FI112076B - A process for the preparation of therapeutically useful ortho-substituted benzoylguanidines - Google Patents

Abstract

Ortho-substituted benzoylguanidines of the formula I <IMAGE> where: R(1) is equal to halogen, alkyl, -X-R(6), where X is equal to O, S, NR(7) or Y-ZO and R(6) is equal to H, (cyclo)(halo)alkyl(methyl), -CnH2n-phenyl, R(3) is equal to H, -X-R(6), R(2) and R(4) are equal to R(11)-SO1-2-, (di)-alkyl-N-SO2-, or one of the two radicals R(2) or R(4) is equal to hydrogen or is defined as R(1), R(5) is equal to H, methyl, F, Cl, methoxy, and their pharmaceutically acceptable salts. They are obtained by a process in which compounds of the formula II <IMAGE> in which R(1) to R(5) have the meaning mentioned and L represents a leaving group which can be easily substituted nucleophilically, are reacted with guanidine. The compounds I are used for producing a medicament for the treatment and the prophylaxis of heart-rhythm disorders and ischaemically induced damage, as well as for producing a medicament for the inhibition of cell proliferation.

Description

, 112076

A process for the preparation of therapeutically useful ortho-substituted benzoylguanidines

The invention relates to a process for the preparation of therapeutically useful ortho-substituted benzoylguanidines of the formula «(1) (I) * (4) Y Π *» 0 ΜΗ, * (5) wherein R (1) is F, Cl, Br , I, C 1-6 alkyl or -XR (6) wherein X is O, S, NR (7) or Y-ZO, wherein Y is O or NR (7) and Z is C or SO, R (6) is hydrogen, C 1-6 alkyl, C 5-7 cycloalkyl, cyclo-15 hexylmethyl, cyclopentylmethyl, - (CH 2) m C p F 2 P + 1 or -C n H 2n -R (8) wherein. m is 0 or 1., ···. p is 1-3, n is 0-4 and 20 R (8) is phenyl which is unsubstituted or substituted with 1-3 substituents F, Cl, CF 3, methyl, methoxy or NR (9) R (10) wherein • * *:. * R (9) and R (10) are hydrogen or C 1-4 alkyl, · · · * ... · R (7) is hydrogen or C 1-4. 3-alkyl, whereby 25 R (6) and R (7) may also be taken together to represent 4 or 5 · · ·, ···. a methylene group and one CH2 group may be replaced by 0, • · S, NH, N-CH3 or N-benzyl, • ·: R (3) is hydrogen or -XR (6) wherein:. X is O, S, NR (7) or Y-ZO, wherein R (7) is hydrogen or C 1-3 alkyl, 2 112076 Y is O or NR (7), Z is C or SO, wherein Y is attached to a phenyl group of formula I, R (6) is hydrogen, C 1-6 alkyl, C 5-7 cycloalkyl, cyclo-5 hexylmethyl, cyclopentylmethyl, - (CH 2) m C p F 2 p + i or -C n H 2n -R (8) wherein m is 0 or 1, p is 1-3, n is 0-4 and 10 R (8) is phenyl which is unsubstituted or substituted with 1-3 substituents F, Cl, CF 3, methyl, methoxy or NR (9) R (10) wherein R (9) and R (10) are hydrogen or C 1-4 alkyl, and R (6) and R (7) may also be taken together to represent 4 or 5 methylene groups and one CH2 group may be replaced by 0, S, NH, N-CH3 or N-benzyl, R (2) and R (4) are the same or different and are R (II) -SOq - or R (12) R (13) N-SO 2 - wherein 20 q is 0 to 2, R (11) is C 1-4 alkyl which is unsubstituted or substituted with phenyl, wherein the phenyl is unsubstituted or substituted with 1 to 3 substituents, J (jf); which is F, Cl, CF 3, methyl, methoxy or NR (9) R (10), wherein R (9) and R (10) are hydrogen or C 1-4 alkyl, *; R (12) and R (13) are the same as R (6) and R (7); or one of R (2) or R (4) is hydrogen or denotes the same as R (1), and R (5) is hydrogen, methyl, F, Cl or methoxy, and pharmaceutically acceptable salts thereof; for the preparation of salts.

