DE2230675A1 - DIURETIC AND ANTIHYPERTENSIVE AGENT - Google Patents

Description

i / BAYER

LEVERKU S EN-Bayerwerk * 2 JUNE IiJ IL Central areafa Patents, trademarks and licenses

II (Pha) KS / HM

Diuretic and antihypertensive agent

The present invention relates to the use of 1-substituted 3-amino-pyrazole- (5) derivatives as medicaments, in particular as diuretics and antihypertensive agents.

1-Aryl-3-aiiino-pyrazolone- (5) are already available as color couplers became known for color photography (A. Weissberger et al., J. Am. Chem. Soc. £ 6, 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 pharmaceutical active ingredients, in particular their use as diuretics and antihypertensive drugs, is new and so far not known.

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

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in which

R stands for an unsubstituted or substituted aryl radical which contains 1 to 3 identical or different substituents from the group consisting of halogen, trifluoromethyl, alkyl, phenyl, alkenyl, alkoxy, or an alkylanino, trifluoromethoxy, nitro, cyano, carbonamldo, sulfonamides - or SO _n -alkyl radical (n = O to 2), optionally together with 1 or 2 substituents from the group consisting of alkyl, alkenyl, alkoxy, halogen or trifluoromethyl,

where optionally 2 substituents on the aryl radical, together a branched or unbranched, saturated one or unsaturated, 5 to 7 membered, isocyclic or heterocyclic ring, the 1-2 May contain oxygen and / or sulfur atoms, form,

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

In addition to the preferred general form (I), the compounds according to the invention can also be present in one of the following tautomeric forms or as mixtures of such tautomeric forms.

NH

CH ₂ -R OH ₂ -R

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Surprisingly, the 3-aminopyrazolones according to the invention show ~ (5) strong diuretic, saluretic and antihypertensive Effects. Of the 3-amino-pyrazolones known from the prior art, pharmaceutical ones are so far Effects, especially diuretic, saluretic and antihypertensive effects have not become known. Regarding of 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 of pharmacy.

The 3-amino-pyrazolones (5) to be used according to the invention are precisely defined by the formula (I).

In the formula (I) stands

R preferably for an anthracenyl or phenanthrenyl radical or for a phenyl or naphthyl radical, which is represented by 1 to straight-chain «the branched alkyl or alkenyl radicals with up to 8 carbon atoms, in particular with up to 4 carbon atoms, a phenyl radical or by 1 to 3 straight-chain ones or branched alkoxy or alkenoxy radicals with up to 6 carbon atoms, or by 1 to 2 cycloalkyl or cycloalkenyl radicals with 5 to 7 carbon atoms, or by 1 to 3 halogen atoms, in particular fluorine, chlorine, bromine, iodine or by 1 to 2 Trifluermetliylreete or by a trifluoromethoxy, nitro, cyano group or a dialkylamino, carbonamido or sulfonamido group, the nitrogen atom of which can be substituted by 1 or 2 straight-chain or branched alkyl groups each having 1 to 4 carbon atoms and the aforementioned alkyl groups together with the nitrogen atom can form a 5 to 7-membered heterocyclic ring, which has an oxygen atom as an additional heterocyclic ring oatom may contain,

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230675

or by an SO -alky! group, where η is 0 to 2, in particular represents 0 or 2, and the alkyl radical is straight-chain or branched and has 1 to 4 carbon atoms contains, is substituted and

where 2 substituents on the phenyl or naphthyl ring together form a branched or unbranched, saturated one or unsaturated 5 to 7-membered, isocyclic or heterocyclic ring, the 1 sulfur and / or can contain 1 to 2 oxygen atoms.

Most of the active ingredients according to the invention are new. The connections can be established in a simple manner by adding hydrazines of the 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)

Y '

^ CH-COX (III)

Y "

in which

X is a hydroxy, alkoxy, aralkoxy, amino, or

Alkylamino radical and Y ¹ stands for hydrogen and Y "stands for cyano or Y ¹ and Y" together for the group

NH ₅

stand, where

Y for an alkoxy, aryloxy, aralkoxy, alkyl mercapto,

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OO Q Π £ \ Π ^ or aralkyl mercapto radical or the amino group,

optionally after isolation of the intermediate amidrazones of the formula (IV)

H ₂ N

^ C = CH-COX (IV)

HN
I.

