CS199728B2 - Method of producing derivatives of 4"-sulphonyl amino oleandomycin - Google Patents

Abstract

Semi-synthetic 4''-sulphonylaminooleandomycins of formulae 1, 2 and 3 are described in which the symbols have the meaning given in Claim 1. These compounds may be prepared from semi-synthetic intermediates of the 4''-deoxy-4''-aminooleandomycin type. Compounds 1, 2 and 3 are useful as antibacterial medicinal products. Pharmaceutical preparations containing these compounds or their addition salts with a pharmaceutically acceptable acid are also described. <IMAGE>

Description

The invention relates to a process for the production of novel antibacterial agents, in particular 4'-deoxy-4'-sulfonylaminooleandomycins and their pharmaceutically acceptable acid addition salts.

Oleandomycin, its production in fermentation broths and its use as an antibacterial agent were first disclosed in U.S. Patent 2,757,123. It is known that a naturally occurring compound has the following structure:

The individual positions of this formula show the commonly used numbering and stereochemistry of oleandomycin and the like.

U.S. Pat. Nos. 3,884,902 and 3,983,103 protect 4 &apos; -erythromycin sulfonates and the like. N-Sulfonylerythromycylamines whose biological properties differ from those of the compounds described herein.

Several synthetic oleandomycin analogs are known, in particular substances in which one to three of the free hydroxyl groups found in the 2 ‘, 4 a and 11 positions are esterified with acetyl groups. Furthermore, U.S. Patent No. 3,022,219 discloses similar analogs in which the acetyl group present in the above esters is replaced by another group, preferably an unbranched lower alkanoyl group having 3 to 6 carbon atoms.

The semisynthetic antibacterial agents of the oleandomycin type according to the invention can be described by the general formula I,

in which

R is C 1 -C 3 alkyl, pyridyl, phenyl, monosubstituted phenyl, wherein the substituent is selected from the group consisting of fluorine, chlorine, bromine and iodine, hydroxy, methoxy, cyano, carboxamido, nitro, amino, methoxycarbonyl, benzyloxycarbonyl, carboxyl, trifluoromethyl, C 1 -C 4 alkyl and acetamido, furthermore represents a dsubstituted phenyl group wherein the substituents are independently selected from the group consisting of chlorine, nitro, amino, methoxy and methyl further denotes trichlorophenyl, hydroxydichlorophenyl, benzyl, naphthyl, thienyl, chlorothienyl, 2-acetamido-5-thiazolyl,. 2-acetamido-4-methyl-5-thiazolyl, 2-benzimidazolyl, dimethyl-2-pyrimidinyl, pyrrolyl, furyl, monosubstituted thienyl, pyrrolyl or furyl, wherein the substituent is selected from methoxycarbonyl and alkyl groups having 1 or 2 carbon atoms, or 1-methyl-5-methoxycarbonyl-3-pyrrolyl, vinyl, 2,2,2-trifluoroethyl or bromoethyl, and

R 1 represents a hydrogen atom or an alkanoyl group having 2 to 3 carbon atoms.

The invention also encompasses pharmaceutically acceptable acid addition salts of these compounds.

Due to the synthetic procedure used in their preparation, the starting amines used in the preparation of the compounds of the invention are a mixture of 4'-epimeric amines. The sulfonamido derivatives of the present invention resulting from these amides are therefore also comprised of a mixture of epimers. Experimentally, it was found that both epimeric sulfonamides are present in the final product in different proportions depending on. selecting the synthetic method used to prepare the starting amine. If the isolated product consists predominantly of one of these epimers, the epimer may be purified by repeated crystallization from a suitable solvent up to a constant melting point. The second epimer, present in minor amounts in the initially isolated solid material, is the predominant product in the mother liquor from which it can be isolated in a manner known per se, for example by evaporation of the mother liquor and repeated crystallization of the residue until constant melting point or chromatography.

Although the above-mentioned epimer mixture can be separated in a manner known per se, for practical reasons it is preferable to use the mixture as isolated from the reaction mixture. However, it is often preferred to purify this epimer mixture by at least one recrystallization from a suitable solvent, column chromatography, shaking in a solvent, or trituration with a suitable solvent. This purification, while not necessarily separating the epimers, removes foreign materials such as starting materials and unwanted by-products. Investigations of the absolute stereochemical alignment of epimers have not yet been completed, but both epimers of the compound exhibit the same type of effect, e.g., anti-bacterial activity.

Preferred compounds of formula (I) are those wherein R is thienyl or substituted thienyl, wherein the substituent is an alkyl group of 1 to 5 carbon atoms. 2 carbon atoms or a methoxycarbonyl group.

In accordance with the invention, the compounds of formula (I) above are prepared by preparing a compound of formula (I),

in which

R1 is as defined above, reacted with one mole of a sulfonyl halide of the formula

RSOžW where

R is as defined above and

W represents a halogen atom.

The above reaction between 4 &apos; -deoxy-4 &apos; -aminooleandomycin and the corresponding sulfonyl halide is carried out in the presence of an acid acceptor in a reaction inert solvent.

In practice, 1 mol of 4 &apos; -aminooleandomycin is contacted with a 1 mol-J-2 to 3% excess sulfonyl halide. The acid acceptor, which may be inorganic or organic, is used in an amount of 1 mol + 4-6% excess.

Acid acceptors may be alkali or alkaline earth metal hydroxides, hydrides or carbonates, as well as tertiary organic amines. Secondary amines such as diisopropylamine, which are sufficiently hindered so that they cannot react with the sulfonyl halide, can also be used. A preferred class of acid acceptors is tertiary amines, with triethylamine being a particularly preferred acid acceptor.

The inert solvent used in the above reaction should be a solvent which substantially dissolves the reactants and does not react in any significant way with either the reactants or the products formed. Polar solvents miscible or immiscible with water are preferred. A particularly preferred solvent is methylene chloride with a mixture of acetone and water.

Since some decomposition occurs with the heating of the aminooleandomycins, it is preferable to carry out the reaction leading to the compounds of the formula I at a temperature of 0 to 25 ° C. According to a particularly preferred embodiment, the reaction is carried out at room temperature.

The reaction time is not critical and depends on the reaction temperature, concentration and reactivity of the reactants. If the reaction is carried out at room temperature and at the concentrations indicated below, it is practically complete in 2 to 48 hours.

After completion of the reaction, the reaction mixture may be worked up in two ways, both of which are known in the art. The first method involves introducing the reaction mixture into water, subsequently separating the water-immiscible solvent containing the desired product, and then removing the solvent to obtain the crude product. When a water-miscible solvent is used as the inert solvent in the reaction, water is added to the reaction mixture and the product is extracted from the resulting mixture with a water-immiscible solvent such as methylene chloride.

The second treatment involves concentrating the reaction mixture to dryness and extracting the product from the salt formed from the acid acceptor base and the by-product hydrogen halide using acetone. By concentrating the acetone extract, the crude product can then be obtained.

