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Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof

A technology of aminoethylpyrazoles and hydroxyethylpyrazoles, which is applied in the field of drug synthesis and can solve the problems of high synthesis difficulty

Inactive Publication Date: 2014-01-15
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, β-secretase inhibitors are safer than γ-secretase inhibitors, but the synthesis of small molecule β-secretase inhibitors is much more difficult than γ-secretase inhibitors

Method used

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  • Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof
  • Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof
  • Hydroxyethyl pyrazole compound or aminoethyl pyrazole compound, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] (Preparation of compound 1)

[0129] Synthetic route 1, reaction steps:

[0130] The epoxy compound (2S,3S)-1,2-epoxy-3-(N-tert-butoxycarbonylamino)-4-phenylpropane (50mg, 0.19mmol) was dissolved in 2mL DMF, and pyrazole was added to the system (13mg, 0.19mmol), catalytic amount of sodium carbonate. React in microwave at 110°C for 1 hour. At the end of the reaction, add 25 mL of water to the system, extract with ethyl acetate (25 mL×2), combine the organic phases, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a white solid (2S,3S)-1 - tert-butyl benzyl-2-hydroxy-3-pyrazolylcarbamate 57 mg,

[0131] The above pyrazole compound (57 mg, 0.17 mmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added to the system, and reacted at room temperature for 2 h. After concentration, the obtained amine was directly used in the next reaction without treatment. Dissolve the amine obtained in ...

Embodiment 2

[0135] (Preparation of Compound 2)

[0136] The synthetic route refers to Example 1. Using 3-methylpyrazole instead of pyrazole, TLC chromatography gave white amorphous solid compound 2 (19 mg, yield: 81.2%).

[0137] 1 H NMR (300MHz, CD 3 OD):δ8.13(s,1H),8.00(s,1H),7.90(s,1H),7.49(m,1H),7.44-7.39(m,2H),7.26-7.22(m,4H) ,7.17-7.13(d,1H),7.05-7.02(t,2H),6.01.(s,1H),5.24-5.21(q,J=7.2Hz,1H),4.39.-4.37(t,1H) ,4.19.-4.00(m,3H),3.34(s,3H),3.03-2.96(m,2H),2.94(s,3H),2.18(s,3H),1.58-1.55(d,J=7.2 Hz,3H)

[0138] LC-MS: m / z622.22[M+H] + ;

Embodiment 3

[0140] (Preparation of Compound 3)

[0141] Referring to Example 1 for the synthetic route, 4-methylpyrazole was used instead of pyrazole, and TLC chromatography gave white amorphous solid compound 3 (71 mg, yield: 72.4%).

[0142] 1 H NMR (300MHz, CD 3 OD): δ8.11(s,1H),7.99(s,1H),7.89(s,1H),7.44-7.38(m,3H),7.26-7.17(m,5H),7.16-7.14(d, 1H), 7.05-7.00(t, 2H), 5.24-5.20(q, J=6.6Hz, 1H), 4.39.-4.34(t, 1H), 4.20-4.16(m, 1H), 4.08-4.00(m ,2H),3.34(s,3H),3.05-3.00(m,2H),2.98(s,3H),2.02(s,3H),1.58-1.56(d,J=6.6Hz,3H)

[0143] LC-MS: m / z622.2[M+H] + ;

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Abstract

The present invention discloses a hydroxyethyl pyrazole compound or aminoethyl pyrazole compound represented by a general formula I, a preparation method and a use thereof. Bioactivity test results demonstrate that the compound has significant beta-secretase inhibition activity, such that the hydroxyethyl pyrazole compound or aminoethyl pyrazole compound can be used as a beta-secretase inhibitor so as to be used for prevention or symptomatic treatment of senile dementia.

Description

technical field [0001] The invention belongs to the field of medicine synthesis. Specifically, the present invention relates to a hydroxyethylpyrazole compound or an aminoethylpyrazole compound and a preparation method thereof, and as a β-secretase inhibitor, used in the preparation for preventing, delaying or treating deposition of Aβ Uses in medicines for induced diseases. Background technique [0002] Alzheimer's disease (Alzheimer's disease, hereinafter referred to as AD), also known as Alzheimer's disease, is a chronic neurodegenerative disease common in the elderly. Abnormal behavior etc. It is a serious threat to the health of the elderly, especially in today's aging society, this situation is getting worse and has aroused widespread concern. [0003] At present, acetylcholinesterase inhibitors are still the main drugs for the clinical treatment of AD. Although they can reverse the learning and memory deficits caused by cholinergic function damage and alleviate the...

Claims

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Application Information

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IPC IPC(8): C07D231/12C07D231/14C07D403/06C07D405/04C07D409/04C07D401/04C07D413/06A61K31/55A61K31/5377A61K31/415A61K31/4439A61K31/4155A61K31/454A61P25/28
CPCC07D231/12C07D231/14C07D401/04C07D403/06C07D403/12C07D405/04C07D409/04C07D413/06
Inventor 沈竞康李佳马兰萍邹贻泉许磊
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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