- Synthesis method of theophylline
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The invention discloses a synthesis method of theophylline, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The preparation method comprisesthe following steps: mixing cyanoacetic acid and acetic anhydride at 30-80 DEG C for reaction, adding a solvent and dimethylurea, cooling to room temperature after reflux reaction is finished, filtering, concentrating filtrate, combining solids to obtain dimethylacetamide, adding liquid caustic soda to adjust the pH to 8-11, and reacting at 80-100 DEG C to generate dimethyl 4AU; completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst and water, keeping the temperature at 30-70 DEG C, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid, thereby obtaining dimethyl FAU; adding dilute sulfuric acid into the dimethyl FAU to adjust the pH value to 36, heating to 90-100 DEG C, allowing the feed liquid to pass through an ozone reactor and a decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline. The method has the advantages of few reaction steps, mild reaction conditions, simple operation, high yield, stable product quality, small discharge capacity, reduction of the environmental protection treatment difficulty, and easy industrialization.
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Paragraph 0030; 0031; 0034; 0035; 0038; 0039; 0042-0045
(2020/12/29)
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- Spectrophotometric investigation of 5-nitroso-6-aminouracil and its methyl derivative in methanol by selective complexation with bivalent metal ions
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6-Amino-5-nitrosouracils are synthesized by the condensation reaction of urea or N,N′-dimethyl urea, cyanoacetic acid and acetic anhydride followed by nitrosation reaction with sodium nitrite. The synthesized compounds are characterized by various spectroscopic techniques like FTIR, NMR, single crystal XRD, and UV–vis absorption spectroscopy. From a single-crystal X-ray crystallography study of DANU, it is found that the compound is crystalline with one water molecule. The binding properties of both compounds with various metal ions are studied using UV–vis spectroscopy, where ANU shows a colour change from colourless to yellow colour-forming complex with cobalt metal ion. While DANU shows a colour change from colourless to dark yellow forming complex with copper and nickel cation, respectively. These compounds showed the job's plots with Cu2+, Ni2+, and Co2+ in various stoichiometric ratios to form the respective metal complex. The association/binding constant (Ka) values are calculated by plotting Benesi–Hilderbrand plots of ANU with Co2+ ion and is found to be 9.524 × 102. Whereas, DANU with Cu2+, Ni2+ are found to be 3.956 × 103, 2.041 × 103, respectively. These cations may be used in metal ions complexation for the respective ligand. The LOD values for ANU-Co2+, DANU-Cu2+ & DANU-Ni2+ are obtained as 33.9428 μM, 93.8082 μM and 48.396 μM, respectively, whereas the LOQ values are found as 102.857 μM, 284.2675 μM and 146.653 μM, respectively.
- Das, Subrata,Hussain, Sahid,Kumar, Brajesh,Kumar, Pramanand,Sugunakara Rao, Mugada
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- Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents
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A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 μM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18–20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 μM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4–8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.
- Hisham, Mohamed,Youssif, Bahaa G.M.,Osman, Essam Eldin A.,Hayallah, Alaa M.,Abdel-Aziz, Mohamed
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p. 117 - 128
(2019/05/21)
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- EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules
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One of the helpful ways to improve the effectiveness of anticancer agents and weaken drug resistance is to use hybrid molecules. therefore, the current study intended to introduce 20 novel xanthine/chalcone hybrids 9–28 of promising anticancer activity. Compounds 10, 11, 13, 14, 16, 20 and 23 exhibited potent inhibition of cancer cells growth with IC50 ranging from 1.0 ± 0.1 to 3.5 ± 0.4 μM compared to doxorubicin with IC50 ranging from 0.90 ± 0.62 to 1.41 ± 0.58 μM and that compounds 11 and 16 were the best. To verify the mechanism of their anticancer activity, compounds 10, 11, 13, 14, 16, 20 and 23 were evaluated for their EGFR inhibitory effect. The study results revealed that compound 11 showed IC50 = 0.3 μM on the target enzyme which is more potent than staurosporine reference drug (IC50 = 0.4 μM). Accordingly, the apoptotic effect of the most potent compounds 11 was extensively investigated and showed a marked increase in Bax level up to 29 folds, and down-regulation in Bcl2 to 0.28 fold, in comparison to the control. Furthermore, the effect of compound 11 on Caspases 3 and 8 was evaluated and was found to increase their levels by 8 and 14 folds, respectively. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking study was adopted to confirm mechanism of action.
