- An expedient synthesis of ethyl 4(5)-alkyl(aryl)thioimidazole-5(4)-carboxylate
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Various ethyl 4-alkyl(aryl)thioimidazole-5-carboxylates have been synthesized by the reaction of ethyl valeramidocyanoacetate with a variety of alkyl(aryl) thiols in the presence of triethylamine and subsequent phosphorus pentachloride/4-dimethylaminopyridine (DMAP) mediated cyclization of the acyclic intermediates.
- Caille,Didierlaurent,Lefrancois,Lelievre,Sury,Aszodi
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- Dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application thereof
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The invention relates to a dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one derivative and application. The preparation method comprises the following steps: by taking ethyl cyanoacetate as an initial raw material, generating a hydroxylamine compound (A) under the action of sodium nitrite and phosphoric acid, reducing with sodium hydrosulfite to obtain ethyl 2-aminocyanoacetate (B), reacting with different substituted acyl chlorides respectively under an alkali condition, generating different substituted oxazole compounds D1-D48 of 5-amino-4-formate under the action of trifluoroacetic acid, and reacting with pyrrolidone under the action of phosphorus oxychloride to obtain a dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidine-9(5H)-one compound E1-E48. According to the invention, the inhibition activity of 48g of the compounds on Hela cervical cancer cells, MCF7 breast cancer cells and A549 lung cancer cells is investigated, and results show that the compounds E5, E10, E13, E16, E18, E19, E24, E42 and E43 have inhibition activity on Hela cervical cancer cells, the compounds E22, E24, E47 and E48 have inhibitory activity on MCF7 breast cancer cells, and the compounds E18 and E20 have inhibitory activity on A549 lung cancer cells.
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- Oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof
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The invention relates to an oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof. Ethyl cyanoacetate is used as a raw material, a hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, 2-amino ethyl cyanoacetate (B) is obtained through reduction with sodium hydrosulfite, the 2-amino ethyl cyanoacetate (B) reacts with different substituted acyl chlorides under alkali conditions, and oxazole compounds (D1-D48) of different substituted 5-amino-4-formate are generated under the action of trifluoroacetic acid, and then react with valerolactam under the action of phosphorus oxychloride to obtain the oxazolo[5,4-d]pyrido[1,2-a]pyrimidone compounds (E1-E48). The inhibitory activity of the 48 compounds on Hela cervical cancer cells, MCF-7 breast cancer cells and A549 lung cancer cells is investigated, and the result shows that 11 compounds have the inhibitory activity on the Hela cervical cancer cells; eight compounds have inhibitory activity on MCF-7 breast cancer cells; and five compounds have inhibitory activity on A549 lung cancer cells. E32, E33, E45, E46 and E47 have inhibitory activity on three tumor cells; and E29 and E42 have inhibitory activity on Hela cervical cancer cells and MCF-7 breast cancer cells.
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- Tetrahydrooxazolopyridino-oxaazaone derivative and application of tetrahydrooxazolopyridino-oxaazaone derivative
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The invention relates to a tetrahydrooxazolopyridino-oxaazaone derivative and application thereof. Specifically, the derivative tetrahydrooxazolo[5',4' : 4,5]pyridino[1, 2-a]oxaaza-11(5H)-one derivatives E1-E48. In anti-tumor activity screening, the positive control of DOX is used; the inhibition effect of the 48 tetrahydrooxazolo[5',4':4,5]pyridino[1, 2-a]oxaaza-11(5H)-one derivatives E1-E48 on Hela human cervical cancer cells, MCF-7 breast cancer cells and A549 lung cancer cells is observed, and the results show that compared with the positive control, the compounds E5, E8, E9, E20, E26, E28, E32, E34, E38, E41, E42, E44, E45, E46, E47 and E48 have the inhibition activity on the Hela cervical cancer cells, the compounds E26, E38, E42, E45, E46 and E47 have inhibitory activity on MCF-7 breast cancer cells; and the compounds E8, E9, E26 and E47 have inhibitory activity on A549 lung cancer cells.
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- 2-substituted tricyclic oxazolo[5,4-d]pyrimidine library: Design, synthesis, and cytotoxicity activity
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We report the design, synthetic route, and cytotoxicity of a library of 49 newly synthesized tricyclic oxazolo[5,4-d]pyrimidines. The condensed pyrimidinones were constructed from ethyl 5-aminooxazole-4-carboxylate building blocks. A tricyclic ring system was built using the naturally occurring mackinazolinone alkaloid with a focus on the molecular diversity at position C-2 of the oxazole ring. Synthesized compounds were evaluated against a panel of human cancer cell lines including MCF-7 (breast), HeLa (cervical), and A549 (lung) in vitro. The results revealed that substitution of halogen-related aromatic fragments at position C-2 of the oxazole ring may serve as promising anticancer drug candidates.
- Aisa, Haji Akber,Bozorov, Khurshed,Nie, Lifei,Ruzi, Zukela,Song, Buer,Zeng, Yan,Zhao, Jiangyu
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- IMIDAZOPYRIDAZINE COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHA RESPONSES
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Compounds of formula I or a stereoisomer or pharmaceutically-acceptable salt thereof, are useful in the modulation of IL-12, IL-23 and/or IFNa, by acting on Tyk-2 to cause signal transduction inhibition. The compounds of formula I are useful for the treatment of inflammatory or autoimmune diseases.