HN - CH ₂ -R

in which

X and R have the meaning given above, if appropriate in the presence of inert solvents and basic or acidic catalysts, such as alkali and Brdalkalihydroxyde and carbonates or as hydrohalic acids, sulfuric acid or sulfonic acids, at temperatures between ⁰ and 100 C.

Examples of the active ingredients according to the invention include:

3-Amino-1- (benzyl) -pyrazolone- (5) 3-amino-1- (4-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (3-chlorobenzyl) -pyrazolone- (5) 3 -Amino-1- (2-chlorobenzyl) -pyrazolone- (5) 3- amino-1- (3,4-dichlorobenzyl) -pyrazolone- (5) 3-amino-1- (2,4-dichlorobenzyl) -pyrazolone - (5) 3-Amino-1- (2,5-dichlorobenzyl) -pyrazolone- (5) 3-amino-1- (2,6-dichlorobenzyl) -pyrazolone- (5) 3-amino-1- (3rd , 5-dichlorobenzyl) pyrazolone (5) 3-amino-1- (3,4,5-trichlorobenzyl) pyrazolone - (- 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) 3 -Amino-1- (4-fluoro-3-bromobenzyl) -pyrazolone- (5)

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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-methylbericyl) -pyrazolone- (5) 3-amino-1- (4 -t-butylbenzyl) -pyrazolone- (5)

3-Amino-1- (2-chloro-3-methylbenzyl) -pyrazolone- (5) 3-Amino-1- (3-chloro-5-methylbenzyl) -pyrazolone- (5) 3-amino-1- (3 -bromo-5-methylbenzyl) -pyrazolone- (5)
3-amino-1- (3,5-dimethylbenzyl) pyrazolone- (5)
3-Amino-1- (4-propyl-3-chlorobenzyl) -pyrazolone- (5) 3-Amino-1- (4-bromo-3-methylbenzyl) -pyrazolone- (5)
3-amino-1- (3,4,5-trimethylbenzyl) 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) -pyrazolone- (5) 3-amino-1- (4 trifluoromethylbenzyl) pyrazolone (5) 3-amino-1- (3-trifluoromethylbenzyl) pyrazolone- (5) 3-amino-1- (4-chloro-3-trifluoromethylbenzyl) pyrazolone- (5) 3-amino -l- (3-chloro-4-trifluoromethylbenzyl) -pyrazolone- (5) 3-amino-l- (4-fluoro-3-trifluoromethylbenzyl) -pyrazolone- (5) 3-amino-l- (4-bromo- 3-trifluoromethylbenzyl) pyrazolone- (5) 3-amino-1- (3-chloro-5-trifluoromethylbenzyl) pyrazolone- (5) 3-amino-1- (4-trifluoromethyl-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-l- (3,4-tr ime thy lbenzyl) - pyrazolon- (5)
3-Amino-1- (3,4-tetramethylene-benzyl) -pyrazolone- (5) 3-amino-1- (3,4-tetramethylene-5-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (4 -methoxybenzyl) -pyrazolon- (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) -pyrazolone- (5) 3-amino-1- (4-methyl-3-methoxybenzyl) -pyrazolone- (5) 3-amino-1- (3-methoxybenzyl) -pyrazolone- (5 )
3-Amino-1- (4— ethoxybenzyl) -pyrazolone- (5)

