- In-situ and one-step preparation of protein film in capillary column for open tubular capillary electrochromatography enantioseparation
-
In this work, the phase-transitioned BSA (PTB) film using the mild and fast fabrication process adhered to the capillary inner wall uniformly, and the fabricated PTB film-coated capillary column was applied to realize open tubular capillary electrochromatography (OT-CEC) enantioseparation. The enantioseparation ability of PTB film-coated capillary was evaluated with eight pairs of chiral analytes including drugs and neurotransmitters, all achieving good resolution and symmetrical peak shape. For three consecutive runs, the relative standard deviations (RSD) of migration time for intra-day, inter-day, and column-to-column repeatability were in the range of 0.3%–3.5%, 0.2%–4.9% and 2.1%–7.7%, respectively. Moreover, the PTB film-coated capillary column ran continuously over 300 times with high separation efficiency. Therefore, the coating method based on BSA self-assembly supramolecular film can be extended to the preparation of other proteinaceous capillary columns.
- Li, Ling,Xue, Xuqi,Zhang, Huige,Lv, Wenjuan,Qi, Shengda,Du, Hongying,Manyande, Anne,Chen, Hongli
-
supporting information
p. 2139 - 2142
(2021/04/07)
-
- Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents
-
Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98–3.70 μM), compared to propranolol (59.5–75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
- Chang, Qi,Long, Jing,Hu, Liqing,Chen, Zhuo,Li, Qianbin,Hu, Gaoyun
-
-
- Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC
-
A triazole-bridged bis(β-cyclodextrin) was synthesized via a high-yield Click Chemistry reaction between 6-azido-β-cyclodextrin and 6-propynylamino-β-cyclodextrin, and then it was bonded onto ordered silica gel SBA-15 to obtain a novel triazole-bridged bis (β-cyclodextrin)–bonded chiral stationary phase (TBCDP). The structures of the bridged cyclodextrin and TBCDP were characterized by the infrared spectroscopy, mass spectrometry, elemental analysis, and thermogravimetric analysis. The chiral performance of TBCDP was evaluated by using chiral pesticides and drugs as probes including triazoles, flavanones, dansyl amino acids and β-blockers. Some effects of the composition in mobile phase and pH value on the enantioseparations were investigated in different modes. The nine triazoles, eight flavanones, and eight dansyl amino acids were successfully resolved on TBCDP under the reversed phase with the resolutions of hexaconazole, 2′-hydroxyflavanone, and dansyl-DL-tyrosine, which were 2.49, 5.40, and 3.25 within 30 minutes, respectively. The ten β-blockers were also separated under the polar organic mode with the resolution of arotinolol reached 1.71. Some related separation mechanisms were discussed preliminary. Compared with the native cyclodextrin stationary phase (CDSP), TBCDP has higher enantioselectivity to separate more analytes, which benefited from the synergistic inclusion ability of the two adjacent cavities and bridging linker of TBCDP, thereby enabling it a promising prospect in chiral drugs and food analysis.
- Shuang, Yazhou,Liao, Yuqin,Wang, Hui,Wang, Yuanxing,Li, Laisheng
-
p. 168 - 184
(2019/11/25)
-
- Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias
-
Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gαs, while they only show weak or even no β-arrestin-2 recruitment at both β1- and β2-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the β2-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser5.46 and Asn6.55, and the aromatic head group of the ligands.
- Stanek, Markus,Picard, Louis-Philippe,Schmidt, Maximilian F.,Kaindl, Jonas M.,Hübner, Harald,Bouvier, Michel,Weikert, Dorothée,Gmeiner, Peter
-
p. 5111 - 5131
(2019/05/28)
-
- Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents
-
Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-α signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases.
- Xu, Yao,Chen, Shujun,Cao, Ying,Zhou, Pingzheng,Chen, Zhipeng,Cheng, Kui
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p. 253 - 266
(2018/05/29)
-
- Carvedilol preparation method
-
The invention discloses a carvedilol preparation method. The carvedilol preparation method comprises the following steps: 1) adding a compound II, sodium hydroxide and a solvent in a reaction vessel, heating the materials to the reaction temperature, stirring the materials to obtain a reaction solution, crystallizing the compound I carvedilol and precipitating the compound I; 2) pumping a reaction solution in a reaction process in a press filtration cylinder, returning a filtrate to the kettle; and 3) after the reaction is complete, scraping a filter cake to obtain the high purity carvedilol. Compared with the prior art, The generated carvedilol is crystallized through a reaction crystallization technology, and is continuously separated to the outside of a system, the conversion rate of a reactant II is greatly increased, continuous production with low energy consumption, simpleness and rapidity can be realized, the yield of the obtained target product I is greater than 86%, and the chemical purity is greater than 99%.
