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Nitrogen-containing heterocycle derivatives and applications thereof

A technology for heterocyclic groups and compounds, applied to nitrogen-containing heterocyclic derivatives and their application fields, can solve the problems of only using injection preparations, high cost, etc., and achieve the effects of enhancing uptake ability, low manufacturing cost, and increasing expression

Inactive Publication Date: 2018-01-05
CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Large pharmaceutical companies are intensively promoting the development of PCSK9 inhibitor drugs. The current research work is mainly focused on the development of biological products (including protein drugs and long-chain nucleic acid drugs) (see the table below), biological products and small molecules When the drug is aimed at treating the same disease, biological drugs have the disadvantages of high cost and limited preparation methods such as injection preparations. At present, no small molecule PCSK9 inhibitor has become a clinical candidate drug

Method used

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  • Nitrogen-containing heterocycle derivatives and applications thereof
  • Nitrogen-containing heterocycle derivatives and applications thereof
  • Nitrogen-containing heterocycle derivatives and applications thereof

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Experimental program
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specific Embodiment approach

[0136] The general method of the present invention is further explained below. The compound of the present invention can be prepared by methods known in the art. The preparation process of the preferred compound of the present invention is used as an example to illustrate in detail below, but the preparation method of the compound of the present invention is not limited thereto. .

[0137] The preparation of the general formula compound (V) disclosed by the present invention is mainly carried out with reference to the following schemes,

[0138]

[0139] The compound represented by the general formula (V) of the present invention, its stereoisomers, its tautomers, its solvates and pharmaceutically acceptable salts thereof, wherein a preparation method comprises the following steps :

[0140]

[0141] X5 and X8 are the starting materials of this scheme, which can be obtained from commercially available products, or prepared according to methods reported in literature. C...

Embodiment 1

[0159]

[0160] Compound 1A (150 mg, 0.458 mmol) was dissolved in dichloromethane (20 mL), then triethylamine (70 μL, 0.504 mmol) was added, stirred at room temperature, and 1B (128 mg, 0.504 mmol) was added in batches, and the addition was completed. React overnight at room temperature. The reaction solution was spin-dried, added saturated aqueous sodium bicarbonate solution and ethyl acetate, extracted and separated, collected the organic phase, dried over anhydrous sodium sulfate, spin-dried, added dichloromethane to the obtained residue, precipitated a solid, stirred for 30 min, and suction filtered. After washing with dichloromethane, the filter cake was collected and dried to obtain compound 1 as a white solid (61 mg, yield 24.4%). 1 H NMR (400MHz, DMSO-d 6 )δ10.10(s,1H),8.14–8.07(m,2H),7.96–7.89(m,2H),6.95–6.86(m,4H),6.85–6.77(m,3H),3.73(s, 6H),3.42(s,2H),3.29(s,3H),3.10–2.99(m,4H),2.49–2.40(m,4H).MS(ESI)m / z[M+H] + ,546.1.

Embodiment 2

[0162]

[0163] Compound 1A (600mg, 1.83mmol) was dissolved in dichloromethane (15mL), then triethylamine (286μL, 2.01mmol) was added, stirred at room temperature, and then a solution of 2B (609mg, 2.01mmol) in dichloromethane was added dropwise , After dropping, react overnight at room temperature. The reaction solution was spin-dried, added saturated aqueous sodium bicarbonate solution and ethyl acetate, extracted and separated, collected the organic phase, dried over anhydrous sodium sulfate, spin-dried, added dichloromethane to the obtained residue, precipitated solid, suction filtered, dichloromethane After washing, the filter cake was collected and dried to obtain off-white solid 2C (510 mg, yield 47.0%).

[0164] Add compound 2C (150mg, 0.253mmol) in 25mL round bottom flask, 2D (44mg, 0.253mmol), Pd(dppf) 2 Cl 2 (18mg, 0.025mmol), potassium acetate (74mg, 0.759mmol), THF / EtOH / water (3mL / 3mL / 3mL) mixed solvent, react overnight in an 80°C oil bath under nitrogen prot...

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Abstract

A nitrogen-containing heterocyclic derivative and application thereof. The present invention relates to the compound of formula (V) and its preparation method and its application in medicine. Specifically, the present invention relates to derivatives and preparation methods of the compound of general formula (V) and its use as a therapeutic agent in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis , Type II diabetes, hyperglycemia, obesity or insulin resistance, metabolic syndrome and use in antineoplastic drugs. The compounds disclosed herein can also reduce total cholesterol, LDL-cholesterol and triglyceride, increase the expression of hepatic LDL receptors, and inhibit the expression of PCSK9.

Description

technical field [0001] The technology of the present invention relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity, metabolic syndrome and Uses, compounds and compositions in antineoplastic. Background technique [0002] Metabolic syndrome (Metabolic Syndrome, MS) is a pathological state in which a variety of metabolic components are abnormally aggregated. [0003] Cardiovascular and cerebrovascular diseases are the number one killer of human health. Its etiology is very complex. Hyperlipidemia, as a key risk factor, has attracted the attention of most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The morbidity and mortality of the disease are significantly increased, and there are related literature reports that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, myocardial ...

Claims

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Application Information

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IPC IPC(8): C07D295/135C07D241/04C07D307/93C07D333/72C07D271/07C07D213/38C07D211/28C07D295/26A61P3/10A61P3/04A61P3/06A61P1/16A61P3/00A61P5/50A61P35/00
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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