384 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 3
Piper et al.
3.06-3.16 (m, 1, C9-H), 4.34 (q, 1, CONHCH), 4.88-5.04 (m,
2, -CH2CHdCH2), 5.58-5.74 (m, 1, CH2CHdCH2), 6.87 (br s,
2, NH2), 7.24 and 7.73 (2d, 4, C6H4), 7.40 (br s, 2, NH2), 8.02
(d, 1, C7-H), 8.42 (q, 1, CONH). Multiple resonances by
protons of the 9,10-bridge, the allyl group, CONH, and C7-H
indicate a diastereomeric mixture. Anal. (C25H28N6O5‚2H2O)
C, H, N.
The remaining 5,10-dideazaaminopterin analogues 2g-j
were prepared by similar coupling of the corresponding pteroic
acid-type precursors 9b-e with diethyl L-glutamate followed
by hydrolysis of the resulting diesters 10b-e (Scheme 2).
5-Meth yl-10-p r op a r gyl-5,10-d id ea za a m in op ter in (2g).
The peptide coupling of 9b (175 mg, 0.48 mmol) with diethyl
L-glutamate‚HCl was conducted as described for 10a to give
diethyl ester 10b (106 mg, 40% yield): MS m/ e 547, MH+.
Hydrolysis of 10b (102 mg, 0.187 mmol) afforded 80 mg of 2g
(81% yield): MS m/ e 491, MH+. Anal. (C25H26N6O5‚2H2O)
C, H, N.
(2) DeGraw, J . I.; Christie, P. H.; Brown, E. G.; Kelly, L. F.; Kisliuk,
R. L.; Gaumont, Y.; Sirotnak, F. M. Synthesis and Antifolate
Properties of 10-Alkyl-8,10-dideazaaminopterins. J . Med. Chem.
1984, 27, 376-380.
(3) DeGraw, J . I. Unpublished results.
(4) Temple, C., J r.; Elliott, R. D.; Montgomery, J . A. Pyrido[2,3-d]-
pyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin,
Methotrexate, Folic Acid, and N10-Methylfolic Acid. J . Org.
Chem. 1982, 47, 761-764.
(5) Taylor, E. C.; Palmer, D. C.; George, T. J .; Fletcher, S. R.; Tseng,
C. P.; Harrington, P. J .; Beardsley, G. P. Synthesis and Biological
Activity of L-5-Deazafolic Acid and L-5-Deazaaminopterin: Syn-
thetic Strategies to 5-Deazapteridines. J . Org. Chem. 1983, 48,
4852-4860.
(6) Piper, J . R.; McCaleb, G. S.; Montgomery, J . A.; Kisliuk, R. L.;
Gaumont, Y.; Sirotnak, F. M. Syntheses and Antifolate Activity
of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate,
Folic Acid, and N10-Methylfolic Acid. J . Med. Chem. 1986, 29,
1080-1087.
(7) Piper, J . R.; McCaleb, G. S.; Montgomery, J . A.; Kisliuk, R. L.;
Gaumont, Y.; Sirotnak, F. M. 10-Propargylaminopterin and
Alkyl Homologues of Methotrexate as Inhibitors of Folate
Metabolism. J . Med. Chem. 1982, 25, 877-880.
(8) Piper, J . R.; Malik, N. D.; Rhee, M. S.; Galivan, J .; Sirotnak, F.
M. Synthesis and Antifolate Evaluation of the 10-Propargyl
Derivatives of 5-Deazafolic Acid, 5-Deazaaminopterin, and
5-Methyl-5-deazaaminopterin. J . Med. Chem. 1992, 35, 332-
337.
(9) Piper, J . R.; Balakrishnan, R.; J ohnson, C. A.; Maddry, J . A.;
Otter, G. M.; Sirotnak, F. M. Further Evaluation of 5-Alkyl-5-
deaza Antifolates. 5-Propyl- and 5-Butyl-5-deaza Analogues of
Aminopterin and Methotrexate. J . Heterocycl. Chem. 1995, 32,
1205-1212.
