3,5-Substituted benzoylguanidines, process for their preparation, their use as a medicament of diagnostic and medicament containing them

Benzoylguanidines of the formula I ##STR1## are described where R(1) is R(4)--SO.sub.m or R(5)R(6)N--SO.sub.z --, where R(4) and R(5) are alk(en)yl or --C.sub.n H.sub.2n --R(7), and where R(7) is a cycloalkyl or phenyl, where R(5) also has the meaning of H, and R(6) is H or C.sub.1 -C.sub.4 -alkyl, R(2) is hydrogen, halogen, alkyl, O--(CH.sub.2).sub.m C.sub.p F.sub.2p+1, --X--R(10), where X is O, S or NR(11), R(10) is H, (cyclo)alkyl(methyl) or --C.sub.n H.sub.2n --R(12) where R(12) is phenyl, and R(3) is defined, inter alia, as R(1), and their pharmaceutically tolerable salts. The compounds I are obtained by reaction of compounds of the formula II ##STR2## with guanidine, in which L is a leaving group which can be easily nucleophilically substituted. Compounds I are outstandingly suitable as antiarrythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively inhibit or greatly reduce the pathophysiological processes during the formation of ischemically induced damage. They are moreover distinguished by strong inhibitory action on the proliferation of cells. They can therefore be used as antiatherosclerotics, agents against late-onset diabetic complications, cancers, and fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidneys. They are effective inhibitors of the cellular sodium/proton antiporter (Na.sup.+ /H.sup.+ exchanger).

The invention relates to benzoylguanidines of the formula I 
in which: 
R(1) is R(4)--SO.sub.m or R(5)R(6)N--SO.sub.2 --, where 
m is zero, 1 or 2, 
R(4) and R(5) are C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 -alkenyl or 
--C.sub.n H.sub.2n --R(7), 
n is zero, 1, 2, 3 or 4, 
R(7) is C.sub.5 -C.sub.7 -cycloalkyl or phenyl which is unsubstituted or 
substituted by 1-3 substituents from the group comprising 
F, Cl , CF.sub.3, methyl, methoxy and NR(8)R(9) where R(8) and R(9) are H 
or C.sub.1 -C.sub.4 -alkyl, 
where R(5) also has the meaning of H, R(6) is H or C.sub.1 -C.sub.4 
-alkyl, 
where R(5) and R(6) together can be 4 or 5 methylene groups, of which one 
CH.sub.2 group can be replaced by O, S, NH, N--CH.sub.3 or N-benzyl, 
R(2) is hydrogen, F, Cl, Br, (C.sub.1 -C.sub.4)-alkyl, O--(CH.sub.2).sub.m 
C.sub.p F.sub.2p+1 or --X--R(10), where 
m is zero or 1, 
p is 1, 2 or 3, 
x is O, S, or NR(11), 
R(10) is H, C.sub.1 -C.sub.6 -alkyl, C.sub.5 -C.sub.7 -cycloalkyl, 
cyclohexylmethyl, cyclopentylmethyl, or --C.sub.n H.sub.2n --R(12) where 
n is zero, 1, 2, 3 or 4 and 
R(12) is phenyl which is unsubstituted or substituted by 1-3 substituents 
from the group comprising 
F, Cl, CF.sub.3, methyl, methoxy and NR(8)R(9) where R(8) and R(9) are H or 
C.sub.1 -C.sub.4 -alkyl 
R(11) is H or C.sub.1 -C.sub.3 -alkyl 
where R(10) and R(11) can also together be 4 or 5 methylene groups and a 
CH.sub.2 group can be replaced by O, S, NH, N--CH.sub.3 or N-benzyl, 
R(3) is defined as R(1), or is C.sub.1 -C.sub.6 -alkyl, nitro, cyano, 
trifluoromethyl, F, Cl, Br, I or --X--R(10) where 
X is O, S or NR(11), 
R(10) is H, C.sub.1 -C.sub.6 -alkyl, C.sub.5 -C.sub.7 -cycloalkyl, 
cyclohexylmethyl, cyclopentylmethyl or --C.sub.n H.sub.2n --R(12) where 
n is from zero to 4 and 
R(12) is phenyl which is unsubstituted or substituted by 1-3 substituents 
from the group comprising 
F, Cl, CF.sub.3, methyl, methoxy and NR(8)R(9) where R(8) and R(9) are H or 
C.sub.1 -C.sub.4 -alkyl, 
R(11) is H or C.sub.1 -C.sub.3 -alkyl, 
where R(10) and R(11) can also together be 4 or 5 methylene groups and a 
CH.sub.2 group can be replaced by O, S, NH, N--CH.sub.3 or N-benzyl, 
and their pharmaceutically tolerable salts, 
but where compounds are excluded in which, at the same time: 
R(1) is R(4)--SO.sub.m where m=zero to 2 or R(5)R(6) NSO.sub.2 --, 
R(2) is halogen, (C.sub.1 -C.sub.4)-alkyl, and 
R(3) is --NR(10)R(11). 
