Discovery and Synthesis of Alimta™, A New and Broadly Effective Antitumor Agent

Discovery and Synthesis of Alimta™, A New and Broadly Effective Antitumor Agent Edward C. Taylor Department of Chemistry Princeton University Princeton, NJ 08544 etaylor@princeton.edu

The Pterin Ring of Folic Acid

Folic Acid, Aminopterin and Methotrexate

The Dideaza Derivative of Aminopterin

Initial Conception of DDATHF

Original Synthesis of DDATHF

Original Synthesis of DDATHF (continued))

Simplified Synthesis of DDATHF

Simplified Synthesis of DDATHF (continued)

Comparison of Antitumor Activity of DDATHF and Methotrexate

de Novo Purine Biosynthesis Pathway

Comparison of the Structures of 10-CHOTHF and DDATHF

Separation of Diastereomers - Preparation of Lometrexol

Elimination of the Stereogenic Carbon

Elimination of the Stereogenic Carbon - Conception of Alimta

Mechanism of Activity of Alimta as an Antitumor Agent

First Synthesis of Alimta

First Synthesis of Alimta (continued)

Solution to the Diiodination Problem

A Michael-Nef Approach to Alimta

Most Economical Synthesis of Alimta

Some Inactive Analogs of Alimta

Some of the Tumors that Respond to Alimta in Clinical Trials

Summary

Summary February, 2004: Alimta, in combination with cisplatin, approved by the FDA for treatment of malignant pleural mesothelioma. September, 2004: Alimta approved by the FDA for treatment of second-line lung cancer. September, 2004: Alimta approved by the European Commission for treatment of both of the above indications in all of the EU countries. Summer, 2004: Alimta approved by Argentina, Australia, Canada and Israel.

Acknowledgements Samuel Watson George Wong Cheol-min Yoon Wendy Young Sanbao Zhong Ping Zhou Prof. G. Peter Beardsley (Yale Medical School) Prof. Richard G. Moran (Massey Cancer Center Medical College of VA) Charles Barnett Gerald Grindey Laura Mendelsohn Homer Pearce Chuan (Joe) Shih (Eli Lilly & Co.)

Discovery and Synthesis of Alimta™, A New and Broadly Effective Antitumor Agent