- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
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supporting information
p. 239 - 246
(2017/05/29)
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- Effect of basic and acidic additives on the separation of some basic drug enantiomers on polysaccharide-based chiral columns with acetonitrile as mobile phase
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The separation of enantiomers of 16 basic drugs was studied using polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase.
- Gogaladze, Khatuna,Chankvetadze, Lali,Tsintsadze, Maia,Farkas, Tivadar,Chankvetadze, Bezhan
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p. 228 - 234
(2015/03/18)
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- OXPRENOLOL COMPOSITIONS FOR TREATING CANCER
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The present invention relates to compositions of S-enantiomer enriched oxprenolol and their use in treating cancer and treating or preventing, in cancer patients, cachexia, body weight loss, lean body mass loss and adipose tissue loss, and improving quality of life and prolonging survival of cancer patients.
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- S-ENANTIOMERICALLY ENRICHED COMPOSITIONS OF BETA BLOCKERS FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS
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The present invention relates to S-enantiomerically enriched compositions of beta blockers and uses thereof, including uses of the beta blocker compositions for treating amyotrophic lateral sclerosis. The beta blocker compositions can also be used for preventing loss of lean mass, preventing body weight loss in subjects, improving quality of life in subjects, and prolonging survival in amyotrophic lateral sclerosis patients. The beta blocker can be oxprenolol or a pharmaceutically acceptable salt thereof.
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- Chiral separation of basic compounds on sulfated β-cyclodextrin-coated zirconia monolith by capillary electrochromatography
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Sulfated β-cyclodextrin (SCD)-coated zirconia monolith was used as the chiral stationary phase in capillary electrochromatography for enantiomeric separation of basic chiral compounds. SCD adsorbed on the zirconia surface provided a stable chiral stationary phase in reversed-phase eluents. Retention, chiral selectivity and resolution of a set of six basic chiral compounds were measured in eluents of varying pH, composition of methanol and buffer. Optimum mobile phase condition for the separation of the compounds was found to be methanol content of 30%, buffer concentration of 30 mM and pH of 4.0.
- Hong, Jong-Seong,Park, Jung Hag
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p. 1809 - 1813
(2013/07/26)
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- Chiral separations of some β-adrenergic agonists and antagonists on AmyCoat column by HPLC
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Sixteen β-adrenergic antagonists namely acebutalol, alprenolol, atenolol, bisoprolol, bopindolol, bufurolol, carazolol, celiprolol, indenolol, metaprolol, nebivolol, oxprenolol, practolol, propranolol, tertalol, and timolol, and two β-adrenergic agonists namely cimeterol and clenbuterol were resolved on AmyCoat (150 x 46 mm, 3 μm size of silica particle) by using (85:15:0.1, v/v/v), (90:10:0.1, v/v/v), and (95:05:0.1, v/v/v) combinations of η-heptane, ethanol, and diethylamine solvents, respectively. The flow rates used were 0.5, 1.0, 2.0, and 3.0 ml/min with detection at 225 nm. The values of capacity, separation, and resolution factors ranged from 0.38 to 19.70, 1.08-2.33, and 1.0 and 4.50, respectively. The maximum and minimum resolutions were achieved for celiprolol and bufurolol, respectively. The chiral recognition mechanisms were also discussed. The values of validation parameters were calculated.
- Ali, Imran,Saleem, Kishwar,Gaitonde, Vinay D.,Aboul-Enein, Hassan Y.,Hussain, Iqbal
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experimental part
p. 24 - 28
(2010/09/14)
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- THERAPY FOR COMPLICATIONS OF DIABETES
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A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
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- ANTIHYPERTENSIVE THERAPY
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A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
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- FLUORESCENCE BASED DETECTION OF SUBSTANCES
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A method for the fluorescent detection of a substance, the method comprising providing particles comprising a metal or a metal oxide core, wherein one or more optionally fluorescently tagged antibodies or human specific peptide nucleic acid (PNA) oligomers for binding to a substance is/are bound, directly or indirectly, to the surface of the metal or metal oxide; contacting a substrate, which may or may not have the substance on its surface, with the particles for a time sufficient to allow the antibody/PNA oligomer to bind with the substance; removing those particles which have not bound to the substrate; if the antibodies or PNA oligomers are not fluorescently tagged, contacting the substrate with one or more fluorophores that selectively bind with the antibody and/or substance, then optionally washing the substrate to remove unbound fluorophores; and illuminating the substrate with appropriate radiation to show the fluorophores on the substrate.
