AU658262B2

AU658262B2 - Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic and medicaments containing them

Info

Publication number: AU658262B2
Application number: AU33014/93A
Authority: AU
Inventors: Udo Albus; Heinrich Englert; Florian Lang; Hans-Jochen Lang; Wolfgang Scholz; Andreas Weichert
Original assignee: Hoechst AG
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1992-02-15
Filing date: 1993-02-12
Publication date: 1995-04-06
Anticipated expiration: 2013-02-12
Also published as: EP0556673A1; EP0556673B1; CA2089440A1; FI930602A0; ZA93985B; FI930602A; ATE158278T1; HU9300369D0; CA2089440C; DK0556673T3; FI112076B; DE59307360D1; JP3558224B2; NZ245895A; JPH069545A; HU220219B; HUT65868A; IL104714A0; NO930511D0; NO179002B

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

Rogulallon 3.2(2) AT ISTRALIA Patents Act 1990 658262

ORIGINAL

COMPLETE SPEC~IFICATION STANDARD PATENT Application Number: Lodged:

S

55

S

S. 59 S S *9 *5

S

*9 S

S

Invention Title: ORTHO-SUBSTITUTED BENZOYLGUANIDINES, PROCESS FOR THEIR PREPARATION, THEIR USE AS A MEDICAMENT OR DIAGNOSTIC AND MED!'GAMENTS CONTAINING THEM The following statement is a full description of this invention, including the best method of performing it known to

I

HOECHST AKTIENGESELLSCHAFT HOE 92/F 035 Dr. vF/As/St Description Ortho- substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic and mnedicaments containing them The invention relates to ortho-substituted benzoylguanidines of the formula I R(2) R(l) R(5)2 where: R(1) is F, Cl, Br, I, C,-C 8 -alkyl or X is 0, S, NR(7) or Y-ZO and Y is 0 or NR(7) and Z is C or SO, R(6) is HI Cl-C-alkyl, C,-C 7 -cycloalkyl, :cyclohexylmethyl, cyclopentylmethyl, 15 (ICH2)mCpF 2 pi., or -CnH 2 n-R(8) m is zero or 1, 9* p is 1 3, n is zero to 4, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the groups F, Cl, CF 3 methyl, methoxy or NR(9)R(10) where R(9) and -2 have the meaning of H or

C

1

-C

4 -alkyl, R(7) is H or Cl-C 3 -alkyl, where R(6) and R(7) can also together be 4 or methylene groups and a CH 2 group can be replaced by 0, S, NH, N-CH 3 or N-benzyl, R(3) is H or where X is 0, S, NR(7) or Y-ZO, R(7) is H or C 1

-C

3 -alkyl, Y is 0 or NR(7), Z is C or SO, where Y is bonded to the phenyl radical in the formula I, R(6) is H, Cl-C-alkyl, C 5

-C

7 -cycloalkyl, cyclohexylmethyl, cyclopentylmethyl

(CH

2

)CPF

2 p+1 Or -CnH 2 -R 8) m is zero or 1, p is 1 3, or. 20 n is zero to 4, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the group comprising F, Cl, CF 3 methyl, methoxy and NR(9)R(10), R(9) and R(l0) are H or C 1

-C

4 -alkyl, too 0R(6) and R(7) can also together be 4 or :methylene groups and a CH 2 group can be replaced by 0, S, NH, N-CH 3 or N-benzyl, 000 30 R(2) and R(4) identical or different are R(ll)-SOq- or too. R(12)R(13)N-S0 2 where 6: q is zero 2, OV0o R(11) is C 1

-C

4 -alkyl which is unsubstituted or carries phenyl as a substituent, where phenyl is unsubstituted or substituted by 1 3 subs!ituents from the group comprising F, Cl, C14F3 methyl, methoxy and NR(9)R(10) where R(9) -3 and R(10) are H or Cl-C 4 -alkyl, R(12) and R(13) are defined as R(6) and R(7); or one of the two radicals R(2) or R(4) is hydrogen or is defined as R(1), R(5) is H, methyl, F, Cl or methoxy, and their pharmaceutically tolerable salts.

