- N-Nitroheterocycles: Bench-Stable Organic Reagents for Catalytic Ipso-Nitration of Aryl- And Heteroarylboronic Acids
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Photocatalytic and metal-free protocols to access various aromatic and heteroaromatic nitro compounds through ipso-nitration of readily available boronic acid derivatives were developed using non-metal-based, bench-stable, and recyclable nitrating reagents. These methods are operationally simple, mild, regioselective, and possess excellent functional group compatibility, delivering desired products in up to 99% yield.
- Budinská, Alena,Katayev, Dmitry,Passera, Alessandro,Zhang, Kun
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supporting information
(2020/03/30)
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- Synthesis method of mosapride citrate
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The invention provides a preparation method of mosapride citrate, namely 4-amino-5-chloro-2-ethoxy-N-((4-(4-fluorophenyl)morpholin-2-yl)methyl)benzamide citrate. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield, simple post-treatment and the like, reduces the cost, has certain technical advantages, and is suitablefor large-scale industrial production.
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Paragraph 0032-0033
(2020/07/15)
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- Discovery of Nonpungent Transient Receptor Potential Vanilloid 1 (TRPV1) Agonist as Strong Topical Analgesic
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Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.
- Ann, Jihyae,Kim, Ho Shin,Thorat, Shivaji A.,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Kim, Minseok,Hwang, Sun Wook,Pearce, Larry V.,Esch, Timothy E.,Turcios, Noe A.,Blumberg, Peter M.,Lee, Jeewoo
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p. 418 - 424
(2019/12/24)
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- SUBSTITUTED PYRAZOLYL-BASED CARBOXAMIDE AND UREA DERIVATIVES BEARING A PHENYL MOIETY SUBSTITUTED WITH A CO-CONTAINING GROUP AS VANILLOID RECEPTOR LIGANDS
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The invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with a CO-containing group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Page/Page column 57; 59; 60; 61
(2013/05/23)
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- Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK)
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Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of log D yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >105 selectivity versus the human TMK homologue.
- Martínez-Botella, Gabriel,Loch, James T.,Green, Oluyinka M.,Kawatkar, Sameer P.,Olivier, Nelson B.,Boriack-Sjodin, P. Ann,Keating, Thomas A.
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p. 169 - 173
(2013/02/23)
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- The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators
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The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.
- Takahashi, Keiji,Hashimoto, Noriaki,Nakama, Chisato,Kamata, Kenji,Sasaki, Kaori,Yoshimoto, Riki,Ohyama, Sumika,Hosaka, Hideka,Maruki, Hiroko,Nagata, Yasufumi,Eiki, Jun-ichi,Nishimura, Teruyuki
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experimental part
p. 7042 - 7051
(2010/01/06)
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- FUSED BICYCLIC DERIVATIVES OF 2,4-DIAMINOPYRIMIDINE AS ALK AND C-MET INHIBITORS
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The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.
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Page/Page column 533
(2008/12/05)
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- PIPERAZINE COMPOUNDS FOR THE INHIBITION OF HAEMATOPOIETIC PROSTAGLANDIN D SYNTHASE
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The present invention relates to compounds of general formula (I): wherein A, Y, X, n and B are as defined herein; and their use in the treatment and prevention of metabolic disorders, inflammatory conditions, allergic conditions, fever, pain including allodynia and nociception, eating disorders, cachexia, brain injuries, cancer of the genitals, sleep apnoea, cardiovascular disease, flush effect associated with nicotinic acid and related compounds or for the promotion of wound healing. Certain compounds of general formula (I) are new and the invention also relates to these compounds and to their use in medicine.
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Page/Page column 92
(2008/12/04)
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- HETEROCYCLE-SUBSTITUTED BENZIMIDAZOLE DERIVATIVE
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Compounds having glucokinase activating effects and being useful as treatments for diabetes, which are represented by the following formula (I): (wherein X1 to X4 represent a carbon atom, etc., ring A represents a 5- or 6-membered heteroaryl having from 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, X5 represent an oxygen atom, etc., X represent a carbon atom, etc., Het represents a 5- or 6-membered aliphatic hetero ring, R1 represents aryl, etc., R2 represents formyl, etc., R3 represents -C1-6 alkyl, etc.), as well as their pharmaceutically acceptable salts.
