Novel phosphonate derivatives of certain nucleosides

Claim 2

Compounds of the formula their tautomeric forms, their optical and geometric isomers, and mixtures thereof, and the pharmaceutically acceptable salts thereof, wherein the dotted line represents a facultative double bond, R 1 is C 1-10 alkyl, CH 3-x F x , C 1-10 alkyl-OH or OR 2 , x is zero, 1, 2 or 3, R 2 is H or C 1-6 alkyl, Z is O, CH 2 0, CF 2 , CCI 2 , CHF, CHCI, CFCI or is deleted, V is (CH 2 ) m or (CH 2 ) m Y-(CH 2 ) n , or is deleted, with m and n being zero, 1, 2, 3 or 4, and Y is -C≡C, or T and Q each are H, F or CI, W is O or is deleted, Y 1 is H, Cl, F or OH, Y 2 is H, CI or F, with the proviso that when the dotted line represents a double bond, then Y 3 is F, Cl, or H, Y 1 is H, F or CI and Y 2 is deleted, Y 3 is N 3 , F, Cl, OH or H, Y 4 is H or N 3 , with the proviso that when Y 3 is N 3 , Y 4 is H, with the provisos that (a) at least one of Z, V and W moieties is other than deleted, (b) the -Z-V-W- moiety is other than oxygen, (c) the -Z-V-W- moiety does not contain an oxygen to oxygen bond, (d) when Y 3 is N 3 , and the -Z-V-W- moiety is CH 2 or -CH 2 0-, then R 1 is other than OR 2 , (e) when B is a pyrimidine nucleic base and Y 4 is H, then the -Z-V-W- moiety is other than CH 2 0, and (f) when the -Z-V-W- moiety is a C 1-5 alkylene and both Y 3 and Y 4 are other than N 3 , then R 1 is other than OR 2 , B is a base selected from the group consisting of and X is OR 2 , X 1 is N or C-Y 7 with Y 7 being H, CH 3 , C 2 H 5 , I, F, Cl, Br, NHS, SR, -C≡CH, CH=CH 2 , CH=CHBr, CH 2 CH 2 CI, -CH 2 CH 2 F, or CH 2 C 6 H 4 OCH 2 C 6 H 5 (meta), and R is H, CH 3 , C 2 H 5 , CH 2 C≡CH, -CH 2 CH=CH or CH 2 CN, X 2 is H, OH, Cl, NH 2 , SCH 3 or SH, X 3 is H, NH 2 , F, Cl, Br or I, X 4 is N or CH, X 5 is N or C-Y 5 with Y 5 being H, OH, NH 2 , NHNH 2 , CH 3 , Cl, Br, or NHMe, X 6 is C-Y 6 with Y 6 being H, F, CH 3 or CH=CHBr, X 7 is S or Se.

Claim 3

A compound of Claim 1 wherein B is selected from the group consisting of thymine, adenine, guanine, cytidine and 5-chlorouracil.

Claim 4

A compound of Claim 1 wherein the -Z-V-W- moiety is CH 2 0.

Claim 5

A compound of Claim 1 wherein the -Z-V-W- moiety is CH=CH.

Claim 6

A compound of Claim 1 wherein the -Z-V-W- moiety is CH 2 OCH 2 CH 2 O-.

Claim 7

A compound of Claim 1 wherein the -Z-V-W- moiety is CF 2 C(O)CH 2 CH 2 O-.

Claim 8

A compound of Claim 1 wherein the -Z-V-W- moiety is CH=CHCH 2 CH 2 .

Claim 9

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CH 2 0-, Y 4 is N 3 , Y 3 is OH, Y 1 and Y 2 are H, and B is thymine.

Claim 10

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CH=CH, Y 4 is N 3 , Y 1 , Y 2 , Y 3 , Y 4 are H, and B is adenine.

Claim 11

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CH 2 OCH 2 CH 2 O-, Y 3 is N 3 , Y 1 , Y 2 and Y 4 are H, and B is guanine.

Claim 12

A compound of Claim 1 wherein R 1 is OH, the -Z-V-X- moiety is CH 2 OCH 2 CH 2 O-, Y 4 is N 3 , Y 3 is OH, Y 1 and Y 2 are H, and B is thymine.

Claim 13

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CH=CH, Y 1 , Y 2 , Y 3 , Y 4 are H, and B is cytidine.

Claim 14

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CF 2 C(0)CH 2 CH 2 0-, Y 3 is F, Y 1 , Y 2 and Y 4 are H, and B is 5-chlorouracil.

Claim 15

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CF 2 C(0)CH 2 CH 2 0-, Y 4 is N 3 , Y 3 is OH, Y 1 and Y 2 are H, and B is thymine.

Claim 16

A compound of Claim 1 wherein R 1 is OH, the -Z-V-W- moiety is CH=CHCH 2 CH 2 0-, Y 3 is N 3 , Y 1 , Y 2 and Y 4 are H, and B is thymine.

