New purines with antiplatelet activity

Article abstract of DOI:10.1002/ardp.200500189

Four purine-2,6-diamines, 4a, b, 5a, b, nineteen N-(purin-2-yl) benzenecarboxamides 6a-q, 7b, and one N-(purin-2-yl)-2-furanecarboxamide 8 were prepared for the first time and tested for their inhibition of blood platelet aggregation. Six compounds, 6a, b

Full text of DOI:10.1002/ardp.200500189

Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
K. Mꢀrschenz et al.
115
Full Paper
New Purines with Antiplatelet Activity
Katrin Mꢀrschenz, Klaus Rehse
Institut fꢁr Pharmazie, Freie Universitꢀt Berlin, Berlin, Germany
Four purine-2,6-diamines, 4a, b, 5a, b, nineteen N-(purin-2-yl)benzenecarboxamides 6a–q, 7b,
and one N-(purin-2-yl)-2-furanecarboxamide 8 were prepared for the first time and tested for
their inhibition of blood platelet aggregation. Six compounds, 6a, b, h, m, o, p, inhibited the
platelet aggregation induced by collagen with IC50 values between 3 and 10 lmol/L in the Born
test. ADP, PAF, and adrenaline were used as specific aggregation inducers to examine the mecha-
nism of the anti-aggregating activity. An astonishing pattern of activities in the nanomolar,
with 6m, 7b, 8 and even subnanomolar range, with 6b, was observed. Compound 6b inhibited
the platelet aggregation induced by ADP with an IC50 = 0.45 nM (6m: 3.5 nM; 8: 30 nM). Com-
pound 7b showed an antagonism against the inducer adrenaline with an IC50 = 1.8 nM (6o: 20
nM; 8: 30 nM). The strongest antagonism against PAF was observed with 7b showing an IC50 = 1
nM (6b: 35 nM; 8: 74 nM).
Keywords: N-(Purin-2-yl)benzenecarboxamides / Antiplatelet properties / Born test / PAF / ADP / Adrenaline antagon-
ism /
Received: August 9, 2005; accepted: November 2, 2005
DOI 10.1002/ardp.200500189
rial is the commercially available 6-chloro-9H-purine-2-
amine 1. The introduction of the hydrophobic moiety
was achieved by reaction with benzylchloride in DMF/
K2CO3 [7–9]. Whatever the reaction conditions are, a mix-
ture of compounds 2 (l80%) and 3 (l20%) is obtained
and can be separated by column chromatography
(dichloromethane/ethanol 9.5:0.5). The assignment is
made via 1H-NMR data of H-8 (2: d = 8.23 ppm; 3: d = 8.55
ppm) as well as the benzylic methylene group (2: d = 5.29
ppm; 3: d = 5.56 ppm) and is based on known NMR-data
[8, 9] for unambiguous syntheses [10–14]. The nucleophi-
lic substitution of 2 or 3 by two diamines in 6-position
gave the type 4 or type 5 compounds, respectively. As bio-
logical test results of the type 4 substances appeared to be
superior to the corresponding type 5 compounds, only
the first ones were transformed by suitable benzoic acid
chlorides to the type 6 and 7 substances. One furanecar-
boxamide 8 (see Experimental) was prepared for compar-
ison of aromatic 6, 7 with heteroaromatic carboxamides.
Introduction
In a number of publications, we have shown that the sub-
stitution of heterocycles rich in nitrogen like indazoles
[2], triazoles [3], oxadiazoles [4], imidazoles [5], or pyrimi-
docinnolines [6] with a carboxamide partial structure
and additional hydrophobic and basic groups leads to a
wide variety of compounds with antiplatelet activities in
micromolar concentrations. In this paper, we wish to
report a number of purine derivatives fulfilling these
structural requirements and, consequently, were promis-
ing to show remarkable antiplatelet activities.
Results and discussion
Chemistry
The synthesis of the desired purinylbenzene-carboxa-
mides 6 and 7 is summarised in Scheme 1. Starting mate-
Biology
Correspondence: Prof. Klaus Rehse, Institut fꢁr Pharmazie – Freie Uni-
versitꢀt Berlin, Kꢂnigin-Luise-Strasse 2 + 4, D-14195 Berlin, Germany.
E-mail: rehiwer@zedat.fu-berlin.de
The results of the Born test [4] with collagen as inducer of
the platelet aggregation are compiled in Table 1. The
starting material 1 (150 lM) and its benzyl derivatives 2
Fax: +49 30 838-53251
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116
K. Mꢀrschenz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
Table 1. In vitro antiplatelet activities (Born test).
