IL34820A - Isoquinoline and benzazepine sulfonyl ureas,their preparation and pharmaceutical compositions containing them - Google Patents

Description

54920/2 i ,ηικ'·η« V'JISVTO |»ητκτί:»ν τ* τ3»ιρητ»κ ϊΐηκ o' aan mnpn 'TtMm †naan Isoqulnoline and benzazepine sulfonyl ureas, their preparation and pharmaceutical compositions containing them -- / 34820/2 This invention relates to novel sulfonylureas having interesting physiological properties.

According to one feature of the present invention there are provided compounds of the general formula [wherein represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms;' a phenyl group optionally substituted by an alkoxy group containing ·■ from 1 to 3 carbon atoms, by a methyl or trifluoromethyl group, by one or two halogen atoms or simultaneously by both a methoxy group in the 2-position and a chlorine atom in the 5-position; or a biphenylyl, a-naphthyi 1,2,'3,4-tetrahydro- ' . · .· · .· f ' · · ··.>..· I. : « '· . ! · ! ···*· iM'n."tyl .«*n!.v f ; naphthyl-(l) , indanyl-(l) or benzoyl group; . . · i ' ,'i . ■ ; » I i X {< t sin: οι: ;··- R2 represents an n-butyl group, a cycloalkyl group containing from 5 to 8 ring carbon atoms optionally substituted by a methyl or ethyl group, or an adamantyl-(l) group; ■ an A represents alkylene group containing from 1 to 5 carbon atoms optionally substituted by a phenyl group or is absent; η Ί and n represents the integer 1 or 2 J and physiologically compatible : salts thereof .

The new compounds- in general exhdlit strong hypoglycemic ' activity even in small quantities; they also have a low -toxicity.

« When in salt form, the compounds according to the invention are conveniently in the form of their alkali metal and alkaline earth metal salts. Preferred compounds according to the invention by virtue of their especially interesting activity include: l-[ 2-( 2-p-bromophenyl-propionyl )-l , 2 , 3, 4-tetrahydroiso- q.uinoline-7-sulfonyl ] -3-cyclohexylurea l-[ 2-( 2-p-chlorophenyl-propionyl ) -1 , 2 , 3 , -tetrahydroiso- quinoline-7-sulfonyl ] -3-cyclohexylurea l-[ 2-( 2-p-methylphenyl-propionyl )-l ,2,3? -tetrahydroiso- quinoline-7-sulfonyl] -3-cyclohexylurea l-[ 2-( 2-( 3 , -dichlorophenyl ) -propionyl ) -1 , 2 , 3 , 4-tetrahydro- isoquinoline-7-sulfonyl ] -3-cyclohexylurea l-[ 2-( 2-p-trifluoromethy1phenyl-pro ionyl ) -1 , 2 , 3 , 4-tetra- hydroisoquinoline-7-sulfonyl ] -3-cyclohexylurea l-[ 2- ( 2-phenylpropionyl )-l , 2 , 3 , -tetrahydroisoquinoline- 7-sulfonyl] -3-cyclohexylurea l-[ 3-( 2-p-bromophenyl-propionyl ) -2 ,3,4, 5-tetrahydro-lH-3- benzazepine-7-sulfonyl ] -3-cyclohexylurea and their physiologically compatible alkali metal and alkaline earth metal salts.

The new compounds may, for example, be prepared by reaction of an acyl-7-sulfonyl compound of formula II X. [wherein , A, and n are as hereinbefore defined and either X represents a free amino group and Y represents an isocyanate group or X represents a carbamate group of formula -NH-COO-Alk (wherein Alk represents a lower alkyl group) and Y represents a free amino group]. This process constitutes a further feature of the present invention.

The reaction of a sulfonamide of formula II with an isocyanate of formula III is preferably carried out in an inert solvent or diluent, preferably in the presence of an inorganic or tertiary organic base, and conveniently at elevated temperatures, advantageously at temperatures between 50 and 150°C. The reaction may, however, also be performed at room temperature; however, the time of reaction will then be considerably longer. Alkali metal hydroxides have proved to be suitable as organic bases. Pyridine is an example of a suitable tertiary organic base. Conveniently an alkali metal salt of the sulfonamide of formula II is first formed by reaction with an alcoholic alkali metal hydroxide solution and by subsequent evaporation to dryness. This salt may then be reacted with the isocyanate of formula III.

The reaction of a sulfonylcarbamate of formula II, in which X represents a -NH-COO-Alk group, with an amine of formula III may also be carried out in an inert organic solvent or diluent conveniently at room temperature or elevated temperatures and preferably at temperatures of Examples of suitable inert solvents or diluents for both variations of the process include dimethyl-formamide, dimethyl sulfoxide and nitrobenzene. These compounds are good solvents for the starting materials used.

The compounds of formula I obtained may be converted, if desired, into their physiologically compatible alkali metal or alkaline earth metal salts, preferably their sodium salts, for. example by means of alkali metal or alkaline earth metal hydroxides.

The sulfonamides and sulfonylcarbamates of formula II used as starting materials are also new compounds,' they may be used as intermediate products for the preparation of sulfonylureas and of other derivatives sub-stituted at the amide nitrogen. Sulfonamides of formula II may be obtained, for example,by reaction of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide or 2, 3, , 5-tetrahydro-lH-3-benzazepine-7-sulfonamide with an acyl-halide of formula 0 II R1 - A - C - Hal IV (wherein R^ and A are as hereinbefore defined and Hal represents a halogen atom) , conveniently in the presence of a solvent such as pyridine, or with a carboxylic acid of formula 0 II R1 - A - C - OH V (wherein R, and A are as hereinbefore defined) in the '4 presence of an activating agent such as thionyl chloride or dicyclohexylcarbodiimide .

Compounds of formula II may also be obtained by reaction of a sulfochloride of formula (wherein R-^ , A and n are as hereinbefore defined) with ammonia .

The sulfonylcarbamates of formula II in which X represents a -NH-COO-Alk-group , may for example be prepared by reaction of the above mentioned new sulfonamides of formula II with an alkyl chloroformate . 1,2,3, -Tetrahydroisoquinoline-7-sulfonamide and 2 , 3 , , 5-tetrahydro-lH-3-benzazepine-7-sulfonamide are not yet described in literature; they may be obtained from 2-acetyl-1 , 2 , 3 , -tetrahydroisoquinoline or 3-acetyl-2 , 3 , 4 , 5-tetrahydro-lH-3-benzazepine respectively by chloro-sulfonation, reaction with ammonia and subsequent splitting off of the acetyl group. 1 , 2 , 3 , 4-Tetrahydro-isoquinoline-7-sulfonamide may also be prepared from 2-acetyl-7-amino-l, 2, 3, -tetrahydroisoquinoline, known from the literature, by conversion of the amino group into a chlorosulfonyl group by means of a modified Sandmeyer reaction (see H. Meerwein et al . , Chem. Ber. 9_0, 8 1 (1957)), reaction with ammonia and splitting off of the acetyl group in the 2-position by means of dilute mineral acids.

The new sulfochlorides of formula VI may be prepared from the corresponding 7-amino-l , 2 , 3 , 4-tetrahydro-isoquinolines acylated in the 2-position or from the corresponding 7-amino-2 , 3 , 4 , 5-tetrahydro-lH-3-benzazepines acylated in the 3-position by replacing the amino group by a chlorosulfonyl group by means of a modified Sandmeyer reaction (see above) or by chlorosulfonation of the corresponding 1 , 2 , 3 , 4-tetrahydroisoquinolines acylated in the 2-position or of the corresponding 2 , 3 , , 5-tetrahydro-lH-3-benzazepines acylated in the 3-position.

According to a still further feature of the present invention there are provided pharmaceutical compositions comprising a compound of formula I, as hereinbefore defined, in association with a pharmaceutical carrier or excipient. The compositions may for example be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms of administration are tablets and gelatin capsules but other coventional forms of administration may be used.

Advantageously, the compositions may be formulated as dosage unitsj for administration to adults each dosage unit preferably contains from 1 to 20 mg, preferably about 5 mg, of active ingredient.

The following examples A - M describe the preparation of the new starting materials: A) 1,2, 3» -Tetrahydroisoquinoline-7-sulfonamide hydrochloride a) 175.2 g (1 mole) of 2-acetyl-l , 2 , 3, -tetrahydro- 4, added dropwise with cooling in ice/sodium chloride at an internal temperature of 8 to 15°C to 844 g (7· 2 mole) of chlorosulfonic acid. After standing overnight at 20°C, the reaction mixture was dropped onto an excess of ice. By extraction with chloroform, drying, filtration and evaporation of the chloroform phase, 232 g of crude sulfochloride having a honeylike consistence were obtained. b) Crude 2-acetyl-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfochloride obtained analogously to example a) was made more fluid by warming and stirred into 600 ml of concentrated aqueous ammonia. The reaction mixture was stirred for 1 hour and kneaded, and the colourless precipitate was then filtered off under suction.

The precipitate was washed several times with water and once with acetone and dried at 80°C/0.1 Torr. 172 g of sulfonamide were obtained. M.p.: 220 - 224°C.

