- Light-Induced Formation/Scission of C-N, C-O, and C-S Bonds Enables Switchable Stability/Degradability in Covalent Systems
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The manipulation of covalent bonds could be directed toward degradable, recyclable, and sustainable materials. However, there is an intrinsic conflict between properties of stability and degradability. Here we report light-controlled formation/scission of three types of covalent bonds (C-N, C-O, and C-S) through photoswitching between equilibrium and nonequilibrium states of dynamic covalent systems, achieving dual benefits of photoaddressable stability and cleavability. The photocyclization of dithienylethene fused aldehyde ring-chain tautomers turns on the reactivity, incorporating/releasing amines, alcohols, and thiols reversibly with high efficiency, respectively. Upon photocycloreversion the system is shifted to kinetically locked out-of-equilibrium form, enabling remarkable robustness of covalent assemblies. Reaction coupling allows remote and directional control of a diverse range of equilibria and further broadens the scope. Through locking and unlocking covalent linkages with light when needed, the utility is demonstrated with capture/release of bioactive molecules, modification of surfaces, and creation of polymers exhibiting tailored stability and degradability/recyclability. The versatile toolbox for photoswitchable dynamic covalent reactions to toggle matters on and off should be appealing to many endeavors.
- Hai, Yu,Li, Ziyi,Lu, Hanwei,Ye, Hebo,You, Lei,Zou, Hanxun
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supporting information
p. 20368 - 20376
(2021/12/03)
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- Method for preparing levamlodipine
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The invention provides a method for preparing levamlodipine and belongs to the technical field of medicine synthesis. The method provided by the invention comprises the following steps: concentratingamlodipine resolution mother liquor to be dry, then mixing with an oxidizing agent and a first solvent, and carrying out an oxidation reaction to obtain 2-((2-aminoethoxy)methyl)-4-(2-chlorphenyl)-6-methyl-3,5-pyridine ethyl methyl diformate, wherein the oxidizing agent is an achiral reagent; mixing the 2-((2-aminoethoxy)methyl)-4-(2-chlorphenyl)-6-methyl-3,5-pyridine ethyl methyl diformate, a reducing agent and a second solvent, and carrying out a reduction reaction to obtain an amlodipine racemate; and mixing the amlodipine racemate, a resolution reagent and a third solvent, and carrying outresolution treatment to obtain levamlodipine. According to the method provided by the invention, the amlodipine in the amlodipine resolution mother liquor can be effectively recycled and converted into high-value levamlodipine.
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Paragraph 0057-0066
(2020/10/14)
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- Two validated stability-indicating chromatographic methods for the separation of two anti-hypertensive combinations in the presence of their degradation products or impurities
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Two RP-HPLC methods were developed, optimized, and validated for the determination of two different anti-hypertensive combinations in the presence of their degradation products or impurities and in their pharmaceutical formulations. The first mixture is Ramipril (RAM) in combination with Amlodipine besylate (AML) [mixture I], while the second one is a combination of Ramipril (RAM), Atorvastatin (ATV), and Aspirin (ASP) [mixture II].The proposed combinations were successfully separated on X-bridge C18column (250 × 4.6?mm i.d, 5?μm p.s.), using a mobile phase of 0.05?M phosphate buffer-acetonitrile-THF (60:40:0.1% by volume) pH 2.5 and an isocratic mobile phase formed of acetonitrile-0.05?M phosphate buffer-THF (60:40:0.1% by volume) pH 2.5 for mixture (I) and (II) at a flow rate of 1?mL/min and 1.2?mL/min, respectively. The compromising components of the mixtures were detected at 218?nm. For the best separation of the mentioned components different parameters were examined and optimized. The two suggested methods were validated in compliance with the ICH guidelines and were successfully applied for the quantification of the cited components in presence of their obtained degradation products as well as in their commercial pharmaceutical formulations. For both methods the obtained results were statistically analyzed and compared to those of the official and reported methods; using Student’s t test and F test showing no significant difference with high accuracy and good precision.
- Samy Mostafa, Noha,AbdElHamid, Ghada,Elsayed Zaazaa, Hala,Mohamed Amer, Sawsan
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p. 2427 - 2439
(2019/07/16)
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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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- RAMIPRIL-AMLODIPINE SALT
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The present invention relates to a ramipril-amlodipine salt.
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Page/Page column 33
(2008/12/06)
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- The effect of ion pairing on the skin permeation of amlodipine
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The purpose of the present study was to evaluate the effect of ion pairing on the skin permeation of amlodipine. Amlodipine base (AM) was first prepared from amlodipine besilate (AM-B), then amlodipine adipate (AM-A), amlodipine oxalate (AM-O) and amlodipine maleate (AM-M) were prepared using AM and the corresponding organic acids. Differential scanning calorimetry (DSC) thermogram studies demonstrated the formation of complexes between AM and the various acids. In vitro percutaneous absorption of AM and its complexes was evaluated through excised rat skin using 2-chamber diffusion cells. The results showed that AM had the greatest steady-state flux and lowest permeability coefficient of the five compounds from the El system (ethanol : isopropyl myristate (IPM) = 2:8), and its four complexes all exhibited a lower flux and higher permeability coefficient than AM.
- Jiang, Yuxuan,Fang, Liang,Niu, Xicao,Ma, Rui,He, Zhonggui
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experimental part
p. 356 - 360
(2009/04/04)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE BESYLATE
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The present invention provides a process for the preparation of amlodipine, which comprises purging of methylamine gas under stirring in phthaloyl amlodipine in presence of an organic solvent selected from the group consisting of toluene and isopropyl alcohol.
