Synthesis and antiplatelet activity of new imidazole-4-carboxylic acid derivatives

Article abstract of DOI:10.1002/ardp.200500150

1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC ₅₀ = 1 μM and COX-1 inhibition (IC₅₀ = 0.4 μM). The carboxamide 6c shows ADP antagonistic properties (IC₅₀ = 2 μM). Compound 6g is as well PAF antagonistic (IC₅₀ = 4 μM) and a COX-1 inhibitor (IC₅₀ = 1 μM). The derivative 6i shows a strong antiadrenergic (IC₅₀ = 0.15 μM) and PAF antagonistic (IC ₅₀ = 0.66 μM) effect.

Full text of DOI:10.1002/ardp.200500150

Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
DOI 10.1002/ardp.200500150
539
Synthesis and Antiplatelet Activity of New Imidazole-
4-Carboxylic Acid Derivatives*
Klaus Rehse, Jens Steege
Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany
1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an
additional secondary amino group were synthesized and identified as antiplatelet agents in a low
micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely
the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two
compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural
criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary
amino function, slight structural modifications are able to shift the pattern of activity among the
above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC50 ϭ 1 µM and COX-
1 inhibition (IC50 ϭ 0.4 µM). The carboxamide 6c shows ADP antagonistic properties (IC50 ϭ 2 µM).
Compound 6g is as well PAF antagonistic (IC50 ϭ 4 µM) and a COX-1 inhibitor (IC50 ϭ 1 µM).
The derivative 6i shows a strong antiadrenergic (IC50 ϭ 0.15 µM) and PAF antagonistic (IC50
0.66 µM) effect.
ϭ
Keywords: Imidazole-4-carboxylic acid esters; Imidazole-4-carboxamides; Inhibition of platelet aggregation;
Adrenaline, ADP and PAF antagonism; COX-1 inhibition
Received: June 2, 2005; Accepted: August 3, 2005
Introduction
sition 2, gives the intermediate 3. Without isolating this
compound, the ring closure to the imidazole 4 is performed
with suitable primary amines giving the position 1 of the
ring. By reaction with 4-chlorophenylsulfonicacidchloride
the type 5 test compounds resulted in a good yield. Amino-
lysis at 100Ϫ120°C in suitable diamines containing one pri-
mary amino group type 6 amides with an additional basic
function are obtained. The diamines which were not com-
mercially available are synthesized by reaction of mono-
amines with acrylnitrile followed by reduction with LiAlH4
(m ϭ 3). For the diamines with m ϭ 2, 1,2-ethane-diamine
was condensed with alicyclic ketones followed by reduction
with sodium triacetoxy-boronhydride.
In a number of publications [1, 2, 3], we have shown that
the substitution of nitrogen-rich heterocycles like indazole
[1], triazoles [2], or oxadiazoles [3] with a carboxamide par-
tial structure and additional hydrophobic and basic groups
leads to a wide variety of compounds with antiplatelet ac-
tivities in micromolar concentrations. In this paper, we wish
to report a number of imidazole derivatives fulfilling these
structural requirements and consequently were expected to
be promising candidates for a remarkable antiplatelet ac-
tivity.
Results and discussion
Chemistry
Pharmacology
In general, the interpretation and comparison of the IC50
values is difficult because solubility of the compounds in
the aqueous system often is so low that some compound
precipitates when mixed with the platelet rich plasma
(PRP). To minimize this complication the incubation time
of the test compound with the PRP has been prolonged
from 4 to 20 min. This should allow the solution equilib-
rium to be shifted to a better access of the platelets so that
no more precipitate is seen. In some cases, however (6l, 6n,
6o), a part of the precipitate remains even when incubated
The synthesis of the desired imidazole compounds was car-
ried out according to the elegant 3 ϩ 1 ϩ 1 method of
Ahn et al. [4]; it is summarized in Figure 1. Starting from
nitrosoaceticacid-ester 1, which contributes the positions 3,
4, and 5 of the imidazole ring system, the aminoaceticacid-
ester 2 is obtained through reduction with sodium dithionite.
Reaction with ortho-formicacidester, which later forms po-
Correspondence: Klaus Rehse, Pharmazeutisches Institut, Freie Uni-
versität Berlin, Königin-Luise-Str. 2ϩ4, D-14195 Berlin, Germany.
Phone: ϩ49 30 838-53290, Fax: ϩ49 30 838-53251, e-mail:
rehiwer@zedat.fu-berlin.de
* Part of the PhD thesis Jens Steege, FU Berlin, Germany, 2004
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540
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
Figure 1. Synthesis of type 4, 5, and 6 imidazole derivates and of the diamines (commercially not available).
for 20 min. In these cases we have to assume that the anti-
platelet effect occurs at lower concentrations than stated in
Table 1.
as well. Hydrolization of the ester in 4-position (e.g. the
carboxylic acid from 5a) results in loss of activity.
The arylalkyl group in the 1-position can be varied in the
number of methylene groups and the substitution of the aro-
matic moiety. If not substituted the best effects are seen in
5d with four methylene groups. If substituted by fluorine or
chlorine one methylene group is sufficient for activity (see
5f or 5h). A similar effect is observed in the type 6 com-
In the type 5 esters the 5-(4-chlorophenylsulfonylamino)
group is an essential structural feature. If a primary amino
group is in this position no activity is observed. The same
is true when a chlorine atom occupies position five. When
the amino group is bissulfonylated the activity is abolished
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Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
Antiplatelet New Imidazole-4-carboxylic Acids
541
Table 1. Inhibition of platelet aggregation (Born test) induced by collagen after an incubation time of 4 and 20 min resp. in the
case of poor solubility of the test compound. The IC50 of acetylsalicylic acid is 175 20 µM (n = 10).
Compound
R1
R2
n
m
IC50 [µmol·L-1]
20 min
4 min
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
H
H
H
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
1
2
3
4
1
1
1
1
1
1
2
3
4
1
1
1
1
1
1
1
1
1
1
1
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
3
3
3
3
3
3
3
3
3
3
2
3
3
140
230
110
54
> 300
62
> 300
59
230
> 300
96
37
100
> 300
190
40
220
> 300
220
> 300
> 300
165
130
100
H
4-phenyl
4-F
4-Cl
3-Cl
2-Cl
H
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclopentyl
cycloheptyl
cyclohexylmethyl
1-adamantyl
190
n.t.
13
n.t.
n.t.
190
2.5
n.t.
13
n.t.
> 300
68
58
43
H
H
H
4-phenyl
4-F
4-Cl
3-Cl
2-Cl
2,6-Cl2
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
6m
6n
6o
3
3
14
n.t.Ϫnot tested.
pounds (see 6c and 6g). In general, the kind and position
of the halogenic substitution influences the antiplatelet ac-
tivity. Examining the type 6 amides the additional second-
ary aliphatic amino function is essential for activity. “Neu-
trally” substituted compounds (e.g. N-hydroxyethyl or pro-
pyl, N-hydroxyethoxyethyl or propyl, N-methoxyethyl or
propyl, N-ethoxypropyl) exhibit no activity (data not
shown).
positions are more (6i) or less (6h, 6j) suitable as well. In
addition, we investigated the influence of alkyl rests at the
secondary amino function and got the following results, i.e.
isopropyl (20 min, IC50 ϭ 34 µM), 3-pentyl (>300 µM),
hexyl (>300 µM). When aryl rests are involved we saw for
phenyl (20 min) an IC50 ϭ 98 µM and for phenylmethyl
lack of activity (IC50 >300 µM). The molecule with a
primary amino group was inactive. The same was true for
tertiary amino functions like N,N-dimethylamino, 1-imida-
zolyl, or 2-pyridyl groups.
Obviously, a cycloalkyl substituent at the secondary amino
group yields by far the most active compounds. This is es-
pecially true when a cyclohexyl ring is used (see 6aϪ6k) but
a cycloheptyl- (6l) or an adamantyl (6o) group is suitable as
well to get active compounds. A distance of one methylene
group between the secondary amino function and the cyclo-
hexylring decreases the activity as the comparison of 6g and
6n shows.
Altogether, there are rather specific structure-activity re-
lationships for the antiplatelet effects we did observe. These
effects are accompanied by antithrombotic activities in vivo
which, however, are much smaller than those of acetylsali-
cylic acid (asa) (see Table 2).