3-Amino-1- (4-propoxybenzyl) -pyrazolone- (5) 3-Amino-1- (4-methoxy-3-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-nitrobenzyl) -pyrazolone- (5) 3-amino-1- (3-nitrobenzyl) -pyrazolone- (5) 3-amino-1 - (4-nitro-3-methylbenzyl) -pyrazolone- (5) 3-amino -1- (3-nitro-4-methoxybenzyl) -pyrazolone- (5) 3-amino-1- (3-nitrobenzyl) -pyrazolone- (5) 3-amino-1- (2-methoxybenzyl) -pyrazolone- ( 5) 3-Amino-1- (2-methoxy-6-methylbenzyl) -pyrazolone- (5) 3-amino-1- (2-methoxy-6-chlorobenzyl) -pyrazolone- (5) 3-amino-1 - (2-nitro-6-methylbenzyl) -pyrazolone- (5) 3-amino-1- (4-cyanobenzyl) -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, N'-dimethylsulfonamidobenzyl) -pyrazolone- (5) 3-amino-1- (4-carbonamido-benzyl) -pyrazolone - (5) 3-Amino-1- (4-N, W-dimethylcarbonamidobenzyl) -pyrazolone- (5) 3-amino-1- (3-N, N'-dimethylcarbonamidobenzyl) -pyrazolone- (5) 3-amino -1- (naphthyl-1-methyl) -p yraz # l * n- (5) 3-Amino-1- (naphtyl-2-methyl) -pyrazelen- (5) 3-amino-1- (1-methy1-naphthalenyl-2-methyl-pyrazolone- ( 5) 3-Amino-1- (3-chloro-naphthaleny1-2-methyl) -pyrazolone- (5) 3-Amino-1- (4-methylsulfonylbenzyl) -pyrazolone- (5) 3-amino-1- ( 4-methylsulfonyl-3-chlorobenzyl) pyrazolone (5) 3-amino-1- (3-methylsulfonyl-4-chlorobenzyl) pyrazolone (5) 3-amino-1- (3-methylsulfonylbenzyl) pyrazolone - (5) 3-Amino-1- (3-methylsulfonyl-4-methylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-methylsulfonyl-3-methylsulfonyl-3-methylbenzyl) -pyrazolone- (5) 3 -Amino-1- (4-sulfonamido-3-chlorobenzyl) -pyrazolone- (5) 3-amino-1- (5,6-dichloro-naphthyl-2-methyl) -pyrazolone- (5) 3-amino-1 - (6,8-dichloro-naphthyl-2-methyl) -pyraz «l # BL- (5) 3-Amino-1- (5-chloro-naphthyl-2-methyl) -pyraz # l # n- (5 )

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I ■ "

y 7 ^ π R

3-Amino-1- (3-ethylbenzyl) -pyrazolone- (5) 3-Amino-1- (3-n-propylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-n-propylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-isopropylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-n-butylbenzyl) pyrazolone- (5) 3-Amino-1- (3.4-diethylbenzyl) pyrazolone- (5) 3-Amino-1- (2-phenylbenzyl) -pyrazolone- (5) 3-Amino-1- (4-ethylmercaptobenzyl) -pyrazolone- (5) 3-Amino-1- (4-chloro-3-sulfonamido-benzyl) -pyrazolon- (5) 3-Amino-1- (2-nitro-4-dimethylaminobenzyl) -pyrazolone- (5) 3-Amino-1- (5-indanylmethyl) -pyrazolone- (5) 3-Amino-1- (2-anthranyleethyl) -pyrazelon- (5) 3-Amino-1- (3-phenanthrylBethyl) -pyriaztloii- (5) 3-Amino-1- (8-chloronaphthyl "2-methyl) -ipyrazole # n- (5) 3-Amino-1- (4-trifluoromethyl-3-chlorobenzyl) -pyrazolone- (5) 3-Amino-1- (8-trifluoromethyl-naphthyl2-2methyl) -

pyrazolone- (5)

3-Amino-1- (4-methylsulfony1-3-bromobenzyl) -pyrazolone- (5) 3-Amino-1- (4-trifluoromethoxybenzyl) -pyrazolone- (5) 3-Amino-1- (3-trifluoromethoxybenzyl) -pyrazolone- (5) 3-Amino-1- (4-trifluoromethoxy-3-chlorobenzyl) -pyrazolone- (5)

3-Amino-1- (3-butoxybenzyl) pyrazolone- (5) 3-Amino-1- (3-chloro-4-butoxybenzyl) -pyrazolone- (5) 3-Amino-1- (3-ß-dimethylamino-ethoxybenzy1) -pyrazolone- (5)

The compounds according to the invention are substances which can be used as medicaments. They cause oral or parenteral use a strong increase in the excretion of water and salt and can therefore be used for treatment edematous and hypertonic conditions and to flush out toxic substances. In addition, the connections be used in acute renal failure.