Preferred compounds of the formula I are those in which: 
R(1) is R(4)--SO.sub.m or R(5)R(6)N--SO.sub.2 --, 
m is zero, 1 or 2, 
R(4) is methyl or --C.sub.n H.sub.2n --R(7), 
n is zero or 1, 
R(7) is phenyl which is unsubstituted or substituted by 1-3 substituents 
from the group comprising Cl, CF.sub.3, methyl and methoxy, 
R(5) is H, C.sub.1 -C.sub.6 -alkyl, allyl or --C.sub.n H.sub.2n --R(7), 
n is zero or 1, 2 or 3 
R(7) is phenyl which is unsubstituted or substituted by 1-3 substituents 
from the group comprising 
F, Cl, CF.sub.3, methyl and methoxy and NR(8)R(9) where R(8) and R(9) are H 
or methyl, 
R(6) is H or methyl, where R(5) and R(6) can together be 4 or 5 methylene 
groups, of which one CH.sub.2 group can be replaced by an O, S, 
N--CH.sub.3 or N-benzyl, 
R(2) is hydrogen, O--CH.sub.2 CF.sub.3 or --X--R(10), where 
X is O, S or NR(11), 
R(10) is H, C.sub.1 -C.sub.6 -alkyl or --C.sub.n H.sub.2n --R(12) where n 
for X having the meaning of oxygen or sulfur is zero, and for X having the 
meaning of NR(12) is zero or 1, and R(12) is phenyl which is unsubstituted 
or substituted by 1-3 substituents from the group comprising 
F, Cl, CF.sub.3 and methyl, 
R(11) is H or (C.sub.1 -C.sub.3)-alkyl, 
where R(10) and R(11) can also together be 4 or 5 methylene groups and a 
CH.sub.2 group can be replaced by O, S, N--CH.sub.3 or N-benzyl, 
R(3) is methyl, nitro, cyano, trifluoromethyl, F, Cl or --X--R(10) where 
X is O, S or NR(11), 
R(10) is H, C.sub.1 -C.sub.6 -alkyl or --C.sub.n --H.sub.2n --R(12) where 
n is zero or 1, 
R(12) is phenyl which is unsubstituted or substituted by 1-3 substituents 
from the group comprising Cl, CF.sub.3, methyl and methoxy, 
R(11) is H or (C.sub.1 -C.sub.3)-alkyl 
where R(10) and R(11) can also together be 4 or 5 methylene groups, 
and their pharmaceutically tolerable salts. 
Particularly preferred compounds of the formula I are those in which: 
R(1) is R(4)--SO.sub.2 -- or R(5)R(6)N--SO.sub.2 -- where 
R(4) is methyl, 
R(5) and R(6) are hydrogen, 
R(2) is hydrogen, --O--CH.sub.2 --CF.sub.3 or X--R(10) where 
X is oxygen or N--R(11), 
R(10) is H, C.sub.1 -C.sub.6 -alkyl or --C.sub.n H.sub.2n --R(12) where 
n=zero or 1 
R(12) is phenyl which is unsubstituted or substituted by a substituent from 
the group comprising F, Cl and methyl, 
R(11) is H or C.sub.1 -C.sub.3 -alkyl, 
R(3) is methyl, F or Cl, and their pharmacologically tolerable salts. 
