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US 2007/0190041 A1Published application
Novel benzothiazepine and bensothiepine compounds
AssigneeAshai Kasei Pharama Corporation
InventorsTakehiko Sasahara, Mitsunobu Mohri, Ken-ichi Kasahara
Life of this patent
Estimating the term…
Abstract
A pharmaceutical useful as a therapeutic agent and a preventive agent for hyperlipemia, and a pharmaceutical useful as a therapeutic agent and a preventive agent for hepatic disorders associated with cholestasis, particularly, primary biliary cirrhosis and primary sclerosing cholangitis, and a pharmaceutical useful as a therapeutic agent and a preventive agent for obesity, fatty liver and steatohepatitis are provided. A benzothiazepine or benzothiepine compound represented by the following formula (1A) having a thioamide bond and a quaternary ammonium substitutent:
Claims40
A compound represented by the following formula (1A):
- wherein R1a and R2a may be the same as or different from each other and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms;
- ma is an integer of 0 to 4;
- Rx represents halogen atom, nitro group, amino group, cyano group, hydroxy group, carboxy group, —CONH2, —SO3H, —NR3R4 (R3 and R4 may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms), alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms;
- wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidil, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO2—, —NHCO—, —NR8a—, and —N+Wa−R9aR10a—(R8a represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms;
- the alkyl group and the alkenyl group in R8a may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxy. R9a and R10a may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, and may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxy. Wa− represents counteranion.);
- the combination of (A1, A2, A3) represents (CH2, NH, CH), (CH2, CH(OH), CH), (NH, CH(OH), CH) or (CH2, CH2, N);
- Y represents any of —NHCS—, —NHCSNH— or —NHCSO—, wherein —NH of —NHCS— represents a bond which binds to the adjacent benzene ring and CS— represents a bond which binds to the adjacent Za, and —NH of —NHCSO— represents a bond which binds to the adjacent benzene ring and CSO— represents a bond which binds to the adjacent Za;
- Za-(N+R5aR6aR7a)n represents alkyl group or alkenyl group having 2 to 10 carbon atoms which is substituted with —N+R5aR6aR7a, the number of the substitutent being n;
- wherein one or more methylenes which constitute Za may be replaced with any of phenylene which may have a substitutent or —O—;
- wherein the substitutent(s) in the phenylene which may have the substitutent are 1 to 4 substitutents selected from the group consisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms, nitro group, halogen atoms, trifluoromethyl group and —CH2N+R5aR6aR7a;
- wherein the substitutents may be the same as or different from each other;
- and wherein n is an integer of 1 or 2;
- and
- each of N+R5aR6aR7a is independently any of the following I), II) or III):
- I) R5a, R6a and R7a may be the same as or different from one another, and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms;
- wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidil, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- and wherein one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO2—, —NHCO—, —NR8—, and —N+W−R9R10—(R8 represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms. The alkyl group and the alkenyl group in R8 may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxy. R9 and R10 may be the same as or different from each other and each represents alkyl group having 1 to 5 carbon atoms or alkenyl group having 2 to 5 carbon atoms, and may be substituted with one or more groups of phenyl, cycloalkyl having 3 to 7 carbon atoms and hydroxy. W− represents counteranion.);
- II) N+R5aR6aR7a represents a monocyclo or bicyclo ring formed of 4 to 9 carbon atoms in addition to the ammonium nitrogen atom, with a proviso that a position of binding to Za is the ammonium nitrogen atom;
- wherein, in the monocyclo and bicyclo rings, one of the carbon atoms which constitutes the ring may be replaced with any of oxygen, nitrogen or sulfur atom;
- and the monocyclo and bicyclo rings may be substituted with one or more groups of hydroxy, oxo, thioxo, cyano, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, carboxy, —CONH2, —SO3H and —R11 (R11 represents alkyl group having 1 to 8 carbon atoms or alkenyl group having 2 to 8 carbon atoms. The alkyl group and the alkenyl group in R11 may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidil, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO2—, —NHCO—, —NR8—, and —N+W−R9R10;
- R8, R9, R10 and W− are the same as the above);
- and the group which is not involved in the formation of the monocyclo ring and the bicyclo ring in R5a, R6a and R7a is the same as the above I);
- and
- III) N+R5aR6aR7a represents a pyridinium ring, a quinolinium ring or an isoquinolinium ring with a proviso that a position of binding to Za is the ammonium nitrogen atom;
- wherein the pyridinium ring, the quinolinium ring and the isoquinolinium ring may be substituted with one or more groups of cyano, nitro, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 5 carbon atoms, carboxy, —CONH2, —SO3H, halogen, hydroxy, tetrahydropyranyl and —R12a (R12a represents alkyl group having 1 to 9 carbon atoms or alkenyl group having 2 to 9 carbon atoms. The alkyl group and the alkenyl group in R12a may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —S—, —O—, —CO2—, —NHCO—, —NR8—, and —N+W−R9R10—;
- R8, R9, R10 and W− are the same as the above);
- and
- X− represents counteranion.
