Biologically Active Pteridine Derivatives
FULL PAPER
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(70:30) to afford products 7, 7Ј and 8, 8Ј, respectively. The trans
stereoisomer 7 and 8 eluted first and the cis isomers 7Ј, 8Ј eluted
as a second fraction.
(d, JCF = 252.0 Hz, C-Ar-F), 164.5 (d, JCF = 252.0 Hz, C-Ar-F)
ppm. IR: ν = 3389 (NH) cm–1. MS (CI) m/z: [M + H] 444. HRMS:
˜
calcd. for C26H23F2N5 (M)+: 443.1922; found 443.1923.
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N-(10H-Dibenzo[3,4:6,7]cyclohepta[1,2-g]pteridin-4-yl)-N-(4-meth-
ylcyclohexyl)amine (7) and (7Ј): Reaction of 3 yielded the trans iso-
mer 7 (25.0 mg) and the cis isomer 7Ј (24.0 mg).
cis Isomer 8Ј: M.p. 247.6–248.6 °C. H NMR (CDCl3, 400 MHz):
δ = 1.00 (d, J = 6.3 Hz, 3 H, CH3-cyclohexyl), 1.18–1.24 (m, 2 H,
H3Јax, H5Јax), 1.36–1.47 (m, 3 H, H2Јax, H6Јax, H4Јax), 1.79–1.86 (m,
2 H, H3Јeq, H5Јeq), 2.16–2.27 (m, 2 H, H2Јeq, H6Јeq), 3.80 (d, J =
13.5 Hz, 1 H, ArCH2Ar), 3.97 (d, J = 13.5 Hz, 1 H, ArCH2Ar),
4.47–4.48 (m, values of constant couplings were derived from
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trans Isomer 7: M.p. 247.5–249 °C. H NMR (CDCl3, 400 MHz):
δ = 0.96 (d, J = 6.4 Hz, 3 H, CH3-cyclohexyl), 1.18–1.24 (m, 2 H,
H3Јax, H5Јax), 1.36–1.47 (m, 3 H, H2Јax, H6Јax, CH4Јax), 1.79–1.85
(m, 2 H, H3Јeq, H5Јeq), 2.16–2.27 (m, 2 H, H6Јeq, H2Јeq), 3.79 (d, J
= 13.5 Hz, 1 H, ArCH2Ar), 3.96 (d, J = 13.5 Hz, 1 H, ArCH2Ar),
4.20–4.24 (m, values of constant couplings were derived from
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homonuclear decoupling experiments: JHCNH = 7.6, Jeq-ax
=
2ϫ2.7, Jeq-eq = 2ϫ2.7 Hz, 1 H, H1Јeq), 7.36–7.46 (m, 7 H, Ar-H,
NH), 7.92 (d, J = 7.2 Hz, 1 H, Ar-H), 8.17 (d, J = 7.2 Hz, 1 H, Ar-
H), 8.83 (s, 1 H, H-pteridine) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 20.9 (CH3), 28.9 (CH), 30.1 (CH2), 30.2 (CH2), 39.8 (ArCH2Ar),
3
3
3
homonuclear decoupling experiments: JHCNH = 8.5, Jax-ax
=
2ϫ11.0, 3Jax-eq = 2ϫ3.5 Hz, 1 H, H1Јax), 7.10 (d, J = 8.5 Hz, 1 H,
NH), 7.36–7.46 (m, 6 H, Ar-H), 7.91 (d, J = 7.2 Hz, 1 H, Ar-H),
8.17 (d, J = 7.2 Hz, 1 H, Ar-H), 8.83 (s, 1 H, H-pteridine) ppm.
13C NMR (CDCl3, 100 MHz): δ = 22.2 (CH3-cyclohexyl), 32.0 (C-
4Ј-cyclohexyl), 32.92 (C-2Ј-cyclohexyl), 32.93 (C-6Ј-cyclohexyl),
33.8 (2 C, C-3Ј,5Ј-cyclohexyl), 40.1 (ArCH2Ar), 50.2 (cyclohexyl-
CHNH), 124.7 (C-pteridine), 126.9, 127.1 (2 C), 127.2, 130.3,
130.8, 131.0, 131.9, (CH-Ar), 135.3 (2 C-Ar), 142.2, 142.3, 150.4,
(C-Ar), 151.8 (C-pteridine-NH), 157.8 (C-Ar), 159.9 (CH-pterid-
2
2
47.4 (CHNH), 114.1 (d, JCF = 22.0 Hz, CH-Ar-F), 114.2 (d, JCF
= 22.0 Hz, CH-Ar-F), 114.4 (d, JCF = 21.6 Hz, CH-Ar-F), 114.5
(d, JCF = 21.6 Hz, CH-Ar-F), 124.7 (C-Ar), 131.5 (d, JCF
3.5 Hz, C-Ar-F), 131.6 (d, JCF = 3.5 Hz, C-Ar-F), 133.0 (d, JCF
2
2
4
=
4
3
3
= 9.0 Hz, CH-Ar-F), 134.2 (d, JCF = 9.0 Hz, CH-Ar-F), 143.5 (d,
3JCF = 8.0 Hz, C-Ar-F), 143.6 (d, JCF = 8.0 Hz, C-Ar-F), 149.1,
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151.6, 156.5, 160.0 (C-Ar), 160.1 (CH-pteridine), 164.1 (d, JCF
252.0 Hz, C-Ar-F), 164.4 (d, JCF = 252.0 Hz, C-Ar-F) ppm.
=
1
ine), 160.3 (C-pteridine) ppm. IR: ν = 3386 (NH) cm–1. MS (CI)
˜
m/z: [M + H] 408. HRMS: calcd. for C26H25N5 (M)+: 407.2110
found 407.2105.
Acknowledgments
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cis Isomer 7Ј: M.p. 271–273.7 °C. H NMR (CDCl3, 400 MHz): δ
= 1.00 (d, J = 6.4 Hz, 3 H, CH3-cyclohexyl), 1.18–1.24 (m, 2 H,
H3Јax, H5Јax), 1.36–1.47 (m, 3 H, H2Јax, H6Јax, H4Јax), 1.79–1.85 (m,
2 H, H3Јeq, H5Јeq), 2.16–2.27 (m, 2 H, H2Јeq, H6Јeq), 3.80 (d, J =
13.5 Hz, 1 H, ArCH2Ar), 3.97 (d, J = 13.5 Hz, 1 H, ArCH2Ar),
4.46–4.47 (m, values of constant couplings were derived from
The authors wish to thank Dr. D. Surleraux and his team from
Tibotec Company for performing the biological tests. We are grate-
ful to B. Demarsin for the HRMS measurements and K. Duerinckx
´
for assisting with the NMR measurements. M. S. thanks
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K. U. Leuven (LRD) for a fellowship and W. M. D. B (postdoc-
toral fellow) thanks the Fund for Scientific Research-Flanders
(FWO), Belgium, for a postdoctoral fellowship received and for a
“Krediet aan Navorsers”.
homonuclear decoupling experiments: JHCNH = 7.6, Jeq-ax
=
2ϫ2.7, Jeq-eq = 2ϫ2.7 Hz, 1 H, H1Јeq), 7.36–7.46 (m, 7 H, Ar-H,
NH), 7.92 (d, J = 7.2 Hz, 1 H, Ar-H), 8.17 (d, J = 7.2 Hz, 1 H, Ar-
H), 8.83 (s, 1 H, H-pteridine) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 20.9 (CH3-cyclohexyl), 28.92 (C-2Ј-cyclohexyl), 28.99 (C-6Ј-cy-
clohexyl), 30.1 (2 C, C-3Ј,5Ј-cyclohexyl), 30.3 (C-4Ј-cyclohexyl),
40.1 (ArCH2Ar), 47.4 (cyclohexyl-CHNH), 124.8 (C-pteridine),
127.0, 127.1 (2 C), 127.3, 130.2, 130.8, 130.9, 131.9, (CH-Ar), 135.4
(2 C-Ar), 142.2, 142.3, 150.4, (C-Ar), 151.7 (C-pteridine-NH),
157.8 (C-Ar), 159.9 (CH-pteridine), 160.2 (C-pteridine) ppm.
