U.S. patent application number 12/769861 was filed with the patent office on 2010-10-28 for tricyclic pyrazole derivatives as cannabinoid receptor modulators.
This patent application is currently assigned to CADILA HEALTHCARE LIMITED. Invention is credited to Braj Bhushan LOHRAY, Vidya Bhushan Lohray, Brijesh Srivastava.
Application Number | 20100273791 12/769861 |
Document ID | / |
Family ID | 35636669 |
Filed Date | 2010-10-28 |
United States Patent
Application |
20100273791 |
Kind Code |
A1 |
LOHRAY; Braj Bhushan ; et
al. |
October 28, 2010 |
TRICYCLIC PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR
MODULATORS
Abstract
The present invention relates to novel compounds of general
formula (I), ##STR00001## their regioisomers, tautomeric forms,
novel intermediates involved in their synthesis. The present
invention also relates to a process of preparing compounds of
general formula (I), their regioisomers, their tautomeric forms,
their pharmaceutically acceptable salts, pharmaceutical
compositions containing them, and novel intermediates involved in
their synthesis.
Inventors: |
LOHRAY; Braj Bhushan;
(Ahmedabad, IN) ; Lohray; Vidya Bhushan;
(Ahmedabad, IN) ; Srivastava; Brijesh; (Ahmedabad,
IN) |
Correspondence
Address: |
LADAS & PARRY LLP
26 WEST 61ST STREET
NEW YORK
NY
10023
US
|
Assignee: |
CADILA HEALTHCARE LIMITED
|
Family ID: |
35636669 |
Appl. No.: |
12/769861 |
Filed: |
April 29, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11632236 |
Aug 24, 2007 |
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12769861 |
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Current U.S.
Class: |
514/232.8 ;
514/254.06; 514/322; 514/406; 514/407; 544/140; 544/371; 546/199;
548/359.1; 548/359.5; 549/355; 549/9; 560/51 |
Current CPC
Class: |
C07D 495/04 20130101;
C07D 495/14 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/232.8 ;
548/359.1; 546/199; 548/359.5; 544/140; 544/371; 514/406; 514/322;
514/407; 514/254.06; 560/51; 549/355; 549/9 |
International
Class: |
A61K 31/416 20060101
A61K031/416; C07D 231/54 20060101 C07D231/54; C07D 491/044 20060101
C07D491/044; C07D 495/04 20060101 C07D495/04; A61K 31/454 20060101
A61K031/454; A61K 31/4162 20060101 A61K031/4162; A61K 31/5377
20060101 A61K031/5377; A61K 31/496 20060101 A61K031/496; C07C
69/738 20060101 C07C069/738; C07D 313/08 20060101 C07D313/08; C07D
337/08 20060101 C07D337/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 12, 2004 |
IN |
745/MUM/2004 |
Claims
1-15. (canceled)
16. A compound of formula (I): ##STR00008## a tautomeric form, or
pharmaceutically acceptable salt thereof, wherein Ar represents a
single or fused group selected from the group consisting of aryl,
heterocyclyl or heteroaryl group, optionally substituted with one
or more groups selected from the group consisting of hydroxy, halo,
amino or optionally substituted groups selected from the group
consisting of linear or branched alkyl, monosubstituted or
disubstituted amino, alkoxy or acyl group wherein the substituted
alkyl, monosubstituted or disubstituted amino, alkoxy or acyl group
is substituted by one or more of hydroxy, halo, amino, linear or
branched alkyl, monosubstituted or disubstituted amino, alkoxy or
acyl group; a) A represents an optionally substituted
heteroaromatic group, and X is selected from the group consisting
of --CH.sub.2--, O, S, SO, SO.sub.2, or NR', where R' represents H
or an optionally substituted group selected from linear or branched
alkyl and cycloalkyl group and m and n represent integers such that
1.ltoreq.m+n.ltoreq.3; b) A represents a substituted aromatic
group, and X is selected from the group consisting of O, S, SO,
SO.sub.2, or NR', where R' represents H or an optionally
substituted group selected from linear or branched alkyl, and
cycloalkyl group and m and n represent integers such that
2.ltoreq.m+n.ltoreq.3; or c) A represents optionally substituted
heterocyclic groups, and X is selected from the group consisting of
--CH.sub.2--, O, S, SO, SO2, or NR', where R' represents H or an
optionally substituted group selected from linear or branched alkyl
and cycloalkyl groups and m and n represent integers such that
1.ltoreq.m+n.ltoreq.3; wherein when A is substituted, the one or
more substituents are the selected from the group consisting of
halogen, hydroxyl, thio, nitro, amino, cyano, or an optionally
substituted group selected from linear or branched alkyl, alkoxy,
thioalkyl, haloalkyl, haloalkoxy, acyl, and aminoalkyl groups;
wherein the substituted alkyl, alkoxy, thioalkyl, haloalkyl,
haloalkoxy, acyl and aminoalkyl groups are substituted by one or
more of halogen, hydroxyl, thio, nitro, amino, cyano, linear or
branched alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl, and
aminoalkyl groups; R.sub.1 represents O, S, or the group
represented by N-Q, where Q represents H or substituted alkyl; or
R.sub.1 represents the group represented by SO.sub.2R'', where R''
represents H, --OH, halogen or a substituted or unsubstituted group
selected from alkyl, aryl, heteroaryl or heterocyclic groups;
R.sub.2 is either H or (C.sub.1-C.sub.6) alkyl; R.sub.3 is
NR.sub.bR.sub.c wherein R.sub.b and R.sub.c are the same or
different and are selected from an optionally substituted group
selected from alkyl, aralkyl or alkenyl or R.sub.b and R.sub.c
together with the nitrogen atom to which they are bonded, form a
saturated or unsaturated heterocyclic or heteroaromatic
radical.
17. A compound as claimed in claim 16, wherein the alkyl group is
selected from a linear or branched alkyl group comprising from one
to eight carbon atoms.
18. A compound as claimed in claim 16, wherein the aryl group is
selected from a monocyclic, bicyclic or tricyclic aryl group.
19. A compound as claimed in claim 16, wherein the aryl group is
selected from phenyl, naphthyl, tetrahydronaphthyl, indane, and
biphenyl group.
20. A compound as claimed in claim 16, wherein the heterocyclyl is
selected from saturated, partially saturated or unsaturated
aromatic or non-aromatic mono, bi or tricyclic groups, containing
one or more heteroatoms selected from N, O, and S.
21. A compound as claimed in claims 16, wherein the heterocycyl
group is selected from the group consisting of aziridinyl,
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl,
3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl,
azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl,
thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran,
dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl,
benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl,
thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl,
benzoxazinonyl, benzothiazinyl, benzothiazinonyl, and thieno
piperidinyl groups.
22. A compound as claimed in claim 16, wherein the heteroaryl group
is selected from optionally fused mono, bi or tricyclic aromatic
heteroaromatic groups containing one or more heteroatoms selected
from O, N and S.
23. A compound as claimed in claim 16, wherein the heteroaryl group
is selected from the group consisting of pyridyl, thienyl, furyl,
pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl,
isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl,
azaindolinyl, pyrazolopylimidinyl, azaquinazolinyl, pyridofuranyl,
pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl,
quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl,
benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl,
phenothiazinyl, phenoxazinyl, benzoxazolyl, and benzothiazolyl
group.
