DE2319280A1 - 1-Substd-pyrazol-5-ones - with diuretic, saluretic, antihypertensive and antithrombotic activity - Google Patents

Abstract

Cpds. of formula (I) and their acid-addn. salts: (where R is H, NH2, alkyl, alkenyl, phenyl, CF3; R' is H, alkyl, aryl, opt. substd. aralkyl; R2 is alkyl; R3 is aryl substd. by 1 or 2 halo, CF3, alkyl, alkenyl, alkoxy; or by 1 alkylamino, -OCF3, NO2, CN, -CONH2, -SO2NH2, SOn-alkyl, where n is 0, 1 or 2, opt. also substd. by 1 or 2 alkyl, alkenyl, alkoxy, halo, CF3; or 2 of the substits. of R3 may form a 5 to 7-membered ring opt. satd. opt. contg. 1 or 2 O- or S-atoms; or R3 is naphthyl or pyridyl) possess diuretic, saluretic, antihypertensive and antithrombotic props. and are used in an amt. of 0.1-10mg/kg/day, parenterally, or 0.5-100mg/kg/day, orally.

Description

1-Substituted pyrazolones- (5). Process for their preparation as well their use as medicaments. The present invention relates to new 1-substituted Pyrazolone- (5), several processes for their preparation and their use as Medicines, especially as diuretics and antihypertensive drugs.

It has already become known that 3-aminopyrazolones are used as color couplers for color photography (A. Weissberger et al, J. Amer. Chem. Soc. 64, 2183 (1942) ) or as intermediate products for the production of color couplers (British Patent 599,919; U.S. Patent 2,267,523; U.S. Patent 2,376,380; U.S. Patent 2,511,231; U.S. Patent 2,600,788; U.S. Patent 2,619,419; U.S. Patent 2,672,417).

It has also become known that pyrazolone (5) derivatives as antipyretics, Analgesics and anti-inflammatory drugs are used (see G. Ehrhart and H. Ruschig, Arzneimittel ", Vol. 1, p. 148 (1972)).

However, their use as diuretics and antihypertensive drugs is new and so far not known.

It has been found that 1-substituted pyrazolones (5) of the general formula I. in which R stands for hydrogen, amino, alkyl, alkenyl or phenyl and R1 stands for hydrogen, alkyl, alkenyl or optionally substituted aryl or aralkyl, and R2 stands for alkyl and R3 for an optionally substituted aryl radical which is up to two identical or different Contains substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy, or an alkylamino, trifluoromethoxy, nitro, cyano, carbonamido, sulfonamido or SOn alkyl group (n = o to 2), optionally together with 1 or 2 substituents.

from the group consisting of alkyl, alkenyl, alkoxy, halogen or trifluoromethyl contains, where optionally two substituents on the aryl radical together have a branched one or unbranched, saturated or unsaturated, 5- to 7-membered isocyclic or form heterocyclic ring, which in turn has 1 to 2 oxygen or sulfur atoms may contain, stands, as such or in the form of their salts, strong diuretic, saluretic, have antihypertensive and antithrombotic properties.

In addition to the form represented by formula I, the compounds according to the invention can also exist in one of the following tautomeric forms or as mixtures of such tautomeric forms: In particular, the 3-aminoprazolones- (5) can also exist in the following imino forms: It has also been found that 1-substituted pyrazolones (5) of the formula I are obtained if A) hydrazine of the formula VI in which R2 and R3 have the meaning given above, with acetic acid derivatives of the formula VII optionally occurring in different tautomeric forms, in which R1 has the meaning given above, X for a hydroxy, alkoxy, aralkoiy, amino or alkylamino radical, I for hydrogen and Y 'for nitrile or for the group are in which Y "denotes a hydrogen atom or an alkyl radical or a phenyl radical, or Y and Y 'together represent the group are, where stands for an alkoxy, aryloxy, aralkoxy, alkylmercapto or aralkylmercapto radical or the amino group, optionally in the presence of inert solvents and basic or acidic catalysts such as alkali and alkaline earth metal hydroxides and carbonates or such as hydrogen halide, sulfuric acid or sulfonic acids Temperatures between 10 and 200 ° C converts.

or B) compounds of the formula VIII in which R2 and R3 have the meaning given above, and A represents a leaving radical such as halogen or the dialkyloxonium, dialkylsulfonium or trialkylammonium radical or the aryl or trifluoromethylsulfonic acid radical, with tyrazolone (5) derivatives of the formula IX in which R and R have the meaning given above, optionally in the presence of inert solvents and inorganic or organic bases such as alkali hydroxides, carbonates, alcoholates, hydrides or amides at temperatures between 10 and 200 ° C or especially for the case that -R in formula I represents an amino group, C) pyrazolone (5) derivatives of the formula X in which R1, R2 and R3 have the meaning given above and Z is chlorine or bromine, allowed to react with ammonia, if appropriate in the presence of inert solvents, at temperatures between 50 and 150 ° C. and under increased pressure.

The novel 1-substituted compounds according to the invention surprisingly show Pyrazolone- (5) potent diuretic, saluretic, antithrombotic, and antihypertensive Effects.

Clay the pyrazolone (5) derivatives known from the prior art are so far diuretic, saluretic, antithrombotic and antihypertensive effects not become known, so that the compounds according to the invention. regarding these special pharmaceutical effects represent a new class of substances and are to be seen as preparation for pharmacy.

Depending on the type of starting materials used, the synthesis of the compounds according to the invention can be represented by the following formula schemes, where 3-amino-1- (o (imethyl-4-chlorobenzyl) pyrazolone- (5), 3-methyl-1- (α -äthylbenzyl) -pyrazolon- (5), 3,4-dimethyl-1- (α-methyl-3-chlorobenzyl) -pyrazolone- (5) and 3-amino-4-methyl-1- (α-ethylbenzyl) - Pyrazolon- (5) chosen as examples and the possible, optionally isolable intermediate stages of the reaction process were not shown.

Process variant A According to process A, a hydrazine of the formula VI with an acetic acid derivative of the formula VII implemented.

