- One-pot synthesis and biological evaluation of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives as potent antibacterial and anticancer agents
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In search of better antibacterial and anticancer agents, a series of novel 4-[3-fluoro-4-(morpholin-4-yl)]phenyl-1H-1,2,3-triazole derivatives were synthesized (6a-l and 8a-j) by using 3-fluoro-4-morpholinoaniline, alkyne, and triflyl azide via an in situ
- Narsimha, Sirassu,Nukala, Sathesh Kumar,Ravinder, M.,Savitha Jyostna, T.,Srinivasa Rao, M.,Vasudeva Reddy, N.
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- Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer
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To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 μM). Bioassay optimization identified a novel and
- Zhou, Wu-Xi,Chen, Chen,Liu, Xiao-Qin,Li, Ying,Lin, Yao-Lan,Wu, Xiu-Tao,Kong, Ling-Yi,Luo, Jian-Guang
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- Novel Linezolid analogues with antiparasitic activity against Hymenolepis nana
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The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of L-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidino
- Alcántar-Zavala, Eleazar,Hernández-Guevara, Esteban,Ochoa-Terán, Adrián,Montes-ávila, Julio,Estrada-Zavala, Edgar A.,Salazar-Medina, Alex J.,Alday, Efraín,Cabrera, Alberto,Aguirre, Gerardo,Miranda-Soto, Valentín,Velazquez, Carlos,Díaz-Camacho, Sylvia P.,Medina-Franco, José L.
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- Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)
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Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to produce a
- Gardiner, James,Nguyen, Xuan,Genet, Charlotte,Horne, Mike D.,Hornung, Christian H.,Tsanaktsidis, John
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- Biofilm inhibition of linezolid-like Schiff bases: Synthesis, biological activity, molecular docking and in silico ADME prediction
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Herein, we report the synthesis and screening of linezolid-like Schiff bases as inhibitors of biofilm formation. The result of biofilm inhibition of Pseudomonas aeruginosa suggested that compounds 5h (IC50 value = 12.97 ± 0.33 μM) and 5i (IC50 value = 15.63 ± 0.20 μM) had more inhibitory activity when compared with standard linezolid (IC50 = 15.93 ± 0.18 μM) without affecting the growth of cells (and thus behave as anti-quorum sensing agents). The compounds 5h (MIC range = 2.5-10 μg/mL) and 5i (MIC range = 3.5-10 μg/mL) with 2-chloroquinolinyl and 2-chloro-8-methylquinolinyl motif, respectively, showed antibacterial activity in comparable range of linezolid (MIC range = 2-3 μg/mL) and were more potent when compared with ciprofloxacin (MIC range = 25-50 μg/mL). Thus, the active derivatives were not only potent inhibitors of P. aeruginosa biofilm growth but also efficient antibacterial agents. The docking study of most active compounds 5h and 5i against PqsD enzyme of P. aeruginosa exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.
- Sangshetti, Jaiprakash N.,Khan, Firoz A. Kalam,Patil, Rajendra H.,Marathe, Sayali D.,Gade, Wasudev N.,Shinde, Devanand B.
