DD297646A5 - BENZOYLGUANIDINES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS A MEDICAMENT AND THE MEDICAMENT CONTAINING THE SAME - Google Patents

Abstract

Benzoylguanidines of the formula (I) where R (1) or R (2) is * or * and the other substituent R (1) or R (2) is H, F, Cl, Br, J, alkyl, alkoxy or phenoxy , * or * and R (6) is alkyl, cycloalkyl, cyclopentylmethyl, cyclohexylmethyl or phenyl, R (7) and R (8) are alkyl or phenylalkyl- or phenyl, and wherein R (7) and R (8) may also together be a C4-C7 chain, and wherein R (7) and R (8) together with the nitrogen atom to which they are attached may denote a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline system, and with * R (4 ) and R (5) is hydrogen, alkyl or R (3) and R (4) together form an alkylene chain or R (4) and R (5) together form an alkylene chain, and n is zero, 1 or 2 and their pharmaceutically acceptable Salts are excellent antiarrhythmics. They are obtained by a process in which compounds of the formula (II) are reacted with a guanidine derivative of the formula (III) in which X is an easily nucleophilically substitutable leaving group. Formulas (I) to (III)

Description

The invention relates to benzoylguanidines of the formula I.

Rd) _c R (S)

R <4) R <2>'^ ^X C ^{X NH}

ir ro)

wherein R (D or R (2) R (6hS (0) "- or R (7)

^ N- 025 - R (BK

and the other substituent R (D or R (2)

H, F, Cl, Br, J, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, phenoxy which is unsubstituted or bears one to three substituents from the groups fluorine, chlorine, methyl or methoxy, R ( 6) -S (0) _n or

R (8

N- means

and wherein ^R6 is Cj-Cg-alkyl, C ₆ -C _r cycloalkyl, cyclopentylmethyl, cyclohexylmethyl, or represents phenyl, which is unsubstituted or carries one of the groups fluorine, chlorine, methyl or methoxy to three substituents, and wherein R ( 7) and R (8) are identical or different and are in the meaning of H, Ci-C _e alkyl or R (7) is phenyl (CH ₂ ) _m - with m = 1-4 or phenyl, the is unsubstituted or carries one to two substituents from the groups fluoro, chloro, methyl or methoxy, and wherein R (7) and R (8) can also together be a straight-chain or branched C ₄ -C ₇ -KeUe, wherein the chain additionally may be interrupted by O, S or NR (9) and R (9) is H or methyl and wherein R (7) and R (8) together with the nitrogen atom to which they are attached are a dihydric indole, tetrahydroquinoline or tetrahydroisoquinoline -System, and R (3), R {4) and R (5) are hydrogen, Ci-C ₂ alkyl, or wherein either R (3) and R (4) together ein e (C 1 -C ₄ ) -alkylene chain or R {4) and R (5) may together form a (C ₄ -C ₇ ) -alkylene chain, and π is zero, 1 or 2, and their pharmaceutically acceptable salts.

If the substituents R (D to R (5) contain one or more centers of asymmetry, compounds of the invention configured both form S and R. The compounds can exist as optical isomers, as diastereoisomers, as racemates, or as mixtures of the same both straight-chain and branched present.

Preference is given to compounds of the formula I in which

R (D is fluorine, chlorine, NR (7) R (8), R (6) -S (O) "- or phenoxy,

R (2) is R (6) -S {O) _n - and R (7) R (8) is N-SO ₂ - and wherein η is zero, 1,2

and R (3), R (4) and R (5) are hydrogen,

and wherein R (6), R (7) and R (8) have the abovementioned meaning and their pharmacologically acceptable salts.

Particular preference is given to compounds of the formula I where R (D in the meaning of R (7) R (8) N- or R (6) -S (O) "-, in which R (6) denotes alkyl having 1-3C- Atoms or phenyl, η = zero and R (7) and R (8) hydrogen, alkyl having 1-4 C atoms or R (7) and R (8) together form a (C ₄ -C ₇ ) -methyl chain and

R (2) is CH ₃ -SO ₂ - or H ₂ N-SO ₂ -, R (3), R (4) and R (5) are hydrogen and their pharmacologically acceptable salts.

Very particular preference is given to 3-methylsulfonyl-4- (1-piperidinyl) benzoylguanidine, 4-phenylthio-3-sulfamoylbenzoylguanidine and 3-methylsulfonyl-4-phenylthiobenzoylguanidine and their pharmacologically acceptable salts.

The compounds I are substituted acylguanidines.

The most prominent precursor of 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.

NH Cl »

• _N '- ^ΝΗ 2

R ''

Amiloride: R ', R "= H

Dimethylamiloride: R ', R "= CH ₃

Ethyl isopropylamiloride: R '= CjH ₆₁ R "= CH (CHj) ₂

In addition, studies have been made that point to antiarrhythmic properties of amiloride (Circulation 79.1257-1263 [1989]). However, a broad application as antiarrhythmic drug is opposed by the fact that this effect is weak and occurs accompanied by a hypotensive and saluretic effect and these side effects in the treatment of cardiac arrhythmias are undesirable.

Evidence of antiarrhythmic properties of amiloride has also been obtained in experiments on isolated animal hearts (Eur. Heart J. 9 [suppl 1J: 167 [1988] [book of abstracts]). For example, it has been found in rat hearts that an artificially induced ventricular fibrillation could be completely suppressed by amiloride. Even more potent than amiloride in this model was the abovementioned amiloride derivative ethylisopropylamiloride.

US Pat. No. 3,780,027 claims acyl guanine structurally similar to the compounds of formula I. The crucial difference from the compounds I is that they are trisubstituted benzoylguanidines derived in their substitution pattern of commercial diuretics such as bumetanide and furosemide, and an amino group in position 2 or 3 important for the desired salidiuretic effect Carry carbonylguanidine group.

Accordingly, strong salidiuretic efficacy is reported for these compounds.

It was therefore very surprising that the compounds of the invention have no undesirable salidiuretic but very good antiarrhythmic properties. The compounds are due to their pharmacological properties as antiarrhythmic drugs with cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris ideally suited, and they can also be used preventively.

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

R (2

with a guanidine derivative of formula III

NR (4) R <5)

^ NHR (3)

HN = C ^

in which R (D to R (5) have the meaning given and X is a leaving group which is readily nucleophilic substitutable.