- -
-
Paragraph 0017; 0018; 0019; 0020; 0021; 0022; 0023-0031
(2017/04/29)
-
- Organocatalytic Regioselective Chlorosilylation of Oxirane Derivatives: Mild and Effective Insertion of Bulky Silyl Chloride by Using 4-Methoxypyridine N-Oxide
-
The highly regioselective organocatalytic chlorosilylation of oxirane derivatives using bulky silyl reagents such as (tert-butyl)diphenylsilyl chloride (TBDPSCl) or triphenylsilyl chloride (Ph3SiCl) was developed. The reaction was effectively catalyzed with 4-methoxypyridine N-oxide in the presence of sodium sulfate (Na2SO4). Several silylated halohydrins were obtained with complete regioselectivity and the reaction was applied to the synthesis of carvedilol. (Figure presented.) .
- Yoshida, Keisuke,Suzuki, Hina,Inoue, Hiroki,Matsui, Kohei,Fujino, Yuta,Kanoko, Yohei,Itatsu, Yukihiro,Takao, Ken-Ichi
-
p. 1886 - 1891
(2016/07/06)
-
- Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the β-Adrenoreceptor Antagonists Carazolol and Carvedilol
-
We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (?)-(S)-carazolol (5) and (?)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.
- Brütting, Christian,Hesse, Ronny,J?ger, Anne,Kataeva, Olga,Schmidt, Arndt W.,Kn?lker, Hans-Joachim
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p. 16897 - 16911
(2016/11/17)
-
- Preparation of a β-cyclodextrin-based open-tubular capillary electrochromatography column and application for enantioseparations of ten basic drugs
-
An open-tubular capillary electrochromatography column was prepared by chemically immobilized β-cyclodextrin modified gold nanoparticles onto new surface with the pre-derivatization of (3-mercaptopropyl)-trimethoxysilane. The synthesized nanoparticles and the prepared column were characterized by transmission electron microscopy, scanning electron microscopy, infrared spectroscopy and ultraviolet visible spectroscopy. When the column was employed as the chiral stationary phase, no enantioselectivity was observed for ten model basic drugs. So β-cyclodextrin was added to the background electrolyte as chiral additive to expect a possible synergistic effect occurring and resulting in a better separation. Fortunately, significant improvement in enantioselectivity was obtained for ten pairs of drug enantiomers. Then, the effects of β-cyclodextrin concentration and background electrolyte pH on the chiral separation were investigated. With the developed separation mode, all the enantiomers (except for venlafaxine) were baseline separated in resolutions of 4.49, 1.68, 1.88, 1.57, 2.52, 2.33, 3.24, 1.63 and 3.90 for zopiclone, chlorphenamine maleate, brompheniramine maleate, dioxopromethazine hydrochloride, carvedilol, homatropine hydrobromide, homatropine methylbromide, venlafaxine, sibutramine hydrochloride and terbutaline sulfate, respectively. Further, the possible separation mechanism involved was discussed.
- Fang, Linlin,Yu, Jia,Jiang, Zhen,Guo, Xingjie
-
-
- STORE OVERLOAD-INDUCED CALCIUM RELEASE INHIBITORS AND METHODS FOR PRODUCING AND USING THE SAME
-
The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1-X1-L-X2-R2, wherein R1, X1, L, X2, and R2 are those defined herein.
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-
- An efficient improved synthesis of carvedilol, via 2-(2-methoxyphenoxy)ethyl 4-methylbenzenesulfonate intermediate
-
A facile synthesis of Carvedilol via a key 2-(2-methoxyphenoxy) ethyl 4-methylbenzenesulfonate intermediate is described and this approach avoids the formation of bis side product (impurity-B) due to weak basic conditions and also operationally suitable for industrial application.
