Heterocyclic compounds, their production and use

Abstract

A compound represented by the formula: wherein m is 1 or 2, R 1 is a halogen or an optionally halogenated C 1-2 alkyl; one of R 2 and R 3 is a hydrogen atom and the other is a group represented by the formula: wherein n is 3 or 4; R 4 is a C 1-4 alkyl group substituted by 1 or 2 hydroxy groups, or a salt thereof shows tyrosine kinase-inhibiting activity.

1 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein m is 1 or 2; 
 R 1  is a halogen atom or an optionally halogenated C 1-2  alkyl group;  
 one of R 2  and R 3  is a hydrogen atom and the other is a group represented by the formula:  
                     
 wherein n is 3 or 4; R 4  is a C 1-4  alkyl group substituted by 1 or 2 hydroxy groups, or a salt thereof.  
 
     
     
         2 . A compound as claimed in  claim 1 , wherein R 1  is fluoro or trifluoromethyl, or a salt thereof.  
     
     
         3 . A compound as claimed in  claim 1 , wherein R 2  is a group represented by the formula:  
       
         
           
           
               
               
           
         
       
       and R 3  is a hydrogen atom; or 
 R 2  is a hydrogen atom and R 3  is a group represented by the formula:  
                     
 or a salt thereof.  
 
     
     
         4 . A compound as claimed in  claim 1 , wherein R 2  is a group represented by the formula:  
       
         
           
           
               
               
           
         
       
       and R 3  is a hydrogen atom, or a salt thereof.  
     
     
         5 . A compound as claimed in  claim 1 , wherein m is 1; 
 R 1  is 4-trifluoromethyl;    R 2  is a group represented by the formula:                          and R 3  is a hydrogen atom, or a salt thereof.    
     
     
         6 . A compound as claimed in  claim 1 , which is 1-4-(4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1-H-1,2,3-triazole, 1-(3-{3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole, or 3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol, or a salt thereof.  
     
     
         7 . A method for producing a compound as claimed in  claim 1  or a salt thereof comprising reacting a compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is a leaving group; the other symbols have the same meanings as defined in  claim 1 , or a salt thereof, with a compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein the symbols have the same meanings as defined in  claim 1 , or a salt thereof.  
     
     
         8 . A pro-drug of a compound as claimed in  claim 1  or a salt thereof.  
     
     
         9 . A pharmaceutical composition containing a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof.  
     
     
         10 . A pharmaceutical composition as claimed in  claim 9 , which is a tyrosine kinase inhibitor.  
     
     
         11 . A pharmaceutical composition as claimed in  claim 9 , which is an agent for preventing or treating cancer.  
     
     
         12 . A pharmaceutical composition as claimed in  claim 11 , wherein the cancer is breast cancer or prostate cancer.  
     
     
         13 . A pharmaceutical composition as claimed in  claim 11 , wherein the cancer is lung cancer.  
     
     
         14 . A pharmaceutical composition which combines a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and other anti-cancer agents.  
     
     
         15 . A pharmaceutical composition which combines a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and hormonal therapeutic agents.  
     
     
         16 . The pharmaceutical composition as claimed in  claim 15 , wherein the hormonal therapeutic agent is a LH—RH modulator.  
     
     
         17 . The pharmaceutical composition as claimed in  claim 16 , wherein the LH—RH modulator is LH—RH antagonist.  
     
     
         18 . The pharmaceutical composition as claimed in  claim 17 , wherein the LH—RH antagonist is leuprorelin or a salt thereof.  
     
     
         19 . A method for inhibiting tyrosine-kinase which comprises administering an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof to mammals.  
     
     
         20 . A method for preventing or treating cancer which comprises administering an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof to mammals.  
     
     
         21 . A method for preventing or treating cancer which comprises combining (1) administering an effective A amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof to mammals and (2) 1 to 3 selected from the group consisting (i) administering an effective amount of other anti-cancer agents to mammals, (ii) administering an effective amount of hormonal therapeutic agents to mammals and (iii) non-drug therapy.  
     
     
         22 . The method as claimed in  claim 21  wherein non-drug therapy is surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         23 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals.  
     
     
         24 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of hormonal therapeutic agents to mammals.  
     
     
         25 . The method as claimed in  claim 24 , wherein the hormonal therapeutic agent is a LH—RH modulator.  
     
     
         26 . The method as claimed in  claim 25 , wherein the LH—RH modulator is LH—RH antagonist.  
     
     
         27 . The method as claimed in  claim 26 , wherein the LH—RH antagonist is leuprorelin or a salt thereof.  
     
     
         28 . A method for preventing or treating cancer which comprises administering an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof to mammals before surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         29 . A method for preventing or treating cancer which comprises administering an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof to mammals after surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         30 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals before surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         31 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals before surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         32 . The method as claimed in  claim 31 , wherein the hormonal therapeutic agent is a LH—RH modulator.  
     
     
         33 . The method as claimed in  claim 32 , wherein the LH—RH modulator is LH—RH antagonist.  
     
     
         34 . The method as claimed in  claim 33 , wherein the LH—RH antagonist is leuprorelin or a salt thereof.  
     
     
         35 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals after surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         36 . A method for preventing or treating cancer which comprises administering in combination of an effective amount of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof and an effective amount of other anti-cancer agents to mammals after surgery, hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy, laser cauterization and/or radiotherapy.  
     
     
         37 . The method-as claimed in  claim 36 , wherein the hormonal therapeutic agent is a LH—RH modulator.  
     
     
         38 . The method as claimed in  claim 37 , wherein the LH—RH modulator is LH—RH antagonist.  
     
     
         39 . The method as claimed in  claim 38 , wherein the LH—RH antagonist is leuprorelin or a salt thereof.  
     
     
         40 . Use of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof for preparing a tyrosine kinase inhibitor.  
     
     
         41 . Use of a compound as claimed in  claim 1  or a salt thereof or a pro-drug thereof for preparing an agent for preventing or treating cancer.  
     
     
         42 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1a  is fluoro or trifluoromethyl, X 1  is a leaving group, and n is 3 or 4, or a salt thereof.  
     
     
         43 . A compound as claimed in  claim 42 , wherein X 1  is a halogen atom.  
     
     
         44 . Use of a compound as claimed in  claim 42  or a salt thereof for preparing a compound as claimed in  claim 1.