Antiviral nucleosides

Claim 2

A pharmaceutical formulation comprising, as active ingredient, 3' - azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier therefor.

Claim 3

A formulation according to claim I wherein the carrier is other than water.

Claim 4

A formulation according to claim 1 or 2 which is sterile.

Claim 5

A formulation according to claim 3 adapted for administration by injection.

Claim 6

A formulation according to claim 4 contained in a sealed vial.

Claim 7

A formulation according to either of claims 3 and 4 wherein the carrier is sterile water.

Claim 8

A formulation according to claim I or 2 adapted for oral administration.

Claim 9

A formulation according to claim I, 2 or 7 in the form of a tablet or capsule.

Claim 10

A formulation according to claim I, 2 or 3 providing sustained release of the active ingredient after oral administration.

Claim 11

A formulation according to claim 7 further comprising a flavouring agent.

Claim 12

II. A formulation according to any of claims 1 to 10 comprising a unit dose of the active ingredient, or a multiple thereof.

Claim 13

A formulation according to claim I wherein the unit dose is between 5 and 1500mg of the active ingredient.

Claim 14

A formulation according to claim 1 wherein the unit dose is between 10 and 1000mg of the active ingredient.

Claim 15

A formulation according to claim I wherein the unit dose is between 20 and 700mg of the active ingredient.

Claim 16

A formulation according to any of claims 1 to 14 wherein the active ingredient is 3'-azido-3'-deoxythymidine.

Claim 17

A process for the preparation of a formulation according to any of claims 1 to 15 which comprises bringing 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof into association with the said pharmaceutically acceptable carrier.

Claim 18

Pharmaceutically acceptable derivatives of 3'-azido-3'-deoxythymidine which, upon administration to a human subject, are capable of providing (directly or indirectly) 3'-azido-3'-deoxythymidine, or an anti-retrovirally active metabolite or residue thereof, other than the following 5'- derivatives, namely the monophosphate, disodium monophosphate, 2-cyanoethyl monophosphate, triphosphate, p-toluene sulphonate, acetate, methanesulphonate and triphenylmethyl derivatives and where the 5'-C of 3'-azido-3'-deoxythymidine is linked to a further nucleotide or nucleoside derivative.

Claim 19

Pharmaceutically acceptable derivatives of 3'-azido-3'-deoxythymidine which, upon administration to a human subject, are capable of providing (directly or indirectly) 3'-azido-3'-deoxythymidine, or an anti-retrovirally active metabolite or residue thereof, other than the following 5'- derivatives, namely the monophosphate, disodium monophosphate, 2-cyanoethyl monophosphate, triphosphate, p-toluene sulphonate, acetate, methanesulphonate and triphenylmethyl derivatives and where the 5'-C of 3'-azido-3'-deoxythymidine is linked to a further nucleotide or nucleoside derivative.

Claim 20

Pharmaceutically acceptable derivatives as claimed in claim 17 in the form of pharmaceutically acceptable salts, esters or salts of such esters of 3'-azido-3'-deoxythymidine.

Claim 21

A derivative as claimed in claim 17 selected from the group consisting of the 5'-diphosphate, 5'-(3-methy(-butyrate), 5'-octanoate, 5'-pa(mitate, 5'-(3'-chlorobenzoate), S'-benzoate, S'-hydrogen succinate and 5'-pivalate esters of 3'-azido-3'-deoxythymidine.

Claim 22

A process for the preparation of any of the compounds according to any of claims 17 to 19 comprising either (A) reacting a compound of formula: HO (wherein M represents a precursor group for the 3'-azido group) or a derivative (e.g. an ester or salt) thereof, with an agent or under conditions serving to convert the said precursor group into the desired azido group; or (B) reacting a compound of formula: N 3 (wherein R represents a precursor group for the hydroxy group, or for a pharmaceutically acceptable derivative group thereof) with an agent or under conditions serving to convert the said precursor group into the corresponding desired group: or (C) reacting a compound of formula or a functional equivalent thereof, with a compound serving to introduce the desired ribofuranosyl ring at the 1-position of the compound of formula (IV); or (D) reacting a compound of formula R 1 (wherein R 1 is hydroxy or R as defined above), with an agent under conditions serving to convert the said compound into 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof; and (i) when 3'-azido-3'-deoxythymidine is formed, converting the said compound into a pharmaceutically acceptable deriative thereof, or (ii) when a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine is formed, optionally converting the said derivative simultaneously or thereafter into 3'-azido-3'-deoxythymdine or a different derivative thereof.

