- Synthesis and characterization of process-related impurities of antidiabetic drug linagliptin
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Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, 1H-NMR, 13C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin.
- Huang, Yiwen,He, Xiaoqing,Wu, Taizhi,Zhang, Fuli
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- Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
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Fibroblast activation protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
- Jansen, Koen,De Winter, Hans,Heirbaut, Leen,Cheng, Jonathan D.,Joossens, Jurgen,Lambeir, Anne-Marie,De Meester, Ingrid,Augustyns, Koen,Van Der Veken, Pieter
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- Preparation method of hypoglycemic drug linagliptin intermediate
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The invention provides a preparation method of a hypoglycemic drug linagliptin intermediate, wherein the method comprises the steps: in the presence of a catalyst and an organic solvent, carrying out condensation reaction on o-aminoacetophenone (1) and 2-chloroacetamide (2) to obtain an intermediate II; carrying out condensation, bromination, substitution and other reactions on 4-(methylamino)-1H-imidazol-5-carboxamide (3) to generate an intermediate III; and finally, carrying out alkylation reaction on the intermediate II and the intermediate III to generate an intermediate I. According to the preparation method, generation of side reactions are avoided. Moreover, the reaction cost is saved, the operation conditions are mild, the yield is high, the post-treatment is simple, and the method is suitable for industrial large-scale production.
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Paragraph 0036-0048
(2021/04/21)
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- Synthesis method of linagliptin intermediate 2 - chloromethyl -4 - methyl quinazoline (by machine translation)
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The invention relates to the technical field of drug synthesis, and particularly discloses a synthesis method of a melatine intermediate 2 - chloromethyl -4 - methylquinazoline. The synthesis method of the fluoxine intermediate 2 - chloromethyl -4 -methyl quinazoline comprises the following steps: taking o-aminoacetophenone and chloroacetonitrile as a reaction raw material, 1,4 - dioxane as a reaction solvent, and carrying out catalytic ring closing reaction under acidic conditions to synthesize 2 - chloromethyl -4 -methyl quinazoline. The method is wide in raw material source, low in cost, high in safety, easy to control in reaction process, low in reaction condition requirement, and high in reaction product yield and purity. (by machine translation)
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Paragraph 0007; 0023; 0026-0027; 0029; 0032-0034; 0037-0038
(2020/06/09)
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- Preparation method of linagliptin for treating diabetes
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The invention provides a preparation method of linagliptin. The preparation method comprises the following steps: in the presence of cuprous chloride catalyst, cyclizing 2-aminoacetophenone and a corresponding amide, which are taken as starting materials, to obtain a quinazoline compound; and in addition, sulfonyl is easier to remove compared with halogen, and is introduced into reaction raw materials, sulfonyl is easier to be replaced in subsequent substitution reaction, and a high-yield coupling product is obtained. The method has the advantages of short reaction route, high yield and few byproducts, lowers the production cost, and is beneficial to industrial production.
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Paragraph 0030-0032
(2020/01/03)
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- METHOD FOR PRODUCING CHIRAL 8-(3-AMINO-PIPERIDIN-1-YL)-XANTHINES
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The invention relates to an improved method for producing enantiomer-free 8-(3-amino-piperidin-1-yl)-xanthines.
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Page/Page column 9
(2008/06/13)
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- NOVEL 8-(PIPERAZINE-1-YL)- AND 8-([1,4]DIAZEPAN-1-YL)-XANTHINE, THE PRODUCTION AND USE THEREOF IN THE FROM OF A DRUG
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The invention relates to a substituted XANTHINE of formula (I), wherein R1 to R3 and n are such as defined in claims from 1 to 8 and tautomers, enantiomers, diastereomers, mixtures, prodrugs and the salts thereof, said substances exhibiting valuable pharmacological properties, in particular an inhibition on the activity of dipeptidylpeptidasa-IV enzyme (DPP-IV).
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Page/Page column 20
(2008/06/13)
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