EP0350287B1
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EP
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Lipid derivatives of antiviral nucleosides, liposomal incorporation and method of use
Assignee: Chimerix Inc
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Filing: 1989-07-05
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Granted: 2000-09-27
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Expires: 2009-07-05
Abstract
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 min 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.
Inventors
- 👤 Karl Y. Hostetler
- 👤 Raj Kumar
- 👤 Louise M. Stuhmiller
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-08 23:38
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/02; C07H15/12; C07H15/04; A; A01; A01N; A01N43/00; A01N43/34; A01N43/40; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/542; A61K47/543; A61K47/544; A61K47/548; A61K9/00; A61K9/10; A61K9/127; A61P; A61P31/00; A61P31/12; A61P31/14; A61P31/18; C07C; C07C17/00; C07C17/093; C07C25/00; C07C25/02; C07C25/13; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/61; C07D213/62; C07D213/63; C07D213/64; C07D213/70; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07H19/16
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
208 words
Use in the preparation of a composition for the treatment of a viral or retroviral
infection in a mammal of a liponucleotide compound comprising a conjugate of an antiviral nucleoside analogue which does not occur naturally in
the mammal to be treated and which is characterized by the ability to exert antiviral
activity on DNA or RNA viruses, and a lipid moiety linked to the 5' position of the
nucleoside analogue wherein the conjugate has the formula (L) m -(W) n -A-Q-Z wherein Z is the base portion of a nucleoside analogue; Q is a pentose residue or an acyclic fragment thereof or a carbocyclic
analogue; A is O or S; W is phosphate; n is 1 to 3; and L is a lipid moiety, wherein m = 1 to 5; wherein L is linked directly to W,
and wherein L is selected from wherein R, R 1 and R 2 independently have from 0 to 6 sites of unsaturation, and have the
structure CH 3 -(CH 2 ) a -(CH=CH-CH 2 ) b -(CH 2 ) c -Y wherein the sum of a and c is from 1 to 23; 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-.
Claim 2
Dependent Claim
30 words
Use according to claim 1, wherein the non-naturally occurring nucleoside
component is an analogue with modification of a naturally occurring base or pentose by
virtue of substitution, deletion or replacement.
Claim 3
Dependent Claim
28 words
Use according to claims 1 or 2, wherein the pentose residue is a 2',3'-deoxy, 2',3'-dideoxy-2',3'-didehydro,
azido or halo derivative of ribose, or an acyclic hydroxylated
fragment of ribose.
Claim 4
Dependent Claim
42 words
Use according to claims 1 to 3, wherein the group -A-Q-Z is selected from the
group consisting of 2',3'-dideoxycytidine; 2',3'-dideoxythymidine; 2',3'-dideoxyguanosine; 2',3'-dideoxyadenosine; 2',3'-dideoxyinosine; 2,6-diaminopurine-2',3'-dideoxyriboside; 2',3'-dideoxy-2',3'-didehydrothymidine; 2',3'-dideoxy-2',3'-didehydrocytidine carbocyclic; 2',3'-dideoxy-2',3'-didehydroguanosine; 3'-azido-3'-deoxythymidine; 3'-azido-3'-deoxyguanosine; 2,6-diaminopurine-3'-azido-2',3'-dideoxyriboside 3'-fluoro-3'-deoxythymidine; 3'-fluoro-2',3'-dideoxyguanosine; 2',3'-dideoxy-2'-fluoro-ara-adenosine; 2,6-diaminopurine-3'-fluoro-2',3'-dideoxyriboside 9-(4'-hydroxy-1',2'-butadienyl)adenine; 3-(4'-hydroxy-1',2'-butadienyl)cytosine; 9-(2-phosphonylmethoxyethyl)adenine; 3-phosphonomethoxyethyl-2,6-diaminopurine; acyclovir or ganciclovir.
Claim 5
Dependent Claim
27 words
Use according to any one of the preceding claims, wherein the nucleotide
compound is present in a liposome or is capable of forming a liposome by itself.
