Modulators of peroxisome proliferator activated receptors

A compound selected from the group consisting of:

• 2-[4-(2-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-5-methyloxazol-4-yl}-ethoxy)-phenoxy]-2-methylpropionic acid;
• 2-methyl-2-[4-(2-{5-methyl-2-[4-(1H-pyrrol-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]propionic acid;
• 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid;
• 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid;
• 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-{5′-methylthiophen-2-yl}-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• and
• pharmaceutically acceptable salts, solvates and hydrates thereof.

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and at least one compound represented by the following structural formula:

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• n is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each, independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl;
• and
• R6 is H, a C1-C4 alkyl. or an aminoalkyl.

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and at least one compound selected from the group consisting of:

• 2-[4-(2-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-5-methyloxazol-4-yl}-ethoxy)-phenoxy]-2-methylpropionic acid;
• 2-methyl-2-[4-(2-{5-methyl-2-[4-(1H-pyrrol-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]propionic acid;
• 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid;
• 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-5-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid;
• 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-{5′-methylthiophen-2-yl}-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid;
• and
• pharmaceutically acceptable salts, solvates and hydrates thereof.

A method of modulating a peroxisome proliferator activated receptor, comprising the step of contacting the receptor with at least one compound represented by the following structural formula:

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• n is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each, independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl;
• and
• R6 is H, a C1-C4 alkyl, or an aminoalkyl.

A method of treating hyperinsulemia, diabetes mellitus, or a combination thereof in a patient. comprising the step of administering to the patient a therapeutically effective amount of at least one compound represented by the following structural formula:

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof wherein:
• n is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each, independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl, and
• R6 is H, a C1-C4 alkyl, or an aminoalkyl.

A method of treating a patient having cardiovascular disease or one or more risk factor for cardiovascular disease, comprising the step of administering to the patient a therapeutically effective amount of at least one compound represented by the following structural formula;

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• n is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each, independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl;
• and
• R6 is H, a C1-C4 alkyl. or an aminoalkyl, wherein the risk factor for cardiovascular disease is selected from the group consisting of elevated low density lipoproteins, elevated triglycerides, decreased high density lipoproteins, and combinations thereof.

A method of treating Syndrome X in a patient, comprising the step of administering to the patient a therapeutically effective amount of at least one compound represented by the following structural formula:

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof, wherein:
• a is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl;
• and
• R6 is H, a C1-C4 alkyl, or an aminoalkyl.

A compound for use in therapy for a disorder modulated by a peroxisome proliferator activated receptor, wherein the compound is represented by the following structural formula:

• and/or pharmaceutically acceptable salts, solvates and hydrates thereof wherein:
• n is 2, 3, or 4;
• W is O, S, or SO2;
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R2 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, a cycloalkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthyl;
• R3 are each, independently, H, a C1-C6 alkyl, an aryl-C1-C6 alkyl, a cycloalkyl-C1-C4 alkyl, an aryl, or a cycloalkyl;
• R4 are each, independently, H, a C1-C4 alkyl, an aryl, or benzyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, provided that at least one R5 is a substituted or unsubstituted heteroaryl;
• and
• R6 is H, a C1-C4 alkyl, or an aminoalkyl.

A method of preparing a 2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole represented by the following structural formula:

• wherein:
• R1 is H, a C1-C4 alkyl, phenyl or trifluoromethyl;
• R5 are each, independently, H or a substituted or unsubstituted heteroaryl, comprising the steps of:
• a) condensing a dionemonooxime represented by the following structural formula:
• with a bromobenzaldehyde represented by the following formula:
• in the presence of an acid to form an oxazole n-oxide represented by the following structural formula:
• b) treating the oxazole n-oxide with phosphorous oxychloride to form a 2-(bromophenyl)-4-chloromethyl-5-substituted-oxazole represented by the following structural formula:
• c) treating the 2-(bromophenyl)-4-chloromethyl-5-substituted-oxazole with a cyanide salt and an iodide salt to form 2-(bromophenyl)-4-cyanomethyl-5-substituted-oxazole represented by the following structural formula:
• d) treating the 2-(bromophenyl)-4-cyanomethyl-5-substituted-oxazole with an alkali metal hydroxide to form 2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole represented by the following structural formula:
• e) treating the 2-(bromophenyl)-4-carboxymethyl-5-substituted-oxazole with boron-tetrahydrofuran complex to form a 2-(bromophenyl)-4-(2-hydroxyethyl)-5-substituted-oxazole represented by the following structural formula: