DE1163337B - Process for the preparation of trihydroxamic acids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school KL: C 07 c;

C07d

German class: 12q-13

Number: 1 163 337

File number: C 25241IV b / 12 q

Filing date: October 10, 1961

Opened on: February 20, 1964

· * · Method of manufacture

The German patent 1,123,436 describes the production of trihydroxamic acids

the ferrioxamines as well. As stated there

the latter are compounds containing iron and nitrogen. The iron can be removed from them, if you mix the red-brown, a ferrioxamine-containing solution with a mineral acid or a strong Alkali treated. The colorless solution obtained in this way and containing a desferri-ferrioxamine is allowed to enter Ferric salt, e.g. B. iron (III) chloride act, it shows again the typical for the ferrioxamines Coloring.

It has now been found that the desferri-ferrioxamines are 7,18,29-trihydroxy-8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-triacontanes. Desferri-ferrioxamine B is the 30-methyl derivative, Desferri- 15 ferrioxamine G is the 30- (jS-carboxyethyl) derivative, Desferri-ferrioxamine D _{1 is} the 1-acetyl-30-methyl derivative of 7,18,29 - trihydroxy - 8, 11,19,22,30 - pentaoxo-1,7,12,18,23,29-hexaaza-triacontans and desferri-ferrioxamine E is the 33-membered, ring-closed compound in which the terminal carboxyl group in the 30- (jS -Carboxyethyl) -7,18,29-trihydroxy-8, ll, 19,22,30-pentaoxo-l, 7,12,18,23,29-hexaaza-triacontane is connected to the N ₁ -atOM. 2

The invention relates to a process for the preparation of trihydroxamic acids of the general formula

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dipl.-Ing. E. Splanemann, patent attorney,

Hamburg 36, Neuer Wall 10

Named as inventor:

Dr. Ernst Gäumann,

Dr. Vladimir Prelog, Zurich,

Dr. Hans Bickel, Binningen,

Dr. Ernst Vischer, Basel (Switzerland)

Claimed priority:
Switzerland of October 11, 1960 (No. 11 395)
Switzerland of November 23, 1960 (No. 13 147)
Switzerland of April 7, 1961 (No. 4075)
Switzerland of August 11, 1961 (No. 9451)
Switzerland of September 27, 1961 (No. 11 208)

R ₁ -HN- (CH ₂ ) ₅ —N —C— (CH _a ) ₂ - CNH- (CHa) ₆ -NC- (CH ₂ ), —CNH-

R ₂ OO

R ₂ O O

¹ AN v ^ vy ** ~~~ Avg

R ₂ O

in which R _{1 is} hydrogen, an acyl radical or the 2,4-dinitrophenyl radical, R ^ is hydrogen or an acyl radical, CO - R _{3 is} an acetyl or free or esterified succinyl _{radical or R 1} and R ₃ together represent the remainder of succinic acid, whose second carboxyl group is connected to the N ¹ atom, the salts and metal complexes of these compounds.

An acyl radical R ₁ or R ₂ is, for. B. an aliphatic acyl radical, in particular an alkanoyl or alkenoyl radical, such as the formyl, acetyl, propionyl, butyryl, valeryl, stearyl or oleyl radical, or a substituted alkanoyl radical, e.g. B. a free or functionally modified, z. B. esterified succinyl or glutaryl, or an amino acid residue, in particular one of the natural "amino acid residues, such as the glycyl, alanyl, valyl or leucyl residue, also an aroyl and aralkanoyl residue, for example an unsubstituted or substituted benzoyl residue, such as salicyl -, p-Hydroxy-benzoyl, p-amino-salicyl, p-methoxy-benzoyl, p-ethoxy-benzoyl, p-ethoxy-ethoxy-benzoyl or p-ethoxy-polyethyleneoxy-benzoyl, a naphthoyl, free or esterified Phthaloyl, carbobenzoxy or phenylacetyl radical.

_{If R 1} does not represent an acyl radical, the trihydroxamic acids of the above formula are bases which form salts with acids. For the preparation of such salts, especially therapeutically applicable acids are used, either inorganic acids, e.g. B. hydrohalic acids, such as hydrochloric acid or hydrobromic acid, further perchloric acid, nitric acid or thiocyanic acid, sulfuric or phosphoric acids, or organic acids such as formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, Amber, maleic, fumaric, malic, tartaric, citric, benzoic, phenylacetic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic acid.

The O-unsubstituted compounds also show acidic character and can therefore with bases Form salts. The latter are preferably those of

409 509/440

therapeutically applicable alkali or alkaline earth metals, such as sodium, potassium or calcium, or of organic bases, e.g. B. aliphatic amines. The O-unsubstituted compounds can continue to form metal complexes. Preferred metals for this purpose are above all those of a physiological type Meaning, in particular iron, cobalt or magnesium, also copper or antimony.

Due to their properties with metals, e.g. B. to form the above-mentioned, very stable complexes, the process products have valuable pharmacological properties. So they prevent z. B. the Deposition of iron-containing pigments in the tissue or in cases of iron deposition in the Organism excretion of iron, e.g. B. in hemochromatosis and hemosiderosis as well as in Cirrhosis of the liver. They can also be used to eliminate other metals from the body be e.g. B. of copper. The metal complexes of these compounds, primarily the iron and cobalt ao complex, have anti-anemic properties and can accordingly be used as remedies, for example in bleeding anemia and iron deficiency anemia. Also as starting or intermediate products the compounds mentioned above can be used for the production of other valuable substances.

Particularly valuable compounds are the abovementioned process products corresponding to the desferri-ferrioxamines B, G, E and D ₁ and their salts.

The trihydroxamic acids mentioned above are obtained when one

a) l-Arylamino-5-hydroxylaminopentanes of the general Formula I.

