CROSS REFERENCE TO RELATED APPLICATION 
This application is a nonprovisional application claiming benefit of 
provisional application Ser. No. 60/008,196, filed Dec. 5, 1995. 
BACKGROUND OF THE INVENTION 
This invention is concerned with new antibiotics. In particular, this 
invention relates to compounds which are derivatives of the 3-deoxy 
macrolide antibiotics which have been derived from rosaramicin, 
repromicin, 5-mycaminosyltylonolide, desmycosin, lactenocin, 
O-demethyllactenocin, cirramycin A.sub.1, and 
23-deoxymycaminosyltylonolide; to the pharmaceutically-acceptable acid 
addition salts of such derivatives; to methods of using such derivatives 
in the treatment of illnesses in animals caused by bacterial and 
mycoplasmic pathogens; and to pharmaceutical compositions useful therefor. 
The term "animals" includes mammals, fish and birds. 
There are numerous agents known to combat bacterial infectious diseases in 
animals, but for many specific diseases the current agents of choice leave 
much to be desired. In some instances the agents may not persist long 
enough in the host and, therefore, require frequent dosing to maintain 
therapeutically effective blood and/or tissue levels. For meat producing 
animals (e.g., cattle, poultry, sheep and swine) this will require 
considerable labor intensive animal handling which is costly to the 
producer. In other cases, the agent may be poorly tolerated or even toxic 
to the host at therapeutically effective doses. Agents with increased 
potency, a longer half-life, an increased therapeutic index and a broader 
spectrum of antibacterial activity as well as--agents with greater oral 
absorption would improve the scope of animal diseases that could be more 
effectively treated. Thus, the need for new antibacterial and 
anti-mycoplasmic agents with improved properties endures. 
Diseases of particular concern are: bovine respiratory disease, the 
principal causative bacterial pathogens of which are Pasteurella 
haemolytica, P. multocida and Haemophilus somnus; pasteurellosis in swine, 
goats, sheep and poultry LP. multocida); swine pleuropneumonia 
(Actinobacillus pleuropneumoniae); swine streptococcus infections 
(Streptococcus suis); and for all of the above mentioned hosts, infections 
by Mycoplasma spp. 
Derivatives of tylosin and its related macrolides have been shown to be 
effective against infections in poultry, cattle and swine caused by 
certain gram-positive and gram-negative bacteria: Kirst et al., U.S. Pat. 
Nos. 4,920,103; Tao et al., 4,921,947; Kirst et al., U.K. Patent 
Application GB 2135670A. 
Other antibiotic macrolides have been claimed in co-pending U.S. 
applications, application Ser. No. 08/362,496 filed Jan. 11, 1995 
(published in WO 94/02496) and application Ser. No. 08/311,285 filed Sep. 
22, 1994, and in co-pending PCT applications, application Ser. No. 
PCT/US94/00095 filed Jan. 6, 1994 published in WO 94/21657 and application 
Ser. No. PCT/IB94/00199 filed Jul. 4, 1994 published in WO 95102594, all 
of which are assigned to the assignee hereof. 
SUMMARY OF THE INVENTION 
This invention is concerned with new antibiotics which are derivatives of 
3-deoxy macrolide antibiotics which have been derived from repromicin, 
rosaramicin, 5-mycaminosyltylonolide, desmycosin, lactenocin, 
O-demethyllactenocin, cirramycin A.sub.1, and 
23-deoxymycaminosyltylonolide and to the acid addition salts of such 
derivatives. These new antibiotics have enhanced potency against bacterial 
pathogens over the parent compounds and are active against mycoplasmic 
pathogens. 
The compounds of the present invention are of the formula (I) or (II) 
##STR1## 
or the pharmaceutically acceptable salts thereof, wherein m is 1 or 2; 
Z.sup.1 is H, OH or mycarosyloxy; 
represents a single or a double bond wherein the double bond results in 
either the cis or trans geometry; 
Q is selected from the group consisting of H, OH, fluoro, chloro, bromo, 
iodo, OX.sup.1, 
##STR2## 
azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 
3,3-dimethylpiperidin-1-yl, hexahydroazepin-1 -yl,octahydroazocin-1-yl, 
octahydroindol-1-yl, 1,3,3a,4,7,7a-hexahydroisoindol-2-yl, 
decahydroquinol-1-yl, decahydroisoquinol-2-yl, 
1,2,3,4-tetrahydroisoquinol-2-yl, 1,2,3,6-tetrahydropyridin-1-yl, 
4-alkylpiperazin-1-yl having 1 to 4 carbons in the alkyl portion, 
morpholino, 2,6-dimethylmorpholin-4-yl, thiomorpholino, and --NX.sup.2 
X.sup.3 ; 
X.sup.1 is selected from the group consisting of optionally substituted 
alkyl having 1 to 4 carbons, optionally substituted cycloalkyl having 4 to 
8 carbon atoms, and an optionally substituted aryl, aralkyl or heteroaryl 
group selected from the group consisting of phenyl, benzyl, pyridinyl, 
quinolinyl, isoquinolinyl, quinazolinyl, pyrimidinyl, imidazolyl, 
oxazolyl, thiazolyl, benzimidazolyl, indolyl, benzoxazolyl and 
benzthiazolyl; 
where the optionally substituted aryl, aralkyl and heteroaryl groups are 
optionally substituted with 1 or 2 substituents independently selected 
from the group consisting of alkyl having 1 to 4 carbons, fluoro, chloro, 
bromo, acetyl, amino, nitro, cyano, trifluoromethyl, N-alkylamino having 1 
to 4 carbons, N,N-dialkylamino having a total of 2 to 6 carbons, carboxyl, 
carboalkoxy having 1 to 4 carbons, carboxamido, sulfonamido, hydroxyalkyl 
having 1 to 4 carbons, aminoalkyl having 1 to 4 carbons, N-alkylaminoalkyl 
having 1 to 4 carbons in each of the alkyl portions, and 
N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino 
portion and 1 to 4 carbons in the alkyl portion; 
X.sup.2 and X.sup.3 are each independently selected from the group 
consisting of hydrogen, alkyl having 1 to 4 carbons, hydroxyalkyl having 2 
to 4 carbons, cycloalkyl having 3 to 8 carbons, alkenyl having 3 or 4 
carbons, alkoxyalkyl having 1 to 4 carbons in the alkoxy portion and 2 to 
4 carbons in the alkyl portion and alkoxyalkoxyalkyl having 1 to 4 carbons 
in each of the alkoxy portions and 2 to 4 carbons in the alkyl portion; 
T is 
--C(.dbd.O)(Z.sup.3), --CH.sub.2 --N(B)(CH.sub.2).sub.a 
--C(.dbd.O)(Z.sup.3), --CH.sub.2 --N(Z.sup.2)(C.dbd.O)--(CH.sub.2).sub.a 
--Z.sup.3, --CH.sub.2 --N(B)(CH.sub.2).sub.g --N(B)(CH.sub.2).sub.a 
--C(.dbd.O)(Z.sup.3), --CH.dbd.CH--(CH.sub.2).sub.n --(Z.sup.4)(Z.sup.5), 
--CH(Z.sup.8)N(Z.sup.5)(Z.sup.6)(Z.sup.7), 
##STR3## 
--CH.sub.2 --N(Z.sup.12)(SO.sub.2 Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(C(.dbd.O)--Z.sup.14 --Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(CH.sub.2).sub.g --N(Z.sup.15)(C(.dbd.O)--Z.sup.14 
--Z.sup.13) or --CH.sub.2 --N(Z.sup.12)(CH.sub.2).sub.g 
--N(Z.sup.15)(SO.sub.2 --Z.sup.13); 
wherein n is an integer from 1 to 4; 
B for each occurrence is independently selected from the group consisting 
of hydrogen, (C.sub.1 -C.sub.4)alkyl, an aminoacyl group and a dipeptidyl 
group; 
Z.sup.2 is hydrogen or (C.sub.1 -C.sub.4)alkyl; 
Z.sup.3 is --N(R.sup.1 R.sup.2), --NH--CH(R.sup.3)--(CH.sub.2).sub.e 
--COOR.sup.4 or --NH--CH(R.sup.3)--(CH.sub.2).sub.e 
--C(.dbd.O)--NH--(CH.sub.2).sub.f --COOR.sup.4 ; 
R.sup.1 and R.sup.2 are each independently selected from the group 
consisting of hydrogen, methyl, optionally substituted alkyl having 2 to 6 
carbons, optionally substituted cycloalkyl having 3 to 8 carbons, 
aminoalkyl having 2 to 6 carbons, hydroxyalkyl having 2 to 6 carbons, 
N-alkylamino-alkyl having 1 to 4 carbons in the alkylamino portion and 2 
to 4 carbons in the alkyl portion, optionally substituted benzyl, 
optionally substituted phenyl, alkoxyalkyl having 2 to 4 carbons in the 
alkyl portion and 1 to 4 carbons in the alkoxy portion, 
N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino 
portion and 2 to 4 carbons in the alkyl portion, --(CH.sub.2).sub.g 
-morpholino, --(CH.sub.2).sub.g -piperidino, --(CH.sub.2).sub.g 
-pyrrolidino, --(CH.sub.2).sub.g -azetidin-1-yl, and --(CH.sub.2).sub.g 
-hexahydroazepin-1-yl; 
or R.sup.1 and R.sup.2 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; 
R.sup.3 corresponds to just the side chain portion of amino acids and for 
each occurrence is independently selected from the side chain of the group 
of amino acids consisting of the D- or L-form, when applicable, of 
alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic 
acid, glutamine, glycine, histidine, hydroxylysine, hydroxyproline, 
isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, 
threonine, tryptophan, tyrosine, valine, .beta.-alanine, .beta.-lysine, 
.alpha.,.alpha.-dimethylglycine, .alpha.-aminobutyric acid, 
