DE2230792A1 - 3-AMINO-PYRAZOLONE- (5), METHOD FOR MANUFACTURING AND USING IT AS A MEDICINAL PRODUCT - Google Patents

Description

2230792 FARBENFABRIKEN BAYER AG

LEVERKUSEN-Bayerwerk 2 JUNE 2, 1972 Central area Patents, trademarks and licenses

KS / HM Ia (Pha)

3-Amino-pyrazolone- (5), process for their preparation as well as their use as pharmaceuticals

The present invention relates to new, 1-substituted ones 3-Amino-pyrazolone- (5)> a process for their preparation and their use as medicaments, in particular as biuretics and antihypertensive agents.

1-Aryl-3-amino-pyrazolone- (5) have already become known as color couplers for color photography (A. Weiesberger et al., J. Am. Chea. Soc. 64., 2133 (1942)

Furthermore, some 3-aminopyrazolone- (5) are also available as Intermediates have been used to make color couplers (British Patent 599,919; U.S. Patent 2,367,523; 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.

Their use as active pharmaceutical ingredients, in particular their use as biuretics and antihypertensive drugs is new ' and so far not known.

It has been found that the new 3-amino-pyrazolone- (5) the formula

(D

309883/1378

Le A 14 440 - 1 -

in which

R stands for a phenyl radical which is identical or different by 1 to 2 Substituents from the group alkyl, alkenyl, phenyl, trifluoromethoxy, nitro, cyano, carbonamido, Sulfonamido, alkylamino or fluorine, bromine or iodine substituted is, where optionally two substituents on the phenyl ring together form a branched or unbranched, saturated one or unsaturated five- to seven-membered isocyclic or heterocyclic ring, the oxygen and / or May contain sulfur atoms, form,

or for a phenyl radical which is substituted by an SO -alkyl group (n = O to 2), an alkoxy group or the grouping -O- (CH ₂ ) _n -N (alkyl) ₂ (n = 2 to 3), or for a phenyl radical which is substituted by two identical substituents from the alkoxy or trifluoromethyl group,

or for a phenyl radical which is substituted by two different substituents from the group comprising alkyl, alkenyl, phenyl, halogen, alkoxy, trifluoromethyl, trifluoromethoxy, alkylamino, cyano, carbonamido, SuIfonamido, SO _n -alkyl (n = O to 2), and nitro ,

or for a phenyl radical which is substituted by three chlorine atoms,

or for a naphthyl radical substituted by 1 to 2 identical or different halogen atoms and / or alkyl,

or represents an unsubstituted β-naphthyl radical, anthryl radical or phenanthryl radical,

as such or in the form of their salts, strong diuretic, saluretic and have anti-hypertensive properties.

Ie A 14 440 - 2 -

309883/1378

In addition to the delayed perm (i), the compounds according to the invention can also be used in one of the following tautomeric Form as a mixture of such tautomeric fennels

are present.

r— ^ ¹

HO N

HO

OH ₂ -R

CH ₂ -R

OH ₂ -R

It has also been found that 3-Amino-pyrazolone- (5) of the formula (I) is obtained if
Hydrazines of formula (II)

R-CH ₂ -NH-NH ₂

(II)

in which

R has the meaning given above,

with acetic acid derivatives of the formula (III)

N) H-COX

(III).

in which

X for a hydroxy, alkoxy, aralkoxy, amino,

or alkylamino radical, and
Y ^{1 represents} hydrogen and
Y "stands for nitrile, or
Y 'and Y "together for the group

Le A U 440

309883/1 378

^, NHp
= C

stand, where

Y for an alkoxy, aryloxy, aralkoxy, alkyl mercapto, or aralkyl mercapto radical or the amino group,

possibly after isolation of the intermediate anidraMne of the? #sleeve (IV)

H ₂ K

^ C = CH-COX (IV) HN
HN - GH ₂ -R

in which

X and R have the meaning given above,

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 20 ° and 100 ⁰ G reacted.

Surprisingly, the 3-aminopyrazolones (5) according to the invention show strong diuretic, saluretic and antihypertensive effects. Of the 3-amino-pyrazolones known from the prior art, pharmaceutical effects, in particular diuretic, saluretic and antihypertensive effects, have not yet become known. With regard to these special pharmaceutical effects, the compounds according to the invention represent a novel class of substances and are therefore to be regarded as an enrichment in pharmacy. Le AU 440 - 4 -

309883/1378

Depending on the type of starting materials used, the synthesis of the compounds according to the invention can be carried out by one of the following Reaction schemes are shown, where 3-Amino-1- (p-bromobenzyl) pyrazolone- (5) was chosen as an example and the reproduction of the intermediate (formula (IV) J) was omitted.

NH ₂ JT ~ j

₂ VcH ₂ -NHNH ₂ + CNCH ₂ COOC ₂ H ₅ - * JT ~ j + c _Η

^ü N

OH ■ Br

b) Br-fVcH uHjra ₊

H ₂ N '

'C = CH-COOC ₂ H ₅

+ 2C ₂ H ₅ OH

In formula II

R-CH ₂ -NH-NH ₂

(II)

stands

preferably for a phenyl radical, which is represented by 1 to 2 identical or different substituents from the group alkyl, alkenyl, phenyl, trifluoromethoxy, carbonamides), Sulfonamido, cyano, nitro, alkylamino or fluorine, bromine or iodine is substituted, said alkyl and alkenyl radicals having up to 8 carbon atoms, in particular up to to 4 K "hl" "st # ffatome, and where the amide tick off by 1 or 2 straight-chain or branched alkyl

Ie A U 440

309883/1378

groups with 1 to 4 carbon atoms, can be substituted and these alkyl groups with the amide nitrogen can form a 5- to 7-membered heterocyclic ring, which has an oxygen atom as an additional heteroatom may contain and where 2 adjacent substituents on Phenyl radical together a branched or unbranched, saturated or unsaturated 5- to 7-membered, isocyclic or heterocyclic ring, the 1 sulfur and / or can contain 1 to 2 oxygen atoms, can form,

or

for a phenyl radical, which is replaced by an SO -alkyl group, where η is 0 to 2, in particular 0 or 2, and the alkyl radical is straight-chain or branched and

