Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-25
2001-06-12
Owens, Amelia (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S354000, C549S358000
Reexamination Certificate
active
06245806
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. 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.
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).
Applicants have discovered that certain tetracyclic aromatic ketones 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 cultures Sterile Fungus MF6388 (ATCC 74478) and Ascochyta sp. MF6591 (ATCC 74477) are also disclosed, as well as processes for making compounds of the present invention employing the cultures.
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:
wherein:
R is selected from:
(a) —CH
2
OH, and
(b) —CH(═O);
or a pharmaceutically acceptable salt thereof.
Particular compounds of structural Formula I include:
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. 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. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from:
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
This invention also discloses the culture MP6388 (ATCC 74478) identified as Sterile Fungus. A culture of MF6388 (ATCC 74478) is defined as substantially free of its natural soil contaminants and capable of forming a compound of Formula (I) in a recoverable amount. The culture should be free from viable contaminating microorganisms deleterious to the production of a compound of Formula (I). A biologically pure culture of MF6388 (ATCC 74478) may also be employed. In one embodiment, the present invention includes a culture of MF6388 (optionally biologically pure), or a mutant thereof, capable of producing in a recoverable amount a compound of Formula (I).
Suitable mutant strains of MF6388 can be obtained by chemically induced mutagenesis using mutagens such as nitrosoguanidine, 1-methyl-3-nitro-1-nitrosoguanidine, ethyl methane sulfonate, 2-aminopurine, and the like. Mutant strains can also be obtained by radiation-induced mutagenesis, such as by irradiation with ultraviolet light (e.g., using a germicidal lamp), X-rays, or gamma rays (e.g., using a cobalt-60 source). Recombinant DNA techniques such as protoplast fusion, plasmid incorporation, gene transfer and the like may also be employed. Further description of mutagenic technqiues can be found in Vinci and Bing, “Strain Improvement by Nonrecombinant Methods”, in
Manual of Industrial Microbiology and Biotechnology
1999, 2d edition, edited by Demain et al., ASM Press, 103-113; and in Carlton and Brown, “Gene Mutation”, Chapter 13 in
Manual of Methods for General Bacteriology
1985, edited by Gerhardt et al., ASM Press, 222-229.
In addition, compounds of the present invention may be prepared by fermentation of the culture MF6388, ATCC 74478.
The present invention also relates to the preparation of compounds of structural Formula I comprising:
(a) fermenting a culture of MF6388 (ATCC 74478), Sterile Fungus 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.
This invention also discloses the culture MF6591 (ATCC 74477) identified as Ascochyta sp. A culture of MF6591 (ATCC 74477) is defined as substantially free of its natural soil contaminants and capable of forming a compound of Formula (I) in a recoverable amount. The culture should be free
Dombrowski Anne
Hazuda Daria
Pelaez Fernando
Singh Sheo
Teran Ana
Merck & Co. , Inc.
Owens Amelia
Walton Kenneth R.
Winokur Melvin
LandOfFree
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