HU180279B - Process for preparing 4"- deoxy-4"-sulphonyloxy-amino-olendomycin derivatives - Google Patents

Abstract

The invention relates to novel antibacterial agents, in particular a series of 4-deoxy-4-sulfonylamine oleandomycines and their pharmaceutically acceptable acid addition salts. oleandomycin prepared by adding to methylene chloride

Description

Process for the preparation of 4 "-deoxy-4 '' - silylphonylamino-oleandomycin derivatives

The present invention relates to antimicrobial agents, in particular 4 '-deoxy-4-sulfinylamino-oleandomycin derivatives, and their acid addition salts with pharmaceutically acceptable acids.

The production of oleandomycin after fermentation and its use as an antimicrobial agent was first disclosed in U.S. Patent 2,757 * 123 # As is known, natural oleandomycin is represented by Formula I. The formula indicates the numbering and position of the substituents commonly used for oleandomycin and other compounds of similar structure *

U.S. Patent Nos. 3,884,902 and 3,983,103 disclose and require erythromycin-4-sulfonic acid ester derivatives and N-sulfonyl erythromycylamine derivatives having a biological activity different from that of the compounds of the present invention. .

Several synthetic methods are known for altering the structure of oleandomycin, in particular by converting one, two or three of the three hydroxyl groups at the 2 *, 4 'and 11 positions of the oleandomycin into an ester group. In addition, similar structural changes are disclosed in U.S. Patent No. 3,022,219, which discloses the use of lower alkanoyl groups of 3-6 carbon atoms other than acetyl.

-1183.279

The present invention relates to a process for use as an antibacterial agent of formula (11), (III) and (IV) wherein R is an alkyl group having 1 to 3 carbon atoms;

pyridyl; 1,1,1-trifluoroethyl group; flax, or optionally with fluorine, chlorine, bromine or iodine, hydroxy. methoxy, cyano, carboxamido, nitro. phenyl, trichloro monosubstituted with amino, methoxycarbonyl, benzyloxycarbonyl, carboxyl, trifluoroethyl, alkyl or acetamido containing 1 to 4 carbon atoms or substituted with chlorine, nitro, amino, methoxy or methyl groups; - phenyl; feni1 hydroxy-methylene group; benzyl; naftilesoport; thienyl; chloro-thienyl; 2-acetamido-tiazo1-5-13 group; 2-acetamido-4-methylthiazol-5-yl; benzimiclazol-2-yl; dimethylpyrimidin-2-yl-4-pyrryl; furan; thienyl, pyrril or furyl, monosubstituted with methoxycarbonyl or alkyl having 1 to 2 carbon atoms; cut 1-methyl-3-methoxycarbonylpyrryl;

R 1 is C 1 -C 3 alkanoyl;

R ₂ is phenyl, which is unsubstituted or optionally substituted with chloro or fluoro, methyl, methoxy or trifluoromethyl; or thienyl, unsubstituted or optionally substituted with 1 to 2 carbon atoms in the alkyl group;

X and Y are both hydrogen or taken together to represent a carbon-carbon ridge; and

Z represents a hydrogen atom, a bromine atom, a lower alkylamino group having a di- (1-3C) group, a lower alkylmercapto group containing a (1-3C) atom, a phenylmercapto group, a 2-hydroxyethylmercapto- or a morphilin-1-yl group;

with the proviso that when X and Y together represent a carbon-carbon bond, then Z is hydrogen.

Due to their preparation, the amine intermediates of the compounds of the present invention are mixtures of epimers / isomers at the 4 "optical center. Therefore, the sulfonamides of the present invention prepared from said amines are also mixtures of epimers. In our experiments, we have found that the final sulfonamides contain both epimers and the proportion thereof depends on the synthetic method used to prepare the amine intermediate. If the isolated product is predominantly composed of one epimer, the epimer may be obtained in pure form by recrystallization of the product from a suitable solvent until the melting point is no longer changed. In this case, the smaller amount of the other epimer is enriched in the mother liquor and can be isolated therefrom by conventional means, for example by distilling off the solvent and recrystallizing the residue or purifying it by chromatography.

It is true that a mixture of the above-mentioned epimers can be separated into its components by methods known per se, but for practical reasons it is preferable to use the dense mixture of epi-2180.279 as isolated from the reaction mixture. However, it is often preferred to recrystallize said mixture of epimers from a suitable solvent at least once by column chromatography, solvent partitioning, or trituration with a suitable solvent. In fact, such purification operations can, if not necessarily to separate the epimers, remove foreign impurities such as unreacted starting material and unwanted by-products.

'The absolute configuration of each epimer has not been determined. Both epimers of a given compound exhibit the same type of activity, e.g., an antibacterial activity.

Preferred compounds of formula (TL) according to the invention are those in which R is thienyl which is unsubstituted or substituted by lower alkyl or methoxycarbonyl containing 1 to 2 carbon atoms.

Preferred compounds of formula (III) according to the invention are those in which R1 is phenyl or thienyl substituted with unsubstituted or lower alkyl having from 1 to 2 carbon atoms.

Preferred compounds of formula IV according to the invention are those wherein X and Y are both hydrogen and R 1 is acetyl.

Among the compounds of the invention, 11-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) -oleandomycin, 11-acetyl-4-deoxy-4- / 3-thienyl are preferred for their antibacterial activity. sulfonylamino-oleandomycin, 11-acetyl-4-deoxy-4- (3-methyl-2-thienylsulfonylamino) -oleandomycin, 4 "-doxy-4 ^M - [(p-chlorophenyl) -sulfonylamino-oleandomycin, 4 ^n- deoxy-4 "- / 2-thienylsulfonylamino-oleandomycin, 4-deoxy-4" - / 3-thienylsulfonylamino / -oleandomycin, 4 " - deoxy-4 "- (3-methyl-2-thienylsulfonylamino) -oleandoiricin, 11-acetyl-4" -deoxy-4 '' - (2-bromoethylsulfonylamino) -oleandomycin, 11-acetyl-4 ', ^1- deoxy-4- (2-methylmercaptoethylsulfonylamino) oleandomycin and 11-acetyl-4''- deoxy [4- (vinylsulfonylamino) -] oleandomycin.

The preparation of the 4'-deoxy-4-sulfonylamino-oleandomycin derivatives of formula (11) and (111) according to the invention is illustrated in Reactions A and B. In the formulas (11), (111) and (V) and in the reagents used for the necessary transformations, R, R 1 and R ₂ are as defined above.

Reactions illustrated in Reaction Equations A and B according to a preferred embodiment of the process of the invention are carried out by reacting ε 4-deoxy-4-amino-oleandomycin or a derivative thereof in the presence of an acid scavenger with an appropriate sulfonic acid halide in an inert solvent. .

In practice, a molar 4 '-aminooleandomycin derivative is reacted molar with 2-3% excess sulfonic acid halide. The acid acceptor can be organic or inorganic and is used in an molar excess of 4-6% molar per mol of 4-amino oleandomycin.

The acid scavenger may be, for example, an alkali metal or alkaline earth metal hydroxide, anhydride, or carbonate, an agent.

-3180,279 chisels, tertiary amines, or secondary amines that are sufficiently spatially inhibited to be unreacted, such as diisopropylamine. Preferably, tertiary amines are used as the acid scavenger. Within this group, triethylamine is particularly preferred.

The inert solvent used for the reaction must be such as to dissolve the starting materials sufficiently and not to react with either the starting materials or the products. Preferably, water-miscible or water-immiscible polar solvents are used. A particularly preferred solvent is methylene chloride and a mixture of acetone and water.

Since the amino-oleandomycin derivatives are partially decomposed upon heating, the compounds of formula (11) and (111) are preferably prepared at a temperature of 0 ° C to 25 ° C.

The duration of the reaction is not critical and always depends on the reactivity of the particular starting materials, the concentration of the solution and the reaction temperature. If the reaction is carried out at room temperature in the concentrated solutions described below, the conversion is essentially complete within 2-48 hours.

Once the reaction is complete, the reaction mixture can be worked up by two methods known per se. In the first method, the mixture is poured into water, the water-immiscible solvent is separated with the product dissolved therein, and the crude product is obtained by distilling off the solvent. If the reaction is carried out in a water miscible solvent, the reaction mixture is poured over water and extracted with a water immiscible solvent such as methylene chloride.

A second method for working up the reaction mixture is to distil off the solvent from the reaction mixture and dissolve the product in acetone with the base used as the acid scavenger and the hydrochloric acid salt liberated during the reaction. Distillation of the acetone yields the crude product.

The crude product or its solution in acetone can be purified by column chromatography or by recrystallization according to methods known per se.

