- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
- Xue, Xiaoqian,Zhang, Yan,Wang, Chao,Zhang, Maofeng,Xiang, Qiuping,Wang, Junjian,Wang, Anhui,Li, Chenchang,Zhang, Cheng,Zou, Lingjiao,Wang, Rui,Wu, Shuang,Lu, Yongzhi,Chen, Hongwu,Ding, Ke,Li, Guohui,Xu, Yong
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p. 542 - 559
(2018/05/24)
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- Synthesis method of clopidogrel hydrogen sulfate
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The invention discloses a synthesis method of clopidogrel hydrogen sulfate. The synthesis method takes o-phenylphthalic chloroacetic acid and 4,5,6,7tetrahydrothiophene[3,2-c] as raw materials and comprises the following steps: (1) carrying out acylation reaction; (2) carrying out bromination reaction; (3) carrying out esterification reaction; (4) preparing a clopidogrel base crude product; (5) extracting clopidogrel base; (5) carrying out racemic racemate reductionresolution; (7) preparing the clopidogrel hydrogen sulfate. According to the synthesis method of the clopidogrel hydrogen sulfate, disclosed by the invention, reasonable raw material selection and process route design are carried out, so that on one hand, a process flow is simplified and synthesis operation is easy to realize; on the other hand, reaction conditions are reduced, the reaction conditions are moderate and the method is easily smoothly carried out; the obtained finished product clopidogrel hydrogen sulfate has high yield and good quality; industrial production is easy to realize and a market prospect is wide.
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Paragraph 0018
(2017/12/27)
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- Copper(II)-catalyzed synthesis of pyrazinones from α-Azido-N- allylamides under an oxygen atmosphere
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A copper(II)-catalyzed reaction of -azido-N-allylamide synthetic under an oxygen atmosphere resulted in the formation of 2-formyl pyrazinones. The present transformation was characterized by the following steps: 1) 1,3-dipolar cycloaddition of the azido part onto the intramolecular alkene to give bicyclic aziridine intermediates; 2) further copper(II)-catalyzed oxygenation-oxidation of the aziridines to give 2-formyl pyrazinones. Georg Thieme Verlag Stuttgart · New York.
- Zhang, Line,Lee, Jian-Yuan,Yamazaki, Naomi,Chiba, Shunsuke
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supporting information; experimental part
p. 2167 - 2170
(2011/10/18)
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- N-PHENYL HYDRAZIDES AS MODULATORS OF THE GHRELIN RECEPTOR
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The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: each R1 is independently selected from the group consisting of Cl, Br, CH3 and CF3; X is carbon or nitrogen; R1a is H or a straight C1-3 alkyl group; R2a is H or a methyl group R2 is selected from the group consisting of C1-3alkyl, H and -(CH2)n-, wherein n is 3 or 4 and the terminal carbon of the chain is bonded to the carbon atom adjacent to the nitrogen bearing the R2 group, such that a fused 6,5 or 6,6-bicyclic ring is formed. Y is selected from the group consisting of: phenyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, C1-3alkoxy, halogen, C1-3alkyl substituted by 1 to 7 fluoro atoms and C1-3alkoxy substituted by 1 to 7 fluoro atoms; pyridyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of C1-3alkyl, OCH3, CF3, CN, and halogen; naphthyl which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of F and OCH3; pyrimidinyl; imidazo[1,2-a]pyridine-6-yl; benzothiophen-2-yl; benzothiophen-5-yl; benzofuran-2-yl; dibenzo[b,d]furan-3-yl; dibenzo[b,d]thiophen-2-yl; dibenzo[b,d]thiophen-4-yl; 1,3- benzodioxol-5-yl; 2,3-dihydro-1,4-benzodioxin-5-yl; 2,3-dihydro-1,4-benzodioxin-6-yl; 2,3- dihydro-1-benzofuran-4-yl; 2,2-difluoro-1,3-benzodiox-4-yl; pyridazinyl; imidazolyl; oxazolyl; pyrazolyl; thiazolyl; and triazolyl; with the proviso that when Y is 2,3-dihydro-1,4-benzodioxin-6-yl, R1 is not Cl; processes for their preparation, intermediates useble in these processes, pharmaceutical compositions containing them and their use in therapy, for example as modulators of of the growth hormone secretagogue receptor (also referred to as the ghrelin receptor or GHSR1a receptor) and/or for the treatment and/or prophylaxis of a disorder mediated by the ghrelin receptor.
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Page/Page column 53-54; 68-69
(2009/01/24)
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