- Conversion of a nitrosocarbonyl hetero Diels-Alder cycloadduct to useful isoxazoline-carbocyclic aminols
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A new approach to useful precursors for the synthesis of isoxazoline-carbocyclic nucleosides is detailed, starting from the readily available N-benzoyl-2,3-oxazanorborn-5-ene and introducing more polar and hydrophilic functionalities through 1,3-dipolar cycloaddition of carbethoxyformonitrile oxide, generated either from the corresponding hydroximoyl chloride or, more conveniently, by catalyzed condensation with ethyl nitroacetate.
- Quadrelli, Paolo,Bovio, Bruna,Piccinini, Achille,Caramella, Pierluigi,De Sarlo, Francesco,Machetti, Fabrizio
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Read Online
- Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses
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Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC50 values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.
- Egorova, Anna,Ekins, Sean,Jahn, Birgit,Kazakova, Elena,Makarov, Vadim,Schmidtke, Michaela
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- Synthesizing method of isoxadifen-ethyl for industrialized production
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The invention provides a synthesizing method of isoxadifen-ethyl for industrialized production. The synthesizing method comprises the following steps of using chlorobenzene as a raw material, using tetrahydrofuran as a solvent, and reacting with magnesium, so as to obtain a phenyl magnesium chloride Grignard reagent; performing nucleophilic addition reaction with acetophenone to generate 1,1-diphenylethanol; adding p-toluenesulfonic acid to dewater, so as to generate 1,1-diphenylethene; reacting with ethyl 2-chloro-2-(hydroxyimino)acetate, so as to generate an isoxadifen-ethyl product, whereinthe purity can reach 99%.
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Paragraph 0024; 0027; 0029; 0038
(2018/09/12)
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- Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles
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Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.
- Kesornpun, Chatchai,Aree, Thammarat,Mahidol, Chulabhorn,Ruchirawat, Somsak,Kittakoop, Prasat
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supporting information
p. 3997 - 4001
(2016/03/19)
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- CENTRALLY ACTIVE AND ORALLY BIOAVAILABLE ANTIDOTES FOR ORGANOPHOSPHATE EXPOSURE AND METHODS FOR MAKING AND USING THEM
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In alternative embodiments, the invention provides nucleophilic hydroxyimino- acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino- acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi- chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.
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Page/Page column 52
(2014/09/03)
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are isoform selective histone deacetylase inhibitors of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds are isoform selective inhibitors of HDACs and are useful as a therapeutic or ameliorating agent for diseases that are involved in cellular growth such as cancer, malignant tumors, autoimmune diseases, skin diseases, fungal infections, protozoal infections, HIV, inflammation and CNS disorders.
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Page/Page column 40-41
(2012/09/21)
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- POLYMERIZABLE COMPOSITION COMPRISING AN OXIME SULFONATE AS THERMAL CURING AGENT
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The present invention relates to a polymerizable composition comprising at least one ethylenically unsaturated, polymerizable compound and at least one oxime sulfonate compound of the formula (I) QAaBbCc where a is 0, 1, 2
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Page/Page column 127
(2012/08/08)
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- Synthesis and biological evaluation of novel GSK-3β inhibitors as anticancer agents
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A series of isoxazol-indolin-2-one was designed for GSK-3β inhibitors as novel anticancer agents based on their binding mode analysis in GSK-3β crystal structure. Total 21 compounds were synthesized and evaluated for their inhibitory activity against two tumor cell lines (DU145 and HT29). Most of the synthesized compounds were potent with above 80% inhibitory activity at 100 μM, and several compounds were examined for inhibitory activity against GSK-3β. Among them, 15(Z) (R1=H, R2=3-Cl-phenyl) was most active with 78% inhibition of tumor cell line (HT29) at 20 μM and 72% inhibition of GSK-3β at 20 μM.
- Choi, Min Jeong,Oh, Da Won,Jang, Jae Wan,Cho, Yong Seo,Seo, Seon Hee,Jeong, Kyu Sung,Ko, Soo Young,Pae, Ae Nim
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scheme or table
p. 2015 - 2020
(2012/01/06)
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- Suzuki-Miyaura cross-coupling of benzylic bromides under microwave conditions
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A procedure for benzylic Suzuki-Miyaura cross-coupling under microwave conditions has been developed. These conditions allowed for heterocyclic compounds to be coupled. Optimum conditions found were Pd(OAc)2, JohnPhos as the catalyst and ligand
- McDaniel, Steven W.,Keyari, Charles M.,Rider, Kevin C.,Natale, Nicholas R.,Diaz, Philippe
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supporting information; experimental part
p. 5656 - 5658
(2011/11/06)
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- HETEROCYCLIC INHIBITORS OF HISTAMINE RECEPTORS FOR THE TREATMENT OF DISEASE
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The present invention relates to compounds and methods which may be useful as inhibitors of H1R and/or H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
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Page/Page column 215
(2011/10/05)
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- Novel isoxazolinyl spiropyrrolidinediones: 1,3-dipolar cycloaddition of 1-benzyl-3,3-dimethyl-5-methylenepyrrolidin-2,4-dione
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A simple and highly efficient methodology for the first synthesis of isoxazolinyl spiropyrrolidinedione starting from keto ester, is presented. Georg Thieme Verlag Stuttgart - New York.
