- ENZYMATIC HYDROLYSIS OF CYCLOPROPYL ACETATE, A FACILE METHOD FOR MEDIUM- AND LARGE-SCALE PREPARATIONS OF CYCLOPROPANOL
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Enzymatic hydrolysis of cyclopropyl acetate at neutral pH, using commercially available enzyme preparations, results in a mixture from which cyclopropanol can be isolated by simple extraction.
- Jongejan, Jaap A.,Duine, Johannis A.
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Read Online
- Synthesis and Optimization of Kv7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity
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Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5, resulting in a selectivity index SI > 10. RL-56 is remarkably potent, EC2x 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for Kv7.4/Kv7.5 over Kv7.2/Kv7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF3, and SF5, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.
- Liu, Ruiting,Tzounopoulos, Thanos,Wipf, Peter
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supporting information
p. 929 - 935
(2019/06/13)
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- SELECTIVE POTASSIUM CHANNEL AGONISTS
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Selective potassium channel agonists and methods of use thereof are disclosed. A compound, or a pharmaceutically acceptable salt thereof, having a formula (I) wherein R1 is H or optionally-substituted alkyl; R2 is optionally-substituted C1-C6 alkyl or optionally- substituted cyclopropyl; R3 and R4 are each independently H or optionally- substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, optionally- substituted alkyl, or R6 and R7 together form a carbocycle; R8 is substituted phenyl or optionally-substituted pyridinyl, provided that if R8 is substituted phenyl, then R2 is optionally-substituted cyclopropyl; and R9, R10 and R11 are each independently H, halo, or optionally- substituted alkyl.
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Page/Page column 32-33
(2019/11/12)
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- BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
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Page/Page column 356
(2018/03/25)
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- ALK KINASE INHIBITOR, AND PREPARATION METHOD AND USE THEREOF
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An ALK kinase inhibitor compound as represented by Formula I, pharmaceutical composition containing the compound, and preparation method and use thereof in the preparation of drugs serving as an ALK inhibitor for treating cancer.
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Paragraph 0103; 0104; 0105
(2017/04/18)
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- The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen
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Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
- Riggs, Jennifer R.,Nagy, Mark,Elsner, Jan,Erdman, Paul,Cashion, Dan,Robinson, Dale,Harris, Roy,Huang, Dehua,Tehrani, Lida,Deyanat-Yazdi, Gordafaried,Narla, Rama Krishna,Peng, Xiaohui,Tran, Tam,Barnes, Leo,Miller, Terra,Katz, Jason,Tang, Yang,Chen, Ming,Moghaddam, Mehran F.,Bahmanyar, Sogole,Pagarigan, Barbra,Delker, Silvia,Lebrun, Laurie,Chamberlain, Philip P.,Calabrese, Andrew,Canan, Stacie S.,Leftheris, Katerina,Zhu, Dan,Boylan, John F.
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supporting information
p. 8989 - 9002
(2017/11/14)
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- ANTIVIRAL PHOSPHODIAMIDE COMPOUNDS
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Compounds of Formula (I): and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.
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Page/Page column 36-37
(2017/02/09)
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- Cyclic amine derivative and pharmaceutical use thereof
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The purpose of the present invention is to provide a compound that exerts a strong analgesic action against on pain, in particular, against neuropathic pain and/or fibromyalgia syndrome. The present invention provides a cyclic amine derivative represented by chemical formula, a prodrug thereof or a pharmaceutically acceptable salt thereof.
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Paragraph 0322
(2016/10/09)
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- CYCLIC AMINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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A compound exerts a strong analgesic effect against pain, in particular, neuropathic pain and/or fibromyalgia syndrome. The cyclic amine derivative is represented by formula, a prodrug thereof or a pharmacologically acceptable salt thereof: wherein A represents a group represented by Formula (IIa), (IIb) or (IIc): wherein R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R4 represents a hydrogen atom or an alkylcarbonyl group having 2 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms and optionally substituted with an alkylcarbonylamino group having 2 to 6 carbon atoms and n represents 1 or 2, in which when R3 and R4 each independently represent an alkyl group having 1 to 6 carbon atoms, R1 represents an alkyl group having 1 to 6 carbon atoms and substituted with a hydroxyl group, an amino group or a carboxyl group.
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Paragraph 0411; 0412
(2016/08/07)
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- PYRIDINYL-SUBSTITUTED PYRAZOLYL CARBOXAMIDES
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The invention relates to pyrazolyl-based carboxamide compounds useful as ICRAC inhibitors, to pharmaceutical compositions containing these compounds and to methods of using these compounds for the treatment and/or prophylaxis of diseases and/or disorders, in particular inflammatory diseases and/or inflammatory disorders.
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Paragraph 0328; 0329; 0330
(2015/06/24)
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- N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE DERIVATIVES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and compounds I for use to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
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Paragraph 000295
(2015/05/19)
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- SUBSTITUTED PYRROLOPYRIMIDINE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are Pyrrolopyrimidine Compounds having the following structure: wherein R1, R2, R3, and L are as defined herein, compositions comprising an effective amount of a Pyrrolopyrimidine Compound, and methods for treating or preventing breast cancer, more particularly triple negative breast cancer, comprising administering an effective amount of such Pyrrolopyrimidine Compounds to a subject in need thereof.
