U.S. patent application number 12/006765 was filed with the patent office on 2008-05-08 for pharmaceutical use of substituted amides.
This patent application is currently assigned to Novo Nordisk A/S. Invention is credited to Henrik Sune Andersen, Inge Thoger Christensen, Gita Camilla Tejlgaard Kampen, John Paul Kilburn, Annette Rosendal Larsen, John Patrick Mogensen.
Application Number | 20080108598 12/006765 |
Document ID | / |
Family ID | 33163358 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108598 |
Kind Code |
A1 |
Andersen; Henrik Sune ; et
al. |
May 8, 2008 |
Pharmaceutical use of substituted amides
Abstract
The use of substituted amides for modulating the activity of
11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1) and the
use of these compounds as pharmaceutical compositions, are
described. Also a novel class of substituted amides, their use in
therapy, pharmaceutical compositions comprising the compounds, as
well as their use in the manufacture of medicaments are described.
The present compounds are modulators and more specifically
inhibitors of the activity of 11.beta.HSD1 and may be useful in the
treatment, prevention and/or prophylaxis of a range of medical
disorders where a decreased intracellular concentration of active
glucocorticoid is desirable.
Inventors: |
Andersen; Henrik Sune;
(Lyngby, DK) ; Kampen; Gita Camilla Tejlgaard;
(Naerum, DK) ; Christensen; Inge Thoger; (Lyngby,
DK) ; Mogensen; John Patrick; (Herlev, DK) ;
Larsen; Annette Rosendal; (Lyngby, DK) ; Kilburn;
John Paul; (Haslev, DK) |
Correspondence
Address: |
NOVO NORDISK, INC.;PATENT DEPARTMENT
100 COLLEGE ROAD WEST
PRINCETON
NJ
08540
US
|
Assignee: |
Novo Nordisk A/S
Bagsvaerd
DK
|
Family ID: |
33163358 |
Appl. No.: |
12/006765 |
Filed: |
January 3, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11265794 |
Oct 11, 2005 |
|
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12006765 |
Jan 3, 2008 |
|
|
|
PCT/DK2004/000250 |
Apr 6, 2004 |
|
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11265794 |
Oct 11, 2005 |
|
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Current U.S.
Class: |
514/214.03 ;
514/217.11 |
Current CPC
Class: |
C07D 209/02 20130101;
C07D 403/12 20130101; A61P 3/00 20180101; C07D 487/08 20130101;
A61K 31/415 20130101; A61K 31/16 20130101; C07D 401/06 20130101;
C07D 401/12 20130101; A61P 3/10 20180101; A61P 3/04 20180101; A61K
45/06 20130101 |
Class at
Publication: |
514/214.03 ;
514/217.11 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61P 3/10 20060101 A61P003/10 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2003 |
DK |
PA 2003 00565 |
Jun 27, 2003 |
DK |
PA 2003 00972 |
Jun 30, 2003 |
DK |
PA 2003 00988 |
Jun 30, 2003 |
DK |
PA 2003 00989 |
Jun 30, 2003 |
DK |
PA 2003 00990 |
Feb 7, 2003 |
DK |
PA 2003 00998 |
Dec 22, 2003 |
DK |
PA 2003 01910 |
Jan 6, 2004 |
DK |
PA 2004 00009 |
Claims
1. A method of modulating of the activity of 11.beta.HSD1, or
inhibiting 11.beta.HSD1, comprising administering to a patient in
need of such method a therapeutically effective amount of a
substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture or tautomeric forms
thereof.
2. A method for the treatment, prevention and/or prophylaxis of any
disorder and disease where it is desirable to modulate the activity
of 11.beta.HSD1, or inhibit 11.beta.HSD1, comprising administering
to a patient in need of such method a therapeutically effective
amount of a substituted amide, a prodrug thereof, or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture or any tautomeric
forms thereof.
3. The method according to claim 2, wherein the substituted amide
or a prodrug thereof is of formula (I) ##STR256## wherein R.sup.1
is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl, hetcycloalkyl,
alkyl, arylalkyl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.4. R.sup.2 is
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.5; or R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system
containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14; R.sup.3 is C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkenyl, C.sub.1-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and
hetaryl groups independently are optionally substituted with one or
more of R.sup.7; R.sup.4 and R.sup.5 independently are hydrogen,
hydroxy, oxo, cyano, halo, methylendioxo, NR.sup.8R.sup.9,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethyloxy, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.3-C.sub.10cycloalkenyl, aryl,
hetaryl, hetarylSO.sub.n, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkyl-carboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15; R.sup.6 is oxygen,
sulphur, SO.sub.n or NR.sup.16; R.sup.7 is hydrogen, halo, hydroxy,
cyano, nitro, COOR.sup.17, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
methylendioxo, trihalomethyl, trihalomethyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl, arylthio, hetarylthio,
R.sup.18carbonylNR.sup.8, arylSO.sub.n, hetarylSO.sub.n,
R.sup.19SO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.11; or R.sup.8 and R.sup.9
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulfur,
the ring system optionally being substituted with at least one
halo, cyano, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, hydroxy, oxo, halo, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, NR.sup.12R.sup.13,
methylendioxo, trihalomethyl or trihalomethyloxy; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or
aryloxy; R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
CONR.sup.8R.sup.9 or COOR.sup.17; R.sup.16 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, aryloxyC.sub.1-C.sub.6alkyl,
hetaryloxyC.sub.1-C.sub.6alkyl, arylthioC.sub.1-C.sub.6alkyl or
hetarylthioC.sub.1-C.sub.6alkyl; wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.10; R.sup.17 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl or arylC.sub.1-C.sub.6alkyl; R.sup.18 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl or
R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally
substituted with R.sup.15; R.sup.19 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl; m
is 1 or 2; n is 0, 1 or 2; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
4. The method according to claim 3, wherein the substituted amide
or a prodrug thereof is of formula (I) ##STR257## wherein R.sup.1
is C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl, wherein the cycloalkyl, hetcycloalkyl,
alkyl, arylalkyl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.4; R.sup.2 is
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.5; or R.sup.1 and R.sup.2 are together
with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6alkylcarboxy wherein the alkyl and aryl
groups independently are optionally substituted with one or more of
R.sup.14; R.sup.3 is C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkenyl,
C.sub.1-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and
hetaryl groups independently are optionally substituted with one or
more of R.sup.7; R.sup.4 and R.sup.5 independently are hydrogen,
hydroxy, oxo, cyano, halo, methylendioxo, NR.sup.8R.sup.9,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethyloxy, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.3-C.sub.10cycloalkenyl, aryl,
hetaryl, hetarylSO.sub.n, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkyl-carboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15; R.sup.6 is oxygen,
sulphur, SO.sub.n, NR.sup.16; R.sup.7 is hydrogen, halo, hydroxyl,
cyano, nitro, COOR.sup.7, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
methylendioxo, trihalomethyl, trihalomethyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylalkyl, arylcarbonylNR.sup.8, arylthio,
hetarylthio, arylSO.sub.n, hetarylSO.sub.n, arylSO.sub.mNR.sup.8,
arylthioC.sub.1-C.sub.6alkyl, hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.11; or R.sup.8 and R.sup.9
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulfur,
the ring system optionally being substituted with at least one
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, hydroxy, oxo, halo, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, NR.sup.12R.sup.13,
methylendioxo, trihalomethyl or trihalomethyloxy; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or
aryloxy; R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or
COOR.sup.17; R.sup.16 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
alkylcarbonyl, arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
aryloxyC.sub.1-C.sub.6alkyl, hetaryloxyC.sub.1-C.sub.6alkyl,
arylthioC.sub.1-C.sub.6alkyl or hetarylthioC.sub.1-C.sub.6alkyl;
wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.10; R.sup.17 is hydrogen, C.sub.1-C.sub.8alkyl, aryl or
arylC.sub.1-C.sub.6alkyl; m is 1 or 2; n is 0, 1 or 2; or a salt
thereof with a pharmaceutically acceptable acid or base, or optical
isomer or mixture of optical isomers, racemic mixture, or
tautomeric forms thereof.
5. The method according to claim 3, wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, wherein
the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.4.
6. The method according to claim 3, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.5.
7. The method according to claim 3, wherein R.sup.1 and R.sup.2
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14.
8. The method according to claim 3, wherein R.sup.3 is
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of
R.sup.7.
9. The method according to claim 3, wherein R.sup.4 and R.sup.5
independently are hydrogen, hydroxy, oxo, halo,
C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.15.
10. The method according to claim 3, wherein R.sup.5 is oxygen.
11. The method according to claim 3, wherein R.sup.7 is hydrogen,
halo, hydroxy, cyano, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
trihalomethyl, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl,
R.sup.18carbonylNR.sup.8, R.sup.19SO.sub.mNR.sup.8, wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10.
12. The method according to claim 3, wherein R.sup.8 and R.sup.9
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulfur,
the ring system optionally being substituted with at least one
halo, cyano, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy.
13. The method according to claim 3, wherein R.sup.15 is
CONR.sup.8R.sup.9.
14. The method according to claim 3, wherein R.sup.18 is
C.sub.1-C.sub.6alkyl.
15. The method according to claim 3, wherein the substituted amide
or a prodrug thereof of formula (I) is selected from the group
consisting of:
3-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-1-[4-(1H-imidazol-4-yl)-piperid-
in-1-yl]-propan-1-one;
4-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-1-[4-(3H-imidazol-4-yl)-piperid-
in-1-yl]-butan-1-one; 2,4-Bis-benzyloxy-benzamide;
(1H-Indol-4-yl)-piperidin-1-yl-methanone;
N-(1,4-Dioxo-1,4-dihydro-naphthalen-2-yl)-benzamide;
N-(2,3-Dihydroxy-propyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone;
(2-Chloro-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-methan-
one;
3-Cyclopentyl-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-pro-
pan-1-one;
(3-Chloro-thieno[2,3-b]thiophen-2-yl)-thiomorpholin-4-yl-methanone;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-[4-(4-methoxy-phenyl)-piperazin--
1-yl]-ethanone;
1-(4-Benzyl-piperazin-1-yl)-2-[2-(4-chloro-phenyl)-adamantan-2-yl]-ethano-
ne;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-(4-methyl-piperazin-1-yl)-et-
hanone;
1-[4-(6-Chloro-pyridin-2-yl)-piperazin-1-yl]-2-(2-phenyl-adamanta-
n-2-yl)-ethanone;
4-Chloro-N-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid
(2-cyano-ethyl)-cyclohexyl-amide;
2-[2-(Bicyclo[2.2.1]hept-5-en-2-ylamino)-4-oxo-4,5-dihydro-thiazol-5-yl]--
N-(2-chloro-phenyl)acetamide;
[3-(4-sec-Butyl-phenoxy)-phenyl]-piperidin-1-yl-methanone;
3-(6-Chloro-pyridin-2-yloxy)-N-ethyl-benzamide;
N-Benzyl-2,4-dichloro-N-pyridin-2-yl-benzamide;
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid butyl
ester; 2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid
pentyl ester;
3-(4-Fluoro-phenyl)-1-(4-phenyl-piperidin-1-yl)-but-2-en-1-one;
N-(1,7,7-Trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
1-(3-Cyclopentyl-propionyl)-piperidine-3-carboxylic acid ethyl
ester; 4-Phenyl-1-phenylacetyl-piperidine-4-carbonitrile;
1-Octanoyl-4-phenyl-piperidine-4-carbonitrile;
2,2-Dimethyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propan-1-on-
e;
(4-Chloro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-metha-
none;
N-[1-(4-Methanesulfonyl-phenyl)-ethyl]-N-(tetrahydro-furan-2-ylmeth-
yl)-benzamide;
2-(2-Amino-phenylsulfanyl)-1-(5-fluoro-2,3-dihydro-indol-1-yl)-ethanone;
N-(1-Methyl-2,3-dihydro-1H-indol-5-ylmethyl)-N-(tetrahydro-furan-2-ylmeth-
yl)-benzamide; 1-Benzoyl-piperidine-2-carboxylic acid ethyl ester;
N-(2-Chloro-phenyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide;
(Decahydro-naphthalen-1-yl)-(4-methyl-piperazin-1-yl)-methanone;
(4-Methyl-piperazin-1-yl)-(2-p-tolylsulfanyl-phenyl)-methanone;
Adamantane-1-carboxylic acid
(3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3,4,5-trimethoxy-phenyl-
)-methanone; N-Bicyclo[2.2.1]hept-2-yl-3-cyclopentyl-propionamide;
(2-Benzo[1,2,5]oxadiazol-5-yl-thiazol-4-yl)-piperidin-1-yl-methanone;
Thiophene-2-carboxylic acid
[4-(4-fluoro-phenyl)-4-hydroxy-butyl]-isopropyl-amide;
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
2-[(Adamantane-1-carbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid
methyl ester; Adamantane-1-carboxylic acid
[3-(1H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-amide;
N-Benzyl-N-(1-cyclopropyl-ethyl)-4-fluoro-benzamide;
Thiophene-2-carboxylic acid
2-[2-(2-phenyl-adamantan-2-yl)-acetylamino]-ethyl ester;
N-(4-Acetyl-phenyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-N-(2-hydroxy-ethyl)-acetamide;
(4-Benzoyl-piperidin-1-yl)-thiophen-2-yl-methanone;
N-(2-Benzoyl-4-methyl-phenyl)-3-phenyl-acrylamide;
N-(2-Benzoyl-4-methyl-phenyl)-2-fluoro-benzamide;
Adamantane-1-carboxylic acid (4-ethoxy-benzothiazol-2-yl)-amide;
Adamantane-1-carboxylic acid
(5-benzoyl-4-phenyl-thiazol-2-yl)-amide;
3-(2-Hydroxy-phenyl)-1,3-di-piperidin-1-yl-propan-1-one;
N-(1-Methyl-2-phenyl-ethyl)-3-phenyl-propionamide;
4-Oxo-4-piperidin-1-yl-butyric acid 4-tert-butyl-cyclohexyl ester;
N-tert-Butyl-N-(4-methoxy-benzyl)-4-nitro-benzamide;
{4-[(Adamantane-1-carbonyl)-amino]-phenoxy}-acetic acid;
2-(4-Isobutyl-phenyl)-N-(1-phenyl-ethyl)-propionamide;
Adamantane-1-carboxylic acid
4-[(adamantane-1-carbonyl)-amino]-2,6-dimethyl-pyridin-3-yl ester;
2-Phenyl-1-(3-phenyl-pyrrolidin-1-yl)-ethanone;
Adamantane-1-carboxylic acid
4-[(adamantane-1-carbonyl)-amino]-2-ethyl-6-methyl-pyridin-3-yl
ester;
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-hydroxy-phenyl-
)-benzamide; Biphenyl-4-yl-piperidin-1-yl-methanone;
Azepan-1-yl-(3,5-dichloro-phenyl)-methanone;
Azepan-1-yl-biphenyl-4-yl-methanone;
Azepan-1-yl-(4-chloro-phenyl)-methanone;
3-Heptylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;
Adamantan-1-yl-azepan-1-yl-methanone;
N,N-Dibenzyl-3,4-dimethoxy-benzamide;
N-Benzyl-N-isopropyl-4-nitro-benzamide;
N-[2-(1H-Indol-3-yl)-1-methyl-ethyl]-2-(4-isobutyl-phenyl)-propionamide;
N-tert-Butyl-2-(4-isobutyl-phenyl)-propionamide;
Adamantane-1-carboxylic acid (2-acetyl-phenyl)-amide;
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-fluoro-phenyl)-benzami-
de; (Octahydro-quinolin-1-yl)-phenyl-methanone;
(7-Hydroxy-octahydro-quinolin-1-yl)-phenyl-methanone;
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-p-tolyl-benzamide;
N,N-Dibenzyl-4-methyl-benzamide;
(2-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
[4-Bromo-3-(piperidine-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone;
2-Chloro-N-(3,4-dimethyl-phenyl)-benzamide;
1-Azepan-1-yl-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-ethan-
one; N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-butyramide;
N-Benzo[1,3]dioxol-5-yl-2-chloro-benzamide;
(4-Benzyl-piperidin-1-yl)-(2-chloro-phenyl)-methanone;
2-(Benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
Cyclohexanecarboxylic acid
(7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide;
2,4-Dichloro-N-ethyl-N-o-tolyl-benzamide;
(4-Benzyl-piperidin-1-yl)-(4-fluoro-phenyl)-methanone;
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-N-methyl-butyramide;
3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-adamantane-1-carboxylic
acid; Morpholin-4-yl-(3-p-tolyl-adamantan-1-yl)-methanone;
N-Benzyl-2,4-dichloro-N-methyl-benzamide; Thiophene-2-carboxylic
acid dibenzylamide; Azepan-1-yl-(2-bromo-phenyl)-methanone;
(3,4-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
N,N-Dibenzyl-3,4-dichloro-benzamide;
4-(2,4-Dichloro-phenoxy)-1-piperidin-1-yl-butan-1-one;
N,N-Dibenzyl-2-fluoro-benzamide;
(2-Chloro-phenyl)-piperidin-1-yl-methanone;
2-Chloro-N-(3-trifluoromethyl-phenyl)-benzamide;
N-Benzyl-N-ethyl-2-phenyl-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-p-tolyl-methanone;
Thiophene-2-carboxylic acid benzyl-ethyl-amide;
N-Adamantan-1-yl-2-dibenzylamino-acetamide;
N-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamid-
e; Thiophene-2-carboxylic acid cycloheptylamide;
N-Cyclohexyl-3-diethylsulfamoyl-4-methyl-benzamide;
4-Benzoyl-N-methyl-N-phenyl-benzamide;
N-Benzyl-2-bromo-N-methyl-benzamide;
2-Chloro-N-methyl-N-phenyl-benzamide;
4-Chloro-N-ethyl-N-o-tolyl-benzamide;
N-Benzyl-4,N-dimethyl-benzamide;
2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Benzyl-2-bromo-N-isopropyl-benzamide;
3-(2-Chloro-phenyl)-N-cyclohexyl-N-methyl-acrylamide;
N-Phenyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide;
N-m-Tolyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide;
(3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
Adamantane-1-carboxylic acid (5-methyl-pyridin-2-yl)-amide;
3-Bromo-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbo-
nyl)-butyl]-benzamide;
4-Chloro-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carb-
onyl)-butyl]-benzamide;
4-Methyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carb-
onyl)-butyl]-benzamide; Cyclohexanecarboxylic acid
[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)butyl]-
-amide;
3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]-
octane-6-carbonyl)-butyl]-propionamide;
2-Chloro-N-[2-(4-ethyl-benzoylamino)-ethyl]-N-(4-fluoro-phenyl)-benzamide-
;
N-{1-Benzyl-2-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-2-oxo-ethyl}-
-3-cyclopentyl-propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclopentyl-N-[2-(1H-indol-3-yl)-e-
thyl]-propionamide;
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-2,4-dichloro-N-[2-(1H-indol-3-yl)-et-
hyl]-benzamide; Naphthalene-2-carboxylic acid
(2-oxo-azepan-3-yl)-thiophen-3-ylmethyl-amide;
3,4,5-Trimethoxy-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-benz-
amide;
3-Cyclopentyl-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]--
propionamide;
N-(3,4-Dimethoxy-benzyl)-3-methoxy-N-[6-(pyridin-2-ylamino)-hexyl]-benzam-
ide; N,N-Dimethyl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-acetamide;
Adamantane-1-carboxylic acid
[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-p-tolyl-amide;
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-N-(2-trifluoromethyl-phe-
nyl)-butyramide;
2-(4-Chloro-2-methyl-phenoxy)-N-(2-trifluoromethyl-phenyl)-propionamide;
4-(2,4-Dichloro-phenoxy)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-butan-1-o-
ne;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(piperidine-1-sulfonyl)-phenyl]-met-
hanone; Acetic acid 4-(azepane-1-carbonyl)-phenyl ester;
N-Adamantan-1-ylmethyl-benzamide;
[3-(4-Nitro-phenyl)-adamantan-1-yl]-piperidin-1-yl-methanone;
N-(1,1-Dimethyl-hexyl)-2-morpholin-4-yl-acetamide;
Adamantyl-1-carboxylic acid (2-methoxy-ethyl)-amide;
N-(4-Adamantan-1-yl-2-methyl-phenyl)-acetamide;
3-p-Tolyl-adamantane-1-carboxylic acid (2,5-dichloro-phenyl)-amide;
(3-Chloro-adamantan-1-yl)-pyrrolidin-1-yl-methanone;
2-Amino-5-cyclohexylcarbamoyl-4-methyl-thiophene-3-carboxylic acid
ethyl ester;
N-(2-Chloro-phenyl)-2-{3-[(2-chloro-phenylcarbamoyl)-methyl]-adam-
antan-1-yl}-acetamide; 3-p-Tolyl-adamantane-1-carboxylic acid
(2,4-difluoro-phenyl)-amide; Adamantyl-1-carboxylic acid
tert-butylamide; 2-Adamantan-1-yl-N-tert-butyl-acetamide;
N-Methyl-N-phenyl-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(1-Adamantan-1-yl-ethyl)-2-fluoro-benzamide;
Adamantane-1-carboxylic acid
[2-(3,4-dimethoxy-phenyl)-ethyl]-amide; Adamantane-1-carboxylic
acid dimethylamide;
N-Benzyl-4-chloro-N-(1-cyclopropyl-vinyl)-benzamide;
3,5-Dimethyl-adamantane-1-carboxylic acid benzylamide;
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide;
N-Adamantan-1-yl-2,4-dichloro-N-ethyl-benzamide;
2-[(3-p-Tolyl-adamantane-1-carbonyl)-amino]-propionic acid methyl
ester; N-Adamantan-1-yl-3-morpholin-4-yl-propionamide;
3-p-Tolyl-adamantane-1-carboxylic acid isopropylamide;
N-Adamantan-1-yl-2-benzylamino-acetamide;
N-Benzyl-2,4-dichloro-N-(1-cyclopropyl-ethyl)-5-methyl-benzamide;
2-[(Adamantane-1-carbonyl)-amino]-benzoic acid ethyl ester;
N-Benzyl-N-isopropyl-4-methyl-3-nitro-benzamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone;
N-Ethyl-2-fluoro-N-phenyl-benzamide;
2-Phenethyl-N-(2-trifluoromethyl-phenyl)-benzamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-o-tolyloxy-ethanone;
2-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
Cyclohexanecarboxylic acid (2-propoxy-phenyl)-amide;
2-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-isoindole-1,3-dio-
ne; N-Cyclopentyl-2-(2,4-dichloro-phenoxy)-propionamide;
Adamantane-1-carboxylic acid (2-trifluoromethyl-phenyl)-amide;
(4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
4-(2-Ethyl-phenyl)-4-aza-tricyclo[5.2.2.0.sup.2,6]undec-8-ene-3,5-dione;
2-Phenyl-N-(2-trifluoromethyl-phenyl)-butyramide;
N-Adamantan-1-yl-4-chloro-2-nitro-benzamide;
3-p-Tolyl-adamantane-1-carboxylic acid (2,3-dimethyl-phenyl)-amide;
N-Benzyl-3-methyl-4-p-tolyl-butyramide;
N-(2-Cyclohex-1-enyl-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propi-
onamide;
(4-tert-Butyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanon-
e;
2-[1-(4-Chloro-benzenesulfonyl)-1H-benzoimidazol-2-ylsulfanyl]-N-thiop-
hen-2-ylmethyl-acetamide;
2-Phenoxy-1-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethanone;
Cyclohexanecarboxylic acid
[5-(2-fluoro-benzylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-amide;
4-Methyl-2-phenyl-thiazole-5-carboxylic acid naphthalen-1-ylamide;
4-Fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phe-
nyl]-benzenesulfonamide;
(3-Methoxy-phenyl)-(4-o-tolyl-piperazin-1-yl)-methanone;
N-Adamantan-1-yl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
N-Cyclooctyl-2-methoxy-3-methyl-benzamide;
2-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-isoi-
ndole-1,3-dione;
(2,3-Diphenyl-quinoxalin-6-yl)-(2,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone;
Adamantan-1-yl-(1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-methanone;
N-{4-[1-(Naphthalene-2-sulfonyl)-piperidin-3-yl]-butyl}-N'-p-tolyl-oxalam-
ide; N-Benzyl-N-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide;
(4-Amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone-
;
1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-isopropyl-5-methyl-phenoxy)-
-ethanone; Adamantane-1-carboxylic acid benzyl-pyridin-2-yl-amide;
Adamantan-1-yl-piperidin-1-yl-methanone;
Adamantan-1-yl-pyrrolidin-1-yl-methanone;
(3,4-Dihydro-2H-quinolin-1-yl)-o-tolyl-methanone;
Adamantyl-1-carboxylic acid benzylamide; Pyridine-2-carboxylic acid
adamantan-2-ylamide;
(3-Chloro-adamantan-1-yl)-piperidin-1-yl-methanone;
Adamantan-1-yl-(4-methyl-piperidin-1-yl)-methanone;
2-[3-(Azepane-1-carbonyl)-phenyl]-isoindole-1,3-dione;
2-[3-(Piperidine-1-carbonyl)-phenyl]-isoindole-1,3-dione;
4-(Benzyl-methanesulfonyl-amino)-N-furan-2-ylmethyl-benzamide;
(4-Nitro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone-
; 1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(4-chloro-3-nitro-phenyl)-amide;
N-(2-Chloro-phenyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-acetamide;
3-(4-Hydroxy-phenyl)-N-isochroman-1-ylmethyl-3-phenyl-propionamide;
(4-Ethoxy-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(3-chloro-phenyl)-amide;
N-[4-(Benzyl-isopropyl-sulfamoyl)-phenyl]-acetamide;
N-(3,4-Dimethyl-phenyl)-N-[4-(piperidine-1-carbonyl)-benzyl]-methanesulfo-
namide;
2-(5-Phenyl-1H-imidazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-buty-
l)-acetamide;
2-(Benzothiazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetamide;
2-(Benzooxazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetamide;
2-(Naphthalen-2-ylcarbamoylmethylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)--
acetamide; Acetic acid
4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl
ester;
[1-(4-Chloro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-
-1-yl)-methanone;
(4-Fluoro-phenyl)-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-methanone;
N-Adamantan-1-yl-2-ethoxy-acetamide;
2-(2-Oxo-2-phenothiazin-10-yl-ethyl)-hexahydro-isoindole-1,3-dione;
Adamantane-1-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
2-Bromo-N-cycloheptyl-benzamide;
Bicyclo[2.2.1]hept-2-yl-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;
N-Furan-2-ylmethyl-2-phenyl-2-phenylsulfanyl-acetamide;
Adamantane-1-carboxylic acid benzyl-methyl-amide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-3-(4-fluoro-phenyl)-propenone;
Adamantan-1-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
4-Methyl-N-homoadamantyl-3-yl-benzamide;
(3,5-Dimethyl-piperidin-1-yl)-(3-methyl-4-nitro-phenyl)-methanone;
Quinoline-2-carboxylic acid cyclooctylamide;
Adamantane-1-carboxylic acid
[2-(2,4-dimethoxy-phenyl)-ethyl]-amide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-o-tolyl-methanone;
(3,6-Dichloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
3-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyl-propionamide;
Propionic acid 2-amino-4-methyl-5-p-tolylcarbamoyl-thiophen-3-yl
ester;
2-Cyclohexyl-N-(2,6-dimethyl-phenyl)-N-furan-2-ylmethyl-acetamide;
(3-Methoxy-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinolin-1-yl-
)-methanone;
1-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrr-
olidine-2,5-dione;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(1-naphthalen-1-yl-1H-tetrazol-5-ylsul-
fanyl)-ethanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-o-tolyl-methanone;
(4-Benzyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
N-(2-Cyano-phenyl)-2-(9-ethyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-a-
cetamide;
N-(2-Cyano-phenyl)-2-(9-methyl-9H-1,3,4,9-tetraaza-fluoren-2-yl-
sulfanyl)-acetamide;
1-(Thiophene-2-carbonyl)-2,3-dihydro-1H-quinolin-4-one;
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
(4-Bromo-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-acetamide;
9-Oxo-9H-fluorene-1-carboxylic acid (3-methyl-butyl)-amide;
[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone-
; N-Cycloheptyl-3-diethylsulfamoyl-benzamide;
(4-Methoxy-phenyl)-(3-phenyl-piperidin-1-yl)-methanone;
3-Amino-N-cyclohexyl-N-methyl-benzamide;
N-Ethyl-3,4-dimethyl-N-phenyl-benzamide;
N-Benzyl-3,4,N-trimethyl-benzamide;
(4-Fluoro-phenyl)-(3-phenyl-piperidin-1-yl)-methanone;
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-(3-methoxy-phenyl)-methanone;
Furan-2-carboxylic acid
[4-(4-methyl-piperidine-1-sulfonyl)-phenyl]-amide;
N-(2-Cyclohex-1-enyl-ethyl)-2-o-tolyloxy-acetamide;
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid
(1-bicyclo[2.2.1]hept-2-yl-ethyl)-amide;
3-(2-Chloro-phenyl)-1-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-propenone;
N-[3-(Azepane-1-carbonyl)-phenyl]-benzamide;
[3-(Piperidine-1-carbonyl)-pyrazol-1-yl]-o-tolyl-methanone;
N-(1-Phenyl-cyclopentylmethyl)-2-piperidin-1-yl-propionamide;
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-propionamide;
N-[4-(Azepane-1-sulfonyl)-phenyl]-2,2,2-trifluoro-acetamide;
2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide;
N-Adamantan-1-yl-2-(3-methoxy-phenoxy)-acetamide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid
(2-cyano-ethyl)-phenyl-amide;
[4-(4-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
[4-(2-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone;
3-[5-(4-Fluoro-phenyl)-furan-2-yl]-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1-
]oct-6-yl)-propenone;
2-(3-Fluoro-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3--
carboxylic acid methyl ester;
N-(2-Ethyl-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide;
2-(2-Methoxy-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-
-carboxylic acid methyl ester; 1-Phenyl-cyclopentanecarboxylic acid
(4-phenyl-tetrahydro-pyran-4-ylmethyl)-amide;
4-(2,4-Dichloro-phenoxy)-1-(4-phenyl-piperazin-1-yl)-butan-1-one;
Naphthalene-1-carboxylic acid cycloheptylamide;
N-Indan-5-yl-2-methyl-3-nitro-benzamide;
N-Cyclohexyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide;
2-Methoxy-N-(1-phenyl-cyclopentylmethyl)-benzamide;
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-
-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2-methyl-piperidin-1-yl)-methanon-
e; 5-(2-Methoxy-phenoxymethyl)-furan-2-carboxylic acid
cycloheptylamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-[1-(2-nitro-benzenesulfonyl)-piperidin--
3-yl]-methanone; N-Cyclooctyl-2-(4-methoxy-phenoxy)-acetamide;
N-(2,3-Dimethyl-phenyl)-4-[methyl-(toluene-4-sulfonyl)-amino]-butyramide;
N-Phenyl-N-[4-(piperidine-1-carbonyl)-benzyl]-benzenesulfonamide;
N-[4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-benzyl]-N-(3,4-dimethyl-phe-
nyl)-methanesulfonamide; 2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic
acid bicyclo[2.2.1]hept-2-ylamide;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
cycloheptylamide;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-fluoro-benzenesulfonamide;
1-(2,6-Dimethyl-morpholin-4-yl)-3,3-diphenyl-propan-1-one;
N-Bicyclo[2.2.1]hept-2-yl-4-morpholin-4-ylmethyl-benzamide;
[3-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
N-Adamantan-1-yl-2-(4-methyl-quinolin-2-ylsulfanyl)-acetamide;
Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide;
(4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
3-Cyclohexyl-N-(3-phenyl-propyl)-propionamide;
2-[1-(2,5-Dimethyl-phenyl)-1H-tetrazol-5-ylsulfanyl]-N-isopropyl-N-phenyl-
-acetamide;
N-{2-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-ethyl}-acetamide-
;
N-Benzyl-N-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-benzenesulfonamide-
; [4-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
N-Cycloheptyl-3-phenyl-propionamide;
(3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
N-Cycloheptyl-2,4-dimethoxy-benzamide;
N-(3-Chloro-phenyl)-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.su-
p.2,7]undeca-2(7),3,5-trien-5-ylsulfanyl)-acetamide;
N-(2-Nitro-phenyl)-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup-
.2,7]undeca-2(7),3,5-trien-5-ylsulfanyl)-acetamide;
N-Phenyl-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup.2,7]undec-
a-2(7),3,5-trien-5-ylsulfanyl)acetamide;
N-Ethyl-3-methyl-N-o-tolyl-benzamide;
N-[5-(2,4-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-p-
ropionamide; 4-Bromo-1-ethyl-1H-pyrazole-3-carboxylic acid
(2-methylsulfanyl-phenyl)-amide; 5-Benzoyl-furan-2-carboxylic acid
diisopropylamide;
N-{2-[2-(4-Bromo-phenyl)-2-oxo-ethylsulfanyl]-benzothiazol-6-yl}-acetamid-
e; 2-(6-Amino-benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
N-(2-Cyclohexylcarbamoylmethylsulfanyl-benzothiazol-6-yl)-2-methoxy-benza-
mide; Benzofuran-2-yl-(4-phenyl-piperidin-1-yl)-methanone;
1-(2-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
1-(4-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
5-Bromo-furan-2-carboxylic acid adamantan-2-ylamide;
3,3-Dimethyl-pentanedioic acid bis-[(2,4-difluoro-phenyl)-amide];
2-(3-Bromo-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-bromo-benzenesulfonamide;
1-(2,3-Dihydro-indol-1-yl)-2-p-tolylsulfanyl-ethanone;
[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-furan-2-yl-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-meth-
anone; 5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid
diethylamide; 5-(2-Bromo-phenoxymethyl)-furan-2-carboxylic acid
diethylamide; 5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid
methyl-phenyl-amide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methano-
ne;
[3-(2,5-Dichloro-phenoxymethyl)-phenyl]-pyrrolidin-1-yl-methanone;
[5-(4-Ethoxy-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methano-
ne;
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-methyl-cyclohexyl)-propi-
onamide;
3-(3,4-Dihydro-2H-quinoline-1-carbonyl)-N-phenyl-benzenesulfonam-
ide;
[3-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-(3,4-dihydro-2H-quinolin--
1-yl)-methanone;
[3-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone-
; N-Cyclohexyl-3-(2-hydroxy-4-methyl-phenyl)-3-phenyl-propionamide;
2-Diethylamino-N-(1-phenyl-cyclopentylmethyl)-propionamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-trifluoromethyl-pheny-
l)-methanone;
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-metha-
none; N-Benzyl-4-bromo-N-ethyl-benzamide;
(3-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone-
; Azepan-1-yl-[5-(2-chloro-phenoxymethyl)-furan-2-yl]-methanone;
(4-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone-
;
Azepan-1-yl-[5-(2,4-dichloro-phenoxymethyl)-furan-2-yl]-methanone;
N-Cycloheptyl-4-(4-methoxy-2-methyl-phenyl)-butyramide;
2-(4-Benzothiazol-2-yl-piperazin-1-yl)-N-cyclohexyl-acetamide;
N-Cycloheptyl-2-(2,6-dimethyl-phenoxy)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-(3-iodo-phenyl)-methanone;
N-Cycloheptyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide;
Azepan-1-yl-[4-(2-chloro-phenoxymethyl)-phenyl]-methanone;
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-2-yloxymethyl)-phenyl]-metha-
none; Azepan-1-yl-[3-(4-ethoxy-phenoxymethyl)-phenyl]-methanone;
Benzo[b]thiophene-3-carboxylic acid
(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-(4-Chloro-2-methyl-phenoxy)-N-cycloheptyl-acetamide;
2,4-Dichloro-N-cyclohexyl-N-methyl-benzamide;
N-Cyclooctyl-2-p-tolyloxy-acetamide;
(3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
Biphenyl-4-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
N-Cyclohexyl-4-fluoro-N-methyl-benzamide;
N-[4-(Azepane-1-carbonyl)-phenyl]-N-methyl-benzenesulfonamide;
N-Cycloheptyl-2-fluoro-benzamide; N-Cycloheptyl-4-methyl-benzamide;
(3-Methyl-piperidin-1-yl)-p-tolyl-methanone;
[2-(3,4-Dimethoxy-phenylcarbamoyl)-piperidin-1-yl]-acetic acid
benzyl ester;
N-[4-(2-Methyl-piperidine-1-sulfonyl)-phenyl]-acetamide;
2-(2,4-Dichloro-phenoxy)-N-(2-methyl-butyl)-propionamide;
[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-(4-methoxy-phenyl)-methanone-
; N-Cyclohexyl-4-(4-methoxy-3-methyl-phenyl)-butyramide;
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2--
yl)-methanone;
2-(4-Methyl-benzylsulfanyl)-1-piperidin-1-yl-ethanone;
N-Cyclohexyl-N-[(4-phenyl-thiazol-2-ylcarbamoyl)-methyl]-benzamide;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-isopropyl-phenyl)-methanesulfonamide;
N-Adamantan-1-yl-3-p-tolylsulfanyl-propionamide;
6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic
acid; (4-Butyl-cyclohexyl)-morpholin-4-yl-methanone;
(3,4-Dichloro-phenyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
N-(2-Cyclohex-1-enyl-ethyl)-3-methoxy-benzamide;
N-Adamantan-2-yl-3-(1,5-dimethyl-1H-pyrazol-4-yl)-acrylamide;
N-Adamantan-1-yl-N-methyl-4-(4-nitro-pyrazol-1-ylmethyl)-benzamide;
5-(4-Chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-carboxylic
acid adamantan-2-ylamide;
2-(4-Chloro-phenoxy)-N-(2-fluoro-5-methyl-phenyl)-2-methyl-propionamide;
N-Adamantan-1-yl-2-(4-chloro-3,5-dimethyl-phenoxy)-acetamide;
2-[(3-Carboxy-bicyclo[2.2.1]heptane-2-carbonyl)-amino]-5,6-dihydro-4H-cyc-
lopenta[b]thiophene-3-carboxylic acid propyl ester;
2-Adamantan-1-yl-N-[1-(2,5-dimethyl-phenyl)-ethyl]-acetamide;
3-Methyl-thiophene-2-carboxylic acid cyclooctylamide;
N-p-Tolyl-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup.2,7]unde-
ca-2,4,6-trien-5-ylsulfanyl)propionamide;
Azepan-1-yl-[5-(4-chloro-5-methyl-3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-
-methanone;
N-Adamantan-2-yl-3-(4-bromo-3-nitro-pyrazol-1-ylmethyl)-benzamide;
N-Bicyclo[2.2.1]hept-2-yl-2-chloro-benzamide;
[5-(3-Chloro-phenoxymethyl)-furan-2-yl]-piperidin-1-yl-methanone;
1-(4-Ethyl-benzoyl)-6-methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one;
6-Fluoro-2-methyl-1-{3-[4-(propane-1-sulfonyl)-phenoxymethyl]-benzoyl}-2,-
3-dihydro-1H-quinolin-4-one;
N-Cycloheptyl-2-(naphthalen-1-yloxy)-acetamide;
N-Cyclohexyl-4-o-tolyloxy-butyramide;
(2-Benzylsulfanyl-phenyl)-morpholin-4-yl-methanone;
(2-Chloro-5,6-difluoro-3-methyl-phenyl)-(4-methyl-piperidin-1-yl)-methano-
ne;
(3-Bromo-phenyl)-[4-(4-chloro-2-nitro-phenyl)-piperazin-1-yl]-methano-
ne; 2-Bromo-N-(1,1,3,3-tetramethyl-butyl)-benzamide;
N-Adamantan-1-yl-2-(2-benzoyl-5-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-3-methyl-4-p-tolyl-butyramide;
[5-(4-Methyl-2-nitro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methan-
one;
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-metha-
none; 5-(4-Chloro-2-nitro-phenoxymethyl)-furan-2-carboxylic acid
adamantan-1-ylamide;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
cyclohexylamide; 4-Chloro-1,5-dimethyl-1H-pyrazole-3-carboxylic
acid adamantan-1-yl-methyl-amide;
4-(4-Methoxy-3-methyl-phenyl)-N-(2-methyl-cyclohexyl)-butyramide;
3-Benzo[1,3]dioxol-5-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-propenone;
N-Bicyclo[2.2.1]hept-2-yl-3-phenylsulfanyl-propionamide;
Azepan-1-yl-[5-(2-nitro-phenoxymethyl)-furan-2-yl]-methanone;
N-Benzyl-2-(4-chloro-phenylsulfanyl)-N-methyl-acetamide;
1-(4-Benzyl-piperidin-1-yl)-2-benzylsulfanyl-ethanone;
2-(4-tert-Butyl-phenoxy)-1-(4-ethyl-piperazin-1-yl)-ethanone;
[4-(4-Ethoxy-phenoxymethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
5-(4-Bromo-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-carboxylic acid
adamantan-2-ylamide;
1-Azepan-1-yl-3-(4-chloro-phenylsulfanyl)-propan-1-one;
N-Bicyclo[2.2.1]hept-2-yl-2-(2-chloro-benzylsulfanyl)-acetamide;
2-(2-Methyl-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone;
N-[2-(1-Benzo[1,3]dioxol-5-yl-3-furan-2-yl-3-oxo-propylsulfanyl)-phenyl]--
acetamide; (3,5-Dimethyl-piperidin-1-yl)-(3-iodo-phenyl)-methanone;
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(6-fluoro-2-methyl-3,4-dihydro-2H--
quinolin-1-yl)-methanone;
N-Benzyl-N-cyclohex-1-enyl-isonicotinamide;
1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-benzylsulfanyl)-ethano-
ne;
2-(2-Bromo-4-methyl-phenoxy)-N-(2-cyclohex-1-enyl-ethyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-1-piperidin-1-yl-e-
thanone; 5-(4-Nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid
adamantan-2-ylamide;
3-Benzo[1,3]dioxol-5-yl-3-(2-methoxy-phenyl)-1-pyrrolidin-1-yl-propan-1-o-
ne; N-Adamantan-2-yl-3,4-dichloro-benzamide;
Benzo[b]thiophen-3-yl-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-me-
thanone;
2-Adamantan-1-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone;
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
(2-cyclohex-1-enyl-ethyl)-amide; Benzo[b]thiophene-3-carboxylic
acid (3,3,5-trimethyl-cyclohexyl)-amide;
2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
4-Bromo-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide;
N-Benzo[1,3]dioxol-5-ylmethyl-2-(2-cyano-phenylsulfanyl)-benzamide;
N-Adamantan-1-yl-2-(naphthalen-2-yloxy)-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-morpholin-4-yl-methanone;
Thiophene-2-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide;
Benzo[1,3]dioxol-5-yl-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid cyclooctylamide;
2-[2-Morpholin-4-yl-1-(4-nitro-benzyl)-2-oxo-ethyl]-isoindole-1,3-dione;
2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enecarboxylic acid
phenylamide;
(2,4-Dichloro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
Adamantane-1-carboxylic acid furan-2-ylmethyl-p-tolyl-amide;
Azocan-1-yl-(4-tert-butyl-phenyl)-methanone;
3-Chloro-benzo[b]thiophene-2-carboxylic acid benzyl-methyl-amide;
Adamantane-1-carboxylic acid (2-fluoro-phenyl)-amide;
2-(Piperidine-1-carbonyl)-5-piperidin-1-yl-oxazole-4-carbonitrile;
N-(4,6-Dimethyl-5-nitro-pyridin-3-yl)-benzamide;
Adamantan-1-yl-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
(2-Methyl-piperidin-1-yl)-o-tolyl-methanone;
N-Benzyl-4-chloro-N-isopropyl-3-nitro-benzamide;
N-(3-Hexylsulfanyl-[1,2,4]thiadiazol-5-yl)-3-methyl-butyramide; 4,
N-Dimethyl-N-[4-(piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;
Azepan-1-yl-(5-tert-butyl-2H-pyrazol-3-yl)-methanone;
2-Amino-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic
acid ethyl ester; 5-Methyl-furan-2-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide;
(3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2-y-
l)-methanone; N-Adamantan-1-yl-2-trifluoromethyl-benzamide;
(3-Bromo-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinolin-1-yl)--
methanone; Benzo[1,3]dioxole-5-carboxylic acid dipropylamide;
N-(3,3-Diphenyl-propyl)-4-methoxy-benzamide;
[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-p-tolyl-methanone;
Furan-2-yl-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-methanone;
3-(2-Chloro-6-fluoro-phenyl)-1-(3,4-dihydro-2H-quinolin-1-yl)-propenone;
2-Chloro-N-cycloheptyl-benzamide;
1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-3-phenyl-propan-1-one;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
(1-Adamantan-1-yl-4-bromo-1H-pyrazol-3-yl)-morpholin-4-yl-methanone;
2-Phenyl-cyclopropanecarboxylic acid cyclooctylamide;
3-[4-(2-Ethoxy-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
[3-(4-Bromo-pyrazol-1-ylmethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methano-
ne; 2-Azepan-1-yl-N-biphenyl-2-yl-acetamide;
N-[5-(3,4-Dimethoxy-benzyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-butyramide;
Adamantan-1-yl-(4-phenyl-piperidin-1-yl)-methanone;
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-ethoxy-phenyl)-4-methylsulfanyl-benzen-
esulfonamide; 1-Adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic
acid diethylamide;
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methan-
one;
3-[4-(2,3-Dimethyl-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
N-Cyclooctyl-2-(2-methoxy-phenoxy)-acetamide;
N-Cyclohexyl-N-methyl-2-nitro-benzamide; Adamantane-1-carboxylic
acid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide;
N-Adamantan-2-yl-2-(4-chloro-phenyl)-acetamide;
(2,4-Dichloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone;
2-(4-tert-Butyl-phenoxy)-N-cyclooctyl-acetamide;
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(2-methoxy-phenyl)-methanone;
(3-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-(3-methyl-piperidin-1-yl)-methan-
one; (2,5-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
N-[5-(3,4-Dichloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-propionam-
ide;
4-(4-Chloro-2-methyl-phenoxy)-1-(3,4-dihydro-2H-quinolin-1-yl)-butan-
-1-one;
(3,4-Dichloro-phenyl)-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-me-
thanone; Cyclooctanecarboxylic acid
[1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-amide;
1-Butyl-pyrrolidine-2-carboxylic acid benzo[1,3]dioxol-4-ylamide;
5-Methyl-furan-2-carboxylic acid dibenzylamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(4-phenyl-piperazine-1-sulfonyl)-phenyl-
]-methanone;
Bicyclo[2.2.1]hept-2-yl-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanon-
e; N-Adamantan-1-yl-2-benzoyl-benzamide;
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methano-
ne; (3,5-Dimethyl-piperidin-1-yl)-(2-iodo-phenyl)-methanone;
1-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyclooctylamide;
(3,4-Dimethoxy-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-m-
ethanone;
3-(2,6-Dichloro-phenyl)-1-(2-ethyl-piperidin-1-yl)-propenone;
N-(3,4-Difluoro-phenyl)-2,6-difluoro-benzamide;
2,6-Difluoro-N-naphthalen-1-yl-benzamide;
(4-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
N-[4-(2,6-Dimethyl-piperidine-1-carbonyl)-phenyl]-2-(naphthalen-2-yloxy)--
acetamide; (2-Chloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone;
N-{2-[4-(Piperidine-1-sulfonyl)-phenyl]-ethyl}-acetamide;
N-Biphenyl-2-yl-2-(pyridin-2-ylsulfanyl)-acetamide;
Azepan-1-yl-[5-(4-chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-yl]-met-
hanone; Acetic acid 4-(4-methyl-piperidine-1-carbonyl)-phenyl
ester; Acetic acid 4-(4-benzyl-piperidine-1-carbonyl)-phenyl ester;
Benzo[1,3]dioxole-5-carboxylic acid cycloheptylamide;
2-(2,4-Dimethyl-phenoxy)-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-y-
l)-ethanone; Acetic acid
4-(3,4-dihydro-2H-quinoline-1-carbonyl)-phenyl ester;
Azepan-1-yl-(3,5-dibromo-phenyl)-methanone;
(3,5-Dibromo-phenyl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
N-Cyclooctyl-4-isopropyl-benzamide;
N-Cyclooctyl-2-(4-methoxy-phenyl)-acetamide;
(4-tert-Butyl-piperidin-1-yl)-phenyl-methanone;
N-(4-tert-Butyl-3-nitro-phenyl)-acetamide;
(2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-fura-
n-2-yl]-methanone;
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamid-
e; 2-(4-Chloro-3-methyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
N-Cyclopentyl-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzenesulfonamide;
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3-dimethylamino-phenyl)-methanone;
3-Cyclohexylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid
isopropyl ester;
1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(2-methoxy-phenyl)-ethanone;
N-Benzyl-N-cyclohex-1-enyl-benzamide;
[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[-
3.2.1]oct-6-yl)-methanone;
N-Adamantan-1-yl-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(morpholine-4-sulfonyl)-phenyl]-methano-
ne;
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(pyrrolidine-1-sulfonyl)-phenyl]-me-
thanone;
(3,4-Dihydro-2H-quinolin-1-yl)-[1-(thiophene-2-sulfonyl)-piperid-
in-4-yl]-methanone;
(1-Benzenesulfonyl-piperidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-meth-
anone;
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]nonane-3-carboxylic
acid cyclohexylamide;
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]nonane-3-carboxylic
acid (2-chloro-phenyl)-amide;
(6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]non-3-yl)-piperidin-1-yl-met-
hanone;
2-(5,6-Dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulf-
anyl)-N-furan-2-ylmethyl-acetamide;
N-Allyl-2-(5,6-dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulf-
anyl)-acetamide;
N-Adamantan-1-yl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-
-ylsulfanyl)-acetamide;
1-(3,4-Dihydro-2H-quinoline-1-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[2.2-
.1]heptan-3-one;
1-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[-
2.2.1]heptan-3-one;
Azepan-1-yl-(6,7-dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]non-3-yl)-methan-
one; 2,5-Dimethyl-furan-3-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide;
1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(3-cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-amide;
2-(2-Cyano-phenylsulfanyl)-N-cyclopentyl-benzamide;
[5-(2-Methoxy-4-propyl-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-y-
l)-methanone;
(4-tert-Butyl-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[4-(2-Methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-(4-methoxy-phenyl)-m-
ethanone;
(3,4-Dichloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
(4-Ethoxy-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
2-Phenethyl-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
N-Cycloheptyl-2-phenoxy-benzamide; Adamantane-1-carboxylic acid
(2-ethoxy-phenyl)-amide; N-Adamantan-2-yl-2-o-tolyloxy-acetamide;
(2-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
1-Morpholin-4-yl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-ethanone;
2-Dimethylamino-N-(2-nitro-phenyl)-benzamide;
N-Benzyl-2-(4,4,6-trimethyl-1-p-tolyl-1,4-dihydro-pyrimidin-2-ylsulfanyl)-
-acetamide;
[4-(3,5-Dinitro-phenoxy)-phenyl]-(2-ethyl-piperidin-1-yl)-methanone;
1-(4-Chloro-benzoyl)-2,3-dihydro-1H-benzo[g]quinolin-4-one;
2-[(Adamantane-1-carbonyl)-amino]-3-phenyl-propionic acid methyl
ester; [Benzyl-(4-nitro-benzoyl)-amino]-acetic acid ethyl ester;
9-Oxo-9H-fluorene-3-carboxylic acid methyl-(4-nitro-phenyl)-amide;
Adamantane-1-carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-amide;
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(4-fluoro-phenyl)-methanone;
2-Benzylsulfanyl-N-[2-(2-methoxy-phenoxy)-ethyl]-acetamide;
N-Adamantan-1-yl-2-(2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide;
2-Bromo-N-tricyclo[3.2.1.0.sup.2,4]oct-6-ylmethyl-benzamide;
Adamantane-1-carboxylic acid (2,6-dimethoxy-pyrimidin-4-yl)-amide;
Hexanedioic acid
(2,7,7-trimethyl-bicyclo[2.2.1]hept-1-yl)-amide(1,7,7-trimethyl-bicyclo[2-
.2.1]hept-2-yl)-amide; 2-Chloro-N-(2-cyclohexyl-ethyl)-benzamide;
2-[3-(2-Ethyl-piperidin-1-yl)-3-oxo-propyl]-isoindole-1,3-dione;
N-Adamantan-1-yl-2-hydroxy-2,2-diphenyl-acetamide;
Adamantane-1-carboxylic acid (naphthalen-1-ylmethyl)-amide;
Adamantane-1-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide;
1-(Azepane-1-carbonyl)-fluoren-9-one;
2-(Quinolin-2-ylsulfanyl)-N-p-tolyl-acetamide;
2,4-Dichloro-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide;
2-Chloro-4,5-difluoro-N-(3,3,5-trimethyl-cyclohexyl)-benzamide;
2-(2-Chloro-benzylsulfanyl)-N-p-tolyl-acetamide;
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-pyrrolidin-1-yl-methanone;
N-Adamantan-1-yl-N-methyl-isonicotinamide;
Azepan-1-yl-[4-(4-chloro-phenylsulfanylmethyl)-phenyl]-methanone;
(2-Chloro-phenyl)-(1,5,7-trimethyl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-meth-
anone;
(3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperidin-1-yl)-methano-
ne; Benzoic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
2-(3-Bromo-benzylsulfanyl)-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethano-
ne;
4-Methyl-N-[2-(phenoxazine-10-carbonyl)-phenyl]-benzenesulfonamide;
2-[1-(Azepane-1-carbonyl)-2-methyl-propyl]-isoindole-1,3-dione;
2-(3-Bromo-benzylsulfanyl)-1-piperidin-1-yl-ethanone;
1-[3-(4-Bromo-phenyl)-1-furan-2-yl-3-oxo-propyl]-pyrrolidin-2-one;
2-Chloro-N-cyclooctyl-4,5-difluoro-benzamide;
2,4-Dichloro-N-(2-furan-2-ylmethyl-cyclohexyl)-benzamide;
N-(4-Benzoyl-furazan-3-yl)-2-fluoro-benzamide;
N-Adamantan-1-yl-2-(3-cyano-4-methoxymethyl-6-methyl-pyridin-2-ylsulfany)-
-acetamide; 4-tert-Butyl-N-cyclooctyl-benzamide;
N-Adamantan-1-yl-2-phenyl-butyramide;
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
(3,7-Dichloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
Acetic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
2-Bromo-N-methyl-N-phenyl-benzamide;
N-Benzo[1,3]dioxol-5-yl-2,4-dichloro-benzamide;
(3-Chloro-6-fluoro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
N-(1,2,3,5,6,7-Hexahydro-s-indacen-1-yl)-2-piperidin-1-yl-acetamide;
2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-met-
hyl-butyric acid methyl ester;
2-(6-Oxo-6-piperidin-1-yl-hexyl)-isoindole-1,3-dione;
2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-met-
hyl-butyric acid methyl ester; Adamantane-1-carboxylic acid
(2,6-dihydroxy-pyrimidin-4-yl)-amide; Adamantane-1-carboxylic acid
methyl-phenyl-amide; 3-Chloro-benzo[b]thiophene-2-carboxylic acid
dibenzylamide;
N-Adamantan-1-yl-2-(3-cyano-6-methyl-4-trifluoromethyl-pyridin-2-ylsulfan-
yl)-acetamide; 2-(3-Oxo-3-phenyl-propenyl)-isoindole-1,3-dione;
N-[5-(5-Chloro-benzooxazol-2-yl)-2-methyl-phenyl]-2-methoxy-benzamide;
