WO1991013868A1 - Phenylthioalkylcarboxylic acid derivatives, method for preparing them and drugs containing these compounds - Google Patents

Abstract

The invention relates to compounds of formula (I), where R?1 stands for aryl or an aralkyl group or an aralkenyl group the aryl residue of which may be substituted by one or more times by halogen, cyan, alkyl, trifluormethyl, alkoxy, alkylthio, trifluormethoxy, hydroxy or carboxy, n is a whole number from 1 to 3, m is a whole number from 0 to 2, p is a whole number from 1 to 6, R?2 stands for hydrogen, an alkyl, aralkyl or acyl group, R?3 stands for hydrogen, halogen, trifluormethyl, alkyl, aralkyl or alkoxy, R?4 stands for hydroxy, alkoxy or a possibly substituted amino group. The invention also relates to a process for preparing these compounds and thromboxane-antagonistic drugs containing them.

Description

Phenylthioalkylcarboxylic acid derivatives, processes for their preparation and medicaments containing these compounds

The present invention relates to new sulfonamides of the general formula I.

in which

R ^{1 represents} aryl, aralkyl or an aralkenyl group, the aryl radical of which can optionally be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, trifluoromethoxy, hydroxy or carboxy, n is an integer from 1 to 3, m is an integer from 0 to 2,

p is an integer from 1 to 6,

R ^{2 can be} hydrogen, an alkyl, aralkyl or acyl group,

R ^{3 represents} hydrogen, halogen, trifluoromethyl, alkyl, aralkyl or alkoxy,

R ⁴ denotes hydroxy, alkoxy or a group,

worin

wherein

R ⁵ and R ^{6 are the} same or different and are hydrogen,

 Alkyl, aryl, aralkyl or acyl, or

R ^{4 is} a tetrazolyl radical

can be, or R ⁴ for a group

steht, in der

stands in the

R ⁷ denotes hydrogen or a lower alkyl group with 1-3 C atoms, which may be terminated by carboxyl, aminocarbonyl, alkoxycarbonyl, by alkylthio, hydroxyl,

 Phenyl or substituted by an imidazol-4-yl group, and

R ⁸ can be hydrogen, or R ^{7 together} with R ⁸ forms an alkylene chain with 3 or 4 carbon atoms.

The compounds of the formula I in which R ^{4 has} the last-mentioned meaning thus represent carboxamides with amino acids as the amine component.

As far as the compounds of general formula I

Let salts, esters or amides form, they are - if physiologically harmless - the subject of the invention. If the compounds I contain asymmetric carbons, so are their pure optical isomers (enantiomers) or their

 Mixtures (racemates) included in the claim.

The new compounds of general formula I show an excellent antagonistic action against thromboxane A ₂ and against prostaglandin endoperoxides. They inhibit activation platelets and other blood cells and prevent the constriction of the smooth muscles of the bronchi and blood vessels as well as the contraction of magnesium lines and similar cells with contractile properties.

This effect makes them valuable remedies for the treatment of cardiovascular diseases such as acute heart and brain infarction, cerebral and coronary ischemia, migraines, peripheral arterial occlusive disease and venous and arterial diseases

Thrombosis. Furthermore, their early application can have a beneficial effect on the occurrence of organ damage in shock patients. They are also suitable for preventing the drop in platelets and leukocytes during interventions with an extracorporeal circuit and during hemodialysis. Their addition to platelet concentrates stabilizes the platelets and thus increases the shelf life of the canned food.

Since thromboxane is a mediator of the inflammatory response in bronchial asthma, the use of these thromboxane receptor blockers can, in particular, weaken or even eliminate the hyperreactivity characteristic of chronic asthma.

The new thromboxane receptor blockers have a protective effect against gastritis and ulcer tendency and can therefore be used to prevent recurrence. In a model of experimental acute pancreatitis, the course could be improved by using a thromboxane antagonist. It is therefore to be expected that at least certain forms of acute pancreatitis in humans can be improved in their prognosis by using these thromboxane antagonists. In addition, they are able to inhibit the incorporation of acetate into cholesterol and are therefore also suitable for the treatment of fat metabolism diseases, which are associated with increased cholesterol synthesis. Of particular note is their pronounced anti-atherogenic effect with elevated serum cholesterol values, which is shown by a reduction in plaque formation, particularly in the coronary arteries and in the aorta.

Since diabetes is accompanied by increased thromboxane formation, the chronic use of these thromboxane antagonists can delay or even prevent the typical late damage to the kidney and eye vessels.

Also with a number of immunologically or non-immunologically related kidney diseases, e.g. Increased excretion of thromboxane B2 in the urine was observed in glomerulonephritis, acute renal failure, graft rejection and kidney damage due to nephrotoxic substances. In these diseases, an intervention with the new thromboxane antagonists is promising in terms of maintaining kidney function.

Since an increased thromboxane synthesis was detected in tumor cells and at the same time the proliferation of these cells could be inhibited by the administration of thromboxane antagonists, these represent an effective adjuvant therapy.

In pathological pregnancy, a disturbance in the balance of the prostaglandins is considered to be the cause. Blocking the thromboxane and PGF2alpha receptors can therefore, in particular, interrupt premature labor and a more favorable course can be achieved with gestational gestation or eclampsia. In addition, the prostaglandin-related symptoms of dysmenorrhea and premenstrual syndrome can be treated.

In all cases, alkyl means a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkyl having 1 to 6 carbon atoms is preferred. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl or isooctyl.

In all cases, alkoxy stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

In all cases, alkylthio is understood to mean a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via a sulfur atom. Is preferred

Lower alkylthio with 1 to 6 carbon atoms. An alkylthio radical having 1 to 4 carbon atoms is particularly preferred. Examples include methylthio, ethylthio, propylthio, iso-propylthio, butylthio, isobutylthio, pentylthio, isopentylthio,

Hexylthio, Isohexylthio, Heptylthio, Isoheptylthio, Octylthio or Isooctylthio called. In all cases, aryl is intended to mean an aromatic radical having 6 to 14 carbon atoms. Preferred aryl radicals are

Phenyl, naphthyl, biphenyl or fluorenyl. The aryl radical can be substituted one or more times in all possible positions, the substituents being halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆

Acylamino, C ₁ -C ₆ acyl or azide come into question. The phenyl radical is preferred, which is halogen, preferably chlorine and bromine, cyan, methyl, trifluoromethyl, 4-chlorophenyl or acetyl

can be substituted.

Aralkenyl means an aryl residue with 6 - 14 carbon atoms which is bonded via 2-6 unsaturated carbon atoms. Aralkenyl radicals having 2 to 4 carbon atoms in the alkenyl part are preferred. The styryl radical and the 4-chlorostyryl radical may be mentioned as examples.

In all cases, aralkyl stands for an aryl radical with 6 to 14 carbon atoms bonded via an alkylene chain. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkyl radicals may be mentioned as examples: benzyl, naphthylmethyl, phenethyl or phenylpropyl.

The acyl radicals R ^{2 are} derived from aliphatic carboxylic acids with 2-16 C atoms, from araliphatic and from aromatic carboxylic acids. Preferred acyl groups are acetyl, isobutyroyl, cinnamoyl, benzoyl, 4-chlorobenzoyl and 4-aminobenzoyl as well as n-octanoyl or n-hexadecanoyl. Halogen is fluorine, chlorine, bromine or iodine, preferably

Fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine. n is preferably the number 2.

R ⁸ is preferably a hydrogen atom, or R ⁸ together with R ⁷ forms an alkylene chain with 3 or 4 carbon atoms, ie there is a 5- or 6-ring which contains a nitrogen atom. Compounds with 5 rings, such as proline, are preferred here.

