- Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists
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GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76percent inhibition at 0.3 μM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1, exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model.
- Sun, Nannan,Huang, Yafei,Yu, Mingcheng,Zhao, Yunpeng,Chen, Ji-An,Zhu, Chenyu,Song, Meiqi,Guo, Huimin,Xie, Qiong,Wang, Yonghui
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- BIARYL UREA DERIVATIVE OR SALT THEREOF, AND MANUFACTURING AND APPLICATION OF SAME
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The present invention discloses a biaryl urea RORγt inhibitor, and specifically relates to a biaryl urea derivative, as represented by formula I, with an RORγt inhibiting activity, and a preparation process thereof, and a pharmaceutical composition comprising the compound. Further disclosed is use of the compound for treating an RORγt-related disease.
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Paragraph 0221
(2019/05/10)
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- Dual Ligand-Enabled Nondirected C-H Cyanation of Arenes
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Aromatic nitriles are key structural units in organic chemistry and, therefore, highly attractive targets for C-H activation. Herein, the development of an arene-limited, nondirected C-H cyanation based on the use of two cooperatively acting commercially available ligands is reported. The reaction enables the cyanation of arenes by C-H activation in the absence of directing groups and is therefore complementary to established approaches.
- Chen, Hao,Mondal, Arup,Wedi, Philipp,Van Gemmeren, Manuel
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p. 1979 - 1984
(2019/02/19)
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- Photodriven Transfer Hydrogenation of Olefins
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An improved practical method for the photodriven diimide reduction of olefins was investigated. This catalyst-free procedure proceeds at ambient temperature, utilizes air as oxidant and a lower hydrazine loading, and produces inert nitrogen gas as the sole byproduct. Several functional groups were tolerated, and in some cases, the reaction was chemoselective. Challenging substrates such as cinnamate ester derivatives and trans-stilbene were reduced in excellent yields. The small amount of UVA rays emitted from a household compact fluorescent light bulb was proposed to enable the cis/trans isomerization of the diimide and to promote the loss of hydrogen from the diimide.
- Leow, Dasheng,Chen, Ying-Ho,Hung, Tzu-Hang,Su, Ying,Lin, Yi-Zhen
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p. 7347 - 7352
(2016/02/18)
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- Oxadiazole derivatives as S1P1 receptor agonists
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New compounds having the chemical structure of formula (I) or pharmaceutically acceptable salts or N-oxides thereof wherein A is selected from the group consisting of -N-, -O- and -S-; B and C independently are selected from the group consisting of -N- and -O-, with the proviso that at least two of A, B and C are nitrogen atoms; G1 is selected from the group consisting of nitrogen atoms and -CRC- groups, wherein RC represents a hydrogen atom, a halogen atom, a C1-4 alkyl group or a C1-4 alkoxy group; R1 is selected from the group consisting of hydrogen atoms, C1-4 alkyl groups, C1-4 alkoxy groups, C3-4 cycloalkyl groups, and -NRdRe groups wherein Rd and Re are independently selected from hydrogen atoms and C1-4 alkyl groups; R2 and R3 are independently selected from the group consisting of hydrogen atoms and C1-4 alkyl groups; R4, R5 and R7 are independently selected from the group consisting of hydrogen atoms, halogen atoms, C1-4 alkyl groups, C1-4 alkoxy groups and C1-4 haloalkyl groups; R6 represents a C1-4 alkyl group or a C1-4 hydroxyalkyl group; or R6 is selected from the group consisting of -S(O)2-NRaRb groups, -(CRfRg)n-(CRhRi)x-(CRjRk)y-NRaRb groups, -(CH2)n-NRaRb groups, -O-(CH2)n-NRaRb groups, -(CH2)n-COOH groups, -(CH2)n-NRa-CO-Rb' groups, -(CH2)n-NRa-(CH2)p-(NH)q-SO-CH3 groups and -(CH2)n-CO-NRaRb groups, wherein n, p, x and y are each independently integers from 0 to 3, q is 0 or 1, Rf, Rg, Rh, Ri, Rj and Rk independently represent hydrogen atoms or halogen atoms, Rb' is selected from the group consisting of methylsulphonyl groups, C1-4 alkyl groups, C1-4 hydroxyalkyl groups, C1-4 carboxyalkyl groups, and C1-4 haloalkyl groups; Ra and Rb are independently selected from the group consisting of hydrogen atoms, methylsulphonyl groups, C1-4 alkyl groups, C1-4 hydroxyalkyl groups, C1-4 carboxyalkyl groups, and C1-4 haloalkyl groups, or Ra and Rb together with the nitrogen atom to which they are attached form a 4 to 6 membered, saturated heterocyclic group, which contains, as heteroatoms, one or two nitrogen atoms and which is substituted by a carboxyl group or a C1-4 carboxyalkyl group; or Rc together with R6 form a C5-8 carbocyclic ring optionally substituted by - NHR' wherein R' represents a hydrogen atom or a 61-4 carboxyalkyl group.
