U.S. patent application number 11/947967 was filed with the patent office on 2008-06-12 for spiro-piperidine derivatives.
Invention is credited to Caterina Bissantz, Christophe Grundschober, Raffaello Masciadri, Hasane Ratni, Mark Rogers-Evans, Patrick Schnider.
Application Number | 20080139554 11/947967 |
Document ID | / |
Family ID | 39295880 |
Filed Date | 2008-06-12 |
United States Patent
Application |
20080139554 |
Kind Code |
A1 |
Bissantz; Caterina ; et
al. |
June 12, 2008 |
SPIRO-PIPERIDINE DERIVATIVES
Abstract
The present invention is concerned with novel
indol-2-yl-carbonyl-spiro-piperidine derivatives as V1a receptor
antagonists, their manufacture, pharmaceutical compositions
containing them and their use for the treatment of anxiety,
depressive disorders and other diseases. The compounds of present
invention are represented by the general formula (I) ##STR00001##
wherein R.sup.1 to R.sup.1, X and Y are as defined 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, CH) ; Schnider; Patrick;
(Bottmingen, CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
39295880 |
Appl. No.: |
11/947967 |
Filed: |
November 30, 2007 |
Current U.S.
Class: |
514/235.2 ;
514/253.03; 514/291; 514/292; 544/230; 544/70; 546/18 |
Current CPC
Class: |
A61P 15/08 20180101;
A61P 1/16 20180101; C07D 491/10 20130101; A61P 25/22 20180101; A61P
13/12 20180101; C07D 519/00 20130101; A61P 9/12 20180101; A61P
25/00 20180101; C07D 471/10 20130101; A61P 9/00 20180101; A61P
43/00 20180101; A61P 25/24 20180101; A61P 9/04 20180101 |
Class at
Publication: |
514/235.2 ;
514/292; 546/18; 514/291; 514/253.03; 544/70; 544/230 |
International
Class: |
A61K 31/438 20060101
A61K031/438; C07D 401/14 20060101 C07D401/14; A61K 31/496 20060101
A61K031/496; A61K 31/5377 20060101 A61K031/5377 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 7, 2006 |
EP |
06125634.3 |
Claims
1. A compound of the general formula (I) ##STR00073## wherein X and
Y are selected from the combinations of: X-Y is --C.dbd.C-- or
--CH.sub.2CH.sub.2--; R.sup.1 is hydrogen, C.sub.1-6-alkyl,
optionally substituted by CN or OH, or
--(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b; R.sup.2 is hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
--(C.sub.1-6-alkylene)-NR.sup.cR.sup.d,
--(C.sub.1-6-alkylene)-C(O)R.sup.f, benzyl, optionally subsitituted
by one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano, or
phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; R.sup.3 is hydrogen, halo,
or C.sub.1-6-alkyl; R.sup.4 is hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, or
--O--C.sub.2-10-alkenyl R.sup.5 is hydrogen, halo, C.sub.1-6-alkyl,
or C.sub.1-6-alkoxy; or R.sup.4 and R.sup.5 are bound together to
form a ring with the benzo moiety, wherein --R.sup.4--R.sup.5-- is
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; R.sup.6 is
hydrogen, C.sub.1-6-alkyl, optionally substituted by CN or OH,
--(C.sub.1-6-alkylene)-NR.sup.gR.sup.h,
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, --O-benzyl,
optionally subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, nitro, halo, cyano, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkyl, --(C.sub.1-6-alkylene)-C(O)R.sup.f, phenyl,
optionally subsitituted by halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, --(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a
5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3
to 6-membered cycloalkyl, each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; or R.sup.5 and R.sup.6 are
bound together to form a ring with the benzo moiety, wherein
--R.sup.5--R.sup.6 is --O--(CH.sub.2).sub.n--C(O)--,
--C(O)--(CH.sub.2).--O--, or --O--(CH.sub.2), --O-- wherein n is 1
or 2; R.sup.7 is hydrogen or C.sub.1-6-alkyl; R.sup.8, R.sup.9,
R.sup.10, and R.sup.11 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
halo-C.sub.1-6alkoxy; R.sup.a, R.sup.b, R.sup.i and R.sup.j are
each independently hydrogen, C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-NR.sup.kR.sup.l, wherein R.sup.k and R.sup.l
are each independently hydrogen or C.sub.1-6-alkyl, or R.sup.a and
R.sup.b, or R.sup.i and R.sup.j 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; R.sup.c, R.sup.d, R.sup.g and R.sup.h are each
independently hydrogen, C.sub.1-6-alkyl, --C(O)R.sup.e, or
--S(O).sub.2R' wherein R.sup.e is selected from the group of
hydrogen, C.sub.1-6-alkyl, and phenyl, optionally substituted by
one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; or
R.sup.c and R.sup.d, or R.sup.g and R.sup.h 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; or R.sup.c and R.sup.d, or
R.sup.g and R.sup.h together with the nitrogen to which they are
bound form isoindole-1,3-dione; R.sup.f is selected from hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy; or phenyl, optionally
substituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R.sup.a and R.sup.b, R.sup.c
and R.sup.d, R.sup.i and R.sup.j, or R.sup.g and R.sup.h together
with the nitrogen atom to which they are attached form piperazine,
4-(C.sub.1-6-alkyl)-piperazine, 4-methylpiperazine, morpholine,
piperidine or pyrrolidine.
3. The compound of claim 1, wherein R.sup.a and R.sup.b, R.sup.c
and R.sup.d, R.sup.i and R.sup.j, or R.sup.g and R.sup.h together
with the nitrogen atom to which they are attached form
4-methylpiperazine or morpholine.
4. The compound of claim 1, wherein R.sup.m is a 5- to 6-memered
heteroaryl selected from the group consisting of pyridine,
pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, and
isoxazole.
5. The compound of claim 1, wherein R.sup.m is a 4- to 6-membered
heterocycloalkyl group selected from the group consisting of
pyrrolidine, oxethane, tetrahydropyrane, piperidine, morpholine,
and piperazine.
6. The compound of claim 1, wherein R.sup.1 is hydrogen,
C.sub.1-6-alkyl, optionally substituted by CN or OH, or
--(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, wherein R.sup.a and
R.sup.b are each independently hydrogen or C.sub.1-6-alkyl.
7. The compound of claim 1, wherein R.sup.2 is hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
--(C.sub.1-6-alkylene)-NR.sup.cR.sup.d, wherein R.sup.c and R.sup.d
are each independently hydrogen, --C(O)R.sup.e, or --S(O).sub.2R'
wherein R.sup.e is selected from the group of hydrogen,
C.sub.1-6-alkyl, or phenyl, optionally substituted by one or more
halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, or R.sup.cC and R.sup.d
together with the nitrogen to which they are bound form
isoindole-1,3-dione, --(C.sub.1-6-alkylene)-C(O)R.sup.f, wherein
R.sup.f is selected from hydrogen, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, or phenyl, optionally substituted by one or more
halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; benzyl, optionally
subsitituted by halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano, or
phenyl, optionally subsitituted by halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano.
8. The compound of claim 1, wherein R.sup.3 is hydrogen,
C.sub.1-6-alkyl or C.sub.1-6-alkoxy.
9. The compound of claim 1, wherein R.sup.3 is hydrogen or
halo.
10. The compound of claim 1, wherein R.sup.4 is hydrogen, halogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, and
O--C.sub.2-10-alkenyl.
11. The compound of claim 1, wherein R.sup.5 is hydrogen, halogen,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy.
12. The compound of claim 1, wherein R.sup.4 and R.sup.5 together
are --O--CH.sub.2--O--.
13. The compound of claim 1, wherein R.sup.6 is hydrogen,
C.sub.1-6-alkyl, optionally substituted by CN or OH,
--(C.sub.1-6-alkylene)-NR.sup.8R'' wherein R.sup.g and R.sup.h are
each independently selected from hydrogen, or C.sub.1-6-alkyl; or
wherein R.sup.g and R.sup.h 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; --(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j wherein
R.sup.i and R.sup.j are each independently hydrogen;
C.sub.1-6-alkyl; --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l; wherein
R.sup.k and R.sup.l are each independently hydrogen or
C.sub.1-6-alkyl; or R.sup.i and R.sup.j 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; --O-benzyl, optionally subsitituted by
one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C-.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; nitro;
halo; cyano; C.sub.1-6-alkoxy; halo-C.sub.1-6-alkoxy;
halo-C.sub.1-6-alkyl; --(C.sub.1-6-alkylene)-C(O)R.sup.f; wherein
R.sup.f is selected from the group of hydrogen; C.sub.1-6-alkyl;
C.sub.1-6-alkoxy; or phenyl, optionally substituted by one or more
halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, phenyl, optionally
subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano; --(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a
5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3
to 6-membered cycloalkyl, each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano.
14. The compound of claim 1, wherein R.sup.6 is hydrogen,
C.sub.1-6-alkyl, optionally substituted by CN or OH,
--(C.sub.1-6-alkylene)-NR.sup.8R'', wherein R.sup.g and R.sup.h are
each independently selected from hydrogen, or C.sub.1-6-alkyl, or
wherein R.sup.g and R.sup.h 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 and
oxygen, --(C.sub.1-6-alkylene)-C(O)--NR.sup.kR.sup.l, wherein
R.sup.i and R.sup.j are each independently hydrogen,
C.sub.1-6-alkyl, --(C.sub.1-6-alkylene)-NR.sup.kR.sup.I, wherein
R.sup.k and R.sup.l are each independently hydrogen or
C.sub.1-6-alkyl; or R.sup.i and R.sup.j 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 and oxygen.
15. The compound of claim 1, wherein R.sup.7 is hydrogen or
alkyl.
16. The compound of claim 1, wherein R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are hydrogen.
17. The compound of claim 1, wherein R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are each independently hydrogen or halogen.
18. The compound of claim 1, wherein R.sup.9 is fluoro and R.sup.8,
R.sup.10, and R.sup.11 are hydrogen.
19. The compound of claim 1, wherein R.sup.8, R.sup.9, and R.sup.11
are hydrogen and R.sup.10 is bromo.
20. The compound of claim 1, wherein R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are each independently hydrogen or methyl.
21. The compound of claim 1, wherein R.sup.8, R.sup.9, and R.sup.10
are hydrogen and R.sup.11 is methyl.
