PL80584B1 - Isoquinoline derivatives used to lower blood-sugar content [CH540911A] - Google Patents

Abstract

Isoquinoline derivs. used to lower blood-sugar content. These isoquinoline derivs. (I): (where R1 is H, Cl, Br or 1-4C alkoxy and R2 is cyclohexyl or adamantyl-1) or their alkali salts, are prepd. by (a) ring-closure of (II): (where one A or B is -NH-CH2-CH2-C6H4-p-SO2-NH- CO-NH-R2 and the other group A or B is OH or a reactive gp.); or (b) by replacing S by O in isoquinoline thiourea; or (c) by methylating (I) where CH3 is H; or (d) by reacting sulphonylisocyanate deriv. with an amine H2N-R2; or (e) by reacting sulphonamide deriv. with Y-CO-NH-R2 (where Y is halogen, amino, OH or SH opt. substd. by (ar)alkyl or aryl) in presence of a base; or (f) by reacting a sulphonyl halide deriv. with a parabanic acid (III): or (g) by reacting with amine H2N-R2 or (h) by dealkylating a substd. urea deriv. using HCl, or (i) in prepn. of (I) where R1 is 1-4C alkoxy, alkylating a 7-hydroxyisoquinoline deriv. [CH540911A]

Description

Patent holder: Dr. Karl Thomae GmbH, Biberach n/Riss (Federal Republic of Germany) Method for preparing new isoquinoline derivatives The subject of the invention is a method for preparing new isoquinoline derivatives of the general formula 1, in which Ri is a hydrogen, bromine, chlorine atom or an alkoxy radical with 1 -4 carbon atoms and R2 is a cyclohexyl or adamantyl radical, optionally in the form of their salts with alkali metals, which have a very good effect on lowering blood sugar levels in low doses, with little toxicity and little side effect on blood pressure. New compounds of the general formula 1 are prepared by the following methods: by reacting a sulfonamide of the general formula 2, in which Ri has the above-mentioned meaning, especially its alkali metal salt, with an isocyanate of the formula 0=C=N- R2, in which R2 has the meaning given above. The reaction is preferably carried out by dissolving the sulfonamide of formula II in an inert solvent, preferably in a dipolar, aprotic solvent such as dimethylformamide, acetone or N-methylpyrrolidone, then preferably with a strong, anhydrous base, for example an alkoxide such as potassium tert-butylate, an alkali metal hydride or an alkali metal hydroxide, convert to the appropriate alkali metal salt and then add, while cooling, an isocyanate of the formula 0=C=N-R2 . The reaction is completed at a low or moderately elevated temperature, but especially at a temperature between -5°C and ambient temperature. Compounds of formula 1 are also prepared by cyclization of a compound of general formula 3, in which Ri has the above-mentioned meaning and the groups A or B denote a group of the general formula 4, in which R2 has the above-described meaning and one of the groups A or B denotes a hydroxyl group or an in situ reactable group such as a halogen atom, an alkoxy group - acidic, acyloxy or amine. The reactions are optionally carried out in a solvent such as toluene, pyridine, dimethylformamide or alcohol, preferably at temperatures from 0°C to 200°C. When A or B is a hydroxyl group, the reaction is preferably carried out in the presence of a water-separating agent, for example in the presence of cyclohexylcarbodiimide, phosphorus oxychloride, phosphorus pentachloride or an acid or water-separating device. The reaction can also be carried out using the compound of formula 3 as the starting product, without its prior isolation. Then, the compounds of formula 1 are prepared by replacing the sulfur atom with an oxygen atom in isoquinolinothiourea of the general formula 5, in which Ri and R2 have the meaning given above and R3 represents a hydrogen atom or an optionally substituted alkyl, aryl alkyl or aryl radical. The replacement of the sulfur atom with an oxygen atom is carried out by means of an oxidizing agent, for example by means of hydrogen peroxide, permanganate potassium or iodine, preferably in a solvent such as glacial acetic acid and at temperatures from 0°C to 50°C or, if R8 is hydrogen, also with a heavy metal oxide such as mercuric oxide, preferably in neutral solution a solvent such as benzene and at an elevated temperature, for example at the boiling point of the solvent used. 10 Compounds of formula 1 are further prepared by methylating a compound of general formula 6, in which Ra and R2 have the meanings given above, or an alkali metal salt thereof. The reaction is carried out using a methylating agent, for example methyl iodide , preferably in a solvent such as dimethylformamide, and especially in the presence of a base such as an alkali metal alkoxide, alkali metal hydroxide or carbonate, for example at temperatures from 0°C to 120°C. The reaction can also be carried out without a solvent. Another method of preparing compounds of formula 1 consists in reacting a sulfonyl isocyanate of the general formula 7, in which Ri has the above-mentioned meaning, with an amine of the general formula NH2-Ra, in which R2 has the meaning given above. The reactions are preferably carried out in an inert solvent such as benzene and at temperatures up to the boiling point of the solvent used. However, the amine of the general formula H-R2 may also serve as a solvent. Compounds of the formula 1 are also prepared by reacting a sulfonamide of the general formula 2, in which Ri has the above-mentioned meaning, or its salt with an alkali metal, with a compound of the general formula 8, in which R2 has the meaning given above and Y represents a halogen atom, an amino group or a hydroxyl or mercaptan group, optionally substituted with an alkyl, arylalkyl or alkyl radical. The reaction is optionally carried out in the presence of an inorganic base such as potassium carbonate in a melt, for example at temperatures of 50°C-200°C, or in an inert solvent such as dimethylformamide, especially in the presence of a base such as an alkali metal alkoxide and at low temperature, at example at a temperature of 0°C - 50°C. Then the compounds of formula 1 are prepared by reacting sulfonic acid chloride of the general formula 9, in which Ri has the above meaning and Hal is a chlorine or bromine atom, with parabanic acid of the formula general 10, in which R2 has the meaning given above - 55 and subjecting the reaction product to hydrolysis. The reaction is preferably carried out in an anhydrous solvent, for example in absolute benzene or toluene and in the presence of an inorganic or organic tertiary base, especially 60 in a stoichiometric amount, for example triethylamine, at elevated temperature, on. example at the boiling point of the solvent used. Then, the produced parabanic acid sulfonyl compound is hydrolyzed, both in acidic and alkaline media. If the hydrolysis is carried out under mild conditions, for example at ambient temperature, an intermediate product of the general formula 11 is obtained, in which Ri and R have the meanings given above, which is then, for example at elevated temperature, subjected to complete hydrolysis. Compounds of formula 1 are also prepared by reacting a compound of general formula 12, wherein Ri has the meaning given above and Z is a halogen atom, a hydroxyl or mercapto group, an optionally substituted alkyl, arylalkyl or aryl group, or an optionally amino group optionally mono- or di-substituted, with an amine of the general formula NH-R, in which R2 has the meaning given above. The reaction is preferably carried out in a solvent such as dioxane, optionally in the presence of an inorganic base or a tertiary organic base, example of triethylamine, at temperatures from 0°C to 200°C, but especially at the boiling point of the solvent used. In this reaction, the amine with the general formula NH-R2 can also play the role of a solvent, and it is also advantageous to carry out this reaction in the presence of a substance that accelerates the reaction, for example in the presence of a salt of the amine with the general formula NH-Rj, such as its acetate. formula 1 is also prepared by dealkylation of a urea of general formula 13, in which Ri and R2 have the meanings given above and R4 represents an optionally substituted alkyl, aralkyl or aryl group. The reaction is preferably carried out in an aqueous solvent, for example water/ dioxane and in the presence of an