Troglitazone compounds for treating climacteric and cancer

A method of treating a tumor in a subject, comprising the administration to a host suffering therefrom a therapeutically effective amount of a compound of Formula II:

• wherein R11 is substituted or unsubstituted alkyl, alkoxy, cycloalkyl, phenylalkyl, phenyl, aromatic acyl group, a 5- or 6-membered heterocyclic group including 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or a group of the formula
• wherein R13 and R14 are the same or different and each is lower alkyl or R13 and R14 are combined to each other either directly or as interrupted by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur to form a 5- or 6- membered ring;
• wherein R12 means a bond or lower alkylene group;
• and
• wherein L1 and L2 are the same or different and each is hydrogen or lower alkyl or L1 and L2 are combined to form an alkylene group;
• or a pharmaceutically acceptable salt thereof.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula IV:

• wherein the dotted line represents a bond or no bond;
• V is —CH═CH—, —N═CH—, —CH═N— or S;
• D is CH2, CHOH, CO, C═NOR17 or CH═CH;
• X is S, O, NR18, —CH═N or —N═CH
• Y is CH or N;
• Z is hydrogen, (C1-C7)alkyl, (C3-C7)cycloalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the same or different groups which are (C3-C3)alkyl, trifluoromethyl, (C1-C3)alkoxy, fluoro, chloro, or bromo;
• Z1 is hydrogen or (C1-C3)alkyl;
• R17 and R18 are each independently hydrogen or methyl;
• and
• n is 1, 2, or 3;
• the pharmaceutically acceptable cationic salts thereof;
• and
• the pharmaceutically acceptable acid addition salts thereof when the compound contains a basic nitrogen.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula V:

• wherein the dotted line represents a bond or no bond;
• A and B are each independently CH or N, with the proviso that when A or B is N, the other is CH;
• X1 is S, SO, SO2, CH2, CHOH, or CO;
• n is 0 or 1;
• Y1 is CHR20 or R21, with the proviso that when n is 1 and Y1 is NR21, X1 is SO2 or CO;
• Z2 is CHR22, CH2CH2, CH═CH,
• OCH2, SCH2, SOCH2 or SO2CH2;
• R19, R20, R21, and R22 are each independently hydrogen or methyl;
• and
• X2 and X3 are each independently hydrogen, methyl, trifluoromethyl, phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, or fluoro;
• a pharmaceutically acceptable cationic salt thereof;
• or
• a pharmaceutically acceptable acid addition salt thereof when A or B is N.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula VII:

• or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• A2 represents an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group wherein the alkylene or the aryl moiety may be substituted or unsubstituted;
• A3 represents a benzene ring having in total up to 3 optional substituents;
• R24 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the alkyl or the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
• or A2 together with R24 represents substituted or unsubstituted C2-3 polymethylene group, optional substituents for the polymethylene group being selected from alkyl or aryl or adjacent substituents together with the methylene carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
• R25 and R26 each represent hydrogen, or R25 and R26 together represent a bond;
• X4 represents O or S;
• and
• n represents an integer in the range from 2 to 6.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula VIII in unit dosage form:

• or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• R27 and R28 each independently represent an alkyl group, a substituted or unsubstituted aryl group, or an aralkyl group being substituted or unsubstituted in the aryl or alkyl moiety;
• or R27 together with R28 represents a linking group, the linking group consisting of an optionally substituted methylene group or an O or S atom, optional substituents for the said methylene groups being selected from alkyl-, aryl, or aralkyl, or substituents of adjacent methylene groups together with the carbon atoms to which they are attached form a substituted or unsubstituted phenylene group;
• R29 and R30 each represent hydrogen, or R29 and R30 together represent a bond;
• A4 represents a benzene ring having in total up to 3 optional substituents;
• X5 represents O or S;
• and
• n represents an integer in the range from 2 to 6.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula IX:

• or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• A5 represents a substituted or unsubstituted aromatic heterocyclyl group;
• A6 represents a benzene ring having in total up to 5 substituents;
• X6 represents O, S, or NR32 wherein R32 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
• Y2 represents O or S;
• R31 represents an alkyl, aralkyl, or aryl group;
• and
• n represents an integer in the range from 2 to 6.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula X:

• or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• A7 represents a substituted or unsubstituted aryl group;
• A8 represents a benzene ring having in total up to 5 substituents;
• X8 represents O, S, or NR39 wherein R39 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
• Y3 represents O or S;
• R37 represents hydrogen;
• R38 represents hydrogen or an alkyl, aralkyl, or aryl group or R37 together with R38 represents a bond;
• and
• n represents an integer in the range from 2 to 6.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula XI:

• or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• A1 represents a substituted or unsubstituted heterocyclyl group;
• R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
• A2 represents a benzene ring having in total up to 5 substituents;
• and
• n represents an integer in the range of from 2 to 6.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula XII or XIII:

• or a pharmaceutically acceptable salt thereof wherein the dotted line represents a bond or no bond;
• R is cycloalkyl of three to seven carbon atoms, naphthyl, thienyl, furyl, phenyl or substituted phenyl wherein said substituent is alkyl of one to three carbon atoms, alkoxy of one to three carbon atoms, trifluoromethyl, chloro, fluoro or bis(trifluoromethyl);
• R1 is alkyl of one to three carbon atoms;
• X is O or C═O;
• A is O or S;
• and
• B is N or CH.

A method of treating a tumor in a subject comprising administering to a host suffering therefrom a therapeutically effective amount of a compound selected from the group consisting of

• (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy]phenyl]methyl]-2,4-thiazolidinedione:
• (troglitazone);
• 4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide;
• 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;
• 5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione;
• 5-[4-[2-[N-methyl-N-(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione;
• 5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione;
• 5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione;
• 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;
• 5-[4-[(1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione:
• (ciglitazone);
• 5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiadiazolidine-2,4-dione;
• 5-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiadizolidione-2,4-dione;
• 5-[4-[2-(5-ethylpyridin-2-yl)ethoxyl]benzyl]thiadiazolidine-2,4-dione:
• (pioglitazone);
• 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiadiazoline-2,4-dione:
• (englitazone);
• 5-[[2-(2-naphthylmethyl)benzoxazol]-5-ylmethyl]thiadiazoline-2,4-dione;
• 5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiadiazoline-2,4-dione;
• 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzy]thiadiazoline-2,4-dione;
• 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiadiazoline-2,4-dione;
• 5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]-oxazolidine -2,4-dione;
• 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione (BRL49653);
• and
• 5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-oxazolidine-2,4-dione.