
44
methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB-334867-
A)),
CB1 antagonists/inverse agonists, H3 antagonists/inverse agonists (e.g. 3-
cyclohexyl-l-
(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt
(WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-
trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF
BP
antagonists (e.g. urocortin), urocortin agonists, (33 agonists (e.g. 1-(4-
chloro-3-
methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-
yloxy)ethylamino]ethanol;
hydrochloride (WO 01/83451 )), MSH (melanocyte-stimulating hormone) agonists,
CCK-A
agonists (e.g. { 2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-
cyclohexylethyl)thiazol-2-
o ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt
(WO 99/15525));
serotonin reuptake inhibitors (e.g. dexfenfluramines), mixed serotoninergic
and
noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3-
ethylbenzofuran-7-
yl)piperazine oxalic acid salt (WO 01/09111), BR53 agonists, galanin
antagonists, ghrelin
antagonists, MCH antagonists, mGluRS antagonists, opioid antagonists, growth
hormone
(e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-
(2-
diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid
tert-
butyl ester (WO 01/85695)), CNTF, CNTF derivatives (e.g. Axokine), TRH
agonists (see,
for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin
agonists (see, for
example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina;
Grasso,
Patricia. Leptin agonists as a potential approach to the treatment of obesity.
Drugs of the
Future (2001), 26(9), 873-881), DA agonists (e.g. bromocriptine, Doprexin),
lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO
00/78312),
RXR modulators or TR-~3 agonists.
In one embodiment of the invention, the further active ingredient is leptin.
In one embodiment, the further active ingredient is dexamphetamine,
amphetamine,
mazindole or phentermine.
In one embodiment, the compounds of the formula I are administered in
combination with medicaments
having effects on the coronary circulation and the vascular system, such as,
for example, ACE inhibitors (e.g.
ramipril), medicaments which act on the angiotensin-renin system, calcium
antagonists,
beta Mockers etc.
In one embodiment, the compounds of the formula I are administered in
combination with
medicaments having an antiinflammatory effect.
CA 02554138 2006-07-20
In one embodiment, the compounds of the formula I are administered in
combination with
medicaments which are employed for cancer therapy and cancer prevention.
It will be appreciated that every suitable combination of the compounds of the
invention
5 with one or more of the aforementioned compounds and optionally one or more
other
pharmacologically active substances is to be regarded as covered by the scope
of protection
of the present invention.
In two articles which appeared simultaneously in Nature (Nature 400, 261-264,
1999;
Nature 400, 265-269, 1999), a highly specific receptor for melanine
concentrating hormone
o (MCH) was described separately by two research groups. MCH assumes important
Functions in controlling food intake. Compounds acting on the MCH receptor
therefore
have an anorectic effect and are suitable for the treatment of obesity.
Testing for an
anorectic effect of the compounds of the invention of the formula I was
therefore carried
out as follows.
1S
Functional measurements to find IC50 values
The cloning of the cDNA for the human MCH receptor, preparation of a
recombinant
HEK293 cell line which expresses the human MCH receptor, and functional
measurements
2o with the recombinant cell line took place in analogy to the description by
Audinot et al. (J.
Biol. Chem. 276, 13 554-13 562, 2001). A difference from the reference was,
however, the
use of the plasmid pEAK8 from EDGE Biosystems (USA) to construct the
expression
vector. The host used for the transfection was a transformed HEK cell line
named "PEAK
Stable Cells" (likewise from EDGE Biosystems). The functional measurements of
the
25 cellular calcium flux after addition of agonist (MCH) in the presence of
ligand of the
invention took place with the aid of the FLIPR apparatus from Molecular
Devices (USA)
using the protocols of the apparatus manufacturer.
Biological activity testing
The IC50 values measured for exemplary compounds 33, 96 and 97 under the
o aforementioned conditions were of the order of from 0.01 to 10 ~,M.
CA 02554138 2006-07-20
46
Genera( explanations
a) Mode of drawing the structural formulae
Only non-H atoms are depicted for clarity in the structural formulae of the
given examples.
Carbon atoms are not written out as "C".
b) Salt forms
Many of the compounds of the invention are bases and can form salts with
appropriately
strong acids. In particular, after purification of the compounds by HPLC
chromatography
o using a trifluoroacetic acid-containing mobile phase they may be in the form
of
hydrotrifluoroacetates. These can be converted into the free bases shown by
simple
treatment of a solution of the salts for example with sodium carbonate
solution.
c) Units of the characterizing data
.5 The unit of the stated molecular weights is "g/mol". Peaks observed in the
mass spectrum
are indicated as integral quotient of the molar molecular ion mass and the
charge of the
molecular ion (mlz).