R ₁ '- NH - (CHo) ₅ - NHOH

in which R ₁ 'represents an acyl radical, with functional derivatives of succinic acid either to form 1-amino-5- (N-succinylhydroxylamino) pentanes of the formula II

R ₁ '- NH - (CH ₂ ) ₅ - NH - CO - (CH ₂ ) ₂ - COOH

OH

(Π)

or from it by dehydration to give N- (5'-aminopentyl) -tetrahydro-3,6-dioxo-1,2-oxazines of formula III

CO

R ₁ '- NH - (CH ₂ ) ₅ - N
O

CH ₂
CH ₂

(III)

CO

condensed, the acyl radical R ₁ 'is split off and the free amino compound is reacted with a compound of the formula II or III to give l-amino-6,17-dihydroxy-7,10,18-trioxo-20-carboxy-6, l 1,17 -triaza-eikosanen of the general formula VI

R ₁ '- NH - (CH ₂ ) ₅ - N - CO - (CH ₂ ), - CO - NH - (CH ₂ ) ₅ - N - CO (CH ₂ ) ₂ - COOH

OH

or the corresponding oxazines of the formula V

OH

(IV)

R ₁ '- NH - (CH _{2) 5} - N - CO - (O) ₂ - CO - NH - (CH _{2) ä} - N

OH

CO

CO

CH ₂
CH ₂

(V)

condensed, this with l-amino-5- (N-acylhydroxylamino) pentanes or l-amino-5- (N, O-diacylhydroxylamino) pentanes of formula IV

NH ₂ - (CH ₂ ) ₅ - N - R ₃

! (VI)

OR ₃ '

in which R ₃ 'is hydrogen or R ₃ to l-amino-6,17,28-trihydroxy-7,10,18,21-tetraoxo-28-acyl-6,11,17,21,28-pentaaza -oktaeikosanen of the general formula VII

R ₁ 'NH (CH ₂ ) ,,

CO- (CHo) ₂ CO NH- (CH ₂ ) ₅ N-CO- (CH ₂ ) ₂ CO NH- (CH ₂ ) ₅ N-CO R ₃

OH OH

OH

or the 29-COR ₃ derivative or

b) a compound of the formula II or III is reacted with l-amino-5-nitropentane, the resulting nitro compound reduced to the hydroxylamino compound and this with a functional derivative of succinic acid to a compound of formula IV or V and then either treated as under a) or condensed again with l-amino-5-nitropentane, the compound thus obtained to the hydroxylamine derivative reduced and then acylated to compound VII or its tri- (O-acyl) derivative or

(VII)

c) a compound of formula II or III is condensed with l-amino-5-nitropentane, the nitro compound obtained is reduced to the hydroxylamino compound, this is acylated, the group R ₁ 'is split off and the compound obtained is reacted again with a compound of formula II or III or

d) a compound of the formula II or III is reacted with 1-amino-5- (N-acylhydroxylamino) pentane, the group R ₁ 'is split off and the free amino compound obtained is in turn condensed with a compound of the formula II or III or

e) l-amino-5-nitropentane with a functional Derivative of succinic acid to form 1-succinylamino-5-nitropentane converts this to the 5-hydroxylamino compound of the formula VIII

HOOC - (CH ₂ ) ₂ - CO

NH - (CH ₂ ) ₆ - NHOH (VIII)

The compounds obtained according to the process can be in the form of pharmaceutical preparations Find use.

The invention is described in the following examples.

example 1 a) l-carbobenzoxyamino-5-nitropentane (II)

13.2 g of l-amino-5-nitropentane (I) [prepared according to H. Bicke 1 et al., HeIv. Chim. Acta, Vol. 43 (1960), P. 904] are taken up in 1 l of acetone and mixed with 11 Ο, ΐη sodium bicarbonate solution. On that are added while cooling with ice and stirring vigorously

Depending on the method of operation, the compounds are obtained in free form or in the form of their salts. From the The free compounds can be obtained from salts in a manner known per se. The latter can 5 likewise by known methods either in the aforementioned acid addition salts or, if appropriate the alkali or alkaline earth metal salts or the salts of organic bases are converted.

The conversion of the O-unsubstituted Verbinreduziert, fertilize the carboxyl group by esterification io in the metal complex is carried out by re-blocking, the ester with the Ο, Ν-diacetylation setting of the first condensed with a corresponding metal product of compound VIII and the salt, for example the salt of a Mineral acid, such as condensation product after cleavage of the ester, a metal chloride, sulfate or nitrate, or the group with a compound of the formula I reacts salt of an organic acid, such as a metal acetate and optionally from the 15 or - sulfonate, or by reacting the first with products, the group R ₁ 'is split off and given metal alcoholates ^ for example metal ethylates. if compounds in the 1-position are free
Amino group and in the 28-position have a succinic acid residue, with the formation of an amide bond
between the amino group and the second carboxyl-20
group of succinic acid ring closes by means of a carbodiimide and optionally with the according to a)
to e) products obtained salts with inorganic salts
or organic acids without pharmacological
Own effect or iron, cobalt, magnesium, 25
Copper and antimony complexes and or or
Acylation products or l-amino (2 ', 4'-dinitrophenyl) derivatives.

Functional derivatives of succinic acid are z. B.

the anhydride, azide, imide or imidazolide. 30 17.0 g carbobenzoxy chloride, dissolved in 200 ml water

A free, free tetrahydrofuran, which is not involved in the condensation, is slowly admitted and the carboxyl group is expediently left to ^{stand at 0} ° C. for 7 hours by esterification. After completion of the reaction z. B. with methanol, benzyl alcohol or p-nitro, the bulk of the acetone benzyl alcohol is protected in a vacuum. evaporated and the remaining aqueous solution

If the condensation on the free carboxyl 35 is shaken out five times with 100 ml of chloroform each time, group is carried out, one preferably uses a condensing agent such. B. a carbodiimide such as dicyclohexylcarbodiimide.

In the method according to the invention has been found to be

the formation of the N-substituted 40 5-nitropentane with a melting point of 53 ° C. is particularly advantageous. Tetrahydro-3,6-dioxo-1,2-oxazines (compounds III

and V) proved. These can be obtained from the corresponding b) 1-carbobenzoxyamino-S-hydroxylaminopentane (III) open-chain compounds (compounds II and IV)

by treatment with a condensing agent, 24.0 g of 1-carbobenzoxyamino-5-nitropentane become

z. B. a carbodiimide such as Dicyclohexylcarbodi- 45 dissolved in 400 ml of moist 1,2-dimethoxyethane and imid. In a single process step together with 60 g of freshly prepared aluminum, both the terminal amalgam is stirred for 4 hours at 0 ° C. Then the Carboxyl group reactively modified as well as aluminum oxide sludge filtered off and the filtrate the N-hydroxy group is protected. evaporated. The evaporation residue (16.6 g) is

In the compounds thus obtained, in which R ₁ '- 5 ° according to a paper chromatogram (toluene-n-buta system, also a hydrogenolytically separable nol-saturated water) practically uniform. The acid residue, e.g. B. represents the carbobenzoxy radical, can
this can be cut off in a manner known per se.
Compounds obtained with a free α-amino group
can be acylated by known methods, 55
for example with an acid anhydride in buffered
alcoholic solution or with an acid halide,
in an aqueous, weakly alkaline medium. Any O-acyl derivatives formed can 7. B.
by the action of ammonia in the O-unsub- 60
substituted N ¹ * acyl compounds are converted.
The substitution of the α-amino group by the
2,4-Dinitrophenyl also takes place by itself
known methods.

