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Tacrine-pyridinothiophene compounds and preparation method and applications thereof

A tacrine and compound technology, applied in the field of medicine, can solve the problems of difficulty in achieving expected effects, inability to determine the dosage of administration, and difficulty in synthesizing multi-target drug molecules.

Active Publication Date: 2019-08-20
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, there are various problems and challenges in the design and development of GSK-3β / ChE dual-target compounds: (1) In order to meet the requirements of the dual-target drug for the pharmacophore, the dual-target drug molecules are usually compared in terms of molecular size and relative molecular mass. Single-target drug molecules are larger and more complex in structure. Due to the existence of steric hindrance, the synthesis of multi-target drug molecules is often difficult; (2) dual-target drugs need to balance the activity of different targets, so that Reasonable and balanced, if the activity of different targets is quite different, it is impossible to determine the appropriate dosage and it is difficult to achieve the expected effect

Method used

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  • Tacrine-pyridinothiophene compounds and preparation method and applications thereof
  • Tacrine-pyridinothiophene compounds and preparation method and applications thereof
  • Tacrine-pyridinothiophene compounds and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] N-(4-cyanopyridine)cyclopropanecarboxamide (7)

[0078]

[0079] 2-Amino-4-cyanopyridine (6) (2.48g, 20mmol) was dissolved in dry DCM (240mL), a small amount of triethylamine was added to aid dissolution, and then potassium carbonate (14g, 5eq) was added, Stir at room temperature for 10 minutes, and in an ice bath for 10 minutes. Cyclopropylformyl chloride (5.6mL, 3eq) was dissolved in 15mL of DCM, and added dropwise to the reaction solution using a separatory funnel, and finally DMAP (200mg, 0.1eq) was added, and reacted at room temperature for 16 hours after ice bathing for 10 minutes. The completion of the reaction was monitored by TLC. Potassium carbonate was removed by suction filtration with filter paper and diatomaceous earth, the filter cake was washed with DCM, and the filtrate was directly spin-dried for the next reaction. Pure product 2 is a white powder with a yield of 92%.

[0080] (4-carbothiopyridine)carbamoyl chloride (8)

[0081]

[0082] Compoun...

Embodiment 2

[0129] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-methoxy-N-(2-((1,2,3,4-tetrahydroacridine)amino)propyl)thiazole-5- Formamide (2b)

[0130]

[0131] Referring to the synthesis method of Example 1, 12b was substituted for 12a in Example 1 to obtain a yellow solid compound with a yield of 43%. 1 H NMR (300MHz, DMSO-d 6 ,δppm): 11.03(s,1H,-CONH-),8.62(s,1H,-CONH-),8.45(d,J=5.1Hz,1H-N H CH 2 -), 8.35(d, J=8.6Hz, 1H, Ar-H), 7.74-7.82(m, 4H, Ar-H), 7.49-7.56(m, 2H, Ar-H), 4.08(s, 3H ,-OCH 3 ),3.92(d,J=5.7Hz,2H,-C H 2 NH-),3.39(d,J=5.7Hz,2H,-C H 2 NH-), 2.89(t, J=9.1Hz, 2H, Ar-CH 2 -), 2.64(t, J=9.1Hz, 2H, Ar-CH 2 -),2.03(m,1H,-CHCO-),2.01(m,2H,-CH 2 -),1.79(m,4H,-(CH 2 ) 2 -),0.85(m,4H,-(C H 2 )CH-); 13 C NMR (75MHz, DMSO-d 6 ,δppm):173.6,163.2,161.1,160.3,156.36,153.6,149.8,141.0,138.3,133.2,129.3,125.6,125.4,121.2,119.5,115.9,115.5,111.57,110.1,189.7,2 40.5, 40.5, 40.4, 40.3, 40.2, 40.0, 39.9, 39.7, 39.5, 37.1, 30.3, 28.4, 24.3, 21.9, 20.7, 14.8, 8.4; HRMS(m / z...

Embodiment 3

[0133] 2-(2-(Cyclopropanecarboxamido)pyridine)-4-methoxy-N-(2-((1,2,3,4-tetrahydroacridine)amino)hexyl)thiazole-5-carba Amide (2c)

[0134]

[0135] Referring to the synthesis method of Example 1, 12d was substituted for 12a in Example 1 to obtain a yellow solid compound with a yield of 36%. 1 H NMR (300MHz, DMSO-d 6 ,δppm):11.02(s,1H,-CONH-),8.60(s,1H,-CONH-),8.45(dd,J=8.5,2.6Hz,1H,Ar-H),8.31(dd,J= 8.5,2.6Hz,1H,Ar-H),7.86(d,J=8.2Hz,1H,Ar-H),7.78(t,J=8.2Hz,1H,Ar-H),7.58(m,1H, Ar-H),7.51(m,2H,Ar-H),4.11(s,3H,-OCH 3 ),3.78(t,J=6.1Hz,2H,-C H 2 NH-),3.23(d,J=6.1Hz,2H,-C H 2 NH-),2.95(m,2H,Ar-CH 2 -),2.62(m,2H,Ar-CH 2 -),2.03(m,1H,-CHCO-),1.79(m,2H,-CH 2 -),1.70(m,2H,-CH 2 -),1.48(m,2H,-CH 2 -),1.31(m,2H,-CH 2 -),1.29(m,4H,-(CH 2 ) 2 -),0.83(t,J=6.1Hz,4H,-(C H 2 )CH-); 13 C NMR (75MHz, DMSO-d 6 ,δppm): 173.6, 162.9, 161.0, 159.9, 158.6, 158.3, 155.7, 153.6, 151.7, 149.8, 149.0, 141.0, 139.9, 139.1, 135.0, 132.6, 128.2, 125.3, 620.4, 118.5, 119.9, 115.4, 112.0...

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Abstract

The invention belongs to the medicine field, and relates to tacrine-pyridinothiophene compounds and applications thereof. The saccharides of tacrine-pyridinothiophene compounds have activity on inhibiting kinase-3beta acetyl cholinesterase dual targets. The compounds can be used as a precursor for preventing Alzheimer's disease by inhibiting the activity of cholinesterase.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a tacrine-pyridothiophene compound and a preparation method thereof, and the application of the compound in the preparation of a drug for treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is an extremely complex neurodegenerative syndrome of the brain, and so far no conclusion has been drawn about its exact cause. At present, it is believed that AD is the result of a combination of multiple etiologies, and more than a dozen AD theories have been proposed from the perspective of pathogenesis, such as the cholinergic theory, the amyloid (β-amyloid, Aβ) cascade theory, the tau protein theory, and the metalloid theory. Ion theory, oxidative stress theory, immune inflammation theory, nerve cell apoptosis theory, glutamate function theory, etc. The theory of cholinergic damage holds that a large number of cholinergic neurons in the basal layer and cerebral cort...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/473A61P25/28
CPCC07D417/14A61P25/28
Inventor 冯锋孙昊鹏周俊廷蒋学阳曲玮柳文媛
Owner CHINA PHARM UNIV
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