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Camptothecin sulfonyl amidine compound and preparation method and application thereof

A base sulfonamide compound technology, applied in the field of camptothecin sulfonamide compounds and their preparation and application, can solve the problems of non-direct parenteral administration to human body, bone marrow suppression, vomiting and diarrhea, severe side effects, etc. problem, to achieve the effect of excellent application prospect, novel structure and strong inhibitory effect

Active Publication Date: 2016-03-23
成都安满生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Camptothecin was first extracted from China's endemic Davidiaceae plant Camptothecin by Wall in 1966 ( Camptotheca acuminata ) isolated from a quinoline alkaloid with significant cytotoxic activity ( J. Nat. Prod. 2004, 67, 129-135 ), showed a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but in clinical use, it was found that camptothecin would produce myelosuppression, vomiting and diarrhea when exerting its anti-tumor activity and other serious side effects, and because of the special basicity of the nitrogen on the quinoline ring in the molecular structure, the water solubility is poor, and it cannot be directly administered parenterally to the human body
In order to further improve its water solubility and reduce its toxic and side effects, the water-soluble sodium salt of camptothecin was tested in the early 1970s. Although some anti-cancer activity and greatly improved water solubility of this type of drug were observed, further clinical trials were interrupted due to serious and unpredictable toxic and side effects.

Method used

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  • Camptothecin sulfonyl amidine compound and preparation method and application thereof
  • Camptothecin sulfonyl amidine compound and preparation method and application thereof
  • Camptothecin sulfonyl amidine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: the synthesis of target compound Ia

[0019]

[0020] Synthesis of raw material 7-benzylpiperazine-camptothecin: Take 2.5 grams of camptothecin in a round bottom flask, add 60 mL of 75% sulfuric acid solution to stir and dissolve, then add 3.125 grams of sulfuric acid heptahydrate under ice bath conditions Ferrous, stirred for 5min, still under the condition of ice bath, dropwise added 40mL of 40% chloroacetaldehyde solution with the constant pressure funnel, stirred for 5min after the dropwise addition, still under the condition of ice bath, added 12.5mL with the constant pressure funnel, hydrogen peroxide. The ice bath was removed after half an hour of reaction. After reacting for 10 hours at room temperature, put the reaction in an ice bath, then add an appropriate amount of ice water, a large amount of yellow solids precipitated, filter with suction, rinse the filter cake with ice water several times, and then rinse the filter cake with a solution ...

Embodiment 2

[0027] Embodiment 2: the synthesis of target compound Ib

[0028]

[0029] Same as Example 1, only ethylsulfonyl azide is used instead of methylsulfonyl azide. The detection data of the product obtained from the reaction are as follows: yield: 67%; melting point: 233-238 o C; 1 HNMR (DMSO -d 6 ,400MHz) δ :8.40(d,1H, J =8Hz,C9-H),8.15(d,1H, J =8Hz,C12-H),7.84(t,1H, J =8Hz,C10-H),7.70(t,1H,J =8Hz,C11-H),7.36-7.31(m,3H,Ar-H,C14-H),7.28-7.24(m,3H,Ar-H),6.54(s,1H,C20-OH),5.43 (s,2H,C17-H),5.31(s,2H,C5-H),4.39(s,2H,- CH 2 -Ar),4.05(s,2H,- CH 2 -piperazine), 3.67 (s, 2H, piperazine-H), 3.31 (s, 2H, piperazine-H), 3.00-2.92 (m, 2H, -SO 2 - CH 2 -),2.54(s,2H,piperazine-H),2.28(s,2H,piperazine-H),1.92-1.80(m,2H,C19-H),1.26-1.14(m,3H,-SO 2 -CH 2 - CH 3 ),0.88(t,3H, J =8Hz,C18-H); MS-ESIm / z:678.3[M+Na] + ..

Embodiment 3

[0030] Embodiment 3: the synthesis of target compound Ic

[0031]

[0032] Same as Example 1, only phenylsulfonyl azide is used instead of methylsulfonyl azide. The detection data of the product obtained from the reaction are as follows: productive rate: 65%; melting point: 209-212 o C; 1 HNMR (DMSO -d 6 ,400MHz) δ :8.39(d,1H, J =8Hz,C9-H),8.15(d,1H, J =8Hz,C12-H),7.86-7.79(m,3H,C10-H,Ar-H),7.69(t,1H, J =8Hz,C11-H),7.57-7.47(m,3H,Ar-H),7.33-7.21(m,6H,C14-H,Ar-H),6.53(s,1H,C20-OH),5.43 (s,2H,C17-H),5.30(s,2H,C5-H),4.44(s,2H,- CH 2 -Ar),4.04(s,2H,- CH 2 -piperazine), 3.67(s,2H,piperazine-H),3.29(s,2H,piperazine-H),2.54(s,2H,piperazine-H),2.29(s,2H,piperazine-H),1.90- 1.81(m,2H,C19-H),0.87(t,3H, J =8Hz,C18-H); MS-ESIm / z:726.3[M+Na] + ..

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Abstract

The invention discloses a camptothecin sulfonyl amidine compound and a preparation method and application thereof. The camptothecin sulfonyl amidine compound is shown in the formula 1, wherein in the formula, R1 is any one of methyl, ethyl, p-chlorophenyl, p-nitrophenyl, p-methylphenyl, p-fluorophenyl, phenyl, thienyl, pyridyl and naphthyl; R2 is any one of hydrogen, fluorine and methoxy. The preparation method of the camptothecin sulfonyl amidine compound includes the steps that 7-benzylpiperazine-camptothecin trifluoroacetate is dissolved into methylene dichloride, a catalyst (triethylamine) is added for stirring to clarify a solvent, then a sulfonyl azide and alkyne are sequentially added, finally, copper iodide is added for a catalytic reaction, after completion, methylene dichloride is used for a quenching reaction, then the solvent is removed, and a crude product of the target product is obtained. The camptothecin sulfonyl amidine compound can be applied to preparation of medicine for treating all kinds of cancers.

Description

technical field [0001] The present invention relates to a preparation method of a medicinal compound and the use of the prepared medicine. Specifically, the present invention is a new camptothecin compound, a preparation method of this compound and its use in the preparation of antitumor drugs. Background technique [0002] Camptothecin was first extracted from China's endemic Davidiaceae plant Camptothecin by Wall in 1966 ( Camptotheca acuminata ) isolated from a quinoline alkaloid with significant cytotoxic activity ( J. Nat. Prod. 2004, 67, 129-135 ), showed a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but in clinical use, it was found that camptothecin would produce myelosuppression, vomiting and diarrhea when exerting its anti-tumor activity And other serious side effects, and because of the special alkalinity of the nitrogen on the quinoline ring in the molecular structure and poor water solubili...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/496A61P35/00
CPCC07D491/22
Inventor 刘映前宋子龙朱高翔吴小兵王美娟
Owner 成都安满生物医药科技有限公司
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