Synthesis of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl ureas and their inhibition activity to acetylcholinesterase and butyrylcholinesterase

Article abstract of DOI:10.1002/jhet.502

A series of novel 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3- substituted phenyl ureas were synthesized by the condensation of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine with substituted phenyl isocyanates under mild conditions. Their structures were confirmed ¹H, ¹³C, and ¹⁹F NMR spectra, and elemental analyses. The optical activities were confirmed by optical rotation measurements. The inhibition activity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2- yl)ethyl]-3-substituted phenyl ureas to acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) was also tested. Preliminary bioassay indicated that the target ureas displayed excellent acetylcholinesterase and butyrylcholinesterase inhibition activity.

Full text of DOI:10.1002/jhet.502

January 2011
Synthesis of 1-[(1R)-1-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-3-
substituted Phenyl Ureas and Their Inhibition Activity to
Acetylcholinesterase and Butyrylcholinesterase
57
a
Vladimır Pejchal, * Sarka Stepankova, and Pavel Drabina
b
a
ˇ
ˇ
´
´
ˇ ´
´
aFaculty of Chemical Technology, Institute of Organic Chemistry and Technology,
University of Pardubice, Pardubice 532 10, Czech Republic
bFaculty of Chemical Technology, Department of Biological and Biochemical Sciences,
University of Pardubice, Pardubice 532 10, Czech Republic
*E-mail: vladimir.pejchal@upce.cz
Received January 25, 2010
DOI 10.1002/jhet.502
Published online 2 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl ureas were syn-
thesized by the condensation of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine with substituted phe-
1
nyl isocyanates under mild conditions. Their structures were confirmed H, 13C, and 19F NMR spectra,
and elemental analyses. The optical activities were confirmed by optical rotation measurements. The
inhibition activity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl ureas to ace-
tylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) was also tested. Preliminary bioassay indi-
cated that the target ureas displayed excellent acetylcholinesterase and butyrylcholinesterase inhibition
activity.
J. Heterocyclic Chem., 48, 57 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
The search for new and potent cholinesterase inhibi-
tors (CHEIs) is an ongoing quest mobilizing many or-
ganic chemistry groups around the world. It was shown
that these molecules can treat the late symptoms of Alz-
heimer’s disease (AD) and as well as act as neuropro-
tecting agents [1].
The key intermediate, 2 required for the synthesis of
the title compounds was prepared according to the pro-
cedure outlined in the Schemes 1 and 2. (4R)-4-Methyl-
1,3-oxazolidine-2,5-dione (1) was prepared by reaction
of D-alanine with phosgene in THF according to
reported method (Scheme 1) [5]. (1R)-1-(6-Fluoro-1,3-
benzothiazol-2-yl)ethanamine p-toluenesulfonic salt (2)
was prepared by three-step process according to reported
method (Scheme 2) [6,7]. Compound 1 reacted with
water solution of potassium hydroxide in the first step to
give 2-aminobenzothiol potassium salt, which reacted
with compound 1 in the second step to give product 2
hydrochloride. Product 2 p-toluenesulfonic salt was pre-
pared by reaction of product 2 hydrochloride with p-tol-
uenesulfonic acid in water. The measured melting points
as well as the 1H, 13C NMR chemical shifts of the
known compound 1 agree with the literature data [5,8].
A series of unreported ureas 3a–j were synthesized by
the two steps process. Compound 2 p-toluenesulfonic
salt was transformed by 15% aqueous solution of so-
dium hydroxide to compound 2 base in the first step. In
this work, a series of 10 new optical active unsymmetri-
cal ureas 3a–j were synthesized (Scheme 3). Compound
There are two major forms of cholinesterases
(CHEs)—acetylcholinesterase (ACHE, EC 3.1.1.7) and
butyrylcholinesterase—also called pseudocholinesterase
or nonspecific cholinesterase (BCHE, EC 3.1.1.8) in ver-
tebrates. These enzymes belong to the group of serine
hydrolases and are responsible for the breakdown of
neurotransmitter acetylcholine (ACH) and butyrylcholine
(BCH), respectively [2].
In AD, the loss of cholinergic neurotransmission in
the brain is accompanied by a reduced concentration of
ACH and contributes to the salient cognitive and behav-
ioral disturbances characteristic of AD [1].
CHEIs increase the amount of ACH available for neu-
ronal and neuromuscular transmission through their abil-
ity to reversibly or irreversibly inhibit the activity of
CHEs [3]. Therefore, CHEIs have become the main
approach to symptomatic treatment of AD [4].
C
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3
through three bonds with J(19F,1H) ¼ 9 Hz. Because the
Scheme 1. Synthetic route to compound 1.
values of coupling constants J and J(19F,1H) were the
same, the proton signal was displayed doublets of triplets.
The proton 6-H signal was displayed doublets of dou-
blets. The proton signal was coupled by protons through
3
3
4
four bonds with J ¼ 2.5 Hz and by fluorine through
three bonds with J(19F,1H) ¼ 9 Hz. Proton numbering
3
for assignment of 1H NMR shifts is illustrated in
Schemes 4 and 5. The 13C NMR spectrum showed two
peaks in the alkyl region indicating the presence of the
CH3ACHA group. Seven peaks were assignable to 6-
substituted benzothiazole group. Other peaks were as-
signable to substituted phenyl groups. All peaks of 6-sub-
stituted benzothiazole group were duplex by fluorine cou-
pling to doublets. The optical activities were confirmed
by optical rotation measurements. The optical rotation
measurements were performed in aceton (c ¼ 0.2ꢀ1).
Determination of IC50. The effectiveness of the in-
hibitor could be described by the 50% inhibitory con-
centration IC50. The IC50, or the half maximal inhibitory
concentration, represents the concentration of an inhibi-
tor that is required for 50% inhibition of the enzyme.
(Sometime it is referred to as the negative logarithm of
the molar concentration inhibiting the enzyme activity
by 50%, pI50 ¼ ꢀlogIC50). IC50 values are dependent
on conditions under which they are measured. The
results of IC50 determination are compiled in Table 2.
From the obtained results it follows that all tested com-
pounds inhibit ACHE as well as BCHE. Generally, it is pos-
sible to conclude that inhibition of BCHE by the tested com-
pounds is stronger than of ACHE. This could be caused by
several structural differences between the hydrophobic
gorge of active centre in ACHE and BCHE. At the base of
the gorge in ACHE, the binding of the substrate is repre-
sented by two phenylalanine molecules whose aromatic res-
idues protrude into the gorge. In BCHE, these molecules are
replaced by two smaller amino acid molecules—valine and
leucine. This conformational change creates a larger space
within the deepest area of the gorge of BCHE to allow the fit
of larger-size substrates and inhibitors of BCHE [9,10].
In conclusion, a series of novel 1-[(1R)-1-(6-fluoro-
1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl ureas
2 reacted with corresponding substituted phenyl isocya-
nates under mild conditions in good yields (85–88%) in
the second step. Low solubilities of prepared ureas in
toluene were used for preparation of high quality prod-
ucts. Unreacted compound 2-base and isocyanates were
very good soluble in toluene and they could by remove
from products by toluene wash. The structures of the
prepared products were confirmed by 1H, 13C, 19F
NMR, and elemental analyses.
R¼ a: phenyl, b: benzyl, c: 2,6-diisopropylphenyl, d:
3-chloro-4-methylphenyl, e: 3,5-dichlorophenyl, f: 3,5-
dimethylphenyl, g: 4-isopropylphenyl, h: 4-chloro-
phenyl, i: 4-cyanophenyl, j: 4-nitrophenyl.
The structures of substituents, molecular formulas,
yields, and melting points are compiled in Table 1. The
structures of compounds 3a–j were deduced from their
spectroscopic data. 1H NMR spectra of compounds 3
showed the presence of two NH ureas proton peaks typi-
cal for unsymmetrical ureas. The first NH(60-H) proton
signal displayed singlet and second NH(1-H) proton sig-
nal displayed doublet with J ¼ 7 Hz. NH proton (1-H)
was coupled by presence CH group. This CH group was
coupled to quintet by CH3 group proton (2-H) and NH
urea group protons (1-H) with J ¼ 7 Hz too. The proton
4-H signal was displayed doublet with J ¼ 9 Hz. The flu-
orine couplings were not observed in compound 3a–j in
contrast to compound 2. The proton 4-H signal in com-
pound 2 was displayed doublet of doublet with J ¼ 9 Hz
4
and fluorine coupling through four bonds with J(19F,1H)
¼ 4.8 Hz. The proton 5-H signal should be displayed
doublet of doublet of doublet. The proton signal was
3
coupled by proton through three bonds with J ¼ 9 Hz,
4
through four bonds with J ¼ 2.6 Hz and by fluorine
Scheme 2. Synthetic route to compound 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011 Synthesis of 1-[(1R)-1-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted Phenyl Ureas
and Their Inhibition Activity to Acetylcholinesterase and Butyrylcholinesterase
59
Scheme 3. Synthetic route to compound 3.
were synthesized by the condensation of (1R)-1-(6-flu-
oro-1,3-benzothiazol-2-yl)ethanamine with substituted
phenyl isocyanates under mild conditions in good yields
(85–88%). The inhibition activity of 1-[(1R)-1-(6-fluoro-
1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl ureas
to acetylcholinesterase (ACHE) and butyrylcholinester-
ase (BCHE) was also tested. Preliminary bioassay
indicated that the target ureas displayed excellent acetyl-
cholinesterase and butyrylcholinesterase inhibition
activity.
Table 1
Synthesis of compounds 3a–j.
Compounda
R
Mol. formula
Yield (%)
85
Mp (ꢁC)
226–228
3a
C16H14FN3OS
C17H16FN3OS
3b
3c
84
86
214–215
213–214
C22H26FN3OS
3d
3e
C17H15ClFN3OS
86
88
210–211
239–240
C16H12Cl2FN3OS
3f
C18H18FN3OS
86
233–234
3g
3h
3i
C19H20FN3OS
C16H13ClFN3OS
C17H13FN4OS
C16H13FN4O3S
87
86
86
85
175–176
248–249
220–221
224–226
3j
a All the products were characterized by NMR and elemental analyses.
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Scheme 4. Proton numbering for the assignment of 1H NMR shifts
(compound 2).
Table 2
The IC50 values of tested ureas 3a–j.
IC50 (lmol/L)
Acetylcholinesterase
ACHE
Butyrylcholinesterase
BCHE
Compound
3a
3b
3c
3d
3e
3f
3g
3h
3i
39.3
46.1
50.5
15.2
72.7
58.9
60.6
36.9
39.4
26.9
3.65
35
28.8
14.1
35.5
50.8
50.1
43.9
7.54
22.9
EXPERIMENTAL
3j
General data. The purity of ureas was checked by elemen-
tal analysis using an automatic analyzer EA 1108 (Fisons). H,
1
7.48 (d 2H, 10-H, J ¼ 8.0 Hz), 8.09 [dd, 1H, 4-H, J ¼ 9.2 Hz,
13C, and 19F NMR spectra of the model compounds were
measured at 25ꢁC using their solutions in DMSO-d6 on a
Bruker Avance 400 apparatus at 400.13 MHz (1H), 100.62
MHz (13C), 376.46 MHz (19F). The chemical shifts were refer-
enced to the solvent signal. The optical rotation was measured
on a Perkin–Elmer 341 instrument, concentration c is given in
g/100 mL. Melting points were determined by open capillary
method and were uncorrected. Elemental analyses were per-
formed with Fisons Instruments1108 CHN elemental analyzer.
The IC50 values were determined by spectrophotometric Ell-
man’s method [11].
1
3
4J(19F, H) ¼ 4.8 Hz], 8.12 [dd, 1H, 6-H, J ¼ 2.4 Hz, J(19F,
1H) ¼ 8.4 Hz], 8.74 (s, 2H, 1-H) NH2; 13C NMR (100.62
MHz, DMSO-d6): 19.9, 20.9, 48.4, 109.0 [d, 2J(19F, 13C) ¼
2
3
27.4 Hz], 115.5 [d, J(19F, 13C) ¼ 24.9 Hz], 124.3 [d, J(19F,
13C) ¼ 9.6 Hz], 125.7, 128.5, 136.4 [d, 3J(19F, 13C) ¼ 11.9
Hz], 138.5, 144.9, 148.8, 160.1 [d, 1J(19F, 13C) ¼ 243.5 Hz],
169.1; 19F NMR (376.46 MHz, DMSO-d6): d ¼ ꢀ115.21.
Anal. Calcd. for C16H17FN2O3S2 (368.44): C, 52.16; H, 4.65;
N, 7.60. Found: C, 52.00; H, 4.82; N, 17.51.
General procedure for synthesis of ureas 3a–j. To the
suspension of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethan-
amine p-toluenesulfonic salt (2) (0.01 mole) and toluene (50
mL) was added the 15% aqueous solution of sodium hydroxide
(0.011 mole), the mixture was stirred at room temperature for
0.5 h. The toluene phase was separated and filtered. The tolu-
ene solution of R–1-(6-fluorobenzthiazole-2-yl)ethylamine
(0.01 mole) was treated with a solution of corresponding sub-
stituted phenyl isocyanate (0.01 mole) in toluene (20 mL) at
room temperature. The separated solid was collected by filtra-
tion, dried to give compounds 3a–j in 84–88% yields.
The substituted aromatic isocyanates, 6-fluoro-1,3-benzothia-
zol-2-amine, other reagents, and solvents were purchased from
commercial sources (Sigma-Aldrich, Merck). Commercial
grade reagents were used without a further purification.The
required compounds (4R)-4-methyl-1,3-oxazolidine-2,5-dione
(1) and (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine p-
toluenesulfonic salt (2) were synthesized by reported method
1
[5–7]. Their structures of the products were confirmed by H,
13C, NMR, meeting point and elemental analyses.
1
Yields, melting points, H, 13C, and 19F NMR shifts, results
1-[(1R)-1-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-3-phenylurea
(3a). This compound was obtained as white powder. Yield:
of the optical rotation measurings and elemental analyses of
ureas 3a–j are given in the text below.
85%; m.p. 226–228ꢁC; [a]D ¼ þ48.7ꢁ (acetone c ¼ 1); 1H
20
(1R)-1-(6-Fluoro-1,3-benzothiazol-2-yl)ethanamine 4-tolue-
nesulfonate (2) This compound was obtained as white powder.
NMR (400.13 MHz, DMSO-d6): d ¼ 1.60 (d, 3H, 2-H, J ¼
7.2 Hz) CH3, 5.19 (kv, 1H, 3-H, J ¼ 7.2 Hz) CH, 6.93 (t, 1H,
30-H, J ¼ 7.4 Hz), 7.08 (d, 1H, 1-H, J ¼ 7.2 Hz) NH urea,
1
Yield: 81%, m.p. 241–242ꢁC H NMR (400.13 MHz, DMSO-
d6): d ¼ 1.66 (d, 3H, 2-H, J ¼ 6.8 Hz), 2.28 (s, 3H, 30-H),
5.01 (k, 1H, 3-H, J ¼ 6.8 Hz), 7.10 (d, 2H, 20-H, J ¼ 8.0 Hz),
7.37 [dt, 1H, 5-H, J ¼ 2.4, 9.2 Hz, 3J(19F, 1H) ¼ 9.2 Hz],
7.24 (t, 2H, 20-H, 40-H, J ¼ 7.4), 7.37 [dt, 1H, 5-H, J ¼ 2.7,
1
9.0 Hz, 3J(19F, H) ¼ 9.0 Hz], 7.41 (d 2H, 10-H, 50-H, J ¼
0
7.4 Hz), 7.97 (d, 1H, 4-H, J ¼ 8.9 Hz), 7.99 [dd, 1H, 6-H, J
¼ 2.8 Hz, J(19F, H) ¼ 8.9 Hz], 8.67 (s, 1H, 60-H) NH urea;
13C NMR (100.62 MHz, DMSO-d6): 20.9, 48.1, 108.6 [d,
2J(19F, 13C) ¼ 27.2 Hz], 114.5 [d, 2J(19F, 13C) ¼ 25.2 Hz],
117.9, 121.6, 123.6 [d, 3J(19F, 13C) ¼ 9.1 Hz], 128.8, 135.8
[d, 3J(19F, 13C) ¼ 11.1 Hz], 140.0, 149.8 [d, 5J(19F, 13C) ¼
2.0 Hz], 154.6, 159.5 [d, 1J(19F, 13C) ¼ 242.5 Hz], 177.2 [d,
4J(19F, 13C) ¼ 3.0 Hz]; 19F NMR (376.46 MHz, DMSO-d6):
d ¼ ꢀ116.70. Anal. Calcd. for C16H14FN3OS (315.37): C,
60.94; H, 4.47; N,13.32. Found: C, 61.22; H, 4.60; N, 13.38.
1-Benzyl-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]urea
(3b). This compound was obtained as white powder. Yield: 84%;
3
1
Scheme 5. Proton numbering for the assignment of 1H NMR shifts
(compounds 3a–j).
20
1
m.p. 214–215ꢁC; [a]D ¼ ꢀ17.0ꢁ (acetone c ¼ 0.2); H NMR
(400.13 MHz, DMSO-d6): d ¼ 1.59 (d, 3H, 2-H, J ¼ 7.2 Hz),
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January 2011 Synthesis of 1-[(1R)-1-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted Phenyl Ureas
and Their Inhibition Activity to Acetylcholinesterase and Butyrylcholinesterase
61
4.30 (d, 2H J ¼ 6.0 Hz) CH2-benzyl, 5.16 (kv, 1H, 3-H, J ¼ 7.2
Hz), 5.6 (t, 1H, 30-H, J ¼ 6 Hz), 7.02 (d, 1H, 1-H, J ¼ 7.2 Hz) NH
urea, 7.25–7.34 (m, 5H, 10-H, 20-H, 40-H, 50-H), 7.36 [dt, 1H, 5-H,
J ¼ 2.6, 9.0 Hz, 3J(19F, 1H) ¼ 9.0 Hz], 7.99 (d, 1H, 4-H, J ¼ 4.9
142.4, 149.5, 159.5 [d, 1J(19F, 13C) ¼ 242.5 Hz], 176.3 [d,
4J(19F, 13C) ¼ 3.0 Hz]; 19F NMR (376.46 MHz, DMSO-d6): d
¼ ꢀ116.58. Anal. Calcd. for C16H12Cl2FN3OS (384.26): C,
50.01; H, 3.15; N,10.94. Found: C, 50.09; H, 4.26; N, 10.85.
1-(3,5-Dimethylphenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-
2-yl)ethyl]urea (3f). This compound was obtained as white
3
1
Hz), 8.01 [dd, 1H, 6-H, J ¼ 2.6 Hz, J(19F, H) ¼ 8.9 Hz]; 13C
NMR (100.62 MHz, DMSO-d6): 20.9, 42.9, 48.1, 108.6 [d,
2J(19F, 13C) ¼ 27.2 Hz], 114.5 [d, 2J(19F, 13C) ¼ 24.1 Hz], 123.6
[d, 3J(19F, 13C) ¼ 9.1 Hz], 126.7, 127.0, 128.3, 135.7 [d, 3J(19F,
20
powder. Yield: 86%; m.p. 233–234ꢁC; [a]D ¼ þ51.2ꢁ (ace-
tone c ¼ 0.3); 1H NMR (400.13 MHz, DMSO-d6): d ¼ 1.59
(d, 3H, 2-H, J ¼ 7.2 Hz), 2.20 (s, 6H) CH3, 5.16 (kv, 1H, 3-
H, J ¼ 7.2 Hz), 6.56 (s, 30-H, 1H), 7.03 (s, 2H, 10-H, 50-H),
7.06 (d, 1H, 1-H, J ¼ 7.2 Hz) NH urea, 7.37 [dt, 1H, 5-H, J
¼ 2.6, 9.2 Hz, 3J(19F, 1H) ¼ 9.2 Hz], 7.97 (d, 1H, 4-H, J ¼
8.8 Hz), 7.99 [dd, 1H, 6-H, J ¼ 3.0 Hz, 3J(19F, 1H) ¼ 8.9
Hz], 8.50 (s, 1H, 60-H) NH urea; 13C NMR (100.62 MHz,
DMSO-d6): 20.9, 21.1, 48.1, 108.6 [d, 2J(19F, 13C) ¼ 27.2
5
13C) ¼ 11.1 Hz], 140.4, 149.8 [d, J(19F, 13C) ¼ 1.0 Hz], 159.5
[d, 1J(19F, 13C) ¼ 242.5 Hz], 177.9 [d, 4J(19F, 13C) ¼ 3.0 Hz]; 19
F
NMR (376.46 MHz, DMSO-d6): d ¼ ꢀ116.86. Anal. Calcd. for
C17H16FN3OS (329.39): C, 61.99; H, 4.90; N,12.76. Found: C,
61.92; H, 5.02; N, 12.82.
1-(2,6-Diisopropylphenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothia-
zol-2-yl)ethyl]urea (3c). This compound was obtained as white
Hz], 114.5 [d, J(19F, 13C) ¼ 24.1 Hz], 115.7, 123.2, 123.6 [d,
20
powder. Yield: 86%; m.p. 213–214ꢁC, [a]D ¼ þ18.6ꢁ (ace-
2
1
tone c ¼ 1); H NMR (400.13 MHz, DMSO-d6): d ¼ 1.10 (b,
3J(19F, 13C) ¼ 9.1 Hz], 135.7 [d, 3J(19F, 13C) ¼ 12.1 Hz],
137.7, 139.8, 149.8 [d, 5J(19F, 13C) ¼ 2.0 Hz], 159.5 [d,
1J(19F, 13C) ¼ 242.5 Hz], 177.3 [d, 4J(19F, 13C) ¼ 3.0 Hz];
19F NMR (376.46 MHz, DMSO-d6): d ¼ ꢀ116.72. Anal.
Calcd. for C18H18FN3OS (343.42): C, 62.95; H, 5.28; N,
12.24. Found: C, 63.06; H, 5.46; N, 12.18.
3H) CH3-isopropyl, 1.15 (d, 3H, J ¼ 6.8 Hz) CH3-isopropyl,
1.59 (d, 3H, 2-H, J ¼ 7.2 Hz), 3.20 (b, 2H) CH-isopropyl,
5.17 (kv, 1H, 3-H, J ¼ 7.2 Hz), 7.11–7.25 (m, 4H, 1-H, 20-H,
3
1
30-H, 40-H), 7.36 [dt, 1H, 5-H, J ¼ 2.4, 8.8 Hz, J(19F, H) ¼
8.8 Hz], 7.61 (s, 1H, 60-H) NH urea, 7.95 [dd, 1H, 6-H, J ¼
3
1
4.8 Hz, J(19F, H) ¼ 8.8 Hz], 8.01 (d, 1H,4-H, J ¼ 6.8 Hz);
1-(4-Isopropylphenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-
2-yl)ethyl]urea (3g). This compound was obtained as white
13C NMR (100.62 MHz, DMSO-d6): 20.9, 27.8, 48.2, 108.6
2
2
20
[d, J(19F, 13C) ¼ 27.2 Hz], 114.5 [d, J(19F, 13C) ¼ 25.1 Hz],
powder. Yield: 87%; m.p. 175–176ꢁC; [a]D ¼ þ58.7ꢁ (ace-
122.7, 123.5 [d, 3J(19F, 13C) ¼ 10.1 Hz], 126.9, 135.7 [d,
tone c ¼ 1); H NMR (400.13 MHz, DMSO-d6): d ¼ 1.15 (d,
1
3J(19F, 13C) ¼ 11.1 Hz], 146.5, 149.8, 159.5 [d, J(19F, 13C) ¼
6H, J ¼ 6.8 Hz) CH3–isopropyl, 1.59 (d, 3H, 2-H, J ¼ 7.2 Hz),
2.80 (sept., 1H, J ¼ 7.2 Hz) CH-isopropyl, 5.18 (kv, 1H, 3-H, J
¼ 7.2 Hz), 7.03 (d, 1H, 1-H, J ¼ 7.2 Hz) NH urea, 7.10 (d,
2H, 10-H, 50-H, J ¼ 8.4 Hz), 7.32 (d, 2H, 20-H, 40-H, J ¼ 8.4
1
242.5 Hz], 177.7; 19F NMR (376.46 MHz, DMSO-d6): d ¼
ꢀ116.82. Anal. Calcd. for C22H26FN3OS (399.52): C, 66.14;
H, 6.56; N,10.52. Found: C, 66.22; H, 6.46; N, 10.61.
3
1
1-(3-Chloro-4-methylphenyl)-3-[(1R)-1-(6-fluoro-1,3-benzo-
thiazol-2-yl)ethyl]urea (3d). This compound was obtained as
Hz), 7.37 [dt, 1H, 5-H, J ¼ 2.7, 9.2 Hz, J(19F, H) ¼ 9.2 Hz],
7.97 (d, 1H, 4-H, J ¼ 9.2 Hz) 7.99 [dd, 1H, 6-H, J ¼ 3.1 Hz,
3J(19F, H) ¼ 8.9 Hz], 8.58 (s, 1H, 60-H) NH urea; 13C NMR
20
white powder. Yield: 86%; m.p. 210–211ꢁC; [a]D ¼ þ77.9ꢁ
1
1
(acetone c ¼ 1); H NMR (400.13 MHz, DMSO-d6): d ¼ 1.59
(100.62 MHz, DMSO-d6): 20.9, 24.0, 32.8, 48.1, 108.6 [d,
2J(19F, 13C) ¼ 27.2 Hz], 114.5 [d, 2J(19F, 13C) ¼ 24.1 Hz],
118.1, 123.6 [d, 3J(19F, 13C) ¼ 10.1 Hz], 126.4, 135.8 [d,
(d, 3H, 2-H, J ¼ 7.1 Hz), 2.22 (s, 3H) CH3, 5.17 (kv, 1H, 3-
H, J ¼ 7.1 Hz), 7.12–7.20 (m, 3H, 1-H, 40-H, 50-H), 7.36 [dt,
3
1
5
1H, 5-H, J ¼ 2.6, 9.1 Hz, J(19F, H) ¼ 9.1 Hz], 7.66 (d, 1H,
3J(19F, 13C) ¼ 12.1 Hz], 137.7, 141.7, 149.9 [d, J(19F, 13C) ¼
10-H, J ¼ 2.0 Hz), 7.97 (d, 1H, 4-H, J ¼ 8.8 Hz), 7.99 [dd,
1.0 Hz], 159.5 [d, 1J(19F, 13C) ¼ 242.5 Hz], 177.3 [d, 4J(19F,
13C) ¼ 3.0 Hz]; 19F NMR (376.46 MHz, DMSO-d6): d ¼
ꢀ116.73. Anal. Calcd. for C19H20FN3OS (357.45): C, 63.84; H,
5.64; N,11.76. Found: C, 63.75; H, 5.82; N, 11.66.
3
1
1H, 6-H, J ¼ 3.0 Hz, J(19F, H) ¼ 8.9 Hz], 8.80 (s, 1H, 60-H)
NH urea; 13C NMR (100.62 MHz, DMSO-d6): 18.8, 20.8,
2
2
48.2, 108.6 [d, J(19F, 13C) ¼ 27.2 Hz], 114.5 [d, J(19F, 13C)
¼ 24.1 Hz], 116.6, 117.8, 123.6 [d, 3J(19F, 13C) ¼ 10.1 Hz],
1-(4-Chlorophenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]urea (3h). This compound was obtained as white powder.
127.9, 131.1, 133.1, 135.7 [d, J(19F, 13C) ¼ 11.1 Hz], 139.2,
3
149.8 [d, J(19F, 13C) ¼ 1.0 Hz], 154.5, 159.5 [d, J(19F, 13C)
¼ 242.5 Hz], 176.9 [d, 4J(19F, 13C) ¼ 3.0 Hz]; 19F NMR
(376.46 MHz, DMSO-d6): d ¼ ꢀ116.67. Anal. Calcd. for
C17H15ClFN3OS (363.84): C, 56.12; H, 4.16; N,11.55. Found:
C, 56.10; H, 4.26; N, 11.51.
Yield: 86%; m.p. 248–249ꢁC; [a]D ¼ þ68.6ꢁ (acetone c ¼
5
1
20
1
1); H NMR (400.13 MHz, DMSO-d6): d ¼ 1.59 (d, 3H, 2-H, J
¼ 7.2 Hz), 5.18 (kv, 1H, 3-H, J ¼ 7.2 Hz), 7.13 (d, 1H, 1-H, J
¼ 7.3 Hz) NH urea, 7.27 (d, 2H, 10-H, 50-H, J ¼ 9.0 Hz), 7.37
3
1
[dt, 1H, 5-H, J ¼ 2.6, 9.0 Hz, J(19F, H) ¼ 9.0 Hz], 7.45 (d,
1-(3,5-Dichlorophenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-
2-yl)ethyl]urea (3e). This compound was obtained as white
2H, 20-H, 40-H, J ¼ 9.0 Hz), 7.97 (d, 1H, 4-H, J ¼ 9.2
3
1
Hz),7.99 [dd, 1H, 6-H, J ¼ 2.5 Hz, J(19F, H) ¼ 9.0 Hz], 8.82
powder. Yield: 88%; m.p. 239–240ꢁC; [a]D ¼ þ66.9ꢁ (ace-
(s, 1H, 60-H) NH urea; 13C NMR (100.62 MHz, DMSO-d6):
20
tone c ¼ 0.3); 1H NMR (400.13 MHz, DMSO-d6): d ¼ 1.59
(d, 3H, 2-H, J ¼ 7.1 Hz), 5.18 (kv, 1H, 3-H, J ¼ 7.1 Hz),
7.10 (t, 1H, 30-H, J ¼ 1.8 Hz), 7.36 [dt, 1H, 5-H, J ¼ 2.6, 9.2
20.8, 48.1, 108.6 [d, J(19F, 13C) ¼ 27.2 Hz], 114.6 [d, J(19F,
13C) ¼ 25.1 Hz], 119.4, 123.7 [d, 3J(19F, 13C) ¼ 10.1 Hz],
125.0, 128.6, 135.8 [d, 3J(19F, 13C) ¼ 12.1 Hz], 139.0, 149.8,
2
2
3
1
1
4
Hz, J(19F, H) ¼ 9.2 Hz], 7.39 (d, 1H, 1-H, J ¼ 7.1 Hz) NH
154.5, 159.5 [d, J(19F, 13C) ¼ 242.5 Hz], 176.9 [d, J(19F, 13C)
¼ 3.0 Hz]; 19F NMR (376.46 MHz, DMSO-d6): d ¼ ꢀ116.66.
Anal. Calcd. for C16H13ClFN3OS (349.81): C, 54.94; H, 3.75;
N, 12.01. Found: C, 55.02; H, 4.00; N, 12.12.
urea, 7.50 (d, 2H, 10-H, 50-H, J ¼ 1.8 Hz), 7.97 (d, 1H, 4-H, J
3
1
¼ 9.0 Hz), 7.99 [dd, 1H, 6-H, J ¼ 3.3 Hz, J(19F, H) ¼ 8.9
Hz], 9.10 (s, 1H, 60-H) NH urea; 13C NMR (100.62 MHz,
DMSO-d6): 20.4, 48.1, 108.6 [d, J(19F, 13C) ¼ 27.2 Hz], 114.6
[d, 2J(19F, 13C) ¼ 25.2 Hz], 115.8, 120.4, 123.6 [d, 3J(19F,
13C) ¼ 9.1 Hz], 134.1, 135.7 [d, 3J(19F, 13C) ¼ 12.1 Hz],
1-(4-Cyanophenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-
yl)ethyl]urea (3i). This compound was obtained as white pow-
20
der. Yield: 86%; m.p. 220–221ꢁC; [a]D ¼ þ98.2ꢁ (acetone c
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ ˇ
V. Pejchal, S. Stepankova, and P. Drabina
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62
Vol 48
1
¼ 1); H NMR (400.13 MHz, DMSO-d6): d ¼ 1.60 (d, 3H, 2-
Calcd. for C16H13FN4O3S (360.36): C, 53.33; H, 3.64;
N,15.55. Found: C, 53.43; H, 3.46; N, 15.61.
H, J ¼ 7.2 Hz), 5.21 (kv, 1H, 3-H, J ¼ 7.2 Hz), 7.37 [dt, 1H,
5-H, J ¼ 2.6, 9.2 Hz, J(19F, H) ¼ 9.2 Hz], 7.38 (d, 1H, 1-H,
J ¼ 7.2 Hz) NH urea, 7.60 (d, 2H, 10-H, 50-H, J ¼ 8.9 Hz),
7.69 (d, 2H, 20-H, 40-H, J ¼ 8.9 Hz), 7.97 (d, 1H, 4-H, J ¼ 8.5
Hz), 7.99 [dd, 1H, 6-H, J ¼ 2.5 Hz, 3J(19F, 1H) ¼ 8.8 Hz],
9.26 (s, 1H, 60-H) NH urea; 13C NMR (100.62 MHz, DMSO-
3
1
Acknowledgment. The authors thank the Ministry of Education,
Youth, and Sports of the Czech Republic for financial support
(project MSM 0021627501 and MSM 0021627502).
