NO132393B - - Google Patents

Description

The present invention relates to an analogous method for the production of new, tuberculostatically active α-aminooxy-carboxylic acid amide derivatives.

The oldest representative of the α-aminooxycarboxylic acids, aminooxyacetic acid, was already known at the end of the last century [A. Werner, Ber. 26, 1567 (1893); Pray. 27, 3350 (1894)]. However, the bacteriostatic activity of this compound was only recognized much later [C. B. Favour, J„ Bacteriol. 55, 1 (1948)]. Later, other aminooxy derivatives were also prepared [McHale et al., J. Chem. soc, 1960, 225; P. Mamalis and co. , J. Chem. Soc.

196o, 229; E. Testa et al., Heiv. Chim. Acta 46, 766 (1963);

P. Mamalis et al., J. Med. Chem. 6, 684 (1965); V. Markova et al., Chim. Farm. Zh. 3, 13 (1969)], some of which were also examined for bacteriostatic activity [cf. S. A. Price et al., Brit. J. Pharm. 15_>243 (1960)], but so far no compounds have been found which are sufficiently active against mycobacterium tuberculosis.

Surprisingly enough, it has now been shown that the simple α-aminooxycarboxylic acid derivatives of the general formula not yet described in the literature:

(

where X is hydrogen, lower alkanoyl, amino-lower alkanoyl or aminooxy-lower alkanoyl, R is hydrogen, lower alkyl, amino-lower alkyl, phenyl or benzyl, and Z is lower alkyl, cycloalkyl with up to 6 carbon atoms, one optionally with a or two lower alkyl, lower alkoxy, lower alkoxycarbonyl, hydroxy, halogen or nitro groups substituted phenyl or benzyl group, or a pyridyl group, and the therapeutically useful acid addition salts thereof, exhibit very advantageous tuberculostatic activity.

In the novel process compounds of formula I, X is mostly hydrogen, but may also be lower alkanoyl, amino-lower alkanoyl or aminooxy-lower alkanoyl. When in these compounds R is hydrogen, they are aminooxyacetic acid amide derivatives, while

the compounds where R is different from hydrogen are such α-aminebxycarboxylic acid amide derivatives which also contain an asymmetric carbon atom, and thus can exist in optically active forms. Z is for. mostly a substituted or unsubstituted aromatic group.

In the literature there is no instruction to be found on the preparation of the compounds of formula I, nor does the summary publication by A. 0. IlvespHH and A. Marxer, Chimia lg_, 1 (1964) ■ contain any information about this.

The new compounds of formula I are prepared according to the invention by an α-aminooxycarboxylic acid derivative of the general formula:

where A is lower alkanoyl, or an optionally protected amino-lower alkanoyl or aminooxy-lower alkanoyl group,

or when X in the final product is hydrogen, A is a

for preliminary protection of amino groups. suitable protecting group, e.g. a benzyloxycarbonyl or t-butoxycarbonyl group, B is hydroxyl or a group suitable for activating the carboxyl end, preferably a pentachlorophenoxy group, a halogen atom or an N^ group, and R is, as indicated above, reacted with an amine of the general formula:

where Z is as stated above, and that one possibly obtains from the reaction product with the general formula:

where A, R and Z are as indicated above, in a manner known per se, the protective group introduced for preliminary protection of the amino group cleaves off, and that, if desired, the obtained compound of formula i is transferred into a therapeutically applicable acid addition salt and/or if desired, the compound obtained is N-acylated.

The reaction of the starting materials of formula II with the amines of formula m is carried out in organic solvents, preferably in dioxane, at room temperature, the progress of the reaction being monitored by thin-layer chromatography. The preparation of the reaction mixture can be carried out in a simple way, as both possible by-products and the unreacted starting materials can be easily removed by shaking out, resp. by treatment with suitable organic solvents. If the obtained intermediate of formula IV contains a cleavable protecting group (that is, when compounds are to be prepared where X eT is hydrogen), this protecting group, depending on its nature, can be cleaved off by treatment with hydrogen bromide dissolved in glacial acetic acid or with acetic acid ester saturated with hydrogen chloride.

The acid addition salts of the compounds of formula I are insoluble in ether and can therefore be collected in crystalline form from e.g. alcoholic solutions thereof by the addition of ether.

The compounds of formula I where x is hydrogen can optionally be N-acylated by methods known per se, and thus transferred to compounds of formula I where X is acyl.

When optically active compounds of formula II are used as starting material, intermediate products of formula IV, respectively end products of formula I of corresponding configuration, i.e. likewise in optically active form, are obtained. If racemic starting materials of formula II are used, the products obtained in racemic form can likewise be cleaved into the optically active forms in a manner known per se.

In a particularly advantageous embodiment of the method, a t-butoxycarbonyl group or a benzyloxycarbonyl group is used for preliminary protection of the amino group in the starting material of formula I, and the carboxyl group is activated by transfer to the pentachlorophenyl ester or by using dicyclohexylcarbodiimide. on

in this way, the protected intermediates of formula IV are obtained in

yield, and can then by acid treatment be transferred into the desired end products of formula I. The latter can, depending on the reaction conditions used, be obtained in the form of the free bases or acid addition salts. From the acids obtained, the corresponding bases can be liberated in a manner known per se, and the bases can likewise be transferred by methods known per se into appropriate acid addition salts with therapeutically usable acids.

The new process compounds of formula I significantly inhibit in vitro the development of mycobacterium tuberculosis, strain H, R, as well as strains resistant to isonic acid hydra-oiv

zid, p-aminosalicylic acid and streptomycin. The degree of inhibition is particularly striking with certain anilide derivatives, which show inhibition values below 1 mcg/ml.

The new compounds of formula I can be administered in therapy

orally and/or parenterally, in the form of tablets, dragées, injections, infusions or suppositories. For adult patients, the daily dose amounts to approx. 7 - 50 mg/kg.

The production of the new compounds is illustrated in more detail

of the following examples. The chromatographic values given in the examples were determined on silica gel according to Stahl, with the system n-hexane-glacial acetic acid-chloroform 1:1:8, as the development took place at the

usual Cl 2 + toluidine method„

The structure of the prepared compounds was checked by

IR and NMR spectroscopy.

Example 1

a) N-t-butoxycarbonyl-aminooxyedc'.ksy reanilide a^) 8.8 g (20 mmol) of N-t-butoxycarbonyl-aminooxyacetic acid pentachlorophenyl ester was dissolved in 120 ml of dry dioxane, the solution was added to 3.72 ml (40 mmol ) aniline and 2.8 ml (20 mmol) of dry triethylamine, and the reaction mixture was left overnight at room temperature. The solvent was then distilled off under reduced pressure, the dry residue distributed between 100 ml of acetic acid ester and 20 ml of 0.1 N hydrochloric acid, the separated organic phase was shaken with 3 x 20 ml of 0.1 N hydrochloric acid and 2 x 20 ml of water, dried and then

the solvent distilled off under reduced pressure. The residue was crystallized from acetic acid ester, and 4.1 g (77% of the theoretical) of N-t-butoxycarbonylaminooxyacetic acid anilide was obtained, m.p. 126 - 129°C; Rf = 0.65.

Analysis: calculated: C 58.6%, H 6.8%;

found: C 58.6%, H 6.7%.

a2) 2.10 g (0.011 mmol) of N-t-butoxycarbonyl-aminooxyacetic acid was dissolved in 20 ml of absolute dioxane and 0.93 ml (0.10 mmol) of aniline was added. The mixture was cooled to +10°C and 2.26 g (0.011 mmol) of dicyclohexylcarbodiimide was added. The reaction mixture was stirred for 1 hour at +10°C and then at room temperature for 2 hours. The separated dicyclohexylurea was filtered off, the filtrate was evaporated on a water bath at 50°C under reduced pressure, and the residue crystallized from acetic acid ester. In this way, 1,919 were obtained

(72% of theoretical) N-t-butoxycarbonyl-aminooxyacetic acid anilide whose physical constants were identical to those of the product in example a^).

a^) 1.91 g (0.01 mmol) of n-t-butoxycarbonylaminoacetic acid was dissolved in 15 ml of absolute dimethylformamide and the solution cooled to -10°C. Then, with stirring and further cooling, 1.40 ml (0.01 mmol) of absolute triethylamine and 1.30 ml (0.01 mmol) of chloroformic acid isobutyl ester were added, and the reaction mixture was stirred for 15 minutes at -10°C. To the mixture was added 0.93 ml (0.01 mmol) aniline, allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then added to 40 ml of water and extracted with 3 x 20 ml of acetic acid ester. The separated organic phase was dried over sodium sulfate and then evaporated at 50°C under reduced pressure. The residue was crystallized from acetic acid ester, and in this way 1.179 g (44% of the theoretical) of N-t-butoxycarbonyl-aminoacetic acid anilide were obtained whose physical constants were identical to those of the product according to example 1 a^). b) N-benzyloxycarbonyl-aminooxyacetic acid anilide 2.379 (5 mmol) of N-benzyloxycarbonyl-aminooxyacetic acid pentachlorophenyl ester was dissolved in 30 ml of dioxane, 0.93 ml (10 mmol) of aniline and 0.70 ml (5 mmol) of triethylamine were added, and the mixture was provided above. overnight at room temperature. The solvent was then distilled off under reduced pressure, the residue was dissolved in 25 ml of acetic acid ester, and the solution was shaken with 3 x 10 ml of N hydrochloric acid and 3 x 10 ml of water. After drying, the organic phase was evaporated under reduced pressure. The residue was recrystallized from a mixture of acetic acid ester and n-hexane, and in this way 1.49 (93.5% of the theoretical) of N-benzyloxycarbonylaminooxyacetic anilide was obtained, R^= 0.69.

Analysis: calculated: C 64.0%, H 5.4%, N 9.3%;

found: C 64.1%, H 5.5%, N 9.2%.

c) Aminoxyacetic acid anilide hydrobromide

1.1 g (3.7 mmol) N-benzyloxycarbonyl-aminooxyacetic acid anilide

was dissolved in 5 ml of 4 mol/l hydrogen bromide solution in glacial acetic acid while stirring and excluding air humidity. After 30 minutes, 50 ml of dry ether was added to the mixture, the precipitated product was separated by filtration and crystallized from crude ethanol/ether. In this way, 0.75 g (83% of the theoretical) of aminooxyacetic acid anilide hydrobromide, m.p. 143 - 144°C.

Analysis: calculated: C 38.8%, H 4.5%, N 11.3%, Br 32.4%;

found: C 38.7%, H 4.6%, N 11.3%, Br 32.5%.

d) Aminoxyacetic anilide hydrochloride

2.13 g (8 mmol) of N-t-butoxycarbonyl-aminooxyacetic acid anilide were

dissolved in 4 mol/l hydrogen chloride solution in dry acetic acid ester, and the solution was stirred for 30 minutes at room temperature. Absolute ether was then added to the reaction mixture, the precipitated product was separated by filtration and crystallized from ethanol/ether.

1.36 g (84% of the theoretical) of aminooxyacetic acid anilide-

hydrochloride, m.p. 166 - 167°C

Analysis: calculated: C 47.4%, H 5.5%, Cl 17.5%;

found: C 47.5%, H 5.5%, Cl 17.6%.

Example 2

a) N-t-butoxycarbonyl-1-aminooxyacetic acid 2-methoxyanilide 2.1 g (11 mmol) N-t-butoxycarbonyl-an,..noxyacetic acid was dissolved in 20 ml of dioxane and the solution first added 1.12 mol (10 mmol ) o-anisidine and then, under cooling, 2.26 g (11 mmol) of dicyclohexyl- ' carbodiimide. The reaction mixture was allowed to stand overnight and then the separated dicyclohexylurea was filtered off and the filtrate evaporated to dryness under reduced pressure. The residue was crystallized from a mixture of chloroform and n-hexane. 2.2 g (74% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-2-methoxyanilide were obtained,

sm.p. 80-82°c, Rf =0.8.

Analysis: calculated: C 56.7%, H 6.8%;

found: C 56.7%, H 6.7%.

b) Aminoxyacetic acid-2-methoxyanilide hydrochloride 2.2 g of N-t-butoxycarbonyl-aminooxyacetic acid-2-methoxyanilide was

in the manner described in example 1 d) reacted with 4 mol/l hydrogen chloride solution in acetic acid ester. In this way, 1.40 g (82% of the theoretical) of aminooxyacetic acid-2-methoxyanilide hydrochloride was obtained, which after crystallization from ethanol/ether melted at 164 - 166°C. Analysis: calculated: C 46.4%, H 5.6%, Cl 15.3%;

found: C 46.5%, H 5.7%, Cl 15.2%.

Example 3

a) N-t-butoxycarbonyl-aminooxyacetic acid-4-methoxyanilide 2.1 g of N-t-butoxycarbonyl-aminooxyacetic acid was reacted with 1.23 g of p-anisidine in the manner described in example 2 a). 1.74 g (60% of theory) of N-t-butoxycarbonyl-aminooxyacetic acid-4-methoxyanilide were obtained, m.p. 107-108°C (from acetic acid ester), R^ = 0.7. Analysis: calculated: C 56.7%, H 6.8%;

found: c 56.8%, H 6.8%.

b) Aminoxyacetic acid-4-methoxyanilide-hydrochloride 0.52 g N-t-butoxycarbonyl-aminooxyacetic acid-4-methoxyanilide

was reacted according to example 1 d) with hydrogen chloride solution in acetic acid ester. 0.33 g (84% of the theoretical) aminooxy-

acetic acid 4-methoxyanilide hydrochloride, m.p. l8l - l82°C.

Analysis: calculated: C 46.4%, H 5.6%, Cl 15.3%;

found: C 46.5%, H 5.6%, Cl 15.4%.

Example 4

a) N-t-butoxycarbonyl-aminooxyacetic acid-3-bromomanilide 2.1 g of N-t-butoxycarbonyl-aminooxyacetic acid was according to

example 2a) reacted with 1.08 ml of 3-bromoanilide. 1.9 g (57% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-3-bromoanilide were obtained, m.p. 122 - 124°C (from acetic acid ester), Rf = 0.65.

Analysis: calculated: C 45.4%, H 5.0%, Br 23.1%;

found: C 45.4%, H 5.1%, Br 23.2%.

b) Aminoxyacetic acid-3-bromomanilide hydrochloride

0.85 g of N-t-butoxycarbonyl-aminooxyacetic acid-3-bromoanilide was

treated according to example 1 d) with 4 mol/l hydrogen chloride solution in dry acetic acid ester. 3.57 g (83% of theory) of aminooxyacetic acid-3-bromoanilide hydrochloride were obtained, m.p. 151 - 156°C.

Analysis: calculated: C 34.1%, H 3.6%, Br 28.4%, Cl 12.6%;

found: C 34.1%, H 3.8%, Br 28.4%, Cl 12.5%.

Example 5

a) N-t-butoxycarbonyl-aminooxyacetic acid-4-ethoxyanilide 4.39 g N-t-butoxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester

was reacted in the manner described in example 1 a^) with 2.6 ml of p-phenetidine. 2.1 g (68% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-4-ethoxyanilide were obtained, m.p. 119 122°C (from acetic acid ester), Rf = 0.6.

