FI67709C - FOERFARANDE FOER FRAMSTAELLNING AV ANTIBACTERIAL LOW SYNTHETIC 4 "SULPHONYLAMINO-OLEANDOMYCIN DERIVATIVES - Google Patents

Description

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fateut- oeh ragteantyralNn Awekw wd ^ d edi udjfcrWiw piA # wrid 31.01.85 (32X33X31) <* yrdt * r «» oHmi · Βη «ηpierut 11.05.77 06.03.78 USA (US) 795850, 883608 (71) Pfizer Inc. , 235 East 42nd Street, New York, NY, USA (72) Arthur Adam Nagel, Gales Ferry, Connecticut, USA (7A) Oy Kolster Ab

The present invention relates to a process for the preparation of novel 4 "-deoxy-amino-sulphonylamino-olefinyl derivative and pharmaceutically acceptable acid addition salts thereof.

Oleandomycin, its preparation in fermentation broth by fermentation and its use as an antibacterial agent are described in U.S. Patent 2,757,123. The naturally occurring compound is known to have the following structure: 2 N (CH 2) 0 8 ^ 0 HO 2 -F 3 2 67709 "T 'Ά 0i, 1 ° ^ iiiii null 2 /' n * ^ kL 3 3 s ^ p \ t, 0 A "" "°«, 6 "5” ίν ^ ΝΑ / ° on! J4 "3" l ΌΗ 0CH3

The generally accepted numbering and stereochemical structure of oleandomycin and related compounds has been reported in many different publications.

U.S. Patent No. 3,884,902 patents 4 "erythromycin sulfonate esters and U.S. Patent No. 3,983,103 discloses N-sulfonyl erythromycylamines having biological profiles that differ from those of the compounds of the present invention.

Many different synthetic variants of oleandomycin are known, in particular those in which 1 to 3 of the free hydroxyl groups in the 2 ', 4 "and 11 positions are esterified as acyl esters. In addition, U.S. Pat. No. 3,022,219 describes similar variants in which the acetyl of the above esters has been replaced by another, preferably unbranched, lower alkanoyl group having 3 to 6 carbon atoms.

The present invention relates to a process for the preparation of compounds of formulas 67709 NCCH) N (CH3) 2

HOvV r?> H0 ', X

v <XX γΧ XX

k- '° .oX X- ° ^

\ (X Y

SX "'vy' X \ v 0 ^ j j

^ P ^ NHSOjR

1 0C “3 2 0CK3 and pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of 1 to 3 carbon atoms; pyridyl; 1,1,1-trifluoroethyl; phenyl; monosubstituted phenyl substituted with fluorine, chlorine, bromine, iodine, hydroxy, methoxy, cyano, carboxamido, nitro, carbomethoxy, carbobenzyloxy, trifluoromethyl, alkyl having 1-H carbon atoms or acetamido; disubstituted phenyl having substituents selected from chlorine, nitro, amino, methoxy and methyl; trichlorophenyl, hydroxydichlorophenyl; benzyl; naphthyl; thienyl; chlorothienyl; 2-acetamido-5-thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2-pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl or furyl substituted with carbomethoxy or alkyl of 1 to 2 carbon atoms; or 1-methyl-5-carbomethoxy-3-pyrryl; is alkanoyl having 2-3 carbon atoms; and R 1 is phenyl; thienyl; monosubstituted phenyl substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl; or alkyl-substituted thienyl having 1-2 carbon atoms in the alkyl. The process according to the invention is characterized in that of the formula 4 67709 6 H,), 3 2 fCH3> 2 γΚ 'f} ri ° ^ ky0 n0., "Y y' ° ° or \" v \ η xn px 0 'XpV ^ NH2 The compound of γ ^ ΝΗ2 och3 och3 1 '21 is reacted in a reaction-inert solvent at room temperature in the presence of an acid scavenger with 1 mole of an acid halide of formula

RS02W or R2S02W

in which formulas W is halogen.

Due to their synthetic method of preparation, the amine starting materials used to prepare the compounds of the invention consist of two 4 "epimers. Thus, the sulfonamido compounds of the invention prepared therefrom also consist of a mixture of epimers. the second epimer, which was present in the mother liquor originally isolated, is predominantly present in the mother liquor. a constant melting point is obtained, or by chromatography.

5 67709

Although the epimer mixture can be partitioned by methods known in the art, in practice this mixture is most preferably used as isolated from the reaction mixture. However, it is often advantageous to purify the epimer mixture at least once by crystallization from a suitable solvent, column chromatography, partition chromatography or trituration in a suitable solvent. Such purification, while not necessarily separating the epimers, eliminates additional substances such as starting material and unwanted by-products.

The absolute stereochemical structure of the epimers has not been fully elucidated. However, both epimers of a particular compound have the same type of antibacterial activity.

Among the compounds of formula 1, those in which R is thienyl or substituted thienyl substituted by alkyl having 1 to 2 carbon atoms or carbomethoxy are preferred.

Of the compounds of formula 2, those in which R e is phenyl, thienyl or substituted thienyl substituted by alkyl having 2 to 3 carbon atoms are preferred.

Of these, 11-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin, 11-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 and 4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) oleandomycin.

The process according to the invention for the preparation of the antibacterial 4 "-deoxy, 4" -sulfonylamino-oleandomycin derivatives of the formulas 1 and 2 starting from 4 "-deoxy-4" -amino-oleandomycin or its 11-alkanoyl derivative can be described as follows: 6 67709 ^ w (ch3) 2 ~ XHN (CH3> 2 h ^ <XX jf \ Xx> ^ 'CL ~> \ jr £ r Γ 2 5' S-X1 '*' nhso.r OCH, I 1 b OCH , 1 -4 _ N (CH->), XP RV <HN (OH3) 2 # .rka +> wfx V CX Χχχχ och3 I 2 och3 2 in which formulas R 1 and R 2 have the same meaning as above.

These reactions are performed between 4 "-deoxy-4" -amino-oleandomycin and a suitable sulfonyl halide in the presence of a suitable acid scavenger in a reaction-inert solvent.

In practice, the reaction is carried out by reacting 1 mole of 4 "-amino-oleandomycin with a 1 mole + 2-3% excess of sulfonyl halide. An acid scavenger, which may be an inorganic or organic compound, is used in 1 mole + 4- 6% excess.

The acid-binding agent can be an alkali metal or alkaline earth metal hydroxide, hydride or carbonate or also a tertiary organic amine. In addition, secondary amines, such as diisopropylamine, which are sufficiently blocked to react with the sulfonyl halide reactor 7 67709 used may be used. A particularly suitable acid scavenger is triethylamine.