- Abou-Zied, Hesham A.,Youssif, Bahaa G.M.,Mohamed, Mamdouh F.A.,Hayallah, Alaa M.,Abdel-Aziz, Mohamed
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- Iodine/persulfate-promoted site-selective direct thiolation of quinolones and uracils
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A simple and general method for direct thiolation of 4-quinolones with disulfides or thiols under I2/K2S2O8 system has been developed. Under the optimal conditions, the C–S bond coupling can take place effectively with good to decent yields and excellent regioselectivity of the S-linked products. The established metal-free site-selective approach was also applicable to transform a range of uracil substrates to the thio-substituted products under mild conditions. Further transformation to the sulfone derivatives can be conveniently performed in one-pot. These easy-to-handle protocols represent a useful and interesting synthetic alternative with good substrate scope and functional group compatibility.
- Beukeaw, Danupat,Noikham, Medena,Yotphan, Sirilata
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supporting information
(2019/09/03)
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- Pyrimidopteridine N-Oxide Organic Photoredox Catalysts: Characterization, Application and Non-Covalent Interaction in Solid State
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Herein we report the photo- and electrochemical characterization of pyrimidopteridine N-oxide-based heterocycles. The potential of their application as organic photoredox catalysts is showcased in the photomediated contra-thermodynamic E→Z isomerization of cinnamic acid derivatives and oxidative cyclization of 2-phenyl benzoic acid to benzocoumarin using molecular oxygen as a mild oxidant. Furthermore, unprecedented intermolecular non-covalent n–π-hole interactions in solid state are discussed based on crystallographic and theoretical data.
- Hauptmann, Richy,Petrosyan, Andranik,Fennel, Franziska,Argüello Cordero, Miguel A.,Surkus, Annette-E.,Pospech, Jola
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supporting information
p. 4325 - 4329
(2019/03/29)
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- Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding
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Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template-based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2.
- Thinnes, Cyrille C.,Lohans, Christopher T.,Abboud, Martine I.,Yeh, Tzu-Lan,Tumber, Anthony,Nowak, Rados?aw P.,Attwood, Martin,Cockman, Matthew E.,Oppermann, Udo,Loenarz, Christoph,Schofield, Christopher J.
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supporting information
p. 2019 - 2024
(2019/01/11)
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- Structural and conformational studies on carboxamides of 5,6-diaminouracils-precursors of biologically active xanthine derivatives
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8-Arylethynylxanthine derivatives are potent, selective adenosine A2A receptor antagonists, which represent (potential) therapeutics for Parkinson's disease, Alzheimer's dementia, and the immunotherapy of cancer. 6-Amino-5-amidouracil derivatives are important precursors for the synthesis of such xanthines. We noticed an unexpected duplication of NMR signals in many of these uracil derivatives. Here, we present a detailed analytical study of structurally diverse 6-amino-5-carboxamidouracils employing dynamic and two-dimensional NMR spectroscopy, density functional theory calculations, and X-ray analysis to explain the unexpected properties of these valuable drug intermediates.
- Marx, Daniel,Schnakenburg, Gregor,Grimme, Stefan,Müller, Christa E.
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supporting information
(2019/06/21)
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- Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands
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(Table presented.). A new series of 1,3-dimethylxanthine derivatives bearing 8-(2-nitroaryl) residue was synthesized and evaluated for affinity for recombinant human adenosine receptors subtypes. Nitrate esters of 7-substituted-1,3-dimethyl-8-phenylxanthines were also synthesized and tested. Introducing a nitro substituent at the 2-position of the 8-substituted phenyl ring resulted in generally low affinity for adenosine receptors (ARs), selectivity toward the A2A subtype was enhanced in some of the compounds. 8-(4-Cyclopentyloxy-5-methoxy-2-nitrophenyl)-1,3-dimethylxanthine (9e) proved to be a potent compound among the 2-nitrophenyl substituted xanthines exhibiting a Ki = 1 μM at human A2A ARs with at least 30 fold selectivity versus human A1 and A2B ARs. Replacement of 8-chloropropoxy phenyl with 8-nitrooxypropoxy phenyl resulted in a negligible change in binding affinity of the 8-substituted xanthines for various AR subtypes. Drug Dev Res 77 : 241–250, 2016.
- Bansal, Ranju,Kumar, Gulshan,Rohilla, Suman,Klotz, Karl-Norbert,Kachler, Sonja,Young, Louise C.,Harvey, Alan L.
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p. 241 - 250
(2016/08/28)
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- A method of preparing high-purity theophylline
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The invention discloses a method for preparing high-purity theophylline. The method comprises the following steps: performing a methylation reaction of 6-aminouracil, dimethyl sulfoxide, sodium hydride and methyl iodide; adding formic acid for a carboxylation reaction; adding a mixed acid solution formed by mixing fuming nitric acid and concentrated sulfuric acid, and performing heating reflux for a nitrosylation reaction; and finally, adding iron powder and anhydrous acetic acid for a cyclization reaction to obtain theophylline. According to the method disclosed by the invention, the technology is simple, the requirements on the reaction conditions are low, the yield is increased over the prior art, and the obtained theophylline has high purity.
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Paragraph 0026; 0027; 0028
(2017/02/02)
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- A method of synthesis of theophylline
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The invention discloses a method for synthesizing theophylline. The method comprises the following steps: performing a methylation reaction on dimethyl sulfate, 6-aminouracil and a sodium hydroxide solution; adding formic acid for a carboxylation reaction; adding a mixed acid solution formed by mixing fuming nitric acid and concentrated sulfuric acid at a volume ratio of (0.8-1.1):(0.9-1.2), and performing heating reflux for a nitrosylation reaction; and finally, adding iron powder and anhydrous acetic acid for a cyclization reaction to obtain theophylline. According to the method disclosed by the invention, the yield is greatly higher than that of the prior art, the operation process is simple, and the reaction conditions are simple.
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Paragraph 0029
(2016/10/08)
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- Synthesis and antitumor activity of new pyrimidine and caffeine derivatives
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6-Amino-1, 3-dimethyl-1H-pyrimidine-2, 4-dione 2 was prepared by alkylation of 6-amino-1H-pyrimidine-2, 4-dione 1 with methyl iodide. Formylation of 2 with formic acid afforded N-(1, 3-dimethyl-dioxo-tetrahydropyrimidin-4-yl)-formamide 3. The nitration of 3 gave N-(1,3-dimethyl-5-nitro-dioxo-tetrahydropyrimidin-4-yl) formamide 4. Reduction of 4 by zinc dust in glacial acetic acid yielded dimethyl-dihydro-purine-2, 6-dione 5. Addition of bromine to 2 leads to the formation of 6-amino-5-bromo-dimethyl-pyrimidine-2, 4-dione 7, cycloaddition of 7 with formamide afford the same product (theophylline 5), alkylated of 5 with methyl iodide to give caffeine 6. Reaction of 7 with glycine gave 2-(6-amino-dimethyl-dioxo-tetrahydropyrimidin-5-ylamino) acetic acid 8, refluxing of 8 with acetic acid /methanol gave dimethyl-dihydropyrimidopyrazine-trione 9, alkylation of 9 with alkyliodide afforded tetra-alkyldihydropyrimidopyrazine-trione 10a and 10b. The Cytotoxicity screen of the synthesized compounds was evaluated and the result showed that 10a, 10b, 9, 8, 7 and 6 exhibited highly potential antitumor activity.
- Abu-Hashem, Ameen Ali,Hussein, Hoda Abdel Raouf
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p. 471 - 478
(2015/06/22)
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- Ionic liquid mediated one-pot synthesis of 6-aminouracils
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A novel, one-pot synthesis of 6-aminouracils via in situ generated ureas and cyanoacetylureas in the presence of an ionic liquid catalyst, 1,1,3,3-tetramethylguanidine acetate, is described. The catalyst can be recycled for five consecutive runs without loss of activity. The mechanism for the ring closure of cyanoacetylurea to 6-aminouracil is also discussed.
- Chavan, Sunil S.,Degani, Mariam S.