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Page/Page column 60
(2010/11/30)
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- ARYLOXY-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
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A glucokinase activator is provided; and a treatment and/or a preventive for diabetes, or a treatment and/or a preventive for diabetes such as retinopathy, nephropathy, neurosis, ischemic cardiopathy, arteriosclerosis, and further a treatment and/or a preventive for obesity are provided. The invention relates to a compound of a formula (I): [wherein R1 and R2 represent a hydrogen, etc.; R3 represents a hydrogen atom, a halogen atom, etc.; R4 each independently represents a hydrogen atom, a lower alkyl group, etc.; Q represents a carbon atom, a nitrogen atom or a sulfur atom (the sulfur atom may be mono- or di-substituted with an oxo group); R5 and R6 each represent a hydrogen atom, a lower alkyl group, etc.; X1, X2, X3 and X4 each independently represent a carbon atom or a nitrogen atom; Z represents an oxygen atom, a sulfur atom or a nitrogen atom; Ar represents an aryl or heteroaryl group optionally mono to tri-substituted with a group selected from the substituent group β; ring A represents a 5- or 6-membered nitrogen-containing heteroaromatic group; m indicates an integer of from 1 to 6; n indicates an integer of from 0 to 3; p indicates an integer of from 0 to 2 (provided that at least two of X1 to X4 are carbon atoms); q indicates 0 or 1] or its pharmaceutically-acceptable salt, which has an effect of glucokinase activation and is useful as a treatment for diabetes.
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Page/Page column 41
(2010/11/28)
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- Effects of positional and geometrical isomerism on the biological activity of some novel oxazolidinones
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Some novel oxazolidinone derivatives have been synthesized and tested for antibacterial activity. Compound 13 was found to be active against Gram-positive pathogens whereas compound 14 was less active. Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole. However, thioacetamide analogue of 13 produced a potent molecule similar to linezolid in vitro. Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity. Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro. Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than Z-isomer. Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole. Finally, thioacetamide analogue of linear compound gave a lead having activity similar to linezolid in vitro.
- Das, Jagattaran,Rao, C.V. Laxman,Sastry,Roshaiah,Sankar, P. Gowri,Khadeer, Abdul,Kumar, M. Sitaram,Mallik, Arundhuti,Selvakumar,Iqbal, Javed,Trehan, Sanjay
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p. 337 - 343
(2007/10/03)
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- INDAZOLINONE COMPOSITIONS USEFUL AS KINASE INHIBITORS
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The present invention provides compounds of formula (I): These compounds, and pharmaceutically acceptable compositions thereof, are useful generally as kinase inhibitors, particularly as inhibitors of PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, and Aurora-2. Accordingly, compounds and compositions of the invention are useful for treating or lessening the severity of a variety of disorders, including, but not limited to, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases.
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Page 166-167
(2008/06/13)
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- Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors
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Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
- Zhang, Penglie,Zuckett, Jingmei F.,Woolfrey, John,Tran, Katherine,Huang, Brian,Wong, Paul,Sinha, Uma,Park, Gary,Reed, Andrea,Malinowski, John,Hollenbach, Stan,Scarborough, Robert M.,Zhu, Bing-Yan
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p. 1657 - 1661
(2007/10/03)
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- Fluorodenitrations using Tetramethylammonium Fluoride
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Tetramethylammonium fluoride activated by azeotropic drying in situ is an efficient reagent for the fluorodenitration of nitroaromatics.
- Boechat, Nubia,Clark, James H.
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p. 921 - 922
(2007/10/02)
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- Descriptive Photochemistry of Polyfluorinated Azide Derivatives of Methyl Benzoate
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The photochemistry of several polyfluorinated azide derivatives of methyl benzoate have been studied in a variety of solvents.We have photolyzed methyl 3-azido-6-fluorobenzoate, methyl 3-azido-4-fluorobenzoate, methyl 4-azido-2-fluorobenzoate, methyl 3-azido-2,4-difluorobenzoate, methyl 3-azido-2,6-difluorobenzoate, methyl 3-azido-2,4,6-trifluorobenzoate, and methyl 4-azido-2,3,5,6-tetrafluorobenzoate in toluene, cyclopentane, tetramethylethylene, diethylamine, dimethyl sulfide, dimethyl disulfide, and methanol in an attempt to capture the photogenerated reactive intermediates.Adducts were not formed in cyclopentane, dimethyl disulfide, and methanol solvents.Adducts were formed, however, but in modest yields, in the other solvents.In general the yield of adducts increases with the number of fluorine substituents present, and ortho and para fluorine substituents relative to the azide group are more effective in enhancing the yield of adducts relative to meta fluorine substitution.
- Soundararajan, N.,Platz, Matthew S.
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p. 2034 - 2044
(2007/10/02)
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