Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof

A tetrahydrothiophene and hydrocarbon-based technology, applied in the field of medicine and chemical industry, can solve the problems of limited application, limited wide application, and insufficient performance

Inactive Publication Date: 2012-10-17
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Yang Rifang and others designed and synthesized a series of α-aminophosphonic acid derivatives in the previous research, and found that α-aminophosphonic acid derivatives can regulate the function of vascular endothelial cells, and can be used for atherosclerosis and thrombosis, etc. For the prevention and treatment of diseases (such as PPVP and DMHPPP respectively), PPVP has better anti-atherosclerosis and DMHPPP anti-thrombotic potency, but their respective efficacy is insufficient, which limits their further application [Yang Rifang, Wang Hai, et al. ZL01137268. 0; Wang Hai, Yang Rifang, et al. ZL01137272.9, ZL01137273.7; Zhao Lizhi, Yang Rifang, et al. Acta Pharmaceutica Sinica 2006, 41: 342-5; Yang Rifang, et al.Bioorg.Med.Chem.Lett.2004, 14(12): 3017-3025; Yang Rifang, et al. Synthesis 2003, (6): 887-893.]
[0006] Most of the existing drugs for the treatment of cardiovascular and cerebrovascular diseases are to replace or block certain active substances released by vascular endothelial cells, or the wide application in clinical practice is limited due to limited curative effect or adverse reactions.

Method used

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  • Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof
  • Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof
  • Thienopyridine alpha-amino benzylphosphonate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1: α-(2-chlorophenyl)-α-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine Pyridyl) methylphosphonic acid monoethyl ester - preparation of compound 1

[0091]Weigh 6.30g (49.0mmol) of 2-thiopheneethylamine, 8.43g (60.0mmol) of 2-chlorobenzaldehyde and 6.80g (49.0mmol) of diethyl phosphite and add them to 50mL of absolute ethanol to dissolve. React in temperature for 3 days, cool, recover the solvent, add ethanol hydrochloride 17.80mL (58.0g / 500mL, 53.90mmol), paraformaldehyde 1.77g (53.90mmol) and 60mL absolute ethanol, the reaction system is airtight, and the temperature is raised to 60°C, after stirring for one hour, the temperature was raised to reflux for reaction. After 3 days of reaction, the reaction was stopped and column chromatography gave 3.85 g of the product as a white powder with a total yield of 19.3%. mp 188-190°C, 1 H-NMR (CDCl 3 , ppm): δ0.93-0.96 (t, J=7.0Hz, 3H), 3.17-3.30 (m, 4H), 3.52-3.54 (m, 1H), 3.65-3.77 (m, 3H), 4.97-5.01 (d, J=14.85Hz, ...

Embodiment 2

[0092] Example 2: α-(2-fluorophenyl)-α-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine Pyridyl) methyl phosphonic acid monoethyl ester - preparation of compound 2

[0093] According to the method of Example 1, 2-fluorobenzaldehyde was used instead of 2-chlorobenzaldehyde to obtain 3.75 g of the product as a white powder, with a total yield of 19.5%, mp 193-196°C; 1 H-NMR (CDCl 3 , ppm): δ0.87-0.91 (t, J=7.0Hz, 3H), 3.17 (s, 2H), 3.48-3.60 (m, 4H), 4.44 (b s, 1H), 4.77-4.81 (d, J =15.41Hz, 1H), 4.91(b s, 1H), 6.76-6.77(d, J=3.92Hz, 1H), 7.08-7.12(t, J=9.10Hz, 1H), 7.18-7.19(d, J= 5.04Hz, 1H), 7.26-7.30(m, 1H), 7.39-7.48(dd, J=13.72, 6.73Hz, 1H), 8.33-8.36(t, J=6.72Hz, 1H); MS (ESI + , m / z): 356.1 (100%, M+H + ), 245.6 (M-PO(OEt) 2 ) + .

Embodiment 3

[0094] Example 3: α-(3-methoxy-4-hydroxyphenyl)-α-(4,5,6,7-tetrahydrothiophene Preparation of diethyl pheno[3,2-c]pyridyl)methylphosphonate-compound 3

[0095] Weigh 4.00g (26.25mmol) vanillin, 3.48g (25.0mmol) 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 3.80g (27.5mmol) diethyl phosphite, Add to 70mL of ethanol to dissolve. The reaction was carried out at a bath temperature of 70°C for 3 days, the reaction was stopped, the solvent was recovered, and the product was obtained by column chromatography as 7.50 g of a yellow oily liquid, with a yield of 72.9%; 1 H-NMR (CDCl 3 , ppm): δ1.09-1.11(t, J=7.0Hz, 3H), 1.30-1.33(t, J=7.0Hz, 3H), 2.73-2.87(m, 3H), 3.38-3.41(m, 1H ), 3.71-4.03(m, 8H), 4.18-4.20(m, 2H), 5.94(bs, 1H), 6.68-6.69(d, J=5.04Hz, 1H), 6.90-6.95(m, 2H), 7.03-7.04 (d, J=5.04Hz, 1H), 7.16 (s, 1H); MS (ESI + , m / z): 411.9 (100%, M+H + ), 274.1 (90%, (M-PO(OEt) 2 ) + ). The resulting product was converted into hydrochloride to give a white powder, mp 143-145°C....

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Abstract

The invention, belonging to the field of pharmaceutical chemicals, relates to a Thienopyridine alpha-amino benzylphosphonate, a preparation method and an application thereof. concretely, the invention relates to a compound of formula I, its medicinal salt, racemate, stereoisomer, or solvate, wherein each substituent is defined in the specification. The invention further relates to a pharmaceutical composition of the compound. The compound of the invention can effectively resist platelet aggregation and/or protect vascular endothelial cells.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a thienopyridine alpha-aminobenzyl phosphonate, its preparation method and application. The present invention also relates to the pharmaceutical composition of the compound. Background technique [0002] Atherosclerosis is a systemic disease characterized by the accumulation of fat-rich plaques on the walls of large arteries. It is the main pathological basis of cardiovascular and cerebrovascular diseases. Its main clinical manifestations are myocardial infarction, stroke and peripheral vascular disease, often accompanied by Conditions such as high blood pressure, high cholesterol, or diabetes. [0003] At present, anti-atherosclerotic drugs commonly used in clinic include blood lipid-lowering drugs (such as fibrates), hydroxymethylglutaryl coenzyme A reductase (HMG-CoA) inhibitors (such as statins), cholesterol and bile acid Absorption inhibitors (such as cholestyra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P7/02A61P9/10A61P9/12A61P9/04A61P1/16A61P3/10A61P7/06A61P25/00A61P11/00A61P3/06
Inventor 杨日芳李锦徐璇苏瑞斌刘莹吴宁恽榴红
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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