2100 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Fang et al.
allosteric characteroftheM1 receptor interaction of the hybrids
described would counterbalance their improved activity as
AChE inhibitors. For the design of hybrid molecules incorpor-
ating allosteric modulators, special attention has to be given to
the interplay of molecule components at the receptor level with
special regard to receptor activation. For potentially procogni-
tive agents the use of positive allosteric modulators (even with-
out ChE inhibiting properties) seems to be more promising.
(0.8 g, 3 mmol) were dissolved in 15 mL of dry CH2Cl2 and cooled
to -5 ꢀC. CBr4 (2.2 g, 6.5 mmol) dissolved in 5 mL of dry CH2Cl2
was dropped into the reaction solution slowly, controlling the
inside temperature to prevent it from increasing above 5 ꢀC. The
reaction was continued for another 24 h at room temperature.
The reaction solution was then extracted by 10% HCl aqueous
solution (3 ꢀ 15 mL), and the organic phases were discarded. The
aqueous phase was basified to pH 10 with 10% NaOH aqueous
solution. The solution was extracted with CH2Cl2 (3ꢀ 15mL).The
combined organic phases were dried over Na2SO4 and solvent was
removed under reduced pressure to give the crude product. The
purification was performed by column chromatography (eluent
CH2Cl2/MeOH = 10/1, v/v) to give 11 as a yellow oil (0.13 g,
Experimental Section
General Synthetic Methods. Melting points are uncorrected
and were measured in open capillary tubes using a Gallenkamp
melting-point apparatus. 1H NMR and 13C NMR spectral data
were obtained from Bruker Avance 250 (250 and 75 MHz).
Elemental analyses were performed on a Vario EL III apparatus
(Firma Elementar Analysensysteme GmbH, Germany). ESI
mass spectra were recorded using LCQ Advantage by Thermo-
Electron. Silica gel column chromatography utilized silica gel
60, 63-200 μm (Baker). As determined by elemental analysis,
the purity of all target compounds is >95%.
3-[(4-Pyridin-3-yl-1,2,5-thiadiazol-3-yl)oxy]propan-1-ol (8).
Sodium hydride (0.72 g, 30 mmol) was suspended in 30 mL of
freshly dried THF and cooled to 0 ꢀC by ice bath. Propane-1,3-
diol (1.1 mL, 15 mmol) was dropped into the mixture slowly.
The mixture was then refluxed for 1 h. Compound 716,28 (1.4 g,
7 mmol) dissolved in 10 mL of dry THF was added dropwise in
5 min. The reaction solution continued to reflux for 24 h. The
reaction was terminated by adding 10 mL of water to the cooled
solution. The solvent was removed under reduced pressure, and
the residue was extracted by CH2Cl2 (3 ꢀ 10 mL). The combined
organic phases were dried over Na2SO4 and concentrated
under reduced pressure to give the crude product. Purification
was performed by column chromatography (eluent CH2Cl2/
MeOH = 10/1, v/v) to give 8 as a yellow oil (1.04 g, 63%). 1H
NMR (CDCl3): δ 9.35 (s, 1H, arom), 8.65-8.62 (m, 1H, arom),
8.39-8.35 (m, 1H, arom), 7.40-7.35 (m, 1H, arom), 4.58
(t, J = 7.5 Hz, 2H, OCH2CH2), 3.75 (t, J = 7.5 Hz, 2H, CH2-
CH2OH), 2.53-2.48 (m, 2H, CH2CH2CH2) ppm.
1
42%). H NMR (CDCl3): δ 6.92-6.88 (m, 1H, CdCH), 4.51
(t,J=7.5Hz,2H,OCH2CH2),3.51(t,J=7.5Hz,2H,CH2CH2Br),
3.42 (s, 2H, H2CCdCH), 2.61-2.55 (m, 4H, dCHCH2CH2,
dCHCH2CH2), 2.37 (s, 3H, NCH3), 2.10-2.02 (m, 2H, CH2-
CH2CH2) ppm.
General Procedure for the Synthesis of 12a-d. Compounds
3a-d25 (2 mmol), compound 11 (0.64 g, 2 mmol), potassium
carbonate (0.28 g, 2 mmol), and catalytic amounts of potassium
iodide (0.1 g) were added to 5 mL of CH2Cl2 and stirred for 18 h
at room temperature. The mixture was filtered and the filtrate
was concentrated under reduced pressure to give the crude
product. The purification was performed by column chromato-
graphy (eluent CH2Cl2/MeOH = 7/3, v/v, plus 10 mL 25%
ammonia aqueous solution per 1000 mL) to give 12a-d. Full
spectral data for compounds 12a-d are presented in the Sup-
porting Information.
N-(3-{[4-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thi-
adiazol-3-yl]oxy}propyl)-N0-(1,2,3,4-tetrahydroacridin-9-yl)-
butane-1,4-diamine (12b). Brown oil, yield 45%. 1H NMR
(CDCl3): δ 8.11-8.08 (m, 1H, arom), 7.75-7.73 (m, 1H, arom),
7.55-7.52 (m, 1H, arom), 7.37-7.33 (m, 1H, arom), 6.93 (br, 1H,
CdCH), 4.66 (t, J = 7.5 Hz, 2H, OCH2), 3.57-3.54 (m, 2H,
ArNHCH2), 3.34 (s, 2H, H2CCdCH), 3.04 (br, 2H, C4-H2), 2.77
(br, 2H, C1-H2), 2.60 (t, J = 7.5 Hz, 2H, NHCH2CH2CH2O),
2.53-2.30 (m, 6H, CH2NH, dCHCH2CH2, dCHCH2CH2), 2.16
(s, 3H, NCH3), 2.02-1.98 (m, 2H, CH2CH2O), 1.84-1.54 (m, 8H,
C2-H2, C3-H2, ArNHCH2CH2CH2, ArNHCH2CH2) ppm.
