- Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold
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Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.
- Kotoku, Masayuki,Maeba, Takaki,Fujioka, Shingo,Yokota, Masahiro,Seki, Noriyoshi,Ito, Keisuke,Suwa, Yoshihiro,Ikenogami, Taku,Hirata, Kazuyuki,Hase, Yasunori,Katsuda, Yoshiaki,Miyagawa, Naoki,Arita, Kojo,Asahina, Kota,Noguchi, Masato,Nomura, Akihiro,Doi, Satoki,Adachi, Tsuyoshi,Crowe, Paul,Tao, Haiyan,Thacher, Scott,Hashimoto, Hiromasa,Suzuki, Takayoshi,Shiozaki, Makoto
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p. 2837 - 2842
(2019/03/11)
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- Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen
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A continuous-flow protocol utilizing syngas (CO and H2) was developed for the palladium-catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process-intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO-to-H2 stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H2=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good-to-excellent yields (17 examples). In particular, a successful scale-up was achieved over 415 min operation time for the reductive carbonylation of 2-bromo-6-methoxynaphthalene to synthesize 3.8 g of 6-methoxy-2-naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.
- Hone, Christopher A.,Lopatka, Pavol,Munday, Rachel,O'Kearney-McMullan, Anne,Kappe, C. Oliver
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p. 326 - 337
(2018/11/23)
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- Metal-catalyzed formal amidation of alkenes under CO-free condition
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An effective procedure for synthesis of amides from alkenes and [Formula presented] via Pd and Fe catalysts under mild conditions is described. A series of benzamides containing various functional groups can be obtained in reasonable yield and the possible reaction pathway is proposed in this Letter.
- Zhang, Yuanyuan,Ye, Wenjing,Leng, Xue,He, Ying,Zhang, Hui,Xiao, Xiao
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p. 4203 - 4206
(2016/08/24)
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- Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides
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A mild Ni-catalyzed reductive arylation of tertiary alkyl halides with aryl bromides has been developed that delivers products bearing all-carbon quaternary centers in moderate to excellent yields with excellent functional group tolerance. Electron-deficient arenes are generally more effective in inhibiting alkyl isomerization. The reactions proceed successfully with pyridine or 4-(dimethylamino)pyridine, while imidazolium salts slightly enhance the coupling efficiency.
- Wang, Xuan,Wang, Shulin,Xue, Weichao,Gong, Hegui
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supporting information
p. 11562 - 11565
(2015/09/28)
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- AMIDE COMPOUND AND MEDICINAL USE THEREOF
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A compound of formula [I-W]: wherein each symbol is as defined in the description, or a pharmaceutically acceptable salt thereof.
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- Production method of alkylbenzaldehydes
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In the production of an alkylbenzaldehyde by a method comprising a step of preparing a solution of complex of a starting alkylbenzene and a hydrogen fluoride-boron trifluoride catalyst and a step of formylation by bringing the solution of complex into contact with carbon monoxide, an alkylbenzene having at least one primary alkyl group having two or more carbon atoms on its benzene ring is used as the starting alkylbenzene. The preparation of the solution of complex is carried out in the presence of an aliphatic or alicyclic saturated hydrocarbon having 6 to 10 carbon atoms which contains at least one tertiary carbon atom but contains no quaternary carbon atom. By the combined use of the specific alkylbenzene and the aliphatic or alicyclic saturated hydrocarbon, the disproportionation of the alkylbenzene is prevented and the alkylbenzaldehyde is produced at high yields.
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Page/Page column 5-6
(2008/06/13)
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- The effects of 4′-alkyl substituents on the mutagenic activity of 4-amino- and 4-nitrostilbenes in Salmonella typhimurium
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Six derivatives of trans-4-aminostilbene bearing different alkyl groups in the 4′-position and six of the corresponding nitro compounds were synthesized and tested for their mutagenic potency in Salmonella typhimurium strains TA98 and TA100. Regarding the test series in presence of S9-mix, maximum activity was observed for those trans-4-aminostilbenes and trans-4-nitrostilbenes bearing small alkyl substituents like methyl and ethyl. More bulky substituents reduced the mutagenic potential in the order iso-propyl ethyl > iso-propyl > sec-butyl > tert-butyl). These trends have been compared with quantitative structure activity relationship (QSAR) model predictions, leading to the conclusion that steric demand is an important factor for mutagenicity of substituted aminostilbenes and nitrostilbenes. The unexpected result for the tert-butyl nitrostilbene tested with metabolic activation may be attributed to a different metabolic pathway.
- Ludolph, Bj?rn,Klein, Markus,Erdinger, Lothar,Boche, Gernot
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p. 195 - 209
(2007/10/03)
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- Acylamino-substituted hetrazepines
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A hetrazepine of the formula given below and a pharmaceutical composition comprising a therapeutically effective amount of the hetrazepine and a pharmaceutically acceptable inert carrier are disclosed and are useful in treating disease in a warm-blooded animal induced by endogenously formed PAF; STR1 wherein the substituents are defined herein.
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- Regiocontrolled Photooxygenation of Ibuprofen by Pyrimidopteridinetetrone- and Anthraquinone-Oxygen Systems
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Ibuprofen 4 underwent regiocontrolled photooxygenation on the propionic acid and isobutyl moieties in the presence of pyrimidopteridinetetrone 1- and anthraquinone 3- oxygen systems.
- Sako, Magoichi,Oyabu, Iwao,Hirota, Kosaku,Maki, Yoshifumi
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p. 601 - 602
(2007/10/02)
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- In Vivo Characterization of Hydroxamic Acid Inhibitors of 5-Lipoxygenase
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The hydroxamic acid functionality can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase.The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model.Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo.This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme.A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis.Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.
- Summers, James B.,Gunn, Bruce P.,Mazdiyasni, Hormoz,Goetze, Andrew M.,Young, Patrick R.,et al.
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p. 2121 - 2126
(2007/10/02)
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