Com-
R/R1
IC50
pound
[lmol/L]
1
2
3
–
–
–
75
44
52
11
150
23
140
3
4a
4b
5a
5b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
7b
asa
(CH2)3-NH-cyclohexyl
(CH2)3-1-pyrrolidinyl
(CH2)3-NH-cyclohexyl
(CH2)3-1-pyrrolidinyl
4-COOCH3
3-CN
4-OCH3
4-Cl
3-(pyrrolidin-1-yl-sulfonyl)
3-(morpholin-4-yl-sulfonyl)
4-(morpholin-4yl-sulfonyl)
3-(4-methylpiperazin-1-yl-sulfonyl)
4-(pyrimidin-2-yl-piperazin-4-yl-sulfonyl)
3-SO2-NH-phenyl
3-SO2-N-(C2H5)2
3-SO2-NH-(CH2)2-OCH3
4-SO2-NH-(CH2)2-OCH3
3-SO2-NH-(CH2)3-OCH3
4-SO2-NH-(CH2)3-OCH3
3-SO2-N(CH2-CH2-OCH3)2
4-SO2-N(CH2-CH2-OCH3)2
3-CN
3
19
50
19
19
38
10
35
40
25
50
5
75
3
10
75
18
175 l 20
–
IC50 values using collagen as inducer are given (incubation time
209). The standard deviation in this test is a10% (asa, acetylsa-
licylic acid). For 4a, 4b, 5a, and 5b the rest R (see Scheme 1) is
given. For 6a–6q and 7b the rest R1 is stated (compact
Scheme 1).
Scheme 1. Synthesis of N-(6-amino-purin-2-yl)-benzenecar-
boxamides 6 and 7.
(44 lM) and 3 (52 lM) showed small effects. A wide variety
This preference in activity for 5a and 5b however
of amines including hydroxyalkylamines, hydroxyethox- changes, when, according to the rational stated in the
yalkylamines, and furylmethylamines were used for the introduction, the 2-amino group is reacted with various
introduction of an additional substituent in 6-position. benzenecarboxylic acide chlorides to type 6 or type 7
All compounds turned out to be inactive (IC50 S 300 lM) compounds, respectively. Testing 6b and 7b against the
in the Born test (data not shown). According to previous platelet aggregation induced by collagen, an IC50 = 3 lM
experiences, now a number of diamines [2–6] were used is observed for 6b, while 7b (IC50 = 18 lM) is less potent.
for substituting the 6-position. The first trials with 3-(1- Therefore, the experiments were continued with deriv-
pyrrolidinyl)-propylamine led to the compounds 4b (9- atives of 4b, i.e. type 6 compounds.
benzyl) and 5b (7-benzyl) which showed a disappoint-
Comparison of 6a–d shows that the antiplatelet activ-
ingly small antiplatelet activity. As 4b (IC50 = 150 mmol/L) ity is generally enhanced by the aromatic carboxamide
and 5b (IC50 = 140 mmol/L) are equipotent, further studies structure. This effect is sensitive to the kind of substitu-
were performed with 4b because it can be synthesised tion in the aromatic ring. Compounds 6a and 6b, each
from 2 which, in turn, was synthesised from 1 in a 80% with an IC50 = 3 mmol/L, show that electron-withdrawing
yield (3: 20%). At the end of his experiments, Steege [5] substituents are more suitable than electron-donating
identified the cyclohexylaminopropylamine group as ones (6c, 6d). Compounds 6e–6q were synthesised to
very potent concerning anti-aggregatory activities. Intro- investigate the effect of an additional sulfonamide moi-
duction of this amine in 6-position yielded 4a (IC50
=
ety. Compared to the parent amine 4b, this generally
11 lmol) and 5a (23 lmol/L), the most active species of leads to more potent compounds. The series of com-
type 4 and type 5 compounds.
pounds 6e–6i comprises alicyclic sulfonamides which all
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Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
New Antiplatelet Purines
117
Table 2. Inhibition of platelet aggregation induced with ADP,
adrenaline, or PAF by selected type 6–8 purines.
are active in the same order of magnitude. Comparison
of 6f and 6g shows the influence of the position of the sul-
fonamide group in the aromatic ring. There is only a
small difference with a slight advantage for the 3-posi-
tion. Compounds 6k–q are aliphatic sulfonamides. The
N-(2-methoxyethyl) compound 6m (IC50 = 5 lmol/L) and
the N-(3-methoxypropyl)-compound 6o (IC50 = 3 lmol/L)
belong to the most active substances.
