Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-06-11
1994-04-05
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 514318, 514319, 514321, 514326, 514328, 544336, 546193, 546195, 546197, 546205, 546212, 546219, A61K 31445, C07D21188, C07D40104, C07D40514
Patent
active
053005163
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to certain 3-phenylglutarimide 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, oescophageal 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, where m is 1 or 2; together represent --(CH.sub.2).sub.p -- where p is an integer of from 2 to 5; ##STR2## where R.sup.5 and R.sup.6 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.7 R.sup.8, --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.7 R.sup.8 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 2.
R.sup.1 and R.sup.2 are preferably each H or CH.sub.3.
R.sup.3 is preferably methyl, Z is preferably --CH.sub.2 --.
R.sup.4 is preferably a group of the formula: ##STR3## where R.sup.5 and R.sup.6 are each independently selected from H, halo, hydroxy, and C.sub.1 -C.sub.4 alkyl, and X and X.sup.1 are as defined above.
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 the following route: ##STR4##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and m 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. methanesulfonloxy), 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, sodium bicarbonate, 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.
In the preferred technique, the compounds (II) and (III) are refluxed together in acetonitrile in the presence of sodium bicarbonate. The product (I) can be isolated and purified conventionally.
The starting materials of the formula (II) can be obtained by conventional procedures such as those described in the following Preparations section. The starting materials of the formula (III) are in general known compounds which can be prepared by conventional techniques. The preparation of any novel starting materials of the formula (III) used in the Examples is however described in the following Preparations section.
A typical route to the compounds (II) is
REFERENCES:
patent: 2664424 (1953-12-01), Hoffman
patent: 2848455 (1958-08-01), Hoffman
patent: 3125578 (1964-03-01), Jassen
patent: 3963729 (1976-06-01), Gittos
Cross Peter E.
MacKenzie Alexander R.
Chang Celia
Ginsburg Paul H.
Ivy C. Warren
Pfizer Inc.
Richardson Peter C.
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