DE1941261C3 - N to the power of 1-glycyl-N to the power of 2 (2,3,4trihydroxybenzyl) hydrazide, process for its preparation and its acid addition salts and pharmaceuticals containing them - Google Patents

Description

cH ₂ -NH-NH-CO-CH ₂

(I)

HO

OH

^NH2

CO-CH ₂

NH ₁

Ia)

and its acid addition salts.

2. Process for the preparation of N'-Glycyl-N ² - (2,3,4-trihydroxybenzyl) hydrazide

fVcHj-NH-NH-CO-CH, (I) or an acid addition salt thereof hydrogenated or One sat in a connection in a manner known per se the general formula

/ "A-CH ₁ -NH-NH-CO-R * (Hb)

HO

OH

NH,

and its acid addition salts according to claim 1, characterized in that one in an known manner a compound of the formula

HO

CH = N-NH-CO-CH ₂ (Ha)

OH

NH,

or an acid addition salt thereof or hydrogenated in a manner known per se in a Compound of the general formula

, -NH-NH-CO-R ₄ (Hb)

35

wherein R ₁ , R ₂ and R _{3 are} hydroxyl groups or groups convertible into hydroxyl groups and R ₄ . denotes the aminomethyl group or a group which can be converted into the aminomethyl group, at least one of the substituents R ₁ , R ₂ and R being different from the hydroxy group or R ₄ from the aminomethyl group. or in an acid addition salt of such a compound which converts the hydroxyl group or the aminomethyl group into the hydroxyl group and / or the group or groups convertible into the aminomethyl group and that a base thus obtained is optionally converted into an acid addition salt.

3. Arzncimiltel with decarboxylase-inhibiting effect, characterized by a content of a compound according to claim 1.

worm R ₁ , R ₂ and R ₃ hydroxyl groups or "hydroxyl groups _{convertible groups and R 4} the SnXl group (" CH ₂ -NH ₂ ) or a group convertible to the aminomethyl group where at least one of the substituents R _1, R and R ₃ is different from the hydroxyl group or R ₄ from the aminomethyl group, or in an acid addition salt of such a compound which converts into the hydroxyl group and / or the group or groups convertible into the aminomethyl group and that one a base obtained in this way is optionally converted into an acid addition salt.

The ^; n of the above formula Hb with R ₁ . R ₂ and R ₁ which can be converted into hydroxy groups are preferably benzyloxy groups. However, these groups can also be acetal groups. which are derived from acetaldehyde, acetone or Tctnihydropvran, z. B. «-Melhoxy-ethoxy. "-Methoxy-isonropoxy and tetrahydropyranyl. These groups can be formed in a manner known per se by hydrogenolysis, expediently by means of catalytic hydrogenation ζ. B. with noble metal catalysts, such as palladium and plaitin catalysts, converted into hydroxyl groups. Further groups R _{1 which can be converted} into hydroxyl groups. R ₂ and R ₃ are, for example, acyloxy groups, such as low molecular weight alkanoyloxy groups, which can be converted into hydroxy groups by hydrolysis.

_{Particularly suitable groups R 4 which} can be converted into the aminomethyl group are:

CH,

The present invention relates to N'-glycyl-N ² -3,4-trihydroxybenzyl) hydrazide of the formula

HO- <fVcH ₂ -NH-NH-CO-CH ₂

NH ₂

(D

HO OH

such as its acid addition salts and a process carbobenzoxyaminomethyl

(Benzyl - OCONH - CH ₂ -). Bcnzylaniinomelhyl ι Benzyl - NH ₂ Benzhydirylaminomethyl

[(C ₆ H ₅ I ₂ CH NH CH ₂ ], benzylidene aminomethyl

(Phenyl - CH = N - CH ₂ -), cyano (- CN), azidomethyl (N ₃ - CH ₂ -). Nitromethyl (O ₂ N - CH ₂ -), phyllazomethyl (phenyl - N = N - CH ₂ -). Hydroximinomethyl (HON = Cl 1 -), iminomethyl (HN = CH-) and phenylhydrazonomethyl

(Phenyl - NH-N = CH -).