... The process according to the invention is characterized by

'! * that compounds of formula II

t »•» 1 »» · »» 3 112076 «(2)« (♦) I if (in '0 R (5) wherein R (1) to R (5) are as defined above and L is readily nucleophilically substitutable starting group, is reacted with guanidine.

Preference is given to compounds of formula I prepared by the process of the invention wherein R (1) is F, Cl, C 1-3 alkyl, CF 3, -XR (6), wherein X is O, S or NR (7), 10 R ( 6) is hydrogen, C1-6 alkyl, - (CH2) mCpF2p + i, -CnH2n-R (8), m is 0 or 1, p is 1-3, n is 0-4, R (8) is phenyl, which is unsubstituted or substituted '· 15 with one to three substituents · · · · originating from the following groups: F, Cl, CF 3, methyl, methoxy, NR (9) R (10), wherein R (9) and R (10) are hydrogen or C 1-4 alkyl, R (7) is hydrogen or methyl, wherein R (6) and R (7) may also be taken together to represent cyclically 20 4 or 5 methylene groups and one CH 2 group may be replaced With 0, Sr, NH, N-CH 3 or N-benzyl, R (3) is hydrogen, R (2) and R (4) are the same or different and represent »1 CH 3 -SO 4 - or R (12) R (13) is N-SO 2 - wherein j q is 0 to 2, R (12) and R (13) are defined as R (6) and R (7), II ·. or one of the two groups R (2) or R (4) is hydrogen or t · »*; ! as defined for R (1), R (5) is hydrogen, 4112076, and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I prepared by the process of the invention wherein R (1) is F, Cl, C 1-3 alkyl, -XR (6), X is O, S or NR (7), R (6). ) is hydrogen, C 1-4 alkyl, -C n H 2n -R (8), n is 0-3, R (8) is phenyl which is unsubstituted or substituted with one to three substituents from the group F, Cl, CF 3, methyl, methoxy, NR (9) R (10) wherein R (9) and R (10) are hydrogen or methyl, R (7) is hydrogen or methyl, wherein R (6) and R (7) may also together denote 4 or 5 methylene groups and one CH2 group may be replaced by 0, S, N-CH3, R (2), R (3) and R (5) denote hydrogen, R (4) ) is CH 3 -SO 2 - or R (12) R (13) N-SO 2 -, wherein R (12) is -C n H 2n -R (8), 20 n is 1-3,. R (8) is phenyl which is unsubstituted or substituted with one to three substituents from the group: F, Cl, CF 3, methyl, methoxy, NR (9) R (10), wherein R (9) and R (10) ??? denote hydrogen or methyl ;,,,,,,,,,,,,, R (13) is hydrogen, where: ·: R (12) and R (13) may also be taken together to represent 4 or 5 methylene groups, and one CH 2 group. may be substituted with 0, S, N-CH 3 or N-benzyl.

: V. If one of the substituents R (l) to R (13) contains an asymmetry center, then the invention relates to both »S and R configured compounds. The compounds may exist as optical isomers, diastereomers, racemates or mixtures thereof.

; The alkyl groups mentioned may be straight-chain or branched.

* »5 112076

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

R (2) * (VRR (,) * (*) T n <n> * o R (5) 5 is reacted with guanidine wherein R (1) to R (5) are as defined above and L is readily nucleophilic a substitutable 10 leaving group.

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

In addition to the carboxylic acid chlorides of formula II (L = Cl), other activated acid derivatives of formula II can also be prepared in a manner known per se: · directly from the basic benzoic acid derivatives (formula II, L = OH), such as Of the methyl esters of formula II wherein L = OCH3 by treatment with gaseous, ···, earthly HCl in methanol, the imidate of formula II

I I

solids by treatment with carbonyldiimidazole (L = <: &gt;: 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), mixed anhydrides II with Cl-COOC2H5 or thiosyl chloride in the presence of triethylamine in an inert solvent, as well as activating benzoic acids with dicyclohexylcarbodiimide (DCC) or 0-6 - [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3- tetramethyluronium tetrafluoroborate ("TOTU") (see Weiss und Krommer, 5 Chemiker Zeitung 98, 817 (1974)). Several suitable methods for preparing activated carboxylic acid derivatives of formula II are disclosed in Quellenliteratur: "J. March, Advanced Organic Chemistry, Third Edition (John Wiley &amp; Sons, 1985), p. 350".

