Heterocyclically substituted benzoylguanidines, process for...

Details Heterocyclically substituted benzoylguanidines, process for... Heterocyclically substituted benzoylguanidines, process for...

2003-01-28

2003-09-09

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S399000, C548S309700, C548S336500

Reexamination Certificate

active

06617344

ABSTRACT:

This application claims the benefit of foreign priority under 35 USC §119 to German patent application no. 19950898.4, filed on Oct. 22, 1999, the contents of which are incorporated by reference herein.
The invention relates to heterocyclically substituted benzoylguanidines of the formula I
in which:
R(1) is —(CF
2
)
c
—CF
3
;
c is zero, 1, 2 or 3;
R(2) is (C
1
-C
9
)-heteroaryl, linked via C or N, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(3) is H, F, Cl, Br, I, CN, NO
2
or (C
1
-C
8
)-alkyl;
R(4) is H, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, F, Cl, Br, I, CN or —(CF
2
)
o
—CF
3
;
o is zero, 1 or 2;
and their pharmaceutically tolerable salts.
Preferred compounds of the formula I are those in which:
R(1) is trifluoromethyl;
R(2) is imidazolyl or benzimidazolyl, linked via C or N, each of which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(3) is H, F, Cl or (C
1
-C
4
)-alkyl;
R(4) is H, (C
1
-C
4
)-alkyl, (C1-C
4
)-alkoxy, F, Cl or CF
3
;
and their pharmaceutically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
R(1) is trifluoromethyl;
R(2) is imidazolyl or benzimidazolyl, linked via N, each of which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
and methoxy;
R(3) is H;
R(4) is H, methyl, methoxy, Cl or CF
3
;
and their pharmaceutically tolerable salts.
(C
1
-C
9
)-heteroaryl is understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups-are replaced by S, NH or O (with formation of a five-membered aromatic ring). In addition, one or both atoms of the condensation site of bicyclic radicals (such as in indolizinyl) can also be nitrogen atoms.
(C
1
-C
9
)-heteroaryl is in particular furanyl, thienyl, pyrrolyl, imidazolyl, benzimidazole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl; very particularly imidazolyl or benzimidazolyl.
If one of the substituents R(1) to R(4) contains one or more asymmetric centers, these can be either of the S or R configuration. The compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof.
The designated alkyl radicals can be either straight-chain or branched.
The invention furthermore relates to a process for the preparation of the compound 1, which comprises
reacting compounds of the formula II
in which R(1) to R(4) have the meaning indicated and L is an easily nucleophilically substitutable leaving group, with guanidine.
The activated acid derivatives of the formula II, in which L is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the underlying carbonyl chlorides (formula II, L═Cl), which in turn can be prepared in a manner known per se from the underlying carboxylic acids (formula II, L═OH), for example using thionyl chloride. In addition to the carbonyl chlorides of the formula II (L═Cl), further activated acid derivatives of the formula II can also be prepared directly from the underlying benzoic acid derivatives (formula II, L═OH) in a manner known per se, such as, for example, the methyl esters of the formula II where L═OCH
3
by treating with gaseous HCl in methanol, the imidazolides of the formula II by treating with carbonyidiimidazole [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II using Cl—COOC
2
H
5
or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzoic acids using dicyclohexylcarbodiimide (DCC) or using O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are indicated stating source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula II with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. Methanol, isopropanol and THF from 20° C. up to the boiling temperature of these solvents have proven suitable here in the reaction of the methyl benzoates (II, L═OMe) with guanidine. Most reactions of compounds II with salt-free guanidine were advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane and dioxane. However, using a base such as, for example, NaOH, water can also be used as a solvent in the reaction of II with guanidine.
If L═Cl, the reaction is advantageously carried out with addition of an acid scavenger, e.g. in the form of excess guanidine for removing the hydrohalic acid.
Some of the underlying benzoic acid derivatives of the formula II are known and described in the literature. The unknown compounds of the formula II can be prepared by methods known from the literature. The benzoic acids obtained are reacted to give compounds I according to the invention according to one of the process variants described above.
The introduction of some substituents into the 2, 3, 4 and 5 positions is possible by methods, known from the literature, of palladium-mediated cross-coupling of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes or organocopper or -zinc compounds.
In general, benzoylguanidines I are weak bases and can bind acid with formation of salts. Possible acid addition salts are salts of all pharmacologically. tolerable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
European Patents EP 602 523 (HOE 92/F 405) and EP 640 588 (HOE 93/F 254) describe benzoylguanidines of similar constitution, which also carry fluorinated alkyl substituents in the 5 position in addition to a multiplicity of other substituents R(1), and can also carry (C
1
-C
9
) heteroaryls in the 4 position in addition to a multiplicity of substituents.
However, it was not to be foreseen that these compounds having fluoroalkyl and hetaryl substitution especially would display an outstanding action.
Surprisingly, the compounds according to the invention are NHE inhibitors which additionally inhibit the noninactivating sodium channel (veratridine-activatable sodium channel) induced during ischemia, to which the outstanding action can be attributed. As a result of their pharmacological properties, the compounds are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment, and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, as a result of inhibition of the cellular Na
+
/H
+
exchange mechanism, as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. This relates to their use as phar

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