R ⁷ preferably represents a hydrogen atom, or R ⁷ is one

 Alkyl chain with 1 to 4 carbon atoms, which may or may not be substituted. The preferred substituents are:

Carboxyl, aminocarbonyl, dialkylaminocarbonyl, 4-subst. Piperazin-1-yl-carbonyl (the 4-position substituent is benzyl or 4-chlorobenzyl), alkoxycarbonyl, alkylthio, aralkylthio, phenylthio, hydroxyl, phenyl or 4-imidazolyl, the ones in these

Substituents optionally contained phenyl nuclei may also contain 1-2 halogen atoms (preferably chlorine).

The particularly preferred substituents are: carboxyl, aminocarbonyl, diethylaminocarbonyl, 4-benzyl- or 4- (4-chlorobenzyl) piperazin-1-yl-carbonyl, methoxy- or ethoxy-carbonyl,

Methylthio, benzyl or (4-chlorobenzyl) thio, phenyl or (4-chlorophenyl) thio, hydroxyl, phenyl or 4-chlorophenyl or 4-imidazolyl. If R _{4 represents} the residue of an amino acid, this should preferably be understood to mean the amino acids - and β-alanine, glycine, phenylalanine, serine, proline or histidine.

As an ester of the carboxylic acids of general formula I with R ⁴ =

-N (R ⁸ ) -CH (R ⁷ ) -COOH come those with lower monohydric alcohols (such as methanol or ethanol) or with polyhydric alcohols

Alcohols (such as glycerol) in question, but also include alcohols which also contain other functional groups, such as Ethanolamine.

Amides of the carboxylic acids of the general formula I with R ⁴ = -N (R ⁸ ) - CH (R ⁷ ) -COOH are those in which the amine component, for example ammonia, a lower dialkylamine such as diethylamine or a hydroxyalkylamine such as ethanolamine or is diethanolamine. Other claimed amine components are alkyl, aralkyl and aryl piperazines.

The claim also includes the pure optical isomers (enantiomers) of the compounds of the general formula I and their mixtures (racemates).

Preferred compounds of the formula I are those in which

R _{1 is} phenyl, 4-chlorophenyl, 4-methylphenyl or 4-trifluoromethyl, R _{2 is} hydrogen, methyl, acetyl or benzyl,

R _{3 is} hydrogen, methyl, methoxy or halogen,

R _{4 is} hydroxy, tetrazolylamino, alanyl, glycyl, phenylalanyl, serinyl or histidinyl, n = 2, m = 0, 1 or 2, p = 1 or 2.

The process according to the invention for preparing the compounds of the formula I is characterized in that compounds of the formula II,

worin die Sulfonylaminoalkylgruppe in ortho-, meta- oder paraStellung zur Mercaptogruppe steht und in welcher ^/

wherein the sulfonylaminoalkyl group is in the ortho, meta or para position to the mercapto group and in which

R ¹ , R ² , R ³ and n have the meaning given above, with halocarboxylic acids of the formula III

X- (CH ₂ ) _p -COR ⁴ (III),

in which X, p and R ^{4 have} the meaning given above, optionally in the presence of a base and a catalyst to give the compounds of the formula IV.

worin

wherein

R ¹ , R ² , R ³ , R ⁴ , n and p have the meaning given above, and if appropriate using suitable oxidizing agents to give the sulfoxides (m = 1) or the sulfones (m = 2)

 Formula I oxidized.

The compounds of the formula II can be obtained in the following ways:

A) A general sulfonic acid is condensed Formula V,

R ¹ -SO ₃ H (V) in which R ^{1 has} the meaning given above, or a reactive derivative thereof, in inert solvents in the presence of bases with an amine of the general formula VI,

in welcher R², R³ und n die oben genannten Bedeutung haben und erhält die Verbindung der Formel VII.

in which R ² , R ³ and n have the meaning given above and receives the compound of formula VII.

Then the compound VII with a halogen sulfone

acid VIII

Hal-SO ₃ H (VIII)

where shark e.g. represents chlorine or bromine, sulfohalogenated to a compound of formula IX.

The compounds IX are now with reducing agents, for example with tin / hydrochloric acid, in the compounds of

 Formula II transferred.

B) Another possibility is to first condense the compounds of the formula II with halocarboxylic acids of the formula III (R ⁴ = OH) to give the thioalkylcarboxylic acids of the formula IV (R ⁴ = OH) and then to convert them into their esters in a manner known per se (R ⁴ = alkoxy) or amides (R ⁴ = NR ⁵ R ⁶ , HN-tetrazolyl or R ⁴ = -N (R ⁸ ) -CH (R ⁷ ) -COOH). The process is outlined again in Scheme A for Examples 4, 5 and 6.

Die Verbindungen der Formel I, in der der Thioalkyl-Rest in meta-Stellung zur Sulfonaminoalkyl-Gruppe steht, lassen sich herstellen, indem man b) ein Amin der Formel XII

The compounds of the formula I in which the thioalkyl radical is in the meta position to the sulfonaminoalkyl group can be prepared by b) an amine of the formula XII

in the R ² , R ³ , R ⁴ , n, m and p the above

 Meaning with a sulfonic acid of the general formula V

R ¹ -SO ₃ H (V) in which R ^{1 has} the meaning given above, or a reactive derivative thereof, in inert solvents in the presence of bases to give the title compound I (R ³ = H):

In the event that m = 0, the thiophenol derivatives of the formula I obtained in this way can be oxidized to the sulfoxides (m = 1) or to the sulfones (m = 2) of the formula I using suitable oxidizing agents. The compounds of the formula I in which m = 0, 1 or 2 and R ⁴ = OH (or reactive derivatives thereof) can furthermore be converted into their esters, amides or pharmacologically acceptable salts, the oxidation of the sulfide (m = 0) into the sulfoxides (m = 1) or sulfones (m = 2) before or after the esterification or amidation.

The compounds of the formula XII are prepared in the following way:

Compounds of formula XIII

in which R ² , R ³ and n has the meaning given above, but preferably R ² = H and n = 2, and Y one

 hydrolytically or hydrogenolytically removable

Represents a protecting group, for example a benzoyl, acetyl, trifluoroacetyl, benzyloxycarbonyl or (including NR ² ) a phthalimido group

with thiocarbamoyl halides of the formula XIV

where Hal = Cl, Br, preferably Cl and R ⁹ = alkyl, preferably methyl, in the presence of strong bases, the O-aryl-dialkylthiocarbamates (XV)

 By heating in high-boiling solvents, such as. B.

Diphenylmethane, diphenyl ether or biphenyl rearrange the thiocarbamates (XV) into the S-aryl-dialkylthiocarbamates of the general formula XVI,

where Y, R ² , R ³ , R ⁹ and n each have the meaning described above.

The thiol carbonic acid amides (XVI) are now hydrolyzed to the mercaptans XVII with dilute bases:

 and by reaction with halocarboxylic acids of the formula III

X- (CH ₂ ) _p -COR ⁴ (III), in which X, p and R ^{4 have} the meaning explained above, optionally in the presence of a base and a catalyst in the thioacetic acid derivatives XVIII (m = 0)

 transferred.

If necessary, the oxidation to the corresponding sulfoxides (m = 1) or sulfones (m = 2) can already take place here.

After deprotection, the amines of the formula XII are obtained.

The production process b) for the compounds described in Examples 20 and 21 is explained again in Scheme B.

