Agouron Pharmaceuticals, Inc.

William H Romines

Michael D Varney

Cynthia Louise Palmer

Judith Gail Deal

Novel derivatives of 5-thia- and 5-selenopyrimidinone are sound to inhibit the enzyme glycinamide ribonucleotide formyl transferase (GARFT) and amino imidazole carboxamide ribonucleotide formyl transferase (AICARFT). Novel intermediates of these compounds are also disclosed. A novel method of preparing such compounds is also disclosed, as well as methods and compositions for employing the compounds as antiproliferative agents.

Antiproliferative substituted 5-thiapyrimidinone and 5-selenopyrimidinone compounds

Novel derivatives of 5-thia- and 5-selenopyrimidinone are found to inhibit the enzyme glycinamide ribonucleotide formyl transferase (GARFT) and amino imidazole carboxamide ribonucleotide formyl transferase (AICARFT). Novel intermediates of these compounds are also disclosed. A novel method of preparing such compounds is also disclosed, as well as methods and compositions for employing the compounds as antiproliferative agents.

The invention relates to methods of making compounds of the formula VII ##STR1## and their enantiomers, where Ar is a substituted or unsubstituted five- or six-membered aromatic group and B is either an amino acid linked through the amino portion to form an amide or a C.sub.1 -C.sub.6 alcohol linked through the alcohol portion to form an ester. These compounds are advantageously employed as intermediates to prepare optically pure compounds that are active GARFT inhibitors. In one method, a compound of the formula ##STR2## is reacted with a compound of the formula ##STR3## where X is a halogen.

Synthesis of optically pure compounds useful as GARFT inhibitors and

The present invention is directed to derivatives of 5-thia- and 5-selenopyrimidinone are useful as inhibitors of the enzyme glycimide ribonucleotide formyl transferase (GARFT) and amino imidozole carboxamide ribonucleotide formyl transferase (AICARFT), pharmaceutical compositions containing these derivatives, and methods of using these derivatives. The present invention is also directed to intermediates useful for preparing these derivatives and methods of preparing these intermediates.

Antiproliferative substituted 5-thiapyrimidinone and

Syntheses of optically pure compounds useful as GARFT inhibitors and

Intermediates for preparing derivatives of 5-thia- and 5-selenopyrimidinone, ##STR1## which are useful as inhibitors of the enzymes glycinamide ribonucleotide formyl transferase (GARFT) and amino imidazole carboxamide ribonucleotide formyl transferase (AICARFT). The present invention is also directed to methods of preparing these intermediates.

Methods for preparing antiproliferative 5-substituted pyrimidone

The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: ##STR1## where n is 0 to 2; A is S, CH.sub.2, O, NH or Se, and when n is 0, A is not CH.sub.2, and when n is 1, A is not CH.sub.2 or NH; X is a substituted or unsubstituted C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R.sub.1 and R.sub.2 are hydrogen or a moiety that forms together with the attached CO.sub.2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

Compounds useful as antiproliferative agents and GARFT inhibitors

Compounds of the Formula I, which are in equilibrium with their 4-hydroxy tautomers and are in the form of diastereomeric mixtures, and their pharmaceutically acceptable salts are potent GARFT inhibitors: ##STR1## In the above formula, A is S, CH.sub.2 or Se, and Z, X, R.sub.1 and R.sub.2 are as defined in the specification. These compounds and their salts are useful as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents.

Compounds useful as antiproliferative agents and garft inhibitors

The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: ##STR1## where n is 0 to 2; A is S, CH.sub.2, O, NH or Se, and when n is 0, A is not CH.sub.2, and when n is 1, A is not CH.sub.2 or NH; X is a substituted or unsubstituted C.sub.1 --C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R.sub.1 and R.sub.2 are hydrogen or a moiety that forms together with the attached CO.sub.2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: ##STR1## where n is 0 to 2; A is S, CH.sub.2, O, NH or Se, and when n is 0, A is not CH.sub.2, and when n is 1, A is not CH.sub.2 or NH; X is a substituted or unsubstituted C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.3 alkenyl, C.sub.2 -C.sub.3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R.sub.1 and R.sub.2 are hydrogen or a moiety that forms together with the attached CO.sub.2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such Compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

Compounds of the invention include those of the following formula: ##STR1## In this formula, A is oxygen, sulfur or selenium; X' is a substituted or unsubstituted C.sub.1 -C.sub.3 alkyl group, a substituted or unsubstituted C.sub.2 -C.sub.3 alkenyl group, a substituted or unsubstituted C.sub.2 -C.sub.3 alkynyl group, a substituted or unsubstituted amino group, sulfur or oxygen; Y is oxygen, sulfur or NH; B is hydrogen or a halogen; C is hydrogen, a halogen or a substituted or unsubstituted C.sub.1 -C.sub.6 alkyl group; and R.sub.6 is hydrogen or a moiety that forms with the attached CO.sub.2 a readily hydrolyzable ester group.

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San Diego, CA, United States of America

William H Romines