C-20- AND C-23-MODIFIED MACROLIDE DERIVATIVES

Abstract: Tylosin-like macrolides modified at C-20 and C-23.

Description: C-20- and C-23-MODIFIED MACROLIDE DERIVATIVES This invention related to macrolide antibiotics, and more specifically to a novel group of C-20 and C-23 modified derivatives of tylosin and tylosin-like macrolides. 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 efficacy, 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 improved properties. A large number of derivatives have been made, but improvement in activity has not previously been obtained to the desired degree. More specifically this invention relates to C-20- and C-23-modified macrolide derivatives having formula (I); EMI2.1 where in R is hydrogen, iodo, bromo, chloro, fluoro, cyano, -OR4, -OAr, -SR5, azido, -NR6R7, N-phthalimido or R9 ; R1 is i) hydrogen or -OH; ii) chloro, fluoro, bromo, iodo -OAr, -O-tetra hydrofuranyl, -o-tetrahydrpyranyl, -SR5, azido, -NR6R71 or N-phthalimido; or R9; R9 is i) a monocyclic amino-group of the formula -N(CH2)n which is optionally substituted at one or more of the carbon atoms by a C1-C3-alkyl, hydroxyl, methoxyl, ethoxyl, -N(R8)2 EMI2.2 carbomethoxy, carboethoxy, or phenyl group; and n is an integer from 4 through 15; ii) a monocylic saturated or unsaturated nitrogen-containing heterocyclic ring bonded through the nitrogen atom, said ring having 1) from 5 to 7 ring atoms which include up to 3 additional hetero atoms selected from nitrogen, oxygen and sulfur, and 2) up to 3 substituent groups selected from methyl, ethyl and phenyl; or iii) a bicyclic or tricyclic secondary amino group selected from 1,2,3,4-tetrahydro quinolin-l-yl; decahydroquinolin-l-yl ; 1,2,3,4-tetrahydroisoquinolin-2-yl; decahydroisoquinolin-2-yl; indolin-l-yl; isoindolin-2-yl; decahydrocyclohepta [b]pyrrol-l-yl; decahydrocyclohepta tc]pyrrol-2-yl; decahydrocyclo pent[c]azepin-2-yl; decahydrocyclo pentEd]azepin-3-yl; 2,3,4,5-tetrahydro lH-2-benzazepin-2-yl; 2,3,4,5-tetrahydro lH-3-benzazepin-3-yl; azabicycloheptanyl; azabicyclooctanyl; azabicyclononanyl; azabicyclodecanyl or azatricyclodecanyl; R2 is hydrogen, optionally substituted Cl-C5 - alkanoyl or optionally substituted benzoyl, phenylacetyl or phenylpropionyl; R3 is hydrogen, hydroxyl, optionally substituted Cl-C5-alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or EMI4.1 (mycarosyloxy) R4 is hydrogen, optionally substituted C1-C4-alkyl, cyclohexyl, optionally substituted berizyl, phenethyl or phenoxyethyl; Ar is i) phenyl, derivatized phenyl, or naphthyl; ; ii) an optionally substituted heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoguinolinyl, quinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxazolyl, benzimidazolyl, carbazolyl, or acridinyl; or iii) optionally substituted C1-C5-alkanoyl; optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxy acetyl or phenylthioacetyl; methane sulfonyl; trifluoromethanesulfonyl; or optionally substituted phenylsulfonyl; R5 is optionally substituted Cl-C4-alkyl; cyclo hexyl; optionally substituted phenyl, benzyl or phenethyl; or an optionally substituted heteroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl1 triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl and furanyl; R6 is hydrogen, optionally substituted C1-C6 - alkyl, phenyl, benzyl, phenethyl or C3-C8-cycloalkyl; R7 is an R6 group or optionally substituted C1-C5 - alkanoyl, optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl, or alkoxycarbonyl; and R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl or the R8 groups taken together form a poly methylene moiety such that -N(R8)2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl; provided 1) that, when R or R4 is hydrogen, RÚ cannot be hydrogen or -OH ; 2) that, when R or RÚ is -NHR6 or R4 or R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen, hydroxyl, or mycarosyloxy and Ar cannot be a type (iii) substituent ; 3) that, when Rê is hydrogen, R must be hydrogen, hydroxyl or mycarosyloxy; 4) when Rl is hydrogen or hydroxy, R is not NR6R7 and to the salts, particularly the acid addition salts, of these compounds. The compounds of this invention are useful as antibiotics and/or as intermediates to antibiotics. Monocyclic saturated or unsaturated nitrogencontaining heterocyclic rings which are bonded through the nitrogen atom and which have from five to seven ring atoms, including up to three additional heteroatoms selected from nitrogen, oxygen and sulfur, include groups such as pyrrolyl, pyrazolyl, imidazolyl, 1,2,4oxadiazinyl, 1,3 ,4-thiadiazinyl, 1,2 ,4-triazolyl, lH-tetrazolyl, 1,4-diazepinyl, morpholino, thiomorpholino, piperazinyl, thiazolidinyl, oxazolidinyl, and tetrahydro-l, 4-thiazin-4-yl. Such rings can have up to three substituents selected from methyl, ethyl and phenyl on appropriate carbon and/or nitrogen ring atoms(s). The term "C1-C5-alkanoyl" as used herein means an acyl moiety derived from a carboxylic acid containing from one to five carbon atoms. In such a moiety, the alkyl group can be straight, branched, or cyclic. When optionally substituted, the alkyl group can bear one to three halo substituents. Halo substituents are selected from the group consisting of Cl, Br and F. Acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, and isovaleryl are examples of such groups. The term "C1-C3-alkanoyloxy" refers to the corresponding acyloxy moiety. The terms "optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl-or phenylthioacetyl", "optionally substituted benzoyl, phenylacetyl or phenylpropionyl", "optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy", "optionally substituted phenyl, benzyl or phenethyl", "optionally substituted benzyl, phenethyl or phenoxyethyl" and "optionally substituted phenylsulfonyl" 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 "derivatized phenyl" refers to a phenyl group which has from one to five halo, methoxyl or C1-C4-alkyl substituents, or from one to two nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, C4-C10-methyleneamino, azido, hydroxy, hydroxymethyl, aminomethyl, (methylamino)methyl, (ethylamino)methyl, (dimethylamino)methyl, (diethylamino )methyl, (C4-C10-methyleneamino )methyl, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, carboxamido, N-methylcarboxamido, N,N-dimethylcarboxamido, cyano, phenyl, phenoxy or benzyl substituents. The term "optionally substituted heteroaryl group" as used herein means that the heteroaryl group may have at least one suitable substituent(s) such as a C1-C4-alkyl, halo, methoxy, ethoxy, hydroxy (or the keto tautomer) or phenyl group. The terms "C1-C3-alkyl", "C1-C4-alkyl" or "C1-C6-alkyl" as used herein mean a straight- or branched-chain alkyl group containing the specified number of carbon atoms. Such groups include methyl, ethyl, isopropyl, n-butyl, tert-butyl, n-hexyl, and the like. "Optionally substituted'1 Cl-C4-alkyl or C1-C6- alkyl means that the alkyl group contains one or more fluoro or chloro substituents. "C3-C8-cycloalkyl" refers to a cycloalkyl group containing from three to eight carbon atoms. Examples of such groups are cyclopropyl, cyclohexyl and cyclooctyl. The term "alkoxycarbonyl" represents a member of a group selected from t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl, The term "C4-C10-methyleneamino" represents a cyclic amino substituent of the formula -N(CH2 3n wherein n is an integer from four to ten. Pyrrolidinyl, piperidinyl, and octahydroazocinyl are examples of such groups. The invention also provides a process for preparing a macrolide of formula (I) by (a) reducing a starting macrolide of formula (II) wherein Q is formyl and Q1is RÚ, provided R1 is not hydroxyl, to give a macrolide of formula (I) wherein R is hydroxyl; EMI9.1 (b) reacting a starting macrolide of formula (II) wherein Q is formyl and Q1is R1 with an amine of the formula HNR6R6 or HR9 in the presence of a reducing agent to give a macrolide of formula (I) wherein R is NR6R6 or R9, or (c) reacting a starting macrolide of formula (II) wherein Q is -CH20H and Q1is R1 with diethylazodicarboxylate or dimethylazodicarboxylate, triphenylphosphine, and a reagent selected from (i) an azide transfer agent, to give a macrolide of formula (I) wherein R is azido, (ii) phthalimide to give a macrolide of formula (I) wherein R is phthalimido, (iii) a phenol of formula ArOH to give a macrolide of formula (I) wherein R is -OAr, where Ar is a category 1) or ii) Ar group, (iv) an alkyl halide or polyhalide to give a macrolide of formula (I) wherein R is Cl, Br. or I, or (v) a metcaptan of formula HSR5 to give a macrolide of formula (I) wherein R is SR5, or (vi) a carboxylic or sulfonic acid of the formula ArOH, where Ar is a category (iii) Ar group, to give a macrolide of formula (I) wherein R is OAr, (d) reacting a starting macrolide of formula (II) wherein Q is -Ch OH and Q1is R1 with triphenylphosphine and a halogen source to give a macrolide of formula (I) wherein R is Cl, Br, or I, (e) reacting a starting material of formula (II) wherein Q is -CH20H and Q1 is R1 with an acylating agent derived from a carboxylic or sulfonic acid of formula ArOH, where Ar is a category (iii) Ar group to give a macrolide of formula (I) wherein R is OAr, or (f) reacting a starting macrolide of formula (II) wherein Q is -CH2L where L is a leaving group and QÚ is RÚ or a leaving group with (i) an alkali metal azide or halide or a tetraalkylammonium azide or fluoride where alkyl is methyl, ethyl, propyl or butyl, to give a macrolide of formula (I) wherein R is azido, F, Cl, Br, or I, or (ii) a mercaptide ion of formula R5 S- to give a macrolide of formula (I) wherein R is R5 S-, or (iii) an amine of the formula NR6R6 or HR9 to give a macrolide of formula (I) wherein R is NR6R6 or R9, or (iv) a source of cyanide ion to give a macro lide of formula (I) wherein R is -CN ; ; (v) an alcohol of the formula HOR4 and a source of silver ion to provide a macro lide of formula (I) wherein R is OR4 where R4 is other than hydrogen (g) hydrolyzing a macrolide of formula (II) wherein Q is CH2R and Q1is EMI11.1 to give a macrolide of formula (I) wherein R1 is hydroxyl, or (h) removing the hydroxy protecting group from a macrolide of formula (II) wherein Q is -CH2R and Ql is protected hydroxy or (i) reacting a starting macrolide of formula (11) wherein Q is -CH2R and Ql is hydroxyl with diethylazodicarboxylate or dimethylazodicarboxylate, triphenylphosphine, and a reagent selected from (i) an azide transfer agent to give a macroide of formula (I) wherein Rl is azido, (ii) phthalimide to give a macrolide of formula (I) wherein R1 is phthalimido, (iii) a phenol of formula ArOH where Ar is a category (i) or (ii) Ar group to give a macrolide of formula (I) wherein R1is -OAr, (iv) an alkyl halide or polyhalide to give a macrolide of formula (I) where R1 is Cl, Br, or I, or (v) a mercaptan of formula HSR5 to give a macrolide of formula (I) wherein R is SR5, or (vi) a carboxylic or sulfonic acid of the formula ArOH, where Ar is a category (i) Ar group, to give a macrolide of formula (I) wherein R1is OAr; or (j) reacting a macrolide of formula (11) wherein Q is -CH2R and Q1 is hydroxyl with an acylating agent derived from a carboxylic or sulfonic acid of formula ArOH where Ar is a category (iii) Ar group to give a macrolide of formula (I) wherein R1 is OAr or (k) reacting a macrolide of formula (II) wherein Q is R and Q1 is hydroxyl with triphenylphosphine and a halogenating agent to give a macrolide of formula (I) wherein R1is Cl, Br or I, or (1) reacting a macrolide of formula (II) wherein Q is -CH2R and Q1 is a leaving group with (i) an alkali metal azide or halide or a tetraalkylammonium azide or fluoride