Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-07-31
1998-05-12
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514256, 514317, 514326, 544242, 544233, 546194, 546208, 546209, 546210, 546213, 546214, 546222, 546224, A61K 31445, A61K 31505, C07D40112, C07D21146
Patent
active
057505403
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/01128 filed Apr. 25. 1996, published as WO96/33973 Oct. 31, 1996.
TECHNICAL FIELD
This invention relates to novel 1,4-di-substituted piperidine derivatives, processes for preparing them, and their use in medicine, especially in the treatment or prophylaxis of various diseases of the respiratory, urinary and digestive systems.
BACKGROUND ART
Compounds having antagonistic activity against muscarinic receptors are known to cause bronchodilation, gastrointestinal hypanakinesis, gastric hyposecretion, thirst, mydriasis, suppression of bladder contraction, 4th ed., APPLETON & LANGE, pp. 83-92 (1989); Drug News & Perspective, 5(6), pp. 345-352 (1992)!.
There are three subtypes of muscarinic receptors. That is, the M.sub.1 receptors are present mainly in the brain, the M.sub.2 receptors in the heart and the like, and the M.sub.3 receptors on smooth muscles and glandular tissues. Up to this time, a large number of compounds have been known to exhibit antagonism against muscarinic receptors. However, the existing compounds non-selectively antagonize the three subtypes of muscarinic receptors. Consequently, when it is tried to use these compounds as therapeutic or prophylactic agents for diseases of the respiratory system, they have the disadvantage of causing side effects such as thirst, nausea and mydriasis, particularly serious side effects associated with the heart, such as tachycardia mediated by the M.sub.2 receptors. Accordingly, it would be highly desirable to overcome this disadvantage.
DISCLOSURE OF THE INVENTION
According to the present invention, there are provided novel ##STR2## and the pharmaceutically acceptable salts thereof, wherein: Ar represents a phenyl group or a five- or six-membered heteroaromatic group having one or two hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in which one or two hydrogen atoms on the ring may be replaced by substituent groups selected from the group consisting of a halogen atom and a lower alkyl group; cycloalkenyl group of 3 to 6 carbon atoms; of 5 to 15 carbon atoms; and present invention have high and selective antagonistic activity against the muscarinic M.sub.3 receptors and can hence be used safely with a minimum of side effects. Accordingly, they are very useful in the treatment or prophylaxis of diseases of the respiratory system, such as asthma, chronic airway obstruction and fibroid lung; diseases of the urinary system accompanied by urination disorders such as pollakiuria, urinary urgency and urinary incontinence; and diseases of the digestive system, such as irritable colon and spasm or hyperanakinesis of the digestive tract.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is more specifically described hereinbelow.
As used herein, the term "halogen atom" comprehends fluorine, chlorine, bromine and iodine atoms.
The term "lower alkyl group" means linear or branched alkyl groups having 1 to 6 carbon atoms, and comprehends, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.
The term "five- or six-membered heteroaromatic group" comprehends, for example, 2-pyrrolyl , 3-pyrrolyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrazolyl, 4-pyrazolyl, 3-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl and 2-pyrazinyl.
The term "cycloalkyl group of 3 to 6 carbon atoms" comprehends, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkenyl group of 3 to 6 carbon atoms" comprehends, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term "saturated or unsaturated aliphatic hydrocarbon radical of 5 to 15 carbon atoms" means linear or branched aliphatic hydrocarbon radicals having 5 to 15 carbon atoms, and comprehends, for
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Kawakami Kumiko
Nishikibe Masaru
Nomoto Takashi
Ohsawa Hirokazu
Ohwaki Kenji
Banyu Pharmaceutical Co. Ltd.
Chang Ceila
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