In a further preferred embodiment of the process according to the invention, compounds of formula IV where X and Y are a carbon-carbon bond and Z is a hydrogen atom are prepared by the use of an 11-alkanoyl-4 The deoxy-4 '' -aminoleandomycin derivative is reacted with 2-molar 2-bromoethanesulfonic acid chloride in the presence of a four-fold molar amount of unperturbed tertiary amine such as triethylamine.

The starting materials were mixed at -78 ° C and the reaction mixture was kept at this temperature for 1-2 hours.

The solvents used to carry out these reactions are the same as those used in the preparation of the compounds of formula (11a) and (111), with the additional proviso that they are not frozen at the preferred reaction temperature. A preferred solvent for this purpose is methylene chloride.

The reaction mixture is worked up in the same manner as in the preparation of compounds of general formula (11) or (111).

Apart from the fact that the 11-alkanoyl-4 "-4180279 thus obtained

-Deoxy-4 ^M - (vinylsulfonylamino) -oleandomycin derivatives themselves have antimicrobial activity and are valuable intermediates from which further antimicrobial compounds can be prepared as detailed below.

If a II-alkanoyl-4 "-deoxy-4 ^,, amino-oleandomycin from about -4 ° C - in, at 0 ° C for 10 to 12-fold molar amount of a hindered amine such as 2 ^ 6-lutidine / 2, In the presence of 6-dimethyl-1-pyridine, in a neutral solvent, 5-7 times molar amounts of 2-bromoethanesulfonic acid chloride are reacted with the appropriate 11-alkanoyl-4 '-deoxy-4- / 2-bromo-m-ethane. and ulfoni-1-a mino / oleando mycine esters are obtained (Formula IV, X and Ϊ are both hydrogen and Z is bromo).

At a temperature of about 0 ° C, the reaction is preferably carried out for 1-2 hours. At this reaction temperature, methylene chloride is preferably used as the solvent.

The product is isolated from the reaction mixture as described in the preparation of compounds of formula (11) and (III) and purified.

For the preparation of the other compounds of formula (IV), an 11-alkanoyl-4 '-deoxy-4' ^, - (vinylsulfonylamino) -oleandomycin derivative is introduced into the appropriate amine or mercaptan, as illustrated in Reaction C, .

In a preferred embodiment of the above process, the vinylsulfonylamine is reacted with a 3 to 10-fold molar amount of a given amine or mercaptan in a semi-solvent at room temperature for 12-48 hours. The solvent requirements are the same as for the preparation of the compounds of formulas (11) and (111). Benzene is preferably used as the solvent.

When mercaptan is used in the above reaction, an organic or inorganic base is used to facilitate the reaction. Preferably, at least the same amount of base is morally used relative to the vinylsulfonylamino compound. Potassium carbonate is preferably used for this purpose.

After completion of the reaction, the solvent and excess reagents can be distilled off under reduced pressure, or the reaction mixture is poured into water, the organic solvent solution is separated off and the solvent is distilled off.

The starting 4 ^H- amino derivatives required for the preparation of the antibacterial compounds of this invention are prepared by oxidation of the natural oleandomycin followed by reductive amylation of the ketone thus obtained, as described in more detail below.

Of course, when utilizing the activity of the compounds of the present invention which are capable of forming salts, they may be used in the form of their pharmaceutically acceptable acid addition salts for use as chemotherapeutic agents. Although some salts cannot be used in the preparation of pharmaceutical formulations due to their poor solubility in water, unfavorable toxicity, or low tendency to crystallize, they may liberate the pharmaceutically acceptable base from poorly water-soluble or toxic salts or convert them into the desired pharmaceutically acceptable acid. salt * ·

-5180.279

Examples of pharmaceutically acceptable acids are hydrochloric acid, hydrobromic acid, iodohydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, gluconic acid, aspartic acid, glutamic acid a-laoglutamic acid.

The novel 4 '* - deoxy-4' aminooleandomycin derivatives of the present invention are active in vitro against a number of Gram-positive microorganisms such as Staphylococcus aures * and Streptococcus pyogenes, and some Gram-negative microorganisms, as opposed to, for example, spherical or ellipsoidal shapes. Their activity against various microorganisms can be readily detected by in-vxtro measurement on a liquid infusion medium (Chapman) using a double dilution series. Due to their in vitro potency, they can be used in the form of ointments, creams and the like for topical treatment, in addition to sterilization, for example, for the sterilization of equipment in a sick room, and as industrial, antimicrobial agents such as water, sludge prevention

For in vitro use, such as topical application, it is often advantageous to admix the active ingredient with a pharmaceutically acceptable carrier, such as a vegetable or mineral oil, or a softening cream. These compounds may also be dissolved or dispersed / finely divided / in liquid vehicles or solvents, such as water, alcohol * glycols or mixtures thereof, or even in other pharmaceutically acceptable media, i.e., media that do not adversely affect the active ingredient. In such formulations, the amount of active ingredient will generally be from about 0.01% to about 10% by weight of the total composition.

In addition, many of the compounds of the present invention have been shown to be effective against Gram-positive microorganisms when administered orally / orally / or parenterally / bypassing the gastrointestinal tract to animals or humans. Their effectiveness in vivc extends to fewer microorganisms. activity is determined in the usual manner: mice of substantially equal body weight are infected with the test microorganism, and the test compound is administered orally or parenterally. This is accomplished in practice by, for example, 10 mice intraperitoneally (intraperitoneally) challenged with amounts of appropriately diluted cultures containing the lowest dose of LD ₁₀ µg / dose to kill approximately 1 to 10 times each animal. At the same time, a control experiment is carried out by increasing the dilution of the control animals to check for changes in the virulence / infectivity of the test microorganism. Half an hour after infection, the test substance is administered, and after 4, 24 and 48 hours, the test substance is repeated. Surviving mice are observed for 4 days and recorded.

When administered in vivo, the compounds of the invention may be administered, for example, orally or parenterally, e.g., subcutaneously / subcutaneously / or intramuscularly / intramuscularly / by injection, at a daily dose of about 1 mg to about 10 mg / kg body weight. target number

Doses of about 61 mg to about 2,780,279 g / day and about 2 mg to about 100 rags per kg body weight, preferably about 2 mg to about 50 mg, are administered. For the preparation of parenteral injectable compositions, aqueous vehicles such as water, isotonic / blood-like osmotic pressure / saline, isotonic dextrose solution, Ringer's solution, or non-aqueous vehicles such as vegetable oil / cotton seed oil may be used. oil, corn oil, sesame oil, dimethyl sulfoxide, or other non-aqueous carrier * which does not affect the pharmaceutical efficacy of the preparation and which is not toxic in the amounts used (glycerol, propylene glycol, sorbitol). In addition, such compositions may be prepared. which are dissolved just before administration. Suitable diluents for the preparation of such compositions are, for example, propylene glycol diethyl carbonate, glycerol, sorbitol and the like; buffer solutions, hyaluronidaz, local anesthetics and inorganic salts; these can be used to achieve the desired therapeutic effect of the composition. Additionally, various pharmaceutically acceptable carriers such as solid diluents, aqueous vehicles, non-toxic organic solvents may be added to the compounds of the present invention to form capsules, tablets, pills, powder mixtures, suspensions, solutions, or suspensions. The amount of the compounds of the invention in each dosage form may range from about 0.5% to about 90% of the total dosage form.

The invention is further illustrated by the following non-limiting examples.

Example 1 II-Acetyl-4-deoxy-4 '- [(2-thienyl) sulfonylamino] -oleandomycin: To 2.9 g / 4.0 mmol / 11-acetyl-4-anhydrous methylene chloride was added. '-Deoxy-4-amino-oleandomycin, 740 mg / 4.1 mmol (2-6) -enylsulfonic acid chloride and 0.58 ml (4.2 mmol) triethylamine, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (50 mL), the organic phase was separated, washed with brine and triturated with sodium sulfate. The solvent was distilled off under reduced pressure and the foam residue was purified by chromatography on silica gel using acetone as eluent. The product-containing fractions were combined and the solvent was distilled off under reduced pressure. Yield: 1.3 g.

NMR / CDC1 _X /: 8 2.03 / 3H / s; 2.30 / 6H / s; 2.63 (2H) d; ^p 3.16 / 3H / s; and 6.8-7.8 (3H / m).

Example 2

By following the procedure described in Example 1, starting from 11-acetate 1-4 '' - deoxy-4 '' - amino-oleandomycin and ε-appropriate sulfonic acid chloride, compounds of formula IIa containing the following groups R are prepared: to characterize the compounds we give their NMR spectra /:

R NMR (CDCl3),?

5-Chloro-2-thienyl-2.08 / 3H / s; 2.30 / 6H / s; 2.67 (2H / m);

- 3.23 / 3H / s; 6.87 and 7.45 / 2H / s.

