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Compound for treating thrombotic diseases

A compound and solvate technology, which is applied in the field of compounds for the treatment of thrombotic diseases, can solve the problems of low utilization efficiency, poor drugability, and poor permeability of simulated peptides.

Pending Publication Date: 2022-01-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, the biggest challenge in the development of antithrombotic drugs is that the difficulty in the development of such drugs is to be able to separate the synchronous platelet thrombus formation from the hemostatic function, that is, to distinguish the outside-to-in signal transduction of platelets from the inside-to-out signal transduction Inhibition, although current studies have found that some oligopeptides or polypeptides can selectively inhibit the platelet outside-in signal (related to thrombus formation) and have little effect on the inside-out signal (related to hemostatic function), but because this type of mimic peptide permeates the membrane Poor drug resistance, low utilization efficiency, difficult to apply to the body, and poor druggability, becoming a major obstacle to drugization and even clinical application
There are no reports of inhibitors of the protein-protein interaction between β3 and c-Src

Method used

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  • Compound for treating thrombotic diseases
  • Compound for treating thrombotic diseases
  • Compound for treating thrombotic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] Embodiment 1: the preparation of compound SYY-C001

[0237]

[0238] step 1:

[0239] Under mechanical stirring, 2-methoxy-3-chloro-5-nitropyridine (37.0g, 196.2mmol) was added in ethanol (500ml), iron powder (40.0g, 716.2mmol) was added at room temperature, ammonium chloride (40.0 g, 747.8 mmol) and water (100 ml), heated to 90° C. for 5 hours, and TLC showed that the reaction was complete. The reaction liquid was filtered, and the filtrate was concentrated to about 150 mL, added ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain gray solid C001-1 (30.5 g, yield 98%).

[0240] Step 2:

[0241] C001-1 (30.5g, 192.3mmol) was dissolved in acetonitrile (400ml), cooled to 0°C, NIS (47.1g, 209.4mmol, dissolved in 300ml of acetonitrile) was added dropwise, and maintained at 0-2°C for 1 hour After dropping, TLC monitors (a small amount of raw mate...

Embodiment 2

[0262] Embodiment 2: Preparation of intermediates C-IN-002 and C-IN-003

[0263]

[0264] step 1:

[0265] N 2 Under protection, the raw material 2-amino-5-bromopyridine (30.0g, 173.40mmol) was dissolved in DMF (200mL), and trifluoroacetic acid (14.2mL, 191.17mmol) and NIS (43.0g, 191.13mmol) were added at room temperature , heated to 50° C. and stirred for 3 hours, TLC showed that the starting material was completely consumed. The reaction solution was cooled to room temperature, the reaction solution was slowly poured into water, extracted with ethyl acetate, the organic phases were combined, and 10% NaS 2 SO 3 solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give IN-002-1 (45g) as a yellow solid.

[0266] Step 2:

[0267] N 2 Under protection, IN-002-1 (2.0g, 6.69mmol) and Et 3 N (1.2mL, 8.63mmol) was dissolved in THF (30mL), and trimethylsilylpropyne (2.0mL, 13.51mmol) was added in portions at room temperature, and P...

Embodiment 3

[0276] Embodiment 3: the preparation of compound SYY-C002

[0277]

[0278] step 1:

[0279] N 2 Under protection, C-IN-002 (1.2g, 8.21mmol) was dissolved in DMF (20mL), and NBS (1.46g, 8.20mmol) was added under an ice-water bath. After 10 minutes of reaction, TLC showed that the raw material was completely reacted. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is subjected to silica gel column chromatography to obtain yellow solid C002-1 (1.5 g, yield 81%). 1 H NMR (400MHz, CDCl 3 )δ2.48(s, 3H), 3.83(s, 3H), 7.10(dd, J=7.8, 4.8Hz, 1H), 7.76(dd, J=7.8, 1.5Hz, 1H), 8.29(dd, J =4.8, 1.5Hz, 1H).

[0280] Step 2:

[0281] N 2 Under protection, C002-1 (1.5g, 6.66mmol) was dissolved in THF (30mL), cooled to -65°C, and n-BuLi (2.8mL, 7.00mmol, 2.5M) was slowly added dropwise, and the addition was completed in - After stirring at 65°C...

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PUM

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Abstract

The invention relates to a compound for treating thrombotic diseases. Specifically, the invention provides a compound as shown in a formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereoisomer thereof, or an atropisomer thereof, or a raceme thereof, or a polymorphic substance thereof, or a solvate thereof, or an isotope labeled derivative thereof. After the compound disclosed by the invention is specifically combined with an SH3 structural domain protein of Src kinase, the interference integrin alpha IIb beta 3 is combined with the Src kinase, so that signal transduction from outside to inside is selectively inhibited, and the signal transduction from inside to outside is not influenced, so that the compound disclosed by the invention does not influence a normal physiological hemostasis function while resisting thrombus, and avoids side effects, and the compound can become a new generation of effective medicine for preventing and treating thrombus-related cardiovascular and cerebrovascular diseases.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a compound for treating thrombotic diseases. Background technique [0002] At present, cardiovascular and cerebrovascular thrombotic diseases such as myocardial infarction and cerebral infarction have become the most important cause of serious threats to human life and health, and have the characteristics of high morbidity and mortality. According to the statistics of the World Health Organization, about 12 million people are prematurely killed by cardiovascular and cerebrovascular diseases every year. The mortality rate of cardiovascular and cerebrovascular diseases is the highest among various diseases. The number of people accounted for about 1 / 3 of the global death toll. Platelets play a key role in the formation of cardiovascular and cerebrovascular thrombosis. When the vascular endothelium is damaged or atherosclerotic plaque ruptures, platelets are activated and lead to pathologi...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D209/42C07D401/04C07D405/04C07D209/40C07D307/84C07D333/68C07D409/12A61K31/437A61K31/4045A61K31/404A61K31/4709A61K31/4725A61K31/343A61K31/381A61K31/4436A61P7/02A61P7/04
CPCC07D471/04C07D209/42C07D401/04C07D405/04C07D209/40C07D307/84C07D333/68C07D409/12A61P7/02A61P7/04A61P9/00C07D209/60
Inventor 罗成奚晓东周兵朱孔凯毛建华刘静秋杨亚玺梅良和阮铮蒋昊奚闻达龙章彪肖兵黄建松蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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