Princeton University

Eli Lilly and Company

Rohm and Haas Company

Emery Industries, Inc.

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Fmc Corporation

Polaroid Corporation

Edward C Taylor

Chuan Shih

George P Beardsley

Stephen R Fletcher

Philip M Harrington

Ping Zhou

Colin Michael Tice

John F White

George S Wong

Gerald B Grindey

Dietmar G Kuhnt

Chih-Shu Chiang

Peter J Harrington

Lynn Stacy Gossett

Alexander McKillop

James M Hamby

Bin Liu

Richard A Brown

Edward R Lavagnino

Peter Viski

James M Greene

Randy A Bull

Stephen F Martin

Lance R Byers

Christopher E Orvig

Andrew J Pike

Cheol-min Yoon

Alan H Katz

Thomas H Schrader

Koo Lee

Loren D Walensky

Hemantkumar H Patel

Gary E Cargill

William J Gill

James T Metz

5,6,7,8-tetrahydropyrido[2,3-D]pyrimidines

4(3H)-X-7H-Pyrrolo[2,3-d]pyrimidines in which X is .dbd.O or .dbd.NH are prepared by treating a 6-amino-4(3H)-X-pyrimidine with a unsubstituted or substituted 1-nitroalk-1-ene to yield a 6-amino-4(3H)-X-pyrimidine which is substituted in the 5-position by a 1-nitroalk-2-yl group; (ii) converting the 5-(1-nitroalk-2-yl)-6-amino-4(3H)-X-pyrimidine to the corresponding 5-(1-oxoalk-2-yl)-6-amino-4(3H)-X-pyr-imidine; and (iii) removing the elements of water from the 5-(1-oxoalk-2-yl)-6-amino-4(3H)-X-pyrimidine to effect cyclization. A typical embodiment involves treating 2,6-diamino-4(3H)-pyrimidone with 1-nitro-4-(4-ethoxycarbonylphenyl)-1-butene to yield 1 -nitro-2-(2,6-diamino-4(3H)-oxopyrimidin-5-yl)-4-(4-ethoxy-carbonylphenyl) butane which is then treated sequentially with base and acid, without isolation of the intermediate aldehyde, to form 4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, a valuable known chemical intermediate for the preparation of N-[4-{2-(2-hydroxy-4-amino-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl}benzoyl] glutamic acid.

Process for the preparation of pyrrolo[2,3-d]pyrimidines

This invention relates to a process for the preparation of pyrimidinone compounds of the formula ##STR1## wherein Ar is an optionally substituted aryl or heteroaromatic moiety,

Process for pyrimidinone compounds

2-Amino-4-hydroxy-4,5,6,7-tetrahydropyrido�2,3-d!pyrimidine derivatives of aromatic amides, such as a benzamide or thienylcarboxamide in which the amino portion of the amide is other than L-glutamic acid are inhibitors of enzymes which utilize folic acid, in particular glycinamide ribonucleotide formyl transferase. A typical embodiment is N-(N-{4-�2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido�2,3-d!pyrimidin-6-y l)ethyl!benzoyl}-L-.gamma.-glutamyl)-D-aspartic acid.

Pyridopyrimidines as nonclassical antifolates

There are described heat-developable photosensitive image-recording elements which have an alkali-generating system incorporated therein. In the alkali-generating system, a slightly water-soluble metal compound is reacted with a salt of 2-hydroxy-pyridine-N-oxide, or its derivatives, in the presence of a fluid such as water, to form an insoluble precipitate and the alkali required for silver image development during processing. The image-recording materials are useful as image-forming materials in thermographic and photothermographic processes.

Image-recording element

Pyrido[2,3-d]pyrimidine compounds are prepared through the reaction of 2,4-diamino-6(1H)-pyrimidone and an activated derivative of a dialdehyde. A typical embodiment utilizes the dinitrile.

Process for the preparation of fused pyridine compounds

N-(Acyl)glutamic acid derivatives in which the acyl group is substituted with 4-hydroxypyrrolo[2,3-d]-pyrimidin-3-yl group are antineoplastic agents. A typical embodiment is N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L-g lutamic acid.

N-(pyrrolo(2,3-d)pyrimidin-3-ylacyl)-glutamic acid derivatives

5-Substituted pyrrolo[2,3-d]pyrimidines are prepared from a nucleophile of the formula R.sup.2 -C(.dbd.NH)NH.sub.2 and a 2-amino-5-substituted-furan carrying a cyano or carboxy group in the 4-position. A typical example is the preparation of ethyl 4-(2-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)ethyl}benzoate, an intermediate for the preparation of the known N-[4-{2-(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)ethyl}benzoyl]-L-glutamic acid, by allowing guanidine and ethyl 4-[2-(2-amino-3-cyanofur-4-yl)ethyl]benzoate to react under mild conditions.

3-Ethynylpyrrolo[2,3-d]pyrimidines are chemical intermediates for antineoplastic N-(acyl)glutamic acid derivatives. A typical embodiment is 3-ethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine.

Pyrrolo(2,3-d)pyrimidines

N-(Acyl)glutamic acid derivatives in which the acyl group is substituted with 4-hydroxypyrrolo[2,3-d]-pyrimidin-3-yl group are antineoplastic agents. A typical embodiment is N-{5-[2-(4-hydroxy-6-aminopyrrolo[2,3-d]pyrimidin-3-yl)ethyl]thien-2-ylcar bonyl}-L-glutamic acid.

N-(6-Amino-(pyrrolo(2,3-d)pyrimidin-3-ylacyl) )-glutamic acid 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-]pyrimidine derivatives

Substituted pyrimidin-5-yl derivatives of L-glutamic acid are anti-neoplastic agents. A typical embodiment is N-{4-[6-(2,6-diamino-4-hydroxypyrimidin-5-yl)hex-1-en-3-yl]benzoyl}-L-glut amic acid.

L-glutamic acid derivatives

N-(Acyl)glutamic acid derivatives in which the acyl group is substituted with 4-hydroxypyrrolo[2,3-d]pyrimidin-3-yl group are antineoplastic agents. A typical embodiment is N-[4-(2-{4-hydroxypyrrolo[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L-glutamic acid.

N-(pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivatives

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Princeton, NJ, United States of America

Edward C Taylor