DE19504805A1 - New benzoyl-guanidine cpds. with base-substd. phenyl- or naphthyl- gp. - Google Patents

Abstract

Basic substd. benzoylguanidine derivs. of formula (I) and their salts are new. One of R1-R3 = Xf-CdH2d-B-A-R6 and the others of R1-R3 = H, F, Cl, Br, I, CN, 1-8C alkyl, 2-8C alkenyl, NR35R36 or Zh-CgH2g-R17; R6 = NR7R8, C(=NR9)NR7R8, NR10-C(=NR9)NR7R8 or basic heteroaromatic ring system with 1-9C; R7-R10 = H or 1-4C alkyl; or R7+R8 = C4H8 or CaH2a (opt. with one CH2 replaced by O, S(O)m or NR11; or R8+R9+R10 or R7+R10 = C2H4 or CcH2c (opt. with one CH2 replaced by O, S(O)m or NR11); A = CbH2b (opt. with one or two CH2 replaced by O, CO, CH(OR20), S(O)m, NR20, CONR20, NHCONR20, NR20SO2NHCO, S(=O)(=NR19)NR20 or SO2NR20, or one CH2 replaced by CHR99); R7+R99 form pyrrolidine or piperidine; B = opt. substd. phenylene or naphthylene gp. of formula (i) or (ii); R12, R13 = H, Me, F, Cl, Br, I, CF3 or S(O)mR14; R14, R19 = H or 1-4C alkyl; X = O, CO, CH(OR21), SOm or NR21; R35, R36 = H or 1-6C alkyl; or R35+R36 = (CH2)4-7, with one CH2 opt. replaced by S, NH, NMe or N-benzyl; Z = O, CO, SOm, NR18, CONR18, NHCONR18 or SO2NR18; R17 = H, cyclopropyl, cyclopentyl, cyclohexyl, 1-3C perfluoroalkyl, 1-, 2- or 3-pyrrolyl (opt. substd. by 1-4 of F, Cl, Br, I, CN, 2-8C alkanoyl, 2-8C alkoxycarbonyl, CHO, COOH, CF3, Me and OMe) or 3-8C cycloalkyl or phenyl (both opt. substd. by 1-3 of F, Cl, CF3, Me, OH, OMe, NR37R38, SO2Me and SO2NH2); R11, R18, R20, R21, R37, R38 = H or Me; R4, R5 = H, 1-4C alkyl, F, Cl, OR32, NR33R34 or 1-4C perfluoroalkyl; R32-R34 = H or 1-3C alkyl; a = 5-7; c = 3-5; d = 0-5; g = 0-4; f, h = 0 or 1; m = 0-2.

Description

The invention relates to benzoylguanidines of the formula I.

in which mean:
R (1) is hydrogen, F, Cl, NH₂, CF₃, alkyl having 1, 2 or 3 C atoms, -OH, alkoxy having 1, 2 or 3 C atoms;
one of the substituents R (2) or R (3)
R (5) -ABD-;
R (5) is a basic protonatable radical, ie an amino group -NR (6) R (7), an amidino group R (6) R (7) NC [= NR (8)] or a guanidino group

R (6), R (7), R (8) and R (9) independently of one another denote hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or
R (6) and R (7) are a group C _α H₂ _α ;
α 4, 5, 6 or 7;
wherein in the case of α = 5, 6 or 7, a C atom of the group C _a H₂ _{α may be} replaced by a heteroatom group O, SO _m or NR (10), or
R (7) and R (8) or R (8) and R (9) or R (6) and R (9) is a group C _a H _2a ;
a 2, 3, 4 or 5;
in the case of a = 3, 4 or 5, a C atom of the group C _a H _{2a may be} replaced by a heteroatom group O, SO _m or NR (10);
m is zero, 1 or 2;
R (10) is hydrogen or methyl; or
R (5) is a basic heteroaromatic ring system with 1-9 C atoms;

• A is a group C _b H _2b ;
  b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  where in group C _b H _{2b is} a C atom by one of the groupings -O-, -CO-, -CH [OR (10)] -, -SO _m -, -NR (10) -, -NR (10 ) -CO-, -NR (10) -CO-NH-, -NR (10) -CO-NH-SO₂- or -NR (10) -SO₂- may be replaced;
• B is a phenylene radical, or
• B is a naphthylene radical R (11) and R (12) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF₃ or -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) independently of one another are hydrogen or alkyl having 1 2, 3 or 4 C atoms;
• D is -C _d H _2d -X _f -;
  d is zero, 1, 2, 3 or 4;
  X is -O-, -CO-, -CH [OR (10)] -, -SO _m - or -NR (10) -;
  f is zero or 1;

and the other substituent R (2) and R (3) and R (4) are independently hydrogen, F, Cl, Br, J, -CN or
R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
R (16) is hydrogen, cycloalkyl having 3, 5 or 6 C atoms or C _k F _{2k + 1} -;
k 1, 2 or 3, or
R (16) is 1-pyrrolyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halogen, CH₃-, -CF₃-, CN; or
R (16) is phenyl which is unsubstituted or monosubstituted with a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-; or polysubstituted with 1-3 substituents selected from the group consisting of F, Cl, CH₃-, HO-, CH₃-O-, and their pharmacologically acceptable salts.

