CN85103264A - 9a-azepine-9a-homoerythromycin derivative - Google Patents

Abstract

Certain novel 9-decarbo-4″-deoxy-4″-amino-9a-aza-9a-homoerythromycin A derivatives; use of novel erythromycin A derivatives for the treatment of bacterial infections in mammals methods; pharmaceutical compositions containing neoerythromycin A derivatives; and intermediates and methods for preparing neoerythromycin A derivatives.

Description

This invention relates to novel compounds having antibacterial activity for use in the chemotherapy of bacterial infections in mammals. More specifically, the novel antibacterial agent of the present invention is the well-known macrolide antibiotic erythromycin A, a derivative of a compound having the following chemical structure:

In more detail, the new antibacterial agent of the present invention is a derivative of erythromycin, where the 14-membered ring lactone is expanded into a 15-membered ring by inserting a nitrogen atom between the 9 and 10 rings, and the 4" - The α-hydroxyl group is substituted with a substituent bonded to the 4″ position via a nitrogen atom (e.g. an amino group).

Like this, antibacterial agent of the present invention can be regarded as the derivant of formula (II) compound:

And in this specification, the structural formula (II) is chemically named as 9a-aza-9a-homoerythromycin A, that is, position 9a is used to indicate the added link in the lactone ring.

The 9a-aza-9a-homoerythromycin A compound is disclosed in Published British Patent Application No. 2,094,293 and U.S. Patent No. 4.328,334, which they call 11-aza-10- Deoxy-10-dihydroerythromycin A compound. 4"-deoxy-4"-ammonia-erythromycin A and 4"-deoxy-4"-amido-erythromycin A antibacterials are known from U.S. Patent Nos. 4.150,220 and 4.180,654.

The present invention provides new macrolide antibiotics of the following formula:

and its pharmaceutically acceptable acid addition salts, wherein:

R ₁ is selected from a group consisting of hydrogen and methyl;

_R2 and _R3 are each selected from the group consisting of hydrogen, ammonia and amido.

If one of ^R2 and ^R3 is always hydrogen, then ^R2 and ^R3 cannot both be hydrogen at the same time.

Examples of amido groups are groups of formula NH-CO-R ⁵ and NH-SO ₂ -R ⁶ wherein:

(I) R ⁵ is selected from the following groups:

Here Alk is an alkyl group of 1-8 carbon atoms; ^Ar is thienyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl; ^X is hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, Nitro, trifluoromethyl, alkyl of 1-3 carbon atoms or alkoxy of 1-3 carbon atoms; X ² is hydrogen, fluorine, chlorine or bromine; n is O or 1; m is 0, 1, 2, 3;

组成的一组基团，这里Ar²是噻吩基或呋喃基，而X³是氢、氯、溴、碘。(II) ^R6 is selected from ^Ar2 and

A group of groups consisting of, where Ar ² is thienyl or furyl, and X ³ is hydrogen, chlorine, bromine, iodine.

In addition, the present invention also provides a method for treating bacterial infections in mammals, which comprises administering to the subject to be treated an effective antibacterial amount of the compound of formula (III) ( ^R1 , ^R2 , and ^R3 in formula III are as defined above); or A pharmaceutical composition comprising a compound of formula (III) wherein R ¹ , R ² and R ³ are as defined above is administered.

A preferred group of compounds of the invention consists of compounds of formula (III) wherein ^R1 is hydrogen or methyl, ^R2 is hydrogen and ^R3 is amino, or ^R2 is amino and ^R3 is hydrogen.

A preferred group of compounds of the present invention consists of compounds of formula (III): R ¹ is methyl, R ² is hydrogen, and R ³ is NH-CO-R ⁵ (here R ⁵ is -(CH ₂ ) _m where m and ^X1 are defined as before).

A third preferred compound of the present invention consists of compounds of formula III in which R ¹ is methyl, R ² is hydrogen, and R ³ is NH-SO ₂ -R ⁶ (wherein R ⁶ is , where ^X3 is defined as before)

Preferred individual compounds of formula (III) are:

9-Deoxo 9a-methyl-4″-deoxy-α-ammonia-9a-aza-9a-homoerythromycin A (compound of formula (Ⅲ), wherein R ¹ is methyl, R ² is amino and R ³ is hydrogen)

9-9a-methyl-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A (compound of formula (Ⅲ), wherein R ¹ is methyl, R ² is hydrogen and ^R3 is amino)

Moreover, the present invention also provides novel compounds of the following formula:

And their acid addition salts, where R ⁴ is selected from the group consisting of hydrogen, acetyl, and propionyl. Formula (Ⅳ) compound is used as the intermediate product of the formula (Ⅲ) antibacterial agent of formula (Ⅲ) defined as before for preparation R ¹ is methyl, R ² and R ³

A particularly useful intermediate of formula (IV) is 9-deoxo-9a-methyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A (formula (IV) compounds wherein ^R4 is hydrogen).

The antibacterial agent of formula (Ⅲ) of the present invention, wherein R ¹ is hydrogen or methyl, R ² is hydrogen and R ³ is amino, or R ² is amino and R ³ is hydrogen, can be easily and conveniently deoxygenated from 4″- -4 "-aminoerythromycin A derivative (prepared as formula (Ⅴ):

wherein ^R2 is hydrogen and ^R3 is amino or ^R2 is amino and ^R3 is hydrogen. It should only be carried out according to Figure A, which only shows part of the structure (see page 7 of the original text, please print according to the original picture)

In the first step of Scheme A, the 4"-deoxy-4"-amino-erythromycin A compound of formula (V) is converted to the oxime of formula (VI). Usually, the compound of formula (Ⅴ) is treated with excess hydroxylamine, or with the acid addition salt of hydroxylamine (such as the addition salt of hydrochloric acid), and the reaction is carried out in a pyridine solution at a temperature of 20°-60°C, and the reaction takes several hours , About 15-50 hours to reach full. The reaction mixture is then diluted with water and the product is isolated and extracted into a volatile, water-insoluble organic solvent such as diethyl ether, ethyl acetate. The organic solvent was dried and the recovered product was evaporated in vacuo.

In the second step of Scheme A, the oxime of formula (VI) undergoes a Beckmann rearrangement to give the ring expanded 9a-aza-9a-homo-amide compound of formula VII. The ring expansion reaction is conveniently carried out by treating the oxime of formula (VI) with excess 4-toluenesulfonyl chloride in the presence of a base at room temperature. One method is that the oxime is added to the acetone aqueous solution containing sodium bicarbonate, then 4-toluenesulfonyl chloride is added and sodium hydroxide solution is added to maintain the pH at about 8. Alternatively, the rearrangement can be carried out in a water-immiscible organic solvent, such as chloroform, by adding a slight excess of tertiary amine to oxime and 4-toluenesulfonyl chloride. The rearrangement proceeds fairly rapidly at room temperature, and in practice the reaction can proceed without external cooling. The reaction is generally complete within 1-2 hours under these conditions. If acetone aqueous solution is used as the reaction solvent, the reaction mixture is diluted with water, and the reaction product is extracted with a volatile, water-insoluble organic solvent when the pH becomes alkaline, and then the solvent is evaporated. If a water-insoluble organic solvent is used for the Beckmann rearrangement, water is used to extract the reaction product into the aqueous phase when the pH is acidic. The aqueous extract is then basified and the product re-extracted into a volatile water-insoluble organic solution, the solvent is dried and evaporated in vacuo to give the desired 9a-aza-9a-homo- amides.

