U.S. patent application number 11/959573 was filed with the patent office on 2008-07-10 for indoles.
Invention is credited to Caterina Bissantz, Christophe Grundschober, Raffaello Masciadri, Hasane Ratni, Mark Rogers-Evans, Patrick Schnider.
Application Number | 20080167344 11/959573 |
Document ID | / |
Family ID | 39198190 |
Filed Date | 2008-07-10 |
United States Patent
Application |
20080167344 |
Kind Code |
A1 |
Bissantz; Caterina ; et
al. |
July 10, 2008 |
INDOLES
Abstract
The present invention is concerned with novel
indol-3-yl-carbonyl-piperidine-benzopyrrolone, -benzoxazolone and
-benzotriazole derivatives as V1a receptor antagonists, their
manufacture, pharmaceutical compositions containing them and their
use for the treatment of anxiety and depressive disorders and other
diseases. In particular, the present invention is concerned with
compounds of formula (I) ##STR00001## wherein X, Y and R.sup.1 to
R.sup.10 are as described in the specification.
Inventors: |
Bissantz; Caterina;
(Village-Neuf, FR) ; Grundschober; Christophe;
(Rodersdorf, CH) ; Masciadri; Raffaello; (Basel,
CH) ; Ratni; Hasane; (Habsheim, FR) ;
Rogers-Evans; Mark; (Oberwil BL, CH) ; Schnider;
Patrick; (Bottmingen, CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
39198190 |
Appl. No.: |
11/959573 |
Filed: |
December 19, 2007 |
Current U.S.
Class: |
514/322 ;
514/321; 514/323; 546/198; 546/199; 546/201 |
Current CPC
Class: |
A61P 13/12 20180101;
A61P 25/00 20180101; A61P 25/22 20180101; A61P 1/16 20180101; A61P
9/00 20180101; C07D 401/14 20130101; A61P 15/00 20180101; A61P
15/08 20180101; A61P 25/24 20180101; A61P 5/00 20180101; A61P 9/04
20180101; A61P 9/12 20180101 |
Class at
Publication: |
514/322 ;
546/198; 546/201; 546/199; 514/321; 514/323 |
International
Class: |
A61K 31/454 20060101
A61K031/454; C07D 401/08 20060101 C07D401/08; A61P 25/00 20060101
A61P025/00; C07D 401/00 20060101 C07D401/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 28, 2006 |
EP |
06127307.4 |
Claims
1. A compound of formula (I-c) ##STR00038## wherein R.sup.1 is H,
C.sub.1-12-alkyl, optionally substituted with CN or OH,
C.sub.1-6-haloalkyl, C.sub.2-12-alkenyl, wherein R.sup.i and
R.sup.ii are independently from each other H, methyl, or ethyl;
wherein m is from 0 to 4; wherein R.sup.a is phenyl, 5- to
6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, which are optionally substituted with one or
more A, or --NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently hydrogen, hydroxy, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
--(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
wherein n is from 0 to 4; wherein R.sup.d is C.sub.1-6-alkoxy,
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen, C.sub.1-6-alkyl, or
--(C.sub.2-6-alkylene)NR.sup.gR.sup.h; wherein R.sup.g and R.sup.h
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl, phenyl, 5- to 6-membered heteroaryl, 3-
to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which
are optionally substituted with one or more A, --S(O).sub.2-phenyl,
wherein phenyl is optionally substituted with one or more halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, nitro, hydroxy or cyano;
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-6-alkyl); A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, R.sup.2 is hydrogen, C.sub.1-6-alkyl,
--C(O)R.sup.n, wherein R.sup.n is C.sub.1-6-alkyl, 3 to 7-membered
heterocycloalkyl, optionally substituted with one, two or three
C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl, or
--S(O).sub.2--C.sub.1-6-alkyl, NR.sup.jR.sup.k, wherein R.sup.j and
R.sup.k are each independently hydrogen, C.sub.1-6-alkyl,
--(C.sub.2-6-alkylene)-NR.sup.lR.sup.m; wherein R.sup.l and R.sup.m
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl; or R.sup.1 together with R.sup.2 forms a
5- to 6-membered heterocycloalkyl moiety fused to the indole core,
bearing one or two ring heteroatoms selected from N, S and O, and
being optionally substituted by one or more A; R.sup.3, R.sup.4,
R.sup.5, R.sup.6 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy; R.sup.7, R.sup.8, R.sup.9, R.sup.10 are each
independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or
a pharmaceutically acceptable salt thereof, with the proviso that
compounds wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are all simultaneously hydrogen are excluded.
2. A compound of claim 1, wherein R.sup.1 is H, C.sub.1-12-alkyl,
optionally substituted with CN or OH, C.sub.1-6-haloalkyl,
C.sub.2-12-alkenyl, --(CR.sup.iR.sup.ii).sub.m--R.sup.a, wherein
R.sup.i and R.sup.ii are independently from each other H, methyl,
or ethyl; wherein m is from 0 to 4; wherein R.sup.a is phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, which are optionally substituted with one or
more A, or --NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently hydrogen, hydroxy, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
--(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
wherein n is from 0 to 4; wherein R.sup.d is C.sub.1-6-alkoxy,
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen, C.sub.1-6-alkyl, or
--(C.sub.2-6-alkylene)NR.sup.gR.sup.h; wherein R.sup.g and R.sup.h
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl, phenyl, 5- to 6-membered heteroaryl, 3-
to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which
are optionally substituted with one or more A, --S(O).sub.2-phenyl,
wherein phenyl is optionally substituted with one or more halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, nitro, hydroxy or cyano;
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-6-alkyl); A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, R.sup.2 is hydrogen, C.sub.1-6-alkyl,
--C(O)R.sup.n, wherein R.sup.n is C.sub.1-6-alkyl, 3 to 7-membered
heterocycloalkyl, optionally substituted with one, two or three
C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl, or
--S(O).sub.2--C.sub.1-6-alkyl, NR.sup.jR.sup.k, wherein R.sup.j and
R.sup.k are each independently hydrogen, C.sub.1-6-alkyl,
--(C.sub.2-6-alkylene)-NR.sup.lR.sup.m; wherein R.sup.l and R.sup.m
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.6 are
each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy;
R.sup.7, R.sup.8, R.sup.9, R.sup.10 are each independently
hydrogen, halo, C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or a pharmaceutically
acceptable salt thereof, with the proviso that compounds wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are all
simultaneously hydrogen are excluded.
3. A compound of claim 1, wherein R.sup.1 is H, C.sub.2-6-alkyl,
optionally substituted with CN or OH, C.sub.1-6-haloalkyl,
(CR.sup.iR.sup.ii).sub.m--R.sup.a, wherein R.sup.i and R.sup.ii are
independently from each other H, methyl, or ethyl; wherein m is
from 0 to 4; wherein R.sup.a is phenyl, 5- to 6-membered
heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered
cyloalkyl, which are optionally substituted with one or more A, or
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
--(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
wherein n is from 0 to 4; wherein R.sup.d is C.sub.1-6-alkoxy,
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen, C.sub.1-6-alkyl, or
--(C.sub.2-6-alkylene)NR.sup.gR.sup.h; wherein R.sup.g and R.sup.h
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl, phenyl, 5- to 6-membered heteroaryl, 3-
to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which
are optionally substituted with one or more A,
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-6-alkyl); A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2), --NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy,
4. The compound of claim 1, wherein R.sup.1 is H, C.sub.2-6-alkyl,
optionally substituted with CN or OH, C.sub.1-6-haloalkyl,
(CR.sup.iR.sup.ii).sub.m--R.sup.a, wherein R.sup.i and R.sup.ii are
independently from each other H, methyl, or ethyl; wherein m is
from 1 to 4; wherein R.sup.a is phenyl, 5- to 6-membered
heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered
cyloalkyl, which are optionally substituted with one or more A, or
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
--(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
wherein n is from 0 to 4; wherein R.sup.d is C.sub.1-6-alkoxy,
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen, C.sub.1-6-alkyl, or
--(C.sub.2-6-alkylene)NR.sup.gR.sup.h; wherein R.sup.g and R.sup.h
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl, phenyl, 5- to 6-membered heteroaryl, 3-
to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which
are optionally substituted with one or more A,
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-6-alkyl); A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl, --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl,
optionally substituted with one, two, or three halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or C.sub.1-6-alkoxy.
5. The compound of claim 1, wherein R.sup.2 is hydrogen or
C.sub.1-6-alkyl.
6. The compound of claim 1, wherein R.sup.3 and R.sup.6 are
hydrogen.
7. The compound of claim 1, wherein R.sup.1 is hydrogen.
8. The compound of claim 1, wherein R.sup.1 is C.sub.1-12-alkyl,
optionally substituted with CN or OH.
9. The compound of claim 1, wherein R.sup.1 is C.sub.1-6-haloalkyl
or C.sub.2-12-alkenyl.
10. The compound of claim 1, wherein R.sup.1 is
--S(O).sub.2-phenyl, wherein phenyl is optionally substituted with
one or more halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, nitro, hydroxy or
cyano.
11. The compound of claim 1, wherein R.sup.1 is
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
--S(O).sub.2NH(C.sub.1-6-alkyl).
12. The compound of claim 1, wherein A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-thioalkyl,
--S(O).sub.2--C.sub.1-6-alkyl, cyano, --CH.sub.2OCH.sub.3,
--C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'', --S(O).sub.2NR'R'',
--NR'C(O)--C.sub.1-6-alkyl, --NR'S(O).sub.2--C.sub.1-6-alkyl,
benzyl, or phenyl wherein R' and R'' are each independently H or
C.sub.1-6-alkyl.
13. The compound of claim 1, wherein R.sup.1 together with R.sup.2
forms a 5- to 6-membered heterocycloalkyl moiety fused to the
indole core, bearing one or two ring heteroatoms selected from N,
S, and O, which is optionally substituted by one or more A.
14. The compound of claim 1, wherein R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 are each independently hydrogen, halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy, or C.sub.1-6-haloalkoxy.
15. The compound of claim 1, wherein R.sup.4 is hydrogen, Cl, F, or
methyl.
16. The compound of claim 1, wherein R.sup.5 is hydrogen, halo,
CF.sub.3, methoxy, or --OCF.sub.3.
17. The compound of claim 1, wherein R.sup.3 and R.sup.6 are
hydrogen, R.sup.4 is hydrogen, F, Cl or methyl, and R.sup.5 is
halo, CF.sub.3, methoxy or OCF.sub.3.
18. The compound of claim 1, wherein R.sup.7, R.sup.8, R.sup.9, and
R.sup.10 are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, or
C.sub.1-6-haloalkoxy.
19. The compound of claim 1, selected from the group consisting of
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one,
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-i-
ndol-1-yl)-N-methylacetamide,
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-
-1-yl)-N,N-dimethylacetamide,
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-
-indol-3-yl]-methanone hydrochloride,
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)--
1H-indol-3-yl]-methanone, and
(4-Benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydr-
o-pyrazino[1,2-.alpha.]indol-10-yl)-methanone.
20. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula I-c ##STR00039## wherein
R.sup.1 is H, C.sub.1-12-alkyl, optionally substituted with CN or
OH, C.sub.1-6-haloalkyl, C.sub.2-12-alkenyl,
--(CR.sup.iR.sup.ii).sub.m--R.sup.a, wherein R.sup.i and R.sup.ii
are independently from each other H, methyl, or ethyl; wherein m is
from 0 to 4; wherein R.sup.a is phenyl, 5- to 6-membered
heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered
cyloalkyl, which are optionally substituted with one or more A, or
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently hydrogen, hydroxy, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
--(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
wherein n is from 0 to 4; wherein R.sup.d is C.sub.1-6-alkoxy,
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen, C.sub.1-6-alkyl, or
--(C.sub.2-6-alkylene)NR.sup.gR.sup.h; wherein R.sup.g and R.sup.h
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl, phenyl, 5- to 6-membered heteroaryl, 3-
to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which
are optionally substituted with one or more A, --S(O).sub.2-phenyl,
wherein phenyl is optionally substituted with one or more halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, nitro, hydroxy or cyano;
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-6-alkyl); A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, R.sup.2 is hydrogen, C.sub.1-6-alkyl,
--C(O)R.sup.n, wherein R.sup.n is C.sub.1-6-alkyl, 3 to 7-membered
heterocycloalkyl, optionally substituted with one, two or three
C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl, or
--S(O).sub.2--C.sub.1-6-alkyl, NR.sup.jR.sup.k, wherein R.sup.j and
R.sup.k are each independently hydrogen, C.sub.1-6-alkyl,
--(C.sub.2-6-alkylene)-NR.sup.lR.sup.m; wherein R.sup.l and R.sup.m
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl; or R.sup.1 together with R.sup.2 forms a
5- to 6-membered heterocycloalkyl moiety fused to the indole core,
bearing one or two ring heteroatoms selected from N, S and O, and
being optionally substituted by one or more A; R.sup.3, R.sup.4,
R.sup.5, R.sup.6 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy; R.sup.7, R.sup.8, R.sup.9, R.sup.10 are each
independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or
a pharmaceutically acceptable salt thereof, with the proviso that
compounds wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are all simultaneously hydrogen are excluded.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 06127307.4, filed Dec. 28, 2006, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Vasopressin is a 9 amino acid peptide mainly produced by the
paraventricular nucleus of the hypothalamus. Three vasopressin
receptors, all belonging to the class I G-protein coupled
receptors, are known. The V1a receptor is expressed in the brain,
liver, vascular smooth muscle, lung, uterus and testis, the V1b or
V3 receptor is expressed in the brain and pituitary gland, the V2
receptor is expressed in the kidney where it regulates water
excretion and mediates the antidiuretic effects of vasopressin.
[0003] In the periphery vasopressin acts as a neurohormone and
stimulates vasoconstriction, glycogenolysis and antidiuresis. In
the brain vasopressin acts as a neuromodulator and is elevated in
the amygdala during stress (Ebner, K., C. T. Wotjak, et al. (2002).
"Forced swimming triggers vasopressin release within the amygdala
to modulate stress-coping strategies in rats." Eur J Neurosci
15(2): 384-8). The V1a receptor is extensively expressed in the
brain and particularly in limbic areas like the amygdala, lateral
septum and hippocampus which are playing an important role in the
regulation of anxiety. Indeed V1a knock-out mouse show a reduction
in anxious behavior in the plus-maze, open field and light-dark box
(Bielsky, I. F., S. B. Hu, et al. (2003). "Profound Impairment in
Social Recognition and Reduction in Anxiety-Like Behavior in
Vasopressin V1a Receptor Knockout Mice." Neuropsychopharmacology).
The downregulation of the V1a receptor using antisense
oligonucleotide injection in the septum also causes a reduction in
anxious behavior (Landgraf, R., R. Gerstberger, et al. (1995). "V1
vasopressin receptor antisense oligodeoxynucleotide into septum
reduces vasopressin binding, social discrimination abilities, and
anxiety-related behavior in rats." Regul Pept 59(2): 229-39).
[0004] The V1a receptor is also mediating the cardiovascular
effects of vasopressin in the brain by centrally regulating blood
pressure and heart rate in the solitary tract nucleus (Michelini,
L. C. and M. Morris (1999). "Endogenous vasopressin modulates the
cardiovascular responses to exercise." Ann N Y Acad Sci 897:
198-211). In the periphery it induces the contraction of vascular
smooth muscles and chronic inhibition of the V1a receptor improves
hemodynamic parameters in myocardial infarcted rats (Van
Kerckhoven, R., I. Lankhuizen, et al. (2002). "Chronic vasopressin
V(1A) but not V(2) receptor antagonism prevents heart failure in
chronically infarcted rats." Eur J Pharmacol 449(1-2): 135-41).
SUMMARY OF THE INVENTION
[0005] The present invention provides novel
indol-3-yl-carbonyl-piperidine-benzopyrrolone, -benzoxazolone and
-benzotriazole derivatives as V1a receptor antagonists, their
manufacture, pharmaceutical compositions containing them and their
use for the treatment of anxiety and depressive disorders and other
diseases.
[0006] In particular, the present invention provides compounds of
formula (I)
##STR00002##
wherein [0007] X is CH.sub.2, and Y is C.dbd.O, [0008] X is O, and
Y is C.dbd.O, or [0009] X--Y is N--N; [0010] R.sup.1 is H,
[0011] C.sub.1-12-alkyl, optionally substituted with CN or OH,
[0012] C.sub.1-6-haloalkyl,
[0013] C.sub.2-12-alkenyl,
[0014] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0015] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0016] wherein m is from 0 to 4; [0017] wherein R.sup.a is [0018]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cylcoalkyl, [0019] which are
optionally substituted with one or more A, or [0020]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0021] hydrogen, [0022] hydroxy, [0023]
C.sub.1-6-alkyl, [0024] --S(O).sub.2--C.sub.1-6-alkyl, or [0025]
--C(O)--C.sub.1-6-alkyl,
[0026] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d [0027] wherein
R.sup.iii and R.sup.iv are each independently H, methyl, or ethyl;
[0028] wherein n is from 0 to 4; [0029] wherein R.sup.d is [0030]
C.sub.1-6-alkoxy, [0031] --NR.sup.eR.sup.f, wherein R.sup.e and
R.sup.f are each independently [0032] hydrogen, [0033]
C.sub.1-6-alkyl, or [0034] --(C.sub.2-6-alkylene)-NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0035] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0036] which are optionally substituted with
one or more A,
[0037] --S(O).sub.2-phenyl, wherein phenyl is optionally
substituted with one or more halo, C.sub.1-6-haloalkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, nitro,
hydroxy or cyano;
[0038] --S(O).sub.2--C.sub.1-6-alkyl,
[0039] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0040] --S(O).sub.2NH(C.sub.1-6-alkyl); [0041] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0042] wherein x is from 0 to 4, [0043]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0044]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0045] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, [0046] R.sup.2 is hydrogen,
[0047] C.sub.1-6-alkyl, or
[0048] --C(O)R.sup.n, wherein R.sup.n is [0049] C.sub.1-6-alkyl,
[0050] 3 to 7-membered heterocycloalkyl, optionally substituted
with one, two or three C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl,
or --S(O).sub.2--C.sub.1-6-alkyl, or [0051] NR.sup.jR.sup.k,
wherein R.sup.j and R.sup.k are each independently [0052] hydrogen,
[0053] C.sub.1-6-alkyl, or [0054]
--(C.sub.2-6-alkylene)-NR.sup.lR.sup.m; wherein R.sup.l and R.sup.m
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl; or [0055] R.sup.1 together with R.sup.2
forms a 5- to 6-membered heterocycloalkyl moiety fused to the
indole core, bearing one or two ring heteroatoms selected from N, S
and O, and being optionally substituted by one or more A; [0056]
R.sup.3, R.sup.4, R.sup.5, R.sup.6 are each independently hydrogen,
halo, C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy; [0057] R.sup.7, R.sup.8, R.sup.9, R.sup.10
are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or
a pharmaceutically acceptable salt thereof, with the proviso that
compounds wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are all simultaneously hydrogen are excluded.
[0058] The compounds of formula (I) can be manufactured by the
methods given below, by the methods given in the examples or by
analogous methods. Appropriate reaction conditions for the
individual reaction steps are known to a person skilled in the art.
Starting materials are either commercially available or can be
prepared by methods analogous to the methods given below, by
methods described in references cited in the text or in the
examples, or by methods known in the art.
[0059] The compounds of formula (I) possess pharmaceutical
activity, in particular they are modulators of V1a receptor
activity. More particular, the compounds are antagonists of the V1a
receptor. Such antagonists are useful as therapeutics in the
conditions of dysmenorrhea, hypertension, chronic heart failure,
inappropriate secretion of vasopressin, liver cirrhosis, nephrotic
syndrome, obsessive compulsive disorder, anxiety and depressive
disorders. The preferred indications with regard to the present
invention are the treatment of anxiety and depressive
disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0060] Unless otherwise stated, the following terms used in the
present description have the definitions given in the following. It
must be noted that, as used in the specification and the appended
claims, the singular forms "a", "an," and "the" include plural
forms unless the context clearly dictates otherwise.
[0061] In the present description, the term "alkyl," alone or in
combination with other groups, refers to a branched or
straight-chain monovalent saturated hydrocarbon radical. The term
"C.sub.1-6-alkyl" denotes a saturated straight- or branched-chain
hydrocarbon group containing from 1 to 6 carbon atoms, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
the isomeric pentyls and the like. A preferred sub-group of
C.sub.1-6-alkyl is C.sub.1-4-alkyl, i.e. with 1-4 carbon atoms.
[0062] In the present invention, the term "alkylene" refers to a
linear or branched saturated divalent hydrocarbon radical. In
particular, "C.sub.1-6-alkylene", means a linear saturated divalent
hydrocarbon radical of one to six carbon atoms or a branched
saturated divalent hydrocarbon radical of three to six carbon
atoms, e.g. methylene, ethylene, 2,2-dimethylethylene, n-propylene,
2-methylpropylene, 1-methyl-ethylene, 2-methyl-ethylene and the
like.
[0063] In the present description, the terms "alkoxy" and
"C.sub.1-6-alkoxy" refer to the group R'--O--, wherein R' is alkyl
or C.sub.1-6-alkyl as defined above. Examples of alkoxy groups are
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
sec-butoxy and the like. A preferred sub-group of C.sub.1-6-alkoxy,
and still more preferred alkoxy groups are methoxy and/or
ethoxy.
[0064] In the present description, the terms "thioalkyl" and
"C.sub.1-6-thioalkyl" refer to the group R'--S--, wherein R' is
alkyl or C.sub.1-6-alkyl as defined above. The term
"--S(O).sub.0-2C.sub.1-6-alkyl" hence refers to the residues
--S--C.sub.1-16-alkyl, --S(O)--C.sub.1-16-alkyl, and
--S(O).sub.2--C.sub.1-16-alkyl wherein C.sub.1-6-alkyl is as
defined above.
[0065] The term "C.sub.1-6-alkyl substituted by OH" is synonymous
with "C.sub.1-6-hydroxyalkyl" or "hydroxyl-C.sub.1-6-alkyl" and
means a C.sub.1-6-alkyl group as defined above wherein at least one
of the hydrogen atoms of the alkyl group is replaced by a hydroxy
group.
[0066] The term "C.sub.1-6-alkyl substituted by CN" is synonymous
with "C.sub.1-6-cyanoalkyl" or "cyano-C.sub.1-6-alkyl" and means a
C.sub.1-6-alkyl group as defined above wherein at least one of the
hydrogen atoms of the alkyl group is replaced by a CN group.
[0067] The terms "halo" and "halogen" refer to fluorine (F),
chlorine (Cl), bromine (Br) and iodine (I) with fluorine, chlorine
and bromine being preferred.
[0068] The term "C.sub.1-6-haloalkyl" is synonymous with
"halo-C.sub.1-6-alkyl" or "C.sub.1-6-alkyl substituted by halo" and
means a C.sub.1-6-alkyl group as defined above wherein at least one
of the hydrogen atoms of the alkyl group is replaced by a halogen
atom, preferably fluoro or chloro, most preferably fluoro. Examples
of C.sub.1-6-haloalkyl include but are not limited to methyl,
ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl
or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as
well as those groups specifically illustrated by the examples
herein below. Among the preferred C.sub.1-6-haloalkyl groups are
difluoro- or trifluoro-methyl or -ethyl.
[0069] The term "C.sub.1-6-haloalkoxy" is synonymous with
"halo-C.sub.1-6-alkoxy" or "C.sub.1-6-alkoxy substituted by halo"
and means a C.sub.1-6-alkoxy group as defined above wherein at
least one of the hydrogen atoms of the alkyl group is replaced by a
halogen atom, preferably fluoro or chloro, most preferably fluoro.
Among the preferred halogenated alkoxy groups are difluoro- or
trifluoro-methoxy or -ethoxy.
[0070] The term "C.sub.2-12-alkenyl," alone or in combination,
denotes a straight-chain or branched hydrocarbon residue of 2 to 12
carbon atoms comprising at least one double bond. A preferred
sub-group of C.sub.2-12-alkenyl is C.sub.2-6-alkyenyl. Examples of
the preferred alkenyl groups are ethenyl, propen-1-yl, propen-2-yl
(allyl), buten-1-yl, buten-2-yl, buten-3-yl, penten-1-yl,
penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl,
hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as those
specifically illustrated by the examples herein below.
[0071] The term "5 or 6 membered heteroaryl" means a monovalent
aromatic ring of 5 or 6 ring atoms as ring members containing one,
two, three or four ring heteroatoms selected from N, O, and S, the
rest being carbon atoms, whereby one, two or three heteroatoms are
preferred, and one or two heteroatoms are even more preferred.
Examples of heteroaryl moieties include, but are not limited to
pyrrolyl, pyrazolyl, imidazolyl, furanyl (synonymous to furyl),
thiophenyl (synonymous to thienyl), oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl. 5 or 6-membered heteroaryl are optionally substituted
with one or more substituents. These optional substitutents include
halo, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR''C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy. Preferred substituents are halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, cyano, --CH.sub.2CN, --CH.sub.2OCH.sub.3,
--S(O).sub.2--C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
--NR'C(O)--C.sub.1-4-alkyl, --C(O)N(C.sub.1-4-alkyl).sub.2,
--C(O)NH(C.sub.1-4-alkyl), --S(O).sub.2N(C.sub.1-4-alkyl).sub.2, or
--S(O).sub.2NH(C.sub.1-4-alkyl), or those substitutents as
specifically indicated herein.
[0072] The term "heterocycloalkyl" means a monovalent saturated
ring, consisting of one ring of 3 to 7, preferably from 4 to 6
atoms as ring members, including one, two, three or four
heteroatoms chosen from nitrogen, oxygen or sulfur, the rest being
carbon atoms, whereby one, two or three heteroatoms are preferred,
and one or two heteroatoms are even more preferred. It is
understood that the number of heteroatoms depends on the ring size,
i.e. 3 and 4-membered heterocycloalkyl preferably contain one
heteroatom, 5 to 7-membered heterocycloalkyl preferably contain
one, two or three heteroatoms, and even more preferably one or two
heteroatoms. Examples of heterocyclic moieties include, but are not
limited to, oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl,
tetrahydro-furanyl, tetrahydro-thiophenyl (synonymous with
tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazidinyl, morpholinyl, or tetrahydropyranyl, each
of which is optionally substituted as described herein. 3 to
7-membered heterocycloalkyl are optionally substituted with one or
more substituents. These optional substitutents include halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, --(CH.sub.2).sub.x--R''',
wherein x is from 0 to 4, R' and R'' are each independently H or
C.sub.1-6-alkyl, or R' and R'' together with the nitrogen to which
they are bound form a 5 or 6-membered heterocycle comprising one or
two heteroatoms selected from N, O and S, and R''' is phenyl or 5-
to 6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy. Preferred substituents are halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, cyano, --CH.sub.2CN, --CH.sub.2OCH.sub.3,
--S(O).sub.2--C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
--NR'C(O)--C.sub.1-4-alkyl, --C(O)N(C.sub.1-4-alkyl).sub.2,
--C(O)NH(C.sub.1-4-alkyl), --S(O).sub.2N(C.sub.1-4-alkyl).sub.2, or
--S(O).sub.2NH(C.sub.1-4-alkyl), or those substitutents as
specifically indicated herein.
[0073] The term "one or more substituents" indicates that in
principle every position in the aryl (in particular phenyl),
heteroaryl, heterocycloalkyl and cycloalkyl residue may bear such a
substituent. The pentafluorophenyl residue may be mentioned as a
preferred example. However, in 5 to 6-membered aromatic rings, one,
two, or three substituents are preferred. In 5 to 6-membered
saturated rings, one, two three or four substituents are preferred.
In 3 to 4-membered rings, one or two substituents are
preferred.
[0074] The term "heterocycle" in the definition "R' and R'',
together with the nitrogen to which they are bound form a five- or
six-membered heterocycle comprising one or two heteroatoms selected
from the group of nitrogen, oxygen and sulfur" means either
heterocycloalkyl or partially unsaturated heterocycloalkyl
(synonymous with heterocycloalkenyl), which may optionally be
substituted with one, two or three substituents selected from halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, nitro, and cyano. Preferred heterocycles are
piperazine, N-methylpiperazine, morpholin, piperidine and
pyrrolidine.
[0075] The term "C.sub.3-7-cycloalkyl" denotes a monovalent or
divalent saturated carbocyclic moiety consisting of a monocyclic
ring containing from 3 to 7 ring carbon atoms. Cycloalkyl can
optionally be substituted with one, two, three or four
substituents, wherein each substituent is independently hydroxy,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halogen, amino, unless otherwise
specifically indicated. Examples of cycloalkyl moieties include
optionally substituted cyclopropyl, optionally substituted
cyclobutyl, optionally substituted cyclopentyl and optionally
substituted cyclohexyl as well as those specifically illustrated by
the examples herein below.
[0076] "Pharmaceutically acceptable," such as pharmaceutically
acceptable carrier, excipient, etc., means pharmacologically
acceptable and substantially non-toxic to the subject to which the
particular compound is administered.
[0077] The term "pharmaceutically acceptable acid addition salt" or
"pharmaceutically acceptable salt" embraces salts with inorganic
and organic acids, such as hydrochloric acid, nitric acid, sulfuric
acid, phosphoric acid, citric acid, formic acid, fumaric acid,
maleic acid, acetic acid, succinic acid, tartaric acid,
methane-sulfonic acid, p-toluenesulfonic acid and the like.
[0078] "Therapeutically effective amount" means an amount that is
effective to prevent, alleviate or ameliorate symptoms of disease
or prolong the survival of the subject being treated.
[0079] The invention further comprises individual optical isomers
of the compounds described herein as well as racemic and
non-racemic mixtures thereof.
[0080] In detail, the present invention relates to compounds of the
general formula (I)
##STR00003##
wherein [0081] X is CH.sub.2, and Y is C.dbd.O, [0082] X is O, and
Y is C.dbd.O, or [0083] X--Y is N.dbd.N; [0084] R.sup.1 is H,
[0085] C.sub.1-12-alkyl, optionally substituted with CN or OH,
[0086] C.sub.1-6-haloalkyl,
[0087] C.sub.2-12-alkenyl,
[0088] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0089] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0090] wherein m is from 0 to 4; [0091] wherein R.sup.a is [0092]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0093] which are
optionally substituted with one or more A, or [0094]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0095] hydrogen, [0096] hydroxy, [0097]
C.sub.1-6-alkyl, [0098] --S(O).sub.2--C.sub.1-6-alkyl, or [0099]
--C(O)--C.sub.1-6-alkyl,
[0100] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d [0101] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0102] wherein n is from 0 to 4; [0103] wherein R.sup.d
is [0104] C.sub.1-6-alkoxy, [0105] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0106] hydrogen, [0107]
C.sub.1-6-alkyl, or [0108] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0109] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0110] which are optionally substituted with
one or more A,
[0111] --S(O).sub.2-phenyl, wherein phenyl is optionally
substituted with one or more halo, C.sub.1-6-haloalkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, nitro,
hydroxy or cyano;
[0112] --S(O).sub.2--C.sub.1-6-alkyl,
[0113] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0114] --S(O).sub.2NH(C.sub.1-6-alkyl); [0115] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0116] wherein x is from 0 to 4, [0117]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0118]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0119] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, [0120] R.sup.2 is hydrogen,
[0121] C.sub.1-6-alkyl, or
[0122] --C(O)R.sup.n, wherein R.sup.n is [0123] C.sub.1-6-alkyl, or
[0124] 3 to 7-membered heterocycloalkyl, optionally substituted
with one, two or three C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl,
or --S(O).sub.2--C.sub.1-6-alkyl, [0125] NR.sup.jR.sup.k, wherein
R.sup.j and R.sup.k are each independently [0126] hydrogen, [0127]
C.sub.1-6-alkyl, or [0128] --(C.sub.2-6-alkylene)-NR.sup.lR.sup.m;
wherein R.sup.l and R.sup.m are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl; or [0129] R.sup.1
together with R.sup.2 forms a 5- to 6-membered heterocycloalkyl
moiety fused to the indole core, bearing one or two ring
heteroatoms selected from N, S and O, and being optionally
substituted by one or more A; [0130] R.sup.3, R.sup.4, R.sup.5,
R.sup.6 are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy;
[0131] R.sup.7, R.sup.8, R.sup.9, R.sup.10 are each independently
hydrogen, halo, C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or a pharmaceutically
acceptable salt thereof, with the proviso that compounds wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are all
simultaneously hydrogen are excluded.
[0132] In the following, certain embodiments of the invention are
disclosed, whereby the combination of these embodiments with each
other is also encompassed by present invention.
[0133] In certain embodiments of the invention, R.sup.1 is
hydrogen. However, not all residues R.sup.1 to R.sup.6 shall
simultaneously be hydrogen.
[0134] In certain embodiments of the invention, R.sup.1 is
C.sub.1-12-alkyl, optionally substituted with CN or OH; or R.sup.1
is C.sub.2-12-alkyl, optionally substituted with CN or OH.
Preferably, R.sup.1 is C.sub.1-6-alkyl, optionally substituted with
CN or OH; or R.sup.1 is C.sub.2-6-alkyl, optionally substituted
with CN or OH.
[0135] In certain embodiments of the invention, R.sup.1 is
C.sub.1-6-haloalkyl or C.sub.2-12-alkenyl. In case R.sup.1 is
alkenyl, C.sub.2-6-alkenyl is preferred.
[0136] In certain embodiments of the invention, [0137] R.sup.1 is
(CR.sup.iR.sup.ii)--R.sup.a [0138] wherein R.sup.i and R.sup.ii are
independently from each other H, methyl, or ethyl; [0139] wherein m
is from 0 to 4; [0140] wherein R.sup.a is [0141] phenyl, 5- to
6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0142] which are optionally substituted with
one or more halo, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, --S(O).sub.0-2C.sub.1-6-alkyl, nitro,
hydroxy, cyano, --(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0143] wherein x is from 0 to 4, [0144]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0145]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0146] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, [0147] --NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each independently [0148] hydrogen, [0149] hydroxy,
[0150] C.sub.1-6-alkyl, [0151] --S(O).sub.2--C.sub.1-6-alkyl, or
[0152] --C(O)--C.sub.1-6-alkyl. In
--(CR.sup.iR.sup.ii).sub.m--R.sup.a, preferably, all R.sup.i and
R.sup.ii are hydrogen, or one R.sup.i is methyl and the other
R.sup.i and R.sup.ii are hydrogen. The following linkers
--(CR.sup.iR.sup.ii).sub.m-- are preferred: --CH.sub.2--,
--CH(CH.sub.3)--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3) CH.sub.2--, or
--CH.sub.2CH.sub.2CH(CH.sub.3)--.
[0153] The variable m in --(CR.sup.iR.sup.ii).sub.m--R.sup.a is 0,
1, 2, 3 or 4. In case R.sup.a is --NR.sup.bR.sup.c, m is preferably
1, 2, 3 or 4.
[0154] When R.sup.a in --(CR.sup.iR.sup.ii).sub.m--R.sup.a is 5 to
6-membered heteroaryl, then 5- to 6-membered heteroaryl is as
defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl
(synonymous to furyl), thiophenyl (synonymous to thienyl),
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl. In case m is 0, pyridinyl is
preferred, in case m is 1, 2, 3 or 4, pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, or thiazolyl are preferred. All these residues are
optionally substituted as described herein.
[0155] When R.sup.a in --(CR.sup.iR.sup.ii).sub.m--R.sup.a is a 3-
to 7-membered heterocycloalkyl, then 3- to 7-membered
heterocycloalkyl is as defined above, namely oxiranyl, thiiranyl,
aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl,
tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl),
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl,
isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,
piperazidinyl, morpholinyl, or tetrahydropyranyl. When R.sup.a is
3- to 7-membered heterocycloalkyl, oxiranyl, oxetanyl,
pyrrolidinyl, piperidinyl, piperazidinyl, morpholinyl, or
tetrahydropyranyl are preferred. All these residues are optionally
substituted as described herein.
[0156] When R''' is 5 to 6-membered heteroaryl, then 5- to
6-membered heteroaryl is as defined above, namely pyrrolyl,
pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl
(synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, or thiazolyl are preferred.
[0157] In certain embodiments of the invention, [0158] R.sup.1 is
--(CR.sup.iiiR.sup.iv) C(O)R.sup.d, [0159] wherein R.sup.iii and
R.sup.iv are independently from each other H, methyl, or ethyl;
[0160] wherein n is from 0 to 4; [0161] wherein R.sup.d is [0162]
C.sub.1-6-alkoxy, [0163] --NR.sup.eR.sup.f, wherein R.sup.e and
R.sup.f are each independently [0164] hydrogen, [0165]
C.sub.1-6-alkyl, or [0166] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0167] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0168] which are optionally substituted with
one or more halo, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, --S(O).sub.0-2C.sub.1-6-alkyl, nitro,
hydroxy, cyano, --(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0169] wherein x is from 0 to 4, [0170]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0171]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0172] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy.
[0173] In --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, preferably,
all R.sup.iii and R.sup.iv are hydrogen, or one R.sup.iii is methyl
and the other R.sup.iii and R.sup.iv are hydrogen. The following
linkers --(CR.sup.iR.sup.ii).sub.n-- are preferred:
--CH.sub.2--, --CH(CH.sub.3)--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3) CH.sub.2--, or
--CH.sub.2CH.sub.2CH(CH.sub.3)--.
[0174] The variable n in --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d
is 0, 1, 2, 3 or 4.
[0175] When R.sup.d in --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d is
5 to 6-membered heteroaryl, then 5- to 6-membered heteroaryl is as
defined above, namely pyrrolyl, pyrazolyl, imidazolyl, furanyl
(synonymous to furyl), thiophenyl (synonymous to thienyl),
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl. When R.sup.d is 5- to
6-membered heteroaryl, optionally substituted pyridinyl is
preferred. All these residues are optionally substituted as
described herein.
[0176] When R.sup.d in --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d is
a 3- to 7-membered heterocycloalkyl, then 3- to 7-membered
heterocycloalkyl is as defined above, namely oxiranyl, thiiranyl,
aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl,
tetrahydro-thiophenyl (synonymous with tetrahydro-thienyl),
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl,
isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,
piperazidinyl, morpholinyl, or tetrahydropyranyl. When R.sup.d is
3- to 7-membered heterocycloalkyl, optionally substituted
piperidinyl, piperazidinyl, or morpholinyl are preferred. All these
residues are optionally substituted as described herein.
[0177] When R''' is 5 to 6-membered heteroaryl, then 5- to
6-membered heteroaryl is as defined above, namely pyrrolyl,
pyrazolyl, imidazolyl, furanyl (synonymous to furyl), thiophenyl
(synonymous to thienyl), oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.
Pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, or thiazolyl are preferred.
[0178] In certain embodiments of the invention, R.sup.1 is
--S(O).sub.2-phenyl, wherein phenyl is optionally substituted with
one or more halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, nitro, hydroxy or cyano.
Halo, CF.sub.3, C.sub.1-4-alkyl, C.sub.1-6-alkoxy, OCF.sub.3 and
cyano are preferred substitutents.
[0179] In certain embodiments of the invention, R.sup.1 is
--S(O).sub.2--C.sub.1-6-alkyl,
--S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
--S(O).sub.2NH(C.sub.1-6-alkyl).
[0180] It is understood that all the above residues R.sup.1 are
encompassed by present invention in all their possible
combinations. Some examples are given below.
[0181] In certain embodiments of the invention, [0182] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl, --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0183] wherein x is from 0 to 4, [0184]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0185]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0186] R''' is phenyl, optionally
substituted with one, two, or three halo, C.sub.1-6-haloalkyl,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy.
[0187] In certain embodiments of formula (I) of the invention,
[0188] A is halo, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, C.sub.1-6-thioalkyl,
--S(O).sub.2--C.sub.1-6-alkyl, cyano, --CH.sub.2OCH.sub.3,
--C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'', --S(O).sub.2NR'R'',
--NR'C(O)--C.sub.1-6-alkyl, --NR'S(O).sub.2--C.sub.1-6-alkyl,
benzyl, or phenyl [0189] wherein R' and R'' are each independently
H or C.sub.1-6-alkyl.
[0190] In certain embodiments of formula (I) of the invention,
[0191] R.sup.1 is H,
[0192] C.sub.2-6-alkyl, optionally substituted with CN or OH,
[0193] C.sub.1-6-haloalkyl,
[0194] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0195] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0196] wherein m is from 0 to 4; [0197] wherein R.sup.a is [0198]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0199] which are
optionally substituted with one or more A, or [0200]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0201] hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
[0202] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0203] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0204] wherein n is from 0 to 4; [0205] wherein R.sup.d
is [0206] C.sub.1-6-alkoxy, [0207] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0208] hydrogen, [0209]
C.sub.1-6-alkyl, or [0210] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0211] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0212] which are optionally substituted with
one or more A,
[0213] --S(O).sub.2--C.sub.1-6-alkyl,
[0214] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0215] --S(O).sub.2NH(C.sub.1-6-alkyl); [0216] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0217] wherein x is from 0 to 4, [0218]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0219]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0220] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy.
[0221] In certain embodiments of formula (I) of the invention,
[0222] R.sup.1 is H,
[0223] C.sub.2-6-alkyl, optionally substituted with CN or OH,
[0224] C.sub.1-6-haloalkyl,
[0225] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0226] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0227] wherein m is from 1 to 4; [0228] wherein R.sup.a is [0229]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0230] which are
optionally substituted with one or more A, or [0231]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0232] hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
[0233] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0234] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0235] wherein n is from 0 to 4; [0236] wherein R.sup.d
is [0237] C.sub.1-6-alkoxy, [0238] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0239] hydrogen, [0240]
C.sub.1-6-alkyl, or [0241] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0242] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0243] which are optionally substituted with
one or more A,
[0244] --S(O).sub.2--C.sub.1-6-alkyl,
[0245] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0246] --S(O).sub.2NH(C.sub.1-6-alkyl); [0247] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl, --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0248] wherein x is from 0 to 4, [0249]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0250]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0251] R''' is phenyl, optionally
substituted with one, two, or three halo, C.sub.1-6-haloalkyl,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy. Preferably, A is selected
from [0252] halo, C.sub.1-6-alkyl, C.sub.1-6-haloalkyl,
C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy,
C.sub.1-6-haloalkoxy, C.sub.1-6-thioalkyl,
--S(O).sub.2--C.sub.1-6-alkyl, cyano, --CH.sub.2OCH.sub.3,
--C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'', --S(O).sub.2NR'R'',
--NR'C(O)--C.sub.1-6-alkyl, --NR'S(O).sub.2--C.sub.1-6-alkyl,
benzyl, and phenyl [0253] wherein R' and R'' are each independently
H or C.sub.1-6-alkyl.
[0254] In certain embodiments of formula (I) of the invention,
R.sup.1 together with R.sup.2 forms a 5- to 6-membered
heterocycloalkyl moiety fused to the indole core, bearing one or
two ring heteroatoms selected from N, S and O, and being optionally
substituted by one or more A. Thereby, A is as defined above.
Preferably, the optional substituents are selected from
C.sub.1-6-alkyl, halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy and
C.sub.1-6-haloalkoxy. Preferably, it is one optional
substituent.
[0255] In certain embodiments of formula (I) of the invention,
[0256] R.sup.1 is H,
[0257] --(C.sup.iR.sup.ii).sub.m--R.sup.a, [0258] wherein R.sup.i
and R.sup.ii are H, and m is 1 or 2; [0259] wherein R.sup.a is
[0260] phenyl, optionally substituted with one or more A,
preferably with halo, [0261] --NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each independently [0262] hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl, or
[0263] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0264] wherein
R.sup.iii and R.sup.iv are H, and n is 1, and R.sup.d is [0265]
--NR.sup.eR.sup.f, wherein R.sup.e and R.sup.f are each
independently hydrogen or C.sub.1-6-alkyl, or [0266] R.sup.1
together with R.sup.2 forms a 6-membered heterocycloalkyl moiety
fused to the indole core, bearing two nitrogen ring heteroatoms,
and being optionally substituted by one or more C.sub.1-6-alkyl,
halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy, [0267] A is halo, C.sub.1-6-alkyl,
C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-cyanoalkyl,
C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-thioalkyl,
--S(O).sub.2--C.sub.1-6-alkyl, cyano, --CH.sub.2OCH.sub.3,
--C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'', --S(O).sub.2NR'R'',
--NR'C(O)--C.sub.1-6-alkyl, --NR'S(O).sub.2--C.sub.1-6-alkyl,
benzyl, or phenyl [0268] wherein R' and R'' are each independently
H or C.sub.1-6-alkyl.
[0269] When R.sup.n in --C(O)R.sup.n of R.sup.2 is a 3- to
7-membered heterocycloalkyl, then 3- to 7-membered heterocycloalkyl
is as defined above, namely oxiranyl, thiiranyl, aziridinyl,
oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl
(synonymous with tetrahydro-thienyl), pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl,
isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, or
tetrahydropyranyl. When R.sup.n is 3- to 7-membered
heterocycloalkyl, piperidinyl, piperazidinyl, or morpholinyl,
optionally substituted with one methyl, are preferred.
[0270] In certain embodiments of the invention, R.sup.2 of the
compounds of formula (I) is hydrogen or C.sub.1-6-alkyl.
[0271] In certain embodiments of the invention, R.sup.1 together
with R.sup.2 of formula (I) forms a 5- to 6-membered
heterocycloalkyl moiety fused to the indole core, bearing one or
two ring heteroatoms selected from N, S and O, and being optionally
substituted by one or more A. Preferably, the optional substituents
are C.sub.1-6-alkyl, halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy. Preferably, R.sup.1 together with R.sup.2 of
formula (I) forms a 6-membered heterocycloalkyl moiety fused to the
indole core, bearing two nitrogen ring heteroatoms, and being
optionally substituted by one or more C.sub.1-6-alkyl, halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy.
[0272] In certain embodiments of the invention, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 are each independently hydrogen, halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy.
[0273] In certain embodiments of the invention, R.sup.3 and R.sup.6
of formula (I) are hydrogen.
[0274] In certain embodiments of the invention, R.sup.4 of formula
(I) is hydrogen, Cl, F or methyl.
[0275] In certain embodiments of the invention, R.sup.5 of formula
(I) is hydrogen, halo, CF.sub.3, methoxy or --OCF.sub.3. If R.sup.5
is hydrogen, R.sup.1 is preferably as defined above, however, with
the exclusion of hydrogen. In further embodiments, R.sup.5 is halo,
CF.sub.3, methoxy or --OCF.sub.3. In further embodiments, R.sup.5
is Cl, F or methoxy; in further embodiments, R.sup.5 is Cl.
[0276] In certain embodiments of the invention, R.sup.3 and R.sup.6
are hydrogen, R.sup.4 is hydrogen, F, Cl or methyl, and R.sup.5 is
halo, CF.sub.3, methoxy or OCF.sub.3.
[0277] In certain embodiments of the invention, R.sup.7, R.sup.8,
R.sup.9, R.sup.10 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy. Preferably, R.sup.7, R.sup.8, R.sup.9,
R.sup.10 are each hydrogen.
[0278] In a certain embodiment the compounds of the invention are
those compounds of formula (I-a):
##STR00004##
[0279] In a certain embodiment the compounds of the invention are
those compounds of formula (I-b):
##STR00005##
[0280] In a certain embodiment the compounds of the invention are
those compounds of formula (I-c):
##STR00006##
[0281] One embodiment of the invention encompasses compounds of
formula (I)
##STR00007##
wherein [0282] X is CH.sub.2, and Y is C.dbd.O, [0283] X is O, and
Y is C.dbd.O, or [0284] X--Y is N.dbd.N; [0285] R.sup.1 is H,
[0286] C.sub.1-12-alkyl, optionally substituted with CN or OH,
[0287] C.sub.1-6-haloalkyl,
[0288] C.sub.2-12-alkenyl,
[0289] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0290] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0291] wherein m is from 0 to 4; [0292] wherein R.sup.a is [0293]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0294] which are
optionally substituted with one or more A, or [0295]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0296] hydrogen, [0297] hydroxy, [0298]
C.sub.1-6-alkyl, [0299] --S(O).sub.2--C.sub.1-6-alkyl, or [0300]
--C(O)--C.sub.1-6-alkyl,
[0301] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0302] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0303] wherein n is from 0 to 4; [0304] wherein R.sup.d
is [0305] C.sub.1-6-alkoxy, [0306] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0307] hydrogen, [0308]
C.sub.1-6-alkyl, or [0309] --(C.sub.2-6-alkylene)-NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0310] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0311] which are optionally substituted with
one or more A,
[0312] --S(O).sub.2-phenyl, wherein phenyl is optionally
substituted with one or more halo, C.sub.1-6-haloalkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, nitro,
hydroxy or cyano;
[0313] --S(O).sub.2--C.sub.1-6-alkyl,
[0314] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0315] --S(O).sub.2NH(C.sub.1-6-alkyl); [0316] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
--S(O).sub.0-2C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--(C.sub.1-6-alkylene)-OR''', --C(O)OC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl, --C(O)OR''', --C(O)R''', --C(O)NR'R'',
--S(O).sub.2NR'R'', --(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl,
--(CH.sub.2).sub.x--C.sub.3-6-cycloalkyl, or
--(CH.sub.2).sub.x--R''', [0317] wherein x is from 0 to 4, [0318]
R' and R'' are each independently H or C.sub.1-6-alkyl, or [0319]
R' and R'' together with the nitrogen to which they are bound form
a 5 or 6-membered heterocycle comprising one or two heteroatoms
selected from N, O and S, and [0320] R''' is phenyl or 5- to
6-membered heteroaryl, optionally substituted with one, two, or
three halo, C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy, [0321] R.sup.2 is hydrogen,
[0322] C.sub.1-6-alkyl, or
[0323] --C(O)R.sup.n, wherein R.sup.n is [0324] C.sub.1-6-alkyl,
[0325] 3 to 7-membered heterocycloalkyl, optionally substituted
with one, two or three C.sub.1-6-alkyl, --C(O)O--C.sub.1-6-alkyl,
or --S(O).sub.2--C.sub.1-6-alkyl, or [0326] NR.sup.jR.sup.k,
wherein R.sup.j and R.sup.k are each independently [0327] hydrogen,
[0328] C.sub.1-6-alkyl, or [0329]
--(C.sub.2-6-alkylene)-NR.sup.lR.sup.m; wherein R.sup.l and R.sup.m
are each independently hydrogen, C.sub.1-6-alkyl, or
--C(O)O--C.sub.1-6-alkyl; [0330] R.sup.3, R.sup.4, R.sup.5, R.sup.6
are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy;
[0331] R.sup.7, R.sup.8, R.sup.9, R.sup.10 are each independently
hydrogen, halo, C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or a pharmaceutically
acceptable salt thereof, with the proviso that compounds wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are all
simultaneously hydrogen are excluded.
[0332] The invention further encompasses an embodiment of formula
(I) wherein
[0333] X is CH.sub.2, and Y is C.dbd.O,
[0334] X is O, and Y is C.dbd.O, or
[0335] X--Y is N.dbd.N; [0336] R.sup.1 is H,
[0337] C.sub.2-6-alkyl, optionally substituted with CN or OH,
[0338] C.sub.1-6-haloalkyl,
[0339] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0340] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0341] wherein m is from 0 to 4; [0342] wherein R.sup.a is [0343]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0344] which are
optionally substituted with one or more A, or [0345]
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
independently [0346] hydrogen, C.sub.1-6-alkyl,
--S(O).sub.2--C.sub.1-6-alkyl, or --C(O)--C.sub.1-6-alkyl,
[0347] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0348] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0349] wherein n is from 0 to 4; [0350] wherein R.sup.d
is [0351] C.sub.1-6-alkoxy, [0352] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0353] hydrogen, [0354]
C.sub.1-6-alkyl, or [0355] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0356] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0357] which are optionally substituted with
one or more A,
[0358] --S(O).sub.2-phenyl, optionally substituted by halo,
[0359] --S(O).sub.2--C.sub.1-6-alkyl,
[0360] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0361] --S(O).sub.2NH(C.sub.1-6-alkyl); [0362] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
C.sub.1-6-thioalkyl, --S(O).sub.2--C.sub.1-6-alkyl,
--S(O)--C.sub.1-6-alkyl, nitro, hydroxy, cyano,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-O--C.sub.1-6-haloalkyl,
--C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'', --S(O).sub.2NR'R'',
--(CH.sub.2).sub.x--NR'R'',
--(CH.sub.2).sub.x--NR'C(O)--C.sub.1-6-alkyl, or
--(CH.sub.2).sub.x--NR'S(O).sub.2--C.sub.1-6-alkyl, [0363] wherein
x is from 0 to 4 and [0364] R' and R'' are each independently H or
C.sub.1-6-alkyl, or [0365] R' and R'' together with the nitrogen to
which they are bound form a 5 or 6-membered heterocycle comprising
one or two heteroatoms selected from N, O and S, [0366]
--(CH.sub.2).sub.y--C.sub.3-6-cycloalkyl,
--(CH.sub.2).sub.y-benzyl, or --(CH.sub.2).sub.y-phenyl, [0367]
wherein y is from 0 to 4, and [0368] wherein benzyl or phenyl are
optionally substituted with one, two, or three halo,
C.sub.1-6-haloalkyl, C.sub.1-6-alkyl, or C.sub.1-6-alkoxy; [0369]
R.sup.2 is hydrogen, or C.sub.1-6-alkyl; [0370] R.sup.3, R.sup.4,
R.sup.5, R.sup.6 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy; [0371] R.sup.7, R.sup.8, R.sup.9, R.sup.10
are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or C.sub.1-6-haloalkoxy; or
a pharmaceutically acceptable salt thereof, with the proviso that
compounds wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 are all simultaneously hydrogen are excluded.
[0372] The invention further encompasses an embodiment of formula
(I) wherein [0373] X is CH.sub.2, and Y is C.dbd.O,
[0374] X is O, and Y is C.dbd.O, or
[0375] X--Y is N.dbd.N; [0376] R.sup.1 is H,
[0377] C.sub.2-6-alkyl, optionally substituted with CN or OH,
[0378] C.sub.1-6-haloalkyl,
[0379] --(CR.sup.iR.sup.ii).sub.m--R.sup.a, [0380] wherein R.sup.i
and R.sup.ii are independently from each other H, methyl, or ethyl;
[0381] wherein m is from 1 to 4; [0382] wherein R.sup.a is [0383]
phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered
heterocycloalkyl or 3 to 7-membered cyloalkyl, [0384] which are
optionally substituted with one or more A, or --NR.sup.bR.sup.c,
wherein R.sup.b and R.sup.c are each independently [0385] hydrogen,
C.sub.1-6-alkyl, --S(O).sub.2--C.sub.1-6-alkyl, or
--C(O)--C.sub.1-6-alkyl,
[0386] --(CR.sup.iiiR.sup.iv).sub.n--C(O)R.sup.d, [0387] wherein
R.sup.iii and R.sup.iv are independently from each other H, methyl,
or ethyl; [0388] wherein n is from 0 to 4; [0389] wherein R.sup.d
is [0390] C.sub.1-6-alkoxy, [0391] --NR.sup.eR.sup.f, wherein
R.sup.e and R.sup.f are each independently [0392] hydrogen, [0393]
C.sub.1-6-alkyl, or [0394] --(C.sub.2-6-alkylene)NR.sup.gR.sup.h;
wherein R.sup.g and R.sup.h are each independently hydrogen,
C.sub.1-6-alkyl, or --C(O)O--C.sub.1-6-alkyl, or [0395] phenyl, 5-
to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to
7-membered cyloalkyl, [0396] which are optionally substituted with
one or more A,
[0397] --S(O).sub.2--C.sub.1-6-alkyl,
[0398] --S(O).sub.2N(C.sub.1-6-alkyl).sub.2, or
[0399] --S(O).sub.2NH(C.sub.1-6-alkyl); [0400] A is halo,
C.sub.1-6-alkyl, C.sub.1-6-haloalkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-cyanoalkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy,
C.sub.1-6-thioalkyl, --S(O).sub.2--C.sub.1-6-alkyl, cyano,
--CH.sub.2OCH.sub.3, --C(O)O--C.sub.1-6-alkyl, --C(O)NR'R'',
--S(O).sub.2NR'R'', --NR'C(O)--C.sub.1-6-alkyl,
--NR'S(O).sub.2--C.sub.1-6-alkyl, benzyl, or phenyl [0401] wherein
R' and R'' are each independently H or C.sub.1-6-alkyl. [0402]
R.sup.2 is hydrogen, or C.sub.1-6-alkyl; [0403] R.sup.3, R.sup.4,
R.sup.5, R.sup.6 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
C.sub.1-6-haloalkoxy; [0404] R.sup.7, R.sup.8, R.sup.9, R.sup.10
are each independently hydrogen or halo; or a pharmaceutically
acceptable salt thereof, with the proviso that compounds wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are all
simultaneously hydrogen are excluded.
[0405] Preferred compounds of formula (I-a) are [0406]
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one, [0407]
1-{1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-piperidin-4--
yl}-1,3-dihydro-indol-2-one, [0408]
2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-in-
dol-1-yl}-N-methyl-acetamide, [0409]
2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbony-
l}-1H-indol-1-yl)-N,N-dimethylacetamide, [0410]
2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-in-
dol-1-yl}-N,N-diethyl-acetamide, [0411]
N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carb-
onyl}-1H-indol-1-yl)ethyl]methanesulfonamide, [0412]
N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carb-
onyl}-1H-indol-1-yl)ethyl]acetamide, and [0413]
1-[1-(6-Chloro-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-
-indol-2-one, [0414]
1-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4--
yl}-1,3-dihydro-indol-2-one hydrochloride, or [0415]
1-{1-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidin--
4-yl}-1,3-dihydro-indol-2-one.
[0416] Preferred compounds of formula (I-b) are [0417]
3-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-3H-benzooxazol-2-one-
, and [0418]
2-{6-Chloro-3-[4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carbonyl]-indol-1--
yl}-N-methyl-acetamide.
[0419] Preferred compounds of formula (I-c) are [0420]
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one, [0421]
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-
-1-yl)-N-methylacetamide, [0422]
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol-
-1-yl)-N,N-dimethylacetamide, [0423]
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-
-indol-3-yl]-methanone hydrochloride, [0424]
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)--
1H-indol-3-yl]-methanone, and [0425]
(4-Benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydr-
o-pyrazino[1,2-.alpha.]indol-10-yl)-methanone.
[0426] The invention also encompasses methods for the treatment of
dysmenorrhea, hypertension, chronic heart failure, inappropriate
secretion of vasopressin, liver cirrhosis, nephrotic syndrome,
obsessive compulsive disorder, anxiety and depressive disorders
which comprises administering a therapeutically effective amount of
a compound of formula (I), (Ia), (Ib), or (Ic).
[0427] The invention also encompasses a pharmaceutical composition
comprising a compound of formula (I), (Ia), (Ib), or (Ic) and a
pharmaceutically acceptable carrier. The pharmaceutical composition
may further comprise at least one pharmaceutically acceptable
excipient.
[0428] In a certain embodiment, the compounds of formula (I) of the
invention can be manufactured according to a process comprising
reacting a compound of formula (II):
##STR00008##
with a compound of formula (III):
##STR00009##
to obtain a compound of formula (I) wherein X, Y, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 are as defined hereinabove for formula (I).
[0429] In another embodiment, the compounds of formula (I) of the
invention can be manufactured according to a process comprising
reacting a compound of formula (I-1), wherein R.sup.1 equals H:
##STR00010##
with a compound of formula R.sup.1-Z (wherein R.sup.1 is different
from H), to obtain a compound of formula (I) wherein X, Y, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 are as defined hereinabove for formula (I) and
Z is halo.
[0430] These processes are described in more details with the
following general schemes and procedures A to C.
##STR00011##
General scheme A
[0431] Compounds of formula (I) can be prepared via an amide
coupling between an indole 3-carboxylic acid (II) and a compound of
formula (III). The usual reagents and protocols known in the art
can be used to effect the amide coupling. Indole 3-carboxylic acids
(II) are either commercially available or readily prepared using a
procedure described in J. Med. Chem. 1991, 34, 140. Alternatively,
they can be prepared following the general scheme C as described
hereinafter. The compounds of formula (III) are either commercially
available or prepared using methods known in the art starting from
commercially available materials. General scheme A is hereinafter
further illustrated with general procedures I and II.
##STR00012##
General procedure B
[0432] Compounds of formula (I) with R.sup.1 different from H can
be prepared using methods known in the art, e.g. by N-deprotonation
of a compound of formula (I-1) (compounds of formula (I) wherein
R.sup.1 is H) followed by treatment with an electrophilic reactant
R.sup.1-Z (wherein Z is a leaving group, e.g. halo) which is either
commercially available or easily prepared according to methods well
known in the art and commercially available starting materials.
General scheme B is hereinafter further illustrated with general
procedure III.
##STR00013##
General procedure C
[0433] The treatment of an indole derivative (IV-1) with
trifluoroacetic anhydride in DMF affords intermediate (V) which can
be hydrolysed with an aqueous sodium hydroxide solution to give the
3-carboxylic acid indole derivative (II-1). Alternatively, (V)
could react with an electrophilic reactant R.sup.1-Z to give (VI),
which is then converted to the corresponding carboxylic acid
derivative (TI) with NaH/H.sub.2O in DMF (see J. Org. Chem., 1993,
10, 2862). Intermediate (VI) can alternatively be obtained by
treatment of an indole derivative (IV-2) with trifluoroacetic
anhydride in a suitable solvent, e.g. DMF, dichloromethane or
1,2-dichloroethane. Addition of a suitable base may be
advantageous.
[0434] The compounds of the present invention exhibit V1a activity,
which may be detected as described below:
V1a Activity
Material & Method:
[0435] The human V1a receptor was cloned by RT-PCR from total human
liver RNA. The coding sequence was subcloned in an expression
vector after sequencing to confirm the identity of the amplified
sequence. To demonstrate the affinity of the compounds from the
present invention to the human V1a receptor binding studies were
performed. Cell membranes were prepared from HEK293 cells
transiently transfected with the expression vector and grown in 20
liter fermenters with the following protocol.
[0436] 50 g of cells were resuspended in 30 ml freshly prepared ice
cold Lysis buffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to
pH=7.4+complete cocktail of protease inhibitor (Roche
Diagnostics)); homogenized with Polytron for 1 min; and sonicated
on ice for 2.times.2 minutes at 80% intensity (Vibracell
sonicator). The preparation was centrifuged 20 min at 500 g at
4.degree. C., the pellet was discarded and the supernatant
centrifuged 1 hour at 43,000 g at 4.degree. C. (19,000 rpm). The
pellet was resuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20%
and homogenized using a Polytron for 1-2 min. The protein
concentration was determined by the Bradford method and aliquots
were stored at -80.degree. C. until use. For binding studies 60 mg
Yttrium silicate SPA beads (Amersham) were mixed with an aliquot of
membrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM
CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50 ul of
bead/membrane mixture was then added to each well of a 96 well
plate, followed by 50 ul of 4 nM 3H-Vasopressin (American
Radiolabeled Chemicals). For total binding measurement 100 ul of
binding buffer were added to the respective wells, for non-specific
binding 100 ul of 8.4 mM cold vasopressin and for compound testing
100 ul of a serial dilution of each compound in 2% DMSO. The plate
was incubated 1 h at room temperature, centrifuged 1 min at 1000 g
and counted on a Packard Top-Count. Non-specific binding counts
were subtracted from each well, and data was normalized to the
maximum specific binding set at 100%. To calculate an IC 50 the
curve was fitted using a non-linear regression model (XLfit), and
the Ki was calculated using the Cheng-Prussoff equation.
TABLE-US-00001 Example No pKi hV1a 1 8.05 2 8.59 3 8.74 4 8.89 5
7.93 6 8.5 7 7.93 8 7.9 10 8.17 13 7.85 14 8.18 15 8.68 17 7.71 18
7.68
[0437] The present invention also provides pharmaceutical
compositions containing compounds of the invention, for example
compounds of formulae (I-a) to (1-e), or pharmaceutically
acceptable salts thereof and a pharmaceutically acceptable carrier.
Such pharmaceutical compositions can be in the form of tablets,
coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The pharmaceutical
compositions also can be in the form of suppositories or injectable
solutions.
[0438] The pharmaceutical compositions of the invention, in
addition to one or more compounds of the invention, contain a
pharmaceutically acceptable carrier. Suitable pharmaceutically
acceptable carriers include pharmaceutically inert, inorganic or
organic carriers. Lactose, corn starch or derivatives thereof,
talc, stearic acid or its salts etc can be used as such excipients
e.g. for tablets, dragees and hard gelatine capsules. Suitable
excipients for soft gelatine capsules are e.g. vegetable oils,
waxes, fats, semi-solid and liquid polyols etc. Suitable excipients
for the manufacture of solutions and syrups are e.g. water,
polyols, saccharose, invert sugar, glucose etc. Suitable excipients
for injection solutions are e.g. water, alcohols, polyols,
glycerol, vegetable oils etc. Suitable excipients for suppositories
are e.g. natural or hardened oils, waxes, fats, semi-liquid or
liquid polyols etc.
[0439] Moreover, the pharmaceutical compositions can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0440] The dosage at which compounds of the invention can be
administered can vary within wide limits and will, of course, be
fitted to the individual requirements in each particular case. In
general, in the case of oral administration a daily dosage of about
10 to 1000 mg per person of a compound of general formula (I)
should be appropriate, although the above upper limit can also be
exceeded when necessary.
[0441] The following Examples illustrate the present invention
without limiting it. All temperatures are given in degrees
Celsius.
EXAMPLE A
[0442] Tablets of the following composition can be manufactured in
the usual manner:
TABLE-US-00002 mg/tablet Active substance 5 Lactose 45 Corn starch
15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight
100
EXAMPLE B
[0443] Capsules of the following composition can be
manufactured:
TABLE-US-00003 mg/capsule Active substance 10 Lactose 155 Corn
starch 30 Talc 5 Capsule fill weight 200
[0444] The active substance, lactose and corn starch can be firstly
mixed in a mixer and then in a comminuting machine. The mixture can
be returned to the mixer, the talc can be added thereto and mixed
thoroughly. The mixture can be filled by machine into hard gelatine
capsules.
EXAMPLE C
[0445] Suppositories of the following composition can be
manufactured:
TABLE-US-00004 mg/supp. Active substance 15 Suppository mass 1285
Total 1300
[0446] The suppository mass can be melted in a glass or steel
vessel, mixed thoroughly and cooled to 45.degree. C.
[0447] Thereupon, the finely powdered active substance can be added
thereto and stirred until it has dispersed completely. The mixture
can be poured into suppository moulds of suitable size, left to
cool; the suppositories then can be removed from the moulds and
packed individually in wax paper or metal foil.
[0448] In the following, the synthesis of compounds of formula (I)
is further exemplified:
The compounds of formula I may be prepared in accordance with the
process variants as described above. The starting materials
described in the Example section are either commercially available
or are otherwise known or derived from the chemical literature, for
instance as cited below, or may be prepared as described in the
Examples section.
EXAMPLES
Acid intermediates of formula II and II-1
Acid 1
6-Chloro-1H-indole-3-carboxylic acid
a) 1-(6-Chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
[0449] To a solution of 1.0 g (6.6 mmol) 6-chloroindole in 13 ml
DMF were added dropwise at 0.degree. C. 2.75 ml (19.8 mmol)
trifluoroacetic anhydride. Stirring at this temperature for 90 min.
was followed by quenching with 30 ml of a 2 M aqueous solution of
sodium carbonate, dilution with 50 ml water and extraction with
three 100-ml portions of tert-butyl methyl ether. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated to give 1.3 g (80%) of the crude title compound as an
off-white solid. ES-MS m/e (%): 246 (M-H.sup.+).
b) 6-Chloro-1H-indole-3-carboxylic acid
##STR00014##
[0451] A mixture of 1.3 g (5.3 mmol)
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone and 26.5 ml of
a 4 M aqueous solution of sodium hydroxide was heated at reflux for
4.5 h. The mixture was cooled to room temperature and washed with
two 100-ml portions of tert-butyl methyl ether. The aqueous layer
was acidified to pH 2-3 by addition of concentrated hydrochloric
acid solution at 0.degree. C. Extraction with three 100-ml portions
of tert-butyl methyl ether, drying over sodium sulfate, filtration
and concentration in vacuo gave 0.80 g (78%) of the crude title
compound as a brown solid.
[0452] ES-MS m/e (%): 194 (M-H.sup.+).
Acid 2
6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid
a)
1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-etha-
none
[0453] A mixture of 2.0 g (9.4 mmol)
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 4.59 g (14.1
mmol) cesium carbonate and 2.14 g (10.4 mmol) 3,5-difluorobenzyl
bromide in 90 ml acetonitrile was heated at 80.degree. C. for 3 h.
After cooling to room temperature addition of 150 ml water was
followed by extraction with three 150-ml portions of tert-butyl
methyl ether. The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
triturated in 30 ml hot cyclohexane. Filtration gave 2.2 g (64%) of
the crude title compound as light brown solid.
[0454] ES-MS m/e (%): 372 (M-H.sup.+).
b) 6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid
##STR00015##
[0456] To a solution of 2.2 g (6.5 mmol)
1-[6-chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethano-
ne in 65 ml DMF were added 1.7 g (36 mmol) sodium hydride (50% in
oil) at room temperature. After stirring for 5 min. 0.59 ml (33
mmol) water were added dropwise. Stirring was continued at room
temperature for 45 min. The reaction mixture was diluted with 150
ml of tert-butyl methyl ether and extracted with two 150-ml
portions of a 1 M aqueous solution of sodium hydroxide. The
combined aqueous layers were acidified to pH 1 with concentrated
hydrochloric acid solution and extracted with three 150-ml portions
of ethyl acetate. The combined organic extracts were dried over
sodium sulfate, filtered and concentrated in vacuo. The residue was
dried in high vacuo at 80.degree. C. to give 2.0 g (95%) of the
crude title compound as a brown solid.
[0457] ES-MS m/e (%): 320 (M-H.sup.+).
Acid 3
6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid
##STR00016##
[0458] a)
2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acet-
amide
[0459] Following general procedure II, the alkylation of
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, with
(commercially available) 2-chloro-N-methyl-acetamide gave the title
compound.
[0460] ES-MS m/e (%): 319.3 (M+H.sup.+).
b) 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid
[0461]
2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetami-
de was suspensed in DCE and treated with (2.2 eq.) of sodium
trimethylsilanolate. After shaking at room temperature for 20 min,
the mixture was concentrated in vacuo and purified by prep. HPLC to
give the title compound in 27% yield.
[0462] ES-MS m/e (%): 265.0 (M-H.sup.+).
Acid 4
6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid
##STR00017##
[0463] a)
2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl--
acetamide
[0464] To a stirred solution of
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20
ml of DMF at 0.degree. C., were added 128 mg (1.1 eq.) of NaH (60%
in oil). The mixture was stirred for 30 min. and then 0.32 ml (1.1
eq.) of dimethylamino-acetyl chloride were added. The mixture was
stirred an additional hour and then poured onto water and extracted
with ethyl acetate. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to afford 598 mg (61%)
of
2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide
as a white solid.
b) 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic
acid
[0465] Using the procedure described for the preparation of
6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid, from
0.50 g of
2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimeth-
yl-acetamide were prepared 0.38 g (76%) of
6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid as a
white solid.
Acid 5
6-Chloro-2-methyl-1H-indole-3-carboxylic acid
a) (6-Chloro-1H-indol-2-yl)-methanol
[0466] To a solution of 2.00 g (8.94 mmol)
6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether
were added 0.475 g (12.5 mmol) lithium aluminum hydride at
0.degree. C. The reaction mixture was heated at reflux for 45 min
and quenched by consecutive addition of 10 ml water, 10 ml aqueous
2 M sodium hydroxide solution and 10 ml water at 0.degree. C. The
aqueous layer was extracted with tert-butyl methyl ether
(3.times.100 ml). The combined organic layers were dried over
sodium sulfate and concentrated in vacuo to give the crude title
compound (1.64 g; 100%) as a white solid.
[0467] MS m/e (%): 180 (M-H.sup.+, 100).
b) 6-Chloro-2-methyl-1H-indole
[0468] A solution of 1.60 g (8.81 mmol)
(6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was
added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml
triethylsilane at 65.degree. C. After 5 min, the reaction mixture
was cooled to room temperature and quenched with water. The pH was
adjusted to 14 by the addition of aqueous sodium hydroxide solution
(32%). The aqueous layer was extracted with tert-butyl methyl ether
(3.times.200 ml). The combined organic layers were dried over
sodium sulfate and concentrated in vacuo. The residue was purified
by flash-chromatography (aminopropyl-modified silica gel,
n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%)
as a white solid.
[0469] MS m/e (%): 164 (M-H.sup.+, 100).
c) 1-(6-Chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone
[0470] To a solution of 0.38 g (2.3 mmol)
6-chloro-2-methyl-1H-indole in 20 ml 1,2-dichloroethane at
0.degree. C. were added 0.35 ml (2.5 mmol) trifluoroacetic
anhydride. The reaction mixture was quenched with aqueous 2 M
sodium carbonate solution after 30 min and extracted with
dichloromethane (3.times.100 ml). The combined organic layers were
dried over sodium sulfate and concentrated in vacuo to give the
title compound (0.57 g; 95%) as an off-white solid.
[0471] MS m/e (%): 260 (M-H.sup.+, 100).
d) 6-Chloro-2-methyl-1H-indole-3-carboxylic acid
##STR00018##
[0473] A solution of 0.57 g (2.2 mmol)
1-(6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in
21.7 ml (86.8 mmol) aqueous 4 M sodium hydroxide solution was
heated at reflux for 45 min. After cooling to room temperature the
reaction mixture was diluted with water and extracted with
tert-butyl methyl ether (2.times.50 ml). The aqueous layer was
cooled to 0-5.degree. C., acidified (pH 1-2) with concentrated
aqueous hydrochloric acid solution and extracted with ethyl acetate
(3.times.100 ml). The combined ethyl acetate layers were dried over
sodium sulfate and concentrated in vacuo to give the title compound
(0.14 g, 31%) as an off-white solid.
[0474] MS m/e (%): 208 (M-H.sup.+, 100).
Acid 6
1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carbox-
ylic acid
a)
{2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic
acid tert-butyl ester
[0475] To a solution of 11.5 g (46.4 mmol)
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml
N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol)
potassium tert-butylate. The temperature was kept below 32.degree.
C. The reaction mixture was allowed to cool to room temperature and
stirred for 20 min. To the resulting brown suspension were added
slowly 12.4 g (55.7 mmol)
2,2-dioxo-2.lamda..sup.6-[1,2,3]oxathiazolidine-3-carboxylic acid
tert-butyl ester. The reaction mixture was stirred at room
temperature until complete consumption of
1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was
monitored by thin layer chromatography. Dilution with 300 ml
tert-butyl methyl ether was followed by washing with 250 ml of a
0.2 M aqueous solution of hydrochloric acid. The aqueous layer was
extracted with two 200-ml portions of tert-butyl methyl ether. The
combined organic layers were washed with water and brine, dried
over sodium sulfate and concentrated in vacuo. The residue, 19.5 g
of a light brown solid, was triturated with 300 ml of warm
tert-butyl methyl ether. After cooling to room temperature the
precipitate was collected by filtration, washed with cold
tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of
the title compound as an off-white solid. The filtrate was
concentrated to dryness. The residue was triturated with 50 ml warm
tert-butyl methyl ether. After cooling to room temperature the
precipitate was collected by filtration, washed with cold
tert-butyl methyl ether and dried in vacuo to give another 3.5 g
(19%) of the title compound as an off-white solid.
[0476] MS m/e (%): 387 (M-H.sup.+, 87).
b)
{2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carba-
mic acid tert-butyl ester
[0477] To a solution of 14.1 g (36.1 mmol)
{2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic
acid tert-butyl ester in 360 ml dry tetrahydrofuran were slowly
added 44 ml (40 mmol) of a 0.91 M solution of potassium
hexamethyldisilazide in tetrahydrofuran at -78.degree. C. After
stirring for 20 min. were added 2.5 ml (40 mmol) iodomethane at
-78.degree. C. Stirring was continued for 15 min. at -78.degree. C.
The cooling bath was removed and the mixture was stirred for
another 3 h at room temperature. Quenching with water was followed
by evaporation of the solvent in a rotary evaporator. The residue
was diluted with a mixture of 200 ml water and 100 ml of a
saturated aqueous solution of ammonium chloride. After extraction
with three 250-ml portions of tert-butyl methyl ether the combined
organic extracts were washed with 200 ml of an ice-cold 0.2 M
aqueous solution of hydrochloric acid and 100 ml brine, dried over
sodium sulfate and concentrated in vacuo to give 14.9 g of the
crude product as a brown oil.
[0478] MS m/e (%): 349 ((M-C4H8)+H.sup.+, 100).
c)
1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-car-
boxylic acid
##STR00019##
[0480] To a solution of 15.4 g (38.0 mmol) crude
{2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carbami-
c acid tert-butyl ester in 380 ml N,N-dimethylformamide were slowly
added 11.0 g (228 mmol) sodium hydride (50%, dispersion in oil)
followed by 3.40 ml (190 mmol) water at 15-22.degree. C. After
stirring for 1 h at room temperature 500 ml water were added
slowly. The mixture was washed with two 300-ml portions of
tert-butyl methyl ether. The combined organic layers were extracted
with 300 ml of a 0.5 M aqueous solution of sodium hydroxide. The
combined aqueous layers were acidified to pH 2 with an ice-cold 4 M
aqueous solution of hydrochloric acid at 0-5.degree. C. and
extracted with two 400-ml portions of ethyl acetate.
[0481] The organic extracts were dried over sodium sulfate and
concentrated in vacuo to give 11.3 g (84.3%) of the title compound
as a light yellow solid.
[0482] MS m/e (%): 351 (M-H.sup.+, 100).
EXAMPLES
Amide Coupling
General Procedure I:
[0483] To a stirred solution of an indole-3-carboxylic acid
derivative (1 mmol) in 10 ml CH.sub.2Cl.sub.2 are added (1.3 mmol)
EDC, (1.3 mmol) HOBt, (1.3 mmol) triethylamine and (1 mmol) of the
amine derivative. The mixture is stirred overnight at RT and then
poured onto water and extracted with CH.sub.2Cl.sub.2. The combined
organic phases are dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. Flash chromatography or preparative HPLC affords an amide
derivative of formula (I).
General Procedure II:
[0484] To a solution of an indole-3-carboxylic acid derivative
(0.13 mmol), N-ethyl diisopropyl amine (0.14 mmol) and TBTU or HATU
(0.14 mmol) in 2 ml dry N,N-dimethylformamide is added the amine
derivative (0.14 mmol) at RT. The reaction mixture is quenched with
0.5 M aqueous sodium hydroxide (20 ml) after 2 h and extracted with
ethyl acetate (2.times.30 ml). The combined organic layers are
washed with water (2.times.30 ml) and brine (1.times.30 ml), dried
over sodium sulfate and concentrated to dryness. Flash
chromatography or preparative HPLC affords an amide derivative of
formula (I).
Indole-N-alkylation:
General Procedure III:
[0485] To a stirred solution of an indole of formula (I-1) wherein
R.sup.1 is H in DMF are added 2. 1 eq. NaH (60% in oil). The
mixture is stirred at RT for 30 min. and then the electrophilic
reagent R.sup.1-Z (1.1 eq.) is added. The mixture is stirred an
additional 14 hours at 60.degree. C. and then poured onto water and
extracted with ethyl acetate. The combined organic phases are dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by
preparative HPLC affords compounds of formula (I) with R.sup.1
different from H.
