Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-14
2001-01-16
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S137000
Reexamination Certificate
active
06174896
ABSTRACT:
TECHNICAL FIELD
This invention relates to medicines, particularly quinuclidine derivatives or their salts, N-oxides 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
1
receptor mainly exists in the brain or the like, the M
2
receptor in the heart or the like, and the M
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
1
, M
2
and M
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
1
, M
2
or M
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
3
receptor among these three subtypes and is free from the cardiac side effects resulting from the M
2
receptor.
The compound represented by the following general formula is described in an unexamined published Japanese Patent Application (kokai) 62-252764.
(wherein L represents NH or O;
X and Y each independently represents a hydrogen atom or a C
1-6
alkyl-group or they may be combined together to form a bond;
R
1
and R
2
each independently represents a hydrogen atom, a C
1-6
alkyl group . . . (omission) . . . ;
R
3
and R
4
each independently represents a hydrogen atom, a halogen atom, CF
3
, a C
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
1-6
alkyl groups or may optionally be N-disubstituted by C
6-8
polyethylene . . . (omission) . . . ;
Z represents
or the like;
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
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
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, N-oxides or quaternary ammonium salts; pharmaceutical compositions comprising said compounds or salts thereof and pharmaceutically acceptable carriers, particularly to muscarinic M
3
receptor antagonists.
(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;
X: a single bond or a methylene group;
R: a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower alkylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group or a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group or a mono- or di-lower alkylamino group;
l: 0 or 1,
m: 0 or an integer of 1 to 3, and
n: an integer of 1 or 2, hereinafter the same apply similarly)
Among the compound (I) of the present invention, particularly preferred compounds are quinuclidine derivatives wherein the ring A represents 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, in which such a ring may be substituted by a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamido group, a lower alkanesulfonamido group, a carbamoyl group, a thiocarbamoyl group, a mono- or di-lower alkylcarbamoyl group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, an ethylenedioxy group, and a lower alkyl group which may be substituted by a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group or a mono- or di-lower alkylamino group, and their salts, N-oxides or quaternary ammonium salts;
quinuclidine derivatives wherein R represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a cyano group, an amino group or a mono- or di-lower alkylamino group, and the ring A represents an aryl group, a cycloalkyl group, a cycloalkenyl group, a 5- or 6-membered monocyclic 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, in which such a ring may be substituted by a halogen- atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a cyano group, an amino group or a mono- or di-lower alkylamino group, and their salts, N-oxides or quaternary ammonium salts;
quinuclidine derivatives wherein m is 0, and the ring A represents an aryl group, a cycloalkyl group or a cycloalkenyl group which may be substituted by a halogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group, or a 5- or 6-membered monocyclic heteroaryl group having 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and their salts, N-oxides or quaternary ammonium salts;
quinuclidine derivatives wherein the ring A represents a phenyl group which may be substituted by a halogen atom or a lower alkyl group, a cycloalkyl group, a pyridyl group, a furyl group or a thienyl group, and their salts, N-oxides or quaternary ammonium salts;
quinuclidine derivatives wherein X represents a single bond, and their salts, N-oxides or quaternary ammonium salts; and
quinuclidine derivatives wherein n is 2, and their salts, N-oxides or quaternary ammonium salts.
The present invention also provides muscarinic M
3
receptor antagonists which comprise quinuclidine derivatives (I) or their salts, N-oxides or quaternary ammonium salts, that is, the compound (I) of the present
Hayakawa Masahiko
Ikeda Ken
Isomura Yasuo
Naito Ryo
Okamoto Yoshinori
Morris Patricia L.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Yamanouchi Pharmaceutical Co. Ltd.
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