U.S. patent application number 17/066702 was filed with the patent office on 2022-01-06 for anodic oxidation of 5-aminouracil.
The applicant listed for this patent is MediBeacon Inc.. Invention is credited to Thomas E. Rogers.
Application Number | 20220002254 17/066702 |
Document ID | / |
Family ID | 1000006034660 |
Filed Date | 2022-01-06 |
United States Patent
Application |
20220002254 |
Kind Code |
A9 |
Rogers; Thomas E. |
January 6, 2022 |
ANODIC OXIDATION OF 5-AMINOURACIL
Abstract
A process for preparing
pyrimido[4,5-g]pteridine-2,4,7,9-tetraol, or a salt thereof, is
provided. A process for the preparation of
3,6-diaminopyrazine-2,5-dicarboxylic acid, or a salt thereof, from
pyrimido[4,5-g]pteridine-2,4,7,9-tetraol, or a salt thereof, is
further provided. A process for preparing a substituted pteridine
compound, or a salt thereof, is further provided. A process for the
preparation of a N-substituted 3,6-diaminopyrazine-2,5-dicarboxylic
acid from a substituted pteridine compound, or a salt thereof, is
further provided.
Inventors: |
Rogers; Thomas E.; (Ballwin,
MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MediBeacon Inc. |
St. Louis |
MO |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20210107881 A1 |
April 15, 2021 |
|
|
Family ID: |
1000006034660 |
Appl. No.: |
17/066702 |
Filed: |
October 9, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62913196 |
Oct 10, 2019 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/28
20130101 |
International
Class: |
C07D 241/28 20060101
C07D241/28 |
Claims
1. A process for preparing divalent salts of
pyrimido[4,5-g]pteridine-2,4,7,9-tetraol, Compound 2, the process
comprising step 1a directed to anodic oxidation of
5-aminopyrimidine-2,4(1H,3H)-dione, Compound 1, in the presence of
an aqueous base to form pyrimido[4,5-g]pteridine-2,4,7,9-tetraol,
Compound 2a, followed by step 1b directed to treatment of compound
2a with a base to form Compound 2 as follows: ##STR00021## wherein
A.sup.+ is a monovalent cation.
2. The process of claim 1, wherein the base in step 1b is KOH and
compound 2 is potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) of the
structure: ##STR00022##
3. The process of claim 1, wherein steps 1a and 1b are done in an
electrochemical cell.
4. The process of claim 3, wherein the electrochemical cell
comprises divided cells.
5. The process of claim 3, wherein the electrochemical cell
comprises undivided cells.
6. The process of claim 1, further comprising hydrolyzing Compound
2, in the presence of a base to form
3,6-diaminopyrazine-2,5-dicarboxylic acid, Compound 3, as follows:
##STR00023##
7. The process of claim 6, further comprising reacting
3,6-diaminopyrazine-2,5-dicarboxylic acid with an acid salt of HNR,
Compound 4, to form Compound 5, as follows: ##STR00024## wherein
each NHR is independently (i) a polypeptide chain that includes one
or more natural or unnatural .alpha.-amino acids linked together by
peptide bonds, or (ii) NH(R.sup.1)(R.sup.2) wherein: each R.sup.1
is independently
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.10CONR.-
sup.11(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.20,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH2).sub.cNR.sup.12CSNR.sup.1-
3(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.21,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cCONR.sup.14(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.22,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.15SO.su-
b.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.23,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cSO.sub.2NR.sup-
.16(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.24,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.17CO(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.25,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.18CO.su-
b.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.26, or
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cOC(O)NR.sup.19-
CO.sub.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.27;
--(CH.sub.2).sub.cOR.sup.68, --CH.sub.2(CHOH).sub.cR.sup.69,
--CH.sub.2(CHOH).sub.cCO.sub.2H, --(CHCO.sub.2H).sub.cCO.sub.2H,
--(CH.sub.2).sub.cNR.sup.70R.sup.71,
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCO.sub.2H,
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCH.sub.2OH,
--CH.sub.2(CHNH.sub.2).sub.cCH.sub.2NR.sup.72R.sup.73,
--(CH.sub.2CH.sub.2O).sub.eR.sup.74,
--(CH.sub.2).sub.tCO(CH.sub.2CH.sub.2O).sub.eR.sup.75,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.58C(O)N-
R.sup.59(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.76,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.60C(S)N-
R.sup.61(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.77,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kC(O)NR.sup.62(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.78,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kS(O).sub.2NR.s-
up.63(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.79,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.64S(O).-
sub.2(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.80,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.65C(O)(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.81,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.66C(O)O-
(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.82, or
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kOC(O)NR.sup.67-
(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.83,
--(CH.sub.2).sub.aSO.sub.3H, --(CH.sub.2).sub.aSO.sub.3.sup.-,
--(CH.sub.2).sub.aOSO.sub.3H, --(CH.sub.2).sub.aOSO.sub.3.sup.-,
--(CH.sub.2).sub.aNHSO.sub.3H, --(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-,
--(CH.sub.2).sub.aPO.sub.3.sup.=,
--(CH.sub.2).sub.aOPO.sub.3H.sub.2,
--(CH.sub.2).sub.aOPO.sub.3H.sup.-, or --(CH.sub.2).sub.aOPO.sup.3;
each of R.sup.2, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.58,
R.sup.59, R.sup.60, R.sup.61, R.sup.62, R.sup.63, R.sup.64,
R.sup.65, R.sup.66 and R.sup.67 is independently --H or --CH.sub.3;
each of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.26, and R.sup.27 is independently --H, --CH.sub.3,
--(CH.sub.2).sub.fNR.sup.28C(O)NR.sup.29(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.38,
--(CH.sub.2).sub.fNR.sup.30CSNR.sup.31(CH.sub.2).sub.g(CH.sub.2CH.sub.2O)-
.sub.hR.sup.39,
--(CH.sub.2).sub.fC(O)NR.sup.32(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.40,
--(CH.sub.2).sub.fS(O).sub.2NR.sup.33(CH.sub.2).sub.g(CH.sub.2CH.-
sub.2O).sub.hR.sup.41,
--(CH.sub.2).sub.fNR.sup.34S(O).sub.2(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).-
sub.hR.sup.42,
--(CH.sub.2).sub.fNR.sup.35C(O)(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.43,
--(CH.sub.2).sub.fNR.sup.36C(O)O(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.44,
--(CH.sub.2).sub.fOC(O)NR.sup.37(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.h-
R.sup.45, --CO(AA), or --CONH(PS); each of R.sup.28, R.sup.29,
R.sup.30, R.sup.31, R.sup.32, R.sup.33, R.sup.34, R.sup.35,
R.sup.36, R.sup.37, R.sup.38, R.sup.39, R.sup.40, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 is independently --H or --CH.sub.3; each of R.sup.68,
R.sup.69, R.sup.70, R.sup.71, R.sup.72, R.sup.73, R.sup.74,
R.sup.75, R.sup.76, R.sup.77, R.sup.78, R.sup.79, and R.sup.80 is
independently --H, --CH.sub.3,
--(CH.sub.2).sub.pS(O).sub.2NR.sup.84(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.81,
--(CH.sub.2).sub.pNR.sup.85S(O).sub.2(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.83,
--(CH.sub.2).sub.pNR.sup.86C(O)(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.sR-
.sup.85,
--(CH.sub.2).sub.pNR.sup.86C(O)O(CH.sub.2).sub.q(CH.sub.2CH.sub.2-
O).sub.sR.sup.87, or
--(CH.sub.2).sub.pOC(O)NR.sup.88(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.s-
R.sup.89; each of R.sup.81, R.sup.82, R.sup.83, R.sup.84, R.sup.85,
R.sup.86, R.sup.87, R.sup.88, and R.sup.89 is independently --H or
--CH.sub.3; each (AA) is independently a polypeptide chain that
includes one or more natural or unnatural .alpha.-amino acids
linked together by peptide bonds; each (PS) is independently a
sulfated or non-sulfated polysaccharide chain comprising one or
more monosaccharide units connected by glycosidic linkages; each of
t and u is independently 1, 2, 3, 4, or 5; each of a, d, g, l, and
q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each of c,
f, k, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and each of b, j, e, h, o, and s is independently 0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99 or 100, wherein each NHR moiety
optionally comprises a protecting group.
8. The process of claim 7, wherein NHR is D-serine comprising a
benzyl protecting group.
9. The process of claim 7, wherein each HNR moiety comprises a
protecting group, PG, and wherein said protecting group is cleaved
to form compound 6 as follows: ##STR00025##
10. The process of claim 9, wherein NR is D-serine and compound 6
is
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid) of the following structure: ##STR00026##
11. A process for preparing a substituted pteridine compound, the
process comprising step 1a directed to anodic oxidation of compound
7, or a salt thereof, in the presence of a base and a solvent to
form compound 8, or a salt thereof, as follows: ##STR00027##
wherein R.sup.i and R.sup.ii are independently selected from:
hydrogen, where only one of R.sup.i and R.sup.ii may be hydrogen;
optionally substituted alkyl; optionally substituted ester;
optionally substituted cycloalkyl or optionally substituted
heterocycloalkyl; optionally substituted aryl or optionally
substituted heteroaryl; optionally substituted alkoxy; optionally
substituted --C(O)-alkyl; optionally substituted amino; optionally
substituted polyol ethers and optionally substituted polyethers; a
polypeptide chain (AA); and polysaccharide chain (PS).
