DE2411500A1 - DERIVATIVES OF ESTERS OF DIUMYCIN A AND DIUMYCIN A ' - Google Patents

Description

¹¹ derivatives of esters of diumycins A and diumycins A ^{1 l}}

Priority: March 14, 1973, V.St.A., No. 341 015 January 18, 1974, V.St.A., No. 434 522

The invention relates to derivatives of esters of diumycin A or Diumycins A 'in which the group

CH-O- of the chromophore

r:

R-

: h-o

fj

by a remainder of the general formula

r:

or

-NH-

3 4
is replaced, in which R and R are identical or different and Viasserstoff a tome, alkyl radicals with 1 to 6 carbon atoms, cycloalkyl radicals with 3 to 6 carbon atoms, "benzyl, phenethyl, monohalogen-substituted benzyl or monohalogen-substituted phenethyl groups or alkyl radicals with 1 to 5 carbon atoms which are substituted by a 5- or 6-membered nitrogen-containing heterocyclic radical,

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the optionally a second oxygen, sulfur or

3 λ contains nitrogen heteroatom, or R and R together with the Nitrogen atom to which they are attached, a 5- or 6-membered saturated nitrogen-containing heterocyclic Form a remainder, which may contain a second oxygen, sulfur

5 contains 6 free or nitrogen heteroatom, R and R are the same or are different and hydrogen atoms, "alkyl radicals with 1 to 6 carbon atoms, phenyl or by a fluorine, chlorine, Bromine or iodine atom, an alkyl or alkoxy radical with 1 to 3 carbon atoms or a nitro group substituted phenyl group mean, or R and R together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic Form ring, which optionally contains an oxygen, sulfur or nitrogen heteroatom, and which in the UV absorption spectrum absorb in aqueous solution in the range of about 274 to about 285 mu.

The derivatives of esters of diuniycins A and diumycins A ¹ are made by aminolysis or hydrazinolysis of lower alkyl or aryl-lower alkyl esters of diumycins A or diumycins A ¹ with an excess of amine or hydrazine, subsequent hydrolysis of the compounds obtained with an inorganic base a higher pH or by hydrolysis of lower alkyl or aryl-lower alkyl esters diumycins A and diumycins A ¹ with ammonium hydroxide or another inorganic base at a higher pH.

The esters of diumycin A and diuroycinol A ¹ are, for example, alkyl esters with 1 to 6 carbon atoms in the ester group and

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Phenyl lower alkyl esters. For the production of these esters Diumycin A or Diumycin A 'with a diazo compound of the general formula

^R ^ CN ₂

1 2

in which R and R are hydrogen atoms, alkyl radicals having 1 to 5 carbon atoms, phenyl groups, phenyl groups substituted by a halogen atom, such as a fluorine, chlorine, bromine or iodine atom, or an alkoxy or alkyl group having 1 to 3 carbon atoms, in a molar ratio of 1: at least 3 implemented. The reaction proceeds relatively quickly at temperatures from about ⁰ ° C. to about room temperature, for example over a period of about 5 minutes to about 1 hour. The reaction is carried out in the presence of an alcohol such as methanol, ethanol or propanol or a mixture of an alcohol and an ether such as methanol and diethyl ether or methanol and dimethoxyethane. As a result of the reaction, in the starting compound Diumycin A cderDiumycin A ^! one of the acidic hydrogen atoms, including the hydrogen atom in the chromophoric residue

^r1
through the rest ^ "" ^ _CH _

R ²

replaced. As diazo compounds, for example, diazomethane, diazoethane, diazopropane, diazohexane, phenyldiazomethane, Diphenyldiazomethane, 4-methylphenyldiazomethane and 4-methoxyphenyldiazomethane used.

0 9: 839/1 0 27

The UV absorption of the esters of diumycin auxiüiumycins A ^T in aqueous solution is in the range from about 252 to about 254 μm.

By reacting the lower alkyl and aryl lower alkyl esters of diumycin A or diumycin A ¹ with at least 2 molar equivalents of a base per mole of diumycin A or diumycin A ¹ at a pH of about 10 to about 11.5, preferably at about 11, the hydrolysis derivatives are produced. For example, ammonium hydroxide or an aqueous solution of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide, such as calcium or barium hydroxide, can be used as the base. The reaction is carried out in a period of about 30 minutes to about 16 hours in a temperature range of about ⁰ ° C to about 40 ° C.

The UV absorption of the compounds obtained in aqueous solution is at a pH of about 2.2 at about 248 mu and at pH values of 5 and 11 at about 258 mu.