160 279

Nuclear Magnetic Resonance Spectrum (CDCl3),

2-Acetamido-4-methyl- 2.09 / 3H / j 2142 / 6H / j 2.70 / 2H / m -5-thiazole and 3, > 26 / 3H / s. 2-Acetamido-5-Lymphoma 2.0 / 3H / a; í 1.33 / 6H / s; ; 2.40 / 3H / s; azoli1 group 2.66 /2 H/ d. 3.33 / 3H / the; and 7.86 / 1H / s. 3 Piridi1 group 2.03 / 3H / 9J 2.33 / 6H / the; 2.66 / 2H / dj 3.03 / 3H / d; and 7, > 40-9, 16 / 4H / m. Benzimidazol-2-yl 2.06 / 3H / s; 2.36 / 6H / j 2.71 / 2H / · s, -group 3.28 / 3H / SJ 7,36- -7.56 and 7.66 to 7.92 / 4H / m. Pyrimidine-4,6-Dimeti1 2.08 / 3H / the; 2.31 / 6H / 3J 2.59 / 6H / the; -2-yl 2.65 /2 H/ j 3.01 / 3H / sj and 7.11 / 1H / s. 3 Tieni1 group 2.07 / 3H / j 2.32 / 6H / s; 2.67 / 2H / j 3.20 / 3H / the; 7.32 / 1H / m; 7.43 / 1H / m; and 8, , 02 / 1H / m. 2-pyrryl group 2.06 / 3H / the; 2.29 / 6H / s; 2.64 / 2H / mj 3.26 / 3H / j 6.52 / 1H / m; 6.77 / 1H / and 7, , 29 / 1H / m. 1-Meth1-2-Me Toxic Car- 2.07 / 3H / j 2.62 / 6H / s; 3.25 / 3H / sj carbonyl-3-pirri1 tubes 3.83 / 3H / s; 3.95 / 3H / the; and 7.30 / 2H / powder m. 3 Füri1 group 2.08 / 3H / Ski 2.31 / 6H / s; 2.68 / 2H / m; 3.25 / 3H / 3J 6.74 / 1H / mj 7.48 / 1H / mj and 8 | , 00 / 1H / m.

Example 3.

ll-acetyl-4-deoxy-4- / p-amino-benzolszulfoni1 / -oleandoraicin

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 '* -deoxy- ^4H- amino-oleandomycin and 528 µl / 4.2 mmol / triethylamine in 20 ml of methylene chloride was added in small portions 855 p-chlorobenzenesulfonic acid chloride (4.1 mg) was added and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was triturated with acetone (10 mL). The insolubles were filtered off and the filtrate was chromatographed on 160 g of silica gel using acetone as eluent. Fractions of 10 ml were collected. 51-63. fractions were combined and the solvent was distilled off under reduced pressure to give 857 mg of pure product. 42-52.and 64-92. fractions yielded an additional 1.21 g of less pure product.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 2.12 / 32 / s; 2.36 / 6H / s; 2.73 / 2H / d;

3.13 / 3H / s; and 7.3-8.2 / 4H / q.

Alternatively, 20 g of ^ll-acetyl-4 "-deoxy-4-amino oleandotnicinből ^H, 7.24 g of p-chlorobenzenesulfonic acid chloride and 5.26 g of triethylamine and the reaction starting from 350 ml of acetone and 350 ml of water as a solvent, the desired product crystallizes from the reaction mixture, yield 17.1 g,

-8180.279 m.p. 202-203.5 0 ° · A sample is recrystallized from aqueous ethanol for analysis.

EXAMPLE 4 Starting from 11-Acetyl-4 '* - deoxy-4' -amino-oleandomycin and the corresponding sulfonic acid chloride, following the procedure described in Example 3, the following compounds of formula IIa are obtained:

1 H NMR (CDCl 3) / s cf

p-iodophenyl group 2.08 / 3H / 3.11 / 3K / p-Fluorophen1-cs opportun 2.08 / 3H / 3.06 / 3H / m-chlorophenyl group 2.03 / 3H / 3.10 / 3E / p-Chloro-feni1 group 2.03 / 3E / 3.23 / 3E / p-Fluorophenyl group 2.13 / 3E / 2.90 / 3H / p-bromo-phenyl 2.10 / 3H / 3.10 / 3H /

s; 2.33 / 6H / s; 2.70 </ 2H / d; s; and 7.5-8.2 / 4H / q.

s; 2.31 / 6H / s; 2.66 δ / 2H / d;

s; and 7.0-8.4 / 4H / m.

S 2.33 / 6H / s; 2.66 / 2H / d; sj and 7.3-8.0 / 4H / m.

s; 2.33 / 6H / s; 2.63 (2H) d;

s; and 7.2-8.4 / 4H / m.

s; 2.35 / 6H / a 2.70- / 2H / d; sj and 7.0-8.2 / 4H / m.

s; 2.33 / 6H / s; 2.66 / 2H / d; sj and 7.5-7-93 / 4H / m.

Example 5

11-Acet 11-4-Deoxy-4 '' - o -o-1-sulfonylamino / -oleandomycin

2.9 g of A, 0 mmol / 11-acyl-4-deoxy-4'-amino-oleandomycin, 780 mg / 4.1 mmol / o-tolylsulfonyl chloride, 0.58 mL / 4.2 mmol A mixture of triethylamine and 30 ml of methylene chloride was stirred at room temperature for 48 hours. The reaction mixture was poured into water (50 mL), the organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the yellow foamy residue was chromatographed on a 3 cm column on 200 g silica gel. Acetone was used as eluent and 10 ml fractions were collected. The TLC fractions containing pure product were combined and the solvent was distilled off under reduced pressure to give 1.3 g of product.

Nuclear Magnetic Resonance Spectrum (CDC1,): O 2.06 / 3B / sj 2.33 / 6H / sj 2.46 / 2H / d;

⁹ 2.73 / 3H / s and 7.1 to 8.2 / 4H / m.

EXAMPLE 6 Starting from 11-Acetyl-4 "-deoxy-4" -amiro-oleandomycin and the corresponding sulfonic acid chloride and following the procedure described in Example 5, R is prepared with the following general formula (IIa): compounds of formula:

_R NMR / CDC ^ /, p-methoxyphenyl group

2.03 / 3H / s; 2.30 / 6H / s; 2.66 / 2H / d;

3.06 / 3H / sj 3.83 / 3H / sj and 6.8-8.2 AH / m.

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R Nuclear Magnetic Resonance Spectrum (GDCl3),? p-tertiary-Butylphenyl o-Methoxyphenyl 2.03 / 3H / s; 2.33 / 6H / s; 2.66 '/ 2 H / d; 3.06 / 3H / a; and 7.3-8.0 (4H / m). 2.08 / 3H / s; 2.30 / 6H / s? 2.66 / 2H / dj 2.83 / 3H / s ₍ 4.03 / 3H / s) and 6.8-8.2 / 4H / m. p-tolyl 2.06 / 311 / ski 2.30 / 6H / e; 2.43 / 3H / s; 3.10 / 3H / s; 2.66 / 2H / d | 7.23-7.40 / 2H / d _? 7.76-7.93 / 2H / d.

Example 7 11-Acetyl-4 '' - deoxy-4-bis-bis-bisulfonylamino-oleandomycin

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 424 mg / 4.2 mmol / triethylamine in 30 ml of methylene chloride was added in an ice-bath. mg (4.1 mmol) of benzenesulfonyl chloride. After 10 minutes, the cooling bath was removed and the mixture was stirred overnight. The reaction mixture was poured into 50 ml of water *, the organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was distilled off and the crude product thus obtained was purified by chromatography on silica gel (160 g). Acetone was used as eluent and 10 ml fractions were collected. TLC 61-93 showed pure product by TLC. fractions were combined and the solvent was distilled off under reduced pressure to give 1.5 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 2.06 / 3H / s; 2.30 / 6H / s; 2.63 </ 2H / d;

3.06 / 3H / s; and 7.3-8.2 / 5H / m.

Using the appropriate starting materials and following the procedure described above, the following two compounds were also obtained: 11-acetyl-4 ' ^, -deoxy-4' - (2-naphthalenesulfonylamino) -oleandomycin,

Nuclear Magnetic Resonance Spectrum (CDC1), 2.03 (3H) s; 2.26 / 6H / s; 2.65 / 2H (d ⁶⁾ 2.96 (3H); and 7.4-8.6 (7H / m).

