Therapeutic benzothiazole compounds

Abstract

Compounds of the formula (I) for use as an estrogen receptor -β-selective ligand are described wherein: X is O or S; and R 1 , R 3 -R 6 are as described in the specification. The use of these compounds in treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis and prostate cancer is described; as are processes for making them.

1 - 17 . (canceled)  
     
     
         18 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein: 
 X is S;  
 R 1  is C 1-8 alkyl, phenyl or a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the C 1-8 alkyl or heterocycle is substituted by 0, 1, 2 or 3 substituents selected from —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro and C 1-3 haloalkyl and the phenyl is substituted by 0, 1, 2 or 3 substituents selected from —R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O) R a , —NR a S(═O) R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , S(═O) 2 R a , halogen, cyano, nitro and C 1-3 haloalkyl;  
 R 3  is —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl; or R 3  is C 1-3 alkyl containing 1 or 2 substituents selected from —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano and nitro;  
 R 4  is —R a , —OR a , —SR a , —NR a R a , —CO2R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl;  
 R 5  is —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro or C 1-3 haloalkyl;  
 R 6  is —R a , —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano, nitro and or C 1-3 haloalkyl; or R 6  is C 1-3 alkyl containing 1 or 2 substituents selected from —OR a , —SR a , —NR a R a , —CO 2 R a , —OC(═O)R a , —C(═O)NR a R a , —NR a C(═O)R a , —NR a S(═O)R a , —NR a S(═O) 2 R a , —C(═O)R a , —S(═O)R a , —S(═O) 2 R a , halogen, cyano and nitro; and  
 R a  is H, C 1-6 alkyl, C 1-3 haloalkyl, phenyl or benzyl; with the provisos that when the compound is in free base form and:  
 a) R 1  is phenyl, the benzene ring of the benzthiazole is not substituted by 4-methoxy, 5,6-dimethoxy, 6-hydroxy or 6-methoxy;  
 and b) R 1  is 4-methylphenyl, the benzene ring of the benzthiazole is not unsubstituted and is not substituted by 4-, 5- or 6-fluoro, 4-, 6- or 7-methoxy, 5-chloro, 4-, 5-, 6- or 7-hydroxy, 4-, 5-, 6- or 7-acetoxy or 6-nitro;  
 and R 1  is not 4-chloro- or 4-fluorophenyl when the benzene ring of the benzthiazole is substituted by 5-hydroxy or 5-mercapto.  
 
     
     
         19 . (canceled)  
     
     
         20 . (canceled)  
     
     
         21 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 1  is unsubstituted or substituted phenyl.  
     
     
         22 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 1  is an unsubstituted or substituted 5- or 6-membered ring heterocycle.  
     
     
         23 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 1  is halophenyl, C 1-4 alkylphenyl, cyanophenyl or trifluoromethylphenyl.  
     
     
         24 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 3  is halo, cyano, carbamoyl or C 1-6 alkyl.  
     
     
         25 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 3  is hydrogen.  
     
     
         26 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 4  is halo, hydroxy or C 1-6 alkoxy.  
     
     
         27 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 4  is hydrogen.  
     
     
         28 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 5  is halo, hydroxy or C 1-6 alkoxy.  
     
     
         29 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 5  is hydrogen.  
     
     
         30 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 6  is halo, C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, carboxy, C 1-4 alkoxycarbonyl, cyano, halomethyl, cyanoC 1-4 alkyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl.  
     
     
         31 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 6  is hydrogen.  
     
     
         32 . (canceled)  
     
     
         33 . The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  wherein R 6  is cyano or carboxy; R 4  is hydroxy; and R 3  and R 5  are both hydrogen.  
     
     
         34 . A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 18  and a pharmaceutically acceptable carrier.  
     
     
         35 . (canceled)  
     
     
         36 . A method for achieving selective targeting of the β-estrogen receptor, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18 .  
     
     
         37 . A method for treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis or prostate cancer, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  to a patient in need of such treatment.  
     
     
         38 . (canceled)  
     
     
         39 . A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in  claim 18  which comprises: 
 a) cyclizing a compound of the formula:                          wherein X, R 1 , and R 3 -R 6  are as defined in  claim 18  and L is hydrogen or a leaving group; or    b) cyclizing a compound of the formula:                          wherein R 1 , R 3 -R 6  and X are as defined in  claim 18  and L is hydrogen or a leaving group; or    c) cyclizing a compound of the formula:                          wherein R 1  and R 3 -R 6  are as defined in  claim 18;  and thereafter, desired, 
 forming a pharmaceutically acceptable salt.  
   
     
     
         40 . A method for treating a condition for which ERT has a beneficial effect, which comprises administering an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to  claim 18  to a patient in need of such treatment.