NO882030L - PROCEDURE FOR THE PREPARATION OF HYDRAZINE DERIVATIVES FOR USE AS ANTIHYPERTENSIVE AGENTS. - Google Patents

Description

The present invention relates to new hydrazine derivatives which have particularly proven to be useful as antihypertensive agents. The invention also relates to a method for producing the derivatives.

Hydrazine derivatives having pharmacological properties are known. Examples of these derivatives are the substituted carbazine acid esters which are described in US patent 3,867,425 and which have the formula:

where R and R~ in particular are hydrogen, R^ and R2 e.g. is hydrogen or chlorine and R 1 is hydrogen or an alkyl group. These compounds are useful in the treatment of nasal viral diseases.

US patents 3,746,703, 3,836,580 and 3,859,281 where 2,6-dichlorobenzylidene hydrazides are described can also be mentioned. These compounds have an antidepressant activity and in most cases also an antihypertensive activity. They have the formula:

where R e.g. is an alkyl, a hydroxyalkyl, an alkenyl, an alkynyl or a heterocyclic group.

These compounds seem to lie in the research area linked to "clonidine", where the two chlorine atoms in the 2- and 6-positions seem to play a decisive role for the activity.

Further hydrazine derivatives have also been described which have pharmacological properties. These have the formula:

where

X is a halogen group, such as chlorine or bromine,

R<1> is in particular an alkyl group substituted with a tertiary amino group, a heterocyclic group, a di- or tri-substituted phenyl group or an amino group.

Regarding these compounds, reference is made to the following works: Journal of Medicinal Chemistry, Vol 14, no. 10, 1971, p. 1017-1020,

Il Farmaco Ed. Sc, Vol 36, phase. 4, 1981, p. 269-273,

Il Farmaco Ed. Sc, Vol 33, phase 12, 1978, p. 963-971,

Journal of Medicinal Chemistry, Vol 20, No 11, 1977, pp 1520-1521.

According to the present invention, a new family of hydrazine derivatives has been produced which have antihypertensive properties and which are less toxic than the previously described compounds.

The hydrazine derivatives according to the present invention are characterized by having the formula:

where

X is a C-^-C^-alkyl or trifluoromethyl group or a halogen atom in the form of chlorine (in o- or m-position), fluorine or bromine,

R 1 is a C 1 -C 4 -alkyl group and

R 2 is hydrogen, a branched C 1 -C 4 alkyl group,

a C₁-C₁ alkoxy group, preferably ethoxy,

a group of the formula -CR^R^R^, where

R^ is an OR^, SRg or NR^Rg group, where

R 8 is hydrogen or a C 1 -C 4 alkyl group, and

<R>^ and Rg are hydrogen, a C-^-C^-alkyl group, a C2-C^-acyl group or a benzoyl group, or R^ and Rg may together with the nitrogen atom to which it is attached form a 5- membered or 6-membered heterocyclic group,

R 4 and R^ are the same and are hydrogen or a C-^-C^-alkyl group, or R^ is hydrogen and R^ is either a C^-C^-alkyl group which is optionally substituted with a hydroxyl group or a phenyl group, or

R^, R^ and R^ together with the carbon atom to which it is attached form an amido group, a phenyl group which is optionally substituted with a hydroxyl group, or a 5-membered or 6-membered heterocyclic group.

As examples of suitable heterocyclic groups, the following groups can be mentioned: morpholinyl, piperidyl, pyridyl or pyrrolidonyl.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula VI when these exist. These salts are prepared by conventional methods which include conversion to salt with pharmaceutically acceptable acids. The hydrochloride is the particularly preferred salt.

The connection also relates to the E and Z isomers C=N bond.

It should be noted that the compounds according to the invention are characterized by the following points: the substitution of the benzylidene carbon with a C^-C^-alkyl group (1^),

monosubstitution of the phenyl group,

the position of the heteroatom in the R_ radical when this is present (R^ is 0Rg, SRg or NR^R 8 ) on the o carbon in the CO group.

A special class of the compounds according to the invention are the compounds of the formula IV where R2 is a group of the above-mentioned formula CHR^R^<g>t especially the compounds of the formula IV where R2 is the group -CHR^R^g, X is halogen and R 1 is methyl.

The process according to the invention for the production of the hydrazine derivatives with the formula IV is characterized by

a) that in a first step an acylhydrazine with the formula (1) is prepared:

where R2 is as indicated above,

by reacting a hydrazine derivative with an ester with the formula R2-COOR (2),

where R 2 is as indicated above and R is an alkyl group, and

b) that the compound with the formula (1) is reacted with an aryl alkyl ketone with the formula (3):

where R^ and X are as indicated above.

The two steps in the method are preferably carried out by refluxing in an alcoholic medium, e.g. in ethanol or in an ethanol/water mixture. The compounds according to the invention are then recovered from the reaction medium in a conventional manner. They are obtained in solid form and are also stable.

The compounds according to the invention have low toxicity in relation to the valuable pharmacological activities which they exhibit. These activities mainly have antihypertensive properties combined with sedative, analgesic and anti-inflammatory properties.

The compounds according to the invention can therefore be used in therapy, in particular for the treatment of high blood pressure.