N-[2-(2-Bromo-phenyl)-benzooxazol-5-yl]-2-methoxy-benzamide;
2-(4-Chloro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
2,2-Dimethyl-N-(5-propyl-[1,3,4]thiadiazol-2-yl)-propionamide;
2-[2-(2,6-Dimethyl-morpholin-4-yl)-1-methyl-2-oxo-ethyl]-isoindole-1,3-di-
one;
2-(2-Cyano-phenylsulfanyl)-N-(2-trifluoromethyl-phenyl)-benzamide;
Azepan-1-yl-(3,6-dichloro-benzo[b]thiophen-2-yl)-methanone;
Benzo[1,3]dioxol-5-yl-(4-benzyl-piperidin-1-yl)-methanone;
Azepan-1-yl-(3-chloro-6-methyl-benzo[b]thiophen-2-yl)-methanone;
N-(5-Hexyl-[1,3,4]thiadiazol-2-yl)-isobutyramide;
(3-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
(2-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
2-Amino-5-(azepane-1-carbonyl)-4-methyl-thiophene-3-carboxylic acid
ethyl ester;
Adamantan-1-yl-(4-cyclopropyl-1,4,6,7-tetrahydro-imidazo[4,5-c]py-
ridin-5-yl)-methanone;
Adamantan-1-yl-(4-trifluoromethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridi-
n-5-yl)-methanone;
Adamantan-1-yl-[4-(1H-benzoimidazol-2-ylsulfanyl)-piperidin-1-yl]-methano-
ne;
Adamantan-1-yl-(1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methan-
one;
[4-(1H-Imidazol-4-yl)-piperidin-1-yl]-(4-pentyl-phenyl)-methanone;
3-Cyclohexyl-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one;
1-(4-Propyl-piperazin-1-yl)-3-(4-trifluoromethyl-phenyl)-propan-1-one;
N-(2-Hydroxy-benzyl)-3-thiophen-3-yl-N-(2-thiophen-2-yl-ethyl)-acrylamide-
;
N-(1,3-Dimethyl-pentyl)-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetam-
ide;
N-Cyclobutyl-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Cyclobutyl-N-(4-hydroxy-benzyl)-4-trifluoromethyl-benzamide;
N-(3-Hydroxy-benzyl)-2-methyl-3-nitro-N-(4-sulfamoyl-benzyl)-benzamide;
N-(4-Bromo-benzyl)-N-(4-hydroxy-benzyl)-2-naphthalen-1-yl-acetamide;
6-(2-Bromo-phenylsulfanyl)-hexanoic acid
(3-amino-2,2-dimethyl-propyl)-amide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[2-(2-isopropyl-phenylsulfanyl)-ethyl]--
benzamide;
N-(3-Amino-2,2-dimethyl-propyl)-4-[4-(4-chloro-phenyl)-pyrimidin-2-ylsulf-
anylmethyl]-3-nitro-benzamide;
4-(4-Bromo-phenyl)-N-(2-hydroxy-benzyl)-4-oxo-N-thiophen-2-ylmethyl-butyr-
amide;
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N-(4-hydroxy-benzyl)-2-thiophen--
3-yl-acetamide;
N-(2-Chloro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-2-yl-acetamide;
Heptanoic acid benzyl-(4-hydroxy-benzyl)-amide;
N-(4-Fluoro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide;
4-Methyl-pentanoic acid (4-fluoro-benzyl)-(4-hydroxy-benzyl)-amide;
N-Allyl-2-(4-chloro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
N-Allyl-2-benzo[b]thiophen-3-yl-N-(4-hydroxy-benzyl)-acetamide;
Heptanoic acid (3-ethoxy-propyl)-(4-hydroxy-benzyl)-amide;
Dec-3-enoic acid
(4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide;
6-Oxo-6-phenyl-hexanoic acid
(4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide;
2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetam-
ide; 2-Methyl-pent-4-enoic acid
(3-hydroxy-benzyl)-[2-(2-methoxy-phenyl)-ethyl]-amide; Heptanoic
acid (3-hydroxy-benzyl)-(4-isopropyl-benzyl)-amide;
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid
(naphthalen-1-ylmethyl)-amide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(5-methyl-1H-benzoimi-
dazol-2-ylsulfanyl)ethyl]-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-phenoxy-pyrimidin--
2-ylsulfanyl)-ethyl]-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfa-
nyl)-ethyl]-benzamide;
4-(2,6-Dichloro-phenylsulfanyl)-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylme-
thyl)-butyramide;
5-(3-Methylsulfanyl-[1,2,4]thiadiazol-5-ylsulfanyl)-pentanoic acid
(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amide;
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid
[2-(3-trifluoromethyl-phenyl)-ethyl]-amide;
4-[2-(2,6-Dichloro-phenylsulfanyl)-ethyl]-N-[2-(2-fluoro-phenyl)-ethyl]-b-
enzamide; 2-Cyclohexylamino-thiazole-4-carboxylic acid
(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(3-chloro-4-hydroxy-phenyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1,2-dimethyl-propyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1-ethyl-propyl)-amide; 2-Cyclohexylamino-thiazole-4-carboxylic
acid [3-(1-hydroxy-ethyl)-phenyl]-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1-ethynyl-cyclohexyl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(2-methoxy-dibenzofuran-3-yl)-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
[2-(4-hydroxy-phenyl)-ethyl]-amide;
2-Cyclohexylamino-thiazole-4-carboxylic acid
(4-hydroxy-cyclohexyl)-amide;
2-(2,6-Difluoro-benzylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-aceta-
mide;
4-{4-[2-(4-Dimethylamino-phenyl)-acetyl]-piperazin-1-yl}-3-(2-pheny-
l-propylamino)-benzamide;
2-(2-Ethyl-phenylsulfanyl)-3-[methyl-(2-pyridin-4-yl-ethyl)-amino]-N-prop-
-2-ynyl-propionamide; 4-Methyl-cyclohexanecarboxylic acid
{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-prop-2-yny-
l-amide;
2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylc-
arbamoyl]-methyl}-N-(2-methoxyethyl)-acetamide;
4-[2-(5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-ethyl]--
N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-benzamide;
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-2-p-tolyloxy-acetamide;
Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid
[4-(2,5-difluoro-phenoxy)-butyl]-amide;
4-Trifluoromethyl-cyclohexanecarboxylic acid
[6-(2,6-difluoro-phenoxy)-hexyl]-amide;
N-Cyclopropyl-3-methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl-
)-benzamide;
3-Methoxy-N-(2-methoxy-ethyl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-ca-
rbonyl)-benzamide;
3-Methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-N-(tetrahydr-
o-furan-2-ylmethyl)benzamide;
3-Methoxy-N-(2-oxo-azepan-3-yl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2--
carbonyl)-benzamide;
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-N-(2-piperidin-4-yl-ethyl)-
-5-(pyridine-2-carbonyl)benzamide;
3-Methoxy-N-methyl-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-ben-
zamide;
[2-({Cyclopropyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amin-
o}-methyl)-phenoxy]-acetic acid;
(2-{[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(3-methyl-butyl)-amino]--
methyl}-phenoxy)acetic acid;
[2-({Cyclopentyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methy-
l)-phenoxy]-acetic acid;
[2-({(2-Methoxy-ethyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-
-methyl)-phenoxy]-acetic acid;
[2-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-m-
ethyl)-phenoxy]-acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-meth-
yl)-phenoxy]-acetic acid;
[2-({Cyclopropylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-
-methyl)-phenoxy]-acetic acid;
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-methyl-amino}-methyl)-ph-
enoxy]-acetic acid;
[4-(4-Hydroxy-benzyl)-piperazin-1-yl]-[3-methoxy-5-(pyridine-2-carbonyl)--
phenyl]-methanone;
{Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-aceti-
c acid;
{(3-Imidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benz-
oyl]-amino}-acetic acid;
{[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-acetic
acid;
[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(2-oxo-azepan-3-yl)-a-
mino]-acetic acid;
3-Methoxy-N-(2-methoxy-ethyl)-N-piperidin-3-ylmethyl-5-(pyridine-2-carbon-
yl)-benzamide;
4-[3-Methoxy-5-(pyridine-2-carbonyl)-benzoylamino]-piperidine-1-carboxyli-
c acid ethyl ester;
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-5-(pyridine-2-carbonyl)-be-
nzamide;
3-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]--
amino}-methyl)-benzoic acid;
3-({(3-Imidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]--
amino}-methyl)-benzoic acid;
4-Amino-N-(3-hydroxy-benzyl)-N-indan-2-yl-2-propionylamino-butyramide;
5-Amino-2-propionylamino-pentanoic acid
(3-hydroxy-benzyl)-indan-2-yl-amide;
N-Ethyl-2-hexylamino-N-(4-hydroxy-benzyl)-acetamide;
2-Hexylamino-N-(4-hydroxy-benzyl)-N-methyl-acetamide;
1-[1-(6-Phenyl-hexanoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;
1-[1-(3-Cyclohexyl-propionyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol--
2-one; N-(2-Hydroxy-benzyl)-N-isobutyl-benzamide;
N-(2-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide;
N-(4-Hydroxy-benzyl)-N-isobutyl-benzamide;
4-Hydroxy-N-(4-hydroxy-benzyl)-N-isobutyl-benzamide;
N-(4-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide;
N-(2-Ethoxy-ethyl)-4-hydroxy-N-(4-hydroxy-benzyl)-benzamide;
N-(4-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
N-(3-Hydroxy-benzyl)-N-(4-methyl-pentyl)-benzamide;
N-(3-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-(4-methyl-pentyl)-acetamide;
N-(3-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide;
N-(4-Hydroxy-benzyl)-N-(6-hydroxy-hexyl)-4-propyl-benzamide;
N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide; and
N-[2-(4-Fluoro-benzylamino)-thiazol-4-ylmethyl]-N-phenethyl-butyramide;
or a salt thereof with a pharmaceutically acceptable acid or base,
or optical isomer or mixture of optical isomers, racemic mixture,
or tautomeric forms thereof.
16. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 3, together with
one or more pharmaceutically acceptable carriers or excipients.
17. The pharmaceutical composition according to claim 16, wherein
the pharmaceutical composition is for oral, nasal, buccal,
transdermal, pulmonal or parenteral administration.
18. The pharmaceutical composition according to claim 16, wherein
the pharmaceutical composition is in unit dosage form, comprising
from about 0.05 mg to about 2000 mg/day, from about 0.1 mg to about
1000 mg, or from about 0.5 mg to about 500 mg per day of the
compound.
19. A method for the treatment, prevention and/or prophylaxis of
conditions, disorders or diseases wherein a modulation or an
inhibition of the activity of 11.beta.HSD1 is beneficial, the
method comprising administering to a subject in need thereof an
effective amount of a compound according to claim 3.
20. The method according to claim 19, wherein the treatment,
prevention and/or prophylaxis is of any conditions, disorders and
diseases that are influenced by intracellular glucocorticoid
levels.
21. The method according to claim 19 or 20, wherein the condition,
disorder or disease is the metabolic syndrome, insulin resistance,
dyslipidemia, hypertension and obesity.
22. The method according to claim 19 or 20, wherein the condition,
disorder or disease is type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG).
23. The method according to claim 19 or 20, for the delaying or
prevention of the progression from IGT to type 2 diabetes.
24. The method according to claim 19 or 20, for the delaying or
prevention of the progression of the metabolic syndrome into type 2
diabetes.
25. The method according to claim 19 or 20, wherein the condition,
disorder or disease is diabetic late complications including
cardiovascular diseases; arteriosclerosis; atherosclerosis.
26. The method according to claim 19 or 20, wherein the condition,
disorder or disease is neurodegenerative and psychiatric
disorders.
27. The method according to claim 19 or 20, for the treatment,
prevention and/or prophylaxis of adverse effects of glucocorticoid
receptor agonist treatment or therapy.
28. A compound of formula (II) ##STR258## wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl,
wherein the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.4; R.sup.2 is
hydrogen, C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl, wherein
the alkyl and aryl groups independently are optionally substituted
with one or more of R.sup.5; or R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system
containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14; R.sup.3 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl or hetaryl, wherein the alkyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently
are optionally substituted with one or more of R.sup.7; R.sup.4 and
R.sup.5 independently are hydrogen, hydroxy, oxo, cyano, halo,
methylendioxo, NR.sup.8R.sup.9, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, trihalomethyl, trihalomethyloxy,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, aryl, hetaryl, hetarylSO.sub.n,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15; R.sup.6 is oxygen,
sulphur, SO.sub.n or NR.sup.16; R.sup.7 is hydrogen, halo, hydroxy,
cyano, nitro, COOR.sup.17, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
methylendioxo, trihalomethyl, trihalomethyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.mNR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl, arylthio, hetarylthio,
R.sup.18carbonylNR.sup.8, arylSO.sub.n, hetarylSO.sub.n,
R.sup.19SO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
C.sub.1-C.sub.6alkylSO.sub.m, arylSO.sub.m,
arylC.sub.1-C.sub.6alkylSO.sub.m, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.11; or R.sup.8 and R.sup.9 together with the nitrogen to
which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from
4 to 10 carbon atoms and from 0 to 2 additional heteroatoms
selected from nitrogen, oxygen or sulfur, the ring system
optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, hydroxy, oxo, halo, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyl-oxy, NR.sup.12R.sup.13,
methylendioxo, trihalomethyl or trihalomethyloxy; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or
aryloxy; R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
CONR.sup.8R.sup.9 or COOR.sup.17; R.sup.16 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, aryloxyC.sub.1-C.sub.6alkyl,
hetaryloxyC.sub.1-C.sub.6alkyl, arylthioC.sub.1-C.sub.6alkyl or
hetarylthioC.sub.1-C.sub.6alkyl; wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.10; R.sup.17 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl or arylC.sub.1-C.sub.6alkyl; R.sup.18 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy or
R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally
substituted with R.sup.15; R.sup.19 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl; m
is 1 or 2; n is 0, 1 or 2; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
29. A compound according to claim 28, wherein R.sup.1 is
C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl,
wherein the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.4.
30. A compound according to claim 28, wherein R.sup.2 is hydrogen
or C.sub.1-C.sub.8alkyl.
31. A compound according to claim 28, wherein R.sup.1 and R.sup.2
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14.
32. A compound according to claim 28, wherein R.sup.3 is aryl or
hetaryl, wherein the aryl and hetaryl groups independently are
optionally substituted with one or more of R.sup.7.
33. A compound according to claim 28, wherein R.sup.4 and R.sup.5
independently are hydrogen, hydroxy, oxo, halo,
C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.15.
34. A compound according to claim 28, wherein R.sup.7 is hydrogen,
halo, hydroxy, cyano, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
trihalomethyl, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, R.sup.18carbonylNR.sup.8,
R.sup.19SO.sub.mNR.sup.8; wherein the aryl and hetaryl groups
independently are optionally substituted with one or more
R.sup.10.
35. A compound according to claim 28, wherein R.sup.8 and R.sup.9
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulfur,
the ring system optionally being substituted with at least one
halo, cyano, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy.
36. A compound according to claim 28, wherein R.sup.15 is
CONR.sup.8R.sup.9.
37. A compound according to claim 28, wherein R.sup.18 is
C.sub.1-C.sub.6alkyl.
38. A compound according to claim 28, which is:
(4-Tetrazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone; N-Cyclohexyl-N-methyl-2-phenoxymethyl-benzamide;
4-Amino-N-cyclohexyl-N-methyl-benzamide;
N-Cycloheptyl-N-methyl-2-phenoxymethyl-benzamide;
N-Cyclohexyl-N-methyl-benzamide;
2-Chloro-N-cyclohexyl-6-fluoro-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-trifluoromethoxy-benzamide;
N-Cyclohexyl-2,3, N-trimethyl-benzamide;
3,5-Dichloro-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-2-phenoxy-benzamide;
2,4-Bis-benzyloxy-N-cyclohexyl-N-methyl-benzamide;
2-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-phenoxy-benzamide;
4-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-phenoxymethyl-benzamide;
2-Chloro-N-cyclohexyl-N-ethyl-4-nitro-benzamide;
4-Chloro-N-cyclohexyl-N-ethyl-3-nitro-benzamide;
6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid
cyclohexyl-methyl-amide; Azepan-1-yl-(2-chloro-phenyl)-methanone;
Azepan-1-yl-(3-chloro-phenyl)-methanone;
Azepan-1-yl-phenyl-methanone;
2-(Biphenyl-4-yloxy)-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-2-(3,5-dimethoxy-phenoxy)-N-methyl-benzamide;
N-Cyclohexyl-2-(2,3-dimethoxy-phenoxy)-N-methyl-benzamide;
2,4-Dichloro-N-(3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-N-methyl-ben-
zamide; 2,4-Dichloro-N-methyl-N-(4-oxo-cyclohexyl)-benzamide;
N-Cyclohexyl-2-hydroxy-N-methyl-benzamide;
N-Cyclohexyl-3-methoxy-N-methyl-benzamide;
Benzo[1,3]dioxole-5-carboxylic acid cyclohexyl-methyl-amide;
3-Benzyloxy-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-3-hydroxy-N-methyl-benzamide;
[4-(Morpholine-4-sulfonyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]o-
ct-6-yl)-methanone;
N-Benzyl-3-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzen-
esulfonamide;
[4-Fluoro-3-(morpholine-4-sulfonyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicycl-
o[3.2.1]oct-6-yl)-methanone; Thiophene-2-sulfonic acid
[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-amide;
N-Phenyl-4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benze-
nesulfonamide;
(4-Phenoxy-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methano-
ne;
N-(2,4-Dimethyl-phenyl)-3-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
-6-carbonyl)benzenesulfonamide;
(2-Phenoxymethyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-N,N-dipropyl-benzenes-
ulfonamide; 2-Bromo-N-cyclohexyl-N-methyl-benzamide;
N-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acet-
amide;
(4-Dimethylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct--
6-yl)-methanone;
(4-Pyrrol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-met-
hanone;
(4-Imidazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone;
(4-Amino-2-methoxy-phenyl)-(trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-metha-
none;
(4-Methanesulfonyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone;
(3-Methanesulfonyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone;
(4-Benzenesulfonyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone;
Azepan-1-yl-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-methanone;
Azepan-1-yl-(4-morpholin-4-ylmethyl-phenyl)-methanone;
[4-(3-Trifluoromethyl-pyrazol-1-yl)-phenyl]-(1,3,3-trimethyl-6-aza-bicycl-
o[3.2.1]oct-6-yl)-methanone;
(4-[1,2,4]Triazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone;
(4-Pyrazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone; 2-Benzyloxymethyl-N-cyclohexyl-N-methyl-benzamide;
N-Cyclohexyl-N-methyl-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzami-
de;
5-Methyl-2-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-
-phenyl]-2,4-dihydropyrazol-3-one;
(9H-Carbazol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methano-
ne;
[4-(3,5-Dimethyl-pyrazol-1-yl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone;
Phenyl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Azepan-1-yl-(2-bromo-phenyl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2-bromo-phenyl)-methanone;
(4-Benzyl-piperidin-1-yl)-quinolin-2-yl-methanone;
(2-Methyl-piperidin-1-yl)-quinolin-2-yl-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-quinolin-2-yl-methanone;
Quinoline-2-carboxylic acid cyclohexyl-methyl-amide;
Quinolin-2-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
1-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrr-
olidine-2,5-dione;
Pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Pyridin-4-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
Pyridin-2-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(6-Pyrazol-1-yl-pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6--
yl)-methanone;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-benzoic
acid;
Imidazo[2,1-b]thiazol-6-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone;
8-(4-Dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one;
(4-Dimethylamino-phenyl)-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methano-
ne;
(4-Dimethylamino-phenyl)-(3-hydroxy-3-methyl-8-aza-bicyclo[3.2.1]oct--
8-yl)-methanone; and Trifluoro-acetic acid
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl ester; or
a salt thereof with a pharmaceutically acceptable acid or base, or
optical isomer or mixture of optical isomers, racemic mixture, or
tautomeric forms thereof.
39. A compound of formula (III): ##STR259## wherein R.sup.1 is
aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
of R.sup.6 independently; R.sup.2 is halo, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted
with one or more R.sup.7; R.sup.3 is C.sub.1-C.sub.6alkyl
optionally substituted with one or more of R.sup.8; R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.8; or R.sup.3 and
R.sup.4 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated bicyclic/bridge ring
system containing from 7 to 12 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy,
wherein the alkyl and aryl groups independently are optionally
substituted with one or more of R.sup.9; R.sup.5 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.9; R.sup.6 and R.sup.7 independently are
hydrogen, hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6-alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl,
arylC.sub.1-C.sub.6alkyloxycarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.8 and R.sup.9
independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6-alkyl, hydroxy,
oxo, cyano, NR.sup.10R.sup.11, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and
R.sup.11 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6-alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
40. A compound according to claim 39, wherein R.sup.1 is aryl or
hetaryl optionally substituted with one or more R.sup.6
independently; R.sup.2 is halo, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted
with one or more R.sup.7; R.sup.3 is C.sub.1-C.sub.6alkyl
optionally substituted with one or more of R.sup.8; R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.8; R.sup.5 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.9; R.sup.6 and R.sup.7 independently are
hydrogen, hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6-alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl,
arylC.sub.1-C.sub.6alkyloxycarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.8 and R.sup.9
independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6-alkyl, hydroxy,
oxo, cyano, NR.sup.10R.sup.11, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and
R.sup.11 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetaryl C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6-alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, a prodrug thereof, or
tautomeric forms thereof.
41. A compound according to claim 39, wherein R.sup.1 is aryl,
arylC.sub.1-C.sub.6alkyl or hetaryl optionally substituted with one
or more of R.sup.6.
42. A compound according to claim 39, wherein R.sup.2 is
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
arylC.sub.1-C.sub.6alkyl, or hetarylC.sub.1-C.sub.6alkyl wherein
the alkyl, cycloalkyl and aryl groups independently are optionally
substituted with one or more R.sup.7.
43. A compound according to claim 39, wherein R.sup.3 is
C.sub.1-C.sub.6alkyl optionally substituted with one or more of
R.sup.8.
44. A compound according to claim 39, wherein R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, or C.sub.6-C.sub.10hetcycloalkyl,
wherein the cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.3.
45. A compound according to claim 39, wherein R.sup.6 and R.sup.7
independently are hydrogen, hydroxy, oxo, halo, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl or
arylC.sub.1-C.sub.6alkyloxycarbonyl.
46. A compound according to claim 39, wherein R.sup.8 and R.sup.9
independently are hydrogen, C.sub.1-C.sub.6alkyl, hydroxy, oxo,
C.sub.1-C.sub.6alkyloxy or arylC.sub.1-C.sub.6alkyloxy.
47. A compound according to claim 39, wherein R.sup.10 and R.sup.11
independently are hydrogen or C.sub.1-C.sub.8alkyl.
48. A compound according to claim 39, which is
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide, or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, or tautomeric forms thereof.
49. A compound according to claim 39, selected from the group
consisting of:
1-(4-Chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
[1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone;
[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone; and
[1-(3,5-Dichloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-
-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
50. A compound according to claim 39, selected from the group
consisting of: 1-(Phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(2-Methyl-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(4-Amino-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide;
1-(2-Pyridyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; and
1-(2-Pyridyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, or tautomeric forms thereof.
51. A compound of formula (IV): ##STR260## wherein R.sup.1 is
hydrogen, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetaralkyl, wherein the alkyl,
aryl and hetaryl groups independently are optionally substituted
with one or more of R.sup.8; R.sup.2, R.sup.3, R.sup.4 and R.sup.5
independently are hydrogen, halo, nitro, cyano, hydroxy,
NR.sup.9R.sup.10, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetaralkyl, wherein the alkyl,
aryl and hetaryl groups independently are optionally substituted
with one or more of R.sup.8; or R.sup.2 together with R.sup.3 are
forming a saturated or partially saturated cyclic ring system
containing from 3 to 6 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.3 together with R.sup.4
are forming a saturated or partially saturated cyclic ring system
containing from 3 to 6 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.4 together with R.sup.5
are forming a saturated or partially saturated cyclic ring system
containing from 3 to 6 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.6 is aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; R.sup.7 is C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; or R.sup.6 and R.sup.7, together with
the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system
containing from 6 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6-alkylcarboxy wherein the alkyl and
aryl groups independently are optionally substituted with one or
more of R.sup.8; R.sup.9 and R.sup.10 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; or R.sup.9 and R.sup.10, together
with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8; R.sup.8 and R.sup.11 independently are
hydrogen, halo, hydroxy, oxo, nitro, cyano, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6-alkyloxy or aryloxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, a prodrug thereof, or
tautomeric forms thereof.
52. A compound according to claim 51, wherein R.sup.1 is hydrogen
or C.sub.1-C.sub.6alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.8.
53. A compound according to claim 51, wherein R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are hydrogen.
54. A compound according to claim 51, wherein R.sup.6 and R.sup.7,
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional nitrogen or oxygen atoms, the ring system optionally
being substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8.
55. A compound according to claim 51, which is:
pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; or a salt thereof with a pharmaceutically acceptable
acid or base, or optical isomer or mixture of optical isomers,
racemic mixture, a prodrug thereof, or tautomeric forms
thereof.
56. A compound according to claim 51, which is selected from:
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; and Pyrazolo[1,5-a]pyridine-3-carboxylic
acid cyclohexyl-methyl-amide; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
57. A compound of formula (V): ##STR261## wherein R.sup.1 is
hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6SO.sub.2, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or
hetarylC.sub.1-C.sub.6alkylSO.sub.2 optionally substituted with one
or more R.sup.8; R.sup.2 and R.sup.5 independently are hydrogen,
halo, nitro, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.9; and either
R.sup.3 is hydrogen; and R.sup.4 is C(O)NR.sup.7R.sup.8; or R.sup.3
is C(O)NR.sup.7R.sup.8; and R.sup.4 is hydrogen; R.sup.6 is
hydrogen, halo, cyano, trihalomethyl, NR.sup.12R.sup.13,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl,
hetaryl and hetarylalkyl groups independently are substituted with
one or more R.sup.9; and R.sup.7 and R.sup.8 independently are
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.9 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
C(O)NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and
R.sup.11 independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.8alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture, a prodrug thereof,
or tautomeric forms thereof.
58. A compound according to claim 57, of formula (Va): ##STR262##
wherein R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl optionally
substituted with one or more R.sup.8; R.sup.2 and R.sup.5
independently are hydrogen, halo, nitro, cyano, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl,
hetaryl and hetarylalkyl groups independently are substituted with
one or more R.sup.8; and either R.sup.3 is hydrogen; and R.sup.4 is
C(O)NR.sup.6R.sup.7; or R.sup.3 is C(O)NR.sup.6R.sup.7; and R.sup.4
is hydrogen; R.sup.6 and R.sup.7 independently are
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.6 and R.sup.7
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10; R.sup.8 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.11R.sup.12,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.9 and R.sup.10 independently
are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.11 and
R.sup.12 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carboxyC.sub.1-C.sub.6alkyl; or R.sup.11 and
R.sup.12 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture, a prodrug thereof,
or tautomeric forms thereof.
59. A compound according to claim 57, wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or
hetarylC.sub.1-C.sub.6alkylSO.sub.2 all of which is optionally
substituted with one or more R.sup.8.
60. A compound according to claim 57, wherein R.sup.2 and R.sup.5
are hydrogen.
61. A compound according to claim 57, wherein R.sup.3 is hydrogen
and R.sup.4 is C(O)NR.sup.7R.sup.8.
62. A compound according to claim 57, wherein R.sup.3 is
C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen.
63. A compound according to claim 57, wherein R.sup.6 is hydrogen,
NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl or hetaryl wherein
the alkyl, aryl and hetaryl independently are substituted with one
or more R.sup.9.
64. A compound according to claim 57, wherein R.sup.7 and R.sup.8
independently are C.sub.1-C.sub.8alkyl or
C.sub.3-C.sub.10cycloalkyl, wherein the alkyl and cycloalkyl groups
independently are optionally substituted with one or more of
R.sup.10.
65. A compound according to claim 57, wherein R.sup.9 is hydrogen,
hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.12R.sup.13, C(O)NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl.
66. A compound according to claim 57, wherein R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl.
67. A compound according to claim 57, which is:
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide, or a
salt thereof with a pharmaceutically acceptable acid or base, or
optical isomer or mixture of optical isomers, racemic mixture, a
prodrug thereof, or tautomeric forms thereof.
68. A compound according to claim 57, selected from the group
consisting of: 1-Benzyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; and
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone; or a salt thereof with a pharmaceutically acceptable acid
or base, or optical isomer or mixture of optical isomers, racemic
mixture, a prodrug thereof, or tautomeric forms thereof.
69. A compound according to claim 57, selected from the group
consisting of:
Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; 1-Benzyl-1H-benzoimidazole-5-carboxylic
acid cyclohexyl-methyl-amide;
2-Methyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide;
2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide;
2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide;
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone;
(2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[-
3.2.1]oct-6-yl)-methanone;
(2-Amino-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct--
6-yl)-methanone;
(2-Benzo[1,3]dioxol-5-yl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzoimid-
azol-2-yl]-benzoic acid methyl ester;
(2-Thiophen-2-yl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.-
2.1]oct-6-yl)-methanone; and
[2-(2-Nitro-phenyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, a prodrug thereof, or
tautomeric forms thereof.
70. A compound of formula (VI): ##STR263## wherein X is oxygen or
(CR.sup.1R.sup.2).sub.n; R.sup.1, R.sup.2, R.sup.3, and R.sup.4
independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more R.sup.8 independently; or
R.sup.1 and either R.sup.3 or R.sup.4 together are forming a
saturated or partially saturated ring system containing from 4 to 8
carbon atoms, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.6alkyl, hydroxy, oxo, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl; or R.sup.1
and either R.sup.3 or R.sup.4 together with the single bond are
forming a carbon-carbon double bond; R.sup.5 is
C.sub.1-C.sub.8alkyl optionally substituted with one or more of
R.sup.9; R.sup.6 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.5 and R.sup.6
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10; R.sup.7 is hydrogen, halo, nitro,
NR.sup.12R.sup.13, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
hetaryloxy or hetarylC.sub.1-C.sub.6-alkyloxy optionally
substituted with one or more R.sup.11 independently; R.sup.8 and
R.sup.9 independently are hydrogen, hydroxy, oxo, halo, nitro,
cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy;
R.sup.11 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy or
hetaryloxy; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6alkyloxycarbonyl; or R.sup.12 and R.sup.13 are
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6alkylcarboxy; n is 1 or 2; or a salt
thereof with a pharmaceutically acceptable acid or base, or optical
isomer or mixture of optical isomers, racemic mixture, a prodrug
thereof, or tautomeric forms thereof.
71. A compound according to claim 70, wherein X is
(CR.sup.1R.sup.2).sub.n.
72. A compound according to claim 70, wherein X is oxygen.
73. A compound according to claim 70, wherein R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 independently are hydrogen,
C.sub.1-C.sub.6alkyl or arylC.sub.1-C.sub.6alkyl, optionally
substituted with one or more R.sup.8.
74. A compound according to claim 70, wherein R.sup.1 and either
R.sup.3 or R.sup.4 together with the single bond are forming a
carbon-carbon double bond.
75. A compound according to claim 70, wherein R.sup.5 is
C.sub.1-C.sub.8alkyl optionally substituted with one or more of
R.sup.9.
76. A compound according to claim 70, wherein R.sup.6 is
C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10hetcycloalkyl, each
of which is optionally substituted with one or more of R.sup.9.
77. A compound according to claim 70, wherein R.sup.5 and R.sup.6
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10.
78. A compound according to claim 70, wherein R.sup.7 is hydrogen,
halo, NR.sup.12R.sup.13, trihalomethyl, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryloxy optionally
substituted with one or more R.sup.11 independently.
79. A compound according to claim 70, wherein R.sup.8 and R.sup.9
independently are hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl or
NR.sup.12R.sup.13.
80. A compound according to claim 70, wherein R.sup.10 is hydrogen
or C.sub.1-C.sub.8alkyl.
81. A compound according to claim 70, selected from the group
consisting of: 2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide;
2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; Benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; 2,3-Dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; and Chroman-8-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.
82. A compound according to claim 70, selected from the group
consisting of: 2,3-Dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; Benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone;
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide;
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; and Chroman-8-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.
83. A compound of formula (VII): ##STR264## wherein R.sup.1 is
hydrogen, C.sub.1-C.sub.8alkyl, hetaryl, arylC.sub.1-C.sub.6alkyl
or hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or
more R.sup.9; R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
independently are hydrogen, halo, nitro, cyano, trihalomethyl,
carboxy, N(R.sup.12R.sup.13), C(O)NR.sup.7R.sup.8,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl wherein the
alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.9; R.sup.7 is
hydrogen or C.sub.1-C.sub.8alkyl optionally substituted with one or
more of R.sup.10; R.sup.8 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.9 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl wherein the
alkyl and aryl groups independently are optionally substituted with
one or more of R.sup.11, wherein R.sup.11 is as defined above; or
R.sup.12 and R.sup.13 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic,
bicyclic or tricyclic ring system containing from 4 to 10 carbon
atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture, a prodrug thereof,
or tautomeric forms thereof.
84. A compound according to claim 83, wherein R.sup.1 is hydrogen,
C.sub.1-C.sub.8alkyl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.9; R.sup.2 and R.sup.5 independently are hydrogen, halo,
nitro, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6-alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl,
hetaryl and hetarylalkyl groups independently are substituted with
one or more R.sup.9; and either R.sup.3 is C(O)NR.sup.7R.sup.8, and
R.sup.4 is hydrogen; or R.sup.3 is hydrogen, and R.sup.4 is
C(O)NR.sup.7R.sup.8; R.sup.6 is C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6-alkyl,
aryloxyC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl; R.sup.7 is
C.sub.1-C.sub.8alkyl optionally substituted with one or more of
R.sup.10; R.sup.8 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.9 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl; or R.sup.12
and R.sup.13 together with the nitrogen to which they are attached,
are forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
85. A compound according to claim 83, wherein R.sup.2 is
C(O)NR.sup.7R.sup.8 and R.sup.3, R.sup.4, and R.sup.5 are
hydrogen.
86. A compound according to claim 83, wherein R.sup.3 is
C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen.
87. A compound according to claim 83, wherein R.sup.4 is
C(O)NR.sup.7R.sup.8 and R.sup.3 is hydrogen.
88. A compound according to 83, wherein R.sup.5 is
C(O)NR.sup.7R.sup.8 and R.sup.2, R.sup.3, and R.sup.4 are
hydrogen.
89. A compound according to claim 83, wherein R.sup.6 is
C(O)NR.sup.7R.sup.8.
90. A compound according to claim 83, selected from the group
consisting of:
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-metha-
none; and 1H-Indole-6-carboxylic acid cyclohexyl-methyl-amide; or a
salt thereof with a pharmaceutically acceptable acid or base, or
optical isomer or mixture of optical isomers, racemic mixture, a
prodrug thereof, or tautomeric forms thereof.
91. A compound according to claim 83, selected from the group
consisting of:
(1H-Indol-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-metha-
none;
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-meth-
anone; 1H-Indole-6-carboxylic acid adamantan-2-ylamide;
(6-Aza-bicyclo[3.2.1]oct-6-yl)-(1H-indol-6-yl)-methanone;
1H-Indole-6-carboxylic acid
(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;
1H-Indole-5-carboxylic acid adamantan-2-ylamide;
(6-Aza-bicyclo[3.2.1]oct-6-yl)-(1H-indol-5-yl)-methanone;
(1H-Indol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(1H-Indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone-
;
(1H-Indol-2-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanon-
e;
(1-Methyl-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-indol-3-yl)-methanone;
1-Methyl-1H-indole-3-carboxylic acid cycloheptylamide;
1-Methyl-1H-indole-3-carboxylic acid adamantan-1-ylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1-methyl-1H-indol-3-yl)-methanone;
(1-Methyl-1H-indol-3-yl)-(4-methyl-piperazin-1-yl)-methanone;
1-Methyl-1H-indole-3-carboxylic acid
(3-hydroxy-adamantan-1-yl)-amide; 1-Methyl-1H-indole-3-carboxylic
acid azepan-1-ylamide; 1-Methyl-1H-indole-3-carboxylic acid
(2-oxo-azepan-3-yl)-amide;
(4-Benzyl-piperidine-1-yl)-(1-methyl-1H-indol-3-yl)-methanone;
1-Methyl-1H-indole-3-carboxylic acid
(2,6-dimethyl-piperidin-1-yl)-amide;
1-Methyl-1H-indole-3-carboxylic acid
(2-methyl-piperidin-1-yl)-amide;
(1-Cyclopropylmethyl-6-fluoro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyc-
lo[3.2.1]oct-6-yl)-methanone;
Azepan-1-yl-(1-methyl-1H-indol-3-yl)-methanone;
(5-Benzyloxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone;
(5H-[1,3]Dioxolo[4,5]indol-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone;
(5-Chloro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
(6-Trifluoromethyl-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicycl-
o[3.2.1]oct-6-yl)-methanone;
(6-Methyl-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
(6-Nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oc-
t-6-yl)-methanone;
(5-Methoxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)--
methanone;
(6-Fluoro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
(6-Methoxy-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]-
oct-6-yl)-methanone;
(7-Nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone;
(1H-Indol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
2-(1H-Indol-3-yl)-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6--
yl)-ethanone;
1-(3-Aza-bicyclo[3.2.2]non-3-yl)-2-(1H-indol-3-yl)-ethanone;
1-(3-Aza-bicyclo[3.2.2]non-3-yl)-2-(1-methyl-1H-indol-3-yl)-ethanone;
2-(1-Methyl-1H-indol-3-yl)-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-y-
l)-ethanone;
[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-6-ylo-
xy]-acetic acid tert-butyl ester;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid ethyl ester;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid ethyl ester;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid ethyl ester;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid ethyl ester;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid;
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid ethyl ester;
[3-(Piperidine-1-carbonyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[-
3.2.1]oct-6-yl)-methanone;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid cyanomethyl-amide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid benzylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid dimethylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid allylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (2-dimethylamino-ethyl)-methyl-amide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (2-methoxy-ethyl)-amide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid 4-methoxy-benzylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
[3-(2-Methoxymethyl-pyrrolidine-1-carbonyl)-1H-indol-5-yl]-(1,3,3-trimeth-
yl-6-aza-bicyclo-[3.2.1]oct-6-yl)-methanone;
[3-(2,6-Dimethyl-morpholine-4-carbonyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-
-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid 4-trifluoromethyl-benzylamide;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (furan-2-ylmethyl)-amide;
[3-(2,3,5,6-Tetrahydro-[1,2']bipyrazinyl-4-carbonyl)-1H-indol-5-yl]-(1,3,-
3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (2H-tetrazol-5-ylmethyl)-amide;
[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-5-yl]-
-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
3-{[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-
-carbonyl]-amino}-propionic acid ethyl ester;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid (4-methoxy-phenyl)-amide;
3-{[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-
-carbonyl]-amino}-propionic acid;
Azepan-1-yl-(1H-indol-5-yl)-methanone; 1H-Indole-5-carboxylic acid
dibenzylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-indol-5-yl)-methanone;
(4-Benzyl-piperidin-1-yl)-(1H-indol-5-yl)-methanone;
8-(1H-Indole-5-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;
[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-(1H-indol-5-yl)-methanone;
1-[1-(1H-Indole-5-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2--
one; (4-tert-Butyl-piperidin-1-yl)-(1H-indol-5-yl)-methanone;
1-(1H-Indole-5-carbonyl)-4-phenyl-piperidine-4-carbonitrile;
(1H-Indol-5-yl)-(4-phenyl-piperidin-1-yl)-methanone;
(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1H-indol-5-yl)-methanone;
(1H-Indol-5-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
1H-Indole-5-carboxylic acid
(5-hydroxy-1,3,3-trimethyl-cyclohexylmethyl)-amide;
1H-Indole-5carboxylic acid
(3,4-dihydrospiro(1H-indene-1,4-piperidine)-amide;
(3-Methanesulfonylmethyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.-
2.1]oct-6-yl)-methanone;
(3-Dimethylaminomethyl-1H-indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.-
1]oct-6-yl)-methanone;
1-{3-Acetyl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)--
1H-indol-3-yl]-2,3-dihydro-imidazol-1-yl}-ethanone;
1-Ethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-i-
ndol-3-yl]-pyrrolidine-2,5-dione;
(3-Thiazol-2-yl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone;
(3-Iodo-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-met-
hanone;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indo-
le-3-carbonitrile;
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
bonitrile;
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
boxylic acid amide;
[3-(2H-Tetrazol-5-yl)-1H-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1-
]oct-6-yl)-methanone;
N-[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-7-y-
l]-acetamide;
(1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oc-
t-6-yl)-methanone;
(1-Benzenesulfonyl-2-methyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone;
(1-methyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-m-
ethanone;
(1-Benzyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]o-
ct-6-yl)-methanone;
[6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-ac-
etic acid ethyl ester;
[1-(2-Ethoxy-ethyl)-1H-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]o-
ct-6-yl)-methanone;
{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-indol-6-yl}-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
propionic acid ethyl ester;
(1-Phenethyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone;
[1-(Tetrahydro-furan-2-ylmethyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone;
2-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]--
acetamide;
[1-(4-Trifluoromethoxy-benzyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bicy-
clo[3.2.1]oct-6-yl)-methanone;
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzoic acid methyl ester; and
4-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-ylme-
thyl]-benzonitrile; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, or tautomeric forms thereof.
92. A compound of formula (VIII): ##STR265## wherein X is NR.sup.4,
S or O; R.sup.1 and R.sup.2 independently are hydrogen, halo,
cyano, trihalomethyl, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6alkyloxy, wherein the alkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.3 is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the
alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups
independently are optionally substituted with one or more of
R.sup.7; R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently
are optionally substituted with one or more of R.sup.7; R.sup.5 is
hydrogen, and R.sup.6 is adamantyl optionally substituted with
hydroxy, C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.7; or R.sup.5 and R.sup.6 are together with the nitrogen to
which they are attached, forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7; R.sup.7 are independently hydrogen, halo,
hydroxy, oxo, nitro, NR.sup.9R.sup.10, cyano, COOR.sup.8,
CONR.sup.9R.sup.10, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.8 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl,
wherein the alkyl, aryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.9 and
R.sup.10 independently are hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; or R.sup.9 and R.sup.10
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.11 is hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; provided that hetcycloalkyl is not
7-aza[2,2,1]bicycloheptane; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
93. A compound according to claim 92, wherein X is NR.sup.4, S or
O; R.sup.1 and R.sup.2 independently are hydrogen, halo, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy,
wherein the alkyl groups independently are optionally substituted
with one or more of R.sup.7; R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylthio, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the
alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups
independently are optionally substituted with one or more of
R.sup.7; R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6-alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently
are optionally substituted with one or more of R.sup.7; R.sup.5 is
hydrogen, and R.sup.6 is adamantyl optionally substituted with
hydroxy, C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.7; or R.sup.5 and R.sup.6 are together with the nitrogen to
which they are attached, forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7; R.sup.7 are independently hydrogen, halo,
hydroxy, oxo, nitro, NR.sup.5R.sup.6, cyano, COOR.sup.8,
CONR.sup.5R.sup.6, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy,
aryloxy or hetaryloxy; R.sup.8 is hydrogen, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, wherein the alkyl,
aryl and hetarylalkyl groups independently are optionally
substituted with one or more of R.sup.7; provided that
hetcycloalkyl is not 7-aza[2,2,1]bicycloheptane; or a salt thereof
with a pharmaceutically acceptable acid or base, or optical isomer
or mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
94. A compound according to claim 92, wherein X is NR.sup.4 or
S.
