Indole derivatives for the treatment of osteoporosis

Abstract

A compound of formula (I): or a salt thereof, or a solvate thereof, wherein Ra represents a group R 5 which is hydrogen, alkyl or optionally substituted aryl and Rb represents a moiety of formula (a):  wherein X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR s R t wherein R s and R t each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s and R t together with the nitrogen to which they are attached form a heterocyclic group; RI represents an alkyl or a substituted or unsubstituted aryl group; and R 2 , R 3 and R 4 each independently represent hydrogen, alkyl, aryl or substituted aryl R 6 and R 7 each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R 6 and R 7 together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and R 8 represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine

1 . A selective inhibitor of the biological activity of human osteoclast cells, providing that such an inhibitor does not include any specific Example disclosed in WO 96/21644.  
     
     
         2 . An inhibitor according to  claim 1 , which is selective for the vacuolar H + -ATPase located on the ruffled border of human osteoclasts.  
     
     
         3 . An inhibitor according to  claim 1  or  claim 2 , which interacts specifically with the 16 kDa subunit or the 116 kDa subunit of the vacuolar H + -ATPase located on the ruffled border of human osteoclasts.  
     
     
         4 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a salt thereof, or a solvate thereof, wherein: 
 Ra represents a group R 5  which is hydrogen, alkyl or optionally substituted aryl and Rb represents a moiety of formula (a):  
                     
  wherein X represents a hydroxy or an alkoxy group wherein the alkyl group may be substituted or unsubstituted or X represents a group NR s R t  wherein R s  each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s  and R t together with the nitrogen to which they are attached form a heterocyclic group; R 1  represents an alkyl or a substituted or unsubstituted aryl group; and R 2 , R 3  and R 4  each independently represent hydrogen, alkyl, aryl or substituted aryl  
 R 6  and R 7  each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifloromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl alkylcarbamoyl, or R 6  and R 7  together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and  
 R 8  represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or aminosulphonyl; providing that such an inhibitor does not include any specific Example disclosed in WO 96/21644.  
 
     
     
         5 . A compound according to  claim 4 , wherein R 1  represents methyl.  
     
     
         6 . A compound according to  claim 4  or  claim 5 , wherein R 2 , R 3  and R 4  each independently represent hydrogen, alkyl or phenyl.  
     
     
         7 . A compound according to any one of  claims 4  to  6 , wherein R 5  is hydrogen.  
     
     
         8 . A compound according to any one of  claims 4  to  7 , wherein R 6  and R 7  are hydrogen, halo, trifluoromethyl and alkoxy.  
     
     
         9 . A compound according to any one of  claims 4  to  8 , wherein R 6  is 5-chloro and R 7  is 6-chloro.  
     
     
         10 . A compound according to any one of  claims 4  to  9 , wherein R 8  represents hydrogen.  
     
     
         11 . A compound according to any one of  claims 4  to  10 , wherein X represents NR s R t .  
     
     
         12 . A compound according to  claim 11 , wherein R s  and R t  each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, 
 optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group.    
     
     
         13 . A compound according to claims  11  or  12 , wherein R s  and R t  together represent a heterocyclic group.  
     
     
         14 . A compound according to  claim 13 , wherein R s  and R t  together represent is a moiety of formula (H1):  
       
         
           
           
               
               
           
         
       
       wherein Z 1  is N or CX 5  wherein X 5  is selected from hydrogen, alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl and Z 2 , X 3  and X 4  are each independently selected from hydrogen, alkyl, aryl, cyano, amino, heterocyclyloxy, alkoxy carbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy, aminoalkylamino, aminoalkenylamino (especially aminomethyleneamino) and alkanoylamino.  
     
     
         15 . A compound according to  claim 13 , wherein R s  and R t  together represent a group of formula (H2):  
       
         
           
           
               
               
           
         
       
       wherein X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12  and X 13  are each independently selected from hydrogen, hydroxy, alky, suitably C 1-6  alkyl, cycloalkyl (suitably spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionally alkylated or acylated at nitrogen); 
 or one of X 6  with X 12  and X 8  with X 10  represents a C 2-4  alkylene chain and the remaining variables X 7 , X 13 , X 9  and X 11  each independently represent hydrogen, hydroxy, alkyl , suitably C 1-6  alkyl, cycloalkyl (suitably spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionally alkylated or acylated at nitrogen); and X 14  represents hydrogen or lower alkyl, mono or polyhydroxyalkyl, mono or diaminoalkyl, aminocarbonyl, alkyl, carboxyalkyl, carbalkoxyalkyl, aryl, heterocyclyl, acyl, carbamoyl, alkylamino(cyanimidoyl), aminoalkanoyl, hydroxyalkanoyl.  
 X 6 , X 7 , X 12  and X 13  each represent hydrogen.  
 
     
     
         16 . A compound according to  claim 15 , wherein X 8 , and X 9  each independently represent hydrogen or alkyl.  
     
     
         17 . A compound according to  claim 15 , wherein X 10  and X 11  each independently represent hydrogen or alkyl.  
     
     
         18 . A compound according to  claim 15 , wherein X 14  represents alkyl  
     
     
         19 . A compound according to  claim 15 , wherein X 8 , X 9 , X 10  and X 11  each independently represent methyl and X 6 , X 7 , X 12  and X 13  each represent hydrogen.  
     
     
         20 . A compound according to  claim 1 , wherein R 1  is C 1-6  alkyl, R 2 , R 3 , R 4  and R 8  are hydrogen, R 6  is 5-halo, R 7  is 6-halo, and X is a moiety NR s R t  wherein R t  is hydrogen and R s  is a moiety of formula (f) or a moiety (H1) or (H2).  
     
     
         21 . A compound according to  claim 1 , being selected from any one of examples 1 to 79; or a salt thereof, or a solvate thereof.  
     
     
         22 . A compound according to  claim 1 , being selected from examples, 31, 32 34, 35, 47, 51, 55, 56, 59, 68 and 74; or a salt thereof, or a solvate thereof.  
     
     
         23 . A process for the preparation of a compound of formula (I) or a salt thereof or a solvate thereof, which process comprises reacting a compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein R 2 , R 3 , R 4,  R 6,  R 7  and R 8  are as defined in relation to formula (I), with a reagent capable of converting a moiety of formula  
       
         
           
           
               
               
           
         
       
       into a moiety of the above defined formula (a); and thereafter, as necessary, carrying out one or more of the following reactions: 
 (i) converting one compound of formula (I) into another compound of formula (I);  
 (ii) removing any protecting group;  
 (iii) preparing a salt or a solvate of the compound so formed.  
 
     
     
         24  A pharmaceutical composition comprising a selective inhibitor of the pharmacological activity of human osteoclast cells according to  claim 1 , and a pharmaceutically acceptable carrier therefor.  
     
     
         25 . An inhibitor of a mammalian osteoclasts according to  claim 1 , for use as an active therapeutic substance.  
     
     
         26 . The use of a selective inhibitor of the biological activity of human osteoclast cells according to  claim 1 , for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with over activity of osteoclasts in mammals.  
     
     
         27 . A method for the treatment and/or prophylaxis of diseases associated with over activity of osteoclasts in mammals which method comprises the administration of an effective non-toxic, pharmaceutically amount of a selective inhibitor of mammalian osteoclasts according to  claim 1.