20-AMINO MACROLIDE DERIVATIVES

Abstract: C-20 modified derivatives of tylosin and tylosin-like macrolides useful as antibiotics and as intermediates to other antibiotics.

Description: 20-AMINO MACROLIDE DERIVATIVES This invention relates to macrolide antibiotics, and more specifically to a novel group of C-20 modified derivatives of tylosin, desmycosin, macrocin, lactenocin, 2' ''-O-demethylmacrocin (DOMM), 2'µ-O-demethylacetenocin (DOML), dihydrotylosin (relomycin), dihydrodesmycosin, dihydromacrocin, dihydrolactenocin, dihydro-DOMM, dihydro-DOtG, and 4'-deoxy- desmycosin, which are useful as antibiotics and as intermediates to antibiotics. Improved antibiotics are continually in demand. In addition to antibiotics which are useful for treating human diseases, improved antibiotics are also needed in the veterinary field. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy1 and improved pharmaceutical properties (such as greater oral absorption, higher blood or tissue concentrations, longer body half life, and more advantageous rate or route of excretion and rate or pattern of metabolism) are some of the goals for improved antibiotics. Tylosin is a well-known therapeutic agent in the veterinary field. (See, for example, Tetrahedron Letters 1970, 2339 and U.S. Patent No. 3,178,341). Tylosin and tylosin-like macrolides have been modified in an attempt to obtain derivatives having improve properties. A large number of derivatives have been made, but improvement in activity has ot reviously been obtained to the desired degree. We have now discovered that reductive amination of the C-20 aldehyde g-roup of tylosin and the aforementioned tylosin-like macrolides using certain cyclic amines as aminating agents results in derivatives with significantly increased activity. More specifically, the invention provides macrolide derivatives nf the formula (I) EMI2.1 wherein R is a monocyclic saturated or unsaturated ring containing one nitrogen atom as a sole hetero atom, the ring being bonded through the nitrogen atom and including from 5 to 16 ring atoms, or a bicyclic or tricyclic saturated or unsaturated ring containing one nitrogen atom as the sole heteroatom, the ring being bonded through the nitrogen atom and in cluding from 8 to 20 ring atoms, the mono cyclic, bicyclic, or tricyclic ring being optionally substituted at one or more of the carbon atoms by C1-C4 alkyl, hydroxyl, ei-(C1-C4 alkyl) amino, EMI3.1 C1-C4 alkoxycarbonyl, phenyl, phenyl substituted by 1, 2, or 3 groups selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, amino, and mono or di-(C1-C-4 alkyl)amino, benzyl, C2-C4 alkenyl, C2 -C4 alkynyl, C1-C4 alkoxy, Cl-C4 alkanoyloxy, halo, halo-(C1-C4 alkyl)-, cyano, ethylenedioxy; R1 is hydrogen or a hydroxyl protecting group; R2 is hydrogen, optionally substituted C1-C5- alkanoyl, optionally substituted phenyl acetyl, optionally substituted phenyl propionyl, or optionally substituted benzoyloxy; R3 is hydrogen, iodo, hydroxy, optionally sub stituted Cl-C5-alkanoyloxy, optionally substituted benzoyloxy, optionally sub stituted phenylacetoxy, optionally sub stituted phenoxyacetoxy; or EMI4.1 (mycarosyloxy) 4. R is EMI4.2 wherein R1 is as defined above, or an acid addition salt thereof, provided that if is hydrogen or iodo then R3 is EMI4.3 When R is an unsaturated ring, representative groups are 1,2,5,6-tetrahydropyridin-1-yl; 1,2,3,4tetrahydroquinolin-l-yl; 1,2,3,4-tetrahydroisoquinolin2-yl; indol-l-yl; isoindol-2-yl; indolin-l-yl; isoindolin-2-yl; 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl; 2,3,4,5-tetrahydro-lH-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-lH-3-benzazepin-3-yl; pyrrol-l-yl; lH-azepin-l-yl; carbazol-9-yl; acridin-l0-yl; and acridin-9-one-l0-yl. When R is a saturated bicyclic or tricyclic ring, representative groups include decahydroquinolin-l-yl; decahydroisoquinolin-2-yl; decahydrocyclohepta [b] -pyrrol- 1-yl; decahydrocyclohepta[c]pyrrol-2-yl; decahydrocyclopent[c] azepin-2-yl; decahydrocyclopent[d] azepin-3-yl; an azabicycloheptanyl group such as 3-azabicyclo [3.2.0] - heptan-3-yl; an azabicyclooctanyl group such as 6 azabicyclo [3.2.1] octan-6-yl; an azabicyclononanyl group such as 3-azabicyclo[3.2.2]nonan-3-yl; an azabicyclodecanyl group such as 4-azabicyclo[5.3.0]decan-4-yl; an azatricyclotetradecanyl group such as 2-azatri cyclo[6.2.2.2316]tetradecan-2-yl; l-azaspiro[4.5]decan-l-yl; and dodecahydrocarbazol-9-yl. When R is a substituted ring representative R groups include 1,3,3-trimethyl-6-azabicyclo[3.2.1]- octan-6-yl; 4-piperidinopieridin-1-yl; 3,3,5-trimethylhexahydroazepin-l-yl; 4-hydroxypiperidin-l-yl; 3-(N,N-diethylcarbamoyl)piperidin-1-yl; and the like. In moietiescontaining a "C1-C4-alkyl group", the alkyl group can be straight, branched, or cyclic. The term "C1-C5-alkanoyl'± as used herein refers to an acyl moiety derived from a carboxylic acid containing from one to five carbon atoms. When optionally substituted, the alkyl group can bear one to three halo substituents. Halo substituents are selected from the group consisting of C1, Br and F. Acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, and isovaleryl are examples of such groups. The term "C1-C5-alkanoyloxy" refers to the corresponding acyloxy moiety. The terms "optionally substituted benzoyl, phenylacetyl or phenylpropionylt' and "optionally substituted benzoyloxy, phenylacetoxy or phenoxyacetoxy" mean that the phenyl portion of the moiety is optionally substituted- by from one to five halo or methyl groups or by from one to two methoxyl, nitro or hydroxyl' groups. The term "hydroxyl-protecting group" refers to a substituent which is not removed under the reaction conditions but which can be readily removed after the reaction has been completed to liberate the original hydroxyl group. Hydroxyl-protecting groups are well known in the art (see, for example, T. W. Greene, "Protective Groups in Organic Synthesis", Wiley-Interscience, 1981, pp. 10-86). One especially suitable hydroxyl-protecting group is the tetrahydropyranyl group. Preparing Macrolides of Formula (I) Macrolides of formula (I) are prepared from corresponding macrolides of formula (II) EMI7.1 where R1, R2, R3, and R4 are as previously defined in formula (I) and R5 is -CHO or -CH2L. L represents a leaving group capable of undergoing displacement by an amine of formula HR where R is as defined in formula (I) Thus, in accordance with one aspect of the invention, macrolides of formula (I) are prepared by reductive amination of aldehydes of formula (II) wherein R5 is -CHO. Aldehyde starting materials include the following known macrolides of formula (II): EMI8.1 <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <tb> tylosin <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> mycinosyloxy <tb> desmycosin <SEP> H <SEP> H <SEP> OH <SEP> mycinosyloxy <tb> 4'-deoxydesmycosin <SEP> H <SEP> H <SEP> H <SEP> mycinosyloxy <tb> macrocin <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> # <tb> lactenocin <SEP> H <SEP> H <SEP> OH <SEP> # <tb> 2'''-O-demethylmacrocin <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> # <tb> (DOMM) <tb> 2'''-O-demethylactenocin <SEP> H <SEP> H <SEP> OH <SEP> # <tb> (DOML) <tb> Tylosin and its preparation by fermentation of Streptomyces fradiae NRRL 2702 or 2703 are described in U.S. Patent No. 3,178,341. Desmycosin and preparation of desmycosin by mild acid hydrolysis of tylosin are also described in U.S. Patent No. 3,178,341. 