Synthesis and evaluation of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety as selective β3-adrenergic receptor agonists

Article abstract of DOI:10.1248/cpb.60.647

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol- 4-yl)acetamides with phenoxypropanolamine m

Full text of DOI:10.1248/cpb.60.647

May 2012
Regular Article
Chem. Pharm. Bull. 60(5) 647–658 (2012)
647
Synthesis and Evaluation of N-Phenyl-(2-aminothiazol-4-yl)acetamides
with Phenoxypropanolamine Moiety as Selective β3-Adrenergic Receptor
Agonists
Tatsuya Maruyama,* Kenichi Onda, Takayuki Suzuki, Masahiko Hayakawa, Takumi Takahashi,
Tetsuo Matsui, Toshiyuki Takasu, Itsuro Nagase, and Mitsuaki Ohta
Drug Discovery Research, Astellas Pharma Inc.; 21 Miyukigaoka, Tsukuba, Ibaraki 305–8585, Japan.
Received January 29, 2012; accepted March 8, 2012
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs
for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-
4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against
human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-
yl)acetamide (4g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)-
aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with func-
tional selectivity over the β1- and β2-ARs. In addition, these compounds exhibited significant hypoglycemic
activity in a rodent model of diabetes.
Key words β3-adrenergic receptor; agonist; 2-aminothiazole; phenoxypropanolamine; diabetes
A major increase in the prevalence of obesity, non-insulin selectivity, we decided to apply this structure part in the
dependent (type 2) diabetes and related cardiovascular disor- phenoxypropanolamine analogue instead of the phenyletha-
ders has led to the search for new pharmacological approaches nolamine one. We therefore synthesized simple N-phenyl-(2-
in the treatment of these conditions.1,2) In the 1980s and 1990s, aminothiazol-4-yl)acetamide 4a, which showed good partial
the β3-adrenergic receptor (AR) was identified as a possible agonistic activity at the β3-AR (EC50=0.98µM, IA=0.48)
therapeutic target for the treatment of type 2 diabetes and and functional selectivity over β1- and β2-ARs. This result
obesity.3,4) Early potent and selective β3-AR agonists, such encouraged us to attempt further modification of 4a (Fig. 2).
as BRL-373445) and CL-316243,6) were reported to be effec-
Here, we describe the synthesis and structure–activity
tive anti-obesity and anti-diabetic agents in rodents7) (Fig. relationships (SARs) of these newly designed N-phenyl-(2-
1). Human clinical trials with these agents for use in treating aminothiazol-4-yl)acetamides with phenoxypropanolamine
metabolic disorders, however, have been disappointing due moiety as β3-AR agonists.
to a lack of efficacy or an unfavorable side-effect profile.8,9)
Chemistry The syntheses of N-phenyl-(2-aminothiazol-
The clinical failure of such compounds has been attributed 4-yl)acetamides 4a–m are shown in Chart 1. Treat-
to a lack of sufficient β3-AR potency and selectivity relative ment of aniline intermediate 221) with the appropriate
to β1- and β2-ARs resulting from pharmacologic differences (2-aminothiazol-4-yl)acetic acids in the presence of 1-ethyl-
between rodent and human receptors, a notion supported by 3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, fol-
the discovery, cloning, and characterization of the human, rat, lowed by deprotection of the tert-butoxycarbonyl (Boc) group
and mouse β3-ARs.10–12)
with hydrochloric acid, afforded the desired products 4a–m.
Recent studies have indicated that, in addition to adi- N-Phenyl-(2-phenylaminothiazol-4-yl)acetamides 6a–m were
pocytes, the β3-AR is also distributed in human urinary also prepared from aniline intermediate 2 in the same manner
bladder detrusor tissue and its relaxation occurs mainly via as 4 (Chart 2). Compounds 9a and b and 11 were synthesized,
β3-AR.13–15) Several companies have reported developing as illustrated in Chart 3. Aniline intermediates 7a and b21)
a new generation of β3-AR agonists over the past few de- were coupled with (2-phenylaminothiazol-4-yl)acetic acid, fol-
cades, including L-796568,16) rafabegron,17) ritobegron18) and lowed by cleavage of the Boc protecting group to afford the
solabegron19) (Fig. 1). The availability of appropriate human desired products 9a and b. Meanwhile, treatment of 2 with
receptors has facilitated the design and synthesis of a new (2-methylphenylaminothiazol-4-yl)acetic acid,22) followed by
generation of highly potent β3-AR agonists. Subtype selectiv- deprotection with Boc group, afforded the desired product 11.
ity for β3-AR agonists must be kept specifically in mind, since As starting materials, novel (2-aminothiazol-4-yl)acetic acids
activation of the β1- or β2-ARs could lead to undesirable side 14a–c were synthesized from the treatment of methyl chloro-
effects such as increased heart rate or muscle tremors.
acetylacetate with the appropriate thioureas 12a–c, followed
We previously described efforts in this area that included by saponification of 13a–c (Chart 4).
the disclosure of acetanilide-based phenylethanolamine 1,
which showed potent β3-AR agonistic activity with func-
tional selectivity over β1- and β2-ARs and oral hypoglycemic
Results and Discussion
The prepared compounds were evaluated for their agonistic
activity in diabetic kk mice.20) Given our assumption that activities in stimulating an increase in cyclic AMP (cAMP)
the (2-aminothiazol-4-yl)acetamide moiety of 1 might be a levels in Chinese hamster ovary (CHO) cells expressing
favorable pharmaocophore for β3-AR agonistic activity and cloned human β3-, β2-, and β1-ARs. The results for the refer-
ence compound, isoproterenol (ISO; non-selective β-AR ago-
The authors declare no conflict of interest.
nist), are also shown for comparison in Table 1.
*To whom correspondence should be addressed. e-mail: tatsuya.maruyama@astellas.com
© 2012 The Pharmaceutical Society of Japan

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Vol. 60, No. 5
Fig. 1. Chemical Structure of β3-AR Agonists
Fig. 2. Design of N-Phenyl-(2-aminothiazol-4-yl)acetamide Derivatives
Reagents and conditions: (a) substituted 2-aminothiazol-4-ylacetic acid, EDC·HCl, HOBt, DMF; (b) 4M HCl-EtOAc, MeOH.
Chart 1

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649
Reagents and conditions: (a) substituted 2-phenylaminothiazol-4-ylacetic acid, EDC·HCl, HOBt, DMF; (b) 4 M HCl–EtOAc, MeOH.
Chart 2
Reagents and conditions: (a) 2-phenylaminothiazol-4-ylacetic acid, EDC·HCl, HOBt, DMF; (b) 4 M HCl–EtOAc, MeOH; (c) 2-methylphenylaminothiazol-4-ylacetic acid,
EDC·HCl, HOBt, DMF.
Chart 3
Reagents and conditions: (a) methyl chloroacetylacetate, MeOH, reflux; (b) 10% HClaq., reflux; (c) 1 M NaOHaq., MeOH, reflux.
Chart 4
Initially, introduction of substituent on the amino group of functional selectivity over β1- and β2-ARs, 2-acetylamino de-
2-aminothiazole moiety in 4a was investigated as shown in rivative (4b) and 2-methanesulfonylamino derivative (4c) ex-
Table 1. When N-phenyl-(2-aminothiazol-4-yl)acetamide con- hibited an extreme decrease in β3-AR agonistic activity. Fur-
taining phenoxypropanolamine moiety 4a showed good partial ther, 2-guanidino derivative (4d) showed 5-fold less agonistic
agonistic activity at the β3-AR (EC50=0.98µM, IA=0.48) and activity against β3-AR (EC50=4.6µM) than did 4a. These

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Vol. 60, No. 5
Table 1. β-AR Agonistic Activity Substituted N-Phenyl-(2-aminothiazol-4-yl)acetamides
EC50, μM (IAb))
a)
Compound
R
β3-AR
0.98 (0.48)
β2-AR
β1-AR
4a
4b
4c
4d
4e
4f
H
COMe
SO2Me
C(=NH)NH2
Me
>100 (0)
>100 (0)
>100 (0)
>100 (0.01)
>100 (0.01)
>100 (0.02)
>100 (0.01)
>100 (0)
>100 (0)
>100 (0.35)
14 (0.71)
>100 (0.04)
>100 (0.04)
11 (0.16)
4.6 (0.60)
22 (0.58)
0.44 (0.15)
0.39 (0.12)
>100 (0.06)
>100 (0.06)
c-Hex
0.13 (0.55)
0.56 (0.90)
1.6 (0.19)
4g
4h
Ph
4i
3.5 (0.73)
>100 (0.05)
0.65 (0.27)
4j
4k
4l
CH2Ph
0.45 (0.79)
0.51 (0.53)
4.6 (0.53)
>100 (0)
>100 (0.02)
>100 (0.05)
>100 (0.06)
0.71 (0.11)
0.85 (0.34)
CH2CH2Ph
4m
0.91 (0.41)
0.10 (1.00)
>100 (0.05)
0.68 (0.30)
ISO
0.003 (1.00)
0.012 (1.00)
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing β-ARs. b) Values in parentheses represent the intrinsic activity (IA) given as
a fraction of the maximum stimulation with isoproterenol.
Table 2. β-AR Agonistic Activity of Substituted N-Phenyl-(2-phenylaminothiazol-4-yl)acetamides
EC50, μM (IAb))
a)
Compound
R
β3-AR
0.56 (0.90)
β2-AR
>100 (0.01)
>100 (0.01)
>100 (0)
β1-AR
>100 (0.06)
0.59 (0.15)
0.54 (0.15)
>100 (0.08)
>100 (0.10)
>100 (0.06)
4.3 (0.13)
4g
6a
6b
6c
6d
6e
6f
H
2-Cl
0.16 (0.51)
0.28 (0.46)
0.16 (0.67)
0.30 (0.58)
0.49 (0.56)
0.32 (0.65)
0.25 (0.70)
2.2 (0.39)
3.0 (0.24)
0.87 (0.58)
0.98 (0.17)
3.6 (0.29)
11 (0.46)
2-OMe
3-F
>100 (0)
3-Cl
>100 (0.01)
>100 (0.02)
>100 (0.01)
>100 (0)
>100 (0)
>100 (0.01)
>100 (0)
>100 (0)
>100 (0)
>100 (0.10)
3-CF3
3-CN
3-OMe
4-Cl
6g
6h
6i
>100 (0.07)
>100 (0.06)
>100 (0.04)
>100 (0.10)
>100 (0.07)
>100 (0.07)
>100 (0.05)
4-CF3
4-CN
4-NO2
4-OMe
4-iPr
6j
6k
6l
6m
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing β-ARs. b) Values in parentheses represent the intrinsic activity (IA) given as
a fraction of the maximum stimulation with isoproterenol.
results suggested that the basic amino group of 2-aminothia- (4e) resulted in a considerable decrease in agonistic activ-
zole moiety might be required for β3-AR agonistic activity. ity against β3-AR (EC50=22µM) and an increase in agonistic
Introduction of methyl group at the 2-aminothiazole moiety activity against β1-AR. In contrast, the agonistic activity of

