Histone Deacetylase 6 Selective Inhibitors for the Treatment of Bone Disease

Abstract

This invention relates to methods for treating bone disease associated with osteoclast activation using HDAC6 selective inhibitors, e.g., small molecule inhibitors such as reverse amide compounds.

1 .- 16 . (canceled) 
     
     
         17 . A method of treating, or reducing risk of, a bone disorder associated with abnormally high bone catabolism selected from the group consisting of osteoporosis, Paget's disease, and bone metastasis in breast, lung, and prostate cancers in a subject, the method comprising administering to the subject a therapeutically effective amount of a reverse amide compound of formula IVa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         ring B is phenyl; 
         R 1  is phenyl, which may be optionally substituted by OH or halo; and 
         R is H or C1-8-alkyl. 
       
     
     
         18 . The method of  claim 17 , wherein the reverse amide compound is 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, (Compound A): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 17 , wherein the abnormally high bone catabolism is associated with increased osteoclastogenesis in the subject, decreased osteoblastogenesis in the subject, increased osteoclast activity in the subject, decreased osteoblast activity in the subject, an imbalance of osteoclastogenesis and osteoblastogenesis in the subject, or an imbalance of osteoclast and osteoblast activity in the subject. 
     
     
         20 . The method of  claim 17 , further comprising administering an additional active agent selected from the group consisting of bisphosphonates, RANKL inhibitors, bortezomib, Carfilzomib, lenalidomide, and Pomalidomide. 
     
     
         21 . The method of  claim 17 , further comprising administering a bisphosphonate. 
     
     
         22 . The method of  claim 17 , wherein the bone disorder associated with abnormally high bone catabolism is Paget's disease. 
     
     
         23 . The method of  claim 17 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in breast cancer, lung, and prostate cancers. 
     
     
         24 . The method of  claim 17 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in lung cancer. 
     
     
         25 . The method of  claim 17 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in prostate cancer. 
     
     
         26 . A method of treating a bone disorder associated with abnormally high bone catabolism selected from the group consisting of osteoporosis, Paget's disease, and bone metastasis in breast, lung, and prostate cancers in a subject, the method comprising administering to the subject a therapeutically effective amount of a reverse amide compound of formula IVa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         ring B is phenyl; 
         R 1  is phenyl, which may be optionally substituted by OH or halo; and 
         R is H or C1-8-alkyl. 
       
     
     
         27 . The method of  claim 26 , wherein the reverse amide compound is 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, (Compound A): 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 26 , wherein the abnormally high bone catabolism is associated with increased osteoclastogenesis in the subject, decreased osteoblastogenesis in the subject, increased osteoclast activity in the subject, decreased osteoblast activity in the subject, an imbalance of osteoclastogenesis and osteoblastogenesis in the subject, or an imbalance of osteoclast and osteoblast activity in the subject. 
     
     
         29 . The method of  claim 26 , further comprising administering an additional active agent selected from the group consisting of bisphosphonates, RANKL inhibitors, bortezomib, Carfilzomib, lenalidomide, and Pomalidomide. 
     
     
         30 . The method of  claim 26 , further comprising administering a bisphosphonate. 
     
     
         31 . The method of  claim 26 , wherein the bone disorder associated with abnormally high bone catabolism is Paget's disease. 
     
     
         32 . The method of  claim 26 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in breast cancer, lung, and prostate cancers. 
     
     
         33 . The method of  claim 26 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in lung cancer. 
     
     
         34 . The method of  claim 26 , wherein the bone disorder associated with abnormally high bone catabolism is bone metastasis in prostate cancer.