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Aromatic-ring azacyclo derivatives and application thereof

A technology of heterocyclyl and heterocyclylalkyl, which is applied in the field of aromatic ring aza-heterocyclic derivatives and its application, and can solve problems such as visual impairment, allergic reactions, skin diseases, and itching

Inactive Publication Date: 2016-07-20
CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Disadvantages: Its side effects are inevitable, such as: rhabdomyolysis, myositis, and the enhancement of various enzyme activities in the liver, etc. In addition, some patients failed to adapt to the treatment of statins, more importantly Unfortunately, a single statin therapy often cannot achieve the desired ideal effect
[0014] Disadvantages: Adverse reactions often occur in the digestive tract, occasionally allergic reactions, visual impairment, because this type of drug increases the concentration of cholesterol in bile, it may also cause gallstones
[0016] Disadvantages: The effect of lowering blood lipids in diabetic patients is not obvious, and side effects such as: liver poisoning, hyperglycemia are more obvious, skin disease, itching and other adverse reactions often occur
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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  • Aromatic-ring azacyclo derivatives and application thereof
  • Aromatic-ring azacyclo derivatives and application thereof
  • Aromatic-ring azacyclo derivatives and application thereof

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Experimental program
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specific Embodiment approach

[0256] 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, and the preparation method 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 .

[0257] The preparation of the general formula compound (V) disclosed by the present invention is mainly prepared according to the following scheme:

[0258]

[0259]

[0260] The above preparation route is described as follows: X1 and X2 are the starting materials of this scheme, which can be obtained from commercially available products, or prepared according to methods reported in literature. Compound V is obtained by linking X1 and X2 under certain reaction temperature conditions and in the presence of certain basic reagents.

[0261] Taking the representative synthetic preparation proc...

Embodiment 1

[0311]

[0312] Add 1A (242mg, 0.951mmol) to a 50mL round bottom flask, dissolve in dichloromethane (10mL), add triethylamine (331μL, 2.38mmol), stir for 5min, then add compound 1B (126μL, 0.951mmol), at room temperature Stirred for another 2 h, concentrated and purified by silica gel column chromatography (dichloromethane:methanol 50:1) to obtain the white solid product 1 (27 mg, yield 6.9%). 1 HNMR (400MHz, CDCl 3 )δ7.52–4.47(m,1H),7.47–7.36(m,2H),7.29–7.10(m,5H),7.03–6.98(m,1H),6.83(d,J=2.5Hz,1H) ,6.76(dd,J=8.5,2.6Hz,1H),6.68(d,J=8.5Hz,1H),3.80(s,2H),3.72(s,2H),2.94(t,J=5.6Hz, 2H),2.88–2.76(m,2H); MS(ESI)m / z[M+H] + : 413.34.

Embodiment 2

[0314]

[0315] Add sodium hydroxide (8g) into a 100mL round bottom flask, dissolve it in water (50mL), cool to room temperature, add 2A (10.0g, 0.066mol), stir to dissolve, then add 2B (12.6g, 0.066mol) in batches, Stir overnight. The reaction solution was adjusted to pH 4 with hydrochloric acid aqueous solution (2mol / L), and the solid was precipitated, filtered with suction, washed with water, the filter cake was dissolved with aqueous sodium hydroxide solution (2mol / L) again, filtered with suction, and the filtrate was filtered with aqueous hydrochloric acid (2mol / L) The pH was adjusted to 4, and a solid was precipitated, filtered with suction, washed with water, and dried to obtain a white solid 2C (7.05 g, yield 36.5%).

[0316] Add 2C (500mg, 1.71mmol) and dichloromethane (20mL) to a 100mL round bottom flask to dissolve, then add methyl chloroformate (146μL, 1.88mmol), triethylamine (285μL, 2.05mmol), stir at room temperature for 2h, and then Add 2D (432 mg, 1.88 mmo...

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Abstract

Aromatic-ring azacyclo derivatives and an application thereof are provided. The invention relates to compounds represented by the formula (V), and a preparation method and an application thereof in medicines. In particular, the invention relates to derivatives of the compounds represented by the general formula (V), and a preparation method and the application thereof as therapeutic agents in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, type-II diabetes, hyperglycemia, obesity or insulin resistance syndromes and metabolic syndromes. The compounds disclosed by the invention also can reduce total cholesterol, LDL-cholesterol and triglycerides, 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 Cancer uses, compounds and compositions. 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 infarction,...

Claims

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Application Information

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IPC IPC(8): C07D217/04C07D471/04C07D209/08C07D409/14C07D209/44C07D215/06C07D401/06C07D495/04C07D409/06C07D295/096C07D487/04C07D491/048C07D401/12C07D405/12A61P3/04A61P3/06A61P3/00A61P3/10A61P5/50A61P35/00A61P1/16
CPCC07D217/04C07D209/08C07D209/44C07D215/06C07D295/096C07D401/06C07D401/12C07D405/12C07D409/06C07D409/14C07D471/04C07D487/04C07D491/048C07D495/04
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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