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Application of triptolide amide derivatives in the preparation of drugs for the treatment of autoimmune diseases

A technology of tripterygium amide and immune diseases, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of toxicity, narrow safe treatment range, and limited clinical application, etc., achieves small toxic and side effects, significant curative effect, and relieves rheumatoid The effect of arthritis

Active Publication Date: 2022-08-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its toxicity and narrow safe therapeutic range limit its clinical application

Method used

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  • Application of triptolide amide derivatives in the preparation of drugs for the treatment of autoimmune diseases
  • Application of triptolide amide derivatives in the preparation of drugs for the treatment of autoimmune diseases
  • Application of triptolide amide derivatives in the preparation of drugs for the treatment of autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] Triptolide 22mg (0.048mmol) was dissolved in 1mL of anhydrous DMF, followed by adding PyBop (50mg, 0.096mmol), N,N-diisopropylethylamine (20μL, 0.12mmol), methylamine hydrochloride ( 0.05 mmol), and reacted at room temperature for 24 hours. Add 15 ml of deionized water, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter and spin dry to obtain the crude product. Column chromatography (dichloromethane / methanol) gave a red solid (compound I) in 61% yield.

[0026] 1 H NMR (600MHz, CDCl 3 )δ H 7.00(1H,d,J=8.0Hz,H-6),6.99(1H,s),6.51(1H,s,H-1),6.32(1H,d,J=8.0Hz,H-7), 5.80(1H,s,NH), 2.66(3H,s,NHCH3), 2.19(3H,s,H-23), 1.42(3H,s,H-25), 1.24(3H,s,H-26) ,1.14(3H,s,H-30),1.11(3H,s,H-28),0.60(3H,s,H-27); 13 C NMR (100MHz, CDCl 3 )δ C 178.5(C-2), 178.3(C-29), 170.4(C-8), 164.8(C-10), 146.0(C-3), 134.1(C-6), 127.4(C-5), 119.5 (C-1), 118.0(C-7), 117.1(C-4), 45.1(C-14), 44.4(C-18), 43.0(C-9), 40.3(C-20)...

Embodiment 2

[0028]

[0029] Triptolide 22mg (0.048mmol) was dissolved in 1mL of anhydrous DMF, followed by adding PyBop (50mg, 0.096mmol), N,N-diisopropylethylamine (20μL, 0.12mmol), ethylamine hydrochloride ( 0.05 mmol), and reacted at room temperature for 24 hours. Add 15 ml of deionized water, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter and spin dry to obtain the crude product. Column chromatography (dichloromethane / methanol) gave a red solid (compound II) in 54% yield.

[0030] 1 H NMR (400MHz, CDCl 3 )δ H 7.02(1H,d,J=8.0Hz,H-6),7.01(1H,s),6.53(1H,s),6.34(1H,d,J=8.0Hz,H-7),5.69(1H, s,NH), 3.16(2H,m,H-1'), 2.21(3H,s,H-23), 1.43(3H,s,H-25), 1.26(3H,s,H-26), 1.15(3H,s,H-30), 1.12(3H,s,H-28), 0.65(3H,s,H-27); 13 C NMR (100MHz, CDCl 3 )δ C178.1(C-2), 177.5(C-29), 170.5(C-8), 164.8(C-10), 145.9(C-3), 134.2(C-6), 127.2(C-5), 119.3 (C-1), 117.9(C-7), 117.0(C-4), 44.9(C-14), 44.2(C-18), 42.9(C-9), 40.0(C-20), 39....

Embodiment 3

[0032] In vitro cell activity studies of triptolide amide derivatives

[0033] experiment material

[0034] CCK-8 cell viability assay kit was purchased from Dojindo Laboratories. Fetal bovine serum and RPMI 1640 medium were purchased from Invitrogen. Methotrexate was purchased from Shanghai Oriental Pharmaceutical Technology Experiment Co., Ltd. Red blood cell lysate was purchased from Jiangsu Kaiji Biotechnology Co., Ltd. Concanavalin A (ConA) was purchased from Sigma. Male BALB / c mice (6-8 weeks old, 18-25 g) were purchased from the Model Animal Center of Nanjing University.

[0035] experiment method

[0036] The Balbc mice were sacrificed by dissecting their cervical vertebrae, immersed in 75% alcohol for 3 minutes, and the spleen was isolated. The spleen was ground and passed through a 200-mesh sterile filter. After removal of cell debris and clumps, single cell suspensions were prepared. Red blood cells are lysed in red blood cell lysis buffer. Then, the cell p...

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Abstract

The invention discloses the use of triptolide amide derivatives represented by formula III or pharmaceutically acceptable salts thereof in preparing medicines for treating autoimmune diseases, wherein R is selected from C1-C6 alkyl groups; Autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. The invention also discloses a medicine for treating autoimmune diseases, comprising an effective therapeutic dose of triptolide amide derivative or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The triptolide amide derivative has high efficiency and low toxicity, can be used as a new type of immunosuppressant with high efficiency and low toxicity, and has the prospect of treating autoimmune diseases, especially rheumatoid arthritis.

Description

technical field [0001] The invention belongs to the fields of medicinal chemistry and drug therapy, and relates to the application of a triptolide amide derivative in preparing a medicine for treating autoimmune diseases, Background technique [0002] Autoimmune diseases (AD) refer to diseases caused by the body's immune response to self-antigens, resulting in damage to its own tissues. The third leading cause of illness and death after heart disease and cancer. Common ADs include rheumatoid arthritis (Rheumatoid arithritis), systemic lupus erythematosus (Systemic lupuserythematosus), and multiple sclerosis (Multiple sclerosis). At present, immunosuppressive agents (immunosuppressive agents) are the main drugs for the clinical treatment of AD. Most of the representative immunosuppressive drugs are developed from microbial secondary metabolites, such as cyclosporine A, rapamycin, tacrolimus, etc. Although the above-mentioned immunosuppressants have satisfactory therapeutic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/56A61P37/02A61P19/02
CPCA61K31/56A61P37/02A61P19/02
Inventor 汪豪胡晓龙冯家豪何其伟
Owner CHINA PHARM UNIV