- HMOX1 inducers
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The present invention is related to compounds of structure (I) as heme oxygenase 1 (HMOX 1) inducers. The present invention is also related a method of controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase 1 in a mammalian subject. The definitions of the variables are provided herein.
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Page/Page column 122
(2020/09/18)
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- One-Pot Protocol to Synthesize 2-Aminophenols from Anilines via Palladium-Catalyzed C-H Acetoxylation
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This paper describes a facile one-pot protocol to synthesize 2-aminophenol derivatives via a palladium-catalyzed C-H acetoxylation strategy with 5-nitropyrimidine as a directing group (DG), which can be easily preinstalled and readily removed under mild condition after the coupling. In addition, the transformation is operationally simple, has high functional group tolerance, and is amenable to gram-scale. Moreover, several examples were shown that introduction/removal of 5-nitropyrimidine and the C-H oxylation sequence could be integrated in one pot.
- Zhao, Junhao,Huang, Yifeng,Ma, Guojian,Lin, Ling,Feng, Pengju
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p. 2084 - 2091
(2019/05/21)
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- Synthesis of benzoxazoles via the copper-catalyzed hydroamination of alkynones with 2-aminophenols
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We describe herein the synthetic method to benzoxazole derivatives via the copper-catalyzed hydroamination of alkynones with 2-aminophenols. The method produced a wide variety of functionalized benzoxazole derivatives in good yields. Preliminary mechanistic experiments revealed that the reaction would proceed through the copper-catalyzed hydroamination of alkynones and the sequential intramolecular cyclization of β-iminoketones/elimination of acetophenone promoted by the copper catalyst.
- Oshimoto, Kohei,Tsuji, Hiroaki,Kawatsura, Motoi
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supporting information
p. 4225 - 4229
(2019/05/10)
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- Ortho-aminophenol derivative and preparation method thereof
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The invention first discloses a preparation method of an ortho-aminophenol derivative. The preparation method comprises the following steps: (1) by adopting an aryl amine compound as a substrate and 2-chloro-5-nitropyridine as a guiding base, reacting in acetonitrile, thus obtaining a pyridine aryl amine compound intermediate; (2) catalyzing the pyridine aryl amine compound intermediate in step (1) to make C-H activation reaction in a solvent by using iodobenzene diacetate as an oxidant and palladium acetate as a catalyst, thus obtaining an acetoxylation aniline derivative, draining, and thenperforming the chromatographic separation and purification; and (3) enabling the acetoxylation aniline derivative in step (2) to react in a tetrahydrofuran solvent for 30 min at a normal temperature by virtue of hydrazine hydrate, thus obtaining the ortho-aminophenol derivative, quenching, washing, extracting, drying, draining, and performing the chromatographic separation and purification. The invention also discloses the ortho-aminophenol derivative prepared by the method.
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Paragraph 0080; 0087; 0088; 0088
(2018/07/15)
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS AS CRAC MODULATORS
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The invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium release-activated calcium (CRAC) channel modulators. wherein, ring D is Formula (a) or Formula (b): A and B, which may be same or different, are independently CR3 or N; Y is CR3 or N; L is selected from —NR2C(O)—, —C(O)NR2— and —NR2CRaRb—; Ra and Rb are independently hydrogen, halogen or substituted or unsubstituted alkyl; ring E is selected from the Formula (i) to (vii).
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Paragraph 0258; 0287
(2016/06/13)
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- Enhanced treatment regimens using mTor inhibitors
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The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
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- Discovery of anilinopyrimidine-based naphthamide derivatives as potent VEGFR-2 inhibitors
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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive strategy for the treatment of cancer. Herein, we describe the design, synthesis, and biological evaluation of anilinopyrimidine-based naphthamide derivatives as potent VEGFR-2 inhibitors. Among the new derivatives, compound 3k exhibited high VEGFR-2 inhibitory potency in both enzymatic and VEGF-induced HUVEC cellular proliferation assays (IC50 = 0.5 and 9.8 nM, respectively). Kinase selectivity profiling revealed that 3k was a highly selective VEGFR-2 inhibitor. Moreover, 3k effectively inhibited angiogenesis in HUVEC tube formation assay.