Für den Fall, daß R⁴ = N-Tetrazol-5-ylamin bedeutet, setzt man die Carbonsäure der allgemeinen Formel I (R⁴ = OH),

In the event that R ⁴ = N-tetrazol-5-ylamine, the carboxylic acid of the general formula I (R ⁴ = OH) is used,

in welcher R¹, R², R³, n, m und p die oben genannte Bedeutung haben, oder ein reaktives Derivat hiervon, wobei hierunter Ester, wie Methyl-, Cyanmethyl-, Ethyl- und p-Nitrophenylester, Anhydride, Amide wie Imidazolide und Säurehalogenide wie Säurechloride oder Säurebromide verstanden werden, mit 5-Amino-1,2,3,4-tetrazol (X), gegebenenfalls in Form des Hydrats

in which R ¹ , R ² , R ³ , n, m and p have the meaning given above, or a reactive derivative thereof, including esters such as methyl, cyanomethyl, ethyl and p-nitrophenyl esters, anhydrides, amides such as Imidazolides and acid halides such as acid chlorides or acid bromides are understood, with 5-amino-1,2,3,4-tetrazole (X), optionally in the form of the hydrate

um. Die Tetrazolylamide lassen sich anschließend gegebenenfalls in ihre pharmakologisch undenklichen Salze überführen. Die Darstellung der Verbindungen der allgemeinen Formel I mit R⁴ = -N(R⁸)-CH(R⁷)-COOH:

around. The tetrazolylamides can then optionally be converted into their pharmacologically acceptable salts. The representation of the compounds of general formula I with R ⁴ = -N (R ⁸ ) -CH (R ⁷ ) -COOH:

worin

wherein

R ¹ , R ² , R ³ , R ⁷ , R ⁸ , n, m and p have the meaning given above, for example by reacting the free carboxylic acid of the formula I (R ⁴ = OH) with compounds of the formula XI

In formula XI, R ⁷ and R ^{8 have} the meaning given above. X is a group COOR ⁹ , where R ^{9 is} a hydrogen atom or an equivalent of a metal ion, or a lower alkyl, aralkyl or. Represents silyl group. X can also represent an acid amide group or a residue which, after condensation has occurred, in an acid amide group or is converted into the -COOR ⁹ group, whereupon, if necessary, a certain substituent R ^{9 is converted} into another substituent R ⁹ in a manner known per se and the compounds obtained are converted into pharmacologically acceptable salts. c) It is also possible to use the sulfonic acids

To implement formula V-derived sulfonyl halides with amines VI (R ² = H), to prepare the thioalkylcarboxylic acids I as described (R = H) and then with alkyl halides or acyl halides, advantageously in the presence of bases, to give compounds of the general formula I (R ² - Alkyl) to alkylate or acylate.

The condensation of the mercaptans II or XVI with haloalkyl carboxylic acids or with their esters or their amides is advantageously carried out with the addition of an acid-binding agent, e.g. an alkali metal carbonate, an alkali metal oxide, an alkali metal bicarbonate or an organic amine (e.g. pyridine, triethylamine) in an inert solvent. Examples include acetone, chloroform, low

 Alcohols, methylene chloride, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or a mixture thereof. However, all other methods suitable for thiophenyl ether formation can also be used, e.g. phase transfer catalysis.

The oxidation of the sulfenyl compounds IV and XVIII to the sulfinyl and sulfonyl compounds takes place either with an inorganic oxidizing agent such as H ₂ O ₂ , NaJO ₄ , KMnO ₄ , NaCIO or Oxon ^R (potassium hydrogen peroxomonosulfate), or with an organic peracid such as m-chloroperbenzoic acid. As

Solvents come water, lower aliphatic carboxylic acids such as Acetic acid, or chlorinated hydrocarbons in

Consideration.

The reaction of the sulfonic acid of the formula V with a compound of the formula VI or XII is advantageously carried out in a solvent such as dichloromethane, ether, tetrahydrofuran, dioxane or benzene or in a solvent mixture thereof.

If appropriate, the process is carried out in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the latter two also being able to serve as solvents at the same time. The presence of an acid activating or dehydrating agent such as thionyl chloride or phosphorus pentachloride is advantageous. However, preference will be given to working with a reactive derivative of a sulfonic acid of the formula V, for example with its anhydride or halide. The reaction temperatures are between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.

The sulfohalogenation of sulfonamides VII with halogen sulfonic acids VIII, preferably with chlorosulfonic acid, is carried out using methods known from the literature (e.g. Oranikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1984). The halosulfonic acid is used in excess, and one can work with or without a solvent. Common solvents are

Chloroform, methylene chloride or carbon tetrachloride. At the Working without solvents, the reaction temperatures range between -20ºC and 150ºC, preferably between -10ºC and + 120ºC. If solvents are used, the reaction temperatures are between -20 ° C and the boiling point of the solvent used.

The reduction of the sulfohalides IX to the mercaptans II takes place according to the methods described in the literature (e.g. Houben-Weyl, Methods of Organic Chemistry, Volume "Sulfur Compounds"). The metal powders of zinc, tin, iron or calcium are suitable, but tin (II) chloride, zinc or aluminum amalgam can also be used. The reduction is carried out in the presence of acids; In addition to hydrochloric acid, sulfuric acid and glacial acetic acid mixed with hydrogen chloride gas or with concentrated hydrochloric acid are used.

The reduction can also be carried out electrolytically or with metal hydrides, for example with lithium aluminum hydride, aprotic solvents such as ether, THF or dioxane serving as the reaction medium.

Another method for reducing the sulfohalides is the reaction with phosphorus in the presence of iodine or hydrogen iodide. m-Hydroxyphenetylamine is known from the literature [J. Med. Chem. 27, 1323 (1984); Helv. 49, 798 (1966); J. Am. Chem. SOC. 55, 3388 (1933), Chem. Ber. 71 (1938).]

The N-protected m-hydroxyphenetylamines are e.g. T. also described in the literature, [z. B. in CA 108 (3), 21512 g (Y = benzoyl); Chem. Pharm. Bull 1973, 21 (3), 629-33 (Y = acetyl);

DE 3,610,643 (Y = acetyl); CA 110, 173252 b (Y = F ₃ CSO ₂ -);

 Heterocvcles 1984, 22 (9), 1995-2005 (Y = subst. Benzylcarbonyl);

J. Am. Chem. Soc. 1990 in print (Y = BOC);] or can be easily prepared from m-hydroxyphenethylamine. For this purpose, the OH group is first converted into the THP ether, for example with dihydropyran, but other OH protective groups are also possible, such as, for. B. the methoxymethyl (MOM) -,

Benzyloxymethyl, t-butoxymethyl or trimethylsiyl (TMS) group (see e.g. T.W. Greene Protective Groups in organic

Chemistry, John Wiley & Sons, New York 1981). The N group is then protected by reaction with acid chlorides, e.g. B. acetyl chloride, benzoyl chloride or p-nitrobenzoyl chloride. Other protecting groups are also possible, such as the t-butyl carbamate (BOC) and benzyl carbamate (CBZ) group. Numerous others are described in the literature (see e.g. McOmie, Protective Groups in Organic Chemistry, Plenum Press London and New York, 1973).

The O-protecting group is then split off again.

The preparation of the O-aryl-dialkylthiocarbamate (XV) was carried out analogously to a general process described in Organic Synthesis, Vol. 51, 138 (1971). For this purpose, a thiocarbamyl halide XIV, preferably dimethylthiocarbamyl chloride, is reacted with a phenolate in the presence of bases.

Dimethylthiocarbamic acid chloride XIV (R ⁹ = Me) is commercially available (e.g. Aldrich-Chemie GmbH, Steinheim, Germany) or can be prepared using methods known from the literature (see Methods of Organic Chemistry (Houben-Weyl) Vol. IX, Sulfur Compounds, pp. 829, 830 or Org. Syn. Coll Vol. 4, 310 (1963) or Org. Syn. Vol. 51, 140 (1971).

The reaction of the carbamic acid chloride XIV with the phenolate produced from a phenol and a base is generally carried out in an aqueous medium, the acid chloride, dissolved in inert but water-miscible solvents, such as. B. THF, glyme or diglyme, is added dropwise to the aqueous solution of the phenolate.

In addition to K0H, NaOH, Ca (OH) ₂ , NaOEt, NaH, KO ^t Bu and others can also be used as bases. The reaction temperatures are generally between 0 ° and 25 ° C, preferably between 0 ° and 5 ° C.

The rearrangement of the O-aryl-dialkylthiocarbamate XV in the S-aryl-dialkylthiocarbamate XVI and their hydrolysis to the

 Thiols XVII is also described in Org. Syn. Vol. 51, 140 (1971).

