Lipid derivatives of phosphonoacids for liposomal incorporation and method of use

• US 5,194,654 A
• Filed: 11/22/1989
• Issued: 03/16/1993
• Est. Priority Date: 11/22/1989
• Status: Expired due to Term

• Current Assignee: Chimerix Incorporated
• Original Assignee: Vical, Inc. (Fresh Tracks Therapeutics, Inc.)
• Inventors: Hostetler, Karl Y., Kumar, Raj
• Primary Examiner(s): Lee, Mary C.
• Assistant Examiner(s): AMBROSE, MICHAEL GEORGE
• Application Number:
  US07/440,898
• Time in Patent Office: 1,210 Days
• Field of Search: 558/169, 558/180, 558/181, 558/152, 558/170
• US Class Current: 558/152
• 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: 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

Compounds are disclosed for treating viral infections due to herpes, influenza, hepatitis B, Epstein-Barr, and varicella zoster viruses, as well as cytomegalovirus and human immunodeficiency virus (HIV) by means of lipid derivatives of antiviral agents. The compounds consist of lipid derivatives of phosphonoacids having antiviral activity which are linked, commonly through the phosphate group of the phosphonoacid, to one of a selected group of lipids.

The lipophilic nature of these compounds provides advantages over the use of the phosphonoacids alone. It also makes it possible to incorporate them into the lamellar structure of liposomes when combined with similar molecules. In the form of liposomes, these antiviral molecules are preferentially taken up by macrophages and monocytes, cells which have been found to harbor the target human immunodeficiency virus (HIV). 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 phosphonoacids are phosphonoformic acid or phosphonoacetic acid; lipid groups may be glycolipids, sphingolipids, phospholipids, glycerolipids, or fatty acids. The compounds persist, after intracellular hydrolysis, as the antiviral phosphonoacids. The compounds are effective in improving the efficacy of antiviral phosphonoacids 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 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, phospholipids, glycerolipids, and fatty acids.

2. The compound of claim 1 wherein said lipid is a 1-O-alkyl-2,3-glycerol.

3. The compound of claim 1 wherein said 1-O-alkyl glycerol is 1-O-hexadecyl-2,3-glycerol.

4. The compound of claim 1 wherein said lipid moiety is a monoacylglycerol or a diacylglycerol.

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

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

7. The compound of claim 1 wherein said lipid moiety comprises from 1 to 4 fatty acid moieties, each said moiety comprising from 2 to 24 carbon atoms.

8. A compound according to claim 7, wherein at least one fatty acid moiety of said lipid moiety is unsaturated, and has from 1 to 6 double bonds.

9. A compound according to claim 1, having the formula:

space="preserve" listing-type="equation">(L).sub.m --(V).sub.n --W--T

wherein

W is ##STR18## T is (CH₂)_p --C(O)--O--;

p=0 or 1;

L is a lipid selected from the group consisting of sphingolipids, phospholipids, glycerolipids, and fatty acids;

m=1 to 3;

V is phosphate;

n=0 to 2 and

wherein each L is linked directly to V by a phosphoester bond and T is linked to W by a phosphonate bond.

10. A compound according to claim 1, having the formula:

##STR19## wherein T is (CH₂)_p --C(O)--O;

p is 0 or 1;

V is phosphate;

n is 0 or 1;

W is ##STR20## L is a lipid moiety;

L₁ is (CH₂ --CHOH--CH₂); and

L and L₁ are linked to V by a phosphoester bond and T is linked to W by a phosphonate bond.

11. A compound according to any one of claims 9 or 10 wherein each L is independently selected from the group consisting of R;

##STR21## wherein R, R₁ and R₂ are independently C₂ to C₂₄ groups of the formula;

space="preserve" listing-type="equation">CH.sub.3 --(CH.sub.2).sub.a --(CH═

CH--CH.sub.2).sub.b --(CH.sub.2).sub.c --Y

wherein the sum of a and c is from 0 to 22; and

b is 0 to 6; and

wherein Y is C(O)O--, C--O--, C═

C--O--, C(O)S, C--S, or C═

C--S.

12. A compound according to claim 11, wherein R₂ is an hydroxyl group.

13. A liposome formed in part from the compound of any one of claims 1 through 12.