- Palladium-Catalyzed Domino Heck/C-H Activation/Decarboxylation: A Rapid Entry to Fused Isoquinolinediones and Isoquinolinones
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A new palladium-catalyzed tandem cyclization of various alkene-tethered aryl iodides has been presented. In this protocol, o-bromobenzoic acids are employed as coupling parters to achieve the insertion of aromatic rings by the cleavage of C(sp2)-Br and decarboxylation, thus assembling various dibenzoisoquinolinediones and dibenzoisoquinolinones. In addition, a seven-membered ring can be constructed by the use of 8-bromo-1-naphthoic acid. Notably, this approach enables regioselective product formation and features broad substrate scope.
- Luo, Xiai,Zhou, Liwei,Lu, Haiyan,Deng, Guobo,Liang, Yun,Yang, Chunming,Yang, Yuan
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Read Online
- α-Oxocarboxylic Acids as Three-Carbon Insertion Units for Palladium-Catalyzed Decarboxylative Cascade Synthesis of Diverse Fused Heteropolycycles
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A novel palladium-catalyzed decarboxylative cascade cyclization for the assembly of diverse fused heteropolycycles by employing α-oxocarboxylic acids as three-carbon insertion units is reported. This protocol enables the synthesis of isoquinolinedione- and indolo[2,1-a]isoquinolinone-fused benzocycloheptanones in moderate to good yields by the use of different aryl iodides, including alkene-tethered 2-iodobenzamides and 2-(2-iodophenyl)-1H-indoles. Notably, the approach achieves simultaneous construction of both six- and seven-membered rings via sequential intramolecular carbopalladation, C-H activation, and decarboxylation.
- Zhou, Liwei,Qiao, Shujia,Zhou, Fengru,Xuchen, Xinyu,Deng, Guobo,Yang, Yuan,Liang, Yun
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supporting information
p. 2878 - 2883
(2021/05/05)
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- Palladium-Catalyzed Amination/Dearomatization Reaction of Indoles and Benzofurans
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This report describes a palladium-catalyzed dearomatization and amination tandem reaction of 2,3-disubstituted indoles and benzofurans via the Catellani strategy. This reaction provides a new method for the construction of amino-substituted indoline-fused cyclic and benzofuran spiro compounds in good yields. The reaction has broad functional group compatibility and substrate scope.
- Zhang, Zhe,Zhang, Bo-Sheng,Li, Kai-Li,An, Yang,Liu, Ce,Gou, Xue-Ya,Liang, Yong-Min
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p. 7817 - 7839
(2020/07/16)
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- Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8
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Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.
- Padilla-Salinas, Rosaura,Anderson, Rachel,Sakaniwa, Kentaro,Zhang, Shuting,Nordeen, Patrick,Lu, Chuanjun,Shimizu, Toshiyuki,Yin, Hang
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p. 10221 - 10244
(2019/11/29)
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- IODONIUM SALT COMPOUND, PHOTOACID GENERATOR AND COMPOSITION CONTAINING THE SAME, AND METHOD FOR MANUFACTURING DEVICE
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PROBLEM TO BE SOLVED: To provide an iodonium salt compound which can be used as a chemical amplification type photoacid generator for resist and a photocationic polymerization initiator, has high sensitivity to an i-line at a wavelength of 365 nm, and has high solubility to an organic solvent and a resin. SOLUTION: A new iodonium salt compound is represented by the following iodonium salts 2, 5 and 10. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0086; 0088; 0129; 0130
(2019/01/06)
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- CHEMICAL COMPOUNDS
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The invention relates to a novel compound of formula (I) or a stereoisomer, or a racemate or a mixture or a pharmaceutically acceptable salt thereof: wherein: R is phenyl or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, N and O, such rings may be optionally substituted with n groups Q; Q is selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN, SO2CH3 or a group —O[(CR1R2]pQ1; or Q may be a group Q2; Q1 is phenyl, which may be optionally substituted with n substituents selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN, or a group Q2; or corresponds to 2,2-difluoro-benzo[d][1,3]dioxol-4-yl; Q2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, which may optionally substituted with n substituents selected from a group consisting of: Cl C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN; P is a 6-membered heteroaryl or a 8-1 1 membered bicyclic heteroaryl group, which may be substituted with n substituents selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN; R1 is hydrogen or C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; n is 1, 2 or 3; p is 0, 1 or 2; and with the proviso that when R corresponds to phenyl, P is substituted by at least one CF3; processes for the preparation of those compounds, pharmaceutical compositions containing one or more compounds of formula (I) and their use as dual antagonists of the Orexin 1 and Orexin 2 receptors.
