- Method for preparing apabetalone, intermediates and preparation method of intermediates
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The invention provides a preparation method of apabetalone. The preparation method comprises the step of reacting a first intermediate, namely 2-bromo-4,6-dimethoxybenzoic acid with a second intermediate, namely 4-(2-hydroxyethoxy)-3,5-dimethylbenzamidine hydrochloride in an alkali-containing organic solvent under the action of a catalyst so as to obtain apabetalone. According to the invention, total yield is 33.4% or above, raw materials are easy to obtain, process is simple, reaction conditions are mild, post-treatment method is simple, the yield of each step and the total yield are high, and cost can be reduced. Apabetalone is a medicine for treating cardiovascular diseases such as atherosclerosis and the like, and has good application prospects. The invention also provides the intermediate 4-(2-hydroxyethoxy)-3,5-dimethylbenzamidine hydrochloride for synthesizing apabetalone and a preparation method thereof, and a preparation method of the compound 2-bromo-4,6-dimethoxybenzoic acid.
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Paragraph 0085-0092
(2020/05/30)
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- Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation
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Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 ? has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.
- Liu, Zhiqing,Chen, Haiying,Wang, Pingyuan,Li, Yi,Wold, Eric A.,Leonard, Paul G.,Joseph, Sarah,Brasier, Allan R.,Tian, Bing,Tian, Bing,Zhou, Jia,Zhou, Jia,Zhou, Jia
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p. 5242 - 5256
(2020/07/10)
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- Design, synthesis and biological evaluation of hypolipidemic compounds based on BRD4 inhibitor RVX-208
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Bromodomain-containing protein 4 (BRD4) is a new therapeutic target for the treatment of diseases including cardiovascular diseases, cancer, inflammation and central nervous system (CNS) disorders. In this study, we introduced the pharmacophore of fibrates to a BRD4 inhibitor, RVX-208, to design dual-active hypolipidemic compounds, and found that some of new analogues showed favorable hypolipidemic activities. Synthetic accessibility towards this class of compounds optimized RVX-208 as well as would supply more thoughts on hypolipidemic drugs.
- Yu, Ping,Liu, Wenjing,Ren, Jinghui,Wang, Yingying,Ning, Yao,Huang, Mingqi,Hu,Wei, Lili,Ji, Min,Cai, Jin
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p. 2168 - 2172
(2019/07/03)
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- Synthesis technology of cardiovascular medicine Apabetalone
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The invention discloses a synthesis technology of a cardiovascular medicine Apabetalone, and relates to the technical field of organic synthesis of medicines. The synthesis technology comprises the following steps: with 3,5-dimethoxyaniline as a raw material, firstly performing a condensation reaction on the 3,5-dimethoxyaniline, hydroxylamine sulfate and chloral hydrate to obtain N-(2,4-dimethoxyphenyl)-2-(oximido)acetamide, then performing a cyclization reaction to obtain 5,6-dimethoxy isatin under the effect of concentrated sulfuric acid, then performing an oxidation reaction on the 5,6-dimethoxy isatin and ammonia water or ammonia gas to obtain 2-amino-4,6-dimethoxybenzonitrile in the presence of divalent copper and an oxidant, finally performing a condensation reaction on the 2-amino-4,6-dimethoxybenzonitrile and 4-(2-hydroxyethoxy)-3,5-dimethylbenzaldehyde in an organic solvent under the effect of an alkaline substance to obtain the Apabetalone. Compared with the synthesis technology recorded in the existing literature, the synthesis technology provided by the invention has the advantages as follows: the raw material is cheap and easy to obtain, a reaction condition is mild,high-temperature and high-pressure conditions are not required, the posttreatment operation is simple, a synthesis route is short, and industrial production is easy.
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- Based on BRD4 inhibitor RVX - 208 of the derivative and its preparation method and application (by machine translation)
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The invention discloses a method based on BRD4 inhibitor RVX - 208 of the derivative and its preparation method and application. Derivatives of the structure shown in formula I. The preparation method comprises: type 8 compound of formula 9 compound reaction, [...] 10 compound; type 10 compounds with malonic acid, d di-acid or fifth heavenly stem II acid after the reaction, with vinyl carbonate, 2 - halo of isobutyric acid or 4 - halo [...] butyric acid reaction; or, the type 10 compound directly with ethylene carbonate, 2 - halo of isobutyric acid or 4 - halo [...] butyric acid reaction. The invention also provides its application. The present invention provides based on BRD4 inhibitor RVX - 208 of the derivatives, can improve the activity or at the same time reducing cholesterol lowering cholesterol and triglyceride levels. (by machine translation)
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Paragraph 0041
(2018/09/21)
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- Preparation method for Apabetalone
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The invention relates to a preparation method for Apabetalone, and particularly discloses a synthesis method for Apabetalone. The preparation method comprises the following steps: (1) a first intermediate, i.e., 2-bromo-4,6-dimethoxy benzamide, is prepared; (2) a second intermediate, i.e., 4-{2-[(t-butyldimethylsilicon)oxy]ethyoxyl}-3,5-dimethyl benzaldehyde, is prepared; (3) the first intermediate and the second intermediate are sealed under the conditions of cuprous bromide, cesium carbonate, L-proline and ammonia hydroxide to react, so that Apabetalone is obtained. The preparation method disclosed by the invention is simple, and yield is high.
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- NITRIC OXIDE-RELEASING PRODRUG MOLECULE
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Provided are a type of compounds that can be used for treating cardiovascular diseases and compositions containing the compounds. The compounds and the compositions can improve lipid metabolism disorders by increasing high-density lipoprotein cholesterol in blood; in addition, the compounds and the compositions can also release nitric oxide, and reduce the onset risk of cardiovascular diseases by means of relaxing blood vessels, lowering blood pressure, inhibiting platelet adhesion and aggregation and maintaining vascular tension, and thus play an important role in preventing and treating the occurrence and development of cardiovascular diseases.
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- Used for the prevention and treatment of cardiovascular diseases
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The invention relates to compounds that can be used for adjusting the expression of apolipoprotein A-I (ApoA-I) and usage of the compounds in treating and preventing cardiovascular diseases and related diseases, including the disorder related to cholesterol or lipids such as atherosclerosis.
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- TREATMENT OF DISEASES BY EPIGENETIC REGULATION
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The present disclosure provides non-naturally occurring polyphenol compounds that inhibit the bromodomain and extra terminal domain (BET) proteins. The disclosed compositions and methods can be used for treatment and prevention of cancer, including NUT midline carcinoma, Burkitt's Lymphoma, Acute Myelogenous Leukemia, and Multiple Myeloma; autoimmune or inflammatory diseases or conditions, and sepsis.
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- METHODS OF PREPARING QUINAZOLINONE DERIVATIVES
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The present disclosure relates to methods for preparing compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-l), and in the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
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Page/Page column 16-17
(2010/01/30)
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- COMPOUNDS FOR THE PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASES
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The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotei? A-I (ApoA-l), and their use for the treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
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- COMPOUNDS FOR THE PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASES
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The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
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Page/Page column 33
(2008/12/07)
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