EP1226124A1

EP1226124A1 - Heterocyclically substituted benzoylguanidine, method for the production thereof, the use thereof as a medicament or means of diagnosis and a medicament containing the same

Info

Publication number: EP1226124A1
Application number: EP00966135A
Authority: EP
Inventors: Andreas Weichert; Udo Albus; Hans-Willi Jansen; Heinz-Werner Kleemann; Hans-Jochen Lang
Original assignee: Aventis Pharma Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1999-10-22
Filing date: 2000-10-07
Publication date: 2002-07-31
Also published as: US20010049446A1; US20020099222A1; AR026179A1; CN1373757A; AU7663000A; CZ20021218A3; WO2001030761A1; JP2003512457A; EE200200142A; US6617344B2; US20030139607A1; DE19950898A1

Abstract

The invention relates to heterocyclically substituted benzoylguanidine of formula (I), wherein the substituents R(1) to R(4) have the meanings given in the claims. These compounds (I) are suitable for use as anti-arrhythmic medicaments containing a cardio-protective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris. The benyozlguanadines also preventively inhibit the pathophysiological processes arising from ischaemically induced traumas, in particular during the triggering of ischaemically induced cardiac arrhythmia.

Description

description

HETEROCYCLICALLY SUBSTITUTED BENZOYLGUANIDINE AND THEIR USE AS CLOSE INHIBITORS

The invention relates to heterocyclically substituted benzoylguanidines of the formula I.

in which mean:

R (1) - (CF ₂ ) c-CF ₃ ; c zero, 1, 2 or 3;

R (2) (C- | -Cg) - heteroaryl, linked via C or N, which is unsubstituted or substituted with 1 - 3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino,

Methylamino and dimethylamino; R (3) H, F, Cl, Br, I, CN, NO ₂ or (C <| -C8) alkyl,

R (4) H, (C1-C4) alkyl, (C <| -C) alkoxy, F, Cl, Br, I, CN or - (CF ₂ ) ₀ -CF ₃ ; o zero, 1 or 2; and their pharmaceutically acceptable salts.

Preferred compounds of the formula I are those in which: R (1) trifluoromethyl;

R (2) imidazolyl or benzimidazolyl, linked via C or N, which are unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy,

Amino, methylamino and dimethylamino; R (3) H, F, Cl or (C <| -C ₄ ) alkyl; R (4) H, (C-1-C4) alkyl, (C-1-C4) alkoxy, F, Cl or CF _3; and their pharmaceutically acceptable salts.

Compounds of the formula I are very particularly preferred in which: R (1) trifluoromethyl;

R (2) imidazolyl or benzimidazolyl, linked via N, which are unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, CH3 and methoxy;

R (3) H; R (4) H, methyl, methoxy, Cl or CF3; and their pharmaceutically acceptable salts.

Under (C1-C9) - heteroaryl are understood residues that differ from phenyl or

Derive naphthyl in which one or more CH groups are replaced by N and / or in which at least two adjacent CH groups (to form a five-membered aromatic ring) are replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.

As (C1-C9) heteroaryl, furanyl, thienyl, pyrrolyl, imidazolyl,

Benzimidazole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, c especially imidazolyl or benzimidazolyl.

If one of the substituents R (1) to R (4) contains one or more centers of asymmetry, these can be configured both S and R. The compounds can exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.

The designated alkyl radicals can be either straight-chain or branched. The invention further relates to a process for the preparation of compound I, characterized in that

Compounds of formula II

wherein R (1) to R (4) have the meaning given and L represents an easily nucleophilically substitutable leaving group, reacted with guanidine ,.

