- 1H, 13C and 15N NMR spectral and theoretical studies of some methyl and alkylamino derivatives of 4-halopyridine N-oxides
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Nine new and three earlier known 4-halogen (Cl and Br) substituted pyridine N-oxides have been prepared and their 1H, 13C and 15N NMR chemical shifts assigned based on PFG 1H, X (X=13C and 15N) HMQC and HMBC experiments as well as the comparison with our earlier results for substituted pyridine N-oxide derivatives. The 15N resonances of the pyridine nitrogen are 27-40 ppm more shielded in 4-halo-2-alkylamino-6-methyl-5-nitropyridine N-oxide than in parent 4-halopyridine N-oxide. According to quantum chemical ab initio HF/6-311G** calculations the amino tautomer of 4-chloro-2- methylamino-6-methyl-5-nitropyridine N-oxide is more stable than its imino form. Using B3LYP/6-311G** optimized structures both 13C and 15N shifts were calculated by density functional B3LYP/6-311G ** CSGT methods for the amino and imino tautomers as well as for the dimeric structure for 4-chloro-2-methylamino-6-methyl-5-nitropyridine N-oxide. The 15N NMR and DFT calculations suggest the prevailing of the dimeric amino form for one congener, which is further supported by ESI-TOF MS data.
- Laihia,Puszko,Linnanto,Kolehmainen
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- CXCR4 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00452; 00453
(2018/04/11)
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- Synthesis and green metric evaluation of 2-(chloromethyl)-3-methyl-4-(methylsulfonyl)pyridine
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2-[[(2-pyridinyl) methyl] sulfinyl]-1H-benzimidazoles are the prominent motif's that belong to the class of prazoles. These are used in the treatment of gastroesophageal reflux disease (GERD) ulcers and other gastric acid related diseases. The present article describes the modified synthesis of 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine (an intermediate utilized in the synthesis of Dexlansoprazole). The advantages of this modification involves (i) N-oxidation of 2,3-lutidine with catalytic quantity of RuCl3 in presence of oxygen (ii) One pot synthesis of 2,3-dimethyl-4-(methylthio) pyridine-N-oxide using 30% NaSH, methyl iodide and tetra butyl ammonium hydroxide (iii) Oxidation of methythio pyridine-N-oxide with 30% H2O2 followed by N-deoxygenation with RuCl3.H2O to produce 2,3-dimethyl-4-(methylsulfonyl)pyridine (iv) Chlorination of the penultimate step using trichloroisocyanuric acid to obtain the desired 2-chloromethyl-4-methanesulfonyl-3-methyl pyridine. Furthermore, green metrics assessment was calculated for the above modified scheme based on the parameters viz., atom economy (AE), reaction mass efficiency (RME) and E-factor. It was observed that, in case of step 4 (oxidation of thiomethyl pyridine-N-oxide), the E-factor value is very less 3.2 which is indicative of less waste generation, when compared to the various steps that are involved in the synthesis.
- Gilbile, Rohidas,Bhavani, Ram,Vyas, Ritu
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p. 930 - 936
(2017/05/29)
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- Diversified synthesis of novel quinoline and dibenzo thiazepine derivatives using known active intermediates
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The novel drug development to control resisting infections in conventional drug therapy is a need of today. Few antiulcer relative derivatives developed by approaching convergent synthesis. The derivatives synthesized successfully are dibenzo thiazepine-pyridine (SLN11-SLN15) and benzimidazole-hydroquinoline based derivatives (SLN16-SLN20). It involved the coupling through microwave, sonication and conventional techniques at final step. The efficient technology identified as sonication technique basically time and yield. The reported compounds were structural characterized by elemental analysis and spectral studies such as 1H, 13C NMR and MS.
- Sharada,Satyanarayana Reddy,Sammaiah,Sumalatha
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p. 7959 - 7966
(2013/09/23)
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- Development of a scalable and safe process for the production of 4-chloro-2,3-dimethylpyridine- N -oxide as a key intermediate in the syntheses of proton pump inhibitors
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2-(Pyridin-2-ylmethanesulfinyl)-1H-benzimidazole-based drugs belong to the most prominent and successfully applied proton pump inhibitors. To fulfill the demand for a flexible and safe procedure for the synthesis of early-stage intermediates which are known to possess a strong exothermal decomposition potential, we have developed a high-yielding telescoped procedure for the synthesis of a key intermediate in the synthesis of these drugs. This strategy turned out to be highly reproducible in laboratory as well as on pilot-plant scale. As the starting material, as well as some of the intermediates, shows a highly exothermal decomposition potential, extensive safety investigations were undertaken. The whole process was adapted in a safe and reliable manner based on the outcome of this systematic approach. Considering these precautions, no safety issues were observed, neither in the laboratory nor in the pilot plant.
