Substituted aromatic compounds and pharmaceutical compositions for the prevention and treatment of osteoporosis

Abstract

The present invention concerns the use of compounds for preventing and/or treating osteoporosis, for stimulating bone formation, for stimulating bone remodeling, for stimulating the differentiation and mineralization of osteoblasts, for inhibiting bone resorption and for modulating serum level of adiponectin in a subject. These uses have been found for compounds represented by Formula I and pharmaceutically acceptable salts thereof. wherein A is C 5 alkyl, C6 alkyl, C 5 alkenyl, C 6 alkenyl, C(O)—(CH 2 ) n —CH 3 or CH(OH)—(CH 2 ) n —CH 3 wherein n is 3 or 4; R 1 is H, F or OH; R 2 is H, F, OH, C6 alkyl, C 5 alkenyl, C 6 alkenyl, C(O)—(CH 2 ) n —CH 3 or CH(OH)—(CH 2 ) n —CH 3 wherein n is 3 or 4; R 3 is H, F, OH or CH 2 Ph; R 4 is H, F, or OH; Q is 1) (CH 2 ) m C(O)OH wherein m is 1 or 2, 2) CH(F)—C(O)OH, 3) CF 2 —C(O)OH or 4) C(O)—C(O)OH.

1 - 34 . (canceled) 
     
     
         35 . A method for the prevention and/or treatment of osteoporosis, comprising the step of administering to a subject in need thereof a compound represented by Formula I or a pharmaceutical acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         A is C 5  alkyl, C 6  alkyl, C 5  alkenyl, C 6  alkenyl, C(O)—(CH 2 ) n —CH 3  or CH(OH)—(CH 2 ) n —CH 3  wherein n is 3 or 4; 
         R 1  is H, F or OH; 
         R 2  is H, F, OH, C 5  alkyl, C 6  alkyl, C 5  alkenyl, C 6  alkenyl, C(O)—(CH 2 ) n —CH 3  or CH(OH)—(CH 2 ) n —CH 3  wherein n is 3 or 4; 
         R 3  is H, F, OH or CH 2 Ph; 
         R 4  is H, F or OH; and 
         Q is
 1) (CH 2 ) m C(O)OH wherein m is 1 or 2, 
 2) CH(F)—C(O)OH, 
 3) CF 2 —C(O)OH, or 
 4) C(O)—C(O)OH. 
 
       
     
     
         36 . The method of  claim 35 , wherein A is C 5  alkyl or C 6  alkyl. 
     
     
         37 . The method of  claim 35 , wherein R 2  is H, F, OH, C 5  alkyl or C 6  alkyl. 
     
     
         38 . The method of  claim 35 , wherein R 3  is H, OH or CH 2 Ph. 
     
     
         39 . The method of  claim 35 , wherein Q is (CH 2 ) m C(O)OH where m is 1 or 2. 
     
     
         40 . The method of  claim 35 , wherein:
 A is C 5  alkyl or C 6  alkyl;   R 2  is H, F, OH, C 5  alkyl or C 6  alkyl;   R 3  is H, OH or CH 2 Ph; and   Q is (CH 2 ) m C(O)OH where m is 1 or 2.   
     
     
         41 . The method of  claim 35 , wherein:
 A is C 5  alkyl;   R 1  is H;   R 2  is H or C 5  alkyl;   R 3  is H;   R 4  is H; and   Q is (CH 2 ) m C(O)OH where m is 1.   
     
     
         42 . The method of  claim 35 , wherein said compound is selected from the group consisting of the compounds represented by the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutical acceptable salts thereof. 
       
     
     
         43 . The method of  claim 42 , wherein said compound is represented by the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutical acceptable salt thereof. 
       
     
     
         44 . The method of  claim 42 , wherein said compound is represented by the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutical acceptable salt thereof. 
       
     
     
         45 . The method of  claim 35 , wherein the pharmaceutically acceptable salt is a base addition salt comprising a metal counterion selected from the group consisting of sodium, potassium, calcium, magnesium lithium, ammonium, manganese, zinc, iron, or copper. 
     
