Retinoid compound, preparation method therefor, intermediates thereof and application thereof

Abstract

Disclosed are a retinoid compound, a preparation method therefor, intermediates thereof and an application thereof. The retinoid compound I of the present invention has a good tumor growth inhibition rate.

1 .- 14 . (canceled) 
     
     
         15 . A compound represented by formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, U is CR 9a  or N; V is CR 9b  or N; X is CR 9c  or N; W is CR 9d  or N; 
         in the definition of U, V, X and W, each of R 9a , R 9b , R 9c  and R 9d  is independently hydrogen, hydroxy, nitro, cyano, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted with halogen, C 1 -C 6  alkoxy, —NR 10 R 11 , 
       
       
         
           
           
               
               
           
         
       
       or —COOR 14 ;
 each of R 10 , R 11 , R 12 , R 13  and R 14  is independently hydrogen or C 1 -C 6  alkyl; 
 A, E, G together with Z form the ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         each of R 2 , R 3  and R 5  is independently hydrogen, hydroxy, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkyl substituted with halogen, C 1 -C 6  alkoxy, C 1 -C 6  acyl, C 6 -C 10  aryl or “C 3 -C 6  heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen”; 
         m is 0, 1, 2 or 3; 
         when there are more than one substituents of R 1 , the substituents are identical or different; R 1  is hydrogen, hydroxy, nitro, cyano, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted with halogen, C 1 -C 6  alkoxy, —NR 6 R 7  or —COOR 8 ; 
         each of R 6 , R 7  and R 8  is independently hydrogen or C 1 -C 6  alkyl; 
         Y is —CN, —COOR 15  or —CO 2 NHR 16 ; 
         each of R 15  and R 16  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 1 -C 6  alkylacyl. 
       
     
     
         16 . The compound represented by formula I as defined in  claim 15 , wherein,
 when each of R 2 , R 3  and R 5  is independently halogen, the “halogen” is fluorine, chlorine, bromine or iodine;   when each of R 2 , R 3  and R 5  is independently “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when each of R 2 , R 3  and R 5  is independently “C 2 -C 6  alkenyl”, the “C 2 -C 6  alkenyl” is vinyl or propenyl;   when each of R 2 , R 3  and R 5  is independently “C 1 -C 6  alkyl substituted with halogen”, the “C 1 -C 6  alkyl substituted with halogen” is trifluoromethyl;   when each of R 2 , R 3  and R 5  is independently “C 1 -C 6  alkoxy”, the “C 1 -C 6  alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;   when each of R 2 , R 3  and R 5  is independently “C 1 -C 6  acyl”, the “C 1 -C 6  acyl” is acetyl or formyl;   when each of R 2 , R 3  and R 5  is independently “C 6 -C 10  aryl”, the “C 6 -C 10  aryl” is phenyl;   when each of R 2 , R 3  and R 5  is independently “C 3 -C 6  heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen”, the “C 3 -C 6  heteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen” is pyridinyl or pyrimidinyl;   when R 1  is “halogen”, the “halogen” is fluorine, chlorine, bromine or iodine;   when R 1  is “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when R 1  is “C 1 -C 6  alkyl substituted with halogen”, the “C 1 -C 6  alkyl substituted with halogen” is trifluoromethyl;   when R 1  is “C 1 -C 6  alkoxy”, the “C 1 -C 6  alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;   when each of R 6 , R 7  and R 8  is independently “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when each of R 9a , R 9b , R 9c  and R 9d  is independently “halogen”, the “halogen” is fluorine, chlorine, bromine or iodine;   when each of R 9a , R 9b , R 9c  and R 9d  is independently “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when each of R 9a , R 9b , R 9c  and R 9d  is independently “C 1 -C 6  alkyl substituted with halogen”, the “C 1 -C 6  alkyl substituted with halogen” is trifluoromethyl;   when each of R 9a , R 9b , R 9c  and R 9d  is independently “C 1 -C 6  alkoxy”, the “C 1 -C 6  alkoxy” is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy;   when each of R 10 , R 11 , R 12 , R 13  and R 14  is independently “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when each of R 15  and R 16  is independently “C 1 -C 6  alkyl”, the “C 1 -C 6  alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl;   when each of R 15  and R 16  is independently “C 2 -C 6  alkenyl”, the “C 2 -C 6  alkenyl” is vinyl or propenyl;   when each of R 15  and R 16  is independently “C 1 -C 6  acyl”, the “C 1 -C 6  acyl” is formyl or acetyl.   
     
