CA1236830A - C-20- and c-23-modified macrolide derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Described herein are novel C-20 and C-23 modified derivatives of tylosin and tylosin-like macro-lides having the following formula:

(I) wherein R is hydrogen or a halo, cyano, hydroxy, alkoxy, aryloxy, azido, amino, amido or -SR5 group, where R5 is a C1-C4 alkyl, cyclohexyl, aryl or heteroaryl group;
R1 is hydrogen, hydroxy, halo, -OAr, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SR5 (as defined above), azido, amino, or amido;
R2 is hydrogen, or an optionally substituted alkanoyl, benzoyl, phenylacetyl or phenylpropionyl group' and R3 is hydrogen, hydroxyl, or an optionally substituted C1-C5 alkanoyloxy, benzoyloxy, phenylacetoxy or phenyl propionyloxy group, or a mycarosyloxy group, and salts thereof. These compounds - ii -are useful as antibiotics and/or as intermediates for the preparation of antibiotics.

Description

i236830 C-20- and C-23-MODIFIED CRAWLED DERIVATIVES
This invention relates to MacWorld anti-bionics, 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 viva efficacy, and improved pharmaceutical properties (such as greater oral absorption, higher blood or tissue concentrations, longer body half life, and more Advent-genus 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 MacWorld derivatives having formula (I);

I. ,.
;. Jo ~3G830 I/ Shea Shut/ sty I

SHEA \ /
OH' (I) 15 wherein R is hydrogen, idea, broom, sheller, flyer, cyan -or, -Oar, -SO , Acadia, -NO R7, N-phthalimido or R9;
Al is i) hydrogen or -OH;
ii) sheller, flyer, broom, idea -OAR, -O-tetra-hydrofuranyl, -O-tetrahydropyranyl, -SO , Acadia, -NR6R7, or N-phthalimido; or R ;
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, o -N(R8)2, -C-N(R8)2, carbomethoxy, !!
,, 12;~;1!330 carboethoxy, or phenol 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, sand ring having 1) from 5 to 7 ring atoms which include up to 3 additional hotter-atoms selected from nitrogen, oxygen and sulfur, and 2) up to 3 substituent groups selected from methyl, ethyl end phenol;
or iii) a bicyclic or tricyclic secondary amino group selected from 1,2,3,4-tetrahydro-quinolin-1-yl; decahydroquinolin-1-yl;
1,2,3,4-tetrahydroisoquinolin-2-yl;
decahydroisoguinolin-2-yl; indolin-1-yl;
isoindolin-2-yl; decahydrocyclohepta-[b]pyrrol-1-yl; decahydrocyclohepta-[c]pyrrol-2-yl; decahydrocyclo-pent[c]azepin-2-yl; decahydrocyclo-pent[d]azepin-3-yl; 2,3,4,5-tetrahydro-1~-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1~-3-benzazepin-3-yl; azabicycloheptanyl;
azabicyclooctanyl; azabicyclononanyl;
azabicyclodecanyl or azatricyclodecanyl;
R2 is hydrogen, optionally substituted Cluck-alkanoyl or optionally substituted bouncily, phenylacetyl or phenylpropionyl;

lZ3~

R3 is hydrogen, hydroxyl, optionally substituted Cl-C5-alkanoyloxy or optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy or OH
SHEA

Ho (mycarosyloxy) R4 is hydrogen, optionally substituted Cl-C4-alkyl, cyclohexyl, optionally substituted bouncily, phenethyl or phenoxyethyl;
An is i) phenol, derivatized phenol, or naphthyl;
ii) an optionally substituted heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, personnel, triazinyl, indolyl, isoquinolinyl, quinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxazolyl, benzimidazolyl, carbazolyl, or acridinyl;
or Sue iii) optionally substituted Cl-C5-alkanoyl;
optionally substituted bouncily, phenylacetyl, phenylpropionyl, phonics-acutely or phenylthioacetyl; methane-S sulfonyl; trifluoromethanesulfonyl; or optionally substituted phenylsulfonyl;
R5 is optionally substituted Cl-C4-alkyl; cycle-Huxley; optionally substituted phenol, bouncily or phenethyl; or an optionally substituted heteroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, personnel, pyridazinyl, triazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thinly and lo furanyl;
R6 is hydrogen, optionally substituted Cl-C6-alkyl, phenol, bouncily, phenethyl or C3-C8-cycloalkyl;
R7 is an R6 group or optionally substituted Cluck-alkanoyl, optionally substituted bouncily, 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 polyp ethylene 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, Al cannot be hydrogen or -OH; 2) that, when R or Al is -NHR6 or R4 or R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen, ~2:~6830 X-628~ -6-hydroxvl, or mycarosyloxy and or cannot be a type (iii) substituent; 3) that, when R2 is hydrogen, R3 must be hydrogen, hydroxyl or mycarosyloxy; 4) when R 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 nitrogen-containing heterocyGlic rings which are bonded therewith nitrogen atom and which have from five to seven ring atoms, including up to tree additional heteroatoms selected from nitrogen, oxygen and sulfur, include groups such as puerilely, pyrazolyl, imidazolyl, 1,2,4-oxadiazinyl, 1,3,4-thiadiazinyl, 1,2,4-triazolyl, l~-tetrazolyl, 1,4-dia~epinyl, morpholino, trio-morpholino, piperazinyl, thiazolidinyl, oxazolidinyl, and tetrahydro-1,4-thiazin-4-yl. Such rings can have up to three substituents selected from methyl, ethyl and I phenol on appropriate carbon and/or nitrogen ring atoms(s).
The term "Cl-C5-alkanoyl" as used herein means an azalea moiety derived from a carboxylic acid containing from one to five carbon atoms. In such a moiety, the alkyd group can be straight, branched, or cyclic. When optionally substituted, the alkyd group can bear one to three halo substituents. halo substituents are selected from the group consisting of Of, By and F. Acutely, chloroacetyl, trichloroacetyl, trifluoroacetyl, prop-nil, n-butyryl, isobutyryl, n-valeryl, and isovaleryl are examples of such groups. The term "Cl-C5-alkanoyloxy"
refers to the corresponding acyloxy moiety.
The terms "optionally substituted bouncily, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenol-thioacetyl", "optionally substituted bouncily, phenylacetylor phenylpropionyl", "optionally substituted benzoyloxy, phenylacetoxy or phenylpropionyloxy'i, "optionally substituted phenol, bouncily or phenethyl", "optionally substituted bouncily, phenethyl or phenoxyethyl" and "optionally substituted phenylsulfonyl" mean that the phenol portion of the moiety is optionally substituted by from one to five halo or methyl groups or by from one to two methoxyl, vitro or hydroxyl groups.
The term "derivatized phenol" refers to a phenol group which has from one to five halo, methoxyl or Cl-C4-alkyl substituents, or from one to two vitro, amino, methyl amino, ethyl amino, dimethylamino, deathly-amino, C4-ClO-methyleneamino, Acadia, hydroxy, hydroxy-methyl, amino methyl, (methylamino)methyl, (ethylamino)methyl, (dimethylamino)methyl, (deathly-amino methyl (C4-ClO-methyleneamino)methyl, formal, acutely, bouncily, methoxycarbonyl, ethoxycarbonyl, carboxamido, N-methylcarboxamido, N,N-dimethylcarbox-amino, cyan, phenol, phonics or bouncily substituents.
The term "optionally substituted heteroaryl group" as used herein means that the heteroaryl group may have at least one suitable substitu~ent(s) such as a Cl-C4-alkyl, halo, methoxy, ethics, hydroxy (or the veto tautomer) or phenol group.

~236830 The terms "Cl-C3-alkyl", "Cl-C4-alkyl" or "Cl-C6-alkyl" as used herein mean a straight- or branched-chain alkyd group cartooning the specified number of carbon atoms. Such groups include methyl, ethyl, isopropyl, n-butyl, tert-butyl, r.-hexyl, and the like. "Optionally substituted" Cl-C4-alkyl or Cluck-alkyd means that the alkyd group contains one or more flyer or sheller 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, methoxy arbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phonics-carbonyl and benzyloxycarbonyl.
The term "C4-C10-methyleneamino" represents a cyclic amino substituent of the formula -N(CH2)n wherein n is an integer from four to ten. Pyrrolidinyl, piper-vinyl, and octahydroazocinyl are examples of such groups.
The invention also provides a process for preparing a MacWorld of formula (I) by (a) reducing a starting MacWorld of formula (I) wherein Q is formal and Al is R1, provided Al is not hydroxyl, to give a MacWorld of formula (I) wherein R is hydroxyl;

123~B30 g ITCH

Q --SHEA/ I \ ( I I ) lo by ( SHEA ) 2 I
I

(b) reacting a starting MacWorld of formula (II) wherein Q is formal and Q1 is Al with an amine of the formula HNR6R6 or HR9 in the presence of a reducing agent to give a MacWorld of formula (I) wherein R is NR6R6 or R9, or (c) reacting a starting MacWorld of formula (II) wherein Q is -SHEA and I is Al with diethylazodi-25 carboxylate or dimethylazodicarboxylate, triphenyl- -phosphine, and a reagent selected from (i) an aside transfer agent, to give a MacWorld of formula (I) wherein R is Acadia, ~Z36 930 x-6286 -10-(ii) phthalimide to give a MacWorld of formula (I) wherein R is phthalimido, (iii) a phenol of formula ARCH to give a MacWorld of formula (I) wherein R is -OAR, where AR is a category i) or ii) AR
group, (iv) an alkyd halide or polyhalide to give a MacWorld of formula (I) wherein R is C1, Bra or I, or (v) a mercaptan of formula HER to give a MacWorld of formula (I) wherein R is SO, or (vi) a carboxylic or sulfonic acid of the formula ARCH, where AR is a category (iii) AR group, to give a MacWorld of formula (I) wherein R is OAR, (d) reacting a starting MacWorld of formula (II) wherein Q is -SHEA and Q is R with triphenyl-phosphine and a halogen source to give a MacWorld of formula (I) wherein R is Of, Bra or I, (e) reacting a starting material of formula (II) wherein Q is -SHEA and Q is R with an assaulting agent derived from a carboxylic or sulfonic acid of formula ARCH, where AR is a category (iii) AR group to give a MacWorld of formula (I) wherein R is OAR, or (f) reacting a starting MacWorld of formula (II) wherein Q is -SHELLEY where L is a leaving group and Q is R or a leaving group with (i) an alkali metal aside or halide or a tetraalkylammonium aside or fluoride I.

