New pyrimido[5,4-c]cinnolines with antiplatelet activities

Article abstract of DOI:10.1002/ardp.200500152

Twenty one new pyrimido[5,4-c]cinnolines containing different lipophilic moieties (viz. phenyl, 4-methoxyphenyl, 2-furanyl, 2-thienyl) in position 2 and additional basic groups (e.g., alkylaminopropyl, dialkylaminopropyl and cyclohexylaminopropyl) in posi

Full text of DOI:10.1002/ardp.200500152

590
DOI 10.1002/ardp.200500152
Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
New Pyrimido[5,4-c]cinnolines with Antiplatelet
Activities*
Klaus Rehse, Hedwig Gonska
Institut für Pharmazie, Freie Universität Berlin, Germany
Twenty one new pyrimido[5,4-c]cinnolines containing different lipophilic moieties (viz. phenyl, 4-meth-
oxyphenyl, 2-furanyl, 2-thienyl) in position 2 and additional basic groups (e.g., alkylaminopropyl,
dialkylaminopropyl and cyclohexylaminopropyl) in position 4 of the title ring system have been pre-
pared and investigated for antiplatelet effects (Born test). Ten of them inhibited the platelet aggregation
induced by collagen with an IC50 below 10 µmol/L (6a, 6b, 6c, 6g, 6h, 6i, 6k, 6m, 6q, 6u). A closer
inspection of the antiplatelet effect with other inducers showed antagonism against adrenaline (6m),
ADP antagonist (6i) and PAF antagonist activities (6m, 6i, 6u) in nanomolar (IC50) concentration
ranges.
Keywords: Pyrimido[5,4-c]cinnolines; Antiplatelet activities; ADP antagonism; Antiadrenergic effects; PAF
antagonism
Received: June 6, 2005; Accepted: July 27, 2005
Introduction
4-amino cinnoline-3-carboxamide 3. Reaction with aryl-
carboxylic acid chlorides gave pyrimido[5,4-c]cinnolines (4),
which were treated with POCl3 to give the 4-chloro com-
pounds (5). Nucleophilic substitution with suitable diamines
yielded the completely new type 6 title test compounds.
In a number of publications [1Ϫ3], we have shown that the
substitution of heterocycles such as indazoles [1], triazoles
[2] or oxadiazoles [3] with a carboxamide partial structure
and additional hydrophobic and basic groups leads to a
wide variety of compounds with antiplatelet activities at
micromolar concentrations. In this paper, we wish to present
a number of cinnoline derivatives fulfilling these structural
requirements, thus being potential antiplatelet agents.
Biology
The type 6 compounds were assayed in the Born test for
their ability to inhibit the aggregation of blood platelets in-
duced by collagen. The results for the most active com-
pounds and a number of substances that further elucidate
the structure-activity relationships are summarized in Table
1. Variation of R1 shows that in all groups studied, com-
pounds with IC50 values lower than 10 µM have been found.
This is true for R1 ϭ phenyl (6a, 6b, 6e), substituted phenyl
(6g, 6h, 6i, 6k), furyl (6m, 6q) and thienyl (6u). Less suitable
lipophilic moieties are 4-cyanophenyl, 4-fluorophenyl, and
2-fluorophenyl (IC50 ϭ 30Ϫ200 µM, data not shown in
Table 1), presumably due to the lowered electron density in
the aromatic ring compared to the methoxyphenyl group.
The antiplatelet effect further depends on sterical factors in
R1. Compounds with space-consuming substituents such as
4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl and
phenylvinyl show low effects (IC50 ϭ 30Ϫ300 µM, data not
shown in Table 1).
Pyrimido[5,4-c]cinnolines are a very rare class of com-
pounds. Indeed, only a few studies on this type of com-
pounds have been reported. Gewald [4] synthesized the type
4 with R1 ϭ H (see Figure 1). On the basis of this synthesis,
Menon and Purushotaman [5Ϫ7] prepared a number of
these compounds and tested them for antibacterial and
fungicidal activity. Effects were observed only at high
concentrations (100 mM). Nargund et al. [8] prepared pyr-
azolyl derivatives with weak anti-inflammatory potency
(250 mg/kg).
Results and discussion
Chemistry
The synthesis of 6 is shown in Figure 1. Aniline (1) was
converted into benzene diazonium salt, which reacted with
cyanoacetamide to 2. Cyclization with AlCl3 gave the
In each R1-group, the observed antiplatelet effects markedly
depend on the R2 substituent in the 4-amino function. In
general, secondary and tertiary amines are potent antiplate-
Correspondence: Klaus Rehse, Pharmazeutisches Institut, Freie
Universität Berlin, Königin-Luise-Str. 2 ϩ 4, D-14195 Berlin,
Germany. Phone: ϩ49 30 83853290, Fax: ϩ49 30 83853251, e-mail:
rehiwer@zedat.fu-berlin.de
* Part of the PhD thesis Hedwig Gonska, FU Berlin, Germany 2004
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
New Antiplatelet Pyrimidocinnolines
591
Figure 1. Synthesis of new pyrimido[5,4-c]cinnolines.
let compounds (6a, 6b, 6c, 6g, 6h, 6i, 6m, 6q, 6u). Interest-
ingly, the three most active compounds (6i, 6q, 6u) all have
R2 ϭ cyclohexylamino combined with R1 ϭ 4-methoxy-
phenyl (6i), 2-furyl (6q) or 2-thienyl (6u).
Table 1. In vitro antiplatelet activities (Born test). IC50 values
using collagen as inducer are given (incubation time, 20 min).
The standard deviation in this test is Յ 10% (see acetylsali-
cylic acid, asa).
To get an idea concerning the mechanism of action of the
antiplatelet compounds, we investigated other inducers than
collagen in the Born test. The results are summarized in
Compound
R1
R2
IC50,
µmol/L
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
phenyl
phenyl
phenyl
phenyl
phenyl
NH-CH3
NH-C3H7
N(C2H5)2
7
9
7
48
16
71
4
5
3
26
8
96
7
40
15
13
Table 2. Inhibition of platelet aggregation induced with ADP,
adrenaline or PAF by selected type 6 cinnolines. Incubation
time, 20 min. Standard deviation Յ 10%.
NH-cyclohexyl
NH-CH-CH2OH
N(CH3)2
NH-C3H7
N(C2H5)2
NH-cyclohexyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
Compound
IC50, µmol/L
Adrenaline
ADP
PAF
Collagen
4-methoxyphenyl NH-CH2-CH2-OH
2-methoxyphenyl
4-chlorophenyl
2-furyl
NH-cyclohexyl
N(C2H5)2
NH-CH3
NH-C3H7
N(CH3)2
N(C2H5)2
NH-cyclohexyl
NH-CH2-OH2-OH
NH-C3H7
6a
25
17
3
14
0.15
7
15
120
16
0.8
16
48
30
40
0.8
0.15
0.18
Ϫ
7
4
5
3
7
6g
6h
2-furyl
2-furyl
2-furyl
2-furyl
6i
6m
6u
21
Ϫ
3
Ϫ
3
19
19
15
3
19
Phentolamine
mesylate
NECA§
Apafant
asa
2
2-furyl
6s
6t
6u
6v
asa
2-thienyl
2-thienyl
2-thienyl
2-thienyl
Ϫ
Ϫ
Ϫ
Ϫ
1
Ϫ
Ϫ
Ϫ
0.6
Ϫ
Ϫ
Ϫ
175
N(C2H5)2
NH-cyclohexyl
1-imidazolyl
Ϫ
175 20
§
5-(N-Ethylcarboxamido)-adenosine
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

592
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
1592; 1561; 1508; 1491; 1478; 1378; 1286; 1247; 771. 1H-NMR/400
MHz ([D6]DMSO): δ (ppm) ϭ 3.77 (s, 3H, OCH3), 7.01 (dd, J ϭ
7.6/7.3 Hz, 1H, ph-5-H), 7.09 (d, J ϭ 8.2 Hz, 1H, ph-3-H), 7.38
(ddd, J ϭ 8.0/7.6/1.8 Hz, 1H, ph-4-H), 7.51 (dd, J ϭ 7.4/1.7 Hz,
ph-6-H), 7.83 (ddd, J ϭ 7.6/6.5/1.0 Hz, 1H, ar-9-H), 7.95 (ddd, J ϭ
7.7/7.6/1.2 Hz, ar-8-H), 8.44 (d, J ϭ 8.3 Hz, ar-7-H), 8.69 (d, J ϭ
7.7 Hz, 1H, ar-10-H). MS (70 eV): m/z (%) ϭ 304 (14) [Mϩ•], 289
(30), 287 (89), 159 (30), 148 (100), 147 (30), 146 (54), 133 (78), 129
(30), 128 (27), 118 (35), 114 (43), 105 (43), 103 (30), 102 (30), 91
(30), 90 (32), 88 (30), 77 (38), 41 (32), 39 (35).
Table 2. A rather differentiated pattern of effects can be
observed. Only compounds 6a and 6g are most sensitive
against collagen-based platelet aggregation. For 6h a dual
action, i.e. on collagen- (IC50 ϭ 5 µM) and adrenaline-in-
duced platelet aggregation (IC50 ϭ 3 µM), has been shown.
