DE1915829C3 - Lower acyljosamycins, process for their preparation and medicinal products containing these compounds - Google Patents

Description

CH ₃

where R is a hydrogen atom, a lower acyl radical having 2 to 5 carbon atoms, with the proviso that both Rs do not represent a hydrogen atom at the same time.

2.10-propionyljosamycin.

3. Process for the preparation of lower acyl-josamycins of the general formula given in claim 1, characterized in that that one josamycin in a manner known per se either

a) with an approximately equimolar amount of an aliphatic carboxylic acid having 2 to 5 carbon atoms, or ^e:, nem reactive Deri vat the same in the presence of an inert organic solvent or b) with more than twice the equimolar amount of the acylating agent according to a) under basic Reacts reaction conditions and the diacyljosamycin formed then optionally. In Usually hydrolyzed in the presence of a water-containing inert organic solvent. 4. Medicines, indicated by a

Content of a compound according to Claim 1 as an active ingredient.

The invention relates to lower acyljosamycins of the general formula R O

CHO

OCH.,

wherein R is a hydrogen atom, a lower acyl radical having 2 to 5 carbon atoms, with the Provided that not both R represent a hydrogen atom at the same time and process for their preparation as well as medicaments containing these compounds.

The macrolide antibiotic iosamycin is a useful drug for treating infections caused by Gram-positive bacteria. (Iosamycin has a very bitter content, which leads to visual impairment when administered orally. If iosamycin is administered orally, for example in the form of tablets, the tablets must be coated with gelatin or gelatin to mask the hittereri Oesc hm, ic kes iihcr / ogcn be.

It has now been found that the HO

"O-

CH.

(J CH ₃

Acyljosamycins do not have the bitter taste of losamycins while being at least as good or better effects against bacterial infections.

The properties and effects of some compounds according to the invention were tested in the following tests checked against the iosamycin.

1. Test of bitter taste

Versuehsdu raw guide

The bitter taste of the compounds to be tested was made by 12 blindfolded adults (8 men. 4 I rough) by tasting checked. The results obtained are as follows Table I reproduced.

Table 1 Very bitter

Slightly bitter Hardly bitter Completely free from bitter taste

Josamycin (known) 2'-acetyljosam; a (Ex. 1) 10-Acetyljosamycin (Ex. 7 b) 2 ', 10-Diacetyljosamycin (Ex. 4) 10-Propionyl-josamycin (Ex. 9 b) 2 ', 10-Dipropionyl-josamycin (Ex. 9a) 10-butyryl-josamycin (Ex, 11)

11th

1 10 1 11th 12th 12th 12th 12th

2. Antibacterial activity

a) in vitro test execution

The minimum inhibitory concentration (MIC) of some compounds of the invention and of J & sdmycin was made according to the usual agar dilution method

Table 2

Minimum inhibitory concentration in mcg / ml *) determined on agar medium. The results are in Table 2 below

Microorganisms

Josamycin

2'-acetyljosamycin

10-acetyljosarnycin

2 ', 10-diacetyljosamycin

Staphylococcus aureus FDA 209P Staphylococcus aureus Smith Staphylococcus aureus PC, SM, TC, EM, SA, resistant

Staphylococcus aureus PC, CP, TC, SA, resistant Bacillus subtilis ATCC 6633 Myobactcriu-n 607 Escheria coli 0-1

Klebsieila pneumoniae PCI Salmonella typhi H90IW Shigella flexneri 2a 1675

Table 2 (continued)

0.39 0.39 0.39 0.39 0.39 0.39 0.39 0.39 > 100 > 100 > 100 > 100 0.78 0.78 0.78 0.78 0.39 0.39 '3.39 0.39 3.1 3.1 3.1 3.1 > 100 > 100 > 103 > 100 125 125 125 125 > 100 > 100 > 103 > 100 50 50 50 100

10-l'ropionyljosamycin 2 ', 10-propion)' - josamycin

10-butyryljosamycin

Staphylococcus aureus FDA 209P Staphylococcus aureus Smith

Staphylococcus aureus PC, SM, TC, KM, SA, resistant **) Staphylococcus aureus PC, CP, TI), SA, resislcnt ** Bacillus subtilis ATCC 6633 Mycobactcrium 607 lischcria coli 0- I
KIchsieila pneumoniae PCI Salmonella lyphi J90IW llexneri 2a 1675