- Tatendra Reddy,Suneel Kumar,Omprakash,Dubey
-
p. 1615 - 1618
(2015/02/02)
-
- Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release
-
Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
- Smith, Chris D.,Wang, Aixia,Vembaiyan, Kannan,Zhang, Jingqun,Xie, Cuihong,Zhou, Qiang,Wu, Guogen,Chen, S. R. Wayne,Back, Thomas G.
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p. 8626 - 8655
(2013/12/04)
-
- Lewis acid mediated nucleophilic ring-opening of 1-Benzhydryl Azetidine-3-ol with aryl alcohols: A formal synthesis of carvedilol
-
Lewis acid mediated nucleophilic azetidine ring opening of 1-benzhydrylazetidine-3-ol with phenolic oxygen as nucleophile is reported. This approach was also utilized successfully to synthesize, carvedilol a β-adrenergic blocking agent.
- Krishna Reddy,Ramamohan,Ganesh,Srinivas,Mukkanti,Madhusudhan
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p. 3468 - 3472
(2012/07/30)
-
- Convenient synthesis of Carvedilol utilizing 3-(9H-carbazol-4-yloxy)-1- chloropropan-2-yl phenyl carbonate as a key intermediate
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Convenient synthesis of pharmaceutically important moiety Carvedilol, 1 (β-adrenergic blocking agent) has been reported utilizing 3-(9H-carbazol-4-yloxy)-1-chloropropan-2-yl phenyl carbonate 8 as a key intermediate. The synthetic scheme involves the reaction of intermediate 8 with 2-(2-methoxy phenoxy)- ethanamine 5 by using N,N-Dimethyl-4-aminopyridine (DMAP) in N,N-dimethylformamide (DMF) which yield 3-(2-(2- methoxyphenoxy)ethyl)-5- ((9H-carbazol-4-yloxy)methyl)oxazolidin- 2-one 7 via 1-(9H-carbazol-4-yloxy)-3- chloropropan-2-yl 2- (2-methoxyphenoxy)ethylcarbamate 6. The resulted compound 7 has further been converted to the required Carvedilol and this approach could be useful for the preparation of many β-amino alcohols without formation of Impurity B.
- Kumar, B. Anand,Ashrafuddin,Rajesh,Parveen, Sadhika,Madhusudhan
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p. 780 - 784
(2012/06/30)
-
- Synthesis of racemic and chiral Carvedilol starting from corresponding 5-(chloromethyl)oxazolidin-2-one
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The synthesis of racemic Carvedilol ((±)-1) has been achieved starting from 2-(chloromethyl) oxirane ((±)-2) in a four-step sequence. 5-(Chloromethyl) oxazolidin-2-one ((±)-3) and 5-((9Hcarbazol-4-yloxy) methyl) oxazolidin-2-one ((±)-4) are intermediates. A similar sequence starting from (R)- or (S)-2-(chloromethyl)oxirane 2 give corresponding chiral 5-((9Hcarbazol-4-yloxy)methyl) oxazolidin-2-one 4 followed by chiral Carvedilol 1. The synthetic sequence followed avoids the formation of impurity B (bis impurity). This approach can be useful for the preparation of pharmaceutically important moieties containingβ-amino alcohols without formation of bis impurity.
- Anand Kumar,Veera Babu,Rao, Rama Koteshwar,Srinivas, Kumbam,Madhusudhan,Mukkanti
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p. 1430 - 1435
(2012/11/06)
-
- A facile synthesis of carvedilol via β-amino alcohol intermediate
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A facile synthesis of Carvedilol via a key β-amino alcohol intermediate is described and this approach avoids the formation of bis side product (impurity B).
- Tatendra Reddy,Suneel Kumar,Omprakash,Dubey
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p. 251 - 254
(2013/09/24)
-
- Synthesis and characterization of potential impurities of carvedilol, an antihypertensive drug
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Carvedilol (Coreg) is a nonselective -adrenergic blocking agent with vasodilating activity. It is used for the treatment of congestive heart failure and hypertension. During the bulk synthesis of carvedilol, we have observed six impurities: Imp-I, Imp-II, Imp-III, Imp-IV, Imp-V, and Imp-VI. The present work describes the synthesis and characterization of these impurities. Copyright
- Rao, Somisetti Narender,Sitaramaiah, Devarasetty,Srimannarayana, Kema,Rao, Challa Nageswar,Rao, Peddi Srinivasa,Babu, K. Sudhakar
-
-
- A facile synthesis of carvedilol, β-adrenergic blocking agent, via a key 5-substituted-.-oxazolidinone intermediate
-
A facile synthesis of Carvedilol via a key 5-substituted-.-oxazolidinone intermediate is described and this approach avoids the formation of bis side product (impurity B). This approach could be useful for the preparation of many β-amino alcohols without formation of bis impurity.