The reaction-inert solvent used in the above process should be one that sufficiently dissolves the reaction participants and does not react to a greater extent with either the reaction participant or the product formed. Polar solvents that are miscible or immiscible with water are preferred. Particularly preferred are methylene chloride and acetone-water.

Since the amino-oleandomycins decompose somewhat on heating, it is preferable to carry out the preparation of the compounds of formulas 1 and 2 at 0-25 ° C. It is particularly preferred to carry out the reaction at room temperature.

The reaction time is not critical and depends on the reaction temperature, the concentrations of the starting reagents and the reactivity with respect to each other. When the reactions are carried out at room temperature and using the concentrations of reagents indicated below, the reaction is practically complete in 2 to 48 hours.

Upon completion of the reaction, the reaction mixture can be treated in two different ways, both of which are known in the art. In another method, water is added to the reaction mixture, a water-immiscible solvent containing the desired product is separated off, and then the crude product is separated from the solvent. When a water-miscible solvent is used as the reaction-inert solvent, the product is extracted from the reaction mixture to which water has been added as a water-immiscible solvent such as methylene chloride.

In another method, the reaction mixture is evaporated to dryness and the product is separated by extraction with acetone from a salt formed from an acid scavenger and a hydrogen halide by-product. The acetone extract can then be evaporated to dryness to give the crude product.

The crude product or its acetone solution is purified by a known method by chromatography on silica gel, or by crystallization.

8 67709

The 4 "amino starting materials used in the preparation of the antibacterial agents of the present invention are synthesized by oxidizing natural oleandomycin followed by amination of the resulting ketone as described below.

Of course, in utilizing the chemotherapeutic activity of the compounds of the present invention that form salts, it is preferred to use pharmaceutically acceptable salts. Although water insolubility, high toxicity, or lack of crystalline nature may make a salt species unsuitable or less desirable for pharmaceutical use as such, water-insoluble and toxic salts can be converted to the corresponding pharmaceutically acceptable bases by any suitable acidification, or by decomposition with a suitable base. addition salt.

Examples of acids which form pharmaceutically acceptable anions include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric or sulfuric acid, phosphorus, acetic, lactic, citric, tartaric, succinic, malenic, gluconic, aspartic, glutamic, pyroglutamic and lauric sulfuric acid.

The novel 4 "-deoxy-4" -amino-oleandomycin derivatives described herein have in vitro activity against a variety of gram-positive microorganisms, such as Staphylococcus aureus and Streptococcus pyogenes, and certain gram-negative microorganisms. such as spherical and elliptical microorganisms (cocci). Their activity can be easily demonstrated by in vitro experiments with various microorganisms in a brain-heart infusion medium by a standard double dilution technique. In order to demonstrate the advantage of the compounds of formulas 1 and 2 over previously known compounds, in vitro experiments were performed on different strains of several gram-positive and gram-negative bacteria by determining the minimum concentration inhibition (MIC) using DE 421 488 for comparison. the compound of Example 3 having the formula 119 67709 n HN (CH.) 0 vo 1 3 2 0 <*.

For example, for several Staphylococcus aureus strains, the MIC values of the compound of Example 3 of the invention were 0.025 mcg / ml and the compound of Example 27 was 0.10-0.20 mcg / ml when the reference compound was in the range of 0.4-1.5 mcg. / ml. Similarly, for several strains of gram-negative bacteria, such as Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium, the MIC values of the compounds of the invention were clearly more preferable.

Due to their in vitro activity, the new compounds are useful for topical use as ointments, creams, etc., for sterilization, e.g., sterilization of hospital equipment, and as industrial antimicrobes, e.g., for water treatment, air control, and as paint and wood preservatives.

For in vitro use, e.g. topical use, it is often convenient to form the product of the selected compound with a pharmaceutically acceptable carrier such as a vegetable or mineral oil or ointment base. The compound may also be dissolved or dispersed in a liquid carrier or solvent such as water, alcohol, glycols or mixtures thereof, or other pharmaceutically acceptable inert media, i.e. media which do not adversely affect the active ingredient. The active ingredient is generally used for these purposes in an amount of from about 0.01% to about 10% by weight of the composition.

In addition, many of the compounds of the invention are active against gram-positive microorganisms when administered orally and / or parenterally to animals, including humans. In vivo susceptibility to microorganisms is more limited and can be determined by conventional methods by infecting mice of substantially equal weight with the test organism and then treating the mice orally or subcutaneously with the test compound. In practice, the experiment is performed by intraperitoneally administering to mice (e.g. 10) an appropriately diluted inoculum containing 1 to 10 times the amount of LD50 (the lowest concentration of the microorganism which causes 100% death) in the micro- organisms. Simultaneously, control experiments are performed in which mice are given more diluted inoculations to control for possible variation in the viability of the test organism. The test compound is administered 0.5 hours after infection, and the administration is repeated after four, 24 and 48 hours. Surviving mice are observed for four days after the last treatment and the number of survivors is recorded.

When used in vivo, these novel compounds may be administered orally or parenterally, e.g., by subcutaneous or intramuscular injection, at a dose of about 1 to about 200 mg / kg of body weight per day. The preferred dosage range is about 2 to 100 mg / kg per day and the most preferred range for all is about 2 to about 50 mg / kg per day.

The following examples are intended to illustrate the invention.

Example 1 11-Acetyl-4H-deoxy-4 "- (2-thienylsulfonylamino) olandomine To 30 ml of dry methylene chloride is added 2.9 g (4.0 mmol) of 11-acetyl-4" -deoxy- 4'-Amino-oleandomycin, 740 mg (4.1 mmol) of 2-thienylsulfonyl chloride and 0.58 ml (4.2 mmol) of triethylamine, and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 50 ml of water, and then washed with saturated brine and dried over sodium sulfate. The solvent is removed under reduced pressure and the residual foam is purified by chromatography on a column of silica gel using acetone as solvent and eluent. The product-containing fractions are combined and evaporated to dryness in vacuo to give 1.3 g.

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

Example 2

Using 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and the appropriate sulfonyl chloride as starting materials in the process of Example 1, the following compounds are obtained: 67709 ro n (ch3) 2 ch3co, t & w> v / ^ vHnhso2r OCH 3 NMR (δ, CDCl 3) R t 2.08 (3H) s; 2.30 (6H) s; 2.67 (2 H) m; Jj ^ 3.23 (3H) s and 6.87 and 7.45 (2H) s.

O _γΌΗ 2.09 (3H> s; 2.42 (6H) a; 2.70 (2H) m CH3Chh4 ^ - and 3.26 (3H) S.

