Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-27
2003-02-11
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S253050, C514S254020, C514S254060, C514S254100, C514S255030, C514S331000, C514S357000
Reexamination Certificate
active
06518272
ABSTRACT:
This invention provides compounds which act upon the mammalian 5-HT
1A
receptor and methods for their use in treating, preventing or ameliorating diseases associated therewith, including anxiety, depression, enhancement of antidepressant activity, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, stroke/cerebral ischemia, nausea and vomiting, and in the treatment of prostate cancer and for use in promoting smoking cessation.
BACKGROUND OF THE INVENTION
Compounds having selective partial agonist activity at the 5-HT
1A
receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone, Buspar®, U.S. Pat. No. 3,717,634). 5-HT
1A
agonists and antagonists may find use in the treatment of several diseases such as anxiety, depression, enhancement of antidepressant activity, schizophrenia, cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, stroke/cerebral ischemia, nausea and vomiting, and in the treatment of prostate cancer and smoking cessation (for reviews, see: K. Rasmussen and V. P. Rocco, Recent Progress in Serotonin (5-HT
1A
Receptor Modulators, in
Annual Reports in Medicinal Chemistry
, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995); L. E. Schechter and M. G. Kelly, An overview of 5-HT1A Receptor Antagonists: Historical Perspective and Therapeutic Targets, in
Current Drugs Serotonin ID Research Alert
, 2, 299-309 (1997)).
5-HT1A Agonists/Partial Agonists
Anxiety—The role of serotonin in anxiety has been well established (S. D. Iversen,
Neuropharmacol
., 23, 15530 (1984); J. E. Barrett and K. E. Vanover,
Psychopharmacol
., 112, 1 (1993)). 5-HT
1A
partial agonists and full agonists have demonstrated anxiolytic activity in both preclinical animal models of anxiety (R. J. Rogers, et al.,
Pharmacol. Biochem. Behav
., 48, 959 (1994), P. F. Curle, et al.,
Drug Dev. Res
., 32, 183 (1994); S. E. File and N. Andrews,
Behav. Pharmacol
., 5, 99 (1994)) and in clinical trials for anxiety (D. S. Chaney, et al.,
Ann. Rev. Med
., 41, 437 (1990); R. D. Chiaie, et al.,
J. Clin. Psychopharamacol
., 15, 12 (1995); L. D. Bedford.
Abstracts. Am. Coll. Neuropsycho
-
pharmacol
., San Juan, Puerto Rico, 167 (1994); H. G. M. Westenberg and J. A. Den Boer,
Pharmacopsychiatry
, 26, 30 (1993)).
Depression—There is evidence that 5-HT
1A
agonists and high-efficacy partial agonists possess antidepressant activity (J. De Vry,
Drug and News Perspectives
, 9, 270 (1996)). This activity is thought to be the result of the drug's ability to exert agonist activity on post-synaptic receptors and desensitize pre-synaptic autoreceptors. Buspirone showed weak antidepressant activity and flexinoxan, a 5-HT
1A
full agonist, entered clinical trials for depression (A. Sambunaris, et al.,
J. Clin. Psychiatry
, 58 (suppl 6), 40 (1997)).
Nausea and Vomiting—Animal studies have shown that 5-HT
1A
agonists are effective antiemetics against a broad spectrum of conditions, including motion sickness and xylazine- and cis-platinin-induced vomiting (J. B. Lipcot and G. H. Crampton,
Pharmacol. Biochem. Behav
., 33, 627 (1989)). Flesinoxan, a 5-HT
1A
full agonist, was found to be particularly active in these models (J. B. Lipcot,
Eur. J. Pharmacol
., 253, 53 (1994)).
Stroke/Cerebral Ischemia—Glutamate is a predominant neurotransmitter in the central nervous system and has been associated with the ischemia-induced pathophysiology seen in both acute neurodegenerative disorders such as stroke, transient ischemic attack, fetal hypoxia and spinal/brain trauma, and chronic neurodegenerative disorders such as epilepsy, Alzheimer's Disease, amyotrophic lateral sclerosis, Huntingdon's Disease, Parkinson's Disease, AIDS dementia and retinal diseases (W. F. Holt, et al., Glutamate in Health and Disease: The Role of Inhibitors, In
Neuroprotection in CNS Diseases
, P. R. Bar and M. F. Beal, eds., Marcel Dekker, Inc., News York, 1997, pp. 87-119). Therefore, compounds which inhibit or attenuate the release of glutamate represent potential neuroprotective agents. Cerebral ischemia can also result from surgery where the blood flow must be halted for a period of time (e.g., coronary bypass surgery) due to the resulting anoxia and hypoglycemia (J. E. Arrowsmith, et al., A Randomized Trial of Remacemide During Coronary Artery Bypass in 171 Patients,
Stroke
, 29, 2357 (1998)). Compounds which inhibit or attenuate glutamate release would be expected to provide neuroprotection in these scenarios as well.