Compounds of formula III wherein R ¹ is hydrogen, R ² is hydrogen and R ³ is amino or R ² is amino and R ³ is hydrogen, can be obtained by reducing the 9,9a-amido group of the compound of formula (VII) For the preparation, any known reducing agent for the reduction of amides to amines can be used, but a particularly suitable reducing agent in this case is sodium borohydride. If sodium borohydride is used, the solution of raw material amide dissolved in lower alkanol such as methanol is treated with excess sodium borohydride at a temperature of 0°-30°C, usually at room temperature. The reaction proceeds smoothly and rapidly at room temperature, usually within 1-2 hours. The reaction mixture is then diluted with water and a volatile, water-insoluble organic solvent such as ethyl acetate. The pH was raised to about 10, the organic layer was separated and dried. The desired compound of formula III is obtained after evaporation of the organic layer.

Formula III wherein R ¹ is methyl, R ² is hydrogen and R ³ is amino or R ² is amino and R ³ is a compound of hydrogen, the N-9a-position methyl of the corresponding R ¹ is hydrogen compound of formula III chemical preparation. However, before methylation of N-9a, it is best to protect the amino group on C-4 ", because this group is also easy to methylate. Like this, conversion R ¹ is the formula III compound of hydrogen for the corresponding R ¹ A preferred method for compounds of formula III which are methyl involves protection of the amino group at C-4", followed by methylation at N-9a, followed by removal of the protecting group at C-4".

A variety of amino protecting groups can be used to protect the primary amino function at C-4", but particularly suitable groups are benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl. These groups are attached to C-4" , and can be separated from C-4 by conventional methods known in the art. For example, the compound of formula III is treated with a slight excess of benzyloxyacyl chloride or 4-nitrobenzyloxyacyl chloride, reacted in the presence of pyridine In the presence of tertiary amines such as , triethylamine, at room temperature, carry out in an inert reaction solvent.The reaction is carried out very quickly, usually completes within one hour. When using a water-insoluble solvent such as chloroform, under acidic pH value (e.g. pH=2) extract the product into water, then back-extract into a volatile, water-insoluble organic solvent at a basic pH (e.g., pH 10) and evaporate the solvent to obtain C-4" ammonia protected group compound. When using a water-insoluble solvent, dilute the reaction mixture with water and use a volatile, water-insoluble organic solvent to extract and isolate the reaction product at a basic pH value (such as PH10), and then evaporate the solvent to obtain the product.

R ¹ is hydrogen C-4 "The methylation of the compound of formula III with an ammonia protecting group can pass through smoothly in an inert organic solvent (such as chloroform) with excess formaldehyde or formic acid, and the reaction temperature is usually maintained at 60-100 ° C, usually several Hours, such as 2-6 hours tend to be complete. Reaction finishes, and mixture is cooled, and this R ¹ is a methyl group, C-4 " the formula III compound of band amino protection, separates R as described above ¹ is a hydrogen band amino group The protected compound of formula III is isolated in exactly the same manner.

According to conventional methods, the benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl protecting group can be removed by hydrogenation in glacial acetic acid using a palladium-carbon catalyst. The reaction temperature is room temperature, the hydrogen pressure is 1-10kg/cm ² , and the reaction is usually completed within several hours, for example, 4-10 hours. The catalyst is then removed by filtration, and a volatile water-insoluble solvent such as ethyl acetate is added at a pH of 8-10 hours, so that the acetic acid solution of the product is separated between water and the solvent. The organic layer is separated, dried and evaporated to give a compound of formula III wherein ^R1 is methyl.

New 9a-aza-9a homoerythromycin A derivatives of formula III, wherein R ¹ is methyl, R ² is hydrogen and R ³ is amino or R ² is amino and R ³ is hydrogen, also can be obtained by the formula Preparation of known 9a-aza-9a-homoerythromycin A derivatives of VIII:

To prepare such compounds of formula III, i.e. ^R1 is methyl, ^R2 is hydrogen and ^R3 is amino or vice versa ^R2 is amino ^{and R3} is hydrogen, the compound of formula VIII is first converted into the corresponding formula (IX) The 4″-keto compound:

The conversion of the compound of formula VIII to the compound of formula IX involves protecting the 2'-hydroxyl group, followed by oxidation of the 4"-hydroxyl group to a keto group, and removal of the protecting group from the 2'-hydroxyl group.

The 2'-hydroxyl is usually protected using a lower alkanoyl protecting group such as acetyl or propionyl. The compound of formula VIII is treated with a slight excess of acetic anhydride or propionic anhydride in chloroform to attach the acetyl or propionyl group to the 2'-hydroxyl group. This reaction is carried out in a conventional manner at room temperature for several hours. Then in the presence of a base, the corresponding 2'-0-acetyl-4"-deoxy-4" ketone (or its 2'-0-propionyl analog). The carbodiimide used is preferably N-ethyl-N'-(N,N-dimethylaminopropyl)carbodiimide, and the base used is preferably pyridinium trifluoroacetate. Finally, solvent separation with methanol can remove 2'-0-acetyl or 2'-0-propionyl. This reaction is completed at 10-30°C in 1-2 days, and then the methanol is evaporated in vacuo.

To prepare a compound of formula III wherein ^R1 is methyl, ^R2 is amino and ^R3 is hydrogen, the compound of formula IX is converted to its C-4" oxime, which is then reduced with hydrogen over a Raney nickel catalyst.

The oxime is prepared by treating the ketone of formula IX with excess hydroxylamine hydrochloride in methanol solution at room temperature for several hours. The solvent was then removed in vacuo to isolate the oxime. The C-4 "oxime reduction principle of formula IX compound is as follows: at room temperature, on Raney nickel catalyst, in low alkanol solvent (such as ethanol), pressure 1-10kg/cm ² , 4-5kg/cm ² more It was then treated with hydrogen, the catalyst was removed by filtration, and the product was recovered by evaporation of the solvent.