acid, for example in the presence of concentrated hydrochloric acid, which itself may serve as a solvent, at an elevated boiling point of the solvent used. To prepare compounds of the general formula 1, in which Ri is an alkoxy group with 1-4 carbon atoms, they are subjected to alkylation a 7-hydroxyisoquinoline derivative of the general formula 14, in which R2 has the above-mentioned meaning or an alkali metal salt thereof. The alkyl group having 1 to 4 carbon atoms is introduced by means of an alkylating agent, preferably in a solvent such as dimethylformamide and preferably in the presence an inorganic or tertiary organic base, for example an alkali metal alkoxide, an alkali metal hydroxide or its carbonate, and at temperatures up to the boiling point of the solvent used. The reactions can also be carried out without a solvent. The methyl group is introduced using methyl iodide or dimethyl sulfate in the presence of an inorganic or tertiary organic base. The compounds of general formula 1 prepared by the above-mentioned methods are optionally converted into their alkali metal salts. Starting products used in the processes of the invention are partly known and can be prepared by known methods. For example, a sulfonamide of the general formula 2, in which Ri is a hydrogen, chlorine or bromine atom, is prepared by reacting a benzenesulfonamide of the general formula 15, in which Rs is a hydrogen atom or an acyl group, with a homophthalic acid derivative water having an activated carboxyl group or with 4-halogenhomophthalic acid. The reaction is carried out in the melt or in an inert organic solvent, at temperatures from 150°C to 200°C. The sulfonamides thus prepared are then methylated with a methyl halide in the presence of an inorganic base such as sodium hydroxide or sodium alkoxide. However, it is also possible to use a suitable methyl derivative of homophthalic acid as the starting product. Sulfonamides of general formula 2, in which Ri is an alkoxy group, are prepared by condensation of 4-aminosulfonylphenylethyl-(2)-amine with 1,2,3 ,4-tetrahydro-4,4-dimethyl-7-alkoxy-isochroman-dione-(1,3). The reaction is preferably carried out in a solvent, for example xylene, and at the boiling point of the solvent used, using a water separation device. 1,2,3,4-tetrahydro-4,4-dimethyl-7-alkoxy-isochromanediones-(1,3) is prepared by alkylation of 2,4,4-trimethyl-7-hydroxy-isoquinolinedione - -(1,3), heating with sodium hydroxide solution under a reflux condenser, and then acidification. 2,4,4-trimethyl-7-hydroxy-isoquinolinedione-(1,3) can in turn be prepared by nitration of 2,4,4-trimethyl-isoquinolinedione-(1,3) and catalytic reduction of the nitro group , diazotization and heating to boiling of the produced diazonium compound. The compound of the general formula 3 is prepared by reacting a urea of the general formula 16, in which R2 has the meaning given above and R5 is a hydrogen atom or an acyl group, with a homophthalic acid derivative or an acid anhydride, respectively. homophthalic. It is not necessary to isolate the compound of the general formula 3. Isoquinolinthiourea of the general formula 5 is prepared, for example, by condensing 4-aminosulfonylphenylethyl-(2)-amine with a corresponding homophthalic acid derivative in the melt and then subjecting the prepared urea of the formula general formula 2, especially its alkali metal salt, reaction with an appropriate thioisocyanate and optionally alkylation. The compound of general formula 6 is prepared, for example, by condensation of the appropriate homophthalic acid with 4-aminosulfonylethyl-(2)-amine in a melt, and then reacting the produced urea, especially its alkali metal salt, with an appropriate isocyanate. The sulfonyl isocyanate of the general formula 7 is prepared, for example, by reacting the urea of the general formula 2 with phosgene. A sulfonic acid halide of the formula general 9 is prepared, for example, by chlorosulfonation of the corresponding phenyl compound, which in turn is prepared by condensation of phenylethyl-(2)-amine with the corresponding hoinophthalic acid derivative. * The compound of the general formula 12 is prepared, for example, by reacting a urea of the general formula 2 with the appropriate formic acid ester or by adding the appropriate mercaptan or amine to the sulfonyl isocyanate of the general formula 7. The compound of the formula general formula 13 is prepared, for example, by reacting a sulfonic acid halide of the general formula 9 with the appropriate O-alkylated urea in the presence of a stoichiometric amount of an inorganic or tertiary organic base. The 7-hydroxyisoquinoline derivative of the general formula 14 is prepared, for example, by melt condensation of an appropriate homophthalic acid derivative with urea, of the general formula 16. As already mentioned, the new compounds of the general formula 1 exhibit very low toxicity at low doses and with low toxicity. good blood sugar-lowering effect. The blood sugar-lowering effect of the following compounds was tested: A = JST-cyclohexyl-N/-{4-[2-(l,2,3,4-tetrahydro-l,3- 25 -diceto-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-urea, B = N-cyclohexyl-N'-{4-[2-(7-chloro-1,2,3) ,4-tetra-hydro-1,3-dioketo-4,4-dimethyl-isoquinolinq-(2)-ethyl]-benzenesulfonyl}-urea, 80 C = N-cyclohexyl-N'-{4-[2M7 -bromo-l,2,3,4-tetra- hydro-l,3-diceto-4,4-dimet! yl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-urea, D = N-adamantyl-(l)-N/-{4-[2-(l,2,3,4-tetrahydro--l) ,3-Diketo-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-urea, * E = N-adamantyl-(l)-N'-{4-[2-( 7-chloro-1,2,3,4-tetrahydro-1,3-dioketo-4,4methyl-isoquinoyl-(2)-ethyl]-benzenesulfonyl}-urea, F = N-adamantyl- (l)-N,-{4-[2-(7-bromo-1,2,3,4-tetranydro-1,3-diceto-4,4-dimethyl-isoquinoline- -/2/) -ethyl]-benzenesulfonyl}^urea and G = N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4 -dimethyl-isoquinoline--(2)-ethyl]-benzenesulfonyl}-urea compared with H = N-(4-chloro-benzenesulfonyl)-N'-n-propyl urea. Determination of the lowest oral effective dose ki and the resulting reduction in blood sugar levels (in mg%) were carried out on male rats (fed) with an average body weight of 180 g. Sodium salts of substances A-H were suspended in methylcellulose and introduced into the stomach through a gavage. . Blood was collected hourly from the 56th tail (20 /l/ sample). The glucose content was determined automatically using a Technicon autoanalyzer (U, Harding G. Heinzel, Zeitschrift f. kli. Chem. u. kli. Biochem. 7, volume 6, /l969/), using the hexokinase 60 method (glucose phosphorylation via with ATP to glucose 6-phosphate, then reduction with glucose-6-phosphate dehydrogenase to gluconate 6-phosphate, measurement of NADPH2 formed simultaneously with NADP was performed photometrically at 15 334 nm). The effect on blood pressure of sodium salts of 80,584 substances A-H was studied with simultaneous recording of respiration and heart rate in anesthetized cats (-D-/+/-glucochloralose 50 mg/kg intravenously; urethane 250 mg/kg intravenously). with a body weight of 2-3 kg using direct recording according to 8 Grass. The tested substances were injected each time into the right femoral vein (vena femoralis). The values obtained are given in the table below: Substance A B C D E F G H Lowest effective dose mg/kg orally 0.62 0.62 0.31 0.31 0.62 0.31 0.20 10.0 Reduction in blood sugar level in mg % — 14 — 12 — 8 — 9 — 20 — 11 — 10 — 20 Side effect on blood pressure after an oral dose of 8 mg/kg none 8 mg/kg none 8 mg/kg none 8 mg/kg none 16 mg/kg none 16 mg/kg none 16 mg/kg no significant effect 16 mg/kg long-term lowering of blood pressure Acute toxicity: a) Acute intravenous toxicity of sodium salts tests The substances were tested on groups of 10 white, unanesthetized mice from our own breeding, weighing 18-25 g. The substances were administered to animals that had been starving for 16 hours. Each compound was tested in at least 4 doses, using 10 animals per dose. For this purpose, sodium salts were dissolved in 0.01 N sodium hydroxide solution and 0.2 ml/10 g of body weight of the dissolved substance was injected into the vein in the animal's tail within 30 seconds. DLso, the dose at which intravenous administration causes 50% of animals to die within 7 days, was