This invention relates to novel tetramic acid-type compounds, pharmaceutical compositions containing them and their use as CCR-5 antagonists to treat Human Immunodeficiency Virus-1 (xe2x80x9cHIV-1xe2x80x9d) infections in humans. The compounds of this invention were isolated from a CCR-5 active complex which is produced by fermentation, under controlled conditions, of a biologically pure culture of the microorganism, Chaetomium globosum Kunze SCH 1705, ATCC 74489.
M. P. Singh et al., The Journal of Antibiotics, December 1998, Vol. 51, No. 12, p 1109-1112 disclosed novel antibiotics produced by an unknown fungus and including LL-49F233d containing an N-methyl tetramic acid moiety attached to a bicyclic hydrocarbon skeleton. These antibiotics are disclosed to be active against vancomycin and methicillin-resistant bacteria but no anti-HIV-1 activity is disclosed. S. B. Singh et al., Tetrahedron Letters, 39 (1998) 2243-2246 disclose that the N-methyl tetramic acid derivatives, equisetin and phomasetin, which are isolated from microbial extracts, are inhibitors of HIV-1 integrase. Neither reference discloses the compounds of the present invention.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The CCR5 chemokine receptor has been identified as co-receptor for HIV-1 entry in cells. Therefore, CCR5 antagonists that interfere with the interaction between the CCR5 receptor and HIV-1 can block HIV-1 entry into the cell.
The global health crisis caused by HIV-1, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find new drug therapies to control HIV-1 infections.
The present invention embraces Chaetomium globosum Kunze SCF 1705, ATCC 74489 and mutants and variants thereof having the identifying characteristics of Chaetomium globosum Kunze.
Another aspect of the invention provides CCR5-active complex produced by cultivating a biologically pure strain of Chaetomium globosum Kunze SCF 1705 having the identifying characteristics of Chaetomium globosum Kunze ATCC 74489 in a pH and temperature controlled medium having assumable sources of carbon and nitrogen under submerged aerobic conditions until a composition of matter having substantial anti HIV-1 activity is produced.
The present invention is also directed to three components of the CCR5-active complex, i.e. compounds represented by formulas I, II and III. 
in substantially chemically pure form, or a pharmaceutically acceptable salt thereof.
The present invention relates to methods of using compounds of formulas I, II or IIIxe2x80x94which are CCR5 antagonistsxe2x80x94as monotherapy or in association with pegylated interferon-alfa to treat patients having immunodeficiency virus type-1(xe2x80x9cHIV-1xe2x80x9d) infections.
The present invention also relates to methods of treating patients having HIV-1 infections by administering a therapeutically effective amount of HAART in association with a therapeutically effective amount of a compound of formulas I, II or III sufficient to lower HIV-1-RNA.
The present invention also relates to methods of treating patients having HIV-1 infections by administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a compound of formulas I, II or III sufficient to lower HIV-1-RNA.
The present invention also provides a method of treating pediatric patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III.
The present invention also provides a method of treating patients co-infected with HIV-1 and HCV which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of ribavirin and a therapeutically effective amount of HAART and a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III. 
in substantially chemically pure form, or a pharmaceutically acceptable salt thereof.