Contains 1 to 4 carbon atoms, is substituted,

or

for a phenyl radical, which by an alkoxy group, whose Alkyl radical can be straight-chain or branched and contains 2 to 4 carbon atoms,

•the ·

for a phenyl radical which is substituted by the grouping -O- (CH ₂ ) _n -N (alkyl) r ₎ , where η is the same

2 to 3 and the alkyl radicals can contain a total of 2 to 4 carbon atoms,

or

for. a phenyl radical, which by two identical substituents from the group alkoxy with 1 to 4 carbon atoms or Trifluoromethyl is substituted,

or

for a phenyl radical which has two different substituents from the group halogen, such as fluorine, chlorine, bromine, iodine, or trifluoromethyl, trifluoromethoxy, nitro, cyano, phenyl, alkyl or alkoxy, each with 1 to 8 carbon atoms, in particular with 1 to 4 carbon atoms, Alkenyl with 2 to 4 carbon atoms, carbonamido, sulfonamides, where the amide nitrogen can be substituted by 1 or 2 alkyl groups with 1 to 4 carbon atoms, or SO _n -alkyl-

Ie A 14 440 - 6 -

309883/1378

Group (η = O or 2) where the alkyl radical. Contains 1 to 4 carbon atoms,

or

for a phenyl radical which is substituted by 3 chlorine atoms,

- or

for a naphthyl radical, which is replaced by 1 to 2 identical or different halogen atoms, in particular chlorine or bromine, and / or alkyl radicals having 1 to 4 carbon atoms is substituted, ■

or

for an unsubstituted ß-naphthyl radical, phenanthryl radical or anthryl radical.

The hydrazines of the formula II used as starting materials are known from the literature or can be used according to those known from the literature Methods (compare for example HOUBEN-WEYL, "Methods of Organic Chemistry, Volume X, 2, page 6).

Examples are:

2-methylbenzylhydrazine, 3-methylbenzylhydrazine, 4-methylbenzylhydrazine, 3-ethylbenzylhydrazine, 4-ethylbenzylhydrazine, 3-n-propylbenzylhydrazine, 4-n-propylbenzylhydrazine, 4-isopropylbenzylhydrazine, 4-n-butylbenzylhydrazine, 4-tert.-butylbenzylhydrazine, 4-isobutylbenzylhydrazine, 4-phenylbenzylhydrazine, 2-phenylbenzylhydrazine, 4-cyclopentylbenzylhydrazine, 4-cyclohexylbenzylhydrazine, 3,4-dimethylbenzylhydrazine, 2,5-dimethylbenzylhydrazine, 2,4-dimethylbenzylhydrazine, 3,4-diaethylbenzylhydrazine, 3-methyl-4-propylbenzylhydrazine, 4-vinylbenzylhydrazine, 2-fluorobenzyl hydrazine, 3-plurobenzyl hydrazine, 4-fluorobenzyl hydrazine, 2-bromobenzyl hydrazine, 3-bromobenzyl hydrazine, 4-bromobenzyl hydrazine, 3-iodobenzyl hydrazine, 4-iodobenzyl hydrazine, 2-nitrobenzylhydrazine, 3-nitrobenzylhydrazine, 4-nitrobenzylhydrazine, 3-cyanobenzylhydrazine, 4-cyanobenzylhydrazine, 3-trifluoromethoxybenzyl hydrazine, 4-trifluoromethoxybenzyl hydrazine,

Le AU 440 .3 ^ 883/1378

3-carbonamidobenzyhydrazine, 4-methylaminocarbonylbenzylhydrazine, 4-sulfonamidobenzylhydrazine, 4-dimethylsulfonamindobenzylhydrazine, 4-methylaminobenzylhydrazine, 4-methylmercaptobenzylhydrazine, 4-ethyl mercaptobenzyl hydrazine, 4-ethylsulfonylbenzylhydrazine, 3-butoxybenzylhydrazine, 4-butoxybenzylhydrazine, 3-ethoxybenzylhydrazine, 3- (ß-diaethylaminoethoxy) -benzylhydrazine, 3,4-dimethoxybenzyl hydrazine, 3,4-methylenedioxybenzylhydrazine, 3,5-dimethoxybenzylhydrazine, 3,5-diaethoxybenzylhydrazine, 3,4-bis-trifluoromethylbenzylhydrazine, 3-chloro-4-methylbenzylhydrazine, 4-chloro-3-methylbenzylhydrazine, 3-cyano-4-methylbenzylhydrazine, 3-methyl-4-nitrobenzylhydrazine, 4-trifluoromethyl-3-methylbenzylhydrazine, 3-trifluoromethyl-4-methylbenzylhydrazine, 4-chloro-3-trifluoromethylbenzylhydrazine, 4-trifluoromethyl-3-chlorobenzylhydrazine, 4-chloro-3-bromobenzylhydrazine, 4-bromo-3-chlorobenzylhydrazine, 3,4-dibromobenzylhydrazine, 2-fluoro-5-chlorobenzylhydrazine, 2-chloro-4-fluorobenzylhydrazine, 4-chloro-3-sulfonamidobenzyl hydrazine, 4-chloro-3-methoxybenzylhydrazine, 4-chloro-3-butoxybenzyl hydrazine, 2-nitro-4-dimethylaminobenzylhydrazine, 2,4,5-trichlorobenzylhydrazine, 5-hydrazinomethylindane, 2-hydrazinomethyl naphthalene, 2-hydrazinomethyl-5,6,7,8-tetrahydronaphthalene, 2-hydrazinomethyl-5-methylnaphthalene, 2-hydrazinomethyl-5-chloronaphthalene, 2-hydrazinomethyl-8-chloronaphthalene, 2-hydrazinomethyl-8-chloronaphthalene, 3-hydrazine ethyl phenantrenene.

