DE2820411A1 - SEMI-SYNTHETIC 4 "SULPHONYLAMINO OLEANDOMYCINE DERIVATIVES - Google Patents

Description

Semi-synthetic 4 "sulfonylamino-oleandomycin derivatives

The invention relates to new antibacterial agents, and more particularly to one Series of 4 "-deoxy-4" -sulfonylamino-oleandomycins and their pharmaceutically acceptable acid addition salts.

Oleandomycin, its manufacture in fermentation broths and its uses antibacterial agents were first described in U.S. Patent 2,757,123. The naturally occurring compound is known to possess following structure:

HO Ti

OCH,

The conventionally adopted numbering scheme and stereochemical Representation of oleandomycin and similar compounds is given for a variety of positions.

In U.S. Patents 3,884,902 and 3,983,103 are 4 "erythromycin sulfonate esters or N-SuIfonylerythromycylamine described, which different from the compounds described in the present invention, possess biological profiles.

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Various synthetic modifications of oleandomycin are known in particular those in which one to three of the free hydroxyl groups present in the 2 ', 4 "and 11-positions are esterified as acetyl esters are. Furthermore, US Pat. No. 3,022,219 describes similar modifications in which the acetyl radical is in the aforementioned Esters is replaced by another radical, preferably by unbranched, lower alkanoyl radicals having 3 to 6 carbon atoms.

The invention relates to semi-synthetic oleandomycin derivatives, which as antibacterial agents are suitable and have the following formulas:

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N (CH ₃ ),

OCH-

N (CH ₃ ),

HO ,,,,

OCH-

RO ',. "

HO,

X Y

ι ι

NHSO ₀ CH-CH-Z

OCH

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and their pharmaceutically acceptable acid addition salts, in which R is an alkyl radical having 1 to 3 carbon atoms, a pyridyl radical, the 1,1,1-trifluoroethyl radical, the phenyl radical, a fluorine, chlorine, bromine, iodine, hydroxy, methoxy, cyano, carboxamido, nitro , Amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoromethyl, alkyl with 1 to 4 carbon atoms or acetamido monosubstituted phenyl radical, a phenyl radical disubstituted by chlorine, nitro, amino, methoxy or methyl, a trichlorophenyl radical, hydroxydichlorophenyl radical, chlorophenyl radical, benzyl radical, naphthyl radical 2-acetamido-5-thiazolyl, 2-acetamido-A-methyl-S-thiazolyl, 2-benzimidazolyl, dimethyl-2-pyrimidinyl, pyrryl, furyl, thienyl, pyrryl or monosubstituted by carboraethoxy or alkyl with 1 to 2 carbon atoms Furyl radical or the 1-methyl-S-carbomethoxy-S-pyrryl radical, R. is an alkanoyl radical with 2 to 3 carbon atoms, R _{2 is} a phenyl radical, thienyl radical, through chlorine, Fl uor, methyl, methoxy or trifluoromethyl monosubstituted phenyl radical or a thienyl radical substituted by alkyl having 1 to 2 carbon atoms, X and Y, when present separately, are each hydrogen atoms, or X and Y taken together represent a carbon-carbon bond and Z is Hydrogen atom, bromine atom, dialkylamino radical in which alkyl has I to 3 carbon atoms, an alkylthio radical in which alkyl has 1 to 3 carbon atoms, phenylthio radical, 2-hydroxyethylthio radical or 1-morpholino radical, with the proviso that when X and Y are a carbon Are carbon bonds, Z is a hydrogen atom.

The amine starting materials leading to the compounds according to the invention consist of two 4 "-epimeric amines because of the synthesis method used for their preparation. Therefore, the sulfonamido compounds according to the invention consist of which are formed from these amines, also from a mixture of epimers. It was found experimentally that both epimeric sulfonamides are present in the final product in different proportions, depending on the synthetic method used to prepare the amine intermediate. If the isolated product consists predominantly of one of the epimers

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is, this epimer by repeated recrystallization from a suitable solvent to be purified to a constant melting point. The other epimer, namely the one in smaller quantities in the original epimers present in isolated, solid material, is the predominant product present in the mother liquor. It can be derived from this Methods known per se to those skilled in the art can be obtained, for example by evaporating the mother liquor and repeated recrystallization of the residue to a product of constant melting point or by means of chromatography.

Although this mixture of epimers is known per se to the person skilled in the art Methods can be split, it is advantageous for practical reasons to use this mixture as it is isolated from the reaction. However, it is often advantageous to recrystallize the mixture of the epimers by at least one recrystallization from a suitable solvent, by performing column chromatography, by solvent partitioning or by trituration in a suitable solvent clean. This purification, while not necessarily cleaving the epimers, removes such foreign materials as starting materials and undesirable by-products.

The absolute stereochemical assignment for the epimers has not yet been established completely completed. Both epimers of a given compound, however, show the same type of activity as, for example, antibacterial Middle.

Preferred compounds according to the aforementioned formula 1 are those in which R is a thienyl radical or a thienyl radical substituted by alkyl having 1 to 2 carbon atoms or carbomethoxy.

Preferred compounds of the aforementioned formula 2 are those in which R _{2 is} a substituted phenyl radical, a thienyl radical and a thienyl radical substituted by alkyl having 1 to 2 carbon atoms.

Preferred compounds of the aforementioned formula 3 are those in which X and Y each represent a hydrogen atom and R. is the acetyl radical.

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Among these compounds are because of their antibacterial usefulness preferred: 1l-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin, 1l-acetyl-4 "-deoxy-4" - (3-thienylsulfonylamino) -oleandomycin, 11-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) -oleandomycin, 4 "-deoxy-4" - (p-chlorophenylsulfonylamino) -oleandomycin, 4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin, 4 "-Deoxy-4" - (3-thienylsulfonylamino) -oleandomycin, 4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) -oleandomycin, 11-acetyl-4 "-deoxy-4" - (2 -bromoethylsulfonylamino) -oleandomycin, 11-Acetyl-4 "-deoxy-4" - (2-methylthioethylsulfonylamino) -oleandomycin and 1l-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin.

In accordance with the synthetic procedure for that of 4 "-deoxy-4" -sulfonylamino-oleandomycin 'Derived antibacterial agents' of formulas I and 2, the following scheme is illustrative, whereby from 4 "-deoxy-4" -amino-oleandomycin or an 11-alkanoyl derivative is assumed:

S (CH ₃ ) i

RSO ₂ Cl ^R l ° "'

OCH,

^ NHSO ₂ R

OCH,

OCH-

HO ,,,,

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in which R, R. and R "have the meanings given above.

The reactions given above are between a 4 "-deoxy-4" -aminooleandomycin and a suitable sulfonyl halide in the presence of an acid scavenger in a reaction inert solvent .

In practice, 1 mole of the 4 "-amino-oleandomycin is mixed with 1 mole of the sulfonyl halide plus a 2-3% excess of this halide. The acid scavenger can be inorganic or organic Be compound and is used in an amount of 1 mole plus an excess of 4-6%.

The scavenger can be made from alkali metal or alkaline earth metal hydroxides, hydrides or carbonates or also consist of a tertiary »organic amine. In addition, secondary amines such as diisopropylamine can also be used are sterically hindered enough to interact with the sulfonyl halide reactant can not respond can also be used. The preferred class of acid scavengers are tertiary amines. Particularly triethylamine is preferred within this class.

The reaction-inert one used in the process described above Solvent should be one that solubilizes the reactants in an appreciable manner, and not in any appreciable manner Extent occurs with one of the reactants or the products formed in reaction. Polar solvents are preferred, which may or may not be miscible with water. Methylene chloride and acetone-water are particularly preferred.

As a heating of amino-oleandomycins leads to some decomposition leads, it is preferred to carry out the process which leads to compounds of the formula I or 2 at O-25 ° C. Particularly preferred is a reaction carried out at ambient temperature or room temperature.

The reaction time is not critical and depends on the reaction temperature, concentration and that of the initial reactants

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Responsiveness. If the reactions occur at room temperature in the If the concentrations mentioned below are carried out, the reaction is essentially complete in 2 to 48 hours.

The reaction mixture can after the completion of the reaction in one of the be worked up in the following two ways, both of which are known per se to the person skilled in the art. The first work-up method involves the addition the reaction mixture to water, then the separation of the water-immiscible solvent which contains the desired product, as well as its subsequent removal to obtain the crude product. When using a water-miscible solvent as the reaction-inert The solvent is the product from the reaction mixture mixed with water using a water-immiscible solvent extracted as methylene chloride.

The second work-up method involves concentrating the reaction mixture to dryness, followed by extraction of the product from the salt derived from the scavenger base and hydrogen halide by-product

Use of acetone follows. The acetone extract can be used for extraction of the crude product are concentrated.

The crude product or an acetone solution thereof is determined by chromatography on silica gel, a procedure known per se, or by recrystallization cleaned.

The manufacture of antibacterial agents according to formula 3, wherein X and Y represent a carbon-carbon bond and Z is a hydrogen atom, is carried out by contacting 1 mole of the appropriate 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycins with 2 moles of ß-bromoethanesulfonyl chloride and 4 moles of an unhindered tertiary amine such as triethylamine.

