- ION CHANNEL MODULATORS
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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 38
(2021/06/04)
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- ION CHANNEL MODULATORS
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Provided, in part, are compounds of Formula I pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with the activity of sodium channels. 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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Paragraph 0369-0370
(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 Dravet syndrome or epilepsy are also provided herein.
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Paragraph 0243; 0245
(2020/12/13)
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- COMPOUNDS AND THEIR METHODS OF USE
-
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; 63
(2019/03/05)
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- ION CHANNEL MODULATORS
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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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Paragraph 00424
(2019/12/25)
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- Characterization of two carbonyl reductases from Ogataea polymorpha NBRC 0799
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The enzyme responsible for the enantioselective production of (S)-1,1,1-trifluoro-2-propanol ((S)-TFP) from 1,1,1-trifluoroacetone (TFA) has been identified in Ogataea polymorpha NBRC 0799. We purified two carbonyl reductases, OpCRD-A and OpCRD-B from this strain, and revealed their characteristics. Both enzymes were specific to NADH, but the following characteristics were different: The molecular mass of subunit OpCRD-A was 40?kDa and that of OpCRD-B was 43?kDa. Amino acid sequences of both enzymes were only 21% identical. OpCRD-B contained 4?mol of zinc per mole of enzyme, but OpCRD-A did not. The optimal pH, temperature, pH stability, thermostability, and inhibitor specificity were also remarkably different. With regard to substrate specificity, both enzymes exhibited high reductase activity toward a wide variety of ketones, aldehydes and fluoroketones, and dehydrogenase activity toward 2-propanol and 2-butanol. The reductase activity was much higher than the dehydrogenase activity at acidic pH. OpCRD-A enantioselectively produced (S)-TFP from TFA, but OpCRD-B preferentially produced (R)-TFP. Thus, we concluded that OpCRD-A plays the main role in the production of (S)-TFP by a reaction of O. polymorpha NBRC 0799 cells and that OpCRD-A has great potential for efficient production of (S)-TFP, as it is an S-specific enzyme and does not catalyze the dehydrogenation of (S)-TFP.
- Isobe, Kimiyasu,Miki, Shinsuke,Ueda, Ryoko,Shichida, Sayaka,Matsui, Daisuke,Oku, Yuko,Asano, Yasuhisa
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p. 1307 - 1316
(2017/12/26)
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- Bitopertin synthetic method and intermediate
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The present invention discloses a new synthesis method and intermediates of Bitopertin. According to the Bitopertin synthesis method, 5-methylsulfonyl-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzoic acid is adopted as a raw material, and continuous multi-step operations such as chlorination, acylation, deprotection, condensation and re-crystallization are subjected to performed to obtain the Bitopertin, wherein the intermediates in each step do not require further purification, and the total yield can achieve more than or equal to 80%.
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Paragraph 0051; 0059; 0060
(2018/03/26)
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- Trifluoro isopropyl-substituted taxol derivatives, and applications thereof
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The invention relates to novel trifluoro isopropyl-substituted taxol derivatives. The trifluoro isopropyl-substituted taxol derivatives are compounds represented by formula I, and isomers, corresponding compounds, or pharmacologically acceptable salts of the compounds, wherein R is used for representing hydrogen atom, or C1-C4 straight-chain paraffins or branched chain paraffins, or C2-C4 straight-chain acyl or branched chain acyl. The invention also provides a preparation method of the trifluoro isopropyl-substituted taxol derivatives, and applications of the trifluoro isopropyl-substituted taxol derivatives in preparing antitumor drugs.