In formula VI, R2 preferably represents an alkyl radical with 1 to 4 carbon atoms and R³ preferably for a phenyl or naphthyl radical, in particular for a phenyl radical formed by 1 to 2 straight-chain or branched alkyl or Alkenyl create with up to 8 carbon atoms, in particular by 1 to 2 alkyl radicals with 1 to 4 carbon atoms, or preferably by 1 - 2 alkoxy radicals with up to to 6 carbon atoms, especially with up to 4 carbon atoms, or through 1 cycloalkyl or cycloalkenyl radical with 5 to 7 carbon atoms, or by 1 to 2 halogen atoms such as fluorine, chlorine or bromine or by 1 to 2 trifluoromethyl radicals or by a trifluoromethoxy, nitro, cyano group or a dialkylamino, carbonamido or sulfonamido group whose nitrogen atom is straight or branched with 1 or 2 Alkyl groups each with 1 to 4 carbon atoms can be substituted and whereby the aforementioned alkyl groups together with the nitrogen atom form a 5- to 7-membered one can form a heterocyclic ring, which has an oxygen atom as an additional heteroatom may contain, or by an SOn-alkyl group, where n is 0 to 2, in particular stands for 0 or 2, and the alkyl radical is straight-chain or branched and 1 to 4 Contains carbon atoms, is substituted and where 2 substituents on phenyl or Naphthyl ring together a branched or unbranched, saturated or unsaturated 5- to 7-membered, isocyclic or heterocyclic ring, the 1 sulfur or 1 It can contain 2 oxygen atoms, can form.

The hydrazine of the formula VI used as starting materials are known from the literature or can be prepared by methods known from the literature (cf.e.g. Houben-Weyl, "Methods of Organic Chemistry", Volume X, 2, page 6).

Examples include: α-methyl-3-chlorobenzylhydrazine, α-methyl-3-bromobenzylhydrazine, α-methyl-4-chlorobenzylhydrazine, α-methyl-4-bromobenzylhydrazine, α-methyl-3,4-dichlorobenzylhydrazine, α-methyl-3,4-dibromobenzylhydrazine, α-methyl-3-hrom-4-chlorobenzylhydrazine, o5-methyl-4-bromo-3-chlorobenzylhydrazine, cc -Methy1-4-methylbenzylhydrazine, α-methyl-3-methylbenzylhydrazine, α-methyl-3-ethylbenzylhydrazine, α-methyl-4-trifluoromethylbenzylhydrazine, α-methyl-3-chloro-4-methylbenzylhydrazine, α-methyl-4-chloro-3-methylbenzylhydrazine, α-methyl-4-methyl-3-trifluoromethylbenzylhy drazin, o methyl 1-3-chloro-4-trifluoromethylbenzylhydrazine, α-methyl-4-chloro-3-trifluoromethylbenzylhydrazine, α-methyl-4-sulfonamidobenzylhydrazine, α-methyl-4-chloro-3-sulfonamidobenzylhydrazine, α-methyl-4-methoxybenzylhydrazine, α- (naphthyl- (2) -) ethyl hydrazine, α-methyl-3,4-tetramethylene benzyl hydrazine, α-methyl-3,4-methylenedioxybenzylhydrazine, α-ethyl-4-chlorobenzylhydrazine, α-ethyl-3-chlorobenzylhydrazine, α-ethyl-7,4-dichlorobenzylhydrazine, α-ethyl-4-bromo-3-chlorobenzylhydrazine, α-ethyl-3-chloro-4-methyl-benzylhydrazine.

In Formula VII R1 preferably represents hydrogen, an alkyl or alkenyl radical with up to 4 carbon atoms, a phenyl or benzyl group, which is optionally substituted by an alkoxy group with 1 to 2 carbon atoms, X preferably represents hydroxyl, an optionally branched alkoxy group with 1 to 6 carbon atoms , in particular an alkoxy group with 1 to 2 carbon atoms, a benzyloxy, an amino ', an alkylamine or a dialkylamino group with 1 to 4 carbon atoms per alkyl group Y preferably for hydrogen and Y' preferably for nitrile or preferably for the group where Y "preferably represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms or a phenyl group, or Y and Y 'together preferably represent the group where Y "'denotes an alkoxy or alkyl mercapto radical each having 1 to 6 carbon atoms in the alkyl group or a benzyloxy, phenoxy, benzyl mercapto radical or an amino group.

The acetic acid derivatives used as starting materials according to formula VII are known from the literature or can be prepared by processes known from the literature (cf. Org. Synth., Coll. 1, 249; Org. Synth. 41, 50; Cope, J. Aus. chem. Soc.

67, 1047 (1945); C. C. Steele, J. Amer. chem. Soc. 53: 286 (1931); A. H. Cook, J. chem. Soc. (London) 1949, 3224).