~236830 where alkyd is methyl, ethyl, propel or bottle, to give a MacWorld of formula (I) wherein R is Acadia, F, Of, Bra or I, or (ii) a marketed ion of formula R5S- to give a MacWorld of formula (I) wherein R is RUSS-, or (iii) an amine of the formula NR6R6 or HR9 to give a MacWorld of formula (I) wherein R
is NR6R6 or R9, or (iv) a source of cyanide ion to give a macro tide of formula (I) wherein R is -ON;
TV an alcohol of the formula Horn and a source of silver ion to provide a macro-tide of formula (I) wherein R is or where R4 is other than hydrogen;
(g) hydrolyzing a MacWorld of formula (II) wherein Q is CHAR and Al is Ho Ho fH3 Ho--/ \~, Ho I or H0_\--Q\~
OUCH Jo bCH3 OWE

.~...~

~23683~

X-52~5 -12-to give a MacWorld of formula (I) wherein R1 is hydroxyl, or (h) removing the hydroxy protecting group from a MacWorld of formula IT wherein Q is -CHAR and Q is protected hydroxy or (i) reacting a starting MacWorld of formula (II) wherein Q is -CHAR and Al is hydroxyl with deathly-azodicarboxylate or dimethylazodicarboxylate, triphenyl-phosphine, and a reagent selected from (i) an aside transfer agent to give a MacWorld of formula (I) wherein Al is Acadia, (ii) phthalimide to give a MacWorld of formula (I) wherein Al is phthalimido, (iii) a phenol of formula Arch where An is a category (i) or (ii) An group to give a MacWorld of formula (I) wherein R1 is -Oar, (iv) an alkyd halide or polyhalide to give a MacWorld of formula (I) where Al is Of, Bra or I, or (v) a mercaptan of formula HSR5 to give a MacWorld of formula (I) wherein R is SO , or (vi) a carboxylic or sulfonic acid of the formula Awry, where An is a category (i) An group, to give a MacWorld of formula (I) wherein Al is Oar or (j) reacting a MacWorld of formula (II) wherein Q is -CRY and Al is hydroxyl with an assaulting agent derived from a carboxylic or sulfonic acid of lZ36830 formula ARCH where AR is a category (iii) AR group to give a MacWorld of formula (I) wherein R is OAR or (k) reacting a MacWorld of formula (II) wherein Q is R and Q1 is hydroxyl with triphenyl-phosphine and a halogenating agent to give a MacWorld of formula (I) wherein R is Of, By or I, or (1) reacting a MacWorld of formula (II) wherein Q is -CHAR and Al is a leaving group with (i) an alkali metal aside or halide or a tetraalkylammonium aside or fluoride where alkyd is methyl, ethyl, propel, or methyl to give a MacWorld of formula (I) wherein R is Acadia, F, Of, Bra or I, (ii) a marketed ion of formula R S- to give a MacWorld of formula I wherein R is R S-, or (iii) an amine of the formula HNR6R6 or HO to give a MacWorld of formula (I) wherein R1 is HR6R6 or R, or (m) reducing a MacWorld of formula (II) wherein Q is -SHEEHAN and Q is Al or Q is R and Q1 is Acadia to give a MacWorld of formula (I) wherein R is -SHEEHAN or R is amino, or (n) assaulting a MacWorld of formula (II) wherein Q is -SHUNNER or R is NHR6 to give a MacWorld of formula (I) wherein R is -SHUNNER or R is -NR6R7, or (o) esterifying a MacWorld of formula (I), or (p) salifying a MacWorld of formula (I), or (q) hydrolyzing a MacWorld of formula (I) wherein R3 is mycarosyloxy in acid solution at a pi I., lZ36~30 below 4 to give a MacWorld of formula (I) wherein R3 is hydroxy, or r) deoxygenating a MacWorld of formula (I) wherein R3 is hydroxy to give a MacWorld of formula (I) S wherein R3 is hydrogen, (s) reacting a MacWorld of formula (II) wherein Q is SHEA and Al is I with a reducing agent to give a compound of formula I) wherein R is hydrogen, or (t) reacting a MacWorld of formula (II) wherein Q is -C~2- sulfonate and Q1 is R1 with a source of iodide ion to give a MacWorld of formula (I) wherein R is idea.
In general, macrolides of formula (I) are prepared by effecting a modification at the C-20 post-lion of a MacWorld that has the desired group at thwack position, or by effecting a modification at the C-23 position of a MacWorld 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) may be modified at 2'-, 4'-, 20-, and 23- positions using known methods to produce other macrolides of formula (I).
The following aye known macrolides which are useful in preparing the macrolides of this invention:
demycinosyltylosin (DOT), 20-dihydro-23-demycinosyltylosin (dihydro-DMT), 23-de(mycinosyloxy)tylosin (DOT), 20-dihydro-23-de(mycinosyloxy)tylosin (dihydro-DMOT), 5-O-mycaminosyltylonolide (OUT), dodder-mycaminosyltylonolide (dihydro-OMT), Dixie-mycaminosyltylonolide (DOT), 20-dihydro-23-deoxy-5-O-I

.

mycaminosyltylonolide (dihydro-DOMT), dodder-deo~y-23-demycinosyltylosin (DH-DO-DMT and dodder-20-deoxy-5-O-mycaminosyltylonolide (DH-DO-OMT).
DOT, dihydro-DMT, DOT, dihydro-DMOT, DOT, and dihydro-DOMT are antibiotics described by Richard I.
Waltz, Gene M. Wild, and Eugene T. Steno in U.S. Patents 4,321,361 and 4,321,362, both of which issued on March 23, 1982. DH-D0-DMT and DH-DO-OMT are described by Richard I.
Waltz, Herbert A. First, Gene H. Wild and Eugene T. Steno in U.S. Patent 4,304,856, which issued December 8, 1981.
OUT and dihydro-OMT are described by Marvin Norman and Robert D. Moron in U.S. Patent 3,459,853, issued on August 5, 1969.
The structures of the starting antibiotics are shown in formulas 2-11:

2 0 f SHEA

Shelley/ SCHICK

CH3--CH2~ --OH y f (I ~N-CH3 \~_~Q2 Ho ~Z36~30 Q Al Q2 2 DOT: ECHO -OH mycarosyl

3 dihydro-DMT: -SHEA OH "

4 OUT: ECHO -OH H

5 5 dihydro-OMT: -SHEA -OH

6 DOT: ECHO mycarosyl

7 dihydro-DMOT: . -SHEA H

8 DOT: ECHO H H

9 dihydro-DOMT: -SHEA H

10 10 DH-DO-DMT -SHEA -OH mycarosyl

11 DH-DO-OMT -SHEA -OH H

Other known macrolides are also useful starting Metro-also as will be clear from the following discussion.
Methods for modifying the Causation 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 US -SHEA include dihydro-DMT (3), dihydro-OMT (5), dodder-DOT (1), and dihydro-DOMT (9).
Macrolides of formula (I) or (II) wherein R is hydroxyl or Q is SHEA can be prepared by reducing a MacWorld of formula (II) wherein Q is formal to provide the corresponding dodder compound. Chemical ~23~

