- Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding
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An unprecedented 1,4-cycloaddition (vs 3,6-cycloaddition) of 1,2,4,5-tetrazines is described with preformed or in situ generated aryl-conjugated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) that is conducted under mild reaction conditions (0.1 M HFIP, 25 °C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddition across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed by a formal retro [4 + 2] cycloaddition loss of a nitrile and aromatization to generate a 1,2,4-triazine derivative. The factors that impact the remarkable change in the reaction mode, optimization of reaction parameters, the scope and simplification of its implementation through in situ enamine generation from aldehydes and ketones, the reaction scope for 3,6-bis(thiomethyl)-1,2,4,5-tetrazine, a survey of participating 1,2,4,5-tetrazines, and key mechanistic insights into this reaction are detailed. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines under mild conditions from readily accessible starting materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP) provide products of the conventional 3,6-cycoladdition, the enhanced hydrogen bonding capability of HFIP uniquely results in promotion of the unprecedented formal 1,4-cycloaddition. As such, the studies represent an example of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddition by hydrogen bonding catalysis but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddition.
- Zhu, Zixi,Glinkerman, Christopher M.,Boger, Dale L.
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supporting information
p. 20778 - 20787
(2020/12/22)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir 1.1) channel. The compounds act as diuretics and natriuretics and are valuable pharmaceutically active compounds for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension and conditions resulting from excessive salt and water retention.
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Page/Page column 57
(2013/05/21)
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- Continuous-flow synthesis of monoarylated acetaldehydes using aryldiazonium salts
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Anilines and ethyl vinyl ether can be used as precursors for a process that is the synthetic equivalent of the α-arylation of acetaldehyde enolate. The reaction manifests a high level of functional group compatibility, allowing the ready preparation of a number of synthetically valuable compounds.
- Chernyak, Natalia,Buchwald, Stephen L.
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supporting information; experimental part
p. 12466 - 12469
(2012/09/05)
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- Facile, environmentally friendly synthesis of benzaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives
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A facile environmentally friendly synthesis of bezaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives is described. Oxidation of the styrylamines by H2O2 H2O2 affords benzaldehydes in moderate yields, while the hydrolysis of styrylamines afforded phenylacetaldehyde analogs in good yields. Copyright
- Dai, Liyan,Yu, Jie,Chen, Yingqi,Yu, Shichao
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p. 3078 - 3084
(2011/09/14)
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- Novel Urokinase Inhibitors
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The present invention relates to novel compounds with inhibitory activity towards urokinase plasminogen activator (uPA); to methods for preparation of said uPA inhibitor compounds; to pharmaceutical compositions comprising said uPA inhibitor compounds; to
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Page/Page column 28-29
(2009/01/24)
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- NOVEL UROKINASE INHIBITORS
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The present invention relates to novel compounds with inhibitory activity towards urokinase plasminogen activator (uPA); to methods for preparation of said uPA inhibitor compounds; to pharmaceutical compositions comprising said uPA inhibitor compounds; to
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Page/Page column 68-70; 75
(2010/11/27)
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- 2-Pyridyl substituted imidazoles as ALK5 and/or ALK4 inhibitors
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Compounds of the formula: wherein R1, R2, R3, A1 and A2 are as defined herein, which are used advantageously in inhibiting the TGF-β and/or activin signaling pathway in mammals.