C11H1 N2°3S (25 ·2) Calc: C 51.97 H 5-55 N 11.02 Found: 52.40 5-79 10.58 c) 172 g of 2-acetyl-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonamide were refluxed for 3 hours in 1.4 1 of half concentrated hydrochloric acid. Finally, charcoal was added and the reaction mixture was filtered hot through a celite layer. The solution was evaporated in vacuo until it began to crystallize and was then cooled. After suction filtration and drying, 105 g of the hydrochloride of the desired compound were obtained. M.p.: 212 - 217°C. (The free base melted at 176 - 180°C) Calc . : c 43.50 H 5.27 N 11.24 Found : 43.30 5.35 10.89 B) 1 , 2 , 3 « 4-Tetrahydroisoquinoline-7-sulfonamide hydrochloride a) 7.6I g (0.040 mole) of 2-acetyl-7-amino-l , 2 , 3 , 4-tetrahydroisoquinoline of m.p. 107 - 108°C (lit. m.p. 109 - 111°C, E. Ochiai and T. Nakagome, Chem. Pharm.

Bull. (Jap.) 6, 497 (1958)) were dissolved in 8.4 ml of concentrated hydrochloric acid and diazotized at a maximum temperature of +5°C with a solution of 3.04 g (0.044 mole) of NaNO^ in 6 ml of water.

The diazonium salt solution was admixed with 3.04 g (Ο.Ο32 mole) of anhydrous magnesium chloride, warmed to 30°C and stirred quickly into 40 ml of glacial acetic acid saturated with sulfur dioxide containing 2.2 g (0.0129 mole) of CuCl2.2 HgO, at 30°C. By external heating the internal temperature was adjusted to 48°C and the reaction mixture was stirred for 25 minutes.

After this time, little development was still to be observed.

The dark-brown reaction solution was diluted with 60 ml of water and extracted cold with ether. The ethereal extract was washed with dilute solution of pH-value 8 - 9 and with water, dried over sodium sulfate and evaporated in vacuo. 7.0 g of crude sulfochloride of honey-like consistence were obtained. b) 30 ml of concentrated ammonia were poured over 6.2 g (22.6 millimole) of crude sulfochloride obtained according to a). The mixture was then kneaded for 1 hour acetone, 4. 3 g of sulfonamide were obtained. M.p.: 223 - 226°C.

C11H1 N2°3S ( 25^ . 2 ) Calc: C 51 .97 H 5. 55 N 11.02 Found: 52.10 5 . 57 10.70 c) 4.0 g of the 2-acetyl-l , 2, 3, 4-tetrahydroisoquinoline-7-sulfonamide obtained according to b) and 60 ml of 10^ hydrochloric acid were refluxed for 2. 5 hours and finally boiled with some charcoal. The solution was filtered over celite and evaporated in vacuo. After recrystallisation from methanol, 3.3 g of the hydrochloride of the desired compound were obtained. M.p.: 215 - 218°C.

C9H13C1N202S (248. 7 ) Calc: C 3. 50 H 5 . 27 N 11.24 Found: 43.60 5 .41 10. 99 C) 2-( 3-Phenylpropionyl )-l , 2 , 3 » 4-tetrahydroisoquinoline- 7-sulfonamide To a suspension of 548 g (2.2 mole) of 1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride (m.p.: 212 - 217°C) in 4 1 of pyridine (distilled over BaO) were added dropwise 373 g (2.2 mole) of hydrocinnamic acid chloride, with stirring and cooling such that the internal temperature did not exceed +15°C. After 4 hours' stirring at 20°C the pyridine was distilled off in vacuo. The pasty residue was triturated with 3 1 of water, then suction filtered, again triturated with 4 1 of water and again suction filtered. By recrystallisation of the dried solid product from methanol/dimethylformamide ( 3:l) were obtained 440 g of the desired sulfonamide. M.p.: C18H20N2°3S (344.4) Calc: C 62.78 H 5.85 N 8.13 Found: 63.00 5.80 8.l6 D) 2-( 2-Phenylpropionyl )-l , 2 , 3.4-tetrahydroisoquinoline- 7-sulfonamlde To 15.O g (O.IO mole) of hydratropic acid and 24.9 g (O.IO mole) of 1 , 2, 3, 4-tetrahydroisoquinoline-7-sulfon-amide hydrochloride (m.p.: 212 - 217°C) in 250 ml of pyridine (distilled over BaO) were added dropwise slowly at a temperature of +5° - +7°C, 13.1 g (O.ll mole) of freshly distilled thionyl chloride. After stirring overnight at 20°C, the pyridine was distilled off in vacuo. On trituration of the greasy residue with water there was obtained a solid product which was filtered under suction and which was subsequently boiled in ethyl acetate. After cooling, the precipitate was suction filtered, washed with ethyl acetate and dried at 80°C/20 mmHg. I9.2 g of the desired sulfonamide were obtained.

M.p. : 199 - 201°C.

C18H20N203S (344.4) Calc: C 62.78 H 5.85 N 8.13 Found: 62.80 5.93 8.03 E) Ethyl Ν-Γ2-( 5-phenylpro ionyl )-l ,2, 3 , 4-tetrahydro- isoquinoline-7-sulfonyl] -carbamate .2 g (O.O6 mole) of 2-( 3-phenylpropionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 222 - 227°C), 33.2 g (0.24 mole) of potassium carbonate and 26.0 g (0.24 mole) of ethyl chloroformate were refluxed for 24 hours together in 350 ml of anhydrous acetone. The filtered acetone solution was evaporated in vacuo. The residue (31 g) was dissolved in chloroform.

The chloroform solution was shaken out several times with dilute alkali (pH 8 - 9). The aqueous alkaline solution was then acidified with hydrochloric acid and extracted with chloroform. On evaporation of the dried acidic chloroform extract there remained 12.9 g of crude sulfonylurethane (congealed foam; homogenous in thin-layer chromatography) .

From the chloroform solution treated with aqueous alkalis was obtained, after drying and evaporation, crude N, N-biscarbethoxy-2-( 3-phenylpropionyl ) -1 , 2 , 3, -tetrahydroisoquinoline-7-sulfonamide (18.2 g) of honeylike consistency. This crude product was admixed with 3 equivalents of sodium hydroxide solution with addition of some water (exothermic reaction) and after evaporation in vacuo it was twice further evaporated with ethanol.

The residue was dissolved in hot water. The alkaline solution was extracted with chloroform, then acidified with hydrochloric acid and again shaken out with chloroform. The acid chloroform extract contained a further 11.4 g of the desired sulfonylurethane . By recrystallisa-tion of the crude product (11.4 g + 12.9 g) from ethyl acetate/ether were obtained 18.25 g of colorless sulfonylurethane. M.p.: 138 - 1 1°C (decomp.).

C21H2 N2°5S ( 16·5) Calc. : N 6.75 S 7.52 Found: 6.77 7.73 V F) Ethyl Ν-Γ2-( 2-phenylpropionyl )-l , 2 , 3 , 4-tetrahydro isoquinoline-7-sul onyl ] -carbamate 8.4 g (0.0244 mole) of 2-( 2-phenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 199 - 201°C), 10.8 g (0.10 mole) of ethyl chloroformate and 14.0 g (0.10 mole) of potassium carbonate were refluxed for 32 hours in 200 ml of anhydrous acetone. Subsequently, the solution was suction filtered from the solid materials and the filtrate was evaporated. The evaporation residue was taken up in dilute sodium hydroxide solution. From the alkaline solution may be extracted with chloroform 3.5 g and after acidification with hydrochloric acid 8.1 g. The 3· g extracted from the alkaline solution were admixed with sodium hydroxide solution and ethanol. After evaporation at 60°C on a rotary evaporator, water was added to the mixture and the alkaline solution was extracted. Subsequently, hydrochloric acid was added and the acidified solution was extracted. The 2.7 g obtained from the acid extract were united with the 8.1 g obtained formerly and treated with charcoal in ethanol. After evaporation and vigorous drying were obtained 9·2 g of the homogenous foam-like urethane.

G) Ethyl Ν-Γ2-( 3-p enyl-butyryl ) -1 , 2 , 3 , 4-tetrahydro- isoquinoline-7-sulfonyl1-carbamate 21.5 g (O.O6 mole) of 2-(3-phenylbutyryl)-l, 2,3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 164 - l66°C), 26.I g (0.24 mole) of ethyl chloroformate and 33.2 g (0.24 mole) of potassium carbonate were refluxed for 32 hours in 600 ml of anhydrous acetone. The reaction mixture was There were obtained two acid chloroform extracts of 11.6 g and 10.2 g which were together recrystallized from ethyl acetate with addition of ether. l6.0 g of the homogenous urethane were obtained.

M.p. : 105 - 108°C.

C22H26N205S (430.5) Calc: C 61.39 H 6.09 N 6.51 Found: 61.20 6.07 6.68 H) Ethyl N-f 2-( 2-p-chlorophenylpropionyl )-l , 2 , 3,4- tetrahydroisoquinoline-7-sulfonyl ] -carbamate .35 g (27.4 millimole) of 2-( 2-p-chlorophenylpropionyl)-! , 2, 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 1 7 - 150°C), 12.2 g (112 millimole) of ethyl chloroformate and 15· 5 g (112 millimole) of potassium carbonate were refluxed for 3 hours in 200 ml of anhydrous acetone. Subsequently, the mixture was suction filtered from solid materials and the filtrate was evaporated. The evaporation residue was dissolved in 2N sodium hydroxide solution. From the alkaline solution .6 g were extracted with chloroform and after acidification with hydrochloric acid, a further 0.1 g. The I5.6 g extracted alkaline were devided among chloroform and dilute hydrochloric acid. From the chloroform phase were isolated 12.7 g of a yellowish foam. This product was subjected for complete purification to chromatography on a silica gel column ( cyclohexane : acetone : glacial acetic acid = 60 : 20 : 0.6). 8.0 g of homogenous glassy urethane were obtained (iR-band at 1760 cm-1 for C = 0).

