Camptothecin 20-site modified sulfonylurea compound as well as preparation method and application thereof

A technology for alkali sulfonylureas and compounds is applied in the field of preparing anti-tumor drugs, which can solve problems such as decreased anti-tumor activity, and achieve the effects of strong inhibitory effect, high product purity and simple synthesis process.

Inactive Publication Date: 2020-09-22
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to its camptothecin-anti-tumor structure-activity relationship research (SAR research), the stability of the camptothecin lactone ring in the body is an important factor affecting the anti-tumor activity, and the α-hydroxylactone ring is easily hydrolyzed and opened to generate Water-soluble sodium salt, resulting in reduced antitumor activity

Method used

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  • Camptothecin 20-site modified sulfonylurea compound as well as preparation method and application thereof
  • Camptothecin 20-site modified sulfonylurea compound as well as preparation method and application thereof
  • Camptothecin 20-site modified sulfonylurea compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Embodiment 1: the synthesis of target compound 1

[0015]

[0016] The synthesis of compound 1 is carried out according to the following chemical reaction formula 2:

[0017]

[0018] Synthesis of intermediate 1a: Dissolve N-Boc-glycine (6mmol) in dry dichloromethane, add camptothecin (3mmol), N,N'-diisopropylcarbodiethylene Amine (DIPC) (9 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (6 mmol). After reacting at 0°C for about 0.5h, remove the ice bath and react overnight at room temperature. TCL detection, after the reaction is completed, filter, the reaction mixture is washed with 6% sodium bicarbonate solution, water, and saturated sodium chloride solution in turn, then dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through the column to obtain the yield Intermediate Compound 1a.

[0019] Synthesis of intermediate 2a: Dissolve the synthesized intermediate 1a (3 mmol) in 10 mL of dry dichloromethane, then slowly ...

Embodiment 2

[0021] Embodiment 2: the synthesis of target compound 2

[0022]

[0023] The experimental procedure is the same as in Example 1, except that ethyl methanesulfonylcarbamate is replaced by n-butylsulfonylcarbamate. The detection data of the product are as follows: Yield: 38%; Melting point: 197-198°C; 1 HNMR (DMSO-d 6 ,400MHz)δ:10.54(s,1H,SO 2 NH),8.70(s,1H,C7-H),8.15(m,2H,C12-H,C9-H),7.88(t,1H,J=6.8Hz,C10-H),7.73(t,1H ,J=7.2Hz,C11-H),7.22(s,1H,C14-H),6.92(br,1H,L-glycine- NH ),5.51(s,2H,C17-H),5.31(s,2H,C5-H),4.16(dd,1H,J=4.8,17.6Hz,C23-H),4.01(dd,1H,J= 5.2,18.0Hz,C23-H),3.17(m,2H,- CH 2 CH 2 CH 2 CH 3 ),2.09-2.15(m,2H,C18-H),1.52-1.55(m,2H,-CH 2 CH 2 CH 2 CH 3 ),1.15-1.2(m,2H,-CH 2 CH 2 CH 2 CH 3 ),0.93(t,3H,J=7.6Hz,-CH 2 CH 2 CH 2 CH 3 ),0.68(t,3H,J=7.2Hz,C19-H);Anal.Calcd For C 27 h 28 N 4 o8 S: C, 57.03; H, 4.96; N, 9.85. Found: C, 56.97; H, 5.02; N, 9.74. MS-ESI m / z: 591.1 [M+Na] + .

Embodiment 3

[0024] Embodiment 3: the synthesis of target compound 3

[0025]

[0026] The experimental procedure is the same as in Example 1, only ethyl benzenesulfonylcarbamate is used instead of ethyl methylsulfonylcarbamate. The detection data of the product are as follows: Yield: 40%; Melting point: 173-174°C; 1 H NMR (DMSO-d 6 ,400MHz)δ:11.08(s,1H,SO 2 NH ),8.71(s,1H,C7-H),8.00-8.17(m,2H,C9-H,C12-H),7.45-7.90(m,7H,C10-H,C11-H,Ph-H) ,7.16(s,1H,C14-H),6.96(br,1H,L-glycine- NH ),5.48(s,2H,C17-H),5.31(s,2H,C5-H),4.01(m,2H,C23-H),1.98(m,2H,C18-H),0.75(m, 3H,C19-H); Anal. Calcd ForC 29 h 24 N 4 o 8 S: C, 59.18; H, 4.11; N, 9.52. Found: C, 59.12; H, 4.02; N, 9.44. MS-ESI m / z: 611.5 [M+Na] + .

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Abstract

The invention relates to a camptothecin 20-site modified sulfonylurea compound shown as a formula (I), a preparation method of the compound, and application of the compound in preparation of antitumordrugs. The chemical general formula of the compound is shown as a structural formula (I). The preparation method of the compound in the formula (I) is characterized in that different 20-amino acid-camptothecin trifluoroacetate reacts with different substituted sulfonyl ethyl carbamate to obtain the compound. Cytotoxic activity test proves that the compounds have good cytotoxic activity, the antitumor activity of most of the compounds is higher than that of a clinical control drug irinotecan, the antitumor activity of part of the compounds is equivalent to that of a clinical control drug topotecan, and the compounds can be used for preparing antitumor drugs. The preparation method is simple, raw materials are cheap and easy to obtain, and product purity is high.

Description

technical field [0001] The present invention relates to a novel camptothecin 20-modified sulfonylurea compound, a preparation method of the compound and its use in the preparation of antitumor drugs. It belongs to the field of medicine. Background technique [0002] Camptothecin (CPT for short) is a quinoline alkaloid with significant cytotoxic activity extracted from Camptotheca involucrata in my country in 1966 by American chemists Wall M.E and Wani M.C. . Am. Chem. Soc. 1966, 88, 3888-3890). It shows a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but when camptothecin is used in clinical practice, due to serious side effects, such as vomiting, bone marrow suppression and diarrhea, etc. (Current Medicinal Chemistry- Anticancer Agents, 2005,5(1):1-13.), while the water solubility of unmodified natural camptothecin is extremely poor, so the water-soluble sodium salt of camptothecin was used in early clini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61P35/00
CPCC07D491/22A61P35/00
Inventor 刘映前高建梅杨程杰李虎宋子龙雷蒙·科布拉·劳威
Owner LANZHOU UNIVERSITY
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