In the compounds obtained with free carboxyl 65 6.4 g succinic anhydride and 15 hours group, z. B. in Desferri-ferrioxamine G, the free can be left to stand at 22 ⁰ C under a nitrogen atmosphere. Carboxyl group according to the methods known in peptide chemistry. The pyridine is then evaporated in vacuo to be esterified. away. The residue [l-carbobenzoxyamino-S-tN-succi-

The one with a little 2N hydrochloric acid, saturated sodium bicarbonate solution and water washed and dried over sodium sulfate chloroform extracts on evaporation 25.8 g of 1-carbobenzoxyamino-

Hydroxylamine obtained forms a hydrochloride with a temperature of 83 to 85 ° C, which is easily soluble in ethanol and Is chloroform.

In an analogous manner, 1-benzoylamino-5-nitropentane can be used the 1-benzoylamino-5-hydroxylaminopentane hydrochloride has a melting point of 78 ° C from 132 to 133 ° C.

c) 1 -Carbobenzoxyamino-S-iN-succinylhydroxyl-

amino) pentane (IV) and N- (5 '~ carbobenzoxyaminopentyl) tetrahydro-3,6-dioxo-1,2-oxazine (V)

16 grams of l-carbobenzoxyamino-5-hydroxylaminopentane (III) are dissolved in 150 ml of absolute pyridine, with

nylhydroxylamino) pentane, 20.5 g], recrystallized from ethanol-diethyl ether, melts at 115 to 116 ° C. Heating with dicyclohexylcarbodiimide gives N- (5'-carbobenzoxyaminopentyl) tetrahydio-3,6-dioxo-1,2-oxazine, which melts at 84 to 85 ° C. after crystallization from diethyl ether. In an analogous manner, 1-benzoylamino-5-hydroxylaminopentane is used to obtain l-benzoylamino-5- (N-succinylhydroxylamino) pentane with a melting point of 114 ° to 115 ° C., a compound which is readily soluble in ethanol and ethyl acetate and sparingly soluble in diethyl ether, and from this the N - (5 '- Benzoylaminopentyl) - tetrahydro-3,6-dioxo-1,2-oxazine from a temperature of 104 to 106 ^° C.

d) 1-carbobenzoxyamino-5- [N- (5'-nitropentylamino-succinyl) -hydroxylamino] -pentane (VI)

20.0 g of N- (5'-carbobenzoxyaminopentyl) tetrahydro-3,6-dioxo-1,2-oxazine (V) are dissolved together with 8.0 g of 5-nitro-1-aminopentane in 300 ml of tetrahydrofuran and heated to boiling for _{2V for 2} hours under a nitrogen atmosphere. After evaporation in vacuo, 27.1 g of crude 1-carbobenzoxyamino-5 - [N - (5 '- nitropentylamino - succinyl) - hydroxylamino] pentane are obtained. This is chromatographed on 1 kg of silica gel. The portions (10.3 g) that can be eluted with chloroform-methanol (9: 1) contain, strongly enriched, the compound VI (an acidic group titratable, iron chloride test positive), it melts at 104 to 105 ^° C.

In an analogous manner, N- (5-benzoylaminopentyl) tetrahydro-3,6-dioxo-1,2-oxazine is obtained the 1 - benzoylamino - 5 - [N - (5 '- nitropentylaminosuccinyl) hydroxylamino] pentane from 114 to 116 ° C, a readily soluble in ethanol, in ethyl acetate and chloroform-soluble and sparingly soluble in diethyl ether compound.

benzoxyamino - 5 - [N - (5 '- hydroxylaminopentylamino-succinyl) hydroxylamino] pentane, that is used directly.

1-Benzoylamino-5 is obtained in an analogous manner from the corresponding 1-benzoylamino derivative - [N - (5 '- hydroxylaminopentylamino-succinyl) -hydroxylaminoj-pentane, its 5'-monoacetyl derivative melts at 165 ° C; the triacetyl derivative was called colorless viscous oil obtained. The 5'-monoacetyl derivative can be obtained from N- (5'-benzoylamino-pentyl) -tetrahydro-3,6-dioxo-1,2-oxazine [see. d] by reaction with 1 - amino - 5 - (N - acetyl - hydroxylamino) pentane getting produced.

f) l-carbobenzoxy-5- {N- [5 '- (tetrahydro-3 ", 6" -dioxo-1 ", 2" -oxazin-2-yl) -pentylamino-
succinyl] hydroxylamino} pentane (VIII)

6.3 g (VII) are mixed with 1.4 g of succinic anhydride ao in 60 ml of absolute pyridine, as indicated under c), implemented. This results in 7.4 g (VIII).

g) l-carbobenzoxy-8,11,19,22,30-pentaoxo _a5 1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-

30-methyl-triacontane (IX)

A conversion carried out analogously to paragraph d) of 7.3 g (VIII) with 2.2 g of l-amino-5- (N-acetyl-hydroxyI-amino) pentane in 100 ml of tetrahydrofuran yields 9.4 g of crude (IX) which is chromatographed on 350 g of silica gel will. (IX) is found again in the fractions (3.8 g) eluted with chloroform-methanol (7: 3).

Instead of using l-amino-5- (N-acetyl-hydroxylamino) pentane, (VIII) can also be used with l-amino-5- (N-succinyl - monomethyl ester) - O - acetyl - hydroxylaminopentane of the formula

H ₈ N

- N - CO - (CH ₂ ) ₂ - COOCH ₃

e) l-carbobenzoxyamino-5- [N- (5'-hydroxylaminopentylamino-succinyl) -hydroxylamino] -

pentane (VII) ₄₀ OCO-CH ₃

10.0 g of the compound (VI) obtained according to d) react, which is obtained from (IV) by esterification, acetylic

are in the same way as described in b), with generation and hydrogenolytic cleavage of the carbon

30 g of aluminum amalgam in 100 ml of moist 1,2-dibenzoxy group had been prepared. The received

methoxyethane reduced. 6.5 g of 1-carbo- (IXa) is obtained, which has the formula

<f ... _{- CH 2} O - CONH - (CH ₂ ) S- N-CO - (CHg) ₂ -CONH- (CH ₂ ) S- N- CO

OH OH

- CONH N - CO - (CHa) ₂ -CO-OCH ₃
j
Ο —COCH ₃

h) 1-carbobenzoxy-8,11,19,22,30-pentaoxo-

1,7,12,18,23,29-hexaaza-7,18,29-triacetyloxy-

30-methyl-triacontane (X)

