Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-07-31
1999-11-02
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546208, 546209, 546210, A61K 31445, C07D41304, C07D41704
Patent
active
059771429
DESCRIPTION:
BRIEF SUMMARY
This invention relates to substituted oxadiazole and thiadiazole derivatives. The compounds of the invention are muscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac muscarinic sites and which do not have any significant antihistaminic activity. Thus the compounds are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases include irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.
The compounds are also useful as cognition enhancers, and are thus useful in treating diseases involving memory impairment such as Alzheimer's disease and age-related memory disorder.
According to the invention there are provided compounds of the formula: ##STR2## wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl, halo-(C.sub.1 -C.sub.6 alkyl), C.sub.3 -C.sub.7 cycloalkyl, C.sub.2 -C.sub.6 alkynyl, hydroxy-(C.sub.2 -C.sub.6 alkynyl), (C.sub.1 -C.sub.4 alkoxy)-(C.sub.2 -C.sub.6 alkynyl), aryl, aryl-(C.sub.1 -C.sub.4 alkyl), heteroaryl or heteroaryl-(C.sub.1 -C.sub.4 alkyl); cycloalkyl; O--;
By halo is meant chloro, bromo, fluoro or iodo.
Preferred aryl groups are phenyl and naphthyl both optionally substituted by up to 3 substituents each independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, halo and trifluoromethyl.
More preferably, the aryl groups are selected from phenyl optionally substituted by 1 or 2 substituents each independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, halo and trifluoromethyl; and naphthyl.
Most preferably, the aryl group is phenyl, fluorophenyl, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.
Preferred heteroaryl groups are thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl and pyrimidinyl, all optionally substituted by 1 or 2 substituents each independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy and halo.
More preferred heteroaryl groups are thienyl, pyridyl, thiazolyl and benzothiazolyl.
Preferred alkyl groups are methyl and ethyl. Preferred alkoxy groups are methoxy and ethoxy. Preferred halo groups are chloro, bromo and fluoro. Preferred cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclobutyl. The preferred alkynyl group is ethynyl. Preferred hydroxy-(C.sub.2 -C.sub.6 alkynyl) groups are HO--CH.sub.2 C.tbd.C-- and HO--(CH.sub.2).sub.4 --C.tbd.C--. The preferred haloalkyl groups are trifluoromethyl and pentafluoroethyl.
R.sup.1 is preferably C.sub.1 -C.sub.6 alkyl; pentafluoroethyl; C.sub.4 -C.sub.6 cycloalkyl; ethynyl; --C--C--CH.sub.2 OH; --C.tbd.C--(CH.sub.2).sub.4 OH; a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and hydroxy; naphthyl; or a heterocyclic group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, all optionally substituted by halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or hydroxy.
R.sup.2 is preferably H or CH.sub.3.
R.sup.3 is preferably either phenyl optionally substituted by 1 or 2 substituents each independently selected from halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and hydroxy; 2,3-dihydrobenzofuranyl; C.sub.4 -C.sub.7 cycloalkyl or thienyl.
X is preferably O.
Y is preferably a direct link, --CH.sub.2 -- or --CH.sub.2 O--.
The pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts such as the hydrochloride, hydrobromide, hydrofluoride. sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts. For a more comprehensive list of pharmaceutically acceptable salts see, for example, the Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. These salts can be prepared conventionally, e.g. by mixing a
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Saunders et al., J. Med. Chem., 33, 1128-38 (1990).
MacLeod et al. J. Med Chem., 33,2052-59 (1990).
Bidaut-Russell et al. "Muscarinic pharmacology of the inhibition of . . . " Ca 108:31798, 1987.
Bass Robert John
MacKenzie Alexander Roderick
Wood Anthony
Benson Gregg C.
Chang Ceila
Pfizer Inc.
Raymer Gregory P.
Richardson Peter C.
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