where alkyl is methyl, ethyl, propyl, or methyl to give a macrolide of formula (I) wherein R1 is azido, F, Cl, Br, or I, (ii) a mercaptide ion of formula R5S- to give a macroide of formula I wherein RÚ is R5S-, or (iii) an amine of the formula HNR6R6 or HR9 to give a macrolide of formula (I) wherein R1is HR6R6 or R9 or (m) reducing a macrolide of formula (II) wherein Q is -CH2N3 and Q1is R1 or Q is R and Q1 is azido to give a macrolide of formula (I) wherein R is -CH2NH2 or R1 is amino, or (n) acylating a macrolide of formula (II) wherein g is -CH2NHR6 or R1 is NHR6 to give a macrolide of formula (I) wherein R is -CH2NHR7 or R1 is -NR6R7, or (o) esterifying a macrolide of formula (I), or (p) salifying a macrolide of formula (I), or (q) hydrolyzing a macrolide of formula (I) wherein R3 is mycarosyloxy in acid solution at a pH below 4 to give a macrolide of formula (I) wherein R3 is hydroxy, or (r) deoxygenating a macrolide of formula (I) wherein R3 is hydroxy to give a macrolide of formula (I) wherein R3 is hydrogen. (s) reacting a macrolide of formula (II) wherein Q is CH2 I and Q1 is R1 with a reducing agent to give a compound of formula (I) wherein R is hydrogen, or (t) reacting a macrolide of formula (II) wherein Q is -Ci2- sulfonate and This R1 with a source of iodide ion to give a macrolide of formula (I) wherein R is iodo. In general, macrolides of formula (I) are prepared by effecting a modification at the C-20 position of a macrolide that has the desired group at the C-23 position, or by effecting a modification at the C-23 position of a macrolide that has the desired group at the C-20 position, or by effecting modifications at the 20- and 23- positions simultaneously. In addition, macrolides of formula (I) maybe modified at 2'-, 4l-, 20-, and 23- positions using known methods to produce other macrolides of formula (I). The following are known macrolides which are useful in preparing the macrolides of this invention: demycinosyltylosin (DMT), 20-dihydro-23-demycinosyltylosin (dihydro-DMT), 23-de(mycinosylox-y)tylosin (DMOT), 20-dihydro-23-de(mycinosyloxy)tylosin (dihydro-DMOT), 5-O-mycaminosyltylonolide (OMT), 20-dihydro-5-O- mycaminosyltylonolide (dihydro-OMT), 23-deoxy-5-Omycaminosyltylonolide (DOMT)1 20-dihydro-23-deoxy-5-O mycaminosyltylonolide (dihydro-DOMT), 20-dihydro-20deoxy-23-demycinosyltylosin (DH-DO-DMT) and 20-dihydro20-deoxy-5-O-mycaminosyltylonolide (DH-DO-OMT). DMT, dihydro-DMT, DMOT, dihydro-DMOT, DOMT, and dihydro-DOMT are antibiotics described by Richard H. Baltz, Gene M. Wild, and Eugene T. Seno in U.S. Patents 4,321,361 and 4,321,362, both of which issued on March 23, 1982. DH-DO-DMT and DH-DO-OMT are described by Richard H. Baltz, Herbert A. Kirst, Gene H. Wild and Eugene T. Seno in U.S. Patent 4,304,856, which issued December 8, 1981. OMT and dihydro-OMT are described by Marvin Gorman and Robert D. Morin in U.s. Patent 3,459,853, issued on August 5, 1969. The structures of the starting antibiotics are shown in formulas 2-11: EMI15.1 @ @Ú @ê 2 DMT: -CHO -OH mycarosyl 3 dihydro-DMT: -CH2OH -OH " 4 OMT: -CHO -OH H 5 dihydro-OMT: -CH2OH -OH H 6 DMOT: -CHO H mycarosyl Z dihydro-DMOT: -CH2OH H 8 DOMT: -CHO H H 9 dihydro-DOMT: -CH2OH H H 10 DH-DO-DMT 3 -OH mycarosyl 11 DH-DO-OMT -CH -OH H Other known macrolides are also useful starting materials, as will be clear from the following discussion. Methods for modifying the C-20-position The desired group at the C-20 position can be obtained by using a known starting material that already has the desired group, or by modifying the C-20 position of an available starting material. The C-20 position may be modified before or after the other required modifications, if any, are made in the starting material Known macrolides of formula (II) wherein Q is -CH2OH include dihydro-DMT (3), dihydro-OMT (5), dihydro DMOT (1), and dihydro-DOMT (9). Macrolides of formula (I) or (II) wherein R is hydroxyl or Q is CH2OH can be prepared by reducing a macrolide of formula (II) wherein Q is formyl to provide the corresponding 20-dihydro compound. Chemical reduction can be effected, for example, by treating the macrolide with an approximately stoichiometric amount of sodium borohydride in an alcoholic solvent. Macrolides of formula (I) or (II) wherein R is OH or Q is CH2OH may be converted to other macrolides of formula (I) by modifying the C-20 hydroxyl group, using any of a variety of known synthetic methods. Several methods are described hereinafter. Known macrolides of formula (II) wherein Q is methyl include DH-DO-DMT (10) and DH-DO-OMT (11). Macrolides of formula (I) or (II) wherein R is hydrogen or Q is methyl can be prepared by reacting a macrolide of formula (II) wherein Q is -CH2I withe reducing agent such as a hydride, for example sodium borohydride in a dipolar aprotic solvent such as dimethyl sulfoxide, dimethylformamide, or sulfolane, or an organotin hydride such as tri-n-butyltin hydride, or a metal, for example powdered zinc, in a nonreactive organic solvent such as toluene or nitromethane. Macrolides of formula (I) or (II) wherein R is Cl, Br, or I, or Q is -CH2C1, -CH2Br, or -CH2-I are prepared by reacting a macrolide of formula (II) where Q is -CH2OH with triphenylphosphine and a halogenating agent in a nonreactive organic solvent such as dichloromethane. Suitable halogenating agents include alkyl halides and polyhalides, such as carbon tetrachloride. Macrolides of formula (I) or (II) wherein R is C1, Br, or I, or Q is -CH2C1, -CH2Br, or -CH2 I are also prepared by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, diethylazodicarboxylate or dimethylazodicarboxylate, and an alkyl halide or polyhalide. The di)alkyl)azodicarboxylate/triphenylphosphine reaction and its various applications are described in O. Mitsunobu, Synthesis, I (1), 1-28 (1981). The reaction generally produces dehydration between an alcohol ROH and an acidic component EX to provide a product RX. Macrolides of formula (I) or (II) wherein R is F, Cl, Br, or I, or Q is -CH2F, -CH2Cl, -CH2Br, or -CB2I are also prepared by reacting a macrolide of formula (II) wherein Q is -CHO with an alkali metal or tetra (alkyl)ammonium halide in a nonreactive organic solvent such as tetrahydrofuran. Macrolides of formula (I) or (11) wherein R is azido or Q is -CH2N3 are prepared by reacting a macrolide of formula (II) wherein Q is -CHO with an alkali metal or tetra(alkyl)ammonium azide in a nonreactive organic solvent. Macrolides of formula (I) or (II) wherein R is azido or Q is -CH2N3 are also prepared by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, diethylazodicarboxylate or dimethylazodicarboxylate, and an azide transfer agent, such as diphenylphosphoryl azide, in a nonreactive organic solvent such as tetrahydrofuran. Macrolides of formula (I) or (II) wherein R is cyano or Q is -CH2CN are prepared by reacting a macrolide of formula (II) wherein Q is -CH2L, where L is halide or a sulfonic ester group, with a cyanide salt in a nonreactive organic solvent, such as dimethylsulfoxide. Macrolides of formula (I) or (II) wherein R is 4 oR4 or Q is CH20R4 are prepared by reacting a macrolide of formula (II) wherein Q is CH2L with an alcohol of the formula HOR4, where R4 is other than hydrogen in the presence of a source of silver ion. Macrolides of formula (I) or (II) wherein R is OAr or Q is CH2OAr are prepared by reacting a macrolide of formula (II) wherein Q is. -CH2OH, with triphenylphosphine, di(alkyl)azodicarboxylate, where alkyl is methyl or ethyl, and a phenol of formula AroH, where Ar is a category i) or ii) Ar group. Macrolides of formula (I) or (II) wherein R is OAr or Q is CH2OAr and Ar is optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl, or phenylthioacetyl are prepared by reacting a macrolide of formula (II) wherein Q is -CH2OH with an acylating agent derived from a carboxylic acid of formula ArOH, where Ar is as defined above. Typical acylating agents include anhydrides, acid halides (usually in combination with a base or other acid scavenger), and active esters. Suitable organic solvents include pyridine and triethylamine. Acylation can also be achieved using a mixture of an organic acid and a dehydrating agent such as N,N'-dicyclohexylcarbodiimide. Macrolides of formula (I) or (II) wherein R is OAr or Q is CH2OAr and Ar is an acyl group as defined in the previous paragraph are also prepared using the di(alkyl)azodicarboxylate/triphenylphosphine procedure, i.e., by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, di(alkyl)azodicarboxylate, and a carboxylic acid of the formula ArOH. Macrolides of formula (I) or (II) wherein R is OAr or Q is CH2OAr and Ar is methanesulfonyl, trifluoromethanesulfonyl or optionally substituted phenylsulfonyl are prepared by reacting a macrolide of formula (I) wherein Q is -CH2OH with an activated derivative, such as the anhydride or acid halide, of a sulfonic acid of the formula ArOH. If the acid halide is used, the reaction is carried out in the presence of a base, usually pyridine. Macrolides of formula (I) or (II) wherein R is OAr or Q is CH2OAr and Ar is defined in the previous paragraph are also prepared using the di ( alkyl ) azodi- carboxylate/triphenylphosphine procedure, i e., by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, di(alkyl)azodicarboxylate and a sulfonic acid of the formula ArOH. Macrolides of formula (I) or (II) wherein R is SR5 or Q is -CH2SR5 are prepared by reacting a macrolide of formula (II) wherein Q is -CH2L with mercaptide ion of the formula R9S # L may be halide or a sulfonic or sulfonic ester group. Macrolides of formula (I) or (II) wherein R is SR5 or Q is -CH2SR5 are also prepared using the di(alkyl) azodicarboxylate/triphenylphosphine procedure, i. e., by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, di(alkyl)azodicarboxylate and a mercaptan of formula HSR5. Macrolides of formula (I) or (II) wherein R is 67 67 @@ @ @@ @ @@ @@ @@@@@ @ @@@ @@@@@@@ @@ @@@@@@ @ macrolide of formula (II) wherein Q is -CH2NHR6 with an acylating agent derived from a carboxylic acid of the formula HOR7. Macrolides of formula (I) or (II) wherein R is phthalimido, or Q is -CH2-phthalimido are prepared by reacting a macrolide of formula (II) wherein Q is -CH2OH with triphenylphosphine, di(alkyl)azodicarboxylate, and phthalimide. Compounds of formula (I) or (II) wherein R4 or L is methanesulfonyl, trifluoromethanesulfonyl or optionally substituted phenylsulfonyl, as well as compounds wherein R or L is iodo or bromo, are useful as intermediates for the preparation of additional compounds of this invention via SNÚ or SN2 substitution reactions. Suitable reaction conditions for displacing a leaving group by a nucleophile via either an SN1 or SN2 mechanism are well exemplified in the art of nucleophilic substitution reactions. The formula (I) or (Il) compounds wherein R is 7 and R7 is an acyl group are prepared via the 20-azido derivative (R--N3). The 20-azido derivative is first reduced to the 20-amino derivative (R = triphenylphosphine in aqueous tetrahydrofuran (THF) is an example of a suitable reducing agent for this purpose. The 20-amino derivative can then be selectively acylated on the amino group, using standard acylation procedures, to give those derivatives wherein R7 is an acyl group. Macrolides of formula (I) or (II) wherein R is -N(R6)2 or R9 or Q is CH2N(R6)2 or CH2R9 can be prepared by reductive amination of the C-20 aldehyde group of DMT, OMT, DMOT, and DOMT using one of two methods. Method 1: A derivative with a leaving group at C-20 (iodo, triflate, etc.), prepared as described supra, is reacted with the appropriate amine in a suitable solvent, such as acetonitrile, until the desired 