Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl)acetylerythromycin A derivatives

Article abstract of DOI:10.1021/jm020568d

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-stre

Full text of DOI:10.1021/jm020568d

2706
J . Med. Chem. 2003, 46, 2706-2715
Syn th esis a n d An tiba cter ia l Activity of a Novel Ser ies of Acylid es:
3-O-(3-P yr id yl)a cetyler yth r om ycin A Der iva tives
Tetsuya Tanikawa,*,†,‡ Toshifumi Asaka,† Masato Kashimura,† Keiko Suzuki,† Hiroyuki Sugiyama,†
Masakazu Sato,† Kazuya Kameo,† Shigeo Morimoto,† and Atsushi Nishida‡
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi,
Saitama 331-9530, J apan, and Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba-shi, Chiba 263-8522, J apan
Received December 17, 2002
A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and
evaluated. These compounds have significant potent antibacterial activity against not only
Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLSB)-
resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae.
6,9:11,12-Dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than
azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests.
However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity
against almost all of the main causative pathogens of community-acquired pneumonia tested,
exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.
Ch a r t 1
In tr od u ction
Second-generation macrolide antibiotics such as
clarithromycin1 (CAM, 6-O-methylerythromycin A) and
azithromycin2 (AZM, 15-membered azalide) (Chart 1)
have been widely prescribed for upper and lower res-
piratory tract infections (RTIs) because of their superior
antibacterial activity and pharmacokinetic properties
and fewer gastrointestinal (GI) side effects3 compared
to the first-generation macrolide erythromycin A (Ery
A).
However, the therapeutic utility of these macrolides
has been severely compromised by the emergence of
resistant pathogens. The increasing resistance of com-
munity-acquired respiratory tract infections (CARTIs)
to various antimicrobials is a pandemic phenomenon,
and this trend represents a significant threat.4 Strep-
tococcus pneumoniae, Haemophilus influenzae, Mo-
raxella catarrhalis, Streptococcus pyogenes, Staphylo-
coccus aureus, atypical (Mycoplasma pneumoniae) and
intercellular (Chlamydia pneumoniae, Legionella pneu-
mophila) pathogens are all known to cause CARTIs. In
particular, S. pneumoniae is the main causative patho-
gen of community-acquired pneumonia (CAP). The
infectious disease caused by S. pneumoniae remains a
leading cause of morbidity and mortality.5 The increas-
ing prevalence of penicillin-resistant S. pneumoniae
(PRSP) is of concern, since most of the pathogens have
acquired resistance to many antimicrobials including
macrolides.6 Macrolide-resistant S. pneumonia pos-
sesses the mef(A) gene and/or the erm(B) gene. The mef-
(A) gene, which codes for a membrane protein efflux
pump, is considered to confer intermediate resistance,
while the erm(B) gene, which codes for a ribosomal
methylase, is considered to result in high-level resis-
tance.7 It is also of concern that the prevalence of
â-lactamase-positive strains of H. influenzae, the second-
most common cause of CAP, has progressively increased
in the U.S.,8 Europe, and Asia.9 The infectious pathogen
is often unknown during the acute phase of the infec-
tion, and thus, the initial therapy tends to be empirical.
Accordingly, the next generation of macrolide antibiotics
should be effective against these pathogens.
To address these therapeutic problems, novel mac-
rolides, such as ketolides10 (3-oxo-6-O-methylerythro-
mycin A derivatives) exemplified by telithromycin
(HMR3647),11 cethromycin (ABT-773),12 and TE-80213
and (9S)-erythromycylamine 4′′-carbamates exemplified
by CP-544372,14 have been investigated over the past
decade (Chart 2).
We recently reported the discovery of 3-O-acyleryth-
romycin A derivatives, which we named “acylides”,15 as
a novel class of macrolide antibiotics. The introduction
of an adequate acyl group to the 3-O position of CAM
not only restored the abolished antibacterial activity but
also conferred activity against resistant pathogens. 3-O-
(4-Nitrophenyl)acetyl-5-O-desosaminyl-6-O-methyleryth-
ronolide A (TEA0777) showed potent antibacterial
activity against Gram-positive pathogens including in-
ducibly macrolide-lincosamide-streptogramin B (MLSB)-
resistant S. aureus and efflux-resistant S. pneumoniae,
whereas its activity against H. influenzae was insuf-
ficient. We sought to further optimize the acyl group
* To whom correspondence should be addressed. Phone: 81-48-669-
3063. Fax: 81-48-652-7254. E-mail: tetsuya.tanikawa@po.rd.taisho.co.jp.
† Taisho Pharmaceutical Co. Ltd.
‡ Chiba University.
10.1021/jm020568d CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/20/2003

3-O-(3-Pyridyl)acetylerythromycin A Derivatives
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2707
Ch a r t 2
Sch em e 1a
a
(a) (i) RCO2H, EDC‚HCl, DMAP, CH2Cl2 or RCO2H, PivCl,
Et3N, DMAP, CH2Cl2, -15 °C to room temperature or PhCH2COCl,
DMAP, pyridine, (ii) MeOH, 29-84% yield in two steps.
Sch em e 2a
and to chemically modify the macrolide skeleton. In this
report, we describe a novel series of acylides, 3-O-(3-
pyridyl)acetylerythromycin A derivatives, that showed
significantly potent antibacterial activity against Gram-
positive pathogens and improved activity against H.
influenzae.
a
(a) Trichloromethyl chloroformate, pyridine, CH2Cl2, 0 °C, 80%
yield; (b) (i) 3-pyridylacetic acid, PivCl, Et3N, DMAP, CH2Cl2, -15
°C to room temperature, (ii) MeOH, reflux, 82% yield in two steps.
Ch em istr y
activity, the 11,12-carbonate derivative of acylide 12 and
the carbamate analogue were synthesized. Formation
of the 11,12-carbonate was carried out with trichlorom-
ethyl chloroformate in a mixture of CH2Cl2 and pyridine
at 0 °C (Scheme 2). In this reaction, the 3-hydroxyl
group in 14 was restored by quenching the 3-O-chloro-
carbonate with ice-water. 3-O-(3-Pyridyl) acetylation
of 14 followed by deprotection of the 2′-O-acetyl group
provided the desired 11,12-carbonate acylide 15 in 82%
yield.
The 11,12-carbamate acylide 19 was prepared from
12-O-acylimidazolide 1612b as shown in Scheme 3.
Treatment of 16 with liquid ammonia in THF provided
the 12-O-carbamoyl intermediate, which was further
treated with sodium hydride in situ to afford the 11,-
12-carbamate 17 via intramolecular Michael addition.17
Subsequent removal of L-cladinose by treatment with
aqueous HCl followed by the typical sequential proce-
dure for 3-O-(3-pyridyl) acetylation provided the desired
11,12-carbamate acylide 19.
To reveal the effect of the substituent on the phenyl
group in antibacterial activity, 6-O-methylacylides 2-13
were prepared in yields of 29-84% from 2′-O-acetyl-5-
O-desosaminyl-6-O-methylerythronolide A 115a by 3-O-
acylation and subsequent selective methanolysis of the
2′-O-acetyl group (Scheme 1). Treatment of 1 with
phenylacetyl chloride in pyridine followed by metha-
nolysis afforded the 3-O-phenyl acetate 2, as previously
reported.15a Compounds 3-6 and 8-10 were prepared
by condensation of 1 with the corresponding carboxylic
acid using 1-[3-(dimethylamino)propyl]-3-ethylcarbodi-
imide hydrochloride (EDC‚HCl), 4-(dimethylamino)-
pyridine (DMAP) in dichloromethane (CH2Cl2) followed
by methanolysis. To prepare compounds 7 and 11-13,
mixed anhydrides prepared from the corresponding
carboxylic acid and pivaloyl chloride were used instead.
