DK148845B - ANALOGY PROCEDURE FOR PREPARING 4 '' - DEOXY-4 '' - SULPHONYLAMINO-OLEANDOMYCIN DERIVATIVES OR THEIR ACID ADDITION SALTS - Google Patents

Description

148845

The present invention relates to an analogous process for the preparation of novel 4, -, deoxy-4 "sulfonylamino-ole-andomycins having good antibacterial activity or their pharmaceutically acceptable acid addition salts.

Oleandomycin, its preparation in fermentation media and its use as an antibacterial agent have first been described in U.S. Patent 2,757,123. The naturally occurring compound is known to have the following structure; 148845 2 H (CH3) - 8a \ "0 \ 'j7 t>, o 6 * 0 y / 10 6 * C /' ''

Ho Tip 5] · JLk / [13 3i <^ '' O 6 »if 1 *

T Π "T

2 ** 1 Jit11 3 * T "'ΌΗ OCH3

The commonly accepted numbering method and stereochemical illustration of oleandomycin and similar compounds are shown at a large number of positions.

U.S. Patent Nos. 3,884,902 and 3,983,103 relate to 4 "-rythromycin sulfonate esters and N-sulfonylerythromycinamines, respectively, having biological profiles different from those of the compounds of the present invention.

Several synthetic modifications of oleandomycin are known, in particular modifications, from which one to three of the free hydroxyl groups in the 2'-, 4'- and 11-positions are esterified as acetyl esters. Additionally, U.S. Patent 3,022,219 discloses similar modifications in which the acetyl group of the above esters is replaced by another, preferably unbranched lower alkanoyl group of 3-6 carbon atoms.

The semi-synthetic antibacterial oleandomycin derivatives prepared according to the present invention have one of the following formulas: 148845 3 S (CHJ9

. * Y

Y 1 ..0 nJ I i · 1 n> 1 tf %% * ·

R-ku. ^ Y

I.mL

YX »·, o 1 Cx

^ Y ^ NHSO-R

OCH3 N (CH-) i? · "Λ ΟγΚ, o ^ 'HO-i'p y' V" ° -Y ° r α 2

In NHSC ^ IT

and3 2

Herein R represents alkyl of 1-3 carbon atoms, pyridyl / phenyl, mono-substituted phenyl wherein the substituent is selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyano, carboxamido, nitro, amino, carbomethoxy , carbobenzyloxy, carboxy and acetamido, disubstituted phenyl wherein the substituents are each selected from the group consisting of chloro, nitro, amino, methoxy and methyl, trichlorophenyl, hydroxydichlorophenyl, naphthyl, thienyl, chlorothienyl, 2-acetamido-5-thiazolyl, 2- acetamido-4-methyl-5-thiazolyl, dimethyl-2-pyrimidinyl, furyl or mono-substituted thienyl or furyl, wherein the substituent is selected from the group consisting of carbomethoxy and alkyl of 1 or 2 carbon atoms, R is alkanoyl of 2 or 3 carbon atoms and R is phenyl, thienyl, monosubstituted phenylf wherein the substituent is selected from the group consisting of chloro, fluoro, methyl and methoxy, or alkyl-substituted thienyl, wherein the alkyl group has 1 or 2 carbon atoms.

148845 4

The amine starting materials leading to the compounds of this invention consist of two 4 "epimeric amines as a result of the synthesis used in their preparation. Accordingly, the de-sulfonamido compounds prepared from said amines # also consist of an epimeric mixture It has been found by experiment that both of the epimeric sulfonamides are present in the final product in varying amounts according to the synthesis method used to prepare the amine intermediate. If the isolated product is predominantly one of the epimers, this epimer can be purified. The second epimer, the one present in least amount in the initially isolated solid, is the predominant product in the mother liquor, it can be recovered from this known per se. methods such as evaporation of the mother liquor and repeated recrystallization of the residue into a product of constant melting point or the like by chromatography.

Although said mixture of epimers can be subdivided by methods known to those skilled in the art, it is advantageous for practical reasons to use the mixture as isolated from the reaction. However, it is frequently advantageous to purify the mixture of epimers with at least one recrystallization of a suitable solvent, subject it to column chromatography, solvent separation or trituration in a suitable solvent. Said purification, while not necessarily causing separation of the epimers, will result in the removal of such foreign substances as starting materials and undesirable by-products.

The determination of the absolute stereochemical structure of the epimers has not yet been completed. However, both of the epimers of a given compound show the same type of activity e.g. as anti-bacterial agents.

Preferred compounds within the compound group of formula - 1 are compounds wherein R represents thienyl and substituted thienyl wherein the substituent is alkyl of 1-2 carbon atoms or carbomethoxy.

Preferred compounds within the compound group 2 are 2 compounds wherein R is substituted phenyl, thienyl and alkyl-substituted thienyl, wherein the alkyl group has 1-2 carbon atoms.

Preferred compounds within these compounds, preferred because of their utility as antibacterial agents.

5 148865 is 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 and 4 "-deoxy-4 (p-chlorophenylsulfonylamino) oleandomycin.

The process of the present invention for the preparation of the subject compounds is characterized by the characterizing part of claim 1.

The process of claim 1 for the synthesis of 4 "-deoxy-4" -sulfonylamino-oleandomycin derivatives of formulas 1 or 2 can be illustrated by the following scheme, starting with 4 "-deoxy-4" -amino-oleandomycin or an alkanoyl derivatives thereof.

• N (CH) - HO, 1 3 2 • rf Yx (Y? & R1 ° O * ........ 0 o, * 0 u., Y <.., ·· * 0 o C " '^ f \ "Λ"' Ό 0vA ,, ',' n

ff% o RSO-C1 T SO

- y;

In tube2 NHSCLR

'r ° ™ 3 1 0CH3 2 N (ch3) 2 JSiCH) y? Λ Yx HO J y

"I o 0 I

°> JN "Ό R ^ SO Cl * 0. # 0 Q \ h2 ° ^^ 2 OCH. L OCH, 2 3 2 3 a 2 * ft 148845 6 1 2 wherein R, R and R have the meaning given above.

The above reactions are carried out between a 4 "deoxy-4" amino-oleandomycin and a sulfonyl halide in the presence of an acid-binding agent in a reaction-inert solvent.

In practice, one mole of · 4 "-deo-4 ,,-artdno-oleandnycin is contacted with one mole of the sulfonyl halide plus a 2-3% excess of the halide.

The acid binding agent which is lean inorganic or organic nature is used in an amount of one mole plus an excess of 4-6%.

The acid-binding agent may consist of alkali metal or alkaline earth metal hydroxides, hydrides or carbonates or a tertiary organic amine. In addition, secondary amines, such as diisopropylamine, which are sufficiently hindered can be used so that they do not react with the sulfonyl halide reactant. The preferred class of acid binding agents are tertiary amines. Particularly preferred for this class is triethylamine.

The reaction-inert solvent used in the above process must be an agent which significantly solubles the reactants and does not significantly react with the reactants or products formed. Polar solvents which are miscible or immiscible with water are preferred. In particular, methylene chloride and acetone water are preferred.

As heating of amino-oleandomycins leads to some decomposition, it is preferred to carry out the process leading to the compounds of formula 1 or 2 at 0-25 ° C. In particular, it is preferable to carry out the reaction at ambient or room temperature.

The reaction time is not critical and it depends on the reaction temperature, the concentration and the reactivity of the starting compounds.

When the reactions are carried out at room temperature at the concentrations discussed below, the reaction will be substantially complete within 2 to 48 hours.

When the reaction is complete, the reaction mixture can be worked up in one of two ways, both of which are well known to those skilled in the art.

The first work-up method consists in adding the reaction mixture to water followed by separation of the water-immiscible solvent containing the desired product and subsequent removal of solvent to obtain the crude product.

When a water-miscible solvent is used as the reaction-inert solvent, the product is extracted from the water-cooled reaction mixture using a water-immiscible solvent such as methylene chloride.

The second work-up method consists in concentrating the reaction mixture to dryness followed by extracting the product from the salt resulting from the acid binder base and hydrogen halide by-products using acetone. The acetone extract can be concentrated to give the crude product.

The crude product or an acetone solution thereof can be purified by chromatography on silica gel, a process well known in the art, or recrystallization.

The 4 "deoxy-4" amino compounds used as starting materials for the synthesis of the antibacterial agents herein are synthesized by oxidation of the natural oleandomycin followed by a reductive amination of the resulting ketone as will be described later.

In utilizing the chemotherapeutic effect of the salts forming compounds, pharmaceutically acceptable salts are used.

Examples of acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, glyconic, aspartic, glutamic and glutamic,

The presently disclosed 4 "deoxy-4" amino-oleandomycin derivatives show better in vitro activity against a large number of Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and to certain Gram-negative microorganisms such as spherical or ellipsoid form organisms. (cocci) than the known oleandomycin compounds. Their effect is readily demonstrated by in vitro tests against various microorganisms in a brain-lined infusion medium by the usual dual serial dilution technique. Their in vitro action makes them useful for topical use in the form of ointments, creams and the like.

For in vitro use, e.g. for topical application, it will often be convenient to combine the selected product with a pharmaceutically acceptable carrier such as a vegetable or mineral oil or a softening cream. Also, they may be dissolved or dispersed in liquid carriers or solvents such as water, alcohols, glycols or mixtures thereof or other pharmaceutically acceptable inert media, i.e. media that have no adverse effect on the active ingredient. For such purposes, it will generally be acceptable to use concentrations of the active ingredients from ca. 0.01% to approx. 10% based on the weight of the total composition.