12. The process of claim 11, further comprising step 1b directed to
contacting compound 8, or a salt thereof, with a base in the
presence of a solvent to form pyrazine compound 9, or a salt
thereof, as follows ##STR00028##
13. The process of claim 12, further comprising contacting compound
9, or a salt thereof, with a base in the presence of a solvent to
form pyrazine compound 10, or a salt thereof, as follows
##STR00029##
14. The process of claim 13, further comprising reacting compound
10, or a salt thereof, with NHR acid salt compound 4 in a solvent
to form compound 11, or a salt thereof, as follows: ##STR00030##
wherein each NHR is independently (i) a polypeptide chain that
includes one or more natural or unnatural .alpha.-amino acids
linked together by peptide bonds, or (ii) NH(R.sup.1)(R.sup.2)
wherein: each R.sup.1 is independently
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.10CONR.-
sup.11(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.20,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.12CSNR.-
sup.13(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.21,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cCONR.sup.14(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.22,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.15SO.su-
b.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.23,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cSO.sub.2NR.sup-
.16(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.24,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.17CO(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.25,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.18CO.su-
b.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.26, or
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cOC(O)NR.sup.19-
CO.sub.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.27;
--(CH.sub.2).sub.cOR.sup.68, --CH.sub.2(CHOH).sub.cR.sup.69,
--CH.sub.2(CHOH).sub.cCO.sub.2H, --(CHCO.sub.2H).sub.eCO.sub.2H,
--(CH.sub.2).sub.cNR.sup.70R.sup.71,
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCO.sub.2H,
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCH.sub.2OH,
--CH.sub.2(CHNH.sub.2).sub.cCH.sub.2NR.sup.72R.sup.73,
--(CH.sub.2CH.sub.2O).sub.eR.sup.74,
--(CH.sub.2).sub.tCO(CH.sub.2CH.sub.2O).sub.eR.sup.75,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.58C(O)N-
R.sup.59(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.76,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.60C(S)N-
R.sup.61(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.77,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kC(O)NR.sup.62(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.78,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kS(O).sub.2NR.s-
up.63(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.79,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.64S(O).-
sub.2(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.80,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.65C(O)(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.81,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.66C(O)O-
(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.82, or
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kOC(O)NR.sup.67-
(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.83,
--(CH.sub.2).sub.aSO.sub.3H, --(CH.sub.2).sub.aSO.sub.3.sup.-,
--(CH.sub.2).sub.aOSO.sub.3H, --(CH.sub.2).sub.aOSO.sub.3.sup.-,
--(CH.sub.2).sub.aNHSO.sub.3H, --(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-,
--(CH.sub.2).sub.aPO.sub.3.sup.=,
--(CH.sub.2).sub.aOPO.sub.3H.sub.2,
--(CH.sub.2).sub.aOPO.sub.3H.sup.-, or --(CH.sub.2).sub.aOPO.sup.3;
each of R.sup.2, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.58,
R.sup.59, R.sup.60, R.sup.61, R.sup.62, R.sup.63, R.sup.64,
R.sup.65, R.sup.66 and R.sup.67 is independently --H or --CH.sub.3;
each of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.26, and R.sup.27 is independently --H, --CH.sub.3,
--(CH.sub.2).sub.fNR.sup.28C(O)NR.sup.29(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.38,
--(CH.sub.2).sub.fNR.sup.30CSNR.sup.31(CH.sub.2).sub.g(CH.sub.2CH.sub.2O)-
.sub.hR.sup.39,
--(CH.sub.2).sub.fC(O)NR.sup.32(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.40,
--(CH.sub.2).sub.fS(O).sub.2NR.sup.33(CH.sub.2).sub.g(CH.sub.2CH.-
sub.2O).sub.hR.sup.41,
--(CH.sub.2).sub.fNR.sup.34S(O).sub.2(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).-
sub.hR.sup.42,
--(CH.sub.2).sub.fNR.sup.35C(O)(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.43,
--(CH.sub.2).sub.fNR.sup.36C(O)O(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.44,
--(CH.sub.2).sub.fOC(O)NR.sup.37(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.h-
R.sup.45, --CO(AA), or --CONH(PS); each of R.sup.28, R.sup.29,
R.sup.30, R.sup.31, R.sup.32, R.sup.33, R.sup.34, R.sup.35,
R.sup.36, R.sup.37, R.sup.38, R.sup.39, R.sup.40, R.sup.41,
R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 is independently --H or --CH.sub.3; each of R.sup.68,
R.sup.69, R.sup.70, R.sup.71, R.sup.72, R.sup.73, R.sup.74,
R.sup.75, R.sup.76, R.sup.77, R.sup.78, R.sup.79, and R.sup.80 is
independently --H, --CH.sub.3,
--(CH.sub.2).sub.pS(O).sub.2NR.sup.84(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.81,
--(CH.sub.2).sub.pNR.sup.85S(O).sub.2(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.83,
--(CH.sub.2).sub.pNR.sup.86C(O)(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.sR-
.sup.85,
--(CH.sub.2).sub.pNR.sup.86C(O)O(CH.sub.2).sub.q(CH.sub.2CH.sub.2-
O).sub.sR.sup.87, or
--(CH.sub.2).sub.pOC(O)NR.sup.88(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.s-
R.sup.89; each of R.sup.81, R.sup.82, R.sup.83, R.sup.84, R.sup.85,
R.sup.86, R.sup.87, R.sup.88, and R.sup.89 is independently --H or
--CH.sub.3; each (AA) is independently a polypeptide chain that
includes one or more natural or unnatural .alpha.-amino acids
linked together by peptide bonds; each (PS) is independently a
sulfated or non-sulfated polysaccharide chain comprising one or
more monosaccharide units connected by glycosidic linkages; each of
t and u is independently 1, 2, 3, 4, or 5; each of a, d, g, l, and
q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each of c,
f, k, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and each of b, j, e, h, o, and s is independently 0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99 or 100, wherein each NHR moiety
optionally comprises a protecting group.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application No. 62/913,196 filed Oct. 10, 2019, the contents of
which are incorporated in their entirety.
BACKGROUND OF THE DISCLOSURE
[0002] The field of the disclosure relates generally to anodic
oxidation chemistry.
[0003] More particularly, the disclosure relates to the anodic
oxidation of 5-aminouracil to form potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) that may then
be hydrolyzed to form 3,6-diaminopyrazine-2,5-dicarboxylic acid.
3,6-diaminopyrazine-2,5-dicarboxylic acid is an intermediate used
in the preparation of higher value products, such as imaging
agents.
[0004] Methods for the preparation of potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) and
3,6-diaminopyrazine-2,5-dicarboxylic are known in the art.
Problematically, the prior art methods use toxic and
environmentally hazardous materials.
[0005] A need therefore exists for new processes for preparing
potassium 4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) and
3,6-diaminopyrazine-2,5-dicarboxylic that reduce environmental
burden and reduce industrial hygiene issues.
BRIEF DESCRIPTION
[0006] In some aspects of the disclosure, a process for preparing
divalent salts of pyrimido[4,5-g]pteridine-2,4,7,9-tetraol
(Compound 2a) is provided. The process comprises step 1a directed
to anodic oxidation of 5-aminopyrimidine-2,4(1H,3H)-dione (Compound
1), in the presence of an aqueous base to form
pyrimido[4,5-g]pteridine-2,4,7,9-tetraol (Compound 2a) followed by
step 1b directed to treatment of Compound 2a with a base to form
Compound 2 as follows:
##STR00001##
where A+ is a monovalent cation.
[0007] In some aspects of the disclosure, a process for preparing a
substituted pteridine compound, or a salt thereof, is provided. The
process comprises step 1a directed to anodic oxidation of compound
7 in the presence of a base and a solvent to form compound 8 as
follows;
##STR00002##
R.sup.i and R.sup.ii are independently selected from: optionally
substituted alkyl; optionally substituted cycloalkyl; optionally
substituted aryl; optionally substituted alkoxy; optionally
substituted --C(O)-alkyl; optionally substituted amino; optionally
substituted polyol ethers and optionally substituted polyethers; a
polypeptide chain (AA); and polysaccharide chain (PS).
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 depicts a process for preparing
3,6-diaminopyrazine-2,5-dicarboxylic acid according to the present
disclosure. FIG. 1 further depicts a process of the present
disclosure for preparing
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid) from 3,6-diaminopyrazine-2,5-dicarboxylic
acid.
