cas 5440-00-6, 5,6-DIAMINO-1,3-DIMETHYL URACIL

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5,6-amino -1,3-dihydrocarbyl substituted uracil and preparation method thereof (by machine translation)
The invention belongs to the technical field of fine chemical engineering, and particularly relates to 5,6 -amino - 1111,dihydrocarbyl substituted uracil and a preparation method, of the dihydrocarbyl-substituted uracil 5,6 - diamino - 1111, 3-dihydrocarbyl- R substituted uracil, 5,6 - as shown in Formula (I). 1 And R2 Hydrochloride gas 1 - 10, each independently selected from hydrogen or carbon chain lengths of, carbon atoms according to the present invention 5,6 - of the present invention PVC diamino - 1111, 3-dihydrocarbyl-substituted uracil capable of absorbing, degradation processes, can also produce synergistic effect PVC by substituting labile chlorine atoms, with zinc stearate and calcium stearate PVC in combination with zinc stearate and calcium stearate for PVC to have better stabilization effect, The process performance, is improved PVC DEG, with good, stabilization effect PVC in combination. Heat stability 5,6 - can also be produced by the method, of the PVC present invention, for PVC, % of the stable effect of the present invention. (by machine translation)
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Paragraph 0044; 0047

(2020/05/09)

Synthesis method of theophylline
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 0049-0050

(2020/12/29)

Method for synthesizing caffeine
The invention discloses a method for synthesizing caffeine, 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; the method comprises the following steps: completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst, 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 water and liquid caustic soda into dimethyl FAU, and carryingout a ring-closure reaction to obtain theophylline sodium salt; the theophylline sodium salt is subjected to methylation reaction and refining to obtain caffeine. The method has the advantages of accessible raw materials, mild and controllable reaction conditions, fewer steps, high yield and greatly higher product quality, is simple to operate, and can easily implement industrial production.
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Paragraph 0056-0057

(2021/01/04)

Preparation method of theophylline sodium salt
The invention relates to the technical field of pharmaceutical chemicals, and particularly discloses a preparation method of theophylline sodium salt. The preparation method of theophylline sodium salt comprises the following process steps: mixing cyanoacetic acid and acetic anhydride for reaction to obtain mixed anhydride, and performing a condensation reaction on the mixed anhydride and 1,3-dimethylurea to obtain 1,3-dimethyl cyanoacetylurea; sequentially carrying out cyclization, nitrosation, hydrogenation and acylation on the 1,3-dimethyl cyanoacetylurea to obtain 1,3-dimethyl-4-amino-5-formylamino uracil; subjecting the 1,3-dimethyl-4-amino-5-formylamino uracil to ring closing to obtain the theophylline sodium salt. According to the preparation method, the reaction conditions are mildand easy to control, the product yield is high, byproducts are few, strong ammonia gas smell is avoided, the cost is low, and generated pollution wastes are few.
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Paragraph 0041; 0045; 0050-0051; 0055; 0058; 0065; 0069

(2020/09/08)

Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents
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
p. 117 - 128
(2019/05/21)

EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules
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
(2019/05/29)

Structural and conformational studies on carboxamides of 5,6-diaminouracils-precursors of biologically active xanthine derivatives
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.
supporting information

(2019/06/21)

For the treatment of diabetes type II a pharmaceutical intermediates preparation method (by machine translation)
The invention belongs to the technical field of chemical industry, and in particular relates to a medicament for the treatment of diabetes type II intermediate preparation method. The invention to PdCl2 . 2 H2 O and ammonium metatungstate as precursor, the silicon nitride film as the catalyst carrier, depositing a - precipitation method to prepare a new kind of ammonium metatungstate modified palladium metal catalyst; said catalyst can be used for catalytic 6 - amino - 5 - nitroso - 1 - methyl uracil reduction preparation of 5, 6 - diamino - 1 - methyl uracil, high selectivity and conversion, green is pollution-free; at the same time the materials can be added one time, avoiding the traditional sodium dithionite reduction system batch add to the shortcoming of the operating requirement is high. (by machine translation)
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Paragraph 0024

(2018/05/30)

N a caffeinum intermediate, N-1,3-dimethyl -4,5-b [...] method for the preparation of
The invention relates to a preparation method of the caffeine intermediate N,N-1,3-dimethyl-4,5-diamido urazine and belongs to the technical field of synthesis and preparation of organic compounds. According to the preparation method, a hydrogen addition reaction is carried out under heated and pressurized conditions with N,N-1,3-dimethyl-4-imido-5-isonitroso urazine as the starting material and raney nickel as the catalyst, an aqueous solution containing metal halide and alkaline substances is used as the reaction medium, the preparation method has the advantages of being smooth and controllable in reaction, high in catalytic activity and stable in quality of dimethyl-DAU, and the yield and the quality of the dimethyl-DAU are improved.
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Paragraph 0021; 0022

(2017/04/03)

Synthesis and Evaluation of a New Series of 8-(2-Nitroaryl)Xanthines as Adenosine Receptor Ligands
(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.
p. 241 - 250
(2016/08/28)