Preferred compounds of the formula I are those where: R(1) is F, Cl, Cl-C 3 -alkyl, CF 3 or where X is 0, S or NR(7), R(6) is H, Cl-C.-alkyl, -(CH 2 )mCPF,,,+i or -C.H 2 m is zero or 1, p is 1. 3, n is zero to 4, R(8) is phenyl which is unsubstituted or subs' 'ituted by 1 3 substituents from the group comprising F, Cl, CF., methyl, methoxy and NR(9)R(10) where R(9) and R(10) are H or C 1

-C

4 **alkyl, 20 R(7) is H or methyl, where R(6) and R(7) can also together be 4 or :0~0.methylene groups and a CH 2 group can be replaced by 0, S NH, N-CH 3 or N-benzyl, R(3) is H, R(2) and R(4) identical or different are CH 3 -SOq- or R(12)R(13)N-S0 2 q is zero 2, R(12) and R(13) are R(6) and R(7), or one of the two radicals R(2) or R(4) is H or is defined as R(1), is H, 4 0:0.

0 0 *i

S

and their pharmaceutically tolerable salts.

Particularly preferred compounds of the formula I are those where: R(1) is F, Cl, Ci-C 3 -alkyl or X is O, S or NR(7), R(6) is H, Ci-C 4 -alkyl or -CnHzn-R(8), n is zero to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the group comprising F, Cl, CF 3 methyl, methoxy and NR(9)R(10) where R(9) and L(10) are H or methyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or 5 methylene groups and a CH 2 group can be replaced by O, S, N-CH 3 or N-benzyl, R(3) and R(5) are hydrogen, R(4) is CH 3 -SO2- or R(12)R(13)N-SO 2 where R(12) is -CnH 2 n-R(8), 20 n is 1 to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the groups F, Cl, CF 3 methyl, methoxy or NR(9)R(10) where R(9) and R(10) have the 25 meaning of H or methyl, R(13) is H, or R(12) and R(13) can also together be 4 or methylene groups, and their pharmaceutically tolerable salts.

If one of the substituents R(1) to R(13) contains a center of asymmetry, the invention includes compounds having both the S and R configuration. The compounds can be present as optical isomers, as diastereomers, as 5 racemates- or as mixtures thereof.

The designated alkyl radicals can be present either in straight-chain or branched form.

The invention furthermore relates to a process for the preparation of the compounds I, which comprises reacting compounds of the formula II R(2) I R(I) R .L (II) R(4) with guanidine, in which R(1) to R(5) have the given meaning and L is a leaving group which can be easily nucleophilically substituted.

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

•e In addition to the carbonyl chlorides of the formula II (L Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the benzoic acid derivatives (formula II, L OH) on which they are based, such as, for example, the methyl esters of the formula II where L OCH 3 by treatment with gaseous HC1 in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole (L 1imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 6 351 367 (1962)), the mixed anhydrides II using Cl-COOC 2

H

5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzoic acids using dicyclohexylcarbodiimide (DCC) or using O-6-[(cyano- (ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoborate ("TOTU") (Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)). A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are given under details of source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative of the formula I with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. Methanol or THF between 20°C and the boiling p6int of these solvents have proven suitable in the reaction of the methyl benzoates (II, L OMe) 20 with guanidine between 20°C and the boiling point of these solvents. In most reactions of compounds II with salt-free guanidine, the reaction was advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane or dioxane. However, water can also be 25 used as a solvent in the reaction of II with guanidine.

If L Cl, the reaction is advantageously carried out with the addition of an acid scavenger, for example in the form of excess guanidine for binding the hydrohalic acid.

30 Some of the underlying benzoic acid derivatives of the *4ee* formula II are known and described in the literature. The unknown compounds of the formula II can be prepared by methods known from the literature, by converting, for example, 2-chloro- or acid with ammonia or an amine into a 5-aminosulfonyl-2- 7 chloro- or -fluorobenzoic acid or with a weak reductant such as sodium bisulfite and subsequent alkylation into a 5-alkylsulfonyl-2-chloro- or -2-fluorobenzoic acid and reacting the benzoic acid derivatives thus obtained by one of the process variants described above to give the compounds I according to the invention.

Carboxylic acids of this type or their esters of the formula II, where -OH or, for example, -0-methyl and where R(1) and/or R(3) have the meaning of halogen, can also be used, however, as starting compounds for other carboxylic acids, it being possible to replace the halogen in the R(1) and/or R(4) position very conveniently in the known manner by numerous nucleophilic reagents, such as mercaptans R(6)-SH or primary amines R(6)R(7)NH, with the formation of further benzoic acid derivatives II where L -OH or -0-methyl.