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supporting information; experimental part
p. 296 - 299
(2012/03/26)
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- An X-ray crystallographic study of C-5 and C-6 substituted 1,3-dimethyl-6-aminouracil architectures
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Uracil, one of the four RNA bases is a vital component in the complex processes of molecular genetics. The correct functioning of these processes depends on the types of bonds formed by uracil with the surroundings. This communication elaborates the versatile potential of 1,3-dimethyl-6- aminouracil (L1) to form its 5-, 6- position substituted derivatives with different significant molecular packing behaviours. Presently, five crystals (L2-L6) have been synthesised and their crystallographic architectures are glimpsed in this paper. Analysis of crystal packing shows supra-molecular behaviours through hydrogen bonding and π- π interactions among the molecules in maintaining the integrity of the structures. The ligand 6,6'-diamino-1,1',3,3'-tetramethyl-5,5'-(benzylidene) bis[pyrimidine-2,4(1H,3H)- dione] was observed to be stabilised in a helical arrangement. Springer Science+Business Media, LLC 2012.
- Saikia, Binoy K.,Das, Subrata,Sridhar, Balasubramaniam,Thakur, Ashim J.
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experimental part
p. 711 - 720
(2012/10/07)
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- Design and synthesis of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors
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Monoamine oxidase-B (MAO-B) inhibitor has been used as neuroprotectants to treat the motor deficits of Parkinson's disease (PD). We designed and synthesized a class of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors. The compounds have various inhibitory effects, with compound 6a having a Ki value of 0.26 lM. Their promising activity in vitro suggests potential use in the treatment of PD.
- Song, Bo,Xiao, Tong,Qi, Xiaolu,Li, Ling-Na,Qin, Kuiyou,Nian, Siyun,Hu, Guo-Xin,Yu, Yinfei,Liang, Guang,Ye, Faqing
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scheme or table
p. 1739 - 1742
(2012/04/04)
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- Design, synthesis and inhibitory activities of 8-(substituted styrolformamido) phenyl-xanthine derivatives on monoamine oxidase B
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The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3′ may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.
- Hu, Suwen,Nian, Siyun,Qin, Kuiyou,Xiao, Tong,Li, Ngna,Qi, Xiaolu,Ye, Faqing,Liang, Guang,Hu, Guoxin,He, Jincai,Yu, Yinfei,Song, Bo
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experimental part
p. 385 - 390
(2012/05/04)
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- Design and synthesis of new 8-anilide theophylline derivatives as bronchodilators and antibacterial agents
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Theophylline derivatives have long been recognized as potent bronchodilators for the relief of acute asthma. Recently, it was found that bacterial infection has a role in asthma pathogenesis. The present work involves the design and synthesis of 8-substituted theophylline derivatives as bronchodilators and antibacterial agents. The chemical structures of these compounds were elucidated by IR, 1H-NMR, mass spectrometry, and elemental analyses. The bronchodilator activity was evaluated using acetylcholine-induced bronchospasm in guinea pigs, and most of the compounds showed significant anti-bronchoconstrictive activity in comparison with standard aminophylline. In addition, the antibacterial activity of all the target compounds was investigated in vitro against Gram-positive and Gram-negative bacteria using ampicillin as a reference drug. Results showed that some of the tested compounds possessed significant antibacterial activity. A pharmacophore model was computed to obtain useful insight into the essential structural features of bronchodilator activity. A structure activity relationship was also discussed.
- Hayallah, Alaa M.,Talhouni, Ahmad A.,Abdel Alim, Abdel Alim M.
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p. 1355 - 1368
(2013/01/15)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Approach to the library of fused pyridine-4-carboxylic acids by combes-type reaction of acyl pyruvates and electron-rich amino heterocycles
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A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.
- Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Plaskon, Andrey S.,Dmytriv, Yuri V.,Grygorenko, Oleksandr O.,Mykhailiuk, Pavel K.,Krotko, Dmitriy G.,Pushechnikov, Alexei,Tolmachev, Andrey A.
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scheme or table
p. 510 - 517
(2010/09/05)
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- Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands
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The present paper describes the synthesis of a series of 8-(cyclopentyloxy)phenyl-xanthines and their evaluation for affinity for A 1 and A2 adenosine receptors using radioligand binding assays. The effects of moving the cyclopentyloxy substituent with or without an ortho methoxy group on the various positions of the 8-phenyl ring have been studied. The vanilloid based xanthines 8-[4-(cyclopentyloxy)-3-methoxyphenyl]-1, 3-dimethylxanthine (6a) (Ki = 100 nM) and 8-[(4-cyclopentyloxy)-3- methoxyphenyl]-3-methyl-1-propylxanthine (12) (Ki = 150 nM) displayed the highest affinity at A2A receptors as well as over 1000 fold selectivity over the A1 adenosine receptor subtype. ECV · Editio Cantor Verlag, Aulendorf (Germany).