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- Novel 3-fluoro-4-morpholinoaniline derivatives: Synthesis and assessment of anti-cancer activity in breast cancer cells
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Heterocyclic morpholine compounds are well-known for their anti-cancer activity. In this study, novel morpholine and its sulfonamide derivatives were designed and synthesized as potential anti-tumor agents. The new compounds were obtained from amine derivatives via nucleophilic addition reactions, providing the desired products in 70 to 90% yield. The docking analysis was performed for all thirty-one compounds. Out of them, we represent the docking poses for compounds NAM-5 and NAM-7 as representatives. After docking analysis, compounds NAM-5 and NAM- 7 were tested for in vitro antitumor activity against breast cancer cell lines (MCF-7 and MDA-MB-231) and healthy mouse embryonic fibroblast cell line (3T3L-1). Amongst these, sulfonamide group-containing compound NAM-5 showed significant anti-proliferative activity with IC50 of 1.811 μM and 2.143 μM for MCF-7 and MDA-MB-231 cells, respectively. On the other hand, NAM-7 showed good anti-proliferative activity against MCF-7 (IC50 1.883 μM) but slightly lower activity against MDA-MB-231 cells (IC50 4.688 μM). The activity of both the compound was also tested on 3T3L-1 Cell line which showed activity similar to clinically approved anti-cancer drug doxorubicin (DOX). The cell death analysis by flow-cytometry confirmed apoptosis mediated cell death in 3T3L-1, MCF-7 and MDA-MB-231 cells when treated with the NAM-5 and NAM-7, respectively. The results demonstrated that the synthesized sulfonamide derivatives have significant potential as anti-cancer agents and have a substantial importance in cancer therapeutics with favourable safety profile. Structural analysis of docked poses of sulfonamide derivatives attempts to shed light on the structural basis of sulfonamide derivatives based anti-cancer effect.
- Gajbhiye, Jayant M.,Gajbhiye, Virendra,Jadhao, Nitin L.,Meshram, Rohan J.,More, Namita A.,Sabane, Jagjivan K.,Salve, Rajesh A.,Sawant, Sanskruti N.,Tambe, Prajakta
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- Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis
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Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC90 values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.
- Fernandes, Guilherme F. S.,Campos, Débora L.,Da Silva, Isabel C.,Prates, Jo?o L. B.,Pavan, Aline R.,Pavan, Fernando R.,Dos Santos, Jean L.
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supporting information
p. 1268 - 1282
(2021/02/16)
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- Synthesis of covalent bonding MWCNT-oligoethylene linezolid conjugates and their antibacterial activity against bacterial strains
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Nowadays, infectious diseases caused by drug-resistant bacteria have become especially important. Linezolid is an antibacterial drug active against clinically important Gram positive strains; however, resistance showed by these bacteria has been reported. Nanotechnology has improved a broad area of science, such as medicine, developing new drug delivery and transport systems. In this work, several covalently bounded conjugated nanomaterials were synthesized from multiwalled carbon nanotubes (MWCNTs), a different length oligoethylene chain (Sn), and two linezolid precursors (4and7), and they were evaluated in antibacterial assays. Interestingly, due to the intrinsic antibacterial activity of the amino-oligoethylene linezolid analogues, these conjugated nanomaterials showed significant antibacterial activity against various tested bacterial strains in a radial diffusion assay and microdilution method, including Gram negative strains asEscherichia coli(11 mm, 6.25 μg mL?1) andSalmonella typhi(14 mm, ≤0.78 μg mL?1), which are not inhibited by linezolid. The results show a significant effect of the oligoethylene chain length over the antibacterial activity. Molecular docking of amino-oligoethylene linezolid analogs shows a more favorable interaction of theS2-7analog in the PTC ofE. coli.
- Alatorre-Barajas, José A.,Alcántar-Zavala, Eleazar,Alonso-Nú?ez, Gabriel,Cabrera, Alberto,Estrada-Zavala, Edgar,Gil-Rivas, M. Graciela,Gochi-Ponce, Y.,Medina-Franco, J. L.,Montes-ávila, Julio,Ochoa-Terán, Adrián,Reynoso-Soto, Edgar A.,Rivera-Lugo, Yazmin Yorely,Trujillo-Navarrete, Balter
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p. 28912 - 28924
(2021/09/22)
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- Synthesis, anti-inflammatory activity and in silico studies of some novel morpholine based carboxamides
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Two series of carboxamides were synthesized from 3-fluoro-4-morpholinoaniline and different substituted aromatic/heterocyclic carboxylic acids. All the compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral data. The n
- Honavar, Premanand M.,Kumar, Vasantha,Nikhil,Kumar, Naveen,Sreenivasa,Vishwanatha,Poojary, Boja,Holla, B. Shivarama
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p. 901 - 906
(2020/03/24)
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- New linezolid synthesis method
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The invention belongs to the field of organic synthesis, and particularly relates to a new linezolid synthesis method, which comprises: synthesizing 3-fluoro-4-morpholinophenyl isocyanate by using 3,4-difluoronitrobenzene as a starting raw material, carrying out cyclization on the 3-fluoro-4-morpholinophenyl isocyanate and (R)-epichlorohydrin under the catalysis of MgI2 or MgBr2 in the absence ofa solvent to obtain (R)-3-fluoro-4-morpholinophenyl oxazolidone, and carrying out azide group substitution, reduction and acetylation to obtain linezolid. According to the present invention, by usingthe new linezolid synthesis method, the reaction rate can be significantly accelerated, the yield can be increased, the cost can be reduced, the environment can be protected, the operation is simple,the post-treatment is convenient, and the method is suitable for industrial production.