I ) 2-( 2-p-bromophenylpropionyl )-l ,2, 5.4-tetrahydro- isoquinoline-7-sulfonamide hydrochloride, 7.20 g ( 31.4 millimole) of p-bromohydratropic acid, 3.18 g (31-milliraole) of triethylamine and 7 . 22 g ( 62.8 millimole) of N-hydroxysuccinimide in 500 ml of anhydrous dimethyl- formamide was added at -22°C a solution of 12. 96 g ( 62.8 millimole) of dicyclohexylcarbodiimide in 83 ml of dimethylformamide . After 2 hours at -22°C and 20 hours at 20°C the mixture was suction filtered from the precipitate formed and evaporated at 12 mm Hg. The residue was dissolved in ethyl acetate and shaken with NaHCO^ solution, 2N hydrochloric acid and water. From the dried and filtered ethyl acetate solution were obtained 13 g of crude product which was subjected to column-chromatography on silica gel ( cyclohexane : acetone = 3 : 2 ) .

M.p.: 146 - 148°C (from ethyl acetate); yield: 5 . g.

C18H19BrN203S (423-4) Calc: C 51.07 H 4. 52 N 6 .62 Found: 51 - 30 4.38 6.74 K) 3-( 2-p-bromophenylpropionyl ) -2 , 3 , 4 , 5-tetrahydro-lH-3- benzazepine-7-sulfonamide 14.0 g ( 66 millimole) of 1 , 2 , 3 , -tetrahydroisoquinol ine 7-sulfonamide were dissolved hot in 850 ml of anhydrous dioxan. 12. 2 g ( 66 millimole) of p-chlorohydratropic acid were added to the still warm solution. After cooling to 10°C a solution of 14.9 g (72 millimole) of dicyclohexylcarbodiimide in 70 ml of dioxan was introduced within 10 minutes. After 5 minutes the solution became turbid and a colorless precipitate originated. After 16 evaporated at 12 mm Hg. The light-yellow viscous oil ( 37 g) obtained was dissolved in much chloroform and extracted with 2N sodium hydroxide solution until no sulfonamide at all could be monitored by chromatography in the organic phase. The united sodium hydroxide solution extracts were stirred into ice/hydrochloric acid. On re-extraction with chloroform, 17.4 g of crude product, which were purified by column-chromatography on silica gel ( cyclohexane : acetone : lacial acetic acid = 60 : 40 : 0.4) were obtained. By crystallisation from ethyl acetate were obtained 10 . 3 g of colorless sulfonamide. M.p.: 147 - 150°C.

C18H19C1N2°3S (378.9) Calc: C 57 . 06 H 5 - 05 N 7- 39 Found: 56 . 95 5.18 7.20 L) 3- ( 2-p-bromophenylpropionyl )-2 , 3 , 4 , 5-tetrahydro-lH-5- benzazepine-7-sulfonamide Solvent-free p-bromohydratropic acid chloride, produced from 8.0 g ( 35 millimole) of p-bromohydratropic acid with S0C12 in chloroform, was added at +5°C to 7.92 g ( 35 millimole) of 2 , 3 , 4 , 5-tetrahydro-lH-3-benzazepine 7-sulfonamide in 100 ml of anhydrous pyridine. After standing overnight at 20°C, the pyridine was distilled off in vacuo. The residue was suction filtered after trituration with water/hydrochloric acid, dissolved hot in 2N sodium hydroxide solution and extracted with chloroform. The alkaline aqueous phase was stirred into ice/hydrochloric acid. The mixture was extracted with chloroform and the chloroform phase was thoroughly 7.9 g of foam-like sulfonamide were obtained.

C19H21BrN2°3S (437.4) Calc: C 52.16 H 4.84 N 6.41 Found: 52.00 4.6l 6.39 M) 2 , 3 » , 5-tetrahydro-lH-5-Penzaze ine-7-sulfonamide a) I3O.6 g (0.688 mole) of 3-acetyl-2 , 3 , 4 , 5-tetrahydro-lH-3-benzazepine (m.p.: 60 - 63°C) were introduced portion-wise at -5°C to 0°C into 588 g (5.Ο6 mole) of chlorosulfonic acid over 1 l/2 hours. After stirring for 4 hours at -5°C to 0°C the reaction mixture was poured onto ice and extracted with benzene. 164 g of viscous oil remained from the dried and evaporated benzene extract. b) The crude sulfochloride obtained according to a) and 400 ml of concentrated ammonia were warmed slightly on a water bath. From the clear solution which quickly originated were crystallized after cooling 84.7 g of colorless 3-acetyl-2, 3,4, 5-tetrahydro-lH-3-benzazepine-7-sulfonamide of m.p. 177 - 180°C. By extraction of the mother liquor with ethyl acetate were obtained a further 7.6 g.M.p. : 176 - 178°C.

C12H16N2°3S (268·3) Calc: C 53.72 H 6.01 N 10.44 Found: 53.50 6.10 10.20 c) 92.3 g of the sulfonamide obtained according to b) were refluxed for 15 hours in 1 1 of half-concentrated hydrochloric acid. The residue, obtained by evaporation to dryness and evaporation with ethanol several times, was admixed with an equivalent of IN sodium hydroxide solution. By warming, triturating and cooling, 72.8 g (2/l) there resulted 47.2 g of colorless 2,3,4,5- tetrahydro-lH-3-henzazepine-7-sulfonamide . M.p. : 225 228°C.

C10H14N2°2S (226·3) Calc: C 53.07 H 6.25 N 12.37 Found: 52.50 6.17 12.24 The new sulfonamides of formula II specified in the following table have been prepared according to the processes described in Examples C, D, K, I and Acylation analogously n A M.p. to.

Ri example : 3-Methy1phenyl- 1 - 240 - 247°C C -Methy1phenyl 1 - 230 - 235°C C 2-Methoxyphenyl- 1 - 232 - 238°C C -Methoxyphenyl- 1 - 220 - 225°C C 3-Trifluoro- methylphenyl- 1 - 250 - 255°C C Naphthyl-(l)- 1 - 240 - 2 5°C C 1,2,3, -tetra-hydronaphthyl- 1 -CH2- foamy D (1) Indanyl-( 1 )- 1 -CH2- 160 - 165°C D Phenyl- 1 -CH2- 182 - 187°C C Phenyl- 1 -CH- 199 - 201°C D CH3 Phenyl- 1 -CH- 158°C D 1 C2H5 Benzoyl- 1 -CH2- 151 - 153°C ·* 1 -CHg-CHg- 187 - 189°C D Phenyl- 1 -CHg-CHg- 222 - 227°C C 4-Methy1phenyl- 1 -CH2-CH2- 154 - 160°C D -Chlorophenyl- 1 -CHg-CHg- 155 - l6l°C D 3-Chlorophenyl- 1 -CH2-CH2- 172 - 17 °C D -Trifluoro-methylphenyl- 1 -CH2~CH2- 184 - 186°C D *) from benzoyl ethyl acetate and 1 , 2 , 3 , 4-tetrahydro- Acyla- tion analog¬ A M.p.

Rl n ously to example: -Methoxyphenyl- 1 166-167°C D 2-Methoxyphenyl- Γ -CH2-CH2- 1 5_1 6°C D Phenyl- 1 -CH9-CH- 214-215°C C CH3 Phenyl- 1 -CH-CH2- 16 -166°C C CH3 Phenyl- 1 -CH-CH9- solid foam D C2H5 Phenyl- 1 - H2- 130-13 °C D Phenyl- 1 -CH-CH9- 16 -169°C C CH(CH3)2 Phenyl- 1 -CH-CHQ- 2 6-250°C C C6H5 Phenyl- 1 -CHg-CHg-CHg- 140-1½6°C C The following examples illustrate the preparation of the compounds according to the invention and also the preparation of pharmaceutical compositions containing them as active ingredient: Example 1 1—Γ2—( -phenylpropionyl ) -1 , 2 , 3» 4-tetrahydroisoquinoline-7-sulfonyl ] -3-cyclohexylurea 1. g (0.12 mole) of 2-( 3-phenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 222 - 227°C) were evaporated in vacuo with an equimolar quantity of IN sodium hydroxide solution (120 ml) and 200 ml of ethanol. After drying for 30 minutes at 80°C/l2 mm Hg the thus prepared sodium salt of the sulfonamide was suspended in 1 1 of nitrobenzene and added dropwise to 15.05 g (0.I2 mole) of cyclohexyl isocyanate. After 5 hours stirring at an internal temperature of 95°C the reaction mixture was cooled. The centrifuged precipitate was dissolved in hot water, the solution was extracted with ether after cooling and stirred into an excess of con-centrated hydrochloric acid/ice. The preceipitate was washed with much water, well dried and taken up in ethanol. After evaporation in vacuo the residue was taken up in hot ethyl acetate. The ethyl acetate solution dried with sodium sulfate was filtered and evaporated in such a way that the solution remained clear at the boiling point. On cooling the solution, there crystallized 31.5 g of sulfonylurea.

