PL116228B1 - Process for preparing novel derivatives of 4"-desoxyaminoerythromycin a" - Google Patents

Description

The invention relates to a method for preparing new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula IIIa, wherein R1 and R2 represent a hydrogen atom or an alkanoyl radical with 2-3 carbon atoms, R3 represents a hydrogen atom, or R2 and R3 together represent a -C(O)- group, when R' represents an OH group, R represents a bond to the carbon atom to which R' is attached, or when R' represents =O, R represents a hydrogen atom, and when R2 represents a hydrogen atom, R also represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof. Erythromycin is an antibiotic produced by culturing a strain of Streptomyces erythreus in a suitable medium, as described in U.S. Patent No. 2,653,899. Erythromycin is produced in two forms A and B of the general formula 5, wherein the compound of formula 5, in which R is a hydroxyl group, is erythromycin A, and the compound of formula 5, in which R is a hydrogen atom, is erythromycin B. As can be seen from formula 5, this antibiotic consists of three main parts, namely a sugar fragment called cladinose, a second sugar fragment containing a basic amino substituent, called desosamine, and a 14-membered lactanyl ring, called erythromycin A or B or a macrolide ring. In formula 5, the macrolide ring has positions marked 1-13, desosamine has positions marked 1'-6', and the positions in cladinose are marked 1"-6". In order to obtain erythromycins with different A number of erythromycin derivatives with biological and pharmacodynamic properties have already been prepared. US Patent No. 3,417,077 describes the reaction product of erythromycin with ethylene carbonate, which is a compound with very high antibacterial activity, and US Patent No. 3,884,903 discusses 4"-deoxy-4"-ketoerythromycin A and B derivatives as useful antibiotics. Erythromycylamine, i.e., the 9-amino derivative of erythromycin A, has been the subject of numerous studies [British Patent No. 1,100,504, Tetrahedron Letters, 1645/1967 and Croatian Chemica Acta, 39, 273]. (1967)], although there is some divergence of views on the structure of this compound [Tetrahedron Letters, 157 (1970) and British Patent No. 1,341,022J. According to US Patent No. 3,983,103, sulfonamide derivatives of erythromycylamine are useful as antibacterial agents, and other derivatives are also mentioned as having antibacterial activity in vivo [Ryden et al., J. Med. Chem., 16, 1059 (1973) and Massey et al., G. Med. Chem., 17, 105 (1974)]. It has now been found that new derivatives have exceptionally advantageous properties as antibacterial agents. 4/-deoxy-4/-aminoerythromycin A of general formulae 3 and 4, wherein R1 is a hydrogen atom or an alkanoyl radical with 2 or 3 carbon atoms, in formula 3 R2 is an alkanoyl radical with 2 or 3 carbon atoms and R3 is a hydrogen atom, or R2 and R3 together represent a -C(O)- group, and in formula 4 R4 is a hydrogen atom or an alkanoyl radical with 2 or 3 carbon atoms and R3 is a hydrogen atom, or R3 and R4 together represent a -C(O)- group. Compounds of formula 3, and especially those in which R2 and R3 together constitute a -C(O)- group, have particularly advantageous chemotherapeutic properties. ^1 Compounds of formula 3 also have advantageous properties. Formula 4, and especially those in which R4 is a hydrogen atom and those in which R3 and R4 together represent a -C(O)- group. Pharmacologically acceptable addition salts of compounds of formulae 3 or 4 also have very good antibacterial properties. Compounds of formulae 3 and 4 can be represented by one general formula 3a, in which the substituents have the meanings given above. Intermediate products in the preparation of compounds of formulae 3 and 4 are compounds of formulae 1a and 2a, in which R1 has the meanings given above, in formula 1a Y represents a =NOH group or a =N-O-C(O)CH3 group, and in formula 2a R2 represents an alkanoyl radical with 2 or 3 carbon atoms and R3 represents a hydrogen atom, or R2 and R3 together represent a -C(O)- group. Particularly preferred intermediate products are are compounds of formulas Ia and £a, in which Ri is a hydrogen atom or an acetyl radical. Derivatives of erythromycin B, corresponding to formulas 1 and 2, are also useful as intermediates and are prepared by the same synthesis as derivatives of erythromycin A. Derivatives of erythromycin B are converted into amine derivatives using the methods described below. erythromycin B, corresponding to the compounds of formulas 3 and 4. Preferred intermediate products are: 11,12-carbonate of 2'-acetyl-4"-deoxy-4"-ketoerythromycin A and 11,12-carbonate of 4"-deoxy-4"-6,9-hemiketal -ketoerythromycin A. Method according to the invention for preparing new ones 4''-deoxy-4''-aminoerythromycin A derivatives of general formula 3a, wherein the substituents have the meanings given above, and their pharmaceutically acceptable acid addition salts, consists in reducing a compound of general formula Ib, wherein R, R', R1, R2 and R3 have the meanings given above, and Y represents a =N-OH or =N-OCOCH3 group, or when Y represents an oxygen atom, the compound of formula Ib is condensed with an ammonium salt of an alkanoic acid, and then reduced, and then the optionally obtained compounds in which R1 or R2 represent hydrogen atoms are converted into compounds in which R1 or R2 represent alkanoyl groups and/or when R1 or R2 represent alkanoyl groups, they are converted into hydrogen atoms, and then the optionally obtained compounds are The compounds of formula III are prepared from compounds of formula IIa by condensation with an ammonium salt of a lower alkanoic acid and subsequent in situ reduction of the resulting imine. The term "lower alkanoic acid" here means acids having 2 to 4 carbon atoms. In practice, a solution of the ketone of formula IIa in a lower alkanol, such as methanol or isopropanol, is treated with an ammonium salt of a lower alkanoic acid, such as acetic acid, and the cooled reaction mixture is treated with a reducing agent, such as sodium cyanoborohydride. The reaction is carried out at room temperature for several hours, after which the mixture is hydrolyzed and the product isolated. Although 1 mole of ammonium alkanoate is required for 1 mole of ketone, the reaction proceeds