The reaction of the activated carboxylic acid derivative of the formula I with guanidine takes place in a manner known per se in a protic or aprotic polar but inert organic solvent. The reaction temperature of the benzoic acid methyl ester (II, L = OMe) with guan-15-dine in methanol or THF is preferably between 20 ° C and the boiling point of these solvents. Most of the reactions between the compounds of formula II and the salt-free guanidine III preferably worked in aprotic inert solvents such as THF, dimethoxyethane, dioxane. However, water can also be used as a solvent in the reaction between the compounds of formula II and guanidine.

* ... * If L = Cl, then work preferably with the addition of an acid binding agent, e.g., excess guanidine: 4:25 to bind the hydrochloric acid.

Some of the underlying Bent-soic acid derivatives of formula II are known and described in the literature. Unknown compounds of formula II can be prepared according to methods known in the literature by, for example, converting 2-chloro or 2-fluoro-5-> · * 'F chlorosulfonylbenzoic acid into ammonia or' '. with an amine to 5-aminosulfonyl-2-chloro or -fluorobenzoic: acid or a weak reducing agent such as sodium bisulfyl: ', and finally alkylating 5-alkylsulfonyl-2-chloro! 35 or -2-fluorobenzoic acid and the resulting benzoic acid * * '' 'derivatives are reacted according to one of the above described process alternatives to the compounds of the formula I according to the invention.

Such carboxylic acids of formula II, or esters thereof, wherein L = -OH or, for example, -O-methyl 5 and R (1) and / or R (3) represent halogen, may also serve as starting compounds for other carboxylic acids, wherein R (1) - and / or the halogen at the R (4) position can be conveniently converted in a manner known per se to a number of nucleophilic reagents such as mercaptans R (6) -SH or R (6) R (7) NH primary amines to form other benzoic acid derivatives II. , wherein L = -OH or -O-methyl.

Similarly, starting from 5-nitro-2-chlorobenzoic acid, the group R (1) can be nucleophilically attached at position 2 (exchange to Cl) and further converted to the nitro group, for example by reduction to No, followed by alkylation or removal, e.g. reaction, other benzoic acid derivatives (II, L = -OH).

Benzoylguanidines I are generally weak bases and can bind acid when salts are formed. Suitable acid addition salts are salts of all pharmacologically usable acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methyl sulfonates, p-25 toluenesulfonates.

The compounds of formula I are substituted acylguanidines.

The most prominent representative of acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a ka-30 lumina-sparing diuretic. Several other amiloride-type compounds are described in the literature, such as; Dimethylamiloride or ethylisopropylamiloride.

1 »»

»I

1 1 • · · 112076

O

IS H

n 11 11 X'c ^ 'N5> c ^' Cxn''c \ «· ,,, JJ HHt>» \ hH2 R ”

Amiloride: R ', R "= H Dimethylamiloride: R', R" = CH3 Ethylisopropylamiloride: R '= C2H5, R "= CH (CH3) 2- In addition, studies are known which indicate the antiarrhythmic properties of amiloride. (Circulation 79, 1257-1263 (1989). However, the widespread use of the compound as an antiarrhythmic agent is that this effect is only mild and occurs in addition to the antihypertensive and saluretic effects, and these side effects are undesirable in the treatment of cardiac arrhythmias.

References to the anti-arrhythmic properties of amiloride were also obtained in isolated hearts of animals: *. * in experiments performed (Eur. Heart J.) (suppl. 1): 167 * · (1988) (book of abstracts). So, for example, it was found. ·. using the hearts of the rats, that the artificially-induced, ···, ventricular fibrillation could be completely prevented by amiloride!! *! Sat. Even more potent than amiloride in this experimental model was the above-mentioned amiloride derivative ethyl iso- 'propyl amiloride.

EP-A-416 499 (HOE 89 / F 288) describes »1» benzoylguanidines containing groups R (1)

I «I

25 and R (2) at the corresponding positions on the hydrogen atom.

; ·. U.S. Pat. No. 3,780,027 discloses an acyl glucurate.

, ···, anidines structurally close to Formula I

Compounds of the invention are derived from commercially available i "Ιοορ" diuretics such as bumetanide. Similarly, these compounds are known to have saluretic diuretics. The N-amidino-3-9112076 furfurylamino-4-chloro-5-methylsulfonylbenzamide described in this patent was re-synthesized and did not show any antiarrhythmic activity in our experimental models.

