IL42560A - 1-arylmethyl-3-amino-pyrazol-5-ones and salts thereof and process for their manufacture - Google Patents

Abstract

1391051 Aminopyrazolones BAYER AG 22 June 1973 [23 June 1972] 29785/73 Heading C2C The invention comprises compounds of the tautomeric formulae and their salts, wherein R is (a) a phenyl radical carrying one or two identical or different substituents selected from alkyl, phenyl, trifluoromethyl, trifluoromethoxy, nitro, nitrile, carbamoyl, sulphamoyl, alkylamino, fluorine, bromine and iodine radicals but cannot be a phenyl radical carrying trifluoromethyl only as one substituent, or (b) a phenyl radical carrying an annellated, branched or unbranched, saturated or unsaturated, five to seven-membered isocyclic or heterocyclic ring (the heterocyclic ring containing one or more oxygen and/or sulphur atoms); or (c) a phenyl radical carrying as substituent an SO n -alkyl group (n = 0, 1 or 2), an alkoxy group, or an -O-(CH 2 ) n -N(alkyl) 2 group (n = 2 or 3); or (d) a phenyl radical carrying two identical substituents selected from alkoxy and trifluoromethyl groups; or (e) a phenyl radical carrying two different substituents selected from alkyl, phenyl, halogen, alkoxy, trifluoromethyl, trifluoromethoxy, alkylamino, nitrile, carbamoyl, sulphamoyl, -SO n alkyl (n = 0, 1 or 2) and nitro radicals; or (f) a trichlorophenyl radical; or (g) a naphthyl radical carrying one or two identical or different substituents selected from halogen atoms and alkyl groups; or (h) an unsubstituted #-naphthyl, anthryl or phenanthryl radical. These compounds are prepared by reacting RCH 2 NHNH 2 with CNCH 2 COX or where X is OH, alkoxy, aralkoxy, NH 2 or alkylamino, and Y is alkoxy, aryloxy, aralkoxy, alkylmercapto, aralkylmercapto or NH 2 . Therapeutic compositions having diuretic, saluretic and antihypertensive activity comprise compounds of the above formulae, and may be administered orally, parenterally, rectally, topically or by means of a spray. [GB1391051A]

Description

42560/2 ο » a 1 κ-5-7 i t ST a— 13 » &κ-3-,> *n»V * τκ-1 said salts thereof, and process for their manufacture BAYER AESIEtiGESEILSCHAK? The present invention relates to certain new 1- substituted 3-amino-pyrazol-5-one compounds and to a process for their production. The new compounds are diuretics and anti-hypertensive agents. l-Aryl-3-amino-pyrazolones-( 5) have already been disclosed as colour-coupling agents for colour photography (A.

Weissberger et al. , J. Am. Chem. Soc. 64., 2133 (1942).

Furthermore, some 3-a-minopyrazol-5-ones have also been used as intermediate products for the manufacture of colour coupling agents (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 pharmaceutical use, especially their use as diuretics and anti-hypertensive agents, is new and has not previously been disclosed.

This invention now provides compounds which are 3-amino-pyrazol-5-ones of the following general formula or their salts :- CH2-R in which: - R is either (a) a phenyl radical substituted by one or two identical lower alkyl, phenyl, nitro, trifluoromethyl, trifluoro- methoxy groups or fluorine, bromine and iodine atoms; or (b) an indanyl, tetralinyl or benzodioxyl radical; or (c) a phenyl radical carrying a lower alkoxy or cyano group; or (d) a phenyl radical carrying two different substituents selected from a group consisting of lower alkyl, lower . (e) a trichlorophenyl radical; or ψ (f) a naphthyl radical substituted by one or two halogen atoms; or (g) an unsubstituted β-naphthyl radical.

The general formula^ I is only one of a number of tautomeric structures that can be assumed by the 3-amino-pyrazol-5-ones according to the invention. Although general formula I is preferred, the invention applies to all the tautomeric forms of the 3-aciino-pyrazol-5-ones and their salts whether present singly or as a mixture of two or more forms.

The other tautomeric structures referred to above are as follows :- CH, The invention further provides a process for the production of a new compound as defined above in which a hydrazine of the general formula: - R-CH2-NH-UH2 (II) is reacted with an' acetic acid derivative of the general formula:- l_in which general formulae :- R is as defined above; X is a hydroxyl, alkoxy, aralkoxy, amino or alkylamino radical; and either (a) Y' is a hydrogen atom and Y" is a rcyafto ~ grouP> or (b) Y1 and Y" together represent the group:- HH2 =0 in , hich Y is an alkoxy, aryloxy, aralkoxy, alkylmercap o, aralkylmercapto or amino group] .

In this reaction an amidrazone of the general formula:' Le A U 440-RTF - 4 - is formed as an intermediate. It may be isolated as an intermediate and then cyclized thermally or in the presence of a basic condensation catalyst, or the whole reaction may be carried through in one stage.

Surprisingly, the 3-amino-pyrazol-5-.ones and their salts according to the invention show strong diuretic, saluretic and anti-hypertensive effects. Pharmaceutical effects, especially diuretic, saluretic and anti-hypertensive effects, have not hitherto been disclosed for known 3-amino- pyrazolones. In respect of these special pharmaceutical effects the compounds according to the invention represent a novel class of substances and must therefore be regarded as an enrichment of pharmacy.

Depending on the nature of the starting substances used, the synthesis of the compounds according to the invention can be represented by one of the following reaction schemes, with 3-amino-l-(p-bromobenzyl)-pyrazol-5-one being shown by way of example and the intermediate amidrazone (Formula (IV)) not being shown: Le A 1 440-RTF - 5 - The hydrazines of the general formula II used as ^ starting substances are known from the literature or can be ' produced according to methods known from the literature (compare, for example, HOUBEN-WEYL, "Methoden der organischen Chemie (Methods of Organic Chemistry), volume X» 2, page 6).