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- Method for treating resistant hypertension
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A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
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- Application of cyclam-capped β-cyclodextrin-bonded silica particles as a chiral stationary phase in capillary electrochromatography for enantiomeric separations
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Two novel types of substituted cyclam-capped β-cyclodextrin (β-CD)-bonded silica particles have been prepared and used as chiral stationary phases in capillary electrochromatography (CEC). The two stationary phases have a chiral selector with three recognition sites: β-CD, cyclam, and the latter's sidearm. They exhibit excellent enantioselectivities in CEC for a wide range of compounds as a result of the cooperative functioning of the anchored β-CD and cyclam. After inclusion of the metal ion (Ni2+) from the running buffer into the substituted cyclams and their sidearm ligands, the bonded stationary phases become positively charged and can provide extra electrostatic interactions with ionizable solutes and enhance the dipolar interactions with some polar neutral solutes. This enhances the host-guest interaction with some solutes and improves chiral recognition and enantioselectivity. These new types of stationary phases exhibit great potential for fast chiral separations in CEC.
- Gong, Yinhan,Lee, Hian Kee
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p. 1348 - 1354
(2007/10/03)
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- Determination of the enantiomeric purity and the configuration of β- aminoalcohols using (R)-2-fluorophenylacetic acid (AFPA) and fluorine-19 NMR: Application to β-blockers
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A method has been developed for determining the enantiomeric purity and the absolute configuration of β-aminoalcohols of type ArOCH2CH(OH)CH2NHR (R = iPr, tBu). To determine enantiomeric purity, the amine function was first protected by a benzyl group, then the compound formed was esterified using the acid chloride of (R)-2-fluorophenylacetic acid (AFPA). The 19F NMR analysis of the derivative obtained revealed the presence of two distinctly separate signals (~2.5 ppm), the one for the RS-SR pair being the most deshielded. The configuration was determined directly on the aminoalcohol by using the acid. In stoichiometric conditions, when R = iPr, the amide function was obtained very preponderantly. The 19F NMR spectrum of the amide presented four distinct signals when derivatization was carried out by means of a reaction between the (±)-β-aminoalcohol and the (R)-AFPA. The extreme signals, which were over 3.5 ppm apart, did not belong to the same diastereomer. With R = tBu essentially the ester function was obtained. The first studies revealed the presence of two signals, though not as clearly separated as in the previous cases. Each experiment was simple to perform, and purification was not necessary. Mosher's acid gave unsatisfactory results in each case. (C) 2000 Elsevier Science Ltd.
- Apparu, Marcel,Ben Tiba, Younes,Leo, Pierre-Marc,Hamman, Sylvain,Coulombeau, Christian
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p. 2885 - 2898
(2007/10/03)
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- A study of the relationship between the structure of homologous series of oxprenolol at various pH values
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Stability of series of O-acyl esters of oxprenolol prepared as potential pro-drugs, is investigated over the pH range 0,4-10 at 37°C. Maximum stability of all esters occurred at pH 3-4. The most stable derivative was found to be pivaloyl ester. The relationship between Charton Steric parameters (V) and the catalytic rate constant of hydrolysis is investigated.