     
         46 . The method of  claim 45 , wherein the pharmaceutically acceptable salt is sodium. 
     
     
         47 . The method of  claim 35 , wherein the osteoporosis is selected from the group consisting of post-menopausal osteoporosis (primary type 1), primary type 2 osteoporosis, secondary osteoporosis abnormally high osteoclastogenesis, osteomalacia-like osteoporosis, osteopenia, osteogenesis imperfecta, osteopetrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia and combinations thereof. 
     
     
         48 . The method of  claim 47 , wherein osteoporosis is post-menopausal osteoporosis (primary type 1), primary type 2 osteoporosis or secondary osteoporosis. 
     
     
         49 . The method of  claim 47 , wherein osteoporosis is post-menopausal osteoporosis (primary type 1). 
     
     
         50 . The method of  claim 35 , wherein administration of said compound results in one or more of the following biological activities in the subject:
 inhibition of osteoclastogenesis;   reduction of osteoclastogenesis;   stimulation of interleukin-12 (IL-12) production in bone;   reduction of acid phosphatase activity in bone;   reduction of Receptor activator of NF-κB ligand/Osteoprotegerin ratio (RANKL/OPG ratio) in bone;   increase of collagen content in bone; and   modulation of the serum level of adiponectin.   
     
     
         51 . A method for preventing and/or reducing bone loss, comprising the step of administering to a subject in need thereof a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 . 
     
     
         52 . The method of  claim 51 , wherein said compound reduces loss of calcium. 
     
     
         53 . The method of  claim 51 , wherein the subject is afflicted by or susceptible of osteoporosis. 
     
     
         54 . The method of  claim 35 , wherein the subject is a postmenopausal woman. 
     
     
         55 . A method for inhibiting osteoclastogenesis, comprising contacting an osteoclast precursor cell with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 , wherein said compound inhibits differentiation of the precursor cell into an osteoclast cell. 
     
     
         56 . A method for stimulating interleukin-12 (IL-12) production by a stimulated osteoclast precursor cell, comprising contacting said stimulated osteoclast precursor cell with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 , wherein an increased IL-12 production is measurable in presence of said compound. 
     
     
         57 . A method for reducing acid phosphatase activity in bone cells comprising contacting said bone cells with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 , wherein a reduced phosphatase activity is measurable in presence of said compound. 
     
     
         58 . A method for reducing expression and/or activity of receptor activator of NF-κB ligand/Osteoprotegerin ratio (RANKL/OPG ratio) in bone cells, comprising contacting said bone cells with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 . 
     
     
         59 . A method for increasing collagen content in bone, comprising contacting said bone with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 . 
     
     
         60 . A method for stimulating bone formation and/or for stimulating bone remodeling and/or for stimulating the differentiation and mineralization of osteoblasts and/or for inhibiting bone resorption, comprising contacting osteoblasts in said bone with a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 . 
     
     
         61 . A method for modulating serum level of adiponectin in a subject, comprising the step of administering to a subject in need thereof a compound represented by Formula I or a pharmaceutical acceptable salt thereof as defined in  claim 35 . 
     
     
         62 . The method of  claim 61 , wherein the compound is selected from the group consisting of the compounds represented by the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutical acceptable salt thereof. 
       
     
     
         63 . The method of  claim 61 , wherein said compound is represented by the following structure: 
       
         
           
           
               
               
           
         
         or pharmaceutical acceptable salt thereof. 
       
     
     
         64 . The method of  claim 61 , wherein the subject is obese and/or diabetic. 
     
     
         65 . The method of  claim 35 , further comprising the step of administering concomitantly a drug selected from the group consisting of: bisphosphonates, Odanacatib, Alendronate, Risedronate, Etidronate, Zoledronate, Pamidronate, Teriparatide, Tamoxifen, Raloxifene, and Denosumab.