DE1941261A1 - A hydrazide and its acid addition salts - Google Patents

Description

Df. Ing. L , von der Werth Dr. Fronz Lcderer. 1 "3 AlIG-1969 PATENT AGENT - ^J " ^MUÜ · ¹³⁰³

RAN 4007/15

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

A hydrazide and its acid addition salts

The present invention relates to the new hydrazide of the formula

CH ₂ -NH-NH-CO-CH ₂

NH

i as well as acid addition salts thereof * a procedure 2jür Servant Verblndttingett and their

Since «« rfindunfieemlee · procedure is thereby gektnnzeioh ·

- - 009849 / 2ÖII

net that you can get a compound of the formula

CH-N-NH-CO-CH

Ha

NH,

Hi

or an acid addition salt thereof, hydrogenated, or that one in a compound of the general formula

CH ₂ -NH-NH-CO-R ₄ lib

where R ,, R ₂ and R, hydroxyl groups or groups convertible into hydroxyl groups and Rj, the aminomethyl group (-CHp-NH ₂ ) or a group convertible into the aminomethyl group, where at least eleventh the substitute tert R ₁ , R, ϊύ and R ^ different from the Hyelföxy group or from the aminomethyl group

or in an acid additipttssaiz an isölctiefi

in the Hydroxygru |> pe unet 6ζ * ϊ * öde ^ those in dii ÜieiiliÖirliif i Örtippe- t & tf «ÖPiipam ίϋ di transferred to the A "inoai" thy group and due to an o

ORIQiWAL INSPECTED

-> - 194126 T

base obtained optionally converted into an acid addition salt .

Those labeled JL, PU and R in the above formula lib Groups which can be converted into hydroxyl groups are preferred Benzyloxy groups. However, these groups can also be acetal groups, which differ from acetaldehyde, aoetone or derived from tetrahydropyran, e.g. a-methoxy-ethoxy, a-methoxy-isopropoxy and tetrahydropyranyloxy. These groups can be formed in a manner known per se by hydrogenolysis, preferably by means of catalytic hydrogenation, e.g. with noble metal catalysts such as palladium and platinum catalysts, in hydroxyl groups be transferred. Other groups R, R and R ^ which can be converted into hydroxyl groups are, for example, acyloxy groups, such as lower alkanoyloxy groups which are formed by hydrolysis are convertible into hydroxyl groups.

As groups Rl which can be converted into the aminomethyl group especially the following:

Carbobenzoxyaminomethyl (Benzyl-OCONH-CHp-), Benzylaminomethyl (Benzyl-NHp-GHp-) i Benzhydrylinomethyl ((C ₆ H ₅ ) ^ CH Benzyiidenaminomethyl "(Pheny 1 ^ CH = N- ^; Cyanio (-CN)> Azidomethyl (N ₃ -CH ₂ -), ^ ltromlthyl (O ₂ N ^ CH ₂ -),

'' Phenylazoifethyl ^; (¥ heny 1-N = N-CHp ^ - K

009 8 4l ^ Ö2 δ

* ■ - ■ "Hydroximinomethyl (HON = CH-),
Iminomethyl (HN = CH-) and
Phenylhydrazonomethyl (phenyl-NH-N = CH-).

These groups can be converted into the aminomethyl group in a manner known per se by hydrogenation. Both catalytic hydrogenation and reduction with chemical reducing agents are suitable for this. As catalysts both Edelmetallkafcalysatoren as palladium and platinum catalysts can _t as well as nickel and cobalt catalysts are used. Metal hydrides, for example, are suitable as chemical reducing agents.

Other groups that can be converted into the aminomethyl group are:

. Pormylaminomethyl (OHC-NH-CH ₃ -),

Trifluoroacetylaminomethyl (F ^ C-CONH-CH ₂ -),, tritylaminomethyl [(C ₆ H ₅ ), C-NH-CH ^], o-nitrophenylsulfonylaminomethyl (o-nitrophenyl-S-NH-CHp-),

is. -C

Alkoxycarbonylaminomethyl (alkyl-O-CONH-CH ^) and Phthalimidomethyl.