Preference is given to compounds of the formula I in which
R (1) is H or Cl;
R (2) and R (4) are identical or different and are hydrogen, F, Cl or R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
m is zero, 1 or 2;
R (16) is hydrogen, cycloalkyl having 5 or 6 C atoms, C _k F _{2k + 1} -;
k is 1, 2 or 3;
or, if g and h are equal to zero,
R (16) is 1-pyrrolyl which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, CH₃-, -CF₃-, CN or
R (16) is phenyl which is unsubstituted or monosubstituted with a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-; or substituted with 1-3 substituents selected from the group consisting of F, Cl, CH₃-, HO-, CH₃-O-;
R (3), R (5) -ABD-;
R (5) -NR (6) R (7), R (6) R (7) NC [= NR (8)] - or a guanidino group

R (6), R (7), R (8) and R (9) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 C atoms; or
R (6) and R (7) are a group C _a H₂ _α ;
α 4, 5, 6 or 7;
in the case of α = 5, 6 or 7, a C atom of the group C _α H₂ _{α may be} replaced by a heteroatom group O, SO _m or NR (10),
or
R (7) and R (8) are a group C _a H _2a ;
a 2, 3, 4 or 5;
in the case of a = 3, 4 or 5, a C atom of the group C _a H _{2a may be} replaced by a heteroatom group O, SO _m or NR (10);
m is zero or 2;
R (10) is hydrogen or methyl; or
R (5) imidazolyl, pyridyl, quinolyl or isoquinolyl;

• A is a group C _b H _2b ;
  b is 1, 2, 3, 4 or 5;
  in which 1 C atom of the group C _b H _{2b is represented} by one of the groupings -O-, -CO-, -CH [OR (10)] -, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, -NR (10) - CO-NH-SO₂- or -NR (10) -SO₂- may be replaced;
• B phenylene; or
• B naphthylene R (11) and R (12) are independently hydrogen, methyl, CF₃, F, Cl, -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D is -C _d H _2d -X _f -;
  d is zero, 1, 2, 3 or 4;
  X is -O-, -CO-, -CH [OR (10)] -, -SO _m - or -NR (10) -;
  f is zero or 1;
  and their pharmacologically acceptable salts.

Particular preference is given to compounds of the formula I in which
R (1) is hydrogen;
R (2) and R (4) are identical or different and are hydrogen, F, Cl or R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
m and R (10) as defined above;
R (16) is hydrogen, cycloalkyl having 5 or 6 carbon atoms, CF₃, or 1-pyrrolyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halogen, CH₃-, -CN; or
R (16) phenyl which is unsubstituted or monosubstituted by a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-, or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, CH₃- ;
R (3), R (5) -ABD-;
R (5) -NR (6) R (7), R (6) R (7) NC [= NR (8)] - or a guanidino group

R (6), R (7) and R (8) are independently hydrogen or methyl; or
R (6) and R (7) is a group C _a H₂ _α
α 4, 5, 6 or 7;
wherein in the case of α is 5, 6 or 7, a C atom of the group C _α H₂ _{α may be} replaced by NR (10); or
R (7) and R (8) are a group C _a H _2a ;
a 2, 3, 4 or 5;
or
R (5) imidazolyl;

• AC _b H _2b ;
  b is 1, 2, 3, 4 or 5;
  wherein 1 C atom may be replaced by a group -CH [OR (10)] -, -CO- or -SO₂-, or
  in which 1 C atom is replaced by a group -O-, S, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH- or -NR (10) -SO₂- can be when b is 2, 3, 4 or 5;
  m is 1 or 2;
  R (10) is hydrogen or methyl;
• B phenylene; R (11) and R (12) are independently hydrogen, methyl, CF₃, F, Cl, -SO _m -R (13);
  R (13) is methyl or NR (14), R (15);
  R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D is -CH₂-, -O-, -CO-, -SO _m - or -NR (10) -;
  m is zero or 2;
  R (10) is hydrogen or methyl;
  and their pharmacologically acceptable salts.

Very particular preference is given to the following compounds of the formula I:

3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine, -
2-trifluoromethyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine, -
4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine,
4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguani-din,
4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylg-uanidin,
4 - [(4-Guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine,
3-trifluoromethyl-4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] benzoylguanidine,
3-trifluoromethyl-4- [4- (2-dimethylaminoethylthio) phenoxy] benzoylguani-din

and their pharmacologically acceptable salts.  

The designated alkyl radicals can be both straight-chain and branched.

By (C₁-C₉) -Heteroaryl be understood in particular radicals which are different from Cyclopentyl, phenyl or naphthyl in which one or more CH- Groups are replaced by N. Heteroaryl is in particular imidazolyl, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolyl, Isoquinolyl.

Halogen is F, Cl, Br or J.

If the compounds of formula I contain asymmetric centers, so describes Formula I, both the individual optical antipodes and their possible Enantiomers.

The invention further relates to a process for the preparation of the compound I, characterized in that compounds of the formula II

with guanidine, wherein R (1) to R (4) have the meaning given and L is an easily nucleophilically substitutable leaving group, and that optionally in a pharmacologically acceptable salt transferred.

The activated acid derivatives of formula II, wherein L is an alkoxy, preferably a methoxy group, a phenoxy group, phenylthio, methylthio, 2 Pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, means obtained advantageously in a known manner from the underlying Carboxylic chlorides (formula II, L = Cl), which in turn turn into  known manner from the underlying carboxylic acids (formula II, L = OH), for example with thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II (L = Cl) can also be further activated acid derivatives of the formula II in a known manner directly from the produce underlying benzoic acid derivatives (formula II, L = OH), for example, the methyl ester of formula II with 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 ClCOOC₂H₅ or Tosyl chloride in the presence of triethylamine in an inert solvent, such as also the activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O [(cyano (ethoxycarbonyl) methylene) aminol-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 Range of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II is quoting source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350 specified.

The reaction of an activated carboxylic acid derivative of the formula I with guanidine takes place in a known manner in a protic or aprotic polar, but inert organic solvents. Here, in the implementation of the Benzoic acid methyl ester (II, L = OMe) with guanidine, methanol, isopropanol or THF at temperatures of 20 ° C to the boiling point of these solvents proven. For most reactions of compounds II with salt-free Guanidine has been advantageously used in aprotic inert solvents such as THF, Dimethoxyethane, dioxane, worked. But also water can under use a base, for example NaOH, as a solvent in the reaction of II and III are used.  

If L = Cl, one works advantageously with the addition of one Acid scavenger, z. B. in the form of excess guanidine for setting the Hydrohalic acid.