The crude product or its acetone solution is purified in a manner known per se by chromatography on silica gel or by recrystallization.

The starting 4'-amino compounds used in the synthesis of the antibacterially active compounds of the invention are prepared by oxidation of the natural oleandomycin followed by reductive amination of the resulting ketone as described below.

Of course, as the chemotherapeutic agents, those salt-forming compounds of the invention are preferably used in the form of pharmaceutically acceptable salts. While insolubility in water, high toxicity or non-crystalline character may make certain types of salts unsuitable or less desirable for a given pharmaceutical application, water-insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposing the salt with a suitable base or alternatively converted to other desirable pharmaceutically acceptable acid addition salts.

Examples of acids providing pharmaceutically acceptable anions include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic, aspartic, glutamic, pyroglutamic, lauryl sulfuric acid.

The novel 4 &apos; -deoxy-4 &apos; -aminoolendomycin derivatives of the invention show in vitro activity against a number of gram positive organisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain gram negative organisms such as spherical or elliptical gram negative organisms. The efficacy of these compounds can easily be demonstrated by in vitro assays against various microorganisms in a brain and heart extract environment using a conventional dilution series. In vitro efficacy makes these substances useful for topical application in the form of ointments, creams, etc., for sterilization purposes, for example for sterilization of hospital room equipment, and as industrial antimicrobial agents, for example water treatment, antimicrobial treatment of sludge with paint and wood protection .

For in vitro use, for example for topical application, it is often expedient to combine the compound with a pharmaceutically acceptable carrier, such as a vegetable or mineral oil, or a skin softening cream base. Likewise, these substances can be dissolved or dispersed in a liquid carrier or solvent, such as water, alcohol, glycols or mixtures thereof, or other pharmaceutically acceptable inert media which are meant to have no adverse effect on the active ingredient. Generally, concentrations of active ingredients of about 1 to 3 are used for this purpose. from 0.01 to 10% by weight of the total composition.

In addition, many of the compounds of the invention are effective against Gram positive microorganisms when administered orally and / or parenterally to animals, including humans. Their in vivo potency with respect to the susceptibility of microorganisms is somewhat more limited and can be determined in a conventional manner by infecting mice of virtually identical weight with the test microorganism and following oral or subcutaneous administration of the test compound. In practice, mice (e.g., 10 specimens) are treated intraperitoneally with appropriately diluted cultures of microorganisms containing microorganisms at a concentration corresponding to about one to ten times the LD 10 value (the lowest microorganism concentration resulting in the killing of 100% of the test animals). At the same time, control tests are performed in which mice receive a more dilute inoculum to examine possible variations in the virulence of the test microorganism. The test compound is administered 0.5 hours after inoculation and the application is repeated for a further 4, 24 and 48 hours. Surviving mice are observed for 4 days after the last treatment and then the number of surviving specimens is recorded.

When used in vivo, the novel compounds can be administered orally or parenterally, for example by subcutaneous or intramuscular injection, at a dose of about 1 mg / kg to about 200 mg / kg body weight per day. A suitable dose range is about 2 mg to 100 mg / kg body weight per day, a preferred dose range is about 2 mg to 50 mg / kg body weight per day. - Carrier media suitable for parenteral injection may be either aqueous media such as water, isotonic saline, isotonic dextrose or Ringer's solution, or non-aqueous media such as fatty oils of vegetable origin (cottonseed oil, peanut, corn, sesame) , dimethylsulfoxide and other non-aqueous vehicles that do not adversely affect the therapeutic efficacy of the preparation and are non-toxic in the volume or dose used (glycerin, propylene glycol, sorbitol). It is furthermore possible to produce formulations from which application solutions are prepared prior to administration. Such compositions may contain liquid diluents such as propylene glycol, diethyl carbonate, glycerin, sorbitol and the like, buffers, hyalaronidase, local anesthetics, and inorganic salts, which impart the desired pharmacological properties to them. The disclosed compounds may also be combined with various pharmaceutically usable inert carriers, including solid diluents, aqueous vehicles, as well as non-toxic organic solvents, to form capsules, tablets, lozenges, troches, dry mixtures, suspensions, solutions, elixirs, and solutions or suspensions. for parenteral administration. In these various dosage forms, the active compounds described are generally present in a concentration of about 0.5 to 90% by weight, based on the total weight of the composition.

The invention is illustrated by the following non-limiting examples. The abbreviations used to describe NMR spectra have the following meanings:

s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.

Example 1 11-Acetyl-4'-deoxy-4'- (2-thienylsulfonylamino) oleandomycin

2.9 g (4.0 mmol) of 11-acetyl-4 ' -deoxy-4 &apos; -aminoolendomycin, 740 ml (4.1 mmol) of 2-thienylsulfonyl chloride and 0.58 ml (4 ml) were added to 30 ml of dry methylene chloride. (2 mmol) of triethylamine, the mixture is stirred at room temperature for 18 hours, then poured into 50 ml of water and washed with saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated under reduced pressure and the foamed residue was purified by chromatography. on a silica gel column using acetone as eluent. The product containing fractions were combined and concentrated to dryness in vacuo to give 1.3 g of the desired product.

NMR (CDCl3):

2.03 (3H) s,

2.30 (6H) s,

2.63 (2H) d,

3.16 (3H) s a

6.8-7.8 (3H) m.

Example 2

Using the procedure described in Example 1, starting from 11-acetyl-4 &apos; -dexy-4 &apos; -amino-oleandeamycin and the corresponding sulfonyl chloride, the following compounds were obtained:

осн ₃

R NMR (<5 CDCl3) «43- 2.08 (3H) s, 2.30 (6H) s, 2.67 (2H) m, 3.23 (3H) s and 6.87 and 7.45 (2H) s. 0 L / - / ^c ^ ³ CKCNH ~ ^ _S X 2.09 (3H) s, 2.42 (6H) S, 2.70 (2H) m and 3.26 (3H) s.

H

2.0 (3H) s, 2.33 (6H) s, 2.40 (3HJ s,

2.66 (2H) d, 3.33 (3H) s and 7.86 (1H) s.

2.03 (3H) s, 2.33 (6H) s, 2.66 (2H) d,

3.03 (3H) s and 7.40-9.16 (4H) m.

2.06 (3H) s, 2.36 (6H) s, 2.71 (2H) s,

3.28 (3H) s and 7.36-7.56 and 7.66-7.92 (4H) m.

2.08 (3H) s, 2.31 (6H) s, 2.59 (6H) s,

2.65 (2H) s, 3.01 (3H) s, and 7.11 (1H) s.

2.07 (3H) s, 2.32 (6H) s, 2.67 (2H) s,

3.20 (3H) s, 7.32 (1H) m, 7.43 (1H) m, and 8.02 (1H) m.

2.06 (3H) s, 2.29 (6H) s, 2.64 (2H) m,

3.26 (3H) s, 6.52 (1H) m, 6.77 (1H) m and

7.29 (1 H) m.