Claim 23

3'-Azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of human retrovirus infections.

Claim 24

3'-Azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of human retrovirus infections.

Claim 25

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of human retrovirus infections.

Claim 26

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of human retrovirus infections.

Claim 27

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of AIDS.

Claim 28

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of AIDS.

Claim 29

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of progressive generalised lymphadenopathy.

Claim 30

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of progressive generalised lymphadenopathy.

Claim 31

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of AIDS related complex.

Claim 32

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of AIDS related complex.

Claim 33

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of an AIDV infection.

Claim 34

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of an AIDV infection.

Claim 35

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of a human T-cell lymphotropic virus infection.

Claim 36

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of a human T-cell lymphotropic virus infection.

Claim 37

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of an HTLV-I or HTLV-11 infection.

Claim 38

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of an HTLV-I or HTLV-11 infection.

Claim 39

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of the AIDV carrier state.

Claim 40

3'-Azido-3'-deoxythymidine for use in the treatment or prophylaxis of the AIDV carrier state.

Claim 41

3'-Azido-3'-deoxythymidine for use in the treatment of an human subject having anti-AIDV antibodies.

Claim 42

3'-Azido-3'-deoxythymidine for use in the treatment of an human subject having anti-AIDV antibodies.

Claim 43

Pharmaceutically acceptable derivatives of 3'-azido-deoxythymidine for use in such treatment or prophylaxis as is defined in any of claims 22 to 29.

Claim 44

Pharmaceutically acceptable derivatives as claimed in claim 21 or 30 in the form of pharmaceutically acceptable salts or esters of 3'-azido-3'-deoxythymidine.

Claim 45

Use of 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of a human retrovirus infection.

Claim 46

Use of 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of a human retrovirus infection.

Claim 47

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of AIDS.

Claim 48

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of AIDS.

Claim 49

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of PGL.

Claim 50

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of PGL.

Claim 51

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of AIDS-related complex.

Claim 52

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of AIDS-related complex.

Claim 53

Use of 3'-azido-3'-deoxythymidine, as claimed in claim 33 wherein the infection is an AIDV infection.

Claim 54

Use of 3'-azido-3'-deoxythymidine, as claimed in claim 33 wherein the infection is a human T-cell lymphotropic virus infection.

Claim 55

Use of 3'-azido-3'-deoxythymidine, as claimed in claim 33 wherein the infection is an HTLV-I or HTLV-II infection.

Claim 56

Use of 3'-azido-3'-deoxythymidine, as claimed in claim 33 wherein the infection is an HTLV-I positive leukaemia or lymphoma.

Claim 57

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of the AIDV carrier state.

Claim 58

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment or prophylaxis of the AIDV carrier state.

Claim 59

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment of an human subject having anti-AIDV antibodies.

Claim 60

Use of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for the treatment of an human subject having anti-AIDV antibodies.

Claim 61

Use of pharmaceutically acceptable derivatives of 3'-azido-3'-deoxythymidine in the manufacture of a medicament for such treatment or prophylaxis as is defined in any of claims 33 to 40.

Claim 62

Use of pharmaceutically acceptable derivatives of 3'-azido-3'-deoxythymidine as claimed in claim 41 in the form of pharmaceutically acceptable salts, esters or salts o' such esters of 3'-azida-3'-deoxythymidine.

Claim 63

A formulation of 3'-Azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, as described in any of claims 1 to 15, for use as described in any of claims 21 to 32.

