CS199568B2 - Method of producing substituted derivatives of alpha aminooxycarboxylic acids hydrazides and addition salts thereof with acids - Google Patents

Abstract

Substituted alpha -aminooxycarbohydrazide derivatives of the formula I <IMAGE> are obtained by reacting an alpha -aminooxycarbohydrazide with a compound of the general formula X = O. The substituents have the following meaning: X is a cycloalkylidene radical or a methylene group which is substituted by an alkyl radical with 1-5 carbon atoms and/or phenyl or furyl radical which is optionally substituted by halogen, hydroxyl, nitro and/or amino groups; R is hydrogen or a benzyl radical Y is hydrogen Z is an acyl radical derived from a pyridinecarboxylic acid or Y and Z together are one of the substituents which X can represent. The compounds are valuable tuberculostatics. Compounds substituted on the hydrazide group by isonicotinoyl or 5-nitrofurfurylidene group are particularly effective.

Description

The invention relates to a process for the preparation of novel substituted .alpha.-aminooxycarboxylic acid hydrazides and their addition salts, which are used in particular as tuberculostatics.

British Patent No. 1,323,170 discloses a series of tuberculostatically active derivatives of .alpha.-aminooxycarboxylic acid hydrazides with a free or acyl substituted aminooxy group.

The reaction of α-amino oxycarboxylic acids with carbonyl compounds has long been used for analytical purposes (M. Anchel, R. Schoenheimer: J. Biol. Chem. 114, 1936, 539). Examining the Schiff bases produced by this response to biological effects, some compounds have been found to affect plant growth (MS Newmann et al .: J. Am. Chem. Soc. 69, 1947, 718), while others exhibit a vitamin K-like effect (British Patent No. 621,934).

Without further data on biological effects, some aldoximes and ketoximes of aminooxyacetic acid as well as their ethyl ester and K. Undheim (Acta Chemica Scandinavica 19, 1965, 317) are described by A. Richardson (J. Med. Chem. 7, 1964, 824) in connection with with the examination of semi-synthetic penicillins of Schiff's bases. some α-aminooxycarboxylic acids.

In investigating the bacteriostatic effect of various Schiff bases of aminooxycarboxylic acid derivatives, E. Test and co-workers have been found. (Helvetica Chimica Acta 46, 1963, 766) that the existence of a free aminooxy group is necessary for an effect on various microorganisms.

GP Ellis and GB West (Progress in Medicinal Chemistry, London, Butterworths, Vol. 5, 1967, p. 348), who investigated the bacteriostatic effects of various compounds having a nitrofurfurylidene group, do not mention that compounds having this group have anti microorganisms causing. tuberculosis.

It has now surprisingly been found. that certain compounds which contain an aminooxy group in the form of their oximes formed with aldehydes or ketones have valuable therapeutic effects.

Accordingly, the present invention provides a process for the preparation of substituted α-aminooxycarboxylic acid hydrazide derivatives of the general formula. AND

Η O Η Y

I III / x = N — O — C — C — N — N

I. \

SS (I) where

X represents a cycloalkylidene radical, a substituted azacycloalkylidene radical or a methylene radical substituted with phenyl or oxygenated heterocyclic radicals, both of which are at least once substituted by C1 -C5 alkyl and / or halogen, hydroxy, nitro and / or amino,

R is hydrogen, benzyl. or (C 1 -C 5) alkyl optionally substituted by at least one methylthio group,

Y represents a hydrogen atom and

Z represents a hydrogen atom or an acyl radical derived from a pyridine carboxylic acid, or

Y and Z taken together represent the substituents listed for X, and their acid addition salts.

Preferably it comprises a cycloalkylidene. a radical which may be X, optionally Y and Z together, having from 4 to 6 carbon atoms, in particular a cyclopentylidene or cyclohexylidene radical.

It is preferred that the substituted azacycloalkylidene radical which may be X, optionally Y and Z together is a heterocyclic radical having a 5 or 6 membered ring. It is further preferred that the substituted azacycloalkylidene radical, which may be represented by X and optionally Y and Z together, has as alkoxycarbonyl radical containing from 1 to 4, in particular 1 or 2, carbon atoms in the alkoxy moiety as substituents on nitrogen. Particularly suitable is a substituted azacycloalkylidene radical which may be X or Y, respectively. and Z taken together, and an N-alkoxypyperidylidene residue, in particular an N-ethoxycarboxypyperidylidene residue.

Special alkyl radicals which may be substituted for a methylene radical which may be X @ 1. optionally Y and Z. taken together are methyl, n-propyl, isopropyl, n-butyl, isobutyl and pentyl. Preferably, these alkyl radicals with which the methylene radical may be substituted have 1 to 3, in particular 1 or 2, carbon atoms.

it is also preferred that the oxygen-containing heterocyclic radicals,. which may be. substituted methylene. the rest that can. X or Y and Z taken together are substituted by 1 or more halogen atoms, hydroxy, nitro and / or amino groups, nitro groups being particularly preferred. The halogen atoms with which the phenyl radicals or the oxygen-containing heterocyclic radicals which can be substituted for the methylene radical, which may represent X and optionally Y and Z together, include chlorine, bromine and / or iodine. Preferably, these oxygen-containing heterocyclic radicals, optionally substituted, may be substituted by a methylene radical, which may represent X or Y and Z together, a 5 or 6-membered ring. It is particularly preferred that the methylene radical substituted with oxygen-containing heterocyclic radicals optionally substituted is a furfurylidene or nitrofurfurylidene radical.

