- Developing novel classes of protein kinase CK1δ inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems
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Protein kinase CK1δ expression and activity is involved in different pathological situations that include neuroinflammatory and neurodegenerative diseases. For this reason, protein kinase CK1δ has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems that resemble adenine of ATP represent optimal scaffolds for the development of a new class of ATP competitive CK1δ inhibitors. In particular, a new series of [1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as the presence of a free amino group able to interact with the residues of the hinge region at the 5- and 7- positions of the [1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or the presence of a 3-hydroxyphenyl or 3,5-dihydroxyphenyl moiety at the 2- position of both nuclei. Molecular modeling studies identified the key interactions involved in the inhibitor-protein recognition process that appropriately fit with the outlined structure-activity relationship. Considering the fact that the CK1 protein kinase is involved in various pathologies in particular of the central nervous system, the interest in the development of new inhibitors permeable to the blood-brain barrier represents today an important goal in the pharmaceutical field. The best potent compound of the series is the 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 μM) that was predicted to have an intermediate ability to cross the membrane in our in vitro assay and represents an optimal starting point to both studies the therapeutic value of protein kinase CK1δ inhibition and to develop new more potent derivatives.
- Grieco, Ilenia,Bissaro, Maicol,Tiz, Davide Benedetto,Perez, Daniel I.,Perez, Conception,Martinez, Ana,Redenti, Sara,Mariotto, Elena,Bortolozzi, Roberta,Viola, Giampietro,Cozza, Giorgio,Spalluto, Giampiero,Moro, Stefano,Federico, Stephanie
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- 4 - Chloro -2 - a sulfur pyrimidine -5 - carboxylic acid ethyl ester
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The invention belongs to the field of organic synthetic technology, in particular to a 4 - chloro - 2 - methyl pyrimidine - 5 - carboxylic acid ethyl ester, to second grade oxygen methylene, S - methyl isothiourea sulfate as a main raw material, sodium hydroxide as the alkali, ethanol - water as a reaction solvent, cyclization process for preparing the intermediate; with the ethanol and water mixed solution of the reaction solvent, the solubility of the material is ensured, but also so that the sodium hydroxide can be completely dissolved, conducive to carrying out the reaction, avoiding the BuLi and danger, so that the productivity of the reaction raw material cost and greatly improve the; intermediate using toluene as the solvent, thionyl chloride with phosphorus oxychloride is chloro reagent, synthesis of 4 - chloro - 2 - methyl pyrimidine - 5 - carboxylic acid ethyl ester; using toluene as reaction solvent, greatly reduces the consumption of the chlorination reagent, i.e. so that the reaction can greatly improve the safety, but also reduces the cost, simplifies the post-processing operation; to thionyl chloride and phosphorus oxychloride is mixed chlorinated reagent, so that the yield of the reaction have a greater degree of lift.
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Paragraph 0028; 0029; 0030; 0031; 0032; 0033
(2019/05/11)
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- Method for synthesizing high-purity 4-chloro-2-methylthiopyrimidine-5-ethyl carboxylate
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The invention discloses a method for synthesizing high-purity 4-chloro-2-methylthiopyrimidine-5-ethyl carboxylate. The method comprises the following steps: reacting S-methylisothiourea sulfate and diethyl ethoxy-methylene malonate in an ethanol-sodium hydroxide solution, concentrating to remove ethanol and regulating the pH to be acidic to obtain an intermediate, namely 4-hydroxy-2-hydroxyhydroxypyrimidine-5-carboxylic acid ethyl ester, wherein the molar ratio of the S-methylisothiourea sulfate to the diethyl ethoxy-methylene malonate is 1 to 1.9-2.4; enabling the obtained 4-hydroxy-2-hydroxyhydroxy pyrimidine-5-carboxylic acid ethyl ester to react with thionyl chloride to obtain a target product, wherein the molar ratio of the 4-hydroxy-2-hydroxyhydroxy pyrimidine-5-carboxylic acid ethyl ester to the thionyl chloride is 1 to 1-1.8. The improved method provided by the invention can improve the yield, increase the reaction safety and reduce the cost.
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Paragraph 0015-0018
(2018/06/26)
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- Preparation method of avanafil
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The invention provides a preparation method of avanafil, and specifically relates to the technical field of pharmaceutical chemistry. The preparation method of avanafil comprises the following steps:sequentially carrying out cyclization and chlorination reactions on methyl thiourea sulfuric acid and diethyl ethoxymethylene malonate which serve as initial raw materials to obtain 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester; then substituting and hydrolyzing with 3-chloro-4-methoxybenzylamine; condensing with 2-pyrimidinemethanamine to obtain a key intermediate, namely, 4-[(3-chloro-methoxybenzyl)amino]-2-methylthio-N-(2-pyrimidine methyl)-5-pyrimidine formamide; oxidizing the intermediate and reacting with L-prolinol to generate the avanafil. The preparation method has theadvantages of easy availability of raw materials, easiness and convenience in operation, mild reaction conditions and higher product yield.