- Lv, Yongcong,Li, Mengyuan,Cao, Sufen,Tong, Linjiang,Peng, Ting,Wei, Lixin,Xie, Hua,Ding, Jian,Duan, Wenhu
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supporting information
p. 1375 - 1380
(2015/07/15)
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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- COMBINATION PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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The present invention provides for methods and pharmaceutical compositions for treating proliferative disorders. In one aspect, the method comprises administration of two cell-cycle suppressors having a synergistic effect. In another aspect, two cell-cycle suppressors having a synergistic effect are provided in a pharmaceutical composition.
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- Discovery of a new series of naphthamides as potent VEGFR-2 kinase inhibitors
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Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a new series of naphthamides as potent inhibitors of VEGFR-2. Among these compounds, 14c exhibited high VEGFR-2 inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with IC50 values of 1.5 and 0.9 nM, respectively. Kinase selectivity profiling revealed that 14c was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-β, and RET. Furthermore, 14c effectively blocked tube formation of HUVEC at nanomolar level. Overall, 14c might be a promising candidate for the treatment of cancer.
- Lv, Yongcong,Li, Mengyuan,Liu, Ting,Tong, Linjiang,Peng, Ting,Wei, Lixin,Ding, Jian,Xie, Hua,Duan, Wenhu
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supporting information
p. 592 - 597
(2014/06/09)
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- Polymer-anchored peroxo compounds of molybdenum and tungsten as efficient and versatile catalysts for mild oxidative bromination
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A polymer supported peroxomolybdate(VI) compound of the type [MoO 2(O2)(CN)2]-PAN [PAN = poly(acrylonitrile)] (PANMo) was obtained by reacting H2MoO4 with 30% H 2O2 and the macromolecular ligand, PAN at near neutral pH. The macrocomplex has been characterized by elemental analysis (CHN and EDX analysis), spectral (IR, UV-Vis and 13C NMR, 95Mo NMR), thermal (TGA-DTG) as well as SEM studies. The catalytic activity of PANMo and its previously reported tungsten containing analog PANW, in oxidative bromination of organic substrates has been explored. The supported complexes could serve as efficient heterogeneous catalysts for the oxidative bromination of a variety of structurally diverse aromatic compounds, with H 2O2 as terminal oxidant, to afford bromo organics in impressive yields under environmentally clean conditions. The catalysts afforded regeneration and could be reused for a minimum of six reaction cycles.
- Boruah, Jeena Jyoti,Das, Siva Prasad,Borah, Rupam,Gogoi, Sandhya Rani,Islam, Nashreen S.
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p. 246 - 254
(2013/05/23)
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- Synthesis and in vitro antimycobacterial and isocitrate lyase inhibition properties of novel 2-methoxy-2′-hydroxybenzanilides, their thioxo analogues and benzoxazoles
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A new series of 2-methoxy-2′-hydroxybenzanilide derivatives and their thioxo analogues have been synthesised and characterised by IR, NMR and elemental analysis. These compounds were investigated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis 331/88, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80, clinically isolated M. kansasii 6509/96 and the ability to act as in vitro isocitrate lyase inhibitors. The best ICL inhibitors were two compounds from the thiobenzanilide group (8f, 8m), which exhibited an inhibition potential that was equal to the standard compound, 3-nitropropionic acid. In addition, the best antimycobacterial properties were exhibited by benzanilide derivatives 6h, 6k and 6l with 5-Cl and 4′ or 5′ Cl/Br substitution. For all the thiobenzanilide derivatives tested, two conformers were observed in the NMR spectra, which is most likely due to the hindered rotation of the C-N bond.