Pharmaceutical preparations contain the hydrazine derivative with the formula (IV) as active ingredient, and a pharmaceutically acceptable vehicle.

The preparations can be in the form of oral preparations (e.g.

tablets or gelatin capsules) or in the form of injectable preparations.

For the treatment of high blood pressure, doses of from 5 to 25 mg per day have generally been found to be appropriate.

The invention will be explained in more detail in the following examples.

Example 1

Preparation of 1-(2-hydroxyisobutyroyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine, hereafter referred to as compound MP 440:

a) 100 ml ethanol, 2 g (0.04 mol) hydrazine hydrate and 5 g (0.038 mol) ethyl 2-hydroxyisobutyrate were introduced in turn into a

conical bottle equipped with a magnetic tube system and a cooler above. The reaction mixture was refluxed for 3 hours. After cooling, the solution was treated on a rotary evaporator, whereby a solid was obtained which was filtered and washed with cold ethanol and then with ether.

Yield: 90%, mp: 98°C.

b) 100 ml ethanol, 3.8 g (0.03 2 mol) (2-hydroxyisobutyroyl)hydrazine and 5 g (0.03 2 mol) o-chloroacetophenone were added in turn

introduced into a conical flask equipped with a magnetic tube system and a cooler above. The mixture was refluxed for 3 hours. After cooling, the solution was concentrated on a rotary evaporator and then filtered. The filter cake was recrystallized from ethanol.

Yield: 70%, mp: 128°C.

<1>H NMR, DMSO-dg, ppm: 1.4 (s, 6H, 2CH3); 2.25 (s, 3H, CH3~C=N);

5.8 (exch. D 2 O, 1H, OH); 7.5 (m, 4H, arom.); 10.1 (exch. D 2 O, 1H, NH).

E and Z isomers of the compound MP 440

The crude compound MP 440 was analyzed by chromatography on a plate of Merck 60 F 254 silica with butanone as the developing solvent. Observation under UV at 254 nm showed that there were two isomers, hereafter referred to as MP 440E and MP 440Z.

Rf for MP 440E: 0.8, and Rf for MP 440Z: 0.7.

The geometric isomers were separated in two steps. In a first step, recrystallization from ethanol or butanone gave crystals of MP 440E. Concentration of the mother liquors enabled collection of a further precipitate of the Z + E isomers.

The mother liquors, which thus contained a mixture of E and Z isomers (approx. 40:60), were treated by chromatography in a column of Merck Silikagel 60 with 50:50 toluene/butanone as eluent. MP 440E was recovered before the Z isomer.

The isomers differ from each other by the following:

1) by their melting points: m.p. = 14 6°C before the Z-isomer and 160°C for the E-isomer.

2) by their IR spectra (KBr):

MP 440E: 1685 cm"<1>; 3100 cm"<1>(wide); 3365 cm"<1>(sharp);

3440 cm<-1> (wide).

NO 440Z: 1680 cm"<1>; 3260 cm"<1>(wide); 3340 cm"<1>(sharp);

3430 cm"<1>(wide).

3) by their<1>H NMR spectra (CDCl 3 , TMS):

4) by their<13>C NMR spectra (CDC13, TMS):

The compounds 2-38 in Table I below were prepared by the method described in example 1 or by the methods and variants indicated below. The NMR spectra of these compounds are given below together with the starting compounds used in their preparation.

Example 2

1-(2,2,2-trimethylacetyl)-2-(1-o-chlorophenyl-1-ethylidene)-hydrazine was prepared from 2,2,2-trimethylacetylhydrazine and 2'-chloroacetophenone.

<1>H NMR, DMSO-dg, ppm: 1.2 (s, 9H, 3CH3); 2.25 (s, 3H, CH3-C=N);

7.5 (m, 4H, arom.); 10.2 (exch. D2O, 1H,

NH).

