- Tunable Electrosynthesis of Anthranilic Acid Derivatives via a C-C Bond Cleavage of Isatins
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A facile and direct electrocatalytic C-C bond cleavage/functionalization reaction of isatins was developed. With isatins as the amino-attached C1 sources, a variety of aminobenzoates, and aminobenzamides were synthesized in moderate to good yields under mild conditions.
- Qian, Peng,Liu, Jiaojiao,Zhang, Yan,Wang, Zhiyong
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p. 16008 - 16015
(2021/07/31)
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- Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators
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Neurotensin receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.
- Pinkerton, Anthony B.,Peddibhotla, Satyamaheshwar,Yamamoto, Fusayo,Slosky, Lauren M.,Bai, Yushi,Maloney, Patrick,Hershberger, Paul,Hedrick, Michael P.,Falter, Bekhi,Ardecky, Robert J.,Smith, Layton H.,Chung, Thomas D. Y.,Jackson, Michael R.,Caron, Marc G.,Barak, Lawrence S.
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supporting information
p. 8357 - 8363
(2019/09/10)
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- Oxidative ring-opening of isatins for the synthesis of 2-aminobenzamides and 2-aminobenzoates
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An efficient and practical isatin-based oxidative domino protocol has been developed for the facile synthesis of 2-aminobenzamides and 2-aminobenzoates. The robust nature of this reaction system is reflected by accessible starting materials, room temperature and high-yield gram-scale synthesis.
- Wang, Yu-Wei,Zheng, Lei,Jia, Feng-Cheng,Chen, Yun-Feng,Wu, An-Xin
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p. 1497 - 1503
(2019/02/13)
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- Compound as well as preparation method and application thereof as c-Met inhibitor
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The invention provides a compound as well as a preparation method and application thereof as a c-Met inhibitor. The compound has a structure as shown in a formula (X) or an isomer of the compound in the formula (X) or a pharmaceutically acceptable slat of the compound, wherein A is hydrogen or B is shown as the specification or C does not exist or is a benzene ring, and C forms a quinazoline grouptogether with a parent nucleus structure when being the benzene ring; L1 is -NH-CH2- or -O-; L2 does not exist or is -NH-; X is C or N; Y is O or S; R1 is halogen or -NO2; R2 is shown as the specification or is -COR5; R3 is selected from halogen, alkyl and alkoxy; each of R4 and R5 is an independent C3-C6 saturated or unsaturated cycloalkyl, aryl or heteroaryl; and the cycloalkyl, aryl or heteroaryl is substituted or unsubstituted, the substituent group is selected from halogen, nitryl, alkyl and substituent alkyl.
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Paragraph 0175; 0176; 0177
(2019/10/01)
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- Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene
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Alkenes can be cleaved by means of the (3+2) cycloaddition and subsequent cycloreversion of 1,3-dipoles, classically ozone (O3), but the azide (R?N3) variant is rare. Chemoselectivity for these azide to alkene diazo group transfers (DGT) is typically disfavored, thus limiting their synthetic utility. Herein, this work discloses a palladium-catalyzed intramolecular azide to alkene DGT, which grants chemoselectivity over competing aziridination. The data support a catalytic cycloreversion mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloadditions. Kinetics experiments reveal an unusual mechanistic profile in which the catalyst is not operative during the rate-controlling step, rather, it is active during the product-determining step. Catalytic DGT was used to synthesize N-heterocyclic quinazolinones, a medicinally relevant structural core. We also report on the competing aziridination and subsequent ring expansion to another N-heterocyclic core structure of interest, benzodiazepinones.
- Frost, Grant B.,Mittelstaedt, Michaela N.,Douglas, Christopher J.
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supporting information
p. 1727 - 1732
(2019/01/09)
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- Method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile
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The invention discloses a method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile. The method comprises the following steps of: S1, adopting 2-amino-4-halo benzoic acid as a starting material, and performing esterification on simple fatty alcohol under the action of a catalyst so as to produce 4-halo-2-aminobenzoate; S2, performing a reaction between 4-halo-2-aminobenzoate and 3-dimethylaminoacrylonitrile under the action of an acidic catalyst so as to produce 4-halo-2-((2-cyanovinyl)amino) benzoate; S3, performing cyclization on 4-halo-2-((2-cyanovinyl)amino) benzoate under the action of strong base so as to produce 7-halo-1,4-dihydroquinoline-4-one-3-carbonitrile; and S4, performing nitrification on 7-halo-1,4-dihydroquinoline-4-one-3-carbonitrile in the presence ofa mixture of strong acid and nitric acid to obtain 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile. According to the method for preparing 7-halo-6-nitro-1,4-dihydroquinoline-4-one-3-carbonitrile, the process route is novel, the novel intermediates are obtained, and the total yield is more than 35%; the method has the advantages of a novel process route, mild reaction conditions and the like.
