Lipid derivatives of phosphonoacids for liposomal incorporation and method of use

• US 5,744,461 A
• Filed: 05/26/1995
• Issued: 04/28/1998
• Est. Priority Date: 11/22/1989
• Status: Expired due to Term

• Current Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Original Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Inventors: Hostetler, Karl Y., Kumar, Raj
• Primary Examiner(s): Carr, Deborah D.
• Application Number:
  US08/451,221
• Time in Patent Office: 1,068 Days
• Field of Search: 514/547, 514/885, 514/141, 514/723, 534/78, 534/80, 568/8, 568/9, 568/672
• US Class Current: 514/141
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07F 9/3891 Acids containing the structure -C(=X)-P(=X)(XH)2, (X = O, S, Se)
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4065 Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Lipid-containing prodrugs are provided for treating viral infections due to herpes, influenza, hepatitis B, Epstein-Barr, and varicella zoster viruses, as well as cytomegalovirus and derivatives of antiviral agents. The compounds comprise phosphonoacids having antiviral activity which are linked, either through the phosphate group or carboxyl group of the phosphonoacid, to one of a selected group of lipids. Phosphonoacetic acid and phosphonoformic acid are thus linked to phospholipids, glycerolipids, sphingolipids, glycolipids, or fatty acids. The compounds persist, after intracellular hydrolysis, as the antiviral phosphonoacids. The lipid prodrugs are effective in improving the efficacy of antiviral phosphonoacids by prolonging their antiviral activity following administration.

Claims

1. A method for treating a viral infection in a mammal, comprising administering to a mammal in need thereof an effective antiviral amount of a compound of the formula ##STR15## wherein n is 0 or 1, and R₁ is a linear, branched or cyclic aliphatic group having 0 to 6 double bonds, and is covalently linked to a C atom of a glycerol group through an ether or vinyl ether bond.

2. A method for treating a viral infection in a mammal, comprising administering to a mammal in need thereof an effective antiviral amount of a compound of the formula ##STR16## wherein n=0 or 1, and R₁ and R₂ are independently C₂ to C₂₄ linear, branched or cyclic aliphatic groups having 0 to 6 double bonds, and are each linked to C1 or C2 carbon of a glycerol group through an acyl ester bond.

3. A method according to claim 2 wherein said antiviral compound is a 1,2-diacyl-glycero-3-oxycarbonyl-phosphonoacid.

4. A method according to claim 3 wherein said antiviral compound is a 1,2-dimyristoyl-glycero-3-oxycarbonyl-phosphonoacid.

5. A method according to claim 3 wherein said antiviral compound is a 1,2-dipalmitoyl-glycero-3-oxycarbonyl-phosphonoacid.

6. A method according to claim 5 wherein said antiviral compound is a 1-O-alkyl-glycero-3-oxycarbonyl-phosphonoacid.

7. A method according to claim 5 wherein said antiviral compound is a 1-O-hexadecyl-glycero-3-oxycarbonyl-phosphonoacid.

8. A method according to claim 6 wherein said antiviral compound is a 1-O-octadecyl-glycero-3-oxycarbonyl-phosphonoacid.

9. A method for treating a viral infection in a mammal, comprising administering to a mammal in need thereof an effective antiviral amount of a compound of the formula ##STR17## wherein n=0 or 1 and R₁ is a C₂ to C₂₄ linear, branched or cyclic aliphatic group having 0 to 6 double bonds, and is covalently linked to a C atom of a glycerol group through an ether or vinyl ether bond.

10. A method according to claim 9 wherein said antiviral compound is a 1-O-alkyl-glycero-3-phosphonoacid.

11. A method according to claim 9 wherein said antiviral compound is a 1-O-hexadecyl-glycero-3-phosphonoacid.

12. A method according to claim 9 wherein said antiviral compound is a 1-O-octadecyl-glycero-3-phosphonoacid.

13. A method for treating a viral infection in a mammal, comprising administering to a mammal in need thereof an effective antiviral amount of a compound of the formula ##STR18## wherein n is 0 or 1, and R₁ and R₂ are independently C₂ to C₂₄ linear, branched or cyclic aliphatic groups, having 0 to 6 double bonds, which are linked to the C1 and C2 carbons of a glycerol group through an acyl ester bond.

14. A method according to claim 13 wherein said antiviral compound is a 1,2-diacyl-glycero-3-phosphonoacid.

15. A method according to claim 14 wherein said antiviral compound is a 1,2-dimyristoyl-glycero-3-phosphonoacid.

16. A method according to claim 14 wherein said antiviral compound is a 1,2-dipalmitoyl-glycero-3-phosphonoacid.

17. A method for treating a viral infection in a mammal, comprising administering an effective antiviral amount of a compound comprising:

a phosphonoacid selected from the group consisting of phosphonoformic acid and phosphonoacetic acid; and

a lipid selected from the group consisting of sphingolipids, glycolipids, ceramide or glycerolipids,

wherein said phosphonoacid is covalently linked to said lipid by a carboxyester bond;

provided that when the lipid is a single glycerol group, the phosphonoacid is linked thereto at the glycero-3 or the glycero-1 position.

19. A method according to claim 17 or 18 wherein said lipid moiety is a glycerolipid selected from the group consisting of monoacylglycerols, monoalkylglycerols, diacylglycerols, dialkylglycerols, 1-acyl-2-O-alkylglycerols, and 1-O-alkyl-2-acylglycerols.

20. A method according to claim 17 or 18 wherein said mammal is a human infected with human immunodeficiency virus (HIV).

21. A method according to claim 20 further comprising the step of administering an effective antiretroviral amount of AZT (3'"'"'-deoxy-3'"'"'-azidothymidine) to said mammal.

22. A method for treating HIV infection in a mammal wherein the retrovirus has developed resistance to AZT and other nucleoside analogues comprising administering an effective antiviral amount of said nucleoside analogues in combination with an effective antiviral amount of a compound according to claim 17 or 19 to said mammal.

23. A method according to claim 17 or 18 wherein said phosphonoacid is phosphonoformic acid.

18. A method for treating a viral infection in a mammal, comprising administering an effective antiviral amount of a compound comprising:

a phosphonoacid selected from the group consisting of phosphonoformic acid and phosphonoacetic acid; and

a lipid moiety selected from the group consisting of sphingolipids, glycolipids, ceramide or glycerolipids,

wherein said phosphonoacid is covalently linked to said lipid through a phosphoester bond.