In a similar manner, starting from 5-nitro-2chlorobenzoic acid, further benzoic acid derivatives (II, L -OH) can be prepared by nucleophilic introduction of a radical R(1) in position 2 (replacement by Cl) and further modification of the nitro group, such as reduction to NH 2 and subsequent alkylation or displacement, for example by diazotization and Sandmeyer reaction.

S 25 In general, benzoylguanidines I are weak bases and can bind acid with the formation of salts. Possible acid addition salts are salts of all pharmacologically tolero able acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methanesulfonates and p-toluenesulfonates.

The compounds I are substituted acylguanidines.

8 A prominent ester representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloridci type are described in the literature, such as, for example, dimethylamiloride or ethylisopropylamiloride.

0 NH II II SC NHC

R"

Amiloride8 R" H Dimethylamiloride: R" CH3 Ethylisopropylamiloride: R' C 2

H

5 R" CH(CU 3 2 Investigations have moreover been disclosed which point to antiarrhythmic properties of amiloride (Circulation 79, 1257 63 (1989)). Obstacles to wide use as an antiarrhythmic are, however, that this effect is only slightly pronounced and occurs accompanied by a hypoten- S 15 sive and saluretic action and these side effects are undesired in the treatment of cardiac arrhythmias.

.e Indications of antiarrhythmic properties of amiloride were also obtained in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl.l): 167 (1988) (book of 20 abstracts)). For instance, it was found in rat hearts that an artificially induced ventricular fibrillation could be suppressed completely by amiloride. The above- S'mentioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride in this model.

European Offenlegungsschrift 416,499 (HOE 89/F 288) describes benzoylguanidines which carry hydrogen in the positions corresponding to the radicals R(1) and In 9 US Patent 3,780,027, acylguanidines are described which are structurally similar to the compounds of the formula I and are derived from commercially available loop diuretics, such as bumetanide. A strong salidiuretic activity is correspondingly reported for these compounds.

The N-amidino-3-furfurylamino-4-chloro-5-methylsulfonylbenzamide described in this patent was resynthesized and in our models showed no antiarrhythmic action.

It was therefore surprising that the compounds according to the invention have no undesired and disadvantageous salidiuretic properties, but very good antiarrhythmic properties, as occur, for example, in the case of oxygen deficiency symptoms. As a result of their pharmacological properties, the compounds are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively prohibit or greatly decrease the pathophysiological processes in the formation of ischemically 20 induced damage, in particular in the production of ischemically induced cardiac arxhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used as a result of inhibition of the cellular Na+/H exchange mechanism as a pharmaceutical for the treatment of all acute or chronic damage caused by ischemia or primary or secondary diseases induced thereby. This relates to their use as pharmaceuticals for surgical interventions, for example 30 in organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the body of the recipient. The compounds are also useful protective pharmaceuticals during the performance of angioplastic surgical interventions, for example in the 10 heart and in peripheral vessels. In accordance with their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular the central nervous system, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment of forms. of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial sh;-sk, Moreover, the compounds of the formula I according to the invention are distinguished by potent inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. The compounds of the formula I can therefore be considered as useful therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against late-onset diabetic complications, cancers, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the idneys, organ hypertrophy and hyperplasia, in particular in prostate hyperplasia or prostate hypertrophy.

The compounds according to the invention are active 25 inhibitors of the cellular sodium-proton antiporter exchanger), which is raised in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in those cells which are easily accessible to ee* measurements, such as, for example, in erythrocytes, 30 thrombocytes or leucocytes. The compounds according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis or of diabetes, proliferative diseases etc. Moreover, the compounds of the formula I are suitable for 11 preventive therapy for the prevention of the formation of high blood pressure, for example of essential hypertension.

Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular type of the disease.

The compounds I can be used on their own or together with pharmaceutical auxiliaries, to be precise in veterinary and in human medicine.

The auxiliaries which are suitable for the desired pharmaceutical formulation are familiar to the person skilled in the art on the basis of his knowledge. In addition to solvents, gelling agents, suppository bases, tabletting auxiliaries and other active compound excipients, antioxidants, dispersants, emulsifiers, antifoams, flavor correctants, preservatives, solubilizers or colorants, for example, can be used.