3-O-Acylation of 2, 6, 7, and 9 resulted in a low yield
because of recovery of the unreacted 3-hydroxy inter-
mediate. In the preparation of 3-(2-methoxy)phenyl
acetate 6, an equal amount of the corresponding car-
bonic acid was used to avoid the production of undesir-
able 3,11-diphenyl acetate.
9-Oxime acylide 22 was prepared from 5-O-desosami-
nyl-6-O-methylerythronolide A 9-oxime 2014 in three
steps and was further converted to the corresponding
11,12-carbonate 23 in poor yield along with the unre-
acted starting 11,12-diol intermediate and unisolated
polar byproducts (Scheme 4).
On the basis of previous reports16 that the introduc-
tion of a cyclic carbonate or carbamate to the 11,12-
position of CAM derivatives enhanced the antibacterial

2708 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Tanikawa et al.
Sch em e 3a
Sch em e 5a
a
(a) (i) Ac2O, Me2CO, 85% yield (ii) 3-pyridylacetic acid,
EDC‚HCl, DMAP, CH2Cl2, (iii) MeOH, 69% yield in two steps; (b)
(i) Ac2O, Me2CO, (ii) 3-pyridylacetic acid, EDC‚HCl, DMAP,
CH2Cl2, (iii) MeOH, reflux, 79% yield in three steps.
Sch em e 6a
a
(a) Liquid NH3, THF, -78 °C to room temperature and then
NaH, 92% yield; (b) 2 N HCl, EtOH, 80% yield in two steps; (c) (i)
3-pyridylacetic acid, PivCl, Et3N, DMAP, CH2Cl2, -15 °C to room
temperature, (ii) MeOH, reflux, 77% yield in two steps.
Sch em e 4a
a
(a) Ac2O, Na2CO3, CH2Cl2, 97% yield; (b) 3-pyridylacetic acid,
PivCl, Et3N, DMAP, CH2Cl2, -15 °C to room temperature, 58%
yield; (c) MeOH, reflux, 91% yield; (d) NaNO2, 2 N HCl, MeOH,
H2O, 0 °C, 35% yield; (e) NaBH4, EtOH, 0 °C, 34% yield; (f) (i)
trichloromethyl chloroformate, pyridine, CH2Cl2, 0 °C, (ii) MeOH,
90% yield in two steps; (g) NaNO2, 2 N HCl, MeOH, H2O, 0 °C to
room temperature, 20% yield; (h) NaBH4, MeOH, 0 °C, 84% yield.
a
(a) Ac2O, Me2CO; (b) (i) 3-pyridylacetic acid, PivCl, Et3N,
DMAP, CH2Cl2, -15 °C to room temperature, (ii) MeOH, reflux,
50% yield in three steps; (c) (i) Ac2O, Me2CO, (ii) trichloromethyl
chloroformate, pyridine, CH2Cl2, 0 °C, 10% yield in two steps, (iii)
MeOH, reflux, 79% yield.
similar manner after converting the 11,12-diol 30 to the
corresponding 11,12-cyclic carbonate.
In anticipation of inheriting the beneficial antibacte-
rial profile of AZM against H. influenzae, the hybridized
acylide 25 was prepared from 3-O-descladinosylazithro-
mycin 2418 in a manner similar to 3-O-(3-pyridyl)
acetylation. Tricyclic acylide 27 was obtained in 79%
yield from the synthetic intermediate 2612 of the unique
tricyclic ketolide TE-802 (Scheme 5).
To investigate the effect of a carbonate group at
various locations in the macrolide skeleton, 9,11-carbon-
ate acylide 39 was prepared from (9S)-9-dihydroeryth-
romycin A 9,11-carbonate 3720 (Scheme 7). The treat-
ment of 37 with 2 N HCl afforded the desired 3-O-
descladinosyl product 38 in 68% yield, along with the
unexpected 9,11-descarbonate byproduct in 24% yield.
Subsequently, the typical sequential procedure for 3-O-
(3-pyridyl) acetylation provided the desired 9,11-carbon-
ate acylide 39 in 58% yield.
A straightforward approach to 6,9:11,12-dicarbonate
by treating (9S)-2′-O-acetyl-9-dihydroerythromycin A
with trichloromethyl chloroformate in pyridine resulted
in preferential formation of the 9,11-carbonate. There-
fore, the desired 6,9:11,12-dicarbonate acylide 47 was
synthesized from (9S)-9-dihydroerythromycin A 11,12-
cyclic carbonate 40.21
Since the treatment of erythromycin A derivatives
with acid to cleave L-cladinose without protection of the
C-9 ketone group causes the formation of undesired 6,9-
enol ether, 6-OH acylide 32 was prepared via the
9-oxime derivative 2819 as shown in Scheme 6. After the
introduction of a (3-pyridyl)acetyl group to the 3-O
position of 28 in three steps, the 9-oxime acylide 31 was
converted to the corresponding ketone 32 by treatment
with sodium nitrite in a mixture of aqueous HCl and
MeOH. Reduction of the ketone with NaBH4 in EtOH
stereoselectively gave the 9(S)-OH derivative 33. The
11,12-carbonate analogues 34-36 were prepared in a
To validate the antibacterial effect of the 3-O-(3-
pyridyl)acetyl group against H. influenzae, the pyridine

3-O-(3-Pyridyl)acetylerythromycin A Derivatives
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2709
Sch em e 7a
their potency in a ribosomal binding assay. Therefore,
3-O-(3-methoxy)benzoyl-6-O-methylerythromycin A de-
rivative 3, its phenyl acetate analogue 4, and its phenyl
propionate analogue 5 were prepared to compare their
antibacterial activities. Among them, the phenyl acetate
derivative 4 was found to be the most effective against
all of the pathogens tested except S. aureus SR138 and
S. pneumoniae 211. This result is consistent with results
of our previous investigation.15
To probe the effect of the substituent on the phenyl
group on antibacterial activity, we introduced a methoxy
group as an electron-donating group and a nitro group
as an electron-withdrawing group at each position of the
phenyl in acylide 2. While the antibacterial activities
of methoxyphenyl acetates 6 and 7 were less than those
of the parent phenyl acetate 2, (3-methoxy)phenyl
acetate 4 was about twice as active against almost all
of the pathogens tested. In contrast, all of the nitrophe-
nyl acetates 8, 9, and 10 (TEA0777) showed remarkably
improved activity against almost all of the pathogens
tested. (3-Nitro)phenyl acetate 9 was 4 times as active
as the parent compound against the targeted H. influ-
enzae (MIC ) 25 µg/mL). Considering the possible
carcinogenic and mutagenic effects of aromatic nitro
compounds,24 the nitrophenyl group was replaced by a
pyridyl group, which is an electron-deficient aromatic
group. Although the activities of the pyridyl acetates
11-13 against Gram-positive pathogens were 2- to
8-fold less than those of the nitrophenyl acetates 8-10,
(3-pyridyl) acetate 12 showed a 2- to 4-fold higher
activity against the targeted H. influenzae (MIC ) 12.5
µg/mL). Consequently, we used a (3-pyridyl)acetyl group
as an 3-O-acyl group and continued further chemical
modification focusing on the macrolide skeleton to
obtain potential next-generation macrolides.
a
(a) (i) 2 N HCl, 68% yield; (b) (i) Ac2O, Me2CO, 98% yield, (ii)
3-pyridylacetic acid, Et3N, DMAP, CH2Cl2, -15 °C to room
temperature, (iii) MeOH, 59% yield in two steps; (c) Ac2O, Me2CO,
91% yield; (d) trichloromethyl chloroformate, pyridine, CH2Cl2, 0
°C; (e) MeOH, 49% yield in two steps; (f) 1 N HCl, 68% yield; (g)
Ac2O, Me2CO, 99% yield; (h) (i) pyridylacetic acid, EDC‚HCl or
PivCl and Et3N, DMAP, CH2Cl2, (ii) MeOH, 49-78% yield in two
steps.
isomers 46 and 48 were also prepared from the common
3-OH intermediate 45 in respective yields of 78% and
49%.