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The new active ingredients can be converted into the customary formulations in a known manner, such as tablets, capsules, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90 percent by weight of the total mixture, ie in amounts which are sufficient to achieve the stated dosage range.

The formulations are prepared, for example by stretching 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.

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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 natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic Rock flour (e.g. highly dispersed silica, silicates), sugar (e.g. raw, milk and grape sugar); Emulsifier, such as non-ionic and anionic emulsifiers (e.g. polyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, Alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, waste liquor, 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 use, tablets can of course also be used in addition to the carrier substances mentioned Additives such as sodium citrate, calcium carbonate and dicalcium phosphate along with various additives such as Contain starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as Magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of watery ones Suspensions and / or elixirs which are intended for oral use can contain the active ingredients except those mentioned above Various flavor enhancers or colorings are added to auxiliaries.

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J 7 ^ DR 7 ζ

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 are obtained when using 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-hydroxymethyl-methane, glucosamine, N-methylglucosamine. Such salts can also for the oral use of the compounds according to the invention are of increased importance in that they have the Accelerate or delay absorption as required. Except for 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 / kg 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

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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 a few cases it can be sufficient with less than the aforementioned minimum amount to get along, while in other cases the upper limit mentioned is exceeded must become. If larger amounts are to be applied, it may be advisable to split them up in several To distribute individual items over the day.

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

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

To demonstrate the diuretic and saluretic action of the compounds according to the invention, the procedure described in Example 1 3-Amino-1- (4-chlorobenzyl) pyrazolone- (5) described Administered to dogs and rats.

1. Dog experiment:

a) method

Female Beagle dogs were given on study day by gavage every 30 minutes 1 ml / kg of a solution containing 0.4 ° / o of NaCl and KCl 0.2 fi. The urine produced in the first few minutes was discarded. Thereafter, the test preparation was administered orally in 0.5 mg / kg 0.1% tragacanth rash and the urine was collected for 2 hours. The urine volume (ml / kg) and the measured electrolyte concentration (mmol / l) were used to calculate the renal excretion in / u Val / kg / 2 hours. The determination of sodium and potassium was carried out by flame photometry, that of chloride potentiometrically.

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ft

Td) results

The results are shown in Table 1. Renal sodium and water excretion is after oral Administration of the test preparation increased considerably. The effect is dose-dependent. After 10 mg / kg p.o. the sodium excretion is increased tenfold compared with the treated control animals. The excretion of potassium is only doubled after this dose.

Table I.

control Elimination in ml or yuVal / kg / 2 hours. sodium
240 + 74 chloride
501 + 64 potassium
250 + 72 3 mg / kg p.o. water
5.2 + 0.5 773 + 0.3 1087 + 11S 289 + 51 10 mg / kg p.o. 8.5 + 0.8 2370 + 499 2826 + 56? 471 + 54 30 mg / kg p.o. 18.5 + 2.3 3531 + 478 4070 + 593 848 + 273 30.1 + 5.0

Effect of 3-amino-1- (4-chlorobenzyl) -pyrazolone- (5) on renal electrolyte and water excretion in conscious dogs. Mean values and spread of 4 animals each.

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2nd rat experiment:

a) Methods

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

b) Results

The results of the tests are shown in Table 2, In rats too, oral administration of the test preparation leads to a dose-dependent increase in the HaCl and water excretion. As in dogs, the sodium excretion is influenced to a much greater extent than that Potassium excretion.

Table II

Elimination in ml or juVal / kg / 5 hours. sodium chloride potassium control water 10 mg / kg p.o. 470 + 89 947 + 136 597 + 54 30 mg / kg p.o. 20 + 1.6 694 + 125 1232 + 104 771 + 64 100 mg / kg p.o. 28.0 + 2.5 1471 + 101 2249 + 129 763 + 75 51.9 + 1.9 4973 + 275 6956 + 253 1246 + 94 66.4 + 2.8

Electrolyte and water excretion in rats

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under the administration of 3-amino-1- (4-chlorobenzyl) -pyrazolone- (5). Mean values and spread of 16 animals each.