4-hydroxyphenylglycine, phenylglycine, .alpha.,.gamma.-diaminobutyric 
acid, ornithine and homoserine; 
e is 0 or 1, provided that when e is 1 then R.sup.3 corresponds to the side 
chain of .beta.-lysine or .beta.-alanine; 
f is 0 or 1, provided that when f is 1 then R.sup.3 corresponds to the side 
chain of .beta.-lysine or .beta.-alanine; 
R.sup.4 is H, alkyl having 1 to 4 carbons or benzyl; 
Z.sup.4 is selected from the group consisting of hydrogen, an aminoacyl 
group, a dipeptidyl group, alkenyl having 3 to 5 carbons provided that the 
double bond is not adjacent to the nitrogen to which Z.sup.4 is attached, 
alkynyl having 3 to 5 carbons provided that the triple bond is not 
adjacent to the nitrogen to which Z.sup.4 is attached, hydroxyalkyl having 
2 to 4 carbons in the alkyl portion, Q.sup.10, Q.sup.20, Q.sup.30, and 
alkoxyalkyl having 2 to 4 carbons in the alkyl portion and 1 to 4 carbons 
in the alkoxy portion; 
Z.sup.5 is selected from the group consisting of hydrogen, alkenyl having 3 
to 5 carbons provided that the double bond is not adjacent to the nitrogen 
to which Z.sup.5 is attached, alkynyl having 3 to 5 carbons provided that 
the triple bond is not adjacent to the nitrogen to which Z.sup.5 is 
attached, hydroxyalkyl having 2 to 4 carbons in the alkyl portion, 
Q.sup.10, Q.sup.20, Q.sup.30, alkoxyalkyl having 2 to 4 carbons in the 
alkyl portion and 1 to 4 carbons in the alkoxy portion and --R.sup.6 
--N(R.sup.7 R.sup.8); 
Q.sup.10 for each occurrence is independently 
##STR4## 
where u is an integer from 1 to 5 and Q.sup.15 for each occurrence is 
independently selected from the group consisting of (C.sub.1 
-C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, fluoro, chloro, bromo, iodo, 
nitro, amino, cyano, hydroxy, trifluoromethyl and carboalkoxy having 1 to 
4 carbons; 
Q.sup.20 for each occurrence is independently an optionally substituted 
(C.sub.1 -C.sub.4)alkyl, optionally substituted with a substituent 
selected from the group consisting of hydroxy, cyano, N-alkylamino having 
1 to 5 carbons and N,N-dialkylamino having a total of 2 to 6 carbons; 
Q.sup.30 for each occurrence is independently 
##STR5## 
where d is an integer from 1 to 5 and Q.sup.35 is selected from the group 
consisting of hydroxy, cyano, N-alkylamino having 1 to 5 carbons and 
N,N-dialkylamino having a total of 2 to 6 carbons; 
R.sup.6 is (C.sub.2 -C.sub.4)alkylene; 
R.sup.7 is selected from the group consisting of hydrogen, alkyl having 1 
to 4 carbons, cycloalkyl having 3 to 8 carbons and alkoxyalkyl having 2 to 
4 carbons in the alkyl portion and 1 to 4 carbons in the alkoxy portion; 
R.sup.8 is selected from the group consisting of alkyl having 1 to 4 
carbons, an optionally substituted hydroxyalkanoyl having 1 to 6 carbons, 
an aminoacyl group and a dipeptidyl group, 
wherein the optionally substituted hydroxyalkanoyl group is optionally 
substituted with an optionally substituted phenyl group; 
or R.sup.7 and R.sup.8 are taken together with the nitrogen to which they 
are attached and form a cyclic amine having 3 to 6 carbon atoms; 
or Z.sup.4 and Z.sup.5 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; 
Z.sup.6 is an aminoacyl group, a dipeptidyl group or is independently 
selected from the same group as defined for R.sup.1 ; 
Z.sup.7 is independently selected from the same group as defined for 
R.sup.1 or from the group consisting of 
##STR6## 
--(CH.sub.2).sub.g --R.sup.12 !.sub.q --(CH.sub.2).sub.g 
--N(Z.sup.16).sub.2 and --R.sup.9 --N(R.sup.10 R.sup.11); 
wherein q is 1, 2 or 3; 
R.sup.9 is (C.sub.2 -C.sub.4)alkylene optionally substituted with (C.sub.1 
-.sub.4)alkyl or hydroxy provided that the hydroxy can only be attached to 
the C2 of the alkylene group when the alkylene is three carbon atoms long 
or to the C3 of the alkylene group when the alkylene is four carbon atoms 
long; 
R.sup.10 is selected from the group consisting of hydrogen, methyl and 
ethyl; 
R.sup.11 is selected from the group consisting of an optionally substituted 
hydroxyalkanoyl having 1 to 6 carbons, an amino acyl group, and dipeptidyl 
group, 
the optionally substituted hydroxyalkanoyl group is optionally substituted 
with an optionally substituted phenyl; 
or R.sup.10 and R.sup.11 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; 
R.sup.12 is S or O; 
Z.sup.16 for each occurrence is independently selected from the group 
consisting of an aminoacyl group, dipeptidyl group and the same group of 
substituents as is defined hereinbelow for Z.sup.12, Z.sup.13 and Z.sup.15 
; 
or Z.sup.6 and Z.sup.7 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; 
Z.sup.8 is H or CN; 
Z.sup.9 is (C.sub.1 -.sub.6)alkyl, amino acyl group, dipeptidyl group, 
hydroxyalkanoyl having 1 to 6 carbons, aminoalkyl having 2 to 6 carbons, 
hydroxyalkyl having 2 to 4 carbons, N-alkylaminoalkyl having 1 to 4 
carbons in the alkylamino portion and 2 to 4 carbons in the alkyl portion, 
alkoxyalkyl having 2 to 4 carbons in the alkyl portion and 1 to 4 carbons 
in the alkoxy portion, N,N-dialkylaminoalkyl having a total of 2 to 6 
carbons in the dialkylamino portion and 2 to 4 carbons in the alkyl 
portion, --CO--Z.sup.14 --Z.sup.13 or --SO.sub.2 --Z.sup.13 ; 
Z.sup.12, Z.sup.13 and Z.sup.15 for each occurrence are each independently 
selected from the same group as defined for R.sup.1, provided that 
Z.sup.13 is hydrogen only when Z.sup.14 is NH; 
Z.sup.14 for each occurrence is independently O or NH; 
a for each occurrence is independently 1 or 2; 
for each occurrence of the amino acyl group and dipeptidyl group, the amino 
acyl group and the amino acyl groups of the dipeptidyl group are 
independently selected from the group consisting of the D- or L-form, when 
applicable, of alanyl, arginyl, asparagyl, aspartyl acid, cysteinyl, 
cystyl, glutamyl acid, glutamyl, glycyl, histidyl, hydroxylysyl, 
hydroxyprolyl, isoleucyl, leucyl, iysyl, methionyl, phenylalanyl, prolyl, 
seryl, threonyl, tryptophyl, tyrosyl, valyl, .beta.-alanyl, .beta.-lysyl, 
N,N-dimethylglycyl, .alpha.,.alpha.-dimethylglycyl, .alpha.-aminobutyryl, 
4-hydroxyphenylglycyl, phenylglycyl, .alpha.,.gamma.-diaminobutyryl, 
ornithyl, homoseryl, bicyl, N,N-diethyl-.beta.-alanyl, 
N,N-dimethyl-.gamma.-aminobutyryl and sarcosyl, provided that N, 
N-dimethylglycyl, bicyl, N,N-diethyl-.beta.-alanyl or N, 
N-dimethyl-.gamma.-aminobutyryl can only be the terminal aminoacyl when in 
a dipeptidyl group; 
for each occurrence of an optionally substituted alkyl or optionally 
substituted cycloalkyl, the optionally substituted alkyl or optionally 
substituted cycloalkyl is independently selected from an optionally 
substituted alkyl or optionally substituted cycloalkyl optionally 
substituted with 1, 2 or 3 substituents independently selected from the 
group consisting of hydroxy, cyano, fluoro, trifluoromethyl, optionally 
substituted amino, optionally substituted N-alkylamino having 1 to 4 
carbons, N,N-dialkylamino having a total of 2 to 6 carbons, 
N--(hydroxyalkyl)amino having 2 to 4 carbons, N,N-bis(hydroxyalkyl)amino 
wherein each alkyl portion has 2 to 4 carbons, alkoxy having 1 to 4 
carbons, alkoxycarbonyl having 1 to 4 carbons in the alkoxy portion, 
N,N-dialkylaminoalkoxy having a total of 2 to 6 carbons in the 
dialkylamino portion and 2 to 4 carbons in the alkoxy portion, 
alkoxyalkoxy having 1 to 4 carbons in each of the alkoxy portions, 
alkoxyalkoxyalkoxy having 1 to 4 carbons in each of the alkoxy portions, 
spirocycloalkyl having 4 to 6 carbons, 
##STR7## 
wherein the optionally substituted amino and the optionally substituted 
N-alkylamino are each independently optionally mono-substituted with an 
aminoacyl group or a dipeptidyl group; 
R.sup.13 and R.sup.14 are each independently selected from the group 
consisting of hydrogen and alkyl having 1 to 4 carbons; 
or R.sup.13 and R.sup.14 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; 
R.sup.15, R.sup.16, and R.sup.17 are each independently selected from the 
group consisting of hydrogen, (C.sub.1 -C.sub.4)alkyl, an aminoacyl group 
and a dipeptidyl group; 
R.sup.18 is NH, S, N-(C.sub.1 -C.sub.4)alkyl, N--(amino acyl group), or 
N-(dipeptidyl group); 
R.sup.19 is selected from the group consisting of C, CH, CH.sub.2, N and 
NH; 
R.sup.20 is alkyl having 1 to 4 carbons or --COOR.sup.21 ; 
R.sup.21 for each occurrence is independently H or alkyl having 1 to 4 
carbons; 
R.sup.22 is selected from the group consisting of H, alkyl having 1 to 4 
