- Coordination polymers as potential solid forms of drugs: Three zinc(ii) coordination polymers of theophylline with biocompatible organic acids
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The biocompatible organic acids such as acetic acid (Hac), benzoic acid (Hbz) and nicotinic acid (Hnit), have been employed as second ligands to assemble biocompatible coordination polymers of theophylline (Hthp), respectively. As a result, three coordination polymers [Zn2(thp) 2(ac)(OH)]n (1), [Zn2(thp)2(bz)(OH)] n (2) and [Zn(thp)(nit)]∞ (3) have been synthesized through hydrothermal and mechanochemical reactions. Theophylline could be released rapidly in simulated gastroenteric fluid (phosphate-buffered solution, PBS) and slow release of theophylline could be achieved from the three polymers in pure water at 37 °C with continuous stirring.
- Lou, Benyong,He, Fengdan
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Read Online
- Comparison of the Mass Spectra of 6-Thiotheophyllines and 6-Sulfinyltheophyllines
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Under electron impact, 6-thiotheophyllines eliminate various fragments from the pyrimidine moiety.In a retro Diels-Alder reaction, they lose the fragment X=C=NCH3 from positions 1 and 2 of the pyrimidine ring.In 6-sulfinyltheophyllines, the sulfinyl group is the main target for fragmentation; it can lose either oxygen or sulfur, and the abundance of + and + is much higher than the abundance of the molecular ion.Elimination of the sufur atom of the 6-sulfinyl substituent, with retention of its oxygen, may be explained by intermediate formation of a ring.All further fragmentation of the 6-sulfinyl derivatives proceed by a primary loss of oxygen or sulfur, followed by elimination of fragments from the pyrimidine moiety, similar to the primary processes, observed in the mass spectra of the 6-thiotheophyllines.
- Bergmann, Felix,Rahat, Miriam,Frank, Arie,Deutsch, Joseph
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Read Online
- Isolation and characterization of 1,3-dimethylisoguanine from the Bermudian sponge Amphimedon viridis
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The new compound 1,3-dimethylisoguanine has been isolated and characterized from the Bermudian sponge Amphimedon viridis. Chemical conversion of the natural product to theophylline and 2D NMR methods were used to determine the position of the methyl groups on the purine ring. Analysis of the mass spectral fragmentation pattern allowed assignment of the purine ring as isoguanine.
- Mitchell,Whitehill,Trapido-Rosenthal,Ireland
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Read Online
- Inhibition of radical-induced DNA strand breaks by water-soluble constituents of coffee: Phenolics and caffeine metabolites
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Epidemiological studies have associated coffee consumption with an inverse risk of developing Parkinson's disease, hepatocellular carcinoma and cirrhosis. The molecular mechanisms by which low concentrations of the constituents of coffee measured in human plasma can reduce the incidence of such diseases are not clear. Using an in vitro plasmid DNA system and radiolytically generated reactive oxygen species under constant radical scavenging conditions, we have shown that coffee chlorogenic acid, its derivatives and certain metabolites of caffeine reduce some of the free radical damage sustained to the DNA. A reduction in the amount of prompt DNA single-strand breaks (SSBs) was observed for all compounds whose radical one-electron reduction potential is a limited antioxidant role for such compounds in their interaction with DNA radicals.
- Rathod,Patel,Das,Tipparaju,Shinde,Anderson, Robert F.
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Read Online
- SERS multiplexing of methylxanthine drug isomersviahost-guest size matching and machine learning
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Multiplexed detection and quantification of structurally similar drug molecules, methylxanthine MeX, incl. theobromine TBR, theophylline TPH and caffeine CAF, have been demonstratedviasolution-based surface-enhanced Raman spectroscopy (SERS), achieving highly reproducible SERS signals with detection limits down to ～50 nM for TBR and TPH, and ～1 μM for CAF. Our SERS substrates are formed by aqueous self-assembly of gold nanoparticles (Au NPs) and supramolecular host molecules, cucurbit[n]urils (CBn,n= 7, 8). We demonstrate that the binding constants can be significantly increased using a host-guest size matching approach, which enables effective enrichment of analyte molecules in close proximity to the plasmonic hotspots. The dynamic range and the robustness of the sensing scheme can be extended using machine learning algorithms, which shows promise for potential applications in therapeutic drug monitoring, food processing, forensics and veterinary science.