faster if an excess of ammonium salt is used, up to 10:1. Such an excess of ammonium salt does not adversely affect the quality of the product. The reducing agent, i.e., sodium cyanoborohydride, is preferably used in an amount of about 2 moles per 1 mole of ketone. The duration of the reaction depends on the concentration of the reactants and their reactivity, as well as on the temperature. At room temperature the reaction takes 2-3 hours. If methanol is used as solvent, the alkanoyl group in the 2'-position is solvolyzed to a large extent and in order to avoid cleavage of this group, isopropanol is preferably used as solvent. Ammonium acetate is preferably used as ammonium alkanoate. In the isolation of the obtained derivatives of 4"-deoxy-4"-aminoerythromycin A, the basic nature of the obtained products is used in order to separate them from any non-basic by-products and from the starting product. Namely, the aqueous solution of the product is extracted at a gradually increasing pH value so that neutral or non-basic substances are extracted at lower pH values, while 20 product at a pH value above 5. Ethyl acetate or diethyl ether is used as extraction solvents, the extracts are washed with brine and water, dried over sodium sulfate and the product is isolated by removing the solvent. If necessary, the product is purified by column chromatography on silica gel using known methods. As mentioned above, the alkanoyl group in the 2'-position of the 2'-alkanoyl-4'-deoxy-4'-aminoerythromycin derivative A can be removed by lysing the compound by leaving a solution in methanol for several hours at room temperature. If compounds of formula 2a, in which R2 and R3 together represent a -C(O)- group and R1 is an alkanoyl radical with 2 or 3 carbon atoms or a hydrogen atom, are subjected to reductive amination, then amines b in both formulae 3 and 4 are obtained, as shown in Scheme 2. The resulting mixture is separated into individual amines by selective amination. crystallization from diethyl ether. Recrystallization of this mixture from acetone with water 40 gives rise to the formation of the amine hemiketal of formula 4 and enables the isolation of the amine of formula 3. In a manner analogous to that described above, by condensing compounds of formula I with ammonium alkanocarboxylate and then reducing the resulting imine in situ with sodium cyanoborohydride, compounds of formula 4 are prepared. Compounds of formula 4, wherein R 1 , R 3 and R 4 have the meanings given above, are also prepared by reducing the above-mentioned imine with hydrogen in the presence of a suitable catalyst. A solution of the ketone of formula Ia in a lower alkanol, e.g. methanol or isopropanol, is treated with an ammonium salt of a lower alkanocarboxylic acid. acetic acid, in the presence of a hydrogenation catalyst, and the mixture is shaken under a water atmosphere until the reaction is complete. Although 1 mole of ketone 55 requires 1 mole of ammonium salt, it is advantageous to use even a tenfold excess of salt, because then the imine formation reaction proceeds more rapidly. Such an excess of ammonium alkanoate has no detrimental effect on the quality of the product. Various hydrogenation catalysts can be used in this process, but Raney nickel or 5-10% palladium on charcoal are most preferably used. The catalysts are used in various amounts, depending on the desired reaction rate, and the preferred amount of catalyst is 10-200% by weight relative to the amount of compound of formula 1. Effect-116 228 5 The reaction rate is also influenced by the hydrogen pressure in the reaction vessel. Preferably, an initial pressure of 466.5 Pa is used and the reaction is carried out at room temperature. The reaction time depends on a number of factors, including temperature, pressure, concentration of the reactants and their reactivity. Under the above-mentioned preferred conditions, the reaction is complete within 12-24 hours. The product is isolated by filtering off the spent catalyst and evaporating the solvent under reduced pressure. The residue is treated with water and the product is separated from non-basic by-products by extraction from an aqueous solution at a varied pH as described above. As indicated above, when methanol is used as the solvent, the alkanoyl radical at the 2'-position undergoes significant solvolysis and in order to To avoid splitting off this radical, the reaction is carried out in isopropanol. Compounds of formula 4 can also be prepared by first converting compounds of formula 1 into their oximes or oxime derivatives of formula Ia, where Y is the =NOH group or the =N-OC(O)-CH3 group, and then reducing the resulting oxime or derivative. Compounds of formula Ia, where Y is the =NOH group, are ketone oximes, are prepared from compounds of formula 1 by reaction with hydroxylamine hydrochloride and barium carbonate in methanol or isopropanol at room temperature. In practice, it is advantageous to use up to a threefold excess of hydroxylamine, because then compounds of formula Ia are obtained in good yield. When an excess of hydroxylamine is used and the reaction is carried out at room temperature, the reaction takes 1-3 hours. Barium carbonate is used in an amount of 2 moles per 1 mole of hydroxylamine hydrochloride. The product is isolated by pouring the reaction mixture into water, basifying to pH 9.5 and extracting with a water-immiscible solvent, such as ethyl acetate. Alternatively, the mixture can be filtered, the filtrate evaporated to dryness and the residue shaken with a water-immiscible solvent at a pH of 9.0-9.5. O-acetyloximes, i.e. compounds of formula Ia, where Y represents the =N-OC(O)CH3 group, are prepared by acetylation of the corresponding oximes. The process can be carried out by treating 1 mole of oxime with with 1 mole of acetic anhydride in the presence of 1 mole of pyridine or triethylamine, but preferably a 30-40% excess of acetic anhydride and pyridine is used. The reaction is preferably carried out in a non-protic solvent, such as benzene or ethyl acetate, at room temperature for several hours. After the reaction is completed, the pH of the mixture is adjusted to 9.0 and the product dissolved in the solvent is separated. Preferred compounds of the formula Ia for the preparation of 4"-deoxy-4"-aminoerythromycin A derivatives with antibacterial properties are: 2'-acetyl-4"-deoxy-4"-ketoerythromycin A oxime, O-acetyloxime 2'-acetyl-4"-deoxy-4"-ketoerythromycin A, 4"-deoxy-4"-ketoerythromycin A oxime and 4"-de-xoxy-4"-ketoerythromycin A O-acetylpoxime. Reduction of compounds of formula Ia is carried out by catalytic hydrogenation in solution at a lower alkanol, such as isoffropanol, with shaking in the presence Raney nickel in a hydrogen atmosphere with an initial pressure of 19331 Pa, at room temperature, for several hours. 