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Paragraph 0021
(2018/07/30)
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- Iodine(III) Reagent-Mediated Intramolecular Amination of 2-Alkenylanilines to Prepare Indoles
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A variety of 3-substituted and 2,3-disubstituted indoles were synthesized efficiently in good yields through the intramolecular amination of 2-alkenylanilines promoted by readily available iodine(III) reagents in a short reaction time. Mechanistic studies showed that the reaction pathway went through a nitrenium ion and that 3-acetoxy indoline was the key intermediate in the indole formation. The indole product was easily prepared on a gram scale and amination also proceeded smoothly using catalytic 3,5-dimethylphenyl iodine in the presence of mCPBA. Furthermore, the indolo[3,2-a]carbazole scaffold was prepared in good yield in six steps from commercial ortho-iodoaniline. (Figure presented.).
- Zhao, Chun-Yang,Li, Kun,Pang, Yu,Li, Jia-Qing,Liang, Cui,Su, Gui-Fa,Mo, Dong-Liang
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supporting information
p. 1919 - 1925
(2018/03/28)
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- Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist
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A series of potent quinazolinedione sulfonamide antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N-[7-isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)-induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X-ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.
- Orain, David,Tasdelen, Engin,Haessig, Samuel,Koller, Manuel,Picard, Anne,Dubois, Celine,Lingenhoehl, Kurt,Desrayaud, Sandrine,Floersheim, Phillip,Carcache, David,Urwyler, Stephan,Kallen, Joerg,Mattes, Henri
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p. 197 - 201
(2017/02/15)
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- A method for preparing the methyl two sulphur are prosperous (by machine translation)
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The invention discloses a method for synthesizing the methyl two sulphur are prosperous, belongs to the pesticide chemical field, the synthetic method is to 4 - chloro - 2 - aminobenzoic acid as the raw materials, by esterification, diazo, through sulfur dioxide, oxychloride, ammoniation ring, nitrogen methylation, carbonitriding, reduction, open-loop, a sulfonylation and condensation of the eleven step to make the methyl two sulphur are prosperous. The invention synthetic the methyl two sulphur are prosperous, the raw material is cheap, simple operation, mild condition, low equipment requirements, high yield, is suitable for industrial production, and the practicability is strong. (by machine translation)
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Paragraph 0047; 0052; 0053; 0073; 0074
(2017/08/25)
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- Synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate
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The invention provides a synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate. The technical scheme is that 4-chloro-2-aminobenzoic acid is taken as a raw material and has an esterification reaction, a product is subjected to diazotization and the Sandmeyer reaction, methyl 4-chloro-2-(chlorosulfonyl)benzoate is prepared and subjected to condensation with N-methylaniline, and 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate is obtained. The synthetic method has the advantages of conciseness, high efficiency, mild conditions, no need of purification of an intermediate and simple operation, the total yield of three steps of reactions is as high as 65%, and the method is quite suitable for industrial production.
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Paragraph 0021; 0023
(2016/11/07)
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- PARASITICIDAL COMPOSITIONS COMPRISING INDOLE DERIVATIVES, METHODS AND USES THEREOF
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The invention relates to oral, topical or injectable compositions for combating liver fluke parasites in mammals, comprising at least one indole derivative active agent. The invention also provides for an improved method for eradicating and controlling liver fluke parasite infections and infestations in a mammal comprising administering the compositions of the invention to the mammal in need thereof.
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Paragraph 0146
(2016/03/08)
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- Palladium-catalyzed direct coupling of 2-vinylanilines and isocyanides: An efficient synthesis of 2-aminoquinolines
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Palladium-catalyzed oxidative coupling of 2-vinylanilines and isocyanides constitutes a direct, facile, and efficient approach to 2-aminoquinolines. The procedure, employing palladium acetate and silver carbonate, is attractive in terms of assembly efficiency, functional group tolerance, and operational simplicity. A variety of 2-aminoquinolines were prepared in good to excellent yields.
