CS241533B2 - Method of n-methyl-11-aza-10-deoxo-10-dihydroarythromycin a production - Google Patents

Description

The present invention relates to a process for the preparation of an N-methyl derivative of 11-aza-10-decxo-10-dihydroerythromycin A, which is useful as an intermediate for the production of antibacterial agents. In particular, the invention relates to a process for the preparation of a N-methyl derivative and pharmaceutically acceptable acid addition salts thereof.

Erythromycin A is a macrolide antibiotic which is produced by fermentation and is described in U.S. Patent No. 2,553,899. Numerous derivatives of this substance have been prepared in an effort to modify biological and / or farraacodynamic properties. Esters of erythroihycin A with monocarboxylic and dicarboxylic acids are described in Antibiotics Annual, 1953-1954, Proc. Symposium Antibiotics (Washington D. C.), pp. 500-513 and 514-521. U.S. Pat. No. 3,417,077 discloses a cyclic carbonate as an erythromycin A ester, which is a reaction product of erythromycin A and ethylene carbonate and is an effective antibacterial agent.

U.S. Pat. No. 4,328,334

May 4, 1982 describes 11-aza-10-deoixo-10-dihydroerythromycin A, certain N-acyl and N- (4-substituted benzenesulfonyl) derivatives having antibacterial properties, and a process for their preparation.

The present invention provides a method for producing N-methyl-11-aza-10-deoxo-10-dihydro-erythromycin A of formula I

characterized in that a compound of formula III is reacted

wherein n is 0 or 1 in a reaction-inert solvent with hydrogen.

As suitable as the compound of formula I, the acid addition salts thereof are pharmacologically acceptable. Such salts include, for example, hydrochlorides, hydrobromides, sulfates, phosphates, formates, acetates, propionates, butyrates, citrates, glyclates, lactates, tartrates, malate, maleate, fumarates, gluconates, stearates, mandelic acid salts, pamoates, benzoates, succinates , lactates, p-toluenesulfonates and aspartic acid salts.

The reduction is carried out using an alkylated monooxide and a bis-oxide of formula III. Catalytic reduction was performed at room temperature 18-25 ° C at a hydrogen pressure of 1 to 70 times Ю ⁵ Pa, in a solvent inert under the reaction conditions. Higher temperatures and higher pressures can be used, but no other advantages are achieved.

Suitable catalysts are noble metals, preferably supported metals, and salts and oxides thereof. Suitable catalysts are, for example, palladium or rhodium on activated carbon, PtO 2 and Raney nickel. The ratio of catalyst to substrate is usually in the range of 1: 1 to 1: 2.

Typical solvents for the reduction step are C 1 -C 4 alcohols, especially ethanol, ethyl acetate, and ethers such as tetrahydrofuran and dioxane.

Acid addition salts can be readily obtained by treating the compounds of formula I with at least an equimolar amount of the appropriate acid in a solvent inert to the reaction conditions, or in the presence of the hydrochloride also with pyridinium hydrochloride. Since the compound of formula (I) contains more than one basic group, it is possible to add multiple acid addition salts by addition of sufficient acid. The acid addition salt is isolated by filtration if it is insoluble in the solvent used to effect the reaction, or the salt may be precipitated by the addition of a non-soluble solvent or the solvent may be evaporated and the salt recovered as a residue.

A variety of gramopositive microorganisms and some gram-negative microorganisms, such as those having an elliptical or spherical shape (coca), are sensitive to the compounds of Formula I. In vitro efficacy is readily demonstrated by routine tests against various microorganisms in the brain and heart broth by conventional double dilution. In vitro efficacy shows that the compounds can be used at least in the form of lubricants, creams and the like for topical use, and can also be used to sterilize, for example, various items in hospitals or as industrial antimicrobial agents such as water sterilization, for the sterilization of paints and wood.

For topical use, it is often desirable to admix the active ingredient with a pharmaceutically acceptable carrier, for example a vegetable or emollient cream. Similarly, it can be dissolved or dispersed in liquid carriers or solvents, for example, in water, glycols or mixtures thereof, or in another inert, pharmaceutically acceptable inert environment, i.e., in an environment that is neither harmful to the living organism nor to the active ingredient. The active ingredient is usually present in the composition at a concentration of 0.01 to 10% by weight of the total composition.

In addition, the compound produced by the method of the invention is effective against Gram-positive and certain gram-negative microorganisms in vivo when administered orally and / or parenterally in animals, including humans. In vitro efficacy is somewhat limited due to the susceptibility of the organisms and can be determined by a conventional method of infecting mice of approximately the same weight with the test microorganism and then treating it orally or subcutaneously with the test substance. For example, when 10 mice are infected intraperitoneally with a diluted culture containing approximately 1 to 10 times a dose of LD 10, the lowest concentration of microorganism that otherwise causes 100% death of the test animals. Control experiments are carried out on mice that are infected with several different doses of microorganisms to detect possible changes in the virulence of the test microorganism. The test substance is administered half an hour after injection and repeated after 4, 24 and 48 hours. Surviving mice are caged and observed for 4 days after the last treatment, and the number of surviving mice is recorded.

