- Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor
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Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.
- Barnes, David M.,Shekhar, Shashank,Dunn, Travis B.,Barkalow, Jufang H.,Chan, Vincent S.,Franczyk, Thaddeus S.,Haight, Anthony R.,Hengeveld, John E.,Kolaczkowski, Lawrence,Kotecki, Brian J.,Liang, Guangxin,Marek, James C.,McLaughlin, Maureen A.,Montavon, Donna K.,Napier, James J.
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p. 4873 - 4892
(2019/02/05)
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- 1-(DIHYDRONAPHTHALENYL)PYRIDONES AS MELANIN-CONCENTRATING HORMONE RECEPTOR 1 ANTAGONISTS
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Provided are 1-(dihydronaphthalenyl)pyridones which are antagonists at the melanin-concentrating hormone receptor 1 (MCHR1), pharmaceutical compositions containing them, processes for their preparation, and their use in therapy for the treatment of obesity and diabetes.
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Page/Page column 35-36
(2013/10/22)
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- 1-(DIHYDRONAPHTHALENYL)PYRIDONES AS MELANIN-CONCENTRATING HORMONE RECEPTOR 1 ANTAGONISTS
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This invention relates to novel 1-(dihydronaphthalenyl)pyridones which are antagonists of the melanin-concentrating hormone receptor 1 (MCHR1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy
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Page/Page column 53
(2013/12/03)
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- PHENANTHRENONE COMPOUNDS, COMPOSITIONS AND METHODS
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The present invention is directed to compounds of Formula (I) or salt thereof, which are modulators of the glucocorticoid receptor. The compounds and salts of the invention are useful in the treatment of conditions mediated by glucocorticoid receptor activity.
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Page/Page column 14-15
(2010/04/03)
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- Tricyclic Compound, Compositions, and Methods
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The present invention is directed to compounds of Formula I: or salt thereof, which are modulators of the glucocorticoid receptor. The compounds and salts of the invention are useful in the treatment of conditions mediated by glucocorticoid receptor activity.
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Page/Page column 12
(2008/12/07)
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- Heteroaryl β-tetralin ureas as novel antagonists of human TRPV1
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We report on a series of α-substituted-β-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
- Jetter, Michele C.,Youngman, Mark A.,McNally, James J.,McDonnell, Mark E.,Zhang, Sui-Po,Dubin, Adrienne E.,Nasser, Nadia,Codd, Ellen E.,Flores, Christopher M.,Dax, Scott L.
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p. 6160 - 6163
(2008/03/18)
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- Novel ligands for the human histamine H1 receptor: Synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes
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This paper reports the synthesis of a novel series of (±)-2-dimethylamino- 5- and 6-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (5- and 6-APTs), and, corresponding affinity, functional activity, and, molecular modeling studies with regard to drug des
- Ghoneim, Ola M.,Legere, Jacqueline A.,Golbraikh, Alexander,Tropsha, Alexander,Booth, Raymond G.
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p. 6640 - 6658
(2007/10/03)
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- Structure-activity relationship of linear peptide Bu-His-DPhe-Arg-Trp-Gly-NH2 at the human melanocortin-1 and -4 receptors: Histidine substitution
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Systematic substitution of His6 residue using non-selective hMC4R pentapeptide agonist (Bu-His6-DPhe7-Arg8-Trp9-Gly 10-NH2) as the template led to the identification of Bu-Atcsu
- Cheung, Adrian Wai-Hing,Danho, Waleed,Swistok, Joseph,Qi, Lida,Kurylko, Grazyna,Rowan, Karen,Yeon, Mitch,Franco, Lucia,Chu, Xin-Jie,Chen, Li,Yagaloff, Keith
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p. 133 - 137
(2007/10/03)
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- Pharmaceutically active benzoquinazoline compounds
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Compounds of formula (I) or salts thereof, wherein the dotted line represents a single or double bond, R1is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R2, R3, R4and R5are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O)nR8wherein n is the integer 0, 1 or 2 and R8is halo or alkyl or a group NR9R10wherein R9and R10are both hydrogen, a group NR11R12wherein R11and R12are the same or different and each is hydrogen or alkyl, a group OR13wherein R13is hydrogen or C1-4alkyl optionally substituted by halo; a C1-4aliphatic group optionally substituted by a group OR14or NR14R15wherein R14and R15are the same or different and each is hydrogen or alkyl; or two of R2to R5are linked together to form a benzo group, or one of R2to R5is a group -X-Y-R16wherein X is CH2, NR17, CO or S(O)m, and Y is CH2, NR17, O, or S(O)m, or -X-Y- is a group -O-, -NR17-, -CH=CH- or -N=N-, are disclosed as pharmacological agents useful in the treatment of tumours. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also described.
