Eli Lilly and Company

Gerald E Gutowski

Jean C Miller

Allen S Katner

VLB 3-(2-chloroethyl)carboxamide, the corresponding 4-desacetyl derivative and salts thereof, useful in treatment of neoplasms in pharmaceutical dosage forms.

Use of VLB 3-(2-chloroethyl) carboxamide in treating neoplasms

3-Spiro-5'-oxazolidine-2',4'-dione derivatives of Vinca alkaloids, useful as anti-tumor agents and as intermediates.

Vinca alkaloid intermediates

Oxazolidinedione derivatives of Vinca alkaloids

Vincaleukoblastine (VLB, vinblastine) is reacted with thionyl chloride to form a bis-sulfite ester which is converted to various 5'-oxygenated derivatives.

5' Acetoxy vinblastine 4' bis-sulfite

Vincaleukoblastine (VLB, vinblastine) is converted to leurosidine, its 4' epimer, by reaction with thionyl chloride to form a bis-sulfite ester followed by treatment of the bis-sulfite ester with silver perchlorate. The bis-sulfite ester is covertible to novel 4' ethers by treatment with a lower alkanol or 4' esters of leurosidine perchlorate with acetic anhydride.

Preparation of leurosidine and novel leurosidine 4'-ethers and esters

A process for preparing new compounds which are N- and O-acylates of pyrazofurin comprises first selective mono-N-acylation under non-basic conditions in an organic solvent. The mono-N-acylate so formed is further acylated under mild basic conditions to provide a tetra-acylated or penta-acylated pyrazofurin derivative, depending upon the duration of reaction. Mild solvolysis of either a tetra-acylate or a penta-acylate provides a tri-acylated pyrazofurin derivative. In the presence of a strong base, the mono-N-acylate is further acylated to provide different tetra-acylates or penta-acylates of pyrazofurin, again depending upon the duration of reaction. Pyrazofurin acylates are useful as antiviral, antipsoriatic, and antifungal agents, as well as intermediates for new C-nucleosides.

Acylation of pyrazofurin

Dimeric Vinca alkaloids are converted to three separable anhydro derivatives, useful as mitotic inhibitors or as intermediates for the preparation of other oncogenetically active alkaloids.

Growing community of inventors

Indianapolis, IN, United States of America

Gerald E Gutowski