6 Then the catalyst is filtered off and the solvent is removed, obtaining the compound of formula 4. If methanol is used as the solvent, then there is a possibility of cleavage of the alkanoyl radical at the 2'-position to the 5-position as a result of solvolysis. In order to avoid this side reaction, it is advantageous to use isopropanol. Of the compounds of formulae 3 and 4, the two epimers of 4"-deoxy-4"-aminoerythromycin A 11,12-carbonate, 6,9-hemiketal, 4"-iso-deoxy-4"-aminoerythromycin A and 4"-deoxy-4"-aminoerythromycin A 11,12-carbonate have particularly advantageous antibacterial properties. Those compounds of formulae 3 or 4 which form salts are preferably used in the form of their pharmacologically acceptable salts, wherein salts which are not suitable for pharmacological use because of their insolubility in water, high toxicity or lack of crystallization can be converted into the corresponding bases or other salts. acid addition compounds suitable for use in medicine. Examples of acids yielding pharmacologically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfurous, phosphoric, acetic, lactic, citric, succinic, maleic, glyconic, and aspartic acids. As mentioned above, the stereochemical structure of the starting products from which compounds with antibacterial properties are prepared according to the invention is that of the corresponding compounds of natural origin. Oxidation of the hydroxyl group in the 4" position to a ketone group and subsequent conversion of this group to an amino group in the 4" position provides one possibility of stereochemically changing the substituent in the 4" position and producing products with structures different from those of the naturally occurring products. Namely, by processing compounds of formulae 1, 2, 1a or 2a in the manner described above into their corresponding amine derivatives, it is sometimes possible to obtain mixtures of both epimers of amines of formulae 3 and 4, it being found that the content of these epimers in the mixture depends on the method of carrying out the process. If the isolated product contains mainly one epimer, this epimer can be purified by repeated recrystallization from a suitable solvent until a product with a constant melting point is obtained. The second epimer, present in smaller amounts, is then the main component of the mother liquors and can be isolated therefrom by known methods, e.g. by evaporating the mother liquor and recrystallizing the residue until a product with a constant melting point is obtained. Although the epimeric mixture can be separated into individual epimers, it is preferred to use the mixture without separation, and it is often advisable to use at least one of recrystallization from a suitable solvent, purification by column chromatography or by high pressure liquid chromatography, extraction or trituration in a suitable solvent. Such purification is carried out not to separate the epimers, but to remove impurities in the form of starting products and undesirable by-products. The stereochemical phenomenon associated with both epimers has not been fully investigated, but it has been found that for a given compound both epimers exhibit the same type of activity, e.g. antibacterial activity. The new derivatives of 4"-deoxy-4"-aminoerythromycin A discussed in this description exhibit in vitro activity against various Gram-positive microorganisms, rip.7 Staphylococcus aureus and Streptococcus pyogenes, and against some Gram-negative microorganisms, such as spherical or ellipsoidal microorganisms (cocci). Their in vitro activity against various microorganisms in the cerebrocardial infusion environment is readily demonstrated by studies conducted using the well-known double-dilution method. This activity makes these compounds useful for topical application in the form of ointments, creams, etc., for sterilizing, for example, objects in a patient's room, and as microbicidal agents on a technical scale, for example, for disinfecting water and sludge and for preserving paints and wood. For in vitro use, for example, for topical administration, it is often advantageous to use these compounds with a pharmacologically acceptable carrier, such as vegetable or mineral oil, or an emollient cream. They can also be dissolved or dispersed in liquid vehicles or solvents such as water, alcohol, glycols or mixtures thereof or other pharmacologically acceptable substances that are inert, i.e. do not adversely affect the active substance. In such preparations, the content of active substance is usually 0.01-10% by weight of the total preparation. Many of the compounds according to the invention and their acid addition salts also exhibit in vivo activity, when administered orally and/or parenterally to animals, including humans, against Gram-positive and some Gram-negative microorganisms. Their in vivo activity is more limited with respect to the organisms susceptible to the action of these compounds and is determined by conventional methods, by infecting mice of essentially the same body weight with the test microorganism and then administering the test compound to the mice orally or subcutaneously. In practice, these tests are carried out in such a way that a group of, for example, 10 mice is infected by intraperitoneally administering appropriately diluted cultures of the test microorganism. microorganism, containing a concentration of the microorganism 1-10 times higher than the LD100 concentration, i.e., the lowest concentration necessary to achieve 100% mortality in mice. Control trials are conducted simultaneously, in which mice receive the infective culture in lower dilutions to determine possible deviations in the virulence of the tested microorganism. The test compound is administered 0.5 hour after infection and again after 4, 24, and 48 hours. The