- Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
-
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonyl)-1,5-dimethylquinazoline-2,4(1H,3H)-dione (9bj), displayed excellent potency against AtHPPD, with an IC50 value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC50 = 1359 nM) and 2.7-fold more potent than mesotrione (IC50 = 226 nM). Furthermore, the co-crystal structure of the AtHPPD-9bj complex (PDB ID 6LGT) was determined at a resolution of 1.75 ?. Similar to the existing HPPD inhibitors, compound 9bj formed a bidentate chelating interaction with the metal ion and a π-πstacking interaction with Phe381 and Phe424. In contrast, o-chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds 9aj and 9bi not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.
- Chen, Qiong,Hao, Ge-Fei,He, Bo,Lin, Hong-Yan,Wu, Feng-Xu,Wu, Lei,Yang, Guang-Fu,Yang, Wen-Chao,Yu, Liang-Kun
-
-
Read Online
- Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide
-
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD
- Qu, Ren-Yu,Nan, Jia-Xu,Yan, Yao-Chao,Chen, Qiong,Ndikuryayo, Ferdinand,Wei, Xue-Fang,Yang, Wen-Chao,Lin, Hong-Yan,Yang, Guang-Fu
-
-
Read Online
- Preparation method of 2-methoxy-6-methylbenzoic acid
-
The invention discloses a synthesis process of 2-methoxy-6-methylbenzoic acid, which comprises the following steps: (1) reduction hydrogenation reaction: by taking 2-methyl-6-nitrobenzoic acid or methyl 2-methyl-6-nitrobenzoate as a raw material, methanol as a solvent, hydrogen as a hydrogen source and palladium on carbon or platinum on carbon as a catalyst, carrying out hydrogenation reduction to prepare 2-amino-6-methylbenzoic acid or methyl 2-amino-6-methylbenzoate; (2) diazotization, hydrolysis and esterification one-pot reaction: by taking the reduction product as a raw material, and methanol as a solvent, performing diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent to prepare methyl 2-hydroxy-6-methylbenzoate; (3) methylation reaction: with methyl 2-hydroxy-6-methylbenzoate as a raw material and dimethyl sulfate as a methylation reagent, carrying out methylation reaction in the presence of alkali to prepare methyl 2-methoxy-6-methylbenzoate; and (4) hydrolysis reaction: mixing the methyl 2-methoxy-6-methylbenzoate with alkali and water, conducting heating for hydrolysis, conducting cooling after the reaction is completed, adjusting the pH value to 1-3 by using acid, separating out a product, and conducting filtering and drying to obtain the 2-methoxy-6-methylbenzoic acid.
- -
-
Paragraph 0041; 0048
(2021/07/08)
-
- Compound containing benzotriazinone structure, preparation method and application thereof, and herbicide
-
The invention relates to the field of pesticide compounds, and discloses a compound containing a benzotriazinone structure, a preparation method and application thereof, and a herbicide, and the compound has a structure represented by a formula (I). The c
- -
-
Paragraph 0123-0124; 0126
(2020/12/30)
-
- Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators
-
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.
-
supporting information
p. 8357 - 8363
(2019/09/10)
-
- TETRAZOLINONE COMPOUND AND USE THEREOF
-
The compound represented by formula (1): wherein R4 and R5 each represents a hydrogen atom, a halogen atom, or a C1-C3 alkyl group; R6 represents a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or the like; R7, R8, and R9 each represents a hydrogen atom, a halogen atom, or the like; R10 represents a C1-C3 alkyl group, or the like; R13 represents a C1-C3 alkyl group, or the like; and Q represents a phenyl group, or the like; has an excellent control effect on pests.