- Madhusudhan,Kumar, B. Anand,Chintamani,Rao, M. Narasimha,Udaykiran,Suresh,Kumar, V. Kiran,Mukkanti
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experimental part
p. 606 - 610
(2010/12/25)
-
- Isomorphism, disorder, and hydration in the crystal structures of racemic and single-enantiomer carvedilol phosphate
-
Understanding the crystalline structure of racemic carvedilol phosphate hemihydrate presents several challenges that were overcome using a combination of single-crystal X-ray diffraction, solid-state NMR (SSNMR), and other analytical techniques. Initial attempts to obtain a crystal structure were hampered by difficulties with twinning and problematic disorder in the final refinements. Multinuclear SSNMR analysis localized the disorder to portions of the molecule near the chiral center. As a result, single-enantiomer carvedilol phosphate was prepared and was found to crystallize in a phase that was isomorphous with the racemate, while SSNMR spectra of the single enantiomers did not contain the disorder observed in the racemate. The single-crystal X-ray structure of the (R)-enantiomer was solved and used as a starting point to successfully progress the solution of the disordered racemic crystal structure. Thermal analysis and construction of a phase diagram, along with crystallographic and spectroscopic analysis, found the crystal structure of the racemate to be a solid solution of (R)- and (S)-enantiomers, with the conformation of the molecule adjusting to fit. The crystal structures show the stoichiometry of the both the racemate and (R)-enantiomer to be a hemihydrate. The phase isomorphically dehydrates below relative humidity values of 1% and above temperatures of 125 °C as assessed by water vapor sorption studies, powder X-ray diffraction, and SSNMR. Single-crystal diffraction detected significant changes in the unit cell dimensions as the phase dehydrated, which was related to the visual appearance of opacity in a single crystal of the (R)-enantiomer. The mechanism of water incorporation was further probed spectroscopically via exchange with deuterium, 17O-, and 18O-labeled water; the results suggest that dehydration and rehydration likely proceed via narrow tunnels in the crystal structure, combined with the formation of fissures in the crystal. 2H SSNMR experiments showed that the water does not engage in solid-state jump motion even at higher temperatures.
- Vogt, Frederick G.,Copley, Royston C. B.,Mueller, Ronald L.,Spoors, Grant P.,Cacchio, Thomas N.,Carlton, Robert A.,Katrincic, Lee M.,Kennady, James M.,Parsons, Simon,Chetina, Olga V.
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experimental part
p. 2713 - 2733
(2011/12/02)
-
- PROCESS FOR PREPARATION OF 1-(9H-CARBAZOL-4-YLOXY)-3-[[2-(2- METHOXYPHENOXY) ETHYL] AMINO]-2-PROPANOL
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The present invention relates to a process for preparation of l-(9H-carbazol-4-yloxy)-3- [[2-(2-methoxyphenoxy) ethyl] amino]-2-propanol and its salts comprising; a)reacting 1- (9H-carbazol-4-yloxy)-3-arylmethylamino-2-propanol or its 9-substituted derivatives with 2-(2-methoxyphenoxy)-haloethane; and b) deprotecting the resulting intermediate to obtain l-(9H-carbazol— 4— yloxy)-3-[[2-(2-methoxyphenoxy)ethyl] amino]-2-propanol in free form or its acid addition salt, which are pharmaceutically valuable compounds.