These groups can be converted into the aminomethyl group by hydrolysis in a manner known per se. Pure the Hydrolysis of the Pörniylaminomethylgruppe is suitable for example

009849/2028 -

wise dilute alcoholic hydrochloric acid, while the trifluoroacetylaminomethyl group can also be hydrolyzed with dilute aqueous ammonia. For the conversion of the phthalimidomethyl group into the aminomethyl group is advantageously Used hydrazine.

Other groups that can be converted into the aminomethyl group are:

Halomethyl groups (Hal-CHp-),

Alkylsulfonyloxymethyl groups (alkyl-SOp-O-CHp-), Arylsulfonyloxymethyl groups (Aryl-SOp-O-CHp-).

These groups can by reaction with ammonia in The presence or absence of a solvent can be converted into the aminomethyl group.

Further groups which can be converted into the aminomethyl group are:

Carboxamidomethyl (HpN-CO-GHp-),
Carbohydrazidomethyl (H ₂ N-NH-CO-CH ₂ -), carboxazldomethyl (N-.QC-CHq-) and carbalkoxyhydroxamidomethyl (alkyl-COONH ^ CO-CHp).

These groups can be used in a manner known per se according to 00984972028

the Hofmann's view, the Curtius's view, the Schmidt's view and converted into the aminomethyl group after Lossen's breakdown will.

Another group that can be converted into the aminomethyl group is the ct-carboxy-a-aminomethyl group, which by decarboxylation, e.g. can be converted into the aminomethyl group by gentle heating.

If the base is obtained as the product of the process, it can be converted into an acid addition salt with an inorganic or an organic acid, for example the hydrochloride the sulfate, the acetate, the oxalate, etc. are transferred. the Salts are because of their greater resistance to the Base preferred.

A preferred embodiment of the erfinduhgsgemässen The process consists in that an acid addition salt of N -glycine-N - (2,3,4-trihydroxy-benzylidene) hydrazide, in particular the hydrochloride, is catalytically hydrogenated, preferably using a palladium-carbon catalyst. Man

12 directly holds the corresponding salt of N -Glycine-N (2,3 j ^ - trihydroxybenzyl ) hydrazide.

The same product can expediently also be obtained thereby

1 2 are that k is an acid addition salt of the N-glycine N ~ (2, J>, ~

009849/2018

tribenzyloxy-benzylidene) hydrazines catalytically hydrogenated, preferably using a palladium-carbon catalyst. Here, hydrogenolysis of the benzyloxy groups and occurs first afterwards hydrogenation of the benzylidene group, with also

1 2
a salt of N -Gly.cln.-N - (2,3,4-trihydroxybenzyl) hydrazide is obtained.

The compounds of the formula "IIa and lib and their salts used as starting materials in the process according to the invention can be obtained by methods known per se. The compound of the formula Ha is obtained by reacting an acid addition salt of glycine hydrazide with 2.3"
hydroxybenzaldehyde.

Starting materials of the formula Hb, in which the substituents FL, R_, R, and Rj, from the hydroxy group and from the aminomethyl group, respectively are different, by reacting a correspondingly substituted glycine hydrazide with a corresponding substituted benzaldehyde and subsequent hydrogenation the benzylidene compound obtained, e.g. by means of a platinum catalyst, can be obtained.

The obtained by the process according to the invention

0096 * 9/2028

Compounds (the hydrazide of the formula I and its acid addition salts) have a pharmacological effect, and indeed have they have a decarboxylase-inhibiting effect.

However, these compounds are of particular interest in that, in combination with L-Dopa, they are excellent agents for treating Parkinsonism. Further they have an antidepressant effect in combination with L-Dopa and this combination also increases the antidepressant effect of tricyclic antidepressants, for example from Imipramln, exponentiated.