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Paragraph 0009
(2019/05/16)
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- Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification
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Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h?1.
- Russell, M. Grace,Jamison, Timothy F.
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supporting information
p. 7678 - 7681
(2019/05/16)
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- Reconfigurable system for automated optimization of diverse chemical reactions
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Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (SNAr), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus.
- Bédard, Anne-Catherine,Adamo, Andrea,Aroh, Kosi C.,Russell, M. Grace,Bedermann, Aaron A.,Torosian, Jeremy,Yue, Brian,Jensen, Klavs F.,Jamison, Timothy F.
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p. 1220 - 1225
(2018/10/04)
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- Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)
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Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.
- Wagner, Rolf,Randolph, John T.,Patel, Sachin V.,Nelson, Lissa,Matulenko, Mark A.,Keddy, Ryan,Pratt, John K.,Liu, Dachun,Krueger, A. Chris,Donner, Pamela L.,Hutchinson, Douglas K.,Flentge, Charles,Betebenner, David,Rockway, Todd,Maring, Clarence J.,Ng, Teresa I.,Krishnan, Preethi,Pilot-Matias, Tami,Collins, Christine,Panchal, Neeta,Reisch, Thomas,Dekhtyar, Tatyana,Mondal, Rubina,Stolarik, Deanne F.,Gao, Yi,Gao, Wenqing,Beno, David A.,Kati, Warren M.
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supporting information
p. 4052 - 4066
(2018/05/14)
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- Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor
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The invention provides a method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using a micro-channel reactor. The micro-channel reactor comprises a preheating module group composed of one or more parallely-connected preheating modules and a reactio
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The invention relates to the field of medicine, discloses new nitrogen heterocyclic derivatives, preparation method thereof and as medicament in particular as the treatment and prevention of treating tissue fibrosis of the medicament. The invention also discloses a pharmaceutically acceptable compound of the present invention comprise a pharmaceutical composition and methods for using the composition for the treatment of the human or animal tissue fibrosis of diseases, in particular for treating the human or animal renal interstitial fibrosis, glomerular sclerosis, hepatic fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, after the operation of adhering, benign prostate hypertrophy, bone-myocardial, scleroderma, multiple sclerosis, pancreas fibrosis, liver cirrhosis, myosarcoma, neurofibromatosis, interstitial pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis disease in use. (by machine translation)
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Page/Page column 123; 124
(2018/06/01)
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- Design and Synthesis of 4-Alkylidene-β-lactams: Benzyl- and Phenethyl-carbamates as Key Fragments to Switch on Antibacterial Activity
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The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a β-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-β-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate β-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2–4 mg L?1.
