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N-substituted gardenamide A derivative and synthesis method and application thereof

A synthesis method and technology of derivatives, applied in the preparation of drugs for the treatment of senile dementia, N-substituted gardenamide A derivatives and its synthesis field, can solve problems such as poor stability, achieve mild reaction conditions, high yield, The effect of high product purity

Inactive Publication Date: 2013-04-24
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In order to overcome the defect of poor stability of genipin, the primary purpose of the present invention is to provide a kind of N-substituted gardenamide A derivative, which uses genipin as a structural template and transforms genipin by chemical modification Obtained after; the derivative has high stability and strong neuroprotective activity

Method used

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  • N-substituted gardenamide A derivative and synthesis method and application thereof
  • N-substituted gardenamide A derivative and synthesis method and application thereof
  • N-substituted gardenamide A derivative and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation, separation and purification of N-methyl gardenamide A (i.e. compound 1) includes the following steps:

[0048] (1) Preparation of 7-(O-dimethyltert-butylsilyloxy)methylgenipin: Add genipin 0.339g (1.5mmol) and 0.5mL dry DMF into a 10mL reaction flask, then add imidazole 0.204 g (3.0mmol), and finally a DMF solution containing 0.27g (1.8mmol) of dimethyl tert-butylsilyl chloride (TBS-Cl) was added dropwise, stirred at room temperature for 1h, then added 100mL DCM for extraction, washed 3 times with water (3 ×100ml), the organic phase was dried with anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a light yellow oily solid, which was separated by column chromatography of a mixed solution of petroleum ether-ethyl acetate (volume ratio 9:1) to obtain a white solid 0.453 g, yield 89.0%.

[0049] The structural characterization data of the product are as follows, which is 7-(O-dimethyltert-butylsilyloxy)methylgenipin. ...

Embodiment 2

[0059] The preparation and separation and purification of N-isopropyl gardenamide A (i.e. compound 3), the steps and raw materials are the same as in Example 1, only in step 3, 0.1ml (1.2mmol) of isopropylamine was used instead of methylamine hydrochloride, and finally After separation and purification by HPLC, 20.7 mg of a white solid compound was obtained, with a yield of 52%.

[0060] The structural characterization data of the product are: 1 H NMR (300MHz, CDCl 3 )δ:7.29(s,1H),5.81(s,1H),4.90-4.81(m,1H),4.37-4.27(m,2H),3.76(s,3H,-OCH 3 ),3.64(d,J=11.1Hz,1H),3.51-3.45(m,1H),2.91-2.83(m,1H),2.25-2.16(m,1H),1.21(t,J=6.9Hz, 6H); 13 C NMR (75MHz, CDCl 3 )δ: 169.96(C-11), 166.89(C-1), 141.30(C-3), 132.58(C-8), 129.27(C-7), 111.57(C-4), 60.99(C-10 ),51.60(-OCH 3 ),50.65(-NCH),45.25(C-9),40.00(C-6),36.82(C-5),21.06(-CH( C h 3 ) 2 ),20.54(-CH( C h 3 ) 2 );ESI-MS(m / z):288.2[M+Na] + . 1 H NMR spectrum see figure 1 , proving that the structure of the product is like com...

Embodiment 3

[0062]Preparation, separation and purification of N-phenyl gardenamide A (namely compound 6), the steps and raw materials are the same as in Example 1, only in step 3, 0.1ml (1.1mmol) of aniline was used instead of methylamine hydrochloride, and finally separated by HPLC After purification, 27.4 mg of white solid compound was obtained, with a yield of 61%.

[0063] The structural characterization data of the product are: 1 H NMR (300MHz, CDCl 3 )δ:7.47-7.37(m,4H,Ar-H),7.27-7.24(m,1H,Ar-H),7.24(s,1H),5.88(s,1H),4.36(q,J=13.5 Hz,2H),3.89(d,J=11.1Hz,1H),3.76(s,3H,-OCH 3 ),3.70-3.61(m,1H),3.04-2.94(m,1H),2.43-2.33(m,1H); 13 C NMR (75MHz, CDCl 3 )δ: 170.27(C-11), 166.71(C-1), 141.21(C-3), 139.78(C 6 h 5 ), 137.91(C-8), 129.38(C 6 h 5 ), 129.14(C-7), 128.25(C 6 h 5 ), 126.36 (C 6 h 5 ), 111.34 (C-4), 60.88 (C-10), 51.64 (-OCH 3 ),50.45(C-9),40.11(C-6),37.34(C-5);ESI-MS(m / z):300.2[M+H] + . The structure of the product was proved to be compound 6.

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Abstract

The invention discloses an N-substituted gardenamide A derivative and a synthesis method and application of the N-substituted gardenamide A derivative. The N-substituted gardenamide A derivative has a structure as the general formula (I). The starting material of the N-substituted gardenamide A derivative is genipin, first, hydroxide radicals are selectively protected and converted into lactone under the action of oxidant, and then the lactone directly reacts with an amine compound to obtain an adduct after acid treatment. The N-substituted gardenamide A derivative and the synthesis method of the N-substituted gardenamide A derivative are not reported in literature. Due to the synthesis method of the N-substituted gardenamide A derivative, the application of the N-substituted gardenamide A derivative to preparation of drugs for treating neurodegenerative diseases, in particular to drugs for treating senile dementia is reported for the first time. The synthesis method has the advantages of being mild in reaction conditions, simple and convenient in experimental procedure, high in yield, high in product purity, economical, practical and the like. The general formula (I) is as follows.

Description

technical field [0001] The invention belongs to the field of drugs for treating neurodegenerative diseases, and in particular relates to an N-substituted gardenamide A derivative which has a protective effect on nerve cell damage, its synthesis method and its application in the preparation of drugs for treating senile dementia. Background technique [0002] Alzheimer's Disease (AD) is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. The main clinical symptoms at the initial stage are memory and thinking ability decline. The patient's condition deteriorates rapidly, and soon there will be difficulty in recognizing directions, language barriers, inability to recognize relatives, sluggishness and desirelessness, and finally loss of self-care ability. Statistics from the World Health Organization and the International Alzheimer's Association in 2008 show that there are currently about 20 million...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/04A61P25/28
Inventor 陈河如罗军郑文华王日康杨健黄照
Owner JINAN UNIVERSITY
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