- COMPOUNDS AND THEIR METHODS OF USE
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The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
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Paragraph 0243; 0244
(2020/12/13)
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- COMPOUNDS AND THEIR METHODS OF USE
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The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
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Page/Page column 62
(2019/03/05)
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- Method for Industrial Production of Optically Active Fluoroalkyl Ethylene Oxide
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It is possible to produce an optically active fluoroalkyl chloromethyl alcohol with a high optical purity and a good yield by treating a fluoroalkyl chloromethyl ketone with a microorganism having an activity for asymmetrically reducing the ketone or an enzyme having the activity. Then, it is possible to obtain a fluoroalkyl ethylene oxide by treating the alcohol with a base. Industrial implementation of the production method of the present invention is easy.
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Paragraph 0139; 0140
(2018/11/21)
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- PYRAZOLYLAMINOBENZIMIDAZOLE DERIVATIVES AS JAK INHIBITORS
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The present invention provides compounds of the formula below (I'): where R, and R1-R3 are as described herein, methods of treating patients for certain types of autoimmune diseases and cancer, and processes for preparing the compounds.
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Page/Page column 12; 13
(2018/03/26)
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- OXYSTEROLS AND METHODS OF USE THEREOF
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Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R2, R3, R4, R5, and and R6 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
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Paragraph 00353; 00355; 00705
(2018/05/16)
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- JAK1 inhibitors
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The present invention relates to certain benzimidazole compounds, or pharmaceutically acceptable salts thereof, that inhibit Janus kinase 1 (JAK1), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat certain types of cancer.
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Page/Page column 7; 8
(2017/02/24)
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- ISOSELECTIVE POLYMERIZATION OF EPOXIDES
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The present invention provides novel bimetallic complexes and methods of using the same in the isoselective polymerization of epoxides. The invention also provides methods of kinetic resolution of epoxides. The invention further provides polyethers with high enantiomeric excess that are useful in applications ranging from consumer goods to materials.
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Page/Page column 69; 77-78
(2009/04/25)
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- NEW CHIRAL SALEN CATALYSTS AND METHODS FOR THE PREPARATION OF CHIRAL COMPOUNDS FROM RACEMIC EPOXIDES BY USING THEM
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The present invention relates to new chiral salen catalysts and the preparation method of chiral compounds from racemic epoxides using the same. More specifically, it relates to new chiral salen catalysts that have high catalytic activity due to new molecular structures and have no or little racemization of the generated target chiral compounds even after the reaction is completed and can be also reused without catalyst regeneration treatment, and its economical preparation method to mass manufacture chiral compounds of high optical purity, which can be used as raw materials for chiral food additives, chiral drugs, or chiral crop protection agents, etc., using the new chiral salen catalysts.
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Page/Page column 39
(2009/01/24)
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- Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein
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A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [3H] cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF2CF2H (42, IC50 0.14 μM in buffer, 5.6 μM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF3 (67), and C(CF3)2OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC50 0.02 μM in buffer, 0.6 μM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.
- Durley, Richard C.,Grapperhaus, Margaret L.,Hickory, Brian S.,Massa, Mark A.,Wang, Jane L.,Spangler, Dale P.,Mischke, Deborah A.,Parnas, Barry L.,Fobian, Yvette M.,Rath, Nigam P.,Honda, Dorothy D.,Zeng, Ming,Connolly, Daniel T.,Heuvelman, Deborah M.,Witherbee, Bryan J.,Melton, Michele A.,Glenn, Kevin C.,Krul, Elaine S.,Smith, Mark E.,Sikorski, James A.
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p. 3891 - 3904
(2007/10/03)
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- (R)-chiral halogenated substituted N-benzyl-N-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
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The invention relates to substituted aryl and heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanol compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Novel high yield, stereoselective processes for the preparation of the chiral substituted alkanol compounds from chiral and achiral intermediates are described.
