CA2445565C - Compositions and methods of double-targeting virus infections and cancer cells - Google Patents

Compositions and methods of double-targeting virus infections and cancer cells Download PDF

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CA2445565C
CA2445565C CA2445565A CA2445565A CA2445565C CA 2445565 C CA2445565 C CA 2445565C CA 2445565 A CA2445565 A CA 2445565A CA 2445565 A CA2445565 A CA 2445565A CA 2445565 C CA2445565 C CA 2445565C
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compound
virus
alkyl
pharmaceutically acceptable
mammal
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CA2445565A1 (en
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Louis S. Kucera
Ronald A. Fleming
Khalid S. Ishaq
Gregory L. Kucera
Susan L. Morris-Natschke
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University of North Carolina at Chapel Hill
Wake Forest University Health Sciences
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Wake Forest University Health Sciences
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    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/22Antivirals for DNA viruses for herpes viruses
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    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/06Phosphorus compounds without P—C bonds
    • C07F9/08Esters of oxyacids of phosphorus
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    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract

The invention includes compositions and methods useful for treatment of a virus infection in a mammal by double-targeting the virus (i.e. targeting the virus at more than one stage of the virus life cycle) and thereby inhibiting virus replication. The compositions of the invention include compounds of formula III (shown below), which comprise a phosphocholine moiety covalently conjugated with one or more therapeutic agents (e.g. nucleoside analogue, protease inhibitor, etc.) to a lipid backbone. The invention also includes pharmaceutical compositions for use in treatment of a virus infection in mammals. The methods of the invention comprise administering a compound of the invention, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition of the invention, in an amount effective to treat the infection, to a mammal infected with a virus. Additionally, the invention includes compositions and methods useful for combating a cancer in a mammal and facilitating delivery of a therapeutic agent to a mammalian cell. The compositions of the invention include compounds, which comprise an alkyl lipid or phospholipid moiety covalently conjugated with a therapeutic agent (e.g., a nucleoside analogue). The invention also includes pharmaceutical compositions for combating cancer and facilitating delivery of a therapeutic agent to a mammalian cell. The methods of the invention comprise administering a compound of the invention, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition of the invention, in an amount effective to combat a cancer or to facilitate delivery of a therapeutic agent to a mammalian cell.
(see formula III)

Description

TITLE OF THE INVENTION
COMPOSITIONS AND METHODS OF
DOUBLE-TARGETING VIRUS INFECTIONS AND CANCER CELLS
BACKGROUND OF THE INVENTION
Acquired immunodeficiency syndrome (AIDS) is a degenerative disease of the immune system and central nervous system (CNS) resulting from infection of humans by HIV virus. AIDS is responsible for a rapidly growing fatality rate in the world population. At present, no cure has been found, and clinically approved drugs are limited in number. These drugs include nucleoside reverse transcriptase (RT) inhibitors such as 3'-azido-3'-deoxythymidine (AZTTm, Zidovudine), dideoxyinosine (ddI, Didanosine), dideoxycytidine (ddC, Zalcitabine), 2', 3'-dideoxy-3'-thiacytidine (3TCTm, Lamivudine), and 2', 3'-didehydro-3'-deoxythymidine (d4T, Stavudine), a non-nucleoside RT inhibitor (Niverapine), and protease inhibitors such as saquinavir (Inverase), ritonavir (Norvir), indinavir (CrixivanTm), and nelfinavir (ViraceptTm).
Nucleoside RT inhibitors generally have similar structures (2', 3'-dideoxynucleosides) and act at an early stage in virus replication to inhibit provirus DNA
synthesis (De Clercq, 1995, Journal of Medicinal Chemistry, 38:2491-2517). However, AZTTm, the recommended initial therapeutic agent, and the other nucleoside analogues have several limitations, including adverse side effects such as bone marrow depression and anemia (Gill et al., 1987, Annals of Internal Medicine, 107:502-505; Richman et al., 1987, New England Journal of Medicine, 317:192-197). Peripheral neuropathy is also a major and common side effect. AZTTm is rapidly eliminated from the plasma with a half-life of about one hour (Surbone et al., 1988, Annals of Internal Medicine, 108:534-540) and is quickly metabolized in the liver to its corresponding 5'-glucuronide, which is inactive.
Presently, only a small number of antiviral drugs are available for treatment of virus infections. A complication to the development of such drugs is that mutant strains of virus which are resistant to currently available antiviral drugs are developing at an alarming rate. Combinations of new drugs having unique modes of action are urgently needed to replace drugs that have lost their potency against viruses as a result of virus mutations. A further complication to the development of antiviral drugs is that development of viral resistance to available compounds is not the same in different body compartments and fluids. For example, evolution of drug resistance among HIV-1 clinical isolates is often discordant in blood and semen of HIV-1 positive males (Eron et al., 1998, AIDS 12:F181-F189).
Further, currently available drugs useful for antiviral therapy sometimes ineffectively penetrate the genital tract. This is a serious drawback to the use of these drugs to combat viruses which infect the genital tract. If an antiviral drug promotes development of resistance in the genital tract and the virus is commonly transmitted from this body site, the drug will rapidly become ineffective for treatment of the virus infection in the population at risk for transmission. Hence, drug-resistant mutants of certain viruses can be rapidly spread by sexual contact in the human population. It is known that viruses such as HIV, hepatitis B, hepatitis C, herpes simplex virus, cytomegalovirus, papilloma viruses, and many others are transmitted via sexual contact by both males and females. Thus, therapeutic drugs that fully suppress virus infections in the genital tract are a high public health priority.
Another limitation of presently available antiviral drugs is that rapid emergence of drug resistant mutant virus can lead to decreased sensitivity to the drug within a patient or within a patient population (Larder et al., 1989, Science, 243:1731-1734). Thus, the beneficial effects of drugs such as AZT are limited in duration.
The anti-HIV chemotherapy era which started a decade ago has recently made significant progress toward better control of HIV-1 infection by the introduction of protease inhibitors and the use of combinations of nucleoside and non-nucleoside RT inhibitors with protease inhibitors. Monotherapy (e.g. administration of a single drug) using a nucleoside or non-nucleoside RT inhibitor or a protease inhibitor is no longer a recommended form of therapy for treatment of a patient with a virus infection such as HIV-1 infection. Although combinations of AZT, 3TC, and a protease inhibitor have reduced virus load in the plasma of patients to below detectable levels (i.e. fewer than 200 copies of viral RNA per milliliter of plasma) with a concomitant increase in CD4 + cell count, some drug combinations have been associated with increased toxicity in a person receiving multiple drug therapies. Also, although reduction in virus burden in the plasma of patients to non-detectable levels achieved using some drug combinations is impressive, drug resistance is an escalating problem due to both use and misuse of drug therapy (De Clercq, 1995, Journal of Medicinal Chemistry, 38:2491-2517; Bartlett, 1996, Infectious Diseases in Clinical Practice, 5:172-179) and evolution of resistant mutants in blood and seminal fluids (Eron et al., 1998, AIDS, 12:F181-F189).
The pathogenic events in HIV disease have recently been reviewed by Fauci (1996, Nature {New Biology}, 384:529-534). The current understanding is that entry of HIV into cells varies with the virus strain and cell type. Primary infection of humans is associated with macrophage tropic (M-tropic) virus that utilize the receptor and a beta-chemokine co-receptor (CCR5) for entry into macrophages.
As HIV infection progresses, the initial M-tropic viruses are usually replaced by T-tropic viruses that enter T-lymphocytes via the CD4 receptor and co-receptor CXCR4 (fusin).
The viral determinant of cellular tropism maps to the gp 120 subunit of H1V-1 Env protein, particularly the 3rd variable region or V3 loop of gp120. Upon entry into these cells, HIV probably infects dendretic cells, which then carry the virus to CD4+ cells in the lymphoid organs. Infection is then established in the lymphoid organs and a burst of infectious virus seeds itself throughout the body, including the CNS, brain, and lymphoid tissues and sexual organs (e.g. testes). Current drugs used in therapies for HIV infection and AIDS noted above have a limited capacity and half-life for absorption from the stomach to the blood, accumulation into lymphoid organs, crossing the blood-brain barrier into the CNS, or entering the sexual organs (e.g.
testes) to attack sanctuaries for HIV replication.
Synthetic phosphocholine lipid (PC lipid) analogues such as, for example, 1-decanamido-2-decyloxypropy1-3-phosphocholine (INK-11) have demonstrated a low incidence of unwanted side effects in mice such as reduction of bone marrow precursor cells and have exhibited high differential selectivity (i.e. the ratio of TC50 for cytotoxicity to EC50 for antiviral activity, DS=1342 for INK-11) in human leukocytes in cultured cells. At a dosage of 50 milligrams per kilogram of body weight per day for 21 days, INK-11 inhibited Friend leukemia virus-(FLV-) induced pathogenesis by 42% in infected mice, as indicated by significant activity against splenomegaly. The observation that use of INK-11 resulted in only moderate suppression against RT activity compared with AZT alone (42% vs 98%, respectively) suggests that INK-11 induces production of defective virus, similar to the effect achieved using other lipid compounds alone (Kucera, et al., 1990, AIDS
Research &
Human Retroviruses 6:491-501).
Other synthetic phospholipids which do not comprise a phosphocholine moiety (non-PC lipids) have been conjugated with antiviral chemotherapeutic agents.
For example, thioether lipid-nucleoside conjugates have exhibited improved antineoplastic activity in tumor-bearing mice (Hong et al., 1990, Journal of Medicinal Chemistry 33:1380-1386). Also, natural phospholipids coupled to AZT or to dideoxynucleosides (ddT, ddC) have proven to be markedly active against HIV by inhibiting viral RT activity (Steim et al., 1990, Biochemical & Biophysical Research Communications 171:451-457; Hostetler et al., 1990, Journal of Biological Chemistry 265:6112-6117; Hostetler et al., 1991, Journal of Biological Chemistry 266:11714-11717). Studies of phospholipid antiviral efficacy have also included chemically conjugating AZT or ddI, through a phosphate-ester bond, to selected synthetic phosphatidic acid lipid analogues (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414). Synthetic phosphate-ester linked lipid-nucleoside conjugates were found to be markedly active against infectious HIV-1 production in both acutely- and persistently- infected cells, and were 5- to 10-fold less cytotoxic compared with AZT alone (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414). Results of preliminary studies indicated that synthetic lipid-AZT
conjugates block reactivity of HIV-1-induced gp160/gp120 proteins with specific monoclonal antibodies on the surface of infected and treated cells and on the surface of treated HIV-1 particles, as measured by flow cytometry. These conjugate compounds also caused inhibition of HIV-1-induced cell fusion (Kucera et al., 1992, In:
Novel Membrane Interactive Ether Lipids With Anti-Human Immunodeficiency Virus Activity, Aloia et al., eds., Membrane Interactions of HIV, pp.329-350;
Krugner-Higby et al., 1995, AIDS Research & Human Retroviruses 11:705-712). However, these phosphate ester-linked lipid-AZT conjugates (non-PC lipid-AZT conjugates) were not very active against AZT-resistant clinical isolates of HIV-1. Moreover, after intracellular metabolism of the conjugate with resulting release of AZT-monophosphate, the lipid moiety exhibited only moderate to non-detectable antiviral activity (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414).
As with the antiviral agents, the development of anticancer agents for treating cancer effectively has also been problematic. Barriers such as cellular mechanisms of anticancer drug resistance, overcoming the blood-brain barrier to provide adequate delivery of drug to the brain and CNS, inadequate uptake of drug by lymphoid and hematopoietic tissues, toxicity, achieving oral bioavailability, overcoming short drug half-life, and preventing extracellular metabolism of the anticancer agent are faced by the skilled artisan.
In order to improve bioavailability to CNS and brain tissue, nucleoside analogues have been encapsulated in liposomes or used with modifying agents to disrupt the blood-brain barrier (Braekman, et al., 1997, Proc. Amer. Soc. for Clinical Oncology, Abstract #810). Implantable devices have been used to provide more sustained drug delivery to increase the pharmacokinetics of anticancer agents (Del Pan, et al., 1997, Proc. Amer. Soc. for Clinical Oncology, Abstract #1384).
Additionally, attempts to improve the efficacy of nucleoside analogues in cancer therapy have included the use of multidrug combinations and high-dose nucleoside analogue therapy (Capizzi, 1996, Investigational New Drugs 14:249-256). None of these methods have adequately overcome the problems discussed above with regard to anticancer agents.
Another attempt to circumvent the problems associated with conventional nucleoside analogue cancer therapy has been the conjugation of these molecules to phospholipids. Thus far, the conjugation of nucleoside analogues to phospholipid molecules has focused on ara-C and a limited number of diacyl, alkylacyl and thioether phospholipids (Hong, 1990, Cancer Res. 50:4401-4406). Although these conjugates have shown efficacy in the treatment of hematologic malignancies, these drugs must be administered intraperitoneally or intravenously and do not overcome the problems discussed above regarding anticancer agents. These conjugates are degraded by phospholipase A and phospholipase B extracellularly and do not provide the option of oral administration.
Despite the promising attributes of compounds such as PC lipids, and non-PC lipid-nucleoside analogue conjugates, currently available antiviral and anticancer agents such as nucleoside analogues and anti-HIV nucleoside drugs have severe inherent limitations. Although such drugs are capable of delaying the onset of symptoms of virus infection and extending survival time for patients, new compounds having the attributes of increased tolerability, potency, and selectivity against specific viruses, differential mechanisms of action, ability to cross the blood-brain barrier, and freedom from myelosuppressive side effects are urgently needed for improved treatment of virus infections. Also, new antiviral and anticancer compounds are needed which more effectively combat cancers or target multiple aspects of the virus life cycle, which facilitate delivery of an anticancer agent to cells and tissues not normally accessible to anticancer agents (e.g. CNS and lymphoid tissues), which combine lipophilic (e.g. phospholipid) and antiretroviral or anticancer agents within the same molecule (e.g. conjugate compounds) in order to yield a drug with a more sustained antiviral or anticancer effect, which decrease the rate of emergence of drug-resistant virus strains, and which inhibit virus replication in a wider range of cellular or tissue reservoirs of virus infection. The present invention satisfies these needs.
BRIEF SUMMARY OF THE INVENTION
The invention includes a compound having the structure of Formula III:
H2C __________________________________ X11 R11 Ri2' R _ x 12 12-C H
0 "'N
H 2 C __ x13 0 _________________________________________________________ R13 0 ¨ n (III) wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is (C1-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
X11 is -0-, -S-, -NH2-, or -NHC(0)-;
x12 is -0-, -S-, S-, -N112-, or -NHC(0)-;
X13 is -0-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
R3 is (Ci-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-Cs) alkoxy;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention includes another compound having the structure of Formula III:
H2C __________________________________ X 11 ¨R11 R12' R12¨x12¨C H

