3′-substituted nucleoside derivative

Abstract

The invention relates to a 3'-substituted nucleoside derivative represented by the following general formula (1):wherein B means a nucleic acid base which may have a substituent, Z represents a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the formula:in which Ra, Rb and Rc are individually a lower alkyl group or a phenyl group, or an oxiranyl group which may have at least one lower alkyl group, R1 and R2 individually represent H or an ester-forming residue capable of easily leaving in a living body, and R3 is H, a mono- or polyphosphoric acid residue, or an ester-forming residue capable of easily leaving in a living body, with the proviso that the sugar moiety is ribose, or a pharmaceutically acceptable salt thereof. The 3'-substituted nucleoside derivative according to the invention has an excellent antitumor activity and is hence useful for treatment for and prevention of cancers.

We claim:  
     
       1. A 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:                    
       wherein B represents a nucleic acid base which may have a substituent, 
       wherein Z represents:  
       (i)  a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):                    
        in which R a , R b  and R c  may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or  
       (ii) an oxiranyl group which may be substituted by at least one lower alkyl group,  
       wherein R 1  and R 2  individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R 3  is a hydrogen atom, a mono- or polyphosphoric  mono- , di -  or tri - phosphoric  acid residue, or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B.  
     
     
       2. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein B is cytosine, thymine, uracil, adenine, guanine, 5-fluorocytosine, 5-fluorouracil, N 6 -benzoyladenine, N 2 -acetylguanine or 2-chloroadenine  selected from the group consisting of  1 - cytosinyl,  1   - thyminyl,  1   - uracilyl,  9   - adeninyl,  9   - guaninyl,  5   - fluoro -   1   - cytosinyl,  5   - fluoro -   1   - uracilyl, N   6 - Benzoyl -   9   - adeninyl, N   2 - acetyl -   9   - guaninyl and  2   - chloro -   9   - adeninyl.    
     
     
       3. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein B is cytosine, uracil, adenine, 5-fluorocytosine or 5-fluorouracil  selected from the group consisting of  1 - cytosinyl,  1   - uracilyl,  9   - adeninyl,  5   - fluoro -   1   - cytosinyl and  5   - fluoro -   1   - uracilyl.    
     
     
       4. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 - 3 , wherein Z is a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the general formula (2):                    
       in which R a , R b  and R c  may be the same or different from one another and individually represent a lower alkyl group or a phenyl group. 
     
     
       5. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 4 , wherein the group represented by the general formula (2) is a trimethylsilyl, triethylsilyl, triisopropylsilyl or triphenylsilyl group. 
     
     
       6. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 - 3 , wherein Z is an ethynyl, propynyl, butynyl, ethenyl, trimethylsilylethynyl, triethylsilylethynyl, triisopropylsilylethynyl or triphenylsilylethynyl group. 
     
     
       7. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 ,  2  or  3 , wherein R 1  and R 2  are hydrogen atoms, and R 3  is a hydrogen atom, or a mono- or polyphosphoric  mono- , di - or tri - phosphoric  acid residue. 
     
     
       8. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 ,  2  or  3  wherein R 1  and R 2  are hydrogen atoms, and R 3  is a hydrogen atom, or a monophosphate, diphosphate or triphosphate group. 
     
     
       9. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 ,  2  or  3  wherein the ester-forming residues of  R 1 , R 2  and R 3  are said aliphatic acyl groups  group or said aromatic acyl group. 
     
     
       10. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein B is cytosine, thymine, uracil, adenine, guanine, 5-fluorocytosine, 5-fluorouracil, N 6 -benzoyladenine, N 2 -acetylguanine or 2-chloroadenine  selected from the group consisting of  1 - cytosinyl,  1   - thyminyl,  1   - uracilyl,  9   - adeninyl,  9   - guaninyl,  5   - fluoro -   1   - cytosinyl,  5   - fluoro -   1   - uracilyl, N   6 - benzoyl -   9   - adeninyl, N   2 - acetyl -   9   - guaninyl and  2   - chloro -   9   - adeninyl , Z is a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the general formula (2):                    
       in which R a , R b  and R c  may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, R 1  and R 2  are hydrogen atoms, and R 3  is a hydrogen atom, or a mono- or polyphosphoric  mono- , di - or tri - phosphoric  acid residue. 
     
     
       11. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein B is cytosine, uracil, adenine, 5-fluorocytosine or 5-fluorouracil  selected from the group consisting of  1 - cytosinyl,  1   - uracilyl,  9   - adeninyl,  5   - fluoro -   1   - cytosinyl and  5   - fluoro -   1   - uracilyl , Z is an ethynyl, propynyl, butynyl, ethenyl, trimethylsilylethynyl, triethylsilyl-ethynyl, triisopropylsilylethynyl or triphenylsilylethynyl group, R 1  and R 2  are hydrogen atoms, and R 3  is a hydrogen atom or a diphosphate group. 
     
