DE1770675A1 - New viomycin derivatives and processes for their preparation - Google Patents

Description

ϋτ. 0. Dittmann K. L Schiff Dr. A. ν. Funer

PATENT LAWYERS

a Munich 90, Bereiteranger 15, Tel. 297369 DA-2104

description

to the

Patent application for

INSTYTUT ANTYBIOTYKOW Warsaw / Poland,
Staroscinskastrasse 5

concerning

New Viomycin derivatives and processes for their production.

(Priority 12/1/1968 - Poland P-124 654 24/6/1967 - Poland P-12-1, 126).

The invention relates to new vionycin derivatives

-5;

with (other) antibiotics and their derivatives, as well as the process for their production «,

Viomycin, an antibiotic widely used in tuberculosis therapy, is being used made in SuIfatforra.

Pharmacological and clinical studies regarding the toxicity of the viomycin sulfate used in therapy have shown that the toxicity This is due, among other things, to the presence of sulfate ion, which binds the body calcium.

More favorable healing results were therefore obtained with simultaneous administration of Viomyciiisulfat together.

109846/1892

men achieved with pantothenic acid. Sa was also a process for the production of Viomyoln pantothenate, daa eich in comparison with vionycin sulphate due to a lower toxicity, as well as a process for the production of derivatives of this antibiotic with amino acids and vitamins elaborated from the acidic character.

The invention relates to viomycin derivatives of antibiotics or their derivatives, of the general formula

R. 3X

where R is viomycin and X is any natural or semi-synthetic penicillin, in particular bensyl, cC-aminobenzyl-, phenoxymethyl-, phenoxyethyl-, phenoxypropyl-, S-methyl-S-phenoxy-i-isoxasolyl-, 5-methyl-3-p-chlorophenyl-4-iaoxazolyl- or 2,6-dimethoxyphenyl- or a chloramphenicol derivative of the formula

HOOC - (ClHY) _n - 000 - R ₁

where R-, a chloramphenicol radical, η · 0-8 and Y is hydrogen, halogen, OH, alkyl, _r alkoxyl or aryl group.

These compounds are distinguished by good vase solubility, low toxicity and a wide spectrum of antibiotics. These derivatives are suitable for use in various pharmaceutical forms.

109846/1892

The manufacturing device according to the invention of Viomycin derivatives of antibiotics also includes antibiotics the tetracycline group. There KMsrden connections of the formula

(R ₁ - GH ₂ ) _m - R .3Z

obtained wherein R is the Viomycinrest, R, the Tatracyelinrest or its derivative with a Karbamylgruppe on the carbon atom in the position 2 m * 1 ~ 3 and 'Z represents a al.lphatIsche monocarboxylic acid or Pyridinkarbcnsäure.

These compounds are characterized by a & n widened antibiotic range of action

The method according to the invention of viomycin compounds with penicillins or chloraiaphenicol derivatives is based on the fact that the corresponding antibiotic or its derivative, which has a free carboxyl group in the molecule, is converted into a salt of a finished metal by extraction from an acidic water solution ether and ether is Reesräraktion from lögung with what = ser containing a zveiwertiges MetalIhjdroxjii transferred.

A stoichiometric amount of the e. bigs V'eise obtained aqueous solution of the ssneiwertigan Arttibiatitiunaieialleer. = ses effect and narrow after the. Atf: ir.triezan des ausfä'.l »

ORIGINAL BATHROOM 109846/189?

th salt obtained due to the double reaction, the filate dissolves to a small extent and dissolves in methanol. The product is precipitated by adding ethyl ether or another organic solvent in which the vlomycin compounds are insoluble. The finished product can also be obtained by lyophilizing the clear water solutions. In both cases, products are obtained in an overall yield of 82.5 - 92.0 % .

The vioeycin compounds obtained have high antibiotic activity; with a small one

Tcxiaitätgrad on (Tab. I).