surviving mice are kept for 4 days after the last treatment, and the number of live mice is counted. When used in vivo, the new compounds can be administered orally or parenterally, e.g., by subcutaneous or intramuscular injection, in daily doses of about 1-200 mg/kg, preferably about 5-100 mg/kg, and especially about 5-50 mg/kg. Parenteral injection vehicles can be aqueous vehicles such as water, isotonic saline, isotonic dextrose or Ringer's solution, or non-aqueous vehicles such as fatty oils of vegetable origin, e.g., cottonseed, peanut, corn or sesame oil, or dimethyl sulfoxide, as well as other vehicles which, in the doses used, do not affect the pharmacological action of the active substance and are non-toxic, e.g., glycerin, propylene glycol and sorbitol. Preparations which are converted into solutions immediately before use can also be prepared. Such preparations may contain liquid diluents, e.g., propylene glycol, Diethyl carbonate, glycerin and sorbitol, buffer substances, hyaluromidases, local anesthetics and inorganic salts, which impart the desired pharmacological properties. These compounds can also be mixed with various pharmacologically acceptable inert carriers, including solid diluents, aqueous diluents, and non-toxic organic solvents, and formulated into capsules, tablets, lozenges, lozenges, dry mixtures, suspensions, solutions, elixirs and solutions or suspensions for parenteral administration. In these preparations, the active substance constitutes about 0.5-90% by weight. Example I. 2'-Acetyl-4"-deoxy-4"-keto-erythromycin oxime A. Up to 500 ml of methanol are added 10.8 g of 2'-acetyl-4"-deoxy-4"-ketoerythromycin A, 1.94 g of hydroxylamine hydrochloride and 11.0 g of barium carbonate and the suspension obtained is stirred at room temperature for 3.5 hours, then filtered and the filtrate is evaporated under reduced pressure. The foamy residue is dissolved in ethyl acetate and washed with water at pH 9.5, the organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure to give 10.6 g of the expected product. NMR (S CDCl3): 3.33 (3H)s, 2.30 (6H)s and 2.06 (3H)s. Example: 2'-Acetyl-4"-deoxy-4"-ketoerythromycin A O-acetyloxime. To a solution of 330 mg of 2'-acetyl-4"-deoxy-4"-ketoerythromycin A oxime in 30 ml of ethyl acetate was added 64.2 microliters of acetic anhydride with stirring and stirred overnight at room temperature. Then, a further 15.8 microliters of acetic anhydride and 23.4 microliters of triethylamine were added and stirred for 4 hours. The reaction mixture was poured into water, basified to pH 9.0, the organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure, yielding 300 mg of the desired product. NMR (Sy, CDCl): 3.38 (3H)s, 2.25 (6H)s, 2.20 (3H)s, 2.05 (3H)s~ il.56(3H)s. In a similar manner, using 2'-propio- nyl-4"-deoxy-4"-ketoerythromycin A and 4"-deoxy-4"-ketoerythromycin A oxime, the corresponding O-acetyl derivatives are prepared. Example -III. 2'-acetyl-4"-deoxy-4"-aminoerythromycin A. 14.0 g O-acetyloxime 2'-acetyl-4"-deoxy-4"-ketoerythromycin A and 60 g of Raney nickel washed with isopropanol is stirred in 400 ml of isopropanol under a hydrogen atmosphere under a reduced pressure of 9331 Pa for 50 minutes at room temperature, then the catalyst is filtered off and the filtrate is evaporated. The foamy white residue is dissolved in 400 ml of isopropanol, mixed with 50 g of Raney nickel freshly washed with isopropanol and hydrogenated overnight at room temperature under an initial hydrogen pressure of 9331 Pa. The catalyst is then filtered off and the filtrate is evaporated to dryness under reduced pressure, yielding 8.1 g of the desired product. Example IV. In an analogous manner to that described in Example III, using the appropriate O-acetyloximes, compounds of formula 4 are prepared, in which where R3 and R4 are hydrogen atoms and Ri is either a hydrogen atom or a propionyl group. *" Example V. 4"-Deoxy-4"-aminoerythromycin A. 65 A solution of 2.17 g of 2'-acetyl-4'-desoxy-4"-aminoerythromycin A in 50 ml of methanol was stirred at room temperature overnight, then the solvent was evaporated under reduced pressure. The foamy residue was treated with a mixture of 50 ml of chloroform and 50 ml of water, the aqueous layer was basified to pH 9.5, and the layers were separated. Fresh water was added to the organic layer and acidified to pH 4.0. The pH of the acidic aqueous layer was then gradually adjusted to pH 5, 6, 7, 8, and 9 with a base, and at each of these pH values the solution was extracted with chloroform. Extracts at pH 6 and 7 were extracted with chloroform. 7 contain the main part of the product, they are combined and at pH 4 fresh water is added, the pH of the aqueous layer is adjusted successively to pH 5, 6 and 7 and at each of these values extracted with chloroform. The extract at pH 6 is dried over sodium sulfate and evaporated, giving 249 mg of product as a mixture of both epimers. NMR (S, CDCl3): 3.30 (1H)s, 3.26 (2H)s, 2.30 (6H)s and 1.46 (3H)s. In an analogous manner, 4"-deoxy-4"-aminoerythromycin A is prepared by solvolysis of 2'-propionyl-4"-deoxy-4"-aminoerythromycin A. Example VI 4'-Deoxy-4'-aminoerythromycin A. To a solution of 3.0 g of 4'-deoxy-4'-ketoerythromycin A in 30 ml of methanol, 3.16 g of anhydrous ammonium acetate is added under stirring under nitrogen, and after 5 minutes, 188 mg of sodium cyanoborohydride is rinsed into the mixture with 5 ml of methanol and stirred overnight at room temperature. The resulting light yellow solution is poured into 300 ml of water, the pH is adjusted to 6.0, and then extracted successively at pH 6, 7, 7.5, 8, 9, and 10 using 125 ml of diethyl ether each time. The extracts at pH 8, 9, and 10 are combined, washed, and 125 ml of fresh water, the aqueous layer is separated and extracted with 100 ml of ether at pH 7, 100 ml of ethyl acetate at pH 7, 100 ml of ether at pH 7.5, 100 ml of ethyl acetate at pH 7.5 and 100 ml of ethyl acetate at pH 8, 9 and 10. The ethyl acetate extracts at pH 9 and 10 are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure to give 30 mg of an epimeric product mixture of ivory foam. Example VII: 4,β-Deoxy-4"-aminoerythromycin A (single epimer). A solution of 10.0 g of the epimeric mixture of 2'-acetyl-4"-deoxy-4"-amichoerythromycin A in 150 ml of methanol was stirred under nitrogen at room temperature for 72 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in a mixture of 150 ml of water and 200 ml of chloroform with stirring. The aqueous layer was discarded, fresh water was added, the pH of the aqueous layer was adjusted to 5 and the organic layer was separated. The pH of the aqueous phase is adjusted successively to 5.5, 6, 7, 8 and 9 and at each of these values it is extracted with 100 ml of fresh chloroform. The extracts at pH values of 6, 7 and 8 are combined, washed successively with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated under reduced pressure. 