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Pyrrolobenzodiazepine compound as well as preparation method and application thereof

A compound, diazepine technology, applied in the field of medicine, can solve problems such as limiting the scope of clinical applications

Active Publication Date: 2022-07-19
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HDACi can achieve good tumor suppression effect, but the big problem of broad-spectrum HDACi is that it generally has side effects such as nausea, vomiting and bone marrow suppression, which greatly limits its clinical application range

Method used

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  • Pyrrolobenzodiazepine compound as well as preparation method and application thereof
  • Pyrrolobenzodiazepine compound as well as preparation method and application thereof
  • Pyrrolobenzodiazepine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1(S)-10-(N-hydroxy-p-toluamide)-1,5,10,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-][1, 4] Diaza -3,11(2H)-dione (A1)

[0062] The o-nitrobenzyl bromide was dropped into DMF, and NaH was added in batches in an ice-water bath. After one hour of reaction, L-pyroglutamic acid methyl ester was added, and the reaction was continued for two hours at room temperature. post-processing. The solid powder was dissolved in acetic acid, and reduced iron powder was added, and the temperature was raised to reflux for 2 hours. The solution was then concentrated in vacuo and the resulting black viscous material was diluted with ethyl acetate and most of the insoluble material was removed by filtration. The filtrate was purified by flash chromatography on silica gel using ethyl acetate-petroleum ether (10:1 v / v) to give an off-white solid. Anhydrous DMF was added to the solid, sodium hydride was added in portions, and methyl p-bromomethylbenzoate was added after stirring for half ...

Embodiment 2

[0064] Example 2 (S)-10-(N-hydroxy-p-methylphenylacetamide)-1,5,10,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-][1, 4] Diaza -3,11(2H)-dione (A2)

[0065] The compound preparation method of embodiment 2 is the same as that of embodiment 1, except that methyl p-bromomethyl phenylacetate is used instead of methyl p-bromomethyl benzoate in the third step. A white solid powder was obtained with a yield of 25.9%. mp: 180.1-182.6°C.

[0066] 1 H NMR (600MHz, DMSO) δ 10.61(s, 1H), 8.79(s, 1H), 7.52(d, J=8.0Hz, 1H), 7.46–7.42(m, 1H), 7.39(d, J= 7.4Hz, 1H), 7.24 (t, J=7.3Hz, 1H), 7.16–7.10 (m, 4H), 5.36 (d, J=15.2Hz, 1H), 4.85 (d, J=15.1Hz, 1H) ,4.61(d,J=13.6Hz,1H),4.03(t,J=7.0Hz,1H),3.69(d,J=13.5Hz,1H),3.20(s,2H),2.49–2.42(m, 1H), 2.34–2.28 (m, 2H), 1.95–1.88 (m, 1H).

Embodiment 3

[0067] Example 3 (S)-10-(N-hydroxybutyramide)-1,5,10,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-][1,4]diazepine miscellaneous -3,11(2H)-dione (A3)

[0068] The compound preparation method of embodiment 3 is the same as that of embodiment 1, except that methyl 4-bromobutyrate is used instead of methyl p-bromomethylbenzoate in the third step. A white solid powder was obtained with a yield of 25.9%. mp: 180.1-182.6°C. The yield was 21.1%. mp: 178.3-179.6°C.

[0069] 1 H NMR(600MHz, DMSO)δ10.34(s,1H),8.66(s,1H),7.48(d,J=9.9Hz,3H),7.31(s,1H),4.70(d,J=13.7Hz ,1H),4.26–4.15(m,1H),3.93(d,J=11.4Hz,2H),3.66–3.56(m,1H),2.41(s,1H),2.29(d,J=7.4Hz, 2H), 1.91(d, J=6.8Hz, 2H), 1.87(d, J=7.3Hz, 1H), 1.18(t, J=6.8Hz, 2H).

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Abstract

The invention relates to the technical field of medicines, and relates to a pyrrolobenzodiazepine compound and a preparation method thereof, and application of the pyrrolobenzodiazepine compound in preparation of anti-fibrosis, anti-tumor metastasis and anti-tumor growth medicines. The compound and the pharmaceutically acceptable salt thereof are shown in a general formula I or II, and R1, R2, R3, R4, m, n and p are shown in the claims and the specification. The compound and the pharmaceutically acceptable salt thereof disclosed by the invention can be prepared into a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient. The compound, the pharmaceutically acceptable salt and the pharmaceutical composition of the compound and the pharmaceutically acceptable salt can be prepared into tablets, capsules, injection solutions or ampoules, suppositories, patches, inhalable powder preparations, suspensions, emulsions and ointments, and can be used for resisting fibrosis, tumor metastasis and tumor growth.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to pyrrolobenzodiazepines A compound and its preparation method, and its application in the preparation of anti-fibrosis, anti-tumor metastasis and anti-tumor growth drugs. Background technique [0002] 1. Histone deacetylase 6 inhibitors [0003] Histone deacetylases (HDACs) are enzymes that play an important role in epigenetic regulation, regulating the acetylation levels of various proteins such as histones, transcription factors, molecular chaperones, and signaling molecules. HDACs are often associated with condensation of chromatin and silencing of multiple transcribed genes. Therefore, HDAC inhibitors (HDACi) can be used to treat various diseases such as cancer, inflammation, neurodegenerative diseases and metabolic disorders. While general HDACi are non-selective or partially selective inhibitors, they usually cause many side effects, such as fatigue, dysgeusia, nausea, vo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P35/00
CPCC07D487/04A61P35/00Y02P20/55
Inventor 马恩龙马超邓勇张金王艳娟李艳春
Owner SHENYANG PHARMA UNIVERSITY