NMR (δ CDCh)

2.07 (3H) s, 2.62 (6H) s, 3.25 (3H) s,

3.83 (3H) s, 3.95 (3H) s, and 7.30 (2H) m.

2.08 (3H) s, 2.31 (6H) s, 2.68 (2H) m,

3.25 (3H) s, 6.74 (1H) m, 7.48 (1H) m and 8.00 (1H) m.

Example 3 11-Acetyl-4'-deoxy-4'- (p-chlorophenylsulfonylamino) oleandomycin

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 528 μiet (4.2 mmol) of triethylamine in 20 ml of methylene chloride is added portionwise 865 mg (4.1 mmol). p-chlorophenylsulfonyl chloride, the reaction mixture is stirred at room temperature overnight, then concentrated to dryness in vacuo and the residue is stirred with 10 ml of acetone. The suspension is filtered and the filtrate is chromatographed on 160 g of silica gel using acetone as eluent to collect 10 ml fractions. Fractions 51-63 are combined and concentrated under reduced pressure to give 857 mg of pure product. From fractions 42-52 and 64-92, 1.21 g of less pure product was obtained.

NMR (δ CDCl 3):

2.13 (3H) s.

2.36 (6H) s,

2.73 (2H) d,

3.13 (3H) s a

7.3-8.2 (4H) q.

Similarly, by reaction of 20 g of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin, 7.24 g of p-chlorophenylsulfonyl chloride and 5.36 g of triethylamine in a solvent system of 350 ml of acetone and 350 ml of water gives 17.1 g of the desired product. which crystallizes from the reaction mixture and has a melting point of 202-203.5 ° C. The analytical sample was recrystallized from aqueous ethanol.

Example 4

Following the procedure described in Example 3, starting from the appropriate sulfonyl chloride and 11-acetyl-4 &apos; -deoxy-4 &apos; -aminoolendomycin, the following compounds were obtained:

2.08 (3H) s, 2.33 (6H) s, 2.70 (2H) d,

3.11 (3H) s and 775-8.2 (4HH q.

2.08 (3H) s, 2.31 (6H) s,

2.66 (2H) d, 3.06 (3H) s and 7.0-8.4 (4H) m.

NMR (<5, CDCl 3)

2.03 (3HJ s, 2.33 (6H) s, 2.66 (2H) d,

3.10 (3H) s and 7.3-8.0 (4H) m.

Cl

2.03 (3HJ s, 2.33 (6H) s, 2.63 (2H) d,

3.23 (3H) s and 7.2-8.4 (4H) m.

2.13 (3H) s, 2.35 (6H) s, 2.70 (2HJ d,

2.90 (3H) s and 7.0-8.2 (4H) m.

2.10 (3H) s, 2.33 (6H) s, 2.66 (2H) d,

3.10 (3H) s and 7.5-7.93 (4H) m.

Example 5 11-Acetyl-4 "-deoxy-4" - (o-tolylsulfonylamine Joleandomycin)

A solution of 2.9 g (4.0 mmol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin, 780 mg (4.1 mmol) of o-tolylsulfonyl chloride and 0.58 ml (4.2 mmol) of triethylamine in 30 ml of ethyl acetate. of methylene chloride was stirred at room temperature for 48 hours. The reaction mixture was poured into 50 ml of water. The organic layer was separated, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the yellow foam residue is chromatographed over 200 g of silica gel packed in a 3 cm diameter column. Acetone was used as the eluent and 10 ml fractions were collected. Fractions containing the desired product according to thin layer chromatography were combined and concentrated to dryness under reduced pressure to dryness to give 1.3 g of product.

NMR (<5, CDCl 3)

2.06 (3H) s,

2.33 (6H) s

2.46 (2H) d,

2.73 (3H) s a

7.1-8.2 (4H) m.

Example 6

The procedure described in Example 5 was repeated except that the respective sulfonyl chloride and 11-acetyl-4'-deoxy-4'-amino-oleandomycin were used as starting materials. The following compounds are obtained:

NMR (α, CDCl 3)

2.03 (3H) s, 2.30 (6H) s, 2.66 (2H) d,

3.06 (3H) s, 3.83 (3H) s and 6.8-8.2 (4H) m.

2.03 (3H) s, 2.33 (6H) s, 2.66 (2H) d,

3.06 (3H) m and 7.3 and 8.0 (4H) m.

Example 7 11-Acetyl-4'-deoxy-4'-phenylsulfonylaminooleandomycin

To a solution of 2.91 g [4.0 mmol] of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 424 mg (4.2 mmol) of triethylamine in 30 ml of methylene chloride was added 722 mg (4, 1 mmol) of benzenesulfonyl chloride. After 10 minutes, the cooling bath is removed, the reaction mixture is stirred at room temperature overnight, then poured into 50 ml of water, the organic layer is washed with saturated sodium chloride solution and dried over sodium sulfate.

After evaporation of the solvent, the crude product is further purified by chromatography on 160 g of silica gel using acetone as eluent. Fractions of 10 ml are collected. Fractions 61-93, which contained pure product by TLC, were combined and concentrated under reduced pressure to dryness to give 1.5 g of the desired product.

NMR (δ, CDCl 3).

2.06 (3H) s,

2.30 (6H) s,

2.63 (2H) d,

3.06 (3H) s a

7.3-8.2 (5H) m.

Following the procedure of Example 7, the following compounds were also obtained using the appropriate starting materials:

11-acetyl-4'-deoxy-4'- (2-naphthylsulfonylamino) oleandomycin

2.08 (H) s, 2.30 (6H) s, 2.66 (2H) d,

2.83 (3H) s, 4.03 (3H) s and 6.8-8.2 (4H) m.

2.06 (3H) s, 2.30 (6H) s, 2.43 (3H) s,

3.10 (3H) s, 2.66 (2H) d, 7.23-7.40 (2H) d, and 7.76-7.93 (2H) d.

NMR (<5, CDCl 3): 2.03 (3H) δ,

2.26 (6H) s,

2.65 (2H) d, 2.96 (3H) and 2.00 (3H) s, 11-acetyl-4'-deoxy-4'-benzylsulfonylaminooleandomycin

NMR (<5, CDCl 3): 2.30 (6H) s,

2.63 (2H) d,

3.46 (3H) s,

4.33 (2H) s a

7.36 (5H) s.

7.4-8.6 (7H) m, a

Example 8 11-Acetyl-4'-deoxy-4'- (p-benzyloxycarbonylphenylsulfonylamino) oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4'-deoxy-4 '-aminooleanedomycin, 1.12 g (3.6 mmol) of p-benzyloxycarbonylphenylsulfonyl chloride and 379 mg (3.75 mmol) of triethylamine in 25 ml of methylene chloride After stirring overnight at room temperature, the solvent was evaporated in vacuo and the residue was triturated with 10 ml of acetone. The solids were filtered off and the filtrate was chromatographed on 280 g of silica gel using acetone as eluent to collect 10 ml fractions. Fractions 90 to 203, which according to thin-layer chromatography contain the majority of the pure product, are combined and concentrated by evaporation under reduced pressure to obtain

1.25 g of the desired product.