After the method described in the above rat experiment, the effects of the compounds of Preparation examples 7 and 12 tested on rats. The results of this exemplary test are in the following Tables III and IV shown.

Analogous to the test results for the compound of the preparation example 1 it can be assumed that the compounds of Examples 7 and 12 also have a show a much stronger effect.

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Table III

Elimination in ml or yuVal / kg / 5 hours. sodium chloride potassium control water 30 mg / kg p.o. 817-81 T011 ± 72 364 ± 35 100mg / kg p.o. 20.5 ± 0.8 627 ± 72 917 ± 87 335 ± 51 1281 ± 289 2095 ± 358 710 ± 75 22.6 ± 2.9

Electrolyte and water excretion in rats under the Exposure to the compound of Example 12 mean values and scatter of 10 animals each.

Table IV

Elimination in ml or jiVal / kg / 5 hours. sodium chloride potassium control water 30 mg / kg p.o. 817 ± 81 1011 ± 72 364 ± 35 100mg / kg p.o. 20.5 ± 0.8 1254 ± 92 1911 ± 91 453 ± 28 21.7 ± 1.1 4394 ± 218 5837 ± 162 1304 ± 51 49.8 ± 0.8

Electrolyte and water excretion in rats under the action of the compound of Example 7 Mean values and spread of 10 animals each.

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Examples; example 1

174 g (10 % excess) ß-amino-ß-ethoxy-acrylic acid ethyl ester are introduced into 500 ml of ethanol. 156 g of 4-chlorobenzylhydrazine are added with stirring. The temperature rises to 30 - 40 °. The mixture is stirred for a further 2 hours and the reaction mixture is then left to stand for 12 hours. Precipitated crystals are filtered off with suction, the solvent is driven off, the residue is taken up in water and made alkaline with 2N NaOH. The aqueous alkaline phase is extracted with ether, the ether discarded. The crystals already obtained from the reaction solution are dissolved in the sodium-alkaline phase, stirred for 30 minutes with animal charcoal and filtered. The reaction product is obtained by introducing CO ₂ or by acidifying it with dilute acetic acid, which is reprecipitated again for further purification or is recrystallized from alcohol. 138 g of matted, colorless needles with a pp. 134 ° are obtained. (Yield: 62 $ of theory)

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Example 2

35 g (10 % excess) of ß-amino-ß-ethoxyacrylic acid ethyl ester are introduced into 100 ml of ethanol. 32 g of 3-chlorobenzylhydrazine in 50 ml of ethanol are added with stirring. It is worked up as above. 18.9 g of colorless matted needles of pp. 132 are obtained. (Yield: 42 # of theory).

Example 3

From 35 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 32 g of 2-chloro-benzylhydrazine, 17.5 g of colorless crystals of pp. 153 ° are obtained in an analogous procedure. (Yield: 40 $ of theory).

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Example 4 Cl

From 35 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 38 g of 2,6-dichlorobenzylhydrazine, 24 g of colorless crystals corresponding to 46 % of theory with a pp. 225 ° are obtained.

Example 5

144 g (10 io excess) .beta.-amino-.beta.-methoxy-methyl acrylate are introduced in..500 ml of dioxane. While flushing with nitrogen, 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture. The mixture is stirred for 2 hours at 60 °, the solvent is driven off on a rotary evaporator, the residue is worked through with 600 ml of 2N NaOH, extracted with ether and the aqueous phase is stirred for 1/2 hour with animal charcoal. After filtration, the pH is adjusted to 5 with dilute acetic acid. The initially oily product becomes crystalline when rubbed and is recrystallized again from alcohol for final cleaning. 139 g are obtained, corresponding to approx. 54 fi of theory. matted colorless needles with a melting point of 159 °.

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2230B75

Example 6

V ₁

-CH ₂ -N _x

9.2 g of metallic sodium are dissolved in 200 ml of ethanol, then a mixture of 25 g is made at room temperature Ethyl cyanoacetate and 35g ρ-bromobenzylhydrazine in 50 ml of ethanol are added. The mixture is heated to 60 ° for 2 hours, the precipitated substance is filtered off with suction and the filtrate is evaporated a. 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 matted needles with a melting point of 13.9 ° are obtained, corresponding to 36 <fo of theory.