carbons, hydroxy, alkoxy having 1 to 3 carbons, amino, N-alkylamino having 
1 to 4 carbons and N,N-dialkylamino having a total of 2 to 6 carbons; 
or R.sup.21 and R.sup.22 are taken together and form an oxo group; 
Z.sup.100 for each occurrence is independently selected from the group 
consisting of 
##STR8## 
where R.sup.23 is selected from the group consisting of C, CH, CH.sub.2, 
N, NH, N(amino acyl) or N(dipeptidyl group); 
R.sup.24 is alkyl having 1 to 4 carbons, --CO--(C.sub.1 -C.sub.4)alkyl or 
--COO--(C.sub.1 -C.sub.4)alkyl; 
R.sup.25 is O or S; 
R.sup.26 is selected from the group consisting of alkyl having 1 to 4 
carbons, an optionally substituted hydroxyalkanoyl having 1 to 6 carbons, 
an amino acyl group and a dipeptidyl group, 
wherein the optionally substituted hydroxyalkanoyl group is optionally 
substituted with an optionally substituted phenyl group; 
R.sup.27 is H or alkyl having 1 to 4 carbons; 
R.sup.28 is H, alkyl having 1 to 4 carbons, hydroxy, alkoxy having 1 to 3 
carbons, amino, N-alkylamino having 1 to 4 carbons or N,N-dialkylamino 
having a total of 2 to 6 carbons; 
or R.sup.27 and R.sup.28 are taken together and form an oxo; 
g for each occurrence is independently 2, 3, or 4; 
b for each occurrence is independently 0, 1 or 2; and 
for each occurrence of the optionally substituted phenyl or optionally 
substituted benzyl, the optionally substituted phenyl or optionally 
substituted benzyl is optionally substituted with 1 or 2 substituents 
independently selected from the group consisting of alkyl having 1 to 4 
carbons, fluoro, chloro, bromo, acetyl, amino, nitro, cyano, 
trifluoromethyl, N-alkylamino having 1 to 4 carbons, N,N-dialkylamino 
having a total of 2 to 6 carbons, --NH--CO--CH.sub.3, carboxyl, 
carboalkoxy having 1 to 4 carbons, carboxamido, sulfonamido, hydroxyalkyl 
having 1 to 4 carbons, aminoalkyl having 1 to 4 carbons, N-alkylaminoalkyl 
having 1 to 4 carbons in each of the alkyl portions, and 
N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino 
portion and 1 to 4 carbons in the alkyl portion; 
with the following provisos: 
(1) that when T is --C(.dbd.O)(Z.sub.3), --CH.sub.2 --N(B)(CH.sub.2).sub.a 
--C(.dbd.O)(Z.sup.3), --CH.sub.2 --N(Z.sup.2)(C.dbd.O)--(CH.sub.2).sub.a 
--Z.sup.3 or --CH.sub.2 --N(B)(CH.sub.2).sub.9 --N(B)(CH.sub.2).sub.a 
--C(.dbd.O)(Z.sup.3) wherein Z.sup.3 is --N(R.sup.1 R.sup.2) where R.sup.1 
or R.sup.2 is a substituted alkyl or substituted cycloalkyl, then the 
substituent at the 1-position of the substituted alkyl or substituted 
cycloalkyl cannot be fluoro, chloro or a heteroatom attached substituent; 
and 
(2) when any of the substituents defined above which may be a substituted 
cycloalkyl is a substituted cycloalkyl, then the substituent at the 
1-position of the substituted cycloalkyl cannot be fluoro, chloro or a 
heteroatom attached substituent. 
The term "loweralkyl" denotes an alkyl having 1 to 4 carbons. The term 
"alkyl" is meant to encompass both straight chain and branched alkyls. 
Those skilled in the art will recognize that some of the compounds of the 
present invention possess stereochemical centers. In those cases where 
stereo-chemical centers are present it is understood that all of the 
stereoisomers are within the scope of this invention. Further, in those 
cases where the bond between the C2 and C3 of the macrolide is a double 
bond both the cis and trans form are within the scope of this application. 
The amino acyl groups are derivatives of the corresponding amino acids and 
are well known in the art. The following D- or L-amino acids, where 
applicable, are used to derive the amino acyl groups of this invention: 
alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic 
acid, glutamine, glycine, histidine, hydroxylysine, hydroxyproline, 
isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, 
threonine, tryptophan, tyrosine, valine, .beta.-alanine, .beta.-lysine, 
N,N-dimethylglycine, .alpha.,.alpha.-dimethylglycine, .alpha.-aminobutyric 
acid, 4-hydroxyphenylglycine, phenylglycine, 
.alpha.,.alpha.-diaminobutyric acid, ornithine, homoserine, bicine, 
N,N-diethyl-.beta.-alanine, N,N-dimethyl-.gamma.-aminobutyric acid, and 
sarcosine. 
The dipeptidyl groups comprise derivatives of any possible combination of 
two of the amino acids listed hereinabove which can be coupled by 
conventional peptide synthesis methods well known to those skilled in the 
art. 
A group of preferred compounds are those compounds having the formula (I) 
or the pharmaceutically acceptable salts thereof wherein m is 1 and 
Z.sup.1 is H or OH. 
A group of more preferred compounds are those compounds having the formula 
(I) or a pharmaceutically acceptable salt thereof wherein m is 1; Z.sup.1 
is H or OH; T is --CH.sub.2 --N(B)(CH.sub.2).sub.a --C(.dbd.O)(Z.sup.3), 
--CH.sub.2 --N(Z.sup.2)(C.dbd.O)--(CH.sub.2).sub.a --Z.sup.3, --CH.sub.2 
--N(B)(CH.sub.2).sub.g --N(B)(CH.sub.2).sub.a --C(.dbd.O)(Z.sup.3), 
--CH.dbd.CH--(CH.sub.2).sub.n --N(Z.sup.4)(Z.sup.5), 
--CH(Z.sup.8)N(Z.sup.6)(Z.sup.7), 
##STR9## 
--CH.sub.2 --N(Z.sup.12)(SO.sub.2 Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(C(.dbd.O)--Z.sup.14 --Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(CH.sub.2).sub.g --N(Z.sup.16)(C(.dbd.O)--Z.sup.14 
--Z.sup.13) or --CH.sub.2 %13 N(Z.sup.12)(CH.sub.2).sub.g 
--N(Z.sup.15)(SO.sub.2 Z.sup.13) where a, g, n, Q, Z.sup.2, Z.sup.3 
Z.sup.4, Z.sup.5, Z.sup.6, Z.sup.7 Z.sup.8, Z.sup.9, Z.sup.12, Z.sup.13, 
Z.sup.14 and Z.sup.15 are as defined hereinabove. 
A group of an even more preferred group of compounds are those compounds 
having the formula (I) or a pharmaceutically acceptable salt thereof 
wherein m is 1; Z.sup.1 is H or OH; T is --CH.dbd.CH--(CH.sub.2).sub.n 
--N(Z.sup.4)(Z.sup.5), --CH(Z.sup.8)N(Z.sup.6)(Z.sup.7), 
##STR10## 
--CH.sub.2 --N(Z.sup.12)(SO.sub.2 Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(C(.dbd.O)--Z.sup.14 --Z.sup.13), --CH.sub.2 
--N(Z.sup.12)(CH).sub.g --N(Z.sup.1 .sup.5)(C(.dbd.O)--Z.sup.14 
--Z.sup.13) or --CH.sub.2 --N(Z.sup.12)(CH.sub.2).sub.g 
--N(Z.sup.15)(SO.sub.2 --Z.sup.13) where a, g, n, Q, Z.sup.4, Z.sup.5, 
Z.sup.6, Z.sup.7, Z.sup.9, Z.sup.12, Z.sup.13, Z.sup.14 and Z.sup.15 are 
as defined hereinabove and Z.sup.8 is H. 
Yet a group of even more preferred compounds are those compounds having the 
formula (I) or a pharmaceutically acceptable salt thereof of formula (I) 
wherein m is 1; Z.sup.1 is H or OH; T is --CH.dbd.CH--(CH.sub.2).sub.n 
--N(Z.sup.4)(Z.sup.5), --CH.sub.2 --N(Z.sup.6)(Z.sup.7) or 
##STR11## 
where n is 1; Z.sup.4 and Z.sup.5 are each independently selected from the 
group consisting of hydrogen, alkenyl having 3 to 5 carbon atoms provided 
that the double bond is not adjacent to the nitrogen to which the alkenyl 
is attached, alkynyl having 3 to 5 carbons provided that the triple bond 
is not adjacent to the nitrogen to which the alkynyl is attached, 
hydroxyalkyl having 2 to 4 carbons in the alkyl portion, Q.sup.10, 
Q.sup.20, Q.sup.30 and alkoxyalkyl having 2 to 4 carbons in the alkyl 
portion and 1 to 4 carbons in the alkoxy portion, or Z.sup.4 and Z.sup.5 
are taken together with the nitrogen to which they are attached and form 
Z.sup.100 ; and a, Q, Z.sup.6, Z.sup.7, Z.sup.9, Q.sup.10, Q.sup.20, 
Q.sup.30, Z.sup.100 are as defined hereinabove for the formulae (I) and 
(II). 
A group of especially more preferred compounds are those compounds having 
the formula (I) or a pharmaceutically acceptable salt thereof wherein m is 
1; Z.sup.1 is H or OH; T is --CH.sub.2 --N(Z.sup.6)(Z.sup.7) or 
##STR12## 
where Z.sup.6 is independently selected from the same group of 
substituents as R.sup.1 ; Z.sup.7 is independently selected from the same 
group of substituents as R.sup.1 or is --R.sup.9 --N(R.sup.10 R.sup.11); 
or Z.sup.6 and Z.sup.7 are taken together with the nitrogen to which they 
are attached and form Z.sup.100 ; and Z.sup.9 is amino acyl group, 
aminoalkyl having 2 to 6 carbons, hydroxyalkyl having 2 to 4 carbons, 
N-alkylaminoalkyl having 1 to 4 carbons in the alkylamino portion and 2 to 
4 carbons in the alkyl portion, alkoxyalkyl having 2 to 4 carbons in the 
alkyl portion and 1 to 4 carbons in the alkoxy portion, 
N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino 
portion and 2 to 4 carbons in the alkyl portion or --CO--Z.sup.14 
--Z.sup.13 ; and a, Q, R.sup.1, R.sup.9, R.sup.10, R.sup.11, Z.sup.13, 
Z.sup.14, Z.sup.100 are as defined hereinabove for formulae (I) and (II). 
