DE3108753A1 - Substituted alkylphenylsulphonylguanidines with a heterocyclic radical - Google Patents

Description

Degussa Aktiengesellschaft Weissfrauenstrasse 9 - 6000 Frankfurt / Main

New substituted alkyl-phenylsulfonylguanidines with a heterocyclic residue

description

Compounds of the general formula

N-X I

Het - (CH ₂ ) -Z- (CH ₂ ) -NH-C - NHR

where R _{1 is} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and Het is a nitrogen-containing 5- or 6-membered heterocyclic radical, Z is a sulfur or oxygen atom, an NH or methylene group, m and η are 0 or whole Are numbers with a value from 1 to 4, and the sum of m and η has the value 2 to 4, X is a COR ₃ -, CSR -.-, SO-R.- or N = CHRj - group, or if Z represents a methylene group, represents a nitro group, R _{3 represents} an alkyl or alkoxy radical having 1 to 4 carbon atoms, an optionally substituted aryl radical, a trifluoromethyl or amino group, R ₄ and R _{5 represent} an optionally substituted aryl radical and theirs

Salts are known (see German Offenlegungsschrift 2 344 833).

Furthermore, by the German Offenlegungsschrift 27 34 070 aminoalkylfuran derivatives of the general formula

- 6a -

2 ⁾ n ~ ^X " ^(CH 2 ⁾ _m - ^NH -

R ₂

their salts and N-oxides are known, in which R ₁ and R ₂ , which can be the same or different, represent hydrogen , ' lower alkyl, cycloalkyl, lower alkenyl, aralkyl or lower alkyl which is interrupted by an oxygen atom or a group -N-,

^Ir 4
where R _{4 has} the meaning hydrogen or lower alkyl, or where R ₁ and R ~ together with the nitrogen atom to which they are attached can form a heterocyclic ring which can contain 0 and / or -N- as heteroatoms, in which further ^R 4

R _{3 is} hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl, X is -CH ₂ -, O or S, Y is = S, = 0, = NR ₅ or = CHRg, Alk is

is a straight-chain or branched alkylene chain with 1 to 6 carbon atoms, R _{5 is} H ₇ nitro, cyano, lower alkyl, aryl, alkylsulfonyl or arylsulfonyl, R _{6 is} nitro, arylsulfonyl or alkylsulfonyl, m is an integer from 2 to 4 and η has the value 1 or 2, or when X is sulfur or -CH ₂ -, η has the value 0.1 or 2

An antihistamine action of the H ^ blocker type is indicated for these previously known compounds: They prevent the secretion of gastric juice when this is _{stimulated by histamine H 2} receptors.

However, these known compounds are only relative

weakly effective.
15th

The invention relates to what is defined by the claims defined objects.

The compounds according to the invention are pharmacodynamically active. For example, they inhibit gastric juice secretion, especially that of gastric acid, and • have a strong antihistamine effect of the "H ₂ blocker" type. In addition, they have an ulcer-healing effect.

The invention is therefore based on the object of providing compounds with favorable pharmacodynamic properties to make available that can be used as pharmaceuticals.

The effect of the compounds according to the invention is surprising with regard to the compounds previously known from the above-mentioned German Offenlegungsschrift, since it is known that substituents in the aryl nucleus, that is in the phenyl nucleus of the guanidino group of the right part of the molecule such as halogen atoms or alkyl groups, lead to ineffective compounds;

- IS -

] In addition, all of these compounds are only effective for a short time. In contrast, the compounds according to the invention are surprisingly stronger and longer effective than the previously known compounds. The alkyl, alkoxy, alkoxycarbonyl and alkylene groups occurring in the formula I (for example the ^ -C. -alkyl group in the form of the di-C.-C.-alkylamino-C -C.-alkyl group) can be straight or branched. Examples of the alkylene group are: -CH ₂ -, -CH ₂ -CH ₂ -, - (CH ₂ J ₃ -— 'CH ^ J a "1 CH-CH« -, —CH- (CH ^) ^ -, —CH— —CH — CH——. CH ₃ CH ₃ CH ₃

^ O If one of the radicals R ₅ or R _{g is} a C ₃ -Cg cycloalkyl group, it is, for example, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group. If one of the radicals R ~ or R- is the group -SOJSIHR, -, R _{5 is} in particular ethyl, propyl, isopropyl, tert-butyl or

'5 isobutyl radical.

The heterocyclic radical X is preferably linked to the rest of the molecule via the 2-position ( oi -position) of X. A possible substituent of X is preferably in the 5-position of X. ■

^to If it is the halophenyl radical or if the radicals Rp and / or R-. Sharks represent, in particular, fluorine, chlorine and bromine. If one of the radicals R ₅ or R, is a substituted phenyl radical, then this preferably contains two or three of the substituents mentioned (fluorine, chlorine, bromine, ^ΔΌ methyl, methoxy, nitro group). Examples of the dialkylamino · Cj-Cj-alkyl group are ß-diethylamino-ethyl group, ß-dimethylaminoethyl group, ^^ iethylaitiino-propyl group, J ^ -dimethylamino-propyl group. Examples of the C.-C.-alkoxycarbonyl group are: Carb-

methoxy / carbäÜioxy-, carbpropoxy group. 30th

The process products can optionally be alkylated. This involves, for example, the introduction of the radical R ₁ , if this is a C ₁ -C ₄ -alkyl group, into a compound I in which R ₁ - 9 -

Represents hydrogen and / or the introduction of the radicals R ₅ and R ₆ , if these C.-C.-alkyl groups or a di-C.-C.-alkylamino-C.-C.-alkyl group or C ₃ -C 6 -cycloalkyl group in compounds of the formula I in which R- and / or R _{3 represent} the group -CONH ₂ and / or -SO ₃ NH ₂ , the last-mentioned groups on the N atom already being a Cj-C alkyl group, Cj-Cg-cycloalkyl group or di-C.-C.-alkylamino-C.-C ₄ -alkyl group.

These alkylations are carried out in a manner known per se. Examples of suitable alkylating agents are: esters of the formula R ¹ _{Hal, ArSO 2} OR ¹ and

₂ J ₂ 'where Hai is a halogen atom (especially chlorine, bromine or iodine) and Ar is an aromatic radical such as, for example, a phenyl or naphthyl radical optionally substituted by one or more lower alkyl radicals and R ^{1 is} an alkyl group with 1 to 4 carbon atoms , a C -C -cycloalkyl radical or a di-Cj-C.-alkylamino-CC.-alkylresi: is. Examples are p-toluenesulfonic acid C.-C.-alkyl esters, p-toluenesulfonic acid (di-C.-C.-alkylamino) -CC.-alkyl esters, lower C ₁ -C ₄ -dialkyl sulfates, C 1 -C 4 -alkyl halides , C ₃ -C 6 cycloalkyl halides or di-C.-C.-alkylamino-C.-C.- «c alkyl halides and the like. The alkylation reaction is optionally with addition of conventional acid-binding agents such as alkali metal hydroxides, Alkal carbonates or alkali hydrides, at temperatures between 0 and 150 ⁰ C in inert solvents such as dioxane, dimethylformamide, ο "dimethyl sulfoxide, aromatic hydrocarbons (such as benzene, toluene) or acetone made!. If Rc and Rg represent different substituents, for example R _{5 is} a CC-alkyl radical and R _{g is} a C ₃ -Cg alkyl radical, the alkylation is carried out in two stages, for example by first taking the

- 10 -

Alkyl radical and then introduces the cycloalkyl radical or vice versa. The same applies if R _{5 is,} for example, a Cj-C.-alkyl radical and Rg is a di-C.-C.-alkylamino-C.-C ₄ -alkyl radical.

The alkylation can also be carried out in the presence of tetraalkylammonium salts {especially the halides) in combination with alkali hydroxides at temperatures between 0-100 ° C, preferably 20-80 ° C in an aprotic solvent. As apro-

IQ tables solvents come into consideration, for example: Tertiary amides (dimethylformamide, N-methyl-pyrrolidone, Hexamethylphosphoric acid triamide), dimethyl sulfoxide, acetonitrile, dimethoxyethane, acetone, tetrahydrofuran The last-mentioned method is preferably suitable

• each for the alkylation of a -CONH ₂ -GrUpPe.