Special alkyl radicals, optionally substituted with one or more radicals. several methylthio radicals which may be R are ethyl, propyl, butyl and pentyl. Such an alkyl radical optionally substituted by one or more methylthio radicals preferably contains 1 to 3, in particular 1 or 2, carbon atoms.

When R has a meaning other than hydrogen, these are compounds with an asymmetric carbon atom.

Preferably, the acyl radical derived from pyridinecarboxylic acid, which may be Z, is an isonicotinoyl radical.

Particularly preferred compounds of the invention are:

N- [N ”- (isopropylidene) -aminooxyacetyl] -N’-

- (isonicotinoyl) hydrazine hydrobromide,

N- [N '- (m-nitrobenzal) -aminooxyacetyl] -N´-

- (isonicotinoyl) -hydrazine,

N- [N '- (o-chlorobenzal i -aminooxyacetyl) -N' - (isonicotinoyl) hydrazine,

N- [N ”- (cyclopentylene) -aminooxyacetyl] -N '- (isonicotinoyl) -hydrazine, ·

N- [N ”- (furfurylene) -aminooxyacetyl] -N’-

- (isonicotinoyl) -hydrazine,

N- (N '- (5-nitro furfurylene) -aminooxyacetyl] -Ν' - (isonicotinoyl) -hydrazine,

N- [N '- (5-nitrophenylurfuryliden) -D-α-aminooxybutyr 1] -Ν' - (isonicotinoyl) hydrazine,

N- [Nt] - (5-nitrophenyluride) -D-N-aminooxy-

- (χ-methylthio) -butyryl] -N '- (isonicotinoyl) -hydrazine,

N- [N '- (5-nitrophenylfurylidene) -D-α'-aminooxy-

- (β-phenyl) -propionyl] -Ν '- (isonicotinoyl) -hydrazine hydrochloride,

N- (N '- [p-amino- [T (methyl)] -benzalyl-aminooxyacetyl) -N' - (isonicotinoyl) -hydrazine,

N- [N '- (p-hydroxybenzal) -aminooxyacetyl] -Ν' - (isonicotinoyl) -hydrazine,

N- {N ”- [T- (methyl) -benzal] -aminooxyacetyl} -N '- (isonicotinoyl) -hydrazine and

N- [N '- (5-nitropurfurylene) -aminooxyacetyl] - (5-nitropurfurol) -hydrazone.

Medicaments which contain one or more of the abovementioned compounds as active ingredient or active ingredients, conveniently with customary carriers and auxiliaries.

In fact, the compounds according to the invention have valuable pharmacological effects. In particular, they are good tuberculostatics. Compounds substituted on the hydrazide group by isonicotinoyl or 5-nitrofurfurylidene groups are particularly effective. In addition to their potent activity, the compounds having the 5-nitrofurfurylidene group are also effective also against resistant strains of the mycobacterium tuberculosis strain. The compounds of the invention are the first 5-nitrofurfurylidene derivatives to be active against tuberculosis-causing microorganisms.

Culture medium containing 2.5% albumin was used for the in vitro examination. The broth containing the test compounds was inoculated with 0.01 mg of fresh bacterial culture and propagated at 37 ° C for 3 weeks. Growth inhibition values were then determined. The following strains of bacteria were examined: mycobacterium tuberkulosis H37R _V , isonicotinic hydrazide (INH _res ) resistant mycobacterium tuberculosis, streptomycin resistant (Strepto _res ) mycobacterium tuberculosis, and mycobacterium kansasii. The results of the microbiological examination of the compounds of the invention are shown in the following table.

Compound Growth suppression values in χ / cm ³

Mycobacterium against hydrazide against sreeptomycin Mycobacteriun tuberculosis isonicotin-resistant acids (Strepto _res ) kansasii

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This results in an excellent tuberculostatic effect of the compounds of the invention.

The compounds of the invention may be used in the form of conventional pharmaceutical preparations such as tablets, dragees, injectable solutions, infusion solutions or suppositories. The compounds are preferably administered orally and / or parenterally. In mammals, a suitable daily dose is 2 to 80 mg / kg, preferably 10 to 50 mg / kg, and is preferably divided into smaller doses during the day or administered in retard form.

The principle of the preparation of the substituted .alpha.-aminooxycarboxylic acid hydrazide derivatives and their acid addition salts by the process according to the invention is that the .alpha.-aminooxycarboxylic acid hydrazide of the formula II is reacted.

Η O ΗY

I II I /

H2N — О — С — C — N — N

AND\

R2 (II), wherein R, Y and Z are as defined above, or an acid addition salt thereof, with an oxo compound of formula IV

X = O (IV), wherein X is as defined above, or reacted with a Schiff base of formula III

HIM

I II

X = N — O — C — C — O — R ’

R (III), wherein X and R are as defined above and R 'is hydrogen, C 1 -C 5 alkyl or phenyl substituted with at least one halogen or nitro group, with a hydrazine derivative. of formula V

H / H2N — N \

Q (V) wherein Q is hydrogen, pyridylcarboxylic acid acyl, C 1 -C 5 alkoxycarbonyl or benzyloxycarboxylic acid protecting group, and optionally protecting group is removed, and optionally the base obtained is converted into an addition salt with with acid, or a base is liberated from the addition salt, or the addition salt is converted into another salt.