24. A compound as claimed in claim 16, selected from the group
consisting of:
4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2--
diaza-benzo[e]azulene-3-yl]-methylamino-methylene}-benzenesulfonamide
and its pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid-(4-hydroxy-piperidin-1-yl-amide and its
pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-yl amide and its
pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide
and its pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid morpholine-4-yl-amide and its
pharmaceutically acceptable salts;
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid (4-methyl-piperazine-1-yl)-amide and its
pharmaceutically acceptable salts;
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts;
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid pyrrolidin-1-ylamide and its pharmaceutically
acceptable salts;
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid morpholin-4-ylamide and its pharmaceutically
acceptable salts;
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid N'-cyclopropyl-hydrazide and its
pharmaceutically acceptable salts;
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts;
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts;
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-ylamide and its
pharmaceutically acceptable salts;
1-(4-chloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts;
1-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza--
cyclopenta [e]azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts;
8-Chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza-cycl-
openta [e]azulene-3-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide and its pharmaceutically
acceptable salts;
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6,7-dithia-1,2-diaza-cycl-
openta[e]azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts;
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-inda-
cene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts;
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-inda-
cene-3-carboxylic acid (hexahydro-cyclopenta [c]pyrrol-2-yl)-amide
and its pharmaceutically acceptable salts;
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-thia-1,2-diaza-benzo[e]-
azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; and
8-Bromo-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]az-
ulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts.
25. A pharmaceutical composition which comprises a compound as
claimed in claim 16 and at least one of a pharmaceutically
acceptable carrier, diluent or excipient.
26. A pharmaceutical composition which comprises a compound as
claimed in claim 24 and at least one of a pharmaceutically
acceptable carrier, diluent or excipient.
27. A method of treatment of a disease associated with cannabinoid
receptors by administering a therapeutically recommended amount of
the compound as claimed in claim 16 to a mammal, in need of such
treatment.
28. A method of treatment of a disease associated with cannabinoid
receptors by administering a therapeutically recommended amount of
the composition as claimed in claim 24 to a mammal, in need of such
treatment.
29. A method of treatment of a disease associated with cannabinoid
receptors by administering a therapeutically recommended amount of
the composition as claimed in claim 25 to a mammal, in need of such
treatment.
30. A method of treatment of a disease associated with cannabinoid
receptors by administering a therapeutically recommended amount of
the composition as claimed in claim 26 to a mammal, in need of such
treatment.
31. The method according to claim 27, wherein the mammal is a
human.
32. A process for preparing a compound of formula (I) as claimed in
claim 16, wherein Ar, A, X, R.sup.1, R.sup.2, R.sup.3, m and n are
as defined in claim 16, comprises the steps of: i) converting a
compound of formula (2) to compound of formula (4) by reacting with
a substituted hydrazine hydrochloride of formula (3), ##STR00009##
wherein A, X, m and n are as defined in claim 16 and R is an alkyl
group ii) hydrolyzing the compound of formula (4) to obtain the
acid of formula (5), ##STR00010## wherein A, X, m and n are as
defined in claim 16; and R is an alkyl group; iii) converting the
compound of formula (5) to compound of formula (I) by treating with
suitable substituted amine of formula NR.sub.2R.sub.3, where
R.sub.2 and R.sub.3 are as defined in claim 16, ##STR00011## iv)
alternatively, converting the compound of formula (5) to a compound
of formula (7) by treatment with a compound of formula NH.sub.2Q,
where Q is as defined in claim 16, ##STR00012## v) converting the
compound of formula (7) to compound of formula (8) ##STR00013##
where Ar, A, X, Q, m and n are as defined in claim 16; and vi)
converting the compound of formula (8) to a compound of formula (I)
by treatment with a substituted amine of formula NR.sub.2R.sub.3,
where R.sub.2 and R.sub.3 are as defined in claim 16
##STR00014##
33. An intermediate of formula (2) ##STR00015## wherein: a) A
represents an optionally substituted heteroaromatic group, and X is
selected from the group consisting of --CH.sub.2--, O, S, SO,
SO.sub.2, or NR', where R' represents H or a optionally substituted
group selected from linear or branched alkyl and cycloalkyl groups
and m and n represent integers such that 1.ltoreq.m+n.ltoreq.3; b)
A represents a substituted aromatic group and X is selected from
the group consisting of O, S, SO, SO.sub.2, or NR', where R'
represents H or a optionally substituted group selected from linear
or branched alkyl, and cycloalkyl group and m and n represents
integers such that 2.ltoreq.m+n.ltoreq.3; c) A represents an
optionally substituted heterocyclic group, and X is selected from
the group consisting of --CH.sub.2--, O, S, SO, SO.sub.2, or NR,
where R' represents H or an optionally substituted group selected
from linear or branched alkyl and cycloalkyl groups and m and n
represents integers such that 1.ltoreq.m+n.ltoreq.3; or d) A
represents an optionally substituted alicyclic group, and X is
selected from the group consisting of --CH.sub.2--, O, S, SO,
SO.sub.2, or NR', where R' represents H or an optionally
substituted group selected from linear or branched alkyl and
cycloalkyl groups and m and n represents integers such that
1.ltoreq.m+n.ltoreq.3; and R represents an alkyl group.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel compounds of general
formula (I), their regioisomers, tautomeric forms, novel
intermediates involved in their synthesis, their pharmaceutically
acceptable salts and pharmaceutical compositions containing them.
The present invention also relates to a process of preparing
compounds of general formula (I), their regioisomers, their
tautomeric forms, their pharmaceutically acceptable salts,
pharmaceutical compositions containing them, and novel
intermediates involved in their synthesis.
##STR00002##
BACKGROUND AND PRIOR ART
[0002] Cannabinoids are present in Indian hemp Cannabis saliva and
have been well known for their medicinal properties for ages.
Cannabinoids as a therapeutic agents is however a recent
phenomenon. (Williamson E. M. & Evans E. J. Drugs 2000
December; 60(6): 1303-14) Research in this area over the last
decade have provided very important information on the cannabinoid
receptors and their agonists and antagonists. Development of
central Cannabinoid receptor ligands with lower lipophilicity. (J.
Med. Chem. 2003; 46:642-645) Further cloning and isolation of two
different subtypes of cannabinoid receptors--CB.sub.1 (central
subtype) and CB.sub.2 (peripheral subtype) and the first endogenous
ligand N-arachidonyl ethanolamine amide(AEA); anadamide (Matsuda L
A et. al., Nature 1990; 346:561-4; Devane W A et. al. J. Med. Chem.
1992; 35:2065-9; Munro, S. et. al., Nature 1993, 365, 61-5) have
stimulated research in this field. There has also been an increased
interest among the different pharmaceutical companies in developing
drugs for the treatment of diseases connected with disorders of the
cannabinoid systems (Greenberg D. A., Drugs News & Perspectives
1999; 12: 458; Kulkarni S. K. & Ninan, Indian Journal of
Pharmacology 2001; 33: 170-184; Piomelli D et. al., Trends
Pharmacol Sci. 2000 June; 21(6): 218-24). Several compounds which
are either CB.sub.1 &/or CB.sub.2 antagonists have been
reported and are under various stages of development for e.g.
SR-141716 A(Sanofi), CP-272871(Pfizer), LY-320135 (Eli Lily),
AM-630 (Alexis), SR-144528(Sanofi) etc. Novel compounds which are
selective CB1 and/or CB2 antagonists, their preparation and their
use in medicine have also been reported in U.S. Pat. No. 5,925,768,
U.S. Pat. No. 6,344,474, U.S. Pat. No. 6,028,084, U.S. Pat. No.
5,462,960, EP 0656354, U.S. Pat. No. 6,432,984, U.S. Pat. No.
6,509,367 B1, U.S. Pat. No. 5,624,941, EP1230222, EP 122952, FR
2816938, FR 2761266, FR 2800375, EP 0656354, EP 0576357, WO
03027076, WO 03026648, WO 03026647, WO 03020217, WO 0158450, WO
0185092, WO 0132663, WO 0132629 which are incorporated as
references in their entirety.
[0003] Synthesis and biological evaluation of novel
4,5-dihydro-1H-benzo[g] indazole-based ligands for cannabinoid
receptors has been described in Bioorg. Med. Chem., 2005, 13,
3309-3320.