The aminolysis derivatives of the lower alkyl or aryl-lower-alkyl esters of diumycin A or diumycin A ¹ are prepared by reacting at least 3 molar equivalents of ammonia or a primary or secondary amine per mole of diumycin A or diumycin A ¹ in a period of about 1 to about 48 hours at temperatures from about room temperature up to 100 ⁰ C produced. In this implementation, the group is substituted

\ / the chromophoric group ^R ^ _r __ _n

_R A ₀

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in which R and R have the preceding meaning, by a substituted amino group of the general formula

-N or -N-N

- H

in which R ^, R, R and R have the preceding meaning. Provided the amine is a liquid under the reaction conditions, it can also be used as a solvent dienone, otherwise an inert solvent such as dimethylformamide (DMF), tetramethylurea (THH), dioxane or dimethoxyethane, used. Examples of amines are monoalkyl and dialkyl amines with 1 to 6 carbon atoms per alkyl radical, such as methylamine, ethylamine, propylamine, isopropylamine, tert-butylamine, Dimethylamine or diethylamine, or cycloalkylamines with 3 to 6 carbon atoms, such as cyclopropylamine, cyclobutylamine, cyclopentylamine, Cyclohexylamines or phenyl-substituted alkylamines, such as benzylamine, dibenzylamine, phenethylamine, 2,2-diphenylethylarain, or halophenyl-substituted alkylamines, such as p-fluorobenzylamine, m-bromobenzylamine, ß- (p-chlorophenyl) ethylamine, ß- (p-bromophenyl) ethylamine, or 5- or 6-membered saturated heterocyclic amines which have 1 or 2 heteroatoms, such as Nitrogen, oxygen or sulfur atoms, such as pyrrolidine, thiazolidine, piperidine, morpholine, thio-norpholine, N-methylpiperazine, 4-methylpiperidine, or 5- or 6-membered heterocyclic substituted alkylarines, the alkyl radical of which is 1 to 5 carbon atoms and their heterocyclic ring, optionally 1 or 2 heteroatoms, such as oxygen, nitrogen and Sulfur atoms, - contains. Specific examples are N- (2-aminoethyl) piperidine, 4-pyridylmethylamine, N-methyl-N'-

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(2-aminoethyl) piperazine and N- (3-aminopropyl) thiomorpholine. Further examples of amines are hydrazines of the general formula _D 5

in which R and R are the same or different and are hydrogen atoms, Alkyl radicals with 1 to 6 carbon atoms, phenyl groups or phenyl groups substituted by halogen atoms, alkyl or alkoxy groups with 1 to 3 carbon atoms or nitro groups, mean, such as hydrazine, methylhydrazine, ethylhydrazine, Propylhydrazine, hexylhydrazine, Ν, Ν-dimethylhydrazine, N, N-diethylhydrazine, Phenylhydrazine, N, N-diphenylhydrazine, N-methyl-N-phenylhydrazine, p-iodophenylhydrazine, m-bromophenylhydrazine, o-chlorophenylhydrazine, o-methylphenylhydrazine, p-ethylphenylhydrazine, m-methoxyphenylhydrazine or p-nitro

5 6
phenylhydrazine, or R and R form a heterocyclic ring with 3 to 6 atoms with the nitrogen atom to which they are bound, which optionally contains a further oxygen, sulfur or nitrogen heteroatom, such as N-aminoethylene amine, N-aminopyrrolidine, N-aminopiperidine, N ~ aminomorpholine, N-aminothiomorpholine or N-aminopiperazine.

The UV absorption of the aminolysis derivatives of the esters of diumycin A or diumycin A ¹ in aqueous solution is in the range from about 274 to about 285 μm.

The aminolysis-hydrolysis derivatives of the esters of diumycins A or diumycins A ¹ , the. nor the chromophoric group

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are prepared as free acids or salts by reacting the aminolysis derivatives of the esters of diumycin A or diumycin A ¹ , which contain one of these chromophoric groups, with an excess of aqueous base at a higher pH. 6 Di reaction is conducted at a pH in the range of about 10 to about 11.5 »preferably at a pH of about 11, for a period of about 30 minutes to about 16 hours at temperatures of about 0 to 40 ⁰ C. carried out. At least two equivalents of the base per mole of aminolysis derivative of diumycin A or diumycin A 'are used. Examples of bases are ammonium hydroxide or aqueous solutions of alkali metal hydroxides, such as lithium, sodium or potassium hydroxide, or aqueous solutions of alkaline earth metal hydroxides, such as calcium or barium hydroxide. The salts obtained are optionally converted into the corresponding free acids by treatment with a cation exchanger in the Η form. Other salts, such as the magnesium salt or a TrialkylainiBonium salt, each with 1 to 6 carbon atoms in the alkyl radicals, are optionally prepared from the free acid in a manner known per se.

