CH631461A5 - Semi-synthetic derivatives of 4''-sulphonylaminooleandomycin - Google Patents

Description

The present invention relates to novel bacterial anti-Z agents, namely 4 "deoxy-4" -sulfonylamino-olean-domycins and their acid addition salts suitable for pharmacy.

Oleandomycin, its production in iron-65 broths and its use as a bacterial agent were described for the first time in US Patent No. 2,757,123. It is known that the natural compound responds to the following structural formula:

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ho 'ï

2

n (ch3) 2

io

15

och,

och,

so2r2

and

20

The classic numbering scheme and stereochemical representation for oleandomycin and similar compounds are shown on this structural formula.

US Pat. Nos. 3,884,902 and 3,983,103 respectively claim 4 "Erythromycin sulfonic esters and N-sulfonylerythromycyl amines having different biological profiles from those of the compounds of the present invention .

Various synthetic modifications of oleandomycins are known, in particular those in which two to three of the free hydroxyl radicals present in positions 2 ′, 4 ″ and 11 are esterified in the form of acetyl esters. United States of America No. 3 022219 describes similar modifications in which the acetyl radical of the abovementioned esters is replaced by another radical which is preferably an unbranched lower alkanoyl radical containing three to six carbon atoms.

The semi-synthetic oleandomycins useful as antibacterial agents of the invention are compounds corresponding to the formulas:

RjO

25

r o -.,. 1

30

35

0ch,

40 where R represents an alkyl radical containing one to three carbon atoms; pyridyle; 1,1,1-trifluoroethyl; phenyl; monosubstituted phenyl, the substituent of which is chosen from a fluorine, chlorine, bromine or iodine atom, hydroxy, methoxy, cyano, carboxamido, nitro, amino, car-45 bomethoxy, carbobenzyloxy, carboxy, trifluoromethyl, alkyl groups one to four carbon atoms and acetamido; disubstituted phenyl, the substituents of which are each chosen from chloro, nitro, amino, methoxy and methyl; tri-chlorophenyl; hydroxydichlorophenyl; benzyl; naphthyl; so thienyl, chlorothienyl; 2-acetamido-5-thiazolyl; 2-acet-amido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2-pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl and furyl, the substituent of which is chosen from a carbomethoxy or alkyl radical containing one or two 55 carbon atoms; or 1-methyl-5-carbomethoxy-3-pyrryl; Ri represents an alkanoyl radical containing two or three carbon atoms; R2 represents a phenyl radical; thienyl; monosubstituted phenyl, the substituent of which is chosen from chloro, fluoro, methyl, methoxy and trifluoromethyl; 60 or thienylealkyl-substituted in which the alkyl fragment contains one or two carbon atoms; X and Y independently represent a hydrogen atom or together form a carbon-carbon bond; and Z represents a hydrogen atom, a bromine atom, a dialkylamino group in which the 65 alkyl moiety has one to three carbon atoms, alkylthio in which the alkyl moiety has one to three carbon atoms, phenylthio, 2-hydroxyethylthio or 1 -morpho-lino, provided that when X and Y represent a bond

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carbon-carbon, Z represents a hydrogen atom; and their pharmaceutically acceptable acid addition salts.

The amino group starting materials which lead to the compounds of the invention consist, due to the synthetic process used for their preparation, of the two epimeric 4 "amines. Therefore, the sulfamido compounds of the invention formed from these amines are also made up of an epimeric mixture. Experience shows that the two epimeric sulfonamides are present in the final product in variable ratios depending on the synthesis process used to prepare the intermediate amine. one of the epimers, this epimer can be purified by repeated recrystallizations from a suitable solvent until a constant melting point is obtained. The other epimer which is present in lower amounts in the solid material originally isolated is the product which predominates in the mother liquor. It can be recovered therein according to processes known to those skilled in the art such as for example the evaporation of the mother liquor and the recris repeated tailing of the residue until a product having a constant melting point or chromatography is obtained.

Although this mixture can be separated from the epimers according to methods well known to those skilled in the art for the practical reasons indicated, it is advantageous to use this mixture as isolated from the reaction. However, it is often advantageous to purify the mixture of epimers by subjecting it to at least recrystallization from an appropriate solvent, column chromatography, partitioning with solvents or trituration from an appropriate solvent. This purification, although it does not necessarily separate the epimers, removes a certain amount of foreign matter such as starting materials and undesirable by-products.

The stereochemical configuration of the epimers has not been determined. However, the two epimers of a given compound exhibit the same kind of activity, e.g. activity

B (CH3) 2

antibacterial.

The preferred compounds corresponding to formula 1 are those where R represents a thienyl or substituted thienyl radical, the substituent of which is an alkyl radical containing one or two carbon atoms or a carbomethoxy radical.

The preferred compounds of formula 2 are those where Ra represents a substituted phenyl, thienyl or alkyl-substituted thienyl radical in which the alkyl fragment contains one or two carbon atoms.

The preferred compounds of formula 3 are those where X and Y each represent a hydrogen atom and Ri represents an acetyl radical.

Among these compounds, particularly preferred, because of their antibacterial utility: 1 l-acetyl-4 "-deoxy-4" - (2-thienylsulfonyIamino) oleandomycin, ll-acetyl-4 "-deoxy-4" - ( 3-thienylsulfonylamino) oleando-mycin, ll-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonyl-amino) oleandomycin,

4 "-deoxy-4" - (p-chlorophenylsulfonylamino) oleandomy-cine, 4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomy-cine,

4 "-deoxy-4" - (3-thienylsulfonylamino) oleandomycin, 4 "-deoxy-4" - (3-methyl-2-thienyIsulfonylamino) oleander-mycin,

11 -acetyl-4 "-deoxy-4" - (2-bromoethylsulfonylamino) olean-domycin, the

11-acetyl-4 "-desoxy-4" - (2-methylthioethylsulfonyl-amino) oleandomycin and ll-acetyl-4 "-desoxy-4" - (vinylsulfonylamino) oleandomycin. The invention will now be described in detail.

The preferred method of synthesis of antibacterial agents of type 4 "-deoxy-4" -sulfonylamino-oleandomycin of formulas 1 and 2 from 4 "-deoxy-4" -amino-oleandomyin or a derivative 11- The corresponding alkanoyl is illustrated by the following diagrams:

H? ^ 2) 2

nhs02r och,

^ ^ ti (CH ^) 2

to V I "*

^ ■ NHS02R2

5

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where R, Ri and R2 have the same definition as before.

These reactions are carried out between a 4 "-deoxy-4" -amino-oleandomycin and an appropriate sulfonyl halide in the presence of an acid scavenger in an inert solvent.

In practice, one mole of 4 "-amino-oleandomyomy is contacted with one mole of a sulfonyl halide with up to 2-3% excess of this halide. The acid fixative is used , which can be mineral or organic in nature, at a rate of 1 mole with an excess of up to 4 to 6%.

The acid fixative can consist of hydroxides, hydrides or carbonates of alkali or alkaline earth metal or of a tertiary amine. In addition, secondary amines such as diisopropylamine which are sufficiently hindered so that they do not react with the sulfonyl halide can also be used. Tertiary amines are preferred as acid scavengers. Particularly preferred among them is triethylamine.

The inert solvent which is used in the abovementioned process must appreciably dissolve the reactants and not react appreciably with them or with the products formed. Polar solvents miscible or immiscible with water are preferred. Particular preference is given to methylene chloride and a mixture of acetone and water.

As the heating of amino-oleandomycins causes a certain decomposition, it is preferred to prepare the compounds of formula 1 or 2 between 0 and 25 ° C. It is particularly preferred to carry out the reaction at room temperature.

The reaction time has no particular limitation and it depends on the reaction temperature, the concentration and the specific reactivity of the starting reactants. When the reaction is carried out at room temperature, at the aforementioned concentrations, the reaction is practically completed in 2 to 48 hours.

After completion of the reaction, the reaction mixture can be treated in two different ways well known to those skilled in the art. The first treatment method consists in adding the reaction mixture to water, then in separating the water-immiscible solvent containing the desired product and then in removing the solvent to obtain the crude product. When a water-miscible solvent is used as the inert solvent, the product is extracted from the reaction mixture after the reaction has been stopped by adding water, with a water-immiscible solvent such as methylene chloride.

The second treatment process consists in concentrating the reaction mixture to dryness and then in extracting the product from the salt formed between the base fixing the acids and the halogenated hydracid.

"(Ch3î2

formed as a by-product with acetone. The acetone extract can be concentrated to obtain the crude product.

The crude product or its acetone solution is purified by chromatography on silica gel which is a process well known in the art or by recrystallization.

To prepare the antibacterial agents of formula 3 where X and Y represent a carbon-carbon bond and Z represents a hydrogen atom, one puts a mole of 11-alca-noyl-4 "-deoxy-4" -amino-oleandomycin suitable in contact with 2 moles of β-bromoethanesulfonyl chloride and 4 moles of a tertiary amine without steric hindrance such as triethylamine.

The reaction is maintained at -78 ° C during the contact time but the reaction time is between 1 and 2 hours.

Solvents suitable for this process are the same as those used in the process for the preparation of compounds 1 and 2 except that, in addition, these solvents must not freeze at the preferred reaction temperature. The preferred solvent is methylene chloride.

The reaction mixture is treated as previously described in the process for the preparation of the compounds of formulas 1 and 2.

In addition to their activity as antibacterial agents, the 11-alca-25 nucleus-4 "-deoxy-4" - (vinylsulfonylamino) oleandomycins prepared by this process are also useful intermediates making it possible to obtain other antibacterial agents according to a process described below.

