α1b-adrenergic receptor antagonists

A method for treating circulatory disease comprising administering to a patient a therapeutically effective amount of an aiB adrenoceptor compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof:

• (wherein Ar is idolyl, naphthalenyl, quinolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzisoxazolyl, or 2-ketobenzimidazolinyl, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 1 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, alkenyl having 2 to 9 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms;
• B—N—R1 forms a ring structure and is piperidine or 2,3,6-trihydropyridine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
• n denotes an integer of 0 or 1;
• A is alkylene having 2 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• Q is:
• 1) —NR2R3,
• wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbons atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or —NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, 2-piperidone, 2-pyrrolidone, indoline, 2,3,4-trihydroquionoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, benzothiane, phthalamide, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having, 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diatylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• or
• (wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring)).

A method for treating hypertension comprising administering to a patient a therapeutically effective amount of an α1 B adrenoceptor compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof:

• (wherein Ar is indolyl, naphthalenyl, quinolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzisoxazolyl, or 2-ketobenzimidazolinyl, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 1 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• R1 is hydrogen, alkyl having 1 to 6 carbon atoms, aryl having 6 to 12 carbon atoms, alkenyl having 2 to 9 carbon atoms, or cycloalkyl having 3 to 8 carbon atoms;
• B—N—R1 forms a ring structure and is piperidine or 2,3,6-trihydropyridine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
• n denotes an integer of 0 or 1;
• A is alkylene having 2 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• Q is:
• 1) —NR2R3,
• wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylarnino group having 12 to 20 carbons atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or —NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, 2-piperidone, 2-pyrrolidone, indoline, 2,3,4-trihydroquionoline, 2,3,4-trihydroquinoxaline, dihydrobenzoxazine, benzothiane, phthalamide, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• or
• (wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring)).

A compound represented by the formula (III), or a pharmacologically accet table acid addition salt thereof:

• Ar2—A—A—Q2 (III)
• (wherein D represents one of the following formulae 1) to 5), each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, hydroxyalkyl group having 1 to 8 carbon atoms, alkylcarbonyl group having 2 to 9 carbon atoms, arylcarbonyl group having 7 to 16 carbon atoms, and aralkyl group having 7 to 15 carbon atoms;
• Ar2 is indolyl, quinolinyl, benzimidazolyl, benzofuiranyl, or benzothiophenyl, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• A is alkylene having 3 to 8 carbon atoms, phenylene, or cycloalkylene having 3 to 8 carbon atoms, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• Q2 is:
• 1) —NR2R3,
• wherein each of R2 and R3 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylmino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms, where R2=R3=H and R2=R3=ethyl are excluded), or —NR2R3 together forms piperidine, pyrrolidine, 1,3,4-trihydroisoquinoline, isoindoline, piperazine, morpholine, 2-piperidone, 2-pyrrolidone, indoline, 2,3,4-trihydroquinoline, 2,3,4trihydroquinoxaline, dihydrobenzoxazine, or guanidine, each of which is unsubstituted or substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms;
• or
• (wherein each of R4, R5, R6 is independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, aryl having 6 to 15 carbon atoms, or aralkyl having 7 to 15 carbon atoms (wherein the aryl moiety of the aryl and aralkyl may be substituted with the groups selected from the group consisting of halogen, nitro group, acylamino group having 1 to 9 carbon atoms, amino group, alkylamino group having 1 to 8 carbon atoms, arylamino group having 6 to 15 carbon atoms, dialkylamino group having 2 to 16 carbon atoms, diarylamino group having 12 to 20 carbon atoms, hydroxy, alkyl group having 1 to 8 carbon atoms, aryl group having 6 to 15 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 15 carbon atoms, haloalkyl group having 1 to 8 carbon atoms, haloalkoxy group having 1 to 8 carbon atoms, cyano group, aminosulfonyl group having 0 to 15 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 9 carbon atoms, aminocarbonyl group having 1 to 15 carbon atoms, alkylthio group having 1 to 8 carbon atoms, and arylthio group having 6 to 15 carbon atoms), or R4 and R5 together form an imidazoline ring)).