Compared to the parent 11,12-diol acylide 12, the
carbonate derivative 15 and the carbamate analogue 19
showed dramatically improved activity against all of the
pathogens tested except MLSB-resistant S. aureus SR138
and S. pneumoniae 211. This result is consistent with
results from previous reports16 that the introduction of
a cyclic carbonate or carbamate into the 11,12-position
of CAM derivatives enhanced their antibacterial activ-
ity. In particular, the carbamate acylide 19 (TEA0929)
showed more potent activity against susceptible Gram-
positive pathogens than both CAM and AZM. Further-
more, 19 was highly effective against the inducibly
MLSB-resistant S. aureus B1 (MIC ) 0.39 µg/mL) and
efflux-resistant S. pneumoniae 210 (MIC ) 0.10 µg/mL),
while second-generation macrolides were either less
active or inactive.
Resu lts a n d Discu ssion
St r u ct u r e-Act ivit y R ela t ion sh ip s of Acylid es.
All of the acylides synthesized, as well as clarithromycin
and azithromycin as references, were tested for in vitro
antibacterial activity against three strains each of S.
aureus and S. pneumoniae and two strains of H.
influenzae. The activities are reported in Table 1 as
minimum inhibitory concentrations (MICs) determined
according to the J apan Society of Chemotherapy.22
S. aureus 209P-J C and S. pneumoniae IID553 are
erythromycin-susceptible strains, S. aureus B1 is an
inducibly MLSB-resistant strain encoded by the erm(C)
gene, and S. aureus SR138 is a constitutively MLSB-
resistant strain encoded by the erm(A) gene. S. pneu-
moniae 210 is an efflux-resistant strain encoded by the
mef(A) gene, and S. pneumoniae 211 is an MLSB-
resistant strain encoded by the erm(B) gene. H. influ-
enzae ATCC43095 is an ampicillin (AMP)-susceptible
strain that does not produce â-lactamase. H. influenzae
ATCC33533 is an AMP-resistant strain that produces
â-lactamase. None of the macrolides tested were active
against constitutively MLSB-resistant S. aureus SR138
or MLSB-resistant S. pneumoniae 211.
In our investigation of the macrolide skeleton, chemi-
cal modification of the C-9 ketone group was found to
have little effect on the activity against H. influenzae
(12 vs 22, 15 vs 23, 32 vs 31 and 33, and 35 vs 34 and
36). While 6-hydroxyacylides were slightly less active
against Gram-positive pathogens than the correspond-
ing 6-O-methylacylides, their activities against H. in-
fluenzae were maintained (32 vs 12, 31 vs 22, 34 vs 23,
and 35 vs 15).
We presumed that chemical modification that affects
the conformation might affect their ability to bind to
bacterial ribosomes, in contrast to simple substitution
of functional groups. Acylide 25 hybridized with AZM
Previously, LeMahieu et al.23 reported that 3-O-
benzoylerythromycin A 9-oxime derivatives showed
limited antibacterial activity, which was consistent with

2710 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Tanikawa et al.
Ta ble 1. Antibacterial Effects of Acylides against Selected Respiratory Pathogens
MIC (µg/mL)
S. aureus
S. pneumoniae
H. influenzae
compd
209P-J Ca
B1b
SR138c
IID553a
210d
211e
ATCC43095f
ATCC33533g
2
3
4
5
6
7
8
9
1.56
25
6.25
50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.78
1.56
0.39
0.78
1.56
0.78
0.20
0.10
0.20
0.39
0.39
0.39
0.05
0.05
0.20
0.025
0.78
0.05
0.39
0.20
0.78
0.025
0.05
0.10
0.10
0.10
0.78
0.05
0.025
0.05
0.10
0.05
0.78
1.56
0.39
0.78
1.56
0.78
0.20
0.20
0.20
0.39
0.39
0.39
0.20
0.10
0.39
0.10
0.78
0.20
0.78
0.78
0.78
0.10
0.20
0.20
0.39
0.39
1.56
0.20
0.10
0.20
0.78
0.78
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
100
>100
50
100
>100
100
50
25
50
50
12.5
50
3.13
3.13
12.5
3.13
1.56
6.25
12.5
12.5
12.5
3.13
3.13
3.13
12.5
1.56
50
100
100
25
100
100
50
50
25
50
25
1.56
3.13
3.13
1.56
0.39
0.20
0.20
1.56
0.78
0.78
0.20
0.05
0.78
0.20
3.13
0.20
1.56
1.56
3.13
0.39
0.20
0.78
0.78
0.10
12.5
0.20
0.10
0.20
0.39
0.10
3.13
3.13
12.5
12.5
0.78
0.78
0.39
1.56
1.56
1.56
0.39
0.39
1.56
0.39
6.25
0.39
1.56
6.25
6.25
0.39
0.39
0.78
1.56
>100
>100
0.78
0.20
0.39
>100
>100
10 (TEA0777)
11
12
13
12.5
50
15
3.13
3.13
12.5
6.25
1.56
3.13
12.5
12.5
12.5
3.13
3.13
6.25
6.25
1.56
100
6.25
0.78
6.25
1.56
3.13
19 (TEA0929)
22
23
25
27
31
32
33
34
35
36
39
43
44
46
6.25
0.78
12.5
1.56
6.25
47 (FMA0122)
48
AZM
CAM
100
>100
>100
>100
a
b
S. aureus 209P-J C, S. pneumoniae IID553: erythromycin-susceptible strain. S. aureus B1: inducibly MLSB-resistant strain encoded
by the erm(C) gene. c S. aureus SR138: constitutively MLSB-resistant strain encoded by the erm(A) gene. S. pneumoniae 210: efflux-
d
resistant strain encoded by the mef(A) gene. e S. pneumoniae 211: MLSB-resistant strain encoded by the erm(B) gene. f H. influenzae
g
ATCC43095 is an ampicillin-susceptible strain that does not produce â-lactamase. H. influenzae ATCC33533 is an ampicillin-resistant
strain that produces â-lactamase.
was prepared to examine the properties of the 15-
membered 9a-azalide skeleton. As expected, 25 inher-
ited the beneficial activity profile against H. influenzae
(MIC ) 1.56 µg/mL), but its activity against Gram-
positive pathogens was insufficient. We examined an
alternative modification involving bridged derivatives
to fix the macrolide skeleton in an adequate conforma-
tion. Tricyclic acylide 27, in which the 11,12-carbamate
is tethered to a C-9 ketone group by iminoethylene,
showed no improvement in activity compared to the
parent carbamate 19. However, the introduction of a
cyclic carbonate system to tetraol 33 at the 11,12- and
9,11-positions significantly enhanced the antibacterial
activity (33 vs 36 and 39). As for the activity against
ampicillin-susceptible H. influenzae, the 11,12-carbon-
ate 36 was 4-fold more potent than the 9,11-carbonate
39 (MIC for 36 is 3.13 µg/mL; that for 39 is 12.5 µg/
mL).
