Substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists

Abstract

The present invention relates to novel substituted benzofurans and benzothiophenes compounds that are antagonists of alpha V (αv) integrins, for example α v β 3 and α v β 5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment of pathological conditions mediated by α v β 3 and α v β 5 integrins, including such conditions as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis. The compounds have the general formula I: where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n, i, j and k are defined herein.

1 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein 
 R 1  represents hydrogen, alkyl, haloalkyl, aryl or aralkyl;  
 R 2 , R 3  and R 4  independently represent hydrogen, alkyl, haloalkyl, aryl or aralkyl;  
 Y is oxygen;  
 R 5 , R 6 , R 7  and R 8  independently represent: hydrogen; hydroxy; alkyl; haloalkyl; alkoxy; haloalkoxy; cycloalkyl; aryl; or heterocycle having 5-14 ring members, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, haloalkyl, alkoxy, aryl or arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkyl sulfinyl, alkylalkoxyaryl, mono- or di-alkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl, carboxyalkyl; further wherein: aryl or the aryl group of any aryl-containing moiety may be optionally substituted by one or more of: halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl, mono- or di-alkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl, carboxyalkyl;  
 or R 5  and R 7  are taken together to form —(CH 2 )S—, wherein s is 0 or 1 to 4, while R 6  and R 8  are defined as above; or R 6  and R 8  are taken together to form —(CH 2 ) t —, wherein t is 2 to 8, while R 5  and R 7  are defined as above; or R 7  and R 8  are taken together to form —(CH 2 ) U — wherein u is 2 to 8, while R 5  and R 6  are defined as above;  
 i is from 0 to 4;  
 j is from 0 to 4; and  
 k is 0 or 1;  
 R 9  is hydrogen or a functionality which acts as a prodrug, selected from the group consisting of: alkyl, haloalkyl, aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl;  
 R 10 , R 11 , R 12  and R 13  independently represent hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, aryl or aralkyl;  
 or R 10  and R u  are taken together to form —(CH 2 ) p —, where p is 2-8, while R 12  and R 13  are defined as above; or R 12  and R 13  are taken together to form —(CH 2 ) q —, where q is 2-8, while R 10  and R 11  are defined as above; or R 10  and R 12  are taken together to form —(CH 2 ) r —, while r is zero, 1 or 2, while R 11  and R 13  are defined as above;  
 X represents; oxygen, sulfur, CH 2  or NH;  
 n is from O to 4;  
 m is from 0 to 4;  
 W is:  
                     
 wherein:  
 A, G and M are independently oxygen, sulfur, CH 2 , CH—R a , C(R a )(R b ), NH or N—R a , wherein R a  and R b , are independently selected from alkyl, haloalkyl or aryl;  
 Y′ is NH, sulfur or CH;  
 Z is N or CH;  
 R 15  is hydrogen, alkyl, haloalkyl, aryl or aralkyl; and  
 R 14  is hydrogen, alkyl, haloalkyl or halogen.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  represents hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 6-10  aryl or C 6-10  ar(C 1-6 )alkyl.  
     
     
         3 . The compound of  claim 2 , wherein R 1  represents hydrogen, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, phenyl, benzyl or phenylethyl.  
     
     
         4 . The compound of  claim 1 , wherein R 2 , R 3  and R 4  independently represent hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 6-10  aryl, or C 6-10  ar(C 1-6 )alkyl.  
     
     
         5 . The compound of  claim 1 , wherein R 2 , R 3  and R 4  are hydrogen, C 1-4  alkyl or C 1-4  haloalkyl.  
     
     
         6 . The compound of  claim 1 , wherein R 10 , R 11 , R 12  and R 13  independently represent hydrogen, C 1-4  alkyl or C 1-4  haloalkyl.  
     
     
         7 . The compound of  claim 1 , wherein X is oxygen or CH 2 .  
     
