Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-05
1997-02-11
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462817, A61K 3144, C07D40504
Patent
active
056021526
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/03445 now WO 94/13658.
The subject of the present invention is new heterocyclic compounds having a pharmacological activity in the activation of potassium channels.
Activators of potassium channels or potassium agonists have the property of activating the potassium channels of the cell membrane by opening these channels or prolonging their opening. This results in transmembrane ionic movements and, inter alia, a decrease in free intracellular Ca.sup.++ ions which causes relaxation of smooth muscle fibres.
This therapeutic potentiality makes it possible today for great hopes to be placed in potassium agonists. Among the most studied fields, arterial hypertension, angina and asthma are the most often mentioned. Large families of activators of potassium channels are already recognized for their relaxant properties.
A family of benzopyran derivatives has formed the subject of many publications in this field.
These compounds correspond to the following general formula A: ##STR3##
EP-0,076,075 describes compounds of general formula A, where ##STR4## represents a pyrrolidone. DE-3,726,261 describes compounds of general formula A, where ##STR5## represents a pyridone.
Another benzopyran family corresponds to the formula B below; it is described in EP-0,298,452: ##STR6##
W0-89/11477 and EP-0,360,131 relate to benzoxepines of general formula C: ##STR7## where X represents a nitrogenous ring connected via the nitrogen atom to the 5-position of the benzoxepines, such as a 2-oxo-1-pyrrolidinyl and 2-oxo-1-pyridyl group for the first and a 2-oxo-1-pyridyl group or a 4-fluorobenzoylamino group for the second.
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 represent a hydrogen atom or a lower alkyl group and R.sub.1 and R.sub.2 a hydrogen atom or a nitrile, arylsulfonyl or nitro group.
Novel compounds possessing a benzocycloheptene or benzoxepine ring system, which show notable effects on the activation of potassium channels, have now been discovered.
The subject of the invention is compounds of general formula: ##STR8## in which: X represents O, or CHR, R being a hydrogen atom or R, taken together with R.sub.1, forming a bond, represent a hydrogen atom or a C.sub.1 -C.sub.7 alkyl group, it being possible for R.sub.1 to additionally form a bond with R; together with R.sub.7, forms a bond or a >O; group; ##STR9## in which R.sub.10 and R.sub.11, taken together with the carbon atom to which they are attached, form an optionally aromatic mono- or bicyclic nitrogenous heterocyclic group having from 3 to 11 members, including 1 or 2 nitrogen atoms, optionally substituted on the carbon atoms by 1 to 7 groups chosen from hydroxyl, nitro, cyano, C.sub.1 -C.sub.7 alkyl or C.sub.1 -C.sub.7 alkoxy, it being possible for at least one of the nitrogen atoms of the heterocycle to be N-oxidized; or C.sub.1 -C.sub.7 acyloxy group or R.sub.5 and R.sub.7 together form a bond or a >O group; or halogen atom, a hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, pentafluoroethyl, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 acylthio, C.sub.1 -C.sub.7 alkylsulfonyl or C.sub.1 -C.sub.7 alkylsulfinyl group, a group of formulae: ##STR10## in which R.sub.12 and R.sub.13, which are identical or different, represent a hydrogen atom or a C.sub.1 -C.sub.7 alkyl group, or R.sub.8 and R.sub.9 represent a C.sub.6 -C.sub.10 aryl, (C.sub.6 -C.sub.10)arylsulfonyl or (C.sub.6 -C.sub.10)arylsulfinyl group, optionally substituted by one to six substituents chosen from halo, hydroxyl, nitro, cyano, carboxyl, carbamoyl, trifluoromethyl, trifluoromethoxy, pentafluoroethyl, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 acylthio, C.sub.1 -C.sub.7 alkylsulfonyl or C.sub.1 -C.sub.7 alkylsulfinyl, heterocycle having from 3 to 11 members in the ring including 1 to 4 hetereoatoms, which are identical or different, chosen from O, S and N, optionally substituted by one to six substituents chosen from halo, hydroxyl, nitro, cyano, carboxy
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Tatsuoka et al. CA 118:101953, 1993.
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Chemical Abstracts, vol. 93, No. 1, Jul. 7, 1980, Abstract No. 7854K, Jendrichovsky, et al. (CSA 180377).
Berthelon Jean J.
Brunet Michel
Durbin Philippe
Guerrier Daniel
Luong Trong N.
Fan Jane
Merck Patent Gesellschaft mit beschrankter Haftung
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