- ?-LACTAMASE INHIBITOR AND USE THEREOF
-
Provided are a β-lactamase inhibitor of formula (I), or an ester, a stereoisomer or a pharmaceutically acceptable salt thereof, and a method of preparing the same. Further provided is a pharmaceutical composition comprising the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or pharmaceutically acceptable salt thereof. In addition, the present invention relates to a method for treating diseases caused by bacterial infection, which comprises administering the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or the pharmaceutically acceptable salt thereof to a patient or a subject in need.
- -
-
Paragraph 0247; 0248
(2020/12/10)
-
- High-efficiency preparation method of D-dencichine
-
The invention relates to a high-efficiency synthesis method of a hemostasis compound D-dencichine, comprising the following steps: firstly enabling D-serine to react with di-tert-butyl dicarbonate ester to generate Boc-D-serine, then generating Gabriel reaction with hydroxy of methylsulfonyl chloride activated Boc-D--serine to obtain N-alpha-Boc-D-alpha, beta-diaminopro, finally condensing with oxalate mono-methyl ester sylvite then performing hydrolytic acidification to obtain a dencichine crude product, and purifying to obtain a dencichine competitive product, with the product content reaching more than 99.8%. Compared with existing D-dencichine synthesis methods, the reaction condition is more mild, the operation is simple and convenient, the material cost is relatively low, and the hemostasis compound D-dencichine is environment-friendly, is suitable for industrial production, and solves the problem of resource for later development of clinical trial of D-dencichine.
- -
-
Paragraph 0016; 0017
(2019/01/21)
-
- Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles
-
The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.
- Zhang, En,Bai, Peng-Yan,Cui, De-Yun,Chu, Wen-Chao,Hua, Yong-Gang,Liu, Qin,Yin, Hai-Yang,Zhang, Yong-Jie,Qin, Shangshang,Liu, Hong-Min
-
p. 1489 - 1509
(2017/11/13)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to an improved process for the synthesis of (R)- Lacosamide in which free base of O-methyl-N-benzyl-D-Serinamide is not isolated before acylation. The process avoids the use of column chromatography and chiral resolution for the preparation of different stages of Lacosamide.
- -
-
Page/Page column 16-17
(2018/04/17)
-
- Total Synthesis of Plusbacin A3 and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction
-
Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis. The JU-3CR using alkyl isocyanides in 1,1,1,3,3,3-hexafluoroisopropanol provided the trans products, and the coupling of the fragments to prepare the macrocyclization precursor proceeded smoothly. However, attempts toward the macrolactonization did not provide the desired product. Then, the second strategy that included esterification in an initial stage was investigated. Methods for constructing trans-Pro(3-OH) were examined using a convertible isocyanide, which could be converted to a carboxylic acid required for the following amidation. Ester bond formation was achieved through an intermolecular coupling using a hydroxyl-Asp derivative and the corresponding alcohol, and the amidation afforded a linear depsipeptide. The macrolactamization of the linear peptide gave the cyclic depsipeptide, and then the global deprotection accomplished the total synthesis of 1 and its dideoxy derivative.
- Katsuyama, Akira,Yakushiji, Fumika,Ichikawa, Satoshi
-
p. 7085 - 7101
(2018/07/15)
-
- In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3-Amino-1-carboxymethyl-β-lactams as Inhibitors of Penicillin-Binding Proteins of Resistant Bacteria
-
As a complement to the renowned bicyclic β-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten-step synthesis of eleven nocardicin-like enantiomerically pure 2-{3-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-2-oxoazetidin-1-yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-β-lactams to inhibit penicillin-binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α-benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β-lactamase classes was observed, while weak inhibition of class C β-lactamase P99 was demonstrated.