The pyrolysis is carried out in high-boiling solvents, for example diphenylmethane, diphenyl ether or biphenyl, but can also be carried out without a solvent. The reaction is advantageously carried out under an inert gas, for. B. nitrogen or argon. The reaction temperatures are between 250 ° and 300 ° C., preferably between 265 ° and 275 ° C. The reaction time is 30-60 minutes, but usually about 45 minutes.

The hydrolysis of the S-aryl-dialkylthiocarbamides XVI to the thiols XVII is carried out using the customary bases, for example KOH, NaOH, Ca (OH) ₂ , KO ^t Bu, K ₂ CO ₃ or Na ₂ CO ₃ . It can join the pyrolysis in a one-pot reaction. After the reaction apparatus has cooled, it has proven expedient to add a water-miscible solvent, for example ethylene glycol. The hydrolysis is generally carried out at a reaction temperature which corresponds to the boiling point of the solvent mixture.

Preparation of tetrazolylamides I

The preferred method for reacting the carboxylic acids of the general formula I (R ⁴ = OH) with the aminotetrazole (X) consists in the reaction of approximately equimolar amounts of the amine and the acid in the presence of a dehydrating agent.

As such, for example, polyphosphoric acid, which then simultaneously serves as a solvent, or isobutyl chloroformate in the presence of an aprotic polar solvent, such as. B. Dimethylformamide.

The reactions take place between 50 ° C and 200 ° C. The tetrazolamides of the general formula I generally fall behind

 Add water or aqueous mineral acid, such as hydrochloric acid or sulfuric acid, and are purified by filtration by recrystallization or by column chromatography.

Another preferred method for the preparation of tetrazolamides of the general formula I consists in the reaction of about equimolar amounts of the amine (X) with the acid I (R ⁴ = OH) in a suitable solvent with about an equivalent amount of a halogenating agent such as phosphorus trichloride,

Phosphorus pentachloride or thionyl chloride, at temperatures between room temperature and the reflux temperature of

Mixture. Suitable solvents are methylene chloride, carbon tetrachloride, diethyl ether, toluene, xylene or chlorobenzene. In general, the product precipitates out of the solution and is obtained by filtration. If necessary, the reaction mixture can be concentrated to a point where the product begins to precipitate out of solution. Acidic cation exchangers, sulfonium salts, sulfuric acid halides, 2-halopyridinium salts, phosphonium salts and N, N'-dicyclohexylcarbodiimide are suitable as further condensing agents in this reaction.

If their esters are used instead of the carboxylic acids, then one works in the presence or absence of special solvents at temperatures in the range from 20 ° C. to the boiling point of the mixture. The reaction of approximately equimolar amounts of the amine and the ester in polyphosphoric acid at 50 ° C. to 200 ° C. is preferred, but it is also best in an inert solvent such as methylene chloride, benzene, toluene, chlorobenzene in the presence of a little more than one equivalent a base such as sodium ethanolate or butyllithium or sodium hydride in dimethyl sulfoxide.

If one uses their anhydrides instead of the carboxylic acid I (R ⁴ = OH), the reaction with the amine (X) can already be carried out at temperatures between room temperature and 60 ° C. It is preferred to work in an inert solvent such as Dichloromethane, diethyl ether, benzene, toluene. The amine and the anhydride are combined in approximately equimolar amounts, an exothermic reaction generally starting. After the reaction has subsided, it is gently warmed for a while to complete the reaction.

If an acid halide is used instead of the carboxylic acid, it is best to work at temperatures between -10 ° C and room temperature. It is preferred to proceed in such a way that

Schotten-Baumann added to the aqueous solution of the amine, which also contained a base such as alkali hydroxide, sodium carbonate or pyridine, slowly added the acid chloride while cooling with ice and then left to stand at room temperature for some time. This reaction is possible not only in water, but also in organic solvents such as methylene chloride, ether, benzene or toluene. Even without acid-binding agents, the amines can be acylated almost quantitatively by carboxylic acid chlorides if the amine and the carboxylic acid chloride are boiled in an inert solvent such as methylene chloride, benzene or toluene until the evolution of gas has ended, which takes 1 to 24 hours. However, if a slight excess is added to an acid-binding agent such as triethylamine or pyridine, the reaction takes place at temperatures between -10 ° C. and room temperature.

The tetrazolamides of the general formula I can also be prepared by converting the carboxylic acid of the general formula I (R ⁴ = OH) into its imidazolide, advantageously by reacting the acid with N, N-carbonyldiimidazole in an organic solvent such as tetrahydrofuran, toluene , Benzene or diethyl ether, the carboxylic acid imidazolide in one reactive ester converts, for example, the nitrophenyl ester, which can be reacted with the tetrazolylamine X to give the carboxylic acid tetrazolylamide I.

Production of amino acid amides I

For the implementation of the carboxylic acids I (R ⁴ = OH) with the

Amines XI have proven to be expedient to use the carboxylic acids in the form of reactive derivatives. Suitable acid halides, anhydrides, imidazolides, the mixed anhydrides of the carboxylic acid and a chloroformate, active esters such as nitrophenyl ester or hydroxyphthalimide or hydroxysuccinimide ester are suitable. The condensation between free carboxylic acid I and amine component XI in the presence of water-releasing agents such as dicyclohexylcarbodiimide is also favorable. In many cases, the acid function of the amine component can be in the salt form, but it is often more favorable to start from the esterified aminocarboxylic acid XI, the use of the trialkylsilyl esters having proven to be particularly advantageous. In the preparation of the trialkylsilyl esters, the amino group is optionally silylated at the same time, so that trialkylsilyl esters of N-trialkylsilylamino result. These can be condensed with the activated carboxylic acids X in the same way as non-silylated amino acid esters on nitrogen. The amino group of the amino acids or their esters can optionally also be reacted in the salt form. Possible solvents are: water-alcohol mixtures (e.g. for the reaction of hydroxysuccinimide esters of carboxylic acids I with the sodium salts of amino acids XI (X = -COONa); methylene chloride, tetrahydrofuran, dimethylformamide and, in cases of low solubility, dimethyl sulfoxide.

The optionally subsequent N-alkylation of a compound of the general formula I in which R ² = hydrogen can be carried out by known methods, preferably by reacting it with an alkyl halide or a dialkyl sulfate in the presence of an acid-binding agent such as potassium carbonate.

An acyl group R ^{2 is introduced} into a sulfonamide of the general formula I (R ² = H) under conditions which are customary for the acylation of amines:

 Reacting with an active carboxylic acid derivative, e.g. one

 Acid halide, a mixed anhydride or an active ester, in an inert solvent in the presence of bases.

Examples of inert solvents are methylene chloride, benzene, dimethylformamide and the like. in question.

As substituents X of the general formula XI, which in the

-COOR ⁹ group can be converted, for example the nitrile, carbaldehyde, hydroxymethyl, aminomethyl and formyl groups are suitable. The conversion of the substituent R ^{9 which may be} carried out after the condensation is carried out, for example, by saponification of the carboxylic acid esters (R ⁹ = alkyl) to the corresponding carboxylic acids (R ⁹ = hydrogen) with mineral acids or alkali metal or alkaline earth metal hydroxides in a polar solvent, for example Water, aqueous methanol, aqueous ethanol or aqueous dioxane) at ice bath temperatures or at temperatures up to 40 ° C. The respective conditions depend on the saponifiability of the amide bond present in the molecule.

Conversely, it is also possible to esterify the carboxylic acids (R ⁹ = H) in the customary manner or to convert esters with a certain R ⁹ radical to an ester with another R ⁹ radical by transesterification. The esterification of the carboxylic acids is expediently carried out in the presence of an acidic catalyst, such as, for example, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid or a strong acidic ion exchange resin. In contrast, transesterifications require the addition of a small amount of a basic substance, for example an alkali metal or alkaline earth metal hydroxide or an alkali metal alcoholate. In principle, all alcohols are suitable for the esterification of the carboxy group or for a transesterification. The lower monohydric alcohols, such as methanol, ethanol or propane, and polyhydric alcohols, for example glycerol or alcohols with other functional groups, such as ethanolamine or glycerol ether, are preferred.