O N - v 2.0 (3H) s; 2.33 (6H) s; 2.40 (3H) s; ΓΗ ΓΝΗ-ί> 2.66 (2H) d; 3'33 (3H) S 33 7'86 L 3L S (1H) s.

I 2.03 (3H) s; 2P 33 (6H) s; 2.66 (2 H) d; Δ 3.03 (3H) s and 7.40-9.16 (4H) m.

H 'aN \ 2.06 (3H) s; 2.36 (6H) s; 2.71 (2 H) s; 3.28 (3H) s and 7.36-7.56 7.66-1.72 (4H) m.

CH. OF

I | "Y 2.08 (3H) s; 2.31 (6H) s; 2.59 (6H) s; N 2.65 (2H) s; 3.01 (3H) s and 7.11 (1) s.

ch3 12 67709 2.07 (3H) s; 2.32 (6H) s; 2.67 (2H) sj jj-ζ 3.20 (3H) s; 7.32 (1H) mj 7.43 (1H) m> S 'and 8.02 (1H) m.

2.06 (3 H) s; 2.29 (6H) s; 2.64 (2 H) m; 3.2 δ (3H) s; 6.5 2 (1H) m-, 6.7 7 (1H) m f and 7.29 (1H) m.

B

- / 2.07 (3H) s; 2.62 (6H) s; 3.25 (3 H) s; J! ') 3.83 (3H) s; 3.95 (3H) s and 7.30 (2H) m.

CH3 ° 2C f ΓΗ 3 2.08 (3H ^ i 2.31 (6H) s; 2.68 (2H) m; 3.25 (3H) s; 6.74 (1H) m; 7.48 (1H) m 0 and 8.0 0 (1H) m .

Example 3 11-Acetyl-4n-deoxy-4t '- (p-chlorophenylsulfonylamino) oleandomycin

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 528 μΐ (4.2 mmol) of triethylamine in 20 mL of methylene chloride is added 865 mg (4.1 mmol) of p-chlorophenyl sulfonyl chloride are added portionwise, and the reaction mixture is stirred at room temperature overnight. The mixture is evaporated to dryness in vacuo and the residue is taken up in 10 ml of acetone. The suspension is filtered and the filtrate is chromatographed on 160 g of silica gel using acetone as eluent. Collect 10 ml fractions, collecting fractions 51-63 and evaporate under reduced pressure to give 857 mg of pure product. Fractions 42-52 and 6, 92 contain 1.21 g of less pure product.

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

In a similar manner, 20 g of 11-acetyl-4 "-deoxy-1H" -amino-oleandomycin, 7.24 g of p-chlorophenylsulfonyl chloride and 5.36 g of triethylamine are obtained in acetone (350 ml) and water (350 ml). ml) of the mixture 17.1 g of the desired product which crystallized from the reaction mixture, m.p. 202-203.5 ° C. The analytical sample is crystallized from ethanol / water.

Example 4 Using the procedure of Example 3 starting from the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, the following compounds are obtained:

II

67709 HN (CH3) 2 CH3CO (λmax, λmax and R NMR (δ, CDCl3) / = \ 2f08 (3H) s; 2.33 (6H) s; 2.70 (2H) d; X- 3.11 (3H) s, and 7.3-8.2 (4H) q.

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

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

Cl f = 2.03 (3H) s; 2.33 (6H) s; 2.63 (2 H) d; ν v 3.23 (3H) s and 7.2-8.4 (4H) m.

F

Δ = 2.13 (3H) s; 2.35 (6H) s; 2.70 (2 H) d; \\ /) - 2.90 (3H) s and 7.0-8.2 (4H) s.

Λ max 2.10 (3H) s; 2.33 (6H) s; 2.66 (2 H) d;

Br ~ \ v, / f ~ 3.10 (3H) s and 7.5-7.93 (4H) m.

14 67709

Example 5 11-Acetyl-4 "-deoxy-4- (o-tolylsulfonylamino) olearoyl

A solution of 2.9 g (4.0 mmol) of 11-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, stirred at room temperature for 48 hours. The reaction mixture is poured into 50 ml of water, the separated organic phase is washed with saturated brine and dried over sodium sulfate. The solvent is removed in vacuo and the yellow foam obtained is chromatographed on a 3 cm diameter column of 200 g of silica gel. The product is eluted from the column with acetone to collect 10 ml fractions. The pure product-containing fractions determined by thin layer chromatography are combined and evaporated to dryness under reduced pressure to give 3.1 g of the title compound.

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

Example 6

The procedure of Example 5 is repeated using the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-Olean domycin as starting materials to give the following compounds: 67709 N (CH3) 2 ch3co νΑΛ 'ν ^ Οΰ och3 NMR (<5, CDC1-) K.

Δ = \ 2.03 (3H) s; 2.30 (6H) s; 2.66 CH 0 ~ \\, V (2H) d; 3.06 (3 H) s; 3.83 (3 H) s; 3 '- 6.8-8.2 (4H).

2.03 (3H) s; 2.33 (6H) s; 2.66, rH, r 2 / V (2H) d; 3.06 (3 H) s; 7.3- (CH3) 3C 8.0 (4H) m.

OCH 3 r = / 2.08 (3H) s; 2.30 (6H) s; 2.66 / β- (2H) d; 2.83 (3 H) s; 4.03 (3 H) s; V δ 6.8-8.2 (4H) m.

r = 2.06 (3H) s; 2.30 (6H) s; 2.43 CH V (3H) s; 3.10 (3H) s; 2.66 (2 H) d; J 1 - / 7.23-7.40 (2H) d; 7.76-7.93 (2H) d.

67709 16

Example 7 11-Acetyl-4 "-deoxy-4" -phenylsulfyl oil-oleo-andomycin In an ice bath cooled solution of 2.91 g (4.0 mmol) of 11-acetyl -4 "-deoxy-4" -amino-oleandomycin and 424 mg (4.2 mmol) of triethylamine in 30 ml of methylene chloride are added, 722 mg (4.1 mmol) of benzenesulfonyl chloride. After 10 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature overnight. 50 ml of water are poured into the reaction, the organic phase is washed with saturated brine and dried over sodium sulfate. Removal of the solvent gives a crude product which is further purified by chromatography on 160 g of silica gel eluting with acetone. TLC fractions (10 ml each) 61-93 show pure product, these fractions are combined and evaporated to dryness under reduced pressure to give 1.5 g of the desired product.