4'-Deoxydesmycosin and a method of preparing it from desmycosin are described in A. Tanaka et al., J. Antibiotics 34, 1381-84 (1981). Macrocin and its preparation by fermentation of Streptomyces fradiae NRRL 2702 or 2703 are described in U.S. Patent No. 3,326,759. Lactenocin and preparation of lactenocin by mild acid hydrolysis of macrocin are also described in U.S. Patent No. 3,326,759. DOMM and its preparation by fermentation of Streptomyces fradiae ATCC 31669 are described in EPO published specification 45157. DOML and preparation of DOML by mild acid hydrolysis of DOMM are also described in EPO published specification 45157. - Idehyde starting materials of formula (II) which are 2'- or 4'-monoesters, or 2',4'-diesters of the above described known macrolides, i.e., macrolides of formula (II) wherein R is other than hydrogen or R3 is other than hydroxyl, or both, are prepared by known acylation procedures. Typical acylating agents include activated carboxylic acid derivatives such as anhydrides, acid halides (usually in combination with a base or other acid scavenger) and active esters. Suitable organic solvents for this reaction include pyridine and triethylamine. Acylation can also be achieved using a mixture of an organic acid and a dehydrating agent such as N,N'-dicyclohexylcarbodi- imide. Once formed, the acyl derivative can be separated and purified by known techniques. Aldehyde starting materials of Formula (11) which are 2'-monoester derivatives can be prepared by selective esterification of compounds of formula (II) wherein R2 is hydrogen and R3 is hydroxyl using the technique described in U.S. Patents 4,321,361 and 4,-321,362. 2'-Hydroxyl groups are more facile to esterification than 4'-hydroxyl groups. Acco-rdingly, the 2'-monoester derivative can be selectively prepared by, for example, treating the macrolide starting material with a stoichiometric quantity (or a slight excess) of an acylating agent, such as an acyl anhydride, at about room temperature for from about 1 to about 24 hours until esterification is substantially complete. The 2'-monoester can be isolated from the reaction mixture by standard procedures such as extraction, chromotography and crystallization. Aldehyde starting materials which are 2',4'diester derivatives are prepared from macrolides of formula (II) wherein R2 is hydrogen and R3 is hydroxyl using the procedure described in published European Patent specification 82,003. Thus, symmetrical 2',4'-diester derivatives are prepared by treating the known macrolide of formula (II) wherein R2 is hydrogen and R3 is hydroxyl with a stoichiometric quantity (or a slight excess) of an acylating agent, such as an acyl anhydride, in a neutral solvent such as acetone, at about room temperature for from 1 to about 24 hours until esterification of the 2' and 4' hydroxyl groups is complete. Unsymmetrical 2',4'diester derivatives, i.e., compounds of formula (11) wherein OR2 and R3 are different, can be prepared by acylation of appropriate 2'-monoesters. The aldehyde starting materials of formula (II) are converted to the amines of formula (I) by reduction in the presence of an amine of formula HR, where R is as defined in formula (I). The preferred reducing agent is a cyanoborohydride of formula MBH3CN where M is a group 1A metal or ammonium. Sodium cyanoborohydride is the reducing agent of choice. The reaction is preferably conducted using an excess of the amine of formula HR, typically from 2 to 3 equivalents. The solvent for the reaction will normally be an inert polar solvent such as a C1-C4 alkanol, preferably methanol. The reaction temperature may be from 0 to 600C., preferably 20 to 400C. Neutral conditions (pH 6 to 8) are preferred. Dehydrating agents such as 4A molecular sieve or anhydrous sodium or magnesium sulfate can advantageously be used in the reaction. Amines of formula (I) can also be prepared by reacting an amine of the formula HR where R is as defined informula (I) with a macrolide of formula (II) where R5 is -CH2L and L is a leaving group capable of undergoing displacement by the amine. Suitable leaving groups include, for example, trifluoromethanesulfonyl (triflate), and iodo. Starting materials of formula (II) wherein R5 is -CH2L are conveniently prepared from the following known macrolides of formula (II) wherein R5is -CH2OH: EMI12.1 <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <tb> dihydrotylosin <SEP> (relomycin) <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> mycinosyloxy <tb> dihydrodesmycosin <SEP> H <SEP> H <SEP> OH <SEP> mycinosyloxy <tb> dihydromacrocin <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> # <tb> dihydrolactenocin <SEP> H <SEP> H <SEP> OH <SEP> # <tb> dihydro-DOMM <SEP> H <SEP> H <SEP> mycarosyloxy <SEP> # <tb> dihydro-DOML <SEP> H <SEP> H <SEP> OH <SEP> # <tb> These macrolides are prepared by reducing the aldehyde group of tylosin, desmycosin, macrocin, lactenocin, DOMM, and DOML, respectively. The C-20 hydroxyl group of the foregoing macrolides are then converted to the desired leaving group L by methods known per se. For example, the C-20 hydroxyl group can be converted to the triflate group by reacting the macrolide with an activated derivative of trifluoromethane sulfonic acid such as trifluoromethane sulfonic anhydride or trifluoromethane sul fonylchioride in the presence of a base in a nonreactive organic solvent. If desired, the triflate group may be converted to the iodo group, for example by reacting the unisolated sulfonic ester intermediate with a source of iodide ion such as tetra n-butylammonium iodide, or sodium iodide. In case of dihydrodesmycosin, dihydrolactenocin, and dihydro-DOML, the 20-iodo derivative can be formed directly by adding iodine dissolved in a suitable solvent, such as dimethylformamide, to a solution of the 20-dihydro macrolide derivative and triphenylphosphine under nitrogen. The leaving group at C-20 can then be displaced by reaction with the amine HR in a suitable nonreactive organic solvent such as acetonitrile, to yield compounds of formula (I). When a product of formula (I) is one in which R3 is mycarosyloxy, the corresponding macrolide of formula (I) wherein R3 is hydroxyl can be prepared by acid hydrolysis of the initial product. More specif ically, the mycarose sugar can be hydrolytically cleaved at a pH of less than 4, preferably in the range from 0.5 to 2.0, at a temperature in the range of from 0 to 600C, conveniently at about room temperature. The hydrolysis can be effected using a strong aqueous mineral acid such as hydrochloric or sulfuric acid or a strong organic acid such as p-toluenesulfonic acid. As previously mentioned, a method of preparing 4'-deoxydesmycosin is described in J. of Antibiotics 34, 1381-84 (1981). The process involves (1) treatment of desmycosin with acidic ethanol in accordance with a procedure described in Antibiot. & BR< Chemoth. 1', 320-27 (1961), to obtain the corresponding diethylacetal; (2) acylation of the diethylacetal with acetic anhydride in acetonitrile in the absence of external base, in accordance with a procedure described in J. Org. Chem. 44, 2050-52 (1979), to obtain the 2',4t-di-O-acetyl derivative; (3) reacting the 2',4'di-O-acetyl derivative with 2,3-dihydrofuran in dichloromethane in the presence of pyridinium p-toluenesulfonate in the manner described in J. Org. Chem. 42, 3772-74 (1974) to obtain the 3,4''-bis(O-tetrahydro- furanyl)derivative; (4) removal of the 2' and 4'-Oacetyl groups by dissolving the product of step (3) in methanol (500C, overnight); (5) reacting the product of step (4) with 1.5 mole equivalent of benzenesulfonyl chloride in pyridine at -400C for 4 hours, to provide the 4'-O-benzenesulfonyl derivative; (6) immediately reacting the 4'-O-benzenesulfonyl derivative with 1.5 equivalent of sodium iodide in methyl ethyl ketone at 1800C, for 15 minutes to obtain 4' iodo derivative; (7) reductively deiodinating the 4'-iodo derivative using tri(n-butyl)stannane in benzene in the presence of 2,2'-azobis-isobutyronitrile at 80 > C for 2 hours; and (8) deblocking the diethylacetal and tetrahydrofuranyl groups by hydrolysis of the product of step (7) in .1M aqueous hydrochloric acid-acetonitrile (2.5:1 v/v) for 30 minutes at 250C to obtain 4'deoxydesmycosin. The 4'-deoxydesmycosin thus prepared may then be modified at the C-20, and optionally at the 2 position as described above. Alternatively, a C-20 modified derivative of 4'-deoxydesmycosin may be prepared by deoxygenating a C-20 modified derivative of desmycosin, for example by treating the C-20 modified derivative in accordance with steps 2 through 6 or 2 through 8 of the process