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3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof

A technology of peroxyandrosteroids and derivatives, which is applied in the application field of cancer and immune disease drugs, can solve the problems of drug resistance, toxic side effects, and restrictions on chemotherapeutic drugs, and achieve mild reaction conditions, proliferation inhibition, and simple steps Effect

Inactive Publication Date: 2018-10-26
QIQIHAR MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a variety of antineoplastic drugs have been used clinically, these drugs have limited curative effect, drug resistance problems, and due to the lack of selectivity for tumor cells and normal cells, there are varying degrees of toxic and side effects. Use of Chemotherapeutic Drugs

Method used

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  • 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof
  • 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof
  • 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of 3β-hydroxy-5α,8α-peroxyandrost-6-ene-17-(isatin)hydrazone

[0038] (a) Preparation of 3β-acetoxy-5-androsten-17-one

[0039]

[0040] The raw material dehydroepiandrosterone (28.8g, 0.1mol) was dissolved in a single-necked round bottom flask containing 100mL of dichloromethane and 20mL of pyridine, and 40mL of acetic anhydride was added dropwise with a constant pressure dropping funnel, and the dropping time was controlled at 20 minutes After dropping, the system was stirred and reacted for 4-6 hours, and the reaction process was detected by TLC. After the raw materials disappeared, the reaction was stopped. After adding 30mL of water and stirring, it was extracted with 40mL×3 ethyl acetate, and the organic phases were combined and washed with saturated sodium bicarbonate and Washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and precipitated under reduced pressure to obtain 32 g of a white solid product with a yield of 98%....

Embodiment 2

[0067] Preparation of 3β-hydroxy-5α,8α-peroxyandrost-6-ene-17-(5-fluoro-isatin)hydrazone

[0068] Steps (a), (b), (c), (d), (e), (f) are the same as in Example 1.

[0069] (g) Preparation of 3β-hydroxy-5α,8α-peroxyandrost-6-ene-17-(5-fluoro-isatin)hydrazone

[0070]

[0071]3β-Hydroxy-5α,8α-peroxyandrost-6-ene-17-hydrazine (100mg, 0.30mmol) and 5-fluoro-isatin (54.5mg, 0.33mmol) obtained in step (f) were dissolved in Put 20mL of absolute ethanol in a 50mL single-necked flask, heat the above system to 50°C and react for 2-4 hours, wait until there is no raw material, and then end the reaction. Precipitation under reduced pressure and purification on a silica gel column gave 113.53 mg of a yellow solid product with a yield of 79%.

[0072] 1 H NMR (400MHz, CDCl 3 , δppm) 10.93(bs, 1H), 7.85(q, J=8Hz, 1H), 6.87-6.82(m, 1H), 6.70(q, J=8Hz, 1H), 6.55(d, J=8.4Hz, 1H), 6.33(d, J=8.4Hz, 1H), 4.62(d, J=8Hz, 1H), 2.48-1.95(m, 10H), 1.85-1.15(m, 10H), 1.01(s, 3H) , 0.99(s, 3H); ...

Embodiment 3

[0074] Preparation of 3β-hydroxy-5α, 8α-peroxyandrost-6-ene-17-(5-chloro-isatin)hydrazone

[0075] Steps (a), (b), (c), (d), (e), (f) are the same as in Example 1.

[0076] (g) Preparation of 3β-hydroxy-5α,8α-peroxyandrost-6-ene-17-(5-chloro-isatin)hydrazone

[0077]

[0078] 3β-Hydroxy-5α,8α-peroxyandrost-6-ene-17-hydrazine (100 mg, 0.30 mmol) and 5-chloro-isatin (59.7 mg, 0.33 mmol) obtained in step (f) were dissolved in Put 20mL of absolute ethanol in a 50mL single-necked flask, heat the above system to 50°C and react for 2-4 hours, wait until there is no raw material, and then end the reaction. Precipitation under reduced pressure and purification on a silica gel column yielded 120.3 mg of a yellow solid product with a yield of 81%.

[0079] 1 H NMR (CDCl 3 , 400MHz, δppm) 10.65(bs, 1H), 7.84(q, J=8Hz, 1H), 6.89-6.83(m, 1H), 6.72(q, J=8Hz, 1H), 6.55(d, J=8.4 Hz, 1H), 6.35(d, J=8.4Hz, 1H), 4.63(d, J=8Hz, 1H), 2.49-1.97(m, 10H), 1.84-1.15(m, 10H), 1.01(s, 3H), 0.99(...

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Abstract

The invention discloses a 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative, as well as preparation and application thereof, belonging to the technical field of medicinal chemistry. The structural formula of the 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative is as shown in the description, wherein R1 represents -H, -F, -Cl, -Br, -I, -NO2, -OCH3, -OCF3 or -CH3; R2 represents -H, -Cl or -Br. The preparation comprises the following steps: preparing 3beta-acetoxyl-5-androstene-17-ketone by using dehydroepiandrosterone as a raw material; performing bromination reaction and debromination reaction to obtain 3beta-acetoxyl-5,7-diene androstane-17-ketone intermediate, and hydrolyzing to reduce hydroxyl; constructing a 5alpha, 8alpha-peroxide bridge by illuminating; reacting with hydrazine hydrate to prepare 3beta-hydroxyl-5alpha, 8alpha-peroxy-androstane-6-alkene-17-hydrazine intermediate; and finally performing a condensation reaction to generate the 3beta-hydroxyl-5alpha,8alpha-peroxy-androstane-6-alkene-17-(isatin substituted) hydrazone derivative. The compound has an effect of preventing and treating cancers such as liver cancer, breast cancer and the like.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to peroxysterol derivatives, preparation and application, in particular to 3β-hydroxyl-5α, 8α-peroxyandrost-6-ene-17-(isatin-substituted) hydrazone derivatives and their The preparation method and the application as medicines for preventing and treating liver cancer, breast cancer and other cancers and immune diseases. Background technique [0002] Cancer is a malignant disease that seriously threatens human survival, and its morbidity and mortality continue to rise. In 2012, 14 million people worldwide were diagnosed with cancer. The World Health Organization predicts that by 2025, the annual number of new cancer cases worldwide will increase to 19 million, to 22 million by 2030, and to 24 million by 2035. million, that is to say, it will increase by nearly 50% in 20 years. 4.2 million people worldwide die of cancer every year. As the global population grows and ages, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61P35/00
CPCA61P35/00C07J71/0005
Inventor 卜明王海君王静林宇李宏铃马玉坤
Owner QIQIHAR MEDICAL UNIVERSITY
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