Example 9

The following compounds were prepared as described in Example 8 using the appropriate sulfonyl chloride and 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin as starting materials:

NMR (d, CDCl 3)

O = c _s

OCH _£

2.06 (3H) s, 2.30 (6H) s, 2.66 (2H) d,

3.03 (3H) s, 3.96 (3H) s and 7.3-9.0 (4H) m.

2.05 (3H) s, 2.30 (6H) s, 2.65 (2H) d,

3.01 (3H) s, 5.43 (2H) d, 7.46 (5H) s and 7.33-8.70 (4H) m.

2.06 (3H) s, 2.30 (6H) s, 2.66 (2H) d,

3.06 (3H) s, 4.0 (3H) s and

7.8-8.4 (4H) m.

2.10 (3H) s, 2.30 (8H) s, 2.70 (2H) d, 3.0 (1H) s and 4.10 (3H) s.

Example 11-Acetyl-4'-deoxy-4'- (p-carboxyphenylsulfonylamino) oleandomycin

A suspension of 400 ml of 10% palladium on carbon in 40 ml of ethyl acetate containing 800 mg of 11-acetyl-4 &apos; -deoxy-4 &apos; After an additional 250 mg of catalyst was added, the reaction was continued for 2 hours, then the catalyst was filtered off and the solvent was evaporated in vacuo to give 450 mg of the desired product.

NMR (<5 CDCl3):

2.06 (3H) s,

2.86 (6H) s,

2.68 (2H) d,

3.30 (3H) s a

7., 5-8.4 (4H) m.

Example 11 11-Acetyl-4'-deoxy-4'- (o-nitrophenylsulfonylamino) oleandomycin

5 g (6.8 mmol) of 11-acetyl-4 ' -deoxy-4 ' -aminooleandomycin, 1.5 g (7.0 mmol) of o-nitrobenzenesulfonyl chloride and 0.98 ml of triethylamine are added in 50 ml of methylene chloride. After stirring at room temperature for 48 hours, an equal volume of water was added. The organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product as a foam which was purified by chromatography on a 140 g silica gel column packed in a 3 cm diameter column. The column is eluted with acetone, collecting 50 ml fractions. Fractions 20-30 are combined and concentrated to dryness to give 3.4 g of the title compound.

- (m-nitrophenylsulfonylamino) oleandomycin,

NMR (δ, CDCl 3):

2.06 (3H) s,

2.30 (6H) s,

2.66 (2H) d,

3.06 (3H) s a

7.4-9.0 (4H) m, and a

11-acetyl-4 "-deoxy-4" -

- (p-nitrophenylsulfonylamino) oleandomycin,

NMR (δ, CDCl 3):

2.10 (3H) s

2.35 (6H) s,

2.68 (2H) d,

3.06 (3H) s a

8.0-8.6 (4H) m.

Example 12 11-Acetyl-4 "-deoxy-4" -

- (p-hydroxyphenylsulfonylamino), oleandomycin

A solution of 11.05 g (3.5 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin, 701 mg (3.65 mmol) of p-hydroxyphenylsulfonyl chloride and 51.8 µl of triethylamine in 25 ml of methylene chloride was added for 48 hours. After stirring at room temperature, the solvent is evaporated off under vacuum and the residue is stirred with 10 ml of acetone. The insolubles were filtered off and the filtrate was chromatographed on 200 g of silica gel. using acetone as eluent. Fractions No. 116-175, which contained pure product by TLC, were combined and concentrated to dryness under reduced pressure to give 500 mg of the desired product.

NMR ([delta], CDCl3):

2.0 (3H) s,

2.33 (6H) s,

2.68 (2H) d,

3.06 (3H) s a

8.6-8.0 (4H) m.

Example 13 11-Acetyl-4 "-deoxy-4" -

- (m-carboxamidophenylsulfonylamino) oleandomycin

To 20 ml of methylene chloride containing

2.91 g (-4.0 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin and 434 mg (4.2 mmol) of triethylamine are added 898 mg (4.1 mmol) of m-carboxamidophenylsulfonyl chloride and the resulting mixture is stirred for 48 hours. The solvent was evaporated in vacuo, the residue was stirred with 25 ml

NMR (<5, CDCl 3):

2.10 (3H) s,

2.33 (6H) s,

4.36 (2H) d,

2.90 (3H) s a

7.4-8.4 (4H) m.

The following compounds were also obtained using the corresponding starting materials as described above:

11-Acetyl-4'-deoxy-4'-199728 acetone, triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel. 50 ml fractions were collected and monitored by thin layer chromatography to determine product purity. Fractions 66-93 are combined and concentrated under reduced pressure to give 800 mg of the desired product.

NMR (δ, CDCl 3):

2.06 (3H) s,

2.33 (6H) s,

2.70 (2H) s, '

3.10 (3H) s a

9.4-9.0 (4H) m.

Example 14 11-Acetyl-4 "-deoxy-4" -

- (p-acetamidophenylsulfonylamino) oleandomycin

A solution of 2.91 g (4.0 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin, 955 mg (4.1 mmol) of p-acetamidophenylsulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 20 ml of methylene chloride After stirring at room temperature for 48 hours, the reaction mixture is concentrated under reduced pressure to a fifth residue which is stirred with 10 ml of acetone. The insoluble triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 160 g of silica gel using acetone as eluent. Fractions 42-86, which according to thin layer chromatography contained most of the pure product, were concentrated in vacuo to give 1.2 g of the desired product.

NMR (δ, CDCl 3):

2.06 (4H) s,

2.23 (3H) s,

2.35 (6H) s,

2.70 (2H) s,

3.13 (3H) s a

7.0-8.2 (4H) m.

Example 15 11-Acetyl-4 "-deoxy-4" -

- (p-cyanophenylsulfonylamino) oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4'-deoxy-4 '-aminooleandomycin, 734 mg (3.65 mmol) of p-cyanophenylsulfonyl chloride and 518 μΐ (3.75 mmol) of triethylamine in 25 ml of methylene chloride After stirring overnight at room temperature, the solvent is removed in vacuo and the residue is stirred with 10 ml of acetone. Insoluble materials were filtered off and the filtrate was chromatographed on 120 g of silica gel using acetone as eluent to collect 10 ml fractions. Fractions 47-83 were combined and concentrated under reduced pressure to give 281 mg of the desired product.

NMR (δ, CDCl 3):

2.10 (3H) s,

2.36 (6H) s

2.71 (2H) d,

3.06 (3H) s a

7.7-8.4 (4H) m.

Example 16 11-Acetyl-4 "-deoxy-4" -

- (p-trifluoromethylphenylsulfonylamino) oleandomycin

To a solution of 2.55 g (3.5 mmol) of H 4 -cyclohexyl-4'-deoxy-4'-amino-oleandomycin and 5.18 µl (3.75 mmol) of triethylamine in 25 ml of methylene chloride 891 mg (3.65 mmol) of p-trifluoromethylphenylsulfonyl chloride was added and the reaction mixture was stirred for 18 hours. The solvent was evaporated under reduced pressure and the residue was triturated with 15 ml of acetone. Fixed. The aliquots were filtered off and the filtrate was chromatographed on silica gel to give 287 mg of the desired product.