If necessary, the alkylation can also proceed as follows: that one first prepares an alkali compound of the compound to be alkylated by making it in an inert solvent such as dioxane, dimethyl

2Q formamide, benzene or toluene with an alkali metal, alkali hydride or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150 ° C and then adding the alkylating agent (for example if you start from a compound in which R ₁ and / or R ₅ and / or R_ are hydrogen).

Instead of the listed alkylating agents, others commonly used in chemistry can also be chemically equivalent means can be used (see, for example, also: L. F. and Mary Fieser "Reagents for Organic Synthesis ", John Wiley and Sons, Inc. New York, 1967, Vol. 1, pages 1303-4 and Vol. 2, page 471).

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Regarding procedure a)

The process is carried out, for example, in a polar solvent at temperatures between -20 and + 200 ° C, preferably 50-150 ° C, made with or without the addition of basic substances (alkali hydroxides). With volatile amines you have to use a closed system optionally work under pressure (for example up to 100 bar). Polar solvents such as water or alcohols (methanol, ethanol / n-propanol, iso-propanol, Butanol) straight-chain ethers such as dimethyl ether, diethyl ether or glycol dimethyl ether, cyclic ethers such as tetrahydrofuran, or Dioxane, also dipolar aprotic solvents such as dimethylformamide, dimethylacetamide; Dimethyl sulfoxide, hexaitethylphosphoric acid triamide or sulfolane, furthermore acetonitrile or aromatic solvents such as benzene, toluene or xylene as well as excess amine.

The starting materials for this process, which are not known, can for example be produced analogously to the processes described in German Offenlegungsschriften 22 11 454 and 23 44 779 are described.

Starting materials of the formula II in which T is the group X-CH ₂ -S- (CH ₂ ) ₂ -NH can be obtained, for example, as follows: A benzenesulfonamide of the formula

R ₃

in a solvent (dimethylacetamide-water Dimethylformatnid water) in the presence of alkali, for example potassium 3Q hydroxide, sodium hydroxide, at a temperature between 0 ⁰ C and 100 ° C first with carbon disulfide and then Urd with an alkylating agent (C.-C ^ Alkylhalcgenic, in particular C ₁ -C ₄ -alkyl iodide, C ₁ -C.-Pialkylsulfat) implemented.

The one obtained in this way, substituted by R- ,, K _{3 and R in the phenyl nucleus}

Phenylsulfcmylinnino-dithiocarbonic acid-C- -C. -Dialkyl ester is then mixed with the amine of the formula X-CH ₂ -S- (CH-) ^ -NH? ^ ^{11 6} ^ ¹¹⁶¹¹¹ solvent (lower

- 12 -

. Alcohols such as methanol, ethanol, n-propanol, isopropanol / aromatic solvents such as toluene and xylene as well as acetonitrile) at temperatures between 0 ° C and 100 ° C implemented.

The starting benzenesulfonic amides of the formula

, 0 N ^ y- ^S ° 2 ^NH 2

are known or can, for example, from the corresponding benzenesulfonic acid halides (chlorides) or also benzenesulfonic acid dihalides (dichlorides) in a manner known for this by stirring for several hours with excess aqueous ammonia (25%) if necessary can be obtained in a solvent at temperatures between 20-80 ° C.

Alkyl sulfamoyl benzoates or alkyl disulfamoyl benzoates are obtained, for example, by reacting the corresponding chlorosulfonyl benzoic acid chlorides with the corresponding alkanol in an aromatic hydrocarbon (toluene) and then reacting the unreacted sulfochloride groups with aqueous ammonia. The corresponding sulfamoyl- or disulfamoyl-benzonitrile can be obtained from a sulfamoylbenzoic acid amide or a disulfamoylbenzoic acid amide by boiling with POCl. Reaction of such a benzonitrile with hydrogen sulfide gives, for example, the corresponding thioamide. Benzenesulfonamides in which one or both of the radicals R ₂ and R _{3 are} carboxy groups can be obtained from the corresponding carbalkoxy compounds by alkaline saponification.

- 13 -

N-alkylated benzene-disulphonic acid amides can be obtained, for example, by reacting sulphamoyl-benzenesulphonic acid chlorides with an appropriate acid in an inert solvent (dioxane) at temperatures between 20.degree. Possible amines of this type are: C ₁ -C ₄ -ALkYIaItIJjIe, C_-Cg-Cycloalky! Amines, di-C ₁ -C ^ -alkylamino-C ..- C.-alkylamines; Phenylamines, which can also be substituted in the phenyl ring by halocene, nitro groups, C ₁ -C ₄ alkoxy groups or C ₁ -C ₄ alkyl groups, or hydroxylamine - ^ - Cg-acyl ethers; The primary amines indicated above, in which the second nitrogen atom is substituted by a C.-C.-alkyl radical, are also suitable. The preparation of such an N-mono-alkylated benzene-disulfonic acid amide is illustrated below:

irHtfitrobenzenesulfonic acid chloride is converted into the m-nitrobenzenesulfonic acid amide with aqueous ammonia (25%) at room temperature. This is hydrogenated in methanol over Raney nickel at 100 ° C. and 50-60 bar, the catalyst is suctioned off and the filtrate is evaporated. 23.8 g of this residue (crude 3-aminobenzenesulfonic acid amide) are suspended in 120 ml of concentrated HCl and 45 ml of glacial acetic acid, plus a solution ^{at -5 to 0 ° C.} of 11.9 g of sodium nitrite in 21 ml of water were added dropwise. This mixture is then poured into a 32% strength solution of sulfur dioxide in glacial acetic acid containing 14 g of copper (2) chloride at 10 ° C. and stirred for 2 hours. 600 ml of ice water are then added, the mixture is stirred for 1 hour, filtered off with suction and washed thoroughly.

This crude 3-sulfamoylbenzenesulfonic acid chloride (mp 137-138 ° C.) is then reacted in dioxane with the amine in question; For example, 24.7 g of this crude semi-chloride are dissolved in 200 ml of dry dioxane and 6.8 g of methylamine in 25 ml of dioxane are added thereto at 20-30 ° C. After one hour, the mixture is evaporated in vacuo, the residue is dissolved in 100 ml of water, filtered, brought to pH 1 with hydrochloric acid and 250 ml of water are added. The 3-sulfamoylbenzenesulfonic acid-N-methylamide which crystallizes out is filtered off with suction

(M.p. 114-117 ° C).
35

- 14 -

3106753

The preparation of a direct starting compound is exemplified by N- (3-sulfamoylphenylsulfonyl) -N'-f2- / T5-dimethylaminomethyl-2-furanyl) -methylthio / -äthylj -S-methylisothiourea illustrates:

/ -

A solution of 9.5 g of 2- ■ £ / 5- (Dimethylamine) -methyl-

2-furanyl7-methylthioethanamine and 15 g of 3-sulfamoylphenyl-sulfonylimino-dithiocarbonic acid dimethyl ester in 250 ml of methanol are stirred for 75 minutes at 30.degree.-40.degree. Methyl mercaptan develops in the process. Then it is evaporated in vacuo. The residue, a syrup, is further converted directly into a compound of the formula I (yield: 22 g).
The 3-sulfamoyl-phenyl-sulfonylimino-dithiocarbonic acid dimethyl ester is obtained as follows:

A solution of 47.3 g (0.2 mol) of m-benzenedisulfonic acid diamide in 350 ml of dimethylformamide with 43.8 g (0.35 mol) of 32% sodium hydroxide solution for 30 minutes at room temperature touched. 14.5 ml (0.24 mol) of carbon disulfide are then added and the mixture is stirred for a further 45 minutes at 20 ° C. 33.2 ml (0.35 mol) of dimethyl sulfate are then added with cooling (at 25-30 ° C.) added in pots and then stirred for a further 30 minutes at 20-25 ° C. The reaction is shown in a thin layer chromatogram tracked. In addition to the desired compound, about 30-40% of the corresponding bis-imidodithiocarbonic acid ester is formed. This can be fractionally precipitated by carefully adding 300 ml of water will; to achieve complete precipitation, the mixture is stirred overnight and then filtered off with suction. Here will be 9.2 g of the bis-imidodithiocarbonic acid ester (by-product) obtain. The filtrate is mixed with a further 2 liters of water while stirring, the desired compound crystallized out.

