Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-09
2000-10-10
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546194, A61K 31445, C07D40106
Patent
active
061302325
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention is useful in the field of drugs. More specifically, the novel substituted heteroaromatic ring derivatives of the invention are useful as therapeutic or prophylactic agents of various diseases of the respiratory, urinary and gastrointestinal systems. In particular, the compounds of the present invention do not affect other organs such as the brain and heart, although they exhibit potent bronchodilating and bladder contraction-suppressing actions. Hence they are useful as therapeutic or prophylactic agents of respiratory diseases such as asthma, chronic airway obstruction and pulmonary fibrosis, etc.; urinary diseases which induce such urination disorders as pollakiurea, urgency and urinary incontinence, etc.; and gastrointestinal diseases such as irritable bowel syndrome, spasm of gastrointestinal tract and gastrointestinal hyperkinesis.
BACKGROUND ART
Compounds having antagonism to muscarinic receptors are known to cause bronchodilation, gastrointestinal hypanakinesis, gastric hyposecretion, dry mouth, mydriasis, suppression of bladder contraction, hypohidrosis, tachycardia and the like [cf. Seitai no Kagaku (biochemistry), Vol. 42, p. 381 (1991)].
There are three subtypes of muscarinic receptors: M.sub.1 receptors are present mainly in the brain, M.sub.2 receptors, mainly in the heart, and M.sub.3 receptors, on smooth muscles and glandular tissues. While a large number of compounds having antagonism to muscarinic receptors became known to date, those known compounds non-selectively antagonize the three subtypes of muscarinic receptors. Hence, attempts to use these compounds as therapeutic or prophylactic agents for diseases of the respiratory system have caused undesirable side effects such as tachycardia, dry mouth, nausea and mydriasis. In particular, side effects associated with the heart such as tachycardia induced by M.sub.2 receptors pose problems, and their improvement has been in strong demand.
DISCLOSURE OF THE INVENTION
We have conducted concentrative research work on compounds which exhibit antagonism selective for M.sub.3 muscarinic receptors, and have discovered that substituted heteroaromatic ring derivatives which are represented by formula [I] below: ##STR2## [in the formula, R.sup.1 and R.sup.2 may be same or different and each signifies hydrogen, halogen or lower alkyl; R.sup.3 signifies C.sub.3 -C.sub.6 cycloalkyl or cycloalkenyl; R.sup.4 signifies a heteroaromatic ring group which may be condensed with benzene ring and which has 1 or 2 hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur atoms (said heteroaromatic ring group being optionally substituted with lower alkyl, halogen, lower alkoxy, amino or hydroxymethyl); and X stands for O or NH] antagonism selective for M.sub.3 muscarinic receptors; and that they are useful as safe and effective therapeutic or prophylactic agents exhibiting little side effects, of respiratory diseases such as asthma, chronic airway obstruction and pulmonary fibrosis, etc., urinary diseases which indue urination disorders such as pollakiurea, urgency and urinary incontinence, etc., and gastrointestinal diseases such as irritable bowel syndrome, spasm of gastrointestinal tract and gastrointestinal hyperkinesis. The present invention is thus completed.
Accordingly, therefore, the present invention relates to the substituted heteroaromatic ring derivatives which are represented by the general formula [I] and their pharmaceutically acceptable salts; their production processes and their use.
Definitions of terms used in this specification are explained hereinafter.
Halogen denotes fluorine, chlorine, bromine and iodine atoms.
Lower alkyl denotes C.sub.1 -C.sub.6 linear or branched alkyl groups, eg., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl and isohexyl.
Examples of C.sub.3 -C.sub.6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
Examples of C.sub.3 -C.sub.6 cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and
REFERENCES:
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Chemical Abstracts, vol. 114, No. 91, Jan. 7, 1991, abstract No. 671, Tejani-But, Shanaz M. et al.
Scheithauer, S., Pharmazie, 43 (2), 86-90, 1988. "Synthesis of some metabolites of the bladder spasmolytic propiverine hydrochloride ".
Japanese language publication "Seitai no Kagaku" (biochemestry), vol. 42(5), p. 380-385, 1991 and partial English translation.
Chem. Parm. Bull., vol. 32, No. 3, (1984), Sugia, Saburo et al, "Studies on Spasmolytics I. Synthesis and Spasmolytic . . . piperidines", p. 967-976.
Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo et al., "Studies on Spasmolytics. II. Synthesis . . . Compounds", p. 977-985.
Chem. Pharm. Bull., vol. 32, No. 3, (1984), Sugai, Saburo et al., "Studies on Spasmolytics. III. Synthesis . . . Salts", p. 1126-1134.
Chem. Pharm. Bull., vol. 33, No. 2, (1985), Yoshida, Seiichiro et al., "Structure-Activity Relationship . . . piperidine Derivatives", p. 818-822 .
Kobayashi Kensuke
Mase Toshiaki
Mitsuya Morihiro
Noguchi Kazuhito
Banyu Pharmaceutical Coaltd
Chang Ceila
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