11-acetyl-4-deoxy-4- (benzylsulfonylamino) -oleandomycin; 2.30 / 6H / s; 2.63 (2H) d;

3.46 / 3H / s; 3.33 / 2H / s; and 7.36 / 5H / So

Example 8 11-Acetyl-4 ' ^, -deoxy-4' ^, 1'-p-benzyloxycarbonyl-1-benzenesulfonylamino-oleand omycin

2.55 g (3.5 mmol) of 11-acetyl-4 '' - deoxy-4 '' - amino oleandomycin, 1.12 g / 3.6 mmol of p-benzyloxycarbonylbenzenesulfonyl chloride, 379 A mixture of mg (3.75 mmol) of triethylamine and 25 ml of methylene chloride was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was triturated with 10 ml of acetone. The solids were filtered off. and the filtrate was chromatographed on 280 g of silica gel. Elution solvent acetone was used and fractions of 10 ml were collected. TLC showed pure

90-205 containing -10180.279 products. Fractions 1 to 4 are combined and the solvent is distilled off under reduced pressure. 1.25 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDClj) δ 2.04 / 33/3; 2.30 / 6H / s; 2.66 / 2H / d;

3.01 / 33 / a? 5.48 / 2H / m and 8.03-8.53 / 4H / m.

EXAMPLE 9 Starting from 11-Acetyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonic acid chloride and following the procedure described in Example 8, the compounds of formula IIa containing the following R groups are obtained. _R NMR spectrum (CDCl3),

m-Me Toxicarbone1- 2.06 / 3H / s; 2.30 / 6H / Ski 2.66 / 2H / d; phenyl; 3.03 / 33 / SJ 3.96 / 3H / Ski and 7.3-9.0 / 4H / m. o-Benzyloxycarbonyl-1- 2.05 / 33 / s? 2.30 / 6H / sj 2.65 / 2H / d _? phenyl; 3.01 / 33 / Ski 5.43 /2 H/ dt 7.46 / 5H / ski and 7, , 33-8, 70 / 4H / m. p-Me t oxycarboxyl-1- 2.06 / 33 / Ski 2.30 / 6H / ski 2.66 / 2H / d; phenyl; 3.06 / 33 / Ski 4.0 / 3H / s; and 7.8-8.4 / 4H / m. p-methoxycarbonyl- 2.10 / 33 / Ski 2.30 / 6H / Ski 2.70 / 2H / charge phenyl; 3.0 / 33 / Ski and 4, , 10/33 / s.

Example 10 11-Acetyl "4" -deoxy-4- (p-carboxybenzenesulfonylamino) -oleandomycin

A solution of 800 mg of 11-acetyl-4-deoxy-4' ^, [p-benzyloxycarbonyl-benzenesulfonylamino] -oleandomycin in 43 ml of ethyl acetate in the presence of 400 mg of 10% palladium on carbon at room temperature, 50 pounds per square inch. hydrogenation under initial pressure for 2 hours. An additional 250 mg of catalyst was added and hydrogenation continued for a further 2 hours. The catalyst is then filtered off and the solvent removed from the filtrate under reduced pressure. 450 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl,) δ 2.06 / 33 / s; 2.86 / 6H / sj 2.68 / 2H / d;

3.30 / 3.11 / sj and 7.5-8.4 / 4H / m.

Example 11 11-Acetyl-4 &apos; -deoxy-4 &apos; -N-tetrobenzenesulfonylamino-oleandomycin

5.0 g / 6.8 mmol / l-acetyl-4-deoxy-4 '' -aminoleandomycin, 1.5 g / 7.0 mmol / o-nitrobenzenesulfonyl chloride. A mixture of 0.98 mL of triethylamine and 50 mL of methylene chloride was stirred at room temperature for 48 hours. Then, an equal volume of water is added to the reaction mixture, the organic phase is separated off, washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the foamy solid residue was charged with 140 g of silica gel 3x5x in diameter.

-11180.279 column chromatography. Acetone was used as eluent and fractions of 50 ml were collected. 20-30. fractions were combined and the solvent was distilled off to give 3.4 g of the title compound.

Nuclear Magnetic Resonance Spectrum (GDCY) δ 2.10 / 3H / s; 2.33 / 6H / s; 2.36 / 2H / d;

2.90 / 3H / s; and 7.4-8.4 / 4H / m.

Using the appropriate starting materials and following the procedure described above, the following two compounds were obtained:

ll-acetyl-4 "-deoxy-4" - / m-benzenesulfonyl nitj'o "amino / -oleandomicin,

Nuclear Magnetic Resonance Spectrum (CDCl,) δ: 2.06 / 3H / s; 2.30 / 6H / s ·, 2.66 / 2H / d;

3.06 / 3H / s? and 7.4-9.0 (4H / m); 11-acetyl-4'-deoxy-4 '- (p-nitrobenzenesulfonylamino) oleandomycin, NMR spectrum (CDCK)? 2.10 / W s; 2.35 / 6H / s; 2.68 / 2H / d;

3.06 / 3H / s; and 8.0-8.6 (4H / m).

Example 12 11-Acetyl-4'-deoxy-4 '- (p-hydroxybenzenesulfonylamino) -oleandomycin

2.55 g / 3.5 mmol / 11-acetyl-4-deoxy-4-amino-oleandomycin, 701 mg / 3.65 mmol / p-hydroxybenzenesulfonyl chloride, 518 µl triethylamine and 25 ml the methylene chloride mixture was stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure and the residue was triturated with 10 ml of acetone. The insolubles were filtered off and the filtrate was chromatographed on 200 g of silica gel. Acetone was used as eluent. TLC 116-175 showed pure product by TLC. Fractions 1 to 4 are combined and the solvent is distilled off under reduced pressure. 550 mg of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 2.0 / 3H / s; 2.33 / 6H / s; 2.68 / 2H / d;

⁹ 3.06 / 3H / s and 6.6 to 8.0 / 4H / m.

Example 13 11-Acetyl-4 "-deoxy-4" - _[(D -carboxamidobenzenesulfonylamino) -oleandomycin

To a solution of 2.91 g / 4.0 mmol / l-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin and 434 mg / 4.2 mmol / triethylamine in 20 mL of methylene chloride was added 898 mg / 4, 1 mM m-carboxamidobenzenesulfonyl chloride and stirred for 48 hours. The solvent was distilled off under reduced pressure and the residue was triturated with 25 µl of acetone. The triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel * 50 ml fractions are collected and the purity of the fractions is checked by thin layer chromatography. 66-93. fractions were combined and the solvent was distilled off under reduced pressure to give 800 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDC1I): δ 2.06 / 3H / sj 2.33 / 6H / s; 2.70 / 2H / s;

⁹ 3.10 / 3H / s; and 7.4-9.0 (4H / m).

Example 14

-12180 279 11-Acetyl-4-deoxy-4 '- [? - acetamido-benzenesulfonylamino] -oleandomycin

2.91 g / 4.0 mmol / l of ethyl 1-4 '' -deoxy-4 '-amino-oleandomycin, 955 mg / 4.1 mmol / p-acetamidobenzenesulfonyl chloride, 424 mg / 4, A mixture of 2 mM trimethylamine and 20 ml methylene chloride was stirred at room temperature for 48 hours. The solvent was then distilled off under reduced pressure and the resulting foam was triturated with 10 mL of acetone. The residual triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 160 g of silica gel using acetone as eluent. Thin layer chromatography revealed that most of the pure material contained 42-86. Fractions 1 to 4 are combined and the solvent is distilled off under reduced pressure. This way

1.2 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 2.06 / 3H / s; 2.23 / 3H / s; 2.35 / 6H / s;

2.70 / 2H / s; 3.13 (3H) a; and 7.6-8.2 / 4H / m.

11-Acetyl-4 "-deoxy-4 / p-benzenesulfonylamino / -oleandomicin

2.55 g (3.5 mmol) of 11-acetyl-4-deoxy-4 '-amino-oleanaomomine, 734 mg / 3.65 mmol of p-cyanobenzenesulfonyl chloride, 518 µl / 3.75 mmol · triethyl amine and 25 ml of methylene chloride were stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was triturated with 10 ml of acetone. The insolubles were filtered off and the filtrate was chromatographed on 120 g of silica gel. Acetone was used as eluent and 10 ml fractions were collected. 47-83. fractions were combined and the solvent was distilled off under reduced pressure to give 281 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCU /) δ 2.10 δ H / s; 2.36 / 6H / s; 2.71 / 2H / d;

3.06 / 3H / sj and 7.7-8.4 / 4H / m.

Example 16

11-Acetyl-4 "-doxy-4" -? - trifluoromethyl-benzenesulfonylamino-oleand omicin

To a solution of 2.55 g (3.55 mmol) of 11-acetyl-4 * '- deoxy-4' -amino-oleandomycin and 518/11 / 3.75 mmol / triethylamine in 25 mL of methylene chloride was added 891 mg (3.65 mmol) p-trifluoromethylbenzenesulfonyl chloride and stirred for 18 hours at room temperature. The solvent was distilled off under reduced pressure and the residue was triturated with 15 ml of acetone. The solids were filtered off and the filtrate was chromatographed on silica gel. 287 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl,) δ: cT 2.03 / H / s; 2.31 / 6H / s; 2.63 (2H) d;

3.40 / JH / s; and 7.15-8.3 (4H / m).