H2C __________________________________ X13 ________ 0 ___ R13 \-.0 (M) wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R.12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
¨12' K is (C1-C16) phenalkyl or alkoxy or anhydride or hydroxy, with the proviso that when R12' is not hydroxy, it is linked to X12 through an ether oxygen and wherein R12' is terminally substituted with a therapeutic agent;
Xil -S-;
5X12 =
ls -0-;
X13 is -0-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention includes another compound having the structure of Formula III:
H2C __________________________________ X 11 ¨R11 1 2' 1 2 1 2 R ¨R ¨x ¨C H
c. 0 I
H2 C _________________________________ X13 __ 0 ________________________________________________________ R13 0 ¨ n (III) wherein, is -k-,1211255 R12 is -(CH2)8, -(CH2)105 or 4CH2)12;
R12' is -02CCH2CO2AZT or -OH;
is -0-;
X13 is -0-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention also includes a method of treating a virus infection in a mammal. The method comprises administering to the mammal, in an amount effective to treat the infection, a compound, or a pharmaceutically acceptable salt or a prodrug thereof, having the structure of Formula III:
H2C __________________________________ X ¨Rii R12' R12 x12¨C H
P.. 0 H2C __________________________________ X13 __ P 0 ___ R13 n (III) wherein, Rn is C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
IS.12' Is (l-,1-µ,16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NTIC(0)-;
X11 is -0-, -S-, -NH2-, or -NHC(0)-;
X12 is _0_, _S-, -NH2-, or -NHC(0)-;
X13 is -0-, -S-, -CH2-, anhydride, or (Ci-C16) allcoxY;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
The invention includes another method of treating a virus infection, including an infection by a herpes virus or HIV. The method comprises administering to a mammal, in an amount effective to treat the infection, a compound, or a pharmaceutically acceptable salt or a prodrug thereof, having the structure of Formula III:
H 2 C ________________________________ X 11 ¨R11 R12' al 2 x12_C H

I
H2C __________________________________ x13 __ 0 _________________________________________________________ R13 0 ¨ n (III) wherein, R11 is -C12H25;
R12 is (CH2)12 or (CH2)8;
R12' is -OH or -02CCH2CO2AZT;
)(11 is -s-;
X12 is -0-;
X13 is -0-;
R13 is -R3N(R6)(R)R8;
R3 is -CH2CH2.; and R6, R7 and R8 are each independently methyl.
The invention also includes a method of inhibiting virus replication in a cell. The method comprises administering to the cell, in an amount effective to inhibit virus replication in the cell, a compound, or a pharmaceutically acceptable salt or a prodrug thereof, having the structure of Formula III:
H2C¨Xi1¨R11 õ_µ12 12 K ¨K ¨X ¨U
I I
H 2 C ¨X13 __________________________________ P 0 ___ R13 ¨ n (III) wherein, ¨11 K is (C1-C16) alkyl, branched alkyl, allonyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
X12' is (C1-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is -- optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
xii is - u S-, -NH2-, or -NHC(0)--;
X12 is -0-, -S-, S-, -NH2-, or -NHC(0)-;
X13 is -0-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
The invention also includes a method of combating a cancer in a mammal. The method comprises administering to the mammal, in an amount effective to combat a cancer in the mammal, a compound, or a pharmaceutically acceptable or a prodrug salt thereof, having the structure of Formula III:
H 2 C _________________________________ X 11¨R11 12' 12 12 R ¨R ¨x ¨C H

I I
H2C¨X 13 ____________________________________ P 0 ____ R13 (HD
wherein, R11 is ¨1-(u C16) alkyl, branched alkyl, alkenyl or alkynyl;
¨12 x is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is (Ci-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
X11 is -0-, -S-, -NH2-, or -NHC(0)-;
X12 is -0-, -S-, -NH2-, or -NHC(0)-;
x13 is -0-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
The invention further includes a method of treating a disease in a mammal. The method comprises administering to the mammal, in an amount effective to treat the disease, a compound, or a pharmaceutically acceptable salt or a prodrug thereof, having the structure of Formula III:
H2C __________________________________ X 11¨R11 R.12' R12¨x12¨C H

II
H2 C _________________________________ X13 ________ 0 ____ R13 0 ¨ n (III) wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is (C1-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
X11 is -0-, -S-, -NH2-, or -NHC(0)-;

is S-, -NH2-, or -NHC(0)-3 X13 is -0-, -S-, -CH2-, anhydride, or (C1-C16) alkoxY;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C i-C8) alkoxy.
The invention also includes a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:
H 2 C ¨X11 ¨R11 12' 12 12 R¨R ¨CH

____________________________________________ I I
H2 C --X 13 P 0 ____ R13 0 ¨ n (III) wherein, R11 is --1_ (u C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
¨12' K is (C1-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
xii is U S-, -NH2-, or -NHC(0)-;
x12 is -0-, -S-, S-, -NH2-, or -NHC(0)-;
X13 is -0-, -S-, -CH2-, anhydride, or (Ci-C16) alkoxy;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(R7)R8;
53 i R s (CI-Cs) alkylene; and R6, R7 and R8 are each independently -H, (Ci-C8) alkyl or (C1-C8) alkoxy;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention also includes another pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:
H2 C _________________________________ X11 ¨R11 12' 12 12 R ¨R ¨x ¨C H

H2C _________________________________ X 13 __ P 0 ____ R13 ¨ n (III) wherein, 1 5R 11 =
is (C1-C16) alkyl, branched alkyl, alkenyl or allcynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alk3myl;
R12' is (C1-C16) phenalkyl or alkoxy or anhydride or hydroxy, with the proviso that when R12' is not hydroxy, it is linked to X12 through an ether oxygen and wherein R12' is terminally substituted with a therapeutic agent;
X12 is -0-;
x13 is -0-;
R13 is -R3NR6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts or prodrugs thereof.
The invention also includes another pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:
H2C __________________________________ X11¨R11 R R¨ x 12' 12 12¨C H

H2 C _________________________________ x13 __ ___________________________________________________ 0 ___ R13 =- 0 ¨
(III) wherein, 1µ. r125;
R12 is -(CH2)8, -(CH2)10, or -(CH2)12;
¨12' x is -02CCH2CO2AZT or -OH;
X12 is -0-;
X13 is -0-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts and prodrugs thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.
Figure 1, comprising Figures 1A, 1B, 1C and 1D is a series of formulae depicting the chemical structures of several anticancer agents. Figure lA
depicts the chemical structure of BM21.1290. Figure 1B depicts the chemical structure of gemcitabine. Figure 1C depicts the chemical structure of ara-C. Figure 1D
depicts the chemical structure of 5-azacytidine.
Figure 2 is a reaction scheme depicting the synthesis method for preparing a lipid backbone (i.e. an alkyl lipid) for the compounds of the invention.
Figure 3 is a reaction scheme depicting the synthesis method for preparing an AZT-malonic acid (AZT-MA) compound, which is an intermediate compound in the synthesis of the double targeting PC lipid-AZT conjugate compounds of the invention.
Figure 4 is a reaction scheme depicting the synthesis method for preparing a double targeting PC lipid-AZT conjugate compound of the invention (INK-20).
Figure 5 is a graph depicting the concentrations of radiolabeled BM21.1290 in plasma and various lymphoid tissue samples after administration of radiolabeled BM21.1290 to female C57BI/6 mice for a two week period. The data indicate the preferential uptake of BM21.1290 into lymphoid tissue of mice.
Figure 6 is a graph depicting the concentrations of radiolabeled BM21.1290 in plasma and brain tissue samples after administration of different doses of radiolabeled BM21.1290 to female C57BI/6 mice for a two week period. The data indicate that the concentration of BM21.1290 in brain tissue samples is equivalent to .
the concentration of the compound in plasma, indicating that the compound effectively crosses the blood-brain barrier in mice.
Figure 7, comprising Figures 7A and 7B, is a pair of formulae depicting the chemical structures of exemplary compounds of Formula III.
Figure 8, comprising Figures 8A and 8B, is a pair of formulae depicting the chemical structures of exemplary compounds of Formula N.
Figure 9 is a formula depicting the chemical structure of an exemplary compound of Formula V.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods and compositions useful in drug delivery for treatment of a virus infection in a mammal by targeting the virus at two or more stages of the virus life cycle and thereby inhibiting virus replication. This mode of use of antiviral compositions is referred to herein as double-targeting a virus infection. The compositions of the invention include compounds comprising at least two chemically combined (e.g. covalently conjugated) antiviral agents which have different modes of action. Because the antiviral agents have different modes of action, they target the virus life cycle at two or more different stages. By way of example and not by limitation, the compositions of the invention include compounds having a nucleoside analogue or protease inhibitor moiety conjugated with a phosphocholine lipid (PC lipid) moiety. Also by way of example and not by limitation, the targets in the viral life cycle of the compounds of the invention may include stages involving reverse transcription, protease activity, and virus assembly. The methods and compositions of the invention are particularly useful in combating drug-resistant mutants of viruses because viruses resistant to nucleoside analogues and protease inhibitors are still sensitive to inhibition by phospholipids. As used herein, the term "conjugated with" means covalently attached to the same molecule.
The targeted virus may be any type of virus, and non-limiting exemplary viruses include HIV-1, HIV-2, hepatitis virus (e.g. hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E viruses), and hetpesviru.ses (e.g.
herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein Barr virus, and human herpes viruses types 6, 7, and 8).
The compounds of the invention exhibit biological properties which are superior to currently available antiviral drugs, including (i) reduced cytotoxicity accompanied by the ability of the mammal to tolerate a higher dose of the drug compared with nucleoside analogues or protease inhibitors alone, (ii) ability to target multiple distinct stages of virus replication (e.g. reverse transcription, protease processing of viral proteins and virus assembly, leading to non-replication or to production of defective progeny virus) (iii) ability to simultaneously deliver constant amounts of multiple antiviral agents (e.g. phosphocholine lipid and a nucleoside analogue or phosphocholine lipid and a protease inhibitor) to virus-infected cells with preferential uptake into the CNS, lymphoid tissues, and male and female genital tracts, (iv) intracellular metabolism of the conjugate compound and simultaneous release of two antiviral agents in cells in which virus is multiplying, (v) increased half-life of the compound in vivo compared with nucleoside analogues or protease inhibitors alone, (vi) prolonged duration of biological effect, presumably owing to protection of nucleoside analogue from rapid glucuronide formation in the liver of intact animals, and (vii) capacity to conjugate other small molecular weight compounds to the phosphocholine (PC) lipid backbone for treatment of other diseases of the central nervous system (e.g. Alzheimer's, cancer), in addition to diseases such as AIDS, resulting from virus infection.
Previous studies have established that a PC moiety is an essential component for a phospholipid to exhibit optimal antiviral activity (Piantadosi et al., 1991, J. Med. Chem. 34:1408-1414; Krugner-Higby et al., 1995, AIDS Res. &
Human Retrovir. 11:705-712). Compounds comprising phosphatidic acid, phosphoethanolamine, phosphoalkylpyridine, alcohol, or quaternary amine salt moieties were less active, more toxic, exhibited much lower differential selectivities, or some combination of these, relative to the corresponding PC lipids. In certain preferred compounds of the invention, a PC moiety is incorporated into the lipid backbone to result in compounds which exhibit optimal antiviral activity, can accumulate into lymphoid tissues, testes, and vaginal secretions, and can pass the blood-brain barrier into the CNS. These anatomical sites serve as important reservoirs of virus during infection by viruses such as HIV-1, and also serve as sources of transmission of drug-resistant mutants.
The invention also includes methods of treating a virus infection in a cell or in a mammal, such as a human, comprising administering to the cell or mammal a compound of the invention in an amount effective to alleviate or eliminate the virus infection or to alleviate a symptom associated with the infection.
The present invention also includes methods and compositions useful in drug delivery for facilitating delivery of a therapeutic agent to a mammalian cell. As used herein, the term "facilitating delivery"or "to facilitate delivery" of a therapeutic agent to a mammalian cell means enhancing the uptake of a therapeutic agent in a mammalian cell to a level higher than the level of uptake of the therapeutic agent in an otherwise identical mammalian cell which is not administered a compound or composition of the invention. The uptake of a therapeutic agent can be enhanced, by way of example and not by limitation, by any one or more of the following means: by bypassing the requirement for a cellular active transport mechanism for uptake of the therapeutic agent into a cell; by providing the therapeutic agent (i.e. a drug) intracellularly in an activated form, (i.e. the monophosphorylated form in the case of a nucleoside analogue anticancer drug) thereby bypassing the requirement for intracellular activation of the therapeutic agent by an enzyme such as an intracellular kinase; by overcoming a physiological barrier to uptake of the therapeutic agent in a desired cell, such as low solubility, poor absorption from the stomach or small intestine, or impermeability to the blood-brain barrier, to enable delivery of the therapeutic agent to sites not normally accessible thereto (i.e. CNS and lymphoid tissues).
The present invention also includes methods and compositions useful in drug delivery for combating a cancer in a mammal or for treating or alleviating a disease in a mammal. As used herein, the term "combating a cancer" or "to combat a cancer" in a mammal means, for example, any one or more of the following: to increase survival of a mammal, to decrease or arrest tumor size in a mammal, or to increase the time period of remission of cancer regrowth in a mammal, relative to an otherwise identical mammal which was not administered a composition or compound of the invention.
As used herein, the term "therapeutic agent" means any compound or composition, which, upon entering a mammalian cell, is capable of being of benefit in alleviating or treating a disease in a mammal. By way of example and not by limitation, such compounds and compositions include small organic molecules, peptides, nucleoside analogues, anticancer agents, antiviral agents, ribozymes, protease inhibitors, polymerase inhibitors, reverse transcriptase inhibitors, antisense oligonucleotides and other drugs. The disease may be any disease experienced by a mammal. By way of example and not by limitation, such diseases include diseases of the brain, CNS, lymphatic system, reproductive system, cardiovascular system, renal system and liver, among others.
As used herein, "alleviating a disease" means reducing the severity of a symptom of the disease. As used herein, "treating a disease" means reducing the frequency with which a symptom of the disease is experienced by a mammal.
As used herein, the term "anticancer agent" means a therapeutic agent which is capable of exhibiting efficacy at combating a cancer in a mammal or in a mammalian cell, or any compound which is capable of being converted intracellularly to a compound which is capable of exhibiting efficacy at combating a cancer in a mammal or in a mammalian cell.
The mammalian cell can be any type of mammalian cell, including both cancerous and non-cancerous cells. Examples of preferred cells include, but are not limited to, CNS and lymphoid cells. Preferred lymphoid cells include lymphoma, spleen and thymus cells. Preferred CNS cells include brain cells, astrocytes, and glial cells. The cancer can be any type of cancer in a mammal. Preferably, the cancer is one or more of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
The compositions of the invention include compounds which comprise an alkyl lipid or a phospholipid moiety covalently conjugated with a therapeutic agent.
As used herein, the term "alkyl lipid" means that portion of any of the compounds of Formulae I-VI, as described herein without the therapeutic agent moiety.
The invention also includes pharmaceutical compositions and kits for combating a cancer and/or for facilitating delivery of a therapeutic agent to a mammalian cell.
The invention also includes methods which comprise administering a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in an amount effective to combat a cancer or in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell.
As used herein, the following terms are defined as follows, unless otherwise described: halo is fluor , chloro, bromo, or iodo. Alkyl, alkoxy, alkylene, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" being specifically referred to.
The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
Compounds of the invention having a chiral center can exist in and be isolated in distinct optically active or racemic forms. The present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures of such forms of a compound of the invention. Preparation of optically active forms of a compound is well known in the art (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). Determination or assessment of antiviral activity can be performed using standard tests described herein or other tests known in the art.
Specific and preferred definitions listed below for radicals and substituents are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents described herein.
C1-Cs alkyl moieties include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, sec-pentyl, iso-pentyl, hexyl, sec-hexyl, iso-hexyl, heptyl, sec-heptyl, iso-heptyl, and octyl moieties. C1-C8 alkoxy moieties include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, sec-pentoxy, iso-pentoxy, hexyloxy, sec-hexyloxy, heptoxy, sec-heptoxy, iso-heptoxy, and octyloxy moieties. C1-C8 alkylene moieties include, for example, methylene, ethylene, propylene, isopropylene, butylene, iso-butylene, sec-butylene, pentylene, sec-pentylene, iso-pentylene, hexylene, sec-hexylene, iso-hexylene, heptylene, sec-heptylene, iso-heptylene, and octylene moieties. C6-C15 alkyl moieties include, for example, hexyl, heptyl, sec-heptyl, iso-heptyl, octyl, sec-octyl, iso-octyl, nonyl, sec-nonyl, iso-nonyl, decyl, sec-decyl, iso-decyl, undecyl, sec-undecyl, iso-undecyl, dodecyl, sec-dodecyl, iso-dodecyl, tridecyl, sec-tridecyl, iso-tridecyl, tetradecyl, sec-tetradecyl, iso-tetradecyl, and pentadecyl moieties.