The amides according to the invention, derived from the carboxylic acids of the general formula I, are preferably prepared by methods known per se from the carboxylic acids or their reactive derivatives (such as, for example, carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides) by reaction with amines . Examples of amino components are ammonia, alkylamines,

Dialkylamines, but also amino alcohols such as Ethanolamine and 2-aminopropanol in question. Other valuable amine components are alkyl, aralkyl and aryl piperazines.

The compounds of general formula I according to the invention can also contain asymmetric carbon atoms.

The invention therefore also relates to diastereomers, racemates and the optically active forms of the compounds of the general formula I according to the invention. If diastereomers are obtained in the synthesis of the compounds according to the invention, they can be separated into the corresponding racemates by column chromatography.

The optically active compounds can be prepared from their racemic mixtures by methods known per se.

Basic or acidic racemic mixtures can e.g. are split into their optically active forms via their diastereomeric salts. For racemate resolution e.g. Tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, dibenzoyl tartaric acid, cinchonine, phenethylamine, brucine or quinine can be used.

Neutral racemic mixtures can be separated chromatographically into the optically active forms on chiral phases.

For the production of salts with physiologically compatible organic or inorganic bases such as, for example Sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine, triethylamine or ethanolamine can the compounds of formula I with the

corresponding bases are implemented. Mixtures of the acidic compounds with a suitable alkali carbonate or

-hydrogen carbonate come into consideration.

For the preparation of medicaments, the compounds of general formula I are known in a manner known per se with suitable pharmaceutical carriers, aroma, flavor and

 Dyes mixed and for example as tablets or

 Dragees molded or with the addition of appropriate auxiliaries in water or oil, such as. B. olive oil, suspended or dissolved.

The substances of the general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.

Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can optionally contain flavorings and sweeteners.

The dosage administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired. The daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Typically 0.5 to 40 and preferably 1.0 to 20 mg / kg are effective in one or more applications per day to achieve the desired results.

For the purposes of the invention, in addition to the compounds of the formula I mentioned in the examples and their salts, the following compounds are particularly suitable:

1) 4- [2- (4-Trifluoromethylbenzene-N-methylsulfonamido) ethyl] phenylsulfenyl acetic acid

2) 4- [2- (4-Trifluoromethylbenzene-N-methylsulfonamido) ethyl] sulfinyl acetic acid

3) 4- [2- (4-trifluoromethylbenzene-N-methylsulfonamido) ethyl] phenylsulfonyl acetic acid 4) 4- [2- (4-Methylbenzene-N-acetylsulfonylamido) ethyl] phenylsulfenyl acetic acid

5) 4- [2- (4-Methylbenzene-N-acetylsulfonamido) ethyl] phenylsulfinyl acetic acid

6) 4- [2- (4-Methylbenzene-N-acetylsulfonamido) ethyl] phenylsulfonyl acetic acid

7) 4- [2- (4-Chlorobenzene-sulfonamido) ethyl] phenyl-sulfenyl-acetic acid (1H-tetrazol-5-yl) amide

8) 4- [2- (4-chlorobenzene-sulfonamido) ethyl] phenyl-sulfinyl-acetic acid- (1H-tetrazol-5-yl) amide

9) 4- [2- (4-Chlorobenzene-sulfonamido) ethyl] phenyl-sulfonyl-acetic acid (1H-tetrazol-5-yl) amide

10) N- {4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} alanine

11) N- {4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} alanine

12) N- {4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} alanine

13) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl propionic acid 14) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl-propionic acid

15) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl propionic acid

16) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfenyl-propionic acid (1H-tetrazol-5-yl) amide

17) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl-propionic acid (1H-tetrazol-5-yl) amide

18) 5-Methyl-2- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl-propionic acid (1H-tetrazol-5-yl) amide

19) N- {5-Methyl-2 - [- (4-chlorobenzenesulfonamido) ethyl] phenylsulfenyl] propionyl} alanine

20) N- {5-Methyl-2 - [- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] propionyl} alanine

21) N- {5-Methyl-2 - [- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] propionyl} alanine

22) 5-methoxy-2- [2- (4-chlorobenzene-N-benzylsulfonamido) ethyl] phenylsulfenyl acetic acid

23) 5-Methoxy-2- [2- (4-chlorobenzene-N-benzylsulfonamido) ethyl] phenylsulfinyl acetic acid 24) 5-methoxy-2- [2- (4-chlorobenzene-N-benzylsulfonamido) ethyl] phenylsulfonyl acetic acid

25) N - {[3- [2- (4-Chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} alanine

26) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} alanine

27) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} glycine

28) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} glycine

29) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} glycine

30) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} phenylalanine

31) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} phenylalanine

32) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} phenylalanine

33) N - {[3- [2- (4-Chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} serine 34) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} serine

35) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl) serine

36) N - {[3- [2- (4-Chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} histidine

37) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl] acetyl} histidine

38) N - {[3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl] acetyl} histidine

39) 2-Fluoro-4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl acetic acid

40) 2-Fluoro-4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl acetic acid

41) 2-Fluoro-4- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl acetic acid

example 1

2- (4-chlorobenzenesulfonamido) ethylbenzene

A mixture of 90.6 g (0.75 mol) of phenethylamine, 750 ml of ethyl acetate and 156 ml (1,125 mol) of triethylamine is added to

Ice cooling, a solution of 187.5 g (0.9 mol) of 4-chlorobenzenesulfonyl chloride in 750 ml of ethyl acetate was added dropwise so slowly that the temperature did not rise above 20 ° C. After the addition has ended, the mixture is stirred at room temperature for 5 hours, then hydrolyzed with 2N hydrochloric acid, the acid phase is separated off and the organic phase is washed three times each with water, saturated sodium bicarbonate solution and again with water, the ethyl acetate phase is dried with sodium sulfate and evaporated in Vacuum on. 239.5 g of crude product are obtained, 149.3 g (67%) of colorless crystals crystallize from ether, mp. 88-90 ° C.

Example 2

4- [2- (4-chlorobenzenesulfonamido) ethyl] benzenesulfonyl chloride

59.0 g (0.2 mol) of the sulfonamide from Example 1 are carefully added to 100 ml (1.5 mol) of chlorosulfonic acid at 0-10 ° C. A strong foaming occurs here. After the addition has ended, the mixture is stirred for a further 3 hours at room temperature, poured onto ice and extracted three times with 300 ml of ethyl acetate each time. The organic phase is three times with 100 ml of water, saturated sodium bicarbonate solution and water again shaken out, the ethyl acetate phase dries with sodium sulfate and evaporates in vacuo. 73.8 g of crude product of mp. 93-95 ° C. are obtained, which can be recrystallized from ethyl acetate / n-heptane. The pure yield is 43.5 g (55%), colorless crystals, mp. 109-11 ° C.

Example 3

4- [2- (4-chlorobenzenesulfonamido) ethyl] thiophenol

39.0 g (100 mmol) of the sulfochloride from Example 2 are suspended in 250 ml of conc. Hydrochloric acid and add 80.0 g (0.67 mol) of tin in portions. After stirring for 1 hour at room temperature, the mixture is heated under reflux for about 4 hours until all undissolved crystals have melted. Upon cooling, the product crystallized out in the form of pale yellow crystals. The yield is 21.75 g (66%), mp. 84-86 ° C.

Example 4

4- [2- (4-chlorobenzene-sulfonamido) ethylIphenyl-sulfenyl-acetic acid

50 ml (50 mmol) are added to a solution of 8.0 g (25 mmol) of the thiophenol from Example 3 in 70 ml of ethanol.

