GSK-3beta/ChE double inhibitor as well as preparation method and application thereof
A technology of inhibitors and solvates, applied in the field of medicine, can solve problems such as reduction and loss of binding effects
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[0111] Example 1
[0112] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxylic acid ethyl ester ( 2a)
[0113]
[0114] Compound 4 (666mg, 2mmol) and 9i (727mg, 3mmol) were dissolved in 55mL THF, triphenylphosphonium (1.57g, 6mmol) was added, and DIAD (1.2mL, 6mmol) was slowly added dropwise under the protection of argon under ice bath conditions. ), after the addition, the ice bath is removed and the reaction is at room temperature for 24 hours. The reaction solution was spin-dried, DCM was dissolved and separated by column chromatography to obtain the product (DCM / MeOH=30 / 1, v / v). The product was a pale yellow solid with a yield of 52%. 1 H NMR(300MHz, DMSO-d 6 ,δppm): 11.04(s,1H,-CONH-),8.51(m,1H,-NHCH 2 -), 8.42(m,2H,Ar-H),7.41-7.77(m,3H,Ar-H),7.41-7.49(m,2H,Ar-H),4.16(m,2H,-OCH 2 CH 3 ), 4.18(t,J=9.1Hz,2H,-CH 2 NH-), 3.29(m, 2H, -CH 2 NH-),2.99(m,2H,Ar-CH 2 -), 2.60(m,2H,Ar-CH 2 -),2.07(m,1H,-CHCO-),1.76(m,4H,-(CH 2 ) 2...
Example Embodiment
[0115] Example 2:
[0116] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxylic acid (2b)
[0117]
[0118] Dissolve 2a (55.7mg, 0.1mmol) in 3mL THF / MeOH mixed solution (THF / MeOH=2 / 1, v / v), add LiOH solution (400μL, 1.5mmol / mL) dropwise under ice bath, remove the ice After bathing, react at room temperature for 7 hours. TLC detects the completion of the reaction, removes the THF in the reaction solution by rotary evaporation at low temperature, adds 2 times the amount of water, adjusts the acid, and precipitates the solid. Suction filtration obtains a light yellow crystalline product (60.1 mg) with a yield of 87%. 1 H NMR(300MHz, DMSO-d 6 ,δppm): 10.94(s,1H,-CONH-),8.45(m,1H,-NHCH 2 -), 8.39 (m, 1H, Ar-H), 7.89 (m, 1H, Ar-H), 7.78 (m, 1H, Ar-H), 7.69 (t, J = 8.2 Hz, 1H, Ar-H ), 7.57(m,1H,Ar-H),7.38(t,J=8.2Hz,2H,Ar-H),4.83(t,J=8.2Hz,2H,-NHCH 2 -), 4.29(m,2H,-NHCH 2 -), 2.95(t,J=8.2Hz,2H,Ar-CH 2 -), 2.66(t,J=8.2Hz,2H,Ar-CH 2 -)...
Example Embodiment
[0119] Example 3:
[0120] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-(2-((1,2,3,4-tetrahydroacridine)amino)ethoxy)thiazole-5-carboxamide (2c)
[0121] Dissolve 2b (55.7mg, 0.1mmol) in 8mL DMF, add DIPEA (49.5μL, 0.3mmol) and HATU (53.2mg, 0.14mmol), activate for 3 hours at room temperature under argon protection and add NH 4 Cl (31.8 mg, 0.6 mmol) was reacted at room temperature under argon protection for 18 hours. The completion of the reaction was detected by TLC, the reaction solution was spin-dried to make sand, and a yellow solid product (DCM / MeOH=10 / 1, v / v) was obtained through column chromatography. The yield was 38%. 1 H NMR(300MHz, DMSO-d 6 ,δppm):11.00(s,1H,-CONH-),8.44(m,1H,-NHCH 2 -),8.31-8.42(m,3H,Ar-H),7.81(d,J=6.1Hz,1H,Ar-H),7.68(m,2H,-CONH 2 ), 7.30-7.40 (m, 2H, Ar-H), 6.97 (s, 1H, Ar-H), 4.81 (t, J = 8.2 Hz, 2H, -NHCH 2 -), 4.28(d,J=6.1Hz,2H,-NHCH 2 -), 2.91(t,J=8.2Hz,2H,Ar-CH 2 -), 2.65(d,J=8.2Hz,2H,Ar-CH 2 -),2.03(m,1H,-CHCO-),1.73(d,J=8.2Hz,4H,-(CH 2 ) 2 -),0.84(...
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