To get an idea of the mechanism of the antiplatelet effect,
we investigated the test compounds which were most active
against collagen with other inducers than collagen in the
Born test. In addition, the inhibition of COX-1 was assayed
in a cell free system. The results are summarized in Table 3.
It is obvious that despite their structural similarities the test
compounds show a rather different pattern of antiplatelet
activities. Ester 5c shows a dual action as COX-1 inhibitor
and PAF-antagonist in concentrations of about 1 µM. The
The distance between the secondary amino function and the
amide group is more crucial. A number of three methylene
groups led to 6g which turned out to be the most active
substance with an IC50 ϭ 2.5 µM. If there are only two
methylene groups and the other substituents remain con-
stant the activity is totally lost (see 6k).
Regarding the aromatic ring of the arylalkyl group a 4-
chloro substituent seems to be most favorable (6g) but other
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542
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
Table 2. Antithrombotic effects of type 5 an type 6 compounds 2 h after p.o. administration of 60 mg/kg of the test compounds
to rats.
Compound
m
n
R1
R2
Venules
sx
Arterioles
sx
%
α
%
α
5c
6b
6g
6i
6k
6n
asa
Ϫ
3
3
3
2
3
2
1
1
1
H
H
4-Cl
2-Cl
4-Cl
4-Cl
Ϫ
Ϫ
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexylmethyl
Ϫ
5
5
3
3
2
0
1
0.02
0.02
0.2
0.1
0.2
0.05
0.002
10
7
7
9
7
10
48 10
2
2
2
2
2
2
0.002
0.02
0.05
0.01
0.01
0.01
0.002
1
1
1
1
1
5
3
Ϫ
1
Ϫ
20
Statistics: Wilcoxon, Man, Whitney, U-test, n.s. ϭ not significant.
Table 3. IC50 values for type 5 and type 6 compounds using different inducers of platelet aggregation. The relative standard
deviation is <10%. For 5c and 6g the inhibition of COX-1 is added (Flurbiprofen = 0.7 µM). The IC50 values of standard inhibitors
are: 1 µM (NECA = 5-(N-ethylcarboxamido)-adenosine); 2 µM (Phentolamine); 0.6 µM (Apafant = WE 2086).
Compound
IC50 [µmol/L]
Collagen
COX-1 Inhib.
ADP
Adrenaline
PAF
5c
6c
6g
6i
12
13
2.5
13
0.42
0.94
10
1.9
11
38
7
30
0.7
54
4
14
0.15
0.66
carboxamide derivative 6c turned out to have ADP antag-
onistic properties accompanied by antiadrenergic effects in
the same order of magnitude. Compound 6g which differs
from 6c only in the hydrophobic moiety at 1-position of the
imidazole ring retains the COX-1 inhibition but shows a
tenfold stronger PAF antagonism. Substance 6i which dif-
fers from 6g only in the position of the chlorine atom in
the aromatic ring shows a strong antiadrenergic and PAF
antagonistic effect.
Experimental
Chemistry
2-Amino-2-cyano-acetic acid ester 2 was prepared by the method
of Caille [5]. The 1-arylalkyl-5-amino-1H-imidazole carboxylic acid
esters 4 were synthesized using the methods of Brown [6], Bridson
[7], and Machod [8]. The 5-(4-chlorophenylsulfonamino)-derivatives
5 were prepared according to the methods of Hultquist [9] and
Wamhoff [10].
General procedure for the preparation of type 6 carboxamides
In conclusion, the substitution of heterocycles rich in nitro-
gen with amide and sulfonamide partial structures ac-
companied by hydrophobic moieties and a basic function at
a suitable distance often show high platelet affinity. Slight
structural modifications are sufficient to shift the peak ac-
tivity to different platelet receptors.
The esters 5aϪi were suspended in 5Ϫ10 mL of the amine and
stirred at 100Ϫ120°C for 4Ϫ96 h. The reaction is controlled by
TLC (Alugram SIL G/UV254, 0.25 mm, Macherey-Nagel, Düren,
Germany). Eluent: CH2Cl2/ethanol 7:3, saturated with gaseous
NH3. When the complete reaction is indicated the mixture is pored
on ice which has been acidified with 10 mL 6N hydrochloric acid
followed by adjustment to pH ϭ 6 with 6 N HCl or 6 N NaOH.
The mixture is extracted five times with small quantities of CH2Cl2.
The organic phases are combined and dried over Na2SO4, filtered,
and concentrated in vacuo. The mixture was kept in the refrigirator
at 5°C for 24 h. In case crystallization occurred the supernatant
was sucked off and the crystals were recrystallized from the solvent
stated. If no crystals appeared the solvent was removed and the
residue was tested with other solvents to initiate crystallization. In
case no crystals formed at all the purification is performed by CC
(Silicagel Merck, 63-200 µm; Merck, Darmstadt, Germany).
Acknowledgments
We thank Prof. Dr. G. Wurm and R. Steinberg for the
COX-1 inhibition measurements. All other biological
experiments were skilfully performed by N. Reitner and
H. Scheffler.
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Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
Antiplatelet New Imidazole-4-carboxylic Acids
543
5-(4-Chlorophenylsulfonylamino)-1-phenylmethyl-1H-imidazole-4-
carboxylic acid ethylester (5a)
CH2-CH2-N), 3.74 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 7.14Ϫ7.28
(m, 5H, ph), 7.18 (s, 1H, 2-imidazole-H), 7.32 (“d”, J ϭ 8.5 Hz,
2H, 3,5-H chloroph), 7.52 (“d”, J ϭ 8.5 Hz, 2H, 2,6-H chloroph).
Ϫ MS (70 eV, 40°C): m/z (%) ϭ 461 (10) [Mϩ•], 370 (4), 286 (36),
240 (100), 91 (84).
From 4a (7.3 g, 30 mmol). White powder (CC, silica gel,
eluent: ethylacetate), mp 142°C, yield: 5.3 g (42%). Ϫ Anal.
C19H18ClN3O4S (419.9). Ϫ IR (KBr): ν ϭ 3441 cmϪ1; 3238; 3128;
3090; 3064; 3033; 2980; 2821; 2737; 1915; 1715 (CϭO); 1573; 1503;
1474; 1456; 1400; 1380; 1369; 1346; 1268; 1212; 1169; 1091; 1035;
1013; 992; 969; 950; 904; 860; 847; 828; 784; 756; 719; 668; 618. Ϫ
1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.00 (t, J ϭ 7.1 Hz,
3H, O-CH2-CH3), 3.69 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 5.28 (s,
2H, CH2-ph), 7.20 (d, J ϭ 7 Hz, 2H, 2,6-H ph), 7.30Ϫ7.39 (m, 3H,
3, 4, 5-H ph), 7.58 (“d”, J ϭ 8.7 Hz, 2H, 3,5-H chloroph), 7.62
(“d”, J ϭ 8.8 Hz, 2H, 2, 6-H chloroph), 7.86 (s, 1H 2-imidazole-
H), 10.48 (s, 1H, D2O exchange, R-NH-SO2). Ϫ MS (70 eV, 40°C):
m/z (%) ϭ 419 (8) [Mϩ•], 244 (37), 198 (11), 91 (100).
1-(1,1Ј-Biphenyl-4-ylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-4-carboxylic acid-ethylester (5e)
From 4e (0.6 g, 1.9 mmol). Slightly yellow crystals (eluent: ethyl-
acetate/ethanol 1 : 1), mp 218°C, yield: 0.3 g (32%). Ϫ Anal.
