Retroviral protease inhibiting compounds

Details Retroviral protease inhibiting compounds Retroviral protease inhibiting compounds

2001-04-18

2002-10-29

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C540S488000, C540S492000, C540S531000, C544S088000, C544S097000, C544S332000, C546S220000, C546S243000, C548S229000, C548S233000, C548S324100, C548S331500, C548S550000

Reexamination Certificate

active

06472529

ABSTRACT:

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 inhibiting a retroviral infection and in particular an HIV infection, processes for making the 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, 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. 58 899 (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), 2′,3′-dideoxyinosine (DDI), d4T and 3TC 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 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.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, there is a compound of the formula I:
wherein R
1
and R
2
are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;
R
3
is loweralkyl, hydroxyalkyl or cycloalkylalkyl;
R
4
is aryl or heterocyclic;
R
5
is
wherein n is 1, 2 or 3, m is 1, 2 or 3, m′ is 1 or 2, X is O, S or NH, Y is —CH
2
—, —O—, —S— or —N(R
6
)— wherein R
6
is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y″ is —CH
2
— or —N(R
6″
)— wherein R
6″
is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y′ is —N(R
6′
)— wherein R
6′
is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and
L
1
is
a) —O—,
b) —S—,
c) —N(R
7
)— wherein R
7
is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,
d) —O-alkylenyl-,
e) —S-alkylenyl-,
f) —S(O)-alkylenyl-,
g) —S(O)
2
-alkylenyl-,
h) —N(R
7
)-alkylenyl- wherein R
7
is defined as above,
i) -alkylenyl-O—,
j) -alkylenyl-S—,
k) alkylenyl-N(R
7
)— wherein R
7
is defined as above,
i) alkylenyl or
m) alkenylenyl;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
Preferred compounds are compounds of the formula I wherein R
1
and R
2
are arylalkyl, R
3
is loweralkyl, R
4
is aryl, R
5
is
wherein X, Y, Y′, Y″, Z, R
6″
, n, m and m′ are defined as above and L
1
is —O-alkylenyl.
More preferred compounds are compounds of the formula I wherein R
1
and R
2
are benzyl or R
1
is benzyl and R
2
is loweralkyl, R
3
is loweralkyl, R
4
is (a) phenyl which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo or (b) pyridyl or pyrimidinyl either of which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo, R
5
is
wherein n is 1 or 2, X is O or S and Y is —CH
2
or —NH—,
wherein m is 1 or 2, X is O, Y is —CH
2
— and Z is O,
wherein m is 1, X is O, Z is O and Y is —NH—,
wherein m′ is 1, X is O, Y″ is —NH— and Y′ is —NH— or
wherein X is O and R
6″
is hydrogen and
L
1
is —O—CH
2
—.
Even more preferred compounds are compounds of the formula I wherein R
1
and R
2
are benzyl or R
1
is benzyl and R
2
is isopropyl, R
3
is loweralkyl, R
4
is
2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R
5
is
wherein n is 1 or 2, X is O or S and Y is —CH
2
or —NH—,
wherein m is 1 or 2, X is O, Y is —CH
2
— and Z is O,
wherein m′ is 1, X is O, Z is O and Y is —NH—,
wherein m′ is 1, X is O, Y″ is —NH— and Y′ is —NH— or
wherein X is O and R
6″
is hydrogen and
L
1
is —O—CH
2
—.
Most preferred compounds are compounds of the formula I wherein R
1
and R
2
are benzyl or R
1
is benzyl and R
2
is isopropyl, R
3
is loweralkyl, R
4
is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R
5
is
wherein n is 1 or 2, X is O or S and Y is —CH
2
or —NH—,
wherein m′ is 1, X is O, Z is O and Y is —NH—,
wherein m′ is 1, X is O, Y″ is —NH— and Y′ is —NH— or
wherein X is O and R
6″
is hydrogen and
L
1
is —O—CH
2
—.
Most highly preferred compounds are compounds of the formula I wherein R
1
and R
2
are benzyl or R
1
is benzyl and R
2
is isopropyl, R
3
is loweralkyl, R
4
is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R
5
is
wherein n is 1 or 2, X is O or S and Y is —CH
2
or —NH— and
L
1
is —O—CH
2
—.
Examples of highly and most highly preferred compounds of the formula I are selected from the group consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethyl butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-th

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