20-modified derivative is formed via displacement of the C-20 leaving group by the nucleophilic amine. Method 2: In this method, the aldehyde group of compound 2, 4, 6, or 8 is reacted directly with the corresponding amine in the presence of a suitable reducing agent in an appropriate solvent until the desired product is formed. Sodium cyanoborohydride is an example of a suitable reducing agent, and anhydrous methanol is a useful solvent for this reaction. The reaction may be carried out under a nitrogen atmosphere, but this is usually not required. With less reactive amines, more forcing conditions for forming the intermediate iminium complex between the macrolide and amine may be required, e.g. heating, use of a drying agent or water scavenger or heating under conditions of azeotropic removal of water in solvents such as benzene or toluene. Methods for modifying the C-23-position The desired group at the C-23 position is likewise obtained by using an available starting material that already has the desired group at the C-23 position, or by modifying the C-23 position of an available starting material. Known macrolides of formula (II) wherein Q1is hydroxyl include DMT (2), dihydro-DMT (3), OMT (4), dihydro-OMT (5), DH-DO-DMT (10), and DH-DO-OMT (11). Macrolides of formula (I) or (II) wherein R1 or qs Q1 is hydroxyl can be prepared by acid hydrolysis of a macrolide of formula (II) wherein Q1 is EMI23.1 The hydrolysis is carried out at a pH between 1.5 and 2.5, as described in U.S. Patent No. 3,459,853. Macrolides of formula (I) or (II) wherein R1 or Q1 is hydroxyl can be modified to give other macrolides of formula (I) using the methods described hereinbefore for converting a C-20 hydroxyl group to the desired group. Thus, the DEAD reaction may be used to effect many of the C-23 modifications. Other procedures for modification of the C-23 position are described by A. Tanaka et al in J. Antibiotics 35 (1) 113-116 (1982). Another process applicable to C-23 modifications is a 'two-step process in which the 23-hydroxyl group is first converted to a leaving group, and the leaving group is then displaced by a suitable nucleophile. First, the 23-hydroxyl group is converted to a suitable leaving group, such groups being well known in the art. The triflate anion is a preferred leaving group. With very reactive nucleophiles, however, other leaving groups, such as the mesylate anon, the tosylate anion, iodide or bromide may also be suitable. The 23-O-triflate is preferably prepared by reaction of the 23-OH intermediate with an activated derivative of trifluoromethanesulfonic acid, such as the anhydride, preferably in the presence of a hindered pyridine derivative such as 2,6-lutidine or s-collidine at a temperature of from -800c to room temperature. The hydroacyl groups at positions other than 23- may be protected by acetyl groups which can be removed by methanolysis, for instance by refluxing in methanol. Using this procedure, the 23-O-triflate can be prepared without concomitant reactions at the other hydroxyl groups which are present. A similar reaction can be used to prepare the corresponding mesylate or tosylate directly. When triflate is used as the leaving group, it is not necessary to isolate the intermediate triflate derivative; displacement with the appropriate nucleophile can be carried out in situ. When less reactive leaving groups are used, the intermediate is sufficiently stable and may be isolated prior to the displacement reaction if so desired. The second step in the preparation of the C-23 modified derivatives involves displacement of the leaving group by the appropriate nucleophile under suitable conditions which are well exemplified in the art of displacement reactions. When is is desired to prepare compounds of formula (II) in which QÚ is SR5 the most convenient nucleophile is a compound of formula HSR5. For preparation of an azide, the nucleophile is preferably an alkali metal azide such as lithium azide. The pyridinium compound is preferably prepared by reaction with pyridine base. When Q1 is NR6R7 or R9, the nucleophile is an amine of the formula HNR6R7 or BUR9. The nucleophilic displacement reaction is preferably conducted at temperatures in the range from -800C to 1000C, typically room temperature using an inert organic solvent such as a chlorinated hydrocarbon like dichloromethane. The C-23 derivatives wherein R1 is -NHR7 can be prepared via the 23-azido derivative (R=N3). The 23-azido derivative is first reduced to the 23-amino derivative using a reducing agent specific to azido groups, such as chromous chloride or triphenylphosphine. Aqueous organic solvents such as ethereal solvents, for example tetrahydrofuran (THF) are useful for this purpose. The reduction can be effected at temperatures in the range from 0 to 1000C, The 23-amino derivative can then be selectively acylated using standard acylation procedures, to give those derivatives wherein R7 is an acyl group. As will be appreciated by those skilled in the art the acylation can be effected at temperatures in the range of from -20 to 700C. It should be noted thatr when the compounds of formulas 3 or 5 are used as starting materials, two primary hydroxyl groups are present which react in a similar manner. The primary hydroxyl group at C-20, however, is usually replaced more rapidly than the hydroxyl group at C-23. Although many of the procedures described supra give mixtures of 20-monosubstituted derivatives and 20,23-disubstituted derivatives, such mixtures can be readily separated by techniques known in the art, such as, for example, chromatography using silica gel as the adsorbant. Formation of C-20-monosubstituted derivatives may be optimized by not carrying the reaction to completion, for example, by using less than two molar equivalents of reactant(s). Conversely, when C-20, C-23-disubstituted derivatives are sought, the reaction should be carried to completion and two molar equivalents or an excess of reactant(s) should be used. Compounds wherein the substituent R1 differs from the substituent R can be prepared by modifying the hydroxyl group at C-23 before reducing the aldehyde at C-20. When preparing formula (I) compounds wherein R is hydrogen, compounds 10 and 11 may be used as starting materials and modified at the C-23 hydroxyl group as previously described. An alternate method for preparing compounds with different substituents at C-20 and C-23 is to modify the C-20 position of a macrolide not having a free C-23 hydroxyl group. One example of this approach is to prepare a C-20-modified derivative of desmycosin, tylosin, macrocin, lactenocin, demethylmacrocin and demethyllactenocin, followed by hydrolysis at the neutral sugar(s), using procedures known in the art (see, for example, U.S. Patent 3,459,853). By this procedure, a 20-modified derivative of OMT can be selectively prepared, which in turn can be modified at the C-23 position, as discussed supra. Use of a protecting group for the hydroxyl group at C-23 of OMT and DMT prior to reduction of the aldehyde also permits selective modification of C-20. Removal of the protecting group after appropriate modification of C-20 yields C-20-modified derivatives having a hydroxyl group at C-23, which may then be modified as outlined previously. Examples of useful protecting groups are ester moieties, such as acetyl and trichloroacetyl, and groups such as tetrahydropyranyl and tetrahydrofuranyl. The tetrahydropyranyl and tetrahydrofuranyl protecting groups are described, for example, by Tanaka et al., supra. The modified derivatives of OMT, DOMT and DH-DO-OMT can also be prepared by acidic hydrolysis of mycarose from the corresponding modified derivatives of DMT, DMOT and DH-DO-DMT, respectively, prepared by the methods previously described. Procedures for the acidic hydrolysis of mycarose from DMT and DMOT to form OMT and DOMT, respectively, are found in U.S. Patents 4,321,361 and 4,321,362. Acidic hydrolysis of DH-DO-DMT to give DH-DO-OMT is described in U.S. Patent 4,304,856. More specifically, 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. 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. & Chemoth. 11, 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',4'-di-O-acetyl derivative; (3) reacting the 21,4'-di-O-acetyl derivative with 2,3-dihydrofuran in dichloromethane in the presence of pyridinium p-toluenesulfonate in the manner described in J. Orq. Chem. 42, 3772-74 (1974) to obtain the 3,4 " -bis(O- tetrahydrofuranyl)derivative; (4) removal of the 2' and 4'-O-acetyl 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 800C 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'-deoxy derivatives of this invention, i.e. the compounds of formula (I) wherein R3 is hydrogen, are readily prepared by procedures analogous to those described supra, using 4'-deoxy-OMT, 4'-deoxy-DOMT or 4'-deoxy-DH-DO-OMT as the starting material. These starting materials can be prepared via procedures outlined in J. Antibiotics 34, 1381-1384 (1981). Alternatively, deoxygenation at 4' may be accomplished in OMT, DOMT or DH-DO-OMT subsequent to modification of the C-20 and/or C-23 positions. The formula (I) compounds which are ester derivatives are prepared by esterifying the respective C-20 and/or C-23-modified derivative on the 2', 4', and/or 23-hydroxyl groups (when present) by treatment with acylating agents, using standard methods exemplified in the art. The preparation of 2'-O-ester derivatives of the C-20- and/or C-23-modified derivatives is accomplished by procedures similar to those described by Baltz et El. in U.S. Patents 4,321,361 and 4,321,362. Esterification of the 2', 4' and/or 23-hydroxyl groups of these modified derivatives may be accomplished by acylation of the hydroxyl groups using similar procedures as outlined in the previously discussed applications serial Nos. 330,341, 330,295, and 330,294. Alternatively, the formula (I) compounds which are esters may be prepared by starting with the appropriate esters of compounds 2-11, prepared as described supra. Furthermore, it should be noted that the formula (I) ester compounds can be hydrolyzed to yield the corresponding formula (I) compounds, thus utilizing the esters as protecting groups during reactions to modify the C-20 and/or C-23 positions. 