- NEW SYNTHESIS OF PIPECOLIC ACID AND ANALOGS
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Pipecolic acid congeners are synthesised from α-cyanoamides, obtained by substitution of α-methoxyamides with trimethylsilyl cyanide and in an alternative route via oxidation of amidoalkylationproducts of the α-methoxyamides.
- Asher, Vikram,Becu, Christian,Anteunis, Marc J. O.,Callens, Roland
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- Synthesis and aqueous chemistry of α-acetoxy-N-nitrosomorpholine: Reactive intermediates and products
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α-Acetoxy-N-nitrosomorpholine (7) has been synthesized starting by the anodic oxidation of N-acetylmorpholine in methanol. The 55% yield of N-nitrosomorpholinic acid, after cyanide-for-methoxy group exchange and hydrolysis, is an improvement of ~10-fold over our original 10-step method, and this is readily converted to 7. A study of the kinetics of decomposition of 7 in aqueous media at 25 °C and 1 M ionic strength was conducted over the pH range from 1 to 12. The reaction exhibited good first-order kinetics at all values of pH, and a plot of the log of k0, the buffer-independent rate constant for decomposition, against pH indicated that a pH-independent reaction dominates in the neutral pH region whereas acid- and base-catalyzed reactions dominate in the low and high pH regions, respectively. Reaction at neutral pH in the presence of increasing concentrations of acetate ion results in a decrease in the value of kobsd, to an apparent limiting value consistent with a common-ion inhibition by the capture, and competing base-catalyzed hydration of, an N-nitrosiminium ion intermediate The 100-fold smaller reactivity of 7 at neutral pH compared with its carbon analogue, α-acetoxy-N-nitrosopiperidine, is also consistent with the electronic effects expected for such a reaction. The dinitrophenylhydrazones derived from pH-independent and acid-catalyzed reactions are identical in kind and quantity, within experimental error, to those observed in the decay of α-hydroxy-N-nitrosomorpholine. Decay of 7 in the presence of benzimidazole buffer results in the formation of 2-(2-(1H-benzo[d]imidazol-1-yl)ethoxy) acetaldehyde (12) and 2-(1H-benzo[d]imidazol-1-yl)ethanol (13). Independent synthesis and study of 12 indicates that it is stable at 80 °C in 0.1 M DCl, but it slowly decomposes to 13 in neutral and basic media in a reaction that is stimulated by primary and secondary amines, but not by tertiary amines and carbonate buffer. The benzimidazole trapping studies and those of the stability of 12 indicate the possibility that metabolic activation of N-nitrosomorpholine by hydroxylation α to the nitroso nitrogen can result in the deposition of a metastable ethoxyacetaldehyde adduct on the heteroatoms of DNA.
- Zink, Charles N.,Kim, Hyun-Joong,Fishbein, James C.
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- Compound as apoptosis protein inhibitor, and application thereof
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The present invention belongs to the field of medical chemistry, relates to a class of compounds of apoptosis protein inhibitors, and applications thereof, and particularly provides a compound represented by a formula I, or an isomer thereof, a pharmaceut
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Paragraph 0285; 0287; 0288; 0289
(2018/09/12)
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- DIHYDROPYRIMIDINE COMPOUNDS AND THEIR APPLICATION IN PHARMACEUTICALS
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Provided herein are dihydropyrimidine compounds and their pharmaceutical applications, especially for use in treating and preventing HBV diseases. Specifically,provided herein are compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the variables of the formulas are as defined in the specification. Also provided herein is the use of the compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof for treating and preventing HBV diseases.
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Paragraph 00236; 00238
(2014/03/25)
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- Heterocyclic core analogs of a direct thrombin inhibitor
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Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were p
- Blizzard, Timothy A.,Singh, Sanjay,Patil, Basanagoud,Chidurala, Naresh,Komanduri, Venukrishnan,Debnath, Samarpita,Belyakov, Sergei,Crespo, Alejandro,Struck, Alice,Kurtz, Marc,Wiltsie, Judyann,Shen, Xun,Sonatore, Lisa,Arocho, Marta,Lewis, Dale,Ogletree, Martin,Biftu, Tesfaye
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p. 1111 - 1115
(2014/03/21)
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- Enzymatic synthesis of cyclic amino acids by N-methyl-l-amino acid dehydrogenase from Pseudomonas putida
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A new enzymatic system for the synthesis of enantiomerically pure cyclic amino acids (CAA) from the corresponding diamino acids or racemic CAA is described. α,ω-Diamino acids were oxidized to α-keto acids with amino acid oxidases (AAO). The α-keto acids were spontaneously transformed into cyclic imino acids in the reaction medium. The resulting imines were reduced to the l-form CAA with N-methyl-l-amino acid dehydrogenase (NMAADH) from Pseudomonas putida ATCC12633 using NADPH as a cofactor. l-Form CAA were also obtained from racemic CAA using d-amino-acid oxidase and NMAADH. Using this method, a new compound [1,4]-thiazepane-3-carboxylic acid (Fig. 1) was synthesized from aminopropylcystein.
- Yasuda, Mari,Ueda, Makoto,Muramatsu, Hisashi,Mihara, Hisaaki,Esaki, Nobuyoshi
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p. 1775 - 1779
(2007/10/03)
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