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Cancer Patent 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 which comprise a phosphocholine moiety
covalently conjugated with one or more antiviral agents (e.g. nucleoside
analogue, protease inhibitor, etc.) to a lipid backbone. The invention
also includes pharmaceutical compositions and kits 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 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 for 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 an anticancer
agent (e.g. a nucleoside analogue). The invention also includes
pharmaceutical compositions and kits for combating a cancer and
for 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 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.
Cancer Patent Claims
What is claimed is:
1. A compound having the structure of Formula III: ##STR00014##
wherein, R.sup.11 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl
or alkynyl; R.sup.12 is (C.sub.1-C.sub.16) alkyl, branched alkyl,
alkenyl or alkynyl; X.sup.11 is O, S, or NHC.dbd.O; X.sup.12 is
O, S, or NHC.dbd.O; X.sup.13 is O or S; n is 0, 1 or 2, and R.sup.13
is an anticancer agent, wherein, each and alkynyl of R.sup.11, R.sup.12,
and R.sup.13 is, optionally, substituted with 1, 2, 3, or 4 substituents
independently selected from the group consisting of halo, nitro,
trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy,
aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H and (C.sub.1-C.sub.8)
alkyl, and wherein, if n is 1 or 2, the compound is a phospholipase
C substrate and is not a phospholipase A substrate, and further
wherein, 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.
2. The compound of claim 1, wherein, R.sup.11 is a C.sub.12 alkyl,
branched alkyl, alkenyl or alkynyl; R.sup.12 is C.sub.8H.sub.16
alkyl or branched alkyl; n=1, and R.sup.13 is an anticancer agent
selected from the group consisting of gemcitabine, 5-azacytidine,
cladribine, fludarabine, fluorodeoxyuridine, cytosine arabinoside
and 6-mercaptopurine, wherein the phosphorus atom of the phosphate
moiety is covalently linked in a phosphate ester linkage to the
oxygen atom of the 5' hydroxyl group of a sugar moiety of R.sup.13.
3. A compound having the structure of Formula IV: ##STR00015##
wherein, R.sup.21 is (C.sub.6 to C.sub.16) alkyl, branched alkyl,
alkenyl, or alkynyl; R.sup.22 is (C.sub.1 to C.sub.12) alkyl, branched
alkyl, alkenyl, or alkynyl; X.sup.21 is O, S, or NHC.dbd.O; X.sup.22
is O, S, or NHC.dbd.O; X.sup.23 is O or S; n is 1 or 2; R.sup.23
is an anticancer agent, and wherein, each and alkynyl of R.sup.21,
R.sup.22, and R.sup.23 is, optionally, substituted with 1, 2, 3,
or 4 substituents independently selected from the group consisting
of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8)
alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.8) alkyl.
4. The compound of claim 3, wherein, R.sup.21 is C.sub.12 alkyl;
R.sup.22 is C.sub.10 alkyl; n=1, and R.sup.23 is an anticancer agent
selected from the group consisting of gemcitabine, 5-azacytidine,
cladribine, fludarabine, 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 R.sup.23.
5. A compound having the structure of Formula V: ##STR00016## wherein,
R.sup.31 is (C.sub.1 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl; R.sup.32 is (C.sub.1 to C.sub.16) alkyl, branched alkyl,
alkenyl, or alkynyl; X.sup.31 is O, S, or NHC.dbd.O; X.sup.32 is
O, S, or NHC.dbd.O; X.sup.33 is --O, S or amino; R.sup.33 is an
anticancer agent, and wherein, each and alkynyl of R.sup.31, R.sup.32,
and R.sup.33 is, optionally, substituted with 1, 2, 3, or 4 substituents
independently selected from the group consisting of halo, nitro,
trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy,
aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H and (C.sub.1-C.sub.8)
alkyl.
6. The compound of claim 5, wherein, R.sup.31 is (C.sub.6-C.sub.16)
alkyl, branched alkyl, alkenyl or alkynyl; R.sup.32 is (C.sub.1-C.sub.8)
alkyl, branched alkyl, alkenyl or alkynyl, and R.sup.33 is an anticancer
agent 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 X.sup.33.
7. The compound of claim 1, wherein said compound is suspended
in a pharmaceutically acceptable carrier and is present in an amount
effective to combat a cancer in a mammal.
8. The compound of claim 7, wherein said cancer is a cancer selected
from the group consisting of a carcinoma, a sarcoma, a neuroblastoma,
a leukemia, a lymphoma and a solid tumor.
9. The compound of claim 1, wherein said compound is present in
an amount effective to facilitate delivery of a therapeutic agent
to a mammalian cell.
10. The compound of claim 9, wherein the cell is in a mammal.
11. The compound of claim 10, wherein the cell is a cell selected
from the group consisting of a CNS cell and a lymphoid cell.
12. The compound of claim 11, wherein the CNS cell is an astrocyte
or a glial cell.
13. A pharmaceutically acceptable salt of the compound of claim
1.
14. The pharmaceutically acceptable salt of claim 13, wherein the
compound is present in an amount effective to facilitate delivery
of an anticancer agent to a mammalian cell.