It was found that small doses were used in rats

1 2
(12 mg / kg) of N-glycine-N - (2,3,4-trihydroxybenzyl) hydrazide hydrochloride for at least 4 hours obtained by intraperitoneal or oral administration of L-3,4-dihydroxyphenylalanine (L-Dopa) Induced increase of this amino acid in the blood and in the brain. At the same time, the increase in catecholamines (CA) and their metabolites, phenol carboxylic acids, in the blood and other peripheral organs (heart, kidneys, spinal cord) is greatly reduced / in the brain, however, considerably increased As a result of the decrease in the catecholamine content in the periphery, the peripheral aedrenergic stimulation is also reduced.

It is believed that these effects are the result of a

relatively selective inhibition of decarboxylase

1> * "
the N -Glyoin - / (2,3i ^ -trihydroxybenzyl) hydrazide hydrochloride is in the extraeerebral organs. As a result of the increased dopa concentration in the blood, larger amounts of amino acids reach the brain, where decarboxylation to catecholamines takes place, since cerebral decarboxylase is practically not inhibited. This selective action of the glycine (2,3 * 4-trihydroxybenzyl) hydrazide is probably the result of the very low penetration capacity of this compound into the brain. For example, the decarboxylase activity in the brain of animals into which the glycine (2,3,4-trihydroxybenzyl) hydrazide hydrochloride was injected is not noticeably inhibited up to doses of 50 mg / kg, while in the heart it is about 80% Inhibition is already observed at a dose of 25 mg / kg. On the other hand, when added to homogenized tissue, the compound causes the same decarboxylase inhibition in both the brain and heart.

To determine the effectiveness on those caused by dopa

induced increase in catecholamine levels in the brain

1 2
the N -Glycine-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride administered orally to the test animals (rats) in doses of 3-100 mg / kg. Thirty minutes later, 3 mg / kg of L-dopa was administered orally and the animals were sacrificed 1 hour later.

It was found that 12-24 mg / kg of the hydrazide

the maximum increase in cateohyllium in the rat brain induc-

00 984 9/202 8

This value is about 60 times higher than the one which is obtained with the administration of L-Dopa alone,

For the purpose of anti-Parkinson treatment, as well as for The combination of the compounds obtainable by the process according to the invention can be used for the treatment of depressive states (of the hydrazide of the formula I and its acid addition salts) with the L-Dopa both as the actual combination in a single dosage form, as well as separately in two dosage forms administered. Since it has been found to be useful that the L-Dopa only after the hydrazide, namely preferably about 150-60 minutes after the hydrazide, in the body should be released when a single dosage form is administered in this the L-dopa is present in such a form that it is only released after the hydrazide. One Such a combination with delayed dopa release can, for example, consist of a core of L-Dopa with an enteric Coating exist. This core can have an outer layer which contains the hydrazide or the hydrazide can be in the form of granules together with the coated L-Dopa core can be housed in a capsule. When the combination is administered parenterally, the hydrazide is expediently used first intramuscularly and, about 3Ο-6Ο minutes later, the L-dopa administered intravenously.

009849/2028

The quantitative ratio is of essential importance from Hjrdrazld to L-Dopa. This should be 0.5-2 weight points, preferably i part by weight per part by weight of L-Dopa, be. 225-600 mg of hydrazide and 450-600 mg L-Dopa (divided into 3-4 administrations) applied,

Example 1 "

24 g of N ¹ -glycine-N ² - (2,3 »4-trihydroxybenzirliden) -hydrazidhydrochlorld are suspended in 300 ml of water and hydrogenated with palladium-carbon. Everything dissolves when 2.5 liters of hydrogen are absorbed fairly quickly. The catalyst is removed, the solution is concentrated to 40-50 ml under reduced pressure and diluted with 200 ml of absolute ethanol. The crystallization takes place in a few seconds. Utaer is left standing in the refrigerator for a night, suction filtered and washed out with ethanol, ether and petroleum ether. The crude product is dissolved and further purified in 4o ml of water at a maximum of 40-50 ° ⁱ by the addition of 120 ml of methanol to crystallize *