(10) J ones, T. R.; Calvert, A. H.; J ackman, A. L.; Brown, S. J .; J ones,
M.; Harrap, K. R. A Potent Antitumor Quinazoline Inhibitor of
Thymidylate Synthetase: Synthesis, Biological Properties and
Therapeutic Results in Mice. Eur. J . Cancer 1981, 17, 11-19.
(11) Marsham, P. R.; Hughes, L. R.; J ackman, A. L.; Hayter, A. J .;
Oldfield, J .; Wardleworth, J . M.; Bishop, J . A. M.; O’Connor, B.
M.; Calvert, A. H. Quinazoline Antifolate Thymidylate Synthase
Inhibitors: Heterocyclic Benzoyl Ring Modifications. J . Med.
Chem. 1991, 34, 1594-1605.
N -[5-[2-(2,4-Dia m in o-5-d e a za -6-p t e r id in yl)e t h yl]-2-
th en oyl]-L-glu ta m ic Acid (2h ). Peptide coupling of 9c with
diethyl L-glutamate mediated by i-BuOCOCl in DMF contain-
ing Et3N afforded diethyl ester 10c (120 mg, 36% yield) after
purification on silica gel (TLC Rf 0.5; CHCl3-MeOH, 5:1): MS
m/ e 501, MH+ for C23H28N6O5S. Ester 10c was then subjected
to the same ester hydrolysis procedure as described under the
preparation of 2f to give 2h in 37% yield (43 mg): MS m/ e
445, MH+. Anal. (C19H20N6O5S‚2H2O) C, H, N.
5,10-Did ea za -3′-a za a m in op ter in (2i). Coupling of 9d
with diethyl L-glutamate‚HCl to give the diethyl ester 10d was
done as described above. The yield of 10d , homogeneous by
TLC (CHCl3-MeOH, 5:1; Rf 0.5), was 18% (215 mg from 740
mg, 2.38 mmol, of 10d ). The yield was lowered by solubility
problems in the chromatographic purification system: MS m/ e
496, MH+ for C24H29N7O5. Hydrolysis of the ester groups of
this product (175 mg, 0.353 mmol) led to pure 2i in 77% yield
1
(119 mg): MS m/ e 440; H NMR δ 1.95, 2.08 (2m, 2, Glu-3-
CH2), 2.34 (t, 2, CH2CO), 3.06 (m, 2, C9H2), 3.17 (m, 2, C10H2),
4.38 (m, 1, CONHCH), 6.85 (s, 2, NH2), 7.36 (d, 1, pyridyl-3-
H), 7.84 (s, 2, NH2), 8.12 (m, 1, pyridyl-4-H), 8.37 (d, 1, C5-H),
8.54 (d, 1, C7-H), 8.68 (d, 1, CONH), 8.97 (d, 1, pyridyl-6-H,
between N and carboxamide). Anal. (C20H21N7O5‚3H2O) C,
H, N.
(12) Taylor, E. C.; Harrington, P. J .; Fletcher, S. R.; Beardsley, G.
P.; Moran, R. G. Synthesis of the Antileukemic Agents 5,10-
Dideazaaminopterin and 5,10-Dideaza-5,6,7,8-tetrahydroami-
nopterin. J . Med. Chem. 1985, 28, 914-921.
(13) DeGraw, J . I.; Tagawa, H.; Christie, P. H.; Lawson, J . A.; Brown,
E. G. Synthesis of 5,10-Dideazaminopterin. J . Heterocycl. Chem.
1986, 23, 1-4.
5-Meth yl-5,10-d id ea za -3′-a za a m in op ter in (2j). Com-
pound 9e (407 mg, 1.16 mmol) was coupled with diethyl
L-glutamate as described above. After the DMF had been
removed in vacuo, the residue was taken up in CH3OH and
the solution was treated with 2 g of silica gel. The mixture
was evaporated to dryness, and the residual dispersion was
pulverized and applied to a column of silica gel in CHCl3-
CH3OH (5:1). The column was eluted with the same solvent
system, and the fractions homogeneous by TLC (Rf 0.31;
CHCl3-CH3OH, 3:1) were pooled and evaporated. The residue
was stirred with Et2O, collected, washed with H2O, and dried
to give the diester 10e: yield 44% (281 mg); MS m/ e 510, MH+.