C25H22ClN3O4S (495.1). Ϫ IR (KBr): ν ϭ 3426 cmϪ1; 3127; 3030;
2979; 2936; 2821; 2726; 2361; 1711 (CϭO); 1574; 1501; 1470; 1401;
1372; 1344; 1273; 1211; 1169; 1089; 1037; 1011; 909; 846; 826; 753;
700; 669; 620. Ϫ 1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.01
(t, J ϭ 7.1 Hz, 3H, O-CH2-CH3), 3.70 (q, J ϭ 7 Hz, 2H, O-CH2-
CH3), 5.34 (s, 2H, ph-CH2), 7.28 (d, J ϭ 8.2 Hz, 2H, 2Ј,6Ј-bi-
phenyl), 7.35 (t, J ϭ 7.1 Hz, 1H, 4Ј-biphenyl), 7.45 (t, J ϭ 7.8 Hz,
2H, 3Ј,5Ј-biphenyl) 7.59-7.65 (m, 8H, 3, 5, 2, 6-biphenyl ϩ 2, 6, 3,
5-chloroph), 7.92 (s, 1H, 2-imidazole-H), 10.50 (s, 1H, D2O ex-
change, R-NH-SO2). Ϫ MS (70 eV, 120°C): m/z (%) ϭ 495 (8)
[Mϩ•], 320 (11), 167 (100).
5-(4-Chlorophenylsulfonylamino)-1-(2-phenylethyl)-1H-imidazole-4-
carboxylic acid ethylester (5b)
From 4b (15.4 g, 60 mmol). White powder (CC, silica gel,
eluent: ethylacetate), mp 163°C, yield: 15.4 g (60%). Ϫ Anal.
C
20H20ClN3O4S (433.1). Ϫ IR (KBr): ν ϭ 3441 cmϪ1; 3308; 3156;
3088; 3063; 3028; 2979; 2938; 2866; 2739; 2364; 2342; 1956; 1922;
1709 (CϭO); 1673; 1627; 1603; 1584; 1574; 1509; 1475; 1406; 1380;
1343; 1276; 1254; 1201; 1167; 1091; 1032; 1014; 969; 911; 830; 786;
5-(4-Chlorophenylsulfonylamino)-1-(4-fluorophenylmethyl)-1H-
imidazole-4-carboxylic acid-ethylester (5f)
1
755; 701; 668; 620. Ϫ H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ
From 4f (15.8 g, 60 mmol). Beige powder (ethanol), mp 180°C,
yield: 12.6 g (48%). Ϫ Anal. C19H17ClFN3O4S (437.1). Ϫ IR (KBr):
ν ϭ 3285 cmϪ1; 3051; 2944; 2856; 2755; 2447; 2388; 2254; 1889;
1734; 1655 (CϭO); 1608; 1512; 1434; 1415; 1358; 1318; 1297; 1239;
1158; 1095; 1042; 1016; 963; 930; 855; 819; 773; 690. Ϫ 1H-NMR/
400MHz ([D6]DMSO): δ (ppm) ϭ 1.00 (t, J ϭ 7.1 Hz, 3H, O-CH2-
CH3), 3.69 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 5.27 (s, 2H, CH2-ph),
7.19-7.30 (m, 4H, fluoroph), 7.58 (“d”, J ϭ 8.5 Hz, 2H, 3,5-chlor-
oph), 7.61 (“d”, J ϭ 8.7 Hz, 2H, 2,6-chloroph). Ϫ MS (70 eV,
60°C): m/z (%) ϭ 437 (7) [Mϩ•], 262 (36), 109 (100).
1.03 (t, J ϭ 7.1 Hz, 3H, O-CH2-CH3), 3.03 (t, J ϭ 7.6 Hz, 2H,
ph-CH2-CH2-N), 3.74 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 4.16 (t,
J ϭ 7.6 Hz, 2H, ph-CH2-CH2-N), 7.16Ϫ7.32 (m, 5H, 4H chloroph,
2-imidazole-H), 10.50 (s, 1H, D2O exchange, R-NH-SO2). Ϫ MS
(70 eV, 50°C): m/z (%) ϭ 433 (3) [Mϩ•], 329 (32), 258 (6), 212 (100),
105 (56), 104 (18), 91 (7).
5-(4-Chlorophenylsulfonylamino)-1-(3-phenylpropyl)-1H-imidazole-
4-carboxylic acid ethylester (5c)
From 4c (10.7 g, 39 mmol). White powder (CC, silica gel, eluent:
ethylacetate/cyclohexane 7:3), mp 129°C, yield: 4.7 g (54%). Ϫ
Anal. C21H22ClN3O4S (447.9). Ϫ IR (KBr): ν ϭ 3295 cmϪ1; 3085;
3061; 3027; 2966; 2942; 2851; 2714; 2336; 1945; 1870; 1708 (CϭO);
1655; 1604; 1573; 1530; 1496; 1474; 1452; 1441; 1395; 1366; 1345;
1303; 1279; 1233; 1168; 1089; 1029; 1014; 906; 874; 828; 780; 755;
732; 715; 697; 668; 640; 619. Ϫ 1H-NMR/400 MHz ([D6]DMSO):
δ (ppm) ϭ 1.04 (t, J ϭ 7.1 Hz, 3H, O-CH2-CH3), 1.90-2.08 (tt, J ϭ
7.7 Hz, 2H, ph-CH2-CH2-CH2-N), 2.53 (t, J ϭ 7.6 Hz, 2H, ph-
CH2-CH2-CH2-N), 3.75 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 3.96 (t,
J ϭ 7.3 Hz, 2H, ph-CH2-CH2-CH2-N),7.18Ϫ7.31 (m, 5H, ph), 7.58
(“d”, J ϭ 8.8 Hz, 2H, 3, 5-H chloroph), 7.62 (“d”, J ϭ 8.7 Hz,
2H, 2,6-H chloroph), 7.86 (s, 1H 2-imidazole-H), 10,43 (s, 1H, D2O
exchange, R-NH-SO2). Ϫ MS (70 eV, 120°C): m/z (%) ϭ 447 (3)
[Mϩ•], 118 (14), 91 (53).
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-4-carboxylic acid-ethylester (5g)
From 4g (17.3 g, 62 mmol). Beige crystals (ethylacetate), mp 187°C,
yield: 11.4 g (40%). Ϫ Anal. C19H17Cl2N3O4S (454.3). Ϫ IR (KBr):
ν ϭ 3420 cmϪ1; 3094; 2983; 2743; 1913; 1717 (CϭO); 1573; 1524;
1498; 1475; 1449; 1396; 1344; 1258; 1169; 1091; 1033; 1016; 875;
828; 756; 705; 667; 618. Ϫ 1H-NMR/400 MHz ([D6]DMSO): δ
(ppm) ϭ 1.00 (t, J ϭ 7.1 Hz, 3H, O-CH2-CH3), 3.69 (q, J ϭ 7.1
Hz, 2H, O-CH2-CH3), 5.28 (s, 2H, CH2-ph), 7.20 (“d”, J ϭ 8.4 Hz,
2H, 2,6-1-chloroph), 7.43 (“d”, J ϭ 8.4 Hz, 2H, 3,5-1-chloroph),
7.57 (“d”, J ϭ 8.7 Hz, 2H, 3,5-5-chloroph), 7.62 (“d”, J ϭ 8.7 Hz,
2H, 2,6-5-chloroph), 7.88 (s, 1H, 2-imidazole-H), 10.46 (s, 1H, D2O
exchange, R-NH-SO2). Ϫ MS (70 eV, 70°C): m/z (%) ϭ 453 (8)
[Mϩ•], 278 (40), 125 (100).
5-(4-Chlorophenylsulfonylamino)-1-(4-phenylbutyl)-1H-imidazole-
1-(3-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
4-carboxylic acid ethylester (5d)
imidazole-4-carboxylic acid-ethylester (5h)
From 4d (16.2 g, 56 mmol). White powder (CC, silica gel, eluent:
ethylacetate/cyclohexane 7:3), mp 141°C, yield: 4.5 g (52%). Ϫ
Anal. C22H24ClN3O4S (462.0). Ϫ IR (KBr): ν ϭ 3409 cmϪ1; 3302;
3129; 3085; 3059; 3026; 2987; 2938; 2861; 2741; 2365; 1941; 1908;
1876; 1714 (CϭO); 1671; 1622; 1579; 1509; 1474; 1466; 1451; 1397;
1367; 1345; 1293; 1266; 1225; 1192; 1167; 1134; 1116; 1091; 1039;
1013; 990; 966; 910; 846; 824; 786; 757; 699; 668; 649; 621. Ϫ 1H-
NMR/400MHz ([D6]DMSO): δ (ppm) ϭ 1.01 (t, J ϭ 7.1 Hz, 3H,
O-CH2-CH3), 1.36Ϫ1.44 (m, 2H, ph-CH2-CH2-CH2-CH2-N), 1.51-
1.58 (m, 2H, ph-CH2-CH2-CH2-CH2-N), 3.26 (t, J ϭ 7.6 Hz, 2H,
ph-CH2-CH2-CH2-CH2-N), 3.70 (t, J ϭ 8.0 Hz, 2H, ph-CH2-CH2-
From 4h (15.2 g, 54 mmol). Slightly yellow crystals (ethylacetate),
mp 182°C, yield: 12.2 g (50%). Ϫ Anal. C19H17Cl2N3O4S (454.3).
