Phosphorsulfide derivatives of deoxynucleosides or deoxynucleotides and their uses

Claim 2

A phosphorsulfide of a deoxynucleoside or deoxynucleotide of general formula (I): ##STR107## wherein R 1 is a hydroxy-protecting group; R 2 is a phosphate-protecting group; R 3 is an aryl group; B 1 and B 2 may be the same or different and each are a base residue which may have a protecting group; and n is zero or an integer, provided that when n is 2 or larger, the respective B 2 may be the same or different.

Claim 3

A compound according to claim 1 wherein n is zero.

Claim 4

A compound according to claim 1 wherein n is 1.

Claim 5

A compound according to claim 1 wherein R 1 is a triarylmethyl, pixyl, alkoxycarbonyl, aryloxycarbonyl, arylthioalkyloxycarbonyl or trialkylsilyl group.

Claim 6

A compound according to claim 1 wherein R 2 is an alkyl, allyl, cyanoalkyl, haloalkyl, arylsulfonylalkyl, aryl or haloaryl group, the alkyl moiety having up to 5 carbon atoms.

Claim 7

A compound according to claim 1 wherein R 3 is phenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl or α-naphthyl group.

Claim 8

A compound according to claim 1 wherein B 1 and B 2 each are thymine residue unprotected or protected protected on the 3-position or a, cytosine residue unprotected or protected on the 4-amino group or an, adenine residue unprotected or protected on the 6-amino group or a guanine residue unprotected or protected on the 1-amido, 2-amino and 6-keto groups.

Claim 9

A compound according to claim 7 wherein the protecting groups are selected from triarylmethyl, trialkylsilylalkyl, arylthioalkyl, phthaloyl, aryloxycarbonyl, alkoxycarbonyl, dialkylcarbamoyl, diarylcarbamoyl, arylcarbonyl, alkylcarbonyl and 1,2-dialkylcarbonyloxyethylene groups.

Claim 10

A compound according to claim 1 selected from: 5'-O-dimethoxytritylthymidine-3'-O-(2-chlorophenyloxy-2-methylphenylthio)phosphine; 5'-O-dimethoxytritylthymidine-3'-O-(methoxy-2-methylphenylthio)phosphine; 5'-O-dimethoxytritylthymidine-3'-O-(2-chlorophenyloxy-2,6-dimethylphenylthio)phosphine; 5'-O-dimethoxytrityl-N 4 -benzoyl-2'-deoxycytidine-3'-O-(2-chlorophenyloxy-2-methylphenylthio)phosphine; 5'-O-dimethoxytrityl-N 6 -phthaloyl-2'-deoxyadenosine-3'-O-(2-chlorophenyloxy-2-methylphenylthio)phosphine; 5'-O-methoxytrityl-O 6 -diphenylcarbamoyl-N 2 -propionyl-2'-deoxyguanosine-3'-O-(2-chlorophenyloxy-2-methylphenylthio)phosphine; 5'-O-dimethoxytritylthymidine-3'-O-(allyloxy-2-methylphenylthio)phosphine; and 5'-O-dimethoxytritylthymidine-3'-O-(2-cyanoethyloxy-2-methylphenylthio)phosphine.

Claim 11

A compound according to claim 1 which is selected from: P-2-chlorophenyl-5'-O-dimethoxytritylthymidyl-3'-O-[(2-chlorophenyloxy-2-methylphenylthio)phosphino]-(3'→5')thymidine; P-2-chlorophenyl-5'-O-dimethoxytrityl-N 4 - benzoyl-2-deoxycytidyl-3'-O-[(2-chlorophenyloxy-2-methylphenylthio)phosphino]-(3'→5')thymidine; P-2-chlorophenyl-5'-O-dimethoxytrityl-N 6 -benzoyl-2'-deoxyadenyl-3'-O-[(2-chlorophenyloxy-2-methylphenylthio)phosphino]-(3'→5')thymidine; and P-2-chlorophenyl-5'-O-methoxytrityl-N 2 -i-butyryl-2'-deoxyguanosinyl-3'-O-[(2-chlorophenyloxy-2-methylphenylthio)phosphino]-(3'→5')thymidine.

Claim 12

A process for the preparation of a deoxynucleotide or an oligodeoxynucleotide of general formula (XXIV): ##STR108## wherein R 1 is a hydroxy-protecting group; R 2 is a phoshate-protecting group; R 7 is a hydroxy-protecting group which is or is not bonded to a polymer-support; B 1 , B 2 , B 3 and B 4 may be the same or different and each are a base residue which does or does not have a protecting group; n is zero or an integer; and m is zero or an integer, provided that when n or m is 2 or larger, respective B 2 or B 4 may be the same or different which comprises reacting a phosphorsulfide of a deoxynucleoside or deoxynucleotide of general formula (I): ##STR109## wherein R 1 , R 2 , B 1 and B 2 and n have the meanings as defined above and R 3 is an aryl group with a deoxynucleoside or deoxynucleotide compound of general formula (XXV): ##STR110## wherein R 2 , R 7 , B 3 , B 4 and m have the meanings as defined above in the presence of a trialkylstannyl azole compound of general formula (XXVI) and a base of general formula (XXVII): R.sup.8.sub.3 SnX (XXVI) R.sup.9 NR.sup.10.sub.2 (XXVII) wherein R 8 is an alkyl group; R 9 is hydrogen atom or an alkyl or aryl group; R 10 is an alkyl group or R 10 together with the adjacent nitrogen atom represent a heterocyclic group which may contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur atoms; and X is an azolyl group, followed by oxidizing the resulting reaction product.

Claim 13

A process for the preparation of a deoxynucleotide or an oligodeoxynucleotide of general formula (XXIV): ##STR108## wherein R 1 is a hydroxy-protecting group; R 2 is a phoshate-protecting group; R 7 is a hydroxy-protecting group which is or is not bonded to a polymer-support; B 1 , B 2 , B 3 and B 4 may be the same or different and each are a base residue which does or does not have a protecting group; n is zero or an integer; and m is zero or an integer, provided that when n or m is 2 or larger, respective B 2 or B 4 may be the same or different which comprises reacting a phosphorsulfide of a deoxynucleoside or deoxynucleotide of general formula (I): ##STR109## wherein R 1 , R 2 , B 1 and B 2 and n have the meanings as defined above and R 3 is an aryl group with a deoxynucleoside or deoxynucleotide compound of general formula (XXV): ##STR110## wherein R 2 , R 7 , B 3 , B 4 and m have the meanings as defined above in the presence of a trialkylstannyl azole compound of general formula (XXVI) and a base of general formula (XXVII): R.sup.8.sub.3 SnX (XXVI) R.sup.9 NR.sup.10.sub.2 (XXVII) wherein R 8 is an alkyl group; R 9 is hydrogen atom or an alkyl or aryl group; R 10 is an alkyl group or R 10 together with the adjacent nitrogen atom represent a heterocyclic group which may contain one or two additional heteroatoms selected from nitrogen, oxygen and sulfur atoms; and X is an azolyl group, followed by oxidizing the resulting reaction product.

Claim 14

A process according to claim 11 wherein said deoxynucleoside phosphorsulfide is of the general formula (IA): ##STR111##

Claim 15

A process according to claim 11 wherein said dideoxynucleotide phosphorsulfide of general formula (IB): ##STR112##