Abbreviations
Unless indicated otherwise, the abbreviations in the examples below have the
following
meaning:
NaBH3CN = sodium cyanoborohydride
DMF = N,N-dimethylformamide
EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
THF = tetrahydrofuran
DMSO = dimethyl sulfoxide
HOBt = 1-hydroxybenzotriazole
HOAt = 1-hydroxy-7-azabenzotriazole
3o HCl = hydrochloric acid
HPLC = high performance liquid chromatography
PyBOP = benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate
CA 02554138 2006-07-20
47
TOTU - O[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium
tetratluoroborate
eq = equivalents
Example 1
( 1- { 4-[5-(4-Butoxyphenyl )-[ 1,3,4]oxadiazol-2-yl] phenyl } pyrrol idin-3-
yl)dimethylamine
O N
W O N
v/
N-N
Method A
to A mixture of 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg), 4-
butoxy
benzoic acid (78 mg), 2-chloro-1,3-dimethyl-2-imidazolium hexafluorophosphate
(112 mg), N,N-diisopropylethylamine (0.14 ml) and dichloromethane (5 ml) was
stirred for
12 hours. Volatiles were removed, and the residue was purified by preparative
HPLC. The
product with the molecular weight of 406.53 (C24H30N402) was obtained in this
way;
I5 MS (ESI): 407 (M+H+).
4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide
A mixture of ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate (2.0 g),
hydrazine hydrate
(3.8 g) and ethanol (7 ml) was boiled under reflux for 15 hours. After cooling
to 5°C, the
2o resulting precipitate was filtered off with suction. The product with the
molecular weight
of 248.33 (C 13H20N40) was obtained in this way; MS (ESn: 249 (M+H+).
Ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate
A mixture of ethyl 4-fluorobenzoate (4.47 g), dimethylpyrrolidin-3-ylamine
(3.04 g),
25 potassium carbonate (3.68 g) and dimethyl sulfoxide (20 ml) was heated at
130°C for 7
hours. After cooling, the mixture was diluted with water and extracted with
methyl tert
butyl ether. The organic phase was washed with water, dried over magnesium
sulfate,
filtered and concentrated. The product with the molecular weight of 262.35
(C15H22N2O2) was obtained in this way; MS (ESI): 263 (M+H+).
CA 02554138 2006-07-20
48
Example 2
Dimethyl-( 1-{ 4-[5-(2-phenoxyethylsulfanylmethyl)-[ 1,3,4]oxadiazol-2-
yl]phenyl } -
pyrrolidin-3-yl)amine
N
o~s o _ NJ
i ~,
/ N_N
S
4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was reacted with (2-phenoxy-
ethylsulfanyl)acetic acid by Method A. The product with the molecular weight
of 424.57
(C23H28N402S) was obtained in this way; MS (ESI): 425 (M+H+).
Example 3
Dimethyl-( 1- { 4-[5-(4-phenoxyphenyl) ( 1,3,4]oxadiazol-2-yl]phenyl }
pyrrolidin-3-yl)amine
Method B
A mixture of N'-[4-(3-dimethylaminopyrrolidin-1-yl)benzoyl]-4-
phenoxybenzohydrazide
(178 mg), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess'
reagent) (96
2o mg) and 5 ml of toluene was stirred at 60°C for 1 h. After the
reaction was complete, the
reaction mixture was filtered, and the filtrate was washed twice with ethyl
acetate. The
combined organic phases were subsequently washed with 5% strength sodium
carbonate
solution and then dried over Chromabond XTR. Volatiles were removed and the
residue
CA 02554138 2006-07-20
49
was purified by preparative HPLC. The product with the molecular weight of
426.21
(C26H26N4O2) was obtained in this way; MS (ESI): 427.21 (M+H+).
N'-[4-(3-Dimethylaminopyrrolidin-1-yl)benzoyl)-4-phenoxybenzohydrazide
A mixture of 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg),
4-phenoxybenzoic acid (77.5 mg), 1-propanephosphonic anhydride 50% in
dichloromethane (256 mg), N,N-diisopropylethylamine (0.208 ml) and DMF (3 ml)
was
stirred at room temperature for 72 h. The reaction mixture was then filtered,
washed twice
with ethyl acetate and shaken with O.SN NaOH. Volatiles were removed and the
residue
m was purified by preparative HPLC. The product with the molecular weight of
444.54 was
obtained in this way; MS (ESI): 445.24 (M+H+).
4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was prepared as described in
method
A, with 1 eq of Burgess' reagent being added once again in some cases after
heating for 1 h
~5 in the cyclization step, and then heating at 60°C being continued
for 1 hour.
Compounds 4-93 in table 1 were synthesized by method B.
CA 02554138 2006-07-20
Ex Structure ~ ~ v Molecu4ar formula ~ MW MW
', ~ ~~~ ~~
calc. measured
C27H28N402 440.22441.24
-
~.
~- y
~~y- ~ J .
~
', ~ C26H34N402 434.27435 28
.
_
I,
_ . ..
C27H28N402 440.22441.27
'
I ;l r _ ,..
0
__, ~. .f! /
,"
!J N
~'~~ G26H30N402 430.24431.27
7
ir'\; ~ r.' ,
i
~l \
r;~~ ,
N . r;
',,__ C27H34N402 446.27447 27
I
;,.,;,,N.,',
_, y., ~
g '~__, C27H32N402 444.25445.26
o.
II '~~ ~ 1~N-N
C22H26N40 362.21363.22
~--
'u
N n.