of J. Antibiotics 34, 1381-84 (1981) as described above. -*She procedures used to prepare 2' and 4' esters of the starting macrolides of formula (II) were described above. Macrolides of formula (I) can be acylated using identical procedures to obtain 2'- and 4'-monoesters and 2',4'-diesters of formula (I). The C-20-modified derivatives of this invention form salts, particularly acid addition salts. These acid addition salts are also useful as antibiotics and are a part of this invention. In another aspect, such salts are useful as intermediates, for example, for separating and purifying the derivatives. In addition, the salts have an improved solubility in water. Representative suitable salts include those salts formed. by standard reactions with both organic and inorganic acids such as, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids. Accordingly, the present invention provides a process for preparing a macrolide of formula (I) or a pharmaceutically-acceptable salt-thereof, which comprises (a) reducing an aldehyde of formula (III) EMI16.1 where R1, R2, R3 and R4 are as defined in formula (I) in the presence of an amine of formula HR where R is as defined in formula (I), or (b) reacting an amine of formula HR, where R is as defined in formula (I) with a macrolide of formula (IV) EMI17.1 wherein L is a leaving group capable of being displaced by the amine HR, in a nonreactive organic solvent, or (c) cleaving the mycarose sugar from a macrolide of formula (I) in which R3 is mycarosyloxy by acid hydrolysis to provide a macrolide of formula (I) wherein R3 is hydroxy, or (d) converting a sulfonic ester of the formula (v) EMI17.2 wherein R and R1 are as defined in formula (I) to the corresponding 4'-iodide by reacting the sulfonic ester with a source of iodide ion in an inert organic solvent, and if R1 is other than hydrogen, optionally hydrolyzing to provide the corresponding macrolide wherein R1 is hydrogen or (e) reductively deiodinating a macrolide of formula (VI) EMI18.1 wherein R is as defined in formula (I) and each R1is a hydroxyl protecting group to produce a macrolide of formula (I) wherein R is H, and optionally removing the hydroxyl protecting groups to provide a macrolide of formula (I) wherein R1 and R3 are hydrogen, and (f) if necessary, esterifying or salifying, or both, a product of reaction (a), (b), (c), (d) or (e). Pharmaceutically acceptable acid addition salts are an especially preferred group of salts of this invention. Illustrative C-20-modified derivatives of this invention include the compounds listed in Tables I - VIII. Table I Illustrative C-20 Modified Derivatives of Tylosina Compound No. R T1 pyrrolidin-l-yl T2 piperidin-l-yl T3 4-hydroxypiperidin-1-yl T4 4-phenylpiperidin-1-yl T5 hexahydroazepin-l-yl T6 octahydroazocin-l-yl T7 octahydro-1H-azonin-l-yl T8 decahydroazecin-l-yl T9- azacycloundecan-l-yl T10 azacyclotridecan-l-yl Tll 1,2,3,4-tetrahydroquinolin-1-yl T12 1,2,3,4-tetrahydroisoquinolin-2-yl T13 3-azabicyclo[3.2.2]nonan-3-yl a EMI19.1 R2 = H; and R3 = mycarosyloxy Table II Illustrative C-20 Modified Derivatives of Desmycosina Compound No. R R3 Dl pyrrolidin-1-yl OH Dla " H D2 piperidin-l-yl OH D2a " H D3 4-hydroxypiperidin-1-yl OH D3a " H D4 4-phenylpiperidin-1-yl OH D4a " H D5 hexahydroazepin-l-yl OH D5a " H D6 octahydroazocin-l-yl OH D6a " H D7 octahydro-lH-azonin-l-y1 OH D7a " H D8 decahydroázecin-l-yl OH D8a n H D9 azacycloundecan-l-yl OH D9a " H D10 azacyclotridecan-l-yI OH DlOa n a EMI20.1 R2 = H; and R3 = OH Table II continued Compound No. R R3 D11 1,2,3,4-tetrahydroquinolin-1-yl OH Dlla " H D12 1,2,3,4-tetrahydroisoquinolin-2-yl OH D12a " H D13 4-piperidinopiperidin-l-yl OH D13a " H D14 3-azabicyclof3.2.2]nonan-3-yl OH D14a " H D15 3-(N,N-diethylcarbamoyl)piperidin l-yl OH D15a " H D16 4-(N,N-dimethylamino)hexahydro azepin-l-yl OH D16a " H D17 2-azabicyclo[2.2.2]octan-2-yl OH D17a " H D18 decahydrocyclopent[d]azepin-3-yl OH D18a " H D19 1-azaspiro[4.5]decan-1-yl OH D19a n H D20 decahydroquinolin-l-yl OH D20a " H D21 1,3,3-trimethyl-6-azabicyclo [3.2.1]octan-6-yl OH D2la " H D22 1,2,3,6-tetrahydropyridin-1-yl OH D22a " H Table II continued Compound No. R R D23 3,3,5-trimethylhexahydro azepin-l-yl (isomer 1) OH D23a n H D24 " (isomer 2) OH D24a n @ H D25 dodecahydrocarbazol-9-yl OH D25a " H D26 4-phenyl-1,2,3,6-tetra hydropyridin-l-yl OH D26a " H D27 4-benzyl-piperidin-1-yl OH D27a n H D28 4- (ethylenedioxy) - piperidin-l-yl OH D28a " H D29 decahydroisoquinolin-2-yl OH D29a " H D30 7-azabicyclo[2.2.1]heptan- OH 7-yl D30a n H D31 Pyrrol-l-yl OH D31a " H D32 Carbazol-9-yl OH D32a " H Table III Illustrative C-20 Modified Derivatives of Macrocin a Compound No. R M1 pyrrolidin-l-yl M2 4-phenylpiperidin-l-yl M3 hexahydroazepin-l-yl M4 octahydroazocin-l-yl M5 octahydro-lH-azonin-l-yl M6 azacyclotridecan-1-yl M7 1,2,3,4-tetrahydroisoquinolin-2-yl M8 3-azabicyclo[3.2.2]nonan-3-yl a EMI23.1 R2 = H; and R3 = mycarosyloxy Table IV Illustrative C-20 Modified Derivatives of Lactenocin a Compound No. R L1 pyrrol idin-l-yl L2 piperidin-l-yl L3 4-phenylpiperidin-1-yl L4 hexahydroazepin-l-yl L5 octahydroazocin-1-yl L6 octahydro-1H-azonin-1-y1 L7 azacyclotridecan-l-yl L8 1,2,3,4-tetrahydroisoquinolin 2-yl L9 3-azabicyclo[3.2.2]nonan-3-yl L10 1,3,3-trimethyl-6-azabicyclo[3.2.1] octan-6-yl a EMI24.1 R2 = H; R3 = OH Table V Illustrative C-20-Modified Derivatives of DOMMa Compound No. R C1 pyrrolidin-l-yl C2 4-phenylpiperidin-l-yl C3 hexahydroazepin-l-yl C4 octahydroazocin-l-yl C5 azacyclotridecan-l-yl a EMI25.1 R2 = B; and R3 = mycarosyloxy Table VI Illustrative C-20-Modified Derivatives of DOMIa Compound No. R N1 pyrrolidin-1-yl N2 4-phenylpiperidin-l-yl N3 hexahydroazepin-1-yl N4 octahydroazocin-1-yl 5 octahydro-lH-azonin-l-yl N6 azacyclotridecan-l-yI N7 1,2,3,4-tetrahydroquinolin-1-yl a EMI26.1 R2 = H; R3 = OH Table VII Illustrative C-20-Modified Ester Derivatives of Tylosina Compound No. R R (2')b E1 hexahydroazepin-1-yl propionyl E2 octahydroazocin-1-yl propionyl E3 piperidin-1-yl acetyl a EMI27.1 R = mycarosyloxy b position number of esterified hydroxyl group in parentheses Table VIII Illustrative C-20-Modified Ester Derivatives of Desmycosina Compound No. R Rê (2')b R (4')b E4 hexahydroazepin-1-yl propionyl H E5 hexahydroazepin-1-yl propionyl propionyl E6 octahydroazocin-1-yl acetyl H E7 octahydroazocin-1-yl acetyl acetyl E8 piperidin-1-yl propionyl H a EMI28.1 b position number of esterified hydroxyl group in partentheses The derivatives of this invention inhibit the growth of pathogenic bacteria, especially grampositive bacteria, Mycoplasma species and gram-negative bacteria such as Pasteurella species. The derivatives are particularly useful against Pasteurella species such as P. multocida and P. hemolytica and against Mycoplasma species such as M. gallisepticum and M. hyopneumoniae (the causative agent of mycoplasmal pneumonia in. swine). The minimal inhibitory concentrations (MIC's) at which illustrative compounds inhibit certain bacteria are given in Tables IX and X. The MTC's in Table IX were determined by standard agar-dilution assays. The MIC's in Table X were obtained using conventional broth-dilution microtiter tests. Table IX Antibiotic Acitivity of C-20 Modified Derivativesa Test Organism Test Compoundb D1 D4 D5 D5a D6 D10 D14 M3 L5 Staphylococcus aureus Xl.1 2 0.5 0.5 0.5 0.5 0.25 0.25 4 1 " " 2 0.5 0.5 0.5 0.5 0.25 0.25 8 1 " " 2 0.5 1 1 0.5 0.25 0.5 32 2 " " 2 0.5 0.25 0.5 0.5 0.25 0.25 8 1 Staphylococcus epidermidis EPIl 2 0.5 0.5 0.5 0.5 0.25 0.5 8 1 " " 1 0.25 0.12 0.25 0.25 0.12 0.12 2 0.5 Streptococcus pyogenes C203 1 0.25 0.5 0.25 0.5 NTh NT 4 0.5 " pneumoniae Park I 0.5 0.25 0.5 0.25 0.5 0.25 0.5 2 0.5 " Group D X66 32 1 8 2 4 4 4 - 16 " " 9960 16 2 8 2 8 4 4 - 16 Haemophilus influenzae C.L.e 16 8 16 8 16 4 4 128 32 " " 76f 16 8 128 8 16 8 8 128 16 Escherichia coli N10 -g 64 128 64 64 32 32 - " " EC14 - 64 4 128 128 64 32 - " " TEM 128 32 8 8 16 8 16 - 16 Table IX continued Antibiotic Activity of C-20 Modified Derivativesa Test Organism Test Compound M4 L4 T6 T13 D2 D3 D7 D11 D12 