Antiviral compounds and methods of administration

Details Antiviral compounds and methods of administration Antiviral compounds and methods of administration

1997-02-28

2004-02-03

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S026800

Reexamination Certificate

active

06686462

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel nucleoside and phosphonoacid lipophilic conjugates and methods of treatment such as treatment of virally infected cells by administering one or more of the conjugates of the invention. Compounds of the invention include phosphonoacid
ucleoside conjugates where the carboxyl group and phosphonyl groups of the phosphonoacid are esterified whereby the compound contains at least one lipophilic group and at least one nucleoside group.
2. Background
The human immunodeficiency virus type 1 (HIV-1, also referred to as HTLV-III, LAV or HTLV-III/LAV) and, to a lesser extent, human immunodeficiency virus type 2 (HIV-2) is the etiological agent of the acquired immune deficiency syndrome (AIDS) and related disorders. See, for example, Barre-Sinoussi et al.,
Science
, 220:868-871 (1983); Gallo et al.,
Science
, 224:500-503 (1984).
Methods for treating individuals infected by HIV have focussed on preventing integration of the virus into the host cell's chromosome or on stages other than provirus. Thus one area of interest has been drugs that affect reverse transcriptase of HIV.
A number of dideoxy nucleosides have shown activity as reverse transcriptase inhibitors. In particular, AZT (zidovudine, 3′-azido-3′-deoxythymidine), ddI (2′,3′-dideoxyinosine), ddC (2′,3′-dideoxycytidine), d4T (2′,3′-dideoxy-2′,3′-dihydro-thymidine), (−) 2′,3′-dideoxy-3′-thiacytosine (3TC), (−) 2′,3′-dideoxy-5-fluoro-3′-thiacytosine (FTC) and 1592U89 (Glaxo-Wellcome) have been used clinically for treatment of HIV infections.
Foscarnet, the trisodium salt of phosphonoformic acid (PFA, HOOCP(═O)(OH)
2
) is also a potent inhibitor of reverse transcriptase from human immunodeficiency virus type 1 (HIV-1). PFA inhibits replication of the virus in vitro and has been used clinically against AIDS. See E. Helgstrand et al.,
Science
, 201:819-821 (1978); B. Oberg,
Pharmacol. Ther
., 40:213-285 (1989); H. Sundquist et al.,
J. Gen. Virol
., 45:273-281 (1979); L. Vrang et al.,
Antimicrob. Agents Chemother
., 29:8967-872 (1986); E. G. Sandstrom et al.,
Lancet, ii
: 1480-1482 (1985); J. Gaub et al.,
AIDS Res
., 1:27-33 (1987); M. A. Jacobson,
J. Infect. Dis
., 158:862-865 (1988); and C. V. Fletcher et al.,
Antimicrob. Agents Chemother
., 38:604-607 (1994). PFA also inhibits DNA polymerase from cytomegalovirus (CMV), herpes simplex virus (HSV) and other DNA viruses, and PFA has been particularly useful in treating cytomegalovirus. See B. Eriksson et al.,
Biochim. Biophys. Acta
, 607:53-64 (1980); C. S. Crumpacker,
Am. J. Med
., 92:3-7S (1992); O. Ringden et al.,
Lancet, i
: 1502-1504 (1985); M. A. Jacobsen et al.,
Antimicrob. Agents Chemother
., 33:736-741 (1989); A. G. Palestine et al.,
Ann. Intern. Med
., 115:665-673 (1991); S. Safrin et al.,
N. Engl. J. Med
., 325:551-555 (1991); and M. M. Reddy,
J. Infect. Dis
., 166:607-610 (1992). Phosphonoacetic acid (PAA, HOOCCH
2
P(═O)(OH)
2
) also exhibits antiviral activity. See U.S. Pat. No. 4,771,041 to Eriksson et al.
These known agents have well recognized limitations. For example, therapy with AZT (zidovudine), 3TC and other dideoxynucleosides has not prevented the breakdown of the immune system in many patients after a number of years of treatment. Still further, HIV strains have been reported that exhibit substantial resistance to AZT therapy and treatment with other known dideoxy nucleosides such as ddC, ddI, d4T and 3TC.
PFA does not have a high degree of oral absorption and consequently is generally administered intraveneously. PFA therapy also can result in toxicity to kidneys and hypocalcemia. Crisp et al.,
Drugs
, 41:109-129 (1991).
Clinical resistance to PFA is known to occur after prolonged treatment. PFA resistant HIV-1 strains also have been produced in the laboratory by random as well as site-specific mutagenesis, and the pattern of cross resistance of such mutants to other reverse transcriptase inhibitors has been extensively analyzed. Mellors et al.,