- Giacomini, Daria,Martelli, Giulia,Piccichè, Miriam,Calaresu, Enrico,Cocuzza, Clementina Elvezia,Musumeci, Rosario
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p. 1525 - 1533
(2017/09/25)
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- Novel pazopanib derivatives and pharmaceutical composition comprising the same
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The present invention relates to novel pazopanib derivatives or a salt thereof having inhibition activities of angiogenesis and epidermal growth factors at the same time, and to a pharmaceutical composition comprising the same as an active ingredient. The pazopanib derivatives have inhibition activities of angiogenesis and epidermal growth factors at the same time unlike pazopanib, thereby more effectively treating and preventing EGFR-related cancer diseases such as lung cancer, colon cancer or breast cancer through a multiple aim target, and effectively treating and preventing non-small-cell lung cancer which Iressa or Tarceva cannot have an effect on.COPYRIGHT KIPO 2017
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Paragraph 0116; 0118; 0122; 0123
(2017/05/10)
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- Facile aromatic nucleophilic substitution (SNAr) reactions in ionic liquids: An electrophile-nucleophile dual activation by [Omim]Br for the reaction
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A facile aromatic nucleophilic substitution (SNAr) reaction in recyclable [Omim]Br under relatively mild conditions has been described. An electrophile-nucleophile dual activation by [Omim]Br is also discovered based on control experiments, 1H NMR and IR spectroscopies. This chemistry provides an efficient and metal-free approach for the generation of Caryl-X (XS, N, O) bonds, many of which are significant synthetic intermediates or drugs, making this methodology attractive to both synthetic and medicinal chemistry.
- Zhang, Xiao,Lu, Guo-Ping,Cai, Chun
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p. 5580 - 5585
(2016/10/21)
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- A process for the preparation of linezolid
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The invention relates to a linezolid (1) preparation method. The method comprises the following steps: reacting a raw material 3,4-difluoronitrobenzene with morpholine, reducing, reacting with benzyl chloroformate to obtain N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline, carrying out a ring closure reaction of N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline and (S)-N-(2,3-epoxypropyl)phthalimide, ammonolyzing, and acetylating to obtain linezolid (1).
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Paragraph 0032; 0054-0055
(2017/01/05)
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- A kind of linezolid intermediate, preparation method thereof, and method for preparing and enduring zolamide
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The invention discloses a novel Linezolid intermediate, its preparation method and a novel preparation method of Linezolid, a structure of the Linezolid key intermediate is shown as a formula (I), in the formula (I), X is fluorine, chlorine, bromine or iodine. According to the invention, the Linezolid intermediate solves the problems of poor solubility of the Linezolid intermediate, and low yield and purity of the synthesized Linezolid in the prior art. The preparation methods of the invention have the advantages of easy preparation process, easy raw material acquisition, low cost, easy purification of intermediate product and final product, high yield and purity, and are suitable for large-scale industrial production.
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Paragraph 0036; 0037
(2017/04/04)
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- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 0518
(2015/03/31)
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- Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis
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Given the huge dependence on dipolar, aprotic solvents such as DMF, DMSO, DMAc, and NMP in nucleophilic aromatic substitution reactions (SNAr), a simple and environmentally friendly alternative is reported. Use of a "benign-by-design" nonionic surfactant, TPGS-750-M, in water enables nitrogen, oxygen, and sulfur nucleophiles to participate in SNAr reactions. Aromatic and heteroaromatic substrates readily participate in this micellar catalysis, which takes place at or near ambient temperatures.
- Isley, Nicholas A.,Linstadt, Roscoe T. H.,Kelly, Sean M.,Gallou, Fabrice,Lipshutz, Bruce H.
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supporting information
p. 4734 - 4737
(2015/10/12)
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- Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives
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Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5′-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity.
- Phillips, Oludotun A.,D'Silva, Roselyn,Bahta, Teklu O.,Sharaf, Leyla H.,Udo, Edet E.,Benov, Ludmil,Eric Walters
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p. 120 - 131
(2015/11/24)
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- PROCESS FOR PREPARATION OF LINEZOLID
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The present invention discloses an in-situ process for preparation of Linezolid polymorphic Form II free of impurities.