The underlying benzoic acid derivatives are known in part. They are prepared by methods known from the literature, for example by giving the final radical R (5) -ABC _d H _2d -X _f - or a precursor thereof by replacing halogen in a 3- or 4-Halogenbenzoesäurederivat of the formula

wherein one of the substituents R 'or R "has the meaning of R (2) or R (3) and the other is halogen. The reactions are described in the literature, for example as a nucleophilic substitution reaction, as a free-radical Ullmann reaction or palladium-catalyzed reactions. Analogously, in compounds R (5) -ABC _d H _2d -Hal or their precursors can also be reacted with compounds of the formula III in which one of the substituents R 'or R "has the meaning of R (2) or R (3) has and the other is a substituent X with the meaning -O⁻, -S⁻, -SO₂⁻, R (10) NH-.

The compounds used as precursors R (5) -ABC _d H _2d -X _f - and R (5) -AB- C _d H _2d -Hal are largely known and z. T. also commercially available as reagents. They are prepared by methods known from the literature, which are known to the person skilled in the art.

The introduction of some substituents in the 4- and 5-position succeeds by literature methods of palladium-mediated cross-couplings of  Aryl halides with, for example, organostannanes, organoboronic acids or Organoboranes or organocopper or zinc compounds.

Benzoylguanidines I are generally weak bases and can be acid bind with the formation of salts. The acid addition salts are salts of all pharmacologically acceptable acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, Phosphates, methylsulfonates, p-toluenesulfonates.

The compounds I are substituted acylguanidines.

The most prominent representative of the acylguanidines is the pyrazine derivative amiloride, which is used as a potassium-sparing diuretic in therapy. numerous other amiloride-type compounds are described in the literature, such as dimethylamiloride or ethylisopropylamiloride.

Amiloride: R ', R''= H
Dimethylamiloride: R ', R "= CH₃
Ethylisopropylamiloride: R '= C₂H₅, R "= CH (CH₃) ₂

In addition, investigations have become known on indicate antiarrhythmic properties of amiloride (Circulation 79, 1257 to 1263 (1989)). However, it is widely used as an antiarrhythmic drug contrary, because this effect is weak and of a hypotensive and saluretic effect accompanies and occurs Side effects undesirable in the treatment of cardiac arrhythmias are.  

Evidence of antiarrhythmic properties of amiloride has also been reported Experiments on isolated animal hearts were obtained (Eur. Heart J. 9 (supplement 1): 167 (1988) (book of abstracts)). For example, rat hearts have been found that artificially induced ventricular fibrillation is completely suppressed by amiloride could be. Even more potent than Amiloride was the one in this model mentioned amiloride derivative ethylisopropylamiloride.

US Pat. No. 5,091,394 (HOE 89 / F 288) discloses benzoylguanidines described in the position corresponding to the rest R (1) only one Carry hydrogen atom, and in which none of the substituents have the meaning of R (5) -A-B-D- has. In European published patent application 0 556 674 A (HOE 92 / F 034) 3,5-substituted benzoylguanidines are proposed, in but which does not have the substituent R (2) according to the present invention has claimed meaning of R (5) -A-B-D-.

US Pat. No. 3,780,027 claims acylguanidines which structurally similar to the compounds of formula I and are commercially available derived loop diuretics, such as bumetanide derived. Accordingly, for these compounds have reported potent salidiuretic efficacy.

It was therefore surprising that the compounds of the invention no undesirable and adverse salidiuretic, but very good have antiarrhythmic properties against such arrhythmias as they For example, occur in oxygen deficiency symptoms. The connections are due to their pharmacological properties as antiarrhythmic Medicines with cardioprotective component for infarction prophylaxis and the Infarct treatment and for the treatment of angina pectoris outstanding suitable, while they also preventively the pathophysiological processes in Emergence of ischemic induced damage, especially in the triggering ischemic-induced cardiac arrhythmias, inhibit or greatly reduce. Because of its protective effects against pathological hypoxic and ischemic situations, the compounds of the invention  Formula I due to inhibition of the cellular Na⁺ / H⁺ exchange mechanism as Medicines for the treatment of all acute or chronic by ischemia triggered or primary or secondary induced diseases be used. This concerns their use as medicines for surgical Interventions, z. In organ transplants, which compounds are useful for both the protection of organs in the donor before and during collection, for protection taken organs, for example, during treatment with or their storage in physiological bath fluids, as well as in the transfer to the Recipient organism can be used. The connections are also valuable, protective drugs in the implementation angioplasty surgery, for example, on the heart as well as on peripheral vessels. According to their protective effect against ischemic induced damage, the compounds are also used as a drug for treatment of ischemia of the nervous system, in particular of the CNS, being suitable z. B. are suitable for the treatment of stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are suitable also for the treatment of forms of shock, such as the allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of the formula I according to the invention are distinguished by strong inhibitory effect on the proliferation of cells, For example, fibroblast cell proliferation and proliferation of the smooth Vascular muscle cells, out. Therefore, the compounds of formula I come as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and therefore can be considered Antiatherosclerotics, remedies for diabetic late complications, Cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophy and hyperplasia, especially in Prostatic hyperplasia or prostatic hypertrophy.

The compounds according to the invention are effective inhibitors of cellular sodium proton antiporter (Na⁺ / H⁺ exchanger) at  numerous diseases (essential hypertension, atherosclerosis, diabetes etc.) is also increased in such cells, the measurements are easily accessible, such as in erythrocytes, platelets or leukocytes. The Compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as Diagnostics for the determination and differentiation of certain forms of Hypertension, but also atherosclerosis, diabetes, proliferative Diseases, etc. In addition, the compounds of the formula I are for preventive therapy to prevent the genesis of hypertension, For example, the essential hypertension, suitable.

In addition to a very strong inhibitory effect on the Na⁺ / H⁺ exchanger have the compounds of the invention over the known Compounds significantly improved water solubility. That's why they are much better suited for i.v. applications.

Medicaments containing a compound I may be administered orally, parenterally, be administered intravenously, rectally or by inhalation, with the preferred Application is dependent on the particular appearance of the disease. The compounds I can be alone or together with galenic Excipients are used, both in the veterinary as also in human medicine.

Which excipients are suitable for the desired drug formulation, is familiar to the person skilled in the art on the basis of his specialist knowledge. In addition to solvents, Gelling agents, suppository bases, tablet excipients, and others Active substance carriers may, for example, be antioxidants, dispersants, Emulsifiers, defoamers, flavoring agents, preservatives, Solubilizers or dyes are used.

