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1-(arylthioalkyl, arylaminoalkyl, or arylmethylenealkyl)-4-(heteroaryl)piperazines and related compounds useful as antipsychotics and analgesics

a technology of arylthioalkyl and arylmethylenealkyl, which is applied in the field of heteroarylpiperidines, pyrrolidines and piperazines, can solve the problems of known neuroleptics producing unwanted side effects, unable to cure psychotic patients, and almost certainly relapse, and achieves long-acting effects

Inactive Publication Date: 2001-12-18
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • 1-(arylthioalkyl, arylaminoalkyl, or arylmethylenealkyl)-4-(heteroaryl)piperazines and related compounds useful as antipsychotics and analgesics
  • 1-(arylthioalkyl, arylaminoalkyl, or arylmethylenealkyl)-4-(heteroaryl)piperazines and related compounds useful as antipsychotics and analgesics
  • 1-(arylthioalkyl, arylaminoalkyl, or arylmethylenealkyl)-4-(heteroaryl)piperazines and related compounds useful as antipsychotics and analgesics

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanon e

(A) 2-Bromobenzoic acid 2-phenylsulfonylhydrazide

To a solution of 2-bromobenzoic acid hydrazide (132 g) in pyridine (1.2 L) cooled to about 10 C. with an ice bath, was added benzensulfonyl chloride (78.3 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.degree.-156.degree. C.

(B) .alpha.-Chloro-2-bromobenzaldehyde phenylsulfonylhydrazone

A mixture of 2-bromobenzoic acid phenylsulfonylhydrazide (125 g, 350 mmol) and thionyl chloride (265 ml) was stirred and refluxed for 2 hours. 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 solid was collected to afford 124 g...

example 2

1-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-1-methyoxyphenyl] -ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20 mmol), K.sub.2 CO.sub.3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methyoxyphenyl]ethanone (5.3 g, 22 mmol), 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 (MgSO.sub.4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxypehenyl ]ethanone, m.p.=102.degree.-104.degree. C., as colorless needles.

ANALYSIS: Calculated for C.sub....

example 3

1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methox y-phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K.sub.2 CO.sub.3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90.degree. C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO.sub.4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-metho xyphenyl]-ethanone as a beige solid, m.p.=118.degree.-120.degree. C.

ANALYSIS: Calculated for C.sub.24 H.sub.27 FN.sub.2 O.sub.4 : 67.60% C 6.38% H 6.57% N 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 amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects 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

BACKGROUND OF THE INVENTIONThis invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines having antipsychotic activity and to their use as antipsychotic drugs.The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. 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. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, and t...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/445A61K31/495C07D405/00C07D403/04C07D403/00C07D405/04C07D401/00C07D401/04A61K31/415A61K31/42A61K31/425A61K31/44A61K31/4427A61K31/4453A61K31/47A61K31/496A61K31/505A61K31/55A61P23/00A61P25/00A61P25/04A61P25/18C07C45/45C07C45/67C07C45/71C07C49/84C07C233/25C07C233/33C07C255/54C07C323/22C07D207/08C07D221/04C07D231/56C07D239/02C07D261/20C07D275/04C07D275/06C07D277/82C07D401/12C07D401/14C07D403/12C07D403/14C07D413/04C07D413/12C07D413/14C07D417/00C07D417/04C07D417/14C07D419/00C07D471/04C07F7/18
CPCC07C45/45C07C45/673C07C45/71C07C233/25C07C233/33C07C255/54C07C323/22C07D207/08C07D231/56C07D261/20C07D275/04C07D275/06C07D277/82C07D401/04C07D401/12C07D401/14C07D403/12C07D413/04C07D413/12C07D413/14C07D417/04C07D417/14C07D471/04C07F7/1804A61P23/00A61P25/00A61P25/04A61P25/18A61P29/00C07C49/84C07C49/755C07C47/575A61K31/495A61K31/41
Inventor STRUPCZEWSKI, JOSEPH T.HELSLEY, GROVER C.GLAMKOWSKI, EDWARD J.CHIANG, YULINBORDEAU, KENNETH J.
Owner AVENTIS PHARMA INC
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