- Preparation method of linagliptin for treating type II diabetes mellitus
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The invention provides a preparation method of linagliptin for treating type II diabetes mellitus, which comprises the following steps: by using methylurea and ethyl cyanoacetate as raw materials, carrying out cyclization reaction to form a compound II, carrying out bromination reaction on the compound II to generate a compound III, carrying out condensation reaction on the compound III and 1-amino-2-butyne to generate a compound IV, making the compound IV, formic acid and an iodine source react in an organic solution to generate a compound V, reacting the compound V and a compound VI under the conditions of DMF and anhydrous potassium carbonate, reacting with (R)-3-Boc-aminopiperidine (VIII), and recrystallizing to obtain a pure target compound I, namely linagliptin. The invention provides a novel preparation method of linagliptin, which has the advantages of simple method, high reaction yield, avoidance of side reaction, cheap raw materials, reduction of the reaction cost, increase of the yield of the target compound, and suitableness for industrial large-scale production.
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Paragraph 0055-0060
(2021/03/30)
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- Discovery of MK-4688: An Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction
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Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
- Altman, Michael D.,Bogen, Stephane,Cai, Mingmei,Cammarano, Carolyn,Chen, Dapeng,Christopher, Matthew,Cryan, John,Daublain, Pierre,Dussault, Isabelle,Fradera, Xavier,Geda, Prasanthi,Goldenblatt, Peter,Hill, Armetta D.,Kemper, Raymond A.,Kutilek, Victoria,Li, Chaomin,Machacek, Michelle R.,Marshall, C. Gary,Martinez, Michelle,McCoy, Mark,Nair, Latha,Pan, Weidong,Reutershan, Michael H.,Scapin, Giovanna,Shizuka, Manami,Spatz, Marianne L.,Steinhuebel, Dietrich,Sun, Binyuan,Thompson, Christopher F.,Trotter, B. Wesley,Voss, Matthew E.,Wang, Xiao,Yang, Liping,Yeh, Tammie C.
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p. 16213 - 16241
(2021/11/16)
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- Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms
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Reactive oxygen species (ROS) play crucial roles in maintaining redox balance and regulating physiological processes, ROS levels in cancer cells are relatively higher than those in normal cells. Therefore, elevating cellular ROS levels may be a viable strategy for selective killing of cancer cells. In this work, we synthesized a series of new theobromine derivatives and evaluated their cytotoxicity against gastric cancer cells MGC-803, SGC-7901 and HGC-27. Particularly, MQS-14 potently inhibited cell growth of MGC-803, SGC-7901 and HGC-27 cells at low micromolar levels. Mechanistic studies showed that compound MQS-14 decreased cell viability of MGC-803 cells and inhibited cell division revealed by the CFDA and EdU staining assays. MQS-14 increased cellular ROS levels and activated the MAPK pathway accompanied by the decreased p-ERK and increased p-JNK expression. MQS-14 also induced DNA damage and apoptosis in MGC-803 cells. To conclude, MQS-14 induced cell death of MGC-803 cells partly through elevating cellular ROS levels.
- Ma, Ting,Ma, Qi-Sheng,Yu, Bin,Liu, Hong-Min
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- Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors
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Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for th
- Ma, Qi-Sheng,Yao, Yongfang,Zheng, Yi-Chao,Feng, Siqi,Chang, Junbiao,Yu, Bin,Liu, Hong-Min
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p. 555 - 567
(2018/11/26)
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- HYDROXYL PURINE COMPOUNDS AND USE THEREOF
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Disclosed are a series of hydroxyl purine compounds and the use thereof as PDE2 or TNFα inhibitors, in particular, the compounds as shown in formula (I), or tautomers thereof or pharmaceutically acceptable salts thereof.
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Paragraph 0378; 0379
(2018/04/05)
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- Xanthine LSD1 inhibitor and preparation method and application thereof
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The invention belongs to the field of medicinal chemistry, and discloses a xanthine structure containing LSD1 inhibitor, a synthesizing method and related application. The xanthine LSD1 inhibitor is characterized in that the structure formula is shown in the description, wherein R1 is benzyl; R2 is 1-3 alkyl and carboxylic acid derivates; R3 is heteroatom substituted hexatomic ring. The LSD1 enzymatic activity detection result shows that the xanthine compound of such series is good in effect on inhibiting LSD1 and can be used as a lead compound, and on that basis, a novel LSD inhibitor is further designed (refer to Specification).
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Paragraph 0017; 0043-0047
(2018/06/15)
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- Hydroxypurine compound and use thereof
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The invention discloses a hydroxypurine compound and a use of the hydroxypurine compound as a PDE2 or TNFa inhibitor and concretely discloses a compound shown in the formula (I) and its tautomer or pharmaceutically acceptable salt.
