Substituted azepino[4,5b]indole derivatives

Details Substituted azepino[4,5b]indole derivatives Substituted azepino[4,5b]indole derivatives

2001-09-20

2003-06-24

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S580000

Reexamination Certificate

active

06583135

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinoindole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).
2. Brief Description of Related Technology
Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, and schizophrenia. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
Because of the broad distribution of serotonin within the body, a heightened interest exists for drugs that affect serotonergic systems. In particular, agonists, partial agonists, and antagonists of serotonergic systems are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
The major classes of serotonin receptors (5-HT
1-7
) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al.,
Neuroscience and Behavioral Reviews
, 1990, 14, 35; and D. Hoyer, et al.
Pharmacol. Rev
. 1994, 46, 157-203.
For example, the 5-HT
2
family of receptors contains 5-HT
2A
, 5-HT
2B
, and 5-HT
2C
subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three 5-HT
2
subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT
2
subtypes in a mammal. The 5-HT
2B
and 5-HT
2A
receptors are widely distributed in the peripheral nervous system, while the 5-HT
2C
receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al.
Trends in Pharnacol. Sci
. 1995, 16, 105-110.
Subtype 5-HT
2A
has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, while subtype 5-HT
2C
has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT
2B
receptor. See F. Jenck, et al.,
Exp. Opin. Invest. Drugs
, 1998, 7, 1587-1599; M. Bos, et al.,
J. Med. Chem
., 1997, 40, 2762-2769; J. R. Martin, et al.,
The Journal of Pharmacology and Experimental Therapeutics
, 1998, 286, 913-924; S. M. Bromidge, et al.,
J. Med. Chem
., 1998, 41, 1598-1612; G. A. Kennett,
Drugs
, 1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology
, 1999, 38, 415-423.
U.S. Pat. Nos. 3,553,232 and 3,622,673 disclose 4-(1,4,5,6-tetrahydroazepine[4,5-b]indole-3(2H)-yl) butyrophenones that are reported to be useful in the treatment of mental or emotional disorders.
U.S. Pat. Nos. 3,652,588, 3,676,558, and 3,839,357 disclose 6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles and aneroxigenic compounds thereof that are reportedly useful to tranquilize and otherwise sedate mammals or suppress hunger in mammals.
U.S. Pat. No. 3,525,750 discloses 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to produce an antitussive effect in mammals.
European Patent Application EP 466548A, and counterpart Australian Patent Application Number AU-B-79293/91, disclose substituted hexahydroazepino[4,5-b]indoles that are reported to be useful for treating certain specified central nervous system disorders.
European Patent Specification 0 028 381 reports certain 6-phenyl substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to exhibit anti-depressant, anti-allergic, and neuroleptic activity.
JP Public Patent Disclosure Bulletin Number 63-163347 discloses indole compounds that are reported to prevent fading of organic coloring substances.
International Patent Application Publication Number WO 01/0573 A1 discloses 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles that are reported to be useful for treating depression, obesity, and other CNS disorders.
Despite the above-cited publications, there remains a need for pharmaceutical agents that are useful in treating a variety of diseases, disorders, and conditions that are associated with serotonin (5-HT) receptors.
SUMMARY OF THE INVENTION
Generally, the present invention is directed to methods and compositions useful in treating a disease, disorder, and/or condition in a mammal wherein a 5-HT receptor is implicated, and modulation of a 5-HT function is desired, by using a novel compound disclosed herein.
In accordance with the present invention, novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. More specifically, the invention provides a compound of Formula (I):
wherein R
1
is selected from the group consisting of hydrogen, C
1-8
alkyl, and C
1-8
hydrocarbylene Ar;
each R
2
, independently, is selected from the group consisting of C
1-8
alkyl, and OH;
R
3
is hydrogen, C
1-8
alkyl, Ar, Het, R
7
C(═O)—, R
7
OC(═O)—, R
5
R
6
NC(═O)—, R
7
C(═S)—, R
7
SC(═O)—, R
5
R
6
NC(═S)—, R
7
SO
2
—, R
5
R
6
NSO
2
—, R
7
S(═O)—, R
5
R
6
NS(═O)—, R
c
C
1-8
hydrocarbylene-, or R
c
C
1-8
hydrocarbyleneC(═O)—;
each R
4
, independently, is selected from the group consisting of Ar, C
1-8
alkyl, ArO—, C
1-8
alkoxy, Het, halo, OH, CN, NO
2
, CF
3
, CF
3
O, NR
a
R
b
, N═NR
a
R
b
, R
7
S, C
1-8
hydrocarbyleneAr, and C
1-8
hydrocarbyleneOR
a
;
each R
5
and R
6
is independently hydrogen, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, haloC
1-8
alkyl, C
3-8
cycloalkenyl, Ar, or —C
1-8
hydrocarbyleneAr; or R
5
and R
6
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R
7
is independently hydrogen, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, haloC
1-8
alkyl, C
3-8
cycloalkenyl, Ar, or —C
1-8
hydrocarbyleneAr;
R
a
and R
b
, independently, are selected from the group consisting of hydrogen, C
1-8
alkyl, Ar, C
1-3
hydrocarbyleneAr, SO
2
Ar, SO
2
C
1-4
alkyl, (C
3-8
cycloalkyl)C
1-8
alkyl, and Het;
R
c
is Ar, Het, R
7
CO
2
—, R
7
C(═O)—, R
7
OC(═O)—, R
7
O—, R
7
C
1-8
alkyleneO—, R
7
S—, R
7
C(═S)—, R
7
S(═O)—, R
7
S(═O)
2
—, R
7
SC(═O)—, R
7
C(═O)N(R
7
)—, R
7
C(═S)N(R
7
)—, R
5
R
6
N—, R
5
R
6
NC(═O)—, R
5
R
6
NC(═S)—, R
5
R
6
NS(═O)—, R
5
R
6
NSO
2
—, R
7
S(═O)N(R
7
)—, R
7
SO
2
N(R
7
)—, or R
7
N(R
7
)C(═O) N(R
7
)—;
each Ar is independently aryl or heteroaryl;
p is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
wherein any Ar of R
1
, R
3
-R
7
, R
a
, R
b
and R
c
is optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents independently selected from halo, CN, NO
2
, OR
e
, methylenedioxy, ethylenedioxy, CF
3
, OCF
3
, SR
e
, SO
2
R
e
, NR
f
R
g
, CONR
f
R
g
, COR
e
, R
e
, and C
1-8
hydrocarbyleneR
d
;
each R
d
is independently hydroxy, C
1-8
alkoxy, cyano, SR
h
, or C(═O)R
h
;
each R
e
is independently selected from the group consisting of hydrogen, C
1-8
alkyl, Ar, C
1-3
hy

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