As a result, it was surprising that the mu-5 crude compounds of the invention did not exhibit any undesirable and deleterious saluretic properties, but they nevertheless act very effectively in preventing arrhythmias such as those associated with, for example, oxygen deficiency. Because of their pharmacological properties, the compounds are well suited as antiarrhythmic drugs with excellent cardioprotective component for prophylaxis and treatment of infarction and for the treatment of angina pectoris, and are also effective in preventing or reducing pathophysiological events such as ischemic heart disease, arrhythmias. Because of their protective action on pathological, hypoxic and ischemic states, the compounds of the invention may be used as drugs for all acute and chronic primary or secondary ischemic injury due to the inhibition of the cellular Na + / H + exchange mechanism. for the treatment of diseases. This applies to their use as pharmaceuticals in operative procedures such as organ transplants, whereby the compounds can be used both for protecting donor organs prior to and during transplantation, for protecting transplanted organs, for example during processing and / or storage in physiological saline fluids, and for transplantation. Compounds are also valuable, protective drugs when performing angioplastic surgery; '** for example in the heart as well as in peripheral blood vessels. Compounds for ischemic injury; because of their protective effect on them, they apply »I * 'i]! They can also be used as medicaments for the treatment of ischemic diseases of the nervous system, especially the central nervous system, for example for the treatment of stroke or cerebral edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, cardiac, volume depletion and bacterial shock.

In addition, the compounds of the invention according to the invention are effective in inhibiting cell proliferation, e.g., proliferation of fibroblasts or connective tissue cells, and proliferation of vascular smooth muscle cells. As a result, the compounds of formula I are useful as therapeutic agents in diseases in which cell proliferation is the primary or secondary cause and can therefore be used as agents for the prevention of atherosclerosis or arteriosclerosis, for the treatment of late , as drugs for the treatment of hyperplasia of the organs (hypertrophy and hyperplasia), especially hyperplasia of the prostate (due to an increase in the number of cells) or hyperplasia of the prostate (due to cell enlargement).

t 'The compounds of the invention efficiently inhibit: 1': 25 sodium membranes in the opposite direction through the cell membrane; proton transport ("antiporter") (Na + / H + exchange), which is increased in a number of diseases (autonomic hypertension, atherosclerosis, diabetes, etc.) also in cells which can be easily measured, such as> »30 in erythrocytes, thrombocytes or leukocytes. The compounds of the present invention are therefore suitable as excellent and simple scientific tools, for example when used as diagnostic agents for the determination of specific forms of hypertension and for the separation of f1. 35 11112076, but also for the diagnosis and resolution of atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of the formula I are suitable for preventive therapy to prevent the development of hypertension, in particular essential hypertension, i.e., independent hypertension.

containing a compound of the formula I, 5 to lääkeainei can then be administered orally, parenteraalises-acetate, intravenously, rectally or inhaloimal-Ia, wherein the preferred route of administration is dependent on the severity of each disease. The compounds of formula I can then be used alone or in combination with galenical excipients, namely in veterinary as well as in medicine.

The expert will know, based on his or her own expertise, which excipients are suitable for each desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients and other carriers used in active ingredients, for example, antioxidants, dispersants, emulsifiers, anti-foaming agents, flavoring agents, preservatives or flavoring agents may be used. dyes.

'. "l For oral administration, the active compounds are admixed with suitable additives such as carriers, stabilizers or inert diluents, and are converted, by conventional means, into suitable dosage forms, such as tablets. As inert carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk glucose, glucose, glucose, glucose, glucose, In this case, the preparation may take place in the form of either a dry granulate or a moist granulate. * Oily carriers or solvent oils may be obtained, for example, from vegetable or animal origin, such as sunflower oil or cod liver oil. .

When administered by injection into the subcutaneous tissue or intravenously, the active compounds are optionally formulated in a solution, suspension or emulsion with conventional substances such as solubilizers, emulsifiers or other excipients. Suitable solvents are, for example, water, physiological saline or alcohols, e.g. ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol, or mixtures of the various solvents mentioned.

Solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable Liu-15 receiver, such as, in particular, ethanol or water, or a mixture of such solvents, are suitable as a pharmaceutical preparation for administration in aerosol or spray form. The preparation may also contain other pharmaceutical excipients, such as tensides, emulsifiers and stabilizers, as well as propellant gas, if necessary. Such a preparation will usually contain an active ingredient in a concentration of about 0.1 to about 10, in particular, about 0.3 to about 3% by weight.

J '. The dosage and frequency of administration of the active ingredient of the formula I depend on the potency and duration of action of the compounds used; in addition, the type and severity of the disease being treated and the sex, age, weight and individual response of the patient being treated.

* · 30 The average daily dose of a compound of formula I in a patient weighing approximately 75 kg is at least • * ·· 0.001 mg / kg, preferably 0.01 mg / kg to 10 mg / kg, preferably! (*: 1 mg In the acute phase of the disease, such as immediately after having a myocardial infarction, even larger and, above all, more frequent dosing may be required, for example up to 4 times 13 to 112076 doses / day, especially intravenous dosing. , for example, in an infarction patient in intensive care, it may be necessary to administer the active ingredient up to 200 mg / day.

5 Experimental section

General Procedure for Preparation of Benzoyl Guanidines (I) of Formula I from Benzoic Acids (II, L = OH) 0.01 M benzoic acid derivative of formula II is dissolved or suspended in 60 ml of anhydrous tetrahydrofuran (THF) and then 1.78 g is added. (0.011 M) carbonyldiimidazole. After stirring for more than 2 hours at room temperature, 2.95 g (0.05 M) guanidine is added to the reaction solution. After stirring overnight, THF is distilled under reduced pressure (rotary evaporator), water is added, the pH is adjusted to 6-7 with 2N HCl, and the corresponding benzoylguanidine (Formula I) is filtered off.

The benzoylguanidines thus obtained can be converted by treatment with aqueous or methanolic hydrochloric acid or other pharmacologically useful acids to the corresponding salts.

• ·

Example 1: 2-Chloro-5-methylsulfonylbenzoyl-guanidine - ::: hydrochloride · · ·: -: Cl

/ N ^ / NH2 f ^. HOI

o nh2 • * ♦ i · ·: .. f 25 * it>: colorless crystals having m.p. 208-210 ° C, ·. From 2-chloro-5-methylsulfonylbenzoic acid (m.p. 182-186 ° C).

> # i

(I

* * »T> *» * *

Example 2: 2-Chloro-5-piperidylsulfonylbenzoylguanidine 14 112076 ^ nh2 5 colorless crystals having m.p. of 226-229 ° C from 2-chloro-5-piperidylsulfonylbenzoic acid (m.p. 207-210 ° C).

Example 3: 10-Colorless crystals of 2-chloro-5- (1-pyrrolidinylsulfonyl) benzoylguanidine-N H2, m.p. of 195-198 ° C, from * 2-chloro-5- (1-pyrrolidinylsulfonyl) benzoic acid 15 (m.p. 205 ° C).

Example 4: * 2-Chloro-5-N-methylsulfamoyl-benzoyl-guanidine hydrochloride

/ - «Ο, Γ VY η. HCl

CH '0 NH2 20: ·. colorless crystals having m.p. mp 201-203 ° C, ·. ; From 2-chloro-5-N-methylsulfamoylbenzoic acid (m.p. 169 ': 170 ° C).

Example 5: 2-Chloro-5-N, N-dipropylsulfamoylbenzoylguanidine Hydrochloride

^ NO2s I. HCl

o 5 colorless crystals having m.p. of 170-173 ° C from 2-chloro-5-N, N-dipropylsulfamoylbenzoic acid (m.p. 102-104 ° C).

Example 6: 2-Chloro-5- (2-phenylethylsulfamoyl) benzoyl-guanidine hydrochloride

W ^ N02S / N / Y ^. HCl

..0 NH2 • * · • · 15 »'1'. colorless crystals having m.p. is 70 ° C from 2-chloro-5- (2-phenylethylsulfamoyl) benzoic acid (m.p. 160-163 ° C).

. . . Example 7: 2-Chloro-5-N-methyl-N- (2-phenylethyl) sulfamoyl. benzoyl-guanidine hydrochloride · 6 L ;,

if 1. HCl

; λ 0 NH2 ie 112076 colorless crystals having m.p. of 186-188 ° C from 2-chloro-5-N-methyl-N- (2-phenylethyl) sulfamoyl-benzoic acid (m.p. 127-129 ° C).

