HIV integrase inhibitors

Details HIV integrase inhibitors HIV integrase inhibitors

2001-08-09

2003-04-01

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S529000, C514S557000, C514S561000, C560S119000, C562S501000

Reexamination Certificate

active

06541515

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to certain compounds, pharmaceutical compositions containing the compounds, and the microbial production of the compounds. The compounds are useful as HIV integrase inhibitors.
References are made throughout this application to various published documents in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′ termini of the linear proviral DNA; covalent joining of the recessed 3′ OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame (Ratner et al.,
Nature
1985, 313: 277). Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease (Toh et al.,
EMBO J.
1985, 4: 1267; Power et al.,
Science
1986, 231: 1567; Pearl et al.,
Nature
1987 329: 351). All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase. The applicants additionally demonstrate that inhibition of integrase in vitro is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Hensens et al.,
J. Org. Chem.
1995, 60: 1772-1776, discloses australifungin and australifunginol. U.S. Pat. No. 5,276,055 discloses australifungin and related compounds, and their use as antifungal agents. U.S. Pat. No. 5,304,485 discloses
Sporormiella australis
(MF5672, ATCC 74157) and its cultivation in a suitable nutrient medium for the provision of australifungin. U.S. Pat. No. 5,441,987 discloses australifunginol and its use as an antifungal agent.
SUMMARY OF THE INVENTION
Applicants have discovered that certain novel compounds are potent inhibitors of HIV integrase. These compounds are useful for the treatment of HIV infection or AIDS. More particularly, the present invention includes compounds of Formula (I):
wherein
one of R
1
and R
2
is —H, and the other of R
1
and R
2
is —OH; or R
1
and R
2
together form oxo;
R
3
is —OH, —OC(O)CH
3
or —OR
a
;
R
4
is —CH
2
OH, —CH
2
OC(O)CH
3
, —CHO, or —CO
2
H;
one of R
5
and R
6
is —H, and the other of R
5
and R
6
is —OH; or R
5
and R
6
together form oxo;
R
7
is —H, —R
a
, —NH
2
, or —NR
a
R
b
;
each R
a
is independently —C
1
-C
4
alkyl; and
R
b
is —H or —C
1
-C
4
alkyl;
or a pharmaceutically acceptable salt thereof.
The present invention also includes use of these compounds in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV, and the treatment of AIDS and/or ARC, wherein the compounds are used per se or as their pharmaceutically acceptable salts or hydrates (when appropriate), either alone or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. The present invention further includes the culture Cytospora sp. MF 6608 (ATCC PTA-1691) and processes for making Compound A (described below) of the present invention employing the culture.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.


REFERENCES:
patent: 4438277 (1984-03-01), Terahara et al.
patent: 4719229 (1988-01-01), Reamer et al.
patent: 5116870 (1992-05-01), Smith et al.
patent: 5256811 (1993-10-01), Todd et al.
patent: 5276055 (1994-01-01), Cabello et al.
patent: 5276177 (1994-01-01), Yoshida et al.
patent: 5304485 (1994-04-01), Bills et al.
patent: 5441987 (1995-08-01), Harris et al.
patent: 5449684 (1995-09-01), Tanaka et al.
L. Ratner et al., “Complete Nucleotide sequence of the AIDS virus, HTLV-III”, Nature, vol. 313, pp. 277-284 (Jan. 24, 1985).
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 leukaemia virus”, The EMBO Journal, vol. 4, No. 5, pp. 1267-1272 (1985).
M. D. Power et al., “Nucleotide Sequence of SRV-1, Type D Simian Acquired Immune Deficiency Syndrome Retrovirus”, Science, vol. 231, pp. 1567-1572 (1986).
L. H. Pearl et al., “A structural model for the retroviral proteases”, Nature, vol. 329, pp. 351-354 (Sep. 24, 1987).
O. D. Hensens et al., “Structure Elucidation of Australifungin, a Potent Inhibitor of Sphinganine N-Acyltransferase in Sphingolipid Biosynthesis fromSporormiella australis”, J. Org. Chem., vol. 60, No. 6, pp. 1772-1776 (1995).

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