To prepare compounds of formula III wherein ^R1 is methyl, ^R2 is hydrogen and ^R3 is amino, compounds of formula IX can be reductively aminated. The compound of formula IX can be reacted with excess ammonium acetate, using lower alkanol such as methanol as solvent, and then reducing the resulting adduct with sodium cyanoborohydride. In fact, the compound of formula III in which ^R1 is methyl, ^R2 is hydrogen and ^R3 is amino thus formed also includes its C-4" epimer. Certain corresponding C-4" hydroxy compounds are also formed (Formula Ⅷ compound and its C-4" epimer). And the C-4" hydroxyl compound is easily removed during processing. The whole reaction product was separated between ethyl acetate and water at pH 6, under which conditions the C-4"-hydroxy compound was extracted into the organic layer, while the C-4" amino compound remained in the aqueous phase. Here, the ethyl acetate layer is separated and discarded, the pH of the aqueous layer is raised to 9-10, and the 4-C"amino compound can then be extracted into the organic phase, separated, dried and evaporated in vacuo. ^R1 can be separated by chromatography is methyl, ^R2 is hydrogen and ^R3 is amino, and the compound of formula III was isolated from its C-4" epimer.

Compounds of formula III according to the present invention, wherein ^R is hydrogen or methyl, R is ^hydrogen and ^R is acylated amino or ^R is acylated amino and ^R is hydrogen antibacterial agents prepared from the corresponding compounds of formula III, Such compounds of formula III wherein ^R1 is hydrogen or methyl, ^R2 is hydrogen and ^R3 is amino or ^R2 is amino and ^R3 is hydrogen. Thus, post-processing involves acylation of R ² or R ³ which is an amino group to NH-CO-R ⁵ or NH-SO ₂ -R ⁶ , wherein R ⁵ and R ⁶ are as defined above.

^R2 or ^R3 which is amino can be acylated using conventional techniques, for example, a suitable compound of formula III where ^R2 or ^R3 is amino can be derivatized by activation of a suitable acid of formula ^R5 - _COOH or ^R6SO2OH It can be acylated by treatment with substances such as acid chlorides. The reaction is usually carried out in the following way; R ² or R ³ is an amino compound of the formula II and 1 molar equivalent or a slight excess (such as 1.0-1.3 molar equivalents) of the formula R ⁵ -CO-OH or R ⁶ -SO ₂ -OH acid The activated derivatives are contacted in an inert solvent at a temperature ranging from 0-40°C, 20-25°C. Common solvents used are halogenated hydrocarbons such as methylene chloride and chloroform; low molecular weight ethers such as diethyl ether, tetrahydrofuran, dioxane; low molecular weight ketones such as acetone and methyl isobutyl ketone; low molecular weight esters such as ethyl acetate ; and mixtures thereof. In addition, when acid chlorides are used as activated derivatives, it is generally more appropriate to add 1 molar equivalent of an acid antagonist such as triethylamine, pyridine or NN-dimethylaniline. The reaction proceeds fairly quickly and is normally completed within a short period of time such as 0.5-24 hours. After the reaction is finished, when the pH is 2-4, the reaction mixture is separated in a water-insoluble organic solvent and water. The organic layer is removed, the pH value of the aqueous phase is raised to 6.5-10, the product is extracted into a volatile, water-insoluble organic solvent, dried and evaporated to obtain the acylated product (III, ^R2 or R ³ is NH-CO-R ⁵ or NH-SO ₂ -R ⁶ )

Another method for converting the ^R2 or ^R3 amino group to ^R2 or ^R3 as NH-CO- ^R5 is that the acid of formula ^R5 -COOH can be activated by conversion into a mixed anhydride. For this purpose, the carboxylate of an acid of formula R ⁵ -CO-OH is reacted with one equivalent of a lower alkane chloroformate at a reaction temperature of -40-0°C, preferably about -15°C. Common carboxylic acid salts are amine salts, such as triethylamine or N-methylmorpholine salts. The same solvent is used for the preparation of mixed anhydrides and acylation reactions, so that they can be used directly without separation.

In addition, in order to convert the R ² or R ³ amino group to R ² or R ³ representing NH-CO-R ⁵ , it is also possible to combine the formula R ⁵ -CO-OH carboxylic acid with certain reagents known in the art that can form peptide bonds The reaction activates it. Such reagents include carbobiimides such as dicyclohexylcarbobiimide; ethoxyacetylene and N-ethoxycarbonyl-?-ethoxy-1.2-dihydroquinoline.

Thus, compounds of formula III, wherein R ¹ is methyl, R ² is hydrogen and R ³ is amide or R ² is amide and R ³ is hydrogen, can be corresponding by acylation, R ¹ is methyl, R ² is hydrogen and R ³ is amino or R ² is amino and R ³ is hydrogen compounds of formula III prepared however the former can also be prepared by methylation of its corresponding compound of formula III R ¹ is hydrogen. Methylation can be carried out with excess formaldehyde and formic acid in an inert solvent, as previously described for the methylation of N-9a.

If necessary, the formula III antibacterial agent of the present invention and the intermediate products of formulas VI, V, VI, VII and IX can be purified by conventional processing methods of macrolide compounds. These methods include recrystallization, column chromatography, preparative thin-layer chromatography, and countercurrent distribution.

The antibacterial compounds of formula III and the intermediates of formula IV are basic and therefore they will form acid addition salts. All such salts are within the scope of this invention and can be prepared by conventional methods applicable to macrolide compounds. Compounds of formulas III and IV contain multiple base centers and thus can be prepared as mono-, di-, and tri-acid addition salts. As for mono-, di-, and tri-acid addition salts, their negative counter ions may be the same or different. In general, to prepare an acid addition salt, a compound of formula III or IV is combined with a stoichiometric amount of the appropriate acid in an inert solvent, the solvent is then evaporated to recover the salt, and if it naturally precipitates it is filtered directly, or used in a non-solvent The precipitate was filtered again. Common salts that can be prepared include sulfate, hydrochloride, hydrobromide, nitrate, phosphate, citrate, tartrate, pamoate (Pamoate) sulfo aqueous phase salt, methanesulfonic acid Salt, phenylsulfonate and 4-toluenesulfonate.

The starting material of formula V, wherein R ² is hydroxyl and R ⁵ is amino or R ² is amino and R ³ is hydroxyl can make 4 "-deoxy-4"-oxo-erythromycin A, i.e. the compound of formula X:

Prepared by reductive amination.

In order to prepare such a compound of formula V in which R ² is hydrogen and R ³ is amino, the mixture of compound X and excess ammonium acetate in methanol is hydrogenated at room temperature at a pressure of about 4 kg/cm ² with 10% Aluminum-carbon catalyst. In this way, C-4″-β-amino compounds are mainly obtained, and pure products can be developed in ether.

In order to prepare the compound of formula V in which R ² is amino and R ³ is hydrogen, the mixture of the compound of formula X and excess ammonium acetate in methanol can be hydrogenated, the reaction is carried out at room temperature, the hydrogen pressure is 4 kg/cm ² , and Raney Nickel catalyst, which mainly goes to C-4″-α-amino compound. It can be purified by repeated recrystallization in a solvent such as isopropanol.

4″-deoxy-4″-oxo-erythromycin A, the compound of formula X, can be prepared according to the method described in US Patent No.4150220.

