- Synthesis, evaluation and in silico studies of novel BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold
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Abstract: The BRD4 protein is associated with various diseases, which has been an attractive target for the treatment of cancer and inflammation. This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold. The SARs focused on exploration of the 2′ or 3′ position to afford novel inhibitors that may avoid potential metabolically unstable site. The most potent inhibitor 13f exhibited high binding affinity to BRD4(1) with a ΔTm value of 7.8 °C as evaluated in thermal shift assay (TSA). The potent activity was also demonstrated by a peptide competition assay with an IC50 value of 0.21?μM. The docking studies revealed the binding mode of the compounds with the active site of BRD4(1). In addition, in silico predictions indicated that these compounds possessed good drug-likeness and pharmacokinetic profile. Graphic abstract: This paper is a follow-up to our previous studies, in which we report the structure-based design,synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazolscaffold.[Figure not available: see fulltext.].
- Zhang, Maofeng,Liu, Zhuyun,Wang, Lizhong,Li, Yan,Ma, Yonggang
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- Fused tetracyclic compound and application thereof in medicines
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The invention relates to a fused tetracyclic compound and application thereof in medicines, in particular to application of the fused tetracyclic compound as a medicine for treating and/or preventing hepatitis B. Specifically, the invention relates to a c
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Paragraph 0199-0204
(2021/07/21)
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- Fused tetracyclic compound and application thereof in medicine
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The invention relates to a fused tetracyclic compound and an application thereof in medicine, in particular to an application of a fused tetracyclic compound as a medicament for treating and/or preventing hepatitis B. More specifically, the present invention relates to a compound represented by general formula (I) or a stereoisomer thereof. Use of a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and as a medicament, in particular as a medicament for the treatment and/or prevention of hepatitis B. The variables are as defined in the specification.
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Paragraph 0252-0255
(2021/09/29)
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- Green bromination method
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The invention discloses a green bromination method, and belongs to the field of green organic chemistry. Under the conditions of room temperature, opening and neutrality, reaction raw materials are aromatic hydrocarbon, olefin, alkyne, tryptamine, tryptophane and derivatives thereof with different functional groups, a bromine source is MBrx (M is Fe , Fe , Ce and the like, and x is 2-3), and the unique oxidant is H2O2. Brominated alkanes, alkenes, aromatic hydrocarbons, pyrrolo-indolines and furo-indolines and derivatives thereof can be produced. The bromination reaction is carried out by using easily available and cheap reagents (such as FeBr2, CeB3 and H2O2) in the market and the solvent, and the method has the characteristics of mild reaction conditions, wide substrate application range, simple steps, easiness in operation and no need of separation, is a green, environment-friendly and safe bromination reaction method, and has a good application prospect.
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Paragraph 0047-0049
(2021/06/13)
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- Fused tetracyclic compounds and application thereof in medicines
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The invention relates to fused tetracyclic compounds and an application thereof in medicines, and in particular, relates to the application of the fused tetracyclic compounds as medicines for treatingand/or preventing hepatitis B. Specifically, the invention relates to the compounds represented by a general formula (I) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, wherein the variables are defined in the specification. The invention further relates to the application of the compounds represented by the general formula (I) or the stereoisomers, the tautomers, the nitric oxides, the solvates, the metabolites, the pharmaceutically acceptable salts or the prodrugs thereof as medicines, and in particular, relates tothe application of the compounds as the medicines for treating and/or preventing hepatitis B.
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Paragraph 0393; 0395-0398
(2020/04/17)
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- Method for synthesizing benzofuran heterocyclic sulfonyl chloride
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The invention provides a method for synthesizing benzofuran heterocyclic sulfonyl chloride. The benzofuran heterocyclic sulfonyl chloride has a structural formula of a formula I shown in the specification. The method comprises the following steps: 1) by taking a compound 1, that is, 2,3-dihydrobenzofuran, as a raw material, and dichloromethane as a solvent, under catalysis of pyridine, performingelectrophilic addition on a benzene ring by using bromine so as to obtain a compound 2, that is, 5-2,3-dihydrobenzofuran; and 2) performing a chlorosulfonation reaction on a benzene ring by using a compound 2 through chlorosulfonic acid so as to obtain a compound of the formula I shown in the specification, that is, 5-2,3-dihydrobenzofuran-7-sulfonyl chloride, wherein the mole ratio of the compound 2 to the chlorosulfonic acid is 1:(2-20), the reaction temperature is 0-60 DEG C, and the reaction time is 0.5-12 hours. The preparation process of the derivative is not reported in either domesticor overseas documents at present. The invention designs a novel synthesis route, condition optimization is implemented for key reaction steps in the route, and optimal process conditions are confirmed. The novel process has the characteristics of being cheap in initial raw material, easy in initial raw material obtaining, short I step, easy in aftertreatment, high in yield, and the like, and is applicable to industrial production.