Claim 17

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

Claim 18

The derivatives according to any one of claims 1 to 15 as pharmaceutically active compounds.

Claim 19

Use of the derivatives according to any one of claims 1 to 15 for the preparation of drugs useful for the treatment or prophylaxis of viral infections.

Claim 20

Use of the derivatives according to any one of claims 1 to 15 for the preparation of drugs useful as antimicrobial and anti-tumoral agents.

Claim 21

A process for preparing a compound of the formula their tautomeric forms, their optical and geometric isomers, and mixtures thereof, and the pharmaceutically acceptable salts thereof, wherein the dotted line represents a facultative double bond, R 1 is C 1-10 alkyl, CH 3-x F x , C 1-10 alkyl-OH or OR 2 , x is zero, 1, 2 or 3, R 2 is H or C 1-6 alkyl, Z is O, CH 2 0, CF 2 , CCI 2 , CHF, CHCI, CFCI or is deleted, V is (CH 2 ) m or (CH 2 ) m Y-(CH 2 ) n , or is deleted, with m and n being zero, 1, 2, 3 or 4, and Y is -C≡C, or T and Q each are H, F or CI, W is O or is deleted, Y 1 is H, CI, F or OH, Y 2 is H, CI or F, with the proviso that when the dotted line represents a double bond, then Y 3 is F, Cl, or H, Y 1 is H, F or CI and Y 2 is deleted, Y 3 is N 3 , F, Cl, OH or H, Y 4 is H or N 3 , with the proviso that when Y 3 is N 3 , Y 4 is H, with the provisos that (a) at least one of Z, V and W moieties is other than deleted, (b) the -Z-V-W- moiety is other than oxygen, (c) the -Z-V-W- moiety does not contain an oxygen to oxygen bond, (d) when Y 3 is N 3 , and the -Z-V-W- moiety is CH 2 or -CH 2 0-, then R 1 is other than OR 2 , (e) when B is a pyrimidine nucleic base and Y 4 is H, then the -Z-V-W- moiety is other than CH 2 0, and (f) when the -Z-V-W- moiety is a C 1-5 alkylene and both Y 3 and Y 4 are other than N 3 , then R 1 is other than OR 2 , B is a base selected from the group consisting of and X is OR 2 , X 1 is N or C-Y 7 with Y 7 being H, CH 3 , C 2 H 5 , I, F, Cl, Br, NHR, SR, -C≡CH, CH=CH 2 , CH=CHBr, CH 2 CH 2 CI, -CH 2 CH 2 F, or CH 2 C 6 H 4 OCH 2 C 6 H 5 (meta), and R is H, CH 3 , C 2 H 5 , CH 2 C≡CH, -CH 2 CH=CH or CH 2 CN, X 2 is H, OH, Cl, NH 2 , SCH 3 or SH, X 3 is H, NH 2 , F, Cl, Br or I, X 4 is N or CH, X 5 is N or CY 5 with Y 5 being H, OH, NH 2 , NHNH 2 , CH 3 , Cl, Br, or NHMe, X 6 is CY 6 with Y 6 being H, F, CH 3 or CH=CHBr, X 7 is S or Se, which comprises (a) de-esterifying a compound of the formula the tautomers, optical and geometrical isomers and mixtures thereof, wherein R' 1 is C 1-10 alkyl, CH 3-x F x , C 1-10 alkylOalkyl, or OR' 2 , x is zero, 1, 2 or 3, R' 2 is OC 1-6 alkyl, Z, V, W, T, Q, Y 1 , Y 2 , Y 3 and Y 4 are as defined, B' is a purine, pyrimidine, triazole or imidazole nucleic base selected from the group consisting of and wherein X' is OH, OR 2 , or a moiety transformable thereto, X' 1 is N or C-Y 7 with Y 7 being H, CH 3 , C 2 H 5 , I, F, Cl, Br, NHR, SR, -C≡CH, CH=CH 2 , CH=CHBr, CH 2 CH 2 CI, -CH 2 CH 2 F, or CH 2 C 6 H 4 OCH 2 C 6 H 5 (meta), and R is H, CH 3 , C 2 H 5 , CH 2 C≡CH, -CH 2 CH=CH or CH 2 CN" or a moiety transformable thereto, X' 2 is H, OH, Cl, NH 2 , SCH 3 or SH" or a moiety transformable thereto, X' 3 is H, NH 2 , F, Cl, Br or I, or a moiety transformable thereto, X' 5 is N or C-Y 5 with Y 5 being H, OH, NH 2 , NHNH 2 , CH 3 , Cl, Br, or NHMe, or a moiety transformable thereto, X 4 , X 6 and X 7 being as previously defined, by reaction with TMSBr or TMSI, and when necessary chemically transforming a transformable moiety of X', X' 1 , X' 2 , X' 3 , or X' 5 to the desired X, X 1 , X 2 , X 3 , or X 5 moiety, respectively, or (b) chemically transforming a compound of Formula II, to the desired X, X 1 , X 2 , X 3 , or X 5 moiety, and optionally de-esterifying the phosphonate moiety by reaction with TMSBr or TMSI, followed by optionally forming the desired pharmaceutically acceptable salts thereof.