In secondary aliphatic sulfonamides, the 4-position
appears favourable as the comparison of the pairs 6l, 6m
and 6n, 6o suggests.
Tertiary sulfonamides show antiplatelet effects as well
(see 6k, 6p, 6q). Here, the 3-position seems favourable
(IC50 = 6p: 10 lmol/L, 6o: 75 lmol/L). Even aromatic substi-
tution is accepted (see 6f).
Compound
Collagen
IC50 [lmol/L]
ADP
25
0.00045
43
50
0.0035
6
15
6.5
0.03
Adrenaline PAF
6a
6b
6h
6j
6m
6o
6p
7b
3
3
10
40
5
7.5
3.5
14
30
4.8
7
0.035
1.4
4
0.35
0.4
7
3
0.02
4
10
18
32
175
–
0.0018
0.03
–
0.001
0.074
–
8
asa
–
NECAa)
–
–
–
1
2
–
–
phentolamine
apafant (WEB-
2086)
–
–
To get an idea of the mechanism of action of the anti-
platelet compounds, the Born test was performed with
ADP, adrenaline, and Platelet Activating Factor (PAF) as
inducers of the platelet aggregation. The results are sum-
marised in Table 2.
–
0.6
Incubation time 209, Standard deviation f10%.
a)
NECA = 5-(N-Ethylcarboxamido)-adenosine.
The selected compounds show a very differentiated
pattern of antiplatelet activities. Comparing 6a with 6b,
which differ only in the substituent R1 (see Table 1), chan-
ging from an ester to a nitrile function a dramatic
increase of the ADP antagonistic activity is observed (6a:
25 lM; 6b: 0,45 nM). The difference comprises five orders
of magnitude. Comparing 6b with 7b differing only
slightly in the substituent in 6-position (6b: 1-pyrrolidi-
nylpropyl; 7b: cyclohexylaminopropyl) the ADP antagon-
ism of 6b is decreased by four orders of magnitude and
shifted to adrenaline (IC50 = 1.8 nM) and PAF (IC50 = 1 nM)
antagonism. Compound 6m exhibits a rather specific
ADP antagonism which is hundredfold stronger than the
anti-PAF activity and thousandfold stronger than the
effect on collagen- or adrenaline-induced platelet aggre-
gation. Compounds 6h, 6j, and 6p show comparable
activity against all inducers in 1–50 lM concentrations.
Compound 6o is especially adrenaline-antagonistic. The
2-furyl-carboxamide derivative 8 shows that the benzene
moiety can be replaced by a heteroaromatic one with IC50
values in the 30–74 nanomolar range against ADP, PAF,
and adrenaline, while the antiplatelet effect against col-
test results or for synthetical reasons. Nevertheless, it
might be attractive to compare the prerequisites for peak
activities in the different classes of heterocycles. In gen-
eral, it turns out that similar substitution patterns are
observed with this respect. Figure 1 shows the most
active aggregation inhibitors (inducer collagen) in each
class of compounds. Suitable lipophilic moieties are phe-
nylmethyl 10, 6b, substituted phenylmethyl 9, 14, biphe-
nylmethyl 11, biphenyl 12, 13, or simply 4-methoxyphe-
nyl 15. The link between the basic function and the het-
erocycle can be a carboxamide function, 9, 11, 12, 13, 14,
or simply an amino group, 6b, 10, 15. The length of the
connecting carbon chain consists of two (see 9, 10) or pre-
ferably three (see 6b, 11, 12, 13, 14, 15, 16) methylene
groups. An additionally substituted benzenesulfonamido
14 or benzenecarboxamido group 6b is well tolerated
and leads to high activities.
Experimental
lagen stays in the usual micromolar concentration (IC50
32 lM).
=
Chemistry
Mp. (uncorreted), Linstrꢀm-Elementar analysis: Elementar vario
EL. – NMR: Bruker DPX 400 (Bruker, Rheinstetten, Germany) EI-
MS: CH-7A-Varian MAT (70 eV). – FAB-MS: CH-5-DF-MAT-Varian
(Varian, Braunschweig, Germany). All compounds of type 4–8
were prepared for the first time. For assignment of NMR signals,
following abbreviations are used: cyhex: cyclohexyl; pyr: pyridi-
nyl; pyrr: pyrrolidinyl; SO2pyrr: pyrrolidinylsulfonyl; suph: sul-
fonylphenyl; morph: morpholin; mepipera: methylpiperazinyl;
pipera: piperazinyl; pyrim: pyrimidinyl; piperapyrim: pyrimidi-
nylpiperazinyl
It has been suggested to extend the discussion on the
comparison of the purine derivatives with other hetero-
cycles having an identical substibution pattern e.g. inda-
zoles 9 [2], triazoles 11 [3], oxadiazoles 12, 13 [4], imida-
zoles 14 [5], pyrimidocinnolines [6], and phthalazines 10
[6a], which already have been investigated by our group.