- -
-
Paragraph 0811
(2015/11/16)
-
- TETRAZOLINONE COMPOUND AND APPLICATIONS THEREOF
-
Disclosed is a tetrazolinone compound having a high pest control effect and represented by the formula (1): wherein R1, R2, R3, and R11 each represent a halogen atom, a C1-C6 alkyl group, or the like; R4 and R5 each represent a hydrogen atom, a halogen atom, a C1-C3 alkyl group, or the like; R6 represents a C1-C3 alkyl group which may have a halogen atom(s) or the like; R7, R8, and R9 each represent a hydrogen atom, a halogen atom, or the like; R10 represents a C1-C3 alkyl group or the like; R12 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or the like, and R13 represents a C1-C6 alkyl group, a C2-C6 alkenyl group, or the like.
- -
-
Paragraph 0785
(2015/11/24)
-
- Double C(sp3)-H bond functionalization mediated by sequential hydride shift/cyclization process: Diastereoselective construction of polyheterocycles
-
Described herein are two novel types of double C(sp3)-H bond functionalizations triggered by a sequential hydride shift/cyclization process: (1) construction of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and [1,5]-hydride shift sequence and (2) sequential [1,4]- and [1,5]-hydride shift mediated construction of a linear tricyclic skeleton.
- Mori, Keiji,Kurihara, Kazuki,Yabe, Shinnosuke,Yamanaka, Masahiro,Akiyama, Takahiko
-
supporting information
p. 3744 - 3747
(2014/04/03)
-
- TETRAZOLINONE COMPOUNDS AND ITS USE AS PESTICIDES
-
The present invention provides a compound having an excellent efficacy for controlling pests. A tetrazolinone compound of a formula (1): [wherein R1 represents an C6-C16 aryl group, an C1-C12 alkyl group, or a C3-C12 cycloalkyl group, etc., which each optionally be substituted; R2, R3, R4 and R5 represent independently of each other a hydrogen atom, a halogen atom or an C1-C3 alkyl group, etc.; R6 represents an C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen atom, a C1-C6 haloalkyl group, an C2-C6 alkenyl group, an C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, etc.; R7, R8 and R9 represent independently of each other a hydrogen atom, a halogen atom, or an C1-C4 alkyl group, etc.; X represents an oxygen atom or a sulfur atom; and R10 represents an C1-C6 alkyl group, etc.] shows an excellent controlling efficacy on pests.
- -
-
Page/Page column 547
(2013/11/18)
-
- Synthesis of substituted indole from 2-aminobenzaldehyde through [1,2]-aryl shift
-
A mild, efficient, and simple method for the synthesis of 3-ethoxycarbonylindoles has been developed. Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords the indole core. As opposed to other common approaches for the synthesis of indole, this method displays both excellent functional group tolerance and perfect regiochemical control. This allowed the synthesis of a variety of useful indole building blocks from 2-aminobenzaldehydes derived from readily available anthranilic acids.
- Levesque, Patrick,Fournier, Pierre-Andre
-
supporting information; experimental part
p. 7033 - 7036
(2010/11/18)
-
- Total synthesis of the aspercyclides
-
Two different approaches to the eleven-membered biaryl ether lactones of the aspercyclide family are disclosed. The core regions of these highly strained targets, which are able to interfere with the binding of immunoglobulinE to its high affinity receptor, can either be forged by ring-closing olefin metathesis (RCM) or by a highly diastereoselective chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction. Whereas the RCM approach turned out to be responsive to minor changes in the substitution pattern of the substrate, the NHK route is more generally applicable. The preparation of the required cyclization precursor 43 hinged on a palladium-catalyzed orthoiodination reaction of 2-methylbenzoic acid, an efficient copper-catalyzed Ullmann coupling, and a Takai-Utimoto olefination as the key steps. Moreover, the esterification of the 2,6-disubstituted benzoic acid 34 with the sterically hindered secondary alcohol 37 was far from trivial. However, this and related transformations were accomplished by recourse to the corresponding acid fluorides, which provided excellent yields in cases in which the more commonly used acid chlorides or mixed anhydrides failed to afford any of the desiredproducts.