These groups can be used in a known manner can be converted into the aminomethyl group by hydrogenation. Both the catalytic «; Hydrogenation as well as reduction with chemical reducing agents. Can be used as catalysts both noble metal catalysts such as palladium and platinum catalysts and nickel and cobalt catalysts be used. Suitable chemical reducing agents are, for example, metal hy-

Others convertible into the aminomethyl group Groups are:

Formylaminomethyl (OHC - NH - CH, -), Trifluoroacetylaminomethyl

(F ₃ C-CONH-CH, -), tritylaminomethyl [(C _n H ₅ J ₃ C-NH-CH ₂ -], o -nitrophenylsulfonylaminomethyl

(o-nitrophenyl - S - NH - CH ₂ -), alkoxycarbonylaminomethyl

(Alkyl - O - CONH - CH ₂ -) and Phlhalimidomethyi.

One embodiment of the process according to the invention consists in that an acid addition salt of N ¹ - glycine - N ² - (2,3,4 - trihydroxy - benzylidene) hydrazide, in particular the hydrochloride, is catalytically applied

hydrogenated, usually using a palladium-carbon catalyst. The corresponding salt of N'-glycine-N ² - (2,3,4-trihydroxybenzyl) -hyd razid is obtained directly.
The same product can also be useful through this

ίο can be obtained by catalytically hydrogenating an acid addition salt of N ¹ - glycine - N ² - (2,3,4 - tribenzyloxy - benzylidene) hydrazine, generally using a palladium-carbon catalyst. Hydrogenolysis of the benzyloxy-

groups and then hydrogenation of the benzylidene group, a salt of N'-glycine-N ² - (2,3,4-trihydroxybenzyl) hydrazide also being obtained. The compounds of the formula Ha and III used as starting materials in the process according to the invention and their salts 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 2,3,4-trihydroxybenzaldehyde.

Starting materials of the formula Hb, in which the substituents R ₁ . R ₂ and R ₃ are different from the hydroxy group or R ₄ from the aminomethyl ^ group, can by reacting a correspondingly substituted glycine hydrazide with a

These groups can be converted into the aminomethyl group by hydrolysis in a manner known per se will. For the hydrolysis of the form \ l- »minomethylgruppe, for example, dilute ones are suitable alcoholic hydrochloric acid, while the Trifluorlicetylaminomethylgruppe can also be hydrolyzed with dilute aqueous ammonia. For the

Conversion of the phthalimidomethyl group into the 30 correspondingly substituted benzaldehyde and post-aminomethyl group v \ ^: rd advantageously hulrazine following hydrogenation of the benzylidene compounds obtained

binding, e.g. B. with the help of a platinum catalyst. he

used.

Others in the aminomethyl group Groups are:

Halomethyl groups (Hal-CH ₂ -), alkylsulfonyloxymethyl groups (alkyl -SO ₂ - 0-CH ₂ -). Arylsulfonyloxymethyl groups (aryl — SO ₂ —O —CH ₂ -).

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

will hold.

According to the method according to the invention

Holding compounds (the hydrazide of the formula I and its acid addition salts) have pharmacological Effect on. namely, they have a decarboxylase-inhibiting effect.

However, the compounds are of particular interest in that they can be used in combination with i.-Dopa are excellent agents for treating Parkin ionism. They also work in combination with L-Dopa antidepressant, and this combination also increases the antidepressant effect of tri-

Further cyclic antidepressants which can be converted into the aminomethyl group are potentiated.

Groups are:

Carboxamidomethyl (H ₂ N - CO - CH ₂ carbohydrazidomethyl

(H ₂ N-NH-CO-CH ₂ ), carboxazidomethyl (N ₃ OC-CH ₂ -) and carbalkoxyhydroxamidomethyl (alkyl - COONH - CO - CH ₂ ).

It was found that in rats small doses (12 mg / kg) of N ¹ - glycine - N ² - (2,3,4 - trihydroxybenzyl) hydrazide hydrochloride for at least 4 hours by intraperitoneal or Oral administration of L-3,4-dihydroxyphenylalanine (L-Dopa) induced elevations of this amino acid in the blood and amplify the brain. At the same time, the increase in catecholamines (CA) and their metabolites, the phenol carboxylic acids, in the blood and other peripheral organs

according to Hofmann's and Curtius's. the heart, kidneys, spinal cord). Schmidtschen and Lossenschcn degradation in the brain is considerably increased. As a result of Aminomethyl group are converted. Decrease in the catecholamine content in the periphery

Peripheral adrenergic stimulation is also converted into the aminomethyl group The bare group is the u-carboxy-a-aminomelhyl group, reduced. On the other hand, the catecholamines become by decarboxylation, e.g. B. by mild 60 depots in the extrapyramidal brain centers out of heating can be converted into the aminomethyl group. neatly greatly increased.

