- Dyphylline prodrugs: Plasma hydrolysis and dyphylline release in rabbits
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Ester hydrolysis of prodrugs of dyphylline [7-(2,3-dihydroxypropyl)theophylline] followed first-order kinetics in both human and rabbit plasma. Rate constants were estimated by linear regression analysis of initial conversion rates, determined at different initial prodrug concentrations. Release of dyphylline from different prodrugs was 1.3 to 13 times faster in rabbit plasma than human plasma. However, relative rates of drug release (lability order) followed the same patterns in rabbit and human plasma. Dyphylline concentrations in rabbit plasma were extended slightly following intravenous administration of dyphylline 2',3'-dipivaloate. Oral dosing of the prodrug in rabbits greatly sustained plasma dyphylline concentrations.
- Huang,Ayres
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- Chemoenzymatic synthesis of enantiomerically enriched diprophylline and xanthinol nicotinate
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A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) – diprophylline and xanthinol nicotinate – is reported for the first time. The decisive step is an enantioselective lipase-mediated methanolysis of racemic chlorohydrin-synthon acetate, namely 1-chloro-3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propan-2-yl acetate, performed under kinetically-controlled conditions on a preparative 500 mg-scale. The best results in terms of reaction enantioselectivity (E = 14) were obtained for the enantiomers resolution performed with lipase type B from Candida antarctica immobilized on acrylic resin (CAL-B, Novozym 435) suspended in homophasic acetonitrile-methanol mixture. The elaborated biocatalytic system furnished the key chlorohydrin intermediate (in 71% ee and 38% yield), which was then smoothly converted into enantioenriched active agents: (R)-(–)-diprophylline (57% ee) and (S)-(+)-xanthinol nicotinate (65% ee). To support the assignment of absolute configurations of EKR-products as well as to confirm the stereochemical outcome of the remaining reaction steps, docking studies toward the prediction of enantiomers binding selectivity in CAL-B active site as well as the respective chemical correlations with enantiomerically enriched analytical standards obtained from commercially available (R)-(–)-epichlorohydrin, were applied. In addition, single-crystal X-ray diffraction (XRD) analyses were performed for the synthesized optically active APIs furnishing by this manner a first crystal structures of nicotinic acid salt of xanthinol.
- Borowiecki, Pawe?,M?ynek, Mateusz,Dranka, Maciej
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supporting information
(2020/11/27)
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- Synthesis method of diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine
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The invention relates to a synthesis method of a diprophylline drug active pharmaceutical ingredient 7-(2,3-dihydroxypropyl)-theine, which comprises the following steps: adding 300ml of potassium bisulfite solution and 0.71 mol of stannous chloride into a reaction vessel which is provided with a stirrer, a reflux condenser, a dropping funnel and a thermometer, controlling the stirring rate at 130-160 rpm, heating the solution to 60-65 DEG C, slowly adding 0.56 mol of theine, heating the solution to 80-85 DEG C, reacting for 90-120 minutes, cooling the solution to 50-55 DEG C, and dropwisely adding 1.2-1.4 mol of 3-amino-1,2-propanediol; and after finishing addition, continuing reacting for 120-160 minutes, heating the solution to 130-140 DEG C, continuing reacting for 60-70 minutes, distilling under reduced pressure to remove water, cooling, adding hexane, heating under reflux until the condensate is completely dissolved, filtering while the solution is hot, washing the filter cake with ethyl acetate, cooling the washing solution to precipitate a solid, carrying out vacuum filtration, washing with a salt solution, washing with acetonitrile, and recrystallizing in nitromethane to obtain the crystal 7-(2,3-dihydroxypropyl)-theine, wherein the mass percent of the potassium bisulfite solution is 15-20%.
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Paragraph 0013-0014
(2017/03/08)
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- Synthesis and activity against HBV of novel tetra-seconucleoside analogues of dyphlline having the acyclic chains of ACV and HBG
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Selective alkylation of dyphylline (1) with (2-acetoxyethoxy)methyl bromide (2a) or 4-acetoxybutyl bromide (2b) afforded 3′-O-[(acetoxyethoxy)methyl] dyphylline (3a) and 3′-O-(4-acetoxybutyl)-dyphylline (3b), respectively. A trans esterification process rather than alkylation of the dihydroxy-propyl side chain in 1 had taken place during the reaction with 2-p-toluoyloxy)ethyl chloride (5) to afford the respective 3′-toluoyloxy derivative 7 and not the anticipated 3′-O-[(p-toluoyloxy)ethyl]-dyphylline (6). Deacylation of 3a,b and 7 afforded 4a,b and 1, respectively. Viral screening of selected compounds against HBV has been investigated. Copyright Taylor & Francis Group, LLC.
- Ashry, El Sayed H. El,Awad, Laila F.,Rashed, Nagwa,AbdelRahman, Adel,Rasheed, Hana A.
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p. 309 - 317
(2008/09/18)
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- Method for treating benign prostate hyperplasia
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A method of treating and/or preventing renal dysfunction in a patient, such as renal colic or contrast nephropathy by administering to a patient, a compound of the formula: is described herein. Administration of dyphylline in a sustained release oral dosage form is preferred.
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- Method of kidney treatment
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A method of treating and/or preventing renal dysfunction in a patient, such as renal colic or contrast nephropathy by administering to a patient, a compound of the formula: is described herein. Administration of dyphylline in a sustained release oral dosage form is preferred.
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