Analysis: calculated: C 58.0%, H 7.2%;

found: C 58.1%, H 7.2%.

b) N-benzyloxycarbonyl-aminooxyacetic acid-4-ethoxyanilide 2.0 g of N-benzyloxycarbonyl-aminooxyacetic acid pentachlorophenyl ester was reacted with 1.18 ml of p-phenetidine in the manner described in example 1 a^). 1.1 g (77% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-4-ethoxyanilide were obtained, m.p. 105- lo6°C (from acetic acid ester), R, = 0.7.

Analysis: calculated: C 62.7%, H 5.9%, N 8.1%;

found: C 62.6%, H 5.9%, N 8.2%.

c) Aminoxyacetic acid-4-ethoxyanilide hydrochloride 1.1 g of N-t-butoxycarbonyl-aminooxyacetic acid-4-ethoxyanilide was

according to example 1 d) treated with hydrogen chloride dissolved in acetic acid ester. 0.7 g (81% of the theoretical) aminooxyacetic acid-4-ethoxyenilide hydrochloride was obtained, m.p. 17C - 173°C.

Analysis: calculated: C 48.7%, H 6.1%, Ci 14>4%;

found: C 48.7%, H 6.1%, Cl 14.'+%.

d) Aminoxyacetic acid-4-ethoxyanilide hydrobromide 1.0 g of N-benzyloxycarbonyl-aminooxyacetic acid-4-ethoxyanilide was

in the manner described in example 1 c) treated with hydrogen bromide dissolved in glacial acetic acid. 0.75 g (89% of theory) of aminooxyacetic acid-4-ethoxyanilide hydrobromide was obtained, m.p. 162 - 166°C (from ethanol/ether).

Analysis: calculated: C 41.2%, H 5.2%, Br 27.5%;

found: C 41.1%, H 5.3%, Br 27.5%.

Example 6

a) N-t-butoxycarbonyl-aminooxyacetic acid-4-ethylanilide 4.39 g of N-t-butoxycarbonyl-aminooxyacetic acid pentachlorophenyl ester was, as described in example 1 a-^), reacted with 2.5 ml of p-ethylaniline. 2.15 g (73% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-4-ethylanilide were obtained, m.p. 100 - 101°C (from acetic acid ester), Rf = 0.8.

Analysis: calculated: C 61.2%, H 7.5%;

found: C 61.2%, H 7.7%.

b) Aminoxyacetic acid-4-ethylanilide hydrochloride 1.45 g of N-t-butoxycarbonyl-aminooxyacetic acid-4-ethylanilide was

as in example 1 d) treated with hydrogen chloride dissolved in acetic acid ester. 0.939 (82% of theoretical) aminooxyacetic acid-4-ethylanilide hydrochloride was obtained, m.p. 167 - 171°C (from ethanol/ether). Analysis: calculated: C 52.1%, H 6.6%, Cl 15.4%;

found: C 52.3%, H 6.6%, Cl 15.4%.

Example 7

a) N-t-butoxycarbonyl-aminooxyacetic acid-4-chloroanilide 8.8 g N-t-butoxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester

was reacted according to example 1 a.^) with 5.12 g of p-chloroaniline. 4.7 g (79% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-

4-chloroanilide, m.p. 157 - 159°C (from acetic acid ester), Rf = 0.65.

Analysis: calculated: C 52.0%, H 5.7%, Cl 11.8%;

found: C 52.1%, H 5.6%, Cl 11.9%.

b) N-benzyloxycarbonyl-aminooxyacetic acid-4-chloroanilide 2.37 g of N-benzyloxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester was reacted according to example 1 a^) with 1.28 g of p-chloroaniline.

1.15 g (69% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-4-chloroanilide were obtained, m.p. 105°C (from acetic acid ester/hexane),

Rf = 0.68.

Analysis: calculated: C 57.3%, H 4.5%, N 8.45%, Cl 10.6%;

found: C 57.3%, H 4.6%, N 8.4%, Cl 10.5%.

c) Aminoxyacetic acid-4-chloroanilide hydrochloride 3.55 g of N-t-butoxycarbonyl-aminooxyacetic acid-4-chloroanilide was

as in example 1 d) treated with hydrogen chloride dissolved in acetic acid ester. 2.13 g (79% of theory) of aminooxyacetic acid-4-chloroanilide hydrochloride were obtained, m.p. 168 - 172°C (from ethanedl/ether).

Analysis: calculated: C 40.5%, H 4.2%, Cl 29.9%;

found: C 40.5%, H 4.2%, Cl 29.9%.

d) Aminoxyacetic acid-4-chloroanilide hydrobromide 0.5 g of N-benzyloxycarbonyl-aminooxyacetic acid-4-chloroanilide was

according to example 1 c) treated with hydrogen bromide dissolved in glacial acetic acid. 0.35 g (83% of theory) of aminooxyacetic acid-4-chloroanilide hydrobromide was obtained, m.p. l6o - l63°C (from ethanol/ether).

Analysis: calculated: C 32.4%, H 3.6%, N 10.0%, Br 28.4%, Cl 12.6%

found: C 34.0%, H 3.7%, N 10.0%, Br 28.4%, Bl 12.7%

Example 8

a) N-t-butoxycarbonyl-aminooxyacetic acid-2,6-dimethylanilide 4.39 g of N-t-butoxycarbonyl-aminooxyacetic acid pentachlorophenyl ester was reacted according to example 1 a^) with 2.44 g of o-xylidine. 1.15 g (69% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid were obtained acid 2,6-dimethylanilide, m.p. 133 - 135°C (from acetic acid ester),

Rf = 0.58.

Analysis: calculated: C 61.2%, H 7.5%;

found: C 61.1%, H 7.5%.

b) Aminoxyacetic acid-2,6-dimethylanilide hydrochloride 1.65 g of N-t-butoxycarbonyl-aminooxyacetic acid-2,6-dimethylanilide was treated according to example 1 d) with hydrogen chloride dissolved in acetic acid ester. 1.4 g (81% of the theoretical) of aminooxyacetic acid-2,6-dimethylanilyl hydrochloride were obtained, m.p. 163 - 164°C.

Analysis: calculated: C 52.1%, H 6.6j0, Cl 15.4%;

found: C 52.3%, H 6.7%, Cl 1 5,rö.

Example 9

a) N-benzyloxycarbonyl-aminooxyacetic acid-4-chlorobenzylamide 2.06 g (4.3 mmol) of N-benzyloxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester was dissolved in 25 ml of dry dioxane and 0.75 ml (5.5 mmol) of p-chlorobenzylamine was added . The reaction mixture was allowed to stand for 1 hour at room temperature, and then evaporated to dryness under reduced pressure. The residue was dissolved in 25 ml of acetic acid ester and the solution shaken with 3 x 6 ml of N hydrochloric acid and 2 x 6 ml of water. It

separated organic phase was evaporated under reduced pressure and the residue crystallized from a mixture of ethanol and n-hexane. 1.42 g (81.7% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-4-chlorobenzylamide were obtained in this way, m.p. 112 C, Rf = 0.59.

Analysis: calculated: C 58.5%, H 4.9%, N 8.1%, Cl 10.15%;

found: C 58 , 5%-, H 5 .1% , N 8 .1%, Cl 10.2%.

b) Aminoxyacetic acid-4-chlorobenzylamide hydrobromide 1.0 g N-benzyloxycarbonyl-aminooxyacetic acid-4-chlorobenzylamide

was according to example 1 c) treated with hydrogen bromide dissolved in glacial acetic acid. 0.8 g (94% of the theoretical) aminooxyacetic acid-4-chlorobenzylamide hydrobromide was obtained, m.p. 147 - 148°C.

