Indomethacin analogs for the treatment of castrate-resistant prostate cancer

Abstract

Provided are compositions for inhibiting a biological activity of an aldo-keto reductase family 1, member C3 (AKR1C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

What is claimed is: 
     
         1 . A compound having one of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is selected from the group consisting of OH, OCH 3 , OCH 2 CH 3  and HNSO 2 X; 
 R2 is hydrogen or R- or S-C 1 -C 6  alkyl; 
 R3 is hydrogen or R- or S-C 1 -C 6  alkyl; 
 R4 is C 1  to C 6  alkyl; 
 R5 is hydrogen, C 1  to C 6  alkoxy or halogen; 
 R6 is C 1  to C 6  alkyl or C 1  to C 6  alkylcarboxylic acid or C 1  to C 6  alkyl-C(O)OR 12  or C 1  to C 6  alkyl-C(O)N(H)SO 2 X; 
 R7 is hydrogen or C 2  to C 6  alkyl or C 2  to C 6  alkylcarboxylic acid or C 2  to C 6  alkyl-C(O)OR 12  or C 2  to C 6  alkyl-C(O)N(H)SO 2 X; 
 R8 is hydrogen or R- or S-carboxylic acid or C(O)OR 12  or C(O)N(H)SO 2 X; 
 R9 is hydrogen or R- or S-carboxylic acid or C(O)OR 12  or C(O)N(H)SO 2 X; 
 the ring to which R8 or R9 are bound is cyclopentyl or cyclohexyl; 
 R10 is present in two, three, four, or five positions in the phenyl ring and each instance is independently selected from the group consisting of hydrogen, halogen, nitro, C 1  to C 6  alkyl, singly or multiply halogen substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, amino, and hydroxy; 
 X is methyl or singly or multiply halogen substituted methyl; 
 phenyl, optionally singly or multiply substituted phenyl or thiophenyl, wherein the single or multiple substitutions of the phenyl or thiophenyl are each independently selected from the group consisting of halogen, nitro, C 1  to C 6  alkyl, singly or multiply halogen substituted C 1  to C 6  alkyl, trifluoromethyl, acetyl, isopropyl, C 1  to C 6  alkoxy, trifluoromethyloxy, phenoxy, cyano, hydroxy, and amino; 
 Y and Z are each individually CH or N; 
 m and n are each individually 0 or 1. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . A method for producing an indomethacin derivative that substantially lacks cyclooxygenase inhibitory activity but that has aldo-keto reductase family 1, member C3 (AKR1C3) inhibitory activity, the method comprising modifying indomethacin, or a derivative or salt thereof, to produce a compound with one of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is selected from the group consisting of OH, OCH 3 , OCH 2 CH 3  and HNSO 2 X; 
 R2 is hydrogen or R- or S-C 1 -C 6  alkyl; 
 R3 is hydrogen or R- or S-C 1 -C 6  alkyl; 
 R4 is C 1  to C 6  alkyl; 
 R5 is hydrogen, C 1  to C 6  alkoxy or halogen; 
 R6 is C 1  to C 6  alkyl or C 1  to C 6  alkylcarboxylic acid or C 1  to C 6  alkyl-C(O)OR 12  or C 1  to C 6  alkyl-C(O)N(H)SO 2 X; 
 R7 is hydrogen or C 2  to C 6  alkyl or C 2  to C 6  alkylcarboxylic acid or C 2  to C 6  alkyl-C(O)OR 12  or C 2  to C 6  alkyl-C(O)N(H)SO 2 X; 
 R8 is hydrogen, R- or S-carboxylic acid or C(O)OR 12  or C(O)N(H)SO 2 X; 
 R9 is hydrogen, R- or S-carboxylic acid or C(O)OR 12  or C(O)N(H)SO 2 X; 
 the ring to which R8 or R9 are bound is cyclopentyl or cyclohexyl; 
 R10 is present in two, three, four, or five positions in the phenyl ring and each instance is independently selected from the group consisting of hydrogen, halogen, nitro, C 1  to C 6  alkyl, singly or multiply halogen substituted C 1  to C 6  alkyl, C 1  to C 6  alkoxy, amino, and hydroxy; 
 X is methyl or singly or multiply halogen substituted methyl; phenyl, optionally singly or multiply substituted phenyl or thiophenyl, wherein the single or multiple substitutions of the phenyl or thiophenyl are each independently selected from the group consisting of halogen, nitro, C 1  to C 6  alkyl, singly or multiply halogen substituted C 1  to C 6  alkyl, trifluoromethyl, acetyl, isopropyl, C 1  to C 6  alkoxy, trifluoromethyloxy, phenoxy, cyano, hydroxy, and amino; 
 Y and Z are each individually CH or N; 
 m and n are each individually 0 or 1. 
 
