Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-03-08
1991-12-31
Shen, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544368, A61K 31495, A61K 3141, C07D41714
Patent
active
050772953
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to bridged bicyclic imides substituted on the nitrogen thereof with the 4-[4-(3-benzisothiazolyl)-1-piperazinyl]butyl group and their use as antipsychotics.
A variety of antipsychotic agents are known to date. These include tricyclic compounds such as chlorpromazine (2-chloro-N,N-dimethyl-10H-phenothiazine-10-propenamine); butyrophenone compounds such as haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butan one); and certain spiroimide compounds such as busprione (8-[4-(2-pyrimidinyl)-1-piperazinylbutyl]-8-azaspiro[4,5]decane-7,9-dione) and tiaspirone (8-[4-(3-benzisothiazolyl)-1-piperazinyl butyl]-8-azaspiro[4,5]decane-7,9-dione). More recently, antipsychotics in which the azaspiro group is replaced by a fused bicyclic imide group and which allegedly exhibit fewer extra pyramidal side effects than previously described antipsychotics have been reported (see below). However, there remains a need for anti-psychotic agents which exhibit selectivity of action.
2. Description of the Prior Art
Certain glutarimide and succinimide compounds, substituted on nitrogen by a (4-aryl-1-piperazinyl)alkyl or (4-heteroaryl-1-piperazinyl)alkyl group, and having tranquillizing, antianxiety and/or anti-emetic properties are known from U.S. Pat. Nos. 3,717,634 and 3,907,801; 4,411,901 and 4,452,799; 4,182,763; 4,423,049; 4,507,303 and 4,543,355; 4,562,255; and EP-196,096. Korgaonka et al., J. Indian Chem. Soc., 60 874 (1983), disclose a number of N-(3-[4-aryl-1-piperazinyl]propyl) -camphorimides, which are alleged to have sedative properties in mice.
The most pertinent compounds of the above references have the general formula: ##STR1## wherein the values of A and B are: U.S. Pat. No. 3,717,634 ##STR2## and U.S. Pat. No. 3,907,901: ##STR3## U.S. Pat. No. 4,182,673: ##STR4## U.S. Pat. No. 4,423,049: ##STR5## U.S. Pat. No. 4,411,901 ##STR6## and U.S. Pat. No. 4,452,799: ##STR7## U.S. Pat. No. 4,507,303 ##STR8## and U.S. Pat. No. 4,543,355; ##STR9## and U.S. Pat. No. 4,562,255: ##STR10## and EP 0196096 ##STR11##
SUMMARY OF THE INVENTION
The compounds of this invention have the formula (I) ##STR12## and the pharmaceutically-acceptable acid addition salts thereof, wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --; and alike or different, is hydrogen or methyl; and methyl or ethyl.
The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically-acceptable acid addition salt thereof and a pharmaceutically-acceptable carrier or diluent and to the use of formula (I) compounds or a pharmaceutical composition thereof for the treatment of a psychotic disorder in a human being suffering therefrom.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula (I) are conveniently prepared by reacting N-(3-benzisothiazolyl)piperazine with a compound of formula (II) ##STR13## wherein Z is halo (especially chloro, bromo, iodo) or other readily displaced (leaving) group such as tosyloxy or mesyloxy. The reaction is carried out in a reaction-inert solvent (i.e., one in which at least one of the reactants is partially soluble and which does not adversely interact with reactants or product), generally at or near the reflux temperature of said solvent until substantially complete. The reaction temperature may range from 50.degree. C. to about 200.degree. C. In general, however, temperatures of from about 50.degree. C. to 150.degree. C. are adequate. The time required for substantially complete reaction is, of course, dependent upon the reaction temperature and the value of Z in the formula (II) reactant. A favored solvent, especially when Z in the formula (II) is tosyloxy is methyl isobutyl ketone. Other suitable, and typical, reaction-inert solvents are hydrocarbons such as benzene, toluene, xylene and decalin; the methyl and ethyl ethers of ethylene glycol, propylene glycol and diethylene glycol; and cyclic ethers such as tetrahydrofur
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Bright Gene M.
Love, III John A.
Lumb J. Trevor
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Shen Cecilia
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