US2002173515A1PendingUtilityA1
Antiproliferative substituted 5-thiapyrimidinone and 5-selenopyrimidinone compounds
Priority: Dec 16, 1992Filed: Oct 23, 2001Published: Nov 21, 2002
Est. expiryDec 16, 2012(expired)· nominal 20-yr term from priority
A61P 37/06A61P 29/00A61P 31/00A61P 33/02A61P 33/00A61P 33/10A61P 31/04C07D 409/12A61P 31/12C07D 239/56
53
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A compound having the formula I
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;
R 1 and R 2 represent, independently, H or C 1 to C 6 alkyl or other readily lyzable groups; and
R 3 represents H or a straight, branched or cyclic C 1 to C 6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups; or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 having the formula II
wherein:
A is sulfur or selenium;
Z is -(group)-(ring)-,
wherein (group) represents a non-cyclic spacer which separates A from (ring) by 1 to 5 atoms, said atoms being independently selected from carbon, oxygen, sulfur, nitrogen and phosphorous and optionally carrying one or more substituents independently selected from C 1 to C 6 alkyl or C 2 to C 6 alkenyl groups, C 1 to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C 6 )alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocyclic carbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings;
and wherein (ring) represents one or more of a substituted or unsubstituted monocyclic carbo- or heterocyclic ring or a fused or non-fused polycarbocyclic or heterocyclic ring optionally substituted with one or more substituents selected from those recited for (group);
R 1 and R 2 represent, independently, H, C 1 to C 6 alkyl or other readily lyzable groups; and
R 3 represents hydrogen or a straight, branched or cyclic C 1 to C 6 alkyl group optionally carrying halogen, hydroxyl or amine substitution; or a pharmaceutically acceptable salt thereof.
3 . A compound according to claim 1 wherein the moiety Z is represented by Q—X—Ar wherein:
Q represents a C 1 -C 5 alkylene, or a C 2 -C 5 alkenylene or alkynylene radical optionally carrying one or more substituents independently selected from C 1 to C 6 alkyl or C 2 to C 6 alkenyl groups, C 1 to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C 6 )alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocyclic carbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings;
X represents a methylene, monocyclic carbo- or heterocyclic ring, sulfur, oxygen or amino radical, optionally carrying one or more substituents independently selected from C 1 to C 6 alkyl or C 2 to C 6 alkenyl groups, C 1 to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C,)alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocyclic carbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings; and
Ar represents a monocyclic carbo- or heterocyclic aromatic ring or a bicyclic carbo- or heterocyclic ring, all or a portion of which may be aromatic, and wherein the Ar may be fused to the monocyclic carbo- or heterocyclic ring of X, and wherein the Ar optionally carries one or more substituents independently selected from C 1 to C 6 alkyl or C 2 to C 6 alkenyl groups, C 1 to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C 6 )alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocycliccarbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings;
or a pharmaceutically acceptable salt thereof.
4 . A compound or salt according to claim 2 , wherein the moiety (group) represents a C 1 to C 4 alkylene group; and
the moiety (ring) represents a substituted or unsubstituted, fused or non-fused carbocyclic or heterocyclic bicyclic ring system, or a substituted or unsubstituted, carbocyclic or heterocyclic monocyclic ring system, or at least two monocyclic ring systems linked by a single bond, said monocyclic ring systems being independently substituted or unsubstituted.
5 . A compound having the formula III
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
R 1 and R 2 , 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 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is methylene, Ar is phenylene and R 1 and R 2 are hydrogen.
7 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is methylene, Ar is 2,5-thienyl and R 1 and R 2 are hydrogen.
8 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is S, Ar is phenylene and R 1 and R 2 are hydrogen.
9 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is —NH—, Ar is phenylene and R 1 and R 2 are hydrogen.
10 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is methylene, Ar is phenylene and R 1 and R 2 are alkyl radicals having 1 to 6 carbon atoms.
11 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is methylene, Ar is 2,5-thienyl and R 1 and R 2 are ethyl groups.
12 . A compound or salt according to claim 5 wherein n is 2, A is sulfur, X is sulfur, Ar is phenylene and R 1 and R 2 are ethyl groups.
13 . A compound or salt according to claim 5 , wherein n is 2, A is sulfur, X is —NH—, Ar is phenylene and R 1 and R 2 are ethyl groups.
14 . An antiproliferative composition comprising a compound having the formula III
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
R 1 and R 2 , 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.
15 . A composition according to claim 14 wherein n is 2, A is sulfur, X is methylene, and Ar is phenylene.
16 . A composition according to claim 14 wherein n is 2, A is sulfur, X is methylene, and Ar is 2,5-thienyl.
17 . A composition according to claim 14 wherein n is 2, A is sulfur, X is S, and Ar is phenylene.
18 . A composition according to claim 14 wherein n is 2, A is sulfur, X is —NH—, and Ar is phenylene.
19 . An antiproliferative composition comprising a compound having the formula I:
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;
R 1 and R 2 represent, independently, H, C 1 to C 6 alkyl or other readily lyzable groups; and
R 3 represents H or straight, branched or cyclic C 1 to C 6 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.
20 . 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 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;
R 1 and R 2 represent, independently, H, C 1 to C 6 alkyl or other readily lyzable groups; and
R 3 represents H or straight, branched or cyclic C 1 to C 6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups; or a pharmaceutically acceptable salt thereof.
21 . 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
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
R 1 and R 2 , which can be the same or different, are hydrogen or alkyl radicals having 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
22 . A process according to claim 21 wherein n is 2, A is sulfur, X is methylene and Ar is phenylene.
23 . A process according to claim 21 wherein n is 2, A is sulfur, X is methylene and Ar is 2,5-thienyl.
