Substituted -1,3-oxathiolanes with antiviral properties

Claim 2

A 1,3-oxathiolane of formula (I), the geometric and optical isomers thereof, and mixture of those isomers: wherein: R₁ is hydrogen; R₂ is a purine or pyrimidine base or an analogue or derivative thereof; Z is selected from a group consisting of S, S=O or SO₂; and pharmaceutically acceptable derivatives thereof.

Claim 3

A compound of formula (I) as defined in claim 1 in the form of its cis isomer.

Claim 4

A compound of formula (I) as defined in claim 1 or claim 2 wherein Z is S.

Claim 5

A compound of formula (I) as defined in any one of claims 1 to 3 wherein R₂ is selected from: wherein: R₃ is selected from the group of hydrogen or C₁₋₆ alkyl groups; R₄ and R₅ are independently selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted, saturated or unsaturated C₁₋₆ alkyl, bromine, chlorine, fluorine, or iodine; R₆ is selected from the group of hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, or thiocarbamoyl; and X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxyl groups.

Claim 6

A compound according to any one of claims 1 to 4 wherein R₂ is wherein R₃ is selected from the group of hydrogen or C₁₋₆ alkyl groups and R₄ is selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted, saturated or unsaturated C₁₋₆ alkyl, bromine, chlorine, fluorine, or iodine.

Claim 7

A compound selected from the group consisting of: Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-hydroxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-­1,3-oxathiolane, trans -2-hydroxymethyl-5-(N₄′-acetyl­cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-­yl)-1,3-oxathiolane, trans -2-benzoyloxymethyl-5-(N₄′-­acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; and Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-­oxathiolane; Cis -2-hydroxymethyl-5-(N-dimethylamino-methylene cytosin-1′-yl)-1,3-oxathiolane; Bis- Cis -2-succinyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-­yl)-1,3-oxathiolane; trans -2-benzoyloxymethyl-5-(6′-­chloropurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane; Cis -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane; and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.

Claim 8

A compound selected from the group consisting of: Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-hydroxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-­1,3-oxathiolane, trans -2-hydroxymethyl-5-(N₄′-acetyl­cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-­yl)-1,3-oxathiolane, trans -2-benzoyloxymethyl-5-(N₄′-­acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; and Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-­oxathiolane; Cis -2-hydroxymethyl-5-(N-dimethylamino-methylene cytosin-1′-yl)-1,3-oxathiolane; Bis- Cis -2-succinyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-­yl)-1,3-oxathiolane; trans -2-benzoyloxymethyl-5-(6′-­chloropurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane; Cis -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane; and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.

Claim 9

Cis - 2-hydroxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and pharmaceutically acceptable derivatives thereof.

Claim 10

Cis - 2-hydroxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and pharmaceutically acceptable derivatives thereof.

Claim 11

A compound according to any one of claims 1 to 7 in the form of a racemic mixture.

Claim 12

A compound according to any one of claims 1 to 7 substantially in the form of a single enantiomer.

Claim 13

A compound of formula (I) as defined in any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof for use as an active therapeutic agent.

Claim 14

A compound of formula (I) as defined in any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof for use in the manufacture of a medicament for the treatment of a viral infection.

Claim 15

A pharmaceutical formulation comprising a compound of formula (I) as defined in any one of claims 1-9 or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier therefor.

Claim 16

A pharmaceutical formulation according to claim 12 additionally comprising a further therapeutic agent.

Claim 17

A 1,3-oxathiolane of formula (VIII), the geometric and optical isomers thereof, and mixtures of those isomers: wherein: R₁ is hydrogen or a hydroxyl protecting group; and L is an alkoxy carbonyl group, iodine, bromine, chlorine or -OR where R is selected from the group consisting of a substituted or unsubstituted, saturated or unsaturated alkyl group and a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic acyl group.

Claim 18

A 1,3-oxathiolane of formula (VIII), the geometric and optical isomers thereof, and mixtures of those isomers: wherein: R₁ is hydrogen or a hydroxyl protecting group; and L is an alkoxy carbonyl group, iodine, bromine, chlorine or -OR where R is selected from the group consisting of a substituted or unsubstituted, saturated or unsaturated alkyl group and a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic acyl group.

Claim 19

The ester of formula (IV) the geometric and optical isomers thereof, and mixtures of those isomers: wherein: W is PO₄⁻, SPO₃⁻, or -O- -(CH₂) n - -O- where n is an integer of 1 to 10; J is any nucleoside or nucleoside analog or derivative thereof; Z is S, S=O, or SO₂; and R₂ is a purine or pyrimidine base or analogue or derivative thereof.

Claim 20

The ester of formula (IV) the geometric and optical isomers thereof, and mixtures of those isomers: wherein: W is PO₄⁻, SPO₃⁻, or -O- -(CH₂) n - -O- where n is an integer of 1 to 10; J is any nucleoside or nucleoside analog or derivative thereof; Z is S, S=O, or SO₂; and R₂ is a purine or pyrimidine base or analogue or derivative thereof.