11 C23H26N403 406.20407 22
~7-- ~
_ ,
r' I
i
CA 02554138 2006-07-20
51
~ C22H23N502 389 390.16
12 ' 19
N_
,,ri_
o ;;:
~
13 'y _ C27H28N402 ~ 440.22441.23
i
__
_;i 'W . ,:
N-N
14 N_ C28H30N4C~3 ~ 470.23471.21
I
rd.
~~~ _.
~y
'.
I ..Y
,~, i
i ~__i' _ "
~
j 'N C28H30N402 454.24455.25
15
r
;~. : J_ _
y ...
I
1 ;,. _ i
16 ~ ~ , C26H26N402 426.21427
29
~_ .
N. ; - I
i' ~ i
, ,
_ _ _ _
~
_ _ _
17 ~_ C27H28N402 440.22441.23
O i
,
I
u_
i1:, _ I
___
~ -
8 C27H28N40 425.231 425.24
" ...I I
19 C27H26N402 438.21439.28
,,
;
a \ N. ..
_,:
20 C24H23CIN402 434.15436.02
..
N. :~
~i
i
~I' ~ " N N
i
CA 02554138 2006-07-20
52
21 C26H32N40 416.26417.36
iV
:.~.. N ,,
,._ ,
_
..
.
-
,
,
.,
1
..
NN
22 ~ C24H30N4O3 422.23424.02
'
i
, - '';', ;1
n: _ rJ
23 C27H28N4O2 440.22441.27
_.
'' ;' a J._,
'
;,
N-ni
' ~ ~
24 ' G22H26N403 394.20395.21
~,~-
L. : ~. o i
'~a u"
.V--N
25 N_ C28H30N4O3 470.23471.25
_. , .. -, ;
26 ';._- C29H29N5O2 479.23480.39
,\ : _
27 C22H23F3N4O3 448.17449.22
;,
a , _ ' ~~N -N
28 C22H28N40S 396 397
20 22
rJ- . .
_N, -
O~~
c
.
. .
_ N_u
s'
29 '~,_- C25H25CIN4O3S2 528.11530,08
_
:.. ~ o
!
30 C25H25CIN4O2 448.17449.22
I ' _.
'
-
,'.
-.., ~
i- ,'~. ;.,
,
,,,
r; N
CA 02554138 2006-07-20
53
~ 'rJ G25H38N40 ~ 410.31411.32
31
__
w-n i
32 '~_ C23H28N402 392.22393.24
f '' .
l
l
N _. ~,j
-
-
33 , 24H30N402...._._..__.._.._____.______406.24407
C 25
N-_ .
-..~
c,
~~o..=. " ".
__-.__.___ ......-__.- I
34 C23H28N403S 440.19441.20
I
,' _
I
n_ ,.' I :, r.
'e\
J
35 r,; C26H29BrN60 520.16521.16
',
I
_ ~-1. I
rJ j
,v_ ,.: , , ; _.
:;r- -!.., l~r--;u
~
36 ' C25H27N502 429.22430
23
N .
37 C24H27BrN602 510.14512.13
.; ~ ,
o. ~'
38 ~ C26H32N403 448 449
25 26
rJ _ . .
_ ri.
_ i1 _
~~~ _ i J'
3g '~,, C25H23F3N402 468.18469.21
I
CA 02554138 2006-07-20
54
40 ' I C25H25N5O4 ~ ~ 459.19460.21
N_
-,
-
=
~'
'
',;
;r
->,y
o'
i N ;;
41 '.1__ C25H22CIF3N402 502.14503.18
i
i
' ~
42 ~ C25H30N4O3 434.23435.24
h, ,_
.\ _.1 _ , .,.;
.t
O_ .: -r I
N N
i. y
43 C25H29N50S 447 448.21
21
N-
:, ~-=;;~..N. ,:
'
: N._.:w~ O, .:~
:-I
~~
44 'N_ C28H28N60 ' ~ 464.23465.27
,~ :,
_~
~
_-;,~
'N~
~~
~
~'
='
_
N
_..';
:
_..
I
-_
45 ' C32H33N50S 535.24536.25
~
-'
a ;
;N Iu
,.... '
46 C26H26N40 410.21411.23
N __
N_ ~ i
~.
I
a -N
I ~ C28H30N40 438.24439.27
47
N
'
,
~zT- ~.
o
-
/ .=
_
..~
i
48 C29H29N50 463.24464
26
N__ .
-s?, ri_ ,
i
l V
_. ~' _,. v .._:,
n _.~ .:;-
CA 02554138 2006-07-20
49 ~ '~ j C25H30N4O2 418.24419.24
I ~ I
i; ~ I
_., .: ~~; :- 1
';~_h
i _
50~~ C25H29N502 w_._..._.__......___..__- 431.23432.25
N
i
'
'. '-~ '
'
i
51 ~', C24H30N40S 422.21423.23
,.. I
--< .I_,; i
'i _ _ _ ,iJ_
4,i a w . i '
~,..t..._
52 '~y ,- ; C24H29FN40 408.23409.24
i
i
' '
'.