0.39 i \ 7; j 0.78 - 0.78 : ,, y) 0.7: i 1.56 - 1.56 ') > 100 > 100 > 10 () 0.78 1.56 > I (XI 0.39 0.7U > 10 () 3.13 3.1.) ~ Sullaar / ne > KX) > 100 25th > H) O > KH) > 100 J rwhromuin. Cl ' (hloLimphciiKol. SA

! ■ (l'cmcillin. SM Streptomycin. I C I clr.Kvdin. IM n.imilch SuHadimclhoxin, SilU'adui / in. SiiH'amei.i / in

* l Du. · .icylicrlcn Josamyciile were \ cirtentlcl. which is to Jos.ini> cin äi | invalenl.
"ι Independent (jatlungen.

b) in vivo

(i) Therapeutic tests for
subcutaneous bacterial infections in mice

Carrying out the experiment

6 groups of 5 mice each were ^{inoculated subcutaneously in the back with 10 8} lines (in 0.1 ml volume) of Staphylococcus aureus strain No. 226. Immediately after infection, iosamycin or 10-acyljosamycin was administered orally. No drug was added to the control group (blind test). After 48 hours the animals were soldered. The back of each mouse was cut open and the size of the subcutaneous abscess was measured. The results are compiled in Table 3 below.
Table 3

Administered Abs / cUgrül.le Dose of antibiotic

10-acetyljosamycin

10-acyljosaniycin

Control

\ request

Josamycin

10-l'ropionyl-

ArI the
administration

dose

(mg / kg)

Number Aihl the der l'nerle-Mausc bendcn

on ". I.it

(mg / kg)

(ΠΙΠΊ ")

Control - 88.2

Josamycin 200 4.19

Josamycin 50 21.2

10-acetyljosamycin 2 (X) *) 0.64

*) The amount administered; in I () - acetyljosamycin corresponded one that is equivalent to josamycin

Carrying out the experiment

(ii) protecting the mouse against
Staph infection of the organism

6 groups of 5 mice each were injected intraperitoenally with 1000 times the minimum lethal dose (with an addition of 5% mucin) Staphylococcus aureus Smith inoculated. Immediately after infection a single dose of each antibiotic to be tested was administered orally. The effect of the Josamycins on the survival of the mice was after 7

TicTAn K ^ nKa ^ hlpt n # »r KnntmWaninnn iRlinHvprQiirM

consisting of 10 mice, no antibiotic was administered. The results are in the following Table 4 compiled.

Table 4

dto.
dto.

10-n-bulyryljosamycin
(Ex. 11)

dto.
dto.

10-isovaleryljosamycin
(Ex. U) I

dto.
dto.

orally orally

orally orally orally

orally

orally
orally

orally

orally
orally

orally

orally
orally

150 *) 50 *)

4 (X)
2 (X)
KX)

4 (X)

2 (X)
KX)

4 (X)

2 (X)
100

400

200
100

10

5 5 p

* l The amounts of the respective acyljosamycin corresponded those that are equivalent to josamycin

From these results, in connection with the experiments under 1, it can be seen that 10-propionyl-josamycin has particularly advantageous properties.

To check the levels of josamycin and

of 10-propionyljosamycin in body tissue and in the The following experiments were carried out in plasma

Groups of three, three-week-old Sprague-Dawley rats that were previously kept fasting 18 hours were orally 400 mg (josamycin equivalent) 10 pC'i / kg of josamycin ^I4-C or C-10 ^{M-Propionyljosamycin,} suspended in 0.5% sodium chloride solution, administered. One, two, four and six hours after the administration, blood was drawn from the underlying vena cava with a heparinized cannula syringe under ether anesthesia. The liver, kidneys, lungs, spleen and plasma were then separated. The ¹⁴ CO ₂ value obtained from a 180 to 200 mg aliquot sample of each tissue oxidized with a Packard Model 305 Sampler was determined for radioactivity with a Packard Model! 3380 liquid scintillation counter measured. The results obtained are shown in Table 5 below.