reduction can be effected, for example, by treating the MacWorld with an approxlmatelv stoichiometric amount of sodium bordered in an alcoholic solvent.
Macrolides of formula (I) ox (II) wherein R is OH or Q is SHEA 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 IT wherein Q is methyl include D~-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 MacWorld of formula (II) wherein Q is -SHEA with a reducing agent such as a hydrides for example sodium bordered in a bipolar aprotic solvent such as dimeth-ye sulfoxide, dimethylformamide, or sulf~lane, or an organotin hydrides such as tri-n-butyltin hydrides or a metal, for example powdered zinc; in a nonreactive organic solvent such as Tulane or nitromethane.
Macrolides of formula (I) or (II) wherein R is Of, Bra or I, or Q is -Shekel, -Shabbier, or -KIWI are prepared by reacting a MacWorld of formula (II) where Q
is -SHEA with triphenylphosphine and a halogenating agent in a nonreactive organic solvent such as dichloro-25' methane. Suitable halogenating agents include alkyd halides and polyhalides, such as carbon tetrachloride.
Macrolides of formula (I) or (II) wherein R is Of, Bra or I, or Q is -C~2Cl, -Shabbier, or -SHEA are also prepared by reacting a MacWorld of formula (II) wherein Q is -SHEA with triphenylphosphine, diethylazodicarboxylate or dimethylazodicarboxylate, and an alkyd halide or polyhalide.
The di(alkyl)azodicarboxylate/triphenyl-phosphine reaction and its various applications are - 5 described in O. Mitsunobu, Synthesis 1 (l), 1-28 (1981). The reaction generally produces dehydration between an alcohol ROW and an acidic component HO to provide a product RX.
Macrolides of formula (I) or (II) wherein R is 10F, at, Bra or I, or Q it -CHEF, -Shekel, -C~2Br, or -SHEA
are also prepared by reacting a MacWorld of formula (II) wherein Q is ECHO with on alkali metal or twitter-(alkyl)ammonium halide in a nonreactive organic solvent such as tetrahydrofuran.
15Macrolides of formula (I) or (II) wherein R is Acadia or Q is -SHEEHAN are prepared by reacting a MacWorld of formula (II) wherein Q is ECHO with an alkali metal or tetra(alkyl)ammonium aside in a nonreactive organic solvent. Macrolides of formula (I) or (II) wherein R is Acadia or Q is -SHEEHAN are also prepared by reacting a MacWorld of formula (II) wherein Q is -SHEA with triphenylphosphine, diethylazodicarboxylate or dim ethyl-azodicarboxylate, and an aside transfer agent, such as diphenylphosphoryl aside, in a nonreactive organic solvent such as tetrahydrofuran.
Macrolides of formula (I) or (II) wherein R is cyan or Q is -CHICANO are prepared by reacting a MacWorld of formula (II) wherein Q is -SHELLEY, where L is halide or a sulfonic ester group, with a cyanide salt in a non-reactive organic solvent, such as dimethylsulfoxide.

joy Macrolides of formula (I) or (II) wherein R is or or Q is SHARI are prepared by reacting a MacWorld of formula (II) wherein Q is SHELLEY with an alcohol of the formula Herr where R4 is other than hydrogen in the presence of a source of sliver ion.
Macrolides of formula (I) or (II) wherein R is Oar or Q is Shari are prepared by reacting a MacWorld of formula (II) wherein Q is -SHEA, with triphenyl-phosphine, di(alkyl)azodicarboxylate, where alkyd is methyl or ethyl, and a phenol of formula Arch, where An is a category i) or ii) An group.
Macrolides of formula (I) or (II) wherein R is Oar or Q is Shari and An is optionally substituted bouncily, phenylacetyl, phenylpropionyl, phenoxyacetyl, or phenylthioacetyl are prepared by reacting a MacWorld of formula (II) wherein Q is -KIWI with an assaulting agent derived from a carboxylic acid of formula Arch, where An is as defined above. Typical assaulting agents include androids, acid halides (usually in combination with a base or other acid scavenger), and active esters.
Suitable organic solvents include pyre dine and triethyl-amine. 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 Shari and An is an azalea group as defined in the previous paragraph are also prepared using the di(alkyl)a~odicarboxylate/triphenylphosphine procedure, i.e., by reacting a MacWorld of formula (II) wherein Q
is -SHEA with triphenylphosphine, ~Z3G830 X-~286 -20-di(alkyl)azodicarboxylate, and a carboxylic acid of the formula Awry.
Macrolides of formula (I) or IT wherein R is Oar or Q is Corey and An is methanesulfonyl, trifler-methanesulfonyl or optionally substituted phenylsulfonylare prepared by reacting a MacWorld of formula (I) wherein Q is -SHEA with an activated derivative, such as the android or acid halide, of a sulfonic acid of the formula Awry. If the acid halide is used, the reaction is carried out in the presence of a base, usually pardon.
Macrolides of formula (I) or (II) wherein R is Oar or Q is Shari and An is defined in the previous paragraph are also prepared using the delocalized-carboxylate/triphenylphosphine procedure, i.e., by reacting a MacWorld of formula (II) wherein Q is -KIWI
with triphenylphosphine, di(alkyl)azodicarboxylate and a sulfonic acid of the formula Arch.
Macrolides of formula (I) or (II) wherein R is SR5 or Q is -CHAUCER are prepared by reacting a MacWorld of formula IT wherein Q is -SHELLEY with marketed 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 -CHIHUAHUAS are also prepared using the di(alkyl)-azodicarboxylate/triphenylphosphine procedure, i.e., by reacting a MacWorld of formula tip) wherein Q is -SHEA
with triphenylphosphine, di(alkyl)azodicarboxylate and a mercaptan of formula HSR5.

~Z36~30 Macrolides of formula (I) or (II) wherein R is NR6R7 or Q is -CH2NR6R7 are prepared by reacting a MacWorld of formula (II) wherein Q is -SHUNNER with an assaulting agent derived from a carboxylic acid of the formula Horn.
Macrolides of formula (I) or (II) wherein R is phthalimido, or Q is -CH2-phthalimido are prepared by reacting a MacWorld of formula (II) wherein Q is -SHEA
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 idea or broom, are useful as intermediates for the preparation of additional come pounds of this invention via Sol or SNOW substitution reactions.- Suitable reaction conditions for displacing a leaving group by a nucleophile via either an Sol or SNOW mechanism are well exemplified in the art of nucleon Philip substitution reactions.
The formula (I) or (II) compounds wherein R is-NHR7 and R7 is an azalea group are prepared via the Acadia derivative (R=N3). The Acadia derivative is first reduced to the 20-amino derivative (R = No triphenylphosphine in aqueous tetrahydrofuran (TEN) is an example of a suitable reducing agent for this pun-pose. The 20-amino derivative can then be selectively assaulted on the amino group, using standard acylation procedures, to give those derivatives wherein R7 is an azalea group.

~236~30 Macrolides of formula (I) or (II) wherein R is -NOR I or R9 or Q is SHUNNER or CHAR can be prepared by reductive lamination of the C-20 alluded grollp of DOT, OUT, DOT, and DOT using one of two methods.
Method 1:
A derivative with a leaving group at C-20 (idea, inflate, etc.), prepared as described swooper, 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 alluded 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 an hydrous 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 amine, more forcing conditions for forming the intermediate iminium complex between the MacWorld 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 Bunsen or Tulane.

f'- !

1;~3~30 Methods for modifying the C-23-position The desired group at the C-23 position is likewise obtained by using an available starting Metro-at 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 Al is hydroxyl include DOT (2), dihydro-DMT (3), OUT (4), dihydro-OMT (5), DH-DO-DMT (10), and DH-DO-OMT (11).
Macrolides of formula (I) or (II) wherein Al or Q1 is hydroxyl can be prepared by acid hydrolysis of a MacWorld of formula (II) wherein Q1 is Ho ITCH Of Ho HO , HO_\ Jo , o r HO_\ I
OUCH/ SHEA Ohs OH/ OH

The hydrolysis is carried out at a pi between 1.5 and 2.5, as described in U.S. Patent No. 3,459,853.
Macrolides of formula (I) or (II) wherein or Al is hydroxyl can be modified to give other macrolides of formula (I) using the methods described :~236~30 herein before 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 at in J. Antibiotics 35 (1) 113-116 (1982).
Another process applicable to C-23 modifica-lions is a two step process in which the 23-hydroxyl group is first converted to a leaving group, and the leaving group is then displeased 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 inflate anion is a preferred leaving group. With very reactive nucleophiles, however, other leaving groups, such as the mesylate anion, the tessellate 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 android, preferably in the presence of a hindered pardon derivative such as letdown or s-collidine at a temperature of from -80C to room temperature. The hydroacyl groups at positions other than 23- may be protected by acutely 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 tessellate directly.

~Z36830 When inflate is used as the leaving group, it is not necessary to isolate the intermediate inflate 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 IT in which Al is SR5 the most convenient nucleophile is a compound of formula HSR5. For prep ration of an aside, the nucleophile is preferably an alkali metal aside such as lithium aside. The pyre-Dunham compound is preferably prepared by reaction with pardon base. When Al is NR6R7 or R9, the nucleophile is an amine of the formula EAGERER or HR9.
The nucleophilic displacement reaction is preferably conducted at temperatures in the range from -80C to 100C, typically room temperature using an inert organic solvent such as a chlorinated hydrocarbon like dichloromethane.
The C-23 derivatives wherein Al is -NHR7 can be prepared via the Acadia derivative (R=N3). The Acadia derivative is first reduced to the 23-amino derivative using a reducing agent specific to Acadia groups, such as crimes chloride or triphenylphosphine.

lZ361~30 Aqueous organic solvents such as ethereal solvents, for example tetrahydrofuran (THY) are useful for this purpose. The reduction can be effected at temperatures in the range from 0 to 100C. The 23-amino derivative 5 can then be selectively assaulted using standard azalea- -lion procedures, to give those derivatives wherein R7 is an azalea 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 70C.
It should be noted that, 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 swooper 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 adsorbent. Formation of C-20-monosub-stituted 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 Al differs from the substituent R can be prepared by modifying the hydroxyl group at C-23 before reducing the alluded at C-20.

