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Epipodophyllotoxin derivatives, preparation method and application in the preparation of antitumor drugs

A technology for epipodophyllotoxin and anti-tumor drug, applied in the field of medicine, can solve the problems of toxic and side reactions, narrow anti-tumor spectrum, etc., and achieves simple and controllable preparation method and post-processing, good tumor inhibitory activity, and good market. The effect of developing prospects

Active Publication Date: 2022-04-05
江苏百奥信康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As Topo II inhibitors, VP-16 and VM-26 still have deficiencies such as narrow anti-tumor spectrum, myelosuppression, and gastrointestinal toxicity. Research on the first generation of podophyllotoxin compounds, obtaining new compounds with a wider anti-tumor spectrum and less toxic side effects is the direction of research and development of new anti-tumor drugs

Method used

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  • Epipodophyllotoxin derivatives, preparation method and application in the preparation of antitumor drugs
  • Epipodophyllotoxin derivatives, preparation method and application in the preparation of antitumor drugs
  • Epipodophyllotoxin derivatives, preparation method and application in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Preparation of 4β-4-(2"-thiopheneacrylamide)-4-deoxy-4'-desmethyl epipodophyllotoxin (I-1)

[0070]

[0071] 3-(2-thienyl)acrylic acid (1.15 mmol) was fed and post-treated according to the proportion of method 2 to prepare compound I-1, 181 mg of white solid, with a yield of 29.42%.

[0072] ESI-MS m / z:536,[M+H] + ;558,[M+Na] +

[0073] 1 H-NMR (400MHz, CDCl 3 )δppm: 7.66-7.62 (m, Ar-H, 2H), 7.56 (d, J = 15.6Hz, Hb, 1H), 7.15-7.13 (m, Ar-H, 1H), 6.84 (d, J = 15.6 Hz,1H),6.80(s,Ar-H,DMEP-H,1H),6.55(s,Ar-H,DMEP-H,1H),6.03-6.05(s,H-2',6',2H ),5.98((d,J=6.0Hz,OCH 2 O, 2H), 5.72(d, J=7.6Hz, NH, heavy water not exchanged, 1H), 5.41-5.44(s, m, H4+OH, OH heavy water exchanged, 2H), 4.62(d, J=4.8Hz ,1H),4.45-4.49(m,DMEP-H,H11a,1H),3.85-3.90(m,DMEP-H,H11b,1H),3.80(s,OCH 3 ,6H),3.40-3.44(m,DMEP-H,H3,1H),2.88-2.93(m,DMEP-H,H2,1H).

Embodiment 2

[0075] Preparation of 4β-4-((4”-bromo)-2”-thiopheneacrylamide)-4-deoxy-4′-desmethyl epipodophyllotoxin (I-2)

[0076]

[0077] 3-(4-bromo-2-thienyl)acrylic acid (1.15mmol) and 4β-amino-4'-desmethyl epipodophyllotoxin II (1.15mmol) were fed and post-treated according to method 2 to prepare compound I -2, white solid 275 mg, yield 39.01%.

[0078] ESI-MS m / z:614,[M+H] + ;636,[M+Na] +

[0079] 1 H-NMR (400MHz, CDCl 3 )δppm: 7.50-7.58 (m, Ar-H, 2H), 7.55 (d, J = 15.6Hz, Hb, 1H), 6.84 (d, J = 15.6Hz, 1H), 6.81 (s, Ar-H, DMEP-H,1H),6.54(s,Ar-H,DMEP-H,1H),6.02-6.04(s,H-2',6',2H),5.97((d,J=6.0Hz,OCH 2 O, 2H), 5.74(d, J=7.6Hz, NH, heavy water not exchanged, 1H), 5.41-5.44(s, m, H4+OH, OH heavy water exchanged, 2H), 4.62(d, J=4.8Hz ,1H),4.34-4.39(m,DMEP-H,H11a,1H),3.75-3.80(m,DMEP-H,H11b,1H),3.73(s,OCH 3 ,6H),3.40-3.45(m,DMEP-H,H3,1H),2.93-2.98(m,DMEP-H,H2,1H).

Embodiment 3

[0081] Preparation of 4β-4-((3”-methyl)-2”-thiopheneacrylamide)-4-deoxy-4′-desmethyl epipodophyllotoxin (I-3)

[0082]

[0083] 3-(3-methyl-2-thienyl)acrylic acid (1.15mmol) and 4β-amino-4'-desmethyl epipodophyllotoxin II (1.15mmol) were fed and post-treated according to method 2 to prepare the compound I-3, white solid 255 mg, yield 40.39%.

[0084] ESI-MS m / z:550,[M+H] + ;574,[M+Na] +

[0085] 1 H-NMR (400MHz, CDCl 3 )δppm: 7.66 (d, Ar-H, 1H), 7.55 (d, J = 15.6Hz, Hb, 1H), 7.11 (m, Ar-H, 1H), 6.84 (d, J = 15.6Hz, 1H) ,6.81(s,Ar-H,DMEP-H,1H),6.57(s,Ar-H,DMEP-H,1H),6.28(s,H-2',6',2H),5.99((d ,J=6.0Hz,OCH 2 O, 2H), 5.72(d, J=7.6Hz, NH, heavy water not exchanged, 1H), 5.38-5.42(s, m, H4+OH, OH heavy water exchanged, 2H), 4.57(d, J=5.2Hz ,1H),4.35-4.39(m,DMEP-H,H11a,1H),3.75-3.80(m,DMEP-H,H11b,1H),3.65(s,OCH 3 ,6H),3.38-3.44(m,DMEP-H,H3,1H),2.96-3.05(m,DMEP-H,H2,1H),2.26(s,CH3,3H).

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Abstract

The invention discloses an epipodophyllotoxin derivative, which has a structure shown in general formula I: wherein, R is a substituted or unsubstituted C4-C15 aryl group, a substituted or unsubstituted C2-C15 heteroaryl group, a substituted or Unsubstituted C6-C15 fused aryl, substituted or unsubstituted C4-C-15 condensed heteroaryl. Experiments of the present invention prove that the epipodophyllotoxin derivative disclosed by the present invention has good tumor suppressing activity, can be used as an antitumor drug, and is effective for diseases such as leukemia, liver cancer, and lung cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an epipodophyllotoxin derivative, a preparation method and an application in preparation of antitumor drugs. Background technique [0002] Podophyllotoxin is a natural anti-tumor active ingredient isolated from American podophyllum and Himalayan podophyllum, but its clinical application is limited due to severe side effects. Podophyllotoxin drugs such as etoposide (VP-16) and teniposide (VM-26) have been successfully marketed after structural modification. Etoposide (VP-16), as the first semi-synthetic podophyllotoxin derivative on the market, is mainly used for the treatment of small cell lung cancer, and also for acute leukemia, malignant lymphoma, bladder cancer, prostate cancer, gastric cancer, ovarian cancer, etc. efficient. [0003] A series of podophyllotoxins with new chemical structure modifications discovered in recent years not only have obvious effects ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/381A61K31/365A61K31/4178A61K31/443A61K31/405A61P35/00A61P35/02
CPCC07D493/04A61P35/00A61P35/02
Inventor 肖旭华李淼
Owner 江苏百奥信康医药科技有限公司
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