Aqueous triptolide alcohol derivative with high immunesuppressive activity and its application

A technology of triptolide and its derivatives, applied in the treatment of diseases related to immunosuppression, in the field of water-soluble triptolide derivatives, which can solve the problems of inability, low water solubility, poor oral effect, etc.

Inactive Publication Date: 2004-03-24
成都达远药物有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although the immunosuppressive activity of triptolide is quite high, its clinical application is limited due to the following disadvantages: 1. high toxicity, its LD 50 0.85mg / kg body weight, and reproductive toxicity
2. Low water solubility, unable to be used for intravenous (iv) injection
3. The cell membrane permeability is low (we have not published the experimental results), and the oral effect is not good
US Patent 6,150,539 gives some water-soluble triptolide derivatives, but does not give the immunosuppressive activity experimental data of these water-soluble triptolide derivatives

Method used

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  • Aqueous triptolide alcohol derivative with high immunesuppressive activity and its application
  • Aqueous triptolide alcohol derivative with high immunesuppressive activity and its application
  • Aqueous triptolide alcohol derivative with high immunesuppressive activity and its application

Examples

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Comparison scheme
Effect test

Embodiment 1

[0039] The present invention will be described in detail in the following 12 examples. Example 1: Preparation of 12-β-thiocyanate triptolide-13-α-14-β-sodium phosphate (hereinafter referred to as WDY1)

[0040]

[0041] Under nitrogen protection, add 251 mg of T-SCN (0.600 mmol) to the three-necked flask, then add 20 ml of pyridine, and add 0.28 ml of POCl 3 (3.000 mmol), finally added 40 mg of DMAP, sealed, reacted at room temperature for 24 hours, cooled with an ice bath for hydrolysis, and adjusted the pH to 8. Concentrate to dryness under reduced pressure, dissolve the sample with acetonitrile, and remove inorganic salts. TLC detection: n-butanol: water: glacial acetic acid (10:1:1) developed, the main point is the product point WDY1, containing a very small amount of T-SCN and other by-products. Acetonitrile was dissolved, 2g of 75-300 mesh silica gel was added to mix the samples, the acetonitrile was removed, and 75-300 mesh silica gel column chromatography was used...

Embodiment 2

[0043] 31 PNMR, δppm: 4.57. Example 2: Preparation of 12-β-thiocyanato-13-α-hydroxytriptolide-14-β-succinic acid monoester (hereinafter referred to as WDY6)

[0044]

[0045] At room temperature, 80 mg of 12-β-thiocyanato-13-α-14-β-hydroxy triptolide (T-SCN) (0.191 mmol), 8 ml of pyridine, 4 ml of DMF and 4 ml of DMF were added to a 50 ml three-necked flask. 24 mg of DMAP, finally added 3.2 g of succinic anhydride (3.820 mmol), sealed and stirred for a week, poured the reaction solution into ice water, extracted with dichloromethane several times, combined with dichloromethane, checked by TLC: chloroform: methanol (10 : 1), the main point is WDY6 and a very small amount of unreacted 12-β-thiocyanato-13-α-14-β-hydroxy triptolide. Concentrate under reduced pressure, evaporate the solvent to dryness, and use H silica gel, chloroform:methanol (14:1) column chromatography to obtain pure product. The yield was 90%. Rf: 0.30. The melting point is 127-129°C. Water solubility i...

Embodiment 3

[0049] 13 CNMR, δppm: 14.3(18-C), 15.7(17-C), 16.3(16-C), 16.8(2-C), 22.2(6-C), 28.8~28.9(-CH2CH2-), 29.4( 15-C), 30.1(1-C), 35.2(10-C), 39.5(5-C), 50.9(12-C), 57.7(11-C), 59.0(8-C), 62.1(7 -C), 67.1(9-C), 70.6(19-C), 74.2(14-C), 75.6(13-C), 114.0(SCN), 123.5(3-C), 162.2(4-C) , 170.8(-CO-), 173.38~173.43(-COOH, 20-C). Example 3: Preparation of the preparation method of triptolide-14-β-disodium phosphate (hereinafter referred to as WDY 7)

[0050]

[0051] Under nitrogen protection, 180mgT (0.500mmol), 10ml pyridine were added to the three-necked flask, and 0.14ml POCl was slowly added dropwise. 3 (1.50 mmol), the dropwise addition was completed, the reaction was sealed for 2 to 3 hours, cooled in an ice bath for hydrolysis, adjusted to pH=9 with sodium bicarbonate, concentrated to dryness under reduced pressure, dissolved in methanol to remove inorganic salts. TLC check: n-butanol: water: glacial acetic acid (4:1:1), the main point is WDY7, containing a very small amoun...

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Abstract

The present invention relates to the following water-soluble triptolide derivatives with immunosuppression activity. Said invention provides their structure formulas and their synthesis method, and their application for curing acive immunodeficiency disease and immunosuppression associated inflammation.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more particularly, the present invention relates to water-soluble triptolide derivatives with high immunosuppressive activity, a preparation method thereof and the use of these derivatives in the treatment of diseases related to immunosuppression . Background technique [0002] Immunosuppressive factors are widely used in the treatment of rheumatoid arthritis, asthma, systemic lupus erythematosus (SLE), psoriasis, multiple scleroderma, atherosclerosis, nephritis, type I diabetes and other autoimmune deficiency diseases and immune-related diseases inflammation. Immunosuppressive factors are also the most effective treatments for allogeneic rejection after organ transplantation. The most commonly used immunosuppressive factors are azathyopurine, corticosterroids, methotrexate, cyclophospamide, 6-mercaptopurine, vincristine ( vincristine), celebrox, cyclosporine A, FK506, etc. However,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P37/06C07D493/22
CPCC07D493/22A61P3/10A61P9/10A61P13/12A61P17/00A61P17/06A61P19/02A61P29/00A61P37/06A61P43/00
Inventor 王大元谭鸿孔焱
Owner 成都达远药物有限公司
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