- Chio, Weng-I Katherine,Dinish, U. S.,Jones, Tabitha,Lee, Tung-Chun,Liu, Jia,Olivo, Malini,Parkin, Ivan P.,Perumal, Jayakumar
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supporting information
p. 12624 - 12632
(2021/10/06)
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- 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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- Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines
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The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-epoxyisoalantolactone, 2′,2′-dichloro-4H-spiro[cyclopropane-1′,4-eudesma-11(13)-en-8β,12-olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine, 8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was revealed that the yield and product ratio depends on the reaction conditions and the structure of methylene lactone. The effectiveness of Pd(OAc)2–caffeine catalytic system has been demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound 27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7 and C-8 of the xanthine core showed moderate activity with IC50 value of 40?μM.
- Patrushev, Sergey S.,Rybalova, Tatyana V.,Ivanov, Igor D.,Vavilin, Valentin A.,Shults, Elvira E.
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p. 2717 - 2726
(2017/04/14)
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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 0027; 0028; 0032
(2016/10/08)
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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 0014; 0026; 0027; 0031
(2017/02/02)
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- A coffee because of the intermediate 1, 3-dimethyl-4-amino-5-Carbamoyl [...] closed-loop reaction method
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The invention relates to a ring-closure reaction method of a caffeine intermediate 1,3-dimethyl-4-amino-5-formyl aminoureazine (FAU), and belongs to the technical field of synthesis and preparation of organic compounds. The method comprises the following step: carrying out a ring-closure reaction by catalyzing the 1,3-dimethyl-4-amino-5-FAU in water via an catalyst system containing ethyl amine, wherein the weight ratio of the dimethyl FAU to the water to the catalyst system is 1 to (4-8) to (0.5-2). The ring-closure reaction method can be used for obviously increasing the yield of theophylline, and is low in environment-friendly treating pressure and production cost, high in quality of the caffeine intermediate 1,3-dimethyl-4-amino-5-FAU, moderate in reaction condition, as well as simple and convenient to operate, and reaction conditions are easily controlled.
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Paragraph 0040; 0041
(2017/01/05)
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- Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors
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Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38–90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5–125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.
- Shelke, Rupesh U.,Degani, Mariam S.,Raju, Archana,Ray, Mukti Kanta,Rajan, Mysore G. R.
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p. 602 - 613
(2016/08/28)
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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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- Examining the robustness of a theophylline cocrystal during grinding with additives
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The robustness of theophylline-p-hydroxybenzoic acid cocrystal (TP·pHBA) while grinding with additives in the solid state was evaluated through a series of solvent-drop grinding experiments with coformers containing various functional groups. Powder X-ray diffraction was used to qualitatively analyse the powders after grinding and identify the species present. The TP·pHBA cocrystal was found to be robust in the presence of benzoic acid (BA), p-nitrobenzoic acid (pNBA), p-(N,N-dimethylamino)benzoic acid (dMABA), m-hydroxybenzoic acid (mHBA), p-nitrophenol (pNP), hydroquinone (HDQ) and benzamide (BZA), but it disintegrates in the presence of salicylic acid (SA), 3,5-dinitrobenzoic acid (dNBA), acetamide (ACA) and melamine (MLM).
- Abourahma, Heba,Urban, Jennifer M.,Chan, Benny,Morozowich, Nicole
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p. 6163 - 6169,7
(2020/08/31)
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- Hair Treatment Means With Cloudberry Extract
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Extract of cloudberries (Rubus chamaemorus) for use in agents for treating keratin fibers, particularly human hair, for improving the moisture in the fiber, repairing and restructuring the fibers and for protecting the fibers from oxidants and UV radiation, and for improving the color retention and color intensity when the fibers are colored hairs is disclosed.
