Lipid derivatives of antiviral nucleosides: liposomal incorporation and method of use

• US 6,448,392 B1
• Filed: 04/03/1995
• Issued: 09/10/2002
• Est. Priority Date: 03/06/1985
• Status: Expired due to Term

• Current Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Original Assignee: Chimerix Incorporated
• Inventors: Hostetler, Karl Y., Kumar, Raj, Stuhmiller, Louise M.
• Primary Examiner(s): PRATS, FRANCISCO CHANDLER
• Application Number:
  US08/415,769
• Time in Patent Office: 2,717 Days
• Field of Search: 536/26.1, 536/26.23, 536/26.8, 536/26.2, 536/26.21, 536/26.22
• US Class Current: 536/26.1
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Compounds are disclosed for treating AIDS, herpes, and other viral infections by means of lipid derivatives of antiviral agents. The compounds consist of nucleoside analogues having antiviral activity which are linked, commonly through a phosphate group at the 5′ position of the pentose residue, to one of a selected group of lipids. The lipophilic nature of these compounds provide advantages over the use of the nucleoside analogue alone. It also makes it possible to incorporate them into the lamellar structure of liposomes, either alone or combined with similar molecules. In the form of liposomes, these antiviral agents are preferentially taken up by macrophages and monocytes, cells which have been found to harbor the target HIV virus. Additional site specificity may be incorporated into the liposomes with the addition of ligands, such as monoclonal antibodies or other peptides or proteins which bind to viral proteins. Effective nucleoside analogues are dideoxynucleosides, azidothymine (AZT), and acyclovir; lipid groups may be glycolipids, sphingolipids, phospholipids or fatty acids. The compounds persist, after intracellular hydrolysis, as phosphorylated or non-phosphorylated antiviral nucleosides. The compounds are effective in improving the efficacy of antiviral nucleoside analogues by prolonging the antiviral activity after the administration of the drug has ended, and in preventing retroviral replication in HIV infections which have become resistant to therapy with conventional forms of the antiretroviral agents.

Claims

1. A liponucleoside compound comprising

an antiviral nucleoside analogue having the ability to selectively inhibit at least one viral polymerase enzyme comprising a pentose moiety selected from the group consisting of dideoxyribose;

didehydroribose;

acyclic hydroxylated ribose fragment;

azide derivative of ribose, deoxyribose, dideoxyribose or didehydroribose;

halo derivative of ribose, dideoxyribose, didehydroribose, deoxyarabinose or dideoxyarabinose; and

a ribose, deoxyribose, dideoxyribose or a didehydroribose with an S or O atom substituted for a C atom; and

a lipid moiety selected from the group consisting of glycerolipids having the structure

wherein said R₁ and R₂ independently have from 0 to 6 sites of unsaturation, and have the structure

2. A compound according to claim 1 wherein said lipid moiety is selected from the group consisting of 1,2-O-alkylglycerols.

3. A compound according to claim 1 wherein said lipid moiety is selected from the group consisting of 1,2-S-alkylglycerols.

4. A compound according to claim 1 wherein said pentose residue is a 2′

,3′

-dideoxyribose.

5. A compound according to claim 4 wherein the antiviral liponucleotide is selected from the group consisting of:

2′

,3′

-dideoxycytidine;

2′

,3′

-dideoxythymidine;

2′

,3′

-dideoxyguanosine;

2′

,3′

-dideoxyadenosine;

2′

,3′

-dideoxyinosine; and

2,6-diaminopurine-2′

,3′

-dideoxyriboside.

6. A compound according to claim 1 wherein said pentose residue is a 2′

,3′

-didehydroribose.

7. A compound according to claim 6 wherein the antiviral liponucleotide is selected from the group consisting of

2′

,3′

-didehydrothymidine;

2′

,3′

-didehydrocytidine carbocyclic; and

2′

,3′

-didehydroguanosine.

8. A compound according to claim 1 wherein said pentose residue is an azido derivative of ribose, deoxyribose, didehydroribose or dideoxyribose.

9. A compound according to claim 8 wherein the antiviral nucleotide is selected from the group consisting of

3′

-azido-3′

-deoxythymidine;

3′

-azido-3′

-deoxyguanosine; and

2,6-diaminopurine-3′

-azido-2′

,3′

-dideoxyriboside.

10. A compound according to claim 1 wherein said pentose residue is a halo derivative of ribose, dideoxyribose or didehydroribose.

11. A compound according to claim 10 wherein said antiviral nucleoside is selected from the group consisting of

3′

-fluoro-3′

-deoxythymidine;

3′

-fluoro-2′

,3′

-dideoxyguanosine;

2′

,3′

-dideoxy-2′

-fluoro-ara-adenosine; and

2,6-diaminopurine-3′

-fluoro-2′

,3′

-dideoxyriboside.

