LU82949A1 - NOVEL AMINO-BENZAMIDES, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO THE TREATMENT OF HYPERTENSION - Google Patents

Description

- 1 - ι The invention relates to new organic compounds having a valuable pharmaceutical activity. It particularly relates to amino-benzamide compounds having antihypertensive and diuretic activity and a process for their preparation.

The subject of the invention is compounds corresponding to formula s

NOT

.10 h r4 (I) R, C-Ar * R- - 0 in which Ar and Ar 'independently represent alicyclic, aromatic or heterocyclic groups, R ^ is a substituent replacing a hydrogen atom in the nucleus and which can independently be a hydroxyl, alkyl or alkoxyl group, a halogen atom, a nitro, amine, monoalkylamine, dialkylamine, sulfhydryl, alkyl-mercaptan, sulfonaraide, carboxyl, carbalkoxy or trihalogenyl group, n is an integer of O to 5 inclusive,

Rj and independently represent hydrogen atoms, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl or cycloalkyl groups and R ^ and R ,. independently represent halogen atoms or trihalogenomethyl groups, with the proviso that when Ar and Ar * are both phenyl groups and that n 0, R ^ and R ^ are not both atoms hydrogen.

Preferably, the alkyl, alkenyl and alkynyl groups contain a maximum of 6 carbon atoms and they may be straight or branched chain, the cycloalkyl groups contain 3 to 7 carbon atoms and Ar * is a phenyl group.

According to the invention, to prepare these compounds, a sulfamylaroyl halide, preferably a / / chloride, corresponding to the formula "/ fj t - 2 - X-C-Ar · - Rs (II)" ^ 602NH2 is reacted.

O

5 or an equivalent acyl derivative; "in which X is a halogen atom, preferably chlorine, on a hydrazine corresponding to the formula"? (III)

10 N

/ \ D H * 3 in which R ^, R2, R ^, R,., Ar and ß have the meaning indicated above ·

Hydrazines are easily prepared by conventional methods by nitrosating an amine of the formula t li

H

(R.) -Ar-N ^ (IV) x n R2 in which R2 does not represent a hydrogen atom, to form nitrosamine i

NO

(R ^ -Ar-N ^ ------- "(V)

Ra which is then reduced to obtain 1 * hydrazine corresponding to the formula i (B,) -Ar-Nif (VI) 1 n \ nh2

When R ^ does not represent a hydrogen atom, the substituent R ^ can be introduced by conventional methods by reacting the derivative on a halide of R ^, for example by alkylating it with alkyl halides, to introduce alkyl groups, or using reagent J

———— f -3-.

\ ♦ i such reactions ·

For the compounds of formula I in which R2 and / or R3 represent something other than a hydrogen atom, the corresponding compounds of formula I in which and / or R3 represent a hydrogen atom are reacted with halides respective substituents R ^ and R ^, under the usual conditions for alkylation of amines ·

To carry out the above-mentioned nitrosation reaction, the initial secondary amine is reacted with nitrous acid 1 10 formed by the reaction of a soluble nitrite salt with a mineral acid. The reaction is normally carried out at low temperature, for example in below about 10 ° C # in one! organic solvent preferably miscible with water, since sodium nitrite is usually added in the form of an aqueous solution. Lower alkanols such as inethanol and ethanol are suitable as solvents ·

The reduction of the nitrosamine compound of formula V is preferably carried out by means of metal hydrides such as lithium hydruroaluminate and lithium hydruroborate in an organic solvent such as a dialkyl ether, for example diethyl ether.

To convert, as indicated above, the compounds in which R2 and / or R ^ represent H into compounds in which R ^ or R ^ represent a substituent as defined above, the compounds are reacted with a halogenide of R2 or do R ^, preferably in the presence of a hydrogen halide acceptor such as alkoxides, hydroxides, carbonates or bicarbonates. The reaction can be carried out roughly between room temperature and the reflux temperature of the solvent.