     
     
         4 . The method of  claim 3 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A method for producing an indomethacin derivative that substantially lacks cyclooxygenase inhibitory activity but that has aldo-keto reductase family 1, member C3 (AKR1C3) inhibitory activity, the method comprising performing a microwave-assisted reaction between (a) a C 1  to C 6  alkoxy- or halo-substituted phenylhydrazine or salt thereof and (b) a cyclic or acyclic aliphatic ketoacid or alkyl ester thereof thereby providing an indole alkyl carboxylic acid or ester thereof, wherein the indole alkyl carboxylic acid or ester is a synthetic precursor of the indomethacin derivative. 
     
     
         6 . The method of  claim 5 , wherein the microwave-assisted reaction is performed in the presence of sulfuric acid. 
     
     
         7 . The method of  claim 5 , wherein the microwave-assisted reaction is performed in an alcoholic solvent, preferably methanol. 
     
     
         8 . The method of  claim 5 , wherein the C 1  to C 6  alkoxy- or halo-substituted phenylhydrazine or salt thereof is a compound of Formula V: 
       
         
           
           
               
               
           
         
       
       wherein R11 is C 1  to C 6  alkoxy or halogen and Z is halogen, optionally Cl. 
     
     
         9 . The method of  claim 5 , wherein the cyclic or acyclic aliphatic ketoacid or alkyl ester thereof is a compound of Formula VI or Formula VII: 
       
         
           
           
               
               
           
         
       
       wherein:
 R11 is C 1 -C 6  alkyl; 
 R12 is H, methyl or ethyl; 
 q is an integer from 0 to 2; and 
 n is 0 or 1. 
 
     
     
         10 . The method of  claim 9 , wherein the cyclic or acyclic aliphatic ketoacid or alkyl ester thereof is selected from the group consisting of 3-oxopentanoic acid, 4-oxobutanoic acid, 4-oxopentanoic acid, 5-oxohexanoic acid, 4-oxohexanoic acid, 4-oxoheptanoic acid, 4-oxocyclohexanecarboxylic acid, 3-oxocyclohexanecarboxylic acid or a methyl or ethyl ester thereof. 
     
     
         11 . The method of  claim 5 , wherein the indole alkyl carboxylic acid or ester has a structure of one of Formula VIII or Formula IX: 
       
         
           
           
               
               
           
         
       
       wherein:
 R5 is hydrogen, C 1  to C 6  alkoxy or halogen; 
 R6 is C 1  to C 6  alkyl or C 1  to C 6  alkylcarboxylic acid or C 1  to C 6  alkyl-C(O)OR 12 ; 
 R7 is C 2  to C 6  alkylcarboxylic acid or C 2  to C 6  alkyl-C(O)OR 12 ; 
 R12 is H, methyl or ethyl; and 
 n is 0 or 1. 
 
     
     
         12 . The method of  claim 5 , further comprising reacting the indole alkyl carboxylic acid or ester thereof with an aliphatic or aromatic acid halide to introduce an acyl substituent at the indole nitrogen atom, thereby providing a N-acylated indole alkyl carboxylic acid or ester thereof. 
     
     
         13 . The method of  claim 12 , wherein the reacting is performed by contacting the indole alkyl carboxylic acid or ester with an alkoxide, preferably sodium or potassium tert-butoxide, thereby deprotonating the indole nitrogen atom; and contacting the deprotonated indole alkyl carboxylic acid or ester with the aliphatic or aromatic acid halide. 
     
     
         14 . The method of  claim 13 , wherein one or both of the contacting steps are performed in tetrahydrofuran (THF). 
     
     
         15 . The method of  claim 12 , wherein the aliphatic or aromatic acid halide is an acid chloride. 
     
     
         16 . The method of  claim 15 , wherein the acid chloride is selected from the group consisting of 4-chlorobenzoyl chloride, 4-fluorobenzoyl chloride, 3-(trifluoromethyl)benzoyl chloride, 4-(trifluoromethyl)benzoyl chloride, 4-methoxybenzoyl chloride, 4-methylbenzoyl chloride. 4-(chloromethyl)benzoyl chloride, and 2-(4-chlorophenylacetyl chloride. 
     
     
         17 . The method of  claim 12 , further comprising hydrolysis of an ester group in an N-acylated indole alkyl carboxylic ester to provide a N-acylated indole alkyl carboxylic acid. 
     
     
         18 . The method of  claim 17 , wherein the hydrolysis is performed using trimethyltin hydroxide and microwave radiation. 
     
     
         19 . The method of  claim 18 , wherein the hydrolysis is performed using 1,2-dichloroethane as a solvent.