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Page/Page column 9
(2015/11/16)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
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Paragraph 00270
(2014/02/15)
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- Convenient synthesis of the antibiotic linezolid via an oxazolidine-2,4-dione intermediate derived from the chiral building block isoserine
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We describe a new synthesis of the 5-(aminomethyl)oxazolidin-3-one core of linezolid in enantiomerically pure form. The expedient cyclization of the α-hydroxy amide derived from isoserine and 3-fluoro-4-morpholinoaniline to give the corresponding (aminomethyl)oxazolidine-2,4-dione, followed by its mild selective reduction at the C(4)-position, gave linezolid in almost quantitative overall yield. The 1,3-oxazolidin-2-one core of linezolid was obtained from isoserine in just three steps and with almost quantitative overall yield; the key features of the protocol are the expedient formation of the intermediate oxazolidine-2,4-dione, and its regioselective reduction at the 4-position.
- Greco, Arianna,De Marco, Rossella,Tani, Sara,Giacomini, Daria,Galletti, Paola,Tolomelli, Alessandra,Juaristi, Eusebio,Gentilucci, Luca
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supporting information
p. 7614 - 7620
(2015/04/22)
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- PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID
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The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.
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Page/Page column 15
(2013/06/05)
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- Novel promising linezolid analogues: Rational design, synthesis and biological evaluation
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A new series of 5-substituted oxazolidinones derived from linezolid, having urea and thiourea moieties at the C-5 side chain of the oxazolidinone ring, were prepared and their in vitro antibacterial activity was evaluated. The compound 10f demonstrated high antimicrobial activity, comparable to that of linezolid against Staphylococcus aureus.
- De Rosa, Margherita,Zanfardino, Anna,Notomista, Eugenio,Wichelhaus, Thomas A.,Saturnino, Carmela,Varcamonti, Mario,Soriente, Annunziata
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p. 779 - 785
(2013/10/22)
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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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Paragraph 0022; 0044-0045
(2014/01/07)
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- Synthesis of linezolid-like molecules and evaluation of their antimicrobial activities
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3-Fluoro-4-(morpholin-4-yl)aniline (2), prepared from 3,4- difluoronitrobenzene, was converted to the corresponding Schiff base (3) by treatment with indol-3-carbaldehyde. The treatment of thiourea 4 and carbothioamide derivatives 9 with ethyl bromoacetate or 4-substituted phenacyl bromides generated the corresponding thiazolidinone (5 and 13) and thiazoline (6 and 12) derivatives, respectively. The acidic or basic treatment of carbothioamide 9 produced 1,3,4-thiadiazole (11) or 1,2,4-triazole (10) compounds, respectively. The structural assignments of the new compounds were based on elemental analysis and spectral (IR, 1H-NMR, 13C-NMR, and LC-MS) data. The antimicrobial activity study revealed that all compounds showed good antitubercular activities. TUeBITAK.
- Basoglu, Serap,Yolal, Meltem,Demirbas, Ahmet,Bektas, Hakan,Abbasoglu, Rza,Demirbas, Neslihan
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experimental part
p. 37 - 53
(2012/04/10)
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- A facile solvent-free synthesis of chiral oxazolidinone derivatives catalyzed by MgI2 etherate: An approach to enantiopure synthesis of linezolid
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A highly efficient and stereoselective cycloaddition of aryl isocyanates with chiral oxiranes catalyzed by MgI2 etherate under solvent-free conditions was developed to prepare the chiral oxazolidinone derivatives. This methodology has been applied into the practical synthesis of antibacterial drug linezolid.
- Zhang, Xingxian,Zhao, Chengfeng,Gu, Yue
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p. 1143 - 1146,4
(2020/09/16)
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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4- morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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Page/Page column 9
(2012/09/11)
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- PROCESSES FOR PREPARING LINEZOLID
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Processes and intermediates for preparing linezolid, and pharmaceutically acceptable salts thereof, are described herein.
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- PROCESS FOR THE PREPARATION OF LINEZOLID
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The present invention provides an improved process for the preparation of Linezolid of formula (D. The present invention relates to preparation of intermediate (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl |-2-oxo-5-oxazolidinyl] methanol of formula (II), Linezolid amine of formula (Ia) and their use in the preparation of Linezolid. The present invention further provides process for the preparation of Form I of Linezolid of formula (I).
