2'-Substituted nucleosides and oligonucleotide derivatives

Abstract

The invention relates to an oligonucleotide derivative which comprises at least one nucleoside building block of the formula (I) The invention furthermore relates to nucleoside building blocks, intermediates and processes for preparing the oligonucleotide derivatives and the nucleoside building blocks. The invention also relates to pharmaceutical compositions and to uses of the oligonucleotide derivatives and the nucleoside building blocks.

1 . An oligonucleotide derivative comprising at least one nucleoside building block of the formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which 
 R 1  and R 2  are, independently of each other 
 H,  
 C 1 -C 10 alkyl,  
 a radical of the formula II  
   —(CH 2 —CH 2 —X) m —R 5   (1),  
 in which each X is, in each case independently of each other, O or N(R 6 ), R 5  and R 6  are, in each case independently of each other, H, C 1 -C 10 alkyl, amino-C 2 -C 10 alkyl, N-mono-C 1 -C 10 alkylamino-C 2 -C 10 alkyl or N,N-di-C 1 -C 10 alkylamino-C 2 -C 10 alkyl, and m is an integer from 1 up to and including 3,  
 amino-C 3 -C 10 alkyl,  
 N-mono-C 1 -C 10 alkylamino-C 3 -C 10 -alkyl, or  
 N,N-di-C 1 -C 10 alkylamino-C 3 -C 10 alkyl; or in which  
 —N(R 1 )(R 2 ) are together a radical of the formula (III),  
                     
 in which Y is O, S, SO, SO 2  or N(R 7 ), and R 7  is H or —CH 3 ;  
 
 R 3  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl; or  
 
 A is a radical of the formula (IVa) or (IVb)  
                     
 in which R, independently, has the meaning of R 1  or R 2 , and U is O or CH 2 ;  
 R 4  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl;  
 n is 0, 1 or 2;  
 B is the radical of a nucleic acid base; and  
 V and W are, independently of each other, the same or different radicals of an internucleosidic bridging group or are a terminal radical;  
 and a salt thereof;  
 where those compounds are excepted in which, in the radical A, two heteroatoms are linked to the same carbon atom.  
 
     
     
         2 . An oligonucleotide derivative according to  claim 1 , in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which 
 R 1  and R 2  are, independently of each other, H, C 1 -C 5 alkyl, amino-C 2 -C 5 alkyl, N-mono-C 1 -C 3 alkylamino-C 2 -C 5 alkyl, N,N-di-C 1 -C 3 alkylamino-C 2 -C 5 alkyl or a radical of the formula II  
   —(CH 2 —CH 2 —X) m —R 5   (II),  
 in which X is O or N(R 6 ), R 5  and R 6  are, independently of each other, H, C 1 -C 3 alkyl, amino-C 2 -C 3 alkyl, N-mono-C 1 -C 3 alkylamino-C 2 -C 5 alkyl or N,N-di-C 1 -C 3 alkylamino-C 2 -C 5 -alkyl, and m is 1.  
   
     
     
         3 . An oligonucleotide derivative according to  claim 2 , in which 
 R 1  and R 2  are, independently of each other, H, methyl, ethyl, aminoethyl, aminopropyl, N-monomethylaminoethyl, N-monomethylaminopropyl, N-monoethylaminoethyl, N-monoethylaminopropyl, N,N-dimethylaminoethyl, N,N-dimethylaminopropyl, N,N-diethylaminoethyl, N,N-diethylaminopropyl, or a radical of the formula II      —(CH 2 —CH 2 —X) m —R 5   (II),    in which X is O or N(R 6 ), R 5  and R 6  are, independently of each other, H, methyl, ethyl or propyl, and m is 1.    
     
     
         4 . An oligonucleotide derivative according to  claim 3 , in which 
 R 1  and R 2  are, independently of each other, H, methyl, ethyl, aminoethyl, N-monomethylaminoethyl, N-monoethylaminoethyl, N,N-dimethylaminoethyl or N,N-diethylaminoethyl.    
     