With 6m a strong influence both on the adrenaline- (IC50 ϭ
0.15 µM) and PAF-induced (IC50 ϭ 0.15 µM) platelet aggre-
gation has been demonstrated, at a far lower concentration
than that of the respective standard inhibitors Phentolamine
(IC50 ϭ 2 µM) and Apafant (IC50 ϭ 0.6 µM), respectively.
Compound 6i shows a dual effect directed against ADP-
(IC50 ϭ 0.8 µM) and PAF-induced (IC50 ϭ 0.8 µM) platelet
aggregation, which is in the range of the standard inhibitors
of NECA or Apafant, respectively. For 6u a specific antag-
2-(4-Methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-ole (4c)
From 1.1 g (5.5 mmol) 3 and 4.6 g (27 mmol) 4-methoxyben-
zoylchloride. 60°C, 2.5 h. Yellow crystals, mp. >360°C, yield 1.1 g
(66%). Anal. C17H12N4O2 (304.3). IR (KBr): ν ϭ 3574 cmϪ1, 3389
(OH); 3073; 1580; 1559; 1531; 1507; 1482; 1444; 1424; 1403; 1376;
1283; 1250; 1164; 1028; 829; 770; 759. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 3.85 (s, 3H, OCH3), 7.03 (d, J ϭ 8.9 Hz,
2H, ph-3,5-H), 7.85 (ddd, J ϭ 7.5/7.5/0.9 Hz, 1H, ar-9-H), 7.94
(ddd, J ϭ 7.7/7.5/1.3 Hz, 1H, ar-8-H), 8.40 (d, J ϭ 8.2 Hz, 1H, ar-
7-H), 8.54 (d, J ϭ 8.8 Hz, 2H, ph-2,6-H), 8.88 (d, J ϭ 7.9 Hz, 1H,
ar-10-H). MS (70 eV): m/z (%) ϭ 304 (100) [Mϩ•], 303 (27), 276
(12), 275 (11), 143 (10), 134 (32), 133 (16), 119 (21), 115 (15), 103
(13), 91 (10), 90 (14), 63 (10), 44 (18), 41 (14), 39 (13), 31 (12).
onism against PAF-induced platelet aggregation (IC50
ϭ
0.18 µM) has been observed, which is stronger than that of
the standard inhibitor Apafant.
Experimental
General
2-(4-Chlorophenyl)-pyrimido[5,4-c]cinnolin-4-ole (4d)
Mp. (uncorr.), Linström. Elemental analysis: Elementar Vario EL.
IR: Perkin Elmer 1420 Ratio Recording IR-Spectrophotometer and
ATI Mattson Genesis Serie FTIR. NMR: Bruker Avance/APX 400.
EI-MS: CH-7A-Varian MAT (70 eV). The synthesis of 3 has already
been reported [4]. All other compounds were prepared for the first
time.
From 1.2 g (6.1 mmol) 3 and 5.6 g (32 mmol) 4-chlorobenzoylchlor-
ide. 50°C, 1.5 h. Yellow crystals, mp. >360°C, yield 1.3 g (69%).
Anal. C16H9ClN4O (308.7). IR (KBr): ν ϭ 3403 cmϪ1 (OH); 1587;
1561; 1533; 1509; 1481; 1392; 1373; 1283; 770. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 7.56 (dd, J ϭ 7.0/1.6 Hz, 2H, ph-3,5-H),
7.90 (ddd, J ϭ 7.5/7.4/0.9 Hz, 1H, ar-9-H), 7.99 (ddd, J ϭ 8.3/7.0/
1.3 Hz, 1H, ar-8-H), 8.46 (d, J ϭ 8.2 Hz, 1H, ar-10-H), 8.59 (d,
J ϭ 8.6 Hz, 2H, ph-2,6-H), 8.91 (d, J ϭ 7.6 Hz, 1H, ar-7-H). MS
(70 eV): m/z (%) ϭ 310 (33) [Mϩ•], 309 (26), 308 (100) [Mϩ•], 307
(26), 280 (17), 143 (11), 138 (22), 137 (18), 115 (38), 114 (10), 102
(14), 88 (20), 75 (13), 44 (13), 36 (17), 28 (14).
General procedure for the synthesis of type 4 (see Fig. 1) pyrimido-
[5,4-c]cinnoline-4-ones
Of 3, 5 mmol suspended in 10 mL pyridine is mixed with a
5Ϫ10-fold excess of the acid chloride and stirred for 1Ϫ2.5 h at the
temperature stated. While cooling with ice, 50 mL water is added.
The crystalline precipitate is sucked off and resuspended in 50 mL
ethanol/water (1:1). Now, 10 mL NaOH (20%) and 2 mL H2O2
(30%) are added. The mixture is kept for 1 h at 90°C. Mostly at
this temperature, a voluminous precipitate of 4 forms, which is
sucked off and washed with water and ethanol.
2-(2-Furyl)-pyrimido[5,4-c]cinnolin-4-ole (4e)
From 1.4 g (7.1 mmol) 3 and 5.4 g (41 mmol) 2-furoylchloride.
60°C, 2 h. Yellow crystals, mp. >360°C, yield 1.5 g (80%). Anal.
C
14H8N4O2 (264.2). IR (KBr): ν ϭ 3401 cmϪ1 (OH); 1602; 1575;
1560; 1531; 1509; 1475; 1451; 1410; 1367; 1370; 1293; 769; 750. 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 6.66 (dd, J ϭ 3.3/1.6 Hz,
1H, fur-4-H), 7.29 (d, J ϭ 3.2 Hz, 1H, fur-5-H), 7.84Ϫ7.88 (m, 2H,
fur-3H, ar-9H), 7.95 (ddd, J ϭ 7.7/7.6/1.3 Hz, 1H, ar-8-H), 8.41 (d,
J ϭ 8.2 Hz, 1H, ar-10-H), 8.79 (d, J ϭ 7.9 Hz, 1H, ar-7-H). MS
(70 eV): m/z (%) ϭ 264 (1) [Mϩ•], 44 (100), 28 (33).
2-Phenyl-pyrimido[5,4-c]cinnolin-4(3H)-one (4a)
From 1.3 g (6.6 mmol) 3 and 4.3 g (31 mmol) benzoylchloride.
80°C, 2.5 h. Yellow crystals, mp. > 360°C (EtOH/H2O/DMF), yield
1.0 g (61%). Anal. C16H10N4O (274.3). IR (KBr): ν ϭ 3422 cmϪ1
(NH); 1708 (CϭO); 1552; 1499. 1H-NMR/400 MHz ([D6]DMSO):
δ (ppm) ϭ 7.47Ϫ7.51 (m, 3H, ph-3,4,5-H), 7.85 (dd, J ϭ 7.9/7.0
Hz, 1H, ar-9-H), 7.94 (dd, J ϭ 7.6/7.4 Hz, 1H, ar-8-H), 8.53Ϫ8.59
(m, 3H, ar-7-H, ph-2,6-H), 8.90 (d, J ϭ 8.0 Hz, 1H, ar-10-H). 13C-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 122.44 (C-10a), 123.18
(C-10), 128.16 (ph-C-3,5), 128.71 (ph-2,6-C), 128.95 (ph-C-4),
130.16 (C-8), 130.29 (C-9), 131.01 (C-7), 135.15 (ph-C-1), 139.65
(C-10b), 143.49 (C-6a), 149.14 (C-4a), 165.48 (C-2), 171.30 (C-4).
Ϫ MS (70 eV): m/z (%) ϭ 274 (10) [Mϩ•], 105 (100), 77 (35).
2-(2-Thienyl)-pyrimido[5,4-c]cinnolin-4-ole (4f)
From 1.1 g (5.5 mmol) 3 and 4.4 g (30 mmol) 2-thienylcarboxylic
acid chloride. 60°C, 2.5 h. Yellow crystals, mp. >360°C, yield 1.2 g
(78%). Anal. C14H8N4OS (280.3). IR (KBr): ν ϭ 3389 cmϪ1 (OH);
1696; 1585; 1561; 1508; 1477; 1430; 1409; 1376; 1338; 1286; 771;
743; 710; 617. 1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 7.19
(dd, J ϭ 3.9/3.7 Hz, 1H, thi-4-H), 7.67 (d, J ϭ 4.5 Hz, 1H, thi-5-
H), 7.87 (dd, J ϭ 7.3 Hz, 1H, ar-9-H), 7.94Ϫ7.99 (m, 2H, ar-8-H,
thi-3-H), 8.42 (d, J ϭ 8.2 Hz, 1H, ar-10-H), 8.80 (d, J ϭ 7.9 Hz,
1H, ar-7-H). MS (70 eV): m/z (%) ϭ 280 (100) [Mϩ•], 279 (13), 252
(11), 115 (11), 110 (16), 38 (10), 36 (28), 32 (51).