22. The compound of claim 1, wherein the compound of formula (I) is
a compound of formula (If) ##STR00074##
23. The compound of claim 1, wherein the compound of formula (I) is
a compound of formula (Ig) ##STR00075##
24. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula (I), ##STR00076## wherein
X and Y are selected from the combinations of: X-Y is --C.dbd.C--
or --CH.sub.2CH.sub.2--; R.sup.1 is hydrogen, C.sub.1-6-alkyl,
optionally substituted by CN or OH, or
--(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b; R.sup.2 is hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
--(C.sub.1-6-alkylene)-NR.sup.cR.sup.d,
--(C.sub.1-6-alkylene)-C(O)R.sup.f, benzyl, optionally subsitituted
by one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano, or
phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; R.sup.3 is hydrogen, halo,
or C.sub.1-6-alkyl; R.sup.4 is hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, or
--O--C.sub.2-10-alkenyl R.sup.5 is hydrogen, halo, C.sub.1-6-alkyl,
or C.sub.1-6-alkoxy; or R.sup.4 and R.sup.5 are bound together to
form a ring with the benzo moiety, wherein --R.sup.4--R.sup.5-- is
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; R.sup.6 is
hydrogen, C.sub.1-6-alkyl, optionally substituted by CN or OH,
--(C.sub.1-6-alkylene)-NR.sup.gR.sup.h,
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, --O-benzyl,
optionally subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, nitro, halo, cyano, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkyl, --(C.sub.1-6-alkylene)-C(O)R.sup.f, phenyl,
optionally subsitituted by halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, --(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a
5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3
to 6-membered cycloalkyl, each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; or R.sup.5 and R.sup.6 are
bound together to form a ring with the benzo moiety, wherein
--R.sup.5--R.sup.6 is --O--(CH.sub.2).sub.n--C(O)--,
--C(O)--(CH.sub.2).--O--, or --O--(CH.sub.2), --O-- wherein n is 1
or 2; R.sup.7 is hydrogen or C.sub.1-6-alkyl; R.sup.8, R.sup.9,
R.sup.10, and R.sup.11 are each independently hydrogen, halo,
C.sub.1-6-alkyl, halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or
halo-C.sub.1-6alkoxy; R.sup.a, R.sup.b, R.sup.i and R.sup.j are
each independently hydrogen, C.sub.1-6-alkyl,
--(C.sub.1-6-alkylene)-NR.sup.kR.sup.l, wherein R.sup.k and R.sup.l
are each independently hydrogen or C.sub.1-6-alkyl, or R.sup.a and
R.sup.b, or R.sup.i and R.sup.j 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; R.sup.cC, R.sup.d, R.sup.g and R.sup.h are each
independently hydrogen, C.sub.1-6-alkyl, --C(O)R.sup.e, or
--S(O).sub.2R' wherein R.sup.e is selected from the group of
hydrogen, C.sub.1-6-alkyl, and phenyl, optionally substituted by
one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; or
R.sup.c and R.sup.d, or R.sup.g and R.sup.h 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; or R.sup.c and R.sup.d, or
R.sup.g and R.sup.h together with the nitrogen to which they are
bound form isoindole-1,3-dione; R.sup.f is selected from hydrogen,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy; or phenyl, optionally
substituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano; or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
25. The composition of claim 28, wherein the compound of formula
(I) is a compound of formula (If) ##STR00077##
26. The composition of claim 28, wherein the compound of formula
(I) is a compound of formula (Ig) ##STR00078##
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 06125634.3, filed Dec. 7, 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 T 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-2-yl-carbonyl-spiro-piperidine 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 and Y are selected from the combinations of:
[0008] X is C.dbd.O, and Y is O, [0009] X is CH.sub.2, and Y is O,
[0010] X is O, and Y is CH.sub.2, [0011] X is NR.sup.7, and Y is
C.dbd.O, [0012] X is NR.sup.7, and Y is CH.sub.2, or [0013] X-Y is
--C.dbd.C-- or --CH.sub.2CH.sub.2--; [0014] R.sup.1 is hydrogen,
[0015] C.sub.1-6-alkyl, optionally substituted by CN or OH, or
[0016] --(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, [0017] R.sup.2
is hydrogen, [0018] C.sub.1-6-alkyl, [0019] C.sub.1-6-alkoxy,
[0020] --(C.sub.1-6-alkylene)-NR.sup.cR.sup.d, [0021]
--(C.sub.1-6-alkylene)-C(O)R.sup.f, [0022] benzyl, optionally
subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, or [0023] phenyl, optionally subsitituted by one or more
halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0024] R.sup.3 is hydrogen,
halo, or C.sub.1-6-alkyl; [0025] R.sup.4 is hydrogen, [0026] halo,
[0027] C.sub.1-6-alkyl, [0028] halo-C.sub.1-6-alkyl, [0029]
C.sub.1-6-alkoxy, [0030] halo-C.sub.1-6-alkoxy, or [0031]
--O--C.sub.2-10-alkenyl; [0032] R.sup.5 is hydrogen, halo,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy; [0033] or R.sup.4 and R.sup.5
are bound together to form a ring with the benzo moiety, wherein
[0034] --R.sup.4--R.sup.5-- is --O--(CH.sub.2).sub.n--O-- wherein n
is 1 or 2; [0035] R.sup.6 is hydrogen, [0036] C.sub.1-6-alkyl,
optionally substituted by CN or OH, [0037]
--(C.sub.1-6-alkylene)-NR.sup.gR.sup.h, [0038]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, [0039] --O-benzyl,
optionally subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, [0040] nitro, [0041] halo, [0042] cyano, [0043]
C.sub.1-6-alkoxy, [0044] halo-C.sub.1-6-alkoxy, [0045]
halo-C.sub.1-6-alkyl, [0046] --(C.sub.1-6-alkylene)-C(O)R.sup.f,
[0047] phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, [0048]
--(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a 5- to
6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to
6-membered cycloalkyl, [0049] each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0050] or R.sup.5 and
R.sup.6 are bound together to form a ring with the benzo moiety,
wherein [0051] --R.sup.5--R.sup.6 is --O--(CH.sub.2).sub.n--C(O)--,
[0052] --C(O)--(CH.sub.2).sub.n--O--, or [0053]
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; [0054] R.sup.7 is
hydrogen or C.sub.1-6-alkyl; [0055] R.sup.8, R.sup.9, R.sup.10, and
R.sup.11 are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or halo-C.sub.1-6alkoxy;
[0056] R.sup.a, R.sup.b, R.sup.i and R.sup.j are each independently
hydrogen, [0057] C.sub.1-6-alkyl, [0058]
--(C.sub.1-6-alkylene)-NR.sup.kR.sup.l, [0059] wherein R.sup.k and
R.sup.l are each independently hydrogen or C.sub.1-6-alkyl, [0060]
or R.sup.a and R.sup.b, or R.sup.i and R.sup.j 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; [0061] R.sup.c, R.sup.d,
R.sup.g and R.sup.h are each independently [0062] hydrogen, [0063]
C.sub.1-6-alkyl, [0064] --C(O)R.sup.e, or --S(O).sub.2R' [0065]
wherein R.sup.e is selected from the group of [0066] hydrogen,
[0067] C.sub.1-6-alkyl, and [0068] phenyl, optionally substituted
by one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; [0069] or
R.sup.c and R.sup.d, or R.sup.g and R.sup.h 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; [0070] or R.sup.c and
R.sup.d, or R.sup.g and R.sup.h together with the nitrogen to which
they are bound form isoindole-1,3-dione; [0071] R.sup.f is selected
from the group of [0072] hydrogen, [0073] C.sub.1-6-alkyl, [0074]
C.sub.1-6-alkoxy; and [0075] phenyl, optionally substituted by one
or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; or a
pharmaceutically acceptable salt thereof.
[0076] 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.
[0077] 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. The invention also provides methods for treating
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
[0078] 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.
[0079] 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.
[0080] 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, and the like.
[0081] In the present description, the terms "alkoxy" and
"C.sub.1-6-alkoxy" refer to the group R'--O--, wherein R' is
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.
[0082] In the present description, the terms "thioalkyl" and
"C.sub.1-6-thioalkyl" refer to the group R'--S--, wherein R' is
C.sub.1-6-alkyl as defined above.
[0083] The terms "C.sub.1-6-hydroxyalkyl" and "C.sub.1-6-alkyl
substituted by OH" denote 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 hydroxyl group.
[0084] The term "C.sub.1-6-cyanoalkyl" or "C.sub.1-6-alkyl
substituted by CN" denotes 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.
[0085] The terms "halo" and "halogen" refer to fluorine (F),
chlorine (Cl), bromine (Br) and iodine (I) with fluorine, chlorine
and bromine being preferred.
[0086] The term "halo-C.sub.1-6-alkyl" denotes 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 halo-C.sub.1-6-alkyl
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.
[0087] Among the preferred halo-C.sub.1-6-alkyl groups are
difluoro- or trifluoro-methyl or -ethyl.
[0088] The term "halo-C.sub.1-6-alkoxy" denotes 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.
[0089] 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-alkenyl. 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.
[0090] The term "5 or 6 membered heteroaryl" means an aromatic ring
of 5 or 6 ring atoms as ring members containing one, two, or three
ring heteroatoms selected from N, O, and S, the rest being carbon
atoms. 5 or 6 membered heteroaryl can optionally be substituted
with one, two, three or four substituents, wherein each substituent
may independently be selected from the group consisting of hydroxy,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl, halo,
cyano, nitro, halo-C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-alkoxycarbonyl, amino, C.sub.1-6-alkylamino,
di(C.sub.1-6)alkylamino, aminocarbonyl, or carbonylamino, unless
otherwise specifically indicated. Preferred substituents are halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, and cyano. Examples of heteroaryl
moieties include, but are not limited to, optionally substituted
imidazolyl, optionally substituted oxazolyl, optionally substituted
thiazolyl, optionally substituted pyrazinyl, optionally substituted
pyrrolyl, optionally substituted pyrazinyl, optionally substituted
pyridinyl, optionally substituted pyrimidinyl, optionally
substituted furanyl, and those which are specifically exemplified
herein.
[0091] The term "heterocycloalkyl" means a monovalent saturated
moiety, consisting of one ring of 3 to 7, preferably from 4 to 6,
atoms as ring members, including one, two, or three heteroatoms
selected from nitrogen, oxygen and sulfur, the rest being carbon
atoms. 3 to 7 membered heterocycloalkyl can optionally be
substituted with one, two, or three substituents, wherein each
substituent is independently hydroxy, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-thioalkyl, halo, cyano, nitro,
halo-C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-alkoxycarbonyl, amino, C.sub.1-6-alkylamino,
di(C.sub.1-6)alkylamino, aminocarbonyl, or carbonylamino, unless
otherwise specifically indicated. Preferred substituents are halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, and cyano. Examples of heterocyclic
moieties include, but are not limited to, optionally substituted
tetrahydro-furanyl, optionally substituted piperidinyl, optionally
substituted pyrrolidinyl, optionally substituted morpholinyl,
optionally substituted piperazinyl, and the like or those which are
specifically exemplified herein.
[0092] The term "heterocycle" in the definition "R.sup.a and
R.sup.b, R.sup.c and R.sup.d, R.sup.g and R.sup.h, R.sup.i and
R.sup.j, 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 heteroaryl in the above-given sense,
which may optionally be substituted as described above. Preferably,
the "heterocycle" may optionally be substituted with one, two or
three substituents selected from halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
and cyano. Preferred heterocycles are piperazine,
N-methylpiperazine, morpholine, piperidine and pyrrolidine.
[0093] The phrase "one or more" substituents preferably means one,
two or three optional substituents per ring.
[0094] The term "3 to 6-membered cycloalkyl" denotes a cyclic
aliphatic ring, having from 3 to 6 carbon ring atoms, for example,
cyclopropyl, cyclopentyl or cyclohexyl.
[0095] "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.
[0096] The term "pharmaceutically acceptable acid addition salts"
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.
[0097] "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.
