Synthesis and evaluation of novel phenylethanolamine derivatives containing acetanilides as potent and selective b 3-adrenergic receptor agonists

Article abstract of DOI:10.1248/cpb.58.533

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human β3-, β2-, and β1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5- methylthiazol- 4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3- ylacetanilide (36h) derivatives showed potent agonistic activity at the β3-AR with functional selectivity over the β1- and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.

Full text of DOI:10.1248/cpb.58.533

April 2010
Chem. Pharm. Bull. 58(4) 533—545 (2010)
533
Synthesis and Evaluation of Novel Phenylethanolamine Derivatives
b
containing Acetanilides as Potent and Selective 3-Adrenergic
Receptor Agonists
Tatsuya MARUYAMA,* Kenichi ONDA, Masahiko HAYAKAWA, Takayuki SUZUKI, Tetsuya KIMIZUKA,
Tetsuo MATSUI, Toshiyuki TAKASU, Itsuro NAGASE, Noritaka HAMADA, and Mitsuaki OHTA
Drug Discovery Research, Astellas Pharma Inc.; 21 Miyukigaoka, Tsukuba, Ibaraki 305–8585, Japan.
Received November 30, 2009; accepted January 26, 2010; published online January 27, 2010
In the search for potent and selective human b3-adrenergic receptor (AR) agonists as potential pharma-
cotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series
of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human
b3-, b2-, and b1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthia-
zol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic
activity at the b3-AR with functional selectivity over the b1- and b2-ARs. In addition, these compounds exhib-
ited significant hypoglycemic activity in a rodent diabetic model.
Key words b3-adrenergic receptor; agonist; phenylethanolamine; acetanilide; diabetes
A major increase in the prevalence of obesity and non-in- high potency. Subtype selectivity for b3-AR agonists must
sulin dependent (type II) diabetes and related cardiovascular be kept specifically in mind, since activation of the b1- or
disorders has led to the search for new pharmacological ap- b2-ARs would cause undesirable side effects such as in-
proaches in the treatment of these conditions.1,2) In the early creased heart rate or muscle tremors.
1980s, the b3-adrenergic receptor (AR) was identified as a
We previously described efforts in this area, including the
possible therapeutic target for the treatment of type II dia- disclosure of acetanilide analogues exemplified by 2-pyridyl-
betes and obesity.3,4) Early potent and selective b3-AR ago- acetanilide 1, which showed potent b3-AR agonistic activity
nists, such as BRL-373445) and CL-316243,6) were reported with modest functional selectivity over b1-AR and oral
to be effective anti-obesity and anti-diabetic agents in rodents hypoglycemic activity in diabetic kk mice (Fig. 2).16) Com-
(Fig. 1).7) Human clinical trials with these agents for the pound 1 was found, however, to exhibit poor bioavailability
treatment of metabolic disorders, however, have been disap- in rats (Fꢀ2%), probably due to the rapid metabolism of the
pointing due to a lack of efficacy or an unfavorable side- 4-hydroxyphenoxy moiety on the left-hand side. Many kinds
effect profile.8,9) The clinical failure of such compounds has of phenylethanolamine-based b3-AR agonists have been re-
been attributed to a lack of sufficient b3-AR potency and ported (Fig. 3)4,17) and we therefore decided to explore the al-
selectivity relative to b1- and b2-ARs resulting from phar- ternative structures to the 4-hydroxyphenoxymethyl moiety.
macologic differences between rodent and human receptors, Subsequently, we attempted to modify the central part and
which was supported by the discovery, cloning, and charac- the pyridyl moiety on the right-hand side (Fig. 2). In this
terization of the human, rat, and mouse b3-ARs.10—12) Recent paper, we describe the synthesis and structure–activity rela-
studies indicated that, in addition to adipocytes, the b3-AR is
also distributed in human urinary bladder detrusor tissue and
its relaxation occurs mainly via b3-AR.13—15) The availability
of appropriate human receptors has given rise to the design
and synthesis of a new generation of b3-AR agonists with
Fig. 2. Design of Phenylethanolamine Derivatives containing Acetanilides
Fig. 1. Chemical Structure of Early b3-AR Agonists
based on Compound 1
Fig. 3. Chemical Structure of Phenylethanolamine-based b3-AR Agonists
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: tatsuya.maruyama@jp.astellas.com

534
Vol. 58, No. 4
i
Reagents and conditions: (a) benzaldehyde, toluene, reflux; (b) NaBH4, MeOH; (c) ArCOCH2Br; Pr2NEt, 2-butanone, reflux; (d) H2, Pd–C, MeOH, then 4 M
HCl–EtOAc, MeOH; (e) Fe, HCl aq., MeOH; (f) RCO2Ac, CHCl3; (g) Na2CO3, MeOH aq.; (h) ArCH(O)CH2, EtOH, reflux, and then 4 M HCl–EtOAc, EtOH.
Chart 1
i
Reagents and conditions: (a) (R)-styrene oxide, PrOH, reflux; (b) Fe, HCl aq., MeOH; (c) ArCH2CO2Me, xylene, reflux, or ArCH2CO2H, EDC·HCl, HOBt, THF,
DMF; (d) H2, Pd–C, MeOH, and then 4 M HCl–EtOAc, MeOH.
Chart 2
tionships (SARs) of these newly designed phenylethanol- priate arylacetic acid derivatives, followed by deprotection of
amine derivatives containing acetanilides as b3-AR agonists. the benzyl group by hydrogenolysis afforded the desired
Chemistry The synthesis of 2-pyridylacetanilides 5a— products 14a—d.
c, 8a, b, and 9a—d are shown in Chart 1. Treatment of 4ꢁ-(2-
Chart 3 shows the synthesis of compounds 20a, b, and 23.
aminoethyl)-2-pyridylacetanilide (2)16) with benzaldehyde, Treatment of a commercially available 4-nitrophenylacetone
followed by reduction with sodium borohydride yielded a (15) with benzylamine, followed by reduction with sodium
benzylamine intermediate (3). Compound 3 was coupled borohydride gave compound 16. The coupling of 16 with
with the appropriate phenacyl bromides in the presence of (R)-styrene oxide yielded the corresponding diastereomers
diisopropylethylamine, followed by reduction of the ketone 17a and 17b. The S configuration of the carbon atom that
with sodium borohydride to yield the benzylamine deriva- bound to the methyl group of 17b was determined using sin-
tives 4a—d. Deprotection of the benzyl groups by hy- gle-crystal X-ray analysis (Fig. 4). Nitro compounds 17a, b
drogenolysis in 4a—c afforded the desired products 5a—c. were reduced with iron powder, followed by coupling with 2-
Reduction of the nitro compound 4d was accomplished by pyridylacetic acid to yield 2-pyridylacetanilides 19a, b. De-
treatment with iron powder and provided aniline 6, which protection of the benzyl group by hydrogenolysis in 19a, b
was converted to the anilides 7a, b by acylation. Deprotec- afforded the desired products 20a, b. Meanwhile, hydrogena-
tion of the benzyl groups by hydrogenolysis in 7a, b afforded tion of tert-butyl N-[2-methyl-1-(4-nitrophenyl)-2-propyl]-
the desired products 8a, b. Meanwhile, the coupling of com- carbamate (21)19) followed by coupling with 2-pyridylacetic
pound 2 with the appropriate styrene oxide afforded the de- acid yielded compound 22. Deprotection of the tert-butoxy-
sired products 9a—d.
carbonyl (Boc) group by treatment with hydrochloric acid in
Acetanilides 14a—d were prepared from the aniline inter- 22, followed by coupling with (R)-styrene oxide afforded the
mediate 12 as illustrated in Chart 2. Compound 12 was syn- desired product 23.
thesized from N-benzyl-2-(4-nitrophenyl)ethylamine (10)18)
Compounds 28a, b were synthesized as illustrated in Chart
and (R)-styrene oxide, followed by reduction of the nitro 4. 4-(4-Nitrophenyl)butyric acid (24) was treated with
group with iron powder. The coupling of 12 with the appro- diphenyl phosphoryl azide (DPPA) in the presence of trieth-

April 2010
535
Reagents and conditions: (a) benzylamine, toluene, reflux; (b) NaBH4, MeOH, THF; (c) (R)-styrene oxide, heat; (d) Fe, HCl aq., MeOH; (e) 2-pyridylacetic acid hy-
drochloride, EDC·HCl, HOBt, THF, DMF, or methyl 2-pyridylacetate, xylene, reflux; (f) H2, Pd–C, MeOH, and then 4 M HCl–EtOAc, MeOH; (g) H2, Pd–C, EtOH, THF;
(h) 4 M HCl–EtOAc, MeOH; (i) (R)-styrene oxide, iPrOH, MeOH, reflux, and then 4 M HCl–EtOAc, MeOH.
Chart 3
Fig. 4. The Molecular Structure of 17b with the Crystallographic Numbering Scheme
t
Reagents and conditions: (a) DPPA, Et3N toluene, reflux; (b) BuOH, reflux; (c) H2NCH2CH2OH, NaH, THF; (d) (Boc)2O, THF; (e) H2, Pd–C, EtOH, THF; (f) 2-
pyridylacetic acid hydrochloride, EDC·HCl, HOBt, THF; (g) 4 M HCl–EtOAc, MeOH; (i) (R)-styrene oxide, iPrOH, reflux, and then 4 M HCl–EtOAc, MeOH.
Chart 4
ylamine, followed by refluxing in tert-butanol to yield tert-
butyl N-[3-(4-nitrophenyl)propyl]carbamate (26a). Mean-
while, treatment of 4-fluoronitrobenzene (25) with 2-
aminoethanol in the presence of sodium hydride, followed by
protection with the Boc group gave tert-butyl N-[2-(4-nitro-
phenoxy)ethyl]carbamate (26b). The nitro compounds 26a, b
were subjected to catalytic hydrogenation in the presence of
palladium on charcoal, followed by coupling with 2-pyridyl-
acetic acid to yield compounds 27a, b. Deprotection of the
Boc group in 27a, b by treatment with hydrochloric acid fol-
Reagents and conditions: (a) H2, Raney-Ni, conc. NH3 aq., EtOH, THF; (b) (R)-
styrene oxide, iPrOH, reflux, and then 4 M HCl–EtOAc, MeOH.
Chart 5
Another process employing the aniline intermediate 34 is
lowed by coupling with (R)-styrene oxide afforded the de- illustrated in Chart 6. A commercially available 2-(4-nitro-
sired products 28a, b. phenyl)ethylamine hydrochloride (31) was treated with (R)-
The acetanilides 30a, b were prepared from the correspon- styrene oxide, followed by protection of the amine with a
ding acetanilides 29a, b,16) as illustrated in Chart 5. Reduc- Boc group to provide nitro compound 33. Hydrogenation of
tion of compounds 29a, b was accomplished by hydrogena- 33 in the presence of palladium on charcoal gave the aniline
tion in the presence of Raney-nickel, followed by coupling intermediate 34. The coupling of 34 with the appropriate
with (R)-styrene oxide to afford the desired products 30a, b.
arylacetic acids, followed by deprotection of the Boc group

536
Vol. 58, No. 4
Reagents and conditions: (a) (R)-styrene oxide, iPrOH, reflux; (b) (Boc)2O, THF; (c) H2, Pd–C, EtOH; (d) ArCH2CO2H, EDC·HCl, HOBt, DMF; (e) H2, Pd–C, HCl,
MeOH; (f) 4 M HCl–EtOAc, EtOH; (g) BrCH2COBr, iPr2NEt, CHCl3; (h) azole, K2CO3, MeCN; (i) CF3CO2H, tetramethylbenzene, and then 4 M HCl–EtOAc, EtOH.
Chart 6
by treatment with hydrochloric acid, afforded the desired b3-AR agonistic activity and functional selectivity over b2-
products 36a, b and 36d—h. The 4-nitrobenzyl group in 1- and b1-ARs. The b3-AR agonistic activity of the 3-hydroxy-
(4-nitrobenzyl)imidazol-2-ylacetanilide (35d) was removed phenyl analogue (5b) was partial, and relative to 5a there
by hydrogenation in the presence of palladium on charcoal, was no improvement in selectivity over b2- and b1-ARs. In-
followed by deprotection of the Boc group to afford imida- troduction of a formamido group (8a) at 3-position of the
zol-2-ylacetanilide (36c). Meanwhile, the aniline intermedi- phenyl ring in 5a resulted in a dramatic increase in potency
ate 34 was coupled with 2-bromoacetyl bromide to yield bro- at the b2-AR while maintaining b3- and b1-AR agonistic ac-
moacetanilide 37. The treatment of 37 with the appropriate tivity, revealing that compound 8a was a non-selective b-AR
azoles in the presence of potassium carbonate, followed by agonist. In contrast, introduction of an acetamido group (8b)
deprotection of the Boc group afforded the desired products at 3-position of the phenyl ring in 5a led to a decrease in po-
39a, b. Deprotection of both the benzyl and Boc groups by tency at all b-ARs relative to 5a. The 4-hydroxy-3-methane-
treatment with trifluoroacetic acid in 35b afforded the de- sulfonylaminophenyl analogue (5c) showed a 20-fold in-
sired product 40.
crease in potency at the b3-AR (EC50ꢀ0.081 mM) relative to
5a, but adequate selectivity was not met over b2- and b1-
ARs. These results indicated that replacement of the 4-hy-
Results and Discussion
The prepared compounds were evaluated for their agonis- droxyphenoxymethyl moiety in 1 with several hydroxyphenyl
tic activities in stimulating an increase in cyclic AMP moieties was tolerable and maintained potency at the b3-AR,
(cAMP) levels in Chinese hamster ovary (CHO) cells ex- but this change may decrease functional selectivity over b2-
pressing cloned human b3-, b2-, and b1-ARs. The results for and b1-ARs. Interestingly, removal of the 4-hydroxyl group
the reference compound, isoproterenol (ISO; non-selective (14a) in 5a resulted in a substantial loss of both b2- and b1-
b-AR agonist), BRL-37344 and CL-316243, are also shown AR agonistic activity while maintaining b3-AR agonistic ac-
for comparison in Table 1.
tivity (EC50ꢀ0.41 mM, IAꢀ0.67). We therefore selected the
Modification of the 4-hydroxyphenoxymethyl moiety on phenyl derivative (14a) as our new leading candidate and ex-
the left-hand side of 1 with several aryl moieties, which con- amined the modification of its phenyl ring. There was partial
verted to phenylethanolamine derivatives, was investigated agonistic activity of the 4-fluorophenyl (9b) and 3-fluo-
(Table 1). Initially, replacement of the 4-hydroxyphenoxy- rophenyl (9c) derivatives at the b3-AR (IAꢀ0.13 and 0.43,
methyl of 1 with the 4-hydroxyphenyl group (5a) resulted respectively), while the 3-chlorophenyl derivative (9a),
in slightly improved potency at the b3-AR (50% effective known as a favorable b3-AR agonist chemical moiety and il-
concentration (EC50)ꢀ0.16 mM) with high intrinsic activity lustrated in Fig. 2, exhibited a considerable decrease in selec-
(IAꢀ0.80), although there was an extreme decrease in the tivity over b2- and b1-ARs while maintaining the same ago-
functional selectivity over both the b1- and b2-ARs. This nistic activity at the b3-AR (EC50ꢀ0.56 mM, IAꢀ0.59) as
prompted us to examine further phenylethanolamine ana- 14a. The 3-pyridyl derivative (9d) showed a 5-fold decrease
logues possessing 2-pyridylacetanilide in order to improve in potency at the b3-AR relative to 14a.