General Procedure for the Synthesis of 14a-l. Compounds
13a-l27 (2 mmol), compound 10 (0.52 g, 2 mmol), potassium
carbonate (0.28 g, 2 mmol), and catalytic amounts of potassium
iodide (0.1 g) were added to 5 mL of CH2Cl2 and stirred for 18 h
at room temperature. The mixture was filtered and the filtrate
was concentrated under reduced pressure to give the crude
product. The purification was performed by column chromato-
graphy (eluent CH2Cl2/MeOH = 7/3, v/v, plus 10 mL 25%
ammonia aqueous solution per 1000 mL) to give 14a-l. Full
spectral data for compounds 14a-l are presented in the Sup-
porting Information.
2-(3-{[4-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thi-
adiazol-3-yl]oxy}propoxy)-N-[8-(1,2,3,4-tetrahydroacridin-
9-ylamino)octyl]acetamide (14i). Yellow oil, yield 34%. 1H NMR
(CDCl3): δ 8.36-8.32 (m, 1H, arom), 7.81-7.77 (m, 2H, arom),
7.57-7.53 (m, 1H, arom), 6.98 (br, 1H, CdCH), 4.71 (t, J =
7.5 Hz, 2H, CH2OCdN), 3.85 (s, 2H, OCH2CO), 3.72 (t, J =
7.5 Hz, 2H, OCH2CH2CH2), 3.42 (s, 2H, dCCH2N), 3.40-3.29
(m, 4H, ArNHCH2, CH2NHCO), 3.01 (br, 2H, C4-H2), 2.74-2.68
(m, 4H, C1-H2, dCHCH2CH2), 2.51-2.48 (m, 5H, dCHCH2-
CH2, NCH3), 2.04-2.01 (m, 2H, C3-H2), 1.93-1.40 (m, 16H,
ArNHCH2(CH2)6, C2-H2, CH2CH2O) ppm.
Experimental Procedures for the Pharmacological Investiga-
tions. Acetyl- and Butyrylcholinesterase Inhibition Assay. AChE
(E.C. 3.1.1.7, type VI-S, from Electric Eel) and BChE (E.C.
3.1.1.8, from equine serum) were purchased from Sigma-Aldrich
(Steinheim, Germany). DTNB (Ellman’s reagent) and ATC and
BTC iodides were obtained from Fluka (Buchs, Switzerland).
The assay was performed as described in the following
procedure:19,27 stock solutions of the test compounds were
3-[4-(3-Hydroxypropoxy)-1,2,5-thiadiazol-3-yl]-1-methylpyri-
dinium Iodide (9). CH3I (0.31 mL, 5 mmol) was added to a
solution of compound 8 (0.47 g, 2 mmol) in 5 mL of acetone. The
reaction solution was stirred at room temperature for 18 h, and a
yellow deposit formed. The deposit was filtered off, washed with
diethyl ether, and dried under reduced pressure to give 9 as a
yellow powder (0.67 g, 89%). Mp 164-166 ꢀC. 1H NMR
(CD3OD): δ 9.15 (s, 1H, arom), 8.76 (d, J = 7.5 Hz, 1H, arom),
8.49 (d, J = 7.5 Hz, 1H, arom), 7.79-7.72 (m, 1H, arom), 4.33
(s, 3H, NCH3), 4.28 (t, J = 7.5 Hz, 2H, OCH2CH2), 3.32 (t, J =
7.5 Hz, 2H, CH2CH2OH), 2.43-2.39 (m, 2H, CH2CH2CH2) ppm.
3-{[4-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-
3-yl]oxy}propan-1-ol (10). Compound 9 (0.85 g, 2.25 mmol) was
dissolved in 15 mL of absolute methanol and cooled to -5 ꢀC by
ice-salt bath. NaBH4 (0.25 g, 6.5 mmol) was carefully added to
the solution under strong gas formation. The reaction solution
was stirred for 24 h at room temperature. Then the reaction was
terminated by adding 10 mL of water. The sovent was removed
under reduced pressure, and the residuce was extracted with
CH2Cl2 (3 ꢀ 10 mL). The combined organic phases were dried
over Na2SO4 and concentrated under reduced pressure to give
the crude product. The purification was performed by column
chromatography (eluent CH2Cl2/MeOH = 10/1, v/v) to give 10
1
as a yellow oil (0.46 g, 81%). H NMR (CDCl3): δ 7.02-6.99
(m, 1H, CdCH), 4.58 (t, J = 7.5 Hz, 2H, OCH2CH2), 3.75 (t,
J = 7.5 Hz, 2H, CH2CH2OH), 3.42 (s, 2H, H2CCdCH), 2.59-
2.54 (m, 4H, dCHCH2CH2, dCHCH2CH2), 2.43 (s, 3H, NCH3),
2.10-2.02 (m, 2H, CH2CH2CH2) ppm.
5-[4-(3-Bromopropoxy)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-
tetrahydropyridine (11). Compound 10 (0.25 g, 1 mmol) and PPh3