M.p.: 135-1½0°C (DC 1 spot).

C25H31N30 S (469.6) Analogously to this process were obtained: a) 1-Γ 2-(2-Phenylpropionyl)-l,2< 3 , 4-tetrahydro- isoquinoline-7-sul onyl] -3-cyclohexylurea from 10.3 g of 2-( 2-phenylpropionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 199-201°C) and 3.7 g of cyclohexyl isocyanate.

Yield: 10.6 g; m.p.: 195 - 197°C (from ethanol).

C25H31N3o4S (469.5) Calc: C 63.95 H 6.65 N 8.95 Found: 63.80 6.75 8.80 b) l-r2-Acetyl-i , 2, 5 , 4-tetrahydroisoquinoline-7- sulfonyl1 -3-cyclohexylurea from 11.1 g of 2-acetyl-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 220 - 224°C) and 5. 6 g of cyclo-hexyl isocyanate.

Yield: 8.4 g, m.p.: 100 - 110°C (acid precipitation) C18H25N304S (379.4) Calc: C 56.98 H 6.64 N 11.07 Found: 56.80 6.71 10.70 c) l-r2-Benzoyl-l , 2, 3 4-tetrahydroisoquinoline-7- sulfonyl1 -3-cyclohexylurea from 18.0 g of 2-benzoyl-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 222 - 224°C) and 7.15 g of cyclohexyl isocyanate, Yield: 10.4 g, m.p.: 150-155°C (methyl ethyl ketone) C23H2?N30 S (441.5) Calc: C 62.57 H 6.16 N 9.52 Found: 62.60 6.12 9.31 d) 1-Γ 2-( 3-Methylbenzoyl)-l , 2, 3, 4-tetrahydroisoquinoline- - - - isoquinoline-7-sulfonamide (m.p.: 240 - 247°C) and 7.5 g of cyclohexyl isocyanate.

Yield: 5.2 g,m.p.: 154 - 158°C (obtained by trituration with ether after column chromatography) .

C2 H29N3° S (455.6) Calc: C 63.3Ο H 6.42 N 9.22 Found: 63.00 6.27 8.79 e) 1-Γ2-(4-Methylbenzoyl )-l , 2 , 3.4-tetrahydroisoquinoline- 7-sulfonyll -3-cyclohexy.lurea from 21.4 g of 2-(4-methylbenzoyl)-l , 2, 3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 230 - 235°C) and 8.14 g of cyclohexyl isocyanate.

Yield: 6.2 g m.p.: 130 - 135°C (obtained by trituration with ether after column chromatography) .

C24H29N3°4S ( 55-6) Calc: C 63.30 H 6.42 N 9.22 Found: 63.00 6.40 8.79 f) l-r2-(2-Methyl-5-Phenyl-propionyl)-l, 2, 3,4- tetrahydrois quinoline-7-sulfonyll -3-cyclohexylurea from 14.34 g of 2-(2-methyl-3-phenyl-propionyl)- 1 , 2, 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 214 -215°C) and 5.01 g of cyclohexyl isocyanate.

Yield: 9.8 g,m.p.: 104 - 110 °C (acid precipitation) C26H33N30 S (483.7) Calc: C 64.58 H 6.88 N 8.69 Found: 64.50 6.93 8.72 g) 1-Γ2-( c-Naphthoyl )-l , 2 , 5. -tetrahydroisoquinoline-7- sulfonyll -3-cyclohexylurea from 18.3 g of 2-(a-naphthoyl)-l, 2, 3,4-tetrahydro- of cyclohexyl isocyanate.

Yield: 4.5 g,m.p.: 170 - 175°C (obtained by trituration with acetone after column chromatography).

C2?H29N30 S (491.6) Calc: C 66.00 H 5.95 N 8.55 Found: 65-90 5.85 8.74 h) 1-Γ2-( 2-Methoxybenzoyl )-l , 2 , 3 , 4-tetrahydroisoquinol ine- 7-sulfonyl ] -3-cyclohexylurea from 13.9 g of 2-( 2-methoxybenzoyl )-l , 2 , 3 , 4-tetrahydro-isoquinoline-7-sulfonamide (m.p.: 232 - 238°C) and 5.02 g of cyclohexyl isocyanate.

Yield: 9.5 g m.p.: 145 - 150°C (ethanol).

C24H29N3°5S (^71.6) Calc: C 61.14 H 6.20 N 8.91 Found: 6Ο.6Ο 6.18 9-09 i ) 1-f 2-( -Methoxybenzoyl )-l , 2 , 3 , -tetrahydroisoquinoline- 7-sulfonyl] -3-cyclohexylurea from 13.9 g of 2-(4-methoxybenzoyl)-l , 2, 3,4-tetrahydro-isoquinoline-7-sulfonamide (m.p.: 220 - 225°C) and 5.02 g of cyclohexyl isocyanate.

Yield: 7.0 g m.p.: 196 - 198°C (methyl ethyl ketone).

C24H29N3°5S (471.6) Calc: C 61.14 H 6.20 N 8.91 Found: 60.80 6.17 8.86 j ) l-r2-Phenacetyl-l , 2, 3< 4-tetrahydroisoquinoline-7- sulfonyl1-3-cyclohexylurea from 5.57 g of 2-phenacetyl-l, 2, 3, -tetrahydro-isoquinoline-7-sulfonamide (m.p.: 182 - 187°C) and 2.12 g of cyclohexyl isocyanate. acetate and ether) .

C2 H29N3° S 55 . 6 ) Calc: C 63.28 H 6.42 N 9.22 Found: 63 .00 6 . 52 9.14 k) 1—Γ2-( 3, 3-Diphenylpropionyl )-l , 2, 3 , 4-tetrahydro- isoquinoline-7-sulfonyl ] -3-cyclohexylurea from 12.6 g of 2-( 3 , 3-diphenyl-propionyl ) -1 , 2 , 3 , 4-tetra-hydroisoquinoline-7-sulfonamide (m.p.: 2 6 - 250°C) and 3.80 g of cyclohexyl isocyanate.

Yield: 9.55 g^.p.: 171 - 174°C (acetone and addition of water) .

C31H35N304S (5^5.7) Calc: C 68. 23 H 6 .46 N 7. 70 Found: 68.20 6.34 7 . 65 1 ) l-Γ2-( 4-Phenylbutyryl ) -1 , 2, 3 , 4-tetrahydroisoquinol ine- 7-sulfonyl ] -3-cyclohexylurea from 7 . 17 g of 2-(4-phenylbutyryl)-l,2,3,4-tetra-hydroisoquinoline-7-sulfonamide (m.p. : 140 - 146°C) and 2. 51 g of cyclohexyl isocyanate.

Yield: 2.7 g,m.p. : 77 - 85°C (ether and addition of petroleum ether) . ' C26H33N30 S (483.7) Calc: C 64.58 H 6.88 N 8 . 69 Found: 64.80 6.79 8.39 m) 1-Γ2-( 3-Benzoyl-propionyl )-l ,2, 3, 4-tetrahydroisoquinoline-7-sulfonyl1-3-cyclohexylurea from 3.37 g of 2-( 3-benzoyl-propionyl )-l , 2, 3,4-tetrahydroisoquinoline-7-sulfonamide (m.p. : 187 - 189°C) and 1.14 g of cyclohexyl isocyanate.

C26H31N305S (497.7) Calc: C 62.77 H 6.28 N 8.45 Found: 62 . 50 6.20 8. 26 n) 1-Γ2-( 3-p-methylphenyl-propionyl )-l , 2 , 3 , 4-tetrahydro- isoquinoline-7-sulfonyll-3-cyclohexylurea from 6.10 g of 2-( 3-p-methylphenyl-propionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 15 - 160°C) and 2 . 13 g of cyclohexyl isocyanate.

Yield: 4.5 g,m.p.: 134 - 136°C (ethyl acetate).

C26H33N304S (483.7) Calc: C 64.58 H 6.88 N 8 . 69 Found: 64. 50 6.89 8 . 52 o) 1-Γ2-( 3-P-trifluoromethylphenyl-propionyl )-l , 2 , 3 » 4-tetrahydroisoquinoline-7-sulfonyl1-3-cyclohexylurea from 3. 10 g of 2-( 3-p-trifluoromethylphenyl-propionyl )- 1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 184- 186°C) and 0.95 g of cyclohexyl isocyanate.

Yield: 1.7 g,m.p.: 130 - 133°C (ethyl acetate).

C26H30F3N3°4S (5 7'6) Calc: C 58. 09 H 5 . 63 N 7.82 Found: 58.10 5-80 7.81 p) 1-Γ2-( 3-( 2-Methoxyphenyl ) -propionyl )-l , 2, 3, 4-tetra-hydroisoquinoline-7-sulfonyl1-3-cyclohexylurea from 11.2 g of 2-( 3-( 2-methoxyphenyl )-propionyl )-1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 232 - 238°C) and 3. 76 g of cyclohexyl isocyanate.

Yield: 11.1 g, m.p. : 194 - 196°C (decomp . ) ( ethanol ) .

