Bis-amino acid sulfonamides as HIV protease inhibitors

Details Bis-amino acid sulfonamides as HIV protease inhibitors Bis-amino acid sulfonamides as HIV protease inhibitors

2002-09-18

2003-05-13

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S354000, C546S314000, C549S449000, C549S467000, C564S123000

Reexamination Certificate

active

06562848

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to bis-amino acid sulfonamides useful as HIV protease inhibitors, pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.
BACKGROUND OF THE INVENTION
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink,
Arch. Virol.
98 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford et al.,
J. Virol.
53 899 (1985); Katoh et al.,
Virology
145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya,
Nature
325 775 (1987).
As evidenced by the protease inhibitors presently marketed and in clinical trials, a wide variety of compounds have been studied as potential HIV protease inhibitors. One core, hydroxyethylamino-sulfonamides, has received significant attention. For example, PCT Applications WO94/05639, WO94/04492, WO95/06030, and WO96/28464 generically describe sulfonamides of the formula:
and methods of preparing them. Though some of the present compounds appear to fall within the generic descriptions of some of the above publications, they are not specifically disclosed, suggested, or claimed therein.
Even with the current success of protease inhibitors, it has been found that HIV patients can become resistant to a single protease inhibitor. Thus, it is desirable to develop additional protease inhibitors to further combat HIV infection.
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is to provide novel protease inhibitors.
The present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
The present invention provides a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
The present invention provides pharmaceutical compositions with protease inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least-one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
The present invention provides a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
The present invention provides a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both.
The present invention provides novel compounds for use in therapy.
The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of HIV infection.
These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
wherein R
1
, R
2
, and R
3
are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective protease inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides a novel compound of Formula I:
 or a pharmaceutically acceptable salt form thereof, wherein:
R
1
is selected from R
4
and —O—R
4
;
R
2
and R
3
are selected from H and NH
2
, or alternatively, R
2
and R
3
together form —OCH
2
O— or —CH
2
CH
2
O—; and
R
4
is selected from methyl, ethyl, propyl, isopropyl, butyl, i-butyl, t-butyl, phenyl, benzyl, cyclopentyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
[2] In another embodiment, the present invention provides a novel compound of Formula I: wherein
R
2
is H; and
R
3
is NH
2
.
[3] In another embodiment, the present invention provides a novel compound of Formula I: wherein
R
4
is selected from i-propyl, phenyl, cyclopentyl, 2-pyridyl and 3-pyridyl.
[4] In another embodiment, the present invention provides a novel compound of Formula I, wherein:
R
1
is R
4

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