A first group of most preferred compounds are those compounds having the 
formula (I) or a pharmaceutically acceptable salt thereof wherein m is 1; 
Q is OH; Z.sup.1 is H; and T is --CH.sub.2 --N(Z.sup.6)(Z.sup.7) where 
Z.sup.6 is hydrogen, methyl or optionally substituted alkyl having 2 to 6 
carbon atoms; Z.sup.7 is N-alkylaminoalkyl having 1 to 4 carbons in the 
alkylamino portion and 2 to 4 carbons in the alkyl portion, optionally 
substituted alkyl having 2 to 6 carbon atoms or optionally substituted 
cycloalkyl having 3 to 8 carbons; or Z.sup.6 and Z.sup.7 are taken 
together with the nitrogen to which they are attached and form 
pyrrolidino, piperidino 3,4-dehydropiperidino or azabicyclononan-3-yl. 
Especially preferred within the foregoing first group of most preferred 
compounds are those compounds or a pharmaceutically acceptable salt 
thereof wherein said optionally substituted alkyl of Z.sup.6 is propyl; 
said optionally substituted alkyl of Z.sup.7 is propyl, 
3-(dimethylamino)-propyl or 2-spirocyclo-pentyl-3-hydroxypropyl; and said 
optionally substituted cycloalkyl of Z.sup.7 is cyclohexyl. 
A second group of most preferred compounds are those compounds having the 
formula (I) or a pharmaceutically acceptable salt thereof wherein m is 1; 
Q is OH; Z.sup.1 is H; and T is --CH.sub.2 --N(Z.sup.6)(Z.sup.7) where 
Z.sup.6 hydrogen or methyl; Z.sup.7 is methyl, 2-fluoroethyl, 
2,2-dimethyl-3-hydroxypropyl, 2-hydroxyethyl, propyl, 3-hydroxypropyl, 
2,5-(dihydroxy)-cyclohexyl or 3-aminopropyl; or Z.sup.6 and Z.sup.7 are 
taken together with the nitrogen to which they are attached and form 
4-methylpiperazino, azetidino, 4-hydroxypiperidino, morpholino or 
3-hydroxypiperidino. 
A third group of most preferred compounds are those compounds having the 
formula (I) or a pharmaceutically acceptable salt thereof wherein m is 1; 
Q is OH; Z.sup.1 is OH; and T is --CH.sub.2 --N(Z.sup.6)(Z.sup.7) where 
Z.sup.6 is hydrogen; Z.sup.7 is 2,2-dimethyl-3-hydroxypropyl; or Z.sup.6 
and Z.sup.7 are taken together with the nitrogen to which they are 
attached and form hexahydroazepin-1-yl. 
A fourth group of most preferred compounds are those compounds having the 
formula (I) or a pharmaceutically acceptable salt thereof wherein m is 1; 
the bond between C2-C3 of the macrolide is a double bond, Q is OH; Z.sup.1 
is OH; and T is --CH.sub.2 --N(Z.sup.6)(Z.sup.7) where Z.sup.6 is 
hydrogen, methyl or propyl; Z.sup.7 is 2,2-dimethyl-3-hydroxypropyl, 
methyl, propyl or 3-(dimethylamino)propyl; or Z.sup.6 and Z.sup.7 are 
taken together with the nitrogen to which they are attached and form 
hexahydroazepin-1-yl or 3-azabicyclononan-3-yl. 
Thus, in a further aspect, the invention provides pharmaceutical 
compositions comprising a compound of the formula (I) or (II), or a 
pharmaceutically acceptable salt thereof, and a pharmaceutically 
acceptable carrier or diluent. 
This invention also provides methods of treating a bacterial infection or a 
mycoplasmic infection in an animal in need thereof, which methods comprise 
administering to said animal a bacterial or mycoplasmic treating amount of 
a compound of the formula (I) or (II), or a pharmaceutically acceptable 
salt thereof. 
This invention further provides a method of using the compounds of claim 1 
or the pharmaceutically acceptable salts thereof prophylactically in 
treating animals susceptible to a bacterial or mycoplasmic infection. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the present invention, having the formula (I) or (II), as 
defined above, are readily and generally prepared by reductive amination 
reactions of the appropriate 3-deoxy macrolide derivatives of rosaramicin, 
repromicin, 5-mycaminosyl-tylonolide, desmycosin, lactenocin, 
O-demethyllactenosin, cirramycin A.sub.1, or 
23-deoxy-mycaminosyltylonolide, with an amine, optionally followed by 
conversion to the acid addition salt as shown in the methods of the 
Examples hereinbelow, in methods analogous thereto and by the methods 
described immediately below. 
Repromicin was prepared according to the following fermentation procedure. 
Fermentor scale: 
To prepare frozen lots for use as standard inoculum, Micromonospora 
rosaria, ATCC 55709, deposited Sep. 5, 1995, is inoculated into JDYTT 
medium (cerelose 10 g/L, corn starch 5 g/L, corn steep solids 2.5 g/L, NZ 
Amine YTT 5 g/L, COCl.sub.2.6H.sub.2 O 0.002 g/L, P-2000 (polyglycol, 
available from George Mann & Co., Inc., 175 Terminal Road, Providence, 
R.I.) 1 ml/L, CaCO.sub.3 3 g/L) and shaken (250 rpm, 30.degree. C., 2 inch 
throw) for about three days. The JDYTT medium, adjusted to about pH 7.0, 
was sterilized at about 121.degree. C. for about 30 minutes prior to use. 
Glycerol (final concentration 20%) is added as a cryoprotectant, and the 
culture is stored at about -80.degree. C. To prepare the inoculum, 5 ml of 
the frozen culture lot is transferred to 1 liter of JDYTT medium in a 2.8 
L fernbach flask. The culture is grown for about 3 days at about 
30.degree. C. with shaking (250 rpm, 2 inch throw). The entire contents of 
the fernbach are transferred to 8 L of production medium RSM-6 in a 14 L 
fermentor jar (New Brunswick Scientific, New Brunswick, N.J.) with two 
43/4 inch agitator blades. The composition of RSM-6 is corn starch 50 g/L, 
cerelose 10 g/L, ardamine PH 5 g/L (available from Champlain Industries 
Inc., 79 State Street, Harbor Beach, Mich.), Pharmamedia 8-10 g/L 
(available from The Buckeye Cellulose Corporation, P.O. Box 8407, Memphis, 
Tenn.), MgHPO.sub.4.3H.sub.2 O 10 g/L, casein hydrolysate 2.5 g/L 
(available from Sheffield Chemical, Norwich, N.Y.), asparagine 0.5 g/L, 
FeSO.sub.4.7H.sub.2 O 0.028 g/L, MgSO.sub.4.7H.sub.2 O 0.5 g/L, K.sub.2 
HPO.sub.4 0.75 g/L, CuSO.sub.4.5H.sub.2 O 0.003 g/L, MnCl.sub.2.4H.sub.2 O 
0.003 g/L, ZnSO.sub.4.7H.sub.2 O 0.003 g/L, COCl.sub.2.6H.sub.2 O 0.003 
g/L, P2000 1 ml/L. RSM-6 is adjusted to about pH 7.0 and autoclaved for 
about 99 minutes at about 121.degree. C. prior to use. The fermentation is 
run at about 30.degree. C., 450 rpm, 0.34 v/vim air, with pH controlled 
between 6.7 and 7.3 with NaOH/H.sub.2 SO.sub.4 or by addition of 6 g/L 
MOPS to production medium. Repromicin titers typically peak between 69 and 
116 hours. Samples are extracted into a solvent mixture (3.5:6.5 
methanol:0.1M KH.sub.2 PO.sub.4 buffer, pH 3.5). 
Flask scale: 
Inoculum is prepared as described above or by adding 2 ml of frozen culture 
lot to 30 ml JDYTT inoculum medium in a 300 ml Erlenmeyer flask. The 
culture is grown for about 3 days at about 30.degree. C. with shaking (250 
rpm, 2 inch throw). Two ml of inoculum are transferred into about 30 ml 
modified RSM-5 medium (corn starch 30 g/L, 10 g/L pharmamedia, 10 g/L 
cerelose, 5.0 g/L ardamine PH, 0.5 g/L asparagine, FeSO.sub.4.7H.sub.2 O 
0.028 g/L, MgSO.sub.4.7H.sub.2 O 0.5 g/L, K.sub.2 HPO.sub.4 0.75 g/L, 
CUSO.sub.4.5H.sub.2 O 0.002 g/L, MnCl.sub.2.4H.sub.2 O 0.003 g/L, 
ZnSO.sub.4.7H.sub.2 O 0.003 g/L, MOPS 6 g/L, casein hydrolysate 2.5 g/L 
and MgHPO.sub.4.3H.sub.2 O 10 g/L, P-2000 1 ml/L, pH 7.0, and are 
autoclaved at about 121.degree. C. for about 20 minutes) in a 300 ml 
Erlenmeyer flask. The flasks are shaken for 3-4 days at about 30.degree. 
C. Fermentation broth is extracted as described above. 
Derivatization of the parent macrolide at the C-23 position is carried out 
according to a method analogous to the method well known to those of 
ordinary skill in the art and as described in J. Antibiotics, 40(6), pp. 
823-842, 1987, the contents of which are incorporated herein by reference. 
5-OMT was obtained according to the method set out in R. B. Morin and M. 
