- Preparation method of 3-bromo-5-(propyn-1-yl)pyridine
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The invention discloses a preparation method of 3-bromo-5-(propyn-1-yl)pyridine, comprising the steps of S1, subjecting N-methyl-N-methoxy-5-bromo-nicotinamide and ethyl carbon anion reagent to condensation reaction to generate (5-bromopyridine-3-yl)ethanone; S2, subjecting (5-bromopyridine-3-yl)ethanone and a chlorination reagent to reaction to obtain 3-bromo-5-(1,2-dichloropropene-1-yl)pyridine;S3, subjecting 3-bromo-5-(1,2-dichloropropene-1-yl)pyridine and a reducing agent to reaction to obtain 3-bromo-5-(propyn-1-yl)pyridine. The synthetic route is novel and has few steps; the target product can be prepared just via three steps of reaction; the yield is higher than 40%; using noble metal reagents is not required; the preparation method features mild reaction conditions and the like; materials used herein are easy to obtain and low in cost, and no special operating procedure is required; the requirement on equipment is low; the preparation method is suitable for industrial production.
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- Development of a Continuous-Flow Sonogashira Cross-Coupling Protocol using Propyne Gas under Process Intensified Conditions
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The development of a continuous-flow Sonogashira cross-coupling protocol using propyne gas for the synthesis of a key intermediate in the manufacturing of a β-amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, currently undergoing late stage clinical trials for a disease-modifying therapy of Alzheimer's disease, is described. Instead of the currently used batch manufacturing process for this intermediate that utilizes TMS-propyne as reagent, we herein demonstrate the safe utilization of propyne gas, as a cheaper and more atom efficient reagent, using an intensified continuous-flow protocol under homogeneous conditions. The flow process afforded the target intermediate with a desired product selectivity of ~91% (vs the bis adduct) after a residence time of 10 min at 160 °C. The continuous-flow process compares favorably with the batch process, which uses TMS-propyne and requires overnight processing, TBAF as an additive, and a significantly higher loading of Cu co-catalyst.
- Znidar, Desiree,Hone, Christopher A.,Inglesby, Phillip,Boyd, Alistair,Kappe, C. Oliver
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p. 878 - 884
(2017/06/23)
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- COMPOUNDS AND THEIR USE AS BACE1 INHIBITORS
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The present invention relates to compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X, Y, Z, Q, W, m, u, ring (A), R2, R3, R4, R5 and R6, are as defined in the specification and claims. The present invention provides a pharmaceutical composition containing the compounds of Formula (I) and a therapeutic method of treating and/or preventing Downs syndrome, β-amyloid angiopathy, disorders associated with cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative diseases, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, Alzheimer's disease and/or Down syndrome, age-related macular degeneration (AMD), glaucoma, olfactory function impairment, traumatic brain injury, progressive muscle diseases, Type II diabetes mellitus and cardiovascular diseases (stroke).
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Page/Page column 106; 107
(2016/11/17)
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- 4,6-DIARYLAMINOTHIAZINES AS BACE1 INHIBITORS AND THEIR USE FOR THE REDUCTION OF BETA-AMYLOID PRODUCTION
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Compounds of formula (I), including pharmaceutically acceptable salts thereof, are set forth herein: (I) wherein R1 and R2 are independently hydrogen, or -CH3; or R1 and R2 can join together in a ring by adding -(CH2)4-; R3 is hydrogen or C1-C3 al-kyl; Y and Z are independently a C6-C10- aryl group or a 5-10 membered heterocyclic group which can be further substituted with from 0-3 substituents selected from the group of halogen, hydroxy, amino, C1-4 alkylamino, C1-4 dialkylamino, halo C1-4 alkyl, CN, C1-C6, alkyl or cycloalkyl, C1-C6 alkoxy, -C=OC1-4 alkyl, -SO2C1-4 alkyl, and C2-C4 alkynyl; A is selected from the group of phenyl, ben-zyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and pyrazinyl groups which can be further substituted with from 0-3 substituents selected from the group of halogen, hydroxy, amino, C1-4 alkylamino, C1-4 dialkylamino, haloC1-4 alkyl, hydroxyC1-6 alkyl, CN, C1-C6 alkyl or cycloalkyl, C1-C6 alkoxy, and C2-C4 alkynyl; L is -NHCO-, or is a single bond; and L and Z to-gether can be absent
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Page/Page column 32
(2014/07/08)
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- FUSED AMINODIHYDROPYRIMIDINE DERIVATIVE
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The present invention provides, for example, the following compound: wherein ring A is a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, X1—X2═X3 is CR5—CR6═CRs
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Paragraph 0252; 0253
(2013/08/28)
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- 2H-IMIDAZOL-4-AMINE COMPOUNDS AND THEIR USE AS BACE INHIBITORS
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2H-imidazol-4-amine compounds, therapeutically acceptable salts thereof, processes for preparation thereof, therapeutic uses of such compounds for treating Αβ-related pathologies such as Down's syndrome, β-amyloid angiopathy, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration methods of therapy, and pharmaceutical compositions containing such compounds. Formula (I) wherein A is -O- or -CH2-, n is 1 or 1.
