Use of Hdac Inhibitors for the Treatment of Myeloma

Abstract

The present invention relates to the use of an HDAC inhibitor, especially an HDAC inhibitor of formula I, wherein the radicals and symbols have the meanings as defined in the specification, for the preparation of a medicament for the treatment of myeloma, in particular multiple myeloma, especially myeloma which is resistant to conventional chemotherapy; to a combination comprising an HDAC inhibitor and a compound effecting apoptosis of myeloma cells, preferably bortezomib, for simultaneous, separate or sequential use; to methods of treating myeloma; and to a pharmaceutical composition comprising said combination.

1 . The use of an HDAC inhibitor for the preparation of a medicament for the treatment of myeloma. 
     
     
         2 . Use according to  claim 1 , wherein the HDAC inhibitor is a compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H; halo; or a straight-chain C 1 -C 6 alkyl, especially methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for alkyl substituents; 
 R 2  is selected from H; C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, e.g., methyl, ethyl or —CH 2 CH 2 —OH; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 -C 9 heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; —(CH 2 ) n C(O)R 6 ; —(CH 2 ) n OC(O)R 6 ; amino acyl; HON—C(O)—CH═C(R 1 )-aryl-alkyl-; and —(CH 2 ) n R 7 ; 
 R 3  and R 4  are the same or different and, independently, H; C 1 -C 6 alkyl; acyl; or acylamino, or 
 R 3  and R 4 , together with the carbon to which they are bound, represent C═O, C═S or C═NR 8 , or 
 R 2 , together with the nitrogen to which it is bound, and R 3 , together with the carbon to which it is bound, can form a C 4 -C 9 heterocycloalkyl; a heteroaryl; a polyheteroaryl; a non-aromatic polyheterocycle; or a mixed aryl and non-aryl polyheterocycle ring; 
 R 5  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; acyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl; non-aromatic polyheterocycles; and mixed aryl and non-aryl polyheterocycles; 
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n 1  is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ; 
 X and Y are the same or different and independently selected from H; halo; C 1 -C 4 alkyl, such as CH 3  and CF 3 ; NO 2 ; C(O)R 1 ; OR 9 ; SR 9 ; CN; and NR 10 R 11 ; 
 R 6  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR 12 ; and NR 13 R 14 ; 
 R 7  is selected from OR 15 ; SR 15 ; S(O)R 16 ; SO 2 R 17 ; NR 13 R 14 ; and NR 12 SO 2 R 6 ; 
 R 8  is selected from H; OR 15 ; NR 13 R 14 ; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; 
 R 9  is selected from C 1 -C 4 alkyl, e.g., CH 3  and CF 3 ; C(O)-alkyl, e.g., C(O)CH 3 ; and C(O)CF 3 ; 
 R 10  and R 11  are the same or different and independently selected from H; C 1 -C 4 alkyl; and —C(O)-alkyl; 
 R 12  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 -C 9 heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; 
 R 13  and R 14  are the same or different and independently selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl; or 
 R 13  and R 14 , together with the nitrogen to which they are bound, are C 4 -C 9 heterocycloalkyl; heteroaryl; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle; 
 R 15  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; and (CH 2 ) m ZR 12 ; 
 R 16  is selected from C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH 2 ) m ZR 12 ; 
 R 17  is selected from C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; aromatic polycycles; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR 13 R 14 ; 
 m is an integer selected from 0-6; and 
 Z is selected from 0; NR 13 ; S; and S(O), 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . Use according to  claim 2 , wherein the compound of formula (I) is N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide having the formula (III) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . Use according to any one of  claims 1 - 3 , wherein the myeloma is resistant to conventional chemotherapy. 
     
     
         5 . Use according to any one of  claims 1 - 3 , wherein the warm-blooded animal is a human. 
     
     
         6 . Use according to any one of  claims 1 - 5 , wherein the disease is multiple myeloma. 
     
     
         7 . A method of treating myeloma comprising administering a therapeutically effective amount of an HDAC inhibitor to a warm-blooded animal in need thereof. 
     