Staphylococcus aureus Xl.1 4 2 4 4 0.5 8 0.5 0.5 0.5 " " V41c 4 2 4 4 0.5 8 0.5 0.5 0.5 " " X400d 8 2 8 8 1 16 0.5 0.5 0.5 " " S13E 4 2 4 4 0.5 8 0.5 0.5 0.5 Staphylococcus epidermidis EPIl 4 2 4 4 1 8 0.5 0.5 0.5 " " EPI2 2 1 2 2 0.5 4 0.25 0.25 0.25 Streptococcus pyogenes C203 2 1 2 4 0.25 1 0.06 0.5 0.5 " pneumoniae Park I 32 8 8 16 16 8 0.5 " Group D X66 - 32 - 128 16 128 4 " " 9960 - 16 - - 16 32 8 Haemopilus influenzae C.L.e 128 16 64 128 16 64 16 " " 76f 128 16 - 128 16 64 16 Escherichia coli N10 - - - - - - 64 " " EC14 - - - - - - 64 " " TEM - - - - 16 - 16 Table IX continued Antibiotic Activity of C-20 Modified Derivativesa Test Organism Test Compoundb D13 D15 D19 D20 D21 D22 D23 D24 D25 Staphylococcus aureus Xl.1 0.5 2 1 0.5 1 1 0.5 0.5 0.5 " " V41c 1 2 1 0.5 1 0.5 0.5 0.5 0.5 " " X400d 1 4 1 0.5 1 1 1 1 1 " " S13E 1 2 1 0.5 1 0.5 0.5 0.5 0.5 Staphylococcus epidermidis EPIl 1 2 1 0.5 1 0.5 0.5 0.5 0.5 " " EPI2 0.25 1 0.25 0.25 0.5 0.25 0.5 0.25 0.25 Streptococcus pyogenes C203 2 0.5 0.5 0.25 0.5 0.25 0.5 0.25 0.25 " pneumoniae Park I 2 1 0.25 0.12 0.5 1 0.5 1 0.5 " Group D X66 2 32 16 8 4 8 4 4 4 " " 9960 2 32 16 8 8 8 8 8 4 Haemopilus influenzae C.L.e 16 32 16 16 32 16 16 32 16 " " 76f 8 32 16 16 16 8 8 8 8 Escherichia coli N10 - - 128 128 64 - 64 64 128 " " EC14 - - 128 128 64 - 64 64 128 " " TEM - 64 32 32 32 64 32 32 32 Table IX continued Antibiotic Activity of C-20 Modified Derivativesa Test Organism Test Compoundb D26 D27 D28 Staphylococcus aureus Xl.1 0.5 1 2 " " V41c 0.5 1 2 " " X400d 0.5 1 4 " " S13E 0.5 1 2 Staphylococcus epidermidis EPIl 0.5 1 2 " " EPI2 0.25 0.25 1 Streptococcus pyogenes C203 0.25 0.25 0.5 " pneumoniae Park I 0.25 0.5 2 " Group D X66 1 2 8 " " 9960 2 4 8 Haemophilus influenzae C.L.e 32 32 32 " " 76f 8 16 32 Escherichia coli N10 128 128 " " EC14 128 128 " " TEM 32 32 64 Table IX continued Test Organism Test Compoundb D1 D4 D5 D5a D6 D10 D14 M3 L5 Klebsiella X26 16 32 -g 8 16 16 8 - 16 aMIC in mcg/ml eAmpicillin-sensitive strain bCompound numbers from fAmpicillin-resistant Tables I-IV strain cPenicillin-resistant gNot active at 128 mcg/ml, strain the highest level tested dMethicillin-resis- hNot tested tant strain Table IX continued Test Organism Test Compoundb M4 L4 T6 T13 D2 D3 D7 D11 D12 Klebsiella X26 - 16 - - 16 64 - - 32 Table IX continued Test Organism Test Compoundb D13 D15 D19 D20 D21 D22 D23 D24 D25 D26 D27 D28 Klebsiella X26 16 32 32 16 64 64 128 128 128 64 64 64 Table X Antibiotic Activity of C-20 Modified Derivativesa Test Organism Test Compoundb D1 D2 D3 D4 D5 D6 D7 D10 D11 D12 Staphylococcus aureus 0.78 0.78 12.5 0.39 1.56 0.78 1.56 0.39 1.56 1.56 Streptococcus sp. 80 6.25 6.25 12.5 0.09 3.12 0.78 3.12 0.78 3.12 3.12 Pasteurella multocida 17Ec 6.25 25 50 6.25 3.12 3.12 6.25 1.56 12.5 6.25 " " 60Ad 6.25 6.25 50 6.25 3.12 6.25 6.25 3.12 50 12.5 Pasteurella hemolytica 22C 6.25 3.12 50 6.25 1.56 1.56 3.12 1.56 25 3.12 Mycoplasma gallisepticum 12.5 3.12 25 0.39 1.56 1.56 0.39 0.097 < 0.048 < 0.048 " synoviae 0.39 0.78 6.25 < 0.05 0.39 0.78 0.39 < 0.048 0.78 0.39 " hyorhinis 50 > 50 50 50 50 50 25 12.5 6.25 12.5 " hyopneumoniae 12.5 12.5 6.25 0.78 1.56 1.56 1.56 0.78 1.56 3.12 Table X cont'd. Antibiotic Activity of C-20 Modified Deriviativesa Test Organism Test Compoundb D13 D14 D15 D19 D20 D21 D22 D23 D24 D25 L5 Staphylococcus aureus 3.12 0.78 6.25 0.78 0.78 0.78 1.56 3.12 3.12 3.12 1.56 Streptococcus sp. 80 6.25 1.56 12.5 3.12 3.12 1.56 3.12 1.56 3.12 3.12 0.78 Pasteurella multocida 17Ec 12.5 3.12 12.5 3.12 3.12 3.12 12.5 6.25 12.5 12.5 6.25 " " 60Ad 12.5 3.12 12.5 3.12 3.12 3.12 12.5 12.5 6.25 12.5 12.5 Pasteurella hemolytica 22C 12.5 1.56 25 3.12 3.12 3.12 3.12 3.12 6.25 3.12 12.5 Mycoplasma gallisepticum 6.25 1.56 3.12 1.56 0.78 1.56 0.78 0.097 0.39 0.39 6.25 " synoviae 1.56 0.39 1.56 0.39 0.195 0.39 0.78 0.097 0.097 0.097 3.12 " hyorhinis 50 50 > 50 > 50 50 - 25 6.25 25 12.5 50 " hyopneumoniae 3.12 0.78 3.12 3.12 0.78 0.195 1.56 0.78 0.78 0.39 NTe aMIC in mcg/ml dAvian isolate bCompound numbers from eNot tested Tables II and IV cBovine isolate <RTI ID=39.1> Table X cont'd. Antibiotic Activity of C-20 Modified Derivativesa Test Organism Test Compoundb D26 D27 D28 D5a L4 T6 T13 M3 M4 Staphylococcus aureus 3.12 3.12 3.12 0.39 6.25 12.5 6.25 12.5 12.5 Streptococcus sp. 80 0.78 0.78 3.12 0.78 6.25 50 50 50 12.5 Pasteurella multocida 17Ec 6.25 6.25 6.25 6.25 12.5 > 50 > 50 > 50 > 50 " " 60Ad 12.5 12.5 25 3.12 12.5 > 50 > 50 > 50 > 50 Pasteurella hemolytica 22C 12.5 12.5 25 3.12 25 50 50 50 > 50 Mycoplasma gallisepticum #0.048 #0.048 0.097 0.78 12.5 3.12 1.56 6.25 3.12 " synoviae 0.78 #0.048 0.195 0.195 1.56 0.78 1.56 25 6.25 " hyorhinis 25 25 25 3.12 50 > 50 > 50 > 50 > 50 " hyopneumoniae 0.78 0.39 1.56 0.195 1.56 12.5 25 12.5 6.25 aMIC in mcg/ml dAvian isolate bCompound numbers from eNot tested Tables I-IV cBovine isolate The C-20 modified derivatives of this invention have shown in vivo antimicrobial activity against experimentally-induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with S. pyogenes C203, the activity observed was measured as an ED50 value [effective dose in mg/kg to protect 50% of the test animals: see Warren Wick, et al., J. Bacteriol. 81, 233-235 (1961)1. ED50 values observed for illustrative compounds are given in Table XI. Table XI ED50 Values of C-20-Modified Derivatives vs. Streptococcus pyogenes C203 in Micea Test Compoundb Subcutaneous Oral D1 1.2 > 50 D2 0.9 50 D4 6.0 19 D5 1.3 50 D5a 1.5 34 D6 0.7 14 D7 1.6 12 D10 > 10 68 Dll 7.5 19 D12 2.0 < 6.3 D14 1.0 50 D19 2.9 46 D20 1.7 34 D21 1.0 10 D22 0.8 40 L5 1.8 100 M3 > 10 > 100 T6 > 10 44 T13 > 10 30 ang/kg x 2; doses given 1 and 4 hours post infection compound numbers from Tables I-IV. Many of the C-20 modified derivatives of this invention have also shown in vivo antibacterial activity against infections induced by gram-negative bacteria. Tables XII and XIII summarize the results of tests in which illustrative compounds were evaluated against a Pasteurella infection in one-day-old chicks. The compounds were administered parenterally or orally after challenge of the chicks with Pasteurella multo cida (0.1 ml of a 10 z dilution of a twenty-hour tryp- tose broth culture of an avian P. multocida given subcutaneously). In these tests, unless indicated otherwise, all non-medicated infected chicks died within 24 hours of Pasteurella challenge. In the tests summarized in Table XII, the compounds were administered by subcutaneous injection at a dosage of 30 mg/kg, 1 and 4 hours post-challenge of the chicks with P. multocida. In the tests summarized in Table XIII the compounds were administered in medicated drinking water (at a level of 2 g/gal) available from 4 to 20 hours prior to challenge of the chicks with P. multocida and during the 3-day test period. Table XII Activity of C-20-Modified Derivatives Administered Subcutaneously to Pasteurella multocida-Infected Chicks@ Test Compoundb Number of Deaths/Number Treated Dl 0/10 D2 0/10 D4 9/10 D5 0/10 D6 0/10 D7 3/10 D10 10/10 D11 10/10 D12 9/10 D14 2/10 D19 0/10 D21 7/10 D22 0/10 D23 8/10 D24 2/10 D25 0/10 D26 10/10 D27 8/10 D28 0/10 L5 0/10 aAdministered subcutaneously; ; 30 mg/kg x 2 compound numbers from Tables II and IV Table XIII Activity of C-20-Modified Derivatives Administered Orally to Pasteurella multocida-Infected Chicks@ Test Compoundb Number of Deaths/Number Treated D1 9/10 D2 5/10 D4 6/10 D5 2/10 D6 1/10 D7 2/10 D11. 