[0009] FIG. 2 depicts a first prior art process for preparing
3,6-diaminopyrazine-2,5-dicarboxylic acid. FIG. 2 further depicts a
prior art process for preparing
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid) from 3,6-diaminopyrazine-2,5-dicarboxylic
acid.
[0010] FIG. 3 depicts a second prior art process for preparing
3,6-diaminopyrazine-2,5-dicarboxylic acid.
[0011] FIG. 4 depicts a proposed process for preparing a
substituted pyrazine-2,5-dicarboxylic acid.
[0012] FIG. 5 depicts a proposed process for preparing a
substituted pyrazine-2,5-dicarboxylic acid.
[0013] FIG. 6 depicts a proposed process for preparing a
substituted pyrazine-2,5-dicarboxylic acid.
DETAILED DESCRIPTION
[0014] The present disclosure is generally directed an improved
process for the preparation of salts of
pyrimido[4,5-g]pteridine-2,4,7,9-tetraol (Compound 2) by anodic
oxidation of 5-aminouracil (5-aminopyrimidine-2,4(1H,3H)-dione)
(Compound 1). In some aspects, Compound 2 may be converted by basic
hydrolysis to form 3,6-diaminopyrazine-2,5-dicarboxylic acid
(Compound 3), that is useful as an intermediate for the preparation
of higher values products. In some such aspects, Compound 3 is used
as an intermediate in the preparation of medical imaging agents.
One such imaging agent is 3,6-diaminopyrazine-2,5-dicarboxylic acid
that is useful as a fluorescent dye, for instance and without
limitation, for evaluating renal function and for imaging
vasculature, such as eye vasculature. A process of the present
disclosure for preparing Compound 3 is depicted in FIG. 1 as steps
1 and 2. One particular aspect of the present disclosure directed
to a process for preparing
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid) (Compound 6), from Compound 3 is depicted in
FIG. 1 as steps 3 and 4.
[0015] One prior art process for preparing
3,6-diaminopyrazine-2,5-dicarboxylic acid is depicted in FIG. 2 as
steps 1 and 2. In step 1, 3,6-diamino-2,5-pyrazinedicarbonitrile
(Compound 7) is contacted with sulfuric acid to form
3,6-diaminopyrazine-2,5-dicarboxamide (Compound 8).
Problematically, this prior art process starts with Compound 7 that
is typically prepared by a complex process and environmentally
dangerous process, such as taught in U.S. Pat. No. 5,294,711. US
'711 teaches that diphenyldisulfide is reacted with hydrogen
cyanide in an organic solvent (e.g., di-methoxyethane,
acetonitrile, xylene, chloroform, methanol or benzene) to form
2,3-diamino-3-(phenylthio)acrylonitrile ("DAAN"), where DAAN is
thereafter converted to Compound 7 by contact with citric acid. In
FIG. 2, step 2, Compound 8 is contacted with KOH to form
3,6-diaminopyrazine-2,5-dicarboxylic acid (Compound 3). FIG. 2
further depicts a prior art process for preparing dibenzyl
2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-h-
ydroxypropanoate) (Compound 5) by contacting Compound 3 with benzyl
D-serinate hydrochloride (Compound 4) in dimethylformamide ("DMF")
solvent in the presence of hydroxybenzotriazole ("HOBt", a
racemization inhibitor),
1-ethyl-3-(3-imethylaminopropyl)carbodiimide ("EDC", a carboxyl
activating agent), and N,N-diisopropylethylamine ("i-PrNEt", a
base). FIG. 2 further depicts a prior art process for preparing
Compound 6 by contacting Compound 5 with a palladium catalyst in an
ethanol/water solvent.
[0016] Another prior art process for preparing
3,6-diaminopyrazine-2,5-dicarboxylic acid is depicted in FIG. 3 as
Steps 1 and 2. In Step 1, Compound 1 is contacted with potassium
ferrocyanide (K.sub.3Fe(CN).sub.6) in aqueous KOH to form potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) (Compound 9).
In Step 2, Compound 9 is converted by basic hydrolysis to Compound
3. Problematically, potassium ferrocyanide is an irritant to
personnel, can release toxic hydrogen cyanide upon contact with
acid, and is classified as an environmental hazard due to harmful
effects on aquatic life. The prior art process of FIG. 3 is taught,
for instance, by Oskar Baudisch, et al., The Oxidation of
5-Aminouracil, J. Biol. Chem., 71:497-499 (1927), by E. C. Taylor,
et al., Pyrimidopteridines by Oxidative Self-condensation of
Aminopyrindines, J. Am. Chem. Soc., 77, (8), 2243-2247 (1955), and
by D. Kaminsky, et al., Some Congeners and Analogs of Dipyridamole,
J. Med. Chem., 9, 610 (1966).
[0017] The Applicant has discovered an anodic oxidation process for
preparing pyrimido[4,5-g]pteridine-2,4,7,9-tetraol (Compound 2a),
and salts thereof, that is environmentally benign and avoids the
use of toxic and hazardous reactants. The reaction is depicted as
steps 1a and 1b in FIG. 1 and is generally directed to anodic
oxidation of Compound 1 in the presence of an aqueous base to form
Compound 2a followed by formation of Compound 2 by further
treatment with as base as follows:
##STR00003##
where A.sup.+ is H.sup.+ or a monovalent cation. The yield of
compound 2 based on compound 1 is at least 20%, at least 30%, or at
least 40%, such as for instance 20%, 25%, 30%, 35% or 40%.
[0018] Under one theory, and without being bound to any particular
theory, it is believed that the step 1 reaction mechanism is as
follows, where the base KOH is illustrated:
##STR00004##
The number of A.sup.+ cations (e.g., K.sup.+) relates to the
stoichiometry of base to the free acid. The salt form may be mono,
di, tri, or tetra.
[0019] Bases within the scope of the present disclosure comprise a
cation and an anion and include inorganic and organic bases.
Inorganic bases include sodium, potassium, ammonium, calcium,
magnesium, iron, zinc, copper, manganese, and aluminum salts.
Non-limiting examples include phosphates such as dipotassium
monohydrogen phosphate, potassium dihydrogen phosphate,
tripotassium phosphate, disodium monohydrogen phosphate, sodium
dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen
phosphate, ammonium dihydrogen phosphate and triammonium phosphate;
acetates such as potassium acetate, sodium acetate and ammonium
acetate; formates such as potassium formate and sodium formate;
carbonates such as potassium carbonate, sodium carbonate, potassium
hydrogen carbonate and sodium hydrogen carbonate; and alkali metal
hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, rubidium hydroxide caesium hydroxide magnesium
hydroxide, calcium hydroxide, manganese (II) hydroxide, iron
hydroxide, cobalt hydroxide, nickel (II) hydroxide, copper (II)
hydroxide, zinc hydroxide, and cadmium hydroxide. Organic bases are
of the general formulae R-amine (e.g., R.sub.4N+OH.sup.-) and
OR.sup.- where R is an organic moiety such as alkyl, aryl, etc.
Examples of organic bases include primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, and cyclic amines such as pyridine,
isopropylamine, trimethylamine, diethylamine, triethylamine,
triethanolamine, diisopropylamine, ethanolamine,
2-diethylaminoethanol, trimethylamine, di cyclohexylamine,
ethylenediamine, purines, piperazine, piperidine,
N-ethylpiperidine, and alkali metal alkoxides (e.g., sodium
methoxide). In some aspects, the base is a strong base, such as
alkali metal hydroxide base. Non-limiting examples of suitable
bases include sodium hydroxide and potassium hydroxide.
[0020] In some aspects, the solvent is a polar solvent. In some
aspects, the solvent is a polar protic solvent. Non-limiting
examples of suitable polar protic solvents include water, methanol,
ethanol, n-propanol, i-propanol, n-butanol, acetic acid, and
combinations thereof. In some aspects, the solvent is water. In
some aspects, the solvent is a polar solvent. In some aspects, the
solvent is a polar protic solvent. Non-limiting examples of
suitable polar protic solvents include water, methanol, ethanol,
n-propanol, i-propanol, n-butanol, acetic acid, and combinations
thereof. In some aspects, the solvent is water. In some aspects,
compound 2 is the potassium salt of Compound 2a as follows:
##STR00005##
potassium 4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate).
[0021] Electrochemical cells known in the art are generally
suitable for practicing the present disclosure, and may include
divided or undivided cells. For instance, and without limitation,
the electrochemical cell may be a divided flow cell. Divided flow
cells generally comprise two parallel rectangular electrode plates
separated by a membrane placed generally equidistantly from each
electrode. The electrode package is typically housed in a
chemically stable, non-conductor, (e.g. polypropylene) constructed
to both house the electrodes and separating membrane thereby
allowing for separate generally uniform solvent flow over both
electrodes. Solvent flow may be produced a recirculating pumping
system where anolyte and catholyte are circulated through their
respective compartments. Heat exchangers may be optionally
incorporated to keep the reaction temperature within certain set
boundaries.