Gorman, Tet. Let., 2339 (1964). The starting macrolide rosaramicin is 
produced and isolated according to the method described by Wagman et al. 
in Journal of Antibiotics, Vol. XXV, No. 11, pp. 641-646, November 1972. 
Desmycosin, lactenocin, O-demethyllactenocin and 
23-deoxymycaminosyltylonolide are produced and isolated according to the 
method described in Journal of Antibiotics, 35(12), pp. 1675-1682, 1982. 
Cirramycin A.sub.1, is produced and isolated according to the method 
described in Journal of Antibiotics, 22, p. 61, 1969. The contents of the 
above references are incorporated herein by reference. All other starting 
materials and reagents required for the synthesis of the compounds of the 
present invention are readily available commercially or can be prepared 
according to methods known in the art. 
Compounds of the present invention of formula (I) or (II) where m is 2 can 
be prepared by application of Wittig chemistry using the ylide prepared 
from (methoxymethyl)triphenylphosphonium chloride. Typically, the 
phosphonium salt is suspended in an aprotic solvent such as THF, diethyl 
ether, or dioxane. To this mixture is added a base, such as potassium 
t-butoxide, n-butyllithium, or sodium hydride, usually at about 
-20.degree. to 30.degree. C., and the solution is then stirred for about 
10 to 120 minutes. A solution of the 3-deoxy macrolide is then added and 
the resulting solution is stirred for 1 to 24 hours at room temperature. 
After a standard extractive work-up, the crude product is dissolved in a 
solvent such as THF or dioxane, and aqueous acid, e.g. 1N HCl, is added. 
Stirring for 2 to 12 hours and extractive work-up produces a macrolide 
aldehyde that can be used for other reactions described herein. 
This invention relates to compounds which are derivatives of 3-deoxy 
macrolide antibiotics. Several methods are known to those skilled in the 
art for converting 3-hydroxy macrolides to the 3-deoxy analogs. Usually 
the C3 alcohol of a suitably protected macrolide is derivatized as a 
sulfonate or an acetate, preferably as the mesylate. This is typically 
done with methanesulfonyl chloride in pyridine. The activated group is 
then eliminated, usually by treatment with a base such as potassium 
carbonate or an amine. The preferred method is to use ammonium hydroxide 
in methanol. In certain cases, the resulting double bond is reduced, 
usually by hydrogenation with a metal catalyst such as Raney nickel. 
Some of the compounds described in this invention require the formation of 
ureas and sulfonamides from a starting amine. Ureas are formed using 
standard conditions, such as reaction of the amine in an inert solvent 
(e.g., toluene or CH.sub.2 Cl.sub.2) with an isocyanate. An external base 
such as triethylamine may be used. Some isocyanates are commercially 
available or can be prepared by the reaction of a primary amine with 
phosgene or an equivalent (e.g., triphosgene). Other methods for 
isocyanate formation are suitable as well, such as Hofmann, Curtius, 
Lossen, and Schmidt rearrangements from carboxylic acid derivatives. 
Sulfonamides are most readily formed by reaction of an amine with a 
sulfonyl chloride, usually done in an inert solvent such as DMF with a 
base such as sodium carbonate. 
The following procedure is used for a Wittig reaction when T is 
--CH.dbd.CH--(CH.sub.2).sub.n --N(Z.sup.4)(Z.sup.5). To a solution of 
excess phosphonium bromide (usually 3-fold excess over the macrolide), 
prepared as described below, in a reaction inert solvent such as toluene, 
is added an equimolar amount of base, such as potassium 
bis(trimethylsilyl)amide, 0.5M in toluene. The reaction mixture is stirred 
for about 5 to 90 minutes, usually for about 15 minutes, at about 
5.degree. to 35.degree. C., usually at ambient temperature. To the 
yellow-orange mixture is added solid 3-deoxy macrolide aldehyde, followed 
by stirring at about 0.degree. to 80.degree. C., usually at ambient 
temperature. After having been stirred for about 30 minutes to 24 hours, 
preferably about one hour, the desired olefin product is isolated by 
standard techniques well known to those skilled in the art, such as silica 
gel chromatography or recrystallization. 
The phosphonium bromide reagents used for the above Wittig reactions can be 
prepared by a number of methods. (2-Aminoethyl)triphenyl-phosphonium 
bromides generally are synthesized by reacting a secondary amine with 
vinyltriphenylphosphonium bromide, usually without additional solvents, 
and stirring the mixture at about 25.degree. to 150.degree. C., usually at 
about 80.degree. C., for 0.5 to 3 days, usually for one day. (Procedure 
modified from J. Org. Chem. 29, pp. 1746-1751, 1964). At this time, the 
reaction mixture is mixed with an aprotic solvent, preferably diethyl 
ether, and the solids collected by filtration and rinsed well with the 
same solvent. Subsequent to drying, these products are used directly in 
the subsequent olefination procedures. Another route to obtaining 
amine-containing phosphonium bromides is by treating an appropriate amino 
alcohol with triphenylphosphine hydrobromide (Helv. Chim. Acta, 61, 
pp.1708-1720, 1978). Some of the phosphonium bromides are commercially 
available. 
Phosphonium bromides can also be prepared using diamines, usually with one 
of the amines protected, with t-BOC as one of the preferred protecting 
groups. Subsequent to Wittig olefination, the t-BOC group can be removed 
by conventional methods and the newly exposed amine can be further 
functionalized with an aminoacyl, dipeptidyl, or hydroxyalkanoyl group 
according to the following procedure. A dichloromethane solution of a 
N-protected amino acid, or N-protected dipeptide (t-BOC is one of the 
preferred protecting groups), or an O-protected hydroxyalkanoic acid 
(acetate is one of the preferred protecting groups), 
dicyclohexylcarbodiimide and often a coupling agent, such as 
hydroxybenzotriazole, (all of which are present in equimolar amounts) is 
cooled to about 0.degree. C. To the cold solution is added a macrolide 
derivative wherein T is --CH.dbd.CH--(CH.sub.2).sub.n 
--N(Z.sup.4)(Z.sup.5) where Z.sup.4 is as defined above, Z.sup.5 is 
'R.sup.6 --N(R.sup.7 R.sup.8) where R.sup.6 and R.sup.8 are as defined 
hereinabove and R.sup.7 is hydrogen. The solution is allowed to warm to 
room temperature and stirring is continued for about 6 to 72 hours, 
followed by standard work-up procedures well-known to those skilled in the 
art. The crude product is isolated by conventional methods such as 
chromatography. The N-protected aminoacyl, N-protected dipeptidyl, or 
O-protected hydroxyalkanoyl derivative is then deprotected by conventional 
methods to yield desired products. 
In all of the following syntheses if the bond between the C.sub.2 -C.sub.3 
positions of the macrolide is a double bond, then the reductive aminations 
are preferably carried out using the formic acid conditions described 
hereinbelow. 
The particular reaction conditions and reagents used to synthesize a 
compound of formula I or II where T is --CH(Z.sup.8)N(Z.sup.6)(Z.sup.7) or 
##STR13## 
are dictated by the kind of amine that is used in the reaction. When a 
secondary amine of the formula HN(Z.sup.6)(Z.sup.7), where Z.sup.6 and 
Z.sup.7 are not hydrogen and are as defined above for formula I or II is 
used in the reductive amination, the following procedure is utilized. A 
solution of a 3-deoxy derivative of the appropriate macrolide aldehyde is 
mixed with an excess, usually about 1.5 molar equivalent, of a secondary 
amine in a reaction inert solvent such as ethyl acetate. The reaction 
mixture is heated to about 60.degree. C. to 80.degree. C., preferably 
about 70.degree. C., with stirring. A slight excess of formic acid, 
usually about 1.1 molar equivalent, is added dropwise to the reaction 
mixture and the temperature of the reaction mixture is lowered by about 
5.degree. C. The reaction is stirred for an additional four to seven 
hours, but usually for about five hours. The reaction is stopped by 
cooling to room temperature and the desired amino derivative of the 
3-deoxy macrolide is isolated by standard techniques well known to those 
skilled in the art, such as column chromatography or crystallization. 
The compounds of formula (I) or (II) where T is 
--CH(Z.sup.8)--N(Z.sup.6)(Z.sup.7) where Z.sup.8 is hydrogen and 
--N(Z.sup.6)(Z.sup.7) are derived from a primary amine employs the 
following method. A methanol solution of the 3-deoxy macrolide aldehyde is 
mixed with the appropriate amine and stirred at room temperature for 
approximately 30 minutes. The reaction mixture is then cooled to about 
0.degree. C. and an equimolar amount of glacial acetic acid is added to 
the mixture and the reaction allowed to stir. After about ten minutes of 
stirring, a methanol solution of sodium cyanoborohydride is added to the 
reaction mixture, and the resulting solution is stirred for about one hour 
at about 0.degree. C. The reaction is stopped by warming to room 
temperature and concentrating the reaction mixture, and then the desired 
3-deoxy macrolide derivative is isolated. A preferred method of 
accomplishing the same type of reaction is as follows. To a stirring 
solution of the 3-deoxy macrolide aldehyde in methanol is added the 
appropriate amine and the reaction is stirred for about 30 minutes. The 
solution is then cooled to about 0.degree. C. and sodium borohydride is 
added to it. After stirring for about 2 hours, the solution is 
concentrated to near dryness and the desired compound is isolated by 
conventional methods well known in the art. The cyano derivative, where 
Z.sup.8 is CN, is also produced in the reaction and can be isolated by 
standard techniques well known to those skilled in the art. The cyano 
derivatives of the compounds of formula (I) or (II) wherein T is 
--CH(Z.sup.8)--N(Z.sup.6)(Z.sup.7) where --N(Z.sup.6)(Z.sup.7) are as 
defined and Z.sup.8 is CN, can also be synthesized separately by the 
following method. A solution of zinc iodide and an appropriate 3-deoxy 
macrolide aldehyde is made in methanol. Trimethylsilylcyanide is added to 
the methanol solution and is stirred for about 15 minutes then the 
appropriate amine is added and the solution is heated at about 40.degree. 
