Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-28
2000-01-25
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546137, A61K 31435, C07D45302
Patent
active
060179279
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to medicines, particularly quinuclidine derivatives or their salts, or quaternary ammonium salts having muscarinic receptor antagonistic activities and also to pharmaceutical compositions containing such compounds.
BACKGROUND ART
Studies have been made on the muscarinic receptor, and it is known that compounds having muscarinic receptor antagonistic activities cause bronchodilation, suppression of gastrointestinal motility, suppression of acid secretion, dry mouth, mydriasis, suppression of bladder contraction, hypohidrosis, tachycardia, or the like. It is known that the muscarinic receptor includes at least three subtypes. The M.sub.1 receptor mainly exists in the brain or the like, the M.sub.2 receptor in the heart or the like, and the M.sub.3 receptor in the smooth muscles or gland tissues.
A number of such compounds having muscarinic receptor antagonistic activities are hitherto known and, for example, atropine is a typical example ("The MERCK INDEX, ELEVENTH EDITION", p. 138). However, atropine antagonizes the M.sub.1, M.sub.2 and M.sub.3 receptors non-selectively, so that it is difficult to use it for the treatment of a specific disease. In recent years, according to the progress of the studies on the subtypes of the muscarinic receptor, compounds having selective antagonistic activities against the M.sub.1, M.sub.2 or M.sub.3 receptor have been investigated (an unexamined published British Patent Application No. 2,249,093, an unexamined published Japanese Patent Application (kokai) 1-131145, and an unexamined published Japanese Patent Application (kokai) 3-133980). There is a demand for a compound having selective antagonistic activity against muscarinic M.sub.3 receptor among these three subtypes and is free from the cardiac side effects resulting from the M.sub.2 receptor.
The compound represented by the following general formula is described in an unexamined published Japanese Patent Application (kokai) 62-252764. ##STR2## (wherein L represents NH or O; X and Y each independently represents a hydrogen atom or a C.sub.1-6 alkyl group or they may be combined together to form a bond; C.sub.1-6 alkyl group . . . (omission) . . . ; halogen atom, CF.sub.3, a C.sub.1-6 alkyl group . . . (omission) . . . , a phenyl group, an amino group which may optionally be N-substituted by one or two groups selected from phenyl, C.sub.1-6 alkyl groups or may optionally be N-disubstituted by C.sub.6-8 polyethylene . . . (omission) . . . ; ##STR3## p is 1 or 2; and q is 1-3.
The compound described in the above patent literature is disclosed as a 5-HT antagonist and no disclosure about the muscarinic receptor antagonistic activity is found. The above compound is clearly distinguished from the compound according to the present invention in pharmacological effects.
DISCLOSURE OF THE INVENTION
The inventors of the present application have carried out extensive studies on compounds having the above-described muscarinic M.sub.3 receptor antagonistic activities. As a result, we created novel quinuclidine derivatives having a basic skeleton different from that of the conventional compound, and found that such compounds have excellent selective antagonistic activity against muscarinic M.sub.3 receptor, resulting in the completion of the present invention.
Thus, the compounds of the present invention relate to quinuclidine derivatives represented by the following general formula (I); their salts, or quaternary ammonium salts; pharmaceutical compositions comprising said compounds or salts thereof and pharmaceutically acceptable carriers, particularly to muscarinic M.sub.3 receptor antagonists. ##STR4## (symbols in the formula have the following meanings: Ring A: an aryl group, a cycloalkyl group, a cycloalkenyl group, a heteroaryl group having 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom or a 5- to 7-membered saturated heterocyclic group, wherein said ring may be substituted by an optional substituent; group, a lower alkox
Hayakawa Masahiko
Ikeda Ken
Isomura Yasuo
Naito Ryo
Okamoto Yoshinori
Morris Patricia L.
Yamanouchi Pharmaceutical Co. Ltd.
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