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- METHOD AND PRODUCT
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The present invention provides a method of producing a co-crystal, the method comprising the steps of providing a first substance and a second substance, wherein the first and second substances are compatible to form a co-crystal, mixing said first and second substances together, and exposing the mixture of said first and second substances to prolonged and sustained conditions of pressure and shear, sufficient to form a co-crystal of said first and second substance. The prolonged and sustained conditions of pressure and shear are preferably applied in an extrusion process. Associated compositions and uses thereof are also provided.
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- HAIR TREATMENT PRODUCTS COMPRISING POLYMERS
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The invention relates to hair treatment products, comprising at least one copolymer made of 0.1 to 50% (in relation to the total number of monomers in the copolymer) monomers of the formula (I), wherein the unknowns are defined as in claim 1, and A2) are monomers from the group of acrylic acid, methacrylic acid and the like, and—optionally non-ionic monomers from the group of acrylamide, vinyl alcohol, and the like, wherein the monomers A2 and A3 together represent 50 to 99.9% (in relation to the total number of monomers in the copolymer) of the copolymer, at least one silicon and at least one selected care product, wherein the products result in advantageous effects for skin and hair.
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- Pteridines. Part CXIX: A new pteridine - Purine transformation
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A variety of pyrimidine precursors 12-25 were converted into a series of new 7-hydroxylumazines (=7-hydroxypteridine-2,4(1H,3H)-diones) 26-35 which functioned as starting materials for the transformation into the corresponding 7-chlorolumazines 36-45. Subsequent reaction with hydrazine led to the 7-hydrazinolumazines 46-55 which gave on nitrosation the 7-azidolumazines 1 and 56-64. These compounds were subjected to short heating in xylene whereby 1 and 56-61 showed a new pteridine-purine interconversion in forming a new type of 1,3-disubstituted or 3-substituted xanthin-8-amine-derived nitrilium ylides (2,3,6,7-tetrahydro-N-methylidyne-2,6-dioxo-1H-purin-8-aminium ylides) 11 and 65-70. The presence of an additional 6-alkyl substituent in the 7-azidolumazines 63 and 64 or of an unsubstituted N(3) position in 62 caused further rearrangement to xanthine-9-carbonitriles 71-73. Prolonged heating of 7-azido-1,3-dimethyllumazine (1) also afforded theophylline-9-carbonitrile (=1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purine-9-carbonitrile; 5). The nitrilium ylide function was established by NMR and UV spectra as well as by elemental analyses. Confirmation of the nitrilium ylide structures was suggested by the result of the heating of 1,3-dimethyl-N-methylidynexanthin-8-aminium ylide 11 in EtOH or of 1 in pentan-1-ol leading to 8-aminotheophylline (=8-amino-3,7-dihydro-1,3-dimethyl-1H-purin-2,6-dione; 74).
- Pfleiderer, Wolfgang
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experimental part
p. 338 - 353
(2009/02/07)
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- Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: The pathway and concentration dependence
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The aim of the present study was to estimate the relative contribution of rat P450 isoforms to the metabolism of caffeine and to assess the usefulness of caffeine as a marker substance for estimating the activity of P450 in rat liver and its potential for
- Kot, Marta,Daniel, Wladyslawa A.
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p. 1538 - 1549
(2008/09/16)
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- The relative contribution of human cytochrome P450 isoforms to the four caffeine oxidation pathways: An in vitro comparative study with cDNA-expressed P450s including CYP2C isoforms
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The aim of the present study was to estimate the relative contribution of cytochrome P450 isoforms (P450s), including P450s of the CYP2C subfamily, to the metabolism of caffeine in human liver. The experiments were carried out in vitro using cDNA-expresse
- Kot, Marta,Daniel, Wladyslawa A.