Total synthesis method for theacrine
The invention relates to a total synthesis method for theacrine. The total synthesis method comprises the following steps: 6-amino-1,3-dimethyluracil is taken as a raw material and subjected to a nitrosation reaction, and an intermediate 6-amino-1,3-dimethyl-5-nitrosouracil is obtained; 6-amino-1,3-dimethyl-5-nitrosouracil is subjected to a reduction reaction, and an intermediate 1,3-dimethyl-5,6-diaminouracil is obtained; 1,3-dimethyl-5,6-diaminouracil is subjected to a cyclization reaction, and an intermediate 1,3-dimethyluric acid is obtained; 1,3-dimethyluric acid is reacted with a methylation reagent, and a product is obtained. Theacrine prepared with the method can be synthesized massively in industrial application without restriction of raw materials; the conversion rate and the yield are high, the synthesis is convenient, post-processing is simpler, and the method is suitable for large-scale production and can be widely popularized and applied; the method is not needed to be performed under a high pressure condition, has low requirement for equipment and reduces the incidence rate of danger; with adoption of recrystallization for preparing the target product, the product purity is high.
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Paragraph 0071; 0072; 0073; 0074; 0075; 0076

(2016/12/22)

8-TRIAZOLYLXANTHINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS ADENOSINE RECEPTOR ANTAGONISTS
The invention relates to derivatives of the general formulae (I) and (II) to processes for the production thereof, to pharmaceutical preparations containing said compounds and/or physiologically compatible salts or solvates or prodrugs which can be produced therefrom as well as to the pharmaceutical use of said compounds, the salts or solvates thereof as adenosine receptor antagonists, in particular for the treatment of neurodegenerative disorders, e.g. stroke, amylotrophic lateral sclerosis, dementia, Alzheimer's disease, Parkinson's disease, ischemia/reperfusion injury, inflammation, and/or neurological disorder. The blockade of adenosine receptors could also be useful for other indications regarding the metabolism, e.g. diabetic retinopathy, diabetes mellitus, hyperbaric oxygen - induced retinopathy and/or obesity. Applications could also be the treatment of allergic diseases and autoimmune diseases, including mast cell degranulation, asthma, bronchoconstriction, pulmonary fibrosis, inflammatory or obstructive airways disease and/or chronic obstructive pulmonary disease (COPD). In addition, they could be used to treat cancer. The diseases associated with adenosine receptors are also diabetes, diarrhea, inflammatory bowel disease and/or gastrointestinal tract disorders. Adenosine receptor antagonists could be effective for treating a hepatic disease or condition for reducing fat deposition in the liver or fibrosis of the liver. The use of compounds of general formulae I or II can be associated with many applications e.g., scleroderm arthritis, atherosclerosis, urticaria, myocardial infarction, myocardial reperfusion after ischemia, vasodilation, hypertension, hypersensitivity, myocardial ischemia, heart attack and/or retinopathy of prematurity.
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Page/Page column 27; 30

(2012/06/30)

Design, synthesis and inhibitory activities of 8-(substituted styrolformamido) phenyl-xanthine derivatives on monoamine oxidase B
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
experimental part
p. 385 - 390
(2012/05/04)

Design and synthesis of new 8-anilide theophylline derivatives as bronchodilators and antibacterial agents
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.
p. 1355 - 1368
(2013/01/15)

Design and synthesis of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors
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
scheme or table
p. 1739 - 1742
(2012/04/04)

Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands
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.
body text
p. 131 - 136
(2011/07/30)

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
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.
body text
p. 2122 - 2127
(2009/09/30)

Immunosuppressive effects of 8-substituted xanthine derivatives
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 3

(2008/06/13)

XANTHINE DERIVATIVES, PROCESSES FOR PREPARING THEM AND THEIR USES
The present invention concerns xanthine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
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Page/Page column 24

(2008/06/13)

Extraction of radio-labelled xanthine derivatives by artificial receptors: Deep insight into the association behaviour
Association constants for the interaction of almost insoluble substrates with triphenylene ketal-based receptors in toluene have been determined by means of an extraction method employing the corresponding radio-labelled substrates. Flexible and more polar receptors tend to aggregate and exhibit inferior extraction qualities. Binding constants in toluene were found to be in the range 105-107 M-1, which is significantly higher than in dichloromethane. X-ray analyses indicate the direct participation of a water molecule in the binding process, which may account for the surprisingly small effect of moisture in the solvent on the stability of the complexes.
Bomkamp, Martin,Siering, Carsten,Landrock, Karin,Stephan, Holger,Froehlich, Roland,Waldvogel, Siegfried R.
p. 3724 - 3732
(2008/02/08)

Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: High affinity and selective A2B adenosine receptor antagonists
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
p. 3682 - 3692
(2007/10/03)

SULFONAMIDE SUBSTITUTED XANTHINE DERIVATIVES FOR USE AS PEPCK INHIBITORS
The present invention is concerned with sulfonamide substituted xanthine derivatives of formula (I) or a pharmaceutically acceptable salts or prodrugs thereof, wherein R1, R2 and R3 are as defined in the specification. Compounds of formula (I) and pharmaceutically acceptable salts or prodrugs thereof show activity as modulators of gluconeogenesis.
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Page 43-44