alkylene moieties include, for example, hexylene, heptylene, sec-heptylene, iso-heptylene, octylene, sec-octylene, iso-octylene, nonylene, sec-nonylene, iso-nonylene, decylene, sec-decylene, iso-decylene, undecylene, sec-undecylene, iso-undecylene, dodecylene, sec-dodecylene, iso-dodecylene, tridecylene, sec-tridecylene, iso-tridecylene, tetradecylene, sec-tetradecylene, iso-tetradecylene, and pentadecylene moieties. C8-C12 alkyl moieties include, for example, octyl, sec-octyl, iso-octyl, nonyl, sec-nonyl, iso-nonyl, decyl, sec-decyl, iso-decyl, undecyl, sec-undecyl, iso-undecyl, and dodecyl moieties. C8-C12 alkylene moieties include, for example, octylene, sec-octylene, iso-octylene, nonylene, sec-nonylene, iso-nonylene, decylene, sec-decylene, iso-decylene, undecylene, sec-undecylene, iso-undecylene, and dodecylene moieties.
The present invention includes compounds, which exhibit antiviral activity and are particularly useful because they exhibit antiviral activity against drug-resistant viruses. These compounds are also useful in drug delivery for treating or alleviating a disease and for facilitating delivery of a therapeutic agent to a mammalian cell. Accordingly, the invention includes a compound having the chemical structure of Formula I or a pharmaceutically acceptable salt thereof.
Formula I is I I
H2C¨Xl¨R1 _________ 0 C R4----C 0 CHf ____________ Z1 _ 11 HC¨X2 R2 __________ 0 C¨R ¨C--0¨CH

I I
112C X3 _______ P 0 ____ R- +N ____ R7 (I) wherein n and m are each independently 0 or 1, but n and m are not both 0;
5 R1 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl if n is 0 and (C1-C16) alkylene, alkenyl or alkynyl if n is 1;
R2 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl if m is 0 and (Ci-C16) alkylene, alkenyl or alkynyl if m is 1;
R3, R4 and R5 are each independently (C1-C8) alkylene;
R6, R7 and R8 are each independently (C1-C8) alkyl;
X1 and X2 are each independently S, 0, NHC=0, OC=0 or NH;
X3 is 0 or S;
El is H, S, halo or N3;
Z1 is H, S, or halo; or El and Zl together are a covalent bond;
15B2 =
is H, S, halo, or N3;
Z2 is H, S, or halo; or E2 and Z2 together are a covalent bond, and D1 and D2 are each independently selected from the group consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine, hypoxanthine, inosine, uracil and ring modifications thereof, including 0, N, and S substitutions.
In Formula I, each alkyl, alkylene, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R1, R2, R3, R4, R5, R6, R7, R8, D1, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoro, trifluoromethyl, trifluoromethoxy, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (Ci-C8) alkyl.
The following are examples of definitions for radicals and substituents of Formula Tin preferred embodiments. These examples are not limiting, but are instead provided as examples of several preferred embodiments which are included in the invention.
In preferred embodiments, R1 can be one of (C2-C16) alkylene, -(CH2)12-, and ¨CH CH-.-- In these embodiments, R1 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In preferred embodiments, R2 can be one of (C2-C16) alkylene, -(CH2)8-, -(CH2)10- , -(CH2)11- , -(CH2)12- , and ¨CH=CH- . In these embodiments, R2 is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(ta)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
R3 is preferably -CH2CH2-, optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (Ci-C8) alkyl.
R4 is preferably -CH2-, optionally substituted with 1 or 2, substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
R5 is preferably -CH2-, optionally substituted with 1 or 2 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In one preferred embodiment, each of R6, R7 and R8 is -CH3, each optionally substituted with 1 or 2 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
X1 is preferably S, 0 or NHC=0.
X2 is preferably S, 0 or NHC=0.
X3 is preferably 0 or S.
El is preferably N3 S, or H.
Z1 is preferably H.
E2 is preferably N3 S or H.
Z2 is preferably H.
D1 is preferably cytosine, guanine, inosine or thymine, wherein DI is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
D2 is preferably cytosine, guanine, inosine or thymine, wherein D2 is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (Ci-C8) alkyl.
The invention also includes a compound, which exhibits antiviral activity having the chemical structure of Formula II or a pharmaceutically acceptable salt thereof. This compound is also useful in drug delivery for treating or alleviating a disease or virus infection in a mammal. This compound is also useful for facilitating delivery of a therapeutic agent to a mammalian cell.
Formula II is H2c¨X1¨R1 HC ____________________ C R C 0 CH2 ____________ -o R6 _______________________ 3 + I E2 I

wherein, R1 is (C6-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R2 is (C4-C12) alkylene;
R3 is -CH2C1-12-;
R5 is -CH2-;
R6, R7 and R8 are each CH3;
X1 and X2 are each independently S, 0 or NHC:----0;
E2 is H or N3, and D2 is selected from the group consisting of thymine, cytosine, guanine and inosine.
In Formula II, each alkyl, branched alkyl, alkenyl, alkynyl, thymine, cytosine, guanine, and inosine of R1, R2, R3, R5, R6, R7, R8, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb), wherein Ra and Rb are each independently selected from the group consisting of H and (Ci-C8) alkyl.
The present invention also includes compounds, which exhibit antiviral activity and are useful in drug delivery for treating or alleviating a disease or virus infection or combating a cancer in a mammal. These compounds are also useful for facilitating delivery of a therapeutic agent to a mammalian cell. Accordingly, the invention includes a compound having the chemical structure of Formula III or a pharmaceutically acceptable salt or a prodrug thereof.
Formula III is H2C¨X11¨R11 12' 12 R ¨R ¨x12¨C H