2-(2-Methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-ole (4b)
From 1.1 g (5.5 mmol) 3 and 4.8 g (28 mmol) 2-methoxyben-
zoylchloride. 60°C, 2.5 h. Yellow crystals, mp. >360°C, yield 0.8 g
(47%). Anal. C17H12N4O2 (304.3). IR (KBr): ν ϭ 3430 cmϪ1 (OH);
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
New Antiplatelet Pyrimidocinnolines
593
General procedure for the synthesis of type 5 4-chloropyrimido [5,4-
c]cinnolines
8.1 Hz, 1H, ar-7-H), 9.02 (d, J ϭ 7.6 Hz, 1H, ar-10-H). MS (70
eV): m/z (%) ϭ 284 (33) [Mϩ•], 283 (15), 282 (100) [Mϩ•], 219 (19),
164 (12), 163 (30), 161 (94), 126 (40), 100 (16), 99 (14), 93 (12), 75
(11), 51 (15), 50 (11), 39 (25), 28 (18).
Of the type 4 pyrimido[5,4-c]cinnoline-4(3H)-one or 4-ole, 5 mmol
was refluxed with 10 mL POCl3 and 3 mL N,N-diethylaniline for
the time stated. After cooling to room temperature, the mixture is
pored carefully on 200 mL ice water, which is stirred vigorously. The
precipitate is sucked off and washed with a small amount of 1 M
HCl and finally with ethanol.
4-Chloro-2-(2-thienyl)-pyrimido[5,4-c]cinnoline (5f)
From 0.8 g (2.9 mmol) 4f, 1.5 h. Light brown crystals, mp. 193°C,
yield 0.54 g (62%). Anal. C14H7ClN4S (298.7). IR (KBr): ν ϭ 1575
cmϪ1; 1554; 1536; 1491; 1343; 1406; 1378; 1357; 1075; 831; 780; 761;
729. 1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 7.37 (dd, J ϭ
4.9/3.9 Hz, 1H, thi-4-H), 8,08 (dd, J ϭ 5.0/1.0 Hz, 1H, thi-5-H),
8.24 (ddd, J ϭ 7.6/7.5/1.1 Hz, 1H, ar-9-H), 8.29Ϫ8.33 (m, 2H, Ar-
8-H, thi-3-H), 8.83 (d, J ϭ 8.1 Hz, 1H, ar-7-H), 9.04 (dd, J ϭ 8.0/
1.0 Hz, 1H, ar-10-H). MS (70 eV): m/z (%) ϭ 300 (38) [Mϩ•], 299
(16), 298 (100) [Mϩ•], 263 (12) [Mϩ-Cl], 235 (16), 163 (14), 161 (42),
126 (21), 28 (10).
4-Chloro-2-phenyl-pyrimido[5,4-c]cinnoline (5a)
From 0.8 g (2.9 mmol) 4a, 2.5 h. Light brown crystals, mp. 201°C,
yield 0.6 g (69%). Anal. C16H9ClN4 (292.7). IR (KBr): ν ϭ 1574
cmϪ1; 1556; 1529; 1502; 1373; 845; 743; 691. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 7.63Ϫ7.73 (m, 3H, ph-3,4,5-H), 8.26 (ddd,
J ϭ 7.6/7.4/0.9 Hz, 1H, ar-9-H), 8.33 (ddd, J ϭ 8.2/7.6/1.3 Hz, ar-
8-H), 8.68Ϫ8.71 (m, 2H, ph-2,6-H), 8.87 (d, J ϭ 8.0 Hz, 1H, ar-7-
H), 9.20 (d, J ϭ 7.7 Hz, 1H, ar-10-H). MS (70 eV): m/z (%) ϭ 294
(34) [Mϩ•], 293 (20), 292 (100) [Mϩ•], 257 (19) [Mϩ-Cl], 229 (19),
163 (14), 161 (46), 126 (34), 77 (10).
General procedure for the synthesis of the type 6 test compounds
Of the type 5 chlorocinnoline, 1 mmol is dissolved with stirring in
15 mL ethanol and warmed to 60°C. Of the amine, 10 mmol is
slowly added and refluxed for 20 min. After cooling to 4°C, mostly
crystals are formed and sucked off. If no crystals are obtained, the
solution is concentrated to 5 mL and dropwise added to 100 mL
water. The precipitate is sucked off and washed first with 20 mL
ethanol and then with 20 mL water. The compounds are recrys-
tallized from the solvent stated.
4-Chloro-2-(2-methoxyphenyl)-pyrimido[5,4-c]cinnoline (5b)
From 0.8 g (2.6mmol) 4b, 1 h 45 min. Yellow crystals, mp. 215°C,
yield 0.56 g (65%). Anal. C17H11ClN4O (322.8). 1H-NMR/400
MHz ([D6]DMSO): δ (ppm) ϭ 3.92 (s, 3H, OCH3), 7.19 (dd, J ϭ
7.5/7.4 Hz, 1H, ph-5-H), 7.29 (d, J ϭ 8.3 Hz, 1H, ph-3-H),
7.60Ϫ7.65 (m, 1H, ph-4-H), 7.99 (dd, J ϭ 7.6/1.4 Hz, ph-6-H), 8.25
(dd, J ϭ 7.4/7.2 Hz, 1H, ar-9-H), 8.33 (dd, J ϭ 7.27.0 Hz, ar-8-H),
8.88 (d, J ϭ 8.1 Hz, ar-7-H), 9.05 (d, J ϭ 7.8 Hz, 1H, ar-10-H).
N-Methyl-NЈ-[(2-phenyl)-pyrimido[5,4-c]cinnolin-4-yl]propane-
1,3-diamine (6a)
4-Chloro-2-(4-methoxyphenyl)-pyrido[5,4-c]cinnoline (5c)
From 1.0 g (3.3 mmol) 4c, 1 h 45 min. Brown crystals, mp. 194°C
(dec.), yield 0.65 g (61%). Anal. C17H11ClN4O (322.8). IR (KBr):
ν ϭ 1606 cmϪ1; 1573; 1554; 1531; 1517; 1491; 1374; 1259; 1166;
From 0.30 g (1.02 mmol) 5a and 1.2 g (16.6 mmol) N-methylpro-
pane-1,3-diamine. Light brown crystals, mp. 64°C (ethanol/ethyl-
acetate), yield 0.24 g (69%). Anal. C20H20N6 (344.4). IR (KBr): ν ϭ
1
845; 767. H-NRM/400 MHz ([D6]DMSO): δ (ppm) ϭ 3.90 (s, 3H,
1
3401 cmϪ1; 1596; 1577; 1547; 1401; 1376; 1316; 1298; 754; 706. H-
OCH3), 7.16 (d, J ϭ 8.9 Hz, 2H, 2H, ph-3,5-H), 8.23 (m, 1H, ar-9-
H), 8.29 (ddd, J ϭ 8.2/7.6/1.2 Hz, 1H, ar-8-H), 8.60 (d, J ϭ 8.9 Hz,
ph-2,6-H), 8.81 (d, J ϭ 8.1 Hz, 1H, ar-7-H), 9.13 (d, J ϭ 7.9 Hz,
1H, ar-10-H). MS (70 eV): m/z (%) ϭ 324 (39) [Mϩ•], 323 (21), 322
(100) [Mϩ•], 287 (36), 216 (22), 161 (29), 134 (14), 133 (61), 127
(12), 126 (90), 103 (26), 100 (19), 99 (19), 90 (38), 77 (17), 76 (21),
75 (20), 64 (18), 63 (19), 51 (22), 50 (16), 39 (17), 38 (12), 36 (22).
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.94 (tt, J ϭ 6.7 Hz, 2H,
ar-NH-CH2-CH2-CH2), 2.34 (s, 3H, NH-CH3), 2.65 (t, J ϭ 6.6 Hz,
2H, ar-NH-CH2-CH2-CH2), 3.86 (t, J ϭ 6.6 Hz, 2H, ar-NH-CH2),
7.57Ϫ7.61 (m, 3H, ph-3,4,5-H), 8.08 (ddd, J ϭ 7.6/7.4/0.8 Hz, 1H,
ar-9H), 8.14 (ddd, J ϭ 7.7/7.5/1.2 Hz, 1H, ar-8-H), 8.64 (d, J ϭ 8.2
Hz, 1H, ar-7-H), 8.67Ϫ8.69 (m, 2H, ph-2,6-H), 9.01 (d, J ϭ 8.0 Hz,
1H, ar-10-H), 9.78 (s, 1H, ar-NH, D2O exchange). MS (70 eV): m/z
(%) ϭ 344 (11) [Mϩ•], 301 (16), 287 (23), 276 (19), 275 (100), 274
(46), 126 (11), 70 (26), 44 (28).