- Nogowska
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p. 353 - 357
(2007/10/03)
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- Process for the preparation of 3-amino-2-hydroxy-1-propyl ethers
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PCT No. PCT/JP97/03220 Sec. 371 Date Apr. 28, 1999 Sec. 102(e) Date Apr. 28, 1999 PCT Filed Sep. 12, 1997 PCT Pub. No. WO98/12171 PCT Pub. Date Mar. 26, 1998A process for preparation of 3-amino-2-hydroxy-1-propyl ether of the formula wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring, R2 and R3 are the same or different hydrogen atom, a substituted or unsubstituted alkyl, or may form a ring together with an adjacent nitrogen atom, which ring may be interrupted with nitrogen atom, oxygen atom or sulfur atom, which is characterized in reacting an epoxy compound of the formula wherein X is halogen, in the presence of a fluoride salt, with an alcohol and then reacting an amine. According to the above method, an intermediates for synthesis of medicines is obtained in good yield and highly optical purity.
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- Physico-chemical properties and hydrolysis of oxprenolol caproil and 2-chlorbenzoil esters
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Caproil (Cap-OXP) and 2-chlorbenzoil (2-Cl-Benz-OXP) esters of oxprenolol were synthesized. The compounds were identified by elemental analysis and their purity was established by TLC. Their chemical structure was confirmed by UV, IR, 1H-NMR and 13C-NMR spectra. Decomposition of the ester group of oxprenolol esters (E-OXP) was studied in aqueous solutions. All reaction were followed by VIS spectrophotometry. The pH-rate profile was accounted for the specific acid- and base-catalyzed reactions and also by assuming spontaneous or water-catalyzed decomposition of both dissociated and undissociated molecules to occur.
- Nogowska, Maria
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p. 195 - 199
(2007/10/03)
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- CsF in organic synthesis. Regioselective nucleophilic reactions of phenols with oxiranes leading to enantiopure β-blockers
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The two modes of the paths in the reaction of oxiranes with phenols are completely controlled by CsF. Glycidyl nosylate undergoes exclusive substitution at the C1 position whereas the ring-opening (C-3 attack) occurs with epichlorohydrin, glycidol, and 1,2-epoxyalkanes. These reactions provide convenient access to enantiopure β-blockers.
- Kitaori, Kazuhiro,Furukawa, Yoshiro,Yoshimoto, Hiroshi,Otera, Junzo
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p. 14381 - 14390
(2007/10/03)
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- A study of the relationship between the structure and physicochemical parameters of a homologous series of oxprenolol esters at various pH values and temperatures
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A number of β-adrenergic blockers, including timolol and propranolol, are administered in eyedrops for the treatment of glaucoma, but their therapeutic value is limited by a relatively high incidence of cardiovascular and respiratory, side effects. Because of poor ocular bioavailability, many ocular drugs are applied in high concentrations, which give rise to both ocular and systemic side effects. Methods to increase ocular bioavailability include (a) the development of drug delivery devices designed to release drugs at controlled rates, (b) the use of various vehicles that retard precorneal drug loss, and (c) the conversion of drugs to biologically reversible derivatives (prodrugs) with increased cornea penetration properties, from which the active drugs are released by enzymatic hydrolysis. A homologous series of aliphatic esters of oxprenolol were synthesized and investigated as potential prodrugs for ocular use. The stability of each O- acyl derivative was investigated in aqueous solutions over the pH range 2.2- 9.0 at 37°C. The observed rate constants (k(obs)), shelf-lives (t90), lipophilicities, and Arrhenius parameters were determined for each ester. A study of the relationship between the structure and physicochemical parameters of the homologous series of oxprenolol esters at various pH values and temperatures was made.
- Jordan, C. Geraldine M.
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p. 1085 - 1091
(2007/10/03)
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- Continuous and preparative enantioseparation of oxprenolol with cellulose tris(3,5-dimethylphenylcarbamate)-coated belt
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Enantiomer enrichment of oxprenolol up to 68% enantiomeric excess was achieved by using a cellulose tris(3,5-dimethylphenylcarbamate) (CTPC)-coated rayon-belt. The chiral belt was successfully used for the first time in the continuous, rapid and preparative resolution of oxprenolol.