95. A compound according to claim 92, wherein R.sup.1 and R.sup.2
independently are hydrogen, halo, trihalomethyl or
C.sub.1-C.sub.6alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.7 wherein R.sup.7.
96. A compound according to claim 92, wherein R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6-alkyl, hetaryl or
hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with
one or more of R.sup.7 wherein R.sup.7.
97. A compound according to claim 92, wherein R.sup.4 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl, wherein the alkyl, aryl, hetaryl, groups
independently are optionally substituted with one or more of
R.sup.7 wherein R.sup.7.
98. A compound according to claim 92, wherein R.sup.5 and R.sup.6
are together with the nitrogen to which they are attached, forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylalkyl, hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7.
99. A compound according to claim 92, which is selected from:
(4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone;
(2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; and
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; or a salt thereof with a pharmaceutically
acceptable acid or base, or optical isomer or mixture of optical
isomers, racemic mixture, a prodrug thereof, or tautomeric forms
thereof.
100. A compound according to claim 92, selected from the group
consisting of:
[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethy-
l-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thiazol-5-yl)-methanone;
(1H-Imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methano-
ne;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-metha-
none; 2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide;
Azepan-1-yl-(2,4-dimethyl-thiazol-5-yl)-methanone;
2,4-Dimethyl-thiazole-5-carboxylic acid adamantan-1-ylamide;
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-imidazol-4-yl)-methanone;
2,4-Dimethyl-thiazole-5-carboxylic acid
(3-hydroxy-adamantan-1-yl)-amide;
(1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-y-
l)-methanone;
[1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyc-
lo[3.2.1]oct-6-yl)-methanone; and
[1-(4-Chloro-benzyl)-5-methyl-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or optical isomer or
mixture of optical isomers, racemic mixture, or tautomeric forms
thereof.
101. A compound according to any one of claims 28, 38, 39, 48, 49,
50, 51, 55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99
or 100, which is an agent useful for the treatment, prevention
and/or prophylaxis of any conditions, disorders and diseases
wherein a modulation or an inhibition of the activity of
11.beta.HSD1 is beneficial.
102. A compound according to any one of claims 28, 38, 39, 48, 49,
50, 51, 55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83, 90, 91, 92, 99
or 100, which is an agent useful for the treatment, prevention
and/or prophylaxis of any conditions, disorders and diseases that
are influenced by intracellular glucocorticoid levels.
103. A compound according to claim 101 or 102, which is an agent
useful for the treatment, prevention and/or prophylaxis of
conditions, disorders or diseases selected from the group
consisting of the metabolic syndrome, insulin resistance,
dyslipidemia, hypertension and obesity.
104. A compound according to claim 101 or 102, which is an agent
useful for the treatment, prevention and/or prophylaxis of type 2
diabetes, impaired glucose tolerance (IGT), impaired fasting
glucose (IFG).
105. A compound according to claim 101 or 102, which is an agent
useful for the delaying or prevention of the progression from IGT
into type 2 diabetes.
106. A compound according to claim 101 or 102, which is an agent
useful for delaying or prevention of the progression of the
metabolic syndrome into type 2 diabetes.
107. A compound according to claim 101 or 102, which is an agent
useful for the treatment, prevention and/or prophylaxis of adverse
effects of glucocorticoid receptor agonist treatment or
therapy.
108. A pharmaceutical composition comprising, as an active
ingredient, at least one compound according to any one of claims
28, 38, 39, 48, 49, 50, 51, 55, 56, 57, 58, 67, 68, 69, 70, 81, 82,
83, 90, 91, 92, 99 or 100, together with one or more
pharmaceutically acceptable carriers or excipients.
109. The pharmaceutical composition according to claim 108 which is
for oral, nasal, buccal, transdermal, pulmonal or parenteral
administration.
110. The pharmaceutical composition according to claim 108 or 109,
in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from
0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the
compound.
111. A method for the treatment, prevention and/or prophylaxis of
any conditions, disorders or diseases wherein a modulation or an
inhibition of the activity of 11.beta.HSD1 is beneficial, the
method comprising administering to a subject in need thereof an
effective amount of a compound according to any one of claims 28,
38, 39, 48, 49, 50, 51, 55, 56, 57, 58, 67, 68, 69, 70, 81, 82, 83,
90, 91, 92, 99 or 100.
112. The method according to claim 111, wherein the conditions,
disorders or diseases are selected from the group consisting of the
metabolic syndrome, insulin resistance, dyslipidemia, hypertension
and obesity.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/265,794 filed Oct. 11, 2005, which is a continuation of
International Application No. PCT/DK2004/000250, filed Apr. 6,
2004, which claims priority from Danish Patent Application Nos. PA
2003 00565, filed Apr. 11, 2003; PA 2003 00972, filed Jun. 27,
2003; PA 2003 00988, filed Jun. 30, 2003; PA 2003 00989, filed Jun.
30, 2003; PA 2003 00990, filed Jun. 30, 2003; PA 2003 00998, filed
Jul. 2, 2003; PA 2003 01910, filed Dec. 22, 2003; and PA 2004
00009, filed Jan. 6, 2004; and U.S. Patent Application Nos.
60/467,800, filed May 2, 2003; 60/486,095, filed Jul. 10, 2003;
60/486,097, filed Jul. 10, 2003; 60/486,094, filed Jul. 10, 2003;
60/486,078, filed Jul. 10, 2003; 60/486,098, filed Jul. 10, 2003;
and 60/537,099, filed Jan. 16, 2004.
FIELD OF INVENTION
[0002] The present invention relates to use of substituted amides
and pharmaceutical compositions comprising the compounds for
treating disorders where it is desirable to modulate the activity
of 11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1).
[0003] The present invention also relates to novel substituted
amides, to their use in therapy, to pharmaceutical compositions
comprising the compounds, to the use of said compounds in the
manufacture of medicaments, and to therapeutic methods comprising
the administration of said compounds. The present compounds
modulate the activity of 11.beta.-hydroxysteroid dehydrogenase type
1 (11.beta.HSD1) and are accordingly useful in the treatment of
diseases in which such a modulation is beneficial, such as the
metabolic syndrome.
BACKGROUND OF THE INVENTION
[0004] The metabolic syndrome is a major global health problem. In
the US, the prevalence in the adult population is currently
estimated to be approximately 25%, and it continues to increase
both in the US and worldwide. The metabolic syndrome is
characterised by a combination of insulin resistance, dyslipidemia,
obesity and hypertension leading to increased morbidity and
mortality of cardiovascular diseases. People with the metabolic
syndrome are at increased risk of developing frank type 2 diabetes,
the prevalence of which is equally escalating.
[0005] In type 2 diabetes, obesity and dyslipidemia are also highly
prevalent and around 70% of people with type 2 diabetes
additionally have hypertension once again leading to increased
mortality of cardiovascular diseases.
[0006] In the clinical setting, it has long been known that
glucocorticoids are able to induce all of the cardinal features of
the metabolic syndrome and type 2 diabetes.
[0007] 11.beta.-hydroxysteroid dehydrogenase type 1 (11.beta.HSD1)
catalyses the local generation of active glucocorticoid in several
tissues and organs including predominantly the liver and adipose
tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium,
ocular tissue and certain parts of the central nervous system.
Thus, 11.beta.HSD1 serves as a local regulator of glucocorticoid
actions in the tissues and organs where it is expressed (Tannin et
al., J. Biol. Chem., 266, 16653 (1991); Bujalska et al.,
Endocrinology, 140, 3188 (1999); Whorwood et al., J Clin Endocrinol
Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000);
Davani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al.,
Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis.
Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450
(1990)).
[0008] The role of 11.beta.HSD1 in the metabolic syndrome and type
2 diabetes is supported by several lines of evidence. In humans,
treatment with the non-specific 11.beta.HSD1 inhibitor
carbenoxolone improves insulin sensitivity in lean healthy
volunteers and people with type 2 diabetes. Likewise, 11.beta.HSD1
knock-out mice are resistant to insulin resistance induced by
obesity and stress. Additionally, the knock-out mice present with
an anti-atherogenic lipid profile of decreased VLDL triglycerides
and increased HDL-cholesterol. Conversely, mice that overexpress
11.beta.HSD1 in adipocytes develop insulin resistance,
hyperlipidemia and visceral obesity, a phenotype that resembles the
human metabolic syndrome (Andrews et al., J. Clin. Endocrinol.
Metab., 88, 285 (2003); Walker et al., J. Clin. Endocrinol. Metab.,
80, 3155 (1995); Morton et al., J. Biol. Chem., 276, 41293 (2001);
Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997);
Masuzaki et al., Science, 294, 2166 (2001)).
[0009] The more mechanistic aspects of 11.beta.HSD1 modulation and
thereby modulation of intracellular levels of active glucocorticoid
have been investigated in several rodent models and different
cellular systems. 11.beta.HSD1 promotes the features of the
metabolic syndrome by increasing hepatic expression of the
rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate
carboxykinase and glucose-6-phosphatase, promoting the
differentiation of preadipocytes into adipocytes thus facilitating
obesity, directly and indirectly stimulating hepatic VLDL
secretion, decreasing hepatic LDL uptake and increasing vessel
contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94,
14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001);
Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al.,
Steroids, 67, 195 (2002), Brindley & Salter, Prog. Lipid Res.,
30, 349 (1991)).
[0010] WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO
01/90094 discloses various thiazol-sulfonamides as inhibitors of
the human 11.beta.-hydroxysteroid dehydrogenase type 1 enzyme, and
further states that said compounds may be useful in treating
diabetes, obesity, glaucoma, osteoporosis, cognitive disorders,
immune disorders and depression.
[0011] We have now found substituted amides that modulate the
activity of 11.beta.HSD1 leading to altered intracellular
concentrations of active glucocorticoid. More specifically, the
present compounds inhibit the activity of 11.beta.HSD1 leading to
decreased intracellular concentrations of active glucocorticoid.
Thus, the present compounds can be used to treat disorders where a
decreased level of active intracellular glucocorticoid is
desirable, such as e.g. the metabolic syndrome, type 2 diabetes,
impaired glucose tolerance (IGT), impaired fasting glucose (IFG),
dyslipidemia, obesity, hypertension, diabetic late complications,
cardiovascular diseases, arteriosclerosis, atherosclerosis,
myopathy, muscle wasting, osteoporosis, neurodegenerative and
psychiatric disorders, and adverse effects of treatment or therapy
with glucocorticoid receptor agonists.
[0012] One object of the present invention is to provide compounds,
pharmaceutical compositions and use of compounds that modulate the
activity of 11.beta.HSD1.
DEFINITIONS
[0013] In the following structural formulas and throughout the
present specification, the following terms have the indicated
meaning:
[0014] The term "halo" includes fluorine, chlorine, bromine, and
iodine.
[0015] The term "trihalomethyl" includes trifluoromethyl,
trichloromethyl, tribromomethyl, and triiodomethyl.
[0016] The term "trihalomethoxy" includes trifluorometoxy,
trichlorometoxy, tribromometoxy, and triiodometoxy.
[0017] The term "alkyl" includes C.sub.1-C.sub.8 straight chain
saturated and methylene aliphatic hydrocarbon groups,
C.sub.3-C.sub.8 branched saturated hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
shall include but is not limited to methyl (Me), ethyl (Et), propyl
(Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu),
tert-butyl (t-Bu), secbutyl (s-Bu), isopentyl, neopentyl, and the
like.
[0018] The term "alkenyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and branched
C.sub.3-C.sub.6 unsaturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
shall include but is not limited to ethenyl, propenyl, butenyl,
pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
[0019] The term "alkynyl" includes C.sub.2-C.sub.6 straight chain
unsaturated aliphatic hydrocarbon groups and C.sub.4-C.sub.6
branched unsaturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, this definition
shall include but is not limited to ethynyl, propynyl, butynyl,
pentynyl, hexynyl, methylbutynyl, and the like.
[0020] The term "saturated or partially saturated cyclic, bicyclic
or tricyclic ring system" represents but are not limit to
aziridinyl, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl,
2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl,
piperidinyl, thiomorpholinyl, piperazinyl, phthalimide,
1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl,
1,2,3,4-tetrahydro-quinoxalinyl, indolinyl,
1,6-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[4.1.1]octane,
2-aza-bicyclo[3.2.1]octanyl, 7-aza-bicyclo[4.1.1]octanyl,
9-aza-bicyclo[3.3.2]decanyl,
4-aza-tricyclo[4.3.1.1.sup.3,8]undecanyl,
9-aza-tricyclo[3.3.2.0.sup.3,7]decanyl.
[0021] The term "saturated or partially saturated cyclic ring
system" represents but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl,
tetrahydrofuranyl or tetrahydropyranyl.
[0022] The term "saturated or partially saturated aromatic ring
system" represents but are not limited to cyclopentyl, cyclohexyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl,
tetrahydropyranyl, phenyl, pyridyl or pyrimidinyl.
[0023] The term "cycloalkyl" (e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,
cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl,
norbonyl, norcaryl, adamantyl and the like) represents a saturated,
mono-, bi-, tri- or spirocarbocyclic group having the specified
number of carbon atoms.
[0024] The term "cycloalkylalkyl" (e.g. cyclopropylmethyl,
cyclobutylethyl, adamantylmethyl and the like) represents a
cycloalkyl group as defined above attached through an alkyl group
having the indicated number of carbon atoms or substituted alkyl
group as defined above.
[0025] The term "cycloalkenyl" (e.g. cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,
cyclodecenyl and the like) represents a partially saturated, mono-,
bi-, tri- or spirocarbocyclic group having the specified number of
carbon atoms.
[0026] The term "cycloalkylcarbonyl" (e.g. cyclopropylcarbonyl,
cyclohexylcarbonyl) represents an cycloalkyl group as defined above
having the indicated number of carbon atoms attached through a
carbonyl group.
[0027] The term "hetcycloalkylcarbonyl" (e.g.
1-piperidin-4-yl-carbonyl,
1-(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl) represents an
hetcycloalkyl group as defined above having the indicated number of
carbon atoms attached through a carbonyl group.
[0028] The term "cycloalkylalkylcarbonyl" (e.g.
cyclohexylmethylcarbonyl, cycloheptylethylcarbonyl and the like)
represents a cycloalkyl group as defined above attached through an
alkyl group having the indicated number of carbon atoms or
substituted alkyl group as defined above.
[0029] The term "hetcycloalkyl" (tetrahydrofuranyl,
tetrahydropyranyl, tertahydrothiopyranyl, piperidine, pyridzine and
the like) represents a saturated mono-, bi-, tri- or
spirocarbocyclic group having the specified number of carbon atoms
and one or two additional heteroatoms or groups selected from
nitrogen, oxygen, sulphur, SO or SO.sub.2.
[0030] The term "hetcycloalkylalkyl" (e.g. tetrahydrofuranylmethyl,
tetrahydropyranylethyl, tertahydrothiopyranylmethyl, and the like)
represents a hetcycloalkyl group as defined above attached through
an alkyl group having the indicated number of carbon atoms or
substituted alkyl group as defined above.
[0031] The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy,
allyloxy, cyclohexyloxy) represents an alkyl group as defined above
having the indicated number of carbon atoms attached through an
oxygen bridge.
[0032] The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like)
represents an alkyloxy group as defined above attached through an
"alkyl" group.
[0033] The term "aryloxyhetaryl" (e.g. 2-phenoxy-pyridyl and the
like) represents an aryloxy group as defined below attached through
a "hetaryl" group.
[0034] The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like)
represents an aryl group as defined below attached through an
oxygen bridge.
[0035] The term "hetaryloxy" (e.g. 2-pyridyloxy and the like)
represents a hetaryl group as defined below attached through an
oxygen bridge.
[0036] The term "arylalkyloxy" (e.g. phenethyloxy,
naphthylmethyloxy and the like) represents an arylalkyl group as
defined below attached through an oxygen bridge.
[0037] The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the
like) represents a hetarylalkyl group as defined below attached
through an oxygen bridge.
[0038] The term "alkyloxycarbonyl" (e.g. methylformiat,
ethylformiat and the like) represents an alkyloxy group as defined
above attached through a carbonyl group.
[0039] The term "aryloxycarbonyl" (e.g. phenylformiat,
2-thiazolylformiat and the like) represents an aryloxy group as
defined above attached through a carbonyl group.
[0040] The term "arylalkyloxycarbonyl" (e.g. benzylformiat,
phenyletylformiat and the like) represents an "arylalkyloxy" group
as defined above attached through a carbonyl group.
[0041] The term "alkylthio" (e.g. methylthio, ethylthio and the
like) represents an alkyl group as defined above attached through a
sulphur bridge.
[0042] The term "arylthio" (e.g. benzenthiol, naphthylthiol and the
like) represents an aryl group as defined below attached through a
sulphur bridge.
[0043] The term "hetarylthio" (e.g. pyridine-2-thiol,
thiazole-2-thiol and the like) represents an hetaryl group as
defined below attached through a sulphur bridge.
[0044] The term "arylthioalkyl" (e.g. methylsulfanyl benzene,
ethylsulfanyl naphthalene and the like) represents an arylthio
group as defined below attached through an alkyl group having the
indicated number of carbon atoms.
[0045] The term "hetarylthioalkyl" (e.g. 2-methylsulfanyl-pyridine,
1-ethylsulfanyl-isoquinoline and the like) represents a hetarylthio
group as defined below attached through an alkyl group having the
indicated number of carbon atoms.
[0046] The term "hetaryloxyaryl" (e.g. 1-phenoxy-isoquinolyl,
2-phenoxypyridyl and the like) represents a hetaryloxy group as
defined above attached through an "aryl" group as defined
below.
[0047] The term "hetaryloxyhetaryl" (e.g.
1-(2-pyridyloxy-isoquinoline), 2-(imidazol-2-yloxypyridine) and the
like) represents a hetaryloxy group as defined above attached
through a "hetaryl" group as defined below.
[0048] The term "aryloxyalkyl" (e.g. phenoxymethyl,
naphthyloxyethyl and the like) represents an aryloxy group as
defined above attached through an "alkyl" group having the
indicated number of carbon atoms.
[0049] The term "aryloxyaryl" (e.g. 1-phenoxy-naphthalene,
phenyloxyphenyl and the like) represents an aryloxy group as
defined above attached through an "aryl" group as defined
below.
[0050] The term "arylalkyloxyalkyl" (e.g. ethoxymethyl-benzene,
2-methoxymethylnaphthalene and the like) represents an arylalkyloxy
group as defined above attached through an "alkyl" group having the
indicated number of carbon atoms.
[0051] The term "hetaryloxyalkyl" (e.g. 2-pyridyloxymethyl,
2-quinolyloxyethyl and the like) represents a hetaryloxy group as
defined above attached through an "alkyl" group having the
indicated number of carbon atoms.
[0052] The term "hetarylalkyloxyalkyl" (e.g.
4-methoxymethyl-pyrimidine, 2-methoxymethylquinoline and the like)
represents a hetarylalkyloxy group as defined above attached
through an "alkyl" group having the indicated number of carbon
atoms.
[0053] The term "arylalkyl" (e.g. benzyl, phenylethyl,
3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like)
represents an aryl group as defined below attached through an alkyl
having the indicated number of carbon atoms or substituted alkyl
group as defined above.
[0054] The term "hetarylalkyl" or "hetaralkyl" (e.g.
(2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl,
(3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl
and the like) represents a hetaryl group as defined below attached
through an alkyl having the indicated number of carbon atoms or
substituted alkyl group as defined above.
[0055] The term "alkylcarbonyl" (e.g. octylcarbonyl,
pentylcarbonyl, 3-hexenylcarbonyl) represents an alkyl group as
defined above having the indicated number of carbon atoms attached
through a carbonyl group.
[0056] The term "arylcarbonyl" (e.g. benzoyl) represents an aryl
group as defined below attached through a carbonyl group.
[0057] The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl,
3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like)
represents a hetaryl group as defined below attached through a
carbonyl group.
[0058] The term "carbonylalkyl" (e.g. acetyl and the like)
represents a carbonyl group attached through alkyl group as defined
above having the indicated number of carbon atoms.
[0059] The term "alkylcarbonylalkyl" (e.g. propan-2-one,
4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl
group as defined above attached through an alkyl group as defined
above having the indicated number of carbon atoms.
[0060] The term "arylcarbonylalkyl" (e.g. 1-phenyl-propan-1-one,
1-(3-chloro-phenyl)-2-methylbutan-1-one and the like) represents a
arylcarbonyl group as defined above attached through an alkyl group
as defined above having the indicated number of carbon atoms.
[0061] The term "hetarylcarbonylalkyl" (e.g.
1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2-yl)propan-1-one and
the like) represents a hetarylcarbonyl group as defined above
attached through an alkyl group as defined above having the
indicated number of carbon atoms.
[0062] The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl,
phenylethylcarbonyl and the like) represents an arylalkyl group as
defined above having the indicated number of carbon atoms attached
through a carbonyl group.
[0063] The term "hetarylalkylcarbonyl" (e.g.
imidazolylpentylcarbonyl and the like) represents a hetarylalkyl
group as defined above wherein the alkyl group is in turn attached
through a carbonyl.
[0064] The term "alkylcarbonylamino" (e.g. methylcarbonylamino,
cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl)
represents an "alkylcarbonyl" group as defined above wherein the
carbonyl is in turn attached through the nitrogen atom of an amino
group. The nitrogen atom may itself be substituted with an alkyl or
aryl group.
[0065] The term "alkylcarbonylaminoalkyl" (e.g. N-propyl-acetamide,
N-butyl-propionamide and the like) represents an
"alkylcarbonylamino" group attached through an alkyl group as
defined above having the indicated number of carbon atoms.
[0066] The term "arylalkylcarbonylamino" (e.g. phenylacetamide,
3phenyl-propionamide and the like) represents an
"arylalkylcarbonyl" group as defined above attached through an
amino group.
[0067] The term "arylalkylcarbonylaminoalkyl" (e.g.
N-ethyl-phenylacetamide, N-butyl-3-phenyl-propionamide and the
like) represents an "arylalkylcarbonylamino" group attached through
an alkyl group as defined above having the indicated number of
carbon atoms.
[0068] The term "arylcarbonylamino" (e.g. benzamide,
naphthalene-1-carboxylic acid amide and the like) represents an
"arylcarbonyl" group as defined above attached through an amino
group.
[0069] The term "arylcarbonylaminoalkyl" (e.g. N-propyl-benzamide,
N-Butyl-naphthalene-1-carboxylic acid amide and the like)
represents an "arylcarbonylamino" group attached through an alkyl
group as defined above having the indicated number of carbon
atoms.
[0070] The term "alkylcarboxy" (e.g. heptylcarboxy,
cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl
group as defined above wherein the carbonyl is in turn attached
through an oxygen bridge.
[0071] The term "arylcarboxy" (e.g. benzoic acid and the like)
represents an arylcarbonyl group as defined above wherein the
carbonyl is in turn attached through an oxygen bridge.
[0072] The term "alkylcarboxyalkyl" (e.g. heptylcarboxymethyl,
propylcarboxy tert-butyl, 3-pentylcarboxyethyl) represents an
[0073] The term "arylalkylcarboxy" (e.g. benzylcarboxy,
phenylpropylcarboxy and the like) represents an arylalkylcarbonyl
group as defined above wherein the carbonyl is in turn attached
through an oxygen bridge.
[0074] The term "arylalkylcarboxyalkyl" (e.g. benzylcarboxymethyl,
phenylpropylcarboxypropyl and the like) represents an
arylalkylcarboxy group as defined above wherein the carboxy group
is in turn attached through an alkyl group as defined above having
the indicated number of carbon atoms.
[0075] The term "hetarylcarboxy" (e.g. pyridine-2-carboxylic acid
and the like) represents a hetarylcarbonyl group as defined above
wherein the carbonyl is in turn attached through an oxygen
bridge.
[0076] The term "hetarylalkylcarboxy" (e.g.
(1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl-propionic acid
and the like) represents a hetarylalkylcarbonyl group as defined
above wherein the carbonyl is in turn attached through an oxygen
bridge.
[0077] The term "aryl" includes but is not limited to a carbocyclic
aromatic ring system being either monocyclic, bicyclic, or
polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl,
phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl,
biphenylenyl and the like. Aryl is also intended to include the
partially hydrogenated derivatives of the carbocyclic aromatic
systems enumerated above. Non-limiting examples of such partially
hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,
1,4-dihydronaphthyl and the like.
[0078] The term "aryl1" includes phenyl, biphenyl, naphthyl,
anthracenyl, phenanthrenyl, and fluorenyl.
[0079] The term "aryl2" includes phenyl, biphenyl, and
naphthyl.
[0080] The term "hetaryl" includes but is not limited to pyrrolyl
(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl
(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,
1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl
(2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl,
3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl,
3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl,
pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl
(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl,
7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl,
8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl,
3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl,
6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl
(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),
4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo-[b]furanyl),
6-(2,3-dihydro-benzo-[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)),
benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,
4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,
7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl
(2-(2,3-dihydro-benzo[b]thiophenyl),
3-(2,3-dihydro-benzo[b]thiophenyl),
4-(2,3-dihydro-benzo[b]thiophenyl),
5-(2,3-dihydro-benzo[b]thiophenyl),
6-(2,3-dihydro-benzo[b]thiophenyl),
7-(2,3-dihydro-benzo[b]thiophenyl)),
4,5,6,7-tetrahydro-benzo[b]thiophenyl
(2-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
3-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
4-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
5-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
6-(4,5,6,7-tetrahydro-benzo[b]thiophenyl),
7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)),
thieno[2,3-b]thiophenyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl
(4-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
5-4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
6-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl),
7-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl)), indolyl (1-indolyl,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl),
isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl), 1,3-dihydro-isoindolyl
(1-(1,3-dihydro-isoindolyl), 2-(1,3-dihydro-isoindolyl),
3-(1,3-dihydro-isoindolyl), 4-(1,3-dihydro-isoindolyl),
5-(1,3-dihydro-isoindolyl), 6-(1,3-dihydro-isoindolyl),
7-(1,3-dihydro-isoindolyl)), indazole (1-indazolyl, 3-indazolyl,
4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl
(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl,
5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,
8-benzimidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl),
benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl,
4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7-benzothiazolyl), benzo-[1,2,5]oxadiazolyl,
(4-benzo[1,2,5]oxadiazole, 5-benzo[1,2,5]oxadiazole), carbazolyl
(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),
piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl),
pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl).
[0081] The term "alkylSO.sub.m" (e.g. ethylsulfonyl, ethylsulfinyl
and the like) represents an alkyl group as defined above, wherein
the alkyl group is in turn attached through a sulphur bridge
wherein the sulphur is substituted with m oxygen atoms.
[0082] The term "arylSO.sub.m" (e.g. phenylsulfinyl,
naphthyl-2-sulfonyl and the like) represents an aryl group as
defined above, wherein the aryl group is in turn attached through a
sulphur bridge wherein the sulphur is substituted with m oxygen
atoms.
[0083] The term "hetarylSO.sub.m" (e.g. thiazol-2-sulfinyl,
pyridine-2-sulfonyl and the like) represents a hetaryl group as
defined above, wherein the hetaryl group is in turn attached
through a sulphur bridge wherein the sulphur is substituted with m
oxygen atoms.
[0084] With respect to formula I and II, the term
"NR.sup.4R.sup.5carbonylalkyl" (e.g. N,N-dimethyl-propionamide,
N-isopropyl-N-methyl-propionamide and the like) represents
NR.sup.4R.sup.5 substituted by a carbonylalkyl group as defined
above.
[0085] With respect to formula I and II, the term
"alkylR.sup.6alkyl" (e.g. 2-ethoxymethyl, N-ethyl-N-methy amine,
methyl-propyl-amide, ethanesulfonic acid methylamide and the like)
represents an alkyl group as defined above, substituted by R.sup.6,
which is substituted by an alkyl group as defined above.
[0086] With respect to formula I and II, the term
"arylR.sup.6alkyl" (e.g. ethoxy-benzene,
N-ethyl-N-methyl-phenyl-amine, N-ethyl-benzamide,
N-isobutyl-benzenesulfonamide and the like) represents an aryl
group as defined above, substituted by R.sup.6, which is
substituted by an alkyl group as defined above.
[0087] With respect to formula I and II, the term
"arylalkylR.sup.6alkyl" (e.g. benzyloxymethyl,
N-ethyl-N-methyl-benzyl-amine, N-ethyl-benzylamide and the like)
represents an arylalkyl group as defined above, substituted by
R.sup.6, which is substituted by an alkyl group as defined
above.
[0088] With respect to formula I and II, the term
"hetarylR.sup.6alkyl" (e.g. 2-ethoxy-1H-imidazol,
ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid,
methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and
the like) represents a hetaryl group as defined above, substituted
by R.sup.6, which is substituted by an alkyl group as defined
above.
[0089] With respect to formula I and II, the term
"arylcarbonylNR.sup.15" (e.g. N-benzyl-N-methyl-benzamide and the
like) represents an arylcarbonyl group as defined above,
substituted by NR.sup.15.
[0090] With respect to formula I and II, the term
"arylSO.sub.mNR.sup.8" (e.g. N-methyl-benzenesulfonamide and the
like) represents an aryl group as defined above, wherein the aryl
group is in turn attached through a SO.sub.mNR.sup.8 group wherein
the sulphur is substituted with m oxygen atoms and the nitrogen
atom substituted by R.sup.8.
[0091] With respect to formula III, the term "alkylNR.sup.5alkyl"
(e.g. N-ethyl-N-isobutyl-amine, N,N-dimethylamine and the like
wherein the amino group (N) is substituted with R.sup.5 as defined
below) represents an alkylNR.sup.5 group as defined above attached
through an "alkyl" group.
[0092] With respect to formula III, the term
"arylalkylNR.sup.5alkyl" (e.g. N-benzyl-N-methyl-amine,
N-phenethyl-N-ethyl-amine and the like wherein the amino group (N)
is substituted with R.sup.5 as defined below) represents an
arylalkylNR.sup.5 group as defined above attached through an
"alkyl" group.
[0093] Certain of the above defined terms may occur more than once
in the structural formulae, and upon such occurrence each term
shall be defined independently of the other.
[0094] The term "optionally substituted" as used herein means that
the groups in question are either unsubstituted or substituted with
one or more of the substituents specified. When the groups in
question are substituted with more than one substituent, the
substituents may be the same or different.
[0095] The term "treatment" is defined as the management and care
of a patient for the purpose of combating or alleviating the
disease, condition or disorder, and the term includes the
administration of the active compound to prevent the onset of the
symptoms or complications, or alleviating the symptoms or
complications, or eliminating the disease, condition, or
disorder.
[0096] The term "pharmaceutically acceptable" is defined as being
suitable for administration to humans without adverse events.
[0097] The term "prodrug" is defined as a chemically modified form
of the active drug, said prodrug being administered to the patient
and subsequently being converted to the active drug. Techniques for
development of prodrugs are well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
[0098] In one aspect, the present invention provides the use of a
substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms for
a) modulation of the activity of 11.beta.HSD1; or
b) inhibition of 11.beta.HSD1,
in a patient in need thereof.
[0099] In another aspect, the present invention provides the use of
a substituted amide, a prodrug thereof, or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of any
disorder and disease where it is desirable to
a) modulate the activity of 11.beta.HSD1; or
b) inhibit 11.beta.HSD1,
in a patient in need thereof.
[0100] In another embodiment, the invention provides the present
use of substituted amides, or a prodrug thereof of the general
formula (I) ##STR1## wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl, wherein
the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl
groups independently are optionally substituted with one or more of
R.sup.4. R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.5; or R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system
containing from 4 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14; R.sup.3 is C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkenyl, C.sub.1-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and
hetaryl groups independently are optionally substituted with one or
more of R.sup.7; R.sup.4 and R.sup.5 independently are hydrogen,
hydroxy, oxo, cyano, halo, methylendioxo, NR.sup.8R.sup.9,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethyloxy, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.3-C.sub.10cycloalkenyl, aryl,
hetaryl, hetarylSO.sub.n, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkyl-carboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15; R.sup.6 is oxygen,
sulphur, SO.sub.n or NR.sup.16; R.sup.7 is hydrogen, halo, hydroxy,
cyano, nitro, COOR.sup.17, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
methylendioxo, trihalomethyl, trihalomethyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl, arylthio, hetarylthio,
R.sup.18carbonylNR.sup.8, arylSO.sub.n, hetarylSO.sub.n,
R.sup.19SO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.11; or R.sup.8 and R.sup.9
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulfur,
the ring system optionally being substituted with at least one
halo, cyano, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, hydroxy, oxo, halo, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, NR.sup.12R.sup.13,
methylendioxo, trihalomethyl or trihalomethyloxy; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or
aryloxy; R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
CONR.sup.8R.sup.9 or COOR.sup.17; R.sup.16 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, aryloxyC.sub.1-C.sub.6alkyl,
hetaryloxyC.sub.1-C.sub.6alkyl, arylthioC.sub.1-C.sub.6alkyl or
hetarylthioC.sub.1-C.sub.6alkyl; wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.10; R.sup.17 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl or arylC.sub.1-C.sub.6alkyl; R.sup.18 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl or
R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally
substituted with R.sup.15; R.sup.19 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl; m
is 1 or 2; n is 0, 1 or 2; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0101] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the above
general formula (I) wherein
[0102] R.sup.1 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl, wherein
the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl
groups independently are optionally substituted with one or more of
R.sup.4;
R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.5; or
[0103] R.sup.1 and R.sup.2 are together with the nitrogen to which
they are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6alkylcarboxy wherein the alkyl and aryl
groups independently are optionally substituted with one or more of
R.sup.14;
[0104] R.sup.3 is C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkenyl,
C.sub.1-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and
hetaryl groups independently are optionally substituted with one or
more of R.sup.7;
[0105] R.sup.4 and R.sup.5 independently are hydrogen, hydroxy,
oxo, cyano, halo, methylendioxo, NR.sup.8R.sup.9,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethyloxy, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, C.sub.3-C.sub.10cycloalkenyl, aryl,
hetaryl, hetarylSO.sub.n, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylR.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkyl-carboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15;
R.sup.6 is oxygen, sulphur, SO.sub.n, NR.sup.16;
[0106] R.sup.7 is hydrogen, halo, hydroxyl, cyano, nitro,
COOR.sup.17, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, methylendioxo, trihalomethyl,
trihalomethyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylalkyl, arylcarbonylNR.sup.8, arylthio,
hetarylthio, arylSO.sub.n, hetarylSO.sub.n, arylSO.sub.mNR.sup.8,
arylthioC.sub.1-C.sub.6alkyl, hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10;
R.sup.8 and R.sup.9 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.11; or
[0107] R.sup.8 and R.sup.9 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulfur, the ring system optionally being
substituted with at least one C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkyl-carboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy;
R.sup.10 and R.sup.11 independently are hydrogen, hydroxy, oxo,
halo, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
NR.sup.12R.sup.13, methylendioxo, trihalomethyl or
trihalomethyloxy;
R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl or arylC.sub.1-C.sub.6alkyl;
R.sup.14 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or aryloxy;
R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or
COOR.sup.17;
[0108] R.sup.16 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
alkylcarbonyl, arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
aryloxyC.sub.1-C.sub.6alkyl, hetaryloxyC.sub.1-C.sub.6alkyl,
arylthioC.sub.1-C.sub.6alkyl or hetarylthioC.sub.1-C.sub.6alkyl;
wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.10;
R.sup.17 is hydrogen, C.sub.1-C.sub.8alkyl, aryl or
arylC.sub.1-C.sub.6alkyl;
m is 1 or 2;
n is 0, 1 or 2; or
a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[0109] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl wherein the cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.4 as defined above.
[0110] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl
optionally substituted with one or more of R.sup.4 as defined
above.
[0111] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.2 is hydrogen or C.sub.1-C.sub.8alkyl,
wherein the alkyl group is optionally substituted with one or more
of R.sup.5 as defined above.
[0112] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.2 is C.sub.1-C.sub.8alkyl optionally
substituted with one or more of R.sup.5 as defined above.
[0113] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.3 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
aryl-R.sup.6--C.sub.1-C.sub.6alkyl,
hetaryl-R.sup.6--C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of
R.sup.7.
[0114] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.3 is aryl or hetaryl, wherein the aryl
and hetaryl groups are optionally substituted with one or more of
R.sup.7 as defined above.
[0115] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.3 is phenyl optionally substituted with
one or more of R.sup.7 as defined above.
[0116] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.3 is phenyl optionally substituted
independently in position 2(ortho) or 4(para) with one or more of
R.sup.7 as defined above.
[0117] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.4 and R.sup.5 independently are hydrogen,
hydroxy, oxo, halo, C.sub.1-C.sub.8alkyl, wherein the alkyl group
is optionally substituted with one or more of R.sup.15.
[0118] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.6 is oxygen.
[0119] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.7 is hydrogen, halo, hydroxy, cyano,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, trihalomethyl, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl,
R.sup.18carbonylNR.sup.8, R.sup.19SO.sub.mNR.sup.8, wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10.
[0120] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.8 and R.sup.9 together with the nitrogen
to which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from
4 to 10 carbon atoms and from 0 to 2 additional heteroatoms
selected from nitrogen, oxygen or sulfur, the ring system
optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy.
[0121] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.15 is CONR.sup.8R.sup.9.