In the formula (III)

Y '
^ • GH-COX (III)

Y "

X preferably represents hydroxyl, an alkoxy group with 1 to 6 carbon atoms, in particular a branched one Alkoxy group with 3 to 6 carbon atoms, a benzyloxy group, an amino, an alkylamino or a dialkylamino group each having 1 to 4 carbon atoms per alkyl group, and

Le AH 440 " ₈ 5.0 9 8 8 3/1 3 7 8

Y 'preferably represents hydrogen and

Y "preferably for nitrile or ■ *"

Y ^f and Y "together preferably for the group = C, where

Y preferably represents an alkoxy or alkyl mercapto radical with 1-6 carbon atoms in each case in the alkyl group, or represents a benzyloxy, phenoxy, _t benzyl mercapto radical or an alino group.

The acetic acid derivatives of the formula III used as starting materials are known from the literature or can be prepared by literature methods (see a.) Org.Synth., CoIL ₁ I, 249 or Org.Synth. 4J_ _f 50 and b) Cope, J.Am.Chem.Soc. 67, 1047 (1945)).

Examples are:

a) methyl cyanoacetate, ethyl cyanoacetate, Propyl cyanoacetate, isopropyl cyanoacetate * Cyanoacetic acid n-butyl ester. (cf. Org.Synth. 41., p. 5) » Isobutyl cyanoacetate, tertibutyl cyanoacetate, Hexyl cyanoacetate, benzyl cyanoacetate, Cyanoacetic acid amide, cyanoacetic acid methylamide, cyanoacetic acid diethylamide, Cyanoacetic acid butylamide.

b) ß-Amino-ß-methoxyaerylic 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-benzyloxyacrylic acid ß-amino-ß-butoxyacrylic acid-benzyl ester ß-amino-ß-benzyloxyacrylic acid-benzyl-ester
ß-Amino-ß-äthoxyacrylsäurediethylämid 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.

Xa A 14 44Q - 9 -

$ 309,883 / $ 137

Suitable diluents are all inert ones and, if they are miscible with water, organic ones that are optionally diluted with water Solvent in question. These preferably include Hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene; Alcohols such as methanol, Ethanol, propanols butanol, benzyl alcohol, glycol monomethyl etherj Ethers such as tetrahydrofuran, dioxane, glycol dimethyl ether; Amides such as dimethylformamide, dimethyl acetamide, H-methylpyrrolidone, hexamethylphosphoric triamide; Sulphoxides such as dimethyl sulphoxide, sulphones such as SuIfolan and tertiary bases such as pyridine, picoline, collidine, and lutidine Ghinolin. Inorganic and organic bases are used as basic condensation agents. These preferably include Alkali hydroxides such as sodium hydroxide, potassium carbonate and alcoholates such as sodium alcoholate and potassium carbonate.

Inorganic and organic acids are used as acidic catalysts. These preferably include hydrogen halides, Sulfuric acid and sulfonic acids such as toluenesulfonic acid and trifluoromethylsulfonic acid.

The reaction temperatures can be varied within a wide range. In general, between 10 and 200 ^° C., preferably between 20 and 100 ^° C., is carried out at normal pressure, but it is also possible to work in closed vessels at higher pressure.

When carrying out the method according to the invention (variant a)) one puts one mole on one mole of the hydrazine (il) of the cyanoacetic acid derivative (III) and 1-3 mol, preferably 2 mol, of the basic condensing agent. The invention Connections fall in this work

Ie A 14 440 - 10 -

309683/1378

instruct in the form of their salts and can through treatment be set free with equivalent amounts of a dilute acid. They can be easily removed by crystallization from a suitable solvent or by dissolving with. dilute sodium hydroxide solution, filtration in the presence of animal charcoal and reprecipitation using dilute acids clean.

When carrying out the process according to the invention (variant b)), one mole of the hydrazine (II) and one mole of the acetic acid derivative (III) (β-aminoacrylic acid derivative) are reacted. You can start from the ß-aminoacrylic acid derivative in free form as well as from its acid addition salts. In the latter case, one mole of a base is expediently added in order to set the β-aminoacrylic acid derivative free. If you work with the hydrazine and β-aminoacrylic acid derivative in free form, it is advisable to add 1 to 10 % of an acidic catalyst. It is also possible to proceed in such a way that a correspondingly smaller amount of a base is added to the reaction mixture to neutralize the salt of the aminoaeryl acid derivative.

The reaction can be directed so that first the amidrazones (IV) arise and this then in a second reaction step thermally or through the action of a basic condensation agent to the compounds according to the invention cyclize. However, the single-stage synthesis is particularly advantageous.

The following new active ingredients are mentioned in detail:

3-Amino-1 - (3,4,5-t ri ch.lt> rbenzyl) -pyrazolon- (5) 3-Amino-1- (4-fluorobenzyl) -pyrazolone- (5) 3-Amino-1- (4-bromobenzyl) -pyrazolone- (5) 3-Amino-1- (4-chloro-3-bromobenzyl) -pyrazolone- (5) 3-Amino-1- (4-fluoro-3-chlorobenzyl) -pyrazolone- (5) 3-Amino-1- (3,4-dibromobenzyl) -pyrazolone- (5) 3-Amino-1- (4-bromo-3-chlorobenzyl) -pyrazolone- (5)