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Page/Page column 12
(2009/10/22)
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- AN IMPROVED PROCESS FOR PREPARATION OF CARVEDILOL INVOLVING HALOHYDRIN DERIVATIVE
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The present invention relates to a cost effective and industrially viable process for th preparation of Carvedilol involving halohydrin derivative
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- PROCESS FOR THE PREPARATION OF CARVEDILOL VIA SILYL PROTECTION OF SUBSTITUTED AMINE
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The invention provides new process for preparing Carvedilol by reaction of 4-(oxiran-2- yl-methoxy)-9H-carbazole and substituted silyl protected 2-(2-methoxy phenoxy)-ethylamine compound to give silyl protected Carvedilol intermediate. The silyl protected Carvedilol intermediate on desilylation gives Carvedilol. The invention also provides a novel substituted silyl protected 2-(2-methoxy phenoxy)-ethylamine as key intermediate for the preparation of Carvedilol.
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Page/Page column 5
(2009/10/22)
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- SYNTHESIS OF L-(CARBAZOL-4-YLOXY)-3-[[2-(O- METHOXYPHENOXY)ETHYL]AMINO]-2-PROPANOL
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The present invention relates to an improved process for the preparation of Carvedilol, wherein, the process involves the use of organic base in the reaction of 4-(oxirane-2ylmethoxy)-9H-carbazole with 2-(2-methoxyphenoxy) ethylamine in presence of a solvent. While preparing Carvedilol minimum amount of bis-impurity was obtained without purification.
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Page/Page column 6
(2010/01/30)
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- NOVEL CRYSTALLINE FORM OF CARVEDILOL DIHYDROGEN PHOSPHATE AND RELATED PROCESSES
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The present patent application relates to a novel crystalline form (Form S) of Carvedilol dihydrogen phosphate and a process for its preparation. It also relates to an improved process for the preparation of Carvedilol dihydrogen phosphate.
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Page/Page column 10
(2009/10/30)
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- PREPARATION OF 2-(2-ALKOXY PHENOXY) ETHYLAMINE, AN INTERMEDIATE OF CARVEDILOL AND TAMSULOSIN
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The present patent application relates to a process for the preparation of 2-(2-Alkoxy phenoxy) ethylamine or a salt thereof, which is a useful intermediate in the preparation of several active pharmaceutical ingredients including Carvedilol and Tamsulosin. It also provides 2-(2-methoxy phenoxy) ethylamine in solid form.
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Page/Page column 11
(2009/12/02)
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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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- A PROCESS FOR THE PREPARATION OF CARVEDILOL
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The present invention provides a more simplified, cost effective, commercially feasible process for the preparation of Carvedilol (I) comprising a step of reacting 4-hydroxy oarbazole (II) with epichlorohydrin and directly isolating the intermediate 4-(2,3- epoxypropoxy) carbazole (III) which on purification followed by reaction with 2-(2- methoxyphenoxy) ethylamine (IV) yields crude Carvedilol (I). The crude Carvedilol (I) is converted to pure product either through solvent crystallization (without salt formation) or through salt formation followed by salt cleavage and solvent crystallization resulting in highly pure (i.e. ICH grade) Carvedilol.
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Page/Page column 11-12
(2010/11/30)
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- Process for the preparation of carvedilol
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Disclosed herein is a process for preparation of carvedilol substantially free from its bis-impurity comprises the reaction of 4- (2,3- epoxypropoxy)carbazole and 2-(2-methoxyphenoxy)ethylamine in a polar aprotic solvent media; followed by isolation of carvediol from the reaction mass as an acid addition salt and subsequent conversion into pure carvedilol.
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Page/Page column 2-3; 6
(2008/06/13)
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- Process for the preparation of carvedilol and its salts
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Disclosed herein is a process for preparation of carvedilol substantially free from its bis-impurity comprises the reaction of 4-(2,3-epoxypropoxy)carbazole and 2-(2-methoxyphenoxy)ethylamine in a polar aprotic solvent media; followed by isolation of carvediol from the reaction mass as an acid addition salt and subsequent conversion into pure carvedilol.
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Page/Page column 4
(2008/06/13)
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- Ryanodine receptor inhibitors and methods relating thereto
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The present invention provides novel ryanodine receptor type 2 (RyR2) inhibitors and methods of their use in the treatment of cardiac conditions. In general, the RyR2 inhibitors of the present invention assist in the normalization of intracellular calcium homeostasis. In certain embodiments, the RyR2 inhibitors are store-overload-induced Ca2+ release (SOICR) inhibitors that minimally inhibit or do not inhibit Ca2+-induced Ca2+ release (CICR), thereby providing beneficial effects in cardiac therapy.