C26H33 305S (499.6) Calc: C 62 . 51 H 6.66 N 8.41 q) l-Γ2-( 2-Phenylbutyryl )-l , 2 , , 4-tetrahydroisoquinoline-7-sulfonyl1-5-cyclohexylurea from 6.9 g of 2-( 2-phenylbutyryl )-l , 2 , 3 , 4-tetra-hydroisoquinoline-7-sulfonamide (m.p.: 158°C) and 2.41 g of cyclohexyl isocyanate.

Yield: 5-7 g,m.p.: 181 - 185°C (ethanol).

C26H33N3O^S (483.7) Calc: C 64.58 H 6.88 N 8.69 Found: 64.60 7-02 8.70 Example 2 Sodium salt of 1-f 2-( 3-m-chlorophenyl-propionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl1-3-cyclohexylurea 11.4 g (0.03 mole) of 2-( 3-m-chlorophenyl-propionyl )-1,2,3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p. : 172 - 174°C), a solution of 1.68 g (0.03 mole) of potassium hydroxide solution in 20 ml of water and 100 ml of ethanol were together evaporated in vacuo. The dry potassium salt of the sulfonamide was taken up in 300 ml of nitrobenzene. 3.76 g (0.03 mole) of cyclohexyl isocyanate were dropped into the reaction mixture which was then stirred for 5 hours at 100°C. The nitrobenzene was removed by means of steam distillation. The residue obtained was dissolved in hot water. The hot solution was filtered through a G 3 frit into a stirred mixture of ice and an excess of concentrated hydrochloric acid. The precipitate was treated after suction filtration with charcoal in a hot ethanolic solution. 1 equivalent of sodium hydroxide solution, dissolved in a minimal quantity of water, was added to the filtered ethanolic solution. On coolin there cr stallized 6. of the desired sodium salt. Decomposition at 280°C.

C^H ClN^S a ( 526.1) Calc: C 57.08 H 5.56 N 7-99 Found: 57-30 .67 7.80 Example 3 Sodium salt of 1-Γ2-( 3-phenyl-butyryl )-l .2 , 3 , 4-tetrahydro-isoquinoline-7-sulfonyl1-3-cyclohexylurea .12.53 g (0.035 mole) of 2-(3-phenylbutyryl)-l,2,3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 164 - l66°C), 35 ml of IN sodium hydroxide solution and 100 ml of ethanol were evaporated in vacuo. The dry sodium salt of the sulfonamide was suspended in 300 ml of nitrobenzene and admixed dropwise with .38 g (0.035 mole) of cyclo-hexyl isocyanate. After 5 hours stirring at 100°C the reaction mixture was centrifuged. The precipitate was dissolved in hot water. The cooled solution was extracted with ether, the aqueous solution was again heated and filtered through a G 3 frit into a stirred mixture of ice and an excess of concentrated hydrochloric acid. The precipitate was dissolved, after suction filtration, in ethanol and mixed with a solution of 0.035 mole of sodium hydroxide solution dissolved in a minimal quantity of water. 8.3 g of colorless sodium salt were obtained. M.p.: 280 - 285°C (decomp).

C26H32N30 SNa (5Ο5.6) Calc: C 61.72 H 6.38 N 8.30 Found: 61.40 6.42 8.30 Analogously to Example 2 were obtained the following compounds: a) Sodium salt of l-f2-butyryl-l , 2 , 3, 4-tetrahydroiso- quinoline-7-sulfonyl1 -3-cyclohexylurea from 8.46 g of 2-butyryl-l , 2 , 3, 4-tetrahydroiso-quinoline-7-sulfonamide (m.p. : 159 - l62°C) and 3.76 g of cyclohexyl isocyanate.

Yield: 10.0 g of sodium salt; m.p.: > 300°C (ethanol).

C20H28N3° SNa ( 29·5) Calc: C 55.93 H 6.57 N 9.78 Found: 55.60 6.68 9.66 b) Sodium salt of 1 f 2-( 3-phenylpropionyl )-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonyl1-5-n-butylurea from 10.3. g of 2-( 3-phenylpropionyl)-l , 2 , 3, -tetra-hydroisoquinoline-7-sulfonamide (m.p.: 222 - 227°C) and 2.98 g of butyl isocyanate.

Yield: 10.1 g of sodium salt; m.p. 244 - 245°C (decomp.) (ethanol ) .

C23H28N3°4SNa ^65.6) Calc: C 59.35 H 6.06 N 9.02 Found: 59.20 6.24 8.92 c) Sodium salt of l-f2-( 3-methoxyphenylpropionyl )- 1,2, 3.4-tetrahydroisoquinoline-7-sulfonyll-3-cyclohexyl-urea from 6.75 g of 2-( 3-p-methoxyphenylpropionyl )-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: l66 - l67°C) and 2.26 g of cyclohexyl isocyanate.

Yield: 6.8 g of sodium salt; m.p.:> 255°C (decomp), (ethanol).

C26H32N305SNa (521.6) Calc: C 59.87 H 6.18 N 8.06 Found: 9-70 6.37 8.0 d) Sodium salt of l-f2-( 3-phenylhexanoyl )-l , 2, 3, 4- tetrahydroisoquinoline-7-sulfonyll -3-cyclohexylurea from 11.6 g of 2-( 3-phenylhexanoyl ) -1 , 2, 3,4-tetra- hydroisoquinoline-7-sulfonamide (m.p.: 130 - 134°C) and 3.76 g of cyclohexyl isocyanate.

Yield: 5.65 g of sodium salt; m.p.: 255 - 260°C (methanol).

C28H36 30 SNa (533.7) Calc: C 63.ΟΟ H 6.81 N 7.88 Found: 63.30 7.05 7.59 e) Sodium salt of 1-f 2-( 5-phenylpropionyl )-l , 2 , 3, 4- tetrahydroisoquinoline-7-sulfonyll -3-adamantyl-( 1 )-urea from 6.22 g of 2-( 3-phenylpropionyl )-l , 2 , 3 , 4-tetra- hydroisoquinoline-7-sulfonamide (m.p. : 222 - 227°C) and 3.20 g of adamantyl-( 1 ) isocyanate.

Yield: 1.08 g of colorless sodium salt; decomp. >26.0°C (acetone and addition of water).

C29H3 N30 SNa (5 3.7) Calc: C 64.06 H 6.3Ο N 7.73 Found: 64.20 6.6Ο 7.57 . f ) Sodium salt of l-[2-( 3-phenyl-valeryl )-l , 2, 3,4- tetrahydroisoquinoline-7-sulfonyl] -3-cyclohexylurea from 13.6 g of 2-( 3-phenylvaleryl )-l , 2, 3, -tetrahydro-isoquinoline-7-sulfonamide and 5·0 g of cyclohexyl isocyanate .

Yield: 7.65 g of sodium salt; m.p.: 272 - 280°C (decomp.) ( ethanol ) .

C27H3 N30 SNa ( 19.6) Calc: C 62.40 H 6.60 N 8.10 Found: 62.20 6.73 8.00 g) Sodium salt of l-f2-( -P-chlorophenylpropionyl ) -1 , 2 , - , 4-tetrahydroisoquinoline-7-sulfonyl1-3-cyclohexylurea from .55 g of 2-( 3-p-chlorophenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 155 - l6l°C) and 1.5 g of cyclohexyl isocyanate.

Yield: 3.5 g of sodium salt; m.p.: 260 - 263°C (decomp.) ( ethanol ) .

C25H29Cl 30 SNa (526.1) Calc: C 57.08 H 5.56 N 7.99 Found: 56.90 5. 3 7.80 h) Sodium salt of l-r2-isovaleryl-l , 2, 5 , 4-tetrahydro-isoquinoline-7-sulfonyl] -3-cyclohexylurea from 10.4 g of 2-isovaleryl-l , 2, 3 , 4-tetrahydro-isoquinoline-7-sulfonamide (m.p.: 142 - 145°C) and 4.38 g of cyclohexyl isocyanate.

Yield: 8.4 g of sodium salt; m.p.: 290°C (decomp). (ethanol) C21H30N30 SNa (443.6) Calc: C 56.87 H 6.82 N 9.47 Found: 56.80 6.87 9.30 i ) Sodium salt of l-f2-( 3-trifluoromethylhenzoyl )- 1,2, 3.4-tetrahydroisoquinoline-7-sulfonyll-3-cyclohexylurea from 11.4 g of 2-( 3-trifluoromethyl-benzoxy)-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 250 - 255°C) and 3.73 g of cyclohexyl isocyanate.

Yield: I.65 g of sodium salt; m.p.: 280 - 285°C (decomp.) (ethanol + ether).

C24H25F3N3°4SNa (531.6) Calc: C 5 .23 H 4.76 N 7.91 Found: 53.90 5.02 7.70 j ) Sodium salt of l-r2-benzoylacetyl-l , 2, 3, -tetra- hydrolsoquinollne-7-sulfonyl]-3-cyclohexylurea from 1.88 g of 2-benzoylacetyl-l , 2 , 3 , -tetrahydro- isoquinoline-7-sulfonaraide (m.p. : 151 - 153°C) and 0.66 g of cyclohexyl isocyanate.

Yield: 0.5 g of sodium salt; m.p.: 230 - 231°C (decomp.) After recrystallisation from methanol and column chromatography.