Gos For a form for oral administration, the active compounds are mixed with the additives suitable for this purpose, S 20 such as excipients, stabilizers or inert diluents, and are brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatine capsules, or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for 25 example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in -particular corn starch. Preparation can be carried out here both as dry and as moist granules. Suitable oily excipients or solvents are, for example, vegetable or 30 animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired using the substances customary for this purpose such as solubilizers, emulsifiers or other 12 auxiliaries. Suitable solvents are, for example: water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.

Pharmaceutical formulations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of these solvents.

If required, the formulation can also contain still other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant gas. Such a preparation contains the active compound customarily in a concentration from about 0.1 to 10, in particular from about 0.3 to 3 by weight.

s*$ The dose of the active compound of the formula I to be 0* administered and the frequency of administration depend S 20 on the potency and duration of action of the compounds S used and additionally on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.

V

On average, the daily dose of a compound of the formula I in a patient of weight about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, *"06 preferably 1 mg/kg of body weight. In acute episodes of the disease, for example immediately after suffering a cardiac infarct, even higher and in particular more frequent dosages may be necessary, for example up to 4 individual doses per day. In particular when administered for example in the case of an infarct patient in the intensive care ward, up to 200 mg per day may be necessary.

13 Experimental Section General procedure for the preparation of benzoylguanidines from benzoic acids (II, L OH) 0.01 mol of the benzoic acid derivative of the formula II is dissolved or suspended in 60 ml of anhydrous tetrahydrofuran (THF) and then treated with 1.78 g (0.011 mol) of carbonyldiimidazole. After stirring for 2 hours at room temperature, 2.95 g (0.05 mol) of guanidine are introduced into the reaction solution. After stirring overnight, the THF is distilled off under reduced pressure (Rotavapor), the residue is treated with water, the mixture is adjusted to pH 6-7 with 2N HC1 and the corresponding benzoylguanidine (formula I) is filtered off.

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

Example 1: 2-Chloro-5-methylsulfonylbenzoylguanidine hydrochloride, I C H 3 0 2z S N 2/ N H 2 S•

HCI

0 NH 2 colorless crystals, melting point 208-210 0

C,

from 2-chloro-5-methylsulfonylbenzoic acid (melting point 182-186 0

C).

Example 2: Cl 0

NHH

colorless crystals, melting point 226-229 0

C,

I I 14 from 2-chloro--5-piperidylsulfonylbenzoic acid (melting point 207-210*C).

Example 3: -pyrrolidinylsulfonyl) benzoylguanidine, IN -0 2 S NH colorless crystals, melting point 195-198*C, from 2-chloro-5-f 1-pyrrolidinylsulfonyl)benzoic acid (melting point 205*C).

Example 4: 2 hydrochloride, N HH colorless crystals, melting point-' 201-203*C, from 2-chloro-5-N-methylsulfamoylbenzoic acid (melting point 169-170*C).

Example hydrochl.ide, C1 ~N 0 2 r 'I HCI 0 NH 2 colorless crystals, melting point 170-173*C, from 2-chloro-5-N,N-dipropylsu3.famoylbenzoic acid (melting point 102-104*C).

I 15 Example 6: (2-phenylethylsulfamoyl )benzoylguanidine hydrochloride, C1 N0 2 S

HCI

0 NH 2 colorless cyrstals,. melting point from 2-chloro-5- (2-phenylethylsulfamoyl) benzoic acid ne'lting point 160-163*C).

Example 7: (2-phenylethyl) sulfamoylbenzoylguanidine hydrochloride, C1 N0 2 2 10 colorless crystals, melting point 186-188*C, from 2-chloro-5-N-methyl-N- (2-phenylethyl) sulfamoylbenzoic acid (melting point 127-129*C).

Example 8: No 0 HNO colorless crystals, melting point 247*C, from 2-piperidyl-5-sulfamoylbenzoic acid (melting point 248*C, prepared from 2-chloro-5-sulfamoylbenzoic acid in mol of piperidine under inert gas for 24 hours by boiling under ref lux, distilling off the excess piperidine and treating the residue with water/dilute hydrochloric acid at pH 1-2).