determined using the Behrens-Karber method. b) Oral DL5o was determined analogously. For this purpose, sodium salts or free acids (ground: grain size 10 μl) of the tested substances homogenized in 1% methylcellulose were administered, with the tested substance contained in 2 ml/25 g of body weight of suspension in methylcellulose. Below the table below lists the found values: Substance A B C D E F G H Toxicity of sodium salts DL 50 g/kg orally 2.0 — 2.0 2.0 2.5 2.5 2.5 1.5 1.116 DL 50 mg/kg intravenously 234 260 210 191 300 400 Free acids DL 50 g/kg orally 15 15 15 15 15 1.25 j The examples given below explain the invention in more detail. Example I. N-cyclohexyl-N'-{4-[2-(l,2, 3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-urea 0.5 g N-cyclohexyl-N'-{4-[ 2-(2-hydroxylcarbonyl-dimethyl-methyl-(benzamido)-ethyl]-benzenesulfonyl}-urea with a melting point of 125°C in 10 ml of ethanol or toluene is heated to reflux for 4 hours Then the solvent is distilled off under reduced pressure and the residue is recrystallized from methanol to obtain substances with a melting point of 179°C-181°C. Example II. N-cyclohexyl-N'-{4-[2-(1,2,3,4--tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl }-urea 0.5 g of N-cyclohexyl-N'-{4-[2-(2-hydroxylcarbonyl-dimethyl-methyl-(benzamido))-ethyl]-benzenesulfonyl}-urea is dissolved in 3 ml dimethylformamide and 0.5 ml of thionyl chloride. The reaction mixture is left overnight and water is added, the precipitated product is filtered off and, after crystallization from methanol, a substance with a melting point of 179°-181°C is obtained. The reaction can also be carried out by using phosphorus pentachloride or phosphorus oxychloride instead of thionyl chloride. .Example III. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrohydro-1,3-dioketo-4,4-dimethyl-isoquinoline-/2/) -ethyl]-benzenesulfonyl}-urea Prepared from N-cyclohexyl-JT'-{4-[2-(2-hydroxylcarbonyl-dimethyl-methyl-(5-methoxy-benzamido)-ethyl]- benzenesulfonyl}-urea with a melting point of 145°C analogously to Example I or II. Melting point: 180°C-182°C 10.5 g N-cyclohexyl-N'-{4-[2-(7-methoxy- 1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline- (2)]-benzenesulfonyl}-urea is dissolved in 500 ml of acetone and at a temperature of -5°C to 0°C, a stoichiometric amount of sodium ethoxide dissolved in 20 ml of ethanol was added dropwise. 10.1 g of the basic sodium salt are obtained in the form of colorless crystals, softening at a temperature of 160°C. Example IV. N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline-/2/) -ethyl]-benzene-sulfonyl}-urea N-cyclohexyl-N'-{4-[2-(2-methoxy-carhonyl-dimethyl-methyl)-5-methoxy-benzamido-ethyl] -benzenesulfonyl}-urea with a melting point of 88°C-90°C analogously to Examples I or II. Melting point: 180°C-182°C Example V. N-cyclohexyl-N'-{4- [2-(1,2,3,4--tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-urea Prepared from N-cyclohexyl-N '-{4-[2-(2-hydroxy|carboylHdume1;ylmethyl-(be-nzaniidlO')-ethyl)]-benzenesulfonyl}-urea in the presence of N,N'-dicyclohexytocarbodiimide analogously to Example II Melting point: 179°C - I810C Melting point of the sodium salt: from 178°C Example 6 N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4-tetrahydro) -1,3,-dike(to-4,4-dimethyl-isoquinolinol-(2))-ethyl]-benzensulfonyl}-urea 5.5 g N-cyclohexyl-P^'-[4-( 2-amino-ethyl)-benzenesulfonyl]-urea, melting point 200°C, prepared from N-cyclohexyl-N'-[4-(2-ace-v tamido-ethyl)-benzenesulfonyl]-urea, melting point melting point 178°C by saponification of the wines with sodium hydroxide solution: dioxane = 6:1, converted into sodium salt in 150 ml of ethanol with an equivalent amount of sodium ethylene. The sodium salt is heated in 20 ml of absolute dimethylformamide with 5.5 g of 1,2,3,4-tetrahydro-4,4-dimethyl-7-methoxy-isochromanedione-(1,3) with a melting point of 95°C. 97°C for one hour at a temperature of 105°C-115°C. After cooling, 100 ml of 1N HCl are added and the separated crude product is recrystallized from methanol and methylethyl ketone. Melting point: 180°C-182 °C.Example VII. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinoline-/2/ )-ethyl]-benzene-sulfonyl}-urea 2 g of 1,2,3,4-tetrahydro-4,4-dimethyl-7-methoxy-isochromanedione-(1,3) and 8 g of N-cyclohexyl-N '- 10 -[4-(2-amino-ethyl)-benzenesulfonyl]-urea is condensed without solvent at a bath temperature of 140°C-150°C. The obtained melt is extracted hot with acetone, the solvent is distilled off under reduced pressure and the residue is treated with 0.1 N hydrochloric acid for further purification. The crude product obtained is recrystallized from methyl ethyl ketone and methanol. Melting point: 170°C-182° C Example VIII. N-cyVohexyl-N'- {4- [2-(1,2,3, 20% 4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-/2)-ethyl]- benzenesulfonyl}-urea Prepared from N-cyclohexyl-N'-[4-(2-amino-ethyl)-benzene-sulfonyl]-urea and 1,2,3,4-tetra-hydro-4,4-dimethyl -isochromanedione-(l,3) with a melting point of 78°C-81°C similarly to Examples VI and VII. Melting point: 179°C-181°C. Example IX. N-cyclohexyl-N'-{4-[2-(7-ethoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-30-isoquinolyl-(2)) -ethyl]-benzenesulfonyl}-urea Prepared from N-cyclohexyl-N'-[4-(2-amino-ethyl)-benzenesulfonyl]-urea and 1,2,3,4-tetrahydro-4,4 -dimethyl-7-ethoxy-isochromanedione-(l,3) with a melting point of 122°C-124°C, similarly to Examples VI and VII. Melting point: 90°C Melting point of the sodium salt: 175°C. Example X. N-cyclohexyl-N7-{4-[2-(7-chloro-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyliso-quinolyl-(2))-ethyl ]-benzenesulfonyl}-urea Prepared from N-cyclohexyl-N'-[4-(2-amino-ethyl)-benzene-sulfonyl]-urea and 1,2,3,4-tetra-hydro-4,4 -dimethyl-7-chloro-isochromanedione- . -(1,3) with a melting point of 98°C-104°C, similarly to Examples VI and VII. Melting point: 177°C. Example XI. N-cyclohexyl-N'-{4-[2-(7-bromo-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinol-(2))- ethyl]-benzenesulfonyl}-urea 50 Prepared from N-cyclohexyl-N'-[4-(2-amino-ethyl)-benzene-sulfonyl]-urea and 1,2,34-tetra-hydro-4,4 -dimethyl-7-bromo-isochromanedione--(1,3) with a melting point of 124°C-132°C, similarly to Examples VI and VII. 55 Melting point: 179°C Example XII. a) N-cyclohexyl-N'-{4-[2-(1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]- benzenesulfonyl}-thiourea 10 g of 1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-amino-60 sulfonyl-phenylethyl-(2)-isoquinolinedione-(1,3) dissolves in 50 ml of dimethylformamide, 3 g of potassium tert-butylate are added and then 5.6 g of cyclohexyl isothiocyanate are added dropwise at 10° C. After stirring for 4 hours at 10° C, water is added to the reaction mixture. 80 584 11 12 is filtered and acidified with 2N hydrochloric acid. The precipitated product is filtered off and recrystallized from ethyl acetate. Melting point: 198°C b) N-cyclohexyl-N'- {4-[2-(l,2,3, 4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinolyl-(2)ethyl]-benzenesulfonyl}-urea 0.5 g N-cyclohexyl-N'r{4-[2-(l 2,3,4-tetrahydro-1,3-dioxo-4,4-dimethyl-isoquinolyl-(2)_-ethyl]-benzenesulfonyl}-thiourea is dissolved in 5 ml of glacial acetic acid and 0. 