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Novel anti-tumor Pt(IV) complex capable of being orally taken, and preparation method and application thereof

An anti-tumor and complex technology, applied in the field of the preparation of new anti-tumor Pt complexes, can solve the problems of complex synthesis process of JM216, difficult combination chemotherapy, high treatment cost, avoid drug resistance, and the synthesis process is simple and easy to operate. , the effect of simple and easy operation

Active Publication Date: 2019-08-30
KUNMING GUIYAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although JM216 has entered clinical trials in 1992 and has been in the market for several decades, it has been unable to be marketed for a long time. There are three main problems: (1) Most of the current cancer chemotherapy uses combination drugs, which are combined with platinum drugs Most antineoplastic drugs have the best curative effect in the form of intravenous injection, so it is difficult to find a combined chemotherapy regimen for oral administration; (2) In terms of curative effect, compared with cisplatin and carboplatin, JM216 has the advantage of oral activity Not prominent; (3) The synthesis process of JM216 is complicated, and there are problems such as the large dose required for oral administration, resulting in high treatment costs

Method used

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  • Novel anti-tumor Pt(IV) complex capable of being orally taken, and preparation method and application thereof
  • Novel anti-tumor Pt(IV) complex capable of being orally taken, and preparation method and application thereof
  • Novel anti-tumor Pt(IV) complex capable of being orally taken, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Embodiment 1: Preparation of compound (C-1) shown in formula II, namely:

[0067]

[0068] Dissolve 1.5g (1.1mol) of the Pt(II) compound prepared in step 3 in 20mL of acetic acid, weigh 0.524g (1.1mol) of N-chlorosuccinimide and add it to the reaction system, and stir evenly at room temperature overnight . After the reaction was completed, 66 was evaporated and concentrated under reduced pressure to remove the solvent, and dried to obtain 0.45 g of a Pt(IV) complex with a lipophilic group in the axial direction. Yield: 24.051%. Its hydrogen spectrum is as figure 1 As shown, its mass spectrum is shown as figure 2 shown.

[0069] IR(ν,cm-1):v(NH)br 3188,3073cm-1,vs(CH),vas(CH):2931,2855cm-1, δ(NH):1448cm-1,v(C-O): 1698,1615cm-1, v(C-C):1177cm-1, v(Pt-O):897cm-1, v(Pt-Cl):694cm-1, v(Pt-N):638cm-1.

[0070] 1H NMR(600MHz,DMSO):δ3.12-3.57(s,3H,CH3),2.65-2.87(s,1H,CH), 1.46-2.22(m,6H,CH2),0.97-1.38(m,4H ,CH2).

[0071] HR-MS (m / z): [C8H19Cl3N2O2Pt+H]+=476.0233 (10...

Embodiment 2

[0072] Embodiment 2: Preparation of compound (C-2) shown in formula III, namely:

[0073]

[0074] Dissolve 1 g (1.1 mol) of the Pt(II) compound prepared in Step 5 in 20 ml of acetic acid, weigh 0.34 g (1.1 mol) of N-chlorosuccinimide and add it to the reaction system, and stir evenly at room temperature overnight. After the reaction was completed, the solvent was evaporated and concentrated under reduced pressure, and freeze-dried to obtain 0.33 g of a Pt(IV) complex having a lipophilic group in the axial direction. Yield: 26.70%. Its hydrogen spectrum is as image 3 As shown, its mass spectrum is shown as Figure 4 shown.

[0075] IR(ν,cm-1):v(NH)br 3197,3076cm-1,vs(CH),vas(CH):2935,2857cm-1, δ(NH):1451cm-1,v(C-O): 1674,1613cm-1, v(C-C):1298cm-1, v(Pt-O):916cm-1, v(Pt-Cl):697cm-1, v(Pt-N):535cm-1.

[0076] 1H NMR(600MHz,DMSO):δ6.38-6.52(m,3H,NH3),2.69-2.79(s,1H,CH),2.00-2.10(m,2H,NH2),1.93-1.97(s,3H ,CH3),1.51-1.72(m,4H,CH2), 1.05-1.44(m,6H,CH2).

[0077] HR-MS (m / ...

Embodiment 3

[0078] Embodiment 3: Preparation of compound (C-3) shown in formula IV, namely:

[0079]

[0080] Dissolve 0.96g (1.1mol) of the Pt(II) compound prepared in step 4 in 20mL of acetic acid, weigh 0.28g (1.1mol) of N-chlorosuccinimide and add it to the reaction system, and stir evenly at room temperature overnight . After the reaction was completed, the solvent was evaporated and concentrated under reduced pressure, and freeze-dried to obtain 0.35 g of a Pt(IV) complex having a lipophilic group in the axial direction. Yield: 30.17%. Its hydrogen spectrum is as Figure 5 As shown, its mass spectrum is shown as Image 6 shown.

[0081]IR(ν,cm-1):v(NH)br 3164,3078cm-1,vs(CH),vas(CH):2939,2858cm-1, δ(NH):1454cm-1,v(C-O): 1680,1655cm-1, v(C-C):1208cm-1, v(Pt-O):901cm-1, v(Pt-Cl):697cm-1, v(Pt-N):573cm-1.

[0082] 1H NMR(600MHz,DMSO):δ6.08-6.39(m,4H),2.64-2.70(s,1H,CH), 2.44-2.46(m,3H,NH3),1.99-2.07(m,2H), 1.89-1.91(s,3H,CH3),1.75-1.82(m,2H,CH2),1.48-1.70(m,4H,CH2),1.19-1.33(...

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Abstract

The invention discloses a novel anti-tumor Pt(IV) complex capable of being orally taken. The complex has a structure as shown in a formula I. The invention discloses a preparation method of the novelanti-tumor Pt(IV) complex capable of being orally taken. An asymmetric amine ligand with amino and cyclohexylamine is an important component for overcoming the drug resistance of classic platinum drugs, a lipophilic group is reserved at one end in the axial direction for oral taking, and a chloride is introduced to the other end, so that the negative value of the redox potential of the platinum complex is reduced and reduction power is increased. Leaving group potassium oxalate of oxaliplatin and carboplatin, and 1,1-cyclobutanedicarboxylic acid are taken as leaving ligands of the complex provided by the invention, water solubility of a novel Pt(IV) compound is added, and the lipid-water partition coefficient of the Pt(IV) complex is adjusted, so that a drug can enter tumor cells more easily through transmembrane. The complex has certain anti-tumor activity, and auxiliary toxicity is reduced. Meanwhile, the preparation method is simple, the conditions are mild, operation is easy, and the method is suitable for large-scale production. In the formula, R is selected from a group consisting of Cl or the following two compounds.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method and application of a new oral anti-tumor Pt (IV) complex. Background technique [0002] Cancer is one of the health diseases that seriously threaten human beings, and about 7 million people die of cancer every year in the world. In recent years, due to people's bad living habits and environmental pollution, the morbidity and mortality of cancer have risen sharply, which has become an urgent problem for human beings to overcome. In order to reduce the incidence of cancer and reduce the mortality of cancer patients, it is imperative to continuously develop a treatment plan suitable for cancer treatment. Chemotherapy is currently one of the three major means of treating cancer that is relatively safe and less harmful to the human body. Among the many chemotherapeutic drugs in clinical use, platinum-based drugs are widely used in cancer treatment ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61P35/00A61K31/555A61K31/28
CPCC07F15/0093A61P35/00
Inventor 普绍平高传柱蔡林祥丛艳伟彭娟王应飞刘其星张林涛陈红娟
Owner KUNMING GUIYAN PHARMA
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