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Derivative of RVX-208 based on BRD4 inhibitor as well as preparation method and application of derivative

An RVX-208, inhibitor technology, applied in the field of pharmaceutical and chemical industry, can solve the problems of complex pharmacokinetics of drug interactions, and achieve the effect of improving drug safety, mild conditions and high yield

Active Publication Date: 2018-09-04
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, drug-drug interactions and complex pharmacokinetic issues may occur in combination

Method used

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  • Derivative of RVX-208 based on BRD4 inhibitor as well as preparation method and application of derivative
  • Derivative of RVX-208 based on BRD4 inhibitor as well as preparation method and application of derivative
  • Derivative of RVX-208 based on BRD4 inhibitor as well as preparation method and application of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Synthesis of Example 1 Lead Compound RVX-208

[0082] The synthetic route of BRD4 inhibitor RVX-208 provided by the present invention is as follows:

[0083]

[0084] (1) Preparation of intermediate 2 (i.e. compound 2): 3,5-dimethoxybenzoic acid

[0085]

[0086]Add 3,5-dihydroxybenzoic acid (1.54g, 10mmol) into a 100mL single-necked flask, add 20mL of acetone to dissolve it, add potassium carbonate (4.14g, 30mmol) at room temperature, and simultaneously add 3.5mL of dimethyl sulfate dropwise, Heated to 55°C and the reaction was refluxed overnight. After the reaction is complete, concentrate under reduced pressure to recover acetone, add 30mL of water, and then add 30% sodium hydroxide solution to adjust the pH to 14, react at 75°C for 4 hours, and cool the system to room temperature after hydrolysis is complete. The pH was adjusted to about 6 with concentrated hydrochloric acid, and a large amount of white solid precipitated out. After filtering, washing with w...

Embodiment 2R

[0130] The synthesis of embodiment 2RB-X

[0131]

[0132] The synthesis method of the target compound RB-X is similar to that of RVX-208, the difference is that compound 9A is replaced by 9B, the corresponding compound is 10B, and 10B reacts with compound 11 to obtain RB-X. specific,

[0133] (1) Preparation of compound 8

[0134] The synthesis of compound 8 refers to Example 1.

[0135] (2) Preparation of compound 10B

[0136] Preparation of Intermediate 10B: 2-(4-Hydroxy-3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

[0137]

[0138] Compound 8 (1.96g, 10mmol) was added to a 100mL single-necked flask, and 30mL N,N-dimethylformamide was added to dissolve it, while compound 9B, namely 3,5-dimethoxy-4-hydroxybenzaldehyde (2.00 g, 11mmol), sodium bisulfite (0.95g, 5mmol) and p-toluenesulfonic acid monohydrate (1.25g, 12 mmol), after stirring evenly, the system was heated to 120°C and refluxed for 16 hours. After the reaction, add 20 mL of water to the reacti...

Embodiment 3

[0147] The synthesis of embodiment 3 compound RA-G

[0148] The synthetic route of RA-G provided by the present invention is as follows:

[0149]

[0150] Preparation of target compound RA-G: (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl 2-bromo- 2-Methylpropionate

[0151]

[0152] Add compound 13, 2-bromoisobutyric acid (2.00g, 12mmol) into a 100mL single-necked bottle, add 20mL N, N-dimethylformamide to dissolve it, and add EDCI (3.83 g, 20mmol), DMAP (1.22g, 10mmol), after 0.5 hours, compound 10A (3.26g, 10mmol) was added and reacted at room temperature for 16 hours. After the reaction, add 30 mL of water to the system, extract three times with ethyl acetate (3*20 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain the mixture, which is separated and purified by column chromatography (elution The solution was dichloromethane / methanol, the volume ratio was 20:1), and a white ...

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Abstract

The invention discloses a derivative of RVX-208 based on a BRD4 inhibitor as well as a preparation method and application of the derivative. The structure of the derivative is shown in formula I. Thepreparation method comprises the following steps: ensuring that a compound shown in formula 8 and a compound shown in formula 9 react, so as to obtain a compound shown in formula 10; ensuring that thecompound shown in formula 10 reacts with malonic acid, succinic acid or glutaric acid, and then reacts with ethylene carbonate, 2-halogenated isobutyric acid or 4-halogenated phenoxy isobutyric acid;or ensuring that the compound shown in formula 10 directly reacts with ethylene carbonate, 2-halogenated isobutyric acid or 4-halogenated phenoxy isobutyric acid. The invention further provides the application of the derivative. The derivative can improve the activity for reducing cholesterol or reduce the level of cholesterol and triglyceride at the same time.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a derivative based on BRD4 inhibitor RVX-208 and its preparation method and application. Background technique [0002] Abnormal levels of acetylation, which in turn lead to transcriptional abnormalities, are an important feature of many human diseases. The acetylation level of histone lysine is mainly controlled by histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain proteins (BRDs). [0003] BRD is a kind of protein domain that can specifically recognize histone acetylated lysine (Acetylated lysine, KAc). The 61 BRDs found in the human body exist in 46 proteins, which are divided into 8 families according to their functions, among which bromodomain and extraterminal domain (BET) belong to the second BRD family classes, including BRD2, BRD3, BRD4, and BRDT. The BRD4 protein has two tandem bromodomains, BD1 and BD2. BET protei...

Claims

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Application Information

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IPC IPC(8): C07D239/91A61K31/517A61P9/00A61P9/10A61P9/12A61P3/06
CPCA61P3/06A61P9/00A61P9/10A61P9/12C07D239/91
Inventor 蔡进刘文景吉民王莹颖宁瑶麦地努尔·吐尔逊许红芹
Owner SOUTHEAST UNIV
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