15. The pharmaceutically acceptable salt of claim 14, wherein the
cell is in a mammal.
16. The pharmaceutically acceptable salt of claim 15, wherein the
cell is a cell selected from the group consisting of a CNS cell
and a lymphoid cell.
17. The pharmaceutically acceptable salt of claim 13, wherein said
compound is present in an amount effective to combat a cancer in
a mammal.
18. A pharmaceutically acceptable salt of the compound of claim
2.
19. The pharmaceutically acceptable salt of claim 18, wherein said
compound is present in an amount effective to facilitate delivery
of an anticancer agent to a mammalian cell.
20. The pharmaceutically acceptable salt of claim 19, wherein said
cell is in a mammal.
21. The pharmaceutically acceptable salt of claim 19, wherein said
cell is a cell selected from the group consisting of a CNS cell
and a lymphoid cell.
22. The pharmaceutically acceptable salt of claim 13, wherein said
compound is present in an amount effective to combat a cancer in
a mammal.
23. A drug delivery agent comprising a pharmaceutical composition,
said composition comprising a compound of claim 1 or a pharmaceutically
acceptable salt thereof, in an amount effective to facilitate delivery
of an anticancer agent to a mammalian cell.
24. The drug delivery agent of claim 23, wherein said cell is in
a mammal.
25. The drug delivery agent of claim 23, wherein said cell is a
cell selected from the group consisting of a CNS cell and a lymphoid
cell.
26. A drug delivery agent comprising a pharmaceutical composition,
said composition comprising a compound of claim 1 or a pharmaceutically
acceptable salt thereof, in an amount effective to combat a cancer
in a mammal.
27. The drug delivery agent of claim 26, wherein said cancer is
a cancer selected from the group consisting of a carcinoma, a sarcoma,
a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
28. A drug delivery agent comprising a pharmaceutical composition,
the composition comprising a compound of claim 2 or a pharmaceutically
acceptable salt thereof, in an amount effective to facilitate delivery
of an anticancer agent to a mammalian cell.
29. The drug delivery agent of claim 28, wherein the cell is in
a mammal.
30. The drug delivery agent of claim 28, wherein said cell is a
cell selected from the group consisting of a CNS cell and a lymphoid
cell.
31. A drug delivery agent comprising a pharmaceutical composition,
said composition comprising a compound of claim 2 or a pharmaceutically
acceptable salt thereof, in an amount effective to combat a cancer
in a mammal.
32. The drug delivery agent of claim 31, wherein said cancer is
a cancer selected from the group consisting of a carcinoma, a sarcoma,
a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
33. A method of facilitating delivery of an anticancer agent to
a mammalian cell, said method comprising administering to said cell
a pharmaceutical composition comprising a compound of claim 1 or
a pharmaceutically acceptable salt thereof, in an amount effective
to facilitate delivery of said anticancer agent to said cell.
34. The method of claim 33, wherein said cell is in a mammal.
35. The method of claim 33, wherein the cell is a cell selected
from the group consisting of a CNS cell and a lymphoid cell.
36. A method of facilitating delivery of an anticancer agent to
a cell, said method comprising administering to said cell a pharmaceutical
composition comprising a compound of claim 2 or a pharmaceutically
acceptable salt thereof, in an amount effective to facilitate delivery
of said anticancer agent to said cell.
37. The method of claim 36, wherein said cell is in a mammal.
38. The method of claim 36, wherein said cell is a cell selected
from the group consisting of a CNS cell and a lymphoid cell.
39. A method of combating a cancer in a mammal comprising administering
to said mammal a pharmaceutical composition comprising a compound
of claim 1 or a pharmaceutically acceptable salt thereof, in an
amount effective to combat a cancer in the mammal.
40. The method of claim 39, wherein said cancer is a cancer selected
from the group consisting of a carcinoma, a sarcoma, a neuroblastoma,
a leukemia, a lymphoma and a solid tumor.
41. A kit for combating a cancer in a mammal, said kit comprising
a) a composition selected from the group consisting of a compound
of claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutical
composition comprising a compound of claim 1, and b) an instructional
material.
42. A kit for facilitating delivery of an anticancer agent to a
mammalian cell, said kit comprising a) a composition selected from
the group consisting of a compound of claim 1, a pharmaceutically
acceptable salt thereof, and a pharmaceutical composition comprising
a compound of claim 1, and b) an instructional material.
43. The compound of claim 1, wherein, R.sup.11 is a C.sub.12 alkyl,
branched alkyl, alkenyl or alkynyl; R.sup.12 is C.sub.8H.sub.16
alkyl or branched alkyl; n=1, and R.sup.13 is an anticancer agent
selected from the group consisting of gemcitabine, 5-azacytidine,
cladribine, fludarabine, fluorodeoxyuridine, cytosine arabinoside,
6-mercaptopurine, 6-thioguanine, 5-deoxyfluorouridine, ftorafur,
capecitabine, 5-deoxy-5-fluorocytidine, 5-aza-cystine arabinoside,
troxacitabine, and pentostatin, wherein the phosphorus atom of the
phosphate moiety is covalently linked in a phosphate ester linkage
to the oxygen atom of the 5' hydroxyl group of a sugar moiety of
R.sup.13.