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 20 g 4-bromobenzylhydrazine by stirring in alcohol for 5 hours at 50 °, after working up as described in Example 1, 15.6 g corresponding to 58% of theory are obtained. colorless crystals from Mp. 139 ° obtained.

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Example 8

-CH ₂ -N ^

-NH ₃

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

Example 9

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 with a melting point of 129 ° were obtained.

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Example 10

17.5 g of ß-amino-ß-äthoxyacrylsäUreäthylester 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 under reduced pressure. The residue will
a solution of 4.6 g of Na in 100 ml of ethanol was added and the mixture was 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 being dissolved from alcohol, melts at 149 °. The yield is 7.3 g, corresponding to 36 i> d.Th.

Example 11

-NH ₂
CH ₃

4.6 g of Na are dissolved in 100 ml of ethanol. One admits
this solution is a mixture of 12 g of ethyl cyanoacetate and 13.6 g of 3-methylbenzylhydrazine. The mixture is heated to boiling for 5 hours while stirring and passing in N ^.
After the solvent has been chased off, taken up in water, etherified and clarified with animal charcoal, colorless crystals are obtained after acidification with acetic acid

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Dissolve from ethanol melt at 92 °. The yield is 10.3 g, corresponding to 51 i ° of theory.

Example 12

CH ₃

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

Example 13

NH _S

CH ₃

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 15 g 2,4-Dimethylbenzylhydrazine analogous to the procedure described in Example 1, 14.3 g corresponding to 66 56 of theory. of m.p. 151 °.

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Example 14

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 16.7 g 4-Nitrobenzylhydrazine, analogous to the procedure described in Example 1, gives 17.3 g of yellowish crystals with a melting point of 182 ° corresponding to 74 $ d. Th. Received.

Example 15

O ₂ NQ

NH ₂

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

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2230: 67

Example 16

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 14.7 g of 4-cyanobenzylhydrazine analogous to the procedure described in Example 1, 11.3 g, corresponding to 49 i ° of theory, are obtained, which after drying Melt in the drying tube at 187. When it falls over or dissolves from aqueous solvents, the compound crystallizes with one mole of water of crystallization.

Example 17

4.6 g of Na are dissolved in 200 ml of ethanol. In the cold you carry 42 g of ß-amino-ß-ethylmercaptoacrylic acid ethyl ester as

Hydrochloride. Then 38 g of 4-trifluorobenzylhydrazine entered into the mixture. The mixture is stirred for 2 hours at 60 ° and left to stand for 12 hours at room temperature. Man the solvent is distilled off, 200 ml of water and 200 ml of ether are added, the ether phase is separated off and acidified the aqueous phase .an. The crude product is recrystallized from alcohol for further purification. 33 g are obtained matted needles with a melting point of 130 ° corresponding to 63 $ of that.

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Example 18

32.8 g of ß-amino-ß-ethoxy-acrylic acid ethyl ester were dissolved together with 1 g of p-toluenesulfonic acid in 120 ml of ethanol and 39 g of 2,5-dichlorobenzylhydrazine were added under nitrogen. After two hours of stirring , the precipitated product was left to stand overnight suctioned off and recrystallized from Aethanel. M.p .: 195-196 ° C, 23 g (43%).

Example 19
Cl

V ₁

To a solution of 49.6 g of ß-amino-ß-ethoxyacrylic acid ethyl ester in 220 ml of ethanol, after addition of 1 g of p-toluenesulfonic acid, 59 g of 3,5-dichlorobenzylhydrazine were added dropwise under nitrogen. The solution was left to stand overnight, the precipitated solids melt after recrystallization from ethanol at 175-176 ° C. 40 g (48

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Example 20

Cl Cl

16.7 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were combined with 1 g of p-toluenesulfonic acid dissolved in 100 ml of ethanol and treated with 20.2 g of 2,3-dichlorobenzylhydrazine. After standing The precipitate which had separated out was filtered off with suction and dissolved in 2 η sodium hydroxide solution overnight at room temperature. The alkaline The solution was extracted again with ether and then weakly acidified with dilute acetic acid. Included fiöl the product, the melting point was after recrystallization from ethanol at 161 ~ 162 ° C. 11 g (40 $ S).