16 Example 9:

H

N

H

2

NO

2 S

N,

4

NK

0 NH 2 colorless crystals, melting point 191-193 0

C,

from 2-benzylamino-5-sulfamoylbenzoic acid (melting point 246 0 C, ).repared from 2-chloro-5-sulfamoylbenzoic acid in equivalents of benzylamine over the course of 8 hours at 130WC/inert gas and treatment with water/dilute HC at pH 1-2).

Example 2-N-Methyl-N-(2-phenylethyl)amino-5-sulfamoylbenzoylguanidine hydrochloride,

H

:C N H1NO, II HCI H 2 No 2

S--

0 NH 2 :colorless crystals, melting point 180 0

C,

from 2-N-methyl-N-(2-phenylethyl) acid (melting point 240 0 C, preparation by heating 15 2-fluoro-5-sulfamoylbenzoic acid and N-methyl-2-phenylethylamine for 10-15 hours in dimethylacetamide in the presence of 4 equivalents of ethyldiisopropylamine at 120 0 C, evaporating the solvent and treating the residue with water and dilute HU at pH 1-2).

Example 11: 2-N-Methyl-N-(2-phenylethyl)amino-5-methylsulfonylbenzoylguanidine hydrochloride,

CH

3

H

3 C-0 2 S' N/ ".NH HCI o NH 17 colorless crystals, melting point 1230C, from 2-N-methyl-N-(2-phenylethyl)amino-5-methylsulfonylbenzoic acid (amorphous oil, preparation from 2-chloroacid and N-methyl-2-phenylethylamine analogously to Example over the course of 8 hours at 140°C).

Example 12: 5-N-Methyl-N-(2-phenylethyl)sulfamoyl-2-piperidinobenzoylguanidine,

COH

3

NQ

N SI

NH

2 0 NH 2 10 colorless crystals, melting point .from 5-N-methyl-N-(2-phenylethyl)sulfamoyl-2-piperidinobenzoic acid (amorphous intermediate without defined melting point, preparation from 2-chloro-5-N-methyl-N-(2phenylethyl)sulfamoylbenzoic acid and piperidine analogously to Example 8).

Example 13: 2-(2-Chlorophenylthio)-5-methylsulfonylbenzoylguanidine hydrochloride, .S H C I 0

NH

2 colorless crystals, melting point 284-286*C, from 2-(2-chlorophenylthio)-5-methylsulf;nylbenzoic acid (melting point 210-2161C, prepared by reaction of methyl with 1 eq. of 2-chlorothiophenol and excess K 2 CO in DMF at 90°C for 7 hours and hydrolysis of the methyl 2-(2-chlorophenylthio)-5-methylsulfonylbenzoate (melting point 145 0 C) thus obtained in a mixture of dioxane and sodium hydroxide 18 solution at room temperature).

Example 14: 2- 6-Dichlorophenylthio) guanidine hydrochloride, C1 S- CII

CH

3 0 2 S N. zz<NH 2 0 HH 2 colorless crystals, melting point 288-290 0

C,

from 2- 6-dichlorophenylthio) acid (melting point 244*C, prepared analogously to Example 13 from methyl with 1 eq. of 2,6-dichlorrcthiophenol and hydrolysis of .:94 10 the methyl 2- 6-dichlorophenylthio) benzoate (melting point 139*C) thus obtained analogously to Example 13.

j A Example 5-Methylsulfonyl-2-piperidinobenzoylguanidine hydrochloride,

NO

CH

3

O

2 S N H colorless crystals, meltiAng point 124-130*C, prepared from 5-methylsulfonyl-2-piperidinobenzoic acid (melting point 198*C, preparation by reaction of acid by boiling for several hours in 10 eqivalents of piperidine under a ref lux condenser, evaporation of the excess piperidine and subsequent treatment with water/dilute HUl at pH 1- 2).

Example 16 2, 4-Dichloro-5-sulfamoylbenzoylguanidine hydrochloride 19 M eO0 2 S) NY

NH

0 N H 2 colorless crystals, melting point 240*C, by reaction of 2,4-dichloro-5-sulfamoylbenzoic acid with guanidine according to the general procedure described above.

Example 17 2 hydrochloride C1

NH

2 N H 0:6H 2 NO0 2 S N <NH2 xH colrles crstlsmelting point 318-320*C, by reaction of 2-arino-4-chloro-5-sulfamoylbenzoic acid 10 with guanidine according to the general procedure described above.

