Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-07-26
1992-10-06
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546209, 546192, 546201, 546282, 546 16, 546183, 514278, 514258, 514299, 514317, 514323, 544282, A61K 31445, A01N 4340, C07D21140
Patent
active
051532069
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new and useful arylpiperidine derivatives of interest to those in the field of medicinal chemistry and chemotherapy. More particularly, it is concerned with a novel series of N-alkyl or oxyalkyl arylpiperidine compounds, including their pharmaceutically acceptable acid addition salts, that are further substituted on the alkyl or oxyalkyl side chain by certain aryl or heterocyclic ring groups. These particular compounds are useful in therapy as neuroleptic agents for the control of various psychotic disorders.
BACKGROUND ART
In the past, various attempts have been made to obtain new and better anti-psychotic agents. These efforts have involved the synthesis and testing of various N-alkyl-N-arylpiperazine derivatives that are further substituted on the alkyl side chain by various aryl or heterocyclic ring groups. For instance, in U.S. Pat. Nos. 2,927,924 and 3,170,926, there are disclosed various N-phenylethyl-N'-arylpiperazine compounds that are reported to be useful for these purposes, while in U.S. Pat. No. 4,558,060 and in Published European Patent Application Nos. 279,598 (published on Aug. 24, 1988) and 281,309 (published on Sept. 7, 1988), there are disclosed the corresponding N-heterocyclylalkyl-N'-arylpiperazine compounds. Other efforts have involved the synthesis and testing of various arylpiperidine derivatives in this area, for example, U.S. Pat. No. 4,458,076 and Published European Patent Application No. 196,132 both teach a series of N-substituted 1,2-benzoisothiazol-3-ylpiperidine derivatives, which are also reported to be useful as anti-psychotic agents. However, none of the foregoing references teach or suggest the heretofore unavailable N-alkyl arylpiperidine derivatives or their use for anti-psychotic purposes.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, it has now been found that certain novel N-alkyl or oxyalkyl derivatives of various arylpiperidine compounds are useful in therapy as neuroleptic agents for the control of various psychotic disorders. More specifically, the novel compounds of this invention are N-substituted arylpiperidines of the formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein Ar is phenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl, methoxyphenyl, tolyl or naphthyl optionally substituted with fluorine, chlorine, trifluoromethyl or methoxy; n is an integer of from two to four, inclusive; X is oxygen, sulfur or a direct link; and R is phenyl, hydroxyphenyl, methoxyphenyl, tolyl, 2-amino-4-thiazolylphenyl, 5-oxindolyl, 2-methyl-4-oxo-4H-pyrido[1,2a]pyrimidin-3-yl, 7,9-dioxo-8-azaspiro[4.5]decan-8-yl or 1,8,8-trimethyl-2,4-dioxo-3-azabicyclo-[3.2.1]octan-3-yl. These novel compounds are dopamine-2 antagonists and additionally possess the ability to reverse haldol-induced catalepsy in animals, so that they are useful in treating various psychotic disorders in mammals without causing any untoward side effects.
A preferred group of compounds of the present invention of particular interest is that of the aforesaid formula I wherein Ar is phenyl, trifluoromethylphenyl, methoxyphenyl or naphthyl, X is oxygen or a direct link and R is phenyl, hydroxyphenyl, 2-amino-4-thiazolylphenyl, 5-oxindolyl, 2-methyl-4-oxo-4H-pyrido[1,2a]pyrimidin-3yl, 7,9-dioxo-8-azaspiro[4.5]decan-8-yl or 1,8,8-trimethyl-2,4-dioxo-3-azabicyclo[3.2.1]octan-3-yl. Especially preferred compounds within this group include those members where Ar is 2-methoxyphenyl or 1-naphthyl, X is a direct link and R is 2-amino-4-thiazolylphenyl, 5-oxindolyl, 2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl or 1,8,8-triethyl-2,4-dioxo-3-azabicyclo]3.2.1]-octan-3yl.
Of especial interest in this connection are such typical and preferred compounds of the invention as 4-{{4-{2-[4-(2-methoxyphenyl)-1-piperidinyl]ethyl}-phenyl{{thiazole-2-amin e, 4-{{4-{4-[4-(2-methoxyphenyl)-1-piperidinyl]-n-butyl}phenyl}}thiazole-2-am ine, 3-{4-[4-(2-methoxyphenyl)-1-piperidinyl]-n-butyl}-1,8,8-trimethyl-3-azabic yclo-[3.2.1]octa
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Ginsburg Paul H.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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