The activated acid derivatives of the formula II, in which L is an alkoxy, preferably a methoxy, a phenoxy group, phenylthio, methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the underlying carboxylic acid chlorides (formula II, L = Cl), which in turn can in turn be prepared in a manner known per se from the underlying carboxylic acids (formula II, I = OH), for example with thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II (L = Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the underlying benzoic acid derivatives (formula II, L = OH), such as, for example, the methyl esters of the formula II L = OCH3 by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with CI-COOC2H5 or tosyl chloride in

Presence of triethylamine in an inert solvent, as well as the activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with 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 row suitable methods for the production of activated carboxylic acid derivatives

Formula II are given in J. March, Advanced Organic, citing source literature

Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

An activated carboxylic acid derivative of the formula II is reacted with guanidine in a manner known per se in a protic or aprotic polar but inert organic solvent. In the reaction of the methyl benzoates (II, L = OMe) with guanidine, methanol, isopropanol and THF from 20 ° C. to the boiling point of these solvents have proven successful. Most of the reactions of compounds II with salt-free guanidine were advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane and dioxane. However, water can also be used as a solvent in the reaction of II with guanidine using a base such as NaOH.

If L = Cl, one works advantageously with the addition of an acid scavenger, e.g. B. in the form of excess guanidine for setting 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 formula II can be prepared by methods known from the literature. The benzoic acids obtained are converted into compounds I according to the invention by one of the process variants described above.

The introduction of some substituents in the 2-, 3-, 4- and 5-position succeeds through literature-known methods of palladium-mediated cross-coupling of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes or organocopper or zinc compounds.

Benzoylguanidines I are generally weak bases and can bind acid with the formation of salts. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates,

Methyl sulfonates, p-toluenesulfonates.

European patents EP 602 523 (HOE 92 / F 405) and EP 640 588 (HOE 93 / F 254) describe benzoylguanidines of a similar constitution which, in the 5-position, also carry fluorinated alkyl substituents in addition to a large number of other substituents R (1) , and in the 4-position can also carry (C ₁ -C ₉ ) heteroaryls in addition to a large number of substituents. However, it was not foreseeable that these compounds with fluoroalkyl and hetaryl substitution would have an outstanding effect.

Surprisingly, the compounds according to the invention are NHE inhibitors which additionally inhibit the non-inactivating sodium channel (veratridine-activatable sodium channel) induced during ischemia, whereupon the outstanding effect can be attributed. As a result of their pharmacological properties, the compounds are outstandingly suitable as antiarrhythmic medicaments with cardioprotective components for the prevention of infarction and the treatment of infarction, and for the treatment of angina pectoris, and they also prevent or inhibit the pathophysiological processes in the occurrence of ischemically induced damage, particularly when triggering ischemically induced cardiac arrhythmias greatly decrease. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention, owing to inhibition of the cellular Na + / H + exchange mechanism, can be used as a medicament for the treatment of all acute or chronic damage caused by ischemia or diseases which are primarily or secondarily induced thereby. This affects their use as medicines for surgery, e.g. B. in organ transplants, the compounds can be used both for protecting the organs in the donor before and during removal, for protecting removed organs, for example during treatment with or their storage in physiological bath fluids, as well as for the transfer into the recipient organism , The compounds are also valuable, protective drugs when performing angioplasty, such as heart surgery also on peripheral vessels. Corresponding to their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular the CNS, whereby they are suitable, for example, for the treatment of stroke or brain edema. In addition, the compounds of formula I according to the invention are also suitable for the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of the formula I according to the invention are notable for a strong inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of smooth vascular muscle cells. The compounds of the formula I are therefore useful therapeutic agents for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, agents for late diabetic complications,

Cancer diseases, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy can be used.

The compounds according to the invention are effective inhibitors of the cellular sodium proton antiporter (Na + / H + exchanger), which is increased in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in cells which are easily accessible, for example in erythrocytes, platelets or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for determining and differentiating certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of the formula I are for preventive therapy to prevent the genesis of high blood pressure, for example essential hypertension.

Medicaments which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred one Application depends on the particular appearance of the disease. The

Compounds I can be used alone or together with pharmaceutical auxiliaries

Application, both in veterinary and in

Human medicine.

The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulation on the basis of his specialist knowledge. In addition to solvents,

Gelling agents, suppository basics, tablet excipients, and others

Active substance carriers can, for example, antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives,

Solubilizers or dyes are used.

