200643-77-2Relevant articles and documents
SELECTIVE INHIBITORS OF NLRP3 INFLAMMASOME
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Paragraph 0542, (2019/02/15)
The present disclosure relates to compounds of Formula (I): (I); and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as autoinflammatory and autoimmune diseases and cancers.
BIARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS
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Page/Page column 49, (2017/07/06)
The present invention relates to biaryl monobactam compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A1, Q, A2, M, W, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt therof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.
BICYCLIC ARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS
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Page/Page column 59, (2017/09/27)
The present invention relates to bicyclic aryl monobactam compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein A1, L, M, W, X, Y, Z, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a bicyclic aryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of one or more beta-lactamase inhibitor compounds.
Cis-Dihydroxylation of electron deficient olefins catalysed by an oxo-bridged diiron(III) complex with H2O2
Kejriwal, Ambica,Biswas, Sachidulal,Biswas, Achintesh N.,Bandyopadhyay, Pinaki
, p. 77 - 84 (2016/01/09)
Room temperature oxidation of olefins catalysed by a symmetrical (μ-oxo)(μ-hydroxo)diiron(III) complex (1) based on the amino pyridyl ligand bpmen (bpmen = N,N′-dimethyl-N,N′-bis(2-pyridyl methyl)ethane-1,2-diamine) with hydrogen peroxide under the conditions of limiting substrate is described. Excellent substrate conversions have been achieved under ambient reaction conditions. The olefin oxidation efficacy of the 1/H2O2 system has been found to get improved in presence of acetic acid. The catalytic system has been shown to oxidise electron-deficient olefins to the corresponding cis-diols, while epoxidation is favoured in case of electron-rich olefins. The μ-oxo diiron(III) core of the catalyst 1 has been found be regenerated after the catalytic turnovers. Addition of a second batch of substrate and oxidant at the end of the olefin oxidation results in the formation of almost identical amounts of epoxides/diols. Moreover, the regenerated catalyst exhibits a significantly higher preference towards the oxidation of electron-deficient olefins.
The crystal structure of an LLL-configured depsipeptide substrate analogue bound to isopenicillin N synthase
Ge, Wei,Clifton, Ian J.,Stok, Jeanette E.,Adlington, Robert M.,Baldwin, Jack E.,Rutledge, Peter J.
scheme or table, p. 122 - 127 (2010/04/06)
Isopenicillin N synthase (IPNS) is a non-heme iron(II) oxidase, which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide δ-L-α-aminoadipoyl-L-cysteinyl-D-valine (LLD-ACV) in a remarkable oxidative bicyclisation reaction. The natural substrate for IPNS is the LLD-configured tripeptide. LLL-ACV is not turned over by the enzyme, but inhibits turnover of the LLD-tripeptide. The mechanism by which this inhibition takes place is not fully understood. Recent studies have employed a range of LLD-configured depsipeptide substrate analogues in crystallographic studies to probe events preceding β-lactam closure in the IPNS reaction cycle. Herein, we report the first crystal structure of IPNS in complex with an LLL-configured depsipeptide analogue, δ-L-α-aminoadipoyl-L-cysteine (1-(-R)-carboxy-2-thiomethyl)ethyl ester (LLL-ACOmC). This report describes the crystal structure of the IPNS:Fe(II):LLL-ACOmC complex to 2.0 A resolution, and discusses attempts to oxygenate this complex at high pressure in order to probe the mechanism by which LLL-configured substrates inhibit IPNS catalysis. The Royal Society of Chemistry 2010.
Isopenicillin N synthase mediates thiolate oxidation to sulfenate in a depsipeptide substrate analogue: Implications for oxygen binding and a link to nitrile hydratase?
Ge, Wei,Clifton, Ian J.,Stok, Jeanette E.,Adlington, Robert M.,Baldwin, Jack E.,Rutledge, Peter J.
supporting information; experimental part, p. 10096 - 10102 (2009/02/03)
Isopenicillin N synthase (IPNS) is a nonheme iron oxidase that catalyzes the central step in the biosynthesis of β-lactam antibiotics: oxidative cyclization of the linear tripeptide δ-L-α-aminoadipoyl-L-cysteinyl- D-valine (ACV) to isopenicillin N (IPN). The ACV analogue δ-L-α- aminoadipoyl-L-cysteine (1-(S)-carboxy-2-thiomethyl)ethyl ester (ACOmC) has been synthesized as a mechanistic probe of IPNS catalysis and crystallized with the enzyme. The crystal structure of the anaerobic IPNS/Fe(II)/ACOmC complex was determined to 1.80 A resolution, revealing a highly congested active site region. By exposing these anaerobically grown crystals to high-pressure oxygen gas, an unexpected sulfenate product has been observed, complexed to iron within the IPNS active site. A mechanism is proposed for formation of the sulfenate-iron complex, and it appears that ACOmC follows a different reaction pathway at the earliest stages of its reaction with IPNS. Thus it seems that oxygen (the cosubstrate) binds in a different site to that observed in previous studies with IPNS, displacing a water ligand from iron in the process. The iron-mediated conversion of metal-bound thiolate to sulfenate has not previously been observed in crystallography studies with IPNS. This mode of reactivity is of particular interest when considered in the context of another family of nonheme iron enzymes, the nitrile hydratases, in which post-translational oxidation of two cysteine thiolates to sulfenic and sulfinic acids is essential for enzyme activity.