9-Decarboxy-9a-methyl-9a-aza-9a-homoerythromycin A, the compound of formula VIII, may be prepared by the method of Published British Patent Application No. 2094,293. See Example I of the above-mentioned British Patent Application 2094,293, in which compound VIII is named N-methyl-11-aza-10-decarbony-10-dioxy-erythromycin A. See also U.S. Patent No. .4,328,344 and West German Publication DE-OS 3,012,533.

Compounds of formula III, wherein R ¹ is hydrogen or methyl, R ² and R ³ are each hydrogen, amino, NH-CO-R ³ or NH-CO-R ⁶ , provided that one of R ² and R ³ is hydrogen Then R ² and R ³ can not both be hydrogen of this type of compound used as an antibacterial agent in vivo or in vitro, and their activity range is similar to erythromycin A. Thus, they can be used for the same purpose, in the same manner as erythromycin A. In general, antibiotics such as compounds of formula III and their salts exhibit in vitro activity against various Gram-positive microorganisms, such as anti-Staphylococcus aureus and Streptococcus aureus, and can also resist certain Gram-negative microorganisms. Microorganisms, such as those of spherical form and ellipsoidal shape. Their activity is readily demonstrated by in vitro tests against various microorganisms in brain-injured infection media using the Sinfold serial dilution technique. Their in vitro activity determines their main uses; they can be used for disinfection, such as utensils in wards; they can be used for industrial sterilization such as water treatment, sludge control, paint and wood preservation. For the main use in vitro, it is usually better to formulate it into a pharmaceutical composition, wherein the compound of formula III can be combined with a pharmaceutically acceptable carrier or diluent, such as cartilage and cream. Suitable carriers and diluents for use herein include mineral and vegetable oils, solvents such as water, alcohols, glycerin and mixtures thereof. The pharmaceutical combination generally contains the weight ratio of the pharmaceutically acceptable carrier and the compound of formula III in the range of 4:1-1:4.

（使100％致死的最低细菌浓度）量的适当的稀释细菌培养物，接种较低稀释细菌量的鼠的对照实验也同时进行，用来作为一个试验细菌可能的致病力变化的对照。实验化合物在接种后0.5小时给药，4、24、48小时后分别再给一次。最后治疗以后四天尚存的老鼠算作存活老鼠，将其数记下。Antibacterial compounds of formula III and pharmaceutically acceptable salts thereof are active in vivo against various Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes, and also have activity against certain Gram-negative bacteria, giving Animals including humans are administered orally or parenterally. For sensitive organisms, their activity in vivo is more limited than in vitro, which can be determined by the usual method, that is, a number of rats of about the same body weight are infected with the microorganism under test and then given orally with the test compound or subcutaneous injections. In the experiment, 10 mice were inoculated with about 1-10 times the LD

(The lowest bacterial concentration that makes 100% lethal) amount of appropriate diluted bacterial culture, the control experiment of mice inoculated with lower diluted bacterial amount is also carried out at the same time, which is used as a control for the possible pathogenicity change of the experimental bacteria. The test compound was administered 0.5 hour after inoculation and again 4, 24 and 48 hours later. The mice that survived four days after the last treatment were counted as surviving mice, and their numbers were recorded.

For the treatment of bacterial infection in mammals, especially humans, the compound of formula III and its salts can be administered alone, but preferably in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent. Such compositions can be formulated into tablets and capsules for oral or parenteral administration, including subcutaneous and intramuscular injection. Pharmaceutically acceptable carriers depend on the mode of administration, such as lactose, sodium citrate, phosphate salts, together with disintegrants such as starch and lubricants such as magnesium stearate, sodium lauryl sulfonate and talc ) can be used as a pharmaceutically acceptable carrier for tablets. The pharmaceutical carrier that can be used as a capsule is lactose and high molecular weight polyethylene glycol (that is, molecular weight 2000-4000), and it can be made into a disinfectant or suspension for parenteral drugs, and the pharmaceutically acceptable carrier is Aqueous (such as water, isotonic saline, and isotonic dextrose solution) or nonaqueous (such as vegetable fatty oils such as cottonseed or peanut oil, or polyols such as glycerol or propylene glycol)

The pharmaceutical composition of the compound of formula III and its salt for in vivo use usually contains a pharmaceutically acceptable carrier and the compound of formula III or blue salt in a weight ratio of 4:1-1:4.

When using in vivo to treat bacterial infection in mammals, oral or parenteral administration, the daily dose of formula III antibacterial compound or its salt is 5-100 mg/kg body weight, especially 10-50 mg/kg body weight is more commonly used, once taken or divided into several doses.

The following examples and preparations are only used to further illustrate the present invention. The proton nuclear magnetic resonance spectrum ('H-NMR spectrum) is measured with deuterochloroform (CDCl ₃ ) solution to identify the absorption peak position per million (PPm) downfield parts Recorded from endotetramethylsilane. The following abbreviations are used to indicate peak shape: S - single-line bs - broad single line, d - double line, m - multiple line.

example 1

9-deoxo-9a-methyl-4″-deoxy-4″-β-amino-9a-aza-9a homoerythromycin A

A. 9-deoxy-4″-deoxy-4″-β-benzyloxycarboxamido-9a-aza-9a-homoerythromycin A

A solution of 0.15 ml (1.0 mmol) of benzyloxyformyl chloride (benzyl chloroformate) in 5 ml of dichloromethane was added to stirred 0.5 g (0.68 mmol) of 9-deoxy-4″-deoxy- A solution of 4″-β-amino-9a-aza-9a-homoerythromycin A and 0.11 ml (0.1 mmol) pyridine in 20 ml dichloromethane. The reaction mixture was stirred at room temperature for 30 minutes, then excess water was added. The pH of the aqueous phase was adjusted to 2, and the organic layer was separated and discarded. The pH of the aqueous layer was raised to 5, then the aqueous layer was extracted with chloroform and the chloroform extract was discarded. Then the pH value of the aqueous layer was raised to 8 and extracted again with chloroform. The last chloroform extract was washed with water, dried and evaporated in vacuo to yield 0.43 g of the 4"-β-benzyloxycarboxamide derivative.

B. 9-deoxy-9a-methyl-4″-deoxy-4″-β-benzyloxycarboxamide-9a-aza-9a-homoerythromycin A

A mixture of the product from Part A (0.43 g), 0.2 ml of 37% aqueous formaldehyde, 0.05 ml of 98% formic acid and 30 ml of chloroform was heated at reflux for 3.5 hours. The reaction mixture was then cooled and diluted with excess water. The pH was adjusted to 9, and the mixture was extracted with chloroform. The chloroform extract was washed with water, dried and evaporated in vacuo to give 0.40 g of the 9a-methyl derivative.

