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US 2002/0173515 A1Published application
Antiproliferative substituted 5-thiapyrimidinone and 5-selenopyrimidinone compounds
OwnerMichael D. Varney, William H. Romines +2inventors
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.
Claims51
A compound having the formula I
- 39
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein when said non-cyclic spacer is bonded to A, said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms and further wherein when said non-cyclic spacer is bonded to —C(O)—, said non-cyclic spacer separates —C(O)— from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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.
7 more elements
A compound having the formula III
- 41
- wherein:
- n represents an integer from 0 to 5;
- A represents sulfur or selenium;
- X is methylene, monocyclic carbo- or heterocyclic ring, O, S, or —NH—;
- Ar is an aromatic radical, wherein Ar can form a fused bicyclic ring system with said ring of X;
- and
- R1 and R2, which can be the same or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms;
- or a pharmaceutically acceptable salt thereof.
6 more elements
An antiproliferative composition comprising a compound having the formula III
- 42
- wherein n represents an integer from 0 to 5;
- A is sulfur or selenium;
- X is methylene, monocyclic carbo- or heterocyclic ring, O, S, or —NH—;
- Ar is an aromatic radical, wherein Ar can form a fused bicyclic ring system with said ring of X;
- and
- R1 and R2, which can be the same or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms;
- or
- a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
6 more elements
An antiproliferative composition comprising a compound having the formula I:
- 43
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein when said non-cyclic spacer is bonded to A, said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms and further wherein when said non-cyclic spacer is bonded to —C(O)—, said non-cyclic spacer separates —C(O)— from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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.
8 more elements
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
- 44
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein when said non-cyclic spacer is bonded to A, said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms and further wherein when said non-cyclic spacer is bonded to —C(O)—, said non-cyclic spacer separates —C(O)— from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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.
7 more elements
A process for inhibiting the growth and proliferation of the cells of microorganisms and higher organisms, which process comprises administering to a host in need of such treatment an effective amount of a compound having the structural formula III
- 45
- wherein:
- n represents an integer from 0 to 5;
- A represents sulfur or selenium;
- X is methylene, monocyclic carbo- or heterocyclic ring, O, S, or —NH—;
- Ar is an aromatic radical, wherein Ar can form a fused bicyclic ring system with said ring of X;
- and
- R1 and R2, which can be the same or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms;
- or a pharmaceutically acceptable salt thereof.
6 more elements
A process for preparing a 5-substituted pyrimidinone compound having the formula V
- 46
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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
- 47
- wherein hal is bromine, chlorine, iodine, or fluorine, and R3 is as defined above, with a compound having the formula IV
- 48
- wherein A, Z, and R4 are as defined above, in the presence of a nonnucleophilic 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.
12 more elements
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:
- 49
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein when said non-cyclic spacer is bonded to A, said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms and further wherein when said non-cyclic spacer is bonded to —C(O)—, said non-cyclic spacer separates —C(O)— from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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.
7 more elements
A compound of the formula X
- 50
- wherein:
- A represents sulfur or selenium;
- Ar represents an unsubstituted phenylene or thienylene radical;
- R1 and R2 represent, individually, hydrogen or C1 to C6 alkyl or other readily lyzable groups;
- R3 represents hydrogen or a straight, branched or cyclic C1-C6 alkyl group, optionally carrying one or more halogen, hydroxyl or amine groups;
- or
- a pharmaceutically acceptable salt thereof.
5 more elements
A compound having the formula V
- 51
- wherein:
- A represents sulfur or selenium;
- Z represents 1) 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;
- 2) a substituted or unsubstituted mono- or fused or nonfused poly-carbocyclic or heterocyclic radical;
- or 3) a combination of at least one of said non-cyclic spacer and at least one of said carbocyclic or heterocyclic radical, wherein said non-cyclic spacer separates A from one of said carbocyclic or heterocyclic radicals by 1 to 10 atoms;
- 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.
7 more elements
A process for inhibiting AICARFT comprising the step of administering to a host in need of such inhibition an effective amount of a compound having the formula X:
- 52
- wherein:
- A represents sulfur or selenium;
- Ar represents an unsubstituted phenylene or thienylene radical;
- R1 and R2 represent, individually, hydrogen or C1 to C6 alkyl or other readily lyzable groups;
- R3 represents hydrogen or a straight, branched or cyclic C1-C6 alkyl group, optionally carrying one or more halogen, hydroxyl or amine groups;
- or
- a pharmaceutically acceptable salt thereof.
5 more elements
Dependencies are inferred from the claim text.