It is believed that these effects are the result of a relatively selective inhibition of decarboxylase by the N ¹ -glycine-N ² - (2,3,4-trihydroxy-

If the base is obtained as the product of the process, it can be converted into an acid addition salt with an inorganic one or an organic acid, for example

wise to the hydrochloride, the sulfate, the acetate, the benzyl) hydrazide hydrochloride in the extracerebral Oxalatusw. be transferred. The salts are because of organs. As a result of the increased doping

tration in the blood, larger amounts of amino acids reach the brain, where decarboxylation to catechol-

their greater resistance to the base hevr> r7iiet

amines takes place, since the cerebrate cecarboxylase is practically not inhibited. This selective effect of glycin (2,3,4-trihydrQxybenzyl) hydrazide is well the result of the very poor penetration of this compound into the brain. This is how the De carboxylasc activity in the brain of animals which are glycine (2,3,4-trihydroxybenzyl) hydrazide hydrochloride was not noticeably inhibited up to doses of 50 mg / kg, while in the heart a about 8u% inhibition is observed even at a dose of 25 mg / kg. On the other hand caused the compound, when added to homogenized tissue, both in the brain and in the heart same decarboxylase inhibition.

To determine the effectiveness on the increase in the catecholamine level in the brain induced by dopa, the N ^l -glycine-N ² - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride was given to the test animals (rats) in doses of 3 to 100 mg / kg administered orally. Thirty minutes later, 3 mg / kg of L-dopa was orally administered and the animals were sacrificed 1 hour later.

It was found that 12 to 24 mg / kg of the hytiracide induce the maximum increase in catecholamines in the rat brain. This value is approximate 60 times higher than that obtained with the administration of L-dopa alone.

For the purpose of anti-Parkinson's treatment as well as for the purpose of treating depressive conditions can be the combination of the compounds obtainable by the process according to the invention (of the hydrazide of the formula I and its acid addition salts) with the L-Dopa both as an actual combination in a single dosage form and to be given separately in two dosage forms.

Since it has been found to be useful that the L-Dopa only after the hydrazide, namely Preferably about 30 to 60 minutes after the hydrazide is released in the body, when administered a single dosage form in which the L-dopa is in such a form that it trst after the hydrazide is released. Such a combination with delayed dopa delivery can be for example consist of a core of L-Dopa with an inagen juice-resistant coating. This core may have an outer layer containing the hydrazide, or the hydrazide may be in the form tine granules together with the coated L-Dopa core in a capsule. at Fiarenteral administration of the combination is expediently first the hydrazide intramuscularly and. about 30 to 60 minutes later, the L-Dopa was administered intravenously.

The quantitative ratio of hydrazide to L-dopa is of essential importance. This should 0.5 to 2 parts by weight, preferably 1 part by weight per part by weight of L-Dopa. Become daily appropriately 225 to 600 mg hydrazide and 450 to 600 mg L-Dopa (divided into 3 to 4 administrations) applied.

The hydrochloride as acid addition salts, ie N ¹ - L - glycyl - N ² - (2,3,4 - trihydroxybenzyl) - hydrazide hydrochloride, is particularly suitable for medical application because it can be applied particularly well.

The superiority of the compounds according to the invention of formula 1 in comparison with compounds known from German patent specification 1165607 was proven as follows:

L-dopa-induced increases in catecholamines (CA) in the brain were determined by use from

1.12 mg / kg N '- P ₁ L - serine - N ² - (2,3,4 - irihydraxybenzyl) - hydrazide - hydrochloride. Product of example 3 of German patent specification 1 16S607 (compound E in the table below).

2. an equimolar amount of N'-iu-alanine-N ² - (2,3,4 - trihydroxybenzyl) - hydrazide hydrochloride, product of example 6 of the same patent specification (compound F), and

3 an equimolar amount of the invention

'N ¹ - Glycine - N ² - (2,3,4 - trihydroxybenzyl) - hydrazid-hydrochlorids (Compound G)

measured in rats, with the following values:

link

Increase in CA in
arbitrary units

100

11.5

It follows that the reagent compound G has a greater decarboxylase-inhibiting effect than the known compounds H and F.

example 1

24 g of N'-glycine-N ² - (2,3,4-trihydroxybenzene) hydrazide hydrochloride are suspended in 300 ml of water and hydrogenated with palladium-carbon. With a fairly rapid uptake of 2.5 liters of hydrogen, everything dissolves. One sucks off the catalyst. the solution is concentrated under reduced pressure to 40 to 50 ml and diluted with 200 ml of absolute ethanol. The crystallization takes place in a few seconds. It is left to stand in the refrigerator overnight. sucks off and washes out with ethanol, ether and petroleum ether. For further purification, the crude product is dissolved in 40 ml of water at a maximum of 40 to 50 ° C. and crystallized by adding 20 ml of methanol. The N'-glycine-N ² - (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 to 182 C.