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p. 543 - 551
(2008/12/20)
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- Synthesis of deuterium labeled standards of 1-benzylpiperazine, fenetylline, nicocodeine and nicomorphine
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Increasingly abused, 1-benzylpiperazine (BZP), fenetylline, nicocodeine and nicomorphine are central nervous system stimulants with neurotoxic properties. In recent years, many controlled substance analogs (designer drugs) with a large variety of structures have reached illegal markets, making their identification difficult. This work studies the synthesis of BZP-d7, fenetylline-d4, nicocodeine-d4 and nicomorphine-d 8, as internal standards for use in gas chromatography-mass spectrometry (GC-MS) analysis for identification of these controlled substances.
- You, Zong-Yi,Chen, Yi-Jing,Wang, Yu-Yun,Chen, Chinpiao
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experimental part
p. 663 - 667
(2009/05/07)
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- Efficient synthesis of 1,3,7-substituted xanthines by a safety-catch protection strategy
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An efficient synthesis of selectively N-substituted xanthine derivatives is described. Cyclocondensation of a suitably protected aminoimidazole with methyl-2-phenylthioethyl carbamate, followed by oxidation of sulfur to the sulfone, provides access to an orthogonally 1,7-protected xanthine, which may then be regioselectively alkylated and deprotected under mild conditions.
- Allwood, Matthew B.,Cannan, Booma,van Aalten, Daan M.F.,Eggleston, Ian M.
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p. 12294 - 12302
(2008/03/12)
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- Light Emitting Probes
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This invention relates to a composition comprising at least two chemically different fluorophores, providing a donor and an acceptor respectively, connected together by at least one linker moiety and bonded to a binder moiety.
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- Synthesis, hydrolyses and dermal delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide and thiol containing drugs
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Synthesis, characterization and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of substituted phenols, theophylline (Th) and 6-mercaptopurine (6MP) were carried out. The mechanism of hydrolysis was further investigated by synthesis, characterization and hydrolysis of N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of phenols. The hydrolysis follows pseudounimolecular first order kinetics and operates by way of an SN1-type mechanism. Topical delivery of selected derivatives of acetaminophen (APAP), Th and 6MP was examined in in vitro diffusion cell experiments from IPM across hairless mice skins. The prodrug of APAP and 6MP increased permeation across the skin by about 2- and 4-fold, respectively, compared to the parent drug. NANAOCAM promoieties can act as novel prodrug derivatives of phenol, imide and thiol containing drugs for enhancing topical absorption.
- Majumdar, Susruta,Sloan, Kenneth B.
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p. 3590 - 3594
(2007/10/03)
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- A novel method of caffeine synthesis from uracil
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An inexpensive and novel method of caffeine synthesis starting from uracil in six simple steps is described. Uracil 1 is first converted to I, 3-dimethyluracil 2, followed by nitration, reduction, and cyclization to theophylline and finally methylation of theophylline forms caffeine.
- Zajac, Matthew A.,Zakrzewski, Anthony G.,Kowal, Mark G.,Narayan, Saraswathi
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p. 3291 - 3297
(2007/10/03)
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- LIQUID PHARMACEUTICAL FOR ORAL DELIVERY
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A liquid pharmaceutical for oral delivery wherein at the time of use, a solid unit dosage form is added to the liquid wherein the unit dosage form is comprised of a substrate soluble in the liquid and a particulate pharmaceutically active material in a pharmaceutically effective amount. At the time of use, the unit dosage form is added to the liquid, without requiring measurement of the liquid, and the entire liquid is consumed to provide for oral delivery of the pharmaceutically effective amount of material.