i The reaction of the compounds of formula II with the hydrazine of formula III is an acylation reaction forming the corresponding hydrazide · For this purpose, any derivative having acylation1 properties corresponding to chloride of acyl of formula II · Such derivatives, / include lower alkyl esters, anhydrides, f! / \ /, / "- 4 - mixed anhydrides and the like, as well as the acyl halide which is preferred · Preferably , the formation of hydrazide, i.e. the acylation reaction, takes place in an organic solvent, usually in the presence of a base such as alkoxides, hydroxides, bicarbonates or alkali carbonates, particularly when an acyl halide is used as the acylating agent. The acylation reaction is normally carried out at or near room temperature, for example between 25 ° C and> 10 temperatures as low as 5 ° C. Higher temperatures are not necessary, but can be applied for digestion · The solvent used is preferably an organic solvent miscible with water such as lower alkanols and organic solvents equiva-15 ·

The invention will be fully illustrated by the following examples · These are given by way of illustration and should not be considered as limiting · EXAMPLE 1 20 N-nitroso-N-isopropvlaniline

Maintaining at 10 ° C a mixture of 36 g (0.125 mol) of N-isopropylaniline, 45 ml of hydrochloric acid and 100 g of ice, while adding in the space of 10 minutes! a solution of 25 g (0.36 mol) of sodium nitrite in 90 ml of water. Once the addition is complete, the mixture is continued to stir for 1 hour. When the stirring ceases, an oily layer separates · The oil is removed and combined with toluene, used to wash the aqueous layer · The solution obtained is dried over magnesium sulfate, filter and the solvent is removed under reduced pressure to obtain the compound N-nitroso · EXAMPLE 2

1-Isopropyl-1-phenvlhvdrazine hydrochloride The N-nitroso compound of Example 35 1 is easily reduced by gradually adding a solution of 12.8 g (0.08 mol /

of this compound in 100 ml of glacial acetic acid at a f L

\ // - 5 - »* vigorously stirred suspension of 25 g of zinc powder | in 35 ml of water. During the whole addition, the temperature is maintained between 10 and 20 ° C. After the addition is complete, the mixture is stirred for 15 minutes at room temperature, then heated to 80 ° C in a steam bath. The unaltered zinc is separated from the hot reaction mixture by filtration and washed three times with 15 ml of warm 5% hydrochloric acid. The combined washing liquids and filtrate are cooled and the precipitated zinc hydroxide is redissolved, adding 150 ml of sodium hydroxide to 40% · The separating oily layer is removed and combined with the portions of ether used to wash the aqueous layer. This solution is dried over magnesium sulfate and filtered. By acidifying with gaseous hydrochloric acid, the hydrazine salt is obtained, which separates as an oil and is removed from the ethereal solution.

EXAMPLE 3 1 lMiBOPropvl-1-phenvl-2- (3-sulfamvl-4-chlorobenzovl) -hvdrazine To neutralize the hydrazine hydrochloride of Example 2, it is stirred with 19.6 g (0.21 mol ) sodium bicarbonate in 100 ml isopropanol. When the evolution of gas ceases (1 1/2 hours), the system is cooled in an ice bath and 25 g (0.1 mol) of 3-sulfamyl-4 chlorobenzoyl chloride are added in several portions. During all this addition, the temperature is maintained between 5 and 20 ° C. After the addition, the mixture is stirred overnight at room temperature. The mixture is then cooled to 0-5 ° C, diluted with 80 ml of water and stirred for an additional 2.5 hours. The precipitating solid is collected and washed with three 40 ml portions of cold 60% isopropanol.

By recrystallizing from the methylene chloride / ether mixture, crystals are obtained, melting point 112 at 124 ° C.

EXAMPLE 4 1-phenyl-1-n-propylhydrazine ^ /

The N-nitroso ^ N-propylaniline / ^ - 6 - prepared from Nn-propylaniline is conveniently reduced by the process described in Example 1 using lithium hydruroaluminate · The lithium hydruroaluminate is heated to reflux for 15 minutes in 450 ml of ether eec and a solution of 32.8 g (0.2 mol) of crude nitrose compound in 250 ml of dry ether is added dropwise to 5 drops · The mixture is continued to stir for 3 hours before quenching the reaction by adding dropwise 12 ml of water and 14 ml of 20% sodium hydroxide "The suspension obtained is filtered to éliminer0 remove the mineral salts, it is dried and the solvents are removed under reduced pressure · By distilling off the residue, the desired compound is obtained, boiling point 55 & 57 ° C at 0.16 mbar · EXAMPLE 5 15 ln-propvl-l-phenvl-2- (3-sul famvI-4 -chlorobenzoyl) -hydrazjne Shaking vigorously a mixture of 14.0 g (0.1 mol) of 1-phenyl-ln-propylhydrazine, 8.4 g (0.1 mol) of sodium bicarbonate and 100 ml of isopropano 1, it is cooled to 0 to 5 ° C, 20 g (0.09 mol) of 3-sulfamyl-4-chlorobenzoyl chloride are added all at once and the mixture is stirred for several hours while reheating gradually to room temperature. By diluting with water and refrigerating overnight, a solid is obtained which is collected and which is recrystallized in the acetone / water mixture, melting point 112 ° C. (decomposition). EXAMPLE 6 1-cvclohexyl-1-phenvlhvdrazine After having prepared N-cyclohexyl-N-nitrosoaniline 30 <from N-cyclohexylaniline by the process described in Example 1, it is reduced to hydrazine by means of hydruro-aluminate of lithium by the process described in Example 4 · /