- Decuyper, Lena,Deketelaere, Sari,Vanparys, Lore,Juki?, Marko,Sosi?, Izidor,Sauvage, Eric,Amoroso, Ana Maria,Verlaine, Olivier,Joris, Bernard,Gobec, Stanislav,D'hooghe, Matthias
-
supporting information
p. 15254 - 15266
(2018/09/25)
-
- New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
-
A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
- Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
-
supporting information
p. 2127 - 2132
(2017/10/31)
-
- Improved preparation method of modified lacosamide
-
The invention discloses an improved preparation method of modified lacosamide, which is simple to operate, high in chiral purity and low in cost. According to the improved preparation method, in step 1, amidation is carried out on amino by utilizing di-tert butyl dicarbonate (Boc for short), wherein conditions are moderate and the chiral purity is high and at least reaches 90 percent or more; in step 4, high-selectivity dimethyl sulfate is used as a methylation reagent; the cost is low and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application. The improved preparation method has the most important innovation points that the Boc is used as an N-protection agent and a Boc protecting group can be simply and conveniently removed by adding acid and a hydrogenation removal means does not need to be used. Secondly, the low-price dimethyl sulfate is used for carrying out methylation and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application.
- -
-
Paragraph 0036-0039
(2017/08/31)
-
- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
-
The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
-
p. 202 - 214
(2017/04/06)
-
- Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes
-
A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles without any significant loss of selectivity.
- Cortes-Clerget, Margery,Gager, Olivier,Monteil, Maelle,Pirat, Jean-Luc,Migianu-Griffoni, Evelyne,Deschamp, Julia,Lecouvey, Marc
-
supporting information
p. 34 - 40
(2016/01/25)
-
- A rakow amide preparation method
-
A preparing process of lacosamide is disclosed. D-serine is adopted as an initial raw material. The method includes: performing amino protection, performing methylation, condensing with benzylamine under a condition of existence of a carboxyl activator, removing an amino protection group, and performing amidation to obtain the lacosamide. The total yield is higher than 66%. The method is high in yield, simple and convenient to operate, high in product purity and especially suitable for industrial production.
- -
-
Paragraph 0095; 0096
(2016/10/17)
-
- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
-
Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
- -
-
Page/Page column 732; 733
(2016/04/10)
-
- SAR and structural analysis of siderophore-conjugated monocarbam inhibitors of pseudomonas aeruginosa PBP3
-
A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.
- Murphy-Benenato, Kerry E.,Dangel, Brian,Davis, Hajnalka E.,Durand-Réville, Thomas F.,Ferguson, Andrew D.,Gao, Ning,Jahi?, Haris,Mueller, John P.,Manyak, Erika L.,Quiroga, Olga,Rooney, Michael,Sha, Li,Sylvester, Mark,Wu, Frank,Zambrowski, Mark,Zhao, Shannon X.
-
supporting information
p. 537 - 542
(2015/05/27)
-
- Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
-
Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
- Ikubo, Masaya,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Sayama, Misa,Otani, Yuko,Uwamizu, Akiharu,Suzuki, Keisuke,Kishi, Takayuki,Shuto, Akira,Ishiguro, Jun,Okudaira, Michiyo,Kano, Kuniyuki,Makide, Kumiko,Aoki, Junken,Ohwada, Tomohiko
-
supporting information
p. 4204 - 4219
(2015/06/08)
-
- Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid
-
Several strategies aimed to "freeze" natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson's and Alzheimer's and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3-C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction.
- Bechi, Beatrice,Amantini, David,Tintori, Cristina,Botta, Maurizio,Di Fabio, Romano
-
p. 1114 - 1120
(2014/06/09)
-
- Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in Vitro cytotoxic evaluation
-
We have previously reported the discovery of cytotoxic and pro-Apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3- oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-Apoptotic potential.
- Andrade, Saulo F.,Campos, Edmar F.S.,Teixeira, Claudia S.,Bandeira, Cristiano C.,Lavorato, Stefania N.,Romeiro, Nelilma C.,Bertollo, Caryne M.,Oliveira, M?nica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
-
p. 609 - 618
(2014/11/07)
-
- NOVEL PROCESS FOR THE PREPARATION OF (R)-N-BENZYL-2-ACETAMIDO-3-METHOXYPROPIONAMIDE
-
The invention is a novel process for the preparation of lacosamide by employing novel intermediates of formula III and IV:
- -
-
Paragraph 0042
(2014/11/11)
-
- PROCESS FOR THE PREPARATION OF LACOSAMIDE USING NOVEL INTERMEDIATES
-
The present invention provides an improved and commercial process for the preparation of Lacosamide having formula (I). Further, the present invention also provides the novel intermediate compounds of formula (VI) and (VII) and their process for the preparation. Present process utilizes compound of formula (VI) and (VI)I as key novel intermediates for the preparation of Lacosamide.