When 1 mole of 1 l-alkanoyl-4 "-deoxy-4" -30 suitable amino-oleandomycin is brought into contact with 5 to 7 moles of p-bromoethanesulfonyl chloride in the presence of 10 to 12 moles of an amine to steric hindrance such as 2,6-lutidine at a temperature of about -4 to 0 ° C in an inert solvent, the corresponding 11 -alkanoyl-4 "-deoxy-4" - (ß-35 bromoethylsulfonylamino) oleandomycin is obtained (X, Y = H; Z = Br).

Preferred is a reaction temperature of about 0 ° C and a reaction time of 1 to 2 hours. The preferred solvent at these reaction temperatures is methylene chloride.

The product is obtained and is purified according to a process similar to that described for the syntheses of the compounds of formulas 1 and 2.

The other compounds represented by formula 45 3 are prepared according to a Michael addition reaction between the appropriate amine or thiol and the 1 l-alkanoyl-4 "-deoxy-4" - (vinylsulfonylamino) oleandomycin required according to the following diagram:

»(Ch3) 2

r-0 h. "J" - h 1

jl z-H 1 r

*> * - <y

hs02ch = ch2

och.

nhs02chch2z

In practice, the vinylsulfonyl 65 type compound is put in the same conditions as in the synthesis of the forammo compounds in contact with a triple molar excess of ten times mules 1 and 2. The preferred solvent is benzene.

amine or thiol in an inert solvent at temperature When a thiol is used as the reactant, it is ordinary for 12 to 48 hours. The solvent must fill them also uses a mineral base or a tertiary amine

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6

to facilitate the reaction. It is preferred to use a molar amount of base at least equal to the vinylsul-fcnylamino compound. The preferred base is potassium carbonate.

When the reaction is complete, the product is obtained either by elimination of the solvent and of the excess of reacting compound under reduced pressure, or by stopping the reaction in water then separation of the organic phase and concentration to dryness.

The type 4 "-amino compounds used in the synthesis of the antibacterial agents of the invention are synthesized by oxidation of natural oleandomycin and then reductive amination of the ketone obtained as described below.

To take advantage of the chemotherapeutic activity of the compounds of the invention which form salts, it is of course preferred to use salts which are suitable in pharmacy. Certain particular salts are unsuitable or unsuitable for pharmaceutical application due to their insolubility in water, their high toxicity or their non-crystalline character, but the salts which are insoluble in water or toxic in corresponding bases suitable in pharmacy by decomposing the salt with an appropriate base or otherwise transform them into any desired acid addition salt suitable in pharmacy.

Examples of acids providing anions which are suitable in pharmacy are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic, aspartic, glutamic acids, pyro-glutamic and laurylsulfuric.

The new 4 "-deoxy-4" -amino-oleandomycin derivatives of the invention are active in vitro against various Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain Gram-negative microorganisms such as those of form spherical or ellipsoidal (cocci). It is easy to demonstrate their activity according to in vitro tests with various microorganisms in a broth with heart infusion and brain infusion according to a usual technique of serial dilution to half. Their in vitro activity makes them useful for local application in the form of ointments, creams or the like; for the sterilization, for example, of patient room equipment; and as industrial antimicrobials, for example for water treatment, sludge control and the preservation of paints and woods.

For outdoor use, it is often practical to combine the chosen product with a suitable support in pharmacies such as vegetable or mineral oil or emollient cream. Likewise, it can be dissolved or dispersed in liquid carriers or solvents such as water, alcohol, glycol-collars or their mixtures or other inert media suitable for use in pharmacies; these media must not have an adverse effect on the active ingredient. For this purpose, it is generally possible to use concentrations of active ingredient of between approximately 0.01% and approximately 10% by weight relative to the whole of the composition.

In addition, many of the compounds of the invention are active against Gram-positive microorganisms by oral and / or parenteral administration in animals including humans. Their in vivo activity is more limited with regard to sensitive organisms and it is determined according to the usual methods which consist in inoculating the organism to be studied in mice of practically uniform weight and then in treating the mice by oral or subcutaneous route with the compound studied. In practice, mice, for example 10 mice, are administered an intraperitoneal inoculation of suitably diluted cultures containing about 1 to 10 times the LD10 (minimum concentration of organisms causing 100% mortality). Control tests are carried out simultaneously in which mice receive an inoculum at a lower dilution in order to control a possible variation in the virulence of the organisms studied. The test compound is administered 0.5 hours after inoculation and the administration is repeated 4.24 and 48 hours after. The surviving mice are kept 4 days after the last treatment and the number of survivors is noted.

When used in vivo, the new compounds of the invention must be administered orally or parenterally, for example by subcutaneous or intramuscular injection, at a daily dose of approximately 1 mg / kg, to approximately 200 mg / kg bodyweight. The preferred daily dosage is between about 2 mg / kg and about 100 mg / kg of body weight and better still between about 2 mg / kg and about 50 mg / kg of body weight. Vehicles suitable for parenteral injection can be either aqueous such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous such as vegetable fatty oils (cottonseed oil, peanut oil , corn oil, sesame oil), dimethyl sulfoxide and other non-aqueous vehicles which do not reduce the therapeutic activity of the preparation and are not toxic by the volume or proportion used (glycerol, propylene glycol, sorbitol ). Also, compositions suitable for the extemporaneous preparation of solutions can be advantageously prepared before administration. These compositions may contain liquid diluents, for example propylene glycol, diethyl carbonate, glycerol, sorbitol, etc., as well as buffering agents, hyaluronidase, local anesthetics and mineral salts providing desirable pharmacological properties . These compounds can also be combined with various inert supports suitable for pharmacy, including solid diluents, aqueous vehicles, non-toxic organic solvents in the form of capsules, tablets, lozenges, cachets, dry mixtures, suspensions, solutions, elixirs and solutions or suspensions for parenteral use. In general, the compounds are used in the various forms of administration at concentrations between about 0.5% and about 90% of the total weight of the composition.

The invention is illustrated by the following nonlimiting examples:

Example 1

11 - Acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) olean-domycin.

To 30 ml of anhydrous methylene chloride is added 2.9 g (4.0 mmol) of 1 l-4-acetyl-4-deoxy-4-amino-oleandomomy-cine, 740 mg (4.1 mmol) of 2-thienylsulfonyl chloride and 0.58 ml (4.2 mmol) of triethylamine and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 50 ml of water and then washed with a saturated saline solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residual foam is purified by column chromatography on silica gel with acetone as solvent and as eluent. The fractions containing the product are combined and concentrated to dryness under vacuum, their total weight is 1.3 g.

NMR (5, CDCb): 2.03 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.16 (3H) s and 6.8-7.8 (3H) m.

Example 2

From the 1-acetyl-4 "-deoxy-4" -amino-oleandomomy-cine and appropriate sulfonyl chloride, the following compounds are prepared according to the procedure of Example 1.

5

10

15

20

25

30

35

40

45

50

55

60

65

7

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0

ch, co, 3 'u n (ch3) 2

R

Cl

-o-

ch ch.

n cnh s y-

0 n - \

w.ì-

Gr

• not

_ h a>

"■ yV

n ch.

// \\ s-

/ n n!

h ch3O2C

ch.

/

a och.

NMR (S, CDCh)

2.08 (3H) s; 2.30 (6H) s; 2.67 (2H) m; 3.23 (3H) s and 6.87 and 7.45 (2H) s.

2.09 (3H) s; 2.42 (6H) s; 2.70 (2H) m and 3.26 (3H) s.

2.0 (3H) s; 2.33 (6H) s; 2.40 (3H) 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 (1H) m.

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

The procedure of example 1 is repeated with sulfonyl chloride and 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin suitable for obtaining the following compounds:

1 l-propionyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (2-acetamido-5-thiazolylsulfo-noamylino) oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (2-benzimidazolylsulfonyl-amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (4,5-dimethyl-2-pyrimidinylsulfonylamino) oleandomycin; 11 -propionyl-4 "-deoxy-4" - (4,6-dimethyl-2-pyrimidinylsul-fonylamino) oleandomycin; ll-propionyl-4 "-deoxy-4" - (3-chloro-2-thienylsulfonyl-amino) oleandomycin; the

11 -acetyl-4 "-deoxy-4" - (4-chloro-2-thienylsulfonyl -20 amino) oleandomycin; the

11-4-acetyl-4-deoxy-4 - (2-chloro-4-thienylsulfonyl-amino) oleandomycin; the

11 -acetyl-4 "-deoxy-4" - (2-pyridylsulfonylamino) oléando-mycine; the

1 l-propionyl-4 "-deoxy-4" - (3-pyridylsulfonylamino) olean-domycin; ll-acetyl-4 "-deoxy-4" - (4-pyridylsulfonylamino) oléando-mycine; ll-acetyl-4 "-deoxy-4" - (2-furylsulfonylamino) oleandomy-cine; the

11 -propionyl-4 "-deoxy-4" - (2-pyrrylsulfonylamino) olean-domycin; ll-propionyl-4 "-desoxy-4" - (1-methyl-5-carbomethoxy-3-pyrrylsulfonylamino) oleandomycin and 35 1 l-propionyl-4 "-desoxy-4" - (3-thienylsulfonylamino) olean- domycin.

Example 4

ll-Acetyl-4 "-deoxy-4" - (p-chlorophenylsulfonyl-40 amino) oleandomycin

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 528 μl (4.2 mmol) of triethylamine in 20 ml of methylene chloride, 865 mg (4.1 mmol) of 45 p-chlorophenylsulfonyl chloride are added in portions and the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated to dryness under vacuum and the residue is treated with 10 ml of acetone. The suspension is filtered and the filtrate is chromatographed on 160 g of silica gel, using acetone as the eluent. Fractions 51 to 63 were each collected containing a volume of 10 ml and concentrated under reduced pressure to obtain 857 mg of pure product. Fractions 42 to 52 and 64 to 92 provide 1.21 g of less pure product.

