HIV protease inhibitors based on amino acid derivatives

Details HIV protease inhibitors based on amino acid derivatives HIV protease inhibitors based on amino acid derivatives

2002-09-17

2003-08-19

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S403000, C548S482000

Reexamination Certificate

active

06608100

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention concerns amino acid derivatives possessing aspartyl protease inhibitory properties, in particular N&egr;-amino acid substituted L-lysine derivatives (and analogs) possessing aspartyl protease inhibitory properties. It describes also the synthetic methodology used to make these derivatives and their biological applications. In addition, this invention relates to different pharmaceutical compositions comprising these compounds. The compounds and the pharmaceutical compositions of this invention have been shown to inhibit the activity of HIV aspartyl protease, an enzyme essential for virus maturation. The 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 responsible for causing the disease known as AIDS (acquired immunodeficiency syndrome). 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 syndrome called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS.
As the first step of its replication cycle, the HIV-1 retrovirus attaches primarily to 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)). The HIV genetic material, in the form of RNA, is then transcribed into DNA by a viral enzyme carried by the virus called reverse transcriptase. The viral DNA now called provirus is then transported into the cell nucleus in the form of a preintegration complex and attached to the cell DNA by another viral enzyme called integrase. Following integration, the viral DNA then serves as a template for viral gene expression by the host transcription system 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, Tat and Rev. The viral proteins are expressed mainly in the form of polyproteins. After the infected cell has produced all the different HIV polyproteins and genetic material, they assemble at the cell membrane and are released from the cell in the form of an immature viral particle. A third viral enzyme known as protease then cleaves the polyproteins to give the mature, infectious viral particle. The polyproteins that are cleaved by the HIV protease are the Gag and Gag-Pol precursors, whose cleavage gives rise to structural proteins and viral enzymes.
A number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV, although only those developed against the viral enzymes have reached the market so far. The latter include compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), or the viral protease (for example, ritonavir and indinavir). Although these drugs have improved significantly the survival time and quality of life of AIDS patients, the administration of most of these agents leads to 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 by the viral protease. The antiviral potential of HIV protease inhibitors was first demonstrated using peptidic inhibitors. Such peptidic compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and limited stability in the body. New compounds devoid of these drawbacks are urgently needed to treat HIV infections. In addition, mutations arising during HIV replication lead to resistance to the currently available protease inhibitors, so new compounds with original structure are desirable to fight these resistant viral strains.
SUMMARY OF THE INVENTION
The present invention provides a novel class of compounds, including their pharmaceutically acceptable derivatives. These compounds have an affinity for aspartyl proteases, in particular, HIV aspartyl protease. Therefore, these compounds are useful as inhibitors of such proteases. These compounds can be used alone or in combination with other therapeutic or prophylactic. agents for the treatment or prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells, by inhibiting the ability of HIV aspartyl protease to catalyse the hydrolysis of peptide bonds present in viral Gag and Gag-Pol polyproteins. 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 are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and HIV-2, which may result in asymptomatic infection, AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS), AIDS-related dementia, or similar diseases of the immune system, and related viruses such as HTLV-I and HTLV-II, and simian immunodeficiency virus.
It is the m objective of this invention to provide a novel class of molecules that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors.
The present invention relates to a class of N&egr;-amino acid substituted L-lysine derivatives (including its lower and higher homologues and analogs) 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
a compound of formula II
and when the compound of formula I and II comprises an amino group pharmaceutically acceptable ammonium salts thereof,
wherein n is 3 or 4
wherein Y is O, S or N—CN
wherein Cx is selected from the group consisting of —COOM, COOR
6
, —CHO, —CH
2
OR
7
, —CH
2
OCOR
8
, —CONHR
9
and —CONR
10
R
11
, wherein M is an alkali metal (e.g. Na, K, Cs, etc.) or alkaline earth metal (Ca, Mg, etc.),
wherein R
1
is selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
wherein R
2
is selected from the group consisting of a benzenesulfonyl group of formula III,
 and a thiophenesulfonyl group of formula IV,
 wherein R
3
is selected from the group consisting of H, a straight or branched alkyl group of 1 to 6 carbon atoms, a phenyl or a benzyl group
wherein R
4
is selected from the group consisting of H, a group of formula IIIa
 a group of formula IVa
 C
6
H
11
—, C
5
H
10
N—CH
2
CH
2
—, OC
4
H
8
N—CH
2
CH
2
— (i.e. morpholine-4-CH
2
CH
2
—), C
6
H
5
CH
2
CH
2
—, 2,3-(CH
3
O)
2
C
6
H
3
CH
2
—, C
6
H
5
—, 2-C
5
H
4
N (i.e. 2-pyridinyl), 3-C
5
H
4
N (i.e. 3-pyridinyl), 4-C
5
H
4
N (i.e. 4-pyridinyl), 3-quinolyl, C
6
H
5
CS—, 2-naphthyl-SO
2
— and a group of formula R
4C
—CO—, R
4C
being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g. CH
3
—, iso-butyl, iso-propyl, tert-butyl, tert-butyl-CH
2
—), CF
3
, 1-pyrrolidinyl, 4-morpholinyl, tetrahydro-3-furanyloxy, 4-CH
3
OC
6
H
4
NH—, CH
3

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