4-Chloro-2-(4-chlorophenyl)-pyrimido[5,4-c]cinnoline (5d)
From 1.2 g (3.9 mmol) 4d, 1.5 h. Yellow/green crystals, mp. 221°C
(dec.), yield 0.95 g (74%). Anal. C16H8Cl2N4 (327.2). IR (KBr): ν ϭ
1573 cmϪ1; 1554; 1532; 1400; 1371; 1075; 846; 763. 1H-NMR/400
MHz ([D6]DMSO): δ (ppm) ϭ 7.73 (d, J ϭ 8.6 Hz, 2H, ph-3,5-H),
8.26 (ddd, J ϭ 7.6/7.4/0.8 Hz, 1H, ar-9-H), 8.33 (ddd, J ϭ 7.7/7.6/
1.3 Hz 1H, ar-8-H), 8.69 (d, J ϭ 8.6 Hz, 2H, ph-2,6-H), 8.87 (d,
J ϭ 8.1 Hz, 1H, ar-7-H), 9.20 (d, J ϭ 7.8 Hz, 1H, ar-10-H). MS
(70 eV): m/z (%) ϭ 330 (10), 329 (13), 328 (55) [Mϩ•], 327 (19), 326
(100) [Mϩ•], 291 (13), 263 (15), 228 (11), 163 (21), 161 (61), 126
(44), 100 (13), 75 (15).
N-[(2-Phenyl)-pyrimido[5,4-c]cinnolin-4-yl]-NЈ-propylpropane-1,3-
diamine (6b)
From 0.25 g (0.85 mmol) 5a and 1.2 g (10.3 mmol) N-propylpro-
pane-1,3-diamine. Light brown needles, mp. 123°C (ethanol), yield
0.18 g (56%). Anal. C22H24N6 (372.5). IR (KBr: ν ϭ 3433 cmϪ1
;
1596; 1546; 1546; 1400; 1316; 707. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 0.86 (t, J ϭ 7.3 Hz, 1H, NH-CH2-CH2-
CH3), 1.39Ϫ1.48(m, 2H, NH-CH2-CH2-CH3), 1.93 (tt, J ϭ 6.6 Hz,
2H, ar-NH-CH2-CH2-CH2), 2.46Ϫ2.48 (m, 2H, NH-CH2-CH2-
CH3), 2.69 (t, J ϭ 6.5 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.87 (t, J ϭ
6.4 Hz, 2H, ar-NH-CH2), 7.56Ϫ7.63 (m, 3H, ph-3,4,5-H), 8.08
(ddd, J ϭ 7.6/7.4/1.2 Hz, 1H, ar-9-H), 8.14 (ddd, J ϭ 8.2/7.0/1.3
Hz, 1H, ar-8-H), 8.63 (d, J ϭ 8.1 Hz, 1H, ar-7H), 8.66Ϫ8.70 (m,
2H, ph-2,6-H), 9.02 (dd, J ϭ 8.0/0,8 Hz, 1H, ar-10-H), 9.84 (s, 1H,
ar-NH, D2O exchange). MS (70 eV): m/z (%) ϭ 372 (11) [Mϩ•], 301
(18), 300 (11), 287 (17), 276 (19), 275 (100), 274 (32), 98 (39, 30 (16).
4-Chloro-2-(2-furyl)-pyrimido[5,4-c]cinnoline (5e)
From 1.0 g (3.8 mmol) 4e, 1 h. Green crystals, mp. 216°C, yield
0.58 g (54%). Anal. C14H7ClN4O (282.7). IR (KBr): ν ϭ 3433
1
cmϪ1; 1572; 1552; 1530; 1498; 1471; 1366; 1075; 761. H-NMR/400
MHz (D6]DMSO): δ (ppm) ϭ 6.89 (dd, J ϭ 3.5/1.7 Hz, 1H, fur-4-
H), 7.76 (d, J ϭ 3.5 Hz, 1H, fur-5-H), 8.19Ϫ8.24 (m, 2H, fur-3-H,
ar-9-H), 8.31 (ddd, J ϭ 7.7/7.7/1.2 Hz, 1H, ar-8-H), 8.82 (d, J ϭ
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

594
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
N-[(2-Phenyl)pyrimido[5,4-c]cinnolin-4-yl]-Nο,Nο-diethylpropane-
1,3-diamine (6c)
H), 9.00 (d, J ϭ 7.8 Hz, 1H, ar-10-H), 9.67 (t, J ϭ 5.7 Hz, ar-NH,
D2O exchange). MS (70 eV): m/z (%) ϭ 388 (3) [Mϩ•], 317 (19),
304 (28), 85 (16), 84 (100), 58 (61), 32 (34), 28 (99).
From 0.25 g (0.85 mmol) 5a and 1.8 g (13.8 mmol) N,N-diethylpro-
pane-1,3-diamine. Yellow crystals, mp. 88°C, yield 0.16 g (48%).
Anal. C23H26N6 (386.5). IR (KBr): ν ϭ 3356 cmϪ1; 2969; 1593;
1546; 1398; 1367; 1314; 705. 1H-NMR/400 MHz ([D6]DMSO: δ
(ppm) ϭ 1.01 (t, J ϭ 7.1 Hz, 6H, 2 ϫ CH3), 1.95 (tt, J ϭ 6.7 Hz,
2H, ar-NH-CH2-CH2-CH2), 2.55Ϫ2.56 (m, partly overlapped from
DMSO, 4H, N-(CH2-CH3)2), 2.60Ϫ2.61 (br. 2H, ar-NH-CH2-CH2-
CH2), 3.82Ϫ3.87 (m, 2H, ar-NH-CH2), 7.56Ϫ7.64 (m, 3H, ph-3,4,5-
H), 8.07 (ddd, J ϭ 7.5/7.5/1.1 Hz, 1H, ar-9-H), 8.14 (ddd, J ϭ 7.6/
7.5/1.4 Hz, 1H, ar-8-H), 8.65 (d, J ϭ 8.3 Hz, 1H, ar-7-H), 8.67Ϫ8.69
(m, 2H, ph-2,6-H), 9.01 (dd, J ϭ 8.0/0.9 Hz, 1H, ar-10-H), 9.87 (t,
J ϭ 5.6 Hz, 1H, ar-NH, D2O exchange). MS (70 eV): m/z (%) ϭ
386 (11) [Mϩ•], 287 (12), 112 (100), 86 (46).
N-[2-(4-Methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-yl]-NЈ-propyl-
propane-1,3-diamine (6g)
From 0.20 g (0.62 mmol) 5c and 1.2 g (10.3 mmol) N-propylpro-
pane-1,3-diamine. Light brown needles, mp. 83°C, yield 0.22 g
(87%). Anal. C23H26N6O (402.5). IR (KBr): ν ϭ 1593 cmϪ1; 1575;
1546; 1402; 1308; 1251; 1164; 769. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 0.86 (t, J ϭ 7.4 Hz, 3H, NH-CH2-CH2-
CH3), 1.39Ϫ1.48 (m, 2H, NH-CH2-CH2-CH3), 1.92 (tt, J ϭ 6.5 Hz,
2H, ar-NH-CH2-CH2-CH2), 2.47 (t, partly overlapped by DMSO,
J ϭ 7.1 Hz, 2H, NH-CH2-CH2-CH3), 2.69 (t, J ϭ 6.4 Hz, 2H, ar-
NH-CH2-CH2-CH2), 3.86Ϫ3.88 (m, 5H, ar-NH-CH2, OCH3), 7.12
(d, J ϭ 8.8 Hz, 2H, ph-3,5-H), 8.06 (dd, J ϭ 7.6/7.2 Hz, 1H, ar-9-
H), 8.12 (dd, J ϭ 7.3/7.1 Hz, 1H, ar-8-H), 8.61Ϫ8.64 (m, 3H, ar-7-
H, ph-2,6-H), 8.99 (d, J ϭ 8.0 Hz, 1H, ar-10-H), 9.76 (br, s, 1H, ar-
NH, D2O exchange). MS (EI, 70°C): m/z (%) ϭ 402 (14) [Mϩ•],
331 (13), 317 (18), 306 (20), 305 (100), 304 (38), 126 (11), 98 (30),
30 (17), 28 (16).
N-Cyclohexyl-NЈ-[(2-phenyl)-pyrimido[5,4-c]cinnolin-4-yl]pro-
pane-1,3-diamine (6d)
From 0.12 g (0.41 mmol) 5a and 1.4 g (8.9 mmol) N-cyclohexylpro-
pane-1,3-diamine. Light yellow crystals, mp. 131°C, yield 0.16 g
(95%). Anal. C25H28N6 (412.5). IR (KBr): ν ϭ 3360 cmϪ1; 2927;
2851; 1593; 1576; 1545; 1449; 1397; 1364; 1317; 1299; 707. 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 0.96Ϫ1.04 (m, 2H, cyc-
3a,5a-H), 1.09Ϫ1.23 (m, 3H, cyc-3e,4a,5e-H), 1.50Ϫ1.53 (m, 1H,
cyc-4e-H), 1.62Ϫ1.65 (m, 2H, cyc-2a,6a-H), 1.81Ϫ1.84 (m, 2H, cyc-
N,N-Diethyl-Nο-[(2-(4-methoxyphenyl)pyrimido[5,4-c]cinnolin-4-
yl)propane-1,3-diamine-semihydrate (6h)
2e,6e-H), 1.91 (tt,
J ϭ 6.4 Hz, 2H, ar-NH-CH2-CH2-CH2),
From 0.25 g (0.77 mmol) 5c and 1.7 g (13.1 mmol) N,N-diethylpro-
pane-1,3-diamine. Yellow crystals, mp. 138°C, yield 0.19 g (59%).
