Yoshitomi Pharmaceutical Industries, Ltd.

Tsutomu Yamanaka

Osamu Yaoka

Toshio Seki

Tohru Nakajima

Mineo Tsuruda

Hiroshi Yasuda

Shinro Setoguchi

Toshihiro Kobayakawa

Mitsuhiro Konishi

Chiaki Kitami

Kuniki Ikeda

Hideki Ao

Minoru Obata

Mitsuharu Sano

Hiroshi Mikashima

Kunio Osuga

A benzopyran compound of the general formula (I) ##STR1## wherein A represents --OR.sup.1 or --NH--COR.sup.2 ; R.sup.3 represents hydrogen, a lower alkyl, a lower alkoxy, amino, a mono- or di-lower alkylamino, an amino-lower alkyl, a hydroxy-lower alkyl, a halo-lower alkyl, a lower alkoxy-lower alkyl, an acyloxy-lower alkyl, a lower alkoxycarbonyl-lower alkyl, an aryl or a heteroaryl, or R.sup.2 and R.sup.3 combinedly together form an alkylene having 1 to 2 carbon atoms; R.sup.4 and R.sup.5 are the same or different, and respectively represent hydrogen or a lower alkyl, or combinedly together form an alkylene having 2 to 5 carbon atoms; R.sup.6 represents hydroxyl group, formyloxy, an alkanoyloxy, a haloalkanoyloxy, a lower alkoxycarbonyloxy, an aroyloxy, a heteroaroyloxy, carbamoyloxy, a mono- or di-lower alkylcarbamoyloxy and R.sup.7 represents hydrogen, or R.sup.6 and R.sup.7 combinedly together form a bond and X and Y are the same or different, and respectively represent hydrogen, halogen, nitro, cyano, a lower alkyl, a lower alkoxy, a halo-lower alkyl, carboxyl, formyl, an alkanoyl, an aroyl, a halo-alkanoyl, carbamoyl, a lower alkylsulfinyl, an arylsulfinyl, a lower alkylsulfonyl, an arylsulfonyl, sulfonamido or a mono- or di-lower alkylsulfonamido, or their pharmaceutically acceptable salts and its pharmaceutical use.

Benzopyran compound and its pharmaceutical use

The present invention provides an industrially valuable method for preparing an optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compound which is useful as a starting material for an optically active benzopyran compound with antihypertensive, coronary blood flow-increasing activities and the like, provides a diastereomeric ester compound which is useful as an intermediate for said epoxy compound and also provides a use of said diastereomeric ester compound in making of said epoxy compound, and further an optically active benzopyran compound which is useful as medicine.

Process for making an optically active

The present invention provides a new diastereomer ester compound which is useful as an intermediate in the making of an optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compound.

Diastereomeric ester compound useful as an intermediate in the making of

The present invention provides an industrially valuable method for preparing an optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compound which is useful as a starting material for an optically active benzopyran compound with antihypertensive, coronary blood flow-increasing activities and the like, and also provides a diastereometric ester compound with a 3-halo-4-hydroxy-2H-1-benzopyran compound which is useful as an intermediate for said epoxy compound.