5 ml of 30% hydrogen peroxide. After standing overnight, water is added and the initially blurry precipitate is recrystallized from methanol. Melting point: 179°C-181°C. Example XIII. a) N-cyclohexyl-N'-{4-[2-(1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquino-yl-(2)-ethyl]- benzenesulfonyl}-S-methylisothiourea 6 g N-cyclohexyl-N'- {4-[2-(1,2,3,4-tetrahydro- -1,3-dioketo-4,4-dimethyl-isoquinolyl-/ 2)-ethyl-benzenesulfonyl}-thiourea is dissolved in 50 ml of dimethylformamide, mixed with a solution of 0.5 g of sodium hydroxide in 3 ml of water and, after adding 2 g of methyl iodide, stirred for 12 hours at 40°C. -50°C. Then water is added and the precipitated product is filtered off. Melting point: 80°C b). N-cyclohexyl-N'-{4-[2-(1,2,3,4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]--benzenesulfonyl} -urea Prepared from N-cyclohexyl-N'-{4-[2-(1,2,3,4--tetrahydro-1,3^sub-4,4^dium,ethyl-isoquinolyl- (2)-ethyl]-benzene-sulfonyl}-S-methyl-isothiourea analogously to Example XII b. Melting point: 179°C-181°C Example XIV. N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-/2/) - ethyl]-benzene-sulfonyl}-thiourea..Prepared from 1,2,3,4-tetranydro-4,4-dimethyl-2-(4-aminosulphenyl-(2)-7-methoxy-isoquinoline - dione-(1,3) and cyclohexyl isothiocyanate analogously to Example XII a. Melting point: 198°C b) N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2, 3,4-tetrohydro-1,3-dioketo-4,4-dimethyl-isocninolyl- (2)-ethyl]-benzene-sulfonyl}-urea Prepared from N-cyclohexyl-N'- {4- [2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}thiourea analogously to in Example XII b. Melting point: 180°C-182°C Example XV. a) N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/2/) )-ethyl]-benzene-sulfonyl}-S-methyl-isothiourea Prepared from N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3i4-tetrahydro-1) 3-Diketo-4,4-dimethyl-isoquinoline-(2)-ethyl]-benzenesulfonyl}-thiourea analogously to Example XIII a. Melting point: 90°C 20 30 b) N-cyclohexyl-N - {4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl--(2)-ethyl]-benzene-sulfonyl }-urea* Prepared from N-cyclohexyl-N*- {4- [2- (7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl- -isoquinolyl-(2)-ethyl]-benzenesulfonyl}-S-methyl-thiourea analogously to Example XII b. Melting point: 180°C-182°C Example XVI. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-1ieti^hydro-»l,3^wiuk«to-4,4-dimethyl-isoquinolyl -(2)-ethyl]-benzenesulfonyl}-urea Prepared by refluxing N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4--tetrahydro-1) ,3-Diketo-4,4-dimethyl-isoquinolyl-18-(2)-ethylJ-benzenesulfonyl}-urea and mercuric oxide in benzene. Melting point: 180°C-182°C Example XVII. N-cyclohexyl-N'-{4-[2-(1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl} -urea To a solution of 11.2 g of 4-[2-(1,2,3,4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonamide o melting point 213°C-214°C and 70 ml of 1,2,4-trichlorobenzene are introduced at 150°C-200°C excess phosgene. The sulfonyl isocyanate obtained after distilling the solvent under reduced pressure (infrared band of the sulfonyl isocyanate group 2,225 cm-1 in 1,2,4-trichlorobenzene) is reacted in 150 ml of absolute benzene with 3 g cyclohexylamine at ambient temperature. After briefly heating in a water bath, the benzene is distilled off under reduced pressure and the crude product is precipitated with 1N hydrochloric acid. For further purification, it is recrystallized from methyl acetate. Melting point: 179°C-181°C. Example 18. N-cyclohexyl-N'- {4-[2-(7-40-methoxy-1,2,3,4-tetrahyd1:o-1,3-dikefto-4,4-dimethyl-isoquinolyl-/2/) -ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinblil-/2 ()-ethyl]-4g-benzenesulfonyl-isocyanate (infrared band of the sulfonyl isocyanate group: 2,225 cm-1 in 1,2,4-trichlorobenzene, prepared from 4-[2-(7-methoxy-1,2 ,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)]-benzenesulfonamide, melting point 203°C-205°C and phosgene) and cyclohexylamine at ambient temperature. After distilling off the solvent under reduced pressure, the residue is treated with 0.1 N hydrochloric acid, the precipitated product is filtered off and, for further purification, recrystallized from ethyl acetate and methanol. Melting point: 180°C-182°C. Example XIX. N-adamantyl-(l)-N'-{4-[2- - (1,2,3,4-tetrahydro-l,3-diceto-4,4-dimethyl-iso-60-quinolyl-/2/ )-ethyl]-benzenesulfonyl}-urea * Prepared from 4-[2-(1,2,3,4-tetrahydro-1,3-dice-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzene-silfonyl d-adamantyl-i(l) isocyanate - analogously to Examples XVII and XVIII. 66 Melting point: 199°C-201°C80 584 13 14 Melting point of sodium salt: 232°C^235°C with decomposition Example XX. N-adamantyl-(l)-N'-{4-[2-(7--methoxy-1,2,3,4-tetrahydiro-1,3-dioketo-4,4-dimethyl-isoquinolyl-) 2)-ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl) -(2)-ethyl]-benzenesulfonylisocyanate and adamantyl-(l)-amine similarly to Examples 17 and 18. Melting point of the sodium salt: 235°C-238°C. Example XXI. N-cyclohexyl-N'-{4-[2-(7-ethoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-, -isoquinolyl-/2/) -ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-ethoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)) -ethyl]-benzenesulfonyl-isocyanate (infrared band of the sulfonyl isocyanate group: 2,225 cm"1 in 1,2,4-trichlorobenzene, prepared from 4-[2--(7-ethoxy-1,2,3, 4-tetrahydro-1,3-dioketo-4,4-di-methyl-isoquinolyl-(2)-ethyl]-benzenesulfonamide, melting point 149°C and phosgene) and cyclohexylamine analogously to Example 17 and XVIII. Melting point: 90°C Example XXII. N-adamantyl-(l)-N'-{4-[2- -(7-ethoxy-l,2,3,4-tetrahydro-l,3-diketo -4,4-di-methyl-isoquinolyl(2)-ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-ethoxy-1,2,3,4-tetrahydro-1,3 -diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl-isocyanate and adamantyl-(l)-amine similarly to Examples XVII and XVIII. Melting point: 107°C. Melting point of the sodium salt: 225°C. Example XXIII. N-cyclohexyl-N'-{4-[2-(7-iso-propoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)) -ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-iso-propoxy-1,2,3,4-tetra-hydro-1,3-dioketo-4,4-dimethyl-isoquinoline) -/2/)- -ethyl]-benzenesulfonyl-isocyanate (IR band of the sulfonyl-isocyanate group: 2,225 cm-1 in 1,2,4-trichlorobenzene, prepared from 4-[2-(7-isopropoxy-1, 2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfone/amide with a melting point of 154°C and phosgene) and cyclohexylamine, analogously to in Example 17 and 18. Melting point: 124°C. Melting point of the sodium salt: 183°C. Example XXIV. N-cyclohexyl-N'-{4-[2-(7- -n-butoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2/ )-ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-n-butoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl) -(2)-ethyl]-benzenesulfonylisocyanate (infrared band of the sulfonyl isocyanate group: 2,225 cm-1 in 1,2,4-trichlorobenzene, prepared from 4-[2-(7-n-butoxy-1) 2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonamide with a melting point of 107°C and phosgene and cyclohexylamine, similarly to Examples XVII and XVIII. Melting point: 95°C. Melting point of the sodium salt: 225°C. Example XXV. N-cyclohexyl-N'-{4-[2-(7-chloro-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}-urea Prepared from 4-[2-(7-chloro-1,2,3,4-tetrahydro-10-1,3-diceto-4,4-dimethyl-isoquinolyl-/2 ()-ethyl]-benzenesulfonyl-isocyanate (infrared band of the sulfonyl isocyanate group: 2,225 cm-1 in 1,2,4-trichlorobenzene, prepared from 4-[2-(7-.-chloro-1,2 3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-15-isoquinolyl-(2)-ethyl]-benzenesulfonamide, melting point 193°C, and phosgene) and cyclohexylamine, similarly to the example XVII and XVIII. Melting point: 177°C Example XXVI. N-adamantyl-(l)-N'-{4-[2- -(7-chloro-l,2,3,4-tetrahydro-l,3-diceto-4,4-dimethyl-isochiholyl-/ 2)-ethyl]-benzenesulfonyl}urea Preparated from 4-[2-(7-chloro-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl- (2)-ethyl]-benzenesulfonyl-isocyanate and adamantyl-(l)-amine, similarly to Examples XVII and XVIII. Melting point: 184°C. Example XXVII. N-cyclohexyl-N'-(4-[2- -(7-bromo-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2/) - ethyl]-benzenesulfonyl} - -urea Prepared from 4-[2-(7-bromo-1,2,3,4-tetrahydro-1. 3-dioketo-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl-isocyanate (infrared band of the sulfonyl isocyanate group: 2,225 cm-1 in 1,2,4-trichlorobenzene, prepared from 4-[2- - (7-bromine,o-1,2,3, 4-teVahydro-1,3-dioketo-4,4-di-methyl-isoquinolyl-(2)-ethyl]-benzenesulfonamide with a melting point of 186°C and phosgene) and cyclohexylamine analogously to Examples 17 and 18. 45 Melting point: 179°C Example XXVIII N-adamantyl-(l)-N'-{4-[2- -(7-bromo-l,2,3,4-tetrahydro-l,3-diceto-4 ,4-di-methyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea 50 Prepared from 4-[2-(7-bromo-1,2,3,4-tetrahydro-1, 3-Diketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonylisocyanate and adamantyl-(l)-amine, similarly to Examples XVII and XVIII. 55 Melting point: 119°C Melting point of the salt sodium: 226°C with decomposition. Example XXIX. N-cyclohexyl-N'-{4-[2-(1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl }-urea 4.9 g sodium salt 4-[2-(1,2,3,4-tetrahydro-1,3-di- keto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benze - the sulfonamide is thoroughly mixed with 4.3 g of ethoxy-carbonyl-cyclohexylamide and heated for one hour at a temperature of 130°C-140°C. Then, the cooled melt is transferred to 1N hydrochloric acid and the precipitated crude product is filtered off. For further purification, it is crystallized from methanol. Melting point: 179°C-181°C. Example XXX. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}-urea Prepared from the sodium salt of 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl- (2)-ethyl]-benzenesulfonamide and ethoxy-carbonyl-cyclohexylamide, analogously to Example XXIX. Melting point: 180°C-182°C. Example XXXI. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-^-methyl-isoquinolyl-(2)) -ethyl]-benzenesulfonyl}-urea 7.8 g of sodium salt of 4-[2-(7-metQxy-1,2,3,4-tetra-hydro-1,3-dioketo-4,4-dimethyl- isoquinolyl-(2)-ethyl]-benzenesulfonamide is thoroughly mixed with 7.5 g of ethylthiocarbonyl-cyclohexylamide with a melting point of 67°C and 3 g of potassium carbonate and heated for one hour at a temperature of 90°C-100°C. °C, and ethylmercaptan is released. The cooled melt is treated with 1N hydrochloric acid and the crude product is purified by crystallization from methanol and methyl ethyl ketone. Melting point: 180°C-182°C - Example XXXII. N-cyclohexyl-N'-{4-[2- -(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2/) - ethyl]-benzenesulfonyl} - -urea 16.1 g 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-di- keto-4,4-dimethyl-isoquinolyl-/2 ()-ethyl]-benzenesulfonamide and 4.5 g of potassium tert-butylate are dissolved in 100 ml of absolute dimethylformamide and, after adding 7.5 g of ethylthio-carbonyl-cyclohexylamide dissolved in 50 ml of dimethylformamide, in temperature 0°C for 16 hours. The sulfonylurea is precipitated from the reaction mixture with dilute hydrochloric acid and purified by crystallization from methanol and methyl ethyl ketone. Melting point: 180°C-182°C. Example XXXIII. N-cyclohexyl-N'-{4-[2- -(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}-urea 4.2 g sodium salt of 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl- (2)-ethyl]-benzenesulfonamide dissolved in 80 ml of absolute dimethylformamide are left, after adding 1.6 g of cyclohexyl-aminocarbamic acid chloride in 10 ml of dimethylformamide, at 0°C for 16 hours. The sulfonylurea is then precipitated from the reaction mixture with dilute hydrochloric acid and purified by crystallization from methanol and methyl ethyl ketone. Melting point: 180°C-182°C. Example XXXIV. N-cyclohexyl-N'- {4-[2- -(7-methoxy^1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2/)- ethyl]-benzenesulfonyl}-urea 2 g of 4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/2) sodium salt ()-ethyl]-benzenesulfonamide and 0.56 g of cyclohexylurea are mixed thoroughly and heated for 15 minutes at 200°C. The cooled melt is transferred to dilute hydrochloric acid and the precipitated product is recrystallized from methyl ethyl ketone. io Example XXXV. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}-urea 2 g of 4-[2-(7-methoxy-1,2,3,4-tetra-hydro-1,3-dioketo-4,4-dimethyl-isoquinolyl- (2)-ethyl]-benzenesulfonic acid (melting point: 126°C-127°C, prepared from 7-methoxy-1,2,3,4-tetrahydro-4,4-dimethyl-2-phenylethyl- (2)-isoquinolinedione-(1.3) with a melting point of 68°C and chlorosulfonic acid) are heated in 50 ml of absolute toluene with 0.93 g of cyclohexylparabanic acid with a melting point of 182°C-186°C and 0.57 g of triethylamine for three hours at a temperature of 115°C-125°C. After cooling, the precipitated triethylamine hydrochloride is filtered off and N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diketo) acid is obtained from the mother liquors. -4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-parabanic acid. 30 larny 581). The compound obtained is then saponified either by heating to boiling point for 24 hours in 10% hydrochloric acid: dioxane = 1:1 or by heating in n/10 ammonia for 1-10 hours. After distilling off the piodine solvent under reduced pressure, the residue is suspended in dilute hydrochloric acid, the crude product is filtered off and, for further purification, recrystallized from methanol and methylethyl ketone. 40 Melting point: 180°C-182°C Example XXXVI. N-cyclohexyl-N'- {4- [2- -(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2)- ethyl]-benzenesulfonyl}- urea 1 g N-cyclohexyl-N-formyl-N'- {4- [2- (7-methoxy-1,2,3,4-tetrahydro-1,3-diaketo- 4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea (melting point 186°C-188°C, prepared from N-cyclohexyl-N'- {4- [2- (7- methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-parabanic acid by careful hydrolysis diluted with hydrochloric acid at 20 °C) is saponified by heating to boiling point for 24 hours in 10% hydrochloric acid: dioxane = 1:1. After distilling off the solvent, the sulfonylurea is extracted with chloroform and, for further purification, crystallized from methyl ethyl ketone and methanol. Melting point: 180°C-182°C. Example XXXVII. N-cyclohexyl-N'- {4-[2- -(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}- -urea 50 55 6080 584 17 18 1.38 g N-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-) acid methyl ester diketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-carbamate, melting point 146°C-148°C, is dissolved in 4 ml of absolute dioxane. 0.3 g of cyclohexylamine are added and the reaction mixture is heated for 3 hours in a bath at 120° C., distilling off the methanol formed and part of the dioxane through a Vigreux column. The remaining part of the dioxane is distilled off under reduced pressure. The residue is treated with water, acidified with glacial acetic acid and the precipitated viscous reaction product is separated. For further purification, it is recrystallized from methanol and ethyl acetate. , Melting point: 179°C-181°C Example XXXVIII. N-adamantyl-(1)-N'-{4- -[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/2 /)-ethyl-benzenesulfonyl}-urea Prepared from N-{4--[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4), 4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-carbamate and adamantyl-(1)-amine analogously to Example XXXVII. Melting point of the sodium salt: 235°C-238°C Example XXXIX . N-cyclohexyl-N'-{4-[2- - (7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2/) - ethyl]-benzenesulfonyl}-urea Solution 1.0 g of N-{4- -[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-) -dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-carbamate and 0.3 g of cyclohexylamine in 5 ml of absolute dioxane are heated for 2 and 1/2 hours at 100°C. The solvent is distilled off under reduced pressure, water and some glacial acetic acid are added to the residue and the product is extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The remaining oil crystallizes after several triturations with ether or ethyl acetate. Melting point: 177°C-179°C. Example XL. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))- benzenesulfonyl}-urea 300 mk N-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinolyl-(2))-ethyl ]-benzenesulfonyl}-urea with a melting point of ISO4° and 90 mg of cyclohexylamine are heated in a mixture of 11 ml of absolute toluene and 1 drop of glacial acetic acid for 1 hour to the boil. The precipitate is filtered off and the filtrate is evaporated under reduced pressure. The oily residue gradually solidified upon addition of ethyl acetate, and the product obtained crystallized from methanol. . Melting point: 179°C-181°C. Example XLI. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))- ethyl]-benzenesulfonyl}-urea Mixture of 4.6 ml of toluene, 0.2 ml of glacial acetic acid, 1.07 g of N-benzyl-N'-{4-[2-<7-methoxy- ^1,2,3j4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea 5 with a melting point of 167°C-169°C and 2, 0 g of cyclohexylamine is heated for 4 hours at 115°C. After distilling off the solvent under reduced pressure, the residue is treated with water. It is acidified with glacial acetic acid to a pH of 5, decanted and the residue with toluene is distilled off under reduced pressure. The remaining crude product is recrystallized several times from methanol. Melting point: 177°C-179°C! 5 Example XLII. N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)) - ethyl]-benzenesulfonyl}-urea Mixture 1.55 g N-morpholinocarbonyl-4-[2-(7-20-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4- dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonamide, 3.0 g of cyclohexylamine, 7 ml of toluene and 0.3 ml of glacial acetic acid are heated for 3 hours at 115°C. The reaction mixture is distilled under reduced pressure, the residue is treated with water and glacial acetic acid, decanted, toluene is added to the oily product and distilled off again under reduced pressure. The crude product is then purified by column chromatography on silica gel (chloroform) acetone = 9(1). Melting point: 177°C-179°C Example XLIII. N-cyclohexy-N,-{4-[2-i(7-methoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/2/) )-ethyl]-benzenesulfonyl}-urea 1 g of N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diketp-) methyl ester 4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-iso-urea, melting point 110°C, (prepared from 4-[2-(7-methoxy-1, 2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonic acid, melting point 126°C-127°C, and methyl ether N -cyclohexyl isourea (oil, prepared from the corresponding toluenesulfonylate with a melting point of 148°C - 151°C) in toluene in the presence of a stoichiometric amount of triethylamine at a temperature of 90°C - 10°C / is heated in 20 ml of concentrated hydrochloric acid or 20 ml of concentrated hydrochloric acid: dioxane = 1:1 for 10-15 minutes at 90°C-100°C. The crude product obtained is purified by crystallization from methanol and methyl ethyl ketone. Melting point: 180°C-182° C Example XLIV. a) 7-methoxy-isochromanedione-(l,3) 40.4 g of 2-carboxymethyl-5-hydroxy-benzoic acid, melting point 212°C, dissolved in a solution of 25 g of sodium hydroxide in 400 ml of water and slowly add 83.5 ml of dimethyl sulfate dropwise at a temperature of 40°C-50°C. . By appropriately adding 2 N sodium hydroxide solution, a constant alkaline reaction of the solution is achieved. After 5 hours, it is acidified with 2N hydrochloric acid and extracted four times with 300 ml of ether. The organic layer is dried and the solvent is evaporated under reduced pressure. The residue is heated to reflux with 200 ml of acetic anhydride, the solvent is distilled off and the residue is distilled in a high vacuum (molecular distillation). Melting point: 138°C-132°C, b) N-cyclohexyl-N'- {4- [2- (7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-isoquinolyl) -(2)-ethylol-benzenesulfonyl-}-urea 1.03 7-methoxy-isochromanedione^(1.3) and 1.87 g of sodium salt N-cyclohexyl-N7-[4-(2-amino- ethyl)-benzenesulfonyl]-urea is stirred in 20 ml of glycol for 3 hours at 100°C and then for 31 1/2 hours at 140°C. After cooling, it is acidified with a methanol solution of hydrogen chloride, diluted with 80 ml of water and the precipitated greasy product, left overnight, recrystallized from chlorobenzene. Melting point: 190°C. ^ c) N-cyclohexyl-N7-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl- */2/ )-ethyl]-benzenesulfonyl}-urea 200 mg N-cyclohexyl-N'-{4-[2-(7-methoxy-1,2,3, 4-tetrahydro-1,3-dioketo-isoquinolyl-/2/ )-ethyl]-benzenesulfonyl}-urea is dissolved in 5 ml of absolute dimethylformamide and then 135 mg of potassium tert-butylate are added and then, at ambient temperature, 114 mg of methyl iodide, dissolved in 2 ml of dimethylformamide. After stirring for 4 hours, it is acidified with 2N hydrochloric acid, diluted with water and filtered; the reaction product is precipitated and recrystallized from methanol. Melting point: 180°C-182°C. Example XLV. N-cyclohexyl-N'-{4-12-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))-ethyl ]-benzenesulfonyl}-urea 2 g of 7-hydroxy-4,4-dimethylisochromanedione--(1,3) (melting point: 170°C-173°C), prepared from dimethylhomophthalic acid by nitration, group reduction nitro acid, diazotization and heating the diazonium solution to boiling), and $.5 g of sodium salt of N-cyclohexyl-N7-[4-(2-amino-ethyl)-benzenesulfonylol-urea are stirred in 20 ml of glycol for 5 hours at 140°C. After cooling, it is acidified with a methanolic hydrochloride solution, diluted with water, the precipitate is filtered off and recrystallized from chlorobenzene. The obtained contaminated product (2.5 g) is dissolved in 20 ml of dimethylformamide and 1 g of potassium tert-butylate and 0.8 g of methyl iodide are added. After stirring for 3 hours at ambient temperature, it is acidified with 2N hydrochloric acid, diluted with water and the precipitated reaction product recrystallized from methanol. Melting point: 180°C-182°C. Example XLVI. a) 1,2,3,4-tetrahydro-4,4-di-methyl-2-(4)-aminosulfonyl-phenyl-ethyl-(2)-7-methoxy-isoquinolinedione-(1,3)4 g 1,2,3,4-tetrahydro-4,4-dimethyl-7-methoxy-isochromanedione-(1,3) with a melting point of 05°C-97°C and 2.53 g 4-aminosulfonylphenylethyl-(2) - 584 20-amine in 150 ml of xylene is heated to boiling for 2 hours using a water separation device. After cooling, it is filtered off and the residue is recrystallized from n-propanol with the addition of activated carbon. Yield: 2.9 g (58% of theoretical yield). Melting point: 203°C—205°C dimethyl-isoquinolyl-(2)-ethylol-benzenesulfonyl}-urea 32.2 g l,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2))-7 -methoxy-isoquinoline-dione-(1,3) is dissolved in 700 ml of dimethylformimide, 9.1 g of potassium tert-butyl 15 are added and, while cooling, 14.9 g of cyclohexyl isocyanate are added dropwise. The mixture is then stirred for another 5 hours while cooling on ice, and the reaction mixture is left overnight at -2°C. Water is added, the precipitate is filtered off and the filtrate is added, after 20 seconds water is added and the mixture is acidified with hydrochloric acid. An oily precipitate forms, which becomes crystalline when heated to boiling with methanol. Yield: 26 g (85% of theoretical yield). Melting point: 18JD°C—182°C 25 10.5 g N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4- -tetrahydro-1,3-diketo- 4,4-dimethyl-isoquinolyl-»(2)-ethyl]-benzenesulfonyl}-urea is dissolved in 500 ml of acetone and a stoichiometric amount of sodium ethate is slowly added dropwise at a temperature from -5°C to 0°C. , dissolved in 20 ml of ethanol. 10.1 g (91% of theoretical yield) of sodium salt N-cyclohexyl-N7-{4-[2-(7-methoxy-1, 2,3,4-tetrahydro-1, 3-Diketo-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea in the form of colorless crystals, softening at temperatures above 160°C. Example XLVII. N-adamantyl-(1)-N'-{4-[2- -(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-) 2/)-ethyl]-benzenesulfonyl}--urea Prepared from 1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2)-7-methoxy-iso-quinolinedione -(l,3) and adamantyl isocyanate, 4B analogously to Example XLVI b. Melting point of the sodium salt: 235°C-238°C Example XLVIII. N-cyclohexyl-N7-{4-[2- -(7-ethoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))-ethyl ]-benzenesulfonyl}-urea- 59 Prepared from 1,2,3,4-tetrahydro-4,4-dimethyl--2-(4-aminosulfonylphenylethyl-(2))-7-ethoxy-iso-quinolinedione-( 1,3) (melting point 149°C, prepared from 1,2,3,4-tetrahydro-4,4-dimethyl-7-55-ethoxy-isochromanedione-(1,3) and 4-aminosulfonyl-ethyl-(2 )-amine, analogous to Example XLVI a) and cyclohexyl isocyanate, analogous to Example XLVI b. ,n Melting point: 90°C Melting point of sodium salt: 175°C Example XLIX. N-adamantyl-/1/-N7- {4-{2- -(7-ethoxy-1,2,3,4-te1iahydro-1,3-diceto-4,4-di-methyl-isoquinolyl-/2 /-ethyl]-benzenesulfonyl}-es-urea80 584 21 22 Prepared from 1,2,3,4-tetrahydro-4,4-dimethyl*-2-(4-aminosulfonylphenylethyl-(2))-7-ethoxy-iso - quinolinedione-(1,3) and adamantyl isocyanate, similarly to Example XLVI b. Melting point: 107°C Melting point of sodium salt: 225°C Example L. N-cyclohexyl-N'- {4- [2- ( 7-isopropoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl-benzenesulfonyl}-urea. Prepared from 1, 2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2))-7-iso-propoxy-isoquinolidione-(1,3) (melting point: 154°C, prepared with 1,2,3,4-tetrahydro-4,4-dimethyl-7-isopropoxy-isochromanedione-(1,3) and 4-aminosulfonylethyl-(2)-amine, analogously to Example XLVI a) and cyclohexyl isocyanate, analogously to Example XLVI b. Melting point: 124° C. Melting point of the sodium salt: 183° C. Example LI. : N-cyclohexyl-N'-(4-[2-(7-n--butoxy-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/2) /)-ethyl]-benzenesulfonyl}-urea Prepared from 