M. Baumgarth et al., (2-METHYL-5-(METHYLSULFONYL)BENZOYL)GUANIDINE NA+ H+ ANTIPORTER INHIBITORS/, Journal of medicinal chemistry, 40(13), 1997, pp. 2017-2034
The inhibition of the Na+/H+ exchanger during cardiac ischemia and rep
erfusion has been shown to be beneficial for the preservation of the c
ellular integrity and functional performance. The aim of the present i
nvestigation was to come up with potent and selective benzoylguanidine
s as NHE inhibitors for their use as an adjunctive therapy in the trea
tment of acute myocardial infarction. During the course of our investi
gations it became clear that the substitution ortho to the acylguanidi
ne was of crucial importance for the potency of the compounds. 4-Chlor
o- and 4-fluoro-2-methylbenzoic acids 6 and 7 were prepared using the
directed ortho metalation technique with the carboxylic acid as the di
recting group. With the LDA/methyl iodide system the 2-methyl group co
uld be extended to an ethyl group. 4-Alkyl groups were inserted by the
palladium-catalyzed cross-coupling reaction into the 4-bromo-2-methyl
benzoic acid methyl ester (20). Starting with benzoic acids 6-19, the
methylsulfonyl group was introduced by a sequence of standard reaction
s (sulfochlorination, reduction, and methylation). 4-Aryl derivatives
6875 were synthesized by the palladium-catalyzed Suzuki reaction. A la
rge number of nucleophilic displacement reactions in the 4-position we
re carried out with S-, O-, and N-nucleophiles as well as with the cya
no and trifluoromethyl group. Using the ester method, acid chlorides,
or Mukaiyama's procedure, the 5-(methylsulfonyl)benzoic acid derivativ
es were finally converted to the (5-(methylsulfonyl)benzoyl)guanidines
165-267 with excessive guanidine. In some cases nucleophilic substitu
tions with pyridinols and piperidine derivatives were carried out at t
he end of the reaction sequence with the N-(diaminomethylene)-5-(methy
lsulonyl)-benzamides. Variations in the 4-position were most reasonabl
e, but the volume of the substituents was of crucial importance. Subst
itution in the 3- and particularly in the 6-position led to considerab
le worsening of the inhibitory effects of the Na+/H+ exchanger. The 2-
methyl compounds, however, showed without exception higher in vitro ac
tivities than their respective demethyl counterparts as they are exemp
lified by the reference compounds 266 and 267, obviously caused by a c
onformational restriction of the acylguanidine chain. The development
compound thyl-5-(methylsulfonyl)-4-pyrrolobenzoyl)guanidine methanesul
fonate (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 in
duced ischemia, but also curatively after the onset of symptoms of acu
te myocardial infarction when given prior to the induction of reperfus
ion.