C.9-Deoxy-9a-methyl-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

The product from part B (0.40g) was dissolved in 5ml of glacial acetic acid and 100mg of 10% palladium on carbon catalyst was added under nitrogen. The resulting mixture was shaken for 5.5 hours in hydrogen at a pressure of about 4 kg/cm ² , and then the catalyst was separated by filtration. Ethyl acetate and water were added to the filtrate, and the pH of the aqueous phase was adjusted to 9.5. The ethyl acetate layer was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined ethyl acetate solutions were washed with water and dried. The dried solution was evaporated to give 0.04 g of 9-deoxo-9a-methyl-4"-deoxy-4"-β-amino-9a-aza-9a-homoerythromycin A.

The 'H-NMR spectrum of the product showed absorption at 2.13 (broad singlet, 9H) and 3.28 (singlet, 3H) ppm.

Example 2

9-deoxo-9a-methyl-4″-deoxy-4″-α-amino-9a-aza-9a-homoerythromycin A

The title compound can be prepared from 9-deoxo-4"-deoxy-4"-α-amino-9a-aza-9a-homoerythromycin A using the three-part procedure of A, B and C of Example 1, 9-Deoxo-4"-deoxy-4"-α-amino-9a-aza-9a-homoerythromycin A was used to react with benzyloxycarbonyl chloride, followed by reaction with formaldehyde-formic acid, followed by reduction with hydrogen.

Example 3

9-deoxo-4″-deoxy-4″-α-amino-9a-aza-9a-homoerythromycin A

A. 4″-deoxy-4″-α-amino-erythromycin A oxime

A mixture of 6.4 g (8.6 mmol) of 4″-deoxy-4″-α-amino-erythromycin A, 3.2 g (4.6 mmol) of hydroxylamine hydrochloride and 65 ml of pyridine was heated to 50°C and maintained at this temperature for about 18 hours . The reaction mixture was then added to a mixture of diethyl ether and water and the pH of the aqueous layer was adjusted to 10. The layers were separated and the aqueous layer was further extracted with ether. The combined ether solutions were washed _with water, followed by saturated sodium chloride solution, and the ether solutions were dried ( _Na2SO4 ). Evaporation of the ether solution gave a foam. To the foam was added more ether and the mixture was heated on a steam bath and then allowed to cool. The solid material was filtered off to give the first desired oxime (3.86g). Evaporation of the ethereal filtrate in vacuo gave a second time the desired oxime (1.9g).

B. 4″-deoxy-4″-α-amino-9a-aza-9a-homoerythromycin A

1.5 g (18 mmol) of sodium bicarbonate were added to a solution of the oxime (1.9 g; 2.5 mmol) from the second run in part A in a mixture of 40 ml of acetone and 30 ml of water and the mixture was cooled to ice bath temperature. A solution of 1.0 g (5.0 mmol) of 4-toluene-sulfonyl chloride in about 10 ml of acetone was added dropwise to the resulting mixture with stirring over a period of 10 minutes. Aqueous sodium hydroxide solution was added during the dropwise addition in order to maintain a pH value of approximately 8. Stirring was continued for 30 minutes, then the reaction mixture was poured into a mixture of water and dichloromethane. The pH of the aqueous layer was adjusted to 5, and the dichloromethane layer was separated. The aqueous residue was extracted with dichloromethane at pH 6.0, 6.5 and 10. Evaporate under vacuum at pH The dichloromethane solution extracted at a value of 10 and the residue recrystallized from ether afforded the desired 9a-aza-9a-homocompound for the first time. The dichloromethane solution extracted at pH 6.5 was evaporated under vacuum to give the desired 9a-aza-9a-homo compound a second time. Evaporation of the mother liquor recrystallized from diethyl ether under vacuum afforded the desired 9a-aza-9a-homocompound a third time. The three results were combined to give 1.0 g of the desired 9a-aza-9a-homo compound.

C. 9-deoxo-4″-deoxy-4″-α-amino-9a-oxime-9a-homoerythromycin A

A solution of the product from part B (1.0 g; 1.3 mmol) in 40 ml of methanol was cooled to ice bath temperature and 2.0 g of sodium borohydride were added portionwise with stirring. Stirring was continued for 1 hour, then the reaction mixture was diluted with water and ethyl acetate. The pH was adjusted to 9, the ethyl acetate layer was separated, washed with water and dried. Evaporation of the ethyl acetate solution afforded 50 500 mg of 9a-deoxo-9a-aza-9a-homocompound.

The 9a-deoxo-9a-aza-9a-homocompound was combined with the same 1.28 g additional compound prepared in a similar manner and the mixture was purified by column chromatography on silica gel with chloroform/methanol/hydrogen Ammonium oxide (9:5:0.05) was used as eluent. Evaporation of the appropriate fractions afforded 600 mg of 9-deoxo-4"-deoxy-4"-α-amino-9a-aza-9a-homoerythromycin A.

The 'H-NMR spectrum of the product showed absorption at 2.29 (singlet, 6H) and 3.33 (singlet, 3H) ppm.

Example 4

9-deoxo-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

A. 4″-deoxy-4″-β-amino-erythromycin A

50 g (68 mmol) 4″-deoxy-4″-β-amino-erythromycin A, A mixture of 25 g (360 mmol) of hydroxylamine hydrochloride and 250 ml of pyridine was stirred at room temperature for 2 days. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 10. The ethyl acetate layer was separated, dried and evaporated in vacuo to give a foam. The foam was recrystallized from ether to give 14 g of the desired oxime. Evaporation of the mother liquor in vacuo gave a foam which was triturated under petroleum ether and then recrystallized from diethyl ether to give an additional 6 g of the desired oxime.

The mother liquor from the second recrystallization was evaporated and the residue was treated as above with 15 g of hydroxylamine hydrochloride in 60 ml of pyridine to give an additional 4.5 g of the desired oxime.

B. 4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

14.0 g (18.7 mmol) of 4″-deoxy-4″-β-amino-erythromycin A from part A, 53 g (28 mmol) of 4-toluenesulfonyl chloride, 4.2 ml (30 mmol) of Ethylamine and 100 ml of chloroform were stirred to form a mixture. The temperature was raised to 33°C, and then the reaction mixture was cooled to room temperature with a water bath. The reaction mixture was stirred at room temperature for 1 hour, then excess water was added. The pH of the aqueous phase was adjusted to 5 with 1N hydrochloric acid, and the aqueous layer was separated. The pH of the aqueous layer was adjusted to 10, followed by extraction with ethyl acetate. The ethyl acetate extracts were dried and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 7.0 g of the desired 9a-aza-9a-homocompound.