9846 / 1ii? BATH ORIGINAL

1 , 0 Tabel 2 3 0 4th 56 5 A. Acute
Toxic
did 2 5 3 4th 0 5 1 6th , 56 ag / fca designation
dex connection 25, 5 i Ϊ 100.0 100, 0 'O ₁ 3 0 , 05 ■ ⁷ ι 1 12, O 75.0 100, 0 1 1 , 4 385 Viomycin-Benzylpeni-
cillat ' 12, 25.0 100, 0 O. 0 0 Λ 461 Viomycin- ⁰ ^ -Amino-
benzyl panicillate 25, 50.0 25, 25th 0, 0 0 57 395 Viomycin Phenoxy
ethyl psnicillate 6, 12.5 75 8th 0. 0 O ₁ 92 405 Vionyci n-phenoxy-
ethyl penicillate 25, Minimal bacterial growth
inhibiting concentration χ /
jag / αϊ 100.0 X, 64 100, 0 1, _s 369 Vioatycin phenoxy
propyl penicillate 25, 100.0 0, 0 166, 0, 0 570 Viomycin-3-phenyl · = ■
5-methy.L ~ 4-i soxa-
zolyl penicillate 25, 25.0 X. IOC, ORlQl 8th, 570 Vi © "ycin" 3-o ° chlorine-
phenyl = -3-methyl -4-
isoxazolylpenicil-
lat 16, 41.7 25, 2S, 75 650 Viomycin 2,6 dime
thoxyphenylpeni-
cillat ^ L ₂ , 10.4 - - 253 Compound of chlorine
aiaphenikol ^ amber-
acid monoesters with
Viomycin 109846 / 1892 BATH NAL 174 fat. Er ζ our mi a d JiCX Bi 25th O O O 6th

^x 'the ssur test used bacterial stfimoo:

1 - Mycobacterium phlei

2 - Mycobacterium emegaatie

3 - Bacillus subtilia ATCC 6633

4 - Bacillus cereus 6579

5 - Niorococcus pyogenes var. Aureus 209-P

The inventive method of preparation of Vioaycinderivaten ait antibiotics άέχ Tetraoyclinruppe in the molecule is based on the fact that tetracycline or its derivatives with a carbamyl group on carbon 2 with a Viomycin salt of an aliphatic carboxylic acid or with pyridinecarboxylic acid 2: acted with Tetracycline in a Molecular carboxylic acid. 1 or 3t1 is applied and the reaction is carried out in the presence of formaldehyde in an alcohol medium (preferably methanol) After the components have reacted completely, the product is blown by thickening the solution in a vacuum evaporator and filtering off the precipitate or by precipitation on addition of ethyl ether or another organic solvent in which the compounds obtained are sparingly soluble, the precipitates obtained are isolated after comminution in a vacuum scraper on P ₃ O ₅ . Weight dried or subjected to lyophilization with a small amount of water.

Depending on the isolation method to be used, the end product is obtained in a yield of 50-90%.

109846/18 * 2 bath original

The antihiotic activity and the acute toxicity of the Viomycin derivatives to be discussed, the antibiotics in the molecule the tetracycline group is contained in Table II shown.

109846/1892 bad

ORIGINAL

Table II

Connecting
designation Minimal wax
tumbling we
kung of the prepa
rates at the test
stem of the micro
coccus pygenes
var.aureus 209-P
mcg / ml Minimal wax
tumble-inhibiting we
kung of the prepa
rates at the test
stem of the Myco-
bacterium smag-
matis
mcg / ml Acute
Toxiai-
activity
Mice
against
above Viomycine acetate tetra
cyclinomethyl 0.67 0.60 103 Vi omyci n & zet at -Oxy -
totraeyclinomethyl 1.88 1.37 108 V-omyainpropionate oxy »
t fit ι ady cl inomethy). ι, εο 0.70 109 Ttit raeycl inomethyl »
Viouiyclnifcotinat 1.50 0.50 93 O; ^ yt et r &? Ycl inmethyl-
Viomycin tricotinate 1.S8 0.92 103 Does racyclinomethyl ~
Vi.oitycinisonicotinate 1.25 0.60 101 Oj-ryt et ι acy u I i norae t hy J, -
Vromycinigpnikotirifit 1, ^ 5 0.70 99 Dioxytetιaoyslinomethyl-
Yioryoin nicotinate 4.68 1.96 167 Tx ioxy tetrficp 3lixi & -
methyl "Viomycinieoni-
cctinate ι, εδ 1, S6 191 'ϊε tr-acycline 0.41 0, B0 166 C.7: ytetracyciline 0, S6 0.80 178 Vnonactan * Frod, CrE ^! - 10.4 174

109846/189?