Example 17 11-Acetyl-4 '' - deoxy-4- / 2,2,2-trifluoro-ethanesulfonyl-amino-oleandomicin

2.55 g / 3.5 mmol / 11-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin, 666 mg / 3.65 mmol / 2,2,2-trifluoroethanesulfonyl-

-13183,279

chloride, 379 mg / 3.75 mmol / triethylamine and 25 ml of methylene chloride are stirred at room temperature for 30 hours. Then, 333 mg of the above sulfonic acid chloride and 270 µl of triethylamine are added, followed by another 4 hours. stirring. The solvent was distilled off under reduced pressure and the residue was triturated with 20 ml of acetone. The insolubles were filtered off and the filtrate was chromatographed on 110 g of silica gel. Acetone was used as eluent and 10 ml fractions were collected. 50-80. Fraction 1 was combined and the solvent was distilled off. 385 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl1) δ 2.06 / 3H / s, 2.26 / 6H / s; 2.60 / 2H / d; ^P and 3.36 / 3H / s.

Example 18 ll-acetyl-4 ^"-deoxy-4" - / metánazulfonil amino / -oleandomicin

2.91 g / 4.0 mmol / 11-acetyl-4 '-deoxy-4-amino-oleandomycin, 467 mg / 4.1 mmol / methanesulfonyl chloride, 424 mg / 4.2 mmol / triethylamine and ml of methylene chloride was stirred overnight at room temperature. The solvent was distilled off and the residue was triturated 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. Acetone was used as eluent and 6 ml fractions were collected. 67-133. Fractions 1 to 4 are combined and the solvent is distilled off under reduced pressure. 1.2 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (GDC 1), J 2.06 / 3H / s; 2.28 / 6H / s; 3.06 / 3H / s;

² 2.61 / 2Η / d; and 8.40 (3H) a.

Example 19

11-Acetyl-4-deoxy-4 '* - [3,5-dichlorobenzenesulfonylamino] -oleandomycin

2.9 g (4.0 mmol) of 11-acetyl-4-deoxy-4'-amino-oleandomycin, 1.0 g / 4.1 mmol of 3,4-dichlorobenzenesulfonyl chloride, 0.57 mL A mixture of (4.2 mmol) of triethylamine and 30 ml of methylene chloride was stirred at room temperature for 18 hours. Water (50 mL) was added, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on 150 g of silica gel using acetone as eluent. TLC showed that the product-containing fractions were combined and the solvent was distilled off under reduced pressure. 1.3 g of the title compound are obtained. .

Nuclear Magnetic Resonance Spectrum (CDCl./J) 2.0 / 5H / s; 2.30 / 6H / s; 2.60 / 2H / d;

⁹ 3.06 / 3H / s; and 7.2-8.1 / 3H / m.

Using the appropriate starting materials and following the procedure described in Example 19, the compounds of formula IIa containing the following groups are obtained as R:

-14180,279

Nuclear Magnetic Resonance Spectrum (CDC13)

2,5-Dichloro-phenyl

2,4-Dichloro-phenyl

2-Methyl-4-chlorophenyl group

2.0 / 3H /

3.33 / W

2.10 / 3H /

3.30 / 3H /

2.03 / 38 /

3.10 / 38 / ski a; the; the;

g; a j d {d;

bi

3-Nitro-4-chloro-phenyl

2-Nitro-4-chloro-phenyl

2-Nitro-4-methoxy-phenyl

2,4-dinitro-phenyl group

2.36 / 68 / s; 2.70 (2H) and 7.3-8.6 (3H).

2.31 (6H) and 2.66 (28) and 7.2-8.4 (3H).

2.30 / 6H / s; 2.66 (38) and 7.1-8.1 (3H) (au) as a solvent in a mixture of dimethylsulfoxide and deuterochloroform.

2.06

3.13

2.06 3.25. .

/ As a solvent in a mixture of dimethylsulfoxide and deuterochloroform ·

2.06 / 3: 1 / s; 2.33 / 6H / s; 2.63 / 28 / d;

2.81 / 38 / s; 3.63 / 3H / s; and 7.0-8.2 / 3H / m.

/ In a mixture of dimethylsulfoxide and deutero-kίστοί orm · as solvent.

2.06 / 3H / s; 2.36 (6H) a; and 8.4-9.0 (3H / m).

In dimethylsulfoxide / deuterochloroform as solvent; 3B / 3H / 3K / 3H / a;

s; ski

Example 21 11-Aoethyl-4 "-deoxy-4" - (2,3,4-trichlorobenzenesulfonylamino) -oleandomycin

2.9 g / 4.0 mmol of U-acetyl-4 &apos; -deoxy-4 &apos; -aminooleandomycin, 1.15 g / 4.1 mmol / 2,3,4-trichlorobenzenesulfonyl chloride, A mixture of 0.57 ml (4.2 mmol) of triethylamine and 30 ml of methylene chloride is stirred for 18 hours at room temperature. The solution was washed with water (50 mL) followed by brine (50 mL) and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on 150 g of silica gel. Acetone was used as eluent and fractions of 7 »l were collected. 60-1C0. Fraction 1 was combined and the solvent was distilled off. 800 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 2.06 / 3H / s; 2.33 / 6H / s; 2.63 / 28 / d;

3.2 / 3H / m and 7.2-8.2 / 2H / m.

Example 22 11-Acetyl- ^4H- deoxy-4 '- (2-hydroxy-3,5-dichlorobenzenesulfonylamino) -oleandomycin.

-15180,279

2.55 g / 3.0 mmol / ll-acetyl-4 '' - deoxy-4 ^,, amino-oleandomycin, 954 mg / 3 »65 mmoles / of 2-hydroxy-3,5-dichloro-benzenesulfonyl chloride, Starting from a mixture of 518 µl of triethylamine and 25 ml of methylene chloride and purification by chromatography on 220 g of silica gel as in Example 33, 483 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (ODCl 2 / dimethylsulfoxide): δ

2.03 / 3H / s; 2.50 / 6H / s; 3.05 / 3H / s; and 7.2-7.8 (2H / m).

Example 23 ^ll-acetyl-4 "-deoxy-4/3-amino-4-chloro-benzenesulfonic onyl-amino / -oleandomicin

A solution of 1.0 g of 11-acetyl-4'-deoxy-4- [3-nitro-4-chlorobenzenesulfonylamino] -oleandomycin in 50 ml of ethyl acetate in the presence of 500 mg of 10% palladium on carbon overnight Hydrogenate at an initial pressure of 50 pounds per square inch. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The resulting white foam was chromatographed on silica gel (160 g), eluting with acetone and collecting fractions (50 mL). The product-containing fractions were combined and the solvent was distilled off under reduced pressure. 450 mg of the title compound are obtained in NMR (CDCl 3) 2.04 / 3H / s; 2.33 / 6H / s; 2.66 / 2H / d;

^p 3.16 / 311 / s; and 7.2-8.0 (3H / m).

Starting from the appropriate nitro derivatives obtained in the same manner as in Example 11, the following compounds were prepared:

11-Acetyl-4 "-deoxy-4 '' - [m-aminobenzenesulfone 1-a] -o-oleandomycin,

Nuclear Magnetic Resonance Spectrum (CDCl3), 2.03 (3H) s; 2.30 / 6H / s; 2.63 (2H) d;

^p 3.10 / 3H / s; and 7.0-7.8 (4H / m); and 11-Acetyl-4 '' -deoxy-4 '- (p-aminobenzenesulfone 1-a) ol-oleandomycin

Nuclear Magnetic Resonance Spectrum (CDCl3), 2.06 / 311 / s; 2.31 / 6H / s; 3.02 / 3H / s; and 6.4-7.8 / 4H / dd.

Example 24 11-Acetyl-4 '' - deoxy-4- [3-methyl-2-thienylsulfonylamino] -oleandomycin

To a solution of 100 g / 0.13 mol / l-acetyl-4 '-deoxy-4' '-aminoleandomycin in 900 ml of methylene chloride was added 593 ml of triethylamine and the solution was stirred for 10 minutes. A solution of $ 41.9 (0.213 M) 3-methyl-2-thienylsulfonyl chloride in 300 mL of methylene chloride was added dropwise over 1 hour, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was separated, washed with water (2 x 250 mL) and brine (1 x 250 mL), and filtered through sodium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on a 105 x 6.5 cm (1.5 kg) silica gel column using acetone as eluent. The product comes down from column volume 16180.279 between 2.3 liters and 6 liters of eluate. These fractions were combined and the solvent was distilled off under reduced pressure. Trituration of the resulting foam with diethyl ether gave 66.4 g of the title compound, m.p. 185-185.5 ° C.