H2C __________________________________ x13 __ 0 _________________________________________________________ R13 0 ¨ n (III) wherein, Rli is ¨1_ (c C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is ¨1-(c C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is (C1-C16) alkyl, branched alkyl, alkenyl, alkynyl, aryl, phenalkyl, or alkoxy or hydroxy, anhydride, or hydrogen, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through a linker moiety L and wherein R12' is optionally terminally substituted with a therapeutic agent, wherein L is -0-, -S-, -NH2-, or -NHC(0)-;
X11 is -0-, -S-, -NH2-, or -NHC(0)-;
X12 is -0-, -S-, -NH2-, or -NHC(0)-;
X13 is -0-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is a therapeutic agent or -R3N(R6)(127)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
In Formula III, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of Ril, R12, and R13 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In Formula III, if n is 1 or 2, the compound is a phospholipase C
substrate and is not a phospholipase A substrate. Also, if n is 1 or 2, the compound is converted to an alkyl lipid and a moiety selected from the group consisting of a nucleoside monophosphate and a nucleoside analogue monophosphate intracellularly in a mammal, and is not converted to an alkyl lipid and a moiety selected from the group consisting of a nucleoside monophosphate and a nucleoside analogue monophosphate extracellularly in a mammal.
The conjugate compounds of Formula III can be faimulated in pharmaceutical compositions as described herein, which have the advantageous properties of being suitable for oral administration, can be readily absorbed from the gastrointestinal tract, can cross the blood-brain barrier and be of value in the treatment of CNS diseases and cancers. These conjugates can be used in a number of different cell lines including, by way of example and not by limitation, brain tumor cells, lymphoid cells and pancreatic tumor cells.
In compounds of Formula III, which have at least one phosphate group (i.e., 11= 1 or 2) the phosphate ester linkage is cleaved intracellularly in a mammal by the action of a phospholipase C-like activity to release intracellularly a phospholipid and an anticancer agent. These compounds are substrates of phospholipase C, but not substrates of phospholipase A. Because the phospholipase C activity is intracellular, the conjugates are only converted to a phospholipid and a nucleoside monophosphate intracellularly, and not extracellularly. The metabolism of these compounds by an intracellular phospholipase C-like activity enables the compounds to be used in methods which circumvent the rate limiting step for the activation of nucleoside analogue prodrugs, namely, the conversion of nucleoside analogue to nucleoside analog monophosphate. Because they are metabolized intracellularly to release a nucleoside analogue monophosphate, the administration of these compounds results in the ability to provide an anticancer agent which can be effective in cancer cells which lack a kinase enzyme such as, for example, deoxycytidine kinase, as a mechanism of cellular anticancer drug resistance. Additionally, the phospholipid moiety can affect signal transduction pathways involving protein kinase C and MAP kinase signaling cascades.
The released nucleoside monophosphate serves two purposes. First, it bypasses the rate limiting step in the activation of several nucleoside prodrugs, namely, deoxycytidine kinase. Second, the polar phosphate group "locks" the nucleoside within the cell. The phospholipid conjugate also serves as a reservoir for the drug, increasing the drugs half-life. The capacity to conjugate other small molecular weight compounds to the phospholipid backbone for the treatment of other diseases of the central nervous system (i.e. Alzheimer's) is also of great utility. For example, an ether-lipid moiety can be used as a backbone for conjugation to a variety of therapeutic agents including nucleoside analogues, anticancer and antiviral agents, ribozymes and antisense oligonucleotides. Since the ether-lipid backbone is lipophilic, these conjugates can cross the blood-brain barrier and be used as prodrugs in the treatment of CNS
diseases, such as Alzheimer's and neurologic degenerative diseases. The lipophilic property of the conjugates enables them to cross the blood-brain barrier, and thus bypass the requirement for an active transport system in the cell in which uptake of the drug is desired.
In a preferred compound of Formula III, R12 .s (C8-C12) alkyl, branched alkyl, alkenyl or alkynyl;
¨12' K is (Ci-C16) phenalkyl or alkoxy or hydroxy or anhydride, with the proviso that when R12' is not hydroxy, it is optionally linked to X12 through an ether oxygen;
R13 is -R3N(R6)(1e)R8; and x12 is In more preferred compounds of Formula III, R12' is -OH or -02CCH2CO2-, wherein R12' is terminally substituted with a therapeutic agent.
A
particularly preferred compound of Formula III is described below as Formula VI.
The therapeutic agent may be an anticancer agent or an antiviral agent.
These agents include protease inhibitors, polymerase inhibitors, and nucleoside analogues. Preferably, the anticancer agent is selected from the group consisting of gemcitabine, ara-C, 5-azacytidine, cladribine, fluclarabine, fluorodeoxyuridine, cytosine arabinoside, and 6-mercaptopurine. If the anticancer agent is linked to the third carbon, the phosphorus atom of the phosphate moiety is covalently linked in a phosphate ester likage to the oxygen atom of the 5' hydroxyl group of a sugar moiety of R13. A preferred antiviral agent is AZT.
The invention includes additional compounds, which are useful in drug delivery for treating or alleviating a disease or combating a cancer in a mammal. The compounds are also useful for facilitating delivery of a therapeutic agent to a mammalian cell. Accordingly, the invention includes a compound having the chemical structure of Formula IV or a pharmaceutically acceptable salt thereof Formula IV is H2c ___.x21¨R21 R22¨X22¨CH

[-H2C ____________________________ X23 P ¨ CH2 ¨R23 I
0 - - n (IV) wherein, R21 is (C6 to C16) alkyl, branched alkyl, alkenyl, or alkynyl;
R22 is (Ci to C12) alkyl, branched alkyl, alkenyl, or alkynyl;
¨21 A is 0, S, or NHC=0;
X22 is 0, S, or NHC=0;
X23 iS 0 or S;
n is 1 or 2, and R23 is a therapeutic agent.
In Formula IV, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R2i, R22, and R23 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (CI-C8) alkyl, (Ci-C8) alkoxy, aryl, and N
(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In preferred compounds of Formula IV, 1( iS Ci2 alkyl;
R22 is C10 alkyl;
n = 1, and R23 is an anticancer agent.
Preferably, the anticancer agent is selected from the group consisting of gemcitabine, ara-C, 5-azacytidine, cladribine, fluclarabine, fluorodeoxyuridine, cytosine arabinoside and 6-mercaptopurine, wherein the methylene group of the phosphonate moiety is covalently linked to the oxygen atom of the 5' hydroxyl group of a sugar moiety of R23.
The invention includes additional compounds, which are useful in drug delivery for treating or alleviating a disease or combating a cancer in a mammal. The compounds are also useful for facilitating delivery of a therapeutic agent to a mammalian cell. Accordingly, the invention includes a compound having the chemical structure of Formula V or a pharmaceutically acceptable salt thereof.
Formula V is:
H2C ________________ X31¨R31 R32 ____)c32 ¨ CH

(V) wherein, R31 is (Ci to C16) alkyl, branched alkyl, alkenyl, or alkynyl;
R32 is (C1 to C16) alkyl, branched alkyl, alkenyl, or alkynyl;
X31 is 0, S, or NHC=0;
X32 is 0, S, or NHC=0;
X33 is ¨OH, ¨SH, or amino, and R33 is a therapeutic agent.
In Formula V, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R31, .K ¨32, and R33 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8) alkyl, (C1-C8) allcoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In preferred compounds of Formula V, R31 is (C6 ¨C16) alkyl, branched alkyl, alkenyl or alkynyl;
R32 is (C1 ¨C8) alkyl, branched alkyl, alkenyl or alkynyl, and R33 is an anticancer agent.
Preferably, the anticancer agent is selected from the group consisting of mitoxanthrone, methotrexate and CPT-11, and is covalently linked via an ester, amido or carbamate linkage to the ¨SH, OH or amino group of X33.
Compounds of Formula I and Formula II and some compounds of Formula III can be prepared according to procedures known to the skilled artisan (See, for example, Marx et al., 1988, Journal of Medicinal Chemistry 31:858-863;
Meyer et al., 1991, Journal of Medicinal Chemistry 34:1377-1383; Morris-Natschke et al., 1986, Journal of Medicinal Chemistry 29:2114-2117; Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414; and Surles et al., 1993, Lipids 28:55-57).
An example of such a procedure is illustrated in Figures 2-4. The structures presented in the reaction schemes of Figures 2-4 are representative and not meant to limit the compounds of the invention. Modifications to the reactions in Figures 2-4 using different compounds are apparent to the skilled artisan.
Briefly, a compound of Formula I or Formula II is prepared by reacting a lipid backbone moiety, prepared as shown in Figure 2, for example, with an AZT-malonic acid (AZT-MA) moiety, for example, prepared as shown in Figure 3. Synthetic methods for the preparation of a lipid backbone as described in Figure 2 are known in the art.
For example, the synthesis method for preparing a lipid backbone for a thiophosphocholine is described in Morris-Natschke et al., 1986, Journal of Medicinal Chemistry 29(10):2114-2117, except one would substitute the benzyloxy alkyl bromide for the C-2 alkyl chain described in the reference. To prepare an amidophosphocholine, for example, one would follow the synthesis method described in Kucera et al., 1998, Antiviral Chemistry and Chemotherapy, 9:157-165. However, one would substitute C6H5CH20(CH2)8Br (8-benzyloxyoctyl bromide) for CH3(CH2)7Br (octyl bromide) described in the reference. To prepare a lipid backbone for various other phosphocholine syntheses, one would follow the synthesis procedures described in Meyer et al., 1991, Journal of Medicinal Chemistry 34(4):1377-1383 and Morris-Natschke et al., 1993, Journal of Medicinal Chemistry 36(14) 2018-2023. Again, one would substitute the benzyloxy alkyl bromide for the C-2 alkyl chain described in the references.
A preferred compound of the invention (e.g. INK-20, a PC lipid-AZT
conjugate) can be prepared as described in the Examples herein and depicted in Figure 4 by reacting the lipid backbone moiety generated as shown in Figure 2 with the AZT-malonic acid (AZT-MA) moiety generated as shown in Figure 3. The AZT-MA
moiety can be prepared, for example, as described in the Examples herein.
Figures 2-4 together illustrate the reaction scheme for preparation of certain preferred compounds of the invention, wherein AZT is linked to a PC lipid at the terminal functionality of position-2 on a modified thioglycerol backbone. The intermediate thiophosphocholine in Figure 4 has a terminal hydroxyl group on the position-2 side chain, which is used as a site for conjugating AZT to the PC lipid. An antiviral agent such as, for example, AZT or a protease inhibitor can be linked to the PC lipid via a malonic ester.
This synthetic pathway allows manipulation of the rate of esterase-catalyzed hydrolysis of the AZT moiety in the cell by incorporation of substituted malonic linking groups.
While not wishing to be bound by any particular theory, it is expected that as with accepted prodrug strategy, the ester bond linking the PC lipid with the AZT
moiety is cleaved by the action of esterase-like activity in vivo, thereby releasing both active antiviral agents (e.g. nucleoside or protease inhibitor and PC lipid) inside treated cells (See Chapter 47, "Chemotherapy of Microbial Agents," pp. 1130 and 1141, respectively, in Goodman and Gilman, 1996, "The Pharmacological Basis of Therapeutics", Ninth Ed.).
The following compounds are illustrative of compounds having =
structures according to one or both of Formula I, Formula II, and Formula III, as described herein. These compounds can be prepared by the procedures described herein, or by variations thereof which are apparent to those skilled in the art in view of the instant disclosure. Exemplary compounds include 1NK-20, INK-25 and INK-26.