- Bansal, Ranju,Kumar, Gulshan,Gandhi, Deepika,Yadav, Rakesh,Young, Louise C.,Harvey, Alan L.
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scheme or table
p. 131 - 136
(2011/07/30)
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- A mild and efficient method for the deformylation of 5-formyl uracils and synthesis of 4,4¢-methylidenebis(1-phenyl-3-methyl-5-pyrazolone)
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6-Substituted 5-formyl uracils undergo an interesting reaction with 1-phenyl-3-methyl-5-pyrazolone in the presence of base catalyst to afford deformylated uracils and 4,4¢-methylidenebis(1-phenyl-3-methyl-5- pyrazolone) in excellent yields. Georg Thieme V
- Deb, Mohit L.,Majumder, Swarup,Bhuyan, Pulak J.
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scheme or table
p. 1982 - 1984
(2010/03/26)
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- Synthesis of a series of 8-(substituted-phenyl)xanthines and a study on the effects of substitution pattern of phenyl substituents on affinity for adenosine A1 and A2A receptors
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A new series of 8-(substituted-phenyl)xanthines have been synthesized and compounds were evaluated for their affinity for A1 and A2 adenosine receptors (AR) using radioligand binding assays. The effects of varying the positions of 8-phenyl substituents on affinity and selectivity at A1 and A2A adenosine receptors have been studied. Isovanilloid 1,3-dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)phenylxanthine (9d) displayed the highest affinity and selectivity towards A2A AR subtypes with Ki = 100 nM over A1 receptors (Ki > 100 mM). It has been observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at adenosine receptors, with A2A tolerating bulkier substituents than did A1 receptors.
- Bansal, Ranju,Kumar, Gulshan,Gandhi, Deepika,Young, Louise C.,Harvey, Alan L.
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body text
p. 2122 - 2127
(2009/09/30)
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- Immunosuppressive effects of 8-substituted xanthine derivatives
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The invention relates to a novel use of 8-substituted xanthine derivatives for the manufacture of a medicament for the treatment of auto-immuno disorders.
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Page/Page column 4
(2008/06/13)
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- Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: High affinity and selective A2B adenosine receptor antagonists
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Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A2B adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A2B AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A 2B AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (Ki = 9 nM) for the A2B AdoR, but it is only 2-fold selective versus the A1 AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A2B AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF3 at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A2B AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and 36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A2B AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A2B AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A2B AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (Ki = 1 nM) A2B AdoR antagonist with high selectivity (990-, 690-, and 1000-) for the human A1, A2A, and A3 AdoRs.
- Kalla, Rao V.,Elzein, Elfatih,Perry, Thao,Li, Xiaofen,Palle, Venkata,Varkhedkar, Vaibhav,Gimbel, Arthur,Maa, Tennig,Zeng, Dewan,Zablocki, Jeff
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p. 3682 - 3692
(2007/10/03)
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- An expedient method for the synthesis of 6-substituted uracils under microwave irradiation in a solvent-free medium
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Condensation of malonic acid 1 and ureas 2a-f proceeds smoothly in the presence of acetic anhydride 3 under microwave irradiation in solvent-free conditions to give 6-hydroxy-uracils 4 in excellent yields. Under identical conditions, the condensation of cyanoacetic acid 5 and ureas 2a,b,g and h in the presence of acetic anhydride 3, followed by cyclization in the presence of sodium hydroxide affords 6-amino-uracils 6 in high yields. The work-up procedures are simple and products need no purification.
- Devi, Ipsita,Bhuyan, Pulak J.
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p. 5727 - 5729
(2007/10/03)
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- A novel ring closure reaction for the preparation of 6-aminouracils with an α-branched 1-substituent
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The preparation of 6-aminouracil derivatives is described involving a novel, silicon-promoted ring closure reaction. Condensation of N-substituted urea with cyanoacetic acid yields cyanoacetylureas, which are heated in hexamethyldisilazane/trimethylchlorosilane to afford N-substituted 6- aminouracils. Previously unaccessible derivatives bearing an α-branched 1- substituent, including 6-amino-1-(1-phenylethyl)uracil were obtained.
- Fuelle, Friederike,Mueller, Christa E.