A slow stream of ketene is passed into an ice-cooled solution of for 1 hour 3.7 g (IX) in 200 ml tetrahydrofuran. It is then evaporated in vacuo in 200 ml of ethyl acetate taken up and washed with a little 2N hydrochloric acid, 2N sodium carbonate and water. the Leaves a solution dried over sodium sulfate

6o on evaporation 3.1 g (X) as a colorless, neutrally reacting resin.

i) 8,11,19,22,30-Pentaoxo-l, 7,12,18,23,29-hexaaza-7,18,29-triacetyloxy-30-methyl-triacontane (XI)

3.0 g of (X), dissolved in 100 ml of glacial acetic acid, are hydrogenated at 22 ° C. in the presence of 300 mg of 10% palladium carbon. After 1 mole of hydrogen has been taken up (about ½ hour), the reaction has ended. To
Filter off the catalyst and evaporate the
The filtrate in vacuo gives 2.4 g (XI).

10

k) S.lU ^^ SO-Pentaoxo-lJ.l ^ lS ^ a ^ -hexaaza- C ₅₃ H ₆₄ O ₁₂ N ₆ :

7,18,29-trihydroxy-30-methyl-triacontane (XII) Calculated ... C 65.14, H 6.60%;

found ... C 65.40, H 6.55%.

2.3 g (XI) are dissolved in 50 ml with ammonia at ⁰ ° C.

dissolved in saturated methanol and stand for 18 hours- 5 m) l-benzoyl-8.il, 19,22,30-pentaoxo-l, 7,12,18,

calmly. After evaporation of the solution, 23,29-nexaaza-7,18,29-tnhydroxy-30-methyl-

one 2.1 g of a powder, which three times with diethyl triacontane (XIV)

ether is extracted. (XII) remains as insoluble 275 mg (XIII) are ^{saturated in 25 ml at 0} ° C

Residue (1.4 g). For further purification, (XII) methanolic ammonia is dissolved and 16 hours

dissolved in a minimum of methanol and left to stand with io. The evaporation residue becomes four times

Diethyl ether precipitated. (XII) represents the 30-methyl extracted with ether and the one insoluble in ether

7,18,29 - trihydroxy - 8,11,19,22,30 - pentaoxo-1,7,12, compound (XIV) recrystallized from methanol,

18,23,29-hexaaza-triacontane (Desferri-ferrioxamine B) F. 179 to 181 ⁰ C.

whose hydrochloride melts at 171 to 173 ° C. C ₃₂ H ₅₂ O ₉ N ₆ :

Its 1-acetyl derivative melts at 185 ⁰ C. 15 Calculated ... C 57.81, H 7.88, N 12.66%;

The (IXa) described in g) can be found under h) ... C 57.61, H 8.10, N 12.45%.
described further acetylated and according to i) and k)

decarbobenzoxylated and deacetylated. One (XIV) agrees according to the melting point and mixer hold so the 30 - (/? - carbomethoxyethyl) -7,18,29-tri-melting point corresponds to the corresponding hydrohydroxy - 8,11,19,22,30 - pentaoxo - 1,7,12,18,23, 20 lysate from the Ο, Ο ', Ο' ', Ν-tetrabenzoyl derivative of 29-hexaaza-triacontane. Ferrioxamine B.

n) iron trihydroxamate complex of 8,11,19,22,30-

1-v 1 t> 1 ο 11 m -νon * 1 τ <i 10 -η Pentaoxo-l, 7,12,18,23,29-hexaaza-

1) l-Benzoyl-8 11 19,22,30-pentao _X ol, 7,12 18,23, 7,18,29-trih _y droxy-3b-methyl-triacontans (XIIa)

29-hexaaza-7,18,29-tπbenzoyloxy-30-methyl-trl- 25 '' ^{JJJ v} '

acontan (XIII) 500 mg (XII) are taken up in 100 ml of water and 400 mg of iron (III) containing water of crystallization -

280 mg (XII) are added to 30 ml Ο, ΐη sodium hydroxide solution chloride (FeCl ₃ 6 H ₂ O) in 20 ml water,

dissolved, mixed with 350 mg of benzoyl chloride and the reaction mixture immediately

IV shaken at 0 ^° C. for _{2 hours.} Five times extra 30 oxamine takes on typical color. After 15 minutes

hieren the reaction mixture with chloroform, standing shaken three times with 20 ml of chloroform

Dry the extract over sodium sulfate and form-phenol (1: 1), wash the extracts with it

Evaporation of the same gives an oily residue, a little water and treated with 200 ml of diethyl

ether precipitates from methanolic solution with water, whereupon the iron trihydroxamate complex des

becomes [290 mg (XIII)]. Drying for analysis: 35 8,11,19,22,30 - Pentaoxo - 1,7,12,18,23,29 - hexaaza-

12 hours at 8O ⁰ C and 0.001 Torr over phosphorus 7,18,29 - trihydroxy - 30 - methyl - triacontans, ferric

pentoxide. oxamine B, in the form of the hydrochloride of the formula XIIa

Cl ⁹ H ₃ N- (CH ₂ ) ₅ - NC- (CH ₂ ) ,, - CONH- (CH ₂ ) ₅ - N - C- (CHg) ₂ -CONH- (CH ₂ ) ₅ --N - C- CH ₃

IiI I!

ο ο!

precipitates as an amorphous, red-brown precipitate. The phes, orange powder (XIIb), which after three times

Preparation washed several times with diethyl ether, precipitated and dried for analysis at 70 ° C

agrees in the following properties with authentic and 0.01 Torr over phosphorus pentoxide the following

Material corresponds: absorption spectra in the UV, visual composition has:

baren and IR; Paper chromatogram, electro 50

phoresis, antagonism test with ferrimycins and ^ 31H ₄₇ Ui _{2 8} e.

N- (2,4-dinitrophenyl) derivative [cf. O)]. Calculated ... C 47.76, H 6.08, N 14.38, Fe 7.16%;

,,,, "," ^. Found ... C 43.31, H 6.38, N 13.93, Fe 7.02%. o) iron trihydroxamate complex of l- (2,4-dinitro-

a!; d?! ^ t \; ™; 55 Even according to the UV absorption spectrum, there is

aza-7,18,29-tnhydroxy-30-methyl-tnacontans (XIIb) _dukt χιν identical to the authentic derivative

A solution of 225 mg (XIIa) and 225 mg of ferrioxamine B.