1-cyclohexyl-1-phenylhydrazine distills between 102 and r <J 105 "C & 0.27 mbar. Dd / 4f \" - 7 - EXAMPLE 7 l-cyclohexyl-l-phenvl ^ -O-Bulfamvl ^ -chlorobenzoyD- hydrazing

A mixture of 8.5 g (0.045 mol) of 1-cyclohexyl-1-phenylhydrazine in 50 ml of isopropanol 5 and 4.7 g (0.045 mol) of sodium bicarbonate is stirred and cooled. 11.36 g (0.045 mol) of 3-aulfamyl-4-chlorobenzoyl chloride are added in several portions. The mixture is stirred for 2 hours at room temperature and for 2.5 hours at 40 to 50 ° C. By diluting the mixture with water, a solid is obtained which is recrystallized from aqueous ethanol, melting point 216 at 217 ° C.

EXAMPLE 8 l-phenvl-2- (3-sulfainvl-4-chlorobenzoyl) -hvdrazine In a 1 liter round-bottomed flask, 54.1 g (0.5 mol) of phenylhydrazine, 50.5 g ( 0.5 mol) of triethylamine and 150 ml of 1,2-dimethoxyethane # Then the mixture is cooled. the mixture at the temperature of the ice bath and, with good stirring, a solution of 61 g (0.24 mol) of 3-sulfamyl-4-20 chloride is added dropwise over 10 minutes 97.1% chlorobenzoyl in 150 ml of 1,2-diraethoxyethane.

The mixture is allowed to take room temperature. After 6 days of standing, the solvent is evaporated in vacuo and the residue is taken up in 500 ml of ethyl acetate. The organic phase is washed twice with 2N H 2 SO 4, 25 with water and finally with an IM solution of sodium bicarbonate. The ethyl acetate phase is separated, dried over magnesium sulfate, clarified and concentrated until crystallization. 35 g of product are obtained, melting point 189 at 190 ° C.

30 <EXAMPLE 9 l-allvl‘-l ~ phenyl "2 ~ (3-sulfainyl ~ 4-chlorobenzovl) ~ hvdrazine

48.8 g (0.15 mol) of the compound of Example 8/35 and 125 are placed in a 1 liter round-bottomed reactor with three pipes, equipped with a mechanical stirrer and a reflux condenser. ml of hexamethylphosphorotriaraide · We heat Ί »r / mixture between 80 and 85 ° C under nitrogen with stirring · To this / f /

: '; . V

Solution is added in portions 126 g (1.5 mol) of sodium bicarbonate powder, then 20 g (0.17 mol) of allyl bromide. After 2.25 hours, an additional 1.6 g (0.015 mol) of allyl bromide is added. After 29 hours of heating, the mixture is cooled to room temperature, diluted with 700 ml of ethyl acetate and the slurry is washed alternately with water and diluted brine. The ethyl acetate is separated, dried over magnesium sulfate, clarified and dried in vacuo. The crude mixture is crystallized from chloroform and 26.2 g of chemically pure product are obtained, melting point 99 at 101 ° C.

EXAMPLE 10 i l-phenvl-l-propvnvl-2- (3-sulfamvl-4-chlorobenzovl) -hvdrazine In a 1 liter round-bottom reactor with three lute pipes, equipped with a mechanical stirrer and a condenser at reflux, 97.5 g (0.3 mol) of the compound of Example 8 and 200 ml of hexamethylphosphorotriaioide are put · The mixture is heated under nitrogen between 80 and 90 ° C with stirring until the solid dissolves. 252 g (3 mol) of powdered sodium bicarbonate are added to the solution, with stirring.