     
         8 . Method according to  claim 7 , comprising administering a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H; halo; or a straight-chain C 1 -C 6 alkyl, especially methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for alkyl substituents; 
 R 2  is selected from H; C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, e.g., methyl, ethyl or —CH 2 CH 2 —OH; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 -C 9 heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; —(CH 2 ) n C(O)R 6 ; —(CH 2 ) n OC(O)R 6 ; amino acyl; HON—C(O)—CH═C(R 1 )-aryl-alkyl-; and —(CH 2 ) n R 7 ; 
 R 3  and R 4  are the same or different and, independently, H; C 1 -C 6 alkyl; acyl; or acylamino; or 
 R 3  and R 4 , together with the carbon to which they are bound, represent C═O, C═S or C═NR 8 ; or 
 R 2 , together with the nitrogen to which it is bound, and R 3 , together with the carbon to which it is bound, can form a C 4 -C 9 heterocycloalkyl; a heteroaryl; a polyheteroaryl; a non-aromatic polyheterocycle; or a mixed aryl and non-aryl polyheterocycle ring; 
 R 5  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; acyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl; non-aromatic polyheterocycles; and mixed aryl and non-aryl polyheterocycles; 
 n, n 1 , n 2  and n 3  are the same or different and independently selected from 0-6, when n 1  is 1-6, each carbon atom can be optionally and independently substituted with R 3  and/or R 4 ; 
 X and Y are the same or different and independently selected from H; halo; C 1 -C 4 alkyl, such as CH 3  and CF 3 ; NO 2 ; C(O)R 1 ; OR 9 ; SR 9 ; CN; and NR 10 R 11 ; 
 R 6  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR 12 ; and NR 13 R 14 ; 
 R 7  is selected from OR 15 ; SR 15 ; S(O)R 16 ; SO 2 R 17 ; NR 13 R 14 ; and NR 12 SO 2 R 6 ; 
 R 8  is selected from H; OR 15 ; NR 13 R 14 ; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; 
 R 9  is selected from C 1 -C 4 alkyl, e.g., CH 3  and CF 3 ; C(O)-alkyl, e.g., C(O)CH 3 ; and C(O)CF 3 ; 
 R 10  and R 11  are the same or different and independently selected from H; C 1 -C 4 alkyl; and —C(O)-alkyl; 
 R 12  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 -C 9 heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; 
 R 13  and R 14  are the same or different and independently selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl, or 
 R 13  and R 14 , together with the nitrogen to which they are bound, are C 4 -C 9 heterocycloalkyl; heteroaryl; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle; 
 R 15  is selected from H; C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; and (CH 2 ) m ZR 12 ; 
 R 16  is selected from C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH 2 ) m ZR 12 ; 
 R 17  is selected from C 1 -C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; aromatic polycycles; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR 13 R 14 ; 
 m is an integer selected from 0-6; and 
 Z is selected from O; NR 13 ; S; and S(O), 
 
       or a pharmaceutically acceptable salt thereof to a warm-blooded animal in need thereof. 
     
     
         9 . A method according to  claim 7  wherein the myeloma is multiple myeloma. 
     
     
         10 . A combination comprising an HDAC inhibitor and a compound effecting apoptosis of myeloma cells, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use. 
     
     
         11 . Combination according to  claim 10 , wherein the HDAC inhibitor is N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide having the formula (III) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . Combination according to  claim 10  or  11 , wherein the compound effecting apoptosis of myeloma cells is bortezomib. 
     
     
         13 . Combination according to any one of  claim 10  or  11 , for simultaneous, separate or sequential use in the treatment of myeloma. 
     
     
         14 . A method of treating myeloma comprising administering a combination as defined in  claim 10 , in an amount which is jointly therapeutically effective against myeloma to a warm-blooded animal in need thereof. 
     
     
         15 . A pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against myeloma, of a combination according to  claim 10  and at least one pharmaceutically acceptable carrier. 
     
     
         16 . A commercial package comprising an HDAC inhibitor and a compound effecting apoptosis of myeloma cells, together with instructions for simultaneous, separate or sequential use thereof in the treatment of myeloma.