The UV absorption of the aminolysis-hydrolysis derivatives of the esters of diumycin A or diumycin A 'in aqueous solution is in the range from about 274 to about 285 μm. IR spectra of the aminolysis and aminolysis-hydrolysis derivatives of the invention show an intense decrease ^{in the range from about 1550 to about 1580 cm "1.}

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sorption band, which distinguishes the aminolysis and
Aminolysis-hydrolysis derivatives of the stated esters of their hydrolysis derivatives are allowed.

The compounds of the invention and their salts are valuable
Medicinal substances. Both in vitro and in experiments on infected animals, such as mice and rats, they show an antibiotic effect against gram-positive bacteria such as Staphylococcus
aureus, Bacillus subtilis and Streptococcus pyogenes. The compounds of the invention can be used as drugs in the form of
Injection preparations and administered in doses similar to Diuir / cin A and Diumycin A ¹ . Furthermore, the connections
of the invention as growth-promoting additives in animal feed
for pigs and poultry in the same way as diumycin A and diumycin A *.

The process according to the invention was explained using the alkyl and aralkyl esters of diumycin A and diumycin A ¹ as starting compounds. To prepare the aminolysis or aminolysis-hydrolysis derivatives, any desired esters of the can of course
Diumycins A and Diumycins A 'can be used provided the
Ester group reacts in a manner similar to that described above.

The examples illustrate the invention.

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Example 1 Methyl ester of diumycin A

233 mg of diumycin A in the acid form are dissolved in 2 ml of methanol. The solution is ^{cooled to 0} ° C. and then alternately with 6 ml of a solution of diazomethane in diethyl ether and 6 ml of methanol, both solutions are also made up. O ⁰ C cooled, treated until the reaction mixture retains the yellow color. The excess of diazomethane is removed by blowing in nitrogen. After evaporation of the solvent, 234 g of the methyl ester of diumycin A are obtained as a white powder.

150 mg of the compound obtained are applied to a column (2.5 cm 80 cm) charged with a molecular sieve (Sephadex LH-20), which was slurried with methanol and chromatographed. Fractions of 6 ml each are collected and their UV absorption is measured at 254 μm. The residue of 123 mg obtained by combining fractions Nos. 38 to 43 and subsequent evaporation is taken up in methanol, reprecipitated with diethyl ether and dried under reduced pressure. The title compound is obtained as a white powder with the following data.
UV absorption F.

^ mIx ^{= 252} T ' ^E ' ^{196 = 80 170} ° ^C (yellow-brown)

176 ° C (brown) 180 ⁰ C (black)

Analysis: CH "NP OCH ₃ 0

found: 48.64 6.57 4.11 1.83 7.24 36.85 (as difference

calculated) Neutralization equivalent for anhydrous titration in perchloric acid-acetic acid: 1900.

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- ίο -

Molecular weight through ultracentrifuge: 1730 (ethanol), 140,000 (aqueous buffer solution pH 6.85). The ester is in water, lower alcohols, pyridine, dioxane, Dimethylformamide and dimethyl sulfoxide soluble.

Example 2 Methyl esters of diumycin A and diumycin A '

400 mg of a mixture of approximately equal amounts of diumycin A and diumycin A ¹ in the acid form is converted according to Example 1, but the total amount of the ester obtained is chromatographed. From fractions No. 38 to 44, 343 mg of a mixture of the title compounds are obtained as a white powder with the following UV absorption:
λ SlS - 254 _T. K W- 85.

A paper chromatogram on paper pretreated with acid gives an R ^ value of 0.94 compared to an R for the mixture of the compounds obtained in the system n-butanol - pyridine - acetic acid - water - methanol (4: 4: 1: 1: 2) ^ Value of 0.53 of a mixture of diumycin A and diumycin A ^! in the same solvent. In the n-butanol - pyridine - acetic acid - water (6: 4: 1: 3) system, the esters give an R _f value of 0.77 compared to an R _f value of 0.25 for a mixture of diumycin A and Diumycin A · in the same mobile phase. The chromatograms are developed with iodine vapor.

