- The synthesis of γ-Substituted Glutamic Acids via a Glutamic Acid γ-Enolate Synthon.
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Treatment of α-t-butyl γ-methyl N-Z-glutamate (4) with lithium hexamethyldisilazide results in the regiospecific formation of the γ-anion, which reacts with electrophiles to give γ-substituted glutamic acid derivatives.
- Johnstone, Andrew N. C.,Lopatriello, Stefania,North, Michael
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Read Online
- The Discovery of Conformationally Constrained Bicyclic Peptidomimetics as Potent Hepatitis C NS5A Inhibitors
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HCV NS5A inhibitors are the backbone of directly acting antiviral treatments against the hepatitis C virus (HCV). While these therapies are generally highly curative, they are less effective in some specific HCV patient populations. In the search for broader-acting HCV NS5A inhibitors that address these needs, we explored conformational restrictions imposed by the [7,5]-azabicyclic lactam moiety incorporated into daclatasvir (1) and related HCV NS5A inhibitors. Unexpectedly, compound 5 was identified as a potent HCV genotype 1a and 1b inhibitor. Molecular modeling of 5 bound to HCV genotype 1a suggested that the use of the conformationally restricted lactam moiety might have resulted in reorientation of its N-terminal carbamate to expose a new interaction with the NS5A pocket located between amino acids P97 and Y93, which was not easily accessible to 1. The results also suggest new chemistry directions that exploit the interactions with the P97-Y93 site toward new and potentially improved HCV NS5A inhibitors.
- Kazmierski, Wieslaw M.,Miriyala, Nagaraju,Johnson, David K.,Baskaran, Sam
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p. 1649 - 1655
(2021/10/04)
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- Selective Electrochemical Oxidation of Functionalized Pyrrolidines
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A method for the selective electrochemical aminoxyl-mediated Shono-type oxidation of pyrrolidines to pyrrolidinones is described. These transformations show the high selectivity and functional group compatibility. This chemistry also demonstrates the use of an operationally simple ElectraSyn 2.0 and cost-effective stainless-steel electrode for the electrochemical oxidation of functionalized pyrrolidines.
- Deprez, Nicholas R.,Clausen, Dane J.,Yan, Jia-Xuan,Peng, Feng,Zhang, Shaoguang,Kong, Jongrock,Bai, Yanguang
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supporting information
p. 8834 - 8837
(2021/11/20)
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- PREPARATION AND USES OF REACTIVE OXYGEN SPECIES SCAVENGER DERIVATIVES
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Compounds of Formula (I) a or (I) b: including certain quinone derivatives, and the corresponding pharmaceutical compositions, which may serve to modulate ferroptosis in a subject. Also disclosed herein are the preparations of these compounds and pharmaceutical compositions and their potential uses in the manufacture of a medicament in reducing reactive oxygen species (ROS) in a cell and for preventing, treating, ameliorating certain related disorder or a disease.
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Page/Page column 99-100
(2019/03/07)
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- DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
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The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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- NOVEL -LACTAMASE INHIBITOR AND METHOD FOR PRODUCING SAME
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The currently available β-lactamase inhibitors are insufficient to inhibit the incessantly increasing β-lactamase, and novel β-lactamase inhibitors has been required today for the difficult treatment for bacterial infectious diseases caused by resistant bacteria which produce class C β-lactamase, extended-spectrum β-lactamase (ESBL) belonging to class A and D, or class A KPC-2 decomposing even carbapenem as a last resort for β-lactam antibiotic. A compound represented by the the formula (I), preparation process of the same, β-lactamase inhibitors and method for treating bacterial infectious diseases are provided.
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Paragraph 0239
(2015/04/15)
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- DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
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The present invention relates to diazabicyclo[4.3.1 ]decane derivatives (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are specific inhibitors of the FK506 binding proteins (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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- Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
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The present invention relates to diazabicyclo[4.3.1]decane derivatives of formula (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are inhibitors of the FK506 binding protein (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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- Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins
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A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp3-sp2 Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode. (Chemical Equation Presented).
- Bischoff, Matthias,Sippel, Claudia,Bracher, Andreas,Hausch, Felix
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p. 5254 - 5257
(2015/02/19)
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- OPTICALLY-ACTIVE DIAZABICYCLOOCTANE DERIVATIVE AND METHOD FOR MANUFACTURING SAME
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Provided are an optically active diazabicyclooctane derivative defined by formula (F) below, which is useful as a pharmaceutical intermediate for β-lactamase inhibitor, and a process for preparing the same. In formula (F) above, R1 represents CO2R, CO2M, or CONH2, wherein R represents a methyl group, a tert-butyl group, an allyl group, a benzyl group, or a 2,5-dioxopyrrolidin-1-yl group, and M represents a hydrogen atom, an inorganic cation, or an organic cation; and R2 represents a benzyl group or an allyl group.
