- Efficient enantioselective total synthesis of (-)-horsfiline
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A new efficient and concise enantioselective synthetic method for (-)-horsfiline is reported. (-)-Horsfiline could be obtained from diphenylmethyl tert-butyl malonate in 9 steps (32 %,>99 % ee) by using the enantioselective phase-transfer catalytic allylation (91 % ee) as the key step. This approach can be applied as a practical route for the large-scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed. Practical synthesis of a spirooxindole: The total synthesis of (-)-horsfiline was accomplished from diphenylmethyl tert-butylmalonate in nine steps (32 %, >99 % ee) by using a enantioselective phase-transfer catalytic allylation (91 % ee) as the key step (see scheme). Copyright
- Hong, Suckchang,Jung, Myunggi,Park, Yohan,Ha, Min Woo,Park, Cheonhyoung,Lee, Myungmo,Park, Hyeung-Geun
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Read Online
- Synthesis of near-infrared fluorescent rhodamines via an SNArH reaction and their biological applications
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Near-infrared (NIR) dyes are of great interest in biomedicine due to diminished interfering absorption and fluorescence from biological samples, reduced scattering, and enhanced tissue penetration depth. In this context, we report the synthesis of rectili
- Wang, Qing,Huang, Kun,Cai, Songtao,Liu, Chang,Jiao, Xiaojie,He, Song,Zhao, Liancheng,Zeng, Xianshun
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Read Online
- Quinoxaline compound, preparation method and application of quinoxaline compound in medicine
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The invention provides a quinoxaline compound, a preparation method and application of the quinoxaline compound in medicine, and particularly relates to a quinoxaline compound with PAR4 antagonistic activity, a preparation method of the quinoxaline compound, a pharmaceutical composition containing the quinoxaline compound and application of the quinoxaline compound. Specifically, the invention provides a compound shown as a general formula I and/or II or a tautomer or pharmaceutically acceptable salt thereof, a preparation method of the compound, and application of the compound or the tautomer or the pharmaceutically acceptable salt in medicines for preventing and/or treating thromboembolic diseases.
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Paragraph 0191-0194
(2021/07/24)
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- FUSED RING HETEROARYL COMPOUNDS AS RIPK1 INHIBITORS
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The invention provides novel substituted heterocyclic compounds represented by Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided c
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Paragraph 0150
(2021/02/12)
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- Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold
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Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
- Kong, Yi,Li, Shanshan,Liu, Shangde,Xie, Roujie,Yuan, Duo,Zhu, Xiong
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supporting information
(2021/08/16)
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- Benzotriazine compound with PAR4 antagonistic activity and application thereof
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The invention discloses a benzotriazine compound with PAR4 antagonistic activity and application thereof. The present invention relates to a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, solvate or prodrug t
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Paragraph 0109; 0111-0112
(2020/08/02)
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- Method for synthesizing 3-fluoro-4-aminophenol
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The invention provides a method for synthesizing 3-fluoro-4-aminophenol. The method comprises the following steps: (1) preparing a composite catalyst from nickel nitrate, palladium chloride and butyl titanate through a sol-gel method; (2) enabling metallic sodium and 2,4-difluoronitrobenzene and methanol to react so as to prepare 2-fluoro-4-methoxyl-nitrobenzene; (3) performing a demethylation reaction on 2-fluoro-4-methoxyl-nitrobenzene through aluminum chloride so as to prepare 3-fluoro-4-nitrophenol; (4) performing a catalytic hydrogenation reaction on the 3-fluoro-4-nitrophenol by using a composite catalyst, thereby obtaining 3-fluoro-4-aminophenol. The method is relatively high in yield, and the product is also relatively high in purity.
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Paragraph 0044
(2017/02/09)
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- BENZIMIDAZOLE DERIVATIVES AND USES THEREOF
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Benzimidazole derivatives of Formula I, that modulate the activity of ACSS2 are disclosed for therapeutic use. The fused imidazole ring of the compounds disclosed has a diarylmethyl or diarylmethanol moiety attached at the 2-position and the compounds have at least one other substituent at the 5 or 6 position of the benzimidazole. Also disclosed are methods of using the benzimidazole compounds for the treatment of diseases or disorders, such as cancer.