C 9-deoxo-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

4″-Deoxy-4″-β-amino-9a-aza-9a-homoerythromycin (7.0 g; 9.4 mmoles) from Part B was dissolved in 300 ml methanol and cooled in an ice bath to 10-15°C. Under stirring, 7.5 g (0.2 mol) of sodium hydroxide was added to the above solution in portions over about 20 minutes. Stirring was continued for 3 hours, and excess water was then added. The resulting mixture was extracted several times with chloroform, dried, and in vacuo The extract was evaporated. The residue (9.0 g) was dissolved in a mixture of 100 ml acetone and 50 ml water and 9.0 (55 mmol) mannitol was added, followed by 1.7 g (20 mmol Er) sodium bicarbonate. The resulting mixture was stirred at room temperature for 18 hours, then diluted with water and extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated, yielding for the first time 1.5 g of the desired 9-deoxo-9a-aza-9a-homo compound.

The aqueous phase remaining after extraction with ethyl acetate was further extracted with chloroform, and the chloroform solution was dried and evaporated to give 4.5 g of a residue. The residue was dissolved in 300ml of chloroform, and 1150g of silica gel was added. The mixture was stirred at room temperature for 18 hours, then it was filtered. The silica gel was washed with 300 ml of chloroform, followed by 500 ml of chloroform/methanol/ammonium hydroxide (100:1:0.1), followed by 500 ml of chloroform/methanol/ammonium hydroxide (4:1:0.1). After removal of the silica gel the previous filtrate and all silica washes were combined and evaporated under vacuum. The residue was combined with the previously obtained desired 9-deoxo-9a-aza-9a-homocompound in 100 ml of water. The pH was adjusted to 5 and the mixture was stirred at pH 5 for 25 minutes. The pH was raised to 10 and the aqueous phase was extracted with dichloromethane. The dichloromethane extract was dried and evaporated in vacuo to yield 4.3 g of 9-deoxo-4"-deoxy-4"-β-amino-9a-aza-9a-homoerythromycin A.

The 'H-NMR spectrum of the product showed absorption at 2.24 (singlet, 6H) and 3.28 (singlet, 3H) ppm.

Example 5

9-deoxo-9a-methyl-4″-deoxy-4″-α-amino-9a-aza-9a-homoerythromycin A

A 9-deoxo-9a-methyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A oxime.

7.5 g (9.5 mmol) 9-deoxo-9a-methyl-2′-0-acetyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin at 50 The solution in ml methanol was stored at room temperature for two days, after which 3.5 g (50 mmol) of hydroxylamine hydrochloride were added. The resulting mixture was stirred at room temperature for 3 hours, then the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and water, raising the pH of the aqueous phase to 9. The layers were separated and the organic layer was dried and evaporated in vacuo. The residue was recrystallized from ether to give 4.4 g of the desired oxime.

B 9-deoxy-9a-methyl-4″-deoxy-4″-α-amino-9a-aza-9a-homoerythromycin A

A mixture of 4.4 g (5.8 mmol) of oxime from part A and about 4 g of Raney nickel in 100 ml of ethanol was shaken under hydrogen at a pressure of 4.5 kg/ ^cm² for about 75 hours. The mixture was then filtered and the filtrate evaporated in vacuo to give a foam. The foam was dissolved in diisopropyl ether and the solvent was allowed to evaporate slowly. After 24 hours the precipitated white solid was collected to give 2.2 g of 9-deoxy-9a-methyl-4"-deoxy-4"-a-amino-9a-aza-homoerythromycin A.

The 'H-NMR spectrum of the product showed absorption at 2.31 (singlet, 6H), 2.35 (singlet, 3H) and 3.31 (singlet, 3H) pPH.

Example 6

9-deoxo-9a-methyl-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

A. 9-deoxy-9a-methyl-4″-deoxy-4″-oxo-9a-aza-9a homoerythromycin A

0.93g (1.2 mmol) 9-deoxo-9a-methyl-2′-0-acetyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A in 50ml The solution in methanol was stored at room temperature for 20 hours, then the solvent was removed by evaporation in vacuo. This gave 0.74 g of the desired deacetylated material.

The 'H-NMR spectrum of the product showed absorption at 2.30 (singlet, 6H), 2.38 (singlet, 3H) and 3.35 (singlet, 3H) ppm.

B. 9-deoxy-9a-methyl-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A

Prepare 0.50 g (0.67 mmol) of 9-deoxo-9a-methyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A and 0.54 g (6.7 mmol of ammonium acetate solution in 50 ml of methane, then add 7 drops of acetic acid under stirring to adjust the pH value to 6. Continue to stir for 1 hour, then add 0.13 g (2.1 mmol) sodium cyanoborohydride in portions. Continue to add stirring for 2.5 hours, then the reaction mixture was evaporated in vacuo. The residue was distributed between chlorine and water and the pH of the aqueous layer was adjusted to 2. The aqueous layer was separated and the pH was adjusted to 6.2. Extraction was performed at pH 6.2 The aqueous layer was used to separate the 4″-hydroxyl product, and the extract was discarded. The pH of the aqueous layer was then raised to 9.5 and the aqueous layer was further extracted with chloroform. The chloroform extract was dried and evaporated in vacuo. In the case of a pH of 2 The residue was redissolved in water at pH 2. The aqueous solution thus obtained was extracted with chloroform at pH 2, pH 6.2 and pH 9.5. The chloroform solution extracted at pH 9.5 was dried, evaporated and redissolved in water at pH 2. This latter aqueous solution was extracted with chloroform at pH 2, pH 6.2 and pH 9.5. The chloroform solution extracted at pH 9.5 was dried and evaporated in vacuo to yield 0.18 g of 9-deoxy-9a-methyl-4" - 1:1 mixture of deoxy-4"-β-amino-9a-aza-9a-homoerythromycin A and its 4"-α-epimer.

Example 7

9-deoxo-9a-methyl-2′-0-acetyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A

A. 9-deoxy-9a-methyl-2′-0-acetyl-9a-aza-9a —High erythromycin A

A solution prepared from 1.0 g (1.3 mmol) of 9-deoxo-9a-methyl-9a-aza-9a homoerythromycin A and 0.13 ml (1.4 mmol) of acetic anhydride in 15 ml of chloroform was incubated at room temperature Stir for several hours. Add excess water to the solution, keep the pH value at 9 and continue stirring for 30 minutes. The organic phase was then separated off, dried and evaporated to give 1.0 g of the desired 2'-O-acetyl compound.

B. 9-deoxy-9a-methyl-2′-0-acetyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A

7.5 g (9.5 mmol) 9-deoxo-9a-methyl-2′-0-acetoyl-9a-aza-9a-homoerythromycin A, 5.5 g (28 mmol) N-ethyl A mixture of yl-N'-(N,N-diethyl-aminopropyl)carbo=imine and 6.7 ml (95 mmoles) of dimethylsulfoxide in 75 ml of dichloromethane was prepared. With stirring, 5.5 g (28 mmol) of pyridinium trifluoroacetate was added dropwise to the mixture over 3 minutes. The temperature was raised to 39°C and then cooled to room temperature. Stirring was continued for 2 hours, then excess water was added and the pH of the aqueous layer was adjusted to 9. The organic layer was separated, dried and evaporated under vacuum to yield 7.5 g of 9-deoxo-9a-methyl-2'-0-acetyl-4"-deoxy-4"-oxo-9a-aza-9a- High erythromycin A.