Sodium bicarbonate in 15 ml of water is added to 225 mg. ■ ι τ

2,4-Dinitrofluorobenzene in 15 ml of ethanol and Example λ

Left to stand at 23 ^° C. for 5 hours. Then 60 (in this example with Roman numerals

If the ethanol is distilled off in vacuo, the products labeled extracted are identical to those in Example 1

the aqueous phase is identical twice with 30 ml of diethyl ether each time specified in the formula.)
and finally four times with 30 ml of n-butanol each time. the

washed with water and in vacuo _a ) l-carbobenzoxyamino-5-nitropentane (II)

Steamed butanol extracts contain the reddish brown 63

Complex. It is taken up in acetone, which is added to a mixture of 4.1 g of l-amino-5-nitro-

Solution of insolubles filtered off and the filtrate pentane hydrochloride, 20 ml of water and 1.43 g of potassium

treated with diethyl ether. 176 mg of amorlium hydroxide are obtained and 4.5 g ^{are left with stirring at 0 ° C}

Add dropwise carbobenzoxychloride and a solution of 2 g of potassium hydroxide in 10 ml of water, stir then continue for another 10 minutes, acidify weakly with hydrochloric acid and extract the reaction mixture with it Chloroform. The chloroform extract is made with sodium bicarbonate solution washed, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from diethyl ether-petroleum ether, and 1-carbobenzoxyamino-5-nitropentane (II) is obtained with a melting point of 52 to 53 ° C .; Yield 85%

b) l-carbobenzoxyamino-5-hydroxylamino
pentane (III)

A solution of 2 g (II) in 40 ml of ethanol is mixed with a solution of 3 g of ammonium chloride in 30 ml of water and 10 drops of concentrated aqueous ammonia, and 1.5 g of zinc dust is added within 5 to 10 minutes while stirring. Stirring is continued for a further 15 minutes and takes care ao that the temperature does not exceed 30 ^0C. The reaction mixture is then filtered through cellulose powder, the filtrate is evaporated in vacuo, the residue is dissolved in 50 ml of 2N hydrochloric acid and the solution is extracted with ether. The aqueous phase is then made alkaline with aqueous ammonia, extracted with chloroform and the dried chloroform extract is concentrated. When ether is added to the residue, 1-carbobenzoxyamino-5-hydroxylaminopentane (III) crystallizes out; M.p. 102 to 104 ° C. Its hydrochloride melts at 83 to 85 ° C; Yield 71%.

c) 1 -Carbobenzoxyamino-S-iN-succinylhydroxylamino) pentane (IV)

35

A mixture of 1.85 g (III), 20 ml of pyridine and 1.1 g of succinic anhydride is heated IV for ₂ hours to 85 ° C., then the pyridine is evaporated in vacuo and the residue is taken up in chloroform. The chloroform solution is shaken with potassium bicarbonate solution, the last one is then weakly acidified with hydrochloric acid and extracted four times with ethyl acetate. After evaporating the dried extract, 1-carbobenzoxyamino-5- (N-succinylhydroxylamino) pentane (IV) is obtained, which melts at 115 ° C. after being redissolved from ethyl acetate-methanol; Yield 70%.

d) N- (5'-carbobenzoxyaminopentyl) tetrahydro-3,6-dioxo-1,2-oxazine (V)

A mixture of 2.865 g (IV), 1.88 g of dicyclohexylcarbodiimide and 50 ml of absolute tetrahydrofuran is allowed to stand for 2 days at room temperature, the precipitated dicyclohexylurea is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in ethyl acetate and the solution is left to stand in the refrigerator. After a little precipitated dicyclohexylurea has been filtered off, ether is added to the filtrate, whereupon the N- (5'-carbobenzoxyaminopentyl) -tetrahydro-3,6-dioxo-1,2-oxazine (V) formed separates out in colorless needles; M.p. 84 to 85 ° C; Yield 70 ° / ₀ . If the reactions specified under a) to d) are carried out without the respective separation and purification of the intermediate products obtained, (V) is obtained in a total yield of 51%

e) 1-carbobenzoxyamino-5- [N- (5'-nitropentylamino-succinyl) -hydroxylamino] -pentane (VI)

A solution of 1.2 g (V) and 1 g of 1-amino-5-nitropentane hydrochloride in absolute methanol is mixed with a solution of 0.32 g of sodium methylate in methanol. After the mixture has been heated to approximately 50 ^° C. for half an hour, the sodium chloride which has separated out is filtered off and the filtrate is evaporated in vacuo. The residue is crystallized from methanol-ethyl acetate, l-carbonbenzoxyamino-5- [N- (5'-nitropentylamino-succinyl) -hydroxylamino] pentane (VI) having a melting point of 114 ° to 116 ° C. being obtained; Yield 88%.

f) 1-carbobenzoxyamino-5- [N- (5'-hydroxyl-

aminopentylamino-succinyl) -hydroxylamino] -

pentane (VII)

A solution of 0.85 g (VI) in 20 ml of ethanol is mixed with 15 ml of 10% strength and while stirring ammonium chloride solution alkalized with a few drops of aqueous ammonia and 0.5 g of zinc dust, stir 20 minutes further, filtered and the filtrate evaporated in vacuo. The residue is taken in ethanol on, filtered again and the filtrate evaporated to dryness. The 1-carbobenzoxyamino-5 obtained - [N - (5 '- hydroxylaminopentylamino - succinyl) - hydroxylaminoj-pentane (VII) can be processed further without cleaning.

g) 1-carbobenzoxy-8,11,19-trioxo-

1,7,12,18-tetraaza-7,18-diacetyIoxy-

19-methyl-nonadecane (VIIa)

The residue obtained according to f) is dissolved in 10 ml of absolute pyridine and 2 ml of acetic anhydride and let the solution stand at room temperature for 1 day. The reaction mixture is then evaporated in vacuo, the residue is taken up in chloroform, the solution is washed with dilute hydrochloric acid and Sodium bicarbonate solution and chromatographed on silica gel. It is eluted with ethyl acetate Methanol 10: 1 and the triacetyl compound VIIa is obtained in one yield after evaporation of the eluate of 49%; NMR bands at 2.2 ppm (twice O-acetyl) and 1.95 ppm (once N-acetyl).

h) 1-carbobenzoxy-8,11,19-trioxo-1,7,12,18-tetraaza-7,18-dihydroxy-19-methyl-nonadecane (VIIb)

A mixture of 0.15 g (VIIa) and 10 ml of 1N potassium hydroxide solution is allowed to stand for one day at room temperature, then neutralized with dilute hydrochloric acid and evaporated in vacuo. The residue is taken up in warm ethyl acetate — methanol, whereupon, after concentration and cooling, the dried solution VIIb crystallizes out, mp 165 ^° C., NMR band at 1.95 ppm (N-acetyl); Yield 79%.