(2010/02/08)

Design, Synthesis, and Biological Evaluation of New 8-Heterocyclic Xanthine Derivatives as Highly Potent and Selective Human A2B Adenosine Receptor Antagonists
Here we report the synthesis of 8-heterocycle-substituted xanthines as potent and selective A2B adenosine receptor antagonists. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A2B adenosine receptors (ARs) in HEK-293 cells (HEK-A2B) and at other AR subtypes were explored. The synthesized compounds showed A2B adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A1, A2A, A2B, and A3 ARs. We introduced several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, at the 8-position of the xanthine nucleus and we have also investigated different spacers (substituted acetamide, oxyacetamide, and urea moieties) on the heterocycle introduced. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify the derivatives 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6, 7-tetrahydro-1H-purin8-yl)-1-methyl-1H-pyrazol-3-yl] acetamide (29b, MRE2028F20) [Ki(hA2B) = 38 nM, Ki(hA1,hA 2A,-hA3) >1000 nM], N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6, 7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy] acetamide (62b, MRE2029F20) [Ki(hA2B) = 5.5 nM, Ki(hA 1,hA2A,hA3) > 1000 nM], and N-(3,4-dimethoxyphenyl)-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6, 7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy] acetamide (72b, MRE2030F20) [Ki(hA2B = 12 nM, Ki(hA 1,hA2A, hA3) > 1000 nM], which showed high affinity at the A2B receptor subtype and very good selectivity vs the other ARs. Substitution of the acetamide with an urea moiety afforded bioisosteric xanthines with good affinity and selectivity comparable to the acetamide derivatives. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A2B receptor [compound 30b (Ki(hA2B) = 13 nM) vs compound 21b (K i(hA2B = 56 nM)] but did not favor selectivity. The derivatives with higher affinity at human A2B AR proved to be antagonists, in the cyclic AMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC50 values in the nanomolar range, a trend similar to that observed in the binding assay (62b, IC50 = 38 nM; 72b, IC50 = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivatives described herein represent a new family of selective antagonists for the adenosine A 2B receptor.
Baraldi, Pier Giovanni,Tabrizi, Mojgan Aghazadeh,Preti, Delia,Bovero, Andrea,Romagnoli, Romeo,Fruttarolo, Francesca,Zaid, Naser Abdel,Moorman, Allan R.,Varani, Katia,Gessi, Stefania,Merighi, Stefania,Borea, Pier Andrea
p. 1434 - 1447
(2007/10/03)

Inhibitory activities of novel pyrimidine derivatives on the contact hypersensitivity reaction.
In order to obtain novel topically applied anti-inflammatory compounds containing an inexpensive anti-oxidative moiety without chirality, we synthesized compound 2c derivatives having a di-tert-butylphenol moiety, and evaluated by topical administration their anti-inflammatory potentials on picryl chloride-(PC) induced contact hypersensitivity reaction (CHR) in mice. In the course of our structure-activity relationship (SAR) studies on the pyrimidine or the anti-oxidative moiety and the linker between them, the most potent compounds (10, 11) were obtained by the insertion of a C2 unit in compound 2c. The potencies of these compounds were 2-fold greater than that of 1. Compounds 10 and 11 were considered to be useful lead compounds having inexpensive anti-oxidative moieties without chirality.
Isobe, Yoshiaki,Tobe, Masanori,Inoue, Yoshifumi,Goto, Yuso,Obara, Fumihiro,Isobe, Masakazu,Hayashi, Hideya
p. 309 - 312
(2007/10/03)

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
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.
p. 133 - 141
(2007/10/03)

Synthesis of 1,3-Dimethyl-4-amino-5-nitroso-2,6-pyrimidindione and its Derivatives
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Shirsagar,Bhave
p. 649 - 651
(2007/10/03)

PURINES AND PYRIMIDINES AND CONDENSED SYSTEMS BASED ON THEM. 2. SYNTHESIS OF 1-METHYL-9-AMINOXANTHINE AND 9-AMINOTHEOPHYLLINE
The previously unknown 9-aminotheophylline and 1-methyl-9-aminoxanthine were synthesized from 3-methyl-5-amino-6-hydrazinouracil.In the case of 1-methyl-9-aminoxanthine an x-ray diffraction study of an N-amino derivative of an NH heterocycle was made for the first time.
Kuz'menko, V. V.,Kuz'menko, T. A.,Aleksandrov, G. G.,Pozharskii, A. F.,Gulevskaya, A. V.
p. 690 - 697
(2007/10/02)

POLAROGRAPHY OF SOME AROMATIC AND HETEROCYCLIC NITROSO COMPOUNDS
The electrochemical reduction of 4-nitrosodiphenylamine, 3-methyl-4-amino-5-nitrosouracil and 1,3-dimethyl-4-amino-5-nitrosouracil was studied in connection with the development of methods of electrosynthesis of some amino derivatives, intermediate compounds in the production of medicinal preparations and antioxidants of polymeric materials.
Avrutskaya, Inna,Fioshin, Michail
p. 196 - 202
(2007/10/02)