Le A 14 440 - 11 -

309883/1378

3-Amino-1 - (4-fluoro-3-broebenzyl) -pyrazolone- (5) 3-Amino-1- (4-methylbenzyl) -pyrazolone- {5) 3-Amino-1- (4- methyl-3-chlorobenzyl) pyrazolone (5) 3 ~ amino-1- (4-ethylbenzyl) pyrazolone- (5) 3-amino-1- (4-chloro-3-methylbenzyl) pyrazolone- (5) ■ 3-Amino-1- (4-fluoro-3-methylbenzyi) -pyrazolone- (5) 3-Amino-1- (4-t.-butylbenzy1) -pyrasolone- (5) 3-amino-1- (2- chloro-3-methylbenzy1) -pyrazolone- (5) 3-amino-1- (3-chloro-5-methylbenzy1) -pyrazolone- (5) 3-amino-1- (3-bromo5-methylbenzyi) -pyrazolone- ( 5) 3-Amino-1- (3,5-dimethylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-propyl-3-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (4th -bromo-3-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-vinylbenzyl) -pyrazolone- (5) 3-amino-1- (4-phenylbenzyl) -pyrazolone- (5) 3-amino -1- (3-phenylbenzyl) -pyrazolone- (5) 3-amino-1- (3-phenyl ~ 4-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (4-phenyl-3-methylbenzyl) -pyrazolon- (5) 3-amino-1- (4-chloro-3-trifluoromethylbenzyi) -pyrazolon- (5) 3-amino-1- (3-chloro-4-trifluoromethylbenzyi) -pyrazolon- (5) 3-Amino-1- (4-fluoro-3-trifluoromethylbenzyl) pyraz olone- (5) 3-amino-1- (4-bromo-3-trifluoromethylbenzyl) -pyrazolone- (5) 3-amino-1- (3-chloro-5-trifluoromethylbenzyl) -pyrazolone- (5) 3- Amino-1- (4-trifluoromethy1-3-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-methyl-3-trifluoromethylbenzyl) -pyrazolone- (5) 3-amino-1- (3, 4-dimethylbenzyl) pyrazolone (5) 3-amino-1- (2,5-dimethylbenzyl) pyrazolone- (5) 3-amino-1- (3,4-trimethylene benzyl) pyrazolone- (5) 3 -Amino-1- (3 _f 4-th tramethylene-benzy1) -pyrazolone- (5) 3-amino-1- (3,4-tetramethylene-5-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (3 , 4-dimethoxybenzyl) pyrazolone (5) 3-amino-1- (3,4-methylenedioxybenzyl) pyrazolone (5) 3-amino-1- (3-chloro-4-methoxybenzyl) pyrazolone ( 5) 3-Amino-1- (4-chloro-3-methoxy-benzyl) -pyrazolon- (5) 3-Amino-1- (4-methy1-3-methoxybenzyl) -pyrazolon- (5)

I * AU 440 - 12 -

309883/1378

3-Amino-1- (4-raethoxy-3-ynethyll3eiizyl) -pyrazolone- (5} 3 ~ amino-1- (4-nitrobenzyl) -pyrazolone- (5) 3-amino-1 - {2-nitrobenzyl) - Pyrazolone- (5) 3-amino-1 - (4-nitro-3-re thylberizy 1) -pyrazolone- (5) 3-amino-1 - (3-nitro-4-methoxyberi2yl 5 -pyrazolone- (5) 3 -Amino -1- (3-ni trobenzy 1) -pyr £ isolon- (5) 3-amino-1 - (2-methoxy-6-methy! Benzyl) -pyrazolon- (5) 3-amino-1- (2-Methoxy-6-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (2-nitro-6-methylbenzyl) -pyrazolone- (5) 3-amino-1- (3-cyano-4-chlorobenzyl ) -pyrazolone- (5) 3-amino-1- (4-cyano-3-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-cyano-3-methoxybenzyl) -pyrazolone- (5) 3 -Amino-1- (4-sulfonamidobenzyl) -pyrazolone- (5) 3-amino-1- (4-N, ii -dimetiiylsulfonamidobenzyl) -pyrazolone- (5) 3-amino-1- (4-carbonamido-benzyl} -pyrazolone- (5). 3-Amino-1 - (4, H ^ dimethylcarbonamidobenzyl) -pyrazolone- (5) 3-amino-1- (3-N, N -dimethylcarbonamidobenzylJ-pyrazolone-iS) 3-amino -1 - (naphthylmethyl-2) -pyrazolone- (5) 3 * amino-1- (1-methyl-naphthylmethy1-2) -pyrazolone- (5) 3-amino-1- (3-chloro-naphthy Imethyl-2) -pyrazolone- ( 5 ) 3-amino-1- (4-methylsulfonyl-3-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (3-methylsulfonyl-4-chlorobenzyl) -pyrazolone- ( 5) 3-Amino-1- (3-methylsulfony1-4-methylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-methylsulfonyl-3-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-sulfonamido-3-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (5,6-dichloro-naphthylmethyl-2) -pyrazolone- (5) 3-amino-1- (6.8 -dichlor-naphthylmethyl-2) -pyrazolone- (5) 3-amino-1- (5-chloro-naphthylmethyl-2> -pyrazolone- (5 )

3-Amino-1- (4-methylsulfonyl-3-bromobenzyl) -pyrazolone- (5) 3-Amino-1- (4-trifluoromethoxybenzyl) -pyrazolone- (5) 3-Amino-1- (3-trifluornethoxybenzyl) -pyrazolone- (5)

3-Amino-1- (4-trifluoromethoxy-3-chlorobenzyl) pyrazolone- (5) Le A 14 440 - 13 _

^ 09883/1378

The new erfindungsgemäßsn Ysrbiadungen are en as drugs usable substance you 'cause when administered parenterally .or Amvsndung a strong increase in water and salt retention and may therefore serve to treat edematous and hypertonic conditions. In addition, the compounds can be used in acute kidney failure,

The new active ingredients can in a known manner in the common formulations, such as tablets, Capsules, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carrier substances or solvents. Here the therapeutic active compound each in a concentration of about 0.5 to 90 percent by weight of the total mixture be present, i.e. in amounts sufficient to achieve the stated dosage range.

The formulations are produced, for example, by extending the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, optionally organic solvents as auxiliary solvents can be used.

The following are examples of auxiliary materials:

Water, 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

Le A 14 440 - 14 -

309883/1378

flours (e.g. kaolins, clays, talc, chalk), synthetic Rock flour (e.g. highly dispersed silica, silicates), Sugar (e.g. raw, milk and grape sugar); Emulsifiers such as nonionic and anionic emulsifiers (e.g. polyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, Alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, sulfite waste liquors, 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 parenterally. '■

In the case of oral administration tablets can of course apart from the abovementioned carriers, additives such as ¹ Natriuncitrat, Galciumcarbonat and dicalcium phosphate together with various additional substances such as starch, preferably potato starch, gelatine and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs intended for oral use, various flavor enhancers or colorings can be added to the active ingredients in addition to the abovementioned auxiliaries.

