- HETEROCYCLIC SYSTEMS CONTAINING BRIDGEHEAD NITROGEN ATOMS. PART LXVIII. REACTION OF 5-FLUOROBENZIMIDAZOLYL-2-THIONE WITH CHLOROACETIC ACID: STUDIES OF ORIENTATION OF CYCLIZATION IN THE SYNTHESES OF 6-FLUORO- AND 7-FLUOROTHIAZOLOBENZIMIDAZOL-3(2H)-ONES
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4-Fluoroaniline on successive acetylation, nitration and hydrolysis affords 4-fluoro-2-nitroaniline which on reduction with Raney nickel and hydrazine hydrate followed by treatment of the resulting diamine with carbon disulphide in situ gives 5-fluorobenzimidazolyl-2-thione.The thione on condensation with chloroacetic acid yields acetic acid which on cyclization in a mixture of acetic anhydride and pyridine furnishes two isomers viz. 6-fluoro- and 7-fluorothiazolobenzimidazol-3(2H)-ones.The condensation of thione with 1,2-dibromoethane affords sym-bis-(5-fluorobenzimidazo-2-yl-mercapto)ethane.The structural assignments for the 6-fluoro- and 7-fluorothiazolobenzimidazol-3(2H)-ones have been made by 1H-NMR spectral data using two different methods.
- Pujari, H. K.,Sharma, B. R.,Dahiya, Rajender,Kumar, Sudhir,Murakami, Yasuoki,Tani, Masanobu
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Read Online
- Method for synthesizing 4-fluoro -2- nitroaniline through microchannel reactor (by machine translation)
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The method is characterized in, after 4 - reaction is carried out at, by using: a high-throughput continuous flow micro-channel, reactor at a flow rate 1:1.0-1.5 of, 20%-40% -fluoroacetanilide acetic acid-acetic anhydride solution 68% and, nitric acid 40.0-100.0mL/min, 4.0-30.0mL/min, are then; stirred through hydrolysis reaction and then stirred for 30 °C -70 °C hours in 50-200s DEG C to 90 °C -100 °C; prepare orange solid 2-4h, 0 °C -5 °C 0.5h fluorine - 2 nitroaniline, and then the, reaction process, is safe, 4 - and stable . The method 83%-94%. comprises, the following, steps, of: times short efficiency high by-product of the present invention; and drying and then drying the filter, into a weakly acidic or neutral mixture of acetic acid and then drying the filter cake. (by machine translation)
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Paragraph 0015-0023
(2020/05/01)
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- A preparation method for 4-methoxy-2-nitrobenzoic acid
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An industrial preparation method for 4-methoxy-2-nitrobenzoic acid is disclosed. In the method, p-difluorobenzene is adopted as an initial raw material and subjected to nitration, ammonolysis, diazotization bromination, cyaniding, methoxylation and hydrolysis which are six steps to synthesize the 4-methoxy-2-nitrobenzoic acid. The 4-methoxy-2-nitrobenzoic acid obtained by the method is white powdered solid with purity being 98.5%, the raw material conversion ratio in each step is 100%, and the total yield of the whole process is 35.8%.
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- Harnessing the pyrroloquinoxaline scaffold for FAAH and MAGL interaction: Definition of the structural determinants for enzyme inhibition
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This paper describes the development of piperazine and 4-aminopiperidine carboxamides/carbamates supported on a pharmacogenic pyrroloquinoxaline scaffold as inhibitors of the endocannabinoid catabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Structure-activity relationships and molecular modelling studies allowed the definition of the structural requirements for dual FAAH/MAGL inhibition and led to the identification of a small set of derivatives (compounds 5e, i, k, m) displaying a balanced inhibitory profile against both enzymes, with compound 5m being the frontrunner of the subset. Favorable calculated physico-chemical properties suggest further investigation for specific analogues.
- Brindisi, Margherita,Brogi, Simone,Maramai, Samuele,Grillo, Alessandro,Borrelli, Giuseppe,Butini, Stefania,Novellino, Ettore,Allarà, Marco,Ligresti, Alessia,Campiani, Giuseppe,Di Marzo, Vincenzo,Gemma, Sandra
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p. 64651 - 64664
(2016/07/23)
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- Palladium(II)-catalyzed, heteroatom-directed, regioselective C-H nitration of anilines using pyrimidine as a removable directing group
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A new palladium-catalyzed, heteroatom-directed strategy for C-H nitration of anilines is described. This C-H functionalization reaction is highly ortho-selective and results in very good yields. The highlight of the work is the use of pyrimidine as the removable directing group. This approach constitutes one of the rare methods of ortho-nitration of anilines, a reaction that is normally very difficult to achieve via traditional approaches.
- Pawar, Govind Goroba,Brahmanandan, Abhilashamole,Kapur, Manmohan
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p. 448 - 451
(2016/02/18)
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- Indole and indazole compounds as an inhibitor of cellular necrosis
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The present invention refers to a formula (1) compounds of, pharmaceutically acceptable salts or isomers thereof thereof, and characterized by by containing as active ingredients-associated diseases, cell death and method for the prevention or treatment of relates and compositions. [Formula 1] In formula said R 1, R 2, R 3, R 4, R 5, R 6, A, X, n and m to equal the specification.
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Paragraph 0339; 0344-0346; 0349
(2016/10/08)
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- Discovery and optimization of benzotriazine Di-N-oxides targeting replicating and nonreplicating mycobacterium tuberculosis
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Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC 50) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.
- Chopra, Sidharth,Koolpe, Gary A.,Tambo-Ong, Arlyn A.,Matsuyama, Karen N.,Ryan, Kenneth J.,Tran, Tran B.,Doppalapudi, Rupa S.,Riccio, Edward S.,Iyer, Lalitha V.,Green, Carol E.,Wan, Baojie,Franzblau, Scott G.,Madrid, Peter B.