[0122] In another embodiment, the invention provides the present
use of a substituted amide, or a prodrug thereof of the general
formula (I) wherein R.sup.18 is C.sub.1-C.sub.6alkyl optionally
substituted with R.sup.15; [0123] In another embodiment, the
invention provides the present use of a substituted amide, or a
prodrug thereof of general formula (I), selected from the group
consisting of: [0124]
3-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-1-[4-(1H-imidazol-4-yl)-piperid-
in-1-yl]-propan-1-one; [0125]
4-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-1-[4-(3H-imidazol-4-yl)-piperid-
in-1-yl]-butan-1-one; [0126] 2,4-Bis-benzyloxy-benzamide; [0127]
(1H-Indol-4-yl)-piperidin-1-yl-methanone; [0128]
N-(1,4-Dioxo-1,4-dihydro-naphthalen-2-yl)-benzamide; [0129]
N-(2,3-Dihydroxy-propyl)-2-(2-phenyl-adamantan-2-yl)-acetamide;
[0130]
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone;
[0131]
(2-Chloro-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl-
)-methanone; [0132]
3-Cyclopentyl-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-propan-1-
-one; [0133]
(3-Chloro-thieno[2,3-b]thiophen-2-yl)-thiomorpholin-4-yl-methanone;
[0134]
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-[4-(4-methoxy-phenyl)-pi-
perazin-1-yl]-ethanone; [0135]
1-(4-Benzyl-piperazin-1-yl)-2-[2-(4-chloro-phenyl)-adamantan-2-yl]-ethano-
ne; [0136]
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-1-(4-methyl-piperazin-1-yl)-ethano-
ne; [0137]
1-[4-(6-Chloro-pyridin-2-yl)-piperazin-1-yl]-2-(2-phenyl-adamantan-2-yl)--
ethanone; [0138]
4-Chloro-N-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
[0139] 3-Chloro-benzo[b]thiophene-2-carboxylic acid
(2-cyano-ethyl)-cyclohexyl-amide; [0140]
2-[2-(Bicyclo[2.2.1]hept-5-en-2-ylamino)-4-oxo-4,5-dihydro-thiazol-5-yl]--
N-(2-chloro-phenyl)acetamide; [0141]
[3-(4-sec-Butyl-phenoxy)-phenyl]-piperidin-1-yl-methanone; [0142]
3-(6-Chloro-pyridin-2-yloxy)-N-ethyl-benzamide; [0143]
N-Benzyl-2,4-dichloro-N-pyridin-2-yl-benzamide; [0144]
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid butyl
ester; [0145]
2-[Benzoyl-(3-chloro-4-fluoro-phenyl)-amino]-propionic acid pentyl
ester; [0146]
3-(4-Fluoro-phenyl)-1-(4-phenyl-piperidin-1-yl)-but-2-en-1-one;
[0147] N-(1,7,7-Trimethyl-bicyclo[2.2.1]hept-2-yl)-benzamide;
[0148] 1-(3-Cyclopentyl-propionyl)-piperidine-3-carboxylic acid
ethyl ester; [0149]
4-Phenyl-1-phenylacetyl-piperidine-4-carbonitrile; [0150]
1-Octanoyl-4-phenyl-piperidine-4-carbonitrile; [0151]
2,2-Dimethyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-propan-1-on-
e; [0152]
(4-Chloro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanon-
e; [0153]
N-[1-(4-Methanesulfonyl-phenyl)-ethyl]-N-(tetrahydro-furan-2-ylmethyl)-be-
nzamide; [0154]
2-(2-Amino-phenylsulfanyl)-1-(5-fluoro-2,3-dihydro-indol-1-yl)-ethanone;
[0155]
N-(1-Methyl-2,3-dihydro-1H-indol-5-ylmethyl)-N-(tetrahydro-furan--
2-ylmethyl)-benzamide; [0156] 1-Benzoyl-piperidine-2-carboxylic
acid ethyl ester; [0157]
N-(2-Chloro-phenyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide;
[0158]
(Decahydro-naphthalen-1-yl)-(4-methyl-piperazin-1-yl)-methanone;
[0159]
(4-Methyl-piperazin-1-yl)-(2-p-tolylsulfanyl-phenyl)-methanone;
[0160] Adamantane-1-carboxylic acid
(3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide; [0161]
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3,4,5-trimethoxy-phenyl-
)-methanone; [0162]
N-Bicyclo[2.2.1]hept-2-yl-3-cyclopentyl-propionamide; [0163]
(2-Benzo[1,2,5]oxadiazol-5-yl-thiazol-4-yl)-piperidin-1-yl-methanone;
[0164] Thiophene-2-carboxylic acid
[4-(4-fluoro-phenyl)-4-hydroxy-butyl]-isopropyl-amide; [0165]
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
[0166]
2-[(Adamantane-1-carbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid
methyl ester; [0167] Adamantane-1-carboxylic acid
[3-(1H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-amide; [0168]
N-Benzyl-N-(1-cyclopropyl-ethyl)-4-fluoro-benzamide; [0169]
Thiophene-2-carboxylic acid
2-[2-(2-phenyl-adamantan-2-yl)-acetylamino]-ethyl ester; [0170]
N-(4-Acetyl-phenyl)-2-(2-phenyl-adamantan-2-yl)-acetamide; [0171]
2-[2-(4-Chloro-phenyl)-adamantan-2-yl]-N-(2-hydroxy-ethyl)-acetamide;
[0172] (4-Benzoyl-piperidin-1-yl)-thiophen-2-yl-methanone; [0173]
N-(2-Benzoyl-4-methyl-phenyl)-3-phenyl-acrylamide; [0174]
N-(2-Benzoyl-4-methyl-phenyl)-2-fluoro-benzamide; [0175]
Adamantane-1-carboxylic acid (4-ethoxy-benzothiazol-2-yl)-amide;
[0176] Adamantane-1-carboxylic acid
(5-benzoyl-4-phenyl-thiazol-2-yl)-amide; [0177]
3-(2-Hydroxy-phenyl)-1,3-di-piperidin-1-yl-propan-1-one; [0178]
N-(1-Methyl-2-phenyl-ethyl)-3-phenyl-propionamide; [0179]
4-Oxo-4-piperidin-1-yl-butyric acid 4-tert-butyl-cyclohexyl ester;
[0180] N-tert-Butyl-N-(4-methoxy-benzyl)-4-nitro-benzamide; [0181]
{4-[(Adamantane-1-carbonyl)-amino]-phenoxy}-acetic acid; [0182]
2-(4-Isobutyl-phenyl)-N-(1-phenyl-ethyl)-propionamide; [0183]
Adamantane-1-carboxylic acid
4-[(adamantane-1-carbonyl)-amino]-2,6-dimethyl-pyridin-3-yl ester;
[0184] 2-Phenyl-1-(3-phenyl-pyrrolidin-1-yl)-ethanone; [0185]
Adamantane-1-carboxylic acid
4-[(adamantane-1-carbonyl)-amino]-2-ethyl-6-methyl-pyridin-3-yl
ester; [0186]
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-hydroxy-phenyl-
)-benzamide; [0187] Biphenyl-4-yl-piperidin-1-yl-methanone; [0188]
Azepan-1-yl-(3,5-dichloro-phenyl)-methanone; [0189]
Azepan-1-yl-biphenyl-4-yl-methanone; [0190]
Azepan-1-yl-(4-chloro-phenyl)-methanone; [0191]
3-Heptylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;
[0192] Adamantan-1-yl-azepan-1-yl-methanone; [0193]
N,N-Dibenzyl-3,4-dimethoxy-benzamide; [0194]
N-Benzyl-N-isopropyl-4-nitro-benzamide; [0195]
N-[2-(1H-Indol-3-yl)-1-methyl-ethyl]-2-(4-isobutyl-phenyl)-propionamide;
[0196] N-tert-Butyl-2-(4-isobutyl-phenyl)-propionamide; [0197]
Adamantane-1-carboxylic acid (2-acetyl-phenyl)-amide; [0198]
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-(4-fluoro-phenyl)-benzami-
de; [0199] (Octahydro-quinolin-1-yl)-phenyl-methanone; [0200]
(7-Hydroxy-octahydro-quinolin-1-yl)-phenyl-methanone; [0201]
N-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-N-p-tolyl-benzamide;
[0202] N,N-Dibenzyl-4-methyl-benzamide; [0203]
(2-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone; [0204]
[4-Bromo-3-(piperidine-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone;
[0205] 2-Chloro-N-(3,4-dimethyl-phenyl)-benzamide; [0206]
1-Azepan-1-yl-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)-ethan-
one; [0207] N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-butyramide;
[0208] N-Benzo[1,3]dioxol-5-yl-2-chloro-benzamide; [0209]
(4-Benzyl-piperidin-1-yl)-(2-chloro-phenyl)-methanone; [0210]
2-(Benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide; [0211]
Cyclohexanecarboxylic acid
(7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide;
[0212] 2,4-Dichloro-N-ethyl-N-o-tolyl-benzamide; [0213]
(4-Benzyl-piperidin-1-yl)-(4-fluoro-phenyl)-methanone; [0214]
N-Cyclohexyl-4-(2,4-dichloro-phenoxy)-N-methyl-butyramide; [0215]
3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-adamantane-1-carboxylic
acid; [0216] Morpholin-4-yl-(3-p-tolyl-adamantan-1-yl)-methanone;
[0217] N-Benzyl-2,4-dichloro-N-methyl-benzamide; [0218]
Thiophene-2-carboxylic acid dibenzylamide; [0219]
Azepan-1-yl-(2-bromo-phenyl)-methanone; [0220]
(3,4-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone; [0221]
N,N-Dibenzyl-3,4-dichloro-benzamide; [0222]
4-(2,4-Dichloro-phenoxy)-1-piperidin-1-yl-butan-1-one; [0223]
N,N-Dibenzyl-2-fluoro-benzamide; [0224]
(2-Chloro-phenyl)-piperidin-1-yl-methanone; [0225]
2-Chloro-N-(3-trifluoromethyl-phenyl)-benzamide; [0226]
N-Benzyl-N-ethyl-2-phenyl-acetamide; [0227]
(3,4-Dihydro-2H-quinolin-1-yl)-p-tolyl-methanone; [0228]
Thiophene-2-carboxylic acid benzyl-ethyl-amide; [0229]
N-Adamantan-1-yl-2-dibenzylamino-acetamide; [0230]
N-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionamid-
e; [0231] Thiophene-2-carboxylic acid cycloheptylamide; [0232]
N-Cyclohexyl-3-diethylsulfamoyl-4-methyl-benzamide; [0233]
4-Benzoyl-N-methyl-N-phenyl-benzamide; [0234]
N-Benzyl-2-bromo-N-methyl-benzamide; [0235]
2-Chloro-N-methyl-N-phenyl-benzamide; [0236]
4-Chloro-N-ethyl-N-o-tolyl-benzamide; [0237]
N-Benzyl-4,N-dimethyl-benzamide; [0238]
2-(4-Chloro-3,5-dimethyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
[0239] N-Benzyl-2-bromo-N-isopropyl-benzamide; [0240]
3-(2-Chloro-phenyl)-N-cyclohexyl-N-methyl-acrylamide; [0241]
N-Phenyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide; [0242]
N-m-Tolyl-N-(2,2,5-trimethyl-hex-4-enyl)-acetamide; [0243]
(3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
[0244] Adamantane-1-carboxylic acid (5-methyl-pyridin-2-yl)-amide;
[0245]
3-Bromo-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-
-6-carbonyl)-butyl]-benzamide; [0246]
4-Chloro-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carb-
onyl)-butyl]-benzamide; [0247]
4-Methyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carb-
onyl)-butyl]benzamide; [0248] Cyclohexanecarboxylic acid
[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)butyl]-
-amide; [0249]
3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-
-carbonyl)-butyl]-propionamide; [0250]
2-Chloro-N-[2-(4-ethyl-benzoylamino)-ethyl]-N-(4-fluoro-phenyl)-benzamide-
; [0251]
N-{1-Benzyl-2-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-2-ox-
o-ethyl}-3-cyclopentyl-propionamide; [0252]
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3-cyclopentyl-N-[2-(1H-indol-3-yl)-e-
thyl]-propionamide; [0253]
N-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-2,4-dichloro-N-[2-(1H-indol-3-yl)-et-
hyl]-benzamide; [0254] Naphthalene-2-carboxylic acid
(2-oxo-azepan-3-yl)-thiophen-3-ylmethyl-amide; [0255]
3,4,5-Trimethoxy-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-benz-
amide; [0256]
3-Cyclopentyl-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-propion-
amide; [0257]
N-(3,4-Dimethoxy-benzyl)-3-methoxy-N-[6-(pyridin-2-ylamino)-hexyl]-benzam-
ide; [0258]
N,N-Dimethyl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-acetamide;
[0259] Adamantane-1-carboxylic acid
[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-p-tolyl-amide;
[0260]
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-N-(2-trifluoromethyl-phe-
nyl)-butyramide; [0261]
2-(4-Chloro-2-methyl-phenoxy)-N-(2-trifluoromethyl-phenyl)-propionamide;
[0262]
4-(2,4-Dichloro-phenoxy)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-b-
utan-1-one; [0263]
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(piperidine-1-sulfonyl)-phenyl]-methano-
ne; [0264] Acetic acid 4-(azepane-1-carbonyl)-phenyl ester; [0265]
N-Adamantan-1-ylmethyl-benzamide; [0266]
[3-(4-Nitro-phenyl)-adamantan-1-yl]-piperidin-1-yl-methanone;
[0267] N-(1,1-Dimethyl-hexyl)-2-morpholin-4-yl-acetamide; [0268]
Adamantyl-1-carboxylic acid (2-methoxy-ethyl)-amide; [0269]
N-(4-Adamantan-1-yl-2-methyl-phenyl)-acetamide; [0270]
3-p-Tolyl-adamantane-1-carboxylic acid (2,5-dichloro-phenyl)-amide;
[0271] (3-Chloro-adamantan-1-yl)-pyrrolidin-1-yl-methanone; [0272]
2-Amino-5-cyclohexylcarbamoyl-4-methyl-thiophene-3-carboxylic acid
ethyl ester; [0273]
N-(2-Chloro-phenyl)-2-{3-[(2-chloro-phenylcarbamoyl)-methyl]-adamantan-1--
yl}-acetamide; [0274] 3-p-Tolyl-adamantane-1-carboxylic acid
(2,4-difluoro-phenyl)-amide; [0275] Adamantyl-1-carboxylic acid
tert-butylamide; [0276] 2-Adamantan-1-yl-N-tert-butyl-acetamide;
[0277] N-Methyl-N-phenyl-4-(pyrrolidine-1-sulfonyl)-benzamide;
[0278] N-(1-Adamantan-1-yl-ethyl)-2-fluoro-benzamide; [0279]
Adamantane-1-carboxylic acid
[2-(3,4-dimethoxy-phenyl)-ethyl]-amide; [0280]
Adamantane-1-carboxylic acid dimethylamide; [0281]
N-Benzyl-4-chloro-N-(1-cyclopropyl-vinyl)-benzamide; [0282]
3,5-Dimethyl-adamantane-1-carboxylic acid benzylamide; [0283]
2,4-Dichloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzamide; [0284]
N-Adamantan-1-yl-2,4-dichloro-N-ethyl-benzamide; [0285]
2-[(3-p-Tolyl-adamantane-1-carbonyl)-amino]-propionic acid methyl
ester; [0286] N-Adamantan-1-yl-3-morpholin-4-yl-propionamide;
[0287] 3-p-Tolyl-adamantane-1-carboxylic acid isopropylamide;
[0288] N-Adamantan-1-yl-2-benzylamino-acetamide; [0289]
N-Benzyl-2,4-dichloro-N-(1-cyclopropyl-ethyl)-5-methyl-benzamide;
[0290] 2-[(Adamantane-1-carbonyl)-amino]-benzoic acid ethyl ester;
[0291] N-Benzyl-N-isopropyl-4-methyl-3-nitro-benzamide; [0292]
(3,4-Dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methanone; [0293]
N-Ethyl-2-fluoro-N-phenyl-benzamide; [0294]
2-Phenethyl-N-(2-trifluoromethyl-phenyl)-benzamide; [0295]
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-o-tolyloxy-ethanone; [0296]
2-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
[0297] Cyclohexanecarboxylic acid (2-propoxy-phenyl)-amide; [0298]
2-{3-[4-(2-Chloro-phenyl)-piperazin-1-yl]-3-oxo-propyl}-isoindole-1,3-dio-
ne; [0299] N-Cyclopentyl-2-(2,4-dichloro-phenoxy)-propionamide;
[0300] Adamantane-1-carboxylic acid
(2-trifluoromethyl-phenyl)-amide; [0301]
(4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
[0302]
4-(2-Ethyl-phenyl)-4-aza-tricyclo[5.2.2.0.sup.2,6]undec-8-ene-3,5-
-dione; [0303] 2-Phenyl-N-(2-trifluoromethyl-phenyl)-butyramide;
[0304] N-Adamantan-1-yl-4-chloro-2-nitro-benzamide; [0305]
3-p-Tolyl-adamantane-1-carboxylic acid (2,3-dimethyl-phenyl)-amide;
[0306] N-Benzyl-3-methyl-4-p-tolyl-butyramide; [0307]
N-(2-Cyclohex-1-enyl-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propi-
onamide; [0308]
(4-tert-Butyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone;
[0309]
2-[1-(4-Chloro-benzenesulfonyl)-1H-benzoimidazol-2-ylsulfanyl]-N--
thiophen-2-ylmethyl-acetamide; [0310]
2-Phenoxy-1-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethanone;
[0311] Cyclohexanecarboxylic acid
[5-(2-fluoro-benzylsulfanylmethyl)-[1,3,4]thiadiazol-2-yl]-amide;
[0312] 4-Methyl-2-phenyl-thiazole-5-carboxylic acid
naphthalen-1-ylamide; [0313]
4-Fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbo-
nyl)-phenyl]-benzenesulfonamide; [0314]
(3-Methoxy-phenyl)-(4-o-tolyl-piperazin-1-yl)-methanone; [0315]
N-Adamantan-1-yl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide;
[0316] N-Cyclooctyl-2-methoxy-3-methyl-benzamide; [0317]
2-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-isoi-
ndole-1,3-dione; [0318]
(2,3-Diphenyl-quinoxalin-6-yl)-(2,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone; [0319]
Adamantan-1-yl-(1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-methanone;
[0320]
N-{4-[1-(Naphthalene-2-sulfonyl)-piperidin-3-yl]-butyl}-N'-p-toly-
l-oxalamide; [0321]
N-Benzyl-N-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide;
[0322]
(4-Amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone-
; [0323]
1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-isopropyl-5-methyl--
phenoxy)-ethanone; [0324] Adamantane-1-carboxylic acid
benzyl-pyridin-2-yl-amide; [0325]
Adamantan-1-yl-piperidin-1-yl-methanone; [0326]
Adamantan-1-yl-pyrrolidin-1-yl-methanone; [0327]
(3,4-Dihydro-2H-quinolin-1-yl)-o-tolyl-methanone;
[0328] Adamantyl-1-carboxylic acid benzylamide; [0329]
Pyridine-2-carboxylic acid adamantan-2-ylamide; [0330]
(3-Chloro-adamantan-1-yl)-piperidin-1-yl-methanone; [0331]
Adamantan-1-yl-(4-methyl-piperidin-1-yl)-methanone; [0332]
2-[3-(Azepane-1-carbonyl)-phenyl]-isoindole-1,3-dione; [0333]
2-[3-(Piperidine-1-carbonyl)-phenyl]-isoindole-1,3-dione; [0334]
4-(Benzyl-methanesulfonyl-amino)-N-furan-2-ylmethyl-benzamide;
[0335]
(4-Nitro-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone-
; [0336] 1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(4-chloro-3-nitro-phenyl)-amide; [0337]
N-(2-Chloro-phenyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)-acetamide;
[0338]
3-(4-Hydroxy-phenyl)-N-isochroman-1-ylmethyl-3-phenyl-propionamide;
[0339] (4-Ethoxy-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
[0340] 1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(3-chloro-phenyl)-amide; [0341]
N-[4-(Benzyl-isopropyl-sulfamoyl)-phenyl]-acetamide; [0342]
N-(3,4-Dimethyl-phenyl)-N-[4-(piperidine-1-carbonyl)-benzyl]-methanesulfo-
namide; [0343]
2-(5-Phenyl-1H-imidazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-aceta-
mide; [0344]
2-(Benzothiazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetamide;
[0345]
2-(Benzooxazol-2-ylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)-acetam-
ide; [0346]
2-(Naphthalen-2-ylcarbamoylmethylsulfanyl)-N-(1,1,3,3-tetramethyl-butyl)--
acetamide; [0347] Acetic acid
4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester; [0348]
[1-(4-Chloro-benzenesulfonyl)-piperidin-3-yl]-(octahydro-quinolin-1-yl)-m-
ethanone; [0349]
(4-Fluoro-phenyl)-(3,4,4a,8a-tetrahydro-2H-quinolin-1-yl)-methanone;
[0350] N-Adamantan-1-yl-2-ethoxy-acetamide; [0351]
2-(2-Oxo-2-phenothiazin-10-yl-ethyl)-hexahydro-isoindole-1,3-dione;
[0352] Adamantane-1-carboxylic acid
(tetrahydro-furan-2-ylmethyl)-amide; [0353]
2-Bromo-N-cycloheptyl-benzamide; [0354]
Bicyclo[2.2.1]hept-2-yl-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;
[0355] N-Furan-2-ylmethyl-2-phenyl-2-phenylsulfanyl-acetamide;
[0356] Adamantane-1-carboxylic acid benzyl-methyl-amide; [0357]
1-(3,4-Dihydro-2H-quinolin-1-yl)-3-(4-fluoro-phenyl)-propenone;
[0358] Adamantan-1-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
[0359] 4-Methyl-N-homoadamantyl-3-yl-benzamide; [0360]
(3,5-Dimethyl-piperidin-1-yl)-(3-methyl-4-nitro-phenyl)-methanone;
[0361] Quinoline-2-carboxylic acid cyclooctylamide; [0362]
Adamantane-1-carboxylic acid
[2-(2,4-dimethoxy-phenyl)-ethyl]-amide; [0363]
(3,4-Dihydro-1H-isoquinolin-2-yl)-o-tolyl-methanone; [0364]
(3,6-Dichloro-benzo[b]thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone;
[0365]
3-(1-Benzyl-1H-imidazol-2-ylsulfanyl)-N-cyclohexyl-propionamide;
[0366] Propionic acid
2-amino-4-methyl-5-p-tolylcarbamoyl-thiophen-3-yl ester; [0367]
2-Cyclohexyl-N-(2,6-dimethyl-phenyl)-N-furan-2-ylmethyl-acetamide;
[0368]
(3-Methoxy-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quino-
lin-1-yl)-methanone; [0369]
1-[4-(2,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrr-
olidine-2,5-dione; [0370]
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(1-naphthalen-1-yl-1H-tetrazol-5-ylsul-
fanyl)-ethanone; [0371]
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-o-tolyl-methanone; [0372]
(4-Benzyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
[0373]
N-(2-Cyano-phenyl)-2-(9-ethyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)-a-
cetamide; [0374]
N-(2-Cyano-phenyl)-2-(9-methyl-9H-1,3,4,9-tetraaza-fluoren-2-ylsulfanyl)--
acetamide; [0375]
1-(Thiophene-2-carbonyl)-2,3-dihydro-1H-quinolin-4-one; [0376]
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
[0377] (4-Bromo-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[0378] 2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-acetamide;
[0379] 9-Oxo-9H-fluorene-1-carboxylic acid (3-methyl-butyl)-amide;
[0380]
[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone-
; [0381] N-Cycloheptyl-3-diethylsulfamoyl-benzamide; [0382]
(4-Methoxy-phenyl)-(3-phenyl-piperidin-1-yl)-methanone; [0383]
3-Amino-N-cyclohexyl-N-methyl-benzamide; [0384]
N-Ethyl-3,4-dimethyl-N-phenyl-benzamide; [0385]
N-Benzyl-3,4,N-trimethyl-benzamide; [0386]
(4-Fluoro-phenyl)-(3-phenyl-piperidin-1-yl)-methanone; [0387]
[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-(3-methoxy-phenyl)-methanone;
[0388] Furan-2-carboxylic acid
[4-(4-methyl-piperidine-1-sulfonyl)-phenyl]-amide; [0389]
N-(2-Cyclohex-1-enyl-ethyl)-2-o-tolyloxy-acetamide; [0390]
5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid
(1-bicyclo[2.2.1]hept-2-yl-ethyl)-amide; [0391]
3-(2-Chloro-phenyl)-1-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-propenone;
[0392] N-[3-(Azepane-1-carbonyl)-phenyl]-benzamide; [0393]
[3-(Piperidine-1-carbonyl)-pyrazol-1-yl]-o-tolyl-methanone; [0394]
N-(1-Phenyl-cyclopentylmethyl)-2-piperidin-1-yl-propionamide;
[0395]
2-Morpholin-4-yl-N-(1-phenyl-cyclopentylmethyl)-propionamide;
[0396] N-[4-(Azepane-1-sulfonyl)-phenyl]-2,2,2-trifluoro-acetamide;
[0397] 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide; [0398]
N-Adamantan-1-yl-2-(3-methoxy-phenoxy)-acetamide; [0399]
3-Chloro-benzo[b]thiophene-2-carboxylic acid
(2-cyano-ethyl)-phenyl-amide; [0400]
[4-(4-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone; [0401]
[4-(2-Nitro-benzyl)-piperidin-1-yl]-phenyl-methanone; [0402]
3-[5-(4-Fluoro-phenyl)-furan-2-yl]-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1-
]oct-6-yl)-propenone; [0403]
2-(3-Fluoro-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3--
carboxylic acid methyl ester; [0404]
N-(2-Ethyl-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide; [0405]
2-(2-Methoxy-benzoylamino)-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-
-carboxylic acid methyl ester; [0406]
1-Phenyl-cyclopentanecarboxylic acid
(4-phenyl-tetrahydro-pyran-4-ylmethyl)-amide; [0407]
4-(2,4-Dichloro-phenoxy)-1-(4-phenyl-piperazin-1-yl)-butan-1-one;
[0408] Naphthalene-1-carboxylic acid cycloheptylamide; [0409]
N-Indan-5-yl-2-methyl-3-nitro-benzamide; [0410]
N-Cyclohexyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide; [0411]
2-Methoxy-N-(1-phenyl-cyclopentylmethyl)-benzamide; [0412]
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4-yl)-
-methanone; [0413]
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2-methyl-piperidin-1-yl)-methanon-
e; [0414] 5-(2-Methoxy-phenoxymethyl)-furan-2-carboxylic acid
cycloheptylamide; [0415]
(3,4-Dihydro-1H-isoquinolin-2-yl)-[1-(2-nitro-benzenesulfonyl)-piperidin--
3-yl]-methanone; [0416]
N-Cyclooctyl-2-(4-methoxy-phenoxy)-acetamide; [0417]
N-(2,3-Dimethyl-phenyl)-4-[methyl-(toluene-4-sulfonyl)-amino]-but-
yramide; [0418]
N-Phenyl-N-[4-(piperidine-1-carbonyl)-benzyl]-benzenesulfonamide;
[0419]
N-[4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-benzyl]-N-(3,4-dimethyl-ph-
enyl)methanesulfonamide; [0420]
2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid
bicyclo[2.2.1]hept-2-ylamide; [0421]
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
cycloheptylamide; [0422]
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-fluoro-benzenesulfonamid-
e; [0423]
1-(2,6-Dimethyl-morpholin-4-yl)-3,3-diphenyl-propan-1-one; [0424]
N-Bicyclo[2.2.1]hept-2-yl-4-morpholin-4-ylmethyl-benzamide; [0425]
[3-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
[0426]
N-Adamantan-1-yl-2-(4-methyl-quinolin-2-ylsulfanyl)-acetamide;
Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide; [0427]
(4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
[0428] 3-Cyclohexyl-N-(3-phenyl-propyl)-propionamide; [0429]
2-[1-(2,5-Dimethyl-phenyl)-1H-tetrazol-5-ylsulfanyl]-N-isopropyl-N-phenyl-
-acetamide; [0430]
N-{2-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-ethyl}-acetamide-
; [0431]
N-Benzyl-N-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-benzenesul-
fonamide; [0432]
[4-(2-Chloro-6-nitro-phenoxy)-phenyl]-piperidin-1-yl-methanone;
[0433] N-Cycloheptyl-3-phenyl-propionamide; [0434]
(3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
[0435] N-Cycloheptyl-2,4-dimethoxy-benzamide; [0436]
N-(3-Chloro-phenyl)-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.su-
p.2,7]undeca-2(7),3,5-trien-5-ylsulfanyl)-acetamide; [0437]
N-(2-Nitro-phenyl)-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup-
.2,7]undeca-2(7),3,5-trien-5-ylsulfanyl)-acetamide; [0438]
N-Phenyl-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup.2,7]undec-
a-2(7),3,5-trien-5-ylsulfanyl)acetamide; [0439]
N-Ethyl-3-methyl-N-o-tolyl-benzamide; [0440]
N-[5-(2,4-Dichloro-benzylsulfanyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-p-
ropionamide; [0441] 4-Bromo-1-ethyl-1H-pyrazole-3-carboxylic acid
(2-methylsulfanyl-phenyl)-amide; [0442]
5-Benzoyl-furan-2-carboxylic acid diisopropylamide; [0443]
N-{2-[2-(4-Bromo-phenyl)-2-oxo-ethylsulfanyl]-benzothiazol-6-yl}-acetamid-
e; [0444]
2-(6-Amino-benzothiazol-2-ylsulfanyl)-N-cyclohexyl-acetamide;
[0445]
N-(2-Cyclohexylcarbamoylmethylsulfanyl-benzothiazol-6-yl)-2-metho-
xy-benzamide; [0446]
Benzofuran-2-yl-(4-phenyl-piperidin-1-yl)-methanone; [0447]
1-(2-Nitro-phenyl)-piperidine-3-carboxylic acid diethylamide;
[0448] 1-(4-Nitro-phenyl)-piperidine-3-carboxylic acid
diethylamide; [0449] 5-Bromo-furan-2-carboxylic acid
adamantan-2-ylamide; [0450] 3,3-Dimethyl-pentanedioic acid
bis-[(2,4-difluoro-phenyl)-amide]; [0451]
2-(3-Bromo-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone;
[0452]
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-benzyl-4-bromo-benzenesulfonamide;
[0453] 1-(2,3-Dihydro-indol-1-yl)-2-p-tolylsulfanyl-ethanone;
[0454]
[4-(4-Bromo-benzenesulfonyl)-piperazin-1-yl]-furan-2-yl-methanone;
[0455]
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(2,6-dimethyl-morpholin-4--
yl)-methanone; [0456] 5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic
acid diethylamide; [0457]
5-(2-Bromo-phenoxymethyl)-furan-2-carboxylic acid diethylamide;
[0458] 5-(2-Chloro-phenoxymethyl)-furan-2-carboxylic acid
methyl-phenyl-amide; [0459]
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-methano-
ne; [0460]
[3-(2,5-Dichloro-phenoxymethyl)-phenyl]-pyrrolidin-1-yl-methanone;
[0461]
[5-(4-Ethoxy-phenoxymethyl)-furan-2-yl]-(4-methyl-piperidin-1-yl)-
-methanone; [0462]
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-methyl-cyclohexyl)-propionam-
ide; [0463]
3-(3,4-Dihydro-2H-quinoline-1-carbonyl)-N-phenyl-benzenesulfonamide;
[0464]
[3-(2,3-Dihydro-indole-1-sulfonyl)-phenyl]-(3,4-dihydro-2H-quinol-
in-1-yl)-methanone; [0465]
[3-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone-
; [0466]
N-Cyclohexyl-3-(2-hydroxy-4-methyl-phenyl)-3-phenyl-propionamid- e;
[0467] 2-Diethylamino-N-(1-phenyl-cyclopentylmethyl)-propionamide;
[0468]
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(3-trifluorometh-
yl-phenyl)-methanone; [0469]
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-metha-
none; [0470] N-Benzyl-4-bromo-N-ethyl-benzamide; [0471]
(3-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-methanone-
; [0472]
Azepan-1-yl-[5-(2-chloro-phenoxymethyl)-furan-2-yl]-methanone;
[0473]
(4-Methyl-piperidin-1-yl)-[4-(naphthalen-1-yloxymethyl)-phenyl]-m-
ethanone; [0474]
Azepan-1-yl-[5-(2,4-dichloro-phenoxymethyl)-furan-2-yl]-methanone;
[0475] N-Cycloheptyl-4-(4-methoxy-2-methyl-phenyl)-butyramide;
[0476]
2-(4-Benzothiazol-2-yl-piperazin-1-yl)-N-cyclohexyl-acetamide;
[0477] N-Cycloheptyl-2-(2,6-dimethyl-phenoxy)-acetamide; [0478]
(3,4-Dihydro-2H-quinolin-1-yl)-(3-iodo-phenyl)-methanone; [0479]
N-Cycloheptyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzamide; [0480]
Azepan-1-yl-[4-(2-chloro-phenoxymethyl)-phenyl]-methanone; [0481]
(2,6-Dimethyl-morpholin-4-yl)-[4-(naphthalen-2-yloxymethyl)-phenyl]-metha-
none; [0482]
Azepan-1-yl-[3-(4-ethoxy-phenoxymethyl)-phenyl]-methanone; [0483]
Benzo[b]thiophene-3-carboxylic acid
(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide; [0484]
2-(4-Chloro-2-methyl-phenoxy)-N-cycloheptyl-acetamide; [0485]
2,4-Dichloro-N-cyclohexyl-N-methyl-benzamide; [0486]
N-Cyclooctyl-2-p-tolyloxy-acetamide; [0487]
(3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
[0488] Biphenyl-4-yl-(2,6-dimethyl-piperidin-1-yl)-methanone;
[0489] N-Cyclohexyl-4-fluoro-N-methyl-benzamide; [0490]
N-[4-(Azepane-1-carbonyl)-phenyl]-N-methyl-benzenesulfonamide;
[0491] N-Cycloheptyl-2-fluoro-benzamide; [0492]
N-Cycloheptyl-4-methyl-benzamide; [0493]
(3-Methyl-piperidin-1-yl)-p-tolyl-methanone; [0494]
[2-(3,4-Dimethoxy-phenylcarbamoyl)-piperidin-1-yl]-acetic acid
benzyl ester; [0495]
N-[4-(2-Methyl-piperidine-1-sulfonyl)-phenyl]-acetamide; [0496]
2-(2,4-Dichloro-phenoxy)-N-(2-methyl-butyl)-propionamide; [0497]
[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-(4-methoxy-phenyl)-methanon-
e; [0498] N-Cyclohexyl-4-(4-methoxy-3-methyl-phenyl)-butyramide;
[0499]
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2-
-yl)-methanone; [0500]
2-(4-Methyl-benzylsulfanyl)-1-piperidin-1-yl-ethanone; [0501]
N-Cyclohexyl-N-[(4-phenyl-thiazol-2-ylcarbamoyl)-methyl]-benzamide;
[0502]
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-isopropyl-phenyl)-methanesulfo-
namide; [0503] N-Adamantan-1-yl-3-p-tolylsulfanyl-propionamide;
[0504]
6-(2,4-Dichloro-phenylcarbamoyl)-3,4-dimethyl-cyclohex-3-enecarboxylic
acid; [0505] (4-Butyl-cyclohexyl)-morpholin-4-yl-methanone; [0506]
(3,4-Dichloro-phenyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
[0507] N-(2-Cyclo hex-1-enyl-ethyl)-3-methoxy-benzamide; [0508]
N-Adamantan-2-yl-3-(1,5-dimethyl-1H-pyrazol-4-yl)-acrylamide;
[0509]
N-Adamantan-1-yl-N-methyl-4-(4-nitro-pyrazol-1-ylmethyl)-benzamide;
[0510]
5-(4-Chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-carboxylic
acid adamantan-2-ylamide; [0511]
2-(4-Chloro-phenoxy)-N-(2-fluoro-5-methyl-phenyl)-2-methyl-propionamide;
[0512]
N-Adamantan-1-yl-2-(4-chloro-3,5-dimethyl-phenoxy)-acetamide;
[0513]
2-[(3-Carboxy-bicyclo[2.2.1]heptane-2-carbonyl)-amino]-5,6-dihydr-
o-4H-cyclopenta[b]thiophene-3-carboxylic acid propyl ester; [0514]
2-Adamantan-1-yl-N-[1-(2,5-dimethyl-phenyl)-ethyl]-acetamide;
[0515] 3-Methyl-thiophene-2-carboxylic acid cyclooctylamide; [0516]
N-p-Tolyl-2-(8,11,11-trimethyl-3,4,6-triaza-tricyclo[6.2.1.0.sup.2,7]unde-
ca-2,4,6-trien-5-ylsulfanyl)propionamide; [0517]
Azepan-1-yl-[5-(4-chloro-5-methyl-3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-
-methanone; [0518]
N-Adamantan-2-yl-3-(4-bromo-3-nitro-pyrazol-1-ylmethyl)-benzamide;
[0519] N-Bicyclo[2.2.1]hept-2-yl-2-chloro-benzamide; [0520]
[5-(3-Chloro-phenoxymethyl)-furan-2-yl]-piperidin-1-yl-methanone;
[0521]
1-(4-Ethyl-benzoyl)-6-methoxy-2-methyl-2,3-dihydro-1H-quinolin-4-one;
[0522]
6-Fluoro-2-methyl-1-{3-[4-(propane-1-sulfonyl)-phenoxymethyl]-ben-
zoyl}-2,3-dihydro-1H-quinolin-4-one; [0523]
N-Cycloheptyl-2-(naphthalen-1-yloxy)-acetamide; [0524]
N-Cyclohexyl-4-o-tolyloxy-butyramide; [0525]
(2-Benzylsulfanyl-phenyl)-morpholin-4-yl-methanone; [0526]
(2-Chloro-5,6-difluoro-3-methyl-phenyl)-(4-methyl-piperidin-1-yl)-methano-
ne; [0527]
(3-Bromo-phenyl)-[4-(4-chloro-2-nitro-phenyl)-piperazin-1-yl]-methanone;
[0528] 2-Bromo-N-(1,1,3,3-tetramethyl-butyl)-benzamide; [0529]
N-Adamantan-1-yl-2-(2-benzoyl-5-methoxy-phenoxy)-acetamide; [0530]
N-Cyclohexyl-3-methyl-4-p-tolyl-butyramide; [0531]
[5-(4-Methyl-2-nitro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methan-
one; [0532]
[5-(2,5-Dichloro-phenoxymethyl)-furan-2-yl]-thiomorpholin-4-yl-methanone;
[0533] 5-(4-Chloro-2-nitro-phenoxymethyl)-furan-2-carboxylic acid
adamantan-1-ylamide; [0534]
4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
cyclohexylamide; [0535]
4-Chloro-1,5-dimethyl-1H-pyrazole-3-carboxylic acid
adamantan-1-yl-methyl-amide; [0536]
4-(4-Methoxy-3-methyl-phenyl)-N-(2-methyl-cyclohexyl)-butyramide;
[0537]
3-Benzo[1,3]dioxol-5-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-propenone;
[0538] N-Bicyclo[2.2.1]hept-2-yl-3-phenylsulfanyl-propionamide;
[0539]
Azepan-1-yl-[5-(2-nitro-phenoxymethyl)-furan-2-yl]-methanone;
[0540] N-Benzyl-2-(4-chloro-phenylsulfanyl)-N-methyl-acetamide;
[0541] 1-(4-Benzyl-piperidin-1-yl)-2-benzylsulfanyl-ethanone;
[0542]
2-(4-tert-Butyl-phenoxy)-1-(4-ethyl-piperazin-1-yl)-ethanone;
[0543]
[4-(4-Ethoxy-phenoxymethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone;
[0544]
5-(4-Bromo-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-carboxylic acid
adamantan-2-ylamide; [0545]
1-Azepan-1-yl-3-(4-chloro-phenylsulfanyl)-propan-1-one; [0546]
N-Bicyclo[2.2.1]hept-2-yl-2-(2-chloro-benzylsulfanyl)-acetamide;
[0547]
2-(2-Methyl-benzylsulfanyl)-1-(4-phenyl-piperazin-1-yl)-ethanone;
[0548]
N-[2-(1-Benzo[1,3]dioxol-5-yl-3-furan-2-yl-3-oxo-propylsulfanyl)-phenyl]-
-acetamide; [0549]
(3,5-Dimethyl-piperidin-1-yl)-(3-iodo-phenyl)-methanone; [0550]
[5-(2-Bromo-phenoxymethyl)-furan-2-yl]-(6-fluoro-2-methyl-3,4-dihydro-2H--
quinolin-1-yl)-methanone; [0551]
N-Benzyl-N-cyclohex-1-enyl-isonicotinamide; [0552]
1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-benzylsulfanyl)-ethano-
ne; [0553]
2-(2-Bromo-4-methyl-phenoxy)-N-(2-cyclohex-1-enyl-ethyl)-acetamide;
[0554]
2-[5-(2-Hydroxy-phenyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-1-piperidi-
n-1-yl-ethanone; [0555]
5-(4-Nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid
adamantan-2-ylamide; [0556]
3-Benzo[1,3]dioxol-5-yl-3-(2-methoxy-phenyl)-1-pyrrolidin-1-yl-propan-1-o-
ne; [0557] N-Adamantan-2-yl-3,4-dichloro-benzamide; [0558]
Benzo[b]thiophen-3-yl-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-me-
thanone; [0559]
2-Adamantan-1-yl-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone;
[0560] 4,5,6,7-Tetrahydro-benzo[b]thiophene-3-carboxylic acid
(2-cyclohex-1-enyl-ethyl)-amide; [0561]
Benzo[b]thiophene-3-carboxylic acid
(3,3,5-trimethyl-cyclohexyl)-amide; [0562]
2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide; [0563]
4-Bromo-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide; [0564]
N-Benzo[1,3]dioxol-5-ylmethyl-2-(2-cyano-phenylsulfanyl)-benzamide;
[0565] N-Adamantan-1-yl-2-(naphthalen-2-yloxy)-acetamide; [0566]
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-morpholin-4-yl-methanone;
[0567] Thiophene-2-carboxylic acid
(3,3,5-trimethyl-cyclohexyl)-amide; [0568]
Benzo[1,3]dioxol-5-yl-(3,4-dihydro-2H-quinolin-1-yl)-methanone;
[0569] 3-Chloro-benzo[b]thiophene-2-carboxylic acid
cyclooctylamide; [0570]
2-[2-Morpholin-4-yl-1-(4-nitro-benzyl)-2-oxo-ethyl]-isoindole-1,3-
-dione; [0571]
2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enecarboxylic acid
phenylamide; [0572]
(2,4-Dichloro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
[0573] Adamantane-1-carboxylic acid furan-2-ylmethyl-p-tolyl-amide;
[0574] Azocan-1-yl-(4-tert-butyl-phenyl)-methanone; [0575]
3-Chloro-benzo[b]thiophene-2-carboxylic acid benzyl-methyl-amide;
[0576] Adamantane-1-carboxylic acid (2-fluoro-phenyl)-amide; [0577]
2-(Piperidine-1-carbonyl)-5-piperidin-1-yl-oxazole-4-carbonitrile;
[0578] N-(4,6-Dimethyl-5-nitro-pyridin-3-yl)-benzamide; [0579]
Adamantan-1-yl-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
[0580] (2-Methyl-piperidin-1-yl)-o-tolyl-methanone; [0581]
N-Benzyl-4-chloro-N-isopropyl-3-nitro-benzamide; [0582]
N-(3-Hexylsulfanyl-[1,2,4]thiadiazol-5-yl)-3-methyl-butyramide;
[0583] 4,
N-Dimethyl-N-[4-(piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;
[0584] Azepan-1-yl-(5-tert-butyl-2H-pyrazol-3-yl)-methanone; [0585]
2-Amino-4-methyl-5-(piperidine-1-carbonyl)-thiophene-3-carboxylic
acid ethyl ester; [0586] 5-Methyl-furan-2-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide; [0587]
(3-Chloro-6-methyl-benzo[b]thiophen-2-yl)-(3,4-dihydro-1H-isoquinolin-2-y-
l)-methanone; [0588] N-Adamantan-1-yl-2-trifluoromethyl-benzamide;
[0589]
(3-Bromo-phenyl)-(2,2,4-trimethyl-4-phenyl-3,4-dihydro-2H-quinoli-
n-1-yl)-methanone; [0590] Benzo[1,3]dioxole-5-carboxylic acid
dipropylamide; [0591] N-(3,3-Diphenyl-propyl)-4-methoxy-benzamide;
[0592]
[4-(2-Chloro-6-nitro-phenyl)-piperazin-1-yl]-p-tolyl-methanone;
[0593]
Furan-2-yl-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-methanone;
[0594]
3-(2-Chloro-6-fluoro-phenyl)-1-(3,4-dihydro-2H-quinolin-1-yl)-pro-
penone; [0595] 2-Chloro-N-cycloheptyl-benzamide; [0596]
1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-3-phenyl-propan-1-one; [0597]
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3,4-dimethyl-phenyl)-methanone;
[0598]
(1-Adamantan-1-yl-4-bromo-1H-pyrazol-3-yl)-morpholin-4-yl-methano-
ne; [0599] 2-Phenyl-cyclopropanecarboxylic acid cyclooctylamide;
[0600]
3-[4-(2-Ethoxy-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
[0601]
[3-(4-Bromo-pyrazol-1-ylmethyl)-phenyl]-(4-methyl-piperidin-1-yl)-methano-
ne; [0602] 2-Azepan-1-yl-N-biphenyl-2-yl-acetamide; [0603]
N-[5-(3,4-Dimethoxy-benzyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-butyramide;
[0604] Adamantan-1-yl-(4-phenyl-piperidin-1-yl)-methanone; [0605]
N-(2-Azepan-1-yl-2-oxo-ethyl)-N-(4-ethoxy-phenyl)-4-methylsulfanyl-benzen-
esulfonamide; [0606]
1-Adamantan-1-yl-4-bromo-1H-pyrazole-3-carboxylic acid
diethylamide; [0607]
(6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(2-fluoro-phenyl)-methan-
one; [0608]
3-[4-(2,3-Dimethyl-phenyl)-piperazine-1-carbonyl]-isochromen-1-one;
[0609] N-Cyclooctyl-2-(2-methoxy-phenoxy)-acetamide; [0610]
N-Cyclohexyl-N-methyl-2-nitro-benzamide; [0611]
Adamantane-1-carboxylic acid
(1,1-dioxo-tetrahydro-thiophen-3-yl)-amide; [0612]
N-Adamantan-2-yl-2-(4-chloro-phenyl)-acetamide; [0613]
(2,4-Dichloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone; [0614]
2-(4-tert-Butyl-phenoxy)-N-cyclooctyl-acetamide; [0615]
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(2-methoxy-phenyl)-methanone;
[0616] (3-Chloro-phenyl)-(2-methyl-piperidin-1-yl)-methanone;
[0617]
(3-Chloro-6-nitro-benzo[b]thiophen-2-yl)-(3-methyl-piperidin-1-yl)-methan-
one; [0618]
(2,5-Dichloro-phenyl)-(4-methyl-piperidin-1-yl)-methanone; [0619]
N-[5-(3,4-Dichloro-benzyl)-[1,3,4]thiadiazol-2-yl]-2,2-dimethyl-p-
ropionamide; [0620]
4-(4-Chloro-2-methyl-phenoxy)-1-(3,4-dihydro-2H-quinolin-1-yl)-butan-1-on-
e; [0621]
(3,4-Dichloro-phenyl)-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanone;
[0622] Cyclooctanecarboxylic acid
[1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-amide; [0623]
1-Butyl-pyrrolidine-2-carboxylic acid benzo[1,3]dioxol-4-ylamide;
[0624] 5-Methyl-furan-2-carboxylic acid dibenzylamide; [0625]
(3,4-Dihydro-2H-quinolin-1-yl)-[3-(4-phenyl-piperazine-1-sulfonyl)-phenyl-
]-methanone; [0626]
Bicyclo[2.2.1]hept-2-yl-[4-(2,3-dimethyl-phenyl)-piperazin-1-yl]-methanon-
e; [0627] N-Adamantan-1-yl-2-benzoyl-benzamide; [0628]
[5-(2-Chloro-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-yl)-methano-
ne; [0629] (3,5-Dimethyl-piperidin-1-yl)-(2-iodo-phenyl)-methanone;
[0630] 1-Benzenesulfonyl-pyrrolidine-2-carboxylic acid
cyclooctylamide; [0631]
(3,4-Dimethoxy-phenyl)-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-
-1-yl)-methanone; [0632]
3-(2,6-Dichloro-phenyl)-1-(2-ethyl-piperidin-1-yl)-propenone;
[0633] N-(3,4-Difluoro-phenyl)-2,6-difluoro-benzamide; [0634]
2,6-Difluoro-N-naphthalen-1-yl-benzamide; [0635]
(4-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone; [0636]
N-[4-(2,6-Dimethyl-piperidine-1-carbonyl)-phenyl]-2-(naphthalen-2-yloxy)--
acetamide; [0637]
(2-Chloro-phenyl)-(3-methyl-piperidin-1-yl)-methanone; [0638]
N-{2-[4-(Piperidine-1-sulfonyl)-phenyl]-ethyl}-acetamide; [0639]
N-Biphenyl-2-yl-2-(pyridin-2-ylsulfanyl)-acetamide; [0640]
Azepan-1-yl-[5-(4-chloro-3,5-dimethyl-pyrazol-1-ylmethyl)-furan-2-yl]-met-
hanone; [0641] Acetic acid
4-(4-methyl-piperidine-1-carbonyl)-phenyl ester; [0642] Acetic acid
4-(4-benzyl-piperidine-1-carbonyl)-phenyl ester; [0643]
Benzo[1,3]dioxole-5-carboxylic acid cycloheptylamide; [0644]
2-(2,4-Dimethyl-phenoxy)-1-(6-fluoro-2-methyl-3,4-dihydro-2H-quin-
olin-1-yl)-ethanone; [0645] Acetic acid
4-(3,4-dihydro-2H-quinoline-1-carbonyl)-phenyl ester; [0646]
Azepan-1-yl-(3,5-dibromo-phenyl)-methanone; [0647]
(3,5-Dibromo-phenyl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;
[0648] N-Cyclooctyl-4-isopropyl-benzamide; [0649]
N-Cyclooctyl-2-(4-methoxy-phenyl)-acetamide; [0650]
(4-tert-Butyl-piperidin-1-yl)-phenyl-methanone; [0651]
N-(4-tert-Butyl-3-nitro-phenyl)-acetamide; [0652]
(2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-fura-
n-2-yl]-methanone; [0653]
N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamid-
e; [0654]
2-(4-Chloro-3-methyl-phenoxy)-N-cyclohexyl-N-methyl-acetamide;
[0655]
N-Cyclopentyl-3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzenesul-
fonamide; [0656]
(3,4-Dihydro-1H-isoquinolin-2-yl)-(3-dimethylamino-phenyl)-methanone;
[0657] 3-Cyclohexylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic
acid isopropyl ester; [0658]
1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-(2-methoxy-phenyl)-ethanone;
[0659] N-Benzyl-N-cyclohex-1-enyl-benzamide; [0660]
[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[-
3.2.1]oct-6-yl)-methanone; [0661]
N-Adamantan-1-yl-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-acetamide;
[0662]
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(morpholine-4-sulfonyl)-phenyl]-methan-
one; [0663]
(3,4-Dihydro-2H-quinolin-1-yl)-[4-(pyrrolidine-1-sulfonyl)-phenyl]-methan-
one; [0664]
(3,4-Dihydro-2H-quinolin-1-yl)-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]--
methanone; [0665]
(1-Benzenesulfonyl-piperidin-3-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-meth-
anone; [0666]
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]nonane-3-carboxylic
acid cyclohexylamide; [0667]
6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]nonane-3-carboxylic
acid (2-chloro-phenyl)-amide; [0668]
(6,7-Dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]non-3-yl)-piperidin-1-yl-met-
hanone; [0669]
2-(5,6-Dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulfanyl)-N--
furan-2-ylmethyl-acetamide; [0670]
N-Allyl-2-(5,6-dimethyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-ylsulf-
anyl)-acetamide; [0671]
N-Adamantan-1-yl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-
-ylsulfanyl)acetamide; [0672]
1-(3,4-Dihydro-2H-quinoline-1-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[2.2-
.1]heptan-3-one; [0673]
1-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-4,7,7-trimethyl-2-oxa-bicyclo[-
2.2.1]heptan-3-one; [0674]
Azepan-1-yl-(6,7-dimethyl-4-oxa-tricyclo[4.3.0.0.sup.3,7]non-3-yl)-methan-
one; [0675] 2,5-Dimethyl-furan-3-carboxylic acid
(1-adamantan-1-yl-ethyl)-amide; [0676]
1-Cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid
(3-cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-amide; [0677]
2-(2-Cyano-phenylsulfanyl)-N-cyclopentyl-benzamide; [0678]
[5-(2-Methoxy-4-propyl-phenoxymethyl)-furan-2-yl]-(3-methyl-piperidin-1-y-
l)-methanone; [0679]
(4-tert-Butyl-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[0680]
[4-(2-Methoxy-naphthalen-1-ylmethyl)-piperazin-1-yl]-(4-methoxy-phenyl)-m-
ethanone; [0681]
(3,4-Dichloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone;
[0682] (4-Ethoxy-phenyl)-(4-methyl-piperidin-1-yl)-methanone;
[0683] 2-Phenethyl-N-(tetrahydro-furan-2-ylmethyl)-benzamide;
[0684] N-Cycloheptyl-2-phenoxy-benzamide; [0685]
Adamantane-1-carboxylic acid (2-ethoxy-phenyl)-amide; [0686]
N-Adamantan-2-yl-2-o-tolyloxy-acetamide; [0687]
(2-Chloro-phenyl)-(3,5-dimethyl-piperidin-1-yl)-methanone; [0688]
1-Morpholin-4-yl-2-[3-(4-nitro-phenyl)-adamantan-1-yl]-ethanone;
[0689] 2-Dimethylamino-N-(2-nitro-phenyl)-benzamide; [0690]
N-Benzyl-2-(4,4,6-trimethyl-1-p-tolyl-1,4-dihydro-pyrimidin-2-ylsulfanyl)-
-acetamide; [0691]
[4-(3,5-Dinitro-phenoxy)-phenyl]-(2-ethyl-piperidin-1-yl)-methanone;
[0692] 1-(4-Chloro-benzoyl)-2,3-dihydro-1H-benzo[g]quinolin-4-one;
[0693] 2-[(Adamantane-1-carbonyl)-amino]-3-phenyl-propionic acid
methyl ester; [0694] [Benzyl-(4-nitro-benzoyl)-amino]-acetic acid
ethyl ester; [0695] 9-Oxo-9H-fluorene-3-carboxylic acid
methyl-(4-nitro-phenyl)-amide; [0696] Adamantane-1-carboxylic acid
[2-(4-methoxy-phenyl)-ethyl]-amide; [0697]
(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-(4-fluoro-phenyl)-methanone;
[0698] 2-Benzylsulfanyl-N-[2-(2-methoxy-phenoxy)-ethyl]-acetamide;
[0699]
N-Adamantan-1-yl-2-(2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide;
[0700] 2-Bromo-N-tricyclo[3.2.1.0.sup.2,4]oct-6-ylmethyl-benzamide;
[0701] Adamantane-1-carboxylic acid
(2,6-dimethoxy-pyrimidin-4-yl)-amide; [0702] Hexanedioic acid
(2,7,7-trimethyl-bicyclo[2.2.1]hept-1-yl)-amide(1,7,7-trimethyl-bicyclo[2-
.2.1]hept-2-yl)-amide; [0703]
2-Chloro-N-(2-cyclohexyl-ethyl)-benzamide; [0704]
2-[3-(2-Ethyl-piperidin-1-yl)-3-oxo-propyl]-isoindole-1,3-dione;
[0705] N-Adamantan-1-yl-2-hydroxy-2,2-diphenyl-acetamide; [0706]
Adamantane-1-carboxylic acid (naphthalen-1-ylmethyl)-amide; [0707]
Adamantane-1-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide;
[0708] 1-(Azepane-1-carbonyl)-fluoren-9-one; [0709]
2-(Quinolin-2-ylsulfanyl)-N-p-tolyl-acetamide; [0710]
2,4-Dichloro-N-[3-(piperidine-1-carbonyl)-phenyl]-benzamide; [0711]
2-Chloro-4,5-difluoro-N-(3,3,5-trimethyl-cyclohexyl)-benzamide;
[0712] 2-(2-Chloro-benzylsulfanyl)-N-p-tolyl-acetamide; [0713]
[4-(4-Chloro-phenylsulfanylmethyl)-phenyl]-pyrrolidin-1-yl-methanone;
[0714] N-Adamantan-1-yl-N-methyl-isonicotinamide; [0715]
Azepan-1-yl-[4-(4-chloro-phenylsulfanylmethyl)-phenyl]-methanone;
[0716]
(2-Chloro-phenyl)-(1,5,7-trimethyl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-met-
hanone; [0717]
(3-Chloro-benzo[b]thiophen-2-yl)-(4-methyl-piperidin-1-yl)-methanone;
[0718] Benzoic acid 1-benzoyl-decahydro-quinolin-4-yl ester; [0719]
2-(3-Bromo-benzylsulfanyl)-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethano-
ne; [0720]
4-Methyl-N-[2-(phenoxazine-10-carbonyl)-phenyl]-benzenesulfonamide;
[0721]
2-[1-(Azepane-1-carbonyl)-2-methyl-propyl]-isoindole-1,3-dione;
[0722] 2-(3-Bromo-benzylsulfanyl)-1-piperidin-1-yl-ethanone; [0723]
1-[3-(4-Bromo-phenyl)-1-furan-2-yl-3-oxo-propyl]-pyrrolidin-2-one;
[0724] 2-Chloro-N-cyclooctyl-4,5-difluoro-benzamide; [0725]
2,4-Dichloro-N-(2-furan-2-ylmethyl-cyclohexyl)-benzamide; [0726]
N-(4-Benzoyl-furazan-3-yl)-2-fluoro-benzamide; [0727]
N-Adamantan-1-yl-2-(3-cyano-4-methoxymethyl-6-methyl-pyridin-2-ylsulfanyl-
)-acetamide; [0728] 4-tert-Butyl-N-cyclooctyl-benzamide; [0729]
N-Adamantan-1-yl-2-phenyl-butyramide; [0730]
(3-Chloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
[0731]
(3,7-Dichloro-6-methoxy-benzo[b]thiophen-2-yl)-piperidin-1-yl-met-
hanone; [0732] Acetic acid 1-benzoyl-decahydro-quinolin-4-yl ester;
[0733] 2-Bromo-N-methyl-N-phenyl-benzamide; [0734]
N-Benzo[1,3]dioxol-5-yl-2,4-dichloro-benzamide; [0735]
(3-Chloro-6-fluoro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone;
[0736]
N-(1,2,3,5,6,7-Hexahydro-s-indacen-1-yl)-2-piperidin-1-yl-acetami-
de; [0737]
2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-met-
hyl-butyric acid methyl ester; [0738]
2-(6-Oxo-6-piperidin-1-yl-hexyl)-isoindole-1,3-dione; [0739]
2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propionylamino]-3-met-
hyl-butyric acid methyl ester; [0740] Adamantane-1-carboxylic acid
(2,6-dihydroxy-pyrimidin-4-yl)-amide; [0741]
Adamantane-1-carboxylic acid methyl-phenyl-amide; [0742]
3-Chloro-benzo[b]thiophene-2-carboxylic acid dibenzylamide; [0743]
N-Adamantan-1-yl-2-(3-cyano-6-methyl-4-trifluoromethyl-pyridin-2-ylsulfan-
yl)-acetamide; [0744]
2-(3-Oxo-3-phenyl-propenyl)-isoindole-1,3-dione; [0745]
N-[5-(5-Chloro-benzooxazol-2-yl)-2-methyl-phenyl]-2-methoxy-benza-
mide; [0746]
N-[2-(2-Bromo-phenyl)-benzooxazol-5-yl]-2-methoxy-benzamide; [0747]
2-(4-Chloro-phenoxy)-N-(4-chloro-3-trifluoromethyl-phenyl)-acetamide;
[0748]
2,2-Dimethyl-N-(5-propyl-[1,3,4]thiadiazol-2-yl)-propionamide;
[0749]
2-[2-(2,6-Dimethyl-morpholin-4-yl)-1-methyl-2-oxo-ethyl]-isoindol-
e-1,3-dione; [0750]
2-(2-Cyano-phenylsulfanyl)-N-(2-trifluoromethyl-phenyl)-benzamide;
[0751] Azepan-1-yl-(3,6-dichloro-benzo[b]thiophen-2-yl)-methanone;
[0752] Benzo[1,3]dioxol-5-yl-(4-benzyl-piperidin-1-yl)-methanone;
[0753]
Azepan-1-yl-(3-chloro-6-methyl-benzo[b]thiophen-2-yl)-methanone;
[0754] N-(5-Hexyl-[1,3,4]thiadiazol-2-yl)-isobutyramide; [0755]
(3-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methanone;
[0756]
(2-Chloro-phenyl)-(10,11-dihydro-dibenzo[b,f]azepin-5-yl)-methano-
ne; [0757]
2-Amino-5-(azepane-1-carbonyl)-4-methyl-thiophene-3-carboxylic acid
ethyl ester; [0758]
Adamantan-1-yl-(4-cyclopropyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5--
yl)-methanone; [0759]
Adamantan-1-yl-(4-trifluoromethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridi-
n-5-yl)-methanone; [0760]
Adamantan-1-yl-[4-(1H-benzoimidazol-2-ylsulfanyl)-piperidin-1-yl]-methano-
ne; [0761]
Adamantan-1-yl-(1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-methanone;
[0762]
[4-(1H-Imidazol-4-yl)-piperidin-1-yl]-(4-pentyl-phenyl)-methanon-
e; [0763]
3-Cyclohexyl-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one;
[0764]
1-(4-Propyl-piperazin-1-yl)-3-(4-trifluoromethyl-phenyl)-propan-1-
-one; [0765]
N-(2-Hydroxy-benzyl)-3-thiophen-3-yl-N-(2-thiophen-2-yl-ethyl)-acrylamide-
; [0766]
N-(1,3-Dimethyl-pentyl)-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl-
)-acetamide; [0767]
N-Cyclobutyl-2-(3-fluoro-phenyl)-N-(4-hydroxy-benzyl)-acetamide;
[0768]
N-Cyclobutyl-N-(4-hydroxy-benzyl)-4-trifluoromethyl-benzamide;
[0769]
N-(3-Hydroxy-benzyl)-2-methyl-3-nitro-N-(4-sulfamoyl-benzyl)-benzamide;
[0770]
N-(4-Bromo-benzyl)-N-(4-hydroxy-benzyl)-2-naphthalen-1-yl-acetami-
de; [0771] 6-(2-Bromo-phenylsulfanyl)-hexanoic acid
(3-amino-2,2-dimethyl-propyl)-amide; [0772]
N-(3-Amino-2,2-dimethyl-propyl)-4-[2-(2-isopropyl-phenylsulfanyl)-ethyl]--
benzamide; [0773]
N-(3-Amino-2,2-dimethyl-propyl)-4-[4-(4-chloro-phenyl)-pyrimidin-2-ylsulf-
anylmethyl]-3-nitro-benzamide; [0774]
4-(4-Bromo-phenyl)-N-(2-hydroxy-benzyl)-4-oxo-N-thiophen-2-ylmethyl-butyr-
amide; [0775]
N-[2-(2,4-Dichloro-phenyl)-ethyl]-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-ac-
etamide; [0776]
N-(2-Chloro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-2-yl-acetamide;
[0777] Heptanoic acid benzyl-(4-hydroxy-benzyl)-amide; [0778]
N-(4-Fluoro-benzyl)-N-(4-hydroxy-benzyl)-2-thiophen-3-yl-acetamide;
[0779] 4-Methyl-pentanoic acid
(4-fluoro-benzyl)-(4-hydroxy-benzyl)-amide; [0780]
N-Allyl-2-(4-chloro-phenyl)-N-(4-hydroxy-benzyl)-acetamide; [0781]
N-Allyl-2-benzo[b]thiophen-3-yl-N-(4-hydroxy-benzyl)-acetamide;
[0782] Heptanoic acid (3-ethoxy-propyl)-(4-hydroxy-benzyl)-amide;
[0783] Dec-3-enoic acid
(4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; [0784]
6-Oxo-6-phenyl-hexanoic acid
(4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; [0785]
2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetam-
ide; [0786] 2-Methyl-pent-4-enoic acid
(3-hydroxy-benzyl)-[2-(2-methoxy-phenyl)-ethyl]-amide; [0787]
Heptanoic acid (3-hydroxy-benzyl)-(4-isopropyl-benzyl)-amide;
[0788] 5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid
(naphthalen-1-ylmethyl)-amide; [0789]
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(5-methyl-1H-benzoimi-
dazol-2-ylsulfanyl)ethyl]-benzamide; [0790]
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-phenoxy-pyrimidin--
2-ylsulfanyl)-ethyl]-benzamide; [0791]
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-4-[2-(4-fluoro-phenylsulfa-
nyl)-ethyl]-benzamide; [0792]
4-(2,6-Dichloro-phenylsulfanyl)-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylme-
thyl)-butyramide; [0793]
5-(3-Methylsulfanyl-[1,2,4]thiadiazol-5-ylsulfanyl)-pentanoic acid
(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-amide; [0794]
5-(2,6-Dichloro-phenylsulfanyl)-pentanoic acid
[2-(3-trifluoromethyl-phenyl)-ethyl]-amide; [0795]
4-[2-(2,6-Dichloro-phenylsulfanyl)-ethyl]-N-[2-(2-fluoro-phenyl)-ethyl]-b-
enzamide; [0796] 2-Cyclohexylamino-thiazole-4-carboxylic acid
(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide; [0797]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(3-chloro-4-hydroxy-phenyl)-amide; [0798]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1,2-dimethyl-propyl)-amide; [0799]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1-ethyl-propyl)-amide; [0800]
2-Cyclohexylamino-thiazole-4-carboxylic acid
