Liponucleotide-containing liposomes

• US 5,223,263 A
• Filed: 06/28/1989
• Issued: 06/29/1993
• Est. Priority Date: 07/07/1988
• Status: Expired due to Term

• Current Assignee: Chimerix Incorporated
• Original Assignee: Vical, Inc. (Fresh Tracks Therapeutics, Inc.)
• Inventors: Hostetler, Karl Y., Kumar, Raj, Stuhmiller, Louise M.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Kunz, Gary L.
• Application Number:
  US07/373,088
• Time in Patent Office: 1,462 Days
• Field of Search: 536/29, 536/27-28, 514/12, 514/808, 514/159, 514/49-51, 424/450, 424/38, 544/276, 544/277
• US Class Current: 424/450
• CPC Class Codes: A01N 43/40 six-membered rings
• 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: A61K 9/127 Liposomes
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07C 17/093 by replacement by halogens
• CPC Class Codes: C07C 25/13 containing fluorine
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/70 Sulfur atoms
• 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 liposome containing as a part of its lipid bilayer the compound phosphatidyl(3'"'"'-azido-3'"'"'-deoxy)thymidine of the formula:

##STR19## wherein R₁ and R₂ are independently selected from the group consisting of fatty acid acyl moieties having from 2 to 24 carbon atoms and from 0 to 6 sites of unsaturation.

2. (3'"'"'azido-3'"'"'-deoxy)thymidine diphosphate diglyceride of the formula:

##STR20## wherein R₁ and R₂ are independently selected from the group consisting of fatty acid acyl moieties having from 2 to 24 carbon atoms and from 0 to 6 sites of unsaturation.

3. 9-[(2-hydroxyethoxy)methyl]guanine diphosphate diglyceride of the formula:

##STR21## wherein n R₁ and R₂ are independently selected from the group consisting of fatty acid acyl moieties having from 2 to 24 carbon atoms and from 0 to 6 sites of unsaturation.

4. (2'"'"',3'"'"'-dideoxy) thymidine diphosphate diglyceride of the formula:

##STR22## wherein R₁ and R₂ are independently selected from the group consisting of fatty acid acyl moieties having from 2 to 24 carbon atoms and from 0 to 6 sites of unsaturation.

5. The compound, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine diphosphate diglyceride of the formula:

##STR23## wherein R₁ and R₂ are independently selected from the group consisting of fatty acid acyl moieties having from 2 to 24 carbon atoms and from 0 to 6 sites of unsaturation.