For an oral form of application, the active compounds are those for suitable additives, such as carriers, stabilizers or inert  Diluent mixed and by the usual methods in the suitable dosage forms such as tablets, dragees, Plug capsules, aqueous, alcoholic or oily solutions. As inert carrier can z. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, Lactose, glucose or starch, in particular corn starch. The preparation may be both dry and wet granules respectively. As oily carriers or as solvents, for example vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds, if desired, with the customary substances such as solubilizers, Emulsifiers or other excipients in solution, suspension or emulsion brought. As a solvent come z. B. in question: water, physiological Saline or alcohols, eg. As ethanol, propanol, glycerol, besides also Sugar solutions such as glucose or mannitol solutions, or even a mixture of the various solvents mentioned.

As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable for. As solutions, suspensions or emulsions of Active ingredient of the formula I in a pharmaceutically acceptable Solvent, such as in particular ethanol or water, or a mixture such solvents.

The formulation may also contain other pharmaceuticals as needed Excipients such as surfactants, emulsifiers and stabilizers and a propellant gas contain. Such a preparation usually contains the active ingredient in one Concentration of about 0.1 to 10, especially from about 0.3 to 3 wt.%.

The dosage of the active ingredient of the formula I to be administered and the frequency The administration depends on the potency and duration of action of the used Connections off; also the type and strength of the treatment  Illness as well as sex, age, weight and individual Responsiveness of the mammal to be treated.

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

List of abbreviations:

AIBN Azo-bis-isobutyronitrile CH₂Cl₂ dichloromethane DCI Desorption-Chemical Ionization DIP diisopropylether DMA dimethylacetamide DME dimethoxyethane DMF N, N-dimethylformamide EE Ethyl acetate (EtOAc) EGG electron impact eq equivalent to IT Electrospray ionization FAB Fast Atom Bombardment HEP n-heptane MeOH methanol mp melting point MTB methyl tert-butyl NBS N-bromosuccinimide RT room temperature THF tetrahydrofuran   TMU Tetramethylurea

Experimental part General procedure for the preparation of benzoylguanidines (I) Variant A: from benzoic acids (II, L = OH)

0.01 M of the benzoic acid derivative of the formula II is dissolved or suspended in 60 ml of anhydrous DMF, DMA or TMU and then treated with 1, 78 g (0.011 M) carbonyldiimidazole. After stirring for 2 hours at RT 2.95 g (0.05 M) guanidine added to the reaction solution. After stirring overnight the THF is distilled off under reduced pressure (Rotavapor), mixed with water, adjust with 2N HCl to a pH between 8 and 9 and filtered the corresponding, slowly separating on ice cooling Benzoylguanidine (formula I) from. The Benzoylguanidine thus obtained can by Treat with aqueous, methanolic or ethereal hydrochloric acid or others pharmacologically acceptable acids converted into the corresponding salts become.

General procedure for the preparation of benzoylguanidines (I) Variant B: from alkyl benzoates (II, L = O-alkyl)

5 mmol of the benzoic acid alkyl ester of the formula II and 25 mmol of guanidine (free base) are dissolved in 15 ml of isopropanol or suspended in 15 ml of THF and to complete conversion (thin layer control) under reflux cooked (typical reaction time 2 to 5 h). The solvent is absorbed distilled off reduced pressure (Rotavapor), taken up in 300 ml EE and Washed 3 × with 50 ml NaHCO₃ solution. It is dried over Na₂SO₄, distilled off the solvent in vacuo and on silica gel with a suitable eluent, for. B. EE / MeOH 5: 1 chromatographed. (Salt formation compare variant A).  

example 1 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine Bis- methanesulfonate

1a) Preparation of 5-carboxy-2-fluorobenzenesulfinic acid
15.6 g (0.124 M) of sodium sulfite are dissolved at 70 ° C in 120 ml of water. While maintaining the temperature is added simultaneously and in portions 23.8 g (0.1 M) of 4-fluoro-3-chlorosulfonylbenzoesäure and 10 n NaOH so that the pH is maintained between 9 and 10 (exothermic reaction). The mixture is stirred for a further 3 hours at 70 ° C, allowed to stir for 15 minutes with A-carbon and then filtered. The filtrate is adjusted to pH 0-1 with external cooling with concentrated hydrochloric acid and the crystalline 5-carboxy-2-fluorobenzenesulfinic acid filtered off. Colorless crystals, mp. 167-170 ° C.

1b) Preparation of 5-carboxy-2-fluorobenzenesulfinic acid disodium salt:
is obtained by introducing 17.2 g (0.084 M) of carboxy-2-fluorobenzenesulfinic acid in a stirred solution of 6.72 g (0.168 M) NaOH in a mixture of 150 ml of methanol and 30 ml of water. After filtration of suspended solids is distilled the solvent is removed and the residue is crystallized under acetone. Colorless crystalline substance, mp: <320 ° C.

1c) Preparation of 4-fluoro-3-methylsulfonylbenzoic acid methyl ester:
A suspension of 15 g (0.06 M) 5-carboxy-2-fluorobenzenesulfinic acid disodium salt in 80 ml of dry DMF is added 30 g (0.21 M) of methyl iodide, stirred for 6 hours at 60 ° C, the solvent is distilled off and the residue is mixed with water. The mixture is stirred for 30 minutes under ice-cooling and filtered from the precipitate.
Colorless crystalline substance, mp .: 102-105 ° C.

1d) Preparation of methyl 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoate
4.64 g (0.02 M) of methyl 4-fluoro-3-methylsulfonylbenzoate are added to a mixture of 60 ml of dimethylacetamide, 3.6 g (0.022 M) of N, N-dimethyl-2- (4-hydroxyphenyl) ethylamine and 9 , 08 g (0.066 M) powdered anhydrous K₂CO₃ and the suspension stirred for 4 hours at 90 ° C. After distilling off the solvent and adding the residue with water is extracted several times with ethyl acetate, the combined organic phases are concentrated under reduced pressure and the substance is obtained as a yellow oily liquid.