     
         5 . An oligonucleotide derivative according to  claim 4 , in which 
 R 1  and R 2  are, independently of each other, H, methyl or ethyl.    
     
     
         6 . An oligonucleotide derivative according to  claim 5 , in which 
 R 1  and R 2  are in each case H, or    R 1  and R 2  are in each case methyl, or    one of the substituents R 1  and R 2  is H and the other is methyl.    
     
     
         7 . An oligonucleotide derivative according to  claim 5 , in which 
 R 1  and R 2  are in each case methyl, or    one of the substituents R 1  and R 2  is H and the other is methyl.    
     
     
         8 . An oligonucleotide derivative according to  claim 1 , in which 
 R 3  and R 4  are, independently of each other, H, —CH 3 , —CH 2 OH or —CH 2 —O—CH 3 .    
     
     
         9 . An oligonucleotide derivate according to  claim 1 , in which n is 0.  
     
     
         10 . An oligonucleotide derivative according to  claim 9 , in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which    R 3  is H, and R 1  and R 2  are defined as in  claim 1 .    
     
     
         11 . An oligonucleotide derivative according to  claim 1 , in which B is a radical of the formula (V1) to (V14)  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which  
         R b1  is —NH 2 , —SH or —OH;  
         R b2  is H, —NH 2  or —OH; and  
         R b3  is H, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 ;  
         R b4  is —NH 2  or —OH; and  
         R b5  is H, F, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 .  
       
     
     
         12 . An oligonucleotide derivative according to  claim 11 , in which B is a radical of the formula (V1), (V2), (V3), (V4) or (V5)  
       
         
           
           
               
               
           
         
         in which  
         R b1  is —NH 2 , —SH or —OH;  
         R b2  is H, —NH 2  or —OH; and  
         R b3  is H, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 ;  
         R b4  is —NH 2  or —OH; and  
         R b5  is H, F, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 .  
       
     
     
         13 . An oligonucleotide derivative according to  claim 12 , in which B is a radical of the formula (V1) or (V5)  
       
         
           
           
               
               
           
         
         in which  
         R b1  is —NH 2 , —SH or —OH;  
         R b2  is H, —NH 2  or —OH;  
         R b4  is —NH 2  or —OH; and  
         R b5  is H, F, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 .  
       
     
     
         14 . An oligonucleotide derivative according to  claim 13 , in which B is selected from the group of the following radicals: xanthine, hypoxanthine, adenine, 2-aminoadenine, guanine, 6-thioguanine, uracil, thymine, cytosine, 5-methylcytosine, 5-propynyluracil, 5-fluorouracil and 5-propynylcytosine.  
     
     
         15 . An oligonucleotide derivate according to  claim 1 , in which 
 V and W, as radicals of an internucleosidic bridging group, are, independently of each other, selected from the following group: 5′-O—P(O)(OH)—O-3′ (phosphodiester), 5′-O—P(O) (SH)—O-3′ (phosphorothioate), 5′-O—P(S) (SH)—O-3′ (phosphodithioate), 5′-O—P(O)(CH 3 )—O-3′ (methylphosphonate), 5′-O—P(O)(NH—R 7 )—O-3′ (phosphoamidate) in which R 7  is C 1 -C 3 alkyl, 5′-O—P(O)(OR 8 )—O-3′ (phosphotriester) in which R 8  is C 1 -C 3 alkyl, 5′-O—S(O) 2 —CH 2 -3′ (sulfonate), 5′-O—S(O) 2 —NH-3′ (sulfamate), 5′-NH—S(O) 2 —CH 2 -3′ (sulfonamide), 5′-CH 2 —S(O) 2 —CH 2 -3′ (sulfone), 5′-O—S(O)—O-3′ (sulfite), 5′-CH 2 —S(O)—CH 2 -3′ (sulfoxide), 5′-CH 2 —S—CH 2 -3′ (sulfide), 5′-O—CH 2 —O-3′ (formacetal), 5′-S—CH 2 —O-3′ (3′-thioformacetal), 5′-O—CH 2 —S-3′ (5′-thioformacetal), 5′-CH 2 —CH 2 —S-3′ (thioether), 5′-CH 2 —NH—O-3′ (hydroxylamine), 5′-CH 2 —N(CH 3 )—O-3′ (methylene(methylimino)), 5′-CH 2 —O—N(CH 3 )-3′ (methyleneoxy(methylimino)), 5′-O—C(O)—NH-3′ (5′-N-carbamate), 5′-CH 2 —C(O)—NH-3′ (amide), 5′-NH—C(O)—CH 2 -3′ (amide II), 5′-CH 2 —NH—C(O)-3′ (amide III) and 5′-C(O)—NH—CH 2 -3′ (amide IV), and the tautomeric forms thereof.    
     
