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Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics

a technology of pyrrolidine and piperazine, which is applied in the direction of ketone active ingredients, group 4/14 element organic compounds, drug compositions, etc., can solve the problems of known neuroleptics producing unwanted side effects, not treating psychotic patients, and almost certainly relaps

Inactive Publication Date: 2006-07-18
AVENTISUB LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0135]This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in an amount sufficient to produce an antipsychotic effect.
[0136]In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.

Problems solved by technology

While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued.
Moreover, some of the known neuroleptics produce unwanted side effects.

Method used

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  • Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
  • Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
  • Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone

(A) Synthesis of 3-bromobenzoic acid 2-phenylsulfonylhydrazide

[0424]To a solution of 2-bromobenzoic acid, hydrazide (132 g) in pyridine (1.2 l) cooled to about 10° with an ice bath, was added benzenesulfonyl chloride (7.3 ml). After complete addition, the reaction was stirred at ambient temperature for four hours, and then poured into ice-hydrochloric acid to precipitate a yellow solid, 135 g. The material was recrystallized from isopropanol to yield 125 g of 2-bromobenzoic acid 2-phenylsulfonylhydrazide, m.p.=154°-156° C.

(B) Synthesis of α-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone

[0425]A mixture of 2-bromobenzoic acid phenylsulfonylhydrazide (125 g, (1.35 mol) and thionyl chloride (265 ml) was stirred and refluxed for 2hours. After about 15 minutes of reflux, the solid went into solution. The reaction was permitted to cool, and then it was poured into hexane. The resultant white soli...

example 2

1-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperadinyl]propoxyl]-3-methoxyphenyl]ethanone

[0445]A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 0.022 mol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90° C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetatediethylamine (2%), eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 26 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone, m.p.=102°101° C., as colorless needles.

ANALYSIS

[0446]Calculated for C24H28N2O4: 70.56% C 6.91% H 6....

example 3

1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperadinyl]propoxy]-3-methoxyphenyl]ethanone

[0448]A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g. 0.04 g, mol), 1-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone (5.3 g, 0.022 mol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hour. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]ethanone as a beige solid, m.p.=118°-120° C.

ANALYSIS

[0449]Calculated for C24H27FN2O4: 67.60% C 6.38% H 6.57% N.

[0450]Found: 67.47% C 6.40% H 6.53% N.

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Abstract

Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents. The compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amounts of one of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation-in-part of application Ser. No. 788,269, filed Nov. 5, 1991 (Attorney Docket No. 02489-0028-03000), now abandoned, which is a continuation-in-part of application Ser. No. 944,705, filed Sep. 5, 1991 (Attorney Docket No. 02489-0028-04000), now abandoned, which is a continuation of application Ser. No. 619,825, filed Nov. 29, 1990 (Attorney Docket No. 02489-0028-02000), now abandoned, which is a continuation of application Ser. No. 456,790, filed Dec. 29, 1989 (Attorney Docket No. 02489-0028-01000), now abandoned, which is a continuation-in-part of application Ser. No. 354,411, filed May 19, 1989, (Attorney Docket Nos. 02489-0028-00000 and HR-1161), now abandoned. The entire disclosure of these applications is relied upon and incorporated by reference herein.BACKGROUND OF THE INVENTION[0002]This invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relat...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/445A61K31/42A61K31/495C07D211/00A61K31/09A61K31/00A61K31/12A61K31/40A61K31/41A61K31/415A61K31/4162A61K31/423A61K31/425A61K31/428A61K31/44A61K31/4427A61K31/4465A61K31/4523A61K31/454A61K31/496A61K31/505A61K31/506A61K31/535A61K31/5375A61K31/5377A61K31/55A61P25/04A61P25/18A61P29/00C07C45/45C07C45/67C07C45/71C07C47/277C07C47/575C07C49/84C07C233/25C07C233/33C07C255/54C07C323/22C07DC07D207/08C07D221/04C07D231/56C07D239/02C07D261/20C07D275/04C07D275/06C07D277/82C07D401/04C07D401/12C07D401/14C07D403/04C07D403/12C07D403/14C07D405/04C07D405/14C07D409/14C07D413/04C07D413/12C07D413/14C07D417/04C07D417/12C07D417/14C07D419/04C07D471/04C07F7/18
CPCC07C45/45C07C45/673C07C45/71C07C233/25C07C233/33C07C255/54C07C323/22C07D207/08C07D231/56C07D261/20C07D275/04C07D275/06C07D277/82C07D401/04C07D401/12C07D401/14C07D403/12C07D413/04C07D413/10C07D413/14C07D417/04C07D417/14C07D471/04C07F7/1804A61P25/04A61P25/18A61P29/00C07C49/84C07C47/575C07C49/755
Inventor STRUPCZEWSKI, JOSEPH T.HELSLEY, GROVER C.CHIANG, YULINBORDEAU, KENNETH J.GLAMKOWSKI, EDWARD J.
Owner AVENTISUB LLC
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