The chemical structures of these compounds are depicted in Table 1 herein.
Other compounds of Formula III, and compounds of Formulae IV and V
can be prepared according to procedures known to the skilled artisan. An example of such a procedure is described, for example, in Piantadosi et al., 1991, J.
Med. Chem.
34:1408-1414. The synthesis of a compound of Formula V involves direct esterification of the lipid portion with the therapeutic agent rather than conjugation of the therapeutic agent with the phosphatidic acid portion of Formulae III and IV.
Exemplary compounds having structures according to Formulae III, IV
and V, are described herein in the Figures. These compounds can be prepared by the procedures described herein, or by variations thereof which are apparent to those skilled in the art in view of the instant disclosure. Structural formulae of exemplary compounds are shown in Figure 7 (Formula III), Figure 8 (Formula IV), and Figure 9 (Formula V).
The compounds of the present invention can be prepared in the form of a pharmaceutically acceptable salt or a non-pharmaceutically acceptable salt.
Non-pharmaceutically acceptable salts are useful, for example, as intermediates for preparation of a pharmaceutically acceptable salt. When the compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, the compounds may be prepared as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects.
Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fiimaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chlorine, bromine, and iodine; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sufate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate.
Pharmaceutically acceptable and non-pharmaceutically acceptable salts may be prepared using procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid comprising a physiologically acceptable anion. Alkali metal (for example, sodium, potassium, or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be made. .
The compounds of Formulae I -VI can be formulated as pharmaceutical compositions and administered to a mammal, such as a human patient by a chosen route of administration. Pharmaceutical compositions that are useful in the methods of the invention can be prepared, packaged, or sold in a variety of formulations which can be suitable for one or more routes of administration such as, for example, oral, intravenous, intramuscular, topical, subcutaneous, rectal, vaginal, parenteral, pulmonary, intranasal, buccal, ophthalmic, or another route of administration.
Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates and mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
Thus, the present compounds can be systemically administered (e.g.
orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1 % (w/w) of active compound.
The percentage of the compositions and preparations can, of course, be varied, for example from about 0.1 % to nearly 100 % of the weight of a given unit dosage form.
The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained upon administration.
The tablets, troches, pills, capsules, and the like can also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch, or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac, sugar, and the like. A syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor. Of course, any material used in preparing a unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained-release preparations. and devices.
The active compound can be administered orally, intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant.
Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
The ultimate dosage form should be sterile, fluid, and stable under conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by formation of liposomes, by the maintenance of the required particle size (in the case of dispersions) or by use of one or more surfactants.
Microbial growth can be prevented using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be achieved using agents which delay absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent, optionally with one or more of the other ingredients enumerated above, followed by filter sterilization. In the case of sterile powders for preparation of sterile injectable solutions, preferred methods of preparation include vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient and any additional desired ingredient present in the previously sterile-filtered solution(s).
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.
Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e. about 20 C) and which is liquid at the rectal temperature of the subject (i.e. about 37 C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for vaginal administration. Such a composition may be in the form of, for example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon, a douche preparation, or a solution for vaginal irrigation.
Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, douche preparations may be administered using, and may be packaged within, a delivery device adapted to the vaginal anatomy of the subject.
Douche preparations may further comprise various additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
Low boiling propellants generally include liquid propellants having a boiling point of below 65 F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzo ate. The droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.
Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the flares.
Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration.
Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other ophthalmahnically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.
For topical administration, the present compounds can be applied in pure form, i.e., as a liquid. However, it will generally be desirable to administer the compounds to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohols, glycols, and blends of two or more of these, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use. The resulting liquid compositions can be applied using absorbent pads, used to impregnate bandages or other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of the invention to the skin are disclosed in Jacquet et al. (U.S.
Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat.
No.
4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Accordingly, the invention includes pharmaceutical compositions comprising one or more compounds of Formula I, Formula II, Formula III, Formula IV
Formula V, Formula VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
In a preferred embodiment, the pharmaceutical composition is adapted for oral, topical, or parenteral administration to a mammal such as a human, and comprises one or more compounds of Formula I, Formula II, Formula III, Formula VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat a virus infection in a mammal or in a cell, particularly wherein the virus is HIV, hepatitis virus, or herpes simplex virus.
As used herein, "treatment" of a virus infection can mean, for example, any one or more of the following: inhibiting the replication of the virus, reducing the virus load within a patient, inhibiting formation of infectious progeny virus, inhibiting infectiousness of virus, killing cells harboring virus, interfering with one or more stages of the virus life cycle, inhibiting one or more viral enzymes or inducing production of non-infectious virus particles that can activate an immune response against infectious virus (e.g. autovaccination).
In another preferred embodiment, the pharmaceutical composition is adapted for oral, topical, or parenteral administration to a mammal such as a human, and comprises one or more compounds of Formulae I-VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to combat a cancer in a mammal and/or to facilitate delivery of a therapeutic agent to a mammalian cell.
Useful dosages of the compounds of Formulae I-VI for inclusion in the pharmaceutical compositions of the invention can be determined by comparing in vitro activity and in vivo activity of the compounds in appropriate animal models.
Methods for the extrapolation of effective dosages in mice and other animal models to humans are known in the art (see, for example U.S. Pat. No. 4,938,949).
Generally, the concentration of the compound(s) of Formulae 1-VI in a liquid composition, such as a lotion, will range from about 0.1 % to about 95 % by weight, preferably from about 0.5 % to about 25 % by weight. The concentration in a semi-solid or solid composition such as a gel or a powder will range from about 0.1 %
to 100% by weight, preferably about 0.5 % to about 5 % by weight. Single doses for intravenous injection, subcutaneous, intramuscular or topical administration, infusion, ingestion or suppository will generally be from about 0.001 to about 5000 mg, and be administered from about 1 to about 3 times daily, to yield levels of about 0.01 to about 500 mg/kg, for adults.
The invention also includes one or more compounds of Formula I, Formula II, Formula III, Formula VI, or any combination thereof, in an amount effective to inhibit virus replication in a mammal. The compound of course is therefore useful for inhibiting virus replication in a cell or neutralization (i.e.
inactivation) of extracellular virus. Additionally, the invention includes one or more pharmaceutically acceptable salts of a compound of Formula I, Formula II, Formula VI, or any combination thereof, wherein the compound is present in an amount effective to inhibit virus replication in a mammal.
As used herein, to inhibit virus replication in a mammal means to reduce the virus load in a mammal to a level which is lower than the level of the virus load in an otherwise identical mammal which was not administered the compound.
Preferably, virus load in a mammal is reduced by about 1 to 12 logsio or more relative to an otherwise identical mammal which was not administered the compound. Virus load in a mammal can be assessed by a number of methods known in the art such as, for example, obtaining a tissue or fluid sample from the mammal and assessing the amount of virus or viral components in the mammal contained therein using technology which is either virological, immunological, biochemical or molecular biological in nature and which is well known to the skilled artisan and which are described elsewhere herein.
Inhibition of virus replication in a cell is assessed using similar or identical assays as those used to assess virus load in a mammal.
The invention also includes a kit for administering a composition of the invention (e.g. a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention) to a mammal for treatment of a virus infection. Preferably, the mammal is a human. The virus infection can be an infection by any one or more of the viruses described herein. The kit comprises the composition of the invention and an instructional material, which describes adventitially administering the composition to the mammal by any of the routes of administration described herein. In another embodiment, this kit comprises a (preferably sterile) solvent suitable for dissolving or suspending the composition of the invention prior to administering the compound to the mammal.
As used herein, an "instructional material" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the invention in the kit for any one or more of the following: effecting treatment of a virus infection in a mammal or in a cell; alleviation or treatment of the symptoms of a virus infection in the mammal;
combating a cancer in a mammal; or for facilitating delivery of an anticancer agent to a mammalian cell. The instructional material of the kit of the invention may, for example, be affixed to a container which contains the composition of the invention or be shipped together with a container which contains the composition.
Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.
The invention also includes a kit for inhibition of virus replication in a cell. The kit comprises a composition of the invention, which can be one or more compounds of Formula I, Formula II, Formula III or any combination thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising one or more compounds of Formula I and Formula II or any combination thereof.
The kit also includes an instructional material.
As used herein, inhibition of virus replication in a cell means a reduction in virus replication in a cell to a level lower than the level in an otherwise identical cell which was not administered the composition of the invention.
Preferably, the reduction in virus replication is by about 90 to about 99.9 % relative to the otherwise identical cell which was not administered the composition of the invention.
The level of virus replication in a cell and therefore virus load in a mammal that is also being assessed, can be assessed by any one of numerous methods known to the skilled artisan. For example, the level of virus replication in a cell can be assessed by evaluating the number of virus particles or amount of a viral component, such as a viral protein, a viral enzyme, or viral nucleic acid, in the cell or in fluid or debris associated with the cell. The number of infectious virus particles in a cell can be evaluated, for example, in a plaque assay. The level of a viral component such as a viral protein or enzyme in a cell can be evaluated using standard analytical techniques of protein biochemistry, such as, for example, using an activity assay for a viral enzyme, or using Western blotting or quantitative gel electrophoresis for a viral protein.
Viral nucleic acid levels in a cell can be evaluated using standard analytical techniques such as Northern blotting and Southern Blotting or quantitation by polymerase chain reaction (PCR).
The invention includes methods for treatment of a virus infection in a mammal. The methods comprise administering to the mammal one or more compounds of Formula I, Formula II, Formula III, Formula VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the virus infection. The compound may be administered by any of the methods described herein. Preferably, the mammal is a human. The virus infection may be caused by any type of virus. Preferably, the virus infection results from infection by a virus selected from the group consisting of HIV-1, HIV-2, hepatitis A virus, hepatitis B
virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, hepatitis G
virus, herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegaloviru.s, rhinovirus, Epstein Barr virus, human herpes virus type 6, human herpes virus type 7 and human herpes virus type 8, parainfluenza viruses and respiratory syncytial viruses.
The invention also includes methods of treating a virus infection in a mammal by contacting the virus in vitro, in vivo or ex-vivo with one or more compounds of Formula I, Formula II, Formula III, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the virus infection (e.g. to inhibit virus replication, infectivity, life cycle processes or pathogenesis). Methods for testing the antiviral activity of a compound in-vitro are known to the skilled artisan, and are described, for example, in Kucera et al., 1990, AIDS Res. and Human Retrovir. 6:494.
The invention further includes methods of using one or more compounds of Formula I, Formula II, Formula III, Formula VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in medical therapy (preferably for use in treating a virus infection) or for the manufacture of a medicament useful for the treatment of a virus infection.
The invention also includes methods of inhibiting virus replication in a cell. The methods comprise administering to the cell one or more compounds of Formula I, Formula II, Formula III, Formula VI or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit virus replication in the cell. Inhibition of virus replication in a cell, as described herein, means a reduction in virus replication in a cell to a level lower than the level in an otherwise identical cell, which was not administered the compound of the invention.
Preferably, the reduction in virus replication is by about 90 % to about 99.9 % relative to the otherwise identical cell, which was not administered the compound of the invention. The level of virus replication in a cell can be assessed by any one of the methods known to the skilled artisan described herein.
The invention also includes one or more compounds of Formulae 1-VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell. Preferably, the therapeutic agent is an anticancer agent, an antiviral agent, a protease inhibitor, a polymerase inhibitor, or a nucleoside analogue.
The protease inhibitors include 2, 4-dioxo-4- (3-hydroxy-phenyl) butyric acid compounds.
In a preferred embodiment, the compound is suspended in a pharmaceutically acceptable carrier and is present in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell. Preferably, the mammalian cell is in a mammal. Also, preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell. Preferred CNS cells include an astrocyte and a glial cell.
Additionally, the invention includes one or more compounds of Formulae or any combination thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount effective to combat a cancer in a mammal. Preferably, the cancer is one or more of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma, and a solid tumor.
In a preferred embodiment, the compound is suspended in a pharmaceutically acceptable carrier and is present in an amount effective to combat a cancer in a mammalian cell. Preferably, the cell is in a mammal. Also, preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
Preferred CNS cells include an astrocyte and a glial cell.
The invention also includes a drug delivery agent comprising a pharmaceutical composition. The pharmaceutical composition comprises one or more compounds of Formulae I-VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell. Preferably, the therapeutic agent is an anticancer agent.
Preferably, the cell is in a mammal. Also, preferably, the cell is one or more of a CNS
cell and a lymphoid cell.
The invention also includes a drug delivery agent comprising a pharmaceutical composition. The pharmaceutical composition comprises one or more compounds of Formulae I-VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to combat a cancer in a mammal.
Preferably, the cancer is one or more of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma, and a solid tumor.
Additionally, the invention includes a method of facilitating delivery of a therapeutic agent to a cell. Preferably, the therapeutic agent is an anticancer agent.
The method comprises administering to the cell a pharmaceutical composition comprising one or more compounds of Formulae I-VI, or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of the therapeutic agent to the cell. Preferably, the cell is in a mammal. A
preferred cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
Further, the invention includes a method of combating a cancer in a mammal. The method comprises administering to the mammal a pharmaceutical composition comprising one or more compounds of Formulae or any combination thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to combat a cancer in the mammal. Preferably, the mammal is a human.
A
preferred cancer is a cancer selected from the group consisting of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma, and a solid tumor.
The invention also includes a method of treating or alleviating a disease in a mammal. The disease can be any disease experienced by a mammal.
Preferably, the disease is one or more of a brain disease, a CNS disease, a lymphatic system disease, a reproductive system disease, a cardiovascular disease, a kidney disease and a liver disease. The method comprises administering to the mammal a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of a therapeutic agent to a cell in the mammal.
-55-.

The invention also includes a kit for administering a composition of the invention (e.g. a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention) to a mammal for combating a cancer in a mammal. Preferably, the mammal is a human. The cancer can be any of the types of cancer described herein. The kit comprises the composition of the invention and an instructional material which describes adventitially administering the composition to the mammal by any of the routes of administration described herein. In another embodiment, this kit comprises a (preferably sterile) solvent suitable for dissolving or suspending the composition of the invention prior to administering the compound to the mammal.
The invention also includes a kit for facilitating delivery of a therapeutic agent to a mammalian cell. Preferably, the therapeutic agent is an anticancer agent.
The kit comprises a composition of the invention, which can be one or more compounds of Formulae I-VI, or any combination thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising one or more compounds of Formulae I-VI, or any combination thereof. The kit also includes an instructional material.
The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention is not limited to these Examples, but rather includes all variations which are evident as a result of the teaching provided herein.
Example 1 Anti-HIV-1 Activity of Double-Targeting PC lipid-AZT Conjugate Compounds The inhibitory effects of PC lipids, non-PC lipid-AZT conjugates, and double-targeting PC lipid-AZT conjugate compounds of the invention on replication of HIV-1 virus in cells was examined using the plaque assay procedure described in Kucera et al. (1990, AIDS Research and Human Retroviruses, 6:491). CEM-SS
cells were seeded at 50,000 cells per milliliter in RPMI growth medium as a monolayer in 96-well dishes, inoculated with 50 to 100 plaque forming units of HIV-1 and overlaid with serial dilutions of either PC lipid, non-PC lipid-AZT conjugate, or PC-lipid-AZT
conjugate in RPMI-1640 growth medium supplemented with 10% fetal bovine serum.
The structures of the tested compounds are described in Table 1. AZT and PC
lipids were used as positive controls. Plaques were counted after incubating the dishes for five days at 37 C to determine the 50% effective concentration (EC50) for the compounds tested. The cytotoxicity of PC lipids, non-PC lipid-AZT conjugates and double targeting PC lipid-AZT conjugates was assessed using the procedure described in Kucera et al. (1990, AIDS Res. And Human Retrovir., 6:496, and 1998, Antiviral Chemistry and Chemotherapy, 9:160).
______________________________________ SC12H25 E(CH2)0 ________________________ q +
______________________________________ OP 03 CH2 CH2N(C113)3 (Formula VI) Table 1 Compound Value of "q" Identity of "E"
in Formula VI in Formula VI

