Pyrimidine compound and medical use thereof

Abstract

wherein each symbol is as defined in the specification and a method of therapeutically or prophylactically treating an undesirable cell proliferation, comprising administering such a compound. The compound of the present invention has superior activity in suppressing undesirable cell proliferation, particularly, an antitumor activity, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, rheumatism, and the like. In addition, the compound of the present invention can be a more effective antitumor agent when used in combination with other antitumor agents such as an alkylating agent or metabolism antagonist.

1 .- 24 . (canceled) 
     
     
         25 . A compound of formula [11]: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  and R 2  are the same or different and each is
 a C 1-6  alkyl group, 
 a C 2-6  alkenyl group,
 wherein the C 1-6  alkyl group and the C 2-6  alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or 
 
 
       
         
           
           
               
               
           
         
         
           wherein m is 0 or an integer of 1 to 4, and 
           ring Cy is a C 3-12  carbon ring group or a heterocyclic group, 
           wherein the heterocyclic group is a saturated or unsaturated ring having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12  carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, 
         
       
       R 3′  is
 a hydroxyl group, 
 a C 1-6  alkyl group, 
 a C 2-6  alkenyl group,
 wherein the C 1-6  alkyl group and the C 2-6  alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, 
 
 a C 3-12  carbon ring group or 
 a heterocyclic group,
 wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12  carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, 
 
 
       R 4  is
 a hydrogen atom, 
 a hydroxyl group, 
 a C 1-6  alkyl group, 
 a C 2-6  alkenyl group,
 wherein the C 1-6  alkyl group and the C 2-6  alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, 
 
 a C 3-12  carbon ring group or 
 a heterocyclic group,
 wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12  carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, and 
 
 
       R C5  is a leaving group, 
       wherein 
       group A is a group consisting of
 1) a halogen atom, 
 2) a nitro group, 
 3) a cyano group, 
 4) a C 1-4  alkyl group, 
 5) —OR A1  wherein R A1  is a hydrogen atom or a C 1-4  alkyl group, 
 6) —SR A2  wherein R A2  is a hydrogen atom or a C 1-4  alkyl group, 
 7) —NR A3 R A4  wherein R A3  and R A4  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 8) —COOR A5  wherein R A5  is a hydrogen atom or a C 1-4  alkyl group, 
 9) —NR A6 COR A7  wherein R A6  is a hydrogen atom or a C 1-4  alkyl group, R A7  is a C 1-4  alkyl group, a C 3-12  carbon ring group or a heterocyclic group, 
 10) —NR A8 COOR A9  wherein R A8  and R A9  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 11) a C 3-12  carbon ring group and 
 12) a heterocyclic group,
 wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, 
 each of the C 1-4  alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8  and R A9  is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and 
 each of the C 3-12  carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7  is optionally substituted by the same or different 1 to 5 substituents selected from the following group C 
 