- -
-
Page/Page column 11-12
(2014/10/15)
-
- The biological consequences of replacing D-Ala in biphalin with amphiphilic α-alkylserines
-
Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α-alkylserines in position 2 and 2′. The incorporation of bulky α,α-disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O,N-migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor-binding assay in the rat brain using [ 3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α-alkylserine, as analogues containing (R)-α-alkylserines displayed higher μ receptor affinity and selectivity than those incorporating the (S)-isomers.
- Fraczak, Oliwia,Lasota, Anika,Lesniak, Anna,Lipkowski, Andrzej W.,Olma, Aleksandra
-
p. 199 - 205
(2014/07/22)
-
- PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
Present invention relates to an improved and commercial process for the preparation of lacosamide ((R)-2-acetami-do-N-benzyl-3-methoxypropanamide) of formula (I). Present process utilizes high purity crystalline solids of formulae (XXXII) and (XIII) as key intermediates. Lacosamide is indicated for the adjunctive treatment of partial onset seizures in patients aged at least 17 years.
- -
-
Paragraph 0031
(2013/03/26)
-
- PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to a novel and improved process for the preparation of lacosamide, wherein the process is a sequential one-pot process.
- -
-
Paragraph 0041
(2013/05/08)
-
- Reactions of carbon nucleophiles with 2,2,3-trisubstituted ethynylaziridines
-
Carbon nucleophiles were used to open a 2,2,3-trisubstituted ethynylaziridine. A cyanide nucleophile opened the ring at the more substituted carbon, proceeding regioselectively with inversion of configuration. In an attempt to expand upon the scope of the reaction, Normant cuprates were reacted with a 2,2,3-trisubstituted ethynylaziridine. This reaction produced chiral allenes via an anti-SN2′ pathway. X-ray analysis of a derivative allowed the absolute stereochemistry of the anti-allenes to be assigned as P.
- Kelley, Brandon T.,Joullie, Madeleine M.
-
p. 1233 - 1239
(2013/10/22)
-
- A facile synthesis of the spiroindoline-based growth hormone secretagogue, MK-677
-
A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677 was described. The key step adopted the Fischer indole/reduction strategy. The preparation of the key intermediates N-protected piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-d-serine (2) are also optimized.
- Qi, Xian Liang,Yang, Er Qun,Zhang, Jun Tao,Wang, Tao,Cao, Xiao Ping
-
scheme or table
p. 661 - 664
(2012/07/03)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
The present invention relates to a novel and improved process for the preparation of lacosamide, wherein the process is a sequential one-pot process.
- -
-
Page/Page column 10-12; 18
(2012/01/14)
-
- NOVEL POLYMORPH OF LACOSAMIDE
-
The present invention provides novel crystalline form of lacosamide, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a process for the preparation of lacosamide amorphous form.
- -
-
Page/Page column 7
(2012/04/23)
-
- Design, Synthesis, and invitro Antibacterial Activity of Fluoroquinolone Derivatives Containing a Chiral 3-(Alkoxyimino)-2-(aminomethyl)azetidine Moiety
-
A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their invitro antibacterial activity against representative strains. Our results reveal that 12 of the target compounds generally show better activity (MIC: -1) against the tested Gram-positive strains including MRSA and MRSE than levofloxacin (LVFX, MIC: 0.125-8μgmL-1). Their activity is similar to that of gemifloxacin (GMFX, MIC: -1). However, they are generally less active than the two reference drugs against Gram-negative strains. Moreover, against clinical strains of S.aureus including MRSA and S.epidermidis including MRSE, the MIC50 values (0.06-16μgmL-1) and MIC90 values (0.5-32μgmL-1) of compounds 16w, y, and z are 2-8- and 2-16-fold less than LVFX, respectively, and 16w (MIC90 range: 0.5-4μgmL-1) was also found to be more active than GMFX (MIC90 range: 1-8μgmL-1).
