- 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action
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Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
- Jiang, Xinbei,Tan, Jiali,Wang, Yixuan,Chen, Jinhua,Li, Jianrui,Li, Jianrui,Jiang, Zhi,Quan, Yanni,Jin, Jie,Li, Yuhuan,Li, Yuhuan,Cen, Shan,Li, Yanping,Peng, Zonggen,Peng, Zonggen,Li, Zhuorong
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Read Online
- Palladium-Catalyzed Tandem Carbonylative Diels-Alder Reaction for Construction of Bridged Polycyclic Skeletons
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A palladium-catalyzed tandem carbonylative lactonization and Diels-Alder cycloaddition reaction between aldehyde-tethered benzylhalides and alkenes has been developed. A range of alkenes and aldehyde-tethered benzylhalides bearing different substituents can be successfully transformed into the corresponding bridged polycyclic compounds in good yields. This strategy provides a unique approach to complex lactone-containing bridged polycyclic compounds.
- Wang, Siyuan,Zhou, Yangkun,Huang, Hanmin
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supporting information
p. 2125 - 2129
(2021/04/05)
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- NEW TYPE OF ANTIVIRAL COMPOUND
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Provided are a new aromatic cyanogen compound and a preparation method thereof. The present invention also relates to the use of such compound in antiviral drugs, in particular the use thereof in anti-HCV drugs.
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Paragraph 0024
(2018/07/06)
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- New trelagliptin preparation process
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The present invention provides a trelagliptin preparation process, which comprises that: 1) a compound 4 and a compound 5 are adopted as raw materials, and are subjected to a condensation reaction in an organic solvent in the presence of an alkali to obtain a compound 6; 2) the compound 6 reacts with an acid HA in an organic solvent to remove the t-butyloxy carbonyl so as to obtain a trelagliptin.HA salt; and 3) the trelagliptin.HA salt is subjected to alkali neutralization treatment and purification to obtain the trelagliptin, wherein the reaction route is defined in the specification. According to the present invention, in the improved preparation process, the 2-site amino of the compound 5 is protected by the t-butyloxy carbonyl, such that the selectivity of the nucleophilic substitution reaction is improved, and the impurity production caused by primary amine substitution is avoided so as to improve the nucleophilic substitution yield and improve the trelagliptin purity.
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- Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate
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The invention discloses a synthetic method of trelagliptin, trelagliptin synthesized through the method and a trelagliptin synthesis intermediate. The synthetic method of trelagliptin comprises the following steps: 1, taking 2-hydroxymethyl-4-fluorobenzonitrile as a starting raw material, and conducting a chlorination reaction, so that 2-chloromethyl-4-fluorobenzonitrile is obtained; 2, taking the 2-chloromethyl-4-fluorobenzonitrile as an intermediate, and conducting a condensation reaction, so that 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile is obtained; 3, taking the 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile as an intermediate, and conducting an ammonolysis reaction, so that trelagliptin alkali is obtained. By means of the method, use of high-toxicity copper cyanide is avoided, safety of the synthesis process is improved, environment friendliness is achieved, the formed chloro intermediate is more stable, and no irritation is caused.
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- Annulation of o-Quinodimethanes through N-Heterocyclic Carbene Catalysis for the Synthesis of 1-Isochromanones
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The activation of 2-(bromomethyl)benzaldehydes using N-heterocyclic carbenes represents a novel approach to the generation of o-quinodimethane (o-QDM) intermediates. Coupling with ketones such as phenylglyoxylates, isatins, or trifluoromethyl ketones via [4 + 2] annulation gives access to functionalized 1-isochromanones.
- Janssen-Müller, Daniel,Singha, Santanu,Olyschl?ger, Theresa,Daniliuc, Constantin G.,Glorius, Frank
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supporting information
p. 4444 - 4447
(2016/09/09)
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- 2-oxo-4-thio-3,4-dihydropyrimidine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors
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The invention provides 2-oxo-4-thio-3,4-dihydropyrimidine derivatives represented by the general formula (I), and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, and a preparation method of the compounds and pharmaceutical compositions containing the compounds. The compounds can inhibit dipeptidyl peptidase IV (DPP-IV) activity, and can be used for treatment of dipeptidyl peptidase IV related diseases.