[3-(1-hydroxy-ethyl)-phenyl]-amide; [0801]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(1-ethynyl-cyclohexyl)-amide; [0802]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(2-methoxy-dibenzofuran-3-yl)-amide; [0803]
2-Cyclohexylamino-thiazole-4-carboxylic acid
[2-(4-hydroxy-phenyl)-ethyl]-amide; [0804]
2-Cyclohexylamino-thiazole-4-carboxylic acid
(4-hydroxy-cyclohexyl)-amide; [0805]
2-(2,6-Difluoro-benzylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-aceta-
mide; [0806]
4-{4-[2-(4-Dimethylamino-phenyl)-acetyl]-piperazin-1-yl}-3-(2-phenyl-prop-
ylamino)-benzamide; [0807]
2-(2-Ethyl-phenylsulfanyl)-3-[methyl-(2-pyridin-4-yl-ethyl)-amino]-N-prop-
-2-ynyl-propionamide; [0808] 4-Methyl-cyclohexanecarboxylic acid
{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-methyl}-prop-2-yny-
l-amide; [0809]
2-Benzylsulfanyl-N-{[2-(2-chloro-6-fluoro-benzylsulfanyl)-ethylcarbamoyl]-
-methyl}-N-(2-methoxyethyl)-acetamide; [0810]
4-[2-(5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-ethyl]--
N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-benzamide; [0811]
N-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethyl)-2-p-tolyloxy-acetamide;
[0812] Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid
[4-(2,5-difluoro-phenoxy)-butyl]-amide; [0813]
4-Trifluoromethyl-cyclohexanecarboxylic acid
[6-(2,6-difluoro-phenoxy)-hexyl]-amide; [0814]
N-Cyclopropyl-3-methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl-
)-benzamide; [0815]
3-Methoxy-N-(2-methoxy-ethyl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-ca-
rbonyl)-benzamide; [0816]
3-Methoxy-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-N-(tetrahydr-
o-furan-2-ylmethyl)benzamide; [0817]
3-Methoxy-N-(2-oxo-azepan-3-yl)-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2--
carbonyl)-benzamide; [0818]
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-N-(2-piperidin-4-yl-ethyl)-
-5-(pyridine-2-carbonyl)benzamide; [0819]
3-Methoxy-N-methyl-N-(2-piperidin-4-yl-ethyl)-5-(pyridine-2-carbonyl)-ben-
zamide; [0820]
[2-({Cyclopropyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methy-
l)-phenoxy]-acetic acid; [0821]
(2-{[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(3-methyl-butyl)-amino]--
methyl}-phenoxy)acetic acid; [0822]
[2-({Cyclopentyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-methy-
l)-phenoxy]-acetic acid; [0823]
[2-({(2-Methoxy-ethyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-
-methyl)-phenoxy]-acetic acid; [0824]
[2-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-m-
ethyl)-phenoxy]-acetic acid; [0825]
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-meth-
yl)-phenoxy]-acetic acid; [0826]
[2-({Cyclopropylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-
-methyl)-phenoxy]-acetic acid; [0827]
[2-({[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-methyl-amino}-methyl)-ph-
enoxy]-acetic acid; [0828]
[4-(4-Hydroxy-benzyl)-piperazin-1-yl]-[3-methoxy-5-(pyridine-2-carbonyl)--
phenyl]-methanone; [0829]
{Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-aceti-
c acid; [0830]
{(3-Imidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-ami-
no}-acetic acid; [0831]
{[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-pyridin-4-yl-amino}-acetic
acid; [0832]
[[3-Methoxy-5-(pyridine-2-carbonyl)-benzoyl]-(2-oxo-azepan-3-yl)-amino]-a-
cetic acid; [0833]
3-Methoxy-N-(2-methoxy-ethyl)-N-piperidin-3-ylmethyl-5-(pyridine-2-carbon-
yl)-benzamide; [0834]
4-[3-Methoxy-5-(pyridine-2-carbonyl)-benzoylamino]-piperidine-1-carboxyli-
c acid ethyl ester; [0835]
3-Methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-5-(pyridine-2-carbonyl)-be-
nzamide; [0836]
3-({Carbamoylmethyl-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]-amino}-me-
thyl)-benzoic acid; [0837]
3-({(3-Imidazol-1-yl-propyl)-[3-methoxy-5-(pyridine-2-carbonyl)-benzoyl]--
amino}-methyl)-benzoic acid; [0838]
4-Amino-N-(3-hydroxy-benzyl)-N-indan-2-yl-2-propionylamino-butyramide;
[0839] 5-Amino-2-propionylamino-pentanoic acid
(3-hydroxy-benzyl)-indan-2-yl-amide; [0840]
N-Ethyl-2-hexylamino-N-(4-hydroxy-benzyl)-acetamide; [0841]
2-Hexylamino-N-(4-hydroxy-benzyl)-N-methyl-acetamide; [0842]
1-[1-(6-Phenyl-hexanoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;
[0843]
1-[1-(3-Cyclohexyl-propionyl)-piperidin-4-yl]-1,3-dihydro-benzoi-
midazol-2-one; [0844] N-(2-Hydroxy-benzyl)-N-isobutyl-benzamide;
[0845]
N-(2-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
[0846] N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide; [0847]
N-(4-Hydroxy-benzyl)-N-isobutyl-benzamide; [0848]
4-Hydroxy-N-(4-hydroxy-benzyl)-N-isobutyl-benzamide; [0849]
N-(4-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-isobutyl-acetamide;
[0850] N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-benzamide; [0851]
N-(2-Ethoxy-ethyl)-4-hydroxy-N-(4-hydroxy-benzyl)-benzamide; [0852]
N-(4-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide; [0853]
N-(3-Hydroxy-benzyl)-N-(4-methyl-pentyl)-benzamide; [0854]
N-(3-Hydroxy-benzyl)-2-(4-hydroxy-phenyl)-N-(4-methyl-pentyl)-acetamide;
[0855] N-(3-Hydroxy-benzyl)-N-(3-isopropoxy-propyl)-benzamide;
[0856] N-(2-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide;
[0857] N-(4-Hydroxy-benzyl)-N-(6-hydroxy-hexyl)-4-propyl-benzamide;
[0858] N-(4-Hydroxy-benzyl)-N-(3-methyl-butyl)-4-propyl-benzamide;
[0859]
N-[2-(4-Fluoro-benzylamino)-thiazol-4-ylmethyl]-N-phenethyl-butyramide;
or a salt thereof with a pharmaceutically acceptable acid or base,
or any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[0860] In another embodiment, the present invention is concerned
the substituted amides or prodrugs thereof of the general formula
(II) ##STR2## wherein R.sup.1 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl, wherein the cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.4; R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, wherein the alkyl and aryl groups
independently are optionally substituted with one or more of
R.sup.5; or R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14; R.sup.3 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl or hetaryl, wherein the alkyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently
are optionally substituted with one or more of R.sup.7; R.sup.4 and
R.sup.5 independently are hydrogen, hydroxy, oxo, cyano, halo,
methylendioxo, NR.sup.8R.sup.9, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxy, trihalomethyl, trihalomethyloxy,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, aryl, hetaryl, hetarylSO.sub.n,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyl-R.sup.6--C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylSO.sub.n,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy, hetarylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.15; R.sup.6 is oxygen,
sulphur, SO.sub.n or NR.sup.16; R.sup.7 is hydrogen, halo, hydroxy,
cyano, nitro, COOR.sup.17, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
methylendioxo, trihalomethyl, trihalomethyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, SO.sub.mNR.sup.8R.sup.9,
NR.sup.4R.sup.5carbonylC.sub.1-C.sub.6alkyl, arylthio, hetarylthio,
R.sup.18-carbonylNR.sup.8, arylSO.sub.n, hetarylSO.sub.n,
R.sup.19SO.sub.mNR.sup.8, arylthioC.sub.1-C.sub.6alkyl,
hetarylthioC.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkylR.sup.6C.sub.1-C.sub.6alkyl; wherein the
aryl and hetaryl groups independently are optionally substituted
with one or more R.sup.10; R.sup.8 and R.sup.9 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
C.sub.1-C.sub.6alkylSO.sub.m, arylSO.sub.m,
arylC.sub.1-C.sub.6alkylSO.sub.m, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.11; or R.sup.8 and R.sup.9 together with the nitrogen to
which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from
4 to 10 carbon atoms and from 0 to 2 additional heteroatoms
selected from nitrogen, oxygen or sulfur, the ring system
optionally being substituted with at least one halo, cyano,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, hydroxy, oxo, halo, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyl-oxy, NR.sup.12R.sup.13,
methylendioxo, trihalomethyl or trihalomethyloxy; R.sup.12 and
R.sup.13 independently are hydrogen, C.sub.1-C.sub.8alkyl or
arylC.sub.1-C.sub.6alkyl; R.sup.14 is hydrogen, halo, hydroxy, oxo,
nitro, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy or
aryloxy; R.sup.15 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
CONR.sup.8R.sup.9 or COOR.sup.17; R.sup.16 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl, hetarylC.sub.1-C.sub.6alkyl, alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, aryloxyC.sub.1-C.sub.6alkyl,
hetaryloxyC.sub.1-C.sub.6alkyl, arylthioC.sub.1-C.sub.6alkyl or
hetarylthioC.sub.1-C.sub.6alkyl; wherein the alkyl, cycloalkyl,
hetcycloalkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.10; R.sup.17 is hydrogen,
C.sub.1-C.sub.8alkyl, aryl or arylC.sub.1-C.sub.6alkyl; R.sup.18 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy or
R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl,
cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally
substituted with R.sup.15; R.sup.19 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl, hetarylC.sub.1-C.sub.6alkyl; m
is 1 or 2; n is 0, 1 or 2; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0861] In another embodiment of the present invention, in formula
(II) R.sup.1 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl, wherein the cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.4 as defined above.
[0862] In another embodiment of the present invention, in formula
(II) R.sup.2 is hydrogen or C.sub.1-C.sub.8alkyl, wherein the alkyl
group is optionally substituted with one or more of R.sup.5 as
defined above.
[0863] In another embodiment of the present invention, in formula
(II) R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.14; as defined above.
[0864] In another embodiment of the present invention, in formula
(II) R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached are 6-aza-bicyclo[3.2.1]octane.
[0865] In another embodiment of the present invention, in formula
(II) R.sup.3 is aryl or hetaryl, wherein the aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.7 as defined above.
In another embodiment of the present invention, in formula (II)
R.sup.3 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl, optionally substituted with one or
more of R.sup.7 as defined above.
[0866] In another embodiment of the present invention, in formula
(II) R.sup.4 and R.sup.5 independently are hydrogen, hydroxy, oxo,
halo, C.sub.1-C.sub.8alkyl, wherein the alkyl group is optionally
substituted with one or more of R.sup.15 as defined above.
[0867] In another embodiment of the present invention, in formula
(II) R.sup.7 is hydrogen, halo, hydroxy, cyano,
C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl, trihalomethyl, aryl,
arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy, hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, R.sup.18-carbonylNR.sup.8, or
R.sup.19SO.sub.mNR.sup.8, wherein the aryl and hetaryl groups
independently are optionally substituted with one or more R.sup.10
as defined above.
[0868] In another embodiment of the present invention, in formula
(II) R.sup.7 is halo, cyano, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10hetcycloalkyl, trihalomethyl, aryl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl,
hetaryloxy, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
NR.sup.8R.sup.9, R.sup.8-carbonylNR.sup.8, or
R.sup.19SO.sub.mNR.sup.8, wherein the aryl and hetaryl groups are
independently optionally substituted with one or more R.sup.10 as
defined above.
[0869] In another embodiment of the present invention, in formula
(II) R.sup.7 is R.sup.18-carbonylNR.sup.8 or
R.sup.19SO.sub.mNR.sup.8; wherein m, R.sup.8, R.sup.18 and R.sup.19
are defined as above.
[0870] In another embodiment of the present invention, in formula
(II) R.sup.8 is C.sub.1-C.sub.6alkyl.
[0871] In another embodiment of the present invention, in formula
(II) R.sup.8 and R.sup.9 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulfur, the ring system optionally being
substituted with at least one halo, cyano, C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy, hetarylcarboxy, arylC.sub.1-C.sub.6alkylcarboxy or
hetarylC.sub.1-C.sub.6alkylcarboxy.
[0872] In another embodiment of the present invention, in formula
(II) R.sup.15 is CONR.sup.8R.sup.9.
[0873] In another embodiment of the present invention, in formula
(II) R.sup.18 is C.sub.1-C.sub.6alkyl, optionally substituted with
R.sup.15 as defined above.
[0874] In another embodiment of the present invention, in formula
(II) R.sup.18 is aryl or hetaryl.
[0875] In another embodiment of the present invention, in formula
(II) R.sup.18 is arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl.
[0876] In another embodiment of the present invention, in formula
(II) R.sup.18 is R.sup.8R.sup.9NC.sub.1-C.sub.6alkyl; wherein
R.sup.8 and R.sup.9 are defined as above.
[0877] In another embodiment of the present invention, in formula
(II) R.sup.19 is aryl or hetaryl
[0878] In another embodiment of the present invention, in formula
(II) the aryl group is phenyl or pyridyl.
[0879] In another embodiment of the present invention, in formula
(II) the hetaryl group is thienyl, imidazolyl, oxazolyl, thiazolyl,
or indolyl.
[0880] In another embodiment of the present invention, the
compounds or prodrugs thereof of the general formula (II) are
selected from the group consisting of the compounds of examples 4
through 8 as described under EXAMPLES, COMPOUNDS OF GENERAL
FORMULAS (I) AND (II).
[0881] In another embodiment, the present invention concerns the
substituted amides or prodrugs thereof of the general formula (III)
##STR3## wherein R.sup.1 is aryl, arylC.sub.1-C.sub.6alkyl, hetaryl
or hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or
more of R.sup.6 independently; R.sup.2 is halo,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
aryl, arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted
with one or more R.sup.7; R.sup.3 is C.sub.1-C.sub.6alkyl
optionally substituted with one or more of R.sup.8; R.sup.4 is
C.sub.6-C.sub.10cycloalkyl, C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.8; or R.sup.3 and
R.sup.4 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated bicyclic/bridge ring
system containing from 7 to 12 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy,
wherein the alkyl and aryl groups independently are optionally
substituted with one or more of R.sup.9; R.sup.5 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.9; R.sup.6 and R.sup.7 independently are
hydrogen, hydroxy, oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6-alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl,
arylC.sub.1-C.sub.6alkyloxycarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.8 and R.sup.9
independently are hydrogen, C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6-alkyl, hydroxy,
oxo, cyano, NR.sup.10R.sup.11, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and
R.sup.11 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6-alkylcarboxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0882] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (III)
wherein:
R.sup.1 is aryl or hetaryl optionally substituted with one or more
R.sup.6 independently;
[0883] R.sup.2 is halo, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkylNR.sup.5C.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, alkenyl, alkynyl,
cycloalkyl and aryl groups independently are optionally substituted
with one or more R.sup.7;
R.sup.3 is C.sub.1-C.sub.6alkyl optionally substituted with one or
more of R.sup.8;
R.sup.4 is C.sub.6-C.sub.10cycloalkyl,
C.sub.6-C.sub.10hetcycloalkyl,
C.sub.6-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl or
C.sub.6-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl wherein the
alkyl, cycloalkyl and hetcycloalkyl groups independently are
optionally substituted with one or more of R.sup.8;
[0884] R.sup.5 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10-cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10hetcycloalkylC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl wherein the
alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.9;
[0885] R.sup.6 and R.sup.7 independently are hydrogen, hydroxy,
oxo, halo, nitro, cyano, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy, trihalomethyl, trihalomethoxy,
NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6-alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl,
arylC.sub.1-C.sub.6alkyloxycarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy;
[0886] R.sup.8 and R.sup.9 independently are hydrogen,
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6-alkyl, hydroxy, oxo, cyano,
NR.sup.10R.sup.11, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkyl-carbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy;
R.sup.10 and R.sup.11 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or
[0887] R.sup.10 and R.sup.11 together with the nitrogen to which
they are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6-alkylcarboxy; or
a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, a prodrug thereof, or any tautomeric forms.
[0888] In another embodiment of the present invention, in formula
(III) R.sup.1 is aryl, arylC.sub.1-C.sub.6alkyl or hetaryl
optionally substituted with one or more of R.sup.6.
[0889] In another embodiment of the present invention, in formula
(III) R.sup.1 is aryl optionally substituted with one or more of
R.sup.6.
[0890] In another embodiment of the present invention, in formula
(III) R.sup.1 is arylC.sub.1-C.sub.6alkyl optionally substituted
with one or more of R.sup.6.
[0891] In another embodiment of the present invention, in formula
(III) R.sup.1 is hetaryl optionally substituted with one or more of
R.sup.6.
[0892] In another embodiment of the present invention, in formula
(III) R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, trihalomethyl,
arylC.sub.1-C.sub.6alkyl, or hetarylC.sub.1-C.sub.6alkyl wherein
the alkyl, cycloalkyl and aryl groups independently are optionally
substituted with one or more R.sup.7.
[0893] In another embodiment of the present invention, in formula
(III) R.sup.2 is C.sub.1-C.sub.6alkyl optionally substituted with
one or more R.sup.7.
[0894] In another embodiment of the present invention, in formula
(III) R.sup.2 is trihalomethyl.
[0895] In another embodiment of the present invention, in formula
(III) R.sup.3 is C.sub.1-C.sub.6alkyl optionally substituted with
one or more of R.sup.8.
[0896] In another embodiment of the present invention, in formula
(III) R.sup.4 is C.sub.6-C.sub.10cycloalkyl, or
C.sub.6-C.sub.10hetcycloalkyl, wherein the cycloalkyl and
hetcycloalkyl groups independently are optionally substituted with
one or more of R.sup.8.
[0897] In another embodiment of the present invention, in formula
(III) R.sup.4 is C.sub.6-C.sub.10cycloalkyl optionally substituted
with one or more of R.sup.8.
[0898] In another embodiment of the present invention, in formula
(III) R.sup.4 is C.sub.6C.sub.6-C.sub.10hetcycloalkyl optionally
substituted with one or more of R.sup.8.
[0899] In another embodiment of the invention, in formula (III)
R.sup.3 and R.sup.4 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated
bicyclic/bridge ring system containing from 7 to 12 carbon atoms
and from 0 to 2 additional heteroatoms selected from nitrogen,
oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy, wherein the alkyl and aryl groups
independently are optionally substituted with one or more of
R.sup.9.
[0900] In another embodiment of the present invention, in formula
(III) the saturated or partially saturated bicyclic/bridge ring
system is 6-aza-bicyclo[3.2.1]octane.
[0901] In another embodiment of the present invention, in formula
(III) R.sup.6 and R.sup.7 independently are hydrogen, hydroxy, oxo,
halo, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, NR.sup.10R.sup.11, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, hetarylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkyloxycarbonyl, aryloxycarbonyl or
arylC.sub.1-C.sub.6alkyloxycarbonyl.
[0902] In another embodiment of the present invention, in formula
(III) R.sup.8 and R.sup.9 independently are hydrogen,
C.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy.
[0903] In another embodiment of the present invention, in formula
(III) R.sup.10 and R.sup.11 independently are hydrogen or
C.sub.1-C.sub.8alkyl.
[0904] In another embodiment of the present invention the compound
of the general formula (III) or a prodrug thereof is
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
forms.
[0905] In another embodiment of the present invention the compounds
of the general formula (III) or a prodrug thereof is selected from
the group consisting of: [0906]
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0907]
[1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; [0908] 1
[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone; [0909]
[1-(3,5-Dichloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-
-bicyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0910] In yet another embodiment of the present invention the
compounds of the general formula (III) or a prodrug thereof is
selected from the group consisting of: [0911]
1-(Phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0912]
1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0913]
1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0914]
1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0915]
1-(2-Methyl-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0916]
1-(4-Amino-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0917]
1-(2-Pyridyl)-5-methyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; [0918]
1-(2-Pyridyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
forms.
[0919] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (IV)
##STR4## wherein R.sup.1 is hydrogen, trihalomethyl,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl
or hetaralkyl, wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of
R.sup.8; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 independently are
hydrogen, halo, nitro, cyano, hydroxy, NR.sup.9R.sup.10,
trihalomethyl, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl
or hetaralkyl, wherein the alkyl, aryl and hetaryl groups
independently are optionally substituted with one or more of
R.sup.8; or R.sup.2 together with R.sup.3 are forming a saturated
or partially saturated cyclic ring system containing from 3 to 6
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy or hetarylC.sub.1-C.sub.6alkyloxy; or
R.sup.3 together with R.sup.4 are forming a saturated or partially
saturated cyclic ring system containing from 3 to 6 carbon atoms
and from 0 to 2 additional heteroatoms selected from nitrogen,
oxygen or sulphur, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy
or hetarylC.sub.1-C.sub.6alkyloxy; or R.sup.4 together with R.sup.5
are forming a saturated or partially saturated cyclic ring system
containing from 3 to 6 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.6 is aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; R.sup.7 is C.sub.1-C.sub.8alkyl,
aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; or R.sup.6 and R.sup.7, together with
the nitrogen to which they are attached, are forming a saturated or
partially saturated cyclic, bicyclic or tricyclic ring system
containing from 6 to 10 carbon atoms and from 0 to 2 additional
heteroatoms selected from nitrogen, oxygen or sulphur, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8; R.sup.9 and R.sup.10 independently are
hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl, wherein the alkyl,
aryl and cycloalkyl groups independently are optionally substituted
with one or more of R.sup.11; or R.sup.9 and R.sup.10, together
with the nitrogen to which they are attached, are forming a
saturated or partially saturated cyclic, bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6-alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8; R.sup.8 and R.sup.11 independently are
hydrogen, halo, hydroxy, oxo, nitro, cyano, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6-alkyloxy or aryloxy; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0920] In one embodiment of the present invention, in formula (IV)
R.sup.1 is hydrogen or C.sub.1-C.sub.6alkyl, wherein the alkyl
group is optionally substituted with one or more of R.sup.8.
[0921] In another embodiment of the present invention, in formula
(IV) R.sup.1 is hydrogen.
[0922] In another embodiment of the present invention, in formula
(IV) R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen.
[0923] In another embodiment of the present invention, in formula
(IV) R.sup.3 together with R.sup.4 are forming a saturated or
partially saturated cyclic ring system containing from 3 to 6
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy
or hetarylC.sub.1-C.sub.6alkyloxy.
[0924] In another embodiment of the present invention, in formula
(IV) R.sup.4 together with R.sup.5 are forming a saturated or
partially saturated cyclic ring system containing from 3 to 6
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy
or hetarylC.sub.1-C.sub.6alkyloxy.
[0925] In another embodiment of the present invention, in formula
(IV) R.sup.6 and R.sup.7, together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8;
[0926] In another embodiment of the present invention, in formula
(IV) R.sup.6 and R.sup.7; together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
bicyclic or tricyclic ring system containing from 6 to 10 carbon
atoms and from 0 to 2 additional heteroatoms selected from nitrogen
or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8.
[0927] In another embodiment of the present invention, in formula
(IV) R.sup.9 and R.sup.10, together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.8.
[0928] In another embodiment of the present invention a compound of
the general formula (IV) or a prodrug thereof is
pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; or a salt thereof with a pharmaceutically acceptable
acid or base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[0929] In another embodiment of the present invention the compounds
of the general formula (IV) or a prodrug thereof are: [0930]
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [0931] Pyrazolo[1,5-a]pyridine-3-carboxylic
acid cyclohexyl-methyl-amide; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[0932] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (V)
Accordingly, the present invention is concerned with compounds or
prodrugs thereof of the general formula (V): ##STR5## wherein
R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6SO.sub.2, arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or
hetarylC.sub.1-C.sub.6alkylSO.sub.2 all of which is optionally
substituted with one or more R.sup.8; R.sup.2 and R.sup.5
independently are hydrogen, halo, nitro, cyano, trihalomethyl,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl,
hetaryl and hetarylalkyl groups independently are substituted with
one or more R.sup.9; and either R.sup.3 is hydrogen; and R.sup.4 is
C(O)NR.sup.7R.sup.8; or R.sup.3 is C(O)NR.sup.7R.sup.8; and R.sup.4
is hydrogen; and R.sup.6 is hydrogen, halo, cyano, trihalomethyl,
NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.9; and R.sup.7
and R.sup.8 independently are C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.9 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
C(O)NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and
R.sup.11 independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.8alkylcarbonyl, hetarylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl; or R.sup.12 and
R.sup.13 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture,
a prodrug thereof, or any tautomeric forms.
[0933] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (Va)
##STR6## wherein R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more R.sup.8; R.sup.2 and
R.sup.5 independently are hydrogen, halo, nitro, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylC.sub.1-C.sub.6alkyl
wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.8; and either
R.sup.3 is hydrogen; and R.sup.4 is C(O)NR.sup.6R.sup.7; or R.sup.3
is C(O)NR.sup.6R.sup.7; and R.sup.4 is hydrogen; R.sup.6 and
R.sup.7 independently are C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.6 and R.sup.7
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10; R.sup.8 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.11R.sup.12,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.9 and R.sup.10 independently
are hydrogen, halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl; R.sup.11 and
R.sup.12 independently are hydrogen, C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyl-carboxyC.sub.1-C.sub.6alkyl; or R.sup.11 and
R.sup.12 together with the nitrogen to which they are attached, are
forming a saturated or partially saturated cyclic, bicyclic or
tricyclic ring system containing from 4 to 10 carbon atoms and from
0 to 2 additional heteroatoms selected from nitrogen, oxygen or
sulphur, the ring system optionally being substituted with at least
one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture,
or any tautomeric forms.
[0934] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
arylSO.sub.2, hetarylSO.sub.2, arylC.sub.1-C.sub.6alkylSO.sub.2 or
hetarylC.sub.1-C.sub.6alkylSO.sub.2 all of which is optionally
substituted with one or more R.sup.8.
[0935] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl all of which
is optionally substituted with one or more R.sup.8.
[0936] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.1 is arylSO.sub.2, hetarylSO.sub.2,
arylC.sub.1-C.sub.6alkylSO.sub.2 or
hetarylC.sub.1-C.sub.6alkylSO.sub.2 all of which is optionally
substituted with one or more R.sup.8.
[0937] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.2 is hydrogen.
[0938] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.3 is hydrogen and R.sup.4 is
C(O)NR.sup.7R.sup.8.
[0939] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.4 is
hydrogen.
[0940] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.5 is hydrogen.
[0941] In another embodiment of the present invention, in formula
(V) R.sup.6 is hydrogen, NR.sup.12R.sup.13, C.sub.1-C.sub.6alkyl,
aryl or hetaryl wherein the alkyl, aryl and hetaryl independently
are substituted with one or more R.sup.9.
[0942] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.7 and R.sup.8 independently are
C.sub.1-C.sub.8alkyl or C.sub.3-C.sub.10cycloalkyl, wherein the
alkyl and cycloalkyl groups independently are optionally
substituted with one or more of R.sup.10.
[0943] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.7 and R.sup.8 together with the nitrogen to
which they are attached, are forming a saturated or partially
saturated bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11.
[0944] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, C(O)NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl.
[0945] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.10 and R.sup.11 independently are hydrogen,
halo, oxo, hydroxy, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl.
[0946] In another embodiment of the present invention, in formula
(V) and (Va) R.sup.11 and R.sup.12 together with the nitrogen to
which they are attached, are forming a saturated or partially
saturated cyclic, bicyclic or tricyclic ring system containing from
4 to 10 carbon atoms and from 0 to 2 additional heteroatoms
selected from nitrogen or oxygen, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkyl-carbonyl,
hetarylC.sub.1-C.sub.6alkylarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy.
[0947] In another embodiment of the present invention the compound
of the general formulas (V) and (Va), or a prodrug thereof is
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; or a
salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[0948] In yet another embodiment of the present invention the
compounds of the general formulas (V) and (Va), or a prodrug
thereof is selected from the group consisting of: [0949]
1-Benzyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0950]
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct--
6-yl)-methanone; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
forms.
[0951] In another embodiment of the present invention, the
compounds of general formulas (V) and (Va), or a prodrug thereof is
selected from the group consisting of: [0952]
Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0953]
1-Benzyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0954]
2-Methyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0955]
2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0956]
2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide; [0957]
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone; [0958]
(2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone; [0959]
(2-Amino-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct--
6-yl)-methanone; [0960]
(2-Benzo[1,3]dioxol-5-yl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; [0961]
3-[5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-benzoimid-
azol-2-yl]-benzoic acid methyl ester; [0962]
(2-Thiophen-2-yl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.-
2.1]oct-6-yl)-methanone; [0963]
[2-(2-Nitro-phenyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, a prodrug
thereof, or any tautomeric forms.
[0964] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (VI)
##STR7## wherein X is oxygen or (CR.sup.1R.sup.2).sub.n; R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 independently are hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl optionally substituted with one or more
R.sup.8 independently; or R.sup.1 and either R.sup.3 or R.sup.4
together are forming a saturated or partially saturated ring system
containing from 4 to 8 carbon atoms, the ring system optionally
being substituted with at least one of C.sub.1-C.sub.6alkyl,
hydroxy, oxo, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyl; or R.sup.1 and either R.sup.3 or
R.sup.4 together with the single bond are forming a carbon-carbon
double bond; R.sup.5 is C.sub.1-C.sub.8alkyl optionally substituted
with one or more of R.sup.9; R.sup.6 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.9; or R.sup.5 and R.sup.6
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 6 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10; R.sup.7 is hydrogen, halo, nitro,
NR.sup.12R.sup.13, cyano, trihalomethyl, C.sub.1-C.sub.6alkyl,
aryl, arylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy,
arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetarylC.sub.1-C.sub.6alkyl,
hetaryloxy or hetarylC.sub.1-C.sub.6-alkyloxy optionally
substituted with one or more R.sup.11 independently; R.sup.8 and
R.sup.9 independently are hydrogen, hydroxy, oxo, halo, nitro,
cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6-alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 is hydrogen,
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy;
R.sup.11 is hydrogen, halo, hydroxy, oxo, nitro, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy or
hetaryloxy; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6alkyloxycarbonyl; or R.sup.12 and R.sup.13 are
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen, oxygen or sulphur,
the ring system optionally being substituted with at least one of
C.sub.1-C.sub.6alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-6alkylcarboxy; [0965] n is 1 or 2; or a
salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, a prodrug thereof, or any tautomeric forms.
[0966] In one embodiment of the present invention, in formula (VI)
X is (CR.sup.1R.sup.2).sub.n, wherein R.sup.1, R.sup.2 and n are as
defined above.
[0967] In another embodiment of the present invention, in formula
(VI) n is 1.
[0968] In another embodiment of the present invention, in formula
(VI) X is oxygen.
[0969] In another embodiment of the present invention, in formula
(VI) R.sup.1, R.sup.2, R.sup.3, and R.sup.4 independently are
hydrogen, C.sub.1-C.sub.6alkyl or arylC.sub.1-C.sub.6alkyl,
optionally substituted with one or more R.sup.8.
[0970] In another embodiment of the present invention, in formula
(VI) R.sup.1 and either R.sup.3 or R.sup.4 together with the single
bond are forming a carbon-carbon double bond.
[0971] In another embodiment of the present invention, in formula
(VI) R.sup.5 is C.sub.1-C.sub.8alkyl optionally substituted with
one or more of R.sup.9.
[0972] In another embodiment of the present invention, in formula
(VI) R.sup.6 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl each of which is optionally
substituted with one or more of R.sup.9.
[0973] In another embodiment of the present invention, in formula
(VI) R.sup.6 is C.sub.3-C.sub.10cycloalkyl optionally substituted
with one or more of R.sup.9.
[0974] In another embodiment of the present invention, in formula
(VI) R.sup.5 and R.sup.6 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.10.
[0975] In another embodiment of the present invention, in formula
(VI) R.sup.7 is hydrogen, halo, NR.sup.12R.sup.13, trihalomethyl,
C.sub.1-C.sub.6alkyloxy, aryloxy, arylC.sub.1-C.sub.6alkyloxy or
hetaryloxy optionally substituted with one or more R.sup.11
independently.
[0976] In another embodiment of the present invention, in formula
(VI) R.sup.8 and R.sup.9 independently are hydrogen, hydroxy, oxo,
halo, nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, or NR.sup.12R.sup.13.
[0977] In another embodiment of the present invention, in formula
(VI) R.sup.10 is hydrogen or C.sub.1-C.sub.8alkyl.
[0978] In yet another embodiment of the present invention, in
formula (VI) the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane
optionally substituted with one or more of
C.sub.1-C.sub.6alkyl.
[0979] In yet another embodiment of the present invention, in
formula (VI) the bicyclic ring system is
1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
[0980] In yet another embodiment of the present invention a
compound of the general formula (VI) or a prodrug thereof is
2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexylmethyl-amide or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
forms.
[0981] In another embodiment of the present invention the compounds
of the general formula (VI) or a prodrug thereof is selected from
the group consisting of: [0982]
2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0983]
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0984]
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0985]
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone; [0986]
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0987] 2-Methyl-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide; [0988]
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [0989] Benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0990] 2,3-Dihydro-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide; [0991]
3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0992] Chroman-8-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, or any tautomeric
forms.
[0993] In another embodiment of the present invention the compounds
of the general formula (VI) or a prodrug thereof is selected from
the group consisting of: [0994] 2,3-Dihydro-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide; [0995] Benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0996]
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0997] 2-Methyl-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide; [0998]
3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [0999]
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo-
[3.2.1]oct-6-yl)-methanone; [1000]
4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [1001]
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide; [1002]
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [1003] Chroman-8-carboxylic acid
cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically
acceptable acid or base, or any optical isomer or mixture of
optical isomers, including a racemic mixture, a prodrug thereof, or
any tautomeric forms.
[1004] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (VII)
##STR8## wherein R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl,
hetaryl, arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl
optionally substituted with one or more R.sup.9; R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 independently are hydrogen, halo,
nitro, cyano, trihalomethyl, carboxy, N(R.sup.12R.sup.13),
C(O)NR.sup.7R.sup.8, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy,
arylC.sub.1-C.sub.6alkylcarboxy, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyloxy,
hetaryloxyC.sub.1-C.sub.6alkyl or
hetarylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl wherein the
alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups
independently are substituted with one or more R.sup.9; R.sup.7 is
hydrogen or C.sub.1-C.sub.8alkyl optionally substituted with one or
more of R.sup.10; R.sup.8 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or R.sup.7 and R.sup.8
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated cyclic, bicyclic or tricyclic
ring system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, oxo, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.9 is hydrogen, hydroxy, oxo, halo,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
trihalomethyl, trihalomethoxy, NR.sup.12R.sup.13,
arylC.sub.1-C.sub.6alkyloxy, C.sub.1-C.sub.6alkylcarbonyl,
arylcarbonyl, arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.6alkylcarboxy, arylcarboxy or
arylC.sub.1-C.sub.6alkylcarboxy; R.sup.10 and R.sup.11
independently are hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl wherein the
alkyl and aryl groups independently are optionally substituted with
one or more of R.sup.11, wherein R.sup.11 is as defined above; or
R.sup.12 and R.sup.13 together with the nitrogen to which they are
attached, are forming a saturated or partially saturated cyclic,
bicyclic or tricyclic ring system containing from 4 to 10 carbon
atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or a salt thereof
with a pharmaceutically acceptable acid or base, or any optical
isomer or mixture of optical isomers, including a racemic mixture,
or any tautomeric forms.
[1005] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (VII)
wherein
R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, hetaryl,
arylC.sub.1-C.sub.6alkyl or hetarylC.sub.1-C.sub.6alkyl optionally
substituted with one or more R.sup.9;
[1006] R.sup.2 and R.sup.5 independently are hydrogen, halo, nitro,
cyano, trihalomethyl, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6-alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, aryloxyC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6-alkyloxy,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, hetaryl or
hetarylC.sub.1-C.sub.6alkyl wherein the alkyl, aryl, arylalkyl,
hetaryl and hetarylalkyl groups independently are substituted with
one or more R.sup.9; and
either R.sup.3 is C(O)NR.sup.7R.sup.8, and R.sup.4 is hydrogen; or
R.sup.3 is hydrogen, and R.sup.4 is C(O)NR.sup.7R.sup.8;
R.sup.6 is C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
N(R.sup.12R.sup.13)C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6-alkyl,
aryloxyC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl;
R.sup.7 is C.sub.1-C.sub.8alkyl optionally substituted with one or
more of R.sup.10;
R.sup.8 is C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.10; or
[1007] R.sup.7 and R.sup.8 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen or oxygen, the ring system optionally being substituted
with at least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11;
[1008] R.sup.9 is hydrogen, hydroxy, oxo, halo, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy, trihalomethyl,
trihalomethoxy, NR.sup.12R.sup.13, arylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy;
R.sup.10 and R.sup.11 independently are hydrogen, halo, oxo,
hydroxy, C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl,
hetaryl or hetarylalkyl;
[1009] R.sup.12 and R.sup.13 independently are hydrogen,
C.sub.1-C.sub.8alkyl, aryl, hetaryl, arylC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
C.sub.3-C.sub.10cycloalkylcarbonyl,
C.sub.3-C.sub.10hetcycloalkylcarbonyl or
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkylcarbonyl; or
[1010] R.sup.12 and R.sup.13 together with the nitrogen to which
they are attached, are forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 4 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.8alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl,
hydroxy, oxo, cyano, C.sub.1-C.sub.6alkyloxy,
arylC.sub.1-C.sub.6alkyloxy, hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyl-oxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy; or
a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[1011] In another embodiment, the present invention, in formula
(VII) R.sup.2 is C(O)NR.sup.7R.sup.8 and R.sup.3 R.sup.4 and
R.sup.5 are hydrogen, wherein R.sup.7 and R.sup.8 are as defined
above.
[1012] In another embodiment, the present invention, in formula
(VII) R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.4 and
R.sup.5 are hydrogen, wherein R.sup.7 and R.sup.8 are as defined
above.
[1013] In another embodiment, the present invention, in formula
(VII) R.sup.4 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.3 and
R.sup.5 are hydrogen, wherein R.sup.7 and R.sup.8 are as defined
above.
[1014] In another embodiment, the present invention, in formula
(VII) R.sup.5 is C(O)NR.sup.7R.sup.8 and R.sup.2 R.sup.3 and
R.sup.4 are hydrogen, wherein R.sup.7 and R.sup.8 are as defined
above.
[1015] In another embodiment, the present invention, in formula
(VII) R.sup.6 is C(O)NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8
are as defined above.
[1016] In another embodiment, the present invention, in formula
(VII) R.sup.3 is C(O)NR.sup.7R.sup.8 and R.sup.4 is hydrogen,
wherein R.sup.7 and R.sup.8 are as defined above.
[1017] In another embodiment, the present invention, in formula
(VII) R.sup.3 is hydrogen and R.sup.4 is C(O)NR.sup.7R.sup.8,
wherein R.sup.7 and R.sup.8 are as defined above.
[1018] In another embodiment, the present invention, in formula
(VII) R.sup.8 is C.sub.3-C.sub.10cycloalkyl or
C.sub.3-C.sub.10hetcycloalkyl, each of which is optionally
substituted with one or more of R.sup.10, wherein R.sup.10 is as
defined above.
[1019] In another embodiment, the present invention, in formula
(VII) R.sup.7 and R.sup.8 together with the nitrogen to which they
are attached, are forming a saturated or partially saturated
bicyclic or tricyclic ring system containing from 6 to 10 carbon
atoms and from 0 to 2 additional heteroatoms selected from nitrogen
or oxygen, the ring system optionally being substituted with at
least one of C.sub.1-C.sub.8alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl, hetarylC.sub.1-C.sub.6alkyl, hydroxy,
oxo, cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyl-oxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11, wherein R.sup.11 is as defined above.
[1020] In a further embodiment of the present invention, in formula
(VII) the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane
optionally substituted with one or more C.sub.1-C.sub.6alkyl.
[1021] In yet a further embodiment of the present invention, in
formula (VII) the bicyclic ring system is
1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
[1022] In another embodiment of the present invention the compounds
of the general formula (VII) or a prodrug thereof is selected from
the group consisting of: [1023]
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone;
[1024] 1H-Indole-6-carboxylic acid cyclohexyl-methyl-amide; or a
salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[1025] In another embodiment of the present invention, the
compounds or prodrugs thereof of the general formula (VII) are
selected from the group consisting of the compounds of examples 3
through 20 as described under EXAMPLES, COMPOUNDS OF GENERAL
FORMULA (VII).
[1026] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the general formula (VIII)
##STR9## wherein X is NR.sup.4, S or O; R.sup.1 and R.sup.2
independently are hydrogen, halo, cyano, trihalomethyl,
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy, wherein the alkyl
groups independently are optionally substituted with one or more of
R.sup.7; R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl
or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with
one or more of R.sup.7; R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cyclo-alkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently
are optionally substituted with one or more of R.sup.7; R.sup.5 is
hydrogen, and R.sup.6 is adamantyl optionally substituted with
hydroxy, C.sub.1-C.sub.6alkyloxy, aryl, arylC.sub.1-C.sub.6alkyl,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryl, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy wherein the alkyl, aryl and hetaryl
groups independently are optionally substituted with one or more of
R.sup.7; or R.sup.5 and R.sup.6 are together with the nitrogen to
which they are attached, forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7; R.sup.7 are independently hydrogen, halo,
hydroxy, oxo, nitro, NR.sup.9R.sup.10, cyano, COOR.sup.8,
CONR.sup.9R.sup.10, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy,
aryloxy, arylC.sub.1-C.sub.6alkyloxy, hetaryloxy or
hetarylC.sub.1-C.sub.6alkyloxy; R.sup.8 is hydrogen,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl,
wherein the alkyl, aryl and hetarylalkyl groups independently are
optionally substituted with one or more of R.sup.7; R.sup.9 and
R.sup.10 independently are hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl, wherein the alkyl,
cycloalkyl and hetcycloalkyl groups independently are optionally
substituted with one or more of R.sup.7; or R.sup.9 and R.sup.10
together with the nitrogen to which they are attached, are forming
a saturated or partially saturated bicyclic or tricyclic ring
system containing from 4 to 10 carbon atoms and from 0 to 2
additional heteroatoms selected from nitrogen or oxygen, the ring
system optionally being substituted with at least one of
C.sub.1-C.sub.8alkyl, arylC.sub.1-C.sub.6alkyl,
hetarylC.sub.1-C.sub.6alkyl, hydroxy, cyano,
C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.11; R.sup.11 is hydrogen, halo, oxo, hydroxy,
C.sub.1-C.sub.6alkyl, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl or
hetarylalkyl; a salt thereof with a pharmaceutically acceptable
acid or base, or any optical isomer or mixture of optical isomers,
including a racemic mixture, or any tautomeric forms.
[1027] In the definitions of R.sup.4, in the above formula (VIII),
hetcycloalkyl cannot be 7-aza[2,2,1]bicycloheptane.