Claim 21

A compound according to claim 15 wherein J is:

Claim 22

A process for the preparation of a compound of formula (I) wherein R₁ is hydrogen; R₂ is a purine or pyrimidine base or an analogue or derivative thereof; Z is S, S=O or SO₂; and pharmaceutically acceptable derivatives thereof, which comprises: (a) reaction of a compound of formula (VIII) wherein R₁ is hydrogen or a hydroxyl protecting group and L is a displaceable atom or a group with a base R₂-H group; (b) base interconversion of one compound of formula (I) into another compound of formula (I); (c) reaction of a compound of formula (IX) with a compound of formula (X) wherein P is a protecting group; or (d) conversion of a compound of formula (XII) to a compound of formula (I) and if necessary or desired subjecting the compound resulting from any of steps (a) to (d) to one or two further reactions comprising: (i) removing any protecting groups; (ii) converting a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof.

Claim 23

A process for the preparation of a compound of formula (I) wherein R₁ is hydrogen; R₂ is a purine or pyrimidine base or an analogue or derivative thereof; Z is S, S=O or SO₂; and pharmaceutically acceptable derivatives thereof, which comprises: (a) reaction of a compound of formula (VIII) wherein R₁ is hydrogen or a hydroxyl protecting group and L is a displaceable atom or a group with a base R₂-H group; (b) base interconversion of one compound of formula (I) into another compound of formula (I); (c) reaction of a compound of formula (IX) with a compound of formula (X) wherein P is a protecting group; or (d) conversion of a compound of formula (XII) to a compound of formula (I) and if necessary or desired subjecting the compound resulting from any of steps (a) to (d) to one or two further reactions comprising: (i) removing any protecting groups; (ii) converting a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof.

Claim 24

A process as defined in claim 17 wherein the compound of formula (I) is obtained in the form of its cis isomer.

Claim 25

A process according to claim 17 or claim 18 wherein Z is S.

Claim 26

A process according to any one of claims 17 to 19 wherein R₂ is: wherein: R₃ is selected from the group of hydrogen, trifluoromethyl or saturated or unsaturated C₁₋₆ alkyl groups; R₄ and R₅ are independently selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted, saturated or unsaturated C₁₋­₆ alkyl, bromine, chlorine, fluorine, or iodine; R₆ is selected from the group of hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, or thiocarbamoyl; and X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxyl groups.

Claim 27

A process according to any of claims 17 to 19 wherein R₂ is: wherein R₃ is selected from the group of hydrogen, trifluoromethyl or saturated or unsaturated C₁₋₆ alkyl groups and R₄ is selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted, saturated or unsaturated C₁₋₆ alkyl, bromine, chlorine, fluorine, or iodine.

Claim 28

A process according to any one of claims 17 to 21 wherein the compound of formula (I) is selected from: Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-hydroxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-­1,3-oxathiolane, trans -2-hydroxymethyl-5-(N₄′-acetyl-­cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-­yl)-1,3-oxathiolane, trans -2-benzoyloxymethyl-5-(N₄′-­acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof; and Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-­oxathiolane; Cis -2-hydroxymethyl-5-(N-dimethylamino-methylene cytosin-1′-yl)-1,3-oxathiolane; Bis- Cis -2-succinyloxymethyl-5-(cytosin-1′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-­yl)-1,3-oxathiolane; trans -2-benzoyloxymethyl-5-(6′-­chloropurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-­1,3-oxathiolane; Cis -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(uracil-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(uracil-N-1′-yl)-1,3-­oxathiolane; Cis -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane, trans -2-benzoyloxymethyl-5-(thymin-N-1′-yl)-­1,3-oxathiolane, and mixtures thereof; Cis -2-hydroxymethyl-5-(thymin-N-1′-yl)-1,3-­oxathiolane; and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.

Claim 29

A process according to any one of claims 17 to 21 wherein the compound of formula (I) is Cis -2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and pharmaceutically acceptable derivatives thereof.

Claim 30

A process according to any one of claims 17 to 23 wherein the compound of formula (I) is obtained in the form of a racemic mixture.

Claim 31

A process according to any one of claims 1 to 7 wherein the compound of formula (I) is obtained substantially in the form of a single enantiomer.

Claim 32

A process according to any one of claims 17 to 25 wherein in step (a) the group L is selected from a group consisting of alkoxy carbonyl, iodine, bromine, chlorine or -OR, where R is a substituted or unsubstituted, saturated or unsaturated alkyl group or R is a substituted or unsubstituted aliphatic or aromatic acyl group.

Claim 33

A process according to any one of claims 17 to 26 wherein step (a) the compound of formula (VIII) is reacted with a silylated purine or pyrimidine base in a compatible solvent in the presence of a Lewis acid or trimethylsilyltriflate.

Claim 34

A method for the preparation of a pharmaceutical formulation comprising admixing a compound of formula (I) as defined in claim 17 or a pharmaceutically acceptable derivative thereof with a pharmaceutically acceptable carrier therefor.