Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Ester derivatives of multi-substituted 4-methylamino-benzamidine as well as preparation method and application of ester derivatives

An aminomethyl, methyl group technology, applied in the field of chemical pharmacy, can solve the problems of large gastrointestinal side effects, increased bleeding risk, low bioavailability, etc.

Active Publication Date: 2014-01-22
HAISCO PHARMA GRP INC
View PDF2 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa inhibitor rivaroxaban have been confirmed in clinical trials, and they can replace warfarin as the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Noparin sodium has become the drug of choice for the prevention of venous thromboembolism in patients after major plastic surgery, but the bioavailability of dabigatran etexilate is low, only 3-7%, so the dosage is large and the gastrointestinal side effects are relatively large ; Due to its pharmacological mode of action, rivaroxaban may cause an increased risk of hidden or overt bleeding in some tissues or organs, which may lead to post-hemorrhagic anemia; the anticoagulant drug melagatran developed by AstraZeneca (melagatran) was also withdrawn from the market due to reports of serious liver injury adverse reactions after listing

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Ester derivatives of multi-substituted 4-methylamino-benzamidine as well as preparation method and application of ester derivatives
  • Ester derivatives of multi-substituted 4-methylamino-benzamidine as well as preparation method and application of ester derivatives
  • Ester derivatives of multi-substituted 4-methylamino-benzamidine as well as preparation method and application of ester derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] 3-{1-Methyl-2-[N-(4-(N-pentyloxycarbonyl)amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid}-( Synthesis and preparation of N-2-pyridyl)amido-propionic acid-2-(n-heptadecylcarbonyloxy)glycerophosphorylcholine-3-yl-ester (compound 1)

[0098]

[0099] (1) Synthesis of 3-(N-2-pyridylamino)-propionic acid ethyl ester

[0100]

[0101] Under the protection of nitrogen, add ethyl acrylate (27.5g, 0.275mol) to 2-aminopyridine (22.5g, 0.25mol), stir and reflux at a temperature higher than 100°C for 24h, filter out the precipitate, concentrate the residue and use a silica gel column Column purification gave 3-(N-2-pyridylamino)-propionic acid ethyl ester (34.9 g, yield 72%) as a white solid. Mass Spectrum (ESI-MS): 195.1 (M+H) + , 217.3 (M+Na) + ;C 10 h 14 N 2 o 2 (194).

[0102] (2) Synthesis of 4-cyanoanilino-acetic acid

[0103]

[0104] Add 150ml of water to 4-cyanoaniline (6.0g, 0.05mol) and 1-chloroacetic acid (10g, 0.11mol), heat to reflux un...

Embodiment 2

[0134] 3-{1-Methyl-2-[N-(4-(N-Hexyloxycarbonyl)amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid}-(N Synthesis and preparation of -phenyl)amido-propionic acid-3-(n-octadecylcarbonyloxy)glycerophosphorylcholine-2-yl-ester (compound 2)

[0135]

[0136] (1) Synthesis of 3-(N-phenylamino)-ethyl propionate

[0137]

[0138] Under the protection of nitrogen, add ethyl acrylate (27.5g, 0.275mol) to aniline (23.3g, 0.25mol), add 10ml of absolute ethanol and 10ml of triethylamine, stir and reflux at a temperature higher than 100°C for 24h, filter out the precipitate The residue was concentrated and purified with a silica gel column to obtain light red solid 3-(N-phenylamino)-propionic acid ethyl ester (36.7g, yield 76%). Mass Spectrum (ESI-MS): 194.1 (M+H) + , 216.3 (M+Na) + ;C 11 h 15 NO 2 (193).

[0139] (2) Synthesis of ethyl 3-(2-nitro-1-methylamino-phenyl-4-yl)-carboxylic acid-(N-phenyl)amidopropionate

[0140]

[0141] 3-(N-Phenylamino)-propionic aci...

Embodiment 3

[0162] 3-{2-[N-(4-(N-Butoxycarbonyl)amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-(N-phenyl)}-amide Synthesis and preparation of -propionic acid-2-(n-hexadecylcarbonyloxy)glycerophosphorylcholine-3-yl-ester (compound 3)

[0163]

[0164] (1) Synthesis of 4-fluoro-3-methoxyacetamido-ethyl benzoate

[0165]

[0166] 17.4g (94.9mmol) 3-amino-4-fluoro-benzoic acid ethyl ester (refer to L.S.Fosdick, A.F.Dodds, J.Amer Chem.Soc.65,2305 (1943)) and 9.67ml (11.47g, 105.4mmol ) A solution of methoxyacetyl chloride in 310 ml of chlorobenzene was stirred at 50°C for 2 hours and then refluxed for 30 minutes. Concentrate under reduced pressure and evaporate to dryness, and purify by silica gel column chromatography (dichloromethane / ethanol=100:1) to obtain the oily product 3-amino-4-fluoro-ethyl benzoate, which solidifies into a solid after a few days (20.1g, yield rate of 83%). R f Value: 0.38 (silica gel: dichloromethane / ethanol = 19:1). Mass Spectrum (ESI-MS): ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides new ester derivatives with a general formula (I) shown in the specification of multi-substituted 4-methylamino-benzamidine or pharmaceutically acceptable salts, wherein A1, A2, A3 and A4 in the formula are as defined in the specification. The compounds have an anticoagulant effect and can be used for preparing medicaments for preventing and treating thromboembolic diseases.

Description

technical field [0001] The invention relates to a new class of ester derivatives of multi-substituted 4-methylaminobenzamidine and its use as medicine, belonging to the field of chemical pharmacy. Background technique [0002] Thrombosis (such as acute myocardial infarction (AMI), venous thromboembolism, etc.) is a type of cardiovascular disease that seriously threatens human health and life. Antithrombotic therapy, which targets thrombin and uses thrombin inhibitors to inhibit the formation of thrombus, is one of the methods for clinical treatment of thrombus. [0003] Blood coagulation is a key process involved in both hemostasis (that is, preventing the loss of blood from damaged blood vessels) and thrombosis (that is, the formation of blood clots in blood vessels, sometimes leading to blockage of blood vessels). Blood coagulation is the result of a complex series of enzymatic reactions, one of the final steps of which is the conversion of the proenzyme prothrombin into ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07F9/6558C07F9/6506C07F9/6541C07F9/572A61K31/685A61K9/08A61P7/02
Inventor 李麒麟李岳党娟龙雨
Owner HAISCO PHARMA GRP INC
Features
  • Generate Ideas
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com