     
         16 . An oligonucleotide derivative according to  claim 15 , in which 
 V and W, as radicals of an internucleosidic bridging group, are, independently of each other, selected from the following group: 5′-O—P(O)(OH)—O-3′ (phosphodiester), 5′-O—P(O)(SH)—O-3′ (phosphorothioate) and 5′-CH 2 —C(O)—NH-3′ (amide).    
     
     
         17 . An oligonucleotide derivative according to  claim 16 , in which 
 one of the radicals V or W, as radicals of an internucleosidic bridging group, is 5′-O—P(O)(OH)—O-3′ (phosphodiester) and the other radical is 5′-O—P(O)(SH)—O-3′ (phosphorothioate).    
     
     
         18 . An oligonucleotide derivate according to  claim 16 , in which 
 V and W as radicals of an internucleosidic bridging group, are in each case 5′-O—P(O)(OH)—O-3′ (phosphodiester) or in each case 5′-O—P(O)(SH)—O-3′ (phosphorothioate).    
     
     
         19 . An oligonucleotide derivative according to  claim 1 , in which 
 V and W, as terminal radicals, are, independently of each other, —OH, —NH 2  or a hydroxyl or amino group which is protected by a protecting group.    
     
     
         20 . An oligonucleotide derivative according to  claim 17 , in which 
 V, as terminal radical, is —OH, —NH 2  or a protected hydroxyl or amino group, and, W is —OH or —NH 2 .    
     
     
         21 . An oligonucleotide derivative according to  claim 1 , which has a length of from 3 to 50 nucleoside building blocks.  
     
     
         22 . An oligonucleotide derivative according to  claim 18 , which has a length of from 10 to 25 nucleoside building blocks.  
     
     
         23 . An oligonucleotide derivative according to  claim 1 , wherein the oligonucleotide derivative has a chimeric structure.  
     
     
         24 . A compound of the formula (Ia)  
       
         
           
           
               
               
           
         
       
       in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which 
 R 1  and R 2  are, independently of each other, 
 H,  
 C 1 -C 10 alkyl,  
 a radical of the formula II  
   —(CH 2 —CH 2 —X) m —R 5   (II),  
 in which each X is, in each case, independently of each other, O or N(R 6 ), R 5  and R 6  are, in each case, independently of each other, H, C 1 -C 10 alkyl, amino-C 2 -C 10 alkyl, N-mono-C 1 -C 10 alkylamino-C 2 -C 10 alkyl or N,N-di-C 1 -C 10 alkylamino-C 2 -C 10 alkyl, and m is an integer from 1 up to and including 3, amino-C 3 -C 10 alkyl,  
 N-mono-C 1 -C 10 alkylamino-C 3 -C 10 alkyl, or  
 N,N-di-C 1 -C 10 alkylamino-C 3 -C 10 alkyl; or in which  
 —N(R 1 )(R 2 ) are together a radical of the formula (III)  
                     
 in which Y is O, S, SO, SO 2  or N(R 7 ), and R 7  is H or —CH 3 ;  
 
 R 3  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl; or  
 
 A is a radical of the formula (IVa) or (IVb)  
                     
 in which R, independently, has the meaning of R 1  or R 2 , and U is O or CH 2 ;  
 R 4  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl;  
 n is 0, 1 or 2;  
 B′ is the radical of a protected or unprotected nucleic acid base; and  
 V a  and W a  are, independently of each other, —OH, —NH 2  or identically or differently protected hydroxyl or amino groups,  
 where those compounds are excepted in which, in the radical A, two heteroatoms are linked to the same carbon atom,  
 and where other reactive groups are present in the protected or unprotected state.  
 
