Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-06-06
1993-03-09
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514357, 514437, 514438, 514431, 514450, 514452, 514455, 514466, 514469, 514648, 514651, 544336, 544408, 546334, 549 12, 549 27, 549 72, 549 75, 549350, 549354, 549362, 549396, 549437, 549443, 549462, 564317, 564352, C07C21710, C07C21712, A16K 31135
Patent
active
051927659
DESCRIPTION:
BRIEF SUMMARY
This invention relates to certain amine 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: ##STR2## and their pharmaceutically acceptable salts, wherein R.sup.1 is a group of the formula: ##STR3## wherein Z and Z.sup.1 are each independently hydrogen, halo or C.sub.1 -C.sub.4 alkyl; --O--, --S-- or --O--; Y is a direct link, O or S; together represent --(CH.sub.2).sub.p -- where p is 2, 3, 4 or 5; ##STR4## where either R.sup.5 and R.sup.6 are each independently hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy-(C.sub.1 -C.sub.4 alkyl), hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, halomethyl, nitro, cyano, sulphamoyl, --CO(C.sub.1 -C.sub.4 alkyl), --OCO(C.sub.1 -C.sub.4 alkyl), --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), carboxy, --(CH.sub.2).sub.q CONR.sup.9 R.sup.10, --(CH.sub.2).sub.q OCONR.sup.9 R.sup.10, --(CH.sub.2).sub.q NR.sup.11 R.sup.12 or --NHSO.sub.2 NH.sub.2 in which R.sup.9 and R.sup.10 are each independently H or C.sub.1 -C.sub.4 alkyl, q is 0, 1 or 2, and either R.sup.11 and R.sup.12 are each independently H or C.sub.1 -C.sub.4 alkyl or R.sup.11 is hydrogen and R.sup.12 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); or represent a group of the formula --O(CH.sub.2).sub.r O-- where r is 1, 2 or 3, --O(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 --; R.sup.7 is H, C.sub.1 -C.sub.4 alkyl or --CONH.sub.2 ; and
"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. The preferred halomethyl groups are trifluoromethyl and bromomethyl.
Preferred groups for R.sup.1 include: ##STR5## Y is preferably a direct link or O. m is preferably 2. p is preferably 4 or 5, most preferably 4. represent --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --.
When R is said optionally substituted phenyl group, then it preferably has the formula: ##STR6## where R.sup.5 and R.sup.6 are as defined for formula (I).
When R is said optionally substituted thiophene group, it is preferably unsubstituted 2- or 3-thienyl.
R.sup.8 is preferably hydrogen.
More preferably, R is a group of the formula: ##STR7## where either one of R.sup.5 and R.sup.6 is hydrogen and the other is hydrogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, hydroxy, hydroxymethyl, halo, sulphamoyl, --CO(C.sub.1 -C.sub.4 alkoxy), carboxy, carbamoyl, --NHSO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CH.sub.2 NHSO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CO(C.sub.1 -C.sub.4 alkyl), halomethyl, cyano, nitro, or aminomethyl; or R.sup.5 and R.sup.6 together represent --OCH.sub.2 O--, --O(CH.sub.2).sub.2 O--, --O(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 --.
Most preferably, R is ##STR8##
The preferred compounds have the formula: ##STR9##
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. ether, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution.
The compoun
REFERENCES:
patent: 2455949 (1948-12-01), Rieveschl, Jr.
patent: 4097528 (1978-06-01), Porta et al.
patent: 4246201 (1981-01-01), Borzatta
Alker David
Bass Robert J.
Cross Peter E.
Dentz Bernard
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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