Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. I. 2-Phenylthiazolidine-3-thiocarboxamides.

Abstract

A series of novel 2-phenylthiazolidine-3-thiocarboxamides (II) was synthesized and tested for positive inotropic activity in the isolated guinea pig heart and in anesthetized dogs. Reaction of the benzaldehydes (VI, XI, XIV and XV) with cysteamine followed by treatment with isothiocyanates readily gave II. Structure-activity relationships were investigated by varying the structural parameters. N-Methyl-2 -phenylthiazolidine -3-thiocarboxamides having an ortho substituent such as a Me or OMe group exhibited significant positive inotropic action, which was not blocked by propranolol.Among the various ortho-alkoxyphenyl derivatives synthesized, the 2-(2-(3-(4-phenylpiperazino)propoxy)phenyl) derivative (I67) was found to exhibit more potent and longerlasting activity than amrinone without any significant effect on heart rate or blood pressure.Keywords 2 -phenylthiazolidine -3-thiocarboxamide ; positive inotropic activity; structureactivity relationship; cardiotonic agent Cardiac glycosides and sympathomimetic agents have been used for the treatment of congestive heart failure (CHF) for many years. Although cardiac glycosides such as digitoxin and digoxin have been the principal agents used for CHF, their use is limited by arrhythmogenic liability and very narrow therapeutic index. The use of sympathomimetic agents such as dobutamine and dopamine is also limited because of their chronotropic liability and oral ineffectiveness.1,2) Thus, the absence of safe, orally effective-, positive inotropic agents for the treatment of CHF has stimulated the development of several new nonglycoside, nonsympathomimetic, cardiotonic agents such as amrinone, milrinone, sulmazole, and fenoximone.3)In the course of our studies on new antiulcer agents, 2-phenylthiazolidine-3-thiocarboxamides (I), conformationally restricted analoguee4) of metiamide, have been synthesized. Unexpectedly, in the isolated guinea pig heart, these compounds were found to display positive inotropic activity which was not blocked by propranolol. In view of the structural novelty of this class of compounds as cardiotonic agents, we have synthesized a large number of derivatives by varying the structural parameters. In this paper, we report the synthesis and cardiotonic activity of a series of new 2-phenylthiazolidines represented by the general formula II and related compounds.Chart I

Predicting the Cis−Trans Dichloro Configuration of Group 15−16 Chelated Ruthenium Olefin Metathesis Complexes: A DFT and Experimental Study

“…The organic phase was dried with sodium sulfate and evaporated, and the residue was purified by column chromatography (hexane 200:3 ether), affording a yellow oil after evaporation (0.765 gr, 27%). 1 H-NMR and 13 C-NMR (200 and 50 MHz, CDCl 3 ) in accordance to literature . GC−MS: m / z M + Calcd 177.12, found 177.10.…”

“…1 H-NMR and 13 C-NMR (200 and 50 MHz, CDCl 3 ) in accordance to literature. 33 GC-MS: m/z M þ Calcd 177.12, found 177.10.…”

Unlocking the Antiviral Arsenal: Multiparametric Optimization of Small-Molecule Inhibitors against RSV and hCoV-229E

“…Since benzylic alcohol 23c was not commercially available, it was synthesized from the corresponding aldehyde 22c via reduction with sodium borohydride, following a known method. 46 Aldehyde 22c had been prepared adapting a literature-known procedure 47 . Benzylic halogenides were either commercially available (27g, 27l, 27n p, 27r t, 27am) or synthesized from the corresponding benzylic alcohols or tolyl derivatives 21/22 following common methods 48,49 .…”

Biomimetic total syntheses of renifolin F and antiarone K

“…8 In order to achieve better results, we have implemented an alternative approach based on oxazoline directed metalation to attain the required regiochemistry and to avoid unwanted isomers (Scheme S1, ESI †). [9][10][11][12][13][14] This approach has furnished an improved overall yield of 35%. The yield was further enhanced finally to an impressive overall 64% by a novel approach (Scheme 2).…”