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A kind of tetravalent platinum naphthalimide complex, its preparation method and application

A technology of platinum naphthalimide and complexes, applied in the field of tetravalent platinum naphthalimide complexes, which can solve the problems of lack of targeting, weak anti-tumor metastasis activity and immunosuppression

Active Publication Date: 2021-09-10
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Lack of targeting, drug resistance, weak anti-metastatic activity and immunosuppression are the main reasons for the failure of platinum-based drugs such as cisplatin and oxaliplatin in the treatment of cancer (including advanced cancer)

Method used

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  • A kind of tetravalent platinum naphthalimide complex, its preparation method and application
  • A kind of tetravalent platinum naphthalimide complex, its preparation method and application
  • A kind of tetravalent platinum naphthalimide complex, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: 6h (p=0)

[0080]

[0081] 1 H NMR (300MHz, Chloroform-d)δ8.45(s,1H),7.79(d,J=8.5Hz,1H),7.71(s,1H),7.41(s,2H),6.43(s,2H) ,3.21(d,J=6.7Hz,5H),2.44(s,2H),2.19(d,J=18.3Hz,2H),1.56(d,J=26.2Hz,3H),1.28(d,J= 19.4Hz,28H),0.85(s,3H). 13C NMR (75MHz, Chloroform-d) δ184.11,181.13,175.16,166.47–163.55(m),138.96,128.45,127.35,126.40,123.36–121.12(m),118.26,116.21,111.78,6472.932(d, , J=6.9Hz), 31.89, 29.26(d, J=12.6Hz), 26.88–21.83(m), 14.08, 8.76.

[0082] Its preparation method is as follows:

[0083] 1) The divalent platinum compound oxaliplatin Oxp. was oxidized with hydrogen peroxide for 4 hours at 60-70°C to prepare the tetravalent platinum compound Oxide-Oxp.; the tetravalent oxaliplatin compound Oxide-Oxp. (1equiv) and palmitic acid (4equiv) were dissolved in DMF, reacted at 70°C for one week under nitrogen protection, and then the oil pump was pumped dry. After adding dichloromethane to precipitate a solid, the compound Oxp(Ⅳ) was prepared by washing wit...

Embodiment 2

[0095] Example 2: 6g (p=0)

[0096]

[0097] 1 H NMR (300MHz, Chloroform-d) δ8.45 (d, J = 7.3Hz, 1H), 8.22 (dd, J = 15.6, 8.3Hz, 2H), 7.52 (t, J = 7.9Hz, 1H), 6.76 (d, J=8.3Hz, 1H), 4.13(t, J=7.0Hz, 2H), 3.74(s, 8H), 2.37(t, J=7.5Hz, 2H), 2.02–1.92(m, 2H) ,1.17(s,16H),0.79(t,J=6.5Hz,3H). 13 CNMR (75MHz, Methanol-d 4 )δ173.95,164.42,151.22,134.31,131.60,128.09,124.46,122.29,119.84,109.91,109.03,77.58,77.16,76.73,51.57,39.20,31.64,29.61,29.57,29.42,29.27,29.23,23.42,22.60,13.96 .

[0098] The difference between the preparation method of embodiment 2 and embodiment 1 is that In place of step 2) in Others are the same as embodiment 1.

[0099] in, The synthetic route of is:

[0100]

[0101] Reaction reagents and conditions in the formula: (a) Na 2 CrO 3 ,CH 3 COOH, 118℃, 12h; (b) HNO 3 ;Pd / c,H 2 (c)K 2 CO 3 ,CH 3 CN, 85°C, 5h.

Embodiment 3

[0102] Example 3: 6h (p=1)

[0103]

[0104] 1 H NMR (300MHz, Chloroform-d) δ8.06–7.93(m,1H),7.83(dd,J=6.3,2.8Hz,1H),7.76–7.71(m,1H),7.50–7.44(m,2H ),4.10(s,6H),3.25–3.09(m,4H),2.66(s,2H),2.47–2.16(m,4H),1.52(d,J=93.6Hz,6H),1.33(d, J=7.3Hz, 24H), 0.88(t, J=6.5Hz, 3H). 13 CNMR (75MHz, Chloroform-d) δ172.38–165.15(m), 154.93, 144.21, 138.17, 132.29, 131.63, 130.69, 120.79, 114.96, 50.80, 46.05, 43.80, 42.41, 35.82, 30.440, 33.3 ,29.69,26.57,17.94,12.59.

[0105] The difference between the preparation method of embodiment 3 and embodiment 1 is that In place of step 2) in Others are the same as embodiment 1.

[0106] in, The synthetic route of is:

[0107]

[0108] Reaction reagents and conditions in the formula: (a) Na 2 CrO 3 ,CH 3 COOH, 118℃, 12h; (b) HNO 3 ;Pd / c,H 2 (c)K 2 CO 3 ,CH 3 CN, 85°C, 5h.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a tetravalent platinum naphthalimide complex, its preparation method and application. The tetravalent platinum naphthalimide complex of the present invention has good antitumor activity, and its antitumor activity is better than that of cisplatin and oxaliplatin, and it is compatible with cisplatin, carboplatin, oxaliplatin, etc. The valence platinum is relatively stable. In the present invention, tetravalent platinum modified by naphthalimide has better targeting to tumor cells, and improves the high selectivity to tumor cells. Different from classic divalent platinum drugs, the complexes of the present invention pass Targeting the high polyamine microenvironment of the tumor to regulate subcellular organelles and nuclear functions reverses drug resistance, and at the same time relieves the immune suppression of T cells around the tumor. The complex of the present invention also solves the problems of poor solubility of divalent platinum-based antitumor drugs, cumbersome clinical compatibility, poor immunity of patients in clinical application of chemotherapeutic drugs, etc., and has good fat solubility and water solubility.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a tetravalent platinum naphthalimide complex, its preparation method and application. Background technique [0002] Lack of targeting, drug resistance, weak anti-metastatic activity and immunosuppression are the main reasons for the failure of platinum drugs such as cisplatin and oxaliplatin in the treatment of cancer (including advanced cancer). In recent years, tetravalent platinum-based antineoplastic drugs as prodrugs of divalent platinum-based drugs have become the focus of research and development of platinum-based drugs. The tetravalent platinum center platinum ion belongs to d 6 electron configuration, in d 2 sp 3 The hybridized orbitals are bonded to form a stable inner orbital complex, which not only retains the broad-spectrum and high-efficiency anti-tumor properties of divalent platinum-based drugs, but also has high stability, less accumula...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00A61P35/00
CPCA61P35/00C07F15/0093Y02P20/55
Inventor 马静王佳佳方东孙华谢松强李迎光李林容岳柯欣
Owner HENAN UNIVERSITY
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