GB1590162A - Oleandomycin derivatives - Google Patents

Abstract

Semi-synthetic 4''-sulphonylaminooleandomycins of formulae 1, 2 and 3 are described in which the symbols have the meaning given in Claim 1. These compounds may be prepared from semi-synthetic intermediates of the 4''-deoxy-4''-aminooleandomycin type. Compounds 1, 2 and 3 are useful as antibacterial medicinal products. Pharmaceutical preparations containing these compounds or their addition salts with a pharmaceutically acceptable acid are also described. <IMAGE>

Description

(54) OLEANDOMYCIN DERIVATIVES (71) We, PFIZER iNC., a Corporation oranised under the laws of the State of Delaware, United States of America, of 235 East 42nd Street, New York, State of New York, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particuarly described in and by the following statement:- This invention relates to novel antibacterial agents and, in particular, to a series of 4"-deoxy-4"-sulfonylamino-oleandomycins and their pharmaceutically acceptable acid addition salts.

Oleandomycin, its production in fermentation broths and its use as an antibacterial agent were first described in U.S. Patent 2,757,123. The naturally occurring compound is known to have the following structure:

The conventionally accepted numbering scheme and stereochemical representation for oleandomycin and similar compounds is shown at a variety of positions.

U.S. Patents 3,884,902 and 3,983,103 claim 4"-erythromycin sulfonate esters and N-sulfonylerythromycylamines, respectively, which have biological profiles different from the compounds claimed in the present invention.

Several synthetic modifications of oleandomycin are known, particularly those in which from one of three of the free hydroxyl groups found at 2', 4" and 11positions are esterified as acetyl esters. In addition, there are described U.S.

Patent 3,022,219 similar modifications in which the actyl group in the abovementioned esters is replaced with another, preferably unbranched lower alkanoyl group of three to six carbon atoms.

The semi-synthetic oleandomycin antibacterial agents of this invention are of the formulae:

and pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl having from one to three carbon atoms; pyridyl; 2,2,2-trifluorethyl; phenyl; monosubstituted pheny wherein said substituent is selected from fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyan, carbamoyl, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoromethyl, alkyl having from one to four carbon atoms and acetamido; disubstituted phenyl wherein said substituents are each selected from chloro, nitro, amino, methoxy and methyl; trichlorophenyl; hydroxydichiorophenyl; benzyl; naphthyl; thienyl; chlorothienyl; 2-acetamido-5thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2pyrimidinyl; pyrryl; furyl; monosubstituted thienyl; pyrryl or furyl wherein said substituent is selected from carbomethoxy and alkyl having one or two carbon atoms; or l-methyl-5-carbomethoxy-3-pyrryl; R, is alk anoyl having two or three carbon atoms; R2 is phenyl; thienyl; monosubstituted phenyl wherein said substituent is selected from chloro, fluoro, methyl, methoxy and trifluoromethyl; or alkyl-substituted thienyl, said alkyl group having one or two carbon atoms; X and Y when considered separately are each hydrogen; or X and Y when considered together represent a carbon-carbon bond; and Z is hydrogen, bromo, dialkylamino, said alkyl group having one to three carbon atoms, alkylthio, said alkyl group having from one to three carbon atoms, phenylthio, 2-hydroxyethylthio or morpholino, with the proviso that when X and Y are a carbon-carbon bond, Z is hydrogen.

The amine starting materials leading to the compounds of the present invention are comprised, because of the synthetic method used in their preparation, of two 4"-epimeric amines. Hence, the sulfonamido compounds of the present invention which are formed from said amines are also comprised of an epimeric mixture. Experimentally, it is observed that both epimeric sulfonamides are present in the final product in varying ratios depending on the choice of synthetic method used to prepare the amine intermediate. If the isolated product consists predominantly of one of the epimers, said epimer can be purified by repeated recrystallization from a suitable solvent to a constant melting point. The other epimer, the one present in smaller amounts in the originally isolated solid material, is the predominant product in the mother liquor. It can be recovered therefrom by methods known to those skilled in the art, as for example, the evaporation of the mother liquor and repeated recrystallization of the residue to a product of constant melting point or chromatography.

Although said mixture of epimers can be separated by methods known to those skilled in the art, for practical reasons it is advantageous to use said mixtures as it is isolated from the reaction. However, it is frequently advantageous to purify the mixture of epimers by at least one recrystallization from an appropriate solvent, subjecting it to column chromatography, solvent partitioning or trituration in an appropriate solvent. Said purification, while not necessarily separating the epimers removes such extraneous materials as starting materials and undesirable by-products.

The absolute stereochemical assignment for the epimers has not been completed. Both epimers of a given compound, however, exhibit the same type of activity, e.g. as antibacterial agents.

Preferred compounds of the formula I are those wherein R is thienyl and substituted thienyl wherein said substituent is alkyl having from one to two carbon atoms or carbomethoxy. R is most preferably 2-thienyl, 3-thienyl or 3-methyl-2thienyl.

Preferred compounds of the formula 2 comprise those wherein R2 is substituted phenyl, thienyl and alkyl-substituted thienyl, said alkyl group having one or two carbon atoms. R2 is most preferably 4-chlorophenyl, 2-thienyl, 3-thienyl or 3-methyl-2-thienyl.

Preferred compounds of the formual 3 are those wherein X and Y are each hydrogen and R, is acetyl.

Preferred among those compounds because of their antibacterial utility are 11 0 - acetyl - 4" - deoxy - 4" - (2 - thienylsulf6nylamino)oleandomycin, 11 acetyl - 4" - deoxy - 4" - )3 - thienylsulfonylamino)oleandomycin, 11 - 0 - acetyl - 4"- deoxy - 4" - (3 - methyl - 2 - thienylsulfonylamino)oleandomycin, 4" - deoxy .4" - (p- chlorophenylsulfonylamino)oleandomycin, 4" - deoxy - 4" - (2 - thienylsulfonyl amino)oleandoinycm, 4" - deoxy - 4" - (3 - thienylsulfonylamino)oleandomycin, 4"deoxy - 4" - (3 - methyl - 2 - thienylsulfonylamino)oleandomycin, 11 - 0 - acetyl- 4" - deoxy - 4" - (2 - bromoethylsulfonylamino)oleandomycin, 11 - 0 - acetyl- 4" - deoxy - 4" - (2 - methylthiosulfonylamino)oleandomycin and 11 - 0 - acetyl 4" - deoxy -4" - (vinylsulfonylamino)oleandomycin.

In accordance with the process for synthesizing the 4"-deoxy-4"-sulfonylamino-oleandomycin antibacterial agents of formulae I and 2, the following scheme, starting with 4"-deoxy-4"-amino-oleandomycin or an 1 1-alkanoyl derivtive thereof, is illustrative.

wherein R, R, and R2 are as previously defined.

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

In practice, one mole of the 4"-amino-oleandomycin is contacted with one mole of the sulfonyl halide plus as much as a 23% molar excess of said halide.

The acid scavenger, which can be inorganic or organic in nature, is employed to the extent of one mole plus as much as 46% molar excess.

The scavenger can consist of alkali metal or alkaline-earth metal hydroxides, hydrides or carbonates as well as a tertiary organic amine. In addition, secondary amines, such as diisopropylamine, which are sufficiently hindered such that they do not react with the sulfonyl halide reactant, can also be employed. The preferred class of acid scavengers is tertiary amines. Especially preferred within this class is triethylamine.

The reaction-inert solvent used in the aforementioned process should be one which appreciably solubilizes the reactants and does not react to any appreciable extent with either the reactants or the products formed. Preferred are polar solvents which are miscible or immiscible with water. Especially preferred are methylene chloride and acetone-water.

Since heating of amino-oleandomycins leads to some decomposition, it is preferred that the process leading to I or 2 be conducted at W25 C. Especially preferred is a reaction conducted at ambient or room temperature.

Reaction time is not critical and is dependent on reaction temperature, concentration and inherent reactivity of the starting reagents. When the reactions are conducted at room temperature at the hereinafter mentioned concentrations, the reaction is essentially complete in 2 to 48 hours.

The reaction, on completion, can be worked-up in one of two manners, both of which are known to those skilled in the art. The first work-up method comprises adding the reaction mixture to water followed by separation of the water immiscible solvent, which contains the desired product, and its subsequent removal to give the crude product. When a water-miscible solvent is employed as the reaction-inert solvent, the product is extracted from the water-quenched reaction mixture using a water-immiscible solvent, such as methylene chloride.

The second method of work-up comprises concentration of the reaction mixture to dryness followed by the extraction of the product from the sale resulting from the scavenger base and hydrogen halide by-product using acetone. The acetone extract can be concentrated to give the crude product.

The crude product or an acetone solution thereof is purified by chromatographing on silica gel, a procedure well known in the art, or recrystallization.

Antibacterial agents of formula 3 wherein X and Y are a carbon-carbon bond and Z is hydrogen are prepared by contacting one mole of the appropriate I 1-0- alkanoyl-4' '-deoxy-4"-amino-oleandomycin with two moles of 13- bromoethane sulfonyl chloride and four moles of a nonhinered tertiary gamine, such as triethylamine.

The reaction temperature is kept at -780C. for the contacting period and for a one to two hours reaction time.

The solvents appropriate for this process are the same as those employed in the process for preparing compounds I and 2 with the further restriction that said solvents do not freeze at the preferred reaction temperature. The preferred solvent is methylene chloride.

The reaction mixture is worked-up in the manner previously described in the process leading to I and 2.

In addition to being an antibacterial agent, the 1 l-O-alkonoyl-4"-deoxy-4" (vinylsulfonylamino)oleandomycins prepared by this process are also useful intermediates leading to other antibacterials by a process hereinafter described.