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- Facile synthesis of 6-aryl-1,3-dimethyl-5H-pyrimido-[4,5-b][1,4]diazepine-2,4(1H,3H)-diones
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A facile procedure for the preparation of 6-aryl-1,3-dimethyl-5H-pyrimido[4,5-b][1,4]diazepine-2,4(1H,3H)-diones 8, 9 from 6-amino-5-arylideneamino-1,3-dimethyluracils 1, 2 and triethyl orthoacetate (3) in a two-step reaction via 6-aryl-8-ethoxy-6,7-dihydro-1,3-dimethyl-5H-pyrimido[4,5-b][1,4]diazepine-2,4(1H ,3H)-diones 6, 7 is described. Condensation of 1 with diethoxymethyl acetate (10) resulted in the formation of (1,3-dimethyl-2,6-(1H,3H)-dioxopurin-7-yl)(phenyl)methyl acetate (11) and a small amount of 1,3-dimethyl-6-phenyl-pyrazino[2,3-d]pyrimidine-2,4(1H,3H)-dione (12). The structures of 6 and 11 were unambiguously confirmed by single-crystal X-ray diffraction analysis.
- Taghavi-Moghadam, Shahriyar,Stumpf, Ruediger,Fischer, Helmut,Pfleiderer, Wolfgang
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p. 313 - 320
(2007/10/03)
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- A high chemical reactivity of 5-azidouracils and its synthetic application: Novel synthesis of 8-substituted 1,3-dimethylxanthine derivatives
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A novel method for the preparation of 8-substituted 1,3-dimethylxanthine derivatives (7 or 8) is described: treatment of 6-alkylamino-5-bromo-1,3-dimethyluracils (6a-e), easily prepared by brornination of the corresponding 6-alkyIamino-1,3-dimethyluracils (5), with sodium azide in DMF at ambient temperature allowed the direct formation of the 8-substituted 1,3-dimethylxanthines (7) proceeding via a transient formation of the corresponding 5-azido-1,3-dimethyluracils. The 5-bromo-1,3-dimethyluracils (6f, g) possessing an α-branched alkylamino group at the 6-position similarly react with sodium azide to afford 8,8-disubstituted 1,3-dimethyl-8H-xanthines (8,8-disubstituted 1,3-dimethyl-3,8-dihydropurine-2,6-diones)(8).
- Hirota, Kosaku,Sako, Magoichi,Sajiki, Hironao
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p. 547 - 554
(2007/10/03)
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- Mechanism of free radical oxidation of caffeine in aqueous solution
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The oxidation of caffeine with persulfate and hydroxyl radicals in aqueous solution has been studied by EPR spectroscopy and HPLC analysis. In both cases the formation of 1,3,7-trimethyluric acid is observed as the main final product. A C8-OH radical adduct is postulated as the intermediate after reaction with OH., and leads to the final product after further oxidation. This radical is too short-lived to be observed by EPR After oxidation of caffeine with SO4.- its radical cation is detected by EPR. This radical reacts with water to produce the above mentioned C8-OH radical adduct after deprotonation. In the presence of dibasic phosphate a spectrum attributed to the C8-phosphate radical adduct is observed. This radical results from the nucleophilic attack of the buffer on the radical cation of caffeine. Hydrolysis and oxidation of the phosphate radical intermediate results in the formation of 1,3,7-trimethyluric acid.
- Telo, Joao P.,Vieira, Abel J. S. C.
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p. 1755 - 1757
(2007/10/03)
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- Process for preparing 1,3-dimethy-4,5-diaminouracil
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The present invention relates to an improved process for preparing 1,3-dimethyl-4,5-diaminouracil by catalytic reduction of 1,3-dimethyl-4-amino-5-nitrosouracil in the presence of a palladium/charcoal catalyst.