[0004] Synthesis of tricyclic pyrazole derivative (NESS 0327) as CB
1 antagonist has been disclosed in J Pharmacology &
Experimental Therapeutics, 2003:306(1), 363-370. Synthesis and
activity of tricyclic pyrazole ligands for CB1 & CB2 receptors
have been disclosed in Bioorg. Med. Chem., 2003, 11, 251-263.
[0005] Structure elucidation of novel ring constrained biaryl
pyrazole CB1 cannabinoid receptor antagonist has been described in
Magn. Reson. Chem. 2003, 41, 265-268.
[0006] Synthesis and biological activity of rigid cannabinoid CB1
cannabinoid receptor antagonists has been disclosed in Chem. Pharm.
Bull. 2002, 50, 1109-1113.
[0007] Tricyclic benzopyrazole derivatives as cyclooxygenase-2
(COX-2) inhibitors have been disclosed in WO 9609304, which is also
incorporated herein as reference.
[0008] Though research in the area of cannabinoids have been going
on for more than a decade there are only few medicines available
which modulate the cannabinoid receptors and fewer with minor side
effects. Looking at the beneficial effects of cannabinoids, it
would be highly desired to develop compounds, which modulate the
cannabinoid receptors, having better or comparable absorption,
metabolic stability, and exhibiting lesser toxicity.
SUMMARY OF INVENTION
[0009] The present invention describes novel compounds useful as
modulators of cannabinoid receptors. The novel compounds are
defined by the general formula (I) below:
##STR00003##
[0010] The compounds of the present invention mimic the actions of
the cannabinoids making them useful for preventing or reversing the
symptoms that can be treated with cannabis, some of its
derivatives, and synthetic cannabinoids in a human or other
mammalian subject. Preferably, the compounds of the present
invention are selective antagonists of the cannabis
CB.sub.I-receptor.
PREFERRED EMBODIMENTS OF THE INVENTION
[0011] The object of the present invention thus is to provide novel
compounds of general formula (I), their tautomeric forms, their
regioisomers, novel intermediates involved in their synthesis,
their pharmaceutically acceptable salts and pharmaceutical
compositions containing them or their mixtures and their use in
medicine.
##STR00004##
[0012] In an embodiment of the present invention is provided a
process for the preparation of novel compounds of general formula
(I), their regioisomers, their tautomeric forms, novel
intermediates involved in their synthesis, pharmaceutically
acceptable salts and pharmaceutical compositions containing
them.
[0013] In another embodiment is provided pharmaceutical
compositions containing compounds of general formula (I), their
tautomeric forms, their regioisomers, their pharmaceutically
acceptable salts and their mixtures having pharmaceutically
acceptable carriers, solvents, diluents, excipients and other media
normally employed in their manufacture.
[0014] In a further embodiment is provided a method of treatment of
diseases which can be treated or whose symptoms can be reversed
with cannabis or their derivatives both natural and synthetic, by
administering a therapeutically effective & non-toxic amount of
the compound of formula (I) or their pharmaceutically acceptable
compositions to the mammals.
DETAILED DESCRIPTION
[0015] The novel compounds of the present invention are defined by
the general formula (I) below:
##STR00005##
wherein `Ar` represents single or fused groups selected from aryl,
aralkyl, heterocyclyl, heteroaryl,
heterocyclyl(C.sub.1-C.sub.12)alkyl &
heteroar(C.sub.1-C.sub.12)alkyl group, each of them independently
may optionally be substituted;
[0016] `A` represents optionally substituted heteroaromatic groups,
"X` is selected from --CH.sub.2--, O, S, SO, SO.sub.2, or NR',
where R' represents H, optionally substituted groups selected from
linear or branched alkyl and cycloalkyl groups and, m & n
represents integers such that 1.ltoreq.m+n.ltoreq.3; or
[0017] `A` represents substituted aromatic group, "X` may be
selected from O, S, SO, SO.sub.2, or NR', where R' represents H,
optionally substituted groups selected from linear or branched
alkyl, and cycloalkyl groups and m & n represents integers such
that 2.ltoreq.m+n.ltoreq.3; or
[0018] `A` represents optionally substituted heterocyclic groups,
"X` may be selected from --CH.sub.2--, O, S, SO, SO.sub.2, or NR',
where R' represents H, optionally substituted groups selected from
linear or branched alkyl and cycloalkyl groups and m & n
represents integers such that 1.ltoreq.m+n.ltoreq.3; or
[0019] `A` represents optionally substituted alicyclic groups, "X`
may be selected from --CH.sub.2--, O, S, SO, SO.sub.2, or NR',
where R' represents H, optionally substituted groups selected from
linear or branched alkyl and cycloalkyl groups and m & n
represents integers such that 1.ltoreq.m+n.ltoreq.3; or
[0020] R.sub.1 represents O, S, or the group represented by N-Q,
where Q represents H, substituted or unsubstituted groups selected
from alkyl, aralkyl, aryl, heteroaryl or heterocyclic groups or the
group represented by SO.sub.2R'', where R'' represents H, --OH,
halogen or substituted or unsubstituted groups selected from alkyl,
aralkyl, aryl, heteroaryl or heterocyclic or alicyclic groups;
[0021] R.sub.2 is either H or (C.sub.1-C.sub.6) alkyl; R.sub.3
is
##STR00006##
or --NR.sub.bR.sub.c where R.sub.a is (C.sub.1-C.sub.6)alkyl or
R.sub.a forms a bridge containing 1-2 atoms, with one of the atoms
of the heterocyclic radical formed by --NR.sub.bRc;
[0022] R.sub.b and R.sub.c represents optionally substituted groups
selected from alkyl, aralkyl or alkenyl or R.sub.b & R.sub.c
together with the nitrogen atom to which they are bonded, form a
saturated or unsaturated heterocyclic or heteroaromatic radical
which may be optionally substituted and may be fused;
[0023] The substituents on `A` may be selected from hydroxyl, oxo,
halo, thio, nitro, amino, cyano, formyl, optionally substituted
groups selected from linear or branched alkyl, haloalkyl,
perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl,
alkoxy, alkenoxy, acyl, acyloxy, acylamino, monosubstituted or
disubstituted amino, carboxylic acid and its derivatives such as
esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,
aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino,
hydroxylamino groups; preferably, the substituents on `A` may be
selected from halogen, hydroxyl, thio, nitro, amino, cyano,
optionally substituted groups selected from linear or branched
alkyl, alkoxy, thioalkyl, haloalkyl, haloalkoxy, acyl, anlinoalkyl
groups;
[0024] The substituents on `Ar` may be selected from hydroxy, halo,
thio, nitro, amino, cyano, formyl, or optionally substituted groups
selected from amidino, linear or branched alkyl, haloalkyl,
perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl,
alkoxy, alkenoxy, monosubstituted or disubstituted amino,
carboxylic acid and its derivatives such as esters and amides,
carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio,
thioalkyl, alkylsulfonylamino, alkylsulfonyloxy,
alkoxycarbonylamino, hydroxylamino, sulfenyl derivatives, sulfonyl
derivatives, sulfonic acid and its derivatives; preferably the
substituents on `Ar` may be selected from hydroxy, halo, amino or
optionally substituted groups selected from linear or branched
alkyl, monosubstituted or disubstituted amino, alkoxy, acyl,
alkylthio, arylthio, alkylsulfonylamino, alkylsulfonyloxy,
carboxylic acid and its derivatives such as esters and amides;
[0025] The substituents on `A`, or `Ar` may further be optionally
substituted by any of the groups as mentioned above.