Claim 6
Dependent Claim
321 words
An antiviral or antiretroviral liponucleotide of formula (L) m -(W) n -A-Q-Z wherein Z is the base portion of a nucleoside analogue; Q is a pentose residue or an acyclic fragment thereof or a carbocyclic analogue; A is O or S; W is phosphate; n is 1 to 3; L is a lipid moiety; m is 1 wherein the lipid moiety is selected from wherein R, R 1 and R 2 independently have from 0 to 6 sites of unsaturation, and have the
structure CH 3 -(CH 2 ) a -(CH=CH-CH 2 ) b -(CH 2 ) c -Y wherein the sum of a and c is from 1 to 23; 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-, with the proviso that the compound is in the form of a liposome, when the pentose residue
is arabinofuranose and the base portion is cytosine or adenine, with the proviso that when the lipid is a 1,2-diradylglycerol, and the linkage is 3-monophosphate,
the nucleoside analogue is not 5-fluoro-uridine, 5-fluorocytidine,
bredinin, tubercidin, arabinosyl-cytosine, arabinosyl-5-fluorocytosine, arabinosyl-5-fluorocytosine,
arabinosyl-adenine, arabinosyl-thymine, 5-fluoro-2'-deoxyribo-uridine,
and neplanocin A; with the proviso that when the lipid moiety is 1,2-diradyl or 1,3-diradylglycerol, and the
linkage is monophosphate, the nucleoside is not cytidine, uridine, arabinosylcytosine,
adenosine, guanosine, cyclocytidine, deoxyadenosine, deoxycytidine, deoxyguanosine,
deoxythymidine, deoxyuridine, or inosine; with the proviso that when the lipid moiety is 1,2-di-O-acylglycerol, and the linkage is 3-diphosphate,
the nucleoside is not cytidine, arabinosylcytosine, arabinosyladenine, 7-deazaadenosine;
provided that when the lipid moiety is 1,2-di-O-alkylglycerol, and the
linkage is 3-diphosphate, the nucleoside is not arabinosylcytosine; provided that when the
lipid moiety is 1,2-di-O-acylglycerol, and the linkage is monophosphate, the nucleoside is
not arabinosylcytosine; and with the proviso that when the lipid moiety is 1-O-alkyl-2-O-acylglycerol, the sugar is
ribose, 2'-deoxyribose, arabinose or 2',2'-dihydroxyribose, and the linkage is diphosphate,
the nucleoside does not contain a base which is adenine, cytosine, 5-fluorouracil, 5-azacytosine,
6-mercaptopurine or 7-deazaadenine.
Claim 7
Dependent Claim
40 words
A compound according to claim 6, wherein the group A-Q-Z is selected from the
nucleosides comprising 2',3'-dideoxycytidine; 2',3'-dideoxythymidine; 2',3'-dideoxyguanosine; 2',3'-dideoxyadenosine; 2',3'-dideoxyinosine; 2,6-diaminopurine-2',3'-dideoxyriboside; 2',3'-dideoxy-2',3'-didehydrothymidine; 2',3'-dideoxy-2',3'-didehydrocytidine carbocyclic; 2',3'-dideoxy-2',3'-didehydroguanosine; 3'-azido-3'-deoxythymidine; 3'-azido-3'-deoxyguanosine; 2,6-diaminopurine-3'-azido-2',3'-dideoxyriboside 3'-fluoro-3'-deoxythymidine; 3'-fluoro-2',3'-dideoxyguanosine; 2',3'-dideoxy-2'-fluoro-ara-adenosine; 2,6-diaminopurine-3'-fluoro-2',3'-dideoxyriboside 9-(4'-hydroxy-1',2'-butadienyl)adenine; 3-(4'-hydroxy-1',2'-butadienyl)cytosine; 9-(2-phosphonylmethoxyethyl)adenine; 3-phosphonomethoxyethyl-2,6-diaminopurine; acyclovir or ganciclovir.
Claim 8
Dependent Claim
23 words
Compounds of claim 6 selected from the group consisting of phosphatidyl(3'-azido-3'-deoxy)thymidine (pAZT); phosphatidyl(2',3'-dideoxy)cytidine (pddC); phosphatidyl(2',3'-dideoxy)thymidine (pddT); (3'-azido-3'-deoxy)thymidine diphosphate diglyceride (AZTdpdg); phosphatidylacyclovir (pACV); 1-O-stearylglycero-rac-3-phospho-5'-(3'azido,3'-deoxy)thymidine.
Claim 9
Dependent Claim
197 words
A liposome formed at least in part from a liponucleotide compound comprising a conjugate of an antiviral nucleoside analogue which does not occur naturally in
the mammal to be treated and which is characterized by the ability to exert antiviral
activity on DNA or RNA viruses, and a lipid moiety linked to the 5' position of the
nucleoside analogue wherein the conjugate has the formula (L) m -(W) n -A-Q-Z wherein Z is the base portion of a nucleoside analogue; Q is a pentose residue or an acyclic fragment thereof or a carbocyclic
analogue; A is O or S; W is phosphate; n is 1 to 3; and L is a lipid moiety, wherein m = 1 to 5; wherein L is linked directly to a W,
and wherein L is selected from wherein R, R 1 and R 2 independently have from 0 to 6 sites of unsaturation, and have the
structure CH 3 -(CH 2 ) a -(CH=CH-CH 2 ) b -(CH 2 ) c -Y wherein the sum of a and c is from 1 to 23; 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-.
Claim 10
Dependent Claim
17 words
A liposome formed at least in part from a liponucleotide according to the formula
of claim 6.
Claim 11
Dependent Claim
16 words
A pharmaceutical composition comprising a liponucleotide compound according
to claim 6 and a pharmaceutically acceptable carrier.
Claim 12
Dependent Claim
23 words
A pharamceutical composition comprising a liponucleotide compound according
to claim 6 and at least one other antiviral compound together with pharmaceutically
acceptable carriers.
References Cited (Backward Citations)
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