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

The following compounds are also prepared from the appropriate starting materials by the method of Example 7: 11-Acetyl-4 "-deoxy-4t- (2-naphthylsulfonylamino) Olean-domycin NMR (δf, 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 11-acetyl-4 "-deoxy-4'-benzylsulfonylamino-olean- also NMR (J, CDCl 3): 2.00 (3H) s; 2.30 (6H) s; 2.63 (2 H) d; 3.46 (3H) s; 4.33 (2H) s; and 7.36 (5H) s.

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

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amihooleandomycin, 1.12 g (3.6 mmol) of p-benzyloxycarbonylphenylsulfonyl chloride and 379 mg (3.75 mmol) of triethylamine in 25 ml of methylene chloride, stirred at room temperature overnight. The solvent is removed in vacuo and the residue is triturated in 10 ml of acetone. The solid is filtered and the filtrate is chromatographed.

II

17 67709 are purified on 280 ml of silica gel, eluting with acetone and collecting 10 ml fractions. Fractions 90-203, which according to thin layer chromatography contain the most pure product, are combined and evaporated under reduced pressure to give 1.25 g of the desired product.

N MR (<f, CDCl 3): 2.04 (3H) s; 2.30 (6H) s; 2.66 (2 H) d; 3.01 (3H) s · 5.48 (2H) s; 7.50 (5H) s; and 8.03 - 8.53 (4H) m.

Example 9 Using the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-oleandomycin as starting materials and following the procedure of Example 8, the following compounds are obtained: 67709 18 K (CH 3> 2 ΓΟ H, J 2

^ JC

- Υ <ΛΑ CHyO ,,, s ^ y * ^ 'λ

O | ^ -NHS02R

0 CH 3 R NMR (δ, CDCl 3) 2.06 (3H) s; 2.30 (6H) s; 2.66 (V (2H) d); 3.03 (3H) s; 3.96 (3H) V 7 s; and 7.3-9.0 (4H) m.

o = c NOCH 3 γ-V 2.05 (3H) s; 2.30 (6H) s; 2r65 (trans (2H) d; 3.01 (3H) s; 5.43 (2H) d; y / 7.46 (5H) s; and 7.33-8.70 (4H) m).

C = 0

NOCH 2 O δ No. 2.06 (3H) s; 2r30 (6H> s: 2r66 3 \\ // - (2H) s, 3.06 (3H) s, 4.0 (3H) s, and 7.8-8.4 (4H) m)

Δ = 2.10 (3H) sj 2.30 (6H) s; 2.70 - (- 2H) d; 3.0 (3H) s; and 4.10 N ((3H) s.

C = O CH 0/1967709

Example 10 11-Acetyl-β-deoxy-U "- (o-nitrophenylsulfonylamino) -oleandomycin To 50 ml of methylene chloride is added 5 g (6.8 mmol) of 11-acetyl-4" -deoxy-4 "-amino- oleandomycin, 1.5 g (7.0 mmol) of o-nitrobenzenesulfonyl chloride and 0.98 ml of triethylamine, and the mixture is stirred at room temperature for 4-8 hours, the same volume of water is poured into the reaction mixture, the organic phase is washed with saturated brine and dried over sodium sulfate. The crude crude product is purified by chromatography on 140 g of silica gel on a column 3 cm in diameter and eluting with acetone Fractions 20-30 (50 ml each) are collected, combined and evaporated to dryness to give 3.4 g of the desired product.

NMR (δ, 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.

In a similar manner, using the appropriate starting materials and the above procedure, the following compounds are obtained: 11-acetyl-4 ', r - deoxy-9' '- (m-nitrophenylsulfonylamino) -oleandomycin NMR (/, CDCl 3): 2, 06 (3H) s; 2.30 (6H) s -, 2.66 (2H) d; 3.06 (3 H) s; and 7.4-9.0 (4H) m and 11-acetyl-4H-deoxy-9,1- (p-nitrophenylsulfonylamino) -oleandomycin NMR (J, CDCl 3): 2.10 (3H) s; 2.35 (6H) s; 2.68 (2 H) d; 3.06 (3 H) s; and 8.0 - 8.6 (4H) m.

Example 11 11-Acetyl-4 "-deoxy-4" - (p-hydroxyphenylsulfonylamino) -oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 701 mg (3.65 mmol) of p-hydroxyphenylsulfonyl chloride and 51.8 g of triethylamine in 25 ml of methylene chloride, stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue is treated with 10 ml of acetone. The insoluble matter is filtered off and the filtrate is chromatographed on 200 g of silica gel and eluted with acetone. Fractions 116-175, which contained pure product according to thin layer chromatography, were combined and evaporated to dryness under reduced pressure to give 550 mg of the desired product.

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

Example 12 11-Acetyl-4 "-deoxy-M-IT- (m-carboxamidophenylsulfonylamino) oleandomycin in 20 ml of methylene chloride with 2.91 g (4.0 mmol) of 11-acetyl-4" -deoxy-4 "-amino-oleandomycin and 434 mg (4.2 mmol) of triethylamine, 898 mg (4.1 mmol) of m-carboxamidophenylsulfonyl chloride are added and the reaction mixture is stirred for 48 hours. The solvent is evaporated off under vacuum. and the residue is treated with 25 ml of acetone, the triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel, 50 ml fractions are collected and the purity of the product is determined by thin-layer chromatography, and fractions 66-93 are combined and evaporated under reduced pressure to give 800 mg. product.

NMR (δ, 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 13 11-Acetyl-4 "-deoxy-4" - (p-acetamidophenylsulfonylamino) oleandomycin

A solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 955 mg (4.1 mmol) of p-acetamidophenylsulfonyl chloride and 424 mg (4, 2 mmol) of triethylamine in 20 ml of methylene chloride, stirred at room temperature for 48 hours. The reaction mixture is evaporated under reduced pressure and the resulting foam is treated with 10 ml of acetone. Insoluble triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 160 g of silica gel and eluted with acetone. Fractions 42-86, which according to thin layer chromatography contain pure product, are evaporated in vacuo to give 1.2 g of the desired product.

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

Example 14 11-Acetyl-4 "-deoxy 1-4 (p-cyanophenylsulfonylamino) -oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deox-21 67709 si-4" -amino-oleandomycin, 734 rag (3.65 ramol) of p-cyanophenylsulfonyl chloride and 518 ( 3.75 mmol) of triethylamine in 25 ml of methylene chloride, stirred at room temperature overnight. The solvent is removed in vacuo and the residue is taken up in 10 ml of acetone. The insoluble matter is filtered off and the filtrate is chromatographed on 120 g of silica gel, eluting with acetone. Collect 10 ml fractions, combine fractions 47-83 and evaporate under reduced pressure to give 281 mg of the desired product.