Example 21

42.4 g of 2-bromobenzyl hydrazine were added dropwise under nitrogen to a solution of 33.4 g of ß-amino-ß-ethoxyacrylic acid methyl ester and 1 g of p-toluenesulfonic acid in 250 ml of ethanol was added. After stirring for 15 hours at room temperature the solution was concentrated in vacuo, the precipitating Sucked off precipitate and dissolved in 2 η sodium hydroxide solution. the alkaline solution was extracted again with ether and then weakly acidified with dilute acetic acid, whereby the product failed. This melted after recrystallization from ethanol at 168-169 °. 27.5g ($ 49).

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Example 22

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

Example 23

Br-OKH ₂ -N _x "

48.8 g of 4-bromo-3-chlorobenzylhydrazine were added dropwise under nitrogen to a solution of 33.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 1.5 g of toluenesulfonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand, and the product began to crystallize out after four hours. It was filtered off with suction and recrystallized twice from ethanol. M.p .: 145-146 °, 23 g (37 $>).

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Example 24
^C1

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>).

Example 25

CHo -N _x

= I - NH ₅

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 added dropwise under nitrogen. 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 <fo) .

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Example 26

CH ₂ -N

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 of ethanol, a solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise under nitrogen. The temperature rose from 22 ° to 32 ⁰ C. 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 from ethanol, melted at 185-186 ° C. 13 g (33%).

Example 27

A solution of 40.5 g of B-hydraein · methylnaphthalene was added under nitrogen 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. The mixture was subsequently stirred for two hours. After a further two hours, the product precipitated and was filtered off with suction and recrystallized from ethanol. M.p .: 156-157 °, 22 g (39 <f>).

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Example 28

H3C O
\ y - i

^ CH ₃ ^NH a

To a solution of 28.2 g of .beta.-amino-.beta.-äthoxyacryls & ureathylester and 1 g of p-Toluolsulf "neäure in 130 ml Aethanel 26.6 g of 2,5-Dimethylbenzylhydrazin were added dropwise, keeping the temperature from 25 to 35 ⁰ C increase. After stirring overnight, the precipitate which had separated out was filtered off and recrystallized from ethanol.
Fp .: 124 °, 20 g (52 f)

Example 29

Au ε 17 ', 5 ß-amino-ß-ethoxyacrylic acid ethyl ester and 19 g of 3-trixluorobenzylhydrazine analogous to the procedure described in Example 1. 9 g of colorless crystals with a melting point of 144 ° are obtained, corresponding to 33 f of theory.

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Example 50

CF, G-

-CH ₅ -

NILE

From 17, S! -.- Amino-p-ethoxyacrylic acid ethyl ester and 20.6 g 4-Trifluoromethoxybenzylhyarazine analogous to that in Example 1 described mode of operation. Kan receives 8.7 g colorless

Crystals with a melting point of 99 ° accordingly

d. Theory.

Example 31

CH ₃ O

From 17: ¹ J g .beta.-amino-.beta.-äthoxyacrylsäureäthylester and 15.2 f 4-Methoxybenzylhydrazin the procedure described in Example 1 analogously. 9.7 g of colorless crystals with a melting point of 161 ° are obtained, corresponding to 44 % of theory.

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 16.6 g 3,4-Methylenedioxybenzylhydrazine analogous to that in Example 1 described mode of operation. 12.1 g of colorless are obtained

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Crystals with a melting point of 218 °, corresponding to 52 ° ^C. according to theory.

example

H ₅ -i;

O.

üH »

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 17.6 g 5,4-Tetramethylene benzyl hydrazine analogous to that in Example 1 described mode of operation. 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.

example

From 17.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester and 20.2 g of 2,4-dichlorobenzylhydrazine analogous to that in Example 1 described mode of operation.

11 g of colorless crystals with a melting point of 189 ° are obtained, corresponding to 40 # of theory.