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651
Table 3. β-AR Agonistic Activity of N-Phenyl-(2-phenylaminothiazol-4-yl)acetamide Derivatives
EC50, μM (IAb))
a)
Compound
R1
R2
β3-AR
β2-AR
β1-AR
4g
9ac)
9bd)
11
H
Me
Me
H
H
H
0.56 (0.90)
0.21 (0.84)
0.23 (0.56)
0.62 (0.39)
>100 (0.01)
>100 (0.06)
>100 (0)
>100 (0.06)
0.031 (0.21)
0.30 (0.20)
2.0 (0.47)
H
Me
3.7 (0.17)
a) Agonistic activity was assessed by measuring cAMP accumulation in CHO cells expressing β-ARs. b) Values in parentheses represent the intrinsic activity (IA) given as a
fraction of the maximum stimulation with isoproterenol. c) Less polar compound of diastereomer. d) High polar compound of diastereomer.
the cyclohexylamino derivative (4f) against β3-AR increased Table 4. Oral Hypoglycemic Activity in kk Mice
7-fold (EC50=0.13µM) relative to that of 4a, but 4f was still
Percent reduction in plasma glucosea)
partial agonist (IA=0.55). Interestingly, 2-phenylamino de-
Compound
rivative (4g) exhibited 2-fold increased potency against β3-AR
with high intrinsic activity (EC50=0.56µM, IA=0.90) relative
to that of 4a without agonistic activity at either β2- or β1-ARs.
Given these findings, we therefore examined the effects of
introducing an aryl-containing group on the amino group of
the 2-aminothiazole moiety in 4a. Both 2-(2-pyridyl)amino
derivative (4h) and 2-(3-pyridyl)amino derivative (4i) showed
decreased agonistic activity at the β3-AR relative to that of
3mg/kg p.o.
10mg/kg p.o.
4g
4j
55**b)
28
58***
46***
50**
6g
23
a) The compounds were administered orally to male kk mice for 4d. b) Statisti-
cally significant at **p<0.01, ***p<0.001.
4g. Meanwhile, 2-benzylamino derivative (4j) exhibited good (EC50=0.87–11µM, IA=0.17–0.58) relative to that of 4g. These
agonistic activity against β3-AR (EC50=0.45µM, IA=0.79) results suggested that introduction of a substituent on the
and functional selectivity over β1- and β2-ARs compared phenyl ring at the 2- and 3-position on the phenyl ring of the
to 4g. The introduction of 2-phenylethyl group (4k) on the 2-phenylaminothiazole moiety in 4g may maintain agonistic
amino group of the 2-aminothiazole moiety in 4a resulted in activity against β3-AR, with similar results possible with both
decreased intrinsic activity at the β3-AR (IA=0.53) related electron-withdrawing and electron-donating groups as sub-
to that of 4g. Both 2-(2-furylmethyl)amino derivative (4l) stituents. Further, the non-substituted phenyl derivative (4g)
and 2-(2-thenylmethyl)amino derivative (4m) showed de- was found to have the most potent agonistic activity against
creased intrinsic activity at the β3-AR relative to that of 4j β3-AR.
and increased agonistic activity against β1-AR. These results
Next, the introduction of a methyl group at the α-position
indicated that phenyl group gave the most satisfied agonistic of the secondary amine on the central part of 4g was inves-
activity against β3-AR and functional selectivity over β1- and tigated, since it was reported to improve β3-AR agonistic
β2-ARs as a substituent on the amino group of the 2-amino- activity in phenoxypropanolamine analogue21) (Table 3). One
thiazole moiety in 4a.
diastereomer of the α-methyl derivative (9a) showed a 3-fold
In order to improve the potency of 4g against β3-AR, increase in potency at the β3-AR (EC50=0.21µM, IA=0.84)
introduction of substituent on the phenyl ring of 2-phenyl- relative to that of 4g, however, its functional selectivity over
aminothiazole moiety in 4g was examined as shown in Table β1-AR was decreased. Another diastereomer of the α-methyl
2. Both 2-chlorophenyl derivative (6a) and 2-methoxyphenyl derivative (9b) showed a decrease in intrinsic activity against
derivative (6b) showed slightly increased agonistic activ- β3-AR (IA=0.56).
ity at the β3-AR (EC50=0.16, 0.28µM, respectively), however,
Lastly, we examined the introduction of a methyl group at
their intrinsic activity at the β3-AR were decreased relative the nitrogen of the 2-phenylaminothiazole moiety in 4g (Table
to that of 4g (IA=0.51, 0.46, respectively). In addition, they 3). This new compound 11 showed a dramatic decrease in
exhibited slightly increased agonistic activity at the β1-AR. intrinsic activity against β3-AR (IA=0.39) and functional se-
The results obtained for agonistic activity at the β3-AR on lectivity over β2- and β1-ARs relative to that of 4g, suggesting
introduction of a substituent at the 3-position on the phenyl that the hydrogen on the amino group of the 2-phenylamino-
ring of the 2-phenylaminothiazole moiety (6c–g) were similar thiazole moiety may play an important role in the functional
to those for introduction at the 2-position on the phenyl ring selectivity over β2- and β1-ARs, as most compounds in this
(EC50=0.16–0.49µM, IA=0.56–0.70), in which the 3-methoxy- series were selective for β3-AR.
phenyl derivative (6g) gave the most satisfying results with
Given the results of the in vitro study, compounds 4g,
respect to β3-AR agonistic activity (EC50=0.25µM, IA=0.70) 4j, and 6g were selected for in vivo evaluation in a rodent
and no agonistic activity for either the β2- and β1-AR. In model of type 2 diabetes (Table 4). The effects on plasma
contrast, introduction of a substituent at the 4-position on glucose following four-day oral administration of compounds
the phenyl ring of the 2-phenylaminothiazole moiety (6h–m) to diabetic kk mice were measured. All compounds induced
resulted in considerably decreased β3-AR agonistic activity a significant reduction in plasma glucose level at 10mg/kg