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

Example 15 11-Acetyl-4''-deoxy-4 "- (p-trifluoromethylphenylsulfonylamino) oleandomycin

To a solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 518 [mu] l (3.75 mmol) of triethylamine in 25 ml of methylene chloride are added 891 mg (3.65 mmol) of p-trifluoromethylphenylsulfonyl chloride, and the reaction mixture is stirred for 18 hours. The solution is evaporated under reduced pressure and the residue is triturated in 15 ml of acetone. The solid is filtered and the filtrate is chromatographed on silica gel to give 287 mg of the desired product.

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

Example 15 11-Acetyl-411-deoxy-4 "- (2,2,2-trifluoroethylsulfonylamino) oleandomycin

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 666 mg (3.65 mmol) of 2,2,2-trifluoroethylsulfonyl chloride and 379 mg (3.75 mmol) of triethylaraine in 25 ml of methylene chloride are stirred for 30 hours at room temperature. An additional 3 33 mg of sulfonyl chloride and 27 0 μm of triethylamine are added to the mixture and stirring is continued for four hours. The solvent is removed in vacuo and the residue is treated with 20 ml of acetone. The solid is filtered and the filtrate is chromatographed on 110 mg of silica gel eluting with acetone and collecting 10 ml fractions. Fractions 50-80 are combined and evaporated to give 385 mg of the desired product.

Δ 6770 δ NMR (δ, CDCl 3): 2.06 (3H) s; 2.26 (6H) s; 2.60 (2H) d; and 3.36 (3H) s.

Example 17 11-Acetyl-4 "-deoxy-4" - (methylsulfonylamino) oleandomycin

A solution of 2.91 g (k, 0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 467 mg (4.1 mmol) of methylsulfonyl chloride and 424 mg (4.2 mmol) of triethylamine in 25 ml of methylene chloride, stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue is taken up in 20 ml of acetone. The triethylamine hydrochloride is filtered off and the filtrate containing the product is chromatographed on 180 g of silica gel, eluting with acetone and collecting 6 ml fractions. Fractions 67-133 are combined and evaporated in vacuo to give 1.2 g of the desired product.

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

Example 18 11-Acetyl-4 "-deoxy-4" - (3,4-dichloro-phenylsulfonylamino) -indomycinyl-11-acetyl-4 "-deoxy-4" -amino-oleandomycin (2.9 g, 4.0 mmol), 1.0 g (4.1 mmol) of 3,4-dichlorophenylsulfonyl chloride and 0.57 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride are stirred at room temperature for 18 hours. To the reaction mixture is added 50 ml of water, the organic phase is washed with saturated brine and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel using acetone to elute. Fractions found to contain product by thin layer chromatography are combined and evaporated to dryness to give 1.3 g of the desired product.

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

Example 19

Following the procedure of Example 18 and using the appropriate reagents, the following compounds are obtained: tt 23 67709 n H H (CH2) n -7 ~ 0 ~ \ \ J 1 o vs V ^ i

ChJJcO ι, γ '"> 1 KoV <\ ^ ΚΛ [!

d ^ f ^^ NHSO R

och 3 R NMR (J, CPCl 3) λ max C 2.0 (3H) s; 2.3 δ (6H) s; 2.7 O - (2H) d; 3.33 (3H) s; and 7.3-8.6 (3H) m.

Cl 2.10 (3H) s; 2.31 (6H) s; 2.66 / - (2H) d; 3.30 (3H) s; and 7.2- C1 8.4 (3H) m.

CH 3 2.03 (3H) s; 2.30 (6H) s; 2.66

Cl / ~ (3H) s; 3.10 (3H) s; and 7.1-8.1 (3H) m1.

v \ _ // _ ^ 2.06 (3H) s; 2.33 (6H) s; 2.70

Cl- (v / V- (2H) d; 3.13 (3H) s; and 7.4-9.6 (3H) m).

) /

WELL

2 NO 2.06 (3H) s; 2.40 (6H) s; 2.66 / = / 2 (2H) d; 3.25 (3 H) s; and 7.2-8.6 (3H) m-1.

C 1-4 2.06 (3H) s 2.33 (6H) s; 2.63

/WELL

2 (2H) d; 2.81 (3 H) s; 3.63 (3 H) s;

ru Π / V

3 // 'and 7.0-8.2 (3H) m 1.

__ / NO 2 2.0 δ (3 H) s ·, 2.3 δ (6H) s; and O 2 N 2 - 8.4-9.0 (3H) m 1.

NMR: DMSO / CDCl 3 δ 67709

Example 20 11-Acetyl-4 "-deoxy-4" - (2,3,4-trichlorophenylsulfonylearning) oleandomycin

A solution of 2.9 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin. 1.15 g (4.1 mmol) of 2,3,4-trichlorophenylsulfonyl chloride and 0.57 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride are stirred at room temperature for 18 hours. The organic layer was washed with water (1 x 50 mL) and brine (1 x 50 mL) and then dried over sodium sulfate. The solvent is evaporated off under vacuum and the residue is chromatographed on 150 g of silica gel and eluted with acetone, collecting 7 ml fractions. Fractions 60-100 are combined and evaporated to dryness to give 800 mg of the desired product.

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

Following the above procedure and using the appropriate starting materials, the following compounds are obtained: 1-acetyl-4 "-deoxy-4" - (3,4,5-trichlorophenylsulfonylamino) oleandomycin, 11-propionyl-4 "-deoxy-4 '- (2,4,6-Trichlorophenylsulfonylamino) leandomycin and 11-acetyl-4 "-deoxy-4" - (2,3,5-trichlorophenylsulfonylamino) oleandomycin.

Example 21 11-Acetyl-4 "-deoxy-4" - (2-hydroxy-3,5-dichlorophenylsulfonylamino) oleandomycin

The procedure of Example 20 is repeated starting from 11-acetyl-4 "-deoxy-4" -amino-oleandomycin as 2.55 g (3.5 mmol), 954 mg (3.65 mmol) of 2-hydroxy-3,5-dichlorophenylsulfonylchloride. and 518 (3.75 mmol) of triethylamine in 25 ml of methylene chloride, chromatography on silica gel (220 g) gives 483 mg of the desired product.