8/10 D12 8/10 D14 0/10 D19 3/10 D20 0/10 D21 3/10 D22 5/10 D23 4/10 D25 7/10 D28 7/10 aAdministered in the available drinking water at a concentration of 2 g/gal bCompound numbers from Table II This invention also relates to methods of controlling infections caused by bacterial and mycoplasmal species. In carrying out the methods of this invention, an effective amount of a compound of formula 1 or 2 is administered parenterally or orally to an infected or susceptible warm-blooded animal. The compounds can also be administered by insufflation, i.e. by blowing the compound, in the form of a medicated dust, into an enclosed space or room wherein the animals or poultry are held. The animals or poultry breathe the medicated dust present in the air; the medicated dust is also taken into the body through the eyes (a process called intraocular injection). The dose which is effective to control the infection will vary with the severity of the infection and the age, weight, and condition of the animal. The total dose required for protection parenterally will generally, however, be in the range of from about 0.1 to about 100 mg/kg and preferably will be in the range of from about 0.5 to about 50 mg/kg. The dose required for oral administration will generally be in the range of from 1 to about 300 mg/kg and preferably will be in the range of from about 1 to about 100 mg/kg. Suitable dosage regimens can be constructed. Often the most practical way to administer the compounds is by formulation into the feed supply or drinking water. A variety of feeds, including the common dry feeds, liquid feeds, and pelleted feeds, may be used. In another aspect, this invention relates to compositions useful for the control of infections caused by bacteria and Mycoplasma species. These compositions comprise a compound of formula 1 or 2 together with a suitable vehicle. Compositions may be formulated for parenteral or oral administration by methods recognized in the pharmaceutical art. The methods of formulating drugs into animal feeds are well-known. A preferred method is to make a concentrated-drug premix which in turn is used to prepare medicated feeds. Typical premixes may contain from about 1 to about 200 grams of drug per pound of premix. Premixes may be either liquid or solid preparations. The final formulation of feeds for animals or poultry will depend upon the amount of drug to be administered. The common methods of formulating, mixing, and pelleting feeds may be used to prepare feeds containing a compound of formula I or 2. Effective injectable compositions containing these compounds may be in either suspension or solution form. In the preparation of suitable formulations it will be recognized that, in general, the water solubility of the acid addition salts is greater than that of the free bases. Similarly, the bases are more soluble in dilute acids or in acidic solutions than in neutral or basic solutions. In the solution form the compound is dissolved in a physiologically acceptable vehicle. Such vehicles comprise a suitable solvent, preservatives such as benzyl alcohol, if needed, and buffers. Useful solvents include, for example, water and aqueous alcohols, glycols, and carbonate esters such as diethyl carbonate. Such aqueous solutions contain, in general, no more than 50% of the organic solvent by volume. Injectable suspension compositions require a liquid suspending medium, with or without adjuvants,- as a vehicle. The suspending medium can be, for example, aqueous polyvinylpyrrolidone, inert oils such as vegetable oils or highly refined mineral oils, or aqueous carboxymethylcellulose. Suitable physiologically acceptable adjuvants are necessary to keep the compound suspended in suspension compositions. The adjuvants may be chosen from among thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin, and the alginates. Many surfactants are also useful as suspending agents. Lecithin, alkylphenol polyethylene oxide adducts, naphthalenesulfonates, alkylbenzenesulfonates, and the polyoxyethylene sorbitan esters are useful suspending agents. - Many substances which affect the hydrophilicity, density, and surface tension of the liquid suspending medium can assist in making injectable suspensions in individual cases. For example, silicone antifoams, sorbitol, and sugars can be useful suspening agents. In order to illustrate more fully the operation of this invention, the following examples are provided. In these examples the abbreviation "20-DH-DO" is used for the term "20-dihydro-20-deoxy". Preparation 1 20-Dihydrotylosin (Relomycin) A solution of tylosin base (30.0 g, 32.8 mmole) in 2-propanol (300 ml) and water (200 ml) was treated with sodium borohydride (315 mg, 8.2 mmole) portionwise, over a five-minute period. Thirty minutes after the addition was completed, the pH of the reaction solution was adjusted to 7.0 by the addition of IN sulfuric acid solution. The neutralized solution was evaporated under vacuum to remove the 2-propanol; the aqueous solution remaining was treated with a saturated sodium bicarbonate solution (500 ml). The mixture was extracted with dichloromethane (3 x 300 ml), and the combined extracts were extracted with saturated sodium chloride solution (200 ml) and dried over sodium sulfate. Filtration followed by evaporation gave a glass which was broken up in n-hexane, collected on a filter and air-dried to yield 28.5 g (95%) of 20dihydrotylosin. Preparation 2 2 0-Dihydrodesmycosin Desmycosin (10 g, 13 mmoles) dissolved in isopropanol:water (1:1, 175 ml), was stirred at room temperature while Na3H4 (125 mg, 3.3 mmoles) was added. After 1/2 hour the pH of the reaction mixture was adjusted to 7.0 with IN H2SO4. The alcohol was removed under reduced pressure. Saturated NaHCO3 solution was added to the aqueous solution, and the product was extracted into CH2Cl2. The organic layer was dried (Na2SO4), and solvent was removed under reduced pressure to give 9.65 g of 20-dihydrodesmycosin (12.5 mmoles, 96% yield) as a white foam. Preparation 3 20-DH-DO-2Q-Iododesmycosin (Method 1) 20-Dihydrodesmycosin (2.0 g, 2.6 mmoles) and tetra n-butylammonium iodide (1.5 g, 3.9 mmoles) were dissolved in CH2C12 (30 ml) with s-collidine (0.6 ml, 4.5 mmoles) added. This solution was cooled to -780C under a nitrogen atmosphere and treated with trifluoromethanesulfonic anhydride (0.6 ml, 3.9 mmoles) dropwise by syringe. The reaction was stirred for 5 minutes at -780C and then allowed to come to room temperature (about 30 minutes). Saturated NaHCO3 solution was added, and the product was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give a red oil which was purified by silica-gel flash chromatography, eluting initially with CH2C12 (400 ml) and then stepwise with CH2Cl2:CH3OH solutions as follows: 98:2 (250 ml); 96:4 (500 ml) 95:5 (250 ml); 94:6 (750 ml) and 92:8 (250 ml). Fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 20-DH-DO-20-iododesmycosin (595 mg, 0.67 moles, 26% yield) as a white foam. Preparation 4 20-DH-DO-20-Iododesmycosin (Method 2) 20-Dihydrodesmycosin (5.0 g, 6.5 mmoles) and triphenylphosphine (2.54 g, 9.70 mmoles) were dissolved in dimethylformamide (DMF) (10 ml). This mixture was stirred at room temperature under N2 while iodine (2.46 g, 9.70 mmoles) in DMF (5 ml) was added dropwise. The reaction mixture was stirred¯for two hours and then poured into cold saturated NaECO3 solution. The product was extracted with CHCl3 (two portions), and the combined CHCl3 extracts were shaken with 0.1M sodium thiosulfate to remove unreacted iodine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure to give a light yellow oil which was purified by silica-gel flash chromatography. The column was eluted initially with CH2Cl2 (500 ml) and then with 250 ml portions of CH2Cl2:CH3OH mixtures as follows: 98:2; 96:4; 95:5; 94:6; 92:8; 88:12; and 86:14. Fractions containing the desired product were identified as in Preparation 3 and combined to give 1.78 g (2.0 mmoles, 31% yield) of 20-DH-DO-20-iododesmycosin as a white foam. Example 1 20-DH-DO-20-(Octahydroazocin-1-yl)desmycosin 20-DX-DO-20-Iododesmycosin (575 mg, 0.65 mmoles) was dissolved in acetonitrile (10 ml), and heptamethyleneimine (0.37 g, 0.41 ml, 3.3 mmoles) was added to this solution. The reaction was stirred at reflux for 1.5 hours. Volatiles were then removed under vacuum. The residue was dissolved in CH2C12 and extracted with saturated NaHCO3 solution. The organic layer was dried (Na2SO4) and then evaporated under reduced pressure to give a light brown foam. This foam was purified by silica-gel flash chromatography, eluting with 250 ml each of the following CH2Cl2:CH3OH mixtures: 98:2; 96:4; 94:6; 9:1; 88:12; 82:18; 