Distribution of radioactivity in tissue after oral administration of josamycin and 10-propionyljosamycin to rough dogs. The radioactivity is given in ■>% josamycin (JM) or; xg 10-propionyljosamycin (JM-P) (; jg or ami)

tissue

liver

antibiotic Type of dose number of number of Appointment Mice survive reaching the on (mg / kg) 7th day Josamycin orally 500 5 5 Josamycin orally 150 5 2 Josamycin orally 50 5 0 10-acetyl orally 500 *) 5 5 josamycin Table 5

1 hour
JM JM-I ' 2 hours
JM JM-P 4 hours
JM JM-P 6 hours
JM JM-P 147.4
± 22.6 163.5
± 25.5 188.!
± 21.7 383.9
± 55.3 109.6
± 20.4 274.4
+ 8.5 99.8
+ 4.3 229.0
+ M 5

7th I Sliiiulc JM Γ 19th 15829 4 slums 8th JMl ¹ 6 hours JM-I ¹ JM 92.6 JM 211.7 JM 214.6 continuation 94.6 ± 6.9 62.4 ± 26.8 63.1 ± 41.1 Cicwehe ± 15.0 119.4 2 hours ± 10.6 285.7 ± 3.0 297.9 40.5 ± 8.0 JM JM-I ' 37.8 ± 14.7 57.6 ± 98.0 N it'.n ± 4.6 83.0 131.5 212.9 ± 5.1 247.4 ± 22.1 278.1 53.4 ± 6.8 ± 19.6 ± 29.8 176.2 ± 13.2 811.7 ± 44.8 lung ± 10.5 18.6 73.4 284.3 + 88.0 34.3 ± 12.8 27.6 31.8 : t 3.0 ± 13.6 ± 28.7 20.8 ± 2.6 18.2 ± 2.3 Mil / ± 2.4 149.4 197.7 ± 4.7 ± 0.5 ± 4.8 ± 39.6 plasma 35.8 47.5 ± 2.7 ± 11.7

The results of the measurements show that, surprisingly, the level values of 10-propionyljosamycin compared with iosamycin in body tissue and in plasma after oral administration are much higher.

Furthermore, the toxicities of 2'-acetyljosamycin, 10-acetyljosamycin and 2,10-diacetyljosamycin Mice checked.

Male mice of the ddN strain weighing 18 to 20 g were given a single dose orally vo. 20 g / kg 2'-acetyljosamycin, 10-acetyljosamycin or 2 ', 10-diacetyljosamycin administered. The mice were observed for seven days. All animals survived and there was no evidence of toxicity or any histological changes in it Autopsy to be determined. This proves that the acyljosamycins in question are only very slightly toxic are.

The compounds of the invention are generally administered orally in the form of conventional pharmaceuticals Preparations administered, for example as tablets. Powder. Granules. SiruD. Chewable tablets. Capsules. Since the compounds according to the invention do not have a bitter taste, it is not necessary To use sugar or gelatin coatings for the tablets or granules or to taste the Improve syrups.

The clinical dose of the acyljosamycins in question is approximately 1–3 g per day, calculated on the basis of iosamycin. The daily dose can be divided into three to six doses and each dose is given at intervals of Administered for 8 to 4 hours. The dosage can vary according to the age and physical constitution of the patient vary.

The lower acyljosamycins of the formula already given are prepared in that one josamycin in a manner known per se either

a) with an approximately equal amount of an aliphatic Carboxylic acid having 2 to 5 carbon atoms or a reactive derivative thereof in Reacts in the presence of an inert organic solvent or

b) with more than twice the equimolar amount of the acylating agent according to a) with a basic reaction

and the diacyljosamycin formed then optionally. In the usual manner in the presence of a water-containing hydrolyzed inert organic solvent.

2 (i in the acylation of josamycin according to a), where as organic solvents for example a lower alcohol, ethyl acetate or acetone is used, the relevant 2'-acyljosamycin is formed. The diacyljosamycin in question is based on the working method

2) b) received. The implementation is for example in Carried out in the presence of pyridine or quinoline.

Since the acylation reaction proceeds slowly at room temperature, it can be done by heating Be decelerated. The hydrolysis of the corresponding

ii) the diacyljosamycins is in an inert organic water-containing solvents, preferably with 10-50% water content, such as aqueous methanol, aqueous ethanol, aqueous isopropanol, aqueous acetone, aqueous methyl ethyl ketone, aqueous di-

j) xan, aqueous dimethylformamide carried out this Hydrolysis reaction is initiated by heating or by adding a basic agent such as sodium carbonate, Ammonia or the like or an acidic agent such as hydrochloric acid. During hydrolysis a different monoacyljosamycin is produced than according to a), namely the 10-acyl compound in question.

