Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-02
1994-09-06
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 514320, 514321, 514324, 514325, 514326, 514331, 546194, 546196, 546197, 546202, 546204, 546205, 546206, 546213, A61K 31445, A61K 3144, C07D21112, C07D40912
Patent
active
053448359
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to certain pyrrolidine and piperidine derivatives.
We have discovered that the pyrrolidine and piperidine derivatives provided by the present 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
German Patentschrift 934890 discloses the preparation of certain benzhydryl ethers. EP-A-0350309 discloses certain 1-arylethyl-3-substituted piperidines as muscarinic receptor antagonists but was published on 10 Jan. 1990.
According to the invention there are provided compounds of the formula: the formula: ##STR1## where Z is --(CH.sub.2).sub.2 --, --CH.dbd.CH--, --CH.sub.2 --S-- or --CH.sub.2 --O--; R is a group of the formula: ##STR2## and A is a group of formula: ##STR3## in which the N atom is attached to the group (CH.sub.2)n; alkyl, hydroxy-(C.sub.1 -C.sub.4 alkyl), hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, trifluoromethyl, nitro, cyano, sulphamoyl, --CO(C.sub.1 -C.sub.4 alkyl), --OCO(C.sub.1 -C.sub.4 alkyl), carboxy, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CH.sub.2).sub.q CONR.sup.4 R.sup.5, --(CH.sub.2).sub.q OCONR.sup.4 R.sup.5, --CH.sub.2).sub.q NR.sup.6 R.sup.7 or --NHSO.sub.2 NH.sub.2 in which R.sup.4 and R.sup.5 are each independently H or C.sub.1 -C.sub.4 alkyl, q is 0, 1 or 2, and either R.sup.6 and R.sup.7 are each independently H or C.sub.1 -C.sub.4 alkyl or R.sup.6 is hydrogen and R.sup.7 is --SO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CO(C.sub.1 -C.sub.4 alkyl) or --CONH(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.
Preferably, R.sup.1 is (Ph).sub.2 CH. m is preferably 1. n is preferably 1, 2 or 3. X is preferably a direct link.
A is preferably a group of the formula: ##STR4##
R is preferably a group of the formula: ##STR5## where R.sup.2 and R.sup.3 are each independently hydroxymethyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, carboxy, sulphamoyl, nitro, amino, carbamoyl, sulphamoylamino, C.sub.1 -C.sub.4 alkanesulphonamido, --CO(C.sub.1 -C.sub.4 alkyl) or --NHCO(C.sub.1 -C.sub.4 alkyl);
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 or ether, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution.
DETAILED DESCRIPTION OF THE INVENTION
The compound of the formula (I) can be prepared by the following reaction: ##STR6##
R, R.sup.1, A, X, m and n 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, sodium bicarbonate, triethylamine or pyridine, and in a suitable organic solvent, e.g. acetonitrile, at up to the reflux temperature. Reaction temper
REFERENCES:
patent: 2974146 (1961-03-01), Biel
patent: 4810713 (1989-03-01), Yanni et al.
patent: 4950674 (1990-08-01), Yanni et al.
Alker David
Cross Peter E.
Butterfield Garth
Cintins Marianne M.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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