Retroviral protease inhibiting compounds

Details Retroviral protease inhibiting compounds Retroviral protease inhibiting compounds

2000-07-20

2003-03-11

Fan, Jane (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S206000, C548S236000, C548S247000

Reexamination Certificate

active

06531610

ABSTRACT:

This invention was made with Government support under contract number Al27220 awarded by the National Institute of Allergy and Infectious Diseases. The Government has certain rights in this invention.
TECHNICAL FIELD
The present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in the 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. 98 1 (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.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, there are retroviral protease inhibiting compounds of the formula A:
wherein R
1
is monosubstituted thiazolyl, monosubstituted oxazolyl, monosubstituted isoxazolyl or monosubstituted isothiazolyl wherein the substituent is selected from (i) loweralkyl, (ii) loweralkenyl, (iii) cycloalkyl, (iv) cycloalkylalkyl, (v) cycloalkenyl, (vi)cycloalkenylalkyl, (vii) heterocyclic wherein the heterocyclic is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and wherein the heterocyclic is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy, (viii) (heterocyclic)alkyl wherein heterocyclic is defined as above, (ix) alkoxyalkyl, (x) thioalkoxyalkyl, (xi) alkylamino, (xii) dialkylamino, (xiii) phenyl wherein the phenyl ring is unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy, (xiv) phenylalkyl wherein the phenyl ring is unsubstituted or substituted as defined above, (xv) dialkylaminoalkyl, (xvi) alkoxy and (xvii) thioalkoxy;
n is 1, 2 or 3;
R
2
is hydrogen or loweralkyl;
R
3
is loweralkyl;
R
4
and R
4a
are independently selected from phenyl, thiazolyl and oxazolyl wherein the phenyl, thiazolyl or oxazolyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy;
R
6
is hydrogen or loweralkyl;
R
7
is thiazolyl, oxazolyl, isoxazolyl or isothiazolyl wherein the thiazolyl, oxazolyl, isoxazolyl or isothiazolyl ring is unsubstituted or substituted with loweralkyl;
X is hydrogen and Y is —OH or X is —OH and Y is hydrogen, with the proviso that X is hydrogen and Y is —OH when Z is —N(R
8
)— and R
7
is unsubstituted and with the proviso that X is hydrogen and Y is —OH when R
3
is methyl and R
7
is unsubstituted; and
Z is absent, —O—, —S—, —CH
2
— or —N(R
8
)— wherein R
8
is loweralkyl, cycloalkyl, —OH or —NHR
8a
wherein R
8a
is hydrogen, loweralkyl or an N-protecting group; or a pharmaceutically acceptable salt, ester or prodrug thereof.
Preferred compounds of the formula A are those wherein R
1
is monosubstituted thiazolyl or monosubstituted oxazolyl; n is 1; R
2
is hydrogen; R
4
is phenyl or thiazolyl; R
4a
is phenyl; R
6
is hydrogen and R
7
is thiazolyl, oxazolyl, isothiazolyl or isoxazolyl.
More preferred compounds of the formula A are those wherein R
1
is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl; n is 1; R
2
is hydrogen; R
4
is phenyl; R
4a
is phenyl; R
6
is hydrogen and R
7
is 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl.
Even more preferred compounds of the formula A are those wherein R
1
is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is loweralkyl; n is 1; R
2
is hydrogen; R
4
is phenyl; R
4a
is phenyl; R
6
is hydrogen; R
7
is 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is —O— or —N(R
8
)— wherein R
8
is loweralkyl.
Most preferred compounds of the formula A are those wherein R
1
is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is ethyl or isopropyl; n is 1; R
2
is hydrogen; R
3
is methyl or isopropyl; R
4
is phenyl; R
4a
is phenyl; R
6
is hydrogen; R
7
is 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is —O—.
Most preferred compounds of the formula A are also those wherein R
1
is 2-monosubstituted-4-thiazolyl or 2-monosubstituted-4-oxazolyl wherein the substituent is ethyl or isopropyl; n is 1; R
2
is hydrogen; R
3
is isopropyl; R
4
is phenyl; R
4a
is phenyl; R
6
is hydrogen; R
7
is 5-thiazolyl, 5-oxazolyl, 5-isothiazolyl or 5-isoxazolyl; and Z is —N(R
8
)— wherein R
8
is methyl.
Most preferred compounds of the formula A are also those wherein the configuration of the carbon atom bearing —CH
2
R
4
is “S” and the configuration of the carbon bearing X is “S” when X is —OH and the configuration of the carbon atom bearing Y is “S” when Y is —OH and the configuration of the carbon atom bearing —CH
2
(R
5
-substituted phenyl) is “S”.
Preferred compounds of the invention are com

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