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, salicylic, methanesulfonic; benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids. Pharmaceutically acceptable acid addition salts are an especially preferred group of salts of this invention. Illustrative formula (I) compounds of this invention are listed in Table I. Table I Illustrative Formula (I) Compounds EMI32.1 Compound NO. R RÚ Rê R 1 phenylacetoxy OH H -OH 2 N-phthalimido " " " 3 phenoxy " " " 4 p-(phenoxy)phenoxy " " " 5 phenylthio " " " 6 (1-methyltetrazol- " " " 5-yl)thio Table I continued Compound No. R RÚ Rê R 7 azido OH H -OH 8 (N-phenylacetyl)amino " " " 9 iodo " " " 10 chloro " " " 11 N-phthalimido " " mycarosyloxy 12 phenoxy " " " 13 azido " " " 14 (1-methyltetrazol 5-yl)thio " " " 15 N-phthalimido H H -OH 16 phenoxy " " " 17 azido " " " 18 N-phthalimido " " mycarosyloxy Table I continued Compound No. R RÚ Rê R 19 phenoxy H H mycarosyloxy 20 azido " " " 21 phenylthio " " " 22 henylacetoxy phenylacetoxy H -OH 23 N-phthalimido N-phthalimido " " 24 phenoxy phenoxy " " 25 phenoxy phenylpropionyloxy " " 26 phenoxy octahydroazocin-1-yl " " 27 (N-phenylacetyl) amino " " " 28 phenylthio azabicyclononanyl " " 29 chloro 4-phenylpiperidino " " 30 N-phthalimido N-phthalimido " mycarosyloxy 31 phenoxy hexahydroazepin-1-yl " " 32 H acetoxy acetyl acetoxy 33 H phenylacetoxy H -OH 34 H phenylthio " " 35 H octahydroazocin-1-yl " " Table I continued Compound No. R RÚ Rê R 36 H 3-(dimethylamino) phenoxy H -OH 37 H 4-hydroxypiperidino " " 38 H (pyridin-3-yl)oxy " " 39 H 2,3-dimethoxy)phenoxy " " 40 H phenoxy " " 41 H 3-azabicyclononan-3-yl " " 42 H 4-phenylpiperidino- " " 43 -OH phenoxy acetyl acetoxy 44 -OH phenylpropionyloxy H -OH 45 -OH octahydroazocin-1-yl H H 46 phenylacetoxy -OH acetyl acetoxy 47 phenylacetoxy phenylacetoxy acetyl acetoxy 48 H octahydroazocin-1-yl acetyl acetoxy 49 -OH octahydroazocin-1-yl H -OH Table I Illustrative Formula (I) Compounds EMI36.1 Compound No. R RÚ Rê R 50 pyrrolidin-1-yl OH H -OH 51 piperidin-1-yl " " " 52 4-hydroxypiperidin-1-yl " " " 53 4-phenylpiperidin-1-yl " " " 54 hexahydroazepin-1-yl " " " 55 octahydroazocin-1-yl " " " 56 octahydro-1H-azonin-1-yl " " " 57 decahydroazecin-1-yl " " " Table I continued Compound No. R RÚ Rê R 58 azacycloundecan-1-yl OH H -OH 59 azacyclotridecan-1-yl " " " 60 1,2,3,4-tetrahydro quinolin-1-yl " " " 61 1,2,3,4-tetrahydroiso quinolin-2-yl " " " 62 3-azabicyclononan-3-yl " " " 63 morpholino " " " 64 octahydroazocin-1-yl octahydroazocin-1-yl " " 65 3-azabicyclononan-3-yl octahydroazocin-1-yl " " 66 3-azabicyclononan-3-yl o-phenyl " " 67 morpholino s-phenyl " " 68 octahydroazocin-1-yl azido " " 69 octahydroazocin-1-yl 3-azabicyclononan-3-yl " " 70 octahydroazocin-1-yl OH " H 71 3-azabicyclononan-3-yl OH " H 72 hexahydroazepin-1-yl H " OH 73 morpholino H " " 74 3-azabicyclononan-3-yl OH acetyl acetoxy The derivatives of this invention inhibit the growth of pathogenic bacteria, especially gram-positive bacteria, and Mycoplasma species. Certain of the derivatives are active against some gram-negative bacteria, such as Pasteurella species. The minimal inhibitory concentrations (MIC's) at which illustrative compounds inhibit certain bacteria are given in Tables II and III. The MIC's in Table II were determined by standard agar-dilution assays. The MICAS in Table III were obtained using a conventional broth-dilution microtiter test. Table II Antibiotic Activity of Formula (I) Compoundsa Test Organism Test Compoundb 1 2 11 15 18 Staphylococcus aureus X1.1 1 4 64 8 64 " " V41c 1 8 64 8 32 " " X400d 2 16 64 32 64 " " S13E 1 8 64 8 64 Staphyococcus epidermidis EPI1 0.5 4 32 8 64 " " EPI2 1 2 32 4 32 Streptococcus pyogenes C203 1 NTh 128 NT 64 " pneumoniae Park I 0.5 2 16 4 8 " Group D X66 2 16 - 16 128 " " 9960 2 16 - 16 Haemophilus influenzae C.L.e 16 64 - 128 " " 76f 16 64 - 128 - Table II continued Antibiotic Activity of Formula (I) Compoundsa Test Organism Test Compoundb 1 2 11 15 18 Escherichia coli EC14 64 - - - " " TEM 16 64 - 128 Klebsiella penumoniae X25 4 16 - 32 " " KAE -g - - - aMIC in mcg/ml eAmpicillin-sensitive strain bCompound numbers from Table I fAmpicillin-resistant strain cPenicillin-resistant strain gCompound not avtive at 128 mcg/ml dMethicillin-resistant strain hNT = not tested Table II continued Test Organism Test Compoundb 22 23 24 25 26 30 32 33 34 35 36 Staphylococcus aureus X1.1 0.25 4 1 1 0.25 64 4 0.5 1 0.5 1 " " V41c 0.25 4 1 1 0.25 16 4 0.5 0.5 0.5 1 " " X400d 0.5 16 2 2 0.5 64 16 0.5 1 1 2 " " S13E 0.25 4 1 1 0.25 32 4 0.5 1 0.5 1 Staphyococcus epidermidis EPII 0.25 4 1 1 0.25 32 4 0.5 0.5 0.5 1 " " EPI2 0.5 NT 1 1 0.12 16 4 0.5 1 0.25 0.5 Streptococcus pyogenes C203 0.25 16 2 2 0.12 - 16 0.5 1 0.12 4 " pneumoniae Park 0.12 2 0.25 0.5 0.12 16 4 0.25 0.12 1 0.5 " Group D X66 0.5 8 0.5 1 2 - 8 1 0.5 1 2 " " 9960 0.5 16 2 2 2 - 8 1 1 2 2 Haemophilus influenzae C.L.e NT - - 128 4 - NT 8 16 4 16 " " 76f NT - - - 8 - NT 8 16 8 16 Table II continued Test Organism Test Compoundb 22 23 24 25 26 30 32 33 34 35 36 Escherichia coli EC14 ¯g - - - - - - 128 - - " " TEM 8 - - - 8 - - 16 - 16 Klebsiells pneumoniae X26 8 - - 32 8 - 16 4 16 4 32 " " KAE - - - - - - - - - - aMIC in mcg/ml eAmpicillin-senaitive strain bCompound numbers from Table I fAmpicillin-resistant strain cPenicillin-resistant strain gCompound not active at 128 mcg/ml dMethicillin-resistant strain bNT = not tested Table II continued Test Organism Test Compoundb 37 38 39 44 45 46 47 Staphyocooccus aureus X1.1 8 1 0.25 0.5 0.5 2 8 " " V41c 16 0.5 0.25 0.5 0.5 2 8 " " X400d 32 2 0.25 1 1 2 8 " " S13E 8 1 0.25 0.5 0.5 2 4 Staphyococcus epidermidis EPII 8 1 0.25 0.5 0.5 2 4 " " EPI2 2 0.25 0.25 0.25 0.25 2 2 Streptococcus pyogenes C203 32 2 0.25 0.25 0.25 1 2 " pneumoniae Park 2 0.5 NT 0.25 0.25 0.5 1 " Group D X66 64 2 0.25 2 2 4 8 " " 9960 128 4 0.25 4 4 4 8 Haemophilus influenzae C.L.e 32 16 32 2 2 NT NT " " 76f 64 16 16 4 4 NT NT Table II Antibiotic Activity of Formula (I) Compoundsa Test Organism Test Compoundb 53 62 63 64 Staphylococcus aureus X1.1 2 1 4 0.5 " " V41c 2 1 4 0.5 " " X400d 2 1 8 0.5 " " S13E 2 1 4 0.5 Staphyococcus epidermidis EPI1 1 1 2 0.5 " " EPI2 0.5 0.25 1 0.25 Streptococcus pyogenes C203 2 2 1 0.125 " pneumoniae Park I 0.25 0.25 0.5 0.125 " Group D X66 2 4 4 0.5 " " 9960 4 8 4 1 Haemophilus influenzae C.L.e 8 4 16 0.5 " " 76f 8 2 4 1 Table II continued Test Organism Test Compoundb 37 38 39 44 45 46 47 Escherichia coli EC14 - - - 64 64 - " " TEM - 128 128 8 8 16 Klebsiella pneumoniae X26 16 4 4 4 2 4 " " KAE - - - - 64 - aMIC in mcg/ml eAmpicillin-senaitive strain bCompound numbers from Table I fAmpicillin-resistant strain cPenicillin-resistant strain gCompound not active at 128 mcg/ml dMethicillin-resistant strain bNT = not tested Table II continued Test Organism Test Compoundb 53 62 63 64 Escherichia coli EC14 32 32 128 4 " " TEM 8 8 64 2 Klebsiella pneumoniae X26 2 2 4 2 " " KAE 64 64 - 8 aMIC in mcg/ml eAmpicillin-senaitive strain bCompound numbers from Table I fAmpicillin-resistant strain cPenicillin-resistant strain gCompound not active at 128 mcg/ml dMethicillin-resistant strain bNT = not tested Table III Antibiotic Activity of Formula (I) Compoundsa Test Organism 1 2 Staphylococcus aureus 3.12 25 Streptococcus sp. 80 3.12 3.12 Pasteurella multocida 17Ec 12.5 50 " " 60Ad 25 50 Pasteurella multocida 22A 25 50 " " 40G 25 50 Pasteurella hemolytica 22C 6.25 25 " " 41D 25 50 " " 23C 12.5 50 Mycoplasma gallisepticum 12.5 50 " " 34159e 3.12 3.12 " " 41313e 6.25 50 " synoviae 50 50 " hyorhinis 50 NT aMIC in mcg/ml dAvian isolate gcontaminated bCompound numbers from Table I eResistant strain cBovine isolate fMIC greater than 50 mcg/ml Table III continued Antibiotic Activity of Formula (I) Compoundsa Test Organism 11 15 18 22 23 24 Staphylococcus aureus - 25 - 1.56 12.5 0.39 Streptococcus sp. 80 50 50 - 0.39 12.5 < 0.48 Pasteurella multocida 17Ec - 50 - 12.5 f 3.12 " " 60Ad - 50 - 6.25 - 3.12 Pasteurella multocida 22A - 50 - 6.25 - 3.12 " " 40G - 50 - 6.25 - 3.12 Pasteurella hemolytica 22C - 50 - 6.25 - 3.12 " " 41D - 50 - 6.25 - 12.5 " " 23C - 50 - 6.25 - 12.5 Mycoplasma gallisepticum 12.5 0.78 12.5 0.78 12.5 0.78 " " 34159e 50 50 50 12.5 25 6.25 " " 41313e 50 50 50 50 25 25 " synoviae NT NT NT 6.25 NT 6.25 " hyorhinis 50 25 50 50 50 50 aMIC in mcg/ml dAvian isolate bCompound numbers from Table I eResistant strain cBovine isolate fMIC greater than 50 mcg/ml Table III continued Antibiotic Activity of Formula (I) Compoundsa Test Organism 25 26 30 32 33 34 35 Staphylococcus aureus 0.78 0.39 25 6.25 0.78 1.56 0.39 Streptococcus sp. 80 0.097 0.78 50 12.5 1.56 1.56 0.78 Pasteurella multocida 17Ec 3.12 3.12 - 25 12.5 25 0.78 " " 60Ad 3.12 6.25 - 12.5 3.12 12.5 0.78 Pasteurella multocida 22A 3.12 6.25 - 25 25 25 1.56 " " 40G 3.12 3.12 - 25 12.5 25 1.56 " " 68C 3.12 3.12 - 12.5 3.12 25 1.56 Pasteurella hemolytica 22C 25 1.56 - 50 12.5 25 0.78 " " 41D 25 3.12 - 25 12.5 25 0.78 " " 23C 25 3.12 - 50 12.5 25 1.56 Mycoplasma gallisepticum 0.78 0.097 50 6.25 3.12 6.25 0.78 " " 34159e 12.5 50 50 - 50 25 " " 41313e 25 25 50 - 50 25 " synoviae 6.25 12.5 NT NT 3.12 6.25 " hyorhinis 50 50 50 50 50 25 50 aMIC in mcg/ml dAvian isolate bCompound numbers from Table I eResistant strain cBovine isolate fMIC greater than 50 mcg/ml Table III continued Antibiotic Activity of Formula (I) Compoundsa Test Organism 36 37 38 39 46 47 Staphylococcus aureus 1.56 12.5 1.56 3.12 0.78 0.78 Streptococcus sp. 80 3.12 1.56 3.12 1.56 3.12 1.56 Pasteurella multocida 17Ec 50 25 12.5 25 12.5 " " 60Ad 25 12.5 12.5 25 6.25 50 Pasteurella multocida 22A 50 12.5 12.5 50 25 " " 40G 25 12.5 12.5 12.5 25 " " 68C 25 12.5 6.25 12.5 6.25 Pasteurella hemolytica 22C - 25 50 25 12.5 " " 41D - 25 25 25 12.5 " " 23C - 25 50 25 12.5 Mycoplasma gallisepticum 3.12 6.25 1.56 1.56 < 0.048 0.097 " " 34159e 12.5 - 50 50 3.12 3.12 " " 41313e 12.5 50 50 50 0.78 0.78 " synoviae 12.5 12.5 6.25 6.25 25 6.25 " hyorhinis 50 - 25 25 50 50 aMIC in mcg/ml dAvian isolate bCompound numbers from Table I eResistant strain cBovine isolate fMIC greater than 50 mcg/ml Table III continued Antibiotic Activity of Formula (I) Compoundsa Test Organism 48 49 Staphylococcus aureus 0.39 0.78 Streptococcus sp. 80 0.195 1.56 Pasteurella multocida 17Ec 1.56 3.12 " " 60Ad 1.56 0.78 Pasteurella multocida 22A 1.56 1.56 " " 40G 1.56 0.39 " " 68C 0.78 1.56 Pasteurella hemolytica 22C 0.78 0.78 " " 41D 0.78 0.39 " " 23C 1.56 0.78 Mycoplasma gallisepticum 0.78 0.39 " " 34159e 50 " " 41313e 50 50 " synoviae 12.5 6.25 " hyorhinis - 25 aMIC in mcg/ml dAvian isolate bCompound numbers from Table I eResistant strain cBovine isolate fMIC greater than 50 mcg/ml Some of the 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 EDS0 value effective dose in mg/kg to protect 50% of the test animals: see Warren Wick, et al., J. Bacteriol. 81, 233-235 (1961)l. ED50 values observed for illustrative compounds are given in Table IV. Table IV so Values of Illustrative Formula (I) Compounds a Test Compoundb Streptococcus pyogenes C203 Subcutaneous Oral 1 > 30 > 100 22 > 30 > 100 24 > 10 > 50 25 > 10 > 50 33 > 25 > 100 34 > 25 78 35 > 12.5 > 100 36 > 10 > 50 37 > 10 > 100 38 > 10 > 100 46 > 10 > 50 amg/kg x 2; doses given 1 and 4 hours post-infection bCompound numbers from Table I. Certain of the formula (I) compounds of this invention have also shown in vivo activity against infections induced by gram-negative bacteria. Table V summarizes the results of tests in which illustrative compounds were evaluated against a Pasteurella infection in one-day-old chicks. The compounds were administered parenterally af-ter challenge of the chicks with Pasteu rella multocida (0.1 ml of a 10 4 dilution of a twenty- hour tryptose 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 V, 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. Table V Activity of Formula (I) Compounds Administered Subcutaneously to Pasteurella multocida-Infected Chicks" Test Compoundb Number af Deaths/Number Treated 1 9/10 22 9/10 26 10/10 35 8/10 37 10/10 38 10/10 aAdministered subcutaneously; 30 mg/kg x 2 bCompound numbers from Table I The compounds which are preferred for in vivo activity against gram-positive microorganisms are those formula (I) compounds wherein R is -N(R6)2. Another preferred group are the formula (I) compounds wherein R is -OH or -OAr and Ar is a group (iii) substituent. Still another group of compounds preferred for in vitro activity against gram-positive bacteria and for activity against MYcoPlasma species are the formula (I) compounds wherein R1 is R9. This invention also relates to methods of controlling infections caused by gram-positive bacteria and Hvcoplasma species. In carrying out the methods of this invention, an effective amount of a specified formula (I) compound is administered parenterally to an infected or susceptible warm-blooded animal. 