Very particularly preferred compounds are 3-chloro-4-N, N-diethylamino-5 
-methylsulfonylbenzoylguanidine hydrochloride and 
3,4-dimethyl-5-sulfaraoylbenzoylguanidine hydrochloride. 
If one of the substituents R(1) to R(12) 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 
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 
with guanidine, in which R(1) to R(3) 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 
1-imidazolyl, 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. 
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.sub.3 by treatment with gaseous HCl in 
methanol, the imidazolides of the formula II by treatment with 
carbonyldiimidazole (L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 
351-367 (1962)), the mixed anhydrides II using Cl--COOC.sub.2 H.sub.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-[(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.degree. C. and the boiling point of these solvents have proven suitable 
in the reaction of the methyl benzoates (II, L=OMe) with guanidine between 
20.degree. 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 used as a solvent in the reaction of 
II and III if a base such as, for example, NaOH is used. 
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. 
Some of the underlying benzoic acid derivatives of the 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. 
Carboxylic acids or their esters of the formula II (for example L=--OH or 
--O-methyl) where R(2) has the meaning of halogen or R(3) has the meaning 
of nitro can be used as versatile starting compounds for other carboxylic 
acids of the formula II, it being possible to replace the halogen in the 
position R(2) very conveniently in a known manner by numerous nucleophilic 
reagents, such as mercaptans R(10)--SH, phenols R(10)--OH or primary or 
secondary amines R(10)R(11)NH with the formation of other benzoic acid 
derivatives II where L=--OH or --O-methyl or it being possible to convert 
nitro, after reductive transformation to NH.sub.2, into other benzoic acid 
derivatives II where L=--OH or --O-methyl in numerous reactions 
(alkylations, acylations or diazotizations followed by Sandmeyer, Ullmann, 
Meerwein etc. reactions). 
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 tolerable acids, for example halides, in particular 
hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, 
phosphates, methanesulfonates and p-toluene-sulfonates. 
The compounds I are substituted acylguanidines. 
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 aniloride type are described in 
the literature, such as, for example, dimethylamiloride or 
ethylisopropylamiloride. 
##STR3## 
Amiloride: R', R"=H Dimethylamiloride: R', R"=CH.sub.3 
Ethylisopropylamiloride: R'=C.sub.2 H.sub.5, R"=CH(CH.sub.3).sub.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 hypotensive and saluretic 
action and these side effects are undesired in the treatment of cardiac 
arrhythmias. 
Indications of antiarrhythmic properties of amiloride were also obtained in 
experiments on isolated animal hearts (Eur. Heart J. 9 (suppl.1): 167 
(1988) (book of abstracts)). For instance, it was found in rat hearts that 
an artificially induced ventricular fibrillation could be suppressed 
completely by amiloride. The above-mentioned amiloride derivative 
ethylisopropylamiloride was even more potent than amiloride in this model. 
U.S. Pat. No. 5,091,394 (HOE 89/F 288) describes benzoylguanidines which 
carry a hydrogen atom in the position corresponding to the radical R(1). 
In U.S. Pat. No. 3,780,027, acylguanidines are claimed 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. 
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 induced 
damage, in particular in the production of ischemically induced cardiac 
arrhythmias. 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.sup.+ /H.sup.+ exchange mechanism as pharmaceuticals 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 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 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 shock. 
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 kidneys, organ hypertrophy and hyperplasia, in 
particular in prostate hyperplasia or prostate hypertrophy. 
The compounds according to the invention are active inhibitors of the 
cellular sodium-proton antiporter (Na.sup.+ /H.sup.+ exchanger), which is 
raised in numerous diseases (essential hypertension, atherosclerosis, 
diabetes, etc.) even in those cells which are easily accessible to 
measurements, such as, for example, in erythrocytes, 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 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, anti-foams, flavor correctants, preservatives, 
solubilizers or colorants, for example, can be used. 