     
         17 . The compound represented by formula I as defined in  claim 15 , wherein,
 one, two, three, or four of U, V, X and W is N atom, or U is CR 9a , V is CR 9b , X is CR 9c , and W is CR 9d .   
     
     
         18 . The compound represented by formula I as defined in  claim 17 , wherein,
 when two of U, V, X and W are N atoms, the compound represented by formula I is selected from the group consisting of   
       
         
           
           
               
               
           
         
         or, when one of U, V, X and W is N atom, the compound represented by formula I is 
       
       
         
           
           
               
               
           
         
         or, when U is CR 9a , V is CR 9b , X is CR 9c , and W is CR 9d , the compound represented by formula I is as compound F, 
       
       
         
           
           
               
               
           
         
         in the definition of compound F, one, two, three, or four of R 9a , R 9b , R 9c  and R 9d  is not hydrogen. 
       
     
     
         19 . The compound represented by formula I as defined in  claim 18 , wherein,
 in compound A, when Y is —COOR 15 , R 15  is hydrogen or ethyl;   and/or, in compound A, A, E, G together with Z form   
       
         
           
           
               
               
           
         
         and/or, in compound B, when Y is —COOR 15 , R 15  is methyl or ethyl; 
         and/or, in compound B, A, E, G together with Z form 
       
       
         
           
           
               
               
           
         
         and/or, in compound C, when Y is —COOR 15 , R 15  is hydrogen or ethyl; 
         and/or, in compound C, A, E, G together with Z form 
       
       
         
           
           
               
               
           
         
         and/or, in compound D, when Y is —COOR 15 , R 15  is hydrogen or ethyl; 
         and/or, in compound D, A, E, G together with Z form 
       
       
         
           
           
               
               
           
         
         and/or, in compound E, Y is CN; 
         and/or, in compound E, A, E, G together with Z form 
       
       
         
           
           
               
               
           
         
         and/or, in compound F, when Y is —COOR 15 , R 15  is hydrogen, methyl or ethyl; 
         and/or, in compound F, A, E, G together with Z form the ring selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound represented by formula I as defined in  claim 15 , wherein, the compound represented by formula I is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A preparation method for the compound represented by formula I as defined in  claim 15 , which comprises conducting a coupling reaction with compound II and III to give compound I; 
       
         
           
           
               
               
           
         
         wherein, X 1  is halogen. 
       
     
     
         22 . A compound represented by formula II, III, IV or V, 
       
         
           
           
               
               
           
         
         wherein, A, E, G, Z, R 1 , m, Y, U, V, X and W are as defined in  claim 15 ; X 1  is halogen; X 2  is halogen. 
       
     
     
         23 . A method for treating a patient in need of a medicament for treating a primary tumor, comprising administering to the patient a medicament comprising an effective amount of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof as defined in  claim 15 . 
     
     
         24 . A method for treating a patient in need of a medicament for preventing and/or treating a metastatic tumor, comprising administering to the patient a medicament comprising an effective amount of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof as defined in  claim 15 . 
     
     
         25 . A method for treating a patient in need of a medicament for preventing and/or treating leukemia and/or lymphoma, comprising administering to the patient a medicament comprising an effective amount of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof as defined in  claim 15 . 
     
     
         26 . A method for treating a patient in need of a medicament for treating the disease selected from the group consisting of animal fetal growth, internal environment stability, vision, morphogenesis, skin aging and cell differentiation control, comprising administering to the patient a medicament comprising an effective amount of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof as defined in  claim 15 . 
     
     
         27 . A pharmaceutical composition, which comprises the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof as defined in  claim 15 , and a pharmaceutically acceptable carrier.