[1028] In another embodiment, the present invention is concerned
with compounds or prodrugs thereof of the above general formula
(VIII) wherein
X is NR.sup.4, S or O;
R.sup.1 and R.sup.2 independently are hydrogen, halo, cyano,
trihalomethyl, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6alkyloxy,
wherein the alkyl groups independently are optionally substituted
with one or more of R.sup.7;
[1029] R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkylthio, aryl, arylC.sub.1-C.sub.6alkyl, hetaryl
or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and
hetarylalkyl groups independently are optionally substituted with
one or more of R.sup.7;
[1030] R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl, aryl, hetaryl,
arylC.sub.1-C.sub.6alkyl,
arylC.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10hetcycloalkyl,
C.sub.3-C.sub.10cycloalkylC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarboxyC.sub.1-C.sub.6alkyl wherein the alkyl,
aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently
are optionally substituted with one or more of R.sup.7;
[1031] R.sup.5 is hydrogen, and R.sup.6 is adamantyl optionally
substituted with hydroxy, C.sub.1-C.sub.6alkyloxy, aryl,
arylC.sub.1-C.sub.6alkyl, aryloxy, arylC.sub.1-C.sub.6alkyloxy,
hetaryl, hetaryloxy or hetarylC.sub.1-C.sub.6alkyloxy wherein the
alkyl, aryl and hetaryl groups independently are optionally
substituted with one or more of R.sup.7; or
[1032] R.sup.5 and R.sup.6 are together with the nitrogen to which
they are attached, forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 5 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7;
R.sup.7 are independently hydrogen, halo, hydroxy, oxo, nitro,
NR.sup.5R.sup.6, cyano, COOR.sup.8, CONR.sup.5R.sup.6,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.6alkyloxy, aryloxy or
hetaryloxy;
R.sup.8 is hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetarylalkyl, wherein the alkyl, aryl and
hetarylalkyl groups independently are optionally substituted with
one or more of R.sup.7; or
a salt thereof with a pharmaceutically acceptable acid or base, or
any optical isomer or mixture of optical isomers, including a
racemic mixture, or any tautomeric forms.
[1033] In one embodiment of the present invention, in formula
(VIII) X is NR.sup.4 or S wherein R.sup.4 is defined as above.
[1034] In another embodiment of the present invention, in formula
(VIII) X is O.
[1035] In another embodiment of the present invention, in formula
(VIII) X is S.
[1036] In another embodiment of the present invention, in formula
(VIII) is NR.sup.4 wherein R.sup.4 is defined as above.
[1037] In another embodiment of the present invention, in formula
(VIII) R.sup.1 and R.sup.2 independently are hydrogen, halo,
trihalomethyl or C.sub.1-C.sub.6alkyl, wherein the alkyl groups
independently are optionally substituted with one or more of
R.sup.7.
[1038] In another embodiment of the present invention, in formula
(VIII) R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl, hetaryl or hetarylalkyl, wherein the
alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups
independently are optionally substituted with one or more of
R.sup.7.
[1039] In another embodiment of the present invention, in formula
(VIII) R.sup.4 is hydrogen, C.sub.1-C.sub.8alkyl, aryl, hetaryl,
hetarylC.sub.1-C.sub.6alkyl, arylC.sub.1-C.sub.6alkyl, wherein the
alkyl, aryl, hetaryl, groups independently are optionally
substituted with one or more of R.sup.7.
[1040] In another embodiment of the present invention, in formula
(VIII) R.sup.5 and R.sup.6 are together with the nitrogen to which
they are attached, forming a saturated or partially saturated
cyclic, bicyclic or tricyclic ring system containing from 6 to 10
carbon atoms and from 0 to 2 additional heteroatoms selected from
nitrogen, oxygen or sulphur, the ring system optionally being
substituted with at least one of C.sub.1-C.sub.6alkyl, aryl,
hetaryl, arylC.sub.1-C.sub.6alkyl, hetarylalkyl, hydroxy, oxo,
cyano, C.sub.1-C.sub.6alkyloxy, arylC.sub.1-C.sub.6alkyloxy,
hetarylC.sub.1-C.sub.6alkyloxy,
C.sub.1-C.sub.6alkyloxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
arylC.sub.1-C.sub.6alkylcarbonyl,
hetarylC.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkylcarboxy,
arylcarboxy or arylC.sub.1-C.sub.6alkylcarboxy wherein the alkyl
and aryl groups independently are optionally substituted with one
or more of R.sup.7.
[1041] In yet another embodiment of the present invention, in
formula (VIII) R.sup.5 and R.sup.6, together with the nitrogen to
which they are attached, are azepane, azocane,
6-aza-bicyclo[3.2.1]octane, 8-aza-bicyclo[3.2.1]octane,
3-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[3.2.1]octane,
3-oxa-6-aza-bicyclo[3.2.1]octane, 6-aza-bicyclo[3.2.2]nonane,
3-aza-bicyclo[3.2.2]nonane,
4-aza-tricyclo[4.3.1.1.sup.3,8]undecane.
[1042] In another embodiment of the present invention the compounds
of the general formulas (VIII) or a prodrug thereof is selected
from the group consisting of: [1043]
(4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone; [1044]
(2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; [1045]
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone; [1046]
[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-a-
za-bicyclo[3.2.1]oct-6-yl)-methanone; [1047]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2,4-dimethyl-thiazol-5-yl)-methanone;
[1048]
(1H-Imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone; [1049]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone-
; [1050] 2,4-Dimethyl-thiazole-5-carboxylic acid cycloheptylamide;
[1051] Azepan-1-yl-(2,4-dimethyl-thiazol-5-yl)-methanone; [1052]
2,4-Dimethyl-thiazole-5-carboxylic acid adamantan-1-ylamide; [1053]
(3-Aza-bicyclo[3.2.2]non-3-yl)-(1H-imidazol-4-yl)-methanone; [1054]
2,4-Dimethyl-thiazole-5-carboxylic acid
(3-hydroxy-adamantan-1-yl)-amide; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[1055] In another embodiment of the present invention the compounds
of the general formulas (VIII) or a prodrug thereof is selected
from the group consisting of: [1056]
(1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl-
)-methanone; [1057]
[1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyc-
lo[3.2.1]oct-6-yl)-methanone; [1058]
[1-(4-Chloro-benzyl)-5-methyl-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bi-
cyclo[3.2.1]oct-6-yl)-methanone; or a salt thereof with a
pharmaceutically acceptable acid or base, or any optical isomer or
mixture of optical isomers, including a racemic mixture, or any
tautomeric forms.
[1059] The compounds of the present invention have asymmetric
centers and may occur as racemates, racemic mixtures, and as
individual enantiomers or diastereoisomers, with all isomeric forms
being included in the present invention as well as mixtures
thereof.
[1060] The present invention also encompasses pharmaceutically
acceptable salts of the present compounds. Such salts include
pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable base addition salts, pharmaceutically acceptable metal
salts, ammonium and alkylated ammonium salts. Acid addition salts
include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric
acids and the like. Representative examples of suitable organic
acids include formic, acetic, trichloroacetic, trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic,
maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,
ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,
gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,
paminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,
sulphates, nitrates, phosphates, perchlorates, borates, acetates,
benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates
and the like. Further examples of pharmaceutically acceptable
inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2
(1977), which is incorporated herein by reference. Examples of
metal salts include lithium, sodium, potassium, barium, calcium,
magnesium, zinc, calcium salts and the like. Examples of amines and
organic amines include ammonium, methylamine, dimethylamine,
trimethylamine, ethylamine, diethylamine, propylamine, butylamine,
tetramethylamine, ethanolamine, diethanolamine, triethanolamine,
meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine,
N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the
like. Examples of cationic amino acids include lysine, arginine,
histidine and the like.
[1061] Further, some of the compounds of the present invention may
form solvates with water or common organic solvents. Such solvates
are encompassed within the scope of the invention.
[1062] The pharmaceutically acceptable salts are prepared by
reacting a compound of the present invention with 1 to 4
equivalents of a base such as sodium hydroxide, sodium methoxide,
sodium hydride, potassium tert-butoxide, calcium hydroxide,
magnesium hydroxide and the like, in solvents like ether, THF,
methanol, tert-butanol, dioxane, isopropanol, ethanol etc. Mixtures
of solvents may be used. Organic bases like lysine, arginine,
diethanolamine, choline, guandine and their derivatives etc. may
also be used. Alternatively, acid addition salts wherever
applicable are prepared by treatment with acids such as
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid,
acetic acid, citric acid, maleic acid salicylic acid,
hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid,
benzoic acid, benzenesulfonic acid, tartaric acid and the like in
solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane
etc. Mixture of solvents may also be used.
[1063] The stereoisomers of the compounds forming part of this
invention may be prepared by using reactants in their single
enantiomeric form in the process wherever possible or by conducting
the reaction in the presence of reagents or catalysts in their
single enantiomer form or by resolving the mixture of stereoisomers
by conventional methods. Some of the preferred methods include use
of microbial resolution, enzymatic resolution, resolving the
diastereomeric salts formed with chiral acids such as mandelic
acid, camphorsulfonic acid, tartaric acid, lactic acid, and the
like wherever applicable or chiral bases such as brucine, (R)- or
(S)-phenylethylamine, cinchona alkaloids and their derivatives and
the like. Commonly used methods are compiled by Jaques et al. in
"Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
More specifically the compound of the present invention may be
converted to a 1:1 mixture of diastereomeric amides by treating
with chiral amines, aminoacids, aminoalcohols derived from
aminoacids; conventional reaction conditions may be employed to
convert acid into an amide; the diastereomers may be separated
either by fractional crystallization or chromatography and the
stereoisomers of compound of formula I may be prepared by
hydrolysing the pure diastereomeric amide.
[1064] Various polymorphs of the compounds forming part of this
invention may be prepared by crystallization of said compounds
under different conditions. For example, using different solvents
commonly used or their mixtures for recrystallization;
crystallizations at different temperatures; various modes of
cooling, ranging from very fast to very slow cooling during
crystallizations. Polymorphs may also be obtained by heating or
melting the compound followed by gradual or fast cooling. The
presence of polymorphs may be determined by solid probe nmr
spectroscopy, ir spectroscopy, differential scanning calorimetry,
powder X-ray diffraction or such other techniques.
[1065] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming active pharmacological
substances. In general, such prodrugs will be functional
derivatives of the present compounds, which are readily convertible
in vivo into the required compound of the present invention.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in "Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[1066] It is a well known problem in drug discovery that compounds,
such as enzyme inhibitors, may be very potent and selective in
biochemical assays, yet be inactive in vivo. This lack of so-called
bioavailability may be ascribed to a number of different factors
such as lack of or poor absorption in the gut, first pass
metabolism in the liver and/or poor uptake in cells. Although the
factors determining bioavailability are not completely understood,
there are many examples in the scientific literature--well known to
those skilled in the art--of how to modify compounds, which are
potent and selective in biochemical assays but show low or no
activity in vivo, into drugs that are biologically active.
[1067] It is within the scope of the invention to modify the
compounds of the present invention, termed the `original compound`,
by attaching chemical groups that will improve the bioavailability
of said compounds in such a way that the uptake in cells or mammals
is facilitated.
[1068] Examples of said modifications, which are not intended in
any way to limit the scope of the invention, include changing of
one or more carboxy groups to esters (for instance methyl esters,
ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters
or other acyloxymethyl esters). Compounds of the invention,
original compounds, such modified by attaching chemical groups are
termed `modified compounds`.
[1069] The invention also encompasses active metabolites of the
present compounds.
[1070] The compounds according to the invention alter, and more
specifically, reduce the level of active intracellular
glucocorticoid and are accordingly useful for the treatment,
prevention and/or prophylaxis of disorders and diseases in which
such a modulation or reduction is beneficial.
[1071] Accordingly, the present compounds may be applicable for the
treatment, prevention and/or prophylaxis of the metabolic syndrome,
insulin resistance, dyslipidemia, hypertension, obesity, type 2
diabetes, impaired glucose tolerance (IGT), impaired fasting
glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type
1 diabetes, diabetic late complications including cardiovascular
diseases, cardiovascular disorders, disorders of lipid metabolism,
neurodegenerative and psychiatric disorders, dysregulation of
intraocular pressure including glaucoma, immune disorders,
inappropriate immune responses, musculo-skeletal disorders,
gastrointestinal disorders, polycystic ovarie syndrome (PCOS),
reduced hair growth or other diseases, disorders or conditions that
are influenced by intracellular glucocorticoid levels, adverse
effects of increased blood levels of active endogenous or exogenous
glucocorticoid, and any combination thereof, adverse effects of
increased plasma levels of endogenous active glucocorticoid,
Cushing's disease, Cushing's syndrome, adverse effects of
glucocorticoid receptor agonist treatment of autoimmune diseases,
adverse effects of glucocorticoid receptor agonist treatment of
inflammatory diseases, adverse effects of glucocorticoid receptor
agonist treatment of diseases with an inflammatory component,
adverse effects of glucocorticoid receptor agonist treatment as a
part of cancer chemotherapy, adverse effects of glucocorticoid
receptor agonist treatment for surgical/post-surgical or other
trauma, adverse effects of glucocorticoid receptor agonist therapy
in the context of organ or tissue transplantation or adverse
effects of glucocorticoid receptor agonist treatment in other
diseases, disorders or conditions where glucocorticoid receptor
agonists provide clinically beneficial effects.
[1072] More specifically the present compounds may be applicable
for the treatment, prevention and/or prophylaxis of the metabolic
syndrome, type 2 diabetes, diabetes as a consequence of obesity,
insulin resistance, hyperglycemia, prandial hyperglycemia,
hyperinsulinemia, inappropriately low insulin secretion, impaired
glucose tolerance (IGT), impaired fasting glucose (IFG), increased
hepatic glucose production, type 1 diabetes, LADA, pediatric
diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia,
decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders
of lipid metabolism, obesity, visceral obesity, obesity as a
consequence of diabetes, increased food intake, hypertension,
diabetic late complications, micro-/macroalbuminuria, nephropathy,
retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases,
arteriosclerosis, atherosclerosis, coronary artery disease, cardiac
hypertrophy, myocardial ischemia, heart insufficiency, congestional
heart failure, stroke, myocardial infarction, arrhythmia, decreased
blood flow, erectile dysfunction (male or female), myopathy, loss
of muscle tissue, muscle wasting, muscle catabolism, osteoporosis,
decreased linear growth, neurodegenerative and psychiatric
disorders, Alzheimers disease, neuronal death, impaired cognitive
function, depression, anxiety, eating disorders, appetite
regulation, migraine, epilepsia, addiction to chemical substances,
disorders of intraocular pressure, glaucoma, polycystic ovary
syndrome (PCOS), inappropriate immune responses, inappropriate T
helper-1/T helper-2 polarisation, bacterial infections,
mycobacterial infections, fungal infections, viral infections,
parasitic infestations, suboptimal responses to immunizations,
immune dysfunction, partial or complete baldness, or other
diseases, disorders or conditions that are influenced by
intracellular glucocorticoid levels and any combination thereof,
adverse effects of glucocorticoid receptor agonist treatment of
allergic-inflammatory diseases such as asthma and atopic
dermatitis, adverse effects of glucocorticoid receptor agonist
treatment of disorders of the respiratory system e.g. asthma,
cystic fibrosis, emphysema, bronchitis, hypersensitivity,
pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, adverse
effects of glucocorticoid receptor agonist treatment of
inflammatory bowel disease such as Crohn's disease and ulcerative
colitis; adverse effects of glucocorticoid receptor agonist
treatment of disorders of the immune system, connective tissue and
joints e.g. reactive arthritis, rheumatoid arthritis, Sjogren's
syndrome, systemic lupus erythematosus, lupus nephritis,
Henoch-Schonlein purpura, Wegener's granulomatosis, temporal
arteritis, systemic sclerosis, vasculitis, sarcoidosis,
dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects
of glucocorticoid receptor agonist treatment of endocrinological
diseases such as hyperthyroidism, hypoaldosteronism,
hypopituitarism; adverse effects of glucocorticoid receptor agonist
treatment of hematological diseases e.g. hemolytic anemia,
thrombocytopenia, paroxysmal nocturnal hemoglobinuria; adverse
effects of glucocorticoid receptor agonist treatment of cancer such
as spinal cord diseases, neoplastic compression of the spinal cord,
brain tumours, acute lymphoblastic leukemia, Hodgkin's disease,
chemotherapy-induced nausea, adverse effects of glucocorticoid
receptor agonist treatment of diseases of muscle and at the
neuro-muscular joint e.g. myasthenia gravis and heriditary
myopathies (e.g. Duchenne muscular dystrophy), adverse effects of
glucocorticoid receptor agonist treatment in the context of surgery
& transplantation e.g. trauma, post-surgical stress, surgical
stress, renal transplantation, liver transplantation, lung
transplantation, pancreatic islet transplantation, blood stem cell
transplantation, bone marrow transplantation, heart
transplantation, adrenal gland transplantation, tracheal
transplantation, intestinal transplantation, corneal
transplantation, skin grafting, keratoplasty, lens implantation and
other procedures where immunosuppression with glucocorticoid
receptor agonists is beneficial; adverse effects of glucocorticoid
receptor agonist treatment of brain absess, nausea/vomiting,
infections, hypercalcemia, adrenal hyperplasia, autoimmune
hepatitis, spinal cord diseases, saccular aneurysms or adverse
effects to glucocorticoid receptor agonist treatment in other
diseases, disorders and conditions where glucocorticoid receptor
agonists provide clinically beneficial effects.
[1073] Accordingly, in a further aspect the invention relates to a
compound according to the invention for use as a pharmaceutical
composition.
[1074] The invention also relates to pharmaceutical compositions
comprising, as an active ingredient, at least one compound
according to the invention together with one or more
pharmaceutically acceptable carriers or diluents.
[1075] The pharmaceutical composition is preferably in unit dosage
form, comprising from about 0.05 mg/day to about 2000 mg/day,
preferably from about 1 mg/day to about 500 mg/day of a compound
according to the invention.
[1076] In another embodiment, the patient is treated with a
compound according to the invention for at least about 1 week, for
at least about 2 weeks, for at least about 4 weeks, for at least
about 2 months or for at least about 4 months.
[1077] In yet another embodiment, the pharmaceutical composition is
for oral, nasal, transdermal, pulmonal or parenteral
administration.
[1078] Furthermore, the invention relates to the use of a compound
according to the invention for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of
disorders and diseases wherein a modulation or an inhibition of the
activity of 11.beta.HSD1 is beneficial.
[1079] The invention also relates to a method for the treatment,
prevention and/or prophylaxis of disorders and diseases wherein a
modulation or an inhibition of the activity of 11.beta.HSD1 is
beneficial, the method comprising administering to a subject in
need thereof an effective amount of a compound according to the
invention.
[1080] In a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment, prevention and/or prophylaxis of any diseases and
conditions that are influenced by intracellular glucocorticoid
levels as mentioned above.
[1081] Thus, in a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment, prevention and/or prophylaxis of conditions and
disorders where a decreased level of active intracellular
glucocorticoid is desirable, such as the conditions and diseases
mentioned above.
[1082] In yet a preferred embodiment of the invention the present
compounds are used for the preparation of a medicament for the
treatment, prevention and/or prophylaxis of the metabolic syndrome
including insulin resistance, dyslipidemia, hypertension and
obesity.
[1083] In yet another preferred embodiment of the invention the
present compounds are used for the preparation of a medicament for
the treatment, prevention and/or prophylaxis of type 2 diabetes,
impaired glucose tolerance (IGT), impaired fasting glucose
(IFG).
[1084] In yet another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the delaying or prevention of the progression from
IGT to type 2 diabetes.
[1085] In yet another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the delaying or prevention of the progression of
the metabolic syndrome into type 2 diabetes.
[1086] In still another preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of
diabetic late complications including cardiovascular diseases;
arteriosclerosis; atherosclerosis.
[1087] In a further preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of
neurodegenerative and psychiatric disorders.
[1088] In yet a further preferred embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment, prevention and/or prophylaxis of
adverse effects of glucocorticoid receptor agonist treatment or
therapy.
[1089] In another embodiment of the present invention, the route of
administration may be any route which effectively transports a
compound according to the invention to the appropriate or desired
site of action, such as oral, nasal, buccal, transdermal, pulmonal,
or parenteral.
[1090] In still a further aspect of the invention the present
compounds are administered in combination with one or more further
active substances in any suitable ratios. Such further active
substances may e.g. be selected from antiobesity agents,
antidiabetics, agents modifying the lipid metabolism,
antihypertensive agents, glucocorticoid receptor agonists, agents
for the treatment and/or prevention of complications resulting from
or associated with diabetes and agents for the treatment and/or
prevention of complications and disorders resulting from or
associated with obesity.
[1091] Thus, in a further aspect of the invention the present
compounds may be administered in combination with one or more
antiobesity agents or appetite regulating agents.
[1092] Such agents may be selected from the group consisting of
CART (cocaine amphetamine regulated transcript) agonists, NPY
(neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin
antagonists, TNF (tumor necrosis factor) agonists, CRF
(corticotropin releasing factor) agonists, CRF BP (corticotropin
releasing factor binding protein) antagonists, urocortin agonists,
.beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists,
MCH (melanocyte-concentrating hormone) antagonists, CCK
(cholecystokinin) agonists, serotonin re-uptake inhibitors,
serotonin and noradrenaline re-uptake inhibitors, mixed serotonin
and noradrenergic compounds, 5HT (serotonin) agonists, bombesin
agonists, galanin antagonists, growth hormone, growth hormone
releasing compounds, TRH (thyreotropin releasing hormone) agonists,
UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists,
DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors,
PPAR (peroxisome proliferator-activated receptor) modulators, PXR
(retinoid X receptor) modulators, TR .beta. agonists, AGRP (Agouti
related protein) inhibitors, H3 histamine antagonists, opioid
antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary
neurotrophic factor.
[1093] In one embodiment of the invention the antiobesity agent is
leptin; dexamphetamine or amphetamine; fenfluramine or
dexfenfluramine; sibutramine; orlistat; mazindol or
phentermine.
[1094] Suitable antidiabetic agents include insulin, insulin
analogues and derivatives such as those disclosed in EP 792 290
(Novo Nordisk A/S), e.g. N.sup..epsilon.B29-tetradecanoyl des (B30)
human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), e.g.
Asp.sup.B28 human insulin, U.S. Pat. No. 5,504,188 (Eli Lilly),
e.g. Lys.sup.B28 Pro.sup.B29 human insulin, EP 368 187 (Aventis),
eg Lantus, which are all incorporated herein by reference, GLP-1
(glucagon like peptide-1) and GLP-1 derivatives such as those
disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated
herein by reference as well as orally active hypoglycaemic
agents.
[1095] The orally active hypoglycaemic agents preferably comprise
sulphonylureas, biguanides, meglitinides, glucosidase inhibitors,
glucagon antagonists such as those disclosed in WO 99/01423 to Novo
Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists,
potassium channel openers such as those disclosed in WO 97/26265
and WO 99/03861 to Novo Nordisk A/S which are incorporated herein
by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
inhibitors of hepatic enzymes involved in stimulation of
gluconeogenesis and/or glycogenolysis, glucose uptake modulators,
compounds modifying the lipid metabolism such as antihyperlipidemic
agents and antilipidemic agents as PPAR.alpha. modulators,
PPAR.delta. modulators, cholesterol absorption inhibitors, HSL
(hormone-sensitive lipase) inhibitors and HMG CoA inhibitors
(statins), nicotinic acid, fibrates, anion exchangers, compounds
lowering food intake, bile acid resins, PXR agonists and agents
acting on the ATP-dependent potassium channel of the
.beta.-cells.
[1096] In one embodiment, the present compounds are administered in
combination with insulin or an insulin analogue or derivative, such
as N.sup..epsilon.B29-tetradecanoyl des (B30) human insulin,
Asp.sup.B28 human insulin, Lys.sup.B28 Pro.sup.B29 human insulin,
Lantus.RTM., or a mix-preparation comprising one or more of
these.
[1097] In a further embodiment the present compounds are
administered in combination with a sulphonylurea e.g. tolbutamide,
glibenclamide, glipizide or glicazide.
[1098] In another embodiment the present compounds are administered
in combination with a biguanide e.g. metformin.
[1099] In yet another embodiment the present compounds are
administered in combination with a meglitinide e.g. repaglinide or
senaglinide.
[1100] In still another embodiment the present compounds are
administered in combination with a thiazolidinedione e.g.
troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds
disclosed in WO 97/41097 such as
5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]th-
iazolidine-2,4-dione or a pharmaceutically acceptable salt thereof,
preferably the potassium salt.
[1101] In yet another embodiment the present compounds may be
administered in combination with the insulin sensitizers disclosed
in WO 99/19313 such as
(-)3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
or a pharmaceutically acceptable salts thereof, preferably the
arginine salt.
[1102] In a further embodiment the present compounds are
administered in combination with an .alpha.-glucosidase inhibitor
e.g. miglitol or acarbose.
[1103] In another embodiment the present compounds are administered
in combination with an agent acting on the ATP-dependent potassium
channel of the .beta.-cells e.g. tolbutamide, glibenclamide,
glipizide, glicazide or repaglinide.
[1104] Furthermore, the present compounds may be administered in
combination with nateglinide.
[1105] In still another embodiment the present compounds are
administered in combination with an antihyperlipidemic agent or
antilipidemic agent e.g. cholestyramine, colestipol, clofibrate,
gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156,
LY-818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin,
simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
[1106] In a further embodiment the present compounds are
administered in combination with more than one of the
above-mentioned compounds e.g. in combination with a sulphonylurea
and metformin, a sulphonylurea and acarbose, repaglinide and
metformin, insulin and a sulphonylurea, insulin and metformin,
insulin, insulin and lovastatin, etc.
[1107] Further, the present compounds may be administered in
combination with one or more antihypertensive agents. Examples of
antihypertensive agents are .beta.-blockers such as alprenolol,
atenolol, timolol, pindolol, propranolol, metoprolol,
bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol,
betaxotol, celiprolol, nebivolol, tertatolol, oxprenolol,
amusolalul, carvedilol, labetalol, .beta.2-receptor blockers e.g.
S-atenolol, OPC-1085, ACE (angiotensin converting enzyme)
inhibitors such as quinapril, lisinopril, enalapril, captopril,
benazepril, perindopril, trandolapril, fosinopril, ramipril,
cilazapril, delapril, imidapril, moexipril, spirapril, temocapril,
zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP
00481522), omapatrilat, gemopatrilat and GW-660511, calcium channel
blockers such as nifedipine, felodipine, nicardipine, isradipine,
nimodipine, diltiazem, amlodipine, nitrendipine, verapamil,
lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine,
azelnidipine, barnidipine, efonodipine, iasidipine, iemildipine,
iercanidipine, manidipine, nilvadipine, pranidipine, furnidipine,
.alpha.-blockers such as doxazosin, urapidil, prazosin, terazosin,
bunazosin and OPC-28326, diuretics such as thiazides/sulphonamides
(e.g. bendroflumetazide, chlorothalidone, hydrochlorothiazide and
clopamide), loop-diuretics (e.g. bumetanide, furosemide and
torasemide) and potassium sparing diuretics (e.g. amiloride,
spironolactone), endothelin ET-A antagonists such as ABT-546,
ambrisetan, atrasentan, SB-234551, CI-1034, S-0139 and YM-598,
endothelin antagonists e.g. bosentan and J-104133, renin inhibitors
such as aliskiren, vasopressin V1 antagonists e.g. OPC-21268,
vasopressin V2 antagonists such as tolvaptan, SR-121463 and
OPC-31260, B-type natriuretic peptide agonists e.g. Nesiritide,
angiotensin II antagonists such as irbesartan,
candesartancilexetil, losartan, valsartan, telmisartan, eprosartan,
candesartan, CL-329167, eprosartan, iosartan, olmesartan,
pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g. fenoldopam and
ketanserin, adenosine A1 antagonists such as naftopidil, N-0861 and
FK-352, thromboxane A2 antagonists such as KT2-962, endopeptidase
inhibitors e.g. ecadotril, nitric oxide agonists such as LP-805,
dopamine D1 antagonists e.g. MYD-37, dopamine D2 agonists such as
nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists such
as treprostinil, beraprost, PGE1 agonists e.g. ecraprost, Na+/K+
ATPase modulators e.g. PST-2238, Potassium channel activators e.g.
KR-30450, vaccines such as PMD-3117, Indapamides, CGRP-unigene,
guanylate cyclase stimulators, hydralazines, methyldopa,
docarpamine, moxonidine, CoAprovel, MondoBiotech-811.
[1108] Further reference can be made to Remington: The Science and
Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995.
[1109] Furthermore, the present compounds may be administered in
combination with one or more glucocorticoid receptor agonists.
Examples of such glucocorticoid receptor agonists are betametasone,
dexamethasone, hydrocortisone, methylprednisolone, prednisolone,
prednisone, beclomethasone, butixicort, clobetasol, flunisolide,
flucatisone (and analogues), momethasone, triamcinolonacetonide,
triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021,
NS-126, P-4112, P-4114, RU-24858 and T-25 series.
[1110] It should be understood that any suitable combination of the
compounds according to the invention with one or more of the
above-mentioned compounds and optionally one or more further
pharmacologically active substances are considered to be within the
scope of the present invention.
Pharmaceutical Compositions
[1111] The compounds of the present invention may be administered
alone or in combination with pharmaceutically acceptable carriers
or excipients, in either single or multiple doses. The
pharmaceutical compositions according to the invention may be
formulated with pharmaceutically acceptable carriers or diluents as
well as any other known adjuvants and excipients in accordance with
conventional techniques such as those disclosed in Remington: The
Science and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed.,
Mack Publishing Co., Easton, Pa., 1995.
[1112] The pharmaceutical compositions may be specifically
formulated for administration by any suitable route such as the
oral, rectal, nasal, pulmonary, topical (including buccal and
sublingual), transdermal, intracisternal, intraperitoneal, vaginal
and parenteral (including subcutaneous, intramuscular, intrathecal,
intravenous and intradermal) route, the oral route being preferred.
It will be appreciated that the preferred route will depend on the
general condition and age of the subject to be treated, the nature
of the condition to be treated and the active ingredient
chosen.
[1113] Pharmaceutical compositions for oral administration include
solid dosage forms such as hard or soft capsules, tablets, troches,
dragees, pills, lozenges, powders and granules. Where appropriate,
they can be prepared with coatings such as enteric coatings or they
can be formulated so as to provide controlled release of the active
ingredient such as sustained or prolonged release according to
methods well-known in the art.
[1114] Liquid dosage forms for oral administration include
solutions, emulsions, suspensions, syrups and elixirs.
[1115] Pharmaceutical compositions for parenteral administration
include sterile aqueous and non-aqueous injectable solutions,
dispersions, suspensions or emulsions as well as sterile powders to
be reconstituted in sterile injectable solutions or dispersions
prior to use. Depot injectable formulations are also contemplated
as being within the scope of the present invention.
[1116] Other suitable administration forms include suppositories,
sprays, ointments, cremes, gels, inhalants, dermal patches,
implants etc.
[1117] A typical oral dosage is in the range of from about 0.001 to
about 100 mg/kg body weight per day, preferably from about 0.01 to
about 50 mg/kg body weight per day, and more preferred from about
0.05 to about 10 mg/kg body weight per day administered in one or
more dosages such as 1 to 3 dosages. The exact dosage will depend
upon the frequency and mode of administration, the sex, age, weight
and general condition of the subject treated, the nature and
severity of the condition treated and any concomitant diseases to
be treated and other factors evident to those skilled in the
art.
[1118] The formulations may conveniently be presented in unit
dosage form by methods known to those skilled in the art. A typical
unit dosage form for oral administration one or more times per day
such as 1 to 3 times per day may contain from 0.05 to about 2000
mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to
about 500 mg., from about 1 mg to about 200 mg, e.g. about 100
mg.
[1119] For parenteral routes, such as intravenous, intrathecal,
intramuscular and similar administration, typically doses are in
the order of about half the dose employed for oral
administration.
[1120] The compounds of this invention are generally utilized as
the free substance or as a pharmaceutically acceptable salt
thereof. Examples are an acid addition salt of a compound having
the utility of a free base and a base addition salt of a compound
having the utility of a free acid. The term "pharmaceutically
acceptable salts" refers to non-toxic salts of the compounds for
use according to the present invention which are generally prepared
by reacting the free base with a suitable organic or inorganic acid
or by reacting the acid with a suitable organic or inorganic base.
When a compound for use according to the present invention,
contains a free base such salts are prepared in a conventional
manner by treating a solution or suspension of the compound with a
chemical equivalent of a pharmaceutically acceptable acid. When a
compounds for use according to the present invention, contains a
free acid such salts are prepared in a conventional manner by
treating a solution or suspension of the compound with a chemical
equivalent of a pharmaceutically acceptable base. Physiologically
acceptable salts of a compound with a hydroxy group include the
anion of said compound in combination with a suitable cation such
as sodium or ammonium ion. Other salts which are not
pharmaceutically acceptable may be useful in the preparation of
compounds for use according to the present invention and these form
a further aspect of the present invention.
[1121] For parenteral administration, solutions of the present
compounds in sterile aqueous solution, aqueous propylene glycol or
sesame or peanut oil may be employed. Such aqueous solutions should
be suitable buffered if necessary and the liquid diluent first
rendered isotonic with sufficient saline or glucose. The aqueous
solutions are particularly suitable for intravenous, intramuscular,
subcutaneous and intraperitoneal administration. The sterile
aqueous media employed are all readily available by standard
techniques known to those skilled in the art.
[1122] Suitable pharmaceutical carriers include inert solid
diluents or fillers, sterile aqueous solution and various organic
solvents. Examples of suitable carriers are water, salt solutions,
alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,
peanut oil, olive oil, syrup, phospholipids, gelatine, lactose,
terra alba, sucrose, cyclodextrin, amylose, magnesium stearate,
talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl
ethers of cellulose, silicic acid, fatty acids, fatty acid amines,
fatty acid monoglycerides and diglycerides, pentaerythritol fatty
acid esters, polyoxyethylene, hydroxymethylcellulose and
polyvinylpyrrolidone. Similarly, the carrier or diluent may include
any sustained release material known in the art, such as glyceryl
monostearate or glyceryl distearate, alone or mixed with a wax. The
formulations may also include wetting agents, emulsifying and
suspending agents, preserving agents, sweetening agents or
flavouring agents.
[1123] The pharmaceutical compositions formed by combining the
compounds of the invention and the pharmaceutically acceptable
carriers are then readily administered in a variety of dosage forms
suitable for the disclosed routes of administration. The
formulations may conveniently be presented in unit dosage form by
methods known in the art of pharmacy.
[1124] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules
or tablets, each containing a predetermined amount of the active
ingredient, and which may include a suitable excipient. These
formulations may be in the form of powder or granules, as a
solution or suspension in an aqueous or non-aqueous liquid, or as
an oil-in-water or water-in-oil liquid emulsion.
[1125] Compositions intended for oral use may be prepared according
to any known method, and such compositions may contain one or more
agents selected from the group consisting of sweetening agents,
flavouring agents, colouring agents, and preserving agents in order
to provide pharmaceutically elegant and palatable preparations.
Tablets may contain the active ingredient in admixture with
non-toxic pharmaceutically-acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatine or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated
herein by reference, to form osmotic therapeutic tablets for
controlled release.
[1126] Formulations for oral use may also be presented as hard
gelatine capsules where the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or a soft gelatine capsule wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil.
[1127] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more colouring agents, one or more flavouring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[1128] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavouring agents may be added
to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[1129] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or welting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavouring, and colouring agents may also be
present.
[1130] The pharmaceutical compositions comprising a compound for
use according to the present invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example, olive oil or arachis oil, or a mineral oil, for example a
liquid paraffin, or a mixture thereof. Suitable emulsifying agents
may be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soy bean,
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of said partial esters with ethylene oxide,
for example polyoxyethylene sorbitan monooleate. The emulsions may
also contain sweetening and flavouring agents.
[1131] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, preservative and
flavouring and colouring agent. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[1132] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the present
invention. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will thus
melt in the rectum to release the drug. Such materials include
cocoa butter and polyethylene glycols, for example.
[1133] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the present
invention are contemplated. For the purpose of this application,
topical applications shall include mouth washes and gargles.
[1134] The compounds for use according to the present invention may
also be administered in the form of liposome delivery systems, such
as small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes may be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[1135] In addition, some of the compounds for use according to the
present invention may form solvates with water or common organic
solvents. Such solvates are also encompassed within the scope of
the present invention.
[1136] Thus, in a further embodiment, there is provided a
pharmaceutical composition comprising a compound for use according
to the present invention, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof, and one or more pharmaceutically
acceptable carriers, excipients, or diluents.
[1137] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatine capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. The amount of solid carrier will vary widely but will
usually be from about 25 mg to about 1 g. If a liquid carrier is
used, the preparation may be in the form of a syrup, emulsion, soft
gelatine capsule or sterile injectable liquid such as an aqueous or
non-aqueous liquid suspension or solution.
[1138] A typical tablet which may be prepared by conventional
tabletting techniques may contain: TABLE-US-00001 Core: Active
compound (as free compound or salt thereof) 5.0 mg Lactosum Ph.
Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite
.RTM.IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating:
Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T**
approx. 0.9 mg *Polacrillin potassium NF, tablet disintegrant, Rohm
and Haas. **Acylated monoglyceride used as plasticizer for film
coating.
[1139] The compounds of the invention may be administered to a
patient which is a mammal, especially a human in need thereof. Such
mammals include also animals, both domestic animals, e.g. household
pets, and non-domestic animals such as wildlife.
[1140] Any novel feature or combination of features described
herein is considered essential to this invention.
[1141] The present invention also relate to the below methods of
preparing the compounds of the invention.
[1142] The present invention is further illustrated in the
following representative examples which are, however, not intended
to limit the scope of the invention in any way.
EXAMPLES
Compounds of General Formulas (I) and (II)
[1143] The following examples and general procedures refer to
intermediate compounds and final products for general formula (I)
and (II) identified in the specification and in the synthesis
schemes. The preparation of the compounds of general formula (I)
and (II) of the present invention is described in detail using the
following examples. Occasionally, the reaction may not be
applicable as described to each compound included within the
disclosed scope of the invention.
[1144] The compounds for which this occurs will be readily
recognised by those skilled in the art. In these cases the
reactions can be successfully performed by conventional
modifications known to those skilled in the art, which is, by
appropriate protection of interfering groups, by changing to other
conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in
the title compounds are presented where appropriate. .sup.1H NMR
shifts (.delta..sub.H) are given in parts per million (ppm) down
field from tetramethylsilane as internal reference standard. M.p.:
is melting point and is given in .degree. C. and is not corrected.
Column chromatography was carried out using the technique described
by W. C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck
silica gel 60 (Art. 9385). HPLC analyses are performed using 5
.mu.m C18 4.times.250 mm column eluted with various mixtures of
water and acetonitrile, flow=1 ml/min, as described in the
experimental section.
Microwave oven synthesis: The reaction was heated by microwave
irradiation in sealed microwave vessels in a single mode Emrys
Optimizer EXP from PersonalChemistry.RTM..
[1145] Preparative HPLC: Column: 1.9.times.15 cm Waters XTerra
RP-18. Buffer: linear gradient 5-95% in 15 min, MeCN, 0.1% TFA,
flow rate of 15 ml/min. The pooled fractions are either evaporated
to dryness in vacuo, or evaporated in vacuo until the MeCN is
removed, and then frozen and freeze dried.
[1146] The abbreviations as used in the examples have the following
meaning:
TLC: Thin layer chromatography
CDCl.sub.3: Deuterio chloroform
CD.sub.3OD: Tetradeuterio methanol
DCM: Dichloromethane
DMF: N,N-dimethylformamide
DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
DIPEA: Diisopropylethylamine
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
EtOAc: Ethyl acetate
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-Hydroxy-benzotriazole
MeCN: Acetonitrile
NMP: N-Methylpyrrolidinone
TFA: Trifluoroacetic acid
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1147] General Method A: ##STR10##
[1148] By allowing an acid (I) wherein R.sup.3 is defined as above
to be coupled with an amine (II) wherein R.sup.1 and R.sup.2 are
defined as above under standard amide forming conditions using a
coupling reagent (III) (e.g. HOBT, EDAC and DIPEA in dry THF)
affording amide (IV) wherein R.sup.1, R.sup.2 and R.sup.3 are
defined as above. General Method B: ##STR11##
[1149] By allowing an acid derivative (I) wherein X is halo,
R.sup.3(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy and R.sup.3 are defined as above to
react with an amine (II) wherein R.sup.1 and R.sup.2 are defined as
above under basic conditions (e.g. triethylamine, K.sub.2CO.sub.3,
NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the
like) affording amide (III); wherein R.sup.1, R.sup.2 and R.sup.3
are defined as above. General Method C: ##STR12##
[1150] By allowing an acid derivative (I) wherein X is halo,
R.sup.20(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.20 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.3 and X are defined as above to
react with an amine (II) wherein R.sup.1 and R.sup.2 are defined as
above under basic conditions (e.g. triethylamine, K.sub.2CO.sub.3,
NaH and the like) in a solvent (e.g. THF, DCM, DMF, NMP and the
like) affording amide (III); wherein R.sup.1, R.sup.2 and R.sup.3
are defined as above; or when X is hydroxy the acid derivative (I)
wherein R.sup.3 is as defined above is coupled with an amine (II)
wherein R.sup.1 and R.sup.2 are defined as above under standard
amide forming conditions using a coupling reagent (a) (e.g. HOBT,
EDAC and DIPEA in dry THF) affording amide (III) wherein R.sup.1,
R.sup.2 and R.sup.3 are as defined above.
Example 1
General Method (A)
4-(Benzo[1,3]-dioxol-5-yloxy)-N-cyclohexyl-N-methyl-butyramide
[1151] ##STR13##
[1152] To a solution of 4-(benzo[1,3]dioxol-5-yloxy)-butyric acid
(1.0 g, 4.46 mmol), HOBT (0.66 g, 4.91 mmol) in dry THF (75 ml) was
added EDAC (0.94 g, 4.91 mmol) and the mixture was stirred for 20
minutes. Di-isopropyl ethyl amine (DIPEA) (860 .mu.l, 4.91 mmol)
and cyclohexyl-methyl-amine (555 mg, 4.91 mmol) was added and the
resulting mixture was stirred for 16 hrs. at room temperature. The
volatiles were evaporated in vacuo and the residue was purified by
silicagel chromatography using a mixture of ethyl acetate/hexane
(1:4) as eluent. Pure fractions were collected and the solvent
evaporated in vacuo to dryness. The oily residue crystallized on
standing affording 1.1 g (77%) of the title compounds as a
solid.
[1153] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.07-1.85 (m,
11H), 2.10 (m, 2H), 2.48 (t, 1H), 2.53 (t, 1H), 2.81 and 2.83
(2.times.s, 3H, N-Me rotamers), 3.96 (t, 2H), 5.90 (s, 2H), 6.32
(dd, 1H), 6.49 (d, 1H), 6.69 (d, 1H).
[1154] Calculated for C.sub.18H.sub.25NO.sub.4;
[1155] C, 67.69%; H, 7.89%; N, 4.39%. Found:
[1156] C, 67.74%; H, 7.99%; N, 4.34%.
Example 2
General Method (A)
N-Methyl-N-(1-methyl-piperidin-4-yl)-4-phenoxy-butyramide
[1157] ##STR14##
[1158] To a solution of 4-phenoxy-butyric acid (1.0 g, 5.55 mmol),
HOBT (0.83 g, 6.1 mmol) in dry THF (75 ml) was added EDAC (1.17 g,
6.1 mmol) and the mixture was stirred for 20 minutes. Di-isopropyl
ethyl amine (DIPEA) (1.06 ml, 6.1 mmol) and
methyl-(1-methyl-piperidin-4-yl)amine (783 mg, 6.1 mmol) was added
and the resulting mixture was stirred for 16 hrs. at room
temperature. The volatiles were evaporated in vacuo and the residue
was purified by silicagel chromatography using a mixture of ethyl
acetate/triethyl amine (1:25) as eluent. Pure fractions were
collected and the solvent evaporated in vacuo to dryness affording
1.1 g (68%) of the title compounds as an oil.
[1159] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.57 (m, 2H), 1.74
(dq, 1H), 1.86-2.18 (m, 5H), 2.28 (t, 3H), 2.52 (m, 2H), 2.82 and
2.85 (2.times.s, 3H, N-Me rotamers), 2.89 (bd, 2H), 3.60 and 4.51
(2.times.dt, 1H), 4.04 (t, 2H), 6.91 (m, 3H), 7.28 (m, 2H).
[1160] Calculated for C.sub.17H.sub.26N.sub.2O.sub.2;
[1161] C, 70.31%; H, 9.02%; N, 9.65%. Found:
[1162] C, 69.72%; H, 9.29%; N, 10.12%.
Example 3
General Method (A)
Azepan-1-yl-(3-chloro-phenyl)-methanone
[1163] ##STR15##
[1164] To a solution of 3-chloro benzoic acid (1.0 g, 6.39 mmol),
HOBT (0.95 g, 7.03 mmol) in dry THF (50 ml) was added EDAC (1.35 g,
7.03 mmol) and the mixture was stirred for 20 minutes. Di-isopropyl
ethyl amine (DIPEA) (1.22 ml, 7.03 mmol) and azepane (697 mg, 7.03
mmol) was added and the resulting mixture was stirred for 4 hrs. at
room temperature. The volatiles were evaporated in vacuo, water (50
ml) was added, the resulting mixture extracted with diethyl ether
(2.times.25 ml), dried (Na.sub.2SO.sub.4), filtered and evaporated
in vacuo. The residue was purified by silicagel chromatography
using a mixture of ethyl acetate/heptane (1:1) as eluent. Pure
fractions were collected and the solvent evaporated in vacuo to
dryness affording 0.9 g (59%) of the title compounds as an oil.
[1165] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.61 (m, 6H), 1.84
(m, 2H), 3.35 (t, 2H), 3.67 (t, 2H), 7.23-7.39 (m, 4H).
Example 4
General Procedure C
(4-Tetrazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone
[1166] ##STR16##
[1167] To a mixture of 4-(1H-tetrazol-5-yl)-benzoic acid (0.5 g,
2.63 mmol) and HOBT (0.39 g, 2.89 mmol) in dry THF (35 mL) was
added EDAC (0.55 g, 2.89 mmol). The resulting mixture was stirred
for 10 min. followed by addition of a mixture of DIPEA (0.50 ml,
2.89 mmol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.49 ml,
2.89 mmol). The reaction mixture was stirred for an additional 6
hrs. and evaporated to dryness. To the residue was added water (10
ml) and the resulting mixture was extracted with diethyl ether
(2.times.10 ml). The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered and evaporated in vacuo. The resulting
residue was purified by column chromatography (silica gel) using a
mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were
collected and evaporated to dryness. To the residue was added
diethyl ether (5 ml) and the precipitate was filtered off, washed
with diethyl ether and dried in vacuo at 50.degree. C. affording
220 mg (26%) of the title compound as a solid.
[1168] TLC: EtOAc-Heptan (2:1), R.sub.f: 0.18
[1169] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 0.95-1.15 (m, 9H),
1.21-1.64 (m, 5.5H), 2.25 (m, 0.5H), 3.17-3.32 (m, 1.5H), 3.63 (d,
0.5H), 3.98 and 4.60 (2.times.t, 1H), 7.68 (t, 2H), 7.78 (m, 2H),
9.06 (s, 1H).