When used in vitro, the novel compound may be administered orally or parenterally, for example, subcutaneously or intramuscularly, at doses of 1 to 200 mg / kg daily. A preferred dose range is 5 to 100 mg / kg per day, especially 5 to 50 mg / kg per day. The solvent suitable for parenteral administration may be water, isotonic sodium chloride solution, isotonic dextrose solution, Ringer's solution or may also be a non-aqueous solvent such as vegetable oils, for example cottonseed oil, peanut oil, corn or sesame oil, dimethylsulfoxide and other non-aqueous solvents which do not interfere with the therapeutic effect of the compound and which are not toxic in the amount used, for example, glycerol, propylene glycol or sorbitol. In addition, formulations can be prepared that are diluted just prior to administration. Propylene glycol, diethyl carbonate, glycerol, sorbitol and the like can be used as a diluent. The composition may also contain buffers, hyaluronizate, topical anesthetic agents and inorganic salts to achieve the desired pharmacological effect. The compound of the present invention may also be mixed with various pharmaceutically acceptable inert carriers, which may be solid, aqueous, non-toxic organic solvents, capsules, tablets, powders, dry mixtures. , a suspension, a solution, an elixir and a solution or suspension for parenteral administration. The compound is usually used at various dosages and concentrations in the range of 0.5 to 90% by weight, based on the total weight of the pharmaceutical composition.

The invention will be illustrated by the following examples which show how the process according to the invention can be practiced. For the time being, the individual examples have not been followed so as to maximize the yield of the product.

Example 1

N-methyl-11- and za-10-dioxo-10-dihydroerythromycin A bis-N-oxide (Formula III)

To a mixture of 4.83 g of N-hydroxy-11-aza-10-deoxo-10-dihydroerythromycin AM'-oxide, 100 ml of methylene chloride and 69.7 g of solid anhydrous potassium carbonate is added dropwise with stirring, 15.7 ml. (35.8 g) of iodomethane in a nitrogen atmosphere over 2 minutes. The mixture was stirred under a nitrogen atmosphere at room temperature for 3.5 hours and the solid obtained was collected for filtration. The filter cake is washed with 250 ml of methylene chloride, the filtrate and the washings are decanted, 300 ml of water are added and the pH is adjusted to 11 with vigorous stirring. The organic phase is separated, dried over anhydrous sodium sulphate and evaporated. , 36 g of crude product as a colorless foam.

The product was pure enough for subsequent reduction, but the sample was purified by known silica gel chromatography as described by W. Clark Still et al., J. Org. Chem. 43, 2923 [1978] using silica gel with a grain diameter of 63 to 38 μηι, the ratio of silica gel to crude material is approximately 45: 1 by weight. The column is eluted with a 4: 1 by volume mixture of acetone and methanol. pure bis-N-oxide is obtained as shown by thin layer chromatography using a 6: 1: 0.1 mixture of methylene chloride, methanol and concentrated ammonium hydroxide, using a mixture of vanillin, 85% phosphoric acid, and ethanol with heating in a spray. Approximately 128 mg of pure bisoxide are obtained from 1 g of crude product.

¹ HNMR-cpectrum (CDGlk) has peaks at delta 3.20 (9H, broad s, aglycone)

AND

CH 3 —N-O

AND

I (CH 3) 2 -N-O],

AND

3.39 (3H, s, N-Cl-Cl).

The mass spectrum has m / e 461, 431, 415 (the last two peaks being diagnostic for the N-oxide aglycone), 159 (cladincsa-derived fragment), 115 (desosamine-N-oxide derived fragment).

The above-mentioned chromatographic procedure also provides a second, less polar product, N-methyl-11-aza-10-deoxo-10-dihydiroerythromycin A desosaminyl-N-oxide in an amount of 246 mg.

XHNMR (CDCl3) has peaks at delta 2.30 (3H, s, aglycone CH3-N-),

AND

3.18 [6H, s (CH 3) 2 — N- »O],

AND

3.37 (3H, s, CH3O-daolinos).

The mass spectrum has major peaks at m / e 461, 156 and 115.