1 2
The N -Glyein-N - (2,3,4-trihydroxy-benzyl) hydrazide hydrochloride obtained in this way is white crystals which are soluble in water with a neutral reaction. Melting point 179-162 °,

- ι

That here as; Starting material used.N -Glycine- ,,

N - (2,3,4-trihydroxy-benzylidene) hydrazide hydrochloride can can be obtained as follows:

15 »4 e 2,3,4-trihydroxybenzaldehyde are in 200 ml Dissolved boiling water and at once with 12.6 g of glycine hydrazide monohydrochloride offset. After a few minutes, the liquid becomes cloudy and quickly solidifies to form a crystal paste. It is cooled in ice water and suction filtered. Little is used to wash Water and a lot of aoeton. The N-glyein-N - (2,3 * 4-trihydrqxy-benzylidene-hydrazide hydrochloride represents white to slightly yellowish crystals and melts below 303-305 ° Decomposition.

example 2

31.5 g of N -carbobenzoxyglycine-fr- (2,3,4-tribenzyloxybehzylidene) hydrazide are suspended in 300 ml of methanol and 5 ml of glacial acetic acid and hydrogenated with palladium-carbon. After the recording the calculated amount of hydrogen becomes 6.1 ml of benzyl chloride added and hydrogenation continues until the hydrogen uptake has ceased again. One sucks off the catalyst and evaporate the solution in vacuo to a crystal slurry. The product obtained is identical to that according to Example 1 obtained connection.

The N-carbobenzoxyglycine-ir- (2,3 * 4-tribenzyloxy-benzylidene) hydrazide used as starting material can

0098 49/2028

can be obtained as follows:

22.3 S carbobenzoxy-glycine hydrazide and 42.4 g of 2,3 * 4-tribenzyloxybenzaldehyde are each dissolved in 300 ml of boiling absolute ethanol, the two solutions are combined with one another ': and cooked for an hour. After cooling in ice water it will sucked and washed with alcohol and ether. The thus obtained

1 '2

N -Carbobenzoxyglycine-N - (2,3,4-tribenzyloxy-benzylidene) hydrazide melts at 1 * 0-142 °.

Example 3

By hydrogenating N -Carbobenzoxyglycine-N - (2,3 * 4-trihydroxy-benzylidene) hydrazide using a palladium-carbon catalyst, in a mixture of methanol, water and glacial acetic acid, addition of the calculated amount of benzyl chloride, further hydrogenation and work-up in analogy to Example 2 a compound identical to the product of Example 2 is obtained.

The N -Carbobenzoxyglyoln-N used here as starting material - (2,3,4-trihydroxy-benzylidene) hydrazide can be obtained as follows:

22.3 g carbobenzoxy-glyoin hydrazide are in 300 ml dissolved in boiling absolute ethanol and mixed with 15 * 4 g of 2,3> 4-tri

009 8 49/2028

added hydroxybenzaldehyde. After a short boil, it is cooled in ice water and sucked. The N -carbobenzoxyglycine-N- (2,3,4-trihydroxy-benzylidene) hydrazide thus obtained melts at 211-212 ^e .

Example 4 N -nitroacetyl-IC-teOA-tribenzyloxy-benzyldenJ-hydrazide

1 2

(obtained from 28 g of N -Bromaoetyl-N - (2,3,4-trlbenzyloxy-benzylidene) hydrazide according to the method described below) is dissolved in 200 ml of methanol and hydrogenated using a palladium catalyst in analogy to Example 2, over the N -Glycine-iT- (2,3,4-trihydroxybenzylidene) hydrazide the N ¹ -Glycine-N ² - (2,3 »4-trihydroxybenzyl) hydrazide, the hydrochloride of which is the one obtained in Example 1 Product corresponds.