As examples of these hydrazines there may be mentioned: 2-iiethylbenzylhydrazine , 3-methylbensylhydrazine , 4-methylbenzylhydrazine , 3-ethylbenzylhydrazine , 4-ethylbenzylhydrazine , 3-n-propylbenzylhydrazine , 4-n-propylbenzylhydrazine , 4-isopropylbenzylhydrazine , 4-n-butylbenzylhydrazine , 4-tert . -butylbenzylhydrazine , 4-isobutylbenzylhvdrazine . 4-phenylbenzylhydrazine , I 2-phenylbenzylhydrazine , 3. -dimethylbenzylhydrazine , 2.5-dimethylbenzylhydrazine , 2 , 4-dimethylbenzylhydrazine , 3 , 4-diethylbenzylhydrazine , 3-methyl-4-propylbenzylhydrazine , 2-fluorobenzylhydrazine , 3-fluorobenzylhydrazine , * 4-fluorobenzylhydrazine , 2-bromobenzyihydrazine , 3-bromobenzylhydrazine , 4-bromobenzylhydrazine , 3-iodobenzylhydrazine , 4-iodobenzylhydrazine , -nitrobenzylhydrazine, 4-rn.trobenzylhydrazine , _cyanobenzylhydra ine , 4_cyanobenzylhydrazine , 3_trifluorometho ybenzylhydrazine, 4_trifl oromethoXybenzylhydrazine, 3-bu oxybenzylhydrazine , 4-butoxybenzylhydrazine , -ethoxybenzylhydrazine , ,4-methylenedioxybenzylhydrazine , ,4-bis-trifluoromethylbenzylhydrazine , -chloro-4-methylbenzylhydrazine , -c loro-3-methylbenzylhydrazine , -trifluoromethyl-3-methylbenzylhydrazine , ~trifluorome h l-4-methylbenzylhydrazine , -chloro-3-trifluoromethylbenzylhydrazine , -trifluorometh l-3-chlorobenzylhydrazine , -chloro-3-bromobenzylhydrazine , -bromo-3-chlorobenzylhydrazine , ,4-dibromobenzylhydrazine, -fluoro-5-chlorobenzylhydrazine , -chlor0-4-fluorobenzylhydrazine , -chloro-3-methoxybenzylhydrazine, -chloro-3-butoxybenzylhydrazine, ,4 , 5-trichlorobenzylhydrazine , -hydrazinomethylindane , -hydrazinoraethylnaphthalene , -hydrazinomethyl-5 ,6,7,8-tetrahydronaphthalene , -hydrazinomethyl-5-chloronaphthalene , or -hydrazinomethyl-8-chloronaphthalene , In the general formula:- X is preferably. an hydroxyl group, an alkoxy group with 1 to 6 carbon atoms (especially a branched alkoxy group with 3 to 6 carbon atoms), or a benzyloxy, amino, alkylamino or dialkylamino group, each with 1 to 4 carbon atoms per 'alkyl group; and either; - .

Y' is a hydrogen atom; and Y" is a cyano group; or (b) and Y" together are the group [in which Y is preferably an alkoxy or alk lmercapto radical with 1-6 carbon atoms in each case, or a benzyloxy, phenoxy, benzylmercapto or amino group].

The acetic acid derivatives according to the general formula III used as starting compounds are known from the literature or can be produced by processes known from the literature |_see (a) Org. Synth., Coll. I , 249 or Org. Synth. 41 , 50 and (b) Cope, 'J. Am. Chem. Soc. §J_, 1047 ( 1945 ] .

According to whether Y* and Y" have the meanings given above at (a) or at (b), the acetic acid derivative of general formula III is either (a) a cyanoacetic acid ester or amide or (b) a β-substituted β-amino-acrylic acid ester or amide.

As examples of compounds of general formula III there may be mentioned: a) Cyanoacetic acid esters and amides; Cyanoacetic acid methyl ester, cyanoacetic acid ethyl ester, cyanoacetic acid propyl ester, cyanoacetic acid isopropyl ester, cyanoacetic acid n-butyl ester (compare Org. Synth cyanoacetic acid isobutyl ester, cyanoacetic acid terto utyl ester, cyanoacetic acid hexyl ester, cyanoacetic acid benzyl ester, cyanoacetic acid amide , cyanoacetic acid Diethylamide , cyanoacetic acid diethylamide and cyanoacetic acid butylamide . b) β-Substituted t)-aminoacryiic acia esters ana amiaes: β-Aπlino-β-methoxyacrylic acid ethyl ester, 3-amino- -ethoxyacrylic acid ethyl ester, -amino^-butoxyacrylic acid butyl ester, -amino- -phenoxyacrylic acid ethyl ester, 3-amino-8-benzyloxyacrylic acid benzyl ester, -amino-3-ethoxyacrylic acid amide, p-amino- -ethoxyacrylic acid diethylamide , -amino- -nethylmercaptoacrylic acid ethyl ester, -amino- -benzylmercaptoacrylic acid ethyl ester, P-amino- -methylmercaptoacrylic acid amide , β , β-diaminoacrylic acid ethyl ester and β , β-diaminoacrylic acid amide.

The process according to the invention can if expedient be carried out in the presence of an inert diluent and basic or acid catalysts.

Possible diluents are all inert organic solvents which, where they are miscible with water, can if expedient be diluted with water. Preferred solvents include hydrocarbons (such as Le A 14 440-RTF - 9 - benzene, toluene and xylene), halogenated hydrocarbons (such as methylene chloride,, chloroform, carbon tetrachloride and J. chlorobenzene) , alcohols (such as methanol, ethanol, propanol, butanol, benzyl alcohol and glycol monomethyl ether), ethers (such as tetrahydrofurane , dioxane and glycol dimethyl ether), amides (such as dimethylformamide , dimethylacetamide , N-methyl-pyrrolidone and hexamethylphosphoric acid triamide), sulphoxides (such as dimethylsulphoxide) , sulphones (such as sulpholane) and tertiary bases (such as pyridine, picoline, collidine, lutidine and quinoline).

As basic condensation agents there may be used inorganic and organic bases. Preferred examples of such agents include alkali metal hydroxides (such as sodium hydroxide), potassium carbonates, and alcoholates (such as sodium alcoholate).

As acid catalysts there may be used inorganic and organic acids. Preferred examples of such catalysts include hydrogen halides, sulphuric acid and sulphonic acids (such as £-toluenesulphonic acid and trifluoromethylsulphonic acid) .