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Paragraph 0319
(2014/07/23)
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- CYSTEINE PROTEASE INHIBITORS
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Compounds of the formula (I) wherein One of A1 and A2 is N-CH3 and the other is CH; R1 is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl or oxetan-3-yl, wherein C3-C6cycloalkyl is optionally substituted with one, two or three fluoro or with CF3; R2a and R2b are independently selected from H, halo, C1-C4alkyl, C1-C4haloalkyl and C1- C4alkoxy; R3 is CH3 or F; n is 1, 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof for the use in the prophylaxis and/or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.
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Page/Page column 29
(2013/02/28)
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- CHEMICAL COMPOUNDS
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The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein Het1, X, R1, R2, R3, R4 and R5 are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain
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Page/Page column 54
(2012/01/15)
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- Novel gamma secretase inhibitors
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This invention discloses novel gamma secretase inhibitors of the formula: wherein: R1 is a substituted aryl or substituted heteroaryl group; R2 is an R1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X—C(O)—Y, —CH—X—C(O)—NR3—Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R3 and each R3A are independently H, or alkyl; R11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.
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- Novel gamma secretase inhibitors
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This invention discloses novel gamma secretase inhibitors of the formula: wherein: R1 is a substituted aryl or substituted heteroaryl group; R2 is an R1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X-C(O)—Y, —CH—X—C(O)—NR3—Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R3 and each R3A are independently H, or alkyl; R11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.
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- GRF analogs with increased biological potency
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The present invention relates to chimeric fatty body-GRF analogs with increased biological potency, their application as anabolic agents and in the diagnosis and treatment of growth hormone deficiencies. The chimeric fatty body-GRF analogs include an hydrophobic moiety (tail), and can be prepared, either by anchoring at least one hydrophobic tail to the GRF, in the chemical synthesis of GRF. The GRF analogs of the present invention are biodegradable, non-immunogenic and exhibit an improved anabolic potency with a reduced dosage and prolonged activity.
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- Hepoxilin analogs
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Compounds of the general structure STR1 are disclosed, wherein X is O, Cn, NH, or S, wherein n is 1, 2, 3 or 4; R1 is OH, CH3, CH2 OH, N3 or CH2 N3 ; R3 is H or CH3 ; R5 is Y-R2, wherein Y is a six-carbon chain optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three; R2 is C1 -C10 alkyl OH, C1 -C10 alkyl N3 or COOR4, wherein R4 is H, a branched or unbranched C1 -C10 alkyl (including substituted alkyl radicals), cycloalkyl, preferably C5 or C6 cycloalkyl, or a five- or six-membered aryl radical (including substituted aryl radicals), i.e. R2 is COOH or an ester of R4; R6 is a seven-carbon chain optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three; and . . . . . . indicates a single, double or triple bond. The compounds are analogs of hepoxilins and are used to modulate hepoxilin activity, for example in the control of inflammation or other processes mediated by intracellular calcium levels.
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- Oxidations of Cyclopropane, Methylcyclopropane, and Arenes with the Mono-oxygenase System from Methylococcus capsulatus
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The mono-oxygenase system from Methylococcus capsulatus oxidises cyclopropane to cyclopropanol, methylcyclopropane to cyclopropylmethanol, and monosubstituted benzenes to para-substituted phenols (with accompanying NIH shift).
- Dalton, Howard,Golding, Bernard T.,Waters, Barry W.,Higgins, Raymond,Taylor, John A.
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p. 482 - 483
(2007/10/02)
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- MIGRATION APTITUDES OF CYCLIC AND POLYCYCLIC BRIDGEHEAD GROUPS IN THE CRIEGEE REARRANGEMENT
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The migration aptitudes of cyclic and polycyclic bridgehead groups in the Criegee Rearrangement support ?-neighbouring group participation by pentacoordinated bonding and vertical charge stabilisation in the migrating group and therefore favour transition state 2b and not 2a.
- Wistuba, Eckehardt,Ruechardt, Christoph
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p. 3389 - 3392
(2007/10/02)
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- Reactions of the Cyclopropanone Hemiketal Magnesium Salt with Some Nucleophilic Reagents
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Cyclopropanol (5), 1-(arylethynyl)cyclopropanol (7), 1-(3-hydroxypropyl)cyclopropanol derivative 10, 1-(2-propynyl)cyclopropanol (14), cyclopropanone cyanohydrin (19), 1-(aminomethyl)cyclopropanol (21) derivatives, benzylidenecyclopropanes 32, and ethyl cyclopropylideneacetate (38) have been prepared from the magnesium salt of cyclopropanone hemiketal 3. 3-Cyclopropylidene-1-propanol (12) and 3-cyclopropylidene-1-propyne (16) have been obtained from the cyclopropanols 10 and 14, respectively. Some reactions of this new synthon were specific. On the other hand, 3 did not undergo the nucleophilic addition of sulfur and nitrogen ylides; it underwent oxidizing ring opening with BrZnCH2COOEt and induced the decomposition of diazomethane.
- Salauen, Jacques,Bennani, Fatima,Compain, Jean-Claude,Fadel, Antoine,Ollivier, Jean
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p. 4129 - 4135
(2007/10/02)
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