1Z362~30 X-628~ -27-When preparing formula ( I ) compounds wherein R
is hydrogen, compounds lo 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 MacWorld not having a free C-23 hydroxyl group. One example of this approach is to prepare a C-20-modified derivative of desmycosin, tylasin, 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 OUT can be selectively prepared, which in turn can be modified at the C-23 position, as discussed Syria.
Use of a protecting group for the hydroxyl group at C-23 of OUT and DOT prior to reduction of the alluded 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 acutely and trichloroacetyl, and groups such as tetrahydropyranyl and tetrahydrofuranyl. The tetrahydropyranyl and tetrahydrofuranyl protecting groups are described, for example, by Tanaka et at., swooper.

~Z36830 X-~286 I -The modified derivatives of OUT, DOT and DH-DO-OMT can also be prepared by acidic hydrolysis of mockers from the corresponding modified derivatives of DOT, DOT and DH-DO-DMT, respectively, prepared by the methods previously described. Procedures for the acidic hydrolysis of mockers from DOT and DOT to form OUT and DOT, respectively, are found in U.S. Patents 4,321,361 - and 4,321,362. Acidic hydrolysis of DH-DO-DMT to give DIMWIT is described in U.S. Patent 4,304,856.
Myra specifically, the mockers sugar can be hydrolytic ally cleaved at a pi of less than 4, prefer-by in the range from 0.5 to 2.0, at a temperature in the range of from 0 to 60C, conveniently at about room temperature. The hydrolysis can ye effected using a lo 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 android in acetonitrile in the absence of external base, in accordance with a procedure described in J. Orcr. Chum. I 2050-52 (1979, to obtain the dustily derivative; I reacting the Dow Octal derivative with 2,3-dihydrofuran in dichloromethane in the presence of pyridinium p-toluenesulfonate in the manner described in J. Or.

~:36830 X-~286 -29-Chum. 42, 3772-74 (1974) to obtain the Boyce-tetrahydrofuranyl)derivative; (4) removal of the 2' and octal groups by dissolving the product of step (3) in methanol (50C, overnight); I reacting the product of step (4) with 1.5 mole equivalent of benzenesulfonyl chloride in pardon at -40C for 4 hours, to provide the 4'-O-benzenesulfonyl derivative; I immediately reacting the 4'-O-benzenesulfonyl derivative with 1.5 equivalent of sodium iodide in methyl ethyl kitten at 180C for 15 minutes to obtain 4' idea derivative; (7) reductively deiodinating the idea derivative using tri(n-butyl)stannane in Bunsen in the presence of 2,2'-azobis-isobutyronitrile at 80C for 2 hours; and (8) Deb locking the diethylacetal and tetrahydrofuranyl groups by hydrolysis of the product of step (7) in elm aqueous hydrochloric acid-acetonitrile (2.5:1 v/v) for - 30 minutes at 25C to obtain 4'-deoxydesmycosin.
The Dixie derivatives of this invention, i.e. the compounds of formula (I) wherein R3 is hydrogen, are readily prepared by procedures analogous to those described swooper, using 4'-deoxy-OMT, 4'-deoxy-DOMT or 4'-deoxy-D~-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 OUT, DOT 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 assaulting agents, using standard methods example-fled in the art. The preparation of ester derive-lives of the C-20- and/or C-23-modified derivatives is accomplished by procedures similar to those described by Waltz et at. 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 prove-dunes similar to those outlined in U.S. Patents Nazi, 4,487,923 and 4,396,613.
Alternatively, the formula (I) compounds which are esters may be prepared by starting with the appear-private esters of compounds 2-11, prepared as described Syria. 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 invent lion 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 volubility in water.
Representative suitable salts include those salts formed by standard reactions with both organic and inorganic acids such as, for example, sulfuric, hydra-caloric, phosphoric, acetic, succinic, citric, lactic, ~Z361~30 malefic, fumaric, palmitic, colic, pamoic, music, D-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, formic, Laurie, Starkey, salicylic, methane-sulfonic, benzenesulfonic, sorbic, picnic, 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.

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o I O it 0 0 0 I 3 z pa a o I us ED CUD a o Jo ~236~30 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 Postural species. The minimal inhibitory concentrations (Micas) at which illustrative compounds inhibit certain bacteria are given in Tables II
and III. The Micas in Table II were determined by standard agar-dilution assays. The Micas in Table III
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, lZ3~i~30 Some of the derivatives of this invention have shown i viva antimicrobial activity against export-mentally induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with S. pvoqenes C203, the activity observed was measured as an EDDY value [effective dose in mg/kg to protect 50% of the test animals: see Warren Wick, et at., J. Bacterial. 81, 233-235 (1961)]. EDDY values observed for illustrative compounds are given in Table IV.

Table IV
EDDY Values of Illustrative Formula (I) Compounds Test Compound Streptococcus pudginess C203 Subcutaneous Oral 1 >30 >100 22 >30 >100 24 >10 >50 >10 >50 33 >25 >100 34 >25 78 US >12.5 >100 36 >10 so 37 >-10 >100 38 >10 >100 46 >10 >50 amg/kg x 2; doses given 1 and 4 hours post-infection compound numbers from Table I.

.

~Z36~30 X-6286 ~53~

Certain of the formula (I) compounds of this invention have also shown in viva activity against infections induced by gram-negative bacteria. Table V
summarizes the results of tests in which illustrative compounds were evaluated against a Postural infection in one-day-old chicks. The compounds were administered parenterally after challenge of the chicks with Pasteup relic multocida (0.1 ml of a lo 4 dilution of a twenty-hour tryouts broth culture of an Asian P. multocida given subcutaneously). In these tests, unless indicated otherwise, all non-medicated infected chicks died within 24 hours of Postural challenge. In the tests Siam-rimed 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 Postural multocida-Infected Chicks Test Com~oundbNumber of Deaths Number Treated l 9/10 22 Lowe 38 Lowe administered subcutaneously; 30 mg/kg x 2 compound numbers from Table I

lZ3~i830 X-6286 -54_ The compounds which are preferred for on viva 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 I
is -OH or soar and An is a group (iii) substituent.
Still another group of compounds preferred for in vitro activity against gram-positive bacteria and for activity against Mycolasma species are the formula (I) compounds wherein Al is R9.
This invention also relates to methods of controlling infections caused by gram-positive bacteria and MycoPlasma 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 regrade 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 rouge-miens can be constructed.
In another aspect, this invention relates to US compositions useful for the control of infections caused by gram-positive bacteria and MYco~lasma species. These compositions comprise a specified compo~md of formula (1) together with a suitable vehicle. Compositions may be formulated for parenteral administration by methods recognized in the pharmaceutical art.

~Z3~830 X-6286 ~55~

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 syllable-try 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 bouncily alcohol, if needed, and buffers. Useful solvents include, for example, water and aqueous alcohols, glycols, and carbonate esters such as deathly 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 adjutants, as a vehicle. The suspending medium can be, for example, aqueous polyvinylpyrrolidone, inert oils such as vegeta-bye oils or highly refined mineral oils, or aqueous carboxymethylcellulose.
Suitable physiologically acceptable adjutants are necessary to keep the compound suspended in suspend soon compositions. The adjutants may be chosen from among thickeners such as carboxymethylcellulose, polyvi-nylpyrrolidone, gelatin, and the alginates. Many surfactants are also useful as suspending agents.
Lecithin, alkylphenol polyethylene oxide adduces, naphthalenesulfonates, alkylbenzenesulfonates, and the lZ36~330 polycxyethylene sorbitan esters are useful suspending agents.
Many substances which affect the hydra-fullest, 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 opera-lion of this invention, the following examples are provided:
Preparation 1 2',4'-Di-O-acetYl-20-dihYdro-OMT
20-Dihydro-OMT (3.1 g, 5.2 Molly) was dissolved in acetone (100 ml) and was treated over a five-minute period with acetic android (2.0 ml, 21.2 Molly). After stirring for nine hours at room temperature, the react lion mixture was quenched into saturated sodium vicar-borate 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 vacua overnight to yield 3.4 g (96%) of 2',4'-di-O-acetyl-20-dihydro-OMT.

Preparation 2 23-Iodo-20,23-dideoxv-20-dihvdro-OMT
20-Deoxy-20-dihydro-OMT (2.0 g, 3.4 Molly), tetrabutylammonium iodide (3.8 g, 10.3 Molly) and s-collidine (1.36 ml, 10.3 Molly) were dissolved in .

Sue X-~285 -57-dichloromethane (40 ml). The solution was cooled to -78 under an argon atmosphere and then was treated drops with triflic android (Owe 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 urea ted starting material was still present, the solution was cooled to -78 again and then treated with additional triflic android (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 vicar-borate solution, dried (Nazi) and filtered. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluding with alienor 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 under reduced pressure to yield 2.0 g of 23-iodo-20,23-dideoxy-20-dihydro-OMT.
thin layer chromatography Example 2',4'-Di-O-acetYl-20-O-phenYlacetYl-20-dihydro-OMT and 2',4'-di-O-acetvl-20,23-di-O-phenYl-acet~l-20-dihvdro-OMT
2',4'-Di-O-acetyl-20-dihydro-OMT (3.0 g, 4.4 Molly) was dissolved in dichloromethar.e (50 ml) and pardon (2 ml). The solution was cooped to -78 and . . .