2.33Ϫ2.38 (m, 1H, cyc-1-H), 2.73 (t, J ϭ 6.1 Hz, 2H, ar-NH-CH2-
CH2-CH2), 3.88 (br, s, 2H, ar-NH-CH2), 7.59Ϫ7.63 (m, 3H, ph-
3,4,5-H), 8.08 (dd, J ϭ 7.6/7.4 Hz, 1H, ar-9-H), 8.15 (dd, J ϭ 8.2/
6.9 Hz, 1H, ar-8-H), 8.65Ϫ8.70 (m, 3H, ar-7-H, ph-2,6-H), 9.03 (d,
J ϭ 8.0 Hz, 1H, ar-10-H), 9.93 (s, 1H, ar-NH, D2O exchange). MS
(70 eV): m/z (%) ϭ 412 (6) [Mϩ•], 287 (12), 276 (16), 275 (100), 274
(19), 138 (57), 56 (18), 30 (15).
Anal. C24H28N6O Ϯ 0.5 H2O (425.5). IR (KBr): ν ϭ 3438 cmϪ1
;
3339; 1599; 1576, 1547; 103; 1308; 1257; 1166; 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 1.00 (t, J ϭ 7.0 Hz, 6H, 2 ϫ CH3), 1.92
(tt, J ϭ 6.7 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.53Ϫ2.55 (partly over-
lapped by the DMSO peak, m, 4H, N-(CH2-CH3)2), 2.59 (t, J ϭ
6.6 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.81Ϫ3.86 (m, 2H, ar-NH-
CH2), 3.88 (s, 3H, OCH3), 7.11 (d, J ϭ 8.8 Hz, 2H, ph-3,5-H),
8.04Ϫ8.08 (m, 1H, ar-9H), 8.13 (ddd, J ϭ 7.3/7.1/1.2 Hz, 1H, ar-8-
H), 8.61Ϫ8.65 (m, 3H, ar-7-H, ph-2,6-H), 8.99 (d, J ϭ 7.9 Hz, 1H,
ar-10-H), 9.77 (t, J ϭ 5.5 Hz, 1H, ar-NH, D2O exchange).
(CF3COOD): δ (ppm) ϭ 1.49 (t, J ϭ 7.3 Hz, 6H, 2 ϫ CH3),
2.60Ϫ2.64 (m, 2H, ar-NH-CH2-CH2-CH2), 3.41Ϫ3.52 (m, 4H, N-
(CH2-CH3)2), 3.58Ϫ3.62 (m, 2H, ar-NH-CH2-CH2-CH2), 4.11 (s,
3H, OCH3), 4.40 (t, J ϭ 7.0 Hz, 2H, ar-NH-CH2), 7.32 (d, J ϭ 9.1
Hz, 2H, ph-3,5-H), 8.54Ϫ8.57 (m, 3H, ar-9-H, ph-2,6-H), 8.67 (dd,
J ϭ 8.2/7.7 Hz, 1H, ar-8-H), 8.89 (d, J ϭ 8.7 Hz, 1H, ar-7-H), 9.28
(d, J ϭ 8.6 Hz, 1H, ar-10-H). MS (70 eV): m/z (%) ϭ 416 (15)
[Mϩ•], 317 (12), 304 (10), 113 (10), 112 (100), 86 (41), 28 (13).
2-[(3-[(2-Phenyl)-pyrimido[5,4-c]cinnolin-4-yl]aminopropyl)-
amino]ethanol (6e)
From 0.19 g (0.65 mmol) 5a and 1.1. g (9.3 mmol) [2-(3-aminoprop-
yl)amino]ethanol. Light green crystals, mp. 198°C (ethylacetate/
DMF), yield 0.14 g (57%). Anal. C21H22N6O (374.5). IR (KBr):
ν ϭ 3412 cmϪ1; 3342; 1597; 1581; 1547; 1401; 1316. 1H-NMR/400
MHz (D6]DMSO): δ (ppm) ϭ 1.91Ϫ1.97 (tt, J ϭ 6.6 Hz, 2H, ar-
NH-CH2-CH2-CH2), 2.62 (t, J ϭ 5.8 Hz, 2H, ar-NH-CH2-CH2-
CH2), 2.74 (t, J ϭ 6.6 Hz, NH-CH2-CH2-OH), 3.49Ϫ3.50 (br, m,
2H, NH-CH2-CH2-OH), 3.87Ϫ3.89 (m, 2H, ar-NH-CH2), 4.45 (s,
1H, OH, D2O exchange), 7.56Ϫ7.62 (m, 3H, ph-3,4,5-H), 8.08 (ddd,
J ϭ 8.0/7.0/1.1 Hz, 1H, ar-9-H), 8.14 (ddd, J ϭ 7.7/7.5/1.4 Hz, 1H,
ar-8-H), 8.65 (d, J ϭ 8.4 Hz, 1H, ar-7-H), 8.67Ϫ8.71 (m, 2H, ph-
2,6-H), 9.02 (dd, J ϭ 8.1/1.1 Hz, 1H, ar-10-H), 9.85 (s, 1H, ar-NH,
D2O exchange). MS (70 eV): m/z (%) ϭ 374 (10) [Mϩ•], 301 (18),
300 (20), 287 (23), 276 (23), 275 (100), 274 (37), 126 (13), 100 (27),
43 (11).
N-Cyclohexyl-NЈ-[2-(4-Methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-
yl]propane-1,3-diamine (6i)
From 0.40 g (1.24 mmol) 5c and 2.5 g (15.9 mmol) N-cyclohexylpro-
pane-1,3-diamine. Yellow crystals, mp. 155°C, yield 0.31 g (56%).
Anal. C26H30N6O (442.6). IR (KBr). ν ϭ 2927 cmϪ1; 1595; 1575;
1546, 1403; 1375; 1309; 1251; 1164; 769. 1H-NMR/400 MHz
N-[(2-(4-Methoxyphenyl)pyrimido[5,4-c]cinnolin-4-yl]-NЈ,NЈ-di-
methylpropane-1,3-diamine (6f)
([D6]DMSO):
δ (ppm) ϭ 0.96Ϫ1.08 (m,, 2H, cyc-3a,5a-H),
1.09Ϫ1.22 (m, 3H, cyc-3e,4a,5e-H), 1.51Ϫ1.53 (m, 1H, cyc-4e-H),
1.62Ϫ1.65 (m, 2H, cyc-2a,6a-H), 1.90 (tt, J ϭ 6.5 Hz, 2H, ar-NH-
CH2-CH2-CH2), 2.33Ϫ2.39 (m, 1H, cyc-1H), 2.73 (t, J ϭ 6.4 Hz,
2H, ar-NH-CH2-CH2-CH2), 3.85Ϫ3.89 (m, 5H, ar-NH-CH2,
OCH3), 7.12 (d, J ϭ 8.9 Hz, 2H, ph-3,5-H), 8.06 (ddd, J ϭ 7.6/7.4/
0.8 Hz, 1H, ar-9-H), 8.12 (ddd, J ϭ 7.7/7.5/1.3 Hz, 1H, ar-8-H),
8.62Ϫ8.64 (m, 3H, ar-7-H, ph-2,6-H), 8.99 (dd, J ϭ 7.6/0.9 Hz, 1H,
ar-10-H), 9.82 (s, 1H, ar-NH, D2O exchange). MS (70 eV): m/z
(%) ϭ 442 (9) [Mϩ•], 317 (13), 306 (21), 305 (100), 304 (25), 138
(37), 56 (20), 30 (18), 28 (33).
From 0.20 g (0.62 mmol) 5c and 1.5 g (14.7 mmol) N,N-dimeth-
ylpropane-1,3-diamine. Light yellow crystals (ethanol), mp. 172°C,
yield 0.14 g (58%). Anal. C22H24N6O (3.88.5). IR (KBr): ν ϭ 3476
cmϪ1; 3423; 1595; 1576; 1547; 1404; 1309; 1253; 1165; 768. 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.91 (tt, J ϭ 6.7 Hz, 2H,
ar-NH-CH2-CH2-CH2), 2.22 (s, 6H, 2 ϫ CH3), 2.45 (t, J ϭ 6.8 Hz,
2H, ar-NH-CH2-CH2-CH2), 3.80Ϫ3.85 (m, 2H, ar-NH-CH2), 7.13
(d, J ϭ 8.9 Hz, 2H, ph-3,5-H), 8.06 (dd, J ϭ 8.0/7.0 Hz, 1H, ar-9-
H), 8.11Ϫ8.14 (m, 1H, ar-8-H), 8.61Ϫ8.65 (m, 1H, ph-2,6-H, ar-7-
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
New Antiplatelet Pyrimidocinnolines
595
2-[(3-[(2-(4-Methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-yl]amino-
propyl)amino]ethanol (6j)
Hz, 1H, fur-5-H); 8.03Ϫ8.08 (m, 2H, fur-3-H, ar-9-H), 8.13 (dd,
J ϭ 8.3/7.0 Hz, ar-8-H), 8.62 (d, J ϭ 8.2 Hz, 1H, ar-7-H), 8.88 (d,
J ϭ 7.9 Hz, 1H, ar-10-H), 9.75 (s, 1H, ar-NH, D2O exchange). MS
(EI; 70°C): m/z (%) ϭ 334 (13) [Mϩ•], 291 (16), 277 (22), 266 (19),
265 (100), 264 (47), 107 (35), 71 (20), 70 (39), 69 (16), 57 (23), 55
(11), 44 (29), 43 (26), 42 (10), 41 (14).