April 2010
537
Table 1. b-AR Agonistic Activity of Arylethanolamine Analogues
EC50, mMa) (IAb))
b2-AR
Compound
Ar
*Config.
b3-AR
b1-AR
5a
5b
RꢂS
RꢂS
0.16 (0.80)
0.39 (0.55)
10 (0.12)
4.0 (0.43)
0.81 (0.55)
2.8 (0.32)
8a
8b
5c
RꢂS
RꢂS
RꢂS
0.11 (0.68)
3.4 (0.38)
0.32 (1.03)
16 (0.25)
1.1 (0.94)
ꢃ100 (0.03)
15 (0.19)
0.081 (0.75)
0.46 (0.63)
14a
9b
R
0.41 (0.67)
0.45 (0.13)
ꢃ100 (0.01)
ꢃ100 (0.06)
ꢃ100 (0.06)
RꢂS
3.2 (0.11)
9c
9a
9d
RꢂS
R
0.41 (0.43)
0.56 (0.59)
2.0 (0.56)
9.8 (0.42)
29 (0.27)
7.2 (0.22)
11 (0.13)
3.9 (0.22)
ꢃ100 (0.04)
RꢂS
1
ISO
BRL-37344
CL-316243
0.29 (0.74)
0.10 (1.00)
0.46 (0.6)
4.43 (0.5)
ꢃ100 (0)
2.7 (0.14)
0.012 (1.00)
1.29 (0.5)
ꢃ100 (0)
0.003 (1.00)
0.36 (0.7)
ꢃ100 (0.1)
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing b-ARs. b) Values in parentheses represent the intrinsic activity (IA) given as
a fraction of the maximum stimulation with isoproterenol.
Next, in order to improve b3-AR agonistic activity while sult in both potency at the b3-AR and functional selectivity
maintaining functional selectivity over b2- and b1-ARs, over b2- and b1-ARs. Meanwhile, introduction of a chloro
modification of the central part and the pyridyl moiety in 14a group at the 6-position on the pyridine ring (36a) resulted in
was examined, as shown in Table 2. Initially, the effects of in- a 5.5-fold improved potency at the b3-AR (EC50ꢀ0.074 mM)
troducing a methyl group to the central methylene part in 14a with lower selectivity over b2- and b1-ARs when compared
were investigated. Both b-methyl (20a) and a-methyl (20b) to 14a, while the 2-pyridon-6-yl analogue (40) showed main-
analogues showed respective 2- and 4-fold increases in po- tained potency at the b3-AR with lower intrinsic activity. In-
tency at the b3-AR (EC50ꢀ0.20 and 0.10 mM, respectively), terestingly, the agonistic activity of the 6-amino-2-pyridyl-
but the functional selectivity over both the b1- and b2-ARs acetanilide derivative (36b) increased 4-fold at the b3-AR
was decreased relative to 14a. A dimethyl group (23) was (EC50ꢀ0.098 mM, IAꢀ0.83) without agonistic activity at the
also introduced on the central methylene part in 14a, which b2- and b1-ARs. These results showed that introduction of
yielded results similar to those of the methyl analogues substituents at the 6-position on the pyridine ring in 14a al-
(20a, b). These results showed that the introduction of a lowed potency at the b3-AR to be maintained, although this
methyl group on the central methylene part in 14a can im- change may affect functional selectivity over b2- and b1-
prove potency at the b3-AR, but may not be efficacious for ARs.
the functional selectivity over b2- and b1-ARs. In contrast,
Lastly, replacement of the pyridine ring in 14a with the
the propylene (28a) and ethylenoxy (28b) analogues exhib- appropriate nitrogen-containing heteroaromatic rings was in-
ited respective 14- and 7-fold decreases in potency at the b3- vestigated as shown in Table 3. The 2-quinolinyl analogue
AR (EC50ꢀ5.9 and 2.8 mM, respectively) with lower selectiv- (30a) showed a considerable decrease in intrinsic activity at
ity over b2- and b1-ARs when compared to 14a, which indi- the b3-AR (IAꢀ0.24). Further, although replacement of the
cated that the ethylene moiety would be a favorable structure pyridine ring in 14a with a 6-membered basic heteroaromatic
as a central part for conferring both potency at the b3-AR ring, such as pyrimidin-2-yl (30b) and pyrazin-2-yl (14b),
and functional selectivity. We then examined the nitrogen po- maintained potency at the b3-AR (EC50ꢀ0.66 and 0.20 mM,
sition and the substituents on the pyridine ring in 14a. The 3- respectively), their intrinsic activities were decreased. The 5-
pyridyl (14c) and 4-pyridyl (14d) analogues were less potent membered basic heteroaromatic analogues, such as imidazol-
at the b3-AR than the 2-pyridyl analogue (14a), results simi- 2-yl (36c), pyrazol-1-yl (39a), 1,2,4-triazol-3-yl (36d), 1,2,4-
lar to those in the 4-hydroxyphenoxypropanolamine deriva- triazol-1-yl (39b) and 2-methylthiazol-4-yl (36f), also
tives.16) These results suggested that changing the position of showed a decrease in intrinsic activity at the b3-AR (IAꢀ
the nitrogen atom on the 2-pyridyl moiety in 14a would re- 0.37—0.54). In contrast, the tetrazol-5-yl derivative (36e) as

538
Vol. 58, No. 4
Table 2. b-AR Agonistic Activity of Pyridylacetanilide Derivatives
EC50, mMa) (IAb))
b2-AR
Compound
R1
R2
X
Ar
b3-AR
b1-AR
14a
20a
20b
23
H
H
CH2
0.41 (0.67)
ꢃ100 (0.01)
ꢃ100 (0.06)
Me
H
H
CH2
0.20 (0.79)
0.10 (0.61)
0.13 (0.55)
5.9 (0.58)
2.8 (0.32)
2.5 (0.26)
3.5 (0.18)
0.074 (0.68)
0.54 (0.56)
2.6 (0.13)
0.28 (0.89)
2.2 (0.23)
3.6 (0.53)
4.1 (0.19)
150 (0.50)
4.9 (0.39)
0.62 (0.51)
10 (0.27)
Me
Me
H
CH2
Me
H
CH2
2.5 (0.25)
ꢃ100 (0.03)
2.7 (0.14)
3.7 (0.12)
4.4 (0.20)
7.9 (0.74)
28a
28b
14c
14d
36a
(CH2)2
CH2O
CH2
H
H
H
H
H
H
CH2
H
H
CH2
40
H
H
H
H
CH2
CH2
0.52 (0.40)
ꢃ100 (0.03)
ꢃ100 (0.02)
5.5 (0.13)
36b
0.098 (0.83)
ꢃ100 (0.09)
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing b-ARs. b) Values in parentheses represent the intrinsic activity (IA) given as
a fraction of the maximum stimulation with isoproterenol.
an acidic heteroaromatic analogue maintained potency and scribed their synthesis and SARs. Among these compounds,
efficacy at the b3-AR (EC50ꢀ0.45 mM, IAꢀ0.89) with func- the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methyl-
tional selectivity over b2- and b1-ARs when compared to thiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-
14a. These results suggested that although replacement of 3-ylacetanilide (36h) derivatives showed potent agonistic
the pyridine ring in 14a with a basic 5- or 6-membered het- activity at the b3-AR (EC50ꢀ0.098, 0.016, and 0.042 mM,
eroaromatic ring allows potency at b3-AR to be maintained, respectively) with agonistic activity completely abolished at
this change may decrease intrinsic activity at the b3-AR. both the b1- and b2-ARs. In addition, these compounds ex-
Since the introduction of an amino group on the pyridine ring hibited significant hypoglycemic activity in diabetic kk mice.
in 14a gave good results (36b vs. 14a), we then examined
some heteroaromatic rings possessing an amino group. In-
trestingly, the 2-amino-5-methylthiazol-4-yl derivative (36g) apparatus and are uncorrected. H-NMR spectra were recorded on a JEOL
Experimental
Melting points were determined with a Yanaco MP-500D melting point
1
EX90, EX400, or GX500 spectrometer, and the chemical shifts are ex-
pressed in d (ppm) values with tetramethylsilane as an internal standard
(NMR description key: sꢀsinglet, dꢀdoublet, tꢀtriplet, mꢀmultiplet, and
brꢀbroad peak). Mass spectra were recorded on a Hitachi M-80 or JEOL
JMS-DX300 spectrometer. The elemental analyses were performed with a
Yanaco MT-5 microanalyzer (C, H, N) and were within ꢄ0.4% of the theo-
retical values. During the work-up, all organic solutions were dried over an-
hydrous magnesium sulfate.
4ꢀ-(2-Benzylaminoethyl)-2-pyridylacetanilide (3) A mixture of 4ꢁ-(2-
aminoethyl)-2-pyridyl-acetanilide (2) (5.1 g) and benzaldehyde (2.1 ml) in
showed a 30-fold increase in potency at the b3-AR (EC50ꢀ
0.016 mM, IAꢀ0.76) without agonistic activity at either b2-
or b1-ARs when compared to 14a, and 36g was the most
potent b3-AR agonist in this study. The 5-amino-1,2,4-thia-
diazol-3-yl derivative (36h) also showed a 10-fold increase
in potency at the b3-AR (EC50ꢀ0.042 mM, IAꢀ0.63) with
agonistic activity completely abolished at both the b2- and
b1-ARs when compared to 14a.
Given the results of the in vitro study, compounds 36b,
36g, and 36h were selected for in vivo evaluation in a rodent
model of type II diabetes (Table 4). The compounds were ad-
ministered orally for 4 d to diabetic kk mice and the effects
on plasma glucose were measured. All compounds induced a
significant reduction in plasma glucose levels at a dose of
10 mg/kg.
toluene (50 ml) was refluxed for 3 h using a Dean–Stark trap. After cooling
to room temperature, the resultant mixture was concentrated in vacuo. To the
solution of the resultant in methanol (50 ml) was added sodium borohydride
(1.0 g) at 0 °C, and the mixture was stirred for 1 h, and then concentrated in
vacuo. The residue was purified using column chromatography on silica gel
with CHCl3/MeOH (50 : 1) as the eluent to yield 3 (4.6 g) as a yellow solid.
1
66% yield; H-NMR (CDCl3) d: 2.76—2.80 (2H, m), 2.84—2.89 (2H, m),
3.78 (2H, s), 3.86 (2H, s), 7.14 (2H, d, Jꢀ8.4 Hz), 7.20—7.32 (7H, m), 7.46
(2H, d, Jꢀ8.0 Hz), 7.67—7.72 (1H, m), 8.61 (1H, d, Jꢀ5.2 Hz), 9.72 (1H,
s); MS (FAB) m/z: 346 (MHꢂ).
Conclusion
4ꢀ-(2-{N-Benzyl-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]amino}-
ethyl)-2-(2-pyridyl)acetanilide (4a) A mixture of 3 (0.34 g), 4-benzyl-
We identified a new series of phenylethanolamine deriva-
tives containing acetanilides as b3-AR agonists, and de- oxyphenacylbromide (0.30 g), and N,N-diisopropyl-N-ethylamine (175 ml)

