Synthesis and QSAR studies in 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives as potential antithrombotic agents

Article abstract of DOI:10.1016/S0968-0896(01)00082-7

A series of 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives have been synthesized via cyclocondensation of N-aryl thioureas with 2-bromoethylamine hydrobromide followed by the reaction of the product thus obtained with aroyl chlorides. Title compounds were evaluated for their antithrombotic activity in vivo in mice where one of these compound 29 provided 65% protection as compared to 77% protection offered by the standard Indomethacin. Quantitative Structure-Activity Relationship (QSAR) studies were performed on these compounds using physicochemical (hydrophobic, electronic, steric) parameter as independent and antithrombic activity as dependent parameter, where antithrombotic activity correlated best (r > 0.8) with electronic parameters (F, σ or μ) having high statistical significance > 99.9% (F_2,22 > 15.0; F_2,22α:0.001 = 11.0) suggesting that hydrophobic, steric and resonance factors are insignificant in this set of molecules for the activity.

Full text of DOI:10.1016/S0968-0896(01)00082-7

Bioorganic & Medicinal Chemistry 9 (2001) 2025–2034
Synthesis and QSAR Studies in 2-(N-aryl-N-aroyl)amino-4,5-
dihydrothiazole Derivatives as Potential Antithrombotic Agents$
Anil K. Saxena,a,* Suresh K. Pandey,a P. Seth,b M. P. Singh,b M. Dikshitb and A. Carpyc
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow-226 001, India
bDivision of Pharmacology, Central Drug Research Institute, Lucknow-226 001, India
c
`
Laboratoire de Physico- & Toxico-Chimie (LPTC) des Systemes Naturels, UMR 5472, CNRS,
Universite de Bordeaux I, 33405 Talence Cedex, France
Received 26December 2000; accepted 16March 2001
Abstract—A series of 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives have been synthesized via cyclocondensation of N-
aryl thioureas with 2-bromoethylamine hydrobromide followed by the reaction of the product thus obtained with aroyl chlorides.
Title compounds were evaluated for their antithrombotic activity in vivo in mice where one of these compound 29 provided 65%
protection as compared to 77% protection offered by the standard Indomethacin. Quantitative Structure–Activity Relationship
(QSAR) studies were performed on these compounds using physicochemical (hydrophobic, electronic, steric) parameter as inde-
pendent and antithrombic activity as dependent parameter, where antithrombotic activity correlated best (r>0.8) with electronic
parameters (F, s or m) having high statistical significance >99.9% (F2,22>15.0; F2,22a:0.001=11.0) suggesting that hydrophobic,
steric and resonance factors are insignificant in this set of molecules for the activity. # 2001 Elsevier Science Ltd. All rights
reserved.
Introduction
has been attributed to its indirect thromboxane A2
inhibition by acetylating the cyclooxygenase enzyme,
but, in view of its non-selectivity to the platelets and
ineffectivity for the preexisting clot, there is a need for
more efficacious agent devoid of above limitations.4,5
The choice of thromboxane A2 synthase inhibitors
(TxSI) or thromboxane A2 receptors antagonists
(TxRA) once considered to have several advantages6,7
over aspirin in terms of selective nature of inhibition as
well as accumulation of prostaglandin (PG) endoper-
oxides leading to the generation of platelet inhibitory
and tissue protective prostaglandin (PG) endoperoxides,
such as prostacyclin has not shown encouraging clinical
results and hence none of the drugs under phase III
trials could get the market approval. Hence, the search
for new chemical entities (NCE’s) for antiplatelet/
antithrombotic activity is of current interest.8
The cardiovascular system disorders related diseases are
the prime cause of mortality and morbidity in the
today’s world leading towards major socio-economic
consequences. Controlled activation of blood coagula-
tion, that is haemostasis is necessary to prevent the
blood loss after fatal injury, where as, uncontrolled
activation could lead to vascular and arterial throm-
bosis, which in turn could result into various serious
thromboembolic diseases and the balance between these
two states is maintained by the thrombin,1 key enzyme
of the blood coagulation cascade. Thrombin is a multi-
functional protein2 and plays a key role in the activation of
platelets. Once platelets are activated, they enhance their
production many folds by activating thromboxane A2.
Aspirin is still the standard reference compound3 for
long term oral treatment for antiplatelet activity, which
Based on our earlier laboratory experiences and the lit-
eratures9,10 where some thiazole containing moieties were
reported to posses antithrombotic activity, it appeared of
interest to explore pharmacophoric character of this
relatively unexploited substituent for antithrombotic
activity. Hence, the title compounds, 2-dis-
ubstitutedamino-4, 5-dihydrothiazoles incorporating this
substructure along with hydrophobic phenyl rings were
designed, synthesized and evaluated for antithrombotic
*Corresponding author. Tel.:+91-522-212411-18, ext. 4268; fax: +91-
522-223405/223938/229504; e-mail: anilsak@hotmail.com (A.K. Saxena);
a.carpy@lpte.u-bordeaux (A. Carpy).
$
CDRI Commun. No. 6107. Part of the work has been presented in
the Fifth IUPAC International Symposium on Bio-organic Chemistry,
ISBOC-5 at National Chemical Laboratory, Pune, India. 30 January–
4 February 2000.
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00082-7

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A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
activity in vivo in mice. Further, the 2-D Quantitative
Structure Activity Relationship (QSAR) studies were
performed using the Hansch (linear free energy rela-
tionship) approach11 keeping physicochemical para-
meters [hydrophobic (p), electronic (s, R, F, m), steric
(MR)] as an independent and antithrombotic activity as
dependent parameter. The details of these studies are
reported here.
thioureas (3a–j). In this route the substituted anilines
(1a–j) were heated with ammonium thiocyanate in pre-
sence of hydrochloric acid as per literature method14 to
give the N-aryl thioureas (3a–j). Except for a few ani-
lines containing strong electron withdrawing groups,
this one step method in general was better than the
previous one in terms of the cost, yield and time. Com-
pounds 3a–j were cyclocondensed with 2-bromoethyla-
mine hydrobromide to give the five member stable
endocyclic15 2-arylamino-4, 5-dihydrothiazoles (4a–j).
Finally, the reaction of 4a–j with aroyl chlorides in dry
acetone or THF using triethyl amine as a base pro-
vided the title compounds 2-(N-aryl-N-aroyl)amino-4,
5-dihydrothiazoles (5–29)16 in good to excellent yields
(Scheme 1). The structures of the final products 5–29
were characterized by routine spectroscopic data and
elemental analyses and finally confirmed by X-ray crys-
tallographic structure (Fig. 1) of one such compound 9.
Chemistry
The key intermediates N-arylthioureas (3a–j) required
for the synthesis of 2-(N-aryl-N-aroyl)amino-4, 5-dihy-
drothiazoles (5–29) were synthesized by the two routes
(Scheme 1). In the first route, substituted anilines (1a–j)
were condensed with benzoylisothiocyanates followed
by the selective hydrolysis of carbonyl group (>C¼O)
of the products (2a–j) thus formed with sodium
hydroxide (NaOH) as per reported method.12,13 In a few
cases, the N-aryl thioureas (3a–e) along with byproduct,
which had different Rf value on TLC from the starting
Antithrombotic activity evaluation
Swiss mice (20–25 g, from CDRI animal colony) were
used in a group of at least 10 animals each. Thrombosis
was induced by infusion of a mixture of 15 mg collagen
and 5 mg adrenaline in a volume of 100 mL into the tail
vein of each mouse. This resulted either death or hind
limb paralysis of 100% animals.
1
material 2, IR and H NMR characteristics similar to
the starting material 2 but with lower molecular mass
(M+À C6H5CSNH) of less intensity unlike that of the
starting material 2 (M+) was obtained. In order to
deduce their structure, byproduct crystals obtained in
the case of aniline and 4-anisidine (2a and 2b respec-
tively) were investigated for their X-ray data which
showed them to be benzamide derivative of aniline (30a)
and 4-anisidine (30b). The structure of the byproduct
(30a) was also confirmed by unambiguous and simple
synthesis involving condensation of aniline (1a) with
benzoyl chloride and comparing the spectroscopic data
of the product thus formed with 30a which were iden-
tical. The byproduct of type 30 was formed in cases
where the hydrolysis was not selective and hydroxide
ion (HOÀ) is free to attack on both, the carbonyl
(>C¼O) and thiocarbonyl (>C¼S) groups. It was
observed that ratio of the byproducts (30a–e) depended
on the electronegativity of the substituent group on the
aniline (Table 1) and the group having high electron
donating ability increased the amount of the byproduct.
The plausible mechanism for the byproduct formation
might be intramolecular carbon to carbon (C-to-C)
migration of the substituted aniline group through a
concerted pathway (Scheme 2).
The compounds (5–29) were administered po (0.5 mM/
kg/mice) 1 h prior to the thrombotic challenge. The
antithrombotic effect of these compounds was asses-
sed by the percent protection (%P) offered by these
agents to mice from death or paralysis following
thrombotic challenge using Indomethacin as a stan-
dard17 (Table 2).
Results and Discussion
2-D QSAR analysis
Most of the title compounds 5–29 exhibited good
antithrombotic activity in vivo in mice and among them
the compounds 25, 28 and 29 showed ꢀ50% protection
in the order 29>28=25 for the thrombosis as compared
to 77% protection offered by the standard Indometha-
cin. In order to gain insight into structure–activity rela-
tivity,
these
compounds
were
analyzed
by
physicochemical based QSAR (Hansch) approach using
Due to the above-mentioned complications, second
route was adopted for the synthesis of the N-aryl
physicochemical parameters such as hydrophobic (p),
Table 1. Ratios of the expected N-aryl thioureas (3) and unexpected N-aryl benzamides (30)
Compd no.
R1
(g) (%)
(g) (%)
(g) (%)
a
b
c
d
e
H
7.5
5.0
5.0
5.0
5.0
3.24 (73)
1.74 (55)
1.67 (54)
1.32 (43)
1.90 (60)
1.60 (27)
1.58 (40)
0.90 (23)
0.50 (13)
0.95 (24)
4-OCH3
2-CH3
4-F
4-C2H5

A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
2027
steric (molar refractivity, MR) electronic (Field F,
Resonance R, Hammett’s constant s and group dipole
moment m) as independent and antithrombotic activity
data [percent protection (%P) at 0.5 mM dose converted
to log (P/100ÀP)] as dependent parameters. The values
of the physicochemical parameters used were taken
from the literature,18,19 and multiparameter linear
regression analysis was carried out on PC-486model
using in house built program GW BASIC and/or
SYSTAT (version 7.0) software.20 Different physico-
chemical parameters such as hydrophobicity (pR1, pR2),
steric (MRR1, MRR2) and electronic (RR1, RR2, FR1,
Scheme 1. (i) Dry acetone, 5 ꢁC; (ii) (a) NaOH; (b) HCl; (c) NH4OH; (iii) NH4SCN, HCl, ꢀ; (iv) (a)Br(CH2)2NH2ꢂ HBr, EtOH, reflux; (b) NH4OH;
(v) dry acetone or THF, Et3N, 30 ꢁC.
Scheme 2. Plausable intramolecular concerted mechanism for the formation of the byproducts (30a–e).

2028
A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
FR2, sR1, sR2, mR1, mR2) where R1 and R2 indicates
substituent(s) in the phenyl and phenyl carbonyl rings,
respectively, were correlated as an independent para-
meters with log[P/100ÀP] as dependent variable (Table
3). In the case of disubstituent, the values were com-
puted by simple algebraic addition of substituent coeffi-
cients for the variables p, MR, R, F, and s, while in the
case of m the resultant value was obtained by vector
addition of the corresponding substituents and con-
sidering their coefficient sign for final value, for example
in the case of compound 29, there are two substituent Cl
and NO2 on the phenyl group at para (4) and meta (3)
positions, respectively. Their resultant mR1 value is com-
puted as follows:
Figure 1. X-ray structure of compound 9 (ORTEP plot). Arbitrary numbering.
Table 2. Physicochemical data of 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazoles (5–29)
Compd
no.
Molecular formula
R1
R2
Molecular
weight
mp ꢁ
C
%(Protection)
P at 0.5 mM/kg
Log
(P/100ÀP)
5
6
7
8
C17H13N2OSF3
C16H13N2OSF
C18H18N2O3S
C17H15N2OSCl
C17H16N2OS
2-CF3
4-F
2,5(OCH3)
2-Cl, 6-CH3
2-CH3
2-CF3
2-CH3
2,5(OCH3)
4-F
2-Cl, 6-CH3
2-CF3
H
H
H
H
H
350
300
342
330.5
296100–01
380
326120
372
330
344.5
364
314
32686
344.5
365
334.5
375
361
409.5
387
372
98–99
101–02
116–17
120–21
30
37.5
30
À0.3679
À0.2218
À0.3679
À0.3679
À0.6020
À0.3679
À0.3679
À0.1760
À0.1760
À0.4771
À0.2218
À0.3679
À0.4771
À0.1760
À0.3011
À0.3017
À0.3679
À0.1760
À0.2218
À0.1241
0.0000
2
30
9
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
C18H15N2O2SF3
C18H18N2O2S
C19H20N2O4S
C17H15N2O2SF
C18H17N2OSCl
C18H15N2OSF3
C17H15N2OSF
C18H18N2O2S
C18H17N2OSCl
C17H14N2OSCl2
C16H12N2SOFCl
C17H15N2OSBr
C16H13N2OSBr
C17H14N2OSBrCl
C18H17N2O5S
C16H12N4O5S
C16H12N2O3SF
C17H15N2SO3
C17H15N3SO4
C16H11N4SO5Cl
4-OCH3
4-OCH3
4-OCH3
4-OCH3
2-CH3
2-CH3
2-CH3
2-CH3
4-Cl
4-Cl
4-Cl
2-Br
2-Br
136–38
30
130
30
40
2
7640
81
130–31
83–84
25
37.5
30
4-F
4-OCH3
4-C2H5
2-Cl, 6-CH3
4-F
–87
25
115
115
105
98
166
118
140
168
93
40
33.3
33.3
30
2-CH3
H
2-Cl, 6-CH3
2,5(OCH3)
4-NO2
4-F
2-CH3
40
2-Br
37.5
42.9
50.0
40
42.1
50.0
64.7
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2
345
341
357
406.5
À0.1760
À0.1383
0.0000
98
110
166
4-OCH3
4-Cl, 3-NO2
0.2631

A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
2029
2
2
1=2
mR1¼½ðmClÞ þ ðmNO2Þ þ 2ðmClÞðmNO2Þcos 60ꢀŠ
FR1, sR1, mR1, and correlated (r>0.6) with FR2,
sR2, mR2.
2
2
1=2
¼ ½ðÀ1:59Þ þ ðÀ4:13Þ þ 2ðÀ1:59ÞðÀ4:13Þð0:5ފ
Considering the above and keeping in view that there is
no colinearity between the two sets (sR1, mR1 and FR1)
and (sR2, mR2 and FR2) of electronic parameters but
they have high intercorrelation (r>0.7) among each
other in each set, the two parameter equations with one
parameter from each set at one time were deduced.
None of these equations (1)–(9) had parameter with
intercorrelation greater than 0.5 (r<0.5). All these nine
two-parameter equations had high correlation coeffi-
cient (r>0.77) with high statistical significance >99.9%
(F2,22 >15.0; F2,22a: 0.001=11.0). The observed ratio of
1:1.5 with regression coefficients of electronic para-
meters corresponding to R1 and R2 positions of mole-
cule suggest that the electronic influence of the groups
positioned in the benzoyl part (R2) of the molecules is
more on the observed antithrombotic activity compared
to the corresponding electronic influence of the
1=2
1=2
¼ ½2:5281 þ 17:0569 þ 6:5667Š ¼ ½26:1517Š
¼ À5:11
(Note: Angle between the Cl and NO2 is 60o and as both
are electron withdrawing groups and are having nega-
tive signs before their coefficients value, overall sign is
taken as negative before the final computed value.)
In the preliminary analysis by analyzing the corre-
lation matrix (Table 4) it is observed that the
antithrombotic activity, log (P/100ÀP) is poorly
correlated (r<0.4) with pR1, pR2, MRR1, MRR2,
RR1 and RR2; slightly correlated (0.4<r<0.6)
Table 3. Physicochemical parameters used in generating 2D QSAR equations for 2-(N-aryl-N-aroyl)amino- 4,5-dihydrothiazoles (5–29)
Comp
no.
R1
R2
m -R1
m-R2
s-R1
s-R2
FR1
FR2
p-R1
p-R2
RR1
RR2
MR-R1 MR-R2
5
6
7
8
2-CF3
4-F
2,5(OCH3)2
2-Cl, 6-CH3
2-CH3
H
H
H
H
H
À2.61
À1.43
À1.30
À1.80
0.360.03
0.03
0.03
0.03
0.03
0.54
0.00
0.38
0.00
0.88
0.00
0.00
0.19
À0.34
À1.02
À0.28
À0.13
0.19
0.00
0.00
0.00
0.00
0.00
À0.51
5.02
0.92
15.74
11.68
5.65
5.02
5.65
15.74
0.92
1.03
1.03
1.03
1.03
1.03
7.87
7.87
7.87
7.87
5.65
5.65
5.65
5.65
6.03
6.03
6.03
8.88
8.88
8.88
0.060.00
À0.54
0.060.00
À0.17
0.54
0.43
0.00
0.14
0.00
À0.04
0.00
0.560.00
0.00
0.00
À0.27
0.52
0.00
0.37
0.00
1.27
9
À0.04
0.00
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2-CF3
2-CH3
4-OCH3 À2.61 À1.30
0.38
0.260.88
0.260.56
0.26
À0.02
4-OCH3 0.36
À1.30 À0.17 À0.27 À0.04
À0.02 À0.13 À0.51
2,5(OCH3)2 4-OCH3 À1.30 À1.30 À0.54 À0.27
0.52
0.43
0.37
0.38
0.43
0.26
À0.05
À0.04 À0.02 À1.02 À0.51
À0.02 À0.02 À0.34 À0.51
4-F
2-Cl, 6-CH3
2-CF3
4-OCH3 À1.43 À1.30
0.06
À0.27
À0.17
À0.17
À0.17
0.26
2-CH3
2-CH3
2-CH3
2-CH3
4-Cl
À1.80
À2.61
À1.43
À1.30
0.39
0.360.06
0.36
0.360.06
0.36
À0.04
À0.04
À0.04
1.27
0.88
0.14
0.56
À0.28 À0.13
À0.13
11.68
5.02
0.92
0.54
0.560.19
0.56
0.56
4-F
À0.34 À0.13
À0.51 À0.13
À0.10 À0.15
À0.28 À0.15
À0.34 À0.15
À0.13 À0.17
À0.17
4-OCH3
4-C2H5
2-Cl, 6-CH3
4-F
2-CH3
H
2-Cl, 6-CH3
2,5(OCH3)2
4-NO2
4-F
2-CH3
À0.27 À0.17
À0.04 À0.02
7.87
À1.59 À0.15
0.23
0.41
1.02
0.71
10.30
11.68
0.92
5.65
1.03
4-Cl
4-Cl
2-Br
2-Br
À1.80 À1.59
0.060.23
0.060.23
0.37
0.43
0.41
0.41
0.14
1.27
0.71
0.71
À1.43 À1.59
0.36
0.03
À1.57 À0.17
0.23
0.23
0.04
0.00
0.44
0.44
0.560.86
0.00
0.86
À1.57
0.00
0.060.23
0.860.00
2-Br
À1.80 À1.57
0.37
0.44
1.27
À0.28 À0.17
11.68
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
À1.30 À4.13 À0.54
0.78
0.78
0.52
0.67
0.67
0.67
À0.04 À0.28 À1.02
0.1615.74
0.160.16 7.36 7.36
7.36
7.36
À4.13 À4.13
À1.43 À4.13
0.78
0.060.78
À0.28 À0.28
0.43 7 0.6 0.14
À0.28 À0.34
0.160.92
0.36
À1.30 À4.13 À0.27
À5.11 À4.13 1.01
À4.13 À0.17
0.78
0.78
0.78
À0.04
0.2760.6
1.08
0.67
0.67
0.56
À0.02 À0.28 À0.51
À0.28 À0.13
0.5165.6 7.36
0.167.87
0.1613.39
2-OCH3
4-Cl, 3-NO2
7.36
7.36
0.43
À0.28
0.01
Table 4. Correlation matrix of the parameters used in 2-D QSAR study
sR1
sR2
pR1
pR2
MRR1 MRR2
FR1
FR2
RR1
RR2
mR1
mR2
Log(P/100ÀP)
sR1
sR2
1.000
0.131
1.000
pR1
pR2
0.125 À0.260
1.000
0.370
0.199 À0.130
À0.197 À0.371
1.000
MRR1
MRR2
FR1
À0.059
0.123
0.647
0.083
0.125
0.083 À0.025
1.000
0.278 À0.053
1.000
0.310 À0.010
0.199 À0.212 À0.357
0.847 À0.253 À0.273
1.000
0.107
FR2
0.085
0.462
1.000
0.008
0.259
RR1
0.610 À0.003
0.411
0.156 À0.494
0.118 À0.270
0.287 À0.202
0.482 À0.109 À0.349 À0.205 À0.968
0.148 0.254 0.514 0.734
0.137 À0.167
1.000
0.031
RR2
0.208
À0.860 À0.181
À0.136 À0.885
0.708 À0.108 À0.268
0.252
1.000
mR1
0.010
0.328
0.014 À0.900 À0.078 À0.217 À0.242
0.027 À0.351
0.038
1.000
0.168
mR2
Log(P/100ÀP)
1.000
0.422
0.681 À0.315 À0.381
0.271 À0.476 À0.768
1.000

2030
A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
substituent present in aryl part (R1) of the the mole-
cules. The positive value of Hammett’s constant (s) at
both positions R1 and R2 suggest that electronic influ-
ence is more than steric and hydrophobic factor and
presence of electron withdrawing groups at these
positions will increase activity. Since the s parameter
takes into account the electronic influence in terms of
resonance (R) and field effect (F) described by Swain
and Lupton, hence the better correlation with field effect
(F), both at R1 and R2 position indicate that the elec-
tronic influence here is primarily governed by the field
effect [eq (5)] over others [eqs (2), (4), (6) and (8)] with
higher correlation coefficient value (r=0.86) of high
statistical significance >99.9% (F2,22=29.9; F2,22a:
0.001=11.0) as that of eq 5.
The 2-D QSAR results are suggesting that it is only the
electronic factors, namely Hammett constant (s),
group dipole moment (m) and field effect (F) that
are crucial for the antithrombotic activity in the
present set of dihydrothiazoles (5–29) and steric/
bulk and hydrophobic factors have got no influence
for the activity and are not playing any important role
here.
The above results also indicate that dihydrothiazoles
may be considered as a good pharmacophore for the
antithrombotic activity and antithrombotic activity in
this series is negatively influenced by the electronic
parameter in terms of group dipole moment (m), field
effect (F) and Hammett’s field constant (s) of the sub-
stituents present in the phenyl and benzoyl rings in the
ratio of approximately 1:1.5. This altogether means the
same thing that the increase in the positive character at
2-amino position of the title compounds positively
contribute for the activity and may be involved in
electrostatic interactions or in the binding with the
anionic site. Further antithrombotic activity can be
increased by polysubstituting the phenyl and benzoyl
rings with groups having highly negatively m values and
highly positive F and s values, namely NO2, CN,
CO2H, CONH2, CONHR, SO2F, SO2OR, NR+3 , N2+,
etc.
Log ðP=100 À PÞ ¼ 0:186ðÆ0:077ÞsR1
þ 0:294ðÆ0:064ÞsR2 À 0:317
n ¼ 25 r ¼ 0:759 s ¼ 0:122 F ¼ 15:00
ð1Þ
ð2Þ
ð3Þ
ð4Þ
ð5Þ
Log ðP=100 À PÞ ¼ 0:199ðÆ0:067ÞsR1
þ 0:458ðÆ0:080ÞFR2 À 0:404
n ¼ 25 r ¼ 0:819 s ¼ 0:108 F ¼ 22:41
Log ðP=100 À PÞ ¼ 0:178ðÆ0:065ÞsR1
À 0:078ðÆ0:013ÞmR2 À 0:384
The reliability of the equations obtained by multiple
regression analysis is reflected by the similarities in
antithrombotic activity observed in vivo testing and
calculated by these equations for the substituted dihy-
drothiazoles (5–29) (Table 5).
n ¼ 25 r ¼ 0:832 s ¼ 0:104 F ¼ 24:78
Log ðP=100 À PÞ ¼ 0:078ðÆ0:093ÞFR1
þ 0:278ðÆ0:063ÞsP2 À 0:389
n ¼ 25 r ¼ 0:783 s ¼ 0:117 F ¼ 17:41
Table 5. Comparision between the observed and calculated antith-
rombotic activity from the 2-D QSAR equations having r>0.80
Log ðP=100 À PÞ ¼ 0:301ðÆ0:076ÞFR1
þ 0:447ðÆ 0:072ÞFR2 À 0:485
Compd Observed
no.
Calculated
n ¼ 25 r ¼ 0:855 s ¼ 0:097 F ¼ 29:88
eq (2)
eq (3) eq (5) eq (6) eq (8) eq (9)
5
6
7
8
À0.3679 À0.296 À0.290 À0.371 À0.354 À0.322 À0.313
À0.2218 À0.392 À0.376 À0.356 À0.342 À0.388 À0.369
À0.3679 À0.434 À0.413 À0.328 À0.319 À0.395 À0.375
À0.3679 À0.392 À0.376 À0.374 À0.357 À0.367 À0.351
À0.6020 À0.438 À0.416 À0.497 À0.461 À0.488 À0.454
À0.3679 À0.177 À0.187 À0.254 À0.256 À0.203 À0.212
À0.3679 À0.319 À0.313 À0.381 À0.363 À0.370 À0.353
À0.1760 À0.315 À0.309 À0.212 À0.220 À0.277 À0.274
À0.1760 À0.273 À0.272 À0.290 À0.243 À0.269 À0.274
À0.4771 À0.411 À0.401 À0.391 À0.387 À0.385 À0.376
À0.2218 À0.315 À0.316 À0.388 À0.379 À0.340 À0.338
À0.3679 À0.411 À0.401 À0.373 À0.366 À0.406 À0.394
À0.4771 À0.476 À0.460 À0.425 À0.410 À0.413 À0.400
À0.1760 À0.246 À0.287 À0.137 À0.344 À0.303 À0.332
À0.3011 À0.204 À0.249 À0.172 À0.237 À0.180 À0.246
À0.3017 À0.204 À0.249 À0.190 À0.222 À0.201 À0.228
À0.3679 À0.237 À0.292 À0.300 À0.343 À0.287 À0.332
À0.1760 À0.203 À0.262 À0.288 À0.332 À0.269 À0.316
À0.2218 À0.191 À0.251 À0.177 À0.238 À0.166 À0.230
À0.1241 À0.127 À0.089 À0.029 À0.010 À0.090 À0.059
0.0000 À0.058 0.0760.015 0.028 09.06 0.075
Log ðP=100 À PÞ ¼ 0:254ðÆ0:079ÞFR1
À 0:074ðÆ0:012ÞmR2 À 0:449
9
n ¼ 25 r ¼ 0:850 s ¼ 0:099 F ¼ 28:56
ð6Þ
ð7Þ
ð8Þ
ð9Þ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Log ðP=100 À PÞ ¼ À0:048ðÆ0:018ÞmR1
þ 0:284ðÆ0:064ÞsR2 À 0:370
n ¼ 25 r ¼ 0:770 s ¼ 0:120 F ¼ 16:00
Log ðP=100 À PÞ ¼ À0:056ðÆ0:015ÞmR1
þ 0:456ðÆ0:074ÞFR2 À 0:468
n ¼ 25 r ¼ 0:846 s ¼ 0:100 F ¼ 27:71
À0.1760 À0.085 À0.052 À0.056 À0.033 À0.082 À0.052
À0.1383 À0.131 À0.094 À0.198 À0.152 À0.183 À0.137
0.0000 À0.154 À0.110 À0.107 À0.076 À0.089 À0.059
Log ðP=100 À PÞ ¼ À0:047ðÆ0:015ÞmR1
À 0:076ðÆ0:012ÞmR2 À 0:435
n ¼ 25 r ¼ 0:845 s ¼ 0:101 F ¼ 27:40
0.2631
0.090 0.105 0.139 0.132 0.124 0.121

A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
2031
Experimental
The product 4j was filtered, washed with water, dried
and recrystallised with methanol.
Preparation of N-phenyl-N0-benzoylthiourea (2a)
A solution of benzoyl isothiocyanate (1.63 g, 0.01 mol)
in dry acetone (20 mL) was added dropwise to a stirred
solution of aniline 1a (0.93 g, 0.01 mol) in dry acetone
(30 mL) at 20 ꢁC over 10 min. After stirring the mixture
at 20 ꢁC for 2 h, it was concentrated, filtered, washed
with a small amount of cold dry acetoneꢁand dried to
give 2a. Yield 2.4 g (94%): MP 145–146 C (lit.13 MP
147.5–148.5 ꢁC).
Yield=2.20 g (60%); mp=150 ꢁC; EIMS (m/z)=257.5
(m+); 1H NMR (CDCl3) (400 MHz)=d 3.37 (t,
J=7.0 Hz, 2H, SCH2 ), 3.74 (t, J=7.0 Hz, 2H, NCH2),
7.15 (dd, J=3.0, 9.0 Hz, 1H, ArH ), 7.42 (d, J=9.0 Hz,
IH, ArH), 7.58 (d, J=3.0 Hz, 1H, ArH); FTIR
(KBr)=689, 822, 887, 1065, 1126, 1211, 1269, 1348,
1475, 1524, 1626, 2363. Anal. calcd for C9H8N3O2SCl:
C 41.95; H 3.13; N 16.3%. Found: C 41.81; H 3.08; N
16.14%.
Similarly, other compounds (2b–j) of this series were
prepared from corresponding substituted anilines.
Preparation of N-(4-chloro-3-nitrophenyl)-N-(4,5-dihy-
dro-1,3-thiazol-2-yl)-4-nitrobenzamide (29, R1=4-Cl, 3-
NO2). 4-Nitrobenzoyl chloride (0.40 g, 2.2 mmol) and
dry triethylamine (0.30 mL, 2.2 mmol) were added to a
solution of (4j) (0.52 g, 2.0 mmol) in dry acetone
(15 mL), and the resulting solution was stirred at room
temperature for 1 h. The reaction mixture was then
concentrated in vacuo and water was added to get the
crude product (29). It was filtered, washed with water,
dried and recrystallised with methanol.
General method for the preparation of N-arylthioureas
Method A: preparation of N-phenylthiourea (3a, R1=
H). 2a (1.28 g, 5.0 mmol) was added in one portion to a
stirring 5% aqueous NaOH (20 mL) solution at 90 ꢁC
and stirring was continued for further 20 min. The hot
reaction mixture was filtered to get byproduct 30a and
the filtrate obtained was cooled, acidified with 15%
aqueous HCl and its pH was adjusted to ꢃ8.0 with
aqueous ammonia to remove benzoic acid. The solid
obtained was filtered, washed with water and dried to
give 3a.
Yield 0.65 g (80%): mp 166 ꢁC; 1H NMR (300 MHz,
CDCl3): d 3.57 (t, J=6.8 Hz, 2H, SCH2), 4.37 (t,
J=6.8 Hz, 2H, NCH2), 7.02 (dd, J=2.6, 8.6 Hz, 1H,
ArH), 7.32 (d, J=2.4 Hz, 1H, ArH), 7.54 (d, J=6.8 Hz,
1H, ArH), 7.97 (d, J=9.0 Hz, 2H, ArH), 8.30 (d,
J=9.0 Hz, 2H, ArH); FTIR (KBr, cmÀ1): 708, 857,
1015, 1161, 1358, 1474, 1531, 1599, 1638, 3082; MS(EI):
m/z 406(M +). Anal. calcd for C16H11N4O5SCl: C
47.24; H 2.73%. Found: C 47.18; H 2.78%.
Yield 0.55 g (73%): mp 152–153 ꢁC (lit.13 mp 154.5–
155.5 ꢁC)
Method B: preparation of N-(4-chloro-3-nitrophenyl)-
thiourea (3j, R1=4-Cl, 3-NO2). A saturated solution of
ammonium thiocyanate (0.76g, 0.01 m) was added to a
clear solution of 4-chloro-3-nitroaniline 1j (1.72 g,
0.01 m) in 15% aqueous HCl (2.06mL, 0.01 m), and the
resultant solution was boiled until a viscous layer or
turbidity appeared (ꢄ2 h). It was then poured into cru-
shed ice and the precipitated product 3j was filtered,
washed with water, dried and used for next step without
further purification.
Similarly, other compounds (5–28) of the series were
prepared and their physicochemical data is given below.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-trifluoromethylphe-
nyl)benzamide(5, R1=2-CF3, R2=H). Yield 68%: mp
98–99 ꢁC; 1H NMR (90 MHz, CDCl3): d 2.20 (t,
J=8.0 Hz, 2H, SCH2), 4.20 (t, J=8.0 Hz, 2H, NCH2),
7.00–7.80 (m, 9H, ArH); IR (KBr, cmÀ1): 1050, 1140,
1180, 1280, 1330, 1620, 1650, 1690; MS(EI): m/z 350
(M+). Anal. calcd for C17H13N2OSF3: C 58.23; H
3.74%; N 8.0. Found: C 58.13; H 3.62; N 7.84%.
Yield 1.75 g (76%): mp 185–87 ꢁC; 1H NMR (200 MHz,
CDCl3+DMSO-d6): d 2.70 (brs, 2H, NH2), 7.46(d,
J=8.7 Hz, 1H, ArH), 7.87 (dd, J=2.3, 8.7 Hz, 1H,
ArH), 8.34 (d, J=2.4 Hz, 1H, ArH), 9.86(brs, 1H, NH);
FTIR (KBr, cmÀ1): 702, 824, 1043, 1258, 1319, 1352,
1460, 1529, 1582, 1608, 3003, 3069, 3125, 3169, 3275,
3433; MS (EI): m/z 231 (M+). Anal. calcd for
C7H6N3O2SCl: C 22.17; H 1.60; N 11.08%. Found: C
22.10; H 1.44; N 11.00%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-fluorophenyl)ben-
zamide (6, R1=4-F, R2=H). Yield 78%: mp 101–
102 ꢁC; 1H NMR (90 MHz, CDCl3):
d 3.25 (t,
J=8.0 Hz, 2H, SCH2), 3.90 (t, J=8.0 Hz, 2H, NCH2),
6.80–7.40 (m, 9H, ArH); IR (KBr, cmÀ1): 1020, 1220,
1300, 1500, 1600, 1620; MS(EI): m/z 300 (M+). Anal.
calcd for C16H13N2OSF: C 63.98; H 4.36; N 9.33%.
Found: C 63.84; H 4.30; N 9.28%.
The other N-arylthioureas (3a–i) of the series were pre-
pared adopting either of the above procedures.
Preparation of 2-(4-chloro-3-nitrophenyl)amino-4,5-dihy-
drothiazole (4j, R1=4-Cl, 3-NO2). A solution of 2-
bromoethylamine hydrobromide (2.05 g, 0.01 m) in
5.0 mL of water was added to a solution of 3j (2.31 g,
0.01 m) in ethanol (40 mL), and the reaction mixture
was refluxed under stirring overnight. Ethanol was dis-
tilled off under reduced pressure and the reaction mix-
ture was basified with dilute aqueous ammonia solution.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(2,5-dimethoxyphe-
nyl)benzamide (7, R1=2,5(OCH3)2, R2=H). Yield
72%: mp 116–117 ꢁC; 1H NMR (90 MHz, CDCl3): d
3.20 (t, J=8.0 Hz, 2H, SCH2), 3.70 (s, 6H, OCH3), 4.30
(t, J=8.0 Hz, 2H, NCH2), 6.30 (d, J=3.0 Hz, 1H, ArH),
6.60 (d, J=3.0 Hz, 1H, ArH), 6.70 (s, 1H, ArH), 7.30–
7.50 (m, 3H, ArH), 7.70–7.90 (m, 2H, ArH); FTIR
(KBr, cmÀ1): 1030, 1050, 1130, 1170, 1340, 1650, 3000;

2032
A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
MS (EI): m/z 342 (M+). Anal. calcd for C18H18N2O3S:
C 63.02; H 5.20; N 8.22%. Found: C 63.20; H 5.28; N
8.15%.
N-(2-Chloro-6-methylphenyl)-N-(4,5-dihydro-1,3-thiazol-
2-yl)-2-methylbenzamide (14, R1=2-Cl, 6-CH3, R2=2-
CH3). Yield 68%: mp 81 ꢁC; 1H NMR (90 MHz,
CDCl3); d 1.80 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.15 (t,
J=8.0 Hz, 2H, SCH2), 4.30 (t, J=8.0 Hz, 2H, NCH2),
6.70–7.30 (m, 7H, ArH); IR (KBr, cmÀ1): 1150, 1300,
1440, 1640, 2940; MS(EI): m/z 344 (M+). Anal. calcd
for C18H17N2OSCl: C 62.69; H 4.97; N 8.12. Found: C
62.60, H 4.86; N 8.06.
N-(2-Chloro-6-methylphenyl)-N-(4,5-dihydro-1,3-thiazol-
2-yl)benzamide (8, R1=2-Cl, 6-CH3, R2=H). Yield
66%: mp 120–121 ꢁC; H NMR (90 MHz, CDCl3): d
1
2.10 (s, 3H, CH3), 3.20–3.50 (m, 2H, SCH2), 3.90–4.15
(m, 1H, NCH2), 4.25–4.45 (m, 1H, NCH2), 6.90–7.90
(m, 8H, Ar); IR (KBr, cmÀ1): 1040, 1180, 1310, 1460,
1630, 1660; MS(EI): m/z 330.5 (M+). Anal. calcd for
C17H15N2OSCl: C 61.72; H 4.57; N 8.47%. Found: C
61.58; H 4.36; N 8.39%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-2-methyl-N-(2-trifluoro-
methylphenyl)benzamide (15, R1=2-CF3, R2=2-CH3).
Yield 82%: mp 130–131 ꢁC; 1H NMR (90 MHz,
CDCl3): d 2.4 (s, 3H, CH3), 3.25 (t, J=8.0 Hz, 2H,
SCH2), 4.40 (t, J=8.0 Hz, 2H, NCH2), 6.70–7.70 (m,
8H, ArH); IR (KBr, cmÀ1): 1120, 1320, 1460, 1640; MS
(EI): m/z 364 (M+). Anal. calcd for C18H15N2OSF3: C
59.33; H 4.15; N 7.69%. Found: C 59.36; H 4.20; N
7.81%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(2-methylphenyl)ben-
zamide (9, R1=CH3, R2=H). Yield 76%: mp 100–
101 ꢁC; 1H NMR (90 MHz, CDCl3): d 1.70 (s, 3H,
CH3), 3.00–3.00 (m, 2H, SCH2), 3.70–4.20 (m, 2H,
NCH2), 6.70–7.50 (m, 9H, ArH); IR (KBr, cmÀ1): 1020,
1170, 1300, 1330, 1610, 1660; MS (EI): m/z 296(M +).
Anal. calcd for C17H16N2OS: C 68.89; H 5.44; N 9.45%.
Found: C 68.80, H 5.40; N 9.38%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-fluorophenyl)-2-
methylbenzamide (16, R1=4-F, R2=2-CH3). Yield
ꢁ
1
81%: mp 83–84 C; H NMR (90 MHz, CDCl3): d 2.35
(s, 3H, CH3), 3.25 (t, J=8.0 Hz, 2H, SCH2), 3.90 (t,
J=8.0 Hz, 2H, NCH2), 6.70–7.20 (m, 8H, ArH); FTIR
(KBr, cmÀ1): 1040, 1240, 1300, 1520, 1620, 1620, 1700;
MS(EI): m/z 314 (M+). Anal. calcd for C17H15N2OSF:
C 64.95; H 4.81; N 8.91%. Found: C 64.91; H 4.76; N
8.84%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-4-methoxy-N-(2-trifluor-
omethylphenyl)benzamide (10, R1=2-CF3, R2=4-
OCH3). Yield 80%: mp 136–138 ꢁC; 1H NMR
(90 MHz, CDCl3): d 3.20 (t, J=8.0 Hz, SCH2), 3.70 (s,
3H, OCH3), 4.20 (t, J=8.0 Hz, 2H, NCH2), 6.70–7.60
(m, 8H, ArH); IR (KBr, cmÀ1): 1030, 1160, 1350, 1530,
1600, 1600, 1660, 2950; MS(EI): m/z 380 (M+). Anal.
calcd for C18H15N2O2SF3: C 56.84; H 3.97; N 7.36%.
Found: C 56.68, H 3.92; N 7.26%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-methoxyphenyl)-2-
methylbenamide (17, R1=4-OCH3, R2=2-CH3). Yield
82%: mp 86–87 ꢁC; 1H NMR (90 MHz, CDCl3)=d 2.30
(s, 3H, CH3), 3.15 (t, J=8.0 Hz, 2H, SCH2) 3.65 (s, 3H,
OCH3), 4.20 (t, J=8.0 Hz, 2H, NCH2), 6.30–6.70 (m,
4H, ArH), 7.00–7.20 (m, 4H, ArH); IR (KBr, cmÀ1):
1060, 1180, 1260, 1360, 1520, 1670; MS(EI): m/z 326
(M+). Anal. calcd for C18H18O2S: C 66.23; H 5.56; N
8.58%. Found: C 62.16; H 5.48; N 8.48%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-4-methoxy-N-(2-meth-
oxyphenyl)benzamide(11, R1=2-CH3, R2=4-OCH3).
ꢁ
1
Yield 79%: mp 120 C; H NMR (90 MHz, CDCl3): d
1.90 (s, 3H, CH3), 3.10 (t, J=8.0 Hz, 2H, SCH2), 3.70
(s, 3H, OCH3), 4.10 (t, J=8.0 Hz, 2H, NCH2), 6.50–
7.10 (m, 8H, ArH); IR (KBr, cmÀ1): 1015, 1161, 1358,
1474, 1531, 1599, 1680, 2950; MS(EI): m/z 326(M +).
Anal. calcd for C18H18N2O2S: C 66.23; H 5.56; N
8.58%. Found: C 66.14; H 5.50; N 8.52%.
4-Chloro-N-(4,5-dihydro-1,3-thiazol-2-yl)-N-(4-ethylphe-
nyl)benzamide (18, R1=4-C2H5, R2=4-Cl). Yield 76%:
mp 115 ꢁC; 1H NMR (90 MHz, CDCl3): d 1.10 (t,
J=9.0 Hz, 3H, CH3), 2.55 (q, J=8.0 Hz, 2H, CH2), 3.20
(t, J=9.0 Hz, 2H, SCH2), 3.85 (t, J=9.0 Hz, 2H,
NCH2), 6.90–7.40 (m, 8H, ArH); IR (KBr, cmÀ1): 1000,
1240, 1450, 1590, 1670, 2960; MS(EI): m/z 344 (M+).
Anal. calcd for C18H17N2OSCI: C 62.69; H 4.97; N
8.12%. Found: C 62.89; H 4.87; N 8.21%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(2,5-dimethoxyphe-
nyl)-4-methoxybenzamide (12, R1=2,5-(OCH3)2, R2=4-
OCH3). Yield 77%: mp 130 ꢁC; 1H NMR (90 MHz,
CD3COCD3): d 3.20 (t, J=8.0 Hz, 2H, SCH2), 3.75 (s,
6H, (OCH3)2), 3.80 (s, 3H, OCH3), 4.20 (t, J=8.0 Hz,
2H, NCH2), 6.20–6.80 (m, 4H, ArH), 7.15–7.30 (m, 1H,
ArH), 7.70 (d, J=9.0 Hz, 2H, ArH); IR (KBr, cmÀ1):
1040, 1260, 1340, 1510, 1600, 1620, 3000; MS (EI): m/z
372 (M+). Anal. calcd for C19H20N2O4S: C 61.27; H
5.41%. Found: C 61.15, H 5.28%.
4-Chloro-N-(2-chloro-6-methylphenyl)-N-(4,5-dihydro-
1,3-thiazol-2-yl)benzamide (19, R1=2-Cl, 6-CH3,
R2=4-Cl). Yield 72%: mp 115 ꢁC; H NMR (60 MHz,
1
CDCl3): d 2.00 (s, 3H, CH3), 3.20 (t, J=8.0 Hz, 2H,
SCH2), 4.25 (t, J=8.0 Hz, 2H, NCH2), 6.70–7.40 (m,
7H, ArH); IR (KBr, cmÀ1): 1000, 1160, 1320, 1400,
1600, 1670, 2920, 2980, 3080; MS(EI): m/z 365 (M+).
Anal. cacld for C17H14N2OSCl2: C 55.90; H 3.86; N
7.67%. Found: C 56.0; H 3.90; N 7.72%.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-fluorophenyl)-4-
methoxybenzamide (13, R1=4-F, R2=4-OCH3). Yield
72%: mp 76 ꢁC; H NMR (90 MHz, CDCl3): d 3.15 (t,
1
J=8.0 Hz, 2H, SCH2), 3.70 (s, 3H, OCH3), 4.10 (t,
J=8.0 Hz, 2H, NCH2), 6.50–6.90 (m, 6H, ArH), 7.6 (d,
J=9.0 Hz, 2H, ArH); IR (KBr, cmÀ1): 1030, 1170, 1300,
1500, 1640; MS (EI): m/z 330 (M+). Anal. calcd for
C17H15N2O2 FS: C 61.80; H 4.58; N 8.48%. Found: C
61.74; H 4.50; N 8.42%.
2-Bromo-N-(4,5-dihydro-1,3-thiazol-2-yl)-N-(4-fluorophe-
nyl)benzamide (20, R1=4-F, R2=2-Cl). Yield 68%: mp
105 ꢁC; 1H NMR (90 MHz, CDCl3):
d 3.20 (t,

A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
2033
J=8.0 Hz, 2H, SCH2), 4.30 (t, J=8.0 Hz, 2H, NCH2),
6.70–7.50 (m, 8H, ArH); IR (KBr, cmÀ1)=1000, 1100,
1320, 1440, 1590, 1630, 2860, 3060, 3450; MS(EI): m/z
334.5(M+).
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(2-methylphenyl)-4-
nitrobenzamide (27, R1=2-CH3, R2=4-NO2). Yield
70%: MP 98 ꢁC; 1H NMR (300 MHz, CDCl3): d 1.85 (s,
3H, CH3), 3.30 (t, J=8.0 Hz, 2H, SCH2), 4.30(t,
J=8.0 Hz, 2H, NCH2), 6.40–6.60 (m, 1H, ArH), 6.80–
7.10 (m 3H, ArH), 7.70 (d, J=9.0 Hz, 2H, ArH), 8.15
(d, J=9.0 Hz, 2H, ArH); IR (KBr, cmÀ1): 1060, 1170,
1200, 1290, 1480, 1570, 1630, 2850, 3100, 3160; MS
(EI): m/z 341 (M+). Anal. calcd for C17H15N2O3S: C
59.76; H 4.43; N 12.31%. Found C 59.82; H 4.52; N
12.26%.
2-Bromo-N-(4,5-dihydro-1,3-thiazol-2-yl)-N-(2-methyl-
phenyl)benzamide (21, R1=2-CH3, R2=2-Br). Yield
70%: mp 98 ꢁC ; H NMR (90 MHz, CDCl3): d 1.70 (s,
1
3H, CH3), 3.30 (t, J=8.0 Hz, 2H, SCH2), 4.30 (t,
J=8.0 Hz, 2H, NCH2), 6.60–7.60 (m, 8H, ArH); IR
(KBr, cmÀ1): 1010, 1120, 1330, 1440, 1530, 1590, 1650,
2880, 3060; MS(EI): m/z 375(M+). Anal. cacld for
C17H15N2OSBr: C 54.41; H 4.03; N 7.46%. Found: C
54.31; H 4.00; N 7.52%.
N-(4,5-dihydro-1,3-thiazol-2-yl)-N-(4-methoxyphenyl)-4-
nitrobenzamide (28, R1=4-OCH3, R2=4-NO2). Yield
68%: mp 131–133 ꢁC; H NMR (200 MHz, CDCl3): d
1
2-Bromo-N-(4,5-dihydro-1,3-thiazol-2-yl)-N-phenylbenza-
mide (22, R1=H, R2=2-Br). Yield 73%: mp 166 ꢁC; H
NMR (90 MHz, CDCl3): d 3.25 (t, J=8.0 Hz, 2H,
SCH2), 4.35 (t, J=8.0 Hz, 2H, NCH2), 6.95–7.50 (m,
9H, ArH); IR (KBr, cmÀ1) 1010, 1330, 1490, 1600,
1640, 2920, 3000; MS(EI): m/z 361(M+).
3.30 (t, J=8.0 Hz, 2H, SCH2), 3.70 (s, 3H, OCH3), 4.25
(t, J=8.0 Hz, 2H, NCH2), 6.40–6.80 (m, 4H, ArH), 7.65
(d, J=9.0 Hz, 2H, ArH), 8.15 (d, J=9.0 Hz, 2H, ArH),
IR (KBr, cmÀ1): 1050, 1180, 1290, 1490, 1635, 1860,
3140; MS (EI): m/z 357 (M+). Anal. calcd for
C17H15N3O4S: C 57.13; H 4.23; N 11.76%; Found C
57.20; H 4.25; N 11.78%.
1
2-Bromo-N-(2-chloro-6-methylphenyl)-N-(4,5-dihydro-
1,3-thiazol-2-yl)benzamide (23, R1=2-Cl, 6-CH3,
X-ray crystallography
R2=2-Br). Yield 72%: mp 118 ꢁC; H NMR (60 MHz,
1
CDCl3): d 1.75 (s, 3H, CH3), 3.10–3.40 (m, 2H, SCH2),
3.80–4.10 (m, 2H, NCH2), 6.70–7.30 (m, 7H, ArH); IR
(KBr, cmÀ1): 1020, 1280, 1330, 1600, 1670, 2860, 2940,
3080; MS(EI): m/z 409.5(M+).
Crystals of general formula C13H11NO (30a) were
obtained by slow evaporation of methanol. The struc-
ture was revealed as the N-phenylbenzamide.
M=197.23, symmetry monoclinic, space group P21/c,
a=24.453(8), b=5.332(1), c=8.014(1) A, b=107.34(2)ꢁb,
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(2,5-dimethoxyphe-
nyl)-4-nitrobenzamide (24, R1=2,5- (OCH3)2, R2=4-
NO2). Yield 76%: mp 140 ꢁC ; 1H NMR (300 MHz,
CDCl3): d 3.25 (t, J=8.0 Hz, 2H, SCH2), 3.62 (s, 3H,
OCH3) 3.66 (s, 3H, OCH3) 3.90 (t, J=8.0 Hz, 2H,
NCH2), 6.60–6.80 (m, 3H, ArH), 7.50 (d, J=9.0 Hz,
2H, ArH), 8.00 (d, J=9.0 Hz, 2H, ArH); FTIR (KBr,
cmÀ1): 1010, 1210, 1300, 1500, 1600, 1670, 2900, 2980;
MS(EI): m/z 397 (M+). Anal. calcd for C18H17N2O5S:
C 55.81; H 4.42; N 10.85%. Found: C 55.68; H 4.36; N
10.68%.
V=997.4(2) A3, Z=4, Dc=1.32 g cmÀ3
.
Crystals of general formula C14H13NO2 (30b) were
obtained by slow evaporation of methanol. The struc-
ture was revealed as N-(4-methoxy)phenylbenzamide.
M=227.26, symmetry monoclinic, space group P21/c,
a=26.766(7), b=5.244(1), c=8.126(1) A, b=97.56(1)ꢁ,
V=1130.6(2) A3, Z=4, Dc=1.33 g cmÀ3
.
Crystals of 2-[N-(2-methylphenyl)-N-benzoyl]amino-
4,5-dihydrothiazole(C17H16N2OS) (9) were obtained by
slow evaporation of methanol.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-4-nitro-N-(4-nitrophe-
nyl)benzamide (25, R1=4-NO2, R2=4-NO2). Yield
77%: mp 168 ꢁC; H NMR (300 MHz, CDCl3); d 3.30
1
(t, J=8.0 Hz, 2H, SCH2), 4.37 (t, J=8.0 Hz, 2H,
NCH2), 6.70 (d, J=9.0 Hz, 1H, ArH,), 6.90–7.50 (m,
3H, ArH), 7.65 (d, J=9.0 Hz, 2H, ArH,), 8.10 (d,
J=9.0 Hz, 2H, ArH); IR (KBr, cmÀ1): 830, 1100, 1150,
1300, 1440, 1520, 1630; MS(EI): m/z 372 (M+). Anal.
calcd for C16H12N4O5S: C 51.61; H 3.25; N 15.05%.
Found: C 51.71, H 3.21; N 15.0%.
M=296.40, symmetry triclinic, space group P-1,
a=8.853(1), b=9.473(1), c=9.977(1) A, a=83.62(1),
b=83.78(1), g=62.97(1)ꢁ, V=739.1(1) A3, Z=2,
Dc=1.33 g cmÀ3
.
A single crystal having approximate dimensions of
0.30ꢅ0.20ꢅ0.20 mm was mounted on a glass fiber in a
random orientation. Preliminary examination and data
collection were performed with CuKa radiation
(l=1.54184 A) on an Enraf-Nonius CAD4 computer
controlled k axis diffractometer equipped with a gra-
phite crystal, incident beam monochromator.
N-(4,5-Dihydro-1,3-thiazol-2-yl)-N-(4-fluorophenyl)-4-ni-
trobenzamide (26, R1=4-F, R2=4-NO2). Yield 71%:
MP 93 ꢁC; 1H NMR (300 MHz, CDCl3): d 3.30 (t,
J=8.0 Hz, 2H, SCH2), 4.25 (t, J=8.0 Hz, 2H, NCH2),
6.40–7.25 (m, 4H, ArH), 7.61 (d, J=9.0 Hz, 2H, ArH),
8.10 (t, J=9.0 Hz, 2H, ArH); IR (KBr, cmÀ1): 1090,
1190, 1270, 1340, 1430, 1440, 1500, 1530, 1530, 1630,
1720, 2860, 3080, 3120, MS (EI): m/z 345 (M+). Anal.
calcd for C16H12N2O3SF: C 51.13; H 3.22; N 11.18%.
Found: C 51.10; H 3.20; N 11.15%.
Cell constants and an orientation matrix for data col-
lection were obtained from least-squares refinement,
using the setting angles of 25 reflections in the range
6<y<27ꢁ, measured by the computer-controlled diag-
onal slit method of centering.

2034
A. K. Saxena et al. / Bioorg. Med. Chem. 9 (2001) 2025–2034
Table 6. Final positions (ꢅ104) with estimated standard deviations in
parentheses, derived from full-matrix least-squares refinement for
compound 9
Acknowledgements
The authors are thankful to Messrs Zahid Ali (T.O), A.
S. Kushwaha (S.T.A.) and S. Srisunder (BITS, Pilani-
trainee). SKP is grateful to CSIR, New Delhi for senior
research fellowship.
Atoms
x
y
z
S(1)
C(2)
N(3)
C(4)
C(5)
N(6)
C(7)
675(1)
2305(3)
3816(3)
3903(4)
2316(4)
1942(2)
304(3)
1028(1)
1636(3)
604(3)
8485(1)
8299(3)
8456(3)
8831(4)
8409(4)
7900(2)
8101(3)
8791(2)
7403(3)
8078(3)
7432(4)
6119(8)
5432(3)
6075(3)
7571(3)
6387(3)
6135(3)
7021(3)
8192(3)
8468(3)
5395(3)
À983(3)
À1015(3)
3232(2)
4449(3)
4201(2)
6044(3)
7363(3)
8875(3)
9064(3)
7753(3)
6244(3)
3572(3)
3059(3)
3424(3)
4237(3)
4736(3)
4402(3)
2160(3)
References and Notes
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2. Tapparelli, C.; Metternich, R.; Ehrhardt, C.; Cook, N. S.
TIPS 1993, 14, 366.
3. Schror, K. Drugs 1995, 50, 7.
O(8)
C(9)
À785(2)
À103(3)
À1268(3)
À1807(4)
À1217(4)
À83(3)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
C(20)
C(21)
4. Altman, J.; Dulas, D.; Bache, R. J. Circ. Res. 1992, 70, 1091.
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481(3)
3385(3)
4408(3)
5777(3)
6129(3)
5088(3)
3713(3)
4084(4)
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Synthesis 1988, 456.
A total of 2514 unique reflections out to y=65ꢁ were
collected. As a check on crystal and electronic stability,
two representative reflections (À124 and 0; 0–5) were
measured every 60 min. The intensities of these stan-
dards remained constant within experimental error
throughout data collection. No decay correction was
applied. Lorentz and polarization corrections were
applied to the data.
The structure was solved by direct methods using
MolEN21 using 308 reflections (minimum E of 1.560)
and 2890 relationships, a total of 16phase sets were
produced. All non-hydrogen atoms were located from
the best E-map. Hydrogen atoms were located and their
positions and isotropic thermal parameters were refined.
The structure was refined in full-matrix least squares.
Only the 2184 reflections having intensities greater than
3.0 times their standard deviation were used in the
refinements. The final cycle of refinement included 254
variable parameters and converged with unweighted
and weighted agreement factors 0.040 and 0.042. The
final difference Fourier map showed no significant resi-
dual electron density. Final positions of the non-hydro-
gen atoms and standard deviations are presented in
Table 6.
14. Joshua, C. P.; Rajasekharan, K. N. Chem. Ind. (London)
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