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p. 347 - 351
(2007/10/03)
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- Molecular and crystal structure of 5,6-diamino-1-methyluracil and 5,6-diamino-1,3-dimethyluracil monohydrate. Semiempirical calculations (AM1 and PM3) on 5,6-diaminouracil derivatives
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The crystal and molecular structures of 5,6-diamino-1-methyluracil and 5,6-diamino-1,3-dimethyluracil monohydrate have been determined from X-ray diffraction. Both compounds are planar and the two amino groups have two different conformations. The substituent at the 5 position seems to be a true primary amino group with a strongly sp3 nitrogen, whereas the one at the 6 position is nearly coplanar with the uracil ring, displaying a predominant sp2 character. Semiempirical calculations were made on 5,6-diaminouracil, 5,6-diamino-2-thiouracil and their endocyclic N-methylated derivatives using the AM1 and PM3 hamiltonians. These indicate that the stability decreases on increasing methylation, the 2-thio compounds always being less stable than the 2-oxo ones.
- Hueso-Urena, Francisco,Moreno-Carretero, Miguel N.,Low, John N.,Masterton, Alison G.
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p. 133 - 141
(2007/10/03)
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- Pyrido[2,3-d]pyrimidines, II [1]. One Step Synthesis of Pyrido[2,3-d]pyrimidines and Pyrimido[4,5-b]quinolines from 6-Amino Uracils
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Reduction of 6-azidouracils 2 with hydrogen palladium or sodium dithionite afforded the corresponding 6-aminouracils 5 which could also be obtained by reaction of 2 with triphenylphosphane via phosphazenes and subsequent hydrolysis (Staudinger reaction). The use of trimethylphosphite instead of phosphanes yields with 2b the expected trimethoxyphosphazene 3c, whereas 2a reacts to the phosphonoaminopyrimidine 4. The syntheses of 5-hydroxy pyrido[2,3-d]pryimidine-2,4,7-triones 6, pyrido[2,3-d]pyrimidine-2,4,5-triones 8, cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-triones 7a, c, and tetrahydro-pyrimido[4,5-b]quinolin-2,4,5-triones 7b, d by condensation of 6-aminouracils 5 with malonates, ethylaceto/benzoylacetate, ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate, respectively, are described.
- Khattab,Kappe
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p. 917 - 925
(2007/10/03)
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- SYNTHESIS OF PYRIDOPYRIMIDINE-2,4-DIONES FROM PYRIMIDO-1,2,4-TRIAZINE-6,8-DIONES BY REVERSED AZADIENE SYNTHESIS
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It as shown that pyrimido-1,2,4-triazine-6,8-diones enter the reversed azadiene synthesis reaction with ketones and vinyl ethyl ether in the presence of diethylamine or boron trifluoride etherate, and also with enamines.As a result of the reaction, pyridopyrimidine-2,4-diones are formed in good yield.Pyrimido-1,2,4-triazine-5,7-diones do not undergo such reactions with acetone.The reasons for the unique behavior of the isomeric pyrimidotriazinediones in the reaction with acetone are discussed.
- Shorshnev, S. V.,Esipov, S. E.,Chernyshev, A. I.,Pozharskii, A. F.,Kuz'menko, V. V.,Gulevskaya, A. V.
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p. 191 - 200
(2007/10/02)
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- Pyrimidine Derivatives and Related Compounds. XLIV. Thermolysis of 6-Azido-1,3-dimethyluracil to a Pyrimidopteridine Derivative
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Thermolysis of 6-azido-1,3-dimethyluracil (1) in formamide gave 1,3,6,8-tetramethylpyrimidopteridine-2,4,5,7(1H,3H,6H,8H)-tetrone (3), while the same reaction in N,N-dimethylformamide (DMF) gave 3-(5-amino-1,3-dimethyluracil-6-yl)-4,6-dimethyltriazolopyrimidine-5,7(4H,6H)-dione (4), which was converted into 3 in refluxing formamide.Compound 4 was also obtained by the treatment of 1 with 4,6-dimethyltriazolopyrimidine-5,7(4H,6H)-dione (5) in refluxing DMF.The mechanism of these reactions is discussed.Keywords - thermolysis; 6-azido-1,3-dimethyluracil; pyrimidopteridine; triazolopyrimidine; aziridine intermediate
- Hirota, Kosaku,Maruhashi, Kazuo,Asao, Tetsuji,Senda, Shigeo
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p. 3377 - 3379
(2007/10/02)
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