[0026] In a preferred embodiment the groups, radicals described
above may be selected from: [0027] the "alkyl" group used either
alone or in combination with other radicals, denotes a linear or
branched radical containing one to eight carbons, selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, iso-hexyl, heptyl,
octyl and the like; [0028] the "alkenyl" group used either alone or
in combination with other radicals, is selected from a radical
containing from two to twelve carbons, more preferably groups
selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the
like; the "alkenyl" group includes dienes and trienes of straight
and branched chains; [0029] the "alkynyl" group used either alone
or in combination with other radicals, is selected from a linear or
branched radical containing two to twelve carbon atoms, more
preferably thynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,
1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. The term
"alkynyl" includes di- and tri-ynes; [0030] the "cycloalkyl" or
"alicyclic" group used either alone or in combination with other
radicals, is selected from a cyclic radical containing three to
seven carbons, more preferably cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and the like; [0031] the
"cycloalkenyl" group used either alone or in combination with other
radicals, are preferably selected from cyclopropenyl,
1-cyclobutenyl, 2-cylobutenyl, 1-cyclopentenyl, 2-cyclopentenyl,
3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
1-cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like;
[0032] the "alkoxy" group used either alone or in combination with
other radicals, is selected from groups containing an alkyl
radical, as defined above, attached directly to an oxygen atom,
more preferably groups selected from methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy,
and the like; [0033] the "alkenoxy" group used either alone or in
combination with other radicals, is selected from groups containing
an alkenyl radical, as defined above, attached to an oxygen atom,
more preferably selected from vinyloxy, allyloxy, butenoxy,
pentenoxy, hexenoxy, and the like; [0034] the "haloalkyl" group is
selected from an alkyl radical, as defined above, suitably
substituted with one or more halogens; such as perhaloalkyl, more
preferably, perfluoro(C.sub.1-C.sub.6)alkyl such as fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl, difluoro ethyl,
trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl,
butyl, pentyl or hexyl groups; [0035] the "haloalkoxy" group is
selected from suitable haloalkyl, as defined above, directly
attached to an oxygen atom, more preferably groups selected from
fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy and the
like; [0036] the "perhaloalkoxy" group is selected from a suitable
perhaloalkyl radical, as defined above, directly attached to an
oxygen atom, more preferably groups selected from trifluoromethoxy,
trifluoroethoxy, and the like; [0037] the "aryl" or "aromatic"
group used either alone or in combination with other radicals, is
selected from a suitable aromatic system containing one, two or
three rings wherein such rings may be attached together in a
pendant manner or may be fused, more preferably the groups are
selected from phenyl, naphthyl, tetrahydronaphthyl, indane,
biphenyl, and the like; [0038] the "heterocyclyl" or "heterocyclic"
group used either alone or in combination with other radicals, is
selected from suitable saturated, partially saturated or
unsaturated aromatic or non aromatic mono, bi or tricyclic
radicals, containing one or more heteroatoms selected from
nitrogen, sulfur and oxygen, more preferably selected from
aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl,
3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl,
azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl,
thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran,
dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl,
benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl,
thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl,
benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno
piperidinyl, and the like; [0039] the "heteroaryl" or
"heteroaromatic" group used either alone or in combination with
other radicals, is selected from suitable single or fused mono, bi
or tricyclic aromatic heterocyclic radicals containing one or more
hetero atoms selected from O, N or S, more preferably the groups
are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl,
thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl,
indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl,
azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl,
quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl,
triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil,
naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl,
benzoxazolyl, benzothiazolyl and the like; [0040] the "the groups
"heteroaryloxy", "heteroaralkoxy", "heterocycloxy",
"heterocylylalkoxy" are selected from suitable heteroaryl,
heteroarylalkyl, heterocyclyl, heterocylylalkyl groups
respectively, as defined above, attached to an oxygen atom; [0041]
the "acyl" group used either alone or in combination with other
radicals, is selected from a radical containing one to eight
carbons, more preferably selected from formyl, acetyl, propanoyl,
butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and
the like, which may be substituted; [0042] the "acyloxy" group used
either alone or in combination with other radicals, is selected
from a suitable acyl group, as defined above, directly attached to
an oxygen atom, more preferably such groups are selected from
acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy
and the like; [0043] the "acylamino" group used either alone or in
combination with other radicals, is selected from a suitable acyl
group as defined earlier, attached to an amino radical, more
preferably such groups are selected from CH.sub.3CONH,
C.sub.2H.sub.5CONH, C.sub.3H.sub.7CONH, C.sub.4H.sub.9CONH,
C.sub.6H.sub.5CONH and the like, which may be substituted; [0044]
the "mono-substituted amino" group used either alone or in
combination with other radicals, represents an amino group
substituted with one group selected from (C.sub.1-C.sub.6)alkyl,
substituted alkyl, aryl, substituted aryl or arylalkyl groups as
defined earlier, more preferably such groups are selected from
methylamine, ethylamine, n-propylamine, n-butylamine, n-pentylamine
and the like; [0045] the `disubstituted amino" group used either
alone or in combination with other radicals, represents an amino
group, substituted with two radicals that may be same or different
selected from (C.sub.1-C.sub.6)alkyl, substituted alkyl, aryl,
substituted aryl, or arylalkyl groups, as defined above, more
preferably the groups are selected from dimethylamino,
methylethylamino, diethylamino, phenylmethyl amino and the like;
[0046] the "arylamino" used either alone or in combination with
other radicals, represents an aryl group, as defined above, linked
through amino having a free valence bond from the nitrogen atom,
more preferably the groups are selected from phenylamino,
naphthylamino, N-methyl anilino and the like; [0047] the "oxo" or
"carbonyl" group used either alone (--C.dbd.O--) or in combination
with other radicals such as alkyl described above, for e.g.
"alkylcarbonyl", denotes a carbonyl radical (--C.dbd.O--)
substituted with an alkyl radical described above such as acyl or
alkanoyl; [0048] the "carboxylic acid" group, used alone or in
combination with other radicals, denotes a --COOH group, and
includes derivatives of carboxylic acid such as esters and amides;
[0049] the "ester" group used alone or in combination with other
radicals, denotes --COO-- group, and includes carboxylic acid
derivatives, more preferably the ester moieties are selected from
alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the
like, which may optionally be substituted; aryloxycarbonyl group
such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which
may optionally be substituted; aralkoxycarbonyl group such as
benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl,
and the like, which may optionally be substituted;
heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the
heteroaryl group, is as defined above, which may optionally be
substituted; heterocyclyloxycarbonyl, where the heterocyclic group,
as defined earlier, which may optionally be substituted; [0050] the
"amide" group used alone or in combination with other radicals,
represents an aminocarbonyl radical (H.sub.2N--C.dbd.O--), wherein
the amino group is mono- or di-substituted or unsubstituted, more
preferably the groups are selected from methylamide, dimethylamide,
ethylamide, diethylamide, and the like; [0051] the "aminocarbonyl"
group used either alone or in combination with other radicals, may
be selected from `aminocarbonyl`, `aminocarbonylalkyl",
"n-alkylaminocarbonyl", "N-arylaminocarbonyl",
"N,N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl",
"N-alkyl-N-hydroxyaminocarbonyl", and
"N-alkyl-N-hydroxyaminocarbonylalkyl", each of them being
optionally substituted. The terms "N-alkylaminocabonyl" and
"N,N-dialkylaminocarbonyl" denotes aminocarbonyl radicals, as
defined above, which have been substituted with one alkyl radical
and with two alkyl radicals, respectively. Preferred are "lower
alkylaminocarbonyl" having lower alkyl radicals as described above
attached to aminocarbonyl radical. The terms "N-arylaminocarbonyl"
and "N-alkyl-N-arylaminocarbonyl" denote amiocarbonyl radicals
substituted, respectively, with one aryl radical, or one alkyl, and
one aryl radical. The term "aminocarbonylalkyl" includes alkyl
radicals substituted with aminocarbonyl radicals; [0052] the
"hydroxyalkyl" group used either alone or in combination with other
radicals, is selected from an alkyl group, as defined above,
substituted with one or more hydroxy radicals, more preferably the
groups are selected from hydroxymethyl, hydroxyethyl,
hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the
like; [0053] the "aminoalkyl" group used alone or in combination
with other radicals, denotes an amino (--NH.sub.2) moiety attached
to an alkyl radical, as defined above, which may be substituted,
such as mono- and di-substituted aminoalkyl. The term "alkylamino"
used herein, alone or in combination with other radicals, denotes
an alkyl radical, as defined above, attached to an amino group,
which may be substituted, such as mono- and di-substituted
alkylamino; [0054] the "alkoxyalkyl" group used alone or in
combination with other radicals, denotes an alkoxy group, as
defined above, attached to an alkyl group as defined above, more
preferably the groups may be selected from methoxymethyl,
ethoxymethyl, methoxyethyl, ethoxyethyl and the like; [0055] the
"alkylthio" group used either alone or in combination with other
radicals, denotes a straight or branched or cyclic monovalent
substituent comprising an alkyl group as defined above, linked
through a divalent sulfur atom having a free valence bond from the
sulfur atom, more preferably the groups may be selected from
methylthio, ethylthio, propylthio, butylthio, pentylthio and the
like or cyclic alkylthio selected from cyclopropylthio,
cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which
may be optionally substituted; [0056] the "thioplkyl" group used
either alone or in combination with other radicals, denotes an
alkyl group, as defined above, attached to a group of formula
--SR', where R' represents hydrogen, alkyl or aryl group, e.g.
thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which
may be optionally substituted. [0057] the "alkoxycarbonylamino"
group used alone or in combination with other radicals, is selected
from a suitable alkoxycarbonyl group, as defined above, attached to
an amino group, more preferably methoxycarbonylamino,
ethoxycarbonylamino, and the like; [0058] the "aminocarbonylamino",
"alkylaminocarbonylamino", "dialkylaminocarbonylamino" groups used
alone or in combination with other radicals, is a carbonylamino
(--CONH.sub.2) group, attached to amino (NH.sub.2), alkylamino
group or dialkylamino group respectively, where alkyl group is as
defined above; [0059] the "amidino" group used either alone or in
combination with other radicals, represents a
--C(.dbd.NH)--NH.sub.2 radical; the "alkylamidino" group represents
an alkyl radical, as described above, attached to an amidino group;
[0060] the "hydrazino" group used either alone or in combination
with other radicals, represents a group of the formula --NHNH--,
suitably substituted with other radicals, selected from those
described above such as an alkyl hydrazino, where an alkyl group,
as defined above is attached to a hydrazino group; [0061] the
"alkoxyamino" group used either alone or in combination with other
radicals, represents a suitable alkoxy group as defined above,
attached to an amino group; [0062] the "hydroxyamino" group used
either alone or in combination with other radicals, represents a
--NHOH moiety, and may be optionally substituted with suitable
groups selected from those described above; [0063] the "sulfenyl"
group or "sulfenyl derivatives" used alone or in combination with
other radicals, represents a bivalent group, --SO-- or R.sub.xSO,
where R.sub.x is an optionally substituted alkyl, aryl, heteroaryl,
heterocyclyl, group selected from those described above; [0064] the
"sulfonyl" group or "sulfones derivatives" used either alone or in
combination with other radicals, with other terms such as
alkylsulfonyl, represents a divalent radical --SO.sub.2--, or
R.sub.xSO.sub.2--, where R.sub.x is as defined above. More
preferably, the groups may be selected from "alkylsulfonyl" wherein
suitable alkyl radicals, selected from those defined above, is
attached to a sulfonyl radical, such as methylsulfonyl,
ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl" wherein
an aryl radical, as defined above, is attached to a sulfonyl
radical, such as phenylsulfonyl and the like.
[0065] Suitable groups and substituents on the groups may be
selected from those described anywhere in the specification.
[0066] Particularly useful compounds of the present invention are:
[0067]
4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaz-
a-benzo[e]azulene-3-yl]-methylamino-methylene}-benzenesulfonamide
and its pharmaceutically acceptable salts; [0068]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; [0069]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid-(4-hydroxy-piperidin-1-yl-amide and its
pharmaceutically acceptable salts; [0070]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-yl amide and its
pharmaceutically acceptable salts; [0071]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide
and its pharmaceutically acceptable salts; [0072]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid morpholine-4-yl-amide and its
pharmaceutically acceptable salts; [0073]
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid (4-methyl-piperazine-1-yl)-amide and its
pharmaceutically acceptable salts; [0074]
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts; [0075]
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid pyrrolidin-1-ylamide and its pharmaceutically
acceptable salts; [0076]
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid morpholin-4-ylamide and its pharmaceutically
acceptable salts; [0077]
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid N'-cyclopropyl-hydrazide and its
pharmaceutically acceptable salts; [0078]
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts; [0079]
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; [0080]
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-ylamide and its
pharmaceutically acceptable salts; [0081]
1-(4-chloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts; [0082]
1-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza--
cyclopenta [e]azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; [0083]
8-Chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza-cycl-
openta[e]azulene-3-carboxylic acid (hexahydro-cyclopenta
[c]pyrrol-2-yl)-amide and its pharmaceutically acceptable salts;
[0084]
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6,7-dithia-1,2-diaza-cycl-
openta[e]azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; [0085]
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-inda-
cene-3-carboxylic acid piperidin-1-ylamide and its pharmaceutically
acceptable salts; [0086]
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-inda-
cene-3-carboxylic acid (hexahydro-cyclopenta [c]pyrrol-2-yl)-amide
and its pharmaceutically acceptable salts; [0087]
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-thia-1,2-diaza-benzo[e]-
azulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts; [0088]
8-Bromo-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]az-
ulene-3-carboxylic acid piperidin-1-ylamide and its
pharmaceutically acceptable salts;
[0089] The compounds of the present invention may be prepared using
the methods described below, together with conventional techniques
known to those skilled in the art of organic synthesis, or
variations thereon as appreciated by those skilled in the art.
[0090] Referred methods include, but are not limited to those
described below, where all symbols are as defined earlier.
Scheme:
[0091] Compound of formula 2 by suitable modification of similar
processes described earlier in the art [Chem. Pharm. Bull. 2002,
50, 1109-1113]. Compound of formula 4 may be prepared by refluxing
2 with suitable substituted hydrazine hydrochloride of formula 3,
where `Ar` is as defined earlier, in suitable solvents such as
MeOH, EtOH, propanol, isopropanol, butanol, t-butanol, acetic acid
and the like or mixtures thereof. Alkaline hydrolysis of 4 using
suitable bases like NaOH, KOH, LiOH, AgNO.sub.3, Na.sub.2CO.sub.3,
CsCO.sub.3 and the like in solvents such as methanol,
methanol/water, methanol/THE or THF/H.sub.2O and the like or
mixtures thereof gives the corresponding acid of formula 5.
Compounds of formula 5 is first converted to their corresponding
acid chloride by treating with suitable halogenating agents
selected from SOCl.sub.2, COCl.sub.2, PCl.sub.3, PCl.sub.5 and the
like in suitable solvents such toluene, benzene, xylene,
dichloromethane, chloroform and the like or mixtures thereof'. The
acid chlorides generated in situ may be subsequently treated with
suitable substituted or unsubstituted amines, bicyclic amines,
substituted or unsubstituted hydrazines, to obtain compounds of
formula (I).
