- The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation
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Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective β1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.
- Rossi, Patrizia,Paoli, Paola,Chelazzi, Laura,Conti, Luca,Bencini, Andrea
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- PROCESS FOR PREPARATION OF PHENOXYPROPANOL AMINES
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The present invention describes an improved method for the preparation of l-[4-{2- (cyclopropylmethoxy)ethyl}phenoxy]-3-[(1-methylethyl)amino]-2-propanol of Formula-(I) and its pharmaceutically acceptable salt, which comprises reacting 4 - [ 2 — (Cyclopropylmethoxy) ethyl] phenol with epichlorohydrin in presence of mild base and polar protic solvent to isolate 1 - {4 - [2 - (cyclopropylmethoxy)ethyl] - phenoxy} - 2, 3 - epoxy propane, which is further reacted with isopropyl amine to get betaxolol formula (I).
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Page/Page column 9
(2010/04/06)
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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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- RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol, process for preparation thereof and process for preparation of RS betaxolol
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The present invention relates to RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of the formula (1), process for preparation thereof by selective allylation of p-hydroxy phenyl ethanol and use thereof in a preparation of RS betaxolol of formula (2)
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Page/Page column 5
(2010/11/08)
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- Process for the selective alkylation of betaxolol intermediates
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The present invention relates to a process for the selective alkylation of intermediates of betaxolol.
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- A chemoenzymatic route to both enantiomers of betaxolol
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Evaluation of some of the possible lipase-catalyzed transformations has been done in order to prepare both enantiomers of betaxolol. Resolution of betaxolol by lipase-catalyzed hydrolysis of its bisacetylated derivatives 4 led to (-)- and (+)-enantiomers with an ee of 20 and 60%, respectively. When the resolution was performed on the chlorohydrin precursor 6 of betaxolol, (-)- and (+)-enantiomers were obtained with an ee of 91 and 75%, respectively.
- Di Bono,Scilimati
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p. 699 - 702
(2007/10/02)
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- Process for preparing substituted phenol ethers via oxazolidine-structure intermediates
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Phenol ethers such as 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol, otherwise known as betaxolol, of formula: STR1 are prepared from p-hydroxyphenethyl alcohol by first reacting at the phenolic group, with epichlorohydrin followed by isopropylamine, to prepare the required secondary amine-hydroxy side chain. Protection of the alcoholic group is not required during these steps. Then the secondary amine-alcohol group is protected by reaction with a suitable aldehyde such as benzaldehyde to form an oxazolidine ring protectant while the alcohol chain is elaborated. The oxazolidine ring protectant is removed by simple acid hydrolysis.
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- Anti-glaucoma agent
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1-{4-[2-(Cyclopropylmethoxy)-ethyl]-phenoxy}-3-isopropylamino-propan-2-ol and its pharmaceutically acceptable salts, in the form of a racemate or optical isomer, are useful as topical anti-glaucoma agents.
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- PHENOL ETHERS
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The invention provides phenol ethers of the formula: STR1 wherein R is branched C 3-4 alkyl, C 3-4 cycloalkyl, branched cyano(C 3-4 alkyl), phenyl(C 2-3 alkyl), halophenyl(C 2-3 alkyl), (C 1-4 alkoxy)phenyl(C 2-4 alkyl), or (C 1-4 acyl) amino(C 1-4 alkyl),alk is C 1-4 alkyl substituted by a 3 to 6 membered cycloalkyl group,X is--O--,--S--or--SO 2--; andR 1 is--C 1-4 alkyl-or--C 1-4 alkoxy-, in their racemic and optically active forms, and their addition salts with pharmaceutically acceptable acids. These compounds are useful in therapy as β-adrenergic blocking agents. Intermediates are also provided.
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