[0022] In other configurations an undivided cell may be employed
where the membrane or porous barrier is removed and electrolytic
solution allowed to freely pass between both electrodes.
[0023] In some aspects, an indirect electrochemical system could be
used. For instance, and without limitation, a complex of iron(II)
could be anodically transformed into iron (III) at high current
efficiency and extent (>90%). The anodic solution containing
Fe(III) could react with Compound 1 to produce Compound 2, or a
salt thereof.
[0024] In another aspect, an electrochemical catalytic system may
be employed where, for instance, and without limitation, a complex
of iron(II) could be anodically transformed into iron(III) in the
presence of Compound 2 to produce Compound 2, or a salt thereof,
regenerating Fe(II) that would be available to be re-oxidized at
the anode to produce more Fe(III). Thus, the reaction would be
catalytic in Fe(II).
[0025] In some aspects, Compound 2, may by hydrolyzed in an aqueous
base to form Compound 3 as depicted in step 2 of FIG. 1. The
reaction scheme is as follows, where A.sup.+ is H.sup.+ or a
monovalent cation:
##STR00006##
[0026] In some such aspects Compound 2 is potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate). In some
aspects, the base is a strong base, such as NaOH or KOH. The
hydrolysis step produces Compound 3 in aqueous solution as a salt
of the base cation. In some further aspects, after the hydrolysis
step, an acid is added to the solution to precipitate Compound 3
(di-acid) from aqueous solution and form a slurry. In some aspects,
the acid is a strong acid, such as for example and without
limitation, HCl. Solid Compound 3 may be isolated from the slurry
by methods known in the art, such as filtration or centrifugation.
Isolated Compound 3 may be optionally further purified by washing
and optionally dried.
[0027] In some aspects, Compound 3 may be reacted with NHR, acid
salt (Compound 4) in a solvent to form the corresponding amide,
Compound 5, as depicted in step 3 of FIG. 1. The reaction scheme is
as follows:
##STR00007##
[0028] General methods of forming amides by coupling a compound
having an amine substituent (e.g., compound 4) and a compound
having a carboxyl substituent (e.g., compound 3) are known to those
skilled in the art. In particular, US 2018/0010881 (incorporated by
reference herein in its entirety) discloses forming compound the
compound
3,6-diamino-N.sup.2,N.sup.5-bis(D-serine)-pyrazine-2,5-dicarboxamide
as follows. In step 1,
3,6-diamino-N.sup.2,N.sup.5-bis(O-benzyl-(D)-serine methyl
ester)-pyrazine-2,5-dicarboxamide was formed as follows. A mixture
of sodium 3,6-diaminopyrazine-2,5-dicarboxylate (300 mg, 1.24
mmol), (D)-Ser(OBn)-OMe-HCl salt (647 mg, 2.64 mmol), HOBt-H2O (570
mg, 3.72 mmol) and EDC-HCl (690 mg, 3.60 mmol) in DMF (25 mL) was
treated with TEA (2 mL). The resulting mixture was stirred for 16 h
and concentrated. The mixture was concentrated to dryness and the
residue was partitioned with EtOAc and water. The layers were
separated and the EtOAc solution was washed with saturated
NaHCO.sub.3 and brine. The solution was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated, which afforded 370 mg
(51% yield) of the bisamide as a bright yellow powder: .sup.1NMR
(300 MHz, CDCl3) .delta. 8.47 (d, J=8.74 Hz, 2H), 7.25-7.37
(complex m, 10H), 5.98 (bs, 4H), 4.85 (dt, J=8.7, 3.3 Hz, 2H), 4.56
(ABq, J=12.6, Hz, Av=11.9 Hz, 4H), 3.99 (one half of an ABq of d,
J=8.7, 3.3, Av obscured, 2H), 3.76-3.80 (one half of an
ABq-obscured, 2H), 3.78 (s, 6H). .sup.13C NMR (75 MHz, CDCl3)
.delta. 170.5 (s), 165.1 (s), 146.8 (s), 138.7 (s) 128.6 (d), 128.1
(d), 127.8 (d), 126.9 (s), 73.5 (t), 69.8 (t), 53.0 (q), 52.9 (q).
LCMS (5-95% gradient acetonitrile with 0.1% TFA over 10 min),
single peak retention time=4.93 min on 30 mm column,
(M+H).sup.+=581. In step 2,
3,6-diamino-N.sup.2,N.sup.5-bis(O-benzyl-(D)-serine)-pyrazine-2,5-
-dicarboxamide was formed as follows. The product from Step 1 (370
mg, 0.64 mmol) in THF (10 mL) was treated with 1.0 N sodium
hydroxide (2.5 mL). After stirring at room temperature for 30 min,
the reaction was judged complete by TLC. The pH was adjusted to
approximately 2 by the addition of 1.0 N HCl and the resulting
solution was extracted (3.times.) with EtOAc. The layers were
combined, dried over sodium sulfate, filtered and concentrated to
afford 353 mg (100% yield) of the di-acid as an orange foam: LCMS
(5-95% gradient acetonitrile in 0.1% TFA over 10 min), retention
time=4.41 min on 30 mm column, (M+H).sup.+=553. In step 3,
3,6-diamino-N.sup.2,N.sup.5-bis(D-serine)-pyrazine-2,5-dicarboxamide
was formed as follows. To the product from Step 2 (353 mg, 0.64
mmol) in methanol (20 mL) was added 5% Pd/C (300 mg) and ammonium
formate (600 mg). The resulting reaction was heated at reflux for 2
h. The reaction was cooled to room temperature, filtered through a
plug of celite and concentrated. The residue was recrystallized
from methanol-ether to provide 191 mg (80% yield) of title compound
Example 2 as a yellow foam: .sup.1NMR (300 MHz, DMSO-d6) .delta.
8.48 (d, J=6.9 Hz, 2H), 6.72 (bs, 4H), 3.95 (apparent quartet,
J=5.1 Hz, 2H), 3.60 (apparent ABq of doublets; down-field group
centered at 3.71, J=9.9, 5.1 Hz, 2H; up-field group centered at
3.48, J=20 9.9, 6.3 Hz, 2H). .sup.13C NMR (75 MHz, CDCl3) .delta.
172.9 (s), 164.9 (s), 147.0 (s), 127.0 (s), 62.9 (d), 55.7 (t).
LCMS (5-95% gradient acetonitrile in 0.1% TFA over 10 min), single
peak retention time=1.45 min on 30 mm column, (M+H).sup.+=373.
UV/vis (100 .mu.M in PBS) .lamda.abs=434 nm. Fluorescence
.lamda.ex=449 nm, .lamda.em=559 nm.
[0029] Those skilled in the art would recognize that
3,6-diaminopyrazine-2,5-dicarboxylate could be reacted with amines
other than (D)-Ser(OBn)-OMe-HCl salt to form an amide of the
structure of compound 6. For instance, US 2018/0010881 further
provides examples for formation of amides where the
(D)-Ser(OBn)-OMe-HCl salt amine is replaced with
(L)-Ser(OBn)-OMe-HCl, is replaced with bis-2-(methoxyethyl) amine,
is replaced with racemic
(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine, is replaced with
tert-butyl 2-aminoethylcarbamate, is replaced with
Asp(OBn)-OMe-p-TosH salt, is replaced with
2-OBn-.beta.-serine-OMe-HCl salt, is replaced with m-dPEG24-amine,
is replaced with benzyl 3-aminopropanoate p-toluene sulfonate, is
replaced with ethyl 4-amino-butyrate HCl salt, is replaced with
3-amino-5-oxo-furane HCl salt, is replaced with
3-dimethyl-beta-alanine ethyl ester HCl salt, is replaced with
ethyl 3-(3-pyridyl)-propanoate HCl salt, and is replaced with
methyl-2-O-benzyl-3-amino-propionate HCl salt.
[0030] In some aspects, the solvent is a polar solvent. In some
aspects, the solvent is a polar aprotic solvent. Non-limiting
examples of suitable solvents include tetrahydrofuran, DMF, ethyl
acetate, and acetonitrile, and combinations thereof. In some
aspects, the solvent is DMF.
[0031] The step 3 reaction mixture may further comprise a
racemization inhibitor, for instance and without limitation, HOBt,
7-aza-1-hydroxybenzotriazole, ethyl
2-cyano-2-(hydroxyimino)acetate, N-hydroxysuccinimide, or
hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine. The step 3 reaction
mixture may further comprise a coupling agent (such as a carboxyl
group activator), for instance and without limitation, EDC or
N,N'-dicyclohexylcarbodimide. The step 3 reaction mixture may
further comprise a base, for instance and without limitation, an
organic amine base such as i-PrNEt or N-methylmorpholine.