~1, i>-
fJ ,y
i C22H26N4O2S 410.18411.21
53
I N j I
. I
I ' i~ V
'I
I
j c I
.
h -h
54 C25H30N40 402.24403.26
~,
'l
'
_,
_- _"
_ _.__.__._
55 ,~J._ C28H30N402 454.24455.25
I .; .. N
I
I J
56 'y C28H29N5O2 467.23468.27
I
I
r~ ' I
57 '~ C23H27CIN40S 442.16~ 443,17
I . N' .
o. , i
,
,yy
;;' ~
;. .: ,
58 ~~ C26H26N4O3S 474.17475.19
rJ~..
ii
s
IJ tJ
CA 02554138 2006-07-20
56
59 N C28H29N5O2 467.27 468.27
N. ,''
~ l r ''~
NN
60 'N-- C24H26N60 414.22 415.23
o ,i w..
N_N
;N _N I
61 ~ 'N_ C24H25N5O5 431.18 432,19
v '.
o ;~'r
y= --
N -r:
62 '~,C27H25N50 435.21 436.23
r;
t .__
N ;, L "
r_._.,, .,
', , ~:, ..
;;.. N
63 "_ C26H24N4O2 ~ 424.19 425,22
<u. '
;,v:J ',,-,,'° ,>-w -
r:~ _v
64 ~,~ G24H23FN40S 434.16 435.19
,,. o
- I
,:' , ._ _,y "' .. ' i
N_N
65 '.,_ C25H29FN4O2 436.23 437.26
,1 , _,
v-N
66 ~ '~N' C27H27FN4O 442.22 443.24
N. /
'=:7-
J J; ,
67 ~ ~~,_ C27H31 FN4O2 ' ' 462.24 464.36
i o
a
I
68 ;, _ ~ C25H25CIN4O3 - -454.16 465.18
~CW 1 _. ;_ h, .
__ _____- _ _.
CA 02554138 2006-07-20
57
C24H24N403 Y ~ 416.19417.20
N, ,
:...
,. '-N,.-,_ J: ',
' / _ .. \.
1.
N-R
70
i N - I C23H23F3N4O2 444.18445.20
_ ;
~~ /; '
N N
~
71 ~~- C23H23N50 385.19386.22
N -.
_I -
72 '~'""' C28H29FN40 456.23457.25
'N
._;,
~ ~~ C26H29FN402 448.23449.24
3
F
=
.
,,:
! f
. i .
-.
i i:
74 ~ C22H23F3N40S 448.15449,16
~'
'
---,: I
-
h-N
!
75 '~y- C24H24CIN50S 465.14466.15
-...
-
~;
N C25H25CIN4O2 448.17449.20
;,:
='
'r
N
.
,I , -
.
<< , _:f;v:' ~ ,~
. -
...-v
77 N_ C24H36N40 396.29397.31
l _..i o -:
78 C29H30N4O2 466.24467.27
i . _
i _ '' . I
_ _ ,....,
CA 02554138 2006-07-20
58
__ .____.__ _._____. y'-- C25H32N403 436.25 437.27 -
Y
v
~,-., .~_
,.. ,, :
.. . ,,
':;~ ~~
_ 80 ~,v _ C24H25CiN6C --y-_..__.,_..__._.__ 44$.18 449.2] - _ _
N,~:' I
r!_ N:
4 N
CI' ~,
__81 _____ ._-. N._- C27H25F3N402 494.19 495.22 l
' a
r w, i: l
N.N i
82 ~l C26H25FN40 428.20 429.23
r.,;,: I
i I
~- I
83 '_ , _..._______..- ,J._ C23H25F3N40 430.20 431.2_0
~,-~' ,-il __. , rj
u- rj ,
84 ~- C25H25CIN402S 480.14 481.17
-N
85 ~ ~N-- C25H22BrF3N4C?2 546.09 547,11
N.y i
;. -.. ~N_rJ
1..
Br
86 C24H22C1N504 479.14 480.15
I
J-,v i
'w rJ_ :'
1 A
LI
87 ~ ,fC27H28N40 424.23 425.24
_ ,
r, rJ
___ i_
88 C25H32N402 420.25 421.26
a ,
CA 02554138 2006-07-20
59
8~ ~JC27H28N40 V- T 424.23 ~ 425.24
rd, ,\f
i
i w
;_ C23H25F3N402 446.19 447.19
F
F l 1-
~. .,-. ~,~-
'~1 '~ry C23H25N50S 419.18 420.11
N~,.
.- .O. ~ Y
\-
;r__. v't In
N-N
C26H28N402 428.22 429.24
~f
I~ ~C.
-_.-._-_-
Example 93
Dimethyl-( I -{ 4-[5-(4-phenoxybutyl)[ 1,3,4]oxadiazol-2-yl]phenyl }pyrrolidin-
3-yl)amine
S
,v,a .... ~i
PyBOP (25.2 mg) was added to a mixture of 4-phenoxybutanohydrazide (10 mg), 4-
(3-
dimethylaminopyrrolidin-1-yl)benzoic acid (12.1 mg), HOAt (6.6 mg),
triethylamine (13.5
t o ~ l) and DMF (0.15 ml) at 0°C. The mixture was stirred at
0°C for 10 min and then at room
temperature for 3 h. Ethyl acetate and water were then added to the reaction
solution. The
organic phase was subsequently washed twice each with 10% strength citric acid
solution,
saturated sodium bicarbonate solution and water and dried over sodium sulfate,
and the
solvent was removed in vacuo.