Claim 64

Use of 3'-azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, according to any of claims 33 to 44, wherein the medicament is a formulation as described in any of claims 1 to 15.

Claim 65

A formulation as described in any of claims 1 to 15 wherein the active ingredient is a compound as described in any of claims 17 to 19.

Claim 66

A formulation as described in any of claims 1 to 15 wherein the active ingredient is a compound prepared by the process of claim 20.

Claim 67

A formulation, use of said formulation, or said formulation for use according to any of claims 45 to 48 when said formulation is prepared according to the process of claim 16.

Claim 68

A process for the preparation of a pharmaceutical Formulation comprising bringing 3 1- azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, as active ingredient, into association with a pharmaceutically acceptable carrier therefor, other than to form a simple, non-sterile, aqueous solution of the active ingredient.

Claim 69

A process for the preparation of a pharmaceutical Formulation comprising bringing 3 1- azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, as active ingredient, into association with a pharmaceutically acceptable carrier therefor, other than to form a simple, non-sterile, aqueous solution of the active ingredient.

Claim 70

A process for the preparation of a formulation according to claim 1 wherein the carrier is other than water.

Claim 71

A process for the preparation of a formulation according to claim 1 or 2 wherein the ingredients are sterile.

Claim 72

A process for the preparation of a formulation according to claim 3 wherein said formulation is adapted for administration by injection.

Claim 73

A process for the preparation of a formulation according to claim 4 further comprising storing in a sealed vial.

Claim 74

A process for the preparation of a formulation according to either of claims 3 and 4 wherein the carrier is sterile water.

Claim 75

A process for the preparation of a formulation according to claim 1 or 2 wherein said formulatin is further adapted for oral administration.

Claim 76

A process for the preparation of a formulation according to claim 1, 2 or 7 wherein said formulation is made in the form of a tablet or capsule.

Claim 77

A process for the preparation of a formulation according to claim 1, 2 or 3 wherein said formulation is further adapted to provide sustained release of the active ingredient after oral administration.

Claim 78

A process for the preparation of a formulation according to claim 7 further comprising the addition of a flavouring agent.

Claim 79

A process for the preparation of a formulation according to any of claims 1 to 10 wherein the active ingredient is present as a unit dose, or a multiple thereof.

Claim 80

A process for the preparation of a formulation according to claim 11 using between 5 and 1500mg of the active ingredient.

Claim 81

A process for the preparation of a formulation according to claim 11 using between 10 and 1000mg of the active ingredient.

Claim 82

A process for the preparation of a formulation according to claim 11 using between 20 and 700mg of the active ingredient.

Claim 83

A process for the preparation of a formulation according to any of claims 1 to 14 wherein the active ingredient is 3'-azido-3'-deoxythymidine.

Claim 84

A process for the preparation of a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine which derivative is, upon administration to a human subject, capable of providing (directly or indirectly) 3'-azido-3'-deoxythymidine, or an anti-retrovirally active metabolite or reside thereof, other than the following 5'-derivatives, namely the monophosphate, disodium monophosphate, 2-eyanoethyl monophosphate, triphosphate, p-toluene sulphonate, acetate, methanesulphonate and triphenylmethyl derivatives and where the 5'C of 3'-azido-3'-deoxythymidine is linked to a further nucleotide or nucleoside derivative, said process comprising either (A) reacting a compound of formula: HO M (wherein M represents a precursor group for the 3'-azido group) or a derivative (e.g. an ester or salt) thereof, with an agent or under conditions serving to convert the said precursor group into the desired azido group; or (B) reacting a compound of formula: R - N (wherein R represents a precursor group for the hydroxy group, or for a pharmaceutically acceptable derivative group thereof with an agent or under conditions serving to convert the said precursor group into the corresponding desired group: or (C) reacting a compound of formula or a functional equivalent thereof, with a compound serving to introduce the desired ribofuranosyl ring at the 1-position of the compound of formula (IV); or (D) reacting a compound of formula R 1 (wherein R is hydroxy or R as defined above), with an agent under conditions serving to convert the said compound into 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof; and (i) when 3'-azido-3'-deoxythymidine is formed, converting the said compound into a pharmaceutically acceptable deriative thereof, or (ii) when a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine is formed, optionally converting the said derivative simultaneously or thereafter into 3'-azido-3'-deoxythymdine or a different derivative thereof.