The alkyl radicals which may be R 'in the compounds of formula III useful as starting materials in the process of the invention may be methyl, ethyl, propyl, butyl and pentyl. Examples of substituted phenyl moieties which R 'may represent in the compounds of formula III useful as starting materials in the process of the invention are p-nitrophenyl and pentafluorophenyl.

A preferred paryldicarboxylic acid-derived acyl radical which may be Q in the compounds of formula V useful as starting materials in the process of the invention is an isonicotinoyl radical. Examples of alkoxycarboxylic protecting groups that may be labeled Q in the compounds of formula V useful as starting materials in the process of the invention are ethoxycarboxylic, propoxycarboxylic, n-butoxycarboxylic and tert-butoxycarboxylic residues.

Optically active compounds can be used as starting materials. Depending on the starting material used, compounds of the invention having an asymmetric carbon atom can be used as racemates or as optically active antipodes. The racemates obtained can be resolved in a manner known per se, for example by formation of a diastereomeric salt pair.

The process of the invention is preferably carried out in a solvent environment. It is also beneficial to carry out this reaction in the presence of an acid acceptor. It is further preferred to carry it out in the presence of a secondary and a tertiary base whose dissociation constant is greater than the aminooxy dissociation constant. It is advantageous to carry out this reaction at temperatures of 0 to 40 ° C, in particular at room temperature. According to a special embodiment of the process according to the invention, 2 moles of the oxo compound of the formula IV are used per mol of unsubstituted α-aminooxycarboxylic acid hydrazides of the formula II.

It is particularly preferred to add the compounds of formula III in active form in the process of the invention. Furthermore, a compound of formula V having a protecting group on its nitrogen atom may advantageously be used as starting material. The cleavage of the protecting group from the product is expediently carried out by acid hydrolysis, preferably with hydrohalic acid in an organic solvent, in particular hydrogen bromide in glacial acetic acid.

According to one preferred embodiment of the process according to the invention, the t-aminooxycarboxylic acid hydrazide derivative is reacted with a free aminooxy group of the formula II or an acid addition salt thereof in an aqueous medium, optionally in the presence of an acceptor and / or organic base, or in an organic solvent, optionally secondary or tertiary organic bases whose dissociation constant is greater than aminooxy groups, with the corresponding oxo199568 compound of formula IV. The reaction mixture is allowed to stand for 1 to 72 hours, preferably about 16 hours, at 0 to 40 ° C, preferably at room temperature. Then, the product is isolated by evaporation or precipitation and optionally purified by extraction or crystallization. If desired, the compound obtained may be added to a physiologically tolerable acid addition salt, such as a hydrohalide, sulfate, bisulfate, phosphate, acetate, citrate or tartrate.

According to a further preferred embodiment of the process according to the invention, 1 mol equivalent of the unsubstituted α-aminooxycarboxylic acid hydrazide of the formula II is reacted in an anhydrous alcohol, preferably in absolute form. ethanol, at elevated temperature, preferably at the boiling point of the mixture, for about 30 minutes with 2 mol equivalents of the corresponding oxo compound of formula IV. The reaction mixture is optionally allowed to stand for a further 1 to 72 hours, preferably about 16 hours at room temperature, the solvent is distilled off and optionally the residue is recrystallized from an alcohol or an alcohol / water mixture. This embodiment of the process according to the invention can be varied by reacting 1 mol of unsubstituted α-aminooxycarboxylic acid hydrazide of the formula II with a known nitrogen protecting group first with 1 mol of the oxo compound of the formula

IV and then, after cleavage of the protecting group in a manner known per se, with 1 mole of another oxo compound of formula IV.

According to a preferred embodiment of the process according to the invention, the Schiff base of the formula III is converted into an active ester, preferably pentachlorophenyl ester, or the Schiff base of the formula III activated on the carboxyl group (R '= H) with N, N'-dicyclohexylcarbodiimide and reacted at room temperature in the presence of an organic solvent, preferably dimethylformamide, with a substituted hydrazine of formula V, preferably isonicotinic hydrazide. The reaction mixture is allowed to stand for 1 to 72 hours, preferably about 16 hours. The by-product formed (pentachlorophenol or Ν, Ν-dicyclohexylurea) is removed by extraction. or by filtration. The product is isolated by evaporation and purified by extraction and recrystallization.

In the case of using N´-alkoxycarbonyloxyhydrazide or N´-benzyloxycarboxyhydrazide as substituted hydrazine of formula

V is preferably operated similarly, but after the reaction, the protective layer is cleaved from the product by acid hydrolysis. Hydrochloric acid in an organic solvent, especially hydrobromic acid in glacial acetic acid, is preferably used for the acid hydrolysis. The product obtained in the form of an acid addition salt is precipitated from the reaction mixture by the addition of a solvent in which the salt is poorly soluble, preferably by addition of diethyl ether.