65:35; 1:1; 1:3 and finally with 300 ml of CH30H. Fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 397 mg (0.46 mmoles, 71% yield) of 20-DH-DO-20-(octahydroazocin-l-yl)desmycosin as a white foam. Example 2 20-DH-DO-20- (Hexahydroazepin-l-yl) desmycosin Desmycosin (10 g, 13 mmoles), dissolved in anhydrous methanol (100 ml), was added rapidly to a solution of NaBH3CN (3.3 g, 52 mmoles) and hexamethyleneimine (6.5 g, 7.5 ml, 65 mmoles) in anhydrous methanol (50 ml) under N2. The reaction mixture was stirred under N2 at room temperature for about three hours and then was evaporated under reduced pressure. -The resultant residue was dissolved in CR2Cl2 with just enough ethyl acetate to aid in dissolving the residue, and this solution was extracted with saturated NaHCO3 solution. The organic layer was separated, dried (Na2SO4), and evaporated under reduced pressure to give a light yellow foam. This foam was purified by silicagel flash chromatography, eluting initially with CH2C12 (1 L), then stepwise with 500-ml portions of CH2C12:- CH3OH mixtures as follows: 98:2; 96:4; 94:6; 92:8 and 9:1, and finally with CH2C12:CH3OH:NH4OH mixtures as follows: 90:10:0.5 (500 ml) and 75:25:0.5 (2 L). Fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 6.035 g (7.07 mmoles) of 20-DH-DO-20-(hexahydroazepinl-yl)desmycosin as a white foam. Other fractions which contained impure product were combined, redissolved in CH2C12, extracted again with saturated NaHCO3 solution, and purified as before, using a silica-gel column packed with CH2C12:CH3OH (9:1) and eluted with CH2C12: cH3OH:NH4OH as follows: 90:10:0.5 (500 ml) and 80:20:0.5 (1 L) to give an additional 1.372 g (I. 61 mmoles) of product. The total yield of 20-DH-DO-20 (hexahydroazepin-l-yl) desmycosin was 7.407 g (8.68 mmoles, 67z). Example 3 20-DH-DO-20-(4-Phenylpiperidin-1-yl) desmycosin Desmycosin (1.5 g, 2 mmole) was dissolved in absolute methanol (60 ml) and treated with 4-phenylpiperidine (640 mg, 4 mmoles) in the presence of Linde 4A molecular sieves. After 0.5 hr, NaBH3CN (500 mg, 8 mmoles) was added, and the mixture was stirred for 2.5 hr, at room temperature. The mixture was poured into saturated NaHCO3 solution (200 ml) and extracted with CE2C12 (3 x 200 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. The residue (3.6 g) was purified by flash chromatography on silica gel, eluting with a gradient of 1 L. CH2Cl2 to 1 L. of MeOE:CH2C12 (5:95) and then with 1 L. of MeOH:CH2C12 (5:95). Frac tions containing the desired product were located by TLC, combined and evaporated to dryness to yield 680 mg of 20-DH-DO-20-(4-phenylpiperidin-1-yl)desmycosin. Example 4 20-DH-DO-20- (Hexahydroezepin-1-yl) -4' -deoxydesmycosin A solution of 4'-deoxyesmycosin (565 mg, 0.75 mmole) in methanol (15 ml) under argon was stirred with activated Linde 3A molecular sieves (2.2 g) for thirty minutes before hexamethyleneimine (0.25 ml, 2.25 mmole) was added. One hour later, sodium cyanoborohydride (141 mg, 2.25 mmole). was added to the reaction. After an additional 45 minutes, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were shaken with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to yield 600 mg of crude product. This product was purified by preparative TLC on silica gel, eluting with dichloromethane/methanol/conc. ammonium hydroxide (90:15:2) to give 150 mg (24% yield) of 20-DE-DO-20-(hexahydroezepin-1-yl)-4'-deoxydesmycosin. Examples 5-6 20-DH-DO-20- (Octahydroazocin-l-yl) desmycosin, prepared by the method of Example 2. 20-DH-DO-20-(Hexahydroa2epin-l-yl)desmycosin, prepared by the method of Example 1. Example 7 20-DH-DO-20- (O¯ctahydroazocin-l-yl )desmycosin (Method 3) Desmycosin (4.0 g, 5.2 mmoles) was dissolved in absolute methanol (30 ml) and treated with heptamethyleneimine (1.2 g, 1.3 ml, 10.4 mmoles) in the presence of 3A molecular sieves. After the reaction mixture had been stirred for 1 hr at room temperature, a solution of NaBH4 (60 mg, 1.6 mmoles) in absolute methanol (10 ml) was quickly added by pipette. The reaction mixture was stirred for 1.5 hr at room temperature, and then another 30 mg of NaBH4 was added (one portion as the solid). The reaction mixture was stirred for another 75 min and then was filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml), and this solution was extracted with water (150 ml) and saturated NaHCO3 solution (100 ml). The ethyl acetate solution was then extracted with pH 6.5, 0.5M NaH2PO4 buffer (150 ml). The buffer extract was evaporated under vacuum to remove residual ethyl acetate and then was rapidly stirred while 5N NaOH was slowly added, yielding a thick white precipitate. The white solid was removed by- filtration, washed with a- small amount of water, and dried to give 3.55 g of 20-DH-DO-20 (octahydroazocin-l-yl) desmycosin. Example 8 20-DH-DO-20-(1-Azaspiro[4.5]decan-1-yl]desmycosin Desmycosin (5.0 g, 6.5 mmoles) was dissolved in absolute methanol (50 ml) and treated with 1 azaspirp[4.S3decane (1.36 g, 9.8 mmoles) in the presence of 3A molecular sieves. After 15 minutes, NaBH3CN (620 mg, 9.8 mmoles) was added, and the mixture was stirred for 17 hrs at room temperature. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and extracted with water (300 ml and 100 ml). The product was then extracted from the ethyl acetate solution with pH 6.5, 0.5M NaH2PO4 buffer (300 ml and 100 ml). The phosphate buffer extracts were combined and evaporated under vacuum to remove residual ethyl acetate. The phosphate buffer solution was then rapidly stirred while 5N NaOH was slowly added, yielding a thick white precipitate. The white solid was removed by filtration, washed with water, and dried to give 20-DH-DO-20-E1-azaspirof4.5]- decan-l.-yl] desmycosin (3.52 g). Example 9 20-DE-DO-20-(1,2,3,4-Tetrahydroquinolin-l-yl)desmycOsin Desmycosin (11.6 g, 15 mmol) was dissolved in dry methanol (100 ml), and 1,2,3,4-tetrahydroquinoline (3.8 ml, 30 mmol) was added. After the mixture was stirred for 30 mintues at room temperature, sodium cyanoborohydride (1.25 g, 20 mmol) was added. The mixture was stirred overnight and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water (100 ml each). The organic layer was then extracted sequentially with pH 6.5 aqueous phosphate buffer (100 ml) and pH 4.5 aqueous phosphate buffer (100 ml). The ethyl acetate layer was dried (sodium sulfate), filtered and evaporated, and the residue (4.6 g) was separated by chromatography on silica gel (Waters Prep 500). The column was eluted with a linear gradient of dichloromethane (4 L) and 5% methanol plus 0.5 conc. ammonium hydroxide in dichloromethane (4 L). Fractions containing the desired product were identified by TLC analysis, collected and evaporated to dryness to yield 3.4 g of the title compound. Example 10 20-DE-DO-20-(1,2,S,4-Tetrakydroisoquinolin-2-yl)desmycosin Desmycosin (11.6 g, 15 mmol) was dissolved in dry methanol (1 ml), and l,2,3,4-tetrahydroisoquinoline (3.8 ml, 30 mmol) was added. After the mixture was stirred for 30 minutes at room temperature, sodium cyanoborohydride (1.25 g, 20 mmol) was added. The mixture was stirred overnight and then was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water (150 ml each). The organic layer was then extracted sequentially with pH 6.5 phosphate buffer (100 ml) and pH 4.5 phosphate buffer (100 ml). After evaporation of the pH 4.5 buffer extract under reduced pressure to remove ethyl acetate, the pH was adjusted to 10 with 5N sodium hydroxide. The precipitate which formed was collected and air--dried to yield 5.6 g of the title compound. Example 11 20-DH-DO-20- (1,2,3, 6-Tetrahydropyridin-l-yl) desmycosin Desmycosin (11.6 g, 15 mmol) was dissolved in dry methanol (100 ml), and l,2,3,6-tetrahydropyridine (2.8 ml, 30 mmol) was added. After the mixture was stirred for 30 minutes at room temperature, sodium cyanoborohydride (1.25 g, 20 mmol) was added. The mixture was stirred overnight and then was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml). This solution was extracted with water (150 ml) and then with pH 6.5 aqueous