Inhibitors of aspartyl protease

Details Inhibitors of aspartyl protease Inhibitors of aspartyl protease

2000-02-09

2001-11-20

Aulakh, C. S. (Department: 7625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C549S435000, C549S414000, C549S060000, C548S526000, C544S148000, C514S452000, C514S444000, C514S422000, C514S233800

Reexamination Certificate

active

06319946

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
BACKGROUND OF THE INVENTION
The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AIDS”)—a disease characterized by the destruction of the immune system, particularly of CD4
+
T-cells, with attendant susceptibility to opportunistic infections—and its precursor AIDS-related complex (“ARC”)—a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., “A Deletion Mutation in the 5′ Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins”,
J. Virol
., 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion (H. Toh et al., “Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus”,
EMBO J
., 4, p. 1267 (1985); L. H. Pearl et al., “A Structural Model for the Retroviral Proteases”,
Nature
, pp. 329-351 (1987); M. D. Power et al., “Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus”,
Science
, 231, p. 1567 (1986)).
A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4
+
T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M. S. Hirsh and R. T. D'Aqulia, “Therapy for Human Immunodeficiency Virus Infection”,
N.Eng.J.Med
., 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al. “Active HIV Protease is Required for Viral Infectivity”
Proc. Natl. Acad. Sci. USA
, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidyl inhibitors. Such peptidyl compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections.
SUMMARY OF THE INVENTION
The present invention provides a novel class of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of aspartyl proteases, in particular, HIV aspartyl protease. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication in human CD
4
+
T-cells. These compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses which may result in asymptomatic infection, AIDS-related complex (“ARC”), acquired immunodeficiency syndrome (“AIDS”), or similar disease of the immune system.
It is a principal object of this invention to provide a novel class of sulfonamides which are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. The novel sulfonamides of this invention are those of formula I:
wherein:
E′ is —CO— or —SO
2
—;
A is selected from H; Ht; —R
1
—Ht; —R
1
—C
1
-C
6
alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C
1
-C
4
alkoxy, Ht, —O—Ht, —NR
2
—CO—N(R
2
)
2
; —SO
2
—R
2
or —CO—N(R
2
)
2
; —R
1
—C
2
-C
6
alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C
1
-C
4
alkoxy, Ht, —O—Ht, —NR
2
—CO—N(R
2
)
2
or —CO—N(R
2
)
2
; or R
7
;
each R
1
is independently selected from —C(O)—, —S(O)
2
—, —C(O)—C(O)—, —O—C(O)—, —O—S(O)
2
, —NR
2
—S(O)
2
—, —NR
2
—C(O)— or —NR
2
—C(O)—C(O)—;
each Ht is independently selected from C
3
-C
7
cycloalkyl; C
5
-C
7
cycloalkenyl; C
6
-C
14
aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, O, or S; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, —OR
2
, SR
2
, —R
2
, —N(R
2
)(R
2
), —R
2
—OH, —CN, —CO
2
R
2
, —C(O)—N(R
2
)
2
, —S(O)
2
—N(R
2
)
2
, —N(R
2
)—C(O)—R
2
, —N(R
2
—C(O)O—R
2
, —C(O)—R
2
, —S(O)
n
—R
2
, —OCF
3
, —S(O)
n
—Q, methylenedioxy, —N(R
2
)—S(O)
2
(R
2
), halo, —CF
3
, —NO
2
, Q, —OQ, —OR
7
, —SR
7
, —R
7
, —N(R
2
)(R
7
) or —N(R
7
)
2
;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, or S; wherein Q is optionally substituted with one or more groups selected from oxo, —OR
2
, —R
2
, —SO
2
R
2
, —SO
2
—N(R
2
)
2
, —N(R
2
)
2
, —N(R
2
)—C(O)—R
2
, —R
2
—OH, —CN, —CO
2
R
2
, —C(O)—N(R
2
)
2
, halo, —CF
3
;
each R
2
is independently selected from H, or C
1
-C
4
alkyl; and wherein said alkyl, when not a substituent of Q, is optionally substituted with Q or —OR
3
; wherein when said R
2
is an —OR
3
substituted moiety, said R
3
in —OR
3
may not be —OR
2
substituted;
B, when present, is —N(R
2
)—C(R
3
)
2
—C(O)—;
each x is independently 0 or 1;
each R
3
is independently selected from H, Ht, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl or C
5
-C
6
cycloalkenyl; wherein any member of said R
3
, except H, is optionally substituted with one or more substituents selected from —OR
2
, —C(O)—NH—R
2
, —S(O)
n
—N(R
2
)(R
2
), —N(R
2
)
2
, —N(R
2
)—C(O)—O(R
2
), —N(R
2
)—C(O)—N(R
2
), —N(R
2
)—C(O)—(R
2
), Ht, —CN, —SR
2
, —CO
2
R
2
, or NR
2
—C(O)—R
2
;
each n is independently 1 or 2;
G, when present, is selected from H, R
7
or C
1
-C
4
alkyl, or, when G is C
1
-C
4
alkyl, G and R
7
are optionally bound to one another either directly or through a C
1
-C
3
linker to for

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