C25H28N305SNa (505.6) Calc: C 59.39 H 5.58 N 8.31 Found: 59.20 5.73 8.14 k) Sodium salt of 1-Γ 2-( 1.2.3. -tetrahydronaphthyl-( 1 ) -acetyl )-l ,2,3. -tetrahydroisoquinoline-7-sulfonyl] -3- cyclohexylurea from 15. g of 2-(l , 2, 3,4-tetrahydronaphthyl-(l)-acetyl)- 1 , 2, 3, -tetrahydroisoquinoline-7-sulfonamide and 5·0 g of cyclohexyl isocyanate.

Yield: 10.0 g of sodium salt; m.p.: 268 - 270°C (decomp.) ( ethanol ) .

C28H3 N30 SNa (531.6) Calc: C 63.28 H 6.45 N 7.90 Found: 63.50 6.76 7.82 1 ) Sodium salt of l-f2-( 3-( 5-chloro-2-methoxyphenyl )-propionyl )-l , 2, 3, -tetrahydroisoquinoline-7-sulfonyl] -3- cyclohexylurea from 20.4 g of 2-( 3-( 5-chloro-2-methoxyphenyl ) -propionyl)-l , 2, 3 , -tetrahydroisoquinoline-7-sulfonamide and 6.26 g of cyclohexyl isocyanate.

Yield: 11.5 g of sodium salt; decomp. > 270°C (ethanol).

C H ClN 0 SNa 6 1 Calc: C 56.16 H 5.62 N 7-56 Found: 55.95 5-62 7.30 m) Sodium salt of 1-Γ2-( indanyl-( 1 ) -acetyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl ] -3-cyclohexylurea from 11.1 g of 2-( indanyl-( 1 )-acetyl )-l , 2 , 3, 4-tetra-hydroisoquinoline-7-sulfonamide (m.p.: l60 - l65°C, decomp.) and 3.76 g of cyclohexyl isocyanate.

Yield: 6.4 g of sodium salt; m.p.: 273 - 276°C (decomp.) ( isopropanol/water) .

C27H32N30 SNa (517.6) Calc: C 62.65 H 6.23 N 8.12 Found: 63.00 6.04 8.35 n) Sodium salt of 1-Γ -( 4-methyl-3-phenylval eryl )-l , 2 , 3, -tetrahydroisoquinoline-7-sulfonyl] -3-cyclohexylurea from 11.6 g of 2-( 4-methyl-3-phenylvaleryl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 164 - l69°C) and 3.7 g of cyclohexyl isocyanate.

Yield: 4.9 g of sodium salt; m.p.: 253 - 259°C (ethanol).

C28H36 30 SNa (533-7) Calc: C 63.02 H 6.80 N 7.87 Found: 62.90 7.08 8.11 o) Sodium salt of 1 -[ 2-( 2-p- luorophenvlnropionvl )-1 t 2r f -tetrahvdroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 3.99 g of 2-( 2-p-fluorophenyl-propionyl )-l , 2, 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 165 - l69°C) and I.52 g of cyclohexyl isocyanate.

Yield: 2.6 g of sodium salt; m.p.: 218 - 223°C (decomp.) ( ethanol ) Calc: C 58.93 H 5-7 N 8.25 Found: 58.60 6.05 8.40 p) Sodium salt of 1— f 2—( 2-( 3.4-dichlorophenyl )-propionyl )-1,2, 3 -tetrahydroisoquinoline-7-sulfonyl 1-3-cyclohexyl-urea from 4.8 g of 2-( 2-( 3, 4-dichlorophenyl ) -propionyl )-1 , 2, 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 200 -202°C) and 1.59 g of cyclohexyl isocyanate.

Yield: 2.47 g of colorless sodium salt; m.p.: 238 - 240°C (decomp.) ( ethanol/benzene ) .

C25H28Cl2N30 SNa (560.5) Calc: C 53.61 H 5.01 N 7.50 Found: 53.60 5-13 7.43 q) Sodium salt of 1-f 2-( 2-p-methylphenyl-propionyl ) -1,2, 3.4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl urea from 8.1 g of 2-( 2-p-methylphenyl-propionyl )-l , 2, 3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 165 - l68°C) and 3.10 g of cyclohexyl isocyanate. The precipitate centri-fuged as in Example 3 under addition of cyclohexane was immediately recrystallized from ethanol/methanol. 6.5 g of colorless sodium salt were obtained. M.p.: 233 - 235°C.

C26H32N3°4SNa (505.6) Calc: C 61.72 H 6.39 N 8.32 Found: 61.70 6.65 . 8.57 r) Sodium salt of 1-f 2-( 2-p-trifluoromethylphenyl propionyl )-l , 2, 3< 4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexylurea from 6.5 g of viscous 2-( 2-p-trifluoromethylphenyl - - - - 2.17 g of cyclohexyl isocyanate. The centrifuged precipitate was shaken with 2N hydrochloric acid and chloroform. The chloroform evaporation residue was purified by means of column chromatography on silica gel ( cyclohexane : acetone : glacial acetic acid = 10: 5:0.1). 2.4 g of foam-like sulfonylurea were obtained from which was prepared in the usual manner the colorless sodium salt. M.p. : 224 - 227°C (decomp) (ethanol and some benzene ) . c 26H29F3N3°4SNa ( 559 . 6 ) Calc: C 55.85 H 5.23 N 7-52 Found: 56.10 ■ 5.17 7.64 s) Sodium salt of l-r2-(2-p-ethoxyphenylpropionyl)-1 , 2 , 3 4-tetrahydroisoquinoline-7-sulfonyl -3-cyclohexyl-urea from 5 · 0 g of foamy 2- ( 2-p-ethoxyphenylpropionyl )-1, 2, 3,4-tetrahydroisoquinoline-7-sulfonamide and 1. 77 g of cyclohexyl isocyanate. After the end of the reaction a 3 to 4 fold volume of absolute ether was added and the light-yellow precipitate was suction filtered. By recrystallisation from ethanol/charcoal 6.0 g of crude sodium salt were obtained.

M.p. : 220 - 224 °C .

To purify this salt, it was dissolved in 2N hydrochloric acid and chloroform. The chloroform evaporation residue ( 5 · 7 g) was subjected to chromatography as described in example 3r and the obtained foamy colorless sulfonylurea was subsequently converted into its sodium salt.

Yield: 1.18 g,m.p.: 224 - 226°C.

Calc: C 60.55 H 6.40 N 7.85 Found: 60.75 6.50 7.80 t) Sodium salt of 1-f 2-( 2-p-n-propoxyphenylpropionyl )-1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyll -3-cyelohexyl-urea from 13.5 g of foamy 2-( 2-p-n-propoxyphenylpropionyl )-1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide and 4.62 g of cyclohexyl isocyanate analogously to example 3s.

M.p. of the colorless sulfonylurea: 122 - 124°C (acetone/ ether) .

C28H37N305S (527.6) Calc: C 63.65 H 7.08 N 7.96 Found: 63. 5 6.88 8.01 M.p. of the sodium salt: 232 - 234°C.

C28H36N3°5SNa - (5*9.6) Calc: C 61.20 H 6.6I N 7.65 Found: 61.25 6.78 7.88 u) Sodium salt of l-f2-( 2-p-Diphenyl-propionyl )- 1,2, 3,4-tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl urea from 6.6 g of 2-(2-p-biphenylpropionyl)-l , 2, 3,4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 188 - 192°C) and 2.I6 g of cyclohexyl isocyanate analogously to example 3s.

Yield: 1.5 g of colorless sodium salt; m.p.: 245 - 250°C (decomp . ) .

C31H3 N30 SNa (567.7) Calc: C 65.57 H 6.04 N 7.41 Found: 65.30 . 6.16 7-50 v) Sodium salt of 1-f 2~ ( 2-( a-naphthyl )-propionyl )-l , 2 , 5 , 4- tetrahydroisoquinoline-7-sulfonyl 1 -3-cyclohexylurea from 2. 65 g of 2-(2-(oc-naphthyl)-propionyl)-l,2, 3,4- tetrahydroisoquinoline-7-sulfonamide (m.p.: 203 - 207°C) and 0.93 g of cyclohexyl isocyanate analogously to example 3q . The obtained residue was recrystallized several times from ethanol/benzene . Ο.65 g of colorless sodium salt were obtained. M.p.: 263 - 265°C (decomp.). C29H32N30 SNa (541.6 ) Calc: C 64 . 31 H 5 .95 N 7 . 76 Found: 64.20 6.02 7 .90 w) 1-Γ 3- ( 2-p-bromophenyl-propionyl )-2 , 3,4, 5-tetrahydro-lH-3-benzazepine-7-sulfonyll-3-cyclohexylurea from 8. 7 g of foamy 3-( 2-p-bromophenyl-propionyl ) -2, 3,4, 5-tetrahydro-lH-3-benzazepine-7-sulfonamide and 2.74 g of cyclohexyl isocyanate. At the end of the reaction absolute ether was added to the mixture and suction filtered from the yellowish precipitate. This precipitate was shaken with 2N hydrochloric acid and chloroform. The chloroform evaporation residue was purified by means of column chromatograpjy on silica gel ( cyclohexane :acetone : glacial acetic acid = 30:10:0.2) and the colorless foamy sulfonylurea was triturated with acetone/methylethylketone which resulted in crystallisation.

