Lipid derivatives of phosphonacids for liposomal incorporation and method of use

• US 5,463,092 A
• Filed: 12/18/1992
• Issued: 10/31/1995
• Est. Priority Date: 11/22/1989
• Status: Expired due to Term

• Current Assignee: Chimerix Incorporated
• Original Assignee: Vestar, Inc. (Advanced Micro Devices, Inc.)
• Inventors: Hostetler, Karl Y., Kumar, Raj
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): Carr, Deborah D.
• Application Number:
  US07/993,133
• Time in Patent Office: 1,047 Days
• Field of Search: 554/79, 554/40, 554/78, 554/80, 514/120, 514/121, 514/885, 514/134, 514/143, 514/148
• US Class Current: 554/40
• 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 compound having antiviral activity, 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 linked to said lipid by a carboxyester linkage provided that when the glycerolipid comprises a single glycerol moiety, the phosphonoacid is linked thereto at the sn-glycero-3-position.

2. The compound of claim 1, having the structure:

##STR16## wherein n=0 or 1, and R₁ is a C_2-24 aliphatic group having 0 to 6 double bonds, and is linked to a C atom of a of a glycerol group through an ether or vinyl ether linkage.

3. The compound of claim 1 having the structure ##STR17## wherein n=0 or 1, and R₁ and R₂ are C_2-24 aliphatic groups having 0 to 6 double bonds, and are linked to the C1 and C2 of a glycerol group through an acyl ester linkage.

4. The compound of claim 1 wherein said lipid is selected from the group consisting of a monoacylglycerol, a monoalkylglycerol, a diacylglycerol, a dialkylglycerol, a 1-acyl-2-O-alkyl-glycerol, and a 1-O-alkyl-2-acyl-glycerol.

5. A compound according to claim 2 that is a 1-O-alkyl-sn-glycero-3-oxycarbonylphosphonoacid.

6. A compound according to claim 5 that is a 1-O-hexadecyl-sn-glycero-3-oxycarbonylphosphonoacid.

7. A compound according to claim 5 that is a 1-O-octadecyl-sn-glycero-3-oxycarbonylphosphonoacid.

8. A compound according to claim 3 that is a 1,2-diacyl-sn-glycero-3-oxycarbonylphosphonoacid.

9. A compound according to claim 8 that is a 1,2-dimyristoyl-sn-glycero-3-oxycarbonylphosphonoacid.

10. A compound according to claim 8 that is a 1,2-dipalmitoyl-sn-glycero-3-oxycarbonylphosphonoacid.

11. The compound of claim 1 wherein said lipid is a ceramide.

12. The compound of claim 1 wherein said lipid is a cardiolipin.

13. A compound having antiviral activity according to claim 1 which is a 1-O-alkyl, 2-O-benzyl-sn-glycero-3-oxycarbonylphosphonoacid.