33400-49-6Relevant articles and documents
Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators
Surur, Abdrrahman S.,Bock, Christian,Beirow, Kristin,Wurm, Konrad,Schulig, Lukas,Kindermann, Markus K.,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
supporting information, p. 4512 - 4522 (2019/05/17)
Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug-like leads. In the present retro-metabolic drug design study, a series of 43 compounds were synthesized and characterized with regard to KV7.2/3 opening activity and efficacy. The most active compound 22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV7.2/3 opener. Limited aqueous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell lines (HEP-G2 and TAMH) in culture. The slightly less active but more soluble compound 25b (EC50 = 11 nM, efficacy 111%) showed an improved toxicity/activity ratio compared to flupirtine by three orders of magnitude and represents an attractive lead structure for the development of safer analgesics and antiepileptics.
Method for preparing flupirtine hydrochloride
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Paragraph 0015; 0033; 0038; 0042; 0043; 0044; 0046, (2019/01/14)
The invention discloses a method for preparing flupirtine hydrochloride. The method comprises the following steps: adopting 2,6-dichloro-3-nitropyridine as an initial material, performing ammonolysis,substituting fluorobenzylamine, purifying, hydrogenating, performing acylation reaction, filtering, precipitating crystals and decompression drying to obtain the flupirtine hydrochloride. The methodis simple in operation, capable of simultaneously performing the hydrogenation and acylation reaction, capable of avoiding the deterioration of polyamino pyridine derivatives as far as possible, capable of titrating ethyl chloroformate without opening a kettle cover, and capable of reducing the harm on the human body.
Synthesis method for flupirtine maleate compound
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Paragraph 0013; 0027; 0028, (2016/12/01)
The invention discloses a synthesis method for a flupirtine maleate compound. The method comprises the steps that 2-amino-3-nitro-6-chloropyridine (a first compound) is used as a starting material to react with fluorobenzylamine (a second compound) to generate 2-amino-3-nitro-6-p-fluorobenzylamine pyridine (a third compound), the third compound is processed through di-tert-butyl dicarbonate ester protection to obtain 2-amino-3-nitro-6-p-fluorobenzylamine pyridine-3-based-tert-butyl acetate (a fourth compound), the fourth compound is processed through hydrogenation reduction and then react with ethyl chloroformate, after reacting is finished, deprotection is performed to obtain flupirtine hydrochloride (a fifth compound), and the fifth compound is salified with maleic acid to obtain flupirtine maleate (the sixth compound). According to the synthesis method, the starting material is cheap and easy to obtain, byproduct generation is avoided through amino protection, therefore, the impurity content is decreased, and the product quality is improved; catalytic reduction is performed by adopting palladium chloride, the reaction condition is mild, the reaction process is easy to operate, and the method is suitable for industrial production.