- Waser, Mario,Obermueller, Roland,Wiegand, John Matthias,Schiek, Wolfgang,Fierz, Hans,Skranc, Wolfgang
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experimental part
p. 562 - 567
(2011/07/08)
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- PROCESS FOR PREPARATION OF PYRIDINYLMETHYLSULPHINYL BENZIMIDAZOLE COMPOUNDS AND PYRIDINE INTERMEDIATES
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Process for preparing 4-chloro-substituted pyridine intermediates of Formula (I), useful for preparation of pyridinylmethylsulphinyl benzimidazole compounds, especially Rabeprazole is disclosed herein. The invention, further describes process for preparation of stable Rabeprazole sodium of high purity in a reproducible and consistent manner.
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Page/Page column 11-12
(2009/10/22)
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- Synthetic studies connected with the preparation of H+/K +-ATPase inhibitors rabeprazole and lansoprazole
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Synthesis of lansoprazole and rabeprazole using common intermediates is devised. The common intermediates, 2-[(4-nitro-3-methylpyridin-2-yl) methanesulfanyl]-1H-benzoimidazole and 2-[(4-chloro-3-methyl-pyridin-2-yl) methanesulfanyl]-1H-benzoimidazole, were prepared in several ways.
- Radl, Stanislav,Klecan, Ondrej,Havlicek, Jaroslav
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p. 1447 - 1453
(2007/10/03)
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- Identification and synthesis of potential impurities of rabeprazole sodium
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Rabeprazole sodium (1, Achiphex) is a gastric proton pump inhibitor. It causes dose-dependent inhibition of acid secretion and is useful as an anti-ulcer agent. In the process for the preparation of 1, two potential unknown impurities were identified in HPLC at levels ranging from 0.05-0.8%. Based on mass spectral data vide LC-MS, the two impurities were characterized as 2-{[(4-chloro-3-methyl-2-pyridinyl) methyl] sulfinyl}-1H-bezimidazole (2, chloro analogue of rabeprazole) and 2-[{(4-methoxy-3-methyl-2-pyridinyl)methyl} sulfinyl]-1H-benzimidazole (3, methoxy analogue of rabeprazole). The structures were unambiguously established by independently synthesizing them and co-injecting in HPLC. To our knowledge, the compounds 2 and 3 have not been reported as process impurities elsewhere.
- Pingili, R. Reddy,Jambula, M. Reddy,Ganta, M. Reddy,Ghanta, M. Reddy,Sajja,Sundaram,Boluggdu, V. Bhaskar
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p. 814 - 818
(2007/10/03)
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- Preparation of substituted pyridine N-oxide compounds
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A process for preparing substituted pyridine N-oxide compounds of the formula in which R1, R2, R3 and R4 are each H, a carboxyl group or a C1-C12-alkyl radical which may contain atoms from the group of N, O and S, or R1 and R2 and/or R3 and R4 together may each form an optionally substituted C4-C20-alkylene radical which may contain atoms from the group of N, O and S, A is benzyl or a (CH2)m group where m may be an integer from 1 to 12, Z1 and Z2 are each independently O or S, and Y is H, a C1-C12-alkyl radical which may optionally contain atoms from the group of N, O and S, a C6-C20-aryl radical or a C5-C20-heterocycle, and the radicals may optionally be substituted, or Z2 and Y together form an optionally substituted ring or ring system, in which case the ring or ring system may contain atoms from the group of N, O and S, from the corresponding 4-halopyridine N-oxide of the formula in which X is chlorine, bromine or iodine, by reacting the compound of the formula (II), in the presence of a phase transfer catalyst and of a base, with a compound of the formula HZ1-A-Z2-Y??(III) in which Z1, Z2, A and Y are each as defined above, at a temperature up to the reflux temperature, to give the corresponding substituted pyridine N-oxide compound of the formula (I), and also a process for preparing the compound of the formula (II).