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Paragraph 0303
(2015/12/31)
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- A Fast Way to Fluorescence: A Fourfold Domino Reaction to Condensed Polycyclic Compounds
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A fast and efficient palladium-catalyzed fourfold domino Sonogashira/double-carbopalladation/C H-activation reaction that converts simple aromatic systems into complex polycyclic hydrocarbons has been developed. A number of substituted products has thus been prepared in yields up to 89 %. The structural assignment has been confirmed by using single-crystal X-ray crystallography. The products show intriguing fluorescence activity and thus might serve as chemical sensors or fluorescent imaging dyes.
- Tietze, Lutz F.,Eichhorst, Christoph,Hungerland, Tim,Steinert, Markus
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supporting information
p. 12553 - 12558
(2016/08/25)
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- WNT PATHWAY ANTAGONISTS
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The present invention relates to novel compounds of formula (I): as herein described and pharmaceutical compositions thereof. The compounds of formula (I) have inhibitory effect on the Wnt pathway and are therefore useful in the preparation of a medicament, in particular for the treatment of cancer.
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Paragraph 0238-0240
(2014/02/15)
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- WNT PATHWAY ANTAGONISTS
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The present invention relates to novel compounds of formula (I) : as herein described and pharmaceutical compositions thereof. The compounds of formula (I) have inhibitory effect on the Wnt pathway and are therefore useful in the preparation of a medicament, in particular for the treatment of cancer.
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Page/Page column 56-57
(2012/10/18)
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- Luminescent bimetallic lanthanide bioprobes for cellular imaging with excitation in the visible-light range
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A series of homoditopic ligands H2LCX (X=4-6) has been designed to self-assemble with lanthanide ions (LnIII), resulting in neutral bimetallic helicates of overall composition [Ln 2(LCX)3] with the aim of testing the influence of substituents on the photophysical properties, particularly the excitation wavelength. The complex species are thermodynamically stable in water (logβ23 in the range 26-28 at pH 7.4) and display a metal-ion environment with pseudo-D3 symmetry and devoid of coordinated water molecules. The emission of EuIII, TbIII and Yb III is sensitised to various extents, depending on the properties of the ligand donor levels. The best helicate is [Eu2(L C5)3] with excitation maxima at 350 and 365 nm and a quantum yield of 9%. The viability of cervix cancer HeLa cells is unaffected when incubated with up to 500 μm of the chelate during 24 h. The helicate permeates into the cells by endocytosis and locates into lysosomes, which co-localise with the endoplasmatic reticulum, as demonstrated by counterstaining experiments. The relatively long excitation wavelength allows easy recording of bright luminescent images on a confocal microscope (μcxc = 405 nm). The new lanthanide bioprobe remains undissociated in the cell medium, and is amenable to facile derivatisation. Examination of data for seven Eu III and TbIII bimetallic helicates point to shortcomings in the phenomenological rules of thumb between the energy gap ΔE( 3ππ*-5DJ) and the sensitisation efficiency of the ligands.
- Deiters, Emmanuel,Song, Bo,Chauvin, Anne-Sophie,Vandevyver, Caroline D. B.,Gumy, Frederic,Buenzli, Jean-Claude G.
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experimental part
p. 885 - 900
(2009/07/01)
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- Regioselective SNAr reactions of substituted difluorobenzene derivatives: practical synthesis of fluoroaryl ethers and substituted resorcinols
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In this Letter, we describe a practical and highly selective method for the preparation of fluoroaryl ethers and differentially substituted resorcinol derivatives. This synthetic strategy relies on a selective SNAr of substituted difluorobenzen
- Ouellet, Stéphane G.,Bernardi, Anna,Angelaud, Remy,O'Shea, Paul D.