1 N sodium methylate solution in ethanol and heated briefly to reflux. After cooling to room temperature, 2.35 g (25 mmol) chloroacetic acid, dissolved in 15 ml of ethanol, was added dropwise and the mixture was stirred at 60 ° C. for 1 hour. The ethanol is distilled off, the residue is taken up in ethyl acetate and extracted with water which has been acidified with 2N hydrochloric acid. The organic phase is then extracted three times with saturated sodium bicarbonate solution, the aqueous phase with

Acidified 2N hydrochloric acid and shaken again three times with ethyl acetate. The organic phase is washed over

Dried sodium sulfate and evaporated to dryness. 10.4 g of a yellow oil are obtained, which is purified by chromatography on RD silica gel (Polyglosyl 40-63) with a methanol-water-formic acid mixture (60: 40: 1) as the eluent.

The resulting pale yellow oil can be recrystallized from ethyl acetate / n-heptane. The yield of the title compound is 6.6 g (47%), colorless crystals, mp. 120-123 ° C.

Example 5

4- [2- (4-chlorobenzenesulfonamido) ethylphenyl sulfinyl acetic acid

The solution of 1.9 g (5 mmol) of the sulfenylacetic acid from Example 4 in 20 ml of glacial acetic acid is at room temperature with 0.5 ml of 30 percent. H ₂ O ₂ (5 mmol) was added and the mixture was stirred for 20 hours. Excess peroxide is removed by adding Pd black. you filter and evaporate the solution. The crude product thus obtained (1.8 g) is purified by chromatography on RP-18 (polyglyosyl 40-63) silica gel using a methanol / water / formic acid mixture (60: 40: 1) as the eluent. 1.1 g (54%) of the racemic title compound are obtained as colorless crystals, mp. 101-106 ° C. (ethanol / water).

Example 6

4- [2- (4-chlorobenzenesulfonamido) ethylIphenylsulfonyl acetic acid

To prepare the sulfonylacetic acid from the sulfenylacetic acid (prepared in Example 4, 1.9 g (5 mmol)), 1.0 ml (10 mmol) 30% is first added to the acetic acid solution (20 ml glacial acetic acid). H ₂ O ₂ , stirred for 4 hours at room temperature and now adds the same amount of H ₂ O ₂ (30%). You leave

 Stir for 12 hours and then work up as described in Example 5. 1.8 g (89%) of the title compound are obtained as colorless crystals, mp. 141-145 ° C. (ethanol / n-heptane).

Example 7

4-chloro [2- (4-chlorobenzenesulfonamido) ethyl] benzene

To a solution of 96.6 g (0.62 mol) of p-chlorophenetylamine in 800 ml of ethyl acetate and 166 ml (1.20 mol) of triethylamine 200 g (0.96 mol) of chlorobenzenesulfonic acid chloride, dissolved in 800 ml of ethyl acetate, are carefully added dropwise with ice cooling, so that 20 ° C. is not exceeded. After the addition has ended, the mixture is stirred for a further 5 hours at room temperature, then hydrolyzed with 2N hydrochloric acid, the acid phase is separated off and the organic phase is washed three times each with water, saturated sodium bicarbonate solution and again with water and the ethyl acetate phase with sodium sulfate and evaporated in vacuo on. 137 g (67%) of colorless crystals, mp. 114-115 ° C., are obtained.

Example 8

2-chloro-5- [2- (4-chlorobenzenesulfonamido) ethylbenzenesulfonyl chloride

100 ml (1.5 mol) of chlorosulfonic acid are added dropwise to 66 g (0.2 mol) of the sulfonamide from Example 7 with ice cooling, so that 5 ° C. is not exceeded. After stirring for 6 hours, the mixture is poured onto ice and worked up as described in Example 2. 33.6 g of the sulfochloride (39% yield) are obtained,

Mp 120-121 ° C. The sulfochloride group was only ortho to the chlorine.

Example 9

2-chloro-5- [2- (4-chlorobenzenesulfonamido) ethyl thiophenol

30 g (70 mmol) of the sulfochloride from the previous example are concentrated in 200 ml. Hydrochloric acid dissolved and by

52.5 g tin dust added to the thiol in portions. After stirring for 1 hour at room temperature, the mixture is heated under reflux for about 4 hours until all the undissolved crystals have melted. On cooling, 18.0 g (71%) of slightly yellow crystals crystallize out, mp. 142-143 ° C.

Example 10

2-chloro-5- [2- (4-chlorobenzene-sulfonamido) ethyl-phenyl-sulfenyl-acetic acid

16.5 g (50 mmol) of the thiophenol from Example 9 are dissolved in 100 ml of ethanol and 100 ml of 1 molar sodium ethylate solution are added. The mixture is heated briefly to reflux, allowed to come back to room temperature and 49 g (50 mmol) of chloroacetic acid, dissolved in 50 ml of ethanol, are slowly added dropwise. The mixture is stirred for 3 hours at 60 ° C. and worked up analogously to Example 4. 21.8 g (52%) of colorless crystals are obtained, mp 125-126 ° C. Example 11

2-chloro-5- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl acetic acid

2.3 g (5.5 mmol) of the sulfenylacetic acid from the previous experiment are dissolved in 20 ml of glacial acetic acid and 0.55 ml (5.5 mmol) of 30 percent is added at room temperature. H ₂ O ₂ solution (in water) and stirred for 24 hours. Working up is carried out analogously to Example 5. 2.2 g (92%) of the title compound, colorless crystals of mp. 144-147 ° C. are obtained

Example 12

2-chloro-5- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl acetic acid

Analogously to Example 6, 2.01 g (5.0 mmol) of

Sulfenylacetic acid from Example 10 and 2.0 ml (20 mmol) 30 percent. aq. H ₂ O ₂ solution in 20 ml glacial acetic acid 1.85 g (85%) the title compound in the form of colorless crystals, mp. 163-165 ° C. (ethanol / n-heptane).

Example 13

O-3- [2- (N-benzoylamino) ethyl] phenyldimethylthiocarbamate

19.2 g (155 mmol) of commercially available dimethylthiocarbamoyl chloride, dissolved in 90 ml of THF, are added to a solution of 30.0 g (124 mmol) of N-benzoyl-2- (3-hydroxyphenyl) ethylamine in 130 ml of dilute potassium hydroxide solution (0.124 molar), while cooling with ice. added dropwise and stirred at 0 ° C. for 30 min and at room temperature for a further 30 min. The batch is then shaken out three times with 50 ml of ethyl acetate each time, the combined organic phases are dried over sodium sulfate and evaporated to dryness. The residue is taken up in methylene chloride for further purification and activated carbon is added. The mixture is left to stir for some time, filtered off and the organic phase is evaporated. The oily residue can be crystallized with isohexane and a little ether. The title compound is obtained in the form of colorless crystals, mp. 98-101 ° C., yield. 35.9 g (88%).

Example 14

S-3- [2- (N-benzoylamino) ethyl] phenyldimethylthiocarbamate

31.0 g (95 mmol) of the O-3- [2- (N-benzoylamino) ethyl] phenyldimethylthiocarbamate from Example 13 are heated to boiling in 300 ml of diphenylmethane for one hour. After cooling to room temperature, the mixture is extracted several times with petroleum ether, the residue is taken up in methylene chloride and filtered through silica gel. After evaporation, 31 g (99%) of a pale yellow oil are obtained. NMR: Sppm ((CD ₃ ) ₂ SO): 3.49 (2H, q), 2.85 (2H, t), 2.95 (3H, s), 3.0 (3H, s), 7.1-7.9 (9H, m), 8.52 (1H, t).