44. The compound of claim 3, wherein, R.sup.21 is C.sub.12 alkyl;
R.sup.22 is C.sub.10 alkyl; n=1, and R.sup.23 is an anticancer agent
selected from the group consisting of gemcitabine, 5-azacytidine,
cladribine, fludarabine, fluorodeoxyuridine, cytosine arabinoside,
6-mercaptopurine, 6-thioguanine, 5-deoxyfluorouridine, ftorafur,
capecitabine, 5-deoxy-5-fluorocytidine, 5-aza-cytsine arabinoside,
troxacitabine, and pentostatin, 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 R.sup.23.
45. The compound of claim 5, wherein, R.sup.31 is (C.sub.6-C.sub.16)
alkyl, branched alkyl, alkenyl or alkynyl; R.sup.32 is (C.sub.1-C.sub.8)
alkyl, branched alkyl, alkenyl or alkynyl, and R.sup.33 an anticancer
agent selected from the group consisting of mitoxanthrone, doxorubicin,
idarubicin, epirubicin, daunorubicin, mitomycin, methotrexate, CPT-11,
SN-38, camptothecin, topotecan, 9-nitrocamptothecin, and 9-aminocamptothecin,
and is covalently linked via an ester, amido or carbamate linkage
to the O, S or amino group of X.sup.33.
Cancer Patent Description
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 (AZT, Zidovudine),
dideoxyinosine (ddI, Didanosine), dideoxycytidine (ddC, Zalcitabine),
2',3'-dideoxy-3'-thiacytidine (3TC, 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 (Crixivan), and nelfinavir (Viracept). 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, AZT, 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. AZT 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.sup.+ 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 CD4 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 HIV-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-decyloxypropyl-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 TC.sub.50 for cytotoxicity
to EC.sub.50 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
I:
##STR00001## wherein,
n and m are each independently 0 or 1, but n and m are not both
0;
R.sup.1 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl if n is 0 and (C.sub.1-C.sub.16) alkylene, branched alkyl,
alkenyl or alkynyl if n is 1;
R.sup.2 is (C.sub.1-C.sub.16) alkyl branched alkyl alkenyl or alkynyl
if m is 0 and (C.sub.1-C.sub.16) alkylene, branched alkyl, alkenyl
or alkynyl if m is 1;
R.sup.3, R.sup.4 and R.sup.5 are each independently (C.sub.1-C.sub.8)
alkylene;
R.sup.6, R.sup.7 and R.sup.8 are each independently (C.sub.1-C.sub.8)
alkyl;
X.sup.1 and X.sup.2 are each independently S, O, NHC.dbd.O, OC.dbd.O
or NH;
X.sup.3 is O or S;
E.sup.1 is H, S, halo or N.sub.3;
Z.sup.1 is H, S, or halo; or E.sup.1 and Z.sup.1 together are a
covalent bond;
E.sup.2 is H, S, halo, or N.sub.3;
Z.sup.2 is H, S, or halo; or E.sup.2 and Z.sup.2 together are a
covalent bond;
D.sup.1 and D.sup.2 are each independently selected from the group
consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine,
hypoxanthine, inosine, uracil and ring modifications thereof, including
O, N, and S substitutions, and
wherein, each alkyl, alkylene, branched alkyl, alkenyl, alkynyl,
adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine,
inosine and uracil of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, D.sup.1, and D.sup.2 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In one aspect, the compound is present in an amount effective to
inhibit virus replication in a mammal.
In another aspect, R.sup.1 is (C.sub.6-C.sub.16) alkyl if n is
0 or --CH.dbd.CH-- if n is 1.
In yet another aspect, R.sup.2 is (C.sub.6-C.sub.16) alkyl if m
is 0 or --CH.dbd.CH-- if m is 1.
In a further aspect, R.sup.3 is --CH.sub.2CH.sub.2--.
In one embodiment, R.sup.4 is --CH.sub.2--.
In another embodiment, R.sup.5 is --CH.sub.2--.
In yet another embodiment, R.sup.6, R.sup.7 and R.sup.8 are each
--CH.sub.3.
In one aspect, X.sup.1 is S, NHC.dbd.O, --NH-- or O.
In another aspect, X.sup.2 is S, NHC.dbd.O or O.
In a further aspect, X.sup.3 is O or S.
In another aspect, E.sup.1 is N.sub.3, S or H.
In one embodiment, Z.sup.1 is H or S.
In another embodiment, E.sup.2 is N.sub.3, S or H.
In a further embodiment, Z.sup.2 is H or S.
In one aspect, n is 0 and m is 1.
In another aspect, n is 1 and m is 0.
In yet another aspect, D.sup.1 is selected from the group consisting
of cytosine, guanine, inosine and thymine.
In a further aspect, D.sup.2 is selected from the group consisting
of cytosine, guanine, inosine and thymine.
In another aspect, the compound is in the form of a pharmaceutically
acceptable salt.
In one embodiment, the compound is present in an amount effective
to inhibit virus replication in a mammal.