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Paragraph 0280; 0281; 0282; 0283; 0284; 0285
(2014/12/09)
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- CHEMICAL COMPOUNDS
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The invention relates to a novel compound of formula (I) or a stereoisomer, or a racemate or a mixture or a pharmaceutically acceptable salt thereof: wherein: R is phenyl or a 5- or 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, N and O, such rings may be optionally substituted with n groups Q; Q is selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN, SO2CH3 or a group -O[(CR1R2]pQ1; or Q may be a group Q2; Q1 is phenyl, which may be optionally substituted with n substituents selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN, or a group Q2; or corresponds to 2,2-difluoro- benzo[d][1,3]dioxol-4-yl; Q2 is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, which may optionally substituted with n substituents selected from a group consisting of: C1 C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN; P is a 6-membered heteroaryl or a 8-1 1 membered bicylic heteroaryl group, which may be substituted with n substituents selected from a group consisting of: C1-C4 alkyl, halogen, halo C1-C4 alkyl, C1-C4 alkoxy, CN; R1 is hydrogen or C1-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; n is 1, 2 or 3; p is 0, 1 or 2; and with the proviso that when R corresponds to phenyl, P is substituted by at least one CF3; processes for the preparation of those compounds, pharmaceutical compositions containing one or more compounds of formula (I) and their use as dual antagonists of the Orexin 1 and Orexin 2 receptors.
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Page/Page column 44; 45
(2013/07/05)
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- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
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Disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
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Page/Page column 87
(2011/05/06)
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- FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
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Certain disubstituted 3,8-diaza-bicyclo[4.2.0]octane and 3,6-diazabicyclo [3.2.0]heptane are described, which are useful as orexin inhibitors. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.
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Page/Page column 59
(2011/05/06)
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- Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models
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There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42 - potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.
- Bonnefous, Céline,Payne, Joseph E.,Roppe, Jeffrey,Zhuang, Hui,Chen, Xiaohong,Symons, Kent T.,Nguyen, Phan M.,Sablad, Marciano,Rozenkrants, Natasha,Zhang, Yan,Wang, Li,Severance, Daniel,Walsh, John P.,Yazdani, Nahid,Shiau, Andrew K.,Noble, Stewart A.,Rix, Peter,Rao, Tadimeti S.,Hassig, Christian A.,Smith, Nicholas D.
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supporting information; experimental part
p. 3047 - 3062
(2010/01/16)
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- Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists
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A series of biphenylaminocyclopropane carboxamide based bradykinin B 1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in t
- Kuduk, Scott D.,Di Marco, Christina N.,Chang, Ronald K.,Wood, Michael R.,Schirripa, Kathy M.,Kim, June J.,Wai, Jenny M. C.,DiPardo, Robert M.,Murphy, Kathy L.,Ransom, Richard W.,Harrell, C. Meacham,Reiss, Duane R.,Holahan, Marie A.,Cook, Jacquelynn,Hess, J. Fred,Sain, Nova,Urban, Mark O.,Tang, Cuyue,Prueksaritanont, Thomayant,Pettibone, Douglas J.,Bock, Mark G.
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p. 272 - 282
(2007/10/03)
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- Peri Fluoro Steric Effects: Syntheses and Comparative Acid-Catalyzed Isomerization of the 8-, 9-, and 11-Fluoro-1,2,3,4-tetrahydro-7,12-dimethylbenzanthracenes to Exo Methylene Tautomers
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Facile and regiospecific syntheses for 8-, 9-, and 11-fluoro-1,2,3,4-tetrahydro-7,12-dimethylbenzanthracenes (4, 5, and 7) from 5,6,7,8-tetrahydro-1-naphthaldehyde and the respective 2-(2-fluoro-6-iodophenyl)oxazoline 14, 2-(2-bromo-5-fluorophenyl)oxazoline 15, and 2-(3-fluorophenyl)oxazoline 16 are described.Comparative acid-catalyzed isomerization of these polycyclic aromatic hydrocarbons (PAH) to exo methylene tautomers in refluxing benzene is compared to our previously published studies employing the parent hydrocarbon 1 and the 5-, 6-, and 10-fluoro analogues(2, 3, and 6).The peri steric effect of 11-fluoro compound 7- was the most dramatic, providing 7-exo methylene isomer 45 in nearly quantitative yield.Substitution of fluorine at peri positions 6 and 8 afforded product ratios at equilibrium, whereas the 7-exo methylene tautomers (41 and 42) also were thermodynamically favored over the parent anthracene PAH or the respective 12-exo methylene isomers (48 and 49).Like the unsubstituted PAH 1, where fluorine does not occupy a peri position such as in the 9- and 10-fluoro species 5 and 6, no appreciable quantities of exo methylene tautomers were detected.Comparative ΔGo values for isomerization of 6-, 8-, and 11-fluoro isomers revealed that sandwiching the C12-CH3 group between the 11-fluoro and C1-CH2 functions in 7 and removing any possible 7-CH2-F interaction in exo methylene product 45 led to a relative relief in steric interaction of approximately 1 kcal/mol.
- Witiak, Donald T.,Goswami, Shyamaprosad,Milo, George E.
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p. 345 - 352
(2007/10/02)
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