The reaction temperatures can be varied over a substantial range. In general, the reaction is carried out at between 10 \ and 200°C, preferably between 20 and 100°G. It is carried out under normal pressure but it can also be carried out in closed vessels at higher pressure.

In carrying out the process (a) according to the invention (when the acetic acid derivative is a cyanoacetic acid ester or amide) one mol of the cyanoacetic acid derivative of general formula (III) and 1-3 mols, preferably 2 mols, of a basic condensation agent are preferably employed per one mol of the hydrazine of general formula (II). In this method of working, salts of the 3-amino-pyrazol-5-ones of general formula (I) according to the invention are obtained and the Le A 14 440-RTF free 3-amino-pyrazol-5-ones can be liberated when required by treatment of the salt with equivalent amounts of a dilute acid. They can easily be purified by recrystallisation from a suitable solvent or by dissolving in dilute sodium hydroxide solution, filtration in the presence of animal charcoal and reprecipitation by means of dilute acids.

In carrying out the process (b) according to the invention (when the acetic acid derivative of general formula (III) is a β-substituted β-amino-acrylic acid ester or amide) one mol of the hydrazine of general formula (II) and one mol of the acetic acid derivative of general formula (III) ( β-aminoacrylic acid derivative) are preferably reacted. Here it is possible to start either from the β-aminoacr lic acid derivative (III) in the free form or from one of its acid addition salts. In the latter case, one mol of a base is appropriately added in order to liberate the β-aminoacrylic acid derivative. If the hydrazine derivative and the β-aminoacrylic acid derivative are used in the free form, it is advisable to add 1 - 1C > of an acid catalyst. Another possible procedure is to add an appropriately smaller amount of a base to the reaction mixture for neutralising the salt of the aminoacrylic acid derivative.

The reaction can be directed in such a way that first a amidrazone (IV) is produced, and that this is then cyclised to give the desired compound according to the invention in a second reaction step, thermally or by the action of a basic condensation agent. However, the one-stage synthesis is particularly advantageous.

In detail, the following may be mentioned as new active compounds: 3-araino-l-(3,4, 5-trichlorobenzyl)-pyrazol-5-one , 3-amino-l-(4-fluorobenzyl)-pyrazol-5-one , 3-amino-l-( 4-bromobenzyl)-pyrazol-( 5) -one , --amino--1- 4-chloro-3-bromobenzyl)-pyrazol-5-one , --amino--1- 4-fluoro-3-chlorobenzyl)-pyrazol- 5-one , --amino- -1- [ 4-dibromobenzyl)-pyrazol-5-one , --amino--1- 14-bromo-3-ehlorobenzyl)-pyrazol-5 -one , --amino--1- [ 4-fluoro-3-bromobenzyl)-pyrazol-5 -one , --amino--1- I 4-methylbenzyl) -pyrazol-5-one , --amino--1- -me hyl-3-chlorobenz 1)-pyrazol- 5-one , --amino--1- ( 4-ethylbenzyl)-pyrazol-5-one , --amino- -1- ( 4-chloro-3-methylbenzyl)-pyrazol- 5-one , --amino- -1- { 4-fluor.o-3-methylbenzyl) -pyrazol- 5-one , --amino- -1- { 4-t . -butylbenzyl)-pyrazol-5-one , --amino--1- I 2-chloro-3-methylbenzyl)-pyrazol- 5-one , --amino--1- { 3-chloro-5^methylbenzyl) -pyrazol- 5-one , --amino- k 3-bromo-5-niethylbenzyl)-pyrazol-5 -one , --aciino--l-< [ > 5-dimethylbenzyl)-pyrazol-5-one --amino- [ 4-propyl-3-chlorobenzyl) -pyrazol- 5-one , --amino- , 4-bromo-3-methylbenzyl)-pyrazol-5 -one , --amino- 4-phenylbenz3rl)-pyrazol-5-one , --amino- 3-phenylbenzyl)-pyrazol-5-one , --amino- 4-chloro-3-trifluoromethylbenzyl) -pyrazol- 5--one , --amino- 3-chloro-4-trifluoromethylbenzyl) -pyrazol- 5--one , --amino- 4-fluoro-3-trifluoromethylbenzyl) -pyrazol- 5--one , --amino- 4-bromo-3-trifluoromethylbenzyl) -pyrazol-5 — Dne , --amino- 3-chloro-5-trifluoromethylbenzyl) -pyrazol- 5· -one , --amino--l-( ^-trifluoromethyl^-methylbenzyl) -pyrazol- •5 -one , --amino--l-( 4-methyl-3-trifluorometh lbenzyl) -pyrazol- ■5 -one , --amino- k 3 > 4-dimethylbenzyl)-pyrazol-5-one --amino--l-< k 2 , -dimethylbenzyl)-pyrazol-5-one --amino- 3 > 4-trimethylenebenzyl)-pyrazol-5 -one , -amino-l- 3 , 4-tetrameth lenebenzyl ) -pyrazol-5-one , -amino-l- 3>4-tetramethylene-5-chlorobenzyl)-pyrazol-5-onp'i 3-amino-l- , 4-me hylenedioxybenzyl)-pyrazol-5-one , 3-amino-l- 3-chloro-4-methoxybenzyl) -pyrazol-5-one , 3-amino-l- 4-chloro-3-methoxybenzyl)-pyrazol-5-one , 3-aiaino-l- 4-methyl-3-methoxybenzyl)-pyrazol-5-one, 3-amino-l- 4-methoxy-3-methylbenzyl)-pyrazol-5-one , 3-amino-l- 4-nitrobenzyl)-pyrazol-5-one , 3-amino-l 2~nitrobenzyl)-pyrazol-5-one , 3-amino-l' 3-nitrobenzyl)-pyrazol-5-one , 3-arnino-l' 2-methoxy-6-raethylbenzyl)-pyrazol-5-one , 3-amino-l' 2-methox5'--6-chlorobenzyl ) -pyrazol-5-one , 3-amino-1 naphthyl-(2)-methyl)-pyrazol-5-one , 3-amino-1 3-chloro-naphthy1-( 2 )-methyl)-pyrazol-5-one , 3-amino-1 5 , 6-dichloro-naphthylmethyl-2 )-pyrazol-5-one , 3-amino-1 6 ,8-dichloro-naphthylmethy1-2 )-pyrazol-5-one , 3-amino-1 5-chloro-naphthylmeth l-2)-pyrazol-5-one, 3-amino-1 4-trifluoroznethoxybenzyl)-pyrazol-5-one, and 3-amino-1 3-trifluoromethoxybenzyl)-pyrazol-5-one.

