3381-73-5Relevant articles and documents
Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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
supporting information, p. 542 - 559 (2018/05/24)
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.
PROCESS
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Page/Page column 27, (2008/06/13)
A process for the preparation of a compound of formula (I) wherein: R is an alkynyl group; R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, phenyl and phenylalkyl, it being possible in turn for all of the receding groups to carry one or more identical or different halogen atoms; alkoxy; alkenyloxy; alkynyloxy; alkoxyalkyl; haloalkoxy; alkylthio; haloalkylthio; alkysulfonyl; formyl; alkanoyl; hydroxy; halogen; cyano; nitro; amino; alkylamino; dialkylamino; carboxyl; alkoxycarbonyl; alkenyloxycarbonyl; or alkynyloxycarbonyl; and n is an integer from 0 to 3, said process comprising: (i) the reaction of a compound of formula (III) wherein R, R1 and n are as hereinbefore defined; m and m' are independently 0 or 1; when m and m' are both 0, A is an alkyl, alkenyl or alkynyl group (suitably having up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxy, alkoxy, C1-4 dialkylamino or cyano; when one of m and m' is 0 and the other is 1, A is an alkanediyl, alkenediyl or alkynediyl group containing at least two carbon atoms (and suitably having up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxy, alkoxy, C1-4 dialkylamino or cyano; when m and m' are both 1, A is an alkanetriyl, alkenetriyl or alkynetriyl group containing at least three carbon atoms (and suitably having up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxy, alkoxy, C1-4 dialkylamino or cyano; and wherein if the group A contains three or more carbon atoms, one or more of the carbon atoms may each optionally be replaced with an oxygen atom, provided that there is at least one carbon atom between any two oxygen atoms in the molecule, with a compound of formula (IV) to give a compound of formula (II) wherein R, R1 and n are as hereinbefore defined, and (ii) the reaction of a compound of formula (II) with , wherein L is a leaving group, to give the compound of formula (I) as hereinbefore defined, is disclosed.
Process for the stereoselective preparation of (-)-halofenate and derivatives thereof
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Page/Page column 12-13, (2008/06/13)
The present invention provides a compounds the formula (IV): and methods for producing an α-(phenoxy)phenylacetic acid compound of the formula: wherein R1 is a member selected from the group consisting of: each R2 is a member indepen