NMR (δ, CDCl 3):

2.03 (3H) s,

2.31 (6H) s,

2.63 (2H) d,

3.40 (3H) s a

7.15-8.3 (4H) m.

Example 17 11-Acetyl-4 "-deo.xy-4" -

- (2,2,2-Trifluoroethylsulfonylamino) oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin, 666 mg (3.65 mmol) of 2,2,2-trifluoroethylsulfonyl chloride and 379 mg (3.75 mmol) of triethylamine in 25 ml of methylene chloride is stirred at room temperature for 30 hours, then an additional 333 mg of sulfonyl chloride and 270 μΐ of triethylamine are added. and stirring was continued for 4 hours. The solvent is evaporated in vacuo, the residue is stirred with 20 ml of acetone, the solids are filtered off and the filtrate is chromatographed on 110 g of silica gel using acetone as eluent, collecting 10 ml fractions. Fractions 50-80 are combined and concentrated to give 385 mg of the desired product.

NMR ( 'δ, CDC1 _3):

2.06 (3H) s,

2.26 (6H) s,

2.60 (2H) d a

3.36 (3H) s.

If 11-propionyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin is used instead of 11-acetyl ester 11-acetylester in the above process, 11-propionyl-4 &apos; -deoxy-4 &quot; luorethylsulfonylamino] oleandomycin.

Example 18

Example 19 11-Acetyl-4'-deoxy-4 '- (3,4-dichlorophenylsulfonylamino) oleandomycin 11-Acetyl-4'-deoxy-4' - (methylsulfonylamino) oleandomycin

A solution of 11.9 g (4.0 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin, 467 mg (4.1 mmol) of methylsulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 25 ml of methylene chloride was passed through After stirring overnight at room temperature, the solvent is evaporated off under reduced pressure and the residue is stirred with 20 ml of acetone, the triethylamine hydrochloride is filtered off and the product-containing filtrate is chromatographed on 180 g of silica gel using acetone as the eluent. Fractions 67-133 were combined and concentrated in vacuo to give 1.2 g of the desired product.

NMR (δ, CDCl 3):

2.06 (3H) s,

2.28 (6H) s,

3.06 (3H) s,

2.61 (2H) d a

8.40 (3H) s.

Dissolve in 30 ml of methylene chloride

2.9 g (4.0 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin, 1.0 g (4.1 mmol) of 3,4-dichlorophenylsulfonyl chloride and 0.57 ml (4.2 mmol) triethylamine and the resulting solution was stirred at room temperature for 18 hours. The reaction is quenched by the addition of 50 ml of water, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on 150 g of silica gel using acetone as eluent. Fractions containing the desired product by thin layer chromatography were combined and concentrated to dryness to give 1.3 g of the desired product.

NMR (δ, CDCl ₃ ):

2.0 (3H) s,

2.30 (6H) s,

2.60 (2H) d,

3.06 (3H) s a

7.2-8.1 (3H) m.

Example 20

Following the procedure of Example 19, using the appropriate starting materials, the following compounds were obtained:

NMR (δ, CDCl 3):

2.0 (3H) s, 2.36 (6H) s, 2.70 (2H) d,

3.33 (3H) s and 7.3-8.6 (3H) m

Cl

2.10 (3H) s, 2.31 (6H) s, 2.66 (2H) d,

3.30 (3H) s and 7.2-8.4 (3H) m

NMR (δ, CDCl 3):

2.03 (3H) s, 2.30 (6H) s, 2.66 (3H) s,

3.10 (3H) s and 7.1-8.1 (3H) m ”

Cl

2.06 (3H) s, 2.33 (6H) s, 2.70 (2H) d,

3.13 (3H) s and 7.4-8.6 ((Hj m

NO _Z

2.06 (3H) s, 2.40 (6H) s, 2.66 (2H) d,

3.25 (1H) m and 7.22-8.6 (3H) m ^-1

2.06 (3H) s, 2.33 (6H) s, 2.63 (2H) d,

2.81 (-3H) s, 3.63 (3H) s and

7.0 - 8.2 (3H) m * -

2.06 (3H) s, 2.36 (6H) s and

8.4-9.0 (3H) m * ¹

Legend:

1 H NMR spectrum measured at _; mixture of dimethylsulfoxide and deuterochloroform.

Example 21 11-Acetyl-4 "-deoxy-4" - (2,3,4-t-chlorophenylsulfonylamino) oleandomycline

A solution of 2.8 g (4.0 mmol) of 11-acetyl-4'-deoxy-4'-amino-oleandomycin, 1.15 g (4.1 mmol) of 2,3,4-trichlorophenylsulfonyl chloride and 0.57 ml of (4, 2 mmol) of triethylamine in 30 ml of methylene chloride was stirred at room temperature for 18 hours, and the organic layer was washed once with 50 ml, water and once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, evaporated in vacuo and chromatographed. 150 g of silica gel using acetone as solvent, collecting 7 ml fractions, fractions 60-100 are combined and concentrated to give 800 mg of the desired product.

NMR (δ, CDCl 3):

2.06 (3H) s,

2.33 (6H) s,

2.63 (2H) d,

3.2 (3H) s a

7.2-8.2 (2H) m.

Example 22 11-Acetyl-4'-deoxy-4 '- (2-hydroxy-3,5-dichlorophenylsulfonylamino) oleandomycin

Analogous to Example 21, 2.55 g (3.5 mmol) of 11-acetyl-4 &quot; deoxy-4 &lt; 4 &gt; 3.75 mmol] of triethylamine in 25 ml of methylene chloride yields 483 mg of the desired product after chromatography on 220 g of silica gel.

NMR (δ, CDCl 3 / DMSO):

2.03 (3H) s,

2.50 (6H) s,

3.05 (3H) s a

7.2 - 7.8 (2H) m.

Example 2 3 11-Acetyl-4 "-deoxy-4" -

- (3-amino-4-chlorophenylsulfonylamino) oleandomycin

A suspension of 500 mg of 10% palladium on carbon in 50 ml of ethyl acetate containing 1.0 g of 11-acetyl-4'-deoxy-4 '- (3-nitro-4-chlorophenylsulfonylamino) -oleandomycin is shaken under hydrogen atmosphere overnight The catalyst is filtered off, the solvent is evaporated off under vacuum and the white foam residue is chromatographed on 160 g of silica gel using acetone as the eluent, collecting 50 ml fractions. and concentrated under reduced pressure to give 450 mg of the desired product.

NMR ([delta], CDCl3):

2.03 (3H) s,

2.33 (6H) s,

2.66 (2H) d,

3.16 (3H) s a

7.2 - 8.0 (3H) m.