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- In vitro metabolism of 1,3-dioxane, 1,3-oxathiolane, and 1,3-dithiane derivatives of theophylline: A structure-metabolism correlation study
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Correlation between structure and metabolism was studied within a series of cyclic acetal and thioacetal theophylline derivatives. All the compounds showed marked regioselectivity in in vitro metabolism, the metabolites arising only from 7-cycloalkyl side chain transformation. The 1,3-dioxane derivative, besides N-dealkylation to theophylline, underwent enzymatic ring cleavage, through the oxidation of the acetal carbon and subsequent rearrangement. Thus the acetal group was converted enzymatically to an ester. A similar transformation, catalyzed by cytochrome P450-dependent monooxygenases, was previously found for the 1,3-dioxolane ring of doxophylline. The cyclic thioacetal derivatives (i.e. 1,3-oxathiolane and 1,3-dithiane) were not cleaved during oxidative metabolism. The metabolites arise only from the oxidation of the sulfur atom, the major nucleophilic center in the molecule. No N-dealkylation to theophylline was observed. Enzymatic sulfoxidation proceeded diastereoselectively in both the 1,3-oxathiolane and 1,3-dithiane rings, the trans isomers being the major ones with a ratio trans: cis 75:25 and 60:40 respectively. The sulfoxides were stable to hydrolysis and were not further metabolized. Neither disulfoxides nor sulfones were detected in the incubations.
- Grosa,Rocco,Ceruti,Dosio,Brusa,Biglino
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p. 677 - 690
(2007/10/02)
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- Controlled release pharmaceutical preparation and method for producing the same
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Disclosed is a controlled release pharmaceutical preparation, comprising a core containing a pharmaceutically active ingredient, and a porous film of a hydrophobic polymeric substance or a hydrophobic polymeric substance and a hydrophilic polymeric substance, the core being coated with the porous film. Disclosed is also a method for producing the same. The controlled release pharmaceutical preparation of this invention posseses a desired dissolution rate by controlling the porosity of the porous film.
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- Selectivities in Photoadditions with Multifunctional Caffeine Derivatives
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Electronically excited stilbene (21*), 4,4'-dichlorostilbene (1*), and 4,4'-dimethoxystilbene (18*) are trapped by caffeine derivatives 2, 13, or 22 with variable results.While 1* and 2 react predominantly at the imino double bond (substitutive and fragmentating additions), 1* or 18* and 13 produce mostly propellanes by photocycloaddition, which hydrolyze or may be hydrolyzed. 21* and the relatively electron-poor compound 22 produce mostly propellanes, which always show a preponderance of the syn-10,anti-11 stereoisomers.These selectivities as well as the competition with reactions at the imino double bonds are rationalized on the basis of diradical mechanisms with the aid of semiempirical AM1 calculations.Earlier results on closely related transformations are also discussed.
- Kaupp, Gerd,Ringer, Ernst
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p. 339 - 345
(2007/10/02)
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- Drug delivery system
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A drug delivery system in which a taste masked solid is suspended in a liquid carrier. The solid has been rendered hydrophillic and its density approximates that of the carrier liquid.
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- SYNTHESIS AND PROPERTIES OF N(7)-β-D-GLUCOFURANOURONOSIDES OF THEOPHYLLIN AND 3-ISOBUTYL-1-METHYLXANTHINE
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Condensation of the trimethylsilyl derivatives of theophyllin and 3-isobutyl-1-methylxanthine with β-D-glucofuranourono-6,3-lactone in the presence of trimethylsilyl trifluoromethanesulfonate has given N(7)-β-D-glucofuranouronosides.Their hydrolytic stability has been examined at pH 1.4 and 7.4.
- Maurin'sh, Yu.A.,Paegle, R.A,,Grigor'eva, V.D,Sakhartova, O.V.,Mikhailopulo, I.A.,Lidak, M.Yu.