- Kozic, Ján,Novotná, Eva,Volková, Marie,Stola?íková, Ji?ina,Trejtnar, Franti?ek,Wsól, Vladimír,Vin?ová, Jarmila
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p. 108 - 119
(2013/01/15)
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- High-efficiency tris(8-hydroxyquinoline)aluminum (Alq3) complexes for organic white-light-emitting diodes and solid-state lighting
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Combinations of electron-withdrawing and -donating substituents on the 8-hydroxyquinoline ligand of the tris(8-hydroxyquinoline)aluminum (Alq 3) complexes allow for control of the HOMO and LUMO energies and the HOMO-LUMO gap responsible for emission from the complexes. Here, we present a systematic study on tuning the emission and electroluminescence (EL) from Alq3 complexes from the green to blue region. In this study, we explored the combination of electron-donating substituents on C4 and C6. Compounds 1-6 displayed the emission tuning between 478 and 526 nm, and fluorescence quantum yield between 0.15 and 0.57. The compounds 2-6 were used as emitters and hosts in organic light-emitting diodes (OLEDs). The highest OLED external quantum efficiency (EQE) observed was 4.6 %, which is among the highest observed for Alq3 complexes. Also, the compounds 3-5 were used as hosts for red phosphorescent dopants to obtain white light-emitting diodes (WOLED). The WOLEDs displayed high efficiency (EQE up to 19 %) and high white color purity (color rendering index (CRI≈85). Whiter than white: Electron-withdrawing and -donating substituents on the tris(8-hydroxyquinoline) AlIII (Alq3) complexes allow for control of the emission and electroluminescence from green (526 nm) to the blue region (487 nm), and of the fluorescence quantum yield (0.15-0.57). The compounds used as emitters in OLEDs show a maximum external quantum efficiency (EQE) of 4.6 %, which is among the highest observed for Alq3 complexes. The complexes were used in white-light emitting OLEDs achieving high efficiency (EQE ≈19 %) and high white color purity (CRI≈85).
- Perez-Bolivar, Cesar,Takizawa, Shin-Ya,Nishimura, Go,Montes, Victor A.,Anzenbacher, Pavel
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p. 9076 - 9082
(2011/10/01)
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- BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
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The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
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Page/Page column 134
(2010/05/14)
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- NEW GPR119MODULATORS
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The application relates to compounds of Formula (Ia): and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomersor N-oxides thereof. The application also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the prophylaxis and treatment of medical conditions relating to disorders of the G-protein- coupled receptor GPR119, such as diabetes, obesity and osteoporosis.
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- Effect of structural factors and solvent nature in bromination of anilines
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Reaction of electrophilic bromination of aniline containing various ortho, meta, and para substituents in the aromatic ring was studied. The optimal conditions for synthesis of mono-, di-, tri-, and tetrabromo derivatives of aniline and brominated analog of Aniline Black were found.
- Bagmanov
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experimental part
p. 1570 - 1576
(2011/06/20)
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- DIAGNOSTIC AND REMEDY FOR DISEASE CAUSED BY AMYLOID AGGREGATION AND/OR DEPOSITION
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To provide a diagnostic drug which binds specifically to an amyloid aggregate and/or an amyloid deposit, to thereby realize imaging and quantification of a disease caused by amyloid aggregation and/or deposition. The invention provides a compound represented by formula (1) : (wherein X1 represents an optionally substituted bicyclic heterocyclic group; X2 represents a hydrogen atom, a halogen atom, or a chelate-forming group; ring A represents a benzene ring or a pyridine ring; and ring B represents an optionally substituted 5-membered aromatic heterocyclic group which is bonded to the benzene ring or the pyridine ring via a carbon atom of ring B), a salt thereof, a solvate of any of these, or a transition metal coordination compound of any of these, and a diagnostic, preventive, or therapeutic drug containing the same.
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Page/Page column 37
(2008/12/07)
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- PROTEIN KINASE INHIBITORS
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Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.
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Page/Page column 48
(2010/11/28)
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- Geldanamycin derivative inhibition of HGF/SF-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation
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Ansamycins, including geldanamycin and the derivative 17-allylamino-17- demethoxygeldanamycin, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90.
- Shen, Yuehai,Xie, Qian,Norberg, Monica,Sausville, Edward,Vande Woude, George,Wenkert, David
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p. 4960 - 4971
(2007/10/03)
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- GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS
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Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.