652
Vol. 60, No. 5
(46–58% decrease), with 4g showing the most potent hypogly- phenyl)ethyl]carbamate (3c) The title compound was pre-
cemic activity with a 55% decrease at 3mg/kg.
pared in the same manner as described for 3a using 2-meth-
anesulfonylaminothiazol-4-ylacetic acid instead of 2-ami-
nothiazol-4-ylacetic acid as a colorless powder. 87% yield;
Conclusion
Here, we have identified a new series of N-phenyl-(2- 1H-NMR (DMSO-d6) δ: 1.36 (9H, s), 2.73 (2H, t, J=7.6Hz),
aminothiazol-4-yl)acetamides with phenoxypropanolamine 2.89 (3H, s), 3.30–3.42 (4H, m), 3.62 (2H, s), 3.79–3.87 (2H,
moiety as β3-AR agonists and described their synthe- m), 3.96 (1H, brs), 5.10–5.18 (1H, m), 6.56 (1H, s), 6.89–6.94
sis and SARs. Among these compounds, N-phenyl- (3H, m), 7.11 (2H, d, J=8.4Hz), 7.28 (2H, t, J=8.8Hz), 7.49
(2-phenylaminothiazol-4-yl)acetamide
benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3- 603 [(M−H)−)].
methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives tert-Butyl
(4g),
N-phenyl-(2- (2H, d, J=8.8Hz), 10.08 (1H, s), 12.47 (1H, s); MS (FAB) m/z:
(S)-N-[2-(4-{[2-(2-Guanidinothiazol-4-yl)-
showed potent agonistic activity against β3-AR (EC50=0.56, acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxy-
0.45, 0.25µM, respectively) with high intrinsic activity propyl)carbamate (3d) The title compound was prepared
(IA>0.70) and had functional selectivity over β1- and β2-ARs. in the same manner as described for 3a using 2-guanidinothi-
In addition, these compounds exhibited significant hypoglyce- azol-4-ylacetic acid instead of 2-aminothiazol-4-ylacetic acid
1
mic activity in diabetic kk mice.
as a colorless powder. 86% yield; H-NMR (CDCl3) δ: 1.45
(9H, s), 2.73–2.83 (2H, m), 3.30–3.48 (4H, m), 3.61 (2H, brs),
3.83–3.95 (2H, m), 4.00–4.11 (1H, m), 6.45 (1H, s), 6.83–7.40
Experimental
Melting points were determined with a Yanaco MP-500D (9H, m) 8.43 (1H, brs); MS (FAB) m/z: 569 (MH+).
1
melting point apparatus and are uncorrected. H-NMR spectra
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-[2-(4-
were recorded on a JEOL EX90, EX400, or GX500 spec- {[2-(2-methylaminothiazol-4-yl)acetyl]amino}phenyl)ethyl]-
trometer, and the chemical shifts are expressed in δ (ppm) carbamate (3e) The title compound was prepared in the
values with tetramethylsilane as an internal standard (NMR same manner as described for 3a using 2-methylaminothiazol-
description key: s=singlet, d=doublet, t=triplet, m=multiplet, 4-ylacetic acid instead of 2-aminothiazol-4-ylacetic acid as a
1
and br=broad peak). Mass spectra were recorded on a Hita- colorless powder. 31% yield; H-NMR (CDCl3) δ: 1.46 (9H, s),
chi M-80 or JEOL JMS-DX300 spectrometer. The elemental 2.65–3.10 (5H, m), 3.30–4.25 (7H, m), 3.61 (2H, s), 6.30 (1H,
analyses were performed with a Yanaco MT-5 microanalyzer s), 6.80–7.55 (9H, m); MS (FAB) m/z: 541 (MH+).
(C, H, N) and were within 0.4% of the theoretical values.
During the work-up, all organic solutions were dried over an- 4-yl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxy-
hydrous MgSO4. propyl)carbamate (3f) The title compound was prepared in
tert-Butyl
(S)-N-[2-(4-{[2-(2-Cyclohexylaminothiazol-
tert-Butyl (S)-N-[2-(4-{[2-(2-Aminothiazol-4-yl)acetyl]- the same manner as described for 3a using 2-cyclohexylami-
amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)carba- nothiazol-4-ylacetic acid instead of 2-aminothiazol-4-ylacetic
1
mate (3a) To a solution of 2 (0.58g) and 2-aminothiazol- acid as a colorless powder. 88% yield; H-NMR (CDCl3) δ:
4-ylacetic acid (0.26g) in N,N-dimethylformamide (20mL) 1.25–1.50 (14H, m), 1.60–1.70 (1H, m), 1.75–1.85 (2H, m),
were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide 2.00–2.20 (2H, m), 2.70–2.90 (2H, m), 3.20–3.50 (5H, m), 3.65
hydrochloride (0.35g) and 1-hydroxybenzotriazole (0.28g), (2H, s), 3.80–4.00 (2H, m), 4.05–4.15 (1H, m), 6.34 (1H, s),
and the mixture was stirred at room temperature for 17h. The 6.80–7.90 (9H, m), 9.30 (1H, brs); MS (FAB) m/z: 609 (MH+).
resulting mixture was concentrated in vacuo and diluted with
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-[2-(4-
ethyl acetate and water. The organic layer was washed with {[2-(2-phenylaminothiazol-4-yl)acetyl]amino}phenyl)ethyl]-
brine, and then dried and concentrated in vacuo. The residue carbamate (3g) The title compound was prepared in the
was purified using column chromatography on silica gel with same manner as described for 3a using 2-phenylaminothiazol-
CHCl3/MeOH (30:1) as the eluent to yield 3a (0.40g) as a 4-ylacetic acid instead of 2-aminothiazol-4-ylacetic acid as a
1
1
colorless powder. 50% yield; H-NMR (CDCl3) δ: 1.46 (9H, s), colorless powder. 51% yield; H-NMR (CDCl3) δ: 1.49 (9H, s),
1.57 (9H, s), 2.75–2.86 (2H, m), 3.30–3.50 (4H, m), 3.71 (2H, 2.70–2.90 (2H, m), 3.30–3.50 (4H, m), 3.69 (2H, s), 3.80–4.00
s), 3.82–4.00 (2H, m), 4.09 (2H, brs), 6.73 (1H, s), 6.89 (2H, d, (2H, m), 4.11 (1H, brs), 6.44 (1H, s), 6.89 (2H, d, J=8.0Hz),
J=7.6Hz), 6.96 (1H, t, J=7.2Hz), 7.03–7.15 (2H, m), 7.29 (2H, 6.95 (1H, t, J=7.2Hz), 7.02–7.14 (3H, m), 7.24–7.32 (2H, m),
d, J=7.6Hz), 7.41 (2H, d, J=7.6Hz), 8.64 (1H, brs); MS (FAB) 7.37–7.44 (6H, m), 9.13 (1H, brs); MS (FAB) m/z: 603 (MH+).
m/z: 527 (MH+).
tert-Butyl
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4-
(S)-N-[2-(4-{[2-(2-Acetylaminothiazol-4-yl)- ({2-[2-(2-pyridylamino)thiazol-4-yl]acetyl}amino)phenyl]-
acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxy- ethyl}carbamate (3h) The title compound was prepared in
propyl)carbamate (3b) The title compound was prepared in the same manner as described for 3a using 2-(2-pyridylamino)-
the same manner as described for 3a using 2-acetylaminothi- thiazol-4-ylacetic acid instead of 2-aminothiazol-4-ylacetic
azol-4-ylacetic acid instead of 2-aminothiazol-4-ylacetic acid acid as a colorless powder. 44% yield; 1H-NMR (CDCl3)
1
as a colorless powder. 98% yield; H-NMR (CDCl3) δ: 1.45 δ: 1.45 (9H, s), 2.70–2.87 (2H, m), 3.30–3.52 (4H, m), 3.73
(9H, s), 2.29 (3H, s), 2.70–2.85 (2H, m), 3.30–3.52 (4H, m), (2H, s), 3.80–4.20 (3H, m), 6.63 (1H, s), 6.86–6.98 (6H, m),
3.72 (2H, s), 3.80–4.00 (2H, m), 4.05–4.15 (1H, m), 6.78 (1H, 7.02–7.13 (2H, m), 7.24–7.30 (1H, m), 7.43 (2H, d, J=8.4Hz),
s), 6.87–6.89 (2H, m), 6.96 (1H, t, J=7.6Hz), 7.02–7.12 (2H, 7.61–7.67 (1H, m), 8.33–8.42 (2H, m), 8.88 (1H, brs); MS
m), 7.27–7.30 (2H, m), 7.39–7.42 (2H, m), 8.51 (1H, brs); MS (FAB) m/z: 604 (MH+).
(FAB) m/z: 569 (MH+).
tert-Butyl
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-[2-(4- [4-({2-[2-(3-pyridylamino)thiazol-4-yl]acetyl}amino)-
{[2-(2-methanesulfonylaminothiazol-4-yl)acetyl]amino}- phenyl]ethyl}carbamate (3i) To solution of methyl
(S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-
a