Processes for preparing optically active

A benzopyran compound of the general formula (I) ##STR1## wherein A represents --OR.sup.1 or --NH--COR.sup.2 (wherein R.sup.1 represents hydrogen, a lower alkyl, formyl, an alkanoyl, an aroyl or an aralkyl and R.sup.2 represents hydrogen, a lower alkyl, a lower alkoxy, amino, mono- or di-lower alkylamino, an amino-lower alkyl, a hydroxy-lower alkyl, a halo-lower alkyl, a lower alkoxy-lower alkyl, an acyloxy-lower alkyl, a lower alkoxycarbonyl-lower alkyl, an aryl or a heteroaryl); R.sup.3 represents hydrogen, a lower alkyl, a lower alkoxy, amino, a mono- or di-lower alkylamino, an amino-lower alkyl, a hydroxy-lower alkyl, a halo-lower alkyl, a lower alkoxy-lower alkyl, an acyloxy-lower alkyl, a lower alkoxycarbonyl-lower alkyl, an aryl or a heteroaryl, or R.sup.2 and R.sup.3 combinedly together form an alkylene having 1 to 2 carbon atoms; R.sup.4 and R.sup.5 are the same or different, and respectively represent hydrogen or a lower alkyl, or combinedly together form an alkylene having 2 to 5 carbon atoms; R.sup.6 represents hydroxyl group, formyloxy, an alkanoyloxy, a haloalkanoyloxy, a lower alkoxycarbonyloxy, an aroyloxy, a heteroaroyloxy, carbamoyloxy, a mono- or di-lower alkycarbamoyloxy and R.sup.7 represents hydrogen, or R.sup.6 and R.sup.7 combinedly together form a bond and X and Y are the same or different, and respectively represent hydrogen, halogen, nitro, cyano, a lower alkyl, a lower alkoxy, a halo-lower alkyl, carboxyl, formyl, an alkanoyl, an aroyl, a halo-alkanoyl, carbamoyl, a lower alkylsulfinyl, an arylsulfinyl, a lower alkylsulfonyl, an arylsulfonyl, sulfonamido or a mono- or di-lower alkylsulfonamido, or their pharmaceutically acceptable salts and its pharmaceutical use. The compounds of the present invention exhibit remarkable and long lasting antihypertensive actions and peripheral vascular relaxant actions and therefore are useful as therapeutic medicines for hypertensive. Since they also display selective coronary vasodilating actions and the duration of actions are very long, they are of use as therapeutic medicines for cardiovascular disturbances such as angina pectoris and cardiac insufficiency.

The present invention provides an industrially valuable method for preparing an optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compound which is useful as a starting material for an optically active benzopyran compound with antihypertensive, coronary blood flow-increasing activities and the like, and also provides a diastereomeric ester compound with a 3-halo-4-hydroxy-2H-1-benzopyran compound which is useful as an intermediate for said epoxy compound.

A benzopyran compound of the general formula (I) ##STR1## wherein A represents --OR.sup.1 or --NH--COR.sup.2 (wherein R.sup.1 represents hydrogen, a lower alkyl, formyl, an alkanoyl, an aroyl or an aralkyl and R.sup.2 represents hydrogen, a lower alkyl, a lower alkoxy, amino, mono- or di-lower alkylamino, an amino-lower alkyl, a hydroxy-lower alkyl, a halo-lower alkyl, a lower alkoxy-lower alkyl, an acyloxy-lower alkyl, a lower alkoxy-carbonyl-lower alkyl, an aryl or a heteroaryl); R.sup.3 represents hydrogen, a lower alkyl, a lower alkoxy, amino, a mono- or di-lower alkylamino, an amino-lower alkyl, a hydroxy-lower alkyl, a halo-lower alkyl, a lower alkoxy-lower alkyl, an acyloxy-lower alkyl, a lower alkoxycarbonyl-lower alkyl, an aryl or a heteroaryl, or R.sup.2 and R.sup.3 combinedly together form an alkylene having 1 to 2 carbon atoms; R.sup.4 and R.sup.5 are the same or different, and respectively represent hydrogen or a lower alkyl, or combinedly together form an alkylene having 2 to 5 carbon atoms; R.sup.6 represents hydroxyl group, formyloxy, an alkanoyloxy, a haloalkanoyloxy, a lower alkoxycarbonyloxy, an aroyloxy, a heteroaroyloxy, carbamoyloxy, a mono- or di-lower alkylcarbamoyloxy and R.sup.7 represents hydrogen, or R.sup.6 and R.sup.7 combinedly together form a bond and X and Y are the same or different, and respectively represent hydrogen, halogen, nitro, cyano, a lower alkyl, a lower alkoxy, a halo-lower alkyl, carboxyl, formyl, and alkanoyl, an aroyl, a halo-alkanoyl, carbamoyl, a lower alkylsulfinyl, an arylsulfinyl, a lower alkylsulfonyl, and arylsulfonyl, sulfonamido or a mono- or di-lower alkylsulfonamido, or their pharmaceutically acceptable salts and its pharmaceutical use. The compounds of the present invention exhibit remarkable and long lasting antihypertensive actions and peripheral vascular relaxant actions and therefore are useful as therapeutic medicines for hypertensive. Since they also display selective coronary vasodilating actions and the duration of actions are very long, they are of use as therapeutic medicines for cardiovascular disturbances such as angina pectoris and cardiac insufficiency.