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Page/Page column 40
(2014/01/09)
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- CYCLOHEXANE-1,2'-NAPHTHALENE-1',2"-IMIDAZOLE COMPOUNDS AND THEIR USE AS BACE INHIBITORS
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Cyclohexane-1,2'-naphthalene-1',2''-imidazole compounds, therapeutically acceptable salts thereof, processes for preparation thereof, therapeutic uses of such compounds for treating Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration, methods of therapy using such compounds, and pharmaceutical compositions containing such compounds.
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Page/Page column 27
(2014/01/09)
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- Discovery of an orally available, brain penetrant BACE1 inhibitor that affords robust CNS Aβ reduction
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Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats.
- Stamford, Andrew W.,Scott, Jack D.,Li, Sarah W.,Babu, Suresh,Tadesse, Dawit,Hunter, Rachael,Wu, Yusheng,Misiaszek, Jeffrey,Cumming, Jared N.,Gilbert, Eric J.,Huang, Chunli,McKittrick, Brian A.,Hong, Liwu,Guo, Tao,Zhu, Zhaoning,Strickland, Corey,Orth, Peter,Voigt, Johannes H.,Kennedy, Matthew E.,Chen, Xia,Kuvelkar, Reshma,Hodgson, Robert,Hyde, Lynn A.,Cox, Kathleen,Favreau, Leonard,Parker, Eric M.,Greenlee, William J.
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supporting information
p. 897 - 902
(2013/01/15)
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- Compounds and their use as BACE inhibitors
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The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 19
(2012/07/13)
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- Compounds and their use as BACE Inhibitors
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The present invention relates to compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 27
(2012/07/13)
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- COMPOUNDS FOR THE REDUCTION OF BETA-AMYLOID PRODUCTION
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Compounds of formula (I), including pharmaceutically acceptable salts thereof, are set forth herein: wherein R1, R2, R3, R4, R5, and R6 are independently hydrogen, C1-C6 alkyl or C1-C6 cycloalkyl; Y and Z are independently a C6-C10- aryl group or a 5-10 membered heterocyclic group, wherein each Y and Z group can be optionally substituted with from 0-3 substituents selected from halogen, amino, C1-4alkylamino, C1-4dialkylamino, haloC1-4 alkyl, OH, CN, C1-C6 alkyl or cycloalkyl, C1-C6 alkoxy, and C2-C4 alkynyl; L is either a bond or is -NHCO-; L and Z together can be absent; and m is 1, 2 or 3.
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Page/Page column 8
(2012/12/13)
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- Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor
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From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F′ subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
- Cumming, Jared N.,Smith, Elizabeth M.,Wang, Lingyan,Misiaszek, Jeffrey,Durkin, James,Pan, Jianping,Iserloh, Ulrich,Wu, Yusheng,Zhu, Zhaoning,Strickland, Corey,Voigt, Johannes,Chen, Xia,Kennedy, Matthew E.,Kuvelkar, Reshma,Hyde, Lynn A.,Cox, Kathleen,Favreau, Leonard,Czarniecki, Michael F.,Greenlee, William J.,McKittrick, Brian A.,Parker, Eric M.,Stamford, Andrew W.
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scheme or table
p. 2444 - 2449
(2012/05/19)
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- S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
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The invention provides novel spirochroman compounds of Formulas I and II that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.
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Page/Page column 84-85
(2011/06/26)
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- NOVEL COMPOUNDS FOR TREATMENT OF NEURODEGENERATION ASSOCIATED WITH DISEASES, SUCH AS ALZHEIMER'S DISEASE OR DEMENTIA
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The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Downs syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 59-60
(2011/02/24)
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- NOVEL COMPOUNDS FOR TREATMENT OF NEURODEGENERATION ASSOCIATED WITH DISEASES, SUCH AS ALZHEIMER'S DISEASE OR DEMENTIA
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The present invention relates to novel compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Downs syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with diseases such as Alzheimer disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 55
(2011/02/24)
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- ASPARTYL PROTEASE INHIBITORS
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Disclosed are compounds of the formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R1, R2, R3, R4, R6, R7 and R7a are as described above in the specification. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula (I) in combination with a cholinesterase inhibitor or a muscarinic m1 agonist or m2 antagonist.
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Page/Page column 50-51
(2008/06/13)
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