Example 8: 5 2-Piperidyl-5-sulfamoyl-benzoyl-guanidine - 'Axi; colorless crystals having m.p. is 247 ° C from 2-piperidyl-5-sulfamoylbenzoic acid (m.p. 248 ° C, 10 prepared from 2-chloro-5-sulfamoylbenzoic acid in 10 moles of piperidine by refluxing in an inert gas for 24 hours, distilling off excess piperidine / diluted hydrochloric acid at pH 1-2).

Example 9: 2-Benzylamino-5-sulfamoyl-benzoyl-guanidine

: ·····: H

ui ΛΛ, ν "" 'o M02s Y ^ nh2 20 colorless crystals having m.p. of 191-193 ° C from 2-benzylamino-5-sulfamoylbenzoic acid (m.p. 246 ° C, prepared from 2-chloro-5-sulfamoylbenzoic acid in 20 equivalents of benzylamine at 130 ° C / inert gas over 8 hours , and by treatment with aqueous / dilute HCl at pH 1-2).

171 12076

Example 10: 2-N-Methyl-N- (2-phenylethyl) amino-5-sulfamoyl-benzoyl-guanidine hydrochloride CH 3 OH.

0 NH2 5 colorless crystals having m.p. is 180 ° C from 2-fluoro-5-sulfamoylbenzoic acid and 2-N-methyl-N- (2-phenylethyl) amino-5-sulfamoylbenzoic acid (m.p. 240 ° C). phenylethylamine in dimethylacetamide for 10-15 hours in the presence of 4 equivalents of ethyl diisopropylamine at 120 ° C, evaporation of the solvent and treatment of the residue with water and dilute HCl at pH 1-2).

Example 11 2-N-Methyl-N- (2-phenylethyl) amino-5-methylsulfonylbenzoyl-guanidine hydrochloride t

HjC-O.S '^ Y \. HCl

o NH2 »i t 20» · ”colorless crystals having m.p. of 123 ° C, from 2-N-methyl-N- (2-phenylethyl) amino-5-methylsulfonylbenzoic acid (amorphous oil, prepared from 2-chloro-5-: methylsulfonylbenzoic acid and N-methyl-2-phenylethyl), 25, respectively, as in Example 10 for 8 hours at 140 ° C).

1fl 112076 Ιο

Example 12 5-N-Methyl-N- (2-phenylethyl) sulfamoyl-2-piperidinobenzoyl-guanidine o colorless crystals having m.p. of 85 ° C from 5-N-methyl-N- (2-phenylethyl) sulfamoyl-2-piperidino-benzoic acid (amorphous intermediate, without defined melting point, Preparation of 2-chloro-5-N-methyl-N- (2- phenylethyl) sulfamoylbenzoic acid and piperidine, respectively, as in Example 8).

Example 13 2- (2-Chloro-phenylthio) -5-methylsulfonyl] -phenyl-15-guanidine hydrochloride: Cl

S-o · HCl

ch.o.s ^ 'YX

. 0 NH2 1 I I colorless crystals having m.p. 284-286 ° C; ', · 20 from 2- (2-chlorophenylthio) -5-methylsulfonylbenzoic acid (m.p. 210-216 ° C, prepared by reacting 2-chloro-5-methylsulfonylbenzoic acid methyl ester with 1 equivalent of 2-chlorothiophenol and excess K 2 CO 3 with DMF at 90 ° C for 7 hours and hydrolyzing the thus obtained 2- (2-chlorophenylthio) -5-methylsulfonyl-benzoic acid methyl ester (m.p. 145 ° C) in a mixture of dioxane and sodium hydroxide solution. at room temperature).

19

Example 14 2- (2,6-Dichlorophenylthio) -5-methylsulfonylbenzoyl-guanidine hydrochloride 112076

Cl

s-fe> · HCl

jQCJv ^ nh, 01,0,3 ΤΛΒΗι 5 colorless crystals having m.p. of 288-290 ° C, 2- (2,6-dichlorophenylthio) -5-methylsulfonylbenzoic acid (m.p. 244 ° C, prepared according to Example 13) by reacting 2-chloro-5-methylsulfonylbenzoic acid methyl ester With 1 equivalent of 2,6-dichlorothiophenol and hydrolyzing the thus obtained 2- (2,6-dichlorophenylthio) -5-methylsulfonylbenzoic acid methyl ester (m.p. 139 ° C), respectively, as in Example 13.

