- Discovery of novel small-molecule inhibitors of pd-1/pd-l1 interaction via structural simplification strategy
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Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer tr
- Du, Huijie,Huang, Shihui,Li, Hui,Liu, Jinchang,Xia, Yu,Xu, Yungen,Yu, Chunqiu,Zhang, Hongbo,Zhu, Qihua,Zou, Yi
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Read Online
- Novel biphenyl derivative as well as preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, and discloses biphenyl derivatives with PD-1/PD-L1 inhibitory activity as well as a preparation method and application of the biphenyl derivatives. The invention further discloses a composition containing the biphenyl derivative with the PD-1/PD-L1 inhibitory activity or the pharmaceutically acceptable salt of the biphenyl derivative and a pharmaceutically acceptable carrier of the biphenyl derivative, and application of the biphenyl derivative in preparation of a PD-1/PD-L1 inhibitor. The compound can be used for treating tumors.
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Paragraph 0037; 0065-0069
(2021/07/21)
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- Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction
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Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for
- Fang, Lincheng,Tian, Jiping,Zhang, Kaixuan,Zhang, Xiaoyi,Liu, Yingqiao,Cheng, Zhibo,Zhou, Jinpei,Zhang, Huibin
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- Method for synthesizing 3 - halogen -2 -alkyl phenol
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The invention discloses a synthesis method of 3 -halo -2 - alkyl phenol, and belongs to the technical field of organic synthesis. At 2, 6 - dihaloalkylbenzene is used as starting material, nucleophilic substitution with dibenzyl alcohol in the presence of an inorganic base followed Pd / C hydrodebenzylation or Grignard exchange with magnesium metal in the presence of n-butylbromide/chloride followed by air/oxygen to give 3 - halo -2 - alkylphenols. The method has the advantages of high regioselectivity, good yield, simple operation process and the like, and the product purity can reach 99.5% or more.
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Paragraph 0048-0050
(2021/11/03)
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- Divergent Enantioselective Synthesis of (Nor)illudalane Sesquiterpenes via Pd0-Catalyzed Asymmetric C(sp3)-H Activation
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A divergent enantioselective synthesis of (nor)illudalane sesquiterpenes was designed by using a Pd0-catalyzed asymmetric C(sp3)-H arylation as a key step to control the isolated, highly symmetric quaternary stereocenter of the targe
- Melot, Romain,Craveiro, Marcus V.,Bürgi, Thomas,Baudoin, Olivier
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supporting information
p. 812 - 815
(2019/01/21)
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- Total Synthesis of (Nor)illudalane Sesquiterpenes Based on a C(sp3)-H Activation Strategy
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Three (nor)illudalane sesquiterpenes were synthesized from a common intermediate in racemic and enantioenriched forms using Pd0-catalyzed C(sp3)-H arylation as a key step. The configuration of the isolated, highly symmetric quaternar
- Melot, Romain,Craveiro, Marcus V.,Baudoin, Olivier
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p. 12933 - 12945
(2019/08/20)
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- Total Synthesis of Marine Alkaloid Hyellazole and its Derivatives
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The total synthesis of the naturally occurring marine alkaloids hyellazole and chlorohyellazole was attempted from the corresponding easily accessible 2-methyl-1-ketotetrahydrocarbazoles obtained through the Japp–Klingemann reaction, followed by Fischer indole cyclization and subsequent Grignard coupling with phenylmagnesium bromide. Grignard coupling with 2-methyl-1-ketotetrahydrocarbazole unfortunately led directly to 2-methyl-1-phenylcarbazole through dehydration followed by aromatization through aerial oxidation, but application of the same reaction conditions to 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one, with careful treatment, led to the isolation of 6-chloro-2-methyl-1-phenyl-4,9-dihydro-3H-carbazole. However, selenium dioxide oxidation of this dihydrochloro derivative led to the formation of 6-chloro-2-methyl-1-phenyl-9H-carbazole. A different route was then adopted: a suitably substituted aromatic amine was used to establish the substitution pattern of the required carbazole derivative with a bromo group at C-1, and the required phenyl group at the 1-postion was then attached through Suzuki–Miyaura cross-coupling to furnish hyellazole.