- Yashima,Noguchi,Okamoto
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p. 1889 - 1890
(2007/10/03)
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- Flash Chiral Chromatography using Carbohydrate Carbamate-coated Silica
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Enantiomers of many chiral compounds are resolved rapidly on a preparative scale by passage through a column packed with flash chromatography silica which has been physically coated with a carbohydrate carbamate.
- Matlin, Stephen A.,Grieb, Sally J.,Belenguer, Ana M.
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p. 301 - 302
(2007/10/02)
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- Drug delivery studies in Caco-2 monolayers. Synthesis, hydrolysis, and transport of O-cyclopropane carboxylic acid ester prodrugs of various β-blocking agents
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A series of O-cyclopropane carboxylic acid ester prodrugs of various β-blocking agents was synthesized. All prodrugs were hydrolyzed to give their parent compounds in aqueous phosphate buffer of pH 7.4 and in 80% human plasma. The half-lives in buffer solutions varied from 4 hours for the timolol prodrug to about I day for the prodrug of alprenolol. In human plasma the half-lives were shorter, ranging from 1 to 7 hours. The formation of the O-cyclopropane carboxylic acid ester derivatives significantly increased the lipophilicities of the β-blockers as measured by the distribution coefficient between n-octanol and aqueous phosphate buffer of pH 7.4. To characterize the biomembrane permeability characteristics of the β-blockers, transport properties across Caco-2 cell monolayers were investigated. An increase in lipophilicity resulted in a higher permeability of the prodrugs as compared to the parent compounds. Hence, acebutolol experienced an increment of a factor 17 on the apparent permeability coefficient, Papp, whereas Papp for the more lipophilic drug propranolol was increased by a factor of only 1.26. Some conversion of the prodrugs to their parent compounds was observed during the transport and appeared to be due to enzymatic intracellular metabolism.
- Hovgaard,Brondsted,Buur,Bundgaard
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p. 387 - 392
(2007/10/03)
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- Enzyme Assisted Preparation of Enantiomerically Pure β-Adrenergic Blockers III. Optically Active Chlorohydrin Derivatives and Their Conversion
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Optical active chlorohydrin derivatives 2a-m and 3a-m of both enantiomeric series were prepared via both enzymatic hydrolyses and acyltransfer reactions catalysed by a highly selective lipase from Pseudomonas sp..The resulting building blocks were further transformed into the corresponding β-blockers of high enantiomeric purity.
- Ader, Ulrich,Schneider, Manfred P.
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p. 521 - 524
(2007/10/02)
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- Process for inverting the configuration in optically active compounds
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The invention relates to a process for inverting the configuration in optically active compounds of the formula STR1 in which Ar1 represents a monocyclic or polycyclic, carbocyclic or heterocyclic radical that has at least one ring of aromatic character and is bonded to the oxygen atom by way of a ring carbon atom, preferably of the ring of aromatic character, and R1 represents an optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, or the salts thereof, characterised in that an optically active compound of the formula STR2 having a R(+) or S(-) configuration, in which R2 represents a monocyclic or polycyclic, carbocyclic or heterocyclic radical, or an optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical, is converted, by treating with a strong oxygen-containing inorganic or organic acid or halides thererof, into an optically active compound of the formula STR3 in which X? represents the anion of a strong, oxygen-containing inorganic or organic acid or of a halogen atom and the resulting compound of the formula III is hydrolysed, optionally by way of the corresponding free base as intermediate, to form a compound of the formula I of a configuration opposite to that of the starting material used and, if desired, a free compound of the formula I is converted into a salt or a resulting salt is converted into the free compound.
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- Enteric coated mixture of 4-(2-hydroxy-3-isopropylamino-propoxy) indole and sodium lauryl sulphate
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The present invention provides a pharmaceutical composition for controlled release of 4-(2-hydroxy-3-isopropylamino-propoxy) indole in the intestinal tract, admixed with sodium lauryl sulphate, and enteric coated.
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