April 2010
539
Table 3. b-AR Agonistic Activity of Phenylethanolamine Derivatives con- MS (FAB) m/z: 572 (MHꢂ).
taining Acetanilides
4ꢀ-(2-{N-Benzyl-N-[2-(4-benzyloxy-3-methanesulfonamidophenyl)-2-
hydroxyethyl]amino}ethyl)-2-(2-pyridyl)acetanilide (4c) The title com-
pound was prepared in the same manner as described for 4a using 4-ben-
zyloxy-3-methanesulfonamidophenacylbromide20) instead of 4-benzyloxy-
phenacylbromide as a colorless powder. 43% yield; 1H-NMR (CDCl3) d:
2.50—2.91 (9H, m), 3.55 (1H, d, Jꢀ13.6 Hz), 3.85 (2H, s), 3.94 (1H, d,
Jꢀ13.6 Hz), 4.56 (1H, dd, Jꢀ10.0, 3.6 Hz), 5.08 (2H, s), 6.83 (1H, br s),
6.94 (1H, d Jꢀ8.4 Hz), 7.04—7.12 (3H, m), 7.22—7.48 (15H, m), 7.69 (1H,
dt, Jꢀ2.0, 8.0 Hz), 8.58—8.63 (1H, m), 9.70 (1H, br s); MS (FAB) m/z: 665
(MHꢂ).
EC50, mMa) (IAb))
b2-AR
Compound
Ar
b3-AR
b1-AR
14a
30a
30b
14b
36c
0.41 (0.67) ꢃ100 (0.01) ꢃ100 (0.06)
4ꢀ-(2-{N-Benzyl-N-[2-(4-benzyloxy-3-nitrophenyl)-2-hydroxyethyl]-
amino}ethyl)-2-(2-pyridyl)acetanilide (4d) The title compound was pre-
pared in the same manner as described for 4a using 4-benzyloxy-3-nitro-
phenacylbromide instead of 4-benzyloxyphenacylbromide as a colorless
powder. 69% yield; 1H-NMR (CDCl3) d: 2.48—2.54 (1H, m), 2.64—2.94
(5H, m), 3.57 (1H, d, Jꢀ13.2 Hz), 3.75 (1H, br s), 3.86 (2H, s), 3.92 (1H, d,
Jꢀ13.2 Hz), 4.53 (1H, dd, Jꢀ10.8, 3.6 Hz), 5.21 (2H, s), 7.03—7.08 (3H,
m), 7.23—7.48 (15H, m), 7.67—7.75 (2H, m), 8.60—8.64 (1H, m), 9.75
(1H, s); MS (FAB) m/z: 617 (MHꢂ).
4ꢀ-(2-{[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino}ethyl)-2-(2-
pyridyl)acetanilide Hydrochloride (5a) To a solution of 4a (0.27 g) in
methanol (10 ml) was added palladium on carbon (10% w/w, 0.12 g), and the
mixture was stirred under hydrogen atmosphere for 2 h. The catalyst was re-
moved by filtration, and the filtrate was concentrated in vacuo. To the solu-
tion of the residue in methanol (5 ml) was added 4 M HCl–EtOAc solution
(450 ml), and the mixture was concentrated in vacuo. The residue was puri-
fied by recrystallization from MeOH–EtOH–Et2O to yield 5a (0.12 g) as a
colorless solid. 60% yield; mp 211—212 °C (MeOH–EtOH–Et2O); 1H-
NMR (DMSO-d6) d: 2.86—3.12 (6H, m), 3.84 (2H, s), 4.80—4.83 (1H, m),
6.00 (1H, d, Jꢀ1.2 Hz), 6.77 (2H, d, Jꢀ8.4 Hz), 7.16—7.19 (4H, m), 7.25—
7.29 (1H, m), 7.39 (1H, d, Jꢀ8.0 Hz), 7.57 (2H, d, Jꢀ8.4 Hz), 7.73—7.78
(1H, m), 8.49 (1H, d, Jꢀ4.8 Hz), 8.71 (1H, br s), 8.91 (1H, br s), 9.46 (1H,
s), 10.29 (1H, s); MS (FAB) m/z: 392 (MHꢂ); Anal. Calcd for
C23H25N3O3·HCl·0.5H2O: C, 63.22; H, 6.23; N, 9.62; Cl, 8.11. Found: C,
63.26; H, 6.04; N, 9.55; Cl, 7.87.
0.56 (0.24) 1.3 (0.28)
0.66 (0.31) 7.8 (0.12)
0.20 (0.51) 9.1 (0.15)
0.54 (0.41) 6.8 (0.35)
4.9 (0.17)
ꢃ100 (0.01)
9.1 (0.22)
0.26 (0.23)
39a
36d
39b
36e
36f
0.59 (0.54) 13 (0.11)
150 (0.34)
0.59 (0.37) ꢃ100 (0.09) ꢃ100 (0.02)
1.7 (0.38) 6.6 (0.22) ꢃ100 (0.09)
0.45 (0.89) ꢃ100 (0.08) ꢃ100 (0.05)
0.31 (0.49) 4.0 (0.18) ꢃ100 (0.01)
36g
36h
0.016 (0.76) ꢃ100 (0.04) ꢃ100 (0.06)
0.042 (0.63) ꢃ100 (0.05) ꢃ100 (0.06)
4ꢀ-(2-{[2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}ethyl)-2-(2-
pyridyl)acetanilide Hydrochloride (5b) The title compound was pre-
pared in the same manner as described for 5a using 4b instead of 4a as a
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells
expressing b-ARs. b) Values in parentheses represent the intrinsic activity (IA) given
as a fraction of the maximum stimulation with isoproterenol.
1
colorless powder. 45% yield; H-NMR (DMSO-d6) d: 2.84—3.03 (3H, m),
3.06—3.20 (3H, m), 3.84 (2H, s), 4.80—4.89 (1H, m), 6.12 (1H, d,
Jꢀ3.6 Hz), 6.70 (2H, dd, Jꢀ2.0, 8.0 Hz), 6.76—6.83 (2H, m), 7.13—7.20
(3H, m), 7.24—7.30 (1H, m), 7.39 (1H, d, Jꢀ8.0 Hz), 7.56—7.60 (2H, m),
7.76 (1H, dt, Jꢀ1.6, 7.2 Hz), 8.47—8.52 (1H, m), 8.72 (1H, br s), 8.92 (1H,
br s), 9.49 (1H, br s), 10.28 (1H, br s); MS (FAB) m/z: 392 (MHꢂ); Anal.
Calcd for C23H25N3O3·1.2HCl·H2O: C, 60.95; H, 6.27; N, 9.27; Cl, 9.39.
Found: C, 61.21; H, 6.08; N, 9.07; Cl, 9.21.
4ꢀ-(2-{[2-Hydroxy-2-(4-hydroxy-3-methylsulfonamidophenyl)-
ethyl]amino}ethyl)-2-(2-pyridyl)acetanilide Hydrochloride (5c) The
title compound was prepared in the same manner as described for 5a using
4c instead of 4a as a colorless solid. 42% yield; mp 191—192 °C (MeOH–
EtOH–Et2O); 1H-NMR (DMSO-d6) d: 2.84—3.01 (6H, m), 3.05—3.17 (3H,
m), 3.84 (2H, s), 4.78—4.88 (1H, m), 6.05 (1H, br s), 6.92 (1H, d,
Jꢀ8.0 Hz), 7.06 (1H, dd, Jꢀ2.0, 8.4 Hz), 7.14—7.29 (4H, m), 7.39 (1H, d,
Jꢀ8.0 Hz), 7.54—7.60 (2H, m), 7.75 (1H, dt, Jꢀ2.0, 8.0 Hz), 8.47—8.51
(1H, m), 10.03 (1H, br s); MS (FAB) m/z: 485 (MHꢂ); Anal. Calcd for
C24H28N4O5S·HCl·0.7H2O: C, 54.02; H, 5.74; N, 10.50; S, 6.01; Cl, 6.64.
Found: C, 54.08; H, 5.66; N, 10.47; S, 6.12; Cl, 6.61.
4ꢀ-(2-{N-Benzyl-N-[2-(3-amino-4-benzyloxyphenyl)-2-hydroxyethyl]-
amino}ethyl)-2-(2-pyridyl)acetanilide (6) To a solution of 4d (1.83 g) in
methanol (40 ml) were added 2.5 M HCl aqueous solution (2 ml) and iron
powder (1.6 g), and the mixture was refluxed for 8 h. After cooling to room
temperature, the resultant mixture was concentrated in vacuo. The residue
was partitioned between chloroform and 1 M NaOH aqueous solution, and
the precipitate was removed by filtration. The organic layer was washed with
brine, and then dried and concentrated in vacuo. The residue was purified
using column chromatography on silica gel with CHCl3/MeOH (30 : 1) as
the eluent to yield 6 (1.31 g) as a colorless powder. 75% yield; 1H-NMR
(CDCl3) d: 2.59—2.88 (6H, m), 3.56 (1H, d, Jꢀ13.2 Hz), 3.67 (1H, br s),
3.81 (2H, br s), 3.86 (2H, s), 3.94 (1H, d, Jꢀ13.2 Hz), 4.49—4.52 (1H, m),
5.05 (2H, s), 6.59—6.79 (3H, m), 7.05—7.07 (2H, m), 7.23—7.46 (14H,
m), 7.67—7.71 (1H, m), 8.61—8.62 (1H, m), 9.71 (1H, br s); MS (FAB)
m/z: 587 (MHꢂ).
Table 4. Oral Hypoglycemic Activity in kk Mice
Compound
Percent reduction in plasma glucosea)
36b
36g
36h
37*b)
50**
50**
a) The compounds were administered orally to male kk mice for 4 d at a dose of
10 mg/kg. b) Statistically significant at ∗ pꢅ0.05, ∗∗ pꢅ0.01.
in 2-butanone (20 ml) was refluxed for 3 h. After cooling to room tempera-
ture, the precipitate was removed by filtration, and the filtrate was then con-
centrated in vacuo. To the solution of the resultant in methanol (10 ml) was
added sodium borohydride (0.12 g) at 0 °C, and the mixture was stirred for
1h, and then concentrated in vacuo. The residue was partitioned between
chloroform and NaHCO3 aqueous solution, and the organic layer was dried
and concentrated in vacuo. The residue was purified using column chro-
matography on silica gel with CHCl3/MeOH (100 : 1) as the eluent to yield
1
4a (0.28 g) as a colorless powder. 50% yield; H-NMR (CDCl3) d: 2.54—
2.94 (6H, m), 3.56 (1H, d, Jꢀ13.6 Hz), 3.86 (2H, s), 3.95 (1H, d,
Jꢀ13.6 Hz), 4.57 (1H, dd, Jꢀ10.0, 4.0 Hz), 5.04 (2H, s), 6.90—6.94 (2H,
m), 7.04—7.08 (2H, m), 7.18—7.48 (16H, m), 7.69 (1H, dt, Jꢀ2.0, 8.0 Hz),
8.62 (1H, d, Jꢀ4.8 Hz), 9.72 (1H, br s); MS (FAB) m/z: 572 (MHꢂ).
4ꢀ-(2-{N-Benzyl-N-[2-(3-benzyloxyphenyl)-2-hydroxyethyl]amino}-
ethyl)-2-(2-pyridyl)acetanilide (4b) The title compound was prepared in
the same manner as described for 4a using 3-benzyloxyphenacylbromide in-
stead of 4-benzyloxyphenacylbromide as a colorless powder. 53% yield; 1H-
NMR (CDCl3) d: 2.56—2.90 (6H, m), 3.56 (1H, d, Jꢀ13.6 Hz), 3.86 (2H,
s), 3.97 (1H, d, Jꢀ13.6 Hz), 4.60 (1H, dd, Jꢀ2.0, 8.0 Hz), 5.04 (2H, s),
6.83—6.90 (2H, m), 6.95—6.98 (1H, m), 7.03—7.08 (2H, m), 7.18—7.48
(15H, m), 7.69 (1H, dt, Jꢀ2.0, 8.0 Hz), 8.60—8.63 (1H, m), 9.72 (1H, br s);
4ꢀ-(2-{N-Benzyl-N-[2-(4-benzyloxy-3-formamidophenyl)-2-hydroxy-

