- Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3)
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STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.
- Huang, Qiuyao,Zhong, Yan,Li, Bingbing,Ouyang, Shumin,Deng, Lin,Mo, Jianshan,Shi, Shuo,Lv, Nan,Wu, Ruibo,Liu, Peiqing,Hu, Wenhao,Zhang, Xiaolei,Wang, Yuanxiang
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- Preparation method of minodronic acid key intermediate
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The invention belongs to the technical field of drug synthesis, and provides a preparation method of a minodronic acid key intermediate. The method comprises the following steps: reacting ethyl 4-chloroacetoacetate with an ammonia organic solution to obtain a compound V, and reacting the compound V with a compound IV under the catalysis of a [Cu] catalyst to obtain a compound III imidazo[1,2-a]pyridine-3-acetamide; and hydrolyzing the compound III with concentrated hydrochloric acid to obtain a compound II imidazo[1,2-a]pyridine-3-acetic acid. The method has the advantages that the reaction conditions are simple, the raw material utilization degree is high, the yield is high, the purity is high, the pollution to the environment is small, and the method is suitable for industrial production.
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Paragraph 0045; 0073; 0075-0076; 0078-0079; 0081-0082; 0084
(2021/02/24)
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- Preparation method of minodronic acid intermediate
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The invention relates to a preparation method of a minodronic acid intermediate. The method comprises the following steps: reacting a compound I-1 raw material with a compound I-2 under the action ofa catalyst cuprous bromide and an acid-binding agent potassium tert-butoxide to obtain an intermediate I-3, hydrolyzing the intermediate I-3 by sodium hydroxide to obtain an intermediate 1-4, and decarboxylating the intermediate 1-4 by cuprous oxide to obtain an intermediate I, namely the minodronic acid intermediate. Compared with the prior art, the method has the advantages of easily available raw material, simple process, convenience in operation, high reaction yield (the three-step yield is as high as 80%), and facilitation of industrial production.
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Paragraph 0087-0094
(2020/04/17)
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- CHROMENOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
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The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula (I); where A1, A2, G, R1, R2, R3, R4, and W are described herein.
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Paragraph 0564
(2019/07/13)
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- Minodronic acid intermediate synthesis system and synthesis process thereof
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The invention discloses a minodronic acid intermediate synthesis system and a synthesis process thereof. The synthesis system comprises an agitating tank and a reaction kettle, the agitating tank comprises a rack, a mixing tank, and agitating assemblies, each agitating assembly comprises an agitating motor, an agitating shaft, agitating blades, and impellers, and a heater is arranged on the external wall of the mixing tank; the reaction kettle comprises a barrel, a feed inlet, a discharge outlet, a support, and a reaction kettle agitator; and the agitating tank is located upon the reaction kettle. The invention further discloses a preparation method of minodronate intermediate 2-(imidazo[1,2-a]pyridine-3-yl)acetate, which comprises the following steps: imidazo[1,2-a]pyridine and oxalyl chloride as starting materials undergo Friedel-Crafts acylation and Huang Ming-long reduction, and thereby the intermediate 2-(imidazo[1,2-a]pyridine-3-yl)acetate is obtained. According to the invention,environmental pollution is reduced, the reaction step is shortened, the whole reaction process is simplified, the preparation of 2-(imidazo[1,2-a]pyridine-3-yl)acetate is easy to control, the reaction conditions are mild, post-treatment is simple, and industrial production is easy.
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Paragraph 0020; 0046-0081
(2018/11/03)
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- 1,5-DIHYDRO-2H-PYRROL-2-ONE COMPOUNDS AND METHODS OF USING SAME
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The present invention relates to 1,5-dihydro-2H-pyrrol-2-one compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells, including inducing the stem/progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.
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Paragraph 0328-0329
(2018/08/20)
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- A preparation method of the minoan phosphine acid
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The present invention belongs to the technical field of medicine synthesis, and relates to preparation of an osteoporosis and hypercalcemia treating drug minodronic acid, wherein 100.0 g of 2-aminopyridine and ethyl trans-4-oxo-2-butenoate are adopted as raw materials to prepare a minodronic acid key intermediate 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid through a one-pot method, and the 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid reacts with phosphorus oxychloride and phosphorous acid in a suitable solvent to obtain the minodronic acid. With the preparation method of the present invention, the production time can be shortened, the cost can be substantially reduced, and the yield and the purity can be improved significantly.
