- Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time
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Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27 - a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.
- Apte, Shruti,Arora, Shilpi,Audia, James E.,Bradley, William D.,Brenneman, Jehrod,Bruderek, Kamil,Cantone, Nico,Cummings, Richard T.,Gehling, Victor S.,Khanna, Avinash,Levell, Julian R.,Moine, Ludivine,Ramakrishnan, Ashwin,Sims, Robert J.,Stuckey, Jacob I.,Trojer, Patrick,C?té, Alexandre
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supporting information
p. 1205 - 1212
(2020/07/04)
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- Preparation method for nitrobenzisothiazole-pyridine dye with good acid-base stability
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The invention discloses a preparation method for a nitrobenzisothiazole-pyridine dye with good acid-base stability. The preparation method comprises the following steps: (1) preparing a compound (i) from 1,4-dimethyl-3-cyano-6-hydroxy-2-pyridone and phosphorus oxychloride; (2) preparing a compound (ii) from the compound (i) and NH2-(CH2)n-O-CH3; (3) preparing a compound (A) from the compound (ii)and NH2-(CH2)n-O-CH3; (4) diazotizing 3-amino-5-nitrobenzoisothiazole by using sodium nitrite so as to obtain diazonium salt; (5) mixing the diazonium salt with the compound (A) for a reaction, and carrying out aging so as to obtain a crude product; and (6) dissolving the crude product, carrying out cooling extraction, and carrying out purifying so as to obtain a compound as shown in a structuralformula (B) which is described in the specification. According to the invention, the nitrobenzisothiazole-pyridine dye with good acid-base stability is synthesized in a functional group conversion mode; and the preparation method provided by the invention is easily-controllable in reaction conditions, simple in operation and high in product yield.
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Paragraph 0028-0029; 0037-0039; 0046-0047
(2020/06/02)
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- Preparation method for nevirapine intermediate
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The invention provides a preparation method for a nevirapine intermediate. The preparation method comprises: performing a cyclization reaction of ammonia water, methyl cyanoacetate and methyl acetoacetate to form a compound hydroxyl: 2,6-dihydroxy-3-cyano-4-methylpyridine; adding triethylamine dropwise, introducing chlorine gas at the temperature until the reaction is complete, and obtaining 2,6-dichloro-3-cyano-4-methylpyridine; adding concentrated sulfuric acid, heating to 120 DEG C to react for 3-5 h, and then cooling to 60 DEG C; adding water to perform hydrolysis reaction, and obtaining 2,6-dichloro-3-amido-4-methylpyridine; adding a degradation reagent sodium hypochlorite, and obtaining a nevirapine intermediate 2,6-dichloro-3-amino-4- methylpyridine by Hofmann reaction. According tothe preparation method, commonly used phosphorus oxychloride is replaced with the directly introduced chlorine gas, which solves the problems that the wastewater content is too high, it is difficultto perform treatment and the odor of phosphorus oxychloride is bad, and the one-time yield of the product is 90.1%.
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Paragraph 0011; 0033; 0043; 0053; 0059; 0062-0063
(2019/01/14)
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- The Guareschi-Thorpe Cyclization Revisited - An Efficient Synthesis of Substituted 2,6-Dihydroxypyridines and 2,6-Dichloropyridines
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DBU as base is key in a practical modified Guareschi-Thorpe cyclization of β-keto esters and 2-cyanoacetamide to allow the synthesis of substituted pyridones in good to excellent yields. The chlorination of DBU salts of pyridones with POCl 3 in the presence of a quaternary ammonium salt under standard atmospheric reflux conditions as opposed to the typical pressure equipment led to high yields of substituted 2,6-dichloropyridines.
- Eriksson, Magnus C.,Zeng, Xingzhong,Xu, Jinghua,Reeves, Diana C.,Busacca, Carl A.,Farina, Vittorio,Senanayake, Chris H.
