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Camptothecin 7-piperazinyl thiocarbamide compounds, and preparation method and application thereof

A technology of camptothecin and compound, applied in the field of medicine, can solve the problems of poor water solubility and cannot be directly administered to the human body parenterally, and achieves the effects of strong inhibitory effect, novel structure and good application prospect.

Inactive Publication Date: 2016-12-07
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Camptothecin is derived from the plant Camptotheca involucrata in my country ( Camptotheca acuminata ), a quinoline alkaloid with significant cytotoxic activity ( J. Nat. Prod. 2004, 67, 129-135 ), showing a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but camptothecin will produce more serious side effects such as bone marrow suppression, vomiting and diarrhea when exerting its anti-tumor activity, And because of its poor water solubility, it cannot be directly administered parenterally to human body

Method used

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  • Camptothecin 7-piperazinyl thiocarbamide compounds, and preparation method and application thereof
  • Camptothecin 7-piperazinyl thiocarbamide compounds, and preparation method and application thereof
  • Camptothecin 7-piperazinyl thiocarbamide compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: Synthesis of target compound Ia (see formula 3 for structural formula)

[0020]

[0021] 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, of 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 rin...

Embodiment 2

[0029] Embodiment 2: Synthesis of target compound Ib (see formula 6 for structural formula)

[0030]

[0031] Same as Example 1, only p-methylphenyl isothiocyanate is replaced with m-chlorophenyl isothiocyanate. The detection data of the product obtained from the reaction are as follows: yield: 66%; 1 H NMR (DMSO - d 6 , 400 MHz) δ : 9.43 (s, 1H, NH-H), 8.50(d, 1H, J =8Hz, C9-H), 8.19 (d, 1H, J =8Hz, C12-H), 7.87 (t, 1H, J =8Hz, C10-H), 7.74 (t, 1H, J =8Hz, C11-H), 7.35-7.25 (m, 4H, C14-H, Ar-H), 7.15-7.13(m, 1H, Ar-H), 6.55 (s, 1H, C20-OH), 5.45 (s, 2H, C17-H), 5.40 (s, 2H, C5-H), 4.18 (s, 2H, - CH 2 - piperazine), 3.89 (s, 4H, piperazine-H), 2.62 (s, 4H,piperazine-H), 1.92-1.84 (m, 2H, C19-H), 0.89 (t, 3H, J =8Hz, C18-H); MS-ESIm / z: 638.2 [M+Na] + ..

Embodiment 3

[0032] Example 3: Synthesis of target compound Ic (see formula 7 for structural formula)

[0033]

[0034] Same as Example 1, only replace p-methylphenyl isothiocyanate with cyclohexyl isothiocyanate. The detection data of the product obtained from the reaction are as follows: yield: 66%; 1 H NMR (DMSO - d 6 , 400 MHz) δ : 8.47 (d, 1H, J =8Hz, C9-H), 8.18 (d, 1H, J =8Hz, C12-H), 7.86 (t, 1H, J =8Hz, C10-H), 7.73 (t, 1H, J =8Hz, C11-H), 7.34 (s, 1H, C14-H), 6.55 (s, 1H, C20-OH), 5.44 (s, 2H, C17-H), 5.37 (s, 2H, C5-H ), 4.16 (s, 2H, - CH 2 - piperazine), 3.86 (s, 4H, piperazine-H), 2.59 (s, 4H, piperazine-H), 2.33-2.31 (m, 1H, cyclohexylamine-H), 1.93-1.84 (m, 2H, C19-H ), 1.70 (s, 2H, cyclohexylamine-H), 1.61-1.58 (m, 2H, cyclohexylamine-H), 1.26-1.07 (m, 6H, cyclohexylamine-H), 0.88 (t, 3H, J =8Hz, C18-H); MS-ESI m / z: 610.4 [M+Na] + ..

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Abstract

The invention relates to novel camptothecin 7-piperazinyl thiocarbamide compounds disclosed as Formula (I), a preparation method of the compounds, and application of the compounds in preparing antineoplastic drugs. The chemical general formula of the compounds is disclosed as Figure (I). The preparation method of the compounds disclosed as Formula (I) comprises the following step: carrying out reaction on 7-benzylpiperazinyl-camptothecin and alkyl / aryl isorhodanate. The cytotoxic activity test proves that the compounds have favorable antineoplastic activity, and part of the compounds have higher activity than the clinical drug irinotecan; and the compounds can be used for preparing antineoplastic drugs. The preparation method has the advantages of simple preparation technique, cheap and accessible raw materials and high product purity.

Description

technical field [0001] The invention relates to a novel camptothecin 7-piperazine thiourea compound, a preparation method of the compound and its use in the preparation of antitumor drugs, belonging to the field of medicine. Background technique [0002] Camptothecin is derived from the plant Camptotheca involucrata in my country ( Camptotheca acuminata ), a quinoline alkaloid with significant cytotoxic activity ( J. Nat. Prod. 2004, 67, 129-135 ), showing a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but camptothecin will produce more serious side effects such as bone marrow suppression, vomiting and diarrhea when exerting its anti-tumor activity, And because of its poor water solubility, it cannot be directly administered parenterally to human body. In order to improve its water solubility and reduce its toxic and side effects, a large number of camptothecin compounds have been designed, synthesized ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/496A61P35/00
CPCC07D491/22
Inventor 刘映前杨程杰王美娟陈海乐成丕乐徐小山
Owner LANZHOU UNIVERSITY
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