May 2012
653
2-(3-pyridylamino)thiazol-4-ylacetate hydrochloride (13i) phenoxypropyl)amino]ethyl}acetanilide
Dihydrochloride
(1.52g) in methanol (10mL) were added 1M NaOH aqueous (4a) To a solution of 3a (0.38g) in methanol (20mL) was
solution (12mL), and the mixture was stirred at reflux for added 4M HCl–EtOAc (10mL), and the mixture was stirred at
2h. The resultant mixture was cooled in ice-water bath, and room temperature for 2h. The resulting mixture was concen-
neutralized by addition of 1M HCl aqueous solution (6mL). trated in vacuo. The crude solid was purified by recrystalliza-
The solvent was concentrated in vacuo, and diluted with tion from ethanol–ethyl acetate to yield 4a (0.25g) as a color-
1
°
water (10mL). The precipitate was removed by filtration, less solid. 70% yield; mp 167–170 C (EtOH–EtOAc); H-NMR
washed with water and diethyl ether, and dried to yield the (DMSO-d6) δ: 2.70–3.50 (6H, m), 3.65 (2H, s), 3.94–4.01 (2H,
corresponding acid (0.91g) as a colorless powder, which was m), 4.23–4.25 (1H, m), 5.91 (1H, brs), 6.56 (1H, s), 6.94–6.97
used in next step. The title compound was prepared in the (3H, m), 7.20 (2H, d, J=8.0Hz), 7.28–7.32 (2H, m), 7.58 (2H,
same manner as described for 3a using above acid instead d, J=8.0Hz), 8.35 (1H, brs), 8.91 (1H, brs), 9.16 (1H, brs),
of 2-aminothiazol-4-ylacetic acid as a colorless powder. 90% 10.38 (1H, s); MS (FAB) m/z: 427 (MH+); Anal. Calcd for
1
yield; H-NMR (CDCl3) δ: 1.46 (9H, s), 2.75–2.85 (2H, m), C22H26N4O3S·2HCl·0.5H2O: C, 51.97; H, 5.75; N, 11.02; S,
3.35–3.45 (4H, m), 3.62 (2H, s), 3.88–3.96 (2H, m), 4.11 (1H, 6.31; Cl, 13.95. Found: C, 51.61; H, 5.53; N, 10.72; S, 5.93; Cl,
brs), 4.68–4.69 (2H, m), 6.31 (1H, s), 6.48 (1H, brs), 6.88–7.06 14.35.
(4H, m), 7.19–7.39 (6H, m), 7.66–7.71 (1H, m), 8.59–8.60 (1H,
(S)-2-(2-Acetylaminothiazol-4-yl)-4′-{2-[(2-hydroxy-3-
phenoxypropyl)amino]ethyl}acetanilide Hydrochloride (4b)
m), 9.32 (1H, brs); MS (FAB) m/z: 604 (MH+).
tert-Butyl
(S)-N-[2-(4-{[2-(2-Benzylaminothiazol-4- The title compound was prepared in the same manner as
yl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-3-phenoxy- described for 4a using 3b instead of 3a as a colorless powder.
propyl)carbamate (3j) The title compound was prepared 49% yield; 1H-NMR (DMSO-d6) δ: 2.11 (3H, s), 2.90–3.23
in the same manner as described for 3a using 2-benzylami- (6H, m), 3.69 (2H, s), 3.94–4.02 (2H, m), 4.22–4.27 (1H, m),
nothiazol-4-ylacetic acid instead of 2-aminothiazol-4-ylacetic 5.00 (1H, brs), 6.93–6.97 (4H, m), 7.18 (2H, d, J=8.4Hz), 7.30
1
acid as a colorless powder. 58% yield; H-NMR (DMSO-d6) δ: (2H, d, J=8.0Hz), 7.59 (2H, t, J=8.4Hz), 8.92 (1H, brs), 9.18
1.36 (9H, s), 2.70–2.75 (2H, m), 3.29–3.38 (4H, m), 3.48 (2H, (1H, brs), 10.26 (1H, s), 12.11 (1H, s); MS (FAB) m/z: 469
s), 3.82–4.84 (2H, m), 3.96 (1H, brs), 4.41 (2H, d, J=6.0Hz), (MH+); Anal. Calcd for C24H28N4O4S·1.3HCl·H2O: C, 53.98;
5.13 (1H, brs), 6.36 (1H, s), 6.89–6.94 (3H, m), 7.08 (2H, d, H, 5.91; N, 10.49; S, 6.00; Cl, 8.63. Found: C, 54.05; H, 5.70;
J=7.8Hz), 7.23–7.35 (7H, m), 7.46 (2H, d, J=8.4Hz), 8.04– N, 10.56; S, 6.06; Cl, 8.72.
8.07 (1H, m), 9.97 (1H, s); MS (FAB) m/z: 617 (MH+).
tert-Butyl
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2- (2-methanesulfonylaminothiazol-4-yl)acetanilide Hydro-
[4-({2-[2-(2-phenylethylamino)thiazol-4-yl]acetyl}amino)- chloride (4c) The title compound was prepared in the
phenyl]ethyl}carbamate (3k) The title compound was same manner as described for 4a using 3c instead of 3a as a
°
prepared in the same manner as described for 3a using colorless solid. 57% yield; mp 249–254 C (decomp.) (MeOH–
1
2-(2-phenylethylamino)thiazol-4-ylacetic acid instead of EtOAc); H-NMR (DMSO-d6) δ: 2.89 (3H, s), 2.92–3.24 (6H,
2-aminothiazol-4-ylacetic acid as a colorless powder. 86% m), 3.33 (2H, s), 3.65 (2H, s), 3.93–4.01 (2H, m), 4.21–4.23
yield; 1H-NMR (DMSO-d6) δ: 1.35 (9H, s), 2.72 (2H, t, (1H, m), 5.90 (1H, d, J=4.8Hz), 6.58 (1H, s), 6.94–6.97 (3H,
J=7.0Hz), 2.84 (2H, t, J=7.0Hz), 3.30–3.45 (6H, m), 3.49 (2H, m), 7.20 (2H, d, J=8.4Hz), 7.31 (2H, t, J=8.0Hz), 7.57 (2H,
s), 3.78–4.00 (3H, m), 6.35 (1H, s), 6.88–7.30 (11H, m), 7.51 d, J=8.4Hz), 8.84 (1H, brs), 9.03 (1H, brs), 10.34 (1H, s),
(2H, d, J=8.0Hz), 7.64 (1H, t, J=6.0Hz); MS (FAB) m/z: 631 12.54 (1H, s); MS (FAB) m/z: 505 (MH+); Anal. Calcd for
(MH+).
tert-Butyl
C23H28N4O5S2·HCl·0.2H2O: C, 50.72; H, 5.44; N, 10.29; S,
(S)-N-{2-[4-({2-[2-(2-Furylmethylamino)- 11.77; Cl, 6.51. Found: C, 50.63; H, 5.29; N, 10.24; S, 11.77;
thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3- Cl, 6.52.
phenoxypropyl)carbamate (3l) The title compound was
prepared in the same manner as described for 3i using phenoxypropyl)amino]ethyl}acetanilide
(S)-2-(2-Guanidinothiazol-4-yl)-4′-{2-[(2-hydroxy-3-
Dihydrochloride
methyl 2-(2-furylmethylamino)thiazol-4-ylacetate hydrochlo- (4d) The title compound was prepared in the same man-
1
ride instead of 13i as a colorless powder. 72% yield; H-NMR ner as described for 4a using 3d instead of 3a as a colorless
(CDCl3) δ: 1.46 (9H, s), 2.66–2.78 (2H, m), 3.30–3.45 (4H, m), powder. 79% yield; 1H-NMR (DMSO-d6) δ: 2.90–3.07 (3H,
3.63 (2H, s), 3.88–3.95 (2H, m), 4.08–4.15 (1H, m), 4.55 (2H, m), 3.14–3.22 (3H, m), 3.94–4.01 (2H, m), 4.22–4.27 (1H, m),
s), 6.30–6.35 (4H, m), 6.82–7.06 (5H, m), 7.22–7.41 (5H, m), 6.93–6.97 (3H, m), 7.12–7.32 (5H, m), 7.59 (2H, d, J=8.6Hz),
9.19 (1H, brs); MS (FAB) m/z: 607 (MH+).
8.38 (4H, brs), 8.92 (1H, brs), 9.18 (1H, brs), 10.41 (1H, s),
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4- 12.60 (1H, brs); MS (FAB) m/z: 469 (MH+); Anal. Calcd for
({2-[2-(2-thenylmethylamino)thiazol-4-yl]acetyl}amino)- C23H28N6O3S·2.1HCl·0.7H2O: C, 49.53; H, 5.69; N, 15.07; S,
phenyl]ethyl}carbamate (3m) The title compound was 5.75; Cl, 13.35. Found: C, 49.40; H, 5.44; N, 15.31; S, 5.92; Cl,
prepared in the same manner as described for 3a using 13.58.
2-(2-thenylmethylamino)thiazol-4-ylacetic acid instead of
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
Dihydrochloride
2-aminothiazol-4-ylacetic acid as a colorless powder. 71% (2-methylaminothiazol-4-yl)acetanilide
1
yield; H-NMR (CDCl3) δ: 1.46 (9H, s), 2.78 (2H, brs), 3.42 (4e) The title compound was prepared in the same manner
(4H, brs), 3.62 (2H, s), 3.88–3.96 (2H, m), 4.11–4.15 (1H, m), as described for 4a using 3e instead of 3a as a colorless solid.
1
°
4.73–4.75 (2H, m), 5.47 (1H, brs), 6.33 (1H, s), 6.85–7.07 (8H, 60% yield; mp 203–204 C (MeOH–EtOH); H-NMR (DMSO-
m), 7.24–7.37 (4H, m), 9.18 (1H, brs); MS (FAB) m/z: 623 d6) δ: 2.95–3.04 (6H, m), 3.14–3.20 (3H, m), 3.70 (2H, s),
(MH+).
3.93–4.01 (2H, m), 4.22–4.25 (1H, m), 6.73 (1H, s), 6.94–6.97
(S)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-3- (3H, m), 7.20 (2H, d, J=8.8Hz), 7.28–7.33 (2H, m), 7.59 (2H,

