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Phenoxy indanone derivatives containing alkylamino side-chain, preparation method and use thereof

A phenoxyindanone and alkylamine-containing technology, applied in the field of compound synthesis, can solve the problems of short action time, low bioavailability, poor central selectivity and the like

Inactive Publication Date: 2008-02-13
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs currently used in clinical practice still have shortcomings such as short action time, poor central selectivity, and low bioavailability. Therefore, research on AChE inhibitors with definite efficacy and high central selectivity is still the main way for people to find drugs for the treatment of AD.

Method used

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  • Phenoxy indanone derivatives containing alkylamino side-chain, preparation method and use thereof
  • Phenoxy indanone derivatives containing alkylamino side-chain, preparation method and use thereof
  • Phenoxy indanone derivatives containing alkylamino side-chain, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 4-[2-(pyrrolidin-1-yl)ethyl]phenol

[0032] Dissolve 0.157g (0.001mol) of 4-(2-chloroethyl)phenol in 2ml of acetonitrile, add 0.41ml (0.003mol) of triethylamine, and add 0.35ml (0.0042mol) of tetrahydropyrrole dropwise in an ice bath. Warm up to reflux and react for 10h. The solvent was evaporated to dryness under reduced pressure, 2ml of 2N hydrochloric acid and 2ml of ethyl acetate were added to the residue, and the organic layer was separated and discarded. The aqueous layer was adjusted to pH 10 with concentrated ammonia, extracted with ethyl acetate (2ml×3), the organic layers were combined, washed with saturated NaCl, anhydrous NaCl 2 SO 4 After drying, the solvent was recovered, and silica gel column chromatography (petroleum ether: ethyl acetate = 1:1, 1% triethylamine) was used to obtain 0.139 g of an oily substance with a yield of 72.4%. 1H-NMR (δ, CDCl 3 ): 6.99-7.01(d, 2H, J=8.4Hz), 6.63-6.65(d, 2H, J=8.4Hz), 2.73-2.78(m, 4H), 2.65(m, 4H), 1.82...

Embodiment 2

[0056] Example 2 1-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)ethanone

[0057] Dissolve 0.108g (0.5mmol) of α-bromo-p-hydroxyacetophenone in 4ml of anhydrous acetonitrile, add 0.21g (2.5mmol) of K 2 CO 3 , add 0.205ml (0.0025mol) tetrahydropyrrole dropwise in an ice bath, keep the temperature at 0-10°C, and react for 0.5h. After filtration, the filtrate was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:2, 1% triethylamine and 1% methanol) to obtain 90 mg of a yellow powdery solid with a yield of 87.3%. 1H-NMR (δ, CH 3 OD): 7.85-7.87(d, 2H, J=8.8Hz), 6.80-6.82(d, 2H, J=8.8Hz), 4.94(s, 2H), 2.80(m, 4H), 1.87(m, 4H ).

[0058] The following compounds can be prepared in the same way:

[0059] 1-(4-Hydroxyphenyl)-2-(piperidin-1-yl)ethanone

[0060] The operation process is the same as in Example 2, except that tetrahydropyrrole is replaced by piperidine, and the yield is 84%.

[0061] 1-(4-hydr...

Embodiment 3

[0065]Example 3 1-(4-hydroxyphenyl)-3-pyrrolidinyl-1-propanone

[0066] Put 0.63g (0.0046mol) of p-hydroxyacetophenone, 0.504g (0.0168mol) of paraformaldehyde, 1.26ml (0.015mol) of tetrahydropyrrole, and 4.2ml of absolute ethanol into the reaction flask, and add 0.21ml of it dropwise under ice cooling Concentrated hydrochloric acid, heated to reflux, reacted for 10h. The solvent was distilled off under reduced pressure, 5 ml of 2N hydrochloric acid and 5 ml of ethyl acetate were added to the residue, and the organic layer was separated and discarded. The pH of the aqueous layer was adjusted to 10 with concentrated ammonia water, a large amount of precipitates formed, filtered, washed, and the filter cake was dried to obtain 0.324 g of off-white powder with a yield of 32.3%. Melting point: 148°C. 1H-NMR (6, CDCl 3 ): 7.83-7.85(d, 2H, J=8.8Hz), 6.82-6.84(d, 2H, J=8.8Hz), 3.04-3.08(t, 2H, J=7.6Hz), 2.70-2.73(t, 2H, J=7.6Hz), 2.41-2.44(m, 4H), 1.63-1.66(m, 4H).

[0067] The f...

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Abstract

The invention provides an indinavir ketone derivative with the alkyl-amino side chain, which is a change for the connecting chain between the benzene ring and tertiary amine nitrogen in the molecule of the phenoxy indinavir ketone compound; the distance between the benzene ring and tertiary amine nitrogen is extended; the connecting chain of the original one-carbon unit (methylene) is changed into a connecting chain with a 2 to 4 carbon atoms, or a connecting chain with the carbonyl, so as to get a series of novel phenoxy indinavir ketone derivative with the alkyl-amino side chain on the benzene ring. The novel synthesized phenoxy indinavir ketone derivative has the strong inhibitory activity for AChE and the weak inhibition for BuChE; the selectivity is high; the compound can be used in the drug for the treatment of the disease of Alzheimer. The method of the invention is reasonable in design, simple in operation and strong in practicality. In the invention, the structure of the indinavir ketone derivative with the alkyl-amino side chain is shown in the formula (see figure).

Description

technical field [0001] The invention belongs to compound synthesis, and mainly relates to phenoxyindanone derivatives, a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a neurodegenerative disease characterized by impairment of memory, cognition, and neurological function. The fourth leading killer after cerebrovascular disease. With the advent of the aging era, the incidence of AD is increasing day by day, and people pay more and more attention to the drug treatment of AD. [0003] At present, the drugs for the treatment of AD mainly include acetylcholinesterase (AChE) inhibitors, M1 receptor agonists, antioxidant drugs, anti-inflammatory and analgesic drugs, drugs that inhibit the formation of Aβ, and nerve growth factors. Among them, acetylcholinesterase inhibitors are the most effective and widely used drugs, which can selectively inhibit the activity of acetylcholinesterase in the br...

Claims

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Application Information

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IPC IPC(8): C07D295/092C07C217/56A61K31/40A61K31/435A61K31/135A61P25/28
Inventor 胡永洲申艳红盛荣杨波何俏军张晶
Owner ZHEJIANG UNIV
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