HIV integrase inhibitors

Details HIV integrase inhibitors HIV integrase inhibitors

1999-06-01

2001-07-17

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S365000, C514S443000, C514S448000, C549S043000, C549S057000, C549S072000, C548S200000

Reexamination Certificate

active

06262055

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 HIV 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. Nos. 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-1-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994).
Applicants have discovered that certain 5-membered sulfur containing heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection.
SUMMARY 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.
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 HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
and tautomers or pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and
0 or 1 nitrogen atoms and substituted on carbon by R
1
, R
2
and R
8
; the
heteroaromatic ring may optionally be fused with a phenyl ring or a C
4-6
cycloalkyl ring, or with two six membered rings to form:
R
1
is selected from:
(1) —H,
(2) —C
1-5
alkyl,
(3) —CF
3
,
(4) —halo,
(5) —NO
2
,
(6) —N(R
4
)(R
5
),
(7) —R
6
,
(8) —C
2-5
alkenyl-R
3
,
(9) —C
2-5
alkynyl-R
3
,
(10) —O—R
6
,
(11) —O—C
1-6
alkyl, and
(12) —C(O)CH
2
C(O)C(O)OR
7
;
R
2
is selected from:
(1) —H,
(2) —R
3
,
(3) —C
1-6
alkyl,
(4) —C
1-6
alkyl substituted with R
3
,
(5) —O—R
6
,
(6) —O—C
1-6
alkyl-OR
6
,
(7) —S(O)n—R
6
,
(8) —C
1-6
alkyl (OR
6
)(R
4
),
(9) —C
1-6
alkyl (OR
4
)(R
6
),
(10) —C
0-6
alkyl-N(R
4
)(R
6
),
(11) —C
1-6
alkyl S(O)n—R
6
,
(12) —C
0-6
alkyl C(O)—R
6
,
(13) —C
0-6
alkyl C(S)—R
6
,
(14) —C
0-6
alkyl NR
4
C(O)—R
6
, and
(15) —C
0-6
alkyl-C(O)N(R
4
)(R
5
);
each R
3
is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen,
(b) C
1-6
alkyl,
(c) C
1-6
alkyloxy-,
(d) phenyl,
(e) —CF
3
,
(f) —OCF
3
,
(g) —CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C
1-6
alkyl,
(iii) —CF
3
, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from:
(a) halogen,
(b) C
1-6
alkyl,
(c) C
1-6
alkyloxy-,
(d) —CF
3
,
(e) —OCF
3
,
(f) —CN,
(g) ═O,
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C
1-6
alkyl,
(d) C
1-6
alkyloxy-,
(e) —CF
3
,
(f) —OCF
3
,
(g) —CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) —C
1-6
alkyl,
(c) —C
1-6
alkyloxy-,
(d) —CF
3
,
(e) —OCF
3
,
(f) —CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C
1-6
alkyl,
(c) C
1-6
alkyloxy-,
(d) —CF
3
,
(e) —OCF
3
,
(f) —CN,
(g) ═O,
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C
1-6
alkyl,
(c) C
1-6
alkyloxy-,
(d) —CF
3
,
(e) —OCF
3
,
(f) —CN,
(g) ═O,
(h) hydroxy;
each R
4
is independently selected from:
(1) —H,
(2) —C
1-3
alkyl,
(3) —CF
3
,
(4) —R
3
,
(5) —C
2-3
alkenyl,
(6) —C
1-3
alkyl-R
3
,
(7) —C
2-3
alkenyl-R
3
,
(8) —S(O)n—R
3
, and
(9) —C(O)—R
3
;
each R
5
is independently selected from:
(1) —H,
(2) —C
1-3
alkyl,
(3) —CF
3
,
(4) —R
3
,
(5)

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