- Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines
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Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phen
- Burgey, Christopher S.,Robinson, Kyle A.,Lyle, Terry A.,Sanderson, Philip E. J.,Lewis, S. Dale,Lucas, Bobby J.,Krueger, Julie A.,Singh, Rominder,Miller-Stein, Cynthia,White, Rebecca B.,Wong, Bradley,Lyle, Elizabeth A.,Williams, Peter D.,Coburn, Craig A.,Dorsey, Bruce D.,Barrow, James C.,Stranieri, Maria T.,Holahan, Marie A.,Sitko, Gary R.,Cook, Jacquelynn J.,McMasters, Daniel R.,McDonough, Colleen M.,Sanders, William M.,Wallace, Audrey A.,Clayton, Franklin C.,Bohn, Dennis,Leonard, Yvonne M.,Detwiler Jr., Theodore J.,Lynch Jr., Joseph J.,Yan, Youwei,Chen, Zhongguo,Kuo, Lawrence,Gardell, Stephen J.,Shafer, Jules A.,Vacca, Joseph P.
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Read Online
- Synthesis and some transformations of all three isomers of α,α-difluoropyridinylacetonitrile
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An effective preparative approach to fluorinated pyridinylacetonitriles, based on electrophilic fluorination of pyridinylacetonitriles, was developed. Their synthetic potential for obtaining new fluorine-containing building blocks and heterocyclic systems was disclosed.
- Shavrina, Oksana M.,Bezdudny, Andrii V.,Rassukana, Yuliya V.
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- PYRROLOPYRIMIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
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Disclosed are chemical entities of formula I: [INSERT CHEMICAL FORMULA HERE] wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
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Paragraph 0262
(2016/04/09)
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- DIFLUOROETHYLPYRIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
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Disclosed are chemical entities of formula (I) wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
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Paragraph 0190
(2016/02/16)
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- Practical selective hydrogenation of α-fluorinated esters with bifunctional pincer-type ruthenium(II) catalysts leading to fluorinated alcohols or fluoral hemiacetals
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Selective hydrogenation of fluorinated esters with pincer-type bifunctional catalysts RuHCl(CO)(dpa) 1a, trans-RuH2(CO)(dpa) 1b, and trans-RuCl2(CO)(dpa) 1c under mild conditions proceeds rapidly to give the corresponding fluorinated alcohols or hemiacetals in good to excellent yields. Under the optimized conditions, the hydrogenation of chiral (R)-2-fluoropropionate proceeds smoothly to give the corresponding chiral alcohol without any serious decrease of the ee value.
- Otsuka, Takashi,Ishii, Akihiro,Dub, Pavel A.,Ikariya, Takao
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supporting information
p. 9600 - 9603
(2013/07/26)
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- METHOD FOR PRODUCING -FLUOROALCOHOL
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A production method of a β-fluoroalcohol includes performing a reaction of an α-fluoroester with hydrogen gas (H2) in the presence of a specific ruthenium complex (i.e. a ruthenium complex of the general formula [2], preferably a ruthenium complex of the general formula [4]). This production method can employ a suitable hydrogen pressure of 1 MPa or less by the use of such a specific ruthenium complex and does not require a high-pressure gas production facility when put in industrial practice. In addition, this production method can remarkably reduce the amount of catalyst used therein (to e.g. a substrate/catalyst ratio of 20,000) in comparison to the substrate/catalyst ratio conventional reduction of α-fluoroalcohol. It is possible by these reduction in hydrogen pressure and catalyst amount to largely reduce the production cost of the β-fluoroalcohol.
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Paragraph 0057
(2013/11/05)
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- 2,6-Diaminopyridine Compounds Suitable For Treating Diseases Associated With Amyloid Or Amyloid-Like Proteins Or For Treating Or Preventing Ocular Diseases Or Conditions Associated With A Pathological Abnormality/Change In The Tissue Of The Visual System
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The present invention relates to 2,6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system.