2.9 g of a mixture of epimers of 4"-deoxy-4"-amino[3-]rythromycin A is obtained. A 1.9 g sample of this mixture is triturated with diethyl ether, causing crystallization of some of the undissolved foamy product. The solid substance is filtered off and dried, yielding 1067 mg of one epimer. 4/-deoxy-4/-aminoerythromycin A, melting point 140-147 °C. Example VIII. 6,9-hemiketal of 11-acetyl-4"-deoxy-4"-aminoerythromycin A. 5 To a solution of 4.4 g of 6,9-hemiketal of 11-acetyl-4"-deoxy-4"-ketoerythromycin A and 4.38 g of ammonium acetate in 75 ml of methanol, 305 mg of 85% is added sodium cyanoborohydride, stir overnight at room temperature and pour into 300 ml of water, then add 10 250 ml of chloroform. The aqueous layer is alkalinized to a pH of 9.8 and the organic layer is separated. The aqueous layer is extracted again with chloroform and combined The chloroform solutions are dried over sodium sulfate and evaporated. The foamy residue is dissolved, with stirring, in 125 ml of water and 125 ml of fresh chloroform, the pH of the solution is adjusted to 4.9, the organic layer is separated and discarded, and the pH of the aqueous layer is adjusted successively to 5, 6, 7, and 8, extracting at each of these pH values with fresh chloroform. The extracts obtained at pH 6 and 7 are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated. 1.72 g of the desired product is obtained as a white foam. This product is dissolved in the smallest possible amount of diethyl ether and added hexane until turbidity occurred. The crystalline precipitate was filtered off and dried, yielding 1.33 g of product, melting at 204.5-206.5°C. NMR (S, CDCl3): 3.31 (2H)s, 3.28 (1H)s, 2.31 (6H)s, 2.11 (3H)s and 1.5 (3H)s. Example IX. In a manner analogous to that described in Example VIII, using the appropriate 4"-deoxy-4"-ketoerythromycin A and isopropanol instead of methanol, compounds of formula III were prepared, wherein R3 is hydrogen and R1 and R2 have the following meanings: R1 R2 CH3C(O)- CH3C(O)- CH3C(O)- CH3CH2C(0)- CH3CH2C(0)- CH3CH2C(0)- CH3CH2C(0)- CH3CH2C(0)- CH3C{0)- 40- Example X. 2'-Acetyl-erythromycin A 6,9-hemiketal 11,12-carbonate. To a solution of 13.2 g of erythromycin A 6,9-hemiketal 11,12-carbonate (US Patent No. 3,417,077) in 150 ml of benzene was added 1.8 ml of acetic anhydride 45 and stirred at room temperature for 1.5 hours. Then the mixture was poured into 200 ml of water and the aqueous layer was basified to pH 9.0. The benzene layer was separated, dried over sodium sulfate and evaporated under reduced pressure. 50. This product was triturated with 50 ml of diethyl ether, causing crystallization, then filtered and dried, yielding 12.6 g of pure product, melting at 224.5-228.5°C. NMR (<5, CDCl3): 3.36 (3H)s, 2.30 (6H)s, 2.06 (3H)s, and 1.61 (3H)s. 55. In an analogous manner, using an equivalent amount of propionic anhydride instead of acetic anhydride, 2'-propionyl-erythromycin-6,9-hemiketal-11,12-carbonate was prepared. Example 11. 11,12-Carbonate 6,9-Hemiketal 4"-deoxy-4"-aminoerythromycin A. To 189 g of 6,9-hemiketal 4"-deoxy-4"-ketoerythromycin A in 1200 ml of methanol, 193 g of ammonium acetate are added with stirring at room temperature. After 5 minutes, the solution is cooled to about -5°C and treated within 45 minutes with 13.4 g of 85% sodium cyanoborohydride in 200 ml of methanol. The cooling bath is then removed and the mixture is stirred at room temperature overnight. The mixture is then concentrated under reduced pressure to a volume of 800 ml with stirring. poured into a mixture of 1800 ml of water and 900 ml of chloroform. The pH of the mixture was adjusted from 6.2 to 4.3 with 6N hydrochloric acid, and the organic layer was separated, mixed with 1 liter of water and adjusted to alkaline pH 9.5. The organic layer was then separated, dried over sodium sulfate, and evaporated under reduced pressure. The foamy white residue was dissolved in a mixture of 1 liter of water and 500 ml of ethyl acetate and acidified to a pH of 5.5. The organic layer was separated, and the aqueous layer was gradually adjusted to alkaline pH 9.5, extracting at intermediate pH values with fresh ethyl acetate in 500 ml portions. Extract The extract obtained at pH 9.5 was dried over sodium sulfate and evaporated to dryness in vacuo, yielding 130 g of a residue. 120 g of this foamy residue was dissolved in a mixture of 1 liter of water and 1 liter of methylene chloride, and the pH of the aqueous layer was adjusted to 4.4, 4.9, and 9.4 by extracting at each pH with 1 liter of fresh methylene chloride. The extract at pH 9.4 was dried over sodium sulfate and evaporated in vacuo, yielding 32 g of a white foamy product. Recrystallization from 250 ml of acetone/water (1:1 v/v) yielded 28.5 g of crystalline solids. NMR 100 Mz (S, CDCl 2 ): 5.20 (1H) m, 3.37 (13) H s, 3.34 (1,5H) s, 2.36 (6H) s, 1.66 (3H) s and 1.41 (3H) s. Example XII. Separation of epimers of 4"-deoxy-4"-aminoerythromycin 6,9-hemiketal 11,12-carbonate. A. 200 mg of the epimer mixture obtained as described in Example XI are added to a high-pressure chromatographic column (1.2 x 9 cm) containing silica gel Gf 254 impregnated with formamide and eluted with chloroform, and the column is then subjected to a pressure of 2239.0 N 4 Pa, giving a flow of 4.76 ml/minute. 