^{The N 1} - glycine - N ² - (2,3,4 - trihydroxy - benzylidcn) - indrazide hydrochloride used here as starting material can be obtained as follows:

15.4 g of 2,3,4-trihydroxybenzaldehyde are dissolved in 200 ml of boiling water and 12.6 g of glycine hydrazide monohydrochloride are added all at once. After a few minutes the liquid becomes cloudy and solidifies in a short time to form a crystal paste. It is cooled in ice water and suction filtered. Washing is done with a little water and a lot of acetone. The N '- glycine - N ² - (2,3,4 - trihydroxy - benzylidcn) - hydrazide hydrochloride obtained in this way is white to pale yellowish crystals and melts at 303 to 305 ° C. with decomposition.

Example 2

31.5 g of N'-carbobenzoxyglycine-N ² - (2,3,4-tribenzyloxy-benzylidene) hydrazide are suspended in 300 ml of methanol and 5 ml of glacial acetic acid and hydrogenated with palladium-carbon. After the calculated amount of hydrogen has been taken up, 6.1 ml of benzyl chloride is added.

give, and hydrogenation continues until the uptake of hydrogen ceases again. One sucks from the catalyst and the solution evaporated in vacuo to a crystal slurry. The received The product is identical to the compound obtained according to Example I.

The N ¹ - carbobenzoxyglycine - N - (2,3,4 - tribenzyloxvoenzylidene) hydrazide used as starting material can be obtained as follows:

22.3 g of carbobenzoxy-glycine hydrazide and 42.4 g of 2,3,4-tribenzyloxybenzaIdehyde are each dissolved in 300 ml of boiling absolute ethanol, the two solutions are combined and boiled for 1 hour. After cooling in ice water, it is sucked and washed with alcohol and ether. The N ¹ -carbobenzoxyglycine-N ² - (2,3,4-triberi7yloxybenzylidene) hydrazide thus obtained melts at 140 to 142.degree

Example 3

By hydrogenating N ¹ -Carbobenzoxyglycine-20 N ² - (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 gives a compound identical to the product of Example 2.

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

22.3 g of carbobenzoxy-glycine hydrazide are dissolved in 300 ml of boiling absolute ethanol, and 15.4 g of 2,3,4-trihydroxybenzaldehyde are added. After a short boil, it is cooled in ice water and sucked. The N ¹ -carbobenzoxyglycine-N ² - (2.3.4-trihydroxy-benzylidene) hydrazide thus obtained melts at 211 to 212 ° C.

Example 4

N ¹ -Nitroacctyl-N ² - (2,3,4-tribenzyloxy-benzylidene) hydrazide (obtained from 28 g of N ¹ - bromoacetyl-N ² - (2,3,4-tribenzyloxy - benzylidene) - hydrazide according to the further method described below) is dissolved in 200 ml of methanol and hydrogenated by means of a palladium catalyst in analogy to Example 2, the N ¹ -glycine via the N 1 -glycine-N ² - (2,3,4-trihydroxy-benzylidene ⁾ hydrazide -N ² - (2.3,4-trihydroxybenzy1) hydrazide is formed, the hydrochloride of which corresponds to the product obtained according to Example 1.

^{The N 1} -nitroacetyl-N ² - (2,3,4-tribenzyloxy-benzylidene) hydrazide used here from the starting material can be prepared as follows:

28 g of N ¹ -bromoacetyI-N ² - (2,3,4-tribenzyloxy-benzylidene) hydrazide are stirred in 200 ml of dimethylformamide at room temperature, 7.7 g of silver nitrite being added in portions to the mixture. The reaction mixture is stirred further overnight at room temperature, the precipitated silver bromide is filtered off and concentrated to about 50 ml under reduced pressure. It is then diluted with chloroform and washed 4 to 5 times with water in a separating funnel, dried with sodium sulfate and evaporated under reduced pressure. The N'-nitroacetyl-N ² - (2,3,4-tribenzyIoxy-benzylidene) hydrazide remains as a yellow, viscous oil.

