- Compounds for treating anginapectoris, preparation method and application
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The invention relates to the field of medicinal chemistry, and particularly relates to compounds I, II and III corporation ranolazine derivatives or pharmaceutically acceptable salt thereof, a preparation method of the compounds, a medicinal composition containing the compounds and medical application of the compounds. Pharmacodynamic experiments prove that the compounds disclosed by the invention have an effect of treating anginapectoris. (the compounds are shown in the specification).
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Paragraph 0039; 0040; 0047; 0048
(2017/09/01)
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- In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drug
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An in silico modelling based biocatalytic approach for the synthesis of drugs and drug intermediates in enantiopure forms is a rationalized methodology over the organo-chemical routes. In this study, enzyme-ligand based docking was carried out using (RS)-ranolazine, as the model drug for the screening of a suitable biocatalyst for the kinetic resolution of the racemic drug. The differential interaction of the two enantiomers with the lipase was analyzed on the basis of docking score and H-bond interaction with the amino acid residues, which helped to define the trans-esterification mechanism. Ranolazine [N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy)-3-(2-methoxyphenoxy)propylpiperazin-1-yl]acetamide], an anti-anginal drug, significantly reduces the frequency of anginal attack and has also been used for the treatment of ventricular arrhythmias, and bradycardia. Various lipases were examined via computational as well as wet lab screening and Candida antartica lipase in the form of CLEA was the most efficient one for the (S)-selective kinetic resolution of (RS)-ranolazine, with highest conversion and enantiomeric excess. This is the first report of the chemo-enzymatic synthesis of (S)-ranolazine where the whole drug molecule was used for lipase catalysis. The present study showed that the combination of in silico studies and a classical wet lab approach could change the paradigm of biocatalysis.
- Sawant, Ganesh,Ghosh, Saptarshi,Banesh, Sooram,Bhaumik, Jayeeta,Chand Banerjee, Uttam
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p. 49150 - 49157
(2016/06/09)
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- "All water chemistry" for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine
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A novel strategy of 'all water chemistry' is reported for a concise total synthesis of the novel class anti-anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the crucial stages of the synthesis are promoted by water and led to the development of new water-assisted chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection, and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in performing the reactions in water have been demonstrated by performing the respective reactions in organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergistic electrophile and nucleophile dual activation role of water. The new 'all water' strategy offers two green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall yields, respectively, and which are devoid of the formation of the impurities that are generally associated with the preparation of ranolazine following the reported processes.
- Kommi, Damodara N.,Kumar, Dinesh,Chakraborti, Asit K.
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p. 756 - 767
(2013/03/29)
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