~Z~683~

treated drops with phenylacetyl chloride (0.725 ml, 5.5 Molly) over a 2-minute period with vigorous stirring.
After 15 minutes at -78, 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 come brined dichloromethane extracts were dried (sodium sulfate) and filtered and the filtrate was evaporated.
The residue (4 g) was separated on a Waters Prep 500 chromatography eluding with a linear gradient of Tulane (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'-di-O-acetyl-20-O-phenylacetyl-20-dihydro-OMTT and 0.6 g of 2',4'-di-O-acetyl-20,23-di-O-phenylacetyl-20-dihydro-OMT.
Example 2 20-O-PhenYlacetyl-2o-dihydro-oMT
2',4'-Di-O-acetyl-20-O-phenylacetyl-20-dihydro-OMT (1.2 g, 1.5 Molly) was dissolved in methanol (80 ml) and water (20 ml) and the solution was reflexed 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.

* Trademark lZ3G830 Example 3 20,23-Di-O-Phenylacetyl-20-dihvdro-OMT
In a manner similar to that of Example 2, 2',4'-di-O-acetyl-20,23-di-O-phenylacetyl-20-dihyddreamt (0.48 g) was hydrolyzed to yield 0.44 g of Dow-phenylacetyl-20-dihydro-OMT.
Example 4 20-N-Methvlamino-20-deoxy-20-dihvdro-OMT
OUT (1.2 g) and methyl amine hydrochloride (1.36 g) were dissolved in dry methanol (40 ml). After stirring for one hour at room temperature, sodium cyanoborohydride (500 my) 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 (Nazi) and filtered. The filtrate was evaporated and the residue (Owe g) was dissolved in dichloromethane and separated by flash chromatography on silica gel Grace 60),' eluding with a linear gradient of l liter of dichloromethane-methanol-gone. ammonium hydroxide (90:10:0.5) and l liter of dichloromethane-methanol-conc. ammonium hydroxide (75:25:0.5). Fractions containing the desired product were located by tic analysis, combined and evaporated under reduced pressure to yield 0.14 g of the title compound.

* Trademark ~23~830 Example 5 - 20-N-Benzylamino-20-deoxv-20-dihydro-OMT
Using a procedure like that of Example 4, OUT
(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, eluding with a linear gradient of dichloro--- methane (4 Lo and dichloromethane-methanol-conc. ammonia us hydroxide (90:10:0.5, 4 L), to yield 0.21 g of the title compound.
Example 6 20-'N-Dimethvlamino-20-deoxY-20-dihYdro-OMT
Using a procedure like that of Example 4, OUT
(1.2 g) and dimethylamine hydrochloride (1.6 g) in methanol (40 ml) were treated with sodium cinnabar-hydrides (0.5 g). After extractive workup and purifica-lion by silica gel chromatography as described in example 5, 0.61 g of the title compound was obtained.
Example 7 20-N-Benzvlamino-20-deoxv-20-dihvdro-DMOT
Using a procedure like that of Example 4, DOT
(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, eluding with a -linear gradient of dichloromethane (1 L) and dichloro-~LZ3~;830 methane-methanol (3:1, 1 L) to yield 0. pa g of the title compound.
Example 8 20-N-Phenethylamino-20-deoxY-20-dihydro-DMT
DOT (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 my The combined extracts were dried (Nazi) 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, eluding with a linear gradient of dichloromethane-methanol-conc.
ammonium hydroxide (1 L of 125:1:0.1 to 1 L of Lyle) followed by an additional 1 L of the latter solvent mixture. Fractions containing the desired product were located by tic analysis, combined and evaporated to yield 2.8 g of the title compound.

Example 9 --20-N-PhenethYlamino-20-deoxv-20-dihydro-OMT
20-N-Phenethylamino-20-deoxy-20-dihydro-DMT
(1.5 g) was dissolved in lo sulfuric acid (60 ml) and stirred for 1 hour at room temperature. The solution was slowly poured into saturated sodium bicarbonate l?Z36~30 solution (500 ml) and the product was extracted into dichloromethane (3 x 300 ml). The combined extracts were dried (Nazi) and filtered and the filtrate was evaporated under reduced pressure to yield 0.88 g of the - 5 title compound.
Example 10 20~23-Di-N-Phthalimido-2ol23-dideoxy-2 d-hYdro-DMT
0-Dihydro-DMT (1.49 g, 2.0 Molly), triphenyl-phosphine (2.1 g, 8 Molly) and phthalimide (1.18 g, 8.0 Molly) were dissolved in tetrahydrofuran (50 ml) under an argon atmosphere. Deathly azodicarboxylate (1.4 g, 8 Molly) was added drops and the solution was stirred for 30 minutes at room temperature. Methanol (about 1 ml) was added to decompose excess reagent an dafter stirring for 10 minutes, the solution was evapo-rated under reduced pressure. The residue was part-toned 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 bicarbon-ate and extracted with dichloromethane. The organic extracts were dried (Nazi) 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, eluding first with dichloro-methane (300 ml) followed by a linear gradient of dichloromethane (1 L) and 9% methanol in dichloromethane (1 L). Fractions containing the desired product were 1236t~30 located by tic analysis, combined and evaporated to dryness to Yield 0.17 g of the title compound.
Example 11 20,23~ N-Phthalimido-20,23-dideoxY-20-dihYdro-OMT
20,23-Di-N-phthalimido-20,23-dideoxy-20-dihydro-DMT (100 my) was dissolved in lo sulfuric acid (10 ml) and Dixon (3 ml) and stirred for 1 ho at room temperature. The reaction was then neutralized with solid sodium bicarbonate and extracted with dichloro-methane twice. The combined extracts were dried (Nazi) and filtered and the filtrate was evaporated to dryness under reduced pressure and then dried in vacua to yield the title compound.
Example 12 20-N-Phthalimido-20-deoxv-20-dihYdro-DMOT
20-Dihydro-DMOT (3.64 g, 5 Molly), triphenyl-phosphine (2.62 g, 10 Molly) and phthalimide (1.47 g, 10 Molly) were dissolved in tetrahydrofuran (40 ml) under a nitrogen atmosphere. The solution was treated drops with deathly azodicarboxylate (1.58 ml, 10 Molly) and then stirred for 1 ho at room temperature. The excess reagent was quenched with methanol (25 ml) and the solution was evaporated under reduced pressure. The residue was dissolved in a small volume of dichloro-methane and separated by flash chromatography on silica gel, eluding with dichloromethane (1 L) followed by a linear gradient of dichloromethane (1 L) and 5% methanol 1236~30 X-~286 -64-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 .
?O-N-Phthalimido-20-deoxv-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 deathly azodicarboxylate (1.4 ml). Since tlc.analysis of the reaction mixture after 30 minutes showed a significant amount of unrequited 20-dihydro-DMT in addition to a mono-substituted and a di~substituted derivative, additional p~thalimide (296 my), triphenylphosphine (523 my) and deathly azodicarboxylate ~0.33 ml), were added. After stirring for an additional 0.5 ho 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-phthal-imido-20-deoxy-20-dihydro-DMT along with 2.16 g of 20,23-di-N-phthalimido-20,23-dideoxy-20-dihydro-DMMT.
Example 14 20-N-Phthalimido-20-deoxy-20-dihYdro-DOMT
20-N-Phthalimido-20-deoxy-20-dihydro-DMOT
(1.0 g) was dissolved in lo sulfuric acid (80 ml) and stirred for 1 ho at room temperature. The solution was slowly added to saturated sodium bicarbonate solution ~36830 (500 ml) and then was extracted with dichloromethane (3 x 300 ml). The combined extracts were dried (Nazi) and filtered and the filtrate was evaporated unsex reduced pressure to yield 0.50 g of the title compound.
Example 15 20-N-Phthalimido-~O-deoxv-20-dihvdro-OMT
20-N-Phthalimido-20-deoxy-2Q-dihydro-D~
(355 my) was hydrolyzed in lo sulfuric acid (50 ml) for 1 hr. After workup as described in example 14, 1~0 my of the title compound was obtained.
Example 16 20,23-Dî-O-~henYl-20-dihvdro-OMT
20-Dihydro-OMT (1 g, 1.7 Molly), _riphenyl-phosphine (1.3 g, 5.1 Molly) and phenol (0.47 g, 5.1 Molly) were dissolved in tetrahydrofuran (30 ml) under a nitrogen atmosphere. The solution was cooled in an ice bath and treated with deathly azcdicarboxylate (0.89 g, 5.1 Molly) over a 2-minute period. The cooling bath was removed and the solution was stirred for 1 ho 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 Tulane 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 (Nazi) and filtered and the filtrate was evaporated. The residue was separated by flash ~Z36~30 chromatography on silica gel, eluding 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 my of 20,23-di-O-phenyl-20-dihydro-OMT.
Preparation Example 17 dodder -O-Pherlylpropionyl-oMT
23-O-Phenylpropionyl-OMT (1.9 g, 2.6 Molly) was dissolved in 1:1 isopropanol:water ~30 ml). Sodium bordered (0.025 g, 0.65 Molly) was added to this solution and the reaction was stirred for 0.5 hr. The pi of the reaction was adjusted from pi 10.5 to pi 7.0 with lo sulfuric acid. The solution was concentrated to aqueous under reduced pressure and saturated Nikko solution was added. The product was extracted into dichloromethane and the extracts were dried (Nazi 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-l-Yl-23-deoxY-OUT
23-Octahydroazocin-l-yl-OMT (900 my, 1.3 Molly) was reduced with sodium bordered (12 my, 0.33 Molly) in 1:1 isopropanol-water (15 ml) as described in example ~.23G~30 17, yielding 815 my ~90%) of the dodder derivative.
Example 19 20-O-Phenvl-20-dihYdro-23-O-~henYlPropion OUT
20-Dihydro-23-O-phenylpropionyl-OMT (1.7 g, 2.3 Molly), triphenylphosphine (1.2 g, 4.6 Molly) and phenol (0.43 g, 4.6 Molly) were dissolved in tetrahydro-Furman ~45 ml) under a nitrogen atmosphere. The solution was cooled in an ice bath and then was treated drops with deathly azodicarboxylate (0.8 g, 4.6 Molly). After 5 minutes, the cooling bath was removed and the solution was stirred for 2 ho at room temperature. Since tic analysis of the reaction indicated tune presence of unrequited starting material, one-half of the initial amounts (2.3 Molly of triphenylphosphine, phenol and dietXyl azodicarboxylate were each added. After stir-ring for another 30 minutes, methanol (10 ml) was added to decompose excess reagent and the solution was evapo-rated under reduced pressure. The residual oil was treated with Tulane and the insoluble material was filtered. The filtrate was evaporated under reduced pressure and the residue was separated by flash chrome-tography on silica gel, eluding step-wise with mixtures of methanol-diChloromethane as follows: 400 ml of 0%, 250 ml of 2%, 250 ml. of 4%, 750 ml of 6% and 250 ml of 8% methanol in dichloromethane. Fractions containing the desired product were located by tic analysis, combined and evaporated under reduced pressure to yield 0.26 g of 20-0-phenyl-20-dihydro-23-O-phenylpropionyl-OUT.