In a preferred embodiment, R.sup.1 is (C.sub.6-C.sub.16) alkyl,
branched alkyl, alkenyl or alkynyl; R.sup.2 is (C.sub.4-C.sub.12)
alkylene; R.sup.3 is --CH.sub.2CH.sub.2--; R.sup.5 is --CH.sub.2--;
R.sup.6, R.sup.7 and R.sup.8 are each CH.sub.3; X.sup.1 and X.sup.2
are each independently S, O or NHC.dbd.O; E.sup.2 is H or N.sub.3;
D.sup.2 is selected from the group consisting of thymine, cytosine,
guanine and inosine, and wherein each alkyl, branched alkyl, alkylene,
alkenyl, alkynyl, thymine, cytosine, guanine, and inosine of R.sup.1,
R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and D.sup.2
can, optionally, be substituted with 1, 2, 3, or 4 substituents
independently selected from the group consisting of halo, nitro,
trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy,
aryl, and N(R.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H and (C.sub.1-C.sub.8)
alkyl.
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 having the
structure of Formula I:
##STR00002## wherein,
n and m are each independently 0 or 1, but n and m are not both
0;
R.sup.1 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl if n is 0 and (C.sub.1-C.sub.16) alkylene, branched alkyl,
alkenyl or alkynyl if n is 1;
R.sup.2 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl if m is 0 and (C.sub.1-C.sub.16) alkylene, branched alkyl,
alkenyl or alkynyl if m is 1;
R.sup.3, R.sup.4 and R.sup.5 are each independently (C.sub.1-C.sub.8)
alkylene;
R.sup.6, R.sup.7 and R.sup.8 are each independently (C.sub.1-C.sub.8)
alkyl;
X.sup.1 and X.sup.2 are each independently S, O, NHC.dbd.O, OC.dbd.O
or NH;
X.sup.3 is O or S;
E.sup.1 is H, S, halo or N.sub.3;
Z.sup.1 is H, S, or halo; or E.sup.1 and Z.sup.1 together are a
covalent bond;
E.sup.2 is H, S, halo, or N.sub.3;
Z.sup.2 is H, S, or halo; or E.sup.2 and Z.sup.2 together are a
covalent bond;
D.sup.1 and D.sup.2 are each independently selected from the group
consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine,
hypoxanthine, inosine, uracil and ring modifications thereof, including
O, N, and S substitutions, and
wherein, each alkyl, alkylene, branched alkyl, alkenyl, alkynyl,
adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine,
inosine and uracil of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, D.sup.1, and D.sup.2 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In one aspect, R.sup.1 is (C.sub.8-C.sub.12) alkyl if n is 0 and
--CH.sub.2CH.sub.2-- if n is 1.
In another aspect, R.sup.2 is (C.sub.8-C.sub.12) alkyl if m is
0 and --CH.sub.2CH.sub.2-- if m is 1.
In yet another aspect, R.sup.3 is --CH.sub.2CH.sub.2--.
In one embodiment, R.sup.4 is --CH.sub.2--.
In another embodiment, R.sup.5 is --CH.sub.2--.
In a further embodiment, R.sup.6, R.sup.7 and R.sup.8 are each
--CH.sub.3.
In another embodiment, X.sup.1 is S or O.
In one aspect, X.sup.2 is S or O.
In another aspect, X.sup.3 is O.
In a further aspect, E.sup.1 is N.sub.3 or H.
In a still further aspect, Z.sup.1 is H.
In one embodiment, E.sup.2 is N.sub.3 or H.
In another embodiment, Z.sup.2 is H.
In yet another embodiment, n is 0 and m is 1.
In one aspect, n is 1 and m is 0.
In another aspect, D.sup.1 is selected from the group consisting
of cytosine, guanine, inosine, and thymine.
In a further aspect, D.sup.2 is selected from the group consisting
of cytosine, guanine, inosine, and thymine.
In a still further aspect, the virus infection is an infection
by a virus selected from the group consisting of HIV, hepatitis
virus, and a herpes virus.
In one embodiment, the HIV is selected from the group consisting
of HIV-1 and HIV-2.
Preferably, the hepatitis virus is selected from the group consisting
of hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis
E viruses.
Preferably, the herpes virus is selected from the group consisting
of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster
virus, cytomegalovirus, Epstein Barr virus, human herpes virus type
6, human herpes virus type 7, and human herpes virus type 8.
In a preferred aspect, R.sup.1 is (C.sub.6-C.sub.16) alkyl, branched
alkyl, alkenyl or alkynyl; R.sup.2 is (C.sub.4-C.sub.12) alkylene;
R.sup.3 is --CH.sub.2CH.sub.2--; R.sup.5 is --CH.sub.2--; R.sup.6,
R.sup.7 and R.sup.8 are each CH.sub.3; X.sup.1 and X.sup.2 are each
independently S, O or NHC.dbd.O; E.sup.2 is H or N.sub.3; D.sup.2
is selected from the group consisting of thymine, cytosine, guanine
and inosine, and wherein each alkyl, branched alkyl, alkylene, alkenyl,
alkynyl, thymine, cytosine, guanine, and inosine of R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and D.sup.2 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b),
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
In one aspect, a pharmaceutically acceptable salt of the compound
is administered to the mammal.