Ϫ IR (KBr): ν ϭ 3423 cmϪ1; 3127; 3101, 3058, 2979; 2821; 2734;
1960; 1913; 1712 (CϭO); 1635; 1599; 1573; 1503; 1475; 1435; 1401;
1379; 1349; 1341; 1302; 1279; 1264; 1212; 1195; 1167; 1091; 1036;
1012; 995; 954; 901; 862; 846; 829; 801; 779; 757; 703; 681; 668; 616.
Ϫ 1H-NMR/400MHz ([D6]DMSO): δ (ppm) ϭ 1.01 (t, J ϭ 7.1 Hz,
3H, O-CH2-CH3), 3.70 (q, J ϭ 7.0 Hz, 2H, O-CH2-CH3), 5.30 (s,
2H, CH2-ph), 7.15-7.18 (m, 1H, 4-1-chloroph), 7.25 (s, 1H, 2-1-
chloroph), 7.38Ϫ7.43 (m, 2H, 5,6-1-chloroph), 7.58 (“d”, J ϭ 8.7
Hz, 2H, 3,5-5-chloroph), 7.62 (“d”, J ϭ 8.7 Hz, 2H, 2,6-5-chlor-
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544
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
oph), 7.91 (s, 1H, 2-imidazole-H), 10.51 (s, 1H, D2O exchange, R-
NH-SO2). Ϫ MS (70 eV, 35°C): m/z (%) ϭ 453 (18) [Mϩ•], 278
(76), 232 (38), 125 (100).
243 (16), 214 (85), 186 (14), 139 (25), 138 (100), 112 (38), 105 (97),
104 (97), 98 (34), 91 (6).
5-(4-Chlorophenylsulfonylamino)-1-(3-phenylpropyl)-1H-imidazole-
N-(3-cyclohexylamino-propyl)-4-carboxamide (6c)
1-(2-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-4-carboxylic acid-ethylester (5i)
From 5c (0.8 g, 1.8 mmol) and 10 mL N-(3-aminopropyl)-cyclohex-
ylamine (9.2 g, 84 mmol), 5 h 120°C. Beige crystals (2-propanol),
mp 123°C, yield: 0.3 g (30%). Ϫ Anal. C28H36ClN5O3S (557.2). Ϫ
IR (KBr): ν ϭ 3401 cmϪ1; 3060; 3026; 2936; 2859; 2669; 2542; 1954;
1909; 1634 (CϭO); 1551; 1474; 1453; 1391; 1364; 1254; 1132; 1088;
1053; 1029; 1014; 962; 913; 827; 788; 754; 701; 662; 624. Ϫ 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.03Ϫ1.10 (m, 1H, 4a-
cyclohexane), 1.17Ϫ1.22 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane),
1.57-1.67 (m, 3H, -CO-NH-CH2-CH2, 4e-cyclohexane), 1.73 (br. s,
2H, 3e-, 5e-cyclohexane), 1.84Ϫ1.91 (m, 2H CH2-CH2-ph), 1.97 (br.
s, 2H, 2e, 6e-cyclohexane), 2.39 (t, J ϭ 7.9 Hz, 2H, CH2-ph), 2.80
(t, J ϭ 7 Hz, 2H, -CO-NH-CH2-CH2-CH2), 2.91 (s, 1H, 1-cyclohex-
ane), 3.01 (dt, J ϭ 6.2/6.2 Hz, 2H, -CO-NH-CH2), 3.68 (t, J ϭ 7.5
Hz, 2H, -CH2-CH2-CH2-ph), 7.14Ϫ7.27 (m, 5H, ph), 7.29 (s, 1H,
2-imidazole-H), 7.41 (“d”, J ϭ 8.5 Hz, 2H, 3,5-chloroph), 7.54 (“d”,
J ϭ 8.5 Hz, 2H, 2,6-chloroph), 8.30 (t, J ϭ 6.2 Hz, 1H, D2O ex-
change, -CO-NH-CH2), 8.32 (br. s, 2H, D2O exchange, -CH2-
NH2ϩ-cyclohexane). Ϫ MS (70 eV, 70°C): m/z (%) ϭ 557 (21)
[Mϩ•], 402 (13), 382 (86), 228 (100), 200 (54), 139 (51), 138 (98),
119 (7), 118 (11), 112 (38), 98 (42), 91 (100).
From 4i (7.9 g, 28.1 mmol). Crystals (ethylacetate), mp 185°C,
yield: 6.9 g (54%). Ϫ Anal. C19H17Cl2N3O4S (454.3). Ϫ IR (KBr):
ν ϭ 3422 cmϪ1; 3237; 3090; 3064; 2980; 2904; 2819; 2728; 2364;
1905; 1843; 1717 (C ϭ O); 1574; 1503; 1476; 1444; 1402; 1381; 1343;
1274; 1167; 1092; 1037; 1015; 905; 828; 752; 707; 668; 620. Ϫ 1H-
NMR/400MHz ([D6]DMSO): δ (ppm) ϭ 1.04 (t, J ϭ 7.1 Hz, 3H,
O-CH2-CH3), 3.75 (q, J ϭ 7.1 Hz, 2H, O-CH2-CH3), 5.34 (s, 2H,
CH2-ph), 6.85 (dd, J ϭ 7,5/1.8 Hz, 1H, 3-1-chloroph), 7.32Ϫ7.40
(m, 2H, 4-1-chloroph, 5-1-chloroph), 7.49 (dd, J ϭ 7.6/1.5 Hz, 1H,
6-1-chloroph), 7.56 (“d”, J ϭ 8.7 Hz, 2H, 3,5-5-chloroph), 7.59
(“d”, J ϭ 8.8 Hz, 2H, 2,6-5-chloroph), 7.79 (s, 1H, 2-imidazole-H),
10.47 (s, 1H, D2O exchange, R-NH-SO2). Ϫ MS (70 eV, 160°C): m/
z (%) ϭ 453 (14) [Mϩ•], 278 (70), 232 (20), 125 (100).
5-(4-Chlorophenylsulfonylamino)-1-phenylmethyl-1H-imidazole-N-
(3-cyclohexylamino-propyl)-4-carboxamide (6a)
From 5a (0.7 g, 1.7 mmol) and 10 mL N-(3-aminopropyl)-cyclohex-
ylamine (9.2 g, 84 mmol), 48 h 100°C. Crystals (CC, eluent: CHCl3/
NH3 saturated methanol 8:2), mp 141°C, yield: 0.2 g (23%). Ϫ
5-(4-Chlorophenylsulfonylamino)-1-(4-phenylbutyl)-1H-imidazole-
N-(3-cyclohexylamino-propyl)-4-carboxamide semihydrate (6d)
Anal. C26H32.5ClN6O3.5S (533.7). Ϫ IR (KBr): ν ϭ 3395 cmϪ1
;
2939; 2858; 2800; 1648; (CϭO); 1586; 1506; 1473; 1453; 1396; 1343;
1259; 1165; 1088; 1014; 970; 892; 827; 756; 722; 701; 656; 623. Ϫ
1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.03Ϫ1.15 (m, 1H,
4a-cyclohexane), 1.21Ϫ1.28 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane),
1.58Ϫ1.62 (m, 3H, 4e-cyclohexane, -CO-NH-CH2-CH2-CH2), 1.73
(br. s, 2H, 3e-, 5e-cyclohexane), 1.97 (br. s, 2H, 2e-, 6e-cyclohexane),
2.77 (t, J ϭ 6.9 Hz, 2H, -CO-NH-CH2-CH2-CH2), 2.91 (br. s, 1H,
1-H), 2.96 (dt, J ϭ 6/6 Hz, 2H, -CO-NH-CH2), 5.03 (s, 2H, -CH2-
ph), 7.15 (d, J ϭ 7 Hz, 2H, 2,6-ph), 7.23 (s, 1H, 2-imidazole-H),
7.26Ϫ7.31 (m, 3H, 3, 4, 5-ph), 7.39 (“d”, J ϭ 8.5 Hz, 2H, 3,5-
chloroph), 7.54 (“d”, J ϭ 8.4 Hz, 2H, 2,6-chloroph), 8.17 (br. s, 2H,
D2O exchange, -CH2-NH2ϩ-cyclohexane), 8.22 (t, J ϭ 6 Hz, 1H,
D2O exchange, -CO-NH-CH2). Ϫ MS (70 eV, 100°C): m/z (%) ϭ
529 (7) [Mϩ•], 354 (25), 200 (34), 139 (9), 138 (47), 112 (12), 91
(100).
