Merck + Co., Inc.

Ali Shafiee

Shieh-Shung T Chen

Deborah L Zink

Byron H Arison

Sheo B Singh

Russell B Lingham

Keith C Silverman

George M Garrity

Louis Kaplan

Brian Heimbuch

Ana M Teran

Haideh Motamedi

Randall R Miller

Paul N Devine

Gerald F Bills

Fernando Pelaez

Michel M Chartrain

John Limanto

Laszlo R Treiber

Suzanne M Mandala

Guy H Harris

David A Boulton

Francis J Dumont

Jon David Polishook

Christopher Roberge

Lawrence F Colwell, Jr

Veena Upadhyay

Patricia M Cameron

Janet M Sigmund

Ralph A Stearns

Mark J Rosenbach

This invention relates to a stereoselective preparation of fluoroleucine alkyl esters.

Process for preparing fluoroleucine alkyl esters

Natural products such as certain chaetochromins are described. These compounds are useful in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

HIV integrase inhibitors

There is disclosed a dual compartment solid phase extraction cartridge comprising a container divided into a top volume and a bottom volume by a porous filter or frit, the top and bottom volumes having a quantity of sorbent. The cartridge is useful in the separation of components of a liquid and solid mixture.

Dual compartment solid phase extraction cartridge

Biotransformation products of a fermentation with Streptomyces sp., (Merck Culture Collection MA7165) ATCC No. 55946 are potent antifungal agents. These products may be useful in the treatment of diseases caused by fungal pathogens such as Candida sp. and Cryptococcus neoformans.

Microbial transformation products with antifungal properties

Natural products such as certain ermophilane sesquiterpenoids and derivatives thereof are described. These compounds are useful in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described. The fungal culture MF6254, Xylaria sp. (ATCC 74397) is also described and disclosed.

Ermophilane sesquiterpenoids as HIV intergrase inhibitors

The present invention is directed to expression cassettes useful in gene expression studies in both homologous and heterologous Streptomyces strains. More specifically the present invention is directed to the construction of two Streptomyces lividans-recombinant strains capable of producing 31-O-desmethylFK-506 O:methyltransferase, which methvlates 31-O-desmethylFK-506 to FK-506. In addition, the present invention is directed to a process for the specific methylation of 31-desmethyl-FK506 to FK506.

Expression cassettes useful in construction of integrative and

Biotransformation products of a fermentation with culture MA7074 are potent HIV protease inhibitors. These products are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Streptomyces sp. MA 7074 (ATCC 55605) used for microbial synthesis of

The present invention provides a process for the stereoselective reduction of phenylalkyl ketones to their corresponding (S)-hydroxy compounds. The process utilizes the novel microorganism Microbacterium MB 5614 to effectuate the chiral reduction. The present invention also provides said novel Microbacterium, which has been deposited with the ATCC and assigned the accession number ATCC 55557.

Microbial method

A process for reducing a phenylalkyl ketone to the corresponding (S)-hydroxy derivative is disclosed. The process comprises contacting the phenylalkyl ketone with Mucor hiemalis IFO 5834 and recovering the (S)-hydroxy derivative.

Reduction of phenylalkyl ketones to the corresponding (S)-hydroxy

Microbial transformation of a macrolide immunosuppressant by the microorganism Streptomyces sp., (Merck Culture Collection MA 6960) ATCC No. 55387 yields a compound of the structural formula (I): ##STR1## This compound is an immunosuppressant useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.

Microbial transformation product having immunosuppressive activity

Described is a new enzyme, 31-O-desmethyl-FK-506 O-methyltransferase (FKMT) and its N-terminal amino acid sequence. This enzyme can specifically and preferentially methylate the C-31 hydroxy group in 31-O-desmethyl FK-506/FR-900506 and other 31-O-desmethyl analogs of FK-506/FR-900506 and related compounds such as 31-O-desmethyl immunomycin type molecules, also designated FK-520 and FR-900520 by Fujisawa. The enzyme can be isolated from a FK-506 producing microorganism Streptomyces sp. (Merck Culture Collection No. MA 6858) ATCC No. 55098. Employing the enzyme in its active form, supplemented with Mg.sup.+2 ion, in the presence of the methyl donor, S-adenosyl methionine (SAM), derivatives of 31-O-desmethyl FK-506, 31-O-desmethyl FK-520 and related 31-O-desmethyl compounds may be prepared.

Methlating enzyme from streptomyces MA6858

Described is a process for producing a new immunosuppressant, a C-31 desmethyl, C-19/C-22 cyclic hemiketal biotransformation analog (Compound I) of FR-900520, under novel fermentation conditions utilizing the novel microorganism, Streptomyces, lavendulae ATCC No. 55209. Also disclosed is the C-31 methylated devivative (Compound II) of Compound I produced by enzymatic methylation using 31-O-desmethylimmunomycin O-methyl transferase, (DIMT), a methyl transferase enzyme. The macrolide immunosuppressants are useful in preventing human host rejection of foreign organ transplants, e.g. bone marrow, liver, lung, kidney and heart transplants.

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Westfield, NJ, United States of America

Ali Shafiee