The reaction temperature is set to -78 ° C for the period of contact and held for a reaction time of 1 to 2 hours.

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Suitable solvents for this procedure are the same as they are were used in the process for the preparation of the compounds of formulas 1 and 2, with the further limitation that these solvents do not freeze at the preferred reaction temperature. The preferred one The solvent is methylene chloride.

The reaction mixture is worked up in the same way as before in the process leading to the compounds of formulas 1 and 2 has been described.

In addition to being antibacterial agents, the 1l ^ alkanoyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycins prepared by this process also useful as intermediates, which lead to further antibacterial agents after one of the following the procedure described below.

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

At a reaction temperature of about 0 ° C, a reaction time of 1-2 hours preferred. The preferred solvent at these "reaction temperatures" is methylene chloride.

The product is made according to a procedure similar to that used for synthesis of the compounds of the formulas 1 and 2 has been described, obtained and purified.

The remaining compounds represented by Formula 3 are represented by obtain a Michael addition of the appropriate amine or mercaptan to the required 1l-alkanoyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin, as shown below:

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ί-0 Η

K (CH ₃ )

OCH.

NHSO CHCH ₂ Z

OCH.

In practice, the vinylsulfonylamino compound with a triple up to a ten fold molar excess of the amine or mercaptan in a reaction inert solvent at ambient temperatures for Brought into contact for 12-48 hours. The solvent should meet the same requirements as before for the synthesis of the compounds 1 and 2 were named. The preferred solvent is benzene.

If a mercaptan is used as one of the reactants, an inorganic base or a base in the form of a tertiary amine is used to facilitate the reaction. Preferably will a molar amount of the base, at least equivalent to the vinylsulfonylamino compound, used. The preferred base is potassium carbonate.

Upon completion of the reaction, the product is either removed by removal of the solvent and the excess of the reactant below reduced pressure or by rapid quenching of the reaction mixture obtained in water and subsequent separation of the organic phase and concentration to dryness.

Those involved in the synthesis of the antibacterial agents of the invention used starting 4 "-amino compounds are by oxidation of natural oleandomycin and subsequent reducing amination of the resulting ketone, as explained below, synthesized.

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When utilizing the chemotherapeutic activity of the invention For compounds which form salts, it is of course preferred to use pharmaceutically acceptable salts. Although a Insolubility in water, high toxicity, or an absence of the crystalline nature of some particular types of salt unsuitable or less beneficial for use Use as such in a given pharmaceutical application can be the water-insoluble or toxic salts converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt with a suitable base, or alternatively they can be converted to any desired pharmaceutically acceptable acid addition salt.

Examples of such acids which provide pharmaceutically acceptable anions, are hydrochloric acid, hydrobromic acid, hydriodic acid, Nitric acid, sulfuric acid, sulphurous acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, Gluconic acid, aspartic acid, glutamic acid, pyroglutamic acid and lauryl sulfuric acid.

The new 4 "-deoxy-4" -amino-oleandomycin derivatives described here show in vitro activity against a variety of Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain gram-negative microorganisms such as those with a spherical or ellipsoidal shape (cocci). Your activity will be easy by in vitro tests against various microorganisms in a brain-heart infusion medium according to the usual two-fold dilution technique shown. Their in vitro activity makes them suitable for local application in the form of ointments, creams and the like, for sterilization purposes. e.g. for devices in hospital rooms and as industrial antimicrobial agents e.g. in water treatment, sludge control, conservation suitable for paints and wood.

For in vitro use, e.g. for a local application, it is often suitable for the selected product with a pharmaceutically acceptable carrier such as a vegetable or mineral oil or

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to mix together a moisturizing cream. In the same way, the Compounds according to the invention in liquid carriers or solvents such as water, alcohol, glycols or mixtures thereof or in others pharmaceutically acceptable, inert media are dissolved or dispersed, i.e. in media which do not adversely affect the active Own ingredient. For such purposes, it is generally acceptable to use concentrations of active ingredients from about 0.01% to about 10% by weight, based on the total composition, to be used.

In addition, many of the compounds according to the invention are active against gram-positive microorganisms by the oral and / or parenteral route of administration in animals and humans. Their in vivo activity is more limited with respect to susceptible organisms and is determined by conventional practice which includes vaccinating mice of substantially equal weight with the test organism and then treating them, orally or subcutaneously, with the test compound. In practice, for example, 10 mice are inoculated intraperitoneally with appropriately diluted cultures which are approximately 1 to 10 times the LD. ₀ , the lowest concentration of organisms causing 100% death. Control tests are carried out simultaneously on mice which receive vaccinations at lower dilutions as a sample of possible variation in the virulence of the test organism. The test compound is applied 0.5 hours after inoculation, this is repeated 4 hours, 24 hours and 48 hours later. The surviving mice are kept for four days after the last treatment and the number of surviving animals is determined.

When used in vivo, the novel compounds according to the invention administered orally or parenterally, e.g. by subcutaneous or intramuscular injection at a dosage of about 1 mg / kg to about 200 mg / kg body weight per day. A convenient dosage range is from about 2 mg / kg to about 100 mg / kg body weight per day, and the preferred one Range is from about 2 mgikg to about 50 mg / kg of body weight per day. Carriers suitable for parenteral injection can either

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aqueous carriers such as water, isotonic saline, isotonic Dextrose solution, Ringer's solution, or non-aqueous vehicles such as fatty or vegetable oils (cottonseed oil, peanut oil, corn oil, sesame oil), dimethyl sulfoxide or other non-aqueous vehicles which do not impair the therapeutic effectiveness of the preparation and in the volume used or the amount used is non-toxic, e.g. glycerine, propylene glycol, sorbitol. In addition, means can be produced which for a preparation of solutions taking place at any point in time prior to application are suitable. Such compositions can be liquid Diluents such as propylene glycol, diethyl carbonate, Glycerin, sorbitol, etc., buffering agents, hyaluronidase, local anesthetics and Inorganic salts contain the desired pharmacological properties to deliver. These compounds can also be mixed with various pharmaceutically acceptable inert carriers including solid diluents, aqueous carriers, non-toxic, organic solvents in the form of capsules, tablets, lozenges, lozenges, dry mixes, Suspensions, solutions, elixirs and parenteral solutions or suspensions can be combined. In general, the connections in various dosage forms with concentration values from about 0.5% by weight to about 90% by weight, based on the total composition, used.

The invention is illustrated in more detail by means of the following examples.

example 1

1l-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin

2.9 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 740 mg = 4.1 mmol of 2-thienylsulfonyl chloride and 0.58 ml = * 4.2 mmol of triethylamine added, and the resulting reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 50 ml of water, then it is saturated with Washed brine and dried over sodium sulfate. The solvent is removed under reduced pressure and that which remains Foam is purified by chromatography on a silica gel column using acetone as solvent and eluate,

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The fractions containing the product are combined and in vacuo concentrated to dryness, 1.3 g of product being obtained.

NMR (i, CDCl ₃ ): 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

When using 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding Sulfonyl chloride and using the procedure of Example 1, the following compounds are prepared:

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CH ₃ CO ",

OCH "

NMR (δ, CDCl ₃ )

Cl

-TS- 2.08 (3H) s; 2 _f 30 (6H) s; 2.67 (2H) m; 3.23 (3H) s and 6.87 and 7.45 (2H) s.

CH ₃ CNH - \ _s 2 _r 09 (3H) s; 2.42 (6H) s; 2.70 (2H) m and 3 _; 26 (3H) s. ·

ON
CNH- ^> 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 _r 16 t4H) 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) ».

CH-2.08 (3H) s; 2.31 (6H) s; 2.59 (6H) s; 2.65 (2H) s; 3.01 (3H) s and 7.11 (l) s.

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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 _f 06 (3H) s; 2.29 (6H) s; 2.64 (2H) m; 3.26 (3H) s; 6.52 (1H) m; 6.77 (lH) m and 7.29 (lH) 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. CH 0 C "

CH ₃

2.08 (3H) s; 2.31 (6H) s; 2.68 (2H) m; (/ \\ 3.25 (3H) s; 6.74 (lH) m; 7.48 (lH) m

^ ^ and 8.00 (lH) m.

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Example 3

The procedure of Example 1 is repeated using the required sulfonyl chloride and 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin as starting materials to give the following related compounds: 1l-propionyl-4 "-deoxy- 4 "- (2-thienylsulfonylamino) oleandomycin; 1l-propionyl-4 "-deoxy-4" - (2-acetamido-5-thiazolylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (2-benzimidazolylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (4,5-dimethyl-2-pyrimidinylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (4,6-dimethyl-2-pyrimidinylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (3-chloro-2-thienylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (4-chloro-2-thienylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (2-chloro-4-thienylsulfonylamino) -oleandomycin; 11-Acetyl-4 "-deoxy-4 ^M - (2-pyridylsulfonylamino) -oleandomycin; 1l-propionyl-4" -deoxy-4 "- (3-pyridylsulfonylamino) -oleandomycin; 1l-acetyl-4" -deoxy-4 "- (4-pyridylsulfonylamino) -oleandomycin; 11-acetyl-4" -deoxy-4 "- (2-furylsulfonylamino) -oleandomycin; 1l-propionyl-4" -deoxy-4 "- (2-pyrrylsulfonylamino) -oleandomycin ; 11 -Propiotiy 1-4 "-deoxy-4" - (1-methyl-5-carbomethoxy-3-pyrrylsulfonylamino) oleandomycin; and 1l-propionyl-4 "-deoxy-4" - (3-thienylsulfonylamino) oleandomycin.