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Paragraph 0019; 0021-0025
(2019/11/28)
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- Intermolecular Aryl C?H Amination through Sequential Iron and Copper Catalysis
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A mild, efficient and regioselective method for para-amination of activated arenes has been developed through a combination of iron and copper catalysis. A diverse range of products were obtained from an operationally simple one-pot, two-step procedure involving bromination of the aryl substrate with the powerful Lewis acid iron(III) triflimide, followed by a copper(I)-catalysed N-arylation reaction. This two-step dehydrogenative process for the regioselective coupling of aromatic C?H bonds with non-activated amines was applicable to anisole-, phenol-, aniline- and acetanilide-type aryl compounds. Importantly, the arene substrates were used as the limiting reagent and required no protecting-group manipulations during the transformation.
- Mostafa, Mohamed A. B.,Calder, Ewen D. D.,Racys, Daugirdas T.,Sutherland, Andrew
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supporting information
p. 1044 - 1047
(2017/02/05)
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- PIPERIDINE DERIVATIVE AS TACHYKININ RECEPTOR ANTAGONIST
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The present invention relates to a compounds represented by the formula. The compounds of the present invention have a superior tachykinin receptor antagonistic action, particularly a substance P receptor antagonistic action, and is useful as pharmaceutical agents, for example, tachykinin receptor antagonists, agents for the prophylaxis or treatment of lower urinary tract symptoms, gastrointestinal diseases or central nerve diseases.
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Page/Page column 94
(2010/11/25)
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- LEWIS ACID CATALYZED HALOGENATION OF ACTIVATED CARBON ATOMS
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A practical and efficient method for halogenation of activated carbon atoms using readily available /V-haloimides and a Lewis acid catalyst has been disclosed. This methodology is applicable to a range of compounds and any halogen atom can be directly introduced to the substrate. The mild reaction conditions, easy workup procedure and simple operation make this method valuable from both an environmental and preparative point of view.
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Page/Page column 23-25
(2008/06/13)
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- Lewis acid catalyzed highly selective halogenation of aromatic compounds
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A simple and efficient procedure for the halogenation of aromatic compounds with NCS, NBS, NIS and NFSI in the presence of catalytic amount of ZrCl 4 is described. Chlorination, bromination, iodination and fluorination of various aromatic compounds are performed with high selectivity under mild reaction conditions. Georg Thieme Verlag Stuttgart.
- Zhang, Yanhua,Shibatomi, Kazutaka,Yamamoto, Hisashi
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p. 2837 - 2842
(2007/10/03)
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- C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors
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A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C 17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Ojida, Akio,Tanaka, Toshimasa,Hara, Takahito,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 4313 - 4336
(2007/10/03)
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- CARBOXYLIC ACID DERIVATIVE AND MEDICINE COMPRISING SALT OR ESTER OF THE SAME
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The present invention provides novel carboxylic acid derivatives useful as an insulin sensitizer, a salt thereof or a hydrate of them, and a medicament comprising the derivative as the active ingredient. Specifically, it provides a carboxylic acid derivative represented by the following formula: (wherein L represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; M represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; T represents a single bond, or a C1 to C3 alkylene group, a C2 to C3 alkenylene group or a C2 to C3 alkynylene group, each of which may have one or more substituent groups; W represents a carboxyl group; X represents a single bond, an oxygen atom, or a group represented by the various substituent groups including -NRX1CQ1O- (wherein Q1 represents an oxygen atom or a sulfur atom; RX1 represents a hydrogen atom, a cyano group, a formyl group, or various groups including a C1 to C6 alkyl group and a C1 to C6 hydroxyalkyl group, each of which may have one or more substituent groups) , ONRX1CQ1-, -NRX1CQ1-, -CQ1NRX1-, -NRX1aCQ1NRX1b-, -Q2SO2- and -SO2Q2-; Y represents a 5 to 14-membered aromatic group which may have one or more substituent groups and one or more hetero atoms, or a C3 to C7 alicyclic hydrocarbon group; and the rings Z and U may be the same as or different from each other and each represents a 5 to 14-membered aromatic group which may have 1 to 4 substituent groups and one or more hetero atoms, and the ring may be partially saturated.), a salt thereof, an ester thereof or a hydrate of them.
