Piperidine derivatives as substance P antagonists

Details Piperidine derivatives as substance P antagonists Piperidine derivatives as substance P antagonists

1997-09-26

1999-03-23

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514321, 546196, 546197, A61K 31445, C07D40512, C07D30779

Patent

active

058860118

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP96/00796 filed Mar. 27, 1996.


TECHNICAL FIELD

The present invention relates to new piperidine derivatives having an antagonism on Substance P, being a peptide neurotransmitter, and pharmaceutically acceptable acid addition salts thereof. The piperidine derivatives and pharmaceutically acceptable acid addition salts thereof of the present invention are useful as a preventive or remedy for respiratory system diseases, central nervous system diseases, digestive system diseases, circulatory system diseases, and a variety of inflammation and pains and the like.


PRIOR ART

Substance P is a tachykinin undecapeptide which is found especially in mammals and which is referred as Neurokinin with Neurokinin A and Neurokinin B etc. The facts that Substance P is involved in a variety of pathological fields such as respiratory system diseases such as asthma, central nervous system diseases such as anxiety, schizophrenia, digestive system diseases such as ulcerative colitis, circulatory system diseases such as hypertension, various inflammation and pains, have been well-known (e.g., Journal of Medicinal Chemistry,25,1009, (1982), Trends in Cluster Headache, 85-97, (1987),ELSEVIER).
In addition, until now, as the non-peptide Substance P antagonist, a compound having a quinuclidine skeleton (JP 3-503768, A), a compound having a piperidine skeleton (JP 4-103570, A), a compound having an isoindolone skeleton (JP 3-176469, A), a compound having an arylalkylamine skeleton (JP 3-206086, A) etc. have been known.
As the compounds having benzofuran ring or benzopyran ring, the compound described in WO93/09116 has been known. The non-aromatic alicyclic compound substituted by an aminomethylene group is disclosed in WO94/13663. A remedy for vomiting is disclosed in JP 7-53362, A. The compounds of the present invention are included in the compounds described in WO94/13663 and JP 7-53362, as subordinate concepts. However, the compounds of the present invention as well as the similar compounds are not disclosed in any publications concretely.


DISCLOSURE OF THE INVENTION

The object of the present invention is to provide piperidine derivatives or pharmaceutically acceptable acid addition salts thereof having an antagonism on non-peptide Substance P.
The present invention provides piperidine derivatives represented by general formula (I) ##STR2## or pharmaceutically acceptable acid addition salts thereof: wherein n represents an integer of 0 or 1; X represents CH.sub.2, O or CH--CH.sub.3 ; R represents hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, substituted aminosulfonyl or nitro; R.sub.1 and R.sub.2 may be the same or different and each represents hydrogen or lower alkyl.
The present invention also provides cis-piperidine derivatives represented by general formula (Ia) ##STR3## or pharmaceutically acceptable acid addition salts thereof: wherein n, X, R, R.sub.1 and R.sub.2 are as defined above.
The present invention also provides cis-piperidine derivatives represented by general formula (Ib) ##STR4## or pharmaceutically acceptable acid addition salts thereof: wherein R, R.sub.1 and R.sub.2 are as defined above.
The present invention also provides the piperidine derivatives or pharmaceutically acceptable acid addition salts thereof having an antagonism on Substance P.
The present invention also provides a pharmaceutical composition comprising an effective amount of the piperidine derivative or pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a preventive or remedy for asthma which comprises the piperidine derivative or pharmaceutically acceptable acid addition salt thereof as an effective component.
The present invention also provides a preventive or remedy for vomiting which comprises the piperidine derivative or pharmaceutically acceptable acid addition salt thereof as an effective component.
The present invention also provides a formulation

REFERENCES:
patent: 5393762 (1995-02-01), Desai et al.
Mishina et al. "Preparation of imidazolybenzene compounds and use thereof as medicines" CA 123:83361, 1995.
Naylor et al. "Preparation of benzofuran derivatives as tachykinin antagonists" CA 123:339709, 1995.

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