Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-06-22
1995-03-14
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548453, C07D48702, C07D48708, A61K 3140
Patent
active
053978005
DESCRIPTION:
BRIEF SUMMARY
This invention relates to certain azabicyclic compounds which are muscarinic receptor antagonists being selective for smooth muscle muscarinic sites over cardiac muscarinic sites. 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: ##STR2## and their pharmaceutically acceptable salts, where R.sup.2 and R.sup.3 are each independently H, halo or C.sub.1 -C.sub.4 alkyl; direct link; ##STR3## where p is 0, 1 or 2, q is 1, 2 or 3, and r is 0, 1, 2 or 3, with the proviso that the sum of p, q and r is at least 3, the N atom of "Het" being attached to the group (CH.sub.2).sub.n in formula (IA) and to the H atom in formula (IB); and ##STR4## where R.sup.4 and R.sup.5 are each independently H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --(CH.sub.2).sub.t OH, halo, trifluoromethyl, cyano, --(CH.sub.2).sub.t NR.sup.6 R.sup.7, --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.t CONR.sup.6 R.sup.7 or --(CH.sub.2).sub.t 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.sup.1 is preferably a group of the formula: ##STR5## where R.sup.4, R.sup.5, X and X.sup.1 are as defined above.
R.sup.1 is more preferably: ##STR6## where X and X.sup.1 are as defined above.
X and X.sup.1 are both most preferably O.
R.sup.2 and R.sup.3 are both preferably H.
m is preferably 0 or 1.
n is preferably 1 or 2.
Y is preferably a direct link.
The sum of p, q and r is preferably 3 or 4.
In "Het", formula (A) , preferably:
It should be understood that the invention includes all the isomers of the compounds (IA) and (IB), e.g., where applicable, the syn and anti, and exo and endo forms, as well as racemates and separated enantiomers.
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 (IA) and (IB) can be prepared by a number of routes, including the following:
Route A
This route to the compounds (IA) can be illustrated as follows: ##STR7##
R.sup.1, R.sup.2, R.sup.3 Y, Het, m and n are as defined for formula (IA) 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 (II) are sometimes most conveniently available as chlorides or bromides the reaction can also be carried out using the compound (I
REFERENCES:
patent: 5104989 (1992-04-01), Cottrell et al.
patent: 5278170 (1994-01-01), Orlek et al.
patent: 5314899 (1994-05-01), Daly et al.
Alker David
Cross Peter E.
Kemp John E. G.
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Rotman Alan L.
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