Preferably, the mammal is a human.
The invention also includes a method of inhibiting virus replication
in a cell. The method comprises administering to the cell a compound
of Formula I in an amount effective to inhibit virus replication
in the cell.
The invention includes a pharmaceutical composition comprising
a compound of Formula I in combination with a pharmaceutically acceptable
carrier.
In one aspect, the compound is present in an amount effective to
inhibit virus replication in a mammal.
In another aspect, the compound is present in an amount effective
to inhibit virus replication in a mammal.
The invention also includes a kit for treatment of a viral infection
in a mammal. The kit comprises a) a composition selected from the
group consisting of a compound of Formula I, a pharmaceutically
acceptable salt thereof, and a pharmaceutical composition comprising
a compound of Formula I, and b) an instructional material.
The invention also includes a kit for inhibition of virus replication
in a cell. The kit comprises a) a composition selected from the
group consisting of a compound of Formula I, a pharmaceutically
acceptable salt thereof, and a pharmaceutical composition comprising
a compound of Formula I, and b) an instructional material.
The invention also includes a compound having the structure of
Formula III:
##STR00003## wherein,
R.sup.11 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl;
R.sup.12 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl;
X.sup.11 is O, S, or NHC.dbd.O;
X.sup.12 is O, S, or NHC.dbd.O;
X.sup.13 is O or S;
n is 0, 1 or 2, and
R.sup.13 is a therapeutic agent,
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.11, R.sup.12, and R.sup.13 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl, and
wherein, if n is 1 or 2, the compound is a phospholipase C substrate
and is not a phospholipase A substrate, and
further wherein, 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.
In a preferred embodiment, R.sup.11 is a C.sub.12 alkyl, branched
alkyl, alkenyl or alkynyl; R.sup.12 is C.sub.8H.sub.16 alkyl or
branched alkyl; n=1, and R.sup.13 is an anticancer agent selected
from the group consisting of gemcitabine, ara-C, 5-azacytidine,
cladribine, fludarabine, fluorodeoxyuridine, cytosine arabinoside,
6-mercaptopurine, 6-thioguanine 5-deoxyfluorouridine, ftorafur,
capecitabine, 5-deoxy-5-fluorocytidine, 5-aza-cytsine arabinoside,
troxacitabine, and pentostatin, wherein the phosphorus atom of the
phosphate moiety is covalently linked in a phosphate ester linkage
to the oxygen atom of the 5' hydroxyl group of a sugar moiety of
R.sup.13.
The invention also includes a compound having the structure of
Formula IV:
##STR00004## wherein,
R.sup.21 is (C.sub.6 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
R.sup.22 is (C.sub.1 to C.sub.12) alkyl, branched alkyl, alkenyl,
or alkynyl;
X.sup.21 is O, S, or NHC.dbd.O;
X.sup.22 is O, S, or NHC.dbd.O;
X.sup.23 is O or S;
n is 1 or 2;
R.sup.23 is a therapeutic agent, and
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.21, R.sup.22, and R.sup.23 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In a preferred aspect, R.sup.21 is C.sub.12 alkyl; R.sup.22 is
C.sub.10 alkyl; n=1, and R.sup.23 is an anticancer agent selected
from the group consisting of gemcitabine, ara-C, 5-azacytidme, cladribine,
fludarabine, fluorodeoxyuridine, cytosine arabinoside, 6-mercaptopurine,
6-thioguanine, 5-deoxyfluorouridine, ftorafur, capecitabine, 5-deoxy-5-fluorocytidine,
5-aza-cytsine arabinoside, troxacitabine, and pentostatin, 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
R.sup.23.
The invention also includes a compound having the structure of
Formula V:
##STR00005## wherein,
R.sup.31 is (C.sub.1 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
R.sup.32 is (C.sub.1 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
X.sup.31 is O, S, or NHC.dbd.O;
X.sup.32 is O, S, or NHC.dbd.O;
X.sup.33 is --OH, --SH, or amino;
R.sup.33 is a therapeutic agent, and
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.31, R.sup.32, and R.sup.33 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In a preferred embodiment, R.sup.31 is (C.sub.6-C.sub.16) alkyl,
branched alkyl, alkenyl or alkynyl; R.sup.32 is (C.sub.1-C.sub.8)
alkyl, branched alkyl, alkenyl or alkynyl, and R.sup.32 is an anticancer
agent selected from the group consisting of mitoxanthrone, doxorubicin,
idarubicin, epirubicin, daunorubicin, mitomycin, methotrexate, CPT-11,
SN-38, camptothecin, topotecan, 9-nitrocamptothecin, and 9-aminocamptothecin,
and is covalently linked via an ester, amido or carbamate linkage
to the --SH, OH or amino group of X.sup.33.
In one aspect, the compound is suspended in a pharmaceutically
acceptable carrier and is present in an amount effective to combat
a cancer in a mammal.
Preferably, the cancer is a cancer selected from the group consisting
of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma
and a solid tumor.