Iron-catalyzed asymmetric olefin cis-dihydroxylation with 97% enantiomeric excess
Suzuki, Ken,Oldenburg, Paul D.,Que Jr., Lawrence
, p. 1887 - 1889 (2008/12/22)
Big cis-ster: The use of an (R,R)-bipyrrolidine backbone with two α-methylpyridine pendant arms affords a tetradentate N4 ligand that coordinates an iron center with cis-α topology (see picture; Fe purple, C gray, N blue, O red, S yellow, F green). This complex catalyzes the reaction between H2O2 and cis-2-heptene to afford a cis-diol product in very high enantioselectivity. (Figure Presented)
Iron-catalyzed olefin epoxidation in the presence of acetic acid: Insights into the nature of the metal-based oxidant
Mas-Balleste, Ruben,Que Jr., Lawrence
, p. 15964 - 15972 (2008/09/18)
The iron complexes [(BPMEN)Fe(OTf)2] (1) and [(TPA)Fe(OTf) 2] (2) [BPMEN = N,N′-bis-(2-pyridylmethyl)-N,N′-dimethyl- 1,2-ethylenediamine; TPA = tris-(2-pyridylmethyl)amine] catalyze the oxidation of olefins by H2O2 to yield epoxides and cis-diols. The addition of acetic acid inhibits olefin cis-dihydroxylation and enhances epoxidation for both 1 and 2. Reactions carried out at 0°C with 0.5 mol % catalyst and a 1:1.5 olefin/H2O2 ratio in a 1:2 CH 3CN/CH3COOH solvent mixture result in nearly quantitative conversions of cyclooctene to epoxide within 1 min. The nature of the active species formed in the presence of acetic acid has been probed at low temperature. For 2, in the absence of substrate, [(TPA)FeIII(OOH) (CH3COOH)]2+ and [(TPA)FeIVO(NCCH 3)]2+ intermediates can be observed. However, neither is the active epoxidizing species. In fact, [(TPA)FeIVO(NCCH 3)]2+ is shown to form in competition with substrate oxidation. Consequently, it is proposed that epoxidation is mediated by [(TPA)FeV(O)(OOCCH3)]2+, generated from O-O bond heterolysis of the [(TPA)FeIII(OOH)(CH3COOH)] 2+ intermediate, which is promoted by the protonation of the terminal oxygen atom of the hydroperoxide by the coordinated carboxylic acid.
Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient
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, (2008/06/13)
Pharmaceutical composition containing aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (1) and the salts thereof as active ingredient (wherein R1is H, alkyl; R2is COOR7, CONHOR8; E is —CONR9—, —NR9CO—, —OCO—,—COO—, —CH2—O—, —(CH2)2—, vinylene, ethynylene; J is bond, alkylene; A is H, alkyl, Ar, alkyl-OH ; R3, R4is H, alkyl, COOR19, hydroxy, —NR20R21, Ar1etc.); R5, R6is H, methyl) and the novel aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (I). The compounds of the formula (I) have inhibitory activity against matrix metalloproteinases, therefore, the compounds of the formula (I) are useful for prevention and/or treatment of rheumatoid diseases, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, autoimmune diseases, diseases caused by vascular emigration or infiltration of leukocytes, arterialization etc.
A stereocontrolled approach to electrophilic epoxides
Meth-Cohn, Otto,Moore, Clive,Taljaard, Heinrich C.
, p. 2663 - 2674 (2007/10/02)
Lithium t-butyl hydroperoxide (easily generated by addition of an alkyl-lithium to anhydrous t-butyl hydroperoxide in THF solution) is a powerful reagent for the epoxidation of electrophilic alkenes at -20 to 0 °C under full stereocontrol. Thus αβ-unsaturated esters, sulphones, sulphoximines, and amides are readily epoxidised with complete regio- and stereo-specificity and with considerable chiroselectivity (20-100%) when appropriate chiral auxiliaries such as menthyl, 8-phenylmenthyl, or a camphor-sulphonamide derivative are used. Asymmetric αβ-unsaturated sulphoximines undergo epoxidation with 100% diastereoselectivity. The only exceptions to stereocontrol noted are heavily substituted maleate esters such as di-t-butyl maleate. The αβ-epoxy amides are shown to be valuable sources of the corresponding epoxy ketones by treatment with an organolithium, allowing a stereo- and chemoselective entry in high yield to these useful intermediates.