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Page/Page column 11; 12
(2011/07/09)
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- PROCESSES FOR THE PREPARATION OF LINEZOLID
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Disclosed herein a process for preparing linezolid, wherein the resultant linezolide is devoid of impurities and involve easy and economical process. The present invention further relates to preparation of linezolid by employing an azide intermediate and process for said intermediate.
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Page/Page column 18
(2011/10/10)
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- NOVEL 2,6-SUBSTITUTED-3-NITROPYRIDINE DERIVATIVE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION INCLUDING SAME
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The present invention relates to a novel 2,6-substituted-3-nitropyridine derivative compound, a method for preparing the same, and a pharmaceutical composition including the same for prevention and treatment of osteoporosis. The 2,6-substituted-3-nitropyr
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Page/Page column 14
(2012/01/03)
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- NOVEL 2,6-SUBSTITUTED-3-NITROPYRIDINE DERIVATIVE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION INCLUDING SAME
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The present invention relates to a novel 2,6-substituted-3-nitropyridine derivative compound, a method for preparing the same, and a pharmaceutical composition including the same for prevention and treatment of osteoporosis. The 2,6-substituted-3-nitropyr
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Page/Page column 21
(2012/01/03)
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- METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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A method for preparing the linezolid (compound 1), which comprises the steps of: (1) carrying out the debenzyl reaction of compound 4 in solvent, to obtain the compound 5 or its acetate; (2) carrying out the acetylation reaction in the amino of the compound 5 or its acetate obtained in step (1) in solvent to obtain the compound 1. The intermediates to prepare the compound 1 and the acetate of compound 5. The present preparation method is easy to obtain the chiral materials and the chiral materials are cheap, the process and the post treatment are simple, the intermediate products and the end product are easy to be purified, the total yield is high, their purities are also high, this preparation method is easy to be used in the industry manufacture.
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Page/Page column 7
(2011/11/13)
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- METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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A method for preparing the linezolid (compound 1), which comprises the steps of: (1) carrying out the debenzyl reaction of compound 4 in solvent, to obtain the compound 5 or its acetate; (2) carrying out the acetylation reaction in the amino of the compound 5 or its acetate obtained in step (1) in solvent to obtain the compound 1. The intermediates to prepare the compound 1 and the acetate of compound 5. The present preparation method is easy to obtain the chiral materials and the chiral materials are cheap, the process and the post treatment are simple, the intermediate products and the end product are easy to be purified, the total yield is high, their purities are also high, this preparation method is easy to be used in the industry manufacture.
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Page/Page column 8
(2011/12/03)
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- Anti-Viral Compounds
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Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
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- Design and synthesis of novel 5-acetylthiomethyl oxazolidinone analogs
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The oxazolidinone class of antimicrobial agents represents a promising advance in the fight against resistant Gram-positive bacterial infections. To improve antibacterial activity and expand the spectrum of activity including Gram-negative bacteria, a series of novel 5-acetylthiomethyl oxazolidinone analogs were designed and synthesized based on the structure-activity relationship studies. The structures of the target compounds and main intermediates were confirmed by 1H NMR, 13C NMR, infrared (IR), mass spectra (MS), and elemental analysis.
- Chen, Lei,Wang, Jian-Wei,Hai, Li,Wang, Guang-Ming,Wu, Yong
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experimental part
p. 789 - 798
(2010/05/18)
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- A new practical synthesis of linezolid: An antibacterial drug
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A novel and practical asymmetric synthesis of (S)-N-[[3-(3-fluoro-4- morpholinyl phenyl)-2-oxo-5-oxazo- lidinyl]methyl]acetamide has been developed by a new approach without recourse to chromatography and it is employed for the synthesis of Linezolid. This involves the reaction of (R)-epichlorohydrin with N-arylcarbamates and subsequent regioselective epoxide ring opening of resulted intermediate by sodium azide.