[0032] In some aspects NHR, acid salt, is a polypeptide chain that
includes one or more natural or unnatural .alpha.-amino acids
linked together by peptide bonds. The polypeptide chain (AA) may be
a homopolypeptide chain or a heteropolypeptide chain, and may be
any appropriate length. For instance, in some embodiments, the
polypeptide chain may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,
63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,
80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,
97, 98, 99 or 100 .alpha.-amino acid(s), 1 to 90 .alpha.-amino
acid(s), 1 to 80 .alpha.-amino acid(s), 1 to 70 .alpha.-amino
acid(s), 1 to 60 .alpha.-amino acid(s), 1 to 50 .alpha.-amino
acid(s), 1 to 40 .alpha.-amino acid(s), 1 to 30 .alpha.-amino
acid(s), 1 to 20 .alpha.-amino acid(s), or even 1 to 10
.alpha.-amino acid(s). In some embodiments, the .alpha.-amino acids
of the polypeptide chain (AA) are selected from aspartic acid,
asparigine, arginine, histidine, lysine, glutamic acid, glutamine,
serine, and homoserine. In some embodiments, the .alpha.-amino
acids of the polypeptide chain (AA) are selected from aspartic
acid, glutamic acid, serine, and homoserine. In some embodiments,
the polypeptide chain (AA) refers to a single amino acid (e.g.,
aspartic acid or serine). In some embodiments the amino acid is
D-serine.
[0033] In some aspects, NHR, acid salt, is NHR.sup.1R.sup.2.
[0034] In such aspects, each R.sup.1 is independently
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.10CONR.-
sup.11(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.20,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.12CSNR.-
sup.13(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.21,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cCONR.sup.14(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.22,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.15SO.su-
b.2 (CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.23,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cSO.sub.2NR.sup-
.16(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.24,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.17CO(CH-
.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.25,
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cNR.sup.18CO.su-
b.2(CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.26, or
--(CH.sub.2).sub.a(CH.sub.2CH.sub.2O).sub.b(CH.sub.2).sub.cOC(O)NR.sup.19-
CO.sub.2 (CH.sub.2).sub.d(CH.sub.2CH.sub.2O).sub.eR.sup.27;
--(CH.sub.2).sub.eOR.sup.68, --CH.sub.2(CHOH).sub.cR.sup.69,
--CH.sub.2(CHOH).sub.cCO.sub.2H, --(CHCO.sub.2H).sub.cCO.sub.2H,
--(CH.sub.2).sub.cNR.sup.70R.sup.71;
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCO.sub.2H,
--CH[(CH.sub.2).sub.fNH.sub.2].sub.cCH.sub.2OH,
--CH.sub.2(CHNH.sub.2).sub.cCH.sub.2NR.sup.72R.sup.73,
--(CH.sub.2CH.sub.2O).sub.eR.sup.74,
--(CH.sub.2).sub.tCO(CH.sub.2CH.sub.2O).sub.eR.sup.75,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.58C(O)N-
R.sup.59(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.76,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j
(CH.sub.2).sub.lNR.sup.60C(S)NR.sup.61(CH.sub.2).sub.l(CH.sub.2CH.sub.2O)-
.sub.oR.sup.77,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kC(O)NR.sup.62(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.78,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kS(O).sub.2NR.s-
up.63(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.79,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.lNR.sup.64S(O).-
sub.2(CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.80,
--(CH.sub.2).sub.u(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.lNR.sup.65C(O)(-
CH.sub.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.81,
--(CH.sub.2)(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kNR.sup.66C(O)O(CH.su-
b.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.82, or
--(CH.sub.2)(CH.sub.2CH.sub.2O).sub.j(CH.sub.2).sub.kOC(O)NR.sup.67(CH.su-
b.2).sub.l(CH.sub.2CH.sub.2O).sub.oR.sup.83,
--(CH.sub.2).sub.aSO.sub.3H, --(CH.sub.2).sub.aSO.sub.3.sup.-,
--(CH.sub.2).sub.aOSO.sub.3H, --(CH.sub.2).sub.aOSO.sub.3.sup.-,
--(CH.sub.2).sub.aNHSO.sub.3H, --(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-,
--(CH.sub.2).sub.aPO.sub.3.sup.=,
--(CH.sub.2).sub.aOPO.sub.3H.sub.2,
--(CH.sub.2).sub.aOPO.sub.3H.sup.-, or
--(CH.sub.2).sub.aOPO.sup.3.
[0035] Each of R.sup.2, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.58, R.sup.59, R.sup.60, R.sup.61, R.sup.62, R.sup.63,
R.sup.64, R.sup.65, R.sup.66 and R.sup.67 is independently --H or
--CH.sub.3.
[0036] Each of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, and R.sup.27 is independently --H, --CH.sub.3,
--(CH.sub.2).sub.fNR.sup.28C(O)NR.sup.29(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.38,
--(CH.sub.2).sub.fNR.sup.30CSNR.sup.31(CH.sub.2).sub.g(CH.sub.2CH.sub.2O)-
.sub.hR.sup.39,
--(CH.sub.2).sub.fC(O)NR.sup.32(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.40,
--(CH.sub.2).sub.fS(O).sub.2NR.sup.33(CH.sub.2).sub.g(CH.sub.2CH.-
sub.2O).sub.hR.sup.41,
--(CH.sub.2).sub.fNR.sup.34S(O).sub.2(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).-
sub.hR.sup.42,
--(CH.sub.2).sub.fNR.sup.35C(O)(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.hR-
.sup.43,
--(CH.sub.2).sub.fNR.sup.36C(O)O(CH.sub.2).sub.g(CH.sub.2CH.sub.2-
O).sub.hR.sup.44,
--(CH.sub.2).sub.fOC(O)NR.sup.37(CH.sub.2).sub.g(CH.sub.2CH.sub.2O).sub.h-
R.sup.45, --CO(AA), or --CONH(PS).
[0037] Each of R.sup.28, R.sup.29, R.sup.30, R.sup.31, R.sup.32,
R.sup.33, R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38,
R.sup.39, R.sup.40, R.sup.41, R.sup.42, R.sup.43, R.sup.44,
R.sup.45, R.sup.46, R.sup.47 and R.sup.48 is independently --H or
--CH.sub.3.
[0038] Each of R.sup.68, R.sup.69, R.sup.70, R.sup.71, R.sup.72,
R.sup.73, R.sup.74, R.sup.75, R.sup.76, R.sup.77, R.sup.78,
R.sup.79, and R.sup.80 is independently --H, --CH.sub.3,
--(CH.sub.2).sub.pS(O).sub.2NR.sup.84(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.81,
--(CH.sub.2).sub.pNR.sup.85S(O).sub.2(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).-
sub.sR.sup.83,
--(CH.sub.2).sub.pNR.sup.86C(O)(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.sR-
.sup.85,
--(CH.sub.2).sub.pNR.sup.86C(O)O(CH.sub.2).sub.q(CH.sub.2CH.sub.2-
O).sub.sR.sup.87, or
--(CH.sub.2).sub.pOC(O)NR.sup.88(CH.sub.2).sub.q(CH.sub.2CH.sub.2O).sub.s-
R.sup.89.
[0039] Each of R.sup.81, R.sup.82, R.sup.83, R.sup.84, R.sup.85,
R.sup.86, R.sup.87, R.sup.88, and R.sup.89 is independently --H or
--CH.sub.3.
[0040] AA is as defined above.
[0041] Each (PS) is independently a sulfated or non-sulfated
polysaccharide chain comprising one or more monosaccharide units
connected by glycosidic linkages. The polysaccharide chain (PS) may
be any appropriate length. For instance, in some embodiments, the
polysaccharide chain may include 1 to 100 monosaccharide unit(s), 1
to 90 monosaccharide unit(s), 1 to 80 monosaccharide unit(s), 1 to
70 monosaccharide unit(s), 1 to 60 monosaccharide unit(s), 1 to 50
monosaccharide unit(s), 1 to 40 monosaccharide unit(s), 1 to 30
monosaccharide unit(s), 1 to 20 monosaccharide unit(s), or even 1
to 10 monosaccharide unit(s). In some embodiments, the
polysaccharide chain (PS) is a homopolysaccharide chain consisting
of either pentose or hexose monosaccharide units. In other
embodiments, the polysaccharide chain (PS) is a
heteropolysaccharide chain consisting of one or both pentose and
hexose monosaccharide units. In some embodiments, the
monosaccharide units of the polysaccharide chain (PS) are selected
from the group consisting of glucose, fructose, mannose, xylose and
ribose. In some embodiments, the polysaccharide chain (PS) refers
to a single monosaccharide unit (e.g., either glucose or
fructose).
[0042] Each of t and u is independently 1, 2, 3, 4, or 5.
[0043] Each of a, d, g, l, and q is independently 0, 1, 2, 3, 4, 5,
6, 7, 8, 9 or 10.
[0044] Each of c, f, k, and p is independently 0, 1, 2, 3, 4, 5, 6,
7, 8, 9 or 10.
[0045] Each of b, j, e, h, o, and s is independently 0, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,
57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,
74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99 or 100.
[0046] Each NHR moiety may optionally comprise a protecting group.
