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Steroid sapogenin derivatives and preparation method and application thereof

A technology of steroidal saponins and derivatives, applied in the field of medicine, can solve the problems of side effects such as inability to inhibit anti-platelet aggregation, intestinal reactions, changes in blood lipid levels, and bleeding tendency

Active Publication Date: 2011-11-16
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aspirin is the drug of choice for clinical antiplatelet therapy, but it cannot inhibit the antiplatelet aggregation induced by agonists such as thrombin, ADP, collagen, and catecholamines. Gastrointestinal side effects (superficial mucosal erosion, ecchymosis, gastrointestinal bleeding) may occur in long-term medication. , peptic ulcer, etc.) and aspirin resistance
[0005] Although the later broad-spectrum antiplatelet drugs such as ticlopidine and clopidogrel partially overcome the aforementioned defects of aspirin, they still have side effects such as gastrointestinal reactions, changes in blood lipid levels, and bleeding tendency, as well as the recently discovered clopidogrel resistance; Glycoprotein IIb / IIIa receptor inhibitors are currently known to be the most powerful class of antiplatelet drugs. At present, several GPIIb / IIIa receptor antagonists are mainly administered intravenously and are only used for AMI or acute coronary syndrome. syndrome patients and the field of interventional cardiology, while long-term antiplatelet therapy and secondary prevention of ischemic events require oral active agents

Method used

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  • Steroid sapogenin derivatives and preparation method and application thereof
  • Steroid sapogenin derivatives and preparation method and application thereof
  • Steroid sapogenin derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0060] Example 13 Synthesis of β-benzoyldiosgenin

[0061] 10.4g (25mmol) of diosgenin was dissolved in 200mL pyridine in an ice-water bath, placed in a 500mL three-neck flask, 5.8mL (50mmol) of benzoyl chloride was added dropwise under electromagnetic stirring, and the reaction was allowed to rise to room temperature naturally for 24 hours. The reaction solution was poured into 1000mL H2O, with CH 2 C 12 Extract, combine the organic phases, wash with water, dilute hydrochloric acid, saturated NaHCO3 solution successively, dry over anhydrous MgSO4, filter, and evaporate the filtrate under reduced pressure (60°C) to obtain a slightly yellow product. Recrystallized with anhydrous EtOH, dried, weighed 10.6g, yield 81.8%.

[0062] Derivative spectral data:

[0063] ESI-MS: 519[M+H]+

[0064] NMR: 1 HNMR (400MHZ, CDCl 3 )δ: 0.85 (3H, s, H-18), 1.02 (3H, s, H-19), 1.15 (3H, d, J=7.2HZ, H-21), 0.69 (3H, d, J=6.0 HZ, H-27), 5.03 (1H, m, H-3), 5.38 (1H, d, J=4.8HZ, H-6), 4.54 (1...

Embodiment 23

[0065] Example 23 Preparation of β-diosgenin succinate monoester (DI 103) and its salt

[0066] 1) Preparation of 3β-diosgenin succinate monoester:

[0067] Weigh 4.14g (10mmol) of diosgenin and 2g (20mmol) of succinic anhydride, place in a 250mL three-necked flask, dissolve in 50mL pyridine, and dissolve. Place in a water bath equipped with an electromagnetic stirring device, react at an oil bath temperature of 80 °C, check the progress of the reaction by TLC (PE:EtOAc=3:1 v:v), and stop the reaction when it is found that the reactants are basically no longer converted. The reaction solution was evaporated under reduced pressure at 80°C to remove a large amount of pyridine. The solution was reddish brown. Add an appropriate amount of acetone and place it in the refrigerator for half a day. Slightly brownish yellow crystals precipitated. PE:EtOAc 5:1 as the mobile phase) method for separation and purification to obtain 0.79g of the product with a yield of 15.4%.

[0068] Der...

Embodiment 33

[0073] Example 33 Preparation of β-diosgenin sulfonate and salts thereof

[0074] 1) Preparation of 3β-diosgenin sulfonate

[0075] Add 1.2g of diosgenin and 40mL of freshly steamed pyridine into a 250mL three-necked bottle equipped with electric stirring and condenser, heat in a water bath at 35°C, start stirring to dissolve completely, and drop 4mL of chlorosulfur into the bottle under stirring Acid, after 20 minutes of dripping, the reaction was violent, producing a large amount of white smoke, recovered with lye, after the addition, continued to stir, TLC (CH2Cl2:MeOH:H2O=10:2:1HCOOH 1d) to detect the reaction progress. The reaction is relatively complete in about 30 minutes. Place in the refrigerator overnight, white crystals precipitate out, filter, wash with ice water, dry and weigh 0.3g, the yield is 21%.

[0076] Derivative spectral data:

[0077] ESI-MS: 493[M+H]+

[0078] NMR: 1 HNMR (400MHZ, CDCl 3 )δ: 0.81 (3H, s, H-18), 0.94 (3H, s, H-19), 1.13 (3H, d, J=7....

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to steroid sapogenin derivatives and a pharmaceutical composition and application thereof in preparing antithrombotic medicaments. The derivatives provided by the invention have stronger activity than that of the existing steroid saponin medicaments, the quality is easy to control, the activity is equivalent to that of the existing anti-platelet aggregation medicaments, but the derivatives provided by the invention have no side effects on the gastrointestinal tract, thus being applicable to patients intolerantto the anti-platelet aggregation medicaments.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a steroidal saponin derivative with antithrombotic effect, its pharmaceutical composition and its medical application. technical background [0002] Platelet aggregation and thrombus formation are important causes of ischemic heart and brain injury. Platelet activation, adhesion and aggregation are one of the initiating factors of thrombosis in arteries, and play a role in the pathogenesis of atherosclerosis, coronary events (unstable angina, acute myocardial infarction, sudden cardiac ischemic death), stroke, etc. key role. Therefore, antiplatelet and anticoagulant therapy has become a hot spot in the treatment of reducing clinical ischemic events. Oral antiplatelet drugs are the most commonly prescribed long-term preventive therapy today. However, due to the relatively weak research pipeline of such drugs, there is still a lack of safe and effective drugs that ca...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61K31/58A61P7/02
Inventor 韩英梅付晓丽张士俊夏广萍赵娜夏
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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