The residue was then taken up in THF (0.4 ml), and EDC (6.1 mg) and
triethylamine (5.5
~ul) were added, and the mixture was stirred at 50°C for 16 h. Ethyl
acetate and water were
CA 02554138 2006-07-20
then added to the reaction solution. The organic phase subsequently washed
twice each
with 10% strength citric acid solution, saturated sodium bicarbonate solution
and water and
dried over sodium sulfate, and the solvent removed in vacuo. The residue was
purified by
preparative HPLC. The product with the molecular weight of 406.53 (C24H30N402)
was
5 obtained in this way; MS (ESI): 407.15 (M+H+).
4-Phenoxybutanohydrazide
A mixture of phenol (100 mg), ethyl 5-bromovalerate (222.2 mg), cesium
carbonate (693
mg) and DMF (1.6 ml) was stirred at room temperature for 12 h. Ethyl acetate
and water
o were then added to the reaction solution, and the aqueous phase was adjusted
to pH 6 with
2N HCl solution. The aqueous phase extracted twice more with ethyl acetate.
The
combined organic phases were then washed with water and dried over sodium
sulfate, and
the solvent was removed in vacuo.
The product obtained in this way was taken up in abs. ethanol (0.5 ml), 37.3
~,1 of
~ 5 hydrazine hydrate were added, and the mixture was heated under rellux for
12 h. Ethyl
acetate and water were then added to the reaction solution, and the aqueous
phase was
neutralized with 2N HCl solution. The aqueous phase was extracted twice with
ethyl
acetate. The combined organic phases were then washed with water and dried
over sodium
sulfate, and the solvent was removed in vacuo. The residue was purified by
preparative
2o HPLC. The product with the molecular weight of 208.11 (C 11 H 16CIN202) was
obtained
in this way; MS (ESI): 209.1 (M+H+).
4-(3-Dimethylaminopyrrolidin-1-yl)benzoic acid
A 1M sodium cyanoborohydride solution (1.32 ml) was added to a mixture of
methyl 4
25 (3-aminopyrrolidin-1-yl)benzoate (300 mg), acetic acid (81 ~,l),
formaldehyde (0.113 ml)
and THF (3 ml). The reaction was stirred at room temperature for 1 h, then the
solvent was
removed in vacuo, and the residue was taken up again in ethyl acetate/water.
The organic
phase was washed with water and dried over sodium sulfate, and the solvent was
removed
in vacuo.
3o The product obtained in this way was dissolved in a THF/water mixture ( 1:1
) (3.1 ml), and
potassium hydroxide (66.2 mg) was added. The reaction was heated at
70°C for 4 h. Ethyl
acetate and water were then added to the reaction solution, and the aqueous
phase was
acidified with 2N HCl solution. The aqueous phase was extracted twice with
ethyl acetate.
CA 02554138 2006-07-20
61
'fhe combined organic phases were then washed with water and dried over sodium
sulfate,
and the solvent was removed in vacuo. The product with the molecular weight of
234.17
(C ( 3H 18N2O2) was obtained in this way; MS (ESI): 235.10 (M+H+).
Methyl4-(3-aminopyrrolidin-1-yl)benzoate
A mixture of 3-(tert-butoxycarbonylamino)pyrrolidine (1 g), methyl 4-
fluorobenzoate
(0.83 ml), cesium carbonate ( 1.7 g) and DMF ( 10 ml) was heated at
100°C for 12 h. Ethyl
acetate and water were then added to the reaction solution. The organic phase
was then
washed twice with water and dried over sodium sulfate, and the solvent was
removed in
I o vacuo.
The product obtained in this way was dissolved in methylene chloride ( 12 ml),
trilluoroacetic acid (6 ml) was added, and the mixture was stirred at room
temperature for
90 min. The solvent was removed in vacuo, and the residue was purified by
preparative
HPLC. The product with the molecular weight of 220.12 (C12H16N2O2) was
obtained in
1S this way; MS (ESI): 221.10 (M+H+).
Example 94
( 1- { 4-[5-(4-Butoxyphenyl)-[ 1,3,4]thiadiazol-2-yl]phenyl } pyrrolidin-3-
yl)dimethylamine
p N-,
~ NJ
n ~ v
N'N
A mixture of N'-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-
yl)benzohydrazide
( 100 mg), Lawesson's reagent ( 191 mg) and toluene (5 ml) was boiled under
reflux for 4
hours. Volatiles were removed, and the residue was purified by preparative
HPLC. The
product with the molecular weight of 422.60 (C24H30N40S) was obtained in this
way;
MS (ESI): 423 (M+H+).
N'-(4-Butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide
A mixture of 4-butoxybenzoic acid ( 156 mg) and DMF ( 10 ml) was mixed with
TOTU
(264 mg) and N,N-diisopropylethylamine (104 mg). After 10 minutes, 4-(3-
CA 02554138 2006-07-20
62
dimcthylaminopyrrolidin-1-yl)benzohydrazide (200 mg) was added. After one
hour, the
mixture was diluted with water and extracted with ethyl acetate. The organic
phase was
washed with water, dried over magnesium sulfate, filtered and concentrated.