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 1 to about 100 mg/kg and preferably will be in the range of from about 1 to about 50 mg/kg. Suitable dosage regimens can be constructed. In another aspect, this invention relates to compositions useful for the control of infections caused by gram-positive bacteria and Mycoplasma species. These compositions comprise a specified compound of formula (1) together with a suitable vehicle. Compositions may be formulated for parenteral administration by methods recognized in the pharmaceutical art. 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, alkylbenenesulfonates, 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 anti foams, sorbitol, and sugars can be useful suspending agents. In order to illustrate more fully the operation of this invention the following examples are provided: Preparation 1 21,4! -Di-O-acetyl-20-dihydro-OMT 20-Dihydro-OMT (3.1 g, 5.2 mmol) was dissolved in acetone (100 ml) and was treated over a five-minute period with acetic anhydride (2.0 ml, 21.2 mmol). After stirring for nine hours at room temperature, the reaction mixture was quenched into saturated sodium bicarbonate solution (500 ml) and the product was extracted into dichloromethane (2 x 250 ml). The combined dichloromethane extracts were dried (sodium sulfate) and filtered and the filtrate was evaporated under reduced pressure. The residue was dried in vacuo-overnight to yield 3.4 g (96%) of 2',4'-di-o-acetyl-20-ihydro-OMTI Preparation 2 23 - Iodo-20, 23-dideoxy-20-dihydrc-ONT 20-Deoxy-20-dihydro-OMT (2.0 g, 3.4 mmol), tetrabutylammonium iodide (3.8 g, 10.3 mmol) and s-collidine (1.36 ml, 10.3 mmol) were dissolved in dichloromethane (40 ml). The solution was cooled to -780 under an argon atmosphere and then was treated dropwise with triflic anhydride (0.7 ml). After 5 minutes at -78 , the cooling bath was removed and the solution was stirred for 30 minutes at room temperature. Since tlca analysis showed unreacted starting material was still present, the solution was cooled to -780 again and then treated with additional triflic anhydride (0.03 ml). The cooling bath was again removed and the reaction was stirred at room temperature for 30 minutes. The solution was extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (1 L) and 5% methanol in dichloromethazie (1 L). Fractions containing the desired product were located by tic analysis, combined and evaporated under reduced pressure to yield 2.0 g of 23-iodo-20,23-dideoxy-20-dihydro-OMT. a thin layer chromatography Example 1 2',4'-Di-0-acetyl-20-O-phenylacetyl-20- dihydro-OMT and 2', 4'-di-0-acetyl-20,23-di-0-phenyl acetvl-2 0-dihydro-OMT 2' ,41-Di-O-acetyl-20-dihydro-OMT (3.0 g, 4.4 mmol3 was dissolved in dichloromethane (50 ml) and pyridine (2 ml). The solution was cooled to -780 and treated dropwise with phenylacetyl chloride (0.725 ml, 5.5 mmol) over a 2-minute period with vigorous stirring. After 15 minutes at -784, the cooling bath was removed and the solution was stirred at room temperature for six hours. The solution was then poured into saturated sodium bicarbonate solution (100 ml) and the product was extracted into dichloromethane (2 x 50 ml). The combined dichloromethane extracts were dried (sodium sulfate) and filtered and the filtrate was evaporated. The residue (4 g) was separated on a Waters Prep 500 chromatograph, eluting with a linear gradient of toluene (4 L) and ethyl acetate (4 L). Fractions containing the desired products were located by tIc analysis, combined and evaporated under reduced pressure to yield 2.3 g of 2',4 t -di-o-acetyl-20-O-phenylacetyl-20-dihydro-OMT and 0.6 g of 2',4 t -di-O-acetyl-20,23-di-O-phenylacetyl-20- dihydro-OMT. Example 2 20-O-PhenTacetyl-2O-dihydro-OMT 2' ,4' -Di-O-acetyl-20-O-phenylacetyl-20- dihydro-OMT (1.2 g, 1.5 mmol) was dissolved in methanol (80 ml) and water (20 ml) and the solution was refluxed for 1.5 hr. After cooling to room temperature, solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (50 ml), dried (sodium sulfate) and filtered. Evaporation of the filtrate yielded 0.92 g of 20-O-phenylacetyl-20-dihydro-OMT. Example 3 20,23-Di-0-Phenylacetyl-20-dihydro-OMT In a manner similar to that of Example 2, 2',4'-di-O-acetyl-20,23-di-O-phenylacetyl-20-dihydro-OMT (0.48 g) was hydrolyzed to yield 0.44 g of 20,23-di-Ophenylacetyl-20-dihydro-OMT. Example 4 20-N-Methylamino-20-deoxy-20-dihydro-OMT OMT (1.2 g) and methylamine hydrochloride (1.36 g) were dissolved in dry methanol (40 ml). After stirring for one hour at room temperature, sodium cyanoborohydride (500 mg) was added. The solution was. stirred for 3 hours and then was poured into saturated sodium bicarbonate solution (200 ml). The product was extracted. into dichloromethane (2 x 200 ml) and the combined extracts were dried (Na2SO4) and filtered. The filtrate was evaporated and the residue (0.9 g) was dissolved in dichloromethane and separated by flash chromatography on silica gel (Grace 60), eluting with a linear gradient of 1 liter of dichloromethane-methanolconc. ammonium hydroxide (90:10:0.5) and 1 liter of dichloromethane-methanol-conc. ammonium hydroxide (75:25:0.5). Fractions containing the desired product were located by tlc analysis, combined and evaporated under reduced pressure to yield 0.14 g of the title compound. Example 5 20-N-BenzYlamino-20-deoxnt-20-dihydro-ONT Using a procedure like that of Example 4, OMT (2.2 g) and benzylamine (4.1 ml) in methanol (60 ml) were treated with sodium cyanoborohydride (1.0 g). After extractive workup, the crude product was purified by silica gel chromatography on a Waters Prep 500 instrument, eluting with a linear gradient of dichloromethane (4 L) and dichloromethane-methanol-conc. ammonium hydroxide (90:10:0.5, 4 L), to yield 0.21 g of the title compound. Example 6 20-N-Dimethylamino-20-deoxy-20-dihydlro-OMT Using a procedure like that of Example 4, OMT (1.2 g) and dimethylamine hydrochloride (1.6 g) in methanol (40 ml) were treated with sodium cyanoborohydride (0.5 g). After extractive workup and purification by silica gel chromtography as described in example 5, 0.61 g of the title compound was obtained. Example 7 20-N-Benzylamino-20-deoxy-20-dihydro-DMOT Using a procedure like that of Example 4, DMOT (1.56 g) and benzylamine (4.0 ml) in methanol (60 ml) were treated with sodium cyanoborohydride (1 g). After extractive workup, the crude product was purified by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (1 L) and dichloro methane-methanol (3:1, 1 L) to yield 0.24 g of the title compound. Example 8 2 0-N-Phenethylamino-2 0-deoxy-20-dihydro-DMT DMT (10.4 g) and phenethylamine (2.8 ml) were dissolved in dry methanol (420 ml) and the solution was stirred for 30 minutes at room temperature. Sodium cyanoborohydride (3.5 g) was added and the solution was stirred for 2.5 hours. The solution was poured into saturated sodium bicarbonate solution (1 1) and the product was extracted into dichloromethane (4 x 500 ml). The combined extracts were dried (Na2SO4) and filtered and the filtrate was evaporated. The residue was dissolved in a small volume of dichloromethane and separated by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane-methanol-conc. ammonium hydroxide (1 L of 125:1:0.1 to 1 L of 100:10:1) followed by an additional 1 L of the latter solvent mixture. Fractions containing the desired product were located by tlc analysis, combined and evaporated to yield 2.8 g of the title compound. Example 9 2 0-N-Phenethylamino-2 0-deoxy-2 0-dihydro-OMT 20-N-Phenethylamino-20-deoxy-20-dihydro-DMT (1.5 g) was dissolved in 1N sulfuric acid (60 ml) and stirred for 1 hour at room temperature. The solution was slowly poured into saturated sodium bicarbonate solution (500 ml) and the product was extracted into dichloromethane (3 x 300 ml). The combined extracts were dried (Na2SO4) and filtered and the filtrate was evaporated under reduced pressure to yield 0.88 g of the title compound. Example 10 20, 23-Di-N-phthalimido-20, 23-dideoxy-20- dihydro-DMT 20-Dihydro-DMT (1.49 g, 2.0 mmol), triphenylphosphine (2.1 g, 8 mmol) and phthalimide (1.18 g, 8.0 mmol) were dissolved in tetrahydrofuran (50 ml) under an argon atmosphere. Diethyl azodicarboxylate (1.4 g, 8 mmol) was added dropwise and the solution was stirred for 30 minutes at room temperature. Methanol (about I ml) was added to decompose excess reagent and, after stirring for 10 minutes, the solution was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and 0.1 M acetic acid (100 ml each) and a few ml of petroleum ether were added to break the emulsion that formed. The aqueous layer was separated, made alkaline with solid sodium bicarbonate and extracted with dichloromethane. The organic extracts were dried (Na2 SO4) and filtered and the filtrate was evaporated. The residue was dissolved in a small volume of dichloromethane and separated by flash chromatography on silica gel, eluting first with dichloromethane (300 ml) followed by a linear gradient of dichloromethane (1 L) and 9% methanol in dichloromethane (I L). Fractions containing the desired product were located by tlc analysis, combined and evaporated to dryness to yield 0.17 g of the title compound. Example 11 20,23-Di-N-Phthalimido-20,23-dideoxv-20- dihydro-OMT 20,23-Di-N-phthalimido-20,23-dideoxy-20dihydro-DMT (100 mg) was dissolved in 1N sulfuric acid (10 ml) and dioxane (3 ml) and stirred for 1 hr at room temperature. The reaction was then neutralized with solid sodium bicarbonate and extracted with dichloromethane twice. The combined extracts were dried (Na2SO4) and filtered and the filtrate was evaporated to.dryness under reduced pressure and then dried in vacuo to yield the title compound. Example 12 20-N-Phthalimido-20-deoxy-20-dihydro-DMO 20-Dihydro-DMOT (3.64 g, 5 mmol), triphenylphosphine (2.62 g, 10 mmol) and phthalimide (1.47 g, 10 mmol) were dissolved in tetrahydrofuran (40 ml) under a nitrogen atmosphere. The solution'was treated dropwise with diethyl azodicarboxylate (1.58 ml, 10 mmol) and then stirred for 1 hr at room temperature. The excess reagant was quenched with methanol (25 ml) and the solution was evaporated under reduced pressure. The residue was dissolved in a small volume of dichloromethane and separated by flash chromatography on silica gel, eluting with dichloromethane (1 L) followed by a linear gradient of dichloromethane (1 L) and 5% methanol in dichloromethane (1 L). Fractions containing the desired product were located by tic analysis, combined and evaporated to dryness to yield 2.44 g of the title compound. Example 13 20-N-Phthalimido-2 0-deoxy-20-dihydro-DMT In a manner analogous to that of example 12, 20-dihydro-DMT (2.96 g), triphenylphosphine (2.0 g) and phthalimide (1.18 g) were dissolved in tetrahydrofuran (35 ml) and treated with diethyl azodicarboxylate (1.4 ml). Since tic analysis of the reaction mixture after 30 minutes showed a significant amount of unreacted 20-dihydro-DMT in addition to a mono-substituted and a di- substituted derivative, additional phthalimide (296 mg), triphenylphosphine (523 mg) and diethyl azodicarboxylate (0.33 ml), were added. After stirring for an additional 0.5 hr at room temperature, the reaction was quenched with methanol and worked up as described in example 12 to yield, from chromatography on silica gel as described above, 0.79 g of 20-N-phthalimido-20-deoxy-20-dihydro-DMT along with 2.16 g of 20,23-di-N-phthalimido-20,23-dideoxy-20-dihydro-DMT. Example 14 20-N-Phthalmrdo-20-deoxo-20-dihodro-DOMT 20-N-Phthalimido-20-deoxy-20-dihydro-DMOT (1.0 g) was dissolved in 1N sulfuric acid (80 ml) and stirred for 1 hr at room temperature. The solution was slowly added to saturated sodium bicarbonate solution (500 ml) and then was extracted with dichloromethane (3 x 300 ml). The combined extracts were dried (Na2SO4) and filtered and the filtrate was evaporated under reduced pressure to yield 0.50 g of the title compound. Example 