- Bathich, Yaser,Syed Monudeen Khan, Sharifah Edayu Binti,Hamzah, Ahmad Sazali
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supporting information; experimental part
p. 1154 - 1156
(2011/07/09)
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- Scale-up of a chemo-biocatalytic route to (2 R,4 R)- and (2 S,4 S)-monatin
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Monatin, a natural sweetener, refers to a collection of four isomers of 2-((1H-indol-3-yl)methyl)-4-amino-2-hydroxypentanedioic acid. A chemo-biocatalytic approach to kilogram quantities of enantiopure 2S,4S-monatin and 2R,4R-monatin from indole is described. Key steps in the process include a (2 + 3) cycloaddition reaction followed by nickel-catalysed reduction to construct the monatin backbone, and a highly selective enzyme resolution of the 2S,4S- and 2R,4R-monatin diastereomeric pair to afford each enantiomer in 99% ee.
- Rousseau, Amanda L.,Buddoo, Subash R.,Gordon, Gregory E. R.,Beemadu, Sharon,Kupi, B. Godfrey,Lepuru, M. Jerry,Maumela, Munaka C.,Parsoo, Arvesh,Sibiya, Duncan M.,Brady, Dean
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experimental part
p. 249 - 257
(2011/10/02)
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- New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases
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We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2- hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mM compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of3 human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/Kox) and maximum reactivation rate (k2), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.
- Sit, Rakesh K.,Radic, Zoran,Gerardi, Valeria,Zhang, Limin,Garcia, Edzna,Katalinic, Maja,Amitai, Gabriel,Kovarik, Zrinka,Fokin, Valery V.,Sharpless, K. Barry,Taylor, Palmer
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scheme or table
p. 19422 - 19430
(2012/04/10)
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- HYDROXAMIC ACID DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS
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The invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, thereof, wherein: G is a group of formula (II); and pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, thereof, wherein A, B. L1-L4 A, B, R1-R4 and m are as defined herein. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and their use in treating a bacterial infection.
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Page/Page column 85
(2010/04/25)
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- HETEROCYCLIC INHIBITORS OF HISTAMINE RECEPTORS FOR THE TREATMENT OF DISEASE
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The present invention relates to compounds and methods which may be useful as inhibitors of H1R and/or H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
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Page/Page column 102
(2010/06/11)
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- Synthesis of new aza-bicyclic 2-isoxazolines by 1,3-dipolar cycloaddition of endocyclic enecarbamates and enamides with nitrile oxides
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Novel aza-bicyclic 2-isoxazolines, 4,5-dihydroisoxazole[5,4-b]pyrrolidines, and 4,5-dihydroisoxazole[5,4-b]piperidines were synthesized in a highly regioselective manner through a 1,3-dipolar cycloaddition reaction of 5- and 6-membered endocyclic enecarba
- de Almeida, Valderes Moraes,dos Santos, Rosiel José,da Silva Góes, Alexandre José,de Lima, José Gildo,Duarte Correia, Carlos Roque,de Faria, Ant?nio Rodolfo
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body text
p. 684 - 687
(2011/02/28)
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- HETEROCYCLIC COMPOUNDS AS ADENOSINE RECEPTOR ANTAGONIST
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Compounds of the present disclosure are fused pyrimidine compounds of formula (I), its tautomers, polymorphs, stereoisomers, prodrugs, solvate or a pharmaceutically acceptable salts thereof, as Adenosine receptor antagonists. Processes of their preparation are also described in the disclosure.
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Page/Page column 113
(2009/10/22)
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- PRODUCTION OF MONATIN ENANTIOMERS
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Methods for the preparation of the high intensity sweetener, monatin, 3-(1-amino-1,3-dicarboxy-3-hydroxy-but-4-yl)indole, its salts and internal condensation products thereof, including methods applicable to the large-scale production of monatin are described.
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Page/Page column 9-10; sheet 1; 4
(2009/04/24)
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- Preparation of novel antibacterial agents. Replacement of the central aromatic ring with heterocycles
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Discovery of novel antibacterial agents is a significant challenge. We have recently reported on our discovery of novel antibacterial agents in which we have rapidly optimized potency utilizing a parallel chemistry approach. These advanced leads suffer from high affinity for human serum albumin (HSA). In an effort to decrease the affinity for HSA we have prepared a series of heterocyclic analogs, which retained antibacterial activity and demonstrated reduced affinity for HSA.