' The new compounds according to the invention can be used as medicines. On oral or parenteral use, they cause a large increase in the excretion of water and salt and can therefore serve for the treiment of oedematous and hypertonic conditions. In addition, the compounds can be employed in cases of renal failure.

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

To demonstrate the diuretic and saluretic effect of the compounds according to the invention, 3-amino-l-(4-chloro-3-bromobenzyl)-pyrazol-5-one described in Example 12 is administered to dogs and rats. 1. Experiment on dogs: a) Method: Beagle bitches received on the day of the experiment, every 30 minutes, 1 ml/kg body weight of a solution which contained 0.4 of NaCl and 0.2 of KCl and was given by means of a probang. The urine formed during the first 60 minutes was discarded. Thereafter, the test preparation was administered orally as 0.5 mg/kg of an 0.1% strength tragacanth mucin, and the urine was collected for 3 hours. The renal excretion in equi alent/k /3 hours was calculated from the volume of urine (ml/kg) and the measured electrolyte concentration (mmol/l) .

Sodium and potassium were determined by flame photometry and chloride was determined potentiometrically. b) Results: The results are shown in Table 1. The renal excretion of sodium and water is substantially increased after oral administration of the test preparation. The effect depends on the dose. Even after only 1 mg/kg administered orally, the excretion of sodium is increased five-fold relative to the treated control animals. On the other hand, the excretion of potassium is only doubled after this dose.

Le A 14 440-RTF Table I Excretion in ml or ueq Electrolyte excretion and water excretion in dogs und bromobenzyl)-pyrazol-5-one . Average values of 2 anim 2. Experiment on rats: a) Methods: Male SPF rats of the Wistar strai received 10 ml/kg of O.lfo strength tragacanth mucin by means of a probang. The test preparation, in mg/kg, was administered with this liquid. The animals were then placed in pairs in diuresis cages. The urine collection period lasted 5 hours. The collected urine was filtered and analysed chemically. b) Results: The results of the experiments are shown in Table 2.

In rats, also, oral administration of the test preparation is followed by a dosage-dependent increase in the excretion of NaCl and of water. As in the case of dogs, the excretion of sodium is substantially more strongly influenced than the excretion of potassium. it Le A 14 440-RTF Table II Excretion in ml or uequiv Excretion of electrolyte and excretion of water in rats ( 4-chloro-3-bromobenzyl)-pyrazol-5-one . Average values time, "p.o." = per os.

Using the method described in the preceding experime of Preparative Examples 7 and 1 on rats were also tested. the nature of an example, are shown in Tables III and IV Table III Excretion of electrolyte and excretion of water in ra of Example 7. Average values and scatter for 10 animals a Table IV Excretion of electrolyte and excretion of water in rats u of Example 1 . Average values and scatter for 10 animals The following Preparative Examples illustrate the preparation of compounds according to the invention by the process of the invention.

Example 1: 3-Amino-1 -( -bromobengyl) -pyrazol-5-one 9.2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of jD-bromobenzylhydrazine in 50 ml of ethanol is then added at room temperature. The mixture is warmed to 60°C for 2 hours, the substance which was precipitated is filtered off and the filtrate is evaporated. The residue is taken up with water, the mixture is shaken with ether and the aqueous phase is acidified with dilute acetic acid. The crude product is purified by twice recrystallising it from alcohol. 17 g of the compound identified above as feQted needles of melting point 139°, corresponding to 36| of theory, are obtained .

Example 2 : 3-Amino-1 -( 4-bromobenzyl) -pyrazol-5-one 17. g of -amino- -ethoxyacrylic acid ethyl ester and 20 g of 4-bromobenzylhydrazine , on stirring for 5 hours in alcohol at 50° and working up as described in Example 1, yield Le A 14 440-RTF - 20 - 15.6 g of the compound identified above, corresponding to 5Q?° of theory, as colourless crystals of melting point 139°.

Example 3: 3-Amino-1 -( -fluorobenzyl)-pyrazol-5-οηβ 17.5 g of -amino-{3-ethoxyacrylic acid ethyl ester and 13 g of 4-fluorobenzylhydrazine , on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 13.2 g of the compound identified above as colourless crystals of melting point 148°, corresponding to 63?» of theory.

Example 4? 3-Amino-1 -(3-fluorobenzyl)-pyrazol-5-one 17.5 g of -amino- -ethoxyacrylic acid ethyl ester and of 3-fluorobenzylhydrazine , on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 11.3 g, corresponding to ^ of theory, of the compound identified above as colourless crystals of melting point 129°. Example 5 ∑ 3-Amino-1-(4-methylbenzyl)-pyrazol-5-one Le A 14 440-R'JF - - 1 7 . 5 g of -araino- -ethoxyacr lic acid ethyl ester and 1 3 .6 g of 4-methylbenzylhydrazine are introduced into 75 ml of pyridine. The mixture is stirred for 8 hours at room temperature and the pyridine is driven off under reduced pressure. The residue is treated with a solution of 4. 6 g of I\ia in 100 ml of ethanol and the mixture is warmed to 60° for 1 hour. The alcohol is driven off and the residue is taken up in 1 00 ml of water. The aqueous phase is extracted with ether, clarified with charcoal and acidified. A yellow-coloured precipitate is obtained, which melts at 149° after recrystal-lisation from alcohol. The yield is 7.3 g of the compound identified above, corresponding to 6^ of theory.

Example 6 ; 3-Amino- 1 - ( 3-methylbenzyl) -py azol-5-one 4.6 g of a are dissolved in 1 00 ml of ethanol. A mixture of 1 2 g of cyanoacetic acid ethyl ester and 1 3 . 6 g of 3-methylbenzylhydrazine is added to this solution. The mixture is heated to the boil for 5 hours whilst stirring and passing N2 into it. After driving off the solvent, taking up the residue in water, extracting with ether and clarifying with animal charcoal, acidification with acetic acid yields colourless crystals which after again being recrystallised from ethanol melt at 92° . The yield is 1 0.3 g of the compound identified above, corresponding to 1'" of theory.