For an oral form of use, the active compounds are mixed with the suitable additives, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions. As inert carriers such. As gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used. The preparation can take place both as dry and as moist granules. Vegetable or animal oils, such as sunflower oil or cod liver oil, are suitable as oily carriers or as solvents.

For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries. As solvents such. B. in question: water, physiological saline or alcohols, e.g. As ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for. B. solutions, suspensions or emulsions of Active ingredient of formula I in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents.

If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and a propellant. Such a preparation usually contains the active ingredient in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3% by weight.

The dosage of the active ingredient of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; also on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

The average daily dose of a compound of the formula I in a patient weighing approximately 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, to at most 10 mg / kg, preferably 1 mg / kg body weight. In acute outbreaks of the disease, such as immediately after suffering a heart attack, even higher and, above all, more frequent doses may be necessary, e.g. B. up to 4 single doses per day. Especially with i. v. Application, for example in an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.

Experimental part

General instructions for the preparation of benzoyl guanidines (I) Variant A: from benzoic acids (II, L = OH)

1.0 eq. the benzoic acid derivative of the formula II is dissolved or suspended in anhydrous THF (5 ml / mmol) and then mixed with 1.1 eq. Carbonyldiimidazole. After stirring for 2 hours at RT, 5.0 eq. Guanidine introduced into the reaction solution. After stirring overnight, the THF is distilled off under reduced pressure (Rotavapor), water is added and the mixture is made up with 2N HCl pH 6 to 7 and the corresponding benzoylguanidine (formula I) is filtered off. The benzoylguanidines thus obtained can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids.

General instructions for the preparation of benzoyl guanidines (I) Variant B: from benzoic acid alkyl esters (II, L = O-alkyl)

1.0 eq. of the benzoic acid alkyl ester of the formula II and 5.0 eq. Guanidine (free base) are dissolved in isopropanol or suspended in THF and heated to reflux until complete conversion (thin-film control) (typical reaction time 2 to 5 h). The solvent is distilled off under reduced pressure (Rotavapor), taken up in EA and washed 3 × with NaHC03 solution. It is dried over Na2S04, the solvent is distilled off in vacuo and on silica gel with a suitable mobile solvent, for. B. EE / MeOH 5: 1 chromatographed. (Salt formation compare variant A)

Experimental part

Abbreviation:

DCI Direct chemical ionization

DMF N, N-dimethylformamide

ES + electrospray ionization eq equivalents

EtOH ethanol h hour

HCI hydrogen chloride

LM solvent

MeOH methanol

NaOH sodium hydroxide solution

RF reflux RT room temperature

Mp melting point

THF tetrahydrofuran

TMEDA tetramethylethylenediamine

Example 1: 4-N-Imidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride: Colorless crystals, mp. 244-248 ° C.

Synthetic route: a) 4-N-imidazolyl-3-trifluoromethyl-benzoylguanidine from 4-fluoro-3-trifluoromethyl-benzoic acid by activation with 1.2 eq carbonyldiimidazole in THF at 50 ° C. After stirring for 1.5 hours, 3 eq of guanidine and 2 eq of imidazole are added, then the mixture is stirred for a further 7 hours at 120 ° C. in DMF and then worked up in water. The product is obtained as a solid and is filtered off, mp. 245-250 ° C, M ⁺ + H = 298 (DCI).

b) 4-N-imidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride from 1 a) with 0.5 N EtOH / HCl at RT, the solid is filtered off with suction.

Example 2: 4-N- (4'-methyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride Colorless crystals, mp. 236 ° C.

Synthesis route: a) 4-fluoro-3-trifluoromethyl-benzoylguanidine from methyl 4-fluoro-3-trifluoromethyl-benzoate by guanidation with 3 eq guanidine in THF for 2 h at the RF, followed by aqueous working up and suction removal of the solid, mp. 165 ° C, M ⁺ + H = 250 (ES ⁺ ).

b) 4-N- (4'-methyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine from 2 a) by nucleophilic exchange of the fluorine atom with 2 eq 4-methyl-imidazole in the presence of 6 eq Potassium carbonate in DMF with heating at 100 ° C for 10h. After aqueous work-up, column chromatographic purification follows, M ⁺ + H = 312 (ES ⁺ ).

c) 4 -N- (4'-methyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride from 2 b) with ether / HCl at RT, solid is filtered off with suction.