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

Example 22 11-Acetyl-4 ', - deoxy-4' - (3-amino-4-chlorophenylsulfonylamino) oleandomycin

A suspension of 500 mg of 10% palladium-carbon in 50 ml of ethyl acetate containing 1.0 g of 11-acetyl-4 "-deoxy-4" - (3-nitro-4-chlorophenylsulfonylamino) oleandomyc i in, rav i s-

II

25 67709 are rolled in a hydrogen atmosphere at an initial pressure of 345 kPa at room temperature overnight. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residual white foam is chromatographed on 160 g of silica gel, eluting with acetone collecting 50 ml fractions. The product-containing fractions are combined and evaporated under reduced pressure to give 450 mg of the desired product.

NMR (c *, CDCl 3): 2.03 (3H) s; 2.33 (5H) s; 2.66 (2H) d ^ 3.16 (3H) s; 3H) m.

In a similar manner, using the appropriate nitro compound prepared in Example 10: 11-acetyl-4 '- deoxy-4' - (m-aminophenylsulfonylamino) oleandomycin NMR (δ CDCl 2): 2.03 (3H) s; 2.30 (6H) S-, 2.63 (2H) d; 3.10 (3H) s; and 7.0-7.8 (4H) m and 11-acetyl-4, f-deoxy-4 "- (p-aminophenylsulfinyl) oleandomycin NMR, (<3 ', CDCl 3): 2.06 (3H) s 2.31 (6H) s, 3.02 (3H) s, and 6.4-7.8 (4H) dd.

Example 23 11-Acetyl-4 "-deoxy-4 '- (3-methyl-2-thienylsulfonylamino) oleandomycin in 100 g (0.13 moles) of 11-acetyl-4" -deoxy-4 "-amino-Olean -domycin in 900 ml of methylene chloride, 593 ml of triethylamine are added and the solution is stirred for 10 minutes, then 3-methyl-2-thienylsulfonyl chloride (41.9 g, 0.213 mol) in 300 ml of methylene chloride is added dropwise over one hour, The reaction mixture is poured into 2 liters of water, the organic layer is separated, washed successively with water (2 x 250 ml) and brine (1 x 250 ml) and dried over sodium sulphate, the solvent is evaporated off under vacuum and the residue is chromatographed for 1.5 hours. kg of silica gel on a 105 x 6.5 cm column, eluting with acetone to give fractions between 2.3 and 6 l. These are combined, the solvent is evaporated off under reduced pressure to give a foam, the foam is treated with diethyl ether to give 66.4 g. g of the desired product, mp. 184-185.5 ° C.

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

To 2 g of the free base obtained above in 15 ml of ethyl acetate-___ 1.

26 67709 tia, 0.12 ml of phosphoric acid are added and the resulting solution is stirred at room temperature. After 20 minutes, crystals begin to form, which after two hours are filtered, washed with ethyl acetate and dried to give 1.3 g of 11-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) oleaindomycin phosphate.

NMR (J, CD 3 OD): 2.01 (3H) s; 2.15 (3H) s, 2.56 (2H) m; 2.83 (6H) s; 3.0 (3H) s; 6.88 and 7.42 (2H).

Example 24

The procedure of Example 23 is repeated starting from the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -arino-Olean domycin to give the following compounds: (ch) 67709 H0 <, „A.

o r i V "xi n - ^" '0'v N x ^ λΛ' '.-! Ί O "* r ', \ W" o 1 i \ ^ r ·.

"" o K0 / r 0 V0 '·, -

V'V

I NHSO R and 3 NMR (J, CDCl 3 2.08 (3 H) s; 2.33 (6 H) s; 2.38 (3 H) s ·, A q \ 2.6 δ (2H) m; 3.27 (3H) s; 6.08 and CK3 6.9 2 (2H).

2.0 δ (3H) s; 2.3 δ (6H) s; 2.68 (2 H) m; 3.30 (3H) s; 3.71 (3 H) s; 6.44-6.70 CH 3 (1H) m and 7.18-7.39 (2H) m.

CH3N_> 2.03 (3H) s; 2.25 (3H) s; 2.51 (6H) s; SV - 2.61 (2H) m ·, 3.15 (3H) s; 7.07 (1H) m and 7.38 (1H) m.

c H \\ _ 2.06 (3H) s; 2.33 (6H) s; 2.65 (2 H) m; 25 S "3.2 2 '(3H) s ·, 6.73 and 7.45 (2H).

__2.08 (3H) s; 2.34 (6H) s; 2.54 (3 H) s; CH 3 2.6 δ (2H) s; 3.2 δ (3H) s; 6.7 3 and 7.46 C2H).

28 67709

Example 25 11-Acetyl-4 "-deoxy-4" - (5-carbomethoxy-2-pyrrylsulfonylamino) oleandomycin

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 is cooled in an ice bath and treated portionwise with 1 0.0 g (0.0044 mol) of 2-carbomethoxy-5-pyrrylsulfonyl chloride. The reaction mixture is allowed to warm to room temperature and stirred for 3.5 hours, then poured into 200 ml of water. The pH of the aqueous layer is adjusted to 9.5 with 1 N aqueous sodium hydroxide solution, and the methylene chloride layer is separated, washed successively with water and saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give 3.8 g of crude product as a white foam. The resulting foam is chromatographed on silica gel in a 3.25 x 38 cm column and eluted with acetone. Fractions of about 10-12 ml are collected and fractions 40-220 are combined. They evaporate the solvent in vacuo to give 3.4 g of the desired product as a white foam.

NMR (J, CDCl 3): 2.05 (3H) s; 2.58 (6H) s 2.67 (2H) m; 3.25 (3H) s; 3.90 (3H) s; 7.20 (1H) m and 7.52 (1H) m.

Example 26

Following the procedure of Example 25 and using the appropriate sulfonyl chloride and 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, the following analogs are obtained:

II

29 67709 N (CU1) _ HO I 2 v <"Λ OTI, 0 o CH3CO u ,, ^ \. ·· '' '; a T IsHSO ^ R 0CH3 R NTMR (6, CDCl3) j ~~ \ 2.09 ( 3H) s: 2.32 (6H) s, 2.69 (2H) m: CH OC -M y - 3.22 (311) s, 3.95 (3H) s, 7.61 and J 7.75 (2H).

CH O C

N-y 2.11 (3H) s; 2.34 (6H) s; 2.70 (2 H) m; (±) - 3.24 (3H) s; 3 r 94 (3H) s; 8.06 and S 8.28 (2H).

j-y 2.08 (3H) s; 2.29 (6H) s; 2.67 (2H) s; CH O C-H Λ_ 318 (3H) s; 3.94 (3H) s; 7.02 and J 10 7.20 (2H).

30 67709

Example 27 4 "-deoxy-4" - (p-chlorophenylsulfonylamino) oleandomycin

A solution of 3.0 g of 4, T-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 taken up in vacuo. The insoluble triethylamine hydrochloride is filtered off and the filtrate is chromatographed on 180 g of silica gel, eluting with acetone collecting 50 ml fractions, fractions 18-27 are combined and evaporated under reduced pressure to give 1.10 g of the expected product.

