- Synthesis of cytotoxic 1,3,4-trisubstituted 2-azetidinones
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A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones were synthesized in order to study the relation between their structure and biological characteristics. Study of the cytotoxic activity of these compounds revealed an anticancer effect
- Veinberg,Bokaldere,Dikovskaya,Vorona,Kanepe,Shestakova,Yashchenko,Lukevics
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- 3-Aminoazetidin-2-one derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors suitable for systemic administration
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N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, preventing PEA degradation by inhibiting NAAA may provide a novel approach for the treatment of pain and inflammatory states. Recently, 3-aminooxetan-2-one compounds were identified as a class of highly potent NAAA inhibitors. The utility of these compounds is limited, however, by their low chemical and plasma stabilities. In the present study, we synthesized and tested a series of N-(2-oxoazetidin-3-yl)amides as a novel class of NAAA inhibitors with good potency and improved physicochemical properties, suitable for systemic administration. Moreover, we elucidated the main structural features of 3-aminoazetidin-2-one derivatives that are critical for NAAA inhibition. Stability is the key: α-Amino-β-lactams were synthesized as amide derivatives, and the effect of the azetidin-2-one ring, the stereochemistry at the α-position, and the functionalization of the α-amino group were studied with regard to N-acylethanolamine acid amidase inhibitory potency and hydrolytic and plasma stability.
- Fiasella, Annalisa,Nuzzi, Andrea,Summa, Maria,Armirotti, Andrea,Tarozzo, Glauco,Tarzia, Giorgio,Mor, Marco,Bertozzi, Fabio,Bandiera, Tiziano,Piomelli, Daniele
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supporting information
p. 1602 - 1614
(2014/07/21)
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- CARBAMATE DERIVATIVES OF LACTAM BASED N-ACYLETHANOLAMINE ACID AMIDASE (NAAA) INHIBITORS
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Described herein are compounds and pharmaceutical compositions which inhibit N-acylethanolamine acid amidase (NAAA). Described herein are methods for synthesizing the compounds set forth herein and methods for formulating these compounds as pharmaceutical compositions which include these compounds. Also described herein are methods of inhibiting NAAA in order to sustain the levels of palmitoylethanolamide (PEA) and other N-acylethanolamines (NAE) that are substrates for NAAA, in conditions characterized by reduced concentrations of NAE. Also, described here are methods of treating and ameliorating pain, inflammation, inflammatory diseases, and other disorders in which modulation of fatty acid ethanolamides is clinically or therapeutically relevant or in which decreased levels of NAE are associated with the disorder.
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Paragraph 0295; 0296
(2014/09/29)
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- MONOCARBAMS
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The invention relates to compounds of formula (I): wherein R1, R2, R3, R4, Rs, and R6 as defined herein. The invention also relates to pharmaceutical compositions and methods of treating bacterial infections using compounds of formula (I)
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Page/Page column 15
(2010/07/04)
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- Serine and threonine β-lactones: A new class of hepatitis A virus 3C cysteine proteinase inhibitors
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Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and infectivity and represents a target for the development of antiviral drugs. A number of serine and threonine β-lactones were synthesized and tested against HAV 3C proteinase. The D-N-Cbz-serine β-lactone 5a displays competitive reversible inhibition with a Ki value of 1.50 × 10-6 M. Its enantiomer, L-N-Cbz-serine β-lactone 5b is an irreversible inactivator with kinact = 0.70 min-1, KI = 1.84 × 10-4 M and kinact/KI = 3800 M-1 min-1. Mass spectrometry and HMQC NMR studies using 13C-labeled 5b show that inactivation of the enzyme occurs by nucleophilic attack of the cysteine thiol (Cys-172) at the β-position of the oxetanone ring. Although the N-Cbz-serine β-lactones 5a and 5b display potent inhibition, other related analogues with an N-Cbz side chain, such as the five-membered ring homoserine γ-lactones 14a and 14b, the four-membered ring β-lactam 33, 2-methylene oxetane 34, cyclobutanone 36, and 3-azetidinone 39, fail to give significant inhibition of HAV 3C proteinase, thus demonstrating the importance of the β-lactone ring for binding.
- Lall, Manjinder S.,Ramtohul, Yeeman K.,James, Michael N.G.,Vederas, John C.