In the case of parenteral use, solutions of the active ingredients can be made using suitable liquid Support materials are used. As particularly advantageous in the case of parenteral use the fact has been found that the compounds according to the invention are readily soluble in water, capable of forming hydrolysis-stable salts. These salts

Le A 14 440 - 15 -

309883/1 378

are obtained when one of the compounds according to the invention in a suitable solvent with the equimolecular amount of a non-toxic inorganic or organic base combined. Examples include: caustic soda, potassium hydroxide, ethanolamine, diethanolamine, Triethanolamine, amino-tris-hydroxymethy1-methane, Glucosamine, N-methylglucosamine. Such salts can also for the oral use of the compounds according to the invention are of increased importance by the Accelerate or delay absorption as required. 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 proven to be advantageous for parenteral administration to use amounts of about 0.01 to 50 mg / kg, preferably to administer about 0.1 to 10 mg / kg of body weight per day for 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 / lg of body weight per day.

Nonetheless, it may be necessary to deviate from the amounts mentioned, depending on the amount on the body weight of the test animal or the type of application route, but also on the basis of the animal species and their individual behavior towards the drug or the type of its formulation and the point in time or the interval at which the administration takes place. So in poor cases it can be sufficient with less than the aforementioned minimum amount, while in other cases the upper limit mentioned is exceeded must become. In the case of the application of larger amounts, it may be advisable to divide them up into several individual doses to distribute the day.

Le A 14 440 - 16 -

309883/1378

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

The following are the pharmaceutical effects of some compounds according to the invention listed by way of example. The other compounds show comparable properties.

To demonstrate the diuretic and saluretic effects of the compounds according to the invention, the 3-amino-1- (4-chloro-3-br »mlaenzyl) -pyraMl # n- (5) described in the example Administered to dogs and rats.

1. Dog experiment:
a) method

On the day of the experiment, female beagle dogs received 1 ml / kg of a solution containing 0.4 $> NaCl and 0.2 <fo KCl every 30 minutes with the gavage. The urine produced in the first 60 minutes was discarded. The test preparation was then administered orally in 0.5 mg / kg 0.1% tragacanth mucus and the urine was collected for 3 hours. The urine volume (ml / kg) and the measured electrolyte concentration (mmol / l) were used to calculate the renal excretion in / u Val / kg / 3 hours. The determination of sodium and potassium was carried out by flame photometry, that of chloride potentiometrically. >

Le A 14 440 - 17 -

309883/1378

b) Results

The results are shown in Table 1. Renal sodium and water excretion is considerably increased after oral administration of the test preparation. The effect depends on the dose. As early as 1 g / kg PE, the sodium excretion is increased by a factor of four compared to the treated Kentrell animals *. The potassium excretion is only doubled after this desie.

Table I.

Elimination in ml or / iVal / lcg / 3 hours.

P O. water sodium chloride Kaiium P- O. control .O. 7.7 ^± 1.8 471 ± 335 787-283 374-100 0.3 mg / kg 7.9 644 966 292 1 mg / kg 20.2 2539 3054 600 3 mg / kg ρ 40.1 4577 5746 1110

Electrolyte and water separation in dogs under the influence of 3-Amine-1- (4-ehler-3-bro »bensvl) -pyraxelen- (5) Average values for every 2 animals (Kentrolle - 5 animals).

Le A14 440

- 18 -

309883/1378

2. rat experiment;

a) Methods

Male SPF rats from the Wistar strain were given the Gavage 10 ml / kg 0.1 «δ tragacanth mucus. With this Liquid, the test preparation was administered in mg / kg. The animals were then placed in diuresis cages in pairs. The urination period lasted 5 hours. The collecting urine was filtered and chemically analyzed.

b) Results ■ '·

The results of the tests are shown in Table 2. Oral administration of the also occurs in rats Test preparation to a dose-dependent increase in NaCl and water excretion. The sodium excretion will how it affects the dog much more than the potassium excretion.

Table II Elimination in ml or jnVal / kg / 5 hours.

mg / kg P. .0. water 1.8. sodium 81 chloride 112 potassium 72 mg / kg P. .0. 4.4 534 601 103 mg / kg P. .0. 19.8 - 3.8 445 - 385 797 ^± 440 561 ± 88 control 32.1 ± 2.7 2010 - 199 -2700 - 288 795 - 61 3 48.8 ± 3819 - 4910 ± 1134 i 10 ei, 2 ± 5916 - 7482 i 1572 ± 30th

Electrolyte and water separation in rats under the influence of T »m 3-amine» -1- (4-chloro-3-laromfeenzyl) pyraz »l.en- (5) mean values and scatter s ^ of 16 each.

Le A 14 440

- 19 -

30 9883/1378

After the method described in the above rat experiment, the effects of the compounds of Preparation Examples 7 and 1 were also tested on rats. The results of this exeraplari see test are shown in Tables III and IV below.

Le A 14 440 - 20 -

309883/1378

X4

Table III

Elimination in ml or / u Val / kg / 5 hours. sodium chloride potassium control water 30 mg / kg p.o. 817 ± 81 1011 ± 72 364 ± 35 100 mg / kg p.o. 20.5 ± 0.8
* 627 ± 72 917 ± 87 335 ± 51 15.3 ± 1.2 ■ 1281 ± 289 2095 ± 358 710 ± 75 22.6 ± 2.9

Electrolyte and water excretion in rats under the action of the compound of Example 12 Mean values and spread of 10 animals each.