- Chakraborty, Suchandra,Saha, Chandan
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p. 2013 - 2021
(2018/05/15)
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- Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C?H Arylation
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Atropo-enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo-enantioselective palladium(0)-catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio-determining CMD to yield configurationally stable eight-membered palladacycles.
- Newton, Christopher G.,Braconi, Elena,Kuziola, Jennifer,Wodrich, Matthew D.,Cramer, Nicolai
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supporting information
p. 11040 - 11044
(2018/07/31)
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- Propionic Acid Derivatives and Methods of Use Thereof
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Provided herein are compounds and pharmaceutical compositions of formula I where R1, R2, R3, R4, R5 and R6 are as described herein. Also provided pharmaceutically acceptable salts or stereoisomers of these compounds. In addition methods are provided for inhibiting the binding of an integrin to treat various pathophysiological conditions.
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Paragraph 1760; 1761
(2018/11/21)
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- Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
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A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
- Jurica, Elizabeth A.,Wu, Ximao,Williams, Kristin N.,Hernandez, Andres S.,Nirschl, David S.,Rampulla, Richard A.,Mathur, Arvind,Zhou, Min,Cao, Gary,Xie, Chunshan,Jacob, Biji,Cai, Hong,Wang, Tao,Murphy, Brian J.,Liu, Heng,Xu, Carrie,Kunselman, Lori K.,Hicks, Michael B.,Sun, Qin,Schnur, Dora M.,Sitkoff, Doree F.,Dierks, Elizabeth A.,Apedo, Atsu,Moore, Douglas B.,Foster, Kimberly A.,Cvijic, Mary Ellen,Panemangalore, Reshma,Flynn, Neil A.,Maxwell, Brad D.,Hong, Yang,Tian, Yuan,Wilkes, Jason J.,Zinker, Bradley A.,Whaley, Jean M.,Barrish, Joel C.,Robl, Jeffrey A.,Ewing, William R.,Ellsworth, Bruce A.
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supporting information
p. 1417 - 1431
(2017/03/08)
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- BIARYL DERIVATIVE AS GPR120 AGONIST
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The present invention relates to a biaryl derivative expressed by the chemical formula 1, a method for producing the biaryl derivative, a pharmaceutical composition comprising same, and use of same, the biaryl derivative expressed by the chemical formula 1, as a GPR120 agonist, promoting GLP-1 generation in the gastro-intestinal tract, reducing insulin resistance in the liver, muscles and the like from anti-inflammatory activity in the macrophage, pancreatic cells and the like, and allowing effective use in prevention or treatment of inflammation or metabolic diseases such as diabetes, complications from diabetes, obesity, non-alcoholic fatty liver disease, fatty liver disease, and osteoporosis.
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Paragraph 0528
(2017/11/17)
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- Examination of Selectivity in the Oxidation of ortho- and meta-Disubstituted Benzenes by CYP102A1 (P450 Bm3) Variants
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Cytochrome P450 CYP102A1 (P450 Bm3) variants were used to investigate the products arising from the P450 catalysed oxidation of a range of disubstituted benzenes. The variants used all generated increased levels of metabolites compared to the wild-type enzyme. With ortho-halotoluenes up to six different metabolites could be identified whereas the oxidation of 2-methoxytoluene generated only two aromatic oxidation products. Addition of an ethyl group markedly shifted the selectivity for oxidation to the more reactive benzylic position. Epoxidation of an alkene was also preferred to aromatic oxidation in 2-methylstyrene. Significant minor products arising from the migration of one substituent to a different position on the benzene ring were formed during certain P450-catalysed substrate turnovers. For example, 2-bromo-6-methylphenol was formed from the turnover of 2-bromotoluene and the dearomatisation product 6-ethyl-6-methylcyclohex-2,4-dienone was generated from the oxidation of 2-ethyltoluene. The RLYF/A330P variant altered the product distribution enabling the generation of certain metabolites in higher quantities. Using this variant produced 4-methyl-2-ethylphenol from 3-ethyltoluene with ≥90 % selectivity and with a biocatalytic activity suitable for scale-up of the reaction.
- Munday, Samuel D.,Dezvarei, Shaghayegh,Lau, Ian C.-K.,Bell, Stephen G.
