Mar-Apr 2002
Synthesis of 4,7,8a,9-Tetrahydro-3H-diimidazo[1,5-a:4',5'-d]pyridine Derivatives
419
Anal. Calcd. for C H N O Cl•1.4H O: C, 51.27; H, 4.21; N,
(CDCl ): δ 2.31 (s, 6H), 2.60-2.69 (m, 3H), 3.14 (dd, 1H, J = 14.8
14 11
4
2
2
3
Hz., J = 5.5 Hz.), 3.69 (t, 2H, J = 6.0 Hz.), 4.13-4.30 (m, 3H),
17.09. Found: C, 51.68; H, 3.99; N, 16.52.
13
4.87 (d, 1H, J = 15.4 Hz.), 7.57 (s, 1H). C-NMR (CDCl ): δ
3
(8aS)-7-(4'-Trifluoromethylphenyl)-4,7,8a,9-tetrahydro-3H-
diimidazo[1,5-a:4',5'-d]pyridine-6,8-dione (6).
24.1, 36.3, 38.2, 45.1, 54.8, 56.4, 123.3, 127.6, 135.5, 154.9,
172.3. α = +10.10° (c 0.20, CHCl ).
D
3
This compound was obtained in 40% yield, mp 130 °C
(dc.)(toluene/hexane). IR υ cm : 3110, 1780, 1710. H-NMR
Anal. Calcd. for C H N O •1.2H O: C, 50.59; H, 6.81; N,
24.59. Found: C, 50.55; H, 6.70; N, 24.62.
12 17
5
2
2
-1
1
(CDCl ): δ 2.97 (dd, 1H, J = 14.8 Hz., J = 11.0 Hz.), 3.34 (dd,
1H, J = 14.8 Hz., J = 4.9 Hz.), 4.38 (d, 1H, J = 15.4 Hz.), 4.44
(dd, 1H, J = 11.0 Hz., J = 4.9 Hz.), 5.07 (d, 1H, J = 15.4 Hz.),
3
(8aS)-7-(3-Dimethylaminopropyl)-4,7,8a,9-tetrahydro-3H-diimi-
dazo[1,5-a:4',5'-d]pyridine-6,8-dione (10).
7.64 (s, 1H), 7.65 (d, 2H, J = 8.5 Hz.), 7.75 (d, 2H, J = 8.5 Hz.).
This compound was obtained in 13% yield, mp 132-134 °C
(ethyl acetate/chloroform). IR υ cm : 3250, 1770, 1710. H-
13
-1
1
C-NMR (CDCl ): δ 24.4, 38.8, 54.8, 122.9, 123.6 (q, J = 270.9
3
Hz.), 125.9, 126.2 (q, J = 3.7 Hz.), 128.3, 130.0 (q, J = 32.9 Hz.),
NMR (CDCl ): δ 1.80-1.85 (m, 2H), 2.24 (s, 6H), 2.37 (t, 2H, J =
3
134.5, 135.4, 153.4, 170.5. α = -21.05° (c 0.19, CHCl ).
7.1 Hz.), 2.76 (dd, 1H, J = 15.4 Hz., J = 10.5 Hz.), 3.19 (dd, 1H,
J = 15.4 Hz., J = 6.0 Hz.), 3.60 (t, 2H, J = 7.1 Hz.), 4.20-4.28 (m,
D
3
Anal. Calcd. for C H N O F •1.5H O: C, 49.58; H, 3.86; N,
15 11
4
2
3
2
13
2H), 4.93 (d, 1H, J = 13.3 Hz.), 7.59 (s, 1H). C-NMR (CDCl ):
15.42. Found: C, 49.57; H, 3.86; N, 15.46.
3
δ 24.1, 25.8, 36.8, 38.2, 44.9, 54.8, 56.4, 123.2, 127.6, 135.3,
(8aS)-7-Allyl- 4,7,8a,9-tetrahydro-3H-diimidazo[1,5-a:4',5'-d]-
pyridine-6,8-dione (7).
154.9, 172.2. α = +94.7° (c 0.11, CHCl ).
D
3
Anal. Calcd. for C H N O •1.7H O: C, 50.71; H, 7.28; N,
13 19
5
2
2
This compound was obtained in 53% yield, mp 48-50 °C
22.75. Found: C, 50.87; H, 7.13; N, 22.29.
-1
1
(toluene). IR υ cm : 3110, 1780, 1710. H-NMR (CDCl ): δ
3
(8aS)-7-(3-Diethylaminoethyl)-4,7,8a,9-tetrahydro-3H-diimi-
dazo[1,5-a:4',5'-d]pyridine-6,8-dione (11).
2.79 (dd, 1H, J = 14.8 Hz., J = 11.2 Hz.), 3.23 (dd, 1H, J = 14.8
Hz., J = 5.2 Hz.), 4.16 (d, 1H, J = 5.5 Hz.), 4.23-4.30 (m, 2H),
4.96 (d, 1H, J = 15.4 Hz.), 5.21 (d, 1H, J = 7.7 Hz.), 5.26 (d, 1H,
This compound was obtained in 20% yield, mp 107-110 °C
-1
1
13
(ethyl acetate/hexane). IR υ cm : 3280, 1760, 1700. H-NMR
J = 14.3 Hz.), 5.80-5.89 (m, 1H), 7.62 (s, 1H). C-NMR
(CDCl ): δ 1.10 (t, 6H, J = 7.1 Hz.), 2.75 (q, 4H, J = 7.1 Hz.),
(CDCl ): δ 24.3, 38.4, 40.8, 55.0, 118.1, 123.2, 128.2, 131.0,
3
3
2.83-2.85 (m, 3H), 3.20 (dd, 1H, J = 14.8 Hz., J = 5.5 Hz.), 3.72
(t, 2H, J = 6.6 Hz.), 4.23-4.29 (m, 2H), 4.92 (d, 1H, J = 15.4 Hz.),
135.3, 154.8, 171.8. α = -121.4° (c 0.21, CHCl ).
D
3
Anal. Calcd. for C H N O : C, 56.89; H, 5.21; N, 24.12.
11 12
4 2
13
7.60 (s, 1H). C-NMR (CDCl ): δ 11.5, 24.2, 36.5, 38.4, 46.9,
Found: C, 57.22; H, 5.55; N, 23.73.
3
49.7, 55.0, 123.2, 128.4, 135.3, 155.1, 172.4. α = +16.5° (c
D
(8aS)-3-Bencyl-7-ethyl-4,7,8a,9-tetrahydro-3H-diimidazo-
[1,5-a:4',5'-d]pyridine-6,8-dione (8).
0.18, CHCl ).
3
Anal. Calcd. for C H N O •0.4H O: C, 56.34; H, 7.31; N,
14 21
5
2
2
This compound was obtained in 40% yield, mp 188-190 °C
23.47. Found: C, 56.51; H, 7.09; N, 23.72.
-1
1
(hexane). IR υ cm : 3080, 1760, 1700. H-NMR (DMSO-d ): δ
6
Acknowledgements.
1.07 (t, 3H, J = 5.5 Hz.), 2.57 (dd, 1H, J = 10.4 Hz., J = 5.5 Hz.),
2.89 (dd, 1H, J = 10.4 Hz., J = 5.5 Hz.), 3.40 (q, 2H, J = 6.7 Hz.),
3.97 (d, 1H, J = 15.2 Hz.), 4.31 (dd, 1H, J = 11.3 Hz., J = 5.5
Hz.), 4.60 (d, 1H, J = 15.2 Hz.), 5.16 (d, 1H, J = 15.8 Hz.), 5.24
The authors wish to thank Professor L. F. Alguacil's group for
the biological evaluation of these compounds. Cristina Guisado
also thanks Ministerio de Educación y Ciencia for the fellowship.
Continous support from San Pablo CEU University is greatfully
acknowledged.
(d, 1H, J = 15.8 Hz.), 7.22 (d, 2H, J = 7.9 Hz.), 7.36-7.39 (m,
13
3H), 7.78 (s, 1H). C-NMR (DMSO-d ): δ 13.3, 25.5, 32.9,
6
35.9, 47.8, 54.7, 121.3, 127.4, 127.8, 128.8, 132.3, 136.7, 137.6,
154.5, 172.1. α = -100.0° (c 0.02, MeOH).
D
REFERENCES
Anal. Calcd. for C H N O •1.1H O: C, 61.85; H, 6.12; N,
17 18
4
2
2
16.97. Found: C, 61.75; H, 6.07; N, 16.89.
[1] S. J. Hill, C. R. Ganellin, H. Timmerman, J.-C. Schwartz,
N. P. Shankley, J. M. Young, W. Schunack, R. Levi and H. L. Haas,
Pharmacol. Rev., 49, 253 (1997).
[2] J.-M. Arrang, M. Garbarg and J.-C. Schwartz, Nature,
302, 832 (1983).
[3] J.-M. Arrang, M. Garbarg and J.-C. Schwartz,
Neuroscience, 23, 149 (1987).
[4] E. Schlicker, B. Malinowska, M. Kathmann and M.
Göthert, Fundam. Clin. Pharmacol., 8, 128 (1994).
[5] H. Stark, E. Schlicker and W. Schunack, Drugs Future, 21,
507 (1996).
General Procedure for the Preparation of the 4,7,8a,9-Tetrahydro-
7-alkyl-3H-diimidazo[1,5-a:4',5'-d]pyridine-6,8-dione
Derivatives 9-11.
A solution of carbonyl diimidazole (18.54 mmol) in dry THF
(50 ml) was added drop wise to the appropriate amine (18.54
mmol) and the reaction mixture was stirred at room temperature
for 4-10 hours (TLC analysis). Then, it was added to a solution of
spinacine (18.54 mmol) in dry DMF (100 ml). The reaction mix-
ture was refluxed for 72 hours. After removal of the solvent, the
residue was purified by flash chromatography (eluent, AcOEt:
MeOH).
[6] R. Leurs, P. Blaudina, C. Tedford and H. Timmerman,
Trends Pharmacol. Sci., 19, 177 (1998).
[7] R. Leurs, R. C. Vollinga and H. Timmerman, Progress in
Drug Research, E. Jacker, Birkhausser Verlag. Basel (Switzerland),
1995, pp. 107-165.
(8aS)-7-(2-Dimethylaminoethyl)-4,7,8a,9-tetrahydro-3H-diimi-
dazo[1,5-a:4',5'-d]pyridine-6,8-dione (9).
This compound was obtained in 30% yield, mp 125-127 °C
(ethyl acetate/hexane). IR υ cm : 3300, 1770, 1710. H-NMR
[8 a] P. de Miguel, N. Martín and M. F. Braña, J.Heterocyclic
Chem., 31, 1235 (1994); [b] M. F. Braña, P. de Miguel, G. Klebe, N.
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1