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Paragraph 0754; 0755; 0756; 0757
(2016/10/08)
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- Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors
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Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38–90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5–125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.
- Shelke, Rupesh U.,Degani, Mariam S.,Raju, Archana,Ray, Mukti Kanta,Rajan, Mysore G. R.
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p. 602 - 613
(2016/08/28)
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- Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway
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Activation of nuclear factor-kappa B (NF-κB) and related upstream signal transduction pathways have long been associated with the pathogenesis of a variety of inflammatory diseases and has recently been implicated in the onset of cancer. This report provi
- Hershberger, Paul M.,Peddibhotla, Satyamaheshwar,Sessions, E. Hampton,Divlianska, Daniela B.,Correa, Ricardo G.,Pinkerton, Anthony B.,Reed, John C.,Roth, Gregory P.
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supporting information
p. 900 - 907
(2013/07/11)
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- Easy preparative scale syntheses of labelled xanthines: Caffeine, theophylline and theobromine
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Several easy preparative scale (0.5-1.5 g) syntheses of deuterium labelled caffeine, theophylline and theobromine are described. Some new selective syntheses of theophylline and theobromine have been developed. Labelled xanthines are of great interest in qualitative or quantitative isotope dilution-mass spectrometry, coupled with gas or liquid chromatography, currently performed in anti-doping and forensic laboratories. Copyright
- Balssa, Frederic,Bonnaire, Yves
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- Microwave-assisted synthesis of 8-mercapto-3-methyl-7-alkyl xanthines - An improved method
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A microwave-assisted synthetic method to prepare novel 8-mercapto-3-methyl- 7-alkyl xanthine compounds is reported. Compared to conventional synthetic route, the new method significantly shortened synthetic steps and reaction time.
- Zhang, Lei,Zhang, Y. John
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p. 775 - 778
(2007/10/03)
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- Thiazolopyrimidines useful as TNF-Alpha inhibitors
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The invention provides derivatives of thiazolo[4,5-d1]pyrimidine and their use as inhibitors of proinflammatory cytokines.
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- Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists
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1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A1, A2A, and A3 receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido-[2,1-f]purine-2,4-diones (2-5). Functionalization at the N3 position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A1, A2A, and A3 receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A3 receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a Ki value of 4.0 ± 0.3 nM against the hA3 receptor. Because xanthine derivatives have traditionally been considered poor A3 antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.
- Priego, Eva-María,Von Frijtag Drabbe Kuenzel, Jacobien,IJzerman, Ad P.,Camarasa, María-José,Pérez-Pérez, María-Jesús
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p. 3337 - 3344
(2007/10/03)
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- Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: Potent A2A- and A3-adenosine receptor antagonistst
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A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A2A or A3 ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified β-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A1 and A2A ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A3 ARS and in functional studies (adenylate cyclase assays) at A1 ARs of rat fat cell membranes, A2A ARs of rat PC 12 cell membranes, and mouse A2B ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A2A ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A2A ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl- imidazo[2,1-i]purinone (S-25) exhibiting a Ki value of 424 nM at rat A2A ARs. The compound was highly selective for A2A receptors vs A1 and A3 ARs. Selectivity vs A2B ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A3 ARs were identified. The most potent A3 antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a Ki value of 2.3 nM and high selectivity for A3 receptors vs all other AR subtypes.
- Müller, Christa E.,Thorand, Mark,Qurishi, Ramatullah,Diekmann, Martina,Jacobson, Kenneth A.,Padgett, William L.,Daly, John W.
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p. 3440 - 3450
(2007/10/03)
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- Synthesis and structure-activity relationships of 3,7-dimethyl-1- propargylxanthine derivatives, A(2A)-selective adenosine receptor antagonists
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A series of 8-substituted derivatives of 3,7-dimethyl-1- propargylxanthine (DMPX) was synthesized and investigated as A(2A) adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored.
- Müller, Christa E.,Geis, Uli,Hipp, Jo,Schobert, Ulrike,Frobenius, Wolfram,Paw?owski, Maciej,Suzuki, Fumio,Sandoval-Ramírez, Jesús
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p. 4396 - 4405
(2007/10/03)
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- 3,7-DIALKYL-8-ALKYL- OR -ARYL-3,7-DIHYDROPURINE-2,6-DIONES
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3,7-Dialkyl-8-alkyl- or -aryl-3,7-dihydropurine-2,6-diones XII-XIV were synthesized from 5-alkylamino-6-amino-1-alkyl-2,4(1H, 3H)-pyrimidinediones VII-IX by three methods: the first is based upon an acid catalyzed cyclization of the starting derivatives V
- Rybar, Alfonz,Hesek, Dusan,Szemes, Fridrich,Alfoeldi, Juraj,Tegza, Marian
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p. 2257 - 2269
(2007/10/02)
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