Aromatic derivatives as HIV aspartyl protease inhibitors

Details Aromatic derivatives as HIV aspartyl protease inhibitors Aromatic derivatives as HIV aspartyl protease inhibitors

2002-12-23

2003-10-14

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S148000, C544S159000, C544S406000, C546S316000, C546S323000, C548S333500, C548S537000, C549S438000, C549S487000, C560S010000, C560S013000, C562S427000, C562S430000, C564S086000

Reexamination Certificate

active

06632816

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention concerns a novel class of aromatic derivatives possessing aspartyl protease inhibitory properties. It describes the synthetic methodology used to make these derivatives from readily available L-lysine analogues 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 and infectivity. 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
HIV, the human immunodeficiency virus, causes AIDS through infection of specialized cells of the immune system carrying CD4 receptors. The HIV retrovirus reproduces in these cells, especially the so-called T-helper cells, and kills them in the process. While the body has the ability to re-generate T-helper cells to some extent, after years of continuous cell destruction by HIV and fighting back by the immune system, the virus eventually emerges as the battle's winner. The progressive destruction of T-helper cells leads to weakening of the immune system which in turn, opens the door to opportunistic pathogens. When this happens, HIV-infected people start to show clinical symptoms. If left unchecked, HIV infection leads to death in a matter of years.
In order to reproduce in infected cells, HIV needs three major enzymes that are carried inside the viral particle. These three enzymes, reverse transcriptase, protease and integrase, thus represent ideal targets for antiviral therapy. Of these, reverse transcriptase has been the first enzyme targeted by the pharmaceutical industry. Inhibitors of the viral protease have been developed more recently and their use as drugs for AIDS treatment began only in 1996.
Although the development of reverse transcriptase and protease inhibitors has improved significantly the survival time and quality of life of HIV-infected patients, their use leads to unwanted side effects, such as anemia, neurotoxicity, bone marrow suppression and lipodystrophy. Most of the currently available anti-protease drugs are large molecules with limited ability to cross the blood-brain barrier. New compounds devoid of these drawbacks are urgently needed to treat HIV infections. In addition, HIV has the ability to develop resistance to the currently available drugs, so new compounds with original structure are desirable to fight these resistant viral strains.
In an international patent application no PCT/CA02/00190 (Stranix et al.) published under No. WO 02/064551, HIV protease inhibitors based on amino acid derivaties are disclosed. This patent application includes, more particularly, N-amino acid substituted L-lysine derivatives (and analogs) possessing aspartyl protease inhibitory properties. However, it would be advantageous to be able to provide alternate compounds with such properties.
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-1 aspartyl protease. They also presents potent antiviral activity when tested on HIV-1 viral strain (NL4.3 as the wild type virus) as well as several mutant strains. 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.
Compounds of the present invention may inhibit HIV viral replication in human cells (e.g., CD4+ T-cells), by inhibiting (reducing, impairing) the ability of HIV aspartyl protease to catalyse the hydrolysis of peptide bonds present in viral Gag and Gag-Pol polyproteins. These novel compounds may serve to reduce the production of infectious virions from acutely and chronically infected cells, and may inhibit (at least partially) 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 HIV-2, which may result in asymptomatic infection, AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS), ADS-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 main objective of this invention to provide an improved class of molecules that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors.
The present invention relates to improved N&egr;-synthetic amino acid substituted L-lysine derivatives (including its lower homologue (i.e. L-ornithine)) as well as their pharmaceutically acceptable derivatives (e.g., salts).
Accordingly, the present invention in accordance with one aspect thereof provides a compound(s) of formula I
and when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof,
wherein n may be 3 or 4,
wherein X and Y, the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF
3
, —OCF
3
, —CN, —NO
2
, —NR
4
R
5
, —NHCOR
4
, —OR
4
, —SR
4
, —COOR
4
, —COR
4
and —CH
2
OH or X and Y together define a alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula —OCH
2
O— and an ethylenedioxy group of formula —OCH
2
CH
2
O—,
wherein R
1
may be selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 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
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula R
2A
—CO—, R
2A
being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl-, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, tert-butyl-CH
2
—, etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), 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. cyclopropyl-CH
2
—, cyclohexyl-CH
2
—, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g. CH
3
O—, CH
3
CH
2
O—, iso-butylO-, tert-butylO-(Boc), etc.), tetrahydro-3-furanyloxy, —CH
2
OH, —CF
3
, —CH
2
CF
3
, —CH
2
CH
2
CF
3
, pyrrolidinyl, piperidinyl, 4-morpholinyl, CH
3
O
2
C—, CH
3
O
2
CCH
2
—, Acetyl-OCH
2
CH
2
—, HO
2
CCH
2
—, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH
3
OC
6
H
4
CH
2
—, CH
3
NH—, (CH
3
)
2
N—, (CH
3
CH
2
)
2
N—, (CH
3
CH
2
CH
2
)
2
N—, HOCH
2
CH
2
NH—, CH
3
OCH
2
O—, CH
3
OCH
2
CH
2
O—, C
6
H
5
CH
2
O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
a picolyl group selected from the group consisting of
a picolyloxy group selected from the group consisting of
a substituted pyridyl group selected from the group consisting of
a group of formula,
a group of formula,
and a group of formula,
wherein X′ and Y′, the same or different, may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF
3
, —NO
2
, —NR
4
R
5
, —NHCOR
4
, —OR
4
, —SR
4
, —COOR
4
, —COR
4
and —CH
2
OH,
wherein R
4
and R
5
, the same or different, may be selected from the group consisting of H, a straight alkyl group o

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