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Camptothecin derivatives with antitumor activity

A technology of camptothecin and analogs, applied in the field of camptothecin derivatives, can solve the problems of poor tumor effect, affecting tissue/plasma distribution ratio, etc.

Inactive Publication Date: 2016-08-03
苏州汉德景曦新药研发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, the product accumulates in the body and does not work well against tumors
In contrast, the high lipophilicity of the lactone form facilitates the adsorption of camptothecin derivatives to cell membranes, especially erythrocytes, affecting the tissue / plasma distribution ratio

Method used

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  • Camptothecin derivatives with antitumor activity
  • Camptothecin derivatives with antitumor activity
  • Camptothecin derivatives with antitumor activity

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Experimental program
Comparison scheme
Effect test

Embodiment 17

[0077] The preparation of embodiment 17-ethyl-10-boronic acid camptothecin (HD-302)

[0078] 1a, Synthesis of 7-ethyl-10-trifluoromethylsulfonyloxycamptothecin

[0079] Suspend SN-38 (0.1g, 0.255mmol) in anhydrous N,N-dimethylformamide (2.5ml) under nitrogen protection, and add triethylamine (52mg, 0.51mmol) to the resulting suspension . Under stirring, N-phenylbis(trifluoromethanesulfonyl)imide (137mg, 0.383mmol) was added thereto, and reacted at room temperature for 16 hours (TLC controlled the complete reaction of the main material). After the reaction was complete, dichloromethane (5ml) and water (2×10ml) were added, stirred and washed, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain an off-white solid (134mg, 0.255mmol).

[0080] 1b, Synthesis of 7-ethyl-10-trifluoromethylsulfonyloxy-16-O-triethylsilylcamptothecin

[0081] Under nitrogen protection, 7-ethyl-10-trifluoromethylsulfonyloxycamptothecin (0.1...

Embodiment 2

[0088] 2a, Synthesis of 7-tert-butoxyiminomethyl-10-hydroxycamptothecin

[0089] Add 10-hydroxy-7-formylcamptothecin (50mg) into ethanol (10ml) and pyridine (1.5ml), then add O-tert-butylhydroxylamine hydrochloride (55mg) under stirring, reflux for 5h, reduce Concentrate under reduced pressure, and purify through column (dichloromethane: methanol) to obtain 30 mg of yellow solid.

[0090] 1 HNMR (400MHz, CD 3 OD):δ0.88(t,H3-18E+H3-18Z,J=7.35Hz),1.35(s,t-BuZ),1.45(s,t-BuE),1.80-1.90(m,H2-19E +H2-19Z),5.10-5.40(m,H2-5E+H2-5Z+H2-17E+H2-17Z),6.53(s,OH),7.25-7.50(m,H-14E+H-14Z+ H-11E+H-11Z+H-9Z),7.70(d,.H-9E,J=2.57Hz)8.05(d,H-12E+H-12Z,J=9.19Hz),8.25(s,CH =NZ), 9.0 (s, CH=NE) 10.35 (s, 10-OH).

[0091] 2b, Synthesis of 7-tert-butoxyiminomethyl-10-trifluoromethylsulfonyloxycamptothecin

[0092] Suspend 7-tert-butoxyiminomethyl-10-hydroxycamptothecin (140mg) in anhydrous N,N-dimethylformamide (2.5ml) under nitrogen protection to obtain a suspension Add triethylamine (52 mg, 0....

Embodiment 3

[0100] 3a, Synthesis of 7-(2'-trimethylsilyl)ethyl-10-hydroxycamptothecin

[0101] Add ferric sulfate heptahydrate (2g) and 30% sulfuric acid (12.5ml) into a 100ml three-necked flask, stir at room temperature for 20min, add trimethylsilyl propanol (4.8g), glycol (50ml) dropwise into the reaction flask and stir 15min. Add this reaction solution dropwise into a reaction bottle containing SN-38 (2.5g), 30% sulfuric acid (137.5ml), and 30% hydrogen peroxide (0.81ml) (about 30min), stir at room temperature for 1h, and then add hydrogen peroxide dropwise (2.43ml), stirred overnight.

[0102] Wash the reaction solution with n-hexane (3×25ml), discard the n-hexane layer, extract the reaction solution with dichloromethane (3×125ml), combine the organic phases, concentrate under reduced pressure at low temperature (below 40°C) to obtain the crude product, add N, N -Dimethylformamide (80ml), heated to 120°C, dissolved and clarified, crystallized at 25°C, filtered with suction, and drie...

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Abstract

The invention discloses a camptothecin derivative with antineoplastic activity. The camptothecin derivative with antineoplastic activity is a compound with a structure represented by formula (I) or formula (II), or an enantiomer or a pharmaceutical salt thereof. The camptothecin derivative possesses beneficial pharmaceutical properties, inhibition effects on topoisomerase I and / or II, and antineoplastic activity. It is confirmed by experiments that the camptothecin derivative possesses antiviral activity, so that the camptothecin derivative can be used for different treatment applications; and the compound with the structure represented by formula (I) or formula (II), and the enantiomer or the pharmaceutical salt thereof are used for preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a camptothecin derivative with antitumor activity, its use as an antitumor medicine and a pharmaceutical composition containing them. Background technique [0002] Camptothecin (Campaotothecin, CPT, J.Am.Chem.Soc., 1966,88:3888) is a pentacyclic alkaloid extracted from Camptotheca acuminata. It is a kind of pyrrole [3,4-b] quinoline alkaloid, its structural formula is: Its structure contains five rings, and there is an S-type chiral center at the 20th position of the E ring, and a lactone structure next to it. Camptothecin has broad-spectrum antineoplastic activity, especially against colon tumors and other solid tumors and leukemias, but has not been used due to its high toxicity, especially in hemorrhagic cystitis, gastrointestinal toxicity, and myelosuppression. In treatment. [0003] So far, a series of semi-synthetic and fully synthetic camptothecin derivatives have ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02C07F7/10A61K31/69A61K31/695A61P35/00
Inventor 李晨曦沈伟生周辉徐立慧
Owner 苏州汉德景曦新药研发有限公司