Using the corresponding nitro compounds of Example 11, the following products were obtained in an analogous manner:

11-acetyl-4 "-deoxy-4" -

- (m-aminophenylsulfonylamino) oleandomycin,

NMR (.delta., CDCl3):

2.03 (3H) s, 2.30 (6H) s, 2.63 (2H) d,

3.10 (3H) s and 7.0-7.8 (4H) m, a

11-acetyl-4'-deoxy-4 '- (p-aminophenylsulfonylamino) oleandomycin,

NMR (d, CDCl 3):

2.06 (3H) s,

2.31 (6H) s

3.02 (3H) s a

7.4-7.8 (4H) dd.

EXAMPLE 2 4 11-Acetyl-4'-deoxy-4 '- (3-methyl-2-thienylsulfonylamino) oleandomycin

To 100 g (0.13 mol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin in 900 ml of methylene chloride was added 593 ml of triethylamine and the resulting solution was stirred for 10 minutes. (0.213 mol) of 3-methyl-2-thienylsulfonyl chloride in 300 ml of methylene chloride, the reaction mixture was stirred at room temperature for 48 hours and then added to 2 L of water. The organic layer was separated, washed successively with water (2 x 250 ml) and brine (250 ml), dried over sodium sulfate and the solvent was evaporated in vacuo. The residue is chromatographed on a column of 1.5 kg of silica gel (105 cm X 6.5 cm). The acetone eluted product is contained in eluate fractions of 2.3 liters to 6 liters. These fractions were combined and the solvent was evaporated under reduced pressure. Treatment of the foamed residue with diethyl ester gave 66.4 g of the desired product, m.p. 184-185.5 ° C.

NMR (CDCl 3):

2.04 (3H) s,

2.41 (6H) s,

2.46 (3H) s,

2.62 (2H) m,

3.02 (3H) s,

6,84 s

7.32 (2H),

To 2 g of the free base prepared above was added 0.12 ml of phosphoric acid in 15 ml of ethyl acetate and the resulting solution was stirred at room temperature. After 20 minutes, crystals began to form, which were filtered off after 2 hours and dried after washing with ethyl acetate. 1.3 g of 11-acetyl-4 &apos; -deoxy-4 &apos;-( 3-methyl-2-thienylsulfonylamino) oleandomycin phosphate are obtained.

NMR (<5 CD 3 OD):

2.01 (3H) s,

2.45 (3H) s,

2.56 (2H) m,

2.83 (6H) s,

3.0 (3H) s,

6.88 with 7.42 (2H).

Example 25

By repeating the procedure described in Example 24 using the appropriate sulfonyl chloride and 11-acetyl-4'-deoxy-4'-amino-oleandomycin as starting material, the following products are obtained:

Ri

NMR (< S, CDCl3)

2.08 (3H) s, 2.33 (6H) s, 2.38 (3H) s,

2.68 (2H) m, 3.27 (3H) s, 6.08 and 6.92 (2H)

2.08 (3H) s, 2.36 (6H) s, 2.68 (2H) m,

3.30 (3HJ 3), 3.71 (3H) 3,

6.44-6.70 (1H) and 7.18-7.39 (2H) m

2.03 (3Ή) s, 2.25 (3H) s, 2.51 (6H) s,

2.61 ((HJ m, 3.15 (3H) s)

7.07 (1H) m and 7.38 (1H) m

2.06 (3H) s, 2.33 (6H) s, 2.65 (2H) m,

3.22 ((H) s, 3.73 and 7.45 ((H) s)

Example 26 11-Acetyl-4'-deoxy-4'- (5-methoxycarbonyl-2-pyrrolylsulfonylamino) oleandomycin

To a solution of 2.96 g (0.0041 mol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 0.62 ml of triethylamine in 50 ml of ice-cold dry methylene chloride is added portionwise ( 0.0044 mol] of 2-methoxycarbonyl-5-pyrrolylsulphonyl chloride The reaction mixture was allowed to warm to room temperature, stirred for 3.5 hours and then poured into 200 ml of water with 1N aqueous sodium hydroxide solution and the pH of the aqueous layer adjusted to 9, 5, the methylene chloride layer is separated, successively for 2.08 (3H) s, 2.34 (6H) s, 2.54 (3H) s,

2.67 (2H) s, 3.25 (3H) s,

6.73 and 7.46 (2H), washed with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent was evaporated under reduced pressure. 3.8 g of crude product are obtained in the form of a white foamy residue.

The foam residue obtained above is chromatographed on a silica gel column of diameter

3.25 cm and a height of 38 cm, using acetone as the eluent, collecting fractions of about 10 to 12 ml. Fractions 40-220 were combined and the solvent was evaporated in vacuo to give 3.4 g of the desired product as a white foamy residue.

NMR (α, CDCl 3)

2.05 (3H) s,

2.58 (6H) s,

2.67 (2H) m,

3.25 (3H) s,

3.90 (3H) s,

7.20 (1H) m and

7.52 (1 H) m.

Example 2 7

By repeating the procedure described in Example 26, using the appropriate sulfonyl chloride and 11-acetyl-4 ' -deoxy-4 &apos; -aminooleandomycin as starting materials, the following analogs are obtained:

NMR (CDCl 3)

Rl

2.09 (3H) s, 2.32 (6H) s, 2.69 (2H) m,

3.22 (3H) s, 3.95 (3HJ s, 7.61 and 7.75 (2HJ) s)

2.11 (3HJ s, 2.34 (6H) s, 2.70 (2HJ m,

3.24 (3H) s, 3.94 (3H) s,

8.06 and 8.28 (2H)

2.08 (3H) s, 2.29 (6H) s, 2.67 (2H) S,

3.18 (3H) s, 3.94 (3HJ s,

7.02 and 7.20 (2H)

Example 28

NMR [δ, CDCl 3]

4 '-Deoxy-4' - (p-chlorophenylsulfonylamino) oleandomycin

A solution of 3.0 g of 4 &apos; -deoxy-4 &apos; -aminooleandomycin, 865 mg of p-chlorophenylsulfonyl chloride and 424 mg of triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight, then the solvent is evaporated in vacuo and . Insoluble triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 180 g of silica gel using acetone as the elution solvent, collecting 50 ml fractions. Fractions 18-2Π were combined and concentrated under reduced pressure to give 1.10 g of the desired product.

2.33 (6H),

2.83 (2H) d,

3.06 (3H) s a

7.2-8.4 (4H) m.

Example 1 9

4'-Deoxy-4 '- (p-toluenesulfonylamino) oleandomycin

In a similar manner to Example 28, 30 g (4.0 mmol) of 4 &apos; -deoxy-4 &apos; -aminooleandomycin, 782 mg (4.1 mmol) of p-toluenesulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 25 ml of methylene chloride are used. After stirring overnight at room temperature, the crude product is chromatographed on 180 g of silica gel, collecting 10 ml fractions of O. 99728. Fractions 90-148 are combined and concentrated to dryness to give 1.4 g of the desired product. product.

NMR (CDCl 3)

2.33 (6H) s

2.46 (ЗЯ) s,

2.83 (2H) d,

3.10 (3H) s a

7.10-8.0 (4H) m.

4 '-Deoxy-4' - (2-thienylsulfonylamino) oleandomycin is also prepared in an analogous manner,

NMR (CDCl 3)

NMR (δ, CDCl ₃ )

2.29 (6H) s,

2.88 (2H) m,

3.2 (3H) s,

5.6 (1H) m a

7.33 (3 H) m.

Example 30 11-Acetyl-4 "-deoxy-4" - (vinylsulfonylamino) oleandomycin

To a solution of 17.1 g (82.3 mmol) of β-bromoethanesulfonyl chloride in 200 ml of methylene chloride cooled to -78 ° C, a solution of 30 g (41.1 mmol) of 11-acetyl-4'-deoxy- Of 4'-aminooleandomycin and 16.7 g (164 mmol) of triethylamine in 100 ml of methylene chloride, cooled to -78 ° C. The mixture was stirred at -78 degrees Celsius for 1.3 hours, then poured into water and adjusted to pH 7.3 by addition of solid sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and evaporated in vacuo to give 43.5 g of a yellow foam which was slurried in ether and filtered. The filtrate, after concentration under reduced pressure, gave 20.3 g of crude product which was chromatographed on 800 g of silica gel using a 95: 5 by volume mixture of chloroform and methanol as the eluent. The fractions containing the product were combined and evaporated to give 5.1 g of the desired product.

NMR (Й, CDCl 3)

2.10 (3H) s

2.37 (6H) s,

2.70 (2H) d,

3.43 (3H) s and

5.7-7.06 (3H) m.

Example 1 a d 3 1

- (β-bromoethylsulfonylamino) oleandomycin

To a solution of 500 mg (0.68 mmol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 882 mg (8.2 mmol) of 2,6-lutidine in 4 ml of methylene chloride cooled to -4 [deg.] C. under a nitrogen atmosphere, a solution of 854 mg (4.0 mmol) of β-bromomethanesulfonyl chloride in 2 mL of methylene chloride cooled to-2 ° C was added. The reaction mixture was stirred at -2 ° C for 1.75 hours, then poured into a mixture of water and methylene chloride and adjusted to pH 7.0 by addition of solid sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and concentrated to an amber oil. Chromatography of the oily residue on 42 g of silica gel using chloroform / methanol (95: 5 by volume) as the eluent gave 52.5 mg of the desired product.

NMR (δ, CDCl ₃ )

2.08 (3H) s,

2.33 (6H) s,

2.65 (2H) s a

3.46 (3H) s.

Example 32 11-Acetyl-4'-deoxy-4'- (2-thienylsulfonylamino) oleandomycin hydrochloride

To 8.7 g of 11-acetyl-4 &apos; -deoxy-4 &apos;-( 2-thienylsulfonylamino) oleandomycin in 50 ml of dry ethyl acetate was added 10 ml of a 1 N solution of hydrogen chloride in ethyl acetate. The resulting solution was concentrated in vacuo to dryness, the remaining monohydrochloride was triturated with ether and then filtered off.

Example 56

U-acetyl-4'-deoxy-4'-

- (2-thienylsulfonylamino) oleandomycin phosphate

To a solution of 15.0 g of 11-acetyl-4'-deoxy-4 '- (2-thienylsulfonylamino) oleandomycin in 100 ml of ethyl acetate was added 1.0 mL of phosphoric acid, and the resulting suspension was stirred at room temperature for 4 hours. After washing with ethyl acetate and drying, 12.5 g of the desired salt melts at 168 DEG C. with decomposition.

Similarly prepared were the 11-acetyl-4 "-deoxy-4" - (3-methyl-2-thíenylsulfonylamino) oleandomycin phosphate, mp 184-188 ° C, and l-acetyl-4 ⁱⁿ -deoxy-4 "- ( 204 DEG-205 DEG C. p-chlorophenylsulfonylamino) oleandomycin phosphate.

11-Acetyl-4'-deoxy-4 ^for 199728

Example A

4'-Deoxy-4'-oxoolendomycins

AND.

11-acetyl-4'-deoxy-4'-oxooleandomycin and 11,2'-Diacetyl-4'-deoxy-4'-oxooleandomycin

To 4.5 g of N-chlorosuccinimide, 50 ml of benzene and 150 ml of toluene in a dried flask equipped with a magnetic stirrer and a nitrogen inlet was added 3.36 ml of dimethylsulfide while cooling to -5 ^° C. The mixture was stirred at 0 ° C for 20 minutes, then cooled to -25 ° C, and 5.0 g of 11,2'-diacetyloleandomycin in 100 ml of toluene was added. Cooling and stirring was continued for a further 2 hours after which time 4.73 ml of triethylamine was added. The reaction mixture was stirred at 0 ° C for 15 min and then poured into 500 mL of water. The pH was adjusted to 9.5 by addition of 1N aqueous sodium hydroxide, the organic layer was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated in vacuo. 4.9 g of the expected product are obtained in the form of a foam.

NMR (δ, CDCl3):

3.48 (3H) s,

2.61 (2H) m,

2.23 (6H) s a

2.03 (6Hj s.

b) 11-Acetyl-4'-deoxy-4'-oxooleandomycin

A solution of 4.0 g of 11,2'-diacetyl-4'-deoxy-4'-oxooleandomycin in 75 ml of methanol was stirred at room temperature overnight. Concentration of the reaction mixture under reduced pressure affords a pan-like product which is dissolved in ether. Addition of hexane gave 2.6 g of the desired product as a white solid, mp 112-117 cc.

NMR [.delta., CDCl3.

3.43 (3H) s,

2.60 (2H) m;

2.23 (6H) s a

2.01 (3HJ s.

In an analogous manner but using 11,2'-dipropionyl-4 "-deoxy-4" -oxooleandomycinu or ll-propionyl-2'-acetyl-4 "-deoxy-4" -oxooleandomycinu obtained ll ^j propionyl 4 "deoxy 4-oxooleandomycin.

II. 4'-Deoxy-4'-oxooleandomycin

(a) 2‘-Acetyl-4'-deoxy-4'-oxooleandomycin

To a cloudy solution of 467 mg of N-chlorosuccinimide in 20 ml of toluene and 6 ml of benzene cooled to -5 ° C was added 0.337 ml of dimethylsulfide under a nitrogen atmosphere. After stirring at 0 ° C for 20 minutes, the mixture was cooled to -25 ° C and 1.46 grams of 2‘-acetyloleandomycin and 15 ml of toluene were added. The reaction mixture was stirred at -20 ° C for 2 hours, then 0.46 ml of triethylamine was added thereto, the mixture was maintained at -20 ° C for a further 5 minutes, then allowed to warm to 0 ° C with stirring. Pour into a mixture of 50 ml of water and 50 ml of ethyl acetate. The pH of the aqueous mixture was adjusted to 9.5 by addition of aqueous sodium hydroxide solution, the organic layer was separated and, after drying over sodium sulfate, concentrated in vacuo. Trituration of a 1.5 g white bovine residue with diethyl ether gave 864 mg of crude product which, after recrystallization twice from methylene chloride / diethyl ether, yielded 212 mg of pure product, melting at 183-185.5 ° C.