In one aspect, 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.
Preferably, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
In one aspect, the CNS cell is an astrocyte or a glial cell.
In one embodiment, the compound is in the form of a pharmaceutically
acceptable salt.
In one aspect, the compound is present in an amount effective to
facilitate delivery of a therapeutic agent to a mammalian cell.
In one embodiment, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
In one aspect, the compound is present in an amount effective to
combat a cancer in a mammal.
In one embodiment, the compound in the pharmaceutically acceptable
salt 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.
In one aspect, the cell is in a mammal.
In one embodiment, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
In one aspect, the compound is present in an amount effective to
combat a cancer in a mammal.
The invention also includes a drug delivery agent comprising a
pharmaceutical composition. The composition comprises a compound
of Formula III or a pharmaceutically acceptable salt thereof, in
an amount effective to facilitate delivery of a therapeutic agent
to a mammalian cell.
In one aspect, the therapeutic agent is an anticancer agent.
In another aspect, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
The invention also includes a drug delivery agent comprising a
pharmaceutical composition. The composition comprises a compound
of Formula III or a pharmaceutically acceptable salt thereof, in
an amount effective to combat a cancer in a mammal.
Preferably, the 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 facilitating delivery of
a therapeutic agent to a mammalian cell. The method comprises administering
to the cell a pharmaceutical composition comprising a compound of
Formula III or a pharmaceutically acceptable salt thereof, in an
amount effective to facilitate delivery of the therapeutic agent
to the cell.
In one aspect, the therapeutic agent is an anticancer agent.
In another aspect, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
The invention also includes a method of facilitating delivery of
a therapeutic agent to a cell. The method comprises administering
to the cell a pharmaceutical composition comprising a compound of
Formula III or a pharmaceutically acceptable salt thereof, in an
amount effective to facilitate delivery of the therapeutic agent
to the cell.
In one aspect, the cell is in a mammal.
In another aspect, the cell is a cell selected from the group consisting
of a CNS cell and a lymphoid cell.
The invention also includes a method of combating a cancer in a
mammal. The method comprises administering to the mammal a pharmaceutical
composition comprising a compound of Formula III or a pharmaceutically
acceptable salt thereof, in an amount effective to combat a cancer
in the mammal.
In one aspect, the 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 a disease in a
mammal. The method comprises administering to the mammal a pharmaceutical
composition comprising a compound of Formula III, or a pharmaceutically
acceptable salt thereof, in an amount effective to facilitate delivery
of a therapeutic agent to a cell in the mammal, thereby treating
the disease.
In one aspect, the disease is a disease selected from the group
consisting 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 invention also includes a kit for combating a cancer in a mammal.
The kit comprises a) a composition selected from the group consisting
of a compound of Formula III, a pharmaceutically acceptable salt
thereof, and a pharmaceutical composition comprising a compound
of Formula III, and b) an instructional material.
The invention also includes a kit for facilitating delivery of
a therapeutic agent to a mammalian cell. The kit comprises a) a
composition selected from the group consisting of a compound of
Formula III, a pharmaceutically acceptable salt thereof, and a pharmaceutical
composition comprising a compound of Formula III, and b) an instructional
material.
Preferably, the therapeutic agent is an anticancer agent.
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.
FIG. 1, comprising FIGS. 1A, 1B, and 1C is a series of formulae
depicting the chemical structures of several anticancer agents.
FIG. 1A depicts the chemical structure of gemcitabine. FIG. 1B depicts
the chemical structure of ara-C. FIG. 1C depicts the chemical structure
of 5-azacytidine.
FIG. 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.
FIG. 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.
FIG. 4 is a reaction scheme depicting the synthesis method for
preparing a double targeting PC lipid-AZT conjugate compound of
the invention (INK-20).
FIG. 5, comprising FIGS. 5A and 5B, is a pair of formulae depicting
the chemical structures of exemplary compounds of Formula III.
FIG. 6, comprising FIGS. 6A and 6B, is a pair of formulae depicting
the chemical structures of exemplary compounds of Formula IV.
FIG. 7 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 herpesviruses (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, 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 Formulas III, IV and
V 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 fluoro, 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.
C.sub.1-C.sub.8 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. C.sub.1-C.sub.8 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. C.sub.1-C.sub.8
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. C.sub.6-C.sub.15
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.
C.sub.6-C.sub.15 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. C.sub.8-C.sub.12 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. C.sub.8-C.sub.12 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. Accordingly, the invention
includes a compound having the chemical structure of Formula I or
a pharmaceutically acceptable salt thereof.