Example 3

1-(2-Hydroxypropanoyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared by a variant of the procedure in example 1, which consisted in that in the second step the hydrazide was dissolved in 50 ml of ethanol/water = 50:50 before mixing with 2*-chloroacetophenone. ;<1>H NMR, DMSO-dg, ppm: 1.3 (d, 3H, CH3); 2.25 (s, 3H, CH3~C=N); ;4.2 (m, 1H, CH-OH); 5.6 (exch. D 2 O, 1H, OH); 7.5 (m, 4H, arom.); 10.0 (exch. D 2 O, 1H, NH). Example 4 1-(2-hydroxyacetyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared by the method in example 1 from 2-hydroxyacetylhydrazine and 2'-chloroacetophenone. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3~C=N); 4.2 (s, 2H, CH2); ;5.4 (exch. D 2 O, 1H, OH); 7.5 (m, 4H, arom.); 10.4 (exch. D 2 O, 1H, NH). ;Example 5;Preparation of 1-(2-hydroxy-2-phenylacetyl)-2-(1-o-chloro-phenyl-1-ethylidene)hydrazine ;5.1. 30 ml of absolute ethanol, 0.1 mol of ethyl 2-hydroxy-2-phenylacetate and then 0.105 mol of hydrazine were introduced into a conical flask equipped with a magnetic tube system and a cooler. The mixture was refluxed in ethanol for 3 hours and then cooled to 0°C. The precipitated hydrazide was filtered off and then washed with cold ethanol and with ether. ;5.2. The 2-hydroxy-2-phenylacetylhydrazide was then reacted with 2<1->chloroacetophenone as described in Example 1. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3-C=N ); 5.05 (s, 1H, ; ; 7.40 (m, 9H, arom.); ; 7.8 (exch. D2O, 1H, OH); 10.8 (exch. D2O, 1H, NH). ;Example 6 ;1-(2-Methoxyacetyl)-2-(1-o-chlorophenyl-1-ethylidene)-hydrazine was prepared from 2-methoxyacetylhydrazide and 2<1->chloroacetophenone as described in example 5. ;< 1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3~C=N); 3.5 (s, 3H, ;CH3-O-); 4.4 (s, 2H, CH2 ); 7.4 (m, 4H, arom.); 9.8 (exch. D2O, 1H, NH). ;Example 7;Preparation of 1-(2-aminoacetyl)-2-(1-o-chlorophenyl- l-ethylidene )hydraz in ;A mixture of 0.10 mol of ethyl glycinate (hydrochloride) and 0.10 mol of hydrazine hydrate was heated for 1 hour at 90° C. After cooling, 100 ml of ether was added, and the mixture was then filtered after treatment. 7.2. 0.05 mol of the hydrazide prepared above dissolved in ethanol/water = 50:50 was reacted with 2<1->chloroacetophenone as described in example 1. ;<1>H NMR, DMSO -dg, ppm: 2.25 (s, 3H, CH3~C=N); 3.8 (s, 2H, CH2); ; 7.5 (m, 4H, arom.); 8.8 (exch. D2O, 3H, NH3+); 10.8 (exch. D2O, 1H, NH). ;The compound, which was obtained as the hydrochloride, was converted to the base as follows: 0.02 mole of the aminoacetylhydrazidone hydrochloride was suspended in 200 ml of methylene chloride. A stream of ammonia was bubbled into the suspension for 5 hours at room temperature with stirring. The mixture was filtered and the aminoacetylhydrazidone was collected by evaporation of the filtrate. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3Hf CH3~C=N); 3.6 (s, 2H, CH2); ;4.5 (exch. D 2 O, 2H, NH 2 ); 7.45 (m, 4H, arom.); 10.8 (exch. D 2 O, 1H, NH). ;Example 8 ;1-(2-methylthioacetyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared from methylthioacetylhydrazide and 2'-chloroacetophenone as described in example 7. ;<1>H NMR, DMSO-dg, ppm: 2.15 (s, 3H, CH3~S-); 2.25 (s, 3H, ;CH 3 -C=N); 3.4 (s, 2H, CH2); 7.4 5 (m, 4H, arom.); 10.5 (exch. D 2 O, 1H, NH). ;Example 9;Preparation of 1-oxamoyl-2-(1-o-chlorophenyl-1-ethylidene)-hydrazine ;9.1. 25 ml of ethyl ether and 0.1 mol of ethyl oxamate were introduced into a conical flask equipped with a magnetic stirrer and a cooler. 0.105 mol of hydrazine hydrate was added dropwise with stirring to the mixture which was kept at 0°C. The mixture was then stirred for 2 hours at room temperature. The precipitate of hydrazide was filtered off and washed with cold ethanol and then with ether. ;9.2. 0.05 mol of the hydrazide obtained was then dissolved in 50 ml of ethanol/water = 50:50 and reacted with 2'-chloroacetophenone as described in ex. 1. ;Yield: 82%, m.p. (ethanol): 175°C. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3-S); 7.5 (m, 4H, arom.); ;7.8 (exch. D 2 O, 2H, NH 2 ); 10.6 (exch. D 2 O, 1H, NH). ;Example 10;Preparation of 1-(2-oxopyrrolidin-5-yl)-2-(1-o-chloro-phenyl)-1-ethylidene)hydrazine ;10.1. (2-oxopyrrolidin-5-yl)hydrazide was prepared from ethyl 2-oxopyrrolidin-5-yl carboxylate by reaction with hydrazine hydrate according to example 5.1. ;10.2. The hydrazide obtained was reacted with 2'-chloroacetophenone according to ex. 1. ;Yield: 65%, m.p. (ethanol/water) (base monohydrate): 119°C. ;<1>H NMR, DMSO-dg, ppm: 2.05 (m, 2H, ; ; 2.25 (s, 3H, CH--C=N); 3.30 (m, 2H, -CH2- CH); 4.5 (m, 1H, ; 7.45 (m, 4H, arom.); 7.8 (exch. D20, 1H, ; ; 10.4 (exch. D20, 1H, ;NH-N =). ;Example 11;1-nicotinoyl-2-(1-o-chlorophenyl)-1-ethylidene)hydrazine was prepared from nicotinoylhydrazide and 2-chloroacetophenone according to example 5. ;Yield: 62%, m.p. (ethanol ): 154° C. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3~C=N); 7.50 (m, 5H, arom.); ;8.20 (m, 1H, arom.); 8.70 (m, 1H, arom.); ; 9.0 (m, 1H, arom.); 10.4 (exch. D2O, 1H, ;NH). ;Example 12;1-formyl-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared from formylhydrazide and 2<1->chloroacetophenone according to example 1. ;Yield: 79%, m.p.: 138°C ( ethanol. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3-C=N); 7.45 (m, 4H, arom.); ; 8.8 (s, 1H , ; 10.2 (exch. D2O, 1H, NH). ;Example 13 ;1-(2-aminoacetyl)-2-(1-p-fluorophenyl-1-ethylidene)hydrazine was prepared from glycinoylhydrazide (hydrochloride) and 4'-fluoroacetophenone according to example 7. ;Yield: 72%, m.p. (hydrochloride) (methanol): >260°C.; m.p. (base (ethanol): 139°C. ;<1>H NMR, DMSO-dg, ppm: Hydrochloride: 2.25 (s, 3H, CH3~C=N); 3.8 (s, ;2H, CH2 ); 7.3 (m, 2H, arom.); ; 7.9 (m, 2H, arom.); 8.8 (exch. D2O, 2H, NH2); 10.4 (exch. D2O, 1H, NH). ;Base: 2.25 (s, 3H, CH3~C=N); 3.6 (s, 2H, ;CH2); 4.6 (exch. D2O, 2H, NH2); 7.3 ( m, 2H, arom.); 7.9 (m, 2H, arom.); ; 10.3 (exch. D 2 O, 1H, NH). ; Example 14 ; 1-(2-hydroxyisobutyroyl)-2-(1 -m-trifluoromethylphenyl-l-ethylidene) hydrazine was prepared from 1-(2-hydroxyisobutyroyl)-hydrazide and m-trifluoroacetophenone in the manner described in ex. 1. ;<1>H NMR, DMSO-dg, ppm : 1.54 (s, 6H, 2CH3); 2.24 (s, 3H, CH3"C=N); ; 3.73 (exch. D2O, 1H, OH); 7.40 (m, 4H, arom .); 8.0 0 (exch. D2O, 1H, NH). ;Example 15 ;1-morpholinoacetyl-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared from morpholinoacetylhydrazide and 2'-chloroacetophenone on the way described in Example 5. ;^ H NMR, DMSO-dg, ppm: 2.42 (s, 3H, CH3); 2.40 (t, 4H, 2 NCH2); ; 3.08 (s , 2H, CH2-C=0); 3.43 (t, 4H, OCH2); ; 3.75 (exch. D2O, 1H, OH); 7, 40 (m, 4H, arom.); 7.75 (exch. D 2 O, 1H, NH). Example 16 1-(2-hydroxyisobutyroyl)-2-(1-o-chlorophenyl-1-propylidene)-hydrazine was prepared from 1-(2-hydroxyisobutyroyl)hydrazide and o-chloropropiophenone in the manner described in e.g. 1. ;<1>H NMR, DMSO-dg, ppm: 1.25 (t, 3H, CH3"CH2); 1.4 (s, 6H, 2CH3); ;2.95 (q, 2H, ; ; ; 5.8 (exch. D2O, 1H, ;OH); 7.5 (m, 4H, arom.); 10.2 (exch. D2O, 1H, NH). ;Example 17 ;1-(2-Hydroxyacetyl )-2-(1-o-fluorophenyl-1-ethylidene)hydrazine was prepared according to example 1 from 2-hydroxyacetylhydrazide and 2'-fluoroacetophenone. ;<1>H NMR, DMSO-dg, ppm: 2.2 5 (s, 3H, CH3-C=N); 4.2 (s, 2H, CH2); 5.4 (exch. D2O, 1H, OH); 7.8 (m, 4H, arom.); 10 ,6 (exch. D 2 O, 1H, NH). ;Example 18 ;1-(2-hydroxyisobutyroyl)-2-(1-m-chlorophenyl-1-propylidene)-hydrazine was prepared from 1-(2-hydroxyisobutyroyl) hydrazide and m-chloropropiophenone in the manner described in Ex. 1. ;<1>H NMR, DMSO-dg, ppm: 1.25 (t, 3H, CH3-CH2); 1.4 (s, 6H, 2CH3) ; ;2.9 (q, 2H, ; ; ; 5.8 (exch. D2O, 1H, ;OH); 7.40 (m, 2H, arom.); 7.80 (m, 2H, arom. .); 9.5 (exch. D2O, 1H, NH). ;Yield: 68%, m.p. (ethanol): 112°C. ;Example 19;Preparation of 1-N-acetylglycyl-2-(1-o-chlorophenyl) -1-ethylidenehydrazine; 20 ml ethanol, 2 ml (0.04 mol) hydrazine hydrate and 5.80 g (0.04 mol) of ethyl N-acetyl glycinate was carried out in turn in a conical flask equipped with a magnetic tube system and an overhead cooler. The mixture was heated for 2 hours at 60°C, and 6.18 g (0.04 mol) of o-chloroacetophenone was then added (without cooling). Stirring was continued for a further 2 hours at 60°C. After cooling, the solution was concentrated on a rotary evaporator and then filtered. The solid obtained was recrystallized from isopropanol. ;Yield: 83%, mp: 188-190°C. ;<1>H NMR, CDCl 3 , ppm: 2.32 (s, 3H, CH 3 -C=N); 2.48 (s, 3H, CH3~C=O); ; 4.60 (d, 2H, CH2); 6.50 (s wide, exch. D2<D, 2H, 2 x NH); 7.50 (p, 4H, arom.). Example 20 1-(2-hydroxyisobutyroyl)-2-(1-o-fluorophenyl-1-ethylidene)-hydrazine