BATH ORIGINAL

The manufacturing process according to the invention of the viomyein compound with antibiotics and their derivatives is illustrated in detail in the following examples .

Example Io - Viomyein Benzylpenicillate -

5.0 g de3 Kalisalses of benzylpenicillin was in 25 ml Dissolved wet, added 50 ml of ethyl ether and vigorously Stirring brought to pH 2.5 with 2 η hydrochloric acid. The separated ether layer was added with vigorous stirring 0.1 η barium hydroxide is added until a pH of 7.5 is reached. The water layer was then separated off and evaporated to dryness in a vacuum evaporator.

4.75 g of the barium salt of benzylpenicillin were obtained, which was dissolved in 50 ml of water and to which 3 g of viomycin sulfate in 30 ml of water were added dropwise with vigorous stirring. After the whole thing had been carried out for 30 minutes, the deposited barium sulfate was filtered off and the filtrate was concentrated at low temperature in a vacuum evaporator. The dry residue was taken up in 40 ml of methanol and 200 ail of ethyl ether were added; the deposited precipitate of panicillin acid viomycin was dried in a vacuum desiccator übar Ρ «/) _ς to constant weight«

There were 5.9 g of product (yield 92.0% that Ba-SaIz des penicillin bezegan) obtained.

BAD ORfG | _NAL 109846/1892

ίο.

Determination of total nitrogen:

calculated 15.65% found 15.24%

Example II .-- Viomycin Phenoxymethylpenicillate -

0.1 η barium hydroxide was added to 4.15 g of phenoxymethylpenicillin until the components had completely reacted. A solution of 3.0 g of viomycin sulfate in 30 ml of water was added dropwise to the clear solution with stirring. After a 30min. Continuous cooling, the deposited barium sulfate was filtered off and the clear filtrate was evaporated to dryness in a vacuum evaporator, after which the residue was dissolved in a small volume of methanol and precipitated as a precipitate by adding 200 ml of ethyl ether. After filtering off, the precipitate was dissolved in 20 ml of water and subjected to lyophilization. Ks were 5.85 g viomycin-Phenoxymethylpenicillat obtained (89% yield based on penicillin V-barium salt).

Determination of the total nitrogen:

calculated 15.20 % found 15.45%

Example III. - Viomycin phenoxyethyl penicillate -

To a solution of 3.05 g of the barium salt of Phenoxyäthy! Penicillin in 40 ml of water with vigorous stirring was a

109846/189 2 _BAD ORIGINAL

- Ii -

Solution of 1.8 g of viomycin sulfate in 20 ml of water was added dropwise and stirred for 30 min. The secluded Barium sulfate was filtered off and the clear solution was evaporated to dryness in a vacuum evaporator at a low temperature. The dry residue was dissolved in 25 ml of methanol and the product was obtained by adding 150 ml of ethyl ether failed.

There were 3.48 g of viomycin phenoxyethyl penicillate (86% yield) obtained after dissolving in a subjected to the lyophilization process in a small amount of water became.

Determination of total nitrogen:

calculated 14.83% found 15.56%

Example IV. - Connection of viomycin with chloramphenic oil succinic acid monoester -

1.3 g sodium salt; of the chloramphenicol succinic acid monoester was dissolved in 25 ml of water, 50 ml of ethyl ether were added and the mixture was acidified to pH 2 with 1 HCl. The ether layer was separated off after the extraction, washed twice with water and then taken up by re-extraction in 0.1 η Ba (OH) ₀ at pH 7. The water layer, which contained the barium salt of the chloramphenicol succinic acid monoester, was evaporated to dryness. The dry residue was dissolved in 50 ml of water, then 0.7 g

BATH ORIGINAL 109846/189 2

~ 12 -

Viomycin sulfate added. After a 10 min The barium sulfate which had separated out was filtered off with stirring, and the filtrate was evaporated to dryness in a vacuum evaporator The dry residue was dissolved in 50 ml of methanol and the product was precipitated by adding 200 ml of ethyl ether. After being filtered off, the obtained precipitate became again dissolved in water and subjected to a lyophilization process. It was 1.5 g of the compound des Vioraycin obtained with chloramphenicol succinic acid ester (in a yield of 82.5%).