15 20-N-Phthalimido-20-deoxy-20-dihydro-OMT 20-N-Phthalimido-20-deoxy-20-dihydro-DMT (355 mg) was hydrolyzed in 1N sulfuric acid (50 ml) for 1 hr. After workup as described in example 14, 170 mg of the title compound was obtained. Example 16 20, 23-Di-O-phenyl-20-dihydro-OMT 20-Dihydro-OMT (1 g, 1.7 mmol), triphenylphosphine (1.3 g, 5.1 mmol) and phenol (0.47 g, 5.1 mmol) were dissolved in tetrahydrofuran (30 ml) under a nitrogen atmosphere. The solution was cooled in an ice bath and treated with diethyl azodicarboxylate (0.89 g, 5.1 mmol) over a 2-minute period. The cooling bath was removed and the solution was stirred for 1 hr at room temperature. Methanol (10 ml) was added and, after stirring for 15 minutes, the solution was evaporated under reduced pressure. The residual oil was treated with toluene and the white insoluble material was filtered. The filtrate was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, dried (Na2SO4) and filtered and the filtrate was evaporated. The residue was separated by flash chromatography on silica gel, eluting with mixtures of methanol-dichloromethane as follows: 400 ml of 0%, 250 ml of 2%, 250 ml of 3%, 500 ml of 4% and 250 ml each of 6%, 8%, 10% and 16% methanol in dichloromethane. Fractions containing the desired product were located by tIc analysis, combined and evaporated to yield 144 mg of 20,23-di-O-phenyl-20-dihydro-OMT. Preparation Example 17 20-Dihydro-23-0-phenylpropionyl-OMT 23-O-Phenylpropionyl-OBT (1.9 g, 2.6 mmol) was dissolved in 1:1 isopropanol:water (30 ml). Sodium borohydride (0.025 g, 0.65 mmol) was added to this solution and the reaction was stirred for 0.5 hr. The pH of the reaction was adjusted from pH 10.5 to pH 7.0 with IN sulfuric acid. The solution was concentrated to aqueous under reduced pressure and saturated NaHCO3 solution was added. The product was extracted into dichloromethane and the extracts were dried (Na2SO4) and filtered. The filtrate was evaporated under reduced pressure to yield 1.75 g (92%) of the title compound as a white foam. Example 18 20-Dihydro-23-Octahydroazocin-1-yl-23-deoxy OMT 23-Octahydroazocin-l-yl-OMT (900 mg, 1.3 mmol) was reduced with sodium borohydride (12 mg, 0.33 mmol) in 1:1 isopropanol-water (15 ml) as described in example 17, yielding 815 mg (90%) of the 20-dihydro derivative. Example 19 20-O-Phensl-20-dihvdro-23-O-chenslpropionyl- OMT 20-Dihydro-23-O-phenylpropionyl-OXT (1.7 g, 2.3 mmol), triphenylphosphine (1.2 g, 4.6 mmol) and phenol (0.43 g, 4.6 mmol) were dissolved in tetrahydrofuran (45 ml) under a nitrogen atmosphere. The solution was cooled in an ice bath and then was treated dropwise with diethyl azodicarboxylate (0.8 g, 4.6 mmol). After 5 minutes, the cooling bath was removed and the solution was stirred for 2 hr at room temperature. Since tlc analysis of the reaction indicated the presence of unreacted starting material, one-half of the initial amounts (2.3 mmol) of triphenylphosphine, phenol and diethyl azodicarboxylate were each added. After stirring for another 30 minutes, methanol (10 ml) was added to decompose excess reagent and the solution was evaporated under reduced pressure. The residual oil was treated with toluene and the insoluble material was filtered. The filtrate was evaporated under reduced pressure and the residue was separated by flash chromatography on silica gel, eluting step-wise with mixtures of methanol-dichloromethane as follows: 400 ml of 0%, 250 ml of 2%, 250 ml. of 4%, 750 my of 6% and 250 ml of 8% methanol in dichloromethane. Fractions containing the desired product were located by tlc analysis, combined and evaporated under reduced pressure to yield 0.26 g of 20-O-phenyl-20-dihydro-23-O-phenylpropionyl OMT, Example 20 20-O-Phenyl-20-dihydlro-23-Octahydroazocin-1 y1-OMT 20-Dihydro-23-octahydroazocin-1-yl-OMT (800 mg, 1.2 mmol), triphenylphosphine (940 mg, 3.6 mmol) and phenol (340 mg, 3.6 mmol) were dissolved in tetrahydrofuran (20 ml). The solution was treated with diethyl azodicarboxylate (630 mg, 3.6 mmol), stirred for 1 hour, and worked up as described in example 19. The crude product was purified by flash chromatography on silica gel, eluting stepwise with mixtures of methanol-dichloromethane as follows: 400 ml of 0%, 250 ml of 2%, 500 ml of 3%, 250 ml each of 4%, 6%, 8%, 12% and 16% methanol in dichloromethane. Fractions containing the desired product were located by tIc analysis, combined and evaporated to yield 90 mg of the title compound. Example 21 2' ,4' , 23-Tri-O-acetyl-20-deoxy-20-dihydro-ONT 20-Deoxy-20-dihydro-OMT (5 g) was dissolved in pyridine (70 ml). The solution was treated with acetic anhydride (4 ml) and then was stirred overnight at room temperature. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane and cyclohexane and then re-evaporated te remove most of the pyridine. The residue was dissolved in dichloromethane, extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was redissolved and re-evaporated to remove pyridine as before and finally was suspended in hexane and filtered. The solid residue (5.3 g) was separated on a Waters Prep 500 chromatograph over silica gel, eluting with a linear gradient of toluene (1 L) and toluene-ethyl acetate (1:3, 1 L). Fractions containing the desired product were located by tIc analysis, combined and evaporated to dryness to yield 3.72 g of 2',4',23-tri-O-acetyl-20deoxy-20-dihydro-OMT. Example 22 23 -O-Phenylacetyl-20-deoxy-20-dihydro-OMT 20-Deoxy-20-dihydro-OMT (2 g, 3.4 mmol) was dissolved in dichloromethane (40 ml) and pyridine (0.55 ml). The solution was cooled to -789 and treated with phenylacetyl chloride (0.55 ml, 4.1 mmol). The cooling bath was removed and the reaction was allowed to warm to room temperature and then stirred for an additional 0.5 hr at room temperature. Since tlc analysis of the reaction showed the presence of starting material, the solution was again cooled to -780 and treated with additional phenylacetyl chloride (0.35 ml). Sequence was repeated again, using 0.08 ml of phenylacetyl chloride the final time. The final reaction mixture was extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was separated by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (1 L) and 20% methanol in dichloromethane (I L). Fractions containing the desired product were identified by tIc analysis, combined and evaporated to yield the title compound Example 23 23-Phenylthio-20,23-dideoxy-20-dihydro-OMT 20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 mmol) was dissolved in dichloromethane (40 ml) and s-collidine (1.36 ml). The solution was cooled to -780 and treated with triflic anhydride (1.0 ml initially, then 0.3 ml additionally); thiophenol (1.25 ml) was added at -780 and the mixture was stirred at -789 for 1.5 hr. The reaction was stirred for another 2.5 hr while warming to room temperature and then was extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated and the residue was washed with hexane and then separated by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (1 L) and 20% methanol in dichloromethane (1 L). Fractions containing the desired product were located by tIc analysis, combined and evaporated to yield 700 mg of the title compound. Example 24 23-Octahydroazocin-1-yl-20,23-dideoxy-20 dihydro-OEa 23-Iodo-2Q,23-dideoxy-20-dihydro-OMT (69 mg) and heptamethyleneimine (0.05 ml) were dissolved in acetonitrile (2 ml) and the solution was refluxed for 2 hr under an argon atmosphere. The solution was cooled to room temperature and poured into saturated sodium bicarbonate solution (10 ml). The product was extracted into dichloromethane and the extracts were dried (Na2SO4) and filtered. The filtrate was evaporated and the residue was separated by preparative tlc on a 20 x 20 cm, 2 mm thick plate of silica gel (E. Merck), developing with dichloromethane-methanol-conc. ammonium hydroxide (90:10:2). The band on the silica gel plate was located by. Uv light and was scraped from the plate, dried in vacuo to remove solvent and then eluted with dichloromethane-methanol (1:1, 50 ml) for 45 minutes. The mixture was filtered and the filtrate was evaporated to dryness to yield 65 mg of the title compound. Example 25 23- (4-Hydroxypiperidino ) -20, 23-dideoxy-20- dihydro -OMT 23-Iodo-20,23-dideoxy-20-dihydro-OMT (1.1 g, 1.6 mmol) and 4-hydroxypiperidine (0.32 g, 3.2 mmol) were dissolved in acetonitrile (20 ml) and refluxed under an argon atmosphere for 2 hr. Additional 4hydroxypiperidine (300 mg) was added to consume unreacted starting material and the solution was refluxed for an additional 3 hr. The solution was cooled to room temperature and then evaporated under reduced pressure. The residue was dissolved in dichloromethane, extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting with a linear gradient of dichloromethane (1 L) and 12% methanol in dichloromethane (1 L). Fractions containing the desired product were located by tIc analysis, combined and evaporated to yield 865 mg of the title compound. Example 26 23-0-(2,3-DimethoxYPhenol3-20-deoxY-20-dihYdro OMT 20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 mmol), triphenylphosphine (2.7 g, 10.3 mmol) and 2,3-dimethoxyphenol (1.59 g, 10.3 mmol) were dissolved in tetrahydrofuran (150 ml) under an argon atmosphere. The solution was treated with diethyl azodicarboxylate (1.7 ml, 10.3 mmol) and then was stirred for 40 minutes at room temperature. Methanol (2 ml) was added to decompose excess reagent and the solution was evaporated to dryness under reduced pressure. The residue was taken up in toluene and the insoluble material was filtered. The filtrate was extracted with saturated sodium bicarbonate solution, dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (Waters Prep 500), eluting with dichloromethane (2 L) followed by a linear gradient of dichloromethane (2 L) and 10% methanol in dichloromethane (2 L); the column was finally eluted with 2 L of the latter solvent. Fractions containing the desired product were located by tic analysis, combined and evaporated to yield 2.06 q (54%) of the title compound. Example 27 23-0- ( 3-Pyridyl )-20 ,23-dideoxv-20-dihydro-OMT 20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 mmol), triphenylphosphine (2.7 g, 10.3 mmol) and 3-hydroxypyridine (979 mg, 10.3 mmol) were dissolved in tetrahydrofuran (50 ml) under an argon atmosphere and treated with diethyl azodicarboxylate (1.7 ml, 10.3 mmol). After workup and chromatography as described in example 26, 0.63 g of the title compound was obtained. Example 28 23-0- (m-Dimethylaminophenyl ) -20-deoxy-20- dihydro-OMT 20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 mmol), triphenylphosphine (2.7 g, 10.3 mmol) and m-dimethylaminophenol (1.4 g, 10.3 mmol) were dissolved in tetrahydrofuran (50 ml) under an argon atmosphere. Diethyl azodicarboxylate (1.7 ml, 10.3 mmol) was added and the solution was stirred for 1 hr at room temperature. Since starting material had not been consumed at this point, additional triphenylphosphine (1.35 g), m-dimethylaminophenol (0.70 g) and diethyl azodicarboxylate (0.85 ml) were added and the solution was stirred for another 0.5 hr. MeOH (about 3 ml) was then added to quench the reaction and the solution was evaporated under reduced pressure. The residue was worked up as described in example 26 and purified by chromatography on silica gel (Waters Prep 500), eluting with dichloromethane (2 L) followed by a linear gradient of dichloromethane (4 L) and 15% methanol in dichloromethane (4 L). Fractions containing the desired product were located by tlc analysis, combined and evaporated to dryness to yield 1.12 g of the title compound as a purple glassy solid. Example 29 20 -Diphenylamino-2 0-deoxv-2 0-dihydro-OMT OMT (3.0 g, 5 mmol) was dissolved in dimethylformamide (10 ml) and the solution was diluted with toluene (100 ml). Diphenylamine (1.69 g, 10 mmol) and -toluenesulfonic acid hydrate (150 mg) were added and the solution was refluxed using a Dean-Stark trap to separate water. After 4 hr, 20 ml of condensate was withdrawn and the solution was refluxed overnight. The solution was cooled td room temperature and evaporated under reduced pressure. The residue was dissolved in a solution of sodium cyanoborohydride (1.25 g) in dry methanol (75 ml) and the solution was stirred for 2 hr at room temperature. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (75 ml) and water (75 ml). The organic layer was separated and then extracted with 0.5 M, pH 6.5 phosphate buffer (75 ml) and with 0.5 M, pH 4.5 phosphate buffer (2 x 75 ml). The combined latter extracts were back-extracted with ethyl acetate (75 ml) and the combined ethyl acetate solutions were dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in a small volume of dichloromethane, filtered and purified by chromatography on silica gel (Waters Prep 500), eluting with a linear gradient of dichloromethane (4 L) and 5% methanol plus 0.5% conc. ammonium hydroxide in dichloromethane (4 L) followed by 3 L of the latter solvent mixture. The fraction containing the desired compound was located by the analysis and was evaporated to dryness to yield 113 mg of the title compound. Example 30 20-DH-DO-20- F3-Azabicyclo (3.2.2) -nonan-3-yl J -OMT OMT (3.0 g., 5.0 mmoles) was dissolved in anhydrous methanol (15 ml.). 3-Azabicyclo[3.2.2]-nonane (1.25 g., 10 mmoles) was dissolved in anhydrous methanol (15 ml.) and filtered to remove a white impurity. The filtrate was added to the OMT solution and the resulting solution was stirred for 5-10 minutes at room temperature in the presence of molecular sieves (3A). NaBH3CN (0.63 g., 10 mmoles) was added, and the reaction was stirred at room temperature for 17 hours. The reaction mixture was filtered, and the filtrate was evaporated under vacuum to give a foam which was redissolved in ethyl acetate (150 ml.). The ethyl acetate solution was washed with water (150 ml.) and separated. A major portion of the product was then extracted from the ethyl acetate solution with 0.5M NaH2PO4 buffer (150 ml., pH 6.5). The phosphate buffer solution was evaporated under vacuum to remove residual ethyl acetate. The pH of the buffer solution was adjusted to about 11 with 5N NaOH, forming a white precipitate which was collected by filtration and dried to give 2.06 g. (58% yield) of 20-DH-DO-20-[3-azabicyclo(3.2.2)nonan-3-yl]OMT. [Titration PKa values: 7.7 and 9.3; FDMS parent ion (M+ + 1) = 707J. Example 31 20-DH-DO-20-Morpholino-OMT Following the procedure outlined in Example I, OMT (3.0 g., 5.0 mmoles), morpholine (0.87 ml., 10 mmoles), NaBH3CN (0.31 g., 5 mmoles) and anhydrous MeOH (30 ml.) were reacted in the presence of molecular sieves (3A). Since a precipitate did not form when the pH of the buffer was adjusted to 11, the product was extracted from the buffer with CH2C12 to give 1.66 g. (50% yield) of 20-DH-DO-20-morpholino-OME as a white foam. [Titration pKa values: 6.5, 8.4; FDMS parent ion (M + 1) = 669J. Example 32 20-DH-DO-20-(4-Phenylpiperidin-1-yl)-OMT OMT (5.97 g., 10 mmoles), 4-phenylpiperidine (3.22 g., 20 mmoles), NaBH2CN (1.25 g., 20 mmoles) and methanol (60 ml.) were reacted using the procedure of Example 1, but substituting a pH 4.5 buffer for extraction, to give 3.7 g. of the title compound [FDMS parent ion (M+ + 1) = 743J. Example 33 gO-DH-DO-23-Deoxy-20,23-di(octahydroazocin-1-yl)-OMT 20,23-di-iodo-OMT (1.2 g., 1.5 mmoles) was dissolved in acetonitrile (20 ml.). Heptamethyleneimine (1.7 g., 1.9 ml;, 15 mmoles) was added to this solution, and the reaction mixture was stirred at reflux for 1.5 hours. Volatiles were removed, and the resulting red oil was dissolved in CE2C12 (150 ml.). This solution was washed with saturated NaHCO3 solution (100 ml.) and the CE2C12 phase was separated and dried over Na2SO4, filtered, and evaporated under vacuum. The residue obtained was subjected to flash column chromatography on silica gel 60 packed in MeOH/CH2C12 (1:9). The column was eluted stepwise with MeOH/CH2C12 as follows: 300 ml. of 1:9, 500 ml. of 1:4, 250 ml. of 3:7, 250 ml. of 2:3, 500 ml. of 1:1, and 500 ml. of 7:3. The desired fractions were combined to give 221 mg. (19% yield) of 20-DH-DO-23-deoxy-20,23-di(octahydroazocin-1-yl)-OMT as a white foam. [Titration pK, values: 6.9, 8.05, 8.9; FDMS parent ion (M+ + 1) = 790]. Examples 34-56 The following compounds can be prepared by the methods of the preceding examples. 20-DH-DO-20-(octahydroazocin-l-yl)DMT 20-DH-DO-20- (piperidin-l-yl )DMOT 20-DH-DO-20-(piperidin-1-yl)DOMT 20-DH-DO-20-(4-hydroxypiperidin-1-yl)DOMT 20-DH-DO-20-(decahydroazecin-1-yl)OMT 20-DH-DO-20-(octahydroazocin-1-yl)DOMT 20-DH-DO-20-(azacyclotridecan-1-yl)OMT 20-DH-DO-20-(hexahydroazepin-1-yl)DMT 20-DH-DO-20-(1,2,3,4-tetrahydroisoquinolin2-yl)OMT 20-DH-DO-20-(1,2,3,4-tetrahydroisoquinolinyl)OMT 20-DH-DO-20-(azacycloundecan-1-yl)OMT 20-DH-DO-20-(4-methylpiperidin-1-yl)OMT 20-DE-DO-20-(pyrrolidin-1-yl)DMT 20-DH-DO-20-(octahydro-1H-azonin-1-yl)OMT 20-DH-DO-20- (octahydroazocin-1-yl )DMOT 20-DH-DO-20-(octahydroazocin-1-yl)DOMT 20-DH-DO-20-(4-phenylpiperidin-1-yl)DMT 20-DH-DO-20-(4-phenylpiperidin-1-yl)-4'-deoxy OMT 20-DH-DO-20-(decahydroazecin-1-yl)-4' <RTI ID=78.4> deoxy-OMI' 20-DH-DO-20-(hexahydroazepin-1-yl)-4' deoxy-OMT 20-DH-DO-20-(1,2,3,4-tetrahydroisoquinolin 2-yl )DOMT 20-DH-DO-20-(decahydrocyclopent[c]azepin 1-yl )CMT' 20-DH-DO-20-(7-azabicyclo[2.2.1]heptan-1-yl)OMT Example 57 Injectable Formulations A) A formula (I) 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 (I) base. C) A solution is prepared as described in Section A except that the solution contains 350 mg/ml of a formula (I) base. D) A solution is prepared as described in Section A except that the solution contains 500 mg/ml of a formula (I) tartrate. E) A suspension is prepared by adding a finely ground formula (I) compound to carboxymethyl cellulose with thorough mixing so that the suspension contains 200 mg of the formula (I) base per ml of suspension. 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. The methods of formulating drugs into animal feeds are well-known. A preferred method is to make a concentrated-drug premis 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). 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 suspending agents. Supplemental Data For Compounds Prepared In The Example Field Desorption UV IR NMR Mass Spectrum #max(s) Most Intense Selected Example (parent ion) (ETOH) Y co (CHCl3) & (CDCl3) 1 801 282 nm (20,200) 1743 cm-1 7.28-7.33 (phenyl) (compound 46) end absorption 2.31 (CH2CO) 2.03, 2.05 (OAc) 1 919 279 nm (21,300) 1790 cm-1 7.20-7.33 (phenyl) (compound 47) end absorption 2.31 (CH2CO) 2.03 (OAc) 2 717 283 nm (21,300) 1720 cm-1 7.22-7.32 (m, phenyl) end absorption 2.48 (s, CH2CO) 3 835 280 nm (21,200) 1730 cm-1 7.22-7.35 (m, phenyl) end absorption 7.50 (s, CH2CO) 10 1001 280 nm (20,000) 1713 cm-1 - 219 nm (76,300) 11 857 280 nm (19,000) 1713 cm-1 - 219 nm (71,400) 12 857 282 nm (20,200) 1710 cm-1 7.26, 7.22-7.76, 219 nm (44,500) 7.94 (aromatic) 13 873 282 nm (20,500) 1711 cm-1 7.28, 7.73-7.78 7.95 (aromatic) EMI82.1 <SEP> Field <tb> <SEP> Desorption <SEP> UV <SEP> IR <SEP> NMR <tb> <SEP> Mass <SEP> Spectrum <SEP> #max(s) <SEP> Most <SEP> Intense <SEP> Selected <tb> Example <SEP> (parent <SEP> ion) <SEP> (ETOH) <SEP> Y <SEP> co <SEP> (CHCl3) <SEP> & (CDCl3) <tb> 14 <SEP> 712 <SEP> 282 <SEP> nm <SEP> (20,000) <SEP> 1710 <SEP> cm-1 <SEP> 7.27, <SEP> 7.72-7.76, <tb> <SEP> 219 <SEP> nm <SEP> (43,300) <SEP> 7.94 <SEP> (aromatic) <tb> 15 <SEP> 728 <SEP> 282 <SEP> nm <SEP> (21,200) <SEP> 1710 <SEP> cm-1 <SEP> 7.28, <SEP> 7.74-7.78 <tb> <SEP> 220 <SEP> nm <SEP> (44,700) <SEP> 7.96 <SEP> (aromatic) <tb> 16 <SEP> 752 <SEP> - <SEP> - <SEP> # <tb> <SEP> # <tb> 17 <SEP> 731 <SEP> - <SEP> - <SEP> 7.10-7.30 <SEP> phenyl <tb> <SEP> ring, <SEP> m <tb> 18 <SEP> 695 <SEP> - <SEP> - <SEP> 1.46 <SEP> broad <SEP> singlet, <tb> <SEP> CH2 <SEP> protons-non <tb> <SEP> amine <SEP> adjacent <SEP> form <SEP> beptamethylene <tb> <SEP> amino <SEP> group. <tb> EMI83.1 <SEP> Field <tb> <SEP> Desorption <SEP> UV <SEP> IR <SEP> NMR <tb> <SEP> Mass <SEP> Spectrum <SEP> #max(s) <SEP> Most <SEP> Intense <SEP> Selected <tb> Example <SEP> (parent <SEP> ion) <SEP> (ETOH) <SEP> Y <SEP> co <SEP> (CHCl3) <SEP> & (CDCl3) <tb> 19 <SEP> 807 <SEP> 279 <SEP> nm <SEP> (21,705) <SEP> - <SEP> # <tb> <SEP> end <SEP> absorption <SEP> # <tb> 20 <SEP> 771 <SEP> 279 <SEP> (11,000) <SEP> - <SEP> # <tb> <SEP> 220 <SEP> (11,250) <tb> <SEP> # <tb> 21 <SEP> 709 <SEP> 279 <SEP> nm <SEP> (21,400) <SEP> 1743 <SEP> cm-1 <SEP> 2,06 <SEP> (2',4'-Ac) <tb> <SEP> 2.35 <SEP> (23-Ac) <tb> Field Desorption UV IR NMR Mass Spectrum #max(s) Most Intense Selected Example (parent ion) (ETOH) Y co (CHCl3) & (CDCl3) 22 701 279 nm (18,500) 1734 cm-1 7.30 (m, phenyl) end absorption 2.60 (s, CH2CO) 23 675 281 nm (22,500) 1714 cm-1 7.40 (m, phenyl) end absorption 24 679 284 (19,000) 1715 cm-1 1,48, 1.52 (CH2) 25 666 283 (17,500) 1715 cm-1 no data 26 719 280 (22,200) 1715 cm-1 3.82, 3.86 (OCH3) 220 sh (11,00) end absorption 27 661 278 (24,000) 1716 cm-1 8.08-8.39 (aromatic) 216 (9,700) 28 702 282 (22,500) 1716 cm-1 7.1-7.26 (aromatic) 258 (18,200) 2.95 (NMe2) 211 (30,000)

Claims: CLAIMS 1. A macrolide of the formula (I): EMI85.1 wherein R is hydrogen, iodo, bromo, chloro, fluoro, cyano, -OR4, -OAr, -sR5 azido, -NR6R7, N-phthalimido or R9; R1 is i) hydrogen or -OH; ii) chloro, fluoro, bromo, iodo -OAr, -O-tetra- hydrofuranyl, -o-tetrahydropyranyl, -SR5, azido, -NR6R7, or N-phthalimido; or R9; R9 is i) a monocyclic amino group of the formula -N(CX2)n which is optionally substituted at one or more of the carbon atoms by a Cl-C3-alkyl, hydroxyl, methoxyl, ethoxyl, o -N(R8)2, -C-N(R8)2, carbomethoxy, carboethoxy, or phenyl group; and n is an integer from 4 through.15; ii) a monocylic saturated or unsaturated nitrogen-containing heterocyclic ring bonded through the nitrogen atom, said ring having 1) from 5 to 7 ring atoms which include up to 3 additional hetero atoms selected from nitrogen, oxygen and sulfur, and 2) up to 3 substituent groups selected from methyl, ethyl and phenyl; or iii) a bicyclic or tricyclic secondary amino group selected from 1,2,3,4-tetrahydro quinolin-1-yl; decahydroquinoluin-1-yl ; 1,2,3,4-tetrahydroisoquinolin-2-yl ; decahydroisoquinolin-2-yl ; indolin-1-yl ; isoindolin-2-yl ; decahydrocyclohepta[b] pyrrol-1-yl; decahydrocycloheptaEc] pyrrol-2-yl ; decahydrocyclopent[c] azepin-2-yl; decahydrocyclopent [dJ - azepin-3-yl ; 2,3,4,5-tetrahydro-1H-2 benzazepin-2-yl ; 2,3,4,5-tetrahydro 1H-3-benzazepin-3-yl ; azabicycloheptanyl ; azabicyclooctanyl; azabicyclononanyl; azabicyclodecanyl or azatricyclodecanyl ; Rê is hydrogen, optionally substituted C1-C5 alkanoyl or optionally substituted benzoyl, phenylacetyl or phenylpropionyl; R3 is hydrogen, hydroxyl, optionally substituted C1-C5-alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or EMI87.1 (mycarosyloxy) R4 is hydrogen, optionally substituted C1-C4-alkyl, cyclohexyl, optionally substituted benzyl, phenethyl or phenoxyethyl; Ar is i) phenyl, derivatized phenyl, or naphthyl; ii) an optionally substituted heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoquinolinyl, quinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxazolyl, benzimidazolyl, carbazolyl, or acridinyl; ; or iii) optionally substituted Cl-C5-alkanoyl; optionally substituted benzoyl, phenyl acetyl, phenylpropionyl, phenoxyacetyl or phenyithioacetyl; methanesulfonyl; trifluoromethanesulfonyl; or optionally substituted phenylsulfonyl; R5is optionally substituted C1-C4-alkyl; cyclo hexyl; optionally substituted phenyl, benzyl or phenethyl; or an optionally substituted heteroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl and furanyl; R6 is hydrogen, optionally substituted Cl-C6-alkyl, phenyl, benzyl, phenethyl or C3-C8-cycloalkyl ; R7is an R6 group or optionally substituted C1-C5- alkanoyl, optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl -or phenylthioacetyl, or alkoxycarbonyl; and R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl or the R8 groups taken together form a poly methylene moisty such that -N(R8)2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl; provided 1) that, when R or R4 is hydrogen, R1 cannot be hydrogen or -OH; 2) that, when R or R1is NHR6 or R4 or R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen, hydroxyl, or mycarosyloxy and Ar cannot be a type (iii) substituent; 3) that, when R2 is hydrogen, R3 must be hydrogen, hydroxyl or mycarosyloxy; 4) when R1 is hydrogen or hydroxy, R is not NR6R7, or a physiologically acceptable salt thereof. 