Yield: 37.5 g, melting point: 168 ° C.

- 14a -

- l-fra -

The. N- (3-sulfamoyl-phenyl-sulfonyl) - {2- [5-methyl-imidazo-IyI- (4) -methylthicT) -e thylj- -S-methyl-isothiourea, is obtained for example:

To a solution of 3.9 g of 4- (2-amino-ethylmercaptomethyl) -5-methyl-imidazole (Dihydrochloride) in 15 ml of methanol and 10 ml of water are added 4.4 g of a 32% strength sodium hydroxide solution. 5.4 g of 3-sulfamoylphenyl) sulfonylimino-dithiocarbonic acid dimethyl ester are added to the clear solution thus formed in 25 ml of dimethyl acetamide and stir for 2 hours

Ί0 20 ° C. During this process, methyl mercaptan develops. Then it will be evaporated in vacuo. The residue is dissolved in 150 ml of butanol, washed several times with water and the butanol phase evaporated again in vacuo. The remaining product is a syrup. Yield: 9 g.

The (3-sulfamic acid phenyl) sulfonylimino-dithiocarbonic acid dimethyl ester is obtained as follows:

To a mixture of 24.5 g of m-benzene disulphonic acid diamide, 13.7 g of potassium hydroxide, 200 ml of dimethylacetamide and 60 ml 6.3 ml of carbon disulfide are added dropwise to water at 35 ° -40 ° C. The mixture is then stirred for 30 minutes and added dropwise 35 - 40 ° C 19.8 ml of dimethyl sulfate. One hour after the end of the dropwise addition, it is poured into 750 ml of water. Of the semi-solid precipitate is sucked off, .the mother liquor

Once more diluted with 1000 ml of water and the product that crystallizes out is filtered off with suction. Both precipitates are boiled with 100 ml of ethanol and the undissolved substance is filtered off (the undissolved substance is benzene-1,3-bis (sulfonylimino-dithiocarbonic acid dimethyl ester). Yield: 2.3 g. ³⁰ F .: 170 - 172 ° C.

The evaporated ethanol extract is subjected to dry column chromatography cleaned. Yield: 3.7 g. F .: 197 199 ° C.

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310875: i η - '■

- 1 * 5 -

Starting material o of the formula II, in which T is the group -NHR ₁ , can, for example, by reacting a phenylsulfonylimino-dithiocarbonic acid-C. -C, dialkyl ester, which is substituted in the phenyl ring by the radicals R2f R and R. and an amine R ₁ NH _{3 can be obtained} at temperatures between 0 and 100.degree. Examples of suitable solvents for this reaction are lower alcohols such as methanol, ethanol, n-propanol, isopropanol, aromatic solvents such as toluene and xylene and also acetonitrile. The same conditions apply as for the reaction with the amine X-CH ₂ -S- (CH ₂ ) ₂ ~ ^NH 2 *

-

-1S-

] The starting amines of the formula X-CH ₂ -S- (CH ₂ ) ₂ ~ ^NH o can be obtained, for example, according to the German Offenlegungsschrift 2 734 070, pages 25-33. In the case of the corresponding thiophene and

c pyrrole compounds is made analogously to the corresponding furan compounds proceed by the corresponding thiophene or pyrrole derivatives are only used instead of the furan starting compounds.

Such starting amines can also be prepared, for example, by reacting compounds of the formula X-CH "-Q, where Q is a hydroxyl or methoxy group or a halogen atom (X can have the meanings given) with a co-aminomercaptan of the formula HS- (CH ^ ) ₇ -NH ₇ according to the conditions given in German Offenlegungsschrift 2 406 166 (pages 8-9) and in the British patent 1 338 169 are obtained. If Q is a halogen atom, this reaction can be carried out in a strongly alkaline medium, for example in the presence of sodium ethoxide, potassium hydroxide, sodium hydroxide, tertiary amines (triethylamine) or strongly basic ion exchangers. It may be necessary to protect the amino group of the ^ i-aminomercaptan starting compound, for example by converting it into a phthalimide group, which is subsequently split off again by acid hydrolysis or hydrazinolysis. If appropriate, the reaction can also take place in an acidic medium, for example in the presence of a hydrohalic acid such as 48 percent aqueous hydrobromic acid or a hydrohalic acid in the presence of glacial acetic acid, if Q represents a hydroxyl group. If Q is a methoxy group, the reaction also proceeds in the presence of 48 percent strength hydrobromic acid.

- · 17 -

-N-, Regarding method b):

The process is carried out, for example, in a solvent or dispersant at temperatures between 20 to 180 ° C / preferably 40-120 ° C. - As a solvent or dispersant come to

Example under consideration: Aromatic hydrocarbons such as benzene, chlorobenzene, mesitylene, toluene, xylene, saturated cyclic ethers such as dioxane, tetrahydrofuran, dipolar aprotic solvents such as dimethylform- ■ | Q amide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide.

If Z or U represents an esterified hydroxyl group, then this is a reactive one Ester. A reactive ester is included

■ each, for example, that of a strong organic or inorganic acid, such as, in particular, a hydrohalic acid, for example chlorine, bromine or Hydriodic acid or a sulfonic acid such as an aryl or alkyl sulfonic acid, for example the

2Q p-toluenesulfonic acid.

In general, the process is carried out in the presence of basic condensing agents such as alkali metal hydroxides, strongly basic ion exchangers, alkali alcoholates such as potassium tert-butoxide or tertiary amines (Trialkylamines, for example triethylamine) carried out. It is also possible, for example, from the to be used mercapto compound in liquid ammonia first an alkali salt by means of alkali hydrides to produce and then to implement this with the other reaction component. If Z or ü means a free hydroxyl group, it is advisable to carry out the reaction in a strongly acidic medium, for example in the presence of mineral acids

- 18 -.

, (48% HBr, 6N-HCl or glacial acetic acid), whereby the agents just mentioned can also serve as solvents or dispersants at the same time.

The starting materials of the formula IV can, for example by reacting compounds of the formula

Ji

N - SO ₂ /

11
TCS- alkyl II

where T is the remainder -NHR. is with a compound H ₂ N-CH ₂ -CH ₂ -Z, in which Z is either a mercapto group or a hydroxyl group optionally esterified by a strong organic, ς or inorganic acid. This reaction takes place, for example, in solvents such as lower aliphatic C.-C ₅ alcohols, acid amides (dimethylacetamide, dimethylformamide) or aromatic hydrocarbons (toluene, xylene), optionally mixed with water, at temperatures between 0-150 ° C, preferably 20 - 120 ° C. If Z is a mercapto group, it is advisable to protect it with a customary sulfhydryl protective group that can be split off under acidic or basic conditions. Suitable sulfhydryl protective groups are, for example, the same protective groups that are used to protect amino groups, for example the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the tert-butyloxycarbonyl group and the like.

In addition, for example, the following S-specific sulfhydryl protective groups are possible: 2 ~ Nitro-1-phenylethyl group, Benzamidomethyl group, acetamidomethyl group, S-ethyl mercapto group, tert-butyloxycarbonylsulfenyl group or benzyloxycarbonylsulfenyl group.

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310875 ·! ^Ii:::: ■

After the reaction has ended, these protective groups become removed again. This cleavage takes place in a known manner, for example in aqueous, aqueous-alcoholic media or also in mixtures of acetone with water and / or alcohols or else in pure alcohols in the presence of alkali such as potassium hydroxide, sodium ethoxide, or potash also tertiary amines or secondary or primary amines, these substances being preferred are present in equivalent amounts. The cleavage can also take place in low molecular weight alcohols Addition of small amounts of strong acids (hydrochloric acid, sulfuric acid, toluenesulfonic acid, hydrogen bromide / Glacial acetic acid). The temperatures for the cleavage of the acyl groups are generally between 0 and 150 ° C. In the case of the benzamidomethyl group or the acetamidomethyl group, the cleavage can, for example can also be done with an aqueous mercury (II) salt solution at room temperature.