Examples include: methyl cyanoacetate, ethyl cyanoacetate, Propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate (cf. Org. Synth. 41, p. 5), isobutyl cyanoacetate, tert-butyl cyanoacetate, Hexyl cyanoacetate, benzyl cyanoacetate, cyanoacetic acid amide, methyl cyanoacetate, Cyanoacetic acid diethylamide. Cyanoacetic acid butylamide, α-cyanopropionic acid methyl ester, ethyl α-cyanopropionate, propyl α-cyanopropionate, isopropyl α-cyanopropionate, α-cyanopropionic acid n-butyl ester, α-cyanopropionic acid isobutyl ester, α-cyanopropionic acid tert. - butyl ester, α-cyanopropionic acid hexyl ester, α-cyanopropionic acid benzyl ester, α-cyanopropionic acid amide, α-cyanopropionic acid methylamide, α-Cyanopropionic acid diethyl ester, α-Cyanopropionic acid butylmmide, α-Cyanobutyric acid ethyl ester, α-cyanobutyric acid tert. - butyl ester, α-cyanobutyric acid diethylamide, ß-amino-ß-methoxyaoryl acid ethyl ester, ß-Amino-ß-ethoxyacrylic acid ethyl ester, ß-amino-ß-butoxy-acrylic acid butyl ester, ß-amino-ß-phenoxyacrylic acid ethyl ester, ß-Amino-ß-benzyloxyacry lsäurebenzylester, ß-Amino-ß-ethoxyacrylic acid amide, ß-Amino-ß-äthoxyaerylsäurediethylamid, ß-Amino-ß-methylmercaptoacrylic acid ethyl ester, ß-Amino-ß-benzylmercaptoacrylic acid ethyl ester, ß-Amino-ß-methylmercapto-acrylic acid amide, ß, ß-diaminoacrylic acid ethyl ester, ß, ß-diamino-acrylic acid amide, ß-Amino-ß-methoxymethacrylic acid ethyl ester, ß-Amino-ß-ethoxymethacrylic acid ethyl ester, ß-Amino-ß-butoxymethacrylic acid butyl ester, ß-amino-ß-phenoxymethacrylic acid ethyl ester, ß-Amino-ß-benzyloxymethacrylic acid ethyl ester, ß-Amino-ß-methylmercaptomethacrylic acid ethyl ester, ß-Amino-ß-benzylmercaptomethacrylic acid ethyl ester, ß-Amino-ß-ethoxymethacrylic acid amide, ß-Amino-ß-ethoxymethacrylic acid diethylamide, ß-amino-ß-methylmercaptomethacrylic acid amide, ß, ß-Diaminomethacrylic acid ethyl ester, ß, ß-Diaminomethaorylsäureamid, ß-Amino-ß-ethoxy-α-ethylacrylic acid ethyl ester, ß-Amino-ß-methylmercapto-α-ethylacrylic acid ethyl ester, ß-amino-ß-ethoxy-α-ethylacrylic acid amide, ß-Amino-ß-ethoxy-α-phenylacrylic acid ethyl ester, ß-amino-ß-ethoxy-oC -benzlacrylic acid ethy lester, α-formyl acetic acid ethyl ester, α-formylpropionic acid ethyl ester, Ethyl acetoacetate, n-butyl acetoacetate, isopropyl acetoacetate, Acetoacetic acid tert-butyl ester, acetoacetic acid diethylamide, propionyl acetic acid ethyl ester, Isopropyl propionylacetate, n-butyl propionylacetate, ethyl benzoylacetate, oL-Acetylpropionic acid ethyl ester -Acet l-propionic acid ethyl ester, ° D-Acetylpropionic acid-n-butyl ester, α-acetylpropionic acid tert-butyl ester, α-propionylpropionic acid ethyl ester, α-propionylpropionic acid isopropyl ester, α-acetylbutyric acid ethyl ester, ethyl α-propionylbutyrate, α-Propionylbutyric acid isopropyl ester, α-Benzoylacetoacetic acid ethyl ester.

All inert and - as far as lit - water are used as diluents miscible - if necessary, organic solvents diluted with water in Question This preferably includes hydrocarbons such as benzene, toluene, xylene, Halogen hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, Chlorobenzene, alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, Glycol monomethyl ether, ethers such as tetrahydrofuran, dioxane, glycol dimethyl ether, amides such as demethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric acid triamide, Sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane and bases such as pyridine, picoline, Collidine, lutidine and quinoline.

The basic condensing agents are inorganic and organic Bases in question.

This includes preferably alkali hydroxides such as sodium hydroxide and potassium carbonate and alcoholates such as sodium alcoholate and potassium alcoholate.

Inorganic and organic acids are used as acidic catalysts in question. These preferably include hydrohalic acids, sulfuric acid and Sulfonic acids such as toluenesulfonic acid and trifluoromethylsulfonic acid.

The reaction temperatures can vary within a wide range will. In general, one works between lo and 200 ° C, preferably between 20 and 100 ° C. You work at normal pressure, but it can also be done in closed Vessels are worked at higher pressure.

When carrying out the process according to the invention according to reaction scheme A 1), 1 mol of the hydrazine VI and 1 mol of the β-aminoacrylic acid derivative VII '(Y and Y' together for brought to reaction. You can start from both the B-amino-acrylic acid derivative in free form and its acid addition salts. In the latter case, it is expedient to add one mole of a base in order to set the B-aminoacrylic acid derivative free. If you are working with the hydrazine and β-aminoacrylic acid derivative in free form, it is advisable to add 1 to 10% of an acidic catalyst. One can also proceed by adding a correspondingly smaller amount of a base to the reaction mixture to neutralize the salt of the β-aminoacrylic acid derivative. When using the acid addition salt, the reaction can also be carried out in such a way that the amidrazones of the formula XI isolated and then cyclized in a second reaction step thermally or by the action of a basic Eondensantsmittel to the compounds according to the invention. However, the single-stage synthesis is particularly advantageous.

When carrying out the process according to the invention according to the reaction scheme A 2j is used to add 1 mol of the cyanoacetic acid derivative VII to 1 mol of the hydrazine VI (Y = H, Y '= nitrile) and 1-3 mol, preferably 2 Moldes of basic condensing agent a. The compounds according to the invention fall in this way of working in the form of their Salts and can be obtained by treatment with equivalent amounts of a dilute acid be set free. They can easily be crystallized out by UmT a suitable solvent or by dissolving with dilute sodium hydroxide solution, filtration Clean in the presence of animal charcoal and reprecipitation with dilute acids.

If the process according to the invention is carried out according to reaction scheme A 3), 1 mol of the hydrazine derivative VI is mixed with 1 mol of the β-eeto acid derivative VII (Y = H, reacted in a suitable diluent, the reaction mixture being stirred at an elevated temperature for two hours after the exothermic initial reaction has ended. The compounds according to the invention, which are usually obtained in crystalline form, can easily be purified by recrystallization from a suitable solvent.

Process variant B According to process B, a compound of the formula VIII with a pyrazolone (5) derivative of the formula IX implemented.

In formula VIII, A stands for a leaving radical such as halogen or the dialkyloxonium, dialkylsulfonium or trialkylammonium radical or the aryl or trifluoromethylsulfonic acid residue, but preferably for chlorine or bromine, and R2 and R3 have the meaning given under process A.