M.p.: 208 - 210°C (decomp.) C26H32BrN30 S ( 562 . 5 ) Calc. : C 55 . 55 H 5.74 N 7.48 Found: 55 . 50 5. 63 7-38 x) 1—Γ3— ( 2-p-chlorophenylpropionyl )-2 , 3, 4 , 5-tetrahydro-lH-3-benzazepine-7-sulfonyl] -3-cyclonexylurea from 1.8 g of foamy 3-( 2-p-chlorophenylpropionyl )-2,3,4, 5-tetrahydro-lH-3-henzaze ine-7-sulfonamide and Ο.63 g of cyclohexyi isocyanate analogously to example 3w.

Crystalline sulfonylurea was obtained. M.p.: 205 - 207°C. C26H32C1N304S (518.1) Calc: C 6Ο.27 H 6.23 N 8.11 Found: 60.10 6.16 7.93 Example 4 1-Γ2-( 5-Phenylpropionyl )-l , 2 , 3, 4-tetrahydroisoquinol ine-7-sulfonyl ] -5-( 4-methy1 cyclohexyi ) -urea 4.0 g (9.6 millimole) of ethyl N-[2-( 3-phenylpropionyl ) - 1,2,3, -tetrahydroisoquinoline-7-su Ifonyl] -carbamate (m.p.: 138 - 141°C) and 1.02 g (10.2 millimole) of 4-methyl-cyclohexylamine (25 of cis-isomer and 75 ■ of trans-isomer approx.) were heated for 1 hour up to 100°C and for ½ hour up to 120°C in 5 ml of dimethylformamide (distilled over phosphorus pentoxide). After evaporation in vacuo the residue was taken up in IN hydrochloric acid.

The insoluble part was suction filtered and recrystallized from ethyl acetate.

Yield: 1.5} g m.p.: 155 - 158°C.

C26H33 30 S (483.7) Calc: C 64.58 H 6.88 N 8.69 Found: 64.70 6.92 8.79 Example 5 Sodium salt of 1-f2-( 3-phenyl-propionyl )-l , 2 , 3 , 4-tetra-hydroisoquinoline-7-sul onyl1-3-cycloheptylurea - - - 1,2, 3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamate (m.p.: 138 - 141°C) and 1.25 g (11 millimole) of cycloheptylamine were heated in 5 ml of anhydrous dimethyl-formamide for 1 hour up to 100°C and for ½ hour up to 130°C. After evaporation in vacuo the residue was treated with charcoal in hot ethanol. 1 equivalent of sodium hydroxide solution, dissolved in a minimal quantity of water, was added to the filtered ethanolic solution which was then cooled. 3.3 g of sodium salt were obtained. M.p.: 268 - 270°C (decomp.).

C26H32N3°4SNa (505.6) Calc: C 61.72 H 6.38 N 8.30 Found: 61.80 6.59 8.10 The following compounds have been prepared according to the same process: a) Sodium salt of 1— f 2- ( -phenylpropionyl )-l , 2, 3, 4-tetrahydroisoquinoline-7-sulfonyll -3-cyclohexylurea from .17 g of ethyl N-[ 2-( 3-phenylpropionyl )-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonyl] -carbamate (m.p. : 138 - 141°C) and 1.40 g of cyclooctylamine .

Yield: 3.8 g of sodium salt; m.p.: 270 - 275°C (decomp). (ethanol) C27H3 N30 SNa (519.7) Calc: C 62.41 H 6.60 N 8.09 Found: 62.10 6.45 7.89 b) Sodium salt of 1-f 2-( 3-phenylpropionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl 1 -5-cyclopentylurea from 4.17 g of ethyl N-[ 2-( 3-phenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl] -carbamate (m.p. : Yield: 3.0 g of sodium salt; m.p.: 260 - 262°C (decomp) ( ethanol ) .

C24H28N3°4SNa ( ^77 . 6 ) Calc: C 60.36 H 5.91 N 8. 80 Found: 60. 30 5- 99 8. 84 c ) Sodium salt of 1—f2—( 2-phenylpropionyl )-l , 2, 3 , 4-tetrahydroisoquinoline-7-sulfonyl ] -3- ( 4-methylcyclohexyl ) -urea from 4.00 g of ethyl N-[ 2-( 2-phenylpropionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl ] -carbamate and 1.02 g of 4-methylcyclohexylamine .

Yield:. 1.3 g of sodium salt; m.p.: 227 - 228°C (ethanol).

C26H32N3°4SNa (505.6) Calc.: C 6I.76 H 6.38 N 8.31 Found: 6I.6O 6 . 60 8.10 d) Sodium salt of 1-Γ2-( 2-phenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyll-5-adamantyl-( 1 ) -urea from 5.Ο5 g of ethyl N-[ 2-( 2-phenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl] -carbamate 2.50 g of adamantyl-( 1 ) -amine hydrochloride and 1.35 g of tri-ethylamine.

Yield: 0.8 g of sodium salt; m.p.: 225 - 229°C (ethanol). C29H3 N30 SNa (543. 7 ) Calc: C 64.07 H 6.30 N 7.73 Found: 63.80 6.30 7.58 e) Sodium salt of 1-Γ2-( 3-phenylbutyryl ) -1 , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonyl1-3- ( 4-methylcyclohexyl ) -urea from 4.5 g of ethyl N-[ 2-( 3-phenylbutyryl )-l , 2 , 3 , 4- Yield: 3.5 g of sodium salt; m.p.: 270 - 275°C (decomp) ( ethanol ) .

C27H3J¾N30 SNa (519.7) Calc: C 62.41 H 6.59 N 8.09 Found: 62.10 6.90 8.04 f ) Sodium salt of 1-f2-( 3-phenylbutyryl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sul onyl1-3-( 4-ethylcyclohexyl )-urea from 4.5 g of ethyl N-[ 2-( 3-phenylbutyryl )-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonylj-carbamate (m.p. : 105 - 108°C) and 1.47 g of 4-ethylcyclohexylamine .

Yield: 3.5 g of sodium salt; m.p.: 268 - 270°C (decomp) ( ethanol ) .

C28H36N30 SNa (533.7) Calc: C 63.02 H 6.80 N 7.87 Found: 62.85 6.86 7.98 g) Sodium salt of 1-f2-( 3-phenylbutyryl ) -1 , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonyl -3-adamantyl-( 1 ) -urea from 4.5 g of ethyl N-[ 2-( 3-phenylbutyryl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl ] -carbamate (m.p. : 105 - 108°C) and 1.74 g of adamantyl-( 1 ) -amine .

Yield: 2.05 g of sodium salt; m.p.: 263 - 265°C (decomp.) ( ethanol ) .

C3QH36N30 SNa (557.7) Calc: C 64.62 H 6.5I 7.5 Found: 64.30 6.83 7.56 h) Sodium salt of 1-f2-( 2-p-chlorophenylpropionyl ) -1,2.314-tetrahydroisoquinoline-7-sulfonyl ] -3-cyclohexyl-urea from 4.51 g of glassy ethyl N-[2-( 2-p-chlorophenyl- carbamate and 1.10 g of cyclohexylamine .

Yield: 0.8 g of sodium salt; m.p.: 228 - 230°C (decomp.) Example 6 1-Γ2-( 2-p-chlorophenylpropionyl ) -1,2, 3 , 4-tetrahydro-isoquinoline-7-sul onyl1 -3-cyclohexylurea A solution of 4. 23 g (11.2 millimole) of 2-(2-p-chlorophenylpropionyl ) -1 , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 1 7 - 150°C) and 1. 26 g (11.2 millimole) of potassium tert . -butylate in 30 ml of anhydrous dimethyl-formamide was admixed dropwise at 0 to +5°C with 1.50 g (11.2 millimole) of cyclohexyl isocyanate. The reaction mixture was stirred for 2 hours at 0 to +5°C. Then it was filtered and acidified with 2N hydrochloric acid.

The originating greasy precipitate was suction filtered and dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and the evaporation residue subjected to chromatography on a column of silica gel ( cyclohexane :acetone :glacial acetic acid = 40:20:0.4). After recrystallisation from ethyl acetate/ether 3.4 g of colourless urea were obtained. M.p.: 110 - 115°C.

C25H30C1N30 S (504.0) Calc: C 59 . 60 H 6.00 N 8.34 Found: 59 .40 6 . 17 8.44 1.0 g (1.985 millimole) of the above obtained urea (m.p. : 110 - 115°C) was dissolved in 2 ml of absolute ethanol with addition of 1.985 ml of IN sodium hydroxide solution. After evaporation to dryness and mixing with benzene and acetone there resulted crystallisation. The washed with cold ethanol, acetone and ether and dried Yield: 1.0 g of sodium salt; m.p.: 227 - 231°C (decomp.) C25H29ClN30 SNa (526.1) Calc: C 57.10 H 5- 6 N 7.99 Found: 57.20 5.62 7.97 The following compound has been prepared according to the same method: a) Sodium salt of 1—Γ 2— ( 2-p-bromophenylpropionyl )-1,2, 3, -tetrahydroisoquinoline-7-sulfonyl]-3-cyclohexyl-urea from 5.20 g of 2-( 2-p-bromophenylpropiony 1 )-l , 2 , 3, 4-tetrahydroisoquinoline-7-sulfonamide (m.p.: 146 - 148°C) and 3.70 g of cyclohexyl isocyanate.

Yield: 1.68 g of colorless sodium salt; m.p.: 222-225°C.