540
Vol. 58, No. 4
ethyl]amino}ethyl)-2-(2-pyridyl)acetanilide (7a) To
a
solution of
6
Cl, 8.36; F, 4.25.
(0.67 g) in chloroform (10 ml) was added the mixture of formic acid and
acetic anhydride (3 : 5, 1.0 ml), and the mixture was stirred at room tempera-
4ꢀ-(2-{[2-(3-Fluorophenyl)-2-hydroxyethyl]amino}ethyl)-2-(2-pyridyl)-
acetanilide Hydrochloride (9c) The title compound was prepared in the
ture for 7 h, and the resulting mixture was then concentrated in vacuo. To the same manner as described for 9a using 3-fluorostyrene oxide instead of (R)-
solution of the residue in methanol (15 ml) and water (1 ml) was added 3-chlorostyrene oxide as a colorless solid. 11% yield; mp 214—215 °C
sodium carbonate (0.49 g), and the mixture was stirred at room temperature
for 2 h. The precipitate was removed by filtration, and the filtrate was then 4.96—5.02 (1H, m), 6.33 (1H, d, Jꢀ3.8 Hz), 7.12—7.31 (6H, m), 7.39—
(EtOH–Et2O); 1H-NMR (DMSO-d6) d: 2.88—3.25 (6H, m), 3.85 (2H, s),
concentrated in vacuo. The residue was partitioned between chloroform and
7.48 (2H, m), 7.58 (2H, d, Jꢀ8.3 Hz), 7.74—7.80 (1H, m), 8.50 (1H, s),
water, and the organic layer was washed with brine, and then dried and con- 8.82 (1H, s), 9.01 (1H, s), 10.30 (1H, s); MS (FAB) m/z: 394 (MHꢂ); Anal.
centrated in vacuo. The residue was purified using column chromatography Calcd for C23H24N3O2F·1.5HCl·0.8H2O: C, 59.72; H, 5.90; N, 9.08; Cl,
on silica gel with CHCl3/MeOH (50 : 1) as the eluent to yield 7a (0.59 g) as a
colorless powder. 84% yield; 1H-NMR (CDCl3) d: 2.53—2.88 (6H, m), 3.55
(1H, d, Jꢀ13.6 Hz), 3.75 (1H, br s), 3.86 (2H, s), 3.94 (1H, d, Jꢀ13.6 Hz),
11.50; F, 4.11. Found: C, 59.58; H, 5.62; N, 9.10; Cl, 11.75; F, 4.06.
4ꢀ-(2-{[2-Hydroxy-2-(3-pyridyl)ethyl]amino}ethyl)-2-(2-pyridyl)ac-
etanilide Hydrochloride (9d) The title compound was prepared in the
4.59—4.62 (1H, m), 5.06—5.08 (2H, m), 6.89—7.22 (5H, m), 7.23—7.48 same manner as described for 9a using 2-(3-pyridyl)oxirane21) instead of
(14H, m), 7.67—7.71 (1H, m), 7.78—8.72 (3H, m), 9.68—9.73 (1H, m); (R)-3-chlorostyrene oxide as a colorless solid. 20% yield; mp 204—205 °C
1
MS (FAB) m/z: 615 (MHꢂ).
(MeOH–Et2O); H-NMR (DMSO-d6) d: 2.85—3.28 (6H, m), 3.85 (2H, s),
4ꢀ-(2-{N-[2-(3-Acetamido-4-benzyloxyphenyl)-2-hydroxyethyl]-N-ben- 5.02—5.14 (1H, m), 6.37 (1H, d, Jꢀ4.0 Hz), 7.14—7.32 (3H, m), 7.36—
zyl-amino}ethyl)-2-(2-pyridyl)acetanilide (7b) The title compound was 7.46 (2H, m), 7.55—7.64 (2H, m), 7.70—7.86 (2H, m), 8.46—8.56 (2H, m),
prepared in the same manner as described for 7a using acetic anhydride in- 8.57—8.65 (1H, m), 9.13 (2H, br s), 10.37 (1H, br s); MS (FAB) m/z: 377
stead of the mixture of formic acid and acetic anhydride as a colorless pow- (MHꢂ); Anal. Calcd for C22H24N4O2·HCl: C, 63.99; H, 6.10; N, 13.57; Cl,
der. 83% yield; 1H-NMR (CDCl3) d: 2.14 (3H, s), 2.58—2.87 (6H, m), 3.54 8.59. Found: C, 63.76; H, 5.90; N, 13.68; Cl, 8.46.
(1H, d, Jꢀ13.2 Hz), 3.74 (1H, br s), 3.86 (2H, s), 3.94 (1H, d, Jꢀ13.2 Hz),
(R)-2-{N-Benzyl-N-[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol
4.56—4.64 (1H, m), 5.10 (2H, s), 6.90 (1H, d, Jꢀ8.4 Hz), 7.02—7.07 (3H, (11) A mixture of N-benzyl-2-(4-nitrophenyl)ethylamine (10) (11.96 g)
m), 7.22—7.46 (12H, m), 7.65—8.77 (2H, m), 8.28—8.32 (1H, m), 8.60— and (R)-styrene oxide (7.21 g) in 2-propanol (80 ml) was refluxed for 20 h.
8.65 (1H, m), 9.69 (1H, s); MS (FAB) m/z: 629 (MH)ꢂ.
After cooling to room temperature, the resultant mixture was concentrated in
4ꢀ-(2-{[2-(3-Formamido-4-hydroxyphenyl)-2-hydroxyethyl]amino}- vacuo. The residue was purified using column chromatography on silica gel
ethyl)-2-(2-pyridyl)acetanilide Hydrochloride (8a) The title compound with n-hexane/EtOAc (10 : 1) as the eluent to yield 11 (13.48 g) as a color-
1
was prepared in the same manner as described for 5a using 7a instead of 4a less powder. 76% yield; H-NMR (CDCl3) d: 2.63—2.99 (6H, m), 3.53—
1
as a colorless solid. 13% yield; mp 217—219 °C (EtOH–EtOAc); H-NMR 3.62 (1H, m), 3.57 (1H, d, Jꢀ13.2 Hz), 3.95 (1H, d, Jꢀ13.2 Hz), 4.65—4.70
(DMSO-d6) d: 2.80—3.00 (3H, m), 3.00—3.20 (3H, m), 4.02 (2H, s), 4.83 (1H, m), 7.20—7.37 (7H, m), 8.09—8.12 (2H, m); MS (FAB) m/z: 377
(1H, d, Jꢀ8.0 Hz), 6.05 (1H, br s), 6.88—6.95 (2H, m), 7.14—7.20 (2H, m), (MH)ꢂ.
7.51—7.65 (4H, m), 8.05 (1H, t, Jꢀ7.2 Hz), 8.14—8.29 (2H, m), 8.64 (1H,
d, Jꢀ4.8 Hz), 8.74 (1H, br s), 9.04 (1H, br s), 9.61 (1H, s), 10.12 (1H, s),
(R)-2-{N-[2-(4-Aminophenyl)ethyl]-N-benzylamino}-1-phenylethanol
(12) The title compound was prepared in the same manner as described for
10.47 (1H, br s); MS (FAB) m/z: 435 (MHꢂ); Anal. Calcd for 6 using 11 instead of 4d as a colorless powder. 93% yield; 1H-NMR (CDCl3)
C24H26N4O4·1.5HCl·1.5H2O: C, 55.84; H, 5.96; N, 10.85; Cl, 10.30. Found: d: 2.56—2.94 (6H, m), 3.40—3.65 (2H, m), 3.80 (1H, br s), 3.95 (1H, d,
C, 55.70; H, 5.62; N, 10.86; Cl, 10.17.
4ꢀ-(2-{[2-(3-Acetamido-4-hydroxyphenyl)-2-hydroxyethyl]amino}- (2H, m), 7.20—7.37 (10H, m); MS (FAB) m/z: 347 (MH)ꢂ.
ethyl)-2-(2-pyridyl)acetanilide Hydrochloride (8b) The title compound (R)-4ꢀ-{2-[N-Benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl}-2-(2-
Jꢀ13.6 Hz), 4.62 (1H, dd, Jꢀ3.2, 10.0 Hz), 6.57—6.66 (2H, m), 6.87—6.98
was prepared in the same manner as described for 5a using 7b instead of 4a pyridyl)acetanilide (13a) A mixture of 12 (4.00 g) and methyl 2-pyridyl-
1
as a colorless solid. 19% yield; mp 216—222 °C (EtOH–EtOAc); H-NMR acetate (1.90 g) in xylene (40 ml) was refluxed for 19 h. After cooling to
(DMSO-d6) d: 2.10 (3H, s), 2.87—3.02 (3H, m), 3.02—3.20 (3H, m), 3.83 room temperature, the resultant mixture was concentrated in vacuo. The
(2H, s), 4.75—4.83 (1H, m), 6.05 (1H, d, Jꢀ3.6 Hz), 6.86 (1H, d,
residue was purified using column chromatography on silica gel with n-
Jꢀ8.4 Hz), 6.94—6.96 (1H, m), 7.17 (2H, d, Jꢀ8.8 Hz), 7.26—7.29 (1H, hexane/EtOAc (1 : 3) as the eluent to yield 13a (2.47 g) as a colorless pow-
1
m), 7.39 (1H, d, Jꢀ8.0 Hz), 7.57 (2H, d, Jꢀ8.8 Hz), 7.76 (1H, dt, Jꢀ8.0, der. 45% yield; H-NMR (CDCl3) d: 2.54—2.98 (6H, m), 3.50—4.02 (5H,
4.0 Hz), 7.81—7.84 (1H, m), 8.50 (1H, d, Jꢀ4.0 Hz), 8.66 (1H, br s), 8.79
m), 3.80 (1H, br s), 4.62 (1H, dd, Jꢀ3.6, 10.0 Hz), 6.80—7.70 (17H, m),
(1H, br s), 9.31 (1H, s), 9.86 (1H, s), 10.26 (1H, br s); MS (FAB) m/z: 449 8.60 (1H, d, Jꢀ5.6 Hz), 9.73 (1H, br s); MS (FAB) m/z: 466 (MH)ꢂ.
(MHꢂ); Anal. Calcd for C25H28N4O4·1.1HCl·0.5H2O: C, 60.34; H, 6.10; N,
11.26; Cl, 7.84. Found: C, 60.18; H, 6.06; N, 11.23; Cl, 7.99.
(R)-4ꢀ-{2-[N-Benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl}-2-
(pyrazin-2-yl)acetanilide (13b) The title compound was prepared in the
(R)-4ꢀ-(2-{[2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-2-(2- same manner as described for 13a using methyl 2-pyrazinylacetate instead
pyridyl)acetanilide Hydrochloride (9a) A mixture of 2 (1.0 g) and (R)-3- of methyl 2-pyridylacetate as a colorless powder. 55% yield; 1H-NMR
chlorostyrene oxide (0.59 g) in ethanol (20 ml) was refluxed for 12 h. After (CDCl3) d: 2.54—3.00 (6H, m), 3.57 (1H, d, Jꢀ13.6 Hz), 3.89 (2H, s), 3.95
cooling to room temperature, the resultant mixture was concentrated in (1H, d, Jꢀ13.6 Hz), 4.61 (1H, dd, Jꢀ3.6, 10.0 Hz), 7.00—7.50 (14H, m),
vacuo. The residue was purified using column chromatography on silica gel 8.45—8.70 (3H, m), 8.91 (1H, br s); MS (FAB) m/z: 467 (MH)ꢂ.
with CHCl3/MeOH (30 : 1) as the eluent to yield the free base product
(0.66 g). To the solution of free base product in ethanol (5 ml) was added 4 M
(R)-4ꢀ-{2-[N-Benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl}-2-(3-
pyridyl)acetanilide (13c) To a solution of 12 (0.43 g) and 3-pyridylacetic
HCl–EtOAc solution (400 ml), and the mixture was concentrated in vacuo. acid hydrochloride (0.26 g) in tetrahydrofuran (5 ml) and N,N-dimethyl-
The residue was purified by recrystallization from MeOH–EtOH to yield 9a formamide (2 ml) were added 1-ethyl-3-(3ꢁ-dimethylaminopropyl)-carbodi-
(0.33 g) as a colorless solid. 18% yield; mp 221—222 °C (MeOH–EtOH);
imide hydrochloride (0.24 g) and 1-hydroxybenzotriazole (0.17 g), and the
1H-NMR (DMSO-d6) d: 2.90—3.25 (6H, m), 3.85 (2H, s), 4.92—5.08 (1H, mixture was stirred at room temperature for 5 h. The resulting mixture was
m), 6.35 (1H, d, Jꢀ3.6 Hz), 7.14—7.23 (2H, m), 7.23—7.31 (1H, m), concentrated in vacuo and diluted with ethyl acetate. The organic layer was
7.33—7.50 (5H, m), 7.54—7.64 (2H, m), 7.76 (1H, dt, Jꢀ1.6, 7.6 Hz), washed with NaHCO3 aqueous solution, and then dried and concentrated in
8.43—8.55 (1H, m), 8.80—9.40 (2H, m), 10.36 (1H, br s); MS (FAB) m/z: vacuo. The residue was purified using column chromatography on silica gel
410 (MHꢂ); Anal. Calcd for C23H24N3O2Cl·HCl: C, 61.89; H, 5.65; N, 9.41; with CHCl3/MeOH (100 : 1) as the eluent to yield 13b (0.25 g) as a colorless
Cl, 15.88. Found: C, 61.81; H, 5.58; N, 9.38; Cl, 15.58.
powder. 43% yield; 1H-NMR (CDCl3) d: 2.54—2.98 (6H, m), 3.50—3.74
4ꢀ-(2-{[2-(4-Fluorophenyl)-2-hydroxyethyl]amino}ethyl)-2-(2-pyridyl)- (3H, m), 3.96 (1H, d, Jꢀ13.6 Hz), 4.59 (1H, dd, Jꢀ3.6, 10.0 Hz), 7.00—
acetanilide Hydrochloride (9b) The title compound was prepared in the 7.80 (16H, m), 8.50—8.62 (2H, m); MS (FAB) m/z: 466 (MH)ꢂ.
same manner as described for 9a using 4-fluorostyrene oxide instead of (R)-
(R)-4ꢀ-{2-[N-Benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl}-2-(4-
pyridyl)acetanilide (13d) The title compound was prepared in the same
3-chlorostyrene oxide as a colorless solid. 18% yield; mp 223—225 °C
(MeOH–EtOH); 1H-NMR (DMSO-d6) d: 2.88—3.06 (3H, m), 3.10—3.20 manner as described for 13c using 4-pyridylacetic acid instead of 3-pyridyl-
1
(3H, m), 3.84 (2H, s), 4.94—5.01 (1H, m), 6.24 (1H, d, Jꢀ4.0 Hz), 7.16— acetic acid as a colorless powder. 35% yield; H-NMR (CDCl3) d: 2.54—
7.30 (5H, m), 7.38—7.46 (3H, m), 7.58 (2H, d, Jꢀ8.8 Hz), 7.76 (1H, dt,
3.02 (6H, m), 3.50—3.75 (3H, m), 3.96 (1H, d, Jꢀ13.6 Hz), 4.59 (1H, dd,
Jꢀ1.6, 7.6 Hz), 8.50 (2H, d, Jꢀ8.8 Hz), 8.83 (1H, s), 9.08 (1H, s), 10.31 Jꢀ4.0, 10.0 Hz), 7.00—7.60 (16H, m), 8.55—8.65 (2H, m); MS (FAB) m/z:
(1H, s); MS (FAB) m/z: 394 (MHꢂ); Anal. Calcd for C23H24N3O2F·HCl: C,
466 (MH)ꢂ.
64.26; H, 5.86; N, 9.77; Cl, 8.25; F, 4.42. Found: C, 64.12; H, 5.90; N, 9.73;
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(2-pyridyl)ac-