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Page/Page column 16
(2010/11/28)
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- PROCESS FOR THE PREPARATION OF HIGHLY OPTICAL PURE CARVEDILOL
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The present invention relates to a process for the efficient preparation of highly optical pure chiral carvedilol. According to the present invention, a chiral oxazolidin-2-one or oxazolidin-2-thione having formula 2, produced from the reaction of N-protected 2-(2-methoxyphenoxy)ethylamine with a chiral glycidol derivative is used as a key intermediate for the preparation of the chiral carvedilol. Specifically, the process for the preparation of the chiral carvedilol comprises a) reacting a compound of formula 2 with a halogenation agent, a sulfonation agent or a mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of formula 7, and b) subjecting the obtained compound of formula 7 to a deprotection reaction in a presence of an inorganic base to produce the targeted chiral carvedilol. The process of the present invention can be accomplished in a mild condition. The process neither requires any extraordinary purification procedure, nor involves decrease of optical purity. Therefore, the process of the present invention provides highly optical pure chiral carvedilol in simple and efficient manner.
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Page/Page column 2-26
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CARVEDILOL AND ITS ENANTIOMERS
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The present invention relates to a process for the preparation of carvedilol as well as of the optically active R and S enantiomers thereof and of mixtures of these enantiomers and, more particularly, relates to an improved process for the preparation of carvedilol and its enantiomers characterized by the use of ethyl acetate as reaction solvent.
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Page/Page column 5-7
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CARVEDILOL
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A process for the preparation of carvedilol of formula (I) (I) either in enantiomeric substantially pure form, or as an enantiomeric mixture, optionally as a pharmaceutically acceptable salt thereof, which process comprises reacting 2,3-eopxypropoxy carbazole of formula (II) (II) or the R or S enantiomer thereof, with N-[2-(2-methoxy-phenoxy)ethyl]-benzylamine of formula (V) (V) to yield benzyl carvedilol of formula (VI) (VI) which is debenzylated by catalytic hydrogenation to yield carvedilol of formula (I), either in enantiomeric substantially pure form, or as an enantiomeric mixture, and if desired reacting the thus formed carvedilol of formula (I) with an inorganic or organic acid to yield a pharmaceutically acceptable salt thereof, and/or, if desired, separating the enantiomers. The above process is characterised in that reaction of said 2,3-epoxypropoxy carbazole of formula (II) with said N-[2-(2-methoxy-phenoxy)ethyl]-benzylamine of formula (V) is carried out in water as the reaction medium. The present invention further provides carvedilol of formula (I) prepared by a process as described above, and pharmaceutical compositions containing the same and therapeutic uses thereof.
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Page/Page column 15
(2008/06/13)
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- PROCESS FOR MANUFACTURE OF RACEMIC CARVEDILOL
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The invention relates to a novel process for the manufacture of Carvedilol of high HPLC purity (>99.5 %) having individual impurity less than 0.1 %. The product is isolated from reaction mass as a salt with suitable organic acids which on further purification is converted into the free base i.e., Carvedilol.
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Page/Page column 8-9
(2010/02/13)
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- A NOVEL PROCESS FOR THE PREPARATION OF 1-(9H-CARBAZOL-4-YLOXY)-3-[[2-(-METHOXYPHENOXY)-ETHYL] AMINO]-PROPAN-2-OL
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The present invention discloses a novel process for preparation of carvedilol by using eco friendly solvents to obtain the said carvedilol in high purity. The said process comprises, reacting 4-hydroxy carbazole of formula (IV) with epichlorhydrin in presence of an organic solvent and a base at temperatures between 10°C - 30°C; further reacting the resultant 4-(2,3-epoxypropoxy)- carbazole of formula (II) with a salt of 2-(2-methoxyphenoxy) ethylamine of formula (III), preferably hydrochloride salt in presence of a base and a hydroxylic solvent at temperatures between 30°C - 90°C.