Analysis: calculated: C 36.3%, H 4.1%, N 9.5%, Cl 12.0%, Br 27.1%;

found: C 36.3%, H 4.2%, N 9.4%, Cl 12.1%, Br 27.1%.

Example lo

a) N-benzyloxycarbonyl-aminooxyacetic acid-benzylamide 1.75 g of N-benzyloxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester was reacted according to example 1 a^) with 0.47 ml of benzylamine. 1.0 g (88% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-benzylamide, m.p. 87 - 88°C (from acetic acid ester),

R f = 0.63.

Analysis: calculated: C 65.0%, H 5.8%, N 8.9%;

found: C 65.0%, H 5.8%, N 8.9%.

b) Aminoxyacetic acid - benzylamide - hydrobromide

0.6 g of N-benzyloxycarbonyl-aminooxyacetic acid-benzylamide was

dissolved in 3 ml of 3.5 M hydrogen bromide solution in glacial acetic acid with stirring, and after 30 minutes the hydrogen bromide was precipitated by adding 30 ml of dry ether. After recrystallization from dry ethanol/ether, 0.46 g (83% of the theoretical) aminooxyacetic acid-benzylamide hydrobromide was obtained, m.p. 135 - 136°C.

Analysis: calculated: C 41.5%, H 5.0%, N 10.8%, Cl 30.6%;

found: C 41.6%, H 5.1%, N 10.7%, Cl 30.7%.

Example 11

a) N-t-butoxycarbonyl-aminooxyacetic acid-cyclopentylamide 4.39 g (10 mmol) N-t-butoxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester was dissolved in 50 ml dioxane, 1.7 g (20 mmol) cyclopentylamine was added, and the reaction mixture was allowed to stand overnight . The solvent was distilled off under reduced pressure, the residue dissolved in 40 ml of acetic acid ester, and the solution shaken with 3 x 10 ml of N hydrochloric acid and then with 10 ml of water. After drying, the organic phase was evaporated under reduced pressure and the residue recrystallized from acetic acid ester. 1.75 g (68% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-cyclopentylamide were obtained, m.p. 163 - 168°C,

R f = 0.45.

Analysis: calculated: C 55.75%, H 8.6%;

found: C 55.8%, H 8.7%.

b) Aminoxyacetic acid cyclopentylamide hydrochloride

0.75 g of N-t-butoxycarbonyl-aminooxyacetic acid-cyclopentylamine was

according to example 1 d) reacted with hydrogen chloride dissolved in acetic acid ester. 0.43 g (77% of the theoretical) aminooxyacetic acid cyclopentylamide hydrochloride was obtained in the form of highly hygroscopic crystals.

Example 12

a) N-t-butoxycarbonyl-aminooxyacetic acid~3-pyridylamide 2.1 g (11 mmol) N-t-butoxycarbonyl-aminooxyacetic acid was dissolved in 20 ml dioxane, the solution was added 0.949 (10 mmol) 3-aminopyridine and 2.26 g (11 mmol) of dicyclohexylcarbodiimide under cooling, and the reaction mixture was left overnight. The separated dicyclohexylurea (2.29 g, 94% of theory) was then removed by filtration and the filtrate evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of acetic acid ester, the solution was shaken with 2 x 10 ml molar sodium bicarbonate solution, and then with 10 ml of water. The organic phase was dried and evaporated to dryness under reduced pressure. After recrystallization of the residue from acetic acid ester, 1.5 g (63% of the theoretical) of N-t-butoxycarbonyl-aminooxyacetic acid-3-pyridylamide was obtained, m.p. 117 - 123°C, Rf = 0.63.

Analysis: calculated: C 54.0%, H 6.4%;

found: C 54.0%, H 6.6%.

b) Aminoxyacetic acid-3-pyridylamide-dihydrochloride 0.36 g of N-t-butoxycarbonyl-aminooxyacetic acid-3-pyridylamide was

according to example 1 d) reacted with hydrogen chloride dissolved in acetic acid ester. 0.39 (93% of the theoretical) aminooxyacetic acid-3-pyridylamide dihydrochloride was obtained, which after crystallization from ethanol/ether melted at 184 - 186°C.

Analysis: calculated: C 35.0%, H 4.7%, Cl 29.5%;

found: C 35.1%, H 4.8%, Cl 29.4%.

Example 13

a) N-(N'-t-butoxycarbonyl-aminooxyacetyl)-aminooxyacetic acid anilide 1.4 g (7 mmol) aminooxyacetic acid anilide hydrochloride was dissolved

in 25 ml of dimethylformamide, 97 ml (7 mmol) of triethylamine was added to the solution while cooling and stirring, and the separated triethylamine salt was removed by filtration after 15 minutes of stirring. To the filtrate was added 3.08 g (7 mmol) of N-t-butoxycarbonyl-aminooxy-

acetic acid pentachlorophenyl ester, and the reaction mixture was allowed to stand overnight. The solvent was then distilled off under reduced pressure and the residue crystallized from acetic acid ester. 1.45 g (65% of the theoretical) N-(N<1->t-butoxycarbonyl-aminooxyacetyl)-aminooxyacetic acid anilide was obtained, m.p. 113 - 117 C, Rf = 0.52.

Analysis: calculated: C 53.1%, H 6.2%;

found: C 53.2%, H 6.3%.

b) N-(aminooxyacetyl)-aminooxyacetic acid anilide hydrochloride 0.33 g of N-(N'-t-butoxycarbonyl-aminooxyacetyl)-aminooxyacetic acid anilide was reacted as in example 1 d) with hydrogen chloride dissolved in acetic acid ester. 0.24 g (87% of the theoretical) N-(aminooxy-acetyl)-aminooxyacetic acid anilide hydrochloride was obtained, which after crystallization from ethanol/ether melted at 108 - 116°C.

Analysis: calculated: C 43.7%, H 5.1%, Cl 12.8%;

found: C 43.7%, H 5.2%, Cl 12.9%.

Example l4 ...

a) N-(N'-benzyloxycarbonyl-glycyl)-aminooxyacetic anilide 1.4 g (7 mmol) aminooxyacetic anilide hydrochloride was dissolved

in 25 ml of absolute dimethylformamide, and 0.97 ml of absolute triethylamine and 3.2 g (7 mmol) of N-benzyloxycarbonyl-glycyl-pentachlorophenyl ester were added to the solution while stirring. The reaction mixture was allowed to stand overnight, then the triethylamine salt was removed by filtration and the filtrate evaporated to dryness under reduced pressure. After crystallization of the residue from acetic acid ester, 2.1 g (84% of the theoretical) N-(N'-benzyloxycarbonyl-glycyl)-aminooxyacetic acid anilide was obtained, m.p. 115 - 117°C, -Rjr••-=- 0.41 • -

Analysis: calculated: C 60.6%, H 5.4%, N 11.7%;

found: C 60.4%, H 5.6%, N 11.4%.

b) N-glycyl- aminooxyacetic anilide hydrobromide 1.85 g N-(N'-benzyloxycarbonyl-glycyl)-aminooxyacetic anilide

was according to example 1 c) reacted with hydrogen bromide dissolved in glacial acetic acid. 1.19 g (75% of the theoretical) of N-glycyl-aminooxyacetic acid anilide hydrobromide were obtained, m.p. 125 - 128°C.

Analysis: calculated: C 39.5%, H 4.6%, Br 26.2%;

found: C 39.5%, H 4.8%, Br 26.3%.