The reaction stages listed under e) to h) without purification and isolation of the intermediates carried out, one obtains (VIIb) in a total yield of 49%.

i) 8,11,19-trioxo-1,7,12,18-tetraaza-7,18-dihydroxy-19-methyl-nonadecane (VIIc)

0.5 g of (VIIb) is dissolved in 50 ml of ethyl acetate, 0.5 g of palladium carbon is added and the mixture is shaken

in a hydrogen atmosphere until there is no more hydrogen uptake. The catalyst is now filtered off from, the filtrate acidified with methanolic hydrochloric acid weakly and evaporated it under reduced Pressure a. The residue can be processed further without purification.

k) 8 J l, 19,22,30-pentaoxo-l, 7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30-methyl-triacontane (XII)

A solution of equimolar amounts of the hydrochloride contained in the above residue of (VIIc), N- (5'-carbobenzoxyaminopentyl) -tetrahydro-3,6-dioxo-1,2-oxazine (V) and sodium methylate in Methanol is worked up as indicated under e). The colorless residue obtained after evaporation (IX) is taken up in ethyl acetate and chromatographed on silica gel. One elutes with Ethyl acetate — methanol 1: 1 and hydrogenolyzed the main fraction, as indicated under i). The solution freed from the catalyst evaporates one on this one.

1) Iron trihydroxamate complex des
8,11,19,22,30-Pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30-methyl-triacontanes (XIIa)

The residue (XII) obtained according to k) is taken up in water, the solution is nitrated clear with cellulose powder, an iron (III) chloride solution is added to the filtrate and the red-brown mixture is extracted three times with chloroform-phenol 1: 1 after standing for one hour. The combined extracts are washed with a little water, treated with diethyl ether, the red-brown precipitate which has separated out is filtered off and washed with diethyl ether. The thus obtained hydrochloride of the iron trihydroxamate complex of 8, ll, 19,22,30-pentaoxo-l, 7,12,18,23, 29 -hexaaza- 7,18,29-trihydroxy-30-methyl-triacontane (XIIa) is identical to authentic ferrioxamine B hydrochloride; Total yield of stages i) to 1) about 50 ° / ₀ .

Example 3

A solution of 300 mg (XIIa) in 10 ml of water is mixed with 20 ml of 1 η sodium hydroxide solution and the precipitated iron (III) hydroxide is centrifuged off. The filtrate is immediately neutralized with 1η hydrochloric acid. The almost colorless solution obtained is extracted several times with n-butanol and the combined extracts are washed with a little water. After the butanol has been evaporated off in vacuo, a crystalline, yellowish residue is obtained. 1 part by weight of this residue is dissolved in 4 parts by weight of hot methanol and the solution is rapidly mixed with 12 parts by weight of warm acetone. The 8,11,19,22,30-pentaoxo-1,7-12,18,23,29-hexaaza-7,18,29-trihydroxy-30-methyltriacontane hydrochloride formed crystallizes out within 24 hours; F. 171 to 173 ⁰ C, yield 240 mg.

Example 4

11.94 g SJl ^
aza - 7,18,29 - trihydroxy - 30 - methyl - triacontane - hydrochloride and 1.64 g of anhydrous sodium acetate are brought into solution in 200 ml of methanol by briefly boiling. It is then cooled rapidly to room temperature and immediately, ie before crystallization occurs, 180 ml of acetic anhydride are added. The mixture is left to stand for 17 hours with exclusion of moisture and then concentrated in vacuo to give an oily residue. This is re-evaporated twice with about 200 ml of butanol in vacuo for the purpose of separating off acetic acid. The oily residue, which mainly contains the tetraacetyl derivative, is taken up in 200 ml of methanol, saturated at ⁰ ° C. with ammonia and then left for 5 hours at room temperature and finally for a while

ίο Stand at O ⁰ C for 15 hours. The colorless crystals which separate out are freed from the ammoniacal solution by decanting and vacuum drying: 11.74 g. After twice recrystallizing from 60 ° / ₀ aqueous methanol, 9.12 g of 1 is - acetyl-8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza - 7.18 , 29 - trihydroxy - 30 - methyl - friacontane with a mp of 185 ° C.

Example 5

650 mg (XIIa) and 82 mg of anhydrous sodium acetate are dissolved in 10 ml of methyl alcohol and 9.5 ml of acetic anhydride are added. After standing for 4 hours at room temperature, it is evaporated to dryness in vacuo. The residue is dissolved in water and saturated with sodium chloride. Now it is extracted four times with chloroform. The chloroform extracts are washed twice with saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. Mao receives 550 mg of a red-brown powder, which in the paper chromatogram shows the same behavior as ferrioxamine D ₁ in two solvent systems, but is still accompanied by small amounts of two by-products, one of which migrates a little further and the other a little less than ferrioxamine D ₁ .

For purification, the acetylation product is chromatographed on a column of 280 g cellulose powder. The cellulose is first moistened with 10% aqueous sodium chloride solution. As an eluent the upper phase of a mixture of 50 parts of tert-butanol and 25 parts is used Water, 25 parts of saturated sodium chloride solution and 1 part of 0.1 η hydrochloric acid. There are factions too collected about 8 ml. In fractions 33 to 44, in addition to the iron trihydroxamate complex, des

y ^
aza-7,18,29-trihydroxy-30-methyl-triacontans which contain one admixture, in fractions 55 to 66 the other. Fractions 45 to 54 contain pure iron trihydroxamate complex of 1-acetyl-8,11,19,22-30 - pentaoxo -1,7,12,18,23,29 - hexaaza - 7,18,29 - trihydroxy-30-methyl -triacontans. They are evaporated to dryness in vacuo, the residue is taken up in chloroform and washed several times with saturated sodium chloride solution. The solution, dried with sodium sulphate, leaves 226 mg of acetylation product on evaporation, which crystallizes from methanol-ether in red-brown needles. When observed in the heatable polarization microscope, the crystals lose their birefringence at 170 to 172 ° C and dissolve at about 197 to 205 ° C to form a red-brown viscous mass. _{Ferrioxamine D 1} , which is obtained directly from Streptomycespilosus extracts according to patent 1,123,436, behaves in exactly the same way. A mixture of the two preparations shows no lowering of the melting point. The IR absorption spectra are the same. The acetylation product purified by crystallization is paper chromato-

graphically uniform and behaves like ferrioxamine D ₁ .