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Example 3

Hydrolysis derivatives I and II of the methyl ester of diumycin A 0.029 η sodium hydroxide solution is added in a nitrogen atmosphere through an automatic burette with stirring to a solution of 130 mg of the methyl ester of diumycin A obtained according to Example 1 in 2.0 ml V / water until a pH is reached -Value of 11 is set. The solution is stirred for 6 hours, the pH value of 11 being maintained by adding sodium hydroxide solution through the automatic burette. After the solvent has been distilled off, the residue is taken up in water and the solution is adjusted to a pH of 2.2 by adding a cation exchange resin in the H form (Dowex 50). After filtering off the exchanger, the filtrate is evaporated to a white powder after adding n-propanol. This is dissolved in the smallest possible amount of methanol and chromatographed on a column (2.5 cm 80 cm) with a molecular sieve (Sephadex LH-20), slurried with methanol. The chromatogram is checked using a flow cell in UV light at 25 μm, and fractions of 6 ml are collected. Fractions No. 38 to 40 are combined and evaporated. The residue (30 mg) is redissolved in methanol and again applied to a column as described above. Fractions No. 38 to 40 of this second chromatogram are combined and evaporated. The residue is dissolved in methanol, reprecipitated with diethyl ether and dried under reduced pressure. Yield 20 mg of the title derivative I in the acid form as a white powder with the following data:

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UV absorption:

AmIx ^{= 248} W ' ^{E 1% = € 8} ' ^{pH = 2} » ²

2 4 S ISQO

HoO _{= 258} ^

F. (decomp.) 175 ° C (yellow-brown)
177 ° C (brown)
185 ⁰ C (black)

Analysis: CHNP OCH ₃ 0

found: 48.15 6.75 3.96 1.84 4.18 39.30 (as difference

calculated)

Water of hydration 6.92; Neutralization equivalent by potentiometric Titration (aqueous sodium hydroxide solution) 1520 and 1620.

The compound obtained is diluted in water, lower alcohols Soluble in acids and dilute bases.

Ground fractions no. 42 to 46 of the first chromatogram combined, evaporated and the 60 mg of the residue obtained again, as described above, dissolved in methanol and chromatographed. Fractions of 6 ml each are collected again. Fractions No. 40 to 46 are combined and evaporated. The residue is dissolved in methanol, precipitated with diethyl ether and evaporated under reduced pressure and dried. Yield 49 mg of the title derivative II in the acid form as a white powder with the following data:

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UV absorption;

= 248 mu, E ^Λ% = 72, pH = 2.2 ^{= 258} Ύ> ^{E 1%} = ¹⁰ * »P ^H = 5.0 ^{= 258} T * ^{E Λ% = 107} '

F. (decomp.) 160 ° C (yellow-brown)
170 ⁰ C (brown)
180 ⁰ C (black)

Analysis: CHNP OCH ₃ 0

found: 47.78 6.84 4.27 1.85 3.92 39.26 (as difference

calculated)

Water of hydration 6.73; Neutralization by potentiometric titration (aqueous sodium hydroxide solution) 1210 and 1090. The compound obtained is diluted in water, lower alcohols Soluble in acids and dilute bases.

Example 4

Aminolysis hydrolysis derivatives (free acids and ammonium salts)

Methyl ester of diumycin A and diumycin A ¹ with isopropylamine

A solution of 176 mg of the mixture of methyl esters obtained in Example 2 in 0.6 ml of tetramethylurea is 0.1 ml Isopropylamine added. The mixture is stirred for 16 hours under nitrogen at room temperature. After adding diethyl ether a precipitate is obtained, which is filtered off, washed with diethyl ether and then dried. Yield 159 mg of one white powder with the following UV absorption results:

^λ III - ² 76 J. E ¹ "= 151.

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24115ÜO

This powder is under nitrogen for 2 hours at room temperature with 3 ml of 2 η aqueous ammonia solution at a pH of 11.0 stirred and then left to stand for 16 hours. After distilling off the aqueous ammonia solution at reduced The ammonium salts of the title compounds are obtained under pressure. Residue. The residue is dissolved in water and with a Cation exchange resin (Dowex-50) in the H form adjusted to a pH value of 2.2. After filtering off the exchanger the filtrate is evaporated after the addition of methanol and n-propanol. The residue is dissolved in methanol with diethyl ether precipitated again and dried. 129 g of the title derivatives are obtained in the acid form as a white powder with the following Data:

UV absorption:
A «i ° -276 _T , E ¹ ^ = I ₆₁

F. (decomp.) 172 ° C (yellow-brown)
176 ° C (brown)
178 ° C (black)

Analysis: CHNP Q

found: 45.56 6.59 5.68 1.84 40.33 (calculated as the difference)