According to a further preferred embodiment of the process according to the invention, hydrazine hydrate is added to the Schiff base of the formula II, optionally produced in situ from an α-aminooxycarboxylic acid ester and an aldehyde or a ketone at a temperature of 0 to 25 ° C, preferably at 0 ° C, optionally in the presence of an organic solvent. The reaction mixture is allowed to stand for 1 to 72 hours, preferably for about 16 hours at 0 to 25 ° C, and then optionally the solvent is distilled off. The precipitated product is filtered, washed and recrystallized from an organic solvent, preferably ethanol, or a mixture of organic solvent and water, preferably a mixture of ethanol and water or a mixture of ethanol and diethyl ether.

The compounds used as starting materials in the process according to the invention are not known in part, but can be obtained in principle by a known method, for example according to Hungarian patent No. 160 181 or by the processes described in the examples.

The purity of the product can be checked by thin layer chromatography.

The invention is further illustrated by the following non-limiting examples. The retention values (Rf-values) of the compounds described in the examples were determined by Stahl on silica gel G using a 1: 1: 8 mixture of n-hexane, glacial acetic acid and chloroform as the liquid. melting point measurement according to Dr. Tottoli. Infrared spectrographic measurements, magnetic resonance imaging and mass spectrograph measurements were used to determine the structure, as appropriate. The specific rotation angle of optically active compounds was measured with an Opton polarimeter.

Example 1

Ν- [N '- (m-nitrobenzal) -aminooxyacetyl] -N´- (isonicotinoyl) -hydrazine

2.60 g (0.007 mol) of N- (aminooxyacetyl) -N '- (isonicotinoyl) -hydropyridine drimide were dissolved in. 10 ml of anhydrous methylformamide was firstly treated with 1.21 g (0.008 mol) of m-nitrobenzaldehyde and then with stirring or shaking at room temperature 1.95 ml (0.014 mol) of anhydrous triethylamine. The reaction mixture was stirred for 1 hour then allowed to stand at room temperature for 16 hours. The precipitated triethylammonium bromide was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate and extracted twice with 10 mL of water. The organic phase was dried over sodium sulfate and then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol. Thus 1.96 g (82% of theory) of )- [N '- (m-nitrobenzal) -aminooxyacetyl] -N' - (isonicotinoyl) hydrazine, m.p. 158-160 ° C, were obtained. R _f = 0.47.

For C15H13O5N5 calculated:

52.5% C, 3.8% H, 20.4% N;

found:

% C, 52.5%;% H, 3.9%;

The following compounds were prepared in a similar manner.

Example 1 a d 2

N- (N '- | p-amino- [1' (methyl)] -benzaljaminooxyacetyl) -N '- (isonicotinoyl) -hydrazine

Yield: 77%. Melting point after recrystallization from ethanol: 175-177 ° C. R _f = 0.58.

For C16H17O3N5 calculated:

C 58.7%, H 5.2%, N 21.4%;

found:

58.7% C, 5.2 Ό / ο H, 21.2% N.

Example 3

N- [N '- (p-hydroxybenzal) -aminooxyacetyl] - Ν- (isonicotinoyl) -hydrazine

Yield: 85%. Melting point after recrystallization from ethanol: 203-204 ° C. Rf = 0.18.

For C15H14O4N4 calculated:

57.4% C, 4.5% H, 17.8% N;

found:

57.5% C, 4.6% H, 17.8 N.

Example 4

N- [N ”- (o-chlorobenzal) -aminooxyacetyl] -N’- (isonicotinoyl) -hydrazine

Yield: 85% of theory. Melting point after recrystallization from ethanol: 147-149 ° C. Rf = O55.

For C 15 H 13 O 3 N 4 Cl calculated:

54.1% C, 3.9% H, 10.7% Cl;

found: '

H, 4.0; H, 10.7 Cl.

Example 5

N- [N '- (cyclopentylidene) -aminooxyacetyl] -N' (isonicotinoyl) -hydrazine

Yield: 82%. Melting point after recrystallization from water: 160-161 ° C.

Rf = 0.67.

For C 13 H 16 O 3 N 4 calculated:

56.5 ° C, 5.8% H, 20.3% N;

found:

56.5% C, 5.8% H, 20.1: 1% N.

Example 6

N- [N ”- (furyfuryllden) -aminooxyacetyl] -N’-

- (isonicotinoyl) -hydrazine

Yield: 73%. Melting point after recrystallization from water: 123-125 ° C. Rf = 0.52.

For C 13 H 12 O 4 N 4 calculated:

% C, 4.2% - H, - 19.4% N;

found:

H, 4.3; N, 19.4.

Example 7

N-N '- [1'- (methyl] -benzal] -aminooxyacetyl} -N' (isonicotinoyl) -hydrazine

Yield: 78 1%. Melting point after recrystallization from ethanol: 160-162 ° C. Rf = 0.72.

For C16H16O3N4 calculated:

61.5% C, 5.1% H, 18.0% N;

found:

61.4% C, 5.3% H, 18.2% N.

Example 8

N- [N '- (cyclopentylidene) -D-n-aminooxy-

- (β-Phenyl) -propionyl] -Ν '- (isonicotinoyl) -hydrazine

Yield: 84%. Melting point after recrystallization from ethanol / water: 191-194 ° C. Rf = 0.75.

[α] ²⁵ = 71 ° (c = 1; ethanol).