12. A compound according to claim 1 wherein said pentose residue is an acyclic hydroxylated fragment of ribose.

13. A compound according to claim 12 wherein the antiviral nucleotide is selected from the group consisting of

9-(4-hydroxy-1′

,2′

-butadienyl)adenine;

3-(4-hydroxy-1′

,2′

-butadienyl)cytosine;

9-(2-phosphonomethoxyethyl)adenine;

3-phosphonomethoxyethyl-2,6-diaminopurine;

acyclovir; and

ganciclovir.

14. A compound according to claim 1 wherein the antiviral nucleoside analogue is 2-chlorodeoxyadenosine.

15. A compound according to claim 1 wherein the antiviral nucleoside analogue is a 3′

-azido-2′

,3′

-dideoxypyrimidine.

16. A compound according to claim 15 wherein the antiviral nucleoside analogue is selected from the group consisting of

3′

-azido-2′

,3′

-dideoxy-5-chlorouridine (AzddClU);

3′

-azido-2′

,3′

-dideoxy-5-methylcytosine (AzddMeC);

3′

-azido-2′

,3′

-dideoxy-5-methylcytosine (AzddMeC);

3′

-azido-2′

,3′

-dideoxy-5-methylcytosine-N4OH (AzddMeC N4-OH);

3′

-azido-2′

,3′

-dideoxy-5-methylcytosine-N4Me, (AzddMeC N4Me);

3′

-azido-2′

,3′

-dideoxy-5-ethyluridine (AzddEtU);

3′

-azido-2′

,3′

-dideoxyuridine (AzddU);

3′

-azido-2′

,3′

-dideoxycytosine (AzddC);

3′

-azido-2′

,3′

-dideoxy-5-fluorocytosine (AzddFC);

3′

-azido-2′

,3′

-dideoxy-5-bromouridine (AzddBrU); and

3′

-azido-2′

,3′

-dideoxyuridine (AzddIU).

17. A compound according to claim 1 wherein the antiviral nucleoside analogue is a 3′

-halopyrimidine dideoxynucleoside.

18. A compound according to claim 17 wherein the antiviral nucleoside analogue is selected from the group consisting of

3′

-fluoro-2′

,3′

-dideoxy-5-chlorouridine (FddClU);

3′

-fluoro-2′

,3′

-dideoxyuridine (3′

FddU);

3′

-fluoro-2′

,3′

-dideoxythymidine (3′

FddT);

3′

-fluoro-2′

,3′

-dideoxy-5-bromouridine (3′

FddBrU); and

3′

-fluoro-2′

,3′

-dideoxy-5-ethyluridine (3′

FddEtU).

19. A compound according to claim 1 wherein said nucleoside analogue is a 2′

,3′

-didehydro-2′

,3′

-dideoxynucloside.

20. A compound according to claim 19 wherein the antiviral nucleoside analogue is selected from the group consisting of

2′

,3′

-didehydro-2′

,3′

-dideoxythymidine (D4T);

2′

,3′

-didehydro-2′

,3′

-dideoxycytidine (D4C);

2′

,3′

-didehydro-2′

,3′

-dideoxy-5-methylcytidine (D4MeC);

and 2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine (D4A).

21. A compound according to claim 1 wherein the antiviral nucleoside analogue is a 2′

,3′

-unsubstituted dideoxypyrimidine nucleoside.

22. A compound according to claim 21 wherein the antiviral nucleoside analogue is selected from the group consisting of

5-fluoro-2′

,3′

-dideoxycytidine (5-F-ddC);

2′

,3′

-dideoxycytidine (ddC); and

2′

,3′

-dideoxythymine (ddT).

23. A compound according to claim 1 wherein the antiviral nucleoside analogue is a 2′

,3′

-unsubstituted dideoxypurine nucleoside.

24. A compound according to claim 23 wherein the antiviral nucleoside analogue is selected from the group consisting of

dideoxyadenosine (ddA);

2,6-diaminopurine-2′

,3′

-dideoxyriboside (ddDAPR);

dideoxyguanosine (ddG);

dideoxyinosine (ddI); and

5-methyl-2′

,3′

-dideoxyadenosine (ddMeA).

25. A compound according to claim 1 wherein the antiviral nucleoside analogue is a sugar-substituted dideoxypurine nucleoside.

26. A compound according to claim 25 wherein the antiviral nucleoside analogue is selected from the group consisting of

3′

-azido-2′

,3′

-dideoxy-diaminopurine (N₃ddDAPR);

3′

-azideo-2′

,3′

-dideoxyguanosine (3-N₃ddG);

3′

-fluoro-2′

,3′

-dideoxy-diaminopurine (3-FddDAPR);

3′

-fluoro-2′

,3′

-dideoxyguanosine (3-FddG);

3′

-fluoro-2′

,3′

-dideoxy-arabinofuranosyl-adenine (3-Fddara-A); and

3′

-fluoro-2′

,3′

-dideoxyadenosine (3-FddA).

27. A compound according to claim 1 wherein the antiviral nucleoside analogue has an S or O atom substituted for a C atom at the 3′

position of dideoxyribose.