[0098] In detail, the present invention relates to compounds of the
general formula (I)
##STR00003##
wherein [0099] X and Y are selected from the combinations of:
[0100] X is C.dbd.O, and Y is O, [0101] X is CH.sub.2, and Y is O,
[0102] X is O, and Y is CH.sub.2, [0103] X is NR.sup.7, and Y is
C.dbd.O, [0104] X is NR.sup.7, and Y is CH.sub.2, or [0105] X-Y is
--C.dbd.C-- or --CH.sub.2CH.sub.2--; [0106] R.sup.1 is hydrogen,
[0107] C.sub.1-6-alkyl, optionally substituted by CN or OH, or
[0108] --(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b; [0109] R.sup.2
is hydrogen, [0110] C.sub.1-6-alkyl, [0111] C.sub.1-6-alkoxy,
[0112] --(C.sub.1-6-alkylene)-NR.sup.cR.sup.d, [0113]
--(C.sub.1-6-alkylene)-C(O)R.sup.f, [0114] benzyl, optionally
subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, or [0115] phenyl, optionally subsitituted by one or more
halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0116] R.sup.3 is hydrogen,
halo, or C.sub.1-6-alkyl; [0117] R.sup.4 is hydrogen, [0118] halo,
[0119] C.sub.1-6-alkyl, [0120] halo-C.sub.1-6-alkyl, [0121]
C.sub.1-6-alkoxy, [0122] halo-C.sub.1-6-alkoxy, or [0123]
--O--C.sub.2-10-alkenyl; [0124] R.sup.5 is hydrogen, halo,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy; [0125] or R.sup.4 and R.sup.5
are bound together to form a ring with the benzo moiety, wherein
[0126] --R.sup.4--R.sup.5-- is --O--(CH.sub.2).sub.n--O-- wherein n
is 1 or 2; [0127] R.sup.6 is hydrogen, [0128] C.sub.1-6-alkyl,
optionally substituted by CN or OH, [0129]
--(C.sub.1-6-alkylene)-NR.sup.gR.sup.h, [0130]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.j, [0131] --O-benzyl,
optionally subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, or [0132] nitro, [0133] halo, [0134] cyano, [0135]
C.sub.1-6-alkoxy, [0136] halo-C.sub.1-6-alkoxy, [0137]
halo-C.sub.1-6-alkyl, [0138] --(C.sub.1-6-alkylene)-C(O)R.sup.f,
[0139] phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, [0140]
--(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a 5- to
6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to
6-membered cycloalkyl, [0141] each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0142] or R.sup.5 and
R.sup.6 are bound together to form a ring with the benzo moiety,
wherein [0143] --R.sup.5--R.sup.6 is --O--(CH.sub.2).sub.n--C(O)--,
[0144] --C(O)--(CH.sub.2).sub.n--O--, or [0145]
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; [0146] R.sup.7 is
hydrogen or C.sub.1-6-alkyl; [0147] R.sup.8, R.sup.9, R.sup.10, and
R.sup.11 are each independently hydrogen, halo, C.sub.1-6-alkyl,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkoxy or halo-C.sub.1-6alkoxy;
[0148] R.sup.a, R.sup.b, R.sup.i and R.sup.j are each independently
hydrogen, [0149] C.sub.1-6-alkyl, [0150]
--(C.sub.1-6-alkylene)-NR.sup.kR.sup.l, [0151] wherein R.sup.k and
R.sup.l are each independently hydrogen or C.sub.1-6-alkyl, [0152]
or R.sup.a and R.sup.b, or R.sup.i and R.sup.j 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; [0153] R.sup.c, R.sup.d,
R.sup.g and R.sup.h are each independently [0154] hydrogen, [0155]
C.sub.1-6-alkyl, [0156] --C(O)R.sup.e, or --S(O).sub.2R.sup.e
[0157] wherein R.sup.e is selected from the group of [0158]
hydrogen, [0159] C.sub.1-6-alkyl, and [0160] phenyl, optionally
substituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano; [0161] or R.sup.c and R.sup.d, or R.sup.g and R.sup.h
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; [0162] or R.sup.c
and R.sup.d, or R.sup.g and R.sup.h together with the nitrogen to
which they are bound form isoindole-1,3-dione; [0163] R.sup.f is
selected from the group of [0164] hydrogen, [0165] C.sub.1-6-alkyl,
[0166] C.sub.1-6-alkoxy; and [0167] phenyl, optionally substituted
by one or more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano; or a
pharmaceutically acceptable salt thereof.
[0168] In certain embodiments of the invention, R.sup.a and
R.sup.b, R.sup.c and R.sup.d, R.sup.i and R.sup.j, or R.sup.g and
R.sup.h together with the nitrogen to which they are bound form
piperazine, 4-(C.sub.1-6-alkyl)-piperazine, 4-methylpiperazine,
morpholine, piperidine or pyrrolidine.
[0169] In certain embodiments of the invention, R.sup.a and
R.sup.b, R.sup.c and R.sup.d, R.sup.i and R.sup.j, or R.sup.g and
R.sup.h together with the nitrogen to which they are bound form
4-methylpiperazine, or morpholine.
[0170] In certain embodiments of the invention, wherein R.sup.m is
a 5- to 6-membered heteroaryl, the preferred heteroaryl is selected
from the group consisting of pyridine, pyrimidine, pyrazine,
pyridazine, imidazole, pyrazole, oxazole, and isoxazole.
[0171] In embodiments of the invention, wherein R.sup.m is a 4- to
6-membered heterocycloalkyl, the preferred heterocycloalkyl is
selected from the group consisting of pyrrolidine, oxethane,
tetrahydropyrane, piperidine, morpholine, and piperazine.
[0172] In certain embodiments of the invention, [0173] R.sup.1 is
hydrogen, [0174] C.sub.1-6-alkyl, optionally substituted by CN or
OH, or [0175] --(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, [0176]
wherein R.sup.a and R.sup.b are each independently hydrogen or
C.sub.1-6-alkyl.
[0177] In certain embodiments of the invention, [0178] R.sup.2 is
hydrogen, [0179] C.sub.1-6-alkyl, [0180] C.sub.1-6-alkoxy, [0181]
--(C.sub.1-6-alkylene)-NR.sup.cR.sup.d, [0182] wherein R.sup.c and
R.sup.d are each independently [0183] hydrogen, [0184]
--C(O)R.sup.e, or --S(O).sub.2R' [0185] wherein R.sup.e is selected
from the group of [0186] hydrogen, [0187] C.sub.1-6-alkyl, and
[0188] phenyl, optionally substituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, or [0189] R.sup.c and
R.sup.d together with the nitrogen to which they are bound form
isoindole-1,3-dione, [0190] --(C.sub.1-6-alkylene)-C(O)R.sup.f,
[0191] wherein R.sup.f is selected from the group of [0192]
hydrogen, [0193] C.sub.1-6-alkyl, [0194] C.sub.1-6-alkoxy, and
[0195] phenyl, optionally substituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0196] benzyl, optionally
subsitituted by halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano, or [0197]
phenyl, optionally subsitituted by halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano.
[0198] In certain embodiments of the invention, R.sup.2 is
hydrogen, C.sub.1-6-alkyl or C.sub.1-6-alkoxy.
[0199] In certain embodiments of the invention, R.sup.3 is hydrogen
or halo.
[0200] In certain embodiments of the invention, R.sup.4 is
hydrogen; halo, preferably fluoro, chloro or bromo;
C.sub.1-6-alkyl, preferably methyl; C.sub.1-6-alkoxy, preferably
methoxy or --O-iso-propyl; halo-C.sub.1-6-alkoxy, preferably
trifluoromethoxy; or --O--C.sub.2-10-alkenyl, preferably allyl.
[0201] In certain embodiments of the invention, R.sup.5 is
hydrogen; halo, preferably bromo; C.sub.1-6-alkyl, preferably
methyl; or C.sub.1-6-alkoxy, preferably methoxy.
[0202] In certain embodiments of the invention, R.sup.4 and R.sup.5
are bound together to form a ring with the benzo moiety, wherein
--R.sup.4--R.sup.5-- is --O--CH.sub.2--O--.
[0203] In certain embodiments of the invention, [0204] R.sup.6 is
hydrogen, [0205] C.sub.1-6-alkyl, optionally substituted by CN or
OH, [0206] --(C.sub.1-6-alkylene)-NR.sup.gR.sup.h [0207] wherein
R.sup.g and R.sup.h are each independently selected from hydrogen,
and C.sub.1-6-alkyl; [0208] or wherein R.sup.g and R.sup.h 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; [0209]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j [0210] wherein R.sup.i
and R.sup.j are each independently [0211] hydrogen; [0212]
C.sub.1-6-alkyl; [0213] --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l;
[0214] wherein R.sup.k and R.sup.l are each independently hydrogen
or C.sub.1-6-alkyl; [0215] or R.sup.i and R.sup.j 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; [0216] --O-benzyl, optionally
subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C-.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro,
or cyano; [0217] nitro; [0218] halo; [0219] cyano; [0220]
C.sub.1-6-alkoxy; [0221] halo-C.sub.1-6-alkoxy; [0222]
halo-C.sub.1-6-alkyl; [0223] --(C.sub.1-6-alkylene)-C(O)R.sup.f;
[0224] wherein R.sup.f is selected from [0225] hydrogen; [0226]
C.sub.1-6-alkyl; [0227] C.sub.1-6-alkoxy; and [0228] phenyl,
optionally substituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, [0229] phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0230]
--(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a 5- to
6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to
6-membered cycloalkyl, [0231] each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano.
[0232] In certain embodiments of the invention, [0233] R.sup.6 is
hydrogen, [0234] C.sub.1-6-alkyl, optionally substituted by CN or
OH, [0235] --(C.sub.1-6-alkylene)-NR.sup.gR.sup.h, [0236] wherein
R.sup.g and R.sup.h are each independently selected from hydrogen,
or C.sub.1-6-alkyl, or wherein [0237] R.sup.g and R.sup.h 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 and oxygen, [0238]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, [0239] wherein
R.sup.i and R.sup.j are each independently [0240] hydrogen, [0241]
C.sub.1-6-alkyl, [0242] --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l,
[0243] wherein R.sup.k and R.sup.l are each independently hydrogen
or C.sub.1-6-alkyl; [0244] or R.sup.i and R.sup.l 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 and oxygen.
[0245] In certain embodiments of the invention, R.sup.7 is hydrogen
or C.sub.1-6-alkyl, preferably hydrogen.
[0246] In certain embodiments all R.sup.8 to R.sup.11 are
hydrogen.
[0247] In certain embodiments, R.sup.8 to R.sup.11 are
independently hydrogen or halo.
[0248] In certain embodiments, R.sup.9 is fluoro, and R.sup.8,
R.sup.10 and R.sup.11 are hydrogen.
[0249] In certain embodiments, R.sup.8, R.sup.9 and R.sup.11 are
hydrogen and R.sup.10 is bromo.
[0250] In certain embodiments, R.sup.8 to R.sup.11 are
independently hydrogen or methyl.
[0251] In certain embodiments, R.sup.8 to R.sup.10 are hydrogen and
R.sup.11 is methyl.