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- GLUCOCORTICOID MIMETICS, METHODS OF MAKING THEM, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
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Compounds of Formula (IA) and Formula (IB) wherein R1, R2, R3, R4, R5, and R6 are as defined herein for Formula (IA) or Formula (IB), or a tautomer, prodrug, solvate,or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
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Page/Page column 137-138
(2010/02/07)
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- Practical asymmetric synthesis of a selective endothelin A receptor (ETA) antagonist
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Equation presented A practical, chromotography-free asymmetric synthesis was developed for the large scale preparation of an endothelin receptor antagonist 2. This synthesis includes a new efficient process for the preparation of 6-bromo-2,3-dihydrobenzof
- Song, Zhiguo J.,Zhao, Matthew,Frey, Lisa,Li, Jing,Tan, Lushi,Chen, Cheng Y.,Tschaen, David M.,Tillyer, Richard,Grabowski, Edward J. J.,Volante, Ralph,Reider, Paul J.,Kato, Yoshiaki,Okada, Shigemitsu,Nemoto, Takayuki,Sato, Hiroki,Akao, Atsushi,Mase, Toshiaki
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p. 3357 - 3360
(2007/10/03)
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- Piperazine compounds as inhibitors of MMP or TNF
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A compound of formula (I) wherein A is a sulfonyl or a carbonyl; R1is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; R2is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R3is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substitued lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substitued amino; R4is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R5is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and R10is a hydroxy or a protected hydroxy, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP- or TNFα-mediated diseases.
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- Anilide derivative, production and use thereof
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This invention is to provide a compound of the formula: wherein R1is an optionally substituted 5- to 6-membered ring; the ring A is an optionally substituted 6- to 7-membered ring; the ring B is an optionally substituted benzene ring; n is an integer of 1 or 2; Z is a chemical bond or a divalent group; R2is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: ?wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5and R6are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5and R6may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof , which is useful for antagonizing CCR5 and also for the prevention and treatment of infectious disease of HIV.
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- UROKINASE INHIBITORS
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Disclosed are benzothiophene and thienothiophene derivatives useful for inhibiting urokinase activity.
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- The Synthesis of 5-Substituted 2,3-Dihydrobenzofurans
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The preparation of 2,3-dihydrobenzofurans 6 from 2-(2-bromophenoxy)ethyl chlorides 3 by reaction with magnesium in a development of the Parham cyclialkylation reaction is described.A high yielding procedure using phase-transfer catalysis has also been developed for the preparation of the intermediate chloroethyl ethers 3 from bromophenols 2.The 5-hydroxy derivative 15 may be obtained from 2,3-dihydrobenzofuran (6a) by reaction with electrophilic reagents followed by oxidation.
- Alabaster, Ramon J.,Cottrell, Ian F.,Marley, Hugh,Wright, Stanley H. B.
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p. 950 - 952
(2007/10/02)
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- Oxygen Heterocycles by the Parham Cyclialkylation
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The addition of butyllithium at -100 deg C to ω-bromoalkyl ethers of o-bromophenol (and its congeners) led to preferential exchange of the aryl bromine at position 2.The resulting organolithium reagents, under suitable conditions, cyclized to afford 2,3-dihydrobenzofurans (6), 3,4-dihydro-2H-1-benzopyrans (13), or 2,3,4,5-tetrahydro-1-benzoxepins (16) in good yields, but less satisfactory results were obtained with the intermediate expected to produce 8-methyl-3,4,5,6-tetrahydro-2H-1-benzoxocin (19). ω-Bromoethyl and ω-bromopropyl ethers of suitable dibromophenols were treated successively with 2 equiv of butyllithium and an electrophile to yield derivatives of 6 and 13.
- Bradsher, Charles K.,Reames, David C.
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p. 1384 - 1388
(2007/10/02)
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