[1170] The following compounds were made in a similar way as
described in example 4 above: TABLE-US-00002 No Molecule MW IUPAC
Name 4-1 ##STR17## 323.43 N-Cyclohexyl-N-methyl-2-phenoxymethyl-
benzamide 4-2 ##STR18## 232.32
4-Amino-N-cyclohexyl-N-methyl-benzamide 4-3 ##STR19## 337.46
N-Cycloheptyl-N-methyl-2-phenoxymethyl- benzamide 4-4 ##STR20##
217.31 N-Cyclohexyl-N-methyl-benzamide 4-5 ##STR21## 269.74
2-Chloro-N-cyclohexyl-6-fluoro-N-methyl- benzamide 4-6 ##STR22##
301.31 N-Cyclohexyl-N-methyl-4-trifluoromethoxy- benzamide 4-7
##STR23## 245.36 N-Cyclohexyl-2,3,N-trimethyl-benzamide 4-8
##STR24## 286.20 3,5-Dichloro-N-cyclohexyl-N-methyl-benzamide 4-9
##STR25## 309.41 N-Cyclohexyl-N-methyl-2-phenoxy-benzamide 4-10
##STR26## 429.56 2,4-Bis-benzyloxy-N-cyclohexyl-N-methyl- benzamide
4-11 ##STR27## 323.43 2-Benzyloxy-N-cyclohexyl-N-methyl-benzamide
4-12 ##STR28## 309.41 N-Cyclohexyl-N-methyl-4-phenoxy-benzamide
4-13 ##STR29## 323.43 4-Benzyloxy-N-cyclohexyl-N-methyl-benzamide
4-14 ##STR30## 323.43 N-Cyclohexyl-N-methyl-4-phenoxymethyl-
benzamide 4-15 ##STR31## 310.78
2-Chloro-N-cyclohexyl-N-ethyl-4-nitro- benzamide 4-16 ##STR32##
310.78 4-Chloro-N-cyclohexyl-N-ethyl-3-nitro- benzamide 4-17
##STR33## 293.34 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid
cyclohexyl-methyl-amide 4-18 ##STR34## 237.73
Azepan-1-yl-(2-chloro-phenyl)-methanone 4-19 ##STR35## 237.73
Azepan-1-yl-(3-chloro-phenyl)-methanone 4-20 ##STR36## 203.28
Azepan-1-yl-phenyl-methanone 4-21 ##STR37## 385.51
2-(Biphenyl-4-yloxy)-N-cyclohexyl-N-methyl- benzamide 4-22
##STR38## 369.46 N-Cyclohexyl-2-(3,5-dimethoxy-phenoxy)-N-
methyl-benzamide 4-23 ##STR39## 369.46
N-Cyclohexyl-2-(2,3-dimethoxy-phenoxy)-N- methyl-benzamide 4-24
##STR40## 386.32 2,4-Dichloro-N-(3,3-dimethyl-1,5-dioxa-
spiro[5.5]undec-9-yl)-N-methyl-benzamide 4-25 ##STR41## 300.18
2,4-Dichloro-N-methyl-N-(4-oxo-cyclohexyl)- benzamide 4-26
##STR42## 233.31 N-Cyclohexyl-2-hydroxy-N-methyl-benzamide 4-27
##STR43## 247.34 N-Cyclohexyl-3-methoxy-N-methyl-benzamide 4-28
##STR44## 261.32 Benzo[1,3]dioxole-5-carboxylic acid cyclohexyl-
methyl-amide 4-29 ##STR45## 323.43
3-Benzyloxy-N-cyclohexyl-N-methyl-benzamide 4-30 ##STR46## 233.31
N-Cyclohexyl-3-hydroxy-N-methyl-benzamide 4-31 ##STR47## 406.54
[4-(Morpholine-4-sulfonyl)-phenyl]-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 4-32 ##STR48##
426.58 N-Benzyl-3-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- benzenesulfonamide 4-33 ##STR49##
424.53 [4-Fluoro-3-(morpholine-4-sulfonyl)-phenyl]-
(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 4-34
##STR50## 418.58 Thiophene-2-sulfonic acid [4-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]- amide 4-35 ##STR51##
412.55 N-Phenyl-4-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)- benzenesulfonamide 4-36 ##STR52##
349.47 (4-Phenoxy-phenyl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-37 ##STR53## 440.60
N-(2,4-Dimethyl-phenyl)-3-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]octane-6-carbonyl)- benzenesulfonamide 4-38
##STR54## 363.50 (2-Phenoxymethyl-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-39 ##STR55## 392.56
4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-N,N-
dipropyl-benzenesulfonamide 4-40 ##STR56## 296.21
2-Bromo-N-cyclohexyl-N-methyl-benzamide 4-41 ##STR57## 314.43
N-[4-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-phenyl]- acetamide 4-42 ##STR58##
300.44 (4-Dimethylamino-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-43 ##STR59## 322.45
(4-Pyrrol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-44 ##STR60## 323.44
(4-Imidazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-45 ##STR61## 302.42
(4-Amino-2-methoxy-phenyl)-(trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-46 ##STR62## 335.46
(4-Methanesulfonyl-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-47 ##STR63## 335.46
(3-Methanesulfonyl-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-48 ##STR64## 397.54
(4-Benzenesulfonyl-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-49 ##STR65## 348.49
Azepan-1-yl-[4-(3,4-dihydro-1H-isoquinolin-2-
ylmethyl)-phenyl]-methanone 4-50 ##STR66## 302.42
Azepan-1-yl-(4-morpholin-4-ylmethyl-phenyl)- methanone 4-51
##STR67## 391.44 [4-(3-Trifluoromethyl-pyrazol-1-yl)-phenyl]-
(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 4-52
##STR68## 324.42 (4-[1,2,4]Triazol-1-yl-phenyl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-53 ##STR69## 323.44
(4-Pyrazol-1-yl-phenyl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-54 ##STR70## 337.46
2-Benzyloxymethyl-N-cyclohexyl-N-methyl- benzamide 4-55 ##STR71##
313.40 N-Cyclohexyl-N-methyl-4-(3-methyl-5-oxo-4,5-
dihydro-pyrazol-1-yl)-benzamide 4-56 ##STR72## 353.46
5-Methyl-2-[4-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-2,4- dihydro-pyrazol-3-one
4-57 ##STR73## 346.47 (9H-Carbazol-3-yl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-58 ##STR74## 351.49
[4-(3,5-Dimethyl-pyrazol-1-yl)-phenyl]-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 4-59 ##STR75##
257.37 Phenyl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
6-yl)-methanone 4-60 ##STR76## 282.18
Azepan-1-yl-(2-bromo-phenyl)-methanone 4-61 ##STR77## 308.22
(3-Aza-bicyclo[3.2.2]non-3-yl)-(2-bromo-phenyl)- methanone 4-62
##STR78## 330.43 (4-Benzyl-piperidin-1-yl)-quinolin-2-yl- methanone
4-63 ##STR79## 254.33 (2-Methyl-piperidin-1-yl)-quinolin-2-yl-
methanone 4-64 ##STR80## 280.37
(3-Aza-bicyclo[3.2.2]non-3-yl)-quinolin-2-yl- methanone 4-65
##STR81## 268.36 Quinoline-2-carboxylic acid cyclohexyl-methyl-
amide 4-66 ##STR82## 308.42 Quinolin-2-yl-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-67 ##STR83## 354.45
1-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-
6-carbonyl)-phenyl]-pyrrolidine-2,5-dione 4-68 ##STR84## 258.36
Pyridin-3-yl-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-69 ##STR85## 258.36
Pyridin-4-yl-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-70 ##STR86## 258.36
Pyridin-2-yl-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone 4-71 ##STR87## 324.42
(6-Pyrazol-1-yl-pyridin-3-yl)-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)-methanone 4-72 ##STR88## 301.38
4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-benzoic
acid 4-73 ##STR89## 303.4
Imidazo[2,1-b]thiazol-6-yl-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)-methanone
Example 5
General Procedure C
8-(4-Dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one
[1171] ##STR90##
[1172] To a mixture of 8-aza-bicyclo[3.2.1]octane (1.8 g, 14.38
mmol), dry THF (75 ml) and TEA (4 ml, 28.76 mmol) was added
dropwise a solution of 4-dimethylamino-benzoyl chloride (3.17 g,
17.26 mmol) in dry THF (75 ml). The resulting mixture was stirred
for 1 hr. at room temperature followed by filtration and
evaporation in vacuo. The residue was purified by column
chromatography (silica gel) using a mixture of EtOAc-Heptane (1:2)
as eluent. Pure fractions were collected and evaporated to dryness.
The residue was crystallized from diethyl ether (25 ml), filtered
off and dried in vacuo at 50.degree. C. affording 1.9 g (48%) of
the title compound as a solid.
[1173] TLC: EtOAc-Heptane (3:1), R.sub.f: 0.4
[1174] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 1.74 (m, 2H), 2.15
(m, 2H), 2.39 (d, 2H), 2.27 (bs, 2H), 3.02 (s, 6H), 4.80 (bs, 2H),
6.68 (d, 2H), 7.50 (d, 2H).
Example 6
General Procedure C
(4-Dimethylamino-phenyl)-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-methanon-
e
[1175] ##STR91##
[1176] To a solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g,
7.34 mmol) in MeOH (75 ml) was added NaBH.sub.4 (0.45 g, 11.02
mmol, pellets). The resulting mixture was stirred for 18 hrs,
evaporated and to the residue was added water (75 ml). The aqueous
phase was acidified to pH 1 with conc. HCl and washed with diethyl
ether (50 ml). The aqueous phase was neutralized to pH 7 with 1N
NaOH. The precipitate was filtered off and washed with water,
diethyl ether and dried in vacuo at 50.degree. C. affording 1.15 g
(57%) of the title compound as a solid.
[1177] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.66-1.95 (m, 6H),
2.22 (d, 2H), 2.99 (s, 6H), 4.17 (m, 1H), 4.22 (bs, 1H), 4.74 (bs,
1H), 6.66 (d, 2H), 7.41 (d, 2H).
Example 7
General Procedure C
(4-Dimethylamino-phenyl)-(3-hydroxy-3-methyl-8-aza-bicyclo[3.2.1]oct-8-yl)-
-methanone
[1178] ##STR92##
[1179] To a solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (200
mg, 0.734 mmol) in dry THF (40 ml) was added dropwise a solution of
methylmagnesium bromide (0.74 ml, 2.20 mmol, 3M in diethyl ether).
The resulting mixture was stirred for 36 hrs. at room temperature
and quenched by addition of saturated aqueous ammonium chloride (50
ml). The aqueous phase was extracted with EtOAc (2.times.100 ml)
and the combined organic phases were dried (Na.sub.2SO.sub.4),
filtered and evaporated in vacuo. The residue was purified by
column chromatography (silica gel) using a mixture of EtOAc-Heptane
(5:1) as eluent. Pure fractions were collected and evaporated to
dryness affording 45 mg (21%) of the title compound as a solid.
TLC: EtOAc, R.sub.f: 0.39
[1180] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.21 (s, 3H), 1.75
(d, 2H), 1.92 (m, 2H), 2.15 (bs, 1H), 2.22 (d, 2H), 3.0 (s, 6H),
4.26 (bs, 1H), 4.77 (bs, 1H), 6.66 (d, 2H), 7.42 (d, 2H).
Example 8
General Procedure C
Trifluoro-acetic acid
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl ester
[1181] ##STR93##
[1182] NaBH.sub.4 (0.3 g, 2 pellets) was added to TFA (20 ml) at
0.degree. C. and stirred for 30 min. To this mixture was added a
solution of
8-(4-dimethylamino-benzoyl)-8-aza-bicyclo[3.2.1]octan-3-one (0.3 g,
1.102 mmol) in DCM (10 ml). The resulting mixture was stirred for
64 hrs. at room temperature, the volatiles evaporated and to the
residue was added water (10 ml). The aqueous phase was neutralized
to pH 7 with 1N NaOH and extracted with diethyl ether (2.times.25
ml). The combined organic phases were evaporated in vacuo and the
residue purified by column chromatography (silica gel) using a
mixture of EtOAc-Heptane (1:2) as eluent. Pure fractions were
collected and evaporated to dryness affording 25 mg (9%) of the
title compound as a solid. TLC: EtOAc-Heptane (2:1), R.sub.f:
0.54
[1183] LC/MS: m/z: 371H.sup.+
[1184] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.81-1.94 (m, 2H),
2.05 (s, 4H), 2.31 (bs, 2H), 3.01 (s, 6H), 4.59 (bs, 2H), 5.35 (t,
1H), 6.67 (d, 2H), 7.42 (d, 2H).
EXAMPLES
Compounds of General Formula (III)
[1185] The following examples and general procedures refer to
intermediate compounds and final products for general formula (III)
identified in the specification and in the synthesis schemes. The
preparation of the compounds of general formula (III) of the
present invention is described in detail using the following
examples. Occasionally, the reaction may not be applicable as
described to each compound included within the disclosed scope of
the invention. The compounds for which this occurs will be readily
recognised by those skilled in the art. In these cases the
reactions can be successfully performed by conventional
modifications known to those skilled in the art, that is, by
appropriate protection of interfering groups, by changing to other
conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in
the title compounds are presented where appropriate. .sup.1H NMR
shifts (8H) are given in parts per million (ppm) down field from
tetramethylsilane as internal reference standard. M.p.: is melting
point and is given in .degree. C. and is not corrected. Column
chromatography was carried out using the technique described by W.
C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel
60 (Art. 9385). HPLC analyses are performed using 5 .mu.m C18
4.times.250 mm column eluted with various mixtures of water and
acetonitrile, flow=1 ml/min, as described in the experimental
section.
[1186] The abbreviations as used in the examples have the following
meaning:
TLC: thin layer chromatography
CDCl.sub.3: deuterio chloroform
CD.sub.3OD: tetradeuterio methanol
DMSO-d.sub.6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1187] The compounds of the invention are prepared as illustrated
in the following reaction scheme 1: ##STR94## General Method:
[1188] By allowing 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's
acid) (I) to react with an acid chloride (II), wherein R.sup.2 is
defined above, in a solvent mixture of pyridine and DCM and the
like affording an acyl Meldrum's acid (III), wherein R.sup.2 is as
defined above. The acyl Meldrum's acid (III) is aminolysed with an
substituted amine (IV), wherein R.sup.3 and R.sup.4 are defined
above, in a solvent such as benzene, toluene, dioxane, and the like
at a temperature interval from 50.degree. C. up to reflux affording
a beta-keto amide (V) wherein R.sup.2, R.sup.3 and R.sup.4 are as
defined above. The beta-keto amide (V) is treated with
ortho-formiate (VI) in a solvent such as acetic acid anhydride and
the like at a temperature interval from 50.degree. C. up to reflux
affording enol ether (VII) wherein R.sup.2, R.sup.3, and R.sup.4
are as defined above. Condensation of the enol ether (VII) wherein
R.sup.2, R.sup.3, and R.sup.4 are as defined above with hydrazide
(VIII) wherein R.sup.1 is as defined above yields pyrazole (IX)
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined
above, in a solvent such as EtOH, i-PrOH, tert-BuOH and the
like.
Example 1
1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide
[1189] ##STR95##
[1190] To a solution of
1-(4-chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic acid (1.0 g,
3.78 mmol), HOBT (0.56 g, 4.16 mmol) in dry THF (50 ml) was added
EDAC (0.8 g, 4.16 mmol) and the mixture was stirred for 10 minutes.
Di-isopropyl ethyl amine (DIPEA) (724 .mu.l, 4.16 mmol) and
cyclohexyl-methyl-amine (0.54 ml, 4.16 mmol) was added and the
resulting mixture was stirred for 16 hrs. at room temperature. The
volatiles were evaporated in vacuo and the residue was purified by
silicagel chromatography using a mixture of ethyl acetate and
heptane (1:4) as eluent. Pure fractions were collected and the
solvent evaporated in vacuo affording 1.1 g (81%) of the title
compounds as an oil.
[1191] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.81 (t, 3H),
1.1-1.86 (m, 13H), 2.81 (t, 2H), 2.98 (s, 3H), 3.89 and 4.50
(2.times.bs, 1H), 7.37 (m, 2H), 7.47 (m, 2H), 7.58 (bs, 1H).
[1192] Calculated for C.sub.20H.sub.26ClN.sub.3O, 0.4H.sub.2O; C,
65.44%; H, 7.36%; N, 11.45%. Found: C, 65.47%; H, 7.89%; N,
11.56%.
[1193] The following compound was made in a similar way as
described in example 1 above
Example 2
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
cyclohexyl-methyl-amide
[1194] ##STR96##
[1195] Calculated for C.sub.18H.sub.19ClF.sub.3N.sub.3O;
[1196] C, 56.04%; H, 4.96%; N, 10.89%. Found:
[1197] C, 56.02%; H, 5.16%; N, 10.76%.
Example 3
[1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone
[1198] ##STR97##
[1199] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.97 (t, 5H), 1.11
(t, 4H), 1.25-1.61 (m, 4H), 1.79 (m, 2H), 2.20 (d, 0.5H), 2.44 (d,
3H), 3.29 (d, 0.5H), 3.40 (d, 0.5H), 3.59 (m, 0.5H), 3.86 (s, 3H),
4.37 (m, 0.5H), 4.60 (m, 0.5H), 6.99 (d, 2H), 7.33 (d, 2H), 7.74
(s, 1H).
EXAMPLES
Compounds of General Formula (IV)
[1200] The following examples and general procedures refer to
intermediate compounds and final products for general formula (IV)
identified in the specification and in the synthesis schemes. The
preparation of the compounds of general formula (IV) of the present
invention is described in detail using the following examples.
Occasionally, the reaction may not be applicable as described to
each compound included within the disclosed scope of the invention.
The compounds for which this occurs will be readily recognised by
those skilled in the art. In these cases the reactions can be
successfully performed by conventional modifications known to those
skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or
by routine modification of reaction conditions. Alternatively,
other reactions disclosed herein or otherwise conventional will be
applicable to the preparation of the corresponding compounds of the
invention. In all preparative methods, all starting materials are
known or may easily be prepared from known starting materials. The
structures of the compounds are confirmed by either elemental
analysis or nuclear magnetic resonance (NMR), where peaks assigned
to characteristic protons in the title compounds are presented
where appropriate. .sup.1H NMR shifts (6H) are given in parts per
million (ppm) down field from tetramethylsilane as internal
reference standard. M.p.: is melting point and is given in .degree.
C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem.
43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses
are performed using 5 .mu.m C18 4.times.250 mm column eluted with
various mixtures of water and acetonitrile, flow=1 ml/min, as
described in the experimental section.
[1201] The abbreviations as used in the examples have the following
meaning:
TLC: Thin layer chromatography
CDCl.sub.3: Deuterio chloroform
CD.sub.3OD: Tetradeuterio methanol
DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
HOBT: 1-Hydroxy-benzotriazole
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1202] The compounds of the invention are prepared as illustrated
in the following reaction scheme 1: ##STR98## General Method:
[1203] By allowing a N-aminopyridinium iodide (I), wherein R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as defined, above to react with a
propiolate (II), wherein alkyl and R.sup.1 are as defined above, in
a solvent such as DMF and the like, with a suitable base, such as
potassium carbonate and the like affording a
pyrazolo[1,5-a]pyridine-3-carboxylic acid ester (III), wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and alkyl are as
defined above. The pyrazolo[1,5-a]pyridine-3-carboxylic acid ester
(III) is hydrolysed with a base affording a
pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV), wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above. The
pyrazolo[1,5-a]pyridine-3-carboxylic acid (IV) is coupled with an
amine (V), wherein R.sup.6 and R.sup.7 are as defined above, under
standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry
THF) affording pyrazolo[1,5-a]pyridine-3-amide (VI), wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7
are as defined above.
Example 1
Pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone
[1204] ##STR99##
[1205] A solution of pyrazolo[1,5-A]pyridine-3-carboxylic acid (97
mg, 0.6 mmol), HOBT (89 mg, 0.66 mmol), EDAC (126 mg, 0.66 mmol)
and di-isopropyl ethyl amine (DIPEA) (115 .mu.l, 0.66 mmol) in dry
THF (10 ml) was stirred for 1 hr. and
1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (101 mg, 0.66 mmol) was
added. The mixture was stirred for 16 hrs. at room temperature. The
mixture was quenched by addition of water (30 ml), extracted with
EtOAc (2.times.50 ml), dried (MgSO.sub.4), filtered and evaporated
in vacuo. The crude product was stirred with water (10 ml) for 30
min., filtered off and dried in vacuo affording 130 mg (73%) of the
title compound as a white solid.
[1206] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.95 (s, 3H), 1.05
(d, 3H), 1.15 (d, 3H), 1.36-1.88 (m, 5.5H), 2.23 (d, 0.5H), 3.37
(d, 0.5H), 3.51 (d, 0.5H), 3.61 (d, 0.5H), 3.73 (d, 0.5H), 4.56 (m,
0.5H), 4.71 (m, 0.5H), 6.92 (m, 1H), 7.33 (m, 1H), 8.19 (s, 1H),
8.47 (m, 2H
[1207] The following compounds were made in a similar way was
described in example 1 above.
Example 2
(2-Methyl-pyrazolo[1,5-a]pyridin-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.-
1]oct-6-yl)-methanone
[1208] ##STR100##
[1209] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (s, 3H), 1.00
(d, 3H), 1.14 (d, 3H), 1.22-1.45 (m, 3.5H), 1.58 (d, 0.5H),
1.80-1.90 (m, 1.5H), 2.40 (d, 0.5H), 2.50 (s, 3H), 3.20 (dd, 1.5H),
3.82 (d, 0.5H), 4.02 (m, 0.5H), 4.57 (m, 0.5H), 6.75 (t, 1H), 7.18
(t, 1H), 7.38 (t, 1H), 8.36 (d, 1H).
Example 3
Pyrazolo[1,5-a]pyridine-3-carboxylic acid
cyclohexyl-methyl-amide
[1210] ##STR101##
[1211] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (m, 1H), 1.39
(m, 2H), 1.57-1.70 (m, 3H), 1.83 (m, 4H), 3.07 (bs, 3H), 4.30 (bs,
1H), 6.89 (t, 1H), 7.30 (d, 1H), 8.08 (m, 2H), 8.48 (d, 1H).
EXAMPLES
Compounds of General Formula (V)
[1212] The following examples and general procedures refer to
intermediate compounds and final products for general formulas (V)
and (Va) identified in the specification and in the synthesis
schemes. The preparation of the compounds of general formulas (V)
and (Va) of the present invention is described in detail using the
following examples. Occasionally, the reaction may not be
applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this
occurs will be readily recognised by those skilled in the art. In
these cases the reactions can be successfully performed by
conventional modifications known to those skilled in the art, that
is, by appropriate protection of interfering groups, by changing to
other conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in
the title compounds are presented where appropriate. .sup.1H NMR
shifts (.delta..sub.H) are given in parts per million (ppm) down
field from tetramethylsilane as internal reference standard. M.p.:
is melting point and is given in .degree. C. and is not corrected.
Column chromatography was carried out using the technique described
by W. C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck
silica gel 60 (Art. 9385). HPLC analyses are performed using 5
.mu.m C18 4.times.250 mm column eluted with various mixtures of
water and acetonitrile, flow=1 ml/min, as described in the
experimental section.
[1213] The abbreviations as used in the examples have the following
meaning:
TLC: Thin layer chromatography
CDCl.sub.3: Deuterio chloroform
CD.sub.3OD: Tetradeuterio methanol
DIPEA: Diisopropylethyl amine
DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-Hydroxy-benzotriazole
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1214] The compounds of the invention are prepared as illustrated
in the following reaction schemes: ##STR102## General Method A
[1215] Benzimidazol carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6 and R.sup.7 are as defined above are
generally prepared as described in the following literature
references; [1216] Sekikawa; Bull. Chem. Soc. Jpn. 31, (1958), 252.
[1217] Zehra; Chem. Ber. 23, (1890), 3629. [1218] Palmer, B. D. et
al.; J. Med. Chem. 41, (1998), 5457-5465. [1219] Chi, Y.-C. and
Sun, C.-M.; Syn. Lett. 5, (2000), 591-594. [1220] Wu, Z. et al.;
Tetrahedron Lett. 41, (2000), 9871-9874.
[1221] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.5, R.sup.6 and R.sup.7 are as defined above to be coupled
with an amine (II) wherein R.sup.1 and R.sup.2 are defined as above
under standard amide forming conditions using a coupling reagent
(a) (e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, Y and Z are
as defined above. General Method B ##STR103##
[1222] By allowing an acid derivative (I) wherein X is halo,
R.sup.8(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.8 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.1, R.sup.2, R.sup.3, R.sup.5,
R.sup.6 and R.sup.7 are defined as above to react with an amine
(II) wherein R.sup.6 and R.sup.7 are defined as above under basic
conditions (e.g. triethylamine, K.sub.2CO.sub.3, NaH and the like)
in a solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide
(III); wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 are defined as above. ##STR104## General Method A
[1223] Benzimidazol carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, and R.sup.6 are as defined above are generally
prepared as described in the following literature references;
[1224] Sekikawa; Bull. Chem. Soc. Jpn. 31, (1958), 252. [1225]
Zehra; Chem. Ber. 23, (1890), 3629. [1226] Palmer, B. D. et al.; J.
Med. Chem. 41, (1998), 5457-5465. [1227] Chi, Y.-C. and Sun, C.-M.;
Syn. Lett. 5, (2000), 591-594. [1228] Wu, Z. et al.; Tetrahedron
Lett. 41, (2000), 9871-9874.
[1229] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.5, and R.sup.6 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.8 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry THF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.5, R.sup.7 and
R.sup.8 are as defined above. General Method B ##STR105##
[1230] By allowing an acid derivative (I) wherein X is halo,
R.sup.9(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.9 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.1, R.sup.2, R.sup.3, R.sup.5 and
R.sup.6 are defined as above to react with an amine (II) wherein
R.sup.7 and R.sup.8 are defined as above under basic conditions
(e.g. triethylamine, K.sub.2CO.sub.3, NaH and the like) in a
solvent (e.g. THF, DCM, DMF, NMP and the like) affording amide
(III); wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are defined as above.
Example 1
1H-Benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide
[1231] ##STR106##
[1232] A solution of 1H-benzoimidazole-5-carboxylic acid (10 g,
61.67 mmol) and HOBT (9.17 g, 67.84 mmol) in dry THF (250 ml) was
stirred for 1 h. EDAC (13 g, 67.84 mmol) was added and the mixture
was stirred for another 1 h. Di-isopropyl ethyl amine (DIPEA) (11.8
ml, 67.84 mmol) and cyclohexyl-methyl-amine (8.8 ml, 67.84 mmol)
was added and the resulting mixture was stirred for 16 hrs. at room
temperature. The precipitate was filtered off and the volatiles
were evaporated in vacuo. To the residue was added water (150 ml)
and diethyl ether (75 ml) and the resulting mixture was stirred for
15 minutes. The precipitate was filtered off and washed with water
followed by diethyl ether and drying in vacuo at 50.degree. C.
which afforded 7.7 g (49%) of the title compounds as a solid.
[1233] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.03 (bs, 2H),
1.53-1.86 (m, 8H), 2.93 (bd, 3H), 3.57 and 4.56 (2.times.bs, 1H),
7.19 (d, 1H), 7.44 (bs, 1H), 7.62 (s, 1H), 7.79 (s, 1H), 11.8 (bs,
1H, NH).
[1234] Calculated for C.sub.15H.sub.19N.sub.3O;
[1235] C, 70.01%; H, 7.44%; N, 16.33%. Found:
[1236] C, 69.63%; H, 7.45%; N, 16.17%.
[1237] The following compounds were synthesised in a similar way as
described in example 1
Example 2
Isopropyl-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide
[1238] ##STR107##
[1239] Calculated for C.sub.19H.sub.24F.sub.3N.sub.3O;
[1240] C, 62.11%; H, 6.58%; N, 11.44%. Found
[1241] C, 62.10%; H, 6.69%; N, 11.66%.
Example 3
1-Benzyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide
[1242] ##STR108##
[1243] Calculated for C.sub.22H.sub.25N.sub.3O;
[1244] C, 76.05%; H, 7.25%; N, 12.09%. Found
[1245] C, 75.89%; H, 7.39%; N, 12.03%.
Example 4
2-Methyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide
[1246] ##STR109##
[1247] Calculated for C.sub.16H.sub.21N.sub.3O;
0.1.times.H.sub.2O;
[1248] C, 70.35%; H, 7.82%; N, 15.38%. Found
[1249] C, 70.09%; H, 7.78%; N, 15.41%.
Example 5
2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide
[1250] ##STR110##
[1251] Calculated for C.sub.16H.sub.21N.sub.3O.sub.2;
[1252] C, 66.88%; H, 7.37%; N, 14.62%. Found
[1253] C, 66.62%; H, 7.50%; N, 14.43%.
Example 6
2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid
cyclohexyl-methyl-amide
[1254] ##STR111##
[1255] LC/MS m/z: 349H.sup.+
[1256] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.03-1.3 (m, 4H),
1.45-1.80 (m, 6H), 2.84 (bd, 3H), 5.65 (bs, 2H), 6.66 (d, 2H), 7.12
(m, 1H), 7.48 (m, 2H), 7.84 (d, 2H), 12.6 (bs, 1H, NH).
Example 7
(1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-met-
hanone
[1257] ##STR112##
[1258] LC/MS m/z: 298H.sup.+
[1259] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.95 (d, 3H), 1.04
(d, 3H), 1.15 (d, 3H), 1.19-1.87 (m, 5.5H), 2.25 (m, 0.5H),
3.24-3.34 (m, 1.5H), 3.69 (d, 0.5H), 3.99 (m, 0.5H), 4.66 (m,
0.5H), 7.60 (t, 1H), 7.84 (t, 1H), 7.94 (d, 1H), 9.08 (s, 1H).
Example 8
(2-Methyl-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct--
6-yl)-methanone
[1260] ##STR113##
[1261] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.93 (d, 3H), 1.02
(d, 3H), 1.15 (m, 3H), 1.19-1.85 (m, 5.5H), 2.27 (m, 0.5H), 2.50
(s, 3H), 3.22-3.35 (m, 1.5H), 3.64 (d, 0.5H), 4.06 (m, 0.5H), 4.64
(m, 0.5H), 7.22 (m, 2H), 7.58 (m, 1H).
Example 9
(2-Amino-1H-benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone
[1262] ##STR114##
[1263] LC/MS m/z: 313H.sup.+
[1264] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.91 (d, 3H), 1.04
(d, 3H), 1.13 (s, 3H), 1.2-1.82 (m, 5.5H), 2.18 (m, 0.5H),
3.22-3.26 (m, 1.5H), 3.62 (d, 0.5H), 4.01 (m, 0.5H), 4.54 (m,
0.5H), 7.21 (m, 3H), 8.14 (m, 2H).
EXAMPLES
Compounds of General Formula (VI)
[1265] The following examples and general procedures refer to
intermediate compounds and final products for general formula (VI)
identified in the specification and in the synthesis schemes. The
preparation of the compounds of general formula (VI) of the present
invention is described in detail using the following examples.
Occasionally, the reaction may not be applicable as described to
each compound included within the disclosed scope of the invention.
The compounds for which this occurs will be readily recognised by
those skilled in the art. In these cases the reactions can be
successfully performed by conventional modifications known to those
skilled in the art, that is, by appropriate protection of
interfering groups, by changing to other conventional reagents, or
by routine modification of reaction conditions. Alternatively,
other reactions disclosed herein or otherwise conventional will be
applicable to the preparation of the corresponding compounds of the
invention. In all preparative methods, all starting materials are
known or may easily be prepared from known starting materials. The
structures of the compounds are confirmed by either elemental
analysis or nuclear magnetic resonance (NMR), where peaks assigned
to characteristic protons in the title compounds are presented
where appropriate. .sup.1H NMR shifts (8H) are given in parts per
million (ppm) down field from tetramethylsilane as internal
reference standard. M.p.: is melting point and is given in .degree.
C. and is not corrected. Column chromatography was carried out
using the technique described by W. C. Still et al., J. Org. Chem.
43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC analyses
are performed using 5 .mu.m C18 4.times.250 mm column eluted with
various mixtures of water and acetonitrile, flow=1 ml/min, as
described in the experimental section.
[1266] The abbreviations as used in the examples have the following
meaning:
TLC: thin layer chromatography
CDCl.sub.3: deuterio chloroform
CD.sub.3OD: tetradeuterio methanol
DMSO-d.sub.6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1267] The compounds of the invention are prepared as illustrated
in the following reaction scheme 1: ##STR115## General Method
A:
[1268] By allowing a carboxylic acid ester (I) wherein R.sup.13 is
C.sub.1-C.sub.6alkyl or arylC.sub.1-C.sub.6alkyl and R.sup.7 is as
defined above to react with an alkene (II) wherein X is halo and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and n are as defined above
under basic conditions using a base (K.sub.2CO.sub.3, TEA, DIPEA in
dry acetone, MIBK and the like) affording aryl ether (III) wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.13 and n are as
defined above. Aryl ether (III) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.7, R.sup.13 and n are as defined above is rearranged
in e.g. NMP at reflux temperature into phenol (IV) wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.13 and n are as defined
above. Treatment of phenol (IV) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.7, R.sup.13 and n are as defined above with 90%
formic acid followed by basic hydrolysis and acidic work up affords
dihydrobenzofurane (V) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.7 and n are as defined above. Dihydrobenzofurane (V) wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7 and n are as defined
above is coupled with an amine (VI) wherein R.sup.5 and R.sup.6 are
defined as above under standard amide forming conditions using a
coupling reagent (a) (e.g. HOBT, EDAC and DIPEA in dry THF)
affording amide (VII) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and n are as defined above. General
Method B: ##STR116##
[1269] By allowing an acid derivative (I) wherein Y is halo,
R.sup.13(C.dbd.O)O--, C.sub.1-C.sub.6alkyloxy or
arylC.sub.1-C.sub.6alkyloxy, R.sup.13 is C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.3, R.sup.4, R.sup.7 and X are
defined as above to react with an amine (II) wherein R.sup.5 and
R.sup.6 are defined as above under basic conditions (e.g.
triethylamine, K.sub.2CO.sub.3, NaH and the like) in a solvent
(e.g. THF, DCM, DMF, NMP and the like) affording amide (III);
wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and X are
defined as above.
[1270] In the following "general methods C to H" is provided
guidelines for synthesis of substituted benzofuranes-,
2,3-dihydrobenzofuranes-7-carboxylic acids and croman-8-carboxylic
acids (compound V in scheme 1) according to literature references;
General Method C: ##STR117## wherein X is halo, R.sup.13 and
R.sup.14 are independently C.sub.1-C.sub.6alkyl or
arylC.sub.1-C.sub.6alkyl and R.sup.1, R.sup.3, and R.sup.7 are
defined as above. [1271] Cherif, M.; Cotelle, P.; Catteau, J.-P.;
Heterocycles (1992), 34, 1749-1758. [1272] Barker, P.; Finke, P.;
Thompson, K.; Synth Commun (1989), (19), 257. General Method D:
##STR118## wherein X is OH or halo; R.sup.13 is
C.sub.1-C.sub.6alkyl or arylC.sub.1-C.sub.6alkyl and R.sup.1,
R.sup.3, and R.sup.7 are defined as above. [1273] Catalyst: AIBN:
Graham, S. R.; Murphy, J. A.; Coates, D.; Tetrahedron Lett., 40,
(1999), 2415-2416. [1274] Catalyst: Pd(OAc).sub.2: Larock, R. C.;
Stinn, D. E.; Tetrahedron Lett.; 29; (1988), 4687-4690. General
Method E: ##STR119## wherein R' is CN or COOR''; R.sup.1 is
hydrogen, C.sub.1-C.sub.6alkyl, aryl, heteroaryl or
arylC.sub.1-C.sub.6alkyl; R.sup.3 is aryl, heteroaryl, cyano,
COR.sup.13, nitro or COOR'', wherein R'' and R.sup.13 independently
are C.sub.1-C.sub.6alkyl, aryl, heteroaryl, or
arylC.sub.1-C.sub.6alkyl; [1275] Lau, C. K. et al.; J. Med. Chem.
32, (1989) 1190-1197. For conversion of R'.dbd.CN to COOH see e.g.
Cagniant; Bull. Soc. Chim. Fr.; (1957), 827-834. General Method F:
##STR120## wherein R' is hydrogen or bromo; R.sup.1, R.sup.3 and
R.sup.7 are defined as above; [1276] Al-bojuk, N. R.; El-Abadelah,
M. M.; Sabri, S. S.; Michel, A.; Voelter, W.; M.-Moessmer, C.;
Al-Abed, Y.; Heterocycles; 55, (2001), 1789-1804. [1277] Stanetty,
P.; Koller, H.; Puerstinger, G.; Monatsh. Chem., 121, (1990),
883-891. General Method H: ##STR121## wherein R.sup.13 is
C.sub.1-C.sub.6alkyl, aryl, heteroaryl, or arylC.sub.1-C.sub.6alkyl
and R.sup.1, R.sup.2 and R.sup.7 are defined as above; [1278]
Kakigami, T.; Baba, K.; Usui, T.; Heterocycles; 48, (1998),
2611-2620.
Example 1
General Method B
2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide
[1279] ##STR122##
[1280] To a solution of
2,3-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (0.5 g, 2.60
mmol), HOBT (0.39 g, 2.86 mmol) in dry THF (25 ml) was added EDAC
(0.55 g, 2.86 mmol). The mixture was stirred for 10 min. followed
by addition of di-isopropyl ethyl amine (DIPEA) (0.5 ml, 2.86 mmol)
and cyclohexyl-methyl-amine (0.37 ml, 2.86 mmol). The resulting
mixture was stirred for 16 hrs. at room temperature, the volatiles
were evaporated in vacuo and to the residue was added water (25 ml)
and diethyl ether (75 ml). The organic phase was separated and
dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated in
vacuo. The residue was dissolved in a mixture of AcOEt/Heptane
(1:1) and filtered through a 2.5 cm silicagel plug. The solvent was
evaporated in vacuo affording 0.7 g (93%) of the title compounds as
an oil.
[1281] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.06 (m, 3H), 1.29
(m, 4H), 1.48 (m, 5H), 1.67-1.8 (m, 4H), 2.77 and 2.97 (d and s,
3H, rotamer), 3.05 and 4.37 (2.times.m, 1H), 3.35 and 4.55
(2.times.m, 1H), 3.39 and 4.89 (2.times.m, 1H), 6.86 (t, 1H), 7.12
(t, 2H).
[1282] Calculated for C.sub.18H.sub.25NO.sub.2, 0.15H.sub.2O
[1283] C, 74.52%; H, 8.79%; N, 4.83%. Found:
[1284] C, 74.54%; H, 8.98%; N, 4.98%.
[1285] The following compounds were synthesised in a similar way as
described in Example 1 (general method B). TABLE-US-00003 No.
Structure MW lupac Name B-1 ##STR123## 259.35
2,3-Dihydro-benzofuran-7-carboxylic acid cyclo- hexyl-methyl-amide
B-2 ##STR124## 257.34 Benzofuran-7-carboxylic acid
cyclohexyl-methyl- amide B-3 ##STR125## 273.38
2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide B-4 ##STR126## 271.36
2-Methyl-benzofuran-7-carboxylic acid cyclohexyl- methyl-amide B-5
##STR127## 287.41 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic
acid cyclohexyl-methyl-amide B-6 ##STR128## 327.47
(2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone B-7 ##STR129##
303.40 4-Methoxy-2-methyl-2,3-dihydro-benzofuran-7- carboxylic acid
cyclohexyl-methyl-amide B-8 ##STR130## 287.41
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid
cyclohexyl-methyl-amide B-9 ##STR131## 313.44
(2-Methyl-2,3-dihydro-benzofuran-7-yl)-(1,3,3-
trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone B-10 ##STR132##
273.37 Chroman-8-carboxylic acid cyclohexyl-methyl- amide
EXAMPLES
Compounds of General Formula (VII)
[1286] The following examples and general procedures refer to
intermediate compounds and final products for general formula (VII)
identified in the specification and in the synthesis schemes. The
preparation of the compounds of general formula (VII) of the
present invention is described in detail using the following
examples. Occasionally, the reaction may not be applicable as
described to each compound included within the disclosed scope of
the invention. The compounds for which this occurs will be readily
recognised by those skilled in the art. In these cases the
reactions can be successfully performed by conventional
modifications known to those skilled in the art, that is, by
appropriate protection of interfering groups, by changing to other
conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by nuclear magnetic resonance (NMR), where peaks assigned
to characteristic protons in the title compounds are presented
where appropriate. .sup.1H NMR shifts (.delta...sub.H) are given in
parts per million (ppm) down field from tetramethylsilane as
internal reference standard. M.p.: is melting point and is given in
.degree. C. and is not corrected. Column chromatography was carried
out using the technique described by W. C. Still et al., J. Org.
Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). LC-MS
analyses are performed using Waters XTerra MS C-3.times.18 mm
RP-C18 column eluted with various mixtures of water and
acetonitrile, flow=1 mL/min, with UV detection at 210 nm and MS
scanning (ES+) from 100-1000 amu. An injection volume of 1 .mu.L
was used.
Microwave oven synthesis: The reaction was heated by microwave
irradiation in sealed microwave vessels in a single mode Emrys
Optimizer EXP from PersonalChemistry.RTM..
Solid-phase synthesis: All reactions were performed in Teflon
apparatus suitable for solid-phase synthesis or on an ACT 496 robot
employing the standard procedures described.
[1287] Preparative HPLC: Column: 1.9.times.15 cm Waters XTerra
RP-18. Buffer: linear gradient 5-95% in 15 min, MeCN, 0.1% TFA,
flow rate of 15 mL/min. The pooled fractions are either evaporated
to dryness in vacuo, or evaporated in vacuo until the MeCN is
removed, and then frozen and freeze dried.
The abbreviations as used in the examples have the following
meaning:
TLC: Thin layer chromatography
CDCl.sub.3: Deuterio chloroform
CD.sub.3OD: Tetradeuterio methanol
DMSO-d.sub.6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-Hydroxy-benzotriazole
EDAC: 1-(3-Ddimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1288] The compounds of the invention are prepared as illustrated
in the following reaction schemes: General Method A ##STR133##
[1289] Indole-7-carboxylic acids (I) wherein R.sup.1, R.sup.3,
R.sup.4, R.sup.5 and R.sup.6 are as defined above are generally
prepared as described in the following literature references;
[1290] Clark, R. D. et al.; J. Heterocycl. Chem. 22, (1985),
121-125. [1291] Kasahara, A. et al.; J. Heterocycl. Chem. 26,
(1989), 1405-1413. [1292] Kamiya, S. et al.; Chem. Pharm. Bull. 43,
(1995), 1692-1695. [1293] Somei, M. et al.; Chem. Pharm. Bull. 34,
(1986), 4116-4125. [1294] Wiedenau, P. et al.; Synth. Commun. 27,
(1997), 2033-2040. [1295] Soederberg, B. C. et al.; J. Org. Chem.
62, (1997), 5838-5845.
[1296] By allowing an acid (I) wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.8 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III)
wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are as defined above. General Method B ##STR134##
[1297] Indole-6-carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.4, R.sup.5 and R.sup.6 are as defined above are generally
prepared as described in the following literature references;
[1298] Kermack; J. Chem. Soc. 125, (1924), 2288. [1299] Tischler,
A. N.; Lanza, T. J.; Tetrahedron Lett. 27, (1986), 1653-1656.
[1300] Gharagozloo, P. et al.; Tetrahedron, 52, (1996),
10185-10192. [1301] Zhang, H.-C. et al.; Tetrahedron Lett. 39,
(1998), 4449-4452. [1302] Kasahara, A. et al.; J. Heterocycl. Chem.
24, (1987), 1555-1556. [1303] Brown, F. J. et al.; J. Med. Chem.
35, (1992), 2419-2439. [1304] Izumi, T. et al.; J. Heterocycl.
Chem. 29, (1992), 1625-1629. [1305] Soederberg, B. C and Shriver,
J. A.; J. Org. Chem. 62, (1997), 5838-5845. [1306] Kitano, M. et
al.; Chem. Pharm. Bull. 47, (1999), 1538-1548. [1307] Snyder et
al.; J. Am. Chem. Soc. 80, (1958), 4622-4624.
[1308] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.4,
R.sup.5 and R.sup.6 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.8 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are as defined above. General Method C ##STR135##
[1309] Indole-5-carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5 and R.sup.6 are as defined above are generally
prepared as described in the following literature references;
[1310] Singer, S., J. Org. Chem. 20, (1955), 1458. [1311] Noland,
W. E. and Reich, C.; J. Org. Chem. 32, (1967), 828-832. [1312]
Street, L. J. et al.; J. Med. Chem. 36, (1993), 1529-1538. [1313]
Bosch, J. et al.; Tetrahedron, 57, (2001), 1041-1048. [1314]
Agarwal, A. et al.; J. Med. Chem. 36, (1993), 4006-4014. [1315]
Kasahara, A. et al.; J. Heterocycl. Chem. 26, (1989); 1405-1413.
[1316] Boettcher, H. and Gericke, R.; Liebigs Ann. Chem. (1988),
749-752. [1317] Somei, M. et al.; Chem. Pharm. Bull. 34, (1986),
4116-4125. [1318] Kamiya, S. et al.; Chem. Pharm. Bull. 43, (1995),
1692-1695. [1319] Odle, R. et al.; J. Org. Chem. 45, (1980),
2709-2710.
[1320] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.5 and R.sup.6 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.8 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are as defined above. General Method D ##STR136##
[1321] Indole-4-carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.6 are as defined above are generally
prepared as described in the following literature references;
[1322] Beswick, P. J. et al.; Tetrahedron 44, (1988), 7325. [1323]
Muchowski, J. M. et al.; Tetrahedron Lett. 28, (1987), 3453. [1324]
Kasahara, A. et al.; J. Heterocycl. Chem. 26, (1989); 1405-1413.
[1325] Kasahara, A. et al.; J. Heterocycl. Chem. 24, (1987),
1555-1556. [1326] Clark, R. D. et al.; J. Heterocycl. Chem. 22,
(1985), 121-125. [1327] Kruse, L. I. Heterocycles, 16, (1981),
1119-1124. [1328] Soederberg, B. C. Org. Synth. 80, (2002), 75.
[1329] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.6 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.8 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are as defined above. General Method E ##STR137##
[1330] Indole-3-carboxylic acids (I) wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as defined above are generally
prepared as described in the following literature references;
[1331] Weissgerber; Chem. Ber. 43, (1910), 3526. [1332] Whalley; J.
Chem. Soc. (1954), 1651. [1333] Bravo, P. et al.; Tetrahedron Lett.
10, (1969), 679. [1334] Sus, O. et al.; Justus Liebigs Ann. Chem.
(1953), 583, 150. [1335] Melzer, M. S. et al.; J. Org. Chem. 27,
(1962), 496. [1336] Amat, M. et al.; J. Org. Chem. 59, (1994),
10-11.
[1337] By allowing an acid (I) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined above to be coupled with an
amine (II) wherein R.sup.7 and R.sup.3 are defined as above under
standard amide forming conditions using a coupling reagent (a)
(e.g. HOBT, EDAC and DIPEA in dry DMF) affording amide (III)
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are as defined above.
Example 1
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
[1338] ##STR138##
[1339] A solution of 1H-indole-5-carboxylic acid (1.0 g, 6.21
mmol), HOBT (0.9 g, 6.83 mmol) in dry THF (50 mL) and EDAC (1.31 g,
6.83 mmol) was stirred for 10 mins. Di-isopropyl ethyl amine
(DIPEA) (1.2 mL, 6.83 mmol) and 6-aza-bicyclo[3.2.1]octyl)-amine
(1.16 mL, 6.83 mmol) was added and the resulting mixture was
stirred for 16 hrs. at room temperature. The volatiles were
evaporated in vacuo and to the residue was added water (25 mL)
followed by extraction with diethyl ether (2.times.25 mL). The
combined organic phases were dried (Na.sub.2SO.sub.4), filtered and
evaporated in vacuo. The residue was purified by silicagel
chromatography using a mixture of ethyl acetate and heptane (1:2)
as eluent. Pure fractions were collected and the solvent evaporated
in vacuo. To the residue was added diethyl ether (10 mL) and the
resulting mixture was stirred for 1 h. The precipitate was filtered
off and dried in vacuo at 50.degree. C. affording 1.3 g (71%) of
the title compounds as a solid.
[1340] MS-ESI m/z 297; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.93-1.44 (m, 13H), 1.62 (m, 1H), 1.76 (m, 1H), 2.29 and 3.28
(2.times.m, 1H), 3.31 and 3.62 (2.times.m, 1H), 4.10 and 4.65
(2.times.m, 1H), 6.59 (s, 1H), 7.22-7.35 (m, 3H), 7.74 (d, 1H),
8.69 (bs, 1H, NH).
Example 2
1H-Indole-6-carboxylic acid cyclohexyl-methyl-amide
[1341] ##STR139##
[1342] A solution of 1H-indole-6-carboxylic acid (1.0 g, 6.21
mmol), HOBT (0.92 g, 6.83 mmol) in dry THF (50 mL) and EDAC (1.31
g, 6.83 mmol) was stirred for 20 mins. Di-isopropyl ethyl amine
(DIPEA) (1.2 mL, 6.83 mmol) and cyclohexyl-methyl-amine (0.9 mL,
6.83 mmol) was added and the resulting mixture was stirred for 16
hrs. at room temperature. To the precipitate was added water (50
mL), the solid filtered off, washed with water followed by diethyl
ether and dried in vacuo at 50.degree. C. which afforded 0.6 g
(38%) of the title compounds as a solid.
[1343] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.05 (bm, 2H),
1.15-1.85 (m, 8H), 2.96 (bs, 3H), 3.65 and 4.55 (2.times.m, 1H),
6.54 (s, 1H), 7.09 (d, 1H), 7.24 (m, 1H), 7.50 (s, 1H), 7.60 (d,
1H), 8.89 (bs, 1H, NH).
[1344] Calculated for C.sub.16H.sub.20N.sub.2O;
[1345] C, 74.97%; H, 7.86%; N, 10.93%. Found: C, 74.90%; H, 8.01%;
N, 10.88%.
Example 3
(1H-Indol-7-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
[1346] ##STR140##
[1347] A solution of 1H-indole-7-carboxylic acid (323 mg, 2 mmol),
HOAt (300 mg, 2.2 mmol) in dry DMF (10 mL) and EDAC (500 mg, 2.6
mmol) was stirred for 10 mins. Triethylamine (TEA) (0.84 mL, 6
mmol) and 6-aza-bicyclo[3.2.1]octyl)-amine (338 mg, 2.2 mmol) was
added and the resulting mixture was stirred for 16 hrs. at room
temperature. The volatiles were evaporated in vacuo and to the
residue was added water (10 mL) followed by extraction with
dichloromethane (DCM, 2.times.25 mL). The combined organic phases
were dried (MgSO.sub.4), filtered and evaporated in vacuo. The
residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 283 mg (47%) of the title compound as a
solid.