N MR (oT, CDCl 3): 2.33 (6H); 2.83 (2 H) d; 3.06 (3 H) s; and 7.2-8.4 (UH) m.

Example 28 H-Deoxy-H "- (p-toluenesulfonylamino) oleandomycin

In a similar manner to Example 27, 30 g (4.0 mmol) of 4 "-deoxy-4" -amino-oleandomycin, 782 g (u.1 mmol) of p-toluenesulfonyl chloride and 424 mg (4.2 mmol) of triethylamine were obtained. ml of methylene chloride to react with stirring overnight at room temperature. Further work-up of the crude product by K-chromatography on 180 g of silica gel and collection of 10 ml fractions gives the combined fractions 90-148 and evaporation to dryness 1.4 g of the desired product.

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

By a similar method, 4lt-deoxy-4 "- (2-thienylsulfonylamino) oleandomycin is also obtained.

NMR (δ, CDCl 3): 2.29 (BH) s -, 2.88 (2H) m; 3.2 (3H) s; 5.6 (1H) m and 7.33 (3H) m.

Example 29 11-Acetyl-4 "-deoxy-4 '' - (2-thienylsulfonylamino) Olean domycin phosphate

To a solution of 15.0 g of 11-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin in 100 ml of ethyl acetate is added 1.0 ml of phosphoric acid. The resulting suspension is stirred for four hours at room temperature. The solid is filtered, washed with ethyl acetate and dried to give 12.5 g of the desired salt, m.p. 16 8 ° C (dec.).

31 67709

In a similar manner, 11-acetyl-N-deoxy-4 '- (3-methyl-2-thienylsulfonylamino) oleandomycin phosphate is prepared, m.p. 184-188 ° C and 11-acetyl-14 "-deoxy-M ·" - (p-chlorophenylsulfonylamino) oleandomycin phosphate, m.p. 204-2Q5 ° C.

Preparation A

4 "-deoxy-H '' - oxo-oleandomycins I. 11-Acetyl-4" -deoxy-4 "-oxo-oleandomycin a. 11,2'-Diacetyl-41'-deoxy-4, t-oxo-oleandomycin i ini

To a dry flask equipped with a magnetic stirrer and a nitrogen inlet tube is added 3.36 ml of dimethyl sulfide to a mixture of N-chlorosuccinimide (4.5 g), benzene (50 ml) and toluene (150 ml) cooled to -5 ° C. After stirring at 0 ° C for 20 minutes, the contents of the flask are then cooled to -25 ° C and 5.0 g of 11,2'-diacetyloleandomycin in 100 ml of toluene are added. Cooling and stirring are continued for two hours, then 4.73 ml of triethylamine are added. The reaction mixture is stirred at 0 ° C for 15 minutes, then the mixture is poured into 500 ml of water, the pH is adjusted to 9.5 with 1N aqueous sodium hydroxide solution, the organic layer is separated, washed with water and brine and dried over sodium sulfate. 4.9 g of the desired product are obtained in the form of a foam.

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

b. 11-Acetyl-4,1-deoxy-4M-oxo-oleandomycin

A solution of 4.0 g of 11,2'-diacetyl-4 "-deoxy-4" -oxo-oleomycin in 75 ml of methanol is stirred at room temperature overnight. The reaction mixture is evaporated to dryness under reduced pressure to give the desired product as a foam. The evaporation residue is dissolved in diethyl ether, the solution is treated with hexane to give 2.6 g of product as a white solid, m.p. 112-117 ° C.

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

Similarly, using 11,2'-dipropionyl-4 "-deoxy-4" -oxo-oleandomycin or 11-propionyl-2'-acetyl-4 "-deoxy-4" -oxo-oleandomycin in the above method, 11- propionyl-4 "-deoxy-4" -oxo-oleandomycin.

67709 II. 4 "-deoxy-4" -oxo-oleandomycin a. 2 * -Acetyl-N, N-deoxy-N-oxo-oleandomycin in a cloudy solution of N-chlorosuccinimide (467 mg) cooled to -5 ° C in 20 ml of toluene and In 6 ml of benzene, dimethyl sulfide (0.337 ml) is added under nitrogen. After stirring at 0 ° C for 20 minutes, the mixture is cooled to -25 ° C and 1.46 g of 2'-acetyloleandomycin and 15 ml of toluene are added. Stirring is continued for two hours at -20 ° C, then 0.46 ml of triethylamine are added to the mixture. The reaction mixture is allowed to stand at -20 ° C for another five minutes, then it is allowed to warm to 0 ° C. The mixture is poured with stirring 50 no water and 50 no ethyl acetate. The pH of the aqueous mixture is adjusted to 9.5 by adding aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness in vacuo to give a white foam (1.5 g). Trituration in diethyl ether gives 864 mg of crude product, which is crystallized twice from methylene chloride-diethyl ether to give 212 mg of pure product, m.p. 183-185.5 ° C.

Analysis for C 11 H 19 N 2 O 2 N: C 61.1 H 8.5 N 1.9

Found: C 60.9 H 8.4 N 1.9 NMR (f, CDCl 3): 5.60 (1H) m; 3.50 (3H) s; 2.73 (2 H) m; 2.23 (6H) s and 2.03 (3H) s.

b. 4''-deoxy-411-oxo-oleandomycin

A solution of 1.0 g of 2'-acetyl-4T, -deoxy-4 "-oxo-Olean domycin in 20 ml of methanol is stirred at room temperature overnight. The solution is evaporated to dryness in vacuo to give the desired product as a white foam, 937 mg. .

NMR (δ S, CDCl 3): 5.60 (1H) m; 3.50 (3H) s; 2.85 (2H) m and 2.26 (6H) s.

Preparation B

4'-Deoxy-4 "-amino-oleandomycin 1. 11-Acetyl-4" -deoxy-4 "-amino-oleandomycin

To a suspension of 10 g of 10% palladium on carbon in 100 ml of methanol is added 21.2 g of ammonium acetate, and the suspension is then treated with a solution of 20 g of 11-acetyl-4 "-deoxy-4" -oxo-oleandomycin in 100 ml. methanol. Suspension 67709 is shaken at room temperature in hydrogen gas at an initial pressure of 345 kPa. After 1.5 hours, the catalyst is filtered off and the filtrate is added with stirring to a mixture of water (1200 ml) and chloroform (500 ml). The pH is adjusted to 6.4 to 4.5, and the organic layer is separated. The aqueous layer is extracted once more with 500 ml of chloroform, then treated with 500 ml of ethyl acetate and adjusted to pH 9.5 with 1N sodium hydroxide. The ethyl acetate layer is separated, and the aqueous layer is extracted once more with ethyl acetate. The ethyl acetate extracts are combined, dried over sodium sulphate and evaporated to dryness to give a yellow foam (18.6 g) which is crystallized from diisopropyl ether to give 6.85 g of pure product, m.p. 157.5-160 ° C.

