Application of substituted 5,6-dihydroisoquinoline [3,2-alpha]isoquinoline-7-onium derivative

A technology of dihydroisoquinoline and isoquinoline, which can be applied to medical preparations containing active ingredients, drug combinations, organic active ingredients, etc. The effect of high selectivity and good application prospects

Inactive Publication Date: 2019-04-26
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The regulation of these enzymes may affect the dynamic balance of m6A modification in RNA, thereby causing the disturbance of some basic biological functions and even leading to diseases.

Method used

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  • Application of substituted 5,6-dihydroisoquinoline [3,2-alpha]isoquinoline-7-onium derivative
  • Application of substituted 5,6-dihydroisoquinoline [3,2-alpha]isoquinoline-7-onium derivative
  • Application of substituted 5,6-dihydroisoquinoline [3,2-alpha]isoquinoline-7-onium derivative

Examples

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Embodiment 1

[0039] This embodiment discloses biopharmaceutical acceptable compounds, salts, and crystal forms with substituted 5,6-dihydroisoquinolino[3,2-α]isoquinolin-7-onium derivatives as the main active ingredient , The use of solvates to prepare inhibitors, the inhibitors can be used directly or in the form of pharmaceutical compositions, and the inhibitory targets are METL3 and METL14.

[0040] The structure of the substituted 5,6-dihydroisoquinolino[3,2-α]isoquinolin-7-onium derivative is shown in formula I:

[0041]

[0042] Where R 1 As -H, -CF 3 , -NO 2 , -OCF 3 , Benzyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, halogen or substituted 5- to 12-membered unsaturated heterocyclic ring; when substituted 5- to 12-membered unsaturated heterocyclic ring, the unsaturated heterocyclic ring contains 1 to 4 heteroatoms, and the heteroatoms are N, O or S;

[0043] R 2 As -H, -CF 3 , -NO 2 , -OCF 3 , Benzyl, C 1 ~C 8 Alkoxy, C 3 ~C 8 Cycloalkyl, halogen or substituted 5- to 12-membered unsaturated h...

Embodiment 2

[0047] This example discloses several compounds based on the compound formula I in the above examples, and the structures are as follows:

[0048]

Embodiment 3

[0050] This embodiment discloses the differential fluorescence scanning test experiment of the seven compounds in the above embodiment, the purpose of which is to detect the stability of the compound to the three-dimensional structure of methyltransferase in vitro. In this experiment, the differential fluorescence scanning (Differential Scanning Fluorimetry) test method was used to test the stability of METL3 in vitro. The stability of the test compound can be expressed by Tm (protein denaturation temperature difference).

[0051] 1. Experimental materials

[0052] Human METTL3, SYPRO orange dye (Sigma, 5000X concentrate in DMSO, S5692), RT-PCR detection system (BIO-RAD CFX96), buffer (20mM Hepes, PH 7.4, and 100mM NaCl).

[0053] All 5,6-dihydroisoquinolino[3,2-α]isoquinoline-7-onium derivatives tested were purchased from Target Molecule (USA).

[0054] For in vitro experiments, it was prepared with 100% DMSO to prepare a 10mM storage solution, stored in a refrigerator at -20°C and ...

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Abstract

The invention belongs to the field of organic synthesis medicine, and specifically relates to application of preparing a biologically and pharmaceutically acceptable compound, salt, a crystal form anda solvate which take a substituted 5,6-dihydroisoquinoline [3,2-alpha]isoquinoline-7-onium derivative as a main active ingredient into an inhibitor. The inhibitor can be directly used or can be usedin a form of a drug composition. Inhibition target spots at which the inhibitor aims are METTL3 and METTL14. The inhibitor which specifically aims at the METTL3 and the METTL14 has high specificity. The invention also discloses a drug for treating or preventing cancer. The drug is the inhibitor or is prepared from a main ingredient-the inhibitor and other auxiliary ingredients of a pharmaceutically acceptable medicinal carrier and / or an excipient which have / has no toxicity and inert to people and animals. The drug has an obvious function of treating or preventing the cancer, new selection is provided for development of METTL3 and METTL14 inhibitors and development of an anti-tumor drug in the field, and a very good application prospect is obtained.

Description

Technical field [0001] The present invention relates to the technical field of organic synthetic drugs, and specifically refers to the use of substituted 5,6-dihydroisoquinolino[3,2-α]isoquinolin-7-onium derivatives. Background technique [0002] At present, more than 100 modifications have been identified in natural cell RNA, including mRNA, tRNA, rRNA, small nuclear RNA (snRNA) and small nuclear RNA (snoRNA). The most common methylated nucleoside in eukaryotic mRNA is N6-methyladenosine (m6A), which accounts for more than 80% of all RNA base methylation and exists in various species. Various studies have shown that this modification plays an important role in basic biological processes, such as RNA translation, cell differentiation, and cell cycle. m6A RNA modification is a dynamic and reversible process. The core methyltransferase complex formed by METL3 and METL14 catalyzes the installation of methyl groups and is cleared by two independent demethylases, FTO and ALKBH5. The...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61K31/473A61K31/4741A61P35/00A61P35/02
CPCA61K31/4375A61K31/473A61K31/4741A61P35/00A61P35/02
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV
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