- Lv, Kai,Sun, Yexin,Sun, Lanyin,Wei, Zengquan,Guo, Huiyuan,Wu, Jinwei,Liu, Mingliang
-
experimental part
p. 1230 - 1236
(2012/08/08)
-
- Solid Forms Of An N-(Phenylmethyl)Propanamide Derivative And Processes Of Preparation
-
The invention relates to solid forms of the anti-epileptic agent lacosamide (I). The invention also relates to mixtures of solid forms of lacosamide. The invention further relates to mixtures of lacosamide enantiomers crystallized in a conglomerate Form and the use thereof in providing enantiomerically enriched lacosamide, preferably lacosamide enriched with the (R)-enantiomer of lacosamide.
- -
-
Page/Page column 7
(2011/02/26)
-
- Synthesis, characterization and antioxidant activity of angiotensin converting enzyme inhibitors
-
Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). ACE also cleaves the terminal dipeptide of vasodilating hormone bradykinin (a nonapeptide) to inactivate this hormone. Therefore, inhibition of ACE is generally used as one of the methods for the treatment of hypertension. 'Oxidative stress' is another disease state caused by an imbalance in the production of oxidants and antioxidants. A number of studies suggest that hypertension and oxidative stress are interdependent. Therefore, ACE inhibitors having antioxidant property are considered beneficial for the treatment of hypertension. As selenium compounds are known to exhibit better antioxidant behavior than their sulfur analogues, we have synthesized a number of selenium analogues of captopril, an ACE inhibitor used as an antihypertensive drug. The selenium analogues of captopril not only inhibit ACE activity but also effectively scavenge peroxynitrite, a strong oxidant found in vivo. The Royal Society of Chemistry 2011.
- Bhuyan, Bhaskar J.,Mugesh, Govindasamy
-
scheme or table
p. 1356 - 1365
(2011/04/23)
-
- A PROCESS FOR THE PREPARATION OF LACOSAMIDE
-
Present invention relates to an improved and commercial process for the preparation of lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropanamide) of formula (I). Present process utilizes high purity crystalline solids of formulae (XXXII) and (XIII) as key intermediates. Lacosamide is indicated for the adjunctive treatment of partial onset seizures in patients aged at least 17 years.
- -
-
Page/Page column 10-11
(2011/09/14)
-
- PROCESS FOR PREPARING (R)-2-ACETAMIDO-N-BENZYL-3-METHOXY-PROPIONAMIDE
-
Processes for preparing and purifying (R)-2-acetamido-N-benzyl-3-methoxy- propionamide of formula-1 and intermediates thereof are provided.
- -
-
Page/Page column 42
(2011/09/15)
-
- Preparation and biological evaluation of key fragments and open analogs of scleritodermin A
-
The synthesis of key fragments of scleritodermin A, their assembly, and their biological evaluation as cytotoxic and anthelmintic were performed.Highlights of the synthetic route include formation of the a-ketoamide linkage and use of stereocontrolled reactions.Open analogs of this natural product were obtained using a convergent strategy.
