Antiproliferative substituted 5-thiapyrimidinone and 5-selenopyrimidinone compounds
AssigneeAgouron Pharmaceuticals, Inc.
InventorsMichael D. Varney, William H. Romines, Cynthia L. Palmer, Judith G. Deal
Life of this patent
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Abstract
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.
Claims9
A compound having the formula I
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted noncyclic spacer which separates A from the carbonyl carbon of the amido group by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R1 and R2 represent, independently, H or C1 to C6 alkyl or other readily lyzable groups;
- and
- R3 represents H or a straight, branched or cyclic C1 to C6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups;
- or a pharmaceutically acceptable salt thereof.
An antiproliferative composition comprising a compound having the formula I:
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted non-cyclic spacer which separates A from the carbonyl carbon of the amido group by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R1 and R2 represent, independently, H, C1 to C6 alkyl or other readily lyzable groups;
- and
- R3 represents H or straight, branched or cyclic C1 to C6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups;
- or a pharmaceutically acceptable salt thereof;
- in combination with a pharmaceutically acceptable carrier.
A process for inhibiting the growth and proliferation of the cells of microorganisms and of higher organisms, which process comprises administering to a host in need of such treatment an effective amount of a compound having the structural formula I
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted non-cyclic spacer which separates A from the carbonyl carbon of the amido group by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R1 and R2 represent, independently, H, C1 to C6 alkyl or other readily lyzable groups;
- and
- R3 represents H or straight, branched or cyclic C1 to C6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups;
- or a pharmaceutically acceptable salt thereof.
A process for preparing a 5-substituted pyrimidinone compound having the formula V
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted non-cyclic spacer which separates A from the carbonyl carbon by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R3 represents H or a straight, branched or cyclic (C1 to C6) alkyl group, optionally carrying one or more hydroxyl or amine groups;
- and
- R4 represents hydroxy, (C1 to C6) alkyloxy group optionally carrying one or more hydroxyl or amine groups, or a protected or unprotected amino acid linked to the acyl group of formula V by the amine portion of the amino acid;
- or a pharmaceutically acceptable salt thereof;
- which process comprises reacting a compound having the formula VI
- wherein Hal is bromine, chlorine, iodine, or fluorine, and R3 is as defined above, with a compound having the formula IV
- wherein A, Z, and R4 are as defined above, in the presence of a non-nucleophilic auxiliary base in a solvent in which at least one of said reactants is at least partially soluble under conditions sufficient to obtain the compound of formula V.
A process for inhibiting GARFT comprising the step of administering to a host in need of such inhibition an effective amount of a compound having the formula I:
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted non-cyclic spacer which separates A from the carbonyl carbon of the amido group by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R1 and R2 represent, independently, H or C1 to C6 alkyl or other readily lyzable groups;
- and
- R3 represents H or straight, branched or cyclic C1 to C6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups;
- or a pharmaceutically acceptable salt thereof.
A compound having the formula V
- wherein:
- A represents sulfur or selenium;
- Z represents a substituted or unsubstituted non-cyclic spacer which separates A from the carbonyl carbon by 1 to 10 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous;
- R3 represents H or a straight, branched or cyclic (C1 to C6) alkyl group, optionally carrying one or more hydroxyl or amine groups;
- and
- R4 represents hydroxy, (C1 to C6) alkyloxy group optionally carrying one or more hydroxyl or amine groups, or a protected or unprotected amino acid linked to the acyl group of formula V by the amine portion of the amino acid;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.