Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-07-08
1999-06-15
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514253, 514255, 514256, 514264, 514456, 544238, 544239, 544242, 544298, 544322, 544333, 544336, 544359, 544382, 544383, 544384, 549399, 549403, A61K 3135, A61K 3150, A61K 31505, C07D31122, C07D23714, C07D23932, C07D24102, C07D40512
Patent
active
059122447
DESCRIPTION:
BRIEF SUMMARY
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.
EP-A-0547523, EP-A-0351720, EP-A-0450415 and EP-A-0400430 disclose benzopyrans with pharmacological activity. EP-A-0552679 describes epoxidation of chromenes.
The present invention provides compounds of the formula: ##STR2## and the pharmaceutically acceptable salts thereof, wherein X is O, S or NH; alkyl or taken together represent C.sub.2 -C.sub.6 alkylene; ring being linked to X by a ring carbon atom, optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by C.sub.1 -C.sub.6 alkyl, hydroxy, --OR.sup.5, halo, --S(O).sub.m R.sup.5, oxo, amino, --NHR.sup.5, --N(R.sup.5).sub.2, cyano, --Co.sub.2 R.sup.5, --CONH.sub.2, --CONHRS, or --CON(R.sup.5).sub.2, with the proviso that R.sup.3 is not an N--(C.sub.1 -C.sub.6 --NHR.sup.5, --N(R.sup.5).sub.2, cyano, --CO.sub.2 R.sup.5, --CONH.sub.2, --CONHR.sup.5, or --CON(R.sup.5).sub.2, with the proviso that R.sup.3 is not an N--(C.sub.1 -C.sub.6 alkyl)pyridonyl group; ##STR3## (c), when X is NH, a group of the formula: ##STR4## R.sup.4 is phenyl substituted by a hydroxy group and optionally further substituted by 1 or 2 substituents each independently selected from hydroxy, C.sub.1 -C.sub.6 alkyl, --OR.sup.5, halo, cyano and nitro; --NHR.sup.9 ; hydroxy, --OR.sup.5, halo, cyano or nitro; and iodo. Alkyl groups containing three or more carbon atoms may be straight-or branched-chain. hetero-atoms, said ring being optionally benzo-fused and optionally substituted by C.sub.1 -C.sub.4 alkyl, hydroxy, halo or oxo, and more preferably said ring is not fully saturated, (b) is a group of the formula: ##STR5## or (c) is a group of the formula: ##STR6## More preferably R.sup.3 is 1,2-dihydro-2-oxo-1H-pyridin-4-yl, 1,2-dihydro-5,6-dimethyl-2-oxo-1H-pyridin-4-yl, 3-hydroxypyridazin-6-yl, 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl, 2,3-dihydro-2-ethyl-3-oxopyridazin-6-yl, 1,2-dihydro-1-oxo-2H-phthalazin-4-yl, 1,2-dihydro-2-methyl-1-oxophthalazin-4-yl, 2-chloropyrimidin-4-yl, 3,4-dioxo-2-ethoxycyclobut-1-en-1-yl or 3-cyano-2-methylisothioureido. 2,3-dihydro-2-methyl-3-oxopyridazin-6-yl. 3,4-dihydroxyphenyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate, and p-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
A compound of the formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of t
REFERENCES:
patent: 4999371 (1991-03-01), Englert et al.
patent: 5112972 (1992-05-01), Gericke et al.
MacKenzie Alexander Roderick
Monaghan Sandra Marina
Benson Gregg C.
Jones James T.
Oswecki Jane C.
Pfizer Inc.
Richardson Peter C.
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