April 2010
541
etanilide Hydrochloride (14a) The title compound was prepared in the phenylethanol (18b) The title compound was prepared in the same man-
same manner as described for 5a using 13a instead of 4a as a colorless solid.
ner as described for 6 using 17b instead of 4d as a colorless powder. 37%
62% yield; mp 223—224 °C (MeOH–EtOH); 1H-NMR (DMSO-d6) d: yield; 1H-NMR (CDCl3) d: 1.04 (3H, d, Jꢀ6.8 Hz), 2.27 (1H, dd, Jꢀ9.6,
2.86—3.22 (6H, m), 3.49 (2H, s), 4.93—5.03 (1H, m), 6.20 (1H, d, 13.2 Hz), 2.62 (1H, dd, Jꢀ10.4, 13.2 Hz), 2.75 (1H, dd, Jꢀ4.0, 13.2 Hz),
Jꢀ4.0 Hz), 7.15—7.43 (9H, m), 7.55—7.62 (2H, m), 7.75 (1H, dt, Jꢀ1.6,
3.30—4.10 (5H, m), 4.42 (1H, dd, Jꢀ4.0, 10.0 Hz), 6.55—6.68 (2H, m),
8.0 Hz), 8.45—8.53 (1H, m), 8.06—9.50 (2H, m), 10.35 (1H, br s); MS 6.83—6.95 (2H, m), 7.20—7.40 (10H, m); MS (FAB) m/z: 361 (MHꢂ).
(FAB) m/z: 376 (MHꢂ); Anal. Calcd for C23H25N3O2·HCl: C, 67.06; H,
6.36; N, 10.20; Cl, 8.61. Found: C, 67.10; H, 6.55; N, 10.15; Cl, 8.53.
4ꢀ-{2-(2R)-[N-Benzyl-N-((2R)-2-hydroxy-2-phenylethyl)amino]-
propyl}-2-(2-pyridyl)acetanilide (19a) The title compound was prepared
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(pyrazin-2-yl)ac- in the same manner as described for 13a using 18a instead of 12 as a color-
etanilide Hydrochloride (14b) The title compound was prepared in the less powder. 40% yield; 1H-NMR (CDCl3) d: 1.00 (3H, d, Jꢀ6.8 Hz),
same manner as described for 5a using 13b instead of 4a as a colorless 2.54—2.65 (3H, m), 2.70—2.82 (1H, m), 3.08—3.20 (1H, m), 3.44—3.98
1
solid. 28% yield; mp 236—238 °C (EtOH–Et2O); H-NMR (DMSO-d6) d: (5H, m), 4.55 (1H, dd, Jꢀ3.6, 10.4 Hz), 6.80—7.60 (16H, m), 7.64—7.74
2.86—3.24 (6H, m), 3.95 (2H, s), 4.91—5.01 (1H, m), 5.44 (2H, s), 6.19 (1H, m), 8.50—8.70 (1H, m), 9.72 (1H, br s); MS (FAB) m/z: 480 (MHꢂ).
(1H, d, Jꢀ4.4 Hz), 7.15—7.22 (2H, m), 7.27—7.43 (5H, m), 7.52—7.62
(2H, m), 8.50—8.69 (3H, m), 8.83 (1H, br s), 9.12 (1H, br s), 10.41 (1H,
br s); MS (FAB) m/z: 377 (MHꢂ); Anal. Calcd for C22H24N4O2·HCl: C,
63.99; H, 6.10; N, 13.57; Cl, 8.59. Found: C, 63.85; H, 6.11; N, 13.54; Cl, less powder. 51% yield; H-NMR (CDCl3) d: 1.02 (3H, d, Jꢀ6.8 Hz), 2.32
8.63.
4ꢀ-{2-(2S)-[N-Benzyl-N-((2R)-2-hydroxy-2-phenylethyl)amino]-
propyl}-2-(2-pyridyl)acetanilide (19b) The title compound was prepared
in the same manner as described for 13a using 18b instead of 12 as a color-
1
(1H, dd, Jꢀ8.8, 12.8 Hz), 2.63 (1H, dd, Jꢀ10.4, 13.2 Hz), 2.75 (1H, dd,
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(3-pyridyl)ac- Jꢀ3.6, 13.2 Hz), 2.95—3.10 (2H, m), 3.70—3.92 (4H, m), 4.44 (1H, dd,
etanilide Hydrochloride (14c) The title compound was prepared in the
same manner as described for 5a using 13c instead of 4a as a colorless solid.
52% yield; mp 236—238 °C (MeOH–EtOH–Et2O); 1H-NMR (DMSO-d6) d:
Jꢀ3.6, 9.6 Hz), 7.00—7.06 (2H, m), 7.16—7.38 (11H, m), 7.62—7.72 (2H,
m), 8.61 (1H, d, Jꢀ4.4 Hz), 9.74 (1H, br s); MS (FAB) m/z: 480 (MHꢂ).
4ꢀ-{2-(2R)-[((2R)-2-Hydroxy-2-phenylethyl)amino]propyl}-2-(2-
2.86—3.23 (6H, m), 3.72 (2H, s), 4.91—5.02 (1H, m), 6.20 (1H, d, pyridyl)acetanilide Hydrochloride (20a) The title compound was pre-
Jꢀ4.0 Hz), 7.15—7.22 (2H, m), 7.27—7.45 (6H, m), 7.53—7.62 (2H, m), pared in the same manner as described for 5a using 19a instead of 4a as
7.73—7.82 (1H, m), 8.40—8.60 (2H, m), 8.84 (1H, br s), 9.16 (1H, br s), a colorless powder. 40% yield; 1H-NMR (DMSO-d6) d: 1.06 (3H, d,
10.35—10.50 (1H, m); MS (FAB) m/z: 376 (MHꢂ); Anal. Calcd for Jꢀ6.4 Hz), 2.50—2.65 (2H, m), 2.90—3.15 (3H, m), 3.83 (2H, s), 4.80—
C23H25N3O2·1.05HCl·0.3H2O: C, 65.91; H, 6.41; N, 10.03; Cl, 8.88. Found: 4.94 (1H, m), 7.10—7.18 (2H, m), 7.23—7.45 (7H, m), 7.52—7.60 (2H, m),
C, 65.86; H, 6.40; N, 10.11; Cl, 8.84.
7.71—7.80 (1H, m), 8.41—8.52 (1H, m), 10.25 (1H, br s); MS (FAB) m/z:
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(4-pyridyl)ac- 390 (MHꢂ); Anal. Calcd for C24H27N3O2·0.7HCl·0.8H2O: C, 67.13; H,
etanilide Hydrochloride (14d) The title compound was prepared in the 6.88; N, 9.79; Cl, 5.78. Found: C, 67.02; H, 7.08; N, 9.65; Cl, 5.98.
same manner as described for 5a using 13d instead of 4a as a colorless
4ꢀ-{2-(2S)-[((2R)-2-Hydroxy-2-phenylethyl)amino]propyl}-2-(2-
1
solid. 66% yield; mp 195—198 °C (EtOH–Et2O); H-NMR (DMSO-d6) d: pyridyl)acetanilide Hydrochloride (20b) The title compound was pre-
2.86—3.22 (6H, m), 3.73 (2H, s), 4.93—5.04 (1H, m), 6.15—6.25 (1H, m), pared in the same manner as described for 5a using 19b instead of 4a as
7.14—7.22 (2H, m), 7.28—7.43 (7H, m), 7.54—7.63 (2H, m), 8.47—8.53 a colorless solid. 52% yield; mp 203—204 °C (EtOH–Et2O); 1H-NMR
(2H, m), 9.07 (2H, br s), 10.50 (1H, br s); MS (FAB) m/z: 376 (MHꢂ); Anal.
(DMSO-d6) d: 1.13 (3H, d, Jꢀ6.4 Hz), 2.55—2.64 (1H, m), 3.00—3.50 (4H,
Calcd for C23H25N3O2·1.25HCl·0.8H2O: C, 63.44; H, 6.45; N, 9.65; Cl, m), 3.84 (2H, s), 4.92—5.02 (1H, m), 6.20 (1H, d, Jꢀ4.0 Hz), 7.13—7.20
10.18. Found: C, 63.33; H, 6.36; N, 9.68; Cl, 10.11.
N-Benzyl-N-[1-(4-nitrophenyl)-2-propyl]amine (16) A mixture of 4-
nitrophenylacetone (15) (5.22 g) and benzylamine (3.43 g) in toluene (50 ml)
(2H, m), 7.24—7.46 (7H, m), 7.54—7.60 (2H, m), 7.73—7.80 (1H, m), 8.51
(1H, br s), 8.67 (1H, br s), 9.13 (1H, br s), 10.31 (1H, br s); MS (FAB) m/z:
390 (MHꢂ); Anal. Calcd for C24H27N3O2·HCl·0.1H2O: C, 67.39; H, 6.64;
was refluxed for 2 h using a Dean–Stark trap. After cooling to room temper- N, 9.82; Cl, 8.29. Found: C, 67.21; H, 6.58; N, 9.74; Cl, 8.34.
ature, the resultant mixture was concentrated in vacuo. To the solution of the tert-Butyl N-[2-Methyl-1-(4-{[2-(2-pyridyl)acetyl]amino}phenyl)-2-
resultant in methanol (100 ml) and tetrahydrofuran (30 ml) was added propyl]carbamate (22) To a solution of tert-butyl N-[2-methyl-1-(4-nitro-
sodium borohydride (1.52 g) at 0 °C, and the mixture was stirred for 2 h at
phenyl)-2-propyl]carbamate (21)19) (0.83 g) in ethanol (5 ml) and tetrahydro-
room temperature, and then concentrated in vacuo. The residue was parti- furan (5 ml) was added palladium on carbon (10% w/w, 0.32 g), and the mix-
tioned between ethyl acetate and water, and the organic layer was dried and ture was stirred under hydrogen atmosphere for 2 h. The catalyst was re-
concentrated in vacuo. The residue was purified using column chromatogra- moved by filtration, and the filtrate was concentrated in vacuo. To the solu-
phy on silica gel with CHCl3/MeOH (100 : 1) as the eluent to yield 16 tion of the resultant and 2-pyridylacetic acid hydrochloride (0.49 g) in
(5.35 g) as a yellow solid. 67% yield; 1H-NMR (CDCl3) d: 1.10 (3H, d, tetrahydrofuran (10 ml) were added 1-ethyl-3-(3ꢁ-dimethylaminopropyl)-car-
Jꢀ6.4 Hz), 2.73 (1H, dd, Jꢀ6.4, 13.2 Hz), 2.89 (2H, dd, Jꢀ6.8, 13.2 Hz), bodiimide hydrochloride (0.54 g) and 1-hydroxybenzotriazole (0.38 g), and
2.95—3.06 (1H, m), 3.76 (1H, d, Jꢀ13.2 Hz), 3.86 (1H, d, Jꢀ13.2 Hz),
the mixture was stirred at room temperature for 9 h, and then concentrated in
vacuo. The residue was partitioned between ethyl acetate and NaHCO3
7.16—7.40 (7H, m), 8.01—8.22 (2H, m); MS (FAB) m/z: 271 (MHꢂ).
2-{(2R)- and (2S)-N-Benzyl-N-[1-(4-nitrophenyl)-2-propyl]amino}- aqueous solution, and the organic layer was dried and concentrated in vacuo.
(1R)-1-phenylethanol (17a, 17b) A mixture of 16 (2.02 g) and (R)-styrene
The residue was purified using column chromatography on silica gel with
oxide (1.01 g) was heated at 150 °C for 5 h. After cooling to room tempera-
CHCl3/MeOH (100 : 1) as the eluent to yield 22 (0.51 g) as colorless oil.
ture, the resultant was purified using column chromatography on silica gel 47% yield; 1H-NMR (CDCl3) d: 1.24 (6H, s), 1.46 (9H, s), 2.93 (2H, s),
with n-hexane/EtOAc (10 : 1) as the eluent to yield 17a (0.87 g) as a yellow 3.87 (2H, s), 4.24 (1H, br s), 7.05—7.13 (2H, m), 7.18—7.33 (2H, m),
oil and 17b (0.75 g) as a yellow solid.
7.42—7.50 (2H, m), 7.66—7.73 (1H, m), 8.58—8.66 (1H, m), 9.73 (1H,
17a: 29% yield; 1H-NMR (CDCl3) d: 1.07 (3H, d, Jꢀ6.4 Hz), 2.50—2.75 br s); MS (FAB) m/z: 384 (MHꢂ).
(3H, m), 2.88 (1H, dd, Jꢀ8.8, 13.6 Hz), 3.15—3.30 (1H, m), 3.51 (1H, d,
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]-2-methylpropyl}-2-(2-
Jꢀ13.2 Hz), 3.88 (1H, d, Jꢀ13.2 Hz), 4.62 (1H, dd, Jꢀ4.0, 10.4 Hz), 6.80— pyridyl)acetanilide Hydrochloride (23) To a solution of 22 (0.49 g) in
7.60 (12H, m), 8.00—8.15 (2H, m); MS (FAB) m/z: 391 (MHꢂ).
17b: 25% yield; H-NMR (CDCl3) d: 1.05 (3H, d, Jꢀ6.4 Hz), 2.47 (1H,
methanol (10 ml) was added 4 M HCl–EtOAc solution (30 ml), and the mix-
ture was stirred at room temperature for 8 h. The resulting mixture was con-
1
dd, Jꢀ10.4, 14.4 Hz), 2.62—2.85 (2H, m), 3.03—3.18 (2H, m), 3.62 (1H, centrated in vacuo and diluted with K2CO3 aqueous solution, and then ex-
br s), 3.75 (1H, d, Jꢀ13.2 Hz), 3.89 (1H, d, Jꢀ13.2 Hz), 4.51 (1H, dd, tracted with chloroform–tetrahydrofuran. The organic layer was dried and
Jꢀ3.2, 9.6 Hz), 7.14—7.44 (12H, m), 8.05—8.20 (2H, m); MS (FAB) m/z: concentrated in vacuo. To the solution of the resultant in 2-propanol (2 ml)
391 (MHꢂ).
and methanol (2 ml) was added (R)-styrene oxide (0.12 g), and the mixture
2-{(2R)-N-Benzyl-N-[1-(4-aminophenyl)-2-propyl]amino}-(1R)-1- was refluxed for 24 h. After cooling to room temperature, the resultant mix-
phenylethanol (18a) The title compound was prepared in the same man- ture was concentrated in vacuo. The residue was purified using column chro-
ner as described for 6 using 17a instead of 4d as a colorless powder. 67% matography on silica gel with CHCl3/MeOH (30 : 1—5 : 1) as the eluent. To
yield; 1H-NMR (CDCl3) d: 1.00 (3H, d, Jꢀ6.8 Hz), 2.45—2.77 (4H, m),
3.13—3.18 (1H, m), 3.40—3.78 (4H, m), 3.91 (1H, d, Jꢀ13.6 Hz), 4.56
the solution of the resultant in methanol (5 ml) was added 4 M HCl–EtOAc
solution (0.1 ml), and the mixture was concentrated in vacuo. The residue
(1H, dd, Jꢀ3.6, 10.4 Hz), 6.55—6.68 (2H, m), 6.80—6.93 (2H, m), 7.13— was purified using column chromatography on octadecylsilyl (ODS) silica
7.40 (10H, m); MS (FAB) m/z: 361 (MHꢂ).
2-{(2S)-N-Benzyl-N-[1-(4-aminophenyl)-2-propyl]amino}-(1R)-1-
gel with 50% MeOHaq. as the eluent to yield 23 (0.04 g) as colorless pow-
der. 7% yield; 1H-NMR (DMSO-d6) d: 1.21 (6H, s), 2.85—3.23 (4H, m),