Example 4

11-acetyl-4 "-deoxy-4" - (p-chlorophenylsulfonylaroino) -oleandomycin

To a solution of 2.91 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin and * 528 μΐ = 4.2 mmol of triethylamine in 20 ml of methylene chloride, 865 mg = 4, 1 mmol of p-chlorophenylsulfonyl chloride is added, and the reaction mixture obtained is stirred at room temperature overnight. The reaction mixture is concentrated to dryness in vacuo and the residue is treated with 10 ml of acetone. The suspension is filtered and the filtrate is chromatographed over 160 g of silica gel using acetone as the eluate. Fractions 51 to 63, each comprising 10 ml, are collected and concentrated under reduced pressure, with 857 mg of the pure product being obtained.

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the. Fractions 42 to 52 and 64 to 92 gave 1.21 g less aH pure product.

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

In the same way, give 20 g of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 7.24 g of p-chlorophenylsulfonyl chloride and 5.36 g of triethylamine in a solvent system from 350 ml of acetone and 350 ml of water, 17.1 g of the desired product which crystallized out of the reaction mixture; F. 202-203.5 C. An analytical sample was recrystallized from ethanol / water.

Example 5

Using the procedure of Example 4 and using the required sulfonylchlorides and of 1l-acetyl-4 "-deoxy-4" -aminooleandomycin the following compounds were prepared as starting materials:

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CH.CO
n,

OCH,

NMR (δ,

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 _f 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.

Cl

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 _t 70 (2H) d; 2.90 (3H) s and 7.0-8.2 (4H) ra.

2 _r 10 (3H) s; 2 _; 33 (6H) s; 2.66 (2H) d; 3.10 (3H) s and 7.5-7.93 (4H) m.

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2820A 11

Example 6

The procedure of Example 4 is repeated, with the corresponding Sulfonyl chloride and 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin as starting materials can be used to obtain the following products: 11-propionyl-4 "-deoxy-4" - (p-chlorophenylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (m-bromophenylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (m-fluorophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (m-iodophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (p-fluorophenylsulfonylamino) -oleandomycin; I1-Propiony1-4 "-deoxy-4" - (p-bromophenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (m -iodophenylsulfonylamino) -oleandomycin and 1l-acetyl-4 "-deoxy-4" - (o-bromophenylsulfonylamino) -oleandomycin.

Example 7

lamino) oleandomycin

A solution of 2.9 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 780 mg = 4.1 mmol of o-tolylsulfonyl chloride and 0.58 ml = 4.2 mmol of triethylamine in 30 ml of methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is quenched in 50 ml of water and the separated organic layer is washed with a saturated saline solution and washed over Dried sodium sulfate. The solvent is removed in vacuo, and the yellow foam that remains is over 200 g of silica gel in a Chromatographed column with a diameter of 3 cm. The product will eluted from the column with acetone and collected in fractions of 10 ml. The fractions containing the pure product, as determined by thin layer chromatography is checked, are combined and concentrated to dryness under reduced pressure to give 1.3 g of product.

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

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The procedure of Example 7 is repeated, using as starting materials the corresponding sulfonyl chloride and 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin can be used to form the following compounds:

• NHS0 ₂ R

OCH,

(6, CDCl ₃ )

CH.

2 _r 03 (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.06 (3H) s; 3.83 (3H) s; and 6.8-8.2 (4K) ra.

2.03 (3H) s; 2 _f 33 (6H) s; 2.66 (2H) d; 3 _; 06 (3H) s; and 7.3-8.0 (4H) ra.

OCH,

2.08 (3H) s; 2 _r 30 (6H) s; 2.66 (2H) d; 2.83 (3H) s; 4.03 (3H) s; and 6.8-8 _; 2 (4)

2.06 (3H) s; 2.30 (6K) s; 2.43 (3H) s; 3 _# 10 (3H) s; 2.66 (2H) d; 7.23-7.40 (2H) d; and 7 _; 76-7.93 ü> H) d.

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Cft! -U! \ 'AL

Example 9

Using the procedure of Example 7 and using the appropriate 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycins and the corresponding Sulfonyl chloride, the following analogous compounds are synthesized: 1 l-acetyl-4 "-deoxy-4" - (m-tolylsulfonylainino) -oleandoinycin; 1l-propionyl-4 "-deoxy-4" - (p-methoxyphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (m-methoxyphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (p-tolylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (p-isopropylphenylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (o-ethylphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (o- ^ n-propyl7-phenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (p- £ s-butyl-phenylsulfonylamino) -oleandomycin; and 11-Propiony1-4 "-deoxy-4" - (p-η-butyl'-phenylsulfonylamino) -oleandomycin.

Example 10

1 l-acetyl ^^ deoxy ^^ phenylsulfonylamino-oleandomycin

To a solution of 2.91 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin and 424 mg = 4.2 mmol of triethylamine in 30 ml of methylene chloride, which is cooled in an ice bath, becomes 722 mg = 4.1 mmol of benzosulfonyl chloride added. After 10 minutes the bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched with 50 ml of water and the organic layer is washed with a saturated saline solution and dried over sodium sulfate. After removing the solvent, the crude product is obtained, which is further purified by chromatography over 160 g of silica gel using acetone as the eluate. The parliamentary groups 61-93 (10 ml each) containing the pure product, as by thin layer chromatography is determined are combined and concentrated to dryness under reduced pressure, giving 1.5 g of the desired Product can be obtained.

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

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Furthermore, following the procedure of Example 10 when using of the corresponding raw materials:

11-Acetyl-4 "~ deoxy-4" - (2-naptithylsulfonylamino) -oleandomycin

NMR (i , CDCl ₃ ): 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 ^^ deoxy ^ Mjenzylsulfonylamino -oleandomycin

NMR U, CDCl ₃ ): 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

1l-acetyl-4 "-deoxy-4" - (p-benzyloxycarbonylphenylsulfonylamino) -oleandomycin

A solution of 2.55 g = 3.5 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.12 g = 3.6 mmol p-benzyloxycarbonylphenylsulfonyl chloride and 379 mg = 3.75 mmol of triethylamine in 25 ml of methylene chloride is left overnight at room temperature touched. 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 over 280 g of silica gel using acetone as the eluate with fraction sizes of 10 ml. The parliamentary groups 90-203, which, according to the thin-layer chromatographic analysis, contain the largest proportion of the pure product, are combined and concentrated under reduced pressure to give 1.25 g of the desired product.

NMR (ί, CDCl ₃ ): 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.

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ij example 12

Using the procedure of Example 11 and using the appropriate one ijSulfonylchlorids and 1l-Acetyl-4 "-deoxy-4" -amino-oleandomycin are the

| get the following connections:

CH ₃ CO ₀ ,

O = C

OCH-

O = C

NHSO ₂ R

OCH,

NMR (δ, CDCl ₃ )

2 _f 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 (6K) s; 2.65 (2H) d; 3.01 (3Ii) s; 5.43 (2H) d; 7.46 (5H) s; and 7.33-8.70 (4H) m.

2, C: (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.06 (3H) s; 4.0 (3H) s; and 7.8-8.4 (4H) n.

C = O

CH ₃ O

2.10 (3H) s; 2 _; 30 (6H) s; 2.70 (2H) d; 3.0 (3K) s; and 4.10
(3H) s.

ORIGINAL

809846/0937

Example 13

The procedure of Example 11 is repeated, using as starting materials the corresponding 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonyl chloride can be used to form the following compounds: 1l-acetyl-4 "-deoxy-4" - (o-benzyloxycarbonylphenylsulfonylamino) -oleandomycins 1l-Propionyl-4 "-deoxy-4" - (p-methoxycarbonylphenylsulfonylamino) -oleandomycins 1l-propionyl-4 "-deoxy-4" - (m -benzyloxycarbonylphenylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (p-benzyloxycarbonylphenylsulfonylamino) oleeandomycin; 1l-propionyl-4 "-deoxy-4" - (o-methoxycarbonylphenylsulfonylamino) -oleandomycin and 11-propionyl-4 "-deoxy-4" - (o-benzyloxycarbonylphenylsulfonylamino) -oleandomycin.

Example 14

11-acetyl-4 "-deoxy-4" - (p-carboxyphenylsulfonylamino) -oleandomycin

A suspension of 400 mg of 10% palladium-on-charcoal in 40 ml of ethyl acetate, the 800 mg of II-acetyl-4 "-deoxy-4" - (p-benzyloxycarbonylphenylsulfonylamino) -oleandomycin contains is in a hydrogen atmosphere at an initial pressure of 3.5 atir. at room temperature for 2 hours shaken. An additional 250 mg of catalyst is added and the reaction is continued for 2 hours. The consumed The catalyst is filtered off, and the solvent is removed in vacuo, being 450 mg of the desired. Product can be obtained.