For C 20 H 22 O 3 N 4 calculated:

C, 65.6; H, 6.1; N, 15.3;

found:

% H, 6.2%;% N, 15.3%;

Example 9

N- [N '- (m-nitrobenzaa) -D-α-aminooxy- ((3-phenyl) -propionyl] -N' - (isonicotinoyl) -hydrazine hydrochloride

2.31 g (0.005 mol) of N- [D-α-aminooxy- (3

-phenyl] -propionyl] -N- (isonicotinoyl) -hydrazinedihydrobromide was dissolved at room temperature with stirring or shaking in 15.0 ml of methanol and 0.78 g (0.0052 mol) of m-nitrobenzaldehyde was first added and then 0.82 g (0.010 mol of sodium acetate in 50 ml of water). The reaction mixture was stirred or shaken for 16 hours at room temperature, then diluted with 25 ml of water - and then extracted 3 times with 15 ml of ethyl acetate each.

The organic phases were combined, washed twice with 10 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The free bases were treated with 20 ml of 0.5 N hydrochloric acid diethyl ether and the acid addition salt obtained was filtered off, dissolved in boiling ethanol and then, after cooling the solution, precipitated with an equal volume of diethyl ether. Thus, 1.80-g (78% of theory) of N- [N &apos;-( m-nitrobenzal) -Da-aminooxy- (N-phenyl) -propionyl] -1- (isonicotinoyl) -hydrazine hydrochloride were obtained at a temperature mp 76-78 ° C. Rf = 0.1 [.alpha.] D @ ²⁸ = + 72 DEG (c = 1; ethanol).

For C22H20O5N5Cl calculated:

56.3% C, 4.3 ^; 1 H, 7.5% Cl;

found:

56.3% C, 4.4% H, 7.4% Cl.

In an analogous manner, but without the formation of an acid addition salt, the following compound was obtained.

Example 10

N- [N '- (5-nitrophenylfurylidene) -aminooxyacetyl] -1'- (isonicotinoyl) -hyrazine

Yield: 93%. Melting point after recrystallization from water: 168-170 ° C. Rf = 0.08.

For C 13 H 11 O 6 N 5 calculated:

46.9% C, 3.3% H, 21.0% N;

found:

46.8% C, 3.3% H, 21.0% N.

Example 11

N- [N '- (p-hydroxybenzal) -aminooxyacetyl] -Ν' - (p-hydroxybenzaldehyde) -hydrazone

1.50 g (0.010 mol of aminooxyacetic acid hydrazide) was dissolved in 10 ml of ethanol, and 2.44 g (0.020 mol) of 4-hydroxybenzaldehyde was added thereto, and the reaction mixture was heated under reflux for 30 minutes and then After standing at room temperature for 16 hours, the solution was distilled off under reduced pressure, and the residue was extracted 3 times with 10 ml of water each time, the product - solid - the filtered crude product being recrystallized from 50% aqueous ethanol. N- (N '- (p-hydroxybenzal) -aminooxyacetyl] -4' - (p-hydroxybenzaldehyde) -hydrazone, m.p. 218 DEG-220 DEG C. _Rf = 0.62.

For C16H15O4N3 calculated:

61.1% C, 4.8% H;

found:

61.0% C, 4.8% H.

The following compound was prepared in an analogous manner:

Example 12

N- [N '- (5-nitroph urfurylidene) -aminooxyacetyl] - Ν- (5-nitroph urfurol) -hydrazone

Yield: 68% of theory: Melting point after recrystallization from ethanol: 225-226 ° C. Rf = 0.22.

For C12H9O8N5 calculated:

C, 41.0; H, 2.6; N, 20.0;

found:

40.8% C, 2.7% H, 20.0% N.

Example 13

N- [N '- (5-nitrophenylfurylidene) -D -? - aminooxybutyryl] -? - (isonicotinoyl) hydrazine

1.0 g (0.00412 mol) of N- (5-niirofurfurylidene) -D-ca-aminooxybutyric acid, 0.55 g (0.004 mol) of isonicotinic hydrazide and 0.85 g (0.00412 mol) of N, N The dicyclohexylcarbodiimide was stirred or shaken for 16 hours at room temperature in 10 ml of anhydrous dimethylformamide. The precipitated Ν, Ν'-dicyclohexylurea was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 15 ml of N hydrochloric acid and extracted 3 times with 5 ml of ethyl acetate. The aqueous phase was neutralized with solid sodium bicarbonate (ph = 7) and the precipitated product was - filtered, washed with water - and recrystallized from -50% aqueous ethanol. There was thus obtained 0.96 g (69%) of N- [N &apos;-( 5-nitroph urfurylidene) -Da-aminooxybutyryl] -N &apos; -isonicotinoyl) hydrazine, m.p. 164-166 [deg.] C. Rf = 0.15. [ _.alpha. ] _{D @} 28 = + 132 DEG (c = 1; ethanol).

For C15H11O6N5 calculated:

H, 4.3; N, 20.0;

found:

49.3% C, 4.4% H, 19.9% N.