The N-nitroacetyl-iT- (2,>, 4-tribenzyloxy-benzylidene) hydrazide used here as starting material can be made as follows:

28 g of M -Bromoacetyl-iT- (2,3,4-tribenzyloxy-benzylidene) hydrazide are in 200 ml of dimethylformamide at room temperature stirred, 7.7 g of silver nitrite being added in portions to the mixture. The reaction mixture is overnight at The mixture was stirred at room temperature, the precipitated silver bromide was filtered off and concentrated to about 50 ml under reduced pressure. It is then diluted with chloroform and

'009 8 49/202 8

funnel washed 4 to 5 times with water, with sodium sulfate dried and evaporated under reduced pressure. The »■ -Kltroacetyl-Iir- (2,3,4-tribenzyloxy-benzy lidene) hydrazide remains as a yellow, viscous oil.

The N -Bromaetyl-N - ^, ^^ - tribenzyloxy-benzylidenj on its part can be prepared as follows:

11 $ ": -%! ^ Ilivirlbenzyi oxy ^ benzaldehyde are dissolved in 200 ml of boiling, absolute ethanol and mixed with a freshly prepared mixture of 6 * 5- & bromaoetylhydrazld-hydrochloride (melting point lo-18l ° C, prepared by reacting 3romacetic acid and N-hydroxysuceinimide in the presence of Ν, Ν'ν dicyclohexylcarbodiimide, reaction of the bromoacetyl-N-hydroxy-succinimide ester obtained in this way with carbobenzoxyhydraÄin in ethyl acetate at Ö- $ * C and treatment of the bromoacetylcarbobenzoxyhydrazide obtained with glacial acetic acid / hydrogen bromide), 3.9 ml friäthyia «i (n and 15 n * X water added, pie reaction takes place very quickly and in 2 to 3 minutes the contents of the flask solidify to a crystal paste. It is allowed to cool, filtered and washed with ethanol and ether. The N -brofflacetyl-N - (2 * 3,4-tribenzyloxy-benzylidene) hydrazide obtained in this way forms white, sparingly soluble crystals which melt at 175-176 °.

00 98Ä9 / 2 0 28

Example 5

N -azidoacetyl-N - (2,5, ^ - tribenzyloxy-benzylidene) hydrazide is hydrogenated in analogy to Example 2, with about the N -Glycine-ϊΓ '- (2> 3,4-trihydroxy-benzylidene hydrazide das

1 2 "'" ■ ""' '■ "■■'" " N -Glyeln-N - (2,3 / 4-trihydroxybenzyl) hydrazide is formed, whose hydrochloride is the product obtained according to Example 1 is equivalent to.

The N -azidoacetyl-N used as starting material - (2,3,4-tribenzyloxy-benzylidene) hydrazide can be like can be obtained as follows:

28 g of N ¹ -Bromac ^ tyl-N ^? _? {2 _r 3 _# 4-tribenÄyloxy-benzylidene) hydrazide are mixed in portions with 3.3 g of sodium azide in 200 ml of dimethylformamide while stirring. After customary working up, the H--Azidoacetyl yerbindüng in the form of a ÖIS.

Example 6

15 g of H ¹ -tritylglycine-N ² - (2,3, ^ - trihydroxy-benzylidene) hydrazide are suspended in% Ö0 ml of methanol and hydrogenated with palladium carbon. After 1 mol of hydrogen has been absorbed, the catalyst is filtered off and 15 ml of glacial acetic acid are added to the piltrate. It is heated on the steam bath for about 10-15 minutes and then cooled in ice water. The precipitated triphenylcarblnol

009849/2028

is removed and the filtrate by adding alcoholic Hydrochloric acid adjusted to pH 2-5. One evaporates under reduced Pressure to 100 ml removes any triphenylcarbinol that has still precipitated by filtration and evaporation continues until the end product begins to crystallize. This product corresponds to the compound prepared according to Example 1.