NMR (έ, CDCl ₃ ): 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

Using the appropriate II-alkanoyl-4 "-deoxy-4" - (benzyloxycarbonylphenylsulfonylamino) -oleandomycin, as described in Examples 12 and 13, as starting material and using the procedure Example 14 produces the following compounds

809846/0937

represents: 11-acetyl-4 "-deoxy-4" - (m-carboxyphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (o-carboxyphenylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (m-carboxyphenylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (p-carboxyphenylsulfonylamino) -oleandomycin and 1l-propionyl-4 "-deoxy-4" - (o-carboxyphenylsulfonylamino) -oleandomycin.

Example 16

11-acetyl-4 "-deoxy-4" - (o-nitrophenylsulfonylamino) -oleandomycin

5g = 6.8 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.5 g = 7.0 mmol o-Nitrobenzenesulfonyl chloride and 0.98 ml of triethylamine are dissolved in 50 ml of methylene chloride combined and stirred at room temperature for 48 hours. The reaction mixture is added rapidly with an equal volume of water, and the organic phase is washed with a saturated salt solution and dried over sodium sulfate. The removal of the solvent under reduced Pressure gives the raw product in the form of a foam. The product is chromatographed over 140 g of silica gel in a column with a diameter of 3 cm using acetone as the eluate. The fractions 20-30, each comprising 50 ml, are collected together combined and concentrated to dryness, 3.4 g of the desired product being obtained.

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

The following compounds are prepared in the same way, the suitable starting materials used and the procedure described above is applied:

11-acetyl-4 "-deoxy-4" - (m-nitrophenylsulfonylamino) -oleandomycin

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

1l-acetyl-4 "-deoxy-4" - (p-nitrophenylsulfonylamino) -oleandomycin

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

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Example 17

II-acetyl-4 "-deoxy-4" - (p-hydroxyphenylsulfonylamino) -oleandomycin

A solution of 2.55 g = 3.5 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 701 mg = 3.65 mmol of p-hydroxyphenylsulfonyl chloride and 51.8 / μl triethylamine in 25 ml of methylene chloride is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue is washed with 10 ml of acetone treated. The insoluble fractions are filtered off and the filtrate is chromatographed over 200 g of silica gel using acetone as the eluate. The fractions 116-175, which according to the thin layer chromatography contain the pure product, are combined and under concentrated to dryness under reduced pressure to give 550 mg of the desired product.

NMR (<f, CDCl ₃ ): 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

Using the procedure of Example 17 and using the appropriate 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycins and the corresponding Sulfonyl chloride as starting materials are used to prepare the following compounds: 1l-acetyl-4 "-deoxy-4" - (m-hydroxyphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (p-hydroxyphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (m-hydroxyphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (o-hydroxyphenylsulfonylamino) -oleandomycin; and 1l-propionyl-4 "-deoxy-4" - (o-hydroxyphenylsulfonylamino) -oleandomycin.

Example 19

1l-acetyl-4 "-deoxy-4" - (m-carboxamidophenylsulfonylamino) -oleandomycin

To 20 ml of methylene chloride containing 2.91 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin and contain 434 mg = 4.2 mmol of triethylamine, 898 mg = 4.1 mmol of m-carboxamidophenylsulfonyl chloride are added, and the reaction mixture obtained is stirred for 48 hours. The solution

809846/0937

-32- 282Q411

medium is removed in vacuo, and the residue is washed with 25 ml of acetone treated. The triethylamine hydrochloride is filtered off and the filtrate is chromatographed over 160 g of silica gel. Each containing 50 ml Fractions are collected and analyzed by thin layer chromatography to determine the purity of the product. The factions 66-93 are combined and concentrated under reduced pressure to give 800 mg of the desired product.

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

Example 20

The procedure of Example 19 is repeated using as starting materials the corresponding II-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonyl chloride can be used and the following analogous compounds are obtained: 1l-propionyl-4 "-deoxy-4" - (m-carboxamidophenylsulfonylamino) -oleandomycins 1l-acetyl-4 "-deoxy-4" - (o-carboxamidophenylsulfonylamino) -oleandomycins 1l-acetyl-4 "-deoxy-4" - (p-carboxamidophenyl- sulfonylamino) oleandomycins 1l-propionyl-4 "-deoxy-4" - (o-carboxamidophenylsulfonylamino) -oleandomycin and 1l-propionyl-4 "-deoxy-4" - (p-carboxamidophenylsulfonylamino) -oleandomycin.

Example 21

1l-acetyl-4 "-deoxy-4" - (p-acetamidophenylsulfonylamino) -oleandomycin

A solution of 2.91 g = 4.0 mmol of II-acetyl-4 "-deoxy-4" -amino-oleandomycin, 955 mg = 4.1 mmol p-acetamidophenylsulfonyl chloride and 424 mg = 4.2 mmol Triethylamine in 20 ml of methylene chloride is stirred for 48 hours at room temperature. The reaction mixture turns into a foam under reduced pressure concentrated, which is then treated with 10 ml of acetone. The insoluble triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel using acetone as the eluate. The factions 42-86, which, according to thin-layer chromatography, has the "largest share of pure product are combined and concentrated in vacuo to give 1.2 g of the desired product.

809846/0937

NMR («J, CDCl ₃ ): 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, using as starting reagents the appropriate 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the required Sulfonyl chloride can be used and the following compounds are obtained: 1l-propionyl-4 "-deoxy-4" - (p-acetamidophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (o-acetamidophenylsulfonylammo) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (m-acetamidophenylsulfonylamino) -oleandomycin and 11-propionyl-4 "-deoxy-4" - (o-acetamidophenylsulfonylamino) -oleandomycin.

Example 23

11-Acetyl-4 "-deoxy-4" - (p -cyanophenylsulfonylamino) -oleandomycin

A solution of 2.55 g = 3.5 mmol 1 l-acetyl-4 "-deoxy-4" -atnino-oleandomycin, 734 mg = 3.65 mmol p-cyanobenzenesulfonyl chloride and 518 μ \ = 3.75 mmol triethylainine in 25 ml of methylene chloride is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is treated with 10 ml of acetone. The insolubles are filtered off and the filtrate is chromatographed on 120 g of silica gel using acetone as the eluate and collecting fractions of 10 ml each. Fractions 47-83 are combined and concentrated under reduced pressure to give 281 mg of the desired product.

NMR (S, CDCl ₃ ): 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

Using the required 1l-alkanoyl-4 "-deoxy-4" -amino.-oleandomycin and the corresponding cyanobenzenesulfonyl chloride and using the procedure from Example 23 the following compounds are synthesized: II-acetyl-4 "-deoxy-4" - (m-cyanophenylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (o-cyanophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (p-cyanophenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (o-cyano-

809846/0937

2620411

phenylsulfonylamino) oleandomycin and 1l-propionyl-4 "-deoxy.-4" - (m-cyanophenylsulfonylamino) -oleandomycin.

Example 25

11-acetyl-4 "-deoxy-4" - (p-trifluoromethylphenylsulfonylamino) -oleandomycin

To a solution of 2.55 g = 3.5 mmol] l-acetyl-4 "-deoxy-4" -amino-oleandomycin and 518 ill = 3.75 imnol triethylamine in 25 ml of methylene chloride are 891 mg = 3.65 mmol of p-trifluoromethylphenylsulfonyl chloride added, and the obtained The reaction mixture is stirred for 18 hours. The solvent is removed under reduced pressure and the residue is washed with 15 ml of acetone rubbed in. The solids are filtered off and the filtrate is over Chromatographed silica gel to give 287 mg of the desired product.

NMR (S, CDCl ₃ ): 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 using as starting materials the appropriate reagents are used and the following, analogous compounds are produced: 1l-Propionyl-4 "-deoxy-4" - (m-trifluoromethylphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (o-trifluoromethylphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (m-trifluoromethylphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (p-trifluoromethylphenylsulfonylamino) -oleandomycin and 1l-propionyl-4 "-deoxy-4" - (o-trifluoromethylphenylsulfonylamino) -oleandomycin.

Example 27

1l-Acetyl-4 "-deoxy-4" - (2,2,2-trifluoroethylsulfonylamino) -oleandomycin

A solution of 2.55 g = 3.5 mmol of 1l-acetyl-4 "-deoxy-4" -amin-oleandomycin, 666 mg = 3.65 mmol of 2,2,2-trifluoroethylsulfonyl chloride and 379 mg = 3.75 mmol Triethylamine in 25 ml of methylene chloride is 30 hours at room temperature

809846/0937

touched. Additional amounts of 333 mg of the sulfonyl chloride and 270 al Triethylamine is added and stirring is continued for an additional 4 hours. The solvent is then removed in vacuo and the residue is treated with 20 ml of acetone. The solids are filtered off and the filtrate is poured onto 110 mg silica gel using acetone Chromatographed as eluate and collecting in 10 ml fractions. The factions 50-80 are combined and concentrated to give 385 mg of the desired product.

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

In the same way, when using 1l-propionyl-4 "-deoxy-4" -aminooleandomycin instead of the 11-acetyl ester and using the above described procedure 1l-propionyl-4 "-deoxy-4" - (2,2,2-trifluoroethylsulfonylamino) -oleandomycin manufactured.