654
Vol. 60, No. 5
d, J=8.8Hz), 8.90 (1H, brs), 9.14 (1H, brs), 10.49 (1H, s); MS m), 4.22–4.26 (1H, m), 4.65 (2H, brs), 6.73 (1H, s), 6.94–6.97
(FAB) m/z: 441 (MH+); Anal. Calcd for C23H28N4O3S·2HCl: C, (3H, m), 7.20 (2H, d, J=8.8Hz), 7.28–7.43 (7H, m), 7.58 (2H,
53.80; H, 5.89; N, 10.91; S, 6.24; Cl, 13.81. Found: C, 53.56; H, d, J=8.8Hz), 8.94 (1H, brs), 9.22 (1H, brs), 10.25 (1H, brs),
5.76; N, 10.88; S, 6.34; Cl, 13.88.
(S)-2-(2-Cyclohexylaminothiazol-4-yl)-4′-{2-[(2-hydroxy- C29H32N4O3S·2HCl: C, 59.08; H, 5.81; N, 9.50; S, 5.44; Cl,
3-phenoxypropyl)amino]ethyl}acetanilide Hydrochloride 12.03. Found: C, 58.97; H, 5.78; N, 9.38; S, 5.33; Cl, 12.00.
(4f) The title compound was prepared in the same manner as (S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
10.52 (1H, s); MS (FAB) m/z: 517 (MH+); Anal. Calcd for
described for 4a using 3f instead of 3a as a colorless powder. [(2-phenylethylamino)thiazol-4-yl]acetanilide Dihydrochlo-
1
15% yield; H-NMR (DMSO-d6) δ: 1.10–1.40 (5H, m), 1.45– ride (4k) The title compound was prepared in the same
1.70 (3H, m), 1.80–2.00 (2H, m), 2.80–3.55 (9H, m), 3.91–4.03 manner as described for 4a using 3k instead of 3a as a color-
1
°
(2H, m), 4.17–4.28 (1H, m), 5.91 (1H, d, J=4.8Hz), 6.33 (1H, less solid. 71% yield; mp 214–215 C (MeOH–EtOH); H-NMR
s), 6.80–7.00 (3H, m), 7.10–7.70 (6H, m), 8.88 (1H, brs), 9.10 (DMSO-d6) δ: 2.91–3.06 (5H, m), 3.13–3.19 (3H, m), 3.65 (2H,
(1H, brs), 10.15 (1H, brs); MS (FAB) m/z: 509 (MH+); Anal. brs), 3.77 (2H, s), 3.94–4.01 (2H, m), 4.22–4.26 (1H, m), 6.72
Calcd for C28H36N4O3S·1.2HCl·0.5H2O: C, 59.90; H, 6.86; N, (1H, s), 6.93–6.97 (3H, m), 7.19–7.35 (9H, m), 7.59 (2H, d,
9.98; S, 5.71; Cl, 7.58. Found: C, 59.60; H, 6.83; N, 10.36; S, J=8.8Hz), 8.93 (1H, brs), 9.19 (1H, brs), 10.53 (1H, s); MS
5.64; Cl, 7.22.
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- 59.70; H, 6.01; N, 9.28; S, 5.31; Cl, 11.75. Found: C, 59.91; H,
(2-phenylaminothiazol-4-yl)acetanilide Dihydrochloride 6.01; N, 9.30; S, 5.31; Cl, 11.91.
(4g) The title compound was prepared in the same man- (S)-2-[(2-Furylmethylamino)thiazol-4-yl]-4′-{2-[(2-
(FAB) m/z: 531 (MH+); Anal. Calcd for C30H34N4O3S·2HCl: C,
ner as described for 4a using 3g instead of 3a as a color- hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide
Dihy-
less powder. 33% yield; 1H-NMR (DMSO-d6) δ: 2.93–3.04 drochloride (4l) The title compound was prepared in the
(3H, m), 3.15–3.20 (3H, m), 3.66 (2H, s), 3.93–4.01 (2H, m), same manner as described for 4a using 3l instead of 3a as
°
4.20–4.27 (1H, m), 6.68 (1H, s), 6.94–6.98 (4H, m), 7.20 (2H, a colorless solid. 60% yield; mp 184–189 C (EtOH–EtOAc);
d, J=8.8Hz), 7.26–7.61 (4H, m), 8.87 (1H, brs), 9.08 (1H, brs), 1H-NMR (DMSO-d6) δ: 2.94–3.05 (3H, m), 3.14–3.18 (3H, m),
10.25 (1H, s), 10.45 (1H, brs); MS (FAB) m/z: 503 (MH+); 3.72 (2H, s), 3.93–4.01 (2H, m), 4.21–4.23 (1H, m), 4.61 (2H,
Anal. Calcd for C28H30N4O3S·1.9HCl·0.7H2O: C, 57.54; H, s), 6.42–6.47 (2H, m), 6.69 (1H, s), 6.94–6.97 (3H, m), 7.20
5.74; N, 9.59; S, 5.49; Cl, 11.52. Found: C, 57.60; H, 5.78; N, (2H, d, J=8.8Hz), 7.28–7.33 (2H, m), 7.58 (2H, d, J=8.4Hz),
9.41; S, 5.13; Cl, 11.57.
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- (FAB) m/z: 507 (MH+); Anal. Calcd for C27H30N4O4S·2HCl: C,
[(2-pyridylamino)thiazol-4-yl]acetanilide Hydrochloride 55.96; H, 5.57; N, 9.67; S, 5.53; Cl, 12.23. Found: C, 55.72; H,
(4h) The title compound was prepared in the same manner as 5.35; N, 9.68; S, 5.45; Cl, 11.95.
7.65 (1H, s), 8.84 (1H, brs), 9.04 (1H, brs), 10.38 (1H, s); MS
described for 4a using 3h instead of 3a as a colorless powder.
20% yield; H-NMR (DMSO-d6) δ: 2.90–3.10 (3H, m), 3.10– [(2-thenylmethylamino)thiazol-4-yl]acetanilide
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
1
Dihydro-
3.25 (3H, m), 3.66 (2H, s), 3.93–4.02 (2H, m), 4.17–4.26 (1H, chloride (4m) The title compound was prepared in the same
m), 5.90 (1H, brs), 6.75 (1H, s), 6.89–7.03 (4H, m), 7.20 (2H, manner as described for 4a using 3m instead of 3a as a color-
°
d, J=8.0Hz), 7.31 (2H, t, J=7.6Hz), 7.60 (2H, d, J=8.8Hz), less solid. 77% yield; mp 204–207 C (MeOH–EtOH–EtOAc);
7.68 (1H, t, J=7.2Hz), 8.28 (1H, d, J=7.2Hz), 8.80 (1H, brs), 1H-NMR (DMSO-d6) δ: 2.95–3.07 (3H, m), 3.14–3.20 (3H, m),
8.96 (1H, brs), 10.19 (1H, s), 11.29 (1H, s); MS (FAB) m/z: 3.77 (2H, s), 3.94–4.02 (2H, m), 4.23–4.26 (1H, m), 4.84 (2H,
504 (MH+); Anal. Calcd for C27H29N5O3S·1.1HCl·0.5H2O: C, s), 6.74 (1H, s), 6.93–7.01 (4H, m), 7.19–7.21 (3H, m), 7.28–7.32
58.67; H, 5.67; N, 12.67; S, 5.80; Cl, 7.06. Found: C, 58.46; H, (2H, m), 7.49–7.51 (1H, m), 7.57–7.60 (2H, m), 8.95 (1H, brs),
5.51; N, 12.73; S, 5.80; Cl, 6.92.
9.22 (1H, brs), 10.11 (1H, brs), 10.50 (1H, s); MS (FAB) m/z:
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- 523 (MH+); Anal. Calcd for C27H30N4O3S2·2HCl: C, 54.45; H,
[(3-pyridylamino)thiazol-4-yl]acetanilide Dihydrochloride 5.42; N, 9.41; S, 10.77; Cl, 11.90. Found: C, 54.22; H, 5.22; N,
(4i) The title compound was prepared in the same manner 9.39; S, 10.77; Cl, 11.87.
as described for 4a using 3i instead of 3a as a colorless solid.
tert-Butyl
(S)-N-{2-[4-({2-[2-(2-Chlorophenylamino)-
51% yield; mp 232–234 C (MeOH–EtOH–EtOAc); 1H-NMR thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3-
(DMSO-d6) δ: 2.95–3.04 (3H, m), 3.13–3.19 (3H, m), 3.75 (2H, phenoxypropyl)carbamate (5a) The title compound was
s), 3.94–4.04 (2H, m), 4.23–4.27 (1H, m), 6.92–7.00 (4H, m), prepared in the same manner as described for 3a using
7.20 (2H, d, J=8.0Hz), 7.24–7.32 (2H, m), 7.62–7.68 (2H, m), 2-(2-chlorophenylamino)thiazol-4-ylacetic acid instead of
7.94–7.98 (1H, m), 8.45 (1H, d, J=5.2Hz), 8.63–8.66 (1H, m), 2-aminothiazol-4-ylacetic acid as a colorless powder. 55%
°
1
8.98 (1H, brs), 9.27 (1H, brs), 9.38 (1H, d, J=2.0Hz), 10.40 yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.65–2.80 (2H, m),
(1H, s), 11.94 (1H, brs); MS (FAB) m/z: 504 (MH+); Anal. 3.28–3.50 (4H, m), 3.72 (2H, s), 3.80–3.95 (2H, m), 4.10 (1H,
Calcd for C27H29N5O3S·2HCl·0.1H2O: C, 56.07; H, 5.44; N, brs), 6.54 (1H, brs), 6.83–7.50 (12H, m), 8.12–8.18 (1H, m),
12.11; S, 5.54; Cl, 12.26. Found: C, 55.79; H, 5.25; N, 12.02; S, 8.99 (1H, s); MS (FAB) m/z: 637 (MH+).
5.58; Cl, 12.56.
(S)-2-(2-Benzylaminothiazol-4-yl)-4′-{2-[(2-hydroxy-3- ({2-[2-(2-methoxyphenylamino)thiazol-4-yl]acetyl}amino)-
phenoxypropyl)amino]ethyl}acetanilide Dihydrochloride phenyl]ethyl}carbamate (5b) The title compound was
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4-
(4j) The title compound was prepared in the same manner prepared in the same manner as described for 3a using
as described for 4a using 3j instead of 3a as a colorless solid. 2-(2-methoxyphenylamino)thiazol-4-ylacetic acid instead of
1
°
62% yield; mp 193–196 C (MeOH–EtOAc); H-NMR (DMSO- 2-aminothiazol-4-ylacetic acid as a colorless powder. 33%
1
d6) δ: 2.95–3.07 (3H, m), 3.14–3.22 (3H, m), 3.94–4.02 (2H, yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.70–2.82 (2H, m),