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Paragraph 0187; 0188
(2013/11/19)
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- Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
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We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
- Miyazaki, Masaki,Naito, Hiroyuki,Sugimoto, Yuuichi,Yoshida, Keisuke,Kawato, Haruko,Okayama, Tooru,Shimizu, Hironari,Miyazaki, Masaya,Kitagawa, Mayumi,Seki, Takahiko,Fukutake, Setsuko,Shiose, Yoshinobu,Aonuma, Masashi,Soga, Tsunehiko
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p. 4319 - 4331
(2013/07/27)
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- OPTICALLY ACTIVE DIAZABICYCLOOCTANE DERIVATIVES AND PROCESS FOR PREPARING THE SAME
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Provided are an optically active diazabicyclooctane derivative defined by formula (F) below, which is useful as a pharmaceutical intermediate for beta-lactamase inhibitor, and a process for preparing the same. In formula (F) above, R1 represents CO2R, CO2M, or CONH2, wherein R represents a methyl group, a tert-butyl group, an allyl group, a benzyl group, or a 2,5-dioxopyrrolidin-1-yl group, and M represents a hydrogen atom, an inorganic cation, or an organic cation; and R2 represents a benzyl group or an allyl group.
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Page/Page column 21
(2012/07/13)
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- Regioselective opening of N-Cbz glutamic and aspartic anhydrides with carbon nucleophiles
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Depending on the experimental conditions, aspartic and glutamic anhydrides can be opened regioselectively with Grignard reagents, thus giving access to different isomers of chiral amino-ketoesters.
- Deguest, Geoffrey,Bischoff, Laurent,Fruit, Corinne,Marsais, Francis
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p. 2120 - 2125
(2007/10/03)
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- ACE-INHIBITORS HAVING ANTIOXIDANT AND NO-DONOR ACTIVITY
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Multifonctional ACE inhibitor compounds are provided, that combine ACE-inhibiting activity with capability to scavenge superoxide and other reactive oxygen species, and that may further function as nitric oxide donors. The compounds are useful for preventing or treating various disorders, including cardiovascular, and diabetes associated disorders.
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Page/Page column 60; 61
(2010/02/07)
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- Inhibitors of hepatitis C virus NS3 protease
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The present invention relates generally to a novel class of pyrimidinones of Formula (I): that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
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- A convenient N-protection of pyroglutamate derivatives
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Esters of pyroglutamic acid were N-protected by conventional protective groups (Z. Boc, and COOMe) in high yield, without racemization, using LiHMDS in THF at -78°C and ZCl, Boc2O, and ClCOOMe, respectively.
- Li,Sakamoto,Kato,Kikugawa
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p. 4045 - 4052
(2007/10/03)
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- Synthesis and Siderophore Activity of Albomycin-like Peptides Derived from N5-Acetyl-N5-hydroxy-L-ornithine
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N5-Acetyl-N5-hydroxy-L-ornithine (1), the key constituent of several microbial siderophores, has been synthesized in 23percent yield overall from N-Cbz-L-glutamic acid 1-tert-butyl ester (6) derived from L-glutamic acid.Reduction of 6 to 7 and treatment with N-(trichloroethoxy)carbonyl>-O-benzylhydroxylamine (8), and diethyl azodicarboxylate and triphenylphosphine followed by deprotection produced the protected N5-acetyl-N5-hydroxy-L-ornithine derivatives 11 and 12 in large quantities (10-20 g).Following α-amino and α-carboxyl deprotections of 11 and 12, EEDQ mediated peptide coupling and final deprotection provided amino acid 1 and six albomycin-like peptides (20, 23, 25, 28, 35, and 36).The growth-promoting ability of each was evaluated with the siderophore biosynthesis mutant Shigella flexneri SA240 (SA 100 iucD:Tn5).These results indicate that substantial modification of the framework of peptide-based siderophores can be tolerated by microbial iron-transport systems.
- Dolence, E. Kurt,Lin, Chia-En,Miller, Marvin J.,Payne, Shelley M.
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p. 956 - 968
(2007/10/02)
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- 1-Hydroxy-3-amino-2-piperidone (δ-N-Hydroxycycloornithine) Derivatives: Key Intermediates for the Synthesis of Hydroxamate-Based Siderophores
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Several routes for the synthesis of δ-N-(benzyloxy)cycloornithine (2) from glutamic acid derived starting materials are described.Efficient methods were developed for the synthesis of glutamic acid γ-semialdehyde and γ-hydroxynorvaline derivatives as key substrates for the preparation of δ-N-hydroxyornithine analogues.Thus, the best approaches to the synthesis of 2 were: (1) reductive cyclization of an N-hydroxysuccinimide ester of the O-benzyloxime 4 of α-amino-protected glutamic acid γ-semialdehyde 5 and (2) cyclization of the N-(benzyloxy)amide of δ-bromonorvaline (7).
- Kolasa, Teodozyj,Miller, Marvin J.
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p. 1711 - 1721
(2007/10/02)
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- Amino Acid Synthesis Using (L)-Pyroglutamic Acid as a Chiral Starting Material
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Deprotonation of protected pyroglutamates 1(c), 1(d), and 1(e) with lithium di-isopropylamine (LDA) or lithium hexamethyldisilazide (LiHDMS) in THF, followed by reaction with electrophiles, leads to the formation of 4-substituted pyroglutamates in good yield.This approach has been used for the synthesis of the novel amino acid (4).Key Words: pyroglutamic acid; chiral amino acid synthesis
- Baldwin, Jack E.,Miranda, Tania,Moloney, Mark,Hokelek, Tuncer
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p. 7459 - 7468
(2007/10/02)
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