Indane Acetic Acid Derivatives and Their Use as Pharmaceutical Agents, Intermediates, and Method of Preparation

Abstract

This invention relates to novel indane acetic acid derivatives which are useful in the treatment of diseases such as diabetes, obesity, hyperlipidemia, and atherosclerotic diseases. The invention also relates to intermediates useful in preparation of indane acetic derivatives and to methods of preparation.

1 . A process for the preparation of a compound of Formula V 
     
       
         
         
             
             
         
       
     
     comprising the step of a stereospecific hydrogenation of a compound of Formula IV 
     
       
         
         
             
             
         
       
     
     in the presence of hydrogen source and a catalyst, 
     wherein
 R 9  is methoxy optionally substituted by fluoro,
 C 2 -C 6  alkoxy, C 1 -C 6  alkyl, or C 4 -C 8  cycloalkyl each optionally substituted by fluoro, methylenedioxyphenyl or phenyl optionally substituted with R 13 ; 
 
 R 10  is hydrogen, fluoro, methyl optionally substituted with fluoro, oxo, or
 C 2 -C 6  alkyl which may be unsubstituted or substituted with C 1 -C 6  alkoxy, oxo, fluoro, or with phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl,
 each of which may be unsubstituted or substituted with R 13 , or 
 
 
 R 10  is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl,
 each of which may be unsubstituted or substituted with R 13 ; 
 
 R 11  is halo or C 1 -C 6  alkyl optionally substituted with oxo; 
 R 12  is hydrogen, methyl optionally substituted with fluoro or oxo,
 C 2 -C 6  alkyl optionally substituted with phenyl, fluoro, or oxo, 
 C 1 -C 6  trialkylsilyl, arylalkylsilyl, COR 14 , COOR 14 , or 
 
 
     
       
         
         
             
             
         
       
       
         
           R 13  is fluoro, CF 3 , C 1 -C 6  alkyl optionally substituted with hydroxy or oxo, or C 1 -C 6  alkoxy optionally substituted with fluoro; 
         
       
       R 14  is C 1 -C 6  alkyl, or phenyl optionally substituted with C 1 -C 6  alkyl or fluoro; 
       R 15  is hydrogen, C 1 -C 6  alkyl or phenyl substituted with R 13 ; 
       R 16  is methyl optionally substituted with fluoro, oxo or
 with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,
 each of which may be unsubstituted or substituted with R 13 , or 
 
 C 4 -C 8  cycloalkyl or C 2 -C 6  alkyl, either of which may be unsubstituted or substituted with fluoro, methoxy, C 2 -C 6  alkoxy optionally substituted with phenyl or 
 C 1 -C 6  alkoxy, oxo or with, phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,
 each of which may be unsubstituted or substituted with R 13 , or 
 
 C 2 -C 6  alkyl which may also be substituted with C 4 -C 8  cycloalkyl or with phenoxy which may be unsubstituted or substituted with R 6  or with phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,
 each of which may be unsubstituted or substituted with R 13 , or 
 
 R 13  is phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, or 1,4-benzodioxanyl,
 each of which may be unsubstituted or substituted with R 13 , or with phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, pyrimidinyl, indolyl, or phenoxy 
 each of which may be unsubstituted or substituted with R 13 , and 
 
 
       X is O or S. 
     
   
   
       2 . The process of  claim 1 , wherein hydrogenation is performed in the presence of a base. 
   
   
       3 . The process of  claim 1 , wherein said compound of Formula V is in the syn form. 
   
   
       4 . The process of  claim 1 , wherein said compound of Formula IV is a racemic mixture. 
   
   
       5 . The process of  claim 1 , wherein said compound of Formula IV is enantiomerically enriched. 
   
   
       6 . The process of  claim 5 , wherein said compound of Formula V is at least about 40% de. 
   
   
       7 . The process of  claim 1 , wherein said catalyst is transition metal based homogenous catalyst. 
   
   
       8 . The process of  claim 1 , wherein said catalyst is selected from the group consisting ClRh[P(Ph) 3 ] 3  (Wilkinson's catalyst), (1,5-cyclooctadiene)tricyclohexylphosphinepyridinoiridium(I) hexafluorophosphate, (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate, (Crabtree's catalysts). 
   