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p. 198 - 202
(2007/10/02)
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- PURINES, PYRIMIDINES, AND CONDENSED SYSTEMS BASED ON THEM. 6. REACTIVITY OF 7- AND 9-AMINOXANTHINES TOWARD OXIDIZING AGENTS AND SOME ELECTROPHILES. SYNTHESIS OF THE ANTIBIOTICS FERVENULIN AND RHEUMYCIN
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The action of various oxidizing agents on 7- and 9-aminotheophyllines and also on 1-methyl-9-aminoxanthine was studied. 7-Aminotheophyllines are oxidized by almost all the oxidizing agents to 6,8-dimethylpyrimido-as-triazine-5,7(6H,8H)-dione (40-90 percent). 1-Methyl-9-aminoxanthine and 9-aminotheophylline are oxidized with greater difficulty.The best results are obtained with hydrogen peroxide, which transforms these amines with yields of ca. 40 percent into the antibiotics rheumycin and fervenulin, respectively.Under certain conditions the action of bromine and nitric acid leads to the bromination and nitration of the N-aminoxanthines at position 8.A series of the physicochemical characteristics of the N-aminoxanthines were investigated.The factors which affect their behavior toward oxidizing agents and electrophiles are discussed.
- Gulevskaya, A. V.,Kuz'menko, V. V.,Pozharskii, A. F.,Kuz'menko, T.A.,Shorshnev, S. V.,et al.
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- Demethylation of N-methylisocyanurate, N-methyluracils and N-methylxanthines by thiophenolate anions
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N-methyls present in the title compounds have been demethylated by sodium thiophenolate at 250-300 deg C under N2 atmosphere.The reaction has been utilised to prepare 1,3-dimethylisocyanuric acid, 1-methyl-6-iminouracil (4) and purine alkaloids 6, 7 and 8 by a new one-step method.
- Mitra, R. B.,Subbarao, A.,Gumaste, V. K.,Likhite, S. M.
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p. 311 - 312
(2007/10/02)
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- PURINES, PYRIMIDINES, AND CONDENSED SYSTEMS BASED ON THEM. V. N-AMINOGROUP AS A PROTECTING FUNCTION IN PRODUCTION OF UNSYMMETRICAL 1,3-DIALKYLXANTHINES FROM 3-METHYLXANTHINE
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3-Methyl-7-aminoxanthine (yield 67percent) and 3-methyl-1,7-diaminoxanthine (7percent) were obtained by the amination of 3-methylxanthine by hydroxylamino-O-sulfonic acid in an alkaline medium.Alkylation of the 3-methyl-7-aminoxanthine potassium salt followed by removal of the N-amino group with nitrous acid led to the formation of 1-R-3-methylxanthines (R = C2H5, C6H5CH2, CH2CN, CH2CO2CH3) with good yields.
- Kuz'menko, V. V.,Gulevskaya, A. V.,Pozharskii, A. F.
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p. 1373 - 1377
(2007/10/02)
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- Controlled release formulation
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A controlled release pharmaceutical formulation which undergoes substantially or approaches zero order release of active drug is provided, preferably in the form of a coated tablet, containing a core portion from which medicament, such as procainamide hydrochloride, is slowly released over a controlled length of time. The core also includes one or more primary hydrocolloid gelling agents which is a hydropropylmethyl cellulose having a viscosity of within the range of from about 1,000 to about 6,000 centipoises in 2% solution at 20° C., and a methoxyl content of 28-30%, optionally a secondary hydrocarbon gelling agent, such as hydroxypropyl cellulose and/or methyl cellulose, one or more non-swellable binders and/or wax binders (where the medicament and/or hydrocolloid gelling agents are non-compressible), one or more inert fillers or excipients, one or more lubricants, and optionally one or more anti-adherents such as silicon dioxide and water. The above-described core is coated with a pharmaceutical coating composition containing a hydrophobic polymer and a hydrophilic polymer.
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- Composition for achieving tumor reversion and its use in cancerology for dogs
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Skin neoformations and sarcomas in dogs are treated with a composition containing by weight percent, in distilled water: 8-22% of polyethylene glycol having a molecular weight within the range of 1000 to 6000, 10-30% of dimethyl sulfoxide, 2.5-7.5% of theophylline.
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- Controlled release formulation
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A controlled release pharmaceutical formulation which undergoes slow release of active drug is provided, preferably in the form of a tablet containing medicament, such as captopril, is slowly released over a controlled length of time. The tablet also includes an acrylic acid polymer or copolymer and one or more lubricants and is formed by a dry granulation technique.