From 5d (1.2 g, 2.6 mmol) and 10 mL N-(3-aminopropyl)-cyclo-
hexylamine (9.2 g, 84 mmol), 5 h 120°C. Crystals (ethylacetate), mp
119°C, yield: 1.0 g (66%). Ϫ Anal. C28H39ClN5O3.5S (581.2). Ϫ IR
(KBr): ν ϭ 3418 cmϪ1; 3060; 3025; 2936; 2859; 2673; 2538; 1949;
1911; 1631 (CϭO); 1551; 1474; 1453; 1391; 1365; 1255; 1224; 1132;
1088; 1050; 1029; 1014; 971; 917; 896; 827; 788; 753; 701; 667; 624.
Ϫ
1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.10 (m, 1H, 4a-
cyclohexane), 1.20Ϫ1.29 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane),
1.31-1.38 (m, 2H, -CH2-CH2-ph), 1.50Ϫ1.57 (m, 3H, CH2-CH2-
CH2-ph, 4e-cyclohexane), 1.61Ϫ1.64 (m, 2H ϪCO-NH-CH2-CH2),
1.73 (br. s, 2H, 3e, 5e-cyclohexane), 1.98 (br. s, 2H, 2e, 6e-cyclohex-
ane), 2.50 (m, hidden under H2O, visible after D2O exchange, 2H,
CH2-ph), 2.79 (t, J ϭ 6.9 Hz, 2H, -CO-NH-CH2-CH2-CH2), 2.91
(s, 1H, 1-cyclohexane), 3.00 (dt, J ϭ 6.2/6.2 Hz, 2H, -CO-NH-CH2),
3.67 (t, J ϭ 7.3 Hz, 2H, -CH2-CH2-CH2-CH2-ph), 7.14Ϫ7.28
(m, 6H, ph-H, 2-imidazole-H), 7.41 (“d”, J ϭ 8.5 Hz, 2H, 3,5-
chloroph), 7.55 (“d”, J ϭ 8.5 Hz, 2H, 2,6-chloroph), 8.00-8.20 (br.
s, 2H, D2O exchange, -CH2-NH2ϩ-cyclohexane), 8.30 (t, J ϭ 6 Hz,
1H, D2O exchange, -CO-NH-CH2). Ϫ MS (70 eV, 60°C): m/z (%) ϭ
571 (30) [Mϩ•] 528 (19), 433 (15), 416 (12), 396 (100), 299 (18), 242
(81), 214 (25), 139 (47), 138 (87), 112 (29), 98 (32), 91 (70).
5-(4-Chlorophenylsulfonylamino)-1-(2-phenylethyl)-1H-imidazole-
N-(3-cyclohexylamino-propyl)-4-carboxamide dihydrate (6b)
From 5b (1.2 g, 2.9 mmol) and 10 mL N-(3-aminopropyl)-cyclohex-
ylamine (9.2 g, 84 mmol), 48 h 120°C. Crystals (ethanol), mp
157°C, yield: 1.1 g (69%). Ϫ Anal. C27H38ClN5O5S (579.2). Ϫ IR
(KBr): ν ϭ 3399 cmϪ1; 3059; 3026; 2939; 2859; 2800; 2752; 2528;
2433; 2363; 2043; 1953; 1914; 1644 (CϭO); 1586; 1506; 1475; 1455;
1396; 1342; 1259; 1222; 1197; 1167; 1133; 1089; 1031; 1014; 968;
896; 828; 755; 702; 660; 622. Ϫ 1H-NMR/400 MHz ([D6]DMSO):
δ (ppm) ϭ 1.08Ϫ1.11 (m, 1H, 4a-cyclohexane), 1.18Ϫ1.29 (m, 5H,
2a-, 3a-, 4e-, 5a-, 6a-cyclohexane), 1.63Ϫ1.68 (m, 2H, -CO-NH-
CH2-CH2), 1.74 (br. s, 2H, 3e-, 5e-cycloheane-H), 1.98 (br. s, 2H,
2e-, 6e-cycloheane), 2.83 (br. s, 2H, -CO-NH-CH2-CH2-CH2),
2.95Ϫ3.01 (m, 3H, CH2-ph, 1-cyclohexane), 3.02 (dt, J ϭ 6.3/6.3
Hz, 2H, -CO-NH-CH2), 4.04 (br. s, 2H, -CH2-CH2-ph), 7.14 (d,
J ϭ 7 Hz, 2H, 2,6-ph), 7.18Ϫ7.23 (m, 2H, 4-ph, 2-imidazole-H),
7.27Ϫ7.31 (m, 2H, 3,5-ph), 7.48 (“d”, J ϭ 8.5 Hz, 2H, 3,5-
chloroph), 7.61 (“d”, J ϭ 8.5 Hz, 2H, 2,6-chloroph), 8.13 (br. s, 1H,
D2O exchange, -CO-NH-CH2), 8.27 (br. s, 2H, D2O exchange,
-CH2-NH2ϩ-cyclohexane). Ϫ MS (70 eV, 40°C): m/z (%) ϭ 543
(24) [Mϩ•], 500 (15), 405 (13), 388 (13), 368 (72), 271 (15), 257 (43),
1-(1,1-Biphenyl-4-ylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(3-cyclohexylamino-propyl)-4-carboxamide (6e)
From 5e (0.3 g, 0.6 mmol) and 5 mL N-(3-aminopropyl)-cyclohexyl-
amine (4.6 g, 42 mmol), 4 h 120°C. Brown crystals (ethanol), mp
157°C, yield: 0.2 g (56%). Ϫ Anal. C32H36ClN5O3S (605.2). Ϫ IR
(KBr): ν ϭ 3430 cmϪ1; 3315; 3059; 3028; 2933; 2856; 2661; 2442;
1949; 1806; 1757; 1617 (CϭO); 1547; 1488; 1475; 1450; 1391; 1363;
1352; 1254; 1228; 1194; 1129; 1088; 1010; 995; 977; 964; 938; 895;
856; 825; 785; 757; 697; 668; 620.
Ϫ
1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 1.10 (m, 1H, 4a-cyclohexane), 1.14Ϫ1.28
(m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane), 1.57-1.67 (m, 3H, -CO-NH-
CH2-CH2-, 4e-cyclohexane), 1.73 (br. s, 2H, 3e, 5e-cyclohexane),
1.97 (br. s, 2H, 2e, 6e-cyclohexane), 2.79Ϫ2.81 (m, 2H, -CO-NH-
CH2-CH2-CH2), 2.91 (br. s, 1H, 1-cyclohexane), 2.97 (dt, J ϭ 5.6/
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
Antiplatelet New Imidazole-4-carboxylic Acids
545
5.6 Hz, 2H, -CO-NH-CH2), 5.11 (s, 2H, CH2-biph), 7.24 (d, J ϭ
8.1 Hz 2H, 2Ј,6Ј-biph-H), 7.34 (t, J ϭ 7.4 Hz, 1H, 4Ј-biph-H), 7.40-
7.56 (m, 5H, 3Ј, 5Ј, 3,5-biph-H, 2-imidazole-H), 7.58 (“d”, J ϭ 8.5
1475; 1453; 1434; 1394; 1379; 1345; 1243; 1197; 1166; 1135; 1088;
1047; 1033; 1015; 973; 898; 822; 804; 771; 754; 708; 680; 670; 623.