1236i330 Example 20 20-0-Phenvl-20-dihYdro-23-OctahYdroazocin-l-yl-OMT
20-Dihydro-23-octahydroazocin-1-yl-OMT (800 my, 1.2 Molly), triphenylphosphine ( 940 my, 3.6 Molly) and phenol (340 my, 3.6 Molly) were dissolved in tetrahydro-Furman (20 ml). The solution was treated with deathly azodicarboxylate (630 my, 3.6 Molly), stirred for 1 hour, and worked up as described in example 19. The crude product was purified by flash chromatography on silica gel, eluding stops with mixtures of methanol-dichloro-methane 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 my of the title compound.

Example 21 2',4',23-Tri-O-acetvl-20-deoxy-20-dih~dro-OMT
I 20-Deoxy-20-dihydro-OMT I g) was dissolved in pardon (70 ml). The solution was treated with acetic android (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 to remove most of the pardon. The residue was dissolved in dichloro-methane, extracted with saturated sodium bicarbonate solution, dried (Nazi) and filtered. The filtrate was -1~6~30 evaporated to dryness and the residue was redissolved and re-evaporated to remove pardon as before and finally was suspended in hexane and filtered. The solid residue (5.3 g) was separated on a Waters Prep 500 chromatography over silica gel, eluding with a linear gradient of Tulane (1 L) and toluene-ethyl acetate (1:3, 1 Lo. 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-20-deoxy-20-dihydro-OMT.
Example 22 23-0-PhenYlacetyl-20-deoxv-20-dihydro-OMT
20-Deoxy-20-dihydro-OMT (2 g, 3.4 Molly) was dissolved in dichloromethane (40 ml) and pardon (0.55 ml). The solution was cooled to -78 and treated with phenylacetyl chloride (0.55 ml, 4.1 Molly). The cooling bath was removed and the reaction was allowed to warm to room temperature and then stirred for an add-tonal 0.5 ho at room temperature. Since tic analysis of the reaction showed the presence of starting Metro-at, the solution was again cooled to -78 and treated with additional phenylacetyl chloride (0.35 ml).
Sequence was repeated again, using 0.08 ml of phenol-acutely chloride the final time. The final reaction mixture was extracted with saturated sodium bicarbonate solution, dried (Nazi and filtered and the filtrate was evaporated to dryness. The residue was separated by flash chromatography on silica gel, eluding with a linear gradient of dichloromethane (1 L) and 20%

~Z36830 methanol in dichloromethane (1 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-dideoxv-20-dihydro-OMT
20-Deoxy-20-dihydro-O~ (3.0 g, 5.15 Molly) was dissolved in dichloromethane (40 ml) and s-collidine (1.36 ml). The solution was cooled to -78 and treated with triflic android (1.0 ml initially, then 0.3 ml additionally); thiophenol (1.25 ml) was added at -78 and the mixture was stirred at -78 for 1.5 hr. The reaction was stirred for another 2.5 ho while warming to room temperature and then was extracted with saturated sodium bicarbonate solution, dried (Nazi) and filtered.
The filtrate was evaporated and the residue was washed with hexane and then separated by flash chromatography on silica gel; eluding with a linear gradient of dichloro-methane (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 my of the title compound.
Example 24 23-Octahvdroazocin-l-vl-20,23-dideoxv-20-dihydro-OMT
23-Iodo-20,23-dideoxy-20-dihydro-OMT (69 my) and heptamethyleneimine (0.05 ml) were dissolved in acetonitrile (2 ml) and the solution was reflexed for 2 ho under an argon atmosphere. The solution was cooled lZ3~330 to room temperature and poured into saturated sodium bicarbonate solution lo ml). The product was extracted into dichloromethane and the extracts were dried Nazi) and filtered. The filtrate was evaporated and the residue was separated by preparative tic or. a 20 x 20 cm, 2 mm thick plate of silica jowl. Merck),'*
developing with dichloromethane-me~hanol-conc. ammonium hydroxide (90:10:2). The band on the silica gel plate was located by W light and was scraped from the plate, lo dried in vacua to remove solvent and then eluded with dichloromethane-methanol (1:1, 50 ml) for 45 minutes.
The mixture was filtered and the filtrate was evaporated to dryness to yield 65 my of the title compound.

Example 25 23-(4-~Ydroxypi~eridino)~20l23-dideoxy-20-dihvdro-OMT
23-Iodo-20,23-dideoxy-20-dihydro-OMT lo g, 1.6 Molly) and 4-hydroxypiperidine (0.32 g, 3.2 Molly) were dissolved in acetonitrile (20 ml) and reflexed under an argon atmosphere for 2 hr. Additional 4-hydroxypiperidi.ne (300 my) was added to consume unrequited starting material and the solution was reflexed 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 (Nazi) and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on * Trademark ~Z36830 silica gel, eluding with a linear gradient of dichloro-methane (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 my of S the title compound.
Example 26 23-0-~2,3-DimethoxyphenYl)-20-deox~-2G-dihYdro-OUT
20-Deoxy-20-dihydro~OMT (3.0 g, 5.15 Molly), triphenylphosphine (2.7 g, 10.3 Molly) and 2,3-dimethoxy-phenol (1.59 g, 10.3 Molly) were dissolved in tetrahydro-Furman (150 ml3 under an argon atmosphere. The solution was treated with ~1iethyl azodicarboxylate (1.7 ml, 10.3 Molly) 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 Tulane and the insoluble material was filtered.
The filtrate was extracted with saturated sodium vicar-borate solution, dried (Nazi) and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (Waters Prep 500), eluding with dichloromethane (2 L) followed by a linear gradient of dichloromethane (2 L) and 10% Matthew-not in dichloromethane (2 L); the column was finallyeluted with 2 L of the latter solvent. Fractions containing the desired product were located by tic analysis, combined and evaporated to yield 2.06 g (54%) of the title compound.

~Z3~830 X-628~ ~73 Example 27 23-0-(3-Pvridyl)-20,23-dideoxy-20-dihYdro-OMT
20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 Molly), triphenylphosphir,e (2.7 g, 10.3 Molly) and 3-hydroxy-S pardon (979 my, 10.3 Molly) were dissolved in twitter-hydrofuran (50 ml) under an argon atmosphere and treated with deathly azodicarboxylate (1.7 ml, 10.3 Molly).
After workup and chromatography as described in example 26, 0.63 g of the title compound was obtained.

Example 28 23-O-(m-DimethylaminoPhenyl)-20-deoxy-20-, dihYdro-OMT
20-Deoxy-20-dihydro-OMT (3.0 g, 5.15 Molly), triphenylphosphine (2.7 g, 10.3 Molly) and m-dimethyl-amino phenol (1.4 g, 10.3 Molly) were dissolved in twitter-hydrofuran (50 ml) under an argon atmosphere. Deathly azodicarboxylate (1.7 ml, 10.3 Molly) was added and the solution was stirred for 1 ho at room temperature.
Since starting material had not been consumed at this point, additional triphenylphosphine (1.35 g), m-dimethyl-amino phenol (0.70 g) and deathly azodicarboxylate (0.85 ml) were added and the solution was stirred for another 0.5 hr. Mesh (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), eluding with dichloromethane (2 L) followed by a linear gradient of dichloromethane (4 L) and 15% methanol in dichlorome~hane (4 L). Fractions containing the desired product were located by tic analysis, combined and evaporated to dryness to yield 1.12 g of the title compound as a purple glassy solid.
Example 29 20-Di~henvlamino-20-deoxv-20-dihYdro-OMI
-OUT (3.0 g, 5 Molly) was dissolved in dim ethyl-formamide (10 ml) and the solution was diluted with Tulane (100 ml). Diphenylamine (1.69 g, 10 Molly) and ~-toluenesulfonic acid hydrate (150 my) were added and the solution was reflexed using a Dean-Stark trap to separate water. After 4 ho, 20 ml of condensate was withdrawn and the solution was reflexed overnight. The solution was cooled to 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 ho 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, pi 6.5 phosphate buffer (75 ml) and with 0.5 M, pi 4.5 phosphate buffer (2 x US ml). The combined latter extracts were back-extracted with ethyl acetate (75 ml) and the combined ethyl acetate solutions were dried (Nazi) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in a small volume Sue X-6285 ~75~

of dichloromethane, filtered and purified by chromatog-rough on silica gel (Waters Prep 500), eluding with a linear gradient of dichloromethane (4 L) and 5% methanol plus 0.5% gone. 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 my of the title compound.

