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Tetrahydroberberine derivative and application thereof

A technology for compounds and solvates, applied to tetrahydroberberine derivatives and their application fields, can solve the problems of insignificant hypolipidemic effect, occurrence of adverse reactions, insufficient research on the relationship between compound structure and activity and efficacy, etc.

Inactive Publication Date: 2016-04-13
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
[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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  • Tetrahydroberberine derivative and application thereof
  • Tetrahydroberberine derivative and application thereof
  • Tetrahydroberberine derivative and application thereof

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specific Embodiment approach

[0213] 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 .

[0214] The preparation of the general formula compound (V) disclosed by the present invention is mainly prepared according to the following scheme:

[0215]

[0216] 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 gl...

specific Embodiment

[0218] Representative process 1: mainly for the preparation of D rings with two important oxo functional groups (D rings have two oxo functional groups, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy , phosphoryloxy, etc.) compounds. Representative process 2: mainly for the preparation of D ring with only one important oxo functional group (D ring has an oxo functional group, such as acetoxy, benzoyloxy, benzyloxy, sulfonyloxy, phosphorus acyloxy, etc.) compounds.

[0219] Representative process 1: Taking the preparation method of a compound containing two important oxo groups in the D ring, one of which is a sulfonyloxy group, as an example, a brief description of the example:

[0220]

[0221] Step 1: Preparation of sulfonyloxy and monohydroxyl-substituted benzaldehydes (S2A):

[0222]

[0223] First, dissolve a commercially available (or prepared according to the literature method) benzaldehyde S1 with one benzyloxy group and the other exposed hydroxyl group in...

Embodiment 1

[0252]

[0253] Preparation of substituted aldehydes: Synthesis of 2-(m-fluorobenzenesulfonate)-3-hydroxybenzaldehyde.

[0254] Take 2,3-dihydroxybenzaldehyde A13.8g (100mmol) in a 250ml round bottom flask, add 100ml acetone to dissolve, then add K 2 CO 3 27.6g (200mmol), benzyl bromide (18.8g, 110mmol) was added at 0°C, slowly heated to 50°C, reacted for 5 hours, added 250ml of ice water, extracted the aqueous phase with ethyl acetate, combined the ethyl acetate layers, And washed 3 times with saturated brine, combined the ethyl acetate layer, dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain 3-benzyloxy-2-hydroxybenzaldehyde B, which was directly put into the next reaction.

[0255] The 3-benzyloxy-2-hydroxybenzaldehyde B obtained in the above steps was washed with 200ml CH 2 Cl 2 Dissolve in a 500ml round bottom flask, slowly add 12.1g (120mmol) triethylamine at 0°C, stir for 30min, then slowly add 21.3g (110mmol) m-fluorobenzenesulf...

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Abstract

The invention relates to a tetrahydroberberine derivative and application thereof and relates to a compound represented by a formula (V) shown in the description, a preparation method therefor and application of the compound in medicine. Particularly, the invention relates to a derivative of the compound represented by the general formula (V), a preparation method for the derivative of the compound and use of the derivative of the compound in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type II diabetes, hyperglycemia, obesity or insulin resistance syndrome and metabolic syndrome. The compound disclosed by the invention can also be used for lowering total cholesterol, LDL (Low-Density Lipoprotein)-cholesterol and triglyceride, improving liver LDL receptor expression and inhibiting 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 and metabolic syndrome 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, etc. ...

Claims

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Application Information

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IPC IPC(8): C07D455/03C07D497/14C07F9/6561A61K31/4375A61K31/5377A61K31/375A61K31/4545A61K31/4725A61K31/4741A61P3/06A61P3/00A61P3/10A61P1/16A61P5/50
CPCA61K31/4375C07D455/03
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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