55

NMR (Ô, CDCh): 2.13 (3H) s, 2.36 (6H) s; 2.73 (2H) d, 3.13 (3H) s and 7.3-8.2 (4H) q.

Similarly, starting from 20 g of 60 11 -acetyl-4 "-deoxy-4" -amino-oleandomycin, 7.24 g of p-chlorophenylsulfonyl chloride and 5.36 g of triethylamine in a solvent system consisting of 350 ml of acetone and 350 ml of water, 17.1 g of the desired product are obtained which crystallizes in the reaction mixture, mp 202-203.5 ° C. The analytical sample is recrystallized in a mixture of ethanol and water.

Example 5

We use the procedure of Example 4 and from

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appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, the following compounds are prepared:

R

\ J

~ o

Cl

Cl

Ó-

och-

NMR (ô, CDCh)

2.08 (3H) s; 2.33 (6H) s; 2.70 (2H) d; 3.11 (3H) s and 7.5-8.2 (4H) q.

2.08 (3H) s; 2.31 (6H) s; 2.66 (2H) d; 3.06 (3H) s and 7.0-8.4 (4H) m.

2.03 (3H) s; 2.33 (6H) s; 2.66 (2H) d; 3.10 (3H) s and 7.3-8.0 (4H) m.

2.03 (3H) 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 (2H) d; 2.90 (3H) s and 7.0-8.2 (4H) m.

amino) oleandomycin; ll-acetyl-4 "-desoxy-4" - (m-iodophenylsulfonylamino) olean-domycin and ll-acetyl-4 "-desoxy-4" - (o-bromophenylsulfonyl-s amino) oleandomycin.

Example 7

11 -Acetyl-4 "-deoxy-4" - (o-tolylsulfonylamino) oléando-mycine.

io A solution of 2.9 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 780 mg (4.1 mmol) of chloride is stirred at room temperature for 48 hours. of o-tolylsulfonyl and 0.58 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride. The reaction is stopped in 50 ml of water and the separated organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is removed in vacuo and the residual yellow foam is chromatographed on 200 g of silica gel in a column 3 cm in diameter. The product from column 2 is eluted with acetone which is collected in 10 ml fractions. The fractions containing the pure product were combined according to thin layer chromatography, and concentrated to dryness under reduced pressure to obtain 1.3 g of product.

NMR (5, CDCh): 2.06 (3H) s; 2.33 (6H) s; 2.46 (2H) d; 2.73 (3H) s and 7.1 -8.2 (4H) m.

Example 8

The procedure of Example 7 is repeated from the appropriate sulfonyl chloride and the

11-acetyl-4 "-deoxy-4" -amino-oleandomycin to obtain the following compounds:

35

40

45

0

II

CH3co

H.? (CS3> 2

Xx nhs02r och,

2.10 (3H) s; 2.33 (6H) s; 2.66 (2H) d; 3.10 R Br /) - (3H) s and 7.5-7.93 (4H) m.

50

Example 6

The procedure of Example 4 is repeated from the sulfonyl chloride and the

I l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin suitable for obtaining the following products:

1 l-propionyl-4 "-deoxy-4" - (p-chlorophenylsulfonyl-amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (m-bromophenylsulfonyl-amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (m-fluorophenylsulfonyl-amino) oleandomycin; the

II -propionyl-4 "-deoxy-4" - (m-iodophenylsulfonyl-amino) oleandomycin; the es

I 4-propionyl-4 "-deoxy-4" - (p-fluorophenylsulfonyl-amino) oleandomycin; the CH

II -propionyl-4 "-deoxy-4" - (p-bromophenylsulfonyl-

NMR (8, CDCh)

/ r == \ 2.03 (3H) s; 2.30 (6H) s; 2.66 (2H) d; CK3Q- \ 3.06 (3H) s; 3.83 (3H) s and 6.8-8.2

(4H) m.

55 (ch3) 3c

60

-Q "

03 (3H) s; 2.33 (6H) s; 2.66 (2H) d; , 06 (3H) s and 7.3-8.0 (4H) m.

OCH.

"" O-

2.08 (3H) 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.

9

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Example 9

From the 1 l-alkanoyl-4 "-deoxy-4" -amino-oléando-mycine and appropriate sulfonyl chloride, the following compounds are synthesized according to the procedure of Example 7:

I 1 -acetyI-4 "-deoxy-4" - (m-tolylsulfonylamino) oléando-mycine; 11-propionyl-4 "-deoxy-4" - (p-methoxyphenyl-sulfonylamino) oleandomycin; 11 -acetyl-4 "-deoxy-4" - (m-methoxyphenylsulfonyl-amino) oleandomycin; ll-propionyl-4 "-deoxy-4" - (p-tolylsulfonylamino) oléando-mycine; the

11 -acetyl-4 "-deoxy-4" - (p-isopropylphenylsulfonyl-amino) oleandomycin; the

11 -acetyl-4 "-deoxy-4" - (o-ethylphenylsulfonylamino) olean-domycin; the

11 -propionyl-4 "-deoxy-4" - (o- [n-propyl] phenylsulfonyl -amino) oleandomycin; the

11 -acetyl-4 "-desoxy-4" - (p - [- butyl] phenylsulfonylamino) -oleandomycin and 11 -propionyl-4 "-desoxy-4" - (p [n-butyl] -phenylsulfonylamino) oleandomycin.

Example 10

ll-Acetyl-4 "-deoxy-4" -phenylsulfonylamino-oléando-mycine.

722 mg (4.1 mmol) of benzene sulphonyl chloride are added to a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 424 mg (4.2 mmol) of triethylamine in 30 ml of methylene chloride and cooled in an ice-water bath. After 10 minutes, the water bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction is stopped with 50 ml of water and the organic phase is washed with saturated salt solution and dried over sodium sulfate. The solvent is removed to obtain the crude product which is purified by chromatography on 160 g of silica gel with acetone as eluent. Fractions 61-93 (10 ml each) which contain the pure product according to thin layer chromatography are combined and concentrated to dryness under reduced pressure to obtain 1.5 g of the desired product.

NMR (5, CDCh): 2.06 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.06 (3H) s; and 7.3-8.2 (5H) m.

The following procedure is also prepared with the appropriate starting materials:

11-acetyl-4 "-deoxy-4" - (2-naphthylsulfonyl-amino) oleandomycin

NMR (8, CDCh): 2.03 (3H) s; 2.26 (6H) s; 2.65 (2H) d; 2.96 (3H); and 7.4-8.6 (7H) m; and 1 l-acetyl-4 "-deoxy-4" -benzylsulfonylamino-oléando-mycine

NMR (8, CDCh): 2.00 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.46 (3H) s; 4.33 (2H) s; and 7.36 (5H) s.

Example 11

11 -Acetyl-4 "-deoxy-4" - (p-benzyloxycarbonylphenylsul-fonylamino) -oleandomycin.

A solution of 2.55 g (3.5 mmol) of 4-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.12 g (3.6 mmol) is stirred at room temperature overnight. p-benzyloxycarbonylphenylsul-fonyl chloride and 379 mg (3.75 mmol) of triethylamine in 25 ml of methylene chloride. The solvent is removed in vacuo and the residue is triturated in 10 ml of acetone. The solids are filtered off and the filtrate is chromatographed on 280 g of silica gel with acetone as eluent and 10 ml fractions are collected. Fractions 90-203 which, according to thin layer chromatography, contain most of the pure product are combined and concentrated under reduced pressure to obtain 1.25 g of the desired product.

NMR (8, CDCh): 2.04 (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.01 (3H) s; 5.48 (2H) s; 7.50 (5H) s; and 8.03-8.53 (4H) m.

Example 12

From the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, the following compounds are prepared according to the procedure of Example 11:

och3

R NMR (8, CDCh)

\> // 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. 0 = c xoch3

2.05 (3H) s; 2.30 (6H) s; 2.65 (2H) d; 3.01

V (3H) s; 5.43 (2H) d; 7.46 (5H) s; and

W 7.33-8.70 (4H) m.

0 = c noch20

0

on n "/ ^ X 2.06 (3H) s; 2.60 (6H) s; 2.66 (2H) d; 3.06

3 \\ /} - (3H) s; 4.0 (3H) s; and 7.8-8.4 (4H) m.

2.10 (3H) s; 2.30 (6H) s; 2.70 (2H) d; 3.0 (3H) s; and 4.10 (3H) s.

Example 13

The procedure of Example 11 is repeated from 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and sulfonyl chloride suitable for obtaining the following compounds:

11-acetyl-4 "-deoxy-4" - (o-benzyloxycarbonylphenylsul-fonylamino) oleandomycin; the

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631461

10

11 -pi opionyl-4 "-deoxy-4" - (p-methoxycarbonylphenylsulfo-nyIamino) oleandomycin; the

I! prcpiony! -4 "-deoxy-4" - (m-benzyloxycarbonylphenyl-sulfonylamino) oleandomycin; the

II -propionyI-4 "-deoxy-4" - (p-benzyloxycarbonylphenyl-sulfonylamino) oleandomycin; ll-propionyl-4 "-deoxy-4" - (o-methoxycarbonylphenylsulfonylamino) oleandomycin and

I 4-propionyl-4-deoxy-4 "- (o-benzyloxycarbonylphenylsul-fonylamino loleandomycin.