Determination of the total nitrogen:

calculated 13.44% found 13.99%

Example V. - Viomycinazetat-Tetracyclinemethyl -

Viomycin acetate in an amount of 4 g was dissolved in 30 ml of methanol and then a solution of 2.25 g of the Tetra ™ cyclin base in 20 ml of methanol was added. 2.7 ml of a 7.2% strength methanol solution of formaldehyde were added to the resulting solution and the mixture was stirred at room temperature for 30 minutes. 50 ml of ethyl ether are then added to the solution that has become cloudy and, after stirring for a further 15 minutes, the deposited precipitate is filtered, washed with ether and dried in a vacuum desiccator over PoOc until constant. 4.35 g of tetracycline ethyl viomycin acetate (68.8%.) Were obtained.

10 9 8 4 6/189? bad original

Determination of total nitrogen:

calculated 15.75% found 16.14%

Example VI. - ViomycinaKetat-Gxytetracyclinmethyl ■ ».

To a solution of 2.33 g of the oxytetracyelin base in 80 ml of methanol, 4.0 g of viomycina acetate, which had previously been dissolved in 30 ml of methanol, were added. Then 2 _? 8 ml of a 7.2% formaldehyde solution (in methanol) was added and the goose was passed through for 30 minutes, after which it was evaporated to half the volume in a vacuum evaporator, 50 ml of ethyl ether were added and the precipitate was deposited was filtered off. Do dsm drying at a temperature of 40 ⁰ C were obtained 4.7 g · Oxy "tetracyclinmethyl-Viomycinazetat (goal for 74.6%) ■ ·

Determination of total nitrogen:.

calculated 15.58% found 15.93 %

Example ¥ 11 "- Oxytetracycline methy1-Viomyciapropionat -

2.22 g of the oxytstracycline base and 4.0 g of vi ^ myoin propionate were dissolved in 120 ml of methanol and, after adding 2.56 ml of a 7.2% formaldehyde solution, allowed to dry for 30 minutes. Dex deposited precipitate was ai; ... led, old. Catch the ether and go to Dijm Loien

109846/189 2 ^BAD

-subjected to lyophilization in 20 ml of water. 5.4 oxytetracycline methyl viomycin propionate, d.i. in a 86% yield obtained

Determination of the total nitrogen:

calculated 15.05 % found 15.55 %

Example VIII. - Tetracycline Methyl Viomycinnicotinate -

4.0 g of viomycinnicotinate were dissolved in 40 ml of methanol, then 2.18 ml of a 7.2% formaldehyde solution were added and a solution of 1.82 g of the tetracycline base in 25 ml of methanol is added with continued stirring. The whole Was stirred for 45 min. After which it was in a vacuum evaporator at a temperature of 35 ° C to a volume of 20 ml was concentrated. From the thickened suspension obtained, the precipitate was filtered off and after

_o in

Dry at a temperature of 40 C / a small amount of water dissolved and lyophilized. There were 4.65 g of tetracycline methyl viomycinnicotinate (Yield 79%).

Determination of the total nitrogen:

calculated 16.55% found 16.68%

Example IX. - Oxytetracycline methyl viomycinnicotinate -

Viomycinnicotinate in a Menga of 4 g was in 35.nl Dissolved methanol. The solution obtained was then poured into it

109846/1892 _ΛΜΑΙ

BATH ORIGINAL

- ■ 15 -

2.27 ml of a 7 _r ~ 2% added IgAN formaldehyde solution and the reaction mixture into a solution of 1.88 g of Oxytetracyclinbase * in 100 ml of methanol is poured. After stirring for 30 minutes, the suspension obtained was concentrated in a vacuum evaporator to half its original volume, the deposited precipitate was filtered off, washed with ether and dried at room temperature under ((vacuum dried j then dissolved in water and lyophilized.

There were 4.6 g of tetracycline methyl viortrycinnicotinate (Yield 77.8%).