Example 28

11-acetyl-4 "-deoxy-4" - (methylsulfonylamino) -oleandomycin

A solution of 2.91 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin 467 mg = 4.1 mmol methylsulfonylchloride and 424 mg = 4.2 mmol triethylamine in 25 ml of methylene chloride is stirred at room temperature overnight. 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 poured over 180 g of silica gel chromatographed using acetone as the solvent and collecting in 6 ml fractions. Fractions 67-133 are pooled and concentrated in vacuo to give 1.2 g of the desired product.

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

Example 29

Using the required alkylsulfonyl halide and the appropriate 1l-Alkanoyl-4 "-deoxy-4" -amino-oleandomycins and using the procedure of Example 28 make the following compounds synthesized:

809846/0937

- ^ o

CH ₃ CO- C ₂ H ₅ - CH ₃ CO- nC ₃ H ₇ CH ₃ CO- 1-C ₃ H ₇ CH ₃ CH ₂ CO- CH ₃ - CH ₃ CH ₀ CO- C ₂ H ₅ - CH ₃ CH ₉ CO- HC ₃ H ₇ CH ₃ CH ₂ CO- 1-C ₃ H ₇

809846/0937

ORIGINAL

Example 30

1 l-Acetyl - ^ - deoxy - ^ - QjA-dichlorphenylsulfonylamincQ-o l eandomyci n

2.9 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.0 g = 4.1 mmol 3,4-dichlorophenylsulfonyl chloride and 0.57 ml = 4.2 mmol of triethylamine combined in 30 ml of methylene chloride, and the resulting solution is at Stirred at room temperature for 18 hours. The reaction mixture is quickly mixed with 50 ml of water (quenched), and the organic phase is with a saturated saline solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is over 150 g Chromatographed silica gel using acetone as the eluate. the fractions containing the product, as indicated by thin layer chromatography, are combined and concentrated to dryness, yielding 1.3 g of the desired product can be obtained.

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

Example 31

Following the procedure of Example 30 and using the Appropriate reagents as starting materials are as follows specified connections established:

(CH ₃ )

R0984R / 0937

Cl

rC

Cl

^ci -Ö-

^C1 A \ /

- 38-

MiR (δ, CDCl ₃ )

2.0 (3H) s; 2.36 (6K) s; 2.70 (2H) d; 3.33 (3H) s; and 7.3-8.6 (3H) m.

2.10 (3H) s; 2.31 (6H) s; 2.66 (2H) d; 3.30 (3H) sj and 7.2-8.4 (3H) m.

2.03 (3H) s; 2.30 (6H) s; 2.66 (3H) s; 3.10 (3H) s; and 7.1-8.1 (3H) m *.

NO

NO,

, NO,

2.06 (3H) s; 2.33 (6H) s; 2 _r 70 (2H) d; 3.13 (3H) s; and 7 _r 4-8.6 (3H) m.

:, 06 (3K) s; 2.40 (6H) s; 2.66 (2H) d; 3.25 (3H) s; and 7,2-ό, 6 (3H) m *.

2.06 (3K) s; 2 _; 33 (6K) s; 2 ^ 63 rZH) d; 2.81 (3H) s; 3.63 (3H) s; and 7.0-8.2 (3K) m *.

2.06 (3K) s; 2.36 (6H) s; and &, 4-9 _; 0 (3H) ra *.

* NMR: DMSO / CDCl,

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Example 32

The procedure of Example 30 is repeated again, using as starting materials the required 1l-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonyl chloride can be used to make the following analogues To make compounds: 1l-acetyl-4 "-deoxy-4" - (2,6-dichlorophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (4-methyl-2-chlorophenylsulfonylamino) -oleandomycin; 1l-Propionyl-4 "-deoxy-4" - (2-methyl-5-chlorophenylsulfonylamino) -oleandomycins II-Propionyl-4 "-deoxy-4" - (2-nitro-4-chlorophenylsulfonylamino) -oleandomycins 1l-Acetyl-4 "-deoxy-4" - (3-nitro-4-chlorophenylsulfonylamino) ■ oleandomycin; 1l-acetyl-4 "-deoxy-4" - (3-nitro-5-chlorophenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (3-methoxy-5-nitrophenylsulfonylamino) -oleandomycin; 11-acetyl-4 "-deoxy-4" - (3-nitro-4-methylphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deox3'-4" - (3,5-dinitrophenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (2,6-dimethoxyphenylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (2,4-dimethoxyphenylsulfonylamino) -oleandomycin; ] 1-acetyl-4 "-deoxy-4" - (2-methyl-5-methoxyphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (2,3-dimethylphenylsulfonylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (2,4-dimethylphenylsulfonylamino) -oleandomycin and 11-acetyl-4 "-deoxy-4" - (3-nitro-4-methylsulfonylamino) -oleandomycin.

Example 33

1l-acetyl-4 "-deoxy-4" - (2,3,4-trichlorophenylsulfonylamino) -oleandomycin

A solution of 2.9 g = 4.0 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 1.15 g = 4.1 mmol of 2,3,4-trichlorophenylsulfonyl chloride and 0.57 ml = 4.2 mmol of triethylamine in 30 ml of methylene chloride is stirred at room temperature for 18 hours. The organic layer is saturated with water (1 χ 50 ml) and one Salt solution (1 × 50 ml) and then washed over sodium sulfate dried. The solvent is removed in vacuo and the residue is poured over 150 g of silica gel using acetone as the solvent chromatographed, each fraction of 7 ml being collected. Fractions 60-100 are combined and concentrated to give 800 mg of the desired product.

NMR (4, CDCl ₃ ): 2.06 (3H) s; 2.33 (6H) s; 2.63 (2H) d; 3.2 (3H) s and 7.2-8.2 (2H) m.

809846/0937

Similarly, using the appropriate reagents as starting materials and following the procedure described above, the synthesis of the following compounds was carried out: 1l-acetyl-4 "-deoxy-4" - (3,4,5-trichlorophenylsulfonylamino) -oleandoinycin; 1l-Propionyl-4 "-deoxy-4" - (2,4,6-trichlorophenylsulfonylamino) -oleandomycin and 1l-acetyl-4 "-deoxy-4" - (2,3,5-trichlorophenylsulfonylamino) -oleandomycin.

Example 34

1l-acetyl-4 "-deoxy-4" - (2-hydroxy-3,5-dichloropheny! Sulfonylamino) -öleandomycin

The procedure of Example 33 is repeated, the starting materials being 2.55 g = 3.5 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin, 954 mg = 3.65 mmol of 2-hydroxy-3,5 dichlorophenylsulfonyl chloride and 518 μΐ = 3.75 mmol of triethylamine in 25 ml of methylene chloride are used and 483 mg of the desired product are obtained after chromatography over 220 g of silica gel.

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

Example 35

When using the required 1] -alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonyl chloride as starting materials and using Following the procedure of Example 33, the following analogous connections are made:

R ₁ 0 ι ,.

ORIGINAL INSPECTED 809846/0937

- L

CH-CO-

CH ₃ CO-

CH ₃ CO-

CH ₃ CO-

CK ₃ CH ₀ CO-

Cl J-Cl OH
ν \
Cl - \ Cl HO

CH ₃ CH ₉ CO-CK ₃ CH ₂ CO- CH ₃ CH ₉ CO-Cl

OH

Cl

HO \

Cl

Cl

Cl

OH

809846/0937

Example 36

11-Acetyl-4 "-deoxy-4" - (3-amino-4-chlorophenylsulfonylamino) -oleandomycin

A suspension of 500 mg of 10% palladium-on-charcoal in 50 ml of ethyl acetate, the 1.0 g of 1l-acetyl-4 "-deoxy-4" - (3-nitro-4-chlorophenylsulfonylamino) -oleandomycin contains, is in a hydrogen atmosphere at a Initial pressure of 3.5 atm at room temperature shaken overnight. The spent catalyst is filtered off and the solvent becomes removed in vacuo. The remaining, white foam is over 160 g of silica gel using acetone as the eluate and collecting 50 ml fractions chromatographed. The fractions containing the product are combined and concentrated under reduced pressure, whereby 450 mg of the desired material can be obtained.

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

In the same way, using the appropriate nitro compound of Example 16 made the following compounds:

1l-acetyl-4 "-deoxy-4" - (m-aminophenylsulfonylamino) -oleandomycin

NMR (i, CDCl ₃ ): 2.03 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.10 (3H) s; and 7.0-7.8 (4H) m and

1l-acetyl-4 "-deoxy-4" - (p-aminophenylsulfonylamino) -oleandomycin

NMR ( α, CDCl3,): 2.06 (3H) s; 2.31 (6H) s; 3.02 (3H) s and 6.4-7.8 (4H) dd.