Over the course of about 0.5 hour, 29.4 ml of an 80% by weight solution of propargyl bromide in toluene (0.315 mol of propargyl bromide) are added with stirring. After the reaction has taken place for 21 hours, an additional 4 ml of the propargyl bromide solution in toluene (0.043 mol of propargyl bromide) is added and the reaction is continued for an additional 68 hours. The mixture is then cooled and diluted with 1 liter of ethyl acetate. The mixture is transferred to a separatory funnel, washed alternately with water and brine, then with 2 mol / l aqueous citric acid I and again with brine. The organic layer is dried over anhydrous magnesium sulphate, clarified and evaporated to obtain 108 g of a λ j dark oil, which is purified by chromatography on /// "'- 9 - gel of silica, to obtain a solid which is recrystallized by the ethyl acetate / hexane mixture, melting point r 168 at 170 ° C.

EXAMPLE 11 5 l-allvl-1-phenvl-2- (3-sulfamyi-4-chlorobenzovl) -hydrazine

5 g (0.015 mol) of l-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine are dissolved in 15 ml of dimethylformamide · 2.8 g (0.023 mol) of allyl bromide are added and the mixture is heated mixing between 95 and 100 ° C for about 1.5 hours. The mixture is cooled, diluted with 30 ml of isopropanol and added slowly to approximately 900 ml of cold water.

The precipitate is collected by filtration, washed with water and dried under reduced pressure to obtain l-allyl-1-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine, melting point 99-101 ° C · EXAMPLE 12 l-allvl-l-phenvl-2- (3-aulfamvl-4-chlorobenzovl) -hydrazine In a 12-liter round bottom flask with three tubes, equipped with a mechanical stirrer and 'a ref-20 managing at reflux, 6.1 liters of isopropanol, 1.3 kg (4.1 mol) of l-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine, 68, 0 g (0.41 mol) potassium iodide, 1.67 kg (19.9 mol) sodium bicarbonate and 768 g (8 mol) allyl bromide ”This mixture is stirred at gentle reflux for approximately 8:25 p.m. then filtered with the pump while it is still hot.

The cake is washed with 300 ml of isopropanol, the filtrate and the washing liquid are combined and diluted with warm water to 2.7 liters. Crystallization occurs in about 0.5 hour. The crystals are filtered and washed with aqueous isopropanol (70% by volume) to obtain the compound, melting point 99 at 101 ° C. EXAMPLE 13 j-phenvl-l-propynvl-2- (3-sulfamvl-4-chlorobenzovl) -hvdrazinf 5 g (0.015 mol) of l-phenyl-2- (3-sulfarayl-é * 35 chlorobenzoyl) -hydrazine are dissolved ml of dimethylformamide. s »T | - 10 - heats the mixture between 95 and 100 ° C for approximately 2 hours · The mixture is concentrated under reduced pressure between 40 and 45 ° C approximately with a rotary evaporator * The concentrate is then diluted with approximately 2 volumes of * Isopropanol and 1 * slowly stirred at approximately 600 ml of vigorously stirred water * The precipitate is collected by filtration ", washed with water and dried under reduced pressure to obtain 1-phenyl-1-propynyl-2- (3- sulfamyl-4-chlorobenzoyl) -hydrazine "melting point 168 at 170 ° C.

.10 Using the methods of the examples above »compounds can be prepared in which R ^ is a hydroxyl group» alkyl »alkoxyl» nitro »a halogen atom» an amine group »trifluoromethyl» mercapto or alkylmercapto et and R ^ alkyl »cycloalkyl or alkenyl groups * When R ^ is a hydroxyl group" amine or mercapto "it is usually protected before the reaction on the sulfamyl halogenobenzoyl halide and the protective group is removed after the reaction *

Following the procedures of the above examples, the following additional compounds can be prepared: 2- [(4-chloro-3-sulfamyl) -benzoyl] -1-crotyl-1-phenyl-hydrazine 2- 2- (4-chloro-3-sulf amyl) -benzoyl-1- (2-butynyl) -10 phenyl-hydrazine "* 25 la 2 - [(4-chloro-3-sulfamyl) -benzoyl] -l- (3- methyl-2- butenyl) -1-phenyl hydrazine "2- [J 4-chloro-3-sulf amyl) -benzoylj -1-phenyl-1-cyclopropyl-methylhydrazine" 2- JJ4-chloro-3-sulfamyl) -benzoylj -l-phenyl-10 cyclopentyl-methylhydrazine "2- [(4-chloro-3-sulfamyl) -benzoylj-1-phenyl-1-cyclobutyl-methylhydrazine"

