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Tetrahydropalmatine derivative and application thereof

A technology of compounds and medicinal salts, applied to tetrahydropalmatine derivatives and their application fields, can solve problems such as visual impairment, allergic reactions, skin diseases, itching and the like

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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  • Tetrahydropalmatine derivative and application thereof
  • Tetrahydropalmatine derivative and application thereof
  • Tetrahydropalmatine derivative and application thereof

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specific Embodiment approach

[0212] 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 .

[0213] The preparation of the general formula compound (VI) disclosed in the present invention is mainly prepared according to the following scheme:

[0214]

[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 r...

Embodiment 1

[0251] Compound 1 of the present invention is implemented according to the following two-step scheme:

[0252] Step 1: Preparation of key intermediate D (3-methoxy-4-hydroxyphenethylamine hydrochloride)

[0253]

[0254] Put vanillin A (30.4, 200mol) and nitromethane (16.1ml, 300mmol) in methanol successively, and add 33% methanol solution (1.5ml). The reaction was stirred at 50°C for 2 hours, the solution was homogeneous, and gradually changed from colorless to dark brown, and a large amount of yellow solid appeared after 1.5 hours. After the reaction was complete by TLC, let it cool and filter with suction. Yellow solid B (33.6 g, 172.3 mmol) washed with a small amount of methanol.

[0255] Add B (33.6 g, 172.3 mmol) obtained in the previous step to 1,4-dioxane (500 mL), stir vigorously, and make it a cloudy liquid for later use. Add ethanol (75mL), 1,4-dioxane (300mL), NaBH 4 (32.0g, 845.9mmol), add the reserved suspension dropwise under stirring, and finish adding wi...

Embodiment 2

[0266] Compound 2 of the present invention was first prepared with reference to the steps of Example 1 to obtain Compound J, and then the following reactions were carried out:

[0267]

[0268] Compound J (300mg, 0.621mmol) was dissolved in 10ml of dichloromethane, trans-9-octadecanoic acid (208mg, 0.74mmol), DCC (164mg, 0.80mmol), DMAP (98mg, 0.80mmol), Stir the reaction at room temperature for 8 h, remove DCU by filtration, wash the filter cake with dry dichloromethane, combine the organic layers, and concentrate under reduced pressure to obtain the crude product of compound 2, and obtain 126 mg of compound 2 (yield 27.2%) by silica gel column chromatography. 1 HNMR (400MHz, CDCl 3)δ8.03–7.97(m,2H),7.72–7.66(m,1H),7.60–7.55(m,2H),7.31(d,J=8.5Hz,1H),6.96(s,1H),6.80 (d, J=8.5Hz, 1H), 6.71(s, 1H), 5.46–5.33(m, 2H), 4.76(d, J=9.8Hz, 1H), 4.24(d, J=16.1Hz, 1H) ,3.81(s,3H),3.71(s,1H),3.60(d,J=16.2Hz,1H),3.45(s,3H),3.19–3.07(m,2H),2.78–2.49(m,5H ),2.02–1.89(m,2H),1.82–1.70(m,...

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Abstract

The invention relates to a tetrahydropalmatine derivative and application thereof, a compound as shown in a formula (VI) and a preparation method thereof, and an application of the compound in medicine. Specifically, the invention relates to a derivative of the compound as shown in the general formula (VI) and a preparation method thereof, and an application of the derivative as a therapeutic agent in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, diabetes type II, hyperglycemia, adiposis, or insulin resistance and metabolic syndrome. The compound disclosed by the invention also can reduce total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increases the expression of a liver LDL receptor and inhibits the expression of proprotein convertase subtilisin / kexin type 9 (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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03C07F9/6561A61K31/4375A61K31/5377A61K31/675A61P3/06A61P1/16A61P3/00A61P3/10A61P3/04A61P5/50
CPCA61K31/4375C07D455/03
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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