 
       group B is a group consisting of
 1) a halogen atom, 
 2) a nitro group, 
 3) a cyano group, 
 4) a C 1-8  alkyl group, 
 5) a C 2-4  alkenyl group, 
 6) a C 2-4  alkynyl group, 
 7) —OR B1  wherein R B1  is a hydrogen atom or a C 1-4  alkyl group, 
 8) —SR B2  wherein R B2  is a hydrogen atom or a C 1-4  alkyl group, 
 9) —NR B3 R B4  wherein R B3  is a hydrogen atom, a C 1-4  alkyl group, a C 3-12  carbon ring group or a heterocyclic group, and R B4  is a hydrogen atom or a C 1-4  alkyl group, 
 10) —NR B5 COR B6  wherein R B5  is a hydrogen atom or a C 1-4  alkyl group, and R B6  is a hydrogen atom, a C 1-4  alkyl group, a C 3-12  carbon ring group or a heterocyclic group, 
 11) —NR B7 COOR B8  wherein R B7  and R B8  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 12) —NR B9 CONR B10 R B11  wherein R B9 , R B10  and R B11  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 13) —NR B12 CONR B13 OR B14  wherein R B12 , R B13  and R B14  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 14) —NR B15 SO 2 R B16  wherein R B15  is a hydrogen atom or a C 1-4  alkyl group, and R B16  is a C 1-4  alkyl group, a C 3-12  carbon ring group or a heterocyclic group, 
 15) —SO 2 —R B17  wherein R B17  is a C 1-4  alkyl group or a heterocyclic group, 
 16) —SO 2 NR B18 R B19  wherein R B18  and R B19  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 17) —P(═O)(R B20 )(R B21 ) wherein R B20  and R B21  are the same or different and each is a C 1-4  alkyl group, 
 18) —COOR B22  wherein R B22  is a hydrogen atom or a C 1-4  alkyl group, 
 19) —CONR B23 R B24  wherein R B23  and R B24  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 20) —NR B25 SO 2 NR B26 R B27  wherein R B25 , R B26  and R B27  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 21) —NR B28 SO 2 NR B29 CONR B30 R B31  wherein R B28 , R B29 , R B30  and R B31  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 22) a C 3-12  carbon ring group and 
 23) a heterocyclic group
 wherein each of the “C 1-8  alkyl group” of the above-mentioned 4), and the C 1-4  alkyl groups for R B1  to R B31  is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A, 
 each of the C 2-4  alkenyl group of 5) and the C 2-4  alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A, 
 the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and 
 each of the C 3-12  carbon ring group of the above-mentioned 22), R B3 , R B6  and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16  and R B17  is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and 
 
 
       group C is a group consisting of
 1) a halogen atom, 
 2) a cyano group, 
 3) a C 1-4  alkyl group, 
 4) —OR C1  wherein R C1  is a hydrogen atom or a C 1-4  alkyl group, 
 5) —NR C2 R C3  wherein R C2  and R C3  are the same or different and each is a hydrogen atom or a C 1-4  alkyl group, 
 6) —COOR C4  wherein R C4  is a hydrogen atom or a C 1-4  alkyl group and 
 7) an oxo group. 
 
     
     
         26 . The compound of  claim 25 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein m is an integer of 1, and ring Cy is a phenyl group substituted by 1 substituent selected from group B. 
     
     
         27 . The compound of  claim 26 , wherein B is —OR B1 , and R B1  is a hydrogen atom or a C 1-4  alkyl group. 
     
     
         28 . The compound of  claim 26 , wherein R 1  is —CH 2 -(4-methoxy-phenyl). 
     
     
         29 . The compound of  claim 28 , wherein R 2  is 2-fluoro-4-iodo-phenyl. 
     
     
         30 . The compound of  claim 28 , wherein R 3′  and R 4  are each methyl. 
     
     
         31 . The compound of  claim 28 , wherein the leaving group is p-toluenesulfonyloxy. 
     
     
         32 . The compound of  claim 25 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       m is an integer of 0, and ring Cy is a phenyl group substituted by 2 substituents selected from group B. 
     
     
         33 . The compound of  claim 32 , wherein each B is a halogen atom. 
     
     
         34 . The compound of  claim 32 , wherein R 2  is 2-fluoro-4-iodo-phenyl. 
     
     
         35 . The compound of  claim 34 , wherein R 3′  and R 4  are each methyl. 
     
     
         36 . The compound of  claim 34 , wherein the leaving group is p-toluenesulfonyloxy. 
     
     
         37 . The compound of  claim 25 , wherein R 3′  is a C 1-6  alkyl group. 
     
     
         38 . The compound of  claim 37 , wherein R 3′  is methyl. 
     
     
         39 . The compound of  claim 25 , wherein R 4  is a C 1-6  alkyl group. 
     
     
         49 . The compound of  claim 39 , wherein R 4  is methyl. 
     
     
         41 . The compound of  claim 25 , wherein the leaving group is a halogen atom, p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy. 
     
     
         42 . The compound of  claim 41 , wherein the leaving group is p-toluenesulfonyloxy. 
     
     
         43 . The compound of  claim 25 , wherein
 R 1  is —CH 2 -(4-methoxy-phenyl),   R 2  is 2-fluoro-4-iodo-phenyl,   R 3′  is methyl, and   R 4  is methyl.   
     
     
         44 . The compound of  claim 43 , wherein the leaving group is p-toluenesulfonyloxy.