Ϫ
1H-NMR/400MHz ([D6]DMSO): δ (ppm) ϭ 1.07Ϫ1.12 (m, 1H,
Hz, 2H, 3,5-chloroph), 7.60 (m, 2H, 2,6-biph-H), 7.62 (“d”, J ϭ 8.5
4a-cyclohexane), 1.17-1.30 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane),
1.58 (br. s, 1H, 4e-cyclohexane), 1.64-1.69 (m, 2H, -CO-NH-CH2-
CH2-CH2), 1.73 (br. s, 2H, 3e, 5e-cyclohexane), 1.97 (br. s, 2H, 2e,
6e-cyclohexane), 2.79 (br. s, 2H, -CO-NH-CH2-CH2-CH2), 2.93 (br.
s, 1H, 1-cyclohexane), 2.97 (dt, J ϭ 6.3/6.3 Hz, 2H, -CO-NH-CH2),
5.16 (s, 2H, -CH2-ph), 7.14Ϫ7.16 (m, 1H, 4-1-chloroph), 7.20 (s,
1H, 2-1-chloroph), 7.33Ϫ7.39 (m, 2H, 5,6-1-chloroph), 7.47 (“d”,
J ϭ 8.5 Hz, 2H, 3,5-5-chloroph), 7.57 (“d”, J ϭ 8.5 Hz, 2H, 2,6-5-
chloroph), 7.64 (s, 1H, 2-imidazole-H), 8.10 (t, J ϭ 5.2, 1H, D2O
exchange, -CO-NH-CH2Ϫ) 8.51 (br. s, 2H, D2O exchange, -CH2-
NH2ϩ-cyclohexane). Ϫ MS (70 eV, 80°C): m/z (%) ϭ 563 (15)
[Mϩ•], 520 (8), 388 (34), 277 (20), 234 (35), 139 (77), 138 (80), 125
(100), 112 (27) 98 (44).
ϩ
Hz, 2H, 2,6-chloroph), 8.19 (br. s, 2H, D2O exchange, -CH2-NH2
-
cyclohexane), 8.28 (br. s, 1H, D2O exchange, -CO-NH-CH2). Ϫ MS
(70 eV, 80°C): m/z (%) ϭ 605 (3) [Mϩ•], 430 (10), 167 (75), 139
(48), 138 (23), 112 (24), 98 (21).
5-(4-Chlorophenylsulfonylamino)-1-(4-fluorophenylmethyl)-1H-
imidazole-N-(3-cyclohexylaminopropyl)-4-carboxamide
sesquihy-
drate (6f)
From 5f (0.7 g, 1.6 mmol) and 10 mL N-(3-aminopropyl)-cyclo-
hexylamine (9.2 g, 84 mmol), 24 h, 120°C. Beige crystals (CC elu-
ent: CH2Cl2 methanol/saturated with NH3 8:2), mp 159°C., yield:
0.3 g (33%). Ϫ Anal. C26H34ClFN5O4.5S (575.0). Ϫ IR (KBr): ν ϭ
3393 cmϪ1; 2939; 2857; 2520; 2431; 2366; 2045; 1917; 1883; 1650
(CϭO); 1512; 1476; 1451; 1397; 1378; 1342; 1261; 1227; 1165; 1090;
1044; 1033; 1014; 973; 890; 826; 755; 705; 660; 622. Ϫ 1H-NMR/
400 MHz ([D6]DMSO): δ (ppm) ϭ 1.03 (br. s, 1H, 4a-cyclohexane),
1.21Ϫ1.27 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane), 1.58Ϫ1.65 (m,
3H, 4e-cyclohexane, -CO-NH-CH2-CH2-CH2), 1.74 (br. s, 2H,
3e,5e-cyclohexane), 1.97 (br. s, 2H, 2e, 6e-cyclohexane), 2.81 (br. s,
2H, -CO-NH-CH2-CH2-CH2), 2.93 (br. s, 1H, 1-cyclohexane), 2.97
(dt, J ϭ 6.4/6.4 Hz, 2H, -CO-NH-CH2), 5.11 (s, 2H, CH2-ph),
7.14Ϫ7.18 (m, 2H, 2,6-fluoroph), 7.24Ϫ7.27 (m, 2H, 3,5-fluoroph),
7.47 (“d”, J ϭ 8.2 Hz, 2H, 3,5-chloroph), 7.57 (“d”, J ϭ 8.2 Hz,
2H, 2,6-chloroph), 7.57 (s, 1H, 2-imidazole-H), 8.12 (br. s, 1H, D2O
1-(2-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(3-cyclohexylaminopropyl)-4-carboxamide (6i)
From 5i (1.0 g, 2.2 mmol) and 10 mL N-(3-aminopropyl)-cyclohexy-
lamine (9.2 g, 84 mmol), 8 h, 100°C. Crystals (ethanol/ethylacetate
1 : 1), mp 145°C, yield 1.0 g (81%). Ϫ Anal. C26H31Cl2N5O3S
(564.5). Ϫ IR (KBr): ν ϭ 3410 cmϪ1; 3062; 2937; 2859; 2552; 2363;
1629 (CϭO); 1552; 1474; 1447; 1392; 1357; 1253; 1199; 1131; 1088;
1045; 1015; 972; 826; 788; 754; 706; 663; 622. Ϫ 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 1.11 (br. s, 1H, 4a-cyclohexane), 1.17Ϫ1.25
(m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane), 1.58 (br. s, 1H, 4e-cyclohex-
ane), 1.64-1.69 (m, 2H, -CO-NH-CH2-CH2-CH2), 1.73 (br. s, 2H,
3e, 5e-cyclohexane), 1.98 (br. s, 2H, 2e, 6e-cyclohexane), 2.83 (t, J ϭ
-
exchange, -CO-NH-CH2 ) 8.34 (br. s, 2H, D2O exchange, -CH2-
NH2ϩ-cyclohexane). Ϫ MS (70 eV, 40°C): m/z (%) ϭ 547 (1) [Mϩ•],
195 (42), 109 (100), 98 (19).
-
7.0 Hz, 2H, -CO-NH-CH2-CH2-CH2 ), 2.94 (br. s, 1H, 1-cyclohex-
ane), 3.03 (dt, J ϭ 6.2/6.2 Hz, 2H, -CO-NH-CH2), 5.05 (s, 2H, -
CH2-ph), 6.69 (“d”, J ϭ 7 Hz, 1H, 3-1-chloroph), 7.23Ϫ7.30 (m,
2H, 4,5-1-chloroph), 7.25 (s, 1H, 2-imidazole-H), 7.34 (“d”, J ϭ 8.5,
2H, 3,5-5-chloroph), 7.41 (“d”, J ϭ 7.7 Hz, 6-1-chloroph), 7.48
(“d”, J ϭ 8.5 Hz, 2H, 2,6-5-chloroph), 8.28 (t, J ϭ 6 Hz, 1H, D2O
exchange, -CO-NH-CH2), 8.29 (br. s, 2H, D2O exchange, -CH2-
NH2ϩ-cyclohexane). Ϫ MS (70 eV, 100°C): m/z (%) ϭ 563 (2)
[Mϩ•], 234 (15), 138 (16), 125 (100), 112 (13).
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(3-cyclohexylaminopropyl)-4-carboxamide monohydrate
(6g)
From 5g (0.7 g, 1.5 mmol) and 10 mL N-(3-aminopropyl)-cyclo-
hexylamine (9.2 g, 84 mmol), 30 h, 120°C. Beige crystals (CC, elu-
ent: CH2Cl2/methanol saturated with NH3 8:2), mp 158°C, yield:
0.3 g (33%). Ϫ Anal. C26H33Cl2N5O4S (582.6). Ϫ IR (KBr): ν ϭ
3420 cmϪ1; 3299; 3061; 3028; 2936; 2858; 2533; 1912; 1732; 1627
(CϭO); 1555; 1493; 1474; 1455; 1393; 1380; 1353; 1252; 1204; 1165;
1131; 1088; 1048; 1015; 971; 826; 780; 753; 707; 664; 649; 622. Ϫ
1H-NMR/400MHz ([D6]DMSO): δ (ppm) ϭ 1.03Ϫ1.14 (m, 1H, 4a-
cyclohexane), 1.18Ϫ1.32 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane), 1.58
(br. s, 1H, 4e-cyclohexane), 1.65Ϫ1.69 (m, 2H, -CO-NH-CH2-CH2-
CH2), 1.74 (br. s, 2H, 3e, 5e-cyclohexane), 1.98 (br. s, 2H, 2e, 6e-
cyclohexane), 2.82 (br. s, 2H, -CO-NH-CH2-CH2-CH2), 2.94 (br. s,
1H, 1-cyclohexane), 3.00 (dt, J ϭ 5.9/5.9 Hz, 2H, -CO-NH-CH2),
5.24 (s, 2H, -CH2-ph), 7.21 (“d”, J ϭ 8.4 Hz, 2H, 2,6-1-chloroph),
7.43 (“d”, J ϭ 8.4 Hz, 2H, 3,5-1-chloroph), 7.55 (“d”, J ϭ 8.4 Hz,
2H, 3,5-5-chloroph), 7.60 (“d”, J ϭ 8.6 Hz, 2H, 2,6-5-chloroph),
7.83 (s, 1H, 2-imidazole-H), 8.00 (br. s, 1H, D2O exchange, -CO-
NH-CH2) 8.52 (br. s, 2H, D2O exchange, -CH2-NH2ϩ-cyclohexane).
Ϫ MS (70 eV, 40°C): m/z (%) ϭ 563 (3) [Mϩ•], 388 (11), 234 (15),
139 (25), 138 (30), 125 (100), 112 (31), 98 (28).
5-(4-Chlorophenylsulfonylamino)-1-(2,6-dichlorophenylmethyl)-1H-
imidazole-N-(3-cyclohexylaminopropyl)-4-carboxamide
sesquihy-
drate (6j)
From 0.7 g (1.1 mmol) 5-[Bis-(4-chlorophenylsulfonyl)-amino]-1-
(2,6-dichlorophenylmethyl)-1H-imidazole-4-carboxylicacidethyl-
ester and 10 mL (9.2 g, 84 mmol) N-(3-aminopropyl)-cyclohexyl-
amine, 8 h, 100°C. Crystals (ethanol), mp 182°C, yield 1.0 g (72%).
Ϫ Anal. C26H3Cl3N5O4.5S (623.0). Ϫ IR (KBr): ν ϭ 3401 cmϪ1
;
3262; 3061; 2938; 2859; 2555; 1914; 1752; 1632 (CϭO); 1582; 1561;
1503; 1475; 1438; 1391; 1356; 1313; 1255; 1198; 1167; 1132; 1088;
1014; 958; 896; 826; 764; 754; 710; 666; 645; 620. Ϫ 1H-NMR/
400MHz ([D6]DMSO): δ (ppm) ϭ 1.11 (br. s, 1H, 4a-cyclohexane),
1.18Ϫ1.28 (m, 4H, 2a-, 3a-, 5a-, 6a-cyclohexane), 1.58Ϫ1.65 (m,
3H, 4e-cyclohexane, -CO-NH-CH2-CH2-CH2), 1.73 (br. s, 2H, 3e,
5e-cyclohexane), 1.98 (br. s, 2H, 2e, 6e-cyclohexane), 2.81 (br. s,
2H, -CO-NH-CH2-CH2-CH2), 2.94 (br. s, 1H, 1-cyclohexane), 2.99
(“dt”, J ϭ 6.4/6.4, 2H, -CO-NH-CH2), 5.03 (s, 2H, -CH2-ph), 6.65
(br. s, 1H, 2-imidazole-H), 7.43Ϫ7.46 (m, 3H, 3,4,5-dichloroph),
7.55 (“d”, J ϭ 8 Hz, 2H, 3,5-chloroph), 7.59 (“d”, J ϭ 8.5, 2H, 2,6-
chloroph), 8.24 (br. s, 1H, D2O exchange, -CO-NH-CH2), 8.33 (br.
s, 2H, D2O exchange, -CH2-NH2ϩ-cyclohexane). Ϫ MS (70 eV,
100°C): m/z (%) ϭ 597 (9) [Mϩ•], 422 (22), 268 (36), 311 (15), 159
(76), 139 (100), 138 (68), 112 (64), 98 (39).
1-(3-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(3-cyclohexyl-aminopropyl)-4-carboxamide
monohy-
drate (6h)
From 5h (0.7 g, 1.5 mmol) and 10 mL N-(3-aminopropyl)-cyclo-
hexylamine (9.2 g, 84 mmol), 3 h, 120°C. Crystals (ethanol/ethyl-
acetate
C
1 : 1), mp 186°C, yield: 0.6 g (65%). Ϫ Anal.
26H33Cl2N5O4S (582.6). Ϫ IR (KBr): ν ϭ 3319 cmϪ1; 3088; 2939;
2859; 2778; 2740; 2557; 2436; 1941; 1914; 1663 (CϭO); 1582; 1542;
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546
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 539−547
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(2-cyclohexylaminoethyl)-4-carboxamide (6k)
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-[3-(cyclohexylmethylamino)-propyl]-4-carboxamide
(6n)
From 5g (0.7 g, 1.5 mmol) and 6 g (42 mmol) N-cyclohexyl-ethane-
1,2-diamine, 18 h, 120°C. Beige crystals (CC, eluent: CH2Cl2/meth-
anol saturated with NH3 85 : 15), mp 158°C, yield: 0.4g (48%). Ϫ
Anal. C25H29Cl2N5O3S (549.2). Ϫ IR (KBr): ν ϭ 3677 cmϪ1; 3434;
3057; 2937; 2859; 2671; 2521; 2419; 1910; 1637 (CϭO); 1545; 1496;
1476; 1451; 1391; 1357; 1254; 1231; 1131; 1088; 1013; 969; 826; 789;
From 5g (0.8 g, 1.5 mmol) and 7 g (41 mmol) N-cyclohexylmethyl-
propane-1,3-diamine, 24 h, 120°C. Beige crystals (CC, eluent:
CH2Cl2/methanol saturated with NH3 85 : 15), mp 162°C, yield 0.9
g (88%). Ϫ Anal. C27H33Cl2N5O3S (577.2). Ϫ IR (KBr): ν ϭ 3370
cmϪ1; 3316; 3056; 2926; 2852; 2399; 1905; 1635 (CϭO); 1551; 1496;
1473; 1449; 1392; 1358; 1254; 1202; 1131; 1088; 1014; 966; 892; 825;
786; 755; 708; 664; 624. Ϫ 1H-NMR/400 MHz ([D6]DMSO): δ
(ppm) ϭ 0.88-0.97 (m, 2H, 1a, 4a-cyclohexane), 1.07Ϫ1.23 (m, 4H,
1e-, 4e-cyclohexane, -CO-NH-CH2-CH2-CH2), 1.60-1.75 (m, 8H,
2a, 3a, 5a, 6a, 2e, 3e, 5e, 6e-cyclohexane), 2.70 (d, J ϭ 6.9 Hz, 2H,
cyclohexyl-CH2), 2.75 (t, J ϭ 7 Hz, 2H, -CO-NH-CH2-CH2-CH2),
2.94 (dt, J ϭ 6.2/6.2 Hz, 2H, -CO-NH-CH2), 5.06 (s, 2H, 1-chlor-
oph-CH2), 7.17 (“d”, J ϭ 8.4 Hz, 2H, 2,6-1-chloroph), 7.29 (s, 1H,
2-imidazole-H), 7.35 (“d”, J ϭ 8.4 Hz, 2H, 3,5-1-chloroph), 7.39
(“d”, J ϭ 8.5 Hz, 2H, 3,5-5-chloroph), 7.53 (“d”, J ϭ 8.5 Hz, 2H,
2,6-5-chloroph), 8.17 (t, J ϭ 6.3 Hz, 1H, D2O exchange, -CO-NH-
CH2), 8.32 (br. s, 2H, D2O exchange, CH2-NH2ϩ-cyclohexane). Ϫ
MS (70 eV, 110°C): m/z (%) ϭ 577 (6) [Mϩ•], 494 (69), 402 (13),
234 (25), 152 (31), 126 (14), 125 (100), 112 (14).