Example 15

N-acetyl- aminooxyacetic acid anilide

1.40 g (7 mmol) of aminooxyacetic acid anilide hydrochloride was dissolved in 20 ml of pyridine and, while cooling, 0.97 ml of triethylamine was added.

The separated triethylamine salt was removed by filtration, 0.57 ml (8 mmol) of acetyl chloride was added to the filtrate while cooling and stirring, and the reaction mixture was stirred for 1 hour at 0°C and then poured onto 60 g of ice. The mixture was acidified with hydrochloric acid and extracted with 4 x 20 ml of acetic acid ester. After drying, the combined organic phases were evaporated under reduced pressure and the residue crystallized from acetic acid ester. 1.05 g (72% of the theoretical) of N-acetyl-aminooxyacetic acid anilide was obtained in this way, m.p. 142 - 144°C, Rf 0.2.

Analysis: calculated: C 57.7%, H 5.8%;

found: C 57.7%, H 5.9%.

Example 16

a) N- t- butoxycarbonyl- g- aminooxy- P- phenyl- propionic anilide

a.^) 3»28 g (6.2 mmol) of N-t-butoxycarbonyl-α-aminooxy-p-phenyl-propionic acid pentachlorophenyl ester was dissolved in 20 ml of absolute dimethylformamide, the solution was added to 1.15 ml (12.4 mmol) aniline and 0.86 ml (6.2 mmol) of absolute triethylamine, and the reaction mixture was allowed to stand overnight. The solvent was then distilled off under reduced pressure, the residue dissolved in 50 ml of acetic acid ester, the solution shaken with 3 x 10 ml of N hydrochloric acid, and then with water, and after drying evaporated under reduced pressure. The residue was recrystallized from acetic acid ester, whereby 1.65 g (74% of theory) of N-t-butoxycarbonyl-α-aminooxy-|3-phenyl-propionic anilide was obtained, m.p. l^O - l4l°C, [a]^<5>= +162° (c = 1, ethanol),

R f = 0.8.

Analysis: calculated: C 67.5%, H 6.8%, N 7.9%;

found: C 67.3%, H 6.6%, N 8.0%.

a2) 2.8 l g (10 mmol) N-t-butoxycarbonyl-α-aminooxy-(3-phenyl-propionic acid) and 0.93 ml (10 mmol) aniline were dissolved in 20 ml dioxane, and the solution was added while cooling and stirring 2, 06 g

(10 mmol) dicyclohexylcarbodiimide. The reaction mixture was allowed to stand overnight, then the separated dicyclohexylurea was filtered off,

and the filtrate was evaporated under reduced pressure. The residue was dissolved

in 25 ml of acetic acid ester, the solution was shaken with 3 x 5 ml of N hydrochloric acid and then 3 x 5 ml of molar sodium bicarbonate solution and finally with water, dried and evaporated under reduced pressure. After recrystallization of the residue from acetic acid ester, 1.76 g of N-t-butoxycarbonyl-g-aminooxy-f3-phenyl-propionic reanilide were obtained, the physical constants of which were identical to those of the product from example 16 a-^).

b) γ-aminooxy-[3-phenyl-propionic acid anilide hydrochloride 0.65 g N-t-butoxycarbonyl-α-aminooxy-|3-phenyl-propionic acid anilide

was according to example 1 d) reacted with hydrogen chloride dissolved in acetic acid ester. 0.439 (83% of theoretical) α-aminooxy-|3-phenyl-propionic anilide hydrochloride was obtained, m.p. 166 - 180°C, [<x]^ = +28.7° (c = 1, ethanol).

Analysis: calculated: C 6l.6%, H 5.8%, Cl 12.1%;

found: C 61.5%, H 5.9%, Cl 12.1%.

Example 17

a) N-t-butoxycarbonyl-g-aminooxy-propionic acid anilide 2.05 g (10 mmol) N-t-butoxycarbonyl-g<->aminooxy-propionic acid and

0.93 ml (10 mmol) of aniline was dissolved in 20 ml of absolute dioxane, 2.06 g of dicyclohexylcarbodiimide was added to the solution while cooling and stirring and left at room temperature for 16 hours. The separated dicyclohexylurea was filtered off and the solvent distilled off under reduced pressure. The residue was dissolved in 25 ml of acetic acid ester, and the solution was shaken with 3 x 5 ml of hydrochloric acid,

then with 3x5 ml molar sodium bicarbonate solution and finally with water. After drying, the solution was evaporated to dryness under reduced pressure and the residue crystallized from chloroform/hexane. 1.7 g (61% of the theoretical) N-t-butoxycarbonyl-g<->aminoxy-propionsy reanilide, m.p. 92°C, [a]p^ = +102.5° (c = 1, ethanol),

R f = 0.71.

Analysis: calculated: C 60.0%, H 7.2%, N 10.0%;

found: C 59.9%, H 7.3%, N 10.2%.

b) g- aminooxy- propionic acid anilide hydrochloride

0.56 g of N-t-butoxycarbonyl-g<->aminooxy-propionic anilide was

according to example 1 d) added hydrogen chloride dissolved in acetic acid ester. 0.379 (86% of the theoretical) was obtained of aminooxy-propionic anilide hydrochloride which, after crystallization from ethanol/ether, melted at 165 - 168°C, [a]^<5>= +133.5° (c = 1, ethanol).

Analysis: calculated: C 49.9%, H 6.0%, Cl 16.4%;

found: C 49.8%, H 6.2%, Cl 16.5%.

Example 18

γ-aminooxypropionic acid o-chloranilide hydrochloride 2.05 g (0.010 mol) γ<->t-butoxycarbonyl-aminooxy-propionic acid was dissolved in 30 ml of absolute acetic acid ester at room temperature, the solution was added to 1.28 g (0.010 mol) of p-chloroaniline, then cooled to 0°C and 2.6 g (0.010 mol) of N,N'-dicyclohexylcarbodiimide added. The reaction mixture was then left at room temperature for 16 hours without further cooling. The separated N,N'-dicyclohexylurea (2.14 g, 96% of theory) was filtered off and the filtrate evaporated under reduced pressure at 50°C. 2.90 g (92% of the theoretical) were obtained of an oily residue which, under the exclusion of atmospheric moisture, was stirred at room temperature for 30 minutes with 15 ml of a 4.0 ml/l solution of hydrogen chloride in absolute acetic acid ester. Then 45 ml of dry ether was added to the mixture, the precipitated crystals were filtered off, washed with ether, dried and then dissolved in boiling ethanol, the solution was cooled to 30°C and an equal volume of ether was added. After drying the crystalline product precipitated in this way, 2.03 g (81% of the theoretical) g-aminooxy-propionic acid-p-chloroanilide hydrochloride was obtained, m.p. 177 - 180°C,

ofl

[<g>]p = +115.0° (c = 1, ethanol).

Analysis: calculated: C43.0%, H4.8%, Cl 28.2%;

found: C 43.1%, H 4.8%, Cl 28.2%.