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- Process to prepare substituted pyridine-N-oxide compounds
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Verfahren zur Herstellung von substituierten Pyridin-N-oxid-verbindungen der Formel in der R1, R2, R3 und R4 H, eine Carboxylgruppe oder ein C1-C12-Alkylrest, der Atome aus der Gruppe N, O, oder S enthalten kann, sein k?nnen, oder R1 und R2 und/oder R3 und R4 gemeinsam einen gegebenenfalls substituierten C4-C20-Alkylenrest bilden k?nnen, der Atome aus der Gruppe N, O, oder S enthalten kann, A Benzyl oder eine Gruppe (CH2)m bedeutet, wobei m eine ganze Zahl von 1 bis 12 sein kann, Z1 und Z2 unabh?ngig voneinander O oder S sind und Y H, einen C1-C12- Alkylrest, der gegebenenfalls Atome aus der Gruppe N, O, oder S enthalten kann, einen C6-C20-Arylrest oder einen C5-C20-Heterocyclus bedeutet, wobei die Reste gegebenenfalls substituiert sein k?nnen, oder Z2 und Y gemeinsam einen gegebenenfalls substituierten Ring bzw. Ringsystem bilden, wobei der Ring oder das Ringsystem Atome aus der Gruppe N, O, oder S enthalten kann, aus dem korrespondierenden 4-Halo-Pyridin-N-oxid der Formel in der X Chlor, Brom oder lod bedeutet, wobei die Verbindung der Formel (II) in Gegenwart eines Phasentransferkatalysators und einer Base mit einer Verbindung der FormelHZ1-A-Z2-Y in der Z1, Z2, A und Y wie oben definiert sind, bei einer Temperatur bis zur Rückflusstemperatur zu der entsprechenden substituierten Pyridin-N-oxid-Verbindung der Formel (I) umgesetzt wird, sowie ein Verfahren zur Herstellung der Verbindung der Formel (II).
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- 4-Oxoquinolizine antimicrobial having 2-pyridone skeleton as partial structure
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A compound represented by the following Formula (I) or a pharmaceutically acceptable salt thereof: 1wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a cyano group, a hydroxyl group or an amino group; R4 represents a hydrogen atom, an amino-protecting group, an alkyl group or a cycloalkyl group, and R5 represents a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, an alkylthio group, a hydroxyl group, an imino group or an amino group.
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- Structure-activity relationship of 2-[[(2-Pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy
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A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]- 1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 μg/mL. The structure - activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds 'that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]3-methyl-2-pyridyl)methyl]thio]-1H- benzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felis model (125 μmol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.
- Kühler, Thomas C.,Swanson, Marianne,Shcherbuchin, Vladimir,Larsson, H?kan,Mellg?rd, Bj?rn,Sj?str?m, Jan-Eric
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p. 1777 - 1788
(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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- Potential antitumor agents. 14. 4 Substituted 2 formylpyridine thiosemicarbazones
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A series of 4 substituted 2 formylpyridine thiosemicarbazones has been synthesized which contain a tertiary N at the 4 position. These materials were obtained by reacting 4 nitro 2 picoline N oxide, either directly or after conversion to the corresponding 4 chloro derivative, with a variety of secondary amines. Rearrangement of the 4 substituted 2 picoline N oxides with Ac2O yielded respective methyl acetates, which upon acid hydrolysis, MnO2 oxidation, and reaction with thiosemicarbazide resulted in the desired compounds. An alternate procedure which consisted of reacting 4 chloro 2 formylpyridine ethylene acetal with various amines, followed by hydrolysis and reaction with thiosemicarbazide, was also employed. Introduction of an alkyl group at the 3 position of the pyridine ring of 4 morpholino 2 formylpyridine thiosemicarbazone was achieved by utilizing 2,3 dimethyl 4 nitropyridine N oxide; this material was converted to the corresponding 4 chloro derivative which was then subjected to nucleophilic substitution. 4 Morpholino 2 formylpyridine thiosemicarbazone was the most active antineoplastic agent of this series in mice bearing Sarcoma 180 ascites cells and was significantly superior to 5 hydroxy 2 formylpyridine thiosemicarbazone in this test system.
- Agrawal,Booth,DeNuzzo andSartorelli
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p. 1209 - 1214
(2007/10/04)
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