1e) Preparation of 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid hydrochloride
1.82 g (0.005 M) of methyl 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoate are refluxed in 40 ml of half-concentrated hydrochloric acid over 5 hours, the aqueous hydrochloric acid is distilled off and the residue is crystallized under acetone , Colorless crystalline substance, mp .: 246-248 ° C.

1f) 3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine
is obtained analogously to the procedure specified in variant A from 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoic acid at a pH between 7 and 8. Colorless crystals, mp.: 214-218 ° C.

3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine bismethanesulfonate
the procedure given in variant A is obtained from 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine by treatment with 2.5 eq methanesulfonic acid in ethanol. Colorless solid, mp .: 102 ° C.

Example 2 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonylbenzo-yl guanidine dihydrochloride

2a) Preparation of 4- (2-dimethylaminoethyl) thiomethyl-phenol
A mixture of 200 mg of p-toluenesulfonic acid, 14.1 g (0.1 M) of 2-dimethylaminoethyl mercaptan hydrochloride and 12.4 g (0.1 M) of 4-hydroxybenzyl alcohol in 250 ml of toluene is after about 5 hours on a water after Coachman and Steudel boiled under reflux, the solvent was sold and the residue filtered after dissolution in methanol. After renewed concentration, the residue is crystallized under acetone, the crystalline product is filtered off and the slightly hygroscopic mass is dried over NaOH in the absence of air. Mp .: 134-140 ° C.

2b) Preparation of 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonylbenzoic acid methyl ester.
A mixture of 3.48 g (0.015 M) of 4- (2-dimethylaminoethyl) thiomethylphenol, 40 ml of anhydrous tetramethylurea, 6.8 g (0.049 M) of anhydrous powdered K₂CO₃ and 3.48 g (0.015 M) of 4-fluoro Methyl- methylsulfonylbenzoate is stirred for 6 hours at 90-100 ° C, the solvent was distilled off and the residue with water. After extraction with ethyl acetate, drying and concentration of the combined organic phases, the desired product is obtained as an oil.

2c) Preparation of 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonylbenzoic acid hydrochloride
is obtained analogously to the procedure described in Example 1 d) by hydrolysis of methyl 4-fluoro-3-methylsulfonylbenzoesäure in 20% HCl. Colorless to pale yellow crystalline substance, mp .: 179-185 ° C.

2d) 4- [4- (2-dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride
the procedure described in Example 1e) is obtained from 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-methylsulfonylbenzoic acid hydrochloride. Hygroscopic substance, mp .: 230 ° C.

Example 3 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguani-din dihydrochloride

3a) Preparation of N, N-dimethyl-2- (4-hydroxyphenylthio) ethylamine
To a solution of 12.6 g (0.1 M) of 4-mercaptophenol in 100 ml of anhydrous DMF is added under an inert gas atmosphere (argon) 17.28 g (0.11 M) of 2-diethylaminoethyl chloride hydrochloride and then 19.38 g ( 0.15M) of ethyldiisopropylamine and heated the reaction mixture to 110 ° C for 12 hours with magnetic stirring. After distilling off the solvent, the residue is combined with water, adjusted with 2N NaOH to pH 8-9, extracted the amorphous precipitate with ethyl acetate several times and the combined organic phases are dried over sodium sulfate. The solvent is distilled off and the residue is eluted on silica gel by column chromatography with a mixture consisting of 8 parts of ethyl acetate and 1 part of methanol. Colorless crystals, mp 108-110 ° C.

3b) Methyl 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoate
is obtained as a yellow oil analogously to the procedure described in 1d) by reacting N, N-dimethyl-2- (4-hydroxyphenylthio) ethylamine with methyl 4-fluoro-3-methylsulfonylbenzoesäure, wherein DMF was used instead of dimethylacetamide as the reaction medium. Yellow oily liquid.

3c) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid
6.8 g of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid methyl ester are boiled in 10 ml of glacial acetic acid and 70 ml of half-concentrated HCl for 5 hours under reflux conditions. After distilling off the solvent, the desired substance is obtained as an amorphous solid having no defined melting point.

3d) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguanidine dehydrochloride
one obtains analogously to the rule specified as variant A. Colorless solid, decomposition point: 160 ° C with foaming.

Example 4 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylg-uanidin dihydrochloride

4a) 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoic acid
To a solution of 3.8 g (0.008 M) of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoic acid in 50 ml of glacial acetic acid is added in portions at 5-10 ° C 6.9 g (0.028 M). 3 Chloroperbenzoic acid and stirred for 12 hours at RT. After addition of water, the precipitate of 3-chlorobenzoic acid is filtered off and extracted from the filtrate further impurities with ethyl acetate. The aqueous phase is concentrated and the amorphous residue is crystallized under ethyl acetate. Colorless crystals, mp. 167-171 ° C.

4b) 4- [4- (2-Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride
the procedure given in variant A is obtained from 4- [4- (2-dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoic acid in TMU as the reaction medium. The dihydrochloride is crystallized under methanol. Colorless crystals, mp: 233-240 ° C (decomposition).

Example 5 4 - [(4-Guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride

5a) Preparation of 4- (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid
By reacting 4-hydroxybenzoate with 4-fluoro-3-methylsulfonylbenzoesäuremethylester analogously to the specified under 1, d) rule the 4- (4-ethoxycarbonylphenoxy) benzoic acid methyl ester as a colorless to pale yellow oil, without further purification measures analogous to that in the regulation 3c) is hydrolyzed to 4- (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid. Colorless crystals, mp. 272-275 ° C.

5b) 4 - [(4-guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride
is obtained analogously to the procedure described in variant A by reacting 0.74 g (0.0022 M) of (4-carboxyphenoxy) -3-methylsulfonylbenzoic acid with 0.78 g (0.0048 M) of carbonyldiimidazole and 1.55 g (0.026 M) Guanidine in DMA. Colorless crystals, mp. 252 ° C (decomposition).

Example 6 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethyl-benzo-ylguanidin dihydrochloride

6a) 4- [4- (2-Dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoic acid methyl ester
the procedure described in Example 2b) is obtained from 4- (2-dimethylaminoethyl) thiomethyl-phenol and 4-fluoro-3-trifluoromethylbenzoate in DMU as the reaction medium as an amorphous, oily product.

6b) 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoic acid
The procedure is analogous to that described in Example 1d) by acid hydrolysis of 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoic acid methyl ester. Colorless hygroscopic crystals, mp 158-168 (decomposition).

6c) 4- [4- (2-Dimethylaminoethyl) thiomethyl-phenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride
the procedure described in variant A is obtained from 4- [4- (2-dimethylaminoethyl) thiomethyl] phenoxy] -3-trifluoromethylbenzoic acid in TMU as the reaction medium. Amorphous, highly hygroscopic solid, decomposed at 80-85 ° C.

Example 7 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluormethylbenzoylguani-din dihydrochloride

7a) Preparation of methyl 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoate
the procedure described in Example 2b) from 4- (2-dimethylaminoethylthio) phenol and methyl 4-fluoro-3-trifluoromethylbenzoate in DMU is obtained as the reaction medium as an amorphous, oily product.

7b) Preparation of 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid
The procedure is analogous to that described in Example 1d) by acid hydrolysis of methyl 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoate. The desired 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid crystallizes under acetone. Colorless crystals, mp 174-182 ° C (decomp.).

7c) 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoylguanidine dine dihydrochloride
the procedure described in variant A is obtained from 4- [4- (2-dimethylaminoethylthio) phenoxy] -3-trifluoromethylbenzoic acid in THF as the reaction medium. Amorphous, hygroscopic crystalline solid, mp. 240 ° C.

Example 8 3-trifluoromethyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine dihydrochloride

a) 4-chloro-3-trifluoromethyl-benzoic acid
From 100 g of 5-bromo-2-chloro-benzotrifluoride and 10.2 g of magnesium in 600 ml of diethyl ether, the Grignard compound is first prepared. Subsequently, a stream of 60 g of anhydrous CO₂ is introduced into this solution at RT. Is added dropwise 500 ml of saturated aqueous NaHSO₄ solution, the phases are separated and extracted with 2 × 100 ml diethyl ether. The organic phase is extracted 3 times with 300 ml of 1 N NaOH, then the aqueous phase washed 3 times with 100 ml of diethyl ether. The aqueous phase is then brought to pH 2 with HCl and diluted to 4 l with water. The product is filtered off with suction and dried in vacuo. 75 g of white powder. Rf (MTB 2% HOAc) = 0.68.

b) methyl 4-chloro-3-trifluoromethylbenzoate
75 g of 4-chloro-3-trifluoromethyl-benzoic acid are dissolved in 500 ml MeOH and 75 ml SOCl₂ added dropwise. The mixture is boiled under reflux for 5 h, then the volatiles are removed in vacuo. With 1 l of EA is taken up and washed with 500 ml of saturated aqueous Na ¥ CO₃ solution. About Na₂SO₄ is dried, the solvent removed in vacuo and distilled in vacuo. Bp 94 ° C (2 torr). Rf (DIP) = 0.49 MS (DCl): 239 (M + H) ⁺.

c) methyl 4- [4- (2- (dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoate
1.9 g of methyl 4-chloro-3-trifluoromethylbenzoate, 1.3 g of 4- (2-dimethylamino) ethyl-phenol, 7.8 g of Cs₂CO₃ are stirred in 50 ml of tetramethylurea for 5 h at 140 ° C. It is allowed to cool, then 300 ml of saturated aqueous NaHCO solution and 150 ml of water are added, and it is extracted 3 × with 100 ml of EA. About Na₂SO₄ is dried, then the solvent removed in vacuo. Chromatography with acetone / water 10: 1 provides 2.0 g of a colorless oil. Rf (acetone / water 10: 1) = 0.15 MS (DCI): 368 (M + H) ⁺.

d) 4- [4- (2- (Dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoylguanidi-n
2.0 g of methyl 4- [4- (2- (dimethylamino) ethyl] phenoxy-3-trifluoromethylbenzoate are guanylated with 1.6 g of guanidine in 60 ml of isopropanol according to variant B. The crude product is converted into the dihydrochloride and extracted from Dimethoxyethane / water 9: 1 recrystallized mp (free base): 164 ° C mp (dihydrochloride): 236 ° C MS (DCI): 395 (M + H) ⁺ water solubility of the dihydrochloride 49 mg / ml (pH = 5.3).

Pharmacological data Inhibition of the Na⁺ / H⁺ exchanger of rabbit erythrocytes

White New Zealand rabbits (Ivanovas) received a standard 2% diet Cholesterol for six weeks to activate the Na⁺ / H⁺ exchange and so the Na⁺ influx into the erythrocytes via Na⁺ / H⁺ exchange to be determined by flame photometry. The blood became the arteries of the ear taken out and made impracticable by 25 IU of potassium heparin. Part of everyone Sample was used for duplicate determination of hematocrit by centrifugation  used. Aliquots of 100 μl were used to measure the Na⁺- Starting content of erythrocytes.

To determine the amiloride-sensitive sodium influx, 100 μl of each were used Blood sample in 5 ml each of a hyperosmolar salt medium (mmol / l: 140 NaCl, 3 KCl, 150 sucrose, 0.1 Ouabain, 20 Tris-hydroxymethyl-aminomethane) incubated at pH 7.4 and 37 ° C. The erythrocytes were then three times with ice-cold MgCl₂-ouabain solution (mmol / l: 112 MgCl₂, 0.1 Ouabain) and hemolysed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry.

Na + net inflow was calculated from the difference between baseline sodium levels and the erythrocyte sodium content after incubation. The amiloride-inhibitable sodium influx was the difference in the sodium content of the erythrocytes after incubation with and without amiloride 3 × 10 ^-4 mol / l. In this way, the procedure was also in the compounds of the invention.

Results

Inhibition of the Na⁺ / H⁺ exchanger

Claims (21)

1. Benzoylguanidines of the formula I. in which mean:
R (1) is hydrogen, F, Cl, NH₂, CF₃, alkyl having 1, 2 or 3 C atoms, -OH, alkoxy having 1, 2 or 3 C atoms;
one of the substituents R (2) or R (3)
R (5) -ABD-;
R (5) is a basic protonatable radical, ie an amino group -NR (6), R (7), an amidino group R (6) R (7) NC [= NR (8)] - or a guanidino group R (6), R (7), R (8) and R (9) independently of one another denote hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or
R (6) and R (7) are a group C _α H₂ _α ;
α 4, 5, 6 or 7;
wherein in the case of α = 5, 6 or 7, a C atom of the group C _a H₂ _{α may be} replaced by a heteroatom group O, SO _m or NR (10), or
R (7) and R (8) or R (8) and R (9) or R (6) and R (9) is a group C _a H _2a ;
a 2, 3, 4 or 5;
in the case of a = 3, 4 or 5, a C atom of the group C _a H _{2a may be} replaced by a heteroatom group O, SO _m or NR (10);
m is zero, 1 or 2;
R (10) is hydrogen or methyl; or
R (5) is a basic heteroaromatic ring system with 1-9 C atoms;

• A is a group C _b H _2b ;
  b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  where in group C _b H _{2b is} a C atom by one of the groupings -O-, -CO-, -CH [OR (10)] -, -SO _m -, NR (10), -NR (10) - CO, -NR (10) -CO-NH-, -NR (10) -CO-NH-SO₂- or -NR (10) -SO₂- may be replaced;
• B is a phenylene radical, or
• B is a naphthylene radical R (11) and R (12) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF₃ or -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D -C _d H _2d X _f -;
  d is zero, 1, 2, 3 or 4;
  X is -O-, -CO-, -CH [OR (10)] -, -SO _m - or -NR (10) -;
  f is zero or 1;

and the respective other substituent R (2) and R (3) and R (4) independently of one another are hydrogen, F, Cl, Br, J, -CN or R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, - NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
R (16) is hydrogen, cycloalkyl having 3, 5 or 6 C atoms or C _k F _{2k + 1} -;
k 1, 2 or 3, or
R (16) 1-pyrrolyl,
which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halogen, CH₃-, -CF₃-, CN; or
R (16) is phenyl which is unsubstituted or monosubstituted with a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-; or polysubstituted with 1-3 substituents selected from the group consisting of F, Cl, CH₃-, HO-, CH₃-O-, and their pharmacologically acceptable salts. 2. A compound of the formula I as claimed in claim 1, characterized in that
R (1) is hydrogen, F, Cl, NH₂, CF₃, alkyl having 1, 2 or 3 C atoms, -OH, alkoxy having 1, 2 or 3 C atoms;
one of the substituents R (2) or R (3) R (5) -ABD-;
R (5) -NR (6) R (7), R (6) R (7) NC [= NR (8)] - or a guanidino group R (6), R (7), R (8) and R (9) independently of one another denote hydrogen or alkyl having 1, 2, 3 or 4 C atoms; or
R (6) and R (7)
a group C _α H₂ _α ;
α 4, 5, 6 or 7;
wherein in the case of α = 5, 6 or 7, a C atom of the group C _α H₂ _{α may be} replaced by a heteroatom group O, SO _m or NR (10), or
R (7) and R (8) or R (8) and R (9) or R (6) and R (9) is a group C _a H _2a ;
a 2, 3, 4 or 5;
in the case of a = 3, 4 or 5, a C atom of the group C _a H _{2a may be} replaced by a heteroatom group O, SO _m or NR (10);
m is zero, 1 or 2;
R (10) is hydrogen or methyl; or
R (5) is a basic heteroaromatic ring system with 1-9 C atoms;

• A is a group C _b H _2b ;
  b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  where in group C _b H _{2b is} a C atom by one of the groupings -O-, -CO-, -CH [OR (10)] -, -SO _m -, NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, -NR (10) -CO-NH-SO₂- or -NR (10) -SO₂- may be replaced;
• B is a phenylene radical, or
• B is a naphthylene radical R (11) and R (12) independently of one another are hydrogen, methyl, F, Cl, Br, J, CF₃ or -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D is -C _d H _2d -X _f -;
  d is zero, 1, 2, 3 or 4;
  x is -O-, -CO-, -CH [OR (10)] -, -SO _m - or -NR (10) -;
  f is zero or 1;

and the respective other substituent R (2) and R (3) and R (4) independently of one another are hydrogen, F, Cl, Br, J, -CN or R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
R (16) is hydrogen, cycloalkyl having 3, 5 or 6 C atoms or C _k F _{2k + 1} -;
k 1, 2 or 3, or
R (16) is 1-pyrrolyl which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halogen, CH₃-, -CF₃-, CN; or
R (16) is phenyl which is unsubstituted or monosubstituted with a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-; or polysubstituted with 1-3 substituents selected from the group consisting of F, Cl, CH₃-, HO-, CH₃-O-. 3. A compound of formula I according to one or more of claims 1 or 2, characterized in that
R (1) is H or Cl;
R (2) and R (4) are identical or different and are hydrogen, F, Cl or R (16) -C _g H _2g -Z _h -;
1g zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
m is zero, 1 or 2;
R (16) is hydrogen, cycloalkyl having 5 or 6 C atoms, C _k F _{2k + 1} -;
k is 1, 2 or 3;
or, if g and h are equal to zero,
R (16) is 1-pyrrolyl which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, CH₃-, CF₃-, CN; or
R (16) is phenyl which is unsubstituted or monosubstituted with a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-; or substituted with 1-3 substituents selected from the group consisting of F, Cl, CH₃-, HO-, CH₃-O-;
R (3) R (5) -ABD-;
R (5) -NR (6) R (7), R (6) R (7) NC [= NR (8)] - or a guanidino group R (6), R (7), R (8) and R (9) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 C atoms;
or
R (6) and R (7) a group C _α H₂ _α
α 4, 5, 6 or 7;
wherein in the case of α = 5, 6 or 7, a C atom of the group C _α H₂ _{α may be} replaced by a heteroatom group O, SO _m or NR (10), or
R (7) and R (8) are a group C _a H _2a ;
a 2, 3, 4 or 5;
in the case of a = 3, 4 or 5, a C atom of the group C _a H _{2a may be} replaced by a heteroatom group O, SO _m or NR (10);
m is zero or 2;
R (10) is hydrogen or methyl; or
R (5) imidazolyl, pyridyl, quinolyl or isoquinolyl;

