High-tension condensed ring nicotine analogue, preparation process and use thereof

A technology for nicotine and analogues, which is applied in the field of ternary condensed ring nicotine analogues, can solve problems such as limiting medicinal value, and achieve the effects of simple synthesis methods, high yields, and good water solubility

Inactive Publication Date: 2002-12-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

Many studies have confirmed that the natural alkaloid nicotine has a certain effect on the treatment and alleviation of Parkinson's disease, Alzheimer's disease and Tourette's disease, but its inherent toxic and side effects on the cardiovascular and digestive system greatly limit its medicinal value[ Chem. Eng. News 2000, 78, 23-26]

Method used

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  • High-tension condensed ring nicotine analogue, preparation process and use thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] n-Butyllithium (2.76 mmol) was added dropwise to a solution of compound 5 (2.3 mmol) in THF (25 mL) at -78°C. After stirring for 30 minutes, a solution of DMF (3.45 mmol) in THF (3 mL) was added dropwise at this temperature. Continue to stir the reaction for 1 hour, add saturated NaCO 3 The reaction was quenched by the solution, the organic solvent was spin-dried at room temperature, and the aqueous phase was washed with CH 2 Cl 2 Extraction, the combined organic phases were washed with brine, MgSO 4 After drying and separation by column chromatography, the intermediate alkene-substituted pyridine-3-carbaldehyde derivative (2) is obtained with a yield of 70-90%.

[0014] The result is as follows:

[0015] 1 H NMR (CDCl 3 , 300MHz) δ: 3.34(s, 3H), 4.63(d, J=6.6Hz, 1H), 4.79(d, J=6.6Hz, 1H), 5.22-5.42(m, 2H), 5.86-5.98(m , 2H), 7.64 (d, J=5Hz, 1H), 8.79 (d, J=5Hz, 1H), 9.01 (s, 1H), 10.31 (s, 1H).

[0016] MS (EI): 207 (M + ).

[0017] 1 H NMR (CDCl 3 , 30...

Embodiment 2

[0022] n-Butyllithium (2.76 mmol) was added dropwise to a solution of compound 5 (2.3 mmol) in ether (25 mL) at room temperature. After the reaction was stirred for 30 minutes, a solution of DMF (3.45 mmol) in diethyl ether (3 mL) was added dropwise at this temperature within 10 minutes. Continue to stir the reaction for 1 hour, add saturated NaCO 3 The reaction was quenched by the solution, the organic solvent was spin-dried at room temperature, and the aqueous phase was washed with CH 2 Cl 2 Extraction, the combined organic phases were washed with brine, MgSO 4 After drying and separation by column chromatography, the intermediate alkene-substituted pyridine-3-carbaldehyde derivative (2) is obtained with a yield of 70-90%.

[0023] 1 H NMR (CDCl 3 , 300MHz) δ: 1.67-1.80(m, 2H), 2.25-2.32(m, 2H), 3.34(s, 3H), 4.58(d, J=3.3Hz, 1H), 4.65(d, J=3.5Hz , 1H), 4.99-5.09(m, 2H), 5.49(t, J=6.2Hz, 1H), 5.77-5.93(m, 1H), 7.64(d, J=5.2Hz, 1H), 8.79(d, J=5.2Hz, 1H), 9.00(s, 1H), ...

Embodiment 3

[0027] Dissolve 4-allylpyridine-3-carbaldehyde derivatives (0.1mmol), N-methylglycine (0.3mmol) and dibutyltin dichloride (0.2mmol) in toluene, and react at 40°C for 5 hours or React at reflux temperature for 1 hour, and the product is separated by column chromatography to obtain a three-membered condensed ring nicotine analog with a yield of 55-80%.

[0028] The result is as follows:

[0029] 1 H NMR (CDCl 3 , 300MHz) δ: 2.19-2.27(m, 2H), 2.49(s, 3H), 3.00-3.13(m, 3H), 3.46(s, 3H), 3.87(d, J=7.8Hz, 1H), 4.80 -4.87(m, 2H), 5.12(d, J=4.5Hz, 1H), 7.32(d, J=5.2Hz, 1H), 8.52(d, J=5.2Hz, 1H), 8.68(s, 1H) .

[0030] 13 C NMR (CDCl 3 ,75MHz)δ:24.38,29.66,40.53,41.78,46.14,52.83,55.69,56.03,57.28,58.62,71.68,72.71,78.17,88.13,95.41,96.65,120.45,120.57,137.88,138.28,146.60,147.26,148.99 , 149.53, 151.70, 152.51.

[0031] MS (EI): 235 (M + +1).

[0032] Elemental analysis (C 13 h 18 N 2 o 2 ): Theoretical (%): C, 66.67; H, 7.69; N, 11.97. Measured (%): C, 66.39; H, 7.87;...

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Abstract

The present invention relates to a ternary fused ring nicotine analogues and its intermediate product. Said invention provides its molecular formula, and said compound is high in chemical stability, good in water soluble property, and can be used for preparing the medicines for curing the diseases (such as senile dementia, etc.) due to nerve degeneration and disturbance.

Description

technical field [0001] The invention relates to a high-tension three-membered fused-ring nicotine analogue (1), which is formed by linking the C4 position of the pyridine ring and the C3' position of the pyrrole ring in the nicotine structural unit (3) through a certain carbon chain. technical background [0002] In the process of developing drugs for treating neurodegenerative diseases, it was found that the nicotine acetylcholine receptor (nAChR) in neurons is an important class of target molecules [Neuropharmacology 1995, 34, 563]. Many studies have confirmed that the natural alkaloid nicotine has a certain effect on the treatment and alleviation of Parkinson's disease, Alzheimer's disease and Tourette's disease, but its inherent toxic and side effects on the cardiovascular and digestive system greatly limit its medicinal value[ Chem. Eng. News 2000, 78, 23-26]. By systematically studying and summarizing the structure-activity relationship of nAChR ligands [J.Med.Chem....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/437A61P25/16A61P25/28C07D213/48C07D471/04
Inventor 翟宏斌刘澎罗盛军方芳王予曼
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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