Formula I is
##STR00006## wherein
n and m are each independently 0 or 1, but n and m are not both
0;
R.sup.1 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl if n is 0 and (C.sub.1-C.sub.16) alkylene, alkenyl or alkynyl
if n is 1;
R.sup.2 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl if m is 0 and (C.sub.1-C.sub.16) alkylene, alkenyl or alkynyl
if m is 1;
R.sup.3, R.sup.4 and R.sup.5 are each independently (C.sub.1-C.sub.8)
alkylene;
R.sup.6, R.sup.7 and R.sup.8 are each independently (C.sub.1-C.sub.8)
alkyl;
X.sup.1 and X.sup.2 are each independently S, O, NHC.dbd.O, OC.dbd.O
or NH;
X.sup.3 is O or S;
E.sup.1 is H, S, halo or N.sub.3;
Z.sup.1 is H, S, or halo; or E.sup.1 and Z.sup.1 together are a
covalent bond;
E.sup.2 is H, S, halo, or N.sub.3;
Z.sup.2 is H, S, or halo; or E.sup.2 and Z.sup.2 together are a
covalent bond, and
D.sup.1 and D.sup.2 are each independently selected from the group
consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine,
hypoxanthine, inosine, uracil and ring modifications thereof, including
O, 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 R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, D.sup.1, and D.sup.2 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoro, trifluoromethyl,
trifluoromethoxy, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy,
aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H and (C.sub.1-C.sub.8)
alkyl.
The following are examples of definitions for radicals and substituents
of Formula I in 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, R.sup.1 can be one of (C.sub.2-C.sub.16)
alkylene, --(CH.sub.2).sub.12--, and --CH.dbd.CH--. In these embodiments,
R.sup.1 is optionally substituted with 1, 2, 3, or 4 substituents
selected from the group consisting of halo, nitro, trifluoromethyl,
(C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
In preferred embodiments, R.sup.2 can be one of (C.sub.2-C.sub.16)
alkylene, --(CH.sub.2).sub.8--, --(CH.sub.2).sub.9--, --(CH.sub.2).sub.10--,
--(CH.sub.2).sub.11--, --(CH.sub.2).sub.12--, and --CH.dbd.CH--.
In these embodiments, R.sup.2 is optionally substituted with 1,
2, 3 or 4 substituents selected from the group consisting of halo,
nitro, trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8)
alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.8) alkyl.
R.sup.3 is preferably --CH.sub.2CH.sub.2--, optionally substituted
with 1, 2, 3, or 4 substituents selected from the group consisting
of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8)
alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.8) alkyl.
R.sup.4 is preferably --CH.sub.2--, optionally substituted with
1 or 2, substituents selected from the group consisting of halo,
nitro, trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8)
alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.8) alkyl.
R.sup.5 is preferably --CH.sub.2--, optionally substituted with
1 or 2 substituents selected from the group consisting of halo,
nitro, trifluoromethyl, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8)
alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.8) alkyl.
In one preferred embodiment, each of R.sup.6, R.sup.7 and R.sup.8
is --CH.sub.3, each optionally substituted with 1 or 2 substituents
selected from the group consisting of halo, nitro, trifluoromethyl,
(C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
X.sup.1 is preferably S, O or NHC.dbd.O.
X.sup.2 is preferably S, O or NHC.dbd.O.
X.sup.3 is preferably O or S.
E.sup.1 is preferably N.sub.3, S, or H.
Z.sup.1 is preferably H.
E.sup.2 is preferably N.sub.3, S or H.
Z.sup.2 is preferably H.
D.sup.1 is preferably cytosine, guanine, inosine or thymine, wherein
D.sub.1 is optionally substituted with 1, 2, 3, or 4 substituents
selected from the group consisting of halo, nitro, trifluoromethyl,
(C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
D.sup.2 is preferably cytosine, guanine, inosine or thymine, wherein
D.sub.2 is optionally substituted with 1, 2, 3 or 4 substituents
selected from the group consisting of halo, nitro, trifluoromethyl,
(C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
The invention also includes a compound which exhibits antiviral
activity having the chemical structure of Formula II or a pharmaceutically
acceptable salt thereof.
Formula II is
##STR00007## wherein,
R.sup.1 is (C.sub.6-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl;
R.sup.2 is (C.sub.4-C.sub.12) alkylene;
R.sup.3 is --CH.sub.2CH.sub.2--;
R.sup.5 is --CH.sub.2--;
R.sup.6, R.sup.7 and R.sup.8 are each CH.sub.3;
X.sup.1 and X.sup.2 are each independently S, O or NHC.dbd.O;
E.sup.2 is H or N.sub.3, and
D.sup.2 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 R.sup.1, R.sup.2, R.sup.3, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, and D.sup.2 can, optionally, be substituted
with 1, 2, 3, or 4 substituents independently selected from the
group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b),
wherein R.sup.a and R.sup.b are each independently selected from
the group consisting of H and (C.sub.1-C.sub.8) alkyl.
The present invention also includes 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 III or a pharmaceutically acceptable salt thereof.
Formula III is
##STR00008## wherein,
R.sup.11 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl;
R.sup.12 is (C.sub.1-C.sub.16) alkyl, branched alkyl, alkenyl or
alkynyl;
X.sup.11 is O, S, or NHC.dbd.O;
X.sup.12 is O, S, or NHC.dbd.O;
X.sup.13 is O or S;
n is 0, 1 or 2, and
R.sup.13 is a therapeutic agent.
In Formula III, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.11, R.sup.12, and R.sup.13 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) 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 formulated 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., n=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 preferred compounds of Formula III,
R.sup.11 is a C.sub.12 alkyl, branched alkyl, alkenyl or alkynyl;
R.sup.12 is C.sub.8H.sub.16 alkyl or branched alkyl;
n=1,
and R.sup.13 is an anticancer agent.