From 0.25 g (0.77 mmol) 5c and 1.3 g (6.9 mmol) [2-(3-aminoprop-
yl)amino]ethanol. Yellow crystals (ethanol/ethylacetate), mp. 145°C,
yield 0.21 g (68%). Anal. C22H24N6O2 (404.5). IR (KBr): ν ϭ 3345
cmϪ1; 1595; 1576; 1546; 1437; 1403; 1378; 1251; 1164; 767. 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.94 (tt, J ϭ 6.6. Hz, 2H,
ar-NH-CH2-CH2-CH2), 2.62 (t, J ϭ 5.8 Hz, 2H, ar-NH-CH2-CH2-
CH2), 2.73 (t, J ϭ 6.5 Hz, NH-CH2-CH2-OH), 3.49 (br, m, 2H,
NH-CH2-CH2-OH), 3.85Ϫ3.86 (m, 2H, ar-NH-CH2), 3.88 (s, 3H,
OCH3), 4.45 (s, 1H, OH, D2O exchange), 7.12 (d, 2H, ph-3,5-H),
8.06 (dd, J ϭ 7.2/7.0 Hz, 1H, ar-9-H), 8.12 (ddd, J ϭ 7.7/7.5/1.2
Hz, 1H, ar-8-H), 8.61Ϫ8.65 (m, 3H, ar-7-H, ph-2,6-H), 8.99 (d, J ϭ
7.4 Hz, 1H, ar-10-H), 9.75 (s, 1H, ar-NH, D2O exchange). MS (70
eV): m/z (%) ϭ 404 (14) [Mϩ•], 331 (14), 330 (21), 319 (23), 318
(11), 309 (20), 307 (100), 306 (45), 127 (13), 126 (20), 100 (27), 56
(11), 45 (10), 44 (14), 31 (15), 30 (14).
N-[2-(2-Furyl)pyrimido[5,4-c]cinnolin-4-yl]-NЈ-propylpropane-1,3-
diamine (6n)
From 0.25 g (0.88 mmol) 5e and 1.4 g (12.1 mmol) N-propylpro-
pane-1,3-diamine. Yellow crystals, mp. 118°C (ethanol), yield 0.15
g (47%). Anal. C20H22N6O (362.4). IR (KBr): 3351 cmϪ1; 2954;
2954; 2931; 2872; 1602; 1574; 1544; 1480; 1432; 1403; 1365; 1318;
1239; 1009; 779; 766; 743. 1H-NMR/400 MHz ([D6]DMSO): δ
(ppm) ϭ 0.86 (t, J ϭ 7.4 Hz, 3H, NH-CH2-CH2-CH3), 1.39Ϫ1.48
(m, 2H, NH-CH2-CH2-CH3), 1.89 (tt, J ϭ 6.5 Hz, 2H, ar-NH-CH2-
CH2-CH2), 2.47 (t, J ϭ 7.1 Hz, 2H, NH-CH2-CH2-CH2), 2.66 (t,
J ϭ 6.4 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.80 (t, J ϭ 6.4 Hz, 2H,
ar-NH-CH2), 6.78 (dd, J ϭ 3.2/1.6 Hz, 1H, fur-4-H), 7.53 (dd, J ϭ
3.3 Hz, 1H, fur-5-H), 8.03Ϫ8.07 (m, 2H, fur-3-H, ar-9-H),
8.11Ϫ8.14 (m, 1H, ar-8-H), 8.62 (d, J ϭ 8.2 Hz, 1H, ar-7-H), 8.88
(d, J ϭ 7.9 Hz, 1H, ar-10-H), 9.81 (s, 1H, ar-NH, D2O exchange).
MS (70 eV): m/z (%) ϭ 362 (7) [Mϩ•]. 291 (13), 290 (10), 277 (17),
266 (16), 265 (100), 126 (11), 98 (75), 72 (16), 70 (11), 56 (13), 44
(14), 43 (22), 42 (11), 41 (18), 39 (12), 20 (68), 28 (18), 27 (12).
N-Cyclohexyl-NЈ-[2-(2-methoxyphenyl)-pyrimido[5,4-c]cinnolin-4-
yl]propane-1,3-diamine (6k)
From 0.20 g (0.62 mmol) 5b and 1.9 g (12.1 mmol) N-cyclohexylpro-
pane-1,3-diamine. Light yellow crystals, mp. 100°C, yield 0.18 g
(66%). Anal. C26H30N6O (442.6). IR (KBr): ν ϭ 3415 cmϪ1; 3338;
2924; 1597; 1546; 1301. 1H-NMR/400 MHz ([D6]DMSO):
δ
(ppm) ϭ 0.89Ϫ0.97 (m, 2H, cyc-3a,5a-H), 1.04Ϫ1.18 (m, 3H, cyc-
3e,4a,5e-H), 1.49Ϫ1.52 (m, 1H, cyc-4e-H), 1.59Ϫ1.62 (m, 2H, cyc-
2a,6a-H), 1.74Ϫ1.77 (m, 1H, cyc-2e,6e-H), 1.87 (tt, J ϭ 6.5 Hz, 2H,
ar-NH-CH2-CH2-CH2), 2.28Ϫ2.33 (m, 1H, cyc-1-H), 2.66 (t, J ϭ
6.3 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.73Ϫ3.75 (m, 2H, ar-NH-
CH2), 3.85 (s, 3H, OCH3), 7.09 (dd, J ϭ 7.5/7.2 Hz, 1H, ph-4-H),
7.20 (d, J ϭ 8.3 Hz, 1H, ph-3-H), 7.50 (ddd, J ϭ 7.9/7.6/1.8 Hz,
1H, ph-5-H), 7.80 (dd, J ϭ 7.6/1.8 Hz, 1H, ph-6-H), 8.04 (dd, J ϭ
8.0/7.1 Hz, 1H, ar-9-H), 8.13 (ddd, J ϭ 7.6/7.6/1.3 Hz, 1H, ar-8-H),
8.66 (d, J ϭ 8.2 Hz, 1H, ar-7-H), 8.84 (d, J ϭ 8.0 Hz, 1H, ar-10-
H), 9.83 (s, 1H, ar-NH, D2O exchange). MS (70 eV): m/z (%) ϭ
442 (3) [Mϩ•], 317 (11), 306 (20), 305 (100), 304 (19), 138 (19), 56
(12), 30 (11).
N-[2-(2-Furyl)pyrimido[5,4-c]cinnolin-4-yl]-NЈ,NЈ-dimethyl-
propane-1,3-diamine (6o)
From 0.30 g (1.06 mmol) 5e and 1.3 g (12.8 mmol) N,N-dimeth-
ylpropane-1,3-diamine. Green crystals, mp. 119°C, yield 0.22 g
(57%). Anal. C19H20N6O (348.4). IR (KBr): 3341 cmϪ1; 1606; 1574;
1544; 1495; 1479; 1436; 1367; 1316; 1265; 1241; 764. 1H-NMR/400
MHz ([D6]DMSO): δ (ppm) ϭ 1.91 (tt, J ϭ 6.7 Hz, 2H, ar-NH-
CH2-CH2-CH2), 2.20 (s, 6H, 2 ϫ CH3), 2.39 (t, J ϭ 6.8 Hz, 2H, ar-
NH-CH2-CH2-CH2), 3.74Ϫ3.79 (m, 2H, ar-NH-CH2), 6.77 (dd, J ϭ
3.4/1.6 Hz, 1H, fur-4-H), 7.52 (d, J ϭ 3.5 Hz, 1H fur-5-H),
8.03Ϫ8.07 (m, 2H, fur-3-H, ar-9-H), 8.13 (ddd, J ϭ 8.2/7.0/1.3 Hz,
1H, ar-8-H), 8.62 (d, J ϭ 7.6 Hz, 1H, ar-7-H), 8.87Ϫ8.90 (m, 1H,
ar-10-H), 9.71 (t, J ϭ 5.7 Hz, ar-NH, D2O exchange). MS (70 eV):
m/z (%) ϭ 348 (3) [Mϩ•], 277 (21), 264 (22), 85 (16), 84 (100),
58 (61).
N-[(2-(4-Chlorophenyl)pyrimido[5,4-c]cinnolin-4-yl]-NЈ,NЈ-di-
ethylpropane-1,3-diamine (6l)
From 0.3 g (0.92 mmol) 5d and 1.7 g (13.1 mmol) N,N-diethylpro-
pane-1,3-diamine. Yellow crystals, mp. 127°C, yield 0.24 g (62%).