was prepared from 1-(2-hydroxyisobutyroyl)hydrazide and o-fluoroacetophenone in the manner described in e.g. 1. ;Yield: 71%, m.p. (ethanol): 142°C. ;^"H NMR, DMSO-dg, ppm: 1.4 0 (s, 6H, 2CH3) ; 2.2 5 (s, 3H, CH3~C=N); ; 5.8 (exch. D2O, 1H , OH); 7.8 (m, 4H, arom.); 10.6 (exch. D2O, 1H, NH). ;Example 21 ;1-(2-Hydroxyisobutyroyl)-2-(1-p-fluorophenyl- 1-ethylidene)hydrazine was prepared from 1-(2-hydroxyisobutyroyl)hydrazide and p-fluoroacetophenone in the manner described in example 1. ;Yield: 58%, mp (ethanol): 134°C.; <1>H NMR, DMSO-dg, ppm: 1.40 (s, 3H, 2CH3); 2.25 (s, 3H, CH3-C=N); ; 5.6 (exch. D2O, 1H, OH ); 7.1 (m, 2H, arom.); 10.8 (exch. D2O, 1H, NH). ;Example 2 2 ;1-(2-Hydroxyisobutyroyl)-2-(1-o-bromophenyl-1 -ethylidene)hydrazine was prepared from 1-(2-hydroxyisobutyroyl)hydrazide and o-bromoacetophenone in the manner described in example 1. ;Yield: 69%, mp (ethanol): 139°C. ;< 1>H NMR, DMSO-dg, ppm: 1.40 (s, 3H, 2CH3); 2.25 (s, 3H, CH3~C=N); ; 5.8 (exch. D2O, 1H, OH) ; 7.6 (m, 4H, arom.); 10.6 (exch. D 2 O, 1H, NH). ; Example 23 ; 1-(2-Hydroxypropanoyl)-2-(1-o-bromophenyl-1-ethylidene )-hydrazine was prepared from 1-(2-hydroxypropano yl)hydrazide and 2-bromoacetophenone in the manner described in ex. 3. ;Yield: 62%, m.p. (ethanol): 115°C. ;<X>H NMR, DMSO-dg, ppm: 1.3 (d, 3H, CH3); 2.25 (s, 3H, CH3"C=N); 4.2 (m, 1H, CH-OH); 5.6 (exch. D2O, 1H, OH); 7.6 (m, 4H, arom.); 10.1 (exch. D2O, 1H, NH). ;Example 24 ;1-(2-hydroxyacetyl)-2-(1-o-bromophenyl-1-ethylidene)hydrazine was prepared from 2-hydroxyacetylhydrazide and 2<1->bromoacetophenone in the manner described in Example 1. ;Yield: 70%, mp (ethanol): 160° C. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3~C=N); 4.2 (s, 2H, CH2); 5.4 (exch. D2O, 1H, OH); 7.6 (m, 4H, arom.); 10 ,4 (exch. D2O, 1H, NH). ;Example 25 ;1-(2-hydroxyisobutyroyl)-2-(1-p-trifluoromethylphenyl-1-ethylidene) hydrazine was prepared from 1-(2-hydroxyisobutyroyl ) hydrazide and m-trifluoroacetophenone in the manner described in Example 1. ;Yield: 69%, mp (ethyl acetate): 160° C. ;<1>H NMR, CDCl 3 , ppm: 1.57 (s, 6H, H3C-C-OH); 2.32 (s, 3H, ;H3C-C=0); 3.05 (exch. D2O, 1H, OH); 7.30 (exch. D2O, 1H, NH) ; 7.65 (d, 2H,J=10Hz, arom.); 7.95 (d, 2H, J=10 Hz, arom.). ;Example 26 ;1-(2-hydroxyisobutyroyl)-2- [1 -(2-chlorophenyl)-1-pentylidene] hydrazine was prepd from 1-(2-chlorophenyl)pentan-1-one. l-(2-chlorophenyl)pentan-l-one was prepared from 2-chlorobenzaldehyde: in the first step, a solution of 0.5 mol of 2-chlorobenzaldehyde in 100 ml of anhydrous ether was added to a suspension of n-butylmagnesium bromide in anhydrous ether (prepared by reacting 0.5 mol of butyl bromide with 13 g of magnesium). After hydrolysis of the reaction medium with 300 ml of 1 N hydrochloric acid, the alcohol was isolated by concentration of the organic phase and then distillation. ;Yield: 78%, boiling point at 0.1 mm Hg: 114-118°C. In the second step, the alcohol was oxidized to 1-(2-chlorophenyl)-pentan-l-one with chromic acid: a solution of a mixture of 0.5 mol of 1-(2-chlorophenyl)-pentan-l-ol and 80 g of sodium bichromate in 100 ml of acetone was cooled to 10°C. A solution of 50 ml of concentrated sulfuric acid in 100 ml of water was added to the mixture without the reaction temperature rising above 20°C. The mixture was then stirred for 12 hours at room temperature, after which it was diluted in 100 ml of water and extracted with ether. The organic solution was washed with an aqueous solution of sodium bicarbonate until the washes were neutral, and then with water. After concentration of the ether phase, 1-(2-chlorophenyl)pentan-1-one was distilled. ;Yield: 91%, boiling point at 0.5 mm Hg: 114-117°C. ;1-(2-hydroxyisobutyroyl)-2-[1-(2-chlorophenyl)-1-pentylidene]-hydrazine was prepared by reacting 1-(2-chlorophenyl)pentan-1-one with 1-(2-hydroxyisobutyroyl ) hydrazine according to e.g. 1. ;Yield: 78%, m.p. (ethyl acetate): 199°C. ;<1>H NMR, CDCl 3 , ppm: 0.95 (m, 3H, H 3 C-CH 2 ); 1.46 (s, 6H, 2CH3); ;1.65 (m, 4H, CH2-CH2-CH3); 2.37 (exch. D 2 O, p, 1H, OH); 2.65 (t, 2H, CH 2 C=O); 7.10-7.30 (m, 4H, arom.); 8.20 (s, 1H, NH). Example 27 1-(2-hydroxypropanoyl)-2-(1-o-fluorophenyl-1-ethylidene)-hydrazine was prepared from 2-hydroxypropanoylhydrazine and 2'-fluoroacetophenone by the method in ex. 3. ;Yield: 