10 ml fractions were collected, retaining fractions 14-21 and 24-36. Fractions 14-21 were combined, concentrated to approximately 50 ml, and 50 ml of water was added, adjusting the pH to 9.0. The organic layer was then separated, dried over sodium sulfate, and evaporated, yielding 106 mg of a white foam residue. This product was triturated with diethyl ether, causing crystallization. The mixture was stirred at room temperature for 1 hour, the crystalline product was filtered off and dried, yielding 31.7 g of product, melting at 194-196°C. NMR 100 Mz (S, CDCl 2 ): 5.24 (1H)d, 5.00 (1H)t, 3.40 (3H)s, 2.40 (6H)s, C66(3H)s and 1.40 (3H)s. % Fractions 24-36 were also combined and treated as described above, yielding 47.1 mg of a white foam, identical to the product obtained in the manner described in Example 17. Example 112. To a suspension of 11.1 g of 2'-acetyl-4'-deoxy-4'-ketoerythromycin-6,9-hemiketal-11,12-carbonate in 300 ml of isopropanol was added 10.7 g of ammonium acetate with stirring at room temperature and after 5 minutes the addition of 747 mg of sodium cyanoborohydride in 130 ml of isopropanol was started over a 30-minute period and then stirred at room temperature overnight. The pale yellow solution obtained was poured into 1100 ml of water and 400 ml of diethyl ether was added, acidified to p.t. 4.5 and the ether layer was separated. The aqueous layer is basified to pH 9.5 and extracted with 2 x 500 ml of chloroform. The extracts are combined, dried over sodium persulfate and evaporated to give 7.5 g of a yellow foamy residue. Recrystallization from diethyl ether gives 1.69 g of product, which is further processed in the same way as the mother liquor. The mother liquor is treated with 75 ml of water, the pH is adjusted to 5.0, the ether layer is separated, 75 ml of fresh ether is added, the pH is adjusted to 5.4, the ether layer is separated, ethyl acetate is added and the pH is basified to pH 10. The basic aqueous layer is extracted with 2 x 75 ml of ethyl acetate, the first The extract was dried over sodium sulfate and evaporated to dryness, yielding 1.96 g of a foamy residue. This product was added to a mixture of 75 ml of water and 50 ml of diethyl ether, the pH was adjusted to 5.05, the ether layer was separated, and the aqueous layer was gradually adjusted to pH 5.4, 6.0, 7.05, and 8.0, extracting at each pH with 50 ml of fresh diethyl ether. Finally, the pH was adjusted to 9.7, and the aqueous layer was extracted with 50 ml of ethyl acetate. The ether extract obtained at pH 6.0 was combined with 75 ml of water, adjusted to pH 9.7, and the ether layer was separated, dried, and evaporated under reduced pressure. pressure, obtaining 460 mg of a white foamy residue, NMR 100 Mz (<5, CDCl): 5.20 (1H) t„ 3.43 (2H) s, 3.40 (1H) s, 2.38 (6H) s, 2.16 (3H) s, 1.70- (3H) s and 1.54 (3H). This analysis indicates that the product is the epimers of 11,12-carbonate of 6,9-hemiketal of 2'-acetyl-4"-deoxy-4"-aminoerythromycin A. The above-mentioned 1.69 g of the product obtained after the first crystallization is dissolved in a mixture of 75 ml of water and 75 ml of diethyl ether, the pH of the solution is adjusted to 4.7, the ether and aqueous layers are separated, The first layer was extracted with 75 ml of fresh ether at pH 5.05 and 5.4 and with two 75 ml portions of ethyl acetate at pH 9.7. The combined ethyl acetate solutions were dried over sodium sulfate and evaporated in vacuo to give 1.26 g of a white foamy residue. Recrystallization gave 411 mg of product melting with decomposition at 193-196°C. The mother liquor was evaporated to dryness, the residue was dissolved in hot ethyl acetate, and the solution was allowed to crystallize overnight at room temperature. The crystalline precipitate was filtered off and dried to give an additional 182 mg of product. it melts with symptoms of decomposition at a temperature of 198-202°C. NMR 100 Mz (S, CDCh): 5.10 (1H)t, 3.34 (2H)s, 3.30 (1H)s, 2.30 (6H)s, 2.08 (3H)s, 1.62 (3H)s and 1.48 (3H)s. This analysis indicates that product 50 is an epimer of 11,12-carbonate, 2'-acetyl-4"-deoxy-4"-aminoerythromycin A. In a similar manner, using 11,12-carbonate of 6,9-hemiketal 2'-propionyl-4"-deoxy-4"-ketoerythromycin as the starting product, 11,12-carbonate 2A-propionyl-4''-deoxy-4"-aminoerythromycin A 6,9-hemi-55 ketal and 2'-propionyl-4"-deoxy-4"-aminoerythromycin A 11,12-carbonate. Example XIV. A solution of 400 mg of 2,-acetyl-4"-desoxy-4"-aminoerythromycin A 11,12-carbonate 6,9-hemiketal in 20 ml of methanol was stirred overnight at room temperature, poured into 100 ml of water, 50 ml of ethyl acetate was added, basified to pH 9.5 and the organic phase was separated. The aqueous layer was then re-extracted with 50 ml of fresh ethyl acetate, the two extracts were combined, dried over sodium sulfate and evaporated to give 392 mg of a white foamy product. This product was dissolved in diethyl ether and crystallized at room temperature by rubbing The crystalline precipitate was filtered off and dried after 30 minutes, yielding 123 mg of product, identical to the product prepared by the method described in Example 16. NMR 100 Mz (S, CDCl 2 ): 3.26 (3H) s, 2.32 (6H) s, 1.61 (3H) s, and 1.44 (3H) s. This analysis indicates that this product is one epimer of 4'-deoxy-4'-aminoerythromycin A-11,12-carbonate. The mother liquor after crystallization of the above-mentioned compound was evaporated to dryness, yielding 244 mg of a foamy product, identical to the product prepared by the method described in Example 11. NMR analysis of this product shows that it is a mixture of epimers of 15 11,12-carbonate 6,9-hemiketal 4"-deoxy-4"-aminoerythromycin A. Example XV. In a manner analogous to that described in Example XXII, by methanolizing the 11,12-carbonate of 2'-propionyl-4''-deoxy-4''-aminoerythromycin A 11,12-carbonate, 4"-deoxy-4"-aminoerythromycin A 11,12-carbonate and 11,12-carbonate 4"-deoxy-4"-aminoerythromycin 6,9-hemiketal A. Example XVI. 8 g of the epimeric mixture of 4(n-deoxy-4)-aminoerythromycin A 11,12-carbonate from the non-crystalline product described in Example 11 was dissolved in 50 ml of diethyl ether and crystallized by rubbing the wall of the vessel with a glass rod. After 20 minutes, the crystalline product was filtered off and dried, yielding 1.91 g of product, melting at 198.5-200°C. NMR 100 Mz (d, CDCl 2 ): 3.26 (3H) s, 2.30 (6H) s, 1.61 (3H) s and 1.45 (3H) s. Analysis shows that this crystalline product is one epimer of 4"-deoxy-4"-aminoerythromycin A 11,12-carbonate and is identical to the compound prepared by the method given in Example 14. Example 17. 1.0 g of the epimer prepared by the method given in Example 16 was dissolved in 20 ml of acetone and heated on a steam bath until boiling. 