[1348] MS-ESI m/z 297; .sup.1H NMR (300 MHz, DMSO) .delta.
0.85-1.40 (m, 13H), 1.50-1.54 (m, 1H), 1.80-1.86 (m, 1H), 2.19-2.24
and 2.43-2.57 (2.times.m, 1H), 3.13 and 3.32 (m, 1H), 3.84-3.87 and
4.47-4.50 (2.times.m, 1H), 6.46-6.49 (m, 1H), 7.00-7.19 (m, 2H),
7.30-7.34 (m, 1H), 7.60-7.63 (m, 1H), 10.97 (d, 1H, NH).
Example 4
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
[1349] ##STR141##
[1350] A solution of 1H-indole-6-carboxylic acid (1 g, 6.2 mmol),
HOAt (929 mg, 6.82 mmol) in dry DMF (20 mL) and EDAC (1.54 g, 8.06
mmol) was stirred for 10 mins. TEA (2.59 mL, 18.6 mmol) and
6-aza-bicyclo[3.2.1]octyl)-amine (1.04 g, 6.82 mmol) was added and
the resulting mixture was stirred for 5 hrs. at room temperature.
The volatiles were evaporated in vacuo and to the residue was added
water (10 mL) followed by extraction with dichloromethane (DCM,
2.times.50 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The residue was
purified by silicagel chromatography using a mixture of ethyl
acetate and heptane (3:7) as eluent. Pure fractions were collected,
the solvent evaporated in vacuo and dried in vacuo at 50.degree. C.
affording 1.6 g (87%) of the title compounds as a solid.
[1351] MS-ESI m/z 297; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.93 (d, 3H), 1.02 (d, 3H), 1.11-1.15 (m, 4H), 1.26-1.39 (m, 2H),
1.56-1.66 (m, 1H), 1.73-1.79 and 2.27-2.33 (2.times.m, 2H),
3.22-3.35 and 3.61-3.65 (m, 2H), 4.07-4.10 and 4.62-4.65
(2.times.m, 1H), 6.52-6.54 (m, 1H), 7.17-7.25 (m, 2H), 7.53-7.63
(m, 2H), 9.03 (bs, 1H, NH).
[1352] The following compounds were synthesised employing a similar
method to the ones described in examples 1, 2, 3 and 4 above:
TABLE-US-00004 MS-ESI No Molecule MW IUPAC Name m/z 4-1 ##STR142##
294.40 1H-Indole-6-carboxylic acid adamantan-2-ylamide 295 4-2
##STR143## 254.33 (6-Aza-bicyclo[3.2.1]oct-6-yl)-
(1H-indol-6-yl)-methanone 255 4-3 ##STR144## 283.37
1H-Indole-6-carboxylic acid (8- methyl-8-aza-bicyclo[3.2.1]oct-
3-yl)-amide 284 4-4 ##STR145## 294.40 1H-Indole-5-carboxylic acid
adamantan-2-ylamide 295 4-5 ##STR146## 254.33
(6-Aza-bicyclo[3.2.1]oct-6-yl)- (1H-indol-5-yl)-methanone 255 4-6
##STR147## 296.40 (1H-Indol-4-yl)-(1,3,3-trimethyl-
6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 297 4-7 ##STR148## 296.40
(1H-Indol-3-yl)-(1,3,3-trimethyl- 6-aza-bicyclo[3.2.1]oct-6-yl)-
methanone 297 4-8 ##STR149## 296.40
(1H-Indol-2-yl)-(1,3,3-trimethyl- 6-aza-bicyclo[3.2.1]oct-6-yl)-
methanone 297 4-9 ##STR150## 310.44
(1-Methyl-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 311 4-10 ##STR151## 268.36
(3-Aza-bicyclo[3.2.2]non-3-yl)- (1H-indol-3-yl)-methanone 269 4-11
##STR152## 270.38 1-Methyl-1H-indole-3- carboxylic acid
cycloheptyl- amide 271 4-12 ##STR153## 308.42 1-Methyl-1H-indole-3-
carboxylic acid adamantan-1- ylamide 309 4-13 ##STR154## 282.39
(3-Aza-bicyclo[3.2.2]non-3-yl)- (1-methyl-1H-indol-3-yl)- methanone
283 4-14 ##STR155## 257.34 (1-Methyl-1H-indol-3-yl)-(4-
methyl-piperazin-1-yl)- methanone 258 4-15 ##STR156## 324.43
1-Methyl-1H-indole-3- carboxylic acid (3-hydroxy-
adamantan-1-yl)-amide 325 4-16 ##STR157## 324.42
1-Methyl-1H-indole-3- carboxylic acid azepan-1- ylamide 325 4-17
##STR158## 285.35 1-Methyl-1H-indole-3- carboxylic acid
(2-oxo-azepan- 3-yl)-amide 286 4-18 ##STR159## 332.45
(4-Benzyl-piperidine-1-yl)-(1- methyl-1H-indol-3-yl)- methanone 333
4-19 ##STR160## 285.39 1-Methyl-1H-indole-3- carboxylic acid
(2,6-dimethyl- piperidin-1-yl)-amide 286 4-20 ##STR161## 256.35
1-Methyl-1H-indole-3- carboxylic acid (2-methyl-
piperidin-1-yl)-amide 257 4-21 ##STR162## 368.50
(1-Cyclopropylmethyl-6-fluoro- 1H-indol-3-yl)-(1,3,3-trimethyl-
6-aza-bicyclo[3.2.1]oct-6-yl)- methanone 369 4-22 ##STR163## 256.35
Azepan-1-yl-(1-methyl-1H- indol-3-yl)methanone 257 4-23 ##STR164##
402.54 (5-Benzyloxy-1H-indol-3-yl)- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 403 4-24 ##STR165## 340.42
(5H-[1,3]Dioxolo[4,5]indol-7- yl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 341 4-25 ##STR166## 330.86
(5-Chloro-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 332 4-26 ##STR167## 364.41
(6-Trifluoromethyl-1H-indol-3- yl)-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 365 4-27 ##STR168## 310.44
(6-Methyl-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 311 4-28 ##STR169## 341.41
(6-Nitro-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 342 4-29 ##STR170## 326.44
(5-Methoxy-1H-indol-3-yl)- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]cct-6-yl)- methanone 327 4-30 ##STR171## 314.40
(6-Fluoro-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 315 4-31 ##STR172## 326.44
(6-Methoxy-1H-indol-3-yl)- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 327 4-32 ##STR173## 341.41
(7-Nitro-1H-indol-3-yl)-(1,3,3- trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 342 4-33 ##STR174## 296.40
(1H-Indol-4-yl)-(1,3,3-trimethyl- 6-aza-bicyclo[3.2.1]oct-6-yl)-
methanone 297 4-34 ##STR175## 310.44 2-(1H-Indol-3-yl)-1-(1,3,3-
trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- ethanone 311 4-35
##STR176## 282.39 1-(3-Aza-bicyclo[3.2.2]non-
3-yl)-2-(1H-indol-3-yl)- ethanone 283 4-36 ##STR177## 296.42
1-(3-Aza-bicyclo[3.2.2]non- 3-yl)-2-(1-methyl-1H-indol-3-
yl)-ethanone 297 4-37 ##STR178## 324.47
2-(1-Methyl-1H-indol-3-yl)-1- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- ethanone 325 4-38 ##STR179## 426.55
[3-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indol-6-yloxy]- acetic acid tert-butyl ester 427
Example 5
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carb-
oxylic acid
[1353] ##STR180##
[1354] To a solution of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1.49 g, 5.02 mmol) in pyridine (0.81 mL, 5.02 mmol) and DCM (25
mL) at 0.degree. C. was added trichloroacetyl chloride after which
cooling was stopped and the resulting mixture was stirred for 16
hrs. at room temperature. The volatiles were evaporated in vacuo
and to the residue was added water (20 mL) followed by extraction
with dichloromethane (DCM, 2.times.50 mL). The combined organic
phases were dried (MgSO.sub.4), filtered and evaporated in vacuo to
afford 2.48 g (100%) of
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone. To
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) was added a
solution of ethanol:THF:1M NaOH solution (20 mL, 1:2:1, v/v/v) and
the mixture was stirred at room temperature for 5 hrs. The organic
solvents were evapourated in vacuo and the aqueous collections were
acidified to pH 1 with concentrated hydrochloric acid followed by
extraction with ethyl acetate (2.times.20 mL). The combined organic
phases were dried (MgSO.sub.4), filtered, evapourated and the
residue after trituration with diethyl ether was filtered and dried
in vacuo at 50.degree. C. affording 56 mg (72%) of the title
compound as a solid.
[1355] MS-ESI m/z 341; .sup.1H NMR (300 MHz, DMSO) .delta. 0.91 (d,
3H), 0.97 (d, 3H), 1.09 (s, 3H), 1.13-1.54 (m, 4H), 1.73-1.78 (m,
1H), 3.13-3.18 (m, 1H), 3.30-3.47 (m, 2H), 3.98-4.02 and 4.38-4.42
(2.times.m, 1H), 7.19-7.28 (m, 1H), 7.53 (d, 1H), 7.99-8.04 (m,
1H), 8.09 (d, 1H), 11.92 (bs, 1H, NH), 12.05 (bs, 1H, OH).
Example 6
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carb-
oxylic acid ethyl ester
[1356] ##STR181##
[1357] To a solution of
2,2,2-Trichloro-1-[6-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbon-
yl)-1H-indol-3-yl]-ethanone (100 mg, 0.22 mmol) in ethanol (2 mL)
was added sodium ethoxide (77 mg, 1.13 mmol) and the resulting
mixture was stirred for 16 hrs. at room temperature. The volatiles
were evaporated in vacuo and the residue was purified by
preparative HPLC, dried in vacuo at 50.degree. C. affording 33 mg
(43%) of the title compound as a solid.
[1358] MS-ESI m/z 369; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.91-1.01 (m, 3H), 1.12 (d, 3H), 1.17-1.36 (m, 1H), 1.40-1.44 (m,
4H), 1.56-1.61 (m, 1H), 1.73-1.78 (m, 1H), 3.20-3.33 and 3.62-3.66
(m, 2H), 4.05-4.08 and 4.58-4.61 (m, 1H), 4.38 (q, 2H), 7.29-7.33
(m, 1H), 7.55 (d, 1H), 7.97-7.99 (m, 1H), 8.15-8.19 (m, 1H), 10.01
(d, 1H, NH).
[1359] The following compounds were synthesised employing a similar
method to the ones described in examples 5 and 6. TABLE-US-00005
MS-ESI No Molecule MW IUPAC Name m/z 6-1 ##STR182## 340.42
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid 341 6-2 ##STR183## 368.47
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid ethyl ester 369 6-3
##STR184## 340.42 4-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid 341 6-4 ##STR185## 368.47
4-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid ethyl ester 369
Example 7
[3-(Piperidine-1-carbonyl)-1H-indol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3-
.2.1]oct-6-yl)-methanone
[1360] ##STR186##
[1361] To 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene
(PS-TFP resin, 100 mg, 1 mmol/g, 100-200 mesh,
polystyrene-divinylbenzene 1%, Argonaut technologies, USA)
pre-swollen in DCM was added a solution of
5-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3--
carboxylic acid (51 mg, 0.15 mmol) in DMF (0.25 mL) followed by a
solution of DMAP (7.3 mg, 0.06 mmol) in DCM (0.75 mL). The mixture
was shaken for 10 min before a solution of
N,N'-diisopropylcarbodiimide (DIC, 56 mg, 0.44 mmol) in DCM (0.25
mL) was added and the resulting mixture shaken for 16 hrs. at room
temperature. The excess solvents were removed by filtration and the
resin was washed with DMF (3.times.1 mL) and DCM (10.times.1 mL).
To the resin was added a solution of piperidine (7.3 mg, 0.085
mmol) in 1,2-dichloroethane (1.2 mL) and DIPEA (0.03 mL, 0.17
mmol). The resulting mixture was shaken for 16 hrs. at room
temperature. The product was removed by filtration and the resin
washed with DCM:MeOH (1 mL, 3:1, v/v). The volatiles were
evaporated in vacuo and the residue was purified by preparative
HPLC, dried in vacuo at 50.degree. C. affording 22 mg (54%) of the
title compound as a solid.
[1362] MS-ESI m/z 408; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.94 (d, 3H), 1.02 (d, 3H), 1.14 (s, 3H), 1.15-1.19 (m, 1H),
1.34-1.46 (m, 3H), 1.58-1.69 (m, 7H), 1.78-1.83 (m, 1H), 2.25-2.31
and 3.27-3.29 (2.times.m, 1H), 3.33-3.34 (m, 1H), 3.64-3.67 (m,
4H), 4.08-4.11 and 4.62-4.64 (2.times.m, 1H), 7.25-7.28 (m, 1H),
7.32-7.37 (m, 1H), 7.47-7.49 (m, 1H), 7.69-7.71 (m, 1H), 9.65 (bd,
1H, NH).
[1363] The following compounds were synthesised employing a similar
method to the ones described in example 7. TABLE-US-00006 MS-ESI No
Molecule MW IUPAC Name m/z 7-1 ##STR187## 378.48
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid cyanomethyl-amide 379 7-2
##STR188## 429.57 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid benzylamide 430 7-3
##STR189## 367.50 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]ootane-6-
carbonyl)-1H-indole-3- carboxylic acid dimethyl- amide 368 7-4
##STR190## 379.51 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid allylamide 380 7-5
##STR191## 424.59 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid (2- dimethylamino-ethyl)-
methyl-amide 425 7-6 ##STR192## 397.52 5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-1H-indole-3- carboxylic acid
(2-methoxy- ethyl)-amide 398 7-7 ##STR193## 459.59
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid 4-methoxy- benzylamide 460
7-8 ##STR194## 423.56 5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-1H-indole-3- carboxylic acid
(tetrahydro- furan-2-ylmethyl)-amide 424 7-9 ##STR195## 437.59
[3-(2-Methoxymethyl- pyrrolidine-1-carbonyl)-1H-
indol-5-yl]-(1,3,3-trimethyl-6- aza-bicyclo[3.2.1]oct-6-yl)-
methanone 438 7-10 ##STR196## 437.59 [3-(2,6-Dimethyl-
morpholine-4-carbonyl)-1H- indol-5-yl]-(1,3,3-trimethyl-6-
aza-bicyclo[3.2.1]oct-6-yl)- methanone 438 7-11 ##STR197## 457.60
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid (1,1-dioxo-
tetrahydro-thiophen-3-yl)- amide 458 7-12 ##STR198## 479.67
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid [3-(4-methyl-
piperazin-1-yl)-propyl]- amide 481 7-13 ##STR199## 497.57
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid 4-
trifluoromethyl-benzylamide 498 7-14 ##STR200## 419.53
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid (furan-2- ylmethyl)-amide
420 7-15 ##STR201## 486.62 [3-(2,3,5,6-Tetrahydro-
[1,2']bipyrazinyl-4-carbonyl)- 1H-indol-5-yl]-(1,3,3-
trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- methanone 487 7-16
##STR202## 421.51 5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carboxylic acid (2H-tetrazol-
5-ylmethyl)-amide 422 7-17 ##STR203## 475.68
[3-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indol-5-yl]- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 476 7-18 ##STR204## 439.56
3-{[5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carbonyl]-amino}-propionic acid ethyl ester
440 7-19 ##STR205## 445.57 5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-1H-indole-3- carboxylic acid
(4-methoxy- phenyl)-amide 446 7-20 ##STR206## 411.51
3-{[5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carbonyl]-amino}-propionic acid 412 7-21
##STR207## 242.32 Azepan-1-yl-(1H-indol-5-yl)- methanone 243 7-22
##STR208## 340.43 1H-Indole-5-carboxylic acid dibenzylamide 341
7-23 ##STR209## 268.36 (3-Aza-bicyclo[3.2.2]non-3-
yl)-(1H-indol-5-yl)- methanone 269 7-24 ##STR210## 318.42
(4-Benzyl-piperidin-1-yl)- (1H-indol-5-yl)-methanone 319 7-25
##STR211## 374.45 8-(1H-Indole-5-carbonyl)-1- phenyl-1,3,8-triaza-
spiro[4.5]decan-4-one 375 7-26 ##STR212## 354.84
[4-(4-Chloro-phenyl)-4- hydroxy-piperidin-1-yl]-(1H-
indol-5-yl)-methanone 356 7-27 ##STR213## 360.42
1-[1-(1H-Indole-5-carbonyl)- piperidin-4-yl]-1,3-dihydro-
benzoimidazol-2-one 361 7-28 ##STR214## 284.40
(4-tert-Butyl-piperidin-1-yl)- (1H-indol-5-yl)-methanone 285 7-29
##STR215## 329.41 1-(1H-Indole-5-carbonyl)-4- phenyl-piperidine-4-
carbonitrile 330 7-30 ##STR216## 304.40 (1H-Indol-5-yl)-(4-phenyl-
piperidin-1-yl)-methanone 305 7-31 ##STR217## 331.42
(5-Benzyl-2,5-diaza- bicyclo[2.2.1]hept-2-yl)-(1H-
indol-5-yl)-methanone 332 7-32 ##STR218## 297.40
(1H-Indol-5-yl)-(4-pyrrolidin- 1-yl-piperidin-1-yl)- methanone 298
7-33 ##STR219## 314.43 1H-Indole-5-carboxylic acid
(5-hydroxy-1,3,3-trimethyl- cyclohexylmethyl)-amide 315 7-34
##STR220## 330.43 1H-Indole-5carboxylic acid (3,4-dihydrospiro(1H-
indene-1,4-piperidine)- amide 331
Example 8
(3-Methanesulfonylmethyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2-
.1]oct-6-yl)-methanone
[1364] ##STR221##
[1365] A solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(300 mg, 1.01 mmol), paraformaldehyde (35 mg, 1.16 mmol), sodium
methylsulfonate (103 mg, 1.01 mmol) and acetic acid (0.1 mL) in DMF
(2 mL) was heated at 90.degree. C. for 3 hrs. After cooling, the
mixture was poured onto water (100 mL) followed by extraction with
DCM (3.times.50 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The residue was
purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 167 mg (43%) of the title compound as a solid.
[1366] MS-ESI m/z 389; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.94 (d, 3H), 1.03 (d, 3H), 1.14-1.17 (m, 4H), 1.29-1.40 (m, 2H),
1.57-1.62 (m, 1H), 1.79-1.84 (m, 1H), 2.67 (d, 3H), 3.25-3.34 and
3.64-3.67 (2.times.m, 2H), 4.08-4.11 and 4.61-4.64 (2.times.m, 1H),
4.39 (s, 2H), 7.22-7.32 (m, 3H), 7.78 (d, 1H), 9.42 (s, 1H,
NH).
Example 9
(3-Dimethylaminomethyl-1H-indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1-
]oct-6-yl)-methanone
[1367] ##STR222##
[1368] To a solution of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(200 mg, 0.67 mmol) in DCM (10 mL) was added N,N-dimethylammonium
iodide and the resulting mixture stirred at room temperature for 16
hrs. The volatiles were evaporated in vacuo and the resulting
residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 54 mg (23%) of the title compound isolated
as the trifluoroacetate salt.
[1369] MS-ESI m/z 354; .sup.1H NMR (400 MHz, DMSO) .delta. 0.90 (d,
3H), 0.97 (d, 3H), 1.08-1.17 (m, 4H), 1.28-1.53 (m, 4H), 1.72-1.79
(m, 1H), 2.76 (s, 6H), 3.14-3.16 (m, 1H), 3.33-3.36 and 3.44-3.47
(2.times.m, 1H), 4.08-4.15 and 4.39-4.42 (2.times.m, 1H), 4.45 (s,
2H), 7.19 (dd, 1H), 7.54 (d, 1H), 7.69 (s, 1H), 7.81 (t, 1H), 9.90
(s, 1H), 11.74 (s, 1H).
Example 10
1-[3-Acetyl-2-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1-
H-indol-3-yl]-2,3-dihydro-imidazol-1-yl]-ethanone
[1370] ##STR223##
[1371] To a solution of imidazole (23 mg, 0.34 mmol) in acetic
anhydride at 125.degree. C. was added dropwise over 40 min a
solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(100 mg, 0.34 mmol) in acetic anhydride (13 mL). The resulting
mixture was heated at 125.degree. C. for 30 min then cooled and
solvents evaporated in vacuo. The resulting residue was purified by
preparative HPLC, dried in vacuo at 50.degree. C. to afford 5.4 mg
(4%) of the title compound as a solid.
[1372] MS-ESI m/z 449; .sup.1H NMR (400 MHz, DMSO) .delta. 0.94 (d,
3H), 0.97 (d, 3H), 1.08-1.17 (m, 4H), 1.28-1.62 (m, 4H), 1.72-1.79
(m, 1H), 2.05-2.08 (m, 6H), 3.14-3.16 (m, 1H), 3.26-3.28 (m, 1H),
3.33-3.36 and 3.63-3.67 (2.times.m, 1H), 4.04-4.06 and 4.61-4.63
(2.times.m, 1H), 6.33-6.40 (m, 2H), 6.96-7.00 (m, 1H), 7.17-7.49
(m, 2H), 7.67-7.82 (m, 1H), 8.94 (s, 1H).
Example 11
1-Ethyl-3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-in-
dol-3-yl]-pyrrolidine-2,5-dione
[1373] ##STR224##
[1374] A solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(100 mg, 0.34 mmol) and N-ethylmaleimide (127 mg, 1.01 mmol) in
acetic acid (2 mL) was heated at 160.degree. C. employing microwave
irradiation for 1 hr. The solvents were evaporated in vacuo and the
resulting residue purified by preparative HPLC, dried in vacuo at
50.degree. C. to afford 25 mg (18%) of the title compound as a
solid.
[1375] MS-ESI m/z 422; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.93-0.96 (m, 3H), 1.01-1.06 (m, 3H), 1.13-1.17 (m, 3H), 1.21-1.25
(m, 3H), 1.28-1.44 (m, 3H), 1.55-1.64 (m, 1H), 1.73-1.81 (m, 1H),
2.05-2.28 (m, 1H), 2.78-2.87 (m, 1H), 3.17-3.34 (m, 1H), 3.57-3.68
(m, 3H), 4.01-4.07 and 4.62-4.64 (2.times.m, 1H), 4.24-4.28 (m,
1H), 7.11-7.12 (m, 1H), 7.22-7.31 (m, 3H), 7.53-7.60 (m, 1H), 8.83
(s, 1H).
Example 12
(3-Thiazol-2-yl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6--
yl)-methanone
[1376] ##STR225##
[1377] To a slurry of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(300 mg, 1.01 mmol) in benzene (8 mL) under an inert atmosphere of
nitrogen was added methylmagnesium iodide (0.34 mL, 1.01 mmol),
after stirring for 10 mins 2-bromothiazole was added where upon the
mixture was heated at 90.degree. C. for 16 hrs. Water (20 mL) was
added and the organics were extracted with DCM (3.times.20 mL). The
combined organic phases were dried (MgSO.sub.4), filtered and
evaporated in vacuo. The residue was purified by preparative HPLC,
dried in vacuo at 50.degree. C. affording 48 mg (25%) of the title
compound as a solid.
[1378] MS-ESI m/z 380; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.93-1.08 (m, 6H), 1.16-1.20 (m, 5H), 1.39-1.47 (m, 2H), 1.59-1.64
(m, 1H), 1.80-1.85 (m, 1H), 3.21-3.24 (m, 1H), 3.34-3.38 and
3.65-3.69 (2.times.m, 1H), 4.01-4.03 and 4.65-4.68 (2.times.m, 1H),
7.31-7.35 (m, 2H), 7.48-7.52 (m, 1H), 7.82 (d, 1H), 7.91 (d, 1H),
8.34 (s, 1H), 9.77 (s, 1H).
Example 13
(3-Iodo-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-meth-
anone
[1379] ##STR226##
[1380] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) and potassium hydroxide (364 mg, 6.75 mmol) in DMF
(40 mL) was added iodine (0.86 g, 3.41 mmol). The reaction mixture
was stirred for 1 hr at room temperature then poured onto water
(100 mL), extracted with DCM (3.times.20 mL). The combined organic
phases were washed with water and brine then dried (MgSO.sub.4),
filtered and evaporated in vacuo. The resulting solid was dried in
vacuo at 50.degree. C. affording 1.18 g (83%) of the title
compound.
[1381] MS-ESI m/z 423; .sup.1H NMR (300 MHz, DMSO) .delta. 0.90 (d,
3H), 0.98 (d, 3H), 1.10 (d, 3H), 1.15-1.45 (m, 4H), 1.50-1.54 (m,
1H), 1.75-1.78 (m, 1H), 3.15-3.18 (m, 1H), 3.30-3.33 and 3.41-3.45
(2.times.m, 1H), 3.98-4.00 and 4.40-4.42 (2.times.m, 1H), 7.22-7.42
(m, 2H), 7.44-7.47 (m, 1H), 7.64 (s, 1H), 11.73 (s, 1H).
Example 14
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carb-
onitrile
[1382] ##STR227##
[1383] To an ice-cooled slurry of
(1H-Indol-6-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) in acetonitrile (25 mL) was added dropwise a
solution of chlorosulfunylisocyanate (0.48 g, 3.37 mmol). The
reaction mixture was stirred for 1 hr at 0.degree. C. then
triethylamine (0.33 g, 3.3 mmol) was added dropwise maintaining an
internal temperature of 0.degree. C. The reaction mixture was
allowed to warm to room temperature over 2 hrs. The solvents were
evaporated in vacuo and the residue treated with DCM (10 mL) and an
ice cold solution of sodium bicarbonate (5%, 10 mL) and the
organics were extracted with DCM (3.times.20 mL). The combined
organic phases were dried (MgSO.sub.4), filtered and evaporated in
vacuo. The residue was purified by preparative HPLC, dried in vacuo
at 50.degree. C. affording 182 mg (17%) of the title compound as a
solid.
[1384] MS-ESI m/z 322; .sup.1H NMR (400 MHz, DMSO) .delta. 0.90 (d,
3H), 0.98 (d, 3H), 1.09 (s, 3H), 1.15-1.54 (m, 5H), 1.74-1.78 (m,
1H), 3.13-3.16 (m, 1H), 3.29-3.32 and 3.44-3.47 (2.times.m, 1H),
3.94-3.98 and 4.40-4.42 (2.times.m, 1H), 7.27-7.35 (m, 1H), 7.60
(d, 1H), 7.66-7.70 (m, 1H), 8.35-8.37 (m, 1H), 12.32 (s, 1H).
[1385] The following compound was synthesised employing a similar
method to the one described in example 14. TABLE-US-00007 MS-ESI No
Molecule MW IUPAC Name m/z 14-1 ##STR228## 321.42
5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-1H-indole-3- carbonitrile 322
Example 15
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-carb-
oxylic acid amide
[1386] ##STR229##
[1387] To a solution of
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
bonitrile (65 mg, 0.2 mmol) in 1,4-dioxane (2 mL) was added sodium
hydroxide solution (2 mL, 1M) and hydrogen peroxide (2 mL) and the
resulting solution was heated at 50.degree. C. for 16 hrs. The
solvents were evaporated in vacuo and the residue was purified by
preparative HPLC, dried in vacuo at 50.degree. C. affording 15 mg
(21%) of the title compound as a solid.
[1388] MS-ESI m/z 340; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.92 (d, 3H), 0.98 (d, 3H), 1.10 (d, 3H), 1.15-1.54 (m, 5H),
1.74-1.79 (m, 1H), 3.18-3.21 (m, 1H), 3.25-3.28 and 3.61-3.64
(2.times.m, 1H), 4.01-4.03 and 4.55-4.58 (2.times.m, 1H), 6.11 (bs,
2H), 7.19-7.23 (m, 1H), 7.34-7.38 (m, 1H), 7.77-7.80 (m, 1H),
7.95-7.99 (m, 1H), 10.80 (s, 1H).
Example 16
[3-(2H-Tetrazol-5-yl)-1H-indol-6-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]-
oct-6-yl)-methanone
[1389] ##STR230##
[1390] A slurry of
6-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-3-car-
bonitrile (100 mg, 0.31 mmol), zinc bromide (70 mg, 0.31 mmol) and
sodium azide (22 mg, 0.34 mmol) in water (0.65 mL) was heated at
200.degree. C. employing microwave irradiation for 6 min. A
solution of sodium hydroxide (3 mL, 0.25 M) was added and the
mixture stirred for 45 min. Filtration of the inorganics followed
by acidification of the filtrate with concentrated HCl to pH 1
yielded after filtration crude product which was purified by
preparative HPLC, dried in vacuo at 50.degree. C. affording 6 mg
(5%) of the title compound as a solid.
[1391] MS-ESI m/z 365; .sup.1H NMR (400 MHz, DMSO) .delta. 0.92 (d,
3H), 0.99 (d, 3H), 1.10 (d, 3H), 1.15-1.55 (m, 5H), 1.74-1.79 (m,
1H), 3.15-3.20 (m, 1H), 3.25-3.32 and 3.45-3.48 (2.times.m, 1H),
4.01-4.03 and 4.41-4.43 (2.times.m, 1H), 7.26-7.35 (m, 1H), 7.61
(d, 1H), 8.15-8.18 (m, 1H), 8.21-8.25 (m, 1H), 11.98 (s, 1H).
Example 17
N-[3-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indol-7-yl-
]-acetamide
[1392] ##STR231##
[1393] To a solution of
(7-nitro-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone (730 mg, 2.14 mmol) in MeOH (40 mL) was added palladium on
activated charcoal (10% Pd, 50% H.sub.2O, 0.2 g). The reaction
mixture was stirred for 16 hrs under an atmosphere of hydrogen. The
catalyst was removed by filtration and the solvents were evaporated
in vacuo and the solid dried in vacuo at 50.degree. C. affording
481 mg (72%) of
(7-amino-1H-indol-3-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone. To a solution of
(7-amino-1H-indol-3-yl)(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-met-
hanone (100 mg, 0.32 mmol) in DCM (1 mL) was added DIPEA (829 mg,
6.4 mmol) and acetic anhydride (327 mg, 3.21 mmol), the solution
was stirred at room temperature for 1 hr. Solvents were evaporated
in vacuo and the residue was purified by preparative HPLC, dried in
vacuo at 50.degree. C. affording 47 mg (42%) of the title compound
as a solid.
[1394] .MS-ESI m/z 354; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.82-1.13 (m, 10H), 1.22-1.54 (m, 6H), 1.75-1.78 (m, 1H), 3.10-3.25
(m, 1H), 3.27-3.37 and 3.59-3.66 (2.times.m, 1H), 4.20-4.22 and
4.49-4.52 (2.times.m, 1H), 6.88-7.01 (m, 1H), 7.02-7.08 (m, 1H),
7.40-7.61 (m, 3H), 8.77 (s, 1H), 11.21 (bd, 1H).
Example 18
(1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-
-6-yl)-methanone
[1395] ##STR232##
[1396] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(1 g, 3.37 mmol) in dry THF (2 mL) at -78.degree. C. under an inert
atmosphere of nitrogen was added a solution of n-butyl lithium
(2.14 mL, 1.65 M in hexane). Cooling was removed and the solution
was allowed to warm to room temperature with stirring. The solution
was cooled to -78.degree. C. where upon benzenesulphonyl chloride
(655 mg, 3.71 mmol) was added and the reaction mixture was stirred
for 16 hrs whilst warming to room temperature. The reaction was
quenched by the addition of sodium bicarbonate solution (5%, 200
mL) and extracted with DCM (3.times.50 mL). The combined organic
phases were washed with water and brine then dried (MgSO.sub.4),
filtered and evaporated in vacuo. The resulting solid was purified
by flash column chromatography (mobile phase ethylacetate: heptane,
1:2). Product fractions were combined, evaporated in vacuo, dried
in vacuo at 50.degree. C. to afford 1.46 g (99%) of the title
compound.
[1397] MS-ESI m/z 437; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.94 (d, 3H), 1.02 (d, 3H), 1.12-1.17 (m, 3H), 1.24-1.40 (m, 2H),
1.45 (s, 1H), 1.50-1.61 (m, 2H), 1.73-1.78 (m, 1H), 3.15-3.25 (m,
1H), 3.26-3.31 and 3.58-3.63 (2.times.m, 1H), 3.96-3.99 and
4.60-4.62 (2.times.m, 1H), 6.68-6.70 (m, 1H), 7.37-7.47 (m, 3H),
7.53-7.63 (m, 3H), 7.84-7.87 (m, 2H), 7.99-8.03 (m, 1H).
Example 19
(1-Benzenesulfonyl-2-methyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[-
3.2.1]oct-6-yl)-methanone
[1398] ##STR233##
[1399] To a solution of
(1-Benzenesulfonyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]o-
ct-6-yl)-methanone (100 mg, 0.23 mmol) in dry THF (2 mL) at
-78.degree. C. under an inert atmosphere of nitrogen was added a
solution of lithium N,N-diisopropylamide (0.165 mL, 1.5 M in
cyclohexane). The mixture was stirred for 1 hr at -78.degree. C.
then cooling was removed and the solution was allowed to warm to
room temperature with stirring. The solution was cooled to
-78.degree. C. where upon methyl iodide (48 mg, 0.343 mmol) was
added and the reaction mixture was stirred for 16 hrs whilst
warming to room temperature. The reaction was quenched by the
addition of saturated ammonium chloride solution (10 mL) and
extracted with DCM (3.times.10 mL). The combined organic phases
were dried (MgSO.sub.4), filtered and evaporated in vacuo. The
residue was purified by preparative HPLC, dried in vacuo at
50.degree. C. affording 12 mg (11%) of the title compound as a
solid.
[1400] MS-ESI m/z 451; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.94 (d, 3H), 1.04 (d, 3H), 1.13-1.15 (m, 3H), 1.25-1.40 (m, 2H),
1.45 (s, 1H), 1.55-1.61 (m, 2H), 1.74-1.80 (m, 1H), 2.60 (s, 3H),
3.17-3.25 (m, 1H), 3.27-3.31 and 3.59-3.64 (2.times.m, 1H),
4.00-4.02 and 4.61-4.63 (2.times.m, 1H), 6.38 (s, 1H), 7.32-7.58
(m, 5H), 7.74-7.77 (m, 2H), 8.16-8.20 (m, 1H).
Example 20
(1-methyl-1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-me-
thanone
[1401] ##STR234##
[1402] To a solution of
(1H-Indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone
(500 mg, 1.69 mmol) in dry DMF (10 mL) at room temperature under an
inert atmosphere of nitrogen was added sodium hydride (53 mg, 2.19
mmol, 60% dispersion in oil), after stirring for 30 min methyl
iodide (263 mg, 1.85 mmol) was added and the reaction mixture was
stirred for 16 hrs at 60.degree. C. The reaction was quenched by
the addition of water (20 mL) followed by extraction with DCM
(3.times.50 mL). The combined organic phases were dried
(MgSO.sub.4), filtered and evaporated in vacuo. The resulting solid
was purified by preparative HPLC, dried in vacuo at 50.degree. C.
affording 261 mg (50%) of the title compound as a solid.
[1403] MS-ESI m/z 311; .sup.1H NMR (300 MHz, DMSO) .delta. 0.89 (d,
3H), 0.96 (d, 3H), 1.07-1.21 (m, 4H), 1.23-1.53 (m, 4H), 1.72-1.78
(m, 1H), 3.10-3.15 (m, 1H), 3.34-3.47 (m, 1H), 3.80 (d, 3H),
4.01-4.04 and 4.38-4.40 (2.times.m, 1H), 6.48-6.50 (m, 1H),
7.18-7.28 (m, 1H), 7.39 (d, 1H), 7.43-7.48 (m, 1H), 7.64 (d,
1H).
[1404] The following compounds were synthesised employing a similar
method to the ones described in example 20. TABLE-US-00008 MS- ESI
No Molecule MW IUPAC Name m/z 20-1 ##STR235## 386.54
(1-Benzyl-1H-indol-5-yl)- (1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 387 20-2 ##STR236## 382.50
[6-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-yl]-acetic acid ethyl ester 383 20-3 ##STR237##
368.52 [1-(2-Ethoxy-ethyl)-1H-indol- 6-yl]-(1,3,3-trimethyl-6-aza-
bicyclo[3.2.1]oct-6-yl)- methanone 369 20-4 ##STR238## 398.54
{1-[2-(2-Methoxy-ethoxy)- ethyl]-1H-indol-6-yl}-(1,3,3-
trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- methanone 399 20-5
##STR239## 396.53 3-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-indol-1-yl]- propionic acid ethyl
ester 397 20-6 ##STR240## 400.56 (1-Phenethyl-1H-indol-5-yl)-
(1,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- methanone 401 20-7
##STR241## 380.53 [1-(Tetrahydro-furan-2- ylmethyl)-1H-indol-5-yl]-
(1,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- methanone 381 20-8
##STR242## 353.46 2-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-indol-1-yl]- acetamide 354 20-9
##STR243## 470.53 [1-(4-Trifluoromethoxy- benzyl)-1H-indol-5-yl]-
(1,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)- methanone 471
20-10 ##STR244## 444.57 3-[5-(1,3,3-Trimethyl-6-aza-
bicyclo[3.2.1]octane-6- carbonyl)-indol-1-ylmethyl]- benzoic acid
methyl ester 445 20-11 ##STR245## 411.55
4-[5-(1,3,3-Trimethyl-6-aza- bicyclo[3.2.1]octane-6-
carbonyl)-indol-1-ylmethyl]- benzonitrile 412
EXAMPLES
Compounds of General Formula (VIII)
[1405] The following examples and general procedures refer to
intermediate compounds and final products for general formula
(VIII) identified in the specification and in the synthesis
schemes. The preparation of the compounds of general formula (VIII)
of the present invention is described in detail using the following
examples. Occasionally, the reaction may not be applicable as
described to each compound included within the disclosed scope of
the invention. The compounds for which this occurs will be readily
recognised by those skilled in the art. In these cases the
reactions can be successfully performed by conventional
modifications known to those skilled in the art, that is, by
appropriate protection of interfering groups, by changing to other
conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed by either elemental analysis or nuclear magnetic
resonance (NMR), where peaks assigned to characteristic protons in
the title compounds are presented where appropriate. .sup.1H NMR
shifts (6H) are given in parts per million (ppm) down field from
tetramethylsilane as internal reference standard. M.p.: is melting
point and is given in .degree. C. and is not corrected. Column
chromatography was carried out using the technique described by W.
C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel
60 (Art. 9385). HPLC analyses are performed using 5 .mu.m C18
4.times.250 mm column eluted with various mixtures of water and
acetonitrile, flow=1 ml/min, as described in the experimental
section.
[1406] The abbreviations as used in the examples have the following
meaning:
TLC: thin layer chromatography
CDCl.sub.3: deuterio chloroform
CD.sub.3OD: tetradeuterio methanol
DMSO-d.sub.6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1-hydroxy-benzotriazole
EDAC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride
min: minutes
hrs: hours
[1407] The compounds of the invention are prepared as illustrated
in the following reaction scheme 1: ##STR246## General Method:
[1408] By allowing a 2-halo-3-oxo-propionic acid ester (I) wherein
Y is halo, R.sup.1 is C.sub.1-C.sub.6alkyl, aryl,
arylC.sub.1-C.sub.6alkyl and R.sup.2 is as defined above to react
with an amide (II), wherein R.sup.3 is as defined above and X is O
or S, in a solvent such as ethanol and the like affording an
thiazole, oxazol or imidazol carboxylic acid ester (III), wherein
R.sup.2 and R.sup.3 is as defined above. The thiazole, oxazol or
imidazol carboxylic acid ester (III) is hydrolysed with base
affording thiazole, oxazol or imidazol carboxylic acid (V), wherein
R.sup.2 and R.sup.3 are as defined above. The thiazole, oxazol or
imidazol carboxylic acid (V) can also be obtained from the
corresponding bromo or iodo substituted thiazole, oxazol or
imidazol (IV) via halogen lithium exchange followed by reaction
with carbon dioxide in a solvent such as THF. The thiazole, oxazol
or imidazol carboxylic acid (V) is coupled with an amine (VI),
wherein R.sup.5 and R.sup.6 are as defined above, under standard
amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF)
affording thiazole, oxazol or imidazol (VII), wherein R.sup.2,
R.sup.3, R.sup.5 and R.sup.6 are as defined above.
Example 1
4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-
-yl)-methanone
[1409] ##STR247##
[1410] A solution of 4-methyl-2-phenyl-1,3-thiazole-5-carboxylic
acid (0.44 g, 2.00 mmol), HOBT (0.297 g, 2.2 mmol), EDAC (0.42 g,
2.2 mmol) and di-isopropyl ethyl amine (DIPEA) (383 .mu.l, 2.2
mmol) in dry THF (30 ml) was stirred for 30 minutes and
1,3,3-trimethyl-6-azabicyclo[3.2.1]octane (0.34 g, 2.2 mmol) was
added. The mixture was stirred for 16 hrs. at room temperature. The
mixture was added water (30 ml) and extracted with ETOAc
(2.times.50 ml), dried (MgSO.sub.4), filtered and evaporated in
vacuo affording 0.67 g (94%) of the title compounds as an oil.
[1411] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94-1.14 (m, 9H),
1.26-1.8 (m, 5H), 2.25 (m, 1H), 2.55 (d, 3H), 3.26 (m, 1H), 3.44
and 3.66 (2.times.d, 1H), 4.18 and 4.60 (2.times.t, 1H), 7.44 (m,
3H), 7.92 (m, 2H).
Example 2
(2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-
-methanone
[1412] ##STR248##
[1413] A solution of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid
(0.47 g, 3.00 mmol), HOBT (0.46 g, 3.3 mmol), EDAC (0.63 g, 3.3
mmol) and di-isopropyl ethyl amine (DIPEA) (575 .mu.l, 3.3 mmol) in
dry THF (50 ml) was stirred for 40 minutes and
1,3,3-trimethyl-6-azabicyclo-[3.2.1]octane (0.51 g, 3.3 mmol) was
added. The mixture was stirred for 16 hrs. at room temperature. The
mixture was added water (30 ml) and extracted with ETOAc
(2.times.50 ml), dried (MgSO.sub.4), filtered and evaporated in
vacuo affording 0.145 g (17%) of the title compounds as an oil.
[1414] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.97-1.15 (m,
9.5H), 1.35-1.63 (m, 4.5H), 2.17 (dd, 1H), 2.53 (d, 3H), 2.89 (d,
3H), 3.24 (m, 1H), 3.4 and 3.67 (2.times.d, 1H), 4.10 and 4.58
(2.times.t, 1H).
Example 3
(4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.-
1]oct-6-yl)-methanone
[1415] ##STR249##
[1416] A solution of
4-methyl-2-(2-pyrazinyl)-1,3-thiazole-5-5-carboxylic acid (0.22 g,
1.00 mmol), HOBT (0.17 g, 1.1 mmol), EDAC (0.21 g, 1.1 mmol) and
di-isopropyl ethyl amine (DIPEA) (192 .mu.l, 1.1 mmol) in dry THF
(10 ml) was stirred for 30 minutes and
1,3,3-trimethyl-6-azabicyclo[3.2.1]octane (0.17 g, 1.1 mmol) was
added. The mixture was stirred for 16 hrs. at room temperature. The
mixture was added water (30 ml) and extracted with ETOAc
(2.times.50 ml), dried (MgSO.sub.4), filtered and evaporated in
vacuo. affording 0.345 g (97%) of the title compounds as an
oil.
[1417] The following compounds were prepared in a similar way as
described in Example 3 above.
Example 4
[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-az-
a-bicyclo[3.2.1]oct-6-yl)-methanone
[1418] ##STR250##
[1419] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (m, 3H), 1.07
(t, 3H), 1.17 (t, 3H), 1.32-1.84 (m, 4.5H), 2.25 (m, 0.5H), 2.58
(d, 3H), 2.86 (d, 0.5H), 3.23 (q, 1H), 3.4 (d, 0.5H), 3.66 (d,
0.5H), 3.80 (m, 0.5H), 4.18 (m, 0.5H), 4.60 (m, 0.5H), 7.68 (t,
2H), 8.04 (d, 2H).
Example 5
(1H-Imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanon-
e
[1420] ##STR251##
[1421] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94-0.99 (m, 6H),
1.15 (d, 3H), 1.37 (d, 1H), 1.44-1.52 (m, 2H), 1.60 (d, 1H), 1.74
(m, 0.5H), 1.83 (m, 0.5H), 2.09 (t, 1H), 3.29 (d, 0.5H), 3.45 (d,
0.5H), 3.61 (d, 0.5H), 3.77 (d, 0.5H), 4.68 (m, 0.5H), 4.80 (bs,
0.5H), 7.49 (d, 1H), 7.69 (d, 1H), 11.45 (bs, 1H).
Example 6
(3-Aza-bicyclo[3.2.2]non-3-yl)-(4-methyl-2-phenyl-thiazol-5-yl)-methanone
[1422] ##STR252##
[1423] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.70 (bs, 10H),
2.48 (s, 3H), 3.75 (bs, 4H), 7.43 (t, 3H), 7.91 (m, 2H).
Example 7
(1-Methyl-1H-imidazol-4-yl)-(1,33-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)--
methanone
[1424] ##STR253##
[1425] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.93 (s, 3H), 0.98
(d, 3H), 1.11 (s, 3H), 1.28-1.46 (m, 3H), 1.55 (d, 1H), 1.69 (m,
0.5H), 1.80 (m, 0.5H), 2.05-2.16 (m, 1H), 3.22 (dd, 0.5H), 3.62
(dq, 1H), 3.71 (s, 3H), 4.12 (d, 0.5H), 4.64 (m, 0.5H), 5.36 (m,
0.5H), 7.39 (d, 1H), 7.58 (d, 1H).
Example 8
[1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicycl-
o[3.2.1]oct-6-yl)-methanone
[1426] ##STR254##
[1427] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.94 (s, 3H), 1.00
(d, 3H), 1.13 (d, 3H), 1.25-1.44 (m, 3H), 1.56 (m, 1H), 1.72 (m,
0.5H), 1.83 (m, 0.5H), 2.08-2.18 (m, 1H), 2.57 (s, 3H), 3.26 (d,
0.5H), 3.65 (q, 1H), 4.16 (d, 0.5H), 4.68 (m, 0.5H), 5.42 (m,
0.5H), 7.12 (d, 1H), 7.18 (d, 1H), 7.72 (t, 1H), 8.24 (s, 1H), 8.35
(s, 1H).
Example 9
[1-(4-Chloro-benzyl)-5-methyl-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bic-
yclo[3.2.1]oct-6-yl)-methanone
[1428] ##STR255##
[1429] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 0.93 (s, 3H), 1.01
(d, 3H), 1.10 (d, 3H), 1.26-1.46 (m, 3H), 1.55 (d, 1H), 1.69 (m,
0.5H), 1.79 (m, 0.5H), 2.04-2.18 (m, 1H), 2.41 (d, 3H), 3.22 (d,
0.5H), 3.59 (d, 1H), 4.06 (d, 0.5H), 4.64 (m, 0.5H), 5.05 (s, 2H),
5.15 (m, 0.5H), 7.00 (d, 2H), 7.32 (d, 2H), 7.43 (d, 1H).
Pharmacological Methods
11.beta.HSD1 Enzyme Assay
Materials
[1430] .sup.3H-cortisone and anti-rabbit Ig coated scintillation
proximity assay (SPA) beads were purchased from Amersham Pharmacia
Biotech, .beta.-NADPH was from Sigma and rabbit anti-cortisol
antibodies were from Fitzgerald. An extract of yeast transformed
with h-11.beta.HSD1 (Hult et al., FEBS Lett., 441, 25 (1998)) was
used as the source of enzyme. The test compounds were dissolved in
DMSO (10 mM). All dilutions were performed in a buffer containing
50 mM TRIS-HCl (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical Co),
0.1% BSA (Sigma Chemical Co), 0.01% Tween-20 (Sigma Chemical Co)
and 0.005% bacitracin (Novo Nordisk A/S), pH=7.4. Optiplate 96
wells plates were supplied by Packard. The amount of
.sup.3H-cortisol bound to the SPA beads was measured on TopCount
NXT, Packard.
Methods
[1431] h-11.beta.HSD1, 120 nM .sup.3H-cortisone, 4 mM .beta.-NADPH,
antibody (1:200), serial dilutions of test compound and SPA
particles (2 mg/well) were added to the wells. The reaction was
initiated by mixing the different components and was allowed to
proceed under shaking for 60 min at 30.degree. C. The reaction was
stopped be the addition of 10 fold excess of a stopping buffer
containing 500 .mu.M carbenoxolone and 1 .mu.M cortisone. Data was
analysed using GraphPad Prism software. TABLE-US-00009 TABLE 1
Inhibition of 11.beta.HSD1 by compounds of the invention
11.beta.HSD1 Formula Example No. IC.sub.50 values (I) 1 0.56 .mu.M
(I) 2 120 .mu.M (III) 1 0.04 .mu.M (V) 1 45 nM (VI) 1 6 nM (VII) 2
118 nM
* * * * *