- Compound with nitrogen-containing bridge ring, spiro or fused ring structure and application thereof
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The invention discloses a compound with a nitrogen-containing bridge ring, spiro or fused ring structure and application of the compound. The compound has an obvious inhibition effect on the activityof protein kinase, can be used as a BTK inhibitor for preparing drugs for treating BTK-mediated diseases including, but not limited to, autoimmune diseases, malignant tumors and the like, and has a wide application prospect.
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Paragraph 0150-0152
(2020/08/12)
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- Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate
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The invention discloses a method for reducing content of a diastereoisomer impurity (Ia) in a Ledipasvir intermediate (1R,3S,4S)-N-t-butyloxycarboryl-2-azabicyalo[2.2.1]heptane-3-carboxylic acid (I). The method comprises the steps of firstly taking a crude product of a compound shown as a formula (I) and containing the diastereoisomer impurity (Ia), dissolving in an organic solvent, adding alkaline organic amine to react with the crude product, separating out a solid, and filtering to obtain an amine salt of the compound shown as the formula (I); acidizing the obtained amine salt in an aqueous phase solution; extracting an obtained aqueous phase, separating out a solid, and separating to obtain the high-purity Ledipasvir intermediate (I). The product obtained by the method has a de value up to more than 99.5 percent, and the yield of more than 80 percent; reaction conditions in the method are mild, raw materials are easy to get, and the method is suitable for industrial application.
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- Preparation method of high-purity Ledipasvir intermediate
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The invention discloses a preparation method of a high-purity Ledipasvir intermediate (1R, 3S and 4S)-N-t-butylcarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylic acid. According to the method, (1R, 3S and 4S)-N-t-butylcarbonyl-2-azabicyalo[2.2.1] heptane-3-carboxylate serves as an initial raw material, and the Ledipasvir intermediate is obtained through enzymatic hydrolysis. A test proves that the high-purity Ledipasvir intermediate is obtained and a feasible path is provided for reducing production cost and improving drug use safety. Meanwhile, the method has the advantages that operation is easy, environment friendliness is achieved, the yield is high, selectivity is high and cost is low; large-scale production can be achieved, and industrial application and popularization are facilitated.
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- DIHYDROPYRIDAZINE-3,5-DIONE DERIVATIVE AND PHARMACEUTICALS CONTAINING THE SAME
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The present invention provides a dihydropyridazine-3,5-dione derivative or a salt thereof, or a solvate of the compound or the salt, a pharmaceutical drug, a pharmaceutical composition, a sodium-dependent phosphate transporter inhibitor, and a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, chronic renal failure, chronic kidney disease, and arteriosclerosis associated with vascular calcification comprising the compound as an active ingredient, and a method for prevention and/or treatment.
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Paragraph 1339; 1340
(2016/01/30)
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- Discovery of ledipasvir (GS-5885): A potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection
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A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.
- Link, John O.,Taylor, James G.,Xu, Lianhong,Mitchell, Michael,Guo, Hongyan,Liu, Hongtao,Kato, Darryl,Kirschberg, Thorsten,Sun, Jianyu,Squires, Neil,Parrish, Jay,Keller, Terry,Yang, Zheng-Yu,Yang, Chris,Matles, Mike,Wang, Yujin,Wang, Kelly,Cheng, Guofeng,Tian, Yang,Mogalian, Erik,Mondou, Elsa,Cornpropst, Melanie,Perry, Jason,Desai, Manoj C.
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supporting information
p. 2033 - 2046
(2014/04/03)
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- 2-AZA-BICYCLO[2.2.1]HEPTANE DERIVATIVES
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The invention relates to novel 2-aza-bicyclo[2.2.1]heptane derivatives of formula (I), wherein A, B, n and R1 are as described in the description, and to the use of such compounds, or of pharmaceutically acceptable salts of such compounds, as m
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Page/Page column 60
(2009/10/18)
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