Le A 14 440-RTj? - Θ"- Example 1: 3-Amino-1 -( .4-dimeth.ylbenzyl)-pyrazol-5-one 17.5 g of ^-amino-p-ethoxyacrylic acid ethyl ester and 15 g of 3 ,4-dimethylbenzylhydrazine yield, analogously to the procedure described in Example 1, 16 g of the compound identified above as colourless small needles of melting point 160°, corresponding to 7 » of theory.

Example 8: 3-Amino-1 -( 1.4-dimethyl)-pyrazol-5-one 17.5 g of P-amino- -ethoxyacrylic acid ethyl ester and 15 g of 2 , 4-dimethylbenzylhydrazine , analogously to the procedure described in Example 1, yield 14.3 g of the compound identified above, corresponding to 66% of theory, of melting point 151° · Example 9: 3-Amino-1 -( 4-nitrobenzyl)-pyrazol-5-one 17.5 g of -amino-p-ethoxyacrylic acid ethyl ester and 16.7 g of 4-nitrobenzylhydrazine , analogously to the procedure described in Example 1 yield 17.3 g of the compound Le A 14 440-R'JF -2 / - identified above as yellowish crystals of melting point 182 , corresponding to 14°/° of theory.

Example 10: 3-Amino-1 -( 3-nitrobenzyl)-pyrazol-5-one 17.5 g of -amino- -ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine , analogously to the procedure described in Example 1 yield 12.3 g of the compound identified above as yellow crystals of melting point 163° » corresponding to 52f° of theory.

Example 11 : 3-Amino-1 -( 1 -bromobenzyl)-pyrazol-5-one 4 422..44 gg ooff 22--bbrrooramoobbeennzzyyllhhyyddrraazziinnee wweerree aaddddeedd ddrrooppwwiissee,, uunnddeerr nniittrrooggeenn,, ttoo aa ssoolluuttiioonn ooff 3333..44 gg ooff pβ--aammiinnoo--ff3i--eetthhooxxyy--aaccrryylliicc aacciidd mmeetthhyyll eesstteerr aanndd 11 gg ooff jjDD--ttoolluueenneessuullpphhoonniicc aacciidd iinn 22500 mmll ooff eetthhaannooll.. AAfftteerr ssttiirrrriinngg ffoorr 1155 hhoouurrss aatt rroooomm tteemmppeerraattuurree,, tthhee ssoolluuttiioonn wwaass ccoonncceennttrraatteedd iinn vvaaccuuoo aanndd tthhee pprreecciippiittaattee wwhhiicchh hhaadd ffoorrmmeedd wwaass ffiilltteerreedd ooffff aanndd ddiissssoollvveedd iinn 22 NN ssooddiiuumm hhyyddrrooxxiiddee ssoolluuttiioonn.. TThhee aallkkaalliinnee ssoolluuttiioonn wwaass aaggaaiinn eexxttrraacctteedd wwiitthh eetthheerr aanndd ssuubbsseeqquueennttllyy sslliigghhttllyy aacciiddiiffiieedd wwiitthh ddiilluuttee aacceettiicc aacciidd,, wwhheerreeuuppoonn tthhee ccoommppoouunndd iiddeennttiiffiieedd aabboovvee pprreecciippiittaatteedd.. AAfftteerr rreeccrryyssttaalllliissaattiioonn ffrroomm mmeetthhaannooll,, tthhiiss pprroodduucctt mmeelltteedd aatt 116688--116699°°.. 2277..55 gg ((4499''//**))..

LLee AA 1144 444400--RRTTFF * Example 12: 3-Amino-1 -(3-bromo-4-chlorobenzyl)-pyrazol-5-one 49 g of -amino-0-ethoxyacrylic acid ethyl ester and 2 g of js-toluenesulphonic acid were dissolved in 225 ml of ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine were added under nitrogen. After standing overnight, the compound identified above had settled out as a precipitate and was filtered off and recrystallised twice from ethanol. Melting point: 171-1720C, 40 g (43'/*).

Example 13 3-Amino-1 -( -chloro-4-bromobenzyl)-pyrazol-5-one 48.8 g of 4-bromo-3-chlorobenzylhydrazine are added dropwise under nitrogen to a solution of 33.2 g of 0-amino- -ethoxyacrylic acid ethyl ester and 1.5 g of toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand and the compound identified above began to crystallise out after four hours. It was filtered off and twice recrystallised from ethanol. Melting point: 145-146°, 23 g (37 · Example 14 ? 3-Amino-l -( 2 , 4 , 5-trichlorobenzyl) -pyrazol-5-one lie A 4 440-RTF - zr- 54.7 g of -amino^-ethoxyacrylic acid ethyl ester and 2 g of £-toluenesulphonic acid were dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4, 5-trichlorobenzylhydra-5 zine in 200 ml of ethanol was added dropwise thereto, under nitrogen. After stirring for a further two hours, the mixture was left to stand overnight and the precipitate which had separated out was filtered off and dissolved in 2 sodium hydroxide solution. The alkaline solution was repeatedly extracted with ether and subsequently slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystallisation from ethanol, this product melted at 195-196°. 38 g (38 ).

Example 15 i , c 3-Amino-1 -( 5-chloro-4-raethylbensyl)-pyrazol-5-one 50 g of 4-methyl-3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.7 g of β-amino- 3-ethoxyacrylic acid ethyl ester and 1.5 g of jo-toluene- sulphonic acid in 200 ml of ethanol. After stirring for a further two hours, the compound identified above precipitated. It was filtered off and recrystallised from ethanol. Melting point: 130-131°, 35 g (50 ).

Le A 14 440-RTF - 3 - Example 16 ; 3-Amino-1 -(4-phenylbe.nzyl)-pyrazol-5-one A solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise, under nitrogen, to a solution of 23.4 g (0.147 mol) of p-amino-B-ethoxyacrylic acid ethyl ester and 1 g of j -toluenesulphonic acid in 100 ml of ethanol. During addition the temperature rose from 22° to 32°C.