May 2012
655
1
3.32–3.50 (4H, m), 3.75 (2H, s), 3.82–3.90 (2H, m), 3.92 (3H, yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.75–2.85 (2H, m),
s), 4.07–4.15 (1H, m), 6.44 (1H, s), 6.77–7.90 (13H, m), 9.24 3.35–3.46 (4H, m), 3.72 (2H, s), 3.80–4.00 (2H, m), 4.10 (1H,
(1H, brs); MS (FAB) m/z: 633 (MH+).
tert-Butyl
t, J=5.5Hz), 6.50 (1H, s), 6.80–7.80 (13H, m), 8.95 (1H, brs);
(S)-N-{2-[4-({2-[2-(3-Fluorophenylamino)- MS (FAB) m/z: 637 (MH+).
thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3-
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4-
phenoxypropyl)carbamate (5c) The title compound was ({2-[2-(4-trifluoromethylphenylamino)thiazol-4-yl]acetyl}-
prepared in the same manner as described for 3a using amino)phenyl]ethyl}carbamate (5i) The title compound
2-(3-fluorophenylamino)thiazol-4-ylacetic acid instead of was prepared in the same manner as described for 3a using
2-aminothiazol-4-ylacetic acid as a colorless powder. 27% 2-(4-trifluoromethylphenylamino)- thiazol-4-ylacetic acid in-
1
yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.71–2.82 (2H, m), stead of 2-aminothiazol-4-ylacetic acid as a colorless pow-
1
3.34–3.48 (4H, m), 3.68 (2H, s), 3.83–3.97 (2H, m), 4.07–4.16 der. 98% yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.71–2.85
(1H, m), 6.42 (1H, s), 6.65–7.45 (13H, m), 9.13 (1H, brs); MS (2H, m), 3.31–3.51 (4H, m), 3.72 (2H, s), 3.81–3.99 (2H, m),
(FAB) m/z: 621 (MH+).
tert-Butyl
thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3- s), 8.08 (1H, brs), 9.03 (1H, brs); MS (FAB) m/z: 671 (MH+).
phenoxypropyl)carbamate (5d) The title compound was tert-Butyl (S)-N-{2-[4-({2-[2-(4-Cyanophenylamino)-
4.25 (1H, brs), 6.50 (1H, s), 6.83–6.98 (3H, m), 7.04 (2H, d,
(S)-N-{2-[4-({2-[2-(3-Chlorophenylamino)- J=8.4Hz), 7.22–7.29 (2H, m), 7.39 (2H, d, J=8.1Hz), 7.57 (4H,
prepared in the same manner as described for 3a using thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3-
2-(3-chlorophenylamino)thiazol-4-ylacetic acid instead of phenoxypropyl)carbamate (5j) The title compound was
2-aminothiazol-4-ylacetic acid as a colorless powder. 27% prepared in the same manner as described for 3a using
1
yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.72–2.84 (2H, m), 2-(4-cyanophenylamino)thiazol-4-ylacetic acid instead of
3.30–3.50 (4H, m), 3.70 (2H, s), 3.82–3.99 (2H, m), 4.05–4.16 2-aminothiazol-4-ylacetic acid as a colorless powder. 76%
1
(1H, m), 6.47 (1H, s), 6.85–7.43 (12H, m), 7.58 (1H, s), 8.02 yield; H-NMR (CDCl3) δ: 1.46 (9H, s), 2.70–2.90 (2H, m),
(1H, brs), 9.11 (1H, brs); MS (FAB) m/z: 637 (MH+).
3.20–3.50 (4H, m), 3.74 (2H, s), 3.80–4.00 (2H, m), 4.03–4.15
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4- (1H, m), 6.61 (1H, s), 6.80–7.70 (13H, m), 8.68 (1H, brs); MS
({2-[2-(3-trifluoromethylphenylamino)thiazol-4-yl]acetyl}- (FAB) m/z: 628 (MH+).
amino)phenyl]ethyl}carbamate (5e) The title compound
tert-Butyl
(S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-
was prepared in the same manner as described for 3a using [4-({2-[2-(4-nitrophenylamino)thiazol-4-yl]acetyl}amino)-
2-(3-trifluoromethylphenylamino)thiazol-4-ylacetic acid in- phenyl]ethyl}carbamate (5k) The title compound was
stead of 2-aminothiazol-4-ylacetic acid as a colorless powder. prepared in the same manner as described for 3a using
1
83% yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.62–2.88 (2H, 2-(4-nitrophenylamino)thiazol-4-ylacetic acid instead of
m), 3.28–3.52 (4H, m), 3.71 (2H, s), 3.80–4.00 (2H, m), 4.03– 2-aminothiazol-4-ylacetic acid as a colorless powder. 38%
1
4.15 (1H, m), 6.51 (1H, s), 6.80–7.10 (5H, m), 7.20–7.76 (8H, yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.70–2.90 (2H, m),
m), 8.86 (1H, brs); MS (FAB) m/z: 671 (MH+).
3.34–3.51 (4H, m), 3.75 (2H, s), 3.88–4.15 (3H, m), 6.59 (1H,
(S)-N-{2-[4-({2-[2-(3-Cyanophenylamino)- s), 6.86 (2H, d, J=8.1Hz), 6.90–7.09 (3H, m), 7.20–7.44 (4H,
tert-Butyl
thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3- m), 7.60 (2H, d, J=9.2Hz), 8.13 (2H, d, J=9.2Hz), 8.77 (1H,
phenoxypropyl)carbamate (5f) The title compound was brs); MS (FAB) m/z: 648 (MH+).
prepared in the same manner as described for 3a using
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4-
2-(3-cyanophenylamino)thiazol-4-ylacetic acid instead of ({2-[2-(4-methoxyphenylamino)thiazol-4-yl]acetyl}amino)-
2-aminothiazol-4-ylacetic acid as a colorless powder. 97% phenyl]ethyl}carbamate (5l) The title compound was
1
yield; H-NMR (CDCl3) δ: 1.45 (9H, s), 2.73–2.85 (2H, m), prepared in the same manner as described for 3a using
3.35–3.46 (4H, m), 3.73 (2H, s), 3.82–3.95 (2H, m), 4.05–4.16 2-(4-methoxyphenylamino)thiazol-4-ylacetic acid instead of
(1H, m), 6.54 (1H, s), 6.80–7.84 (13H, m), 8.76 (1H, s); MS 2-aminothiazol-4-ylacetic acid as a colorless powder. 27%
1
(FAB) m/z: 628 (MH+).
yield; H-NMR (CDCl3) δ: 1.46 (9H, s), 2.73–2.84 (2H, m),
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4- 3.32–3.49 (4H, m), 3.65 (2H, s), 3.82 (3H, s), 3.83–3.98 (2H,
({2-[2-(3-methoxyphenylamino)thiazol-4-yl]acetyl}amino)- m), 4.05–4.14 (1H, m), 6.35 (1H, s), 6.85–7.44 (13H, m), 9.17
phenyl]ethyl}carbamate (5g) The title compound was (1H, s); MS (FAB) m/z: 633 (MH+).
prepared in the same manner as described for 3a using
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[4-
2-(3-methoxyphenylamino)thiazol-4-ylacetic acid instead of ({2-[2-(4-isopropylphenylamino)thiazol-4-yl]acetyl}amino)-
2-aminothiazol-4-ylacetic acid as a colorless powder. 66% phenyl]ethyl}carbamate (5m) The title compound was
1
yield; H-NMR (CDCl3) δ: 1.46 (9H, s), 2.70–2.88 (2H, m), prepared in the same manner as described for 3a using
3.30–3.52 (4H, m), 3.69 (2H, s), 3.82–4.00 (2H, m), 3.82 2-(4-isopropylphenylamino)thiazol-4-ylacetic acid instead of
(3H, s), 4.05–4.17 (1H, m), 6.45 (1H, s), 6.67 (1H, dd, J=4.8, 2-aminothiazol-4-ylacetic acid as a colorless powder. 20%
1
8.0Hz), 6.89 (2H, d, J=8.4Hz), 6.94–6.96 (2H, m), 7.02–7.12 yield; H-NMR (CDCl3) δ: 1.27 (6H, d, J=6.8Hz), 1.46 (9H,
(3H, m), 7.21–7.30 (3H, m), 7.43 (2H, d, J=8.4Hz), 9.08 (1H, s), 2.78 (2H, brs), 2.88–2.96 (1H, m), 3.43 (4H, brs), 3.68 (2H,
s); MS (FAB) m/z: 633 (MH+).
s), 3.88–3.95 (2H, m), 4.11 (1H, brs), 6.41 (1H, s), 6.79–6.97
(S)-N-{2-[4-({2-[2-(4-Chlorophenylamino)- (3H, m), 7.04–7.13 (3H, m), 7.23–7.34 (5H, m), 7.42 (2H, d,
thiazol-4-yl]acetyl}amino)phenyl]ethyl}-N-(2-hydroxy-3- J=8.4Hz), 9.17 (1H, brs); MS (FAB) m/z: 645 (MH+).
phenoxypropyl)carbamate (5h) The title compound was (S)-2-[(2-Chlorophenylamino)thiazol-4-yl]-4′-{2-[(2-
tert-Butyl
prepared in the same manner as described for 3a using hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide Hydro-
2-(4-chlorophenylamino)thiazol-4-ylacetic acid instead of chloride (6a) The title compound was prepared in the
2-aminothiazol-4-ylacetic acid as a colorless powder. 40% same manner as described for 4a using 5a instead of 3a