- Wang, Lijie,Ferguson, Jamie,Zeng, Fanlong
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supporting information
p. 11486 - 11491
(2015/12/04)
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- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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p. 8332 - 8338
(2013/12/04)
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- Synthesis of primary aryl amines through a copper-assisted aromatic substitution reaction with sodium azide
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(Figure Presented) A method is presented by which aryl halides and azides are converted to the corresponding primary aryl amines with copper(I) and sodium azide.
- Markiewicz, John T.,Wiest, Olaf,Helquist, Paul
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supporting information; experimental part
p. 4887 - 4890
(2010/10/19)
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- 5, 7-DIHYDRO- 6H-PYRIMIDO [ 5, 4-D] [ 1 ] BENZAZEPIN-6-THIONES AS PLK INHIBITORS
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This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, and R6 are as described in the specification. The compounds are inhibitors of PLK and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
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Page/Page column 60
(2010/06/20)
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- Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists
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A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT6 antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT6 receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (Ki = 12.3 nM) for 5-HT6 receptor with good selectivity over other serotonin and dopamine (D1-D4) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC50 = 0.61 μM).
- Seong, Churl Min,Park, Woo Kyu,Park, Chul Min,Kong, Jae Yang,Park, No Sang
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p. 738 - 743
(2008/12/23)
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- Synthesis and anti-platelet evaluation of 2-benzoylaminobenzoate analogs
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Fifty-two 2-benzoylaminobenzoate analogs were synthesized and subjected to anti-platelet aggregation assay using arachidonic acid (AA), collagen (Col), thrombin (Thr), and U46619 as inducers. The results revealed that most of 2-benzoylaminobenzoic acid derivatives showed a selectively inhibitory effect on AA-induced platelet aggregation. As a result of the 2-benzoylaminobenzoic acid derivatives (18, 44, and 46), there were no inhibitory effects on platelet aggregation induced by U46619, but these elicited an inhibitory effect on thromboxane B2 formation at 1.0 μM. These 2-benzoylaminobenzoate analogs were therefore proposed as cyclooxygenase inhibitors.
- Hsieh, Pei-Wen,Chiang, Shin-Zan,Wu, Chin-Chung,Lo, Yi-Ching,Shih, Yu-Tzu,Wu, Yang-Chang
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p. 5803 - 5814
(2008/12/21)
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- 3-aryl--3-methyl-quinoline-2, 4-diones, preparation method thereof, and pharmaceutical composition containing the same
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The present invention relates to compounds of 3-aryl-3-methyl-quinoline-2,4-diones acting as a 5HT6 receptor antagonist, a preparation method thereof, and a pharmaceutical composition containing the same for treatment of the central nervous system disorders. The compounds of 3-aryl-3-methyl-quinoline-2,4-diones according to the present invention may be valuably used for treatment of a 5HT6 receptor relating disorders because of its excellent binding affinity for the 5HT6 receptor and excellent selectivity for the 5HT6 receptor over other receptors.
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Page/Page column 8
(2008/06/13)
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- 3-aryl-3-methyl-quinoline-2,4-diones, preparation method thereof and pharmaceutical composition containing same
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The present invention relates to compounds of 3-aryl-3-methyl-quinoline-2,4-diones , or a pharmaceutically acceptable salt thereof acting as a 5HT6 receptor antagonist, a preparation method thereof, and a pharmaceutical composition containing the same for treatment of the central nervous system disorders. The compounds of 3-aryl-3-methyl-quinoline-2,4-diones according to the present invention may be valuably used for treatment of a 5HT6 receptor relating disorders because of its excellent binding affinity for the 5HT6 receptor and excellent selectivity for the 5HT6 receptor over other receptors.
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Page/Page column 10
(2008/06/13)
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- 4-Hydroxy-2-quinolones. 90.* Synthesis and antitubercular activity of 4-methyl-2-thiazolylamides of halo-substituted 4-hydroxy-2-oxo-1,2-dihydro-3- quinolinecarboxylic acids
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Several variants were studied for the synthesis of esters of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids, whose reaction with 2-amino-4-methylthiazole gives the corresponding hetarylamides. Results are given for a study of the antitubercular activity of these products. 2006 Springer Science+Business Media, Inc.