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Page/Page column 40
(2008/06/13)
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- The Effect of Varying Halogen Substituent Patterns on the Cytocrome P450 Catalysed Dehalogenation of 4-Halogenated Anilines to 4-Aminophenol Metabolites
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The cytochrome P450 catalysed biotransformation of 4-halogenated anilines was studied in vitro with special emphasis on the dehalogenation to 4-aminophenol metabolites. The results demonstrated that a fluorine substituent at the C4 position was more easily eliminated from the aromatic ring than a chloro-, bromo- or iodo-substituent. HPLC analysis of in vitro biotransformation patterns revealed that the dehalogenation of the C4-position was accompanied by formation of non-halogenated 4-aminophenol, without formation of NIH-shifted metabolites. Changes in the apparent Vmax for the microsomal oxidative dehalogenation appeared to correlate with the electronegativity of the halogen substituent at C4, the fluorine substituent being the one most easily eliminated. A similar decrease in the rate of dehalogenation from a fluoro- to a chloro- to a bromo- to an iodo-substituent was observed in a system with purified reconstituted cytochrome P450 IIBl, in a tertiair butyl hydroperoxide supported microsomal cytochrome P450 system as well as in a system with microperoxidase 8. This microperoxidase 8 is a haem-based mini-enzyme without a substrate binding site, capable of catalysing cytochrome P450-like reaction chemistry. Together, these results excluded the possibility that the difference in the rate of dehalogenation with a varying C4-halogen substituent arose from a change in the contribution of cytochrome P450 enzymes involved in oxidative dehalogenation with a change in the halogen substituent. Rather, they strongly suggested that the difference was indeed due to an intrinsic electronic parameter of the various C4 halogenated anilines dependent on the type of halogen substituent. Additional in vitro experiments with polyfluorinated anilines demonstrated that elimination of the C4-fluorine substituent became more difficult upon the introduction of additional electron withdrawing fluorine substituents in the aniline-ring. 19F-NMR analysis of the metabolite patterns showed that the observed decrease in 4-aminophenol formation was accompanied by a metabolic switch to 2-aminophenols and N-hydroxyanilines, while products resulting from NIH-type mechanisms were not observed. For a C4-chloro-, bromo-, or iodo-substituted 2-fluoroaniline the Vmax for the oxidative dehalogenation was reduced by the additional electron withdrawing fluorine substituent at the C2 position in a similar way. In conclusion, the results of the present study strongly indicate that the possibilities for cytochrome P450 mediated dehalogenation of 4-halogenated anilines to 4-aminophenol metabolites are dependent on: (i) the characteristics of the halogen that has to be eliminated, the most electronegative and smallest ...
- Cnubben, Nicole H. P.,Vervoort, Jacques,Boersma, Marelle G.,Rietjens, Ivonne M. C. M.
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p. 1235 - 1248
(2007/10/03)
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- Synthesis of Mercapturic Acid Derivatives of Putative Toxic Metabolites of Bromobenzene
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The synthesis and characterization of nine isomerically defined S-arylmercapturic acids of interest in connection with the metabolism of the model hepatotoxin bromobenzene is described.Included are three S-(bromophenyl)-, two S-(bromohydroxyphenyl)-, and three S-(bromodihydroxyphenyl)mercapturic acids of defined substitution pattern.In addition, several related compounds with two or no bromine atoms are described.These syntheses depend on two basic methods, 1,4-addition of various arene thiols to acetamidoacrylic acid or the 1,4-addition of N-acetyl-L-cysteine to various benzoquinone derivatives.In addition, we describe a method for efficient conversion of the mercapturic acids to thioanisole derivatives, regioisomers of which can be separed and detected at low levels by capillary gas-liquid chromatography.
- Hanzlik, Robert P.,Weller, Paul E.,Desai, Jayant,Zheng, Jiang,Hall, Larry R.,Slaughter, Donald E.
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p. 2736 - 2742
(2007/10/02)
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