Example 15

3- [2- (N-Benzoylamino) ethyl] phenyl mercaptan

The oily residue of Example 14 (30.3 g, 92.3 mmol) is taken up in 200 ml of ethylene glycol, 5.5 g of NaOH in 60 ml of water and boiled under reflux for 24 hours. After the reaction mixture has cooled to room temperature, 50 ml are added

 Diethyl ether and 50 ml of petroleum ether, shake vigorously and suck off the emulsion. The aqueous phase is extracted twice with ether, acidified with 6N HCl and shaken out several times with 50 ml of ethyl acetate each time. After drying the combined organic phases over sodium sulfate and evaporation

 16.7 g (71%) of a pale yellow oil are obtained dry.

 This can be done by reversed phase chromatography on RP C18 (Europrep 60-20, 60 A °, 15-25 μ, Eurochrom),

Extractant: CH ₃ OH: H ₂ O = 6: 4, +0.2% CH ₃ COOH) further clean. 10.25 g (43%) of colorless crystals are obtained, mp. 65-68 ° C.

Example 16

3- [2- (N-Benzoylamino) ethyl] phenylthioacetic acid ethyl ester

15.7 g (61 mmol) of the phenyl mercaptan according to Example 15 are taken up in 150 ml of ethanol and 11.3 ml are added under N ₂ protective gas (61 mmol) 30% sodium methylate solution in methanol and 8.2 g (67.1 mmol) ethyl chloroacetate. After stirring for one hour at room temperature, the solvent

removed, the residue mixed with 20 ml of 2NHCl and extracted three times with 30 ml of ether. The combined organic phases are dried over sodium sulfate and evaporated to dryness. 17.0 g (81%) of a pale yellow oil are obtained, which can be purified further by chromatography on silica gel (CH ₂ Cl ₂ : heptane = 9: 1 as eluent). The title compound is obtained in the form of colorless crystals, yield. 13.4 g (64%), mp 58-60 ° C.

Example 17

3- [2- (N-Benzoylamino) ethyl] phenylthioacetic acid

The saponification of 12.0 g (35 mmol) of the ester from Example 16 is carried out with 26 ml of 2N NaOH in 40 ml of methanol. After stirring for 10 minutes at 50 ° C., the solvent is distilled off, acidified with 6N HCl and extracted three times with 40 ml of ethyl acetate each time. To remove by-products, the organic phase is shaken twice with 40 ml of NaHCO ₃ solution, the aqueous solution is acidified with 2N HCl and extracted with ethyl acetate. After drying over sodium sulfate, the organic phase is evaporated to dryness. 7.95 g (72%) of a colorless oil are obtained. NMR: Sppm ((CD ₃ ) ₂ SO): 2.83 (2H, t), 3.48 (2H, q), 3.76 (2H, s), 7.0-7.85 (9H, m), 8.55 (1H, t), 12.85 (1H, s, broadened). Example 18

3- (2-Aminoethyl) phenylthioessioic acid ethyl ester

To remove the protective group, 6.7 g (21.3 mmol) of 3- [2- (N-benzylamino) ethyl] phenylthioacetic acid are heated in 20 ml of 5N sodium hydroxide solution, the reaction is acidified with 6N HCl and the resulting benzoic acid is extracted with ether. In the acidic, aqueous phase is the free thioacetic acid, which can be esterified in a one-pot process. For this

the water is distilled off, the residue is taken up in ethanol and Amberlist 15 ^{R is} added. After heating under reflux for two hours, the mixture is allowed to come to room temperature, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is extracted with ether. 3.9 g (66%) of a colorless oil are obtained. The title compound is in the form of the HCl salt. NMR: Sppm ((CD ₃ ) ₂ SO): 1.2 (3H, t), 2.90 (2H, t),

3.08 (2H, q), 3.85 (2H, s), 4.12 (2H, q), 7.1-7.3 (4H, m), 7.31

(2H, t).

Example 19

3- [2- (4-Chlorobenzenesulfonamido) ethyl] phenylthioacetic acid, ethyl ester

2.76 g (13.1 mmol) of 4-chlorobenzenesulfone chloride are added in portions to a solution of 3.6 g (13.1 mmol) of 3- (2-aminoethyl) phenylthioacetic acid ethyl ester in 50 g of methylene chloride and 4.0 g (39 mmol) of triethylamine while cooling with ice. When the addition is complete, after 30 min at 0 ° C. and 2 Stirred for hours at room temperature. The mixture is then extracted three times with 20 ml of 2NHCl, the organic phase is dried over sodium sulfate and the solvent is distilled off. 5.4 g (99%) of a colorless oil are obtained which is pure enough for the further reactions.

NMR: S _ppm ((CD ₃ ) ₂ SO: 1.17 (3H, t), 2.65 (2H, t), 3.0 (2H, q), 3.85 (2H, s), 4.07 (2H, q), 6.95-7.20 (4H, m), 7.6-7.75

(AA'BB 'system, 4H), 7.82 (1H, t).

Example 20

3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylthioacetic acid

To saponify the phenylthioacetic ester from the previous example, 4.9 g (12.7 mmol) of the substance in 20 ml of 2N NaOH and 20 ml of methanol are heated to 50 ° C. and stirred for 30 minutes. The methanol is then evaporated off and the remaining aqueous phase is acidified with 6N HCl. It is shaken three times with 40 ml of ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated to dryness. For further purification, the oily residue is dissolved in NaHCO ₃ , mixed with activated carbon and shaken vigorously. After filtration, the mixture is acidified, extracted with methylene chloride and dried over sodium sulfate. 3.1 g (64%) of colorless crystals (water), mp. 72-73 ° C. Example 21

3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylthioacetic acid (1H-tetrazol-5-yl) amide

To a solution of 0.8 g (2.1 mmol) of the free phenylthioacetic acid (from Example 20) in 20 ml of abs. THF is added at 45 ° C to 0.34 g (2.1 mmol) of carbonyldiimidazole. After another 10

Minutes of a trace of nitrophenol and 0.18 g (2.1 mmol) of aminotetrazole are added. The mixture is now heated to 60 ° C., stirred for 4 hours and the solvent is distilled off after cooling to room temperature. The residue is mixed with 2N HCl while cooling with ice and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off. The remaining oil can be brought to crystallization by slurrying in a little ice-cold methylene chloride. Educ. 0.9 g (95%), mp. 140 ° C (dec.)

Example 22

N- (3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfenyl) acetylalanine

0.34 g (2.1 mmol) of carbonyldiimidazole are added at 45 ° C. to a solution of 0.8 g (2.1 mmol) of 3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylthioacetic acid in 10 ml of DMSO. After stirring for 10 minutes, a trace of nitrophenol and 0.23 g (2.1 mmol) of the sodium salt of L-alanine are added. The reaction mixture is heated to 80 ° C. and left at this temperature for 4 hours. After cooling to room temperature, pour on Water, decants and takes up the oily residue in ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and chromatographed on RP C18 with Europrep 60-20, 60 A, 15-25 μ from Eurochrom), a methanol-water mixture (60:40 + 0.2% vinegar). 0.5 g (52%) of the title compound is obtained as a colorless oil.

NMR: S _ppm ((CD ₃ ) ₂ SO): 1.25 (3H, d), 2.65 (2H, t), 2.98 (2H, q), 3.67 (2H, s), 4.20 (1H, p), 7.1- 7.2 (4H, m), 7.6-7.75 (4H, AA'BB 'system), 7.80 (1H, t), 8.40 (1H, d), 12.40 (1H, s, common).

Example 23

3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfinyl acetic acid

2.0 g (4.8 mmol) of the phenylthioacetic acid ester from Example 19 are dissolved in 30 ml of methanol and 1.1 g (5.1 mmol) of sodium periodate (NaJO ₄ ), dissolved in 20 ml of water, are added. The mixture is stirred at 50 ° C. for 2 hours, the methanol is then evaporated off and extracted with methylene chloride. The organic phase is over

 Dried sodium sulfate and evaporated. The residue can be further purified by chromatography on silica gel using a methylene chloride / methanol (97: 3) mixture as the eluent. 1.8 g (87%) of ethyl ester are obtained as a colorless oil.

