HIV integrase inhibitors

Details HIV integrase inhibitors HIV integrase inhibitors

2002-12-06

2004-08-17

Richter, Johann (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S482000, C514S563000, C549S296000, C562S422000, C562S444000, C562S448000

Reexamination Certificate

active

06777440

ABSTRACT:

BACKGROUND
Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.
There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavaridine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D.
N. Engl. J. Med.
1998, 338, 853).
Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (<50 copies/ml) (Carpenter, C. C. J.; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.; Schecter, M.; Schoolery, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A.
JAMA
2000, 283, 381). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further.
HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS. However, integrase stands out as being the only viral enzyme not targeted by current therapy. The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3′-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.
A number of inhibitors of the enzyme have been reported. These include, nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y.,
Drug Disc. Today,
1997, 2, 487). However, no clinically active compound has resulted from these leads. Thus, what is needed is a clinically effective inhibitor of the HIV integrase enzyme.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof.
In Formula I,
R
1
is
-aryl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-S(O)
n
-aryl,
—C
1
-C
5
alkyl-O-aryl; or
wherein R
1
is unsubstituted or substituted with 1-3 R
3
;
Each R
3
is independently selected from
—H,
-halo,
—CN,
—C
1
-C
6
alkyl,
—C
3
-C
6
cycloalkyl
—OR
4
,
—C
1
-C
10
alkyl-O—R
4
,
—CO
2
R
5
,
—C
1
-C
10
alkyl-CO
2
R
5
,
——N(R
6
)(R
7
),
—C
1
-C
10
alkyl-N(R
6
)(R
7
),
—CON(R
6
)(R
7
),
—C
1
-C
10
alkyl-CON(R
6
)(R
7
)
—S(O)
n
R
8
,
—C
1
-C
10
alkyl-S(O)
n
R
8
—S(O)
n
N(R
9
)(R
10
),
—C
1
-C
10
alkyl-S(O)
n
N(R
9
)(R
10
),
-aryl,
—O-aryl,
-heteroaryl,
—O-heteroaryl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-heteroaryl,
—C(O)-heterocyclic radical,
—C
1
-C
10
alkyl-C(O)-heterocyclic radical, or
—C
1
-C
6
haloakyl;
R
2
is
—H,
—C
1
-C
10
alkyl,
—C
3
-C
6
cycloakyl,
—C
1
-C
10
haloalkyl,
-aryl,
-heteroaryl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
5
alkyl-O-aryl,
—C
1
-C
6
alkyl-heteroaryl,
—C
1
-C
5
alkyl-O-heteroaryl,
—C
1
-C
10
alkyl-OR
4
,
—C
1
-C
10
alkyl-CO
2
R
5
,
—C
1
-C
10
alkyl-N(R
6
)(R
7
),
—C
1
-C
10
alkyl-CON(R
6
)(R
7
),
—C
1
-C
10
alkyl-S(O)
n
R
8
,
—C
1
-C
10
alkyl-S(O)
n
N(R
9
)(R
10
), or
—C
1
-C
10
alkyl-C(O)-heterocyclic radical;
Each R
4
is independently selected from
—H,
—C
1
-C
6
alkyl,
—C
3
-C
6
cycloalkyl,
—C
1
-C
9
alkyl-CO
2
R
5
,
—C
1
-C
9
alkyl-N(R
6
)(R
7
),
—C
1
-C
9
alkyl-CON(R
6
)(R
7
),
—C
1
-C
9
alkyl-S(O)
n
R
8
, or
—C
1
-C
9
alkyl-S(O)
n
N(R
9
)(R
10
);
Each R
5
is independently selected from
—H,
—C
1
-C
6
alkyl,
—C
3
-C
6
cycloalkyl, or
—C
1
-C
6
alkyl-aryl;
Each R
6
is independently selected from
—H,
—C
1
-C
6
alkyl,
-aryl,
-heteroaryl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-heteroaryl,
—C(O)—C
1
-C
6
alkyl,
—C(O)-aryl,
—C(O)—C
1
-C
6
alkyl-aryl,
—C(O)-heteroaryl,
—C(O)—C
1
-C
6
alkyl-heteroaryl,
—C(NH)NH
2
,
—S(O)
n
—R
8
, or
—C
1
-C
6
alkyl-CO
2
R
5
;
Each R
7
is independently selected from
—H,
—C
1
-C
6
alkyl,
-aryl, or
-heteroaryl;
Each R
8
is independently selected from
—C
1
-C
6
alkyl,
-aryl, or
-heteroaryl;
Each R
9
is independently selected from
—H,
—C
1
-C
6
alkyl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-heteroaryl,
—C(O)—C
1
-C
6
alkyl,
—C(O)-aryl,
—C(O)—C
1
-C
6
alkyl-aryl,
—C(O)-heteroaryl,
—C(O)—C
1
-C
6
alkyl-heteroaryl,
-aryl, or
-heteroaryl;
Each R
10
is independently selected from
—H,
—C
1
-C
6
alkyl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-heteroaryl,
-aryl, or
-heteroaryl;
R
11
is
—H,
-aryl,
-heteroaryl,
—C
3
-C
6
cycloalkyl,
—C
1
-C
6
alkyl,
—C
1
-C
6
alkyl-aryl,
—C
1
-C
6
alkyl-heteroaryl,
—C
1
-C
6
alkyl-CO
2
R
5
, or
—C
1
-C
6
alkyl-N(R
6
)(R
7
);
R
12
is
—H,
—C
1
-C
6
alkyl,
-aryl, or
-heteroaryl;
R
13
is
—H,
—C
1
-C
6
alkyl,
-aryl, or
-heteroaryl;
B
1
is selected from the group consisting of
n is 0, 1 or 2.
The present invention also relates to a method of inhibiting HIV integrase by administering to a patient an effective amount of a compound of Structural Formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
In Formula Ia, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
are as defined for Formula I, whereas B
2
is
The present invention further relates to a method of treating patients infected by the HIV virus, or of treating AIDS or ARC, by administering to the patient an effective amount of a compound of Structural Formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another embodiment includes a pharmaceutical composition, us

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