• A is a group C _b H _2b ;
  b is 1, 2, 3, 4 or 5;
  in which 1 C atom of the group C _b H _{2b is represented} by one of the groupings -O-, -CO-, -CH [OR (10)] -, -SO _m -, NR (10) -, -NR (10) - CO, -NR (10) -CO-NH-, -NR (10) - CO-NH-SO₂- or -NR (10) -SO₂- may be replaced;
• B phenylene; or
• B naphthylene R (11) and R (12) are independently hydrogen, methyl, CF₃, F, Cl, -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D is -C _d H _2d -X _f -;
  d is zero, 1, 2, 3 or 4;
  X is -O-, -CO-, -CH [OR (10)] -, -SO _m - or -NR (10) -;
  f is zero or 1.

4. Compounds of the formula I according to one or more of claims 1 to 3, characterized in that
R (1) is hydrogen;
R (2) and R (4) are identical or different and are hydrogen, F, Cl or R (16) -C _g H _2g -Z _h -;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
Z represents -O-, -CO-, -SO _m -, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH-, or -NR (10) -SO₂- ;
m and R (10)
as defined above;
R (16) is hydrogen, cycloalkyl having 5 or 6 carbon atoms, CF₃, or 1-pyrrolyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of halogen, CH₃-, -CN; or
R (16) phenyl which is unsubstituted or monosubstituted by a substituent selected from the group consisting of CF₃-, CH₃SO₂-, H₂NO₂S-, or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, CH₃- ;
R (3) R (5) -ABD-;
R (5) -NR (6) R (7), R (6) R (7) NC [= NR (8)] - or a guanidino group R (6), R (7) and R (8) are independently hydrogen or methyl; or
R (6) and R (7) a group C _α H₂ _α
α 4, 5, 6 or 7;
wherein in the case of a is 5, 6 or 7, a C atom of the group C _α H₂ _{α may be} replaced by NR (10); or
R (7) and R (8) are a group C _a H _2a ;
a 2, 3, 4 or 5; or
R (5) imidazolyl;

• AC _b H _2b ;
  b is 1, 2, 3, 4 or 5;
  wherein 1 C atom may be replaced by a group -CH [OR (10)] -, -CO- or -SO₂-, or
  in which 1 C atom is replaced by a group -O-, S, -NR (10) -, -NR (10) -CO-, -NR (10) -CO-NH- or -NR (10) -SO₂- can be when b is 2, 3, 4 or 5;
  m is 1 or 2;
  R (10) is hydrogen or methyl;
• B phenylene; R (11) and R (12) are independently hydrogen, methyl, CF₃, F, Cl, -SO _m -R (13);
  R (13) is methyl or NR (14) R (15);
  R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
• D is -CH₂-, -O-, -CO-, -SO _m - or -NR (10) -;
  m is zero or 2;
  R (10) is hydrogen or methyl.

5. A compound of formula I according to any one of claims 1 to 4, characterized characterized in that it is selected from the following group: 3-methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine, 2- Trifluoromethyl-4- [4- (2-dimethylaminoethyl) phenoxy] benzoylguanidine, 4- [4- (2- Dimethylaminoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanid-in, 4- [4- (2-Dimethylaminoethylthio) phenoxy] -3-methylsulfonylbenzoylguanidine, 4- [4- (2- Dimethylaminoethylsulfonyl) phenoxy] -3-methylsulfonylbenzoylguanidine, - 4 - [(4- Guanidinocarbonyl) phenoxy] -3-methylsulfonylbenzoylguanidine, 3-trifluoromethyl- 4- [4- (2-dimethylaminoethyl) thiomethyl-phenoxy] benzoylguanidine, 3 Trifluoromethyl-4- [4- (2-dimethylaminoethylthio) phenoxy] benzoylguanidi-n, and their pharmacologically acceptable salts. 6. A process for the preparation of a compound I, characterized in that a compound of the formula II in which R (1) to R (4) have the stated meaning and L is a leaving group which is slightly nucleophilically substitutable,
with guanidine
and that optionally converted into a pharmacologically acceptable salt. 7. Use of a compound I according to claim 1 for the preparation of a Medicament for the treatment of arrhythmias. 8. Method for treating arrhythmias, characterized in that one an effective amount of a compound I according to claim 1 with the usual Additives added and administered in a suitable dosage form. 9. Use of a compound I according to claim 1 for the preparation of a Medicament for the treatment or prophylaxis of myocardial infarction. 10. Use of a compound I according to claim 1 for the preparation of a Medicament for the treatment or prophylaxis of angina pectoris. 11. 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 Heart.   12. 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. 13. Use of a compound I according to claim 1 for the preparation of a Medicament for the treatment or prophylaxis of ischemic conditions peripheral organs and limbs. 14. Use of a compound I according to claim 1 for the preparation of a Medicament for the treatment of shock conditions. 15. Use of a compound I according to claim 1 for the preparation of a Medicament for use in surgical operations and Organ transplants. 16. Use of a compound I according to claim 1 for the preparation of a Medicament for the preservation and storage of transplants for surgical measures. 17. Use of a compound I according to claim 1 for the preparation of a Drug for the treatment of diseases involving cell proliferation is a primary or secondary cause, and thus its use as Antiatherosclerotics, anti-diabetic late complications, Cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, prostatic hyperplasia. 18. Use of a compound I according to claim 1 for the preparation of a scientific tool for inhibition of the Na⁺ / H⁺ exchanger, for diagnosis hypertension and proliferative diseases. 19. Remedies containing an effective amount of a compound I after one or more of claims 1 to 5.