The further conversion of the starting materials of the formula IV to the process products according to the invention can also be carried out without isolating these compounds, simply by following the reaction described above reaction mixture obtained is further reacted directly with a compound of the formula V.

Regarding procedure c):

The process is carried out in a solvent or dispersant like lower saturated aliphatic alcohols (methanol, ethanol) saturated cyclic ethers (Tetrahydrofuran, dioxane), tertiary acid amides (dimethylformamide, dimethylacetamide) or aromatic Hydrocarbons (toluene, xylene), optionally mixed with water at temperatures between 0 - 100 ° C, preferably 20 - 60 ° C,

- 20th

, carried out. If an alkcxycarbany! Group (as The radical R ~ and / or R-J is hydrolyzed to the carboxy group, it is expedient to work in the presence of alkali or alkali C 1-4 alcoholates. When implementing the Cyano group to thiocarbamoyl group works in the presence of tertiary amines (lower trialkylamines, Pyridine), preferably in an alcoholic solution (e.g. methanol).

_in Depending on the process conditions and starting materials to give the end products of the formula I in free form or in the form of their salts. The salts of the end products can be converted back to the 1 c bases in known manner, for example with alkali or ion exchangers. Salts can be obtained from the latter by reaction with organic or inorganic acids, in particular those which are suitable for the formation of therapeutically useful salts. As such acids are

«Η mentioned for example: hydrohalic acids, Sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids the aliphatic, alicyclic, aromatic or heterocyclic series and sulfonic acids. Examples for this are: Ant, vinegar, propion, amber, glycol, milk, apple, wine, lemon, ascorbic, Maleic, fumaric, hydroxymaleic or pyruvic acid; Phenylacetic, benzoic, p-aminosalicylic acid, emboxylic acid, Methanesulphone, ethanesulphone, hydroxyethanesulphone, Ethylene sulfonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid or 8-chloro-theophylline.

In the above-mentioned processes for the preparation of the compounds according to the invention, in the Starting substances present amino groups that are not

- 21 -

are involved in the reaction, contain known and customary protecting groups. It is here in particular to residues which can easily be split off by hydrolysis or hydrogenolysis and possibly already are split off during the reaction. If such protective groups are not split off during the process reaction are then split off after the reaction. Often the starting compounds contain due to their production already such protective

^ 0 groups.

These protective groups are, for example, acyl groups which can be easily split off by solvolysis or groups which can be split off by hydrogenation. The solvolytic

■ 5 removable protective groups are removed, for example, by saponification with dilute acids or by means of basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, aqueous NH ₃ ) at temperatures between 10 and 150 ° C, in particular

the other 20 - 100 ° C split off. Groups which can be split off by hydrogenation, such as C (-arylalkyl radicals (benzyl radical) or Aralkoxycarbonyl radicals (carbobenzoxy radical) are expediently obtained by catalytic hydrogenation in the presence common hydrogenation catalysts, in particular

^ZJ Palladium catalysts, platinum oxide or Raney nickel, split off in a solvent or suspension medium, optionally under elevated pressure at temperatures between 20-100 ° C., in particular 40-80 ° C. As a solution or suspension

mediums come into consideration, for example: water, lower aliphatic alcohols, cyclic ethers such as Dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide and so on, as well as mixtures

this means.
35

- 22 -

As protective groups that can be split off by hydrogenolysis, for example: benzyl radical, CÄ-phenylethyl radical, benzyl radicals substituted in the benzene nucleus (p-bromine or p-nitrobenzyl radical), carbobenzoxy radical, carbobenzthio radical. Examples of hydrolytic Removable radicals are: trifluoroacetyl radical, phthalyl radical, trityl radical, p-toluenesulfonyl radical and the like as well as lower alkanoyl radicals such as acetyl radical, formyl radical, tert-butyloxicarbonyl radical and the like.

In particular, there are the protective groups customary in peptide synthesis and the cleavage processes customary there in question. Among other things, this also refers to the book by Jesse P. Greenstein and Milton Winitz "Chemistry of Amino Acids", N.Y. 1961, John Wiley

and Sons./ Inc. Volume 2, for example page 883 ff. The alkoxycarbonyl group (for example low molecular weight) is possible.

2Q If there are also alcoholic substances in the raw materials Hydroxy groups and / or primary amino groups can also be present by those mentioned above Protective groups be protected, the cleavage taking place in the same way.

Those compounds of the formula I which contain asymmetric carbon atoms and generally occur as racemates, in a manner known per se, for example with the help of an optically active Acid split into the optically active isomers. But it is also possible to do a to use optically active starting substance, in which case a corresponding optically active substance is then used as the end product or diastereomeric form is obtained.

- 23 -

- 23 -

The present invention thus also includes the D- and L-form as well as the DL mixture for the case that an asymmetric carbon atom occurs in the compound of formula I and in the case of two or more asymmetric carbon atoms as well as the corresponding diastereomeric forms.

The radical R ₂ in the formula I is in particular in the 3-position of the phenyl ring and preferably denotes the group —SO ₀ NHR, -, where R _n . Hydrogen, methyl, δ ο ο

Ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl is.

Those compounds of the formula I in which R ^ is hydrogen, R. is hydrogen, chlorine or the amino group and R ₂ is in the 3-position of the phenyl radical and the group -SO ₂ NHR ₅ , where R _{5 is} the above, have particularly favorable properties has the meanings mentioned.

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Pharmacological or pharmaceutical information

The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active ingredient one or more of the compounds according to the invention, optionally mixed with other pharmacologically or pharmaceutically active substances. The pharmaceuticals are produced in a known manner, it being possible to use the known and customary pharmaceutical auxiliaries and other customary carriers and diluents.
Suitable carriers and auxiliaries of this type are, for example, those substances which are recommended or indicated in the following literature references as auxiliaries for pharmacy, cosmetics and related areas: Ullmanns Encyklopadie der technischen Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 and ff., HvCzetsch-Lindenwald, auxiliaries for pharmacy and adjacent areas? Pharm. Ind., No. 2, 1961, page 72 and ff .; Dr. HP Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas Cantor KG. Aulendorf in Württemberg 1971.

Examples are gelatine, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (e.g. corn starch), alginic acid, tylose, talc, Lycopodium, silicic acid (e.g. colloidal), cellulose, cellulose derivatives (e.g. cellulose ether, in which the cellulose hydroxyl groups partially with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols are etherified, for example methyloxypropyl cellulose),

- 25 -

Stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated (for Example stearates), emulsifiers, oils and fats, especially vegetable (for example peanut oil, castor oil,

Olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, 5

Sunflower seed oil, cod liver oil, mono-, di- and triglycerides of saturated fatty acids ^C <] 2 ^H 24 ° 2 ^to C ₁₈ H ₃₆ O ₂ and their mixtures), pharmaceutically acceptable mono- or polyhydric alcohols and polyglycols such as polyethylene glycols and derivatives thereof , Esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerol, di-

, _ ethylene glycol, pentaerythritol, sorbitol, mannitol and so on Io

further, which may also be ethereal,

Benzyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol _{ethers with C 1} -C ₁₂ -AlkOhOlBn, dimethylacetamide, lactamides, lactates, ethy! Carbonates, "-. Silicones (especially medium viscosity dimethyl polysiloxanes) magnesium carbonate and the like.

For example, water or physiologically compatible organic solvents are used to produce solutions «Σ in question, such as ethanol, Ί, 2-propylene glycol, Polyglycols and their derivatives, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esters of glycerine, Paraffins and the like.