Analysis calculated for C37H61O3.3N

C 61.1%, H 8.5%, N 1.9%, found

C 60.9%, H 8.4%, N 1.9%.

NMR (δ, CDCl 3):

5.60 (1 H) m,

3.50 (3H) s,

2.73 (2H) m;

2.23 (6H) · s and 2.03 (3H) s.

b) 4'-Deoxy-4'-oxooleandomycin

A solution of 1.0 g of 2 &apos; -acetyl-4 &apos; -deoxy-4 &apos; -oxooleandomycin in 20 ml of methanol is stirred at room temperature overnight and then concentrated in vacuo. 937 mg of the expected product is obtained in the form of a white foam.

NMR (<5, CDCl 3):

5.60 (1 H) m,

3.50 (3H) s,

2.85 (2H) m and

2.26 (6H) s.

Example B

4'-Deoxy-4'-amino-oleandomycins

I. 11-Acetyl-4'-deoxy-4'-amino-oleandomycin

To a suspension of 10 g of 10% palladium on carbon in 100 ml of methanol was added 21.2 g of ammonium acetate, and to the resulting suspension was added a solution of 20 g of 11-acetyl-4'-deoxy-4'-oxooleando-

38 mycine in 100 ml of the same solvent. The suspension is shaken under a hydrogen atmosphere at an initial pressure of 50 psi at room temperature. After 1.5 hours, the catalyst is filtered off and the filtrate is added with stirring to a mixture of 1200 ml of water and 500 ml of chloroform. The pH was adjusted from 6.4 to 4.5 and the organic layer was separated. After further extraction with 500 ml of chloroform, 500 ml of ethyl acetate were added to the aqueous layer, and the pH was adjusted to 9.5 with 1 N sodium hydroxide. The ethyl acetate layer was separated and the aqueous layer was re-extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated to a yellow foam residue (18.6 g) which, after crystallization from diisopropyl ether, yielded 6.85 g of purified product, m.p. 157.5-160 ^° C.

NMR (δ, CDCl 3):

3.41 (3H) s,

2.70 (2H) m,

2.36 (6H) s a

2.10 (3H) s.

The second epimer, which is contained in the crude foamed product in an amount of 20-25%, is obtained by gradually concentrating and filtering the mother liquors.

Using the above procedure using 11-propionyl-4'-deoxy-4'-oxooleandomycin as starting material, analogously 11-propionyl-4'-deoxy-4'-amino-oleandomycin is obtained.

II. ^At 4 -deoxy-4 "-aminooleandomycin

A solution of 20 g of 2 &apos; -acetyl-4 &apos; -deoxy-4 &apos; -oxoooleandomycin in 125 ml of methanol is stirred at room temperature overnight, then 21.2 g of ammonium acetate are added. The solution was cooled in ice and 1.26 g of sodium cyanoborohydride was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours, then poured into a mixture of 600 mL of water and 600 mL of diethyl ether. After adjusting the pH from 8.3 to 7.5, the ether layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts were discarded and the pH of the aqueous layer adjusted to 8.25. The diethyl ether and ethyl acetate extracts obtained at this pH were also discarded and the pH increased to 9.9. The diethyl ether and ethyl acetate extracts obtained at this pH were combined, washed successively with water and a saturated sodium chloride solution and dried over sodium sulfate. The latter extracts, obtained at pH 9.9, are concentrated to a foamy residue which is chromatographed on 160 g of silica gel. Chloroform was used to prepare the column and the starting eluent. After collecting 11 fractions of 12 ml, the column was eluted with a mixture of 5% methanol and 95% chloroform. After fraction # 370 was eluted, the column was washed with a mixture of 10% methanol and 90% chloroform, and from fraction 440 a mixture of 15% methanol and 85% chloroform was used. Fractions 85-260 were combined and concentrated in vacuo to dryness to give 2.44 g of the desired product.

NMR (δ, CDCl 3):

5.56 (1H) m;

3.36 (3H) s,

2.9 (2H) m and

2.26 (6H) s.

Claims (2)

A process for the preparation of 4'-sulfonylaminooleandomycin derivatives of the general formula I, in which R is C 1 -C 3 alkyl, pyridyl, phenyl, monosubstituted phenyl wherein the substituent is selected from the group consisting of fluorine, chlorine, bromine and iodine, hydroxy, methoxy, cyano, carboxamido, nitro, amino, methoxy A group, benzyloxycarbonyl, carboxyl, trifluoromethyl, C 1 -C 4 alkyl and acetamido, further denotes a disubstituted phenyl group, wherein the substituents are independently selected from the group consisting of chlorine, nitro, amino, methoxy and methyl, furthermore, is tri-chlorophenyl, hydroxydichlorophenyl, benzyl, naphthyl, thienyl, chlorothienyl, 2-acetamido-5-thiazolyl, 2-acetamido-4-methyl-5-thiazolyl, 2-benzimidazolyl, dimethyl-2-pyrimidinyl, pyrrolyl, furyl, monosubstituted thienyl, pyrrolyl or furyl, wherein the substituent is selected from the group consisting of methoxycarbonyl and alkyl of 1 or 2 carbon atoms, or is 1 -methyl-5-methoxycarbonyl-3-pyrrolyl, vinyl, 2,2,2-trifluoroethyl or bromoethyl a R 1 represents a hydrogen atom or a C 2 -C 3 alkanoyl group and their pharmaceutically acceptable acid addition salts, characterized in that the compound of the formula (A) is an acid acceptor in an inert solvent at room temperature and the product obtained optionally converting it to a pharmaceutically acceptable acid addition salt thereof. 2. A process according to claim 1, wherein the starting materials of the above formulas are used in which: R is C 1 -C 3 alkyl, phenyl, monosubstituted phenyl wherein the substituent is selected from the group consisting of fluorine, chlorine, bromine and iodine, hydroxy, methoxy, cyano, carboxamido, nitro, amino, methoxycarbonyl, benzyloxycarbonyl a carboxyl group, a trifluoromethyl group, a C 1 -C 4 alkyl group and an acetamido group further denotes a disubstituted phenyl group wherein the substituents are independently selected from the group consisting of R1 is as defined above, reacted with one mole of a sulfonyl halide of the formula RSO2W where R is as defined above and W represents a halogen atom, in the presence of chlorine, nitro, amino, methoxy and methyl, further denotes trichlorophenyl, hydroxydichlorophenyl, benzyl, naphthyl, thienyl, chlorothienyl, pyridyl, 2-acetamido-5-thiazolyl, 2-acetamido-4-methyl-5-thiazolyl, A 2-benzimidazolylo group or a dimethyl-2-pyrimidinyl group, R 1 represents an acetyl group and W is as defined in point 1.