Anal. C23H25ClN6 (420.9). IR (KBr): ν ϭ 3431 cmϪ1; 1600; 1576;
1547; 1400; 1310. 1H-NMR/400 MHz (CF3COOD): δ (ppm) ϭ 1.48
(t, J ϭ 7.3 Hz, 6H, 2 ϫ CH3), 2.58Ϫ2.66 (m, 2H, ar-NH-CH2-CH2-
CH2), 3.39Ϫ3.53 (m, 4H, N-(CH2-CH3)2), 3.58Ϫ3.62 (m, 2H, ar-
NH-CH2-CH2-CH2), 4.42 (t, J ϭ 6.9 Hz, 2H, ar-NH-CH2), 7.78 (d,
J ϭ 8.6 Hz, 2H, ph-3,5-H), 8.45 (d, J ϭ 8.6 Hz, 2H, ph-2,6-H),
8.55 (dd, J ϭ 8.0/7.6 Hz, 1H, ar-9-H), 8.65 (dd, J ϭ 8.2/7.5 Hz, 1H,
ar-8-H), 8.95 (d, J ϭ 8.6 Hz, 1H, ar-7-H), 9.27 (d, J ϭ 8.6 Hz, 1H,
ar-10-H). MS (70 eV): m/z (%) ϭ 420 (7) [Mϩ•], 112 (100), 86 (53),
30 (10).
N,N-Diethyl-NЈ-[2-(2-furyl)pyrimido[5,4-c]cinnolin-4-yl]-1,3-
propanediamine (6p)
From 0.30 g (1.06 mmol) 5e and 1.7 g (13.1 mmol) N,N-diethylpro-
pane-1,3-diamine. Yellow green crystals (ethylacetate), mp. 93°C,
yield 0.21 g (51%). Anal. C21H24N6O (376.5). IR (KBr): ν ϭ 3340
cmϪ1; 2969; 2796; 1603; 1575; 1545; 1497; 1480; 1433; 1368; 1318;
1
1241; 1012; 763. H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.00
(t, J ϭ 7.1 Hz, 6H, 2 ϫ CH3), 1.90 (tt, J ϭ 6.7 Hz, 2H, ar-NH-
CH2-CH2-CH2), 2.53Ϫ2.55 (overlapped by DMSO peak, m, 4H, N-
(CH2-CH3)2), 2.59 (t, J ϭ 6.6 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.78
(t, J ϭ 6.4 Hz, 2H, ar-NH-CH2), 6.77(dd, J ϭ 3.3/1.7 Hz, 1H, fur-
4-H), 7.52 (d, J ϭ 3.1 Hz, 1H, fur-5-H), 8.02Ϫ8.07 (m, 2H, fur-3-
H, ar-9-H), 8.11Ϫ8.15 (m, 1H, ar-8-H), 8.63 (d, J ϭ 8.3 Hz, 1H,
ar-7-H), 8.88 (dd, J ϭ 8.0/1.0 Hz, 1H, ar-10-H), 9.85 (t, J ϭ 5.5
Hz, ar-NH, D2O exchange). MS (70 eV): m/z (%) ϭ 376 (13) [Mϩ•],
277 (14), 112 (100), 86 (44).
N-[2-(2-Furyl)pyrimido[5,4-c]cinnolin-4-yl]-NЈ-methylpropane-
1,3-diamine (6m)
From 0.21 g (0.74 mmol) 5e and 1.3 g (18.0 mmol) N-methylpro-
pane-1,3-diamine. Slightly brown crystals, mp. 119°C (ethanol/
ethylacetate), yield 0.14 g (57%). Anal. C18H18N6O (334.4). IR
(KBr): 3343 cmϪ1; 3297; 1605; 1576; 1545; 1480; 1431; 1365; 1316;
N-Cyclohexyl-NЈ-[2-(2-furyl)pyrimido[5,4-c]cinnolin-4-yl]propane-
1,3-diamine (6q)
1
767. H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.89 (tt, J ϭ 6.7
Hz, 2H, NH-CH2-CH2-CH2), 2.29 (s, 3H, NH-CH3), 2.61 (t, J ϭ
6.5 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.79 (t, J ϭ 6.6 Hz, 2H, ar-
NH-CH2), 6.77 (dd, J ϭ 3.2/1.6 Hz, 1H, fur-4-H), 7.54 (d, J ϭ 3.3
From 0.28 g (0.99 mmol) 5e and 1.3 g (8.3 mmol) N-cyclohexylpro-
pane-1,3-diamine. Ochroid small crystals, mp. 118°C, yield 0.38 g
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

596
Rehse et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
(95%). Anal. C23H26N6O (402.5). IR (KBr): ν ϭ 2926 cmϪ1; 1605;
1575; 1545; 1480; 1366; 1315; 766. 1H-NMR/400 MHz
([D6]DMSO): δ (ppm) ϭ 0.96Ϫ1.22 (m, 5H, cyc-3a,3e,4a,5a,5e-H),
1.51Ϫ1.53 (m, 1H, cyc-4e-H), 1.62Ϫ1.65 (m, 2H, cyc-2a,5a-H),
1.81Ϫ1.90 (m, 4H, cyc-2e,6e-H, ar-NH-CH2-CH2-CH2), 2.32Ϫ2.37
(m, 1H, cyc-1-H), 2.68Ϫ2.71 (m, 2H, ar-NH-CH2-CH2-CH2), 3.80
(s. broad, 2H, ar-NH-CH2), 6.77 (dd, J ϭ 3.2/15 Hz, 1H, fur-4-H),
7.53 (d, J ϭ 3.2 Hz, 1H, fur-5-H), 8.03Ϫ8.15 (m, 2H, fur-3-H, ar-
9-H), 8.13 (dd, J ϭ 7.9/7.2 Hz, 1H, ar-8-H), 8.63 (d, J ϭ 8.3 Hz,
1H, ar-7-H), 8.88 (d, J ϭ 7.9 Hz, 1H, ar-10-H), 9.89 (s, 1H, ar-NH,
D2O exchange). MS (70 eV): m/z (%) ϭ 402 (5) [Mϩ•], 277 (14),
266 (16), 265 (100), 56 (21), 30 (14).
1H, ar-10-H), 9.87 (t, J ϭ 5.6 Hz, 1H, ar-NH, D2O exchange). MS
(70 eV): m/z (%) ϭ 392 (9) [Mϩ•], 112 (100), 86 (86), 72 (18), 58
(48), 56 (31), 44 (17), 43 (16), 42 (38), 41 (14), 39 (12), 30 (80), 29
(45), 28 (28), 27 (11).
N-Cyclohexyl-NЈ-[2-(2-thienyl)pyrimido[5,4-c]cinnolin-4-yl]-
propane-1,3-diamine (6u)
From 0.30 g (1.00 mmol) 5f and 1.3 g (8.3 mmol) N-cyclohexylpro-
pane-1,3-diamine. Yellow green crystals, mp. 124°C, yield 0.22 g
(52%). Anal. C23H26N6S (418.6). IR (KBr): ν ϭ 3350 cmϪ1; 2926;
2851; 1593; 1576; 1536; 1524; 1432; 1392; 1366; 1343; 1311; 464;
706. 1H-NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 0.96Ϫ1.22 (m,
5H, cyc-3a,3e,4a,5a,5e-H), 1.51Ϫ1.53 (m, 1H, cyc-4e-H), 1.62Ϫ1.66
(m, 2H, cyc-2a,6a-H), 181Ϫ1.85 (m, 2H, cyc-2e,6e-H), 1.90 (tt, J ϭ
6.4 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.33Ϫ2.39 (m, 1H, cyc-1-H),
2.70Ϫ2.73 (m, 2H, ar-NH-CH2-CH2-CH2), 3.80 (br, s, 2H, ar-NH-
CH2), 4.37 (s, 1H, cyc-NH, partly exchanged), 7.27 (dd, J ϭ 4.9/3.7
Hz, 1H, thi-4-H), 7.87 (dd, J ϭ 5.0/0.9 Hz, 1H, thi-5-H), 8.06 (dd,
J ϭ 7.1/6.8 Hz, 1H, ar-9-H), 8.13 (ddd, J ϭ 7.7/7.5/1.3 Hz, 1H, ar-
8-H), 8.16Ϫ8.17 (m, 1H, thi-3-H), 8.62 (d, J ϭ 8.1 Hz, 1H, ar-7-
H), 8.68 (d, J ϭ 7.5 Hz, 1H, ar-10-H)), 9.91 (s, 1H, ar-NH, D2O
exchange). MS (70 eV): m/z (%) ϭ 418 (7) [Mϩ•], 307 (12), 293 (16),
282 (20), 281 (100), 280 (23), 138 (78), 56 (21), 30 (15).