Preferably, the anticancer agent is selected from the group consisting
of gemcitabine, ara-C, 5-azacytidine, cladribine, fludarabine, fluorodeoxyuridine,
cytosine arabinoside 6-mercaptopurine, 6-thioguanine, 5-deoxyfluorouridine,
ftorafur, capecitabine, 5-deoxy-5-fluorocytidine, 5-aza-cytsine
arabinoside, troxacitabine, and pentostatin, wherein the phosphorus
atom of the phosphate moiety is covalently linked in a phosphate
ester linkage to the oxygen atom of the 5' hydroxyl group of a sugar
moiety of R.sup.13.
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
##STR00009## wherein,
R.sup.21 is (C.sub.6 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
R.sup.22 is (C.sub.1 to C.sub.12) alkyl, branched alkyl, alkenyl,
or alkynyl;
X.sup.21 is O, S, or NHC.dbd.O;
X.sup.22 is O, S, or NHC.dbd.O;
X.sup.23 is O or S;
n is 1 or 2, and
R.sup.23 is a therapeutic agent.
In Formula IV, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.21, R.sup.22, and R.sup.23 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In preferred compounds of Formula IV,
R.sup.21 is C.sub.12 alkyl;
R.sup.22 is C.sub.10 alkyl;
n=1, and
R.sup.23 is an anticancer agent.
Preferably, the anticancer agent is selected from the group consisting
of gemcitabine, ara-C, 5-azacytidine, cladribine, fludarabine, fluorodeoxyuridine,
cytosine arabinoside 6-mercaptopurine, 6-thioguanine, 5-deoxyfluorouridine,
ftorafur, capecitabine, 5-deoxy-5 -fluorocytidine, 5-aza-cytsine
arabinoside, troxacitabine, and pentostatin, 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 R.sup.23.
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
##STR00010## wherein,
R.sup.31 is (C.sub.1 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
R.sup.32 is (C.sub.1 to C.sub.16) alkyl, branched alkyl, alkenyl,
or alkynyl;
X.sup.31 is O, S, or NHC.dbd.O;
X.sup.32 is O, S, or NHC.dbd.O;
X.sup.33 is --OH, --SH, or amino, and
R.sup.33 is a therapeutic agent.
In Formula V, each alkyl, branched alkyl, alkenyl, alkynyl, adenine,
thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine
and uracil of R.sup.31, R.sup.32, and R.sup.33 can, optionally,
be substituted with 1, 2, 3, or 4 substituents independently selected
from the group consisting of halo, nitro, trifluoromethyl, (C.sub.1-C.sub.8)
alkyl, (C.sub.1-C.sub.8) alkoxy, aryl, and N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are each independently selected from the group
consisting of H and (C.sub.1-C.sub.8) alkyl.
In preferred compounds of Formula V,
R.sup.31 is (C.sub.6-C.sub.16) alkyl branched alkyl alkenyl or
alkynyl;
R.sup.32 is (C.sub.1-C.sub.8) alkyl, branched alkyl, alkenyl or
alkynyl, and
R.sup.33 is an anticancer agent.
Preferably, the anticancer agent is selected from the group consisting
of mitoxanthrone, doxorubicin, idarubicin, epirubicin, daunorubicin,
mitomycin, methotrexate, CPT-11, SN-38, camptothecin, topotecan,
9-nitrocamptothecin, and 9-aminocamptothecin, and is covalently
linked via an ester, amido or carbamate linkage to the --SH, OH
or amino group of X.sup.33.
Compounds of Formula I and Formula II 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 FIGS. 2-4. The
structures presented in the reaction schemes of FIGS. 2-4 are representative
and not meant to limit the compounds of the invention. Modifications
to the reactions in FIGS. 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 FIG. 2, for example, with an AZT-malonic acid (AZT-MA)
moiety, for example, prepared as shown in FIG. 3. Synthetic methods
for the preparation of a lipid backbone as described in FIG. 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 C.sub.6H.sub.5CH.sub.2O(CH.sub.2).sub.8Br
(8-benzyloxyoctyl bromide) for CH.sub.3(CH.sub.2).sub.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 FIG. 4 by reacting the lipid backbone moiety generated
as shown in FIG. 2 with the AZT-malonic acid (AZT-MA) moiety generated
as shown in FIG. 3. The AZT-MA moiety can be prepared, for example,
as described in the Examples herein. FIGS. 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 FIG. 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 and Formula II, as described
above. 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 INK-20, INK-25 and INK-26. The chemical structures of these
compounds are depicted in Table 1 herein.
Compounds of Formulae III, 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 FIG. 7 (Formula III), FIG. 8 (Formula IV), and FIG.
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, fumaric, 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-V 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 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.degree. C.)
and which is liquid at the rectal temperature of the subject (i.e.
about 37.degree. 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.degree. 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 methylhydroxybenzoate. 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 nares.
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 ophthalmalmically-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 or Formula V, 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 or
Formula II, 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, "treatmen |