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p. 1536 - 1547
(2007/10/03)
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- Solid-Phase Synthesis of β-Lactams via the Miller Hydroxamate Approach
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(Matrix Presented) β-Lactams were prepared on solid phase starting from serine, threonine, or other β-hydroxyacids derived from naturally occurring amino acids and a resin bound hydroxylamine. The ring closure was carried out under Mitsunobu conditions. The amino group present on the β-lactam was used to assemble a short peptide. After a reductive cleavage with Sml2, β-lactam-containing peptides were obtained.
- Meloni, Marco Massimiliano,Taddei, Maurizio
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p. 337 - 340
(2007/10/03)
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- Penicillin G acylase mediated synthesis of the enantiopure (S)-3-amino-azetidinl-2-one
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A detailed study of the influence of temperature, pH and enzyme amount on the enantiomeric excess in the enzymatic resolution of N-1 protected 3-amino-azetidin-2-ones with supported PGA is presented. Both enantiomers could be obtained in good enantiomeric
- Cainelli, Gianfranco,Giacomini, Daria,Galletti, Paola,DaCol, Marco
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p. 3231 - 3235
(2007/10/03)
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- Reduction process for the preparation of 4-unsubstituted azetidin-2-ones
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Novel process for the preparation of azetidin-2-ones of the formula STR1 wherein R1 and R2 independently from each other are hydrogen, or an organic group linked to the ring carbon via a carbon atom, a nitrogen atom or an oxygen atom, characterized in that a corresponding 4-acyloxyazetidin-2-one, which is substituted by a group --O--CO--R3 at the 4-position, wherein R3 is hydrogen or an organic radical stable at the reaction conditions, is reacted with a complex metal hydride comprising reactive hydride ions, such as, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride or tetraorganoammonium borohydride.
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- Desulfonation process for preparing 2-azetidinones
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A compound having the formula STR1 can be prepared by heating an anion having the formula STR2 with a cation having the formula STR3 or a cation having the formula STR4
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- A NOVEL PREPARATION OF 4-UNSUBSTITUTED β-LACTAMS
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The key intermediate (1) for monobacyam synthesis has been prepared from 6-aminopenicillanic acid (6-APA) without using Raney nickel.Desulfurization was accomplished by a two step process, involving a novel reduction reaction.
- Pfaendler, Hans Rudolf,Hoppe, Heike
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p. 265 - 272
(2007/10/02)
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- Synthesis and antibacterial activity of 3-acylamino-2-azetidinone-1-sulfonic acid derivatives
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Sulfazecin is a monocyclic β-lactam antibiotic isolated from strain G-6302, Pseudomonas acidophila. As a key intermediate for the synthesis of sulfazecin derivatives, 3-amino-2-azetidinone was synthesized from penicillins, and various new compounds were s
- Matsuo,Sugawara,Masuya,Kawano,Noguchi,Ochiai
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p. 1874 - 1884
(2007/10/02)
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- 4-alkylated monobactams. Chiral synthesis and antibacterial activity
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The synthesis of 4-alkylated monobactams by a variety of procedures is described. Two complementary procedures have been developed for the chiral synthesis of monobactams: (1) sulfonation of 4-alkyl-3-(protected)amino-2-azetidinones with various complexes of SO3; and (2) cyclization of β-mesyloxyacyl sulfamates derived from β-alkyl-β-hydroxy-α-amino acids. The most general procedure involves introduction of the alkyl group via a Grignard reaction on 6-APA-derived sulfones 23 or 24 followed by sulfonation. For the specific case of (3S,trans-)-3-amino-4-methylmonobactamic acid (48), cyclization of the β-mesyloxyacyl sulfamate 40 derived from (L)-threonine is the preferred route. The introduction of 4-alkyl groups into monobactams results in a decrease in activity against gram-positive bacteria, an increase in activity against gram-negative bacteria, and an increase in β-lactamase stability. Increasing the size of the alkyl group beyond methyl results in diminished intrinsic antibacterial activity. 4β-Alkylmonobactams display better β-lactamase stability than their 4α-counterparts.
- Cimarusti,Bonner,Breuer,et al.
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p. 2577 - 2589
(2007/10/02)
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- Practical synthetic approaches to intermediates for the preparations of the novel O-sulfonated-N-hydroxy-2-azetidinone antibiotics
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A practical synthesis of intermediates useful for the preparation of a variety of monocyclic β-lactam antibiotics is described. Hydroxaminolysis of N-protected serine esters provided the hydroxamic acids 10. Acylation followed by cyclization yielded the β
- Miller,Biswas,Krook
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p. 2571 - 2575
(2007/10/02)
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