- Sellanes, Diver,Campot, Francisco,Nú?ez, Ivana,Lin, Gerardo,Espósito, Pablo,Dematteis, Sylvia,Salda?a, Jenny,Domílnguez, Laura,Manta, Eduardo,Serra, Gloria
-
scheme or table
p. 5384 - 5395
(2010/08/19)
-
- Total synthesis of the large non-ribosomal peptide polytheonamide B
-
Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 =68 pg ml -1 , mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30A? in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
- Inoue, Masayuki,Shinohara, Naoki,Tanabe, Shintaro,Takahashi, Tomoaki,Okura, Ken,Itoh, Hiroaki,Mizoguchi, Yuki,Iida, Maiko,Lee, Nayoung,Matsuoka, Shigeru
-
supporting information; scheme or table
p. 280 - 285
(2010/09/03)
-
- Synthesis, radiolabeling, and biological evaluation of (R)- and (S)-2-amino-3-[18F]fluoro-2-methylpropanoic acid (FAMP) and (R)- and (S)-3-[18F]fluoro-2-methyl-2-n-(methylamino)propanoic acid (NMeFAMP) as potential PET radioligands for imaging brain tumors
-
The non-natural amino acids (R)- and (S)-2-amino-3-fluoro-2-methylpropanoic acid 5 and (R)- and (S)-3-fluoro-2-methyl-2-N-(methylamino)propanoic acid 8 were synthesized in shorter reaction sequences than in the original report starting from enantiomerically pure (S)- and (R)-R-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[18F]5 and (R)- and (S)-[ 18F]8 in fewer steps than in the original report. (R)- and (S)-[ 18F]5 and(R)-and (S)-[18F]8 were synthesized by no-carrier-added nucleophilic [18F]fluorination in 52-66% decay - corrected yields with radiochemical purity over 99%. The cell assays showed that all four compounds were substrates for amino acid transport and enter 9L rat gliosarcoma cells in vitro at least in part by system A amino acid transport. The biodistribution studies demonstrated that in vivo tumor to normal brain ratios for all compounds were high with ratios of 20:1 to115:1 in rats with intracranial 9L tumors. The (R)-enantiomers of [18F]5 and [ 18F]8 demonstrated higher tumor uptake in vivo compared to the (S)-enantiomers. 2009 American Chemical Society.
- Yu, Weiping,McConathy, Jonathan,Williams, Larry,Camp, Vernon M.,Malveaux, Eugene J.,Zhang, Zhaobin,Olson, Jeffrey J.,Goodman, Mark M.
-
experimental part
p. 876 - 886
(2010/07/05)
-
- A convergent route for the total synthesis of malyngamides O, P, Q, and R
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(Chemical Equation Presented) A convergent, enantioselective and general synthetic route to a class of marine natural products - malyngamides O (1), P (2), Q (3), R (4), 5″-epi-3 and 5″-epi-4 - bearing a novel vinyl chloride structural motif was developed. The key steps involved construction of the vinyl chloride functionality by Wittig reaction, a DCC/HOBt-promoted amidation, an aldol reaction in the construction of the basic backbone of 1, 2, 3, 4, 5″-epi-3, and 5″-epi-4, and methylation of an enol moiety via either base/acid conditions or a Mitsunobu reaction. Moreover, the absolute configuration of the stereogenic center at C-5″ in 3 was further confirmed by synthesis of the natural product and its C-5″ epimer.
- Chen, Jie,Fu, Xiao-Gang,Zhou, Ling,Zhang, Jun-Tao,Qi, Xian-Liang,Cao, Xiao-Ping
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scheme or table
p. 4149 - 4157
(2009/09/08)
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- Evolution of the total syntheses of ustiloxin natural products and their analogues
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Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an SNAr reaction. An NOE study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R,10S)-epi-ustiloxin analogues) were prepared via the second-generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization.
- Li, Pixu,Evans, Cory D.,Wu, Yongzhong,Cao, Bin,Hamel, Ernest,Joullie, Madeleine M.
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p. 2351 - 2364
(2008/09/20)
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- A convenient transformation of α-alkylserines into α-halogenomethyl-α-alkylglycines
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An efficient and facile synthesis of N-Boc-α-chloromethyl- and α-bromomethyl-α-alkylglycines is reported that involves cyclization of N-Boc-α-alkylserines to the corresponding β-lactones under Mitsunobu reaction conditions, followed by ring opening with anhydrous MgCl2 or MgBr2.
