20050245584

11/054226

February 09, 2005

Compounds represented by the following structural formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: n is 2, 3, or 4 and W is CH2, CH(OH), C(O) or O; R1 is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl-alkyl, or t-butyl; R2 is H, alkyl, haloalkyl or phenyl; Y is an unsubstituted or substituted thiophen-2,5-diyl or phenylene; R3 is alkyl or haloalkyl; R4 is a substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl, pyridyl or benzo[1,3]dioxol-5-yl group; and R5 is H, alkyl, or aminoalkyl; are useful for modulating a peroxisome proliferator activated receptor, particularly in the treatment of diabetes mellitus. [chemical expression included]

Brooks, Dawn Alisa (Indianapolis, IN, US); Godfrey, Alexander Glenn (Mooresville, IN, US); Jones, Sarah Beth (Greenwood, IN, US); McCarthy, James Ray (Zionsville, IN, US); Rito, Christopher John (Martinsville, IN, US); Winneroski, Leonard Larry (Greenwood, IN, US); Xu, Yanping (Fishers, IN, US)

1-67. (canceled)

68. A compound represented by the following structural formula: [chemical expression included] or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein: (a) R1 an unsubstituted or substituted group selected from aryl, cycloalkyl, heterocyclo-alkyl, aryl-C1-C4 alkyl, cycloalkyl-C1-C4 alkyl, or t-butyl; (b) R2 is H, C1-C4 alkyl, C1-C4 haloalkyl or phenyl; (c) n is 2, 3, or 4; (d) W is is CH2, CH(OH), C(O) or 0; (e) Y is an unsubstituted or substituted group consisting of thiophen-2,5-diyl or phenylene; (f) R3 is a C1-C4 alkyl or C1-C4 haloalkyl; (g) R4 is a substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyridyl, quinolyl or benzo[1,3]dioxol-5-yl group; and (h) R5 is H, C1-C4 alkyl, or aminoalkyl.

69. The compound of claim 68, wherein n is 2; W is 0; Y is phenylene; R2 and R3 are each methyl; R4 is substituted or unsubstituted phenyl; and R5 is H.

70. A compound represented by the following structural formula: [chemical expression included] or a pharmaceutically acceptable salt, solvates and hydrate thereof, wherein: (a) R1 an unsubstituted or substituted group selected from aryl, cycloalkyl, heterocyclo-alkyl, aryl-C1-C4 alkyl, cycloalkyl-C1-C4 alkyl, or t-butyl; (b) R2 is H, C1-C4 alkyl, C1-C4 haloalkyl or phenyl; (c) R5 is H, C1-C4 alkyl, or aminoalkyl; (d) R6 are each, independently, H, C1-C4 alkyl or C 1-C4 alkoxy; (e) R7 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl or phenyl; (f) R8 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl, phenyl or together with the phenyl to which they are bound form naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl or benzo[1,3]dioxol-5-yl; and (g) R9 is C1-C4 alkyl or C1-C4 haloalkyl.

71. The compound of claim 70, wherein R2 and R9 are each methyl; each R6 is H; and R5 is H.

72. The compound of claim 70, wherein the compound is represented by the following structural formula: [chemical expression included] or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein: (a) R5 is H, C1-C4 alkyl, or aminoalkyl; (b) R6 are each, independently, H, C1-C4 alkyl or C1-C4 alkoxy; (c) R7 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl or phenyl; (d) R8 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl, phenyl or together with the phenyl to which they are bound form naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl or benzo[1,3]dioxol-5-yl; and (e) R10 is an unsubstituted or substituted group selected from phenyl, cyclohexyl or 1-methyl-cyclohexyl.

73. The compound of claim 72, wherein R5 is H.

74. The compound of claim 72, wherein the compound is represented by the following structural formula: [chemical expression included] or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein: (a) R7 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl or phenyl; and (b) R8 are each, independently, H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, methanesulfonyl, C3-C8 cycloalkyl, thienyl, phenyl or together with the phenyl to which they are bound form naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl or benzo[1,3]dioxol-5-yl.

75. The compound of claim 74, wherein the compound is 3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid; or (S)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid.

76. The compound of claim 72, wherein the compound is 3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-p-tolyloxy-propionic acid, or (S)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-p-tolyloxy-propionic acid.

77. A compound represented by the following structural formula: [chemical expression included] or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein: (a) R1 an unsubstituted or substituted group selected from aryl, heteroaryl, cycloalkyl, heterocyclo-alkyl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl, cycloalkyl-C1-C4 alkyl, or t-butyl; (b) R2 is H, C1-C4 alkyl, C1-C4 haloalkyl or phenyl; (c) V is is C, C(OH) or C(O); (d) R3 is a C1-C4 alkyl or C1-C4 haloalkyl; (e) R4 is a substituted or unsubstituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, quinolyl or benzo[1,3]dioxol-5-yl group; and (f) R5 is H, C1-C4 alkyl, or aminoalkyl.

78. The compound of claim 68, wherein the compound is selected from the group consisting of: 2-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(quinolin-6-yloxy)-propionic acid; 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-methyl-2-(quinolin-6-yloxy)-propionic acid; 2-(2-Methoxy-phenoxy)-2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2-methoxy-phenoxy)-2-methyl-propionic acid; 2-Methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl]-ethoxy}-phenyl)-2-o-tolyloxy-propionic acid; 2-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy-phenyl)-2-o-tolyloxy-propionic acid; 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-o-tolyloxy-propionic acid; 2-Methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}phenyl)-2-o-tolyloxy-propionic acid; 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionic acid; 2-(Biphenyl-3-yloxy)-3-4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid ethyl ester; 2-(3-Chloro-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid; and 2-(3-Chloro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid.

79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

80. A method of modulating a peroxisome proliferator activated receptor, comprising the step of contacting the receptor with a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

81. The method of claim 80, wherein the peroxisome proliferator activated receptor is an α receptor or a γ receptor.

82. A method of treating diabetes mellitus in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

83. The method of claim 82, wherein the mammal is a human.

84. The method of claim 82, wherein the compound lowers blood glucose levels.

85. A method of treating cardiovascular disease in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

86. The method of claim 85, wherein the mammal is a human.

87. The method of claim 85, wherein the compound lowers triglycerides, lowers low density lipoproteins, or increases high density lipoproteins.

88. A method of treating Syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

89. The method of claim 88, wherein the mammal is a human.

90. The method of claim 88, wherein the compound lowers blood glucose levels.

91. The method of claim 88, wherein the compound lowers serum concentration of triglycerides, lowers serum concentration of low density lipoproteins, or increases serum concentration of high density lipoproteins.

514374/000

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