d6): 20.7, 48.2, 103.0, 108.7 [d, J(19F, 13C) ¼ 27.2 Hz], 114.6
2
[d, J(19F, 13C) ¼ 24.1 Hz], 117.8, 119.4, 123.7 [d, J(19F, 13C)
¼ 10.1 Hz], 133.3, 135.8 [d, 3J(19F, 13C) ¼ 12.1 Hz], 144.5,
149.7, 154.1, 159.5 [d, 1J(19F, 13C) ¼ 241.5 Hz], 176.4 [d,
4J(19F, 13C) ¼ 3.0 Hz]; 19F NMR (376.46 MHz, DMSO-d6): d
¼ ꢀ116.58. Anal. Calcd. for C17H14FN4OS (340.37): C, 59.99;
H, 3.85; N,16.46. Found: C, 59.89; H, 4.00; N, 16.55.
2
3
REFERENCES AND NOTES
[1] Marcelo, F.; Silva, F. V. M.; Goulart, M.; Justino, J.; Sinay¨,
´
P.; Bleriot, Y.; Rauter, A. P. Bioorg Med Chem 2009, 17, 5106.
´
[2] Massoulie, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette,
F.-M. Prog Neurobiol 1993, 41, 31.
1-(4-Nitrophenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)
ethyl]urea (3j). This compound was obtained as yellowish
ˇ
[3] Stepankova, S.; Komers, K. Curr Enzyme Inhib 2008, 4,
ˇ
ˇ ´
´
20
160.
powder. Yield: 85%; m.p. 224–226ꢁC; [a]D ¼ þ128.0ꢁ (ace-
1
[4] Grutzendler, J.; Morris, J. C. Drugs 2001, 61, 41.
tone c ¼ 1) ; H NMR (400.13 MHz, DMSO-d6): d ¼ 1.62 (d,
[5] Blacklock, T. J.; Shuman, R. F.; Butcher, J. W.; Schearin,
3H, 2-H, J ¼ 7.2 Hz), 5.22 (kv, 1H, 3-H, J ¼ 7.2 Hz), 7.37
W. E.; Budavari, J.; Grenda, V. J. J Org Chem 1988, 53, 836.
[6] Hijikata, Ch. WO Pat. 2,001,074,794, 2001; Chem Abstr
2001, 135, 288775.
[dt, 1H, 5-H, J ¼ 2.5, 9.1 Hz, J(19F, H) ¼ 9.1 Hz], 7.43 (d,
1H, 1-H, J ¼ 7.5 Hz) NH urea,7.65 (d, 2H, 10-H, 50-H, J ¼
9.1 Hz), 7.98 (d, 1H, 4-H, J ¼ 8.8 Hz), 7.99 [dd, 1H, 6-H, J
3
1
[7] Hijikata, Ch. US patent 6,608,207, 2003.
¼ 2.5 Hz, J(19F, H) ¼ 8.8 Hz], 8.15 (d, 2H, 20-H, 40-H, J ¼
9.1 Hz), 9.49 (s, 1H, 60-H) NH urea; 13C NMR (100.62 MHz,
DMSO-d6): 20.7, 48.2, 108.7 [d, 2J(19F, 13C) ¼ 27.2 Hz],
3
1
[8] Itoh, O.; Honnami, T.; Amano, A.; Murata, K.; Koichi, Y.;
Sugita, T. J Org Chem 1992, 57, 7334.
[9] Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman,
A.; Toker, L.; Silman, I. Science 1991, 25, 872.
[10] Vellom, D. C.; Radic, Z.; Li, Y.; Pickering, N. A.; Camp,
S.; Taylor, P. Biochemistry 1993, 32, 12.
114.6 [d, J(19F, 13C) ¼ 25.2 Hz], 117.2, 123.7 [d, J(19F, 13C)
¼ 10.1 Hz], 125.2, 135.8 [d, 3J(19F, 13C) ¼ 11.1 Hz], 140.8,
146.6, 149.7 [d, 5J(19F, 13C) ¼ 1.0 Hz], 154.0, 159.5 [d,
1J(19F, 13C) ¼ 241.5 Hz], 176.2 [d, 4J(19F, 13C) ¼ 4.0 Hz];
19F NMR (376.46 MHz, DMSO-d6): d ¼ ꢀ116.54. Anal.
2
3
ˇ
[11] Zdrazilova, P.; Stepankova, S.; Komers, K.; Ventura, K.;
ˇ
ˇ
´
ˇ ´
´
Cegan, A. Z. Naturforsch 2004, 59c, 293.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet