HIV integrase inhibitors

Details HIV integrase inhibitors HIV integrase inhibitors

1999-10-25

2002-06-11

Jones, Dwayne C. (Department: 1614)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Using fungi

C514S450000, C514S452000, C514S454000, C514S455000, C549S348000, C549S349000, C549S389000

Reexamination Certificate

active

06403347

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 cells. Integration is believed to occur in three stages: 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; repair synthesis by host enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 227 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an 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)].
It is known that some antiviral compounds act as inhibitors of HIV and are effective agents in the treatment of HIV and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase, probably by inhibiting strand transfer and cleavage activity. The particular advantage of the present invention is specific inhibition of HIV integrase.
Applicants have discovered that certain chaetochromins 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.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
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:
wherein:
R
1
is independently selected from:
(a) hydrogen,
(b) C
1-6
alkyl, and
(c) C
1-6
alkylcarbonyl-
 at each occurrence;
—X— is selected from:
(a) a carbon-carbon single bond, and
(b) an oxygen atom bound to adjacent carbon atoms; and
the dotted line, a, is represents a single bond or a double bond; or a pharmaceutically acceptable salt thereof.
In one embodiment of compounds of the present invention are compounds of structural formula (I) wherein:
R
1
is independently selected from:
(a) hydrogen,
(b) methyl, and
(c) methylcarbonyl-
 at each occurrence, or a pharmaceutically acceptable salt thereof.
Compounds representing this embodiment include:
In one subclass of compounds of the present invention are compounds of structural formula (I) wherein R
1
is hydrogen at each occurrence, or a pharmaceutically acceptable salt thereof.
Compounds illustrating this subclass are:
or pharmaceutically acceptable salts thereof.
Also covered by the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. This invention also discloses the fungal culture MF6252 (ATCC 74396), Fusarium sp.
The present invention relates to the preparation of compounds of structural formula I comprising:
(a) fermenting a culture of MF6252 (ATCC 74396), Fusarium sp. or a mutant thereof to produce a fermentation broth,
(b) extracting the fermentation broth with an organic solvent,
(c) isolating the compounds of structural formula I.
The compounds of structural formula I are preferably isolated by partitioning the fermentation extract between the organic solvent and water, followed by size exclusion chromatography and normal or reverse-phase chromatography.
When any variable (e.g., X, Y, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus, the compounds of this invention are commercial products to be sold for these purposes.
Applicants have discovered that certain chaetochromins, recovered from a fungal culture of MF6252 (ATCC 74396), identified as Fusarium sp. (Ascomycotina, Hypocreales), are useful for inhibiting HIV integrase. The compounds of formula (I) are prepared by an aerobic fermentation procedure employing a novel fungal culture MF6252 (ATCC 74396), identified as Fusarium sp., or a mutant thereof. A mutant refers to an organism in which some gene on the genome is modified, leaving the gene or genes responsible for the organism's ability to produce the compounds of formula (I) in recoverable amounts functional and heritable.
ATCC Deposit of MF6252 (ATCC 74396), Identified as Fusarium sp.
Before the U.S. filing date of the present application, a sample of MF6252 (ATCC 74396), Fusarium sp., had been deposited at the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Md. 20852. The culture access designation is 74396. This deposit will be maintained in the ATCC for at least 30 years and will be made available to the public upon the grant of a patent disclosing it. It should be understood that the availability of a deposit does not constitute a license to practice the subject invention in derogation of patent rights granted by government action.
Characteristics of MF6252 (ATCC 74396), Fusarium sp.
Isolated from forest leaf litter, Te Anau, South Island of New Zealand.
In agar culture MF6252=ATCC 74396 exhibits the following characteristics. Observations of micromorphology were made on 1 week-old colonies grown on SNA unless stated otherwise.
Colonies on SNA (Synthet

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