Azepino[4,5-b]pyrano[3,2-e]indoles

Details Azepino[4,5-b]pyrano[3,2-e]indoles Azepino[4,5-b]pyrano[3,2-e]indoles

2001-07-06

2003-01-07

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S578000

Reexamination Certificate

active

06503899

ABSTRACT:

FIELD OF THE INVENTION
The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to uses of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are pyranoazepinoindole compounds, which 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.
BACKGROUND
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 Pharmacol. 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, which 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 reported to be useful to tranquilize and otherwise sedate mammals or to suppress hunger in mammals.
In spite of 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 that 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 H, C
1-8
alkyl and C
1-8
alkylenearyl;
each R
2
, independently, is selected from the group consisting of halo, C
1-8
alkyl, C
1-8
alkoxy, aryl, and OH;
R
3
is selected from the group consisting of hydrogen, C
1-8
alkyl, aryl, heteroaryl, C(═O)R
a
, C(═O)OR
a
, C(═O)NR
a
R
b
, C(═O)SR
a
, C(═S)NR
a
R
b
, SO
2
R
a
, SO
2
NR
a
R
b
, S(═O)R
a
, S(═O)NR
a
R
b
, C(═O)NR
a
C
1-6
alkyleneOR
a
, C(═O)NR
a
C
1-6
alkyleneHet, C(═O)C
1-6
alkylenearyl, C(═O)C
1-6
alkyleneheteroaryl, C
1-6
alkylenearyl, C
1-6
alkyleneheteroaryl, C
1-6
alkyleneHet, C
1-6
alkyleneC(═O)C
1-6
alkylenearyl, C
1-6
alkyleneC(═O)C
1-6
alkyleneheteroaryl, C
1-6
alkyleneC(═O)Het, C
1-6
alkyleneC(═O)NR
a
R
b
, C
1-6
alkyleneOR
a
, C
1-6
alkyleneNR
a
C(═O)R
a
, C
1-6
alkyleneOC
1-6
alkyleneOR
a
, C
1-6
alkyleneNR
a
R
b
, C
1-6
alkyleneC(═O)OR
a
, C
1-6
alkyleneOC
1-6
alkyleneC(═O)OR
a
, C
1-6
alkyleneC(═O)aryl, C
1-6
alkyleneC(═O)heteroaryl, C
1-6
alkyleneOC
1-6
alkylenearyl, C
1-6
alkyleneOC
1-6
alkyleneheteroaryl, C
1-6
alkyleneOC
1-6
alkyleneHet, C
1-6
alkyleneSR
a
, C
1-6
alkyleneSO
2
R
a
, C
1-6
alkyleneS(═O)R
a
; C
1-6
alkyleneSO
2
NR
a
R
b
, and C
1-6
alkyleneNSO
2
R
a
;
each R
4
, independently, is selected from the group consisting of halo, OH, CN, NO
2
, CF
3
, CF
3
O, NR
a
R
b
, C
1-8
alkyl, C
1-8
alkoxy, C
1-8
alkanoyl, C
1-8
alkoxycarbonyl, C
1-8
alkanoyloxy, aryl, heteroaryl, C
1-6
alkylenearyl, and C
1-6
alkyleneheteroaryl;
each R
5
, independently, is selected from the group consisting of halo, C
1-8
alkyl, C
1-8
alkoxy, and OH;
m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
n is 0, 1, 2, 3, 4, 5, or 6;
p is 0, 1, or 2;
bond a and bond b represented by - - - are each independently a single bond or a double bond;
R
a
and R
b
, independently, are selected from the group consisting of hydrogen, C
1-8
alkyl, aryl, heteroaryl, arylC
1-3
alkyl, heteroarylC
1-3
alkyl, C
1-3
alkylenearyl, C
1-3
alkyleneheteroaryl, and Het;
or a pharmaceutically acceptable salt or solvate thereof.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
Still another embodiment of the present invention provides a method of treating a disease, disorder, and/or condition in a mammal (e.g., animal or human), wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, to the mammal.
Yet another embodiment of the present invention comprises a method of modulating 5-HT receptor function comprising contacting the receptor with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
A further embodiment of the present invention provides a method of treating or preventing diseases, disorders, and/or conditions of the central nervous system in a mammal, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, to the mammal.
Specific diseases, disorders, and/or conditions for which the compound of Formula (I) has activity include, but are not limited to, obesity, depression, sc

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