Example 37

When using the required Kitroverbindungen of Examples 31 and Using 32 as starting materials and using the reduction procedure of Example 36, the following amino compounds are prepared: 11-acetyl-4 "-deoxy-4" - (2-amino-4-chlorophenylsulfonylamino) -oleandomycin; 11-acetyl -4 "-deoxy ~ 4" - (2-amino-4-ynethoxyphenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (2,4-diaminophenylsulfgnylamino) -oleandomycin; 11-propionyl-4 "-deoxy-4" - (2-amino-4-chlorophenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (3-amino-4-chlorophenylsulfonylamino) -oleandomycin;

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1] -Acetyl-4 "-deoxy-4" - (3-amino-5-chlorophenylsulfonylainino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (3-methoxy-5-aminophenylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (3-amino-4-methylphenylsulfonylamino) -oleandomycin and 11-Acety1-4 "-deoxy-4" - (3,5-diaminophenylsulfonylamino) -oleandomycin.

Example 38

11-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) -oleandomycin

To 100 g = 0.13 mol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin in 900 ml Methylene chloride is added to 593 ml of triethylamine and the solution is stirred for 10 minutes. Then 41.9 g = 0.213 mol of 3-methyl-2-thienylsulfonyl chloride are obtained in 300 ml of methylene chloride is added dropwise over a period of 1 hour, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is added to 2 l of water and the organic layer is separated off and then with water (2 χ 250 ml) and a salt solution (1 χ 250 ml) washed and dried over sodium sulfate. The solvent is removed in vacuo and the residue is poured over a 1.5 kg silica gel chromatographed containing column of 105 cm χ 6.5 cm. The product, which is eluted with acetone is collected in eluate fractions from 2.3 1 to 6 1. The fractions are combined and the solvent is used removed under reduced pressure to form a foam. Treatment of the remaining foam with diethyl ether yields 66.4 g of the desired product with a F. 184-185.5 C.

NMR («f, CDCl ₃ ): 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).

0.12 ml are added to 2 g of the above-mentioned free base in 15 ml of ethyl acetate Phosphoric acid is added and the resulting solution is at room temperature touched. After 20 minutes the formation of crystals begins, and after 2 hours it is filtered, washed with ethyl acetate and dried, whereby 1.3 g of 1l-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) -oleandomycin phosphate can be obtained.

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NMR (ό , 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 and 7.42 (2H).

Example 39

The procedure of Example 38 is repeated using as starting materials the appropriate sulfonyl chloride and 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin can be used to obtain the following analog connections:

0
ι

CH ₃ CO.

"r

OCH,

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NMR (δ, CI) Cl.,)

.J

2.03 (3H) s; 2.33 (6H) s; 2.38 (3H) s; 2.68 (2H) ra; 3.27 (3H) s; 6.08 _nd 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 (M) m and 7.18-7.39 (2H) m.

CH

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

^{2 5}

2.06 (3H) s; 2.33 (6H) s; 2.65 (2H) m; J, 22 (3H) s; 6.73 _nd 7.45 (2H).

: .D8 (3H) s; 2.3i (6H) s; 2.5Λ (3H) s; 2.07 (2H) s: 3.23 (3H) s; 6.73 and 7. from CH).

Example 40

The procedure of Example 38 is repeated again, using as starting materials the required sulfonyl chloride and the appropriate 11-alkanoyl-4 "-deoxy-4" -amino-oleandonycin can be used to obtain the following analogous compounds: 1l-acetyl-4 "-deoxy-4" - (3-ethyl-2-thienylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (3-methyl-2-thienyl sulfonyl amino) oleandomycins 1 l-acetyl-4 "-deoxy-4" -f £ "-ethyl-2-pyrrylsulfonylamino) oleandomycin; 1l-propionyl-4 "-deoxy-4" - (4-ethyl-2-

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- «- 2820 A11

thienylsulfonylamino) oleandoraycin; 1l-acetyl-4 "-deoxy-4" - (1-ethyl-3-pyrrylsulfonylamino) -oleandomycin; 1l-propionyl-4 "-deoxy-4" - (5-ethyl-2-furylsulfonylamino) -oleandomycin; 1l-acetyl-4 "-deoxy-4" - (4-ethyl-3-furylsulfonylamino) -oleandomycin and 1I-acetyl-4 "-deoxy-4" - (3-ethyl-2-furylsulfonylamino) -oleandomycin.

Example 41

11 -Acetyl ^ "- deoxy ^^ CS-carbomethoxy-Z-pyrrylsulfonylaminoj-oleandoinycin

A solution of 2.96 g = 0.0041 mol of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 0.62 ml of triethylamine in 50 ml of dry methylene chloride at ice bath temperature is cooled, is added in portions with 1.0g = 0.0044 mol Z-carbomethoxy-S-pyrrylsulfonyl chloride. The reaction mixture is allowed to warm to room temperature and stirred for 3.5 hours, then it is poured into 200 ml of water. The pH of the aqueous Layer is adjusted to 9.5 with 1N aqueous sodium hydroxide solution, and the methylene chloride layer is separated, washed successively with water and saturated saline, and dried over sodium sulfate. Removal of the solvent under reduced pressure gives 3.8 g of the raw product in the form of a white foam.

This foam is then placed over a 3.25 cm silica gel column χ 38 cm chromatographed using acetone as the eluate. The factions 40-220, each consisting of about 10-12 ml, were collected and united. Removal of the eluate solvent in vacuo gives 3.4 g of the desired product in forir. of a white foam.

XMR (i, CDCl ₃ ): 2.05 (3H) s; 2.58 (6H) sj 2.67 (2H) m; 3.25 (3H) s; 3.90 (3II) s; 7.20 (lH) m and 7.52 (lH) m.

Example 42

The procedure of Example 41 is repeated using the appropriate Sulfonyl chloride and 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin as starting materials can be used to obtain the following analog connections:

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282Q411

! I
CH ₃ CO π ,,,

'Ό.

OCH

NMR (6, CDCl ₃ )

CH ₃ O ₂ C

2.09 (3H) s: 2.32 (6H) s; 2.69 (2H) m; 3.22 (3H) s; 3.95 (3H) s; 7.61 _nd 7.75 (2H).

CH ₃ O ₉ C

2.11 (3H) s; 2.34 (6H) s; 2.70 (2H) m; 3.24 (3H) s; 3.94 (3H) s; 8.06 and 8 _r 23 (2K).

CH ₃ O ₉ C

2.08 (3H) s; 2.29 (6H) s; 2.67 (2H) s; 3.18 (3H) s; 3.94 (3H) s; 7 ,, 02 and 7.20 (2H).

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2820A11

Example 43 4 "-Deoxy-4" - (p-chlorophenylsulfonylamino) -oleandomycin

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 of acetone. The insoluble triethylamine hydrochloride is filtered off and the filtrate is over 180 g Chromatographed silica gel using acetone as the eluting solvent and collecting 50 ml fractions. Fractions 18-27 are combined and concentrated under reduced pressure to give 1.10 g of the desired product.

NMR (O, CDCl3-): 2.33 (6H); 2.83 (2H) d; 3.06 (3H) s and 7.2-8.4 (4H) m.

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■ Example · 44

[The procedure of Example 43 is repeated using as starting materials the appropriate sulfonyl chloride and 4 "-deoxy-4" -amino-oleandomycin! can be used to obtain the following compounds:

0CH "

^R 2 Cl -

Cl

CF,

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Example 45

4 "-Deoxy-4" - (p-toluenesulfony1amino) -öleandomycin

Using a procedure similar to that in Example 43, 30 g = 4.0 mmol 4 "-deoxy-4" -amino-oleandomycin, 782 mg = 4.1 mmol) p-toluenesulfonyl chloride and 424 mg = 4.2 mmol of triethylamine in 25 ml of methylene chloride at ambient temperature stirred overnight. During work-up, the crude product is chromatographed over 180 g of silica gel while collecting 10 ml of fractions. Fractions 90-148 are combined and concentrated to dryness to give 1.4 of the desired product.

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

Using a similar procedure, 4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin is also used manufactured.

NMR (/, CDCl ₃ ): 2.29 (6H) s; 2.88 (2H) m; 3.2 (3H) s; 5.6 (IH) m and 7.33 (3H) m.

Example 46

Using 4 "-deoxy-4" -amino-oleandomycin and the required Sulfonyl chloride as starting materials and using the procedure of Example 43, the following analogous compounds are synthesized:

HO ""

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CH "

// V

8098A6 / 093?

Example 47

1l-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin

To a solution of 17.1 g = 82.3 mmol ß-Bromäthansulfonylchlorid in 200 ml of methylene chloride, cooled to -78 C and maintained under a nitrogen atmosphere, a cold (-78 ⁰ C) solution of 30 g = 41.1 mmol 11-Acetyl-4 "-deoxy-4" -amino-oleandoinycin and 16.7 g = 164 mmol of triethylamine in 100 ml of methylene chloride were added. After stirring for 1.3 hours at -78 ° C., the reaction mixture is poured into water and the pH is adjusted to 7.3 by adding solid sodium bicarbonate. The organic phase is separated off, dried over sodium sulfate and concentrated in vacuo, 43.5 g of a yellow foam being obtained. The remaining material is slurried in ether and filtered. The filtrate is concentrated under reduced pressure, whereby 20.3 g of crude product are obtained, this is chromatographed over 800 g of silica gel using chloroform-methanol (95: 5 v / v) as the eluting solvent. The fractions containing the product are combined and concentrated to give 5.1 g of product.