Example 14

11 -Acetyl-4 "-deoxy-4" - (p-carboxyphenylsulfonyl-amino) oleandomycin.

A suspension of 400 mg of 10% palladium on carbon in 40 ml of ethyl acetate containing 800 mg of is stirred under a hydrogen atmosphere at an initial pressure of 3.4 bar at ordinary temperature for 2 hours

II-4-acetyl-4-deoxy-4 "- (p-benzyloxycarbonylphenylsul-fonylamino-oleandomycin. 250 mg of catalyst are added and the reaction is continued for 2 hours. The spent catalysts are filtered off and the solvent is removed. under vacuum to obtain 450 mg of the desired product.

NMR (5, CDCh): 2.06 (3H) s; 2.86 (6H) s; 2.68 (2H) d; 3.30 (3H) s; and 7.5-8.4 (4H) m.

Example 15

From the 1 l-alkanoyl-4 "-deoxy-4" - (benzyloxycarbo-nylphenylsulfonylamino) oleandomycin described in Examples 12 and 13, the following compounds are prepared according to the procedure of Example 14:

11-acetyl-4 "-deoxy-4" - (m-carboxyphenylsulfonyl-amino) oleandomycin; 1 l-acetyl-4 "-deoxy-4" - (o-carboxyphenylsulfonylamino) oleandomycin; 11 -propionyl-4 "-deoxy-4" - (m-carboxyphenylsulfonyl-amino) oleandomycin;

11-propionyl-4 "-desoxy-4" - (p-carboxyphenylsulfonyl-amino) oleandomycin and 11-propionyl-4 "-desoxy-4" - (o-carboxyphenylsulfonyl-amino) oleandomycin.

Example 16

11 - Acetyl-4 "-deoxy-4" - (o-nitrophenylsulfonyl-amino) oleandomycin.

5 g (6.8 mmol) of 1 l-4-acetyl-4-deoxy-4 "-amino-oleandomycin, 1.5 g (7.0 mmol) of o-nitrobenzenesulfonyl chloride and 0.98 ml of triethylamine in 50 ml of methylene chloride and stirred at room temperature for 48 hours. The reaction is stopped with an equal volume of water and the organic phase is washed with a saturated salt solution and then dried over sodium sulfate. The solvent is removed under reduced pressure to obtain the crude product in the form of a foam. The product can be purified by chromatography on 140 g of silica gel in a column 3 cm in diameter with acetone as eluent. Fractions 20 to 30 were each collected having a volume of 50 ml, combined and concentrated to dryness to obtain 3.4 g of the desired products.

NMR (8, CDCh): 2.10 (3H) s; 2.33 (6H) s; 4.36 (2H) d; 2.90 (3 H) s; and 7.4-8.4 (4H) m.

NMR (8, CDCh): 2.06 (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.06 (3H) s; and 7.4-9.0 (4H) m and

11 -4-Acetyl-4-deoxy-4 "- (p-nitrophenylsulfonyl-5 amino) oleandomycin

NMR (8, CDCh): 2.10 (3H) s; 2.35 (6H) s; 2.68 (2H) d; 3.06 (3H) s; and 8.0-8.6 (4H) m.

io Example 17

ll-Acetyl-4 "-deoxy-4" - (p-hydroxyphenylsulfonyl-amino) oleandomycin.

A solution of 2.55 g (3.5 mmol) of 15 ll-acetyl-4 "-deoxy-4" -amino-oleandomycin, 701 mg (3.65 mmol) of chloride is stirred at room temperature for 48 hours. of p-hydroxyphenylsulfonyl and 518 µl of triethylamine in 25 ml of methylene chloride. The solvent is removed in vacuo and the residue is treated with 10 ml of acetone. The insoluble materials are separated by filtration and the filtrate is chromatographed on 20 g of silica gel with acetone as eluent. Fractions 116 to 175 which contain the pure product were combined according to thin layer chromatography and concentrated to dryness under reduced pressure to obtain 550 mg of the desired product.

25

NMR (8, CDCh): 2.0 (3H) s; 2.33 (6H) s; 2.68 (2H) d; 3.06 (3H) s; and 6.6-8.0 (4H) m.

Example 18

The procedure of Example 17 is repeated from the appropriate 1-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and sulfonyl chloride and the following compounds are prepared:

11-acetyl-4 "-deoxy-4" - (m-hydroxyphenylsulfonyl-amino) oleandomycin; 11 -propionyl-4 "-deoxy-4" - (p-hyroxyphenylsulfonylamino) olean-domycin; 11-propionyl-4 "-deoxy-4" - (m-hydroxyphé-nylsulfonylamino) oleandomycin; 40 1 l-acetyl-4 "-deoxy-4" - (o-hydroxyphenylsulfonyl-amino) oleandomycin and 11-propionyl-4 "-deoxy-4" - (o-hydroxyphenylsulfonylamino) oleandomycin.

Example 19

45 11 -4-Acetyl-4-deoxy-4 "- (m-carboxamidophenylsulfonyl-amino) oleandomycin.

898 mg are added to 20 ml of methylene chloride containing 2.91 g (4.0 mmol) of 4-acetyl-4 "-deoxy-4" -amino-oleandomycin and 434 mg (4.2 mmol) of triethylamine n / a (4.1 mmol) of m-carboxamidophenylsulfonyl chloride and the reaction mixture is stirred for 48 hours. The solvent is removed in vacuo and the residue is treated with 25 ml of acetone. The triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel. Fractions of 50 ml each are collected and examined by thin layer chromatography to determine the purity of the product. Fractions 69 to 93 are combined and concentrated under reduced pressure to obtain 800 mg of the desired products.

60

NMR (8, CDCh): 2.06 (3H) s; 2.33 (6H) s; 2.70 (2H) s; 3.10 (3H) s; and 7.4-9.0 (4H) m.

The previous procedure is used with the materials Example 20

The following compounds are prepared: 65 The procedure of Example 19 is repeated using 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and 1 l-acetyl-4 "-deoxy -4 "- (m-nitrophenylsulfonyl-sulfonyl chloride suitable for obtaining the following amino compounds) oleandomycin:

11

631461

1 l-propionyl-4 "-deoxy-4" - (m-carboxamidophenylsulfonylamino) oleandomycin; the

11 -acetyl-4 "-deoxy-4" - (o-carboxamidophenylsulfonyl -amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (p-carboxamidophenylsulfonyl-amino) oleandomycin; the

1 l-propionyl-4 "-deoxy-4" - (o-carboxamidophenylsulfonyl-amino) oleandomycin; and ll-propionyl-4 "-deoxy-4" - (p-carboxamidophenylsulfonyl-amino) oleandomycin.

Example 21

ll-Acetyl-4 "-deoxy-4" - (p-acetamidophenylsulfonyl-amino) oleandomycin.

A solution of 2.91 g (4.0 mmol) of

I 4-acetyl-4 "-4-deoxy-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. The reaction mixture is concentrated under reduced pressure to obtain a foam which is treated with

10 ml of acetone. The insoluble triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel with acetone as eluent. Fractions 42 to 86 are combined which, according to thin layer chromatography, contain most of the pure product and are concentrated in vacuo to obtain 1.2 g of the desired product:

NMR (ô, CDCh): 2.06 (3H) s; 2.23 (3H) s; 2.35 (6H) s; 2.70 (2H) s; 3.13 (3H) s; and 7.6-8.2 (4H) m.

Example 22

The procedure of example 21 is repeated with the

II-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and sulfonyl chloride suitable for obtaining the following compounds:

11-propionyl-4 "-deoxy-4" - (p-acetamidophenylsulfonyl-amino) oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (o-acetamidophenyl-sulfonylamino) oleandomycin; the

11-4-acetyl-4-deoxy-4 - (m-acetamidophenylsulfonyl-a mino) oleandomycin; and the

11 -propionyl-4 "-deoxy-4" - (o-acetamidophenylsulfonyl -amino) oleandomycin.

Example 23

11 -Acetyl-4 "-deoxy-4" - (p-cyanophenylsulfonyl-amino) oleandomycin.

Stirred at room temperature overnight a solution of 2.55 g (3.5 mmol) of

11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 734 mg (3.65 mmol) of p-cyanophenylsulfonyl chloride and 518 μl (3.75 mmol) of triethylamine in 25 ml of methylene chloride. The solvent is removed in vacuo and the residue is treated with 10 ml of acetone. The insoluble materials are filtered off and the filtrate is chromatographed on 120 g of silica gel with acetone as eluent and 10 ml fractions are collected. Fractions 47 and 83 are combined and concentrated under reduced pressure to obtain 281 mg of the desired product.

NMR (S, CDCh): 2.10 (3H) s; 2.36 (6H) s; 2.71 (2H) d; 3.06 (3H) s; and 7.7-8.4 (4H) m.

Example 24

The procedure of Example 23 is repeated with the

I-4-alkanoyl-4-deoxy-amino-oleandomycin and cyanobenzenesulfonyl chloride suitable for synthesizing the following compounds:

11-acetyl-4 "-deoxy-4" - (m-cyanophenylsulfonyl-amino) oleandomycin; the

II -propionyl-4 "-deoxy-4" - (o-cyanophenylsulfonyl-amino) oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (p-cyanophenylsulfonyl -amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (p-cyanophenylsulfonyl-amino) oleandomycin; and ll-propionyl-4 "-deoxy-4" - (m-cyanophenylsulfonyl-amino) oleandomycin.

Example 25

ll-Acetyl-4 "-deoxy-4" - (p-trifluoromethylphenylsulfonylamino) oleandomycin.

To a solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 518 μl (3.75 mmol) of triethylamine in 25 ml of methylene chloride, 891 mg (3.65 mmol) of p-trifiuo-romethylphenylsulfonyl chloride are added and the reaction mixture is stirred for 18 hours. The solvent is removed under reduced pressure and the residue is triturated with 15 ml of acetone. The solids are filtered off and the filtrate is chromatographed on silica gel to obtain 287 mg of the desired product.

NMR (8, CDCh): 2.03 (3H) s; 2.31 (6H) s; 2.63 (2H) d; 3.40 (3H) s; and 7.15-8.3 (4H) m.

Example 26

The procedure of Example 25 is repeated with the appropriate starting compounds to obtain the following compounds:

1 l-propionyl-4 "-deoxy-4" - (m-trifluoromethylphenylsul-fonylamino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (o-trifluoromethylphenylsulfonylamino) oleandomycin; 1-acetyl-4 "-deoxy-4" - (m-tri-fluoromethylphenylsulfonylamino) oleandomycin; ll-propionyl-4 "-deoxy-4" - (p-trifluoromethylphenylsulfonylamino) oleandomycin; and 11-propionyl-4 "-deoxy-4" - (o-trifluoromethylphenylsulfonylamino) oleandomycin

Example 27

11 -4-Acetyl-4-deoxy-4 "- (2,2,2-trifluoroethylsulfonyl-amino) oleandomycin.

A solution of 2.55 g (3.5 mmol) of

1 4-acetyl-4 "-4-deoxy-amino-oleandomycin, 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. 333 mg of sulfonyl chloride and 270 µl of triethylamine are added and stirring is continued for 4 hours. The solvent is then removed in vacuo and the residue is treated with 20 ml of acetone. The solids are separated by filtration and the filtrate is chromatographed on 110 mg of silica gel with acetone as eluent, taking 10 ml fractions. Fractions 50 to 80 are combined and concentrated to obtain 385 mg of the desired product.

NMR (8, CDCh): 2.06 (3H) s; 2.26 (6H) s; 2.60 (2H) d; and 3.36 (3H) s.

Similarly, from 11 -propionyl-4 "-

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6314 "!

12

4-deoxy-amino-oleandomycin instead of the 1-acetyl ester, ll-propionyl-4 "-deoxy-4" - (2,2,2-trifluoroethylsulfonyl-amino) is prepared according to the preceding procedure ) oleandomycin.

Example 28

11 -Acetyl-4 "-deoxy-4" -methylsulfonylamino) oléando-mycine.

A solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 467 mg (4.1 mmol) of chloride chloride is stirred at room temperature overnight. methylsulfonyl and 424 mg (4.2 mmol) of triethylamine in 25 ml of methylene chloride. The solvent is removed under reduced pressure and the residue is treated with 20 ml of acetone. The triethylamine hydrochloride is filtered off and the filtrate containing the product is chromatographed on 180 g of silica gel with acetone as solvent, collecting 6 ml fractions. Fractions 67 to 133 are combined and concentrated in vacuo to obtain 1.2 g of the desired product.

NMR (8, CDCh): 2.06 (3H) s; 2.28 (6H) s; 3.06 (3H) s; 2.61 (2H) d; and 8.40 (3H) s.

Example 29

From the appropriate alkylsulfonyl halide and the appropriate 11-alka-nucleus-4 "-deoxy-4" -amino-oleandomycin, the following compounds are synthesized according to the procedure of Example 28:

thin layer and concentrated to dryness to obtain 1.3 g of the desired product.

NMR (8, CDCh): 2.0 (3H) s; 2.30 (6H) s; 2.60 (2H) d; 3.06 s (3H) s; and 7.2-8.1 (3H) m.

Example 31

The procedure of Example 30 is repeated and the following compounds are prepared from the appropriate starting materials:

15

20

r-0 H

lnhs02r och,

25 r

Rl °

30

NMR (8, CDCh)

Cl

V 2.0 (3H) s; 2.36 (6H) s; 2.70 (2H) d; 3.33

\ = J (3H) s; and 7.3-8.6 (3H) m.

Cl

35 cl

40.

0ch „

Cl laughed

CHOCO-

CHsCO-

CHsCO-

CH3CH2CO-

CH3CH2CO-

CH3CH2CO-

CH3CH2CO-

R

C2H5-

n-CsHT-

Ì-C3H7-

CHs-

C2H5-

11-C3H7-

Ì-C3H; -

Example 30

11 -4-Acetyl-4-deoxy-4 "- (3,4-dichlorophenylsulfonyl-aminojoleandomycin.

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, are combined. 57 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride and the solution is stirred at room temperature for 18 hours. The reaction is stopped with 50 ml of water and the organic phase is washed with a saturated saline solution and then dried over sodium sulfate. The solvent is removed in vacuo and the residue is chromatographed on 150 g of silica gel with acetone as eluent. The product containing fractions are combined according to chromatography in

45

50

55

N0 „

.no,

Cl

//

2.06 (3H) s; 2.40 (6H) s; 2.66 (2H) d; 3.25 (3H) s; and 7.2-8.6 (3 H) m *.

N0,

"CH3O

, '1

r = \ 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 *.

~ \ -_ y n ° 2

es n M_ / \ 2.06 (3H) s; 2.36 (6H) s; and 8.4-9.0 ° 2W V // (3H) m *.

* NMR: DMSO / CDCh

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Example 32

The procedure of Example 30 is repeated with the

I l-alkanoyl-4 "-deoxy-3" -amino-oleandomycin and sulfonyl chloride suitable for preparing the following compounds:

11-acetyl-4 "-deoxy-4" - (2,6-dichlorophenylsulfonyl-amino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (4-methyl-2-chlorophenyl sulfonylamino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (2-methyl-5-chlorophenyl-

sulfonylamino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (2-nitro-4-chlorophenylsulfonylamino) oleandomycin;

1 l-4-acetyl-4-deoxy-4 "- (3-nitro-4-chlorophenylsulfonyl-amino) oleandomycin;

1 l-acetyl-4 "-deoxy-4" - (3-nitro-5-chlorophenylsulfonyl-amino) oleandomycin;

1 l-propionyl-4 "-deoxy-4" - (3-methoxy-5-nitrophenyl-sulfonylamino) oleandomycin;

1 l-acetyl-4 "-deoxy-4" - (3-nitro-4-methylphenylsulfonyl-amino) oleandomycin;

1 l-acetyl-4 "-deoxy-4" - (3,5-dinitrophényIsulfonyl-amino) oleandomycin;

11-acetyl-4 "-deoxy-4" - (2,6-dimethoxyphenylsulfonyl-amino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (2,4-dimethoxyphenyl-sulfonylamino) oleandomycin;

11-acetyl-4 "-deoxy-4" - (2-methyl-5-methoxyphenyl-sulfonylamino) oleandomycin;

1 l-acetyl-4 "-deoxy-4" - (2,3-dimethylphenylsulfonyl-amino) oleandomycin;

1-propionyl-4 "-desoxy-4" - (2,4-dimethylsulfonylamino) oleandomycin and 11-acetyl-4 "-desoxy-4" - (3-nitro-4-methylsulfonyl-amino) oleandomycin.

Example 33

Il-AcetyI-4 "-deoxy-4" - (2,3,4-trichIorophenylsulfonyl-amino) oleandomycin.

A solution of 2.9 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.15 g (4.1 mmol) is stirred at room temperature for 18 hours. 2,3,4-trichlorophenylsulfonyl chloride and. 0.57 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride. The organic layer is washed with 50 ml of water and then 50 ml of a saturated salt solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is chromatographed on 150 g of silica gel with acetone as solvent, collecting 7 ml fractions. The fracitons 60 to 100 are combined and concentrated to obtain 800 mg of the desired product.

NMR (S, CDCh): 2.06 (3H) s; 2.33 (6H) s; 2.63 (2H) d; 3.2 (3H) s; and 7.2-8.2 (2H) m.

Similarly, from the appropriate reactants, the following compounds are synthesized according to the above procedure:

II-4-acetyl-4-deoxy-4 "- (3,4,5-trichlorophenylsulfonyl-amino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (2,4,6-trichlorophenyl-sulfonylamino) -oleandomycin; and 4-acetyl-4 "-deoxy-4" - (2,3,5-trichlorophenylsulfonyla-mino) oleandomycin.

Example 34

11 - Acetyl-4 "-deoxy-4" - (2-hydroxy-3,5-dichlorophenyl-sulfonylamino) oleandomycin.

The procedure of Example 33 is repeated with 2.55 g (3.5 mmol) of 4-acetyl-4 "-deoxy-4" -amino-oleandomy-

cine, 954 mg (3.65 mmol) of 2-hydroxy-3,5-dichlorophenylsulfonyl chloride and 518 µl (3.75 mmol) of triethylamine in 25 ml of methylene chloride to obtain, after chromatography on 220 g of silica gel, 483 mg of desired product.

NMR (8, CDCh / DMSO): 2.03 (3H) s; 2.50 (6H) s; 3.05 (3H) s; and 7.2-7.8 (2H) m.

io Example 35

The procedure of Example 33 is repeated with 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and sulfonyl chloride suitable for preparing the following compounds:

15

20

25

H (CH3) 2

/ „

30 R,

CHJCO-

35

40

CHsCO-

45

CH ^ CO-

so

55

CHsCO-

60

och,

r

Cl

0

Oh

Cl

Cl

- ^ - ° H Cl

65 CH3CH2CO-

631,461

14

ch3ch2co-

C1

-0 "

X Cl

OH

CH.CH:CO-

ch3ch2co-

Example 36

ll-Acetyl-4 "-deoxy-4" - (3-amino-4-chlorophenylsulfonyl-amino) oleandomycin.