In addition, many of the compounds of this invention are active against gram-positive microorganisms by oral and / or parenteral administration to animals and humans. Their in vivo action is more limited in terms of sensitive organisms. It is determined by the usual procedure consisting of infecting mice of substantially uniform weight with the test organism and then treating them orally or subcutaneously with the test compound. In practice, the mice, e.g. 10, one intraperitoneal inoculation of suitable diluted cultures containing ca. 1 to 10 times LDioo ^ a lowest concentration of organisms required to induce 100% death). Simultaneous control experiments are performed in which the mice are given inoculum of lower dilutions to control for possible variation in the virulence of the test organism. The test compound is administered 1/2 hour after the inoculation and this is repeated 4, 24 and 48 hours later. Surviving mice are observed for 4 days after the last treatment and the number of surviving mice is noted.

When used in vivo, the compounds of this invention may be administered orally or parenterally, e.g. by subcutaneous or intramuscular injection at a dose of ca. 1 mg / kg to approx. 200 mg / kg body weight per day. day. The preferred dose range is from ca. 2 mg / kg to approx. 100 mg / kg body weight per day. day and the most preferred range is from approx. 2 mg / kg to approx. 50 mg / kg body weight per day. day. Carriers suitable for parenteral injection may be either aqueous, such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous, such as vegetable oils (cotton seed oil, peanut oil, corn, sesame), dimethyl sulfoxide and others not aqueous carriers which will not interfere with the therapeutic effect of the composition and which are non-toxic in the amount used (glycerol, propylene glycol, sorbitol). Furthermore, compositions suitable for improvised preparation of solutions may be prepared prior to administration. Such compositions may comprise liquid diluents, e.g. propylene glycol, diethyl carbonate, glycerol, sorbitol, etc., buffering agents, hyaluronidase, local anesthetics and inorganic salts to produce desired pharmacological properties. These compounds can also be combined with various pharmaceutically acceptable inert carriers including solid diluents, aqueous carriers, non-toxic organic solvents in the form of capsules, tablets, lozenges, trophic disks, dry mixtures, suspensions, solutions, elixirs and parenteral solutions or suspensions. In general, the compounds are used in various dosage forms at concentration levels ranging between about 0.5% by weight and approx. 90% by weight calculated by the total composition.

For demonstration of the good antibacterial properties of the oleandomycin derivatives of the present invention, the following tables show the minimum inhibitory concentration (MIC) in pg / ml against a greater number of microorganisms for a variety of compounds prepared by the present method and for the oleandomycin (page 28) and two other known related connections (pages 28 and 29).

148845 N (CH) ίο ΗΟχ! Χ

RlosJ | // °

"They fiS

v \ v cc,

In NHSO R

and 3 MIC, uq / ml.

R = £ -BrC6H4- R = C6H5- _1 _ CH, CO- -1 = CH CO-

Microorganisms __________ R a j_ · * L __ = - (1) Staph, aur. 01AQ05 ^ 0.10 £ 0.10 (2) "" 01A052 <0.10 0.20 (3) "" 01A109 R 12.5> 200 (4) "" 01A110 -25> 200 (5) "" 01A111 R - £ 0.10 <.0.10 (6) "" 01AQ87 RR £ 0.10 0.39 (7) "" 01A400 R ^ 0.10 0.20 '(8) Str. Fae. 02A006 ° » 39! »56 (9) Str. Pyog. 02C203 £ 0.10 0.20 ·

(10) "" 02C020 R

(11) Myco. Sneaked. 05A001. "" (12) B. sub. 06A001 - ° 't0.

(13) E. coli 51A229 (14) "" 51A266 6'25_

(15) "" 51A125 R

(16) Ps. aerug. 52A104 _ _ (17) Klebs. pn. 53A009 ίί'5 · (18) "" 53A031 R 2qq (19) Prot. mira. 57C064 25 200 (20) Prot. bre. 57G001 · 3 12 6 25 (21) Saln. chol-su. 58B242 12 6 * 25 (22) Sal. typhm. 58D009 fi'25 / 05 (23) «" 58D013-C ^ 39 '0 ^ 8 (24) Fits, multiple. 59A001 53 (25) Ser. Mar. 63A017 12 5 12 5 (26) Ent. Aero. 67A040 50f 50 # (27) Ent. Cloa. 67B003 <.0 10 £ 0.10 (28) Neiss. Sic. 66C00Q 'N (CH3) 2 11 U8845 ij I,>? ** o RO s \ l 1 / fC " ° Jv '"' 0 0 - y;

In NHSO R

and 3 MIC, -ug, / ml.

r * 2-HO-3,5-Cl - R, .2-0 N-4- R a2,4- (NO,) _ C, H + - GHOG6H-C, H_- 2 2 _ 81 = CM ° - »1» ° Φ ° ~ 3 gl, CB, dO- (1) Staph, aur. 01A005 0.39 0.20 0.39 (2) * "" 01A052 0.39 0.20. 0.39 (3) "" 01A109 R> 200 6.25 ·> 200 (4) »» '01A110' > 200> 200> 200 (5) · Τ "01A111 R 0.39 <, 003 0.3? (6) ·· · * 01A087 RR> 200> 200 200 (7)" "01A400 RI / 56 ° * 20 0.39 (8) Strp. fae. 02A006 50 12'5 (9) Strp. pyog. 02C203 ° f78 * 003 0.20 (10) "" 020020 R Γ% 0_78

(11) Myco. s ».g- 05A001 1 ·“ 0.7S

g '· .- *; 06A001 0 78 003 <.003 (14) "" 51A266 *> 25 “0 g”: ““ “g R>“ θ 200> 200 (16) Ps. aerug. 52A104 25 (17) Klebs. pn. 33 ^ °°°> 200 100 100 * (13) "53Α033- R> 200 200 200 (19) Prot. Mira. 57C064> 200 50 100 (20) Prot. Transfer 57G001 50 6.25 50 (21) Salmon Chol-Su. 58B242 200 g 25 25 (22) Sal. Typhm 58D009 6.25 12.5 12.5 (23) "" 5 ^ 3 "C 12 ^ 5 1.56 llse (24) Past, Multo . 59A001> 20o 200> 200 (25) Serr. March 63A017 200 25 100 (26) Exit. Aero. 67A040> 200 50 50 (27) Exit. cloa. 67B003 o, 78 <, 003 <, 003 (28) Neiss. sic. 66C000 N (CH3) 2 168845 12 ^ ΧΛ I nhso2r OCH3. MIC, µg / ml-_ R = * IL-HOCgH 2 - R = j

Microorganism B1 and CH2 CO- R1 "CH2 CO- (I) Staoh. atir. Q1A.0Q5 1.56 0.20 - (2) "01A052 1.56. 0.20 (3) '*' · · 01A109 R '* 200.' 200 (4)" * '' 01A110> 200. > 200 (5) "» 01A111 R 3.12 0.20- (6) "" 01A087 RR 25> 200 (7), r "01A400 R 3.12 0.20 (8) Strp. fae. 02Δ006. 6.25 3.12 (9) Strp. pyog. 02C203 <0.10 <0.10 (10) "" 02C020 R “(II) Myco. smeg. 05A001> 200> 200 (12) B. sub. 06A001 ° / 39 (13) E. coli 51A229 25 50 (14) "" 51A266 25 50 (15) "" 51A125 R 50 50 (16) Ps. aerug. 52A104 2 °° (17) Klebs. pu. 53A009 g · g (18) "" 53A031 R "g

(19) Prot. mira. 57C064 ^ oS

(20) Prot. bre. 57G001 (21) Salmon. chol-su. 58B242 · -g (22) Sal. typhm. 58D009 ^ g * (23) "" 58D013-C 3., (24) ^. ^ 0. 59A001 20o '2QJ'56 (25) Serr. March 63A017 1Q0 1Q0

(26) Ent. aero. 67A040> 200 20Q

(27) Ent. cloa. 67B003 «-in ~ ·.« (28) Neiss. sic. 66C000 13 1Λ 8 δ Λ 5 h (ch3) 2 • λ Ά i vi I -0 ** ο r ° 1 (<y I /. ···

_ · * 'A.

"" Ή 'ο 1 \ η ^ χχ.

In NHSO2R

and3 MIC, lig / ml._ R -Ϊ.-Γ0Λ- R = s-cic6h4- R £ c ° £ "

Microorganisme_r! CH3CO- R1 and CH ^ CO- r! = CH ^ CO- (1) Staph, aur. 01A005 0.39 40.10 40 io (2) "." 01A052 0.39 40, io 40! L0 (3) · "" · 01 & 109 R 100 6.25. 12 5 (4) "* '01A110> 200> 200 200' '(5)" "01A111 R 0.20 40.10 SO 10 (6)" "01A087 RR 3.12 3j12 ^ 56 (7)" "01A400 R 0.20 40.10 40.10 (3) Size p. 02A006 3.12 3.12 in # 56 (9) Size pyog. 02C203 4.0.10 40.10 * 0.10

(10) "" 02C020 R

(11) Myco. smeg. 05A001> 200> 200> 200 (12) B. sub. · 06A001 -0 »10 10.10 40.10 (13) E. coli 51A229 50 100 12.5 (14)" "51A266 ° t25 50 6.25 (15)" "51A125 R ° '25 50 12.5 (16) Ps. Air 52A104 2]? 50 25 (17) Klebs. Pn. 53A009 "50 12.5 (18)" "53A031 R ~ 50 25 (19) Prot. mira. 57C064 ^ 200 100 (20) Prot. bre. 57G001 * 200 '100 (21) Salmon. chol-su. 58B242 25 12.5 (22) Sal. typhm. 58D009 5 25 12.5 (23) "" 58D013-C "7β 50 6.25 (24) Fits, multo. 59A001 ςη '1.56 0.39 (25) Serr. March 63A017 "" JJ 100 (26) Ent. aero. 67A040 cn -c 2 · * (27) Ent. cloa. 67B003, n '25 (28) Neis s. 66C00Q ~ ° '10 £ 0 »10 -0jl ° N (CH) 14 148845 ΗΟχ! \' • V ° Fri

In the NHSO.R

and 3 1 MIC., tig / ml._ ra SjA-Cl ^ CgH ^ - ra 2,3,4-01 ^ - r ^ microorganism_ B1 »CH ^ C0 ~ _ = c ^ ° ~ jjL = * CH3CO0_ (1) Staph, aur. 01A005 .50.10 0.20 1.56 (2) "" 01Δ052 50.10 50.10 1.56 (3) '* · "01A109 R 6.25 ·· 6.25.> 200 (4)" "01A110 50 25> 200 (5)" "01A111 R 50.10 50.10 0.78 (g)" "01A087 RR 0.78 '3.12 6.25 (7)" "01A400 R ^ 0.10 -50.10 0.78

S 5: £. S AS AS

SUL say. SK * --10. > aoo- gSASi S5 ft ft z (14) '· "51A266 Jf 5 ^ '25

(15) '"51A12S E g; | io0 Z

(16) Ps. aerug. 52A104 25 25 'loo (17) Klebs. pn. 53A009 25 50 100 (18) "" 53A031 R 200 100> 200 (19) Prot. mira. 57C064 100 50> 200 (20) Prot. bre. 57G001 · 6.25 6.25 50 (21) Salmon. chol-su. 58B242 3fi2 g 25 50 (22) Sal. typhm. 58D009 6.25 12.5 25 (23) "58D013-C 0.20 0.39 1.56 (24) Fits, Mult. 59A001 100. 50 200 (25) Ser. Mar. 63A017 12t5 _ 50 100 ( 26) Ent. Aero. 67A040 50 50 200 (27) Ent. Cloa. 67B003 £ 0.10 50.10 <0.10 (28) Neiss. Sic. 66C0Q0 N (CH) 15 148845 λΤ V ... ·· 0 * '' Is] / ". Y "v" Ex,

In NHSO R

and 31 µMIC, µg / ml. R - m-CH 3 COCO 6 H 4 -R = R = £ -10

Si microorganism R * ~ a CH ^ CO- _ R ^ a CH ^ CO- g * - »CH ^ CO- (1) Staph. · Aur. 01A005 0.78 0.39 <0.10 (2) "" 01A052 0.78. 0.39 40.10 (3) · M "01Δ109 R 50 ·> 200 · 3« 12 · (4) "M 01A110> 200> 200 100 (5) ·" "01A111 R Ο * 20 ^ 0.10. <0.10 (6) "" 01A087 RR 0.78 .1.56 -0 »10 (7)" "01A400 R °> 78 °» 39 40.10 ¢ 8) Strp. fae. 02Δ006 3 »12 6» 25 s0 »10 (9) Strp. pyog. · 02C203 - ° '10 ° »39 i0» 10 (1 °) "" 02C020 R ~ “~ (11) Myco. smeg. 05A001 188 108 23 (12) B. sub. 0.6A001;? '10 ° '20 (13) 2. coli 51A229 3 ° 23 (14) "" 51A266 3 ° ® »? 5 (15)" "51A125 RJ ° f' 5] 2'5 (16) Ps . aerug. 52A104 "" (17) Klebs. pn. 53A009 "π (18)« "53A031 R> ^ 5 200 (19) Prot. mira. 57C064, 00> 200 50 (20) Prot. bre. 57G001 25 6 25 -1 56 (21) Salmon. chol-su. 58B242 5Q ΥΣ 5 6 * 25 (22) Sal. typhm. 58D009 2c 05 * 6 * 25 (23) "" 58D013-C lf56 i, 56 0 ^ 9

(24) Fits, multo. 59A001 2nn? Nn 9CM

(25) Serr. March 63A017 XQ0 50 25 (26) Ent. aero. 67A040 200 · 200 50 (27) Ent. cloa. 67B003 0.20 <0.20 0.20 (28) Neiss. sic. 66C000 16 148845 n (ch) η ° ^ Χλ. Y% 0Vr γί »

In the NHSO.R

and3 1 _MIC, µg / ml._ R = o-02NC6H4- r = £ -02NC6H4- R = £ -02NC6H4 Microorganism_ · r1 = cHqC0- r1 and CH ^ CO- R1 · = CH0CO- [1) Staph, aur . 01A005 0.78 0.20: 20.10 [2) - "" 01A052 0.78 0.20 <0.10 [3) "" "01Δ109 R 200 100 · 12.5 {4)" "01A110> 200 > 200> 200 [5) "" 01A111 R £ 0.10 <0.10 <0.10 [6) "" 01A087 RR 3.12 1.56 1.56 [7). "" 01A400 R <0, 10 <0.10 0.20 [8) Stage phase 02A006, 3.12 12.5 1.56 [9) Stage pyog 02C203 £ 0 * 10 <0.10 <0.10

[10) "" 02C020 R

ill) Myco. smeg. 05A001 12.5 · <0.10 £ 0.10 (12) B. sub. 06A001 <0.10 <0.10 <0.10 (13) E. coli 51A229 200 25 6.25 (14) "" 51A266 25 12.5 6.25 (15) "" 51A125 R 25 12.5 12 , 5 (16) Ps. aerug. 52A104 · 200 50 (17) Klebs. pn. 53A009 25 25 6.25 (18) "" 53A031 R 25 50 6.25 (19) Prot. OiRA. 57C064 2 °° 200 100 ^ - ^ (20) Prot. bre. · 57G001 25 - “(21) Salmon. chol-su. 58B242 25 3 »“

(22) Sal. typhm. 58D009, 1?, 23 "" 'L

(23) "" 58D013-C ^, 12 6.25 6.25 (24) Past, Multo. 59A001 ° 78 ° 39 ° 39 (25) Serr. March 634017 2? °, 10 ° (26) Ent. aero. 67A040 ^ 50 (27) Ent. cloa. 67B003 "in 5 °. n in '(28) Neiss. sic. 66C000 * 0'10 <0'10 * 0'10, 1 * i i 1.

18 148845 n (ch3) 2 ηο ^ Λ

Ο * Γ "° 10 X

Λ I

* 'I' '; ονΛ '' "'° 0 1 ΧΛ

In NHSO2R

and 3 MIC, Ug / al.

R * 3-H.N-4- R --¾ /) R = CICgH - ^

Microorganism_ r! = CH ^ CO- r! = CH ^ CO- R? ~ ° CH ^ CO- (1) Staph, aur. 01Δ005 0.20 0.39 0.20 (2) "" 01A052 50.10 0.39 0'20 / j \ ii ii. 01A109 R 200. > 200> 200 / I, I. oittio> 200> 200> 200 (5) "" 01A111 R 3 ^ 2 ^ 3 ^ 2 (6) "" 01A087 RR "20 0'39 (7) n" 01A400 R i0 »10 0.20 '(8) Strp. fae. 02A006. 0.78 3.12 1.5 & (9) Strp. pyog. 02C203 i0 »10 -0'10" 0.1 ° (10) "" 02C020 R - ~ ~ (11) Myco. Smeg. 05AQ01 3.12 6.25 25 (12) B. sub. 06A001 f0.10 - 0.10 iu (13) E. coll 51A229 50 50 50 (14) "" 51A266 3'12 "Z 'l nc \ ii ii 51A125 R 50 50 12, a (15) 50 200 100 (16) Ps. aerug. 52A104 25 (17) Klebs. on. 53A009 50 50 (18) "" 53A031 R> 2 “^> 200 (19) Prot. mira. 57C064> 200> 20o (20) Prot. bre. 57G001 2_ 23 5f25 (21) Salmon. chol-su. 58B242 25 25 3.12 (22) Sal. typhm. 58D009 r 25 3.12 (23) "'' 58D013-C or'20 lf56 0.78 (24) Fits, Multo .. 59A001 1Q0 100 50 (25) Ser. Mar 63A017 100 100 50 (26) Ent. aero. 67A040 j_00 50 50 (27) Ent. cloa. 67B003 0 2q £ 0.10 0.20 (28) Neiss. sic, 66C000 'N (CH_> 17 148845 η ° ^ Χλ R1 ° "0 Jx' - 0 "

^ 'V

• NHSO R

and 3 l MIC, ug / ml._ β \ 2 -NO--4- R * o-ClC.H.- R "S -> -Cl R = W2 64 s cic, h3-

Microorganisms_, CH, CO- rI. CH, CO- „l.CH ^ O- (1) Staph, aur. 01A005 0.20 0.20 50.10 (2) '* "0IA052 0.20 £ 0.10 <0.10 (3) η" 01Δ109 II 200 200. > 200 (4) "" · 01A110> 200. > 200> 200 (5) "" 01A111 R 0.20 0.20 j0.10 (δ) "" 01A087 SR> 200> 200> 200 (7) "" 01A400 R ° »20 0.20 £ 0.20 (8) Strp. fae. 02A006 3.12 3.12 6.25 (9) Strp. pyog. 02C203 °> 20 - ° »10 * ° * 10 (10)" "02C020 R“ ~ -nn (11) Myco. smeg. 05A001 200 200 (12) B. sub. 06A001 2qo '100 (13) E. coli 51A229 ^, 5,200 (14) "" 51A266 ^, 5 12.5 5o (15) "" 51A125 R jJj »5 ioo (16) Ps. aerug. 52A104 2- 25 (17) Klebs. pn. 53A009 - 25 100 (18) "" 53A031 R> 2 ~> 20o 100 (19) Prot. mira. 57C064 5Q> 200 50 (20) Prot. bre. 57G001 g 2- 5 50 (21) Salmon. chol-su. 58B242 g25 g'25 6.25 (22) Sal. typhms 58D009 Λ2 / 9ς 12.5 (23) · ”58D013-C 1.56 (24) Fits, multo. 59A001 100> --- 100 (25) Serr. March 63A017 25 23 50 (26) Ent. aero. 67A040 25> 200 100 (27) Ent. cloa. 67B003 _ _ - (28) Neiss. sic. 66C000 148845 19 N (CH-) ΗΟχΑ

ο ·: ν ° XX

E.g., 0Ά% °. ο ^ V.

• NHSO-R

and 3 µMIC, µg / ml. R = 2,5-C12 C6 H3 R

Microorganism r! =. GH ^ CO-_ r1 =. CH3 CO-_ (1) Staph, aur. 01A005 Of 39 0.78 [2) "" 01A052 50.10 0.78 3) "" 01A109 'R -50> 200 (4) "" ni ΑΠΟ> 200> 200 (5) "" 01A111 R i0 * 10 ° f 39 t6) "" 01A087 RR 3.12. 25 f7) "" 01A400 R -0 »10 25 [8) Strp. £ ae. 02A006 iion 2! ™ f9) Strp. pyog. 02C203 ° ^ 20 ° r20 [10) "" 02C020 R “~ 111) Myco. smeg. 05A001 112) B. sub. 06A001 ° '78;? 'I0 [13) E. coli 51A229 f 25 [14) "" · 51A266

[15) «" 51A125 R

[16) Ps. aerug. 52A104 2 °° 50 [17) Klebs. pn. 53A009 ^ "Π8)" "53A031 R f [19) Prot. Mra. 57C0M 2 ™ (20) Prot. bre. 57G001. , (21) Salmon. chol-su. 58B242, 2, 12% [22) Sal. typhm. 58D009 fi * 2s l?% [23) "" 58D013-C ^^ 39 (24) Past, multo. 59A001 200> 200 (25) Serr. March 63A017 200> 200 [26) Ent. aero. 67A040 jqq 25 [27) Ent. cloa. 67B003 q yo, q (28) Neiss. sic. 66C000 1 "* H0 20 148845 n (ch3) 2

o y <o JL

1 »'* · * ® K 0, t H 1 /. ··' ^ \ x.

In NHSO2R

OCH3 _MIC, ii g / ml.

R = o-CH30C6Ha- R = »o-FC6H4-

Microorganisme_. R1 J CHSC0 ~ _ „CH ^ CO- (1) Staph, aur. 01A005 0.39 <0.10 (2) "" 01A052 0.78 0.20 (3) "," 01A109 R · - 100 100 (4) "" 01A110> 200.> 200 (5) "" 01A111 R 0.39 0.39 (6) "" 01A087 RR 3.12 (7). "01A400 R 0.39 0.39 (8) Str. P. 02AQ06 3.12 1.56 (9) Strp. Pyog .02C203 i0> 10 -0/10

(10) "" 02C020 R

(11) Myco. smeg. 05A001 3 »12> 2 °° (12) B. sub. 06A001; ° '10 f ° '10 (13) E. coli 51A229 S ς (14) "" 51A266 f (15) "" 51A125 R 25 12.5 (16) Ps. aerug. 52A104 ΙΌΌ (17) Klebs. pn. 53A009 "t«

(18) "" 53A031 R

(19) Prot. mira. 57C064> 2® ° ”(20) Prot. tomorrow, 57G001 30 ίου (21) Psalm. chol-su. 58B242 -4 ', (22) Sal. typhm. 58D009 (23) "" 58D013-C · ^ (24) Fits, multo. 59A001 vt (25) Serr. March 63A017 __ 12 5 (26) Ent. aero. 67A040 10fl '50 *

(27) Ent. cloa. 67B003 «X <Q .Q

(28) Neiss. sic. 66C000 -0'10 N (CH) 21 148845 ΗΟν \

0 h) I I

i v i i «> *% · 0

R ° T Y

'' 'O ^ i i% Y

° "ο n" "9; I NHSO.R OCH3 MIC, iug / ml.

CH, CH

ft JfX ft R-NS> R - NS> _ 1 CH.CO- pi B (31.03-1 = | CH.CO-

Microorganism__ R1 = * 3_R-3-R-3- (1) Staph, aur. 01A005 5.0.10. <MJ> 0.20 (2) "" 01A052 · £ 0.10 <0.10 0.20 (3) · »" 01A109 R -> 200 ·.> 200> 200 4 Π., 01A110> 200> 200> 200 (5) ”01A111 R 50.10. ^ 0.10 <0.10 (6) "" · 01A087 RR 0.39 ^ 'l5 (7) "" 01A400 R ^ ° »10 9» * ° 9'? 9 (8) Strp. fae. 02A006 1.56 <J '"(9) Strp. pyog. 02C203 ~ '200 (10) "" 02C020 R 50 1 ™ ^ 00 (11) Myco. smeg. 05A001 <0il0 0 20 (12) B. sub. 06A001 Γ? '10 25 Yf (13) E. coli 51A229 ... jqq 25 *

(14) "" 51A266 i? · 5 U

(15) "" 51A125 R 2 "200 200 (16) Ps. Back. 52A104 50 12 5 (17) Klebs. Pn. 53A009 '50 50' (18)" "53A031 R 200 200 (19) Prot. Mira. 57C064 5Q 100 200 (20) Prot. Morning 57G001 .6 25 25 12.5 (21) Salmon chol-su 58B242 6 * 25 12.5 6.25 (22) Sal. Typhm 58D009 3'12 6 , 25 6.25 (23) "" 58D013-C 0'7g 3.12 0.39 (24) Past, Mult. 59A001 5q 100 50 (25) Serial Mar 63A017 25 100 50 (26) Ent. .67A040 25 100 100 (27) Ent. Cloa. 67B003 0 78 £ 0.10 0.78 (28) Neiss. Sic. 66C000 N (CH) 22 148845 • j? 1 vT I,. Ο RO, N.. . *

'T

V'Vr · u,

In NHSO R

and3 MIC. Ua / ml.

E “afii" * '' 2> 4-cWr * £ 0 "

Mcrsörnis ,, ._ „1. CH, R1. CH, CO-_ ^ -. ¾ ^ - (1) Staph, aur. 01A005 0.78 0.20 <.0.10 (2) "" "01A052 °" 78 ° r20 S.0.10 (3) · "" 01A109 R> 200 · 23 6 »25 (4)" "01A110 > 200 50 200 (5) "". 0IA111 R ° * 20 $ 0.1 ° -0 »10 (6).» i. 01A087 RR> 20 ° _Q '10? (7) "" 01A400 R -? »“ (8) Strp. fae. 02A006 ^ in (9) Strp. pyog. 02C203 0.20 -0.1 ° ~ 0 , 1 ° (1 °) "" 02C020 R ~ "(ID Myco. Smeg. 05A001 ° '2 ° (12) B. sub. 06A001 <' 003 fQ'W f ° '10 (13) E. coli 51A229 Γ ™ 50 ίϊ (14) "" 51A266 50 25 (15) "" 52A125 R 50 2j (16) Ps. Air vent. 52A104 50 25 25 (17) Klebs. Pn. 53A009 200 50 100 (18) "" 53A031 R> 20o> 200 200 (19) Prot. Tnira. 57C064 100 200> 200 (20) Prot. Morning 57G001 25 25 12 5 (21) Sala. Chol-su. 58B242 25 6.25 6 ^ 25 (22) Sal. typhm 58D009 6.25 6.25 25 * (23) "" 58D013-C 1.56 lf56 0.20 (24) Past, multiple, 59A001> 2oo 100 100 (25) Serial Mar 63A017 100 25 25 ( 26) Ent. Aero. 67A040 200 · 25 100 (27) Ent. Cloa. 67B003 <, 003 <0.10 A0.10 (28) Neiss. Sic. 66C000 N (CH-)

HO ^ JL

23 148845

0 X jL

r1 °. 0. V "" ° V r

vs

In the NHSO.R

and 3 MIC, µg / ml.

Microorganism e_ Ri = CH ^ CO-_ r! = CH ^ CO-_ (1) Staph, aur. 0.39 0.39.

(2) "" 01A052 0.39 0.39 (3) "" 01A109 R> 200 100-.

(4) "" 01A110> 200. > 20 ° (5) "" 01A211 R 0.20. 0.20 (6) "" 01A087 RR> 20 °> 200 (7) "" 01A400 R ° * 20 ° »39 (8) Strp. fae. 02A006 3'12 6 »25 (9) Strp. pyog. 02C203 -0 »10 °» 39 (10) "" 02C020 R · "> 200 (11) Myco. Smeg. 05A001 10?> 200 (12) B. sub. 06A001 \ '12 ^ ° '10 (13) E . coli 51A229 "100 (14) -" 51A266 50 100 »»: "*> 200> 200 (16) Ps. aerug. 52A104 (17) Klebs. pn. 53A009 (18) "" 53A031 R 200> £ $ (19) Prot. mira. 57C064 2Π0 Voo (20) Prot. bre. 57G001 5 o = (21) Salmon. chol-su. 58B242 12'5 "(22) Sal. typhm. 58D009 6'25 "(23)" "58D013-C .3 ^ 3 12 (24) Past, Mult. 59A001 9qq '(25) Serr, Mar 63A017 23 200 (26) Ent. Aero. 67A040 ^ qq> 2qq (27) Ent. Cloa. 67B003 2 56 1 56 (28) Neiss. Sic. 66C000 T '\ K (CH-), 24 148345

Rlo (> '' ') YNVr

Ice

• NHSO R

and 3 MIC, llg / ml._ R = - ^ - CO 2 CH 2 R .- ^ - CH 3 R .- ^ UO 2 CH 3 Microorganism _; _ R ^ = CH ^ CO-_gl B CH ^ CO- r = CH ^ CO-_ (1 ) Staph, aur. . 01A005 ° »20 °» 39 °> 39 (2) "" 01A052 ° r20 °> 20 ° »20 (3) ·" 01A109 R s 25 '30 6'25 (4) "" oiAllO 200> 200> 200 ( 5) "" 01A111 R ^? '10 G'20 ° 2 ° (6) "" 01Δ087 RR "on (7)" "0IA400 R °' ^ 9 °» 22

(8) Strp. fae. 02A006 J "i" * 2 ^ o'10

(9) Strp. pyog. 02C203> 2 “° '10 ^, 10 -0 10 (10)" "02C020 R 2? °. 2 °° go: (11) Mycc. smeg. 05A001 ί «10 η 20 <0 1 (12) B. sub. 06A001 *? '10 ° '20 -S'1 (13) E. coll 52A229 Γ ™ 50 (14) "" 51A266 jg fQ ^ (15) "" 51A125 R. > 20Q 2oS 200 (16) Ps. aerug. 52A104 50 23 50 (17) Klebs. pn. 53A009 jog, qo> 200 (18) "" 53A031 R> 2 and 200 200 (19) Prot. mira. 57C064> 200 100 50 (20) Prot. bre. 57G001 '50 25 50 (21) Salmon. chol-su. 58B242 '50 25 25 (22) Sal. typhm. 58D009 25 12 5 25 (23) "" 58D013-C 3.12 3 ^ 12 3.12 (24) Past, Multo. 59A001 200 200 200 (25) Serr. March 63A017 IOO 50 100 (26) Ent. aero. 67A040 200 100 200 (27) Ent. cloa. 67B003 1.56 1 56 1, (28) Neiss. sic. 66C000 N (CH.) HO ^ 25 148845. I I, o, · 0 H0 I I '^ v <.

In the NHSO.R

and M2, µg / number.

R2 »£ -ClC6H4- R2» e-CH3C6H4-

Microorganism_________ _ (1) Staph, aur. 01A005 0.20 '0.78 (2) "" 01A052 0.20. 0.39 (3) "" 01A109 R 200> 200 (4) "" 01A110 200> 200 (5) "" 01A111 R SO, 10 0.20 (6) "" 01A087 RR 3.12 12.5 (7) "" 01A400 R ° r39 0.78 (8) Str.page. 02Δ006 3.12 6.25 (9) Str.pyog. 02C203 °> 39 0.39

(10) "" 02C020 R

(11) Myco. smeg. 05A001 200> 200 (12) 3. sub. 06A001 - ° »10 ^ 0.10 (13) E. coli 51A229 25 ~ 50 (14)" "51A266 50 (15)" "51A125 R 50 (16) Ps. aerug. 52A104 “r> 200 (17) Klebs. pn. 53A009 2 \ 100 (18) η "53A031 R 1 °° (19) Prot. Mira. 57C064 ___> 200 (20) Prot. Morning. 57G001"> 200 (21) Psalm. Chol-su. 58B242 "25 (22) ) Sal. Typhm. 58D009% ,, 25 (23) "" 58D013-C i'lt 12 * 5 (24) Past, multo. 59A001 non '1.56 (25) Serr. March 63A017 100> 200 (26) Ent. aero. 67A040 100 200 (27) Ent. cloa. 67B003 <n in 100 (28) Neiss. sic. 66C000 s.0 # 10 N (CH-) HO ^. 26 148865 1 V I I Λ '»* 0 R 0“' · <'O' * * '1 \ v \ r

In NHSO R

and 3 MIC, U-g / ml.

- / COnCHn ---.

EE = "^ 3-C2H5." Pi-CH-CO- pi "CH, CO- (1) Staph, aur. · 01A005 °» 20 °> 20 (2) ", 0IA052 ^ 0.10 0.20 (3) ”. "01A109 R 200> 20 ° '(4)" "OlAllO 200> 200 ¢ 5)" · "01A111 R" nS * 10 (6) - "" 01Δ087, RR ° 2 °> 20 °

(7) "" 01A400 R

(5) Strp. fae. 02A006 ^ in (9) Strp. pyog. 02C203 2Οθ '> 2fJ' (10) ”M 02C020 R n in n in (11) Myco. SAEG. 05A001 S'lO ίο 10 (12) B. sub. 06A001 g? »10 - ° '10 (13) E. coli 51A229" "(14)" "51A266" 5q (15) "" 51A125 R 50 2q0 (16) Ps. Air. 52A104 25 25 (17) Klebs. pn. 53A009 '50 100 (18) "" 53Δ031 R 200> 200 (19) Prot. aira. 57C064 100 100 (20) Prot. Borg. 57G001 12'5 25 (21) Salm. chol-su. 58B242 12 * 5 25 (22) Sal. Typhm. 58D009 ^ 2 5 25 (23) "" 58D013-C 25 50 (24) Past, Mult. 59A001 100 200 (25) Serr. Mar 63A017 50 100 (26) Eat. Aero 67A040 100 200 (27) Ent. Cloa. 67B003 0.20 0.39 (28) Neiss. Sic. 66C000 N (CH-), 27 148845 H0

o r * 0 X JL

'Y ^ yr

Cl

I T NHSO.R

and 3 MIC, µg / ml.

= £ -cic6h4-

Microorganism R = CH 2 CO

(I) Staph, aur. 01A005 0.025 {2) 01A052 0.025 (3) 01A109 R 6.25 (4) OlAllO R> 50 (5) 01A111 R 0.025 (6) ,. 01A087 RR> 50 (7) 01A400 R 0.025 (8) Strp. fae. 02A006 0.39 (9) Strp. pyog. 02C203 £ 0.025 (10) {, {, 02C020 R 6.25 (II) Myco. smeg. 05A001 (12) B. sub. 06A001 (13) E. coli 51A229 (14) I I 51A266 6.25

(15) * V 51A125 R

(16) Ps. aerug 52A104 25 (17) Klebs. pn. 53A009 6.25

(18) ^ j 53A031 R

(19) Prot. mira. 57C064> 50 (20) Prot. bre. 57G001 (21) Salra. chol-su. 58B242 (22) Sal. typhm. 58D009 6.25

(23) 4r I 58D013-C

(24) Fits, multo. 59A001 0.39 (25) Serr. March 63A017> 50 (26) Ent. aero. 67A040 12.5 (27) Ent. cloa. 67BQ03 (28) Neiss. sic. 66Q000 <[0.025 148845 28

ScUftnsnl 'iffiUJKys ** N (CH) compound un i 3 2 • J? #.

1 Cl I ** · * 0 ico, (1 / .. ·· lx * ° .JO-o 0 * χχ

I \> R

OCH3 MIC, uq / ml.

(known from (known from US Pat. 2,757,123) US Pat. 3,022,219) R = H R = CH, CO-1 °

Microorganism. R = H R = H

% - ^^ mm 1) Staph, 'aur. 01A005. 0.78 ° '78 2) “'- 01A052 .___ 1.56 0.78 3) -" "* 01A109 R 100 4)". »01A110__100> 50 5). "" OlAlll R 0.78 6) "" 01A087. RR. 100 7) "H 01A400 R_1 1.56 8) Strp. Fae. 02A006____ 1.56 1.56 9) Strp. Pyog. 02C203 ------ q, 78 0.39 10)" · 02C020 R_. - 11) Myco. sraeg. 05A001_____ 100 12) B. sub. : 06A001_ 0.78 13) E. coli's 51A229_ 100 14) "" · 51Λ266. .100> 50 15) "" 'j 51A12S R. .100> 50 1G) Ps. aerug. 52A104 100> 50 17) Klebs. pn. ·: 53A009 100> 50 13) ”. "53A031 R 100> 50 19) Prot. Mira .., 57C064_______ 20) Prot. Morning. 57G001 100 21) Salnu chol-su. 58B242__.

22) Will. typhia. 58D009 __ 100 23) "58D013-C -" 24) Past, rnulto. 59A001_____ 12'5 25 25) Serr. March 63A017_ 100> 50 26) Ent. aero. .. 67Λ040 100> 50 27) Ent. cloa. '67R003 ”100 28) Weiss, sic. 66C000_ 12/5 12 »5 29 148846

Saitro-luminous Compound N (CH_) _ "3 R I 3 2 RCU" ^ η "* 3 0 k ^ '" "0932CH3" / "" OCH3 MIC, jigi / ml.

R = H (known from

Kikroorqanisne R-, = H ^ 488 = Example 3) (1) Staph, aur. 01A0C5 1.56 (2) 01A052 .1.56 (3) 01A109 R> 50 (4) 01A110 R> 50 (5) 01A111 R 0.39 (5) 01A087 RR> 50 (7) II 01A400 R 50 (8) ) Strp. fae. 02A006 · 0.39 (9) Strp. pyog. 02C203 0.20 (10) i j 02C020 R> 50 (11) Myco. smeg. 05A001> 50 (12) B. sub. 06A001 0.20 (13) E. coli 51A229> 50 (14) II 51A266> 50 (15) (J 51Λ125 R> 50 (16) Ps. Aer. 52A104> 50 (17) Klebs. Pn. 53A009> 50 ( 18) [j. 53A031 R> 50 (19) Prot. Ir. 57C064 - (20) Prot, norg. 57G001> 50 (21) Sal. Chol-su. 58B242 (22) Sal. Typhn. 58D009> 50

(23) \ I 58D013-C

(24) Fits, multo. 59Λ001 12.5 (25) Serr. when. 63A017> 50 (26) Ent. aero. 67A040> 50 (27) Ent. cloa. 67B003> 50 (28) Meiss. sic. 66C000 12.5 148845 30

The process according to the invention is further illustrated by the following examples.

Example 11 11-Acetyl-4 "-deoxy-4 (2-thienylsulfonylamino) oleandomycin.

To 30 ml of dry methylene chloride was 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 resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was poured into 50 ml of water and then washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the remaining foam was purified by chromatography on silica gel column using acetone as solvent and eluent. The fractions containing the desired product were combined and concentrated in units of vacuum to dryness, 1.3 g.

mm (S, CDCl 3) in 2.03 (3H) s; 2.30 (6H) s; 2.63 (2H) d; 3.16 (3H) s and 6.8-7.8 (3H) m.

Example 2

Starting from 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and the sulfonyl chloride in question and using the procedure of Example 1, the following compounds were prepared: n (ch,) - CH 3 CO ^ ^ »VV'o n" y; - 1 NHSO R and 3 1 01 31 148845 R m (6, cdci 3) 2.08 (3H) s; 2.30 (6H) s; 2.67 (2H) m; · JT \ 3.23 (3H) e and 6.87 and 7.45 (2H) s.

0 N _ ^ CH. 2.09 (3H) s; 2.42 (6H) s; 2.70 (2K) m ch3cnh- ^ s> · ° S 3 * 26 (3H) S · 0H-j, 2.0 (3H) s; 2.33 (6H) s; 2.40 (3H) s; CH 2s 4> 2.66 (2H) d; 3 * 33 <3H> S ° g 7 · 86 3 S (1H) s.

I if 2.03 (3H) s; 2.33 (6H) s; 2.66 (2H) d; 3.03 (3H) s and 7.40-9.16 (4H) m.

CH3V-V'l T 2.08 (3H) s; 2.31 (6H) s; 2.59 (6H) s; 2.65 (2H) s; 3.01 (3H) s and 7.11 (1) s.

ch3 rr ~ C 2-07 (3H) s; 2.32 (6H) s; 2.67 (2H) s; 3 · 20 (3H) s; 7.32 7.43 (1Η) τη s ° S 8.02 (1H) nw IJ-S 2.08 (3H) s; 2.31 (6H) s; 2.68 (2H) m; U 3-25 (3H) s; 6.74 (1H) m; 7.48 (1H) m 0 and 8.00 (1H) m.

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

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" amino-oleandomycin and 528 yl (4.2 mmol) of triethylamine in 20 ml of methylene chloride was added in portions of 865 mg. (4.1 mmol) of p-chlorophenylsulfonyl chloride, and the resulting reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was treated with 10 ml of acetone. The suspension was filtered and the filtrate chromatographed on 160 g of silica gel using acetone as eluant. Fractions 51-63 each consisting of 10 ml were collected and concentrated under reduced pressure to give 857 mg of pure product. Fractions 42-52 and 64-92 gave 1.21 g of a less pure product.

NMR (δ, CDCl3): 2.13 (3H) s; 2.36 (6H) s; 2.73 (2H) d; 3.13 (3H) s and 7.3-8.2 (4H) q.

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

Example 4

Using the method of Example 3 and starting from the required sulfonyl chloride and the required 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, the following compounds were prepared: N (ch) H °% Jk.

CH 2 CO,> 0

1 NHSO R

and 33 mm (δ, cdci 3) τ / == \ 2.08 (3H) s; 2.33 (6H) s; 2.70 (2H) d; "Λ // 3.11 (3H) s; and 7.5-8.2 (4H) q.

λ = ν 2.08 (3H) s; 2.31 (6H) sj 2.66 (2H) d; F- / Λ- 3-06 (3H) s 0g 7.0-8.4 (4H) m.

Cl) = 2.0 2.03 (3H) s; 2.33 (6H) s; 2.66 (2H) d; Λ- 3.10 (3H) s; and 7.3-8.0 (4H) m.

Cl / 2.03 (3H) s; 2.33 (6H) s; 2.63 C2H) d; 3.23 (3H) s 0g 7.2-8.4 (4H) m.

F

/ = \ 2.13 (3H); 2.35 (6H) s; 2.70 (2H) d; \\ // ~ 2.90 (3H) s 0g 7.0-8.2 (4H) n.

_ / == \ _ 2.10 (3H) s; 2.33 (6H) s; 2.66 (2H) d;

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

Example 5

A solution of 2.9 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" amino-oleandomycin, 4.1 mmol of the required sulfonyl chloride RSO 2 Cl and 0.58 ml (4.2 mmol) was added. ) Triethylamine in 30 ml of methylene chloride is left stirring at room temperature for 48 hours. The reaction mixture was poured into 50 ml of water and the separated organic layer was washed with a saturated brine and dried over sodium sulfate. The solvent was removed in vacuo and the remaining yellow foam was chromatographed on 200 g of silica gel in a 3 cm diameter column. The product was eluted from the acetone column which was collected in 10 ml fractions. The fractions containing the pure product as obtained by thin layer chromatography were combined and concentrated to dryness under reduced pressure to give the following compounds: 148845 34 N (CH) x1 CH.CO .. * 0

T T

V '"" o n

1 NHSO R

and 31 L R SMR (δ, CDCl 3) / δ V 2.03 (3H) s; 2.30 (6H) s; 2.66 CH3 ° \\ // <2H) d; 3 · 06 (3H) s; 3.83 (3H) s; and 6.8-8.2 (4H) ra.

OCH3 / = (2.08 (3H) s; 2.30 (6H) s; 2.66 \\ // - (2H) d; 2.83 (3H) s; 4.03 (3H) s; \ -J / and 6.8-8.2 (4H) m.

Example 6 11-Acetyl-4 "-deoxy-4" -phenylsulfonylamino-oleandomycin.

To a solution of 2.91 g (4.0 mmol) of 11-acetyl-4 "deoxy-4" amino-oleandomycin and 424 mg (4.2 mmol) of triethylamine in 30 ml of methylene chloride cooled in an ice bath was added. 722 mg (4.1 mmol) of benzenesulfonyl chloride. After 10 minutes, the bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into 50 ml of water and the organic layer was washed with a saturated brine and dried over sodium sulfate. Upon removal of the solvent, the crude product was obtained, which was further purified by chromatography on 160 g of silica gel using acetone as eluent. The fractions (each of 10 ml) 61-93 containing the pure product as determined by thin layer chromatography were combined and concentrated to dryness under reduced pressure. 1.5 g of the desired product were obtained.

NMR (δ, CDCl13): 2.06 (3H) s; 2.30 (6H) s? 2.63 (2H) d; 3.06 (3H) s; and 7.3-8.2 (5H) m.

Further, by the method of Example 6, the following compound was prepared using the following compound: 11-Acetyl-4 "-deoxy-4 (2-naphthylsulfonylamino) oleandomycin.

NMR (δ, CDCl13) δ 2.03 (3H) s; 2.26 (6H) s; 2.65 (2H) d; 2.96 (3H) and 7.4-8.6 (7H) m.

Example 7 11-Acetyl-4 "-deoxy-4" - (p-benzyloxycarbonylphenylsulfonylamino) oleandomycin.

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4 amino-oleandomycin, 1.12 g (3.6 mmol) of p-benzyloxycarbonylphenylsulfonyl chloride and 379 mg (3 75 mmol) of trethylamine in 25 ml of methylene chloride are left stirring at room temperature overnight. The solvent is removed in vacuo and the residue is triturated in 10 ml of acetone. The solid is filtered off and the filtrate is chromatographed on 280 g of silica gel. acetone as eluent and with fraction sizes of 10 ml Fractions 90-203, which, by thin layer chromatography, contained most of the pure product, were combined and concentrated under reduced pressure to give 1.25 g of the desired product.

NMR (δ, CDCl3) δ 2.04 (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.01 (3H) s; 5.48 (2H) s; 7.50 (5H) s and 8.03-8.53 (4H) m.

Example 8

Starting from the required sulfonyl chloride and 11-acetyl-4, -deoxy-4 "-amino-oleandomycin and using the procedure of Example 7, the following compounds were obtained: 148845 36 N (CH-),, yt;" Λ

cs \ J

* '> ^ 1 lis' ° νλ \.

r tr γ \

1 NHSO R

ocr3 NMR (δ, CDCl1) δ 2.06 (3H) s; 2.30 (6H) s; 2.66 / V (2H) d; 3.03 (3H) s; 3.96 (3H) δ y s; 0g 7.3-9.0 (4H) m.

0 = cx OCH3 2.05 (3H) s; 2.30 (6H) s; 2.65 (/ V- (2H> d; 3 · 01 ^ 3H) s) 5 · 43 (2H) d »\ - / 7.46 (5H) s; and- 7.33-8.70 (4H) m.

X) CH 2 0 0 / = \ 2.06 (3H) s 2.30 (6H) s; 2.66 CH 3 ° CA /) - (2H) d; 3.06 (3H) s; 4.0 (3H) s; (4H) m.

f = \ 2.10 (3H) s; 2.30 (6H) s; 2.70 / - - (2H) d; 3.0 (3H) s; and 4.10 Μ; ο ''.

c = ° ch3o

Example 9 11-Acetyl-4 "-deoxy-4 (o-nitrophenylsulfonylamino) oleandomycin.

Five grams (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 were combined in 50 ml. methylene chloride and the reaction mixture was allowed to stir at room temperature for 48 hours. The reaction was quenched by mixing the reaction mixture with an equal volume of water, and the organic phase was washed with a saturated brine solution and dried over sodium sulfate. By removing the solvent under reduced pressure, the crude product was obtained in the form of a foam. The product was purified by chromatography on 140 g of silica gel in a 3 cm diameter column using acetone as the eluent. Fractions 20-30, each of 50 ml, were collected, combined and concentrated to dryness to give 3.4 g of the desired compound.

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.

Similarly, the following compounds were prepared using the required starting materials and repeating the above procedure: 11-acetyl-4 "-deoxy-4" - (m-nitrophenylsulfonylamino) oleandomycin.

NMR (S, CDCl3): 2.06 (3H) s; 2.30 (6H) s; 2.66 (2H) d; 3.06 (3H) s and 7.4-9.0 (4H) m and 11-acetyl-4 "-deoxy-4" - (p-nitrophenylsulfonylamino) oelandomycin.

NMR (δ, CDCl3): 2.10 (3H) s; 2.35 (6H) s; 2.68 (2H) d; 3.06 (3H) s and 8.0-8.6 (4H) m.

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

A solution of 11.5 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandecycin, 701 mg (3.65 mmol) of p-hydroxyphenylsulfonyl chloride and 51.8 μΐ was added. triethylamine in 25 ml of methylene chloride are left stirring at room temperature for 48 hours. The solvent was removed in vacuo and the residue treated with 10 ml of acetone.

The insoluble was filtered off and the filtrate was chromatographed on 200 g of silica gel using acetone as eluent. Fractions 116-175, which, by thin layer chromatography, contained the pure product, were combined and concentrated to dryness under reduced pressure. 550 mg of the desired product was obtained. NMR (δ, CDCl13): 2.0 (3H) s; 2.33 (6H) s; 2.68 (2H) d; 3.06 (3H) s and 6.6-8.0 (4H) m.

148845 38

Example 11 11-Acetyl-4 "-deoxy-4 (m-carboxamidophenylsulfonylamino) oleandomycin.

To 20 ml of methylene chloride containing 2.91 g (4.0 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin and 434 mg (4.2 mmol) of triethylamine was added 898 mg (4, M-carboxamidophenylsulfonyl chloride, and the resulting reaction mixture was allowed to stir for 48 hours. The solvent was removed in vacuo and the residue was treated with 25 ml of acetone. The triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 160 g of silica gel. Fractions of each 50 ml were collected and examined by thin layer chromatography to determine the purity of the product. Fractions 66-93 were combined and concentrated under reduced pressure to give 800 mg of the desired product.

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

Example 12 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 are left stirring for 48 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give a foam which was then treated with 10 ml of acetone. The insoluble triethylamine hydrochloride was filtered off and the filtrate was chromatographed on 160 g of silica gel using acetone as eluant. Fractions 42-86, which, by thin layer chromatography, contained most of the pure product, were combined and concentrated in vacuo to give 1.2 g of the desired product.

NMR (δ, CDCl13) for 2.06 (3H) s; 2.23 (3H) s; 2.35 (6H) s; 2.70 (2H) s; 3.13 (3H) s and 7.6-8.2 (4H) m.

Example 13 11-Acetyl-4 "-deoxy-4" - (p-cyanophenylsulfonylamino) -oleandomycin.

A solution of 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin, 734 mg (3.65 mmol) of β-cyanophenylsulfonyl chloride and 518 μΐ (3 75 moles of triethylamine in 25 ml of methylene chloride are left stirring at room temperature overnight. The solvent was removed in vacuo and the residue was treated with 10 ml of acetone. The insoluble was filtered off and the filtrate was chromatographed on 120 g of silica gel using acetone as eluent and fractions were collected each of 10 ml. Fractions 47-83 were combined and concentrated under reduced pressure to give 281 mg of the desired product.

NMR (δ, CDCl13): 2.10 (3H) s; 2.36 (6H) s; 2.71 (2H) d; 3.06 (3H) s and 7.7-8.4 (4H) m.

Example 14 11-Acetyl-4 "-deoxy-4" - (methylsulfonylamino) oleandomycin.

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

NMR (δ, CDCl3): 2.06 (3H) s; 2.28 (6H) s; 3.06 (3H) s? 2.61 (2H) d and 8.40 (3H) s.

Example 15 11-Acetyl-4 "-deoxy-4" - (3,4-dichlorophenylsulfonylamino) oleandomycin.

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, Triethylamine (2 mmol) was combined in 30 ml of methylene chloride and the resulting solution was allowed to stand at room temperature for 18 hours. The reaction was quenched with 50 ml of water and the organic phase was washed with saturated brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 150 g of silica gel using acetone as eluent. The fractions containing the product as indicated by thin layer chromatography were combined and concentrated to dryness to give 1.3 g of the desired product.

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

Example 16

Following the procedure of Example 15 and starting from the required reactants, the following compounds were prepared: n (ch

»° ... i. 3 2 o 0 p> Il T V .- ° * '"r T ** ° Λ' · ο" 'V.

1 NHSO R

and NM NMR (δ, CDClj)

Cl 2.0 (3H) s; 2.36 (6H) s; 2.70 \ - J (2H) d; 3.33 (3H) s; And 7.3- / 8.6 (3H) m.

Cl

Ci / V 2.10 (3H) s; 2 * 31 (6H> s; 2-66 j / ~ (2H) d; 3.30 (3H) s; and 7.2-8.4 (3H) m).

, CV

_f = \ 2-03 (3H) s; 2.30 (6H) s; 2.66

Cl ~ \ // (3 «) s; 3 · ί0 <3H) s; and 7.1- - 8.1 (3H) m *.

/ = \ 2.06 (3H) s; 2.33 (6H) s; 2.70 C1 V // (2K) d; 3 · 13 (3H> s; And 7.4- / -7 8.6 (3H) m).

NO

* / "° 2 * 2.06 <3H) s; 2.40 (6H) s; 2.66 \ JT (2H) d; 3.25 (3H) s; and 7.2-8.6 (3H) m *.

in nq2 CH 0 - / 2 _ 06 (3H> s; 2 · 33 (SH) s; 2.63 3 (2H) d; 2.81 (3H) s; 3.63 (3H) s; and 7.0-8.2 (3H) raw*.

= <NO2 O N- / 2.06 (3H) s; 2.36 (6H) s; 0g 2 V // 8.4-9.0 (3H) m *.

* NMR: DMSO / CDCl3

Example 17 11-Acetyl-4 "-deoxy-4" - (2,3,4-trichlorophenylsulfonylamino) 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 was added. and 0.57 ml (4.2 mmol) of triethylamine in 30 ml of methylene chloride are left stirring at room temperature for 18 hours. The organic layer was washed with water (1 x 50 ml) and a saturated brine (1 x 50 ml) and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 150 g of silica gel using acetone as the solvent, collecting fractions of 7 ml each. Fractions 60-100 were combined and concentrated to give 800 mg of the desired product.

NMR (δ, CDCl13): 2.06 (3H) s; 2.33 (6H) s; 2.63 (2H) d; 3.2 (3H) s and 7.2-8.2 (2H) m.

Example 18 11-Acetyl-4 "-deoxy-4 (2-hydroxy-3,5-dichlorophenylsulfonylamino) -oleandomycin.

The procedure of Example 17 was repeated starting with 2.55 g (3.5 mmol) of 11-acetyl-4 "-deoxy-4" - amino-oleandomycin, 954 mg (3.65 mmol) of 2-hydroxy -3,5-dichlorophenylsulfonyl chloride and 518 μΐ (3.75 mmol) of triethylamine in 25 ml of methylene chloride to give 483 mg of the desired product after chromatography on 220 g of silica gel.

NMR (δ, CDCL3 / DMSO): 2.03 (3H) s; 2.50 (6H) s; 3.05 (3H) s and 7.8 (2H) m.

Example 19 11-Acetyl-4 "-deoxy-4 (3-methyl-2-thienylsulfonylamino) oleandomycin.

To 100 g (0.13 mol) of 11-acetyl-4 "-deoxy-4" -amino-oleandomycin in 900 ml of methylene chloride were added 593 ml of triethylamine and the solution was allowed to stir for 10 minutes. Then 3-methyl-2-thienylsulfonyl chloride (41.9 g, 0.213 mol) was added dropwise over 300 ml of methylene chloride dropwise over a period of 1 hour, and the reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was added to 2 liters of water and the organic layer was separated and successively washed with water (2 x 250 ml) and brine (1 x 250 ml) and dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on a 105 cm x 6.5 cm column containing 1.5 kg of silica gel. The product eluted with acetone was collected in the eluate fractions from 2.3 liters to 6 liters. The fractions were combined and the solvent was removed under reduced pressure to give a foam. By treating the foam with diethyl ether 66.4 g of the desired product / melting point 184-185 / 5 ° C were obtained.

NMR (<$, CDCl3): 2.04 (3H) s; 2.41 (6H) s; 2.46 (3H) s; 2.62 (2H) m, 3.02 (3H) s; 6.84 and 7.32 (2H).

To 2 g of the above free base in 15 ml of ethyl acetate was added 0.12 ml of phosphoric acid and the resulting solution was allowed to stand unstirred at room temperature. After 20 minutes crystals were formed and after 2 hours, filtered, washed with ethyl acetate and dried to give 1.3 g of 11-acetyl-4 "-deoxy-4 (3-methyl-2-thienylsulfonylamino) oleandomycin phosphate .

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

Example 20

The procedure of Example 19 was repeated, starting with the required sulfonyl chloride and 11-acetyl-4,12-deoxy-4 "-amino-oleandomycin to give the following compounds: N (CH3) .

CH3C0 „„ k. ... · .....

0 "Y 2 γ 2 \ ιιεο2ι? And 3 U8845 44 KMR (6, CDC13) / -v 2.08 (3H) s; 2.33 (6H) s; 2.38 (3H) s;" J! 68 2.68 (2H) δ; 3.27 (3H> s; 6.08 and (^ 3 ° 6 * 92 <2H>)

CH

3 \ -. 2.03 (3H) s; 2.25 (3H) s; 2.51 (6H) s; // \ 2.61 (2H) m; 3.15 (3H) s; 7.07 (1H) m ° S 7 · 38 (1H) m.

C H 2.06 (3H) s; 2.33 (6H) s; 2.65 (2H) m; 2.5X 3.22 (3H) s; 6.73 and 7.45 (2H).

π-λ 2.08 (3H) s; 2.34 (6H) s; 2.54 (3H) s; CH -II> - 2-67 (2H) e; 3 · 25 (3K) s; 6.73 and 7.46 (2H).

Example 21

A solution of 2.96 g (0.0041 mol) of 11-acetyl-4 "-deoxy-4 amino-oleandecycin and 0.62 ml of triethylamine in 50 ml of dry methylene chloride cooled to ice bath temperature was treated portionwise with 0.0044 The temperature of the reaction mixture is allowed to rise to room temperature and stirred for 3 1/2 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 and the methylene chloride layer is separated, washed successively with water and saturated brine, and dried over sodium sulfate. By removing the solvent under reduced pressure, the crude product is obtained as a white foam.

The foam was chromatographed on silica gel column, 3.25 cm x 38 cm, using acetone as eluant. The right fractions, each of approx. 10-12 ml, were collected and combined. Removal of the eluate solvent in vacuo afforded the following compounds: N (CK-).

HO 1 3 2 v? Λ ο τι, 0 0 ii 1 / CH ^ CO ^ ji · '

""> 1 [C

° / · "-'O .. 0 r" ft T T5HS02R and 3 r NMR (δ, CDCX3) γ- \ 2.09 (3H) s: 2.32 (6H) s; 2.69 (2H) m; CH_O0C - \ c / - 3.22 ^ 3H) s5 3 · 95 (3H) S; 7 * 61 08 3 2 S 7.75 (2H).

CH_0 "C

Δ 2> 2.11 (3H) s; 2.34 (6H) s; 2.70 (2K) m; // \ 3.24 (3H) s; 3.94 (3H) s; 8.06 and S 8.28 (2H).

1.08 (3H) s; 2.29 (6H) s; 2.67 (2H) s; CH.CLC_c y- 3.18 (3H) s; 3.94 (3H) s; 7.02 Increase 3 2 V 7.20 (2H).

Example 22 4 "-Deoxy-4 (p-chlorophenylsulfonylamino) oleandomycin.

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

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

Example 23 4 "-Deoxy-4" - (p-toluenesulfonylamino) oleandomycin.

In a procedure similar to Example 22, 30 g (4.0 mmol) of 4 "-deoxy-4" amino-oleandomycin, 782 g (4.1 mmol) of p-toluene sulfonyl chloride and 424 mg (4.2 mmol) were added. ) triathylamine in 25 ml of methylene chloride are left stirring at ambient temperature overnight. At work-up, the crude product was chromatographed on 180 g of silica gel, collecting 10 ml fractions. Fractions 90-148 were combined and concentrated to dryness to give 1.4 g of the desired product.

NMR (δ, CDCl3): 2.33 (6H) s; 2.46 (3H) s; 2.83 (2H) d; 3.10 (3H) s and 7.10-8.0 (4H) m.

In a similar process, 4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin was also prepared.

NMR (δ, CDCl3): 2.29 (6H) s; 2.88 (2H) m; 3.2 (3H) s; 5.6 (1H) m and 7.33 (3H) m.

Example 24 11-Acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin phosphate.

To a solution of 15.0 g of 11-acetyl-4 "-deoxy-4" - (2-thienylsulfonylamino) oleandomycin in 100 ml of ethyl acetate was added 1.0 ml of phosphoric acid. The resulting suspension was allowed to stir for 4 hours at room temperature. The solid was filtered off, washed with ethyl acetate and dried to give 12.5 g of the desired salt, m.p. 168 ° C (dec.).

Similarly, 11-acetyl-4 "-deoxy-4" - (3-methyl-2-thienylsulfonylamino) oleandomycin phosphate, m.p. 184-188 ° C and 11-acetyl-4 "-deoxy-4" - (p-chlorophenylsulfonylamino) oleandomycin phosphate, m.p. 204-205 ° C.

U8845 47

Preparation A

4 "-Deoxy-4" -oxo-oleandomyciner I. 11-Acetyl-4 "-deoxy-4" -oxo-oleandomycin a. 11,2'-Diacetyl-4 "-deoxy-4" -oxo-oleandomycin.

To 4.5 g of N-chlorosuccinimide, 50 ml of benzene and 150 ml of toluene in a dry vessel equipped with a magnetic stirrer and nitrogen inlet and cooled to -5 ° C were added 3.36 ml of dimethyl sulfide. After stirring at 0 ° C for 20 minutes, the contents were cooled to -25 ° C and treated with 5.0 g of 1, 2'-diacetyl-oleandomycin in 100 ml of toluene. Cooling and stirring were continued for 2 hours followed by the addition of 4.73 ml of triethylamine. The reaction mixture was allowed to stir at 0 ° C for 15 minutes and then poured into 500 ml of water. The pH was adjusted to 9.5 with 1 N aqueous sodium hydroxide, and the organic layer was separated, washed with water and brine and dried over sodium sulfate. Removal of the solvent in vacuo gave 4.9 g of the desired product as a foam.

NMR (δ, CDCl13): 3.48 (3H) s, 2.61 (2H) m, 2.23 (6H) s and 2.03 (6H) s.

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

A solution of 4.0 g of 11,21-diacetyl-4 "-deoxy-4" -oxo-oleandomycin in 75 ml of methanol was left stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the product as a foam. A diethyl ether solution of the residue, after treatment with hexane, gave 2.6 g of the product as a white solid. mp. 112-117 ° C.

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

II. 2X-Acetyl-4 "-deoxy-4" -oxo-oleandomycin.

Dimethyl sulfide (0.337 ml) was added to a cloudy solution of 467 mg of N-chlorosuccinimide in 20 ml of toluene and 6 ml of benzene cooled to -5 ° C and kept under a nitrogen atmosphere. After stirring at 0 ° C for 20 minutes, the mixture was cooled to -25 ° C and 1.46 g of 2'-acetyloleandomycin and 15 ml of toluene were added. Stirring was continued for 2 hours at -20 ° C followed by the addition of 0.46 ml of triethylamine. The reaction mixture was kept at -20 ° C for an additional 5 minutes and then allowed to warm to 0 ° C. The mixture was poured into 50 ml of water and 50 ml of ethyl acetate with stirring. The pH of the aqueous mixture was adjusted to 9.5 by the addition of aqueous sodium hydroxide solution. The organic layer was then separated, dried over sodium sulfate and concentrated in vacuo to a white foam (1.5 g). Trituration with diethyl ether gave 864 mg of crude product, which by recrystallization twice of methylene chloride / diethyl ether gave 212 mg of the pure product, 183 to 185.5 ° C.

Analysis: Calculated for C37H16i13N! Ci H: 8.5, N: 1.9.

Found: C: 60.9, H: 8.4, N: 1.9.

NMR (δ, CDCl13): 5.60 (1H) m, 3.50 (3H) s, 2.73 (2H) m, 2.23 (6H) s and 2.03 (3H) s.

Preparation B

4 "-Deoxy-4" -amino-oleandomycins.

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

To a suspension of 10 g of 10% palladium-on-charcoal in 100 ml of methanol was added 21.2 g of ammonium acetate and the resulting porridge treated with a solution of 20 g of 11-acetyl-4 "-deoxy-4" - oxo-oleandomycin in 100 ml of the same solvent. The suspension was shaken at room temperature in a hydrogen atmosphere at an initial 2 pressure of 3.5 kp / cm. After 1.5 hours, the catalyst was filtered off and the filtrate was added with stirring to a mixture of 1200 ml of water and 500 ml of chloroform. The pH was adjusted from 6.4 to 4.5 and the organic layer was separated. After further extraction with 500 ml of chloroform, the aqueous layer was treated with 500 ml of ethyl acetate and the pH was adjusted to 9.5 with 1N sodium hydroxide. The ethyl acetate layer was separated and the aqueous layer was extracted again with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated to a yellow foam (18.6 g) which, upon crystallization of diisopropyl ether, yielded 6.85 g of the purified product, m.p. 157.5 to 160 ° C.

NMR (δ, CDCl1): 3.41 (3H) s, 2.70 (2H) m, 2.36 (6H) s and 2.10 (3H) s.

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

A solution of 20 g of 2, -acetyl-4 "-deoxy-4" -oxo-oleandomycin in 125 ml of methanol, after stirring at room temperature overnight, was treated with 21.2 g of ammonium acetate. The resulting solution was cooled in an ice bath and treated with 1.26 g of sodium cyanoborohydride. The cooling bath was then removed and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was poured into 600 ml of water and 600 ml of diethyl ether and the pH was adjusted from 8.3 to 7.5. The ether layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts were set aside and the pH of the aqueous material was adjusted to 8.25. The diethyl ether and ethyl acetate extracts provided at this pH were also set aside and the pH was raised to 9.9. The diethyl ether and ethyl acetate extracts at this pH were combined, washed successively with water (1 time) and with saturated brine, and dried over sodium sulfate. The latter extracts, taken at pH 9.9, were concentrated to a foam and chromatographed on 160 g of silica gel, using chloroform as application solvent and initial eluant. After eleven fractions of 12 ml per ml. fraction, the eluent was changed to 5% methanol-95% chloroform.

At fraction 370, the eluent was changed to 10% methanol-90% chloroform, and at fraction 440, 15% methanol-85% chloroform was used. Fractions 85-260 were combined and evaporated to dryness in vacuo to give 2.44 g of the desired product.

NMR (δ, CDCl3): 5.56 (1H) m, 3.36 (3H) s, 2.9 (2H) m and 2.26 (6H) s.

Claims (3)

148845 1. Analogous process for preparing 4 "-deoxy-4" -sulfonylamino-oleandomycin selected from the group consisting of A y <oXX R 0 '. ** H0 y' • "> 1 1%“ and 'g Jr *'. ° - <. -O ® Tx 0 XX, I NHSO.I? 1 NHSO 2 R OCH 2 in OCH 3 23 or a pharmaceutically acceptable acid addition salt thereof, in which formulas R represents alkyl of 1-3 carbon atoms; pyridyl; phenyl; monosubstituted phenyl wherein the substituent is fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyano, carboxamido, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy or acetamido; disubstituted phenyl wherein each of the substituents is chloro, nitro, amino, methoxy or methyl; trichlorophenyl; hydroxydichlorphenyl; naphthyl; thienyl; chlorothienyl; 2-acetamido-5-thiazolyl; 2-acetamido-4-methyl-5-thia-zolyl; dimethyl-2-pyrimidinyl; furyl or monosubstituted thienyl or furyl wherein each substituent is carbomethoxy or alkyl of 1 to 1-2 carbon atoms; R represents alkanoyl of 2-3 carbon atoms and R represents phenyl; thienyl; monosubstituted phenyl wherein the substituent is chloro, fluoro, methyl or methoxy; or alkyl-substituted thienyl wherein the alkyl group has 1-2 carbon atoms, characterized in that a corresponding compound selected from the group consisting of