NMR (/, 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 48

1l-acetyl-4 "-deoxy-4" - (ß-bromoethylsulfonylamino) -oleandomycl · n

To a solution of 500 mg = 0.68 mmol of 1l-acetyl-4 "-deoxy-4" -amino-oleandomycin and 882 mg = 8.2 mmol of 2,6-lutidine in 4 ml of methylene chloride, precooled to -4 ° C and under a nitrogen atmosphere, will be 854 mg =
4.0 mmol ß-bromoethanesulfonyl chloride in 2 mL methylene chloride, cooled
to -2 C, added. After stirring at -2 ° C. for 1.75 hours, 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 off, dried over sodium sulfate and
concentrated to an amber oil. The residual oil is chromatographed over 42 g of silica gel using chloroform-methanol (95: 5, vol: vol.) As the eluate solvent, 52.5 mg of the desired
Product can be obtained.

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

Example 49

11-acetyl-4 "-deoxy-4" - (2-diethylaminoethylsulfonylamino) -oleandomycin

To a solution of 1.0g = 1.22 mmol of 1l-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin in 5 ml of benzene, 892 mg = 12.2 mmol of diethylamine are added, and the reaction mixture obtained is under a nitrogen Stirred at ambient temperature for 48 hours. The solvent and the excess diethylamine are removed in vacuo, and the product is obtained as a white foam, which slowly crystallizes, in a yield of 940 mg with a melting point of 85-99 ° C.

NMR (i, CDCl ₃ ): 2.05 (3H) s; 2.30 (6H) s; 2.36-2.73 (4H) q; 2.63 (2H) s; and 3.4 (3H) s.

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282Q411

“Example 50

The procedure of Example 49 is repeated, using as starting materials the appropriate 11-alkanoyl-4 "-deoxy-4" -amino-oleandomycin and the ent-ί speaking, secondary ainin can be used to obtain the following compounds j:

OCH,

CH ₃ CO- N (CH ₃ ) ₂ CH ₃ CO- N (CH ₃ ) C ₂ H ₅ - CH ₃ CO- N (Ii-C ₃ H ₇ ) ₂ CH CO- N (XC ₃ H ₇ ) 2 CH ₃ CO- N (C ₂ H ₅ ) Ii-C ₃ H ₇ CH CO- N (CH ₃ HC ₃ H ₇ CH ₃ CH ₂ CO- N (CH ₃ ) 2 CH ₃ CH ₂ CO- N (CH ₃ ) C ₂ H ₅ . CH ₃ CH ₉ CO- N (C ₂ H ₅ ) ₂ CH ₃ CH ₂ CO- iN Ul-L ₃ H ₇ J ₂ CH ₃ CH ₂ CO- Na-C ₃ H ₇ ) ₂ CH ₃ CH ₂ CO- N (CH ₃ ) 1, -C ₃ H

809846/0937

Example 51

11-Acetyl-4 "-deoxy-4" - (methylthioethylsulfonylamino) -oleandomycin

A suspension of 800 mg = 0.98 mmol of 11-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin and 475 mg = 3 mmol of potassium carbonate in 10 ml of benzene is stirred while methyl mercaptan is in the suspension for 30 see is initiated. The tightly sealed container is over Stirred overnight at room temperature. The excess mercaptan is removed under reduced pressure and the reaction mixture becomes added to a mixture of benzene-water. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo, 805 mg of the product being obtained in the form of an oil.

NMR (j, CDGl _3): 1.98 (3H) s; 2.05 (3H) s; 2.20 (6H) s; 2.57 (2H) s and 3.30 (3H) s.

Example 52

Using the appropriate mercaptan and 11-acetyl-4 "-deoxy-4" - (vinylsulfonylamino) -oleandomycin As starting materials and using the procedure of Example 51, the following compounds are obtained synthesized:

(CH ₃ )

NHSO ₂ CH ₀ CH ₀ -Z

OCH,

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ORIGINAL! NiSPtCTED

NMR (<S,

CH ₃ CH ₂ S-

CH ₃ CH ₂ CH ₂ S-

2.03 (3H) s; 2.30 (6H) s; 2 _; 63 i2H) s; and 3.40 (3H) s.

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

2 _; O7 (3H) s; 2.30 (IH) s; 2.61 (2H) s; and 3.42 (3H) s.

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 again, the suitable 1 l-alkanoyl-4 "-deoxy-4 ^I! - (vinylsulfonyl-

. amino) -oleandomycin and mercaptan can be used to produce the following, analog connections:

OCH,

CH ₃ CO- ( ρττ \ PUC
^ Ln _n ) rtLnj "
J 2 CH ₃ CH ₂ CO- CH S- CH ₃ CIl ₂ CO- CH ₃ CH ₀ S- CH ₃ CH ₉ CO- HIGH ₀ CH ₂ S- CH ₃ CH ₂ CO- C ₆ H ₅ S- CH CH ₂ CO- CH ₃ CH ₂ CH ₂ S

809846/0937

Example 54

11-acetyl-4 "-deoxy-4" - (morpholinoethylsulfony! Amino) -öleandomycin

To a solution of 2.0 g = 2.44 mmol of 1l-acetyl-4 "-deoxy-4 ^ir - (vinyl sulfonylamino) -oleandomycin in 50 ml of benzene, 2, Ig = 24.4 mmol of morpholine are added, and the resulting The reaction mixture is stirred under a nitrogen atmosphere for 40 hours at room temperature. The solvent and excess morpholine are removed in vacuo to give the crude product in the form of a foam. The residue is triturated in hexane for 1 hour, then it is extracted from ethyl acetate-hexane recrystallized, 890 mg of product having a melting point of 95 ° C. being obtained.

NMR (ί, CDCl ₃ ): 2.06 (3H) s; 2.30 (6H) s and 3.42 (3H) s.

Example 55

11 -Acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin hydrochloride

To 8.7 g of 11-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin in 50 ml of dry ethyl acetate are 10 ml of an IN solution of hydrogen chloride added in ethyl acetate. The solution is concentrated to dryness in vacuo, and the monohydrochloride salt that remains is triturated with ether and filtered.

Example 56

1l-Acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin-phosphate

To a solution of 15.0 g of 1l-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin 1.0 ml of phosphoric acid are added to 100 ml of ethyl acetate. The suspension obtained is 4 hours at room temperature touched. The solids are filtered off, washed with ethyl acetate and dried, 12.5 g of the desired salt having a melting point of 168 ° C (dec.) can be obtained.

In a similar manner are prepared: 1l-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) -oleandomycin-phosphate, M.p. 184-188 ° C and

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282Q411

1I-acetyl-4 "-deoxy-4" - (p-chlorophenylsulfonylamino) -oleandomycin-phosphate, M.p. 204-205 ° C.

PREPARATION A

4 "-deoxy-4" -oxo-oleandomycine

I. 11-acetyl-4 "-deoxy-4" -oxo-oleandomycin ^r

a) 11,2'-diacetyl-4 "-deoxy-4" -oxo-oleandomycin ^r

To 4.5 g of N-chlorosuccinimide, 50 ml of benzene and 150 ml of teluene in one dry flasks equipped with a magnetic stirrer and nitrogen inlet, which is cooled to -5 ° C., 3.36 ml of dimethyl sulfide are added. After stirring for 20 minutes at 0 C, the contents are cooled to -25 C and treated with 5.0 g of 1l, 2'-diacetyl-oleandomycin in Treated 100 ml of toluene. Cooling and stirring are continued for 2 hours, then 4.73 ml of triethylamine are added. The reaction mixture is stirred at 0 C for 15 minutes, then it is poured into 500 ml of water. The pH is adjusted to 9.5 with IN aqueous sodium hydroxide solution, and the organic layer is separated, washed with water and a saline solution and dried over sodium sulfate. Removal of the solvent in vacuo gives 4.9 g of the desired product in the form of a Foam,

NMR (4 , CDCl ₃ ): 3.48 (3H) s, 2.61 (2H) m, 2.23 (6H) s and 2.03 (6H) s.

b) 11 -acetyl ^^ deoxy ^^ oxo-oleandomycin

A solution of 4.0 g of 11,2'-diacetyl-4 "-deoxy-4" -oxo-oleandomycin in 75 ml of methanol is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to to receive the product as a foam. A solution of the residue in Diethyl ether on treatment with hexane gives 2.6 g of the product in the form of a white solid with a temperature of 112-117 ° C.

NMR (j, CDCl ₃ ): 3.43 (3H) s, 2.60 (2H) m, 2.23 (6H) s and 2.01 (3H) s.

809846/0937

28204t!

Similarly, using 11,2'-dipropionyl-4 "-deoxy- <4" -oxo-oleandomycin or 1l-propionyl-2'-aeetyl-4 "-deoxy- 4 "-oxo-oleandomycin in the above-mentioned procedure 11-propionyl-4" -deoxy-4 "-oxo-oleandomycin manufactured.