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Paragraph 0062; 0063; 0064
(2016/10/08)
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- Trelagliptin and preparation method of succinate thereof
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The invention discloses a trelagliptin and a preparation method of succinate thereof. The preparation method includes the following steps that a trelagliptin intermediate II and a trelagliptin intermediate III perform nucleophilic substitution reaction in an organic solvent in the presence of phosphate and a phase transfer catalyst to obtain trelagliptin I, and then trelagliptin I reacts with the succinate to produce salt. The operation process of the preparation method is simple and safe, special devices are not needed, the impurity contents of bis-substituted and primary amine substituted isomers can significantly reduced, only one-time recrystallization is needed, the purity of the obtained trelagliptin succinate I' can be above 99.5%, the impurity contents of the bis-substituted and primary amine substituted isomers are both below 0.05%, the contents of all the other impurities are all below 0.05%, the prepared trelagliptin succinate I' is high in purity, the production cost is low, and the trelagliptin and the preparation method are suitable for industrialized production.
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Paragraph 0040; 0041
(2016/11/17)
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- Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV
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The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.
- Zhang, Zhiyuan,Wallace, Michael B.,Feng, Jun,Stafford, Jeffrey A.,Skene, Robert J.,Shi, Lihong,Lee, Bumsup,Aertgeerts, Kathleen,Jennings, Andy,Xu, Rongda,Kassel, Daniel B.,Kaldor, Stephen W.,Navre, Marc,Webb, David R.,Gwaltney, Stephen L.
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p. 510 - 524
(2011/03/20)
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- Discovery of (3 S,3a R)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5- tetrahydro-2 H -benzo[ g ]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy
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We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
- Meyers, Marvin J.,Arhancet, Graciela B.,Hockerman, Susan L.,Chen, Xiangyang,Long, Scott A.,Mahoney, Matthew W.,Rico, Joseph R.,Garland, Danny J.,Blinn, James. R.,Collins, Joe T.,Yang, Shengtian,Huang, Horng-Chih,McGee, Kevin F.,Wendling, Jay M.,Dietz, Jessica D.,Payne, Maria A.,Homer, Bruce L.,Heron, Marcia I.,Reitz, David B.,Hu, Xiao
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experimental part
p. 5979 - 6002
(2010/11/02)
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- DIPEPTIDYL PEPTIDASE INHIBITORS
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Methods of making compounds of the formula (I) wherein the variables are as defined herein. Also, methods of making compounds that may be used to inhibit dipeptidyl peptidase.
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Page/Page column 30
(2009/12/02)
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- PYRAZOLINE COMPOUNDS AS MINERALOCORTICOID RECEPTOR ANTAGONISTS
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Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R1, R2, R3A, R3B, R4, R5, R6, R7, R8, and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.
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Page/Page column 57
(2008/12/05)
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- ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS
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Pharmaceutical compositions comprising 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts thereof are provided as well as kits and articles of manufacture comprising the pharmaceutical compositions as well as methods of using the pharmaceutical compositions.
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Page/Page column 39
(2008/06/13)
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- POLYMORPHS OF SUCCINATE SALT OF 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHY]-4-FLUOR-BENZONITRILE AND METHODS OF USE THEREFOR
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Compositions comprising the succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (referred to herein as Compound I) which has the formula: (I) wherein the Compound I is present in one or more polymorphic forms. Also provided are novel methods for the preparation of the polymorphs of Compound I, and kits and articles of manufacture of the compositions, and methods of using the compositions to treat various diseases.
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Page/Page column 49
(2008/12/06)
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- ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS
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Pharmaceutical compositions comprising 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts thereof are provided as well as kits and articles of manufacture comprising the pharmaceutical compositions as well as methods of using the pharmaceutical compositions.
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Page/Page column 14; 15
(2010/11/26)
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- Facile and convenient syntheses of 6,11-dihydro-5H-indeno[1,2-c] isoquinolin-5-ones and 6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-one
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(Chemical Equation Presented) The synthesis of 6,11-dihydro-5H-indeno[1,2- c]isoquinolin-5-ones from the base-promoted condensation reaction of homophthalic anhydride and 2-(bromomethyl)-benzonitrile and a convenient method for the synthesis of indolo[3,2-c]isoquinolinones are described.
- Jagtap, Prakash G.,Baloglu, Erkan,Southan, Garry,Williams, William,Roy, Aloka,Nivorozhkin, Alexander,Landrau, Nelson,Desisto, Kevin,Salzman, Andrew L.,Szabo, Csaba
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p. 1753 - 1756
(2007/10/03)
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- Dipeptidyl peptidase inhibitors
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Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV inhibitors comprising Formula I: wherein the substituents are as described herein.
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Page/Page column 59
(2008/06/13)
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- Dipeptidyl peptidase inhibitors
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Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising Formula I: wherein M is N or CR4; Q1 and Q2 are each independently selected from the group consisting of CO, SO, SO2, and C=NR9; and each R1, R2, R3, R4 and R9 are as defined herein.
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Page/Page column 54
(2008/06/13)
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