Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-04-29
1995-06-06
Chang, Celia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514321, 546196, 546197, 546205, A61K 31445, C07D40506, C07D40512
Patent
active
054223580
DESCRIPTION:
BRIEF SUMMARY
This invention relates to certain 3-substituted piperidine 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.
According to the invention there are provided compounds of the formula: ##STR3## and their pharmaceutically acceptable salts, wherein --CH.sub.2 S--; ##STR4## 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.
R is preferably --CONH.sub.2.
m is preferably 1.
R.sup.1 is preferably a group of the formula: ##STR5## where R.sup.2 and R.sup.3 are each independently selected from H, halo, hydroxy, hydroxymethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and carbamoyl, and X and X.sup.1 are as defined above.
R.sup.1 is most preferably: ##STR6##
Y is preferably a direct link, --CH.sub.2 --, --(CH.sub.2).sub.2 -- or --CH.sub.2 O--.
Y is more preferably a direct link, --CH.sub.2 -- or --(CH.sub.2).sub.2 --.
Y is most preferably --CH.sub.2 --.
The anticholinergic activity of the present compounds resides substantially in the 3R-forms, i.e., the compounds having R stereochemistry at position 3 of the piperidine ring, hence the preferred compounds are the 3R-- and 3R,S-(racemic) forms of the compounds (I).
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.
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: ##STR7##
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 Cl, Br, I or methanesulfonyloxy.
The reaction is preferably carried out in the presence of an acid acceptor such as 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 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. In the preferred technique, the compounds (II)
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Cross Peter E.
MacKenzie Alexander R.
Benson Gregg C.
Chang Celia
Jones James T.
Pfizer Inc
Richardson Peter C.
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