Determination of the total nitrogen:

calculated 16.40 % ■ found 16.49%

Example X. - Tetracycline methyl viomyainisonicotinate -

For the reaction, 4.0 g of viomycin isoniicotinate, 1.82 g ~

the tetracycline base and 2.18 ml of a 7.2 7 ₀ formaldehyde solution used. The procedure was the same as in Example VIII, but after filtering off the precipitate and drying it, 4.12 g of product were obtained, which represents a yield of 7C%. 100 ml of ethyl ether were then added to the filtrate and the deposited precipitate was separated off and dried.

1 0 9 8 4 6/189? ⁸ AD ORIGINAL

1.46 g of tetracycline methyl viomycin isonicotinate were obtained obtain.

A total of 5.58 g of product (yield 95%) obtain.

Determination of total nitrogen:

calculated 16.55% found 16, S8%

Example XI. - Qxytetracycline methyl viomycin isonicotinate -

4.0 g viomycin isonicotinate, 1.88 g of the oxytetracycline base and 2.27 ml of a 7.2% formaldehyde solution in methanol were used. The procedure was the same as for viomycinnicotinate (Example IX). 4.9 g of xytetracycline methyl viomyoinisonicotinate {yield 82.7 %} were obtained.

Determination of the total nitrogen:

calculated 16.40% found 16.45%

Example XZI. - Dioxytetracyclirur.ethyl-Viom.ycinisonikoti.nat -

2 g viomycin isonicotinate were dissolved in 15 ml of methanol., C. 83 ml of a 39% methanol / formaldehyde solution added and after a few minutes of renewed stirring a solution of 1.89 g of the oxytetracycline base in 120 ml

1098A6 / 189? _BATH

177Q675

Methanol added. The whole was heated to 35 ° C and Stirred for 40 minutes. After cooling down to room temperature the deposited precipitate was filtered off, washed with ether and dried in a vacuum desiccator to constant weight.

.... ' 1.98 g of dioxytetracycline methyl-Vio · =

mycinisonicotinate (yield 50.3%) was obtained.

Determination of the total nitrogen:

calculated 13.85% found 13.51 %

Example XIII. - Trioxytetracyclinemethyl-Viomycinisoniko-

tinat -

Procedure as in Example XII, but with the Qxytetracyclinebase for the reaction in an amount of 2.84 g and the 39% formaldehyde solution in methanol in one Amount of 1.28 ml were used.

The trioxytetracycline methyl viomycin isonicotinate was obtained in an amount of 2.69 g (yield 55 %) «

Determination of the total nitrogen:

calculated 12.32% ■ found 11.95%

Claims

9846/1892 ORIGINAL BATHROOM

Claims (28)