The N ¹ -bromoacetyl-N ² - (Z3,4-tribenzyIoxybenzylidene) hydrazide can be prepared as follows:

Il g of 2,3,4-tribenzyloxy-benzaldehyde are dissolved in 200 ml of boiling, absolute ethanol and mixed with a freshly prepared mixture of 6.5 g of bromoacetylhydrazide hydrochloride (melting point 180 to 18 ° C., prepared by reacting bromoacetic acid and N- Hydroxysuccinimide in the presence of N.N'-dicyclohexylcarbodiimide, reaction of the bromoacetyl-N-hydroxy-succinimide ester obtained with carbobenzoxyhydrazine in ethyl acetate at 0 to 5 ^D C and treatment of the bromoacetylcarbobenzoxyhydrazide obtained with glacial acetic acid / hydrogen bromide), 3.9 ml Triethylamine and 15 ml of water are added. The reaction takes place very quickly and within 2 to 3 minutes the contents of the flask have solidified into a crystal paste. It is allowed to cool, filtered and washed with ethanol and ether. The N'-bromoacetyl-N ² - (2,3,4 - tribenzyloxy - benzylidene) - hydrazide thus obtained forms white, poorly soluble crystals which melt at 175 to 176 ° C.

Example 5

N ¹ -azidoacetyl-N ² - (2,3,4-tribenzyloxy-benzylidcn) -hydrazide is hydrogenated in analogy to Example 2, with the N ¹ -glycine-N ² - (2,3,4-trihydroxy-benzyliuenl-hydrazide the N'-glycine-N ² - (2.3.4-trihydroxybenzy, »- hydrazide is formed whose hydrochloride corresponds to the product obtained according to Example I.

The N'-azidoacctyl - N ² - (2.3.4 - tribenzyloxy - benzylidene) - hydni / id used as starting material can be obtained as follows:

28 g of N ¹ -bromoacetyl-N ² - (2.3.4-tribenzylox-bcn /> lidenl-hydrazide in 200 ml of dimethylformamide are admixed with 3.3 g of sodium in portions with stirring. The N'-azidoacetyl compound is obtained after conventional work-up in the form of an oil

Example 6

15 g of N ¹ -trilylglycine-N ² - (2,3,4-trihydro \\ -bcimlidcn) hydrazide are suspended in 400 ml of methanol and hydrogenated with palladium carbon. After 1 mol of hydrogen has been taken up, the catalyst is filtered off and 15 ml of glacial acetic acid are added to the filtrate. It is heated on the steam bath for about 10 to 15 minutes and then cooled in ice water. The precipitated triphenylcarbinol is pulverized and the filtrate is adjusted to pH 2 to 3 by adding alcoholic hydrochloric acid. It is evaporated to 100 ml under reduced pressure. removes any precipitated "iriphenylcarbinol" by filtration and continues evaporation until the end product begins to crystallize out. This product corresponds to the compound prepared according to Example 1.

^{The N 1} - tritylglycine - N ² - (2,3,4 - trihydroxy - benzylidene) hydrazide used here as starting material can be prepared as follows:

A mixture of 6.6 g of trityl-glycine hydrazide (JACS 78.1359) and 3.1 g of 2,3,4-trihydroxy-benzaldehyde is boiled in 100 ml of alcohol for 2 to 3 hours, and N'-tri tylglycine crystallizes overnight in a refrigerator - N ² - (2,3.4 - trihydroxy - benzylidene) - hydrazic from ⁰ to 150 C from the melting point 148th

Example 7

N'-Formylglycine-N ² - (2,3,4-trihydroxybenzylidene) hydrazide (prepared by reacting 5 l formylglycine hydrazide (J. Chem. Soc. 1954, 1039 with 6.3 g 2,3,4-trihydroxybenzaldehyde) is suspended in 200 ml of methanol in the presence of a palladium

409685Λ1Ι

Hydrogenated coal catalyst. After taking up 1 mole of hydrogen, a solution is formed. The catalyst is filtered off, and the clear filtrate is brought to pH 1 with methanolic hydrochloric acid brought to 2. Then leave the solution at space; stand at temperature for 2 to 3 days, with splitting off of the Formyl group enters. The mixture is concentrated with reduced pressure until crystallization begins, and then left crystallize the product. A compound corresponding to the product of Example 1 is obtained, ic

Example 8

A mixture of 10.6 g of trifluoroacctyl 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 the addition of 7.1 ml of triethylamine hydrogenated with palladium carbon. After 1 mol of hydrogen has been taken up, the catalyst is filtered off and the filtrate is mixed with 10 ml of 2N methanolic ammonia and under nitrogen for 24 hours Left to stand at room temperature. The trifluoroacety group is split off here. One does weakly acidic with alcoholic hydrochloric acid (pH 2.5 to 3) and concentrated under reduced pressure to 100 ml a. Precipitated ammonium chloride is filtered off and the filtrate until crystallization begins concentrated (about 60 ml). The product which precipitates out is the same as that obtained according to Example 1 identical.