II. 4 "-deoxy-4" -oxo-oleandomyci n

a) 2'-acetyl - ^^ deoxy ^^ oxo-oleandomycin

0.337 ml of dimethyl sulfide are added to a cloudy solution of 467 mg of N-chlorosuccinimide in 20 ml of toluene and 6 ml of benzene, cooled to -5 ° C. and kept under a nitrogen atmosphere. After stirring at 0 ° C. for 20 minutes, 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 -20 ° C., then 0.46 ml of triethylamine are added. The reaction mixture is kept at -20.degree. C. for a further 5 minutes, then it is allowed to warm to 0.degree. The mixture is poured into 50 ml of water and 50 ml of ethyl acetate with stirring. The pH of the aqueous mixture is adjusted to 9.5 by adding aqueous sodium hydroxide solution. The organic layer is then separated, dried over sodium sulfate and concentrated in vacuo to give 1.5 g of a white foam. Trituration with diethyl ether gives 864 mg of crude product, which at the twice recrystallization from methylene chloride-diethyl ether 212 mg of pure product with F. supply 183 to 185.5 ⁰ C.

Analysis for CH, 0 N

calculated: C = 61.1; H = 8.5; N = 1.9% found: C = 60.9; H = 8.4; N = 1.9%

NMR (S, CDCl ₃ ): 5.60 (1H) m, 3.50 (3H) s, 2.73 (2H) m, 2.23 (6H) s and 2.03 (3H) s.

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

A solution of 1.0 g of 2'-acetyl-4 "-deoxy-4" -oxo-oleandoinycin in 20 ml of methanol is stirred at room temperature overnight. The solution is concentrated in vacuo to give the desired product is obtained as a white foam in an amount of 937 mg.

NMR (S , CDCl ₃ ): 5.60 (IH) m, 3.50 (3H) s, 2.85 (2H) m and 2.26 (6H) s.

PREPARATION B

4 "-deoxy-4" -amino-oleandomycins

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

To a suspension of 10 g of 10% palladium-on-charcoal in 100 ml Methanol is added to 21.2 g of ammonium acetate and the resulting slurry is mixed with a solution of 20 g of 1l-acetyl-4 "-deoxy-4" -oxo-oleandomycin treated in 100 ml of the same solvent. The suspension is at room temperature in a hydrogen atmosphere shaken at an initial pressure of 3.5 atm. After 1.5 hours the catalyst is filtered off and the filtrate becomes a with stirring A mixture of 1200 ml of water and 500 ml of chloroform was added. The pH is adjusted from 6.4 to 4.5, and the organic Layer is separated. After a further extraction with 500 ml of chloroform, the aqueous layer is treated with 500 ml of ethyl acetate, and the pH is adjusted to 9.5 with IN sodium hydroxide solution. The ethyl acetate layer is separated and the aqueous layer is extracted again with ethyl acetate. The ethyl acetate extracts are combined, dried over sodium sulfate and concentrated to 18.6 g of a yellow foam, which upon crystallization from diisopropyl ether 6.85 g of the purified product with a temperature of 157.5-16O ° C delivers.

NMR ( i , CDCl ₃ ): 3.41 (3H) s, 2.70 (2H) m, 2.36 (6H) s and 2.10 (3H) s.

The other epimer, which is present in the raw foam in an amount of 20-25%, is obtained by gradually concentrating and filtering the mother liquors.

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282Q411

In a similar manner, using 11-propionyl-4 "-deoxy-4" -oxo-oleandomycin in the same procedure 1l-propionyl-4 "-deoxy-4" -amino-oleandomycin obtain'.

II. 4 "-deoxy-4" -amino-oleandomycin

A solution of 20 g of 2 ^f -acetyl-4 "-deoxy-4" -oxo-oleandomycin in 125 ml of methanol is treated with 21.2 g of ammonium acetate after stirring at room temperature overnight. The resulting solution is cooled in an ice bath and treated with 1.26 g of sodium cyanoborohydride. The cooling bath is then removed and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into 600 ml of water and 6 £) 0 ml Diäthylather, and the pH is adjusted from 8.3 to 7.5. The ether layer is separated and the aqueous layer is extracted with ethyl acetate. The extracts are set aside and the pH of the aqueous layer is adjusted to 8.25. The diethyl ether and ethyl acetate extracts adjusted to this pH are set aside and the pH is raised to 9.9. The diethyl ether and ethyl acetate extracts with this pH value are combined, washed successively with water (Ix) and saturated saline solution and dried over sodium sulfate. The latter extracts, taken up at a pH of 9.9, are concentrated to a foam and chromatographed over 160 g of silica gel using chloroform as the loading solvent and initial eluate. After 11 fractions, which amount to 12 ml per fraction, have been removed, the eluate is changed to 5% methanol - 95% chloroform. For fraction 370 the eluate is changed to 10% methanol - 90% chloroform, and for fraction 440 15% methanol - 85% chloroform is used. Fractions 85-260 are combined and concentrated to dryness in vacuo to give 2.44 g of the desired product.

NMR (i , CDCI.): 5.56 (1H) m, 3.36 (3H) s, 2.9 (2H) m and 2.26 (6H) s.

809846/0937

Claims (19)

PATENTANWÄLTE DR.A.VAN DERWERTH DR.FRANZ LEDERER REINER F.MEYER DlPL-ING. (1934-1974) DIPL-CHEM. DlPL-ING. 8000 MUNICH 80 LUCILE-GRAHN-STRASSE TELEPHONE: (089) 472947 TELEX: 524624 LEATHER D TELEGR .: LEATHER PATENT Müncfeen, April 18, 1978 P.C. (Ph) 5870 / A PFIZER INC. East 42nd Street, New York, N.Y. 10017, USA claims 1.J4 "-Sulfonylamino-oleandomycin derivatives of the following general Formula: and the pharmaceutically acceptable acid addition salts thereof, in which R is an alkyl radical having 1 to 3 carbon atoms, the 1,1,1-trifluoroethyl radical, the phenyl radical, one by fluorine, chlorine, bromine, iodine, 809846/0937 Hydroxy, methoxy, cyano, carboxamido, nitro, amino, carbomethoxy, Carbobenzyloxy, carboxy, trifluoromethyl, alkyl of 1 to 4 carbon atoms or acetamido monosubstituted phenyl radical, a phenyl radical disubstituted by chlorine, nitro, amino, methoxy or methyl, a trichlorophenyl, hydroxydichlorophenyl, benzyl, naphthyl, thienyl, Chlorothienyl, pyridyl, 2-acetamido-5-thiazolyl, 2-acetamido-4-methyl-5-thiazolyl, 2-benzimidazolyl, dimethyl-2-pyrimidinyl, pyrryl, Furyl radical, one by carbomethoxy or alkyl with 1 to 2 carbon atoms substituted thienyl, pyrryl or furyl radical or a 1-methyl-5-carbomethoxy-3-pyrryl radical is, and R. is an alkanoyl radical having 2 to carbon atoms. 2. Compound according to claim 1, characterized in that that R is a thienyl radical. 3. A compound according to claim 2, characterized in that R is the 2-thienyl radical and R is the acetyl radical. 4. A compound according to claim 2, characterized in that R is the 3-thienyl radical and R. is the acetyl radical. 5. A compound according to claim 1, characterized in that R is a substituted thienyl radical and R. is the acetyl radical. 6. A compound according to claim 5, characterized in that R is the 3-methyl-2-thienyl radical. 7. 4 "-Sulfonylamino-oleandomycin derivatives of the following formula: 809846/0937 ^0CH 3 and their pharmaceutically acceptable acid addition salts, wherein R " the phenyl radical, a phenyl radical substituted by chlorine, fluorine, methyl, methoxy or trifluoromethyl, a thienyl radical or an alkyl radical is hiienyl radical substituted by 1 to 2 carbon atoms. 8. A compound according to claim 7, characterized in that R _{2 is} a substituted phenyl radical. 9. A compound according to claim 8, characterized in that R "is a 4-chlorophenyl radical. 10. A compound according to claim 7, characterized in that R _{2 is} a thienyl radical. 11. A compound according to claim 10, characterized in that R _{2 is} the 2-thienyl radical. 12. A compound according to claim 10, characterized in that R _{2 is} the 3-thienyl radical. 13. A compound according to claim 7, characterized in that R _{2 is} a thienyl radical substituted by alkyl. IA. Compound according to Claim 13, characterized in that R _{2 is} the 3-methyl-2-thienyl radical. 15. 4 "-Sulfonylamino-oleandomycin derivatives of the following general formula: 8 0 9 8 4 6/0937 ,, OCH ₃ as well as their pharmaceutically acceptable acid addition salts, wherein R. is an alkanoyl radical having 2 to 3 carbon atoms, X and Y either individually each represent a hydrogen atom or X and Y taken together represent a carbon-carbon bond and Z a hydrogen atom, bromine atom, a dialkylamino radical, wherein alkyl I to Has carbon atoms, alkylthio radical, wherein alkyl has 1 to 3 carbon atoms possesses, phenylthio, 2-hydroxyethylthio or 1-morpholino with the proviso that when X and Y represent a carbon-carbon bond, Z represents a hydrogen atom. 16. A compound according to claim 15, characterized in that X and Y are each hydrogen atoms and R. is the acetyl radical. 17. A compound according to claim 16, characterized in that that Z is a bromine atom. 18. A compound according to claim 16, characterized in that Z is a methylthio radical. 19. A compound according to claim 15, characterized in that that X and Y represent a carbon-carbon bond and Z is a hydrogen atom. 809846/0937