Example 5

Aminolysis-hydrolysis derivatives (free acids and ammonium salts) of the methyl esters of diumycin A and diumycin A 'with morpholine 0.2 ml of morpholine is added to a solution of 167 mg of the methyl ester mixture obtained in Example 2 in 1.4 ml of tetramethylurea . The mixture is stirred under nitrogen for 16 hours at room temperature. The precipitate obtained by adding diethyl ether is filtered off and repeated with

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Washed diethyl ether, then dried, dissolved in methanol and reprecipitated with diethyl ether. After evaporation and drying, 159 mg of the corresponding aminolysis derivatives are obtained as a white powder with the following UV absorption:

AmIx = ²⁸³ -J »· E ¹ * = 118. ·

2 η aqueous ammonia solution is to the mixture obtained Aminolysis derivatives in 1 ml 2 η aqueous ammonia solution up to pH value of 11.0 given. The solution is stirred under nitrogen at room temperature for 90 minutes and then for 16 hours ditched. After working up according to Example 4, the filtrate obtained has a pH of 2.2 with the addition of n-propanol evaporated, further work-up according to the example

4 gives 130 mg of the title derivatives in the acid form as white Powder with the following data:

UV absorption:

AmSx = 282mu, E ¹ * = 147

F. (decomp.) 170 ° C (yellow-brown)
174 ⁰ C (brown)
178 ⁰ C (black)

Analysis: CHNPO

"found: 48.29 5.42 6.71 1.97. 37.61 (as difference

calculated)

Example 6

Aminolysis-hydrolysis derivative (ammonium salt) of the ester of Diumycins A with pyrrolidine

5 mg of the ester obtained according to Example 1 in 0.1 ml of tetramethyl urea 0.1 ml of pyrrolidine are added. The mixture is stirred under nitrogen for 16 hours at room temperature.

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The precipitation obtained by adding diethyl ether is three times washed with diethyl ether, then dried and reprecipitated in methanol with diethyl ether. After drying 5 mg of a white powder are obtained.

The compound obtained is dissolved in 1 ml of water, the solution is adjusted to a pH of 11.0 with 5 η aqueous ammonia solution and stirred under nitrogen at room temperature for 16 hours. After adding n-propanol and distilling off the aqueous ammonia solution, 5 mg of the title derivative are obtained in the ammonium salt form as a white powder with the following UV absorption: mu, E ^ = 148.

Example 7

Amino hydrolysis derivative (ammonium salt form) of the methyl ester of diumycin A with N- (2-aminoethyl) piperidine 5 mg of the methyl ester obtained according to Example 1 in 0.1 ml of tetramethylurea are mixed with 0.1 ml of N- (2- Aminoethyl) piperidine added. The mixture is stirred under nitrogen at room temperature for 16 hours and treated as in Example 6. 4 mg of the title derivative are obtained in the ammonium salt form as a white powder with the following UV absorption:
A? 2? = 274

Example 8

Aminolysis hydrolysis derivative (ammonium salt form) of the ester of Diumycins A with N-aminomorpholine

5 mg of the methyl ester obtained according to Example 1 in 0.1 ml of tetramethyl nutrient are under nitrogen with 0.1 ml

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N-aminomorpholine stirred for 16 "hours at room temperature Working up according to Example 6 results in 4 parts of the title derivative in the ammonium salt form as a white powder with the following UV absorption:

^ rnix " ²⁷³ * Ψ> ^E ^ ^{= 1Ü9} *

Example 9

Aminolysis hydrolysis derivative (ammonium salt For m) of the methyl ester of Diumyci ns A with diethyla min 5 mg of the methyl ester obtained according to Example 1 in 0 _s 1 ml of tetramethylurea are under nitrogen with 0.1 ml of diethylamine for 16 hours at room temperature touched. After working up according to Example 6, 5 g of the title derivative are obtained in the ammonium salt form as a white powder with the following UV absorption:

..tr rs -ίο / . - ' .