656
Vol. 60, No. 5
as a colorless powder. 20% yield; 1H-NMR (DMSO-d6) δ: Dihydrochloride (6f) The title compound was prepared in
2.88–3.30 (6H, m), 3.62 (2H, s), 3.93–4.01 (2H, m), 5.89 the same manner as described for 4a using 5f instead of 3a as
°
(1H, d, J=5.4Hz), 6.70 (1H, s), 6.93–7.05 (4H, m), 7.16–7.59 a colorless solid. 46% yield; mp 166–171 C (MeOH–EtOH);
(8H, m), 8.25–8.30 (1H, m), 8.60–8.90 (2H, m), 9.56 (1H, s), 1H-NMR (DMSO-d6) δ: 2.94–3.05 (3H, m), 3.15–3.20 (3H, m),
10.15 (1H, s); MS (FAB) m/z: 537 (MH+); Anal. Calcd for 3.68 (2H, s), 3.93–4.01 (2H, m), 4.21–4.23 (1H, m), 6.76 (1H,
C28H29N4O3S·1.1HCl: C, 58.27; H, 5.26; N, 9.71; S, 5.56; Cl, s), 6.94–7.97 (3H, m), 7.19 (2H, d, J=8.4Hz), 7.28–7.36 (3H,
12.90. Found: C, 57.97; H, 5.19; N, 9.77; S, 5.45; Cl, 12.73.
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- m), 8.25–8.26 (1H, m), 8.84 (1H, brs), 9.04 (1H, brs), 10.26
[(2-methoxyphenylamino)thiazol-4-yl]acetanilide
Hydro- (1H, s), 10.75 (1H, brs); MS (FAB) m/z: 528 (MH+); Anal.
m), 7.44–7.49 (1H, m), 7.61 (2H, d, J=8.4Hz), 7.78–7.81 (1H,
chloride (6b) The title compound was prepared in the Calcd for C29H29N5O3S·2HCl: C, 58.00; H, 5.20; N, 11.66; S,
same manner as described for 4a using 5b instead of 3a 5.34; Cl, 11.81. Found: C, 57.82; H, 5.37; N, 11.60; S, 5.30; Cl,
as a colorless powder. 40% yield; 1H-NMR (DMSO-d6) δ: 11.62.
2.88–2.98 (2H, m), 2.99–3.08 (1H, m), 3.11–3.25 (2H, m),
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
3.61 (2H, s), 3.85 (3H, s), 3.92–4.01 (2H, m), 4.16–4.25 (1H, [(3-methoxyphenylamino)thiazol-4-yl]acetanilide Dihydro-
m), 5.89 (1H, brs), 6.60 (1H, s), 6.81–7.03 (6H, m), 7.20 (2H, chloride (6g) The title compound was prepared in the
d, J=8.6Hz), 7.27–7.34 (2H, m), 7.58 (2H, d, J=8.0Hz), 8.29 same manner as described for 4a using 5g instead of 3a
(1H, d, J=8.0Hz), 8.75 (1H, brs), 8.86 (1H, brs), 9.45 (1H, as a colorless powder. 42% yield; 1H-NMR (DMSO-d6) δ:
brs), 10.18 (1H, s); MS (FAB) m/z: 533 (MH+); Anal. Calcd for 2.93–3.10 (3H, m), 3.10–3.26 (3H, m), 3.66 (2H, s), 3.67 (3H,
C29H32N4O4S·HCl·1.1H2O: C, 59.14; H, 6.02; N, 9.51; S, 5.44; s), 3.94–4.01 (2H, m), 4.22–4.24 (1H, m), 5.71 (1H, brs),
Cl, 6.02. Found: C, 58.91; H, 5.71; N, 9.52; S, 5.38; Cl, 5.77.
6.53 (1H, dd, J=8.0, 2.0Hz), 6.68 (1H, s), 6.94–6.97 (3H, m),
(S)-2-[(3-Fluorophenylamino)thiazol-4-yl]-4′-{2- 7.03–7.06 (1H, m), 7.15–7.21 (3H, m), 7.28–7.40 (3H, m), 7.59
[(2-hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide (2H, d, J=8.8Hz), 8.87 (1H, brs), 9.09 (1H, brs), 10.26 (1H,
Dihydrochloride (6c) The title compound was prepared in s), 10.42 (1H, brs); MS (FAB) m/z: 533 (MH+); Anal. Calcd
the same manner as described for 4a using 5c instead of 3a for C29H32N4O4S·1.9HCl·0.6H2O: C, 56.85; H, 5.77; N, 9.14; S,
as a colorless powder. 44% yield; 1H-NMR (DMSO-d6) δ: 5.23; Cl, 10.99. Found: C, 57.16; H, 5.96; N, 8.94; S, 5.01; Cl,
2.96–3.30 (6H, m), 3.65 (2H, s), 3.92–4.01 (2H, m), 4.12–4.23 10.64.
(1H, m), 5.84–5.92 (1H, m), 6.72 (1H, s), 6.91–6.98 (4H,
(S)-2-[(4-Chlorophenylamino)thiazol-4-yl]-4′-{2-[(2-
m), 7.19 (2H, d, J=8.8Hz), 7.24–7.45 (4H, m), 7.59 (2H, d, hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide Hydro-
J=8.3Hz), 7.90 (1H, t, J=2.0Hz), 8.60–8.80 (2H, m), 10.18 chloride (6h) The title compound was prepared in the
(1H, s), 10.40 (1H, s); MS (FAB) m/z: 521 (MH+); Anal. Calcd same manner as described for 4a using 5h instead of 3a as
°
for C28H29N4O3FS·1.8HCl·0.5H2O: C, 56.50; H, 5.38; N, 9.41; a colorless solid. 36% yield; mp 223–228 C (MeOH–EtOAc);
F, 3.19; S, 5.39; Cl, 10.72. Found: C, 56.24; H, 5.38; N, 9.29; F, 1H-NMR (DMSO-d6) δ: 2.86–3.24 (6H, m), 3.64 (2H, s), 3.92–
2.97; S, 5.14; Cl, 10.74.
4.01 (2H, m), 4.13–4.22 (1H, m), 5.88 (1H, d, J=5.4Hz), 6.68
(S)-2-[(3-Chlorophenylamino)thiazol-4-yl]-4′-{2-[(2- (1H, s), 6.93–6.99 (3H, m), 7.20 (2H, d, J=8.0Hz), 7.26–7.34
hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide Hydro- (4H, m), 7.58 (2H, d, J=8.6Hz), 7.65 (2H, d, J=9.1Hz), 8.69
chloride (6d) The title compound was prepared in the same (1H, brs), 10.16 (1H, s), 10.33 (1H, s); MS (FAB) m/z: 537
manner as described for 4a using 5d instead of 3a as a color- (MH+); Anal. Calcd for C28H29N4O3ClS·HCl·0.15H2O: C,
less powder. 38% yield; 1H-NMR (DMSO-d6) δ: 2.88–3.23 58.30; H, 5.30; N, 9.72; S, 5.56; Cl, 12.31. Found: C, 58.03; H,
(6H, m), 3.64 (2H, s), 3.90–4.01 (2H, m), 4.16–4.26 (1H, m), 4.90; N, 9.77; S, 5.52; Cl, 12.39.
6.68–6.75 (2H, m), 6.93–6.98 (3H, m), 7.17–7.35 (6H, m), 7.59
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(2H, d, J=8.3Hz), 7.75 (1H, dt, J=2.4, 12.2Hz), 8.77 (1H, brs), [(4-trifluoromethylphenylamino)thiazol-4-yl]acetanilide Di-
8.91 (1H, brs), 10.21 (1H, s), 10.49 (1H, s); MS (FAB) m/z: 537 hydrochloride (6i) The title compound was prepared in the
(MH+); Anal. Calcd for C28H29N4O3ClS·1.1HCl·1.5H2O: C, same manner as described for 4a using 5i instead of 3a as
°
55.66; H, 5.52; N, 9.27; S, 5.31; Cl, 12.32. Found: C, 55.54; H, a colorless solid. 83% yield; mp 195–197 C (EtOH–EtOAc);
5.44; N, 9.35; S, 5.25; Cl, 12.09.
1H-NMR (DMSO-d6) δ: 2.88–3.05 (3H, m), 3.14–3.20 (3H, m),
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- 3.77 (2H, s), 3.93–4.01 (2H, m), 4.22 (1H, brs), 5.32 (2H, s),
[(3-trifluoromethylphenylamino)thiazol-4-yl]acetanilide Di- 5.90 (1H, brs), 6.73 (1H, d, J=8.3Hz), 6.94–7.00 (4H, m), 7.20
hydrochloride (6e) The title compound was prepared in the (2H, d, J=8.8Hz), 7.26–7.33 (5H, m), 7.42–7.45 (2H, m), 7.60
same manner as described for 4a using 5e instead of 3a as (2H, d, J=8.3Hz), 7.65–7.70 (1H, m), 8.83 (1H, brs), 9.02 (1H,
a colorless solid. 68% yield; mp 161–163 C (EtOH–EtOAc); brs), 10.28 (1H, s); MS (FAB) m/z: 571 (MH+); Anal. Calcd for
°
1H-NMR (DMSO-d6) δ: 2.93–3.07 (3H, m), 3.14–3.23 (3H, C29H29N4O3F3S·2HCl: C, 54.12; H, 4.86; N, 8.71; F, 8.86; S,
m), 3.68 (2H, s), 3.93–4.01 (2H, m), 4.22–4.25 (1H, m), 6.75 4.98; Cl, 11.02. Found: C, 53.90; H, 4.83; N, 8.62; F, 9.06; S,
(1H, s), 6.93–6.97 (3H, m), 7.20 (2H, d, J=8.0Hz), 7.23–7.33 5.00; Cl, 10.94.
(3H, m), 7.46–7.51 (1H, m), 7.59 (2H, d, J=8.4Hz), 7.86 (1H,
(S)-2-[(4-Cyanophenylamino)thiazol-4-yl]-4′-{2-
d, J=9.2Hz), 8.12 (1H, s), 8.90 (1H, brs), 9.15 (1H, brs), 10.26 [(2-hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide
(1H, s), 10.77 (1H, brs); MS (FAB) m/z: 571 (MH+); Anal. Dihydrochloride (6j) The title compound was prepared
Calcd for C29H29N4O3F3S·2HCl: C, 54.12; H, 4.86; N, 8.71; F, in the same manner as described for 4a using 5j instead of
°
8.86; S, 4.98; Cl, 11.02. Found: C, 53.86; H, 4.89; N, 8.70; F, 3a as a colorless solid. 55% yield; mp 224–225 C (MeOH–
8.81; S, 4.94; Cl, 10.93.
1
EtOAc); H-NMR (DMSO-d6) δ: 2.91–2.99 (3H, m), 3.02–3.08
(S)-2-[(3-Cyanophenylamino)thiazol-4-yl]-4′-{2- (3H, m), 3.70 (2H, s), 3.94–4.02 (2H, m), 4.22–4.26 (1H,
[(2-hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide m), 6.82 (1H, s), 6.93–6.97 (3H, m), 7.21 (2H, d, J=8.4Hz),