     
     
         25 . A compound according to  claim 24 , in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which 
 R 1  and R 2  are, independently of each other, H, C 1 -C 5 alkyl, amino-C 2 -C 5 alkyl, N-Mono-C 1 -C 3 alkylamino-C 2 -C 5 alkyl, N,N-di-C 1 -C 3 alkylamino-C 2 -C 5 alkyl or a radical of the formula II  
   —(CH 2 —CH 2 —X) m —R 5   (II),  
 in which X is O or N(R 6 ), R 5  and R 6  are, independently of each other, H, C 1 -C 3 alkyl, amino-C 2 -C 3 alkyl, N-mono-C 1 -C 3 alkylamino-C 2 -C 5 alkyl or N,N-di-C 1 -C 3 alkylamino-C 2 -C 5 -alkyl, and m is 1.  
   
     
     
         26 . A compound according to  claim 25 , in which 
 R 1  and R 2  are, independently of each other, H, methyl, ethyl, aminoethyl, aminopropyl, N-monomethylaminoethyl, N-monomethylaminopropyl, N-monoethylaminoethyl, N-monoethylaminopropyl, N,N-dimethylaminoethyl, N,N-dimethylaminopropyl, N,N-diethylaminoethyl, N,N-diethylaminopropyl, or a radical of the formula II      —(CH 2 —CH 2 —X) m —R 5   (II),    in which X is O or N(R 6 ), R 5  and R 6  are, independently of each other, H, methyl, ethyl or propyl and m is 1.    
     
     
         27 . A compound according to  claim 26 , in which 
 R 1  and R 2  are, independently of each other, H, methyl, ethyl, aminoethyl, N-monomethylaminoethyl, N-monoethylaminoethyl, N,N-dimethylaminoethyl or N,N-diethylaminoethyl.    
     
     
         28 . A compound according to  claim 27 , in which 
 R 1  and R 2  are, independently of each other, H, methyl or ethyl.    
     
     
         29 . A compound according to  claim 28 , in which 
 R 1  and R 2  are in each case H, or    R 1  and R 2  are in each case methyl, or    one of the substituents R 1  and R 2  is H and the other is methyl.    
     
     
         30 . A compound according to  claim 29 , in which 
 R 1  and R 2  are in each case methyl, or    one of the substituents R 1  and R 2  is H and the other is methyl.    
     
     
         31 . A compound according to  claim 24 , in which 
 R 3  and R 4  are, independently of each other, H, —CH 3 , —CH 2 OH or —CH 2 —O—CH 3 .    
     
     
         32 . A compound according to  claim 24 , in which n is 0.  
     
     
         33 . A compound according to  claim 32 , in which 
 A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ), in which    R 3  is H, and R 1  and R 2  are defined as in  claim 24 .    
     
     
         34 . A compound according to  claim 24 , in which 
 B′ is a radical of the formula (V1) to (V14)                                          in which    R b1  is —NH 2 , —SH or —OH;    R b2  is H, —NH 2  or —OH; and    R b3  is H, Br, I, —CN, —C═C—CH 3 , —C(O)NH 2  or —CH 3 ;    R b4  is —NH 2  or —OH; and    R b5  is H, F, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 ,    with exocyclic amino groups being present in unprotected or protected form.      
     
     
         35 . A compound according to  claim 34 , in which 
 B′ is a radical of the formula (V1), (V2), (V3), (V4) or (V5)                          in which    R b1  is —NH 2 , —SH or —OH;    R b2  is H, —NH 2  or —OH; and    R b3  is H, Br, I, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 ;    R b4  is —NH 2  or —OH; and    R b5  is H, F, Br, 1, —CN, —C≡C—CH 3 , —C(O)NH 2  or —CH 3 ,    with exocyclic amino groups being present in unprotected or protected form.    
     
