cas 6972-78-7, 6-AMINO-1-METHYL-5-NITROSOURACIL

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Linagliptin intermediate compound IV
The invention belongs to the field of pharmaceutical chemicals, and discloses a linagliptin intermediate IV and a novel route for synthesizing an important linagliptin intermediate from the linagliptin intermediate IV. The linagliptin intermediate IV synthesized in the invention has the advantages of high yield, simple operation, substantial reduction of production cost, suitableness for industrial production; and the synthesis route solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art.
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Paragraph 0188; 0190

(2020/09/09)

Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B
Annelated purinedione derivatives have been shown to act as possible multiple-target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO-B: 243 nM) to be identified as the most potent dual-acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure-activity relationships was complemented by molecular-docking studies based on previously published X-ray structures of the protein targets. Such dual-acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease.
Brockmann, Andreas,Doroz-P?onka, Agata,Ja?ko, Piotr,Kie?-Kononowicz, Katarzyna,Kuder, Kamil J.,Latacz, Gniewomir,Müller, Christa E.,Olejarz-Maciej, Agnieszka,Schabikowski, Jakub,Za?uski, Micha?
(2020/04/20)

Synthesis, radiolabelling and initial biological characterisation of 18F-labelled xanthine derivatives for PET imaging of Eph receptors
Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1-40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq μmol-1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.
Belter, Birgit,Caflisch, Amedeo,K?ckerling, Martin,Kinski, Elisa,Mamat, Constantin,Neuber, Christin,Pietzsch, Jens,Pretze, Marc,Steinbach, J?rg
p. 3104 - 3116
(2020/05/08)

Linagliptin intermediate compound V
The invention belongs to the field of pharmaceutical chemicals, and provides a linagliptin intermediate compound V and an important intermediate for synthesizing linagliptin by using the intermediateV. The method solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art, and the synthesized novel intermediate compound V has the advantages of high yield, simple operation, significantly reduced production cost, and suitableness for industrial production.
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Paragraph 0185; 0187; 0196-0197

(2020/09/09)

Substituted xanthine compound and its preparation and use (by machine translation)
The invention discloses substituted xanthine compounds, a preparation method and applications thereof, and specifically relates to compounds represented by the formula (I), stereo isomers and pharmaceutically acceptable salts thereof, wherein the R1 and R2 are defined in the description. The invention also relates to a pharmaceutical composition containing the compounds, an application of the pharmaceutical composition in preparation of drugs for treating diseases or symptoms caused by high activity of DPP-IV or overexpression of DPP-IV, and a method using the pharmaceutical composition to treat related diseases. The provided compounds can effectively inhibit the activity of DPP-IV.
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Paragraph 0173; 0175; 0176

(2018/09/26)

Xanthine compound and pharmaceutical composition and application thereof
The invention discloses a xanthine derivative as shown in the formula (I) and a pharmaceutical composition and application thereof. The xanthine derivative is prepared from a compound as shown in theformula (I) or a stereoisomer, a geometrical isomer, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or prodrug as shown in the description. The invention also relates to application of the compound as shown in the formula (I) and the pharmaceutical composition thereof as a DPP-4 inhibitor, and especially application in preparation of medicines for treating and/or preventingmetabolic disorder diseases such as diabetes.
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Paragraph 0142; 0145; 0146

(2019/07/11)

7,8-substituted-3-methylxanthine compounds as well as preparation method and application thereof
The invention discloses 7,8-substituted-3-methylxanthine compounds as well as a preparation method and an application thereof. The compounds have the structural formula (I) shown in the description, wherein R is aliphatic hydrocarbon, an aromatic ring, an acyl-containing group, a hydroxyl-containing group or a sulfhydryl-containing group; R1 is C1-4 alkyl, halogen substituted C1-4 alkyl, C1-4 alkoxy, halogen, a cyano group, nitryl, acetyl, benzyl, benzyloxy, substituted or unsubstituted C1-4 alkylbenzene, a substituted or unsubstituted amino group, substituted guanidyl, a substituted or unsubstituted phosphate group, a substituted or unsubstituted sulfonic group, a substituted or unsubstituted long-chain fatty alkane or substituted or unsubstituted long-chain fatty amine. The compounds have good inhibition effects on PDE8 (phosphodiesterase type 8), PDE8 is also a potential target of the alzheimer's disease, vascular dementia and diabetes, the compounds take PDE8 as the target, and a drug prepared from the compounds has a better curative effect on alzheimer's disease, vascular dementia and diabetes as well.
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Paragraph 0040; 0041; 0042; 0043