- Reddy, Ganta Madhusudhan,Ramulu, Akula,Reddy, Padi Pratap
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experimental part
p. 45 - 49
(2010/08/13)
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- Syntheses and antibacterial activity studies of new oxazolidinones from nitroso Diels-Alder chemistry
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A series of novel oxazolidinone antibiotics having [2.2.1] and [2.2.2] bicyclic oxazine moieties at the C-5 side chain of the A-ring was synthesized by nitroso Diels-Alder reactions, from three linezolid analogs containing morpholine, piperazine and thiomorpholine, respectively, as the C-ring components. Subsequent N-O bond cleavage generated oxazolidinones with 4-amino cyclo-2-en-1-ol substituents. The in vitro antibacterial activities of these oxazolidinone analogs were evaluated.
- Yan, Shanshan,Miller, Marvin J.,Wencewicz, Timothy A.,Moellmann, Ute
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supporting information; experimental part
p. 1302 - 1305
(2010/06/15)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 106-107
(2009/04/25)
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- An efficient and practical synthesis of antibacterial linezolid
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A convergent and efficient synthesis of linezolid was developed using the cycloaddition of commercially available (R)-epichlorohydrin with morpholine substituted phenylisocyanate catalysed by MgI2 or MgBr2 etherate as the key step in the 50% overall yield.
- Zhang, Xingxian,Chen, Wei,Li, Cheng,Wu, Xiang
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scheme or table
p. 739 - 740
(2010/03/24)
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- PROCESS FOR PREPARATION OF (S) (N-[[3-[3-FLUORO-4-(4-MORPHOLINYL) HEN L -2-OXO-5-OXAZOLIDIN L METHYL]ACETAMIDE
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The present invention provides novel process for preparation of (S)-N-[[3-[3-Fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] -acetamide which comprises combining (R)-N-[3-[3-fluoro-4-morpholinyl phenyl]-2-oxo-5-oxazolidinyl]methylazide in suitable solvent, acetylating agent and acid in presence of a catalyst.
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Page/Page column 13
(2009/06/27)
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- PIPERAZINE COMPOUNDS FOR THE INHIBITION OF HAEMATOPOIETIC PROSTAGLANDIN D SYNTHASE
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The present invention relates to compounds of general formula (I): wherein A, Y, X, n and B are as defined herein; and their use in the treatment and prevention of metabolic disorders, inflammatory conditions, allergic conditions, fever, pain including allodynia and nociception, eating disorders, cachexia, brain injuries, cancer of the genitals, sleep apnoea, cardiovascular disease, flush effect associated with nicotinic acid and related compounds or for the promotion of wound healing. Certain compounds of general formula (I) are new and the invention also relates to these compounds and to their use in medicine.
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Page/Page column 70-71
(2008/12/04)
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- Tandem of nucleophilic substitution of hydrogen and cyclocondensation with participation of nitro group in the synthesis of fluorine-containing 3-amino-1,2,4-benzotriazines
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Reactions of 3-fluoro-1-nitrobenzenes with guanidine hydrochloride in THF in the presence of ButOK gave isomeric 5-and 7-fluoro-containing 3-amino-1,2,4-benzotriazines. Springer Science+Business Media, Inc. 2006.
- Zhumabaeva,Kotovskaya,Perova,Charushin,Chupakhin
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p. 1243 - 1247
(2008/02/03)
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- PIPERIDINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORTER INHIBITORS
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The invention provides a compound of formula (1), or a salt or solvate thereof: wherein R, R5, R6, R7, R8, R9, X, n and Ar are as defined in the specification, and uses of such compounds. The compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.
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Page/Page column 31
(2010/02/15)
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- GLYCINE TRANSPORTER-1 INHIBIRORS
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The invention provides a compound of formula (I) or a salt or solvate thereof: wherein R1, and R3 and R10, X and Ar are as defined in the specification, and uses of such compounds. The compounds inhibit GlyT1 transporters
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Page/Page column 35
(2010/02/12)
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