After standing overnight, the reaction solution was concentrated in vacuo, the precipitate which separated out was dissolved in 2 H sodium hydroxide solution and the alkaline solution was repeatedly extracted with ether. Addition of dilute acetic acid until the mixture reacted weakly acid yielded the compound identified above, which melted at 185-186°C after recrystal-lisation from ethanol. 13 g (33?»).

Example 17 : 3-Amino-1 -( 3-naphthylmethyl)-pyrazol-5-one A A ssoolluuttiioonn ooff 4400..55 gg ooff BB--(( ββ--hhyyddrraazziinnoo--mmeetthhyyllnnaapphhtthhaalleennee )) wwaass aaddddeedd ddrrooppwwiissee,, uunnddeerr nniittrrooggeenn,, ttoo aa ssoolluuttiioonn ooff 3377..55 gg ooff SS--aarrnniinnoo--pp--eetthhooxxyyaaccrr lliicc aacciidd eetthhyyll eesstteerr aanndd 11 gg ooff pp--ttoolluueennee--ssuullpphhoonniicc aacciidd iinn 110000 mmll ooff eetthhaannooll.. TThhee mmiixxttuurree wwaass ssttiirrrreedd ffoorr ttwwoo hhoouurrss lloonnggeerr.. AAfftteerr aa ffuurrtthheerr ttwwoo hhoouurrss,, tthhee pprroodduucctt LLee AA 1144 444400--RRTTFF -- * identified above precipitated and was filtered off and recrystallised from ethanol.

Melting point: 156-157°, 22 g (39#)-.

Example 18: 5-Amino-1 -( 215-dimethy benzyl)-pyrazol-5-one 26.6 g of 2 , 5-diniethylbenzylhydrazine were added drop-wise to a solutio of 28.2 g of 3-amino- -ethoxyacrylic acid ethyl ester and 1 g of jg-toluenesulphonic acid in 130 ml of ethanol, in the course of which the temperature rose from 25 to 35°G. After stirring overnight, the compound identified above separated out, and was filtered off and recrystallised from ethanol.

Melting point: 124°, 20 g (52 ).

Example 19: 3-Amino-1 -( -trifluoromethoxybenzyl) -pyrazol-5-one From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 20.6 g of 4-trifluoromethoxybenzylhydrazine , analogously to the procedure described in Example 1. 8.7 g of the compound identified above as colourless crystals of melting point 99°, corresponding to 32' of theory, are obtained. as Le A 14 440-RTF Example 20 : 3-Amino- -( 3 . 4-methylenediox.vbenzyl)-pyrazol-5-one From 1 7 . 5 g of p-amino- -ethoxyacrylic acid ethyl ester and 16.6 g of 3 , 4-methylenedioxybenzylhydrazine , analogously to the procedure described in Example 1. 12.1 g of the compound identified above, as colourless crystals of melting point 218° , corresponding to 52/S of theory, are obtained.

Example 2 ; 5-Amino- -( 3 « 4-tetramethylenebenzyl)-pyrazol-5-one -From 1 7 . 5 g of -amino-^-ethoxyacrylic acid ethyl ester and 1 7 . 6 g of 3 , 4-tetramethylenebenzylhydrazine , analogously to the procedure described in Example 1. After recrystal- ■ lisation from alcohol, 1 5 . 6 g of the compound identified above, as colourless crystals of melting point 103° , are obtained.

The compound crystallises v/ith one mol of alcohol of recrystallisation. The yield is 54^ of theory.

Example 22 : 3-Amino-1 -( 2-methylbenzyl)-pyrazol-5-one Le A 14 440-RTF 27.5 g of o-methylbenzylhydrazine , dissolved in 100 ml of ethanol, were added dropwise at room temperature to a solution of 3 g of -amino-p-ethoxyacrylic acid ethyl ester and 1.5 g of jD-toluenesulphonic acid in 300 ml of ethanol. After standing overnight, the reaction solution was concentrated in vacuo and the compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 138°, 15 g (37 ).

Example 23: 3-Amino-1 -( 3-broaobenzyl) -pyrazol-5-one 20.5 g of S-amino-p-ethoxyacrylic acid ethyl ester together With 1.5 g of jD-toluenesulphonic acid were dissolved 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 and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 160°, 12 g (35'/*) · Example 24: 3-Amino-1 -( 3-iodobenziyl)-pyrazol-5-one Le A 14 440-HTF - 30 - A solution of 45 g of m-iodobenzylhydrazine in 70 ml of ethanol was added dropwise to a solution of 28.6 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of jD-toluenesulphonic acid in 350 ml of ethanol. After stirring overnight, the compound identified above had separated out as a precipitate and was filtered off and recrystallised from ethanol.

Melting point: 186°, 16 g (28$).

Example 25: 3-Amino-1 -(4-iodobenz.yl)-pyra ol-5-one A solution of 25.5 g of jo-iodobenzylhydrazine in 100 ml of ethanol was added dropwise, under nitrogen, to a solution of 16.2 g of β-amino-p-ethoxyacrylic acid ethyl ester and 1 g of TD-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the compound identified above was obtained as a residue and recrystallised from ethanol.

Melting point: 158°, 15 g (47 ).

Example 26: 3-Amino-1 -( 2-fluoroben∑-,yl)-pyrazol-5-one 30.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 2 g of jD-toluenesulPhonic acid were dissolved in 31 Le A 14 440-R'JF - 39 - 300 nil 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 compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 146°, 11 g (27#).

Example 27: 3-Amino-1 -( 5-chloro-6-fluorobenzyl)-pyrazol-5-one 21.6 g of 2-fluoro-5-chlorobenzylhydra ine were added dropwise under nitrogen to a solution of 19.8 g of β-βπιίηο-β-ethoxj'acrylic acid ethyl ester and 0.5 g of jD-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 20° to 30°. After stirring for two hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 160°, Ϊ7 g (57#).