3-O-(3-Pyridyl)acetylerythromycin A 6,9:11,12-dicar-
bonate 47 (FMA0122), which has an additional carbon-
ate at the 6,9-position compared to the 11,12-carbonate
acylide 36, exhibited significant potent activity against
all of the pathogens tested. Interestingly, the dicarbon-
ate acylide 47 was 2-fold more potent than AZM against
H. influenzae (MIC ) 0.78 µg/mL). On the basis of a
comparison of the regioisomers 46 and 48, the (3-
pyridyl)acetyl group was shown to confer an antibacte-
rial advantage against H. influenzae. In addition,
introducing a pyridylacetyl group instead of L-cladinose
at the 3-O-position in erythromycin derivative 43 led
to the acquisition of activity against inducibly MLSB-
resistant S. aureus B1, against which second-generation
macrolides are inactive.
In Vivo Evalu ation . The in vivo efficacies of acylides,
Ery A, AZM, and CAM were assessed by mouse protec-
tion tests (MPT), using erythromycin-susceptible strains
of S. aureus Smith and S. pneumoniae IID553. The mice
were inoculated intraperitoneally, and the macrolides
were administered orally 1 h after inoculation. The
efficacy of each macrolide was reported as the effective
drug dosage (ED50) that gave a survival rate of 50%
following lethal infection over the duration of the trial
(Table 2).
3-O-(3-Pyridyl) acetate 12, which was designed as an
alternative to nitrophenyl acetates, showed good in vivo
efficacy comparable to (4-nitro)phenyl acetate 10
(TEA0777) despite 2-fold less antibacterial activity
against both pathogens. The 11,12-carbonate acylide 15
was less effective than the parent acylide 12 regardless
of its 4-fold improved activity. The 9-oxime acylide 23
exhibited in vivo efficacy comparable to that of the
9-ketone acylide 15. Further conversion to the 6-hydroxy
analogue 34 resulted in complete attenuation of the
mouse protection effect, especially against S. pneumo-
niae IID553.
In a preliminary MPT, 6,9:11,12-dicarbonate acylide

3-O-(3-Pyridyl)acetylerythromycin A Derivatives
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2711
Ta ble 2. In Vivo Efficacy of Acylides in Mouse Protection
vivo results for these acylides warrant further investi-
gation to overcome MLSB-resistant pathogens and to
develop potential next-generation macrolides.
Testsa
S. aureus Smith
ED50 (95% CLc)
S. pneumoniae IID553
MIC
(µg/mL)
MIC
ED50 (95% CLc)
(mg/kg)
Exp er im en ta l Section
compd
(mg/kg)
(µg/mL)
10 (TEA0777)
12
15
19 (TEA0929)
23
0.39
0.78
0.20
0.20
0.39
0.20
0.20
0.78
0.20
15.4 (11.2-21.1) 0.10
9.57 (4.81-14.9) 0.20
17.5 (10.7-33.4) 0.05
6.99 (4.43-11.0) 0.05
27.6 (19.1-40.2) 0.025 47.4 (31.1-74.3)
51.6 (34.8-78.0) 0.025 142 (89.7-283)
56.6 (40.4-79.2) 0.10
15.7 (10.3-26.5) 0.10
7.60 (4.86-12.0) 0.025 13.5 (8.42-24.4)
39.1 (27.9-55.4)
40.8 (25.7-65.6)
51.1 (35.1-75.0)
17.5 (9.32-36.5)
All reagents and solvents were purchased commercially and
1
used without purification unless otherwise noted. H and 13C
nuclear magnetic resonance (NMR) spectra were recorded in
CDCl3 on a J EOL Alpha 500 or J EOL Lambda 500 spectrom-
eter. Chemical shifts are reported in parts per million (ppm)
with tetramethylsilane (TMS) as an internal standard. Cou-
pling constants (J ) are given in hertz (Hz), and the abbrevia-
tions s, d, t, q, br, and m refer to singlet, doublet, triplet,
quartet, broad, and multiplet, respectively. All assignments
were made based on 1H-1H correlation spectroscopy (COSY),
heteronuclear multiple-quantum coherence (HMQC), and het-
eronuclear multiple-bond correlation (HMBC) methods. Mass
spectra (MS) were obtained with a Micromass Platform LC or
a Micromass Q-Tof 2. Elemental analyses were performed
using a PerkinElmer 2400 CHN analyzer. Melting points were
measured using a Mettler FP61 melting point instrument and
are uncorrected.
34
Ery Ab
AZMb
CAM
111 (65.3-171)
13.9 (8.97-21.1)
a
Mice were inoculated intraperitoneally with 5.80 × 107 CFU/
mouse for S. aureus and 1.47 × 103 CFU/mouse for S. pneumoniae.
Mice were inoculated intraperitoneally with 5.09 × 107 CFU/
b
mouse for S. aureus and 7.05 × 102 CFU/mouse for S. pneumoniae.
c CL: confidence limits.
Ta ble 3. Survival Rates (%) with 6,9:11,12-Dicarbonate
Acylide 47 in Preliminary Mouse Protection Testsa
S. pneumoniae IID553b
5-O-Desosa m in yl-3-O-p h en yla cet yl-6-O-m et h yler yt h -
r on olid e A (2). To a solution of 2′-O-acetyl-5-O-desosaminyl-
6-O-methylerythronolide A 115 (1.26 g, 2.0 mmol) in pyridine
(6.0 mL) was added DMAP (122 mg, 1.0 mmol) and pheny-
lacetyl chloride (0.66 mL, 5.0 mmol) at 0 °C. After being stirred
at room temperature for 22 h, the reaction mixture was
partitioned between EtOAc and brine. The organic layer was
dried over MgSO4 and evaporated in vacuo. The residue was
purified by column chromatography, eluting with acetone/n-
hexane/Et3N (4:10:0.05) to give 2′-OAc-2 (730 mg, 49%), along
with the recovered starting material 1. The product was
refluxed in MeOH (10 mL) for 6 h. After evaporation of the
solvent in vacuo, the residue was purified by column chroma-
tography, eluting with CHCl3/MeOH/25% NH4OH (20:1:0.1)
to give 2 (490 mg, 71%) as a white foam: HRMS (ES) m/z
dose (mg/mouse)
compd
MIC (µg/mL)
3.0
0.3
47 (FMA0122)
AZM
CAM
0.025
0.10
0.05
90
100
100
30
50
50
Mice were inoculated intraperitoneally with 5.05 × 107 CFU/
a
b
mouse. S. pneumoniae IID553: erythromycin-susceptible strain.
Ta ble 4. Pharmacokinetic Parametersa of
6,9:11,12-Dicarbonate Acylide 47 Following a Single 10 mg/kg
Oral Dose
serum
lung
AUC0-8
708.4308, calcd for C38H62NO11 708.4323. Anal. (C38H61NO11
C, H, N.