C. for about 2 hours. The desired cyano derivative is isolated by standard 
methods well known in the art. 
A primary amino derivative of the 3-deoxy macrolide, formed by the above 
method, can be further derivatized by N-methylating the secondary amino 
group which had been just added. This synthesis is carried out by 
suspending the secondary amino 3-deoxy macrolide derivative in water and 
then adding formic acid. To the resulting solution, a 38% solution of 
aqueous formaldehyde is added and the reaction mixture is heated to reflux 
temperature. The reaction mixture is stirred at reflux for about four to 
six hours, preferably about five hours. It is then cooled to room 
temperature and the desired compound is isolated. 
When T is --CH(Z.sup.8)--N(Z.sup.6)(Z.sup.7) where --N(Z.sup.6)(Z.sup.7) is 
derived from a secondary amine the macrolide can be further functionalized 
with an amino acyl group according to the following procedure. A 
dichloromethane solution of a N-protected amino acid or N-protected 
dipeptide (t-BOC is one of the preferred protecting groups), or an 
O-protected hydroxyalkanoic acid (acetate is one of the preferred 
protecting groups), dicyclohexylcarbodiimide, often with a coupling agent, 
such as hydroxy-benzotriazole, (all of which are present in equimolar 
amounts) is cooled to about 0.degree. C. To the cold solution is added a 
secondary amino compound of formula I or II; wherein Z.sup.6 is hydrogen 
and Z.sup.7 is as defined above. The solution is allowed to warm to room 
temperature and stirring is continued for about 48 to 72 hours. The crude 
product is isolated by conventional methods such as chromatography. The 
N-protected amino acyl, N-protected dipeptidyl or O-protected 
hydroxyalkanoyl derivative is deprotected by conventional methods to yield 
the desired product. 
A compound of formula I or II wherein T is 
--CH(Z.sup.8)--N(Z.sup.6)(Z.sup.7) where --N(Z.sup.6)(Z.sup.7) is an 
aminoalkylamino, can be further derivatized at the terminal amine by an 
amino acyl group according to the following procedure. To a stirring 
solution of a compound of formula I or II having an aminoalkylamino group 
at the T-position in dimethylformamide is added an N-protected (t-BOC is 
preferred protecting group) amino acid hydroxysuccinimide ester, or 
N-protected dipeptide (t-BOC is one of the preferred protecting groups), 
or an O-protected hydroxyalkanoic acid (acetate is one of the preferred 
protecting groups), and the mixture is stirred for about 6 hours. The 
crude product is isolated by conventional methods such as silica gel 
chromatography. The N-protected amino acyl derivative, N-protected 
dipeptidyl or O-protected hydroxyalkanoyl derivative is deprotected by 
conventional methods to yield the desired products. 
The compounds of this invention wherein T is --C(.dbd.O)(Z.sup.3) are 
synthesized according to the following procedure. The 3-deoxy macrolide 
aldehyde is oxidized to the carboxylic acid. The intermediate carboxylic 
acid derivative of the 3-deoxy macrolides is then coupled with a variety 
of amines to form amide derivatives. For example, a suitably protected 
3-deoxy macrolide, protected as the 2'-acetate, is treated with 
approximately 1.3 equivalents of sodium chlorite in the presence of 
approximately 1.3 equivalents of sodium phosphate monobasic and an excess 
of 2-methyl-2-butene, about 7.0 equivalents. This oxidation step is 
usually carried out at ambient room temperature (20.degree.-25.degree. C.) 
using a 3:1 mixture of acetonelbutanol as the solvent (0.3 to 0.5 molar 
concentration). In order to form the amide derivatives, the carboxylic 
acid is coupled with primary or secondary amines in the presence of about 
1.1 equivalents of diethyl cyanophosphate and about 1.1 equivalents of 
triethylamine at about 0.degree. C. using anhydrous DMF as the solvent 
(0.1 molar concentration). The reaction is worked up by pouring it into 
saturated aqueous NaHCO.sub.3 and extracting with EtOAc. The isolated 
product is purified by flash chromatography to afford the amide 
derivative. The 2'-acetate group can be removed by dissolving the above 
product in methanol (MeOH). The resulting solution is then stirred at room 
temperature (20.degree.-25.degree. C.) for about 18-24 hours. The reaction 
mixture is concentrated under reduced pressure to afford the deprotected 
amide derivative of the 3-deoxy macrolide. 
Alternatively, compounds of this invention wherein T is 
--C(.dbd.O)(Z.sup.3) are synthesized from the carboxylic acid of the 
2'-acetate of the 3-deoxy macrolides according to the following method. To 
a 0.1M solution of the carboxylic acid in a polar aprotic solvent such as 
CH.sub.2 Cl.sub.2, which has been cooled to about 0.degree. C., is added 
about 5 equivalents of either a primary or a secondary amine. 
Propylphosphonic anhydride (1.4 equivalents) is added as a 50% solution in 
CH.sub.2 Cl.sub.2 and the reaction is allowed to warm to ambient 
temperature. After stirring for about 1-5 hours the reaction mixture is 
concentrated in vacuo and then redissolved in MeOH to cleave the 
2'-acetate. The reaction mixture is concentrated after stirring overnight 
and extracted from a basic aqueous solution to provide the 3-deoxy 
macrolide amide. 
The compounds of this invention wherein T is --CH.sub.2 
--N(Z.sup.2)(C.dbd.O)--(CH.sub.2).sub.a --Z.sup.3 are readily prepared by 
the following method. The desired 3-deoxy macrolide is reductively 
aminated with an amine in the presence of sodium triacetoxyborohydride, or 
formic acid if the bond between C2 and C3 of the 3-deoxy macrolide is a 
double bond, as described hereinabove. The resulting aminated macrolide is 
then coupled with the desired carboxylic acid according to one of the 
coupling methods described hereinabove. 
The amino amide compounds of this invention wherein T is --CH.sub.2 
--N(B)(CH.sub.2).sub.a --C(.dbd.O)(Z.sup.3) or --CH.sub.2 
--N(B)(CH.sub.2).sub.g --N(B)(CH.sub.2).sub.a --C(.dbd.O)(Z.sup.3) can be 
synthesized by the following two general methods. Certain amino amide 
fragments are available commercially or can be prepared from an amino acid 
such as glycine, sarcosine or .beta.-alanine and a variety of amines by 
the same methods described hereinabove for the carboxylic acid derivatives 
of the 3-deoxy macrolides described in this invention. The amine moiety of 
the amino acid portion can then be coupled with the 3-deoxy macrolide 
aldehyde by reductive amination methods known to those skilled in the art. 
The following method can be employed. The desired 3-deoxy macrolide 
aldehyde, an amine, usually about 1.5 equivalents, and acetic acid are 
stirred in a reaction-inert solvent such as methylene chloride for about 
30 to 60 minutes. After cooling to about 0.degree. C., powdered sodium 
sulfate (about 10 equivalents) and sodium triacetoxyboro-hydride, orformic 
acid if the bond between C2 and C3 of the 3-deoxy macrolide is a double 
bond, about 1.1 equivalents, are added and the reaction solution is 
stirred at ambient temperature for about 1 to 12 hours. The desired amino 
3-deoxy macrolide derivative is then isolated by standard techniques well 
known to those of ordinary skill in the art, such as column chromatography 
or crystallization. Alternatively, the reductive amination can first be 
performed with the 3-deoxy macrolide aldehyde and a protected amino acid. 
Following deprotection, the acid can then be coupled to a variety of 
amines by the methods described hereinabove. Further, the reductive 
amination is preferably carried out with formic acid when the bond between 
C2-C3 of the macrolide is a double bond, as described hereinabove. 
The pharmaceutically acceptable acid addition salts of the 3-deoxy 
macrolide derivatives can be obtained by the following general procedure. 
For example, the HCl salts can be isolated by dissolving the 3-deoxy 
macrolide derivative in a methanolic HCl solution and then evaporating the 
volatile components to yield the desired salt. The methanolic HCl solution 
can be prepared by mixing acetyl chloride with methanol. In addition to 
the HCl salts, other preferred pharmaceutically acceptable acid addition 
salts include citrate, phosphate, sulfate, methanesulfonate, 
benzenesulfonate, palmitate, succinate, lactate, malate, tartrate, 
fumerate and stearate salts. All of such salts are prepared in a method 
analogous to the method used to form the HCl salt. 
The antibacterial activity of the compounds of the present invention 
against bacterial pathogens is demonstrated by the compound's ability to 
inhibit growth of Pasteurella multocida and/or Pasteurella haemolytica. 
The following procedures are typical assays. Assay I is utilized to test 
for activity against Pasteurella multocida and Assay II is utilized to 
test for activity against Pasteurella haemolytica. 
Assay I (P. multocida) 
This assay is based on the liquid dilution method in microliter format. A 
single colony of P. multocida (strain 59A067) is inoculated into 5 ml of 
brain heart infusion (BHI) broth. The test compounds are prepared by 
solubilizing 1 mg of the compound in 125 .mu.l of dimethylsulfoxide 
(DMSO). Dilutions of the test compound are prepared using uninoculated BHI 
broth. The concentrations of the test compound used range from 200 
.mu.g/ml to 0.098 .mu.g/ml by two-fold serial dilutions. The P. multocida 
inoculated BHI is diluted with uninoculated BHI broth to make a 10.sup.4 
cell suspension per 200 .mu.l. The BHI cell suspensions are mixed with 
respective serial dilutions of the test compound, and incubated at 
37.degree. C. for 18 hours. The minimum inhibitory concentration (MIC) is 
equal to the concentration of the compound exhibiting 100% inhibition of 
growth of P. multocida as determined by comparison with an uninoculated 
control. 
Assay II (P. haemolvtica) 
This assay is based on the agar dilution method using a Steers Replicator. 
