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Dihydropyrazolone compound as well as preparation method and medical application thereof

A compound and mixture technology, applied in the field of medicine, can solve the problem of low activity

Active Publication Date: 2019-04-30
NAT INST OF PHARMA R & D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds generally have disadvantages such as low activity

Method used

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  • Dihydropyrazolone compound as well as preparation method and medical application thereof
  • Dihydropyrazolone compound as well as preparation method and medical application thereof
  • Dihydropyrazolone compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] Example 1: 2-(6-(2-thia-6-aza-spiro[3.3]hept-6-yl)pyrimidin-4-yl)-4-(1H-1,2,3-triazole Preparation of -1-yl)-1,2-dihydro-3H-pyrazol-3-one

[0174]

[0175] Step 1: Synthesis of ethyl 2-(1H-1,2,3-triazol-1-yl)acetate (Intermediate 1A)

[0176] Add 1H-1,2,3-triazole (100 g, 1.45 mol) into a 1 L reaction flask, add ethyl acetate (300 mL), DIPEA (252 mL, 1.45 mol) therein, and stir for 3 minutes under ice cooling. Ethyl bromoacetate (152 mL, 1.38 mol) was added into 200 mL of ethyl acetate, and then it was slowly added dropwise into the reaction flask. After the dropwise addition was completed, it was stirred overnight at room temperature. After the reaction was complete, filter, wash the filtrate once with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 100 g of the title product as a yellow oil, yield: 44.3%.

[0177] Step 2: Synthesis of ethyl 3-(dimethylamino)-2-(1H-1,2,3-triazol-1-...

Embodiment 2

[0187] Example 2: 2-(6-(2,2-dioxo-2-thia-6-aza-spiro[3.3]hept-6-yl)pyrimidin-4-yl)-4-(1H-1 , Preparation of 2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one

[0188]

[0189] The same preparation method as in Example 1, except that 2-thia-6-aza-spiro[3.3]heptane-2,2-dioxide hydrochloride was used instead of 2-thia-6-azaspiro[ 3.3] Heptane hemioxalate to give the title compound.

[0190] MS:m / z=375.4[M+H] + .

[0191] 1 H NMR(300MHz,DMSO):δppm 4.35(m,4H),4.50(m,4H),7.18(s,1H),7.80(s,1H),8.08(s,1H),8.38(s,1H) ,8.46(s,1H).

Embodiment 3

[0192] Example 3: 2-(6-(2,6-diazaspiro[3.3]heptane-2-yl)pyrimidin-4-yl)-4-(1H-1,2,3-triazole-1 Preparation of -yl)-1,2-dihydro-3H-pyrazol-3-one

[0193]

[0194] The preparation method is the same as in Example 1, except that 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl hemioxalate is used instead of 2-thia-6-azaspiro[3.3] Heptane hemioxalate to give the title compound.

[0195] MS:m / z=326.2[M+H] + .

[0196] 1 H NMR(300MHz,DMSO):δppm 4.20(m,4H),4.36(m,4H),7.00(s,1H),7.86(s,1H),8.26(s,1H),8.36(s,1H) ,8.49(s,1H).

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Abstract

The invention relates to a dihydropyrazolone compound as well as a preparation method and medical application thereof, in particularly relates to a general formula (I) compound shown in the specification, as well as a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a proline hydroxylase (PHD) inhibitor, the compound and the pharmaceutical composition containing the compound can be used in treating and / or preventing of PHD -activity- related diseases such as cardiovascular diseases, chronic kidney disease, anemia, wounds, cancer, autoimmune diseases and the like. In the general formula (I), the definition of each substituent in the formula is the same as that in the specification.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to a dihydropyrazolone compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use for regulating proline hydroxylase (proline hydroxylase domain, PHD) activity , and then for the treatment and / or prevention of diseases associated with PHD activity. Background technique [0002] In a hypoxic environment, the body can spontaneously respond to hypoxia to maintain the body's ability to obtain oxygen. In 1992, Semenza et al. discovered a protein that can specifically bind to the hypoxia response element (HRE) of the erythropoietin gene and affect the expression of certain genes. The protein is called hypoxia-inducible factor (HIF) (Semenza GL et al., Mol. Cell Biol., 1992, 12, 5447-5454). HIF has a wide range of target genes, which can affect the body's hematopoietic function, angiogenesis, iron ion transport, glucose utilization,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/10C07D487/10C07D493/10C07D401/14C07D403/14A61K31/506A61P9/00A61P9/10A61P9/12A61P13/12A61P7/06A61P35/00A61P31/18A61P29/00A61P19/02A61P37/00
CPCA61P7/06A61P9/00A61P9/10A61P9/12A61P13/12A61P19/02A61P29/00A61P31/18A61P35/00A61P37/00C07D401/14C07D403/14C07D487/10C07D493/10C07D495/10
Inventor 殷惠军闫旭宗利斌窦浩帅王卓米帧田卫学
Owner NAT INST OF PHARMA R & D CO LTD
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