25 ml of water was then added and the resulting solution was stirred at room temperature for 40 minutes. After 1 hour, the precipitate was filtered off, yielding 581 mg of product, melting at 147-149°C. NMR 100 Mz (S, CDCh): 5.12 (1H)d, 3.30 (3H)s, 2.30 (6H)s, 1.62 (3H)s, and 1.36 (3H)s. The results of the analysis indicate that the product is one epimer of 11,12-carbonate of 6,9-hemiketal of 4"-deoxy-4"-aminoerythromycin A and it is identical to the epimer obtained from fractions 24-36 in Example XII. Example XVIII. 4"-Deoxy-4"-aminoerythromycin A. 20 g of 4"-deoxy-4"-ketoerythromycin A, 31.6 g of ammonium acetate and 10 g of 10% palladium on charcoal are mixed in 200 ml of methanol and shaken at room temperature overnight under a hydrogen atmosphere with an initial pressure of 466.5 Pa. Then the spent catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is shaken with water and chloroform at a pH of 5.5. The organic layer was separated, dried over sodium sulfate, and evaporated to dryness in vacuo to give 19 g of a foamy white residue. This residue was triturated with 150 ml of diethyl ether at room temperature for 30 minutes, and the precipitate was filtered off to give, after drying, 9.45 g of one epimer, indistinguishable from the product prepared by the method described in Example 7. The filtrate, after crystallization of the product, was evaporated to dryness to give 6.89 g of the other epimer containing some impurities. Example 19: 4"-Deoxy-4"-aminoerythromycin. 2 g of 4,α-deoxy-4,α-ketoerythromycin A, 3.1 g of ammonium acetate and 2.0 g of Raney nickel in 50 ml of methanol are shaken overnight at room temperature in a hydrogen atmosphere at an initial pressure of 466.5 Pa. Then 3.16 g of ammonium acetate and 2.0 g of Raney nickel are added and hydrogenation is continued for a further 5 hours. The mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure, the residue is added to a water-chloroform mixture with stirring and the pH of the mixture is adjusted from 6.4 to 5.5. The aqueous phase was separated, basified to pH 9.6, extracted with fresh chloroform, and the extract was dried over sodium sulfate and evaporated under reduced pressure. 1.02 g of yellow foam was obtained. This product contains mainly the isomer whose configuration at the 4" position is different from that in the compound prepared as described in Example VII. Example XX. 2'-Acetyl-4"-deoxy-4"-aminoerythromycin B. To a solution of 4.5 g of 2'-acetyl-4"-deoxy-4"-ketoerythromycin B (US Patent No. 3,884,903) in 45 ml of isopropanol is added, with stirring under a nitrogen atmosphere, 4.66 g of dry sodium acetate. After 10 minutes, 376 mg of sodium cyanoborohydride is washed into the mixture with 10 ml of isopropanol and stirred at room temperature overnight. The resulting light yellow solution is poured into 400 ml of water and the pH is adjusted to 0.01. The pH of the solution was adjusted to 6.0, after which the solution was extracted successively at pH values of 6, 7, 7.5, 8, 9, and 10, using 250 ml of diethyl ether for each extraction. The extracts at pH values of 8, 9, and 10 were combined and washed with 250 ml of fresh water. The separated aqueous layer was extracted with 100 ml of ether at pH 7, 100 ml of ethyl acetate at the same pH, 100 ml of ether, and then with 100 ml of ethyl acetate at pH 7.5, and 100 ml of ethyl acetate at pH values of 8, 9, and 10. The ethyl acetate extracts obtained at pH 9 and 10 were combined and washed with saturated diethyl ether solution. The mixture is then washed with sodium chloride, dried over sodium sulfate, and the solvent is evaporated off in vacuo to give a mixture of 2'-acetyl-4"-deoxy-4"-aminoerythromycin B epimers as a cream-colored foamy product. In a similar manner, 4"-deoxy-4"-aminoerythromycin B is prepared from 4"-deoxy-4"-ketoerythromycin B. Example XXI: 4β-deoxy-4β-aminoerythromycin B. A solution of 4.34 g of 2'-acetyl-4"-deoxy-4"-aminoerythromycin B in 100 ml of methanol is stirred at room temperature overnight, then the solvent is evaporated off in vacuo, and the foamy residue is treated with A mixture of 100 ml of chloroform with 100 ml of water was used. The pH of the aqueous layer was adjusted to 9.5, the organic layer was separated, mixed with water, and acidified to pH 4.0. The pH of the aqueous layer was then adjusted to 5, 6, 7, 8, and 9 by adding base, and at each of these values it was extracted with fresh chloroform. The extracts at pH 6 and 7, containing the main part of the product, were combined, and at pH 4 it was treated with fresh water. The pH of the aqueous layer is again adjusted to 5, 6 and 7 and at each of these values 15. tosci extracts the solution with fresh chloroform. The extract at pH = 6 is dried over sodium sulfate and evaporated to obtain a mixture of epimers of 4"-deoxy-4"-aminoerythromycin B. Example XXII. Aspartic acid addition salt of 11,12-carbonate of 6,9-hemiketal 4"-deoxy-4"-aine- erythromycin A. This compound is prepared by adding 20 ml of water and then 175 mg of L-aspartic acid to a solution of 1.0 g of 11,12-carbonate of 6,9-hemiketal 4"-deoxy-4"-amino-erythromycin A in 6 ml of acetone, heated to 40°C, and then 175 mg of L-aspartic acid. boiling under reflux condenser The mixture is stirred for 1.5 hours, filtered hot and the acetone is evaporated from the filtrate. From the residue, 1.1 g of a white solid is obtained by freezing. Example XXIII. 4"-Deoxy-4"-aminoerythromycin 6,9-hemiketal 11,12-carbonate dihydrochloride A. To 7.58 g of 4"-Deoxy-4"-aminoerythromycin 6,9-hemiketal 11,12-carbonate in 50 ml of anhydrous ethyl acetate, 20 ml of a 1N solution of HCl in ethyl acetate is added and the mixture is evaporated to dryness under reduced pressure and the residue is triturated with ether to obtain the desired compound. In a similar manner, other compounds are prepared. The monohydrochloride of the above-mentioned ester is prepared in a similar manner to that described in Example 23, but using 10 ml of a 1N solution of hydrogen chloride in ethyl acetate. Other addition salts of the compounds prepared by the method according to the invention are prepared similarly, containing 1 mole of the monobasic acid per 1 mole of the erythromycin derivative. Claims 1. A method for the preparation of new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula IIIa, wherein R1 and R2 represent a hydrogen atom or an