For a form for oral administration, the active compounds are mixed with the 
additives suitable for this purpose, 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 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 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 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. 
The dose of the active compound of the formula I to be administered and the 
frequency of administration depend on the potency and duration of action 
of the compounds 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. 
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 to 10 
mg/kg, 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 
i.v., for example in the case of an infarct patient in the intensive care 
ward, up to 200 mg per day may be necessary. 
Experimental Section 
General procedure for the preparation of benzoylguanidines (I) 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 HCl 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 
##STR4## 
3-Chloro-5-methylsulfonylbenzoylguanidine hydrochloride: Colorless 
crystals, melting point 230.degree. C. Synthesis route: 
a) Reduction of 3-chloro-5-chlorosulfonylbenzoic acid to 
3-chloro-5-carboxybenzenesulfinic acid using sodium bisulfite in water at 
10.degree.-15.degree. C. and a constant pH of 8-9 (NaOH, glass electrode), 
acidify with HCl and filter off the white precipitate. 
b) Disodium 3-chloro-5-carboxybenzenesulfinate from a) using 2 equivalents 
of NaOH in water, evaporate, suspend in acetone and filter off crystals; 
white crystals, melting point &gt;300.degree. C. 
c) Methyl 3-chloro-5-methylsulfonylbenzoate from b) using 1 equivalent of 
methyl iodide in DMF at 80.degree. C./8 hours, distill off solvent, column 
chromatography on silica gel and ethyl acetate/toluene mixture (1:3). 
Colorless crystals, melting point 75.degree. C. 
d) 3-Chloro-5-methylsulfonylbenzoic acid from c) by alkaline hydrolysis and 
acidification with HCl. White crystalline powder, melting point 
214.degree. C. 
e) 3-Chloro-5-methylsulfonylbenzoylguanidine hydrochloride from d) 
according to the general procedure (see above). Colorless crystals, 
melting point 230.degree. C. 
EXAMPLE 2 
##STR5## 
3,4-Dimethyl-5-methylsulfonylbenzoylguanidine hydrochloride; colorless 
crystals, melting point 288.degree. C. Synthesis route: 
a) 2,3-Dimethyl-5-carboxybenzenesulfinic acid from 
5-chlorosulfonyl-3,4-dimethylbenzoylbenzoic acid by reduction with sodium 
bisulfite analogously to Example 1, a), white crystals, melting point 
213.degree. C. 
b) Disodium2,3-dimethyl-5-carboxybenzenesulfinate from 
2,3-dimethyl-5-carboxybenzenesulfinic acid analogously to Example 1, b). 
Colorless crystals, melting point &gt;320.degree. C. 
c) Methyl 3,4-dimethyl-5-methylsulfonylbenzoate from disodium 
2,3-dimethyl-5-carboxybenzenesulfinate analogously to Example 1, c). 
Colorless crystals, melting point 102.degree. C. 
d) 3,4-Dimethyl-5-methylsulfonylbenzoic acid from methyl 
13,4-dimethyl-5-methylsulfonylbenzoate analogously to Example 1, d). 
Colorless crystals from ethanol, melting point 224.degree. C. 
e) 3,4-Dimethyl-5-methylsulfonylbenzoylguanidine hydrochloride according to 
the general procedure from 3,4-dimethyl-5-methylsulfonylbenzoic acid. 
Colorless crystals, melting point 288.degree. C. 
EXAMPLE 3 
##STR6## 
3,4-Dimethyl-5-sulfamoylbenzoylguanidine hydrochloride according to the 
general procedure from 3,4-dimethyl-5sulfamoylbenzoic acid. Colorless 
crystals, melting point 270.degree. C. 