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Page/Page column 4-5
(2010/11/28)
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- PROCESS FOR PREPARING AMLODIPINE
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A process for preparing phthalimidoamlodipine, which is useful as an intermediate for the preparation of amlodipine and its salts.
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Page/Page column 7
(2010/11/28)
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- PROCESS FOR THE PREPARATION OF PURE AMLODIPINE
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The present invention relates to an improved process for the preparation of pure Amlodipine via the effective purification of phthalimido Amlodipine (3-ethyl-5-methyl -2-[(2-phthalimido ethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-dicarboxylate).
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Page/Page column 7
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF AMLODIPINE SALTS
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A process for the preparation of salts of amlodipine comprises subjecting a compound of formula (II) to a deprotection reaction and converting the amlodipine free base thus obtained to a salt (1) without isolating amlodipine free base. Preferably, the maleate, besylate, malate or fumarate salt is made.
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Page/Page column 8-12
(2008/06/13)
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- METHOD FOR PURIFICATION OF AMLODIPINE FREE BASE
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The invention relates to a method for the purification of the deprotected free base of amlodipine, present in the reaction mixture following deprotection of an N-protected amlodipine compound, whereby (i) the reaction mixture, containing the deprotected amlodipine free base, optionally after a preceding filtration, is evaporated to dryness, or the solvent removed from the reaction mixture, (ii) the amlodipine free base, contained in the residue thus obtained, is dissolved in a suitable solvent and (iii) the amlodipine free base is precipitated from said solution.
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Page/Page column 5
(2008/06/13)
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- COMPOSITIONS COMPRISING (S)-AMLODIPINE AND AN ANGIOTENSIN RECEPTOR BLOCKER AND METHODS OF THEIR USE
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A pharmaceutical composition comprising enantiomerically pure (S)-amlodipine, an ARB and optional other active agents, and methods of treating, preventing and managing cardiovascular diseases and disorders, and symptoms thereof, using the composition, are disclosed.
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Page/Page column 33
(2008/06/13)
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- ISOLATION OF DIHYDROPYRIDINE DERIVATIVE AND PREPARATION SALTS THEREOF
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The title compound is isolated in pure form by using a crystallization process and converted to its pharmaceutically acceptable salts. The crystallization process affects stability and purity of the amlodipine salts. All known impurities and one unknown impurity, which forms during the synthesis of the amlodipine salts, were isolated, characterized, and synthesized. A new method allowing the quantitative HPLC analysis of all related impurities of amlodipine salts in a single chromatogram was developed.
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- Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
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Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate [2-{(2-aminoethoxy)-methyl-4-(2-chlorophenyl) 3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate]. Phthalic anhydride is condensed with monoethanol amine at 150-190° C. The resulting N-(2-hydroxyethyl) phthalimide is coupled with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at ?11 to ?15° C. Ethyl-4-[-2(phthalimido) ethoxy] acetoacetate formed is coupled with orthochloro benzaldehyde in the presence of pyridine salt at 70-90° C. Ethyl-2-(2-chloro benzylidine)4-[-2(phthalimido) ethoxy] acetoacetate fanned is condensed with methyl amino crotonate at 20-40° C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2-Phthalimidoethoxy) methyl-3-carboethoxy 1(chlorophenyl)-S-carbomethoxy-6-methyl-1,4-dihydropyridin] which is purified by dissolving in an organic solvent in the ratio 1:2-1:5 w/v and precipitated by the addition of water at 35-60° C. Purified phthaloyl amlodipine is hydrolysed with methylamine in the presence of a protic solvent at 20-50° C. Amlodipine base [2-(aminoethoxy) methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] formed is reacted with benzene sulfonic acid. The resulting amlodipine besylate is purified in an organic solvent at 30-70° C. and precipitated by the addition of an insoluble solvent.
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- DIHYDROPYRIDINE COMPOUNDS HAVING SIMULTANEOUS ABILITY TO BLOCK L-TYPE CALCIUM CHANNELS AND TO INHIBIT PHOSPHODIESTERASE TYPE 3 ACTIVITY
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The present invention provides compounds that possess inhibitory activity against PDE-3 and L-type calcium channels. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine.
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- Crystalline organic acid salt of amlodipine
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A novel crystalline organic acid salt of amlodipine having improved physiochemical properties, a preparation method thereof and a pharmaceutical composition comprising the same are provided.
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- Crystalline organic acid salt of amlodipine
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A novel crystalline organic acid salt of amlodipine having improved physiochemical properties, a preparation method thereof and a pharmaceutical composition comprising the same are provided.
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Page/Page column 3
(2008/06/13)
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- Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]
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The present invention relates to a process for the preparation of [S(?)amlodipine-L(+)-hemi taratarte] from RS amlodipine base using L(+) tartaric acid in the presence of dimethyl sulfoxide.
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- Crystalline material
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The present invention relates to amlodipine free base in a crystalline form, to pharmaceutical formulations comprising such material, processes of manufacture and its use in therapy.
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- Method for preparing amlodipine
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Amlodipine is prepared in a high yield by subjecting a pyrrole derivative, methyl aminocrotonate and 2-chlorobenzaldehyde to a Hantzsch reaction, and converting the pyrrole residue of the resulting 1,4-dihydropyridine derivative to an amine group by the action of hydroxylamine hydrochloride.
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- 1,4-dihydropyridines, N-substituted bicyclic 4-hydropyridines, and bicyclic N-substituted 4,5-dihydropyridines
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The invention relates to a novel process to prepare 1,4-dihydropyridines and in particular amlopidine and in novel intermediates obtained during the synthesis of the 1,4-dihydropyridines which have potential activity as antihypertensive agents.
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