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

The second epimer, which is 20-25% in the foamy crude product, is obtained by gradual concentration and filtration from the mother liquors.

Similarly, using 11-propionyl-4 "-deoxy-4, '- oxo-oleandomycin as a starting material in the above process, 11-propionyl-4" -deoxy-4 "-amino-oleandomycin is obtained.

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

A solution of 20 g of 2'-acetyl-4 "-deoxy-4" -oxo-Olean domycin in 125 ml of methanol is stirred overnight at room temperature, then 21.2 g of ammonium acetate are added. The solution is cooled in an ice bath and 1.26 g of sodium cyanoborohydride are added. The cooling bath is removed and the reaction mixture is stirred at room temperature for two hours. The reaction mixture is poured into 600 ml of water and 600 ml of diethyl ether, the pH is adjusted to 8.3 to 7.5. The ether layer is separated and the aqueous layer is extracted with ethyl acetate. The extracts are collected and the pH of the aqueous phase is adjusted to 8.25. The diethyl ether and ethyl acetate extracts extracted at this pH are likewise recovered, and the pH of the aqueous phase is adjusted to 9.9. The diethyl ether and ethyl acetate extracts extracted at this pH are combined, washed successively with water (1x) and saturated brine, and dried over sodium sulfate. The last extracts obtained (at pH 9.9) are evaporated to dryness and the foam obtained is chromatographed on 160 g of silica gel using chloroform as solvent and first eluent. After collecting 11 12 ml fractions, the eluent is changed to methanol-chloroform (5:95). After fraction 370, methanol-chloroform (10:90) is used as eluent and after fraction 440, methanol-chloroform (15:85). Fractions 85-260 are combined and evaporated to dryness in vacuo to give 2.44 g of the desired product.

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

Claims (2)

35 67709 1. A process for the preparation of therapeutically useful antibacterial 4 "sulfonylamino-oleandomycin derivatives of the formulas N (CH) HO, '3 2 ^ CH3> 2, Vl - 0 0 -.0 nf Λ' VV / xxo- '· 0v ^ 1 1 v | L \\ o ho, L> o 0 x 1!' Λ I Γγ 'o γ ^ ^ 0. o O # 1 "1 o" iro Y “v V \ γ- MHSO PI MR I 2 2 0CHq 2 0CH3 1 3 2 and pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of 1 to 3 carbon atoms, pyridyl, 1,1,1, -trifluoroethyl, phenyl, monosubstituted phenyl having substituent fluorine, chlorine, bromine, iodine, hydroxy, methoxy, cyano, carboxamido, nitro, carbomethoxy, carbobenzyloxy, trifluoromethyl, alkyl having 1 to 4 carbon atoms or acetamido, disubstituted phenyl having substituents selected from chlorine, nitro, amino, methoxy and methyl, trichlorophenyl, hydroxydichlorophenyl, benzyl, naphthyl, thienyl, chlorothienyl, 2-acetamido-5-thiazolyl, 2-acetamido-L'-methyl i-5-thiazolyl; 2-benzimidazolyl; dimethyl-2-pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl or furyl substituted with carbomethoxy or alkyl of 1 to 2 carbon atoms; or 1-methyl-5-carbomethoxy-3-pyrryl; R 2 is alkanoyl containing 2-3 carbon atoms; and R e is phenyl; thienyl; monosubstituted phenyl substituted with chlorine, fluorine, methyl, methoxy or trifluoromethyl; or alkyl-substituted thienyl having 1-2 carbon atoms in the alkyl, characterized in that M (CH) 3; 2 N (CH2) -Ό KO1 of formula 67709; d 1 0 „rJ <YN, -o H0 '" -, I K ·, Λ n S ο ^. -χ I I Ri ° Y ho 4 γ,. κ'χ Λ j f' "'Ί 1¾. or "I 0. The compound of V n η \ Y ^ -NH V OCH„ OCH „z 1 '2' 3 is reacted in a reaction-inert solvent at room temperature in the presence of an acid scavenger with 1 mole of an acid halide of the formula RSO2W or R ^ SO ^ W wherein H is halogen A process according to claim 1, characterized in that the sulfonyl halide is a sulfonyl chloride of the formula RSO 2 Cl A process according to claim 2, characterized in that the acid scavenger is triethylamine. Process according to Claim 3, characterized in that the reaction-inert solvent is methylene chloride Process according to Claim 4, characterized in that R is acetyl and R is 2-thienyl, 3-thienyl or 3-methyl-2-thienyl. A process for the preparation of a therapeutically active antibacterial H "-sulfonylamino-oleandomycin derivative with the form t-q Hn Ψ (CH3} 2 NCCH „) 0 ° γ <'-Λ ° yM ° ΗΟ ,, Χ 3 2 h ° JV O-— il lO' 'f' ,,, I γζ ΊΓ I NHSO2R J ^^ NHSO2R2 0CH„ * 3 0CH3 1 2 and a pharmaceutical form of a compound containing 1 to 3 carbon atoms; pyridyl; 1,1,1-trifluoretyl; biphenyl; monosubstituted phenyl, color substituents such as fluorine, chlorine, bromine, iodine, hydroxy, methoxy, cyano, carboxamido, nitro, carbomethoxy, carbobenzyloxy, trifluoromethyl, alkyl of 1-4 cholatomers or acetamido; disubstituted phenyl, color substituent with chlorine, nitro, amino, methoxy or methyl; triklorfenyl; hydroxidiklorfenyl; benzyl; naphthyl; thienyl; klortienyl; 2-acetamido-5-thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-bensimidazolyl; dimethyl-2-pyrimidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl or furyl, color substituents carbomethoxy or alkyl with 1-2 cholatomers; or 1-methyl-5-carbomethoxy-3-pyrryl; R 1 is alkanoyl with 2-3 cholatomers; and R 2 is phenyl; thienyl; monosubstituted phenyl, color of such substituent chlorine, fluorine, methyl, methoxy or trifluoromethyl; or alkyl substituents of the same type, varying from 1 to 4 alkyl atoms, the radicals being the same as those used in the formulation