Peroxisome proliferator activated receptor agonists

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  • Publication Date:
    November 3, 2005
  • Additional Information
    • Document Number:
      20050245584
    • Appl. No:
      11/054226
    • Application Filed:
      February 09, 2005
    • Abstract:
      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]
    • Inventors:
      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)
    • Claim:
      1-67. (canceled)
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      71. The compound of claim 70, wherein R2 and R9 are each methyl; each R6 is H; and R5 is H.
    • Claim:
      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.
    • Claim:
      73. The compound of claim 72, wherein R5 is H.
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      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.
    • Claim:
      79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 68, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
    • Claim:
      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.
    • Claim:
      81. The method of claim 80, wherein the peroxisome proliferator activated receptor is an α receptor or a γ receptor.
    • Claim:
      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.
    • Claim:
      83. The method of claim 82, wherein the mammal is a human.
    • Claim:
      84. The method of claim 82, wherein the compound lowers blood glucose levels.
    • Claim:
      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.
    • Claim:
      86. The method of claim 85, wherein the mammal is a human.
    • Claim:
      87. The method of claim 85, wherein the compound lowers triglycerides, lowers low density lipoproteins, or increases high density lipoproteins.
    • Claim:
      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.
    • Claim:
      89. The method of claim 88, wherein the mammal is a human.
    • Claim:
      90. The method of claim 88, wherein the compound lowers blood glucose levels.
    • Claim:
      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.
    • Current U.S. Class:
      514374/000
    • Accession Number:
      edspap.20050245584