In some such aspects, NHR is a polypeptide chain that includes one
or more natural or unnatural .alpha.-amino acids linked together by
peptide bonds having a protecting group. In such aspects, the
protecting group may suitably be, without limitation, benzyl
("Bn"), t-butyl, methyl, or p-methoxybenzyl.
[0047] In some aspects, each NHR is a protected single amino acid.
In some such aspects, the amino acid is aspartic acid, asparigine,
arginine, histidine, lysine, glutamic acid, glutamine, serine, or
homoserine. In some such aspects, the amino acid is aspartic acid
or serine. In some embodiments the amino acid is D-serine having a
Bn protecting group.
[0048] In some aspects, compound 5 is dibenzyl
2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-h-
ydroxypropanoate) of the following structure:
##STR00008##
[0049] In protecting group aspects of the present disclosure, the
protecting group may be cleaved from compound 5 to form compound 6
as depicted as step 4 in FIG. 1 as follows:
##STR00009##
[0050] In some aspects, compound 6 is compound 6a,
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid), of the following structure:
##STR00010##
[0051] In some aspects, the solvent is a nonpolar solvent. In some
aspects, the solvent is a polar solvent. In some aspects, the
solvent is a polar protic solvent. Non-limiting examples of
suitable polar protic solvents include water, methanol, ethanol,
n-propanol, i-propanol, n-butanol, acetic acid, and combinations
thereof. In some aspects, the solvent is ethanol and water.
[0052] The deprotection reagent may be a catalyst, an acid, a base,
or an oxidant. Selection of a suitable deprotection reagent depends
on the identity of the protecting group and the protected compound.
For instance, some compounds or moieties, such as amino acids,
peptides and polypeptides may be unstable in strong acid and strong
base. In such aspects, a deprotection catalyst would be suitable
for the practice of the present disclosure. In such aspects, a
suitable catalyst could comprise a catalytically active metal such
as palladium, platinum, cobalt, rhodium, nickel, ruthenium, osmium,
iridium, and combinations thereof. In some aspects palladium on
carbon (Pd--C) is a suitable deprotection catalyst. In some further
aspects, deprotection may be done over the catalyst in the presence
of hydrogen.
[0053] In some aspects, Compound 5 and Compound 6 may have a
molecular weight of no more than 20000. In some such aspects, the
molecular weight is no more than 15000, 14000, 13000, 12000, 11000,
10000, 9000, 8000, 7000, 6000, 5000, 4500, 4000, 3500, 3000, 2500,
2000, 1500, 1000, 900, 800, 700, 600, 500, 400 or 300. In other
aspects, Compound 5 and Compound 6 may have molecular weight that
is greater than 20000. In some aspects, the molecular weight of is
suitably from about 300 to about 1000, or from about 300 to about
750. In some aspects, Compound 6 has a molecular weight of from
about 300 to about 600, or from about 300 to about 500.
[0054] The disclosure provides for an anodic process for preparing
substituted pteridine compound 8, or a salt thereof, and
substituted pyrazine compound 9, or a salt thereof. The reaction
scheme to compound 8 is as follows:
##STR00011##
Without being bound to any particular theory, it is believed that
the anodic oxidation of the substituted 5-aminouracil compound 7 to
substituted pteridine compound 8 proceeds according to the
mechanism as previously disclosed, and where the pyrimidine
heteroatoms that are substituted with R.sup.i and R.sup.ii are not
atoms in the bridging ring of the formed tricyclic pteridine. Under
any theory for forming substituted pteridine compound 8, it is
believed that the substitution of the indicated nitrogen
heteroatoms is suitable for the practice of the present disclosure
because those nitrogen heteroatoms do not participate in the
formation of the bridging ring in the anodic oxidation reaction.
Compound 8 corresponds to the compound depicted in the mechanism
prior to the keto-enol tautomerization, but where one >NH moiety
is substituted with R.sup.i thereby forming >NR.sup.i and the
other >NH moiety is substituted with thereby forming
>NR.sup.ii, and where ">" refers to the bonds of the
hetero-nitrogen atom.
[0055] Preparation of substituted 5-amino uracil compounds, such as
compound 7, is known to those skilled in the art. See, for
instance, Baraldi, P. G., et al., Design, "Synthesis, and
Biological Activity of Hybrid Compounds between Uramustine and DNA
Minor Groove Binder Distamycin A", J. Med. Chem. 2002, 45,
3630-3638, the contents of which are incorporated herein in their
entirety. For instance, in a heterocyclic substitution reaction,
5-nitropyrimidine-2,4(1H,3H)-dione may be reacted with
R.sup.i-leaving group and/or R.sup.ii-leaving group in a solvent in
the presence a reducing agent to form
5-nitropyrimidine-2,4(1H,3H)-dione substituted with R.sup.i and/or
R.sup.ii at the nitrogen heteroatoms. In some aspects, the leaving
group is a halogen anion, for instance Br.sup.-. The substitution
reaction is depicted below.
##STR00012##
[0056] The solvent may suitably be a polar aprotic solvent such as
2-methyltetrahydrofuran, tetrahydrofuran (THF), ethyl acetate,
propyl acetate (e.g., isopropyl acetate, iPrOAc), acetone,
dimethylsulfoxide, N,N-dimethylformamide (DMF), acetonitrile
(CH.sub.3CN), N,N-dimethylacetamide, N-methylpyrrolidone (NMP),
hexamethylphosphoramide, and propylene carbonate. In some aspects,
the solvent is DMF. Suitable reducing agents are known in the art.
In some aspects, the reducing agent is NaH. The substituted
5-nitropyrimidine-2,4(1H,3H)-dione may be reduced with hydrogen in
the presence of a suitable catalyst, such as a Pd catalyst to form
compound 7a. Compound 7a may then be converted to a substituted
pteridine, such as compound 8, as described elsewhere herein. In
one particular aspect as depicted in FIG. 4,
3,6-bis((2-(2-methoxyethoxy)ethyl)amino)pyrazine-2,5-dicarboxylic
acid may be prepared from 5-nitropyrimidine-2,4(1H,3H)-dione and
1-bromo-2-(2-methoxyethoxy)ethane.
[0057] In some such aspects, compound 9 may be contacted with a
base to form compound 10, or a salt thereof, as follows:
##STR00013##
[0058] The conditions for the anodic oxidation reaction, the base
and solvent are as described elsewhere herein.
[0059] R.sup.i and R.sup.ii are independently selected from:
hydrogen, where only one of R.sup.i and R.sup.ii may be hydrogen;
optionally substituted alkyl; optionally substituted cycloalkyl or
optionally substituted heterocycloalkyl; optionally substituted
aryl optionally substituted heteroaryl; optionally substituted
alkoxy; optionally substituted --C(O)-alkyl; optionally substituted
ester; optionally substituted amino; optionally substituted polyol
ethers and optionally substituted polyethers; a polypeptide chain
(AA) as described elsewhere herein; and polysaccharide chain (PS)
as described elsewhere herein. In some embodiments, R.sup.i is H.
In some embodiments, R.sup.i is H and R.sup.ii is an optionally
substituted ester, such as ethyl acetate. In some embodiments,
R.sup.i is H and R.sub.ii is an optionally substituted polyether,
such as 2-(2-methoxyethoxy)ethane or a polyethylene glycol ("PEG"),
such as 12 PEG.
[0060] As used herein, "alkyl" refers to a monovalent linear or
branched saturated hydrocarbon moiety, consisting solely of carbon
and hydrogen atoms, having from one to twenty, one to ten, one to
six, or one to four carbon atoms. Examples of alkyl groups include,
but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the
like. Alkyl groups may be optionally substituted as defined
herein.
[0061] As used herein, "cycloalkyl" refers to a carbocyclic moiety
consisting of monocyclic or polycyclic rings. Cycloalkyl can
optionally be substituted as defined herein. Examples of cycloalkyl
moieties include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and the like. Polycyclic ring
structures include fused and bridged bicyclic, fused and bridged
polycyclic and spirocyclic hydrocarbon ring system such as, for
example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane,
adamantane, and norborene. Cycloalkyls may be saturated or
partially unsaturated (e.g., cycloalkenyl).
[0062] As used herein, the term "heterocycloalkyl" refers to a
saturated or partially unsaturated ring system radical having from
the indicated number of overall number of stated ring atoms and
containing from one to five heteroatoms selected from N, O, and S,
wherein the nitrogen and sulfur atoms are optionally oxidized,
nitrogen atom(s) are optionally quaternized, as ring atoms (e.g., a
3 to 12 membered heterocycloalkyl that would have 3 to 12 ring
atoms and include at least one heteroatom, which also could be
referred to as a C.sub.2-11 heterocycloalkyl). Heterocycloalkyl can
optionally be substituted as defined herein. A "heterocycloalkyl"
ring system can be a monocyclic or a fused, bridged, or spirocyclic
polycyclic (including a fused bicyclic, bridged bicyclic or
spirocyclic) ring system.
