Cyclopenta[b][1,4]diazepino[6,7,1-h...

Details Cyclopenta[b][1,4]diazepino[6,7,1-h... Cyclopenta[b][1,4]diazepino[6,7,1-h...

2001-11-02

2004-08-17

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S555000, C540S556000

Reexamination Certificate

active

06777407

ABSTRACT:

The present invention relates to cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives thereof, which are serotonin 5-hydroxytryptamine 2
c
(5HT
2c
) receptor agonists useful for the treatment of central nervous system disorders including, but not limited to, obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, panic disorder, migraine, sleep disorders, such as sleep apnea, eating disorders, such as hyperphagia, obesity, epilepsy, and spinal cord injury.
BACKGROUND OF THE INVENTION
Obesity is a medical disorder characterized by an excess of body fat or adipose tissue. Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality. As the percentage of obese individuals continues to rise both in the U.S. and abroad, obesity is expected to be a major health risk in the 21
st
Century. The serotonin 5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system. [Wilkinson, L. O. and Dourish, C. T. in
Serotonin Receptor Subtypes: Basic and Clinical Aspects
(ed. Peroutka, S. J. ) 147-210 (Wiley-Liss, N.Y., 1991).] The 5HT
2c
receptor (formerly called the 5HT
1C
receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A. B., Axel, R. Jessell, T. M. Science 241:558-564 (1988).] Studies in several animal species and in humans have shown that the non-selective 5HT
2C
receptor agonist, meta-chlorophenylpiperazine (MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M., Williams, C., Walsh, A. E. S., Fairburn, C. G.
Nature
376: 557 (1995).] Tecott, et al have demonstrated that transgenic mice lacking the 5HT
2C
receptor eat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F., Jullus, D.
Nature
374: 542-546 (1995).] Compounds of this invention are 5HT
2C
receptor subtype selective agonists which are selective over other monoamine receptors, causes a reduction in food intake and result in a reduction in weight gain. Other therapeutic indications for 5HT
2C
agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, and epilepsy.
The non-selective 5-HT
2c
agonist, meta-chlorophenylpiperazine (m-CPP), has been shown to block conditioned avoidance responding (CAR) in the rat, an activity usually associated with antipsychotic activity in man [Martin, Gregory E.; Elgin, Jr., Robert J.; Mathiasen, Joanne R.; Davis, Coralie B.; Kesslick, James M.; Baldy, William J.; Shank, Richard P.; DiStefano, Deena L.; Fedde, Cynthia L.; Scott, Malcolm K.
J. Med. Chem.
1989, 32, 1052-1056]. More recently, additional data suggests that 5-HT
2c
agonism may produce an antipsychotic-like effect in the CAR model [Browning, J. L.; Young, K. A.; Hicks, P. B. Presented at the 29
th
Annual Meeting of the Society for Neuroscience, Miami Beach, Fla., October 1999, Abstract 830.12].
U.S. Pat. No. 3,914,250 (Oct. 21, 1975) describes 1,4-diazepino[6,5,4-jk]carbazoles, having the structures below, as anticonvulsant agents.
Pyrrolo[3,2,1-jk][1,4]benzodiazepines and 4,5-dihydropyrrolo[3,2,1-jk][1,4]-benzodiazepines have been described by Hester et al. (
J. Med. Chem.
1970, 13, 827-835) to have central nervous system activity.
This invention provides cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives which bind to and activate 5HT
2C
receptors in the CNS and are useful for the treatment of CNS disorders which can benefit from modulation of the 5HT
2C
receptor.


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