Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-06-12
1994-01-25
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514255, 514318, 514326, 546193, 546196, 546208, 544336, 544408, 544410, A61K 31445, C07D40514, C07D40104, C07D40114
Patent
active
052816010
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 a direct link, --CH.sub.2 --, --(CH.sub.2).sub.2 --, --CH.sub.2 O-- or --CH.sub.2 S--; and ##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).sub.n 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.4 R.sup.5 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.
m is preferably 1.
R.sup.1 is preferably a group of the formula: ##STR3## where R.sup.2 and R.sup.3 are each independently selected from H, halo and hydroxy, and X and X.sup.1 are as defined above.
R.sup.1 is most preferably: ##STR4##
Y is preferably a direct link, --CH.sub.2 -- or --(CH.sub.2).sub.2 --.
Y is most preferably --CH.sub.2 --.
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: ##STR5##
Y 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 Cl, 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. dimethylformamide or acetonitrile, at up to the reflux temperature. Reaction temperatures of 60.degree.-120.degree. are generally desirable and it is most convenient to carry out the reaction under reflux. Compound (II) can be used in acid-addition salt form (e.g. as a hydrobromide or formate) provided an excess of base is present. Iodo is often a particularly suitable leaving group but since the starting materials (III) are sometimes most conveniently available as chlorides the reaction can also be carried out using the compound (III) as a chloride but in the presence of an iodide such as sodium or potassium iodide. The product (I) can be isolated and purified conventionally.
Starting materials having appropriate stereochemistry at the 3- and 3'-positions should be used so as to o
REFERENCES:
patent: 5037841 (1991-08-01), Schohe
Cross Peter E.
MacKenzie Alexander R.
Chang Celia
Ginsburg Paul H.
Ivy C. Warren
Pfizer Inc.
Richardson Peter C.
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