     
         36 . A compound according to  claim 35 , in which B′ is selected from the group of the following radicals: xanthine, hypoxanthine, adenine, 2-aminoadenine, guanine, 6-thioguanine, uracil, thymine, cytosine, 5-methylcytosine, 5-propynyluracil, 5-fluorouracil and 5-propynylcytosine, with exocyclic amino groups being present in protected or unprotected form.  
     
     
         37 . A compound according to  claim 24 , in which the protecting group for exocyclic amino groups of the nucleic acid base B′ is selected from the following group: —C(O)CH 3 , —C(O)—CH(CH 3 ) 2 , —C(O)-phenyl, —C(O)—CH 2 —O-phenyl, —C(O)—CH-p-(tert-butyl)phenyl, —C(O)—CH 2 —O-p-(tert-butyl)phenyl, —C(O)—CH 2 —O-p-(isopropyl)phenyl, ═CH—N(CH 3 ) 2 , ═CH—N(butyl) 2  and  
       
         
           
           
               
               
           
         
       
     
     
         38 . A compound according to  claim 24 , in which the protecting group for V a  or W a , as a protected hydroxyl or amino group, is a trityl-type protecting group.  
     
     
         39 . A compound according to  claim 38 , wherein the trityl-type protecting group is selected from the following group: trityl, 4-monomethoxytrityl, 4,4′-dimethoxytrityl and 4,4′,4″-tris-tert-butyltrityl.  
     
     
         40 . A process for preparing a compound of the formula (Ia) according to  claim 24   
       
         
           
           
               
               
           
         
       
       in which V a , W a , A and B′ are defined as in  claim 24 , and 
 (a) R 4  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl, and n is 0, which comprises reacting a compound of the formula (A)  
                     
 in which V a  and W a  are, independently of each other, a protected hydroxyl or amino group, and B′ is defined as above, with exocyclic amino groups in B′ being protected by protecting groups,  
 with a compound of the formula (B)  
   X—CH 2 -A  (B),  
 in which X is Cl, Br, I, tosyl-O or mesyl-O, and A is defined as above, with primary and secondary amino groups and primary hydroxyl groups in A being protected by protecting groups; or  
 (b) R 4  is H, —CH 3 , —CH 2 CH 3 , —CH 2 OH or —CH 2 —O—C 1 -C 4 alkyl and n is 1 or 2,  
 which comprises reacting a compound of the formula (A)  
                     
 in which V a  and W a  are, independently of each other, a protected hydroxyl or amino group, and B is defined as above, with exocyclic amino groups in B′ being protected by the protecting groups,  
 with a compound of the formula (C)  
   X—CH 2 —C(H) (R 4 )—[O—CH 2 —C(H)(R 4 )] (n−1) —O—CH 2 -A  (C)  
 in which X is Cl, Br, I, tosyl-O or mesyl-O, and R 4  and A are defined as above, with primary and secondary amino groups and primary hydroxyl groups in A being protected by protecting groups; or  
 (c) R 4  is H and n is 1 or 2,  
 which comprises reacting a compound of the formula (D)  
                     
 in which V a  and W a  are, independently of each other, a protected hydroxyl or amino group, B′ is defined as above, with exocyclic amino groups in B′ being protected by protecting groups, and L is a leaving group,  
 with a compound of the formula (E)  
   HO—(CH 2 —CH 2 ) n-1 —O—CH 2 -A  (E)  
 in which A is defined as above, and with primary and secondary amino groups and primary hydroxyl groups in A being protected by protecting groups; or  
 (d) R 4  is H, n is 0, and A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ),  
 which comprises reacting a compound of the formula (D)  
                     