The compounds of the formula VIII used as starting materials are known from the literature or can be prepared by methods known from the literature (cf.e.g. Houben-Weyl, "Methods of Organic Chemistry", Volume V, 3 (1962) and Volume V, 4 (1960)).

Examples of the halogen compounds used in particular named: α-methyl-3-chlorobenzyl chloride, α-methyl-3-bromo-benzyl chloride, α-methyl-4-chlorobenzyl chloride, α-methyl-4-bromo-benzyl chloride, α-methyl-3,4-dichlorobenzyl chloride, α-methyl-4-bromo-3-chlorobenzyl chloride, α-methyl-4-methyl-benzyl chloride, α-methyl-4-trifluoromethylbenzyl chloride, α-methyl-3-chloro-4-methylbenzyl chloride, α-methyl-4-chlorobenzyl bromide, α-methyl-3,4-dichlorobenzyl bromide, α-methyl-3-chloro-4-methyl-benzyl bromide, α-ethyl-3,4-dichlorobenzyl chloride, α-ethyl-3-chloro-4-methylbenzyl chloride.

In Formula IX R preferably represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, in particular 1 to 2 carbon atoms, or preferably a phenyl group or preferably an amino group and R has the meaning given under A.

The tyrazolone (5) derivatives used as starting materials according to formula IX are known from the literature or can be prepared by methods known from the literature (see e.g. 3.

B. Graham et al, J. Amer. chem. Soc. 71, 983 (1949); R. Jones et al, Tetrahedron 19, 1497 (1963)).

Examples include: 3-methylpyrazolone-5), 3-ethylpyrazolone- (5), 3,4-dimethylpyrazolone- (5), 3-methyl-4-phenyl-pyrazolone- (5), 3-methyl-4-benzyl-pyrazolone- (5), 3-amino-pyrazolone- (5), 3-amino-4-methylpyrazolone- (5), 3-amino-4-phenylpyrazolone- (5).

All inert solvents can be used as diluents. These preferably include hydrocarbons such as benzene, toluene, xylene and alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether, Ethers such as tetrahydrofuran, dioxane, glycol dimethyl ether, amides such as dimethylformamide, Dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric acid triamide, sulfoxides such as dimethyl sulfoxide and sulfones such as sulfolane.

Inorganic and organic bases are suitable as bases.

These preferably include alkali hydroxides and carbonates such as sodium hydroxide and carbonate, alcoholates such as sodium alcoholate, alkali hydrides and amides such as sodium hydride or sodium amide.

The reaction temperatures can vary within a wide range will.

It is preferred to work between 20 and 120.degree. One works under Normal pressure, but you can also work in closed vessels at higher pressure will.

When carrying out the process according to the invention according to the reaction scheme B is in a suitable solvent initially from a mole of the pyrazolone derivative IX a salt with the aid of an equimolar amount of a base shown. One mole of the halogen compound is added to the solution of this salt and the entire reaction mixture is stirred, preferably at an elevated temperature.

The compounds according to the invention are isolated beforehand such that the solvent is distilled off in vacuo and the residue in water absorbs and makes the aqueous mixture slightly acidic. The one in this way of working Accruing compounds according to the invention can be removed by recrystallization easy to clean with a suitable solvent.

Process variant C According to process C, a pyrazolone (5) derivative of the formula 1, in which Z 'is preferably chlorine or bromine and R1, R2 and R3 have the meaning given above, reacted with ammonia.

The xyrazolone (5) derivatives used as starting materials according to formula X can in a simple manner according to the literature Methods made (see e.g. Japanese Patent 2872 (t64) (1961)).

Examples include: 3-chloro-1- (α-methyl-4-chlorobenzyl) pyrazolone (5) 3-chloro-1- (o; -methyl-4-bromobenzyl) -pyrazolone- (5), 3-chloro-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-chloro-1- (α-methyl-4-bromo-3-chlorobenzyl) -pyrazolone- (5), 3-chloro-1- (oD-methyl-3-chloro-4-methylbenzyl) -pyrazolone- (5 ), 3-bromo-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-bromo-1- (α-methyl-4-bromo-3-chlorobenzyl) -pyrazolone- (5), 3-bromo-1- (α-methyl-3-chloro-4-methylbenzyl) -pyrazolone- (5), 3-chloro-1- (α-ethyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-chloro-1- (oW-ethyl-3-chloro-4-methylbenzyl) -pyrazolone- (5), 3-chloro-4-methyl-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-Chloro-4-methyl-1- (α-methyl-4-bromo-3-chlorobenzyl) -pyrazolone- (5), 3-chloro-4-phenyl-1- (α-methyl-3,4-dichlorobenzyl ) -pyrazolone- (5).

Water and all inert and so on are included as diluents Miscible in water - organic solvents diluted with water if necessary in question. These preferably include hydrocarbons such as benzene, toluene, xylene, Alcohols such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether and ethers such as tetrahydrofuran, dioxane and glycol dimethyl ether.

The reaction temperatures can vary within a wide range will. In general, between 20 and 22 ° C, preferably between 50 and 15000. It can be done both under normal pressure and in closed vessels work at higher pressures.

When carrying out the process according to the invention according to the reaction scheme C becomes one mole of the pyrazolone derivative X 2 to 20 times, preferably brought a loof excess of ammonia to the reaction.

It is preferable to work in such a way that the reactants are optionally in an inert solvent in a closed vessel at an elevated temperature implements. The resulting compounds according to the invention can be easily removed Purify by recrystallization from a suitable solvent.

The quantities specified in process variants A to C can be used can of course be varied slightly.

