Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-02
2004-04-13
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S014000, C544S099000, C540S477000, C540S578000, C514S224500, C514S229500
Reexamination Certificate
active
06720316
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides tricyclic hexahydroazepinoindole and indoline derivatives, and more specifically, provides compounds of Formula (I) described hereinbelow. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
BACKGROUND OF THE INVENTION
Serotonin has been implicated in a number of diseases and conditions that originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, ed. Neville V. Osborne, John Wiley and Sons (1982), p 221; D. J. Boullin, Serotonin in Mental Abnormalities 1, John Wiley and Sons (1978), p. 316; J. Barchas, et al., Serotonin and Behavior, Academic Press, New York, N.Y. (1973). 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.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists 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. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
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. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, the 5-HT
2
family of receptors is comprised of 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 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. The 5-HT
2B
and 5-HT
2A
receptors are widely distributed in the periphery, 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 pharmacological 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,
IDrugs,
1998, 1, 4, 456-470; and A. Dekeyne, et al.,
Neuropharmacology,
1999, 38, 415-423.
International Patent Applications WO 00/77001, WO 00/77002, and WO 00/77010 disclose tetracyclic compounds that are reported to possess activity as serotonin agonists and antagonists.
U.S. Pat. No. 4,438,120 discloses polycyclic compounds that are reported to possess tranquilizer activity.
U.S. Pat. No. 4,219,550 discloses tetracyclic compounds that are reported to possess tranquilizer and antidepressant properties.
There is currently a need for pharmaceutical agents that are useful to treat diseases and conditions that are associated with 5-HT receptors.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel compounds which demonstrate useful biological activity, and particularly activity as 5-HT receptor ligands, are provided. Thus, the present invention provides a compound of Formula (I):
wherein Z is —CHR
9
—, —C(O)—, —O—, —S—, —S(O)—, —SO
2
—, —N(R
9
)—, —C(O)N(R
9
)—, or —N(R
9
)C(O)—;
l is 1 or 2;
m is 0, 1 or 2;
n is 1 or 2;
R
1
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, or (C
3-6
cycloalkyl)C
1-6
alkyl; and R
2
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, or (C
3-6
cycloalkyl)C
1-6
alkyl; provided that R
1
and R
2
are not both hydrogen;
R
3
is hydrogen or C
1-6
alkyl;
R
4
, R
5
and R
9
are independently hydrogen, C
1-6
alkyl or arylC
1-6
alkylene;
R
6
, R
7
, and R
8
are independently hydrogen, fluoro, chloro, bromo, CF
3
, —OCF
3
, —N(R
10
)
2
, C
1-6
alkyl, C
1-6
alkoxy, heteroaryl or aryl; and
each R
10
is independently hydrogen, or —C
1-6
alkyl;
wherein any C
1-6
alkyl, C
1-6
alkylene, or C
1-6
alkoxy of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, and R
10
is optionally partially unsaturated; and
wherein any heteroaryl or aryl is optionally substituted with one or two halo, —CF
3
, —OCF
3
, C
1-6
alkoxy, —N(R
10
)
2
, or —C
1-6
alkyl;
or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating a disease or condition in a mammal (e.g. a human) in need thereof wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to the mammal,
a method for treating or preventing a disease or disorder of the central nervous system in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to the mammal,
a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical diagnosis or therapy (e.g. the treatment or prevention of 5-HT related disease such as anxiety, obesity, depression, or a stress related disease),
the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to prepare a medicament useful for treating or preventing a disease or disorder of the central nervous system in a mammal in need thereof, and
a method for modulating 5-HT receptor function, comprising administering an effective modulatory amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates of Formula II and processes disclosed herein that are useful for preparing compounds of Formula (I):
wherein R
1
, R
2
, R
4
, R
5
, R
6
, R
7
, R
8
, l, m, and n, have the definitions of formula I and R
3
is —C(O)-aryl, —C(O)—heteroaryl, —C(O)—C
1-6
alkyl, —C(O)—C
1-6
haloalkyl, —C(O)O—C
1-6
alkyl, or —C(O)O—C
1-6
haloalkyl, where aryl or heteroaryl is optionally substituted with one or two halo, —CF
3
, —OCF
3
, C
1-6
alkoxy, —N(R
10
)
2
, or —C
1-6
alkyl.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are useful for treating or preventing diseases or disorders of the central nervous system. Specific diseases or disorders of the central nervous system for which a compound of Formula (I) may have activity include, but are not limited to: obesity, depression, schizophrenia,
Berch Mark L.
Flynn ,Thiel, Boutell & Tanis, P.C.
Habte Kahsay
Pharmacia & Upjohn Company
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