Article
4-(7-Hydroxyimidazo[2,1-b]benzothiazol-2-yl)-N,N-dimethyl-
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 955
Weber, and Elisabeth Aiwanger for excellent technical support,
Antje Willuweit, Michael Schoor, and Heinzvon der Kammer
for provision of APP/PS1 (Arte10) animals, Prof. Johannes
Buchner and his group for electron microscopy of amyloid
aggregates and Prof. Axel Walch and Andreas Voss for excellent
technical support for fluorescence microscopy. This work was
supported by grants from Deutsche Forschungsgemeinschaft
(DFG) (Nos. HE4560/1-2, DR 445/3-1, and DR 445/4-1),
IRTG 1373 and Elite Network of Bavaria.
benzenamine (4c). Compound 3c (97 mg, 0.3 mmol) was reacted
with BBr3 following a procedure similar to that for compound
4a. The crude product was recrystallized from MeOH (87 mg,
90% yield) and used further for 11C-methylation reaction. LC-
MS-ESI [M þ 1] =310.1; DMSO-d6 1H NMR δ 2.89 (6H,s), 5.88
(1H,s), 6.26 (1H,s) 6.77 (2H,d), 7.65 (2H,d), 7.88 (1H,m), 8.41
(1H, s), 9.85 (1H, s); DMSO-d6 13C NMR δ 38.0, 107.4, 111.6,
113.3, 114.5, 114.9, 125.5, 128.6, 129.3, 130.2, 133.3, 134.6,
136.8, 147.3, 155.8.
4-(7-Methoxyimidazo[2,1-b]benzothiazol-2-yl)-benzenamine (4d).
A mixture of the nitro derivative 3e (321 mg, 0.99 mmol) and SnCl2
(5 equiv, 690 mg) in 20 mL of EtOH was heated for 2 h at reflux
temperature under nitrogen. The reaction mixture was concentrated
under vacuum, and the residue was taken up in 200 mL of ethyl
acetate, the organic phase was washed with 1 M NaOH solution,
followed by water, and subsequently dried over sodium sulfate, and
the solution was concentrated. The crude product was purified by
flash chromatography in DCM/methanol; then the solvents were
evaporated under reduced pressure and dried under high vacuum
(223 mg, 73% yield with HPLC purity of >98%) and directly used
as precursor for radiosynthesis of [11C]5. LC-MS-ESI [M þ 1] =
296.1; DMSO-d6 1H NMR δ 3.81 (3H,s), 5.16 (2H, s), 6.61 (2H,d),
7.11 (1H,dd) 7.48 (2H,d), 7.63 (1H,d), 7.82 (1H,d), 8.37 (1H, s);
DMSO-d6 13C NMR δ 55.8, 106.2, 109.4, 113.5, 113.9, 121.9, 125.6,
130.2, 145.5, 147.2, 148.0, 156.6).
Supporting Information Available: The experimental part of
HPLC purity measurements, animal studies, PET imaging, ex
vivo evaluation, general procedures for radiosynthesis, general
procedures for measurement of log P, and general procedures
for metabolite analyses. This material is available free of charge
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2-(p-Methylaminophenyl)-7-methoxyimidazo[2,1-b]benzothia-
zole (5). Compound 4d (295 mg, 1 mmol) was dissolved in DMF
(10 mL) and treated with potassium carbonate (anhydrous, 2
equiv, 280 mg). One equivalent of methyl iodide was added to
the mixture at 80 °C. The reaction mixture was cooled to room
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omatography. (108 mg, 35% yield with HPLC purity of>98%).
ESI-MS [Mþ1]=310.1; 1H NMR (DMSO-d6) δ 2.7 (d, J=5 Hz,
3H), 3.3 (s, 3H), 5.7 (br s, 1H), 6.6 (d, J=8.5 Hz, 2H), 7.1 (q, JA=
8.5, JB=2.5 Hz, 1H), 7.6 (m,4H), 8.4 (s, 1H); 13C NMR (DMSO-
d6) δ 30.2, 56.3, 106.8, 109.9, 112.1, 114.1, 118.8, 122.2, 126.1,
126.6, 130.7, 146.1, 147.6, 149.7, 157.1.
4-(7-Hydroxyimidazo[2,1-b]benzothiazol-2-yl)-benzenamine (6).
The compound 4d (59 mg, 0.2 mmol) was reacted with BBr3
and workup following a procedure similar to that for 4a, which
afforded the product (52 mg, 93% yield in>98% HPLC purity)
confirmed by LC-MS-ESI [M þ 1] =282.1; DMSO-d6 1H NMR
δ 7.02 (1H,dd), 7.39 (4H,m) 7.85 (3H,m), 8.07 (1H,dd), 8.85 (1H,
s); DMSO-d6 13C NMR δ 94.8, 108.0, 109.7, 114.4, 117.3, 123.0,
125.5, 130.5, 140.5, 142.5, 146.2, 155.7.
2-(p-Methylaminophenyl)-7-hydroxyimidazo[2,1-b] benzothia-
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mol equiv of BBr3 (1 M solution) in 5 mL of dichloromethane
under microwave heating at 150 °C for 30 min. The reaction
mixture was quenched with 10 mL of 1 N HCl and extracted
with 3 ꢀ 10 mL of CH2Cl2. The combined organic phase was
washed with saturated sodium bicarbonate solution (20 mL),
dried over sodium sulfate, and evaporated. The product (45 mg,
76% yield in >98% HPLC purity) was confirmed by LC-MS-
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1
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ESI [M þ 1] = 296.1; H NMR (500 MHz, DMSO-d6) δ 8.33
(1H, s), 7.72 (1H, J = 8.7, 0.4 Hz, dd), 7.57 (2H, J =8.7 Hz, d),
7.34 (1H, J =2.4, 0.4 Hz, dd), 6.93 (1H, J =2.9, 0.4 Hz, dd), 6.57
(2H, J =9.1 Hz, d), 3.33 (1H, s), 2.70 (3H, s); 13C NMR (126
MHz, DMSO-d6) δ 155.2, 150.5, 148.3, 147.4, 130.6, 126.4,
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Acknowledgment. We thank Katrina McGuire, Janette M.
Carlsen, Andrea Alke, Markus Sirl, Sybille Reder, Axel