52%, m.p. (ethanol): 109°C. ;<1>H NMR, DMSO-dg, ppm: 1.3 (d, 3H, CH3); 2.25 (s, 3H, CH3~C=N); ;4.2 (m, 1H, CH-OH); 5.6 (exch. D 2 O, 1H, OH); 7.8 (m, 4H, arom.); 10.8 (exch. D 2 O, 1H, NH). Example 28 1-(2-hydroxyisobutyroyl)-2-(1-m-chlorophenyl-1-ethylidene)-hydrazine was prepared from 2-hydroxyisobutyroylhydrazine and m-chloroacetophenone by the method in ex. 1. ;Yield: 68%, m.p. (ethanol): 136°C. ;<1>H NMR, DMSO-dg, ppm: 1.4 (s, 6H, 2CH3); 2.2 5 (s, 3H, CH3~C=N); ; 5.9 (exch. D 2 O, 1H, OH); 7.4 (m, 2H, arom.); 10.5 (exch. D 2 O, 1H, NH). Example 29 1-(2-hydroxypropanoyl)-2-(1-m-chlorophenyl-1-ethylidene)hydrazine was prepared from 2-hydroxypropanoylhydrazine and m-chloroacetophenone by the method in ex. 3. ;Yield: 61%, m.p. (ethanol): 114°C. ;<1>H NMR, DMSO-dg, ppm: 1.3 (d, 3H, CH3); 2.25 (s, 3H, CH3-C=N); ;4.2 (m, 1H, CH-OH); 5.8 (exch. D 2 O, 1H, OH); 7.7 (m, 2H, arom.); 11.2 (exch. D 2 O, 1H, NH). Example 30 1-(2-hydroxyisobutyroyl)-2-(1-o-methylphenyl-1-ethylidene)-hydrazine was prepared from 2-hydroxyisobutyroylhydrazine and o-methylacetophenone by the method in ex. 1. ;Yield: 65%, m.p. (ethanol): 103°C. ;<1>H NMR, DMSO-dg, ppm: 1.4 (s, 6H, 2CH3); 2.25 (s, 3H, CH3"C=N); ; 4.61 (s, 3H, arom. CH3); 5.8 (exch. D2O, 1H, OH); 7.6 to 8.3 ( m, 4H, arom.); 11.2 (exch. D2O, 1H, NH). ;Example 31;Preparation of S-1-(3-hydroxy-2-aminopropanoyl)-2-[1-(2-chlorophenyl)- 1-ethylidene]hydrazine involved the following steps: 0.4 mol of triethylamine was added to a suspension of 0.3 mol of the hydrochloride of the ethyl ester of L-serine in 100 ml of ethyl acetate. The mixture was stirred for 15 minutes at room temperature and then filtered. The precipitate of triethylamine hydrochloride was washed twice with 10 ml of ethyl acetate. The organic solution was evaporated in vacuo to give the ethyl ester of L-serine as an oil. This oil was dissolved in 50 ml of methanol, and then 0.35 mol of hydrazine hydrate was added. The mixture was stirred for 12 h at room temperature and then concentrated in vacuo. The hydrazide of serine crystallized. It was washed with 5 ml of absolute ethanol and twice with 10 ml of ether. ;Yield: 64%. ;1-(3-hydroxy -2-aminopropanoyl)-2-[1-(2-chlorophenyl)-1-ethylidene]hy drazine was obtained by reacting the hydrazide of L-serine with 2<1->chloroacetophenone according to ex. 1. ;Yield: 71%, m.p. (ethyl acetate): 120-123°C. ;<1>H NMR, CDCl 3 , ppm: 2.35 (s, 3H, CH 3 ); 3.80 (m, 3H, CHCH 2 ); 4.20 ; (exch. D2O, s, 4H, NH + NH2+ OH); 7.25 (s, 4H, arom.). ;Example 32;The hydrochloride of 1-aminoacetyl-2-(1-p-methylphenyl-1-ethylidene)hydrazine was prepared from the hydrochloride of amino-acetylhydrazine and p-methylacetophenone by the method according to ex. 7. ;Yield: 58%, m.p. (ethanol): >260°C. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3-C=N); 2.5 (s, 3H, arom.;CH3); 3.8 (s, 2H, CH2; 7.1 (m, 2H, arom.) ; 7.7 (m, 2H, arom.); 8.8 (exch. D„z0, 3H, NH3 ); 10, 8 (exch. D20, 1H, NH). ;Example 3 3;1-salicoyloxy-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared from salicoylhydrazine and o-chloroacetophenone by the method according to example 1. ;Yield: 71%, mp (ethanol): 216° C. ;<1>H NMR, DMSO-dg, ppm: 2.25 (s, 3H, CH3-C=N); 7.1 (m, 5H, arom.) ; ;7.8 (m, 4H, arom.); 8.4 (exch. D2O, 1H, OH); 10.8 (exch. D2O, 1H, NH). ;Example 34 ;1-( 2-hydroxyisobutyroyl)-2-(1-m-methylphenyl-1-ethylidene)-hydrazine was prepared from 2-hydroxyisobutyroylhydrazine and m-methylacetophenone by the method in example 1. ;Yield: 59%, m.p. (ethanol): 126° C. ;<1>H NMR, DMSO-dg, ppm: 1.4 (s, 6H, 2CH3); 2.25 (s, 3H, CH3~C=N); ;3.6 (s, 3H, CH3); 5.9 (exch. D2O, 1H, OH); ; 6.9 to 7.8 (m, 4H, arom.); 10.8 (exch. D2O, 1H, NH). ; Example 35; 1-(piperidinoglyoxyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine was prepared from piperidinoglyoxylhydrazine and o-chloroacetophenone by the method in ex. 1. ;Yield: 73%, m.p. (ethanol): 141°C. ;<1>H NMR, DMSO-dg, ppm: 1.65 (m, 6H, 3CH3); 2.25 (s, 3H, CH3-C=N); ;3,4 (m, 4H, 2CH2); 7.5 (m, 5H, arom.); 10.8 (exch. D 2 O, 1H, NH). ;Example 3 6;Preparation of S-1-(N-benzoylseryl)-2-[1-(2-chlorophenyl)-1-ethylidene]hydrazine ;The ethyl ester of N-benzoylserine was prepared from the hydrochloride of the ethyl ester of L-serine: the hydrochloride ( 0.4 mol suspended in 10 0 ml of ethyl acetate) was treated