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Page/Page column 11
(2010/02/14)
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- A PROCESS FOR PREPARATION OF 1-[9H-CARBAZOL-4-YLOXY]- 3-[{2-(2-(-(METHOXY)PHENOXY)-ETHYL}-AMINO]-PROPAN-2-OL
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The present invention provides a process for preparation of 1-[9H-carbazol-4-yloxy]-3-[{2-(2-(methoxy)phenoxy)-ethyl}-amino]-propan-2-ol, a compound of formula 1 in racemic form or in the form of optically active R or S enantiomer or its pharmaceutically acceptable salt, comprising, reacting 4-(oxiranylmethoxy)-9H-carbazole, a compound of formula (2) or the R or S enantiomer thereof with a compound of formula (5), wherein R1 is benzyl or substituted benzyl group, in an aprotic organic solvent in presence of a catalyst to obtain a compound of formula (6), or the R or S enantiomer thereof, wherein R1 is as defined above. The resultant compound of formula (6) is subjected to debenzylation reaction by catalytic hydrogenation to obtain the compound of formula (1), if desired converting the resultant compound of formula (1) to a pharmaceutically acceptable salt thereof.
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Page 13; 17-18
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CARVEDILOL FORM-II
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The present invention provides a cost-effective, industrially feasible process for the manufacture of crystalline Carvedilol Form-II using novel Carvedilol salts comprising a step of reacting 4-(2,3-epoxy propoxy) carbazole (II) with 2-(2-methoxy phenoxy) ethyl amine (III) followed by acidification with mineral acid in presence of an organic solvent to yield acid addition salts, treatment of the said salts with base(s) in presence of organic solvent(s), water and isolation from the organic solvent(s) followed by crystallization from ethyl acetate.
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- PROCESS FOR PREPARATION OF CARVEDILOL
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The invention solves a new method of preparation of Carvedilol for pharmaceutical use. In the synthesis of Carvedilol a reaction of 4-(oxirane-2-ylmethoxy)-9H-arbazole (II) with 2-(2-methoxyphenoxy)ethylamine salts (IV) in the presence of a base, in an alcohol having the number of carbons C2 to C5 as a solvent, at an elevated temperature, is used. After processing of the crude reaction mixture crude Carvedilol is obtained, which is purified by crystallization from ethylacetate with an addition of activated carbon and the final substance is formulated by crystallization from ethylacetate.
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- Intermediate for the preparation of carvedilol
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A new intermediate having the formula (V) ???wherein X and Y are leaving groups; and R is phenyl optionally substituted with one or more electrophilic substituents; is disclosed. The new intermediate is useful for the preparation of carvedilol in a synthesis that avoids the use of any oxirane or similar hazardous reagents.
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- Carvedilol-galenics
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The invention relates to a process for the preparation of fast-dissolving pharmaceutical preparations from difficultly soluble active substances, wherein an aqueous suspension is made from active substance and one or more water-soluble adjuvants and then the resulting aqueous suspension is processed, with removal of the water, by methods conventional per se, to form solid pharmaceutical preparations. The invention also relates to fast-dissolving pharmaceutical preparations of active substances having a dissolution rate of at least 70% after 30 minutes, prepared in accordance with the process of the invention.
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- Process for preparing heterocyclic indene analogs
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A process for the preparation heterocyclic indene analogs, especially with the preparation of 4-hydroxycarbazole or N-protected 4-hydroxycarbazole, involves cyclocarbonylation followed by saponification. This process avoids high temperatures and high catalyst loadings.
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- Carvedilol
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This invention relates to an improved process of preparing carvedilol, as well as a new crystalline hydrate and solvate and forms of carvedilol, processes for the manufacture thereof, and pharmaceutical compositions thereof.
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- Process for the preparation of optically-active carbazole derivatives, new R- and S-carbazole derivatives and pharmaceutical compositions containing these compounds
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A process for the preparation of S- or R-carbazole derivatives of the general formula: STR1 in which R is an unsubstituted or substituted amino radical and pharmacologically acceptable salts, by either reacting R-(-)-epichlorohydrin (for the S-carbazole derivative); or reacting an S-epoxide derivative of the general formula: STR2 in which R1 is the residue of a substituted sulphonic acid derivative (for the R-carbazole derivative); with 4-hydroxycarbazole and then with ammonia or a substituted amine of the general formula RH, and recovering the compound or converting it to a pharmacologically acceptable salt. The new R-(+)- and S(-)-carbazole derivatives provided by the inventive process have unexpected beta blocking and vasodilatory properties and are useful in pharmaceutical compositions. R-(+)-carbazole derivatives are also useful for the treatment of glaucoma.
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