[0063] As used herein, "aryl" refers to a monovalent aromatic
hydrocarbon radical of 6-20 carbon atoms (C.sub.6-C.sub.20). Aryl
includes bicyclic radicals comprising an aromatic ring fused to a
saturated, partially unsaturated ring, or aromatic carbocyclic
ring. Typical aryl groups include, but are not limited to, radicals
derived from benzene (phenyl), substituted benzenes, naphthalene,
anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene,
1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are
optionally substituted independently with one or more substituents
described herein. In some aspects, aryl may be substituted with
alkyl, cycloalkyl, halogen, or haloalkyl. Alkyl may be substituted
directly to a heteronitrogen or may be linked to the heteronitrogen
by an alkyl or substituted alkyl.
[0064] As used herein, the term "heteroaryl" refers to aryl ring(s)
that contain from one to five heteroatoms selected from N, O, and
S, wherein the nitrogen and sulfur atoms are optionally oxidized,
and the nitrogen atom(s) are optionally quaternized. A heteroaryl
group can be attached to the remainder of the molecule through a
heteroatom. Heteroaryl groups are optionally substituted
independently with one or more substituents described herein.
[0065] As used herein, "alkoxy" refers to a moiety of the structure
--OR, wherein R is an alkyl moiety as defined herein. Examples of
alkoxy moieties include, but are not limited to, methoxy, ethoxy,
isopropoxy, and the like.
[0066] As used herein, "haloalkyl" refers to an alkyl as defined
herein in which one or more hydrogen atoms have been replaced with
the same or a different halogen. Exemplary haloalkyls include
--CH.sub.2Cl, --CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3, --CF.sub.3,
CHF.sub.2, and the like.
[0067] As used herein, "--C(O)-alkyl" refers to an optionally
substituted aldehyde moiety that forms an amide with the
heteronitrogen, i.e., >N--C(O)-alkyl. Non-limiting examples of
substituted N--C(O)-alkyl includes amide-ol, amide-diol,
amide-polyol, and derivatives thereof.
[0068] As used herein, "polyol ethers" and "poly ethers" are of the
general structure where the hetero-nitrogen refers to the ring atom
to which the polyol ether or poly ether is bound
##STR00014##
where: R.sup.a is optionally substituted C.sub.1-4 alkyl; R.sup.b
is optionally substituted C.sub.1-4 alkyl; R.sup.c is optionally
substituted C.sub.1-4 alkyl; and R.sup.d is optionally substituted
C.sub.1-4 alkyl or hydrogen. x is 1, 2, 3, 4, 5, 10, 15, 20, 25,
30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, and any range
constructed therefrom, such as for instance from 1 to 100, from 1
to 70, from 1 to 50, from 1 to 30, from 1 to 20, from 2 to 20, from
2 to 10, from 3 to 20, from 3 to 10, from 5 to 20, or from 5 to 10.
In some aspects, R.sup.a to R.sup.c are each C.sub.2 and R.sup.d is
H or C.sub.1-2. In one example, the polyether is PEG. In some
non-limiting aspects, branched polyols and branched polyethers are
of the general structure below where the hetero-nitrogen refers to
the ring atom to which the polyol ether or poly ether is bound
##STR00015##
where R.sup.d is as defined herein, and y is 1, 2, 3, 4, 5, 10, 15,
20, 25, 30, 35, 40, 45, or 50, and any range constructed therefrom,
such as for instance from 1 to 50, from 1 to 30, from 1 to 20, from
2 to 20, from 2 to 10, from 3 to 20, from 3 to 10, from 5 to 20, or
from 5 to 10. Non-limiting examples include the following
structures where the hetero-nitrogen refers to the ring atom to
which the polyol ether or poly ether is bound
##STR00016##
[0069] As used herein, "halogen" refers to chlorine, fluorine,
bromine and iodine.
[0070] As used herein, "amino" refers to a moiety of the structure
--NR.sup.xR.sup.y wherein R.sup.x and R.sup.y are each hydrogen,
"monoalkylamino" refers to such a structure where one of R.sup.x
and R.sup.y is hydrogen and the other of R.sup.x and R.sup.y is
alkyl, and "dialkylamino" refers to such a structure where each of
R.sup.x and R.sup.y is alkyl.
[0071] As used herein, "optionally substituted" as used herein
refers to a moiety that may be unsubstituted or substituted with
specific groups. Examples of substituents include, but are not
limited to hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, amino,
monoalkylamino, or dialkylamino.
[0072] In some such aspects, compound 10, or a salt thereof, may be
reacted with NHR acid salt (compound 4) in a solvent to form
compound 11, or a salt thereof, as follows:
##STR00017##
R and R.sup.ii and the reaction are previously defined in
connection with the preparation of compound 5 by the reaction of
compound 3 with compound 4.
[0073] In aspects of the disclosure each HNR moiety comprises a
protecting group, PG, and said protecting group is cleaved to form
compound 13 as follows and as described elsewhere herein in
connection with compounds 5 and 6.
##STR00018##
EXAMPLES
Example 1
[0074] Potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate) was prepared
according to the following reaction scheme:
##STR00019##
[0075] In a first (anode) chamber, the inside wall of a Berzelius
beaker (tall form, 400 mL) was fitted a platinum coated titanium
expanded mesh screen and a graphite felt anode was placed uniformly
over it and lining the inner wall. A stainless steel cathode formed
from 0.25 inch tubing was placed in a separate (cathode) chamber
formed from a pvc tube having an outer diameter of about 3/4 inch
(1.9 cm) and a length of about 6 inches (15.24 cm) that was sealed
at one end with clear silicone room temperature vulcanizing
("RTV"). The tube was perforated by drilling evenly spaced 1/4 inch
(0.64 cm) holes to a distance of about 4 inches (10.2 cm) from the
bottom of an RTV plug. Nafion N324 membrane, 0.15 mm (0.006 inches)
thick, Teflon.TM. fabric reinforced
(Rf[OCF.sub.2CF(CF.sub.3).sub.2].sub.nOCF.sub.2CF.sub.2SO.sub.3H)
was wrapped around the pvc supporting tube with the coarse side
facing the cathode, and then sealed with silicone RTV while being
careful not to contaminate the exposed Nafion surface with RTV. The
Nafion membrane was configured to enclose the tube and prevent
mixing between the two chambers, but allowing for charge transfer
between the two chambers. The Nafion membrane was pre-treated by
immersion (agitated by swirling the solution by hand) in a KOH
solution contained in a 100 mL graduated cylinder. The membrane
initially shrunk to about one half its original diameter, but then
expanded until it contacted the wall of the graduated cylinder. The
membrane was allowed to soak for greater than 0.5 hour. It was
thereafter removed and rinsed with deionized water. The membrane
was kept moist by storing in a plastic baggie. The cell was
constructed so that the graphite felt anode had about a 0.5 inch
(1.27 cm) space at the bottom into which was placed a magnetic stir
bar. The cathode chamber tube was suspended in the middle of the
beaker (anode) assembly by attaching it to a three-pronged
clamp.
[0076] The assembled 2-chamber cell was filled with an aqueous
solution of KOH (4.2 g KOH in 160 mL deionized water) so that both
chambers were filled to an approximately equal level.
5-aminopyrimidine-2,4(1H,3H)-dione (5-aminouracil) (2.0 g, 0.0157
mole) was added to the anolyte and allowed to dissolve. A DC power
supply (Lambda, Model LG-532) was connected, and 1.0 A (5.6 V) was
passed through the cell with continuous stirring until two Faradays
of charge had passed (0.9 hrs). The anolyte turned red during the
course of the reaction (from its initial yellow color).
[0077] The anolyte and catholyte were each analyzed for the
presence of the desired product by reverse phase high performance
liquid chromatography ("reHPLC"). The anolyte was confirmed to
exhibit a significant amount of potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate). The catholyte
was found to not contain a detectable amount of potassium
4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate).
Example 2
[0078] 3,6-diaminopyrazine-2,5-dicarboxylic acid was prepared from
potassium 4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate)
according to the following reaction scheme:
##STR00020##
[0079] In each of two Teflon reaction vessels was placed 0.5 g of
potassium 4,9-dihydroxypyrimido[4,5-g]pteridine-2,7-bis(olate), and
a solution containing 0.3 to 0.4 g sodium hydroxide in 10 mL
deionized water. The vessels were secured in a microwave reactor
and allowed to react for one hour at 170.degree. C. and at about
100 psig pressure. The vessels were allowed to cool to about
50.degree. C., and the contents were filtered to remove a small
amount of solid residue. The bright yellow filtrate was transferred
to a 250 mL round-bottomed flask equipped with a large magnetic
stir bar. The pH was adjusted with stirring to about 3 with
concentrated HCl forming a large amount of red precipitate. A few
more drops of acid were added and the solid was collected by
filtration on a glass frit, wash with cold 1N HCl (1.times.10 mL),
acetonitrile (2.times.30 mL) and diethyl ether (1.times.30 mL),
suctioned dry, and transferred to vacuum oven. The collected solid
was dried overnight at 45-50.degree. C. to yield 0.48 g
3,6-diaminopyrazine-2,5-dicarboxylic acid (79%). C.sup.13 NMR
(D.sub.2O/NaOD, external TMS reference) .delta. 132.35, 147.32,
171.68.
