- Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues
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The interaction between Lymphocyte function-associated antigen 1 (LFA-1) and intercellular-adhesion molecule-1 (ICAM-1) plays important roles in the cell-mediated immune response and inflammation associated with dry eye disease. LFA-1/ICAM-1 antagonists can be used for the treatment of dry eye disease, such as Lifitegrast which has been approved by the FDA in 2016 as a new drug for the treatment of dry eye disease. In this study, we designed and synthesized some new structure compounds that are analogues to Lifitegrast, and their biological activities were evaluated by in vitro cell-based assay and also by in vivo mouse dry eye model. Our results demonstrated that one of these analogues of Lifitegrast (compound 1b) showed good LFA-1/ICAM-1 antagonist activity in in vitro assay; meanwhile, it also significantly reduced ocular surface epithelial cells damage, increased goblet cell density in dry eye mouse and highly improved the symptoms of dry eye mouse. [Figure not available: see fulltext.]
- An, Yuanlong,Du, Guoxin,Du, Weiwei,Gong, Qi,Hao, Feifei,He, Wei,He, Xiangdong,Jiang, Hualiang,Tong, Xiaochu,Wang, Minnan,Zhang, Donglei,Zheng, Mingyue
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- Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery
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Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 μM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 μM). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.
- Solbak, Sara Marie ?ie,Zang, Jie,Narayanan, Dilip,H?j, Lars Jakobsen,Bucciarelli, Saskia,Softley, Charlotte,Meier, Sebastian,Langkilde, Annette Eva,Gotfredsen, Charlotte Held,Sattler, Michael,Bach, Anders
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p. 1156 - 1177
(2020/03/10)
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- Imidazopyridine-fused [1,3]diazepinones: modulations of positions 2 to 4 and their impacts on the anti-melanoma activity
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A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their poten
- Ali, Lamiaa M. A.,Baccon-Sollier, Paul Le,Cuq, Pierre,Lichon, Laure,Malki, Yohan,Masurier, Nicolas,Maye, Morgane,Vincent, Laure-Ana?s
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p. 935 - 949
(2020/04/17)
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- Catalytic Reductions Without External Hydrogen Gas: Broad Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary Amine
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Facile reduction of aryl halides with a combination of 5% Pd/C, B2(OH)4, and 4-methylmorpholine is reported. Aryl bromides, iodides, and chlorides were efficiently reduced. Aryl dihalides containing two different halogen atoms underwent selective reduction: I over Br and Cl, and Br over Cl. Beyond these, aryl triflates were efficiently reduced. This combination was broadly general, effectuating reductions of benzylic halides and ethers, alkenes, alkynes, aldehydes, and azides, as well as for N-Cbz deprotection. A cyano group was unaffected, but a nitro group and a ketone underwent reduction to a low extent. When B2(OD)4 was used for aryl halide reduction, a significant amount of deuteriation occurred. However, H atom incorporation competed and increased in slower reactions. 4-Methylmorpholine was identified as a possible source of H atoms in this, but a combination of only 4-methylmorpholine and Pd/C did not result in reduction. Hydrogen gas has been observed to form with this reagent combination. Experiments aimed at understanding the chemistry led to the proposal of a plausible mechanism and to the identification of N,N-bis(methyl-d3)pyridin-4-amine (DMAP-d6) and B2(OD)4 as an effective combination for full aromatic deuteriation. (Figure presented.).
- Korvinson, Kirill A.,Akula, Hari K.,Malinchak, Casina T.,Sebastian, Dellamol,Wei, Wei,Khandaker, Tashrique A.,Andrzejewska, Magdalena R.,Zajc, Barbara,Lakshman, Mahesh K.
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supporting information
p. 166 - 176
(2020/01/02)
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- TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE
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The present invention provides compounds of Formula (I): wherein A is as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and/or eosinophil peroxidase (EPX) inhibitors, which may be used as medicaments.
