Fatty acid esters of nucleoside analogs
AssigneeNorsk Hydro a.s.
InventorsAre Dalen, Finn Myhren, Bernt Børretzen, Kjell Torgeir Stokke
Life of this patent
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Abstract
New compounds of the general formula (I): Nu-O-Fa, wherein O represents an oxygen, Nu is a nucleoside or nucleoside analogue, and Fa is an acyl group of a mono-unsaturated C18 or 20 fatty acid. The invention also concerns anti viral pharmaceutical and veterinary compositions comprising a compound of formula (I) alone in a combination with a pharmaceutically acceptable carrier.
Claims43
A pharmaceutical composition for the treatment of viral infections comprising a monoester pharmaceutical composition of formula I:
- Nu-O-Fa
- wherein O is an oxygen, Nu is a nucleoside or nucleoside analogue, excluding adenosine, cytidine, guanosine, thymidine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, and uridine, and Fa is an acyl group of a mono-unsaturated C18 or C20 ω-9 fatty acid, which fatty acid is esterified with a hydroxyl group in the 5′-position of the sugar moiety of the nucleoside or nucleoside analogue or with a hydroxyl group on the non-cyclic chain of the nucleoside analogue, wherein Nu-O-Fa is not 5′-O-oleyl-ara-cytidine or 2,2′-anhydro-5′-O-oleyl-ara-cytidine,
- and a pharmaceutically acceptable carrier or excipient.
A method of preparing a pharmaceutical composition for the treatment of a viral infection, comprising the steps of
- (a) selecting a monoester pharmaceutical composition of formula I:
- Nu-O-Fa
- wherein O is an oxygen, Nu is a nucleoside or nucleoside analogue, excluding adenosine, cytidine, guanosine, thymidine, 2′-deoxyadenosine, 2′-deoxycytidine, 2′-deoxyguanosine, and uridine, and Fa is an acyl group of a mono-unsaturated C18 or C20 ω-9 fatty acid, which fatty acid is esterified with a hydroxyl group in the 5′-position of the sugar moiety of the nucleoside or nucleoside analogue or with a hydroxyl group on the non-cyclic chain of the nucleoside analogue;
- wherein Nu-O-Fa is not 5′-O-oleyl-ara-cytidine or 2,2′-anhydro-5′-O-oleyl-ara-cytidine, and
- (b) combining the compound with a pharmaceutically acceptable carrier or excipient.
A method for treatment of a patient suffering from a viral infection wherein a monoester pharmaceutical composition of formula I:
- Nu-O-Fa
- wherein O is an oxygen, Nu is a nucleoside or nucleoside analogue, excluding adenosine, cytidine, guanosine, thymidine, 2′-deoxyadenosine, 2′-deoxycytidine, 2′-deoxyguanosine, and uridine, and Fa is an acyl group of a mono-unsaturated C18 or C20 ω-9 fatty acid, which fatty acid is esterified with a hydroxyl group in the 5′-position of the sugar moiety of the nucleoside or nucleoside analogue or with a hydroxyl group on the non-cyclic chain of the nucleoside analogue;
- wherein Nu-O-Fa is not 2,2′-anhydro-5′-O-oleyl-ara-cytidine, is administered.
A method for the treatment of a patient with a viral infection caused by a hepatitis B virus wherein a monoester pharmaceutical composition of formula I:
- Nu-O-Fa
- wherein O is an oxygen, Nu is a nucleoside or nucleoside analogue, excluding adenosine, cytidine, guanosine, thymidine, 2′-deoxyadenosine, 2′-deoxycytidine, 2′-deoxyguanosine, and uridine, and Fa is an acyl group of a mono-unsaturated C18 or C20 ω-9 fatty acid, which fatty acid is esterified with a hydroxyl group in the 5′-position of the sugar moiety of the nucleoside or nucleoside analogue or with a hydroxyl group on the non-cyclic chain of the nucleoside analogue;
- wherein Nu-O-Fa is not 2,2′-anhydro-5′-O-oleyl-ara-cytidine, in combination with an interferon, is administered.
A monoester pharmaceutical composition of formula I:
- Nu-O-Fa
- wherein O is an oxygen, Nu is a nucleoside or nucleoside analogue, excluding adenosine, cytidine, guanosine, thymidine and uridine, and Fa is an acyl group of a mono-unsaturated C18 or C20 ω-9 fatty acid, which fatty acid is esterified with a hydroxyl group in the 5′-position of the sugar moiety of the nucleoside or nucleoside analogue or with a hydroxyl group on the non-cyclic chain of the nucleoside analogue, wherein Nu is represented by Formula II
- S—B
- wherein S is a moiety selected from the group consisting of:
- 1-β-D-arabinofuranose, 2,3-di-deoxy-3-azido-1-β-D-ribofuranose, 2-hydroxy-ethoxy-methyl, 4-hydroxy-3-(hydroxymethyl)-butyl, 2-hydroxy-1-(hydroxy-methyl)-ethoxy-methyl and 2,3-di-hydroxy-propoxy;
- and B is a heterocyclic base selected from the group consisting of adenine, guanine, cytosine, uracil, thymine, 5-trifluoromethyluracil, and 5-trideutriomethyluracil;
- wherein when B is a purine, S is attached at the N-9 position, and when B is a pyrimidine, S is attached at the N-1 position.
In a method of increasing the therapeutic effectiveness of an antiviral nucleoside or nucleoside analogue by esterifying said nucleoside or nucleoside analogue with an unsaturated fatty acid, said esterification being at the 5′ position of the sugar moiety if a nucleoside is used, and being at a hydroxyl group on the non-cyclic chain if a nucleoside analogue is used, the improvement wherein the unsaturated fatty acid that is used is a mono-unsaturated C18 or C20 fatty acid selected from the group consisting of oleic acid, elaidic acid, cis-eicosenic acid, and trans-eicosenic acid.
In a method of treating a patient having a viral infection by administering to the patient a therapeutically effective amount of an antiviral nucleoside or nucleoside analogue, the improvement wherein the nucleoside or nucleoside analogue is in the form of an ester with a mono-unsaturated C18 or C20 fatty acid selected from the group consisting of oleic acid, elaidic acid, cis-eicosenic acid, and trans-eicosenic acid, the esterification being at the 5′-position of the sugar moiety if a nucleoside is used and being with a hydroxyl group on the non-cyclic chain if a nucleoside analogue is used.
Dependencies are inferred from the claim text.