- Leflunomide analogues as potential antiinflammatory agents.
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A series of leflunomide (1a) analogues were examined for antiinflammatory activity using the carrageenan-induced paw edema assay. Some of the compounds were significantly more potent than leflunomide, particularly those with electron-donating or negative inductive groups situated in the phenyl rings. In contrast, all the nonsubstituted compounds or with further chain-extension in the 4-position of the rings led to a decrease in activity. The LD(50) values of the most active compounds (1d, g-j) in male ICR mice were significantly greater than those of either 1a or its active metabolite 2 and therefore merit further study.
- Huang, Wen-Hsin,Yang, Chiao-Li,Lee, An-Rong,Chiu, Hui-Fen
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Read Online
- Kemp Eliminases of the AlleyCat Family Possess High Substrate Promiscuity
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Minimalist enzymes designed to catalyze model reactions provide useful starting points for creating catalysts for practically important chemical transformations. We have shown that Kemp eliminases of the AlleyCat family facilitate conversion of leflunomid
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Read Online
- In vitro monitoring of ring opening of leflunomide: A surface enhanced Raman scattering and DFT based approach
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The in vitro mechanism of ring opening of leflunomide resulting in the formation of a metabolite A771726 has been studied by time series surface enhanced Raman spectra using NaOH buffer at pH ～10. The decomposition of leflunomide into A771726 through NO bond cleavage was identified by the Raman signature of CN bond of A771726. The experimental results have been correlated with theory by transition state calculations of the reaction using different basic catalysts; OH-, formate and formate + water and water alone. The reaction barrier energy is found to be lowest with OH-as a catalyst.
- Sharma, Poornima,Gangopadhyay, Debraj,Singh, Pushkar,Mishra,Deckert, Volker,Popp, Jürgen,Singh, Ranjan K.
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Read Online
- Preparation process of continuous-flow teriflunomide
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To the preparation process, cyanoacetic acid is used as a starting material, cyanoacetyl chloride is prepared by chlorination, and a tertamine intermediate is synthesized by cyanacetyl chloride and p-trifluoromethylaniline, and an intermediate is synthesized with acetyl chloride. The invention has high safety. The utility model has the advantages of low cost, low energy consumption and high production yield.
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Paragraph 0041; 0049-0053; 0061-0065; 0073-0076
(2021/11/21)
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- Simple preparation method of teriflunomide
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The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.
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Paragraph 0063; 0069-0071; 0072; 0076-0077; 0078; 0082; ...
(2021/07/08)
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- Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
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Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.
- Gerndt, Susanne,Chen, Cheng-Chang,Chao, Yu-Kai,Yuan, Yu,Burgstaller, Sandra,Rosato, Anna Scotto,Krogsaeter, Einar,Urban, Nicole,Jacob, Katharina,Nguyen, Ong Nam Phuong,Miller, Meghan T.,Keller, Marco,Vollmar, Angelika M.,Gudermann, Thomas,Zierler, Susanna,Schredelseker, Johann,Schaefer, Michael,Biel, Martin,Malli, Roland,Wahl-Schott, Christian,Bracher, Franz,Patel, Sandip,Grimm, Christian
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- Preparation method of teriflunomide
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The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. The preparation method includes: (1) mixing cyanoacetic acid, a condensingagent, an aprotic solvent and an alkaline reagent, and c
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Paragraph 0051-0077
(2020/04/02)
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- Exploiting intramolecular hydrogen bonding for the highly (: Z)-selective & metal free synthesis of amide substituted β-aminoenones
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Herein, we report the metal free and intramolecular hydrogen bonding (IMHB) directed (Z)-selective synthesis of amide substituted β-aminoenones. Systematically, we confirm the role of dual IMHB (CO?H-N) on the Z-direction using single-crystal X-ray analysis and 1D and 2D NMR studies. High stereoselectivity, atom efficiency, excellent yields and high purity are achieved by mere filtration. We avoid column purification and the formed by-product in the process is environmentally friendly.
- Subramaniam, Palaniraja,Ramasubbu, Chandrasekaran,Athiramu, Selvaraj
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p. 2541 - 2545
(2017/07/17)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE
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The present invention relates to an improved process for the preparation of Teriflunomide with high yield and high purity. The present invention also relates to a process for the preparation of teriflunomide which is free from genotoxic impurities.
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Page/Page column 5; 7; 8
(2017/07/06)
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- METHOD FOR THE PREPARATION OF TERIFLUNOMIDE
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The present invention relates to a method for preparation of Teriflunomide, comprising steps of: (a) adding Leflunomide to an alcoholic solvent to give solution (I); (b) adding an aqueous sodium hydroxide solution slowly into the solution (I) to give solution (II); (c) acidifying the solution (II) with inorganic acid for precipitation to give solution (III); and (d) filtering the solution (III) to give Teriflunomide.
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Paragraph 0025
(2017/07/23)
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- A NOVEL PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE
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The present invention provides a process for the preparation of Teriflunomide (Formula-I). The present invention describes the synthesis of Teriflunomide without isolating the intermediate Leflunomide. Teriflunomide is prepared from 5-Methyl isoxazole-4-carboxylic acid by converting to its acid chloride and coupling with 4-trifluoromethyl aniline to obtain Leflunomide (which is not isolated) followed by ring opening reaction using aq. Sodium Hydroxide to form Teriflunomide. In other words, the process is telescoped from 5- methylisoxazole-4-carbonyl chloride.