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Paragraph 00363
(2017/03/28)
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- Tunable Ligand Effects on Ruthenium Catalyst Activity for Selectively Preparing Imines or Amides by Dehydrogenative Coupling Reactions of Alcohols and Amines
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Selective dehydrogenative synthesis of imines from a variety of alcohols and amines was developed by using the ruthenium complex [RuCl2(dppea)2] (6 a: dppea=2-diphenylphosphino-ethylamine) in the presence of catalytic amounts of Zn(OCOCF3)2 and KOtBu, whereas the selective dehydrogenative formation of amides from the same sources was achieved by using another ruthenium complex, [RuCl2{(S)-dppmp}2] [6 d: (S)-dppmp=(S)-2-((diphenylphosphenyl)methyl)pyrrolidine], in the presence of catalytic amounts of Zn(OCOCF3)2 and potassium bis(trimethylsilyl)amide (KHMDS). Our previously reported ruthenium complex, [Ru(OCOCF3)2(dppea)2] (8 a), was the catalyst precursor for the imine synthesis, whereas [Ru(OCOCF3)2{(S)-dppmp}2] (8 d), which was derived from the treatment of 6 d with Zn(OCOCF3)2 and characterized by single-crystal X-ray analysis, was the pre-catalyst for the amide formation. Control experiments revealed that the zinc salt functioned as a reagent for replacing chloride anions with trifluoroacetate anions. Plausible mechanisms for both selective dehydrogenative coupling reactions are proposed based on a time-course study, Hammett plot, and deuterium-labeling experiments.
- Higuchi, Takafumi,Tagawa, Risa,Iimuro, Atsuhiro,Akiyama, Shoko,Nagae, Haruki,Mashima, Kazushi
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supporting information
p. 12795 - 12804
(2017/09/06)
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- Unique nanocages of 12CaO·7Al2O3 boost heterolytic hydrogen activation and selective hydrogenation of heteroarenes over ruthenium catalyst
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The chemoselective hydrogenation of heteroarenes is one of the most important synthetic reactions for the production of key intermediates in agrochemicals, pharmaceuticals and various fine chemicals. The development of new heterogeneous catalysts for the environmentally benign synthesis of heterocycle hydrogenated products is a fundamental objective for chemists. Here, we report that 12CaO·7Al2O3 with a unique sub-nanocage structure loaded with Ru nanoparticles exhibits higher activity, chemoselectivity and sustainability for the hydrogenation of heteroarenes in a solvent-free system than traditional oxide-supported metal catalysts. Conversion of >99% and a selectivity close to 99% were achieved for the hydrogenation of quinoline under mild conditions. This catalyst was also successfully applied to the hydrogenation of a variety of N- and O-heteroarenes with high yields. The superior catalytic performance can be attributed to a cooperative effect between the hydrogen-storage ability and large amount of strong basic sites on the surface of the support, which promotes heterolytic H2 cleavage and prevents poisoning of the metal surface caused by the adsorption of heteroarenes.
- Ye, Tian-Nan,Li, Jiang,Kitano, Masaaki,Hosono, Hideo
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p. 749 - 756
(2017/05/22)
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- 6-O-SUBSTITUTED KETOLIDES HAVING ANTIBACTERIAL ACTIVITY
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PROBLEM TO BE SOLVED: To provide 6-O-substituted ketolides with antibacterial activity, having acid stability and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria. SOLUTION: This invention provides 6-O-substituted erythromycin ketolide derivatives such as formula (II) and compositions comprising the compounds. [Y and Z together form a group X; X is ketone, hydroxyimino or the like; or, one of Y and Z is H and the other is hydrogen, hydroxy or the like; Ra is H, hydroxy; Rc is H or a hydroxy protective group; R is a substituted methyl group]. COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0301; 0302
(2016/10/27)
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- Design, synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents
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Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20 compounds was designed and synthesized, among which eight compounds showed equivalent or higher potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3 and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model, compound 1o displayed significant antitumor activity in both continuous and intermittent dosing schedules.
- Cheng, Jianjun,Qin, Jihong,Guo, Sihua,Qiu, Hangdeng,Zhong, Yun
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p. 4768 - 4772
(2015/01/09)
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- Palladium-catalyzed direct hydroxymethylation of aryl halides and triflates with potassium acetoxymethyltrifluoroborate
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Suzuki-Miyaura cross-coupling reactions of aryl halides and triflates with potassium acetoxymethyltrifluoroborate afforded the corresponding aryl and heteroaryl methanol products in moderate to excellent yields.
- Murai, Norio,Yonaga, Masahiro,Tanaka, Keigo
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supporting information; experimental part
p. 1278 - 1281
(2012/04/23)
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- HETEROCYCLIC HYDRAZONE COMPOUNDS AND THEIR USES TO TREAT CANCER AND INFLAMMATION
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The invention relates to compounds of formula (I) and salts thereof: wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).
