Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-08-04
1997-10-14
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 514269, 514274, 514276, 514340, 544238, 544316, 544333, 546243, 5462684, 548252, C07D40504, C07D40514, A61K 3141, A61K 3144
Patent
active
056773242
DESCRIPTION:
BRIEF SUMMARY
This is a National Stage application of PCT/EP94/00637 filed Mar. 4, 1994 and published as WO94/20491 on Sep. 15, 1994.
The present invention relates to benzopyrans. More particularly it relates containing, uses of, processes for the preparation of and intermediates used in the preparation of, such derivatives.
The present derivatives display smooth muscle relaxant activity by a mechanism involving potassium channel opening. They are therefore useful in the curative or prophylactic treatment of diseases associated with the altered tone and/or motility of smooth muscle which can, for example, occur in the lung, bladder, gut, uterus or cardiovascular system. Such diseases include chronic obstructive airways disease, asthma, urinary incontinence, irritable bowel syndrome, diverticular disease, oesophageal achalasia and hypertension. In addition, the present derivatives may be useful in the treatment of peripheral vascular disease, congestive heart failure, pulmonary hypertension, myocardial and cerebral ischaemia, angina, male pattern baldness, cardiac arrhythmia, skeletal muscle fatigue/paralysis (myotonic muscular dystrophy), glaucoma, epilepsy, tinnitus, vertigo and dysmenorrhoea.
The present invention provides compounds of the formula: ##STR2## and the pharmaceutically acceptable salts thereof, wherein the dashed line represents an optional covalent bond;
X is O, NH, S or a direct link;
R and R.sup.1 are either each independently selected from H, fluoro(C.sub.1 -C.sub.4)alkyl and C.sub.1 -C.sub.4 alkyl or taken together represent C.sub.2 -C.sub.6 alkylene;
R.sup.2 is H or C.sub.1 -C.sub.4 alkyl;
R.sup.3 is hydroxy when the dashed line does not represent a covalent bond and R.sup.3 is absent when the dashed line represents a covalent bond;
R.sup.4 is
(a), when X is O, a group of the formula: ##STR3## wherein W and W.sup.1 taken together represent C.sub.1 -C.sub.4 alkylene, said alkylene being optionally benzo-fused when W and W.sup.1 taken together represent C.sub.2 -C.sub.4 alkylene, and optionally substituted, including in the benzo-fused portion, by C.sub.1 -C.sub.6 alkyl, hydroxy, --OR.sup.8, halo, --N(R.sup.8).sub.2, --SR.sup.8 or halo(C.sub.1 -C.sub.4)alkyl,
(b), when X is O, NH or S, hydroxyphenyl optionally substituted by C.sub.1 -C.sub.6 alkyl, --OR.sup.8, halo, --N(R.sup.8).sub.2, --SR.sup.8 or halo(C.sub.1 -C.sub.4)alkyl,
(c) a 4- to 7-membered heterocyclic ring containing either from 1 to 3 N hetero-atoms or one N hetero-atom and one O or one S hetero-atom, said ring being optionally benzo- or C.sub.3 -C.sub.7 cycloalkyl-fused and optionally substituted, including in the benzo- or C.sub.3 -C.sub.7 cycloalkyl-fused portion, by C.sub.1 -C.sub.6 alkyl, hydroxy, hydroxy(C.sub.1 -C.sub.4)alkyl, --OR.sup.8, R.sup.8 O(C.sub.1 -C.sub.4)alkyl, halo, halo(C.sub.1 -C.sub.4)alkyl, --S(O).sub.m R.sup.8, R.sup.8 S(O).sub.m (C.sub.1 -C.sub.4)alkyl, oxo, N-cyanoimino, amino, amino(C.sub.1 -C.sub.4)alkyl, --NHR.sup.8, R.sup.8 NH(C.sub.1 -C.sub.4)alkyl, --N(R.sup.8).sub.2, (R.sup.8).sub.2 N(C.sub.1 -C.sub.4)alkyl, cyano, cyano(C.sub.1 -C.sub.4)alkyl, --CO.sub.2 R.sup.8, R.sup.8 O.sub.2 C(C.sub.1 -C.sub.4)alkyl, --CONH.sub.2, H.sub.2 NCO(C.sub.1 -C.sub.4)alkyl, --CONHR.sup.8, R.sup.8 NHCO(C.sub.1 -C.sub.4)alkyl, --CON(R.sup.8).sub.2 or (R.sup.8).sub.2 NCO(C.sub.1 -C.sub.4)alkyl, or, as appropriate, a ring N- or S-oxide derivative of said heterocyclic ring, with the proviso that said heterocyclic ring is linked by a ring carbon atom when X is O, NH or S, or
(d), when X is NH, a group of the formula: ##STR4##
wherein R.sup.6 is --OR.sup.8, --NHR.sup.8, --SR.sup.8, --NH(aryl) or --NH(pyridinyl) and R.sup.7 is cyano, nitro or C.sub.2 -C.sub.6 alkanoyl;
R.sup.5 is aryl, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl or C.sub.2 -C.sub.12 alkynyl, said C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl and C.sub.2 -C.sub.12 alkynyl being optionally substituted by C.sub.4 -C.sub.7 cycloalkyl, hydroxy, --OR.sup.8, C.sub.2 -C.sub.6 alkanoyloxy, halo, cyano, nitro, amino, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.m R.
REFERENCES:
Bergmann, R. and Gericke, R., J. Med. Chem., 33, 492-503 (1990).
MacKenzie Alexander Roderick
Monaghan Sandra Marina
Benson Gregg C.
Haley Jacqueline
Jones James T.
Pfizer Inc.
Richardson Peter C.
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