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Camptothecin derivatives and preparation method and application thereof

A kind of use and drug technology, applied in the field of medicine, can solve the problems of low selectivity, blocking replication and transcription, and large toxic and side effects

Active Publication Date: 2022-07-15
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The mechanism of action of the early camptothecin compounds is to form a ternary complex with TopI and DNA to block the replication and transcription of DNA, which has the disadvantages of low selectivity and large toxic side effects.

Method used

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  • Camptothecin derivatives and preparation method and application thereof
  • Camptothecin derivatives and preparation method and application thereof
  • Camptothecin derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 120

[0074] Example 1 Preparation of 20(S)-7-phenylbutadienyl-10,11-methylenedioxycamptothecin (compound 1)

[0075] Step (1) (2E,4E)-1-(5-Aminobenzo[d][1,3]dioxo-6-yl)-5-phenylpent-2,4-diene-1- Preparation of ketone (D1)

[0076] At room temperature, concentrated nitric acid (20.7ml) was slowly added dropwise to a solution of 3,4-methylenedioxyacetophenone (8.1g, 49.3mmol) in nitromethane (80ml), and the reaction was stirred for 2h. Slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to neutral and extract three times with dichloromethane, combine the organic phases, wash three times with saturated brine, dry over anhydrous magnesium sulfate and concentrate to obtain a yellow oily liquid, which is subjected to silica gel column chromatography (petroleum ether:ethyl acetate=8:1) for separation and concentration to obtain 7.8 g of light yellow solid 6-nitro-3,4-methylenedioxyacetophenone, yield 76%; mp 110-112°C.

[0077] 6-Nitro-3,4-methylenedioxyacetophenone...

Embodiment 2

[0084] Example 2 Preparation of 20(S)-7-(4-fluorostyryl)-10,11-methylenedioxycamptothecin (compound 3)

[0085] Substitute 4-fluorobenzaldehyde for the cinnamaldehyde in step (1) of Example 1, and the other required raw materials, reagents, and preparation methods are the same as steps (1) and (2) of Example 1, to prepare 20(S)-7 -(4-Fluorostyryl)-10,11-methylenedioxycamptothecin yellow solid compound 3. mp>250℃; MS(ESI): m / z, 513.5[M+H] + .

[0086] 1 H NMR (500MHz, CF 3 COOD)δ8.23(s,1H),8.00(s,1H),7.95(dd,J=7.8,5.4Hz,1H),7.87(d,J=16.5Hz,1H),7.85–7.78(m, 1H), 7.73(s, 1H), 7.30(dd, J=22.8, 14.3Hz, 2H), 7.10(dd, J=36.5, 25.0Hz, 1H), 6.52(s, 2H), 6.03(t, J = 11.9Hz, 1H), 6.01–5.83 (m, 2H), 5.69 (d, J=17.0Hz, 1H), 2.24 (dd, J=17.8, 11.0Hz, 2H), 1.33–1.16 (m, 3H) .

[0087] 13 C NMR (125MHz, CF 3 COOD) δ176.2, 157.4, 152.1, 151.8, 148.9, 145.0, 140.1, 139.8, 138.8, 130.6, 130.0, 130.0, 126.1, 126.0, 121.0, 117.3, 116.1, 116.0, 105.0, 103.4, 10 52.5, 31.0, 11.7, 5.8.

Embodiment 3

[0088] Example 3 Preparation of 20(S)-7-(3-fluorostyryl)-10,11-methylenedioxycamptothecin (compound 4)

[0089] Substitute 3-fluorobenzaldehyde for the cinnamaldehyde in step (1) of Example 1, and the rest of the required raw materials, reagents, and preparation methods are the same as steps (1) and (2) of Example 1, to prepare 20(S)-7 -(4-Fluorostyryl)-10,11-methylenedioxycamptothecin yellow solid compound 4. mp>250℃; MS(ESI): m / z, 513.5[M+H] + .

[0090] 1 H NMR (500MHz, CF 3 COOD)δ8.23(s,1H),8.00(s,1H),7.95(dd,J=7.8,5.4Hz,1H),7.87(d,J=16.5Hz,1H),7.85–7.78(m, 1H), 7.73(s, 1H), 7.30(dd, J=22.8, 14.3Hz, 2H), 7.14(dd, J=36.5, 25.0Hz, 1H), 6.56(s, 2H), 6.03(t, J = 11.9Hz, 1H), 6.21–5.84 (m, 2H), 5.69 (d, J=17.0Hz, 1H), 2.24 (dd, J=17.8, 11.0Hz, 2H), 1.33–1.16 (m, 3H) .

[0091] 13 C NMR (126MHz, CF 3 COOD) δ176.2, 157.4, 152.1, 151.8, 148.9, 145.0, 140.1, 139.8, 138.8, 130.6, 130.4, 130.0, 126.8, 126.0, 121.0, 117.5, 116.1, 116.0, 105.0, 16.1, 3.9, 10 52.5, 31.0, 11.7,...

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Abstract

The present invention relates to a compound having the structure shown in formula (I), its stereoisomer and pharmaceutically acceptable salt form, and also relates to a preparation method of said compound, and a medicament comprising said compound in a therapeutically effective dose Compositions, and their use in the manufacture of the prevention and / or treatment of cancer. The compound provided by the present invention is a kind of camptothecin derivatives with novel structure in which methylenedioxy groups are introduced at the 10 and 11 positions of the parent ring, and different substituent groups are introduced at the 7-position. It is simple, the purification method is simple and quick, and the compound of the present invention has excellent in vitro cytotoxic activity and excellent in vivo antitumor effect, so this kind of compound has wide medicinal prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new class of camptothecin derivatives and a preparation method and application thereof. Background technique [0002] Camptothecin derivatives are known as one of the three major discoveries of anticancer drugs in the 1990s, showing broad-spectrum antitumor activity and great research and application value. The mechanism of action of the early camptothecin compounds is to form a ternary complex with TopI and DNA, blocking the replication and transcription of DNA, and has the disadvantages of low selectivity and large toxic and side effects. With the development of science and technology, molecular-targeted anti-tumor drugs have become a research hotspot in recent years. Such drugs can selectively act on signal transduction pathways related to tumor cell differentiation and proliferation. The present invention uses camptothecin. As a lead compound, it is structural...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCC07D491/22A61P35/00A61K31/4745A61K31/5377A61K31/541
Inventor 江涛吴贯召何雄
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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