The N- (5-nitrophenylidene) -D-α-aminooxybutyric acid used was obtained as follows:

3.10 g (0.020 mol) of · D-t-aminooxobutyric acid hydrochloride were dissolved in 7.0 · ml · water and 1.64 g (0.020 mol) of sodium acetate were added to the solution, followed by stirring or shaking at room temperature. 84 g (0.020 mol) of S-nitrofurfurol in 10.0 ml of methanol. The reaction mixture was allowed to stand for 16 hours at room temperature and then diluted with 23.0 ml of water. The precipitated product was filtered off, dried and recrystallized from ethyl acetate. Thus was obtained 2.12 g ^(88!%) Of N- (5-nitro uryliden URF) -D ^ <N - Init ^ (^ (^? ^ Χ ^ y ^ m ^ i ^ irlné acid with point Mp 117-118 [deg.] C. Rf = 0.77 [[alpha]] D30 = + 34 [deg.] (C = 1; ethanol).

For C 9 H 10 O 6 N 2 calculated:

C, 44.7; H, 4.1; N, 11.6;

found:

44.8% c, 4.0 n / o H, 11.6% N.

The following compound was produced in a similar manner:

Example 14

N- [N '- (5-nitrophenylfurylidene) -D - α-aminooxy- (f-methylthio) -butyryl] - Ν - (isonicotintyl) hydrazine

Yield: 70%. Melting point after recrystallization from ethyl acetate: 130-135 ° C. R f = 0.17. (α D ²⁵ = + 89 ° (c = 1; ethanol).

Calcd for C 16 H 17 O 5 N 5 S:.

47.2% C, 4.2% H, 17.2 -N;

no 1 P7Q11ΓΊ *

H, 4.3%; N, 17.1%.

The N- (5-nitrofurfurylidene) -D-α-amintoxy- (f-methylthio) butyric acid used as the starting compound was obtained as follows:

N- (5-nitrofurfurylidene) -D-α-amino-oxy- (χ-methylthio) butyric acid was prepared similarly to. the starting compound in Example 13 and for better handling. has been converted into its dicyclohexylammonium salt in a manner known per se. Before use, the acid was z. salts released in a manner known per se. M.p .: 158-159 ° C.

For C22H55O6N3S calculated:

% H, 7.5%; N 9.0%;

ΤΊΟ 1 Q7QH Υί ·

56.3% C, 7.4% H, 9.1% N.

Example 15

N- [N '- (5-nitrophenylfurylidene) -D-α-aminooxy- (D-phenyl) -propionyl] Ν' - (isonicotinoyl) -hydrazithydrochltride

1.0 g (0.0018 mol) of N - (.beta.-furfurylidene) -Da-aminooxy- (3-phenyl) -propionic acid pentachlorophenyl ester and 0.25 g (0.0018 mol) of · hydrazide · isonicotinic acid were dissolved in 10 ml of anhydrous dimethylformamide and stirred, if necessary shaken for 6 hours at room temperature. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was extracted 3 times with 5 ml sodium bicarbonate solution and then 2 times with 5 ml water.

The organic phases were combined and dried over sodium sulfate, and then the solvent was purified under reduced pressure. The residue was treated with 20 ml of 0.5 N diethyl ether acidified with hydrochloric acid. The acid addition salt obtained was filtered off, dissolved in boiling ethanol and, after cooling the solution, precipitated with diethyl ether. There was thus obtained 0.64 g (81% of theory) of N- [N &apos;-( 5-nitropfurfurylidene) -Da-aminooxy- ([beta] -phenyl) -propionyl] -N &apos; Mp 75-76 ° C. Rf = 0.08. [ _.alpha. ] _{D @} ²⁸ = + 86 DEG (c = 1; ethanol)

For C 20 H 18 N 5 Cl calculated:

% C, 52.3;% H, 3.9; found:

% C, 52.2;% H, 4.0;

Pentachlorophenyl ester. N- (5-nitrophenylfurylidene) -D-α-aminooxy- (D-phenyl) -propanoic acid used as starting material was obtained as follows:

2.17 g (0.10 mol) of D-α-aminooxy- (β-phenyl) -propionic acid hydrochloride were reacted as described in Example 13 in the preparation of the starting material therein with 1.42 g (0.010) mol) of 5-nitrofurfurol. Thus, 2.75 g (91% of theory) of N- (5-nitrofurfurylidene-D-α-aminooxy- (1H-enyl) -propionic acid, m.p. 156 DEG-158 DEG C.) were obtained. 52. [w) ² d 5 = -8 DEG (c = 0.6, ethanol).

For C14H12O6N2 calculated:

55.2% C, 4.0% H, 9.2% N;

found:

55.2% C, 4.1% H, 9.1% N.

Then · 1.0 g (0.0046 mol) of N- (5-nitrofurfurylidene) -Da-aminooxy - (β-enyl) -propionic acid was dissolved · 1.22 g (0.0046 mol) · of pentachlorophenol and 0.95 g (0.0046 mol) of N, N-dicyclohexylcarbodiimide with stirring or shaking in 10 ml of dioxane. The reaction mixture was allowed to stand for 16 hours and then the precipitated Ν, Ν'-dicyclohexylurea was filtered off. Thus 2.12 g (83% of theory) of N- (5-nitrofurfurylidene) -D-.alpha.-aminooxy- (O-phenyl) -propionic acid pentachlorophenyl ester of melting point 164 DEG-165 DEG C. were obtained. Rf = 0.77. [α] _D 30 = + 134 ° (c = 1; dioxane).