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Page/Page column 49
(2011/05/03)
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- 2,6-Diaminopyridine compounds for treating diseases associated with amyloid proteins or for treating ocular diseases
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The present invention relates to 2,6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compoun
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Page/Page column 49
(2011/05/04)
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- 2,6-DIAMINOPYRIDINE COMPOUNDS SUITABLE FOR TREATING DISEASES ASSOCIATED WITH AMYLOID OR AMYLOID-LIKE PROTEINS OR FOR TREATING OR PREVENTING OCULAR DISEASES OR CONDITIONS ASSOCIATED WITH A PATHOLOGICAL ABNORMALITY/CHANGE IN THE TISSUE OF THE VISUAL SYSTEM
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The present invention relates to 2.6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compoun
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Page/Page column 101
(2011/05/05)
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- PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES
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Improved process for the preparation of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide of formula (I) and its intermediates is provided.
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Page/Page column 6
(2011/05/08)
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- PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES
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An improved process for the preparation of 3-fruoro-2-pyridylmethyl-3-(2,2- difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one- 1 -acetamide and its intermediates.
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Page/Page column 13
(2011/06/11)
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- Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif
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2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (Ki = 1.2 nM) that exhibits robust effica
- Kreutter, Kevin D.,Lu, Tianbao,Lee, Lily,Giardino, Edward C.,Patel, Sharmila,Huang, Hui,Xu, Guozhang,Fitzgerald, Mark,Haertlein, Barbara J.,Mohan, Venkatraman,Crysler, Carl,Eisennagel, Stephen,Dasgupta, Malini,McMillan, Martin,Spurlino, John C.,Huebert, Norman D.,Maryanoff, Bruce E.,Tomczuk, Bruce E.,Damiano, Bruce P.,Player, Mark R.
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p. 2865 - 2870
(2008/12/21)
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- Thiazolinone unsubstituted quinolines
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Thiazolinone quinoline derivatives having no substitution on the quinoline ring active as CDK1 inhibitors which are useful as anti-proliferation agents such as for treating solid tumors.
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Page/Page column 23-24
(2010/02/15)
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- Development of a scaleable synthesis of a 3-aminopyrazinone acetamide thrombin inhibitor
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A scaleable route to 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)-animo]-6- chloro-2-oxohydropyrazinyl}-N-(3-fluoro(2-pyridyl))-methyl]acetamide 1 is described in which various scaleup issues were addressed to provide a safe, efficient, and robust route for th
- Ashwood, Michael S.,Alabaster, Ramon J.,Cottrell, Ian F.,Cowden, Cameron J.,Davies, Antony J.,Dolling, Ulf H.,Emerson, Khateeta M.,Gibb, Andrew D.,Hands, David,Wallace, Debra J.,Wilson, Robert D.
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p. 192 - 200
(2013/09/04)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein b is NY or O; c is CY2or N; d is CY3or N; e is CY4or N; f is CY5or N; g is CY6or N; Y4, Y5, and Y6are independently hydrogen, C1-4alkyl, or halogen; Y1and Y2are independently hydrogen, C1-4alkyl, C3-7cycloalkyl, halogen, NH2, OH or C1-4alkoxy, and Y3is hydrogen, C1-4alkyl, C3-7cycloalkyl, halogen, —CN, NH2, OH or C1-4alkoxy; A is and W, W1, R1, R3, R4, R5, X and Z are defined in the specification.
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure:
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: wherein R3 is hydrogen or halogen, and u is N or CH.
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- Pyrazinone thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein A is
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- Pyrazinone thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: A is ?wherein Y1and Y2are independently hydrogen, C1-4alkyl, C1-4alkoxy, FuHvC(CH2)0-1O—, wherein u and v are either 1 or 2, provided that when u is 1, v is 2, and when u is 2, v is 1, C3-7cycloalkyl, thio C1-4alkyl, C1-4sulfinylalkyl, C1-4sulfonylalkyl, halogen cyano, or trifluoromethyl, and wherein b is 0 or 1.
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- Process for making a thrombin inhibitor
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The invention is a process for preparing 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide which comprises coupling with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a coupling reagent and a base to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide.
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