Example 28: 3-Amino-1 -(5 , -dibromobenzyl)-pyrazol-5-one 12.2 g of -amino--ethoxyacrylic acid ethyl ester to gether with 1 g of £-toluenesulphonic acid were dissolved Le A 14 440-RTF - & - 200 ml of ethanol. A solution of 21.6 g of 3 ,4-dibromobenzyl-hydrazine in 50 ml of ethanol v/as added dropwise thereto, under nitrogen. After stirring overnight, the solvent was concentrated in vacuo and the compound identified above, which had separated out, as a precipitate, v/as filtered off and recrystallised from ethanol.

Melting point: 182°, 11 g (41$).

Example 29: 3-Amino-1 -(3-methyl-4-chlorobenzyl)-pyrazol-5-one 20.5 g of 3-2iethyl-4-chloro'benzylhydrazine were added dropwise, under nitrogen, to a solution of 19.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of jD- oluenesulphonic acid in 200 ml of ethanol. The reaction solution was stirred overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 131°, 10 g (35^).

Example 0? 3-Amino-1 -(4-ter ,butylbenzyl)-pyrazol-5-one 24.6 g of _o-tert . butylbenzylhydrazine were added dro , under nitrogen, to a solution of 22 g of β-απιίηο-β-le A 14 440- TF ethoxyacrylic acid ethyl ester and 1 g of jD-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 24° to 30°C. After stirring overnight, the solvent was distilled off in vacuo and the oily residue solidified after addition of 50. ml of petroleum ether. The compound identified above was filtered off and recrystallised from ethanol.

Melting point: 126°, 8 g (24$).

Example 3 ·' 3-Amino-1 -(4-i «r>pT>p.y benz.yl)-p.yrazol-5--one 32 g of p-isopropylbenzylhydrazine were added, under nitrogen, to a solution of 31.8 g of 3-amino- -ethoxyacrylic acid ethyl ester and 1 g of JD-toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand overnight. The compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 105°, 18.3 g (40'/ό) .

Example 32: 3-Amino-1 -( 3 4-trimethylenebenzyl)-pyrazol-5-one 15.1 g of 5-hydrazinomethylindane-( 3) , dissolved in 50 ml of ethanol, were added dropwise, under nitrogen, to a solution of 14.8 g of β-ami o-β-ethox acrylic acid ethyl ester and 1 g Le A 14 440-RTF - 4 - of _p_-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the compound identified above had precipitated; it was filtered off and recrystallised from ethanol.

Melting point: 146°, 9 g (42^)..

Example 33: 3-Amino-1 -( 2-chloro-4-fluorobenzyl)-pyrazol-5-one 53.8 g of 2-chloro-4-fluorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 49-2 g of β-amino-8-ethoxyacrylic acid ethyl ester and 1 g of __-toluenesulphonic acid in 250 ml of ethanol, in the course of which the temperature rose from 22° to 32°C. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 192°, 25 g (34#).

Example 34: 3-Amino-1 -( 3-n-butoxybenzyl)-pyrazol-5-one 18 g of 3-n-butoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 14.8 g of -amino-^-ethoxy-acrylic acid ethyl ester and a pinch of jD-toluenesulphonic acid in 80 ml of ethanol. After stirring for two hours, the mixture was left to stand overnight. The compound identified Le A 14 440-RTF - - above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 110°, 8 g ( 33/0.

Example 35 ? 3-Aaino-1 -( -methox.y-4-chlorobenz.yl)-p.yrazol-5-one 59 g of 4-chloro-3-methoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 50. 5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1. 5 g of _p_-toluenesulphonic acid in 250 ml of ethanol. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 148°, 30 g . (.38$).

Example 36: 3-Amino-l -( 2-nitrobenzyl)-pyrazol-5-one 47.8 g of o-nitrobenzylhydrazine were added dropwise, under nitrogen, to a solution of 45 · 5 g of p-amino-p-ethoxy-acrylic acid ethyl ester and a pinch of n-toluenesulphonic acid in 200 ml of ethanol. After standing overnight, the solvent was distilled off in vacuo and the residue was treated with a 2 : 1 mixture of ether and ethanol. The compound identified above which thereupon precipitated was filtered off and recrystallised from ethanol.

Melting point: 1 90° , 23 g ( 34> .

Le A 1 4 440-RTF - - Example 37: 3-Amino-l -( -n-propoxy-4-chlorobenzyl)-pyrazol--5--one 77 g of 4-chloro-3-(n)-propoxybenzylhydrazine were added, under nitrogen, to a solution of 55.6 g of β-Βπιί ο- -ethoxyacrylic acid ethyl ester and 1 g of jD-toluenesulphonic acid in 300 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the product which thereupon precipitated was filtered off and recrystallised from ethanol.

Melting point: 143°, 25 g (25°/°).

Example 38: 3-Amino- -( 3-ethoxy-4-chlorobenzyl)-pyrazol-5-one 45.5 g of 4-chloro-3-ethoxybenzylhydrazine were added, under nitrogen, to a solution of 35 g of p-amino-p-ethoxy-acrylic acid ethyl ester and 1 g of p-toluenesul honic acid in 200 ml of ethanol. After stirring overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol.

Melting point: 143°, 15.2 g (26>) .

Example 39 : 3-Ainino-1 -(3~trifluoromethyl-4-chlorobenzyl)-p,yrazol-5-one Le A 14 440-RTF 67 g of 4-chloro-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 46 . 1 g of β-amino- -ethoxyacrylic acid ethyl ester and 2 g of jo-toluene-sulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue, which solidified, was filtered off and recrystallised from ethanol. The product was the compound identified above.

Melting point: 1 32° , 25 g ( 30 ).

Example 40 : 3-Amino- -( 2-trifluoromethylbenzyl)-pyrazol-5-one 46 g of 2-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 33. g of β-anino-8-ethoxyacrylic acid ethyl ester and 2 g of jD-toluenesul honic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallised from ethanol. The product was the compound identified above.

Melting point: 1 84° , 22 g ( 34» .

Example 41 : 3-Afflino- 1 - ( 3-ethylbensyl)-pyra ol-5-one 3? Le A 1 4 440-RTi - AT- 14.2 g of 3-ethylbenzylhydrazine were added dropwise to a solution of 15.1 g of 3-amino^-ethoxyacrylic acid ethyl ester and a pinch of jD-toluenesulphonic acid in 80 ml of ethanol, in the course of which the temperature rose from 22 to 30°. After stirring overnight, the solvent was distilled off in vacuo and the solid residue was recrystallised from ethanol. The product was the compound identified above.