Example 19

Aminoxyacetic acid p-hydroxyanilide hydrobromide

4.50 g (0.020 mol) of N-benzyloxycarbonyl-aminooxyacetic acid were dissolved in 34 ml of absolute ether, the solution was cooled to 0°C and, while stirring and exclusion of atmospheric moisture, 5.0 g (0.022 mol) of phosphorus pentachloride was added. The mixture was stirred for 30 minutes at 0 - 5°C, whereby an almost homogeneous solution was obtained. The minimal insoluble portion present was removed by filtration and the solution was evaporated under reduced pressure in a water bath at no more than 10°C. The residue was triturated with 15 ml of n-hexane, the hexane was evaporated in the same way, and the treatment was repeated once more. In the end, 4.85 g (100% of the theoretical) of an oily residue was obtained, which was dissolved in 40 ml of absolute chloroform at room temperature. dissolve-

to the reaction was added 2.139 (0.0195 mol) p-aminophenol and then 30 ml of sodium bicarbonate solution at a 1 mol/l concentration, and the heterogeneous reaction mixture was stirred vigorously at room temperature for 3 hours. The organic phase was then separated, shaken with 3x7 ml of N hydrochloric acid solution, then with 10 ml of water, then with 3x7 ml of molar sodium bicarbonate solution and finally with 10 ml of water, and then dried over anhydrous sodium sulfate and evaporated at 40°C under reduced pressure. The residue was dissolved in hot acetic acid ester, an equal volume of n-hexane was added, cooled, the separated crystals were filtered off and dried in open air. In this way, 2.90 g (47% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-p-hydroxanilide with a melting point of 115 - 117°C were obtained.

The above product was added to 15 ml mol/l hydrogen bromide solution in glacial acetic acid and stirred for 30 minutes at room temperature while excluding air humidity. Then 150 ml of absolute ether was added to the solution, the separated crystals were filtered off, washed with ether, dried in a desiccator in vacuum over phosphorus pentoxide and recrystallized from ethanol/ether in the manner described. 1.95 g (38.2% of the theoretical) aminooxyacetic acid p-hydroxyanilide hydrobromide, m.p. 175 - 177°C.

Analysis: calculated: C 36.5%, H 4.2%, Br 30.4%;

found: C 36.5%, H 4.3%, Br 30.3%.

Example 20

a) a-N-t-butoxycarbonyl-aminooxy-p-phenyl-propionic acid-isopropyl-amide

3.08 g (0.011 mol) of α-N-t-butoxycarbonyl-aminooxy-p-phenyl-propionic acid was dissolved in 40 ml of absolute dioxane at room temperature, and while stirring and cooling, 0.87 ml (0.Q10 mol) of isopropylamine was added and then 2, 26 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide. The mixture was allowed to stand for 16 hours at room temperature, and then the separated N,N'-dicyclohexylurea (2.34 g, 96% of theory) was removed by filtration. The filtrate was evaporated at 50°C under reduced pressure, the residue dissolved in 30 ml of acetic acid ester, the solution was shaken with 3 x 7 ml of molar sodium bicarbonate solution, once with 10 ml of water, then with 3 x 7 ml of N hydrochloric acid and finally a times with 10 ml of water. The separated organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of acetic acid ester and n-

nexan 1:1. The crystals obtained were dried in the air, and in this way 2.22 g (69% of the theoretical) of α-N t -butoxycarbonyl-aminooxy-p-phenyl-propionic acid-isopropylamide were obtained, m.p. 100 - 101°C, [a]D 28 = +62.5° (c = 1.2, ethanol), Rf = 0.85 (in the system acetic acid ester-pyridine-glacial vinegar-water 30:2.5:0, 75:1.4; adsorbent: silica gel).

Analysis: calculated: C 63.4%, H 8.1%, N 8.7%;

found: C 63.4%, H 8.1%, N 8.7%.

b) g- aminooxy- g- phenyl- propionic acid- isopropylamide- hydrochloride 0.6o g (0.0019 mol) a-N-t-butoxycarbonyl-aminooxy-f3-phenyl -

propionic acid isopropylamide was dissolved in 3.04 ml of a hydrogen chloride solution of 4.0 mol/l concentration prepared with acetic acid ester, the solution was stirred at room temperature under the exclusion of humidity for 20 minutes and then 15 ml of absolute diethyl ether was added. The precipitated crystals were filtered off and recrystallized

from ethanol/ether. After drying, 0.439 (88% of the theoretical) α-aminooxy-(3-phenyl-propionic acid-isopropylamide hydrochloride) was obtained, m.p. 147 - 148°C, [a]p<8>= +28 .0° (c = 1, methanol),

Analysis: calculated: C 55.6%, H 7.4%, Cl 13.7%;

found: C 55.5%, H 7.6%, Cl 13.6%.

Example 21

a) N-benzyloxycarbonyl-aminooxyacetic acid-4-nitroanilide 4.50 g (0.020 mol) of N-benzyloxycarbonyl-aminooxyacetic acid were

the manner described in example 21 transferred into the acid chloride, and the resulting chloride was dissolved in 20 ml of acetic acid ester. The solution was cooled to 0°C and then 2.07 g (0.015 mol) p-nitroaniline was added

and 5.0 ml of pyridine. The mixture was stirred at 0°C for 30 minutes and then at 20°C for 60 minutes, then 20 ml of water was added and stirred at room temperature for a further 10 minutes. The organic phase was separated, shaken with 3 x 10 ml molar sodium bicarbonate solution and then once with 10 ml of water, dried over anhydrous sodium sulfate and evaporated at 40°C under reduced pressure. The residue was recrystallized from a mixture of ethanol and petroleum ether. 2.70 g (52.5% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-4-nitroanilide were obtained, m.p. 104 - 105°C, Rf = 0.47.

Analysis: calculated: C 55.7%, H 4.4%, N 11.2%;

found: C 55.6%, H 4.6%, N 11.3%.

b) Aminoxyacetic acid-4-nitrcanilide hydrobromide

2.40 g (0.007 mol) of N-benzyloxycarbonyl-aminooxyacetic acid-4-nitroanilide was treated according to example ] c) with 12 ml of hydrogen bromide solution in glacial acetic acid (4 mol/l), and the reaction mixture was worked up in the manner described there. 1.90 g (93% of theory) of aminooxyacetic acid-4-nitroanilide hydrobromide were obtained, m.p. 190°C,

R f = 0.37.

Analysis: calculated: C 32.9%, H 3.4%, N 14.4%, Br 27.4%;

found:' C 32.7%, H 3.5%, N 14.3%, Br 27.4%.

Example 22

a) N-benzyloxycarbonyl-amiroxyacetic acid-4-ethoxycarbonyl-anilide 4) 50 g (0.020 mol) N-benzyloxycarbonyl-aminooxyacetic acid was

according to example 21 transferred into the acid chloride, and the resulting chloride was dissolved in 20 ml of acetic acid ester. This solution was reacted in the manner described in example 22 with 2.48 g (0.015 mol) of 4-ethoxycarbonylaniline, and the reaction mixture was worked up in the usual manner. 2.86 g (51.7% of the theoretical) of N-benzyloxycarbonyl-aminooxyacetic acid-4-ethoxycarbonyl-anilide were obtained, m.p. 102 - 103°C, Rf =0.65.

Analysis: calculated: C 61.3%, H 5.4%, N 7.5%;

found: C 61.3%, H 5.4%, N 7.6%.

b) Aminoxyacetic acid-4-ethoxycarbonyl-anilide hydrobromide 1.40 g (0.0038 mol) N-benzyloxycarbonyl-aminooxyacetic acid-4-ethoxyanilide was reacted according to example 1 c) with 7.0 ml hydrogen bromide solution in glacial acetic acid (4 1 mol/1). 1.07 9 (88.5% of theory) of aminooxyacetic acid-4-ethoxycarbonyl-arylide hydrobromide was obtained, m.p. l88°Co

Analysis: calculated: C41.4%, H 4.7%, N 8.8%, Br 25.1%;

found: C 41.3%, H 4.7%, N 8.7%, Br 25.0%.

Example 25

a) DL- g- N- t- butoxycarbonyl- aminooxy- propionic acid- p- ethylanilide 2.20 g (0.0107 mol) DL-g<->N-t-butoxycarbonyl- aminooxypropionic acid

was reacted with 2.21 g (0.0107 mol) N,N'-dicyclohexylcarbodiimide and 1.30 g (0.0107 mol) p-ethylaniline according to example 1 a2), and the reaction mixture was worked up in the described manner. 2.6 l g (79% of the theoretical) DL-g<->N-t-butoxycarbonyl-aminooxyprop-

ionic acid p-ethylanilide, mp» 128 - 130°C, = 0.68.

Analysis: calculated: C 62.5%, H 7.8%, N 9.1%;

found: C 62.4%, H 7.9%, N 9.0%.

b) PL-g-aminooxy-propionic acid-p-ethylanilide hydrochloride 1.60 g (0.0052 mol) of DL-α-N-t-butoxycarbonyl-aminooxy-propionic acid-p-ethylanilide was reacted according to example 1 d) with 8.0 ml hydrogen chloride solution in acetic acid ester (4 mol/l), and the reaction mixture was worked up on the way described there. 1.00 g (78.5% of the theoretical) DL-α-aminooxy-propionic acid p-ethylanilide hydrochloride was obtained, m.p. 164 - 165°C.

Analysis: calculated: C 54.0%, H 7.0%, N 11.4%, Cl 14.5%;

found: C 54.1%, H 6.9%, N 11.3%, Cl 14.6%.

Example 24

a) g-N-t-butoxycarbonyl-aminooxy-propionic acid-2-methoxyanilide 2.27 g (0.01 mol) a-N-t-butoxycarbonyl-aminooxy-propionic acid

was reacted with 2.26 g (0.011 ir.ol) N,N'-dicyclohexylcarbodiimide and 1.12 ml (0.010 mol) o-anisidine according to example 1 a2), and the reaction mixture was worked up in the manner described there. 2.53 g (81.5% of the theoretical) g<->N-t-butoxycarbonyl-aminooxy-propionic acid-2-methoxyanilide were obtained, m.p. 84 - 85°C, [α]^ = +89°

(c = 1, ethanol), Rf = 0.7L

Analysis: calculated: C 58.0%, H 7.1%; N 9.0%;

found: C 57.9%, H 7.2%, N 8.9%.

b) g-amino-propionic acid-2-methoxyanilide-hydrochloride 0.62 g (0.002 mol) g<->N-t-butoxycarbonyl-aminooxy-propionic acid-2-methoxyanilide was reacted according to example 1 d) with 4.0 ml of hydrogen- chloride solution in acetic acid ester (4 mol/l). 0.42 g was obtained

(86% of theory) g<->aminooxy-propionic acid-2-methoxyanilide hydrochloride, m.p. 102 - 103C, [α]D = +75.7 (c = 1, ethanol).

Analysis: calculated: C 48.7%, H 6.1%, Cl 14.4%;

found: C 48.6%, H 6.2%, Cl 14.5%. ,

Example 2 5

a) α-N-1-butoxyca rbony1-aminooxy-(3-phenyl1-propionic acid-2-methoxyanilide

3.08 g (0.011 mol) g-N-t-butoxycarbonyl-aminooxy-|3-phenyl -

propionic acid was reacted according to example 1 a2) with 1.12 ml (0.010 mol) o-anisidine and 2.26 g (0.01 mol) N,N'-dicyclohexylcarbodiimide, and the reaction mixture was worked up in the usual way. 2.89 g (75% of the theoretical) of α-N-t-butoxycarbonyl-aminooxy-|3-phenyl-propionic acid-2-methoxyanilide, m.p. 122 - 124 o C [a.] D 25 = +113 o (c = 1, ethanol), Rf = 0.78.

Analysis: calculated: C 65.4%, H 6.8%, N 7.1%;

• found: C 65.3%, H 6.9%, N 7.0%.

b) g- aminooxy- P- phenyl- pr. ) pionic acid 2-methoxy-anilide hydrochloride 2.71 g (0.007 mol) g<->N-':-butoxycarbonyl-aminooxy-(3-phenyl-propionic acid-2-methoxyanilide) was reacted according to example 1d with 15 ml

hydrogen chloride dissolution sweep in acetic acid ester (4 mol/l), and the reaction mixture was worked up in the usual way. 1.85 g (82.5% of the theoretical) g-aminooxy-(3-phenyl-propionic acid-2-methoxyanilide hydrochloride) was obtained, m.p. 143 - 145°C, [α]^ = +63, 5° (c = 1, ethanol).

Analysis: calculated: C 59.6%, H 5.9%, Cl 11.0%;

found: C 58.7%, H 6.0%, Cl 11.1%.

Example 26

a) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-2-methoxyanilide 1.07 g (0.0039 mol) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid was reacted according to example 1 a2) with 0.31 ml (0 .0038 mol) of o-anisidine and 0.60 g (0.0039 mol) of N,N'-dicyclohexylcarbodiimide. After working up the reaction mixture in the usual way, 1.14 g (81% of the theoretical) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-2-methoxyanilide were obtained, m.p. 128 - 130°C, Rf = 0.70.

Analysis: calculated: c 64.5%, H 6.5%, H 7.5%;

found: C 64.4%, H 6.4%, N 7.4%.

b) DL-aminooxy-phenylacetic acid-2-methoxyanilide hydrochloride 0.80 g (0.0021 mol) of DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-2-methoxyanilide was reacted according to example 1 d) with 4.0 ml hydrogen chloride solution in acetic acid ester (4 mol/l). 0.52 g (80% of the theoretical) of DL-aminooxy-phenylacetic acid-2-methoxyanilide hydrochloride was obtained, m.p. 170 - 172°C.

Analysis: calculated: C 58.4%, H 5.5%, Cl 11.5%;

. found: C 58.4%, H 5.7%, Cl 11.5%.

Example 27

a) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-3-bromomanilide 1.96 g (0.0073 mol) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid was reacted according to example 1 a2) with 0.77 ml (0.007 mol) m-bromoaniline and 1.50 g (0.0073 mol) N,N'-dicyclohexylcarbodiimide.

2.32 g (84.5% of the theoretical) of DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-3-bromoanilide were obtained, m.p. 117 - H9°C, R^. = 0.8l.

Analysis: calculated: C 55.0%, H 5.4%, N 7.1%, Br 17.5%;

found: C 55.1%, H 5.4%, N 7.1%, Br 17.4%.

b) DL-aminooxy-phenylacetic acid-3-bromomanilide hydrochloride 1.22 g (0.0031 mol) DL-N-t-butoxycarbonyl-aminooxy-phenylacetic acid-3-bromomanilide was reacted according to example 1 d) with 10.0 ml of hydrogen chloride in acetic acid ester (4 mol/l), and the reaction mixture was worked up in the usual way. 0.739 (66.5% of the theoretical) DL-aminooxy-phenylacetic acid-3-bromoanilide hydrochloride was obtained, m.p. 162 - 163°C.

Analysis: calculated: C 47.1%, H 4.0%, N 7.8%, Br 9.9%;

found: C 46.9%, H 4.1%, N 7.8%, Br 10.0%.

Example 28

N-(g-aminooxy-propionyl)-aminooxyacetic acid-anilide-hydrochloride 2.27 g (0.005 mol) of α-N-t-butoxycarbonyl-aminooxy-propionic acid-pentachlorophenyl ester was dissolved in 20 ml of absolute dimethylformamide, the solution was added to 1.01 g (0.005 mol ) aminooxyacetic acid-anilide-dihydrochloride, and then 0.70 ml (0.005 mol) of absolute triethylaniline, the temperature of the reaction mixture being maintained at +20°C. The reaction mixture was then left at room temperature for 18 hours, the precipitated triethylammonium hydrochloride was filtered off, and the filtrate was evaporated at +50°C under reduced pressure. The residue was dissolved in 30 ml of acetic acid ester and first shaken with 3 x 7 ml of N hydrochloric acid, then with 10 ml of water, with 3 x 7 ml of molar sodium bicarbonate solution and finally with 10 ml of water. The separated organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo. To the residue was added 10.0 ml of 4 mol/l hydrogen chloride solution in acetic acid ester, and the mixture was stirred at room temperature for 20 minutes while excluding atmospheric moisture. Then 50.0 ml of absolute ether was added to the mixture, the separated crystals were filtered off and recrystallized from ethanol/ether. 1.15 g (79.5% of theory) of N-(α-aminooxy-propionyl)-aminooxyacetic acid-anilide hydrochloride were obtained in this way, m.p. 148 - 151 C, [α]^ = +58.5

(c = 1.5, ethanol).

Analysis: calculated: C 47.3%, H 5.4%, N 14.0%, Cl 11.9%;

found: C 47.2%, H 5.6%, N 14.1%, Cl 12.1%.

Example 29

N-carbamoyl- aminooxyacetic acid anilide

1.40 g (0.0075 mol) of aminooxyacetic acid anilide hydrochloride was dissolved in 7.0 ml of water, 7.5 ml of N hydrochloric acid was added to the solution,

and then, with stirring, C.67 g (0.00825 mol) of solid potassium cyanate was added in small portions. The mixture was stirred further for 30 minutes at room temperature, then the separated crystals were filtered off, washed with water, dried and recrystallized from ethanol. 1.26 g (81% of the theoretical) of N-carbamoyl-aminooxyacetic acid anilide were obtained, m.p. 134 - 135°C.

Analysis: calculated: C 51.6%, H 5.3%, N 20.1%;

found: C 51.6%, H 5.4%, N 20.1%.

Example 30

N- carbamoyl- aminooxyacetic acid- 2- methoxyanilide

2.15 g (0.010 mol) aminooxyacetic acid-2-methoxyanilide hydrochloride was dissolved in 10 ml of water, 10 ml of N hydrochloric acid was added to the solution, and then 0.89 g (0.01 mol) was added at room temperature with stirring solid potassium cyanate in small portions. The reaction mixture was worked up in the manner described in example 29, and 1.80 g (75% of the theoretical) of N-carbamoyl-aminooxyacetic acid-2-methoxyanilide, m.p. 151 - 152°C.

Analysis: calculated: C 50.2%, H 5.5%, N 17.5%;

found: C 50.3%, H 5.6%, N 17.4%.

Example 31

Aminoxyacetic acid t-butylamide hydrobromide

4.73 g (0.010 mol) of N-benzyloxycarbonyl-aminooxyacetic acid-pentachlorophenyl ester was dissolved in 25 ml of absolute dioxane, 1.25 ml (0.012 mol) of t-butylamine was added to the solution and left at room temperature for 24 hours. The solvent was then evaporated at 50°C

under reduced pressure, and the residue was dissolved in 30 ml of acetic acid ester. The solution was shaken with 3 x 10 ml of N hydrochloric acid, and then once with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue was stirred with 5.0 ml of 3.5 mol/l hydrogen bromide solution in glacial acetic acid for 30 minutes at room temperature, while excluding air humidity, and then 50 ml of absolute ether was added to the mixture. The separated crystals were filtered off and recrystallized from ethanol/ether. 0.75 g (55% of the theoretical) aminooxyacetic acid —t-butylamide hydrobromide, m.p. 143 - 144°C, Rf = 0.18

(in the system acetic acid ester-pyridine-glacial vinegar-water 18:6:1.8:3.3).

Analysis: calculated: C 49.0%, H 10.3%, Br 19.1%;

found: C 48.9%, H 10.4%, Br 19.1%.

Example 32

α- Aminoxy-£-aminocaproic anilide-dihydrobromide 3.16 g (0.0054 mol) of α-N-t-butoxycarbonyl-aminooxy-C-N'-benzyloxycarbonyl-aminocaproic acid-dicyclohexylammonium salt was suspended in 50 ml of ether and extracted with 4 x 20 ml of O, 2 N sulfuric acid. The separated organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. 2.20 g of an oily residue was obtained which was dissolved in 15.0 ml of absolute dioxane, the solution was cooled to +5°C and 0.51 ml (0.0054 mol) of aniline and 1.12 g (0.0054 mol ) N,N<1->dicyclohexylcarbodiimide. The mixture was left at room temperature for 16 hours. The precipitated N,N<1->dicyclohexylurea (1.10 g, 91% of theory) was removed by filtration and the filtrate evaporated at 50°C under reduced pressure. The residue was dissolved in 20 ml of acetic acid ester and the solution washed with 2x5 ml of N hydrochloric acid, once with 5 ml of water, then with 2x5 ml of molar sodium bicarbonate solution and finally again with 5 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced Print. The residue was dissolved in hot chloroform, an equal volume of n-hexane was added to the solution and allowed to cool. The precipitated crystals were filtered off and dried. 1.54 g (61% of the theoretical) α-aminooxy-α-aminocaproic anilide was obtained, m.p. 64 - 65°C, [o.]^<0>"<=><+>66°

(c = 1, ethanol), Rf = 0.78.

1.0 g (0.0021 mol) of the above product was stirred for 30 minutes at room temperature with 10.0 ml of 3.5 mol/l hydrogen bromide solution in glacial acetic acid, then 100 ml of absolute ether was added to the mixture, the separated hygroscopic cry ::oduct was filtered out and re-

crystallized from ethanol/ether. In this way, 0.62 g (74% of the theoretical) of a-aminooxy-fc-aminocaproic acid anilide-

dihydrobromide, m.p. 130°C, (dec.), [a.]^<8>= +31° (c = 1, ethanol).

Analysis: calculated: C 36.1%, H 5.3%, Br 40.1%; -

found: C 36.1%, H 5.4%, Br 40.2%.

Claims (1)

Analogous method for the preparation of new, therapeutically active α-aminooxycarboxylic acid derivatives of the general formula: where X is hydrogen, lower alkanoyl, amino-lower alkanoyl or aminooxy-lower alkanoyl, R is hydrogen, lower alkyl, amino-lower alkyl, phenyl or benzyl, and Z is lower alkyl, cycloalkyl with up to 6 carbon atoms, one optionally with a or two lower alkyl-, lower alkoxy, lower alkoxycarbonyl, hydroxy, halogen or nitro groups substituted phenyl or benzyl group, or a pyridyl group, and their therapeutically acceptable acid addition salts, characterized in that an α-aminooxycarboxylic acid derivative of the general formula: where A is lower alkanoyl, or an optionally protected amino-lower alkanoyl or aminooxy-lower alkanoyl group, or when X in the product to be prepared is hydrogen, a protecting group suitable for transient protection of the amino group, e.g. a benzyloxycarbonyl or t-butoxycarbonyl group, B is hydroxyl or a group suitable for activating the carbonyl group, preferably a pentachlorophenoxy group, a halogen atom or an N^ group, and R is, as indicated above, reacted with an amine of the general formula: where Z is as stated above, and that where possible from the obtained reaction product with the general formula: where A, R and Z are as stated above, in a manner known per se, the protecting group introduced for preliminary protection of the amino group is cleaved off, and that optionally the obtained compound of formula I is transferred into a therapeutically applicable acid addition salt, and/or optionally the the compound obtained is N-acylated.