Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-04-05
1992-08-11
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 514389, 514390, 514391, 546210, 548307, 548309, 548318, 548312, 548320, C07D40306, C07D23336, C07D40106, A61K 31415
Patent
active
051379058
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed toward heterocyclic acetylenic amine compounds having central nervous system activity. The compounds exhibit cholinergic activity and are particularly useful for improving mental performance or treating mental deficiencies. As an example, Alzheimer's disease is a cognitive disorder characterized in part by a significant reduction in choline acetyltransferase activity, high affinity choline uptake and synthesis of acetylcholine in the forebrain areas which receive cholinergic input. The reduction in presynaptic markers of the forebrain cholinergic neurons is due to the degeneration of these neuronal pathways. Clinical observations indicate that the central cholinergic system may be involved in the physiology of cognitive functions. Thus there is a medical need for a cholinergic agonist which is likely to have therapeutic efficacy in cognitive disorders. Cholinergic agonists can also be useful as analgesics to treat pain.
Those compounds having cholinergic antagonist activity are useful in the treatment of extrapyramidal motor disorders. The central nervous system activity of the compounds also indicates that they can be useful in the treatment of disorders of the parasympathetic nervous system.
These compounds are related to the cholinergic agonist oxotremorine 1-[4-(1-pyrrolidinyl-2-butynyl)-2-pyrrolidinone], which induces tremors and spasticity in laboratory animals by a cholinergic mechanism at extremely low doses. These undesirable side effects prevent the use of oxotremorine as a drug, and considerable effort has been directed to the preparation of related, clinically useful cholinergic agonists and antagonists.
DESCRIPTION OF RELATED ART
U.S. Pat. No. 3,925,411 discloses an oxotremorine antagonist N-(5-pyrrolidino-3-pentynyl)-pyrrolidin-2-one which is reported to have an increased half life over prior oxotremorine compounds. U.S. Pat. No. 3,959,311 also discloses compounds related to oxotremorine which are agonists, partial agonists and antagonists on isolated guinea pig ileum. These compounds are reported to have greater potency and less side-effects (antagonizing peripheral cholinergic effects) than the prior art compounds. Despite the proliferation of oxotremorine-like compounds there has been a continuing need to find more effective and safe compounds for treating mental disorders, extrapyramidal motor disorders, disorders of the parasympathetic nervous system and glaucoma.
More recently, a series of acetylenic amine compounds have been developed and evaluated for potential value in treating neurological and psychiatric conditions. A series of N-(4-amino-2-butynyl)-5-methyl-2-pyrrolidones were reported in Ringdahl, B, "5-methyl-2-pyrrolidone Analogues of Oxotremorine as Selective Muscarinic Agonists, J. Med. Chem. 31, 683-688 (1988). Another series of tertiary and quaternary analogues of N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl) acetamide were reported to have central antimuscarinic activity as they antagonized oxotremorine-induced tremors in mice as reported in Nilsson, et al., "Derivatives of the Muscarinic Agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide", J. Med. Chem., 31, 577-582 (1988).
SUMMARY OF THE INVENTION
The present invention is directed toward a family of heterocyclic acetylenic amine compounds having central nervous system activity. The compounds are represented by structural Formula I shown on the Formula sheet below including therapeutically acceptable salts thereof wherein R.sub.1 and R.sub.2 are hydrogen, methyl, ethyl or joined to form an azetidine, pyrrolidine, piperidine or imidazole ring which can be substituted with a methyl or ethyl group and the heterocyclic group X is as shown on the Formula sheet wherein R.sub.3 is hydrogen, methyl or ethyl; R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl, phenyl, C.sub.1 -C.sub.6 alkylcarbonyl or C.sub.1 -C.sub.6 alkoxycarbonyl; R.sub.5 and R.sub.6 are hydrogen, methyl, ethyl or, together with the atta
REFERENCES:
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B. Ringdahl, "5-Methyl-2-pyrrolidone Analogues of Oxotremorine as Selective Muscarinic Agonists," Journal of Medicinal Chemistry, 31, pp. 683-688 (1988).
B. M. Nilsson, et al., "Derivatives of the Muscarinic Agent N-Methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide," Journal of Medicinal Chemisty, 31, pp. 577-582 (1988).
Heier Richard F.
Moon Malcolm W.
Corneglio Donald
Miltenberger Lenora A.
Morris Patricia L.
The Upjohn Company
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