542
Vol. 58, No. 4
(1H, m), 8.80—9.50 (2H, m), 10.29 (1H, br s); MS (FAB) m/z: 392 (MHꢂ);
Anal. Calcd for C23H25N3O3·HCl: C, 64.56; H, 6.12; N, 9.82; Cl, 8.28.
Found: C, 64.39; H, 6.11; N, 9.98; Cl, 8.26.
3.89 (2H, s), 4.90—5.00 (1H, m), 6.21 (1H, br s), 7.11—7.19 (2H, m),
7.28—7.50 (7H, m), 7.53—7.62 (2H, m), 7.78—7.90 (1H, m), 8.45—8.60
(2H, m), 9.00—9.10 (1H, m), 10.35 (1H, br s); MS (FAB) m/z: 404 (MHꢂ);
Anal. Calcd for C25H29N3O2·1.3HCl·1.7H2O: C, 62.36; H, 7.05; N, 8.73; Cl,
9.57. Found: C, 62.37; H, 6.98; N, 9.45; Cl, 9.92.
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(quinolin-2-yl)ac-
etanilide Hydrochloride (30a) To a solution of 4ꢁ-cyanomethyl-2-(quino-
lin-2-yl)acetanilide (29a) (0.41 g) and concentrated aqueous ammonia solu-
tion (1 ml) in ethanol (20 ml) and tetrahydrofuran (10 ml) was added Raney-
nickel, and the mixture was stirred under hydrogen atmosphere for 6 h. The
catalyst was removed by filtration over celite, and the filtrate was concen-
trated in vacuo. The residue was added to a solution of (R)-styrene oxide
(0.08 g) in 2-propanol (10 ml), and the mixture was refluxed for 6 h. After
cooling to room temperature, the resultant mixture was concentrated in
vacuo. The residue was purified using column chromatography on silica gel
with CHCl3/MeOH (20 : 1) as the eluent. To the solution of the resultant in
methanol (5 ml) was added 4 M HCl–EtOAc solution (50 ml), and the mixture
was concentrated in vacuo. The residue was purified by recrystallization
from EtOH–Et2O to yield 28a (0.05 g) as a colorless solid. 8% yield; mp
234—235 °C (EtOH–Et2O); 1H-NMR (DMSO-d6) d: 2.94—3.25 (6H, m),
4.07 (2H, s), 4.90—5.02 (1H, m), 6.20 (1H, d, Jꢀ4.0 Hz), 7.16—7.23 (2H,
m), 7.27—7.44 (5H, m), 7.53—7.65 (4H, m), 7.71—7.78 (1H, m), 7.94—
8.00 (2H, m), 8.33 (1H, d, Jꢀ8.0 Hz), 8.50—9.25 (2H, m), 10.46 (1H, br s);
MS (FAB) m/z: 426 (MHꢂ); Anal. Calcd for C27H27N3O2·HCl: C, 70.20; H,
6.11; N, 9.10; Cl, 7.67. Found: C, 69.98; H, 6.26; N, 9.08; Cl, 7.44.
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethyl}-2-(pyrimidin-2-
yl)acetanilide Hydrochloride (30b) The title compound was prepared in
the same manner as described for 30a using 4ꢁ-cyanomethyl-2-(pyrimidin-2-
yl)acetanilide (29b) instead of 29a as a colorless solid. 12% yield; mp 208—
210 °C (EtOH–Et2O); 1H-NMR (DMSO-d6) d: 2.88—3.24 (6H, m), 3.99
(2H, s), 4.90—5.01 (1H, m), 6.20 (1H, d, Jꢀ3.6 Hz), 7.15—7.24 (2H, m),
7.28—7.44 (6H, m), 7.53—7.62 (2H, m), 8.50—9.30 (4H, m), 10.33 (1H,
br s); MS (FAB) m/z: 377 (MHꢂ); Anal. Calcd for C22H24N4O2·HCl: C,
63.99; H, 6.10; N, 13.57; Cl, 8.59. Found: C, 63.77; H, 6.20; N, 13.44; Cl,
8.53.
tert-Butyl N-[3-(4-Nitrophenyl)propyl]carbamate (26a) To a solution
of 4-(4-nitrophenyl)-butyric acid (24) (5.32 g) in toluene (50 ml) were added
diphenyl phosphoryl azide (7.00 g) and triethylamine (6.32 g), and the mix-
ture was refluxed for 1 h. To the mixture was added tert-butanol (2.5 g), and
the mixture was stirred at room temperature for 12 h, and then concentrated
in vacuo. To the resultant was added tert-butanol (10 g), and the mixture was
refluxed for 30 min. After cooling to room temperature, the resultant was
concentrated in vacuo and diluted with ethyl acetate. The organic layer was
washed with water, NaHCO3 aqueous solution, and brine, and then dried and
concentrated in vacuo. The residue was purified using column chromatogra-
phy on silica gel with n-hexane/EtOAc (5 : 1—2 : 1) as the eluent to yield
1
26a (3.52 g) as a colorless solid. 49% yield; H-NMR (CDCl3) d: 1.42 (9H,
s), 1.81—1.88 (2H, m), 2.73—2.77 (2H, m), 3.14—3.20 (2H, m), 4.58 (1H,
br s), 7.34 (2H, d, Jꢀ8.0 Hz), 8.14 (2H, d, Jꢀ8.4 Hz); MS (FAB) m/z: 281
(MHꢂ).
tert-Butyl N-[2-(4-Nitrophenoxy)ethyl]carbamate (26b) To a solution
of 2-aminoethanol (3.25 g) in tetrahydrofuran (100 ml) was added sodium
hydride (65% w/w, 2.00 g), and the mixture was stirred at room temperature
for 30 min. To the mixture was added a solution of 4-fluoronitrobenzene (25)
(5.00 g) in tetrahydrofuran (20 ml), and the mixture was stirred at room tem-
perature for 2 h. After that, to the mixture was added di-tert-butyl dicarbon-
ate (12.00 g), and the mixture was stirred at room temperature for 9 h, and
then concentrated in vacuo. The residue was purified using column chro-
matography on silica gel with n-hexane/EtOAc (10 : 1) as the eluent to yield
26b (6.92 g) as a colorless powder. 69% yield; 1H-NMR (CDCl3) d: 1.46
(9H, s), 3.54—3.60 (2H, m), 4.12 (2H, t, Jꢀ5.1 Hz), 4.95 (1H, br s), 6.93—
6.99 (2H, m), 8.18—8.24 (2H, m); MS (FAB) m/z: 283 (MHꢂ).
tert-Butyl N-[3-(4-{[2-(2-Pyridyl)acetyl]amino}phenyl)propyl]carba-
mate (27a) The title compound was prepared in the same manner as de-
scribed for 22 using 26a instead of 21 as a colorless powder. 54% yield; 1H-
NMR (CDCl3) d: 1.47 (9H, s), 1.70—1.82 (2H, m), 2.59 (2H, t, Jꢀ8.0 Hz),
3.04—3.20 (2H, m), 3.86 (2H, s), 4.52 (1H, br s), 7.05—7.15 (2H, m),
7.20—7.33 (2H, m), 7.40—7.50 (2H, m), 7.69 (1H, dt, Jꢀ2.0, 8.0 Hz),
8.55—8.65 (1H, m), 9.70 (1H, br s); MS (FAB) m/z: 370 (MHꢂ).
(R)-2-{[2-(4-Nitrophenyl)ethyl]amino}-1-phenylethanol (32) 2-(4-Ni-
trophenyl)ethylamine hydrochloride (31) (25.2 g) was partitioned between
ethyl acetate and 1 M NaOH aqueous solution, and the mixture was vigor-
ously stirred at room temperature, and then the organic layer was dried and
concentrated in vacuo. To the solution of resultant in 2-propanol (100 ml)
was added (R)-styrene oxide (15.0 g), and the mixture was refluxed for 12 h.
After cooling to room temperature, the resultant mixture was concentrated in
vacuo. The residue was purified using column chromatography on silica gel
with CHCl3/MeOH (100 : 1—10 : 1) as the eluent to yield 32 (8.05 g) as a
colorless oil. 22% yield; 1H-NMR (CDCl3) d: 2.75 (1H, dd, Jꢀ8.8,
12.4 Hz), 2.85—3.04 (5H, m), 4.70 (1H, dd, Jꢀ3.7, 8.8 Hz), 7.24—7.40
(7H, m), 8.10—8.20 (2H, m); MS (FAB) m/z: 287 (MHꢂ).
tert-Butyl N-[2-(4-{[2-(2-Pyridyl)acetyl]amino}phenoxy)ethyl]carba-
mate (27b) The title compound was prepared in the same manner as de-
scribed for 22 using 26b instead of 21 as a colorless powder. 42% yield; 1H-
NMR (CDCl3) d: 1.45 (9H, s), 3.42—3.60 (2H, m), 3.86 (2H, s), 3.98 (2H,
t, Jꢀ5.2 Hz), 5.00 (1H, br s), 6.77—6.88 (2H, m), 7.21—7.28 (1H, m), 7.22
(1H, d, Jꢀ8.0 Hz), 7.40—7.50 (2H, m), 7.70 (1H, dt, Jꢀ2.0, 8.0 Hz), 8.57—
8.65 (1H, m), 9.68 (1H, br s); MS (FAB) m/z: 372 (MHꢂ).
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-nitrophenyl)ethyl]-
carbamate (33) To a solution of 32 (8.02 g) in tetrahydrofuran (80 ml) was
added di-tert-butyl dicarbonate (6.3 g). The mixture was stirred at room tem-
perature for 12 h, and concentrated in vacuo. The residue was purified using
column chromatography on silica gel with n-hexane/EtOAc (3 : 1) as the elu-
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(2-pyridyl)ac-
etanilide Hydrochloride (28a) To a solution of 27a (1.54 g) in methanol
(10 ml) was added 4 M HCl–EtOAc solution (20 ml), and the mixture was
stirred at room temperature for 2 h, and then concentrated in vacuo. The
residue was partitioned between chloroform and 1 M NaOH aqueous solu-
tion, and the organic layer was dried and concentrated in vacuo. To the solu-
tion of the resultant in 2-propanol (10 ml) was added (R)-styrene oxide
(0.15 g), and the mixture was refluxed for 4 h. After cooling to room temper-
ature, the resultant mixture was concentrated in vacuo. The residue was puri-
fied using column chromatography on silica gel with CHCl3/MeOH (30 : 1—
10 : 1) as the eluent. To the solution of the resultant in methanol (5 ml) was
added 4 M HCl–EtOAc solution (0.1 ml), and the mixture was concentrated
in vacuo. The residue was purified by recrystallization from EtOH–Et2O to
yield 28a (0.07 g) as a colorless solid. 4% yield; mp 183—184 °C (EtOH–
Et2O); 1H-NMR (DMSO-d6) d: 1.85—2.05 (2H, m), 2.53—2.65 (2H, m),
2.83—3.03 (3H, m), 3.05—3.16 (1H, m), 3.88 (2H, s), 4.95 (1H, d,
Jꢀ9.6 Hz), 6.15 (1H, br s), 7.10—7.18 (2H, m), 7.22—7.43 (7H, m), 7.50—
7.60 (2H, m), 7.75 (1H, dt, Jꢀ1.6, 7.2 Hz), 8.45—8.53 (1H, m), 8.91 (2H,
br s), 10.29 (1H, br s); MS (FAB) m/z: 390 (MHꢂ); Anal. Calcd for
C24H27N3O2·HCl: C, 67.67; H, 6.63; N, 9.86; Cl, 8.32. Found: C, 67.56; H,
6.66; N, 9.80; Cl, 8.23.
1
ent to yield 33 (10.8 g) as a colorless oil. 99% yield; H-NMR (CDCl3) d:
1.44 (9H, s), 2.75—3.10 (2H, m), 3.20—3.70 (4H, m), 4.93 (1H, br s),
7.25—7.40 (7H, m), 8.14 (2H, d, Jꢀ8.4 Hz); MS (FAB) m/z: 387 (MHꢂ).
tert-Butyl N-[2-(4-Aminophenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)-
carbamate (34) To a solution of 33 (10.8 g) in ethanol (200 ml) was added
palladium on carbon (10% w/w, 1.0 g), and the mixture was stirred under hy-
drogen atmosphere for 2 h. The catalyst was removed by filtration, and the
filtrate was concentrated in vacuo to yield 34 (9.5 g) as a colorless oil. 95%
yield; 1H-NMR (CDCl3) d: 1.47 (9H, s), 2.55—2.80 (2H, m), 3.20—3.40
(2H, m), 3.45—3.65 (2H, m), 4.87 (1H, br s), 6.57—6.65 (2H, m), 6.83—
7.04 (2H, m), 7.25—7.40 (5H, m); MS (FAB) m/z: 357 (MHꢂ).
tert-Butyl N-[2-(4-{[2-(6-Chloro-2-pyridyl)acetyl]amino}phenyl)ethyl]-
N-(2-hydroxy-2-phenylethyl)carbamate (35a) To
a solution of 34
(0.44 g) and 6-chloro-2-pyridylacetic acid (0.25 g) in N,N-dimethylfor-
mamide (15 ml) were added 1-ethyl-3-(3ꢁ-dimethylaminopropyl)carbodi-
imide hydrochloride (0.24 g) and 1-hydroxybenzotriazole (0.17 g), and the
mixture was stirred at room temperature for 13 h. The resulting mixture was
concentrated in vacuo and partitioned between ethyl acetate and water. The
organic layer was washed with NaHCO3 aqueous solution, and then dried
and concentrated in vacuo. The residue was purified using column chro-
matography on silica gel with n-hexane/EtOAc (1 : 1) as the eluent to yield
35a (0.47 g) as a colorless powder. 75% yield; 1H-NMR (CDCl3) d: 1.46
(9H, s), 2.60—2.80 (2H, m), 3.15—3.55 (4H, m), 3.82 (2H, s), 4.35 (1H,
br s), 4.88 (1H, br s), 6.97—7.16 (2H, m), 7.22—7.38 (7H, m), 7.42—7.48
(R)-4ꢀ-{2-[(2-Hydroxy-2-phenylethyl)amino]ethoxy}-2-(2-pyridyl)ac-
etanilide Hydrochloride (28b) The title compound was prepared in the
same manner as described for 28a using 27b instead of 27a as a colorless
solid. 10% yield; mp 225—226 °C (MeOH–EtOH); 1H-NMR (DMSO-d6) d:
3.02—3.14 (1H, m), 3.18—3.46 (3H, m), 3.84 (2H, s), 4.22—4.35 (2H, m),
4.98—5.08 (1H, m), 6.21 (1H, d, Jꢀ3.6 Hz), 6.90—6.97 (2H, m), 7.23—
7.44 (7H, m), 7.53—7.62 (2H, m), 7.76 (1H, dt, Jꢀ1.6, 7.2 Hz), 8.45—8.54