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- Glucocorticoid receptor modulators
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The present invention provides non-steroidal compounds of Formula I, and prodrugs and pharmaceutically acceptable salts thereof, which are selective modulators (e.g., agonists, partial agonists and antagonists) of a steroid receptor, specifically, the glucocorticoid receptor. The present invention also provides pharmaceutical compositions containing these compounds and methods for using these compounds to treat animals requiring glucocorticoid receptor agonist or antagonist therapy. Glucocorticoid receptor modulators are useful to treat diseases, such as obesity, diabetes, inflammation and others as described below. The present invention also provides processes for preparing these compounds.
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- PHARMACEUTICAL COMPOUNDS
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The present invention relates to novel benzoquinazoline thymidylate synthase inhibitors, to pharmaceutical formulations containing them and to their use in medicine
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- Asymmetric Synthesis of MK-0499
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Described herein is an efficient asymmetric synthesis of the potent antiarrhthymia agent MK-0499.The route is convergent and is highlighted by two stereoselective reactions.A ruthenium-catalyzed, enantioselective hydrogenation of an enamide was developed for the preparation of the key amine intermediate.Oxazaborolidine-mediated ketone reduction was utilized to establish the alcohol stereochemistry.Optimization of this chemistry led to an IPA modified reduction method which provides enhanced stereoselectivity.
- Tschaen, David M.,Abramson, Lee,Cai, Dongwei,Desmond, Richard,Dolling, Ulf-H.,et al.
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p. 4324 - 4330
(2007/10/02)
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- Spirocycles
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Spirocycles of the general structural formulae: STR1 wherein: X is O, CH2 or SOm ; R1 is AlkylSO2 NH--, AlkylO--, AlkylSO2 --, AlkylCONH--, or NO2 --; R2 is --H, --OAlkyl, or --Alkyl; R3 is --NHCOCH2 SOm Phenyl, --NHCOCH2 SOm Alkyl, --NHCOC(CH3)2 OH, or NHSO2 Alkyl; R4 and R5 are --H, or --Alkyl; R6 is STR2 R7 is --H, --CN, --NHSO2 Alkyl, --Br, --OAlkyl, --NH2, --NO2, --NHCOAlkyl, or NHCONHAlkyl; R8 is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO2 Alkyl, --NHCOAlkyl, --SOm Alkyl, or --CO2 Alkyl; and m is 0-2; or a pharmaceutically acceptable salt, hydrate or crystal form thereof; which are Class III antiarrhythmic agents.
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- Hexahydrobenzo (f) quinolinones as 5-alpha-reductase inhibitors
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The invention relates to 1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-ones, pharmaceutical formulations containing those compounds, and their use as steroid 5α-reductase inhibitors.
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- Benzo (f) quinolinones as 5-alpha-reductase inhibitors
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This invention relates to hexa- and octahydrobenzo[f]quinolin-3-ones, pharmaceutical formulations containing those compounds and methods of their use as steroid 5α reductase inhibitors.
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- Process for the preparation of benzo (F) quinolinones
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This invention relates to a process for the preparation of hexa- and octahydrobenzo[f]quinolin-3-ones.
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- HEXAHYDROBENZO[F]QUINOLINONES
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The invention relates to 1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-ones, pharmaceutical formulations containing those compounds, and their use as steroid 5alpha-reductase inhibitors.
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- Benzoquinazoline inhibitors of thymidylate synthase: Enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin- 1(2H)-ones
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The synthesis and thymidylate synthase (TS) inhibitory activity of a series of simple benzo[f]-quinazolin-1(2H)-ones are described. Fully aromatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolated enzyme, and represent the first examples of potent, folate-based TS inhibitors that completely lack any structural feature corresponding to the (p- aminobenzoyl)glutamate moiety of the cofactor. A number of the compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 μM.
- Pendergast,Johnson,Dickerson,Dev,Duch,Ferone,Hall,Humphreys,Kelly,Wilson
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p. 2279 - 2291
(2007/10/02)
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- NITROGEN-CONTAINING SPIROCYCLES
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Spirocycles of general structural formula: STR1 are Class III antiarrhythmic agents.
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