3Q In the manufacture of the preparations, known and customary solubilizers or emulsifiers can be used. As a solubilizer and Emulsifiers can be used, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, Lecithin, acacia, tragacanth, polyoxyethylation

- 26 -

] tes sorbitan monooleate, polyoxyethylated fats, polyoxyethylated olotriglycerides, linolized olotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylenes or fatty acids. Polyoxyethylated here means that the substances in question contain polyoxyethylene chains whose degree of polymerization is generally between 2 and 40 and in particular between 10 and 20. Such polyoxyethylated substances can, for example

] 0 by reaction of compounds containing hydroxyl groups (For example mono- or diglycerides or unsaturated compounds such as those containing oleic acid residues contain) with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of olotriglycerides are olive oil, peanut oil, Castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Fiedler "Lexicon of excipients for pharmacy, Cosmetics and adjacent areas 1971, pages 191 to 195)

In addition, the addition of preservatives is Stabilizers, buffer substances, for example calcium hydrogen phosphate, colloidal aluminum hydroxide, flavoring agents, antioxidants and complexing agents (for example ethylenediaminetetraacetic acid) and the like are possible. Possibly for stabilization of the active ingredient molecule with physiologically compatible acids or buffers to a pK range of approx. 3 to 7 to adjust. In general, a pH value that is as neutral as possible to weakly acidic (up to pH 5) is preferred.

■.

As antioxidants, for example, sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl esters, Butylhydroxyanisole, nordihydroguajaretic acid, tocopherols and tocopherols + synergists (substances bind the heavy metals by complexing, both

- 27 -

-Vl-

for example lecithin, ascorbic acid, phosphoric acid) are used. The addition of the synergists increases the antioxygene Significant effect of tocopherols. Sorbic acid, for example, can be used as a preservative, p-hydroxybenzoic acid ester (for example lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, Phenol, cresol, benzethonium chloride and formalin derivatives are possible.

The pharmaceutical and galenic handling of the invention Connections are made according to the usual standard methods. For example, active ingredient (s) and Auxiliary or carrier materials by stirring or homogenizing (for example using conventional mixing devices) well mixed, in general at temperatures between 20 and 80 ° C, preferably 20 to 50 ° C in particular is worked at room temperature. Otherwise, reference is made to the following standard work: Sucker, Fuchs, Speiser, Pharmaceutical Technology, Thieme-Verlag Stuttgart, 1978.

The application of the active ingredients or the drugs can be on the skin or mucous membrane or in inside the body, for example, oral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intfaarterial, intracardiac, intramuscular, intraperitoneal, intracutaneous, subcutaneous. ■

In particular, the addition of other active pharmaceutical ingredients is also possible or inexpensive.

- 28 -

- 28 -

The compounds according to the invention show, for example a good anti-gastric and anti-ulcer effect. The anti-ulcer effect can, for example on artificially caused rat ulcer. The rat ulcer was, for example, by application caused by a combination of cold stress and the anti-inflammatory drug indomethacin. The experimental method was carried out based on Levine, R.J., Peptic Ulcer by CJ. Pfeiffer Munksgaard, Copenhagen, pp. 92-97 (1971) and Jahn, Adrian, Drug Research (Drug Research) Volume 19 (1969) page 36, with the following changes being made: After application of the The animals were placed in immobilization cages for 3 hours with indomethacins kept in the refrigerator at 4-5 ° C. Except-'** the test substances were administered orally one hour before the indometacing administration.

The gastric acid secretion inhibiting effect can be determined, for example, using the following test models:
a) Model of the gastric urn-perfused rat with pentagastrin stinulation according to MN Ghosh and HO Schild, Brit. J. Pharmacol. J3_ (1958) pages 54-61 and Rosenoer and Schild, The assay of urogastrone J. Physiol. 162 (1962), page 155. The method was modified in that, before the stimulation began, the rat's stomach was not cut open to remove food residues, but only flushed with warm saline solution («vO, 9%).

b) Model of the awake chronic fistula cat with histamine stimulation (Based on Makowitz, Experimental Surgery, 3rd edition, 1954, page 200 ff. Publisher: Williams and Wilkins Company; International Encyclopedia of Pharmacology and Therapeutics, Section 39A, Pharmacology of gastrointestinal motility and secretion, Volume I, pp. 125, 126, 165 (1973)).

c) Model of the awake fistula rat with pentagastrin stimulation (based on A. Lane, A.C. Ivy, Ξ.Κ. Ivy, Am.J.Physiol.

192 (1957) pages 221-228), with pentagastrin instead of histamine being stirrulated (60 micrograms. Pentagastrin pro kg rat per hour, intraperitoneal infusion).

- 29 -

- 29 -

For example, on the model of the gastric lumen perfused Rat with pentacastrine stimulation at a dose of 0.09 mg / kg body weight intravenously in the rat one 50% inhibition of gastric acid secretion found. The gastric acid secretion inhibiting, antiulcerative effect is comparable to the effect of the well-known drug "Ranitidine".

The lowest effective dose in the animal experiments mentioned above is, for example:

5 mg / kg orally (in the model of the rat ulcer artificially caused by cold stress and indomethacin);

0.05. mg / kg intravenously (in the gastric lumen-perfused rat model with pentagastrin stimulation).

As a general dose range for the gastric acid secretion inhibitor, antiulcerative effects are possible, for example:

5-100 mg / kg orally, especially 10-50 mg / kg (in the model of artificially caused by cold stress and Indomethacin-induced rat ulcer);

0.05-20 mg / kg intravenously, especially 1-5 mg / kg (in the model of the gastric lumen-perfused rat with

Pentagastrin stimulation).
30th

Indications for the compounds according to the invention can be considered:

acute or chronic gastritis, ulcer ventriculi et duodeni, nervous irritable stomach, hyperacidity of gastric juice.

- 30 -

- 7ft -

] The pharmaceutical preparations generally contain between 1 to 2000 mg, preferably 2 to 200 mg, of the active component (s) according to the invention.

Administration can take the form of tablets, capsules, pills, coated tablets, suppositories, ointments, jellies, Creams, powders, dusting powders, aerosols or in liquid form. As liquid forms of application come to Example in question: oily or alcoholic relational] 0 wise aqueous solutions as well as suspensions and emulsions. Preferred forms of use are tablets that are between

5 and 100 mg or solutions containing between 0.1 to 20% of active substance.

The single dose of the active components according to the invention can be for example

a) for oral dosage forms between 2 - 2000 ng, preferably 10 - 200 mg,

b) for parenteral dosage forms (e.g. intravenous, intramuscular) between 2 - 200 mg, preferably 5-50 mg,

c) for drug forms for rectal administration between 2-2000 mg, preferably ■ 10-200 mg.

- (The doses are based on the free base) -

- 31 -

For example, 1 to 3 tablets containing 2 to 400 mg of active substance can be used 3 times a day or, for example, in the case of intravenous injection 1 to 3 times a day, an ampoule of 1 to 2 ml content with 1 to 200 mg of substance are recommended. In the case of oral administration, the minimum daily dose is for example 10 mg; the maximum daily dose for oral administration should not exceed 2000 mg.

The acute toxicity of the compounds according to the invention in the mouse (expressed by the LD 50 mg / kg; method according to Miller and Tainter: Proc. Soc. Exper. Biol. A. Med. 57 (1944) 261) is above, for example, when administered orally 100 mg / kg. For some compounds, the LD 50 is above 500 mg or even above 1500 mg / kg.

The drugs can be used in human medicine alone or in a mixture with other pharmacologically active substances be used.

- 32 -25

BeisDiel 1

N- (3-sulfamoyl-phenylsulfonyl) -N'-methyl-N "- / j5-dimethylaminomethyl-2-furanyl) -methylthio / ethyl / guanidine

/ ΓΛ

(CH) ^N " ^CH - \

7.4 g of N- (3-sulfamoyl-phenylsulfonyl) -N '- (2- / T5-dimethylaminomethyl-2-f uranyl] _7-ynethylthio7-ethyl7-S-methyl-isotijiourea are stirred with 25 ml of methylamine and 50 ml of methanol for 30 minutes at room temperature. Methyl mercaptan develops in the process. The solution is evaporated in vacuo and the residue through Purified column chromatography. The substance is amorphous.

The Rp value (retention factor) is in the solvent Chloroform / methanol / 25% ammonia (80: 25: 5, Volume per volume): 0.54 (outside temperature: 25 ° C). Yield: 4 g.