Two to five colonies isolated from an agar plate are inoculated into BHI 
broth and incubated overnight at 37.degree. C. with shaking (200 rpm). The 
next morning, 300 .mu.l of the fully grown P. haemolytica preculture are 
inoculated into 3 ml of fresh BHI broth and are incubated at 37.degree. C. 
with shaking (200 rpm). The appropriate amounts of the test compounds are 
dissolved in ethanol and a series of two-fold serial dilutions are 
prepared. Two ml of the respective serial dilution is mixed with 18 ml of 
molten BHI agar and solidified. When the inoculated P. haemolytica culture 
reaches 0.5 McFarland standard density, about 5 .mu.l of the P. 
haemolytica culture is inoculated onto BHI agar plates containing the 
various concentrations of the test compound using a Steers Replicator and 
incubated for 18 hours at 37.degree. C. Initial concentrations of the test 
compound range from 100-200 .mu.g/ml. The MIC is equal to the 
concentration of the test compound exhibiting 100% inhibition of growth of 
P. haemolytica as determined by comparison with an uninoculated control. 
The in vivo activity of the compounds of formula (I) or (II) can be 
determined by conventional animal protection studies well known to those 
skilled in the art, usually carried out in mice. 
Mice are allotted to cages (10 per cage) upon their arrival, and allowed to 
acclimate for a minimum of 48 hours before being used. Animals are 
inoculated with 0.5 ml of a 3.times.10.sup.3 CFU/ml bacterial suspension 
(P. multocida strain 59A006) intraperitoneally. Each experiment has at 
least 3 non-medicated control groups including one infected with 0.1X 
challenge dose and two infected with 1X challenge dose; a 10X challenge 
data group may also be used. Generally, all mice in a given study can be 
challenged within 30-90 minutes, especially if a repeating syringe (such 
as a Cornwall.RTM. syringe) is used to administer the challenge. Thirty 
minutes after challenging has begun, the first compound treatment is 
given. It may be necessary for a second person to begin compound dosing if 
all of the animals have not been challenged at the end of 30 minutes. The 
routes of administration are subcutaneous or per os. Subcutaneous doses 
are administered into the loose skin in the back of the neck whereas oral 
doses are given by means of a feeding needle. In both cases, a volume of 
0.2 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, 
and 24 hours after challenge. A control compound of known efficacy 
administered by the same route is included in each test. Animals are 
observed daily, and the number of survivors in each group is recorded. The 
P. multocida model monitoring continues for 96 hours (four days) post 
challenge. 
The PD.sub.50 is a calculated dose at which the compound tested protects 
50% of a group of mice from mortality due to the bacterial infection which 
would be lethal in the absence of drug treatment. 
To implement the methods of this invention, an effective dose of a compound 
of formula (I) or (II) or a pharmaceutically acceptable salt thereof is 
administered to a susceptible or infected animal by parenteral (i.v., i.m. 
or s.c.), oral or topical route. The effective dose will vary with the 
severity of the disease, and the age, weight and condition of the animal. 
However, the daily dose will usually range from about 0.25 to about 150 
mg/kg, preferably from about 0.25 to about 25 mg/kg. 
A suitable vehicle for administering the dose parenterally is a solution of 
the compound in sterile water, or a solution of the compound in a solvent 
comprising at least 50% water and a pharmaceutically acceptable cosolvent 
or cosolvents such as methanol, ethanol, isopropyl alcohol, propylene 
glycol, glycerol, carbonate esters like diethyl carbonate, dimethyl 
sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and 1 
-methyl-2-pyrrolidinone. Suspensions are also suitable vehicles for 
administering the compounds of this invention. The suspending medium can 
be, for example, aqueous carboxymethyl cellulose, inert oils such as 
peanut oil, highly refined mineral oils and aqueous polyvinylpyrrolidone. 
Suitable physiologically acceptable adjuvants may be necessary to maintain 
the compound in suspension. These adjuvants may be chosen from among 
thickeners such as carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, 
and the alginates. Surfactants are also useful as suspending agents. These 
surfactants include: lethicin, alkylphenol polyethylene oxide adducts, 
naphthalenesulfonates, alkylbenzenesulfonates and polyoxyethylene sorbitan 
esters. Agents affecting surface tension can also help in making useful 
suspensions. Such agents include silicone anti-foams, sorbitol, and 
sugars. For intravenous use the total concentration of solutes should be 
controlled to render the preparation isotonic. 
The present invention is illustrated by the following examples, but is not 
limited to the details thereof. High Performance Liquid Chromatography 
(HPLC) retention times of the products of this invention are determined on 
a Zorbax RX.RTM., 5 micron C8 column (4.6 mm ID.times.15 cm length) from 
Dupont (available from Mac-Mod Analytical Inc., 127 Commons Court, Chadds 
Ford, Pa. 19317 1-800-441-7508). A 45:55 (vol:vol) mixture of acetonitrile 
to aqueous 50 millimolar ammonium acetate is used as the eluant. The 
column temperature is maintained at 40.degree. C. and the flow rate is 1.0 
ml per minute. Samples are dissolved in the eluant (2 mg/ml) and are 
injected (70 .mu.l) into a Hewlett-Packard 1090 high performance liquid 
chromatography instrument; peaks corresponding to the sample input are 
detected by ultraviolet spectroscopy at either 254 or 280 nm.

EXAMPLE 1 
3,4'-Dideoxy-20-deoxo-20-(hexahydroazepin-1-yl)-5-O-mycaminosyltylonolide 
Method A (using HCO.sub.2 H) 
A mixture of 3,4'-dideoxy-OMT (150 mg; 0.265 mmoles) and hexamethyleneimine 
(40 mg; 0.40 mmoles) was dissolved in ethyl acetate (4 mL) and heated to a 
gentle reflux for about 1.0 hr. The mixture was cooled slightly and formic 
acid (18 mg; 0.39 mmoles) was added. The reaction mixture was again heated 
to gentle reflux for about 0.5 hrs, at which time it was judged to be 
complete by HPLC. The mixture was cooled to room temperature and 
evaporated to a residue (180 mg). The desired product was purified from 
this residue by preparative HPLC: 
Column: Kromasil C.sub.4 (50.times.250 mm) (Available from Bodman 
Industries, Aston Pa. 19014, 1-800-241-8774). 
Mobile phase: linear gradient; buffer/ACN from 84/16 to 77/23 in 140 min 
buffer=50 mM KH.sub.2 PO.sub.4 at pH=3.0 
Flow: 80 ml/min 
Detection: UV at 290 nm 
Fraction volume: 125 mL 
Fractions containing the title compound were combined and evaporated to 
give a white solid (109 mg; 63%); FAB-MS: m/e=649; HPLC retention time: 
5.20 min. 
Method B (using NaBH(OAc).sub.3) 
To a solution of 3,4'-dideoxy-5-O-mycaminosyltylonolide (400 mg, 0.71 mmol) 
and hexamethyleneimine (0.096 mL, 0.85 mmol) in 3.6 mL of CH.sub.2 
Cl.sub.2 at room temperature was added powdered anhydrous Na.sub.2 
SO.sub.4 (1.0 g, 7.1 mmol). After stirring at room temperature for about 
one hour, the mixture was heated to reflux for about one hour. Upon 
cooling to room temperature, acetic acid (0.2 mL, 3.6 mmol) was added and 
stirring was continued for about one hour at room temperature. The 
reaction was then cooled to about 0.degree. C., and NaBH(OAc).sub.3 (180 
mg, 0.85 mmol) was added in one portion. The reaction was allowed to warm 
slowly to room temperature and stirred overnight. The mixture was filtered 
and the filtrate concentrated. The residue was dissolved in CHCl.sub.3, 
and washed with aqueous saturated NaHCO.sub.3 and saturated sodium 
chloride. The organic layer was dried over anhydrous sodium sulfate, 
filtered, and then evaporated under reduced pressure to afford 400 mg of 
product (87% yield, 91.5% pure by HPLC). 
EXAMPLES 2-23 
The compounds of Examples 2-23 have the general formula shown below and 
were synthesized according to a method analogous to the method indicated. 
______________________________________ 
##STR14## 
Prep'n. Mass. 
HPLC 
Ex. No. NZ.sup.6 Z.sup.7 
Method Spec. 
(min.) 
______________________________________ 
2 N-methyl-N- A 664 6.80 
cyclohexylamino 
3 dimethylamino A 596 3.84 
4 2-fluoroethylamine 
B 614 4.37 
5 dipropylamine A 652 6.46 
6 N-methyl-N-propylamino 
B 624 4.93 
7 N-3-(dimethylamino)- 
A 667 3.66 
propyl!-N-methylamino 
8 4-methylpiperazino 
A 651 4.62 
9 2,2-dimethyl-3-hydroxy- 
B 654 4.66 
propylamino 
10 azetidino B 608 N.T. 
11 3-azabicyclononan-3-yl 
B 676 N.T. 
12 N-methyl-N-2-hydroxy- 
B 626 N.T. 
ethylamino 
13 propylamino B 610 N.T. 
14 3-hydroxypropylamino 
B 626 N.T. 
15 2-spirocyclopentyl-3- 
B 680 N.T. 
hydroxy-propylamino 
16 2,5-(dihydroxy)cyclo- 
B 682 N.T. 
hexylamino 
17 3-amino-2,2-dimethyl- 
B 653 N.T. 
propylamino 
18 pyrrolidino A 621 4.15 
19 piperidino A 635 N.T. 
20 4-hydroxypiperidino 
A 651 3.66 
21 morpholino A 637 6.26 
22 3,4-dehydropiperidino 
A 633 4.80 
23 3-hydroxypiperidino 
A 651 N.T. 
______________________________________ 
N.T. = Not taken. 
EXAMPLES 24-25 
The compounds of Examples 24-25 have the general formula shown below and 
were synthesized according to a method analogous to the method indicated. 
______________________________________ 
##STR15## 
Prep'n Mass 
Ex. No. NZ.sup.6 Z.sup.7 
Method Spec. 