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

In addition to the carboxylic acid chlorides of the formula M (X = Cl), further activated acid derivatives of the formula II can be prepared in a manner known per se directly from the underlying benzoic acid derivatives (formula II, X =OH), for example the methyl esters of the formula II with X = OCH ₃ by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole (X = 1-imidazolyl, Staab, Angew. Chem. Int. Ed., Engen, 1,351-367 [1962]), the mixed anhydrides II with CI-COOC ₂ Hs or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activations of benzoic acids with dicyclohexylcarbodiimide (DCC). A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are given with reference to source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p 350.

Another method of preparing in particular those compounds of formula I in which R (4) and / or R (5) is not H, consists in the reaction of an acid chloride or other suitable activated benzoic acid derivative of formula II with 3,5-dimethylpyrazole -i-carboxylic acid amidine nitrate (available from Aldrich) in the presence of caustic soda and subsequent treatment of the N-benzoyl-3,5-dimethylpyrazole-1-carboxylic acid amidine derivative with ammonia or an amine HNR (4) R (5) (Methods Enzymol ., 25b, 558 [1972]).

The reaction of an activated carboxylic acid derivative of the formula I with a guanidine derivative of the formula III is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. Here, in the reaction of methyl benzoate (II, X = OMe) with guanidine methanol or THF between 20 ⁰ C and boiling point of these solvents have been proven. For most reactions of compounds II with salt-free guanidines III, it was advantageous to work in aprotic inert solvents such as THF, dimethoxyethane, dioxane. But water can also be used as a solvent in the reaction of II and III.

When X = Cl, it is advantageous to work with the addition of an acid scavenger, z. B. in the form of excess guanidine to bind the hydrohalic acid.

Part of the underlying benzoic acid derivatives of the formula II and the guanidines of the formula III used are known and described in the literature. The unknown compounds of the formula II can be prepared by literature methods by, for example, 4-chloro or 4-fluoro-3-chloro-suifonylbenzoic acid with ammonia or an amine in a 3-aminosulfonyl-4-chloro- or -fluorobenzoic acid (IVa ) or with a weak reducing agent such as sodium bisulfite and subsequent alkylation in a 3-alkylsulfonyl-4-chloro- or -4-fluorobenzoic acid (IV b, η = 2)

Hol n

Il · IVa): R = R (6)

C ^ ^C \ IVb): R = NR (7) R (8)

R-OnB COOH

transferred and the resulting benzoic acids according to one of the process variants described above to the invention

Compounds I are implemented. However, compounds of the formulas IVa) and b) can also serve as starting compounds of other carboxylic acids, where the Halogen in R (1! Position very convenient against numerous nucleophilic reagents, such as mercaptans R (6) -SH or primary amines R (7) R (8) NH can be exchanged with X = OH to form further benzoic acid derivatives II. Similarly, starting from 3-nitro-4-chlorobenzoic acid by nucleophilic introduction of a Residue R (1) in position 4 (exchange for Cl) and further modification of the nitro group, such as reduction to NH ₂ and

subsequent alkylation or displacement, for example by diazotization and Sandmeier reaction, others

Benzoic acid derivatives (II, X = OH) are produced. Benzoylguanidines I are generally weak bases and can bind acid to form salts. When Acid addition salts are salts of all pharmacologically acceptable acids in question, for example, halides,

in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Medicaments containing a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation

be, with the preferred application of the particular appearance of the disease is dependent. The

Compounds I can be used alone or together with pharmaceutical excipients, both in

veterinary as well as in human medicine.

Which excipients are suitable for the desired drug formulation, the skilled person based on his expertise

common. In addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, it is possible, for example, to use antioxidants, dispersants, emulsifiers, defoamers, flavoring agents,

Preservatives, solubilizers or dyes are used. For an oral application form, the active compounds with the appropriate additives, such as excipients, Stabilizers or inert diluents and mixed by the usual methods in the appropriate Dosage forms brought, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. As inert Carriers can, for. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch,

especially corn starch. The preparation may be both dry and wet granules. Suitable oily carriers or as solvents are, 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 usual Substances such as solubilizers, emulsifiers or other auxiliaries in solution, suspension or emulsion brought. When Solvents come z. B. in question: water, physiological saline or alcohols, eg. Ethanol, propanol, glycerol,

In addition, sugar solutions such as glucose or mannitol solutions, or a mixture of the various mentioned

Solvents. As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable, e.g. Solutions, Suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent, such as

in particular ethanol or water, or a mixture of such solvents. The formulation may also contain, as needed, other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as a propellant. Such

Preparation contains the active ingredient usually in a concentration of about 0.1 to 10, in particular from about 0.3 to 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 the nature and strength of the disease to be treated as well as the sex, age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of formula I in a patient weighing about 75 kg is at least

0.001 mg, preferably 0.01 mg to at most 10 mg, preferably at most 1 mg. In acute outbreaks of the disease, for example, immediately after suffering a heart attack, even higher and above all more frequent dosages may be necessary

z. B. up to 4 single doses per day. In particular i. v. Use, for example in an infarct patient in the intensive care unit, up to 100mg per day may be necessary.

Analogous to the provisions given in the embodiments, the invention listed below Compounds of formula I or their physiologically acceptable salts are prepared:

4-Methoxy-3-methylsulfonylbenzoylguanidine, 4-isobutyloxy-3-methylsulfonylbenzoylguanidine, 4-benzyloxy-3-methylsulfonylbenzoylguanidine, 4- (1-butylthio) -3-methylsulfonylbenzoylguanidine, 4- (1 Butylsulfinyl) -3-methylsulfonylbenzoylguanidine ^ -d-butylsulfonyD-sulfamoylbenzoylguanidine ^ -d-butylsulfonyD-S-methylsulfonylbenzoylguanidine, 4- (2-chlorophenylthio) -3-methylsulfonylbenzoylguanidine, 4-phenoxy-3-methylsulfonylbenzoyl- guanidine, 4-cyclohexylthio-3-methylsulfonylbenzoylguanidine, 4-cyclohexylsulfinyl-3-methylsulfonylbenzoylguanidine, 4-cyclohexylsulfonyl-3-methylsulfonylbenzoylguanidine, 4- (1-piperidino) -3-sulfamoylbenzoylguanidine, 4-methoxy 3-sulfamoylbenzoylguanidine, 4-isobutyloxy-3-sulfamoylbenzoylguanidine, 4-benzyloxy-3-sulfamoylbenzoylguanidine, 4- (1-butylthio) -3-sulfamoylbenzoylguanidine, 4- (1-butylsulfinyl) -3- sulfamoylbenzoylguanidine, 4- (2-chlorophenylthio) -3-sulfamoylbenzoylguanidine ^ -cyclohexylthioJ-S-sulfamoylbenzoylguanidine, 4-cyclohexylsulfonyl-3-sulfamoylbenzoylguanidine, 3-ls o -propylsulfamoyl-4- (1-piperidino) benzoylguanidine, 3- (1-butylsulfamoyl) -4- (1-piperidino) benzoylguanidine, 3- (N, N-di-1-butylsulfamoyl) -4- ( 1-piperidino) benzoylguanidine, 3- (3-methoxypropylsulfamoyl) -4- (1-piperidino) benzoylguanidine, SO.δ-dimethylpiperidino-N-sulfonyD ^ -d-piperidinol-benzoyl-guanidine. S-cyclopentylsulfamoyl ^ -d-piperidino) benzoylguanidine, 4- (3-methoxy-1-propylamino) -3-methylsulphonylbenzoylguanidine, 4- (3-methoxy-1-propylamino) -3-sulphamoylbenzoylguanidine, 4- (N, N, N, N) -butyl) -pyridine; , N-di-1-butylamino) -3-methylsulfonylbenzoylguanidine guanidine, 4- (N ₁ N-DM-butylamino) -3-