1
755; 709; 663; 624. Ϫ H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ
1.10 (br. s, 1H, 4a-cyclohexane), 1.16-1.24 (m, 4H, 2a-, 3a-, 5a-, 6a-
cyclohexane), 1.56 (br. s, 1H, 4e-cyclohexane), 1.71 (br. s, 2H, 3e,
5e-cyclohexane), 1.93 (br. s, 2H, 2e, 6e-cyclohexane), 2.79 (br. s,
2H, -CO-NH-CH2-CH2), 2.87 (br. s, 1H, 1-cyclohexane), 3.08
(ρdtρ, J ϭ 6.6/6.6, 2H, -CO-NH-CH2), 5.05 (s, 2H, -CH2-ph), 7.17
(“d”, J ϭ 8.4 Hz, 2H, 2,6-1-chloroph), 7.28 (s, 1H, 2-imidazole-H),
7.34 (“d”, J ϭ 8.4, 2H, 3,5-1-chloroph), 7.39 (“d”, J ϭ 8.4 Hz, 2H,
3,5-5-chloroph), 7.53 (“d”, J ϭ 8.6 Hz, 2H, 2,6-5-chloroph), 8.11
(t, J ϭ 5 Hz, 1H, D2O exchange, -CO-NH-CH2), 8.17 (br. s, 2H,
D2O exchange, CH2-NH2ϩ-cyclohexane). Ϫ MS (70 eV, 100°C):
m/z (%) ϭ 549 (1) [Mϩ•], 263 (22), 234 (26), 125 (100), 112 (75).
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-(3-cyclopentylaminopropyl)-4-carboxamide (6l)
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
imidazole-N-[3-(adamantyl-amino)-propyl]-4-carboxamide (6o)
From 5g (0.5 g, 1.1 mmol) and 6 g (42 mmol) N-cyclopentyl-
propane-1,3-diamine, 48 h, 120°C. Beige crystals (CC, eluent:
CH2Cl2/methanol saturated with NH3 8 : 2), mp 132°C, yield 0.3 g
(50%). Ϫ Anal. C25H29Cl2N5O3S (549.1). Ϫ IR (KBr): ν ϭ 3410
cmϪ1; 3057; 2960; 2870; 1910; 1630 (CϭO); 1553; 1493; 1475; 1445;
1392; 1358; 1255; 1200; 1133; 1088; 1014; 966; 826; 790; 772; 753;
From 5g (0.8 g, 1.5 mmol) and 7 g (48 mmol) N-adamantyl-
propane-1,3-diamine, 24 h, 120°C. Beige crystals (CC, eluent:
CH2Cl2/methanol saturated with NH3 85:15), mp. 212°C, yield
0.2 g (21%). Ϫ Anal. C30H35Cl2N5O3S (615.2). Ϫ IR (KBr): ν ϭ
3433 cmϪ1; 2914; 2852; 1898; 1629; (CϭO); 1553; 1515; 1493; 1474;
1453; 1392; 1363; 1309; 1251; 1178; 1132; 1088; 1030; 1015; 969;
1
708; 664; 649; 623. Ϫ H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ
1.51Ϫ1.59 (m, 6H, cyclopentane-2a, 3a, 4a, 5a, -CO-NH-CH2-CH2-
CH2), 1.67 (br. s, 2H, cyclopentane-3e, 4e-H), 1.89 (br. s, 2H cyclo-
pentane-2e, 5e-H), 2.72 (t, J ϭ 6.9 Hz, 2H, -CO-NH-CH2-CH2-
CH2), 2.95 (dt, J ϭ 5.9/5.9 Hz, 2H, -CO-NH-CH2), 3.34 (br. s, 1H,
1-cyclopentane), 5.05 (s, 2H, CH2-ph), 7.17 (“d”, J ϭ 8.3 Hz, 2H,
2,6-1-chloroph), 7.26 (s, 1H, 2-imidazole-H), 7.35 (“d”, J ϭ 8.4 Hz,
2H, 3,5-1-chlorop), 7.39 (“d”, J ϭ 8.4 Hz, 2H, 3,5-5-chloroph), 7.52
(“d”, J ϭ 8.5 Hz, 2H, 2,6-5-chloroph), 8.15 (t, J ϭ 5.9 Hz, 1H,
D2O exchange, -CO-NH-CH2), 8.17 (br. s, 2H, D2O exchange, CH2-
NH2ϩ-cyclopentane). Ϫ MS (70 eV, 220°C): m/z (%) ϭ 549 (9)
[Mϩ•], 374 (47), 277 (25), 251 (12), 234 (38), 125 (100), 124 (82), 98
(26), 84 (26).
834; 787; 753; 708; 663; 647; 622.
Ϫ
1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 1.56-1.78 (m, 17H, adamantane, -CO-NH-
CH2-CH2-CH2), 2.70 (t, J ϭ 6.9 Hz, 2H, NH-CH2), 2.97 (dt, J ϭ
6 Hz, 2H, -CO-NH-CH2), 5.07 (s, 2H, 1-chloroph-CH2), 7.17 (“d”,
J ϭ 8.4 Hz, 2H, 2.6-1-chloroph), 7.28 (s, 1H, 2-imidazole-H), 7.35
(“d”, J ϭ 8.4 Hz, 2H, 3,5-1-chloroph), 7.39 (“d”, J ϭ 8.5 Hz, 2H,
3,5-5-chloroph), 7.53 (“d”, J ϭ 8.5 Hz, 2H, 2,6-5-chloroph), 8.26
(t, J ϭ 6.1 Hz, 1H, D2O exchange, -CO-NH-CH2), 8.36 (br. s, 2H,
D2O exchange, CH2-NH2ϩ). Ϫ MS (70 eV, 140°C): m/z (%) ϭ 615
(1) [Mϩ•], 234 (29), 190 (16), 177 (36), 164 (19), 151 (20), 135 (74),
125 (66).
Biology
1-(4-Chlorophenylmethyl)-5-(4-chlorophenylsulfonylamino)-1H-
The Born test was performed as usual [3, 11, 12]. The agonist con-
centration which is necessary to achieve the maximum aggregation
response is always used. This is determined at the beginning of the
test with the platelet rich plasma used. The concentration of the
collagen fibrils varies from 0.16 to 0.32 µg/20 µL. The final concen-
tration of the other inducers in the test cuvette is (in µM): ADP
0.5-1.0; adrenaline 0.1-1.0; PAF 0.25-1.0. The thrombosis model has
been described in detail [13]. The COX-1 inhibition experiments
were carried out as already stated [14].
imidazole-N-(3-cycloheptylaminopropyl)-4-carboxamide (6m)
From 5g (0.7 g, 1.5 mmol) and 9 g (53 mmol) N-cyclopheptyl-
propane-1,3-diamine, 20 h, 120°C. Beige crystals (CC, eluent:
CH2Cl2/methanol saturated with NH3 85 : 1), mp 137°C, yield
0.5 g (58%). Ϫ Anal. C27H33Cl2N5O3S (577.2). Ϫ IR (KBr): ν ϭ
3417 cmϪ1; 3298; 2928; 2858; 2510; 1916; 1890; 1626 (CϭO); 1555;
1492; 1474; 1391; 1359; 1253; 1204; 1129; 1088; 1013; 964; 824; 809;
790; 753; 706; 666; 649; 611. Ϫ 1H-NMR/400 MHz ([D6]DMSO):
δ (ppm) ϭ 1.35-1.58 (m, 10H, 2a, 3a, 4a, 5a, 6a, 7a, 4e, 5e-cyclo-
-
heptane, CO-NH-CH2-CH2-CH2 ), 1.63-1.65 (m, 2H, 3e-, 6e-cyclo-
References
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Hz, 2H, -CO-NH-CH2-CH2-CH2), 2.92 (dt, J ϭ 6.2/6.2, 2H, -CO-
NH-CH2), 3.03 (br. s, 1H 1-cycloheptane), 5.06 (s, 2H, CH2-ph),
7.17 (“d”, J ϭ 8.3 Hz, 2H, 2,6-1-chloroph), 7.26 (s, 1H, 2-imid-
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130°C): m/z (%) ϭ 577 (3) [Mϩ•], 234 (13), 152 (22), 139 (63), 126
(56), 125 (81), 112 (56).
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 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com