______________________________________ 
24 hexahydroazepin-1-yl 
B 666 
25 2,2-dimethyl-3-hydroxy- 
B 670 
propylamino 
______________________________________ 
EXAMPLES 26-31 
The compounds of Examples 26-31 have the general formula shown below and 
were synthesized according to a method analogous to the method indicated. 
______________________________________ 
##STR16## 
Prep'n Mass. 
Ex. No. NZ.sup.6 Z.sup.7 Method* Spec. 
______________________________________ 
26 2,2-dimethyl-3-hydroxy- 
B 668 
propylamino 
27 hexahydroazepin-1-yl 
A (EtOAc) 663 
28 dimethylamino A (THF) 609 
29 dipropylamino B 666 
30 N-3-(dimethylamino)propyl!- 
B 680 
N-methylamino 
31 3-azabicyclononan-3-yl 
A (EtOAc) 689 
______________________________________ 
*The solvent used for the reaction is indicated in the parenthesis. 
Preparation 1 
3-Deoxy-5-O-mycaminosyltylonolide 
To a solution of the bis-ethylene ketal of 5-O-mycaminosyltylonolide (OMT) 
(2.120 g, 3.091 mmol) (prepared as described in Bull. Chem. Soc. Jpn., 
1992, 65, p. 3405) in 10 mL of DMF was added dimethylthexylsilyl chloride 
(829 mg, 4.636 mmol) and imidazole (421 mg, 6.182 mmol). The reaction 
mixture was stirred at room temperature under nitrogen overnight. Solvent 
was removed under vacuum and the residue was taken up in 60 mL CHCl.sub.3 
and washed with 60 mL water. The organic layer was dried over Na.sub.2 
SO.sub.4, filtered, evaporated, and flash chromatographed over silica gel 
(8% MeOH/CH.sub.2 Cl.sub.2 with 0.2% NH.sub.4 OH). Appropriate fractions 
were pooled and evaporated to dryness to yield 2.600 g (55.4%) of the 
dimethylthexylsilyl-diketal intermediate. 
To a solution of the dimethylthexylsilyl-diketal intermediate (2.148 g, 
2.59 mmol) in 20 mL acetonitrile was added acetic anhydride (0.635 g, 6.22 
mmol). The reaction mixture was stirred at room temperature under nitrogen 
overnight. Solvent was removed under vacuum and the residue was taken up 
in 100 mL toluene and washed with saturated NaHCO.sub.3 solution. The 
organic layer was dried over MgSO.sub.4, filtered, and evaporated to 
dryness to yield 1.978 g (83.7%) of the bis-acetylated intermediate. MS 
LSIMS: 912. 
To a solution of the bis-acetylated intermediate (1.412 g, 1.548 mmol) in 2 
mL anhydrous pyridine was added methanesulfonyl chloride (0.433 g, 3.870 
mmol). The cloudy reaction mixture was stirred at room temperature under 
nitrogen for about 3 hours. The solution was added to 50 mL saturated 
NaHCO.sub.3 solution. The mixture was extracted several times with 
toluene. The combined organic layers were dried over MgSO.sub.4, filtered, 
and evaporated to dryness to yield 1.461 g (95.3%) of the mesylated 
intermediate. 
To a solution of the mesylated intermediate (1.420 g, 1.434 mmol) in 30 mL 
methanol was added 10 mL concentrated NH.sub.4 OH. The reaction mixture 
was stirred at room temperature for about 2.5 hours then heated to 
50.degree. C. overnight. Solvent was removed under reduced pressure and 
the residue was partitioned between chloroform and saturated NaCl 
solution. The organic layer was dried over Na.sub.2 SO.sub.4, filtered and 
evaporated to dryness to give 1.101 g (94.8%) of the 2,3-trans olefin 
intermediate. 
To a solution of the 2,3-trans olefin intermediate (0.935 g, 1.154 mmol) in 
33 mL of methanol was added K.sub.2 CO.sub.3 (0.475 g, 3.437 mmol) and 
Raney Nickel (about 0.5 mL suspension in water). The mixture was 
hydrogenated on a Parr shaker at 15 psi for about 10 minutes. The catalyst 
was quickly filtered off and the filtrate evaporated under reduced 
pressure. The residue was taken up in methylene chloride and washed with 
saturated NaHCO.sub.3 solution. The organic layer was dried over Na.sub.2 
SO.sub.4, filtered, and evaporated to dryness to yield 0.914 g (98%) of 
the desired protected intermediate. 
The protected intermediate was taken up in 20 mL of 0.25 N HCl and 5 mL 
acetonitrile and stirred at room temperature for about 2 hours. The 
mixture was poured into 200 mL saturated NaHCO.sub.3 solution. The cloudy 
mixture was extracted several times with chloroform. The combined organic 
layers were dried over Na.sub.2 SO.sub.4, filtered, evaporated to dryness 
and flash chromatographed over silica gel (5% MeOH/CHCl.sub.3 with 0.5% 
NH.sub.4 OH). Appropriate fractions were pooled and evaporated to dryness 
to yield 0.679 g (quantitative) of the title compound as a white solid 
foam. MS El 581.4. 
Preparation 2 
3-Deoxy-2,3-Didehydro-5-O-mycaminosyltylonolide 
To a solution of OMT (5.00 g, 8.36 mmol) in 56 mL EtOH at room temperature 
was added powdered 4A molecular sieves and p-toluenesulfonic acid (2.38 g, 
12.54 mmol). Stirring was continued at room temperature for about 5 hours 
at which time the reaction was quenched with Et.sub.3 N (1.6 mL, 11.7 
mmol). The reaction mixture was filtered and concentrated to dryness. The 
residue was dissolved in CH.sub.2 Cl.sub.2 and washed with aqueous 
saturated NaHCO.sub.3 and brine. The organic layer was dried over Na.sub.2 
SO.sub.4, filtered and concentrated to provide 3.4 g of diethyl acetal 
intermediate (61% yield). 
To a solution of the diethyl acetal intermediate (7.99 g, 11.9 mmol) in 
39.6 mL DMF was added imidazole (1.62 g, 23.8 mmol), followed by 
dimethylthexylsilyl chloride (3.5 mL, 17.85 mmol). After stirring 
overnight at room temperature under nitrogen, additional imidazole (810 
mg, 11.9 mmol) and dimethylthexylsilyl chloride (1.75 mL, 8.9 mmol) was 
added. The reaction was stirred for about an additional 5 hours at which 
time TLC analysis (89:10:1 CHCl.sub.3 :MeOH: NH.sub.4 OH) indicated that 
starting material had been consumed. The solvent was removed under vacuum. 
The residue was dissolved in CH.sub.2 Cl.sub.2 and washed with water and 
brine. The organic layer was dried over Na.sub.2 SO.sub.4, filtered and 
concentrated to a yellow oil which was chromatographed over silica gel (2% 
MeOH/CHCl.sub.3 with 0.1% NH.sub.4 OH) to yield 6.2 g of clean 
23-dimethylthexylsilyl-20-diethyl acetal intermediate (64% yield). MS 
(particle beam) 815. 
To the 23-dimethylthexylsilyl-20-diethyl acetal intermediate (7.6 mmol) in 
38 mL acetonitrile was added acetic anhydride (1.58 mL, 16.7 mmol). The 
reaction was stirred overnight at room temperature under nitrogen. The 
solvent was removed under vacuum and the residue was dissolved in CH.sub.2 
Cl.sub.2, and washed with aqueous saturated NaHCO.sub.3 and brine. The 
organic layer was dried over Na.sub.2 SO.sub.4, filtered and evaporated to 
dryness to yield 6.5 g diacetate intermediate (96% yield). MS (particle 
beam) 899. 
To a solution of the diacetate intermediate (7.2 mmol) in pyridine (72 mL) 
was added methanesulfonyl chloride (1.39 mL, 18 mmol). The cloudy reaction 
mixture was stirred at room temperature under nitrogen for about 5 hours. 
TLC analysis (cyclohexane:acetone 3:1) indicated that the starting 
material had been completely consumed. The solvent was removed under 
vacuum and the residue was dissolved in toluene. The toluene solution was 
washed with aqueous saturated NaHCO.sub.3 and brine. The organic layer was 
dried over Na.sub.2 SO.sub.4, filtered and concentrated to 7.0 g of the 
3-O-mesyl intermediate (99% yield). MS (particle beam) 977, 881. 
To a solution of the 3-O-mesyl intermediate in 180 mL of methanol was added 
dropwise with vigorous stirring, concentrated NH.sub.4 OH (90 mL). The 
gummy precipitate which formed gradually dissipated. The reaction was 
stirred at room temperature for about 3 hours. The solvent was removed 
under vacuum. The residue was redissolved in methanol (90 mL) and the 
reaction was heated to 50.degree. C. overnight. The solvent was removed 
under vacuum. The residue was dissolved in CHCl.sub.3 and washed with 
water and brine. The organic layer was dried over Na.sub.2 SO.sub.4, 
filtered and concentrated to 5.0 g off-white 2,3-trans olefin intermediate 
(88% yield). 
To the 2,3-trans olefin intermediate in acetonitrile (80 mL) was added 
dropwise 0.25 N aqueous HCl (320 mL). The reaction was stirred at room 
temperature for about 4.5 hours, at which time the reaction mixture was 
adjusted to pH 9 with aqueous saturated NaHCO.sub.3. This mixture was 
stirred for about 30 minutes at room temperature and then extracted with 
CHCl.sub.3. The organic layer was washed with brine, filtered and 
concentrated. The residue (3.5g) was chromatographed over silica gel (2% 
MeOH/CHCl.sub.3 with 0.25% aqueous (NH.sub.4 OH). The appropriate 
fractions were pooled and concentrated to yield 1.4 g of the title 
compound as a white foam (38% yield). High Res. MS El 579.3047. 
Preparation 3 
3,4'-Dideoxy-5-O-mycaminosyltylonolide 
This material was prepared as described in Bull. Chem. Soc. Jpn.,1992, 65, 
p. 3405.