- Kudaj, Adam,Olma, Aleksandra
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body text
p. 6445 - 6447
(2009/04/06)
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- Facile stereospecific synthesis and biological evaluation of (S)- and (R)-2-amino-2-methyl-4-[123I]iodo-3-(E)-butenoic acid for brain tumor imaging with single photon emission computerized tomography
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Both enantiomers of 2-amino-2-methyl-4-iodo-3-(E)-butenoic acid (IVAIB, 5) were radioiodoinated in 65-72% yield. (S)-IVAIB entered 9L gliosarcoma cells primarily via A-type transport in vitro with higher uptake than (R)-IVAIB. Biodistribution studies in rats with 9L gliosarcoma brain tumors demonstrated higher tumor to brain ratios with (S)-IVAIB (75:1 at 1 h) than (R)-IVAIB (7.7:1). In this model, (S)-IVAIB is superior to (R)-IVAIB and is a promising radiotracer for brain tumor imaging.
- Yu, Weiping,McConathy, Jonathan,Olson, Jeffrey,Camp, Vernon M.,Goodman, Mark M.
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p. 6718 - 6721
(2008/09/17)
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- Orthogonally protected lanthionines: Synthesis and use for the solid-phase synthesis of an analogue of nisin ring C
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(Chemical Equation Presented) Lanthionine, a thioether analogue of cystine, is a key component of the lantibiotics, a family of modified peptides bearing multiple thioether bridges resulting from posttranslational modifications between side chains. It is also used as a conformational constraint in medicinally active peptides. We have explored two synthetic routes to give lanthionine, orthogonally protected with Alloc/allyl and Fmoc groups. One route utilized a carbamate-protected iodoalanine that yielded a mixture of diastereoisomers, and one utilized a trityl-protected iodoalanine, formed via a Mitsunobu reaction, that gave the single desired lanthionine, in complete regio-and diastereoselectivity. We then used this orthogonally protected lanthionine in the solid-phase synthesis of an analogue of a fragment of nisin containing its ring C. The chemoselective deprotection of the allyl and Alloc groups of the incorporated lanthionine unit was followed by regio- and stereoselective cyclization on resin to give the desired lanthionine-bridged peptide.
- Bregant, Sarah,Tabor, Alethea B.
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p. 2430 - 2438
(2007/10/03)
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- Novel aliphatic compounds, process for their preparation and their usage
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The present invention provides an aliphatic compound represented by the following formula (I) or pharmacologically acceptable salts thereof: where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, the aliphatic compound being an optical isomer of the (2R,3S,2′S) configuration when the 8-position thereof is a double bond, or an optical isomer of the (2S,3R,2′RS) configuration when the 8-position is a single bond; methods for producing the compound or pharmacologically acceptable salts thereof; and uses of the compound in the treatment of cardiovascular diseases (e.g. arteriosclerosis, cardiac diseases), cancer, rheumatism, diabetic retinopathy, and respiratory diseases.
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Page/Page column 11
(2010/02/05)
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- Novel 2-phenylpiperazine derivatives
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Excellent tachykinin receptor antagonistic activity is provided by 2-phenylpiperazine derivatives. The piperazine derivatives exhibit a strong inhibitory action against a tachykinin-induced increase of vascular permeability in in vivo tests. Moreover, the derivatives show a preferred transfer into blood, a long half-life in blood in pharmacokinetic tests of oral administration to rats or guinea pigs, and are very stable in blood plasma of various animals. Consequently, a piperazine derivative of the present invention is very useful as a tachykinin antagonist.
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- Novel 2-phenylpiperazine derivatives
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The present invention is to offer a useful novel compound as a tachykinin antagonist.ψThis invention is a novel 2-phenylpiperazine derivative having an excellent tachykinin antagonistic action.ψA piperazine derivative of the present invention has an excellent tachykinin receptor antagonistic activity and exhibits a strong inhibitory action against tachykinin-induced increase of vascular permeability in vivo tests. Moreover, it shows a preferred transfer into blood and a long half-life in blood in pharmacokinetic tests of oral administration to rats or guinea pigs, and is very stable in blood plasma of various animals. Consequently, a piperazine derivative of the present invention is very useful as a novel tachykinin antagonist.
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- Syntheses of sphingosine-1-phosphate stereoisomers and analogues and their interaction with EDG receptors.
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Sphingosine-1-phosphate (S1P) is considered to be an important regulator of diverse biological processes acting as a natural ligand to EDG receptors. As a preliminary study to develop potent and selective agonist and antagonist for EDG receptors, we report synthesis of S1P stereoisomers and analogues and their binding affinities to EDG-1, -3, and -5.