phosphate buffer solution (2 x 100 ml). The buffer solutions were separately evaporated under reduced pressure to remove ethyl acetate and then adjusted to pH 10 with 5N sodium hydroxide. The precipitates which formed were collected by filtration and air-dried to yield 5.4 g (first extract) and 3.2 g (second extract) of the title compound. Examples 12-31 The following compounds were prepared by the methods of Examples 1, 2, 7 or 8: 20-DH-DO-20- (octahydroazocin-l-yl) lactenocin 20-DH-DO-20- (pyrrolidin-l-yl) desmycosin 20-DH-DO-20- (azacyclotridecan-l-yl) desmycosin 20-DH-DO-20- (4-hydroxypiperidin-.l-yl) desmy- cosin 20-DH-DO-20-(hexahydroazepin-1-yl)macrocin 20-DH-DO-20-[3-azabicyclo[3.2.2]nonan-3-yl]desmycosin 20-DH-DO-20-(piperidin-1-yl)desmycosin 20-DH-DO-20-[3-(N,N-diethylcarbamoyl)piperidin-1-yl]desmycosin 20-DH-DO-20-[(4-piperidino)piperidin-1-yl]desmycosin 20-DH-DO-20-(octahydro-1H-azonin-1-yl)desmycosin 20-DH-DO-20-(decahydroquinolin-1-yl)desmycosin 20-DH-DO-20-[1,3,3-trimethyl-6-azabicyclo [3.2.1]octan-6-yl]desmycosin 20-DH-DO-20-(dodecahydrocarbazol-9-yl)desmycosin 20-DH-DO-20-(octahydroazocin-1-yl)tylosin 20-DH-DO-20-(3-azabicyclo[3.2.2]nonan-3-yl)tylosin 20-DH-DO-20-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)desmycosin 20-DH-DO-20-(4-benzyl-piperidine-1-yl)desmycosin 20-DH-DO-20-[4-(ethylenedioxy)-piperidin-1yl]desmycosin 20-DH-DO-20-(octahydroazocin-1-yl)macrocin 20-DH-DO-20-(hexahydroazepin-1-yl)lactenocin Examples 32-35 20-DE-DO-20-(3,3,5-Trimethylhexahydroazepin- l-yl)desmycosin was prepared by the method of Example 8 and then separated into individual isomers 1 and 2 silica-gel by flash chromatography. 20-DE-DO-20-(Dodecahydrocarbazol-9-yl)desmycosin (compound D25) was a mixture of two isomers. The mixture was separated into two fractions, each of which was rich in one of the isomers, by silica-gel flash chromatography. Each of the isomer-enriched fractions had an activity pattern similar to that of the mixture. Examples 36-37 20-DE-DO-20-(Octahydroazocin-l-yl)desmycosin dihydrochloride and tartrate salts were prepared from 20-DH-DO-20- (octahydroazocin-l-yl) desmycosin, using standard procedures. Tables XIV-XVI summarize certain physical data on exemplified compounds: Table XIV: Physical Characteristics of C-20-Modified Derivatives of Desmycosin FDMS Compounda Parent Ion UV Titratable TLCd 20-Substituent No. (m+ +1) #max (#)b groups Rf Pyrrolidin-1-yl D1 827 7.9, 9.5 0.30 4-phenylpiperidin-1-yl D4 917 283 (21,800) hexahydroazepin-1-yl D5 855 282 (21,500) 7.9 9.6 " D5a 839 282 (21,500) octahydroazocin-1-yl D6 869 282 (21,750) 7.9, 9.4 azocyclotridecan-1-yl D10 939 282 (19,500) 8.0, 9.5 4-piperidinopiperidin-1-yl D13 924 282 (18,600) 6.0, 9.2 3-azabicyclo[3.2.2]nonan-3-yl D14 881 282 (20,500) 7.9, 9.2 piperidin-1-yl D2 841 282 (24,500) 7.8, 9.1 4-hydroxypiperidin-1-yl D3 857 282 (20,750) 7.1, 8.7 octahydro-1H-azonin-1-yl D7 883 282 (20,000) 7.9, 9.0 1,2,3,4-tetrahydroquinolin1-yl D11 888 271 (26,700) 1,2,3,4-tetrahydroisoquinolin- 281 sh (24,500) 2-yl D12 888 283 (20,600) 3-(n,N-diethylcarbamoyl)piperidin-1-yl D15 940 282 (20,500) 7.4, 8.6 1-azaspiro[4,5]decan-1-yl D19 894 282 (21,500) 7.9, 9.8 Table XIV: Physical Characteristics of C-20-Modified Derivatives of Desmycosin cont'd. FDMS Compounda Parent Ion UV Titratable TLCd 20-Substituent No. (m++1) #max (#)b groupsc Rf decahydroquinolin-1-yl D20 895 282 (21,500) 7.9, 9.4 1,3,3-trimethyl-6-azabicyclo [3.2.1]octan-1-yl D21 908 282 (21,000) 8.0, 9.7 1,2,3,6-tetrahydropyridin-1-yl D22 839 282 (21,000) 3,3,5-trimethylhexahydroazepin-1-yl, isomer 1 D23 896 282 (21,130) 7.7, 9.0 3,3,5-trimethylhexahydroazepin-1-yl, isomer 2 D24 897 283 (21.390) 7.9, 9.4 dodecahydrocarbazol-9-yl D25 935 282 (22,500) 7.95, 9.95 octahydroazocin-1-yl D6e 7.9, 9.4 " " D6f 869,151 282 (19,500) 5.4, 7.3, 9.2 aCompound numbers from Table II dSilica-gel 60 plates; CH2Cl2/MeOH/NH4OH (90:10:0.5) solvent bRun in methanol or ethanol edihydrochloride salt cRun in 66% aqueous DMF ftartrate salt Table XV: physical Characteristics of C-20-Modified Derivatives of Macrocin FDMS Compounda Parent Ion UV Titratable TLCd 20-Substituent No. (m++1) #max (#)b groupsc Rf hexahydroazepin-1-yl M3 985 6.91, 9.40 0.26 octahydroazocin-1-yl M4 999 282 (24,000) 6.90, 9.25 aCompound numbers from Tabel III bRun in methanol cRun in 66% aqueous DMF dsilica-gel 60 plates: CH2Cl2/MeOH/NH4OH (90:10:0.5) solvent Table XVI: Physical Characteristics of C-20-Modified Derivatives of Lactenocin FDMS Compounda Parent Ion UV Titratable 20-Substituent No. (m++1) #max (#) groupsc hexahydroazepin-1-yl L4 841 282 (21,500)b 8.0, 9.70 octahydroazocin-1-yl L5 855 282 (21,500)c 7.8, 9.3 aCompound numbers from Table IV bRun in ethanol cRun in methanol dRun in 66% aqueous DMF Table XVI: Physical Characteristics of C-20-Modified Derivatives of Tylosin FDMS Compounda Parent Ion UV 20-Substituent No. (m++1) #max (#) octahydroazocin-1-yl T6 1013 282 (22,000) 3-azabicyclo[3.2.2]nonan-3-yl T13 1025 282 (21,500) Examples 38-61 The following compounds can be prepared by the methods of the preceeding examples. 20-DH-DO-20-(octahydroazocin-1-yl)tylosin 20-DH-DO-20-(piperidin-1-yl)lactenocin 20-DH-DO-20-(4-hydroxypiperidin-1-yl)DOML 20-DH-DO-20-(decahydroazecin-1-yl)desmycosin 20-DH-DO-20- (octahydroazocin-l-yl) macrocin 20-DH-DO-20- (azacyclotridecan-l-yl)lactenocin 20-DH-DO-20-(hexahydroazepin-1-yl) lactenocin 20-DH-DO-20-(1,2,3,4-tetrahydroisoquinolin-2yl)macrocin 20-DH-DO-20-(1,2,3,4-tetrahydroquinolin-1-yl)macrocin 20-DH-DO-20-(azacycloundecan-1-yl) desmycosin 20-DH-DO-20-(4-methylpiperidin-1-yl) desmycosin 20-DH-DO-20- (pyrrolidin-l-yl) lactenocin 20-DH-DO-20-(octahydro-1H-azonin-1-yl) tylosin 20-DH-DO-20-(octahydroazocin-1-yl) DOMM 20-DH-DO-20-(octahydroazocin-1-yl) DOML 20-DH-DO-20-(4-phenyl-piperidin-1-yl) lactenocin 20-DH-DO-20-(4-phenylpiperidin-1-yl)-4'deoxydesmycosin 20-DH-DO-20-(octahydroazocin-1-yl)-4'deoxydesmycosin 20-DH-DO-90-(3-azabicyclo[3.2.2]nonan-3- yl)-4s-deoxydesmycosin 20-DH-DO-20- (1,2,3, 4-tetrahydroisoquinolin- 2-yl)lactenocin 20-DH-DO-20- (3,3, 5-trimethylhexahydroazepin- l-yl) macrocin 20-DH-DO-20-(decahydrocyclopent[c]azepin-1yl) desmycosin 20-DK-DO-20-(7-azabicyclot2.2.1]heptan-7-yl)- desmyco sin 20-DH-DO-20-(decahydroisoquinoli-2-yl)- desmyco sin Example 62 Injectable Formulations A) A formula 1 base is added to propylene glycol. water and benzyl alcohol are added so that the solution contains 50% (by volume) propylene glycol, 4% (by volume) benzyl alcohol, and 200 mg/ml of a formula I base. B) A solution is prepared as described in Section A except that the solution contains 50 mg/ml of a formula 1 base. C) A solution is prepared as described in Section A except that the solution contains 350 mg/ml of a formula 1 base. D) A solution is prepared as described in Section A except that the solution contains 500 mg/ml of a formula 1 tartrate. E) A suspension is prepared by adding a finely ground formula 1 compound to carboxymethyl cellulose with thorough mixing so that the suspension contains 200 mg of the formula 1 base per ml of suspension. Example 63 Chick Ration for Control of Mycoplasma A balanced, high-energy ration adapted to feed chicks for rapid weight gain is prepared by the following recipe: Ingredient % lbs Ground yellow corn SO 1,000 Soybean meal, solvent extracted dehulled, finely ground, 50 percent protein 31.09 621.8 Animal fat (beef tallow) 6.5 130 Dried fish meal, with solubles (60% protein) 5.0 100 Distillers' solubles from corn 4.0 80 Dicalcium phosphate, feed. grade 1.8 36 Calcium carbonate 0.8 16 Vitamin premix (representing vitamins A, D, E, K, and B12, choline, niacin, pantothenic acid, riboflavin, biotin, with glucose bulking agent) 0.5 10 Trace mineral premix (representing MnSO4, ZnO, KI, FeSO4, CaCO3) 0.2 4 2-Amino-4-hydroxybutyric acid (hydroxy analog of methionine) 0.1 2 Formula 1 or 2 compound 0.01 0.2 These substances are mixed in accordance with standard feed-mixing techniques. Chicks fed such a ration, with water ad libitum, are protected against exposure to Mycoplasma infections.