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p. 1455 - 1460
(2018/05/16)
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- Wnt SIGNALING INHIBITOR, COMPOSITION, AND COMPOUND AS USE THEREFOR
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PROBLEM TO BE SOLVED: To provide an inhibitor for Wnt signaling route. SOLUTION: The present invention provides a compound represented by formula I, and a composition comprising the compound (X1-X8 independently represent CR4 or N; Y1 is H or C (R4)3; Y2 and Y3 independently represent H, halogen or C (R3)3; R1 and R2 independently represent H, halogen, C1-6 alkyl, quinolinyl or the like; R3s independently represent H, halogen, cyano, C1-6 alkyl or the like; R4s independently represent H, halogen, cyano, C1-6 alkoxy or the like). SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0079; 0080
(2017/08/15)
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- Inhibiting WNT signal conduction of compound, composition and use thereof (by machine translation)
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The invention relates to a having the general formula (1) compounds and compositions thereof, and the use of the compound or composition thereof to inhibit WNT signal transmission method. The compounds of this invention and its composition can effectively inhibit the secretion of WNT protein, inhibit WNT signal conduction, so the WNT-mediated disease with a very good therapeutic effect. . (by machine translation)
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Paragraph 0171; 0177; 0178; 0179
(2017/12/27)
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- TUMOR BIOMARKERS AND USE THEREOF
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Disclosed herein are biomarkers related to WNT signal transduction pathway, as well as methods and kits comprising the same. Further, the present disclosure relates to the use of the biomarkers in patient selection, companion diagnostics, and treatment of cancer.
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Paragraph 0229-0230
(2016/12/22)
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- Compound as WNT Signaling Inhibitor, Composition, and Use Thereof
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The present invention relates to a compound having the structure of Formula I as inhibitor of WNT signal transduction pathways, as well as a composition comprising the compound. Further, the present invention relates to the use of the compound and the method of inhibiting the WNT signal transduction pathways.
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Paragraph 0175; 0176
(2015/05/05)
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- COMPOUNDS FOR TREATMENT OF CANCER
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The present invention relates to compounds as inhibitor of WNT signal transduction pathway, as well as a composition comprising the same. Further, the present invention relates to the use of the compounds in the treatment of cancer.
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Paragraph 0174; 0175
(2014/10/18)
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- AZAINDENOISOQUINOLINE TOPOISOMERASE I INHIBITORS
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The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
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Paragraph 0144
(2014/02/16)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Paragraph 0307; 0363
(2014/06/25)
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- COMPOUNDS FOR TREATMENT OF FIBROSIS DISEASES
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The present invention relates to compounds as inhibitor of WNT signal transduction pathway, as well as a composition comprising the same. Further, the present invention relates to the use of the compounds in the treatment of fibrosis. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury.
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Paragraph 0160-0161
(2014/10/15)
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- COMPOUND AS WNT SIGNALING INHIBITOR, COMPOSITION, AND USE THEREOF
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The present invention relates to a compound having the structure of Formula I as inhibitor of WNT signal transduction pathways, as well as a composition comprising the compound. Further, the present invention relates to the use of the compound and the method of inhibiting the WNT signal transduction pathways.
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Page/Page column 20
(2014/01/08)
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- A facile synthesis of tetracyclic benzo-pyridonaphthyridines by domino reaction
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A novel methodology for the synthesis of tetracyclic benzo- pyridonaphthyridines, forming a C-C and a C-N bond in concentrated sulfuric acid at 70 °C in a one-pot is reported. The key substrates (9a-m) are prepared by reacting 2-chloro-6-(4-fluorophenyl)-4-methylnicotinenitrile (7) with various anilines followed by dimethylformamide dimethylacetal. The domino reaction is initiated by the protonation of the b-carbon of the enamine group in 9a-m and terminated by the elimination of dimethylamine.
- Basetti, Vishnu,Pallepati, Rangarao,Hosahalli, Subramanya,Potluri, Vijay
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supporting information
p. 2014 - 2017
(2013/04/10)
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- Azaindenoisoquinolines as topoisomerase i inhibitors and potential anticancer agents: A systematic study of structure-activity relationships
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A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.
- Kiselev, Evgeny,Agama, Keli,Pommier, Yves,Cushman, Mark
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experimental part
p. 1682 - 1697
(2012/05/04)
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- BICYCLIC INHIBITORS OF ANAPHASTIC LYMPHOMA KINASE
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Disclosed are compounds of formula (Ⅰ) and their pharmaceutical acceptable salts, wherein R1, R2, R3, X, Y, Z, A, B, G1, m and n are defined in the description. The compositions containing the said compounds used for inhibiting kinases such as anaphastic lymphoma kinase (ALK) and methods of treating diseases such as cancer are disclosed.
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Page/Page column 136
(2012/08/07)
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- BICYCLIC INHIBITORS OF ALK
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The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, Formula (1) wherein R1, R2, R3, X, Y, Z, A, B, G1, m, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.
