Synthesis of Ranolazine Metabolites and Their Anti-myocardial Ischemia Activities

Abstract

Angina pectoris is one of the most frequent clinical syndromes associated with ischemic heart diseases. The incidence of this disease is increasing with the improvement of living standard and the change of the mode of life. It has been generally accepted that an efficient therapeutic approach to ischemic heart diseases is to improve the myocardial oxygen balance between supply and demand in the ischemic heart, by either increasing coronary blood flow or decreasing cardiac mechanical function, or both. The traditional anti-anginal drugs are nitrates, b-blockers and calcium channel blockers, which are thought to improve the myocardial oxygen balance with changes in hemodynamic parameters. But these drugs also bring further injury to the weak cardiac function. So researchers are trying to find more efficient means with fewer side effects to prevent and treat myocardial ischemia.Metabolism modulation is a novel way for the treatment of angina pectoris.1) Ranolazine (Fig. 1) is a piperazine derivative developed by Syntex Laboratories, which has been shown to have anti-ischemic action.2-5) It's a partial fatty acid oxidation (pFOX) inhibitor. Its mechanism has not been fully understood. The possible mechanism involves modulation of the metabolism of myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation.2,6-9) Ranolazine is thought to switch substrate utilization from fatty acids to glucose to improve the efficiency 1218 Vol. 57, No. 11 The anti-anginal drug Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine. Synthesis of Ranolazine Metabolites and Their Anti-myocardial Ischemia Activities

Local Anesthetics via Multicomponent Reactions

“…In this way, we have gained access to novel derivatives in a more straightforward and efficient way than the classic, linear synthesis might be able to deliver. Next, we have demonstrated the potential of our synthetic strategy by the synthesis of the API ranolazine, [33,34] which is partially active due to the nonselective blockade of voltage‐gated sodium channels. Certain drugs in this category bear the specific aminoamide substructure that we are targeting and are employed as antiarrhythmic (AAD) or anti‐epileptic (AED) drugs (Scheme 2, D) [11,35] .…”

“…It was approved in 2006 and was the first drug in a novel class to be approved in the US in more than 20 years for the treatment of this disease condition [46] . Ranolazine can be approached by MCR chemistry, following the aforementioned strategy [33,47] . Our retrosynthetic plan was based on the substructure of the caine 6 , easily accessed by our method.…”

“…[46] Ranolazine can be approached by MCR chemistry, following the aforementioned strategy. [33,47] Our retrosynthetic plan was based on the substructure of the caine 6, easily accessed by our method. An alkylation would deliver the final compound (Scheme 4).…”