The N -tritylglycine-N used here as starting material - (2,3,4-trihydroxy-benzylidene) hydrazide can like can be produced as follows:

A mixture of 6.6 g of trityl-glycine hydrazide (JACS 28.1359) and 3.1 g of 2,3,4-trihydroxy-benzaldehyde is boiled in 100 ml of alcohol for 2-3 hours. Crystallized over night in the refrigerator N -Tritylglycin-N - (2,3,4-trihydroxy-benzylidene) hydrazide of melting point 148-150 ⁰ C out.

Example 7

12th
N -formylglycine-N - (2 _J 3 _J 4-trihydroxybenzylidene 5-hydrazide

(produced by reacting 5.1 g of formyl glyoin hydrazide (J.Chem.Soc. 1954, 1039) with 6.3 g of 2,3,4-trihydroxy-benzaldehyde) is suspended in 200 ml of methanol in the presence of a palladium-carbon Hydrogenated catalyst. A solution is formed after 1 mol of hydrogen has been absorbed. The catalyst is filtered off and the clear filtrate is washed with methanolic salt

009849/2028 · ■:

acid brought to a pH of 1-2. One lets on that • the solution stand at room temperature for 2-3 days, with splitting the formyl group occurs. It is concentrated under reduced pressure until crystallization begins and the product is left crystallize. One receives the product of the example 1 corresponding connection. .

. Example 6

A mixture of 10.6 g of trifluoroacetyl-glycine hydrazide (Chem. Ber.92_ (1959) 313) and 6.3 g of 2,3,4-trihydroxy-benzaldehyde is suspended in 200 ml of methanol and after adding 7.1 ml Triethylamine hydrogenated with palladium carbon »After 1 mol of hydrogen has been absorbed, the catalyst is filtered off and the 10 ml of 2N methanolic ammonia are added to the piltrate and 24 Left to stand under nitrogen at room temperature for hours. The trifluoroacetyl group is split off here. It is made weakly acidic with alcoholic hydrochloric acid (pH 2.5-3) and concentrated under reduced pressure to 100 ml. Precipitated ammonium chloride is filtered off and the Piltrat bis concentrated to the start of crystallization (about 60 ml). That precipitating product is identical to the product obtained according to Example 1.

009849/20 2 8

Example 9

A mixture of 6.25 g of glycine hydrazide and 41.4 g of 2,3,4-tribenzyloxy-benzaldehyde mHpJww in 500 ml of alcohol, boiled for 3-4 hours; The viscous mass that separates after cooling becomes solid in about 2-3 days. It is removed and washed with alcohol and ether. The N - (2,3,4-tribenzyloxybenzylidene-glycine) -ίί - (2,3,4-tribenzyloxy-benzylidene) -hydrazide thus obtained melts in hot IIQ-llfi ⁰ with decomposition.

10 g of the above product are dissolved in 300 ml of methanol suspended and until the end of the hydrogen would take ir.it Palladium carbon hydrogenated. This results in dissolution. The catalyst is filtered off and made with alcoholic * · hydrochloric acid weakly acidic (pH 2.5-3) and concentrated under reduced pressure until crystallization begins. The product thus obtained Is identical to that obtained in Example 1.

