Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-15
2002-09-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S603000, C560S013000, C562S430000
Reexamination Certificate
active
06455587
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel class of compounds with aspartyl protease inhibitory properties. This invention in particular relates to a class of amino acid derivatives with HIV aspartyl protease inhibitory properties that have been characterized by specific structural and physicochemical characteristics. In addition, this invention relates to different pharmaceutical compositions comprising these compounds. The compounds and the pharmaceutical compositions of this invention have been demonstrated 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 susceptible cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in CD4 (+) T-helper lymphocytes and other cells carrying the receptor (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 viral 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 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 serves as a template for viral gene expression by the host transcription system, which leads eventually to the production of new viral particles (Sakai, H al., J. Virol. Vol. 67, p. 1169-1174 (1993)). The preintegration complex consists of integrase, reverse transcriptase, p17 and proviral DNA (Bukrinsky 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 the host cell (Gallay et al., Cell, vol. 80, p. 379-388 (1995)), a necessary step for integration to take place.
The primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II whose activity 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 Gag and Gag-Pol precursors will give rise after cleavage to structural proteins and viral enzymes. The viral protease is the enzyme responsible for the cleavage of 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. The problem of viral resistance also underlines the need for new drugs to fight HIV infections.
It would be advantageous to have a class of derivatives that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to a class amino acid derivatives as well as their pharmaceutically acceptable derivatives (e.g. salts).
Accordingly, the present invention in accordance with one aspect thereof provides a compound of formula I
(as well as pharmaceutically acceptable derivatives thereof) and when the compound of formula I comprises an amino group pharmaceutically acceptable ammonium salts thereof,
wherein W is selected from the group consisting of —(CH
2
)
n
—, and —CH
2
—XX—CH
2
—CH
2
—
wherein n is 1, 2, 3 , 4 or 5,
wherein XX is selected from the group consisting of O, NR
5
, S, SO and SO
2
wherein Cx is selected from the group consisting of —COOM, —COOR
5
, —CH
2
OH, —CONR
5
R
6
, —CONHOH, 9-fluorenylmethoxycarbonyl-lysyl-NH—CO, benzyloxycarbonyl, and tetrazolyl, wherein M is an alkali metal (e.g. Na, K, Cs, etc.) or an alkaline earth metal, wherein R
1
and R
3
, the same or different, are selected (i.e. independently) from the group consisting of H, tert-butoxycarbonyl, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof (e.g. cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, etc.) an arylalkyl group of formula (2)
and a heterocycle-alkyl group of formula heterocycle-(CH
2
)
m
—wherein R
2
and R
4
the same or different are selected (i.e. independently) from the group consisting of H, CHO—, CF
3
—, CH
3
CO—, benzoyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-OH-7-CF
3
-quinoline-3-CO—, 3-indole-CH
2
CH
2
CO—, 3-indole-CH
2
CO—, 3-indole-CO—, 2-indole-CO—, C
6
H
5
OCH
2
CO—, (C
6
H
5
)
2
COHCO—, C
6
H
5
SCH
2
CO—, C
6
H
5
CH
2
CH
2
CS—, cholesteryl-OCO—, 2-quinoline-CO—, xanthene-9-CO—, 4-C
6
H
5
CH
2
CH
2
CONHC
6
H
4
SO
2
—, 2-NO
2
C
6
H
4
CHCHCO—, 3-C
5
H
4
NCHCHCO—, 3-C
5
H
4
NCH
2
CH
2
CO—, fluorene-CH
2
CO—, camphor-10-CH
2
—SO
2
—, (C
6
H
5
)
2
CH—CO—, fluorene-CO—, 1-naphthyl-SO
2
—, 2-naphthyl-SO
2
—, fluorenyl-SO
2
—, phenanthryl-SO
2
—, anthracenyl-SO
2
—, quinoline-SO
2
—, 4-CH
3
COONHC
6
H
4
—SO
2
—, C
6
H
5
CHCH—SO
2
—, 4-NO
2
C
6
H
4
—SO
2
—, an aryalkyl group of for
Bouzide Abderrahim
Sauve Gilles
Sévigny Guy
Stranix Brent Richard
Yelle Jocelyn
Brouillette Robert
Kosie Ronald S.
Patel Subdaker B.
Pharmacor Inc.
Raymond Richard L.
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