[0092] The compound of formula 5 may optionally, after conversion
to its corresponding acid chloride be treated with suitable
compounds of formula 6, where `Q` is as defined earlier, in
solvents selected from triethyl amine, DMSO, DMF, diisopropyl ethyl
amine and the like or mixtures thereof to obtain the compounds of
formula 7.
[0093] The compound of formula 7 on treatment with suitable
halogenating agent such as SOCl.sub.2, COCl.sub.2, PCb, PCl.sub.5
and the like in suitable solvents such toluene, benzene, xylene,
dichloromethane, chloroform and the like or mixtures thereof to
provide compounds of formula 8. The compound of formula 8 is
stirred with suitable amines of formula NHR.sub.2R.sub.3, where
R.sub.2 & R.sub.3 are as defined earlier, in solvents selected
from methanol, ethanol, water, THF and the like to obtain compounds
of formula (I).
##STR00007##
[0094] The compounds of formula (I) may be optionally converted to
their suitable pharmaceutically acceptable salts by suitable
modifications of techniques and processes known to persons skilled
in the art.
[0095] It will be appreciated that in any of the above mentioned
reactions any reactive group in the substrate molecule may be
protected, according to conventional chemical practice. Suitable
protecting groups in any of the above mentioned reactions are those
to used conventionally in the art. The methods of formation and
removal of such protecting groups are those conventional methods
appropriate to the molecule being protected. T. W. Greene and P. G.
M. Wuts "Protective groups in Organic Synthesis", John Wiley &
Sons, inc, 1999, 3.sup.rd Ed., 201-245 along with references
therein gives such conventional methods and are incorporated herein
as references.
[0096] The novel compounds of the present invention can be
formulated into suitable pharmaceutically acceptable compositions
by combining with suitable excipients as are well known.
[0097] The compounds of Formula (I) or pharmaceutical compositions
containing them may be administered either by oral, topical or
parenteral administration.
[0098] The pharmaceutical composition is provided by employing
conventional techniques. Preferably the composition is in unit
dosage form containing an effective amount of the active component,
that is, the compounds of formula (I) according to this
invention.
[0099] The quantity of active component, that is, the compounds of
formula (I) according to this invention, in the pharmaceutical
composition and unit dosage form thereof may be varied or adjusted
widely depending upon the particular application method, the
potency of the particular compound and the desired concentration.
Generally, the quantity of active component will range between 0.5%
to 90% by weight of the composition.
[0100] The invention is explained in greater detail by the examples
given below, which are provided by way of illustration only and
therefore should not be construed to limit the scope of the
invention.
[0101] It will be appreciated that one or more of the processes
described in the general schemes above may be used to prepare the
compounds of the present invention.
[0102] 1H NMR spectral data given in the tables (vide infra) are
recorded using a 300 MHz spectrometer (Bruker AVANCE-300) and
reported in 0.5 scale. Until and otherwise mentioned the solvent
used for NMR is CDCl.sub.3 using tetramethyl silane as the internal
standard.
Example 1
4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-
-benzo[e]azulene-3-yl]methylamino-methylene)-benzenesulfonamide
[0103]
8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo-
[e]azulene-3-carboxylic acid was prepared by suitable modifications
of similar techniques and processes known in the art.
Step A
4-Chloro-N
(8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza--
benzo[e]azulene-3-carbonyl)-benzene-sulfonamide
[0104]
8-Chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo-
[e]azulene-3-carboxylic acid (4.3 g, 10.55 mmol) was converted into
acid chloride using thionyl chloride (2.31 mL, 31.66 mmol) in
toluene by refluxing at ca. 110.degree. C. over a period of 1
h.
[0105] The solvents were evaporated under reduced pressure. The
residue obtained was taken in dichloromethane (20 mL) and the
resulting solution was added to the cooled suspension of 4-chloro
benzene sulfonamide (2.7 g, 4.137 mmol) and TEA (1.97 mL, 14.137
mmol) in dichloromethane (50 mL). The reaction mixture was stirred
at ca. 27.degree. C. over a period of 30 min and diluted with water
(150 mL), extracted with dichloromethane.
[0106] The organic layer was separated, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
crude colorless oil. The oil was purified through column
chromatography to afford
4-Chloro-N-{8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,-
2-diaza-benzo[e]azulene-3-carbonyl)-benzene-sulfonamide (4.75 g,
8.175 mmol) as off white solid.
[0107] .sup.1HNMR (CDCl.sub.3, 300 MHz): .delta. 9.38 (s, 1H), 8.0
(d, J=8.4 Hz, 2H), 7.5 (d, J=8.4 Hz, 2H), 7.4 (m, 3H), 7.2 (dd,
J=9.9, 8.4 Hz, 1H), 6.9 (dd, J=6.3, 1.9 Hz, 1H), 6.5 (d, J=8.4 Hz,
1H), 2.6 (t, J=6.6, 6.3 Hz, 2H), 2.2 (br, 2H) 1.26 (br, 2H).
Step B
4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-
-benzo[e]azulene-3-yl]-methylamino-methylene}-benzenesulfonamide
Compound 1
[0108]
4-Chloro-N-{8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-
-diaza-benzo[e]azulene-3-carbonyl)-benzene-sulfonamide (2.0 g, 3.44
mmol) and PCl.sub.5 (1.56 g, 6.88 mmol) in chlorobenzene (20 mL)
were refluxed at ca. 120.degree. C. over a period of 3.0 h. The
solvents were evaporated under reduced pressure to afford yellow
gummy solid. The gummy solid was taken in dichloromethane (15 mL)
and cooled to 0-5.degree. C. To this cooled solution, 40% aq.
monomethyl amine solution (5.0 mL) was added and stirred at ca.
29.degree. C. over a period of 1 h. The reaction mixture was
diluted with water (100 mL) and extracted with dichloromethane. The
organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4
and evaporated under reduced pressure to afford yellow oil. The oil
was purified through column chromatography to afford
4-Chloro-N-([8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaz-
a-benzo[e]azulene-3-yl]-methylamino-methylene}-benzene sulfonamide
(0.175 g, 0.294 mmol) as title compound 1, a white solid.
[0109] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 7.8 (d, J=7.5 Hz,
2H), 7.4 (d, j=7.5 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.34 (d, J=1.8
Hz, 1H), 7.3 (m, 2H), 7.0 (d, J=8.4 Hz, 1H), 6.5 (d, J=5.4 Hz, 1H),
3.27 (d, J=5.1 Hz, 2H), 3.18 (d, J=5.1 Hz, 1H), 2.6 (m, 3H), 1.5
(s, 3H).
Example 2
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-ylamide
[0110] a)
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa1,2-diaza
benzo[e]azulene-3-carboxylic acid by suitable modifications of
similar techniques and processes known in the art.
[0111] b) Hydrochloride salt of
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa 1,2-diaza
benzo[e]azulene-3-carboxylic acid piperidin-1-yl-amide (Compound
2). 8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa
1,2-diaza-benzo[e]azulene-3-carboxylic acid (0.500 g, 1.221 mmol)
was coupled with 1-amino-piperidine (0.197 mL, 1.832 mmol) in
presence of 1-Hydroxy-benzotriazole monohydrate (HOBt. H.sub.2O),
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC-HCl) and TEA in dichloromethane (25 mL) at ca. 27.degree. C.
over a period of 25-30 min. The reaction was diluted with H.sub.2O
(30 mL) and extracted with dichloromethane. The dichloromethane
layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and
evaporated under reduced pressure to afford brown oil. The brown
oil was taken in anhydrous methanol and treated with ethereal HCl
(ca. 4 mL) at 0-5.degree. C. Solvents were removed under reduced
pressure and residue was triturated in ethyl acetate to afford
solid. The solid was filtered, washed with diethyl ether to afford
title compound 2 (0.435 g, 0.824 mmol) as light brown solid.
.sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.35 (s, 1H), 7.51 (d,
J=1.74 Hz, 1H), 7.40 (m, 2H), 7.34 (m, 1H), 7.14 (d, J=1.95 Hz,
1H), 6.62 (d, J=8.55 Hz, 1H), 4.38 (m, 2H), 4.06 (bs, 3H), 3.48
(bs, 3H), 3.26 (m, 2H), 3.11 (m, 2H), 1.67 (bs, 4H), 1.41 (m, 1H),
1.18 (m, 1H).
[0112] (DMSO-D.sub.6, 300 MHz) .delta. 10.53 (s, 1H), 7.89 (d,
J=2.01 Hz, 1H), 7.78 (d, J=8.49 Hz, 1H), 7.68 (dd, J=10.47, 1.95
Hz, 1H), 7.26 (d, J=1.95 Hz, 1H), 7.03 (dd, J=10.56, 1.95 Hz, 1H),
6.72 (d, J=8.61 Hz, 1H), 4.45 (bs, 1H), 4.25 (bs, 1H), 3.23 (bs,
4H), 3.06 (m, 3H), 1.72 (bs, 4H), 1.42 (bs, 2H), 1.16 (t, 1H), 0.98
(t, 1H).
[0113] Following compounds were prepared by suitable modifications,
variations of reactants, reaction conditions, reaction steps of the
processes described for the synthesis of compound 2,
Compound 3
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid-(4-hydroxy-piperidin-1-yl-amide
[0114] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 10.26 (bs, 1H),
7.9 (d, J=2.1 Hz, 1H), 7.7 (d, J=8.4 Hz, 1H), 7.6 (dd, J=1.8 Hz,
1H), 7.2 (d, J=1.8 Hz, 1H), 7.0 (dd, J=6.8, 2.1 Hz, 1H), 3.38 (bs,
2H), 3.21 (bs, 4H), 3.0 (bs, 4H), 2.7 (bs, 2H).
Compound 4
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-yl amide
[0115] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 8.70 (dd, J=6.66
Hz, 1H), 7.90 (m, 1H), 7.71 (dd, 6.33, 2.19 Hz, 1H), 7.26 (d,
J=2.10 Hz, 1H), 7.03 (dd, J=6.45, 2.16 Hz, 1H), 6.72 (d, J=8.55 Hz,
1H), 4.47 (m, 1H), 4.25 (m, 2H), 1.90-1.80 (bs, 6H), 1.79 (m, 1H),
1.23-1.15 (m, 1H).
Compound 5
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide
[0116] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.24 (s, 1H), 7.60
(s, 1H), 7.51 (m, 2H), 7.15 (d, J=1.86 Hz, 2H), 6.82 (m, 1H), 6.62
(d, J=8.49 Hz, 1H), 4.45 (bs, 2H), 3.96 (bs, 3H), 3.71 (bs, 2H),
3.38 (bs, 2H), 3.27 (bs, 2H), 1.73 (bs, 6H).
[0117] (DMSO-D.sub.6) .delta. 11.03 (s, 1H), 7.90 (d, J=1.86 Hz,
1H), 7.79 (d, J=8.52 Hz, 1H), 7.70 (dd, J=10.41, 1.89 Hz, 1H), 7.26
(d, J=1.83 Hz, 1H), 7.04 (dd, J=10.41, 1.83 Hz, 1H), 6.73 (d,
J=8.58 Hz, 1H), 4.50 (bs, 1H), 4.25 (bs, 2H), 3.69 (bs, 2H), 3.45
(m, 1H), 3.40 (m, 1H), 3.06 (bs, 2H), 2.96 (bs, 2H), 1.71 (bs, 4H),
1.62 (bs, 2H).
Compound 6
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid morpholine-4-yl-amide
[0118] (DMSO-D.sub.6, 300 MHz) .delta. 9.4 (s, 1H), 7.8 (d, J=2.1
Hz, 1H), 7.7 (d, J=8.7 Hz, 1H), 7.6 (dd, J=6.3, 2.1 Hz, 1H), 7.2
(d, J=2.1 Hz, 1H), 7.0 (dd, J=6.4, 2.1 Hz, 1H), 6.7 (d, J=8.4 Hz,
1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.6 (m, 4H), 2.8 (m, 4H), 1.22 (s,
2H).
Compound 7
Hydrochloride salt of
8-chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid (4-methyl-piperazine-1-yl)-amide
[0119] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 9.7 (s, 1H), 7.8
(d, J=2.1 Hz, 1H), 7.7 (d, J=8.7 Hz, 1H), 7.6 (dd, J=6.3, 2.1 Hz,
1H), 7.2 (d, J=2.4 Hz, 1H), 7.0 (dd, J=6.4, 2.1 Hz, 1H), 6.7 (d,
J=8.4 Hz, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.7 (m, 1H), 3.1 (bs, 4H),
2.7 (s, 3H), 1.22 (s, 4H).
Compound 8
Hydrochloride salt of
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide
[0120] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 11.0 (s, 1H),
7.58 (d, J=8.4 Hz, 2H), 7.4 (d, J=8.7 Hz, 2H), 7.2 (d J=2.1 Hz,
1H), 7.0 (dd, J=6.6, 1.8 Hz, 1H), 6.7 (d, J=8.4 Hz, 1H), 4.3 (t,
J=6.6 Hz, 2H), 3.1 (bs, 4H), 2.7 (d, J=4.8 Hz, 211), 1.97 (bs, 4H),
1.4 (bs, 2H).
Compound 9:
[0121] Hydrochloride salt of
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid pyrrolidin-1-ylamide.
[0122] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 9.1 (s, 1H), 7.5
(d, J=8.7 Hz, 2H), 7.4 (d, J=8.7 Hz, 2H), 7.2 (d, J=2.1 Hz, 1H),
7.0 (dd, J=6.3, 2.1 Hz, 1H), 6.7 (d, J=8.4 Hz, 1H), 4.3 (t, J=6.3
Hz, 2H), 3.1 (bs, 4H), 2.7 (d, J=4.8 Hz, 2H), 1.97 (bs, 4H), 1.4
(bs, 2H).
Compound 10
Hydrochloride salt of
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid morpholin-4-ylamide
[0123] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 9.5 (s, 1H), 7.5
(d, J=8.4 Hz, 2H), 7.4 (d, J=8.7 Hz, 2H), 7.2 (d, J=2.1 Hz, 1H),
7.0 (dd, J=6.6, 2.1 Hz, 1H), 6.7 (d, J=8.7 Hz, 1H), 4.3 (t, J=6.6
Hz, 2H), 3.2 (t, J=6.6 Hz, 2H), 3.0 (m, 2H), 2.8 (m, 4H), 2.7 (m,
2H).
Compound 11
Hydrochloride salt of
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid-N'-cyclopropyl-hydrazide
[0124] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 10.7 (s, 1H),
8.3 (d, J=4.5 Hz, 1H), 7.7 (d, J=8.4 Hz, 1H), 7.6 (dd, J=6.3, 2.1
Hz, 1H), 7.2 (d, J=2.1 Hz, 1H), 7.0 (dd, J=6.6, 2.1 Hz, 1H), 6.7
(d, J=8.7 Hz, 1H), 4.4 (m, 4H), 4.0 (m, 4H), 2.8 (m, 2H), 0.5 (m,
5H).
Compound 12
Hydrochloride salt of
8-chloro-1-(4-chloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide
[0125] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 10.66 (s, 1H),
7.52 (s, 3H), 7.39 (d, J=2.9 Hz, 2H), 7.27 (s, 1H), 6.99 (d, J=8.55
Hz, 1H), 4.40 (t, J=5.95 Hz, 2H), 3.56 (t, J=6.0 Hz, 3H), 3.18 (d,
J=6.99 Hz, 4H), 1.74 (s, 3H), 1.43 (s, 2H).
