Indole derivatives and their use for the treatment of osteoporosis amongst other applications

Abstract

A compound of formula (I) or a salt thereof, or a solvate thereof, wherein: R 1 and R 2 each independently represents C 1-6 alkoxy or halo; R 3 and R 4 each independently represents hydrogen, C 1-6 alkoxy, arylC 1-6 alkoxy, hydroxy, carboxyC 1-6 alkoxy, hydroxyC 1-6 alkoxy, dihydroxyC 1-6 alkoxy, mono- and di-(C 1-6 alkyl)aminoC 1-6 alkoxy or aminoC 1-6 alkoxy, and R 5 represents —NR s R t wherein R s and R t each independently represent hydrogen, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted heterocyclyl, a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of the compound or composition in medicine. Particular indole compounds are selective for mammalian osteoclasts, acting to selectively inhibit their bone resorbing activity. These compounds are therefore considered to be particularly useful for the treatment and/or prophylaxis of diseases associated with loss of bone mass, such as osteoporosis and related osteopenic diseases, Paget's disease, hyperparathyroidism and related diseases. These compounds are also considered to possess antitumour activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses), antiulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by Helicobacter pylori ), immunosuppressant activity, antilipidemic activity, antiatherosclerotic activity and to be useful for the treatment of AIDS and Alzheimer's disease. Furthermore, these compounds are also considered useful in inhibiting angiogenesis, i.e., the formation of new blood vessels which is observed in various types of pathological conditions (angiogenic diseases) such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours.

1 . A method for the treatment of tumors, in a human or non-human animal, which comprises administering an effective, non-toxic, amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein; 
 R 1  and R 2  each independently represents C 1-6 alkoxy or halo;  
 R 3  and R 4  each independently represents hydrogen, C 1-6 alkoxy, arylC 1-6 alkoxy, hydroxy, carboxyC 1-6 alkoxy, hydroxyC 1-6 alkoxy, dihydroxyC 1-6 alkoxy, mono- and di-(C 1-6 alkyl)aminoC 1-6 alkoxy or aminoC 1-6 alkoxy and;  
 R 5  represents —NR s R t  wherein R s  and R t  each independently represent hydrogen, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted heterocyclyl;  
 or a salt thereof or a solvate thereof, to a human or non-human mammal in need thereof.  
 
     
     
         2 . A method according to  claim 1  wherein said tumor is selected from leukemia and solid tumors.  
     
     
         3 . A method according to  claim 2 , wherein said solid tumor is selected from renal cancer, melanoma, colon cancer, and lung cancer.  
     
     
         4 . A method according to  claim 1 , wherein R 4  is hydrogen or methoxy.  
     
     
         5 . A method according to  claim 1 , wherein R s  or R t  represent unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted heterocyclyl.  
     
     
         6 . A method according to  claim 1 , wherein R s  or R t  represent 3-[4-(3-methoxyphenyl)piperazin-1-yl]propyl or 3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl.  
     
     
         7 . A method according to  claim 1  wherein R s  or R t  represent an unsubstituted or substituted piperidinyl group.  
     
     
         8 . A method according to  claim 1 , wherein R s  or R t  represent a 1,2,2,6,6-pentamethylpiperidin-4-yl group or a 2,2,6,6-tetramethylpiperidin-4-yl group.  
     
     
         9 . A method according to  claim 1 , wherein R t  is hydrogen.  
     
     
         10 . A method according to  claim 1  wherein R s  is 3-[4-(3-methoxyphenyl)piperazin-1-yl]propyl or 3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl, and R t  is hydrogen or a salt thereof or a solvate thereof.  
     
     
         11 . A method according to  claim 1  wherein R s  is 3-pyridyl or 3-(6-methoxy)pyridyl, and R t  is hydrogen or a salt thereof or a solvate thereof.  
     
     
         12 . A method according to  claim 1  wherein R s  is 2,2,6,6-tetramethylpiperidin-4-yl, R t  is hydrogen, R 3  is 3-ethoxy, and R 1  is 5-chloro or 5-methoxy or a salt thereof or a solvate thereof.  
     
     
         13 . A method according to  claim 1  wherein R s  is 2,2,6,6-tetramethylpiperidin-4-yl, R t  is hydrogen, R 3  is 2-methoxy, 3-methoxy, 3-ethoxy, 3-propoxy, 3-benzyloxy, 3-(2-carboxyethoxy), 3-(2-hydroxyethoxy), 3-(2,3-dihydroxypropoxy), 3-(2-dimethylaminoethoxy) or 3-(3-aminopropoxy) and 3-hydroxy and R 4  is 5-methoxy or hydrogen or a salt thereof or a solvate thereof.  
     
     
         14 . A method according to  claim 1  wherein R s  is 1,2,2,6,6-pentamethylpiperidin-4-yl, R t  is hydrogen, R 3  is 2-methoxy or 3-ethoxy, and R 4  is 5-methoxy or hydrogen or a salt thereof or a solvate thereof.  
     
     
         15 . A method according to  claim 1  wherein; 
 R s  is 1-benzylpiperidin-4-yl, 1-(4-ethoxycarbonyl)butylpiperydin-4-yl, 1-(4-hydroxycarbonyl)butylpiperydin-4-yl and R t  is hydrogen or a salt thereof or a solvate thereof.  
 
     
     
         16 . A method according to  claim 1 , wherein said compound of formula (I) is selected from the group consisting of: 
 4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-3-benzyloxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-3-hydroxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-3-propoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-[3-[4-(3-methoxyphenyl)piperazin-1-yl]propyl]-3-methoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-[3-[4-(2-pyrimidyl)piperazin-1-yl]propyl]-3-methoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-methoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3-ethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(3-pyridyl)-3-ethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(3-(6-methoxypyridyl))-3-ethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(1-benzylpiperidin-4-yl)-3-ethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-2,5-dimethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,5-dimethoxybenzamide;    4-(5-methoxy-6-chloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-ethoxybenzamide;    4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-((1-ethoxycarbonylpentyl)piperidin-4-yl)-benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-3-methoxy-N-((carboxybutyl)piperidin-4-yl)benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-(hydroxycarbonylmethoxy)benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-(2-hydroxy-ethoxy)benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetraethylpiperidin-4-yl)-3-(3-amino-propoxy)benzamide;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-(2-dimethylamino-ethoxy)benzamide, and;    4-(5,6-dichloro-1H-indol-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-3-(2,3-hydroxy-propoxy)benzamide.