Retroviral protease inhibiting compounds

Details Retroviral protease inhibiting compounds Retroviral protease inhibiting compounds

1999-05-10

2001-06-26

Shah, Mukund J. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S254110, C514S249000, C544S367000, C544S377000, C544S349000

Reexamination Certificate

active

06251906

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel compounds compositions and methods for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease. The present invention also relates to compositions and methods for treating a retroviral infection and in particular an HIV infection, and to processes for making such compounds and synthetic intermediates employed in these processes.
BACKGROUND OF THE INVENTION
Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
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. 981 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of 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, 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).
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve administration of compounds such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (DDC) and 2′,3′-dideoxyinosine (DDI) and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Recently the HIV protease inhibitors ritonavir, saquinavir, nelfinavir, and indinavir have been approved in the U.S. for treatment of HIV infections. However, there is a continuing need for improved HIV protease inhibitors.
SUMMARY OF THE INVENTION
The present invention comprises retroviral protease inhibiting compounds having formula I:
wherein R
1
is a thiazolyl group having the formula
and R
2
is a group having the formula:
wherein R
4
group is −WR
5
.
The R
3
group is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is selected from the group consisting of —O—, —S—, or —(CH
2
)
n
—, where n is from 0 to 6, with the proviso that when W is O, or S then Y is CH. R
5
is selected from the group consisting of alkyl, and aryl. Optionally, R
4
and the ring to which it is attached, taken together can form a bicyclic group having the formula:
The R
6
group is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl, Z is —O—, —S—, —CH
2
— or —N(R
7
)—; and R
7
is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
The present invention also comprises retroviral protease inhibiting compounds having formula II:
wherein R
1
is a thiazolyl group having the formula
and R
2
is a group having the formula:
wherein X is —C(O)— or —S(O)
2
— and R
8
is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
R
3
is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R
9
is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl. The Z group is —O—, —S—, —CH
2
— or —N(R
7
)—, and R
7
is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
The alkyl, aryl, heterocyclic, and heteroaryl groups in the compounds of the invention can be optionally substituted with from 1 to 5 substituents and preferrably from 1 to 3 substituents. The substituents are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen. The invention also includes pharmaceutically acceptable salts, esters or prodrugs of compounds I and II.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The present invention comprises retroviral protease inhibiting compounds having formula I:
wherein R
1
is a thiazolyl group having the formula
and R
2
is a group having the formula:
wherein R
4
group is —WR
5
.
The R
3
group is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N. W is selected from the group consisting of —O—, —S—, or —(CH
2
)
n
—, where n is from 0 to 6, with the proviso that when W is O, or S then Y is CH. R
5
is selected from the group consisting of alkyl, and aryl. Optionally, R
4
and the ring to which it is attached, taken together can form a bicyclic group having the formula:
with the proviso that when W is O, or S then Y is CH. The R
6
group is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl, Z is —O—, —S—, —CH
2
— or —N(R
7
)—; and R
7
is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
The present invention also comprises retroviral protease inhibiting compounds having formula II:
wherein R
1
is a thiazolyl group having the formula:
and R
2
is a group having the formula:
wherein X is —C(O)— or —S(O)
2
— and R
8
is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
R
3
is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R
9
is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl, or (heteroaryl)alkyl. The Z group is —O—, —S—, —CH
2
— or —N(R
7
)—, and R
7
is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
The alkyl, aryl, heteroaryl, and heterocyclic groups of the compounds of t

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