INK-19 See structure below The structure of INK-19 is _________________ SCi2H25 The structure of INK-20 is AZT-OPO3CH2CH2N(CH3)3 In the plaque assay, 11IV-1 syncytial plaques are seen as large, multicellular foci (10 to 25 nuclei/syncytium) that appear either brown and granular or clear. Because the number of HIV-1 syncytial plaques was correlated with reverse transcriptase (RT) and p24 core antigen activity in the IIIV-1 infected cell overlay fluids, the syncytial plaque assay could be used to quantify the amount of infectious virus. Reverse transcriptase activity was assayed according to the procedure described by Poeisz et al. (1980, Proc. Natl. Acad. Sci. U.S.A. 77:7415). The activity of p24 core antigen induced by 11IV-1 infection of CEM-SS cells was measured spectrophotometrically using the commercial Coulter enzyme immunoassay (ETA).
The results of these assays are presented in Table 2. These results demonstrate that the double-targeting PC lipid-AZT conjugate compounds of the invention exhibit a higher differential selectivity (DS = ratio of TC50 for cytotoxicity to EC50 for anti-HIV activity) than the PC lipids, the non-PC lipid-AZT
conjugates and the positive control, AZT. For example, the compound I1K-20 exhibited the highest differential selectivity (DS = 7,666) and anti-HIV-1 activity (0.0009 micromolar) of all the compounds tested, while exhibiting a cytotoxicity (6.9 0.6 micromolar) comparable to AZT. The anti-HIV-1 activity of INK-20 was more than ten-fold higher than AZT.
Table 2 Cytotoxicity (TC50) Anti-HIV-1 Activity Differential Compound (12M) (EC50) (1M) Selectivity INK-17 a 49.1 13.2 0.15 1 0.13 327 INK-18 a 50.0 42 1.92 1.8 26 INK-19 b 6.3 1.1 0.006 0.001 1050 INK-20 C 6.9 0.6 0.0009 0.00007 7666 INK-21 a 57.3 10.8 1.50 0.23 38 INK-22 a > 90.5 1 13.4 0.39 1 0.31 >232 INK-23 a > 100.0 0.0 > 1.46 0.76 >68 1NK-24 a 80.6 1 6.2 0.39 1 0.39 207 INK-25 C 13.6 0.02 0.01 682 INK26C 11.6 0.02 0.02 580 BM21-1290 d 38.5 0.02 1925 AZT 3.7 0.009 411 a PC-Lipid b Lipid ester linked-AZT (non-PC lipid-AZT conjugate) c A double-targeting compound of the invention (PC lipid-AZT conjugate) d A thioetherglycerolphospholipid-AZT conjugate (non-PC lipid-AZT conjugate) with AZT at position-3 Data indicating that PC lipids alone can inhibit infectious HIV-1 production, but not reverse transcriptase activity, in acutely infected human lymphocytes (CEM-SS) after 13 days treatment was previously published (Kucera et al., 1990, AIDS Research and Human Retroviruses, 6:497, Table 3). In contrast, the PC lipid-AZT conjugate compounds of the invention can inhibit both infectious production and reverse transcriptase activity in acutely infected human lymphocytes under similar test conditions. hi summary, these data support the hypothesis that the PC lipid-AZT conjugate compounds of the invention inhibit both infectious virus production and reverse transcriptase activity.
Example 2 Sensitivity of AZT-Resistant Human Clinical Isolates of HIV-1 to PC Lipids Alone and Double Targeting PC lipid-AZT Conjugate Compounds Sensitivity of AZT-resistant clinical isolates of HIV-1 to PC lipid alone (INK-17, LNK-18, and INK-24), non-PC lipid-AZT conjugate (INK-19), and double-targeting PC lipid-AZT conjugate compounds of the invention (INK-20, INK-25, and INK-26) were evaluated in matched pairs of clinical isolates of HIV-1 obtained before ("pre-AZT") and after ("post-AZT") administration of AZT to HP/-1 infected humans.
Isolates of HIV-1 obtained following administration of AZT included AZT-resistant virus particles. Evaluation of the clinical isolates to the compounds was performed using the plaque assay procedure described herein in Example 1. The matched pairs of clinical isolates were obtained through the AIDS Research and Reference Reagent Program, NIII, Bethesda, MD. The results of these assays are presented in Table 3.
The data demonstrate that the double-targeting compound of the invention (INK-20) exhibited a much lower-fold increase in AZT-resistance among HIV-1 clinical isolates than did AZT alone (about 20-fold versus about 680- to 1,100-fold for AZT).
Table 3 Compound EC50 (LtM) a EC50 (JIM) a Pre-AZT Post-AZT Fold- Pre-AZT Post-AZT
Fold-G-762 G-691 Increase H112-2 G-910 Increase INK-17 0.26 0.18 0 0.04 0.20 5.1 INK-18 >1.06 0.60 0 0.56 1.04 1.8 INK-19 0.12 1.62 13.5 0.03 >1.7 >55.6 INK-20 0.04 0.74 18.6 0.02 0.44 22.0 AZT 0.001 >1.29 >1.170 0.002 >1.36 >681.7 INK-24 0.19 0.08 0 0.37 0.25 <1.0 INK-25 0.03 0.06 2 0.004 0.01 2.5 1NK-26 0.003 0.06 20 0.02 0.03 1.5 AZT 0.002 0.33 165 0.002 0.09 45.0 a EC50values represent mean values calculated from 2 to 4 independent tests using duplicate wells for each of 4 serial concentrations of compound per test. ">"
indicates that EC50 was not achieved at the highest concentration tested.
Note--designations such as G-762 and H112-2 in the table designate patient codes for the source of the isolates.
Example 3 Anti-Herpes Simplex Virus Type 2 Activity of Double-Targeting PC lipid-AZT
Conjugate Compounds.
Proof-of-concept of the antiviral activity of the double-targeting PC
lipid-AZT conjugate compounds of the invention with respect to herpes simplex virus type 2 was evaluated and compared with that of PC lipid alone and with acyclovir (positive controls). Serial dilutions of PC lipid, PC lipid-AZT conjugate compound, or acyclovir were evaluated for inhibition of the formation of herpes simplex virus type 2 plaques in Vero cells and EC50 values were calculated from the results obtained.
Briefly, the tests for anti-herpes simplex virus (HSV) activity and cytotoxicity of the compounds were performed by seeding 8 x 104 monkey kidney cells (Vero) per ml of D-MEM with 10% fetal bovine serum (FBS) in each well of a 12-well dish. The cultures were incubated at 37 C to form a complete monolayer. To measure anti-HSV
activity and effective concentration 50 (EC50) each cell monolayer was infected with HSV diluted in PBS-A containing about 100 plaque forming units (PFU) per 0.1 ml.
After virus attachment (1 hr., 37 C) the infected monolayers were overlaid with E-MEM containing 2% FBS and 0.5% methyl cellulose with or without added serial concentrations of test compound. After 2 days at 37 C to allow HSV induced plaque formation, the overlay medium was aspirated, the cell monolayers were fixed with 95%
ethanol, stained with 0.1% crystal violet in 20% methanol and distilled water and the number of PFU in the compound treated cultures was divided by the number of PFU in the untreated controls to determine the percent inhibition of PFU. The EC50 values were calculated using a computer generated program.
To measure cytotoxicity of the compounds, the cell monolayers (described above) were treated with a serial concentration of test compound for 48 hours at 37 C and visually examined after crystal violet staining by light microscopy for changes in cell morphology (cell rounding, shrinking, detachment) compared to an untreated control culture. The cytotoxicity (TC50) represents the lowest serial concentration of test compound that caused a detectable change in cell morphology in at least 25% of the cells.
The results of these experiments are presented in Table 4. These results indicate that PC lipid-AZT conjugate compounds of the invention are metabolized intracellularly to release two drugs which can target the virus life cycle.
The PC lipid compound INK-24 and the AZT conjugate corresponding to INK-24 (i.e. INK-26) both exhibit selective activity against herpes simplex virus type 2, exhibiting EC50 values of 13.8 and 12.0 micromolar, respectively. By comparison, the range of EC50values for acyclovir were 12.5, 14.5 and 6.67 micromolar in replicate tests. Because herpes simplex virus is not expected to be inhibited by AZT, the observed inhibition of the virus by INK-26 is most likely due to intracellular metabolism of INK-26, leading to release of biologically active PC lipid. PC lipid should exhibit activity against the herpes simplex virus in a manner and to a degree similar to the anti-herpes virus activity of INK-24. Cytotoxicity attributable to the double-targeting compound INK-26 appeared to be no worse than that of the positive control (acyclovir) and the PC
lipid compound INK-24.
Table 4 Cytotoxicity (TC50) Anti-Herpes Simplex Compound Activity (EC50)a 014 (i-LM) INK-17 toxic @ 4 >4 INK-19 >20 >20 INK-20 toxic @ 20 >20 INK-21 toxic @ 20 >20 INK-22 toxic @ 20 >20 INK-23 >20 >20 INK-24 >20 13.9, 13.8 INK-25 toxic @ 20 >20 INK-26 >20 12.0 Acyclovir >20 14.5, 12.5, 6.67 control a EC50 values represent mean values obtained from 2 independent tests using duplicate wells for each of four serial concentrations of compound per test. ">"
indicates that cytotoxicity or EC50 was not achieved at the highest concentration tested.
Example 4 Data from testing in animals indicating that the phospholipid-AZT
conjugate BM21-1290 (see Figure 1A) is orally bioavailable and preferentially taken up into lymphoid tissues (lymphoma, spleen and thymus) is shown in Figure 5.
Also, in rodents (mice) receiving oral administration of the conjugate, the compound has exhibited the ability to cross the blood-brain barrier and enter the brain.
The data shown in Figure 6 indicates that the concentration of the conjugate compound 1290 in the brain was found to be equivalent to the concentration of BM21-1290 in the plasma. In rodent experiments there was little or no detectable free AZT in the plasma.
These data suggest that as a phospholipid-AZT conjugate the AZT is protected from glucuronide formation in the liver. The half-life of the conjugate compound in rodents was 48 hours compared to 30 minutes to 1 hour for AZT alone.
In another set of experiments the metabolism of the compound BM21-1290 using human lymphocytes in tissue culture was assessed. Results of these experiments indicated that the conjugate is metabolized to form an alkyl-lipid plus a phosphorylated species of AZT (i.e., AZT-MP, AZT-DP, AZT-TP and AZT). The predominant AZT species was AZT-MP with lesser amounts of AZT-DP, AZT-TP and AZT. These data suggest that phospholipid-AZT conjugates are metabolized intracellularly by a phospholipase C enzyme to yield a lipid and various species of AZT. AZT-MP can be activated to AZT-TP the inhibitor of HIV-1 induced reverse transcriptase.
Taken together, data from these experiments indicate that phospholipid-AZT conjugates are orally bioavailable, are preferentially taken up by lymphoid tissues, can cross the blood-brain barrier and are subsequently metabolized inside cells to yield an alkyl-lipid and AZT. Both the alkyl-lipid and AZT can function in double targeting the HIV-1 life cycle.
Example 5 Synthesis of AZT-Malonic Acid One gram of AZT was dissolved in 30 ml of anhydrous acetonittile and added dropwise to a solution of 632 mg of malonyl chloride in 20 ml of acetonitrile at 0 C. The reaction mixture was stirred for 2 hours at 0 C then at 8-10 C for 4.5 hours.
Thin layer chromatography was used to indicate that the reaction was complete.
Water =
(4 ml) was added. Solvents were removed in vacuo and the residue purified by silica gel chromatography eluting with CHC13:Me0H. Pure product was obtained in a 68%

yield.
Example 6 Synthesis of INK-20 The conditions for the first reaction of the synthesis method for INK-20 is described in Kucera et al., 1998, Antiviral Chemistry & Chemotherapy, 9:

at p.159 as the two-step synthesis of 3-dodecanamido-2-octyloxypropyl 2-bromethyl phosphate then 3-dodecanamido-2-octyloxypropyl phosphocholine (INK-3).
However, the lipid used was 3-dodecylthio-2-(8'-benzyloxyoctyloxy)-1-propanol (see Figure 4) rather than 3-dodecanamido-2-octyloxy-l-propanol as described in the reference. The reactions were the same. Hydrogenation with H2-Pd/C was performed as follows.
The phosphocholine [3-dodecylthio-2-(8'-benzyloxyoctyloxy)propyl phosphocholine]
was dissolved in 60 ml absolute Et0H and added to 109 mg of palladium black. This reaction mixture was shaken under 59 psi hydrogen gas for 24 hours. The catalyst was removed by filtration through CeliteTM, solvent was removed in vacuo, and the residue was chromatographed on silica gel using CHC13:Me0H (100:0 to 2:1) as eluent to give 228 mg (43% yield) of [3-dodeceylthio-2-(8'-hydroxyoctyloxy)propyl phosphophocholine]. AZT-MA (AZT-malonic acid) was then added by the following procedure: One gram of lipid, 192 mg of AZT-MA, 144 mg of dicyclohexylcarbodiimide (DCC), and 9 mg of dimethylaminopyridine (DMAP) were added to 10 ml of DMF. This reaction mixture was stirred at room temperature for 42 hours; copious solid appeared after 18 hours of stirring. The solid was filtered and the solvent removed in vacuo. The residue was chromatographed on silica gel using Et0Ac:CHC13:Me0H (2:2:1) as eluent then CHC13:Me0H (4:1 to 2:1) to give 141 mg (36% yield) of INK-20 (Rf ¨ 0.3 in CHC13:MeOH:NH4OH 75:25:5).
Example 7 Inhibition of Defective HIV-1 in Persistently Infected H9IIIB Cells Inhibition of AZT-resistant clinical isolates of HIV-1 to PC lipid alone (INK-17, INK-18, and INK-24), non-PC Lipid-AZT conjugate (INK-19), and double-targeting PC Lipid-AZT conjugate compounds of the invention (INK-20, INK-25, and INK-26) were evaluated for induction of defective HIV-1 in persistently infected H9IIII3 cells.
HIV-1 persistently infected H9IIII3 cells were washed twice to remove extracellular 11W-1, resuspended in fresh growth medium with or without 1.0 M
of compound for a total of 14 days. During the treatment period, the cells were subcultured 1:3 three times a week. In addition, on days 3, 7 and 11, the cells were pelleted to remove extracellular HIV-1 before subculture in fresh growth medium with or without the compound. After 14 or 11 days of treatment, the virus was pelleted (100,000xg, 1 hr, 4C) from the overlay medium to remove free compound, resuspended in fresh medium without compound and assayed for RT activity. The virus suspension was normalized to 500,000 RT DPM and used to infect fresh CEM-SS cells. The infected CEM-SS cells were incubated for a total of 7 or 9 days, and the overlay medium was harvested and assayed for induction of RT activity. The %
inhibition of RT activity was used as a measure of defective virus formation during the treatment period. These results are presented in Table 5.
Table 5 Compound DPM-Bkg % Inhibition Control 6750 0 Control 4630 0 While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention can be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims include all such embodiments and equivalent variations.