Example 3: 4-N- (4 ', 5'-dimethyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 259-262 ° C, M ⁺ + H = 326 (ES ⁺ ).

Synthetic route: a) 4-N- (4 ', 5'-dimethyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine from 2 a) by nucleophilic exchange analogously to 2 b), using 4,5-dimethyl-imidazole. After working up with water, the solid is filtered off with suction, mp. 264 ° C. (dec.), M ⁺ + H = 326 (ES ⁺ ).

b) 4-N- (4 ', 5'-dimethyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride from 3 a) by hydrochloride formation analogously to 2 c).

Example 4: 4-N-benzimidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 183 ° C., M ⁺ + H = 348 (ES ⁺ ).

Synthesis route: a) 4-N-benzimidazolyl-3-trifluoromethyl-benzoylguanidine from 2 a) analogously to 3 a) using benzimidazole. After aqueous work-up, the column is purified by chromatography on silica gel with dichloromethane / methanol (20: 1).

b) 4-N-Benzimidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride from 4 a) analogously to 2 c). Example 5: 4-N- (5 ', 6'-dichlorobenzimidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 226-227 ° C.

Synthesis route: a) 4-Fluoro-3-trifluoromethylbenzoic acid methyl ester from 4-fluoro-3-trifluoromethylbenzoic acid using 1.1 eq carbonyl-bis-imidazole in THF and stirring for 2 h at RT and subsequent addition of an excess of methanol. After a further 2 h at RT an aqueous work-up follows, extraction with ethyl acetate yields a yellowish oil, M ⁺ + H = 223 (DCI).

b) 4-N- (5 ', 6'-dichlorobenzimidazolyl) -3-trifluoromethylbenzoic acid from 5 a) analogously to 2b) using 2 eq 5,6-dichlorobenzimidazole, M ⁺ + H = 375 ( ES ⁺ ).

c) 4-N- (5 ', 6'-dichlorobenzimidazolyl) -3-trifluoromethyl-benzoylguanidine from 5 b) by activation with 1 eq carbonyl-bis-imidazole at RT for 2 h in DMF, and subsequent addition of 5 eq Guanidine hydrochloride and 7 eq N-ethyl-diisopropyl-amine. After stirring at RT for 1 h, an aqueous workup follows, the solid is filtered off with suction, M ⁺ + H = 416 (FAB).

d) 4-N- (5 ', 6'-dichlorobenzimidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride from 5 c) analogously to 2 c).

Example 6: 4-N- (5 ', 6'-dimethyl-benzimidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 255 ° C.

synthesis:

a) 4-N- (5 ', 6'-Dimethyl-benzimidazolyl) -3-trifluoromethyl-benzoic acid from 5 a) by nucleophilic exchange with 2 eq 5,6-dimethyl-benzimidazole in the presence of 3.7 eq potassium carbonate in DMF within 2 h at 120 ° C. Aqueous workup, extraction with ether gives an oil, M ⁺ + H = 335 (ES ⁺ ). b) 4-N- (5 ', 6'-dimethyl-benzimidazolyl) -3-trifluoromethyl-benzoylguanidine from 6 a) by guanidation analogously to 2 a) gives a solid after aqueous work-up, mp. 233 ° C.

c) 4-N- (5 ', 6'-dimethyl-benzimidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride from 5 b) analogously to 2 c).

Example 7: 4-N- (4 ', 5'-dimethyl-imidazolyl) -2-methyl-5-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 235 ° C.