Example 6

535 mg Hydrochloric! of the iron trihydroxamate complex des 8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30 (/? - carboxyethyl) -triacontane are dissolved in 10 ml of methanol, 100 mg of anhydrous sodium acetate and 9 ml of acetic anhydride are added and left to stand for 4 hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in water and the solution saturated with sodium chloride. When shaking out several times most of the brown pigments (acetylation product) go with chloroform organic phase over. Small amounts of starting material and decomposition product remain in the water solved.

The chloroform extracts are washed twice with sodium chloride solution and dried with sodium sulfate and evaporated in a vacuum. 483 g of amorphous brown residue are obtained.

When recrystallizing from methanol-ether, amorphous flakes initially precipitate. After their separation, the mother liquors deliver the iron trihydroxamate complex of 1-acetyl-8,11,19,22,30 - pentaoxo - 1,7,12,18,23,29 - hexaaza-7,18,29-trihydroxy- 30 - ((S-carboxyethyl) -triacontans in fine red brown prisms, mp 201 to 206 ° C (microscope) The birefringence is maintained up to melt, while it disappears already at about 17O ⁰ C in the similar melting ferrioxamine D. _1. A total of 250 mg of crystalline acetylation product are obtained.

Example 7

67 mg 1 - acetyl - 8,11,19,22,30 - pentaoxo -1,7,12,18-23,29-hexaaza-7,18,29-trihydroxy-30 - (/ 3-carboxyethyl) -triacontane are dissolved in 5 ml of methyl alcohol and 2 ml of an approximately 2% ethereal solution of Diazomethane added. After 30 minutes, the mixture is evaporated in vacuo and the residue is removed from methanol-ether recrystallized. The obtained iron trihydroxamate complex of 8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30 - (/? - carbomethoxyethyl) -triacontane melts at 194 to 199 ° C.

Example 8

11.94 g 8.1!, L ^^
aza - 7,18,29 - trihydroxy - 30 - methyl - triacon tan - hydrochloride are suspended in 200 ml of water. The mixture is brought to pH 9 with 5 η sodium hydroxide solution and 2.4 ml portions of n-valeric acid chloride are added with vigorous shaking and stirring using a vibration mixer. At the same time, the mixture is kept at pH 9 by adding 5N sodium hydroxide solution dropwise. After adding the first two portions of the acid chloride, an oily product precipitates from the powdery slurry. Therefore, 200 ml of chloroform are added, as a result of which the mixture separates into two clear phases, which are intensively mixed during the further reaction. After adding a total of 16 ml of n-valeric acid chloride and a total of about 38 ml of 5N sodium hydroxide solution, stirring is continued for a further 15 minutes. The phases are then separated. The aqueous phase is extracted three times with 200 ml of chloroform. The combined chloroform phases are washed with saturated potassium hydrogen carbonate and with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to a syrup. The oily residue (29 g) is taken up in 500 ml of methanol, the solution is saturated ^{with ammonia gas at 0} ° C. and then left to stand at 25 ° C. for 16 hours. It is then evaporated to dryness and dried thoroughly in a high vacuum. The crystalline residue (16.4 g) is boiled in acetone, the

ίο Stand mixture for 15 hours at 0 ° C and filter. That separated white crystal powder is made from a mixture of 150 ml of water and 70 ml of n-propanol 100 ° C recrystallized, l-VaIeryl-8,11,19-22,30 - pentaoxo -1,7,12,18,23,29 - hexaaza - 7,18,29 - trihydroxy-30-methyl-triacontane obtained as colorless crystals with a melting point of 181 to 183 ° C.

The compound obtained, unlike the starting material, is heavy even in hot water soluble. It also does not dissolve well in most common organic solvents. Against it can they are brought into hot solution in mixtures of water and organic solvents.

Example 9

5.97 g of 8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29 - trihydroxy - 30 - methyl - triacontane hydrochloride are dissolved in 40 ml of water and 50 ml of dioxane slurried, with vigorous shaking with a vibration mixer with 5 η-sodium hydroxide solution on one Set pH 9 and then with 10 ml portions of a solution of 18.18 g of stearic acid chloride in 60 ml Dioxane added. The pH of the mixture is adjusted by adding 5 N sodium hydroxide solution drop by drop held at 9. After adding four portions of stearic acid chloride solution, it is mixed with 50 ml of water and 200 ml of chloroform. The mixture separates here into two clear phases that are necessary for the further reaction can be intensively mixed by vigorous shaking with the vibromixer. After finished The acid chloride is added and the mixture is stirred at pn 9 for a further 1 hour. The reaction mixture dilutes by adding 500 ml of water and 1 1 of chloroform, the phases are separated and the extracts aqueous phase two more times with 250 ml of chloroform.

The combined chloroform phases are washed with saturated potassium hydrogen carbonate and sodium chloride solution, dried over sodium sulfate and evaporated. The crystalline residue is dissolved in 500 ml of ether, the solution is treated with 200 ml of methanol and saturated with ammonia gas at room temperature. After standing for 3 days at room temperature, the reaction mixture is evaporated to dryness in vacuo and the residue is boiled several times with petroleum ether in order to separate off stearic acid amide. The remaining colorless crystalline powder (4.3 g) is recrystallized from 66% strength aqueous n-propanol. The 1-stearyl-8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30-methyl-triacontane melts at 194 to 196 ^C C. It is sparingly soluble in water and common organic solvents.

Example 10

The solution of 120 mg of hydrochloride of the iron trihydroxamate complex des 8,11,19,22,30-pentaoxo-1,7,12,18,23,29-hexaaza-7,18,29-trihydroxy-30 - (/ S-carboxyethyl) -triacontane in 1 ml of water and 35 ml of dimethylformamide are allowed to form a mixture of 10 g