Table IV

Elimination in mi O, 8th . respectively. ± 81 / u Val / kg / 5 Hours. potassium ± 35 control water 1, 1 sodium ± 92 ± 28 30 mg / kg p.o. O, 8th ± 218 72 364 ± 51 100 mg / kg p.o. 20.5 + 817 91 453 1254 62 1304 49.8 ± 4394 chloride 1011 ± 1911 ± 5837 ± 1

Electrolyte and water excretion in rats under the action of the compound of Example 7 Mean values and scatter of 10 animals each Le A 14 440 - 21 -

309883/1378

Example 1:

9 »2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of ethyl cyanoacetate and 35 g of p-bromobenzylhydrazine in 50 ml of ethanol is then added at the temperature of the edge. The mixture is heated to 60 ^° C. for 2 hours and sucks off. precipitated substance and evaporates the piltrate. It is taken up in water, shaken through with ether and the aqueous phase is acidified with dilute acetic acid. For purification, the crude product is recrystallized twice from alcohol.

17 g of felted needles with a pp. 139 ° corresponding to 36 ^c / o of theory are obtained.

Example 2:

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 20 g of 4-bromobenzylhydrazine by stirring for 5 hours in alcohol at 50, after working up as described in Example 1, 15 »6 g corresponding to 58 f> d.Th. colorless crystals of pp. 139 ° were obtained.

Le A 14 440 - 22 -

309883/1378

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 13 g of 4-pluobenzylhydrazine by stirring for 5 hours in ethanol at 60 °, 13.2 g of colorless crystals with a mp. 148 ° corresponding to 63 are obtained after working up as described in Example 1 i ° d.Th. obtain.

Example 4:

17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 13 g of 3-fluorobenzylhydrazine are stirred for 5 hours in ethanol at 60 ° after working up as described in Example 1, 11.3 g corresponding to 55 ° of theory. colorless crystals of pp. 129 ° were obtained.

Le A14 440

- 23 -

309883/1378

Example 5 «

17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester are introduced into 75 ml of pyridine together with 13.6 g of 4-methylbenzylhydrazine. The mixture is stirred for 8 hours at room temperature and the pyridine is expelled. reduced pressure. The residue is mixed with a solution of 4.6 g of Ka in 100 ml of ethanol and heated to 60 ° for 1 hour. The alcohol is chased away and taken up with 100 ml of water. The aqueous phase is extracted with ether, clarified with charcoal and acidified. A yellow-colored precipitate is obtained which, after redissolving from alcohol, melts at 149. The yield is 7.3 g, corresponding to 36 io of theory.

Example 6;

4.6 g of Na are dissolved in 100 ml of ethanol. A mixture of 12 g of ethyl cyanoacetate and 13.6 g of 3-methylbenzylhydrazine is added to this solution. While stirring and enticing N _? is heated to boiling for 5 hours. After chasing off the solvent, taking up in water, etherifying and clarifying with animal charcoal, after acidification with ethyl acetate, colorless crystals are obtained, which after repeated

Le A14 440

~ 24 -

309883/1378

The yield is 10.3 g, corresponding to 51 i ° of theory.

Umlöseii from ethanol "melt at 92 °. The yield

example 1\

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 15g 3,4-Dimethylbenzyl hydrazine analogous to that described in Example 1 Method of operation 16 g of colorless needles with a melting point of 160 ° corresponding to 74% of the theory.

Example 8;

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 15 g of 2,4-dimethylbenzyl hydrazine analogous to the procedure described in Example 1, 14.3 g corresponding to 66 % of theory. from pp. 151 °.

Le A 14 440 - 25 -

309883/137 8

Ex iel 9j_

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 16.7 g 4-Nitrobenzylhydrazine analogous to that described in Example 1 The procedure is 17.3 g of yellowish crystals with a P.P. 182 ° corresponding to 74 ° d. Th. Received.

Example 10;

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine analogously to the procedure described in Example 1, 12.3 g of yellow crystals with a melting point of 163 °, corresponding to 52 % of theory, are obtained. obtain.

Example 11:

^ Br
42.4 g of 2-bromobenzyl hydrazine were added under nitrogen

Ie A 14 440 - 26 -

309883/1378

added dropwise to a solution of 33.4 g of ß-amino-ß-ethoxyacrylsäureme-tnyl-es-ter λχώα Λ g of p-toluenesulfonic acid in 250 ml of ethanol. After stirring for 15 hours at room temperature, the solution was concentrated in vacuo, and the precipitate which had separated out was filtered off with suction and dissolved in 2 η sodium hydroxide solution. The alkaline solution was extracted again with ether and then weakly acidified with dilute acetic acid, the product precipitating. This melted after recrystallization from ethanol at 168-169 °. 27.5, g (49/0.

Example 12;
0

Br

49 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were dissolved together with 2 g of p-TοluoIsulphonic acid in 225 ml of ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine were added under nitrogen. After standing overnight, the deposited precipitate was filtered off with suction and recrystallized twice from ethanol. P .: 171-172 ⁰ C, 40 g (43 #). '

Example 13i

Cl '

To a solution of 33.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 x g of toluenesulfonic acid in 150 ml of ethanol 48.8 g of 4-bromo-3-chlorobenzylhydrazine were added dropwise under nitrogen. After two hours of stirring it was left to stand, the crystallization of the product began after four Le A 14 440 - 27 -

309883/1378

Hours. It was filtered off with suction and recrystallized twice from ethanol. Pp .: 145-146 °, 23 g (37 #).

Example 14:

54.7 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were dissolved together with 2 g of p-toluenesulfonic acid in 400 ml of ethanol. To this end, a solution of 77.6 g of 2,4,5-trichlorobenzylhydrazine in 200 ml of ethanol was added dropwise under nitrogen. After two hours of stirring, the mixture was left to stand overnight, and the precipitate which had separated out was filtered off with suction and dissolved in 2 η sodium hydroxide solution. The alkaline solution was extracted several times with ether and then weakly acidified with dilute acetic acid, the product precipitating. This melted after recrystallization from ethanol at 195-196 °. 38 g (38 <fo).

Example 15:

To a solution of 46.7 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 200 ml of ethanol 50 g of 4-methyl-3-chlorobenzylhydrazine were obtained under nitrogen

Le A 14 440 - 28 - ■

3 0 9883/1378

added dropwise. After stirring for a further two hours, the product precipitated. It was filtered off with suction and recrystallized from ethanol. M.p .: 130-131 °, 35 g (50 #).