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Page/Page column 33
(2010/08/07)
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- Indium triiodide catalyzed direct hydroallylation of esters
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The InI3-catalyzed hydroallylation of esters by using hydroand allysilanes under mild conditions has been accomplished. Many significant groups such as alkenyl, alkynyl, cyano, and nitro ones survive under these conditions. This reaction system, provided routes to both homoallylic alcohols and ethers, in which either elimination of the alkoxy moiety or of the carbonyl oxygen atom could be freely selected by changing the substituents on the alkoxy moiety and on the hydrosilane. In addition, the hydroallylation of lactones took place without ring cleavage to produce the desired cyclic ethers in high yields.
- Nishimoto, Yoshihiro,Inamoto, Yoshihiro,Saito, Takahiro,Yasuda, Makoto,Baba, Akio
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supporting information; experimental part
p. 3382 - 3386
(2010/08/19)
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the Formula IX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- 5-membered heterocyclic compounds, processes for preparing them and pharmaceutical compositions containing these compounds
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Compounds of the formula STR1 wherein X1 to X5 are as defined herein, the tautomers, the stereoisomers including the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. The compounds are useful for inhibiting undesirable cell aggregation.
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- Novel Visible-Light-Driven Photocatalyst. Poly(p-phenylene)-Catalyzed Photoreductions of Water, Carbonyl Compounds, and Olefins
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The insoluble yellow powder of poly(p-phenylene) (PPP) prepared by nickel-catalyzed polycondensation of the Grignard reagent from 1,4-dibromobenzene shows photocatalytic activity under visible light toward water, carbonyl compounds, and olefins.Water is photoreduced to H2 in the presence of amines as sacrificial electron donors.The H2 evolution is enhanced 3-20 times by noble-metal deposition, in which Ru deposition is the most effective.Apparent quantum yields (Φ(1/2H2)) for Ru-loaded PPP-catalyzed H2 evolution depend on the irradiation wavelength, reaching a maximum value of 0.015 at 405 nm.On the other hand, nonmetallized PPP can more efficiently photocatalyze the reduction of carbonyls and electron-deficient olefins by triethylamine in methanol compared to Ru-loaded PPP, in cases where the reduction potentials of the substrates are more positive than -2.0 V vs Ag/0.01 M AgNO3.The carbonyls are reduced to the corresponding alcohols and/ or pinacols, whereas the reduction of the olefins to the dihydro compounds is accompanied by rapid cis-trans photoisomerization.From the deuterium incorporation experiments for the photocatalyzed reduction of methyl 4-cyanocinnamate, 6j, in methanol-O-d, disproportionation of one-electron-transfer reduction intermediates is suggested to be responsible for the eventual two-electron reductions and the cis-trans-photoisomerization.The physical and spectral properties of PPP's are characterized, and the mechanism is discussed in terms of the energy structure.