sulfamoylbenzoylguanidine ^ -N-pentamethyleneamino-a-methylsulfonylbenzoylguanidine ^ -N-pentamethyleneamino-S-sulfamoylbenzoylguanidine ^ -cyclopentylamino-S-methylsulfonylbenzoylguanidine, 4-cyclopentylamino-3-sulfamoylbenzoylguanidine, 4- (2-chlorophenylamino) 3-methylsulfonylbenzoylguanidine ₁ 4- (2-chlorophenylamino) -3-sulfamoylbenzoylguanidine, 4- (4-methoxyphenylamino) -3-methylsulfonylbenzoylguanidine, 4- (4-methoxyphenylamino) -3-sulfamoylbenzoylguanidine, 4 - (N-methyl-N-phenylamino) -3-methylsulfonylbenzoylguanidine, 4- (N-methyl-N-phenylamino) -3-sulfamoylbenzoyi-guanyl, 4- (2,4-dimethylamino) -3-methylsulfonylbenzoyl guanidine, 4- (2,4-dimethylamino) -3-sulfamoylbenzoylguanidine, 4- (3-methylphenylamino) -3-methylsulfonylbenzoylguanidine, 4- (3-methylphenylamino) -3-sulfamoylbenzoylguanidine, 4- (3-methylphenylamino) -3-sulfamoylbenzoylguanidine 4-methylphenylthio) -3-sulfamoylbenzoylguanidine, 4- (4-chlorophenylthio) -3-sulfamoylbenzoylguanidine, 4- (4-methoxyphenylthio) -3-sulfamoylbenzoylguanidine, 4-methyl-3-methylsulfonylbenzoylguanidine, 4 methyl-3-sulfa moylbenzoyl-guanidine.

Experimental part

example 1

4-chloro-3-sulfamoylbenzoyl-guanldin hydrochloride

To a methanolic sodium methylate solution, prepared from 1.9 g of sodium in 90 ml of methanol, are added 8.5 g of guanidine hydrochloride and then 5 g of methyl 4-chloro-3-sulfamoylbenzoesäure. After heating dioser mixture for 30 hours under inert gas (nitrogen or argon) to 50-60 ⁰ C, the solvent is distilled off, after taking up the residue with 2 N acetic acid to pH 6 and extracted with ethyl acetate. After acidifying the dried extract (drying over magnesium sulfate) with ethereal hydrochloric acid, the title compound is filtered off.

Colorless crystals, mp 305-30B ⁰ C.

Example 2

S-N, N-Dlethylsulfamoyl ^ -chlorbenzoyl-guanldln hydrochloride

analogously to the procedure given in Example 1 by reacting 0.112 mol of guanidine, prepared from 10.7 g of guanidine hydrochloride and the equimolecule, amount of sodium methylate in 70 ml of methanol.

Colorless crystals, mp 202-205 ° C.

Example 3

4-Chloro-3-methylsulfonylbenzoylguanidine hydrochlorld

is obtained analogously to the procedure given in Example 1 by reacting 42.2mMol guanidine, prepared from 4.03g guanidine hydrochloride and 7.7g sodium (bis-trimethylsilylamide) by heating in methanol over 6 hours at 50 ° C and analogous workup ,

Colorless crystals, mp 220 ° C (dec.).

Example 4 3-Methylsulfonyt-4- (1-plperyl) -benzoyl-guanidine

a) 5-carboxy-2-chlorobenzenesulfinic acid dinatrium salt

is obtained from 186g 5-carboxy-2-chlorobenzene-sulfinic acid, prepared by reduction of 261 g of 5-carboxy-2-chlorobenzenesulfonyl chloride with 157 g of sodium sulfite in 700 ml of water at 70 ° C at pH 9-10 and subsequent acidification with HCl, by neutralization with 67.6 g of caustic soda in 21 water, distilling off and crystallization of the residue under acetone. White crystal powder, mp.> 34O ⁰ C.

b) methyl 4-chloro-3-methylsulfonylbenzoate

52.9 g of the disodium salt shown under 4a) are stirred in 400 ml of anhydrous dimethylformamide with 99.3 g of methyl iodide for 5 hours at 50-60 ⁰ C, the solvent is distilled off and after stirring and washing the residue with water several times, the substance is filtered off

White crystal powder, m.p. 150-153 ⁰ C.

c) 4-chloro-3-methylsulfonylbenzoic acid

14.3 g of the benzoic acid methyl ester derivative shown under 4b) in 120 ml of methanol and 50 ml of 2N sodium hydroxide stirred for 6 hours at room temperature, the solvent was distilled off, after dissolution of the residue in water with 2 N hydrochloric acid to pH 0-1 and filtered off the substance

 White crystal powder, mp 220-224 ° C.

d) 3-Methylsulfonyl-4- (1-piperidino) benzoic acid

92g of 4-chloro-3-methylsulfonylbenzoic acid are refluxed in 460 ml of piperidine for 11 hours, then diluted with 800 ml of water and treated with conc. Hydrochloric acid to pH 2 provided. After crystallization in an ice bath, the solid is filtered off. Colorless crystals of ethanol, mp 234-238 ° C.

e) 3-Methylsulfone ^ 1- (1-plperidino) benzoylchloride

is obtained by refluxing 50 g of 3-methylsulfonyl-4- (1-piperidino) benzoic acid over 4 hours in 400ml of thionyl chloride, carefully distilling off the solvent under reduced pressure and crystallization of the residue under dimethyl ether.

f) 3-methylsulfonyl-4- (1-plperidino) benzoylguanidine

21.8 g of 3-methylsulfonyl-4- (1-piperidino) benzoyl chloride are stirred with 31.4 g of guanidine in 200 ml of 1,2-dimethoxyethane under inert gas for 2 hours at 5-10 ⁰ C, with cooling with 200 ml of water and adjusted to pH 6-7 with 2N HCl. After distilling off half of the solution volume, the crystals are filtered off and recrystallized from methanol. Colorless crystals, mp. 210-213 ⁰ C (dec.).