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- Controlled release formulation
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A controlled release pharmaceutical formulation which undergoes substantially or approaches zero order release of active drug is provided, preferably in the form of a coated tablet, containing a core portion from which medicament, such as procainamide hydrochloride, is slowly released over a controlled length of time. The core also includes one or more hydrocolloid gelling agents having a viscosity of within the range of from about 10,000 to about 200,000 centipoises in 2% solution at 20° C., such as hydroxypropylmethyl cellulose and/or methyl cellulose, one or more non-swellable binders and/or wax binders (where the medicament and/or hydrocolloid gelling agents are non-compressible), one or more inert fillers or excipients, one or more lubricants, and optionally one or more anti-adherents such as silicon dioxide and water. The above-described core is coated with a pharmaceutical coating composition containing a hydrophobic polymer and a hydrophilic polymer.
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- N,N-DIMETHYLCHLOROFORMIMINIUM CHLORIDE IN THE SYNTHESIS OF HETEROCYCLIC COMPOUNDS. THE SYNTHESIS OF N-HETEROARYLFORMAMIDINE HYDROCHLORIDES, OXAZOLO/5,4-D/PYRIMIDINES, FUSED IMIDAZOLES AND OTHER SYSTEMS
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N,N-Dimethylchloroformiminium chloride (DCFC) was used for preparation of N-heteroarylformamidine hydrochlorides (2), fused oxazoles (4), imidazoles (6,8) and thiazoles (10).DCFC is advantageous in those cases in which the undesired further methylation of NH, OH, and SH groups could occur by using N,N-dimethylformamide dimethyl acetal (DMFDMA).
- Stanovnik, Branko,Bajt, OLiver,Balcic, Branko,Koren, Bozidar,Prhavc, Marija,et al.
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p. 1545 - 1554
(2007/10/02)
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- Preparation of caffeine
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Caffeine is prepared from theophylline, carbon monoxide and methanol.
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- Antigen, antiserum and immunoassay for theophylline
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By injecting a host animal with a member of a particular group of antigens [a theophylline-(7)-alkanecarboxylic acid covalently bonded to an immunogenic carrier (IGC) via the carboxyl group], antibodies, advantageously employed in determining small amounts of theophylline in biological liquids by immunoassay methods, are obtained.
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- 1,4-REARRANGEMENT OF 7-(2-ACETAMIDO-2,3-DIDEDOXYHEX-2-ENOPYRANOSYL)THEOPHYLLINE DERIVATIVES
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Treatment of 7-(2-acetamido-2,3-didedoxyhexen-2-enopyranosyl)theophylline derivatives with boron trifluoride etherate in boiling methanol led to the isolation of 7-(methyl 2-acetamido-2,3,4-trideoxyhex-2-enopyranosid-4-yl)theophylline derivatives.Some mechanistic features of this 1,4-rearrangement followed by solvolysis are discussed, and a rationalization of the C-4' derivatives in the fusion reaction of 2-acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol with theophylline is offered.
- Pravdic, Nevenka
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- Decomposition of aminophylline in suppository formulations
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An aminophylline suppository product, when stored at room temperature, was found to be deficient in ethylenediamine content by the USP XIX assay and by a specific method for primary amines. The product also had a melting point that was considerably higher than body temperature. An accelerated decomposition experiment, conducted on normal suppositories of identical original composition, yielded a product refractory at steam bath temperatures and containing no ethylenediamine measurable by the USP assay. The suppositories from both the original samples and the decomposition experiment contained considerable amounts of a white material, which melted at ~150° and which consisted of the diamide products formed by the reaction of ethylenediamine and the fatty acids present in coconut and palm kernel oils. The results, which confirmed the work of Cieszynski, showed that the ethylenediamine constituent of aminophylline can react with suppository base materials to produce insoluble amide decomposition products.
- Brower,Juenge,Page,Dow
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p. 942 - 945
(2007/10/02)
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