When one mole of the appropriate 1 l-O-alkanoyl-4"-deoxy-4"-amino- oleandomycin is contacted with 5-7 moles of p-bromoethanesulfonyl chloride in the presence of 1012 moles of a hindered amine, such as 2,6-lutidine, at about -4 to OOC in a reaction-inert solvent there is obtained the corresponding ll-0- alkanoyl - 4" - deoxy - 4" (p - bromoethylsulfonylamino)oleandomycin (X, Y=H; Z=Br).

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

The product is obtained and purified by a procedure similar to that described for the synthesis of compounds I and 2.

The remaining compounds represented by formula 3 are prepared by a Michael Addition of the appropriate amine or mercaptan to the requisite ll-0- alkanoyl-4"-deoxy-4"-(vinylsulfonylamino)oleandomycin, shown as follows:

In practice, the vinylsulfonylamino compound is contacted with a three to ten fold molar excess of the amine or mercaptan in a reaction-inert solvent, at ambient temperature for 1248 hours. The solvent should meet the same requirements as aforementioned in the synthesis of 1 and 2. The preferred solvent is benzene.

When a mercaptan is employed as one of the reactants, an inorganic or tertiary amine base is used to facilitate the reaction. It is preferred that a molar quantity of base, at least equal to the vinylsulfonylamino compound, be employed. The preferred base is potassium carbonate.

On completion of the reaction the product is obtained by either removal of the solvent and excess reactant under reduced pressure, or by quenching the reaction in water followed by separating of the organic phase and concentrating to dryness.

The starting 4"-amino compounds used in the synthesis of antibacterial agents of the present invention are synthesized by oxidation of the natural oleandomycin followed by a reductive amination of the resultant ketone as hereinafter described.

In the utilization of the chemotherapeutic activity of those compounds of the present invention which form salts, it is preferred, of course, to use pharmaceutically acceptable salts. Although water-insolubility, high toxicity, or lack of crystalline nature may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water-insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt with a suitable base or alternatively they can be converted to any desired pharmaceutically acceptable acid addition salt.

Examples of acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic, aspartic, glutamic, pyroglutamic and lauryl-sulfuric acids.

The novel 4"-deoxy-4"-amino-oleandomycin derivatives described herein exhibit in vitro activity against a variety of Gram-positive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain Gramnegative microorganisms such as those of spherical or ellipsoidal shape (cocci). Their activity is readily demonstrated by in vitro tests against various microorganisms in a brain-heart infusion medium by the usual two-fold serial dilution technique. Their in vitro activity renders them useful for topical application in the form of ointments and creams for sterilization purposes, e.g., sick-room utensils: and as industrial antimicrobials, for example, in water treatment, slime control, and paint and wood preservation.

For in vitro use, e.g., for topical application, it will often be convenient to compound the selected product with a pharmaceutically-acceptable carrier uch as vegetable or mineral oil or an emollient cream. Similarly, it may be dissolved or dispersed in liquid carriers or solvents, such as water, alcohol, glycols or mixtures thereof or other pharmaceutically-acceptable inert media; that is, media which have no harmful effect on the active ingredient. For such purposes, it will generally be acceptable to employ concentrations of active ingredients of from about 0.01 percent to about 10 percent by weight based on total composition.

Additionally, many compounds of this invention are active versus Grampositive microorganisms via the oral and/or parenteral route of administration in animals, including man. Their in vivo activity is more limited as regards susceptible organisms and is determined by the usual procedure which comprises inoculating mice of substantially uniform weight with the test organism and subsequently treating them orally or subcutaneously with the test compound. In practice, the mice, e.g. 10, are given an intraperitoneal inoculation of suitably diluted cultures containing approximately 1 to 10 times the Lid,, (the lowest concentration of organisms required to produce 100% deaths). Control tests are simultaneously run in which mice receive inoculum of lower dilutions as a check on possible variation in virulence of the test organism. The test compound is administered 0.5 hour postinoculation, and is repeated 4, 24 and 48 hours later. Surviving mice are held for four days after the last treatment and the number of survivors is noted.

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

Vehicles suitable for parenteral injection may be either aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution, or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not interfere with therapeutic efficiency of the preparation and are non-toxic in the volume or proportion used (glycerol, propylene glycol, sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may aavantageously be made. Such compositions may include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol and sorbitol; buffering agents, hyaluronidase, local anesthetics and inorganic salts to aford desirable pharmacological properties. These compounds may also be combined with various pharmaceutically-acceptable inert carriers including solid diluents, aqueous vehicles and non-toxic organic solvents in the form of capsules, tablets, lozenges, troches, dry mixes, suspensions, solutions, elixirs and parenteral solutions or suspensions. In general, the compounds are used in various dosage forms at concentration levels ranging from about 0.5 percent to about 90 percent by weight of the total compositiolt The following examples areprovided solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof.

The invention also includes a pharmaceutical composition comprising a compound of the formula 1, 2 or 3 as defined above or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention yet further covers a method of treating an animal, excluding a human being, having an infection caused by Gram-positive micro-organisms, or Gram-negative micro-organisms of spherical or ellipsoidal shape, which comprises administering to the animal an antibacterially effective amount of a compound of the formula 1, 2 or 3 or pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition comprising such a compound as salt together with a pharmaceutically acceptable diluent or carrier.

Example 1.

I l-O-Acetyl-4"-deoxy-4"-(2-thiensulfonylamino)oleandomycin To 30 ml. of dry methylene chloride is added 2.9 g. (4.0 mmoles) of ll-0- acetyl-4"-deoxy-4"-amino-oleandomycin, 740 mg. (4.1 mmoles of 2-thienylsulfonyl chloride and 0.58 ml. (4.2 mmoles) of triethylamine, and the resulting reaction mixture stirred at room temperature for 18 hrs. The reaction mixture is poured into 50 ml. of water and is subsequently washed with a saturated brine solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residual foam purified by chromatographing over a silica gel column using acetone as the solvent and eluate. The fractions containing the product are combined and concentrated in vacuo to dryness, 1.3 g.

NMR (, CDCI3): 2.03 (3H)s; 2.30 (6H); 2.63 (2H)d; 3.15 (3H)s and 6.87.8 (3H)m.

Example 2.

Starting with 1 l-O-acetyl-4"-deoxy-4"-amino-oleandomycin and the appropriate sulfonyl chloride and employing the procedure of Example 1, the following compounds are prepared:

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

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

2.0 (3H)s; 2.33 (6H)s; 2.40 (3H)s; 2.66 (2H)d; 3.33 (3H)s and 7.86 (lH)s.

2.03 (3H)s; 2.33 (6H)s; 2.66 (2H)d; 3.03 (3H)s and 7.409.16 (4H)m.

2.06 (3H)s; 2.36 (6H)s; 2.71 (2H)s 3.28 (3H)s and 7.36-7.56 and 7.66-7.92 (4H)m.

2.08 (3H)s; 2.31 (6H)s; 2.59 (6H)s; 2.65 (2H)s; 3.01 (3H)s and 7.11 (1)s.

2.07 (3H)s; 2.32 (6H)s; 2.67 (2H)s; 3.20 (3H)s; 7.32 (1H)m; 7.43 (1H)m and 8.02 (1H)m.

2.06 (3H)s; 2.29 (6H)s; 2.64 (2H)m; 3.26 (3H)s; 6.52 (1H)m; 6.77 (1H)m and 7.29 (lH)m.

2.07 (3H)s; 2.62 (6H)s; 3.25 (3H)s; 3.83 (3H)s; 3.95 (3H)s and 7.30 (2H)m.

2.08 (3H)s; 2.31 (6H)s; 2.68 (2H)m; 3.25 (3H)s; 6.74 (1H)m; 7.48 (1H)m and 8.00 (1H)m.

Example 3.

The procedure of Example 1 is repeated, starting with the requisite sulfonyl chloride and 1 l-O-alkonoyl-4"-deoxy-4"-amino-oleandomycin, to give the following congeners: 11-O-propionyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(2-acetamido-5-thiazolylsulfonyl- amino)-oleandomycin; 11 -O-propionyl-4"-deoxy-4"-(2-benzimidazolylsulfonylamino)oleandomycin; I 1 -O-acetyl-4"-deoxy-4"-(4,5-dimethyl-2-pyrimidinylsulfonylamino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(4,6-dimethyl-2- pyrimidinylsulfonylamino)-oleandomycin; 11-O-propionyl-4' '-deoxy-4"-(3-chloro2-thienylsulfonylamino)oleandomycin; 11-O-acetyl-4"-deoxy-4"-(4-chloro-2- thienylsulfonylamino-oleandomycin; 11 -O-acetyl-4"-deoxy-4"-(2-chloro-4-thienyl- sulfonylamino)oleandomycin; 11 -O-acetyl-4' '-deoxy-4' '-(2-pyridylsulfonyl- amino)oleandomycin; I 1 -O-propionyl-4"-deoxy-4"-(3-pyridylsulfonyl amino)oleandomycin; 11 l-O-acetyl-4"-deoxy-4"-(4-pyridylsulfonylamino)oleando- mycin; 11 l-O-acetyl-4"-deoxy-4"-(2-furylsulfonylamino)oleandomycin; I l-O- propionyl-4"-deoxy-4"-(2-pyrrylsulfonylamino)oleandomycin 11 -O-propionyl-4"- deoxy-4"-( 1 -methyl-5-carbomethoxy-3-pyrrylsulfonylamino)oleandomycin; and 11 -0-propionyl-4"-deoxy-4"-(3-thienylsulfonylamino)oleandomycin.

Example 4.

I I - O - Acetyl - 4" - deoxy - 4" - (p - chlorophenylsulfonylamino)oleandomycin To a solution of 2.91 g. (4.0 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino- oleandomycin and 528 y1 (4.2 mmoles) of triethylamine in 20 ml. of methylene chloride is added in portions 865 mg. (4.1 mmoles) of p-chlorophenylsulfonyl chloride and the resulting reaction mixture stirred at room temperature overnight.

The reaction is concentrated to dryness in vacuo and the residue treated with 10 ml.

of acetone. The suspension is filtered and the filtrate chromatographed on 160 g. of silica gel using acetone as eluate. Fractions 51 to 63 comprising 10 ml. each are coltected and concentrated under reduced pressure to give 857 mg. of the pure product. Fractions 42-52 and 6492 yielded 1.21 g. of less pure product.

NMR (8, CDCI3): 2.13 (3H): 2.36 (6H)s; 2.73 (2H)d; 3.13 (3H)s and 7.3-8.2 (4H)q.

Similarly, 20 g. of 1 l-O-acetyl-4"-deoxy-4"-amino-oleandomycin, 7.24 g. of pchlorophenylsulfonyl chloride and 5.36 g. of triethylamine in a solvent system comprising 350 ml. of acetone and 350 ml. of water gave 17.1 g. of the desired product which crystallized from the reaction mixture, m.p. 202--203.5"C. The analytical sample is recrystallized from ethanol-water.

Example 5.

Employing the procedure of Example 4 and starting with the requisite sulfonyl chloride and 11-O-acetyl-4"-deoxy-4"amino-oleandomycin, the following compounds are prepared:

NMR.(S, CDCI3) 2.06 (3H)s; 2.30 (6H)s; 2.66 (2H)d; 3.03 (3H)s; 3.96 (3H) s; and 7.3-9.0 (4H)m.

2.05 (3H)s; 2.30 (6H)s; 2.65 (2H)d; 3.01 (3H)s; 5.43 (2H)d; 7.46 (5H)s; and 7.33-8.70 (4H)m.

2.06 (3H)s; 2.30 (6H)s; 2.66 (2H)d; 3.06 (3H)s; 4.0 (3H)s; and 7.8-8.4 (4H)m.

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

Example 13.

The procedure of Example 11 is again repeated, starting with the requisite 11 O-alkanoyl-4"-deoxy-4"-oleandomycin and sulfonyl chloride to give the following compounds: 11 -O-acetyl-4"-deoxy-4"-(o-benzyloxycarbonylphenyl-sulfonyl amino)oleandomycin; I -O-propionyl-4' '-deoxy-4"-(p-methoxycarbonylphenyl- sulfonylamino)oleandomycin; II-O-propionyl-4"-deoxy-4"-(m-benzyloxycarbonyl- phenyl)-sulfonylamino)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(p-benzyloxy carbonylphenyl-sulfonylamino)oleandomycin; I l-O-propionyl-4"-deoxy-4"-(o- methoxycarbonylphenyl-sulfonylamino)oleandomycin; and l -O-propionyl-4"- deoxy-4"-(o-benzyloxycarbonyl-phenylsulfonylamino)oleandomycin.

Example 14.

11 -O-Acetyl-4"-deoxy-4"-(p-carboxyphenylsulfonylamino)oleandomycin A suspension of 400 mg. of 10% palladium-on-charcoal in 40 ml. of ethyl acetate containing 800 mg. of 11 -O-acetyl-4"-deoxy-4"-(p-benzyloxycarbonyl phenylsulfonylamino)oleandomycin is shaken in a hydrogen atmosphere at an initial pressure of 50 p.s.i. at room temperature for 2 hrs. An additional 250 mg. of catalyst is added and the reaction continued for 2 hrs. The spent catalyst is filtered off and the solvent removed in vacuo to give 450 mg. of the desired product.

NMR (8, CDCI3): 2.06 (3H)s; 2.86 (6H)s; 2.68 (2H)d; 3.30 (3H)s; and 7.5-8.4 (4H)m.

Example 15.

Starting with the appropriate 1 l-O-alkanoyl-4"-deoxy-4"-(benzyloxycarbonyl- phenylsulfonylamino)oleandomycin described in Example 12 or 13 and employing the procedure of Example 14, the following compounds are prepared: ll-O-acetyl- 4"-deoxy-4"-(m-carboxyphenylsulfonylamino)oleandomycin; 11-O-acetyl-4"- deoxy-4"-(o-carboxyphenylsulfonylamino)oleandomycin; 11 -O-propionyl-4"- deoxy-4"-(m-carboxyphenylsulfonylamino)oleandomycin, 11 I-O-propionyl-4"- deoxy-4"- (p-carboxyphenyl-sulfonylamino)oleandomycin, - and 1 l-O-propionyl-4"- deoxy-4"-(o-carboxyphenylsulfonylamino)oleandomycin.

Example 16. 11-O-Acetyl-4"-deoxy-4"-(o-nitrophenylsulfonylamino)oleandomycin Five grams (6.8 mmoles) of 11 -O-acetyl-4"-deoxy-4"-amino-oleandomycin, 1.5 g. (7.0 mmoles) of o-nitrobenzenesulfonyl chloride and .98 ml. of triethylamine are combined in 50 ml. of methylene chloride and stirred at room temperature for 48 hrs. The reaction mixture is quenched with an equal volume of water, and the organic phase washed with a saturated brine solution and dried over sodium sulfate. Removal of the solvent under reduced pressure provides the crude product as a foam. The product is purified by chromatographing on 140 g. of silica gel in a 3 cm. diameter column using acetone as the eluate. Fractions 20---30, comprising 50 Also prepared by the procedure of Example 10 when the appropriate starting materials are employed are: 11 -O-acetyl-4"-deoxy-4"-(2 naphthylsulfonylamino)oleandomycin NMR (, CDCl3): 2.03 (3H)s; 2.26 (6H)s; 2.65 (2H)d; 2.96 (3H); and 7.4-8.6 (7H)m; and 1 l-O-acetyl-4"-deoxy-4"-benzylsulfonylamino-oleandomycin NMR (, CDCl3): 2.00 (3H)s; 2.30 (6H)s; 2.63 (2H)d; 3.46 (3H)s; 4.33 (2H)s;

NMR (8, CDCI3) 2.08 (3H)s; 2.33 (6H)s; 2.70 (2H)d; 3.11 (3H)s; and 7.5-8.2 (4H)q.

2.08 (3H)s; 2.31 (6H)s; 2.66 (2H)d; 3.06 (3H)s and 7.08.4 (4H)m.

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

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

2.13 (3H)s; 2.35 (6H)s; 2.70 (2H)d; 2.90 (3H)s and 7.08.2 (4H)m.

2.10 (3H)s; 2.33 (6H)s; 2.66 (2H)d; 3.10 (3H)s and 7.57.93 (4H)m.

Example 6.

The procedure of Example 4 is again repeated starting with the appropriate sulfonyl chloride and 1 l-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin to give the following products: 11-O-propionyl-4"-deoxy-4"-(p-chlorophenylsulfonyl- amino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(m-bromophenylsulfonylamino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(m-fluorophenylsulfonylamino)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(m-iodophenylsulfonylamino)oleandomycin; 11 -Q-propionyl-4"-deoxy-4"-(p-fluornphenylsulfonyl- amino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(p-bromophenylsulfonylamino)oleandomycin; 11-O-acetyl-4"-deoxy-4"-(m-iodophenylsulfonyl- amino)oleandomycin and 11-O-acetyl-4"-deoxy-4"-(o-bromophenylsulfonyl- amino)oleandomycin.

Example 7.

11 - 0 - Acetyl - 4" - deoxy - 4" - (o - tolylsulfonylamino)oleandomycin A solution of 2.9 g. (4.0 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino-oleandomycin, 780 mg. (4.1 mmoles) of o-tolylsulfonyl chloride and .58 ml. (4.2 mmoles) of triethylamine in 30 ml. of methylene chloride is stirred at room temperature for 48 hrs. The reaction is quenched in 50 ml. of water and the separated organic layer washed with a saturated brine solution and dried over sodium sulfate. The solvent is removed in vacuo and the residual yellow foam chromatographed on 200 g. of silica gel in a 3 cm. diameter column. The product is eluted from the column with acetone collected in 10 ml. fractions. Those fractions containing the pure product, as assayed by thin layer chromatography, are combined and concentrated to dryness under reduced pressure to give 1.3 g.

NMR (8, CDCI3): 2.06 (3H)s; 2.33 (6H)s; 2.46 (2H)d; 2.73 (3H)s and 7.1-8.2 (4H)m.

Example 8.

The procedure of Example 7 is repeated, starting with the appropriate sulfonyl chloride and 1 l-O-acetyl-4"-deoxy-4"-amino-oleandomycin, to give the f lowing compounds:

NMR (ô, CDCI3) 2.03 (3H)s; 2.30 (6H)s; 2.66 (2H)d; 3.06 (3H)s; 3.83 (3H)s; and 6.8-8.2 (4H)m.

2.03 (3H)s; 2.33 (6H)s; 2.66 (2H)d; 3.06 (3H)s; and 7.3-8.0 (4H)m.

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

2.06 (3H)s; 2.30 (6H)s; 2.43 (3H)s; 3.10 (3H)s; 2.66 (2H)d; 7.23-7.40 (2H)d; and 7.76-7.93 (2H)d.

Example 9.

Starting with the appropriate 11-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride and employing the procedure of Example 7, the following analogs are synthesized: 11 -O-acetyl-4"-deoxy-4"-(m-tolylsulfonylamino)oleando mycin; 11 -O-propionyl-4"-deoxy-4"-(p-methoxyphenylsulfonylamino)-oleandomycin; Il -O-acetyl-4"-deoxy-4"-(m-methoxyphenylsulfonylamino)oleandomycin; 1 -O-prqpionylA"-deoxyA"-(p-tolylsuffonylamino)oleandomycin; 1 1-O-acetyl-4"- deoxy-4"-(p-isopropylphenylsulfonylamino)oleandomycin; 11 -O-acetyl-4"-deoxy4"-(o-ethylphenylsulfonylamino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(o-[n- propyl]-phenylsulfonylamino)oleandomycin; 11 -O-acetyl-4' '-deoxy-4' '-(p- Is- butyl]phenylsulfonylamino)oleandomycin; and 11 -O-propionyl-4"-deoxy-4"-(p-[n- butyl]phenylsulfonylamino)oleandomycin.

Example 10.

I l-O-acetyl-4"-deoxy-4"-phenylsulfonylamino-oleandomycin To a solution of 2.91 g. (4.0 mmoles)oll-O-acetyl-4"-deoxy-4"-amino- oleandomycin and 424 mg. (4.2 mmoles) of triethylamine in 30 ml. of methylene chloride, cooled in an ice bath, is added 722 mg. (4.1 mmoles) of benzenesulfonyl chloride. After 10 min., the bath is removed and the reaction mixture stirred at room temperature overnight. The reaction is quenched with 50 ml. of water and the organic layer washed with a saturated brine solution and dried over sodium sulfate.

Removal of the solvent provides the crude product which is further purified by chromatographing over 160 g. of silica gel using acetone as the eluate. Cuts (10 ml.

each) 61-93, which contain the pure product as determined by thin-layer chromatography, are combined and concentrated to dry under reduced pressure to give 1.5 g. of the desired product.

NMR (ô, CDCI3): 2.06 (3H)s; 2.30 (6H)s; 2.63 (2H)d; 3.06 (3H)s; and 7.3-8.2 (5H)m.

ml. each, are collected, combined and concentrated to dryness to give 3.4 g. of the desired compound.

NMR (ô, CDCI3): 2.10 (3HJ)s; 2.33 (6H)s; 4.36 (2H)d; 2.90 (3H)s; and 7.4-8.4 (4H)m.

Similarly, when the proper starting materials are employed and the above procedure is repeated the following compounds are prepared: 11-O-acetyl-4"-deoxy-4 "-(m-nitrophenylsulfonylamino)oleandomycin NMR (ô, CDCI3): 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 -O-acetyl4 "-deoxy-4 "-( p-nitrophenylsulfonylamino )oleandomycin NMR (ô, CDCl3): 2.10 (3H)s; 2.35 (6H)s; 2.68 (2H)d; 3.06 (3H)s; and 8.08.6 (4H)m.

Example 17.

11-O-Acetyl-4"-deoxy-4"-(p-hydroxyphenylsulfonylamino)-oleandomycin A solution of 2.55 g. (3.5 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino-oleando- mycin, 701 mg. (3.65 mmoles) of p-hydroxyphenylsulfonyl chloride and 51.8 81. of triethylamine in 25 ml. of methylene chloride is stirred at room temperature for 48 hrs. The solvent is removed in vacuo and the residue treated with 10 ml. of acetone.

The insolubles are filtered off and the filtrate chromatographed over 200 g. of silica gel using acetone as the eluate. Fractions 116-175 by volume, each of 10 ml., which by thin-layer chromatography contains the pure product, are combined and concentrated to dryness under reduced pressure to give 550 mg. of the desired product.

NMR (ô, CDCI3): 2.0 (3H)s; 2.33 (6H)s; 2.68 (2H)d; 3.06 (3H)s; and 6.6-8.0 (4H)m.

Example 18.

Starting with the requisite 1 l-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin an sulfonyl chloride and employing the procedure of Example 17, the following compounds are prepared: 11 l-O-acetyl-4"-deoxy-4"-(m-hydroxyphenylsulfonylamino)-oleandomycin; 1 I-O-propionyl-4"-deoxy-4"-(p-hydroxyphenylsulfonyl- amino)oleandomycin; 1 I-O-propionyl-4"-deoxy-4"-(m-hydroxyphenylsulfonyl- amino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(o-hydroxyphenylsulfonylamino)- oleandomycin; and 11 l-O-propionyl-4"-deoxy-4"-(o-hydroxyphenylsulfonylamino)- oleandomycin.

Example 19.

11-O-Acetyl-4"-deoxy-4"-(m-carbamoylphenylsulfonylamino)oleandomycin To 20 ml. of methylene chloride containing 2.91 g. (4.0 mmoles) of ll-0- acetyl-4"-deoxy-4"-amino-oleandomycin and 434 mg. (4.2 mmoles) of triethylamine is added 898 mg. (4.1 mmoles) of m-carbamoylphenylsulfonyl chloride, and the resulting reaction mixture stirred for 48 hrs. The solvent is removed in vacuo and the residue treated with 25 ml. of acetone. The triethylamine hydrochloride is filtered off and the filtrate chromatographed on 160 g. of silica gel. Fractions containing 50 ml. each are collected and examined by thin-layer chromatography to determine the purity of the product. Fractions 66-93 are combined and concentrated under reduced pressure to give 800 mg. of the desired product.

NMR (, CDCl3): 2.06 (3H)s; 2.33 (6H)s; 2.70 (2H)s; 3.10 (3H)s; and 7.49.0 (4H)m.

Example 20.

The procedure of Example 19 is repeated, starting with the appropriate 11-0alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride to give the following congeners: Il-O-propionyl-4"-deoxy-4"-(m-carbamoylphenyls- conyl- amino)oleandomycin; I l-O-acetyl-4"-deoxy-4"-(o-carbamoylphenylsulfonyl- amino)oleandomycin; I I 11 l-O-acetyl-4"-deoxy-4"-(p-carbamoylphenylsulfonyl- amino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(o-carbamoylphenylsulfonylamino)oleandomycin; and 11 l-O-propionyl-4"-deoxy-4"-(p-carbamoylphenylsul- fonylamino)oleandomycin.

Example 21.

I -O-Acetyl-4"-deoxy-4' '-(p-acetamidophenylsulfonylamino)oleandomycin A solution of 2.91 g. (4.0 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino-oleando- mycin, 955 mg. (4.1 mmoles) of p-acetamidophenylsulfonyl chloride and 424 mg.

(4.2 mmoles) of triethylamine in 20 ml. of methylene chloride is stirred for 48 hrs. at room temperature. The reaction mixture is concentrated under reduced pressure to a foam which is then treated with 10 ml. of acetone. The insoluble triethylamine hydrochloride is filtered off and the filtrate chromatographed on 160 g. of silica gel using acetone as the eluate. Cuts 42-86 by volume, each of 10 ml., which by thin layer chromatography contained most of the pure product, are combined and concentrated in vacuo to give 1.2 g. of the desired product.

NMR (8, CDCI3): 2.06 (3H)s; 2.23 (3H)s; 2.35 (6H)s; 2.70 (2H)s; 3.13 (3H)s; and 7.6-8.2 (4H)m.

Example 22.

The procedure of Example 21 is repeated, employing as starting reagents the appropriate 11 l-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin and requisite sulfonyl chloride, to give the following compounds: Il-O-propionyl-4"-deoxy4"-(p- acetamidophenylsulfonylamino)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(oacetamidophenylsulfonylamino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(m-acet- amidophenylsulfonylamino)oleandomycin; and 1 l-O-propionyl-4"-deoxy-4" (o-acetamidophenylsulfonylamino)oleandomycin.

Example 23.

I -O-Acetyl-4"-deoxy-4' '-(p-cyanophenylsulfonylamino)oleandomycin A solution of 2.55 g. (3.5 mmoles) of l l-O-acetyl-4"-deoxy-4"-amino-oleando- mycin, 734 mg. (3.65 mmoles) of p-cyanophenylsulfonyl chloride and 518 y1. (3.75 mmoles) of triethylamine in 25 ml. of methylene chloride is stirred at room temperature overnight. The solvent is removed in vacuo and the residue treated with 10 ml. of acetone. The insolubles are filtered off and the filtrate chromatographed on 120 g. of silica gel using acetone as the eluate and collecting fractions of 10 ml. each. Fractions 47-83 are combined and concentrated under reduced pressure to give 281 mg. of the desired product.

NMR (S, CDCl3): 2.10 (3H)s; 2.36 (6H)s; 2.71 (2H)d; 3.06 (3H)s; and 7.7-8.4 (4H)m.

Example 24.

Starting with the requisite 1 l-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin and cyanobenzenesulfonyl chloride and employing the procedure of Example 23, the following compounds are synthesized: 11 -O-acetyl-4"-deoxy-4"-(m-cyano- phenylsulfonylamino)oleandomycin; 11 -O-propionyl-4"-deoxy-4"-(o-cyanophenyl- sulfonylamino)oleandomycin; 11 -O-propionyl-4"-deoxy-4"-(p-cyanophenylsul- fonylamino)oleandomycin; 11 -O-acetyl-4"-deoxy-4"-(o-cyanophenylsulfonyl- amino)oleandomycin; and l -O-propionyl-4' '-deoxy-4"-(m-cyanophenylsulfonylamino)oleandomycin.

Example 25.

11 -O-Acetyl-4"-deoxy-4"-(p-trifluoromethylphenylsulfonylamino)oleandomycin To a solution of 2.55 g (3.5 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-aminooleandomycin and 518 y1. (3.75 mmoles) of triethylamine in 25 ml. of methylene chloride is added 891 mg. (3.65 mmoles) of p-trifluoromethylphenylsulfonyl chloride, and the resulting reaction mixture stirred for 18 hrs. The solvent is removed under reduced pressure and the residue triturated with 15 ml. of acetone.

The solids are filtered off and the filtrate chromatographed over silica gel to give 287 mg. of the desired product.

NMR (S, CDCI3): 2.03 (3H)s; 2.31 (6H)s; 2.63 (2H)d; 3.40 (3H)s; and 7.15-8.3 (4H)m.

Example 26.

The procedure of Example 25 is repeated, starting with the appropriate reagents, to give the following congeners: 11 -O-propionyl-4"-deoxy-4"-(m-tri- fluoromethylphenylsulfonylamino)oleandomycin; 11 -O-acetyl-4' '-deoxy-4"-(o-tri- fluoromethylphenylsulfonylamino)oleandomycin; 11 -O-acetyl-4"-deoxy-4"-(m-tri- fluoromethylphenylsulfonylamino)oleandomycin; I 1-O-propionyl-4"-deoxy-4"-(p- trifluoromethylphenylsulfonylamino)oleandomycin; and 1 l-O-propionyl-4"-deoxy4"-(o-trifluoromethylphenylsulfonylamino)oleandomycin.

Example 27.

I -O-Acetyl-4"-deoxy-4"-(2,2,2-trifluoroethylsulfonylamino)oleandomycin A solution of 2.55 g. (3.5 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino-oleando- mycin, 666 mg. (3.65 mmoles) of 2,2,2-trifluoroethylsulfonyl chloride and 379 mg.

(3.75 mmoles) of triethylamine in 25 ml. of methylene chloride is stirred for 30 hrs.

at room temperature. An additional 333 mg. of the sulfonyl chloride and 270 y1. of triethylamine are added and the stirring continued for 4 hrs. The solvent is then removed in vacuo and the residue treated with 20 ml. of acetone. The solids are filtered off and the filtrate chromatographed on 110 mg. of silica gel using acetone as the eluate and taking 10 ml. fractions. Fractions 5080 are combined and concentrated to give 385 mg. of the desired product.

NMR (ô, CDCI3): 2.06 (3H)s; 2.26 (6H)s; 2.60 (2H)d; and 3.36 (3H)s.

Similarly, starting with 11 -O-propionyl-4"-deoxy-4"-amino-oleandomycin in place of the ll-O-acetyl derivative and employing the above procedure there is prepared 11 -O-propionyl-4"-deoxy-4"-(2,2,2-trifluoroethylsulfonylamino)- oleandomycin.

Example 28.

1 l-O-Acetyl-4"-deoxy-4"-(methylsulfonylamino)oleandomycin A solution of 2.91 g. (4.0 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-amino-oleando- mycin, 467 mg. (4.1 mmoles) of methylsulfonyl chloride and 424 mg. (4.2 mmoles) of triethylamine in 25 ml. of methylene chloride is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue treated with 20 ml. of acetone. The triethylamine hydrochloride is filtered off and the filtrate containing the product chromatographed on 180 g. of silica gel using acetone as the solvent and taking 6 ml. fractions. Cuts 67-133 are combined and concentrated in vacuo to give 1.2 g. of the desired product.

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

Example 29.

Starting with the requisite alkyl sulfonyl halide and ll-O-alkanoyl 4"-deoxy4"-amino-oleandomycin, and employing the procedure of Example 28, the following compounds are synthesized:

R, R CH3CO- C2H5- CH3CO- n-C3H7- CH3CO- i-C3H7- CH3CH2CO- CH3- CII3CH2CO- C2H5- CHCH2CO- n-CH7- CH3CH2CO- i-C3H7- Example 30.

1 I -O-A cetyl-4"-deoxy-4"-(3,4-dichlorophenylsulfonylamino)oleandomycin 1 l-O-Acetyl-4"-deoxy-4"-amino-oleandomycin (2.9 g., 4.0 mmoles), 1.0 g. (4.1 mmoles) of 3,4-dichlorophenylsulfonyl chloride and .57 ml. (4.2 mmoles) of triethylamine are combined in 30 ml. of methylene chloride and the resulting solution stirred at room temperature for 18 hrs. The reaction is quenched with 50 ml. of water, and the organic phase washed with a saturated brine solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue chromatographed on 150 g. of silica gel using acetone as the eluate. Those fractions containing the product, as indicated by thin-layer chromatography, are combined and concentrated to dryness to give 1.3 g. of the desired product.

NMR (S, CDCI3): 2.0 (3H)s; 2.30 (6H)s; 2.60 (2H)d; 3.06 (3H)s; and 7.2-8.1 (3H)m.

Example 31.

Following the procedure of Example 30, and starting with the appropriate reagents, the indicated compounds are prepared:

NMR (o, CDCl3) 2.0 (3H)s; 2.36 (6H)s; 2.70 (2H)d 3.33 (3H)s; and 7.3 8.6 (3H)m.

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

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

2.06(3H)s; 2.33 (6H)s; 2.70 (2H)d; 3.13 (3H)s; and 7.4 8.6 (3H)m.

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

2.06(3H)s; 2.33 (6H)s; 2.63 (2H)d; 2.81 (3H)s; 3.63 (3H)s; and 7.0-8.2 (3H)m*.

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

*NMR: DMSO/CDCl3 Example 32.

The procedure of Example 30 is again repeated, starting with the requisite l l-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride, to give the following analogs: 11 -O-acetyl-4"-deoxy-4"-(2,6-dichlorophenylsulfonylamino)- oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(4-methyl-2-chlorophenylsulfonyl amino)oleandomycin; I 11 -O-propionyl-4"-deoxy-4' '-(2-methyl-5-chlorophenylsul- fonylamino)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(2-nitro-4-chlorophenylsulfonylamino)oleandomycin; I l-O-acetylA"-deoxyA"-(3-nitroA-chlorophenyl- sulfonylamino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(3-nitro-5-chlorophenylsulfonylamino)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(3-methoxy-5-nitrophenylsulfonyiamino)oleandomycin; 1 l-O-acetylA"-deoxyA"-(3-nitroA-methyl- phenylsulfonylamino)oleandomycin; 11-O-acetyl-4"-deoxy-4"-(3,5-dinitrophenylsulfonylamino)oleandomycin; I -O-acetyl-4"-deoxy-4"-(2,6-dimethoxy- phenylsulfonylamon)oleandomycin; 1 l-O-propionyl-4"-deoxy-4"-(2,4-dimethoxyphenylsulfonylamino)oleandomycin; 11 l-O-acetyl-4"-deoxy-4"-(2-methyl-5- methoxyphenylsulfonylamino)oleandomycin; 11 -acetyl-4"-deoxy-4"-(2,3-di- methylphenylsulfonylamino)oleandomycin; I l-O-propionyl-4"-deoxy-4"-(2-4-di- methylphenylsulfonylamino)oleandomycin; and I I -O-acetyl-4"-deoxy-4"-(3-nitro4-methylsulfonylamino)oleandomycin.

Example 33.

I l-O-Acetyl-4"-deoxy-4"-(2,3,4-trichlorophenylsulfonylamino)oleandomycin A solution of 2.9 g. (4.0 mmoles) of it 1-O-acetyl-4"-deoxv-4"-amino-oleando- mycin, 1.15 g. (4.1 mmoles) of 2,3,4-trichlorophenylsulfonyl chloride and .57 ml.

(4.2 mmoles) of triethylamine in 30 ml. of methylene chloride is stirred at room temperature for 18 hrs. The organic layer is washed with water (1 x 50 ml.) and a saturated brine solution (1 x 50 ml.) and subsequently dried over sodium sulfate.

The solvent is removed in vacuo and the residue is removed in vacuo and the residue chromatographed on 150 g. of silica gel using acetone as the solvent, taking fractions of 7 ml. each. Fractions 60100 are combined and concentrated to give 800 mg. of the desired product.

NMR (ô, CDCI3): 2.06 (3H)s; 2.33 (6H)s; 2.63 (2H)d; 3.2 (3H)s; and 7.2-8.2 (2H)m.

Similarly, by starting with the appropriate reagents and following the above procedure, the following compounds are synthesized: Il-O-acetyl-4"-deoxy-4"- (3,4,5-trichlorophenylsulfonylamino)oleandomycin; l l-O-propionyl-4"-deoxy-4" (2,4,6-trichlorophenylsulfonylamino)oleandomycin; and 11-O-acetyl-4"-deoxy-4"- (2,3,5-trichlorophenylsulfonylamino)oleandomycin.

Example 34.

II - 0 - Acetyl - 4" - deoxy - 4" - (2 - hydroxy - 3,5 - dichlorophenylsulfonylamino) oleandomycin The procedure of Example 33 is repeated, starting with 2.55 g. (3.5 mmoles), of l -O-acetyl-4"-deoxy-4"-amino-oleandomyc 954 mg. (3.65 mmoles of 2hydroxy-3,5-dichlorophenylsulfonyl chloride and.518 y1. (3.75 mmoles') of triethylamine in 25 ml. of methylene chloride to give, after chromatographing on 220 g. of silica gel, 483 mg. of the desired product.

NMR (s, CDCI3) DMSO/CDCI3: 2.03 (3H)s; 2.50 (6H)s; 3.05 (3H)s; and 7.27.8 (2H)m.

Example 35.

Starting with the requisite 11-O-alkanoyl-4"-deoxy-4"-amino-oleandomycin and sulfonyl chloride and employing the procedure of Example 33, the following congeners are prepared:

R, R CH3CO- CH3CO- CH3CO- CH3CO- CH3CH2CO- CH3CH2CO- CH3CH2CO- CH3CH2CO-

Example 36.

11-O-Acetyl-4"-deoxy-4'-(3-amino-4-chlorophenylsulfonylamono)oleandomycin A suspension of 500 mg. of 10% palladium-on-charcoal in 50 ml. of ethyl acetate containing 1.0 g. of ll-O-acetyl-4"-deoxy-4"-(3-nitro-4-chlorophenylsul- fonylamino)oleandomycin is shaken in a hydrogen atmosphere at an initial pressure of 50 p.s.i. at room temperature overnight. The spent catalyst is filtered off and the solvent removed in vacuo. The residual white foam is chromatographed on 160 g. of silica gel using acetone as the eluate, taking 50 ml. cuts. The fractions containing the product are combined and concentrated under reduced pressure to give 450 mg. of the desired material.

NMR (S, CDCI3): 2.03 (3H)s; 2.33 (6H)s; 2.66 (2H)d; 3.16 (3H)s; and 7.2-8.0 (3H)m.

Prepared in a similar manner, employing the appropriate nitro compounds of Example 16 are: 11-0-A cetyl-4 "-deoxy-4"(m-aminophenyisulfonylamino)oleandomycin NMR (ô, CDCI3): 2.03 (3H)s; 2.30 (6H)s; 2.63 (2H)d; 3.10 (3H)s; and 7.(w7.8 (4H)m and 11 -0-acetyl-4 "-deoxy-4 "-(p-aminophenylsulfonylamino)oleandomydn NMR (o, CDCI3): 2.06 (3H)s; 2.31 (6H)s; 3.02 (3H)s; and 6.4-7.8 (4H)dd.

Example 37.

Starting with the requisite nitro compounds in Example 31 and 32 and employing the reduction procedure of Example 36, the following amino compounds are prepared: 11 -O-acetyl-4"-deoxy-4"-(2-amino-4-chlorophenylsulfonylamino)oleandomycin; 11 -O-acetyl-4"-deoxy-4"-(2-amino-4-methoxy- phenylsulfonylamino)oleandomycin; Il-O-acetyl-4"-deoxy-4"-(2,4-diaminophenyl- sulfonylamino)oleandomycin; 11-O-propionyl-4"-deoxy-4"-(2-amino-4-chloro- phenylsulfonylamino)oleandomycin; 1 l-O-acetyl-4"-deoxy-4"-(3-amino-4-chloro phenylsulfonylamino)oleandomycin; I l-O-acetyl-4"-deoxy-4"-(3-amino-5-chloro- phenylsulfonylamino)oleandomycin; 11 -O-propionyl-4"-deoxy-4"-(3-methoxy-5aminophenylsulfonylamino)oleandomycin; I-O-acetyl-4"-deoxy-4"-(3-amino-4methylphenylsulfonylamino)oleandomycin; and 11 l-O-acetyl-4"-deoxy-4"-(3,5-di- aminophenylsulfonylamino)oleandomycin.

Example 38.

11 -O-Acetyl-4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin To 100 g. (0.13 mole) of 11 -O-acetyl-4"-deoxy-4"-amino-oleandomyc in 900 ml. of methylene chloride is added 593 ml. of triethylamine, and the solution stirred for 10 minutes. 3-Methyl-2-thienylsulfonyl chloride (41.9 g.; 0.213 mole) in 300 ml.

of methylene chloride is subsequently added dropwise over a period of one hour and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture is added to 2 1. of water and the organic layer separated, washed successively with water (2 x 250 ml.) and a brine solution (I x 250 ml.) and dried over sodium sulfate. The solvent is removed in vacuo and the residue chromatographed on a 105 cm. x 6.5 cm. column containing 1.5 kg. of silica gel.

The product, which is eluted with acetone, is collected in the 2.3 1. to 6 1. eluate fractions. The fractions are combined, and the solvent removed under reduced pressure to give a foam. Treatment of the residual foam with diethyl ether gave 66.4 g. of the desired product, m.p. 184--185.5"C.

NMR (ô, CDCI3): 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 is added 0.12 ml. of phosphoric acid and the resulting solution stirred at room temperature. After 20 minutes, crystals commence to form and after 2 hours are filtered off, washed with ethyl acetate and dried to give 1.3 g. of l l -0-acetyl-4"-deoxy4"-(3-methyl-2-thienyl- sulfonylamino)oleandomycin phosphate.

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

Example 39.

The procedure of Example 38 is repeated, starting with the appropriate sulfonyl chloride and ll-O-acetyl-4"-deoxy-4"-amino-oleandomycin to give the following congeners:

NMR (ô, CDCI3) 2.08 (3H)s; 2.33 (6H)s; 2.38 (3H)s; 2.68 (2H)m; 3.27 (3H)s; 6.08 and 6.92 (2H).

2.08 (3H)s; 2.36 (6H)s; 2.68 (2H)m; 3.30(3H)s; 3.71 (3H)s; 6.44--6.70 (1him and 7.18-739 (2H)m.

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

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

2.08 (3H)s; 2.34 (6H)s; 2.54 (3H)s; 2.67 (2H)s; 3.25 (3H)s; 6.73 and 7.46 (2H).

Example 40.

The procedure of Example 38 is again repeated, starting with the requisite sulfonyl chloride an

NMR (6, CDCI3) 2.09 (3H)s; 2.32 (6H)s; 2.69 (2H)m.

3.22 (3H)s; 3.95 (3H)s; 7.61 and 7.75 (2H).

2.11 (3H)s; 2.34 (6H)s; 2.70 (2H)m.

3.24 (3H)s; 3.94 (3H)s; 8.06 and 8.28 (2M).

2.08 (3H)s; 2.29 (6H)s; 2.67 (2H)s; 3.18 (3H)s; 3.94 (3H)s; 7.02 and 7.20 (2H).

Example 43.

4"-Deoxy-4"-(p-chlorophenylsulfonylamino)oleandomycin A solution of 3.0 g. of 4"-deoxy-4"-amino-oleandomycin, 865 mg. of pchlorophenylsulfonyl 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 treated with 20 ml. of acetone. The insoluble triethylamine hydrochloride is filterd off and the filtrate chromatographed on 180 g. of silica gel using acetone as the eluting solvent and taking 50 ml. cuts. Fractions 18-27 are combined and concentrated under reduced pressure to give 1.10 g. of the desired product.

NMR (6, CDCI3): 2.33 (6H); 2.83 (2H)d; 3.06 (3H)s; and 7.2-8.4 (4H)m.

Example 44.

The procedure of Example 43 is repeated, starting with the appropriate sulfonyl chloride and 4"-deoxy-4"-amino-oleandomycin, to give the following compounds:

Example 45.

4"-Deoxy-4"-(p-toluenesulfonylamino)oleandomycin By a procedure similar to Example 43, 30 g. (4.0 mmoles) of 4"-deoxy-4"amino-oleandomycin, 782 mg. (4.1 mmoles) of p-toluenesulfonyl chloride and 424 mg. (4.2 mmoles) of triethylamine in 25 ml. of methylene chloride are stirred at ambient temperature overnight. On work-up the crude product is chromatographed on 180 g. of silica gel, taking 10 ml. cuts. Fractions 9-148 are combined and concentrated to dryness to give 1.4 g. of the desired product.

NMR (6, CDCI3): 2.33 (6H)s; 2.46 (3H)s; 2.83 (2H)d; 3.10 (3H)s; and 7.108.0 (4H)m.

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

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

Example 46.

Starting with 4"-deoxy-4"-amino-oleandomycin and the requisite sulfonyl chloride and employing the procedure of Example 43, the following congeners are synthesized:

Example 47.

11 -O-Acetyl-4"-deoxy-4"-(vinylsulfonylamino)oleandomycin To a solution of 17.1 g. (82.3 mmoles) of -bromoethanesulfonyl chloride in 200 ml. of methylene chloride, cooled to -780C. and maintained under a nitrogen atmosphere, is added a cold (-78"C.) solution of 30 g. (41.1 mmoles) of ll-0- acetyl-4"-deoxy-4"-amino-oleandomycin and 16.7 g. (164 mmoles) of triethylamine in 100 ml. of methylene chloride. After stirring at -780C. for 1.3 hrs. the reaction mixture is poured into water and the pH adjusted to 7.3 by the addition of solid sodium bicarbonate. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give 43.5 g. of a yellow foam. The residual material is slurried in ether and filterd. The filtrate is concentrated under reduced pressure to give 20.3 g. of the crude product which is chromatographed on 800 g. of silica gel using chloroform-methanol (95:5; v:v) as the eluting solvent. The fractions containing the product are combined and concentrated to give 5.1 g.

NMR (ô, CDCl3): (3H)s; 2.37 (6H)s; 2.70 (2H)d; 3.43 (3H)s; and 5.7-7.06 (3H)m.

* Example 48.

I -O-Acetyl-4' '-deoxy-4"-(8-bromoethylsulfonylamino)oleandomycin To a solution of 500 mg. (0.68 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-aminooleandomycin and 882 mg. (8.2 mmoles) of 2,6-lutidine in 4 ml. of methylene chloride, precooled to -4"C. and under a nitrogen atmosphere, is added 854 mg.

(4.0 mmoles) of p-bromoethane-sulfonyl chloride in 2 ml. of methylene chloride cooled to -20C. After stirring at --20C. for 1.75 hrs., the reaction mixture is poured into a mixture of water and methylene chloride and the pH adjusted to 7.0 with solid sodium bicarbonate. The organic phase is separated, dried over sodium sulfate and concentrated to am amber oil. The residual oil is chromatographed on 42 g. of silica gel, using chloroform-methanol (95:5; v:v) as the eluate solvent, to give 52.5 mg. of the desired product.

NMR (8, CDCl3): 2.08 (3H)s; 2.33 (6H)s; 2.65 (2H)s; and 3.46 (3H)s.

Example 49.

11 -O-Acetyl-4' '-deoxy-4' '-(2-diethylaminoethylsufonylamino)oleandomycin To a solution of 1.0 g. (1.22 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-(vinylsul- fonylamino)oleandomycin in 5 ml. of benzene is added 892 mg. (12.2 mmoles) of diethylamine, and the resulting reaction mixture stirred under a nitrogen atmosphere at ambient temperature for 48 hrs. The solvent and excess diethylamine are removed in vacuo and the product obtained as a white foam which slowly crystallizes, 940 mg., m.p. 85--99"C.

NMR (8, CDCl3): 2.05 (3H)s; 2.30 (6H)s; 2.36-2.73 (4H)q; 2.63 (2H)s; and 3.4 (3H)s.

Example 50.

The procedure of Example 49 is repeated, starting with the appropriate 11-0 alkanoyl-4"-deoxy-4"-vinylsulfonylamino-oleandomycin and secondary amine to ive the following compounds:

R1 Z CH3CO- N(CH3)2 CH3CO- N(CH3)C2H5- CH3CO- N(n-C3H7)2 CH3CO- N(i-C3H7)2 CH3CO- N(C2H5)n-C3H7 CH3CO- N(CH3)i-C3H7 CH3CH2CO- N(CH3)2 CH3CH2C0- N(CH3)C2Hs CH3CH2C0- N(C2Hs)2 CH3CH2CO- N(n-C3H7)2 CH3CH2CO- N(i-C3H7)2 CH3CH2CO- N(CH3)i-C3H7 Example 51.

11-O-Acetyl-4"-deoxy-4"-(methylthioethylsulfonylamino)oleandomycin A suspension of 800 mg. (.98 mmole) of 11-O-acetyl-4"-deoxy-4"-(vinylsul- fonylamino)oleandomycin and 475 mg. (3 mmoles) of potassium carbonate in 10 ml. of benzene is stirred while methyl mercaptan is bubbled into the suspension for 30 sec. The tightly stopperd container is stirred overnight at room temperature.

The excess mercaptan is removed under reduced pressure, and the reaction mixture added to a mixture of benzene-water. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to give 805 mg. of the product as an oil.

NMR (#, CDCI3): 1.98 (3H)s; 2.05 (3H)s; 2.20 (6H)s; 2.57 (2H)s; and 3.30 (3H)s.

Example 52.

Starting with the appropriate mercaptan and 1 l-O-acetyl-4"-deoxy-4"-(vinylsulfonylamino)oleandomycin and employing the procedure of Example 51, the following compounds are synthesized:

Z NMR(#, CDCI3) HOCH2CH2S- 2.03 (3H)s; 2.30 (6H)s; 2.63 (2H)s; and 3.40 (3H)s.

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

CH3CH2CH2S- 2.07(3H)s; 2.30(1H)s; 2.61 (2H)s; and 3.42 (3H)s.

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

Example 53.

The procedure of Example 51 is again repeated, starting with the appropriate 1 l-O-alkanoyl-4"-deoxy-4"-(vinylsulfonylamino)oleandomycin and mercaptan to give the following analogs:

R, Z CH3CO- (CH3)2CHS- Ch3CH2CO- CH3S- CH3CH2CO- CH3CH2S- CH3CH2CO- HOCH2CH2S- CH3CH2CO- C6H5S- CH3CH2CO- CH3CH2CH2S- Example 54.

11-O-Acetyl-4"-deoxy-4"-(morpholinoethylsulfonylamino)oleandomycin To a solution of 2.0 g. (2.44 mmoles) of 1 l-O-acetyl-4"-deoxy-4"-(vinylsul- fonylamino)oleandomycin in 50 ml. of benzene is added 2.1 g. (24.4 mmoles) of morpholine, and the resulting reaction mixture stirred under a nitrogen atmosphere for 40 hrs. at room temperature. The solvent and excess morpholine are removed in vacuo to give the crude product as a foam. The residue is triturated in hexane for one hour followed by recrystallization from ethyllactate-hexane, 890 mg., m.p.

95"C.

NMR (ô, CDCI3): 2.06 (3H)s; 2.30 (6H); and 3.42 (3H)s.

Example 55.

11 -O-Acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin hydrochloride To 8.7 g. of 1 l-O-acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin in 50 ml. of dry ethyl acetate is added 10 ml. of a IN ethyl acetate solution of hydrogen chloride is added. The solution is concentrated to dryness in vacuo and the residual mono-hydrochloride salt is triturated with ether and filtered.

Example 56.

1 l-O-Acetyl-4"-deoxy-4"-(2-thienylsulfonylamino)oleandomycin phosphate To a solution of 15.0 g. of 1 l-O-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 solids are filterd off, washed with ethyl acetate and dried to give 12.5 g. of the desired salt, m.p. 168"C. (dec.).

In a similar manner is prepared 1 l-O-acetyl-4"-deoxy-4"-(3-methyl-2-thienylsulfonylamino)oleandomycin phosphate, m.p. 184--188"C. and l l-O-acetyl-4"- deoxy4 "-(p-chtornphenyisulfonylamino )oleandomycin phosphate, m.p. 204--205"C.

Preparation A.

4"-Deoxy-4"-oxo-oleandomycins I. I -O-Acetyl-4"-deoxy-4"-oxo-oleandomycin a. 1 1,2'-Di-O-acetyl-4"-deoxy-4"-oxo-oleandomycin To a 4.5 g. of N-chlorosuccinimide, 50 ml. of benzene and 150 ml. of toluene in a dry flask fitted with a magnetic stirrer and nitrogen inlet and cooled to -50C. is added 3.36 ml. of dimethyl sulfide. After stirring at OOC. for 20 min., the contents are cooled to -250C. and treated with 5.0 g. of 1 1,2'-di-o-acetyl-oleandomycin in 100 ml. of toluene. Cooling and stirring are continued for 2 hrs. followed by the addition of 4.73 ml. of triethylamine. The reaction mixture is stirred at OOC. for 15 min., and is subsequently poured into 500 ml. of water. The pH is adjusted to 9.5 with IN aqueous sodium hydroxide and the organic layer separated, washed with water and a brine solution and dried over sodium sulfate. Removal of the solvent in vacuo gives 4.9 g. of the desired product as a foam.

NMR (ô, CDCI3): 3.48 (3H)s; 2.61 (2H)m, 2.23 (6H)s and 2.03 (6H)s.

b. I l-O-Acetyl-4"-deoxy-4"-oxo-oleandomycin A solution of 4.0 g. of I 1 ,2'-di-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 75 ml. of methanol is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give the product as a foam. A diethyl ether solution of the residue, on treatment with hexane, gives 2.6 g. of the product as a whote solid, m.p. 112--1170C.

NMR (S, CDCI3): 3.43 (3H)s, 2.60 (2H)m, 2.23 (6H)s and 2.01 (3H)s.

Similarly, by employing 11 ,2'-di-O-propionyl-4"-deoxy-4"-oxo-oleandomycin or I l-O-propionyl-2'-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in the above pro cedure, 1 l-O-propioíNyl-4"-deoxy-4"-oxo-oleandomycin is prepared.

II. 4"-Deoxy-4"-oxo-oleandomycin a. 2'-O-Acetyl-4"-deoxy-4"-oxo-oleandomycin Dimethyl sulfide (0.377 ml.) is added to a turbid solution of 467 mg. of Nchlorosuccinimide in 20 ml. of toluene and 6 ml. of benzene cooled to -50C. and maintained under a nitrogen atmosphere. After stirring at OOC. for 20 min. the mixture is cooled to -250C. and 1.46 g. of 2'-O-acetyloleandomycin and 15 ml. of toluene are added. Stirring is continued for 2 hrs. at 20C C. followed by the addition of 0.46 ml. of triethylamine. The reaction mixture is maintained at -200C.

for an additional 5 min and then allowed to warm to OOC. The mixture is poured, with stirring, into 50 ml. of water and 50 ml. of ethyl acetate. The pH of the aqueous mixture is adjusted to 9.5 by the addition of aqueous sodium hydroxide solution.

The organic layer is subsequently separated, dried over sodium sulfate and concentrated in vacuo to a white foam (1.5 g.). Trituration with diethyl ether gives 864 mg. of crude product, which on recrystallization twice from methylene chloride-diethyl ether gives 212 nig. of the pure product, m.p. 183--185.5"C.

Anal.Calc'dforC3,Hs1O,3N:C, 61.1; H, 8.5; N, 1.9.

Found: C, 60.9; H, 8.4; N, 1.9 NMR (ô, CDC1,): 5.60 (1H)m, 3.50 (3H)s, 2.73 (2H)m, 2.23 (6H)s and 2.03 (3H)s.

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

NMR (ô, CDCI3): 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 1-O-Acetyl-4"-deoxy-4"-amino-oleandomycin To a suspension of 10 g. of 10% palladium-on-charcoal in 100 ml. ofmethanol is added 21.2 g. of ammonium acetate and the resulting slurry is treated with a solution of 20 g. of I l-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 100 ml. of the same solvent. The suspension is shaken at room temperature in a hydrogen atmosphere at an initial pressure of 50 p.s.i. After 1.5 hrs., the catalyst is filtered off and the filtrate is added with stirring to a mixture of 1200 ml. of water and 500 ml.

of chloroform. The pH is adjusted from 6.4 to 4.5 and the organic layer is separated. The aqueous layer, after a further extraction with 500 ml. of chloroform, is treated with 500 ml. of ethyl acetate and the pH adjusted to 9.5 with IN sodium hydroxide. The ethyl acetate layer is separated and the aqueous layer extracted again with ethyl acetate. The ethyl acetate extracts are combined, dried over sodium sulfate and concentrated to a yellow foam (18.6 g.), which on crystallization from diisopropyl ether, provides 6.85 g. of the purified product, m.p. l57.5-l600C.

NMR (ô, CDCl3): 3.41 (3H)s, 2.70 (2H)m, 2.36 (6H)s and 2.10 (3H)s.

The other epimer, which exists in the crude foam to the extent of 225%, is obtained by gradual concentration and filtration of the mother liquors.

In a similar manner, starting with 1 l-O-propionyl-4"-deoxy-4"oxo-oleando- mycin in the above procedure, gives 1 l-O-propionyl-4"-deoxy-4"-amino-oleandomycin.

II. 4"-Deoxy-4"-amino-oleandomycin A solution of 20 g. of 2'-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 125 ml. of methanol, after stirring at room temperature overnight, is treated with 21.2 g. of ammonium acetate. The resulting solution is cooled in an ice bath and treated with 1.26 g. of sodium cyanoborohydride. The cooling bath is then removed and the reaction mixture stirred at room temperature for 2 hrs. The reaction mixture is poured into 600 ml. of water and 600 ml. of diethyl ether and the pH adjusted from 8.3 to 7.5. The ether layer is separated and the aqueous layer extracted with ethyl acetate. The extracts are set aside and the pH of the aqueous layer adjusted to 8.25.

The diethyl ether and ethyl acetate extracts made at this pH are also set aside, and the pH raised to 9.9. The diethyl ether and ethyl acetate extracts at this pH are combined, washed successively with water (1 x) and a saturated brine solution and dried over sodium sulfate. The latter extracts, taken at pH 9.9, are concentrated to a foam and chromatographed on 160 g. of silica gel, using chloroform as the loading solvent and initial eluate. After eleven fractions, which amount to 12 ml. per fraction, are taken, the eluate is changed to 5% methanol - 95% chloroform. At fraction 370 the eluate is changed to 10% methanol - 90% chloroform and at fraction 440, 15% methanol - 85% chloroform is used. Fractions 85-260 are combined and concentrated in vacuo to dryness to provide 2.44 g. of the desired product.

NMR (ô, CDCI3): 5.56 (1H)m, 3.36 (3H)s, 2.9 (2H)m and 2.26 (6H)s.

WHAT WE CLAIM IS: 1. Oleandomycins of the formulae:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (16)

**WARNING** start of CLMS field may overlap end of DESC **. NMR (ô, CDC1,): 5.60 (1H)m, 3.50 (3H)s, 2.73 (2H)m, 2.23 (6H)s and 2.03 (3H)s. b. 4"-Deoxy-4"-oxo-oleandomycin A solution of 1.0 g. of 2'-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 20 ml. of methanol is stirred at room temperature overnight. The solution is concentrated in vacuo to give the desired product as a white foam, 937 mg. NMR (ô, CDCI3): 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 1-O-Acetyl-4"-deoxy-4"-amino-oleandomycin To a suspension of 10 g. of 10% palladium-on-charcoal in 100 ml. ofmethanol is added 21.2 g. of ammonium acetate and the resulting slurry is treated with a solution of 20 g. of I l-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 100 ml. of the same solvent. The suspension is shaken at room temperature in a hydrogen atmosphere at an initial pressure of 50 p.s.i. After 1.5 hrs., the catalyst is filtered off and the filtrate is added with stirring to a mixture of 1200 ml. of water and 500 ml. of chloroform. The pH is adjusted from 6.4 to 4.5 and the organic layer is separated. The aqueous layer, after a further extraction with 500 ml. of chloroform, is treated with 500 ml. of ethyl acetate and the pH adjusted to 9.5 with IN sodium hydroxide. The ethyl acetate layer is separated and the aqueous layer extracted again with ethyl acetate. The ethyl acetate extracts are combined, dried over sodium sulfate and concentrated to a yellow foam (18.6 g.), which on crystallization from diisopropyl ether, provides 6.85 g. of the purified product, m.p. l57.5-l600C. NMR (ô, CDCl3): 3.41 (3H)s, 2.70 (2H)m, 2.36 (6H)s and 2.10 (3H)s. The other epimer, which exists in the crude foam to the extent of 225%, is obtained by gradual concentration and filtration of the mother liquors. In a similar manner, starting with 1 l-O-propionyl-4"-deoxy-4"oxo-oleando- mycin in the above procedure, gives 1 l-O-propionyl-4"-deoxy-4"-amino-oleandomycin. II. 4"-Deoxy-4"-amino-oleandomycin A solution of 20 g. of 2'-O-acetyl-4"-deoxy-4"-oxo-oleandomycin in 125 ml. of methanol, after stirring at room temperature overnight, is treated with 21.2 g. of ammonium acetate. The resulting solution is cooled in an ice bath and treated with 1.26 g. of sodium cyanoborohydride. The cooling bath is then removed and the reaction mixture stirred at room temperature for 2 hrs. The reaction mixture is poured into 600 ml. of water and 600 ml. of diethyl ether and the pH adjusted from 8.3 to 7.5. The ether layer is separated and the aqueous layer extracted with ethyl acetate. The extracts are set aside and the pH of the aqueous layer adjusted to 8.25. The diethyl ether and ethyl acetate extracts made at this pH are also set aside, and the pH raised to 9.9. The diethyl ether and ethyl acetate extracts at this pH are combined, washed successively with water (1 x) and a saturated brine solution and dried over sodium sulfate. The latter extracts, taken at pH 9.9, are concentrated to a foam and chromatographed on 160 g. of silica gel, using chloroform as the loading solvent and initial eluate. After eleven fractions, which amount to 12 ml. per fraction, are taken, the eluate is changed to 5% methanol - 95% chloroform. At fraction 370 the eluate is changed to 10% methanol - 90% chloroform and at fraction 440, 15% methanol - 85% chloroform is used. Fractions 85-260 are combined and concentrated in vacuo to dryness to provide 2.44 g. of the desired product. NMR (ô, CDCI3): 5.56 (1H)m, 3.36 (3H)s, 2.9 (2H)m and 2.26 (6H)s. WHAT WE CLAIM IS:

1. Oleandomycins of the formulae:

wherein R is alkyl having from one to three carbon atoms; pyridyl; 2,2,2trifluorethyl; phenyl; monosubstituted phenyl wherein said substituent is fluoro, chloro, bromo, iodo, hydroxy, methoxy, cyano, carbamoyl, nitro, amino, carbomethoxy, carbobenzyloxy, carboxy, trifluoromethyl, alkyl having from one to four carbon atoms or acetamido; disubstituted phenyl wherein said substituents are each selected from chloro, nitro, amino, methoxy and methyl; trichlorophenyl; hydroxydichlorophenyl; benzyl; naphthyl; thienyl; chlorothienyl; 2-acetamido-5thiazolyl; 2-acetamido-4-methyl-5-thiazolyl; 2-benzimidazolyl; dimethyl-2pyrmidinyl; pyrryl; furyl; monosubstituted thienyl, pyrryl or furyl wherein said substituent is carbomethoxy or alkyl having one or two carbon atoms; or I-methyl 5-carbomethoxy-3-pyrryl; R, is alkanoyl having two or three carbon atoms; R2 is phenyl; thienyl; monosubstituted phenyl wherein said substituent is chloro, fluoro, methyl, methoxy or trifluoromethyl; or alkyl-substituted thienyl, said alkyl group having one or two carbon atoms; X and Y when considered separately are each hydrogen; or X and Y when considered together represent a carbon-carbon bond; and Z is hydrogen, bromo, dialkylamino wherein each alkyl group has one to three carbon atoms, alkylthio in which said alkyl group has one to three carbon atoms, phenylthio, 2-hydroxyethylthio or morpholino, with the proviso that when X and Y ara a carbon-carbon bond; Z is hydrogen; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of the formula I as claimed in claim 1 wherein R is thienyl optionally monosubstituted by alkyl or I or 2 carbon atoms or carbomethoxy.

3. A compound as claimed in claim 2 wherein R, is acetyl.

4. A compound as claimed in claim 3 wherein R is 2-thienyl, 3-thienyl or 3methyl-2-thienyl.

5. A compound of the formula 2 as claimed in claim 1 wherein R2 is 4chlorphenyl, 2-thienyl, 3 thienyl or 3-methyl-2-thienyl.

6. A compound of the formula 3 as claimed in claim I wherein X and Y are each hydrogen and R, is acetyl.

7. A compound as claimed in claim 6 wherein Z is bromo or methylthio.

8. A compound of the formula 3 as claimed in claim 1 wherein X and Y are a carbon-carbon bond, Z is hydrogen and R1 is acetyl.

9. A compound as claimed in claim 1 wherein R is other than pyrryl; furyl; monosubstituted thienyl, pyrryl and furyl; and l-methyl-5-carbomethoxy-3-pyrryl; and R2 is other than alkyl substituted thienyl.

10. A process for preparing a compound of the formula I, 2 or 3 or a pharmaceutically acceptable acid addition salt thereof as claimed in claim 1, substantially as described herein.

11. A process as claimed in claim 10 substantially as hereinbefore described in any one of Examples 1, 4 to 37, 43, 44, and 47 to 55.

12. A process as claimed in claim 10 substantially as hereinbefore described in any one of Examples 2, 3, 38 to 42, 45, 46 and 56.

13. An oleandomycin of the formula I, 2 or 3 as claimed in claim I which has been prepared by a process as claimed in any one of claims 10 to 12.

14. A pharmaceutical composition comprising a compound of the formula 1, 2 or 3 or pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims I to 8 and 13, together with a pharmaceutically acceptable diluent or carrier.

15. A pharmaceutical composition comprising a compound of the formula 1,2 or 3 as claimed in claim 9 together with a pharmaceutically acceptable diluent or carrier.

16. A method of treating an animal, excluding a human being, having an infection caused by Gram-positive micro-organisms, or Gram-negative microorganisms of spherical or ellipsoidal shape, which comprises administering to the animal an antibacterially effective amount of a compound as claimed in any one of claims 1 to 9 and 13 or composition as claimed in either of claims 14 and 15.