[0252] In certain embodiments, the invention provides compounds in
which X and Y are selected from the combinations of: [0253] X is
C.dbd.O, and Y is O, [0254] X is CH.sub.2, and Y is O, and [0255] X
is O, and Y is CH.sub.2.
[0256] In certain embodiments of the invention, X is C.dbd.O and Y
is O, i.e. compounds of formula (Ia)
##STR00004##
wherein R.sup.1 to R.sup.11 are as defined herein above.
[0257] In certain embodiments of the invention, X is CH.sub.2, and
Y is O, i.e. compounds of formula (Ib)
##STR00005##
wherein R.sup.1 to R.sup.11 are as defined herein above.
[0258] In certain embodiments of the invention, X is O and Y is
CH.sub.2, i.e. compounds of formula (Ic)
##STR00006##
wherein R.sup.1 to R.sup.11 are as defined herein above.
[0259] In certain embodiments, the invention provides compounds in
which X and Y are selected from the combinations of: [0260] X is
NR.sup.7, and Y is C.dbd.O, and [0261] X is NR.sup.7, and Y is
CH.sub.2.
[0262] In certain embodiments of the invention, X is NR.sup.7 and Y
is C.dbd.O, i.e. compounds of formula (Id)
##STR00007##
wherein R.sup.1 to R.sup.11 are as defined herein above.
[0263] In certain embodiments of the invention, X is NR.sup.7 and Y
is CH.sub.2, i.e. compounds of formula (Ie)
##STR00008##
wherein R.sup.1 to R.sup.11 are as defined herein above.
[0264] In certain embodiments, the invention provides compounds in
which X and Y are selected from the combinations of:
X-Y is --C.dbd.C-- and --CH.sub.2CH.sub.2--.
[0265] In certain embodiments of the invention, --X--Y-- is
--CH.dbd.CH--, i.e. compounds of formula (If)
##STR00009##
wherein R.sup.1 to R.sup.6 and R.sup.8 to R.sup.11 are as defined
herein above.
[0266] In certain embodiments of the invention, --X--Y-- is
--CH.sub.2 CH.sub.2--, i.e. compounds of formula (Ig)
##STR00010##
wherein R.sup.1 to R.sup.6 and R.sup.8 to R.sup.11 are as defined
herein above.
[0267] In certain embodiments of the invention, R.sup.1 to R.sup.6
are not all hydrogen.
[0268] In certain embodiments of the invention, R.sup.1 to R.sup.11
are not all hydrogen.
[0269] The invention further encompasses an embodiment with the
compound of formula (I), wherein [0270] X and Y are selected from
the combinations of: [0271] X is C.dbd.O, and Y is O, [0272] X is
CH.sub.2, and Y is O, [0273] X is O, and Y is CH.sub.2, [0274] X is
NR.sup.7, and Y is C.dbd.O, [0275] X is NR.sup.7, and Y is
CH.sub.2, or [0276] X-Y is --C.dbd.C-- or --CH.sub.2CH.sub.2--;
[0277] R.sup.1 is hydrogen, [0278] C.sub.1-6-alkyl, optionally
substituted by CN or OH, [0279]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, [0280] wherein
R.sup.a and R.sup.b are each independently hydrogen or
C.sub.1-6-alkyl; [0281] R.sup.2 is hydrogen, [0282]
C.sub.1-6-alkyl, [0283] C.sub.1-6-alkoxy, [0284]
--(C.sub.1-6-alkylene)-NR.sup.cR.sup.d, [0285] wherein R.sup.c and
R.sup.d are each independently [0286] hydrogen, [0287]
--C(O)R.sup.e, or --S(O).sub.2R', [0288] wherein R.sup.e is
selected from the group of [0289] hydrogen, [0290] C.sub.1-6-alkyl,
and [0291] phenyl, optionally substituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, [0292] or R.sup.c and
R.sup.d together with the nitrogen to which they are bound form
isoindole-1,3-dione, [0293] --(C.sub.1-6-alkylene)-C(O)R.sup.f,
[0294] wherein R.sup.f is selected from the group of [0295]
hydrogen, [0296] C.sub.1-6-alkyl, [0297] C.sub.1-6-alkoxy; and,
[0298] phenyl, optionally substituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, [0299] benzyl, optionally
subsitituted by halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or cyano, or [0300]
phenyl, optionally subsitituted by halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano; [0301] R.sup.3 is hydrogen, halo, or C.sub.1-6-alkyl; [0302]
R.sup.4 is hydrogen, [0303] halo, [0304] C.sub.1-6-alkyl, [0305]
halo-C.sub.1-6-alkyl, [0306] C.sub.1-6-alkoxy, [0307]
halo-C.sub.1-6-alkoxy, or [0308] --O--C.sub.2-10-alkenyl; [0309]
R.sup.5 is hydrogen, halo, C.sub.1-6-alkyl, or C.sub.1-6-alkoxy;
[0310] or R.sup.4 and R.sup.1 are bound together to form a ring
with the benzo moiety, wherein [0311] --R.sup.4--R.sup.5-- is
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2, [0312] R.sup.6 is
hydrogen, [0313] C.sub.1-6-alkyl, optionally substituted by CN or
OH, [0314] --(C.sub.1-6-alkylene)-NR.sup.gR.sup.h, [0315] wherein
R.sup.g and R.sup.h are each independently selected from hydrogen,
or C.sub.1-6-alkyl; [0316] or wherein R.sup.g and R.sup.h 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, [0317]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, [0318] wherein
R.sup.i and R.sup.j are each independently [0319] hydrogen, [0320]
C.sub.1-6-alkyl, [0321] --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l,
[0322] wherein R.sup.k and R.sup.l are each independently hydrogen
or C.sub.1-6-alkyl; [0323] or R.sup.i and R.sup.j 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, [0324] --O-benzyl, optionally
subsitituted by one or more halo, halo-C.sub.1-6-alkyl,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, halo-C.sub.1-6-alkoxy, nitro, or
cyano, [0325] nitro, [0326] halo, [0327] cyano, [0328]
C.sub.1-6-alkoxy, [0329] halo-C.sub.1-6-alkoxy, [0330]
halo-C.sub.1-6-alkyl, [0331] --(C.sub.1-6-alkylene)-C(O)R.sup.f,
[0332] phenyl, optionally subsitituted by one or more halo,
halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano, [0333]
--(C.sub.1-3-alkylene)-R.sup.m, wherein R.sup.m is phenyl, a 5- to
6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to
6-membered cycloalkyl, [0334] each optionally substituted by one or
more halo, halo-C.sub.1-6-alkyl, C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
halo-C.sub.1-6-alkoxy, nitro, or cyano; [0335] or R.sup.5 and
R.sup.6 are bound together to form a ring with the benzo moiety,
wherein [0336] --R.sup.5--R.sup.6 is --O--(CH.sub.2).sub.n--C(O)--,
[0337] --C(O)--(CH.sub.2).sub.n--O--, or [0338]
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; [0339] R.sup.7 is
hydrogen or C.sub.1-6-alkyl; [0340] R.sup.8, R.sup.9, R.sup.10, and
R.sup.11 are each independently hydrogen, halo, C.sub.1-6-alkyl or
halo-C.sub.1-6-alkyl.
[0341] The invention further encompasses an embodiment with the
compound of formula (I), wherein [0342] X and Y are selected from
the combinations of: [0343] X is C.dbd.O, and Y is O, [0344] X is
CH.sub.2, and Y is O. [0345] X is O, and Y is CH.sub.2, [0346] X is
NR.sup.7, and Y is C.dbd.O, [0347] X is NR.sup.7, and Y is
CH.sub.2, or [0348] X--Y is --C.dbd.C-- or --CH.sub.2CH.sub.2--;
[0349] R.sup.1 is hydrogen, [0350] CR.sub.1-6-alkyl, optionally
substituted by CN or OH, or [0351]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, [0352] wherein
R.sup.a and R.sup.b are each independently hydrogen or
C.sub.1-6-alkyl; [0353] R.sup.2 is hydrogen, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy; [0354] R.sup.3 is hydrogen or halo; [0355]
R.sup.4 is hydrogen, [0356] halo, [0357] C.sub.1-6-alkyl, [0358]
halo-C.sub.1-6-alkyl, [0359] C.sub.1-6-alkoxy, [0360]
halo-C.sub.1-6-alkoxy, or [0361] --O--C.sub.2-10-alkenyl; [0362]
R.sup.5 is hydrogen, halo, C.sub.1-6-alkyl, or C.sub.1-6-alkoxy;
[0363] or R.sup.4 and R.sup.1 are bound together to form a ring
with the benzo moiety, wherein [0364] --R.sup.4--R.sup.5-- is
--O--(CH.sub.2).sub.n--O-- wherein n is 1 or 2; [0365] R.sup.6 is
hydrogen, [0366] C.sub.1-6-alkyl, optionally substituted by CN or
OH, [0367] --(C.sub.1-6-alkylene)-NR.sup.gR.sup.h, [0368] wherein
R.sup.g and R.sup.h are each independently selected from hydrogen,
or C.sub.1-6-alkyl, [0369] or wherein R.sup.g and R.sup.h 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 and oxygen, [0370]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, [0371] wherein
R.sup.i and R.sup.j are each independently [0372] hydrogen, [0373]
C.sub.1-6-alkyl, [0374] --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l,
[0375] wherein R.sup.k and R.sup.l are each independently hydrogen
or C.sub.1-6-alkyl, [0376] or R.sup.i and R.sup.j 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 and oxygen; [0377] R.sup.7 is hydrogen or
C.sub.1-6-alkyl; [0378] R.sup.8, R.sup.9, R.sup.10, and R.sup.11
are each independently hydrogen, halo, C.sub.1-6-alkyl or
halo-C.sub.1-6-alkyl.
[0379] The invention further encompasses an embodiment with the
compound of formula (Ia), wherein [0380] R.sup.1 is hydrogen, or
[0381] --(C.sub.1-6-alkylene)-C(O)--NR.sup.aR.sup.b, [0382] wherein
R.sup.a and R.sup.b are each independently hydrogen or
C.sub.1-6-alkyl; [0383] R.sup.2 is hydrogen; [0384] R.sup.3 is
hydrogen; [0385] R.sup.4 is hydrogen or halo; [0386] R.sup.5 is
hydrogen; [0387] R.sup.6 is hydrogen, or [0388] C.sub.1-6-alkyl,
optionally substituted by CN; [0389] R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are each independently hydrogen or halo.
[0390] The invention further encompasses an embodiment with the
compound of formula (Ib), wherein [0391] R.sup.1 is hydrogen;
[0392] R.sup.2 is hydrogen or C.sub.1-6-alkoxy; [0393] R.sup.3 is
hydrogen or halo; [0394] R.sup.4 is hydrogen or halo; [0395]
R.sup.5 is hydrogen or C.sub.1-6-alkoxy; [0396] R.sup.6 is
hydrogen, [0397] C.sub.1-6-alkyl, optionally substituted by CN,
[0398] --(C.sub.1-6-alkylene)-NR.sup.8R.sup.h, [0399] wherein
R.sup.g and R.sup.h are each independently selected from hydrogen,
or C.sub.1-6-alkyl, [0400] or wherein R.sup.g and R.sup.h 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 and oxygen; [0401]
--(C.sub.1-6-alkylene)-C(O)--NR.sup.iR.sup.j, [0402] wherein
R.sup.i and R.sup.j are each independently [0403] hydrogen, [0404]
C.sub.1-6-alkyl, [0405] --(C.sub.1-6-alkylene)-NR.sup.kR.sup.l,
[0406] wherein R.sup.k and R.sup.l are each independently hydrogen
or C.sub.1-6-alkyl, [0407] or R.sup.i and R.sup.j 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 and oxygen; [0408] R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are each hydrogen.
