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Tetrahydrocoptisine derivative and applications thereof

The technology of a compound and a medicinal salt, which is applied to tetrahydrocoptisine derivatives and their application fields, can solve problems such as visual impairment, gallstones, and insignificant hypolipidemic effect.

Inactive Publication Date: 2016-03-23
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
[0025] It is worth pointing out that the documents WO2010075469 and WO2011006000 reported compounds that inhibit the expression of PCSK9 and have a lipid-lowering effect. The structural types of these compounds are limited, and the relationship between the compound structure and the activity is insufficiently studied

Method used

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  • Tetrahydrocoptisine derivative and applications thereof
  • Tetrahydrocoptisine derivative and applications thereof
  • Tetrahydrocoptisine derivative and applications thereof

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specific Embodiment approach

[0237] 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 .

[0238] The preparation of the general formula compound (VII) disclosed in the present invention is mainly prepared according to the following scheme:

[0239]

[0240] The above preparation route is described as follows: V1 and V2 are the starting materials of this scheme, which can be obtained from commercially available products, or prepared according to methods reported in literature. First, V1 and V2 are dehydrated under a certain reaction temperature to obtain an imine compound V3, and the compound V3 is reduced to an "amine" compound V4. Under certain reaction conditions, V4 reacts with ...

specific Embodiment

[0242]Representative process: Now take the oxo group substitution at the 4th position of the D ring (such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy, phosphoryloxy, etc.) as an example, and give a brief description:

[0243]

[0244] Basic process: First, react substituted phenylethylamine S6 and substituted o-hydroxybenzaldehyde S17 in dichloromethane at 60°C to generate imine compound S18, concentrate dichloromethane under reduced pressure, add methanol solution, Reduction reaction under a certain temperature condition, remove the methanol solvent under reduced pressure, disperse with ethyl acetate, wash with saturated brine for 3 times, combine the ethyl acetate layer, concentrate under reduced pressure to obtain the "amine" compound S19, and S19 with formic acid Disperse, add copper sulfate and glyoxal, reflux reaction at 80°C, then keep warm for 2 hours, a large amount of solids will precipitate, filter the solids, disperse with methanol, add calcium oxide to adjust...

Embodiment approach

[0258]

[0259] Basic process: first, the natural product Z1 is demethylated by vigorous stirring reaction at a high temperature of 200°C to obtain compound Z2, and then prepared by reacting with sulfuryl chloride in a dichloromethane solvent at a low temperature of -10-5°C to room temperature Compound Z3 was reduced by sodium borohydride in methanol solution at low temperature to obtain compound Z4.

[0260] The present invention will be further described below through specific examples, but those skilled in the art should know that the present invention is not limited to these examples.

[0261] Compound structures were determined by nuclear magnetic resonance (NMR) or mass spectroscopy (MS). The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shi...

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Abstract

The present invention relates to a compound as shown in a formula (VII), a preparation method and applications thereof in medicines. In particular, the present invention relates to a derivative of the compound as shown in the formula (VII), a preparation method, and the applications of the derivative used as a therapeutic agent in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, II-type diabetes, hyperglycemia, obesity or insulin resistance syndrome and metabolic syndrome. The compound disclosed by the present invention can also reduce total cholesterol, LDL-cholesterol and triglyceride, and increases expression of a liver LDL receptor and decreases 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 and metabolic syndrome Methods, 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, etc....

Claims

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Application Information

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IPC IPC(8): C07D455/03C07D491/147C07F9/6561A61P3/04A61P3/06A61P3/10A61P5/50A61P1/16A61P3/00
CPCC07D455/03C07D491/147C07F9/6561
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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