HIV integrase inhibitors

Details HIV integrase inhibitors HIV integrase inhibitors

1999-12-13

2001-08-07

Badio, Barbara P. (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C540S061000

Reexamination Certificate

active

06271402

ABSTRACT:

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, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. 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 and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. 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.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-1194 (1997)) describe hydrazide and arylamide FUV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Pat. No. 4,871,727 to Burg et al. describes anti-inflammatory and degenerative compounds isolated from the soil microorganism ATCC 20858 of structural formula A below:
wherein:
R is OH or H;
R
1
and R
2
together form ═CH
2
or —CH
2
O—;
R
3
is H, OH, HSO
3
O, HOCOCH
2
CH
2
CO
2
;
R
4
is OH, HOC
15
H
30
CO
2
, AcO or is H except that when R
4
is H, the double bond in the cyclopentane ring is absent;
R
5
is O═, OH, AcO; and
R
6
is OH or —O—C(O)CH
3
.
Brill et al. (J. Antibiotics, 49(6): 541-546 (1996)), describe particular triterpene sulfates from
Fusarium compactum.
PCT publication WO 98/31371 (Application No. PCT/US98/00766) describe the use of androst-5-ene-30-ol-7,17 dione and metabolizable precursors thereof, such as androst-5-ene-3&bgr;-acetoxy-7,17-dione, for the treatment of HIV-related weight loss, HIV-related cachexia and HIV-related wasting syndrome.
Applicants have discovered that certain natural product compounds derived from Fusarium sp. MF6381 (ATCC 74469) and derivatives thereof are potent inhibitors of HIV integrase. These compounds are useful for the treatment of AIDS or HIV infections.
BRIEF DESCRIPTION OF THE INVENTION
Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
Further, the culture Fusarium sp., MF6381 (ATCC 74469) is also disclosed, as well as processes for making compounds of structural formula I employing the culture Fusarium sp., MF6381 (ATCC 74469).
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by mV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
wherein:
“a” is selected from a single bond or a double bond;
R
1
is selected from:
(a) —OH,
(b) —OC(O)CH
3
,
(c) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
H,
(d) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
CH
3
,
(e) —OC(O)(CH
2
)
2
CO
2
H,
(f) —OC(O)(CH
2
)
2
CO
2
CH
3
,
(g) —OC(O)(CH
2
)
2
CONHOH,
(h) —OCH
2
OCH
3
,
(i) —OC(O)C
6
H
5
,
(j) —OC(O)CH
2
NH—C(O)OC(CH
3
)
3
,
(k) —OSO
2
CH
3
,
(l) —OC(O)CH
2
NH
2
,
(m) —OC(O)—(CH
2
)
15
—OH, and
(n) H;
R
2
is selected from:
(a) —OH,
(b) —OC(O)CH
3
,
(c) ═O,
(d) —OC(O)(CH
2
)
2
CO
2
H,
(e) —OC(O)(CH
2
)
2
CO
2
CH
3
,
(f) —OC(O)(CH
2
)
2
CONHOH,
(g) —OCH
2
OCH
3
,
(h) —OC(O)C
6
H
5
,
(i) —OC(O)CH
2
NHC(O)OC(CH
3
)
3
,
(j) —OSO
2
CH
3
,
(k) —OSO
2
OH, and
(l) —OC(O)CH
2
NH
2
;
or R
1
and R
2
are joined to form:
R
3
is selected from:
(a) —H,
(b) —OH, and
(c) —OC(O)CH
3
;
R
4
is selected from:
(a) —H,
(b) —OH, and
(c) —OC(O)CH
3
;
R
5
and R
6
are independently selected from:
(a) —H,
(b) —OH, and
(c) —CH
3
,
or together form:
(c) ═CH
2
, or
(d) —CH
2
O—;
R
7
is selected from:
(a) H, and
(b) OH;
or a pharmaceutically acceptable salt thereof.
In one class of compounds of the present invention, R
1
is selected from:
(a) —OH,
(b) —OC(O)CH
3
,
(c) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
H,
(d) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
CH
3
,
(e) —OC(O)(CH
2
)
2
CO
2
H,
(f) —OC(O)(CH
2
)
2
CO
2
CH
3
,
(g) —OC(O)(CH
2
)
2
CONHOH,
(h) —OCH
2
OCH
3
,
(i) —OC(O)C
6
H
5
,
(j) —OC(O)CH
2
NH—C(O)OC(CH
3
)
3
,
(k) —OSO
2
CH
3
,
(l) —OC(O)CH
2
NH
2
,
(m) —OC(O)—(CH
2
)
15
—OH, and
(n) H.
In a subclass of compounds of the present invention, R
1
is selected from:
(a) —OH,
(b) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
H,
(c) —OC(O)CH
2
C(CH
3
)(OH)CH
2
CO
2
CH
3
,
(d) —OC(O)(CH
2
)
2
CO
2
H,
(e) —OC(O)(CH
2
)
2
CONHOH,
(f) —OC(O)CH
2
NH
2
, and
(g) —OC(O)—(CH
2
)
15
—OH.
In one class of compounds of the present invention, R
2
is selected from:
(a) —OH,
(b) —OC(O)CH
3
,
(c) ═O,
(d) —OC(O)(CH
2
)
2
CO
2
H,
(e) —OC(O)(CH
2
)
2
CO
2
CH
3
,
(f) —OCH
2
OCH
3
,
(g) —OC(O)C
6
H
5
,
(h) —OC(O)CH
2
NHC(O)OC(CH
3
)
3
,
(i) —OSO
2
OH, and
(j) —OC(O)CH
2
NH
2
.
In a subclass of compounds of the present invention, R
2
is selected from:
(a) —OH,
(b) ═O,
(c) —OC(O)(CH
2
)
2
CO
2
H,
(d) —OSO
2
OH, and
(e) —OC(O)CH
2
NH
2
.
In one class of compounds of the present invention, R
4
is —OC(O)CH
3
.
In another class of compounds of the present invention, R
5
and R
6
independently are selected from:
(a) —H, and
(b) —OH,
or together form:
(c) ═CH
2
, or
(d) —CH
2
O—.
In still another class of compounds of the present invention, R
7
is hydrogen.
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amoun

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