)
Cmax
AUC0-8
Cmax
compd
(µg/mL)
(µg‚h/mL)
(µg/mL)
(µg‚h/mL)
5-O-Desosa m in yl-3-O-(3-m eth oxy)ben zoyl-6-O-m eth yl-
er yth r on olid e A (3). To a solution of 1 (3.0 g, 4.75 mmol) in
CH2Cl2 (30 mL) was added 3-methoxybenzoic acid (2.17 g, 14.3
mmol), EDC‚HCl (2.72 g, 14.2 mmol), and DMAP (0.58 g, 4.75
mmol) at 0 °C. After being stirred at room temperature for 4
days, the reaction mixture was partitioned between EtOAc and
water and the pH of the aqueous layer was adjusted to 8 with
2 N NaOH. The organic layer was washed with saturated NH4-
Cl solution and brine and then dried over MgSO4. After
evaporation of the solvent under reduced pressure, the residue
was purified by column chromatography, eluting with acetone/
n-hexane/Et3N ((1-3):10:0.2) to give 2′-OAc-3 (3.06 g, 84%) as
a white foam, along with recovered starting material 1 (0.26
g, 9%). The product was stirred in MeOH (30 mL) at room
temperature for 2 days. After evaporation of the solvent in
vacuo, the residue was purified by column chromatography,
eluting with CHCl3/MeOH/25% NH4OH (25:1:0.1) to give 3
(2.80 g, 97%) as a white foam: HRMS (ES) m/z 724.4281, calcd
for C38H62NO12 724.4272. Anal. (C38H61NO12) C, H, N.
47 (FMA0122)
CAM
0.12
1.21
0.23
1.31
1.35
14.08
2.46
30.38
a
Data represent the mean in three mice.
47 (FMA0122), which had the best antibacterial profile,
was unfortunately less effective than the second-genera-
tion macrolides (Table 3). This poor efficacy can be
attributed to poor pharmacokinetics (Table 4). Conse-
quently, the carbonate group was shown to significantly
improve antibacterial activity, but the in vivo efficacy
tended to be attenuated. On the other hand, 3-O-(3-
pyridyl)acetyl-5-O-desosaminyl-6-O-methylerythrono-
lide A 11,12-carbamate 19 (TEA0929) had an excellent
mouse protection effect, comparable to those of second-
generation macrolides.
5-O-Desosa m in yl-3-O-(3-m et h oxyp h en yl)a cet yl-6-O-
m eth yler yth r on olid e A (4). The title compound was pre-
pared from 1 (3.24 g, 5.13 mmol) and 3-methoxyphenylacetic
acid (2.56 g, 15.4 mmol) according to the procedure used to
prepare 3. Purification by recrystallization from Et2O gave 4
(1.90 g, 50%) as a white powder: mp 205-206.5 °C; HRMS
(ES) m/z 738.4423, calcd for C39H64NO12 738.4429. Anal.
(C39H63NO12) C, H, N.
5-O-Desosa m in yl-3-O-(3-m eth oxyp h en yl)p r op ion yl-6-
O-m eth yler yth r on olid e A (5). The title compound was
prepared from 1 (1.21 g, 1.92 mmol) and 3-(3-methoxyphenyl)-
propionic acid (1.0 g, 5.55 mmol) according to the procedure
used to prepare 3. Purification by column chromatography,
eluting with acetone/n-hexane/Et3N (6:10:0.2), gave 5 (1.21 g,
84%) as a white foam: HRMS (ES) m/z 752.4579, calcd for
Con clu sion
In summary, extensive optimization of the 3-O-acyl
group led to a novel series of acylides, 3-O-(3-pyridyl)-
acetylerythromycin A derivatives, that have fairly im-
proved activity against H. influenzae.
In particular, 6,9:11,12-dicarbonate acylide 47
(FMA0122) was 2-fold more active than AZM, whereas
its in vivo efficacy was moderate in the MPT. However,
11,12-carbamate acylide 19 (TEA0929), which shows
potent antibacterial activity against the main causative
pathogens of CAP including resistant strains, had an
excellent mouse protection effect comparable to those
of second-generation macrolides. The encouraging in
C
40H66NO12 752.4585. Anal. (C40H65NO12) C, H, N.

2712 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Tanikawa et al.
5-O-Desosa m in yl-3-O-(2-m et h oxyp h en yl)a cet yl-6-O-
m eth yler yth r on olid e A (6). 2′-Acetate of the title compound
was prepared from 1 (1.10 g, 1.74 mmol) and 2-methoxyphe-
nylacetic acid (0.29 g, 1.75 mmol) according to the procedure
used to prepare 3. Purification by column chromatography,
eluting with acetone/n-hexane/Et3N (6:10:0.2), gave 2′-OAc-6
(0.70 g, 51%) as a white foam along with recovered starting
material 1 (0.54 g, 49%). The product was stirred in MeOH
(20 mL) at room temperature for 17 h. After evaporation of
the solvent in vacuo, the residue was purified by column
chromatography, eluting with CHCl3/MeOH/25% NH4OH (30:
1:0.1) to give 6 (376 mg, 57%) as a white foam: HRMS (ES)
5-O-Desosam in yl-3-O-(3-pyr idyl)acetyl-6-O-m eth yler yth -
r on olid e A (12). 2′-Acetate of the title compound was pre-
pared from 1 (2.40 g, 3.8 mmol) and 3-pyridylacetic acid (1.98
g, 11.4 mmol) according to the procedure used to prepare 11.
Purification by column chromatography, eluting with acetone/
n-hexane/Et3N ((4-6):10:0.05), gave 2′-OAc-12 (2.04 g, 72%)
as a white foam. The product was refluxed in MeOH (20 mL)
for 3 h. Evaporation of the solvent in vacuo gave 12 (1.98 g)
as a white foam: HRMS (ES) m/z 709.4288, calcd for C37H61
N2O11 709.4275. Anal. (C37H60N2O11‚H2O) C, H, N.
-
5-O-Desosam in yl-3-O-(4-pyr idyl)acetyl-6-O-m eth yler yth -
r on olid e A (13). 2′-Acetate of the title compound was pre-
pared from 1 (3.16 g, 5.0 mmol) and 4-pyridylacetic acid (2.60
g, 15.0 mmol) according to the procedure used to prepare 11.
Purification by column chromatography, eluting with acetone/
n-hexane/Et3N (6:10:0.2), gave 2′-OAc-13 (2.82 g, 75%) as a
slightly yellow foam. The product (1.48 g, 2.0 mmol) was
refluxed in MeOH (30 mL) for 5 h. After evaporation of the
solvent in vacuo, the residue was purified by recrystallization
from acetone/n-hexane to give 13 (672 mg, 48%) as a white
powder: mp 168-170 °C; HRMS (ES) m/z 709.4279, calcd for
m/z 738.4426, calcd for C39H64NO12 738.4429. Anal. (C39H63
-
NO12‚1/2H2O) C, H, N.
5-O-Desosa m in yl-3-O-(4-m et h oxyp h en yl)a cet yl-6-O-
m eth yler yth r on olid e A (7). 2′-Acetate of the title compound
was prepared from 1 (1.26 g, 1.99 mmol) and 4-methoxyphe-
nylacetic acid (1.10 g, 6.08 mmol) according to the procedure
used to prepare 11. Purification by column chromatography,
eluting with acetone/n-hexane/Et3N ((3-4):10:0.1), gave 2′-
OAc-7 (620 mg, 40%) as a white foam along with the recovered
starting material 1. The product was refluxed in MeOH (10
mL) for 8 h. After evaporation of the solvent in vacuo, the
residue was purified by recrystallization from EtOAc to give
7 (520 mg, 89%) as a white powder: mp 191-195 °C; HRMS
(ES) m/z 738.4430, calcd for C39H64NO12 738.4429. Anal.
(C39H63NO12) C, H, N.