Nuclear Magnetic Resonance Spectrum (CD01O) δ: cT 2.04 / 3H / s; 2.41 / 6H / s; 2.46 / JH / Sj ^D 2.62 / 211 / m; 3.02 / 3H / s; 6.84 and 7.32 (2H).

To a solution of 2.0 g of the base obtained above in 15 ml of ethyl acetate was added 0.12 ml. phosphoric acid, and the mixture is stirred at room temperature. After stirring for 20 minutes, crystalline material begins to precipitate out of the mixture. After stirring for 2 hours, the precipitated crystals were filtered off, washed _with ethyl acetate and dried. 1.3 g of 11-acetyl-4 '' - deoxy-4 '' - (3-methyl-2-thienylsulfonylamino) -oleandomycin phosphate are thus obtained. Nuclear Magnetic Resonance Spectrum (CDOD): .delta. 2.01 / 3H / sj 2.45 / 3H / sj 2.56 / 2H / mj 2.83 / 611 / sj 3.0 / 3H / s; 6.88 and 7.42 (2H).

Example 25 Starting from 11-Acetyl-4 "-deoxy-4" -amino-oleandomycin and the corresponding sulfonic acid chlorides according to the procedure of Example 24, compounds of formula IIa containing the following groups of R are prepared: :

1 H NMR CDCl 3 / δ, cf

5 Meti1-2-furyl 2.08 / 3: 1 / s; 2.33 / 6H / Ski 2.38 73Η / s J -group 2.68 / 211 / m; 5.27 / 3H / the·, 6.08 and 6.92 / 2 H / < 1-Methyl-1-pyrrine 2.08 / 3H / s; 2.36 / 6H / i 2.68 /2 H/ m; -group 3.30 / 1H / / 3H / s; 3.71 / 3H / S, 6,44- -6.70 m; and 1, 7.18-7. , 39 / 2H / m. 4-Methyl-2-thienyl 2.03 / 3H / ski 2.25 / 3H / Ski 2.51 / 6H / Ski -group 2.61 /2 H/ m; 3.15 / 3H / Ski 7.07 / 1H / m;

and 7.38 (1H / m).

5-Et i1-2-my1- 2.06 / 33 / j 2.33 / 6H / Ski 2.65 / 2H / m; -group 3.22 / 3H / · s, 6.73 and 7, Λ5 /2 H/. 5-Me t i1-2-t i eni1- 2.08 /2 H/ · s, 2.34 / 6H / Ski 2.54 / 3H / sj -group 2.67 /2 H/ Ski 3.25 / 3H / Ski 6.73 and 7.46

Example 26

11-Acetyl 1-4-desoxy-4 '' - / 5-methoxycarbonyl-1-2-pyrrolylsulfonyl-a-amino-oleandomicin

To 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 anhydrous methylene chloride is added in portions 1.0 g under ice-cooling. (0.0044 mole) of 2-methoxycarbonyl-5-pyrrylsulfonyl chloride. The mixture was allowed to warm to room temperature and stirred for three and a half hours. The reaction mixture was poured into 200 ml of water, the aqueous portion was adjusted to pH 9.5 with 1 N aqueous sodium hydroxide solution, and the organic portion was separated. The latter was washed with water and then with saturated brine and then dried over sodium sulfate. The solvent was removed under reduced pressure

-17180.279 was distilled to give a white foam

3.8 g of crude product are obtained. The foam obtained in this way was chromatographed on a 3.25 x 38 cm silica gel column. Acetone was used as eluent and fractions of about 10-12 ml were collected. 40-220. The solvent was evaporated under reduced pressure to give 3.4 g of the title compound as a white foam.

Nuclear Magnetic Resonance Spectrum (CDCl3): δ 2.05 / 3H / s; 2.58 / 6H / s; 2.67 / 2H / m;

⁹ 3.25 / 3H / s; 3.90 / 3H / s; 7.20 (1H, m);

and 7.52 (1H / m).

Example 27 Starting from 11-Acetyl-4'-deoxy-4 '' -aminoleandomycin and the corresponding sulfonic acid chlorides and following the procedure described in Example 26, the following general formula (IIa) containing R is prepared: compounds.

R NMR (CDCl3,?)

5-Methoxycarbonyl-1-2- 2.09 / 3H / s; 2.32 / 6H / S, 2.69 (1H) m; thienyl 3.22 / 3H / S; 3.95 / 3H / Ski 7.61 and 7.75 / 2 H / < 1 4-Methoxycarbonyl-1-2- 2.11 Z3H / the; 2.34 / 6H / S Í 2.70 / 2H / m; thienyl 3.24 / 3H / the; 3.94 / 3H / Ski 8.06 sky 8.28 /2 H/ * 5-Methoxy-rb oni1-2- 2.08 / 3H / Ski 2.29 / 6H / Ski 2.67 / 2H / Si -fúri1 group 3.18 / 3H / Ski 3.94 / 3H / Ski 7.02 sky 7.20 /2 H/ •

Example 28

4 "-Deoxy-4- (p-chlorobenzenesulfonylamino) -oleandomycin

A mixture of 3.0 g of 4 '' - deoxy-4-amino-oleandomycin, 865 mg of p-chlorobenzenesulfonyl chloride, 424 mg of triethylamine and 25 ml of methylene chloride was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was triturated with acetone (20 mL). Insoluble triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 180 g of silica gel. Elution solvent acetone was used and 50 ml fractions were collected. 18-27. Fractions 1 to 4 are combined and the solvent is distilled off under reduced pressure

1.10 g of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl3) δ 2.33 (6H); 2.83 / 2H / d; 3.06 / 3H / s;

⁹ and 7.2-8.4 / 4H / m.

29 «Example

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

In a manner similar to that described in Example 43, 3.0 g / 4.0 mmol / 4-deoxy-4 '-aminoleandomycin, 782 mg / 4.1 mmol / p-toluenesulfonyl chloride, 424 mg triethylamine and of methylene chloride was stirred overnight at room temperature. The crude product obtained after usual work-up is chromatographed on 180 g of silica gel, collecting 10 ml fractions. fractions were combined and the solvent was distilled off to give 1.4 g of the title compound.

-18180.2 / 9

Nuclear Magnetic Resonance Spectrum (CDCl,) δ cT 2.33 / 611 / s; 2.46 (3H) a; 2.83 / 2H / d;

3.10 / 311 / s; sky 7.10-8.0 / 4H / m.

In a similar manner, 4 * '- deoxy-4- / 2-thienylsulfonyl-1-amino / -oleandomic int.

Nuclear Magnetic Resonance Spectrum (CDCl3):? 2.29 / 6H / s; 2.88 / 2H / m; 3.2 (3H) a;

^Δ 5.6 / W m; and 7.33 (3H / m). .

Example 30 11-Acetyl-4-deoxy-4 ^K - (vinylsulfonylamino) -oleandomycin

17 »! To a solution of S / 82.3 mmol / 2-bromoethanesulfonyl chloride in 200 mL of methylene chloride cooled to -78 ° C under nitrogen is added 30 g / 41.1 mmol / 11-acetyl-4 '' - deoxy-4 ' A solution of amino-oleandomycin and 16.7 g (164 mmol) of triethylamine in 100 ml of methylene chloride was also cooled to -78 ° C. The mixture was stirred at-78 C ^D 1.3 hours and then poured into water and the pH was adjusted to 7.3 using solid sodium hydrogen carbonate. The organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 43.5 g of a yellow foam are obtained. It is suspended in diethyl ether and the insolubles are filtered off. The filtrate was distilled off under reduced pressure to give 20.3 g of crude product, which was chromatographed on 800 g of silica gel. The eluent was 95: 5 by volume chloroform: methanol. The product-containing fractions were combined and the solvents were evaporated to give 5.1 g of the title compound. Nuclear Magnetic Resonance Spectrum (CD01O,) δ: 2.10 / 311 / s; 2.37 / 6H / s; 2.70 (2H) d;

⁹ 3.43 / 3H / a; δ 5.7-7.06 / 3H / m.

Example 31

11-Acetyl-4 "-desoxy-4" - (2-bromoethane) ulphonylamino / oleandomycin

500 mg / 0.68 mmol / l-acetyl-4 '' - deoxy-4 '-amino-oleandomycin and 882 mg / 8.2 mmol / 2,6-lutidine were prepared in 4 ml of methylene chloride at -4 ° C. A solution of 854 mg (4.0 mmol) of 2-bromoethanesulfonyl chloride in 2 mL of methylene chloride cooled to -2 ° C was added to the cooled solution. After stirring at -2 ° C for one and three-quarter hours, the reaction mixture was poured into water and methylene chloride and the pH adjusted to 7.0 with solid sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was distilled off. The residual yellow oil was chromatographed on silica gel (42 g), eluting with 95: 5 chloroform: methanol. 52.5 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDC1I): δ 2.08 / & &s; 2, 33 / 6H / s; 2.65 / 2H / s;

⁹ δ 3.46 / 3H / s.

