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Compound or medicinal salt thereof for targeted ubiquitination degradation of HMGCR, preparation method and application

A compound and ubiquitination technology, applied in the field of medicine, can solve the problems of unsatisfactory reduction of LDL-C, and achieve the effect of significant degradation activity

Active Publication Date: 2021-10-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

New Study Shows About Half of Patients Taking Statins Have Unsatisfactory LDL-C Lowering After Two Years of Use
Although this defect has been recognized since the advent of statins, there is no effective way to prevent its induced HMGCR accumulation

Method used

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  • Compound or medicinal salt thereof for targeted ubiquitination degradation of HMGCR, preparation method and application
  • Compound or medicinal salt thereof for targeted ubiquitination degradation of HMGCR, preparation method and application
  • Compound or medicinal salt thereof for targeted ubiquitination degradation of HMGCR, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Synthesis of CRBN ligand derivatives. Compound 1 (0.28g, 1.0mmol) was dissolved in anhydrous DMF, and then amine compounds 2a-2c (1.0mmol) of different lengths, DIPEA (0.4g, 3.0mmol), DIPEA (0.4g, 3.0mmol), 90 °C overnight. After the completion of the reaction as detected by TLC, the reaction solution was poured into water, extracted with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain yellow solids 3a-3c.

[0036] The synthetic route is as follows:

[0037]

[0038] Reagents and conditions: (i) N, N-Diisopropylethylamine, DMF, 90℃, 12h

[0039] (1) Synthesis of N-2-(2,6-dioxopiperidin-3-yl)-4-propylcarbamate tert-butyl isoindoline-1,3-dione (3a)

[0040]

[0041] Yellow solid (0.22g, 45% yield). 1H NMR (300MHz, CDCl 3 )δ8.31(s, 1H), 7.53(m, 1H), 7.13(d, J=7.1Hz, 1H), 6.98(d, J=8.6Hz, 1H), 6.49(t, J=5.6Hz, 1H), 5.02(s, 1H), 4.95(dd, J=11.8, ...

Embodiment 2

[0048] Example 2: Synthesis of VHL ligand derivatives. Compound 4 (0.4g, 0.93mmol) was dissolved in anhydrous DMF, and then under nitrogen protection, alkyl acid compounds 5a-2b (0.93mmol) of different lengths, DIPEA (0.3g, 1.86mmol) and HATU (0.35g, 0.93mmol), react overnight at room temperature. After the completion of the reaction as detected by TLC, the reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain yellow solids 6a-6b.

[0049] The synthetic route is as follows:

[0050]

[0051] Reagents and conditions: (i) N, N-Diisopropylethylamine, HATU, DMF, rt, 12h

[0052] (1) tert-butyl (8-(((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl )pyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-8-oxooctyl)formamide (6a) synthesis

[0053]

[0054] Gray solid (0.22g, 35% yield). 1 H NMR (300MH...

Embodiment 3

[0058] Example 3: (4R, 6R)-4-((tert-butyldimethylsilyl chloride)oxy)-6-(2-((1S, 2S, 6R, 8S, 8αR)-8-hydroxyl-2 , 6-dimethyl-1,2,6,7,8,8α-hexahydronaphthalene-1-yl) ethyl) tetrahydro-2H-2-pyrone (8), the route is as follows:

[0059]

[0060] Reagents and conditions: (i) kOH, H 2 O-MeOH, reflux, 12h; (ii) 6M HCl, rt, 6h; (iii) TBSCl, imidazole, CH 2 Cl 2 , rt, 6h; (iv) p-nitrophenyl chloroformate, DMAP, pyridine, rt, 16h;

[0061] Lovastatin (18g, 44.6mmol) was added in the mixed solution of water and methanol (H 2 O / MeOH, 1:5, 132mL), KOH (25.2g, 449mmol) was added, refluxed for 12h, methanol was distilled off under reduced pressure, and the mixture was added H 2 O (500mL), CH 2 Cl 2 (100mL) and 6M HCl, adjust pH=2. React at room temperature for 6h, add saturated NaHCO 3 Neutralization. Extraction with DCM, spin-dried to obtain an oil. Dissolved in DCM (85mL), added TBSCl (4.3g, 30mmol) and imidazole (3.4g, 49.6mmol) to it, reacted at room temperature for 6h. Purifie...

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Abstract

The invention relates to a compound or a medicinal salt thereof for targeted ubiquitination degradation of HMGCR, a preparation method and an application. The structure is shown as a general formula (I). The compound or the medicinal salt thereof can effectively degrade the cholesterol synthesis rate-limiting enzyme HMGCR in the body in a targeting manner, improves the defect that the existing statins induce the compensatory accumulation of HMGCR, can be used for preparing medicines for treating cardiovascular diseases such as hyperlipidemia and atherosclerosis, and is expected to become a blood lipid regulating molecule with a brand new action mechanism.

Description

technical field [0001] The invention belongs to the field of medicine, and particularly relates to a compound targeting ubiquitination and degrading HMGCR or a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. Background technique [0002] Hydroxymethylglutaryl-CoA reductase (HMG-CoA Reductase, HMGCR) is a rate-limiting enzyme mainly distributed in the endoplasmic reticulum (ER) membrane of liver cells, which can catalyze the substrate HMG- CoA produces Mevalonate, a precursor necessary for the synthesis of cholesterol. HMGCR inhibitors (statins) reduce cholesterol synthesis through competitive inhibition of HMGCR, thereby reducing the level of low-density lipoprotein cholesterol (LDL-C) in the blood. [0003] Reducing the level of blood LDL-C by inhibiting the function of HMGCR has become one of the important and effective means to prevent and treat cardiovascular diseases. Seven kinds of HMGCR small-molecule inhibitors (statins) c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/454A61K38/05A61P9/00A61P3/06
CPCC07D405/14C07K5/06034A61P9/00A61P3/06A61K38/00Y02P20/55
Inventor 向华骆国顺林鑫李振邦肖茂旭
Owner CHINA PHARM UNIV
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