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p. 6047 - 6060
(2012/09/05)
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- INDOLE AND INDAZOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to indole or indazole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole or indazole compounds as an active ingredient.
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Page/Page column 12
(2010/08/08)
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- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 18
(2010/08/22)
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- INDOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.
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Page/Page column 60
(2009/04/25)
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- INDOLE AND INDAZOLE COMPOUNDS AS AN INHIBITOR OF CELLULAR NECROSIS
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The present invention relates to indole or indazole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole or indazole compounds as an active ingredient.
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Page/Page column 43
(2009/04/25)
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- Synthesis of novel fluorobenzofuroxans by oxidation of anilines and thermal cyclization of arylazides
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The synthesis of several fluorobenzofuroxans by oxidation of fluoroanilines and thermal cyclization of fluoroarylazides is presented. The fluorobenzofuroxans prepared in this study presented tautomerism as evidenced by their NMR data. Benzofuroxans in general have biological activity and are synthetic intermediates for the preparation of several compounds with important pharmaceutical applications.
- Leyva, Socorro,Castanedo, Víctor,Leyva, Elisa
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p. 171 - 175
(2007/10/03)
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- A convenient copper-catalyzed direct animation of nitroarenes with 9-alkylhydroxylamines
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O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base and a copper catalyst to give aminonitroarenes in good yields, ortho- or para-Animation with respect to the nitro group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to give the sterically most congested 3c-f, 14 and 22g.
- Seko, Shinzo,Miyake, Kunihito,Kavvamura, Norio
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p. 1437 - 1444
(2007/10/03)
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- Synthesis of meta-substituted aniline derivatives by nucleophilic substitution
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Substitution by amines of fluorobenzenes containing a meta- substituted electron withdrawing group (EWG), in DMSO at 100 °C over 60 h gave meta-substituted aniline derivatives in isolated yields of up to 98%. The scope of the reaction is explored in terms of reaction conditions and substrates. It is postulated that facile meta-substitutions are facilitated through field stabilisation of the intermediate anion by EWG substituents.
- Belfield, Andrew J.,Brown, George R.,Foubister, Alan J.,Ratcliffe, Paul D.
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p. 13285 - 13300
(2007/10/03)
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- Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
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Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
- Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
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p. 4906 - 4916
(2007/10/03)
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- Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
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Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy.Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy.The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells.Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and /or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells.Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced.Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxide have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V).The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine.The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity.Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro.In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine.This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.
- Monge, Antonio,Palop, Juan A.,Cerain, Adela Lopez de,Senador, Virginia,Martinez-Crespo, Francisko J.,et al.
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p. 1786 - 1792
(2007/10/02)
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- Hydroxylamine derivative of 5-nitro-8-hydroxy quinoline
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Novel hydroxylamino derivatives of the formula wherein Ar is selected from the group consisting of mono- and polycyclic aromatics and hetero-aromatics, both optionally substituted with at least one member of the group consisting of --OH, halogen, --NO2, --CN, STR1 --R7, --OR8, STR2 --SO2 R12, --SO3 R13, --COOR14, aryl of 6 to 14 carbon atoms, --OR16, --CH2 --CN and --CH2 SO2 --R15, R1, R2, R3, R4, R5 and R6 are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R7 and R8 are optionally unsaturated alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of halogen and cyano, R9, R10, R11, R12 and R13 are alkyl of 1 to 8 carbon atoms, Z is selected from the group consisting of hydrogen, optionally unsaturated alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 2 to 18 carbon atoms, R14 is selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R15 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and aryl of 6 to 14 carbon atoms optionally substituted with an alkyl of 1 to 8 carbon atoms, R16 is aryl of 6 to 14 carbon atoms optionally substituted with a member of the group consisting of alkyl of 1 to 8 carbon atoms, halogen and --NO2, the substituents of Ar being able to form rings containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and their non-toxic agriculturally acceptable acid addition salts with the proviso Ar is not phenyl nor phenyl with one methyl in the 2,3 or 4 position, a nitro in the 2- or 4-position, a chlorine in the 3- or 4-position, a bromine in the 4-position or a --CF3 in the 4-position nor 2,4-dinitrophenyl nor 2-nitro-4-trifluoromethylphenyl nor 2,6-dinitrophenyl nor 2,4,6-trinitrophenyl nor 2,4-dinitro-6-trifluoromethylphenyl useful for increasing vegetation growth and increasing crop yields and their preparation.
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- FLUORINATED TRICYCLIC NEUROLEPTICS WITH PROLONGED ACTION: 7-FLUORO-11--2-ISOPROPYL-10,11-DIHYDRODIBENZOTHIEPIN
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Substitution reaction of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzothiepin with 1-(2-hydroxyethyl)piperazine gave the title compound I which proved a very potent and long acting oral neuroleptic agent ("isofloxythepin").Its resolution by means of dibenzoyl-(+)- and (-)-tartaric acid led to (-)- and (+)-enantiomer out of which the former represents the neuroleptically active component.In the synthetic sequence leading to I, preparation of two key intermediates was re-elaborated using new partial sequences: 4-fluoro-2-iodobenzoic acid (XIII) from 4-fluoro-2-nitroaniline (V) via the nitrile VI and the acids VIII and XII, and acetic acid (XVIII) from XIII via XIV and the compounds XV-XVII.The sulfoxides and N-oxides XIX-XXII were prepared as potential metabolites of isofloxithepin (I).
- Protiva, Miroslav,Jilek, Jiri,Rajsner, Miroslav,Pomykacek, Josef,Ryska, Miroslav,et al.
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p. 698 - 722
(2007/10/02)
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