A suspension of 50 mg of 10% palladium on carbon in 50 ml of ethyl acetate containing 1.0 g of is stirred in a hydrogen atmosphere under an initial pressure of 3.4 bar at room temperature overnight. 11-4-acetyl-4-deoxy-4 "- (3-nitro-4-chlorophenylsulfonyl-amino) oleandomycin. The spent catalyst is filtered off and the solvent is removed in vacuo. The residual white foam is chromatographed on 160 g of silica gel using acetone as eluent and 50 ml fractions are taken. The product containing fractions are combined and concentrated under reduced pressure to obtain 450 mg of the desired product.

NMR (8, CDCh): 2.03 (3H) s; 2.33 (6H) s; 2.66 (2H) d; 3.16 (3H) s; and 7.2-8.0 (3H) m.

Similarly, with the appropriate nitro compound of Example 16, the following are prepared:

11-acetyl-4 "-deoxy-4" - (m-aminophenylsulfonyl-amino) oleandomycin

NMR (8, CDCh): 2.03 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.10 (3H) s; and 7.0-7.8 (4H) m and 11-acetyl-4 "-deoxy-4" - (p-aminophenylsulfonyl-amino) oleandomycin

NMR (8, CDCh): 2.06 (3H) s; 2.31 (6H) s; 3.02 (3H) s; and 6.4-7.8 (4H) dd.

Example 37

From the appropriate nitro compounds of Examples 31 and 32, the following amino-type compounds are prepared according to the reduction process of Example 36:

1 l-acetyl-4 "-deoxy-4" - (2-amino-4-chlorophenylsul-fonylamino) oleandomycin; the

11-4-acetyl-4-deoxy-4 - (2-amino-4-methoxyphenylsulfonylamino) oleandomycin; 11 -acetyl-4 "-deoxy-4" - (2,4-diaminophenylsulfonyl-amino) oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (2-amino-4-chlorophenyl-sulfonylamino) oleandomycin; 11-acetyl-4 "-deoxy-4" - (3-amino-4-chlorophenyl-sulfonylamino) oleandomycin; 11-acetyl-4 "-deoxy-4" - (3-amino-5-chlorophenyl-sulfonylamino) oleandomycin;

11-propionyl-4 "-deoxy-4" - (3-methoxy-5-aminophenyl-sulfonylamino) oleandomycin; the

11 -acetyl-4 "-deoxy-4" - (3-amino-4-methylphenylsulfony 1-amino) oleandomycin; and s 1 l-acetyl-4 "-deoxy-4" - (3,5-diaminophenylsulfonyl-amino) oleandomycin.

Example 38

ll-Acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonyl-10 amino) oleandomycin.

To 100 g (0.13 mole) of 4-11-acetyl-4-deoxy-4-amino-oleandomycin in 900 ml of methylene chloride, 593 ml of triethylamine are added and the solution is stirred for 10 minutes. 41.9 g (0.213 mole) of 3-methyl-2-thienylsulfonyl chloride in 30 ml of methylene chloride are then added dropwise over 1 hour 15 minutes, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is added to 2 liters of water and the organic phase is separated, washed successively with two 250 ml portions of water and a 250 ml portion of salt solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is chromatographed on a 105 cm x 6.5 cm column containing 1.5 kg of silica gel. The product is collected and eluted with acetone in the eluate fractions of 2.31 to 6 liters. The fractions are combined and the solvent is removed under reduced pressure to obtain a foam. The residual foam is treated with ethyl ether to obtain 66.4 g of the desired product; m.p. 184-185.5 ° C.

NMR (8, CDCh): 2.04 (3H) s; 2.41 (6H) s; 2.46 (3H) s; 2.62 (2H) m; 3.02 (3H) s; 6.84 and 7.32 (2H).

To 2 g of the above free base in 15 ml of ethyl acetate, 0.12 ml of phosphoric acid is added and the solution is stirred at room temperature. After 20 minutes, crystals begin to form and after 2 hours, they are separated by filtration, washed with ethyl acetate and dried to obtain 1.3 g of 4-acetyl-4 "phosphate. -deoxy-4 "- (3-methyl-2-thienylsulfonyl-40 amino) oleandomycin.

NMR (8, CD3OD): 2.01 (3H) s; 2.45 (3H) s; 2.56 (2H) m; 2.83 (6H) s; 3.0 (3H) s; 6.88 and 7.42 (2H).

45 Example 39

The procedure of Example 38 is repeated from the appropriate sulfonyl chloride and from 1 l-acetyl-4 "-deoxy-4" -amino-oleandomycin to obtain the following compounds:

50

N (CH-)

"IÒ

65

iHS02R1

OCH.

15

631461

ch.

// \\ 0 '

ch.

Ìh3

'H-

NMR (8, CDCh)

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 (3H) s; 3.71 (3H) s; 6.44-6.70 (1H) m and 7.18-7.39 (2H) m.

2.03 (3H) s; 2.25 (3H) s; 2.51 (6H) s; 2.61 (2H) m; 3.15 (3H) s; 7.07 (1H) m and 7.38 (1H) m.

The above foam is chromatographed on a column of silica gel measuring 3.25 x 38 cm with acetone as eluent. Fractions 40 to 220 are each collected having a volume of about 10 to 12 ml and combined. The solvent is removed from the eluent under vacuum to obtain 3.4 g of the desired product in the form of a white foam.

NMR (8, CDCh): 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 (1H) m.

10

Example 42

The procedure of Example 41 is repeated with the appropriate sulfonyl chloride and the

1 l-4-acetyl-4-deoxy-4-amino-oleandomycin to obtain the following compounds:

HO

n (ck3) 2

C2H5

ch.

-at-

2.06 (3H) s; 2.33 (6H) s; 2.65 (2H) m; 3.22 (3H) s; 6.73 and 7.45 (2H).

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).

20

25

ch3co

Example 40

The procedure of Example 38 is repeated from sulfonyl chloride and from 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin suitable for obtaining the following compounds:

11 -acetyl-4 "-deoxy-4" - (3-ethyl-2-thienylsulfonyl- 35

amino) oleandomycin; the

11 -propionyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonyl-amino) oleandomycin; 11 -acetyl-4 "-deoxy-4" - (5-ethyl-2-py rrylsul-fonylamino) oleandomycin; the 40

I 4-propionyl-4-deoxy-4 "- (4-ethyl-2-thienyIsul-fonylamino) oleandomycin; the

II-4-acetyl-4-deoxy-4 "- (1-ethyl-3-pyrrylsulfonyl-amino) oleandomycin; the

I 4-propionyl-4 "-deoxy-4" - (5-ethyl-2-furylsulfonyl-45 amino) oleandomycin; ll-acetyl-4 "-deoxy-4" - (4-ethyl-3-furylsulfonyl-amino) oleandomycin; and the

II-4-acetyl-4-deoxy-4 "- (3-ethyl-2-furylsulfonyl-amino) oleandomycin. 50

och-

S02R1

RI

NMR (8, CDCh)

/ - \ 2, i CH 3 ° 2C - ('S> - f.

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

22 (3H) s; 3.95 (3H) s; 7.61 and 7.75 (2H).

CH 0 C 2.11 (3H) s; 2.34 (6H) s; 2.70 (2H) m;

J 1 \ v 3.24 (3H) s; 3.94 (3H) s; 8.06 and 8.28

(/ \ y_ (2H).

r— \ 2.08 (3H) s; 2.29 (6H) s; 2.67 (2H) s; CH 0 „C — 1 * 3.18 (3H) s; 3.94 (3H) s; 7.02 and 7.20

J ^ O ^ (2 H).

Example 41

11 -4-Acetyl-4-deoxy-4 "- (5-carbomethoxy-2-pyrrylsulfo-nylamino) oleandomycin.

A solution of 2.96 g (0.0041 mole) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 0.62 ml of triethylamine in 50 ml of anhydrous methylene chloride cooled in ice bath with 1.0 g (0.0044 mol) of 2-carbomethoxy-5-pyrrylsulfonyl chloride. The reaction mixture is allowed to warm to room temperature and is stirred for 3.5 hours and then poured into 200 ml of water. The pH of the aqueous phase is adjusted to 9.5 with an IN aqueous solution of sodium hydroxide and the methylene chloride phase is separated, washed successively with water and saturated brine and dry it on sodium sulfate. The solvent is removed under reduced pressure to obtain 3.8 g of the crude product in the form of a white foam.

Example 43

4 "-deoxy-4" - (p-chlorophenylsulfonylamino) oleandomomy-cine.

55 A solution of 3.0 g of 4 "-deoxy-4" -amino-oleandomycin, 865 mg of p-chlorophenylsulfonyl chloride and 424 mg of triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight . The solvent is removed in vacuo and the residue is treated with 20 ml 60 of acetone. The insoluble triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 180 g of silica gel with acetone as elution solvent and 50 ml fractions are collected. Fractions 18 to 27 are combined and concentrated under reduced pressure 65 to obtain 1.10 g of the desired product.

NMR (8, CDCh): 2.33 (6H) s; 2.83 (2H) d; 3.06 (3H) s; and 7.2-8.4 (4H) m.

631461

16

Example 44

The procedure of Example 43 is repeated from the appropriate sulfonyl chloride and from 4 "-deoxy-4" -amino-oleandomycin to obtain the following compounds:

f.o V

och „

R „

Cl

Cl nhso2R2

NMR (8, CDCh): 2.33 (6H) s; 2.46 (3H) s; 2.83 (2H) d; 3.10 (3H) s; and 7.10-8.0 (4H) m.

In a similar procedure, 4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin is prepared.