In addition to the creation examples given below, there are also the the following active ingredients according to the invention mentioned: 3-Amino-4-methyl-1- (α-methyl-3-chlorobenzyl) pyrazolone (5), 3-Amino-4-methyl-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-amino-4-methyl-1- (α-methyl-3-chloro-4-methylbenzyl ) -pyrazolone- (5), -3-amino-4-methyl-1 - (ot -methyl-4-trifluoromethylbenzyl) -pyrazolone- (5), 3-amino-4-methyl-1- (α-methyl-3-chloro-4-bromobenzyl) -pyrazolone- (5), 3-Amino-4-methyl-1- (α- (naphthyl- (2)) -ethyl) -pyrazolon- (5), 3,4-dimethyl-1- (α-methyl-4-chlorobenzyl) -pyrazolon- (5), 3,4-Dimethyl-1- (α-methyl-3-chloro-4-methylbenzyl) -pyrazolon- (5), 3,4-Dimethy1-1- (04-methyl-4-bromo-3-chlorobenzyl) - pyrazolone- (5), 3,4-dimethyl-1- (α-methyl-4-trifluoromethylbenzyl) -pyrazolone- (5), 3,4-dimethyl-1- (α- (naphthyl- (2)) -ethyl) -pyrazolone- (5 ) 1- (α-methylbenzyl) -pyrazolone- (5), 1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-Amino-1- (α-methylbenzyl) -pyrazolone- (5), 3-Amino-1- (α-methyl-3-chlorobenzyl) -pyrazolone- (5), 3-Amino-1- (α-methyl-3-bromobenzyl) -pyrazolon- (5), 3-hmino-1- (ov-methyl-3-fluorobenzyl) -pyrazolon- (5-), 3-Amino-1- (o> -methy1-4-fluorobenzyl) -pyrazolon- (5), 3-Amino-1- (α-methyl-4-chlorobenzyl) -pyrazolone- (5), 3-Amino-1- (α-methyl-4-iodobenzyl) -pyrazolone- (5), 3-amino-1- (α-methyl-4-trifluoromethylbenzyl) -pyrazolone- (5), 3-Amino-1- (α-methyl-4-trifluoromethoxybenzyl) -pyrazolone- (5), 3-amino-1- (α-methyl-3-trifluoromethyl-4-methylbenzyl) -pyrazolone- (5), 3-Amino-1- (α-methyl-3-chloro-4-bromobenzyl) -pyrazolone- (5), 3-amino-1- (o-methyl-4-chloro-3-sulfonamidobenzyl) -pyrazolone- (5 ) 3-Amino-1- (α-methyl-3-chloro-4-methyl) -pyrazolon- (5), 3-Amino-1- (α- (naphthyl- (2) -ethyl) -pyrazolon- (5) 3-Amino-1- (α-ethyl-4-nitrobenzyl) -pyrazolone- (5), 3-amino-1- (α-ethyl-4-cyanobenzyl) -pyrazolone- (5), 3-Amino-1- (α-n-propyl-2-chloro-4-fluorobenzyl) -pyrazolone- (5) 3-methyl-1- (α-methyl-4-butylbenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3-trifluoromethyl-4-chlorobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-sulfonamidobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-dimethylaminobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3,4-tetramethylenebenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3-chlorobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-2-chlorobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3,5-dichlorobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-fluorobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-chloro-3-bromobenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-fluoro-3-chlorobenzyl) -pyrazolone- (5 ), 3-methyl-1- (α-methyl-3-methylbenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-ethylbenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-chloro-3-methyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-fluoro-3-methyl) -pyrazolone- (5 ), 3-methyl-1- (α-methyl-3-methyl-5-chlorobenzyl) -pyrazolon- (5), 3-methyl-1- (α-methyl-3,5-dimethylbenzyl) -pyrazolon- (5), 3-methyl-1- (α-methyl-3-chloro-4-trifluoromethylbenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3-methyl-4-trifluoromethylbenzyl) -pyrazolone- (5 ) 3-methyl-1- (6 -methy1-3-methopybenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-4-ethoxybenzyl) -pyrazolone- (5), 3-methyl-1- (α-methyl-3-ethylbenzyl) -pyrazolone- (5), 3-ethyl-1- (α-methyl-3-methyl-4-chlorobenzyl) -pyrazolone- (5), 3-ethyl-1- (α-methyl-3-chloro-4-methylbenzyl) -pyrazolone- (5), 3-ethyl-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-ethyl-1- (α-methyl-4-trifluoromethoxybenzyl) -pyrazolone- (5), 3-ethyl-1- (α-methyl-4-methyl-3-trifluoromethylbenzyl) -pyrazolone- (5), 5-Ethy1-1- (oo-methy1-4-bromo-3-chlorobenzyl) -pyrazolone- (5), 3-isopropyl-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-phenyl-1- (oo-methyl-D, 4-dichlorobenzyl) -pyrazolone- (5), 3-phenyl-1- (s methyl-3-chloro-4-methylbenzyl ) -pyrazolon- (5), 3-phenyl-1- (α-methyl-3-methyl-4-chlorobenzyl) -pyrazolon- (5), 3-phenyl-1- (α-n-propylbenzyl) -pyrazolone- (5), 3-phenyl-1- (α-ethyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-phenyl-4-methyl-i- (o & -methylbenzyl) -pyrazolon- (5), 3-phenyl-4-methy 1-1 - (-methyl-4-trifluorme thy lbenzy 1) -pyrazolone- (5), 3-phenyl-4-methyl-1- (α-methyl-3,4-dichlorobenzyl) -pyrazolone- (5), 3-phenyl-4-ethyl-1- (α-methyl-3-chloro-4-methylbenzyl) -pyrazolone- (5), 3-phenyl-4-ethyl-1- (α-ethyl-3,4-dimethylbenzyl ) -pyrazolone- (5).

The new compounds according to the invention can be used as medicaments Substances. They cause an increase in oral or parenteral use the water and salt excretion and can therefore be used to treat edematous and hypertonic conditions and serve to flush out toxic substances. Furthermore the compounds can be used in acute kidney failure.

The new active ingredients can be converted into the customary formulations in a known manner such as tablets, capsules, coated tablets, pills, granules, syrups, emulsions, Suspensions and solutions, using inert, non-toxic, pharmaceutical suitable excipients or solvents. Here the therapeutically active compound each in a concentration of about 0.5 to 90% by weight of the total mixture be present, d. H. in amounts that are sufficient in order to achieve the stated dosage range.