   
       9 . The process of  claim 2 , wherein said base is selected from the group consisting of mono(C 1 -C 6  alkyl)amines, di(C 1 -C 6  alkyl)amines, tri(C 1 -C 6  alkyl)amines, tertiary amines, inorganic bases, and optically active bases. 
   
   
       10 . The process of  claim 1 , wherein said hydrogen source is hydrogen gas. 
   
   
       11 . The process of  claim 10 , wherein said hydrogenation is performed under a hydrogen pressure from about atmospheric pressure to about 1,000 psi. 
   
   
       12 . The process of  claim 11 , wherein said hydrogenation is performed under a hydrogen pressure from about 20 psi to about 100 psi. 
   
   
       13 . A process for the preparation of a compound of Formula V, comprising the steps of:
 forming diastereomeric salts of a compound of Formula IV by treatment with a resolving agent;   separating said diastereomeric salts by crystallization with a crystallization solvent; and   reducing the separated diastereomeric salts by hydrogenation in the presence of catalyst and a solvent,   
     wherein
 the compounds of Formula V and Formula IV are defined as in  claim 1 . 
 
   
   
       14 . The process of  claim 13 , further comprising the step of;
 liberating the antipodes from the separated diastereomeric salts by treatment with an aqueous mineral acid.   
   
   
       15 . The process of  claim 13 , wherein said reduction step is performed in the presence of a base. 
   
   
       16 . The process of  claim 13  or  14 , wherein said resolving agent is an optically active base selected from the group consisting of quinine, cinchonine, (+)-alpha-methylbenzylamine, and (−)-alpha-methylbenzylamine. 
   
   
       17 . The process of  claim 13  or  14 , wherein said crystallization solvent is selected from the group consisting of acetonitrile, acetone, t-butanol, 2-propanol, ethanol, methanol, and mixtures thereof. 
   
   
       18 . A process for the preparation of a compound of Formula V, comprising the steps of:
 reducing a compound of Formula IV to a compound of Formula V
 by hydrogenation in the presence of a hydrogenation catalyst and a solvent; 
 forming diastereomeric salts of the compound of Formula V by treatment with a resolving agent; 
   separating the diastereomeric salts by crystallization in a crystallization solvent; and
 liberating the individual antipodes from the separated salts by treatment with aqueous mineral acid, 
   wherein   the compounds of Formula V and Formula IV are defined as in  claim 1 .   
   
   
       19 . The process of  claim 18 , wherein said reduction step is performed in the presence of a base. 
   
   
       20 . The process of  claim 18  or  19 , wherein said hydrogenation catalyst is selected from the group consisting of ClRh[P(Ph) 3 ] 3  (Wilkinson's catalyst), (1,5-cyclooctadiene)tricyclohexylphosphinepyridinoiridium(I) hexafluorophosphate, and (1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate (Crabtree's catalyst). 
   
   
       21 . The process of  claim 18  or  19 , wherein said resolving agent is selected from the group consisting of quinine, cinchonine, (+)-alpha-methylbenzylamine, and (−)-alpha-methylbenzylamine. 
   
   
       22 . The process of  claim 18  or  19 , wherein said crystallization solvent is selected from the group consisting of acetonitrile, acetone, t-butanol, 2-propanol, ethanol, methanol, and mixtures thereof. 
   
   
       23 . A method of identifying compounds useful for the treatment of diabetes, diabetes-related disorders, obesity, and atherosclerotic disease comprising the step of determining the insulin sensitizing activity of said compound. 
   
   
       24 . The method of  claim 23  further comprising the steps of:
 growing cells to 2-4 days post-confluency;   treating cells with differentiation media; and   assaying for insulin receptor binding activity.   
   
   
       25 . The method of  claim 24 , wherein said differentiation media comprises Insulin-like Growth Factor (IGF-1) and test compounds. 
   
   
       26 . The method of  claim 25 , wherein said Insulin-like Growth Factor is present in an amount from about 0.1 μM to about 1 μM. 
   
   
       27 . The method of  claim 24 , wherein said cells are 3T3-L1 cells.