NMR: S _ppm ((CD ₃ ) ₂ SO): 1.13 (3H, t), 2.75 (2H, t), 3.04 (2H, q), 4.05 (2H, s), 4.10 (2H, q), 7.32- 7.55 (4H, m), 7.6-7.8 (4H, AA 'BB' system), 7.85 (1H, t) For saponification, the oil is dissolved in 20 ml of methanol, 15 ml of 2N NaOH are added and the mixture is heated to 50 ° C. for one hour. you

distilled off the methanol and extracted with methylene chloride. After drying over sodium sulfate, the mixture is chromatographed on a short silica gel column (Lichroprep, Merck) with methylene chloride as the eluent. 1.0 g (63%) of

Title compound as a colorless oil.

NMR: S _ppm ((CD ₃ ) ₂ SO): 2.79 (2H, t), 3.05 (2H, q), 3.72 and 4.0 (2H, AB system), 7.40-7.55 (4H, m), 7.6-7.8 (4H, AA'BB 'system), 7.85 (1H, t)

Example 24

3- [2- (4-chlorobenzenesulfonamido) ethyl] phenylsulfonyl acetic acid

The oxidation of 2.0 g (4.8 mmol) of 3- [2- (4-chlorobenzenesulfonamido) ethyl] phenyl-sulfenyl-acetic acid ethyl ester (Example 19) is carried out analogously to Example 23, but with twice the amount

Sodium periodate (2.2 g, 10.2 mmol). After 4 hours of stirring at room temperature, it was found to be advantageous to add about 1 g of NaJO ₄ again and to let the reaction run at 60 ° C. for one day. The rest of the procedure is the same as in the previous experiment. 0.9 g (54%) of the title compound are obtained as a colorless oil.

NMR: Sppm ((CD ₃ ) ₂ SO): 2.81 (2H, t), 3.03 (2H, q), 4.07 (2H, s), 7.52-7.80 (8H, m), 7.90 (1H, t); Test protocol

1. TX antaconistic effect of human platelets

method

Platelet aggregation is investigated in platelet-rich plasma from healthy blood donors using the method of BORN and CROSS (J. Physiol. 168, 178 (1963). To inhibit coagulation, 3.2% citrate in a volume ratio of 1: 9 is added to the blood.

A stable analogue of the prostaglandin endoperoxide PGH ₂ , U 46619 (Upjohn & Co, Kalamazoo, USA) is used to induce platelet aggregation. U 46619 has been characterized as a selective thromboxane mimetic (COLEMAN et al., Brit. J. Pharmacol. 68, 127P., 1980).

The aggregation test is carried out in a 4-channel aggregometer

(Profiler ^R , Bio / Data, Hatboro, USA). The course of the aggregation is followed over 5 minutes. These values, which are obtained in the presence of different concentrations of the substance to be tested, are used to determine the IC ₅₀ for the TX antagonistic effect.

2. Prevention of U 46619-related pulmonary embolism

method

Male NMRI mice of approximately 25 g body weight are used. The test substance was 1% Suspended methyl cellulose solution and administered to the test animals by gavage. The provocation test consists in that a lethal dose for control animals (800-1000 μ / kg) of the thromboxane mimetic (U 46619 from Upjohn) is quickly injected into the tail vein. The duration of the specific antogonistic effect is tested by comparing the animals with 25 mg / kg of the different test substances

be pretreated and the injection of U 46619 takes place after 4 hours. The survival rate indicates what percentage of the animals used survived the injection of the thromboxane mimetic.

Results see table.

Pharmacological data on the following compounds:

Claims

Claims 1. Compounds of formula I.

in which R ^{1 represents} aryl, aralkyl or an aralkenyl group, the aryl radical of which can optionally be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, trifluoromethoxy, hydroxy or carboxy, n is an integer from 1 to 3, m is an integer from 0 to 2, p is an integer from 1 to 6, R ^{2 can be} hydrogen, an alkyl, aralkyl or acyl group. R ^{3 represents} hydrogen, halogen, trifluoromethyl, alkyl, aralkyl or alkoxy, R ^{4 is} hydroxy, alkoxy or a group means

wherein R ⁵ and R ^{6 are} identical or different and represent hydrogen, alkyl, aryl, aralkyl or acyl, or R ^{4 is} a tetrazolyl radical

can be. or R ⁴ for a group

stands in the R ^{7 is} hydrogen or a lower alkyl group with 1-3 C atoms, which may be terminal  Carboxyl, aminocarbonyl, alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by one  Imidazol-4-yl group is substituted, and R ⁸ can be hydrogen, or R ^{7 together} with R ⁸ forms an alkylene chain with 3 or 4 carbon atoms, their optically active forms and their pharmacologically acceptable salts, esters and amides. 2. Compounds of formula I according to claim 1, in which R _{1 is} phenyl, 4-chlorophenyl, 4-methylphenyl or 4-trifluoromethyl, R _{2 is} hydrogen, methyl, acetyl or benzyl, R _{3 is} hydrogen, methyl, methoxy or halogen, R ₄ hydroxy, tetrazolylamino, alanyl, glycyl,  Phenylalanyl, serinyl or histidinyl, n = 2, m = 0, 1 or 2, p = 1 or 2. 3. Process for the preparation of compounds of formula I.

in which R ^{1 represents} aryl, aralkyl or an aralkenyl group, the aryl radical of which can optionally be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, trifluoromethoxy, hydroxy or carboxy, n is an integer from 1 to 3, m is an integer from 0 to 2, p is an integer from 1 to 6, R ^{2 can be} hydrogen, an alkyl, aralkyl or acyl group, R ^{3 is} hydrogen, halogen, trifluoromethyl, alkyl, Represents aralkyl or alkoxy, R ^{4 is} hydroxy, alkoxy or a group means

wherein R ⁵ and R ^{6 are the} same or different and represent hydrogen, alkyl, aryl, aralkyl or acyl, or R ^{4 is} a tetrazolyl radical

can be or R ⁴ for a group

stands in the R ^{7 is} hydrogen or a lower alkyl group with 1-3 C atoms, which may be terminal  Carboxyl, aminocarbonyl, alkoxycarbonyl, by  Alkylthio, hydroxyl, phenyl or by one  Imidazol-4-yl group is substituted, and R ⁸ can be hydrogen, or R ^{7 together} with R ⁸ forms an alkylene chain with 3 or 4 carbon atoms, their optically active forms and their pharmacologically acceptable salts, esters and amides, characterized in that a) compounds of the formula II

wherein the sulfonylaminoalkyl group is in the ortho, meta or para position to the mercapto group and in which R ¹ , R ² , R ³ and n have the meaning given above, with halocarboxylic acids of the formula III X- (CH ₂ ) _p -COR ⁴ (III), in which X, p and R ^{4 have} the meaning given above, optionally in the presence of a base and a catalyst, to give the compounds of the formula IV,

wherein R ¹ , R ² , R ³ , R ⁴ , n and p have the meaning given above, and if appropriate with suitable ones  Oxidizing agents oxidized to the sulfoxides (m = 1) or to the sulfones (m = 2) of the formula I, or b) in the event that the thioalkyl radical is in the meta position to the sulfonaminoalkyl group, Compounds of formula XII

 wherein Y, R ² , R ³ , R ⁴ , n, m and p have the meaning given above, with sulfonic acids of the formula VR ¹ -SO ₃ H (V), in which R ^{1 has} the meaning given above, or a reactive derivative thereof, in the presence of bases  implemented and then, if desired, compounds of the formula I converted into other compounds of the formula I, and the compounds obtained were converted into pharmacologically acceptable salts, esters or amides. 4. Medicament containing a compound according to claim 1 or 2 in addition to conventional carriers and auxiliaries. 5. Use of compounds according to claim 1 or 2 for the manufacture of pharmaceuticals with  thromboxane antagonistic effect.