Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-26
2004-10-26
Chang, Celia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S234000
Reexamination Certificate
active
06809108
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel amide derivatives, processes for preparing them, pharmaceutics containing them and their use as medicines, especially in the treatment of various diseases of the respiratory, urinary and digestive systems.
BACKGROUND ART
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.
Basic and Clinical Pharmacology
, 4th ed., APPLETON & LANGE, pp. 83-92 (1989) and Drug News & Perspective, 5(6), pp. 345-352 (1992)].
It has recently been made clear that there are at least three subtypes of muscarinic receptors; M
1
receptors being present mainly in the brain; M
2
receptors, mainly in the heart, and M
3
receptors, on smooth muscles and glandular tissues. Whereas, all of the large number of compounds heretofore known to exhibit antagonism to muscarinic receptors non-selectively antagonize the three subtypes of muscarinic receptors. Consequently, attempts to use these compounds as therapeutic or prophylactic agents for diseases of the respiratory system have caused undesirable side effects such as dry mouth, nausea and mydriasis. Still in addition, particularly serious side effects associated with the central nervous system, such as dementia, attributable to M
1
receptors and those associated with the heart, such as tachycardia mediated by M
2
receptors pose problems and their solution has been strongly in demand.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide treating agents of diseases associated with muscarinic M
3
receptors, said agents exhibiting highly selective antagonism to muscarinic M
3
receptors and little side effects, and being safe and effective.
We have discovered that those compounds which are represented by the following general formula [I]
[in which A stands for a group of the following formula [a
0
] or [b
0
]
Ar
1
, Ar
2
and Ar
3
each independently stands for optionally substituted phenyl, the substituent being selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, carbamoyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl; k means 0 or 1; m, n and s each independently means 0, 1 or 2; R
1
stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl; R
2
, R
3
, R
4
and R
5
each independently stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl, or R
2
and R
3
, or R
4
and R
5
, may together stand for, independently of each other, optionally substituted trimethylene, propenylene, tetramethylene or 2-butenylene group, the substituent being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by —R
7
, R
7
standing for optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxycarbonyl and imidazolyl; R
60
stands for hydrogen, C
1
-C
10
alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl; R
61
and R
71
each independently stands for C
1
-C
10
alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl, or R
61
and R
71
may together stand for optionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene group, the substituent being selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxy; X stands for carbonyl or methylene; Y stands for nitrogen or methine; and Q
−
stands for anion]
exhibit highly selective antagonism to muscarinic M
3
receptors, little side effect and high safety, and are very useful for treating various diseases which are associated with muscarinic M
3
receptors, e.g., such respiratory diseases as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic respiratory tract obstruction, fibroid lung, pulmonary emphysema and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, gastroduodental ulcer, convulsion or hyperanakinesia of digestive tract, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary diseases accompanied by dysuria like urinary incontinence, urgency and pollakiuria in nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness; and have completed the present invention.
The present invention relates to the compounds represented by above general formula [I] or salts thereof, processes for their preparation and their use.
Hereafter the invention is explained in further details, in which the terms used mean the following.
“Halogen” means fluorine, chlorine, bromine and iodine atoms.
“Lower alky” means C
1
-C
6
linear or branched alkyl groups, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups.
“Lower alkenyl” means C
2
-C
6
linear or branched alkenyl groups, examples of which include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1 methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl and 4-pentenyl groups.
“Lower alkoxy” means C
1
-C
6
linear or branched alkoxy groups, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy groups.
“Lower alkylcarbamoyl” means carbamoyl groups which are mono-substituted with said lower alkyl groups, examples of which include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl butylcarbamoyl, sec-butylcarbamoyl and tert-butylcarbamoyl groups.
“Di-lower alkylcarbamoyl” means carbamoyl groups which are di-substituted with said lower alkyl groups, examples of which include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl and di-isopropylcarbamoyl groups.
“Lower alkylamino” means amino groups which are mono-substituted with said lower alkyl groups, examples of which include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and tert-butylamino groups.
“Di-lower alkylamino” means amino groups which are di-substituted with said lower alkyl groups, examples of which include dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino and di-isopropylamino groups.
“Imino-lower alkyl” means said lower alkyl groups which are mono-substituted with imino group, examples of which include formimidoyl, acetimidoyl, propanimidoyl, butanimidoyl, pentanimidoyl and hexanimidoyl groups.
“(Imino-lower alkyl) amino” means amino groups which are mono-substituted with said imino-lower alkyl groups, examples of which include formimidoylamino, acetimidoylamino, propanimidoylamino, butanimidoylamino, pentanimidoylamino and hexanimidoylamino groups.
“Lower alkanoy” means C
1
-C
6
linear or branched alkanoyl groups, examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups.
“Lower alkanoyloxy” means alkanoyloxy groups
Fujikawa Toru
Kimura Toshifumi
Naya Akira
Noguchi Kazuhito
Numazawa Tomoshige
Banyu Pharmaceutical Co. Ltd.
Chang Celia
Wenderoth Lind & Ponack LLP
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