     
         8 . The compound of  claim 1 , wherein W is  
       
         
           
           
               
               
           
         
       
       wherein: 
 A, G and M are independently oxygen, sulfur, CH 2 , CH—R a , C(R a )(R b ),NH or N—R a , wherein R a  and R b , are independently selected from C 1-6  alkyl, C 1-6  haloalkyl or C 6-10  aryl;  
 R 15  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl or C 6-10  ar(C 1-6 )alkyl; and  
 R 14  is hydrogen, C 1-4  alkyl or C 1-4  haloalkyl.  
 
     
     
         9 . The compound of  claim 1 , wherein R 5 , R 6 , R 7  and R 8  independently represent hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 3-6  cycloalkyl, C 6-10  aryl, C 6-10  ar(C 1-6 )alkyl, C 1-6  aminoalkyl, mono(C 1-4 )alkylamino(C 1-6 )alkyl, di(C 1-4 )alkylamino(C 1-6 )alkyl, carboxy (C 1-6 ) alkyl, hydroxy, C 1-6  alkoxy, mono(C 1-4 )alkylamino or di((C 1-4 )alkylamino.  
     
     
         10 . The compound of  claim 1 , wherein R 5  and R 6  are taken together to form —(CH 2 ) S — where s is zero or 1 to 4, and R 6  and R 8  are each hydrogen.  
     
     
         11 . The compound of the  claim 1 , wherein R 5  and R 6  are taken together to form —(CH 2 )— t , where t is 2 to 5 and R 7  and R 8  are each hydrogen.  
     
     
         12 . The compound of  claim 1 , wherein i and j are 0.  
     
     
         13 . The compound of  claim 12 , wherein k is 1.  
     
     
         14 . The compound of  claim 1 , wherein R 9  is hydrogen.  
     
     
         15 . The compound of  claim 1 , wherein i and j are each zero; k is one; R 5 , R 6  and R 7  are each hydrogen; and R 8  is hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 6-10  aryl or C 6-10  ar(C 1-4 )alkyl.  
     
     
         16 . The compound of  claim 1 , wherein 
 R 1  is hydrogen or —CH 3 ;    R 2 , R 3 , R 4 , R 10 , R 11 , R 12  and R 13  are hydrogen; X is oxygen or CH 2 ;    n is 0 or 1;    m is 0 or 1;    R 5 , R 6 , R 7  and R 8  independently represent hydrogen, C 1-6  alkyl, C 1-6  haloalkyl or C 6-10  aralkyl;    or one of the combination R 5  and R 7 , R 6  and R 8 , or R 7  and R 8  are taken together to form —(CH 2 ) S —, —(CH)t—, or —(CH2)u—, wherein s t, or u is 1 while the remaining R 5 -R 8  are defined above;    i is 0 or 1;    j is 0 or 1;    k is 0 or 1;    R 9  is hydrogen or alkyl;    W is:                          wherein:    A, G and M are independently oxygen, sulfur, CH 2 , CH—R a , C(R a )(R b ), NH or N—R a , wherein R a  and R b , are independently selected from C 1-6  alkyl, C 1-6 haloalkyl or C 6-10  aryl;    R 15  is C 6-10  ar(C 1-6 )alkyl; and    R 14  is hydrogen, C 1-4 alkyl or C 1-4  haloalkyl.    
     
     
         17 . The compound of  claim 1 , which is one of: 
 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoic acid;    3-quinolin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphhthyridin-2-yl)-]-benzofuran-3-yl}-propionic acid;    3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzofuran-3-yll}-3-quinolin-3-yl-propionic acid;    3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-(2,3-dihyclro-benzofuran-6-yl)-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-benzo[1,3]dioxol-5-yl-3-{6-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-benzo[1,3]dioxol-5-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-benzo[1,3]dioxol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-pyridin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;    3-(5-aryl-pyridin-3-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.    
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         19 . A method of treating a pathological condition selected from the group consisting of tumor growth, metastasis, osteoporosis, restenosis, inflammation, macular degeneration, diabetic retinopathy, rheumatoid arthritis, and sickle cell anemia, in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of  claim 1 .  
     