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Paragraph 0017; 0027-0030
(2018/09/02)
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- A method for preparing minoan phosphine acid (by machine translation)
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The invention relates to a technical field of drug synthesis, in particular relates to a preparation method of minoan phosphine acid. The method mainly comprises the following steps: organic solvent to dissolve the 2 - aminopyridine, added to the solution of organic base, copper catalyst and 4 - chloro acetyl ethyl acetate to obtain the 2 - (imidazo [1, 2 - a] pyridine - 3 - yl) ethyl acetate; 2 - (imidazo [1, 2 - a] pyridine - 3 - yl) ethyl acetate organic solvent to dissolve, sodium hydroxide hydrolysis to obtain 2 - (imidazo [1, 2 - a] pyridine - 3 - yl) acetic acid; according to the prior art phosphorylated preparation minoan phosphine acid. In this method the copper catalyst has improved the yield of the reaction of the ring, reducing the production of the impurity, at the same time the operation of the invention short step and is easy to control, and is suitable for large-scale industrial production. (by machine translation)
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Paragraph 0045; 0046
(2017/08/25)
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- A method for the treatment of osteoporosis minodronic acid preparation method
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The invention discloses a preparation method of minodronic acid for treating osteoporosis. The preparation method comprises the following steps of firstly, reacting a compound as shown in a formula (I) with 2-aminopyridine to obtain a compound as shown in a formula (II); secondly, hydrolyzing the compound as shown in the formula (II) obtained in the first step to obtain a compound as shown in a formula (III); thirdly, phosphorylating the compound as shown in the formula (III) obtained in the second step to obtain the minodronic acid, wherein X is chlorine or bromine, and R is alkyl radicals of C1 to C4; in the first step, a reaction promotor M is added and consists of one or more substances selected from zinc nitrate, silver nitrate and copper nitrate and one or more substances selected from glycine and alanine. According to the preparation method, the yield of a key intermediate in a preparation process of the minodronic acid can be greatly improved; the preparation method has the advantages of few side products, easiness in purification, mild conditions and higher reaction speed, and is suitable for large-scale production and popularization.
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Paragraph 0038; 0041; 0046; 0051; 0056; 0061
(2017/08/25)
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- A method for the treatment of osteoporosis minodronic acid preparation method
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The invention discloses a preparation method of minodronic acid for treating osteoporosis. The method comprises the following steps: (1) reacting a compound expressed by the formula (I) with 2-aminopyridine to obtain a compound expressed as the formula (II); (2) hydrolyzing the compound expressed by the formula (II) obtained by the step (1) to obtain a compound expressed by the formula (III); and (3) phosphorylating the compound expressed by the formula (III) obtained in the step (2) to obtain minodronic acid, wherein the formulae (I), (II) and (III) are described in the specification; in the formulae (I), (II) and (III), X1 and X2 independently represent halogen, and R represents C1-C4 alkyl. Through the method, the yield of key intermediates in the preparation process of minodronic acid can be greatly increased; meanwhile, the method is few in impurities of product, few in by-products and mild in condition, and is suitable for large-scale production and popularization.
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Paragraph 0048; 0051
(2018/04/01)
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- Process for preparing high-purity minodronate
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The invention discloses a process for preparing high-purity minodronate. The process comprises the following process steps: firstly, carrying out ring formation on trans-4-oxo-2-ethyl crotonate and 2-aminopyridine so as to generate 2-(imidazo[1,2a]-3-yl)ethyl acetate, and carrying out hydrolysis so as to obtain 2-(imidazo[1,2a]-3-yl)acetic acid; secondly, reacting 2-(imidazo[1,2a]-3-yl)acetic acid, phosphorous acid with phosphorus trichloride to generate crude minodronate; and finally, refining crude minodronate with hydrochloric acid to obtain a finished product. High-purity minodronate prepared by virtue of the process can be used for effectively treating osteoporosis, and serious diseases such as hip fracture are avoided.
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Paragraph 0021-0023; 0026-0028; 0031-0033
(2017/07/21)
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- Preparation method of minodronic acid
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The invention discloses a preparation method of minodronic acid. The method uses 1-[imidazo(1,2-alpha)pyridine-3-ly]methyl-N,N,N-trimethyliodide and sodium cyanide as raw materials, and comprises the steps of a cyan substitution reaction, a hydrolysis reaction, a phosphorylation reaction and refining. According to the preparation method of minodronic acid provided by the invention, a usage amount of the sodium cyanide is strictly controlled; DMF is used as a solvent, solubility of the raw materials is good, a system is in a homogeneous phase; silicagel columns are used, so that purities with deep colors and large polarities and the ionic compound sodium cyanide can be intercepted, and a nitrile compound, a first midbody, with high purity is acquire, and a basis is established for smoothness of the whole technology.
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- AN IMPROVED PROCESS FOR PREPARING PURE MINODRONIC ACID AND INTERMEDIATES THEREOF
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The present invention relates to an industrially advantageous, cost-effective, and reproducible process for preparation of pure minodronic acid, including salts, hydrates and polymorphs thereof, by using ecofriendly process for preparation of key intermediate, in high yield and high purity.
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Page/Page column 15; 16
(2016/02/29)
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