The product can easily be isolated as it is generally in crystal form from the reaction mixture If necessary, it can fail in the usual way

π by adding an organic reading agent to the reaction mixture and then concentrating the obtained extract can be isolated under reduced pressure.

Suitable acylating agents are, for example

on acetic acid, propionic acid, butyric acid, isovaleric acid. Reactive derivatives are, for example, the acid anhydrides and acid halides.

The josamycin to be used as the starting material can be produced according to FR-F ¹ S 4385 M, for example

r> be.

example 1

1.0 g of josamycin was passed through in 2 ml of isopropanol

w) mild heating and dissolved to the resulting solution 032 g of acetic anhydride were added. The reaction mixture was left to stand for a short time at room temperature, whereupon crystal needles separated out.

The crystals were filtered off and then extracted from 2 ml

to 10% aqueous acetone recrystallized. Man received 810 mg of 2'-acetyljosamycin.

The compound had the following physicochemical properties:

1. Colorless crystal needles with a temperature of 182-183 ° C.

2. Specific rotation [«] ₍ = -86.0 ° (c = 1, CHCI ₃ ).

3. Absorption spectrum:

The ultraviolet absorption spectrum of the compound measured in methanol is shown in FIG. 1 shown. The absorption maximum E 343 is Γ32 ιημ. The ultra-red absorption (KBr) of this compound is shown in FIG. 2 reproduced. The NMR spectrum was measured in heavy chloroform and is shown in FIG. 3 shown.

4. Solubility:

The compound is easily soluble in acetone, methyl ethyl ketone, chloroform, ethyl acetate and benzene, soluble in methanol and ethanol and hardly soluble in water, petroleum ether and η-hexane.

5. Thin layer chromatography:

This compound was placed on a thin-layer plate made of aluminum oxide B-10 and with a Solvent mixture of butyl acetate / methyl ethyl ketone / water (80:18:12) developed. the Compound gave an Rf of 0.50. (The Rf value for iosamycin is 0.46.)

Example 2

In 3 ml of ethyl acetate, 1.0 g of iosamycin was dissolved, and 0.18 g of acetic anhydride was added to the resulting solution admitted. The reaction mixture was allowed to stand at room temperature for 30 minutes, whereby Crystal needles failed. The crystals were filtered off and then extracted from 2 ml of 90% aqueous acetone recrystallized. 780 mg of 2'-acetyljosamycin with a melting point of 182-183 ° C. were obtained.

Example 3

In 50 ml of isopropanol 5.0 g of crude were Iosamycin (purity about 50%) was dissolved by heating to 70 ⁰ C. The insoluble residue was removed by filtration. To the obtained filtrate, 1.35 g of acetic anhydride was added. The reaction mixture was allowed to stand overnight at room temperature, then uuicr verriiiiiuerieiii Diuuk concentrated to about 10 ml. The deposited precipitate was separated off by filtration and recrystallized from ethyl acetate. 2.1 g of 2'-acetyljosamycin with a melting point of 182-183 ° C. were obtained.

Example 4

10 ml of acetic anhydride were added to 0.5 g of iosamycin and 0.05 ml of pyridine added. The reaction mixture was allowed to stand at room temperature for 20 hours and then added to 50 g of ice water. After two hours, the pH of the resulting mixture became Adjusted to about 5 with 2N sodium hydroxide solution. The product precipitated in this way was filtered off and recrystallized from 5 ml of 70% aqueous methanol. There were 395 mg of 2 ', 10-diacetyljosamycin in the form of Obtained crystal needles.

The physico-chemical properties of this compound are as follows:

1. Colorless crystal needles with a temperature of 152 - 153 ° C.

2. Specific rotation [α] = -87.2 ° (t = 1, CHCl ₃ ).

3. Absorption spectrum:

The Ultravioieti-Absorptiorisspckirurr. This compound, measured in methanol, is shown in FIG. 4. The absorption maximum E. 1 333 is at 232 nm. The ultrared absorption (KBr) of this compound is shown in FIG. 5. The deflection at 3500 cm 'shows the absorption by the free tertiary hydroxyl group The NMR spectrum was measured in heavy chloroform and is shown in FIG.

4. Solubility:

The compound is easily soluble in acetone, methyl ethyl ketone, chloroform, ethyl acetate and benzene, Soluble in methanol and ethanol and hardly soluble in water, in petroleum ether and η-hexane.

5. Thin-layer chromatography:

This compound was applied to a thin-layer plate made of aluminum oxide B-10 and with a solvent mixture of butyl acetate / methyl ethyl ketone / water (80: 80: 2).

The compound gave an Rf value of 0.64. (The Rf value for iosamycin is 0.46.)

_{2 ()} Example 5

2.0 g of iosamycin was added to 25 g of propionic anhydride dissolved and added to the resulting solution 0.1 ml of pyridine. The mixture was heated to 60 ° C for 5 hours held and then poured into 200 ml of ice water. After 2 hours, the pH of the resulting mixture became adjusted to about 5 with 2N sodium hydroxide solution. The white precipitate formed was filtered off and then recrystallized from 70% aqueous methanol, 1.01 g of 2 ', 10-dipropionyljosamycin from F.

jo 130-133 ° C were obtained.

Example 6

In 10 g of isovaleric anhydride was 1.5 g of josamycin dissolved and 0.2 ml of the resulting solution

ji pyridine added. The solution was on for 8 hours Heated to 65 ° C and then poured into 200 ml of ice water. The pH of the resulting mixture was determined by Addition of 2N sodium hydroxide solution with stirring adjusted to 8 and for several hours to about 8

to held. The reaction mixture was then extracted twice with 200 ml of ethyl acetate each time. The .purified CAt! aIVIC WUIUCII /.UCI si Ulli 2 "TUIgCl ι << αΙι ~ ιϋΓ! ~ ιι / ιιΖαΓυΟΓιάί solution and then washed with water and then dried over anhydrous sodium sulfate. The 4-i solvent was distilled off under reduced pressure. This gave 1, 4 g of 2 ', 10-diisovaleryljosamycin as a crystalline powder with a temperature of 81 - 86 ° C.

Example 7

ίο a) In 120 ml of acetic anhydride were 6.0 g of josamycin dissolved and added to the resulting solution 3.0 ml of pyridine. The resulting solution became 48 Left to stand for hours at room temperature and then poured into 1 liter of ice water. The received

>> Mixture was left to stand for 2 hours and then

the pH is adjusted to about 5 with 2N sodium hydroxide solution. The white precipitate formed was filtered off and recrystallized from 70% aqueous methanol. There were 4.3 g

W) 2 ', 10-diacetyljosamycin in the form of crystal needles

obtained with a mp of 152-153 ° C.

b) In 120 ml of 80% aqueous methanol were 4.1 g of the 2 ', 10-diacetyljosamycin obtained according to a) dissolved and the resulting solution was heated to 65 ° C for 4 hours. The insoluble residue which was formed as a by-product in a very small amount was removed by filtration removed. The methanol was then distilled off

The precipitated white crystals were filtered off 'ind recrystallized from 80% aqueous methanol. There were 3.0 g of 10-acetyljosamycin obtained as colorless crystals. The compound had the following physico-chemical properties > sell on:

1. Colorless crystal needles with a temperature of 128 - 131 ° C.

2. Specific rotation [«] ■ ;: = -51.1 ° C (c = \. CHCl ₃ ).

3. pKa '= 7.03 (measured in 40% aqueous ι π Methanol).

4. Absorption spectrum:

The ultraviolet absorption spectrum of this Veroir.dung measured in methanol is shown in FIG. 7th shown. The absorption maximum £ "!," "338 r> is at 232 ΐημ. The ultrared absorption spectrum (Kbr) of this compound is shown in FIG. 8 reproduced. The NMR spectrum was in heavier chloroform measured and is in the Fi p. · »Shown. - · < >

5. Solubility:

This compound is readily available in acetone, chloroform, methanol, ethyl acetate and ethyl ether soluble, soluble in carbon tetrachloride and hardly soluble in water, petroleum ether and -> "> n-hexane.

6. Thin layer chromatography:

This compound was applied to a thin-layer plate made of aluminum oxide B-IO and with a mixed solvent of so

Butyl acetate / methyl ethyl ketone / water
(80: 18: 2) developed. The compound gave an RF value of 0.58.