Example 9

A mixture of 6.25 g of glycine hydrazide and 41.4 g of 2,3,4-tribenzyloxy-benzaldehyde is boiled in 500 ml of alcohol for 3 to 4 hours. The viscous mass that separates out after cooling becomes solid in about 2 to 3 days. You suck off and wash off with alcohol and ether. The N '- (2.3.4-triben / yloxy-benzylidene-glycine) -N ² - (2.3,4-tribenzyloxybenzylidene-hydrazide obtained in this way melts at 110 to 115 ° C. with decomposition.

10 g of the above product are suspended in 300 ml of methanol and until the hydrogen uptake has ceased hydrogenated with palladium carbon. This results in dissolution. The catalyst is filtered off. makes weakly acidic with alcoholic hydrochloric acid (pH 2.5 to 3) and concentrates under reduced pressure up to at the beginning of crystallization. The product obtained in this way is identical to that obtained in Example 1.

Example 10 5 <>

Hg phthalylglycine hydrazide (CA .. 52, 14 540 ^rf ) are suspended in 300 ml of boiling alcohol and treated with 6.7 g of 2,3,4-trihydroxy-benzaldehyde. 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 1.5 ml of hydrazine hydrate are added to the filtrate. After standing overnight, the precipitated phthalylhydrazide is filtered off with suction and the filtrate with alcoholic hydrochloric acid

35 weakly acidified (pH 2.5 to 3). It is concentrated to 100 ml under reduced pressure and pre-filtered precipitated hydrazine hydrochloride. The Filtra is further concentrated to 60 ml, whereupon the Rcaktions product starts to fail. It is identical to the substance prepared according to Example I.

Example 11

8.9 g benzyl glycine hydrazide (Arch. Pharm? 95 oJ7) together with 6.7 g of 2.3.4-Trihydroxv benzaldehyde in 300ml methanol refluxed for 3 to 4 hours and then after addition before Palladium carbon hydrogenated. After the uptake of water has ended, the catalyst is filtered off, mil Alcoholic hydrochloric acid weakly acidic (pH 7 < his 3) and concentrated under reduced pressure until crystallization begins. The product obtained is identical to the substance obtained in Example 1.

Example 12

17.8g carbobenzoxyamino - malonic acid - bcn / ylestcr-hydrazide (produced by the action of hydrazine hydrate on benzyl carbobenzoxyamino malonic acid methyl ester) are together with 21.3 u ^ 3 4-tribenzyloxy-benzaldehyde in I I methanol 3 bis «Boiled for hours, slowly dissolving and towards the end of the reaction the product partially precipitates. It is allowed to cool to room temperature and

Ä "h uV ^{went from p} a» adium coal until the cessation of the drifting of water.

Si z.sl rh T ^{U the SOLUTION with} alcoholic acid weakly acidified (pH 2.5 to 3) and up to

^ beginning crystallization under reduced Pressure restricted. The product is identical to the substance obtained in Example I.

Example 13

40

under

tTm yazid (B., 54. 1432) are ^{gClÖSt and with 6} - ⁷ * 2.3.4-Triben / vlf ^r f f ^{one gets} - ^W minutes T ^d u ^ ^{bt hler on} palladium-carbon added K i? ^^ W ^ first reception nrnrf ^ataIysa ; ^{or filtered off} and under reduced

ZfW ^{IT remains a brown oil} .. ^Cooling <n 60 ml more concentrated re dissolved wiH ii r

with

and

if if

? ^stand ^ - on this will

¹¹ I ^{1 diluted} and the sulphate ions '" ^Ba ^ ^mch ' orid removed. According to Ab-Τ ⁸ " ¹ ? ^{1 Will be under} diminished

* ^{Addition of the Methano1 Solu} "g dried. Τ ^ma u ^{mk AIkoho1 a"} f 400ml> sodium chloride from. The filtrate is reduced to dH 2 5 using alcoholic hydrochloric acid

Crystalline

Claims (1)

Claims: Connections. The invention 1, which the above ver 1. N'-Glycyl-NM ^ -trihydroxybenzyli-hydrazide the formula S ÄrrS ^ Tln ^ iÄä.nn.cr way jehnet dSrnan
_inheriting ; _{ng the} formula