5-O-Desosa m in yl-3-O-(2-n itr op h en yl)a cetyl-6-O-m eth -
yler yth r on olid e A (8). The title compound was prepared from
1 (1.57 g, 2.49 mmol) and 2-nitrophenylacetic acid (1.40 g, 7.73
mmol) according to the procedure used to prepare 3. Purifica-
tion by column chromatography, eluting with CHCl3/MeOH/
25% NH4OH (20:1:0.1), gave 8 (1.42 g, 76%) as a slightly brown
C
37H61N2O11 709.4275. Anal. (C37H60N2O11) C, H, N.
5-O-Desosam in yl-3-O-(3-pyr idyl)acetyl-6-O-m eth yler yth -
r on olid e A 11,12-Cyclic Ca r bon a te (15). To a solution of 1
(50.0 g, 0.079 mmol) and pyridine (102.6 mL, 1.27 mol) in CH2-
Cl2 (500 mL) was added dropwise trichloromethyl chlorofor-
mate (25.4 mL, 0.21 mol) in CH2Cl2 (40 mL) at 0 °C. After
being stirred for 5.5 h, the reaction was quenched by adding
pieces of ice in small portions. The reaction mixture was
partitioned between CH2Cl2 and saturated NaHCO3 solution.
The organic layer was washed with brine, dried over MgSO4,
and evaporated in vacuo. The residue was purified by column
chromatography, eluting with acetone/n-hexane/Et3N ((6-10):
10:0.2) to give 14 (41.9 g, 80%) as a white foam. The title
compound was prepared from 14 (10.0 g, 15.2 mmol) according
to the procedure used to prepare 11. Purification by column
chromatography, eluting with CHCl3/MeOH/25% NH4OH (25:
1:0.1), gave 15 (9.10 g, 82%) as a white foam, which was
further purified by recrystallization from CH2Cl2/n-hexane to
give 15 (5.25 g, 47%) as a white powder: mp 231.5-233.5 °C;
HRMS (ES) m/z 735.4076, calcd for C38H59N2O12 735.4068.
Anal. (C38H58N2O12) C, H, N.
5-O-Desosam in yl-3-O-(3-pyr idyl)acetyl-6-O-m eth yler yth -
r on olid e A 11,12-Cyclic Ca r ba m a te (19). To a mixture of
liquid ammonia (500 mL) and THF (200 mL) under cooling
with dry ice/acetone was added dropwise a solution of 2,4-di-
O-acetyl-10,11-anhydro-12-O-imidazolylcarbonyl-6-O-methyl-
erythromycin A 1612b (200.79 g, 0.22 mol) in THF (400 mL)
over 30 min, and the mixture was stirred at that temperature
for 2 h before removing the cold bath. After being stirred at
room temperature for 2 days, 60% sodium hydride dispersed
in oil (2.16 g, 0.054 mol) was added, and the reaction mixture
was stirred for an additional 3 h. The reaction mixture was
partitioned between EtOAc and brine. The organic layer was
dried over MgSO4 and then evaporated in vacuo to give crude
17 (174.4 g) as a colorless crystalline powder. A mixture of
the crude intermediate 17, EtOH (350 mL), and 2 N HCl (700
mL) was stirred at room temperature for 20 h. The reaction
mixture was neutralized with 4 N NaOH, and the resulting
precipitate was collected by filtration and later purified by
column chromatography, eluting with acetone/n-hexane/Et3N
((50-100):100:0.2) to give 18 (116.2 g, 80%) as a white foam.
The title compound was prepared from 18 (2.9 g, 4.42 mmol)
according to the method used to prepare 11. Purification by
column chromatography, eluting with CHCl3/MeOH/25% NH4-
OH (20:1:0.1), gave 19 (2.48 g, 77%) as a white foam, which
was further purified by recrystallization from Et2O to give 19
(1.40 g, 43%) as a white powder: mp 216-219 °C; HRMS
(ES) m/z 734.4227, calcd for C38H60N3O11 734.4228. Anal.
(C38H59N3O11) C, H, N.
foam: HRMS (ES) m/z 753.4163, calcd for
753.4174. Anal. (C38H60N2O13‚H2O) C, H, N.
C38H61N2O13
5-O-Desosa m in yl-3-O-(3-n itr op h en yl)a cetyl-6-O-m eth -
yler yth r on olid e A (9). The title compound was prepared from
1 (1.74 g, 2.75 mmol) and 3-nitrophenylacetic acid (1.50 g, 8.28
mmol) according to the procedure used to prepare 3. Purifica-
tion by column chromatography, eluting with acetone/n-
hexane/Et3N (6:10:0.2), gave 9 (1.00 g, 48%) as a slightly yellow
foam along with 5-O-desosaminyl-6-O-metherythronolide A
(0.37 g, 23%): HRMS (ES) m/z 753.4172, calcd for C38H61N2O13
753.4174. Anal. (C38H60N2O13) C, H, N.
5-O-Desosa m in yl-3-O-(4-n itr op h en yl)a cetyl-6-O-m eth -
yler yth r on olid e A (10). The title compound was prepared
from 1 (5.00 g, 7.91 mmol) and 4-nitrophenylacetic acid (4.30
g, 23.7 mmol) according to the procedure used to prepare 3.
Purification by recrystallization from isopropyl ether gave 10
(3.86 g, 81%) as a white powder: mp 157-159 °C; HRMS
(ES) m/z 753.4189, calcd for C38H61N2O13 753.4174. Anal.
(C38H60N2O13‚1/2H2O) C, H, N.
5-O-Desosam in yl-3-O-(2-pyr idyl)acetyl-6-O-m eth yler yth -
r on olid e A (11). To a solution of 2-pyridylacetic acid (1.15 g,
6.6 mmol) and Et3N (0.93 mL, 6.6 mmol) in CH2Cl2 (30 mL)
was added dropwise pivaloyl chloride (0.83 mL, 6.6 mmol) at
-15 °C. After being stirred for 30 min, a solution of 1 (1.26 g,
2.0 mmol) in CH2Cl2 (10 mL) was added dropwise over 15 min,
and DMAP (0.24 g, 2.0 mmol) was then added before warming
the mixture to room temperature. After being stirred over-
night, the reaction mixture was partitioned between CH2Cl2
and saturated NaHCO3 solution. The organic layer was
washed with brine and dried over MgSO4. After evaporation
of the solvent in vacuo, the residue was purified by column
chromatography, eluting with acetone/n-hexane/Et3N (4:10:
0.05) to give 2′-OAc-11 (1.12 g, 75%) as a slightly yellow foam.
The product was refluxed in MeOH (20 mL) for 5 h. After
evaporation of the solvent in vacuo, the residue was purified
by column chromatography, eluting with CHCl3/MeOH/25%
NH4OH (20:1:0.1) to give 11 (930 mg, 88%) as a white foam,
which was further purified by recrystallization from Et2O/n-
hexane to give a white powder (764 mg, 72%): mp 189-190.5
°C; HRMS (ES) m/z 709.4282, calcd for C37H61N2O11 709.4275.
Anal. (C37H60N2O11) C, H, N.
(E)-5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyl-6-O-m eth yl-
er yth r on olid e A 9-Oxim e (22). To a solution of 5-O-desos-
aminyl-6-O-methylerythronolide 9-oxime A 2014 (5.00 g, 8.27
mmol) in acetone (30 mL) was added acetic anhydride (2.0 mL,

3-O-(3-Pyridyl)acetylerythromycin A Derivatives
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2713
with acetone/n-hexane/Et3N (10:10:0.2) to give 31 (6.64 g, 91%)
21.2 mmol) at room temperature. After being stirred for 2 h,
the reaction mixture was evaporated in vacuo and then
partitioned between CH2Cl2 and saturated Na2CO3 solution.