Example 8 >>

In 150 ml 7O ^(V'oigem aqueous acetone The insoluble residue formed in a very small amount 4i> a, 5 g of obtained according to Example 4 2 ', 10-Diacetyljosamycin dissolved, and the resulting solution was maintained for 8 hours at 60 ⁰ C. By-product

distilled off medium. The white crystalline precipitate that formed was from 80% aqueous methanol recrystallized. There were 33 g of 10-acetyljosamycin 4> obtained from F. 128 - 13 Γ C.

Example 9

a) 2.0 g) osa-> o mycin were dissolved in 25 g of propionic anhydride and 0.1 ml of pyridine was added to the resulting solution. The solution obtained was ^{heated to 60 °} C. for five hours and then poured into 200 ml of ice water. After 2 hours, the pH of the reaction mixture was adjusted to about 5 with 2 >> N sodium hydroxide solution. The white precipitate formed was distilled off and recrystallized from 70% aqueous methanol. 1.01 g of 2 ', 10-dipropionyljosamycin with a melting point of 130-133 ° C. were obtained. wi

b) In 40 ml of 80 ⁰ / pc alcohol aqueous methanol were 1.01 g of the obtained according to a) 2 ', 10-Dipropionyljosamycins dissolved and the solution was kept for 5 hours at 65 ° C. The solvent was then abdestiüiert The white Kristaüpulver t-Λ obtained was dried under reduced pressure were obtained 0.85 g of 10-Propionyljosamycin, mp 119-124 ⁰ C.

Example 10

a) 1.5 g of iosamycin were dissolved in 10 g of isovaleric anhydride and 0.2 ml of pyridine was added to the resulting solution. The solution was heated at 65 ° C. for 8 hours and then poured into 200 ml of ice water. The pH of the mixture obtained was adjusted to about 8 with stirring and addition of 2N sodium hydroxide solution. The mixture was allowed to stand for several hours, maintaining the pH at about 8. The reaction mixture was then extracted twice with 200 ml of ethyl acetate each time. The combined extracts were washed first with 2% sodium bicarbonate solution and then with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 1.4 g of 2 ', 10-diisovaleryljosamycin were obtained as crystal powder with a melting point of 81-86 ° C.

b) In 15 ml of 80% aqueous methanol, 1.4 g of the 2 ', 10-diisovaleryljosa obtained according to a) were added mycins dissolved. The resulting solution was kept at 65 ° C. for 30 hours. The one in very small Amount of by-produced insoluble residue was filtered off. The filtrate became the solvent is distilled off under reduced pressure. The crystalline residue then obtained was dried under reduced pressure. There were 1.16 g of 10-isovaleryljosamycin vom Melting point 69-74 ° C.

Example 11

2.0 g of josamycin were dissolved in 10 ml of n-butyric anhydride, and 0.2 ml of pyridine was added to the resulting solution. The solution obtained was ^{heated to 65 °} C. for 6 hours and then poured into 200 ml of ice water

with 2 N sodium hydroxide solution to about 6 and the mixture was left to stand overnight and then extracted with 200 ml of ethyl acetate. The extract was washed first with 2% sodium bicarbonate solution and then with water and then over dried anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby 1.7 g of 2 ', 10-di-n-butyryl-josamycin as a residue were obtained. The crude product was dissolved in 20 ml of 80% aqueous methanol and the like solution obtained heated to 65 ° C for 8 hours. The solvent was then distilled off, whereby one 1.5 g of amorphous 10-n-butyryljosamycin was obtained. By Recrystallization of the product obtained from aqueous isopropanol gave crystalline 10-n-butyryljosamycin obtained from the mp 119-121 ° C. The crystals obtained never taste bitter.

Example 12

Formulation for a syrup:
Acetyljosamycin

4.0 g

(calculated as
Iosamycin}

I. Polyoxyethylene monostearate 40 1 03 g 9 15 829 14th 5 Calcium bisphosphite M ethyl p-hydroxybenzoate 0.18 g B e i s ρ i e Milk sugar Propyl p-hydroxybenzoate 0.02 g Powder formulation: The above Sodium carboxymethyl cellulose 03 g 10- acetyljosamycin ml usual way to a seh sugar 35.0 g ίο Powder processed. Flavorings in required 3 sheets of drawings Licher amount Distilled water so much for that Whole to 100 to fill up. For this

Claims (1)

Claims: 1. Lower acyljosamycins of the general formula R-O CHO -O ι ν «- \ j —._ A —- ^ n ₃ , COO.