- Lim, Hyun Suk,Oh, Yong Seok,Suh, Pann Ghill,Chung, Sung Kee
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p. 237 - 240
(2007/10/03)
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- Synthesis of 3-Aminochroman Derivatives by Radical Cyclization
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(Equation presented) Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H- 1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from D- or L-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using β-cyclodextrins as a chiral selector.
- Pave, Gregoire,Usse-Versluys, Stephanie,Viaud-Massuard, Marie-Claude,Guillaumet, Gerald
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p. 4253 - 4256
(2007/10/03)
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- Enantioselective synthesis of α-methyl-D-cysteine and lanthionine building blocks via α-methyl-d-serine-β-lactone
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(Matrix presented) We report here the enantioselective synthesis of Boc-α-methyl-D-cysteine(PMB)-OH and lanthionine building blocks through the regioselective ring opening of key intermediate Boc-α -methyl-D-serine-β-lactone.
- Smith, Nicole D.,Goodman, Murray
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p. 1035 - 1037
(2007/10/03)
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- Asymmetric synthesis of α,α-disubstituted α-amino acide derivatives using MABR promoted rearrangement
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An efficient route for the asymmetric synthesis of α,α-disubstituted α-amino acids derivatives (1, 2, and 3) starting from readily available epoxy silyl ethers (6) has been developed. High enantiomeric purity can be realized by the present method using a combination of MABR rearrangement of a chiral epoxide and Curtius rearrangement.
- Matsushita, Masayuki,Maeda, Hana,Kodama, Mitsuaki
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p. 3749 - 3752
(2007/10/03)
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- A simplified route to the (R)-Garner aldehyde and (S)-vinyl glycinol
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An improved procedure for the conversion of D-serine into tert-butyl (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate [the (R)-Garner aldehyde] is described which can be carried out in four operationally simple steps in 88% overall yield. Elaboration of this aldehyde to vinyl glycinol is also described.
- Campbell, Andrew D.,Raynham, Tony M.,Taylor, Richard J. K.
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p. 1707 - 1709
(2007/10/03)
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- The synthesis of 4,5-methano congeners of α-kainic and α-allo-kainic acids as probes for glutamate receptors
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The synthesis of diastereomeric 4,5-methano-L-proline 3-acetic acids is described starting from D-serine. The key reactions include a free-radical carbocyclization and an acid-catalyzed destannylative cyclopropanation of an iminium ion intermediate. Copyright (C) 1996 Elsevier Science Ltd.
- Hanessian, Stephen,Ninkovic, Sacha,Reinhold, Ulrich
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p. 8971 - 8974
(2007/10/03)
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- Enantiospecific and diastereoselective synthesis of 4,4-disubstituted-3- amino-2-azetidinones, starting from D-serine
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A strategy for the preparation of 4,4-disubstituted-3-amino-2- azetidinones, which are useful intermediates for the synthesis of analogues of monosulfactam Tigemonam, was developed. It employs D-serine as chiral starting material and involves, as key steps, the diastereoselective addition of organometal compounds to ketones 9 and the stereospecific cyclization of tertiary alcohols 7 to the β-lactams 6.
- Ageno,Banfi,Cascio,Guanti,Manghisi,Riva,Rocca
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p. 8121 - 8134
(2007/10/02)
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- Synthesis of conformationally restricted analogs of kainic acid. Is the conformation of the C4-substituent of kainoid important to its neuroexcitatory activity?
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Conformationally restricted analogs of kainic acid, which have an azabicyclo[3.3.0]octane system, were synthesized through the intramolecular addition reaction of trimethylenemethane to the α,β-unsaturated ester. Every synthesized isomer showed very weak depolarizing activity. These results indicate that the plane of the isopropenyl group of kainic acid should be diagonal to the pyrrolidine ring to show potent activity.
- Hashimoto, Kimiko,Ohfune, Yasufumi,Shirahama, Haruhisa
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p. 6235 - 6238
(2007/10/02)
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