(2018/09/08)

Synthesis and evaluation of antitumour activities of novel fused tri-And tetracyclic uracil derivatives
Simple one-pot syntheses of indenopyrrolopyrimidines and indolopyrrolopyrimidines were achieved via the cyclocondensation of 6-Aminouracils and, respectively, ninhydrin and isatin in the presence of catalytic amounts of glacial acetic acid. Similarly, 5,6-diaminouracil derivatives were used as starting materials for the synthesis of indenopteridines and indolopteridines via their reaction with ninhydrin and isatin, respectively. The synthesised compounds were evaluated for antitumour activity against a human hepatocellular carcinoma cell line (HepG2), some showing antitumour activity comparable with 5-fluorouracil and imatinib.
Elkalyoubi, Samar,Fayed, Eman
p. 771 - 777
(2017/01/03)

A uracil nitroso amine based colorimetric sensor for the detection of Cu2+ ions from aqueous environment and its practical applications
A simple uracil nitroso amine based colorimetric chemosensor (UNA-1) has been synthesized and screened for its cation recognition ability. Sensor UNA-1 exhibited a high sensitivity and selectivity towards Cu2+ ions in aqueous medium in the presence of a wide range of other competing cations (Ag+, Al3+, Ba2+, Ca2+, Cd2+, Co2+, Cr3+, Cs+, Fe2+, Fe3+, Li+, Mg2+, Mn2+, Na+, Ni2+, Pb2+, Zn2+, Hg2+ and Sr2+). With Cu2+, the sensor UNA-1 gave a distinct color change from colorless to dark yellow by forming a complex of 1:1 stoichiometry. Furthermore, sensor UNA-1 was successfully utilized in the preparation of test strips and supported silica for the detection of Cu2+ ions from aqueous environment.
Patil, Samadhan R.,Nandre, Jitendra P.,Patil, Prashant A.,Sahoo, Suban K.,Devi, Manisha,Pradeep, Chullikkattil P.,Fabiao, Yu,Chen, Lingxin,Redshaw, Carl,Patil, Umesh D.
p. 21464 - 21470
(2015/03/30)

2,6,7 SUBSTITUTED PURINES AS HDM2 INHIBITORS
The present invention provides 2,6,7 substituted purines as described herein or a pharmaceutically acceptable salt thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.
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Page/Page column 98

(2014/08/20)

Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4
A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methylquinazoline- 2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.
Lin, Kuaile,Cai, Zhengyan,Wang, Fei,Zhang, Wei,Zhou, Weicheng
p. 477 - 482
(2013/05/22)

Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4)
The tyrosine kinase EphB4 is an attractive target for drug design because of its recognized role in cancer-related angiogenesis. Recently, a series of commercially available xanthine derivatives were identified as micromolar inhibitors of EphB4 by high-throughput fragment-based docking into the ATP-binding site of the kinase domain. Here, we have exploited the binding mode obtained by automatic docking for the optimization of these EphB4 inhibitors by chemical synthesis. Addition of only two heavy atoms, methyl and hydroxyl groups, to compound 4 has yielded the single-digit nanomolar inhibitor 66, with a remarkable improvement of the ligand efficiency from 0.26 to 0.37 kcal/(mol per non-hydrogen atom). Compound 66 shows very high affinity for a few other tyrosine kinases with threonine as gatekeeper residue (Abl, Lck, and Src). On the other hand, it is selective against kinases with a larger gatekeeper. A 45 ns molecular dynamics (MD) simulation of the complex of EphB4 and compound 66 provides further validation of the binding mode obtained by fragment-based docking. 2009 American Chemical Society.
Lafleur, Karine,Huang, Danzhi,Zhou, Ting,Caflisch, Amedeo,Nevado, Cristina
supporting information; experimental part
p. 6433 - 6446
(2010/03/31)

Selective, high affinity A2B adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines
A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A2B AdoR (Ki = 6 nM and 7 nM, respectively) and greater selectivity for the human A1, A2A, and A3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A2B AdoR.
Kalla, Rao V.,Elzein, Elfatih,Perry, Thao,Li, Xiaofen,Gimbel, Art,Yang, Ming,Zeng, Dewan,Zablocki, Jeff
p. 1397 - 1401
(2008/09/21)