Antimicrobial Agents and Chemotherapy
, 39:1087-1092 (1995); Tachedjian et al.,
J. Virol
., 70:7171-7181 (1996).
Additionally, the triple negative charge of PFA at physiological pH is an impediment to cellular uptake. As a result, the PFA concentration needed to block viral replication in an intact cell or in vivo is orders of magnitude greater than the concentration needed to inhibit the enzyme in a cell-free assay. Further, in vivo clearance of PFA is very rapid, which makes longlasting control of viral infection difficult to achieve.
Certain PFA derivatives have been reported, including certain simple alkyl and aryl esters of the carboxyl and/or phosphonyl moiety of PFA, certain acyloxymethyl esters of the phosphonyl moiety as well as certain ester derivatives in which the carboxyl or phosphonyl group was joined to a nucleoside. See J. O. Noren et al.,
J. Med. Chem
., 26:264-270 (1983); L. R. Phillips et al.,
Tetrahedron Letters
, 30:7141-7144 (1989); R. P. Iyer et al.,
J. Pharm. Sci
, 83:1269-1273 (1994); M. Vaghefi et al.,
J. Med. Chem
., 29:1389-1393 (1986); H. Griengl et al.,
J. Med. Chem
., 31:1831-1839 (1988); A. Rosowsky et al.,
Biochem. Biophys. Res. Commun
., 172:288-294 (1990); J. Sahaet al.,
Nucleosides
&
Nucleotides
, 10:1465-1475 (1991); and A. S. Charvet et al.,
J. Med. Chem
., 37:2216-2223 (1994). However, many of such compounds generally have not provided significant gains in terms of either potency or therapeutic selectivity for virally infected cells.
It thus would be desirable to have new compounds for treatment of virally infected cells, including cells infected with a retrovirus, particularly HIV. It would be especially desirable to have new compounds for treatment of cells infected with HIV strains that are resistant to current HIV therapeutics such as AZT and PFA.
SUMMARY OF THE INVENTION
We have discovered certain lipophilic phosphonoacid
ucleoside conjugates (covalently linked) that exhibit significant antiviral activity.
The invention thus provides methods of treatment against virus infections, including retroviral infections such as HIV infections, and treatment of other diseases caused by or otherwise associated with a virus such as influenza including influenza A and B; diseases associated with viruses of the herpes family, e.g., herpes simplex viruses (HSV) including herpes simplex 1 and 2 viruses (HSV 1, HSV 2), varicella zoster virus (VZV; shingles), human herpes virus 6, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and other herpes virus infections such as feline herpes virus infections; diseases associated with hepatitis viruses including hepatitis B viruses (HBV); and the like.
Particularly preferred compounds of the invention are active against drug-resistant viral strains. Indeed, it has been surprisingly found that compounds of the invention are highly active against HIV strains that are PFA-resistant as well as HIV strains that are AZT-resistant.
Compounds of the invention include phosphonoacid
ucleoside conjugates where the carboxyl group and phosphonyl groups of the phosphonacid are esterified whereby the compound contains at least one lipophilic group and at least one nucleoside group. More specifically, the invention provides compounds of the following Formula I that are highly useful to treat viral infections:
wherein at least one of R, R′ and R″ is present, and at least one of N, N′ and N″ is present;
each R, R′ or R″ are each independently an optionally substituted alkyl having from about 8 to 30 carbon atoms, preferably about 14 to 24 carbons; optionally substituted alkenyl having from about 8 to 30 carbon atoms, preferably about 14 to 24 carbons; optionally substituted alkynyl having from about 8 to 30 carbon atoms, preferably about 14 to 24 carbons; optionally substituted alkoxy having from about 8 to 30 carbon atoms, preferably about 14 to 24 carbons; optionally substituted alkylthio ha

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