Example 3
[0080] An IKA ElectraSyn Pro-Divide two compartment cell equipped
with a 5u porous polypropylene frit divider and stir bars was
charged with 5-aminouracil potassium salt (0.10 g) in 13.0 mL
deionized water, with 6.5 mL in each of the two cell compartments.
The anode was reticulated foam carbon and the anode compartment was
fitted with a thermocouple. The cathode was stainless steel.
[0081] The oxidation was carried out under constant current
conditions (13 mA) for 100 minutes at which point 62% of the
5-aminouracil had been consumed. The major product,
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone was
quantified by HPLC and determined to have been produced in 22%
yield (7 mg) based on consumed 5-aminouracil).
Example 4
[0082] The conditions of Example 3 were repeated except the anode
was replaced with a reticulated foam carbon anode of the same
dimensions. The reaction progress was checked at 32% conversion of
5-aminouracil and was determined to have produced 11.2 mg of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone.
Example 5
[0083] The conditions of Example 4 were repeated, but the polarity
of the electrodes was reversed every 10 seconds. The yield of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone was 26%
based on the amount of 5-aminouracil consumed.
Example 6
[0084] The conditions of Example 3 were repeated, but 27 mg of
potassium ferrocyanide was added to the anolyte. The yield of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone was
39.2% based on the amount of 5-aminouracil consumed.
Example 7
[0085] The conditions of Example 3 were repeated, but controlled
anode potential conditions were employed instead of the controlled
current conditions used in Example 3. The anode potential was held
to 1.2 V vs. Ag.degree./AgCl reference. After 140 minutes, a 41%
yield of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone was
obtained by quantitative rpHPLC analysis based on the amount of
5-aminouracil consumed.
Example 8
[0086] The conditions of Example 3 were repeated, except the anode
was replaced with the following materials, each in an independent
experiment: glassy carbon, graphite, and platinum. A yield of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone similar
to Example 3 was obtained for each of the evaluated anodes.
Example 9
[0087] The conditions of Example 3 were repeated, except the porous
polypropylene frit divider was removed thereby providing an
undivided cell. A yield of
1,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone of 10%
was achieved based on the amount of consumed 5-aminouracil.
Example 10 (Prophetic): Preparation of
1,6-bis(2-(2-methoxyethoxy)ethyl)-1,6-dihydropyrimido[4,5-g]pteridine-2,4-
,7,9(3H,8H)-tetraone (14)
[0088] As depicted in FIG. 4, in step 1,
5-nitropyrimidine-2,4(1H,3H)-dione (14) may be reacted with
1-bromo-2-(2-methoxyethoxy)ethane (15) according to the procedure
of Baraldi, P. G., et al., J. Med. Chem., 2002, 45, 3630-3638 that
is outlined in the Experimental Section under the General Procedure
for the Synthesis of Compounds 4-9 found on page 3634, thereby
producing
1-(2-(2-methoxyethoxy)ethyl)-5-nitropyrimidine-2,4(1H,3H)-dione
(16).
[0089] As depicted in FIG. 4, in step 2, compound 16 may be reduced
to 5-amino-1-(2-(2-methoxyethoxy)ethyl) pyrimidine-2,4(1H,3H)-dione
(17) using 10% Pd on carbon and hydrogen in a suitable solvent,
such as 2-methoxyethanol, using substantially the conditions of
Baraldi, General Procedure for the Synthesis of Compounds 10-15 in
the reference cited in Step 1, page 3635.
[0090] As depicted in FIG. 4, in step 3, Electrochemical anodic
oxidation of 5-amino-1-(2-(2-methoxyethoxy)ethyl)
pyrimidine-2,4(1H,3H)-dione (17) may be done using substantially
the conditions of Examples 1-9 would produce
1,6-bis(2-(2-methoxyethoxy)ethyl)-1,6-dihydropyrimido[4,5-g]pteri-
dine-2,4,7,9(3H,8H)-tetraone (18) that may be isolated by reverse
phase high pressure liquid chromatography, by rpHPLC, or by
precipitation techniques known in the art.
Example 11 (Prophetic): Preparation of
3,6-bis((2-(2-methoxyethoxy)ethyl)amino)pyrazine-2,5-dicarboxylic
acid (20)
[0091] As further depicted in FIG. 4,
1,6-bis(2-(2-methoxyethoxy)ethyl)-1,6-dihydropyrimido[4,5-g]pteridine-2,4-
,7,9(3H,8H)-tetraone (18) may be converted to
3,6-bis((2-(2-methoxyethoxy)ethyl)amino)pyrazine-2,5-dicarboxylic
acid (20) may be effected using substantially the conditions of
Example 2.
Example 12 (Prophetic): Preparation of Preparation of diethyl
2,2'-(2,4,7,9-tetraoxo-2,3,4,7,8,9-hexahydropyrimido[4,5-g]pteridine-1,6--
diyl)diacetate (24)
[0092] As depicted in FIG. 5, in step 1,
5-nitropyrimidine-2,4(1H,3H)-dione (14) may be reacted with ethyl
bromoacetate (21) according to the procedure of Baraldi, that is
outlined in the Experimental Section under the General Procedure
for the Synthesis of Compounds 4-9 found on page 3634, thereby
producing ethyl
2-(5-nitro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate
(22).
[0093] As depicted in FIG. 5, in step 2, Compound 22 may be reduced
to ethyl 2-(5-amino-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate
(23) using 10% Pd on carbon and hydrogen in a suitable solvent,
such as 2-methoxyethanol, using substantially the conditions of
General Procedure for the Synthesis of Compounds 10-15 in the
reference cited in Step 1, page 3635.
[0094] As depicted in FIG. 5, in step 3, electrochemical anodic
oxidation of ethyl
2-(5-amino-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (23) may
be done using substantially the conditions of Examples 1-9 would
produce diethyl
2,2'-(2,4,7,9-tetraoxo-2,3,4,7,8,9-hexahydropyrimido[4,5-g]pteridine-1,6--
diyl)diacetate (24) that may be isolated by rpHPLC, normal phase
silica gel chromatography or by precipitation techniques known in
the art.
Example 13 (Prophetic): Production of diethyl
2,2'-((3,6-dicarbamoylpyrazine-2,5-diyl)bis(azanediyl))diacetate
(26)
[0095] As further indicated in FIG. 5, conversion of diethyl
2,2'-(2,4,7,9-tetraoxo-2,3,4,7,8,9-hexahydropyrimido[4,5-g]pteridine-1,6--
diyl)diacetate (24) to diethyl
2,2'4(3,6-dicarbamoylpyrazine-2,5-diyl)bis(azanediyl))diacetate
(26) may be effected using substantially the conditions of Example
2.
Example 14 (Prophetic): Production of Preparation of
1,6-di(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-1-
,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone (32)
[0096] As depicted in FIG. 6, step 1,
5-nitropyrimidine-2,4(1H,3H)-dione (14) may be reacted with m-12
PEG-bromide (27) according to the procedure of Baraldi, that is
outlined in the Experimental Section under the General Procedure
for the Synthesis of Compounds 4-9 found on page 3634, thereby
producing
1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-5-nit-
ropyrimidine-2,4(1H,3H)-dione (28).
[0097] As depicted in FIG. 6, step 2, compound 24 may be reduced to
5-amino-1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-y-
l)pyrimidine-2,4(1H,3H)-dione (29) using 10% Pd on carbon and
hydrogen in a suitable solvent, such as 2-methoxyethanol, and
substantially the conditions of Baraldi for the Synthesis of
Compounds 10-15 in the reference cited in Step 1, page 3635.
[0098] As depicted in FIG. 6, step 3, electrochemical anodic
oxidation of
5-amino-1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-y-
l)pyrimidine-2,4(1H,3H)-dione (29) using substantially the
conditions of Examples 1-9 would produce
1,6-di(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-1-
,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone (30)
that may be isolated by rpHPLC, normal phase silica gel
chromatography or by precipitation techniques known in the art.
Example 15 (Prophetic): Preparation of
1,6-di(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-1-
,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone (32)
[0099] As further depicted in FIG. 6, conversion of
1,6-di(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-1-
,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone (30) to
1,6-di(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-1-
,6-dihydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetraone (32) may
be effected using substantially the conditions of Example 2.
[0100] This written description uses examples to disclose the
invention, including the best mode, and also to enable any person
skilled in the art to practice the invention, including making and
using any devices or systems and performing any incorporated
methods. The patentable scope of the invention is defined by the
claims, and may include other examples that occur to those skilled
in the art. Such other examples are intended to be within the scope
of the claims if they have structural elements that do not differ
from the literal language of the claims, or if they include
equivalent structural elements with insubstantial differences from
the literal languages of the claims.
* * * * *