Easy preparative scale syntheses of labelled xanthines: Caffeine, theophylline and theobromine
Several easy preparative scale (0.5-1.5 g) syntheses of deuterium labelled caffeine, theophylline and theobromine are described. Some new selective syntheses of theophylline and theobromine have been developed. Labelled xanthines are of great interest in qualitative or quantitative isotope dilution-mass spectrometry, coupled with gas or liquid chromatography, currently performed in anti-doping and forensic laboratories. Copyright
Balssa, Frederic,Bonnaire, Yves
p. 33 - 41
(2007/10/03)

Microwave-assisted synthesis of 8-mercapto-3-methyl-7-alkyl xanthines - An improved method
A microwave-assisted synthetic method to prepare novel 8-mercapto-3-methyl- 7-alkyl xanthine compounds is reported. Compared to conventional synthetic route, the new method significantly shortened synthetic steps and reaction time.
Zhang, Lei,Zhang, Y. John
p. 775 - 778
(2007/10/03)

XANTHINE DERIVATIVES AS A2B ADENOSINE RECEPTOR ANTAGONISTS
Disclosed are compounds that are A2B adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.
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Page 77

(2010/02/09)

A2B adenosine receptor antagonists
Disclosed are novel compounds that are A2B adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.
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Page 37

(2008/06/13)

Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: Potent A2A- and A3-adenosine receptor antagonistst
A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A2A or A3 ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified β-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A1 and A2A ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A3 ARS and in functional studies (adenylate cyclase assays) at A1 ARs of rat fat cell membranes, A2A ARs of rat PC 12 cell membranes, and mouse A2B ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A2A ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A2A ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl- imidazo[2,1-i]purinone (S-25) exhibiting a Ki value of 424 nM at rat A2A ARs. The compound was highly selective for A2A receptors vs A1 and A3 ARs. Selectivity vs A2B ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A3 ARs were identified. The most potent A3 antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a Ki value of 2.3 nM and high selectivity for A3 receptors vs all other AR subtypes.
Müller, Christa E.,Thorand, Mark,Qurishi, Ramatullah,Diekmann, Martina,Jacobson, Kenneth A.,Padgett, William L.,Daly, John W.
p. 3440 - 3450
(2007/10/03)

Compounds for ceramide-mediated signal transduction
Novel isoquinoloine compounds inhibit inflammatory responses associated with TNF-α and fibroblast proliferation in vivo and in vitro. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Preferred compounds of the invention are esters. Methods for the use of the novel compounds to inhibit ceramide-mediated intracellular responses to stimuli in vivo (particularly TNF-α) are also described. The methods are expected to be of use in reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression.
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Page 21

(2010/01/31)

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)

Substituted xanthines, pteridinediones, and related compounds as potential antiinflammatory agents. Synthesis and biological evaluation of inhibitors of tumor necrosis factor α
A series of analogues of pentoxifylline metabolites were prepared in the purine, pteridine, [1,2,5]-thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and evaluated for their ability to inhibit the production of tumor necrosis factor-α (TNFα) in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human neutrophils in order to help determine their mechanism of action. Selected compounds which showed good activity in the in vitro TNFα assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compounds in the TNFα assay, 6, 31, and 58, inhibited TNFα production at an IC50 of approximately 5 μM for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leukopenia induced by TNFα in mice, providing more than 60% protection at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNFα production but are devoid of PDE IV inhibitory properties, may have potential as new antiinflammatory agents.
Cottam, Howard B.,Shih, Hsiencheng,Tehrani, Lida R.,Wasson, D. Bruce,Carson, Dennis A.
p. 2 - 9
(2007/10/03)

Structure-activity relationships in a series of xanthine derivatives with antibronchoconstrictory and bronchodilatory activities
Thirty-one 1,3,7,8-substituted xanthine derivatives have been synthesized and evaluated for bronchodilator and anti-bronchoconstrictory activities in in vitro tracheal relaxation and in vivo bronchospasm inhibition models. Activity tests have been complemented with phosphodiesterase inhibition and toxicological data. Structure-activity relationships are discussed. Compound 21 (1,3-diisobutyl-8-methylxanthine) has been selected for further pharmacological development because of its good activity profile and favourable therapeutic index, which is 14- and 38-fold greater than that of theophylline and IBMX, respectively.
Merlos,Gomez,Vericat,Bartroli,Garcia-Rafanell,Forn
p. 653 - 658
(2007/10/02)