For C 20 H 11 O 6 N 2 Cl 5 calculated:

43.5% C, 2.0% H, 32.0% Cl;

found:

43.6% C, 2.1% H, 31.9% Cl.

Example 16

N- [N '- (cyclohexylidene)] -aminooxyacetic acid hydrazide hydrobromide

0.70 g (0.004 mol) of N-cyclohexyl acid. xylidene-aminooxyacetic acid was dissolved in 10.0 ml of anhydrous dioxane and added to the solution. 0.66 g (0.004 mol) of benzyloxycarboxylichydrazine and 0.82 g (0.004 mol) of N, N'-dicyclohexylcarbodiimide. The reaction mixture was stirred for 2 hours, optionally shaken at room temperature. The precipitated N, N'-dicyclohexylurea was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 20 ml of ethyl acetate and extracted twice with 10 ml of 2 N hydrochloric acid and then once with 10 ml of water and then dried and evaporated to a residue. dry matter. The residue was triturated with 20 ml of petroleum ether. Thus, 0.80 g (61% of theory) of N-N &apos;-( cyclohexylidene) aminooxyacetyl-N &apos;-( benzyloxycarbonyl) hydrazine, m.p. The product was stirred for 25 minutes, optionally shaken with 4.0 mL of 4 M hydrobromic acid in glacial acetic acid at room temperature to remove moisture from the air and then diluted with 40 mL of anhydrous diethyl ether. The precipitated crude product was dissolved in boiling ethanol and, after cooling, precipitated with diethyl ether. 0.45 g (70% of theory) of N- (N '- (cyclohexylidene) -amino-oxy-acetic acid) hydrazide bromide, boiling point 108 DEG-110 DEG C. was obtained, Rf = 0.65.

For C 6 H 16 O 2 N 3 Br calculated:

C, 36.1; H, 6.0; N, 15.7; 30.0%. Br; ndlezeno *

36.4% C ^6, first % H, ^15% 3 N ³⁰ 0 '% Br.

The following compound was produced in a similar manner:

Example 17

Ν-Ν ”- [Γ- (methyl) -benzal] -aminooxyacetic acid hydrazide hydrobromide

Yield: 80% of theory. Melting point after recrystallization from ethanol / ether: 126-128 ° C. Rf = 0.12.

Calcd for C 10 H 21 Cl 2 Br:

C 41.6%, H 4.9%, N 14.5%;

found:

41.5. % C, 4.9% H, 14.3% N.

Example 18

N-N '- (furfurylidene) -aminooxyacetic acid hydrazide

1.50 g (0.015 mol) of aminooxyacetic acid methyl ester, 1.24 ml (0.015 mol) of furfurol and 10.0 ml of ethanol were heated under reflux for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure and 1.50 ml of hydrazine hydrate was added at 0 ° C while stirring or shaking. The reaction mixture was allowed to stand for 16 hours at 0 ° C. The precipitated crystals were filtered off. Thus 1.90 g (69% of theory) of NN- (furfurylidene) -aminooxyacetic acid hydrazide were obtained, m.p. 78-80 ° C. R _f = 0.25.

For C7H9O3N3 calculated:

45.9% C, 4.9% H, 22.9% N; found:

45.5% C, 5.0 ° C, 22.9 ° N.

The following compounds were produced in a similar manner:

Example 19

N-N - (isopropylidene) -aminooxyacetic acid hydrazide

Yield: 86%. Melting point after recrystallization from ethanol-ether: 68-70 ° C. R _f = 0.21.

For C5H11O2N3 calculated:

C 41.4%, H 7.6%, N 29.0%;

found:

% C, 41.3;% H, 7.7%;

Example 20

Hydrazide. N-N '- (p-nitrobenzal) -aminooxyacetic acid

Yield: 98%. Melting point after recrystallization from ethanol:. Mp 180-181 ° C.

Rf = 0.15.

1S

For C 9 H 10 O 4 N 4 calculated:

45.4 O / o C, 4.2% H, 23.1% N;

found:

45.5% C, 4.3% H, 23.5% N.

Example 21

N-N '- (benzal) -aminooxyacetic acid hydrazide

Yield: 53%. Melting point after recrystallization from ethanol: 118-119 ° C.

R ₍ -9.20.

For C 9 H 11 O 2 N 3 calculated:

55.9% C, 5.7% H, 21.7% N;

1 й 1 0 * 6 DM П *

55.9 'O / o C, 5.7% H, 21.7 o / o N.

Example 22

N-N '- (p-chlorobenzal) -amino-oxoacetic acid hydrazide

Yield: 61%. Melting point after recrystallization from ethanol: 112-113 ° C. R _f = 0.21.

For C 9 H 10 O 2 N 3 Cl calculated:

47.4 o / o C, 4.4 o / o H, 18.4% N;

found:

47.1% C, 4.1 O / o H, 18.1% N.

Example 1 a d 23

N-N '- [1' - (phenyl) -benzal] -aminooxyacetic acid hydrazide

Yield: 52%. Melting point after recrystallization from ethanol / water: 61-63 ° C. R _f = 0.62.

For C15H15O2N3 calculated:

66.9% C, 5.6% H, N 15.6;

found:

66.6% C, 5.9% H, 15.8 o / _o N.