24 . A process according to claim 21 wherein n is 2, A is sulfur, X is sulfur and Ar is phenylene.
25 . A process according to claim 21 wherein n is 2, A is sulfur, X is —NH—, and Ar is phenylene.
26 . A process for preparing a 5-substituted pyrimidinone compound having the formula V
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;
R 3 represents H or a straight, branched or cyclic (C 1 to C 6 ) alkyl group, optionally carrying one or more hydroxyl or amine groups; and
R 4 represents hydroxy, (C 1 to C 6 ) 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 R 3 is as defined above, with a compound having the formula IV
wherein A, Z, and R 4 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.
27 . A process according to claim 26 wherein the non-nucleophilic auxiliary base is selected from alkali or earth metal carbonates and trialkyl amines.
28 . A process according to claim 27 wherein the solvent is a dipolar aprotic solvent.
29 . A process according to claim 28 wherein the solvent is selected from dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrolidinone.
30 . A process according to claim 26 wherein A represents sulfur and Z represents —(CH 2 ) n —X—Ar— wherein
n is an integer from 0 to 5,
X represents a methylene, monocyclic carbo- or heterocyclic ring, sulfur, oxygen or amino radical, optionally carrying one or more substituents independently selected from C 1 to C 6 alkyl or C 2 to C 6 alkenyl groups, Cl to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C 6 )alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocyclic carbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings; and
Ar represents a monocyclic carbo- or heterocyclic aromatic ring or a bicyclic carbo- or heterocyclic ring, all or a portion of which may be aromatic, and wherein the Ar may be fused to the monocyclic carbo- or heterocyclic ring of X, and wherein the Ar optionally carries one or more substituents independently selected from C 1 to C 6 alkyl or C 2 .to C 6 alkenyl groups, C 1 to C 6 alkoxy or C 1 to C 6 alkoxy(C 1 to C 6 )alkyl groups, C 2 to C 6 alkynyl groups, acyl groups, halogen, amino groups, hydroxyl groups, nitro groups or mercapto groups, monocyclic carbo- or heterocyclic rings, and fused or non-fused poly-carbocyclic or poly-heterocyclic rings.
31 . A process according to claim 30 wherein the non-nucleophilic auxiliary base is selected from alkali or earth metal carbonates and trialkylamines.
32 . A process according to claim 31 wherein the solvent is a dipolar aprotic solvent.
33 . A process according to claim 32 wherein the solvent is selected from dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrolidinone.
34 . 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 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;
R 1 and R 2 represent, independently, H or C 1 to C 6 alkyl or other readily lyzable groups; and
R 3 represents H or straight, branched or cyclic C 1 to C 6 alkyl group optionally carrying one or more halogen, hydroxyl or amine groups; or a pharmaceutically acceptable salt thereof.
35 . A compound of the formula X
wherein:
A represents sulfur or selenium;
Ar represents an unsubstituted phenylene or thienylene radical;
R 1 and R 2 represent, individually, hydrogen or C 1 to C 6 alkyl or other readily lyzable groups;
R 3 represents hydrogen or a straight, branched or cyclic C 1 -C 6 alkyl group, optionally carrying one or more halogen, hydroxyl or amine groups; or
a pharmaceutically acceptable salt thereof.
36 . A compound according to claim 35 wherein A is sulfur and Ar represents an unsubstituted phenylene radical.
37 . A compound according to claim 35 wherein A is sulfur and Ar represents an unsubstituted thienylene radical.
38 . A compound according to claim 35 wherein A is sulfur, Ar is unsubstituted thienylene; and R 1 , R 2 and R 3 are hydrogen.
39 . A compound according to claim 35 wherein A is sulfur, Ar is unsubstituted phenylene; and R 1 , R 2 and R 3 are hydrogen.
40 . A method for inhibiting the growth and proliferation of the cells of microorganisms and higher organisms, which comprises administering to a host in need of such treatment an effective amount of the compound having the structural formula X as defined in claim 35 , or a pharmaceutically acceptable salt thereof.
41 . A method according to claim 40 wherein A is sulfur and Ar represents an unsubstituted phenylene radical.
42 . A method according to claim 40 wherein A is sulfur and Ar represents an unsubstituted thienylene radical.
43 . A method according to claim 40 wherein A is sulfur, Ar is an unsubstituted thienylene radical; and R 1 , R 2 and R 3 are hydrogen.
44 . A method according to claim 40 wherein A is sulfur, Ar is, an unsubstituted phenylene radical; and R 1 , R 2 and R 3 are hydrogen.
45 . An antiproliferative composition comprising the compound having the formula X as defined in claim 35 or a pharamaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
46 . A composition according to claim 45 wherein A is sulfur and Ar represents an unsubstituted phenylene radical.
47 . A composition according to claim 45 wherein A is sulfur and Ar represents an unsubstitued thienylene radical.
48 . A composition according to claim 45 wherein A is sulfur, Ar is an unsubstituted thienylene radical; and R 1 , R 2 and R 3 are hydrogen.
49 . A composition according to claim 45 wherein A is sulfur, Ar is an unsubstituted phenylene; and R 1 , R 2 and R 3 are hydrogen.
50 . A compound having the formula V
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;
R 3 represents H or a straight, branched or cyclic (C 1 to C 6 ) alkyl group, optionally carrying one or more hydroxyl or. amine groups; and
R 4 represents hydroxy, (C 1 to C 6 ) 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.
51 . 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:
wherein:
A represents sulfur or selenium;
Ar represents an unsubstituted phenylene or thienylene radical;
R 1 and R 2 represent, individually, hydrogen or C 1 to C 6 alkyl or other readily lyzable groups;
R 3 represents hydrogen or a straight, branched or cyclic C 1 -C 6 alkyl group, optionally carrying one or more halogen, hydroxyl or amine groups; or
a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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