NMR (S, CDCh): 2.29 (6H) s; 2.88 (2H) m; 3.2 (3H) s; 5.6 (1H) m and 7.33 (3H) m.

w Example 46

From the 4 "-deoxy-4" -amino-oleandomycin and the appropriate sulfonyl chloride, the following compounds are synthesized according to the procedure of Example 43:

15

20

25

30

I-v \ hso2R2

och.

Ri cf.

-Q -.- O-

35

40

45

50

ch,

cf.

55

och,

Example 45

4 "-Deoxy-4" - (p-toluenesulfonylamino) oleandomycin.

According to a process similar to that of Example 43, the mixture is stirred at room temperature overnight 30 g (4.0 mmol) of 4 "-4-deoxy-amino-oleandomycin, 782 mg (4.1 mmol ) p-toluenesulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 25 ml of methylene chloride. The crude product is then chromatographed on 180 g of 65 silica gel and 10 ml fractions are collected. Fractions 90 to 148 are combined and concentrated to dryness to obtain 1.4 g of the desired product.

ch.

, 0 ~ O-

ch „0

o ~

17

631461

C2H5

CH „

$

Ct

Cl x s

XS

'ÌX

Example 49

ll-Acetyl-4 "-deoxy-4" - (2-diethylaminoethylsulfonyl-amino) oleandomycin.

892 mg (12.2 moles) of diethylamine and the reaction mixture obtained is stirred under a nitrogen atmosphere at room temperature for 48 hours. The solvent and the excess diethylamine are removed in vacuo and 940 mg of product are obtained in the form of a white foam which slowly crystallizes; m.p. 85-99 ° C.

NMR (8, CDCh): 2.05 (3H) s; 2.30 (6H) s; 2.36-2.73 (4H) q; 2.63 (2H) s; and3.4 (3H) s.

15

Example 50

The procedure of Example 49 is repeated from 1 l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and from the appropriate secondary amine to obtain the following compounds:

Example 47

11 - Acetyl-4 "-deoxy-4" - (vinylsulfonylamino) oleandomomy-cine.

To a solution of 17.1 (82.3 mmol) of ß-bro-moethanesulfonyl chloride in 20 ml of methylene chloride cooled to -78 ° C, and maintained under a nitrogen atmosphere, a solution cooled to - 78 ° C of 30 g (41.1 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 16.7 g (164 mmol) of triethylamine in 100 ml of methylene chloride. After 1.3 hours of stirring at -78 ° C, the reaction mixture is poured into water and the pH is adjusted to 7.3 by addition of solid sodium bicarbonate. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to obtain 43.5 g of a yellow foam. The residue is suspended in ether and filtered. The filtrate is concentrated under reduced pressure to obtain 20.3 g of the crude product which is chromatographed on 800 g of silica gel with a 95: 5 mixture by volume of chloroform and methanol as elution solvent. The fractions containing the product are combined and concentrated to obtain 5.1 g of the desired compound.

NMR (8, CDCh): 2.10 (3H) s; 2.37 (6H) s; 2.70 (2H) d; 3.43 (3H) s; and 5.7-7.06 (3 H) m.

Example 48

11 -4-Acetyl-4-deoxy-4 "- (P-bromoethylsulfonyl-amino) oleandomycin.

To a solution of 500 mg (0.68 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 882 mg (8.2 mmol) of 2,6-lutidine in 4 ml of methylene chloride previously cooled to -4 ° C under a nitrogen atmosphere, 854 mg (4.0 mmol) of P-bromoethane-sulfonyl chloride are added in 2 ml of methylene chloride cooled to -2 ° C. After 1.75 hours of stirring at -2 ° C, the reaction mixture is poured into a mixture of water and methylene chloride and the pH is adjusted to 7.0 with solid sodium bicarbonate. The organic phase is separated, dried over sodium sulfate and concentrated in the form of an amber oil. The residual oil is chromatographed on 42 g of silica gel using a 95: 5 by volume mixture of chloroform and methanol as elution solvent to obtain 52.5 mg of the desired product.

NMR (8, CDCh): 2.08 (3H) s; 2.33 (6H) s; 2.65 (2H) s; and 3.46 (3H) s.

25

30

35

v laughed

CHaCO-CHsCO- "CHjCO-CHÎCO-CHsCO-CHaCO-CH3CH2CO-45 CH3CH2CO-CH3CH2CO-CH3CH2CO-CH3CH2CO-CH3CH2CO-

50

och.

N (CH3) 2

N (CH3) C2H5-

N (n-C3H7) 2

N (i-C3H7) 2

N (C2H5) n-C3H7

N (CH3) i-C3H7

N (CH3) 2 ~

N (CH3) C2Hs

N (C2HÎ) 2

N (n-C3H7) 2

N (i-C3H7) 2

N (CH3) i-C3H7

Example 51

11 - Acetyl-4 "-deoxy-4" - (methylthioethylsulfonyl-amino) oleandomycin.

55 A suspension of 800 mg (0.98 mmol) of ll-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) oleandomycin and 475 mg (3 mmol) of potassium carbonate in 10 ml of benzene is stirred while bubbling. in the metha-nethiol suspension for 30 seconds. The closed her-60 container is stirred metrically at room temperature overnight. The excess thiol is removed under reduced pressure and the reaction mixture is added to a mixture of benzene and water. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to obtain 805 mg of the desired product 65 in the form of an oil.

NMR (8, CDCh): 1.98 (3H) s; 2.05 (3H) s; 2.20 (6H) s; 2.57 (2H) s; and 3.30 (3H) s.

631461

18

Example 52

From the appropriate thiol and! 1-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) oleandomomy-cine, the following compounds are synthesized according to the procedure of Example 51:

T "CU

H

T *

".1

0

If

'■ vS

(CH3) 2

CK3CO / f}

. NHS02CH2CH2-Z OCH3

Z NMR (8, CDCh)

hoch2ch2s- 2.03 (3H) s; 2.30 (6h) s; 2.63 (2H) s; and 3.40 (3H) s.

CH3CH2S- 2.07 (3H) s; 2.28 (6H) s; 2.63 (2H) s; and 3.40 (3H) s.

CH3CH2CH2S-2.07 (3H) s; 2.30 (1H) s; 2.61 (2H) s; and3.42 (3H) s.

O, 2.07 (3H) s; 2.28 (6H) s; 2.65 (2H) s; and 3.38 (3H) s.

Example 53

The procedure of Example 51 is repeated, starting with 1 l-alkanoyl-4 "-deoxy-4" - (vinylsulfonylamino) oléando-mycine and thiol suitable for obtaining the following compounds:

Rl °.

och3

R! Z

CH? CO- (CH3) 2chs-

CH3CH2CO- CHhS-

CH3CH2CO- ch3ch2s-

CH3CH2CO- hoch2ch2s-

CH3CH2CO- CfiHsS-

CH3CH2CO- CH3CH2CH2S-

Example 54

11 -Acetyl-4 "-deoxy-4" - (morpholinoethylsulfonyl-amino) oleandomycin.

To a solution of 2.0 g (2.44 mmol) of

11-4-acetyl-4-deoxy-4 "(vinylsulfonylamino) oleandomycin in 50 ml of benzene, 2.1 g (24.4 mmol) of morpholine are added and the reaction mixture obtained is stirred under nitrogen for 40 hours at room temperature.

The solvent and excess morpholine are removed in vacuo to obtain the crude product as a foam. The residue is triturated in hexane for 1 hour and then recrystallized from a mixture of ethyl acetate and hexane to obtain 890 mg of the desired product; m.p. 95 ° C.

10

NMR (8, CDCh): 2.06 (3H) s; 2.30 (6H) s; and 3.42 (3H) s.

Example 55

1 l-4-acetyl-4-deoxy-4 "hydrochloride - (2-thienylsulfo-15 nylamino) oleandomycin.

To 8.7 g of 4-11-acetyl-4-deoxy-4 "- (2-thienylsulfonyl-amino) oleandomycin in 50 ml of anhydrous ethyl acetate, 10 ml of an IN solution of hydrochloric acid are added. in ethyl acetate. The solution is concentrated to dryness under vacuum and the residue consisting of monohydrochloride is triturated with ether and separated by filtration.

Example 56

11-Acetyl-4 "-deoxy-4" phosphate - (2-thienylsulfonyl-25 amino) oleandomycin.

To a solution of 15.0 g of 11-acetyl-4 "-deoxy-4" - (2-thie-nylsuIfonylamino) oleandomycin in 100 ml of ethyl acetate, 1.0 ml of phosphoric acid is added. The suspension is stirred for 4 hours at room temperature. The solids are separated by filtration, washed with ethyl acetate and dried to obtain 12.5 g of the desired salt; m.p. 168 ° C (decomposition).

Similarly, 4-acetyl-4 "-deoxy-4" phosphate (3-methyl-2-thienylsulfonyl-35 amino) oleandomycin is prepared. 184-188 ° C and 11-acetyl-4 "-deoxy-4" phosphate - (p-chlorophenylsulfonyl-amino) oleandomycin, m.p. 204-205 ° C.

Preparation A 40 4 "-Doxy-4" -oxo-oleandomycins.

I. 11 - Acetyl-4 "-deoxy-4" -oxo-oleandomycin.

a) 11.2'-Diacetyl-4 "-deoxy-4" -oxo-oleandomycin.