- Pospisil, Jiri,Mueller, Christoph,Fuerstner, Alois
-
scheme or table
p. 5956 - 5968
(2010/03/03)
-
- Parallel synthesis and spectroscopic analysis of a collection of heterocycles based on the diazabenz[e]aceanthrylene core structure
-
A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.
- Jones, Alan M.,Lebl, Tomas,Patterson, Stephen,van Mourik, Tanja,Früchtl, Herbert A.,Philp, Douglas,Slawin, Alexandra M.Z.,Westwood, Nicholas J.
-
supporting information; experimental part
p. 563 - 578
(2009/04/06)
-
- AROMATIC SULFONE COMPOUND AS ALDOSTERONE RECEPTOR MODULATOR
-
The present invention provides a compound represented by the following formula (I): [wherein, A represents a group of the following formula (A-1): etc., R1 and R2 each independently represent a hydrogen atom etc., Z represents CR3 etc., W represents CR4 etc., Q represents CR5 etc., R3, R4 and R5 each independently represent a hydrogen atom etc., Y represents an oxygen atom or sulfur atom, X represents an oxygen atom etc. and B represents an optionally substituted aryl group or optionally substituted heteroaryl group], the prodrug thereof or the pharmaceutically acceptable salt thereof for preventing or treating various diseases such as hypertesion, cerebral stroke, cardiac failure, etc.
- -
-
Page/Page column 27
(2010/11/28)
-
- A diversity oriented synthesis of 2,10-dioxo-10H-1,2,3,4,4a,5-hexahydropyridazino[3,2-b]quinazolines
-
A parallel method for the synthesis of the title compounds is described. Thus, methyl anthranilates (5) are transformed into 2-aminobenzohydrazides (3) which were treated with 4-oxo acids (4) to afford in high yields and acceptable purity of piridazino[3,2-b]quinazolines (1). Compounds (1) present four diversity centers (R1, R2, R3, and R4). The range of chemically acceptable substituents at each center has been evaluated. The isolation of a possible intermediate in the formation of 1, which presents an amino structure (10), has allowed proposing a complete mechanistic rationalization for the formation of structures (1).
- Schuler, Elisabeth,Juanico, Nacho,Teixidó, Jordi,Michelotti, Enrique L.,Borrell, José I.
-
p. 161 - 173
(2007/10/03)
-
- Total synthesis of aspercyclide C
-
The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide. The Royal Society of Chemistry 2005.
- Fuerstner, Alois,Mueller, Christoph
-
p. 5583 - 5585
(2007/10/03)
-
- COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA
-
Compounds of formula I wherein n, m, p, q, Y, R1 R2, R3, R4, R5, and R6 are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating artherosclerosis and its sequelae.
- -
-
Page/Page column 122
(2008/06/13)
-
- Synthesis and spectroscopic characterization of 1-13C- and 4-13C-plastoquinone-9
-
This paper presents the synthesis of 1-13C- and 4-13C-plastoquinone-9 and their characterization with NMR spectroscopy and mass spectrometry. The synthetic scheme has been further adapted to introduce 13C-labeled plastoquinones on all individual and on each combination of positions in the quinone ring. Also a two-step scheme is disclosed to prepare unlabeled plastoquinone-9. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Boers, Rutger B.,Randulfe, Yolanda Pazos,Van Der Haas, Hendrikus N. S.,Van Rossum-Baan, Marleen,Lugtenburg, Johan
-
p. 2094 - 2108
(2007/10/03)
-
- N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors
-
Described are compounds of formula (I), wherein W is O or S; X is NR8; Y is CR9R10-(CH2)n wherein R9 and R10 are independently of each other hydrogen or lower alkyl, and n is an integer of
- -
-
-
- 2-SACCHARINYLMETHYL ARYL CARBOXYLATES USEFUL AS PROTEOLYTIC ENZYME INHIBITORS AND COMPOSITIONS AND METHOD OF USE THEREOF
-
A compound having the formula: STR1 wherein Ar, R 4 and R 5 are defined herein have pharmaceutical utility as proteolytic enzyme inhibitors.
