Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-06-12
1994-08-23
Brust, Joseph Paul
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514428, 548566, 548568, A61K 3140, C07D20709
Patent
active
053408314
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to certain 3-substituted pyrrolidine 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.
SUMMARY OF THE INVENTION
According to the invention there are provided compounds of the formula: ##STR1## and their pharmaceutically acceptable salts, wherein Y is --CH.sub.2 --, --(CH.sub.2).sub.2 --, --CH.sub.2 --, --(CH.sub.2).sub.2 O-- or --CH.sub.2 S--; R is --CN or --CONH.sub.2 ; and R.sup.1 is a group of the formula: ##STR2## where R.sup.2 and R.sup.3 are each independently H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.n OH, halo, trifluoromethyl, cyano, --(CH.sub.2)NR.sup.4 R.sup.5, --CO(C.sub.1 -C.sub.4 alkyl), --OCO(C.sub.1 -C.sub.4 alkyl), --CH(OH)(C.sub.1 -C.sub.4 alkyl), --C(OH)(C.sub.1 -C.sub.4 alkyl).sub.2, --SO.sub.2 NH.sub.2, --(CH.sub.2).sub.n CONR.sup.6 R.sup.7 or --(CH.sub.2).sub.n COO(C.sub.1 -C.sub.4 alkyl);
"Halo" means F, Cl, Br or I. Alkyl and alkoxy groups of 3 or 4 carbon atoms can be straight or branched chain. The preferred alkyl and alkoxy groups are methyl, ethyl, methoxy and ethoxy.
R is preferably -CONH.sub.2. The compounds in which R is --CN have some activity as muscarinic receptor antagonists but are mainly useful as synthetic intermediates.
Preferably R.sup.2 and R.sup.3 are each independently selected from H, halo, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkanesulphonamido, sulphamoyl, carbamoyl, hydroxymethyl, hydroxy and --CO(C.sub.1 -C.sub.4 alkyl).
Y is preferably --CH.sub.2 --, --(CH.sub.2).sub.2 --, --CH.sub.2 O-- or --(CH.sub.2).sub.2 O--.
The anticholinergic activity of the present compounds resides in both the 3R-forms and 3S-forms, i.e., the compounds having R and S stereochemistry, respectively, at position 3 of the pyrrolidine ring, and of course in the 3R,S-(racemic) forms of the compounds (I). The 3S- forms are generally the most active.
The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts such as the hydrochloride, hydrobromide, 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 solution of the free base and the acid in a suitable solvent, e.g. ethanol, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the formula (I) can be prepared by a number of routes, including the following:
Route A
This can be illustrated as follows: ##STR3##
Y, R and R.sup.1 are as defined for formula (I) and Q is a leaving group, e.g. Br, Cl, I, C.sub.1 -C.sub.4 alkanesulfonyloxy (e.g. methanesulfonyloxy), benzenesulfonyloxy, toluenesulfonyloxy (e.g. p-toluenesulfonyloxy) or trifluoromethanesulfonyloxy. Preferably, Q is C1, Br, I or methanesulfonyloxy.
The reaction is preferably carried out in the presence of an acid acceptor such as sodium bicarbonate, sodium or potassium carbonate, triethylamine or pyridine, and in a suitable organic solvent, e.g. acetonitrile, at up to the reflux temperature. Reaction temperatures of 60.degree.-120.degree. C. are generally desirable and it is most convenient to carry out the reaction under reflux. Iodo is often a particu
REFERENCES:
patent: 4810713 (1989-03-01), Yanni et al.
patent: 4950674 (1990-08-01), Yanni et al.
patent: 5096890 (1992-03-01), Cross et al.
patent: 5233053 (1993-08-01), Cross et al.
D. E. Ames, Synthesis of 1-(1-Methylpyrrolid-3-yl)-1,1-diphenylbutan-2-one J. Chem. Soc., (1960), pp. 2780-2781.
Cross Peter E.
MacKenzie Alexander R.
Brust Joseph Paul
Butterfield Garth
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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