Claim 22

A process for preparing a compound of the formula their tautomeric forms, their optical and geometric isomers, and mixtures thereof, and the pharmaceutically acceptable salts thereof, wherein the dotted line represents a facultative double bond, R 1 is C 1-10 alkyl, CH 3-x F x , C 1-10 alkyl-OH or OR 2 , x is zero, 1, 2 or 3, R 2 is H or C 1-6 alkyl, Z is O, CH 2 0, CF 2 , CCI 2 , CHF, CHCI, CFCI or is deleted, V is (CH 2 ) m or (CH 2 ) m Y-(CH 2 ) n , or is deleted, with m and n being zero, 1, 2, 3 or 4, and Y is -C≡C, or T and Q each are H, F or CI, W is O or is deleted, Y 1 is H, CI, F or OH, Y 2 is H, CI or F, with the proviso that when the dotted line represents a double bond, then Y 3 is F, Cl, or H, Y 1 is H, F or CI and Y 2 is deleted, Y 3 is N 3 , F, Cl, OH or H, Y 4 is H or N 3 , with the proviso that when Y 3 is N 3 , Y 4 is H, with the provisos that (a) at least one of Z, V and W moieties is other than deleted, (b) the -Z-V-W- moiety is other than oxygen, (c) the -Z-V-W- moiety does not contain an oxygen to oxygen bond, (d) when Y 3 is N 3 , and the -Z-V-W- moiety is CH 2 or -CH 2 0-, then R 1 is other than OR 2 , (e) when B is a pyrimidine nucleic base and Y 4 is H, then the -Z-V-W- moiety is other than CH 2 0, and (f) when the -Z-V-W- moiety is a C 1-5 alkylene and both Y 3 and Y 4 are other than N 3 , then R 1 is other than OR 2 , B is a base selected from the group consisting of and X is OR 2 , X 1 is N or C-Y 7 with Y 7 being H, CH 3 , C 2 H 5 , I, F, Cl, Br, NHR, SR, -C≡CH, CH=CH 2 , CH=CHBr, CH 2 CH 2 CI, -CH 2 CH 2 F, or CH 2 C 6 H 4 OCH 2 C 6 H 5 (meta), and R is H, CH 3 , C 2 H 5 , CH 2 C≡CH, -CH 2 CH=CH or CH 2 CN, X 2 is H, OH, Cl, NH 2 , SCH 3 or SH, X 3 is H, NH 2 , F, Cl, Br or I, X 4 is N or CH, X 5 is N or CY 5 with Y 5 being H, OH, NH 2 , NHNH 2 , CH 3 , Cl, Br, or NHMe, X 6 is CY 6 with Y 6 being H, F, CH 3 or CH=CHBr, X 7 is S or Se, which comprises (a) de-esterifying a compound of the formula the tautomers, optical and geometrical isomers and mixtures thereof, wherein R' 1 is C 1-10 alkyl, CH 3-x F x , C 1-10 alkylOalkyl, or OR' 2 , x is zero, 1, 2 or 3, R' 2 is OC 1-6 alkyl, Z, V, W, T, Q, Y 1 , Y 2 , Y 3 and Y 4 are as defined, B' is a purine, pyrimidine, triazole or imidazole nucleic base selected from the group consisting of and wherein X' is OH, OR 2 , or a moiety transformable thereto, X' 1 is N or C-Y 7 with Y 7 being H, CH 3 , C 2 H 5 , I, F, Cl, Br, NHR, SR, -C≡CH, CH=CH 2 , CH=CHBr, CH 2 CH 2 CI, -CH 2 CH 2 F, or CH 2 C 6 H 4 OCH 2 C 6 H 5 (meta), and R is H, CH 3 , C 2 H 5 , CH 2 C≡CH, -CH 2 CH=CH or CH 2 CN" or a moiety transformable thereto, X' 2 is H, OH, Cl, NH 2 , SCH 3 or SH" or a moiety transformable thereto, X' 3 is H, NH 2 , F, Cl, Br or I, or a moiety transformable thereto, X' 5 is N or C-Y 5 with Y 5 being H, OH, NH 2 , NHNH 2 , CH 3 , Cl, Br, or NHMe, or a moiety transformable thereto, X 4 , X 6 and X 7 being as previously defined, by reaction with TMSBr or TMSI, and when necessary chemically transforming a transformable moiety of X', X' 1 , X' 2 , X' 3 , or X' 5 to the desired X, X 1 , X 2 , X 3 , or X 5 moiety, respectively, or (b) chemically transforming a compound of Formula II, to the desired X, X 1 , X 2 , X 3 , or X 5 moiety, and optionally de-esterifying the phosphonate moiety by reaction with TMSBr or TMSI, followed by optionally forming the desired pharmaceutically acceptable salts thereof.