EXAMPLE 4 
##STR7## 
5-(1-Butylsulfamoyl)-3,4-dichlorobenzoylguanidine hydrochloride is obtained 
by reaction of 3,4-dichlorobenzoic acid in chlorosulfonic acid at 
140.degree.-160.degree. C. with the production of 
3,4-dichloro-5-chlorosulfonylbenzoic acid (melting point 203.degree. C.), 
reaction with N-butylamine to give 
5-(1-butylsulfamoyl)-3,4-dichlorobenzoic acid (melting point 
160.degree.-165.degree. C.) and subsequent activation thereof with 
carbonyldiimidazole, reaction with guanidine and treatment with HCl to 
give 5-(1-butylsulfamoyl)-3,4-dichlorobenzoylguanidine hydrochloride, 
melting point 140.degree.-145.degree. C. 
EXAMPLE 5 
##STR8## 
5-N-Benzyl-N-methylsulfamoyl-3,4-dichlorobenzoylguanidine hydrochloride is 
obtained by reaction of 3,4-dichloro-5-chlorosulfonylbenzoic acid with 
N-methylbenzylamine to give 
5-N-benzyl-N-methylsulfamoyl-3,4-dichlorobenzamide, (melting point 
155.degree.-160.degree. C.) and subsequent reaction according to the 
general procedure (see above): 
5-N-benzyl-N-methylsulfamoyl-3,4-dichlorobenzoylguanidine hydrochloride. 
Colorless crystals, melting point 185.degree.-190.degree. C. 
EXAMPLE 6 
##STR9## 
3,4-Dichloro-5-sulfamoylbenzoylguanidine hydrochloride (Colorless 
crystalline substance, melting point 234.degree.-36.degree. C.) is 
obtained from 3,4-dichloro-5-sulfamoylbenzoic acid according to the 
general procedure (see above). 
EXAMPLE 7 
##STR10## 
3,4-Dichloro-5-methylsulfonylbenzoylguanidine hydrochloride, colorless 
crystals, melting point 236.degree.-240.degree. C., is obtained starting 
from 3,4-dichloro-5-chlorosulfonylbenzoic acid by sulfite reduction to 
disodium 2,3-dichloro-5-carboxybenzenesulfinate (melting point 
&gt;300.degree. C.), reaction with excess methyl iodide to give methyl 
3,4-dichloro-5methylsulfonylbenzoate, hydrolysis to 
3,4-dichloro-5methylsulfonylbenzoic acid (196.degree.-199.degree. C.) and 
subsequent reaction according to the general procedure. 
EXAMPLE 8 
##STR11## 
3-Chloro-4-N,N-diethylamino-5-methylsulfonylbenzoylguanidine hydrochloride, 
colorless crystals, melting point: 222.degree.-224.degree. C. is obtained 
starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate by reaction 
with diethylamine in an autoclave (160.degree. C., 12 hours) and 
subsequent alkaline hydrolysis to 
3-chloro-4-N,N-diethylamino-5-methylsulfonylbenzoic acid (melting point 
115.degree.-117.degree. C.) and reaction with guanidine according to the 
procedure (see above). 
EXAMPLE 9 
##STR12## 
3-Chloro-5-methylsulfonyl-4-phenoxybenzoylguanidine hydrochloride, 
colorless crystals, melting point 271.degree.-274.degree. C., is obtained 
starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate by reaction 
with phenol and potassium carbonate in DMF (80.degree. C., 6.5 hours) and 
subsequent alkaline hydrolysis to 
3-chloro-5-methylsulfonyl-4-phenoxybenzoic acid (melting point 
210.degree.-212.degree. C.) and reaction with guanidine according to the 
procedure (see above) . 
EXAMPLE 10 
##STR13## 
3-Chloro-5-methylsulfonyl-4-phenylthiobenzoylguanidine hydrochloride, 
colorless crystals, melting point 228.degree.-230.degree. C., is obtained 
starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate by reaction 
with thiophenol and potassium carbonate in DMF (120.degree. C., 6.5 hours) 
and subsequent alkaline hydrolysis to 
3-chloro-5-methylsulfonyl-4-phenylthiobenzoic acid (melting point 
231.degree.-233.degree. C.) and reaction with guanidine according to the 
procedure (see above). 
EXAMPLE 11 
##STR14## 
3-Benzylsulfonyl-4,5-dichlorobenzoylguanidine hydrochloride, colorless 
crystals, melting point: 262.degree. C. is obtained by reaction of 
disodium 2,3-dichloro-5-carboxybenzenesulfonate with 2 equivalents of 
benzyl chloride in DMF (80.degree. C., 5 hours) and subsequent acidic 
hydrolysis (20% strength aqueous HCl, in glacial acetic acid, 3 hours' 
reflux) to 5-benzylsulfonyl-3,4-dichlorobenzoic acid (melting point 
183.degree. C.) and subsequent reaction with guanidine according to the 
general procedure. 
EXAMPLE 12 
##STR15## 
4-(1-Butylamino)-3-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride, 
colorless crystals, melting point: 200.degree. C. is obtained starting 
from 3,4-dichloro-5-methylsulfonylbenzoic acid (melting point 
215.degree.-220.degree. C.) by reaction with n-butylamine in an autoclave 
(140.degree. C., 12 hours) to give 
4-(1-butyl-amino)-3-chloro-5-methylsulfonylbenzoic acid (melting point 
155.degree.-160.degree. C.) and reaction with guanidine according to the 
procedure (see above). 
EXAMPLE 13 
##STR16## 
4-Amino-3-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride, 
colorless crystals, melting point: 270.degree. C. is obtained starting 
from 4-amino-3-chloro-5-methylsulfonylbenzoic acid (melting point 
255.degree.-261.degree. C.) by reaction with guanidine according to the 
procedure (see above). 
EXAMPLE 14 
##STR17## 
3-Chloro-4-(2,2,2-trifluoroethoxy)-5-methylsulfonylbenzoylguanidine 
hydrochloride, colorless crystals, melting point 261.degree. C. is 
obtained starting from methyl 3,4-dichloro-5-methylsulfonylbenzoate by 
reaction with 2,2,2-trifluoroethanol and potassium carbonate in DMF 
(100.degree. C., 6 hours) and subsequent alkaline hydrolysis to 
3-chloro-4-(2,2,2-trifluoroethoxy)-5-methylsulfonylbenzoic acid (melting 
point 214.degree.-220.degree. C.) and reaction with guanidine according to 
the procedure (see above). 
EXAMPLE 15 
##STR18## 
3-Sulfamoyl-5-trifluoromethylbenzoylguanidine hydrochloride, colorless 
crystals, melting point 235.degree.-238.degree. C. is obtained by reaction 
of 3-trifluoromethylbenzoic acid by nitration (100% strength HNO.sub.3 in 
20% strength oleum, 3 hours at room temperature) to give 
5-nitro-3-trifluoromethylbenzoic acid (melting point 126.degree.-129 
.degree. C.). Catalytic hydrogenation (platinum(IV) oxide in ethanol at 
room temperature, 1 atm) to 5-amino-3-trifluoromethylbenzoic acid (melting 
point 133.degree.-137.degree. C.), Meerwein reaction to give 
5-chlorosulfonyl-3-trifluoromethylbenzoic acid (melting point 
144.degree.-147.degree. C.), reaction with aqueous ammonia (25% strength, 
14 hours at room temperature) to give 5-sulfamoyl-3-trifluoromethylbenzoic 
acid (melting point 235.degree.-240.degree. C.) and reaction with 
guanidine according to the procedure (see above). 
EXAMPLE 16 
##STR19## 
3-Amino-5-methylsulfonylbenzoylguanidine dihydrochloride, colorless 
crystals, melting point 264.degree. C., is obtained by reaction of 
3-methylsulfonylbenzoic acid by nitration (100% strength HNO.sub.3 in 20% 
strength oleum, 3 hours at room temperature) to give 
5-nitro-3-methylsulfonylbenzoic acid (melting point 
218.degree.-220.degree. C.), catalytic hydrogenation (Raney nickel in 
methanol at room temperature, 1 arm) to 5-amino-3-methylsulfonylbenzoic 
acid (melting point 300.degree.-310.degree. C.), and reaction with 
guanidine according to the procedure (see above). 