Amix ^{= 277} T ' ^{E = 113}

Example 10

Aminolysis hydrolysis derivative ( ammonium salt form) of the methyl ester of diumycin A with methylamine

5 mg of the methyl ester obtained according to Example 1 in 0.1 ml of tetramethyl urea are mixed with 0.2 ml of tetramethyl urea, saturated with methylamine. The mixture is stirred under nitrogen for 16 hours at room temperature. After working up according to Example 6, 5 mg of the title derivative are obtained in the ammonium salt form as a white powder with the following UV absorption; I ^ = 275 mu, E ^Λ% = 133. ·

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Example 11

Aminolysis hydrolysis derivative (ammonium salt form) of the methyl ester of diumycin A with isopropylamine A mixture of 80 mg of the methyl ester obtained in Example 1 and 100 ml of isopropylamine in 100 ml of tetramethylurea is stirred under nitrogen at room temperature for 16 hours. The excess of isopropylamine is distilled off under reduced pressure. By adding diethyl ether to the remaining solution, a precipitate is obtained with the following UV absorption:

lx ■ ²⁷⁶ T ' ^{E 1} * ⁼

A solution of the precipitate obtained in methanol is chromatographed according to Example 1. Fractions No. 29 to 32 are combined and evaporated. After dissolving in methanol and reprecipitation with diethyl ether, 25 mg of the corresponding aminolysis derivative are obtained in the ester form as a white powder with the following data:
UV absorption:

mu, E ¹ * = 157.

Analysis: CHNP OCH ₃ 0

found: 50.17 7.34 5.00 1.90 4.14 35.59 (as difference

calculated)

5 mg of the derivative obtained are mixed with aqueous ammonia solution further processed according to example 6. 5 mg of the title derivative are obtained in the ammonium salt form.

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Example 12

Aminolysis hydrolysis derivative (ammonium salt) of the methyl ester of diumvcin A with 4-aminomethylpyridine A mixture of 5 mg of the methyl ester obtained in Example 1 and 100 ml of 4-aminomethylpyridine in 100 ml of tetramethylurea is stirred under nitrogen at room temperature for 16 hours. After working up according to Example 6, 5 mg of the title derivative with the following UV absorption are obtained:

nothing = ²⁷⁶ T ' ^E - ¹⁰⁸

266 mji, E ^ = 103 (sh).

Example 13 Ethyl ester of diumycin A

According to Example 1, but using an equivalent Amount of diazoethane, the title compound is obtained.

Example 14

Benzhydryl esters of diumycin A and diumycin A ¹

The title compounds are obtained according to Example 2, but using an equivalent amount of diphenyldiazomethane.

, Example 15

Aminolysis-hydrolysis derivatives (free acid and ammonium salt) of the methyl ester of diumycin A and diuraycin A ¹ with cyolohexylamine The title derivatives are obtained as in Example 4, but using an equivalent amount of cyclohexylamine.

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Example 16

Aminolvse hydrolysis derivative (ammonium salt) of the methyl ester of Diumycins A with benzylamine

According to Example 11, but using an equivalent Amount of benzylamine, the title derivative is obtained.

Example 17

Aminolysis hydrolysis derivative (ammonium salt) of the methyl ester of diumycin A with cyclobutylamine

The title derivative is obtained according to Example 16, but using an equivalent amount of cyclobutylamine.

B e i s ρ i el 18

Aminolysis hydrolysis derivative (ammonium salt) of the methyl ester of Diumycins A with m-bromobenzylamine

The title derivative is obtained according to Example 16, but using an equivalent amount of m-bromobenzylamine.

Examples 19 "Ms 22

According to Example 6, but using an equivalent amount of one of the heterocyclic amines given below, the corresponding aminolysis-hydrolysis derivatives of the methyl ester of diumycin A are obtained in the ammonium salt form.

Example 19 Thiomorpholine

Example 20 N-methylpiperazine

Example 21 N-Methyl-N '- (2-aminoethyl) piperazine Example 22 N- (3-aminopropyl) thiomorpholine.

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Example 23 Benzyl Esters of Diumvcin A

According to Example 1, but using an equivalent ' Amount of phenyldiazomethane, the title compound is obtained.

Example 24 4-methylbenzyl ester of diumvcin A

According to Example 1, but using an equivalent Amount of 4-methylphenyldiazomethane, the title compound is obtained .

Example 25 p-Methoxybenzyl Ester of Diumycin A

According to Example 1, but using an equivalent Amount of p-methoxyphenyldiazomethane, the title compound is obtained.

Example 26 p-Chlorobenzyl Ester of Diumvcin A

According to Example 1, but using an equivalent Amount of p-chlorophenyldiazomethane, the title compound is obtained.

Example 27

^ drazi nolyse- hydrolysis derivative (ammonium salt) of the methyl ester of diumvcin A.

According to Example 6, but using an equivalent amount of hydrazine ■, gives the title derivative.