Example 10

11 g of phthalyl glycine hydrazide (approx. £ 2, l * 540 ^d ) are suspended in 300 ml of boiling alcohol and treated with 6.7 g of 2,3,4-trihydroxybenzaldehyde. The mixture is boiled for about 2 hours, after which a clear solution has formed. After the addition of palladium-carbon, hydrogenation is carried out until the uptake of hydrogen ceases, the catalyst is filtered off and the filtrate is mixed with 1.5 ml of hydrazine

009849/2028 om® _NAL

• hydrate added. After standing overnight it is from the failed. Phthalylhydrazld suction filtered and the Ftltrat with alcoholic Hydrochloric acid weakly acidified. (pK 2 * 5-3) One concentrates under reduced Pressure / ΓΟΟ ml and filtered off from the precipitated hydrazine hydroehiorid. The filtrate is continued to 60 ml concentrated, whereupon the reaction product begins to precipitate. It Is'identical to the substance prepared according to 3eisplel 1.

Example 11

8.9 g of benzyl glycol hydrazide (Arch.Pharm. 295 .697) are refluxed for 3-4 hours together with 6.7 g of 2,3,4-trihydroxybenenaldehyde in 300 ml of methanol and then after the addition of palladium carbon hydrogenated. When the uptake of hydrogen has ended, the catalyst is filtered off, weakly acidified with alcoholic hydrochloric acid (pH 2.5-3) and concentrated under reduced pressure until crystallization begins. The product obtained is identical to the substance obtained according to Example 1.

Example 12

17 * 8 g carbobenzoxyamino malonic acid benzyl ester hydrazide (produced by the action of hydrazine hydrate on carbobenzoxyiälalonsäure-benzylester-niethylester) are together with 21.3 g of 2,3,4-Trlbenzyloxy-benzaldehyde in 1 liter of methanol for 3-4 hours boiled, with solution slowly entering and towards the end of the

009849/20 2 8

action the product fails partially. It is left to room temperature cool and hydrogenate after the addition of palladium carbon until the hydrogen uptake ceases. The catalyst is filtered off, the solution is weakly acidified with alcoholic hydrochloric acid (pH 2.5-3) and until crystallization begins concentrated under reduced pressure. The product is identical with the substance obtained in Example 1.

Example Γ5

6 g of malonic acid hemihydrazide (B. 5jf. 1432) are in Dissolve 200 ml of alcohol and add 6.7 g of 2,3,4-tribenzyloxy-benzaldehyde offset. The mixture is refluxed for 30 minutes and then added then added palladium carbon and hydrogenated. After the uptake of hydrogen has ended, the catalyst is filtered off and taken under evaporated under reduced pressure. It remains a brown oil back that with cooling in 60 ml of conc. Sulfuric acid is dissolved. 3 * 3 g of sodium azide are added in portions while cooling with ice and leave to stand overnight at room temperature. It is then diluted to 500 ml with ice water and the sulfate ions removed by adding barium chloride. After filtering off the barium sulfate, it is evaporated under reduced pressure and by adding methanol and evaporating the solution several times

dried. Finally, dilute to 400 ml with alcohol and sucks off the sodium chloride. If necessary, the Piltrat is adjusted to pH = 2.5-3 with alcoholic hydrochloric acid and the pH value is adjusted with

009849/2028

Charcoal clarified solution concentrated under reduced pressure until crystallization begins. The product obtained is identical to that prepared according to Example 1.

Example 14

A hard gelatin capsule, from which the L-Dopa component is released with delay, can be produced as follows Becoming

A core consisting of 50 mg L-Dopa, 8 mg corn starch, 15 mg lactose, 1.8 mg talc and 0.2 mg magnesium stearate is coated with a ceilulose acetate phthalate varnish to make it to make enteric-coated.

From 50 mg N -Glyein-Ir -> (2,3 * 4-trihydroxybenzyl) hydrazide hydrochloride, 58 »25 mg mannitol and 23.7 mg polyvinylpyrrolidone granules are produced in the usual way.

The coated core and the granules are placed in a hard gelatin capsule.

