The inhibition of the Na+/H+ exchanger during cardiac ischemia and reperfusion has been shown to be beneficial for the preservation of the cellular integrity and functional performance. The aim of the present investigation was to come up with potent and selective benzoylguanidines as NHE inhibitors for their use as an adjunctive therapy in the treatment of acute myocardial infarction. During the course of our investigations it became clear that the substitution ortho to the acylguanidine was of crucial importance for the potency of the compounds. 4-Chloro- and 4-fluoro-2-methylbenzoic acids 6 and 7 were prepared using the directed ortho metalation technique with the carboxylic acid as the directing group. With the LDA/methyl iodide system the 2-methyl group could be extended to an ethyl group. 4-Alkyl groups were inserted by the palladium-catalyzed cross-coupling reaction into the 4-bromo-2-methylbenzoic acid methyl ester (20). Starting with benzoic acids 6-19, the methylsulfonyl group was introduced by a sequence of standard reactions (sulfochlorination, reduction, and methylation). 4-Aryl derivatives 68-75 were synthesized by the palladium-catalyzed Suzuki reaction. A large number of nucleophilic displacement reactions in the 4-position were carried out with S-, O-, and N-nucleophiles as well as with the cyano and trifluoromethyl group. Using the ester method, acid chlorides, or Mukaiyama's procedure, the 5-(methylsulfonyl)benzoic acid derivatives were finally converted to the (5-(methylsulfonyl)benzoyl)guanidines 165-267 with excessive guanidine. In some cases nucleophilic substitutions with pyridinols and piperidine derivatives were carried out at the end of the reaction sequence with the 4-halo-N-(diaminomethylene)-5-(methylsulfonyl)-benzamides. Variations in the 4-position were most reasonable, but the volume of the substituents was of crucial importance. Substitution in the 3- and particularly in the 6-position led to considerable worsening of the inhibitory effects of the Na+/H+ exchanger. The 2-methyl compounds, however, showed without exception higher in vitro activities than their respective demethyl counterparts as they are exemplified by the reference compounds 266 and 267, obviously caused by a conformational restriction of the acylguanidine chain. The development compound (2-methyl-5-(methylsulfonyl)-4-pyrrolobenzoyl)guanidine, methanesulfonate (246) is a NHE-1 subtype specific NHE inhibitor, being 27-fold more potent toward the NHE-1 than the NHE-2 isoform. 246 was found to act cardioprotectively not only when given before an experimentally induced ischemia, but also curatively after the onset of symptoms of acute myocardial infarction when given prior to the induction of reperfusion.

中文翻译：

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（2-甲基-5-（甲基磺酰基）苯甲酰基）胍Na + / H +反向转运抑制剂。

已显示在心脏缺血和再灌注期间抑制Na + / H +交换剂有利于保存细胞完整性和功能性能。本研究的目的是提出有效和选择性的苯甲酰胍作为NHE抑制剂，以用作辅助治疗急性心肌梗塞。在我们的研究过程中，很明显，邻位酰基胍的取代对于化合物的效力至关重要。使用定向原位金属化技术，以羧酸为导向基团，制备了4-氯-和4-氟-2-甲基苯甲酸6和7。使用LDA /甲基碘系统，可以将2-甲基延伸至乙基。通过钯催化的交叉偶联反应将4-烷基插入4-溴-2-甲基苯甲酸甲酯（20）。从苯甲酸6-19开始，通过一系列标准反应（磺基氯化，还原和甲基化）引入甲基磺酰基。通过钯催化的Suzuki反应合成了4-芳基衍生物68-75。用S-，O-和N-亲核试剂以及氰基和三氟甲基进行了4-位的大量亲核取代反应。使用酯法，酰氯或Mukaiyama方法，最终将5-（甲基磺酰基）苯甲酸衍生物与过量的胍转化为（5-（甲基磺酰基）苯甲酰基）胍165-267。在某些情况下，在与4-卤代-N-（二氨基亚甲基）-5-（甲基磺酰基）-苯甲酰胺的反应序列结束时，用吡啶醇和哌啶衍生物进行亲核取代。4-位的变化是最合理的，但是取代基的体积至关重要。在3-位，特别是在6-位上的取代导致Na + / H +交换剂的抑制作用显着恶化。然而，2-甲基化合物毫无例外地显示出比它们各自的脱甲基对应物更高的体外活性，因为它们明显由酰基胍链的构象限制所引起，如参考化合物266和267所示。显影化合物（2-甲基-5-（甲基磺酰基）-4-吡咯并苯甲酰基）胍，甲磺酸盐（246）是一种NHE-1亚型特异性NHE抑制剂，对NHE-1的效力是NHE-2同种型的27倍。发现246不仅在实验诱导的缺血之前给予，而且在急性心肌梗塞症状发作后（在诱导再灌注之前给予）治愈后，也具有心脏保护作用。