- Ukrainets,Sidorenko,Petrushova,Gorokhova
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- A novel synthesis of substituted quinolines using ring-closing metathesis (RCM): Its application to the synthesis of key intermediates for anti-malarial agents
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A method for synthesizing substituted quinolines using ruthenium-catalyzed ring-closing metathesis as a key step has been developed. Substituted 1,2-dihydroquinolines, 4-silyloxy-1,2-dihydroquinoline and 4-methoxy-1,2- dihydroquinoline, were successfully synthesized in excellent yields via ene-ene metathesis and silyl or alkyl enol ether-ene metathesis, respectively. The synthetic intermediates of the antimalarial agents quinine, chloroquine, and PPMP-quinine hybrid were efficiently synthesized by this methodology.
- Theeraladanon, Chumpol,Arisawa, Mitsuhiro,Nishida, Atsushi,Nakagawa, Masako
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p. 3017 - 3035
(2007/10/03)
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- Synthesis of substituted 1,2-dihydroquinolines and quinolines using ene-ene metathesis and ene-enol ether metathesis
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We describe a novel and convenient method for quinoline synthesis using ring-closing olefin metathesis (RCM), ene-ene metathesis, and ene-enol ether metathesis. We also report the first example of enol silyl ether-ene metathesis to produce cyclic enol silyl ether. Using this method, versatile substituted quinoline derivatives were readily prepared in excellent yield from anthranilic acid derivatives.
- Arisawa, Mitsuhiro,Theeraladanon, Chumpol,Nishida, Atsushi,Nakagawa, Masako
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p. 8029 - 8033
(2007/10/03)
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- 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist
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We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent. Copyright (C) 1999 Elsevier Science Ltd.
- Kondo, Kazumi,Ogawa, Hidenori,Yamashita, Hiroshi,Miyamoto, Hisashi,Tanaka, Michinori,Nakaya, Kenji,Kitano, Kazuyoshi,Yamamura, Yoshitaka,Nakamura, Shigeki,Onogawa, Toshiyuki,Mori, Toyoki,Tominaga, Michiaki
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p. 1743 - 1754
(2007/10/03)
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- Synthesis and structure-activity relationships of 1,2,3,4- tetrahydroquinoline-2,3,4-trione 3-oximes: Novel and highly potent antagonists for NMDA receptor glycine site
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A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism of NMDA receptor glycine site. Glycine site affinity was determined using a [3H]DCKA binding assay in rat brain membranes and electrophysiologically in Xenopus oocytes expressing 1a/2C subunits of cloned rat NMDA receptors. Selected compounds were also assayed for antagonism of AMPA receptors in Xenopus oocytes expressing rat brain poly-(A)+ RNA. QTOs were prepared by nitrosation of 2,4- quinolinediols. Structure-activity studies indicated that substitutions in the 5-, 6-, and 7-positions increase potency, whereas substitution in the 8- position causes a decrease in potency. Among the derivatives evaluated, 5,6,7-trichloro-QTO was the most potent antagonist with an IC50 of 7 nM in the [3H]DCKA binding assay and a K(b) of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a K(b) of 180 nM for AMPA receptors in electrophysiological assays. The SAR of QTOs was compared with the SAR of 1,4-dihydroquinoxaline-2,3-diones (QXs). For compounds with the same benzene ring substitution pattern, QTOs were generally 5-10 times more potent than the corresponding QXs. QTOs represent a new class of inhibitors of the NMDA receptor which, when appropriately substituted, are among the most potent glycine site antagonists known.
- Cai, Sui Xiong,Zhou, Zhang-Lin,Huang, Jin-Cheng,Whittemore, Edward R.,Egbuwoku, Zizi O.,Lü, Yixin,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F. W.
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p. 3248 - 3255
(2007/10/03)
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- 4-Carbamoyl-1-benzazepines as antiinflammatory agents
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4-Arylcarbamoyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-diones, e.g. those of the fromula SPC1 R = h, alkyl or aralkyl Ar = iso- or heterocyclic aryl R',r" = h, alkyl, alkanoyl, alkoxy, halogen or CF3 alkali metal or acid addition salts thereof are antiinflammatory agents.
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- 4-Carbamoyl-1-benzazepines
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4-Arylcarbamoyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-diones, e.g. those of the formula SPC1 R = h, alkyl or aralkyl Ar = iso- or heterocyclic aryl R',r" = h, alkyl, alkanoyl, alkoxy, halogen or CF3 alkali metal or acid addition salts thereof are antiinflammatory agents.
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