with 1 mol of triethylamine. The mixture was cooled to 0°C, and a solution of 0.4 mol of benzoyl chloride in 100 ml of ethyl acetate was then added. After the addition was complete, the mixture was heated at 40°C for 15 minutes. It was filtered and the precipitate was washed twice with 50 ml of ethyl acetate. The filtrate was evaporated in vacuo, leaving the ethyl ester of N-benzoylserine in the form of an oil, which was dissolved in 60 ml of methanol and treated with 45 mol of hydrazine hydrate. After stirring for 12 hours at room temperature, the mixture was concentrated in vacuo. The hydrazide which had crystallized was washed with 10 ml of methanol and then twice with 10 ml of ethyl ether. ;Yield: 84%. The hydrazide of N-benzoylserine was reacted with 1-(2-chloro-phenyl)ethanone in the manner described in ex. 1. ;Yield: 88%, m.p. (ethanol): 183-187°C. ;<1>H NMR, DMSO-dg, ppm: 2.37 (s, 3H, CH3); 3.92 (m, 3H, CH-CHj-OH); ; 5.25 (exch. D 2 O, m, 2H, OH + NHCO); ;7.25-8.15 (m, 9H, arom.); 8.75 (exch.; D 2 O, p, 1H, N-NH). ;A toxicopharmacological study of the compounds according to the invention gave the following results for 1-(2-hydroxyisobutyr-oyl)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine (MP 440): ; Toxicity for two analogous dichlorinated compounds was as follows: ; LD^g intraperitoneal = 71 mg/kg LD5q intraperitoneal = 105 mg/kg LD^q oral = 114 mg/kg LD5q oral = 138 mg/kg; The antihypertensive activity of these two compounds; was found at the following respective doses:;6 .25 mg/kg per os and 1.56 mg/kg per os; (i.e. 1/18 of LD5Q) (1/88 of LD5Q; On the other hand, the antihypertensive activity of the above compound of the invention was 2 mg /kg per os, i.e. 1/485 of LE>5q. ;The compounds according to the invention are consequently much less toxic than the analogous dichlorinated compounds. ;Pharmacology;a) In mice ;1-(2-hydroxyisobutyroyl)-2-( 1-o-chlorophenyl-l-ethylidene)-hydrazine molecule: lowers spontaneous motility in mice ED^ = 10 mg/kg intraperitoneally, ;counteracts hypermotility caused by amphetamine from 12.5 mg/kg intraperitoneally, ;lowers exploratory activity (ED ^q = 27 mg/kg intraperitoneally), ;causes motor incoordination and hypothermia only in strong doses (50 mg/kg intraperitoneally), ;has an analgesic activity t which is weak in the PBQ test and more pronounced with the hot plate (ED,-q = 6 mg/kg intraperitoneally), as well as ;enhancing barbiturate-induced sleep from a dose of 12.5 mg/kg intraperitoneally. ;The compounds are inactive in the yohimbine and apomorphine tests and do not significantly change the oxotremorine test at a high dose. ;b) In rats ;1-(2-hydroxyisobutyroyl)-2-(1-o-chlorophenyl-l-ethylidene)-hydrazine proved to be anti-inflammatory in the carrageenin test (ED^q = 38 mg/kg intraperitoneally). From a cardiovascular point of view, the molecule has the following effects: significant increase in heart rate in normotensive rats without change in arterial blood pressure at a dose of 50 mg/kg intraperitoneally, and significant reduction in arterial blood pressure in spontaneously hypertensive rats (SHR) by a single administration in doses that are very less than the sedative and toxic doses (ED5g = 1.9 mg/kg intraperitoneally). Tests using oral administration confirm the compound's antihypertensive effect: in a single administration (ED^-q = 2 mg/kg), and in repeated administrations over 5 days in a dose of 1.5 mg/kg. ;The animal's heart activity did not change significantly under the indicated experimental conditions. ;The pharmacological profile for 1-(2-hydroxyisobutyroyl)-2-(1-o-chlorophenyl-l-ethylidene)hydrazine is that of an antihypertensive substance that also has sedative, analgesic and anti-inflammatory properties, but in higher doses than those that are necessary for the antihypertensive activity.; The antihypertensive activity (SHR) of other compounds according to the invention was also determined and compared with the activity of known compounds (R^ = H) or alkylated compounds (R^ = alkyl) which differ from the compounds according to the invention by their structure (X and R2^*1 Table II below, the compounds according to the invention are indicated by example numbers and the corresponding comparative examples have the same number with an index a, b, c, etc.