- 33 -

SS
31Q8753 - ^M "

Example 2

N- / 3-N- (Ν, Ν-Diethylaminoethyl) sulfamoyl-phenylsulfonyl / -N'-methyl-N "- {2- / T5-dimethylaminomethyl-2- furanyl) -methyIthio7-e thy I ^ -guanidine

Xl Ώ.

Ch ₉ SCH ₉ CH ₉ NCNCH,
.2 2 2, j 3

10

^S0 <T ^S0 2 ^NCH 2 ° ^H ₂ < _i "

15th

In analogy to Example 1, 4.29 g of N - / _ 3-N- (N, N-diethylaminoethyl) -sulfamoyl-phenylsulfonyl7 ~ N'- · (J2- / T5-dimethylaminomethyl-2-furanyl) -methylthioT "-ethylf-S-methyl-isothiourea with methylamine

20th

brought to reaction. You get a syrupy one

Link.

Rp (retention factor): 0.27

Mobile phase: chloroform / methanol / 25% ammonia (80: 9: 1,

25th

Volume per volume) (outside temperature 25 ° C)

Yield: 2.84 g.

30th

- 34 35

example

N- (3-N-methylsulfamoyl-phenylsulfonyl) -N'-methyl-N " - [2- / T5-dimethylaminomethyl-2-furanyl) -methylthi £ 7-ethyl? -Guanidine

Il ^J N

In analogy to Example 1, 8.75 g of N- (3-N-methylsulf arnoyl-phenylsulfonyl) -N - ^ - / ^ (S-aminomethyl-2-furanyl) -methylthi £ 7 ~ ethylT-S-methyl-

isothiourea reacted with methylamine.

A crystalline compound is obtained.

114-116 ° C; Yield: 5.79 g.

- 35 35

Example 4

N- (2-chloro-4-amino-5-sulfamoyl-phenylsulfonyl) -N ' methyl-N "- {2- / 75-dimethylaminomethyl-2-furanyl) -. methylthioZ-ethylj-guanidine

H H CH "SCHoCHoNCNCH.

J

SOo. SO ₂ NH ₂

In analogy to Example 1, 9 g of N- (2 ~ chloro-4-amino-5-sulfamoyl-phenylsulfonyl) -N '- / 2- / T5-dimethyl- aminomethyl-2-furanyl) -methylthio7-et.hyl'l-S-methyl-

~

isothiourea reacted with methylamine.

An amorphous compound is obtained.

R ^ (retention factor): 0.59

Mobile phase: chloroform / methanol / 25% ammonia (80: 25: 5,

Volume per volume) (outside temperature 25 ° C)

Yield: 6g.
30th

- 36 35

Example 5

N- (3-Carbethoxyphenylsulfonyl) -N'-methyl-N "- • ^ 2- / T5-dimethylaminomethyl-2-furanyl) -methylthio / -e thylV-guanidine

COOC ₂ H ₅

12 g of N- (3-Carbethoxyphenylsulfonyl) -N ^t - {2 -_ / (5-dimethylaminomethyl-2-furanyl) -methylth ^ Z-ethyll-S-

methyl isothiourea are dissolved in 100 ml of ethanol

dissolved and mixed with 20 ml of methylamine with stirring at room temperature. The mixture is stirred for 3 hours at room temperature, concentrated in vacuo and purified by column chromatography. The amorphous compound is at

50 ° C dried in a high vacuum.
25th

R ^ (retention factor): 0.27

Mobile phase: chloroform / methanol / 2 5% ammonia (95: 4: 1,

Volume per volume) (outside temperature: 25 ⁰ C)

Yield: 5 g

- 37 -

Example 6

N- (3-Cyano-phenylsulfonyl-N'-methyl-N "- {2- / T5-dimethyl-

aminomethy1-2-furanyl) -methylthioZ-ethyl] · -guanidine 5

³ ^ "- CH ₂ - ^ ₀ > - CH ₂ -S-CH ₂ CH ₂ -Nh-C-NHCH ₃

17 g of N- (3-cyano-phenylsulfonyl) -N '- ^ 2- / T5-dimethylaminomethyl-2-furanyl) -methylthio7 "-ethyll-S-methylisothiourea are dissolved in 250 ml of methanol

and add 100 ml of methylamine while stirring at 30 ° C

puts. The mixture is stirred for 3 hours at 35 ° C / then concentrated in Vacuum and purify by column chromatography. The crystalline compound is made from ethyl acetate / gasoline recrystallized.

110-112 ° C.

Yield: 11 g.

- 38 35

Example 7

N- (3-Carbamoyl-phenylsulfonyl) -N'-methyl-N " - {2- / J5- dimethylaminomethyl-2-furanyl) -methylthioj-ethyl] ^ guanidine

10 ^H 3 ^C

CONH ₂

15th

7 g of N- (3-carbamoyl-phenylsulfonyl) -N ^I - {2 -_ / (5-dimethylaminomethyl-2-furanyl) -methylthioZ-ethylj-S-methyl-isothioura'ff are dissolved in 50 ml of methanol and

20 ml of methylamine are added while stirring at room temperature. The mixture is stirred for 3 hours at room temperature, concentrated then in vacuo and the desired compound is purified by column chromatography. The connection

is amorphous. ' 25th

R ^ (retention factor): 0.59

Mobile phase: chloroform / methanol / 25% ammonia (80: 25: 5, volume per volume) (outside temperature: 25 ⁰ C)

Yield: 5g.

- 39 -

Example 8

N- (2-Mercapto-4-amino-5-sulfamoyl-phenylsulfonyl) -N ¹ -methyl-N ^II - {2- / T5-dimethylaminomethyl-2-furanyl) -methyl- 'thio7-ethyl] -guanidine

/ * Γ \ ^{H H}

(CH,) ₂ NCHp ^ _n > = - CH ₉ SCH ₉ CH _o NCNCH, j Λ <i υ d. * i Il ^

N

! XjC

HS ^ \ i ^ -NH ₂ 15

6.15 g of N- (2-mercapto-4-amino-5-sulfamoyl-phenylsulfonyl) N ¹ - / 2- / T5-dimethylaminomethyl-2-furanyl) -methylthio7-ethyl | -S-methyl-isothiourea are in 50 ml of methanol and 20 nl of methylamine for 5 hours at room temperature. The solution is concentrated in vacuo and the residue is purified by column chromatography. A crystalline substance is obtained which is boiled twice with 100 ml of methanol each time.

F. 176 - 181 ° C (decomposition)
Yield: 3.68 g.

- 40 -35

- 4-υ -

Example 9

N -. (3-Carbamoyl-5-sulfamoyl-phenylsulfonyl) -N ¹ -methyl-N "- {2 - / _ 75-dimethylaminomethyl-2-furanyl) -methylthio / - * ethyl] -guanidine

Ni CH ^ q ^ CH ₂ -S-CH ₂ Ch ₂ -NH-C-NH-CH ₃ H ₃ / N _ / CONH _£

SO ₂

SO ₂ NH ₂

A solution of N- (3-carbamoyl-5-suifamoyl-phenylsulf onyl) -N · - {2- / T5-dimethylaminomethyl-2-furanyl) -methylthioZ-ethylj-S-methyl-isothiourea, by stirring 3.47 g of 2 - ^ / 5- (Diinethylamino) methyl-2-furanyl7-ynethylthioj-e-thylamine for three hours and 6.21 g of 3-carbamoyl-5-sulfamoylphenyl-sulfonyliminodithio carbonic acid dimet jayl ester is obtained in 75 inl methanol and 5 ml dimethylformamide at 50 - 60 ° C, it is cooled to room temperature and mixed with 35 ml of methylamine. It will be overnight at room temperature stirred, then concentrated in vacuo and purified on a silica gel column. Narrow down and more- ■ repeated evaporation with ethanol in vacuo .liefert an amorphous, thin-layer chromatographically uniform Residue.

R-, (retention factor): 0.29

Mobile phase: chloroform / ethanol / 25% ammonia (85: 14: 1,

Volume per volume) (outside temperature 25 ° C) Yield: 5.2 g.

