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Medicine for preventing and treating coronary heart disease and application thereof

A drug and pharmaceutical technology, applied in the field of indolinone derivatives or their pharmaceutically acceptable salts, can solve the problems of not being able to have a good effect on cardiovascular and cerebrovascular diseases, and achieve the effect of increasing HDL levels

Inactive Publication Date: 2017-07-04
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they themselves cannot have a good effect on certain cardiovascular and cerebrovascular diseases such as coronary heart disease

Method used

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  • Medicine for preventing and treating coronary heart disease and application thereof
  • Medicine for preventing and treating coronary heart disease and application thereof
  • Medicine for preventing and treating coronary heart disease and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0062] The present invention also provides a preparation method of the compound shown in formula 1, the preparation method comprising the following steps:

[0063] Step 1. react the compound shown in formula 2 with the compound shown in formula 3 to prepare the compound shown in formula 4, as shown in following reaction formula 1:

[0064] [Reaction 1]

[0065]

[0066] In Equation 1, R 1 , R 2 , r, s are as defined in formula 1, X represents halogen, preferably chlorine or bromine;

[0067] The reaction is carried out in the presence of a base, which includes inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; and organic bases such as triethylamine, pyridine or piperidine.

[0068] Step 2. react the compound shown in formula 4 with the compound shown in formula 5 to prepare the compound shown in formula 1, as shown in following reaction formula 2:

[0069] [Reaction 2]

[...

Embodiment 1

[0081] Example 1: (Z)-3-((1H-benzo[d]imidazol-7-yl)methylene)-5-methyl-6-(pyridin-2-yl)indoline-2- Ketone (Compound I)

[0082]

[0083] Step 1: Put 1H-benzo[d]imidazole-7-carbaldehyde (2.19g, 15.0mmol) in a 500ml eggplant-shaped bottle, add 150ml of absolute ethanol to dissolve, then add 6-chloro-5-methylind Indolin-2-one and 2ml triethylamine were reacted at room temperature for 3 hours, and a large amount of precipitation appeared. Suction filtration, washing with a small amount of absolute ethanol, drying to obtain yellow solid (Z)-3-((1H-benzo[d]imidazol-7-yl)methylene)-6-chloro-5-methylindole Lin-2-one 4.15g, yield 89.2%, content 98.1%. ESI-MS: 310.07[M+H] + .

[0084] Step 2: Add (Z)-3-((1H-benzo[d]imidazol-7-yl)methylene)-6-chloro-5-methylindoline-2 to a dry Schlenk reaction tube -ketone (3.09g, 10.0mmol), pyridin-2-ylboronic acid dimethyl ester (1.66g, 11.0mmol), tetrakis(triphenylphosphine)palladium (0.12g, 0.1mmol), Na 2 CO 3 (2.12g, 20.0mmol), under the p...

Embodiment 2

[0088] Example 2: (Z)-5-(hydroxymethyl)-3-((5-(methylsulfonyl)-1H-benzo[d]imidazol-7-yl)methylene)-6-( Pyrimidin-2-yl)indolin-2-one (Compound II)

[0089]

[0090] According to the method of Example 1, with 1-(5-(methylsulfonyl)-1H-benzo[d]imidazol-7-yl)-formaldehyde instead of 1H-benzo[d]imidazole-7-formaldehyde, use 6-Bromo-5-(hydroxymethyl)indolin-2-one instead of 6-chloro-5-methylindolin-2-one, pyrimidin-2-ylboronic acid dimethyl ester instead of pyridin-2- Dimethyl boronic acid was used to obtain the title compound as a white solid in a total yield of 63.9% over two steps.

[0091] ESI-MS: 448.47[M+H] +

[0092] Elemental analysis: theoretical value / measured value, C(59.05 / 59.12), H(3.83 / 3.87), N(15.65 / 15.74), O(14.30 / 14.22), S(7.17 / 7.05)

[0093] 1 H NMR (400MHz, CDCl 3)δ12.37(s, 1H), 11.19(s, 1H), 8.81(d, 2H), 8.24(s, 1H), 8.12(s, 1H), 8.00(s, 1H), 7.76(s, 1H ), 7.56 (s, 1H), 7.39 (s, 1H), 7.28 (q, 1H), 5.23 (s, 1H), 4.63 (s, 2H), 3.31 (s, 3H).

[0094] Follo...

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Abstract

The invention relates to an indolinone derivative having excellent lecithin-cholesterol acetyltransferase (LCAT), preferably reversible LCAT activation effect as well as its pharmaceutically acceptable salt. The compound comprises a compound shown in a formula I or its pharmaceutically acceptable salt. The compound has excellent excitement effect on LCAT, has obvious increase effect for HDL level, and is used for preventing and treating cardio cerebrovascular diseases such as coronary heart disease and arteriosclerosis.

Description

technical field [0001] The present invention relates to an indolinone derivative or a pharmaceutically acceptable salt thereof having an excellent lecithin-cholesterol acetyltransferase (ie LCAT) activation effect, preferably a reversible LCAT activation effect, which can be used to prevent And treat cardiovascular and cerebrovascular diseases, such as coronary heart disease, arteriosclerosis, etc. Background technique [0002] Cardiovascular and cerebrovascular diseases caused by hypertension, dyslipidemia, diabetes, etc. are currently major problems. Antihypertensive, antilipidemia and antidiabetic drugs are used to treat hypertension, dyslipidemia and hyperglycemia respectively, such as diuretics, calcium antagonists, ACE inhibitors and A-II antagonists, etc. can be used as antihypertensives Drugs, HMG-CoA reductase inhibitors, nicotinic acid derivatives and clofibrates can be used as anti-dyslipidemia drugs, insulin, sulfonylureas, metformin, glitazones, etc. can be use...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/14A61K31/4439A61K31/506A61P9/00A61P9/10
Inventor 陈涛崔金金
Owner HARBIN MEDICAL UNIVERSITY
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