Example 30 20-DH-DO-20-[3-Azabicvclo(3.2.2)-nonan-3-v~l-OMT

OUT (3.0 g., OWE moles) was dissolved in lo an hydrous methanol (15 ml.). 3-Azabicyclo[3.2.2]-nonane (1.2S g., 10 moles) was dissolved in an hydrous methanol (15 ml.) and filtered to remove a white impurity. The filtrate was added to the OUT solution and the resulting solution was stirred for 5-10 minutes at room tempera-lure in the presence of molecular sieves (PA). NaBH3CN(0.63 g., 10 moles) 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 Nope buffer (150 ml., pi 6.5~. The phosphate buffer solution was evaporated under vacuum to remove residual ethyl acetate. The pi of the buffer solution was adjusted to about 11 with ON
Noah, forming a white precipitate which was collected by ~Z36~30 filtration and dried to give 2.06 g. (58% yield) of 20-DH-DO-20-[3-azabicyclo(3.2.2)nonan-3-yl]OMT. [Tiara-lion Pea values: 7.7 and 9.3; FDMS parent ion (M +
1) = 707].

Example 31 20-DH-DO-20-MorPholino-oMT

Following the procedure outlined in Example 1, OUT (3.0 g., 5.0 moles), morpholine (Owe ml., 10 moles), NaBH3CN (Owe g., 5 moles) and an hydrous Mesh (30 ml.) were reacted in the presence of molecular sieves (PA). Since a precipitate did not form when the pi of the buffer was adjusted to 11, the product was extracted from the buffer with SCHICK to give 1.66 g.
(50% yield) of 20-DH-DO-20-morpholino-OMT as a white foam. [Titration Pea values: 6~5, 8.4; FDMS parent ion (M + 1) = 669].
Example 32 20-DH-DO-20-(4-PhenYlpiperidin-l-yl)-oMT

OUT (5.97 g., 10 moles), 4-phenylpiperidine (3.22 g., 20 moles), NaBH3CN (1.25 g., 20 moles) and methanol (60 ml.) were reacted using the procedure of Example 1, but substituting a pi 4.5 buffer for extract lion, to give 3.7 g. of the title compound [FDMS parent ion (M I 1) = 743].

~Z36830 Example 33 20-DH-DO-23-DeoxY-20,23-di(octahYdroazocin-l-Yl)-OOUT

20,23-di-iodo-OMT (1.2 g., 1.5 moles) was dissolved in acetonitrile (20 ml.). Heptamethyleneimine (1.7 g., 1.9 ml., 15 moles) was added to this solution, and the reaction mixture was stirred at reflex furl hours. Volatile were removed, and the resulting red oil was dissolved in SCHICK ~150 ml.). This solution was washed with saturated Nikko solution (100 ml.) and the SCHICK phase was separated and dried over Nazi, 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 eluded stops 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 my. (19% yield) of 20-DH-DO-23-deoxy-20,23-di(octahydroazocin-1-yl)-OOUT as a white foam. [Titration Pea values: 6.9, 8.05, 8.9;
FDMS parent ion (M + 1) = ~90].

eye The following compounds can be prepared by the methods of the preceding examples.
20-DH-DO-20-(octahydroazocin-1-yl)DMT
20-D~-DO-20-~piperidin-1-yl)DMOT
20-DH-DO-20-(piperidin-1-yl)DOMT
20-DH-DO-20-(4-hydroxypiperidin-1-yl)DOMT

., lZ3GS30 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-D~-DO-20-(1,2,3,4-tetrahydroisoquinolin-2-yl)OMT
- 20-DH-DO-20-(1,2,3,4-tetrahydroquinolin-1-ye omit 20-DH-DO-20-(azacycloundecan-1-yl OMIT
20-DH-DO-29-(4-methylpiperidin-1-yl)OMT
20-DH-DO-20-(pyrrolidin-1-yl)DMT
20-DH-DO-20-(octahydro-lH-azonin-l-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-OUT
20-DH-DO-20-(decahydroazecin-1-yl)-4'-deoxy-OMT
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-25 l-yl)OMT
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 bouncily alcohol are added so that the owe solution contains 50% (by volume) propylene glycol, 4%
(by volume) bouncily alcohol, and 200 mg/ml of a formula (I) base.
B) A solution is prepared as described in Section S 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 (~) tart rate.
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 my 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 premix which in turn is used to prepare medicated feeds. Typical premixes may contain from about 1 to about 200 grams of drug per pound of premix. Premixes may be either liquid or solid preparations.
The final formulation of feeds for animals or poultry will depend upon the amount of drug to be administered. The common methods of formulating, S ' ' A

123G~30 X-62~ -80-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 S medium can assist in making injectable suspensions in individual cases. For example, silicone anti foams, sorbitol, and sugars can be useful suspending agents.

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Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a macrolide of formula (I):

(I) wherein R is 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(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,, 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; decahydroguinolin-l-yl;
1,2,3,4-tetrahydroisoquinolin-2-yl;
decahydroisoquinolin-2-yl; indolin-1-yl;
isoindolin-2-yl; decahydrocyclohepta[b]-pyrrol-1-yl; decahydrocyclohepta[c]-pyrrol-2-yl; decahydrocyclopent[c]-azepin-2-yl; decahydrocyclopent[d]-azepin-3-yl; 2,3,4,5-tetrahydro-lH-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl; azabicycloheptanyl;
azabicyclooctanyl; azabicyclononanyl;
azabicyclodecanyl or azatricyclodecanyl;
R2 is hydrogen, or a C1-C5 alkanoyl group the alkyl moiety of which is optionally substituted with one to three halo substituents, or a benzoyl, phenylacetyl or phenylpropionyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substitutents or with one or two methoxy, nitro or hydroxy substituents;
R3 is hydrogen, hydroxyl,or a C1-C5 alkanoyloxy group the alkyl moiety of which is option-ally substituted with one to three halo substituents, or a benzoyloxy, phenylacetoxy or phenylpropionyloxy group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
or (mycarosyloxy) AR is i) phenyl, 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, di-methylamino, diethylamino, C4-C10-methyleneamino, azido, hydroxy, hydroxy-methyl, aminomethyl, (methylamino)methyl, (ethylamino)methyl, (dimethylamino)methyl, (diethylamino)methyl, (C4-C10-methylene-amino)methyl, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, carbox-amido, N-methylcarboxamido, N,N-dimethyl-carboxamido, cyano, phenyl, phenoxy or benzyl substituents; or naphthyl;
ii) a heteroaryl group selected from pyri-dinyl, pyrimidinyl, pyridazinyl, pyra-zinyl, triazinyl, indolyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxa-zolyl, benzimidazolyl, carbazolyl, or acridinyl optionally substituted with one or more C1-C4 alkyl, halo, methoxy, ethoxy, hydroxy or phenyl substituents;
iii) or a C1-C5 alkanoyl group the alkyl moiety of which is optionally substituted with from one to three halo substituents, or a benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
or a methanesulfonyl or trifluoromethane-sulfonyl group; or a phenylsulfonyl group the phenyl moiety of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
R5 is a C1-C4 alkyl group optionally substi-tuted with from one or more fluoro or chloro substituents; cyclohexyl; a phenyl, benzylor phenethyl group the phenyl moiety of each of which is optionally sub-stituted with from one to five halo or methyl groups or with one or two methoxy, nitro or hydroxy substituents; or a het-eroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyra-zinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxa-diazolyl, thiazolyl, isothiazolyl, thia-diazolyl, thienyl and furanyl; optionally substituted with one or more C1-C4 alkyl, halo, methoxy, ethoxy, hydroxy or phenyl substituents;
R6 is hydrogen, C1-C6 alkyl optionally sub-stituted with from one to three halo substi-tuents, phenyl, benzyl, phenethyl or C3-C8- cycloalkyl;
R7 is an R6 group or a C1-C5 alkanoyl group the alkyl moiety of which is optionally substituted with from one to three halo substituents, or a benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenyl-thioacetyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl sub-stitutents or with one or two methoxy, nitro or hydroxy substituents; or an alkoxycarbonyl group; and R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl or the R8 groups taken together form a polymethylene moiety such that -N(R8)2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl;
provided 1) that, when R1 is -NHR6 or R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen, hydroxyl, or mycarosyloxy and Ar cannot be a type (iii) substituent;
and 2) that, when R2 is hydrogen, R3 must be hydrogen, hydroxyl or mycarosyloxy; or a physiologically accept-able salt thereof;which comprises:

(a) reacting a starting macrolide of formula (II) wherein Q is formyl and Q1 is R1 with an amine of the formula or HR9 in the presence of a reducing agent to give a macrolide of formula (I) wherein R is R9, or (b) reacting a starting macrolide of formula (II) wherein Q is -CH2L where L is a leaving group and Q1 is R1 or a leaving group with an amine of the formula HNR6R6 or HR9 to give a macrolide of formula (I) wherein R is R9, or (c) hydrolyzing a macrolide of formula (II) wherein Q is CH2R and Q1 is to give a macrolide of formula (I) wherein R1 is hydroxyl, or (d) removing the hydroxy protecting group from a macrolide of formula (II) wherein Q is -CH2R and Q1 is protected hydroxy or (e) reacting a starting macrolide of formula (II) wherein Q is -CH2R and Q1 is hydroxyl with diethyl-azodicarboxylate or dimethylazodicarboxylate, triphenyl-phosphine, and a reagent selected from (i) an azide transfer agent to give a macrolide of formula (I) wherein R1 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 R1 is -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 R1 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 (f) reacting a macrolide of formula (II) 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 (g) reacting a macrolide of formula (II) wherein Q is CH2R and Q1 is hydroxyl with triphenyl-phosphine and a halogenating agent to give a macrolide of formula (I) wherein R1 is Cl, Br or I, or (h) reacting a macrolide of formula (II) wherein Q is -CH2R and Q1 is a leaving group with (1) 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, (2) a mercaptide ion of formula R5S- to give a macrolide of formula I wherein R1 is R5S-, or (3) an amine of the formula HNR6R6 or HR9 to give a macrolide of formula (I) wherein R1 is HR6R6 or R9, or (i) reducing a macrolide of formula (II) wherein Q is CH2R and Q1 is azido to give a macrolide of formula (I) wherein R1 is amino, or (j) acylating a macrolide of formula (II) wherein R1 is NHR6 to give a macrolide of formula (I) wherein R1 is -NR6R7, or (k) esterifying a macrolide of formula (I), or (l) salifying a macrolide of formula (I), or (m) 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 (n) deoxygenating a macrolide of formula (I) wherein R3 is hydroxy to give a macrolide of formula (I) wherein R3 is hydrogen.

2. A process according to claim 1, wherein R
is 3-azabicyclo(3.2.2)nonan-3-yl, morpholino, 4-phenyl-piperidin-1-yl, or octahydroazocin-l-yl.

3. A process according to claim 1 or 2, where-in R1 is hydroxy or octahydroazocin-1-yl.

4. A process according to claim 1, wherein step a) is used to prepare 20-dihydro-deoxy-20-[3-azabicyclo(3.2.2)nonan-3-yl]-5-O-mycaminosyltylonolide.

5. A process according to claim 1, wherein step a) is used to prepare 20-dihydro-deoxy-20-morpho-lino-5-O-mycaminosyltylonolide.

6. A process according to claim 1, wherein step a) is used to prepare 20-dihydro-deoxy-20-(4-phenylpiperidin-1-yl)-5-O-mycaminosyltylonolide.

7. A process according to claim 1, wherein step b) is used to prepare 20-dihydro-deoxy-23-di(octa-hydroazocin-1-yl)-5-O-mycaminosyltylonolide.

8. A macrolide of formula (I) as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

9. 20-dihydro-deoxy-20-[3-azabicyclo(3.2.2)-nonan-3-yl]-5-O-mycaminosyltylonolide, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

10. 20-dihydro-deoxy-20-morpholino-5-O-mycaminosyltylonolide, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

11. 20-dihydro-deoxy-20-(4-phenylpiperidin-1-yl)-5-O-mycaminosyltylonolide, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

12. 20-dihydro-deoxy-23-deoxy-20,23-di(octa-hydroazocin-1-yl)-5-O-mycaminosyltylonolide, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

13. A macrolide of formula (I):

(I) wherein R is 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(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, -?-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; decahydroquinolin-1-yl;
1,2,3,4-tetrahydroisoguinolin-2-yl;
decahydroisoquinolin-2-yl; indolin-1-yl;
isoindolin-2-yl; decahydrocyclohepta[b]-pyrrol-1-yl; decahydrocyclohepta[c]-pyrrol-2-yl; decahydrocyclopent[c]-azepin-2-yl; decahydrocyclopenttd]-azepin-3-yl; 2,3,4,5-tetrzhydro-1H-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl; azabicycloheptanyl;
azabicyclooctanyl; azabicyclononanyl;
azabicyclodecanyl or azatricyclodecanyl;
R2 is hydrogen, or a C1-C5 alkanoyl group the alkyl moiety of which is optionally substituted with one to three halo substituents, or a benzoyl, phenylacetyl or phenylpropionyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substitutents or with one or two methoxy, nitro or hydroxy substituents;
R3 is hydrogen, hydroxyl, or a C1-C5 alkanoyloxy group the alkyl moiety of which is option-ally substituted with one to three halo substituents, or a benzoyloxy, phenylacetoxy or phenylpropionyloxy group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
or (mycarosyloxy) AR is i) phenyl, 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, di-methylamino, diethylamino, C4-C10-methyleneamino, azido, hydroxy, hydroxy-methyl, aminomethyl, (methylamino)methyl, (ethylamino)methyl, (dimethylamino)methyl, (diethylamino)methyl, (C4-C10-methylene-amino)methyl, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, carbox-amido, N-methylcarboxamido, N,N-dimethyl-carboxamido, cyano, phenyl, phenoxy or benzyl substituents; or naphthyl;
ii) a heteroaryl qroup selected from pyri-dinyl, pyrimidinyl, pyridazinyl, pyra-zinyl, triazinyl, indolyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, benzotriazolyl, benzoxa-zolyl, benzimidazolyl, carbazolyl, or acridinyl optionally substituted with one or more C1-C4 alkyl, halo, methoxy, ethoxy, hydroxy or phenyl substituents;
iii) or a C1-C5 alkanoyl group the alkyl moietv of which is optionally substituted with from one to three halo substituents, or a benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenylthioacetyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
or a methanesulfonyl or trifluoromethane-sulfonyl group; or a phenylsulfonyl group the phenyl moiety of which is optionally substituted with from one to five halo or methyl substituents or with one or two methoxy, nitro or hydroxy substituents;
R5 is a C1-C4 alkyl group optionally substi-tuted with from one or more fluoro or chloro substituents; cyclohexyl; a phenyl, benzyl or phenethyl group the phenyl moiety of each of which is optionally sub-stituted with from one to five halo or methyl groups or with one or two methoxy, nitro or hydroxy substituents; or a het-eroaryl group selected from imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyra-zinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxa-diazolyl, thiazolyl, isothiazolyl, thia-diazolyl, thienyl and furanyl; optionally substituted with one or more C1-C4 alkyl, halo, methoxy, ethoxy, hydroxy or phenyl substituents;
R6 is hydrogen, C1-C6 alkyl optionally sub-stituted with from one to three halo substi-tuents, phenyl, benzyl, phenethyl or C3-C8- cycloalkyl;
R7 is an R6 group or a C1-C5 alkanoyl group the alkyl moiety of which is optionally substituted with from one to three halo substituents, or a benzoyl, phenylacetyl, phenylpropionyl, phenoxyacetyl or phenyl-thioacetyl group the phenyl portion of each of which is optionally substituted with from one to five halo or methyl sub-stitutents or with one or two methoxy, nitro or hydroxy substituents; or an alkoxycarbonyl group; and R8 is hydrogen, methyl, ethyl, n-propyl or isopropyl or the R8 groups taken togetber form a polymethylene moiety such that -N(R8)2 constitutes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl;
provided 1) that, when R1 is -NHR6 or R8 is hydrogen, R2 must be hydrogen, R3 must be hydrogen, hydroxyl, or mycarosyloxy and Ar cannot be a type (iii) substituent;
and 2) that, when R2 is hydrogen, R3 must be hydrogen, hydroxyl or mycarocyloxy; or a physiologically accept-able salt thereof.

14. 20-dihydro-deoxy-20-[3-azabicyclo(3.2.2) nonan-3-yl]-5-0-mycaminosyltylonolide.

15. 20-dihydro-deoxy-20-morpholino-5-0-mycamin-osyltylonolide.

16. 20-dihydro-deoxy-20-(4-phenylpiperidin-1-yl)-5-0-mycaminosyltylonolide.

17. 20-dihydro-deoxy-23-deoxy-20,23-di (octahydroazocin-1-yl)-5-0-mycaminosyltylonolide.

18. A pharmaceutical formulation comprising, as the active ingredient a macrolide of formula (I) as defined in claim 13, or a physiologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or adjuvant therefor.

19. A pharmaceutical formulation as in claim 18 wherein the active ingredient is 20-dihydro-deoxy-20-[3-azabicyclo(3.2.2)nonan-3-yl]-5-0-mycaminosyltylonolide.

20. A pharmaceutical formulation as in claim 18 wherein the active ingredient is 20-dihydro-deoxy-20-morpholino-5-0-mycaminosyltylonolide.

21. A pharmaceutical formulation as in claim 18 wherein the active ingredient is 20-dihydro-deoxy-20-(4-phenylpyperidin-1-yl)-5-0-mycaminosyltylonolide.

22. A pharmaceutical formulation as in claim 18 wherein the active ingredient is 20-dihydro-deoxy-23-deoxy-20,23-di(octahydroazocin-1-yl)-5-0-mycaminosyltylonolide.