- Shibata, Takuya,Kabumoto, Akira,Shiragami, Tsutomu,Ishitani, Osamu,Pac, Chyongjin,Yanagida, Shozo
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p. 2068 - 2076
(2007/10/02)
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- Redox-photosensitised Reactions. Part 12. Effects of Magnesium(II) Ion on the 2+ -Photomediated Reduction of Olefins by 1-Benzyl-1,4-dihydronicotinamide: Metal-ion Catalysis of Electron Transfer Processes Involving an NADH Model
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Magnesium(II) ion catalyses the photosensitised reduction of carbon-carbon double bonds of dimethylfumarate, derivates of methyl cinnamate, and some other related olefins by 1-benzyl-1.4-dihydronicotinamide (BNAH), which proceeds via sequential two electron transfer initiated by the photoexcitation of +2 (bpy = 2,2'-bipyridine).The metal ion forms a complex with BNAH in methanol as well as in 10:1 (v/v) pyridine-methanol, leading to the retardation of electron transfer from BNAH to luminescent excited-state Ru(ppy)32+.The net metal-ion effects arise from the catalysis of both the first and second one-electron reduction processes.
- Ishitani, Osamu,Ihama, Mikio,Miyauchi, Yoji,Pac, Chyongjin
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p. 1527 - 1532
(2007/10/02)
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- Redox-Photosensitized Reactions. 11. Ru(bpy)32+-Photosensitized Reactions of 1-Benzyl-1,4-dihydronicotinamide with Aryl-Substituted Enones, Derivatives of Methyl Cinnamate, and Substituted Cinnamonitriles: Electron-Transfer Mechanism and Structure-Reactivity Relationship
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Reactions of 1-benzyl-1,4-dihydronicotinamide (BNAH) with aryl-substituted enones and derivatives of methyl cinnamate and cinnamonitrile (1a-u) are photosensitized by Ru(bpy)32+ (bpy = 2,2'-bipyridine).The reduction of carbon-carbon double bonds commonly requires the substitution of either an electron-withdrawing aryl group or two phenyl groups at the β-carbon atom of 1.With enones which possess one aryl substituent with no extra electron-withdrawing group at the β position, the photosensitized reactions result in no two-electron reductions but give 1:1 adducts (4d-h) along with half-reduced dimers of olefins (3d and 3g) and a half-oxidized dimer of BNAH (5).The observed results can be easily interpreted by assuming the intervention of 1-benzyl-3-carbamoyl-1,4-dihydropyridin-4-yl radical (BNA.) and half-reduced species (.1-H) as key intermediates that are formed by mediated electron-proton transfer from BNAH to 1 in which Ru(bpy)32+ acts as a one-electron shuttle upon photoexcitation in the initial electron transfer.Whether BNA. undergoes electron transfer to or a radical-coupling reaction with .1-H depends on steric and electronic properties of .1-H which should be affected by the substituents at the radical center.Mechanistic implications for thermal reactions of NADH models with olefins in the dark are briefly discussed on the basis of these observations.
- Pac, Chyongjin,Miyauchi, Yoji,Ishitani, Osamu,Ihama, Mikio,Yasuda, Masahide,Sakurai, Hiroshi
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- The Transmission of Substituent-Induced 13C NMR Chemical Shifts in para-Substituted 3-Phenyl Propanoic Acid Methyl Esters
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Carbon-13 chemical shifts have been measured of para-substituted 3-phenyl propanoic acid methyl esters.The substituent-induced 13C shifts of the side chain were related to Hammett substituent effects by the dual substituent parameter method.The transmission of substituent effects and the factors that influence 13C shifts are discussed. - Keywords: Dual Substituent Parameters, Polar and Steric Interactions, Conformational Energy, 13C NMR Spectra
- Radeglia, R.,Spassov, S. L.,Stefanova, R.,Simova, S. D.
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p. 934 - 936
(2007/10/02)
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