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Example 55

G of 37.5 g of .beta.-amino ~ ß-äthoxyacrylsäureäthylester and 40.5 (X-hydrazinomethyl-naphthalene in analogy to the procedure described in Example 1. 24 g of colorless crystals of Pp.180 ° corresponding to 50 Jo ⁰ of theory.

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Example 36

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
27.5 g of o-methylbenzylhydrazine, dissolved in 100 ml of ethanol, were added dropwise at room temperature. After standing overnight, the reaction solution was concentrated in vacuo, and the precipitate which separated out was filtered off with suction and extracted from ethanol
recrystallized.
Fp .: 138 °, 15 g (37 f)

Example 37

20.5 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were dissolved together with 1.5 g of p-toluenesulfonic acid in 200 ml of ethanol. 26 g of m-bromobenzylhydrazine were added dropwise to this solution under nitrogen. 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 .: 160 °, 12 g (35 f)

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Example 38

To a solution of 28.6 g of ß-amino-ß-ethoxyacrylic acid. ethyl ester and 1.5 g of p-toluenesulfonic acid in 350 ml of ethanol, a solution of 45 g of m-iodobenzyl hydrazine in 70 ml of ethanol was added dropwise. After stirring overnight, the deposited precipitate was filtered off with suction and recrystallized from ethanol.
Mp .: 186 °, 16 g (28 #)

Example 39

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 was a solution of 25.5 g of p-iodobenzy 1-hydrazine under nitrogen added dropwise in 100 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo, the residue recrystallized from ethanol. Mp .: 158 °, 15 g (47 #)

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Example 4θ

30.2 g of ß-amino-ß-ethoxyacrylic acid ethyl ester were dissolved together with 2 g of p-toluenesulfonic acid in 300 ml of ethanol and
27.1 g of o-fluorobenzylhydrazine were added under nitrogen. 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.
Mp .: 146 °, 11 g (27 #)

Example 41

To giner solution of 19.8 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-fluoro-5-chlorobenzylhydrazine 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.
Mp .: 160 *, 17 g (57 %)

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Example 42

12.2 g of ß-Aniino-ß-ät & oxyacrylic 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-dibromobenzylhydrtizine 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.
Mp .: 182 °, 11 g (£ 41)

Example 43

20.5 g of 3-methyl-4-chlorobenzylhydrazine were added dropwise under nitrogen to a solution of 19.1 g of ß-amino-ß-ethoxyacrylic acid ether and 1.5 g of p-toluenesulfonic acid in 200 ml of ethanol. The reaction solution was stirred overnight, the precipitate which had separated out was filtered off with suction and recrystallized from ethanol.
Mp .: 131 °, 10 g ( $ 35)

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Example 44

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 were added under nitrogen. Butylbenzylhydrazin added dropwise, wherein the T _e mperature rose from 24 ° to 30 ⁰ C. 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. Mp .: 126 °, 8 g (24%)

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Claims (2)

Claims: ^^ gd ^^ OfTI M AΛt_fc { f ^ Diuretic and antihypertensive agent, characterized by a content of at least one 3-amino-pyrazolone- (5) the formula ,. / NH ₂ ο * V ^(I) CH ₂ -R in which R is an unsubstituted or substituted aryl radical, the 1 to 3 identical or different substituents from the group of calogen, trifluoromethyl, alkyl, Contains phenyl, alkenyl, alkoxy or an alkylamino, trifluoromethoxy, nitro, cyano, carbonamide, sulfonamide or SO-alkyl radical (n = 0 to 2), optionally together with 1 or 2 substituents from the group alkyl, alkenyl, Contains alkoxy, halogen or trifluoromethyl, where optionally 2 substituents on the aryl radical,; together a branched or unbranched, saturated or unsaturated, 5 to 7 membered ^,! isocyclic or heterocyclic ring, which can contain 1-2 oxygen and / or sulfur atoms, j as such or in the form of a non-toxic salt. 2) "Process- for the preparation of diuretic and antihypertensive Agents, characterized in that 3-amino-pyrazolone- (5) according to claim 1 is mixed with inert, non-toxic, pharmaceutically suitable carriers. " Le A 14 199 - 39 - 309882/13 5