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- Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)CoIII complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols
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The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)CoIII complex 1·OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H2O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to ≥ 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H2O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (krel) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, krel values for the HKR exceed 50, and in several cases are well in excess of 200.
- Schaus, Scott E.,Brandes, Bridget D.,Larrow, Jay F.,Tokunaga, Makoto,Hansen, Karl B.,Gould, Alexandra E.,Furrow, Michael E.,Jacobsen, Eric N.
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p. 1307 - 1315
(2007/10/03)
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- Chiral Synthesis via Organoboranes. 40. Selective Reductions. 55. A Simple One-Pot Synthesis of the Enantiomers of (Trifluoromethyl)oxirane. A General Synthesis in High Optical Purities of α-Trifluoromethyl Secondary Alcohols via the Ring-Cleavage Reactions of the Epoxide
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An extremely efficient one-pot asymmetric synthesis of either enantiomer of (trifluoromethyl)oxirane (3,3,3-trifluoro-1,2-epoxypropane, 4) in 64percent yield and 96percent ee has been achieved via the asymmetric reduction of the commercially available 1-bromo-3,3,3-trifluoro-2-propanone with either (+)- or (-)-B-chlorodiisopinocampheylborane (Aldrich: DIP-Chloride), followed by ring closure of the intermediate chloroborinate, IpcBCl.The ring cleavage reactions of 4 provide a general synthesis of chiral trifluoromethyl carbinols without loss of optical activity.Thus we have synthesized 1-amino-3,3,3-trifluoro-2-propanol, 1-azido-3,3,3-trifluoro-2-propanol, 1-(diethylamino)-3,3,3-trifluoro-2-propanol, 1-cyano-3,3,3-trifluoro-2-propanol, 1,1,1-trifluoro-2-propanol, 1,1,1-trifluoro-2-octanol, 1-phenyl-3,3,3-trifluoro-2-propanol, 1-ethoxy-3,3,3-trifluoro-2-propanol, and 1,2-dihydroxy-3,3,3-trifluoropropane, in 61-88percent yields and in 96percent ee by the cleavage of 4 with the appropriate nucleophile.
- Ramachandran, P. Veeraraghavan,Gong, Baoqing,Brown, Herbert C.
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- Simple Access to (R)- and (S)-3,3,3-Trifluorolactic Acid and to (R)- and (S)-(Trifluoromethyl)oxirane
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Ethyl trifluoropyruvate (from hexafluoropropylene oxide) is reduced by NaBH4 to rac-trifluorolactic acid which is resolved on a 100-g scale by salt formation with (R,R)- and (S,S)-2-amino-1-phenyl-1,3-propanediol (readily available intermediates of industrial chloroamphenicol synthesis).The enantiomerically pure trifluorolactic acids (>99percent ee by GC analysis on cyclodextrin columns) are converted into (R)- and (S)-(trifluoromethyl)oxirane in an overall yield of 73percent by the following steps: esterification, THP protection of the OH group, LAH reduction and mesylation to the 2-THP-protected mesylate of 3,3,3-trifluoro-1,2-propanediol, and one-pot deprotection (Dowex 50) and cyclization (NaOCH2CH2OH) in ethylene glycol.The enantiomeric purity of the oxirane (b.p. 39 deg C, isolated on a 10-g scale) was determined by GC to be >99percent.Possible synthetic targets are mentioned which should be accessible in enantiomerically pure form from the (trifluoromethyl)oxirane described here. Key Words: Resolution by crystallization of diastereomeric salts / Perfluoropropylene oxide / Trifluoropyruvate / Capillary GC determination of ratios of enantiomers / Cyclodextrine-derived GC columns / Determination of the sense of chirality by chemical correlation / pKs of 3,3,3-trifluoro-2-hydroxypropanoic and 4,4,4-trifluoro-3-hydroxybutanoic acid
- Bussche-Huennefeld, Christoph von .,Cescato, Claudio,Seebach, Dieter
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p. 2795 - 2802
(2007/10/02)
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