The 'H-NMR spectrum of the product showed absorption at 2.05 (singlet, 3H), 2.26 (singlet, 6H), 2.33 (singlet, 3H) and 3.33 (singlet, 3H) ppm.

Example 8

9-deoxo-9a-methyl-2′-0-propionyl-4″-deoxy-4″-oxo-9a-aza-9a-homoerythromycin A

The title compound was prepared by repeating Example 7, but the acetic anhydride used in Part A was replaced by an equimolar propionic anhydride.

Example 9

9-deoxo-4″-deoxy-4″-β-(4-methoxycarboxamido)-9a-aza-9a-homoerythromycin A

Add 0.20 ml (approximately 2 mmol) of triethylamine to stirred 730 mg (1 mmol) of 9-deoxo-4″-deoxy-4″-β-amino-9a-aza-9a-hoerythromycin A solution of element A in 15 ml of dichloroethane, then, under stirring, a solution of 0.17 ml (about 1 mmol) of 4-methoxybenzoyl chloride in 5 ml of dichloromethane was added drop by drop at room temperature. Stirring was continued for 30 minutes at room temperature. Chloroform and water were then added to the reaction mixture and the pH was adjusted to 4.5. The layers were separated, the organic layer was discarded, the pH of the aqueous phase was raised to 7.5, and the aqueous phase was extracted with chloroform. The extract was dried and evaporated in vacuo to afford 610 mg (70% yield of the title product.

The 'H-NMR spectrum of the product is at 2.25 (singlet, 6H) kg3.35 (singlet, 3H), 3.85 (singlet, 3H), 6.95 (doublet, 2H, J=5H ₂ ) and 7.85 (doublet Peak, 2H, J=5H ₂ ) ppm showed absorption.

Example 11

Acylation of 9-deoxo-4"-deoxy-4"-α-amino-9a with benzyl chloroformate (reaction time 0.75 hours) and benzenesulfonyl chloride (reaction time 16 hours) essentially according to the procedure of Example 9 -aza-9a-homoerythromycin A, respectively, to obtain the following compounds:

9-deoxo-4″-deoxy-4″-α-benzyloxycarboxamido-9a-aza-9a-homoerythromycin A (84% yield) and 9-deoxo-4″-deoxy -4″-α-Benzenesulfonamido-9a-aza-9a-homoerythromycin A (24% yield).

Example 12

9-Deoxo-4″-deoxy-4″-β(2-[4-methoxyphenyl]-acetamido)-9a-aza-9a-homoerythromycin A

730 mg (1 mmol) 9-deoxo-4″-deoxy-4″-β-amino-9a-aza-9a-homoerythromycin A, 500 mg (3 mmol) 2-(4-methoxy Base-phenyl) acetic acid and 800 mg (4 mmol) of dicyclohexylcarbodiimide were added to 50 ml of dichloromethane, and the reaction mixture was stirred at room temperature for 2 hours. Water was then added to the reaction mixture to adjust the pH of the aqueous layer to 4. After the layers were separated, the aqueous layer was further extracted with chloroform at pH 4. The dichloromethane layer and the chloroform layer extract were discarded. The pH of the aqueous layer was raised to 6.5, followed by extraction with chloroform three times. The next three extracts were dried and evaporated in vacuo to afford 650 mg (74% yield) of the title compound.

The 'H-NMR spectrum of the product is at 2.25 (singlet, 6H), 3.25 (singlet, 3H), 3.75 (singlet, 3H), 6.90 (doublet, 2H, J=5H ₂ ) and 7.15 (doublet , 2H, J=5Hz) ppm showed absorption.

Example 14

9-deoxo-4″-deoxy-4″-β-12-[4-hydroxyphenyl]-acetylamino)-9a-aza-9a-homoerythromycin A.

The stirred 30ml methylene chloride solution containing 120mg (0.82mmol) of 2-(4-hydroxyphenyl)acetic acid and 0.15ml (1.8mmol) of N-methylmorpholine was cooled to -15°C, and then added 0.18 ml (1.3 mmol) isobutyl chloroformate. The resulting mixture was stirred at -15°C to -10°C for 30 minutes, and then 600 mg (0.82 mmol) of 9-deoxo-4″-deoxy-4″-β-amino-9a-aza-9a-high red A solution of mycin A in 10 ml of dichloromethane was added to the resulting mixture. Stirring was continued at -10°C for 30 minutes, at -5°C for 30 minutes, and at 00°C for 30 minutes. Water was then added to the reaction mixture to adjust the pH of the aqueous layer to 4. The layers were separated and the aqueous layer was further extracted with chloroform at pH 4. The dichloromethane and chloroform extracts were discarded. The pH value of the aqueous layer was raised to 6.5, and then extracted three times with chloroform. The latter three extracts were combined, dried and evaporated in vacuo to give 470 mg (66% yield) of the title compound.

Example 15

9-Deoxo-4″-deoxy-4″-β-(2-[4-aminophenyl]-acetylamino)-9a-aza-9a-homoerythromycin A.

The title product was prepared in 40% yield by 9-deoxo-4″-deoxy-4″-β-amino-9a-phlegm-9a-homoerythromycin A with 2-(4-aminophenyl ) The mixed acid anhydride prepared by the reaction of acetic acid and isobutyl chloroformate is reacted. The procedure of Example 14 was used.

The 'H-NMR spectrum of this product shows absorptions at 2.25 (singlet, 6H) and 7.15 (singlet, 4H) ppm.

Example 16

9-deoxo-9a-methyl-4″-deoxy-4″-β-(4-chlorophenylsulfonylamino)-9a-aza-9a-homoerythromycin A

200mg (0.22mmol) of 9-deoxo-4″-deoxy-4″-β-(4-chlorophenylsulfonylamino)-9a-aza-9a-homoerythromycin A, 0.03ml A mixture of 37% aqueous formaldehyde, 0.01 of 98% formic acid and 10 ml of chloroform was heated under reflux for 16 hours. After the reaction mixture was cooled, water was added to adjust the pH value of the aqueous phase to 9.6, and the liquid phases were separated. The organic layer was washed with water, then dried and evaporated in vacuo to give 200 mg (94% yield) of the title product.

The 'H-NMR spectrum of this product is at 2.25 (singlet, 6H), 3.30 (singlet, 3H), 7.35 (doublet, 2H, J=5H ₂ ) and 7.80 (doublet, 2H, J=5H ₂ ) . Absorption is shown in ppm.

Example 17

Following the procedure of Example 16, the appropriate 9-deoxo-4"-deoxy-4"-β-(amido)-9a-aza-9a-homoerythromycin A compound was methylated with formaldehyde and formic acid, The following compounds were obtained.