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Paragraph 0073; 0074; 0075
(2017/07/22)
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- (S)-1,1,1-trifluoro-2-propanol synthesis method
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The present invention discloses a (S)-1,1,1-trifluoro-2-propanol synthesis method, steps are as follows: hexane or cyclohexane solvent, 1,1,1-trifluoro-2-propanol and a catalyst are added into a Soxhlet extractor extraction flask, and the mass ratio of hexane or cyclohexane solvent to 1,1,1-trifluoro-2-propanol is 3-30: 1; Novozyme 435 is added into a Soxhlet extractor extraction tube; the upper portion of the Soxhlet extractor extraction tube is provided with a condenser for condensing reflux reaction for 10 to 24 hours; reactants in the Soxhlet extractor extraction flask are reacted under reflux conditions for 10 to 24 hours and cooled, then the catalyst is recovered by filtration, the hexane or cyclohexane solvent is recovered by concentration, a 10-20% sodium hydroxide or potassium hydroxide water solution is added for reaction for 5 to 10 hours and then rectification to obtain (S)-1,1,1-trifluoro-2-propanol. The raw materials are simple and easy to get, pollution is less during the reaction, the process is simple, complex equipment is not needed, the synthesis method is safe and reliable, the synthesis yield is high, a product with a high purity can be obtained after refining.
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Paragraph 0007; 0008
(2016/11/24)
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- PHENYL-3-AZA-BICYCLO[3.1.0]HEX-3-YL-METHANONES AND THE USE THEREOF AS MEDICAMENT
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The present inventions relates to substituted phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones of general formula (I) wherein R1, R2, R3, R4, R5 and R6 are as herein described or salts thereof, preferably pharmaceutically acceptable salts thereof. The invention further relates to the manufacture of said compounds, pharmaceutical compositions comprising a compound according to general formula (I), and the use of said compounds for the treatment of various conditions such as conditions concerning positive and negative symptoms of schizophrenia as well as cognitive impairments associated with schizophrenia, Alzheimers Disease and other neurological and psychiatric disorders. The compounds of the invention show glycine transporter-1 (GlyT 1) inhibiting properties.
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Page/Page column 87; 88
(2013/03/26)
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- Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament
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Substituted phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones which are glycine transporter-1 (GlyT1) inhibitors. These are useful for the treatment of schizophrenia, Alzheimer's Disease and other neurological and psychiatric disorders.
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Paragraph 0215; 0216
(2013/08/14)
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- Application of tethered ruthenium catalysts to asymmetric hydrogenation of ketones, and the selective hydrogenation of aldehydes
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An improved method for the synthesis of tethered ruthenium(II) complexes of monosulfonylated diamines is described, together with their application to the hydrogenation of ketones and aldehydes. The complexes were applied directly, in their chloride form, to asymmetric ketone hydrogenation, to give products in excess of 99% ee in the best cases, using 30 bar of hydrogen at 60 °C, and to the selective reduction of aldehydes over other functional groups. Copyright
- Jolley, Katherine E.,Prokes, Ivan,Morris, David J.,Wills, Martin,Zanotti-Gerosa, Antonio,Hancock, Fred,Dyke, Alan,Grainger, Damian M.,Medlock, Jonathan A.,Nedden, Hans G.,Le Paih, Jacques J. M.,Roseblade, Stephen J.,Seger, Andreas,Sivakumar, Vilvanathan
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supporting information
p. 2545 - 2555,11
(2012/12/12)
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- Application of tethered ruthenium catalysts to asymmetric hydrogenation of ketones, and the selective hydrogenation of aldehydes
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An improved method for the synthesis of tethered ruthenium(II) complexes of monosulfonylated diamines is described, together with their application to the hydrogenation of ketones and aldehydes. The complexes were applied directly, in their chloride form, to asymmetric ketone hydrogenation, to give products in excess of 99% ee in the best cases, using 30 bar of hydrogen at 60 °C, and to the selective reduction of aldehydes over other functional groups. Copyright
- Jolley, Katherine E.,Zanotti-Gerosa, Antonio,Hancock, Fred,Dyke, Alan,Grainger, Damian M.,Medlock, Jonathan A.,Nedden, Hans G.,Le Paih, Jacques J. M.,Roseblade, Stephen J.,Seger, Andreas,Sivakumar, Vilvanathan,Prokes, Ivan,Morris, David J.,Wills, Martin
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supporting information
p. 2545 - 2555
(2013/01/14)
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- Process for producing optically active aliphatic fluoroalcohol
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The problem to be resolved by the present invention is to provide a method for efficiently synthesizing optically active lower aliphatic alcohols that have difficulty in separation from organic solvents, without using a special reactor. The present invention relates to a method for producing an optically active aliphatic alcohol having a fluorine atom at α position, wherein an optically active alcohol is produced by reacting an aliphatic ketone having a fluorine atom at α position in water using a formate, under the presence of an asymmetric catalyst represented by general formula (1) and an acid.