The organic layer was washed with brine, dried over MgSO4,
and evaporated in vacuo to give crude 21 (5.50 g). The title
compound was prepared from the crude intermediate 21
according to the procedure used to prepare 11. Purification
by column chromatography, eluting with CHCl3/MeOH/25%
NH4OH ((100:5-10):0.1), gave 22 (2.97 g, 50%) as a white
as
C
a white foam: HRMS (ES) m/z 710.4231, calcd for
36H60N3O11 710.4228. Anal. (C36H59N3O11‚1/2H2O) C, H, N.
5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyler yth r on olid e A
(32). To a solution of 31 (2.00 g, 2.82 mmol) and sodium nitrite
(4.86 g, 70.4 mmol) in MeOH (30 mL) and H2O (10 mL) was
added dropwise 2 N HCl (35.2 mL, 70.4 mmol) over 30 min at
0 °C. After being stirred for 4 h, the reaction mixture was
partitioned between CHCl3 and water and the pH of the
aqueous layer was adjusted to 8 with 2 N NaOH. The organic
layer was dried over MgSO4 and evaporated in vacuo. The
residue was purified by recrystallization from 2-propanol to
give 32 (683 mg, 35%) as a white powder: mp 231-233 °C;
HRMS (ES) m/z 695.4136, calcd for C36H59N2O11 695.4119.
(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(3-p yr id yl)a cet -
yler yth r on olid e A (33). To a solution of 32 (619 mg, 0.89
mmol) in EtOH (10 mL) was added sodium borohydride (51
mg, 1.35 mmol) at 0 °C. After being stirred for 5 h, the reaction
mixture was partitioned between EtOAc and brine. The
aqueous layer was extracted twice with CHCl3. The combined
organic layer was dried over MgSO4 and evaporated in vacuo.
Purification by column chromatography, eluting with CHCl3/
MeOH/25% NH4OH (15:1:0.1), gave 33 (0.21 g, 34%) as a white
foam: HRMS (ES) m/z 724.4391, calcd for
724.4384. Anal. (C37H61N3O11) C, H, N.
C37H62N3O11
(E)-5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyl-6-O-m eth yl-
er yth r on olid e A 9-Oxim e 11,12-Cyclic Ca r bon a te (23). To
a solution of 22 (2.90 g, 4.0 mmol) in acetone (30 mL) was
added acetic anhydride (1.1 mL, 11.7 mmol) at room temper-
ature. After being stirred for 3 h, the reaction mixture was
evaporated in vacuo and then partitioned between CH2Cl2 and
saturated Na2CO3 solution. The organic layer was washed with
brine, dried over MgSO4, and evaporated in vacuo to give crude
2′-OAc-22 acetoxime (2.90 g) as a white foam. 2′-Acetate of
the title compound was prepared from 2′-OAc-22 acetoxime
according to the procedure used to prepare 14. Purification
by column chromatography, eluting with acetone/n-hexane/
Et3N ((6-10):10:0.2), gave 2′-OAc-23 (0.34 g, 10%) as a slightly
yellow foam, along with the recovered starting material 2′-
OAc-22 (1.74 g, 53%). The product was refluxed in MeOH (6
mL) for 3 h. After evaporation of the solvent in vacuo, the
residue was purified by column chromatography, eluting with
CHCl3/MeOH/25% NH4OH (10:1:0.1) to give 23 (0.24 g, 79%)
as a slightly yellow foam: HRMS (ES) m/z 750.4171, calcd for
foam: HRMS (ES) m/z 697.4293, calcd for
697.4275. Anal. (C36H60N2O11‚2H2O) C, H, N.
C36H61N2O11
(E)-5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyler yth r on o-
lid e A 9-Oxim e 11,12-Cyclic Ca r bon a te (34). 2′-Acetate of
the title compound was prepared from 30 (10.35 g, 13.0 mmol)
according to the procedure used to prepare 14. The product
was stirred in MeOH (100 mL) at room temperature overnight.
After evaporation of the solvent in vacuo, the residue was
purified by column chromatography, eluting with CHCl3/
MeOH (95:5) to give 34 (8.59 g, 90%) as a slightly yellow foam,
which was further purified by recrystallization from MeCN
to give 34 (4.87 g, 51%) as a white powder: mp 212-215 °C;
HRMS (ES) m/z 736.4032, calcd for C37H58N3O12 736.4021.
Anal. (C37H57N3O12) C, H, N.
5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyler yth r on olid e A
11,12-Cyclic Ca r bon a te (35). The title compound was pre-
pared from compound 34 (3.21 g, 4.36 mmol) according to the
procedure used to prepare 32. Purification by column chro-
matography, eluting with CHCl3/MeOH/25% NH4OH (15:1:
0.1), gave 35 (0.64 g, 20%) as a white foam: HRMS (ES) m/z
721.3906, calcd for C37H57N2O12 721.3912; NMR analysis
supports the 6,9-hemiketal conformation of 35 in the CDCl3.
Anal. (C37H56N2O12‚1/2H2O) C, H, N.
(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(3-p yr id yl)a cet -
yler yth r on olid e A 11,12-Cyclic Ca r bon a te (36). The title
compound was prepared from compound 35 (0.38 g, 0.53 mmol)
according to the procedure used to prepare 33. Purification
by column chromatography, eluting with CHCl3/MeOH/25%
NH4OH (15:1:0.1), gave 34 (0.32 g, 84%) as a white foam:
HRMS (ES) m/z 723.4077, calcd for C37H59N2O12 723.4068.
Anal. (C37H58N2O12‚H2O) C, H, N.
(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(3-p yr id yl)a cet -
yler yth r on olid e A 9,11-Cyclic Ca r bon a te (39). A mixture
of (9S)-9-dihydroerythromycin A 9,11-carbonate 3720 (1.90 g,
2.49 mmol) and 2 N HCl (20 mL) was stirred at room
temperature overnight. The reaction mixture was partitioned
between EtOAc and water, and the pH of the aqueous layer
was adjusted to 8 with 2 N NaOH. The organic layer was
washed with brine, dried over MgSO4, and evaporated in
vacuo. The residue was purified by column chromatography,
eluting with CHCl3/MeOH/25% NH4OH (20:1:0.1) to give 38
(1.02 g, 68%) as a white foam along with (9S)-5-O-desosaminyl-
9-dihydroerythronolide A (0.34 g, 24%). To a solution of 38
(0.95 g, 1.57 mmol) in acetone (10 mL) was added acetic
anhydride (0.22 mL, 2.33 mmol) at room temperature. After
being stirred for 6 h, the reaction mixture was evaporated in
vacuo and then partitioned between EtOAc and saturated Na2-
CO3 solution. The organic layer was washed with brine, dried
over MgSO4, and evaporated in vacuo. The residue was
purified by column chromatography, eluting with acetone/n-
hexane/Et3N (10:10:0.2) to give 2′-OAc-38 (1.0 g, 98%). The
C
38H60N3O12 750.4177. Anal. (C38H59N3O12‚H2O) C, H, N.
5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyl-9-d eoxo-9a -a za -
9a -m eth yl-9a -h om oer yth r on olid e A (25). To a solution of
3-O-descladinosylazithromycin 2418 (2.44 g, 4.13 mmol) in
acetone (25 mL) was added acetic anhydride (0.43 mL, 4.56
mmol) at room temperature. After being stirred overnight, the
reaction mixture was evaporated in vacuo and then partitioned
between EtOAc and saturated NaHCO3 solution. The organic
layer was washed with brine, dried over MgSO4, and evapo-
rated in vacuo to give 2′-OAc-24 (2.21 g, 85%) as a white
powder. The title compound was prepared from 2′-OAc-24 (0.70
g, 1.11 mmol) according to the procedure used to prepare 3.