[0409] The invention further encompasses an embodiment with the
compound of formula (Ic), wherein [0410] R.sup.1 is hydrogen, or
[0411] C.sub.1-6-alkyl, optionally substituted by CN, [0412]
R.sup.2 is hydrogen or C.sub.1-6-alkyl; [0413] R.sup.3 is hydrogen;
[0414] R.sup.4 is hydrogen, [0415] halo, [0416] C.sub.1-6-alkyl,
[0417] C.sub.1-6-alkoxy, [0418] halo-C.sub.1-6-alkoxy, or [0419]
--O--C.sub.2-10-alkenyl; [0420] R.sup.5 is hydrogen, halo,
C.sub.1-6-alkyl, or C.sub.1-6-alkoxy; [0421] or R.sup.4 and R.sup.5
are bound together to form a ring with the benzo moiety, wherein
[0422] --R.sup.4--R.sup.5-- is --O--(CH.sub.2).sub.n--O-- wherein n
is 1 or 2; [0423] R.sup.6 is hydrogen, or [0424] C.sub.1-6-alkyl,
optionally substituted by CN; [0425] R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are each hydrogen.
[0426] The invention further encompasses an embodiment with the
compound of formula (Id), wherein [0427] R.sup.1 is hydrogen, or
[0428] C.sub.1-6-alkyl, optionally substituted by CN; [0429]
R.sup.2 is hydrogen or C.sub.1-6-alkyl; [0430] R.sup.3 is hydrogen
or halo; [0431] R.sup.4 is hydrogen, halo, or C.sub.1-6-alkoxy;
[0432] R.sup.5 is hydrogen, halo, C.sub.1-6-alkyl, or
C.sub.1-6-alkoxy; [0433] or R.sup.4 and R.sup.5 are bound together
to form a ring with the benzo moiety, wherein [0434]
--R.sup.4--R.sup.5-- is --O--(CH.sub.2), --O-- wherein n is 1 or 2;
[0435] R.sup.6 is hydrogen, or [0436] C.sub.1-6-alkyl, optionally
substituted by CN; [0437] R.sup.7 is hydrogen; [0438] R.sup.8,
R.sup.9, R.sup.10, and R.sup.11 are each independently hydrogen,
halo, or C.sub.1-6-alkyl.
[0439] The invention further encompasses an embodiment with the
compound of formula (Ie), wherein [0440] R.sup.1 to R.sup.3 and
R.sup.5 to R.sup.11 are hydrogen; and R.sup.4 is halo.
[0441] Preferred compounds of formula Ia are [0442]
{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)carbo-
nyl]-1H-indol-7-yl}acetonitrile, [0443]
2-{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)car-
bonyl]-1H-indol-1-yl}-N,N-dimethylacetamide, [0444]
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidi-
n]-3-one, and [0445]
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4'-
-piperidin]-3-one.
[0446] Preferred compounds of formula Ib are [0447]
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H--
indol-7-yl]acetonitrile, [0448]
1'-({5-chloro-7-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indol-2-yl}car-
bonyl)-3H-spiro[2-benzofuran-1,4'-piperidine], [0449]
1-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1-
H-indol-7-yl]-N,N-dimethylmethanamine, [0450]
1'-{[5-chloro-7-(morpholin-4-ylmethyl)-1H-indol-2-yl]carbonyl}-3H-spiro[2-
-benzofuran-1,4'-piperidine], [0451] 1'-[(5-chloro-1H-indol-2-yl)
carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidine], [0452]
2-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1-
H-indol-7-yl]-N-[2-(dimethylamino) ethyl]acetamide, [0453]
1'-[(5-fluoro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidi-
ne], [0454]
1'-({5-chloro-7-[(4-methylpiperazin-1-yl)methyl]-1H-indol-2-yl}carbonyl)--
3H-spiro[2-benzofuran-1,4'-piperidine], and [0455]
1'-[(4-bromo-3-methoxy-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-
-piperidine].
[0456] Preferred compounds of formula Ic are [0457]
1'-[(3,7-dimethyl-1H-indol-2-yl)
carbonyl]spiro[1-benzofuran-3,4'-piperidine], and [0458]
1'-[(3,6,7-trimethyl-1H-indol-2-yl)
carbonyl]spiro[1-benzofuran-3,4'-piperidine].
[0459] A preferred compound of 1d are [0460]
{2-[(5-bromo-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)car-
bonyl]-5-chloro-1H-indol-1-yl}acetonitrile.
[0461] The invention also encompasses methods for treating
dysmenorrhea, hypertension, chronic heart failure, inappropriate
secretion of vasopressin, liver cirrhosis, nephrotic syndrome,
obsessive compulsive disorder, anxiety and depressive disorders by
administering a therapeutically effective amount of a compound
selected from compounds of formula (I), (Ia), (Ib), (Ic), (Id),
(Ie), (If), and (Ig).
[0462] The invention also encompasses a pharmaceutical composition
comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie),
(If), or (Ig) and at least one pharmaceutically acceptable
excipient.
[0463] In a certain embodiment, the compound of the invention can
be manufactured according to a process comprising reacting a
compound of formula (II):
##STR00011##
with an amine of formula 1
##STR00012##
wherein R.sup.1 to R.sup.6 and R.sup.8 to R.sup.11 and X and Y are
as defined above.
[0464] In a certain embodiment, the compound of the invention can
be manufactured according to a process comprising reacting a
compound of formula (I-1):
##STR00013##
with an electophilic reagent of formula R.sup.1-hal, to give a
compound of general formula (I) as defined herein above.
[0465] The synthesis of compounds of general formula (I) will be
described in more detail below and in the examples.
##STR00014##
wherein A is:
##STR00015##
wherein [0466] X and Y are selected from the combinations of:
[0467] X is C.dbd.O, and Y is O, [0468] X is CH.sub.2, and Y is O,
[0469] X is O, and Y is CH.sub.2, [0470] X is NR.sup.7, and Y is
C.dbd.O, [0471] X is NR.sup.7, and Y is CH.sub.2, or [0472] X-Y is
--C.dbd.C-- or --CH.sub.2CH.sub.2--
[0473] Compounds of formula (I) can be prepared via an amide
coupling between an indole 2-carboxylic acid (II) and a compound of
formula (A-H), wherein A is defined as hereinabove. The usual
reagents and protocols known in the art can be used to effect the
amide coupling. Indole 2-carboxylic acids (II) are either
commercially available or readily prepared using procedures
described hereinafter. The compounds of formula (A-H) are either
commercially available or prepared using methods known in the art
starting from commercially available materials.
[0474] General scheme A is hereinafter further illustrated with
general procedure I.
##STR00016##
[0475] Compounds of formula (I-2) (compounds of formula (I) wherein
R.sup.1 is different from H), can be prepared by alkylation of the
indole derivative of formula (I-1), with an electrophilic reagent
of formula R.sup.1-hal (commercially available, wherein hal is
halo, preferably Cl or Br) using standard procedures. Derivatives
(I-1) are prepared using the amide coupling as described in the
general scheme A.
##STR00017##
[0476] Substituted indole 2-carboxylic acids can be prepared
according to the general scheme C. Indoles V are obtained by a
Fischer indole synthesis from an aryl hydrazine III and a
.alpha.-ketoester IV. Saponification gives an acid of formula II-a.
Alternatively, Boc protection of the indole nitrogen gives VI.
Selective bromination of the methyl group in the 7-position of the
indole using NBS affords VII. Subsequent nucleophilic substitution
of 7-bromomethyl indole intermediate VII with NaCN or a secondary
amine yields intermediates VIII and IX, respectively. After
N-deprotection and saponification of the ester moiety, the
corresponding carboxylics acids II-b and II-c are obtained.
[0477] Abbreviations Used:
NBS=N-Bromosuccinimide
Boc=tert-buthoxycarbonyl
EDC=N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide
hydrochloride
HOBt=1-hydroxybenzotriazole
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
DMAP=4-dimethylaminopyridine
TFA=trifluoroacetic acid
[0478] The compounds of the present invention exhibit V1a activity,
which may be detected as described below:
V1a Activity
Material & Method:
[0479] 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.
[0480] 50 g of cells were resuspended in 30 ml freshly prepared ice
cold Lysis buffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl.sub.2
adjusted to pH=7.4+complete cocktail of protease inhibitor (Roche
Diagnostics)). The mixture was 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 were added; and for
compound testing, 100 ul of a serial dilution of each compound in
2% DMSO was added. 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 pKi 1 7.38 2 7.49 4 7.76 5 8.18 6 7.75 8
7.52 9 8.26 10 8.68 11 8.42 12 7.67 13 8.11 14 8.56 15 8.44 24 8.01
26 8.14 46 7.67
[0481] The present invention also provides pharmaceutical
compositions containing compounds of the invention 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.
[0482] 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.
[0483] 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.
[0484] The dosage at which the 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.
[0485] The following Examples illustrate the present invention
without limiting it. All temperatures are given in degrees
Celsius.
EXAMPLE A
[0486] 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
[0487] 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
[0488] 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 is added thereto and mixed
thoroughly. The mixture can be filled by machine into hard gelatine
capsules.
EXAMPLE C
[0489] Suppositories of the following composition can be
manufactured:
TABLE-US-00004 mg/supp. Active substance 15 Suppository mass 1285
Total 1300
[0490] The suppository mass can be melted in a glass or steel
vessel, mixed thoroughly and cooled to 45.degree. C. 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.
[0491] 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 otherwise known or derived from the
chemical literature, for instance as cited below, or may be
prepared as described in the Examples section.
EXAMPLES
General Procedure 1
Amide Coupling
[0492] To a 0.1 M stirred solution of an indole-2-carboxylic acid
derivative of type (II) in CH.sub.2Cl.sub.2 are added EDC (1.3 eq),
HOBt (1.3 eq), Et.sub.3N (1.3 eq) and the amine derivative (A-H, as
defined above, 1 eq). The mixture is stirred overnight at room
temperature 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 a compound of formula (I).
General Procedure II
Alkylation
[0493] To a 0.1 M stirred solution of a derivative of general
formula (I-1) in DMF is added NaH (60% in oil, 2.1 eq.). After
stirring the mixture at room temperature for 30 min. the
electrophilic reactant R.sup.1-hal (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 the corresponding
derivatives of general formula (I-2).
Preparation of Acids II
Acid 1: 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid
##STR00018##
[0494] a) 2-[(4-Chloro-2-methyl-phenyl)-hydrazono]-propionic acid
ethyl ester
[0495] To a stirred solution of 0.55 g (2.85 mmol) of
(4-chloro-2-methyl-phenyl)-hydrazine in acetic acid (5 ml), was
added 0.34 g (2.91 mmol) of ethyl pyruvate. The mixture was stirred
2 hours at 35.degree. C., poured onto an aqueous solution of sat.
NaHCO.sub.3 and then extracted with ethyl acetate. The combined
organic phases were dried over Na.sub.2SO.sub.4 and concentrated in
vacuo, to afford 0.702 g (97%) of
2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester
as a light orange solid.
b) 5-Chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester
[0496] To a solution of 0.70 g (2.75 mmol) of
2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester
in a sealed tube was added toluene (10 ml) and amberlyst 15 (1.60
g). The reaction mixture was heated at 120.degree. C. over the
night. The reaction mixture was concentrated under vacuo and
purified by flash chromatography (SiO.sub.2, EtOAc/Hex 1/6) to
afford 0.22 g (34%) of 5-chloro-7-methyl-1H-indole-2-carboxylic
acid ethyl ester as a white solid. ES-MS m/e (%): 238.1
(M+H.sup.+).
c) 5-Chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester
[0497] To a solution of 0.22 g (0.9 mmol) of
5-chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester in
CH.sub.2Cl.sub.2 (10 ml), 0.21 g of di-tert-butyl dicarbonate, 0.13
ml of Et.sub.3N and 23 mg of DMAP were added. The reaction mixture
was stirred at RT for 2 hours, poured onto an aqueous solution of
HCl 1M and extracted with CH.sub.2Cl.sub.2. The reaction mixture
was concentrated under vacuo and purified by flash chromatography
(SiO.sub.2, EtOAc/Hex 1/9) to afford 0.30 g (97%) of
5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester
2-ethyl ester as a light yellow solid.
d) 7-Bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester
[0498] To a solution of 0.30 g (0.9 mmol) of
5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester
2-ethyl ester in CCl.sub.4 (10 ml), 016 g N-bromosuccinimide (NBS)
and 11 mg of benzoyl peroxide were added. The reaction mixture was
heated at reflux for one hour and cooled down to RT. The
succinimide was filtered off and the solvent removed under reduced
pressure to afford 0.35 g (95%) of
7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester as a light brown solid. This product was
directly used in the next step (unstable).
e) 5-Chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester
[0499] To a solution of 1.00 g (2.4 mmol) of
7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester in DMSO (10 ml) at RT, 012 g of sodium cyanide
was added. The reaction mixture was stirred at RT for one hour,
poored on a saturated aqueous ammonium chloride solution and the
product was extracted with EtOAc. The combined organic phases were
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Flash
chromatography (SiO.sub.2, EtOAc/Hex 9/1) afforded 0.31 g (36%) of
5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester as a light yellow oil.
f) 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl
ester
[0500] To a solution of 0.30 g (0.8 mmol) of
5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester in CH.sub.2Cl.sub.2 (8 ml) at RT was added 2 ml
of TFA. The reaction mixture was stirred at RT for one hour and
concentrated under vacuo. The crude was taken up in EtOAc and
neutralized with aqueous NaHCO.sub.3. The combined organic phases
were dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
Preparative HPLC (30% CH.sub.3CN/H.sub.2O) afforded 81 mg (35%) of
5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester as a
white solid.
g) 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid
[0501] To a solution of 81 mg (0.3 mmol) of
5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester in
THF/EtOH/H.sub.2O (5 ml) at RT was added 39 mg of LiOH.H.sub.2O.
The reaction mixture was stirred at 40.degree. C. for three hours
and then acidified with aqueous HCl IM. The product was extracted
with EtOAc and concentrated under vacuo to afford 71 mg (98%) of
5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid as a white
solid. ES-MS m/e (%): 232.9 (M-H.sup.+).
Acid 2: 5-Chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic
acid
##STR00019##
[0502] a) 5-Chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic
acid ethyl ester
[0503] To a solution of 0.11 g (0.26 mmol) of
7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester in THF (1 ml) at RT, 40 .mu.l of morpholine was
added. The reaction mixture was stirred at 40.degree. C. for one
hour and concentrated under vacuo. The crude was dissolved in
CH.sub.2Cl.sub.2 (1 m) and at RT, 0.2 ml of TFA was added and
stirring was continued over night. Preparative HPLC (30%
CH.sub.3CN/H.sub.2O) afforded 53 mg (62%) of
5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl
ester as colorless oil.
b) 5-Chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid
[0504] To a solution of 53 mg (0.16 mmol) of
5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl
ester in THF/EtOH/H.sub.2O (2.5 ml) at RT was added 21 mg of
LiOH.H.sub.2O. The reaction mixture was stirred at 45.degree. C.
for one hour and then acidified with aqueous HCl 1M. The product
was extracted with EtOAc and concentrated under vacuo to afford 12
mg (25%) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic
acid as a white solid. ES-MS m/e (%): 293.1 (M-H.sup.+).
Acid 3:
5-Chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid
##STR00020##
[0505] a)
5-Chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxyli- c
acid ethyl ester
[0506] To a solution of 0.125 g (0.30 mmol) of
7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester in THF (1 ml) at RT, 55 mg of
1-methyl-piperazine was added. The reaction mixture was stirred at
40.degree. C. for one hour and concentrated under vacuo. The crude
was dissolved in CH.sub.2Cl.sub.2 (1 m) and at R.sub.T 0.2 ml of
TFA was added and stirring was continued over night. Preparative
HPLC (30% CH.sub.3CN/H.sub.2O) afforded 30 mg (29%) of
5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid ethyl ester as colorless oil.
b)
5-Chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid
[0507] To a solution of 30 mg (0.09 mmol) of
5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid ethyl ester in THF/EtOH/H.sub.2O (2.5 ml) at RT was added 6 mg
of LiOH.H.sub.2O. The reaction mixture was stirred at 45.degree. C.
for one hour and then acidified with aqueous HCl IM. The product
was extracted with EtOAc and concentrated under vacuo to afford 10
mg (36%) of
5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid as a white solid. ES-MS m/e (%): 306.2 (M-H.sup.+).
Acid 4: 5-Chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic
acid
##STR00021##
[0508] a) 5-Chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic
acid ethyl ester
[0509] To a solution of 0.200 g (0.48 mmol) of
7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl
ester 2-ethyl ester (previously described) in THF (3 ml) at RT,
0.17 ml of dimethyl amine (5.6 M in EtOH) was added. The reaction
mixture was stirred at RT for one hour and concentrated under
vacuo. The crude was dissolved in CH.sub.2Cl.sub.2 (1 m) and at
R.sub.T 0.2 ml of TFA was added and stirring was continued over
night. Preparative HPLC (30% CH.sub.3CN/H.sub.2O) afforded 67 mg
(50%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid
ethyl ester as colorless oil. ES-MS m/e (%): 281.3 (M+H.sup.+).
b) 5-Chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid
[0510] To a solution of 90 mg (0.32 mmol) of
5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid ethyl
ester in THF/EtOH/H.sub.2O (5 ml) at RT was added 23 mg of
LiOH.H.sub.2O. The reaction mixture was stirred at 45.degree. C.
for one hour and then acidified with aqueous HCl IM. The product
was extracted with EtOAc and concentrated under vacuo to afford 34
mg (42%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic
acid as a white solid. ES-MS m/e (%): 251.3 (M-H.sup.+).
Acid 5: 3,7-Dimethyl-1H-indole-2-carboxylic acid
##STR00022##
[0512] The title compound is prepared by saponification of
3,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester (prepared by
Fischer indole synthesis as described in Tetrahedron Lett. 2003,
44, 5665) using the procedure described above for the synthesis of
5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid (acid 1, step
g)).
Acid 6: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid
##STR00023##
[0514] To a solution of 1.0 eq. of
5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester
(prepared according to Indian Journal of Chemistry, Section B:
Organic Chemistry Including Medicinal Chemistry (1989), 28B(12),
1065-8) in a mixture of THF/H.sub.2O ((9/1) was added LiOH.H.sub.2O
(1.0 eq.) and the R/M stirred 6 h at R/T, acidified to pH2 and then
partially concentrated until precipitation of the crude product
which was filtered off and washed with Et.sub.2O and then dried to
give the desired product as a light yellow solid (84%).
Acid 7: Cyanomethyl-1H-indole-2-carboxylic acid
##STR00024##
[0516] To a solution of 1.0 eq. of
1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester in a mixture
of THF/H.sub.2O ((9/1) was added LiOH.H.sub.2O (1.0 eq.) and the
reaction mixture stirred 6 h at RT, acidified to pH2 and then
partially concentrated until precipitation of the crude product
which was filtered off and washed with Et.sub.2O and then dried to
give the desired product as a light yellow solid (70%).
[0517] ES-MS m/e (%): 199.0 (M-H.sup.+).
EXAMPLES
Example 1
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4'--
piperidin]-3-one
##STR00025##
[0519] Amide coupling according to general procedure I:
[0520] Amine: 5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in WO01/14376),
[0521] Acid: 5-Chloro-1H-indole-2-carboxylic acid,
[0522] ES-MS m/e (%): 399.1 (M+H.sup.+).
Example 2
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidin-
]-3-one
##STR00026##
[0524] Amide coupling according to general procedure I:
[0525] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in J. Org. Chem. 1975, 40, 1427),
[0526] Acid: 5-Chloro-1H-indole-2-carboxylic acid,
[0527] ES-MS m/e (%): 381.1 (M+H.sup.+).
Example 3
2-{5-chloro-2-[(5-fluoro-3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1-
'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide
##STR00027##
[0529] To a stirred solution of 60 mg (0.15 mmol) of
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4'-
-piperidin]-3-one in DMF (4 ml) at RT was added 7 mg (0.16 mmol) of
NaH (in oil, 55%). After 20 minutes, 18 mg (0.015 mmol) of
2-chloro-N,N-dimethyl-acetamide was added and stirring was
continued over night. The reaction mixture was concentrated in
vacuo and purification by preparative HPLC (30%
CH.sub.3CN/H.sub.2O) afforded 70 mg (96%) of
2-{5-chloro-2-[(5-fluoro-3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]--
1-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide as a white
solid.
[0530] ES-MS m/e (%): 484.5 (M+H.sup.+).
Example 4
2-{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)carb-
onyl]-1H-indol-1-yl}-N,N-dimethylacetamide
##STR00028##
[0532] To a stirred solution of 60 mg (0.15 mmol) of
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidi-
n]-3-one in DMF (4 ml) at RT was added 7 mg (0.16 mmol) of NaH (in
oil, 55%). After 20 minutes, 19 mg (0.015 mmol) of
2-chloro-N,N-dimethyl-acetamide was added and stirring was
continued over night. The reaction mixture was concentrated in
vacuo and purification by preparative HPLC (30%
CH.sub.3CN/H.sub.2O) afforded 60 mg (82%) of
2-{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)car-
bonyl]-1H-indol-1-yl}-N,N-dimethylacetamide as a white solid.
[0533] ES-MS m/e (%): 466.3 (M+H.sup.+).
Example 5
{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)carbon-
yl]-1H-indol-7-yl}acetonitrile
##STR00029##
[0535] Amide coupling according to general procedure I:
[0536] Amine: 3H-spiro[2-benzofuran-1,4'-piperidin]-3-one
(described in J. Org. Chem. 1975, 40, 1427),
[0537] Acid: 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic
acid,
[0538] ES-MS m/e (%): 420.1 (M+H.sup.+).