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Paragraph 0027; 0030; 0039; 0048
(2018/11/22)
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- Synthesis and Antifungal Activity Evaluation of Novel Substituted Pyrimidine-5-Carboxamides Bearing the Pyridine Moiety
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A series of novel N-(substituted phenyl/benzyl)-2-methylthio-4-((pyridin-3-ylmethyl)amino)pyrimidine-5-carboxamides were synthesized by multistep reactions. The structures of the target compounds were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Their in vitro antifungal activities against two kinds of plant pathogenic fungi were evaluated by the mycelial growth rate method. The result showed that at the dosage of 100 μg/mL, several of these compounds exhibited moderate activity against Botrytis cinerea with inhibition rates of ~70%, and most compounds (e.g., 5a, 5c, 5e, 5f, and 5h) possessed excellent activity against Sclerotinia Sclerotiorum with more than 90% inhibition rate.
- Wang, Shi-Chun,Wan, Fu-Xian,Liu, Si,Zhang, Shuai,Jiang, Lin
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p. 445 - 451
(2018/01/15)
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- Design, synthesis, and biological evaluation of novel catecholopyrimidine based PDE4 inhibitor for the treatment of atopic dermatitis
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Selective inhibition of phosphodiesterase (PDE) 4B favorably suppresses the synthesis of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective PDE4 inhibition could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD). In this study, a series of novel catechol based compounds bearing pyrimidine as the core have been synthesized and screened for the PDE4 inhibitory properties. The PDE4 selectivity of the active compounds over other PDEs has been investigated. Compound 23 bearing pyrimidine core functionalized with catechol, pyridine and trifluoromethyl groups can effectively inhibit the PDE4B with IC50 value in nanomolar range (IC50 = 15 ± 0.4 nM). Compound 23 exhibited seven fold higher selectivity towards PDE4B over PDE4D. Molecular Docking study confirmed its stronger affinity towards catalytic domain of PDE4B. In-vivo analysis confirmed that compound 23 effectively alleviated the symptoms of atopic dermatitis in DNCB–treated Balb/c mice by suppressing the synthesis of inflammatory mediators such as TNF-α and Ig-E. Taken together, this study suggested that compound 23 could be an effective PDE4 inhibitor for the potential treatment of AD.
- Purushothaman, Baskaran,Arumugam, Parthasarathy,Kulsi, Goutam,Song, Joon Myong
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supporting information
p. 673 - 690
(2018/01/26)
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- PROCESS FOR THE PREPARATION OF (S)-4-[(3-CHLORO-4-METHOXYBENZYL)AMINO]-2-[2- (HYDROXYMETHYL)-1-PYRROLIDINYL]-N-(2-PYRIMIDINYL METHYL-5-PYRIMIDINE CARBOXAMIDE
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The present invention relates to an improved process for the preparation of (S)-4-[(3- chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinyl ethyl)- 5-pyrimidine carboxamide compound of formula-1 represented by the following structural formula.
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Page/Page column 24; 25
(2015/01/16)
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- Scaffold decoration at positions 5 and 8 of 1,2,4-triazolo[1,5- c ]pyrimidines to explore the antagonist profiling on adenosine receptors: A preliminary structure-activity relationship study
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The structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4- triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA2A and hA3 ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA2A antagonists (compound 12: hA2A AR Ki = 3.32 nM; hA1/hA2A = 55.6; hA2A/hA3 = 0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA 3 AR Ki = 4.14 nM, hA1/hA3 = 236; hA2A/hA3 = 25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR.
- Federico, Stephanie,Ciancetta, Antonella,Porta, Nicola,Redenti, Sara,Pastorin, Giorgia,Cacciari, Barbara,Klotz, Karl Norbert,Moro, Stefano,Spalluto, Giampiero
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p. 6210 - 6225
(2014/08/18)
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- SULFONYL AMIDE DERIVATIVES FOR THE TREATMENT OF ABNORMAL CELL GROWTH
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The present invention relates to a compound of the formula I wherein R1 to R6, A, B, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
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Page/Page column 45-46
(2009/04/24)
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- ENZYME MODULATORS AND TREATMENTS
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.
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Page/Page column 354
(2008/06/13)
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- Novel inhibitors of AP-1 and NF-κB mediated gene expression: Structure-activity relationship studies of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)pyrimidine-5-carb oxylate
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In an effort to identify novel inhibitors of AP-1 and NF-κB mediated transcriptional activation, several analogues of ethyl 4-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-2-(trifluoromethyl)pyrimidine-5-carb oxylate (1) were synthesized and tested in two in vitro assays. The 2-(2'-thienyl) substituted compound (11) was identified as the most potent in this series. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Palanki, Moorthy S.S.,Erdman, Paul E.,Manning, Anthony M.,Ow, Arnold,Ransone, Lynn J.,Spooner, Cheryl,Suto, Carla,Suto, Mark
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p. 1645 - 1648
(2007/10/03)
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