Melting point: 73°, 5 g (24;*) Example 42 : 3-Amino- -( 3-chloro-4-trifluoromethylben^yl)-pyrasol-5-one . 33 g of 3-chloro-4-trifluorornethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 23.5 g of β-anino-jS-etlioxyacrylic acid ethyl ester and a pinch of _p_-toluenesulphonic acid in 100 ml of ethanol. After stirring over night, the product which had precipitated was filtered off and recrystallised from ethanol.

Melting point: 83°, 24 g (56¾).

Example 43: 3-Amino-1 -( -tri luororae h l-4-methylbenzyl) -pyrazol-5-one Le Λ 14 440-RTF 34 of 4-metliyl-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 26.5 g of β-amino-P-ethoxyacrylic acid ethyl ester and a pinch of _p_-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the compound identified above, which had precipitated was filtered off and recrystallised from ethanol.

Melting point: 103°, 20 g (447°).

Example 44? 3-Amino-1 -( 1 , 2-dichloronaphthyl-( 7)-methyl)-pyrazol-5-one CI CI 1 5. 1 g of 1 , 2-dichloro-7-liydrazinomethyl-naphthalene were added, under nitrogen, to a solution of 10.3 g of p-amino- -ethoxyacrylic acid ethyl ester and a pinch of j>-toluenesulphonic acid in 1 00 ml of ethanol. After stirring overnight, the precipitate was filtered off and recrystallio from ethanol. The product was the compound identified above ilelting point: 200° , 4.7 g ( 23>,) .

Our copending Patent Specification No. 42562 discloses and claims the pharmaceutical use of 1-substituted 3-amino-pyrazol-5-ones , some of which are known, and which are generally similar to those of the present invention.

Example 45: -Amino- -(4-cyanobenz 1)-pyrazol-5-one 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 14.7 g of 4-cyanobenzylhydrazine yield, analogously to the procedure described in Example 1, 11.3 g» corresponding to 49$ of theory, 'of colourless crystals which melt at 187° after drying in a drying tube. On reprecipitation or recrystallisa-tion from aqueous solvents, the compound identified above crystallizes with one mol of water of crystallisation.

Claims (19)

CLAIKS

1. 3-Amino-pyrazol-5-ones of the following general formula or their salts :- CH2-R in which :- •ii is either (a) a phenyl radical substituted by one or two identical lower alkyl, phenyl, nitro, trifluoromethyl, trifluoro- methoxy groups or fluorine, bromine and iodine atoms; or (b) an indanyl, tetralinyl or benzodioxyl radical; or (c) a phenyl radical carrying a lower alkoxy or cyano group ; or (d) a phenyl radical carrying two different substituents selected from a group consisting of lower alkyl, lower alkoxy, halogen or trifluoromethyl; \pr (e) a trichlorophenyl radical; or (f) a naphthyl radical substituted by one or two halogen atoms; or (g) an unsubstituted β-naphthyl radical.

2. The sodium, potassium, ethanolamine , diethanolamine , triethanolamine, amino-tris-hydroxymethyl-methane , glucosamine, N-methyl glucosamine, magnesium, calcium, aluminium and iron salts of the 3-amino-pyrazol-3-ones of the general formula I, in which R is as defined in Claim 1.

3. The compound of the formula: NH

4. The compound of the formula:-

5. The compound of the formula : -

6. Compounds according to Claim 1 which are hereinbefore specifically mentioned, except those claimed in Claims 3, 4 and 5 and those described in Examples 36 to 45.

7. Compounds according to Claim 1 which are hereinbefore described in Examples 36 to 45.

8. A process for the production of a compound according to Claim 1 in which a hydrazine of the general formula :- R-CH2-NII-NH2 (jj) is reacted with an acetic acid derivative of the general formula : - Y1 CK-COX (III) [in which general formulae :- R is as defined in claim 1 or 2; X is a hydroxy, alkoxy, amino, or alkylamino radical; 42560/2 (a) Y' is a hydrogen atom and Y" is a cyano group; or (b) Y1 and Y» · together represent, the group:- ^^ m whxch Y is an alkoxy, aryloxy, aralkoxy, alkylmercapto, aralkymercapto or amino group].

9. A process according to Claim 8 in which X is a hydroxy1 group, an alkoxy group with 1 to 6 carbon atoms, a benzyloxy group, an amino group, or an alkyl amino or dialkyl amino group with 1 to 4 carbon atoms per alkyl group.

10. A process according to Claim 8 or 9 in which an amidra-zone of the general formula:- HK - CH2-R is isolated as an intermediate and is then cyclized thermally or in the presence of a basic condensation catalyst.

11. A process according to Claim 8, 9 or 10 in which about 1 mol of a cyanoacetic acid derivative of general formula III /in which Y' and Y' » are as defined in Claim 8(a.)7 is reacted with about 1 mol of hydrazine of the general formula II in the presence of 1 to 3 mols of a basic condensation catalyst.

12. A process according to any of Claims 8 to 11 in which the reaction is carried out in the presence of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, or an alkaline earth metal carbonate as a basic condensation catalyst. 42560/2

13. · A process according to Claim 8, 9 or 10 in which about 1 mol of hydrazine of the general formula II and 1 mol of acetic a^id derivative of general formula III /in which Y1 and Y' 1 are as specified in Claim 8(b)7 or a salt thereof, are reacted.

14. A process according to any of Claims 8 to 13 in which the reaction is carried out at 20 to 100°C.

15. A process according to any of Claims 8 to 14 in which the reaction is carried out in the presence of a hydrocarbon, a halo-genated hydrocarbon, an alcohol, an ether, an amide, a sulphoxide, a sulphone or a tertiary base as a diluent.

16. A process for the production of a compound accordin to Claim 1 substantially as hereinbefore described in any of Examples 1 to 35.

17. A process for the production of a compound according to Claim 1 substantially as hereinbefore described in any of Examples 36 to 45.

18. Compounds according to Claim 1 whenever produced by a process according to any one of Claims 8 to Ϊ6.

19. Compounds according to Claim 1 whenever produced by a process according to Claim 17. PC:mz