28 more elements
A compound represented by the following formula (1B):
- wherein R1 and R2 may be the same as or different from each other, and each represents alkyl group having 1 to 10 carbon atoms;
- m is an integer of 1 or 2;
- and R3, R4, A1, A2, A3, Y, Za-(N+R5aR6aR7a), n and X− are the same as the above.
A pharmaceutical composition containing as an active component a compound represented by the following formula (1):
- wherein R1, R2, R3, R4, m, n and X− are the same as the above;
- Y represents any of —NHCS—, —NHCSNH— or —NHCSO—, wherein —NH of —NHCS— represents a bond of binding to the adjacent benzene ring and CS— represents a bond of binding to the adjacent Z, and —NH of —NHCSO— represents a bond of binding to the adjacent benzene ring and CSO— represents a bond of binding to the adjacent Z;
- Z-(N+R5R6R7)n represents alkyl or alkenyl having 2 to 10 carbon atoms which is substituted with —N+R5R6R7, the number of the substitutent being n, and one or more methylenes which constitute Z may be replaced with any of phenylene or —O—;
- and
- each of N+R5R6R7 is independently any of the following I), II) or III):
- I) R5, R6 and R7 may be the same as or different from one another, and each represents alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms or alkynyl group having 2 to 10 carbon atoms;
- wherein the alkyl group, the alkenyl group and the alkynyl group may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, piperidil, pyrrolidyl, morpholyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- and wherein one or more methylenes which constitute the alkyl group, the alkenyl group and the alkynyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —O—, —S—, —CO2—, —NHCO—, —NR8—, and —N+W−R9R10—;
- and R8, R9, R10 and W− are the same as the above;
- II) N+R5R6R7 represents a monocyclo or bicyclo ring formed of 4 to 9 carbon atoms in addition to the ammonium nitrogen atom, with a proviso that a position of binding to Z is the ammonium nitrogen atom;
- wherein, in the monocyclo and bicyclo rings, one of the carbon atoms which constitutes the ring may be replaced with any of oxygen, nitrogen or sulfur atom;
- and the monocyclo and bicyclo rings may be substituted with one or more groups of hydroxy, oxo, thioxo, cyano, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, carboxy, —CONH2, —SO3H and —R11 (R11 is the same as the above);
- and the group which is not involved in the formation of the monocyclo ring and the bicyclo ring in R5, R6 and R7 is the same as the above I);
- and
- III) N+R5R6R7 represents a pyridinium ring, a quinolinium ring or an isoquinolinium ring, with a proviso that a position of binding to Z is the ammonium nitrogen atom;
- wherein the pyridinium ring, the quinolinium ring and the isoquinolinium ring may be substituted with one or more groups of cyano, nitro, phenyl, naphthyl, thienyl, pyridyl, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 5 carbon atoms, carboxy, —CONH2, —SO3H, and —R12 (R12 represents alkyl group having 1 to 9 carbon atoms or alkenyl group having 2 to 9 carbon atoms. The alkyl group and the alkenyl group in R12 may be substituted with one or more groups of phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, cycloalkyl having 3 to 7 carbon atoms, cyano, nitro, hydroxy, oxo, thioxo, carboxy, —CONH2 and —SO3H;
- and one or more methylenes which constitute the alkyl group and the alkenyl group may be replaced with any of phenylene, thienylene, furylene, cyclohexylene, cyclopentylene, —S—, —CO2—, —NHCO—, —NR8—, and —N+W−R9R10—;
- and R8, R9, R10 and W− are the same as the above).
15 more elements
Dependencies are inferred from the claim text.