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Page/Page column 8
(2008/06/13)
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- THERAPEUTIC AGENT FOR RESPIRATORY DISEASE CONTAINING 4-HYDROXYPIPERIDINE DERIVATIVE AS ACTIVE INGREDIENT
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An agent for preventing/treating respiratory diseases contains, as an active ingredient, a compound represented by following Formula (I): wherein A is a group represented by L-W [wherein L is a bond or CH2; and W is O, SOn (wherein n is 0 to 2), or -NR7-(wherein R7 is hydrogen or lower alkyl)]; each of G1 and G2 is (CH2)r (wherein r is 0 to 2), provided that when n is 1, G1 and G2 may be bridged by lower alkylene; Y is a lower alkylene or (substituted) benzylidene; Z is a bond or O, provided that when Z is a bond, Y may form a 5- or 6-membered ring with carbon on the benzene ring; R1 is, for example, NO2, a lower alkoxycarbonyl, (substituted) carbamoyl, (protected) hydroxyl group, (protected) carboxyl, or (protected) N-hydroxycarbamoyl; each of R2and R3 is hydrogen, halogen, (halogenated) lower alkyl, (halogenated) lower alkoxy or NO2; each of R4 and R5 is, for example, hydrogen, halogen, (halogenated) lower alkyl, (halogenated) lower alkoxy, CN, or lower alkylsulfonyl; and R6 is hydrogen or lower alkyl, a salt thereof or a solvate of them. It has excellent antitussive activity when used as an agent for preventing/treating respiratory diseases such as lung cancer, common cold syndrome, pulmonary tuberculosis, pneumonia, acute bronchitis or chronic bronchitis.
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Page/Page column 28-29
(2008/06/13)
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- 4-HYDROXPIPERIDINE DERIVATIVE WITH ANALGETIC ACTIVITY
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A compound represented by the following Formula (I): (wherein A represents oxygen atom or -NR3- (R3 represents hydrogen atom or lower alkyl group); R1 represents nitro group, lower alkoxycarbonyl group, carbamoyl group unsubstituted or mono- or di-substituted by lower alkyl group, unprotected or protected hydroxyl group, unprotected or protected carboxyl group, lower alkyl group substituted by unprotected or protected hydroxyl group, or tetrazolyl group; and R2 represents hydrogen atom, cyano group or lower alkylsulfonyl group, provided that when A is - NR3-, it is excluded that R1 represents unprotected or protected hydroxyl group or lower alkyl group substituted by unprotected or protected hydroxyl group) or its salt, and method for producing the compound, and a pharmaceutical composition containing the compound as active ingredient.
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- Basic α-aminoalkylphosphonate derivatives
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Peptidyl derivatives of diesters of α-aminoalkylphosphonic acids with basic substituents, their use in inhibiting serine proteases with trypsin-like specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.
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- BASIC ALPHA-AMINOALKYLPHOSPHONATE DERIVATIVES
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Peptidyl derivatives of diesters of α-aminoalkylphosphonic acids with basic substitutents, their use in inhibiting serine proteases with trypsin-like specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.
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- Novel Amidine-Containing Peptidyl Phosphonates as Irreversible Inhibitors for Blood Coagulation and Related Serine Proteases
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A series of new peptidyl(α-aminoalkyl)phosphonate diphenyl esters containing the 4-amidinophenyl group were synthesized and tested as irreversible inhibitors for thrombin and other trypsin-like enzymes.These phosphonates irreversibly inhibited several coa
- Oleksyszyn, Jozef,Boduszek, Bogdan,Kam, Chih-Min,Powers, James C.
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p. 226 - 231
(2007/10/02)
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- Polar Effects in Reactions of Carbon-Centered Radicals with Diazonium Salts: Free-Radical Diazocoupling
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Carbon-centered radicals react with diazonium salts by addition, leading under reductive conditions to azo derivatives (free-radical diazocoupling), or by electron-transfer in chain processes.The reaction is highly sensitive to polar effects and it has been investigated by three different processes: (i) alkyl radicals, generated from alkyl iodides, H2O2, Fe(II) salt, and DMSO, have been utilized to develop a new general synthesis of alkylarylazo compounds; (ii) the reaction of aryl radicals with diazonium salts in the presence of Ti(III) or Fe(II) salts has been investigated, also in relation to the fact that the reaction products (azoarenes and biaryls) are often detected as side products in classical organic reactions of diazonium salts, catalyzed by Cu(I) salts, such as the Sandmeyer, Meerwein, and Pschorr reactions; (iii) adducts from addition of aryl radicals to vinyl acetate or vinyl ether react with diazonium salts either by diazocoupling reaction or by electron-transfer; a general synthesis of arylazo compounds has been developed.
- Minisci, Francesco,Coppa, Fausta,Fontana, Francesca,Pianese, Giuseppe,Zhao, Lihua
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p. 3929 - 3933
(2007/10/02)
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