1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2))-7-n-butoxy- - isoquinolinedione-/1,3/ (melting point: 107°C, prepared from 1,2,3,4-tetrahydro-4,4-dimethyl-7-n-butoxy-isochromanedione-/1,3/ and 4- aminosulfonylphenylethyl-(2)-amine, analogously to Example XLVI a) and cyclohexyl isocyanate, analogously to Example XLVI b. Melting point: 95°C Melting point of the sodium salt: 225°C Example LII. a) 1,2, 3,4-tetrahydro-4,4-di-methyl-2-(4-aminosulfonylphenylethyl-(2)-isoquinoline-clion-/l.3/ 26.7 g 1,2,3,4-tetrahydro -2-(4-aminosulfonylphenylethyl-(2)-isoquinoline-dione-(i,3) (melting point: 246°C) is boiled in 170 ml of ethanol and 30 ml of water with 22 g of methyl iodide. At the same time, a solution of 155 moles of sodium ethoxide in 70 ml of ethanol was added dropwise. After adding sodium ethylene, the mixture is heated for another 2-4 hours. The solvents are distilled off and the residue is treated with ice water. Insoluble. the raw product crystallizes from chlorobenzene. Yield: 22.7 g (78.5% of theoretical yield) Melting point: 213°C-214°C b) N-cyclohexyl-N/-{4-[2-(l.2) ,3,4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinol!o-(2)-ethyl]-benzenesulfonyl}-urea 5 g 1,2,3,4-tetrahydro-4 4-Dimethyl-2-(4-amino-sulfonylphenylethyl-(2)-isoquinolinedione-(1,3) is converted into 28 ml of dimethylformamide with 0.64 g of sodium hydride (50% suspension in oil). in sodium salt. After complete dissolution, 1.83 g of cyclohexyl isocyanate are added at 5°C. To complete the reaction, stir for another 1-2 hours at ambient temperature. The reaction mixture is added to 100 ml of water and acidified with glacial acetic acid. The precipitated product is recrystallized from methanol. 25 30 Yield: 2.6 g (39.1% of theoretical yield) Melting point: 179°C-181°C Melting point of sodium salt: from 205°C with decomposition 5 Example LIII. N-adamantyl-/1/-N'-{4-[2-(7--bromo-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-/ 2/)-ethyl]-benzenesulfonyl}-urea Prepared from 7-bromo-1,2,3,4-tetrahydro-4,4-V-dimethyl-2-(4-aminosulfonylphenylethyl-(2/)) - 10 - isoquinolinedione-(1,3) (melting point: 186°C, prepared from 7-bromo-1,2,3,4-tetrahydro-2--(4-aminosulfanylphenylethyl-(2))-isoquinolinedione-(1) ,3) with a melting point of 238°C and methyl iodide analogously to Example LII a) and adamantyl isocyanate analogously to Example LII b. Yield: 14.4% of theoretical yield Melting point: 119°C (methanol ) Melting point of sodium salt: 226°C with decomposition Example LW. N-cyclohexyl-N'-{4-[2-(7-chloro-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-/2/) - ethyl]-benzenesulfonyl}-urea Prepared from 7-chloro-1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2)-iso-quinolinedione-/l, 3/ (melting point: 193°C, prepared from 7-chloro-1,2,3,4-tetrahydro-2-(4-aminosulfonylphenylethyl-(2))-isoquinolinedione-/1,3/ melting point 252°C and methyl iodide analogously to Example LII a) and adamantyl isocyanate analogously to Example LII b. Yield: 40% of theoretical yield Melting point: 177°C (methanol) 35 Example LV. N-adamantyl-(1)-N'-{4-[2-(1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2))-ethyl ]-benzenesulfonyl}-urea Prepared from 1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2))-isoquinoline-40 dione-(l,3) and isocyanate adamantyl, similarly to Example LII b. Yield: 10.4% of theoretical yield. Melting point: 199°C (methanol) Melting point of sodium salt: 232°C-235°C 45 with decomposition. Example LVI. N-adamantyl-(1)-N'-{4-[2-(7--chloro-1,2,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-) 2)-ethyl]-benzenesulfonyl}-urea 50 Prepared from 7-chloro-1,2,3,4-tetrahydro-4,4-dimethyl-2-(4-aminosulfonylphenylethyl-(2))- iso-quinolinedione-(1,3) and adamantyl isocyanate analogously to Example LII b. Yield 10% of theoretical yield 55 Melting point: 184°C (ethanol) Example LVII. N-cyclohexyl-N7-{4-12-(7-bromo0-1'2,3,4^tetohydro^lo-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea Prepared from 7-bromo- 1,2,3,4-tetrahydro-4,4-60-dimethyl-2-(4-aminosulfonylphenylethyl-(2)-iso-quinolinedione-(1,3) and cyclohexyl isocyanate analogously to Example LII b. Yield : 50% of theoretical yield Melting point: 179°C (ethanol) 'f' 65 The compounds prepared according to the invention can be converted into commonly used preparations by known methods. Taking into account the therapeutic indications of these compounds, mainly gelatin tablets and capsules are considered. The average single dose for therapeutic use is 1-10 mg, especially 2.5-5 mg.N-cyclohexyl-N'- {4-[2-(7-methoxy-1,2,3,4-tetrahydro -1,3-diceto-4,4-dimethyl-isoquinolyl-(2)--ethyl]-benzenesulfonyl}-urea Composition: 1 tablet contains: N-cyclohexyl-N'- {4-[2-(7- methoxy-1,2,3,4-tetrahydro-1,3-di- keto-4,4-dimethyl-isoquinolyl- (2)-ethyl]-benzenesulfonyl}-urea 2.5 mg milk sugar 87.5 mg of corn starch 26.0 mg of polyvinylpyrrolidone 3.0 mg of magnesium stearate 1.0 mg 24 120.0 mg Preparation method: The active substance is mixed intensively with milk cream and corn starch and moistened evenly with 12.5% ( 66) a solution of polyvinylpyrrolidone in ethanol. The mass is rubbed through a sieve with a mesh size of 1.5 mm, dried at 45°C and rubbed again through a sieve with a mesh size of 1.0 mm. The granulate thus prepared is mixed with magnesium stearate and pressed into tablets. Tablet weight: 120 mg Punch: 7 mm, flat, with a facet and a groove for dividing the tablet. N-cyclohexyl-N'-{4-[2-(7-methoxy- 1,2,3,4-tetra-hydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea Composition: 1 capsule contains: N-cyclohexyl-N '-{4-[2-(7-methoxy-1,2,3,4-tetrahydro-1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl} -urea 2.5 mg of corn starch, dried 97.5 mg 100.0 mg Preparation method: Intensively mixed substances are sifted through a sieve with a mesh size of 0.75 mm and filled into hard gelatin capsules of appropriate size. Capsule filling: 100 mg In a similar way, gelatin tablets and capsules can be prepared, containing 2.5 mg of the following substance: -1,3-diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea N-adamantyl-(1)-N'-{4-[2-(1,2, 3,4-tetrahydro-1,3--diceto-4,4-dimethyl-isoquinolyl-(2)-ethyl]-benzenesulfonyl}-urea N-adamantyl-/1/-N*- {4- [2 -(7-chloro-1,z,3,4-tetrahydro-1,3-dioketo-4,4-dimethyl-isoquinolyl-(2)-ethyl-k)]-benzenesulfonyl}-urea 25 30 N-adamantyl-(1)-N'-{4-[2-(7-methoxy-1,2,3,4,-tetra-hydro-1,3-diceto-4,4-dimethyl-isoquinolyl-) 2/)-ethyl]-benzenesulfonyl}-urea.PL PL PL PL

Claims (3)

1. Patent claims 1. A method for preparing new isoquinoline derivatives of the general formula 1, in which Ri denotes a hydrogen, chlorine or bromine atom, and R2 denotes a cyclohexyl or adamantyl-(l) group, characterized in that a sulfonamide of the general formula 2, io in which Ri has the meaning given above, and especially its alkali metal salt, is reacted with an isocyanate of the general formula 0=C=N-R2 in which R2 has the meaning given above and the compound obtained of the general formula 15 is optionally converted into an alkali metal salt. 2. A method for preparing new isoquinoline derivatives of the general formula 1, in which Ri is a hydrogen, chlorine or bromine atom or an alkoxy group with 1-4 carbon atoms, and R2 has the meaning given in claim 1. 1, characterized in that the sulfonamide of the general formula 2, in which Ri is an alkoxy group with 1-4 carbon atoms, especially its alkali metal salt, is reacted with an isocyanate of the general formula 0=C=N- R2, in which R2 has the above-mentioned meaning and the obtained compound of general formula 1 is optionally converted into an alkali metal salt. 3. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim 1. 1 or 2, and R2 has the meaning of claim 1. 1, characterized in that the compound of the general formula 3, in which Ri has the above-described meaning, one of the symbols A or B denotes the group of the general formula 4, in which R2 has the above-described meaning, and the other of the symbols A or B means a hydroxyl group or an optionally formed in situ reactable residue, such as a halogen atom, an alkoxy, acyloxy or amino group, is cyclized and the resulting compound of general formula 1 is optionally converted into an alkali metal salt. 4. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Rj has the meaning given in claim 4. 