Synthesis route a) 4-fluoro-2-methyl-5-trifluoromethylbenzoic acid methyl ester by lithiation of 4-fluoro-3-trifluoromethylbenzoic acid with 3 eq s-butyllithium in the presence of 2.95 eq

TMEDA at -90 ° C under argon in THF and subsequent reaction with 3 eq methyl iodide. The mixture is warmed to RT within 1.5 h and worked up in aqueous form. Extraction with ethyl acetate yields an oil which is distilled in a high vacuum in a bulb tube and is obtained as a yellowish oil, M ⁺ + H = 237 (DCI).

b) 4-Fluoro-2-methyl-5-trifluoromethyl-benzoic acid from 7 a) by saponification with 2N NaOH in MeOH at RT overnight, followed by aqueous work-up and extraction with ethyl acetate, M ⁺ + H = 223 (DCI).

c) 4-fluoro-2-methyl-5-trifluoromethyl-benzoylguanidine from 7 b) by reaction with 1.1 eq thionyl chloride in toluene with heating to RF for 1 h. The solvent is then evaporated and the intermediate acid chloride in THF is reacted with a solution of 3 eq guanidine hydrochloride and 5 eq 2N NaOH in THF at RT. After working up with water, the solid is filtered off with suction, mp. 175-177 ° C., M ⁺ + H = 264 (DCI).

d) 4-N- (4 ', 5'-dimethyl-imidazolyl) -2-methyl-5-trifluoromethyl-benzoylguanidine from 7 c) by nucleophilic exchange with 2 eq 4,5-dimethyl-imidazole in the presence of 4 eq Potassium carbonate at 120 ° C in DMF within 12 h. Aqueous workup, extraction with ethyl acetate and subsequent purification by column chromatography (silica gel) with dichloromethane / methanol (20: 1) yields a solid, mp. 245 ° C., M ⁺ + H = 390 (ES ⁺ ).

e) 4-N- (4 ', 5'-dimethyl-imidazolyl) -2-methyl-5-trifluoromethyl-benzoylguanidine dihydrochloride from 7 d) analogously to 2 c).

Example 8: 4-N-Benzimidazolyl-2-methyl-5-trifluoromethyl-benzoylguanidine dihychloride: Colorless crystals, mp. 199-202X

Synthetic route: a) 4-N-benzimidazolyl-2-methyl-5-trifluoromethyl-benzoic acid from 7 a) by nucleophilic exchange of fluorine with benzimidazole analogously to 7 d) and subsequent saponification with NaOH. Aqueous workup gives a solid, M ⁺ + H = 321 (ES ⁺ ).

b) 4-N-Benzimidazolyl-2-methyl-5-trifluoromethyl-benzoylguanidine from 8 a) by guanidation analogously to 5 c), M ⁺ + H = 362 (ES ⁺ ).

c) 4-N-Benzimidazolyl-2-methyl-5-trifluoromethyl-benzoylguanidine dihydrochloride from 8 b) by hydrochloride formation analogously to 2 c).

Example 9: 2-chloro-4-N-benzimidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 193-196 ° C, M ⁺ + H = 382 (ES ⁺ ).

Synthesis route: a) 2-chloro-4-fluoro-5-iodobenzoic acid from 2-chloro-4-fluoro-benzoic acid

Iodination with 1.2 eq N-iodosuccinimide in 12 eq trifluoromethanesulfonic acid at 0 ° C for 2h. The reaction mixture is poured onto ice / H ₂ O and the solid is suction filtered, mp 160-168 ° C., M ⁺ + H = 300 (DCI).

b) methyl 2-chloro-4-fluoro-5-iodo-benzoate from 9a) by esterification in MeOH / HCl at RT for 20 h, aqueous work-up and extraction with ethyl acetate gives a yellow oil, M ⁺ + H = 315 (DCI) ,

c) Methyl 2-chloro-4-fluoro-5-trifluoromethyl-benzoate from 9 b) by trifluoromethylation with 2 eq trifluoroacetic acid potassium salt and 2.05 eq copper (l) iodide in DMF for 4 h at 150 ° C. Aqueous working up, extraction with ethyl acetate and subsequent column chromatography on silica gel with n-heptane / ethyl acetate (9: 1) yields a brownish liquid, M ⁺ + H = 257 (DCI).