May 2012
657
7.27–7.32 (2H, m), 7.61 (2H, d, J=8.8Hz), 7.67–7.70 (2H, m), yield; 1H-NMR (CDCl3) δ: 1.15–1.25 (3H, m), 1.45 (9H, s),
7.81–7.84 (2H, m), 8.95 (1H, brs), 9.20 (1H, brs), 10.30 (1H, 2.62–2.71 (1H, m), 2.98–4.09 (6H, m), 4.52 (1H, brs), 6.43 (1H,
s), 11.01 (1H, brs); MS (FAB) m/z: 528 (MH+); Anal. Calcd s), 6.80–6.97 (4H, m), 7.07–7.13 (4H, m), 7.23–7.30 (4H, m),
for C29H29N5O3S·2HCl·0.3H2O: C, 57.48; H, 5.26; N, 11.56; S, 7.36–7.43 (6H, m), 9.12 (1H, brs); MS (FAB) m/z: 617 (MH+).
5.29; Cl, 11.70. Found: C, 57.50; H, 5.14; N, 11.40; S, 5.16; Cl,
11.42.
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]propyl}-
2-(2-phenylaminothiazol-4-yl)acetanilide Dihydrochloride
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- (9a) The title compound was prepared in the same man-
[(4-nitrophenylamino)thiazol-4-yl]acetanilide Hydrochlo- ner as described for 4a using 8a instead of 3a as a color-
1
ride (6k) The title compound was prepared in the same less powder. 64% yield; H-NMR (DMSO-d6) δ: 1.11 (3H, d,
manner as described for 4a using 5k instead of 3a as a color- J=6.2Hz), 2.58–2.67 (1H, m), 3.07–3.23 (3H, m), 3.41–3.63
°
less solid. 42% yield; mp 227–229 C (MeOH–EtOH–EtOAc); (3H, m), 3.95–4.03 (2H, m), 4.20–4.25 (1H, m), 6.65 (1H, s),
1H-NMR (DMSO-d6) δ: 2.90–3.05 (3H, m), 3.19–3.22 (3H, 6.90–6.98 (4H, m), 7.17–7.33 (6H, m), 7.25–7.62 (4H, m), 8.67
m), 3.70 (2H, s), 3.92–4.00 (2H, m), 4.19 (1H, brs), 5.89 (1H, s), 8.79 (1H, s), 10.18 (1H, s), 10.22 (1H, s); MS (FAB)
(1H, d, J=4.8Hz), 6.88 (1H, s), 6.93–6.97 (3H, m), 7.21 (2H, m/z: 517 (MH+); Anal. Calcd for C29H32N4O3S·2HCl·1.9H2O:
d, J=8.4Hz), 7.28–7.33 (2H, m), 7.60 (2H, d, J=8.4Hz), C, 55.84; H, 6.11; N, 8.98; S, 5.14; Cl, 11.37. Found: C, 55.76;
7.81–7.85 (2H, m), 8.14 (2H, d, J=9.2Hz), 10.22 (1H, s), H, 5.95; N, 9.16; S, 5.24; Cl, 11.43.
11.06 (1H, s); MS (FAB) m/z: 548 (MH+); Anal. Calcd for
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]propyl}-
C28H29N5O5S·HCl·0.1H2O: C, 57.40; H, 5.20; N, 11.95; S, 5.47; 2-(2-phenylaminothiazol-4-yl)acetanilide Dihydrochloride
Cl, 6.05. Found: C, 57.16; H, 5.12; N, 11.90; S, 5.47; Cl, 6.01. (9b) The title compound was prepared in the same man-
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- ner as described for 4a using 8b instead of 3a as a color-
1
[(4-methoxyphenylamino)thiazol-4-yl]acetanilide
Hydro- less powder. 51% yield; H-NMR (DMSO-d6) δ: 1.14 (3H, d,
chloride (6l) The title compound was prepared in the J=6.4Hz), 2.58–2.65 (1H, m), 3.00–3.14 (1H, m), 3.20–3.30
same manner as described for 4a using 5l instead of 3a as a (2H, m), 3.40–3.50 (1H, m), 3.69 (2H, s), 3.90–4.10 (2H, m),
1
°
colorless solid. 43% yield; mp 185–191 C (MeOH–EtOAc); H- 4.24–4.32 (1H, m), 6.71 (1H, s), 6.93–7.03 (4H, m), 7.20 (2H,
NMR (DMSO-d6) δ: 2.85–3.25 (6H, m), 3.63 (2H, s), 3.70 (3H, d, J=8.3Hz), 7.28–7.33 (4H, m), 7.58–7.62 (4H, m), 8.81 (1H,
s), 3.92 (2H, m), 4.13–4.23 (1H, m), 5.88 (1H, d, J=4.9Hz), s), 9.25 (1H, s), 10.32 (1H, s), 10.69 (1H, s); MS (FAB) m/z: 517
6.56 (1H, s), 6.85 (2H, d, J=9.1Hz), 6.93–6.99 (3H, m), 7.20 (MH+); Anal. Calcd for C29H32N4O3S·1.9HCl·1.2H2O: C, 57.33;
(2H, d, J=8.6Hz), 7.28–7.34 (3H, m), 7.50 (2H, d, J=9.1Hz), H, 6.02; N, 9.22; S, 5.28; Cl, 11.09. Found: C, 57.36; H, 6.29;
7.58 (2H, d, J=8.6Hz), 8.70–8.90 (2H, m), 9.94 (1H, s), N, 9.17; S, 5.13; Cl, 10.91.
10.15 (1H, s); MS (FAB) m/z: 533 (MH+); Anal. Calcd for
tert-Butyl
C29H32N4O4S·HCl·0.5H2O: C, 60.25; H, 5.93; N, 9.69; S, 5.55; (4-{[2-(2-methylphenylaminothiazol-4-yl)acetyl]amino}-
Cl, 6.13. Found: C, 60.09; H, 5.81; N, 9.80; S, 5.65; Cl, 6.13. phenyl)ethyl]carbamate (10) The title compound was
(S)-N-(2-Hydroxy-3-phenoxypropyl)-N-[2-
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2- prepared in the same manner as described for 3a using
[(4-isopropylphenylamino)thiazol-4-yl]acetanilide Dihydro- 2-methylphenylaminothiazol-4-ylacetic acid instead of 2-tert-
chloride (6m) The title compound was prepared in the butoxycarbonylaminothiazol-4-ylacetic acid as
a colorless
same manner as described for 4a using 5m instead of 3a as powder. 18% yield; 1H-NMR (DMSO-d6) δ: 1.36 (9H, s),
1
a colorless powder. 70% yield; H-NMR (DMSO-d6) δ: 1.18 2.71–2.75 (2H, m), 3.28–3.43 (7H, m), 3.57 (2H, s), 3.82–3.83
(6H, d, J=6.4Hz), 2.79–3.05 (4H, m), 3.15–3.22 (3H, m), (2H, m), 3.96 (1H, brs), 5.14 (1H, brs), 6.52 (1H, s), 6.89–6.94
3.65 (2H, s), 3.95–3.98 (2H, m), 4.53 (1H, brs), 6.64 (1H, s), (3H, m), 7.09–7.11 (2H, m), 7.25–7.30 (3H, m), 7.41–7.52 (6H,
6.94–6.97 (3H, m), 7.14–7.21 (4H, m), 7.28–7.33 (2H, m), 7.48 m), 10.03 (1H, s); MS (FAB) m/z: 617 (MH+).
(2H, d, J=8.8Hz), 7.59 (2H, d, J=8.4Hz), 8.81 (1H, brs), 8.98
(S)-4′-{2-[(2-Hydroxy-3-phenoxypropyl)amino]ethyl}-2-
(1H, brs), 10.22 (1H, s), 10.33 (1H, brs); MS (FAB) m/z: 545 (2-methylphenylaminothiazol-4-yl)acetanilide Hydrochlo-
(MH+); Anal. Calcd for C31H36N4O3S·1.9HCl·0.75H2O: C, ride (11) The title compound was prepared in the same man-
59.34; H, 6.33; N, 8.93; S, 5.11; Cl, 10.73. Found: C, 59.32; H, ner as described for 4a using 10 instead of 3a as a colorless
6.32; N, 8.92; S, 5.04; Cl, 10.80.
powder. 46% yield; 1H-NMR (DMSO-d6) δ: 2.80–3.50 (9H,
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[3- m), 3.59 (2H, s), 3.91–4.02 (2H, m), 4.13–4.24 (1H, m), 5.89
(4-{[2-(2-phenylaminothiazol-4-yl)acetyl]amino}phenyl)]- (1H, brs), 6.53 (1H, s), 6.92–6.99 (3H, m), 7.16–7.70 (11H, m),
propyl}carbamate (8a) The title compound was prepared 8.60–8.90 (1H, m), 10.13 (1H, brs); MS (FAB) m/z: 517 (MH+);
in the same manner as described for 3a using 7a and Anal. Calcd for C29H32N4O3S·HCl·0.5H2O: C, 61.96; H, 6.10;
2-phenylaminothiazol-4-ylacetic acid instead of 2 and 2-tert- N, 9.97; S, 5.70; Cl, 6.31. Found: C, 61.98; H, 6.01; N, 10.02;
butoxycarbonylaminothiazol-4-ylacetic acid as a colorless oil. S, 5.80; Cl, 6.48.
1
80% yield; H-NMR (CDCl3) δ: 1.20 (3H, d, J=6.8Hz), 1.39
Methyl 2-(2-Guanidinothiazol-4-yl)acetate Hydrochlo-
(9H, s), 2.60–2.80 (2H, m), 3.38 (1H, brs), 3.61–4.12 (5H, m), ride (13a) A mixture of amidinothiourea (12a) (1.18g) and
3.69 (2H, s), 4.93 (1H, brs), 6.44 (1H, s), 6.81–7.31 (8H, m), methyl chloroacetylacetate (1.65g) in methanol (20mL) was
7.36–7.43 (6H, m), 9.11 (1H, brs); MS (FAB) m/z: 617 (MH+).
heated at reflux for 4h. After cooling to room temperature, the
tert-Butyl (S)-N-(2-Hydroxy-3-phenoxypropyl)-N-{2-[3- solvent was concentrated in vacuo. The residue was diluted
(4-{[2-(2-phenylaminothiazol-4-yl)acetyl]amino}phenyl)]- with ethyl acetate, and then triturated. The precipitate was
propyl}carbamate (8b) The title compound was prepared removed by filtration, washed with ethyl acetate, and dried to
1
in the same manner as described for 3a using 7b and 2-phe- yield 13a (2.25g) as a colorless powder. 90% yield; H-NMR
nylaminothiazol-4-ylacetic acid instead of 2 and 2-tert-butoxy- (CDCl3) δ: 3.70 (2H, s), 3.73 (3H, s), 6.81 (1H, s); MS (FAB)
carbonylaminothiazol-4-ylacetic acid as a colorless oil. 72% m/z: 215 (MH+).

658
Vol. 60, No. 5
Methyl 2-[(4-Cyanophenylamino)thiazol-4-yl]acetate Hy- orally once daily for 4d, and the blood sugar level 15 to 18h
drochloride (13b) The title compound was prepared in the after final administration was compared with that before ad-
same manner as described for 13a using 4-cyanophenylthio- ministration (n=6). Blood samples were collected from the
urea instead of amidinothiourea as a colorless powder. 63% tail vein using a glass capillary tube (previously treated with
1
yield; H-NMR (CDCl3) δ: 3.72 (2H, s), 6.62 (1H, s), 7.44–7.48 heparin) after which the blood was deproteinized, and the
(2H, m), 7.56–7.62 (2H, m); MS (FAB) m/z: 274 (MH+).
amount of glucose in the supernatant (mg/dL) was determined
Methyl 2-[(2-Furylmethylamino)thiazol-4-yl]acetate Hy- calorimetrically by means of the glucose oxidase method.
drochloride (13c) The title compound was prepared in the
same manner as described for 13a using 2-furylmethylthio-
Acknowledgment The authors are grateful to the staff of
urea instead of amidinothiourea as a colorless powder. 83% the Division of Analytical Science Laboratories for elemental
1
yield; H-NMR (CDCl3) δ: 3.58 (2H, s), 3.70 (3H, s), 4.43 (2H, analysis and spectral measurements.
s), 6.06 (1H, brs), 6.25–6.35 (3H, m), 7.36 (1H, s); MS (FAB)
m/z: 253 (MH+).
2-(2-Guanidinothiazol-4-yl)acetic Acid Hydrochloride
(14a) A mixture of 13a (0.65g) in 10% aqueous hydrochlo-
ric acid solution (10mL) was heated at reflux for 1h. After
cooling to room temperature, the solvent was concentrated in
vacuo. The residue was diluted with ethyl acetate, and then
triturated. The precipitate was removed by filtration, washed
with ethyl acetate and methanol, and dried to yield 14a (0.6g)
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1
as a colorless powder. 95% yield; H-NMR (DMSO-d6) δ: 3.58
(2H, s), 6.81 (1H, s), 7.72–7.78 (4H, m), 10.73 (1H, brs), 12.38
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2-[(2-Furylmethylamino)thiazol-4-yl]acetic Acid (14c)
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6.25–6.26 (3H, m), 7.30–7.33 (1H, m).
Agonistic Activity on Human β3-, β2-, and β1-ARs The
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1
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’
on a 24-well plate and checking the activity after 2 days
incubation (subconfluent state) using the production of cyclic
AMP (cAMP) as an index. The amount of cAMP produced in
each cell (pmol/mL) was measured using a radioimmunoassay
method with 125I-cAMP. The intensity of action among com-
pounds was compared by calculating the EC50 and intrinsic
activity (IA where the maximum reaction of 10−4 M isopro-
terenol was defined as 1.00) for each from the resulting dose-
reaction curve.
Hypoglycemic Activity in kk Mice The blood sugar lev-
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classified into groups. The test compound was administered
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