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supporting information; experimental part
p. 3776 - 3779
(2009/10/11)
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- 5-O-SUBSTITUTED 3-N-PHENYL-1,3,4-OXADIAZOLONES FOR MEDICAL USE
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The present invention relates to compounds having a 5-O-substituted 3-N-phenyl-1,3,4-oxadiazolone structural unit which have unexpectedly high level of inhibition of FAAH (fatty acid amide hydrolase). (I)
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Page/Page column 70-71
(2009/08/14)
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- Small-molecule modulators of TRP-P8 activity
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Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Trp-p8 antagonists, and compositions comprising small-molecule Trp-p8 agonists as well as methods for identifying and characterizing novel small-molecule Trp-p8 modulators and methods for decreasing viability and/or inhibiting growth of Trp-p8 expressing cells, methods for activating Trp-p8-mediated cation influx, methods for stimulating apoptosis and/or necrosis, and related methods for the treatment of diseases, including cancers such as lung, breast, colon, and/or prostate cancers as well as other diseases, such as benign prostatic hyperplasia, that are associated with Trp-p8 expression.
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Page/Page column 16
(2008/06/13)
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- BENZIMIDAZOLONES WHICH HAVE ACTIVITY AT Ml RECEPTOR
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Compounds of formula (I) and salts and solvates are provided: wherein R6 is selected from hydrogen, halogen, C1-6alkyl, C1-6alkyl substituted with one or more fluorine atoms, C3-6cycloalkyl, C3-6cycloalkyl substituted with one or more fluorine atoms, C1-6 alkoxy, C1-6 alkoxy substituted with one or more fluorine atoms, and cyano, and Q is hydrogen or C1-6alkyl. The compounds are M1 agonists and are useful for therapy, for example in the treatment of psychotic disorders and cognitive impairment.
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Page/Page column 48
(2008/06/13)
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- Benzimidazole- and benzothiazole-quinones: Excellent substrates for NAD(P)H:quinone oxidoreductase 1
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A series of benzimidazole- and benzothiazole-quinones has been synthesized. The ability of these heterocyclic quinones to act as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumour cells,
- Newsome, Jeffery J.,Colucci, Marie A.,Hassani, Mary,Beall, Howard D.,Moody, Christopher J.
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p. 3665 - 3673
(2008/09/21)
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- OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION
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This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.
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Page/Page column 38-39
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.
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Page/Page column 69
(2010/02/15)
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- Process for preparing isomerically pure prodrugs of proton pump inhibitors
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Synthetic methods for preparing isomerically pure N-arylsulfonyl derivatives of proton pump inhibitors which include a substituted benzimidazole nucleus are shown by the synthetic schemes and experimental description.
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Page/Page column 28
(2010/02/10)
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- SPIRO-SUBSTITUTED PYRROLOPYRIMIDINES
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The invention provides compounds of formula (I) or a pharmaceutically acceptable salt or ester thereof formula (I) wherein the symbols have the meaning as defined in the description. Said compounds are inhibitors of cathepsin K and/or cathepsin S and are useful for the treatment of diseases and medical conditions in which cathepsin K and/or cathepsin S is implicated, e.g. various disorders including neuropathic pain, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis and tumours.
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- PRODRUGS OF PROTON PUMP INHIBITORS
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Prodrugs of proton pump inhibitors of Formulas 1 through 4, (I-IV), where the symbols are as defined in the specification, and the R group includes at least one acidic group or its pharmaceutically acceptable salt, have improved aqueous solubility and bioavailability.
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- 2-CYANOPYRROLOPYRIMIDINES AND PHARMACEUTICAL USES THEREOF
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The invention relates to pyrrolo pyrimidines of formula (I), wherein Y represents -(CH2)t-O- or -(CH2)r-S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, or Y is -(CH2)j- or -CH=CH-, j is 1 or 2; p is 1 or 2, or Y is -(CH2)f-, f is 1 or 2, p is 1, and the further radicals and symbols have the meaning as defined herein; their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such a compound for the manufacture of a pharmaceutical preparation for the treatment of neuropathic pain and to a method for the treatment of such a disease in animals, especially in humans.