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Page/Page column 56
(2011/02/24)
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- HETEROCYCLIC OXIME COMPOUNDS
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The invention relates to compounds of formula (I) and salts thereof wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).
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Page/Page column 60
(2011/04/13)
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- NONPEPTIDIC INHIBITORS OF CRUZAIN
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Cruzain is the major cysteine protease of T. cruzi, which is the causative agent of Chagas' disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the Substrate Activity Screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor (38) was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl- oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pTa, with 2,3,5,6-tetrafluorophenoxy methyl ketone (54) identified as one of the most potent inhibitors with a second order inactivation constant of 147,000 s-1M-1. This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemo therapeutics for Chagas' disease.
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Page/Page column 49-50
(2009/07/17)
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- Identification of a new class of nonpeptidic inhibitors of cruzain
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Cruzain is the major cysteine protease of Trypanosoma cruzi, which is the causative agent of Chagas disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the substrate activity screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pKa, with 2,3,5,6- tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation constant of 147,000 s-1 M-1. This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease.
- Brak, Katrien,Doyle, Patricia S.,McKerrow, James H.,Ellman, Jonathan A.
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p. 6404 - 6410
(2008/12/22)
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- NOVEL CYCLIC COMPOUND HAVING QUINOLYLALKYLTHIO GROUP
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The present invention relates to a synthesis study of novel cyclic compounds having a quinolylalkylthio group represented by the formula (1), and pharmacological actions of the compounds. In the formula, the ring X represents: which may have halogen and/or alkyl; R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, aryl or a (non) aromatic heterocycle; R3 represents qinolyl; A represents sulfur, sulfinyl or sulfonyl; and B represents alkylene.
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Page/Page column 15
(2010/11/28)
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- Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use
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Selected compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 27
(2010/02/11)
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- AZOLIDINONE-VINYL FUSED-BENZENE DERIVATIVES
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The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Formula (I), wherein A, X, Y, Z, R1 , R2 and n are as described in the description.
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- Substituted alkylamine derivatives and methods of use
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Selected amines are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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- Quinoline derivatives and medicinal use thereof
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A quinoline derivative represented by the following formula (1): allows PPARα or γ which is an intranuclear transcription factor, to function strongly and is low in toxicity. By using this compound as an active ingredient, there can be provided a preventive or therapeutic agent for various diseases related to PPARα or γ.
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- 6-O-substituted ketolides having antibacterial activity
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Antimicrobial compounds having the formula STR1 as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.
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- Heterocyclic thiazole derivatives and pharmaceutical compositions comprising said derivatives
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The invention concerns a thiazole of the formula I, STR1 wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety continuing up to three nitrogen atoms; R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl; R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and Q2 is optionally substituted thiazolyl; or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
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- HETEROCYCLES FOR USE AS INHIBITORS OF LEUKOTRIENES
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The invention concerns a heterocycle of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R 1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R 2 and R 3 together form a group of the formula --A 2 --X 2 --A 3 -- which, together with the carbon atom to which A 2 and A 3 are attached, defines a ring having 4 to 7 ring atoms, wherein A 2 and A 3, which may be the same or different, each is (1-4C)alkylene and X 2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
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- Heterocyclic derivatives
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The invention concerns a thiazole of the formula I, wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms;, X is oxy, thio, sulphinyl, sulphonyl or imino;, Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety contining up to three nitrogen atoms;, R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl;, R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and, Q2 is optionally substituted thiazolyl;, or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
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- Alpha-aminoacyl-penicillins and cephalosporins
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Antibacterially active and animal growth-regulating novel β-lactam compounds of the formula STR1 in which R1 represents an optionally substituted radical of the formula STR2 Z represents oxygen, sulphur or --N--R13, and A represents
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- ELECTRONIC NATURE OF THE AZA SUBSTITUENT OF PYRIDYL AND QUINOLYL GROUPS FOR REACTIVITIES IN AN INSULATED SYSTEM
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A new set of ?0 values was determined for all positions of pyridyl and quinolyl groups, reliably excluding steric effect by perihydrogen, on the basis of the rates of the alkaline hydrolysis of substituted 2-methylbenzoates and pyridylmethyl and quinolylmethyl 2-methyl-benzoates in 70percent aq acetone.
- Sawada, Masami,Ichihara, Masaharu,Ando, Takashi,Yukawa, Yasuhide,Tsuno, Yuho
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p. 4917 - 4920
(2007/10/02)
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