Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-03-24
1996-10-15
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544230, A61K 31495, C07D47106
Patent
active
055654533
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to certain 2- substituted perhydro-1H-pyrido[1,2-a]pyrazines which are depicted by the formula (I) as defined below, and to pharmaceutical compositions comprising these compounds, and a method of treating psychotic diseases therewith.
Commonly-owned U.S. patent application No. 07/661,791, filed Feb. 27, 1991 U.S. Pat. No. 5,157,034, the disclosure of which is herein incorporated by reference, is directed to both racemic and optically active perhydro-1H-pyrido[1,2-a]pyrazines having the formula ##STR2## wherein Z is H or Cl; ##STR3## where Y.sup.1 is CH.sub.2, S, O or NH; Y.sup.2 and Y.sup.3 are taken separately and Y.sup.2 and Y.sup.3 are each independently hydrogen or methyl, or Y.sup.2 and Y.sup.3 are taken together and are (CH.sub.2).sub.q ; p is 1 or 2, q is 2, 3, 4 or 5; and r is 0 or 1.
U.S. Pat. No. 4,956,368, issued Sep. 11, 1990 discloses various metabolites and prodrug formulations of 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro(4,5)deca ne-7,9-dione which are particularly useful in the treatment of psychotic disorders, especially derivatives thereof which have been oxygenated at specified sites about the original structure, rearranged compounds, and prodrug formulations of these species. One particularly desired group of compounds have the general formula ##STR4## where: R.sup.1 is hydrogen, hydroxyl, alkoxy, acyloxy and oxo;
Perhydro-1H-pyrido[1,2-a]-pyrazines of the formula ##STR5## wherein X.sup.a is N or CH and L.sup.a represents one of certain pyrazolo, triazolo, tetrazolo or cyclic imido radicals have been reported to possess useful anxiolytic activity, Bright and Desai, International Application published under the PCT as publication No. WO 90/08144.
A variety of compounds are reported to be in possession of neuroleptic activity useful in the treatment of psychotic diseases. These include piperidine derivatives of the formula ##STR6## wherein t is 1 or 2, Ar is naphthyl or one of a variety of bicyclic heteroaryl groups, including benzisothiazoyl, and X.sup.b and Y.sup.b together with the attached phenyl group form a similar such bicyclic heteroaryl group (Lowe, III et al., U.S. Pat. No. 4,831,031); and compounds of the formula ##STR7## wherein Q represents certain bicyclic heteroaryl groups, Alk is alkanediyl X.sup.c represents, O, S, NH, or substituted NH (Kennis et al., U.S. Pat. No. 4,957,916).
SUMMARY OF THE INVENTION
The present invention is directed to 2-substituted perhydro-1H-pyrido-[1,2-a]pyrazines having the formula ##STR8## wherein R is H or R.sup.1 C(.dbd.O), wherein R.sup.1 is (C.sub.1 -C.sub.6)alkyl, phenyl or substituted phenyl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to 2a-oxo-substituted perhydro-1H-pyrido[1,2-a]pyrazines having the formula I wherein the stereochemistry at the 2a position is R or S; or a diastereomeric mixture which comprises the compound of formula (I) having 2aR, 7S, 9aS stereochemistry in combination with the compound of formula (I) having 2aS, 7S, 9aS stereochemistry; and a pharmaceutically acceptable acid addition salt thereof; and wherein R is hydrogen or R.sup.1 C(.dbd.O) wherein R.sup.1 is (C.sub.1 -C.sub.6)-alkyl, phenyl or substituted phenyl.
As used in this invention "alkyl" means straight or branched carbon chains of up to six carbon atoms.
"Substituted phenyl" means a phenyl ring having one or two substitutions selected from (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkoxy, halo, nitro and trifluoromethyl.
In another aspect, this invention is directed toward a pharmaceutical composition for the treatment of psychotic disorders which comprises a neuroleptic effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
In yet another aspect, this invention is directed toward a method of treating psychotic disorders which comprises administering to a psychotic patient in need of such treatment a neuroleptic effective amount of a compound of formula I.
A preferred compound of this invention is repre
REFERENCES:
patent: 4831031 (1989-05-01), Lowe, III et al.
patent: 4956368 (1990-09-01), Cipollina et al.
patent: 4957916 (1990-09-01), Kinnis et al.
"Biochemical Profile of Risperidone, A New Antipsychotic", Leysen, J. E., et al., J. Pharm. Exp. Ther., 247, 661-670 at 662, 1988.
"The Oxford Textbook of Clinical Pharmacology and Drug Therapy", pp. 23-24, Grahame-Smith, D. G., et al. 1984.
Goodman and Gilman, "The Pharmacological Basis of Therapeutics", p. 13, 1990.
"Pharmacology of Risperidone (R 64 766), a New Antipsychotic with Serotonin-S.sub.2 and Dopamine-D.sub.2 Antagonistic Properties", Janssen, P. A. J., et al., Pharm. Exp. Ther., 244(2):685 1988.
"Risperidone in the Treatment of Acute Exacerbation of Chronic Schizophrenia", Borison, R. L. et al., Schizophrenia Research, 4(3):314-315, 1991.
"Therapeutic Effect and Safety of Increasing Doses of Risperidone (R 64766) in Psychotic Patients", Mesotten, et al., Psychopharmacology, 99:445-449, 1989.
Bright Gene M.
Desai Kishor A.
Seeger Thomas F.
Smolarek Teresa A.
Berch Mark L.
Butterfield Garth
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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