Serotonin 5-HT
1A
receptors are located in brain areas which are highly sensitive to ischemia, such as the hippocampus and cerebral cortex. It has been demonstrated that 5-HT
1A
receptor agonists and partial agonists are able to attenuate glutamate release, most likely through activation of 5-HT1A receptors located on glutamatergic terminals (S. Matsuyama, et al., Regulation of Glutamate Release via NMDA and 5-HT
1A
Receptors in Guinea Pig Dentate Gyrus,
Brain Res
., 728, 175 (1996)), and that a number of 5-HT
1A
agonists and partial agonists exert neuroprotective properties in vivo in animal models (J. De Vry, et al., BAYx3702
, Drugs of the Future
, 22, 341 (1997) and references cited within).
Therefore, compounds Which possess serotonin 5-HT
1A
agonist or partial activity may be useful as neuroprotective agents for the prevention and/or treatment of ischemia-induced brain damage resulting from acute conditions such as stroke, transient ischemic attack, fetal hypoxia, prolonged cardiac surgery and spinal/brain trauma as well as chronic conditions such as epilepsy, Alzheimer's Disease, amyotrophic lateral sclerosis, Huntingdon's Disease, Parkinson's Disease, AIDS dementia and retinal diseases.
5-HT1A Antagonists
Anxiety—While no clinical trial results have been published, 5-HT
1A
antagonists have demonstrated anxiolytic activity in several animal models, most notably the elevated plus-maze (D. J. Bill and A. Fletcher,
Br. J. Pharmacol
., 111, 151P (1994); J.-L. Moreau, et al.,
Brain Res. Bull
., 29, 901 (1992)) and the light/dark box (R. J. Rodgers and J. C. Cole,
Eur. J. Pharmacol
., 261, 321 (1994). Therefore, 5-HT
1A
antagonists may find use as anxiolytic agents.
Enhancement of Antidepressant Activity—The 5-HT
1A
receptor appears to play a major role in mediating antidepressant response (J. F. Deakin, et al.,
Trends Pharmacol. Sci
., 14, 263 (1993). The delay in onset of antidepressant activity seen with serotonin-specific release inhibitors (SSRI's) is a result of the activation of somatodendritic 5-HT
1A
autoreceptors and a resulting decrease in serotonin release (S. Hjorth and S. B. Auerbach,
Behav. Brain Res
., 73, 281 (1996). Chronic administration of the SSRI leads to an eventual desensitization of the 5-HT
1A
autoreceptor, an increase in neuronal firing and serotonin release and concomitant antidepressant activity.
Co-administration of a 5-HT
1A
antagonist would be expected to inhibit the SSRI-induced activation of pre-synaptic autoreceptors and, thus, hasten the onset of antidepressant action of SSRI's. This hypothesis is supported by results from studies in animal models using more- or less-specific 5-HT
1A
antagonists in combination with SSRI's (K. Briner and R. C. Dodel,
Cur. Pharm. Des
., 4, 291 (1998), and references cited within). Furthermore, clinical trials have shown that co-administration of the 5-HT1A antagonist pindolol significantly reduced the median time needed to achieve a sustained antidepressant response with the SSRI's paroxetine (M. B. Tome, et al.,
Int. Clin. Psy
., 12, 630 (1997) and fluoxetine (V. Perez, et al.,
Lancet
, 349, 1594 (1997).
Therefore, 5-HT
1A
antagonists are expected to enhance the antidepressant activity of SSRI's by reducing the delay in onset of action seen with this class of drugs.
Prostate Cancer—In addition to its role as a neurotransmitter, serotonin can function as a growth factor. Serotonin is found in most neuroendocrine cells of the human prostate, where it may p
Childers Wayne E.
Kelly Michael G.
Palmer Yvette L.
Podlesny Edward J.
Hild Kimberly R.
Jarvis William R. A.
Mazzarese Joseph M.
Wyeth
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