     
       12. The 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein B is cytosine or uracil   1 - cytosinyl or  1   - uracilyl , Z is an ethynyl or trimethylsilylethynyl group, and R 1 , R 2  and R 3  are hydrogen atoms. 
     
     
       13. A pharmaceutical composition comprising the 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of claims  1 ,  2 ,  3 ,  10 ,  11  or  12  and a pharmaceutical carrier. 
     
     
       14. A method of treating a cancer of a mammal in need thereof, which comprises administering an effective amount of the 3′-substituted nucleoside derivative or the pharmaceutically acceptable salt thereof according to any one of  claim 1 ,  2 ,  3 ,  10 ,  11  or  12  to the mammal. 
     
     
       15. A process for the preparation of a 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:                    
       wherein B represents a nucleic acid base which may have a substituent, 
       wherein Z represents:  
       (i)  a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):                    
       in which R a , R b  and R c  may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or 
       (ii) an oxiranyl group which may be substituted by at least one lower alkyl group,  
       wherein R 1  and R 2  individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R 3  is a hydrogen atom, a mono- or polyphosphoric  mono- , di -  or tri - phosphoric  acid residue, or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B, which comprises the step of: 
       reacting a sugar derivative represented by general formula (3):                    
       wherein R 1′ , R 2′  and R 3′  mean individually a protecting group for a hydroxyl group, Ac represents an acetyl group, and Z has the same meaning as defined above, with a nucleic acid derivative represented by general formula (4): 
       
         
           B—Y  (4)  
         
       
       wherein B has the same meaning as defined above, and Y is a silyl protecting group, wherein said reacting occurs in the presence of a Lewis acid in a nonpolar solvent. 
     
     
       16. The process of  claim 15 , wherein the process additionally  further comprises the step of eliminating  removing the protecting group for at least one of the hydroxyl groups, and subsequently introducing an ester capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted or a phosphoric ester  ester( s ). 
     
     
       17. A process for the preparation of a 3′-substituted nucleoside derivative represented by general formula (1), or a pharmaceutically acceptable salt thereof:                    
       wherein B represents a nucleic acid base which may have a substituent, 
       wherein Z represents:  
       (i)  a lower alkynyl or lower alkenyl group which may be substituted by a group represented by general formula (2):                    
       in which R a , R b  and R c  may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or 
       (ii) an oxiranyl group which may be substituted by at least one lower alkyl group,  
       wherein R 1  and R 2  individually represent a hydrogen atom or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, and R 3  is a hydrogen atom, a mono- or polyphosphoric  mono- , di -  or tri - phosphoric  acid residue, or an ester-forming residue capable of easily being removed in a living body  aliphatic acyl group which may be substituted or an aromatic acyl group which may be substituted, with the proviso that Z is in a cis configuration with respect to B, which comprises the steps of:  
       (A) partially hydrolyzing a compound represented by general formula (5):                    
       wherein B has the same meaning as defined above, to form a compound represented by general formula (6):                    
       wherein B has the same meaning as defined above, 
       (B) reacting the resulting compound represented by general formula (6) with a compound represented by formula:  
       
         
           z—x  
         
       
       wherein Z has the same meaning as defined above, and X represents a hydrogen or halogen atom, or MgBr, 
       wherein when X represents a hydrogen or halogen atom, said reacting occurs in the presence of n- butyllithium in tetrahydrofuran; and wherein when X represents MgBr, said reacting occurs in tetrahydrofuran,  to form a compound represented by general formula (7):                    
       wherein B and Z have the same meaning as defined above, and 
       (C) hydrolyzing the resulting compound represented by general formula (7) to give rise to a compound represented by general formula (   1   ).  
     
     
       18. The process of  claim 17 , wherein the process additionally  further comprises the step of forming a phosphoric ester  an ester( s ) of ( i )  a phosphoric acid forming residue;  ( ii ) an ester capable of easily being removed in a living body  aliphatic acyl group which may be substituted, or ( iii )  an aromatic acyl group which may be substituted , with at least one of the hydroxyl groups. 
     
     
       19.  1 -(   3   - C - ethynyl -β- D - ribofuranosyl )  cytosine or a pharmaceutically acceptable salt, or hydrate thereof.   
     
     
       20. A pharmaceutical composition comprising the compound as defined in  claim 19  and a pharmaceutically acceptable carrier. 
     
     
       21. A method of treating a cancer of a mammal in need thereof, which comprises administering an effective amount of the compound as defined in  claim 19  to the mammal. 
     
     
       22. The method according to  claim 21 , wherein said mammal is a human.