Princeton University

Eli Lilly and Company

George P Beardsley

Edward C Taylor

Stephen R Fletcher

Peter J Harrington

Chuan Shih

James M Hamby

2,4-Diamino- and 2-amino-4-hydroxy- derivatives of N-(4-[2-(pyrido[2,3-d]pyrimidin-6-yl)alkyl]benzoyl-)-L-glutamic acids, and the corresponding 5,6,7,8-tetrahydro compounds are antineoplastic agents. The compounds are prepared by hydrolytic or hydrogenolytic removal of carboxylic acid protecting groups from the correspondingly protected glutamic acid derivatives. A typical embodiment is N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)e thyl]benzoyl)-L-glutamic acid.

Pyrido[2,3-]pyrimidine derivatives

The diastereoisomeric forms of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl) ethyl]benzoyl)-L-glutamic acid are antineoplastic agents. The compounds are prepared by separation of the diastereoisomeric form of the correspondingly protected glutamic derivatives and hydrolytic or hydrogenolytic removal of carboxylic acid and/or amino protecting groups. Typical embodiments are the (R,S) and (S,S) forms of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)e thyl]benzoyl)-L-glutamic acid.

Diastereoisomeric tetrahydropyrido-(2,3,d) pyrimidine derivatives

2,4-Diamino- and 2-amino-4-hydroxy- derivatives of N-(4-[2-(pyrido[2,3-d]pyrimidin-6-yl)alkyl]benzoyl)-L-glutamic acids, and the corresponding 5,6,7,8-tetrahydro compounds are antineoplastic agents. The compounds are prepared by hydrolytic or hydrogenolytic removal of carboxylic acid protecting groups from the correspondingly protected glutamic acid derivatives. A typical embodiment is N-)4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)e thyl]benzoyl)-L-glutamic acid.

Pyrido [2,3,d]pyrimidine derivatives

Derivatives of N-[4-(N-[2-amino-4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylme thyl]-amino)benzoyl]-L-glutamic acid are antineoplastic agents. Their preparation and use, and intermediates useful for their preparation are described.

4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives

N-[4-(N'-[2-amino-4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylme thyl]-N'-acylamino)benzoyl]-L-glutamic acid derivatives are antineoplastic agents. The compounds are prepared through acylation of the corresponding N'-amino compound or hydrolysis of a protected N'-acylamino compound. A typical embodiment is N-[4-(N'-[2-amino-4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylm ethyl]-N'-formylamino)benzoyl]-L-glutamic acid.

4 (3H)-oxo-5,6,7,8-tetrahydropyrido-(2,3-d)pyrimidine derivatives

2,4-Diamino- and 2-amino-4-hydroxy- derivatives of N-(4-[1-(pyrido[2,3-d]pyrimidin-6-yl)alk-2-yl]-benzoyl)-L-glutamic acids, and the corresponding 5,6,7,8-tetrahydro compounds are antineoplastic agents. The compounds are prepared by hydrolytic or hydrogenolytic removal of carboxylic acid protecting groups from the correspondingly protected glutamic acid derivatives. A typical embodiment is N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)e thyl]benzoyl)-L-glutamic acid.

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Essex, CT, United States of America

George P Beardsley