The formulations are produced, for example, by stretching of the active ingredients with solvents and / or carrier substances, if appropriate with use of emulsifiers and / or dispersants, see e.g. in the case of use of water as the diluent, optionally organic solvents as auxiliary solvents can be used.

The following are examples of auxiliary substances: water7 non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerine), glycols (e.g. Propylene glycol, polyethylene glycol), solid carriers such as. B. natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic rock flour (e.g. 3.

highly disperse silica, silicates), sugar (e.g. cane, milk and Dextrose), emulsifiers such as non-ionic and anionic emulsifiers (e.g. B. polyethylene fatty acid esters, poly oxyäthy len fatty alcohol ethers, alkyl sulfonates and Arglsulfonate), dispersants (e.g. lignin, methyl cellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenteral.

In the case of oral use, tablets can of course in addition to the carriers mentioned, additives such as sodium citrate and calcium carbonate and calcium phosphate along with various additives such as starch, preferably Contain potato starch, gelatin and the like.

Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate can be used and talc can also be used for tableting.

In the case of aqueous suspensions and / or elixirs, those for oral Applications are intended, the active ingredients can except with the abovementioned auxiliaries can be mixed with various flavor enhancers or colorings.

In the case of parenteral use, solutions of the active ingredients can be used be used using suitable liquid carrier materials. As special In the case of parenteral use, the fact has turned out to be advantageous that the compounds according to the invention are able to form salts which are readily soluble in water. These salts are obtained if the compounds according to the invention are combined in one suitable solvent with the equimolar amount of a non-dead inorganic or organic base combined. Examples include: caustic soda, potassium hydroxide, Ethanolamine, diethanolamine, triethanolamine, amino-tris-hydroxymethyl-methane, glucosamine, N-methylglucosamine. Such salts can also be used for the oral use of the invention Compounds have an increased importance by allowing absorption as desired speed up or slow down. In addition to those already mentioned above, there are examples Salts called: magnesium salts, calcium salts, aluminum salts and iron salts.

In general, it has been found to be beneficial in parenteral use Application amounts of about 0.1 to 50 mg / kg, preferably about 0.1 to 10 mg / kg Body weight per day administer to achieve effective results, and in the case of oral administration, the dosage is about 0.1 to 500 mg / kg, preferably 0.5 to 100 mg / kg body weight per day.

Even so, it may be necessary to use the above Quantities vary, depending on the body weight of the test animal or the type of application route, but also due to the species and their individual Behavior towards the drug or the type of its formulation and the Time or interval at which the administration takes place. It can do so in a few In some cases it is sufficient to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. in the If larger amounts are to be applied, it may be advisable to split them up in several Distribute single doses titer the day.

This information applies both to the application of the invention Connections in both veterinary and hospital medicine.

The following examples may be mentioned of the formulations: 1.) 200 g 3-Amino-1- (α-methyl-4-chlorobenzyl) -pyrazolon- (5) are ground to a powder, mixed with 300 g of lactose and 200 g of potato starch and after moistening with a aqueous gelatin solution granulated through a sieve.

After drying, 60 g of talc and 5 g of sodium lauryl sulfate are added. From this mixture approx.

1,000 tablets with an active ingredient content of 20 mg each compressed.

2.) 20 g of the sodium salt of 3-methyl-1- (α-methyl-3-chlorobenzyl) pyrazolone (5) are dissolved in 1000 ml of propylene glycol and made up to sooo ml with water.

This solution is poured into sterile ampoules under aseptic conditions filled with 5 ml content and 20 mg active ingredient content each.

To demonstrate the diuretic and saluretic effects of the invention Compounds in their time course was the 3-methyl-1- ( * methyl-3,4-dichlorobenzyl) pyrazolone (5) given to dogs.

The other compounds show comparable properties.

The potencies of some compounds are given in Table II.

Diuresis experiment with dogs a) Method Female beagle dogs were used used.

On the day of the experiment, the animals received a tube every 30 minutes 1 ml / kg of a solution which contained 0.4 ffi NaCl and 0.2% KCl. After that, that became Test preparation applied orally and the urine collected. A change in electrolyte excretion was recognized by comparison with control groups that the solvent used received. The amount of urine was not calculated in ml / kg. From the urine volume and the measured electrolyte concentration, the excretion could then be calculated in / uVal / kg will.

The determination of sodium and potassium was carried out by flame photometry, the determination of chloride potentiometrically.

b) Results The results are shown in Tables I and II. Renal sodium and water excretion was determined after oral administration of the test preparation considerably increased. The effect was dose dependent.

T a b e l l e I Elimination in ml or µmol / kg / 30 minutes minutes after application total excretion 1-30 31-60 61-90 91-120 121-150 151-180 after Application control urine 1.1 1.3 1.3 1.4 1.4 0.7 7.2 Na 68 79 45 57 51 36 336 K + 88 88 64 45 42 25 352 1 mg / kg urine 4.5 11.9 4.6 3.9 1.0 0.6 26.5 p.o. Na + 358 1238 535 428 64 14 2637 K + 170 259 165 212 102 67 975 3 mg / kg urine 10.0 16.1 9.8 5.0 2.5 2.0 45.4 p.o. Na + 969 1932 1251 622 283 218 5275 K + 216 259 216 152 119 103 1065 Effect of 3-methyl-1- (α-methyl-3,4-dichlorobenzyl) pyrazolone (5) on the renal electrolyte and water excretion of awake dogs in their temporal Course and its overall effect after 3 hours (mean values of 4 animals each).

Table II Excretion in / uEq or ml / kg / 1 hour Na + K + Control 168 136 2.4 H3 iS CH3 H3C-OP -CH-NX at 3 mg / kg po 1158 358 10.5 CH3 Hs CH, <-CH-N 3 3 mg / kg po 1347 223 11.2 w Ss I. 0H3 \ 3 mg / kg p.0. 397 278 5.7 O -CH- 93 mg / kg po 397 278 5.7 C2H5 H3 3 mg / kg po 472 185 6.5 mg / kg po 472 185 6.5 CHN \ CH 10 mg / kg po 1050 330 14.7 CH3 CH 0 Br- O -CH-N <3 mg / kg po 1106 334 8.7 3 example 1 15 g of ethyl acetate were dissolved in 20 ml of abs. Dissolved ethanol. 16.4 g of α-n-propylbenzylhydrazine in a little abs were slowly added to this solution under nitrogen. Ethanol added. After the exothermic reaction had subsided, the mixture was refluxed for 2 hours.