The results obtained in Table II show that only the compounds according to the invention have antihypertensive activity.

Claims (7)

1. Process for the production of hydrazine derivatives which the formula: where X is a C 1 -C 3 -alkyl or trifluoromethyl group or et halogen atom in the form of chlorine (in o- or m-position), fluorine or bromine, is a C 1 -C 2 -alkyl group and R2 is hydrogen, a branched C 1 -C 3 -alkyl group, a C 1 -C 4 ~ alkoxy group, preferably ethoxy, a group of the formula -CR^R^R^, where R^ is an ORg, SRg or NR^ Rg group, where R 8 is hydrogen or a C 1 -C 2 -alkyl group, and R 1 and R 8 are hydrogen, a C 1 -C 2 -alkyl group, a C 2 -C 3 -ac group or a benzoyl group, or R^ and Rg may together with the nitrogen atom to which it is bound to form a 5-membered or linked heterocyclic group, R 1 and R 2 are either equal and are hydrogen or a C 2 -C 3 -Al group, or R 4 is hydrogen and R 4 is either a C 1 -C 4 alkyl group which is optionally substituted with a hydroxyl group or a phenyl group, or R^ , R^ and R^ form together with the carbon atom as it is attached to an amido group, a phenyl group which is optionally substituted with a hydroxyl group, or a 5-membered or 6-membered heterocyclic group, characterized by that a) that an acyl hydrazide is produced in a first step the formula (1): where R2 is as stated above, by reacting a hydrazine derivative with an ester with the formula R2 -COOR (2), where R2 is as stated above, andb) that the compound with the formula (1) is reacted with an aryl alkyl ketone with the formula (3): where R 1 and X are as indicated above, to form the hydrazine derivative of formula (II). 2. Method in accordance with claim 1, characterized in that the two steps are carried out by boiling with reflux in an alcoholic medium. 3. Method in accordance with claim 1 or 2, characterized in that the alcoholic medium is ethanol or an ethanol/water mixture. 4. Method in accordance with one of claims 1-3, characterized in that an acylhydrazine with the formula (1) is used where R2 is the formula -CR^R^jR^ stated in claim 1. 5. Process in accordance with one of claims 1-4, characterized in that in the arylalkylketone with the formula (3) X is a halogen atom in the form of chlorine (in the m-position), bromine or fluorine, and R^ is as stated in claim 1. 6. Method in accordance with claim 5, characterized in that in the arylalkylketone with the formula (3) X is a halogen atom as stated in claim 1 and a methyl group. 7. Method in accordance with one of claims 1-6, characterized in that in the acylhydrazine with the formula (1) the R~ group and the arylalkyl ketone of formula (3) is R 1 CH 2 and X is o-chloro.