Claims: CLAIMS 1. A macrolide of the formula (I): EMI69.1 wherein R is a monocyclic saturated or unsaturated ring containing one nitrogen atom as a sole heteroatom, the ring being bonded through the nitrogen atom and including from 5 to 16 ring atoms, or a bicyclic or tricyclic saturated or unsaturated ring containing one nitrogen atom as the sole heteroatom, the ring being bonded through the nitrogen atom and including from 8 to 20 ring atoms, the monocyclic, bicyclic, or tricyclic ring being optionally substituted at one or more of the carbon atoms by C1-C4 alkyl, hydroxyl, di-(C1-C4 alkyl) amino, EMI70.1 C1-C4 alkoxycarbonyl, phenyl, phenyl substituted by 1, 2, or 3 groups selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, amino, and mono or di-(Cl-C4 alkyl)amino, benzyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, halo, halo-(C1-C4 alkyl)-, cyano, ethylenedioxy; R1 is hydrogen or a hydroxyl protecting group; R2 is hydrogen, optionally substituted C1-C5 - alkanoyl, optionally substituted phenyl acetyl, optionally substituted phenyl propionyl, or optionally substituted benzoyl oxy; ; R3 is hydrogen, iodo, hydroxy, optionally sub stituted C1-C 5-alkanoyloxy, optionally substituted benzoyloxy, optionally sub stituted phenylacetoxy, optionally substituted phenoxyacetoxy, or EMI71.1 (mycarosyloxy) 4 R is EMI71.2 wherein R1 is as defined above, and the acid addition salts thereof, provided that if R2is hydrogen or iodo then R3 is EMI71.3 2. A macrolide of formula (I) in accordance with claim 1 wherein R is (i) a saturated monocyclic ring of the formula EMI71.4 where n is an integer from 4 through 15, which ring is optionally substituted at one or more of the carbon atoms by C1-C3 alkyl, hydroxy, -N(R )2' where R6 is methyl, ethyl, n-propyl, isopropyl or the R6 groups taken together with the nitrogen atom form pyrrolidinyl, piperidinyl, hexahydroazepinyl, or octahydroazocinyl, EMI72.1 where R6 is as defined above, carbomethoxy, carboethoxy, or phenyl, or (ii) a bicyclic or tricyclic secondary amino group selected from 1,2,3,4-tetrahydroquinolin-1-yl, decahydroquinolin-l-yl, 1,2,3, 4-tetrahydroisoquinolin-2-yl, decahydroisoquinolin-2-yl, indolin-l-yl, -. isoindolin-2-yl, decahydrocyclohepta[b] pyrrol-1-yl, decahydrocyclohepta[c] pyrrol-2-yl, decahydrocyclopent[c] azepin-2-yl, decahydrocyclopent[d] azepin-3-yl, 2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl, 2,3,4,5-tetrahydro-lH-3-benzazepin-3-yl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl, azabicyclodecanyl, or azatricyclodecanyl. 3. A macrolide of formula (I) or a pharmaceutically-acceptable salt thereof as claimed in claim 1, wherein R represents a group selected from octahydroazocin-l-yl, hexahydroazepin-l-yl, 4-phenylpiperidin-l-yl, pyrrolidin-l-yl, azocyclotridecan-l-yl, 4-hydroxypiperidin-l-yl, 3-azabicyclo[3.2.2]nonan-3-yl, piperidin-l-yl, 3-(N,N-diethylcarbamoyl)piperidin-lyl, (4-piperidino)piperidin-l-yl, octahydro-lHazocin-l-yl, decahydroquinolin-l-yl, 1,2,3,4-tetrahydroquinolin-l-yl, 1,2,3,4-tetrahydroisoquinolin-2- yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl, l-azaspiro[4.5]decan-l-yl, 1,2,3,6-tetrahydro-pyridinl-yl, dodecahydrocarbazol-9-yl, 3,3 ,5-trimethylhexa- hydroazepin-1-yl, decahydroazecin-l-yl, azacyclo tridecan-.l-yl, azacycloundecan-l-yl, 4-methylpiperidinl-yl, 4-phenyl-piperidin-l-yl, decahydrocyclopent [c]azepin-l-yl, 7-azabicyclo[2.2.l]heptan-l-yl. 4. A macrolide of formula (I), or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 3, in which R4 is mycinosyloxy and R3 is hydroxyl. 5. A macrolide of formula (I) as claimed in any one of claims 1-4 wherein R is a saturated monocyclic ring. 6. 20-DH-20-DO-[3-azabicyclo[3.2.2]nonan-3yl]-desmycosin. 7. A process for preparing a macrolide of formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-6, which comprises (a) reducing an aldehyde of formula (III) EMI74.1 where R1, R2, R3 and R4 are as defined in formula (I) in the presence of an amine of formula HR where R is as defined in formula (I), or (b) reacting an amine of formula HR, where R is as defined in formula (I) with a macrolide of formula (IV) EMI75.1 wherein L is a leaving group capable of. being displaced by the amine HR, in a nonreactive organic solvent, or (c) cleaving the mycarose sugar from a macrolide of formula (I) in which R3 is mycarosyloxy by acid hydrolysis to provide a macrolide of formula (I) wherein R3 is hydroxy, or (d) converting a sulfonic ester of the formula (V) EMI75.2 wherein R and R1 are as defined in formula (I) to the corresponding 4'-iodide by reacting the sulfonic ester with a source of iodide ion in an inert organic solvent, and if R1 is other than hydrogen, optionally hydrolyzing to provide the corresponding macrolide wherein RÚ is hydrogen or (e) reductively deiodinating a macrolide of formula (VI) EMI76.1 wherein R is as defined in formula (I) and each R1 is a hydroxyl protecting group to produce a macrolide of formula (I) wherein R3 is H, and optionally removing the hydroxyl protecting groups to provide a macrolide of formula (I) wherein R1 and R3 are hydrogen, and (f) if necessary, esterifying or salifying, or both, a product of reaction (a), (b), (c), (d), or (e). 8. A macrolide of formula (I) or a pharmaceutically-acceptable salt thereof as claimed in any one of claims I to 6 for use as an antibiotic in the chemotherapy of warm blooded animals. 9. A feed premix comprising as an active ingredient a macrolide of formula (I), or a pharmaceutically-acceptable salt thereof as claimed in any one of claims 1-6. 10. A veterinary formulation which comprises as an active ingredient a macrolide of formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-6, associated with one or more physiologically-acceptable carriers or vehicles therefor.

Inventors: DEBONO, MANUEL, KIRST, HERBERT ANDREW
Applicants: ELI LILLY AND COMPANY
Application year: 1983
Main classification: C07H17
IPC codes: C07H17, C07D313, C07D315, A61K31, A61P31, C07D309, A23K1, C07H15