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- Comprehensive Study of the Organic-Solvent-Free CDI-Mediated Acylation of Various Nucleophiles by Mechanochemistry
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Acylation reactions are ubiquitous in the synthesis of natural products and biologically active compounds. Unfortunately, these reactions often require the use of large quantities of volatile and/or toxic solvents, either for the reaction, purification or isolation of the products. Herein we describe and discuss the possibility of completely eliminating the use of organic solvents for the synthesis, purification and isolation of products resulting from the acylation of amines and other nucleophiles. Thus, utilisation of N,N′-carbonyldiimidazole (CDI) allows efficient coupling between carboxylic acids and various nucleophiles under solvent-free mechanical agitation, and water-assisted grinding enables both the purification and isolation of pure products. Critical parameters such as the physical state and water solubility of the products, milling material, type of agitation (vibratory or planetary) as well as contamination from wear are analysed and discussed. In addition, original organic-solvent-free conditions are proposed to overcome the limitations of this approach. The calculations of various green metrics are included, highlighting the particularly low environmental impact of this strategy.
- Mtro, Thomas-Xavier,Bonnamour, Julien,Reidon, Thomas,Duprez, Anthony,Sarpoulet, Jordi,Martinez, Jean,Lamaty, Frdric
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supporting information
p. 12787 - 12796
(2015/09/01)
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- Synthesis of some substituted isoxazolo [5,4-d] pyrimidine-4(5H)-ones and their biological evaluation
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Substituted anilines vk'ere condensed Wiih ethyl cyanoacetate in xylene to get corresponding 2-cyano-N-phenylacetamides 1a-1h, which upon reaction with sodium bicarbonate and acetic anhydride gave corresponding compounds 2-cyano-3-hydroxy-N-phenylbut-2-enamides 2a-2h, which further upon reaction with hydroxyl amine hydrochloride in methanol yielded corresponding 5-amino-3-methyl-N-phenylisoxazole-4-carboxamides 3a-3h. 3a-3h when treated with acetic anhydride and triethyl orthoformate, gave substituted isoxazolo [5,4-d] pyrimidin-4 (5H)-ones 4a-4h.
- Godhani,Kaila,Sanghani,Dobariya
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p. 225 - 228
(2013/09/24)
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- MASS SPECTROMETRIC QUANTITATION ASSAY FOR METABOLITES OF LEFLUNOMIDE
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Methods are described for determining the amount of metabolites of leflunomide in a sample. More specifically, mass spectrometric methods are described for detecting and quantifying teriflunomide in a sample.
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- Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery
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The synthesis of various amides has been realised avoiding the use of any organic solvent from activation of carboxylic acids with CDI to isolation of the amides. Mechanochemistry was the key point of the process allowing rapid formation of the amide bond and efficient water-based purification of the final products.
- Metro, Thomas-Xavier,Bonnamour, Julien,Reidon, Thomas,Sarpoulet, Jordi,Martinez, Jean,Lamaty, Frederic
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supporting information
p. 11781 - 11783
(2013/01/15)
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- A PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE
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The present invention provides a process for preparing Teriflunomide of formula (I).
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Page/Page column 7
(2010/04/03)
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- A PROCESS FOR PREPARING TERIFLUNOMIDE
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The present invention relates to a process for preparing Teriflunomide of formula (I).
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Page/Page column 6-7
(2009/12/28)
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- ATP competitive inhibitors of d-alanine-d-alanine ligase based on protein kinase inhibitor scaffolds
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d-Alanine-d-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP
- Triola, Gemma,Wetzel, Stefan,Ellinger, Bernhard,Koch, Marcus A.,Huebel, Katja,Rauh, Daniel,Waldmann, Herbert
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experimental part
p. 1079 - 1087
(2009/08/15)
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- Process for preparing 2-cyano-3-hydroxy-N-(phenyl)but-2-enamides
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A process is described for producing 2-cyano-3-hydroxy-N-(phenyl)but-2-enamide, in which a phenyl-substituted 2-cyano-N-(phenyl)acetamide is reacted in the presence of a base, acetic anhydride and at least one solvent, and the resultant 2-cyano-3-hydroxy-
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Page/Page column 3; 4
(2010/02/08)
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- Inhibitors of the EGF-receptor tyrosine kinase and methods for their use
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Novel compounds and pharmaceutical compositions useful as EGFR tyrosine kinase inhibitors. Methods of the invention include administration of the EGFR TK inhibitors to treat diseases characterized by enhanced expression of EGF, including cancers, particularly breast cancer. Additionally, a homology model representing the structure of EGFR kinase domain is provided, which model is useful for the rationally design and screening of compounds predicted to bind favorably to EGFR and to inhibit EGFR TK.
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- BTK inhibitors and methods for their identification and use
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The invention provides BTK inhibitors, methods for their identification and use, and pharmaceutical compositions comprising BTK inhibitors.
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- Pharmaceuticals for the treatment of rejection reactions in organ transplantations
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The use of compound 1 and/or 2 of the formulae STR1 and of physiologically tolerable salts of compound 2 for the treatment of rejection reactions of the organ recipient to the transplanted organ is described.
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- Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use
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Isoxazole-4-carboxamide derivatives and hydroxyalkylidene-cyanoacetamide derivatives are suitable for the treatment of carcinoses. These compounds can be prepared by known processes. Some of the compounds are novel and are additionally suitable for the treatment of rheumatic disorders.
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- Pharmaceutical for the treatment of skin disorders
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Pharmaceutical for the treatment of skin disorders A compound of the formula I or II STR1 and physiologically tolerable salts of compound of the formula II are suitable for treatment of psoriasis.
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- Method of treating hyperproliferative vascular disease
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A method of preventing or treating hyperproliferative vascular disease in a mammal consists of administering to a mammal an effective amount of carboxyamide compounds.
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