Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-13
2000-11-21
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514217, 514290, 514291, 514321, 514323, 514324, 514325, 540521, 540522, 546 89, 546 93, 546196, 546198, 546200, 546202, 546203, C07D21106, C07D22106, C07D49800, A01N 4346, A01N 4342
Patent
active
06150355&
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel phenylpiperidine derivatives useful as analgesics.
BACKGROUND ART
Although nonsteroidal anti-inflammatory drugs, narcotic analgesics, and antagonistic analgesics are conventionally used as analgesics, there is demand for novel useful analgesics in which the adverse effects of these drugs are reduced.
As compounds having 4-hydroxy-4-phenylpiperidino group and analgesic action, the following compounds are known. For example, compounds represented by Formula (A) are reported in European Journal of Pharmacology, Vol. 43, p253, 1977. ##STR2##
Also compounds represented by Formula (B) are reported in European Journal of Pharmacology, Vol. 72, p305, 1981. ##STR3##
Further compounds (C) are reported in Lzv. Vyssh. Uchebn. Zarved., Khim. Khim. Teknol, Vol. 21, p810, 1978. ##STR4##
DISCLOSURE OF INVENTION
The present invention relates to phenylpiperidine derivatives or pharmaceutically acceptable salts thereof represented by formula (I): ##STR5## wherein X represents CH or N; Y-Z represents CH.sub.2 --O, CH.sub.2 --S, CH.sub.2 --CH.sub.2, CH.dbd.CH or CONR.sup.5 (wherein R.sup.5 represents hydrogen or lower alkyl); R.sup.1 represents hydrogen, lower alkyl, halogen, lower alkoxy or trifluoromethyl; and R.sup.2, R.sup.3 and R.sup.4 are the same or different and each represents hydrogen, lower alkyl or QR.sup.6 (wherein Q represents a single bond or lower alkylene; and R.sup.6 represents hydroxy, lower alkoxyalkoxy, lower alkoxy, lower alkylthio, nitro, halogen, lower alkanoyloxy, lower alkoxycarbonyl, lower alkanoyl or carboxyl).
Hereinafter, compounds represented by formula (I) are referred to as compounds (I), and the same shall apply to compounds of other formula numbers.
In the definition of the groups in formula (I), lower alkyl and the lower alkyl moiety of lower alkoxy, lower alkoxyalkoxy, lower alkylthio and lower alkoxycarbonyl means a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. Lower alkylene and the alkylene moiety of lower alkoxyalkoxy means a bivalent saturated aliphatic group having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, butylene, pentamethylene, amylene, hexametylene and hexylene. Lower alkanoyl and the lower alkanoyl moiety of lower alkanoyloxy may be a straight chain or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutylryl, valeryl and pivaloyl. Halogen means fluorine, chlorine, bromine or iodine.
Examples of the pharmaceutically acceptable salts of compounds (I) include inorganic acid addition salts such as hydrochloride, sulfate and phosphate; organic acid addition salts such as maleates, fumarates, oxalates, citrates and methanesulfonates; ammonium salt; lithium salt; sodium salt; potassium salt; magnesium salt; and calcium salt.
The process for producing compounds (I) are described below.
In the production process below, when the defined groups are changed under the process conditions or are unsuitable for carrying out the process, a desired compound can be obtained by using a method of introducing and eliminating protective groups, which is generally used in synthetic organic chemistry [refer to, for example, Protective Groups in Organic Synthesis, written by T. W. Green, John Wiley & Sons Inc. (1981)].
Production Process 1
##STR6## (wherein X, Y-Z, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined as described above).
Raw material compound (II) is obtained by the process disclosed in, for example, JP,A, 2-250 or in accordance with the process. Compound (III) is commercially available or obtained in accordance with the process described in Collect. Czech. Chem. Commun., Vol. 55, p1828, 1990.
Compound (II) is reacted with 1 to 10 equivalents of a halogenating agent such as thionyl chloride and phosphorus tribromide in a solvent such as methylene chloride and chloroform at an appropriate temperature between 0.
REFERENCES:
patent: 4882351 (1989-11-01), Oshima et al.
patent: 5010087 (1991-04-01), Oshima et al.
patent: 5010104 (1991-04-01), Oshima et al.
patent: 5436255 (1995-07-01), Butler
European Journal of Pharmacology, vol. 43 (1977) 253-267.
European Journal of Pharmacology, vol. 72 (1981) 305-311.
Khim. Khim. Tekhnol, vol. 21 (1978) 810-812.
Aono Shigeru
Ichikawa Shunji
Kitamura Shigeto
Koshimura Hirokazu
Kumazawa Toshiaki
Covington Raymond
Kight John
Kyowa Hakko Kogyo Co. Ltd.
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