- 41 -

Example 10

N- (3-N-Ethylsulfamoyl-pheny! Sulfonyl) -N'-methyl-N "■ i 2- / T5-dimethylaminomethyl-2-furanyl) -methylthio / - ")

^ ethylj-guanidine

ίΓ \ ^{H H}

I PH 1 rJ \\ xA _Ä """" ^. ^^^ ™ ~ ι ι * H f> ^ W * JTVf ^ vlift J ^ W JlwHiy

IV / AI if J (ΛΛΛ vaIQ ^ Λ ~ r ^^ * ^% Ύ ^m ^ ^^ "^". ^^> f. ^

N

I H

A solution of N- (3-N-Ethylsulfamoyl-phenylsulfonyl) N ¹ - ^ - / TS-dimethylaminoinethyl ^ -furanyl) -methylthio / -ethyl * lS-methyl-isothiourea, which by four-

r -

stirring of 2.14 g of 2-jf / _5- (dimethylamine) methyl ^ -furanylZ-methylthioj-ethylamine for hours and 3.69 g of 3-N-ethylsulfamoyl-phenyl-sulfonylimino-dithiocarbonic acid dimethyl ester is obtained in 40 ml of methanol at room temperature, it is treated with 15 ml of methylamine. It will then take another hour Stirred 25 ° C, the solution evaporated in vacuo and the residue purified by column chromatography. The recrystallization takes place from ethanol.

Mp 126 ° C
Yield: 3.76 g.

- 42 -

Example 11

N- (3-Carboxy-pheny! Sulfonyl) -N'-methyl-N "- {2- / j5-dimethylaitiinomethyl-2-furanyl) -nethylthio7- «thyljguanidine

COOH 15

A solution of 2 g of N- (3-carbethoxyphenylsulfonyl-N ¹ -methyl-N "- / 2 - / ^ (5-dimethylaminomethyl-2-furanyl) -methylthio7-ethyl? -Guanidine in 30 ml of ethanol is mixed with one

~

A solution of 0.2 g of sodium hydroxide in 1 ml of water is added and the mixture is stirred at room temperature for 5 hours. Then the solution is neutralized with 2 η acetic acid, concentrated in vacuo and the remaining solution is purified

Residue by column chromatography. The connection 25

dung is amorphous in nature.

Kp, (retention factor): 0.21

Mobile phase: chloroform / methanol / 25% ammonia (80: 25: 5, Volume per volume) (outside temperature: 25 ° C)

Yield: 1.7 g

35 -

- 43 -

Example 12

N- (3-thiocarba; noyl-phenylsulfonyl) -N'-methyl-N "- (2-'j5-dime
guanidine

/ _ (5-dimethylaminomethyl-2-furanyl) -methylthioZ-ethylj-

10 ^H 3 ^C

In a suspension of 5.5 g of N- (3-cyano-phenylsulfonyl) · N ¹ -methyl-N "- | 2 - / _ (5-dimethylaminomethyl-2-furanyl) -methylthio / -ethyl] -guanidine in 70 ml of methanol are used

20 ~

Room temperature 20 ml of triethylarran added and at

20 - 28 ° C hydrogen sulfide introduced. After 5 hours, the solution is concentrated in vacuo and the
oily residue by column chromatography. It will

obtained a colorless oil.
25th

Rp, (retention factor): 0.32

Mobile phase: chloroform / methanol / 25% ammonia (85: 14: 1, volume per volume) (outside temperature 25 ⁰ C)

30 Yield: 5g.

- 44 -

Example 13

N- (3rN, N-dimethylsulfamoyl-phenylsulfonyl) -N'-ynethyl-N " - £ 2- / T5-dimethylaminomethyl-2-furanyl) -methylthio7-e thy Ij -guanidine

in

CH ₂ SCH ₂ CH ₂ -NH-C-NHCh ₃

A solution of N- (3-N, N-dimethylsulfamoyl-phenylsulfonyl) -N ¹ - [2- / T5-dimethylaminomethyl-2-furanyl) -methylthio7-ethyli-S-methyl-isothiourea , which by stirring for five hours of 1, 93 g of 2- i / 5- (dimethylaminomethyl-2-methylthio furanyl7 \ ethylamine and N-dimethylsulfamoylphenyl-sulfonylimino-dithiokohlensäuredimethylester is obtained in 50 ml of methanol at room temperature, 3.66 g of 3-N, is treated with 30 ml of methylamine The mixture is stirred for a further hour at 25 ° C., the solution is concentrated in vacuo and the residue is purified by column chromatography.

The recrystallization takes place from ethanol / gasoline. 177 ° C
Yield: 4.1 g

30 35

- 45 -

Example 14

N- (2-methyl-5-sulfamoyl-phenylsulfonyl) -N'-methyl-N "- £ 2- ^ TS-dimethylaminomethyl ^ -furanyl) -methylthio7-ethy Ij -guanidine

10

₉ ^ Ch ₇ SCH ₉ CH ₉ NH-C-NHCH, ³

15th

A solution of N- (2-methyl-5-sulfamoyl-phenylsulfonyl) -N ¹ - {2- / T5-dimethylaminomethyl-2-furanyl) -methylthio / - ethylj-S-methyl-isothiourea , which is obtained by stirring for 4 hours from 2 , 46 g of 2 - i / ^ - Diinethylaminomethyl-2-furanyl7-methylthioj-ethylamine and 4.28 g of 2-methyl-5-sulfamoylphenyl-sulfonylimino-dithiocarbonic acid dimethyl ester is obtained in 50 ml of methanol at room temperature, it is mixed with 25 ml of methylamine . After stirring for one hour at room temperature, the solution is concentrated in vacuo and the residue is purified by column chromatography. The compound is amorphous in nature.

R ^: 0.31 mobile phase: chloroform / methanol / 25% Ammonia (85: 15: 1), outside temp ;: 24 ° C

Yield: 3.9 g

35

- 46 -

Example 15

N- (3-Sulfamoyl-phenylsulfonyl) -N · -methyl-N "- £ 2- / 5-methyl-4-imidazolyl) -methylthi £ 7-ethyl-guanidine 5

.H ₀ SCH-CH ₀ -NH-C-NHCh
2 2 2 _{| {}

SO NH

A solution of 9 g of K- (3-sulfamoyl-phenylsulfonyl) -N · - ^ - / JS-methyl - ^ - iiaidazolyl) -methylthioZ-ethylj-S-methyl-isothiourea and 25 ml of methylamine in 50 ml of methanol is stirred for 45 minutes at room temperature, then concentrated in vacuo and the residue that remains is purified by column chromatography. The connection is amorphous in nature.

R ^ ₁ : (retention factor) ι 0.46. Eluent: chloroform / methanol / 25% ammonia (70: 30: 0.5)

(Volume per volume) (outside temp .: 24 ° C) Yield: 5.5 g

- 47 -

-HS

Example 16

N- (3-N-Methylsulfamoyl-phenylsulfonyl) -N'-methyl-N "- {2 - / _ (5-methyl-4-imidazolyl) -methylthio7-ethyl} • -guanidine

CH ₉ SCH ₉ CH ₀ NH-C-NHCh, 2 2 2 _H 3

CH,

N-SQ

SO ₂ NHCH ₃

A solution of N- (3-N-methylsulfamoyl-phenylsulfonyl) -N'- ^ 2- / j5-methy 1-4-imidazoIyI) -methylthioZ-ethylj-S-methyl-isothiourea, by stirring 4.17 g of 2- / T5-methyl-4-imidazolyl) -methylthioZ-ethylamine for 4 hours and 7.1 g of 3-N-methylsulfamoyl-phenylsulfonyl-iminodithiocarbonic acid dimethyl ester is obtained in 60 ml of methanol at 50 ° C., it is cooled to room temperature and mixed with 20 ml of methylamine. It will be 18 hours stirred at room temperature, the solution then concentrated in vacuo and the residue that remains by column chromatography cleaned. The compound is amorphous in nature.

