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Substituted phenyl pyrazolone derivative as well as preparation method and application of substituted phenyl pyrazolone derivative

A pyrazoline and phenyl technology, applied in the field of medicine, can solve the problems of neurodegenerative diseases, such as complicated etiology, difficult drug treatment, and incomplete elucidation of pathogenesis

Active Publication Date: 2018-12-14
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The etiology of the above neurodegenerative diseases is extremely complex, and the pathogenesis has not been fully elucidated, which brings many difficulties to drug treatment

Method used

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  • Substituted phenyl pyrazolone derivative as well as preparation method and application of substituted phenyl pyrazolone derivative
  • Substituted phenyl pyrazolone derivative as well as preparation method and application of substituted phenyl pyrazolone derivative
  • Substituted phenyl pyrazolone derivative as well as preparation method and application of substituted phenyl pyrazolone derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 replaces the synthesis of ethyl acetoacetate

[0035] A Ethyl 2-methylacetoacetate (Intermediate 1)

[0036] Ethyl acetoacetate (1.3g, 0.1mol), CH 3 I (6.3mL, 0.1mol) and K 2 CO 3 (13.8g, 0.1mol), add 60mL CH 3 OH, reflux for 3h. After the reaction, the reaction solution was poured into 20 mL of cold water, concentrated under reduced pressure, and extracted three times with 50 mL of EtOAc. The organic layers were combined, washed with 0.5N HCl, washed with water, anhydrous Na 2 SO 4 It was dried and separated by column chromatography (petroleum ether: EtOAc=10:1) to obtain 10.1 g of a colorless liquid. Yield: 70%; ESI-MS: m / z=145[M+H] + .

[0037] B ethyl 2-phenylacetoacetate (intermediate 2)

[0038]Suspend NaH (326mg, 8.15mmol) in 15mL of anhydrous THF, add ethyl phenylacetate (1mL, 6.27mmol) dropwise under ice-cooling, and react at 60°C for 30min after the dropwise addition is complete. The reaction solution was cooled to 0°C, and 2 mL of a TH...

Embodiment 2

[0059] Embodiment 2 Synthesis of 1-phenylpyrazolone intermediate

[0060] A 3,4-Dimethyl-1-(4-benzyloxyphenyl)-2-pyrazolin-5-one (intermediate 13)

[0061] Weigh 500mg 1-benzyloxy-4-phenylhydrazine hydrochloride (2mmol), add to 10mL H 2 O, stirred for 30 min, added an equimolar amount of NaOH 80 mg, and stirred for 30 min. Add ethyl 2-methylacetoacetate (247mg, 1.9mmol) dropwise to the above reaction solution, heat up to reflux for 2.5h, stop heating, cool to room temperature, filter, and filter residue with petroleum ether: EtOAc (5:1) for pulping , Petroleum ether: EtOAc (3:1), washed and dried to give 350 mg of light yellow solid. Yield: 63%; 1 H NMR (500MHz, CDCl 3 ): δ7.79(d, J=9.0Hz, 2H), 7.46-7.33(m, 5H), 7.02(d, J=9.0Hz, 2H), 5.10(s, 2H), 3.23(q, J= 8.0Hz, 1H), 1.46(d, J=8.0Hz, 3H), 1.28(s, 3H); ESI-MS: m / z=295[M+H] + .

[0062] B 3-methyl-4-phenyl-1-(4-benzyloxyphenyl)-2-pyrazolin-5-one (intermediate 14)

[0063] The preparation method is the same as that of i...

Embodiment 3

[0088] The synthesis of embodiment 3 hydrogenolysis products

[0089] A 4,5-Dimethyl-2-(4-hydroxyphenyl)-3-pyrazolone (Intermediate 27)

[0090] Intermediate 13 (820 mg, 2.79 mmol) was dissolved in 20 mL CH 3 160 mg of 10% Pd / C was added to OH, and reacted overnight at room temperature under hydrogen pressure. After the reaction, Pd / C was removed by filtration, and the filtrate was concentrated to obtain 460 mg of light yellow solid, which was washed with a small amount of ice EtOAc. Yield: 81%; 1 H NMR (400MHz, DMSO-d 6 ):δ10.33(s,1H),9.42(s,1H),7.43(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),2.05(s,3H),1.75 (s,3H); ESI-MS: m / z=205[M+H] + .

[0091] B 5-methyl-4-phenyl-2-(4-hydroxyphenyl)-3-pyrazolone (intermediate 28)

[0092] The preparation method is the same as that of intermediate 27, and intermediate 14 is used instead of intermediate 13 to obtain a pale yellow solid. Yield: 71%, 1 HNMR (400MHz, DMSO-d 6 ): δ9.53(s, 1H), 7.57-7.52(m, 2H), 7.48(d, J=8.8Hz, 2H), 7.41(t, J...

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Abstract

The invention provides a substituted phenyl pyrazolone derivative and specifically relates to a 2-phenyl-pyrazoline-3-one compound as well as a pharmaceutically-acceptable salt and solvate thereof. Atarget compound is prepared by carrying out a reflux reaction on substituted ethyl acetoacetate and benzyloxyphenylhydrazine in a sodium hydroxide aqueous solution, then, carrying out hydrogenolysis on a benzyl group under the actions of palladium / carbon and hydrogen to obtain phenylpyrazolone phenol, then, making phenylpyrazolone phenol react with bromochloroalkane to obtain a chloride, and finally, carrying out condensation on the chloride and secondary amine. The substituted phenyl pyrazolone derivative provided by the invention shows good free radial scavenging capability in vitro, has relatively strong H3 receptor inhibiting activity, shows good blood brain barrier penetration capability and has unique double activities so as to have a unique clinic effect on treating neurodegenerative diseases such as cerebral apoplexy, presenile dementia, parkinsonism and amyotrophic lateral sclerosis. The compound provided by the invention is applied to preparation of drugs for treating centralsystem related diseases and inflammatory diseases. A structure of a general formula is shown as the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the preparation of phenylpyrazolone derivatives and their application in the treatment of central system-related diseases and inflammatory diseases. The phenylpyrazolone derivatives also include their pharmaceutically acceptable salts, complexes, solvates and the like. Background technique [0002] Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), progressive freezing syndrome (ALS), narcolepsy, etc., which seriously threaten the health and quality of life of the elderly, and bring huge social burden and economic burden. The etiology of the above-mentioned neurodegenerative diseases is extremely complex, and the pathogenesis has not been fully elucidated, which brings many difficulties to drug treatment. [0003] Unbalanced clearance of free radicals in the brain of neurodegenerative patients, excessive free radicals have lipid ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/12C07D405/04A61K31/4155A61P25/04A61P25/00A61P25/28A61P25/16A61P25/26A61P25/14A61P21/00A61P29/00A61P37/08A61P11/06A61P19/02A61P27/02A61P11/00A61P37/06A61P17/06A61P13/12
CPCA61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P21/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/26A61P25/28A61P27/02A61P29/00A61P37/06A61P37/08C07D261/12C07D405/04
Inventor 盛荣唐黎邵春能胡永洲胡云珍熊晓红张冯敏
Owner ZHEJIANG UNIV
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