C25H29BrN30 SNa (570.5) Calc. : C 52.63 H 5.12 N 7.37 Found: 52.40 -2 7.28 M.p. of the free sulfonylurea: 109 - 112°C.

Example 7 Tablets with 5 mg of the sodium salt of 1—Γ 2— ( 2-p-bromo-phenylpropionyl ) -1 , 2 , 314-tetrahydroisoquinoline-7-sulfonyl ] - 3-cyclohexylurea 1 tablet contains Sodium salt of l-[2-( 2-p-bromophenyl propionyl )-l , 2 , 3 , 4-tetrahydroiso- quinol ine-7-sulfonyl ] -3-cyclohexylurea lactose corn starch polyvinylpyrrolidone Compounding procedure The active ingredient was intimately mixed with lactose and corn starch and evenly moistened with a 12. % (w/w) solution oi the polyvinylpyrrolidone in ethanol.

The mass was granulated through a 1.5 mm mesh screen, dried at 5°C and again passed through a 1 mm mesh screen.

The thus obtained granulate was mixed with magnesium stearate and pressed to tablets.

Weight of tablet: 120 mg Punch: 7 mm, flat, with facet and notch.

Example 8 Gelatin-capsules with.5 mg of the sodium salt of l-f"2-(2-p- bromophenyl propionyl ) -1 , 2 , 3 , -tetrahydroi soouinol ine-7- s l fony11-3-cyclohexylurea, 1 capsule contains Sodium salt of l-[ 2- ( 2-p-bromophenylpropiony1 ) - 1 , 2 , 3 , li-te trahydro! soqu inol itie-7-sulfonyl ] -3- cyclohexylurea 5.0 rag corn starch, dried . 95-0 mg 100.0 mg Compounding procedure: The substances were intimately mixed and granulated through a 0.75 mm mesh screen. The mass was filled into molds of gelatin-capsules of suitable size.

Filling of capsule: 100 mg Other compounds according to the invention may be used in pharmaceutical compositions instead of the compound employed in Examples 7 and 8. For example, the following compounds may be used: l-[ 2- ( 2-p-chloropheiaylp opionyl )-l , 2 , 3, 4-tetrahydroisoquino- tetrahydroisoquinol ine-7-sul ionyl ] -3-cyclohexylurea; sodium salt of 1- [ 2- ( - ( 3 , 4-dichlorophenyl )-propionyl ) -1,2,3, 4-te trahydroisoquinol ine-7-stilfonyl ] -3-cyclohexylurea sodium salt of l-[ 2-( 2-p-trifluoromethylphenylpropionyl )-1,2,3, -tetrahydroi soquinoline-7-sul fonyl ] -3-cyclohexylurea l-[ 3-( 2-p-bromophenyl-propionyl )-2 , 3 , -tetrahydro-lH-3-benzazepine-7-sul fonyl J -3-cyclohexylurea .

Claims (1)

1. [wherein R^ represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms; a phenyl group optionally substituted by a methoxy, methyl or trifluoromethyl group, a chlorine atom or a methoxy group in the 2-position and a chlorine atom in the 5-position; or an a-naphthyl , 1 , 2 , 3 , 4-tetrahydronaph hyl- (l), indanyl-(l) or benzoyl group; R9 and A are as defined in claim 1; and n represents the in eger lj and their physiologically compatible alkali metal and alkaline earth metal salts. 3. Compounds of the general formula [wherein R^ represents a phenyl group substituted by an alkoxy group containin '2 or 3 carbon atoms, by one or two chlorine atoms, or by a methyl or trifluo ome thyl group; or a biphenyl or a-naphthyl group; represents a cyclohexyl group; A represents an ethylidene group; and n represents the integer 1 or 2j and their physiologi cally compatible alkali metal and alkaline earch metal salts. k . l-[ 2-( 2-p-Bromophenyl-propionyl )-l , 2 , 3 } 4-tetrahydro-isoquinoline-7-sulfonyl] -3-cyclohexylurea. 5. l-[ 2-( 2-p-Chlorophenyl-propionyl ) -1 , 2 , , -tetrahydro isoquinoline-7-sulfonyl] -3-cyelohexylurea . 6. l-[ 2-( 2-p-Me thylphenyl -prop ionyl )-l ,2, 3, -tetra- - - - - 7. l-[2-( 2-( 3, -Dichlorophenyl )-propionyl )-l , 2 , 3,4-tetrahydroisoqui oline-7-sulfonyl]-3-cyclohexylurea. 8. l-[ 2- ( 2-p-Trifluoromethylphenyl-propionyl )-l , 2 , 3 , 4-tetrahydroisoquinoline-7-sulfonyl ] -3-cyclohexylurea . . l-[ 2-( 2-Phenylpropionyl )-l ,2,3, 4-tetrahydroiso-quinoline-7-sulfonyl] -3-cyclohexylurea. 10. l-[ 3-( 2-p-Bromophenyl-propionyl ) -2 , 3 , 4 , 5-tetrahydro lH-3-benzazepine-7-sulfonyl J -3-cyclohexylurea . 11. Compounds as claimed in any of claims 1 and 4 to 10 in the form of their physiologically compatible alkali metal and alkaline earth metal salts. 12. Compounds as claimed in any of claims 2,3 and 11 wherein the alkali metal salts are sodium salts. 13. A process for the preparation of compounds as claimed in claim 1 which comprises reacting an acyl-7-sulfonyl compound of formula with a compound of formula Y R0 III [wherein R-^ , A, and n are as defined in claim 1 and either X represents a free amino group and Y represents an isocyanate group or X represents a carbamate group of formula -NH-COO-Alk (wherein Alk represents a lower alkyl group) and Y represents a free amino group] and, if desired, subsequently converting the compound of formula I thus obtained into a salt thereof. 14. A process as claimed in claim 13 wherein the reaction is effected in an inert solvent or diluent. 15. A process as claimed in claim 1 wherein the inert solvent or diluent is dimethylformamide , dimethylsulfoxide or nitrobenzene. 16. A process as claimed in any of claims 13 to 15 wherein a sulfonamide of formula II is reacted with an isocyanate of formula III in the presence of an inorganic or tertiary organic base. 17. A process as claimed in any of claims 13 to l6 wherein a sulfonamide of formula II is reacted with an isocyanate of formula III at a temperature of from 50 to 150°C. 18. A process as claimed in any of claims 13 to 17 wherein an alkali metal salt of a sulfonamide of formula II is first formed and subsequently reacted with an isocyanate of formula III. 19. A process as claimed in any of claims 13 to 15 wherein a sulfonylcarbamate of formula II is reacted with an amine of formula III at a temperature of from 50 to 120°C. 20. A process as claimed in any of claims 13 to 19 wherein a compound of formula is reacted with a compound of formula Y III [wherein R^ , A, and n are as defined in claim 2 and X and Y are as defined in claim 13] whereby a compound of formula I as defined in claim 2 is obtained, the compound of formula I being, if desired, subsequently converted into an alkali metal or alkaline earth metal salt thereof. 21. A process as claimed in any of claims 13 to 19 wherein a compound of formula is reacted \vith a compound of formula Y R2 III [wherein R^ , A, and n are as defined in claim 3 and X and Y are as defined in claim 13] whereby a compound of formula I as defined in claim 3 is obtained, the compound of formula I being, if desired, subsequently converted into an alkali metal or alkaline earth metal thereof. 22. A process as claimed in claim 13 substantially as herein described. 23· A process for the preparation of compounds as claimed in claim 2 substantially as herein described in any of Examples 1 to 5, l(a) to l(q), 3(a) to 3(n) and 5(a) to 5(g)- 2k. A process for the preparation of compounds as claimed in claim 3 substantially as herein described any of Examples 3(o) to 3(x), 5(h), 6 and 6(a). t> 25 . Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 13 to 2k . 26 . Compounds as claimed in claim 2 when prepared by a process as claimed in claim 20 . 27 · Compounds as claimed in claim 3 when prepared by a process as claimed in claim 21 . 28. Pharmaceutical compositions comprising as active ingredient a compound as claimed in claim 1 in association with a pharmaceutical carrier or excipient. 29 . Compositions as claimed in claim 28 in the form of tablets or gelatine-capsules. 30 . Compositions as claimed in claim 28 or claim 29 in the form of dosage units. 31 . Compositions as claimed in claim 30 wherein each dosage unit contains from 1 to 20 mg of active ingredient. 32 . Compositions as claimed in claim 31 wherein each dosage unit contains 5m of active ingredient. 33 . Compositions as claimed in any of claims 28 to 32 wherein the active ingredient is a compound as claimed in claim 3. 34 . Compositions as claimed in any of claims 28 to 30 wherein the active ingredient is a compound as claimed in claim 2. 35 · Compositions as claimed in claim 3½ in the form of dosage units containing from 1 to 10 mg of active ingredient per dosage unit. 36 . Compositions as claimed in claim 35 containing about 5 of active ingredient per dosage unit. 37 . Compositions as claimed in claim 28 substantially as herein described. X 38. Pharmaceutical compositions substantially as herein described in Example 7 or Example 8. Fa oh a nrl PAror nnvpl pnrtipnimrl r-nngg g ITlPtihnd -and composition horoin diooloood . For the Applicants DR. EiNHOLO COHN AND PARTNERS