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Examples 28 to

According to Example 27, but using the hydrazines given below, the corresponding hydrazines are obtained

Nolysis-hydrolysis derivatives of the methyl ester of diumycin A: Examples

28 methylhydrazine

29 hexylhydrazine

30 N ₁ N diet hydrazine

31 phenylhydrazine

32 N-methyl-N-phenylhydrazine

33 o-chlorophenyl hydrazine

34 p-ethylphenyl hydrazine

35 m-methoxyphenyl hydrazine

36 p-nitrophenyl hydrazine

37 N-aminoethyleneimine

38 N-aminopyrrolidine

39 N-aminopiperidine

40 N-aminothiomorpholine

41 N-aminopiperazine.

Example 42

Hydrolysis derivative of the benzyl ester of Diutnycin A The compound obtained according to example 23 is converted into the title derivative according to example.

Example 43

Hydrolysis derivative of the p-methoxybenzyl ester of diumycin A The compound obtained according to example 25 is converted into the title derivative according to example.

Example 44

Hydrolysis derivative of the ethyl ester of diumycin A The compound obtained according to Example 13 is according to Example

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- 23 3 transferred to the title derivative.

Example 45

Aminolysis hydrolysis derivative (ammonium salt ) of p-methoxybenzyl ester of dimycin A with pyrrolidine. The compound obtained according to example 25 is converted according to example 6 into the title derivative.

Example 46

Aminolysis -Hydroly se derivative (Ammoniunsalz) do s Äthy Lester of Diumycin ^ A with cyclohexylamine

The compound obtained according to Example 13 is according to Example 11, but using an equivalent amount of cyclohexylamine, converted into the title derivative.

Example 47

Hydrazinolysis-hydrolysis derivatives (free acids and ammonium salts ) der Benzhydry les ter des Diumycin, '.; A and diumycin,; ·? A 'with N, N diethydrazine

The compounds obtained according to Example 14 are according to Example 5 but 'using an equivalent amount of N, N-diethylhydrazine, converted into the title derivatives.

In Table I below are the minimum inhibitory concentrations (MIC) of compounds of the invention against various pathogens.

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link

Hydrolysis product I of the methyl ester of diumycin A.

Hydrolysis product II of the methyl ester of diumycin A

Aminolysis hydrolysis products (acid form) of Methyl esters of diumycin A and diumycin A '(1: 1) with morpholine

Aminolysis hydrolysis products (acid form) of Methyl esters of diumycin A and diumycin A '(1: 1) with isopropylamine

- 24 -

Table I (MIC in r / ml)

Microorganisms S. aureus S. pyoßenes B. subtilis

3.1

0.8

0.03

0.018

0.05

0.032

0.008

0.003

0.3 0.3 0.06

0.02

Table II shows the effect of some compounds of the invention on the infected animal. Mice are used subcutaneously a lethal dose of Streptococcus pyogenes C? 03.

Table II

in mg / kg body weight)

link

SD

50

Amin'olysis-hydrolysis products (acid form) of the methyl esters of diumycin A and diumycin A ¹ (1: 1) with morpholine

Aminolysis-hydrolysis products (acid form) of the methyl esters of diumycin A and diumycin A ¹ (1: 1) with isopropylamine

0.94

1.49

^"SD 5o" ^{is the} east ^{eni e} g dose at which 50 percent of the treated

50
Animals survive.

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Claims (17)