The product
with the molecular weight of 424.55 (C24H32N4O3) was obtained in this way; MS
(ESI):
425 (M+H+).
Example 95
((R)-3- { 4-[5-(4-Chlorophenoxymethyl) [ 1,2,4]oxadiazol-3-yl]phenyl }
cyclopentyl)-
methylamine
PyBOP (558 mg), HOAt (146 mg) and triethylamine (0.299 ml) were added to a
mixture of
tert-butyl {(R)-1-[4-(N-hydroxycarbamimidoyl)phenyl]pyrrolidin-3-
yl}methylcarbamate
~ 5 (358.5 mg), (4-chlorophenoxy)acetic acid (200 mg) and 3 ml of DMF at
0°C, and the
reaction mixture was stirred at this temperature for 10 min. It was then
stirred at room
temperature for 2 h and ethyl acetate and water were added to the reaction
solution. The
organic phase was then washed twice each with 10% strength citric acid
solution, saturated
sodium bicarbonate solution and water, dried over sodium sulfate and filtered,
and the
20 solvent was removed in vacuo.
The residue was then taken up in 10 ml of THF, and EDC (160 mg) and
triethylamine
(0.144 ml) were added, and the mixture was stirred at 50°C for 16 h.
Ethyl acetate and
water were then added to the reaction solution. The organic phase was then
washed twice
each with 10% strength citric acid solution, saturated sodium bicarbonate
solution and
25 water, dried over sodium sulfate and filtered, and the solvent was removed
in vacuo.
The crude product was taken up in methylene chloride (7.2 ml), and
trifluoroacetic acid
( 1.8 ml) was added. The reaction was stirred at room temperature for 5 h and
then the
solvent was removed in vacuo. The residue was purified by preparative HPLC.
The
CA 02554138 2006-07-20
63
product with the molecular weight of 384.14 (C20H21C1N402) was obtained in
this way;
MS(ESI): 385.26 (M+H+).
(4-Chlorophenoxy)acetic acid
A mixture of 4-chlorophenol (500 mg), methyl bromoacetate (0.368 ml), cesium
carbonate
( 1.9 g) and 5 ml of acetone was stirred at room temperature for 12 h. Ethyl
acetate and
water were then added to the reaction solution, and the organic phase was
washed twice
with water, dried over sodium sulfate and filtered, and the solvent was
removed in vacuo.
The crude product was dissolved in a 1:l THF/water mixture (10 ml), and
potassium
o hydroxide (417 mg) was added. The reaction was stirred at room temperature
for 12 h.
Ethyl acetate and water were then added to the reaction solution, and the
aqueous phase
was adjusted to pH 2 and extracted several times with ethyl acetate. The
combined organic
phases were washed twice with water, dried over sodium sulfate and filtered,
and the
solvent was removed in vacuo. The product with the molecular weight of 186.6
~5 (C8H7C103) was obtained in this way; MS (ESI): 227.0 (M+CH3CN).
{(R)-1-[4-(N-Hydroxycarbamimidoyl)phenyl]pyrrolidin-3-yl}methylcarbamic acid
tort-butyl ester
Sodium hydride (253.4 mg) was added in portions to a solution of tent-butyl
[(R)-1-(4-
2o cyanophenyl)pyrrolidin-3-yl]carbamate ( 1.06 g) in 12 ml of DMF at
0°C. After removal of
the ice bath, methyl iodide (0.498 ml) was added dropwise to the reaction
solution, which
was stirred at room temperature for 4 h. Ethyl acetate and water were then
added to the
reaction solution, and the organic phase was washed twice with water, dried
over sodium
sulfate and filtered, and the solvent was removed in vacuo.
25 The crude product was dissolved in abs. ethanol (12 ml), and hydroxylamine
(0.687 ml)
was added. The reaction solution was heated under reflux for 12 h. Ethyl
acetate and water
were then added to the reaction solution, and the organic phase was washed
twice with
water and dried over sodium sulfate, and the solvent was removed in vacuo. The
residue
was purified by preparative HPLC. The product with the molecular weight of
334.42
30 (C17H26N403) was obtained in this way; MS (ESI): 335.20 (M+H+).
[(R)-1-(4-Cyanophenyl)pyrrolidin-3-yl]carbamic acid
CA 02554138 2006-07-20
64
A mixture of (3R)-(+)-(tort-butoxycarbonylaminopyrrolidine (1.0 g), p-
fluorobenzonitrile
(650 mg), cesium carbonate ( 1.75 g) and 5 ml of DMF was stirred at
50°C for 12 h. Ethyl
acetate and water were then added to the reaction solution, and the organic
phase was
washed twice with water, dried over sodium sulfate and filtered, and the
solvent was
removed in vacuo. The residue was purified by preparative HPLC. The product
with the
molecular weight of 287.36 (C16H21N302) was obtained in this way; M5 (ESI):
288.20
(M+H+).