2. A macrolide of formula (I) as claimed in claim 1 wherein R is R9. 3. A macrolide of formula (I) as claimed in claim 1 wherein R is hydrogen, iodo, bromo, chloro, fluoro, cyano, oR4, -OAr, SR5, azido, NR6R71 or N-phthalimido. 4. A macrolide of formula (I) as claimed in claim 1 wherein R is hydrogen, hydroxy, phenoxy, N-phthalimido, phenylacetoxy, 3-azabicyclo(3 .2.2)- nonan-3-yl, morpholino, 4-phenylpiperidin-1-yl, or octahydroazocin-l-yl. 5. A macrolide of formula (I) as claimed in claim 1 wherein R1 is hydrogen, hydroxy, phenoxy, acetoxy, phenylacetoxy, N-phthalimido, phenylpropionyloxy, phenylthio, octahydroazocin-l-yl, 4-hydroxypiperidino, 2,3-dimethoxyphenoxy, 3-pyridyloxy, or m-dimethylaminophenoxy. 6. A process for preparing a macrolide of formula (I): EMI90.1 wherein R is hydrogen, iodo, bromo, chloro, fluoro, cyano, -OR4, -OAr, -SR5, azido, -NR6R7, N-phthalimido or R9; R1 is i) hydrogen or -OH ; ii) chloro, fluoro, bromo, iodo -OAr, -O-tetra hydrofuranyl, -O-tetrahydropyranyl, -SR5, azido, -NR6R7, or N-phthalimido or R9; R9 is i) a monocyclic amino group of the formula -N( ( )n which is optionally substituted at one or more of the carbon atoms by a C1-C3-alkyl, hydroxyl, methoxyl, ethoxyl, -N(R8)2, EMI90.2 carbomethoxy, carboethoxy, or phenyl group; and n is an integer from 4 through 15; ii) a monocylic saturated or unsaturated nitrogen-containing heterocyclic ring bonded through the nitrogen atom, said ring having 1) from 5 to 7 ring atoms which include up to 3 additional hetero atoms selected from nitrogen, oxygen and sulfur, and 2) up to 3 substituent groups selected from methyl, ethyl and phenyl; or iii) a bicyclic or tricyclic secondary amino group selected from 1,2,3,4-tetrahydro quinolin-l-yl; decahydroquinolin-1-yl; 1,2,3,4-tetrahydroisoquinolin-2-yl; decahydroisoquinolin-2-yl; indolin-l-yl; isoindolin-2-yl; decahydrocyclohepta [b] - pyrrol-l-yl; decahydrocyclohepta[c] pyrrol-2-yl; decahydrocyclopent[c]- azepin-2-yl; decahydrocyclopent[d] azepin-3-yl; 2,3,4,5-tetrahydro-fH-2- benzazepin-2-yl; 2,3,4,5-tetrahydro- lH-3-benzazepin-3-yl; azabicycloheptanyl; azabicyclooctanyl; azabicyclononanyl; azabicyclodecanyl or azatricyclodecanyl; R2 is hydrogen, optionally substituted C1-C5 alkanoyl or optionally substituted benzoyl, phenylacetyl or phenylpropionyl; R3is hydrogen, hydroxyl, optionally substituted C1-C5-alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or EMI92.1 (mycarosyloxy) R4 is hydrogen, optionally substituted C1-C4-alkyl, cyclohexyl, optionally substituted benzyl, phenethyl or phenoxyethyl; Ar is i) phenyl, derivatized phenyl, or naphthyl; ; ii) an optionally substituted heteroaryl group selected frompyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tri azinyl, indolyl, isoquinolinyl, quinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxazolyl, benzimidazolyl, carbazolyl, or acridinyl; or iii) optionally substituted C1-C5-alkanoyl; optionally substituted benzoyl, phenyl acetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl; methanesulfonyl; trifluoromethanesulfonyl; or optionally substituted phenylsulfonyl; R5 is optionally substituted C1-C4-alkyl;cyclo- hexyl; optionally substituted phenyl, benzyl or phenethyl; or an optionally substituted heteroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, - triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl and furanyl; R6 is hydrogen, optionally substituted C1-C6-alkyl, phenyl, benzyl, phenethyl or C3-C8-cycloalkyl; is an R6 group or optionally substituted C1-C5 alkanoyl, optionally substituted benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl, or alkoxycarbonyl; and R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl or the R8 groups taken together form-a poly methylene moiety such that -N(R8)2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl ; provided 1) that, when R or R4 is hydrogen, RÚ cannot be hydrogen or -OH ; 2) that, when R or RÚ is -NHR6 or R4 or R8is hydrogen, R2 must be hydrogen, R3 must be hydrogen, hydroxyl, or mycarosyloxy and Ar cannot be a type (iii) substituent; 3) that, when R2is hydrogen, R3 must be hydrogen, hydroxyl or mycarosyloxy ; 4) when RÚ is hydrogen or hydroxy, R is not NR6R7, or a physiologically acceptable salt thereof which comprises: (a) reducing a starting macrolide of formula (II) wherein Q is formyl and QÚ is RÚ, provided RÚ is not hydroxyl, to give a macrolide of formula (I) wherein R is hydroxyl; EMI94.1 (b) reacting a starting macrolide of formula (II) wherein Q is formyl and Q1 is R1 with an amine of the formula HNR6R6 or HR9 in the presence of a reducing agent to give a macrolide of formula (I) wherein R is ER6R6 or R9, or (c) reacting a starting macrolide of formule (II) wherein Q is -CH2OH and QÚ is RÚ with diethylazodicarboxylate or dimethylazodicarboxylate, triphenylphosphine, and a reagent selected from (i) an azide transfer agent, to give a macrolide of formula (I) wherein R is azido, (ii) phthalimide to give a macrolide of formula (I) wherein R is phthalimido, (iii) a phenol of formula ArOH to give a macrolide of formula (I) wherein R is -OAr, where Ar is a category 1) or ii) Ar group, (iv) an alkyl halide or polyhalide to give a macrolide of formula (I) wherein R is Cl, Br, or I, or (v) a mercaptan of formula HSR5 to give a macrolide of formula (I) wherein R is SR5, or (vi) a carboxylic or sulfonic acid of the formula ArOH, where Ar is a category (iii) Ar group, to give a macrolide of formula (I) wherein R is OAr, (d) reacting a starting macrolide of formula (II) wherein Q is -CH2OH and Q1 is R1 with triphenylphosphine and a halogen source to give a macro Ii de of formula (I) wherein R is C1, Br, or I, (e) reacting a starting material of formula (II) wherein Q is -CH2OH and Q1 is R1 with an acylating agent derived from a carboxylic or sulfonic acid of formula ArOH, where Ar is a category (iii) Ar group to give a macrolide of formula (I) wherein R is OAr, or (f) reacting a starting macrolide of formula (II) wherein Q is -CE2L where L is a leaving group and Q1is R1 or a leaving group with (i) an alkali metal azide or halide or a tetraalkylammonium azide or fluoride where alkyl is methyl, ethyl, propyl or butyl, to give a macrolide of formula (I) wherein R is azido, F, Cl, Br, or I, or (ii) a mercaptide ion of formula R5S- to give a macrolide of formula (I) wherein R is R5S-, or (iii) an amine of the formula NR6R5 or HR9 to give a macrolide of formula (I) wherein R is NR6R6 or R9, or (iv) a source of cyanide ion to give a macro lide of formula (I) wherein R is -CN : (v) an alcohol of the formula HOR4 and a source of silver ion to provide a macro lide of formula (I) wherein R is OR4 where R4 is other than hydrogen (g) hydrolyzing a macrolide of formula (II) wherein Q is CH2R and Q1is EMI96.1 to give a macrolide of formula (I) wherein 7 hydroxyl, or (h) removing the hydroxy protecting group from a macrolide of formula (II) wherein Q is -CH2R and this protected hydroxy or (i) reacting a starting macrolide of formula (II) wherein Q is -CH2R and QÚ is hydroxy with diethylazodicarboxylate or dimethylazodicarboxylate, triphenylphosphine, and a reagent selected from (i) an azide transfer agent to give a macroide of formula (I) wherein R1 is azido, (ii) phthalimide to give a macrolide of formula (I) wherein RÚ is phthalimido, (iii) a phenol of formula ArOH where Ar is a category (i) or (ii) Ar group to give a macrolide of formula (I) wherein R1is -OAr, (iv) an alkyl halide or polyhalide to give a -macrolide of formula (I) where R1 is C1, Br, or I, or (v) a mercaptan of formula HSR5 to give a macrolide of formula (I) wherein R is SR5, or (vi) a carboxylic or sulfonic acid of the formula ArOH, where Ar is a category (i) Ar group, to give a macrolide of formula (I) wherein R1 is OAr; or (j) reacting a macrolide of formula.(II) wherein Q is -CH2R and QÚ I is hydroxyl with an acylating agent derived from a carboxylic or sulfonic acid of formula ArOH where Ar is a category (iii) Ar group to give a macrolide of formula (I) wherein RÚ is OAr or (k) reacting a macrolide of formula (II) wherein Q is R and Q1 is hydroxyl with triphenylphosphine and a halogenating agent to give a macrolide of formula (I) wherein R1 is Cl, Br or I, or (1) reacting a macrolide of formula (II) wherein Q is -CH2R and Q1 is a leaving group with (i) an alkali metal azide or halide or a tetraalkyl ammonium azide or fluoride where alkyl is methyl, ethyl, propyl, or methyl to give a macrolide of formula (I) wherein R1 is azido, F, Cl, Br, or I, (ii) a mercaptide ion of formula R5 S- to give a macroide of formula I wherein RÚ is R5S-, or (iii) an amine of the formula HNR6R6 or HR9 to give a macrolide of formula (I) wherein RÚ is HR6R6 or R9, or (m) reducing a macrolide of formula (II) wherein Q is -CH2N3 and QÚ is RÚ or Q is R and QÚ is azido to give a macrolide of formula (I) wherein R is CH2NH2 or RÚ is amino, or n) acylating a macrolide of formula (II) wherein Q is -CH2NHR6 or RÚ is NHR6 to give a macrolide of formula (I) wherein R is -CHêNHR7 or RÚ is -NR6R7, or (o) esterifying a macrolide of formula (I), or (p) salifying a macrolide of formula (I), or (q) hydrolyzing a macrolide of formula (I) wherein R3 is mycarosyloxy in acid solution at a pH below 4 to give a macrolide of formula (I) wherein R3 is hydroxy, or (r) deoxygenating a macrolide of formula (I) wherein R3 is hydroxy to give a macrolide of formula (I) wherein R3is hydrogen. (s) reacting a macrolide of formula (II) wherein Q is CE2I and Q1 is R1 with a reducing agent to give a compound of formula (I) wherein R is hydrogen, or (t) reacting a macrolide of formula (II) wherein Q is -CH2 - sulfonate and Q1is R1 with a source of iodide ion to give a macrolide of formula (I) wherein R is iodo. 7. A macrolide of formula (I) or a physiologically acceptable salt thereof as claimed in any one of claims 1 to 5 for use as an antibiotic in the chemotherapy of warm blooded animals. 8. A feed premix comprising as an active ingredient a macrolide of formula (I) or a physiologically acceptable salt thereof as claimed in any one of claims 1 to 5. 9. A veterinary formulation which comprises as an active ingredient a macrolide of formula (I) or a physiologically acceptable salt thereof, as claimed in any one of claims 1 to 5, associated with one or more physiologically-acceptable carriers or vehicles therefor.

Inventors: DEBONO, MANUEL, KIRST, HERBERT ANDREW, TOTH, JOHN ELDON
Applicants: ELI LILLY AND COMPANY
Application year: 1984
Main classification: C07H17
IPC codes: C07H17