Example 32

11-Acetyl-4 "-deoxy-4" - (2-diethyl-1-amino-anise) Ulfoni-1-amino / oleandomycin

1.0 g (1.22 mmol) of 11-acetyl-4-deoxy-4 '- / vinylsul19

To a solution of the phenyl amino / oleandomycin -19180.279 in 5 ml of benzene was added 892 mg / 12.2 mmol / diethylamine and the mixture was stirred at room temperature under nitrogen for 48 hours. The solvent and excess diethylamine were distilled off under reduced pressure. 940 mg of the title compound thus obtained in the form of a white foam are slowly crystallized, m.p. 85-99 ° C.

Nuclear Magnetic Resonance Spectrum (CDC1,) δ: 2.05 AH / s; 2.30 / 6H / s-, 2.36-2.73 ^p / 4H / q; 2.63 / 2H / s; and 3.4 / 3H / s.

Example 33 11-Acetyl-4 '' - deoxy-4 '' - / methylmercaptO 'ethanesulfonylamino / oleandomicin

A suspension of 800 mg / 0.98 mmol / l-acetyl-4-deoxy-4 * '- (vinylsulfonylamino) -oleandomycin and 475 mg / 3 mmol / potassium carbonate in 10 mL of benzene was stirred in we lead mercaptan. The reaction vessel was sealed and the mixture was allowed to stand overnight. The excess mercaptan was discarded under reduced pressure and poured into a mixture of benzene and water. The organic layer was separated, dried over sodium sulfate and the solvent was distilled off under reduced pressure. This gave 805 mg of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDCl 2): δ 1.98 / 3H / s; 2.05 / 3H / s; 2 * 20 / 6H / s;

2.57 H ² / s; and 3.50 / 3H / s.

Example 34 Starting from 11-Acetyl-4 '-deoxy-4-vinylsulfonylamino-oleandomycin and the corresponding mercapters and following the procedure described in Example 33, Z containing the groups listed below is prepared / IVa / compounds of the general formula wherein Rj is acetyl:

Z NMR (CDCl3), cT

2-Hydroxy-mercapto-éti1

Et i1-mercap to group

Mercapto-propyl-csoροτυ

Phenylthio group

2.03 AH / s; 2.30 / 6H / s ₅ 2.63 / 2H / s; and 3.40 / 3H / s.

2.07 AH / s; 2.28 / 6H / s $ 2.63 / 2H / s; and 3.40 / 3H / s.

2.07 AH / S ', 2.30 / 1H / s 2.61 / 2H / s; and 3.42 / 3H / s.

2.07 AH / s; 2.28 / 6H / s ·, 2.65 / 2H / s ·, and 3.38 / 3H / s.

steel

11-Acetyl-4-deoxy-4- [m / f] olino-ethanesulfone-1-amino-oleandomycin

To a solution of 2.0 g / 2.44 mmol (11-acetyl-4 '-deoxy-4' '- / vinylsulfonylamino) -oleandomycin in 50 ml benzene is added 2.1 g / 24.4 mmol / morpholine, and stirring the reaction mixture under nitrogen for 40 hours at room temperature. The solvent and the crude morpholine were distilled off under reduced pressure, and the resulting foam was triturated with hexane and allowed to stand for 2 hours. The crude product thus obtained was recrystallized from ethyl acetate-hexane to give 890 mg of the title compound, m.p. 95 ° C.

-20,180.279

Nuclear Magnetic Resonance Spectrum (CDC1I): δ 216 / 3H / s; 2.30 / 6H / s; sky 3.42 / 3H / ⁹ s,

Example 36

11 Aceti1-4 "-deoxy-4" - / 2-sulfonyl tieni1 Araina / -oleandomicin phosphate

To a solution of 15.0 g of 11-acetyl-4 '' - deoxy-4 '- / 2-thienyl 1-sulfonylamino / oleandomycin in 100 ml of ethyl acetate is added 1.0 ml of phosphoric acid. The suspension thus obtained was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with ethyl acetate and dried. This way

12.5 g of the title salt are obtained, m.p.

In a similar manner, 11-acetyl-4-deoxy-4- / 3-methyl-2-thienylsulfonylamino-oleandomycin phosphate was prepared, m.p. 184-188 DEG C., and 11-acetyl-4-. de2Oxl-4 / p-chlorobenzenesulfonylamino-oleandomycin phosphate, m.p. 204-205 C.

Preparation of the starting materials for the reactions described in the Examples - "" "-....., -

4 "-deoxy-4" -oxo-oleandomycin derivatives

I. 11-Acetyl-4-deoxy-4 '' - oxo-oleandomycin a / 11,2 * -Diacetyl-4 '-deoxy-4' ^, -oxo-oleandomycin

Into a dry flask fitted with a magnetic stirrer and a tube fitted with nitrogen gas, 4.5 g of N-chlorosuccinimide, 50 ml of benzene and 150 ml are added. toluene. The mixture was cooled to -5 ° C and dimethylsulfide (3.36 mL) was added. After stirring for 20 minutes at 0 ° C, it is cooled to -25 ° C and a solution of 5.0 g of 11,2-diacetyl oleandomycin in 100 ml of toluene is added. The mixture was stirred under cooling for a further 2 hours, and then added

Triethylamine (4.73 ml) was stirred at 0 ° C for a quarter hour and then poured into water (500 ml). The pH of the mixture was adjusted to 9.5 with 1N aqueous sodium hydroxide solution, the organic layer was separated, washed with water, brine and dried over sodium sulfate. The solvents were distilled off under reduced pressure to give 4.9 g of the title compound as a foam.

Nuclear Magnetic Resonance Spectrum (ODCl 2) δ 3.48 / 3H / s; 2.61 / 2H / m; 2.23 / 6H / s;

⁹ and 2.03 / 6H / s.

b / III-Acetyl-4-deoxy-4-oxo-oleandomycin

A solution of 4.0 g ^of 11,2-diacetyl-4 "-deoxy-4" -oxo-oleandomycin in 75 ml of methanol was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting foam was dissolved in diethyl ether and hexane was added. This gave 2.6 g of the title compound as a white solid, m.p. 112-117 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 3.43 / 3H / s; 2; 60 / 2H / m; 2.23 / 6H / s;

^p and 2.01 / 3H / s.

11.2 * -dipropionyl-4 "-deoxy-4" -oxo-oleandomycin or

11-Propionyl-2'-acetyl-4 "-deoxy-4" -oxo-oleandomycin is prepared in a similar manner from 11-propionyl-4 "-deoxy-4" -oxo-oleandemycin.

II. 4 "-oxo-oleandomycin -rDezoxi 4-a / ^{2-Acetyl-4 '-deoxy-4-oxo-oleandomycin}

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To a cloudy solution of 467 mg of N-chlorosuccinimide in 20 ml of toluene and 6 ml of benzene was added 0.337 ml of dimethylsulfide under nitrogen atmosphere at -5 ° C. After stirring at 0 ° C for 20 minutes, the mixture was cooled to -25 ° C and a solution of 1.46 g of 2-acetyl oleandomycin in 15 ml of toluene was added. The mixture was stirred for an additional 2 hours at -20 ° C and 0.46 ml of triethylamine was added. The mixture was stirred for an additional 5 minutes at -20 ° C. then allow to warm to room temperature. Is it then poured into a mixture of 50 ml of water and 50 ml of ethyl acetate _? and adjusting the pH of the aqueous solution to 9.5 with aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. The resulting white foam, 1.5 g, was triturated with diethyl ether. The crude product thus obtained (864 mg) was recrystallized twice from methylene chloride / diethyl ether to give 212 mg of pure title compound, m.p. 183-185.5 °.

Analysis calculated: C, 61.1; H, 8.5 '; N, 1.9%. Found: C, 60.9; H, 8.4; N, 1.9%.

Nuclear Magnetic Resonance Spectrum (CDCl3): 5.60 (LH / m); 3.50 / 3H / s; 2.73 / 2H / m;

2.23 / 6H / s; and 2.03 / 3H / s.

b / 4-Deoxy-4 '' - oxo-oleandomycin

A solution of 1.0 g of 2'-acetyl-4-deoxy-4-oxo-oleandomycin in 20 ml of methanol was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give 937 mg of the title compound as a white foam.

Nuclear Magnetic Resonance Spectrum (GDC1): 5.60 (LH / m); 3.50 / 3H / s; 2.85 / 2H / m;

and 2.25 / 6H / s.