009849/2028

Example 15 a) Production of tablets with L-Dopa as active ingredient:

Tablets of the following composition are produced in the usual way:

L-Dopa 150 mg

- milk sugar 200 mg

Paint starch 155 mg Magnesium stearate I »5 mg

Talk 15 * 5

■■ """" 1 """■" · "2 'b) Production of tablets with H -Ölyoin! ^ *

trihydroxybenzyl) hydrazine hydrochloride as active ingredient j

Tablets of the following composition are usually produced j "" '"■' -

Active ingredient ■■ 150 mg

Mannitol 200mg

Corn starch 120 mg

Polyvinylpyrrolidone 15

Magnesium stearate 155 mg

Talc 13.5 mg

The tablets a) are about 3Ö-6Ö minutes after the Tablets b) administered.

00 9849/202 8

Claims (1)

Claims Process for the preparation of a hydrazide of the formula H ^ -NH-NH-CO-GK HO OH as well as acid addition salts thereof, characterized in that that you can get a compound of the formula CH = N-NH-GO-GH -CH. NH, Ila Or an acid addition salt thereof, hydrogenated, or that one in a compound of the general formula in which R ₁ , R ₂ and R denotes hydroxyl groups or groups which can be converted into hydroxyl groups and R ₂ denotes the aminomethyl group or a group which can be converted into the aminomethyl group, where at least one of the substituents R., R ₂ , R and Ru is derived from the hydroxyl group or from the Amino " 009 849/202 8 methyl group is different, or in an acid addition salt of such a compound which into the hydroxyl group and / or into the aminomethyl group Convertible group or groups are converted into the hydroxyl group or into the aminomethyl group and that one is obtained in this way If appropriate, base converted into an acid addition salt. 2. The method according to claim 1, characterized in that 1 2 that an acid addition salt of N -Glycyl-N - (2,3,4-trihydroxy-benzylidene) hydrazide, in particular the hydrochloride is catalytically hydrogenated, preferably using a Palladium-carbon catalyst. 009849/2028 >. Process for the manufacture of pharmaceutical -Preparations with decarboxylase-inhibiting effect, characterized « that you get the hydrazide of the formula CH ₂ -NH-NH-CO-CH, or an acid addition salt thereof In one for medical use Administration brings appropriate form. k. Process for the production of a pharmaceutical preparation suitable for the treatment of Parkinson's sinus and depressive states, characterized in that the hydrazide of the formula -NH-NH-CO-CH or an acid addition salt thereof together with L-Dop & or an acid addition salt thereof into one for medical use Administration brings appropriate form. 009849/2028 5 · Pharmaceutical preparation with decarboxylase inhibitor Effect, characterized in that it is the hydrazld of formula CH ₂ -NH-NH-CO- P , or an acid addition salt thereof. 6. PUr the treatment of parkinsonism and depressive states suitable pharmaceutical preparation "thus ^overall: denotes that the Hydrazld of formula CH ₂ -NH-NH-CCM or an acid addition salt thereof and L-dopa or an acid addition salt thereof. 7. Pharmaceutical preparation according to claim 6, characterized 009 8A9 / 20 28 characterized in that the quantitative ratio of hydrazide to L-dopa 0.5-2 parts by weight of hydrazide per part by weight of L-dopa. 009849/2028 8. The hydrazide of the formula CH = N-NH-CO-CH ₂ HO OH as well as its acid addition salts. 9. Hydrazides of the general formula CH ₂ -NH-NH-GO-R ₄ "Hb wherein R ,, Rp and R, hydroxyl groups or groups convertible into hydroxyl groups and -R ^ denotes the aminomethyl group or a group convertible into the aminomethyl group, where at least one of the substituents R-if Rp 3 RT and R ^ from the hydroxyl group or from the Aminomethyl group is different, as well as acid addition salts thereof. ' 00 9 8 49/2028 10. The hydrazide of the formula CH ₂ -NH-NH-CO-CH ₂ HO OH NH " as well as its acid addition salts. 11 · N ^ glycyl-N ² - (2,3,4-trihydröxybenzyl) hydrazide hydrochloride » 0 0 9849/2028