Claims (22)

What is claimed is:
1. A compound having the structure of Formula III:

wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is -O2CCH2CO2AZT.TM.;
X11 is -O-, -S-, -NH-, or -NHC(O)-;
X12 is -O-, -S-, -NH-, or -NHC(O)-;
X13 is -O-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy;
and pharmaceutically acceptable salts thereof.
2. A compound having the structure of Formula wherein, R11 is -C12H25;
R12 is -(CH2)8;
R12 is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
3. A compound having the structure of Formula III:
wherein, R11 is -C12H25;
R12 is (CH2)10;
R12 is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
4. A compound having the structure of Formula III:
wherein, R11 is -C12H25;
R12 is -(CH2)12;
R-12' is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
5. Use of a compound or a pharmaceutically acceptable salt thereof for treating a virus infection in a mammal, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula III:
wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C5) alkyl, branched alkyl, alkenyl or alkynyl;
R12. is ¨O2CCH2CO2AZT.TM.;
X11 is -O-, -S-, -NH-, or -NHC(O)-;
X12 is -O-, -S-, -NH-, or -NHC(O)-;
X13 is -O-, -S-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
le is -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
6. The use of claim 5 wherein the virus infection is an infection by a virus selected from the group consisting of HIV, hepatitis virus, and herpes virus.
7. The use of claim 6 wherein the HIV is selected from the group consisting of HIV-1 and HIV-2.
8. The use of claim 6 wherein the virus is selected from the group consisting of hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, and hepatitis G viruses.
9. The use of claim 6 wherein the virus is selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, rhinovirus, Epstein Barr virus, human herpes virus type 6 human herpes virus type 7, and human herpes virus type 8.
10. The use of claim 5 wherein the mammal is a human.
11. Use of a compound, or a pharmaceutically acceptable salt thereof for treating a herpes virus infection in a mammal, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula III:
<1MG>
wherein, R11 is -C12H25;
R12 is -(CH2)12;
R12' is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;

R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH7-; and R6, R7 and R8 are each independently methyl.
12. Use of a compound, or a pharmaceutically acceptable salt thereof for treating a HIV infection in a mammal, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula III:
wherein, R11 is -C12H25;
R12 is -(CH2)8;
R12' is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl.
13. Use of an effective amount of a compound or a pharmaceutically acceptable salt thereof for inhibiting virus replication in a cell in a mammal, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula III:

wherein, RI1 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C5) alkyl, branched alkyl, alkenyl or alkynyl;
RI2' is ¨O2CCH2CO2AZ.TM.;
X11I is -O-, -S-, -NH-, or -NHC(O)-;
X12 is -O-, -S-, -NH-, or -NHC(O)-;
XI3 is -O-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy:
n is 0, 1 or 2;
R13 is -R3N(R6)(R)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy.
14. The use of claim 13 wherein the cell is a mammalian cell.
15. The use of claim 13 wherein the mammalian cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
16. The use of claim 13 wherein the mammalian cell is a cell selected from the group consisting of an astrocyte or a glial cell.
17. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:

<1MG>
wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C5) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is ¨O2CCH2CO2AZT.TM.;
X11 is -O-, -S-, -NH-, or -NHC(O)-;
X12 is -O-, -S-, -NH-, or -NHC(O)-;
X13 is -O-, -S-, -CH2-, anhydride, or (C1-C16) alkoxy;
n is 0, 1 or 2;
R13 is -R3N(R6)(R7)R8;
R3 is (C1-C8) alkylene; and R6, R7 and R8 are each independently -H, (C1-C8) alkyl or (C1-C8) alkoxy;
and pharmaceutically acceptable salts thereof.
18. The pharmaceutical composition of claim 17 wherein R12 is (C8-C12) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is -O2CCH2CO2AZT.TM.;
R13 is -R3N(R6)(R)R8; and x12 is -O-.
19. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:

<1MG>
wherein, R11 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16) alkyl, branched alkyl, alkenyl or alkynyl;
R12' is ¨O2CCH2CO2AZT.TM.;
X11 is -S-;
)(12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
20. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:

wherein, R11 is -C12H25;
R12 is -(CH2)8;
R12' is -O2CCH2CO2AZT.TM.;

X is -S-;
X12 is -O-;
X" is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof
21. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:

wherein, R11 is -C12H25;
R12 is (CH2)10;
R12' is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
22. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, the compound having the structure of Formula III:

wherein, R11 is -C12H25;
R12 is -(CH2)12;
R12' is -O2CCH2CO2AZT.TM.;
X11 is -S-;
X12 is -O-;
X13 is -O-;
R13 is -R3N(R6)(R7)R8;
R3 is -CH2CH2-; and R6, R7 and R8 are each independently methyl;
and pharmaceutically acceptable salts thereof.
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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1460082A1 (en) * 2003-03-19 2004-09-22 Heidelberg Pharma Holding GmbH Phospholipid esters of clofarabine derivatives
US20050187191A1 (en) * 2004-02-20 2005-08-25 Kucera Louis S. Methods and compositions for the treatment of respiratory syncytial virus
US20050187192A1 (en) * 2004-02-20 2005-08-25 Kucera Pharmaceutical Company Phospholipids for the treatment of infection by togaviruses, herpes viruses and coronaviruses
US8435959B2 (en) 2004-03-29 2013-05-07 University Of South Florida Effective treatment of tumors and cancer with triciribine and related compounds
WO2006066074A2 (en) * 2004-12-16 2006-06-22 The Regents Of The University Of California Lung-targeted drugs
WO2006110656A2 (en) * 2005-04-08 2006-10-19 Chimerix, Inc. Compounds, compositions and methods for the treatment of viral infections and other medical disorders
JP2008535862A (en) * 2005-04-08 2008-09-04 キメリクス,インコーポレイテッド Compounds, compositions and methods for the treatment of poxvirus infections
JP5320284B2 (en) 2006-05-03 2013-10-23 キメリクス,インコーポレーテッド Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates
WO2008118879A2 (en) * 2007-03-23 2008-10-02 Ardea Biosciences, Inc. Antiviral compositions comprising 2 compounds
US9446150B2 (en) 2007-10-09 2016-09-20 Washington University Particles for imaging
US9468607B2 (en) 2007-10-09 2016-10-18 Washington University Ligand directed toroidal nanoparticles for therapy and diagnostic imaging
CN102670628B (en) * 2008-01-25 2015-11-25 奇默里克斯公司 The method for the treatment of viral infection
EP2348864A4 (en) 2008-10-08 2013-07-31 Vascular Biogenics Ltd Oxidized thiophospholipid compounds and uses thereof
CN104788492A (en) * 2008-11-06 2015-07-22 脉管生物生长有限公司 Oxidized lipid compounds and uses thereof
US8614200B2 (en) 2009-07-21 2013-12-24 Chimerix, Inc. Compounds, compositions and methods for treating ocular conditions
AU2010339809B2 (en) 2009-12-17 2016-05-05 The Washington University Antithrombotic nanoparticle
US9808500B2 (en) 2009-12-17 2017-11-07 Washington University Antithrombotic nanoparticle
AU2011216243B2 (en) 2010-02-12 2015-07-09 Chimerix, Inc. Nucleoside phosphonate salts
JP2013527157A (en) * 2010-04-15 2013-06-27 ワシントン・ユニバーシティ Prodrug composition, prodrug nanoparticles and methods of use thereof
AU2011248620B2 (en) 2010-04-26 2015-11-26 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9192680B2 (en) * 2010-06-01 2015-11-24 Aposense Ltd. Pharmaceutical compounds
US8530444B2 (en) * 2010-06-01 2013-09-10 Aposense Ltd. Pharmaceutical compounds
PT2970346T (en) 2013-03-15 2018-11-09 Univ California Acyclic nucleoside phosphonate diesters
RS63250B1 (en) 2014-09-15 2022-06-30 Univ California Nucleotide analogs
JP6717825B2 (en) 2014-11-26 2020-07-08 バスキュラー バイオジェニックス リミテッド Oxidized lipids and methods for treating or preventing fibrosis
US9771385B2 (en) 2014-11-26 2017-09-26 Vascular Biogenics Ltd. Oxidized lipids
EP3875462A1 (en) 2015-09-15 2021-09-08 The Regents of The University of California Nucleotide analogs

