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A kind of medicine for preventing and treating coronary heart disease and preparation method thereof

A technology for drugs and cardiovascular and cerebrovascular diseases, applied in the field of medicinal chemistry, can solve problems such as ineffective treatment of coronary heart disease

Active Publication Date: 2020-10-27
MUDANJIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs help improve certain risk factors for coronary heart disease, such as regulating blood pressure or lowering lipid or glucose levels in the blood, but they are still not effective in treating coronary heart disease

Method used

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  • A kind of medicine for preventing and treating coronary heart disease and preparation method thereof
  • A kind of medicine for preventing and treating coronary heart disease and preparation method thereof
  • A kind of medicine for preventing and treating coronary heart disease and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0045] The present invention also provides a preparation method of the compound of formula I, the preparation method comprising the following steps:

[0046] Reaction of a compound of formula II with a compound of formula III in the presence of a base to prepare a compound of formula I

[0047]

[0048] Among them, R 1 -R 7 as defined herein;

[0049] The base is selected from organic bases such as triethylamine or pyridine; or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0050] The present invention also relates to a pharmaceutical composition comprising at least one of said compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs thereof as an active ingredient. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier or excipient.

[0051] The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form su...

Embodiment 1

[0062] Example 1: (Z)-6-((6-methyl-2-oxoindole-3-methylene)methyl)-4-oxospiro[chroman-2,4'-piperidine ]-1'-tert-butyl formate (compound SP-1)

[0063]

[0064] Put tert-butyl 6-formyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.0mmol) into the flask, add 100m absolute ethanol to dissolve it, and then Then 6-methylindolin-2-one (10.0 mmol) and 2 ml of triethylamine were added, and the reaction was stirred at room temperature for 3 h, and a large amount of precipitation appeared. Suction filtration under reduced pressure, the filter cake was washed with a small amount of absolute ethanol, and dried under vacuum to obtain 4.34 g of the title product as a white solid, with a yield of 91.5%.

[0065] ESI-MS: 475.22[M+H] +

[0066] Elemental analysis: theoretical value C, 70.87; H, 6.37; N, 5.90; O, 16.86

[0067] Found value C, 70.58; H, 6.55; N, 5.79; O, 17.08

[0068] 1 H NMR (400MHz, CDCl 3 )δ11.08(s,1H),7.85(d,1H),7.70(s,1H),7.51(d,1H),7.39(d,1H),7.13(s,1H)...

Embodiment 2

[0069] Example 2: (Z)-6-((5,6-dimethoxy-2-oxoindoline-3-methylene)methyl)spiro[chroman-2,4'-piperidine ]-4-one (SP-2)

[0070]

[0071] According to the method of Example 1, replace 6-formyl-4-oxospiro[chroman-2,4'-piperidine]-6-carbaldehyde with 4-oxospiro[chroman-2,4'-piperidine Pyridine]-1'-carboxylic acid tert-butyl ester, substituting 5,6-dimethoxyindolin-2-one for 6-methylindolin-2-one afforded the title compound as a gray solid, yield 87.9 %.

[0072] ESI-MS: 423.18[M+H] +

[0073] Elemental analysis: theoretical value C, 68.23; H, 6.20; N, 6.63; O, 18.94

[0074] Found value C, 68.35; H, 6.02; N, 6.97; O, 18.66

[0075] 1 H NMR (400MHz, CDCl 3 )δ11.10(s,1H),7.88(d,1H),7.53(s,1H),7.29(s,1H),7.22(s,1H),7.10(d,1H),6.89(d,1H ), 3.85(s,6H), 2.85(t,4H), 2.66(s,2H), 2.02(s,1H), 1.91(t,4H).

[0076] According to a method similar to Example 1, the following compounds were synthesized:

[0077]

[0078] Example of efficacy

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Abstract

The invention relates to an indolinone derivative or pharmaceutically acceptable salt, stereisomer, tautomer, solvate and predrug thereof. The compound disclosed by the invention has an excellent LCATactivation effect, is capable of remarkably increasing the HDL level and therefore can be used as an effective component in a treating agent or a prevention agent for coronary heart diseases (including heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and angiogenic restenosis), arteriosclerosis, arteriosclerotic heart disease, cerebrovascular diseases (including stroke and cerebral infarction), peripheral blood vessel diseases (including diabetic vascular complications), dyslipidemia, low HDL cholesteremia, high LDL cholesteremia or kidney diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, specifically, the invention relates to a medicine capable of effectively activating lecithin-cholesterol acetyltransferase (LCAT), and the invention also relates to a preparation method of the medicine. Background technique [0002] Coronary atherosclerotic heart disease is a heart disease caused by atherosclerotic lesions in the coronary arteries that cause stenosis or blockage of the vessel lumen, resulting in myocardial ischemia, hypoxia or necrosis. It is often called "coronary heart disease". However, the scope of coronary heart disease may be wider, including inflammation, embolism, etc. leading to stenosis or occlusion of the lumen. The World Health Organization divides coronary heart disease into five categories: asymptomatic myocardial ischemia (occult coronary heart disease), angina pectoris, myocardial infarction, ischemic heart failure (ischemic heart disease) and sudden death. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/107A61K31/438A61K31/4427A61P9/00A61P9/10
CPCA61P9/00A61P9/10C07D491/107
Inventor 孔娟唐玉立侯丽媛杨超马小升金涛
Owner MUDANJIANG MEDICAL UNIV
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