Example 1 a d 24

N-N '- [N' '- (ethoxycarbonyl 1] -piperidylidene] -aminooxyacetic acid hydrazide

Yield: 75%. Melting point after recrystallization from ethanol: 116-118 ° C.

R _f = 0.37.

For C10H18O4N4 calculated:

46.8% C, 7.0% H, 21.7 N;

H, 6.9; N, 21.8.

Example 25

N-N '- (n-butylidene) -aminooxyacetic acid hydrazide

Yield: 88%. The product was oily. R _f = 0.33.

For C6H13O2N3 calculated:

45.3% C, 8.2% H;

found:

45.5% C, 8.4% H.

Example 26

N- [N '- (isopropylidene) -aminooxyacetyl] -N' - (isonlcotinoyl) -hydrazine hydrobromide

0.50 g (0.0024 mol) of N- (aminooxyacetyl) -N '- (isonicotinoyl) hydrazine was dissolved in 3.0 ml of acetone and the solution was heated to boiling for 10 minutes. The pale yellow crystals precipitated upon cooling were filtered off and washed with a small amount of acetone 0.58 g (98% of theory) of N- [N '- (isopropylidene) -aminooxyacetyl] -4' - (isonicotinoyl) -hydrazine, m.p. 135 DEG-136 DEG C. _Rf = 0.43.

For C11H14O3N4 calculated:

% C, 52.8;% H, 5.6;% N, 22.4; пя1р7рип *

52.7% C, 5.7% H, 22.4% N.

0.50 g of N- [N '- (isopropylidene) -aminooxyacetyl] -4' - (isonicotinoyl) -hydrazine was then dissolved in 2.0 ml of 36% hydrogen bromide in glacial acetic acid. The salt formed was precipitated with 10.0 ml of anhydrous diethyl ether. Thus, 0.63 g (96 percent of theory) of N '- (isopropylidene) -aminooxyacetyl-N' - (isonicotinoyl) -hydrazine hydrobromide, m.p. 152 ° C, were obtained. R _f = 0.07.

РГО CllH15O3N4Br calculated:

39.9% C, 4.5% H, 24.8% Br;

found:

39.8% C, 4.6% H, 24.9% Br.

Claims (10)

A process for the manufacture of substituted acid hydrazide derivatives. of the .alpha.-aminooxycarboxylic acids of the formula I Η O Η 'Y II I / X = N — o — c — C — N — N (I), AND\ R2 wherein X represents a cycloalkylidene radical, a substituted azacycloalkylidene radical or a methylene radical substituted with phenyl or oxygen heterocyclic radicals, both of which are at least once substituted by C1 -C5 alkyl and / or halogen, hydroxy, nitro and / or amino, R is hydrogen, benzyl or C 1 -C 5 alkyl optionally substituted with at least one methylthio group, Y represents a hydrogen atom and Z represents a hydrogen atom or an acyl residue derived from pyridine carboxylic acid, or Y and Z together represent the substituents mentioned for X, and their acid addition salts, characterized in that the .alpha.-aminooxycarbonyloxy hydrazide of the formula II is reacted. Η O Η Y I II HžN — O — C — C — N — N (II), AND\ R2 wherein R, Y and Z are as defined above, or an acid addition salt thereof, with an oxo compound of Formula IV X = O (IV), wherein X is as defined above, or reacted with a Schiff base of formula III HIM III X = N — O — C — C — O — R '(ΠΙ), where X and R are as defined above and R' is hydrogen, C 1 -C 5 alkyl or phenyl substituted with at least one halogen atom or nitro, with a hydrazine derivative of the general formula V H OF H21N — N (V), \ Q in which Q represents a hydrogen atom, an acyl radical derived from pyridine carboxylic acid, an alkoxycarboxylic acid protecting group having 1 to 5 carbon atoms or a benzyloxycarboxylic acid protecting group, and optionally protecting groups, and the optionally obtained base is converted into an acid addition salt, or the base is liberated from the addition salt, or the addition salt is converted into another salt. 2. Process according to claim 1, characterized in that optically D-active isomers are used as starting materials. 3. A process according to claim 1 wherein the reaction is carried out in a solvent selected from the group consisting of dimethylformamide, dioxane, acetone, ethyl acetate, methanol, ethanol, and isopropanol. 4. The process of claim 1 wherein the reaction is carried out in the presence of an acid acceptor selected from the group consisting of trialkylamine, alkali metal acetate, and normal or acidic alkali metal carbonate. 5. The process of claim 1, wherein the reaction is carried out in the presence of a secondary or tertiary organic base whose dissociation constant is greater than the aminooxy dissociation constant. 6. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of 0 to 40 ° C, in particular at room temperature. 7. Process according to claim 1 or 2 to 6, characterized in that 2 moles of oxo compound of formula IV are used for each mole of unsubstituted .alpha.-aminocarboxylic acid hydrazides of the formula II. 8. The process of claim 1 wherein the compound of formula III is used in the D-active form. 9. A process according to claim 1, wherein the starting material is a compound of formula V having a protecting group on its nitrogen atom which is cleaved at the end of the reaction process. 10. Process according to claim 1, characterized in that the deprotection in the product is carried out by acid hydrolysis, preferably with hydrohalic acid in an organic solvent, in particular hydrobromic acid in glacial acetic acid.