Exam~ple 18 0 5-Methylsulfamoyl-2-piperidylbenzoylguanidine hydrochloride

H

N SN NH 2 x HC I M e S 0

NH

2 colorless crystals, melting point 212-214 0

C,

by reaction of 5-methylsulfamoyl-2-piperidylbenzoic acid with guanidine according to the general procedure described above.

20 Example 19 2,3-Dichloro-5-methylsulfonylbenzoylguanidine hydrochloride C1 MeO 2 N..N H 2 X HCI colorless crystals, melting point 28000, by reaction of 2,3-dichloro-5-methylsulfonylbenzoic acid with guanidine according to the general procedure described above.

Example hydrochloride We V0*0 eO 0 2 ~4H S C 0 NH 2 colorless crystals, melting point 21200, by reaction of 2-methyl-5-methylsUlfonylbenzoic acid with guanidine according to the general procedure described to. 0 :above.

to. Example 21 15 2-(2-Chlorobenzylamino) hydrochloride

H

2

NO

2 SN NH2 x HCI H2N02 O ;N H0 colorless crystals, melting point 137*C, by reaction of 2- (2-Chlorobenzylamino) -5-sulf axoylbenzoic acid with guanidine according to the general procedure described above.

Claims

1. An ortho- substituted benzoylguanidine of the formula R(4) N ><NH 2 0 NH 2 wherein the substituents are defined as follows: R(1) is F, Cl, Br, I, Cl-Cr 6 -alky. or X is 0, S, NR(7) or Y-ZO and Y is 0 or NR(7) and Z is C or SO, R(6) is H, C-C-alkyl C,-C 7 -Cycloalkyl, 10 cyclohexylinethyl, cyclopentylmethyl, -(CH1 2 ).CpF 2 p+l or im is zero or 1, p is 1 3, n is zero to 4, 15 R(8) is phenyl which is unsubstituted *or substituted by 1-3 substituents from the groups F, Cl, CF 3 methyl, methoxy or NR(9)R(10) where R(9) and have the meaning of H or too* Cl 1 C 4 -alkyl R iS H Or C-C 3 -alkyl, where R(6) and R(7) can also together be 4 or methylene groups and a CH 2 group can be replaced by 0, S, NH, N-CH 3 or N-benzyl, R(3) is H or where X is 0, S, NR(7) or Y-ZO, R(7) is H or Cl-C.-alkyl, Y is 0orNR(7), 22 4