EXAMPLE 17 
##STR20## 
3-Amino-4-chloro-5-methylsulfonylbenzoylguanidine dihydrochloride, 
colorless crystals, melting point 279.degree.-281.degree. C., is obtained 
by reaction of 4-chloro-3-methylsulfonylbenzoic acid by nitration (100% 
strength HNO.sub.3 in 20% strength oleura, 4 hours at 
90.degree.-100.degree. C.) to give 
4-chloro-5-nitro-3-methylsulfonylbenzoic acid (melting point 
190.degree.-194.degree. C.), reduction using sodium bisulfite (1 hour, 
100.degree. C. in water) to 5-amino-4-chloro-3-methylsulfonylbenzoic acid 
(melting point 265.degree.-267.degree. C.) and reaction with guanidine 
according to the procedure (see above). 
EXAMPLE 18 
##STR21## 
3-Cyano-5-methylsulfonylbenzoylguanidine hydrochloride, colorless to 
slightly yellow crystals, melting point 275.degree.-278.degree. C. (dec.), 
is obtained by Sandmeyer reaction of 3-amino-5-methylsulfonylbenzoic acid 
with Cu(I) cyanide to give 3-cyano-5-methylsulfonylbenzoic acid (melting 
point 226-228) and subsequent reaction with guanidine according to the 
procedure (see above). 
EXAMPLE 19 
##STR22## 
3-Chloro-4-methyl-5-sulfamoylbenzoylguanidine hydrochloride, colorless 
crystals, melting point 256.degree.-259.degree. C., is obtained from 
3-chloro-4-methyl-5-sulfamoylbenzoic acid by reaction with guanidine 
according to the procedure (see above). 
EXAMPLE 20 
##STR23## 
3-Dimethylamino-5-methylsulfonylbenzoylguanidine dihydrochloride, colorless 
crystals, melting point 278.degree.-290.degree. C. (dec.), is obtained by 
reaction of 3-amino-5-methylsulfonylbenzoic acid with methyl iodide in 
DMF/potassium carbonate (6 hours, 70.degree. C.) and subsequent hydrolysis 
to 3-dimethyl-amino-5-methylsulfonylbenzoic acid (melting point 
200.degree.-203.degree. C.) and subsequent reaction with guanidine 
according to the procedure (see above). 
EXAMPLE 21 
##STR24## 
3-Chloro-4-(4 -chlorobenzylamino)-5-methylsulfonylguanidine hydrochloride 
is obtained according to the procedure from 
3-chloro-4-(4-chlorobenzylamino)-5-methylsulfonylbenzoic acid and 
guanidine. Colorless crystals; melting point 209.degree.-219.degree. C. 
EXAMPLE 22 
##STR25## 
3-(2,5-Dimethoxy-4-methylphenylsulfonyl)-5-trifluoromethylbenzoylguanidine 
hydrochloride is obtained according to the procedure from 
3-(2,5-dimethoxy-4-methylphenylsulfonyl)-5-trifluoromethylbenzoic acid and 
guanidine. Colorless crystals; melting point: 174.degree. C. 
EXAMPLE 23 
##STR26## 
4-Anilino-3-chloro-5-methylsulfonylbenzoylguanidine hydrochloride is 
obtained according to the procedure from 
4-anilino-3-chloro-5-methylsulfonylbenzoic acid and guanidine. Colorless 
crystals; melting point: 174.degree. C. 
4-Anilino-3-chloro-5-methylsulfonylbenzoic acid (melting point 
187.degree.-189.degree. C.) is obtained by 
1. heating methyl 3,4-dichloro-5-methylsulfonylbenzoate in excess aniline 
for 8-10 hours at 120.degree. C. and removal of the methyl 
4-anilino-3-chloro-5-methylsulfonylbenzoate (melting point 
165.degree.-169.degree. C.) by treating the reaction mixture with 1N HCl 
and 
2. by subsequent hydrolysis of the methyl 
4-anilino-3-chloro-5-methylsulfonylbenzoate with methanolic/aqueous NaOH 
and treatment of the residue with 2N HCl after distilling off the solvent 
mixture.