4.5 g of N-chlorosuccinimide, 50 ml of benzene and

150 ml of toluene in a dry reactor fitted with a magnetic stirrer and a nitrogen inlet and cooled to -5 ° C., 3.36 ml of dimethyl sulfide are added. After 20 minutes of stirring at 0 ° C, the contents are cooled to -25 ° C and treated with 5.0 g of 1 l, 2'-diacetyl-oleandomycin in 100 ml of toluene. The cooling and stirring are continued for 50 2 hours and 4.73 ml of triethylamine are added. The reaction mixture is stirred at 0 ° C for 15 minutes and then poured into 50 ml of water. The pH is adjusted to 90.5 with an IN aqueous solution of sodium hydroxide, the organic phase is separated, a saline solution is washed with water and then dried over sodium sulfate. The solvent is removed in vacuo to obtain 4.9 g of the desired product in the form of a foam.

NMR (8, CDCh): 3.48 (3H) s; 2.61 (2H) m; 2.23 (6H) s and 2.03 (6H) s.

60

b) 11 -4-acetyl-4-deoxy-4 "-oxo-oleandomycin

A solution of 4.0 g of 1 l, 2'-diacetyl-4 "-deoxy-4" -oxo-olean-domycin in 75 ml of methanol is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to obtain the product in the form of a foam. A solution of the residue in ethyl ether is treated with hexane to obtain 2.6 g of the product in the form of a white solid, m.p. 112-117 ° C.

NMR (8, CDCh): 3.43 (3H) s; 2.60 (2H) m, 2.23 (6H) s and 2.01 (3H) s.

Similarly, we repeat the above procedure with 11,2'-dipropionyl-4 "-deoxy-4" -oxo-oleandomycin or 1 l-propionyl-2'-acetyl-4 "-deoxy-4 "-oxo-oleandomycin to prepare 1 l-priopionyl-4" -deoxy-4 "-oxo-oleandomycin.

11. 4 "-Doxy-4" -oxo-oleandomycin.

a) 2'-Acetyl-4 "-deoxy-4" -oxo-oleandomycin.

0.337 ml of dimethyl sulfide is added to a cloudy solution of 4.67 mg of N-chlorosuccinimide in 20 ml of toluene and 6 ml of benzene cooled to -5 ° C and maintained under a nitrogen atmosphere. After 20 minutes of stirring at 0 ° C, the mixture is cooled to -25 ° C and 1.46 g of 2'-acetyl-oleandomycin and 15 ml of toluene are added. Stirring is continued for 2 hours at -25 ° C. and 1.46 g of 2 '-acetyl-oleandomycin and 15 ml of toluene are added. Stirring is continued for 2 hours at -20 ° C and 0.46 ml of triethylamine is added. The reaction mixture is kept at -20 ° C for a further 5 minutes, then allowed to warm to 0 ° C. The mixture is poured with stirring into 50 ml of water and 50 ml of ethyl acetate. The pH of the aqueous mixture is adjusted to 9.5 by addition of an aqueous solution of sodium hydroxide. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to obtain 1.5 g of a white foam. Triturated with ethyl ether to obtain 864 mg of crude product which is recrystallized twice from a mixture of methylene chloride and diethyl ether to obtain 212 mg of the pure product, m.p. 183-185.5 ° C.

Theoretical analysis for C37H61O13N: (%)

Calculated: C 61.1 H 8.5 N 1.9 Found: C 60.9 H 8.4 N 1.9

NMR (8, CDCh): 5.60 (1H) m; 3.50 (3H) s; 2.73 (2H) m; 2.23 (6H) s and 2.03 (3H) s.

b) 4 "-Doxy-4" -oxo-oleandomycin.

A solution of 1.0 g of 2'-acetyl-4 "-deoxy-4" -oxo-oleandomomy-cine in 20 ml of methanol is stirred at room temperature overnight. The solution is concentrated under vacuum to obtain the desired product in the form of a white foam weighing 937 mg.

NMR (8, CDCh): 5.60 (1H) m; 3.50 (3H) s; 2.85 (2H) m and 2.26 (6H) s.

Preparation B

4 "-Doxy-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, 21.2 g of ammonium acetate are added and the suspension obtained is treated with a solution of 20 g of 11-acetyl-4 "- 4-deoxy-oxo-oleandomycin in 100 ml of the same solvent. The suspension is stirred at room temperature ordi631461

under an atmosphere of hydrogen at an initial pressure of

3.4 bars. 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 is adjusted between 6.4 and

4.5 and the organic phase is separated. The aqueous phase is again extracted with 500 ml of chloroform and treated with 500 ml of ethyl acetate and then the pH is adjusted to 9.5 with IN sodium hydroxide. The ethyl acetate phase is separated and the aqueous phase is extracted again with ethyl acetate. The extracts are combined in ethyl acetate, dried over sodium sulfate and concentrated to obtain 18.6 g of a yellow foam which is recrystallized from diisopropyl ether to obtain 6.85 g of product purified; m.p. 157.5-160 ° C.

NMR (8, CDCh): 3.41 (3H) s; 2.70 (2H) m; 2.36 (6H) s; and 2.10 (3H) s.

The other epimer is obtained, which is present in the raw foam at a rate of 20 to 25% by gradual concentration and filtration of the mother liquors.

Similarly, we repeat the previous procedure from 11-propionyl-4 "-desoxy-4" -oxo-oléando-mycine to obtain 1 l-propionyl-4 "-désoxy-4" -amino-oléandomycine .

II. 4 "-Deoxy-4" -amino-oleandomycin.

A solution of 20 g of 2'-acetyl-4 "-deoxy-4" -oxo-oleandomycin in 125 ml of methanol is stirred at room temperature overnight, then treated with 21.2 g of acetate. ammonium. The solution obtained is cooled in an ice-water bath and treated with 1.26 g of sodium cyanoborohydride. The cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 600 ml of water and 600 ml of ethyl ether and the pH is adjusted between 8.3 and 7.5. The ethereal phase is separated and the aqueous phase is extracted with ethyl acetate. The extracts are reserved and the pH of the aqueous phase is adjusted to 8.25. The extracts in ethyl ether and ethyl acetate obtained are also stored at this pH and the pH is brought to 9.9. The extracts in ethyl ether and ethyl acetate obtained at this pH are combined, washed successively once with water and a saturated saline solution and dried over sodium sulfate. The pH of the latter extracts is adjusted to 9.9, concentrated in the form of a foam and chromatographed on 160 g of silide gel with chloroform as loading solvent and initial eluent. When 11 fractions of 12 ml each have been collected, a mixture of 5% methanol and 95% chloroform is used as eluent. In fraction 370, a mixture of 10% methanol and 90% chloroform is used as eluent, and in fraction 440, a mixture of 15% methanol and 85% chloroform is used as eluent. Fractions 85 to 260 are combined and concentrated to dryness in vacuo to give 2.44 g of the desired product.

NMR (8, CDCh): 5.56 (1H) m, 3.36 (3H) s; 2.9 (2H) m and 2.26 (6H) s.

19

s

10

15

20

25

30

35

40

45

50

55

B

Claims (9)

CLAIMS 1. Therapeutically active compound, characterized in that it corresponds to one of the formulas 1 to 3: 2. A compound according to claim 1, characterized in that R in formula 1 represents a substituted or unsubstituted 2- or 3-thienyl radical and R 1 represents an acetyl radical. 30 3. Compound according to claim 2, characterized in that R represents a 3-methyl-2-thienyl radical and Ri represents an acetyl radical. 2 where R represents an alkyl radical containing 1 to 3 carbon atoms; 1,1,1-trifluoroethyl; phenyl; monosubstituted phenyl whose substituent is chosen from fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyano, carboxamido, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoro-methyl; alkyl having 1 to 4 carbon atoms or acetamido; disubstituted phenyl, the substituents of which are chosen each from chloro, nitro, amino, methoxy or methyl; tri-chlorophenyl; hydroxydichlorophenyl; benzyl; naphthyl; thienyl; chlorothienyl; pyridyle; 2-acetamido-5-thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimé-thyl-2-pyrimidinyle; pyrryl; furyl; substituted thienyl, pyrryl or furyl, the substituent of which is a carbomethoxy or alkyl radical containing 1 or 2 carbon atoms; and 1-methyl-5-carbomethoxy-3-pyrryl; Ri represents an alkanoyl radical containing 2 or 3 carbon atoms; Rî represents a phenyl radical; substituted phenyl, the killer of which is chloro, fluoro, methyl, methoxy or trifluoromethyl; thienyl; or alkyl-substituted thienyl in which the alkyl fragment contains 1 or 2 carbon atoms; X and Y taken separately each represents a hydrogen atom or together form a carbon-carbon bond; and Z represents a hydrogen atom or a bromine atom, a dialkylamino group in which the alkyl fragment contains 1 to 3 carbon atoms, alkylthio in which the alkyl fragment contains 1 to 3 carbon atoms, phenylthio, 2-hydroxyethylthio or 1-morpholino, provided that when X and Y represent a carbon-carbon bond, Z represents a hydrogen atom; and its acid addition salts suitable in pharmacy. 4. Compound according to claim 1, characterized in that R2 in formula 2 represents a 4-chlorophenyl radical, 2-thienyl, 3-thienyl or 3-methyl-2-thienyl. 5. Compound according to claim 1, characterized in that X and Y in formula 3 each represent an atom e t of hydrogen and Ri represents an acetyl radical. 6. Compound according to claim 5, characterized in that 40 Z represents a bromine atom. 7. Compound according to claim 5, characterized in that ■ Z represents a methylthio radical. 8. Compound according to claim 1, characterized in that X and Y in formula 3 together represent a bond 45 carbon-carbon and Z represents a hydrogen atom. 9. Antibacterial drug, characterized in that it contains, as a therapeutically active principle, a compound of formula 1,2 or 3 or one of its acid addition salts suitable in pharmacy.