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Page/Page column 13
(2012/01/11)
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- Preparation of dihydropyrrol derivatives as intermediates
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The invention is concerned with a new scalable process for the preparation of compounds of formula I comprising a new process for the preparation of the key intermediate, a dihydropyrrole derivative formula II or a salt thereof.
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Page/Page column 9
(2009/06/27)
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- Organic metal compound and process for preparing optically-active alcohols using the same
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The present invention provides an asymmetric reduction catalyst effective in preparing optically-active alcohol compounds having various functional groups, and a process for preparing optically-active alcohol compounds using said asymmetric reduction catalyst. The organic metal compound of the present invention is represented by the following general formula (1): wherein R1 and R2 may be mutually identical or different, and are an alkyl group, a phenyl group, a naphthyl group, a cycloalkyl group, or an alicyclic ring formed by binding R1 and R2, which may have a substituent; R3 is a hydrogen atom or an alkyl group; Cp is a cyclopentadienyl group, which may have a substituent, bound to M1 via a π bond; X1 is a halogen atom or a hydrido group; M1 is rhodium or iridium; and * denotes asymmetric carbon.
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Page/Page column 9; 18
(2009/04/24)
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- Development of a practical synthesis of a p38 MAP kinase inhibitor
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A practical synthesis of the phthalazine-based p38 MAP kinase inhibitor [(S)-2] was needed for an ongoing program. Vibrational circular dichroism provided the assignment of the absolute stereochemistry of the target compound. The selected synthetic route
- Thiel, Oliver R.,Achmatowicz, Michal,Bernard, Charles,Wheeler, Philip,Savarin, Cecile,Correll, Tiffany L.,Kasparian, Annie,Allgeier, Alan,Bartberger, Michael D.,Tan, Helming,Larsen, Robert D.
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supporting information; experimental part
p. 230 - 241
(2010/04/22)
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- Asymmetric hydrogenation of 1,1,1- trifluoroacetone
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The invention relates to the preparation of enantiomerically pure (S)-1,1,1-trifluoro-2-propanol by asymmetric hydrogenation of 1,1,1-trifluoroacetone which process comprises hydrogenating 1,1,1-trifluoroacetone in the presence of a ruthenium phosphine complex catalyst represented by formula [in-line-formulae]Ru(E)(E)(L)(A)[/in-line-formulae] wherein E, E′ are both chloro or E is hydrogen and E′ is BH4; L is a chiral diphosphine ligand; andA is an optionally chiral diaminewherein hydrogenation occurs in the presence of a weak base, with or without an additive, when E and E′ are both chloro orb) in the absence of a base and an additive when E and E′ are hydrogen and BH4.
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Page/Page column 6; 9; 20
(2008/06/13)
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- SYNTHESIS OF GLYT-1 INHIBITORS
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The present invention relates to a process for preparation of a compound of formula I wherein Het, R1, R2, R3, and n are as defined herein and pharmaceutically acceptable acid addition salts thereof, which comprises reacting a compound of formula 21 with a compound of formula 8 to obtain a compound of formula 11 and coupling the compound of formula 11 in the presence of a coupling reagent or the corresponding acid halogenide with a compound of formula 15 to obtain a compound of formula I.