alkanoyl radical of 2-3 carbon atoms, R3 is a hydrogen atom, or R2 and R3 together represent a -C(O)- group, when R' is a CH group, R represents a bond to the carbon atom to which R' is attached, or when R' is =O, R represents a hydrogen atom, and when R2 is a hydrogen atom, R also represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula Ib, in which R, R1, R2 and R3 have the meanings given above, Y represents a =N-OH or =N--OCOCH3 group, is subjected to catalytic reduction, and then the resulting compound is optionally converted into an acid addition salt. 2. A process for the preparation of new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula 3a, wherein R1 and R2 are hydrogen atoms, R3 is hydrogen atom, R' is =O, R is hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula Ib, wherein R, R' and R3 have the above-mentioned meaning, R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, Y is =N-OH or =N-OCOCH3 group, is subjected to catalytic reduction; and then the obtained compounds are hydrolyzed and optionally converted into acid addition salts. 3. A process for the preparation of new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula 3a, wherein wherein R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, R3 is a hydrogen atom, when R' is a CH group, R5 is a bond to the carbon atom to which R' is attached or when R' is = 0, R is a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula Ib, in which R, R' and R3 have the above-mentioned meaning, R1 and R2 are hydrogen atoms, Y is a =N-OH or =N-OCOCH3 group, is subjected to catalytic reduction and then the resulting compounds are acylated and optionally converted into acid addition salts. 4. A method for preparing new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula IIIa, wherein R1 and R2 are hydrogen or an alkanoyl radical with 2-3 carbon atoms, R3 is hydrogen, or R2- and R3 together are a -C(O)- group, when R' is an OH group, R is a bond to the carbon atom to which R' is attached or when R' is =O, R is hydrogen, and when R2 is hydrogen, R also is hydrogen, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula Ib, wherein R, R', R1, R2 and R3 have the above-mentioned meaning, Y is oxygen, is condensed with an ammonium salt of an alkanoic acid, prepared in In this case, the compound of formula Ib, in which Y is an =NH group, is reduced with a metal hydride, and then the obtained compound is optionally converted into an acid addition salt. 5. A method for preparing new derivatives of 4"-deoxy-4-aminoerythromycin A of general formula 3a, in which R1 and R2 are hydrogen atoms, R3 is a hydrogen atom, R' is =O, R is a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula Ib, in which R, R' and R3 have the above-mentioned meaning, R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, Y is an oxygen atom. is condensed with an ammonium salt of an alkanecarboxylic acid, the compound of formula Ib, wherein Y is a =I^H group, generated in situ, is reduced with a metal hydride, and then the resulting compound is hydrolyzed and optionally converted into an acid addition salt. 6. A method for the preparation of new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula 3a, wherein R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, R3 is a hydrogen atom, when R' is a group R is a bond with the carbon atom to which R' is attached or when R' is =O, R is a hydrogen atom, and their pharmaceutically acceptable acid addition salts, characterized in that a compound of the formula Ib, wherein R, R' and R3 have the above-mentioned meaning, R1 and R2 are hydrogen atoms, Y is an oxygen atom, is subjected to condensation with an ammonium salt of an alkanoic acid, the compound of the formula Ib, wherein Y is an =NH group, is subjected to reduction with a -metal hydride, and then the obtained compound is acylated and optionally converted into an acid addition salt. 7. A method for the preparation of new derivatives of 4/-deoxy-4-aminoerythromycin A of the general formula 3a, in which R1 and R2 are a hydrogen atom or an alkanoyl radical with 2-3 carbon atoms, R3 is a hydrogen atom, or R1 and R3 together are a -C(O)- group, when R' is a 6S ÓH group, R1 is a bond to the carbon atom to which R' is attached or when R' is =O, R1 is a hydrogen atom, and when R2 is a hydrogen atom, R1 is also a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of the formula Ib, in which R1, R1, R2 and R3 have the above-mentioned 8. A method for preparing new derivatives of 4"-deoxy-4-aminoerythromycin A of the general formula 3a, wherein R1 and R2 are hydrogen atoms, R3 is hydrogen atom, R' is =O, R is hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula Ib, wherein R1 and R3 are as defined above, R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, Y is oxygen atom, is subjected to condensation with an ammonium salt of an alkanoic acid, the compound of the formula Ib, wherein R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, Y is oxygen atom, condensation with an ammonium salt of an alkanoic acid, the compound of formula Ib, wherein Y is an =NH group, formed in situ is reduced by catalytic hydrogenation and then the resulting compound is hydrolyzed and optionally converted into an acid addition salt. 9. A method for the preparation of new 4"-deoxy-4-aminoerythromycin A derivatives of the general formula IIIa, wherein R1 and R2 are alkanoyl radicals with 2-3 carbon atoms, R3 is a hydrogen atom when R' is an OH group, R is a bond to the carbon atom to which R' is attached or when R' is =O, R is a hydrogen atom, and their pharmaceutically acceptable acid addition salts, characterized in that a compound of the formula Ib, wherein R, R' and R3 have the above-mentioned meaning, R1 and R2 are hydrogen atoms, Y is an oxygen atom, is condensed with an ammonium salt of an alkanoic acid, the compound of the formula Ib, wherein Y is =NH, formed in situ, is reduced by catalytic hydrogenation, and then the resulting compound is subjected to catalytic hydrogenation. is acylated and optionally converted into an acid addition salt.NiCH-:)r Ac N(CH3,? 0CH3 FORMULA la R20 OCI-h WZCJR 2116 228 3'2 WZCiR 1b WZCfR 2a WZCfR 2a NH4OCOCH3 NaCNBHo SCHEME WZCR 3 FORMULA U SCHEME cont.116 228 NICH,), R20..R3o^ OCH, FORMULA 3a WZCJR 3 R^ N(CH3)2 a. FORMULA 5 PL PL PL PL PL PL PL PL PL PL PL

Claims (1)

1.