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Tetrahydroisoquinoline derivative and application thereof

A technology of salts and compounds, applied in the field of tetrahydroisoquinoline derivatives and their applications, can solve problems such as adverse reactions, only injection preparations, gallstones, etc.

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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  • Tetrahydroisoquinoline derivative and application thereof
  • Tetrahydroisoquinoline derivative and application thereof
  • Tetrahydroisoquinoline derivative and application thereof

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Experimental program
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specific Embodiment approach

[0204] 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 .

[0205] The preparation of the general formula compound (V) disclosed by the present invention is mainly prepared according to the following scheme:

[0206]

[0207] 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. Under certain reaction conditions, X1 and X2 can obtain compound X3 through a certain amide connection method. The intermediate X3 is reacted under the action of a dehydrating agent to obtain X4. Further connec...

Embodiment 1

[0226]

[0227] 1A (508μL, 3.01mmol) and 1B (500mg, 3.01mmol) were added to a 25mL round bottom flask, placed in an oil bath, heated to 150°C, melted into a liquid, and stirred for 2.5h. Cool to room temperature, add ethyl acetate, grind the solid, filter with suction, wash with ethyl acetate, and dry to obtain off-white solid 1C (765 mg, yield 77.3%)

[0228]Add 1C (500mg, 1.52mmol), toluene (3mL), and phosphorus oxychloride (750μL) into a 50mL round bottom flask, stir in an oil bath at 110°C for 2h, cool to room temperature, add saturated sodium bicarbonate in an ice bath The aqueous solution was quenched, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain an oil. The oil was dissolved in methanol (15mL), stirred at room temperature, sodium borohydride (115mg, 3.04mmol) was added in batches, after the addition was completed, stirred at room temperature for 20min, the reaction solution was spin-dried, the residue ...

Embodiment 2

[0231]

[0232] 2A (100mg, 0.319mmol) was added to a 50mL round bottom flask, dissolved in dichloromethane (10mL), triethylamine (67μL, 0.479mmol), 2B (69μL, 0.639mmol) were added, stirred at room temperature for 3h, and the reaction solution was vortexed Dry, the residue was extracted with water and ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and spin-dried, the obtained residue was separated and purified by preparative TLC (petroleum ether: ethyl acetate 2:1) to obtain a colorless paste compound 2 ( 121 mg, yield 90.3%). 1 HNMR (400MHz, CDCl 3 )δ7.07–7.00(m,2H),6.85–6.78(m,2H),6.58(s,1H),6.12(s,1H),4.86(t,J=6.9Hz,1H),3.84(s ,3H),3.78(s,3H),3.72(ddd,J=13.6,6.3,2.2Hz,1H),3.62(s,3H),3.38(ddd,J=13.8,11.4,4.6Hz,1H), 3.17(dd,J=13.6,6.4Hz,1H),3.06–2.93(m,2H),2.66–2.55(m,7H); MS(ESI)m / z[M+H] + :421.12

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Abstract

Provided are a tetrahydroisoquinoline derivative and an application thereof. The invention relates to a compound represented by the formula (V) and a preparation method and an application thereof in medicines. In particular, the invention relates to the derivative of the compound represented by the general formula (V) and a preparation method and the application thereof as a therapeutic agent in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, type-II diabetes, hyperglycemia, obesity or insulin resistance syndromes and metabolic syndromes. The compound disclosed by the invention also can reduce total cholesterol, LDL-cholesterol and triglycerides, and increases the expression of hepatic LDL receptors and inhibits 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 Uses, compounds and compositions for cancer. 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 infarct...

Claims

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Application Information

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IPC IPC(8): C07D217/20C07D221/18C07F9/576A61K31/472A61K31/473A61K31/5377A61K31/675A61P3/06A61P3/10A61P3/04A61P5/50A61P35/00A61P3/00
CPCC07D217/20C07D221/18C07F9/5765
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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