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Page/Page column 102; 103
(2018/04/21)
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- SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS NADPH OXIDASE INHIBITORS
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The present application relates to substituted fused heteroaryl and heterocyclic compounds, useful as nicotinamide adenine dinucleotide phosphate oxidase inhibitors (NADPH oxidase inhibitors), processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by NADPH oxidase. (Formula I)
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Page/Page column 114
(2018/12/03)
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- Preparation method of substituted pyrimidone derivative
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The invention provides a preparation method of a substituted pyrimidone derivative. The method comprises the steps of taking 2-amino-ethyl cyanoacetate as a raw material, performing three reactions of acylation, cyclization and hydrolysis, and finally obtaining 2,5,6-triamido-4-pyrimidone. Reaction conditions of the method are mild; the method is relatively low in cost, relatively high in yield and suitable for industrial mass production.
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Paragraph 0029; 0030
(2017/11/18)
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- New efficient synthesis of 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6H)-ones via an oxazolyliminophosphorane
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A new efficient synthesis of 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6H)-ones by consecutive aza-Wittig reaction was developed. The sequential three-component reaction of oxazolyliminophosphorane 4, isocyanates and amines produced 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6H)-ones 7 in good overall yields in the presence of catalytic amount of EtONa.
- Zeng, Guo-Ping,Cai, Chang-Quan,Tan, Fen,Ding, Ming-Wu
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p. 1158 - 1160
(2015/09/01)
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- One-step catalytic enantioselective α-quaternary 5-hydroxyproline synthesis: An asymmetric entry to highly functionalized α-quaternary proline derivatives
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The highly enantioselective cascade reaction between N-protected α-cyanoglycine esters and α,β-unsaturated aldehydes is disclosed. The reaction represents a one-step entry to polysubstituted 5-hydroxyproline derivatives having a quaternary α-stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two-step entry to functionalized α-quaternary proline derivatives.
- Breistein, Palle,Johansson, Jonas,Ibrahem, Ismail,Lin, Shuangzheng,Deiana, Luca,Sun, Junliang,Cordova, Armando
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supporting information; experimental part
p. 1156 - 1162
(2012/05/20)
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- A novel approach to 1,2-dihydro-2-oxo-3-pyridinecarboxylic ester via aromatization induced by deamidation
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A novel approach was developed for the preparation of 4,6-disubstituted-1, 2-dihydro-2-oxo-3-pyridinecarboxylic ester in moderate to good yields. This route involves a reaction sequence of Michael addition, transformation to ene-lactam, and aromatization, featuring easily available material, variable substituents, and good functional compatibility.
- Yu, Gang,Wang, Shaozhong,Wang, Kai,Hu, Yuefei,Hu, Hongwen
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p. 1021 - 1028
(2007/10/03)
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- Sulfonylureas and sulfonylcarbamates as new non-tetrazole angiotensin II receptor antagonists. Discovery of a highly potent orally active (imidazolylbiphenylyl)sulfonylurea (HR 720)
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The synthesis and pharmacological activity of new potent nonpeptide non- tetrazole angiotensin II (AII) receptor antagonists are described. These compounds are 4-thioimidazole derivatives linked on N1 to a biphenylsulfonyl fragment by a methylene spacer. Different acidic sulfonamides such as sulfonylureas 12, sulfonylcarbamates 15, sulfonylamides 16, and sulfonylsulfonamides 17 have been investigated as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activity were evaluated by AII receptor binding assay as well as by in vivo (iv and po) assays such as inhibition of the AII-induced presser response in pithed rats. Most of the synthesized sulfonyl derivatives showed nanomolar affinity for the AT1 receptor subtype. The N-propylsulfonylurea 12d and the ethyl sulfonylcarbamate 15b as representative members of this series exhibited high oral activity in the pithed rat model with ID50 values of 0.38 and 0.4 mg/kg, respectively. Structure-activity relationships on the imidazole ring linked to the methylbiphenyl N-propylsulfonylurea fragment demonstrated similar features to those found in the corresponding tetrazole series. For both class of compounds, the linear butyl chain in position 2 and a carboxylic acid in position 5 were important for high in vitro and in vivo activity. In most cases, replacement of the carboxylic acid was detrimental to in rive activity while maintaining the in vitro binding affinity. Introduction of a methylthio group in position 4 was found to enhance oral activity compared to compounds with chloro or other alkylthio, (polyfluoroalkyl)thio, and arylthio groups. 2-Butyl-4-(methylthio)-1-[[(2'- [[[propylamino)carbonyl]amino]sulfonyl](1,1'-biphenyl)-4-yl]methyl]-1H- imidazole-5-carboxylic acid (12d) as the most promising example of the series was synthesized as its dipotassium salt (50, HR 720). This compound 50 inhibited the specific binding of [125I]-AII to rat liver membranes with an IC50 value of 0.48 nM. In vivo, 50 dose-dependently inhibited the AII- induced presser response in normotensive pithed rats (ID50 = 0.11 mg/kg iv and 0.7 mg/kg po). In addition, this compound produced a marked and long- lasting decrease in blood pressure in high renin animal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 758 or its active metabolite EXP 3174. Compound 50 has been selected for in-depth investigations and is currently undergoing phase II clinical trials.
- Deprez,Guillaume,Becker,Corbier,Didierlaurent,Fortin,Frechet,Hamon,Heckmann,Heitsch,Kleemann,Vevert -,Vincent,Wagner,Zhang
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p. 2357 - 2377
(2007/10/02)
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