An oxodiazine compound of the formula: ##STR1## or a pharamceutically acceptable acid addition salt thereof, wherein each of R.sup.1 and R.sup.2 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy-C.sub.1-4 alkoxy, phenyl-C.sub.1-4 alkyl-oxy which may be optionally substituted by at least one substituent selected from the group consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy on the phenyl nucleus, or phenyl which may be substituted by at least one substituent selected from the group consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy on the phenyl nucleus; X is --S--, --CH.dbd.N-- or --C(R.sup.3).dbd.C(R.sup.4)--, where each of R.sup.3 and R.sup.4 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy-C.sub.1-4 alkoxy or phenyl-C.sub.1-4 alkyl-oxy which may be optionally substituted by at least one substituent selected from the group consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy on the phenyl nucleus; and one of A and B is oxygen, sulfur or --NH-- and the other is --C(R.sup.5) (R.sup.6)--, where each of R.sup.5 and R.sup.6 is hydrogen or C.sub.1-4 alkyl. Such compounds are useful as antithrombotic agents, antianginal agents, coronary circulation improving agent, cerebral circulation improving agents, peripheral circulation improving agents, analgesics and antiinflammatory agents.

Oxodiazine compounds and pharmaceutical compositions thereof

Ortho-aminomethylphenol compounds

2(4-n-Hexadecyl amino or oxy phenyl) 5 ethoxy oxazoleacetic acid

Oxazole- and thiazole-alkanoic acid compounds useful as drugs for the treatment of atherosclerosis with lipid metabolism disorder, and having the formula: ##STR1## wherein R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group, a pyridylmethyl group or a tocopheryl group; each of R.sup.1 and R.sup.2 is a hydrogen atom or a halogen atom; R.sup.3 is a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms; R.sup.4 is a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a trifuloromethyl group; each of X and Y is an oxygen atom or a sulfur atom; and A is a straight or branched alkylene group having 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof are disclosed.

Oxazole- and thiazole-alkanoic acid compounds

2,5-Di-substituted 4-oxazolealkanoic acids and esters thereof of the formula: ##STR1## WHEREIN M REPRESENTS AN INTEGER OF 1 TO 2; R.sup.1 represents an alkyl group having 1 to 4 carbon atoms; n represents an integer of 1 to 2; R represents a mono- or di-substituted phenyl group (in which the substituents are selected from the group consisting of a halogen atom, a methyl group, a methoxy group, a nitro group, a trifluoromethyl group, a phenyl group, a halogen-substituted phenyl group, a phenoxy group and a halogen-substituted phenoxy group), a pyridyl group, a halogen-substituted pyridyl group, a furyl group, a halogen-substituted furyl group, a thienyl group, a halogen-substituted thienyl group, a naphthyl group or a halogen-substituted naphthyl group; when m represents an integer of 1, Y represents an hydrogen atom, an alkyl group having 1 to 2 carbon atoms, a benzyl group or a pyridylmethyl group; and when m represents an integer of 2, Y represents a trimethylene group. These compounds are useful as drugs for the treatment of arteriosclerosis, thrombosis and hypertension with lipid metabolism disorder.

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Nakatsu, Japan

Tsutomu Yamanaka