1 or 2, and R2 has the meaning of claim 1. 1, characterized in that in the isoquinolinethiourea of the general formula 5, wherein R: is as defined in claim 1 or 2.4. R2 is as defined in claim 1. 1 and R8 is a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group, the sulfur atom is replaced by an oxygen atom by means of an oxidizing agent or, in the case where R8 is a hydrogen atom, also by a metal oxide heavy metal and optionally convert the obtained compound of general formula 1 into an alkali metal salt. 605. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim. 1 or 2, and R2 has the meaning of claim 1. 1, characterized in that the compound of general formula 6, in which Ri and R2 66 have the above-mentioned meaning, or an alkali metal salt thereof is effectively methylated in the presence of an inorganic or tertiary organic base and the obtained compound of general formula 1 optionally converts into an alkali metal salt.6. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim 1 or 2, and Re has the meaning of claim 1. 1, characterized in that the sulfonyl isocyanate of the general formula 7, in which Ri has the meaning given above, is reacted with an amine of the general formula HjN-R*, in which R2 has the meaning given above, and the compound of the general formula obtained 1 is optionally converted into an alkali metal salt.7. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim 1 or 2, and R2 has the meaning of claim 1. 1, characterized in that the sulfonamide of the general formula 2, in which R 2 has the above-mentioned meaning, or an alkali metal salt thereof, is reacted with a compound of the formula 8, in which R 2 has the above-mentioned meaning and Y is a halogen atom, an amino group or a hydroxyl or mercapto group substituted with an optionally substituted alkyl, afalkyl or aryl group, optionally in the presence of an inorganic or tertiary organic base, and the obtained compound of general formula I is optionally converted into an alkali metal salt. 8. A method for preparing new isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim 1 or 2, and R2 has the same meaning as in claim 1. 1, characterized in that the sulfonic acid halide of the general formula 9, in which Ri has the above-mentioned meaning and Hal denotes a chlorine or bromine atom, is reacted with par-abanic acid of the general formula 10, in which R2 has the meaning given above, especially in the presence of a stoichiometric amount of an inorganic or tertiary organic base, and is then subjected to acidic or alkaline hydrolysis and the obtained compound of general formula 1 is optionally converted into an alkali metal salt.9. A method of producing new ones. isoquinoline derivatives of the general formula 1, wherein Ri has the meaning given in claim 1 or 2, and Rj has the meaning of claim 1. 1, characterized in that the compound of general formula 12, in which Ri has the above-mentioned meaning and Z represents a halogen atom, a hydroxyl group or a mercapto group, substituted by an optionally substituted alkyl, aralkyl or aryl group, or may a no- or disubstituted amino group is reacted with an amine of the formula H2N-R2, in which R2 has the meaning given above, optionally in the presence of an inorganic or tertiary organic base, and the obtained compound of general formula 1 is optionally converted into alkali metal salt.10. A method for preparing new isoquinoline derivatives of the general formula 1, in which Ri has the meaning given in claim 1 or claim 2, and Rg has the meaning as in claim 1, characterized by that a urea of the general formula 13, in which Ri and R2 have the meanings given above and R4 represents an optionally substituted alkyl, aralkyl or aryl group, is dealkylated in the presence of an acid and the obtained compound of the general formula 1 is optionally converted into alkali metal salt. 11. A method for preparing new isoquinoline derivatives of the general formula 1, in which Ri is an alkoxy group with 1-4 carbon atoms, and R1 has the same meaning as in claim 1, characterized in that the 7-hydroxyisoquinoline derivative of the general formula 14, in which R2 has the above-mentioned meaning, or an alkali metal salt thereof, is preferably alkylated in the presence of an inorganic or tertiary organic base and the obtained compound of the general formula 1 is optionally converted into an alkali metal salt. 12. *12. The method according to claim 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11, characterized in that the reaction is carried out in a solvent.13. The method according to claim 3, characterized in that the reaction is carried out in the presence of a water-repellent agent or water separator, in the case of g4, the symbol A or B denotes a hydroxyl group. 14. The method according to claim 3 or 13, characterized in that the reaction is carried out at temperatures from 0 to 200°C. 15. The method according to claim 4, characterized in that hydrogen peroxide is used as the oxidizing agent and mercury oxide is used as the heavy metal salt. 16. The method according to claim 4 or 15, characterized in that the reactions are carried out at a temperature from 0°C to the boiling point of the solvent used. 17. The method according to claim 5, characterized in that methyl iodide is used as the methylating agent. 18. The method according to claim 5 or 17, characterized in that the reactions are carried out at a temperature from 0° to 120°C. 19. The method according to claim tf, characterized in that the reaction is carried out at a temperature up to the boiling point of the solvent used. 20. The method according to claim 7, characterized in that the reaction is carried out in the presence of potassium carbonate or potassium tert-butoxide. 21. The method according to claim 7 or 20, characterized in that the reactions are carried out at a temperature from 0° to 200°C. 22. The method according to claim 8, characterized in that the reaction is carried out at an elevated temperature, preferably at the boiling point of the solvent used. 23. The method according to claim 8, characterized in that the intermediate product of general formula 11 obtained as a result of gentle hydrolysis, in which Ri and R2 have the meanings given above, is subjected to complete hydrolysis at an elevated temperature. 24. The method according to claim 9, characterized in that the reaction is carried out at a temperature from 0° to 200°C. . . ' " •80 584 27 25. A method according to claim 9 or 24, characterized in that the reaction is carried out in the presence of a reaction accelerator. 26. A method according to claim 9 or 25, characterized in that the reaction accelerator is a salt of the used amine with the formula H2N-R2, e.g. acetate. 27. The method according to claim 10, characterized in that the dealkylation is carried out in the presence of concentrated hydrochloric acid. 28. The method according to claim 10 or 27, characterized in that the reaction is carried out at a temperature up to the boiling point of the solvent used. 28 29. A method according to claim 11, characterized in that an alkyl halide with 1-4 carbon atoms is used as the alkylating agent. 30. A method according to claim 11 or 29, characterized in that that the reaction is carried out at a temperature up to the boiling point of the solvent used. 31. A method according to claim 5 or 11, characterized in that the reaction is carried out in the presence of an excess of inorganic or tertiary organic base. 32. A method according to claim 1 or 2, ~ characterized in that the alkali metal salt of the sulfonamide of general formula 2 is reacted with an isocyanate in an inert solvent while cooling. N-CH2-CH2«y \_so2-NH-C-NH-F FORMULA 1 N-CH2-CH2--/ \-S02-NH2 FORMULA 2 CH CH, ^C-CO-A C-B -NH-CH2-CH2 -/ V-S02-NH-C-NH- FORMULA 480 584 .N-CH2-CH2 SR, ;-^ ^-s02-N=C-NH-F FORMULA 5 H^ ^H N-CH-CH.- f ^WSCL-NH-C-NH-R. '2 ~' "2 \ / ww2 FORMULA 6 N-CH2-CH2 FORMULA 7 r\ S02-N=C=0 Y—C—NH—R2 FORMULA 880 584 -CH2-CH2-^ VSQ2-Hal FORMULA 9 H— N—C—N—R2 C C U II o o WZ0R 10 N-CH2-CH2 r\ O CHO S02-NH-C-N-R? MODEL 11 CK N-CH2-CH2 r\ S02-NH-C—Z MODEL 1280 584 CH "CHS "N-CH OR. -CHW' V-SO-N=C- 2 ^"'2 L \ / WZdR 13 NH-R, N-CH2-CH2-f V-S02-NH-C~NH-R2 WZdR14 . .-NH-CH9-CHr-f -S02- n2 ^n2 2-NH2 FORMULA 15 R5-NH-CH2-CH2 aa S02-NH-C-NH-R2 WZdR 16 PL PL PL PL