 which is defined as above,  
 with a compound of the formula (F)  
   NH(R 1 )(R 2 )  (F)  
 in which R 1 , R 2  or the group —N(R 1 )(R 2 ) are defined as in  claim 24 , and with functional groups in R 1  or R 2  being protected if necessary; or  
 (e) R 4  is H, n is 0 and A is a radical of the formula —C(H)(R 3 )—N(R 1 )(R 2 ),  
 which comprises reacting a compound of the formula (D)  
                     
 which is defined as above,  
 with an azide and subsequent reduction, if necessary using a catalyst, to give a compound of the formula (G)  
                     
 and, if necessary, subjecting the compound of the formula (G) to further derivatization; with in cases (a) to (e), protected groups subsequently being deprotected if necessary.  
 
     
     
         41 . A process for preparing an oligonucleotide derivative according to  claim 1 , which comprises the following steps: 
 (i) converting a compound of the formula (Ia) according to  claim 24  into a form suitable for oligonucleotide synthesis,    (ii) using the compound of the formula Ia according to  claim 24 , which compound is in a suitable form, in the oligonucleotide synthesis.    
     
     
         42 . A use of a compound of the formula (Ia) according to  claim 24  as a nucleoside building block, if desired after converting it into a suitable form for oligonucleotide synthesis, in the oligonucleotide synthesis.  
     
     
         43 . A use of an oligonucleotide derivative according to  claim 1  as an antisense oligonucleotide.  
     
     
         44 . A use, according to  claim 43 , of an oligonucleotide derivative which is defined in  claim 12 .  
     
     
         45 . A use of an oligonucleotide derivative according to  claim 1  as a triplex-forming oligonucleotide.  
     
     
         46 . A use, according to  claim 45 , of an oligonucleotide derivative which is defined in  claim 11 .  
     
     
         47 . A use according to  claim 45  of an oligonucleotide derivative which is defined in  claim 12 .  
     
     
         48 . A pharmaceutical composition, which comprises an oligonucleotide derivative according to  claim 1 , or a pharmaceutically tolerated salt thereof, in a pharmaceutically effective quantity, if desired together with a pharmaceutically tolerated excipient and/or auxiliary substance.  
     
     
         49 . A pharmaceutical composition according to  claim 48 , which additionally comprises a customary cytostatic agent.  
     
     
         50 . An oligonucleotide derivative according to  claim 1 , or a pharmaceutically tolerated salt thereof, for use in the therapeutic treatment of a mammalian subject, including man.  
     
     
         51 . A use of an oligonucleotide derivative according to  claim 1 , or of a pharmaceutically tolerated salt thereof, for preparing a pharmaceutical composition for the therapeutic treatment of a pathological state, in a mammalian subject including man, which is characterized by the expression of a protein or an RNA molecule.  
     
     
         52 . A process for the therapeutic treatment of a pathological state, in a mammalian subject including man, which is characterized by the expression of a protein or an RNA molecule, which comprises administering a pharmaceutical composition according to  claim 48  to the mammalian subject.  
     
     
         53 . A process for modulating the expression of a protein or an RNA molecule in a cell, which comprises bringing the cell, or a tissue or body fluid containing this cell, into contact with an oligonucleotide derivative according to  claim 1  or a pharmaceutical composition according to  claim 48 .  
     
     
         54 . An oligonucleotide derivative according to  claim 1  for use in a diagnostic method.  
     
     
         55 . A compound of the formula (Ia) according to  claim 24  for use in the therapeutic treatment of a mammalian subject, including man.  
     
     
         56 . A compound of the formula (Ic)  
       
         
           
           
               
               
           
         
       
       in which V a , R 4 , A and B′ are defined as in  claim 24 , and Rx is a protecting group.  
     
     
         57 . An oligonucleotide derivative according to  claim 1 , wherein the oligonucleotide derivative is essentially complementary to the region which extends from base position 2484 to base position 2503 of human c-raf mRNA.  
     
     
         58 . An oligonucleotide derivative according to  claim 57 , wherein the oligonucleotide derivative possesses a base sequence according to SEQ.ID.NO.2 or a base sequence which is analogous thereto.