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Page/Page column 4; 9
(2008/12/08)
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- The influence of fluorine on the asymmetric reduction of fluoromethyl ketones
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A comparative study of the asymmetric reduction of representative aryl and alkyl α-fluoro- and α-chloromethyl ketones using (-)-diisopinocampheylchloroborane [(-)-DIP-Chloride] and (-)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane [R-Alpine-Borane] has been made. It was observed that DIP-Chloride is superior in terms of the rate and enantioselectivity for both classes of halo-ketones. While the reduction of monofluoroacetone and trifluoroacetone with DIP-Chloride provided the product alcohols in 61% ee and 96% ee, respectively, the reduction of difluoroacetone yielded only 5% ee. The influence of a lone halogen atom was not observed for monochloroacetone, all of which point towards a chelating effect of monofluoroacetone on the Lewis acidic chloroborane.
- Ramachandran, P. Veeraraghavan,Gong, Baoqing,Teodorovi?, Aleksandar V.
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p. 844 - 850
(2008/03/14)
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- Asymmetric reduction of 1,1,1-trifluoroacetone
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The invention relates to a scalable biocatalytic process for the preparation of S-1,1,1-trifluoro-2-propanol with a enantiomeric excess of >99% by asymmetric microbial reduction of 1,1,1-trifluoroacetone with Baker's yeast.
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Page/Page column 5; 6; 8; 10
(2008/06/13)
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- Bioreductive synthesis of perfluorinated chiral alcohols
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Perfluorinated chiral alcohols are interesting building blocks for pharmaceuticals and agrochemicals. Different chiral (R)- and (S)-configured perfluorinated alcohols were produced by asymmetric reduction of the corresponding ketones. Commercially available alcohol dehydrogenases were used as catalyst in combination with different cofactor regenerating systems. High selectivities of >99% were observed in most cases. The results also demonstrate the influence of the CF3 group on reactivity and enantioselectivity of alcohol dehydrogenases.
- Rosen, Thomas C.,Feldmann, Ralf,Dünkelmann, Pascal,Dau?mann, Thomas
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p. 4803 - 4806
(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.
-
-
- Chiral Synthesis Via Organoboranes. 38 Selective Reductions. 48. Asymmetric Reduction of Trifluoromethyl Ketones by B-Chlorodiisopinocampheylborane in High Enantiomeric Purity
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(-)-B-Chlorodiisopinocampheylborane TM,1>, introduced by us several years ago, has been shown to reduce prochiral aryl and alkyl perfluorinated ketones to the corresponding optically active alcohols in very high ee.For example, 2,2,2-trifluoroacetophenone, trifluoroacetyl-1-naphthalene, and trifluoroacetyl-2-naphthalene are all reduced with 1 within 1-3 d at rt in 90percent ee, 78percent ee and 91percent ee, respectively.The optical purity of 1-phenyl-2,2,2-trifluoroethanol is upgraded to = 99percent ee by crystallizing the initially formed products from pentane. 1,1,2,2,2- pentafluoropropiophenone and 1,1,2,2,3,3,3-heptafluorobutyrophenone are reduced in 3 d with 1 to the corresponding alcohols in 92percent ee and 87 percent ee, respectively.The reagent reduces alkyl trifluoromethyl ketones at a rate faster than that of the aryl derivatives, while still providing the product alcohols in very high ee.Thus, 1,1,1-trifluoroacetone, 1,1,1-trifluorononan-2-one, and 1,1,1-trifluorodecan-2-one are all reduced within 4 - 8 h in 89percent ee, 92percent ee, and 91percent ee, respectively.Even α-sec-alkyl trifluoromethyl ketones are handled by 1 very efficiently.Thus cyclohexyl trifluoromethyl ketone is reduced by 1 at rt in 12 h to the product alcohol in 87percent ee.In all of these cases the trifluoromethyl group acts as the enantiocontrolling larger group as compared to the aryl or alkyl group.This produces alcohol products with stereochemistry opposite to those obtained for the corresponding hydrogen analogs.The steric and electronic influence of the trifluoromethyl group in achieving enantiocontrol in assymmetric reductions is discussed.Keywords: asymmetric reduction; trifluoromethyl ketones; DIP-Chloride; high enantiomeric purity
- Ramachandran, P. Veeraraghavan,Teodorovic, Aleksandar V.,Brown, Herbert C.
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p. 1725 - 1738
(2007/10/02)
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