- Li, Jianke,Wakefield, Brian D.,Ruble, J. Craig,Stiff, Cory M.,Romero, Donna L.,Marotti, Keith R.,Sweeney, Michael T.,Zurenko, Gary E.,Rohrer, Douglas C.,Thorarensen, Atli
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p. 2347 - 2350
(2008/12/21)
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- Substituted piperazines as metabotropic glutamate receptor antagonists
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The invention relates to compounds of formula I or pharmaceutically acceptable salts or solvates thereof: where Ar1, Ar2, Hy, L, R1, m and n are as defined in the description. The invention also includes pharmaceutical compositions and uses thereof, processes for making the compounds, as well as methods for the medical treatment of mGluR5-mediated disorders.
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Page/Page column 16
(2008/06/13)
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- A novel cleavage for polystyrene-supported selenium resins: An efficient route to 3,5-disubstituted isoxazolines and their derivatives
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We report here a novel cleavage method for polystyrene-supported selenium resin using CH3I-NaI under mild conditions to prepare 3,5-disubstituted isoxazolines. The polymer selenium resins can be reused without further transformation. Georg Thie
- Xu, Wei-Ming,Wang, Yu-Guang,Miao, Mao-Zhong,Huang, Xian
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p. 2143 - 2146
(2007/10/03)
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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- An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate
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Ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate was smoothly lithiated at the 5-methyl position, when the 4-acetyl group was protected with a 5,5-dimethyl-1,3-dioxanyl group. The lithio anion was quenched with a variety of electrophiles such as alkyl halides, aldehydes, TMSCl, and Me3SnCl in good to excellent yields. The lithiation of the unprotected compound and the 4-acetyl group protected as 1,3-dioxolanyl both failed. The effects of different bases have been investigated and the addition of LiCl significantly increased yields. Based on variable temperature NMR studies the 5,5-dimethyl-1,3-dioxanyl group appears to occupy a single chair conformation which may facilitate lateral metalation. This represents a facile entry into 5-functionalized 3-isoxazolyl carboxylic acid derivatives as prodrugs for the AMPA glutamate neurotransmitters of the central nervous system.
- Burkhart, David J.,Zhou, Peiwen,Blumenfeld, Alex,Twamley, Brendan,Natale, Nicholas R.
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p. 8039 - 8046
(2007/10/03)
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- An alternative isoxazole route to α-alkoxycarbonyl-β-diketones
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Cycloaddition of oxygen-functionalized nitrite oxides to the enamine from ethyl acetoacetate produces 4-ethoxycarbonyl-5-methylisoxazoles carrying a 3-tetrahydropyranyloxymethyl, 3-diethoxymethyl or 3-ethoxycarbonyl substituent; the 3-formylisoxazole is prepared from the former two and condensed in situ with phosphoranes to give 3-alkenylisoxazoles that are cleaved by hexacarbonylmolybdenum or hydrogenolysis to afford α-alkoxycarbonyl-β-diketones.
- Jones, Raymond C. F.,Dunn, Stephen H.,Duller, Kathryn A. M.
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p. 1319 - 1321
(2007/10/03)
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- Methods for the Stereoselective Cis Cyanohydroxylation and Carboxyhydroxylation of Olefins
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Two valuable reagents for the cis-specific vicinal cyanohydroxylation and carboxyhydroxylation of olefins are described.The cyanohydroxylation process is based on the decarboxylative ring opening of 3-carboxyisoxazolines prepared by the cycloaddition reaction of carbethoxyformonitrile oxide with various alkenes.Fragmentation of the isoxazolines prepared from cis- and trans-2-butene has been found to occur without any crossover in stereochemistry.The carboxyhydroxylation process begins with the dipolar cycloaddition reaction of the nitrile oxide derived from thetetrahydropyranyl ether derivative of 2-nitroethanol.Deprotection, hydrogenation, and oxitative cleavage of the derived dihydroxy ketone yield the stereochemcally pure β-hydroxy carboxylic acid.
- Kozikowski, Alan P.,Adamczyk, Maciej
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p. 366 - 372
(2007/10/02)
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- Process for the production of lower alkyl 2-chloro-2-hydroxyiminoacetates
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Lower alkyl 2-chloro-2-hydroxyiminoacetates are produced by (A) reacting chloral with a lower alkanol and a hydroxylamine salt in the presence of a Lewis acid or a metal oxide which is convertible into said Lewis acid during the course of the reaction to give a lower alkyl 2-hydroxyiminoacetate and then chlorinating the resulting product or (B) reacting chloral oxime with a lower alkanol in the presence of a base to give a lower alkyl 2-hydroxyiminoacetate and finally chlorinating the thus formed product.
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