Claim 85

A process for the preparation of a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine which derivative is, upon administration to a human subject, capable of providing (directly or indirectly) 3'-azido-3'-deoxythymidine, or an anti-retrovirally active metabolite or reside thereof, other than the following 5'-derivatives, namely the monophosphate, disodium monophosphate, 2-eyanoethyl monophosphate, triphosphate, p-toluene sulphonate, acetate, methanesulphonate and triphenylmethyl derivatives and where the 5'C of 3'-azido-3'-deoxythymidine is linked to a further nucleotide or nucleoside derivative, said process comprising either (A) reacting a compound of formula: HO M (wherein M represents a precursor group for the 3'-azido group) or a derivative (e.g. an ester or salt) thereof, with an agent or under conditions serving to convert the said precursor group into the desired azido group; or (B) reacting a compound of formula: R - N (wherein R represents a precursor group for the hydroxy group, or for a pharmaceutically acceptable derivative group thereof with an agent or under conditions serving to convert the said precursor group into the corresponding desired group: or (C) reacting a compound of formula or a functional equivalent thereof, with a compound serving to introduce the desired ribofuranosyl ring at the 1-position of the compound of formula (IV); or (D) reacting a compound of formula R 1 (wherein R is hydroxy or R as defined above), with an agent under conditions serving to convert the said compound into 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof; and (i) when 3'-azido-3'-deoxythymidine is formed, converting the said compound into a pharmaceutically acceptable deriative thereof, or (ii) when a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine is formed, optionally converting the said derivative simultaneously or thereafter into 3'-azido-3'-deoxythymdine or a different derivative thereof.

Claim 86

A process for the preparation of a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine according to claim 16 when the said derivative is a pharmaceutically acceptable salt, ester or salt of such ester of 3'-azido-3'-deoxythymidine.

Claim 87

A process for the preparation of a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine according to claim 16 when the said derivative is selected from the group consisting of the S'-diphosphate, 5'-(3-methyl-butyrate), 5'-octanoate, 5'-palmita*e, 5'-(3-chtorobenzoate), 5'-benzoate, 5'-hydrogen succinate, and 5'-pivalate esters.

Claim 88

A process for the preparation of a formulation according to any of claims 1 to 15 comprising the steps of: (A) preparing 3'-azido-3'-deoxythymidine, or a pharmaceutically acceptable derivative thereof, by (i) reacting a compound of formula HO M (wherein M represents a precursor group for the 3'-azido group) or a derivative (e.g. an ester or salt) thereof, with an agent or under conditions serving to convert the said precursor group into the desired azido group: or (ii) reacting a compound of formula: R (wherein R represents a precursor group for the hydroxy group, or for a pharmaceutically acceptable derivative group thereof) with an agent or under conditions serving to convert the said precursor group into the corresponding desired group; or (iii) reacting a compound of formula or a functional equivalent thereof, with a compound serving to introduce the desired ribofuranosyl ring at the 1-position of the compound of formula (IV); or (iv) reacting a compound of formula R 1 (wherein R 1 is hydroxy or R as defined above), with an agent or under conditions serving to convert the said compound into 3'-azido-3'-deoxythymidine or a pharmaceutically acceptable derivative thereof; and thereafter, or simultaneously therewith, effecting one or more of the following optional conversions: (i) when 3'-azido-3'-deoxythymidine is formed, converting the said compound into a pharmaceutically acceptable derivative thereof, (ii) when a pharmaceutically acceptable derivative of 3'-azido-3'-deoxythymidine is formed, converting the said derivative into 3'-azido-3'-deoxythymidine or a different derivative thereof; and (B) bringing the product of process (A) into association with the said pharmaceutically acceptable carrier therefor.