2-[(3-[(2-Furyl)pyrimido[5,4-c]cinnnolin-4-yl]aminopropyl)-
amino]ethanol (6r)
From 0.30 g (1.06 mmol) 5e and 1.7 g (14.4 mmol) [2-(3-aminoprop-
yl)amino]ethanol. Light green crystals, mp. 183°C (ethanol/H2O/
DMF), yield 0.13 g (36%). Anal. C19H20N6O2 (364.4). IR (KBr):
ν ϭ 3343 cmϪ1; 3311; 2830; 1603; 1574; 1544; 1496, 1476; 1434;
1405; 1367; 1315; 1241; 765. 1H-NMR/400 MHz ([D6]DMSO): δ
(ppm) ϭ 1.90 (tt, J ϭ 5.5 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.61 (t,
J ϭ 5.8 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.70 (t, J ϭ 6.5 Hz, 2H,
NH-CH2-CH2-OH), 3.48Ϫ3.51 (br. m, 2H, NH-CH2-CH2-OH),
3.79 (br, m, 2H, ar-NH-CH2), 4.45 (s, 1H, OH, D2O exchange),
6.76Ϫ6.78 (m, 1H, fur-4-H), 7.54 (d, J ϭ 3.5 Hz, 1H, fur-5-H),
8.02Ϫ8.08 (m, 2H, fur-3-H, ar-9-H), 8.11Ϫ8.15 (m, 1H, ar-8-H),
8.62 (d, J ϭ 8.1, 1H, ar-7-H), 8.87 (d, J ϭ 7.7 Hz, 1H, ar-10-H),
9.84 (s, 1H, ar-NH, D2O exchange). MS (EI, 70°C): m/z (%) ϭ 364
(11) [Mϩ•], 291 (21), 290 (28), 277 (22), 276 (11), 266 (18), 265 (100),
264 (47), 263 (11), 126 (13), 100 (30), 56 (11).
N-[3-(1H-Imidazol-1-yl)propyl]-2-(2-thienyl)-pyrimido[5,4-c]-
cinnolin-4-amine (6v)
From 0.25 g (0.83 mmol) 5f and 2.2 g (17.6 mmol) 3-(1-imidazolyl)-
propylamine. Light brown crystals, mp. 177°C, yield 0.11 g (34%).
Anal. C20H17N7S (387.5). IR (KBr) ν ϭ 3347 cmϪ1 (NH); 1595;
1577; 1536; 1524; 1433; 1393; 1370; 1313; 764; 726. 1H-NMR
([D6]DMSO): δ (ppm) ϭ 2.20Ϫ2.27 (m, 2H, ar-NH-CH2-CH2-
CH2), 3.71Ϫ3.76 (m, 2H, ar-NH-CH2), 4.15 (t, J ϭ 6.8 Hz, 2H, ar-
NH-CH2-CH2-CH2), 6.91 (s, 1H, im-5-H), 7.26 (s, 1H, im-4-H),
7.28 (dd, J ϭ 4.9/3.8 Hz, 1H, thi-4-H), 7.70 (s, 1H, im-2-H), 7.87
(dd, J ϭ 4.8/0.9 Hz, 1H, thi-5-H), 8.07 (m, 1H, ar-9-H), 8.11Ϫ8.15
(m, 2H, ar-8-H, thi-3-H), 8.63 (d, J ϭ 8.1 Hz, ar-7-H), 8.88 (dd,
J ϭ 8.0/0.7 Hz, 1H, ar-10-H), 9.74 (t, J ϭ 5.8 Hz, 1H, ar-NH, D2O
exchange). MS (70 eV): m/z (%) ϭ 387 (68) [Mϩ•], 319 (36), 306
(48), 304 (43), 293 (53), 292 (22), 291 (17), 281 (12), 280 (58), 264
(15), 155 (13), 127 (19), 126 (31), 110 (10), 108 (29), 95 (20), 82 (75),
81 (23), 69 (18), 68 (23), 55 (27), 54 (12), 41 (19), 30 (100), 28 (63),
27 (29), 26 (13).
N-Propyl-NЈ-[2-(2-thienyl)pyrimido[5,4-c]cinnolin-4-yl]propane-
1,3-diamine (6s)
From 0.30 g (1.00 mmol) 5f and 1.5 g (12.9 mmol) N-propylpro-
pane-1,3-diamine. Light brown crystals, mp. 134°C (ethanol/ethyl-
acetate), yield 0.26 g (69%). Anal. C20H22N6S (378.5). IR (KBr):
ν ϭ 3351 cmϪ1; 1595; 1575; 1537; 1524; 1433; 1311; 765. 1H-NMR/
400 MHz ([D6]DMSO): δ (ppm) ϭ 0.86 (t, J ϭ 7.4 Hz, 3H, NH-
CH2-CH2-CH3), 1.39Ϫ1.48 (m, 2H, NH-CH2-CH2-CH3), 1.90 (tt,
J ϭ 6.6 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.47 (partly overlapped by
DMSO peak, m, 2H, NH-CH2-CH2-CH3), 2.68 (t, J ϭ 6.5 Hz, 2H,
ar-CH2-CH2-CH2), 3.80 (d, J ϭ 6.5 Hz, 2H, ar-NH-CH2), 7.28 (dd,
J ϭ 4.8/3.9 Hz, 1H, thi-4-H), 7.87 (dd, J ϭ 5.0/0.8 Hz, 1H, thi-5-
H), 8.06 (dd, J ϭ 7.1/7.0 Hz, 1H, ar-9-H), 8.11Ϫ8.15 (m, 1H, ar-8-
H), 8.17 (dd, J ϭ 3.5/0.9 Hz, 1H, thi-3-H), 8.62 (d, J ϭ 8.1 Hz,
1H, ar-7-H), 8.87Ϫ8.89 (m, 1H, ar-10-H), 9.84 (s, 1H, ar-NH, D2O
exchange). MS (70 eV): m/z (%) ϭ 378 (11) [Mϩ•], 361 (25), 360
(13); 322 (25), 321 (12), 320 (34), 319 (18), 307 (20), 306 (20), 293
(25), 292 (21), 282 (17), 281 (100), 155 (11), 135 (11), 127 (15), 126
(25), 110 (10), 98 (57), 72 (11), 43 (14), 41 (13), 30 (26), 28 (37).
Biology
The Born test was performed as usual [9Ϫ11]. The thrombosis
model has been described in detail [12].
NЈ,NЈ-Diethyl-N-[2-(2-thienyl)pyrimido[5,4-c]cinnolin-4-yl]-
propane-2,3-diamine (6t)
References
[1] A. K. Yildiz, K. Rehse, J.-P. Stasch, E. Bischof, Arch. Pharm.
Pharm. Med. Chem. 2004, 337, 311Ϫ316.
From 0.30 g (1.00 mmol) 5f and 1.3 g (10.0 mmol) N,N-diethylpro-
pane-1,3-diamine. Light green crystals, mp. 91°C, yield 0.35 g
(89%). Anal. C21H24N6S (392.5). IR (KBr): ν ϭ 3351 cmϪ1; 2967;
1595; 1577; 1536; 1524; 1433; 1392; 1367; 1343; 1308; 763; 706. 1H-
NMR/400 MHz ([D6]DMSO): δ (ppm) ϭ 1.00 (t, J ϭ 7.1 Hz, 6H,
2 ϫ CH3), 1.90 (tt, J ϭ 6.8 Hz, 2H, ar-NH-CH2-CH2-CH2), 2.52
(overlapped by DMSO peak, m, 4H, N-(CH2-CH3)2), 2.59 (t, J ϭ
6.7 Hz, 2H, ar-NH-CH2-CH2-CH2), 3.76Ϫ3.81 (m, 2H, ar-NH-
CH2), 7.28 (dd, J ϭ 4.9/3.8 Hz, 1H, thi-4-H), 7.87 (dd, J ϭ 4.9/1.1
Hz, 1H, thi-5-H), 8.04Ϫ8.08 (m, 1H, ar-9-H), 8.13 (ddd, J ϭ 3.7/
1.1 Hz, thi-3-H), 8.63 (d, J ϭ 8.1 Hz, 1H, ar-7-H), 8.87Ϫ8.89 (m,
[2] A. Cwiklicki, K. Rehse, Arch. Pharm. Pharm. Med. Chem.
2004, 337, 156Ϫ163.
[3] K. Bethge, H. H. Pertz, K. Rehse, Arch. Pharm. Chem. Life
Sci. 2005, 338, 78Ϫ86.
[4] K. Gewald, O. Calderon, H. Schäfer, U. Ham, Liebigs Ann.
Chem. 1984, 1390Ϫ1394.
[5] R. G. Menon, E. Purushotaman, J. Ind. Chem. Soc. 1993, 70,
533Ϫ536.
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2005, 338, 590−597
New Antiplatelet Pyrimidocinnolines
597
[6] R. G. Menon, E. Purushotaman, J. Ind. Chem. Soc. 1995, 72,
731Ϫ733.
[9] K. Bethge, H. H. Pertz, K. Rehse, Arch. Pharm. Chem. Life
Sci. 2005, 338, 78Ϫ86.
[10] G. V. R. Born, Nature 1962, 194, 927Ϫ929.
[11] F. Seuter, Haemostasis 1976, 5, 85Ϫ95.
[7] R. G. Menon, E. Purushotaman, Ind. J. Chem. 1996, 35B,
1185Ϫ1189.
[8] L. V. G. Nargund, R. Jose, Y. S. Reddy, Arzneim.-Forsch./Drug
Res. 1994, 44, 156Ϫ158.
[12] K. Rehse, A. Kesselhut, V. Schein, M. Kämpfe, B. Rose,
E. Unsöld, Arch. Pharm. 1991, 324, 301Ϫ305.
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com