Purification by column chromatography, eluting with CHCl3/
MeOH/25% NH4OH (20:1:0.1), gave 25 (0.54 g, 69%) as a white
foam, which was further purified by recrystallization from CH2-
Cl2/n-hexane to give a white powder (0.28 g, 36%): mp 210-
213 °C; HRMS (ES) m/z 710.4601, calcd for C37H64N3O10
710.4592. Anal. (C37H63N3O10) C, H, N.
11-Am in o-9-d eoxo-11-d eoxy-5-O-d esosa m in yl-9-,11-N-
n itr iloeth a n o-3-O-(3-p yr id yl)a cetyl-6-O-m eth yler yth r o-
n olid e A 11,12-Cyclic Ca r ba m a te (27). The title compound
was prepared from 11-amino-9-deoxo-11-deoxy-5-O-desosami-
nyl-9-,11-N-nitriloethano-6-O-methylerythronolide A 11,12-
cyclic carbamate 2612 (3.62 g, 5.65 mmol) according to the
procedure used to prepare 25. Purification by column chro-
matography, eluting with CHCl3/MeOH/25% NH4OH (10:1:
0.1), gave 27 (3.39 g, 79%) as a white foam, which was further
purified by recrystallization from Et2O to give a white pow-
der: mp 226-229 °C; HRMS (ES) m/z 759.4541, calcd for
C
40H63N4O10 759.4544. Anal. (C40H62N4O10‚H2O) C, H, N.
(E)-5-O-Desosa m in yl-3-O-(3-p yr id yl)a cetyler yth r on o-
lid e A 9-Oxim e (31). To a solution of (E)-5-O-desosami-
nylerythronolide A 9-oxime 2819 (15.0 g, 25.4 mmol) and
sodium carbonate (2.69 g, 25.4 mmol) in CH2Cl2 (80 mL) was
added acetic anhydride (7.2 mL, 76.3 mmol) at room temper-
ature. After being stirred for 3 h, the reaction mixture was
partitioned between CH2Cl2 and saturated Na2CO3 solution.
The organic layer was washed with brine, dried over MgSO4,
and evaporated in vacuo to give the 2′-acetate 29 (16.57 g,
97%). 3-O-(3-Pyridyl) acetylation according to the procedure
used to prepare 11 gave 30 (11.15 g, 58%) as a slightly yellow
foam. The product (8.18 g, 10.3 mmol) was refluxed in MeOH
(200 mL) for 9 h. After evaporation of the solvent in vacuo,
the residue was purified by column chromatography, eluting

2714 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13
Tanikawa et al.
title compound was prepared from 2′-OAc-38 (0.50 g, 0.77
mmol) according to the procedure used to prepare 11. Purifica-
tion by CHCl3/MeOH/25% NH4OH (20:1:0.1) gave 39 (0.33 g,
59%) as a white foam along with the recovered starting
material 38 (0.14 g, 30%). 39: HRMS (ES) m/z 723.4063, calcd
for C37H59N2O12 723.4068. Anal. (C37H58N2O12‚2H2O) C, H, N.
Ack n ow led gm en t. The authors thank Mr. Kazuo
Numata for providing in vivo data.
Su p p or tin g In for m a tion Ava ila ble: Complete 1H and
13C NMR peak assignments for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(9S)-9-Dih yd r oer yth r om ycin A 6,9:11,12-Dicyclic Ca r -
bon a te (43). To a solution of (9S)-9-dihydroerythromycin A
11,12-cyclic carbonate 4021 (13.64 g, 17.9 mmol) was added
acetic anhydride (2.5 mL, 26.5 mmol) at room temperature.
After being stirred overnight, the reaction mixture was
evaporated in vacuo and then partitioned between EtOAc and
saturated NaHCO3 solution. The organic layer was washed
with brine, dried over MgSO4, and evaporated in vacuo to give
41 (13.52 g, 91%). To a solution of 41 (3.42 g, 4.3 mmol) in
CH2Cl2 (30 mL) and pyridine (20.6 mL, 0.26 mol) was added
dropwise trichloromethyl chloroformate (3.1 mL, 25.9 mmol)
in CH2Cl2 (30 mL) over 20 min at 0 °C. After being stirred for
5 h, the reaction was quenched by adding pieces of ice in small
portions. The reaction mixture was partitioned between CH2-
Cl2 and water, and the pH of the aqueous layer was adjusted
to 8 with 2 N NaOH. The aqueous layer was extracted twice
with CH2Cl2. The combined organic layer was washed with
brine, dried over MgSO4, and evaporated in vacuo to give crude
42 (3.44 g). The product was stirred in MeOH (35 mL) for 23
h. After evaporation of the solvent in vacuo, the residue was
purified by column chromatography, eluting with CHCl3/
MeOH/25% NH4OH (15:1:0.1) to give 43 (1.65 g, 49%) as a
white foam: HRMS (ES) m/z 788.4441, calcd for C39H66NO15
788.4432. Anal. (C39H65NO15‚1/2H2O) C, H, N.
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(9S)-5-O-Desosa m in yl-9-d ih yd r oer yth r on olid e A 6,9:
11,12-Dicyclic Ca r bon a te (44). The title compound was
prepared from 43 (4.53 g, 5.75 mmol) according to the
procedure used to prepare 39. Purification by column chro-
matography, eluting with acetone/n-hexane/Et3N (10:10:0.2),
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630.3492, calcd for C31H52NO12 630.3490. Anal. (C31H51NO12
C, H, N.
)
(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(3-p yr id yl)a cet -
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overnight, the reaction mixture was evaporated in vacuo and
then partitioned between EtOAc and saturated NaHCO3
solution. The organic layer was washed with brine, dried over
MgSO4, and evaporated in vacuo to give 45 (2.46 g, 99%). The
title compound was prepared from 45 (2.46 g, 3.66 mmol) and
3-pyridylacetic acid (1.9 g, 10.9 mmol) according to the
procedure used to prepare 11. Purification by column chro-
matography, eluting with acetone/n-hexane/Et3N (30:10:0.2),
and recrystallization from 2-propanol gave 47 (1.84 g, 66%)
as a white powder along with the recovered starting material
44 (0.09 g, 4%). 47: mp 217-219.5 °C; HRMS (ES) m/z
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749.3860, calcd for C38H57N2O13 749.3861. Anal. (C38H56N2O13
‚
1/2H2O) C, H, N.
(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(2-p yr id yl)a cet -
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title compound was prepared from 45 (0.16 g, 0.24 mmol) and
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0.1), gave 46 (139 mg, 78%) as a slightly yellow foam: HRMS
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(9S)-5-O-Desosa m in yl-9-d ih yd r o-3-O-(4-p yr id yl)a cet -
yler yth r on olid e A 6,9:11,12-Dicyclic Ca r bon a te (48). The
title compound was prepared from 45 (0.31 g, 0.46 mmol) and
4-pyridylacetic acid (0.27 g, 1.56 mmol) according to the
procedure used to prepare 3. Purification by column chroma-
tography, eluting with CHCl3/MeOH/25% NH4OH (15:1:0.1),
gave 48 (169 mg, 49%) as a white foam: HRMS (ES) m/z
749.3860, calcd for C38H57N2O13 749.3861. Anal. (C38H56N2O13
‚
1/2H2O) C, H, N.

3-O-(3-Pyridyl)acetylerythromycin A Derivatives
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J M020568D