D-mannitol derivatives as HIV aspartyl protease inhibitors

Details D-mannitol derivatives as HIV aspartyl protease inhibitors D-mannitol derivatives as HIV aspartyl protease inhibitors

1999-04-30

2001-11-06

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C568S852000

Reexamination Certificate

active

06313177

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a compounds with aspartyl protease inhibitory properties. This invention in particular relates to D-mannitol derivatives with HIV aspartyl protease inhibitory properties that have been characterized by specific structural and physicochemical features. In addition, this invention also relates to pharmaceutical compositions exploiting these compounds. The compounds including the pharmaceutical compositions of this invention are able to inhibit the activity of HIV aspartyl protease. Accordingly, this inhibitory property may be advantageously used to provide compounds with antiviral properties against HIV viruses, including the HIV-1 and HIV-2 viruses.
BACKGROUND OF THE INVENTION
The HIV (human immunodeficiency virus) retrovirus is the causative agent for AIDS (acquired immunodeficiency syndrome). Thus the HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in T-lymphocytes and CD4 (+) T-helper cells (Lasky L. A. et al., Cell vol. 50, p. 975-985 (1987)). HIV infection is characterized by a period immediately following infection called “asymptomatic” which is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrom called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS.
After entry of the retrovirus into a cell, viral RNA is converted into DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. Vol. 5 2349-2360 (1991)). At least three functions have been attributed to the reverse transcriptase: RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA, ribonuclease H (RNase H) activity which cleaves the RNA template from RNA-DNA hybrids and DNA-dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template (Goff S. P. J. Acq. Imm. Defic. Syndr., vol. 3 p. 817-831 (1990)). The double stranded DNA produced by reverse transcriptase, now called provirus, is then able to be inserted into host genomic DNA.
At the end of reverse transcription, the viral genome now in the form of DNA is integrated into host genomic DNA and serve as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Sakai, H al., J. Virol. Vol. 67, p. 1169-1174 (1993)). The preintegration complex consists of integrase, reverse transcriptase, p17 and proviral DNA (Bulrinsky et al., Proc. Nat. Acad. Sci. USA vol. 89, p. 6580-6584 (1992)). The phosphorylated p17 protein plays a key role in targeting the preintegration complex into the nucleus of host cell (Gallay et al., Cell, vol. 80, p. 379-388 (1995)).
The primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II which is modulated by two virus-encoded proteins called Tat and Rev. The viral proteins are formed as polyproteins.
Post-translational modifications of viral polyproteins include processing and glycosylation of Env (envelope) proteins, and myristylation of the N-terminal residue of the p17 protein in the Gag and Gag-Pol polyproteins. The latter two precursors correspond to structural proteins and viral enzymes. The viral protease is involved in processing polyproteins Gag and. Gag-Pol into mature proteins, a step essential for virus infectivity.
A number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV. These agents include compounds which interfere with viral binding to CD4 T-lymphocytes (for example, soluble CD4), compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), budding of virion from the cell (interferon), or the viral protease (for example Ritonavir and Indinavir). Some of these agents proved ineffective in clinical tests. Others, targeting primarily early stages of viral replication, have no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of many of these agents in effective therapeutic doses has led to cell-toxicity and unwanted side effects, such as anemia, neurotoxicity and bone marrow suppression.
Anti-protease compounds represent the most recent drugs developed to block HIV replication. These compounds inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Thus, the antiviral potential of HIV protease inhibition has been demonstrated using peptidic inhibitors. Such peptidic compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections, such as HIV.
SUMMARY OF THE INVENTION
The present invention relates to mannitol derivatives, including their pharmaceutically acceptable derivatives. These compounds have an affinity for aspartyl proteases, in particular, HIV aspartyl protease. Therefore, these compounds may be useful as inhibitors of such proteases. These compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as antivirals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
Compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells, by inhibiting the ability of HIV aspartyl proteases to catalyze the hydrolysis of peptide bonds. These novel compounds can thus serve to reduce the production of infectious virions from acutely and chronically infected cells, and can inhibit the initial or further infection of host cells. Accordingly, these compounds may be useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses, which may result in asymptomatic HIV-1 infection, AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS), AIDS-related dementia, or similar diseases of the immune system.
Acccordingly, the present invention relates to D-mannitol derivatives that may be used as aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors.
Accordingly, the present invention provides a D-mannitol derivative selected from the group consisting of a compound of formula 1
pharmaceutically acceptable derivatives thereof and where applicable or appropriate pharmaceutically acceptable salts thereof,
wherein R
1
, R
2
, R
3
and R
4
are the same or different and may each independently be selected from among alkyl and aryl (i.e. aromatic including aromatic like) groups. The aromatic (or aromatic like) group may be an aromatic hydrocarbon group, an aromatic heterocyclic group, an allyl group, a cyclopropylmethyl group, a alkylthiothioxo group, an aroyl group and the like.
In addition, this invention provides pharmaceutical compositions in which the D-mannitol derivatives (e.g. derived from D-mannitol) may be used to inhibit aspartyl proteases, including HIV aspartyl proteases, thus providing protection against HIV infection.
The term “heterocycle” “heterocyclic group” and the like refer to a stable 5-7 membered monocycle or bicyclic heterocycle, which may be optionally benzofused or heterocyclofused. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfiir. As used herein, the terms “nitrogen and sulfur heteroatoms” include any oxidized form of nitrogen a

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