University of British Columbia

Forbes Medi-tech Inc.

The United States of America As Represented by the Department of Health

The United States of America As Represented by the Secretary of

N.v. Organon

James P Kutney

Lawrence D Mayer

Jun Nakano

Patricia Liliana Orchansky

Bruce Schmidt

Camille A Boulet

Hiroki Tsukamoto

Michael McHugh

Radka K Milanova

Lewis S L Choi

Brian R James

Phillip M Townsley

Lewis S Choi

Egon Novak

Michael D Fryzuk

Christo Dimitrov Vassilev

Guo-Jun Kang

Roberto Spogliarich

Svetoslav Stefanov Stefanov

Ian S Thorburn

Natalya Velikova Nedelcheva

Peter J Jones

Brian R Worth

Kenneth L Stuart

Phillip J Salisbury

William T Chalmers

William R Cullen

Edward J Herrington

Grigor Spassov

Sterol and stanol nitro derivatives and their use in treating or preventing cardiovascular disease, its underlying conditions and other disorders are disclosed. The disclosed nitro derivatives are synthesized by ester linkage of a nitric oxide (NO)-releasing moiety to a sterol or stanol compound.

Sterol/stanol nitroderivatives and use thereof

Sterol and stanol phosphorylnitro derivatives and their use in treating or preventing cardiovascular disease, its underlying conditions and other disorders are disclosed. The disclosed compounds include a phosphate linker, at least one moiety that releases nitric oxide (NO), and a sterol or stanol moiety. Some compounds additionally include an ascorbyl moiety to make the compound more readily soluble in aqueous and non-aqueous media.

Sterol/stanol phosphorylnitroderivatives and use thereof

The present invention is particularly directed to the use of a derivative of vinblastine, 3&prime;,4&prime;-anhydrovinblastine (AHVB), which differs from vinblastine in that it possesses a double bond at the 3&prime;,4&prime; position of the caranthine nucleus rather than the hydroxyl group that is present in the parent structure, as an anti-neoplastic agent in the therapeutic treatment of cancer.

Anhydrovinblastine for the treatment of cancer

The present invention relates to the synthesis of dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, from an indole unit, such as cantharanthine, and a dihydroindole unit, such as vindoline. A multi-step process is disclosed including the steps of (1) of 1,4-reduction of a first dimeric iminium intermediate to an enamine compound by reaction with a 1,4-dihydropyridine compound; (2) oxidative transformation of the resulting enamine to a second iminium intermediate under controlled aeration; (3) reduction of the second iminium intermediate to form the target dimer alkaloid compounds. The entire process can be conducted in a one-pot operation to obtain the target compounds without isolation of the intermediates.

Process of synthesis of 3&prime;,4&prime;-anhydrovinblastine, vinblastine and vincristine

A novel process for the fermentation of phytosterol compositions to androstenedione (androst-4-ene-3,17-dione, AD) and/or androstadienedione (androsta-1,4-diene-3,17-dione, ADD) is disclosed. The process utilizes the micro-organism Mycobacterium MB 3683, and selected suitable solubilizing agents such as polypropylene glycol or silicone for solubilizing the phytosterol compositions at high concentrations in the nutrient medium. The innoculum of Mycobacterium MB 3683 is grown in a nutrient medium comprising Refiners molasses and inorganic salts.

Process for the microbial conversion of phytosterols to androstenedione

The present invention is particularly directed to the use of a derivative of vinblastine, 3',4'-anhydrovinblastine (AHVB), which differs from vinblastine in that it possesses a double bond at the 3',4' position of the caranthine nucleus rather than the hydroxyl group that is present in the parent structure, as an antineoplastic agent in the therapeutic treatment of cancer. Specifically, the treatment of lymphoma with 3',4'-anhydrovinblastine is disclosed.

Use of anhydrovinblastine

The invention is drawn to a process for isolating and purifying a phytosterol composition from a pulping soap by first extracting a creamy precipitate from the pulping soap using a solvent mixture of water, ketone, and hydrocarbon, and then purifying the cremy precipitate to form the phytosterol composition. The invention also includes the phytosterol composition formed by this method.

Process of isolating a phytosterol composition from pulping soap

Process of synthesis of vinblastine and vincristine

Asymmetric hydrogenation of prochiral N-arylketimines to give optically active secondary amines at a temperature from -40.degree. to 80.degree. C., under a hydrogen pressure of 10.sup.6 to 10.sup.8 Pa and with the addition of catalytic amounts of a rhodium compound of the formula III or IIIa ##STR1## in which X is 2 olefin ligands or a diene ligand, Y is a chiral diphosphine in which the secondary phosphine groups are linked by 2-4 C atoms and which, together with the Rh atom, forms a 5-membered, 6-membered or 7-membered ring, or Y is a chiral disphosphinite in which the phosphinite groups are linked via 2 C atoms and which, together with the Rh atom, forms a 7-membered ring, Z is Cl, Br or I and A.sup.- is the anion of an oxygen acid or complex acid.

Process for the preparation of optically active secondary arylamines

A process for the production of tripdiolide, triptolide and celastrol comprises the steps of: (a) preparing a cellular inoculum from Tripterygium wilfordii Hook F; (b) inoculating a nutrient growth medium with the cellular inoculum and incubating the inoculated growth medium at 20.degree.-30.degree. C. for up to 8 weeks to produce a cellular product; (c) harvesting the cellular product from the inoculated growth medium; and (d) isolating tripdiolide, triptolide and celastrol from the cellular product and supernatant inoculated growth medium.

Method for producing tripdiolide, triptolide and celastrol

A concerted process for the synthesis of a dimer consisting of an indole unit and a dihydroindole unit possessing natural stereochemistry which comprises:

Method for producing dimer alkaloids

Novel 3',4'-dehydro- and 4'-deoxo-vincristine and vinblastine compounds are obtained by coupling an indole unit of the catharanthine series and a dihydroindole unit of the vindoline series. Representative compounds of this series showed superior results when tested for activity against L1210 and P388 mouse leukemia.

Synthetic vinblastine and vincristine derivatives

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Vancouver, Canada

James P Kutney