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p. 2512 - 2522
(2017/07/12)
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- NEW INDANYLOXYDIHYDROBENZOFURANYLACETIC ACID DERIVATIVES AND THEIR USE AS GPR40 RECEPTOR AGONISTS
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The present invention relates to compounds of general formula (I), wherein the groups R1, R2 and m are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Page/Page column 106
(2013/10/21)
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- PYRROLIDINE GPR40 MODULATORS
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The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.
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Page/Page column 46
(2011/04/24)
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- DERIVATIVES OF 1-PHENYL-1,5-DIHYDRO-BENZO[B] [1.4]DIAZEPINE-2.4-DIONE AS INHIBITORS OF HIV REPLICATION
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Compounds of formula (I) wherein m, R1, R2, R3, X and Y are defined herein, are useful as inhibitors of HIV replication.
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Page/Page column 74
(2011/09/19)
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- Total synthesis of new lipocarbazoles isolated from the actinomycete tsukamurella pseudospumae acta 1857
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New lipocarbazoles were synthesized by a sequence of three palladium-mediated coupling reactions and an improved protecting group strategy.
- H?nchen, Anne,Süssmuth, Roderich D.
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body text
p. 2483 - 2486
(2010/01/07)
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- Vitamin D analogues
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The present invention relates to novel triaromatic compounds having the general formula (I): as well as to a method for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, in car
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Page column 19
(2010/02/09)
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- First total synthesis of the neuronal cell protecting carbazole alkaloid carbazomadurin A by sequential transition metal-catalyzed reactions
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The highly oxygenated neuronal cell protecting carbazole alkaloid carbazomadurin A was synthesized in nine steps and 11% overall yield from isovanillic acid.
- Knoelker, Hans-Joachim,Knoell, Jan
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p. 1170 - 1171
(2007/10/03)
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- Reductive Dechlorination of Chloro-phenols and -benzoic acids by Raney Co-Al Alloy in an Alkaline Deuterium Oxide Solution and Preparation of Deuterated Salicylic Acids
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Reduction of monochloro-phenols (1a-c) and -benzoic acids (3a-c) by using Raney Co-Al alloy in 10percent NaOD-D2O gave phenols (2a-c) and benzoic acids (4a-c) in 86-93percent isotopic purities.The reduction of di-, tri-, and tetra-chlorinated derivatives, (1) and (3), gave the deuteriated products, (2) and (4), in somewhat low isotopic purities (70-84percent).In the reduction of polychlorinated benzoic acids (3), the use of a mixed solution (1/1 = v/v) of 10percent Na2CO3-D2O and 10percent NaOD-D2O was effective and gave 4 in 80-89percent isotopic purities.The treatment of chlorosalicylic acids (5) with Raney Co-Al alloy in 10percent NaOD-D2O gave 1> (6) - 3> (6) in 91-93percent isotopic purities.
- Tashiro, Masashi,Tsuzuki, Hirohisa,Matsumoto, Jun-ichi,Mataka, Shuntaro,Nakayama, Kouji,et al.
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p. 2826 - 2851
(2007/10/02)
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- Electrophilic Substitution with Rearrangement. Part 9. Dienones derived from Brominations of o-, m-, and p-Cresol
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Regiospecific protodebromination of ring-substituted bromophenols derived from 2-, 3-, or 4-methylphenol can be effected by heating them with aqueous hydrogen iodide; the synthetic scope of this reaction has been explored.These di- and poly-bromophenols can generally be converted by further bromination in aqueous acetic acid into dienones , which have now been shown to have the 4-bromo-2,5-dienone rather than the 2-bromo-3,5-dienone structure.The rearrangemens of these dienones to ring-substituted polybromophenols by treatment with sulfuric acid have been investigated; where more than one product is formed, the regioselectivity differs from that prevailing in the corresponding direct bromination of the phenol with liquid bromine.The alternative rearrangements of these dienones in aprotic solvents with and without illumination have been compared with results obtained by reaction of methylphenols with bromine under the same conditions.Characteristic differences between the behaviours of 2-, 3-, and 4-methyl-substituted compounds reflect the specific reactions available to the particular dienones.
- Brittain, Judith M.,Mare, Peter B. D. de la,Newman, Paul A.
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