Indole compounds useful for the treatment of cancer

Abstract

The present invention provides novel indole derivatives useful to inhibit cancer or sensitize cancer cells to chemotherapeutic agents, radiation or other anti-cancer treatments.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein R 1  is lower alkyl, lower alkenyl, (hydroxy)lower alkyl, lower alkynyl, phenyl, benzyl or 2-thienyl, R 2 , R 3 , R 4  and R 5  are the same or different and are each hydrogen or lower alkyl; each R 6  is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, n is 1-3, R 7  is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is carbonyl, (CH 2 ) 1-3 , (CH 2 ) 1-3 ,SO 2  or (CH 2 ) 1-3 C(O), and Z is (ω-(4-pyridyl)(C 2 -C 4  alkoxy), (ω-((R 8 )(R 9 ) amino)(C 2 -C 4  alkoxy), wherein R 8  and R 9  are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O; an amino acid ester of (ω-(HO)(C 2 -C 4 ))alkoxy, N(R 8 )CH(R 8 )CO 2 H, 1′-D-glucuronyloxy; or Y-Z is (CH 2 ) 1-3 R8; wherein R 8  is OH, (C 2 -C 4 )acyloxy, SO 3 H, PO 4 H 2 , N(NO)(OH), SO 2 NH 2 , PO(OH)(NH 2 ), or tetrazolyl; or a pharmaceutically acceptable salt thereof.  
     
     
         2 . The compound of  claim 1  wherein Z is the L-valine or L-glycine ester of 2-hydroxyethoxy.  
     
     
         3 . The compound of  claim 1  wherein Z is N-morpholinoethoxy.  
     
     
         4 . The compound of  claim 1  wherein each R 8  is H, CH 3  or i-Pr.  
     
     
         5 . The compound of  claim 1  wherein Z is OCH 2 CH 2 N(CH 3 ) 3   + .  
     
     
         6 . A composition comprising the compound of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         7 . The composition of  claim 6  which is a tablet, granule or capsule.  
     
     
         8 . The composition of  claim 6  wherein the carrier is an aqueous vehicle.  
     
     
         9 . The composition of  claim 8  which is an aqueous solution.  
     
     
         10 - 48 . (canceled)