Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-12-06
2003-02-25
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S359000, C546S001000, C548S246000, C514S252130, C514S252140, C514S253110, C514S379000
Reexamination Certificate
active
06525196
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel heteroaryl-aminoethyl/benzisoxazole substituted azabicyclic compounds, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1D receptors. They are useful in treating or preventing migraine, depression and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful 5-HT1Aligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT1 agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT1 agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT1 ligand in their article “5-HT1D Serotonin Receptors”,
Clinical Drug Res. Dev.,
22, 25-36 (1991).
Glennon's article “Serotonin Receptors: Clinical Implications”,
Neuroscience and Behavioral Reviews,
14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT1D antagonist in combination with a 5-HT1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesia, endocrine disorders such as hyperprolactinemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al.,
J. Neurochem,
66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT1A receptors or for both 5-HT1A and 5-HT1D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein R
1
, R
2
, R
3
and R
4
are selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C
1
-C
4
) alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy optionally substituted with from one to three fluorine atoms, and (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl wherein each of the alkyl moieties may optionally be substituted with from one to three fluorine atoms; and
X is CH or N;
and the pharmaceutically acceptable salts thereof.
Examples of preferred compounds of the formula I are those having the absolute stereochemical configuration defined as 7R, 9aS-trans or as 7S, 9aS-cis.
Other preferred compounds of the formula I are those wherein R
3
and R
4
selected, independently, from hydrogen, fluoro, chloro and methyl.
Examples of specific compounds of this invention are the following compounds of their pharmaceutically acceptable salts:
(7R,9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)-amine;
(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)-amine;
(7R,9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-chloro-pyrimidin-2-yl)-amine;
(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-chloro-pyrimidin-2-yl)-amine;
(7R,9aS)-trans-(5-Chloro-pyrimidin-2-yl)-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-amine;
(7S,9aS)-cis-(5-Chloro-pyrimidin-2-yl)-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-amine;
(7R,9aS)-trans-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-methyl-pyrimidin-2-yl)-amine;
(7S,9aS)-cis-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-methyl-pyrimidin-2-yl)-amine;
(7R,9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyridin-2-yl)-amine;
(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyridin-2-yl)-amine;
(7R,9aS)-trans-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyridin-2-yl)-amine;
(7S,9aS )-cis-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyridin-2-yl)-amine;
(7R,9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine;
(7S,9aS )-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine;
(7R,9aS)-trans-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)-amine;
(7S,9aS)-cis-[2-(5-Fluoro-benzo[d]isoxazol-3-yl )-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)-amine, and
(7R,9aS)-trans-(2-Benzo[d]isoxazol-3yl-octahydro-pyrido[1,2-a]pyrazin-7-yl-methyl)-(5-fluoro-pyrimidin-2-yl)-amine.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretio
Bright Gene M.
Desai Kishor A.
Ginsburg P. H.
Joran A. D.
Patel Sudhaker B
Pfizer Inc.
Raymond Richard L.
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