4. 4 4 4 4. 4e 0 4 Z is C or SO, where Y is bonded to the phenyl radical in the formula I, R(6) is H, Cl-C.-alkyl, C 5 -C 7 -CYCloalkyl, cyclohexylmethyl, cyclopentylmethyl, -(CH.)mCFzp+t or m is zero or 1, p is 1 3, n. is zero to 4, R(S) is phenyl which is unsubstituted or substituted by 1-3 substituents from the group comprising F, Cl, CF 3 methyl, methoxy and NR(9)R(1O), R(9) and R(10) are H or Cj-C 4 alkyl, R(6) and R(7) can also together be 4 or methylene groups and a CH 2 group can be replaced by 0, S, NH, N-CH 3 or N-benzyl, R(2) and R(4) identical or different are R(l1)- 0 q- or R(12)R(13)N-S0 2 where q is zero 2, R(11) is Cl-C 4 -alkyl which is unsubstituted or carries phenyl as a substituent, where phenyl is unsubstituted or substituted by 1 3 substituents from the group comprising F, Cl, CF 3 methyl, niethoxy and NR(9)R(1O) wherci R(9) and R(10) are H Or C 1 ,-C4-alkyl, R(12) and R(13) are defined as R(6) and R(7); or one of the two radicals R(2) or R(4) is hydrogen or is defined as R(1), R(S) is H, methyl, F, Cl or methoxye and their pharmaceutically tolerable salts. 2. A compound as claimed in claim 1, wherein the substituents are defined as follows: 4. 4. 4 4 4 4* 44 4 *4 9 4* 4 *4 4.44 9 4444 40 4 4 44 4 @4 444444 4 4 23 R(1) is F, Cl, C 1 -C 3 -alkyl, CF 3 or where X is 0, S or NR(7), R(6) is H, C 1 -Cr,-alkyl, -(CH 2 )mCpF 2 p+l or -CH 2 ,-R(t3)1 mn is zero or 1, p isl1- 3, n is zero to 4, R(8) is phenyl which is unsubstituted or substituted by 1 3 substituents from the group comprising F, Cl, CF 3 1 methyl, methoxy and NR(9)R(1O) where R(9) and R(10) are H or C-4 alkyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or mnethylene groups and a CH 2 group can be replaced by 0, S, NH, N-CH 3 or N-benzyl, R(3) is H, R(2) and R(4) identical or different are CH 3 -SOq- or R(12)R(13)N-S0 2 q is zero 2, R(12) and R(13) are R(6) and R(7), or one of the two radicals R(2) or R(4) is H or is defined as R(1), to. 25 R(5) is H. 0 :0 A compound as claimed in claim 1, wherein the substituents are defined as follows: R(1) is F, Ci, C,-C-alkyl or X is 0, S or NR(7), R(6) is H, Cl-C 4 -alkyl 02: -CnH 2 n is zero to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the group comprising F, Cl, CF 3 methyl, methoxy and NR(9)R(1O) where S1 f R(9) and R(10) are H or methyl, R(7) is H or methyl, where R(6) and R(7) can also together be 4 or methylene groups and a CH 2 group can be replaced by O, S, N-CH 3 or N-benzyl, R(3) and R(5) are hydrogen, R(4) is CH 3 -SO 2 or R(12)R(13)N-SO 2 where R(12) is -CnH2n-R(8), n is 1 to 3, R(8) is phenyl which is unsubstituted or substituted by 1-3 substituents from the groups F, Cl, CF 3 methyl, methoxy or NR(9)R(10) where R(9) and R(10) have the meaning of H or methyl, 15 R(13) is H, or R(12) and R(13) can also together be 4 or methylene groups, S 4. A process for the preparation of a compound I as claimed in claim 1, which comprises 20 reacting a compound of the formula II SR((2) R(3) R(1) (II) R(4) with guanidine, in which R(1) to R(5) have the given meaning and L is a leaving group which can be easily nucleophilically substituted. m preparing a medicament for the and fr the prophylaxi c 3ac arrhythmias and of gap i-nn 1VN 3' p eAe -A A method of preparation of a medicament for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage comprising admixing in a pharmaceutically effective amount a compound as claimed in claim 1 with pharmacologically suitable excipients.

6. A method of preparation of a medicament for the inhibition of proliferation of cells comprising admixing in a pharmaceutically effective amount a compound as claimed in claim 1 with pharmacologically suitable excipients.

7. A method for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage, which comprises administering an effective amount of a compound I as claimed in claim 1 to a patient requiring such treatment.

8. A method for inhibiting the proliferation of cells, which comprises administering an effective amount of a compound I as claimed in claim 1 to a patient requiring such treatment.

9. A medicament for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage, which contains an effective amount of a compound I as claimed in claim 1 and pharmaceutically customary additives. *oo*:o

10. A medicament for inhibiting the proliferation of cells, which contains an effective amount of a compound I as claimed in claim 1 and pharmaceutically customary additives. DATED this 29th day of December, 1994. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 S~0' AUSTRALIA DBM:CJH:BB AU3301493.WPC DOC i NT 1 HOE 92/F 035 Abstract Ortho-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic and medicaments containing them Ortho-substituted benzoylguanidines of the formula I R(2) R(3) R(1) R(4) R( S0 NH 2 are described where: R(1) is halogen, alkyl or where X is 0, S, NR(7) or Y-ZO and R(6) is H, (cyclo)-(halo)alkyl(methyl) or -CnHzn-phenyl, R(3) is H or R(2) and R(4) are R(1i)-SO0.2- or (di)-alkyl-N-SOz-, or one of the two radicals R(2) or R(4) is hydrogen or is defined as R(1), R(5) is H, methyl, F, C1 or methoxy, and their pharmaceutically tolerable salts. They are obtained by a process in which compounds of the 15 formula II R(3) R(1) R(4) 0 are reacted with guanidine, in which R(1) to R(5) have the given meaning and L is a leaving group which can be easily nucleophilically substituted. The compounds I are used for preparing a medicament for the treatment and for the prophylaxis of cardiac arrhythmias and of ischemically induced damage; as well 2- as for preparing a medicament for inhibiting the proliferation of cells. S S* S S.