82110-21-2Relevant articles and documents
Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions
Yu, Wensheng,Tong, Ling,Selyutin, Oleg,Chen, Lei,Hu, Bin,Zhong, Bin,Hao, Jinglai,Ji, Tao,Zan, Shuai,Yin, Jingjun,Ruck, Rebecca T.,Curry, Stephanie,McMonagle, Patricia,Agrawal, Sony,Rokosz, Laura,Carr, Donna,Ingravallo, Paul,Bystol, Karin,Lahser, Frederick,Liu, Rong,Chen, Shiying,Feng, Kung-I,Cartwright, Mark,Asante-Appiah, Ernest,Kozlowski, Joseph A.
, p. 3984 - 4003 (2018/05/14)
We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
Routes for the synthesis of (2S)-2-methyltetrahydropyran-4-one from simple optically pure building blocks
Anderson, Kevin R.,Atkinson, Stephanie L. G.,Fujiwara, Takahiro,Giles, Melvyn E.,Matsumoto, Takaji,Merifield, Eric,Singleton, John T.,Saito, Takao,Sotoguchi, Tsukasa,Tornos, James A.,Way, Edward L.
experimental part, p. 58 - 71 (2010/05/18)
Routes to (2S)-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of (S)-5-hydroxyhex-1-en-3-one, derived either from an alkyl (S)-3-hydroxybutyrate or (S)-propylene oxide. Formation of the tetrahydropyran ring directly via an intramolecular oxy-Michael reaction under acid-catalysed conditions resulted in loss of optical purity, whereas proceeding through the intermediate (2S)-2-methyl-2,3-dihydropyran-4-one, via an oxidative Pd-catalysed ring closure, followed by hydrogenation of the alkenyl bond, preserved the optical purity. An alternative approach to (2S)-2-methyl-2,3-dihydropyran-4-one is also reported, again starting from an alkyl (S)-3-hydroxybutyrate by elaboration to a carbonyl-protected (6S)-6-methyl-5,6-dihydropyran-2,4-dione derivative, followed by partial reduction and dehydration. Alternatively, the carbonyl group can be reduced out completely in one step to furnish (2S)-2-methyltetrahydropyran-4-one directly after deprotection.
TRICYCLIC INHIBITORS OF 5-LIPOXYGENASE
-
Page/Page column 89, (2010/11/28)
Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of 5-lipoxygenase (5-LO). Also described herein are methods of using such 5-LO inhibitors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions, diseases, or disorders.
5-lipoxygenase inhibitors quinoxalinyl derivatives
-
, (2008/06/13)
The invention concerns a heterocyclic derivative of the formula I STR1 wherein Q is an optionally substituted quinoxalinyl or a hydrogenated derivative thereof X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R1 is (1-6C)alkyl, (3-6C)alkenyl or (3-6C)alkynyl; and R2 and R3 together form a group of the formula --A2 --X2 --A3 -- which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 4 to 7 ring atoms, wherein A2 and A3, which may be the same or different, each is (1-4C)alkylene and X2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
DIARYL ETHER HETROCYCLES
-
, (2008/06/13)
The invention concerns a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, wherein Ar1 is optionally substituted phenyl or naphthyl; X1 is oxy, thio, sulphinyl or sulphonyl; Ar2 is optionally substituted phenylene, or a 6-membered heterocyclene moiety containing up to three nitrogen atoms; Rl is (l-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(l-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R2 and R3 together form a group of the formula ?A2?X2?A3? wherein each of A2 and A3 is (l-4C) alkylene and X2 is oxy, thio, sulphinyl, sulphonyl or imino. The invention also concerns processes for the manufacture of a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, and pharmaceutical compositions containing said heterocycle. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
5-LIPOXYGENASE INHIBITORS QUINOLINE OR ISOQUINOLINE DERIVATIVES
-
, (2008/06/13)
The invention concerns a heterocyclic derivative of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R1 is (1-6C)alkyl, (3-6C)alkenyl or (3-6C)alkynyl; and R2 and R3 together form a group of the formula ?A2?X2?A3? which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 4 to 7 ring atoms, wherein A2 and A3, which may be the same or different, each is (1-4C)alkylene and X2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase
HETEROCYCLES FOR USE AS INHIBITORS OF LEUKOTRIENES
-
, (2008/06/13)
The invention concerns a heterocycle of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R 1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R 2 and R 3 together form a group of the formula --A 2 --X 2 --A 3 -- which, together with the carbon atom to which A 2 and A 3 are attached, defines a ring having 4 to 7 ring atoms, wherein A 2 and A 3, which may be the same or different, each is (1-4C)alkylene and X 2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
Diaryl ether heterocycles
-
, (2008/06/13)
The invention concerns a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, wherein Ar1 is optionally substituted phenyl or naphthyl;, X1 is oxy, thio, sulphinyl or sulphonyl;, Ar2 is optionally substituted phenylene, or a 6-membered heterocyclene moiety containing up to three nitrogen atoms;, R1 is (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and, R2 and R3 together form a group of the formula -A2-X2-A3- wherein each of A2 and A3 is (1-4C)alkylene and X2 is oxy, thio, sulphinyl, sulphonyl or imino. The invention also concerns processes for the manufacture of a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, and pharmaceutical compositions containing said heterocycle. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
