- Synthesis of BACE1 Inhibitors E2609 / E2071 via Oxime-Olefin Cycloaddition following a Process Risk Mitigation Strategy
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Process development of E2609 from the preclinical stage to the clinical stage following a process risk mitigation strategy is described here. Key features include a turbo Grignard reaction monitored by in-situ IR, [3 + 2] cycloaddition in water, chemoselective amide coupling via in-situ protection, and a Reformatsky/decarboxylation approach to install a difluoromethyl group. Toward safe and scalable manufacture of E2071, an analog of E2609, a flow-reaction process for trifluoromethylation of aldehydes is presented here.
- Benayoud, Farid,Bracke, Markus,Chanda, Arani,Dimopoulos, Paschalis,Fang, Francis G.,Farthing, Christopher N.,Hall, Adrian,Ishida, Tasuku,Kaneko, Toshihiko,Kayano, Akio,Khan, Afzal,Kim, Dae-Shik,Kita, Yoichi,Lu, Lily,Mitasev, Branko,Motoki, Takafumi,Nagai, Mitsuo,Omori, Masayuki,Schnaderbeck, Matthew,Suzuki, Yuichi,Takaishi, Mamoru,Takeda, Kunitoshi,Wakasugi, Kazunori,Watanabe, Yuzo,Yamamoto, Noboru,Yoshizawa, Kazuhiro,Zhang, Huiming
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- METHOD FOR PRODUCING 5-(DIFLUOROMETHYL)PYRAZINE-2-CARBOXILIC ACID AND PRODUCTION INTERMEDIATE THEREOF
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5-(Difluoromethyl)pyrazine-2-carboxilic acid, which is a raw material for the construction of 5-(difluoromethyl)pyrazine-2-carboxamide, which is a common partial structural motif of the compound having an A production inhibitory action or a BACE1 inhibitory action, can be industrially advantageously produced by decarboxylating 5-[carboxy(difluoro)methyl]pyrazine-2-carboxylic acid, which is obtainable from 5-chloropyrazine-2-carboxylate.
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- C5-C6 OXACYCLIC-FUSED THIADIAZINE DIOXIDE COMPOUNDS AS BACE INHIBITORS, COMPOSITIONS, AND THEIR USE
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In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula : (I) and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein each of ring A, ring B, ring C, R2, R3, R4, m, n, p, and -L1- is as defined herein. The novel compounds of the invention may be useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including Alzheimer's disease, are also disclosed.
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- FUSED AMINODIHYDROTHIAZINE DERIVATIVES
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The present invention relates to a fused aminodihydrothiazine derivative of formula (I): wherein X is hydrogen or fluorine;A is CH or N;Y is methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, methoxy, ethoxy, methoxymethyl or —C≡N; and pharmaceutically acceptable salts thereof; which compound has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
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- FUSED AMINODIHYDROTHIAZINE DERIVATIVES USEFUL AS BACE INHIBITORS
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The present invention relates to a fused aminodihydrothiazine derivative of formula (I): wherein X is hydrogen or fluorine; A is CH or N; Y is methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, methoxy, ethoxy, methoxymethyl or -C≡N; and pharmaceutically acceptable salts thereof; which compound has an Αβ production inhibitory effect or a BACEl inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Αβ and typified by Alzheimer-type dementia.
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- FUSED AMINODIHYDROPYRIMIDONE DERIVATIVES
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A compound represented by the general formula (I) or pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C6-14 aryl group or the like, L is -NReCO- or the like (wherein Re is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a single bond or the like, Z is a C1-3 alkylene group or the like, R1, R2 and Rx are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, has an Abeta production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Abeta and typified by Alzheimer-type dementia.
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- FUSED AMINODIHYDRO-OXAZINE DERIVATIVES
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A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C6-14 aryl group or the like, L is -NReCO- or the like (wherein Re is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a single bond or the like, Z is a C1-3 alkylene group or the like, R1 and R2 are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
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- NOVEL FUSED AMINODIHYDROTHIAZINE DERIVATIVE
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A compound represented by the general formula: wherein Ring A is a C6-14 aryl group or the like, L is —NRLCO— or the like (wherein RL is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a C1-3 alkylene group or the like, Z is an oxygen atom or the like, R1 and R2 are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, or a pharmaceutically acceptable salt thereof, or a solvate thereof, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
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Page/Page column 49
(2010/04/30)
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- FUSED AMINODIHYDROTHIAZINE DERIVATIVES
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A compound represented by the general formula: or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C6-14 aryl group or the like, L is —NReCO— or the like (wherein Re is a hydrogen atom or the like), Ring B is a C6-14 aryl group or the like, X is a C1-3 alkylene group or the like, Y is a single bond or the like, Z is a C1-3 alkylene group or the like, R1 and R2 are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
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Page/Page column 54-55
(2009/09/05)
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