Example 6
1'-[(5-fluoro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidin-
e]
##STR00030##
[0539] Amide coupling according to general procedure I:
[0540] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine]
[0541] Acid: 5-Fluoro-1H-indole-2-carboxylic acid,
[0542] ES-MS m/e (%): 351.5 (M+H.sup.+).
Example 7
1'-[(6-methoxy-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidi-
ne]
##STR00031##
[0543] Amide coupling according to general procedure I:
[0544] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine]
[0545] Acid: 6-Methoxy-1H-indole-2-carboxylic acid,
[0546] ES-MS m/e (%): 363.5 (M+H.sup.+).
Example 8
1'-[(4-bromo-3-methoxy-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'--
piperidine]
##STR00032##
[0547] Amide coupling according to general procedure I:
[0548] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine]
[0549] Acid: 4-Bromo-3-methoxy-1H-indole-2-carboxylic acid
(described in European Journal of Medicinal Chemistry (1997),
32(3), 253-261),
[0550] ES-MS m/e (%): 441.4 (M+H.sup.+).
Example 9
1'-[(5-chloro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidin-
e]
##STR00033##
[0551] Amide coupling according to general procedure I:
[0552] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine]
[0553] Acid: 5-Chloro-1H-indole-2-carboxylic acid,
[0554] ES-MS m/e (%): 365.0 (M+H.sup.+).
Example 10
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H-i-
ndol-7-yl]acetonitrile
##STR00034##
[0555] Amide coupling according to general procedure I:
[0556] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (described in
J. Org. Chem. 1976, 41, 2628),
[0557] Acid: 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic
acid,
[0558] ES-MS m/e (%): 406.2 (M+H.sup.+).
Example 11
1'-{[5-chloro-7-(morpholin-4-ylmethyl)-1H-indol-2-yl]carbonyl}-3H-spiro[2--
benzofuran-1,4'-piperidine]
##STR00035##
[0559] Amide coupling according to general procedure I:
[0560] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (described in
J. Org. Chem. 1976, 41, 2628),
[0561] Acid: 5-Chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic
acid
[0562] ES-MS m/e (%): 466.3 (M+H.sup.+).
Example 12
1'-({5-chloro-7-[(4-methylpiperazin-1-yl)methyl]-1H-indol-2-yl}carbonyl)-3-
H-spiro[2-benzofuran-1,4'-piperidine]
##STR00036##
[0564] Amide coupling according to general procedure I:
[0565] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (described in
J. Org. Chem. 1976, 41, 2628),
[0566] Acid:
5-Chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic
acid
[0567] ES-MS m/e (%): 479.3 (M+H.sup.+).
Example 13
2-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H-
-indol-7-yl]-N-[2-(dimethylamino) ethyl]acetamide
##STR00037##
[0568] a)
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarb-
onyl)-1H-indol-7-yl]acetic acid
[0569] To a solution of 100 mg (0.25 mmol) of
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H--
indol-7-yl]acetonitrile in acetic acid (5 ml) at RT was added 3 ml
of H.sub.2O and 3 ml of H.sub.2SO.sub.4 conc. The reaction mixture
was heated at 80.degree. C. for one hour and at 80.degree. C. over
night. The product was extracted with EtOAc and concentrated under
vacuo to afford 94 mg (90%) of
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H--
indol-7-yl]acetic acid as a white solid. ES-MS m/e (%): 422.9
(M-H.sup.+).
b)
2-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-
-1H-indol-7-yl]-N-[2-(dimethylamino) ethyl]acetamide
[0570] To a stirred solution of 30 mg (0.070 mmol) of
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H--
indol-7-yl]acetic acid in 3 ml CH.sub.2Cl.sub.2 were added 31 mg
(0.07 mmol) of BOP and 24 .mu.L of Huenig's base. After 30 minutes
6 mg of N,N-dimethyl-methanediamine were added. The mixture was
stirred overnight at RT and then poured onto water and extracted
with CH.sub.2Cl.sub.2. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 9/1) afforded 10 mg (28%) of
2-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1-
H-indol-7-yl]-N-[2-(dimethylamino)ethyl]acetamide_as a white solid.
ES-MS m/e (%): 495.4 (M+H.sup.+).
Example 14
1'-({5-chloro-7-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indol-2-yl}carb-
onyl)-3H-spiro[2-benzofuran-1,4'-piperidine]
##STR00038##
[0572] To a stirred solution of 60 mg (0.14 mmol) of
[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H--
indol-7-yl]acetic acid in 6 ml CH.sub.2Cl.sub.2 were added 25 mg of
HOBt, 35 mg of EDC and 25 mL of Et.sub.3N. After 30 minutes 24
.mu.L of 1-methyl-piperazine was added. The mixture was stirred
overnight at RT and then poured onto water and extracted with
CH.sub.2Cl.sub.2. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 9/1) afforded 10 mg (14%) of
1'-({5-chloro-7-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indol-2-yl}car-
bonyl)-3H-spiro[2-benzofuran-1,4'-piperidine] as a white solid.
ES-MS m/e (%): 508.1 (M+H.sup.+).
Example 15
1-[5-chloro-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-ylcarbonyl)-1H-
-indol-7-yl]-N,N-dimethylmethanamine
##STR00039##
[0574] Amide coupling according to general procedure I:
[0575] Amine: 3H-spiro[2-benzofuran-1,4'-piperidine] (described in
J. Org. Chem. 1976, 41, 2628),
[0576] Acid: 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic
acid
[0577] ES-MS m/e (%): 424.2 (M+H.sup.+).
Example 16
1'-[{5-(trifluoromethoxy)-1H-indol-2-yl]carbonyl}spiro[1-benzofuran-3,4'-p-
iperidine]
##STR00040##
[0579] Amide coupling according to general procedure I:
[0580] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0581] Acid: 5-Trifluoromethoxy-1H-indole-2-carboxylic acid,
[0582] ES-MS m/e (%): 415.5 (M-H.sup.+).
Example 17
1'-[(6-bromo-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00041##
[0584] Amide coupling according to general procedure I:
[0585] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)-Acid: 6-Bromo-1H-indole-2-carboxylic acid,
[0586] ES-MS m/e (%): 409.4 (M-H.sup.+).
Example 18
1'-[(5-methoxy-3-methyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-pip-
eridine]
##STR00042##
[0588] Amide coupling according to general procedure I:
[0589] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0590] Acid: 5-Methoxy-3-methyl-1H-indole-2-carboxylic acid,
[0591] ES-MS m/e (%): 377.4 (M+H.sup.+).
Example 19
1'-[(6,7-dimethyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidin-
e]
##STR00043##
[0593] Amide coupling according to general procedure I:
[0594] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0595] Acid: 6,7-Dimethyl-1H-indole-2-carboxylic acid,
[0596] ES-MS m/e (%): 361.5 (M+H.sup.+).
Example 20
1'-[(5-bromo-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00044##
[0598] Amide coupling according to general procedure I:
[0599] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0600] Acid: 5-Bromo-1H-indole-2-carboxylic acid,
[0601] ES-MS m/e (%): 409.4 (M-H.sup.+).
Example 21
1'-[(5-isopropoxy-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidin-
e]
##STR00045##
[0603] Amide coupling according to general procedure I:
[0604] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0605] Acid: 5-Isopropoxy-1H-indole-2-carboxylic acid,
[0606] ES-MS m/e (%): 391.4 (M+H.sup.+).
Example 22
1'-{[5-(allyloxy)-1H-indol-2-yl]carbonyl}spiro[1-benzofuran-3,4'-piperidin-
e]
##STR00046##
[0608] Amide coupling according to general procedure I:
[0609] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0610] Acid: 5-Allyloxy-1H-indole-2-carboxylic acid (described in
US 2004157841),
[0611] ES-MS m/e (%): 389.4 (M+H.sup.+).
Example 23
1'-(5H-[1,3]dioxolo[4,5-f]indol-6-ylcarbonyl)spiro[1-benzofuran-3,4'-piper-
idine]
##STR00047##
[0613] Amide coupling according to general procedure I:
[0614] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0615] Acid: 5H-[1,3]Dioxolo[4,5-f]indole-6-carboxylic acid,
[0616] ES-MS m/e (%): 377.4 (M+H.sup.+).
Example 24
1'-[(3,6,7-trimethyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperi-
dine]
##STR00048##
[0618] Amide coupling according to general procedure I:
[0619] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0620] Acid: 3,6,7-Trimethyl-1H-indole-2-carboxylic acid,
[0621] ES-MS m/e (%): 375.4 (M+H.sup.+).
Example 25
1'-[(3,5-dimethyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidin-
e]
##STR00049##
[0623] Amide coupling according to general procedure I:
[0624] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0625] Acid: 3,5-Dimethyl-1H-indole-2-carboxylic acid,
[0626] ES-MS m/e (%): 361.4 (M+H.sup.+).
Example 26
1'-[(3,7-dimethyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidin-
e]
##STR00050##
[0628] Amide coupling according to general procedure I:
[0629] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0630] Acid: 3,5-Dimethyl-1H-indole-2-carboxylic acid,
[0631] ES-MS m/e (%): 361.4 (M+H.sup.+).
Example 27
1'-[(6-methoxy-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00051##
[0633] Amide coupling according to general procedure I:
[0634] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0635] Acid: 6-Methoxy-1H-indole-2-carboxylic acid,
[0636] ES-MS m/e (%): 363.4 (M+H.sup.+).
Example 28
1'-[(5-methoxy-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00052##
[0638] Amide coupling according to general procedure I:
[0639] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0640] Acid: 5-Methoxy-1H-indole-2-carboxylic acid,
[0641] ES-MS m/e (%): 363.4 (M+H.sup.+).
Example 29
1'-[(5-fluoro-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00053##
[0643] Amide coupling according to general procedure I:
[0644] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0645] Acid: 5-Fluoro-1H-indole-2-carboxylic acid,
[0646] ES-MS m/e (%): 351.4 (M+H.sup.+).
Example 30
1'-[(5-chloro-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-piperidine]
##STR00054##
[0648] Amide coupling according to general procedure I:
[0649] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0650] Acid: 5-Chloro-1H-indole-2-carboxylic acid,
[0651] ES-MS m/e (%): 367.4 (M+H.sup.+).
Example 31
1'-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]spiro[1-benzofuran-3,4'-pipe-
ridine]
##STR00055##
[0653] Amide coupling according to general procedure I:
[0654] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0655] Acid: 5-Chloro-1-methyl-1H-indole-2-carboxylic acid,
[0656] ES-MS m/e (%): 381.4 (M+H.sup.+).
Example 32
[5-chloro-2-(1'H-spiro[1-benzofuran-3,4'-piperidin]-1'-ylcarbonyl)-1H-indo-
l-1-yl]acetonitrile
##STR00056##
[0658] Amide coupling according to general procedure I:
[0659] Amine: Spiro[benzofuran-3(2H), 4'-piperidine] (prepared as
in WO 2006092731)
[0660] Acid: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic
acid,
[0661] ES-MS m/e (%): 406.4 (M+H.sup.+).