Example 2

N-methyl-11-a za-10-deoxo-10-dihydroerythromycin A

A solution of the crude product of Example 1, which contained N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A desosaminyl-N-oxide and 4.36 g of N-methyl-llazza-10-deoxo10241533

The dihydroerythromycin A bis-N-oxide in 150 ml of absolute ethanol is hydrogenated in a Parr apparatus (35.2 Pa 2 and 8.0 g of 10% palladium on activated carbon catalyst, room temperature). The reaction is allowed to proceed for 1¼ hours. The catalyst was removed by filtration, and the resulting filtrate was evaporated to dryness to give 4.3 g of a colorless foam. The crude product is mixed with 100 ml of methylene chloride and then stirred with 100 ml of water, the pH of the mixture is adjusted to 8.8. The organic and aqueous layers were separated. The aqueous layer is then extracted twice with 50 ml of methylene chloride each time. The three organic extracts were combined, dried over anhydrous sodium sulfate, and evaporated to give 3.0 g of a colorless foam. Dissolve the whole sample in 11 ml of warm ethanol and add water until a slight turbidity develops. The mixture was allowed to stand overnight to give the title compound (1.6 g), m.p. 136 DEG C. with decomposition. After recrystallization, the title compound melted at 142 DEG C. with decomposition.

1 HNMR (CDCl 3) has maxima at delta 2.31 [6H, s, (CH 3) 2 N-], 2.34 (3H, s, aglycone CH 3 -N-),

13CNHR [CDCl3, (CH3) 4 Si as internal standard) ppm 178.3 (lactone, C = O), 102.9 and 94.8 (C-3, C-5), 41.6 (aglycone - CH3-N) -),

AND

40, [[CH 3] 2 -N]].

Mass spectrum m / e 590, 432, 158.

Example 3

The N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A mg of pure N-methyl-H-aza-10-deoxo-10-dihydroerythromycin A bis-N-oxide of Example 1 was hydrogenated according to the procedure of Example 2. For thin layer chromatography using a mixture. methylene chloride, methanol and concentrated ammonium hydroxide · 9: 1: 0.1 using vanillin spray as indicator while heating as in Example 1, it can be shown that it is a single uniform product, JHNMR and Rf in chromatography on The thin layer is in accordance with the same values in Example 2. The yield is 60%.

Example 4

N-methyl-11-azal-10-deoxo-10-dihydroerythromycin A

A crude product solution of Example 1 containing 10.0 g of N-methyl-11-aza-10

LO-deoxo-dihydroerythromycin A desosaminyl · N-oxide and N-methyl-l-aza-lo-deoxo-1-ChI and ^^^^ ^T ocrythromycinu · A bis-N-oxide (10.0 g) in 150 ml of absolute ethanol is hydrogenated in a Paar apparatus [35.2 Pa, 15 g of Raney nickel catalyst in wet form, room temperature] for a total of 1½ hours. The resulting mixture was worked up in a similar manner to Example 2 to give 8.5 grams of the final product, its Rf in thin layer chromatography being consistent with the same value for the product of Example 2.

Example 5

N-methyl-11-azal-10-deoxo-H-dihydruerythromycin A hydrochloride

0.2 g of 0.27 mmol of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A in solution in 50 ml of absolute ethanol are treated with an equimolar amount of hydrogen chloride and the reaction mixture is stirred at room temperature for 1 hour. Removal of the solvent by evaporation under reduced pressure gave the corresponding monohydrochloride.

In a similar manner, other salts of N-methyl-1-aza-10-deoxo-10-dihydroerythromycin A may be obtained, for example hydrobromide, acetate, sulfate, butyrate, citrate, glycolate, stearate, pamoate, p-toluenesulfenate, benzoate and aspartate.

If the process is repeated but twice the amount of acid is used, the double salt of the N-methyl derivative is obtained.

Example 6

N-methylclltaaa-10-deoxo-10cdihydroerythromycin A bis-hydrochloride

To a solution of 2.00 g of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A in 50 ml of methylene chloride is added dropwise over a few minutes a solution of 308 mg of pyridinium hydrochloride in 25 ml of methylene chloride. The mixture is concentrated to 2.35 g of a foam which is then dissolved in the presence of 125 ml of water to a pure solution which is then decanted from an insoluble residue and lyophilized to give N-methyl-11-azalO-deoxo-bis-hydrochloride. 10-dihydroerythromycin A as 1.21 g colorless amorphous foam.

Analysis:

for C38H720nN2. 2HCl calculated:

8.65% Cl found:

8.89% Cl.

thin layer chromatography is the same as for N-methyl-11-aza-10-deoxo-10-dihydrOerythromycin A in free form.

A small portion of the water-soluble product is mixed with an aqueous solution of sodium bicarbonate to give a water-insoluble product whose R _f values at

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A of the formula I, characterized in that the reaction of a compound of the general formula III is reacted with n = 0 or 1 in a reaction-inert solvent with hydrogen .