2- [(4-chloro-3-sulfamyl) -benzoylj -l- (2 »6-dichlorophenyl) -1-cyclopropylmethylhydrazine» and J

35 2- [(4-chloro-3-sulfamyl) -benzoylj -2-methyl-1- / V

phenyl-Oallyl-hydrazine * dDD

- 11 -

Loa compound of the invention exhibit antihypertensive and diuretic activities "thanks to which they are useful in the treatment of hypertension. In particular, 1-allyl-1-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine 5 and 1-propargyl-1-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine have both great diuretic and antihypertensive activity in rats and other mammals. In spontaneously hypertensive rats, l-allyl-1-phenyl-2- (3-sulfamyl-4-chlorobenzoyl) -hydrazine has an ED ^ Q of 3 mg / kg intraperitoneally and 30 mg / kg per bone·

The therapeutic agents of the invention can be administered alone or in combination with pharmaceutically acceptable vehicles, the proportion of which is determined by the solubility and the chemical nature of the compound, the route of administration chosen and the current pharmaceutical practice. they can be administered orally in the form of tablets or capsules containing excipients such as starch, lactose, certain types of clay, etc. They can be administered orally in the form of solutions which may contain colors or flavorings or they can be injected by the parenteral, ie intramuscular, intravenous or subcutaneous route. For parenteral administration, they can be used in the form of a sterile solution containing other solutions, such as enough saline or glucose to make the solution isotonic

The doctor will determine the most appropriate dosage of the therapeutic agents according to the invention, which varies according to the mode of administration and the compound chosen and, moreover, according to the patient treated. Generally, it will be desired to start the treatment with small dosages. , notably lower than the optimal dose of the compound, and increase the dosage / 35 little by little, until the optimal effect, under the / - / conditions in question, is reached · We will find / j / Generally, when the composition is administered orally, larger amounts of active ingredient are required than parenterally to produce the same effect. The compounds are useful in the same way as other diuretics and antihypertensives and the dosage is of the same order of magnitude as is generally applied for these other agents. The therapeutic dosage is generally 10 to 750 mg / day and above, although it can be administered in several doses. The tablets containing 10 10 1250 mg of active agent are particularly useful ^^ / Ί i 1 · '1 <«i

Claims (28)