- -
-
-
- 2-SACCHARINYLMETHYL ARYL AND ARYLOXY ACETATES USEFUL AS PROTEOLYTIC ENZYME INHIBITORS
-
4-R 4--R 5-2-Saccharinylmethyl aryl and aryloxy acetates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R. sup.4--R 5-2-halomethylsaccharin with an aryl or aryloxyacetic acid in the presence of an acid-acceptor.
- -
-
-
- 2-SACCHARINYLMETHYL PHOSPHATES, PHOSPHONATES AND PHOSPHINATES USEFUL AS PROTEOLYTIC ENZYME INHIBITORS AND COMPOSITIONS AND METHOD OF USE THEREOF
-
4-R 1-R 2-R 3-2-Saccharinylmethyl and 4,7-C-4,5, 6,7-tetrahydro-2-saccharinylmethyl phosphates, phosphonates and phosphinates of formulas I and IIA respectively herein, useful in the treatment of degenerative diseases, and compositions containing them, methods for using them to treat degenerative diseases, and processes for their preparation by reaction of the corresponding 2-halomethylsaccharins with a phosphate, phosphonate or phosphinic acid of formula III herein in the presence of an acid-acceptor.
- -
-
-
- 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically Active Anticonvulsants Acting by Antagonism at the Glycine Site of the N-Methyl-D-Aspartate Receptor Complex
-
Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier.By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one.In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 for displacement of -L-689,560 binding of 0.17 μM and Kb against NMDA in the cortical slice of 1.39 μM.Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip.A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the ?-system of the 3-substituent.
- Rowley, Michael,Leeson, Paul D.,Stevenson, Graeme I.,Moseley, Angela M.,Stansfield, Ian,et al.
-
p. 3386 - 3396
(2007/10/02)
-
- Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof
-
Novel 2-substituted saccharins which inhibit the enzymatic activity of proteolytic enzymes, are useful in the treatment of degenerative diseases and have the formula STR1 wherein: L is --O--, --S--, --SO-- or --SO2 --; m and n are each independently 0 or 1; R1 is halo, lower-alkanoyl, 1-oxophenalenyl, phenyl or substituted phenyl, heterocyclyl or substituted heterocyclyl or, when L is --O-- and n is 1, cycloheptatrienon-2-yl or, when L is --S-- and n is 1, cyano or lower-alkoxythiocarbonyl or, when L is --SO2 -- and n is 1, lower-alkyl or trifluoromethyl; R2 is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; and R3 and R4 are each hydrogen or various substituents and processes for preparation and pharmaceutical compositions and method of use thereof are disclosed.
- -
-
-
- 2-SACCHARINYLMETHYL AND 4,5,6,7-TETRAHYDRO-2-SACCHARINYLMETHYL PHOSPHATES, PHOSPHONATES AND PHOSPHINATES USEFUL AS PROTEOLYTIC ENZYME INHIBITORS AND COMPOSITIONS AND METHOD OF USE THEREOF
-
4-R 1-R 2-R 3-2-Saccharinylmethyl, 4-R 4-4-R 5-6-R 6-4,5,6,7-tetrahydro-2-saccharinylmethyl and 4,7-C-4,5, 6,7-tetrahydro-2-saccharinylmethyl phosphates, phosphonates and phosphinates of formulas I, II and IIA respectively herein, useful in the treatment of degenerative diseases, and compositions containing them, methods for using them to treat degenerative diseases, and processes for their preparation by reaction of the corresponding 2-halomethylsaccharins with a phosphate, phosphonate or phosphinic acid of formula III herein in the presence of an acid-acceptor.
- -
-
-
- PROTEOLYTIC ENZYME INHIBITION METHOD
-
4-R 4-R 5-2-Saccharinylmethyl aryl carboxylates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R. sup.4-R 5-2-halomethylsaccharin with an arylcarboxylic acid in the presence of an acid-acceptor.
- -
-
-