d) methyl 2-chloro-4-N-benzimidazolyl-5-trifluoromethylbenzoate from 9c) by reaction with 1.1 eq benzimidazole and 3.2 eq potassium carbonate at RT in DMF within 1.5 h. Aqueous workup and extraction with ethyl acetate yields an oil, M ⁺ + H = 355 (FAB).

e) 2-chloro-4-N-benzimidazolyl-5-trifluoromethyl-benzoic acid from 9 d) by saponification with 2 N NaOH in methanol at RT for 18 h. Aqueous workup gives a solid, M ⁺ = 341 (ES ⁺ ).

f) 2-chloro-4-N-benzimidazolyl-5-trifluoromethyl-benzoylguanidine from 9 e) by reaction with 2.3 eq carbonyl-bis-imidazole for 2 h at RT in THF, followed by

Addition of 4 eq guanidine and stirring for a further 3 h at RT provides, after aqueous work-up, a solid, M ⁺ + H = 382 (ES ⁺ ).

g) Hydrochloride formation of 9 f) analogous to 2 c).

Example 10: 2-chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethylbenzoylguanidine dihydrochloride: colorless crystals, mp. 199-200 ° C.

synthesis: a) 2-chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethyl-benzoic acid methyl ester from 9 c) analogously to 10 a), but using 5,6-dichlorobenzimidazole, colorless oil, M ⁺ + H = 423 (FAB).

b) 2-Chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethylbenzoic acid from 10 a) analogous to 9 e), colorless solid, M ⁺ + H = 409 (ES ⁺ ).

c) 2-Chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethyl-benzoylguanidine from 10 b) analogous to 9 f), colorless solid, M ⁺ + H = 450 (ES ⁺ ).

d) 2-chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethyl-benzoylguanidine dihydrochloride from 10 c) analogously to 2 c).

Claims

claims

1. Heterocyclically substituted benzoylguanidines of the formula I.

wherein: (1) - (CF ₂ ) _C -CF ₃ ; c zero, 1, 2 or 3;

R (2) (C1-C9) - heteroaryl, linked via C or N, which is unsubstituted or substituted with 1 - 3 substituents from the

Group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino,

Methylamino and dimethylamino; R (3) H, F, Cl, Br, I, CN, NO ₂ , (C ^< | -C ₈ ) alkyl, R (4) H, (C-1-C4) - alkyl, (C <| -C ₄ ) - alkoxy, F, Cl, Br, I, CN, - (CF ₂ ) ₀ -CF ₃ ; o zero, 1 or 2; and their pharmaceutically acceptable salts.

2. Compound of formula I according to claim 1, characterized in that therein: R (1) trifluoromethyl;

Amino, methylamino and dimethylamino; R (3) H, F, Cl or (C1-C4) alkyl,

R (4) H, (C1-C4) alkyl, (C- | -C) alkoxy, F, Cl or CF3; and their pharmaceutically acceptable salts.

3. Compound of formula I according to claim 1, characterized in that therein:

R (1) trifluoromethyl;

R (2) imidazolyl or benzimidazolyl, linked via N, which are unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, CH3 and methoxy,

R (3) H;

R (4) H, methyl, methoxy, Cl or CF3; and their pharmaceutically acceptable salts.

4. A process for the preparation of a compound I according to claim 1, characterized in that a compound of formula II

wherein R (1) to R (4) have the meaning given and L represents an easily nucleophilically substitutable leaving group, reacted with guanidine.

5. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions.

6. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of myocardial infarction.

7. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris.

8. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the heart.

9. Use of a compound I according to claim 1 for the preparation of a

Medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke.

10. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

11. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment of shock conditions.

12. Use of a compound I according to claim 1 for the manufacture of a medicament for use in surgical operations and organ transplants.

13. Use of a compound I according to claim 1 for the preparation of a

Medicament for the preservation and storage of grafts for surgical measures.

14. Use of a compound I according to claim I for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause.

15. Use of a compound I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of disorders of the fat metabolism.

16. Medicament, characterized by an effective content of a compound of formula I according to claims 1 to 4.