Add dicyclohexylcarbodiimide and 25 ml of dimethylformamide and stand for 3 weeks at room temperature. Most of the dimethylformamide is evaporated off in vacuo, 20 ml of 1η-acetic acid are added to the residue, while cooling with ice, and the mixture is left to stand overnight. The precipitated dicyclohexylurea is filtered off with suction and the filtrate is evaporated under reduced pressure. The filtered-off dicyclohexylurea is still a little reddish in color and is therefore recrystallized from ethanol. The reddish mother liquors are evaporated and the two evaporation residues are combined. This is subjected to a Craig distribution: n-butanol — benzyl alcohol — 0.001 n-hydrochloric acid — saturated saline solution 2: 1: 3: 0.6, with 37 levels. The red-colored substances are in fractions 15 to 24: iron trihydroxate complex of cyclo-SJl ^ ÄSO ^ -hexaoxo-lJJ ^ lS, 23,29-hexaaza-7,18,29-trihydroxy-tritriacontane, and 28 to 33: iron trihydroxamate complex des 1-acetyl-8,11,19,22,30 - pentaoxo - 1,7,12,18,23,29 - hexaaza-7,18,29 - trihydroxy - 30 - (β - carboxyethyl) - triacontans. The fractions 15 to 24 are combined and treated with diethyl ether, whereby the iron trihydroxamate complex des Cyclo-8,11,19,22,30,33-hexaoxo-1,7,12, 18,23,29 - hexaaza - 7,18,29 - trihydroxy - tritriacontans is completely forced into the aqueous phase. The aqueous phase is mixed with about 20% cooking

saline solution, shake it with chloroform — phenol (1 ml: 1 g) three times and the extract clarifies by filtration on a short column of cellulose powder. That Twice the volume of diethyl ether is added to the filtrate and the mixture is extracted three times with a little water aqueous phases washed twice with ether and then evaporated to dryness in vacuo. It 15 mg of red-brown amorphous powder remain, which is crystallized from about 1 ml of hot methanol, ίο The iron trihydroxamate complex is obtained

aza-7,18,29-trihydroxy-tritriacontans in red-brown fine needles which lose their birefringence at 28O ⁰ C and black, without melting (consistent with authentic material).

With the same work-up, fractions 28 to 33 become 100 mg of crude iron trihydroxamate complex des 1-acetyl-8, ll, 19,22,30-pentaoxo-1, 7,12,18, 23,29-hexaaza-7,18,29-trihydroxy-30 - (/ S-carboxyethyl) -triacontane obtained, which results from the decomposition of the reaction mixture with acetic acid from unreacted Has formed starting material.

Claims (2)

Patent claims: 1. Process for the preparation of trihydroxamic acids of the general formula R ₁ -NH- (CH _{2) 5} -N-C (CH _{2) 2} - CNH (CH _{2) 5} -N-C (CH _{2) a} -CNH- (CH ^ -N-CO-R ₃ R ₂ OO R ₂ O R ₂ O in which R _{1 is} hydrogen, an acyl radical or the formula II 2,4-Dinitrophenylrest, R ₂ hydrogen or a 35 r 'njj Acyl radical, CO - R _{3 represents} an acetyl or free or esterified succinyl _{radical or R 1} and R ₃ together represent the radical of succinic acid, the second carboxyl group of which is connected to the N ^ atom, and their salts and metal complexes, characterized in that man a) l-Arylamino-5-hydroxylamino-pentanes
general formula I. the 45 R ₁ '- NH - - NHOH in which R ₁ 'represents an acyl radical, with functional derivatives of succinic acid either to form 1-amino-5 - (N - succinylhydroxylamino) - pentanes of -CO- (CHa) ₂ -COOH OH Π or from these by elimination of water to give N- (5'-aminopentyl) -tetrahydro-3,6-dioxo-1,2-oxazines of formula III RZ-NH- (CH ₂₎ SN
O CH ₂
CH ₂ condensed, split off the acyl radical R ₁ 'and the free amino compound again with a compound of the formula or III to form 8,11,19-trioxo- y ^
ethyl) nonadecanes of the general formula IV R ₁ '- NH - (CH ₂ ) s - N - CO - (CHa) ₂ - CO - NH OH - N - CO - (CHg) ₂ - COOH OH or the corresponding oxazines of the formula V R ₁ '- NH - (CH ₂ ) ₅ - N - CO - (CH ₂ ) ₂ - CO _{- NH - (CH 2} ) S - N OH CH ₂
CH ₅ , condensed, this with l-amino-5- (N-acylhydroxyl-amino) pentanes or l-amino-5- (N, O-diacylhy- 409 509/440 droxylamino) pentanes of the formula VI NH ₂ - (CHg) ₅ - N - CO - R ₃ OR ₃ ' VI R ₁ 'NH- (CHa) ₅ -N-CO- - (CHg) ₂ CO NH
OH or the 29-COR ₃ derivative or ^ao b) a compound of the formula II or III is reacted with l-amino-5-nitropentane, the nitro obtained reduced compound to the hydroxylamino compound and this with a functional derivative converts the succinic acid to a compound of formula IV or V and then either treated as under a) or condensed again with l-amino-5-nitropentane, the compound thus obtained reduced to the hydroxylamine derivative and then to the compound VII or its tri- (O-acyl) derivative acylated or c) a compound of formula II or III is condensed with l-amino-5-nitropentane, the nitro compound obtained is reduced to the hydroxylamino compound, this is acylated, the group R ₁ 'is split off and the compound obtained is reacted again with a compound of formula II or III or d) a compound of the formula II or III is reacted with l-amino-5- (N-acylhydroxylamino) pentane, the group R ₁ 'is split off and the free amino compound obtained is in turn condensed with a compound of the formula II or III or e) 1 - Amino-5-nitropentane with a functional derivative of succinic acid to form l-succinylamino-5-nitropentane converts this to 5-hydroxyl in which R ₃ 'stands for hydrogen or CO - R ₃ , to 8,11,19,23,30 - Pentaoxo - 1,7,12,18,22,29 - hexaaza-7,18,29-trihydroxy-triacontanes of the general formula VII - N CO (CH ₂ ) -, CO NH (CH ₂ ) ₅ N ^ CO R OH amino compound or formula VIII
HOOC - (CHa) ₂ - CO - NH - (CH ₂ ) ₅ - NHOH VIII reduced, the carboxyl group is blocked by esterification, the ester is condensed with aem O, N-diacetylation product of compound VIII and the condensation product is reacted after cleavage of the ester group with a compound of formula I and optionally the group R from the products obtained according to a) to e) ₁ 'splits off and optionally compounds which have a free amino group in the 1-position and a succinic acid radical in the 29-position, with formation of an amide between the amino group and the second carboxyl group of the succinic acid radical by means of a carbodiimide and, if necessary, with the according to a ) to e) obtained products salts with inorganic or organic acids without pharmacological effects or iron, cobalt, magnesium, copper and antimony complexes and / or acylation products or l-amino- (2 ', 4'-dinitrophenyl) - forms derivatives. 2. The method according to claim 1, characterized in that that one as functional derivatives of succinic acid is the anhydride, azide, imide or Imidazolide used. 409 509/440 2.64 @ Bundesdruckerei Berlin