(retention factor): 0.51

Mobile phase: chloroform / Methanol / 25% ammonia (80: 25: 5)

(Volume per volume) (outside temp .: 25 ° C)

Yield: 8.8 g

- 48 -

- * s -so

Example 17

N- iS- N / N-Dimethylsulfamoyl-phenylsulfonyl I-N'-methyl-N "- {2- / J5-methyl-4-imidazolyl) -methylthio7-ethylj-guanidine

CH ₉ SCH ₉ CH ^ -NH-C-NHCh,

CH ₃ N - SO ₂ - /

CH

A solution of N- (3-N, N-dimethylsulfamoyl-phenylsulfonyl) -N '- £ 2- / T5-methyl-4-imidazolyl) -methylthioZ-ethyl ^ -S-methyl-isothiourea, by stirring 1.7 g of 2- / T5-methyl-4-imidazolyl) -methylthio7-ethylamine for 15 hours and 3.67 g of 3-N, .N-dimethylsulfamoyl-phenylsulfonylimino-dithiocarbonic acid dimethyl ester is obtained in 60 ml of methanol at room temperature, 30 ml of methylamine are added. It is stirred for one hour at room temperature, the solution is concentrated in vacuo and the residue that remains is purified by column chromatography. The connection is amorphous in nature.

(retention factor)

0.32. Mobile phase: chloroform / methanol / 25% ammonia (90: 10: 1)

(Volume per volume) (outside temp .: 25 ° C)

Yield: 3.6g

- 49 -

- 49 - rf- ν

Examples of pharmaceutical preparations Example of "abletten

5 kg of the compound according to Example 13 are mixed with 3.6 kg of lactose and the mixture with a solution granulated from 0.2 kg of gelatin in 1.8 kg of water in a known manner.

After adding 0.9 kg of corn starch and 0.3 kg of magnesium stearate, tablets weighing 200 mg, a diameter of 8 mm and a radius of curvature of 11 mm. The breaking strength of the tablets is 65 to 80 Newtons (Heberlein hardness tester). Each tablet contains 100 mg of active ingredient.

Example of ampoules
20th

325 g of the compound according to Example 13 are mixed with 55.8 g of sodium chloride in 9 liters of water for injections dissolved, the solution made up to 10 liters with water for injections and filtered. 25th

After the solution has been filled into ampoules of 2 ml, it is sterilized in the usual way at 120 ° C 20 minutes. One ampoule contains 65 mg of active substance

in 2 ml.
30th

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Claims (7)

03/03/1981 Degussa Aktiengesellschaft Weißfrauenstrasse 9 - 6000 Frankfurt / Main New substituted alkyl-phenylsulfonylguanidines with a heterocyclic radical Claims Compounds of the formula X - CH ₂ - S - (CH ₂ ) 2- wherein X is a furan, thiophene or pyrrole radical, which in each case can also be substituted by a di-C.-C.-Alkylajnino-C.-C.-alkyl group or wherein X is also an imidazolyl (4) radical or is a 5-methylimidazolyl- (4) radical, R. is hydrogen or a C.-C ₄ -alkyl group, R- is a halogen atom, a nitro group, an amino group, a sulfo group (-SO ₃ H), a cyano group, a Carboxy group, a C ₁ -C ₄ -AIkCKyCaTbOnYIgTUpPe, a formyl group, the group -CSNH ₂ , the group -CONR ₅ R _6. Or the group -SO ₂ -NR ₅ R ₆ , R _{3 is} hydrogen, a Cj-C ^ Alkyl group, a Cj-C ^ alkoxy group, a mercapto group, an amino group, a cyano group, a carboxy group, a ^ -Cv -alkoxycsrbcnylgruppe, a halogen atom, the group -CSNH ₂ , the group -CONR ₅ R ₆ or the group 3106753 ü \ Ό -.'.- 'Ο .:. -SO ₀ NRc-Rc, where R_ and R _{fi are} identical or different and are hydrogen or Cj-C ^ -alkyl groups and one of the radicals R ₅ or Rg is also a di-C.-C.-alkylamino-C. -C ^ -alkyl group, a C ^ -Cg-cycloalkyl group, a Cj-Cg-alkoxy group or a phenyl radical, wherein the phenyl radical can also be substituted by halogen atoms, nitro groups, Cj-C.-alkyl groups or Cj-C ^ -alkoxy groups and R. is hydrogen, a halogen atom or an amino group and their salts. 2. Process for the preparation of compounds of formula
15th " ² '---» 4 N ⁴ ■ ^{Ρ ΖΌ} X - CH ₂ - S - (CH ₂ ) j -NH-C- wherein X is a furan, thiophene or pyrrole radical, which in each case can also be _{substituted by a di-C 1} -C.-alkylamino-C.-C.-alkyl group or wherein X is also an imidazolyl (4) radical or is a 5-methylimidazolyl- (4) radical, R _{1 is} hydrogen or a C.-C ₄ -alkyl group, R_ is a halogen atom, a nitro group, an amino group, a sulfo group (-SO ₃ H) -, a cyano group, a Carboxy group, a C ^ C ^ AlJcoxycarbonylgruppe, a formyl group, the group -CSNH ₂ »the group -CONR ₅ Rg or the group -SO ₂ NR ₅ Rg, R, hydrogen, a C.-C.-alkyl group, a C ₁ -C ₄ - ^OJ alkoxy group, a mercapto group , an amino group, 3106753 ^; J ■ ' ^{] [} :. ^: ■ '".. ·.:. ■ ι a cyano group, a carboxy group, a C ..- C AlkOKycarbon / l group, a halogen atom, the group -CSNH-, the group -CONR ₅ Rg or the group -SO ₂ NR ₅ Rg, where R ₅ and R _ß identical or - are different and are hydrogen or C.-C ^ -alkyl groups and one of the radicals R ₅ or R _{g is} also a di-C.-C.-alkylamino-C ..- C ₄ -alkyl group or a C. ^ -Cg-cycloalkyl group, a C.-Cg-alkoxy group or a phenyl radical can be Ι «, wherein the phenyl radical can also be substituted by halogen atoms, nitro groups, C.-C.-alkyl groups or C.-C.-alkoxy groups and R. is hydrogen, a halogen atom or an amino group and their salts, characterized in that a) a compound of the formula T-C-S alkyl II 20 wherein R ₂ f R3 and R. have the meanings already given and alkyl is a saturated C.-Cg-alkyl radical, with a compound of formula H-V III converts, whereby in the formulas II and III T and V are each different either the group X-CH ₂ -S- (CH ₂ ) ₂ ~ ^NH "* ^{or the} group -NHR ₁ , where X and R _{1 have} the meanings already given or 4th
b) a compound of the formula , R, Λ I W 3 N - SO- ^ " Z - (CH ₂ ) ₂ -NH-C- NHR ₁ '* ^R 4 IV with a compound of the formula X - CH ₂ - UV reacted, where in the formulas IV and VR ₁ , R ₂ , R ₃ , R ₄ and X have the meanings given and Z and U are each different and either a mercapto group or a hydroxyl group, which is also by a strong organic or inorganic acid can be esterified, mean or c) a compound of the formula I in which one or both of the radicals R ₀ and R-, a C ₁ -C - Δ j I 4 Alkoxycarbonyl groups, these hydrolyzed to the carboxy group or _{reacting with an amine HNR 5} Rg, or a compound of the formula I in which one or both of the radicals R ₀ and R- are cyano groups, these Reacts with hydrogen sulfide to the thiocarbamoyl group and optionally the compounds obtained according to processes a) -c) are alkylated. 3. The method according to one or more of the preceding claims, characterized in that the compounds obtained are converted into the salts. ■ γ 4. Process according to one or more of the preceding Claims, characterized / that the starting compounds contain protective groups and this, if necessary, after the reaction c be split off. 5. Medicament, characterized in that it is a compound according to one or the active ingredient several of the above claims together with IQ a common pharmacological carrier and / or contains a diluent. 6. A method for producing a medicament, characterized in that a compound according to one or more of the preceding claims with common pharmaceutical Carriers or diluents processed into pharmaceutical preparations will. 7. Use of compounds according to one of or several of the above claims for the manufacture of pharmaceuticals. - 6 35