Example 16:

To a solution of 23.4 g (0.147 mol) of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 100 ml A solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise to ethanol under nitrogen. the The temperature rose from 22 ° to 32 ° C. in the process. After standing overnight, the reaction solution was concentrated in vacuo, the resulting precipitate was dissolved in 2 η sodium hydroxide solution and the alkaline solution was extracted several times with ether. Addition of dilute acetic acid until a weakly acidic reaction resulted in the product, which after recrystallization melted from ethanol at 185-186 ° C. 13 g ($ 33).

Example 17

To a solution of 37.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 100 ml of ethanol

Le A 14 440 - 29 -

309883/1378

under nitrogen a hole ; - ;; of 40.5 g of N- (ß-hydrazinomethylnaphthalene) were added dropwise. Ea was then stirred for two hours. After a further two hours, the product precipitated and was filtered off with suction and recrystallized from ethanol.
Pp .: 156-157 °, 22 g ( $ 39).

Example 18:

1 ^ UKfH ₂

26.6 g of 2,5-dimethylbenzylhydrazine were added dropwise to a solution of 28.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 130 ml of ethanol,
the temperature rising from 25 to 35 C. After stirring overnight, the deposited precipitate was filtered off with suction
and recrystallized from ethanol.
Pp .: 124 °, 20 g (52 #).

Example 19:

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 20.6 g of 4-trifluoroethoxybenzylhydrazine analogously to the procedure described in Example 1. 8.7 g of colorless are obtained
Crystals of pp. 99 ° corresponding to 32 $ d. Theory.

Le A 14 440 - 30

3G98S3 /

Example 20;

From 17.5 g of ß ~ amino-ß-ethoxyacrylic acid ethyl ester and 16.6 g of 3,4-methylenedioxybenzylhydrazine: i analogous to the procedure described in. Example 1. 12.1 g of colorless crystals of pp. 218 ° are obtained, corresponding to 52 % of theory.

example 21st 0, i ^ V ^CH 2 "

From 17.5 g of ß-Amirio-ß-ethoxyacrylic acid ethyl ester and 17.6 g of 3,4-tetramethylene benzyl hydrazine analogous to the procedure described in Example 1. After recrystallization from alcohol, 15.6 g of colorless crystals with a melting point of 103 ° are obtained. The compound crystallizes with one mole of crystalline alcohol. The yield is 54 % of theory.

Le A 14 440 - 31 -

309883/1378

27.5 g of O-methylbenzylhydrazine, dissolved in 100 ml of ethanol, were added dropwise at room temperature to a solution of 32 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 300 ml of ethanol. After standing overnight, the reaction solution was concentrated in vacuo, and the precipitate which had separated out was filtered off with suction and recrystallized from ethanol.
Mp. 138 °, 15 g (37 %).

Example 23:

20.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were together dissolved with 1.5 g of p-toluenesulfonic acid in 200 ml of ethanol. 26 g of m-bromobenzyl hydrazine were added to this solution under nitrogen dripping in. After stirring for two hours it was over Left to stand overnight, the precipitate which has separated out is filtered off with suction and recrystallized from ethanol. Pp .: 160 °, 12 g (35 #).

Le AU 440 - 32 -

309883/1378

A solution of 45 g of m-iodobenzylhydrazine xn 70 ml of ethanol was added dropwise to a solution of 28.6 g. After stirring overnight, the precipitate was sucked off and recrystallized from ethanol _v.
Mp .: 186 °, 16 g (28? I),

Example 25;

To a solution of 16.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 250 ml of ethanol, a solution of 25.5 g of p-iodobenzylhydrazine in 100 ml of ethanol was added dropwise under nitrogen. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallized from ethanol. Pp .: 158 °, 15 g (47 ^D ß>).

Le A 14 440 - 33 -

309883/1378

30.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ether were combined with 2 g of p-toluenesulfonic acid in 300 ml of ethanol yellow "at and

27.1 g of o-pluobenzylhydrazine were added under nitrogen.

After stirring for two hours, it was left to stand overnight, the precipitate which has separated out is filtered off with suction and extracted from ethanol

recrystallized.

Pp,: 146 °, 11 g (27 #).

Example 27 1

To a solution of 19 _f 8 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 0.5 g of p-toluenesulfonic acid in 100 ml of ethanol
21.6 g of 2-fluorine-5-chlorobenzylyhydrazine were added dropwise under nitrogen, the temperature rising from 20 ° to 30 °.
After stirring for two hours, the mixture was left to stand overnight, and the precipitate which had separated out was filtered off with suction and extracted from ethanol
recrystallized.
Pp .: 160 °, 17 g (£ 57).

Le A- 14 440 - 34 -

3Q9883 / 137S "

Example 28;

12.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were dissolved together with 1 g of p-toluenesulfonic acid in 200 ml of ethanol. To this end, a solution of 21.6 g of 3 »4-dibromobenzylhydrazine in 50 ml of ethanol was added dropwise under nitrogen. After stirring overnight, the solvent was concentrated in vacuo, the precipitate which had separated out was filtered off with suction and recrystallized from ethanol.
Pp .: 182 °, 11 g (41 #)

Example 29;

To a solution of 19 »1 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 200 ml of ethanol, 20.5 g of 3-methyl-4-chlorobenzylhydrazine were added dropwise under nitrogen. The reaction solution was stirred overnight, and the precipitate which had separated out was filtered off with suction and recrystallized from ethanol.
M.p .: 131 °, 10 g (35 %) .

Le A 14 440 - 35 -

309883/1378

UH ₂

To a solution of 22 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 100 ml of ethanol, 24.6 g of p-tert-butylbenzylhydrazine were added dropwise under nitrogen, the temperature rising from 24 to 30.degree. After stirring overnight, the solvent was distilled off in vacuo, and the oily residue solidified after the addition of 50 ml of petroleum ether. The product obtained was filtered off with suction and recrystallized from ethanol. M.p .: 126 °, 8 g (24 ^a />).