4 '. ^1- Deoxy-4 '-amino-oleandomycin

I. To a suspension of 11% acetyl-4 ' ^, deoxy-4' ^, amino-oleandomycin in 10% palladium on charcoal in 100 ml of methanol was added 21.2 g of ammonium acetate followed by 20 g of 11-acetyl-4 ' ^, -deoxy-4 ' ^, -oxo-oleandomycin in 100 ml of methanol. The slurry was hydrogenated at 7.25 mL at an initial pressure of 1.5 hours at room temperature. The catalyst is then filtered off and the filtrate is added with stirring to a mixture of 1200 ml of water and 500 ml of chloroform. The pH of the mixture was adjusted from 6.4 to 4.5 and the organic layer was separated. The aqueous portion was shaken once more with 500 mL of chloroform, then 500 mL of ethyl acetate was added and the pH was adjusted to 9.5 with 1N sodium hydroxide solution. The ethyl acetate portion was separated and the aqueous portion was extracted again with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and the solvent was distilled off. The residue was recrystallized from diisopropyl ether (18.6 g, white foam) to give 6.85 g of purified title compound, m.p. 157.5-160 ° C.

NMR / CDC1 _X /: £ 3.41 / 3H / s; 2/70 / 2H / m; 2.36 / 6H / s;

*. and 2.10 / 3H / s.

-22180,279

The other epimer present in the foam crude product in an amount of 20-25 U may be isolated by gradual concentration of the mother liquors and filtration of the precipitated material.

Starting ^{yl-propionyl-4H} -deoxy-4 "-cxo-oleandomycin and acting in a similar manner to II-propionyl-4-deoxy-4-amino-oleand omicint.

II. A solution of 4 "-Deoxy-4-amino-oleandomycin g 2 * -acetyl-4" -deoxy-4 "-oxo-oleadomycin in 125 ml of methanol was stirred overnight at room temperature, and 21.2 g of ammonium acetate was added. The solution was cooled in an ice bath and 1.26 g of sodium cyanoborohydride was added. Cooling was then stopped and the mixture was stirred at room temperature for 2 hours. Pour into a mixture of water (600 mL) and diethyl ether (600 mL) and adjust the pH of the mixture to 8.3 to 7.5. The diethyl ether portion was separated and the aqueous portion was partitioned between ethyl acetate. The organic solvent extracts are discarded and the pH of the aqueous portion is adjusted to 8.25. The solution is partitioned between diethyl ether and ethyl acetate, the organic solvent extracts are set aside for 1 s and the pH of the aqueous portion is raised to 9.9. Extract with diethyl ether and ethyl acetate, combine the latter organic extracts, wash once with water, then brine, and dry over sodium sulfate. The organic solvent extracts obtained at pH 9 to 9 were distilled off under reduced pressure and the resulting foam was chromatographed on 160 g of silica gel. The residue was dissolved in chloroform and applied to the column and eluted with this solvent. Fractions of 12 ml were collected. After fraction 11, elution with methanol / chloroform (5/95 by volume), after fraction 370 with methanol / chloroform (10:90 by volume) and after fraction 440, methanol / chloroform (15:95 by volume). 85-260. fractions were combined and the solvents were evaporated under reduced pressure to give 2.44 g of the title compound. Nuclear Magnetic Resonance Spectrum (CD? G?):? 5? 56 / 1H / 3 * 36 / 3H / s; 2.9 (2H) m;

^p and 2.26 / 6H / s.

Claims (9)

A process according to formula (11) wherein: R is C 1-3 alkyl; pyridyl; 1,1,1-trifluoroethyl group; unsubstituted or optionally substituted by fluorine, chlorine, bromine or iodine, hydroxy, methoxy, cyano, carboxamido, nitro, amino, methoxycarbonyl, benzyloxycarbonyl, carboxyl, trifluoromethyl - phenyl substituted singly with alkyl or acetamido containing 1 to 4 carbon atoms or twice with chlorine, nitro, amino, methoxy or methyl; trichlorophenyl groups; feni1 hydroxy-methylene group; benzyl; chloro-thienyl; 2 acetamidotiazol-5-yl; yl; thienyl; 2-acetamido-4-methylthiazole-5-c: 3oport; benzimidazol-2-yl; dimethyl-pyrimidin-2-yl; pirrilcsoport; furyl, methoxycarbonyl, or thienyl, pyrryl or furyl monosubstituted with alkyl having 1 or 2 carbon atoms; l-methyl-3-methoxycarbonyl-pyrryl group; A group of the formula -CHX-CHY-Z, wherein -23180.2'9 X and Y are both hydrogen or taken together to represent a carbon-carbon bond, and Z is hydrogen, bromine, di-C 1-3 lower alkylamino-amino, C 1-3 -alkyl-mercapto, phenyl-mercapto, 2-hydroxy-ethyl-mercapto or morpholine. 1-yl; R 1 is hydrogen or C 1-3 alkanoyl; with the proviso that when Rf is hydrogen, phenyl is unsubstituted or optionally substituted with chloro or fluoro, methyl, methoxy or trifluoromethyl; or indispensable. or thienyl optionally substituted with 1 or 2 carbon atoms; with the proviso that when X and Y together represent a carbon-carbon bond, Z is hydrogen and that if f is hydrogen, R and R ₂ are the same compounds as well as their salts with pharmaceutically acceptable acid addition salts thereof, characterized in that R-SO ₂ -W in the presence of an acid acceptor in a reaction-inert solvent at room temperature in the presence of a compound of formula VYI wherein R 1 is as defined above and R * is hydrogen; - wherein R is as defined above and W is halogen, with a sulfonic acid halide; or for the preparation of compounds b / a / IV / formula wherein X and Y = H, Rf and Z are as defined above but Z is other than hydrogen, a / VII / - wherein Rf is as defined above and R 'is -S0 ₂ CH = CH _{2 is} reacted at 0 ° C with a mixture of an inorganic base in a reaction-inert solvent and a compound of formula ZH where Z is according to the present process and optionally a free base formed. to an acid addition salt. / Priority: March 6, 1978 / The process of claim 1 wherein the sulfonic acid halide is a sulfonic acid chloride of the formula R-SO ₂ -Cl, wherein R is as defined in claim 1. / Priority: March 6, 1978 / 3. According to claim 1; A process according to claim 1 or 2 wherein the acid acceptor is triethylamine. / Priority: March 6, 1978 / Process for carrying out the process according to any one of claims a / 2 and 3, characterized in that methylene chloride is used as the neutral solvent under the reaction conditions. '/ Priority: March 6, 1978 / -24180,279 A / and 2-4 according to claim 1. A process for the preparation of a compound according to any one of claims 1 to 11 wherein R 1 is acetyl and R is 2-thienyl, J-thienyl or 3-methyl-2-thienyl, characterized in that Starting from compounds of the formula R-SO ₂ -W, wherein R and R 4 are as defined above, and R 'and W are as defined in claim 1. * / Priority: March 6, 1978 / 6 / A method according to _this embodiment of claim 1, wherein the benzene used as solvent inert under the reaction conditions. / Priority: March 6, 1978 / 7. A process according to claim 1, wherein the base is potassium carbonate. / Priority: March 6, 1978 / A process for the preparation of a compound according to any one of claims b / 6, ₀ or 7 according to claim 1, wherein R is -CHX-CHY-Z, wherein Z is a methyl mercapto group, and Rp X and Y are as defined in claim 1, characterized in that they are starting from compounds of formula VII wherein R and Z are as defined above and X and Y are as defined in claim 1. / Priority: March 6, 1978 / A process for the preparation of a compound according to claim 1, wherein R is C 1-3 alkyl, pyridyl, 1,1,1-trifluoroethyl, unsubstituted or optionally substituted by fluoro, chloro, bromo or iodo, hydroxy, methoxy, cyano, carboxamido, nitro, phenyl, substituted singly with amino, methoxycarbonyl, benzoloxycarbonyl, carboxyl, trifluoromethyl, C 1 -C 4 alkyl or acetamido, or double with chlorine, nitro, amino, methoxy or methyl groups, trichlorophenyl, hydroxy-dichlorophenyl, benzyl, chlorothienyl, 2-acetamidothiazol-5-yl, naphthyl, thienyl, 2-acetamido-4-methylthiazol-5-yl, benzimidazol-2-yl, dimethyl-pyrimidin-2-yl, A group of the formula -CHX-CHY-Z, wherein X and Y are both hydrogen or taken together to represent a carbon-carbon bond, and Z is hydrogen, bromo, di- (1-3C) lower alkylamino-amino, (1-3C) alkyl-mercapto, phenyl-mercapto-moiety, 2-hydroxy-ethyl-mercapto or morpholin-1-yl; R 1 is hydrogen or C 1 -C 3 alkanoyl; provided that if R ^. R is unsubstituted or optionally -25180 279 Phenyl monosubstituted with chloro or fluoro, methyl, methoxy or trifluoromethyl, characterized in that the compounds of formula (VII) and R-SC ^ -W and ZH are starting from where R, R Z is as defined above and W is as defined in claim 1.