S. Weyler et al. / Bioorg. Med. Chem. Lett. 18 (2008) 223–227
227
6. Moriyama, T.; Iida, T.; Kobayashi, T.; Higashi, T.;
Fukuoka, T.; Tsumura, H.; Leon, C.; Suzuki, N.; Inoue,
K.; Gachet, C.; Noguchi, K.; Tominaga, M. J. Neurosci.
2003, 23, 6058.
using a Knauer HPLC instrument equipped with a pump
K1800, a UV detector K-2600, and a Eurospher 100 C 18
column, 10 lM, 250 · 20 mm (ID). An amount of 3 ml
containing 30 mg of product was injected and the separa-
tion was performed for 15 min at a flow rate of 30 mL/min
under the following conditions: isocratic elution
(H2O:methanol = 65:35) for 1 min, followed by a gradient
from H2O:methanol (65:35) to H2O:methanol (26:74) for
14 min.
7. (a) Iqbal, J.; Vollmayer, P.; Braun, N.; Zimmermann, H.;
Muller, C. E. Purinergic Signal. 2005, 1, 349; (b) Iqbal, J.;
¨
Jirovsky, D.; Lee, S.-Y.; Zimmermann, H.; Muller, C.E.
¨
Anal. Biochem. 2007, in press.
8. Fields, R. D.; Burnstock, G. Nat. Rev. Neurosci. 2006, 7,
423.
9. Gla¨nzel, M.; Bultmann, R.; Starke, K.; Frahm, A. W. Eur.
15. Baqi, Y.; Muller, C. E. Org. Lett. 2007, 9, 1271.
¨
16. Compound 13 was prepared according to the general
procedure13 using 2-ethoxyaniline (0.339 g, 0.324 mL).
Yield: 52%; HPLC retention time: 9.1 min. 1H NMR
(DMSO-d6, 500 MHz, 293 K): d [ppm] = 1.33 (t, 3H,
3J = 6.9 Hz, CH3); 4.12 (q, 2H 3J = 7.0 Hz, OCH2);
6.96–7.02 (m, 1H, C40H or C50H); 7.13-7.16 (m, 2H
¨
J. Med. Chem. 2003, 38, 303.
10. Van de Waterbeemd, H. Structure-Property Correlations
in Drug Research; Academic Press and R.G. Landes
Company: USA, 1996.
11. (a) Brown, J.; Brown, C. A. Vascul. Pharmacol. 2002, 39,
309; (b) Tuluc, F.; Bultmann, R.; Gla¨nzel, M.; Frahm, A.
¨
3
C30H or C60H, C40H or C50H); 7.28 (d, 1H, J = 7.6 Hz,
W.; Starke, K. Naunyn-Schmiedeberg’s Arch. Pharmacol.
1998, 357, 111; (c) Gla¨nzel, M.; Bultmann, R.; Starke, K.;
C30H or C60H); 7.48 (br, 1H, NH2); 7.83 (td, 1H,
3J = 7.2 Hz, 4J = 2.1 Hz, C6H or C7H); 7.85 (td, 1H,
3J = 7.2 Hz, 4J = 2.2 Hz, C6H or C7H); 7.95 (s, 1H, C3H);
8.25–8.29 (m, 2H, C5H,C8H); 10.11 (br, 1H, NH2); 11.96
(s, 1H, NH). 13C NMR (DMSO-d6, 125 MHz, 293 K): d
[ppm] = 14.78 (CH3); 64.14 (OCH2); 109.30, 111.57 (C4a,
C9a); 113.49 (C30); 120.95 122.73 (C3); 123.35, 125.19
(C40, C50, C60); 126.11, 126.15 (C5, C8); 128.42 (C10);
132.86, 133.18, 133.81, 134.28 (C6, C7, C8a, C10a);
140.74, 142.58, 144.39 (C1, C2, C4); 151.16 (C20);
181.93, 182.37 (C9, C10). LC-MS m/z (%) = 437.0 (100;
[C22H17N2O6S]ꢀ); 407.9 (47; [C20H12N2O6S]ꢀ); 255.1 (29;
[C14H11N2O3]ꢀ). Purity by HPLC-UV (254 nm)-ESI-MS:
100%. Anal Calcd for C22H17N2O6SÆNaÆ3H2O: C, 51.36;
H, 4.51; N, 5.44. Found: C, 51.39; H, 4.21; N, 5.28. UV
¨
Frahm, A. W. Eur. J. Med. Chem. 2005, 40, 1262; (d)
Gla¨nzel, M.; Bultmann, R.; Starke, K.; Frahm, A. W.
¨
Drug Dev. Res. 2003, 59, 64.
12. (a) Ullmann, F. Chem. Ber. 1903, 36, 2382; (b) Ullmann,
F. Chem. Ber 1904, 37, 853; (c) Lindley, J. Tetrahedron
1984, 40, 143.
13. Synthetic procedure. Bromaminic acid sodium salt (2,
0.250 g, 0.62 mmol), anhydrous copper(II)sulfate (0.015 g,
0.09 mmol), and sodium carbonate (0.085 g, 0.80 mmol)
were added to polypropylene reaction vials (MiniBlockTM
48, Mettler Toledo). Then 2.48 mmol of the corresponding
aniline derivative (see Table 2) and 2–3 mL of water were
added. The reactor was locked and fixed on the shaking-
washing unit (Mettler Toledo). The mixtures were shaken
for 2 days at 90 ꢁC. Then the vials were filtered and the
filter residues were washed 3 times with 2 mL of dichlo-
romethane each. Then the filter residues were suspended in
a mixture of water and methanol (50:50), and the water–
methanol solution was combined with the aqueous layer,
put into round-bottom flasks and the solvent was evap-
orated under reduced pressure. The residue was taken up
in water and washed several times with dichloromethane
until the organic phase was clear and colorless. The
volume of the aqueous phase was reduced by rotary
evaporation and subsequently subjected to lyophilization.
14. HPLC purification method. The lyophilized solid products
were dissolved in 50 mL of a mixture consisting of
water:methanol = 65:35 and filtered through a microfilter
(0.45 lm) to remove insoluble materials. The solutions
were subsequently subjected to HPLC chromatography
absorption (CH3OH):
kmax = 464 nm. Fluorescence
(CH3OH): kmax = 740 nm.
17. Hamprecht, B. Int. Rev. Cytol. 1977, 49, 99.
18. (a) Kaulich, M.; Streicher, F.; Mayer, R.; Muller, I.;
¨
Muller, C. E. Drug Dev. Res. 2003, 59, 72; (b) Knoblauch,
¨
B. H. A.; Muller, C. E.; Ja¨rlebark, L.; Lawoko, G.;
¨
Kottke, T.; Wikstro¨m, M. A.; Heilbronn, E. Eur. J. Med.
Chem. 1999, 34, 809.
19. El-Tayeb, A.; Qi, A.; Muller, C. E. J. Med. Chem. 2006,
49, 7076.
¨
20. Muller, C. E.; Daly, J. W. Biochem. Pharmacol. 1993, 46,
¨
1825.
21. Kassack, M. U.; Ho¨fgen, B.; Lehmann, J.; Eckstein, N.;
Quillan, J. M.; Sadee, W. J. Biomol. Screen. 2002,
7, 233.
22. Baqi, Y.; Muller, C. E. J. Org. Chem. 2007, 72, 5908–5911,
¨
unpublished work.