Example 15: 5-Methylsulfonyl-2-piperidin6-benzoyl-guan-2 · * ·. * dinine hydrochloride K · «· o NH2» · | 20% crystals having m.p. is 124-130 ° C, prepared from 5-methylsulfonyl-2-piperidinobenzoic acid (m.p .: 198 ° C, by reacting 2-chloro-5-methylsulfonobenzylbenzoic acid with boiling for several hours)! 10 equivalents of piperidine at reflux, evaporating the excess piperidine and then treating with water / dilute HCl at pH 1-2).

Example 16: 2,4-Dichloro-5-sulfamoyl-benzoyl-guanidine-5 hydrochloride, ClO nh 2 colorless crystals m.p. 240 ° C by passing 2,4-dichloro-5 of the sulfamoylbenzoic acid with 10 guanidine according to the general procedure described above.

EXAMPLE 17 2-Amino-4-chloro-5-sulfamoyl-benzoyl-guanidine hydrochloride 15: C L / NH 2 O) O (CH 2) 4 · · · · · · · · · · H 2 NO 2 S • VY NNH 2 O •! * »·

* · I

colorless crystals having m.p. 318-320 ° C by reacting 2-amino-4-chloro-5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

• i '»·» j * · 21 1 12076

Example 18 Colorless crystals of 5-methylsulfamoyl-2-piperidylbenzoyl-guanidine hydrochloride, m.p. 212-214 ° C by reacting 5-methylsulfamoyl-2-piperidylbenzoic acid with guanidine as described above. .

Example 19 2,3-Dichloro-5-methylsulfonylbenzoyl-guanidine hydrochloride

C I

1-C 1 .. jOOh <v'nh * * hci

i M «0iSx YT

0 NH 3 15 colorless crystals having m.p. 280 ° C by reacting 2,3-dichloro-5-methylsulfonylbenzoic acid with guanidine according to the general procedure described above.

Example 20 2-Methyl-5-methylsulfonylbenzoylguanidine hydrochloride

M.02S/@YVH1 'HU

o nh2 22 1 12076 colorless crystals having m.p. is 212 ° C by reacting 2-methyl-5-methylsulfonylbenzoic acid with guanidine according to the general procedure described above.

Example 21 2- (2-Chloro-benzylamino) -5-sulfamoyl-benzoyl-guanidine hydrochloride ..... 'O' -C; , C | 0 10 colorless crystals having m.p. is 137 ° C by reacting 2- (2-chlorobenzylamino) -5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

15 * · * «· *» t • * i f t * · »f t t · t ·

I t I

»T I! t f * »♦ * * t * t» *? * »T» »* 'f * |

Claims (11)

23 1 12076 A process for the preparation of therapeutically useful ortho-substituted benzoylguanidines of the formula R (2) (I) * <<> | Π ' 1. NH. R (5) wherein R (1) is F, Cl, Br, I, C 1-6 alkyl or -XR (6) wherein 10. is O, S, NR (7) or Y-ZO, wherein Y is O or NR (7) and Z is C or SO, R (6) is hydrogen, C1-6 alkyl, C5-7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, - (CH2) mCpF2p + i or * * · 15 -C n H 2n -R (8) wherein m is 0 or 1, p is 1 to 3, n is 0 to 4 and · / · · R (8) is phenyl which is unsubstituted or substituted 1-3 with a substituent F, Cl, CF 3, methyl. R1, methoxy or NR (9) R (10), wherein: R (9) and R (10) are hydrogen or C1-4 alkyl, R (7) is hydrogen or C1-3 alkyl, wherein R (6) and R (7) may also together represent 4 or 5 methylene groups and one CH2 group may be replaced by 0,:, S, NH, N-CH3 or N-benzyl, R (3) is hydrogen or -XR (6), wherein 24 1 12076 X is O, S, NR (7) or Y-ZO, wherein R (7) is hydrogen or C 1-3 alkyl, Y is O or NR (7), Z is C or SO, wherein Y is attached to the phenyl group of formula I, R (6) is hydrogen, C1-6 alkyl, C5-7 cycloalkyl, cyclohexylmethyl, cyclopentylmethyl, - (CH2) mCpF2p + or -C n H 2n -R (8) wherein m is 0 or 1, 10. is 1 to 3, n is 0 to 4 and R (8) is phenyl which is unsubstituted or substituted with 1 to 3 substituents F, Cl, CF 3, methyl, methoxy or NR (9) R (10) wherein R (9) and R (10) are hydrogen or C 1-4 alkyl, and R (6) and R (7) may also together denote 4 or 5 methylene groups and one CH 2 group may be substituted with 0 With S, NH, N-CH 3 or N-benzyl, R (2) and R (4) are the same or different and '·' is R (11) -SOq- or R (12) R (13) N-SO 2 - wherein * · ** q is 0 to 2 , * R * (11) is C 1-4 alkyl which is unsubstituted or substituted by phenyl, wherein the phenyl is: * 25 unsubstituted or substituted with 1-3 substituents selected from F, Cl, CF3, methyl, methoxy, or NR (9) R (10), wherein R (9) and R (10) are hydrogen or C1-4 alkyl, t> R, (12) and R (13) are the same other than R (6) and R (7); or one of R (2) or R (4) is hydrogen or denotes (t 30 has the same meaning as R (1), and "·. R (5) is hydrogen, methyl, F, Cl, or methoxy, and pharmaceutically acceptable salts thereof, for the preparation of pharmaceutically acceptable salts thereof, characterized in that the compounds of formula II 251 12076 «(2)» (4 ) T II (II). * R (5) wherein R (1) to R (5) are as defined above and L is a leaving group readily nucleophilically substitutable, is reacted with with anidine. Process according to Claim 1, characterized in that a compound of the formula I is prepared in which R (1) is F, Cl, C 1-3 alkyl, CF 3 or -XR (6) wherein X is O, S or NR (7), R (6) is hydrogen, C 1-6 alkyl, - (CH2) mCpF2p + i or -CnH2n-R (8), where: m is 0 or 1,. 15 p is 1-3,. n is 0 to 4,. ··. R (8) is phenyl which is unsubstituted or substituted with 1 to 3 substituents F, Cl, CF 3, methyl, l, methoxy or NR (9) R (10) in which t 1 R (9) and R (10) are hydrogen or C 1-4 alkyl, i. G. R (7) is hydrogen or methyl, whereby R (6) and R (7) may also be taken together to represent cyclically 4 or 5 methylene groups and one CH2 group may be replaced by: "O, Z, NH, N-CH3 or N-benzyl, R (3) is hydrogen, »: R (2) and R (4) are the same or different and * ·, · are CH 3 -SO 4 - or R (12) R (13) N-SO 2 -, wherein» * q is 0 to 2, 112076 26 R (12) and R (13) are the same as R (6) and R (7), or one of the two groups R (2) or R (-4) is hydrogen or is the same other than R (1) and R 5 (5) are hydrogen. Process according to claim 1, characterized in that a compound of formula I is prepared, wherein R (1) is F, Cl, C 1-3 alkyl or the group -XR (6), wherein X is O, S or NR (7). , R (6) is hydrogen, C 1-4 alkyl or -C n H 2n -R (8) where n is 0 to 3, R (8) is phenyl which is unsubstituted or substituted with 1 to 3 substituents F, Cl, CF 3, methyl-15, methoxy or NR (9) R (10) wherein R (9) and R (10) are hydrogen or methyl, and R (7) is hydrogen or methyl, wherein R ( 6) and R (7) may also be taken together to represent 4 or 5 methylene groups and one CH 2 group may be replaced by 0,. 20 S, N-CH 3 or N-benzyl, R 1 / R (2), R (3) and R (5) are hydrogen, R (4) is CH 3 -SO 2 or R (12) R (13) N-SO 2 -, wherein R (12) is -C n H 2n -R (8), n is 1 to 3, R (8) is phenyl which is unsubstituted or substituted with 1 to 3 substituents F, Cl, CF 3, methyl, methoxy or NR (9) R (10) wherein R (9) and R (10) ) are hydrogen or methyl, R (13) is hydrogen, wherein: R (12) and R (13) may also be taken together to represent 4 or 5: methylene groups and one CH2 group may be replaced by 0, S, N-CH 3 or N-benzyl. 112076 27