April 2010
543
(2H, m), 7.66 (1H, t, Jꢀ8.0 Hz), 9.18 (1H, br s); MS (FAB) m/z: 510 (MH)ꢂ.
tert-Butyl N-[2-(4-{[2-(6-Benzyloxy-2-pyridyl)acetyl]amino}phenyl)-
ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate (35b) The title compound
was prepared in the same manner as described for 35a using 6-benzyloxy-2-
pyridylacetic acid instead of 6-chloro-2-pyridylacetic acid as a colorless
1.45 (9H, s), 2.60—2.75 (2H, m), 3.10—3.55 (4H, m), 3.81 (2H, s), 4.81—
4.87 (1H, m), 6.40—6.55 (2H, m), 7.02 (2H, d, Jꢀ7.3 Hz), 7.22—7.45 (7H,
m), 9.26 (1H, s); MS (FAB) m/z: 496 (MꢆH)ꢆ.
(R)-2-(6-Chloro-2-pyridyl)-4ꢀ-{3-[(2-hydroxy-2-phenylethyl)amino]-
propyl}acetanilide Hydrochloride (36a) To a solution of 35a (0.45 g) in
ethanol (10 ml) was added 4 M HCl–EtOAc solution (10 ml), and the mixture
was stirred at room temperature for 2 h, and then concentrated in vacuo. The
residue was purified by recrystallization from MeOH–EtOH–Et2O to yield
36a (0.25 g) as a colorless solid. 64% yield; mp 248—251 °C (MeOH–
EtOH–Et2O); 1H-NMR (DMSO-d6) d: 2.90—3.08 (3H, m), 3.09—3.21 (3H,
m), 3.88 (2H, s), 5.02 (1H, dd, Jꢀ2.4, 10.0 Hz), 6.20 (1H, br s), 7.16—7.22
(2H, m), 7.28—7.46 (7H, m), 7.57—7.63 (2H, m), 7.84 (1H, t, Jꢀ7.2 Hz),
8.95 (1H, br s), 9.40 (1H, br s), 10.48 (1H, br s); MS (FAB) m/z: 410 (MHꢂ);
Anal. Calcd for C23H24N3O2Cl·HCl: C, 61.89; H, 5.65; N, 9.41; Cl, 15.88.
Found: C, 61.64; H, 5.57; N, 9.36; Cl, 15.82.
(R)-2-(6-Amino-2-pyridyl)-4ꢀ-{3-[(2-hydroxy-2-phenylethyl)amino]-
propyl}acetanilide Dihydrochloride (36b) The title compound was pre-
pared in the same manner as described for 36a using 35c instead of 35a as a
colorless solid. 15% yield; mp 150—152 °C (EtOH–EtOAc); 1H-NMR
(DMSO-d6) d: 2.88—3.07 (3H, m), 3.08—3.21 (3H, m), 3.95 (2H, s), 5.00
(1H, dd, Jꢀ2.8, 10.0 Hz), 6.21 (1H, s), 6.82 (1H, d, Jꢀ7.6 Hz), 6.91 (1H, d,
Jꢀ8.0 Hz), 7.17—7.23 (2H, m), 7.28—7.43 (5H, m), 7.55—7.62 (2H, m),
7.82—8.04 (3H, m), 8.90 (1H, br s), 9.31 (1H, br s), 10.67 (1H, br s), 14.07
(1H, br s); MS (FAB) m/z: 391 (MHꢂ); Anal. Calcd for C23H26N4O2·2HCl·
1.5H2O: C, 56.33; H, 6.37; N, 11.42; Cl, 14.46. Found: C, 56.37; H, 6.00; N,
11.37; Cl, 14.56.
1
powder. 56% yield; H-NMR (CDCl3) d: 1.46 (9H, s), 2.60—2.85 (2H, m),
3.15—3.55 (4H, m), 3.77 (2H, s), 4.33 (1H, br s), 4.87 (1H, br s), 5.64 (2H,
s), 6.77 (1H, d, Jꢀ8.4 Hz), 6.89 (1H, d, Jꢀ7.2 Hz), 6.94—7.12 (2H, m),
7.21—7.41 (10H, m), 7.43—7.48 (2H, m), 7.59 (1H, dd, Jꢀ7.2, 8.4 Hz),
9.05 (1H, br s); MS (FAB) m/z: 582 (MH)ꢂ.
tert-Butyl N-[2-(4-{[2-(6-tert-Butoxycarbonylamino-2-pyridyl)acetyl]-
amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate (35c) The
title compound was prepared in the same manner as described for 35a using
6-tert-butoxycarbonylamino-2-pyridylacetic acid22) instead of 6-chloro-2-
pyridylacetic acid as a colorless powder. 89% yield; 1H-NMR (CDCl3) d:
1.46 (9H, s), 1.55 (9H, s), 2.55—2.85 (2H, m), 3.15—3.55 (4H, m), 3.76
(2H, s), 4.86 (1H, dd, Jꢀ3.2, 8.0 Hz), 6.94—7.15 (3H, m), 7.21—7.48 (6H,
m), 7.63—7.84 (3H, m), 9.03 (1H, br s); MS (FAB) m/z: 591 (MH)ꢂ.
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-{2-[4-({2-[1-(4-nitroben-
zyl)imidazol-2-yl]acetyl}amino)phenyl]ethyl}carbamate (35d) The title
compound was prepared in the same manner as described for 35a using 1-
(4-nitrobenzyl)imidazol-2-ylacetic acid hydrochloride instead of 6-chloro-2-
pyridylacetic acid as a colorless powder. 77% yield; 1H-NMR (CDCl3) d:
1.47 (9H, s), 2.50—2.80 (2H, m), 3.10—3.50 (4H, m), 3.70 (2H, s), 4.85—
4.90 (1H, m), 5.30 (2H, s), 6.96—7.36 (11H, m), 7.41 (2H, d, Jꢀ8.3 Hz),
8.18 (2H, d, Jꢀ8.3 Hz); MS (FAB) m/z: 600 (MH)ꢂ.
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(1H-imidazol-
2-yl)acetanilide Dihydrochloride (36c) The title compound was prepared
in the same manner as described for 36a using 35e instead of 35a as a color-
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-imidazol-2-
yl)acetyl]amino}phenyl)ethyl]carbamate (35e) To a solution of 35d
(0.91 g) in methanol (100 ml) was added 4 M HCl–EtOAc solution (2.0 ml).
The mixture was stirred at room temperature for 5 min and concentrated in
vacuo. To a solution of the residue in methanol (100 ml) was added palla-
dium on carbon (10% w/w, 0.39 g), and the mixture was stirred under hydro-
gen atmosphere for 4 h. The catalyst was removed by filtration, and the fil-
trate was concentrated in vacuo. The residue was partitioned between chlo-
roform and 1 M NaOH aqueous solution. The organic layer was washed with
brine, and then dried and concentrated in vacuo. The residue was purified
using column chromatography on silica gel with CHCl3/MeOH (50 : 1) as
1
less solid. 89% yield; mp 203—207 °C (EtOH–EtOAc); H-NMR (DMSO-
d6) d: 2.92—3.08 (3H, m), 3.10—3.22 (3H, m), 4.28 (2H, s), 5.01 (1H, d,
Jꢀ7.8 Hz), 6.21 (1H, br s), 7.22 (2H, d, Jꢀ8.3 Hz), 7.25—7.63 (4H, m),
8.93 (1H, br s), 9.38 (1H, br s), 10.86 (1H, s); MS (FAB) m/z: 365 (MHꢂ);
Anal. Calcd for C21H24N4O2·2HCl·0.2H2O: C, 57.20; H, 6.03; N, 12.71; Cl,
16.08. Found: C, 57.19; H, 6.06; N, 12.42; Cl, 16.37.
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(1H-1,2,4-tri-
azol-3-yl)acetanilide Dihydrochloride (36d) The title compound was
prepared in the same manner as described for 36a using 35f instead of 35a
as a colorless solid. 78% yield; mp 221—224 °C (EtOH); 1H-NMR (DMSO-
d6) d: 2.90—3.07 (3H, m), 3.10—3.20 (3H, m), 4.05 (2H, s), 5.00 (1H, dd,
Jꢀ2.7, 10.2 Hz), 7.21 (2H, d, Jꢀ8.6 Hz), 7.29—7.42 (5H, m), 7.58 (2H, d,
Jꢀ8.6 Hz), 8.83 (1H, s), 8.91 (1H, br s), 9.32 (1H, br s), 10.62 (1H, s); MS
(FAB) m/z: 366 (MHꢂ); Anal. Calcd for C20H23N5O2·2HCl: C, 54.80; H,
5.75; N, 15.98; Cl, 16.18. Found: C, 54.83; H, 5.80; N, 15.99; Cl, 16.18.
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(1H-tetrazol-5-
yl)acetanilide Hydrochloride (36e) The title compound was prepared in
the same manner as described for 36a using 35g instead of 35a as a color-
1
the eluent to yield 35e (0.31 g) as a colorless powder. 44% yield; H-NMR
(CDCl3) d: 1.46 (9H, s), 2.52—2.80 (2H, m), 3.10—3.60 (4H, m), 3.89 (2H,
s), 4.85—4.95 (1H, m), 6.95—7.40 (9H, m), 7.49 (2H, d, Jꢀ8.4 Hz), 10.16
(1H, br s); MS (FAB) m/z: 465 (MH)ꢂ.
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-1,2,4-triazol-
3-yl)acetyl]amino}phenyl)ethyl]carbamate (35f) The title compound
was prepared in the same manner as described for 35a using 1,2,4-triazol-3-
ylacetic acid hydrochloride23) instead of 6-chloro-2-pyridylacetic acid as a
1
colorless powder. 36% yield; H-NMR (CDCl3) d: 1.46 (9H, s), 2.60—3.36
(6H, m), 3.98 (2H, s), 4.81—4.89 (1H, m), 7.02—7.12 (2H, m), 7.29—7.50
(7H, m), 8.09 (1H, br s), 9.24 (1H, br s); MS (FAB) m/z: 466 (MH)ꢂ.
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-tetrazol-5-
yl)acetyl]amino}phenyl)ethyl]carbamate (35g) The title compound was
prepared in the same manner as described for 35a using tetrazol-5-ylacetic
acid instead of 6-chloro-2-pyridylacetic acid as a colorless powder. 99%
1
less solid. 42% yield; mp 259—261 °C (MeOH–EtOH); H-NMR (DMSO-
d6) d: 2.90—3.10 (3H, m), 3.10—3.25 (3H, m), 4.15 (2H, s), 4.97 (1H, d,
Jꢀ10.8 Hz), 6.20 (1H, d, Jꢀ3.9 Hz), 7.21 (2H, d, Jꢀ8.8 Hz), 7.30—7.42
(5H, m), 7.57 (2H, d, Jꢀ8.8 Hz), 8.85 (1H, br s), 9.14 (1H, br s), 10.58 (1H,
s); MS (FAB) m/z: 367 (MHꢂ); Anal. Calcd for C19H22N6O2·HCl: C, 56.64;
H, 5.75; N, 20.86; Cl, 8.80. Found: C, 56.43; H, 5.92; N, 20.78; Cl, 9.04.
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(2-methylthia-
zol-4-yl)acetanilide Dihydrochloride (36f) The title compound was pre-
pared in the same manner as described for 36a using 35h instead of 35a as a
1
yield; H-NMR (CDCl3) d: 1.45 (9H, s), 2.50—3.50 (6H, m), 4.23 (2H, s),
4.65—4.75 (1H, m), 7.07 (2H, d, Jꢀ8.0 Hz), 7.20—7.80 (7H, m), 9.26 (1H,
br s); MS (FAB) m/z: 467 (MH)ꢂ.
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(2-methylthiazol-
4-yl)acetyl]amino}phenyl)ethyl]carbamate (35h) The title compound
was prepared in the same manner as described for 35a using 2-methylthia-
zol-4-ylacetic acid instead of 6-chloro-2-pyridylacetic acid as a colorless
1
colorless powder. 55% yield; H-NMR (DMSO-d6) d: 2.70 (3H, s), 2.86—
3.27 (6H, m), 3.85 (2H, s), 5.00—5.05 (1H, m), 7.18—7.60 (10H, m), 10.43
(1H, s); MS (FAB) m/z: 396 (MHꢂ); Anal. Calcd for C22H25N3O2S·
2.3HCl·2H2O: C, 51.27; H, 6.12; N, 8.15; S, 6.22; Cl, 15.82. Found: C,
51.59; H, 5.98; N, 7.91; S, 6.32; Cl, 15.86.
1
powder. 99% yield; H-NMR (CDCl3) d: 1.34 (9H, s), 2.89 (3H, s), 3.06—
3.36 (6H, m), 3.73 (2H, s), 4.72 (1H, s), 7.06—7.57 (10H, m), 10.10 (1H, s);
MS (FAB) m/z: 496 (MH)ꢂ.
(R)-2-(2-Amino-5-methylthiazol-4-yl)-4ꢀ-{3-[(2-hydroxy-2-phenyl-
ethyl)amino]propyl}acetanilide Dihydrochloride (36g) The title com-
pound was prepared in the same manner as described for 36a using 35i in-
stead of 35a as a colorless powder. 65% yield; 1H-NMR (DMSO-d6) d: 2.20
(3H, s), 2.90—3.07 (3H, m), 3.10—3.20 (3H, m), 3.74 (2H, s), 5.00 (1H, dd,
Jꢀ2.5, 10.3 Hz), 7.20 (2H, d, Jꢀ8.8 Hz), 7.28—7.42 (5H, m), 7.59 (2H, d,
Jꢀ8.8 Hz), 8.91 (1H, br s), 9.13 (1H, br s), 9.33 (1H, br s), 10.58 (1H, s);
MS (FAB) m/z: 411 (MHꢂ); Anal. Calcd for C22H26N4O2S·2.15HCl·H2O:
C, 52.12; H, 5.99; N, 11.05; S, 6.33; Cl, 15.04. Found: C, 52.30; H, 6.28; N,
11.15; S, 6.50; Cl, 15.28.
tert-Butyl N-[2-(4-{[2-(2-Amino-5-methylthiazol-4-yl)acetyl]amino}-
phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate (35i) The title
compound was prepared in the same manner as described for 35a using 2-
amino-5-methylhiazol-4-ylacetic acid hydrochloride24) instead of 6-chloro-2-
pyridylacetic acid as a colorless powder. 73% yield; 1H-NMR (CDCl3) d:
1.47 (9H, s), 2.25 (3H, s), 2.60—3.50 (6H, m), 3.52 (2H, s), 4.83 (1H, s),
7.27—7.45 (9H, m), 9.01 (1H, br s); MS (FAB) m/z: 511 (MH)ꢂ.
tert-Butyl N-[2-(4-{[2-(5-Amino-1,2,4-thiadiazol-3-yl)acetyl]amino}-
phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate (35j) The title
compound was prepared in the same manner as described for 35a using 5-
amino-1,2,4-thiadiazol-3-ylacetic acid25) hydrochloride instead of 6-chloro-
(R)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-4ꢀ-{3-[(2-hydroxy-2-phenyl-
ethyl)amino]propyl}acetanilide Dihydrochloride (36h) The title com-
pound was prepared in the same manner as described for 36a using 35j
1
2-pyridylacetic acid as a colorless powder. 86% yield; H-NMR (CDCl3) d:

544
Vol. 58, No. 4
instead of 35a as
a
colorless solid. 74% yield; mp 205—208 °C
C, 60.94; H, 6.14; N, 9.27; Cl, 10.95. Found: C, 61.05; H, 6.08; N, 9.31; Cl,
(MeOH–EtOH); 1H-NMR (DMSO-d6) d: 2.90—3.08 (3H, m), 3.10—3.20 10.62.
(3H, m), 3.67 (2H, s), 5.00 (1H, dd, Jꢀ2.4, 10.0 Hz), 7.19 (2H, d,
Agonistic Activity on Human b3-, b2-, and b1-ARs The ability to
Jꢀ8.3 Hz), 7.28—7.42 (5H, m), 7.57 (2H, d, Jꢀ8.3 Hz), 8.90 (1H, s), 9.31 stimulate human b3-, b2-, and b1-AR was investigated using a CHO cell
(1H, s), 10.31 (1H, s); MS (FAB) m/z: 398 (MHꢂ); Anal. Calcd for system (cells in which human b3-, b2-, and b1-ARs were compulsorily
C20H23N5O2S·2HCl: C, 51.06; H, 5.36; N, 14.89; S, 6.82; Cl, 15.07. Found: expressed were used). The agonistic activity of the compound (10ꢆ10 to
C, 50.81; H, 5.19; N, 14.84; S, 6.73; Cl, 14.86.
tert-Butyl N-(2-{4-[(2-Bromoacetyl)amino]phenyl}ethyl)-N-(2-hy- a 24-well plate and checking the activity after 2 days’ incubation (subconflu-
droxy-2-phenylethyl)carbamate (37) To a solution of 34 (1.87 g) and ent state) using the production of cyclic AMP (cAMP) as an index. The
N,N-diisopropyl-N-ethylamine (1.05 g) in chloroform (40 ml) was added amount of cAMP produced in each cell (pmol/ml) was measured using a ra-
dropwise at 0 °C a solution of 2-bromoacetyl bromide (1.07 g) in chloroform
dioimmunoassay method with 125I-cAMP. The intensity of action among
10ꢆ4 M) was investigated by incubating 105 cells/well of each type of cell on
(3 ml), and the mixture was stirred at 0 °C for 1 h. The resultant mixture was compounds was compared by calculating the EC50 and intrinsic activity (IA
washed with 1 M HCl aqueous solution and brine. The organic layer was
dried and concentrated in vacuo. The residue was purified using column
chromatography on silica gel with CHCl3/MeOH (30 : 1) as the eluent to
where the maximum reaction of 10ꢆ4 M isoproterenol was defined as 1.00)
for each from the resulting dose-reaction curve.
Hypoglycemic Activity in kk Mice The blood sugar level of male kk
yield 37 (2.15 g) as a colorless powder. 85% yield; 1H-NMR (CDCl3) d: mice (blood sugar level: not lower than 200 mg/dl) was measured under fed
1.47 (9H, s), 2.60—2.90 (2H, m), 3.16—3.56 (4H, m), 4.01 (2H, s), 4.20— conditions, and then randomly classified into groups. The test compound
4.30 (1H, m), 4.80—4.95 (1H, m), 7.00—7.20 (2H, m), 7.25—7.38 (5H, m), was administered orally once daily for 4 d, and the blood sugar level 15 to
7.44 (2H, d, Jꢀ8.4 Hz), 8.07 (1H, s); MS (FAB) m/z: 477, 479 (MH)ꢂ.
18 h after final administration was compared with that before administration
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-pyrazol-1-yl)- (nꢀ6). Blood samples were collected from the tail vein using a heparin-
acetyl]amino}phenyl)ethyl]carbamate (38a) A mixture of 37 (0.62 g), treated glass capillary tube after which the blood was deproteinized, and the
pyrazole (0.42 g), and potassium carbonate (0.4 g) in acetonitrile (15 ml) was amount of glucose in the supernatant (mg/dl) was determined calorimetri-
heated at 80 °C for 15 h. After cooling to room temperature, the precipitate
was removed by filtration, and the filtrate was then concentrated in vacuo.
The residue was purified using column chromatography on silica gel with
cally by means of the glucose oxidase method.
Single-Crystal X-Ray Diffraction Analysis of 2-{(2S)-N-Benzyl-N-[1-
(4-nitrophenyl)-2-propyl]amino}-(1R)-1-phenylethanol (17b)
A light-
CHCl3/MeOH (10 : 1) as the eluent to yield 38a (0.55 g) as a colorless pow- yellow prismatic crystal of 17b C24H26N2O3 (F.W.ꢀ390.48, 0.43 mmꢇ
der. 91% yield; 1H-NMR (CDCl3) d: 1.47 (9H, s), 2.60—2.88 (2H, m), 0.40 mmꢇ0.32 mm) was mounted on a glass fiber. All measurements were
3.10—3.54 (4H, m), 4.20—4.35 (1H, m), 4.85—4.90 (1H, m), 4.93 (2H, s), made on a Rigaku AFC7R diffractometer with graphite monochromated
6.38—6.40 (1H, m), 7.00—7.15 (2H, m), 7.30—7.40 (7H, m), 7.53 (1H, d, CuKa radiation and a rotating anode generator. Cell constants and an orien-
Jꢀ2.0 Hz), 7.71 (1H, d, Jꢀ2.0 Hz), 8.34 (1H, s); MS (FAB) m/z: 465 tation matrix for data collection, obtained from a least-squares refinement
(MH)ꢂ.
using the setting angles of 25 carefully centered reflections in the range
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-1,2,4-triazol- 59.62ꢅ2qꢅ60.02° corresponded to a primitive triclinic cell (P1, Zꢀ2) with
1-yl)acetyl]amino}phenyl)ethyl]carbamate (38b) The title compound
dimensions: aꢀ9.523(5) Å, bꢀ9.796(6) Å, cꢀ13.333(4) Å, aꢀ71.92(3)°,
was prepared in the same manner as described for 38a using 1,2,4-triazole
bꢀ85.59(3)°, gꢀ63.64(4)°, Vꢀ1056.7(9) Å3, the calculated density is
1
instead of pyrazole as a colorless powder. 84% yield; H-NMR (CDCl3) d: 1.23 g/cm3. The data were collected at a temperature of 25ꢄ1 °C using the
1.46 (9H, s), 2.60—2.84 (2H, m), 3.10—3.50 (4H, m), 4.14—4.28 (1H, m), qꢆ2q scan technique to a maximum 2q value of 120.2°. Of the 3111 reflec-
4.84—4.92 (1H, m), 5.00 (2H, s), 7.02—7.10 (2H, m), 7.30—7.40 (7H, m), tions that were collected, 2890 were unique (Rintꢀ0.011). The intensities of
8.12 (1H, s), 8.24 (2H, s); MS (FAB) m/z: 466 (MH)ꢂ.
three representative reflections were measured after every 150 reflections.
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(1H-pyrazol-1- No decay correction was applied. The linear absorption coefficient, m, for
yl)acetanilide Hydrochloride (39a) The title compound was prepared in CuKa radiation is 6.5 cmꢆ1. An empirical absorption correction based on
the same manner as described for 36a using 38a instead of 35a as a color- azimuthal scans of several reflections was applied which resulted in trans-
less solid. 36% yield; mp 229—232 °C (EtOH); 1H-NMR (DMSO-d6) d: mission factors ranging from 0.71 to 0.81. The data were corrected for
2.90—3.00 (3H, m), 3.10—3.18 (3H, m), 5.00 (1H, dd, Jꢀ2.8, 10.1 Hz), Lorentz and polarization effects. The structure was solved by direct
5.03 (2H, s), 6.27 (1H, t, Jꢀ2.0 Hz), 7.20 (2H, d, Jꢀ8.8 Hz), 7.29—7.42 methods26) and expanded using Fourier techniques.27) The non-hydrogen
(5H, m), 7.46 (1H, d, Jꢀ2.4 Hz), 7.58 (2H, d, Jꢀ8.8 Hz), 7.77 (1H, d, atoms were refined anisotropically. Hydrogen atoms were refined using the
Jꢀ2.0 Hz), 8.91 (1H, s), 9.32 (1H, s), 10.53 (1H, s); MS (FAB) m/z: 365 riding model. The final cycle of full-matrix least-squares refinement28) was
(MHꢂ); Anal. Calcd for C21H24N4O2·1.1HCl·0.4C2H6O: C, 61.90; H, 6.55; based on 2891 observed reflection s (F2ꢃ2.00s(F2), 2qꢅ120.2°) and 575
N, 13.25; Cl, 9.22. Found: C, 62.28; H, 6.23; N, 12.87; Cl, 9.34.
variable parameters and converged (largest parameter shift was 0.00 times
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(1H-1,2,4-tri- its esd) with unweighted and weighted agreement factors of: Rꢀ0.046,
azol-1-yl)acetanilide Hydrochloride (39b) The title compound was pre- Rwꢀ0.159, respectively. The goodness of fit29) was 1.001. The maximum and
pared in the same manner as described for 36a using 38b instead of 35a as a minimum peaks on the final difference Fourier map corresponded to 0.03
colorless solid. 64% yield; mp 237—240 °C (MeOH–EtOH); 1H-NMR and ꢆ0.03 e/Å3, respectively. Neutral atom scattering factors were taken
(DMSO-d6) d: 2.90—3.08 (3H, m), 3.10—3.22 (3H, m), 4.96 (1H, dd, from Cromer and Waber.30) The values for the mass attenuation coefficients
Jꢀ2.0, 10.0 Hz), 5.15 (2H, s), 7.21 (2H, d, Jꢀ8.0 Hz), 7.28—7.42 (5H, m),
7.56 (2H, d, Jꢀ8.4 Hz), 8.03 (1H, s), 8.61 (1H, s), 8.82 (1H, s), 9.09 (1H, s),
10.57 (1H, s); MS (FAB) m/z: 365 (MHꢂ); Anal. Calcd for C20H23N5O2·
are those of Creagh and Hubbel.31) All calculations were performed using
the teXsan32) crystallographic software package of Molecular Structure Cor-
poration and CrystalStructure33,34) crystallographic software package. The
1.8HCl·0.5H2O: C, 54.59; H, 5.91; N, 15.91; Cl, 14.50. Found: C, 54.51; H, X-ray crystallographic data have been deposited at the Cambridge Crystallo-
5.69; N, 15.89; Cl, 14.56.
graphic Centre (CCDC ref. No. 756207).
(R)-4ꢀ-{3-[(2-Hydroxy-2-phenylethyl)amino]propyl}-2-(6-hydroxy-2-
pyridyl)acetanilide Hydrochloride (40) To 35b (0.35 g) were added pen-
Acknowledgment The authors are grateful to the staff of the Division
tamethylbenzene (0.48 g) and trifluoroacetic acid (5 ml), and the mixture was of Analytical Science Laboratories for elemental analysis and spectral meas-
stirred at room temperature for 4 h, and then concentrated in vacuo. The re- urements.
sultant was diluted with K2CO3 aqueous solution, and extracted with chloro-
form–tetrahydrofuran (1 : 1). The organic layer was dried, and then concen- References and Notes
trated in vacuo. The residue was purified using column chromatography on
silica gel with CHCl3/MeOH (10 : 1—5 : 1) as the eluent. To the solution of
the residue in ethanol (5 ml) was added 4 M HCl–EtOAc solution (100 ml),
and the mixture was concentrated in vacuo. The residue was purified by re-
crystallization from EtOH–EtOAc to yield 40 (0.06 g) as a colorless solid.
24% yield; mp 214—216 °C (EtOH–EtOAc); 1H-NMR (DMSO-d6) d:
2.86—3.24 (6H, m), 3.65 (2H, s), 4.98 (1H, dd, Jꢀ2.8, 10.4 Hz), 6.18 (1H,
d, Jꢀ6.8 Hz), 6.28 (1H, d, Jꢀ8.8 Hz), 7.16—7.22 (2H, m), 7.28—7.45 (6H,
m), 7.53—7.59 (2H, m), 8.85 (1H, br s), 9.18 (1H, br s), 10.36 (1H, br s);
MS (FAB) m/z: 392 (MHꢂ); Anal. Calcd for C23H25N3O3·1.4HCl·0.6H2O:
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