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Page/Page column 44-45
(2010/02/08)
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- Pyrimido compounds having antiproliferative activity
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Disclosed are novel pyrimido compounds that are selective inhibitors of both KDR and FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon, lung and prostate tumors. Also disclosed are pharmaceutical compositions containing these compounds and methods of treating cancer.
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Page/Page column 20
(2010/02/08)
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- Elucidation of the vicarious nucleophilic substitution of hydrogen mechanism via studies of competition between substitution of hydrogen, deuterium, and fluorine
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Relations of rates of the vicarious nucleophilic substitution of hydrogen (VNS) and SNAr substitution of fluorine in 2-fluoronitrobenzenes with chloroalkyl aryl sulfone carbanions were determined from competitive experiments carried out at various concentrations of base. The observed dependence of the VNS/SNAr rate ratio on the base concentration confirmed the two-step mechanism of the VNS, which consists of reversible formation of σH adducts of the α-chlorocarbanion to nitroarene, followed by base-induced β-elimination of HCl. It was also evidenced that both of these processes can be the rate-limiting steps: the β-elimination at low base concentration and the nucleophilic addition at high base concentration. Consistent with that conclusion is the finding that the kinetic isotope effect in the VNS reaction decreases from 4.2 (a value typical of a primary KIE) to 0.8 (a value typical of a secondary KIE) with increasing base concentration. Also reported is our discovery that the SNAr substitution of the 2-fluoronitrobenzenes studied in this work was subject to base catalysis under some of the experimental conditions employed in our competitive experiments.
- Makosza, Mieczyslaw,Lemek, Tadeusz,Kwast, Andrzej,Terrier, Francois
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p. 394 - 400
(2007/10/03)
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- 3-[4-(phenylmethoxy)phenyl]-1-substituted-6-haloalkyl-uracil herbicides
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The present application discloses herbicidal 3-[4-(phenylmethoxy)phenyl]-1-substituted-6-haloalkyluracils of the formula STR1 in which M is lower alkyl, lower 2-alkenyl, lower 2-alkynyl, lower alkoxymethyl or lower haloalkyl; T is lower haloalkyl; and U,
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- 2-NITROARYL AND 2-CYANOARYL COMPOUNDS AS REGULATORS OF NITRIC OXIDE SYNTHASE
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2-Nitroaryl or 2-cyanoaryl compounds of the formula pharmaceutical compositions thereof, intermediates useful in the preparation of these compounds, and methods for treating disorders of vascular smooth muscles or diseases of the cartilage, macrophages, neurons, platelets, bronchial smooth muscles, optic muscles and gastrointestinal smooth muscles, in addition to sickle cell anemia, diabetes, synovitis, chondroarthritis and osteoarthritis by employing these compounds.
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- Herbicical 2-[(4-heterocyclic-phenoxymethyl)phenoxy]-alkanoates
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Herbicidal compounds, compositions containing them, and a method for controlling weeds by application of the compositions are disclosed. The herbicidal compounds are 2-[(4-heterocyclic(phenoxymethyl)phenoxy]alkanoates of the formula STR1 in which A is a derivative of an alkanoate bonded to the phenoxy oxygen at the alpha carbon, and Q is 4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl, 3,4,5,6-tetrahydrophthalimid-1-yl, 1-(1-methylethyl)imidazolidin-2,4-dion-3-yl, 1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-on-1-yl, 3-chloro-4,5,6,7-tetrahydroindazol-2-yl, 4-methyl-1,2,4-triazine-3,5-dion-2-yl, 8-thia-1,6-diazabicyclo[4.3.0]nonane-7-on-9-ylimino, or 1-methyl-6-trifluoromethyl-2,4-pyrimidinedione-3-yl; X is hydrogen, fluorine, or chlorine; Y is hydrogen; W is oxygen or sulfur; Z is hydrogen, fluorine, chlorine, bromine, lower alkyl, or methoxy; Z' is hydrogen, fluorine, or chlorine; and the group AO-- may be in the 2, 3, or 4-position of the phenyl ring.
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- SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL N-1-ARYL-6-FLUORO-5-METHYL-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS
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A series of 5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared in which the N-1 position was substituted by various aryl groups.Seven compounds showed excellent in vitro antibacterial activity against Gram-positive and Gram-negative strains.
- Jacquet, Jean-Pierre,Bouzard, Daniel,Cesare, Pierre Di,Dolnic, Nicolas,Massoudi, Massoud,Remuzon, Philippe
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p. 2301 - 2311
(2007/10/02)
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- Lewis Acid Mediated Fluorinations of Aromatic Substrates
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Direct fluorination of aromatic substrates, PhZ (Z=Cl, CHO, CH(OCH2)2, NO2, CO2CH2CH3, OH, NHCH3, OCH3, CH3) in the presence and absence of BCl3 or AlCl3, has been investigated.For PhCl and PhOH, inclusion of boron trichloride increased the percent conversion and the amount of para product.However, AlCl3 caused an increase in the ortho regioselectivity in the reaction with chlorobenzene.For PhCHO, inclusion of a Lewis acid decreased the percent conversion.In the presence of BCl3, the ethylene glycol acetal of PhCHO gave only ortho and para fluorinated derivatives with improved conversion.PhCO2CH2CH3 was unaffected by the inclusion of Lewis acid while the percentage conversion of PhNO2 increased only slightly.Fluorination of PhNHCH3, PhOCH3, or PhCH3 gave complex reaction mixtures. p-Nitroanisole gave rise to only 2-fluoro-4-nitroanisole in the presence or absence of either Lewis acid.
- Purrington, Suzanne T.,Woodard, Daniel L.
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p. 142 - 145
(2007/10/02)
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- Novel 1,2-cyclohexylaminoaryl amides useful as analgesic agents
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Novel 1,2-cyclohexylaminoaryl amides useful as analgesic agents having very high kappa-opioid affinity and selectivity and potency and useful as analgesics, diuretics, antiinflammatory and psychotherapeutic agents are disclosed. Methods for making the com
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- Highly selective κ-opioid analgesics. 3. Synthesis and structure-activity relationships of novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives
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This paper describes the chemical synthesis, μ/κ opioid receptor selectivity and analgesic activity of 14 novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives. The prototype κ-selective agonist, PD117302 (trans-N-methyl-N-
- Halfpenny,Horwell,Hughes,Hunter,Rees
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p. 286 - 291
(2007/10/02)
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- REACTION OF AROMATIC COMPOUNDS WITH NUCLEOPHILIC REAGENTS IN LIQUID AMMONIA. VI. ORIENTATION IN THE REACTIONS OF 2,4-DIFLUORONITROBENZENE WITH ALKALI-METAL ALCOHOLATES AND PHENOLATES
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On the basis of the results from a study of the orientation during the substitution of a fluorine atom in 2,4-difluoronitrobenzene by the action of nucleophiles of the ROM type (R = Me, Et, i-Pr, Ph; M = Na, K) and its temperature dependence for the reactions with sodium methoxide and sodium phenolate in liquid ammonia at -70 to -33 deg C it was shown that the enthalpy control of the ratio of the substitution rates of the fluorine atoms at the ortho and para positions to the nitro group, which was previously found in the reactions of o- and p-fluoronitrobenzenes with sodium methoxide in liquid ammonia, is general.It was shown that the preference for substitution at the ortho position under these conditions increases with change in the nature of the alcoholate in the order MeO- - -.This is evidently due primarily to the increase in the polarizability of the alkyl group of alcoholate in the same order.
- Kizner, T. A.,Shteingarts, V. D.
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p. 2173 - 2178
(2007/10/02)
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