Family Cites Families (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE279249C (en)
US2108765A (en) * 1938-02-15 Preserving and disinfecting media
US2087132A (en) * 1933-04-13 1937-07-13 Alba Pharmaceutical Company In Quaternary ammonium compounds
US2086585A (en) * 1933-04-13 1937-07-13 Alba Pharmaceutical Company In Quaternary ammonium compounds
US2209383A (en) * 1938-03-05 1940-07-30 Rohm & Haas Process of waterproofing fabrics
US2445393A (en) * 1944-03-08 1948-07-20 Rhone Poulenc Sa New amino-derivatives of dioxa-cyclopentane
US2439969A (en) * 1944-04-17 1948-04-20 Rhone Poulenc Sa Amino-dioxacyclopentanes
US2513747A (en) * 1945-10-04 1950-07-04 Ciba Ltd Cyclic amino-acetals
US2606909A (en) * 1947-08-01 1952-08-12 Univ Michigan Basic dioxolanes
US2689790A (en) * 1951-09-26 1954-09-21 Monsanto Chemicals Nitrogenous compound herbicides
NL189533C (en) * 1953-07-29 Ates Componenti Elettron PROCEDURE FOR APPLYING A PLASTIC HOLDER WITH HEAT DISCHARGE AROUND AN INTEGRATED CIRCUIT, AS WELL AS COMBINATION OF A MOLD AND A HEAT DISCHARGE ELEMENT FOR USE IN THIS PROCEDURE.
US3054678A (en) * 1958-04-16 1962-09-18 Michener Harold David Preservation process with quaternary ammonium compounds
DE1619043B2 (en) 1967-04-07 1977-11-03 Hoechst Ag, 6000 Frankfurt AGENT FOR SOFTENING TEXTILES AND AT THE SAME TIME PROVIDING GOOD ABSORPTION
US4119714A (en) * 1970-02-27 1978-10-10 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E. V. Glycerin-alkylether-(1)-phosphoric acid-(3)-monocholine esters as enhancers of the natural resistance of the mammalian organism against non-carcinogenic pathogens
DE2033359C3 (en) * 1970-07-06 1980-02-14 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V., 3400 Goettingen Acylpropanediol- (1,3) -phosphoric acid monocholine ester and process for their preparation
JPS49100224A (en) 1973-01-29 1974-09-21
US4093714A (en) * 1974-03-15 1978-06-06 Icn Pharmaceuticals, Inc. 9β-D-Arabinofuranosylpurine nucleotides and method of use
US4159988A (en) * 1974-08-06 1979-07-03 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Synthetic phospholipids, a process for their manufacture and their use
FR2356425A1 (en) * 1976-07-01 1978-01-27 Roussel Uclaf APPLICATION AS MEDICINAL PRODUCTS FROM ORGANIC DERIVATIVES OF MONTMORILLONITE
US4291024A (en) * 1978-04-10 1981-09-22 Turcotte Joseph G Cytotoxic liponucleotide analogs
DE2820893C2 (en) * 1978-05-12 1986-02-20 A. Nattermann & Cie GmbH, 5000 Köln Structural analogs of natural phospholipids and processes for making these compounds
US4235877A (en) * 1979-06-27 1980-11-25 Merck & Co., Inc. Liposome particle containing viral or bacterial antigenic subunit
US4329302A (en) * 1980-06-27 1982-05-11 Board Of Regents, The University Of Texas System Synthetic phosphoglycerides possessing platelet activating properties
US4444766A (en) * 1980-10-21 1984-04-24 Boehringer Mannheim Gmbh Sulfur-containing phospholipid compounds and therapeutic compositions
JPS5772914A (en) * 1980-10-22 1982-05-07 Takeda Chem Ind Ltd Antitumor agent
US4471113A (en) * 1982-02-03 1984-09-11 The United States Of America As Represented By The Department Of Energy Prodrugs based on phospholipid-nucleoside conjugates
EP0094586A3 (en) 1982-05-13 1984-06-06 Ono Pharmaceutical Co., Ltd. Glycerol derivatives, process for preparing same and pharmaceutical composition containing same
US4661509A (en) * 1982-09-28 1987-04-28 Gordon Arnold Z Methods for treating leukopenia
JPS5988447A (en) 1982-11-11 1984-05-22 Ono Pharmaceut Co Ltd Glycerol derivative, its production and agent containing said derivative
FR2540122B1 (en) * 1983-01-27 1985-11-29 Centre Nat Rech Scient NOVEL COMPOUNDS COMPRISING A SEQUENCE OF OLIGONUCLEOTIDE LINKED TO AN INTERCALATION AGENT, THEIR SYNTHESIS PROCESS AND THEIR APPLICATION
US4559157A (en) 1983-04-21 1985-12-17 Creative Products Resource Associates, Ltd. Cosmetic applicator useful for skin moisturizing
LU84979A1 (en) 1983-08-30 1985-04-24 Oreal COSMETIC OR PHARMACEUTICAL COMPOSITION IN AQUEOUS OR ANHYDROUS FORM WHOSE FATTY PHASE CONTAINS OLIGOMER POLYETHER AND NEW OLIGOMER POLYETHERS
JPS60100544A (en) 1983-11-08 1985-06-04 Ono Pharmaceut Co Ltd Novel glycerin derivative, its preparation and drug containing it
JPS60104066A (en) 1983-11-10 1985-06-08 Ono Pharmaceut Co Ltd Glycerin derivative, its preparation, and drug containing it
JPS60105650A (en) 1983-11-14 1985-06-11 Ono Pharmaceut Co Ltd Glycerol derivative, production thereof and pharmaceutical containing said derivative
US4540521A (en) * 1984-01-16 1985-09-10 National Distillers And Chemical Corporation Liquid quaternary ammonium antistatic compositions
US4622392A (en) * 1984-06-21 1986-11-11 Health Research Inc. (Roswell Park Division) Thiophospholipid conjugates of antitumor agents
US4826823A (en) * 1985-02-05 1989-05-02 Warner-Lambert Company Methods of using 2-chloro-2'-deoxyadenosine-5'-phosphate and its salts
US5223263A (en) 1988-07-07 1993-06-29 Vical, Inc. Liponucleotide-containing liposomes
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
IT1188654B (en) * 1985-04-15 1988-01-20 Toyo Jozo Kk SIDE-PHOSPHOLIPID CORE CONJUGATE
JPS61238793A (en) 1985-04-17 1986-10-24 Toyo Jozo Co Ltd Novel phospholipid derivative
US4619917A (en) * 1985-07-18 1986-10-28 Sandoz Pharm. Corp. Substituted 2-furanyl- or 5-oxo-2-furanyl methoxy phosphoryl alkyl cyclimmonium salts
CA1338627C (en) * 1985-12-04 1996-10-01 Hansjorg Eibl Pharmaceuticals based on phosphoric acid esters for use in tumor therapy, and process for their preparation
US4841039A (en) * 1986-05-01 1989-06-20 Emory University 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents
DE3619748A1 (en) 1986-06-12 1987-12-17 Merz & Co Gmbh & Co ANTIMICROBIAL AGENTS
US4816450A (en) * 1986-09-15 1989-03-28 Duke University Inhibition of protein kinase C by long-chain bases
DE3778626D1 (en) * 1986-09-27 1992-06-04 Toyo Jozo Kk NUCLEOSIDE PHOSPHOLIPID CONJUGATE.
US4880782A (en) * 1986-11-21 1989-11-14 Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften E.V. Method of treating viral infections in humans and compositions therefor
US4820508A (en) 1987-06-23 1989-04-11 Neutrogena Corporation Skin protective composition
JP2598643B2 (en) 1987-07-24 1997-04-09 わかもと製薬株式会社 Antiallergic agent
DE3726945A1 (en) 1987-08-13 1989-02-23 Dietl Hans L-Carnitine derivatives of valproic acid and pharmaceuticals containing these
US4894389A (en) 1987-10-02 1990-01-16 Merrell Dow Pharmaceuticals Inc. Novel aminoalkyl-substituted heterocyclic sulfur compounds
US4997761A (en) * 1987-10-06 1991-03-05 Houston Biotechnology Incorporated Phosphatidyl treatment of viral disease
US4797497A (en) 1988-02-25 1989-01-10 Amoco Corporation Trimellitic anhydride purification process
EP0335396A1 (en) 1988-04-01 1989-10-04 MAGIS FARMACEUTICI S.p.A. Glycero-phosphoric and -diphosphoric acids derivatives of L-carnitine or L-carnitine esters
US4992478A (en) 1988-04-04 1991-02-12 Warner-Lambert Company Antiinflammatory skin moisturizing composition and method of preparing same
GB8815265D0 (en) * 1988-06-27 1988-08-03 Wellcome Found Therapeutic nucleosides
EP0348859A1 (en) 1988-07-01 1990-01-03 MAGIS FARMACEUTICI S.p.A. 1,2-di-O-acyl glycero(DI)phosphate of L-carnitine and its derivatives, a process for their preparation and pharmaceutical formulations which contain them
US5817638A (en) 1988-07-07 1998-10-06 Nexstar Pharmaceuticals, Inc. Antiviral liponucleosides: treatment of hepatitis B
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
CA2001401A1 (en) * 1988-10-25 1990-04-25 Claude Piantadosi Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions
GB8827337D0 (en) 1988-11-23 1988-12-29 Medical Res Council Nucleoside analogues
DD279249A1 (en) 1989-01-01 1990-05-30 Akad Wissenschaften Ddr PROCESS FOR THE PREPARATION OF 2 ', 3'-DIDESOXYTHYMIDIN-5'-DIPHOSPHATE-1,2-DI-O-ALKYLGLYCEROLES AND THEIR SALTS
US5221696A (en) * 1989-03-29 1993-06-22 Alcon Laboratories, Inc. Use of monoacyl phosphoglycerides to enhance the corneal penetration of ophthalmic drugs
FI902821A0 (en) 1989-06-12 1990-06-06 Res Found Mental Hygiene FOERMINSKNING AV INFEKTIONSSPRIDNING MEDELST BLODBEHANDLINGSAPPARATUR.
US5411947A (en) 1989-06-28 1995-05-02 Vestar, Inc. Method of converting a drug to an orally available form by covalently bonding a lipid to the drug
DE3929217A1 (en) 1989-09-02 1991-03-07 Boehringer Mannheim Gmbh USE OF PHOSPHOLIPID DERIVATIVES AS ANTIVIRAL MEDICINAL PRODUCTS AND NEW PHOSPHOLIPIDES
DE3934820A1 (en) 1989-10-19 1991-04-25 Boehringer Mannheim Gmbh USE OF LECITHIN ANALOGA AS AN ANTIVIRAL MEDICINAL PRODUCT AND NEW DERIVATIVES
GB2239243B (en) 1989-12-22 1993-05-12 Scras Glycerol derivatives
MY104575A (en) 1989-12-22 1994-04-30 The Wellcome Foundation Ltd Therapeutic nucleosides.
DE3942933A1 (en) 1989-12-23 1991-06-27 Boehringer Mannheim Gmbh USE OF ALKYLPHOSPHOLIPIDES AS ANTIVIRAL MEDICINAL PRODUCTS AND NEW PHOSPHOLIPID DERIVATIVES
US5026687A (en) * 1990-01-03 1991-06-25 The United States Of America As Represented By The Department Of Health And Human Services Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds
DE4010228A1 (en) 1990-03-30 1991-10-02 Werner E G Prof Dr Mueller Prepn. of antiviral, esp. anti-AIDS agent - by mixing halo-contg. higher alkyl-glycerol-phospho-choline analogues with suitable carrier
US5134394A (en) * 1990-04-12 1992-07-28 Beadle Leigh P Light aircraft navigation apparatus
WO1991018914A1 (en) 1990-05-29 1991-12-12 Vical, Inc. Synthesis of glycerol di- and triphosphate derivatives
WO1991019726A1 (en) 1990-06-15 1991-12-26 Wake Forest University Ether lipid-nucleoside covalent conjugates
US5138045A (en) * 1990-07-27 1992-08-11 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5563257A (en) 1990-08-20 1996-10-08 Boehringer Mannheim Gmbh Phospholipid derivatives of nucleosides
DE4026265A1 (en) 1990-08-20 1992-02-27 Boehringer Mannheim Gmbh NEW PHOSPHOLIPID DERIVATIVES OF NUCLEOSIDES, THEIR PRODUCTION AND THEIR USE AS ANTIVIRAL MEDICINAL PRODUCTS
TW207544B (en) * 1990-08-20 1993-06-11 Boehringer Mannheim Gmbh
ES2073777T3 (en) 1990-10-09 1995-08-16 Vestar Inc INHIBITION OF VIRAL REPLICATION.
AU668873B2 (en) 1991-07-12 1996-05-23 Chimerix, Inc. Antiviral liponucleosides: treatment of hepatitis B
CA2122246C (en) 1991-10-28 1999-04-27 Dennis L. Fost Phospholipid antimicrobial compositions
DE4204031A1 (en) 1992-02-12 1993-08-19 Boehringer Mannheim Gmbh NEW LIPID PHOSPHONIC ACID-NUCLEOSIDE CONJUGATES AND THEIR USE AS ANTIVIRAL MEDICINAL PRODUCTS
DE4204032A1 (en) 1992-02-12 1993-08-19 Boehringer Mannheim Gmbh NEW LIPONUCLEOTIDES, THEIR PRODUCTION AND THEIR USE AS ANTIVIRAL MEDICINAL PRODUCTS
GB9204015D0 (en) 1992-02-25 1992-04-08 Wellcome Found Therapeutic nucleosides
US6602861B1 (en) 1992-04-16 2003-08-05 Research Corporation Technologies, Inc. Acylated phospholipid drugs
US5512671A (en) 1993-02-16 1996-04-30 Wake Forest University Ether lipid-nucleoside covalent conjugates
EP0686043B1 (en) * 1993-02-24 1999-06-23 WANG, Jui, H. Compositions and methods of application of reactive antiviral polymers
IL105244A (en) 1993-03-31 2003-07-31 Dpharm Ltd Prodrugs with enhanced penetration into cells
US6413949B1 (en) 1995-06-07 2002-07-02 D-Pharm, Ltd. Prodrugs with enhanced penetration into cells
ATE226437T1 (en) 1993-06-10 2002-11-15 Univ Wake Forest (PHOSPHO)LIPIDS TO FIGHT HEPATITIS B INFECTION
CA2126601A1 (en) 1993-06-29 1994-12-30 Mitsubishi Chemical Corporation Phosphonate-nucleotide ester derivatives
DE4321978A1 (en) 1993-07-01 1995-01-12 Boehringer Mannheim Gmbh Liponucleotides of deoxynucleosides, their production and their use as antiviral drugs
CA2167537A1 (en) * 1993-07-19 1995-02-02 Tsuneo Ozeki Hepatitis c virus proliferation inhibitor
DE4402492A1 (en) 1994-01-28 1995-08-03 Boehringer Mannheim Gmbh Process for the production of asymmetrical phosphoric acid diesters
DE4418690A1 (en) 1994-05-28 1996-01-11 Boehringer Mannheim Gmbh Nucleoside 5'-mono-phosphate ester(s) of glyceryl di:ether derivs.
DE69535758D1 (en) * 1994-08-29 2008-07-03 Univ Wake Forest LIPID ANALOGUE FOR THE TREATMENT OF VIRAL INFECTIONS
JP3786447B2 (en) 1995-03-31 2006-06-14 エーザイ株式会社 Preventive and therapeutic agent for hepatitis C
US5830905A (en) * 1996-03-29 1998-11-03 Viropharma Incorporated Compounds, compositions and methods for treatment of hepatitis C
US5633388A (en) * 1996-03-29 1997-05-27 Viropharma Incorporated Compounds, compositions and methods for treatment of hepatitis C
US5891874A (en) * 1996-06-05 1999-04-06 Eli Lilly And Company Anti-viral compound
JP3927630B2 (en) 1996-09-27 2007-06-13 エーザイ・アール・アンド・ディー・マネジメント株式会社 Preventive and therapeutic agents for viral infections
US5922757A (en) * 1996-09-30 1999-07-13 The Regents Of The University Of California Treatment and prevention of hepatic disorders
EE04023B1 (en) 1996-10-18 2003-04-15 Vertex Pharmaceuticals Incorporated Serine proteases, especially hepatitis C virus NS3 protease inhibitors
GB9623908D0 (en) 1996-11-18 1997-01-08 Hoffmann La Roche Amino acid derivatives
ES2234144T3 (en) 1997-08-11 2005-06-16 Boehringer Ingelheim (Canada) Ltd. ANALOGS OF INHIBITING PEPTIDES OF HEPATITIS C.
GB9806815D0 (en) 1998-03-30 1998-05-27 Hoffmann La Roche Amino acid derivatives
US6243759B1 (en) * 1998-05-08 2001-06-05 International Business Machines Corporation Method and system for configuring dynamic interfaces
IL131887A0 (en) * 1999-09-14 2001-03-19 Dpharm Ltd Phospholipid prodrugs of anti-proliferative drugs
US6670341B1 (en) * 1999-10-28 2003-12-30 Wake Forest University Health Sciences Compositions and methods for double-targeting virus infections and targeting cancer cells
JP4213841B2 (en) 2000-03-23 2009-01-21 大成建設株式会社 Temporary bearing construction method

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