Example 1
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-o-
ne
##STR00020##
[0487] Amide coupling according to general procedure I:
[0488] Amine: 1-Piperidin-4-yl-1,3-dihydro-indol-2-one,
[0489] Acid: 6-Chloro-1H-indole-3-carboxylic acid,
[0490] ES-MS m/e (%): 393.9 (M+H.sup.+).
Example 2
1-{1-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-piperidin-4-y-
l}-1,3-dihydro-indol-2-one
##STR00021##
[0492] To a suspension of 0.10 g (0.31 mmol)
6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid and
one drop of DMF in 2 ml dichloromethane were added dropwise at
0.degree. C. 0.032 ml (0.37 mmol) oxalyl chloride. The mixture was
allowed to warm to room temperature, stirred for 1 h and
subsequently added dropwise to a solution of 74 mg (0.34 mmol)
1-piperidin-4-yl-1,3-dihydro-indol-2-one and 63 mg (0.62 mmol)
triethylamine in 1 ml dichloromethane at room temperature. After
stirring over night the reaction mixture was concentrated and the
residue was purified by flash chromatography to give 78 mg (48%) of
the title compound as a light yellow solid.
[0493] ES-MS m/e (%): 521 (M+H.sup.+).
Example 3
2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-ind-
ol-1-yl}-N-methyl-acetamide
##STR00022##
[0495] Amide coupling according to general procedure II:
[0496] Amine: 1-Piperidin-4-yl-1,3-dihydro-2H-indol-2-one,
[0497] Acid:
6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid,
[0498] ES-MS m/e (%): 465 (M+H.sup.+, 100).
Example 4
2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbonyl-
}-1H-indol-1-yl)-N,N-dimethylacetamide
##STR00023##
[0500] Amide coupling according to general procedure I:
[0501] Amine: 1-Piperidin-4-yl-1,3-dihydro-indol-2-one (CAS:
16223-25-9),
[0502] Acid:
6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,
[0503] ES-MS m/e (%):479.2 (M+H.sup.+).
Example 5
2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-ind-
ol-1-yl}-N,N-diethyl-acetamide
##STR00024##
[0505] A solution of
1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydroindol-2-o-
ne (1 eq) in dry DMF was treated with NaH (1.1 eq) at RT for 15
mins and then a solution of 2-chloro-N,N-diethyl-acetamide (3.3 eq)
and triethylamine (3.3 eq) in three portions and the mixture heated
to 60.degree. C. for 6 h. Concentration and purification by prep
HPLC gave the title compound.
[0506] ES-MS m/e (%): 507.5 (M+H.sup.+).
Example 6
N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbo-
nyl}-1H-indol-1-yl)ethyl]methanesulfonamide
##STR00025##
[0507] a)
1-{1-[1-(2-Amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-
-4-yl}-1,3-dihydro-indol-2-one
[0508] A solution of
1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one (1 eq) in dry DMF was treated with NaH (1.1 eq) at 0.degree. C.
for 60 min. and then a solution of
2,2-dioxo-2.lamda.6-[1,2,3]oxathiazolidine-3-carboxylic acid
tert-butyl ester (1.1 eq) and triethylamine (1.1 eq) in dry DMF was
added and the mixture stirred at RT for 2 h. After concentration
the mixture was treated with 4 M HCl in dioxan (5 eq) at 50.degree.
C. for 1 h, evaporated to dryness and partitioned between ethyl
acetate and 1 N NaHCO.sub.3. The organic layer was washed with
brine, separated, evaporated and the crude product chromatographed
on silica gel (CH.sub.2Cl.sub.2-MeOH) to give the title
compound.
[0509] ES-MS m/e (%): 437.0 (M+H.sup.+).
b)
N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]ca-
rbonyl}-1H-indol-1-yl)ethyl]methanesulfonamide
[0510] A solution of
1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,-
3-dihydro-indol-2-one (1 eq) in dry CH.sub.2Cl.sub.2 was treated
with methanesulfonyl chloride (1.1 eq) and triethylamine at RT for
15 h. Quenching with H.sub.2O and extraction into CH.sub.2Cl.sub.2
followed by concentration and purification by prep HPLC gave the
title compound.
[0511] ES-MS m/e (%):515.2 (M+H.sup.+).
Example 7
N-[2-(6-Chloro-3-{[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]carbo-
nyl}-1H-indol-1-yl)ethyl]acetamide
##STR00026##
[0513] A solution of
1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,-
3-dihydro-indol-2-one (1 eq) in dry CH.sub.2Cl.sub.2 was treated
with acetyl chloride (1.1 eq) and triethylamine at RT for 15 h.
Quenching with H.sub.2O and extraction into CH.sub.2Cl.sub.2
followed by concentration and purification by prep HPLC gave the
title compound.
[0514] ES-MS m/e (%):479.2 (M+H.sup.+).
Example 8
1-[1-(6-Chloro-2-methyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro--
indol-2-one
##STR00027##
[0516] Amide coupling according to general procedure II:
[0517] Amine: 1-Piperidin-4-yl-1,3-dihydro-2H-indol-2-one,
[0518] Acid: 6-Chloro-2-methyl-1H-indole-3-carboxylic acid,
[0519] ES-MS m/e (%): 406 (M-H.sup.+, 100).
Example 9
3-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-3H-benzooxazol-2-one
##STR00028##
[0521] Amide coupling according to general procedure II:
[0522] Amine: 3-Piperidin-4-yl-3H-benzooxazol-2-one (preparation
described in WO 95/28397),
[0523] Acid: 6-Chloro-1H-indole-3-carboxylic acid,
[0524] ES-MS m/e (%): 394 (M-H.sup.+, 100).
Example 10
2-{6-Chloro-3-[4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carbonyl]-indol-1-y-
l}-N-methyl-acetamide
##STR00029##
[0526] Amide coupling according to general procedure II:
[0527] Amine: 3-Piperidin-4-yl-3H-benzooxazol-2-one (preparation
described in WO 95/28397),
[0528] Acid:
6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid,
[0529] ES-MS m/e (%): 467 (M+H.sup.+, 100).
Example 11
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-o-
ne
##STR00030##
[0531] Amide coupling according to general procedure I:
[0532] Amine:
(4-Benzotriazol-1-yl-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone,
[0533] Acid: 6-Chloro-1H-indole-3-carboxylic acid,
[0534] ES-MS m/e (%): 380.4 (M+H.sup.+).
Example 12
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol--
1-yl)-N-methylacetamide
##STR00031##
[0536] Amide coupling according to general procedure I:
[0537] Amine:
1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one,
[0538] Acid:
6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid,
[0539] ES-MS m/e (%):451.2 (M+H.sup.+).
Example 13
2-(3-{[4-(1H-Benzotriazol-1-yl)piperidin-1-yl]carbonyl}-6-chloro-1H-indol--
1-yl)-N,N-dimethylacetamide
##STR00032##
[0541] Amide coupling according to general procedure I:
[0542] Amine: 1-Piperidin-4-yl-1H-benzotriazole,
[0543] Acid:
6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,
[0544] ES-MS m/e (%):465.1 (M+H.sup.+).
Example 14
1-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-y-
l}-1,3-dihydro-indol-2-one hydrochloride
a)
(2-{6-Chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-
-indol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester
[0545] To a solution of 0.20 g (0.57 mmol)
1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carbo-
xylic acid, 0.11 ml (0.63 mmol) N,N-diisopropylethylamine and 2
drops of N,N-dimethylformamide in 4 ml dicholormethane were added
0.060 ml (0.74 mmol) oxalyl chloride at 0-5.degree. C. After
completed addition the reaction mixture was allowed to warm to room
temperature and stirred for 3 h. A solution of 0.15 g (0.68 mmol)
1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and 0.11 ml (0.63
mmol) N,N-diisopropylethylamine in 2 ml dicholormethane was added.
After stirring for 15 min at room temperature silica gel was added
to the reaction mixture and the solvent was evaporated in vacuo.
The residue was transferred to a silica gel column. Elution gave
0.26 g (82%) of the title compound as an off-white solid.
[0546] ES-MS m/e (%): 551 (M+H.sup.+, 39).
b)
1-{1-[6-Chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin--
4-yl}-1,3-dihydro-indol-2-one hydrochloride
##STR00033##
[0548] A solution of 0.25 g (0.45 mmol)
(2-{6-chloro-3-[4-(2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carbonyl]-i-
ndol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester in 3.6 ml
(4.5 mmol) of a 1.25 M solution of hydrochloric acid in methanol
was stirred for 20 min. at 50.degree. C. The reaction mixture was
concentrated to dryness to give 0.21 g of the title compound as an
off-white solid.
[0549] ES-MS m/e (%): 451 (M+H.sup.+, 100).
Example 15
1-{1-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-
-yl}-1,3-dihydro-indol-2-one
##STR00034##
[0551] A suspension of 0.40 g (1.0 mmol)
1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2--
one, 0.16 g (1.1 mmol) 1-chloro-2-dimethylaminoethane hydrochloride
and 0.69 g (2.1 mmol) cesium carbonate in 10 ml acetonitrile was
heated at 50.degree. C. over night. After cooling to room
temperature the reaction mixture was diluted with a 0.5 M aqueous
solution of sodium hydroxide and extracted with three portions of
ethyl acetate. The combined organic extracts were washed with
brine, dried over sodium sulfate and concentrated in vacuo. Flash
chromatography gave 0.18 g (39%) of the title compound.
[0552] ES-MS m/e (%): 466 (M+H.sup.+, 100).
Example 16
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H--
indol-3-yl]-methanone hydrochloride
##STR00035##
[0554] The title compound was prepared according to the procedures
described for the preparation of
1-{1-[6-chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4--
yl}-1,3-dihydro-indol-2-one hydrochloride using
1-(4-piperidyl)-1H-1,2,3-benzotriazole hydrochloride instead of
1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and a total of 3.2
molar equivalents of N,N-diisopropylethylamine instead of 2.2 molar
equivalents in step a).
[0555] ES-MS m/e (%): 437 (M+H.sup.+, 100).
Example 17
(4-Benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-ethyl)-1-
H-indol-3-yl]-methanone
##STR00036##
[0556] and
Example 18
(4-Benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydro-
-pyrazino[1,2-a]indol-10-yl)-methanone
##STR00037##
[0558] A mixture of 0.20 g (0.41 mmol)
(4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-methylamino-ethyl)-1H-
-indol-3-yl]-methanone hydrochloride, 0.057 ml (0.41 mmol)
triethylamine and 0.10 g (3.3 mmol) paraformaldehyde in 4 ml
methanol was heated at reflux for 7 h. After cooling to 0.degree.
C., 0. were added 052 g (0.82 mmol) sodium cyanoborohydride. The
cooling bath was removed and the reaction mixture was stirred at
room temperature for 16 h. Quenching with 1 M aqueous sodium
hydroxide solution was followed by extraction with two portions of
ethyl acetate. The combined organic extracts were dried over sodium
sulfate and concentrated in vacuo. Flash chromatography gave 0.040
g (22%)
(4-benzotriazol-1-yl-piperidin-1-yl)-[6-chloro-1-(2-dimethylamino-
-ethyl)-1H-indol-3-yl]-methanone as a white solid (ES-MS m/e (%):
451 (M+H.sup.+, 100)) and 0.11 g (60%)
(4-benzotriazol-1-yl-piperidin-1-yl)-(7-chloro-2-methyl-1,2,3,4-tetrahydr-
o-pyrazino[1,2-a]indol-10-yl)-methanone as a white solid (ES-MS m/e
(%): 449 (M+H, 100)).
* * * * *