Example 96
lo ((R)-1-{4-[5-(4-Chlorobenzyloxymethyl)[1,2,4]oxadiazol-3-
yl]phenyl}pyrrolidin-
3-yl)methylamine
~':l
~..,yr ..., .- .,._S ~. ' ~Y_.~ ~.'
//
~~ti~
I5 A solution of (4-chlorobenzyloxy)aeetic acid (70 mg) in thionyl chloride (
1 ml) was stirred
at room temperature for 1 h, and then toluene was added and the solvent was
stripped off in
vacuo. This procedure was repeated twice more. The acid chloride was then
taken up in
methylene chloride (1.4 ml), {(R)-1-[4-(N-
hydroxycarbamimidoyl)phenyl]pyrrolidin-3-
yl } methylcarbamic acid tent-butyl ester ( 116.7 mg), triethylamine (0.05 ml)
were added,
20 and the mixture was stirred at room temperature for 12 h. The volatile
components were
removed in vacuo, and the residue was taken up in ethyl acetatelwater. The
organic phase
was washed twice with water and dried over sodium sulfate, and the solvent was
removed
in vacuo. The residue was purified by preparative HPLC. The product with the
molecular
weight of 398.15 (C21H23C1N402) was obtained in this way; MS (ESI): 399.41
(M+H+).
z5
(4-Chlorobenzyloxy)acetic acid was prepared in analogy to (4-
chlorophenoxy)acetic acid
using 4-chlorobenzyl bromide as precursor. The product with the molecular
weight of
200.62 (C9H9C103) was obtained in this way; MS (ESI): 222.95 (M+Na-H).
3o Example 97
CA 02554138 2006-07-20
4-Ch Toro-N- { 3-[4-(3-dimethylaminopyrrolidin- I -yl)phenyl] [
1,2,4]oxadiazol-
5-ylmethyl } benzamide
5
Method C
TOTU (51.4 mg) and N,N-diisopropylethylamine (0.05 ml) were added to a mixture
of { 1-
[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-yl}dimethylamine
(75.3 mg),
4-chlorobenzoic acid (23.5 mg) and DMF (0.96 ml), and the solution was stirred
at room
o temperature for 12 h. The crude product was purified by preparative HPLC
(RP) and then
purified again by chromatography on silica gel (dichloromethane/MeOH/AcOH/H20
=
90/10/1/1). The product with the molecular weight of 425.16 (C22H24C1N5O2) was
obtained in this way; MS (ESI): 426.17 (M+H).
~5 { 1-[4-(5-Aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-
yl}dimethylamine
PyBOP (546.4 mg), HOAt ( 136.1 mg) and triethylamine (0.279 ml) were added to
a
mixture of 4-(3-dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine (248.3 mg),
tert-
butoxycarbonylaminoacetic acid ( 175.2 mg) and DMF (2.8 ml) at 0°C and
the mixture was
stirred at this temperature for 10 min. It was subsequently stirred at room
temperature for 2
2o h and then ethyl acetate and water were added to the reaction solution. The
organic phase
then washed twice each with 10% strength citric acid solution, saturated
sodium
bicarbonate solution and water, dried over sodium sulfate and filtered, and
the solvent
removed in vacuo. The residue was then taken up in 6.2 ml of THF, and EDC (
105 mg)
and triethylamine (0.09 ml) were added, and the mixture was stirred at
50°C for 16 h. Ethyl
25 acetate and water were then added to the reaction solution. The organic
phase then washed
twice each with 10% strength citric acid solution, saturated sodium
bicarbonate solution
and water and dried over sodium sulfate, and the solvent removed in vacuo.
The crude product was taken up in methylene chloride (9.6 ml), and
trifluoroacetic acid
(2.3 ml) was added. The reaction was stirred at room temperature for 5 h and
then the
3o solvent was removed in vacuo. The residue was purified by preparative HPLC.
The
CA 02554138 2006-07-20
66
product with the molecular weight of 287.37 (C 15H21 N50) was obtained in this
way; MS
(ESI): 288.05 (M+H+).
4-(3-Dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine
A mixture of 3-(dimethylamino)pyrrolidine (1.l g), p-fluorobenzonitrile (1.2
g), potassium
carbonate (2.8 g) and acetonitrile (15 ml) was stirred at 80°C for 12
h. The reaction
solution was then filtered, and the precipitate was washed with acetonitrile,
the solvent was
removed in vacuo, and the residue was taken up again in ethyl acetate. The
ethyl acetate
phase was washed twice with water and then dried over sodium sulfate, and the
solvent
~ o was removed in vacuo.
The product obtained in this way was dissolved in abs. ethanol (48.7 ml), and
hydroxylamine ( 1.4 ml) was added to the solution. The reaction mixture was
heated under
reflux for 12 h. The precipitate obtained after cooling the reaction solution
was filtered off
and washed with a little ethanol.
~ 5 The product with the molecular weight of 248.33 (C 13H20N40) was obtained
in this way;
MS (ESI): 249.15 (M+H+).
Examples 98-110 in table 2 were synthesized by method C.
CA 02554138 2006-07-20
67
EX.-....._._-Structure___.-_Molecularformula__
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.-...M~___._
.__...
i j
talc.
measured
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l l ' ~ - _..___._ ' I
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.- , , ', . ' .' 'J ,'" .
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__.. _~. ~y'a!2i1 ~~V ; ~
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.-._____-. ~_ ' ~ \~Vr ~'~3vi~~~v~~ ~
i~a~'- ' ~ '''
" .,
t
.__ _ ~'yrl::=;f,l;>r.,- ,'J'
_ ':J
i
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2-
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i r. y
.,_._._i
- __~_.,
-_.._~- ~
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\I~J~ ~o
a X21;-~:,Cl 7
I .
~
1
i '
~. _~ I ~.~1~'24~~60z -._._._i
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353.28
' k i ~~~
ii '~ _" .: ~2sN;5~r;50~ [ .JV~.._J
- ~._~ ~ ~H~.~
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I
Example 111
[1-(4-{ 5-[(4-Chlorobenzylamino)methyl][ 1,2,4]oxadiazol-3-yl
}phenyl)pyrrolidin-3-yl]-
dimethylamine
CA 02554138 2006-07-20
68
Method D
Polymer-bound sodium cyanoborohydride (5 eq) was added to a mixture of { 1-[4-
(5-
aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-yl}dimethylamine (40.1
mg),
4-chlorobenzaldehyde (42.2 mg), acetic acid ( 17.2 ~ l), triethylamine (27.9
~.l) and THF
( 1 ml), and the reaction mixture was stirred at room temperature for 12 h.
The polymer-
bound reagent was filtered off and the solvent was removed in vacuo. The
residue was
m purified by preparative HPLC. The product with tire molecular weight of
411.18
(C22H26C1N50) was obtained in this way; MS (ESI): 412.23 (M+H+).
Example 112
[1-(4-{ 5-[(4-Methoxybenzylamino)methyl][1,2,4]oxadiazol-3-yl
}phenyl)pyrrolidin-
3-y]dimethylam.ine
:: -~ ._ ~ '~s ~ ~_ - wf ~ '~_"~ f~'i --_
w _~ ~ .. ,,.~
I ' J __ ~,'f~ '
v.
{ 1-[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl)pyrrolidin-3-
yl}dimethylamine was
2o reacted with p-anisaldehyde by method D. The product with the molecular
weight of
407.23 (C23H29N502) was obtained in this way; MS (ESI): 408.30 (M+H+).
Example 113
( 1-{4-[5-(4-Fluorobenzyloxymethyl)[ 1,2,4]oxadiazol-3-yl]phenyl }pyrrolidin-
3-yl)dimethylamine
CA 02554138 2006-07-20
69
4-Fluorobenzyl bromide (18.9 mg) and potassium carbonate (27.6 mg) were added
to a
mixture of {3-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-
yl}methanol
(28.8 mg) and DMF (0.3 ml). The reaction mixture was stirred at 60°C
for 3 h, filtered and
purified by preparative HPLC. The product with the molecular weight of 396.20
(C22H25FN4O2) was obtained in this way; MS (ES I): 397.27 (M+H+).
{ 3-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl] [ 1,2,4]oxadiazol-5-yl }
methanol
PyBOP (546.4 mg), HOAt ( 136.1 mg) and triethylamine (0.139 ml) were added to
a
0 mixture of 4-(3-dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine (248.3
mg),
benzyloxyacetic acid (0.143 ml) and DMF (3.0 ml) at 0°C, and the
mixture was stirred at
this temperature for 10 min. It was subsequently stirred at room temperature
for 1 h, and
then ethyl acetate and water were added to the reaction solution. The organic
phase was
then washed twice each with 10°70 strength citric acid solution,
saturated sodium
~ 5 bicarbonate solution and water and dried over sodium sulfate, and the
solvent was removed
in vacuo.
The residue was then taken up in 3 ml of THF, and EDC ( 170.8 mg) and
triethylamine
(0.139 ml) were added, and the mixture was stirred at 80°C for 16 h.
Ethyl acetate and
water were then added to the reaction solution. The organic phase was then
washed twice
20 each with l0alo strength citric acid solution, saturated sodium bicarbonate
solution and
water and dried over sodium sulfate, and the solvent was removed in vacuo.
The residue was dissolved in methylene chloride (4.4 ml), and the solution was
cooled to
-78°C. At this temperature, a 1M boron trichloride solution (3 ml) was
added. The reaction
25 was allowed to warm to room temperature overnight, and then ethyl acetate
and water were
added. The product with the molecular weight of 288.2 (C 15H20N4O2) was
obtained in
this way; MS (EST): 289.2 (M+H+).
CA 02554138 2006-07-20
7()
The following examples could be synthesized analogously:
' ~
,_ .;_-~,
_ _.. _.. ._._...~_...__..._..___ _ _;_.. _... i .____..._
_ ....__.._.__.. ._ __........_._.
' .. _
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I7,
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h ~
-
j , ._ . ~ ,.::,'_._.,' '
1...'
'
CA 02554138 2006-07-20
71
,_; _;. I, _ .
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,
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i
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:r;.