Anal. (C25H31N7O5‚2H2O) C, H, N.
(14) Taylor, E. C.; Beardsley, G. P.; Harrington, P. J .; Fletcher, S.
R. U.S. Patent 4 684 653, 1987.
(15) DeGraw, J . I.; Christie, P. H.; Kisliuk, R. J .; Gaumont, Y.;
Sirotnak, F. M. Synthesis and Antifolate Properties of 10-Alkyl-
5,10-dideaza Analogues of Methotrexate and Tetrahydrofolic
Acid. J . Med. Chem. 1990, 33, 673-677.
(16) Piper, J . R.; McCaleb, G. S.; Montgomery, J . A.; Kisliuk, R. L.;
Gaumont, Y.; Thorndike, J .; Sirotnak, F. M. Synthesis and
Antifolate Activity of 5-Methyl-5,10-dideaza Analogues of Ami-
nopterin and Folic Acid and an Alternative Synthesis of 5,10-
Dideazatetrahydrofolic Acid, a Potent Inhibitor of Glycinamide
Ribonucleotide Formyltransferase. J . Med. Chem. 1988, 31,
2164-2169.
(17) Piper, J . R.; J ohnson, C. A.; Otter, G. M.; Sirotnak, F. M.
Synthesis and Antifolate Evaluation of 10-Ethyl-5-methyl-5,10-
dideazaaminopterin and an Alternative Synthesis of 10-Ethyl-
10-deazaaminopterin (Edatrexate). J . Med. Chem. 1992, 35,
3002-3006.
(18) DeGraw, J . I.; Colwell, W. T.; Piper, J . R.; Sirotnak, F. M.
Synthesis and Antitumor Activity of 10-Propargyl-10-deazaami-
nopterin. J . Med. Chem. 1993, 36, 2228-2231.
Hydrolysis of 10e (261 mg, 0.478 mmol) as above afforded
2j: yield 88% (204 mg); MS m/ e 454, MH+; UV (0.1 N HCl)
λ
max 319 nm (ꢀ 7960), 270 (17 600), 228 (38 600); (0.1 N NaOH)
345 (6720), 269 (18 100), 233 (37 400); 1H NMR δ 1.96 and
2.05 (2m, 2, Glu-3-CH2), 2.34 (t, 2, CH2CH2CO), 2.68 (s, 3,
CH3), 3.05 (m, 4, C9H2C10H2), 4.38 (q, 1, CONHCH), 6.90 (br
s, 2, NH2), 7.34 (d, 3, overlap of NH2 and pyridyl-3-H), 8.11 (q,
1, pyridyl-4-H), 8.31 (s, 1, C7-H), 8.63 (d, 1, CONH), 8.96 (d, 1,
pyridyl-6-H between N and carboxamide. Anal. (C21H23
-
N7O5‚1.6H2O) C, H, N.
Ack n ow led gm en t. This work was performed under
(19) Fileti, M.; Baldracco, G. J . Prakt. Chem. [2] 42, 532; through
the sponsorship of Mitsubishi Rayon Co.
Beilstein.
(20) DeGraw, J . I.; Brown, V. H.; Tagawa, H.; Kisliuk, R. L.;
Gaumont, Y.; Sirotnak, F. M. Synthesis and antitumor activity
of 10-alkyl-10-deaza aminopterins. A convenient synthesis of 10-
deazaaminopterin. J . Med. Chem. 1982, 25, 1227-1230.
Refer en ces
(1) DeGraw, J . I.; Colwell, W. T.; Crase, J .; Smith, R. L.; Piper, J .
R.; Waud, W.; Sirotnak, F. M. Analogues of Methotrexate in
Rheumatoid Arthritis. 1. Effects of 10-Deazaaminopterin Ana-
logues on Type II Collagen-Induced Arthritis in Mice. J . Med.
Chem. 1997, 40, 370-376.
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