Example 31

32 g of p-isopropylbenzylhydrazine were added under nitrogen to a solution of 31.8 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 150 ml of ethanol. After stirring for two hours, the mixture was left to stand overnight. The precipitate which had separated out was filtered off with suction and recrystallized from ethanol.

Fp .: 105 °, 18.3 g (40 f.)

Le , .. H 440 - 36 -

3 C S 8 S 3/1 3 7 8

Example 32;

To a solution of 14.8 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 100 ml of ethanol, 15.1 g of 5-hydrazinomethylindane, dissolved in, were added under nitrogen
50 ml of Aethanoi, added dropwise. After stirring overnight it became
the precipitate is suctioned off and recrystallized from ethanol,

Mp .: 146 °, 9 g (42%)

Example 35 t

To a solution of 49.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 250 ml of ethanol, 53.8 g of 2-chloro-4-fluorobenzylhydrazine were added dropwise under nitrogen, v / above the temperature of 22 ° 32 ° C rise.
After standing overnight, the precipitate which had separated out was filtered off with suction and recrystallized from ethanol.

Mp. 192 °, 25 g (34 / _c )

Le A 14440 - 37 -

30M883 / 1378

223Q792

Example 34:

To a solution of 14.8 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and a spatula tip of p-toluenesulfonic acid in 80 ml of ethanol were 18 g of 3-n-butoxyboizy under nitrogen ! hydrazine was added dropwise. After stirring for two hours it was left overnight. The deposited precipitate was filtered off with suction and recrystallized from ethanol.

Mp .: 110 °, 8 g (33 %)

Example 35:

H, CO

To a solution of 50.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulfonic acid in 250 ml of ethanol were 59 g of 4-chloro-3-methoxybenzylhydrazine under nitrogen added dropwise. After standing overnight, the precipitate which had separated out was filtered off with suction and removed Recrystallized ethanol.

Fp .: 148 °, 30 (38 f.)

A 14 440

3-

Claims (4)

Patent claims: 1) '3-Anino-pyra'Jolone- (5) of the formula (D in which R stands for a phenyl radical, which has 1 to 2 identical or different substituents from the group alkyl, "" Alkenyl, phenyl, trifluoromethoxy, nitro, cyano, Carbonamido, sulfonamido, alkylamino or fluorine, Bromine or iodine is substituted, or where optionally two substituents on the phenyl ring together a branched or unbranched, saturated or unsaturated five- to seven-membered isocyclic or heterocyclic ring, which may contain oxygen and / or sulfur atoms, or. for a phenyl radical, which is replaced by an SO -Alklygruppe >'n = O to ?), an alkoxy group or the. Grouping -0- (CH ^) _n -HiAlkyl) ₂ (η = 2 to 3) is substituted, or ■. for a phenyl radical, which is replaced by two identical substituents; from the group alkoxy or trifluoromethyl is substituted, or for a phenyl radical, which is represented by two different substituents from the group alkyl, alkenyl, phenyl, Halogen, alkoxy, trifluoromethyl, trifluoromethoxy, Le A 14 4 -iö - 39 - 3 0 9 8 8 3/1378 BATH ORIGINAL Alkylamino, cyano, carbonamido, sulfonamido, SO _n -alkyl (η = O to 2) and nitro is substituted, or for a phenyl radical which is substituted by three chlorine atoms, or for one by 1 to 2 the same or different Halogen atoms and / or alkyl substituted naphthyl radical, or . , for an unsubstituted ß-naphthyl radical, anthryl radical or phenanthryl radical, 2) Process for the preparation of 3-Amino-pyrazolone- (5) the general formula / 3r GH ₂ -R in which R stands for a phenyl radical which is identical or by 1 to 2 various substituents from the group alkyl, alkenyl, phenyl, trifluoromethoxy, nitro, cyano, Carbonamido, sulfonamido, alkylamino or fluorine, Bromine or iodine is substituted, with optionally two substituents on the phenyl ring together a branched or unbranched, saturated or unsaturated five- to seven-membered isocyclic or heterocyclic ring, which may contain oxygen and / or sulfur atoms, or for a phenyl radical which _n ~ alkyl group substituted by an SO Ie AU 440 - 40 - 30988 3/137 (η = O to 2), an alkoxy group or the grouping -0- (CH ₂ ) _n -N (alkyl) ₂ (n = 2 to 3), or for a phenyl radical which is substituted by two identical substituents from the group Alkoxy or trifluoromethyl is substituted, or for a phenyl radical, which by two different substituents from the group alkyl, alkenyl, phenyl, Halogen, alkoxy, trifluoromethyl, trifluoromethoxy, Alkylamino, cyano, carbonamido, sulfonamides, SO -alkyl (η = 0 to 2) and nitro is substituted, or for a phenyl radical} which is substituted by three chlorine atoms is, or for a naphthyl radical substituted by 1 to 2 identical or different halogen atoms and / or alkyl, or represents an unsubstituted β-naphthyl radical, anthryl radical or phenanthryl radical , characterized in that hydrazines of the formula (II) in which R has the meaning given above with acetic acid derivatives of the formula (III) Y ¹ ^ CH-COX (III) Y " Ie AU 440 - 41 - 303883/1378 in which X stands for a hydroxy, alkoxy, aralkoxy, amino or alkylamino radical and Y 'stands for hydrogen and Y "stands for nitrile or Y ¹ and Y "together for the group stand, where Y for an alkoxy, aryloxy, aralkoxy, alkyl mercapto or aralkylnercapto radical or the amino group stands, optionally after isolation of the intermediates Amidrazones of formula (IV) C = GH-GOX (IV) HN t HN - in which X and R have the meaning given above, 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 20 ° and 100 ⁰ C is reacted. 3) medicament, characterized by a content of at least one 3-amino-pyrazolone- (5) according to claim - 42 - 309883/1378 inooooncen am LllllL 4) Method of making diuretic and antihypertensive Agents, characterized in that Ban 3-amino-pyrazolone- (5) according to claim 1 with inert, non-toxic, pharmaceutically acceptable carriers mixed. Ie A 14 440 309883 / Ί378