Example 33
5-bromo-1'-[(6-bromo-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]-2-
(1H)-one
##STR00057##
[0663] Amide coupling according to general procedure I:
[0664] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein below)
[0665] Acid: 6-Bromo-1H-indole-2-carboxylic acid,
[0666] ES-MS m/e (%): 504.3 (M+H.sup.+).
5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
##STR00058##
[0667] 1,5-Dichloro-3-methyl-3-azapentane, Hydrochloride 3
[0668] Formic acid (10.0 g; 0.2 mol) and 37% formaldehyde (20 ml)
were mixed in a 250 ml round-bottom flask equipped with reflux
condenser. 1,5-Dichloro-3-azapentane, hydrochloride
[0669] (17.0 g; 0.1 mol) was added and the solution was heated with
magnetic stirring at 100.degree. C. After 3 h the temperature was
increased to 120.degree. C. for 20 min and finally allowed to cool
to room temperature before the solvent was evaporated in vacuo to
afford 3 as white solid in quantitative yield. .sup.1HNMR
(CD.sub.3OD, 400 MHz) .delta. 3.0 (s, 3H); 3.45 (br s, 2H); 3.62
(br s, 2H); 4.07 (br s, 4H).
1,2-Benzo-8-methyl-3,8-diazaspiro[4,5]decane-4-one 5
[0670] A solution of oxindole 4 (6.25 g, 47 mmol) in THF (500 ml)
was cooled to -78.degree. C. and to it a solution of sodium
hexamethyldisilazide (43 g, 235 mmol) in THF (300 ml) was added
drop wise under N2 atmosphere. After stirring at -78.degree. C. for
45 min, N-methylbis (2-chloromethyl) amine hydrochloride (9 g, 47
mmol) was added, as a solid. The reaction mixture was stirred at
-78.degree. C. for 1 h and at room temperature for 24 h. After
quenching with H.sub.2O (90 ml), the mixture was extracted with
ethyl acetate (3.times.100 ml). The organic extracts were washed
with brine (25 ml), dried and the solvent removed in vacuo. Silica
gel chromatography (5-50% MeOH/CH.sub.2Cl.sub.2, gradient) gave 6 g
(57%) of 5 as a solid. .sup.1HNMR (CD.sub.3OD, 400 MHz) .delta.
1.84(m, 2H); 2.51 (m, 2H); 2.62 (s, 3H); 3.02 (m, 2H); 3.37 (m,
2H); 6.82 (d, 1H, J=7.68 Hz); 6.94 (t, 1H, J=7.58 Hz); 7.12 (t, 1H,
J=7.7 Hz); 7.26 (d, 1H, J=9 Hz); 9.27 (br s, 1H).
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4'-piperidine]-1'-methyl
6
[0671] A solution of
1,2-Benzo-8-methyl-3,8-diazaspiro[4,5]decane-4-one (6.3 g, 29.1
mmol) in CH.sub.3CN (100 ml) and MeOH (5 ml) was cooled to
-50.degree. C. and NBS (7.8 g, 44 mmol) was slowly added with
stirring. The reaction mixture was stirred for 3.5 h at 0.degree.
C. Solvent was removed by vacuo. The residue was purified by silica
gel chromatography (2-20% MeOH/CH.sub.2Cl.sub.2) to give 6 g as a
solid. The solid compound was dissolved in ethyl acetate (600 ml)
and washed with saturated aqueous NaHCO.sub.3 solution, dried
(Na.sub.2SO.sub.4). Evaporation of the solvent in vacuo gave 4.2 g
(47%) of 6. .sup.1HNMR (CD.sub.3OD, 400 MHz) .delta. 7.51(d, J=1.8
Hz, 1H), 7.35 (dd, J=1.9 and 8.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H),
2.93 (m, 2H), 2.67 (m, 2H), 2.41 (s, 3H), 1.86 (m, 4H).
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4-piperidine]-1-cyano
7
[0672]
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4/-piperidine]-1/-methyl
6 (4.6 g, 15.6 mmol) was dissolved in chloroform (700 ml) and
treated with CNBr (22 g, 209.5 mmol) at room temperature. The
mixture was heated to reflux for 24 h. The reaction mixture was
cooled, diluted with methylene chloride (300 ml) and washed with
10% aqueous K.sub.2CO.sub.3 solution (2.times.100 ml). After the
mixture was dried (Na.sub.2SO.sub.4) and concentrated, the residue
was purified by silica gel chromatography (0-5%
MeOH/CH.sub.2Cl.sub.2) to gave 7 as a solid 3.9 g (82%). .sup.1HNMR
(CDCl.sub.3, 400 MHz) .delta. 7.52 (d, J=1.8 Hz, 1H), 7.37 (dd,
J=1.8 and 8.2 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.83 (m, 2H), 3.41
(m, 2H), 2.00 (m, 2H), 1.86 (m, 2H).
5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one 2
[0673]
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4.sup./-piperidine]-1.su-
p./-cyano 7 (3.3 g, 10.8 mmol) was suspended in ethylene glycol (10
ml). The mixture was treated in NaOH (1.8 g, 45 mmol) and heated to
130.degree. C. for 15 min. It was diluted with methylene chloride
(500 ml) and washed with 10% aqueous K.sub.2CO.sub.3 (2.times.100
m). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated
and residue purified by silica gel chromatography (30%
MeOH/CH.sub.2Cl.sub.2) to gave 2 as a light ceramic white solid 1.8
g (60%), mp 256-258.degree. C. .sup.1HNMR (DMSO-d.sub.6, 400 MHz)
.delta. 10.6(br s, 1H, NH), 7.57 (d, J=1.84 Hz, 1H), 7.36 (d, J=8.2
Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.05 (br s, 1H, NH), 3.06 (m, 2H),
2.84 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), .sup.13C NMR
(DMSO-d.sub.6, 100 MHz) .delta. 180.93, 140.64, 137.98, 130.42,
126.75, 113.20, 111.45, 46.24, 40.92, 32.94. Anal.Calcd for
C.sub.12H.sub.13BrN.sub.2O: C, 51.26; H, 4.66; N, 9.9. Found: C,
50.87; H, 4.91; N, 9.67.
Example 34
5-Bromo-1'-[(5-methoxy-3-methyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-p-
iperidin]-2(1H)-one
##STR00059##
[0675] Amide coupling according to general procedure I:
[0676] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0677] Acid: 5-Methoxy-3-methyl-1H-indole-2-carboxylic acid,
[0678] ES-MS m/e (%): 468.4 (M+H.sup.+).
Example 35
5-Bromo-1'-[(6,7-dimethyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperid-
in]-2(1H)-one
##STR00060##
[0680] Amide coupling according to general procedure I:
[0681] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0682] Acid: 6,7-Dimethyl-1H-indole-2-carboxylic acid,
[0683] ES-MS m/e (%): 452.4 (M+H.sup.+).
Example 36
5-Bromo-1'-[(5-bromo-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]-2-
(1H)-one
##STR00061##
[0685] Amide coupling according to general procedure I:
[0686] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0687] Acid: 5-Bromo-1H-indole-2-carboxylic acid,
[0688] ES-MS m/e (%): 504.3 (M+H.sup.+).
Example 37
5-Bromo-1'-(5H-[1,3]dioxolo[4,5-f]indol-6-ylcarbonyl)spiro[indole-3,4'-pip-
eridin]-2(1H)-one
##STR00062##
[0690] Amide coupling according to general procedure I:
[0691] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0692] Acid: 5H-[1,3]Dioxolo[4,5-f]indole-6-carboxylic acid,
[0693] ES-MS m/e (%): 468.3 (M+H.sup.+).
Example 38
5-Bromo-1'-[(3,6,7-trimethyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-pipe-
ridin]-2(1H)-one
##STR00063##
[0695] Amide coupling according to general procedure I:
[0696] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0697] Acid: 3,6,7-Trimethyl-1H-indole-2-carboxylic acid,
[0698] ES-MS m/e (%): 466.4 (M+H.sup.+).
Example 39
5-Bromo-1'-[(3,7-dimethyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperid-
in]-2(1H)-one
##STR00064##
[0700] Amide coupling according to general procedure I:
[0701] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0702] Acid: 3,7-Dimethyl-1H-indole-2-carboxylic acid,
[0703] ES-MS m/e (%): 452.4 (M+H.sup.+).
Example 40
5-Bromo-1'-[(6-methoxy-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]-
-2(1H)-one
##STR00065##
[0705] Amide coupling according to general procedure I:
[0706] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0707] Acid: 6-Methoxy-1H-indole-2-carboxylic acid,
[0708] ES-MS m/e (%): 454.4 (M+H.sup.+).
Example 41
5-Bromo-1'-[(5-fluoro-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]--
2(1H)-one
##STR00066##
[0710] Amide coupling according to general procedure I:
[0711] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0712] Acid: 5-Fluoro-1H-indole-2-carboxylic acid,
[0713] ES-MS m/e (%): 442.3 (M+H.sup.+).
Example 42
5-Bromo-1'-[(7-methyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]--
2(1H)-one
##STR00067##
[0715] Amide coupling according to general procedure I:
[0716] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0717] Acid: 7-Methyl-1H-indole-2-carboxylic acid,
[0718] ES-MS m/e (%): 438.4 (M+H.sup.+).
Example 43
5-Bromo-1'-[(4-chloro-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-piperidin]--
2(1H)-one
##STR00068##
[0720] Amide coupling according to general procedure I:
[0721] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0722] Acid: 4-Chloro-1H-indole-2-carboxylic acid,
[0723] ES-MS m/e (%): 458.3 (M+H.sup.+).
Example 44
5-Bromo-1'-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]spiro[indole-3,4'-pi-
peridin]-2(1H)-one
##STR00069##
[0725] Amide coupling according to general procedure I:
[0726] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0727] Acid: 5-Chloro-1-methyl-1H-indole-2-carboxylic acid,
[0728] ES-MS m/e (%): 472.3 (M+H.sup.+).
Example 45
{2-[(5-Bromo-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)carb-
onyl]-1H-indol-1-yl}acetonitrile
##STR00070##
[0730] Amide coupling according to general procedure I:
[0731] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0732] Acid: 1-Cyanomethyl-1H-indole-2-carboxylic acid (prepared
herein below),
[0733] ES-MS m/e (%): 463.3 (M+H.sup.+).
Example 46
{2-[(5-Bromo-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-1'-yl)carb-
onyl]-5-chloro-1H-indol-1-yl}acetonitrile
##STR00071##
[0735] Amide coupling according to general procedure I:
[0736] Amine: 5-Bromo-spiro[indole-3,4'-piperidin]-2(1H)-one
(prepared as described herein above)
[0737] Acid: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid
(prepared herein above),
[0738] ES-MS m/e (%): 497.3 (M+H.sup.+).
Example 47
1'-[(5-Chloro-1H-indol-2-yl)carbonyl]-4-methylspiro[indole-3,4'-piperidin]-
-2(1H)-one
##STR00072##
[0740] Amide coupling according to general procedure I:
[0741] Amine: 4-methylspiro[indole-3,4'-piperidin]-2(1H)-one
[0742] Acid: 5-Chloro-1H-indole-2-carboxylic acid,
[0743] ES-MS m/e (%): 394.4 (M+H.sup.+).
* * * * *