Compound 13
Hydrochloride salt of
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid piperidin-1-yl amide
[0126] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.53 (s, 1H), 7.50
(s, 1H), 7.39 (m, 2H), 6.91 (s, 1H), 6.64 (d, J=7.66 Hz, 1H), 6.56
(d, J=8.09 Hz, 1H), 4.13 (bs, 4H), 4.05 (bs, 4H), 3.48 (bs, 3H),
2.28 (s, 3H), 2.06 (s, 4H).
Compound 14
Hydrochloride salt of
1-(2,4-Dichloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]a-
zulene-3-carboxylic acid pyrrolidin-1-ylamide
[0127] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.31 (s, 1H), 7.51
(s, 1H), 7.40 (m, 2H), 6.91 (s, 1H), 6.58 (m, 2H), 4.36 (bs, 2H),
3.90 (bs, 4H), 3.39 (bs, 2H), 2.28 (bs, 6H).
[0128] (DMSO-D.sub.6) 11.70 (s, 1H), 7.99 (d, J=2.13 Hz, 1H), 7.75
(d, J=8.49 Hz, 1H), 7.68 (dd, J=8.52, 2.16 Hz, 1H), 6.95 (s, 1H),
6.71 (d, J=7.35 Hz, 1H), 6.59 (d, J=8.07 Hz, 1H), 4.4 (m, 1H), 4.21
(m, 1H), 3.56 (bs, 1H), 3.34 (m, 2H), 2.21 (s, 3H), 1.21 (bs,
4H).
Compound 15
Hydrochloride salt of
1-(4-chloro-phenyl)-8-methyl-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azule-
ne-3-carboxylic acid piperidin-1-ylamide
[0129] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 11.15 (s, 1H),
7.58 (d, J=8.52 Hz, 1H), 7.40 (d, J=8.52 Hz, 2H), 6.99 (s, 1H),
6.75 (d, J=7.95 Hz, 1H), 6.63 (d, J=8.01 Hz, 1H), 4.30 (bs, 2H),
3.75 (t, 2H), 3.37 (s, 4H), 3.24 (t, 2H), 2.24 (s, 3H), 1.80 (s,
4H), 1.46 (m, 2H).
Compound 16
Hydrochloride salt of
1-([8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza--
cyclopenta [e]azulene-3-carboxylic acid piperidin-1-ylamide
[0130] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.4 (s, 1H), 7.60
(s, 1H), 7.4 (d, 2H), 5.9 (s, 1H), 3.9 (bs, 5H), 3.1 (s, 3H), 2.9
(t, 2H), 2.1 (bs, 6H).
Compound 17
Hydrochloride salt of
8-Chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-7-thia-1,2-diaza-cycl-
openta [e]azulene-3-carboxylic acid (hexahydro-cyclopenta
[c]pyrrol-2-yl)-amide
[0131] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.4 (s, 1H), 7.50
(s, 1H), 7.4 (d, 2H), 5.9 (s, 1H), 4.4 (bs, 2H), 3.9 (bs, 2H), 3.1
(s, 2H), 3.0 (bs, 2H), 2.8 (t, 2H), 2.0 (bs, 2H), 1.9-1.6 (m,
6H).
Compound 18
Hydrochloride salt of
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6,7-2-diaza-cyclopenta
[e]azulene-3-carboxylic acid piperidin-1-ylamide
[0132] .sup.1HNMR: (CDCl.sub.3, 300 MHz) .delta. 9.4 (s, 1H), 7.50
(s, 1H), 7.4 (d, 3H), 6.1 (s, 1H), 3.9 (bs, 4H), 3.4 (d, J=5.8 Hz,
2H), 3.2 (d, J=5.46 Hz, 2H), 2.1 (s, 6H).
Compound 19
Hydrochloride salt of
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,
dithia-1,2-diaza-as-indacene-3-carboxylic acid
piperidin-1-ylamide
[0133] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 10.62 (bs, 1H),
8.10 (s, 1H), 7.85 (d, J=8.49 HZ, 1H), 7.71 (dd, J=8.49, 2.1 Hz,
1H), 6.08 (s, 1H), 4.23 (s, 2H), 2.89 (m, 4H), 1.67 (m, 4H), 1.10
(m, 6H).
Compound 20
Hydrochloride salt of
7-Chloro-1-(2,4-dichloro-phenyl)-1,5-dihydro-4,6-dithia-1,2-diaza-as-inda-
cene-3-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide
[0134] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 11 (s, 1H), 8.04
(d, J=2.1 Hz, 1H), 7.87 (d, J=8.5 HZ, 1H), 7.76 (dd, J=8.5, 2.1 Hz,
1H), 6.06 (s, 1H), 4.2 (s, 3H), 3.6 (bs, 2H), 2.9 (s, 2H), 2.8 (d,
2H), 1.9 (bs, 2H).
Compound 21
Hydrochloride salt of
8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-thia-1,2-diaza-benzo[e]-
azulene-3-carboxylic acid piperidin-1-ylamide
[0135] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 10.55 (s, 1H),
7.88 (d, J=2.01 Hz, 1H), 7.80 (d, J=8.50 Hz, 1H), 7.70 (dd,
J=10.46, 1.93 Hz, 1H), 7.24 (d, J=1.92 Hz, 1H), 7.05 (dd, J=10.56,
1.93 Hz, 1H), 6.75 (d, J=8.63 Hz, 1H), 4.47 (bs, 1H), 4.23 (bs,
1H), 3.25 (bs, 4H), 3.04 (m, 3H), 1.75 (bs, 4H), 1.40 (bs, 2H),
1.18 (t, 1H), 1.00 (t, 1H).
Compound 22
Hydrochloride salt of
8-Bromo-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]az-
ulene-3-carboxylic acid piperidin-1-ylamide
[0136] .sup.1HNMR: (DMSO-D.sub.6, 300 MHz) .delta. 10.52 (s, 1H),
7.86 (d, J=2.01 Hz, 1H), 7.73 (d, J=8.40 Hz, 1H), 7.66 (dd,
J=10.43, 1.98 Hz, 1H), 7.30 (d, J=1.99 Hz, 1H), 7.08 (dd, J=10.44,
1.98 Hz, 1H), 6.73 (d, J=8.50 Hz, 1H), 4.48 (bs, 1H), 4.22 (bs,
1H), 3.25 (bs, 4H), 3.08 (m, 3H), 1.77 (bs, 4H), 1.42 (bs, 2H),
1.18 (t, 1H), 0.99 (t, 1H).
Biological Activity
[0137] Compounds of the present invention in the cAMP accumulation
model, antagonizes the WIN-55, 212-2 inhibition of
forskolin-induced cAMP accumulation in hCB.sub.1-CHO cells [J.
Pharmacol. Exp: Ther., 1998, 284, 291-297]. In a mouse vas deferens
preparation, representative compounds cause rightward shift of the
WIN-55, 212-2 concentration-response curve (Eur. J. Pharm. 1995,
284, 241-247). Representative compounds of the present invention
have shown decrease in sucrose solution intake in rat model (Table
1) [Psychopharmacology, 1997, 132, 104-106].
TABLE-US-00001 TABLE 1 Effect of representative compounds on the
intake of 5% sucrose solution in animal model. Reduction in sucrose
solution consumption w.r.t. control animals Compound No. (%)* 3
-18.9 .+-. 14.0 5 -23.2 .+-. 11.4 6 -24.9 .+-. 8.9 8 -30.4 .+-. 4.3
16 -13.2 .+-. 15.7 * formula for calculation : [ Total consumption
- Mean total consumption of control ] [ Mean total consumption by
control ] .times. 100 number of animals in a group = 6.
##EQU00001##
[0138] No significant adverse effects were observed for any of the
mentioned compounds of invention.
* * * * *