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[1] J. H. Hoofnagle, Hepatology 1997, 26, S15–S20.
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8,12-Difluoro-N-(4-methylcyclohexyl)-10H-dibenzo[3,4:6,7]cyclo-
hepta[1,2-g]pteridin-4-amine (8) and (8Ј): Reaction of compound 4
yielded the trans isomer 8 (30.0 mg) and the cis isomer 8Ј (22.0 mg).
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trans Isomer 8: M.p. 285.7–286.3 °C. H NMR (CDCl3, 400 MHz,
T = 55 °C): δ = 0.96 (d, J = 6.5 Hz, 3 H, CH3-cyclohexyl), 1.31–
1.39 (m, 2 H, H3Јax, H5Јax), 1.67–1.75 (m, 3 H, H2Јax, H6Јax, H4Јax),
1.80–1.86 (m, 2 H, H3Јeq, H5Јeq), 1.89–1.97 (m, 2 H, H2Јeq, H6Јeq),
[7] Y. Ding, J. L. Girardet, K. L. Smith, G. Larson, B. Prigaro,
V. C. H. Lai, W. D. Zhong, J. Z. Wu, Bioorg. Med. Chem. Lett.
2005, 15, 675–678.
3.8 (s, 2 H, ArCH2Ar), 4.20–4.24 (m, values of constant couplings
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were derived from homonuclear decoupling experiments: JHCNH
=
8.5, Jax-ax = 2ϫ11.0, Jax-eq = 2ϫ3.5 Hz, 1 H, H1Јax), 7.0 (d, J =
3
3
[8] R. W. Marquis, Y. Ru, S. M. LoCastro, J. Zeng, D. S. Yamash-
ita, H.-J. Oh, K. F. Erhard, L. D. Davis, T. A. Tomaszek, D.
Tew, K. Salyers, J. Proksch, K. Ward, B. Smith, M. Levy, M. D.
Cummings, R. C. Haltiwanger, G. Trescher, B. Wang, M. E.
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Janson, B. Zhao, M. S. McQueney, K. DЈAlessio, C.-P. Lee, A.
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8.5 Hz, 1 H, NH), 7.05–7.1 (m, 4 H, Ar-H), 7.87 (dd, JHH = 8.5,
4JHF = 5.7 Hz, 1 H, Ar-H), 8.18 (dd, JHH = 8.5, JHF = 5.7 Hz, 1
H, Ar-H), 8.81 (s, 1 H, H-pteridine) ppm. 13C NMR (CDCl3,
100 MHz): δ = 22.1 (CH3), 31.9 (CH), 32.8 (CH2), 33.8 (CH2), 39.8
3
4
2
(ArCH2Ar), 50.3 (CHNH), 114.1 (d, JCF = 22.0 Hz, CH-Ar-F),
114.2 (d, 2JCF = 22.0 Hz, CH-Ar-F), 114.3 (d, 2JCF = 21.5 Hz, CH-
Ar-F), 114.5 (d, 2JCF = 21.5 Hz, CH-Ar-F), 124.7 (C-Ar), 131.5 (d,
4JCF = 3.5 Hz, C-Ar-F), 131.6 (d, JCF = 3.5 Hz, C-Ar-F), 133.2
4
[9] N. A. Domnin, R. C. Kolinskii, Zh. Obshch. Khim. 1960, 30,
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(d, JCF = 9.0 Hz, CH-Ar-F), 134.3 (d, JCF = 9.0 Hz, CH-Ar-F),
143.5 (d, JCF = 8.4 Hz, C-Ar-F), 143.6 (d, JCF = 8.4 Hz, C-Ar-
F), 149.1, 151.8, 156.5, 160.0 (C-Ar), 160.2 (CH-pteridine), 164.1
270–275.
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[10] T. De Paulis, C. R. Betts, H. E. Smith, P. L. Mobley, D. H.
Manier, F. Sulser, J. Med. Chem. 1981, 24, 1021–1026.
Eur. J. Org. Chem. 2007, 2987–2994
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