Example 5

A-MethylsuKonyl ^ -d-plperldlnol-benzoylguanidl-dlyhdrochlorlder is obtained from 3-methylsulfonyl-4- (1-piperidin'o) benzoylguanidine in 10 times the weight of methanol by addition of excess ethereal HCl and stirring the salt precipitate with cooling in an ice bath.

White crystal powder, mp 210-214 ° C (decomp.). Example 6

a-methylsulfonyl-d-plperldinol-benzoylguanil-hydrochloride is obtained by treating 200g of the dihydrochloride (Example 5) with the equivalent amount of a monovalent base (NaOH ₁ NaHCO ₃ , N (C ₂ H ₆ I ₃ , etc.) in Figure 1, From 3 to 1.41 of water or by simple recrystallization of the indicated amount of substance from 1.3 to 1.41 of water.

Colorless crystals, mp 235-237 ⁰ C. Example 7

4-Chloro-3-N, N-Dimethylsulfarnoylbenzoyl-guanldln-hydrochloride is obtained analogously to the procedure given in Example 1 by reacting 2.7 g (0.01 mol) of methyl 4-chloro-3-dimethylsulfamoylbenzoate (mp -96 ⁰ C) with 0.04 mol of guanidine in methanol and then analogous working-up.

White Crystal Powder, m.p. 224-226 ⁰ C (Zers.). Example 8

4-chloro-3- (1-plperidyl-sulfonyl) -benzoylguanldin one hydrochloride is obtained (1-piperidyl-sulfonyl) -benzoic acid methyl ester (mp. 110-112 ⁰ C) analogous to that described in Example 1 from 4-chloro-3- and guanidine in methanol as a solvent.

White crystal powder, mp 232-234 ⁰ C. Example 9 S-N-BenzylsulfamoyM-chlorobenzoylguanidine guanldln-hydrochlorld

The procedure given in Example 1 from 3-N-Benzylsulfamoyl-4-chlorobenzoate (mp.

93-95 ⁰ C.) and guanidine in methanol as Raktionsmedium.

White crystal powder, mp 224-225 ⁰ C. Example 10

4-Sulfamoylbenzoyl-guaneldlner is obtained analogously to the procedure given in Example 1 aus4-sulfamoylbenzoic acid pentafluorophenol ester, prepared from 4-sulfamoylbenzoyl chloride and pentafluorophenol in the presence of 1 mol of pyridine, with guanidine in methanol as

Reaction medium. White crystal powder, mp. 200 ⁰ C (dec.). Example 11

4-Sulfamoylbenzoylguanidine hydrochloride is obtained by treating the compound prepared in Example 10 with ethereal HCl in ethyl acetate.

Colorless crystal powder, mp 282 ^C Example 12

4-N, N-dimethylsulfamoylbenzoylguanidine hydrochloride is obtained analogously to the procedure described in Example 1 from 4-N, N-diethylsulfamoylbenzoic acid pentafluorophenol ester prepared from 4-N, N-diethylsulfamoylbenzoic acid, pentafluorophenol, thionyl chloride and pyridine (mp. 114 ° C), and

Guanidine in methanol as solvent and analogous work-up. White crystal powder, mp 216-218 ⁰ C. Example 13

4- (1-piperidylsulfonyl) benzoylguanidine hydrochloride is obtained analogously to the procedure given in Example 1 from 4- (1-piperidylsulfonyl) benzoate and guanidine in

Methanol as reaction medium. White crystals, mp 281 ⁰ C. Example 14

4-Methylthlobenzoyl-guanidIn hydrochloride is obtained analogously to the procedure given in Example 1 from 4-methylthiobenzoate and guanidine in methanol as a solvent.

White crystal powder, mp. 255-259 ⁰ C. Example 15

4-Phenylthic-3-sulfamoylbenzoyl-guanldin-hydrochlorld

a) is obtained analogously to the procedure given in Example 1 from 4-phenylthio-3-sulfamoylbenzoesäure methyl ester and

Guanidine in methanol as solvent. White crystal powder, mp 275-283 ° C.

b 4-phenylthio-3-sulfamoylbenzoesäuremethylester used) obtained by reaction of 4.4 g of 4-fluoro-3-sulfamoylbenzoesäuremethylester (mp. 127-129 ⁰ C), prepared from 4-fluoro-3-sulfamoylbenzoic acid and thionyl chloride and subsequent methanol treatment with 2.2 g of thiophenol and 1.38 g of anhydrous and ground K ₂ CO ₃ in 20 ml of anhydrous dimethylformamide for 2 hours at 80 ° C, followed by precipitation by addition of about 100 ml of water. White crystals from methanol, mp. 154-157 ⁰ C.

Example 16 3-Methylsulfonyl-4-phenylthlobenzoyl-guanidine hydrochloride

a) obtained analogously to the procedure given in Example 1 from methyl 3-methylsulfonyl-4-phenylthiobenzoesäure and guanidine in methanol as a reaction medium and analogous workup.

Colorless crystals, mp. 279-281 ⁰ C.

b) The 3-methylsulfonyl-4-phenylthiobenzoesäuremethylester used is prepared from 4-chloro-3-methylsulfonylbenzoesäuremethylester according to the procedure given in Rule 15b).

White crystals, mp 155-156 ⁰ C.

Example 17 4-Phenoxy-3-sulfamoylbenzoylguanidine

a) is obtained analogously to the procedure given in Example 1 (without HCl treatment) of 4-phenoxy-3-sulfamoylbenzoesäuremethylester and guanidine in methanol.

White crystal powder, m.p. 178-181 ⁰ C.

b) The methyl 4-phenoxy-3-sulfamoylbenzoate used is obtained analogously to the procedure described in 15b) by reacting 4-fluoro-3-sulfamoylbenzoic acid with phenol in DMF and in the presence of K ₂ CO ₃ with stirring for 6 hours at 80 ° C.

White crystalline solid, mp. 148-151 ⁰ C. Example 18

3-methylsulfonyl-4-N-morpholinobenzoyl-guanidine

the procedure given in Example 4f) is obtained by reacting 3-methylsulfonyl-4-N-morpholinobenzoyl chloride with guanidine in anhydrous tetrahydrofuran.

White Crystal Powder, m.p. 26O ⁰ C (Zers.). The S-MethyisulfonyM-N-morpholino-benzoyl chloride is obtained over several stages

a) starting from the 4-chloro-3-methylsulfonylbenzoic acid which is stirred at 110 ° C. for 5 hours in twice the amount by weight of morpholine and after taking up the reaction mixture in water, from which after acidification with HCl the 3-methylsulfonyl-4-N- morpholinobenzoic acid is obtained (252-255 ⁰ C from methanol mp.).

b) 5 g of 4-chloro-3-methylsulfonylbenzoic acid mentioned under a) are refluxed in 50 ml of thionyl chloride for 2 hours and, after distilling off the liquid constituents, the desired benzoyl chloride derivative is crystallized in diisopropyl ether / petroleum ether mixture. M.p. 98-102 ⁰ C.

Example 19

3-methylsulfonyl-4-N-pyrrolidinobenzoyl-guanldln

The procedure described in Example 4f) is obtained by reacting 5 g of 3-methylsulfonyl-4-N-pyrrolidinobenzoyl chloride with 3.4 g of guanidine in anhydrous tetrahydrofuran at room temperature, pouring into 200 ml of water and extraction with ethyl acetate. After distilling off the extractant, the solid is crystallized under methanol, the solid is dissolved in ethyl acetate and purified by column chromatography on silica gel (eluent ethyl acetate). After evaporation of the eluent, crystallization is carried out under diisopropyl ether. Colorless crystalline compound, mp. 128-135 ⁰ C (dec.).

The used 3-methylsulfonyl-4-N-pyrrolidinobenzoyl chloride is obtained over several stages starting from the

a) 4-chloro-3-methylsulfonyl-benzoic acid analogously to the procedure described in Example 18a) by heating for 5 hours at 100 ⁰ C in pyrrolidine and analogous isolation of the resulting 3-methyl-sulfonyl-4-pyrrolidinylbenzoic acid: colorless crystals of ethanol, m.p. 228-23O ⁰ C.

b) The benzoic acid prepared under a) is converted analogously to Example 18b) into the desired 3-methylsulfonyl-4-N-pyrrolidinobenzoyl chloride (mp 137-139 ⁰ C).

Example 20

4-N-morpholino-3-sulfamoylbenzoyl-guanidln

the procedure given in Example 1 from the 4-N-morpholino-3-sulfamoylbenzoesäuremethylester and

Guanidine by boiling in methanol for 4 hours, isolating the title compound after extraction with ethyl acetate

and column chromatographic purification on silica gel with ethyl acetate as eluent (without subsequent conversion with

HCI in the hydrochloride White crystal powder, mp 239-241 ⁰ C.

The 4-N-morpholino-3-sulfamoylbenzoesäuremethylester used as starting material is obtained by heating 2g of 4-fluoro-3-sulfamoylbenzoesäuremethylester with 1.5g morpholine in 8ml dimethylacetamide over 5 hours at 100 ⁰ C, followed by precipitation of the substance by the addition of water and crystallization of the amorphous ester precipitate under water. Mp 61-64 ⁰ C.

Example 21

3-Methylsulionyl-4- (1-methyl-4-plperazlno) benzoyl-guanldln

is obtained analogously to the procedure given in Example 1 by reacting 1 g of methyl 3-methylsulfonyl-4- (1-methyl-4-piperazino) benzoate and 1 g of guanidine in 25 ml of methanol as the reaction medium for 6 hours at 60 ° C. The

Compound precipitates on standing overnight and is filtered off. Pale yellow crystalline solid, mp 248-250 ° C.

The 3-methylsulfonyl-4- (1-methyl-4-piperazino) -benzoic acid methyl ester used as starting material is obtained via several reaction stages starting from

a) 4.7 g of 4-chloro-3-methylsulfonylbenzoic acid and its reaction with 5.2 g of N-methylpiperazine in 15 ml of dimethylacetamide at 12O ⁰ C for 5 hours, distilling off the solvent, taking up the residue in water, acidification with 2 N Hydrochloric acid and filtering off the precipitate. Crystalline solid, mp.> 300 ⁰ C.

b) reflux of the benzoic acid derivative prepared in a) in thionyl chloride, its distillation and reaction of the residue with methanol and triethylamine. After distilling off the solvent again and treating the residue with water, the desired methyl ester is precipitated, which is crystallized under diisopropyl ether. White crystalline solid, mp. 138-145 ⁰ C.

Example 22

4-N-benzyl-N-methylamino-3-methylsulfonylbenzoyl-guanidine hydrochloride is obtained analogously to the procedure described in Example 4 f) by reacting 4.3 g of 4-N-benzyl-N-methylamino-3-methylsulfonyl-benzoyl chloride with 5.2g guanidine in 30ml abs. Tetrahydrofuran at 5 to 1O ⁰ C. mitmethanolischem Prior to transferring hydrogen chloride, the free benzoylguanidine of the title compound is purified by column chromatography on

Silica gel with a mixture of ethyl acetate (10VoI) + cyclohexane (5VoI) + chloroform (5VoI) + methanol

(5VoI) + NH ₃ -aq. (1 VoI) as eluent.

Colorless crystal powder, mp 234-24O ⁰ C. The described 4-N-benzyl-N-methylamino-3-methylsulfonyl-benzoyl chloride (oily amorphous product, which without further Purification steps is used) is obtained over several stages starting from the 4-chloro-3-methylsulfonylbenzoic acid,

which in analogy to Example 21 a) reacts with N-benzyl-N-methylamine to give 4-N-benzyl-N-methylamino-3-methylsulfonylbenzoic acid (mp 196-202 ° C.), and subsequent reaction with thionyl chloride.

Example 23

4-Benzylam amino-3-methylsulfonylbenzoylguanidine guanldin acetate

is obtained analogously to the method described in Example 4f) by reacting 4-benzyl-3-methylsulfonylbenzoyl chloride with guanidine in anhydrous tetrahydrofuran. The workup is carried out by acidifying with acetic acid aufpH 4; after the solvent has been partially distilled off, in particular the THF fraction, the 4-benzylamino-3-methylsulfonylbenzoylguanidine acetate precipitates in crystalline form.

Light yellow crystalline solid with 2 melting points: m.p. 163-168 ° C, mp. 230-232 ⁰ C. The precursor used as 4-benzylamino-3-methylsulfonylbenzoic acid (m.p.. 230-235 ⁰ C) is obtained in analogy to that of Example 21 described Roassdurchführung of 4-chloro-3-methyl-sulfonylbenzoic acid and benzylamine and in the above Analogy with thionyl chloride, the desired 4-benzyl-3-methylsulfonyl-benzoyl chloride (mp 100-104 ⁰ C). Analogous to the rule given in Example 4f) is obtained from the corresponding benzoyl chlorides of the formula II and Guanidine in anhydrous tetrahydrofuran the following compounds of formula I or their salts: Example 24

3- (3-Methyl-1-butylsulfonyl-4-N-plperldino-benzoylguanidine hydrochloride (mp. 155 ° C./Zere.) With 2-chloro-O-carboxybenzenesulfinic acid disodium salt as starting stage over 4-chloro-3- (3-methyl-1-butylsulfonylbenzoic acid 3-methyl-1-butyl ester (amorphous compound),

4-chloro-3- (3-methyl-1-butylsulfonyl) -benzoic acid (mp. 140-144 ⁰ C),

3- (3-methyl-1-butylsulfonyl) -4-N-piperidino-benzoic acid (mp. 161-165 ⁰ C)

and S-O-MethyM-butylsulfonylM-N-piperidino-benzoylchloridjÖI).

Example 25 S-O-butylsulfonylM-N-pipereldlnobonzoyl-guanidine-1-hydrochloride (m.p. 184 ° C / dec.)

with 2-chloro-5-carboxybenzenesulfinic acid disodium salt as starting stage over 3- (1-butylsulfonyl) -4-chlorobenzoic acid 1-butyl ester (OI),

3- (1-butylsulfonyl) -4-chlorobenzoic acid (mp. 142-146 ⁰ C),

3- (1-butylsulfonyl) -4-N-piperidinobenzoesäure (mp. 156 ⁰ C)

and 3- (1-butylsulfonyl) -4-N-piperidinobenzoyl chloride (oil).

Example 26

4-N- (1-Hexylamlno) -3-methylsulfonylbenzoylguanidine guanldin

To a solution of 2.99 g of 4-N- (1-hexylamino) -3-methylsulfonylbenzoic acid in 40 ml of anhydrous tetrahydrofuran is added

1.78 g of carbonyldiimidazole, stirred for 2 hours at room temperature and 1 hour at 45 ° C and the mixture is then treated at 2O ⁰ C with 4.13g guanidine. The mixture is stirred for 12 hours at room temperature, the solvent is distilled off, with 2N HCl on pH 6-7, stirred for one hour in an ice bath, the solid is filtered off and dissolves this after washing with water from ethanol.

Colorless solid, mp. 135-145 ⁰ C. Precursors of Example 26 starting from 4-chloro-3-methylsulfonylbenzoic acid over 4-N- (1-hexylamino) -3-

Methylsulfonylbenzoesäure (colorless crystals, mp 169 ⁰ C).

Example 27

3-N-Ethyl-N-isopropylsulfamoyl-4- (1-plperldlno) benzoylguanlene is obtained analogously to the example given in the reaction by reacting 3-N-ethyl-N-isopropylsulfamoyl-4- (1-piperidino) benzoic acid, carbonyldiimidazole and guanidine.

Colorless crystals, mp 212 ⁰ C. Precursors of Example 27 starting from 3-chlorosulfonyl-4-fluoro-benzoic acid over 3-N-ethyl-N-isopropylsulfamoyl-4-

fluorobenzoic acid (mp. 108-115 ⁰ C), 3-N-ethyl-N-isopropylsulfamoylbenzoesäure (mp. 138-140 ⁰ C).

Example 28

4-Amlno-3-methylsulfonylbenzoyl-guanldln-hydrochloride is obtained analogously to the procedure given in Example 1 by reacting methyl 4-amino-3-methylsulfonylbenzoate and guanidine in methanol.

White crystal powder, mp 245-248 ⁰ C. Precursors of Example 28 starting from 4-chloro-3-methylsulfonylbenzoic acid via 4-N-hydrazino-3-one

Methy'sulfonylbenzoesäure (mp 243-245 ⁰ C) and its hydrogenolytic NN cleavage with Raney nickel catalyst in

Math lol / NHa-aq. under atmospheric pressure at room temperature to 4-amino-3-methylsulfonylbenzoic acid (m.p.. 258-262 ⁰ C)

and subsequent reaction with thionyl chloride and methanol to give 4-amino-3-methylsulfonylbenzoic acid methyl ester (m.p.

Example 29

1,1-Dimethyl-3- (3-methylsulfonyl-4-N-plperidinobenzoyl) -guanidine-3,6g S, -dimethylpyrazole-M-carboxylic acid-N-methylsulfonyl -d-piperidino-benzoyl-d-carboxamic acid are dissolved in 30 ml of 40% aqueous dimethylamine solution Autoclave heated to 80 ° C over 4 hours, the crystalline precipitate filtered off and recrystallized from ethanol.

Colorless crystals, mp 207 ⁰ C. Precursors of Example 29 starting from a solution of 2.92 g of 3-methylsulfonyl-4-N-piperidino-benzoyl chloride in 10 ml Ess' ^ ester and its dropwise addition to a solution of 3,5-dimethylpyrazole-1-carboxamiditrate (97%, Aldrich) in 12.8ml

10% NaOH at 10-15 ⁰ C, stirring for 2 hours at room temperature, distilling off the solvent and recrystallizing the residue from ethyl acetate (colorless crystalline solid, mp 201-202 ⁰ C).

Example 30

1-methyl-3- (3-methylsulfonyl-4-N-piperldino-benzoyl) -guanldlnerhält man analogously to the procedure given in Example 29 by reaction with 40% aqueous methylamine in the

Autoclave. Colorless crystalline solid, mp. 202-203 ⁰ C (from ethanol). Example 31

4-Chloro-3- (3-phenyl-1-propylsulfonyl) -benzoyl-guanidln-hydrochloride is obtained analogously to the procedure described in Example 26 by reacting 4-chloro-3- (3-phenyl-1-propylsulfonyl) benzoic acid Guanidine and carbonyldiimidazole.

Colorless crystals, mp 178-182 ⁰ C (Zers.). Precursors of Example 31 starting from 2-chloro-5-carboxybenzene-sulfinic acid over 4-chloro-3- (3-phenyl-1-propylsulfonyl) -

benzoic acid (3-phenyl-1-p.'opyl) ester (viscous oil) and 4-chloro-3- (3-phenyl-1-propylsulfonyl) benzoic acid (colorless crystals, mp 126-13O ⁰ C) ,

Example 32

4- (2,3-Dlhydro-1-indolyl) -3-methylsulphonylbenzoylguanine is obtained analogously to the procedure given in Example 26 from 4- (2,3-dihydro-1-indolyl) -3-methylsulphonylbenzoic acid,

Carbonyldiimidazole and guanidine (mp 136 ° C / dec.). Precursors of Example 32 starting from 4-chloro-3-methylsulfonylbenzoic acid over 4- (2,3-dihydro-1-indolyl) -3-

Methylsulfonyl-benzoic acid (mp 158 ⁰ C).

Example 33 S-IS-phenyl-i-fi-propylsulfonylM piperldlnol-benzoyl-guanidln-dlhydrochlorld

is obtained analogously to the procedure given in Example 26 by reaction of 3- (3-phenyl-1-propylsulfonyl) -4- (1-piperidino) benzoic acid, carbonyldiimidazole and guanidine.

Colorless solid, mp. 160 ⁰ C (dec.). Precursors: starting from 4-chloro-3- (3-phenyl-1-propylsulphonyl) benzoic acid (see Ex. 31) via 3- (3-phenyl-1-one)

propylsulfonyl) -4- (1-piperidino) benzoic acid (mp 17O ⁰ C).

Example 34

4- (N-2,4-dichlorobenzyl-N-methylamino) -3-methylsulfonylbenzoyl-quanidin-hydrochloride is obtained analogously to the procedure given in Example 1 by reacting 4- {N-2,4-dichlorobenzyl-N-methylamino) - Methyl 3-methylsulfonylbenzoate and guanidine in methanol as solvent. (Mp. 18O ⁰ C)

Example 35

4- (1-piperidinyl) -3-sulfamoylbenzoyl-guanidine hydrochloride is obtained analogously to the procedure described in Example 26 from 4- (1-piperidino) -3-sulfamido-benzoic acid, carbonyldiimidazole and guanidine.

Colorless crystalline solid, mp 236 ° C (dec.).

Precursors starting from 4-fluoro-3-sulfamoylbenzoic acid over 4- (1-piperidino) -3-sulfamoylbenzoic acid (mp 246-247 ⁰ C). Analogously to the procedure given in Example 26, the following compounds of the formula I are obtained by reacting a benzoic acid derivative of the formula II where X = OH, activating it with carbonyldiimidazole and then reacting with guanidine.

Example 36

4- (3-Mothoxy-1-propylamino) -3-methylsulfonylbenzoylguanidine hydrochloride, colorless crystals, mp 167-169 ° C Precursors starting from 4-chloro-3-methylsulfonylbenzoic acid over 4- (3 Methoxy-1-propylamino) -3-methylsulfonylbenzoic acid (mp 190 ° C / from ethanol).

Example 37

4- (3-phenyl-1-propylamlno) -3-methylsulfonylbonzoyl-guanidine

White crystal powder, mp 177-178 ⁰ C. Precursors starting from 4-chloro-3-methyl sulfonylbenzoic acid over 4- (3-phenyl-1-propylamino) -3-

Methylsulfonylbenzoesäure (mp 172 ⁰ C).

Example 33

4-lsobutylamlno-3-methylsulfonylbenzoylguanidine guanldln-hydrochlorld

White crystal powder, m.p. 163-166 ⁰ C Precursors starting from 4-chloro-3-methylsulfonylbenzoic acid over 4-isopropylamino-3-methylsulfonylbenzoic acid (m.p. Example 39 S-fS-methoxy-i-propylsulfarnoylM-O-benzoyl-plperldinol-guanldln-hydrochlorld White crystal powder, m.p. 209-211 ⁰ C. Precursors starting from 4-chloro-3-chlorosulfonylbenzoesäure over 4-chloro-3 - (; 3-methoxy-1-propylsulfamoyl) benzoic acid

(Mp. 149-150 ° C) and 3- (3-methoxy-1-propylsulfamoyl) -4- (1-piperidino) benzoic acid (mp. 138-14O ⁰ C).

Example 40 S-lsopropylsulfamoyM-d-plperidinol-benzoyl-guanldin-hydrochlorld White crystal powder, m.p. 209-211 ⁰ C. Precursors starting from 4-chloro-3-isopropylsulfamoylbenzoic acid over 3-isopropylsulfamoyl-4- (1-piperidino) benzoic acid

(Mp 186-188 ⁰ C).

Example 41

3- (1-propylsulfamoyl) -4- (1-piperidlno) benzoyl-guanldln hydrochloride

White crystal powder, m.p. 176 ⁰ C (Zers.). Precursors: Starting from 4-chloro-3- (1-propylsulfamoyl) benzoic acid over 3- (1-propylsulfamoyl) -4- (1-piperidino) -

benzoic acid (mp 138-139 ⁰ C).

Example 42

3- (3,5-Dimethyl-1-piperidino-Surfonyl) -4- (1-piperidino) benzoylguanidine

Wait crystal powder, mp 202-204 ⁰ C. Precursors: Starting from 3-chlorosulfonyl-4-fluorobenzoic acid over 3- (3,5-dimethyl-1-piperidinosulfonyl) -4-fluoro-benzoic acid

(Mp. 207 ⁰ C), 3- (3,5-dimethyl-1-piperidinosulfonyl) -4- (1-piperidino) benzoic acid (mp. 198 ⁰ C).

Example 43 S-methylsulfonyl ^ -IN.N-dM-propylamlnoI-benzoyl-guanidine hydrochloride White crystal powder, mp 157-159 ⁰ C. Precursors: Starting from S-methylsulfonyl-chlorobenzoic acid via S-methylsulfonyM-IN.N-di-i-propylaminol-benzoic acid

(Mp 122-124 ⁰ C).

Example 44

4-Cyclopentylamino-3-rnethylsulfonylbenzoyl-guanldln

White crystal powder, mp. 238-24O ⁰ C. Precursors: Starting from 4-chloro-3-methylsulfonylbenzoic acid via 4-cyclopentylamino-3-methylsulfonylbenzoic acid

(Mp 219-222 ⁰ C).

Example 45

4-ethylsulfonyl-3-N-pyrrol! Dlnobenzoyl-guanidln-hydrochlorld

Analogously to Example 2 from 4-ethylsulfonyl-3-N-pyrrolidinobenzoate and guanidine.

M.p. 180-182 ° C

Example 46

4-phenylsulfonyl-3-N-pyrrolidinobenzoyl guanidine hydrochlorld

Analogously to Example 2 from 4-phenylsulfonyl-3-N-pyrrolidinobenzoesäuremethylester and guanidine.

M.p. 226-228 ° C

Example 47

4-cyclohexylsulfonyl-3-N-pyrrolldlnobenzoyl-guanidine

Analogously to Example 2 of e-cyclohexylsulfonyl-S-N-pyrrolidinobenzoate and guanidine. The first received Hydrochloride of the title compound, a H] O is dissolved and precipitated by the addition of 2 N sodium hydroxide solution as the free base and

aspirated.

M.p. 234-236 ⁰ C

Example 48

4-methylsulfonyl-3-N-pyrrolldlnobenzoyl-guanldln

Analogously to Example 2 from 4-methylsulfonyl-3-N-pyrrolidino-benzoic acid methyl ester and guanidine.

M.p. 165-168 ⁰ C

Preparation of Precursors to Examples 45-48: For the preparation of the corresponding benzoic acid methyl esters for Examples 45-48, 4-chloro-3-one is used.

nitrobenzoic acid methyl ester as starting material. Sales with ethylmercaptan (45), thiophenol (46), cyclohexylsulfide (47) or methylmercaptan (48) under standard conditions such as K ₂ CO ₃ in DMF leads to the corresponding 4-thio-3-nitrobenzoic acid methyl esters, which react with H ₂ O ₂ in glacial acetic acid be oxidized to the corresponding 4-sulfonyl-3-nitrobenzoic acid esters. After reduction of the 3-nitro group with succinic anhydride and reduction with NaBH ₄ ZBF ₃ Et ₂ O der

Pyrrolidine radical introduced:

10 g of methyl 3-amino-4-methylsulfonylbenzoate are stirred with 8.7 g of succinic anhydride in the melt at 16O ⁰ C for 5 hours. The solid residue is dissolved in methanol and stirred into water. The precipitated precipitate is sucked off.

Mp 218-22O ⁰ C12.2g of the 4-methylsulfonyl-3-N- (2,5-Dioxopyrrolidinobenzoesäuremethylesters prepared herewith is dissolved in 100 ml

Diglyme and cooled after addition of 14.5ml BF ₃ -Ethorat to 2 ⁰ C then added 4.4g NaBH ₄ and the mixture is stirred

5 hours at this temperature. The mixture is then poured onto ice / water and the ausgefallene4-methylsulfonyl-3-N-pyrrolidinobenzoosäuremethylester (mp. 96-98 ⁰ C) filtered off with suction.

For this purpose, the corresponding benzoic acid esters are obtained analogously to Examples 45,46 and Example 49

4-Cyclohexylthlo-3-methylsulfonylbenzoylguanidine guanldln

Analogously to Example 1, but with 4-cyclohexylthio-3-methylsulfonylbenzoesäuremethylester from starting material.

Mp 201-204 ° C

Harmharmonic data K-Strophantidine-induced ventricular tachycardia in the dog

Method:

Intravenous infusion of 3pg / kg · min Ouabain causes sustained ventricular tachycardia (VT) in 40-60 minutes of pentobarbitone anesthetized beagles. Once VT starts, the Ouabaininfus.'on is aborted, but the VT persists for approximately 2 hours and is tracked by continuous ECG control. The substance to be tested is i.p. 10 min after completion of the ouabain infusion. v. applied.

Results: In 4 of 5 dogs, 10 mg / kg of the compound of Example 34 resulted in normalization of the ECG for 6-11 minutes.

Claims (5)

1. Process for the preparation of a benzoylguanidine of the formula I. R <l)r =? (5) μ R (3) wherein R (1) or R (2) R (6) -S (O) _n - or R (7> y ν - OgS - mean and the other substituent R (1) or R (2) H, F, Cl, Br, J, C ₁ -GrAlkyl, C ₁ -C ₄ -alkoxy, phenoxy which is unsubstituted or one to three Substituents from the groups fluorine, chlorine, methyl or methoxy carries, R (6) -S (0) _n or R (7) ; ^{S |} - means RO) ^y and wherein R ^{6 is} C ₁ -C ₆ -alkyl, C ₆ -C ₇ -cycloalkyl, cyclopentylmethyl, cyclohexylmethyl or for
Phenyl is unsubstituted or carries one to three substituents from the groups fluorine, chlorine, methyl or methoxy, and wherein R (7) and R (8) are identical or different and in the
Meaning of H, C ₁ -C ₆ -Alkyl or R (7) is phenyl (CH ₂ ) _m - with m = 1-4 or phenyl which is unsubstituted or one to two substituents from the groups fluorine, chlorine , Methyl or methoxy, and in which R (7) and R (8) can also together be a straight-chain or branched C ₄ -C ₇ chain, wherein the chain can additionally be interrupted by O, S or NR (9) and R (9) is H or methyl and R (7) and R (8) together with the nitrogen atom to which they are attached
and R (3), R (4) and R (5) are hydrogen, C ₁ -C ₂ alkyl, wherein R (3) and R (4) are in common a (C ₂ -C ₄ alkylene chain and R (4) and R (5) can together form a (C ₄ -C ₇ ) alkylene chain,
and η is zero, 1 or 2, and a pharmaceutically acceptable salt thereof
characterized in that a compound of the formula II RC) _c R (2) ' ^N CO - X with a guanidine derivative of formula III ^K ! R (-1) R (5)
u N = C ( III wherein R (D to R (5) have the meaning given above and X is a light
nucleophilically substitutable leaving group. 2. The method according to claim 1, characterized in that one uses compounds II and III, in which the substituents have the following meaning: R (D is fluorine, chlorine, NR (7) R (8), R (6) -S (O) _n or phenoxy,
R (2) for R (6) -S (O) _n - and R (7) R (8) N-SO ₂ -, wherein η is zero, 1,2
R (3), R (4) and R (5) are hydrogen,
R (6), R (7) and R (8) as defined in claim 1. 3. The method according to claim 1, characterized in that one uses compounds II and III, in which mean: R (DR (7) R (8) N- or R (6) -S (O) _n -, in which R (6) is alkyl having 1-3 C atoms or phenyl, η = zero,
and R (7) and R (8) together form hydrogen (1-4C) or R (7) and R (8) form a (C ₄ -C ₇ ) methylene chain and R (2) represents CH ₃ -SO ₂ - or H ₂ N-SO ₂ - and R (3), R (4) and R (5) are hydrogen. 4. The method according to claim 1, characterized in that the compounds 3-methylsulfonyl-4- (1-piperidinyl) benzoyl-guanidine, 4-phenylthio-3-sulfamoylbenzoyl-guanidine or 3-methylsulfonyl-4-phenylthiobenzoyl-guanidine or their pharmacologically acceptable salts produced. 5. A process for the preparation of a medicament for the treatment of arrhythmias, characterized in that mixing an effective amount of a compound I according to claim 1 with the pharmaceutically customary additives and brings in a suitable dosage form.