USE OF HDAC INHIBITORS FOR THE TREATMENT OF BONE DESTRUCTION

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Patent No.: US None
App. No.: 13/195,897

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Abstract

The present invention relates to the use of HDAC inhibitors for the treatment of bone destruction caused by cancer, inflammatory diseases and osteoporosis.

Claims (246)

1 . A method of treating a patient suffering from bone destruction cause by a proliferative disease comprising administering to the patient an effective amount of a HDAC inhibitor.

2 . The method of claim 1 , wherein the proliferative disease is selected from multiple myeloma, breast cancer, or prostate cancer.

3 . The method of claim 1 , wherein the HDAC inhibitor is 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 O, NR 13 , S and S(O);

or a pharmaceutically acceptable salt thereof.

4 . The method according to claim 1 , 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.

5 . A method of treating a patient suffering from bone destruction cause by an inflammatory disease comprising administering to the patient an effective amount of a HDAC inhibitor.

6 . The method of claim 5 , wherein the HDAC inhibitor is a compound of the formula (I):