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Nitrogen-substituted heterocyclic derivatives and application thereof

A technology of heterocyclyl and heterocyclylalkyl, applied in a class of substituted nitrogen heterocyclic derivatives and its application field, can solve the problems of insignificant blood lipid-lowering effect, adverse reactions, and only injection preparations, etc.

Inactive Publication Date: 2016-07-13
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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  • Nitrogen-substituted heterocyclic derivatives and application thereof
  • Nitrogen-substituted heterocyclic derivatives and application thereof
  • Nitrogen-substituted heterocyclic derivatives and application thereof

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Experimental program
Comparison scheme
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specific Embodiment approach

[0250] 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 .

[0251] The preparation of the general formula compound (V) disclosed by the present invention is mainly prepared with reference to the following scheme:

[0252]

[0253] 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 coupling X1 and X2 under certain reaction temperature conditions and in the presence of certain basic reagents.

[0254] Taking the representative synthetic preparation process in...

Embodiment 1

[0301]

[0302] 1A (332mg, 1mmol) and dichloromethane were added to a 25ml round-bottomed flask, stirred and dissolved, and then 2B (229mg, 1.2mmol) and triethylamine (180μl, 1.3mmol) were added, stirred overnight, TLC detected that the reaction was complete, washed with water, The aqueous layer was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography to obtain the product compound 1 (412 mg, 90%). 1 HNMR (400MHz, CDCl 3)δ7.68 (dd, J=8.1, 4.1Hz, 4H), 7.40–7.28 (m, 4H), 6.79 (dd, J=46.0, 9.1Hz, 4H), 3.17 (ddd, J=9.4, 6.8, 4.0Hz,8H),2.45(s,6H); MS(ESI)m / z[M+H] + : 486.98.

Embodiment 2

[0304]

[0305] Add 2A (332 mg, 1 mmol) and dichloromethane into a 25 ml round bottom flask, stir and dissolve, add 2B (140 μl, 1.2 mmol) and triethylamine (180 μl, 1.3 mmol), stir overnight, TLC detects that the reaction is complete, wash with water, The aqueous layer was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography to obtain the product Compound 2 (331 mg, 92%). 1 HNMR (400MHz, CDCl 3 )δ7.70(dd, J=8.3,1.7Hz,2H),7.43(d,J=1.0Hz,5H),7.31(d,J=7.8Hz,2H),6.92–6.83(m,2H), 6.82–6.74(m,2H),3.45(dd,J=238.2,77.4Hz,8H),2.45(s,3H); MS(ESI)m / z[M+H] + : 375.22.

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PUM

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Abstract

The invention relates to a compound as shown in formula (V), a preparation method of the compound and application of the compound to medicine, in particular to the derivatives of the compound as shown in formula (V), a preparation method of the derivatives, and application of the derivatives which serve as the therapeutic agent to antitumor medicine and medicine for preventing and treating hyperlipemia, hypercholesteremia, hypertriglyceridemia, fatty degeneration of liver, type II diabetes, hyperglycemia, obesity, insulin resistance syndrome and metabolic syndrome.The compound can also lower total cholesterol, LDL-cholesterol and triglyceride, increase liver LDL receptor expression and inhibit PCSK9 expression.

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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/26C07D295/185C07D295/22C07D295/135C07D215/48C07D213/81C07D233/56C07D213/56C07D233/84C07D333/34C07D213/34C07D239/26C07D241/24C07D241/04C07D487/08C07D471/08C07D239/42C07D213/75C07D267/18C07D275/04C07D413/04C07D239/545C07D239/04A61K31/495A61K31/496A61K31/5377A61K31/506A61K31/407A61K31/4995A61K31/5513A61K31/553A61K31/454A61P3/06A61P1/16A61P3/10A61P5/48A61P3/04A61P3/00A61P35/00
CPCA61K31/495A61K31/496A61K31/506A61K31/5377A61K31/675C07D213/81C07D217/26C07D233/56C07D295/182C07D295/26C07D213/34C07D213/56C07D213/75C07D215/48C07D233/84C07D239/04C07D239/26C07D239/42C07D239/545C07D241/04C07D241/24C07D267/18C07D275/04C07D295/135C07D295/185C07D295/22C07D333/34C07D413/04C07D471/08C07D487/08
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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