Claims 1. Derivatives of esters of diumycins A or diumycins A ¹ , in which the group H-O- of the chromophore, R ' by a remainder of the general formula \ or ■ 5 a
is replaced, in which R and R are the same or different and are hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms, cycloalkyl radicals with 3 Ms 6 carbon atoms, benzyl, phenethyl, monohalosubstituted benzyl or monohalosubstituted phenethyl groups or alkyl radicals with 1 to 5 mean carbon atoms which are substituted by a 5- or 6-membered nitrogen-containing heterocyclic radical, the optionally contains a second oxygen, sulfur or stick's 4 material heteroatom, or R and R together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated nitrogen-containing heterocyclic radical, which optionally contains a second oxygen -, sulfur or nitrogen heteroatom, B? and R are identical or different and represent hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms, phenyl or phenyl substituted by fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy radical with 1 to 3 carbon atoms or a nitro group, or R and R together with the nitrogen atom to which they are attached form a 3- to 6-. 409839/1027 membered heterocyclic ring, which optionally forms a Contains oxygen, sulfur or nitrogen heteroatom, and which in the UV absorption spectrum in aqueous solution in the range of absorb about 274 to about 285 mu. 2. Compounds according to claim 1, characterized in that ■ τ. λ R- ^ and R hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms, Cycloalkyl radicals with 3 to 6 carbon atoms, benzyl, phenethyl, monohalo-substituted benzyl or monohalo-substituted ones Mean phenethyl groups. 3. Compounds according to claim 1, characterized in that
R- ⁵ and R represent alkyl radicals with 1 to 5 carbon atoms,
which are substituted by a 5- or 6-membered nitrogen-containing heterocyclic radical which optionally contains a further oxygen, sulfur or nitrogen heteroatom. 4. Compounds according to claim 1, characterized in that R
and R together with the nitrogen atom to which it is attached
are, a 5- or 6-membered saturated nitrogen-containing heterocyclic radical, which is optionally a
further oxygen, sulfur or nitrogen hetero- atom contains. 5. Compounds according to claim 1, characterized in that
that R ⁵ and R ⁶ together with the nitrogen atom to which they are attached
are bound, a 3- to 6-membered heterocyclic
Form ring, which may contain a further oxygen,
Contains sulfur or nitrogen heteroatom. 409839/1027 6. Compounds according to claim 1, characterized in that the chromophoric group is a radical of the general formula or means and at least one of the remaining  ^ ch-O groups has been converted into the free acid, and the compound in the UV absorption spectrum in aqueous solution in the range of about 274 mu to about 285 mu absorbed. 7. Compounds according to claim 6, characterized in that 3 4 R and R hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms, Cycloalkyl radicals with 3 to 6 carbon atoms, benzyl, Denote phenethyl, monohalosubstituted benzyl or monohalosubstituted phenethyl groups. 8. Compounds according to claim 6, characterized in that R and R hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms
atoms, phenyl groups or / by a fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy radical with 1 to 3 carbon atoms or a nitro group substituted phenyl. 9. Compounds according to claim 6, characterized in that 3 4
R and R denote an alkylamino radical with 1 to 4 carbon atoms which is substituted by a 5- or 6-membered nitrogen-containing heterocyclic radical which optionally contains a further oxygen, sulfur or nitrogen heteroatom. 409839/1027 10. Compounds according to claim 6, characterized in that 3 4 R and R together with the nitrogen atom to which they are attached are, form a 5- or 6-membered saturated nitrogen-containing heterocyclic radical, which optionally another oxygen, sulfur or nitrogen heteroatom contains. 11. Compounds according to claim 6, characterized in that that R and R together with the nitrogen atom to which they are attached are bonded, form a 3- to 6-membered heterocyclic ring, which optionally contains a further oxygen, Contains sulfur or nitrogen heteroatom. 12. Compounds according to claim 10, characterized in that the heterocyclic radical is a 6-membered ring, which contains another oxygen heteroatom. 13. Compounds according to claim 1, characterized in that one or two of the alkyl or arylalkyl ester groups of the Esters in the form of the free acid or as an alkali, alkaline earth, ammonium or trialkylammonium salt each with 1 to 6 carbon atoms present in the alkyl radicals, and the compound in the UV absorption spectrum in aqueous solution at a pH of about 2.2 at about 248 mu and at a pH of about 5 and about 11 absorbed at about 258 mu. 14. Process for the preparation of the compounds according to claim 13, characterized in that an alkyl or arylalkyl ester of diumycin A or diumycin A ^f with a primary or secondary amine of the general formula] 409839/1027 H-N - 29 - or a hydrazine of the general formula ^ 4 5 6
in which R-, R, R and R have the meaning given in claim 1, at temperatures from about room temperature to about 100 ^° C. for a period of about 1 'to 48 hours. 15. A process for the preparation of compounds according to claim 13, characterized in that an alkyl or aralkyl ester of diumycin A or diumycin A ^f , in which one or two of the ester groups in the free acid or the corresponding alkali, alkaline earth, ammonium - Or Trialkylammoniumsalζ with 1 to 6 carbon atoms in the alkyl groups are converted, with at least two equivalents of an inorganic base at a pH of about 10 to about 11.5 and at temperatures of about 0 to about 40 ⁰ C for a period of about 30 minutes to about 16 hours. 16. Process for the preparation of compounds according to claim 6, characterized in that one is an aminolysis derivative Alkyl or aralkyl esters of diumycin A or diumycin A · in which the group 409839/1 027 1 N -O of the chromophore by a remainder of the general formula or v. N.- N-NH- I I is replaced, in which R, R, R ⁵ and R have the meaning given in claim 1, with at least two equivalents of an inorganic base at a pH-Y / ert of about 10 to about 11.5 and at temperatures of about 0 to about 40 ° C for a period of about 30 minutes to about 16 hours. 17. Medicaments consisting of a compound according to claim 1 to 13, or its salt and customary carriers and / or diluents and / or auxiliaries. 409839/1027