1, - Compounds corresponding to the formula> (Rl) n-Ar ^ N 5. R. (I) C-Ar'i ^ _ R5 ^ so2nh2 O in which Ar and Ar 'independently represent, alicyclic, aromatic or heterocyclic groups. R ^ is a substituent replacing a hydrogen atom of the nucleus and which can be, independently, a hydroxide, alkyl or alkoxyl group. a halogen atom, a nitro, amine, monoalkylamine, dialkylamine, sulfhydryl group. alkylmercaptan. Sulfonamide, carboxyl. carbalkoxyl or trihalomethyl. ü is an integer from 0 to 5 inclusive. R2 and R ^ independently represent hydrogen atoms, alkyl, alkenyl, alkynyl, cycloalkyl, cyelo-alkenyl, phenyl or cycloalkyl groups and and independently represent halogen atoms or trihalomethyl groups, with the proviso that when Ar and Ar * are both phenyl groups and n - 0, R2 and R ^ are not both hydrogen. 2 · - Compound according to claim 1, characterized by. The fact that Ar and Ar * independently represent phenyl, naphthyl, pyridyl, thienyl or furyl. 3 · - Compound according to claim 1, characterized in that R2 and R ^ are straight or branched chain alkyl groups containing 1 to 10 carbon atoms. __ 30 4 · - Compound according to Claim 1, characterized in that R2 and are alkenyl or alkynyl groups k straight or branched chain containing 2 to 10 carbon atoms. 5 · - Compound according to Claim 1, characterized in that gue-R2 and R ^ are cycloalkyl, cyclo- / alkenyl or cycloalkynyl groups containing 3 to 10 carbon atoms' · / U J - 14 - 6, - Compound according to claim 2, characterized in that Ar and Ar * are phenyl groups · 7 · - Compound according to claim 6, characterized in that represents Cl and that n is 1 or 2. 8. A compound according to claim 1, characterized by the fact that is a hydrogen atom and Rg a chlorine atom or a trifluoromethyl group. 9 · - Compound according to Claim 8, characterized in that the group 1 ° R4 Ar * C- Rs represents / 5V01 1S SÔjlHj 10 · - Compound according to Claim 8 * characterized in that the group R. y 4 Ar'C_Rc V 5 20 ^ S02NH2 represents (5) -% so2m2 t 11 · - Compound according to claim 9, characterized in that Ar is a phenyl group and that n "O. 12 · - Compound according to Claim 10, characterized in that Ar is a phenyl group and that n - O # 13 · - Compound according to one of claims 9 and 10, characterized in that Ar is a phenphenyl group, R ^ 30 a chlorine atom and that n - 1 · 14 · - Compound according to Claim 9, characterized in that (R1> Ar is a 2,6-dichlorophenyl group · I 15 · - Compound according to Claim 11, characterized ^ f *. "Μ" * - * - "1 - 15 - by the fact that R2 is an allyl group and R ^ vin hydrogen atom. 16." Compound according to claim 12, characterized in that is an allyl group and R ^ a hydrogen atom · __ 17 · - Compound according to claim 11, characterized in that R ^ is a propargyl group and R ^ a hydrogen atom. 18.- Compound according to claim 11, characterized in that R ^ is a cyclopropylmethyl group and 'a hydrogen atom. 19 · - Compound according to Claim 14, characterized in that R ^ is a propargyl group and R ^ is a hydrogen atom. · Compound according to Claim 11, characterized in that R ^ is an allyl group and R ^ is a methyl group. 21 · - Compound according to claim 11, characterized in that R ^ is a group CH ^ -OC-CH ^ - and R ^ a hydrogen atom. 1 22 · - Compound according to claim 11, characterized in that R ^ is a group (H ^ C) OC (CH3) -CH ^ - and R ^ 1 a hydrogen atom. 23 · - Compound according to claim 9, characterized by t 25 that is a propyl group and a hydrogen atom. 24 · - Compound according to claim 2, characterized in that R ^ is a propyl group and R ^ is a hydrogen atom. 30 25 · - Application to the treatment of hypertension of a compound according to one of claims 1 to 24.> 26 · - Application according to claim 25, characterized in that, in said compound of claim 1, / Ar is a phenyl group, / / 35 Ar 'is a phenyl group, lu n »0, Lη - 16 - R ^ is an allyl group * R ^ is hydrogen * R. is 4-chloro, 4 Rs is hydrogen * and 6 the group SO ^ NH ^ is in position 3 * 27. Use according to claim 25 * characterized in that * in the said compound of claim 1 * Ar is a phenyl group * Ar 'is a phenyl group * = 10 n * 0, B ^ is a propargyl group * R ^ is hydrogen * R. is 4-chloro * ______ 4 R_ is hydrogen * and 3 15 the group SO ^ NH ^ is in position 3 · 28. Process for the preparation of compounds according to one of claims 1 to 24 * characterized in that a hydrazine corresponding to the formula s (Rl) n-Ar ^ ‘is acylated 20 N • (III) b "· 'by means of an acylation derivative suitable for forming the corresponding hydrazide and that * optionally * the product is converted to introduce substituents R ^ other than hydrogen * 29. Method according to claim 28 * characterized in that the acylation derivative is an acyl halide * preferably a chloride * 30 30 · - Method according to one of claims 28 and 29 * characterized in that Hydrazine is obtained by reduction of the corresponding nitrosamine · 31. The method of claim 30 * characterized in that the reduction is carried out by means of a metal hydride such as hydriraaluminate of lithira ^^ jfc -BW— "" - 17 - or 1 hydruroborate lithium · 32 · - Method according to one of claims 28 and 29, characterized in that the acylation is carried out at ambient temperature or in the vicinity thereof " 33. Process according to claim 30 # characterized in that the nitrosamine is obtained by reaction of the corresponding secondary amine on the nitrous acid At a temperature lower than approximately 10 ° G »Drawings: bends Λ * Υ pages of which - ^ .....- page de, A2__pages de desv: π ___ 5 .__ pages de reven;:; ca.ic ·; ·. · 'Λ - short description Luxembourg, le 20. ΛΛ. Λ $ 80 The agent: / A * \; · T * "i t j"