On cooling, the crude product crystallized out, which was obtained by recrystallization was purified from methanol.

M.p. 125-12700; Yield 15 g (65 ff. Of theory) The following compounds were synthesized analogously to the procedure described in Example 1: No. Structural formula Umkristall- Aus Fp. lization booty o from% ie 2 H3 CH Ethanol 7B H: Ethanol 78 167 - -. 169 0 02H5 OH3 3 O 1H NS ethanol 65 160 O n No. Structural formula Umkristall- Aus Fp. lization booty oC from% d.Th. Hs CK, - 4 H3O -N> methanol 71 1446 0 5 Br-O-GN-NX dimethyl- t 63 150 - formamide 152 O CH3 CH 6 01- O -CH-N >> ethanol 145 -, ethanol 77> 7 145 B. 7 H3C- C3 -L-NC / methanol 80 140 - C1 O Example 8 16.5 g of α-methylbenzylhydrazine were dissolved in about 30 ml of dioxane and added under nitrogen to a solution of 17.5 g of propionyl acetic ester in dioxane, the reaction mixture heating up. After refluxing for 4 hours, the reaction mixture was concentrated. After trituration, the product crystallized out. It was recrystallized from methanol, melting point 114-11600; Yield 9.2 g (6c of theory) Example 9 To a solution of 31.8 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 150 ml of ethanol 41 g of oH-methyl-5,4-dichlorobenzylhydrazine, dissolved in abs. Ethanol, added dropwise. After stirring for two hours and standing overnight, the reaction solution was concentrated to the maximum on a rotary evaporator. The remaining residue was dissolved in 2N sodium hydroxide solution. Possibly unreacted starting products or

By-products were extracted with ether.

The aqueous phase was then brought to pH 5 with acetic acid. The resulting oil was taken up in methylene chloride, the organic phase dried over Na2 SO4. After evaporation of the solvent, the reaction product crystallized the end.

It was recrystallized from methanol.

M.p. 127-12900; Yield 21 g (38.5% of theory) Example 10 23.7 g of 3-chloro-1-α-ethylbenzylpyrazolone (5) were dissolved in 100 ml of ethanol, 17 g of ammonia were added and the mixture was heated to 150 ° C. in a stirred autoclave for 2 hours.

After concentrating the reaction solution, the crude product was obtained. It was recrystallized twice from ethanol.

Mp 170-172 ° C; Yield 3.8 g (8.5 ffi of theory) Example 11 To a solution of 14.4 g (0.1 mol) of α-methyl acetic acid ester in 20 ml of ethanol, 16.4 g (0.1 mol of α- (n) -prospylbenzylhydrazaine in ethanol were added under N2 gas, the The temperature rose to 70 ° C. After the addition had ended, the reaction mixture was heated under reflux for 2 hours.

The reaction product crystallized out on cooling. It turned out Recrystallized methanol.

Mp 146-148 ° C; Yield 14.2 g (59% of theory) Analogously to Example 11, the following were obtained: No. Structural formula recrystalline Aus Fp. sation booty o from% d.Th. / No ethanol 82 158- 12 <-CH-N t ethanol 82 158- 160 H30H3 CH3 OH 13 Cl- 9 ICH3 X CH3 ethanol 6o 1662o - 162 Cl O CH3 CH3 CH3 14 H3C 9 -HN> methanol 50 131 - y 15 H3C 9 XH3 / A CH3 methanol 65 145 - 0 0OH3 147 Example 16 To a suspension of 5. o g. (0.11 mol) of sodium hydride in 100 ml of abs. Dimethylformamide 25.2 g of methyl-4-ethylpyrazolone (5) were added in portions.

After the evolution of H2 had ended, 28.2 g were added to the reaction solution (0.1 mol) α-methylbenzyl chloride added dropwise.

The mixture was then stirred at 60 ° C for 2 hours, the solvent in Distilled off in vacuo, the residue taken up in water and washed with dilute acetic acid acidified. The crude product obtained was made from a mixture of ethanol / Dimethylformamide recrystallized.

Mp 104-106 ° C; Yield 12.6 g (28% of theory) Analogously to the process described in Example 16, the following was obtained: No. Structural formula recrystalline Aus Fp. sation booty o from% ie CH, CH, 17 C1- 9 -CH-N ß ethanol 35 153 - - 155 Ol 0 O2H5 Example 18 17 g (0.1 mol) of allylacetoacetate were added under nitrogen to a mixture of 13.6 g of 4-methylbenzylhydrazine and 30 ml of abs. Given ethanol, a temperature increase to 55 OO took place. The reaction mixture was refluxed for 2 hours. After cooling, the reaction product crystallized out.

Mp 115-117 ° C; Yield 18.3 g (75% of theory) Analogously to Example 18 were obtained: No. Structural formula recrystalline Aus Fp. sation prey 0 from ffi d.Th. CH, FH 20 Cl- fHD NY H3 ethanol 72 124 - ) 1GH2-CICH3 Ol 0 OH2-OH - OH3 No. Structural formula recrystalline Aus Fp. sation booty OC from% d.Th. ? H3N OH3 20 H3C O -OH-N / H3C-CH- 48.5 138 o CH2-CH = CH2 139 OI 21 (4Hz) 2N = "oCH3 petroleum ether / 53 70 - \ = - -CH-N -N ether 72 o CH2-CH = CH2 Example 22 To a solution of 13.6 g (0.1 mol) «-Methylbenzylhydrazine in 20 ml of abs. 20.6 g of α-phenylacetoacetate were added dropwise to ethanol under nitrogen, the temperature of the reaction mixture rising to 55 ° C. After the reaction solution was refluxed for two hours, the reaction product crystallized out on cooling the reaction mixture.