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Page/Page column 71
(2012/08/07)
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- NOVEL PYRIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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This invention relates to novel pyridine derivatives having an inhibitory effect on production of cytokines, which are involved in inflammatory responses, thus suggesting its usefulness as therapeutic agents for treating diseases related to inflammation, immune, chronic inflammation as well as an agent having an anti-inflammatory and analgesic effect. Further, this invention relates to a method of manufacturing the same and a pharmaceutical composition containing the same.
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Page/Page column 65
(2008/06/13)
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- Synthesis of some halogen- and nitro-substituted nicotinic acids and their fragmentation under electron impact
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Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4-methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their amides. The fragmentation pathways of the synthesized compounds under electron impact have been studied.
- Dyadyuchenko,Strelkov,Mikhailichenko,Zaplishny
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p. 308 - 314
(2007/10/03)
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- Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes
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The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2- substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11- cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2- substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
- Proudfoot,Hargrave,Kapadia,Patel,Grozinger,McNeil,Cullen,Cardozo,Tong,Kelly,Rose,David,Mauldin,Fuchs,Vitous,Hoermann,Klunder,Raghavan,Skiles,et al.
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p. 4830 - 4838
(2007/10/03)
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- Synthesis and Reactivity of 2,6-Diamino-4-methyl-3-pyridinecarbonitrile
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2,6-Dihydroxy-4-methyl-3-pyridinecarbonitrile is converted via its 2,6-dichloro analog into the corresponding 2-amino-6-chloro, 2-chloro-6-amino, and 2,6-diamino derivatives.The last reacts with benzenesulfonyl chloride to yield a tris-sulfonyl derivative, the structure of which is demonstrated by X-ray analysis.
- Katritzky, Alan R.,Rachwal, Stanislaw,Smith, Terrance P.,Steel, Peter J.
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p. 979 - 984
(2007/10/02)
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- Regioselective Conversion of 3-Cyano-6-hydroxy-2-pyridones into 3-Cyano-6-amino-2-pyridones
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The reaction of a tautomeric mixture of 1-butyl-1,2-dihydroxy-6-hydroxy-4-methyl-2-oxopyridine-3-carbonitrile and its 2-hydroxy-6-oxo analog with phosphorus oxychloride gave 1-butyl-6-chloro-1,2-dihydro-4-methyl-2-oxopyridine-3-carbonitrile (68percent) and 1-butyl-2-chloro-1,6-dihydro-4-methyl-6-pyridine-3-carbonitrile (3percent).Both chloropyridones were converted to their corresponding aminopyridones by reaction with liquid ammonia.Strong support for the molecular structure of 6-amino-1-butyl-1,2-dihydro-4-methyl-2-oxopyridine-3-carbonitrile was obtained on the basis of nmr techniques.
- Katritzky, Alan R.,Rachwal, Stanislaw,Smith, Terrance P.
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p. 1007 - 1010
(2007/10/03)
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- 2-SUBSTITUTED 1,2-BENZISOTHIAZOL-3(2H)-ONE 1,1-DIOXIDE USEFUL AS AN ANXIOLYTIC AGENT
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There is disclosed the compound 2-[4-[4-(2,7-naphthyridin-1-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3(2 H)-one 1,1-dioxide, and the method of producing said compound, and the pharmaceutically acceptable salts thereof, and the use of said compound as an anxiolytic agent having a low liability for extrapyramidal side effects.
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- Process for the preparation of 2,6-diaminopyridine-azo dyestuffs and of their precursors
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An improved process for producing 2,6-diaminopyridines and azo dyestuffs therefrom involves reacting a 2,6-dihalopyridine with a primary amine in a two-phase system of water and an insoluble or sparingly soluble inert organic solvent in the presence of an inorganic base.
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- Process for the manufacture of 2,6-dichloropyridine derivatives
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The process for the manufacture of a compound of the formula STR1 comprising reacting in the presence of a basic nitrogen compound at elevated temperature phosphorus oxychloride with a compound of the formula STR2 in the molar ratio of phosphorus oxychloride to hydroxypyridine of 1:1 to 1.3:1 wherein R1 is hydrogen, alkyl having 1 to 8 carbon atoms, phenyl, carbalkoxy having 2 to 5 total carbon atoms, carbalkoxymethyl having 3 to 6 total carbon atoms or substituted phenyl having a substituent selected from the group consisting of chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano and nitro and R2 is hydrogen, cyano, nitro or acetyl.
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