Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-13
2004-07-27
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S196000, C546S202000, C549S027000, C549S282000
Reexamination Certificate
active
06768007
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel 3′,4′-di-O-camphanoyl-(+)-cis-khellactone analogs, and the use of such compounds as pharmaceuticals.
2. Background Art
Retroviruses are small, single-stranded positive-sense RNA viruses. A retroviral particle comprises two identical single-stranded positive sense RNA molecules. Their genome contains, among other things, the sequence of the RNA-dependent DNA polymerase, also known as reverse transcriptase. Many molecules of reverse transcriptase are found in close association with the genomic RNA in the mature viral particles. Upon entering a cell, this reverse transcriptase produces a double-stranded DNA copy of the viral genome, which is then inserted into the chromatin of a host cell. Once inserted, the viral sequence is called a provirus. Retroviral integration is directly dependent upon viral proteins. Linear viral DNA termini (the LTRs) are the immediate precursors to the integrated proviral DNA. There is a characteristic duplication of short stretches of the host's DNA at the site of integration.
Progeny viral genomes and mRNAs are transcribed from the inserted proviral sequence by host cell RNA polymerase in response to transcriptional, regulatory signals in the terminal regions of the proviral sequence, the long terminal repeats, or LTRs. The host cell's protein production machinery is used to produce viral proteins, many of which are inactive until processed by virally encoded proteases. Typically, progeny viral particles bud from the cell surface in a non-lytic manner. Retroviral infection does not necessarily interfere with the normal life cycle of an infected cell or organism. However, neither is it always benign with respect to the host organism. While most classes of DNA viruses can be implicated in tumorigenesis, retroviruses are the only taxonomic group of RNA viruses that are oncogenic. Various retroviruses, such as the Human Immunodeficiency Virus (HIV), which is the etiological agent responsible for acquired immune deficiency syndrome (AIDS) in humans, are also responsible for several very unusual diseases of the immune system of higher animals.
Human Immunodeficiency Virus (HIV) is a member of the lentiviruses, a subfamily of retroviruses. Many retroviruses are well-known carcinogens. HIV per se is not known to cause cancer in humans or other animals, but it does present a formidable challenge to the host. The viral genome contains many regulatory elements which allow the virus to control its rate of replication in both resting and dividing cells. Most importantly, HIV infects and invades cells of the immune system; it breaks down the body's immune system and renders the patient susceptible to opportunistic infections and neoplasms. The immune defect appears to be progressive and irreversible, with a high mortality rate that approaches 100% over several years.
HIV-1 is trophic and cytopathic for T4 lymphocytes, cells of the immune system which express the cell surface differentiation antigen CD4, also known as OKT4, T4 and leu3. The viral tropism is due to the interactions between the viral envelope glycoprotein, gp120, and the cell-surface CD4 molecules (Dalgleish et al.,
Nature
312:763-767 (1984)). These interactions not only mediate the infection of susceptible cells by HIV, but are also responsible for the virus-induced fusion of infected and uninfected T cells. This cell fusion results in the formation of giant multinucleated syncytia, cell death, and progressive depletion of CD4 cells in HIV-infected patients. These events result in HIV-induced immunosuppression and its subsequent sequelae, opportunistic infections and neoplasms.
In addition to CD4+ T cells, the host range of HIV includes cells of the mononuclear phagocytic lineage (Dalgleish et al., supra), including blood monocytes, tissue macrophages, Langerhans cells of the skin and dendritic reticulum cells within lymph nodes. HIV is also neurotropic, capable of infecting monocytes and macrophages in the central nervous system causing severe neurologic damage. Macrophage/monocytes are a major reservoir of HIV. They can interact and fuse with CD4-bearing T cells, causing T cell depletion and thus contributing to the pathogenesis of AIDS.
Considerable progress has been made in the development of drugs for HIV-1 therapy during the past few years. There are now 14 drugs approved for use in the U.S., including six nucleoside analog reverse transcriptase inhibitors (AZT, 3TC, ddI, ddC, D4T, and abacavir), three non-nucleoside RT inhibitors (nevirapine, delavirdine, and efavirenz) and five protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir). Combinations of these drugs are particularly effective and can reduce levels of viral RNA to undetectable levels in the plasma and slow the development of viral resistance, with resulting improvements in patient health and life span.
Despite these advances, there are still problems with the currently available drug regimens. Many of the drugs exhibit severe toxicities, have other side-effects (e.g., fat redistribution) or require complicated dosing schedules that reduce compliance and thereby limit efficacy. Resistant strains of HIV often appear over extended periods of time even on combination therapy. The high cost of these drugs is also a limitation to their widespread use, especially outside of developed countries.
There is still a major need for the development of additional drugs to circumvent these issues. Ideally these would target different stages in the viral life cycle, adding to the armamentarium for combination therapy, and exhibit minimal toxicity, yet have lower manufacturing costs.
Previously, suksdorfin, i.e., (3′R,4′R)-3′-acetoxy-4′-isovaleryloxy-(+)-cis-khellactone, was isolated as an anti-HIV principle from the fruit of
Lomatium suksdorfii.
Suksdorfin exhibited inhibitory activity against HIV-1 replication in H9 lymphocyte cells with EC
50
value of 1.3 &mgr;M, and therapeutic index (TI) value of 140. The discovery of suksdorfin led to the syntheses of khellactone derivatives and led to a second lead compound 3′,4′-di-O-(S)-(−)-camphanoyl-(3′R,4′R)-(+)-cis-khellactone (DCK), which showed extremely potent anti-HIV activity with EC
50
value of 2.56×10
−4
&mgr;M and a TI value of 136,719 (Xie, L. et al.,
J. Med. Chem.
42:2662-2672 (1999)).
Xie, L. et al. describe that alkyl and O-alkyl substituents at the 3-, 4-, and 5-positions of DCK produce derivatives with potent anti-HIV activity (
J. Med. Chem.
42:2662-2672 (1999)). DCK derivatives are also described in U.S. Pat. Nos. 5,847,165, 5,637,589, 5,726,204, and 5,612,341.
A need continues to exist for compounds which possess anti-HIV activity with improved biodistribution properties. There is also a need for safe and effective compounds that can be topically applied to vaginal or other mucosa to prevent HIV infection between individuals.
BRIEF SUMMARY OF THE INVENTION
The present invention provides novel 3′,4′-di-O-camphanoyl-(+)-cis-khellactone analogs of Formula I:
or pharmaceutically acceptable salts, esters, or prodrugs thereof; wherein
R
1
and R
4
are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, acyloxy, amino, monoalkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, —CH
2
CONH-alkyl, and C
1-4
alkyl substituted with one or more of halogen, trifluoromethyl, cyano, hydroxy, amino, monoalkylamino, or dialkylamino, wherein at least one of R
1
or R
4
is a substituted C
1-4
alkyl group;
R
2
and R
3
are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, acyloxy, amino, monoalkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, phenyl, and —CH
2
CONH-alkyl;
X and Z are independently selected from the group consisting of O, S and NH; and
where the configurations at 3′ and 4′ can be (R) or (S).
The present invention al
Allaway Graham P.
Lee Kuo-Hsiung
Wild Carl T.
Xie Lan
Covington Raymond
Panacos Pharmaceuticals, Inc.
Rotman Alan L.
Sterne Kessler Goldstein & Fox P.L.L.C.
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