Patent claims 1- New Viomycin "connections with other antibiotics resp. their derivatives of the general formula R. 3X, where R is viomycin and X is any natural or semi-synthetic Penicillin, especially the benzyl dS-aminobenzyl, PhenoxymethAl · = ■, phenoxyethyl, phenoxypropyl, 5-methyl -3-phenoxy-4-isoxazolyl-, 5-methyl- «Vp-chlorophenyl-4-isoxazolyl- or 2,6-dimethoxyphenyl or a chloramphenicol derivative the formula HOGC - CCHY) _n - CDO - R ₃ , where Κ-, a chloramphenicol residue, η * 0 - 8 and Y is hydrogen. Halogen, OH- _s alkyl, alkoxyl or aryl groups represent. 2. New viomycin compounds of antibiotics of the formula .'R, - CH ₉ J _n - R, 3Z where R is the viomycin residue, R, the tetracycline residue or dessan Derivative with a carbamyl group on the carbon atom in Position 2, ia = 1 - 3 and Z aine aliphatic © monocarboxylic acid or represents pyridine carboxylic acid. 3. Viomycin-Bensyipenici Hat 4ο Viomycin- <£ -aminobensylpenicilate .. 5. Viomycin phenoxymethyl panicillate. 6. Viomycin phenoxyethyl penicillate. 109846/1892 BATH ORIGINAL ■ ■ - 19 - 7. Viomycin phenoxypropyl penicillate. 8 «Viomycin-S-phenyl-S-methyl-i-isQx & zolylpenicillate. 9. Viomycin-S-o-chlorophenyl-5-methyl "4" i!? Oxozolyl " penicillate. 10 »Vioaiycin-2, o-Dimethoxyphenylpanicillate. 11. Compound of chloramphenicol succinic acid aioester with viomycin. 12 »Vicmycin acetate tetracyclinomethylο 13. Viomycine zotate oxytetracyolinomethyl. 14 · Vic ^ ycin propionate-oxytetracyclinomsthj ^ l. 15. Tetracycline of ethyl viomycinnicotinate. 16. 0xyt.etracyclinemethyl-Viom3 ^r cinnicotinate. 17. Tetracydinomethyl vioaiycin isonicctinate. IS. Oxytetracyclinomethyl-Vioaycinisonicotinate. 13. Diox ^ rtetracyclinoraethyl-Viomycinisonicotinat 20 · Trioxytetracyclinomethyl-YioHiycinisonicotinate. 109846 / T ₈₉₂ 1770S75 - 20 - 21 · Process for the production of new viomycin derivatives according to Claim 1 or 2, characterized in that that you can add a salt of an antibiotic to the viomyein salt or a salt of an antibiotic derivative »its! carboxyl is substituted by a divalent metal, or an antibiotic, which has a free carbamyl group in the molecule contains, allows it to act. 22 · The method according to claim 21 ,. characterized in that salts of divalent metals of penicillin are used as antibiotic salts, with which the viomyein salt is allowed to act, the reaction being carried out at 10 to 50 ⁰ C, most preferably between 10 and 2Q® €, whereupon the product in a known Weis® is isolated. The method according to claim 2, characterized in that calcium and / or strontium salts are used as divalent metal salts of the penicillins, calcium and / or strontium salts, whereas viaaycine salts are those whose aniom, .namely the sulphate-> Phseph ^ pb- ^ hydrophosphate, metaphosphate and oxalate, form water-insoluble compounds with the gjemaantem divalent metals. 24. The method according to claim 22, characterized in that g e k e η η ζ β i σ h η e t that one can call penicillin © in any natural or semi-synthetic penicillin, of course the benzyl ,, (^ -Äminobenzyl-, Phenoxymethy-l », Phenoxypropyl -, 5-methyl-3-phenyl * 4- BATH ORIGINAL - 21 " 3 «p-chlorophenyl-4-isoxazolyl- or 2,6-dimethoxyphenyIpe '· nicillin used. 25. Modified method according to claim 1, characterized in that salts of divalent metals of monoesters of aliphatic dicarboxylic acids of chloramphenicol are used as antibiotic salts by allowing these salts to act on the viomycin salt, the reaction being -10 to SO ⁰ C, most preferably between 10 and 20 ^° C., with simultaneous stirring for 10 to 20 minutes, and then the product is isolated in a known manner. 26. The method according to claim 25, characterized in that calcium and / or strontium and / or barium salts are used as salts of the divalent metals of monoesters of aliphatic dicarboxylic acids of chloramphenicol, while salts are used as viomycin salts whose anion, namely the sulfate, Phosphate, hydro 'Λ phosphate, metaphosphate and oxalate, forms water-insoluble compounds with the divalent metals mentioned. 27. modified method according to claim 21, characterized GEK e η η ζ calibration η et using as antibiotics, the tetracycline or its derivatives, which have a Karbamylgruppa at the 2-th carbon atom, namely oxytetracycline, chlortetracycline, Bromtetracyclin, deoxytetracycline and demethyltetracycline or its Mixtures used in any ratio, with the reaction in one 9846/1892 ^ÖAD Alcohol ediuitt, preferably methanol medium, in the presence of formaldehyde, in a temperature range from -10 ° to +50 ⁰ C, most preferably between 10 and 20 ° C, carried out and the product obtained is isolated in a known manner. 28. » Process according to claim 27, characterized in that tetracycline or its derivative, the one on the 2nd carbon atom is a free carbamyl group used in a molar ratio to viomycin such as 1: 1, 2sl or 3: 1. 109846/1892 ORIGINAL BATHROOM