     
         20 . The method of  claim 19 , wherein said condition is tumor growth.  
     
     
         21 . The method of  claim 19 , wherein said condition is osteoporosis.  
     
     
         22 . The method of  claim 19 , wherein said condition is restenosis.  
     
     
         23 . The method of  claim 19 , wherein said condition is inflammation.  
     
     
         24 . The method of  claim 19 , wherein said condition is macular degeneration.  
     
     
         25 . The method of  claim 19 , wherein said condition is diabetic retinopathy.  
     
     
         26 . The method of  claim 19 , wherein said condition is rheumatoid arthritis.  
     
     
         27 . The method of  claim 19 , wherein said condition is sickle cell anemia.  
     
     
         28 . A process for preparing a compound of  claim 1 , comprising: reading a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , i, j and k are as defined in  claim 1 , 
 with a compound of Formula III:  
                     
 or a salt, hydrate or solvate thereof, wherein R 14  is as defined in  claim 1 , to form a compound of  claim 1 .  
 
     
     
         29 . A process for preparing compound of  claim 1 , comprising: reacting a compound of Formula II.  
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 , i, j and k are as defined in  claim 1 , 
 with a compound of Formula IV:  
                     
 or a salt, hydrate or solvate thereof, wherein R 10 , R 11 , R 12 , R 13 , R 14 , m and n are as defined in  claim 1 , to form a compound of  claim 1 .  
 
     
     
         30 . A process for preparing a compound of  claim 1 , comprising: reacting a compound of Formula V:  
       
         
           
           
               
               
           
         
       
       or a salt, hydrate or solvate thereof, wherein 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , i, j, k, m and n are as defined in  claim 1 ,  
 with R 15 NCO, where R 15  is as defined in  claim 1 , to form a compound of  claim 1 .  
 
     
     
         31 . A method for treating a central nervous system (CNS) related disorder, selected from the group consisting of: neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, surgery, a neurodegenerative disease, an adverse consequence of overstimulation of one or more excitatory amino acids, anxiety, convulsions, chronic pain, psychosis, anesthesia, and opiate tolerance, in a mammal in need of such treatment, comprising administering to said mammal an effective amount of a compound of  claim 1 .  
     
     
         32 . The method according to  claim 31 , wherein said CNS related disorder is neuronal loss associated with stroke.  
     
     
         33 . The method according to  claim 31 , wherein said CNS related disorder is ischemia.  
     
     
         34 . The method according to  claim 31 , wherein said CNS related disorder is CNS trauma.  
     
     
         35 . The method according to  claim 31 , wherein said CNS related disorder is hypoglycemia.  
     
     
         36 . The method according to  claim 31 , wherein said CNS related disorder is the result of surgery.  
     
     
         37 . The method according to  claim 31 , wherein said CNS related disorder is a neurodegenerative disease.  
     
     
         38 . The method according to  claim 37 , wherein said neurodegenerative disease is selected from Alzheimer's disease or Parkinson's disease.  
     
     
         39 . The method according to  claim 31 , wherein said CNS related disorder results from the adverse consequence of an overstimulation of one or more excitatory amino acids.  
     
     
         40 . The method according to  claim 31 , wherein said CNS related disorder is schizophrenia.  
     
     
         41 . The method according to  claim 31 , wherein said CNS related disorder is anxiety.  
     
     
         42 . The method according to  claim 31 , wherein said CNS related disorder is convulsions.  
     
     
         43 . The method according to  claim 31 , wherein said CNS related disorder is chronic pain.  
     
     
         44 . The method according to  claim 31 , wherein said CNS related disorder is psychosis.  
     
     
         45 . The method according to  claim 31 , wherein said CNS related disorder is anesthesia.  
     
     
         46 . The method according to  claim 31 , wherein said CNS related disorder is opiate tolerance.