Example 17 (continued)

R ³ Reaction Time Yield' H-NMR Spectrum

(hour) (%) (PPm)

Phenylsulfonamido 16 75

Example 18

According to the steps of Example 16, 9-deoxo-4″-deoxy-4″-α-oxycarbonylamino-9a-aza-9a-homoerythromycin A and 9-deoxo-4″-deoxy-4 "-α-phenylsulfonamido-9a-aza-9a-homoerythromycin A is methylated with formaldehyde and formic acid to obtain the following compounds respectively:

9-deoxo-9a-methyl-4″-deoxy-4″-α-benzyloxycarbonylamino-9a-aza-9a-homoerythromycin A (yield 100%) and

9-deoxo-9a-methyl-4″-deoxy-4″-α-phenylsulfonamido-9a-aza-9a-homoerythromycin A (yield 70%).

preparation 1

4″-deoxy-4″-α-amino-erythromycin A

A mixture of 10.0 g (13.6 mmole) of 4″-deoxy-4″-oxo-erythromycin A, 10.5 g of ammonium acetate and 150 ml of methanol containing 10.0 g of Raney nickel at an initial pressure of about 4 kg/cm ² Under hydrogen pressure, shake overnight at room temperature, then add 10.5g of ammonium acetate and 10.0g of Raney nickel, the mixture is about 4kg/ ^cm under hydrogen pressure at an initial pressure, after shaking overnight at room temperature, Filter to remove catalyst, filtrate is concentrated to about 50ml under vacuum, then, the concentrated filtrate is poured in the mixture of 250ml water and 200ml chloroform with stirring, the pH value of aqueous layer is adjusted to 5.4, removes organic layer and discards, in When the pH value was 5.4, the aqueous layer was further extracted with chloroform, the extract was discarded, the pH value of the aqueous phase was adjusted to 9.6, and then the aqueous phase was extracted with chloroform, and the obtained extract was dried with Na ₂ SO ₄ and then in Concentration under vacuum gave 5.74 g of a white foam which was dissolved in 35 ml of hot isopropanol and the solution was cooled to room temperature with stirring. The solid formed was recovered by filtration and dried to give 3.54 g of 4″-deoxy-4″-α - Amino-erythromycin A, which contains 5-10% of its 4"-epimer impurity.

The amount of the 4"-β-amino epimer was reduced by successive recrystallizations from isopropanol.

preparation 2

4″-deoxy-4″-β-amino-erythromycin A

With 20g of 4″-deoxy-4″-oxo-erythromycin A, 31.6g of ammonium acetate and 200ml of methanol solution containing 10g of 10% palladium-carbon catalyst, at room temperature, the initial pressure is about 4kg/ ^cm2 hydrogen pressure After shaking overnight, the spent catalyst was filtered off, and the filtrate was concentrated to dryness under vacuum. When the pH value was 5.5, the residue was partitioned between water and chloroform, and the water layer was separated. The pH value was adjusted to 9.6, and chloroform was added. , the organic layer was separated, dried over sodium sulfate, concentrated to dryness under reduced pressure, and the remaining white foam (19 g) was triturated with 150 ml of ether for 30 minutes at room temperature, filtered and dried to yield 9.45 g of 4″-deoxy - 4"-β-amino-erythromycin A.

Claims (7)

1. The method for preparing the following formula macrolide antibacterial compound or its pharmaceutically acceptable acid addition salt

In the formula R ¹ is hydrogen or methyl; and R ² and R ³ are each hydrogen, amino, -NH-CO-R ⁵ or -NH-SO ₂ -R ⁶ ; If one of ^R2 and ^R3 is hydrogen, both ^R2 and ^R3 cannot be hydrogen; In the formula:

Wherein ALK is an alkyl group having 1 to 8 carbons; Ar is thienyl, furyl, isoxazolyl, ^pyridyl , pyrazinyl or pyrimidinyl; ^X is hydrogen, fluorine, chlorine, bromine, hydroxyl , amino, nitro, trifluoromethyl, alkyl having 1 to 3 carbons or alkoxy having 1 to 3 carbons; ^X is hydrogen, fluorine, chlorine or bromine; n is 0 or 1; and m is 0, 1, 2 or 3; and formic acid is methylated on N-9a, and the protecting group is removed from ^R2 or ^R3 ; (ii) acylation of R ² or R ³ that is amino with an activated derivative of an acid of formula R ⁵ -CO-OH or R ⁶ -SO ₂ -OH; or (B), for the preparation of R' is Methyl, R ² is amino, NH-CO-R ⁵ or NH-SO ₂ -R ⁶ , and R ³ is those formula III compounds of hydrogen, react with the following formula compound with excess hydroxylammonium hydrochloride

It is then reduced with gaseous hydrogen over a Raney nickel catalyst; This is followed, if desired, by acylation with an activated derivative of an acid of formula R ⁵ -CO-OH or R ⁶ -SO ₂ -OH; Or (C), for the preparation of those compounds of formula III wherein R ¹ is methyl, R ² is hydrogen and R ³ is amino, NH-CO-R ⁵ or NH-SO ₂ -R ⁶ , with an excess of ammonium acetate React with sodium cyanoborohydride and the compound of formula

This is then acylated, if desired, with an acid activated derivative of formula R ⁵ -CO-OH or R ⁶ -SO ₂ -OH. 2. The method according to claim 1, wherein ^R2 and ^R3 are each hydrogen or amino. 3. A process according to claim 1(A), wherein ^R2 and ^R3 are each hydrogen or amino, characterized in that the reagent capable of reducing the amide to the amine is sodium borohydride. 4. The method according to claim 3, wherein R ¹ is hydrogen. The reduction temperature is 0° to 30°C with sodium borohydride, and the solvent is a lower alkanol. 5. The method according to claim 3, wherein ^R is a methyl group, the temperature is 0 ° to 30 ° C, the solvent is a low alkanol, and the reduction is carried out with sodium borohydride; Next, the benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl protecting group is attached to ^R2 or ^R3 which is an amino group, methylated on N-9a, and the protecting group is removed by hydrogenolysis. 6. A method according to claim 1 (B), wherein R is amino, characterized in that the reaction with hydroxylamine hydrochloride is carried out at ^room temperature in methanol solution; then at room temperature, on a Raney nickel catalyst, In a low alkanol solvent, treat with hydrogen at a pressure in the range of 1-10 kg/cm ² . 7. A process according to claim 1 (c), wherein ^R3 is amino, characterized in that the reaction with excess ammonium acetate and cyanoborohydride is carried out in a low alkanol solvent at room temperature. (ii) ^R6 from ^Ar2 and

Selected from a group of groups, wherein Ar ² is thienyl or furyl, X ³ is hydrogen, chlorine, bromine or iodine; characterized in that either (A) Compounds of the following formula

Reduction by a reagent capable of reducing an amide to an amine yields a compound of the formula

When needed, one or two of the following transformations follow: (i) attaching a protecting group to ^R2 or ^R3 which is amino, with an excess of formaldehyde and