The extracted crystals were washed with ether and removed from a Recrystallized ethanol / dimethylformamide mixture.

Mp 227-229 ° C; Yield 27 g (75% of theory) According to the procedure shown in Example 22, the following was shown: No. Structural formula P 'Recrystalline Aus Fp. sation booty o from% ie H3 / CH, 23 01- / XN / CH3 dimethyl- 79 214 - <formamid 2-16 C1 formamid 216 Example 24 To a solution of 20.3 g of α- (n) -propylbenzylhydrazine in 30 ml of abs. 31 g of α- (4-methoxybenzyl) -acetoacetic ester were added to ethanol in an inert gas atmosphere, the temperature of the reaction mixture increasing to 60.degree. After refluxing for 2 hours and standing overnight, the product crystallized out and was recrystallized from a mixture of ethanol and a little dimethylformamide.

M.p. 142-144 ° C; Yield 25 g (60% of theory) Analogously to Example 2 4 were obtained: No. Structural formula Umkristall- Aus - Fp. lization booty ° C from ga.rh. Th. u CHg H3C ethanol CH3 ethanol 67 146- OH2-0OH3 0 147 No. Structural formula Umkristall- Aus Fp. lization booty o from ffi d.'Th. CH3 3OH3 26 Cl- o -CH-N X ethanol 64 11774- - 174 Cl OO -OCH3 27 O XH3 / X OH3 ethanol 71 137 - H2- O-OCH3 OH3 OH eH3 w aCH3 ethanol / 28 n -HN dimethyl- 78 158- formamid 160 ° 0 / CH2- formamide O H OH3 \ OH3N / N Dimethy 1- 29 Cl- n 177 formamide / 73 175 - X <ethanol 177 Cl 0 // to OH2- / Example 30 To 19.2 g of ethyl benzoyl acetate in 20 ml of abs. Ethanol, 13.6 g of α-methylbenzylhydrazine in 20 ml of ethanol were dripped under N2 protective gas. After the initial exothermic reaction had ended, the mixture was refluxed for 2 hours.

The crystals obtained after cooling were made of dimethylformamide recrystallized.

Mp 168-170 ° C; Yield 19 g (75% of theory) Analogously to the procedure described in Example 30, the following was obtained: No. Structural formula recrystalline Aus Fp. sation booty ° C from .Th. Ie. O2H5 0 dimethyl- 7o 17o - 31 O -bH-N formamide 172

Claims (4)

Claims 1. 1-Substituted Pyrazolone- (5) of the formula I. in which R represents hydrogen, amino, alkyl, alkenyl or phenyl, and R1 represents hydrogen, alkyl, alkenyl or optionally substituted aryl or aralkyl, and R2 represents alkyl and R3 represents an optionally substituted aryl radical which is up to two identical or contains various substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy or an alkylamino, trifluoromethoxy, nitro, cyano, carbonamido, sulfonamido or SOn-alkyl radical (n = O to 2), optionally together with 1 or 2 substituents from the group consisting of alkyl, alkenyl, alkoxy, ralogen or trifluoromethyl, where optionally two substituents on the aryl radical together form a branched or unbranched, saturated or unsaturated, 5- to 7-membered isocyclic or heterocyclic ring, which in turn forms 1 to 2 May contain oxygen or sulfur atoms. 2. Process for the preparation of 1-substituted pyrazolones (5) of the formula I. in which R represents hydrogen, amino, alkyl, alkenyl or phenyl and R1 represents hydrogen, alkyl, alkenyl or optionally substituted aryl or aralkyl and R2 represents alkyl and R3 represents an optionally substituted aryl radical which has up to two identical or different substituents from the group consisting of halogen, trifluoromethyl, alkyl, alkenyl, alkoxy, or an alkylamino, trifluoromethoxy, nitro, carbonamido, cyano, sulfonamido or SOnAlkYl radical (n = 0 to 2), optionally together with 1 or 2 substituents contains the group alkyl, alkenyl, alkoxy, halogen or trifluoromethyl, where optionally two substituents on the aryl radical together form a branched or unbranched, saturated or unsaturated, 5- to 7-membered isocyclic or heterocyclic ring, which in turn has 1 to 2 oxygen or sulfur atoms may contain, is characterized in that A) hydrazines of the formula VI in which R2 and R3 have the meaning given above, with acetic acid derivatives of the formula VII in which R1 has the meaning given above, X for a hydroxy, alkoxy, aralkoxy, amino or alkylamino radical, Y for hydrogen and Y 'for nitrile or the group in which Y "denotes a hydrogen atom or an alkyl radical or a phenyl radical, or Y and Y 'together for the group are, where fWr is an alkoxy, aryloxy, aralkoxy, alkyl mercapto or aralkyl mercapto group or the amino group, optionally in the presence of inert solvents and basic or acidic catalysts such as alkali and alkaline earth metal hydroxides and carbonates or such as hydrohalic acids, sulfuric acid or sulfonic acids, at temperatures between 10 and 200 ° C, or B) halogen compounds of the formula VIII in which R2 and R3 have the meaning given above and A represents chlorine, bromine or iodine, with tyrazolone (5) derivatives of the formula IX in which R and R1 have the meaning given above, optionally in the presence of inert solvents and inorganic or organic bases such as alkali hydroxides, carbonates, alcoholates, hydrides or amides at temperatures between 10 and 200 ° C, or especially in the case that R in formula I represents an amino group 0 1-substituted pyrasolone (5) derivatives of the formula X. in which R1, R2 and R3 have the meaning given above end 'Z is chlorine or bromine, reacted with ammonia, optionally in the presence of inert solvents at temperatures between 50 and 150 ° C and pressures between 1 and 50 atm. 3. Medicines, characterized by a content of at least one 1-substituted pyrazolone- (5) according to claim 1. 4. Process for the preparation of diuretic and saluretic agents, characterized in that 1-substituted pyrazolone (7) derivatives according to claim 1 mixed with inert, non-toxic, pharmaceutically suitable carriers.