Unfortunately, such a set of data is not available because
the kind of substituents was changed according to the
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118
K. Mꢀrschenz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
Figure 1. Most active platelet aggregation inhibitors in each class of hetero-
cycles.
this is not the case, the purification is performed by column
chromatography (CC) with silica gel.
General procedure for the synthesis of type 4 and type 5
compounds (modified method of Kelley [14])
Method B: Purine 2 or 3 (2 mmol) are mixed with 4 mL of the
amine, heated to 1008C, and kept for 3 h at this temperature.
After 1 h at the latest, a solution is obtained. After cooling to
room temperature, 30 mL water is added and the mixture is
kept in the refrigerator until crystals are formed. They are
sucked off and recrystallised from ethanol/water.
Method A: Purine 2 or 3 (2 mmol) and 6–10 mmol of the amine
are dissolved in 30 mL ethanol and kept at 60 8C. After 12 h, the
progress of the reaction is controlled by TLC (dichloromethane/
ethanol 1:1) and, if necessary, continued until no starting pur-
ine is left. Then, the solvent is removed in vacuo. The resulting
yellow oil is mixed with 30 mL of water and kept for at least 1
day in the refrigerator (58C). If crystals have formed they are
sucked off and recrystallised from the solvent stated. Otherwise
the mixture is extracted with dichloromethane several times.
The combined organic phases are washed with water, dried with
Na2SO4, filtered, and the solvent is removed in vacuo. The residue
is dissolved in warm ethanol and water is added until turbidity
occurs and then is kept in the refrigerator for crystallisations. If
N6-[3-Cyclohexylamino)propyl]-9-phenylmethyl-9H-purin-
2,6-diamine 4a
From 0.5 g (1.92 mmol) of 2 and 1.0 g (7.05 mmol) 3-(cyclohexyla-
mino)propylamine (method A), 24 h. Crystals (ethanol/water),
mp. 1298C, yield 0.6 g (82%). – Anal. C21H29N7 (379.5). – IR (KBr): m
= 3343 cm– 1; 3205; 2927; 2853; 1655; 1600; 1489; 1452; 1402;
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Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
New Antiplatelet Purines
119
1
1342; 789; 726; 644. – H-NMR/400 MHz ([D6]DMSO): d (ppm) =
NH), 7.11 (d, J = 7.1 Hz, 2H, phH-2,6), 7.26–7.35 (m, 3H, phH-
3,4,5), 8.03 (s, 1H, purinH-8). – MS (EI, 1808C): m/z (%) = 351 (35)
[M+9], 268 (60) [M+9–CH2pyrr+H], 267 (47) [M+9–CH2pyrr], 254 (100)
[M+9–CH2CH2pyrr+H], 241 (17) [M+9–CH2=CHCH2pyrr+H], 224 (15),
0.93–1.00 (m, 2H, cyhexH-3a,5a), 1.04–1.19 (m, 3H, cyhexH-
3e,5e,4a), 1.53 (m, 1H, cyhexH-4e), 1.62–1.70 (m, 4H, CH2CH2CH2
and cyhexH-2a,6a), 1.77–1.80 (m, 2H, cyhexH-2e,6e), 2.27–2.33
(m, 1H, cyhexH-1), 2.55–2.59 (t, J = 6.6 Hz, 2H, NHCH2CH2CH2),
3.44 (brs, 2H, NHCH2CH2), 5.19 (s, 2H, CH2Ph), 5.79 (brs, 2H, D2O
exchange, NH2), 7.21–7.35 (m, 6H, 1H, D2O exchange, ph and
NH), 7.76 (s, 1H, purinH-8). – MS (EI, 50 8C): m/z (%) = 379 (8) [M+9],
282 (12) [M+9-NHcyhex+H], 267 (15) [M+9–CH2NHcyhex], 254 (33)
[M+9–CH2CH2NHcyhex+H), 241 (21) [M+9–CH2=CHCH2NHcy-
177 (35), 163 (14), 134 (21), 91 (75) [C7H7 ], 84 (74) [CH2=pyrr+9], 65
+
+
(10) [C5H5 ], 42 (19).
General procedure for the synthesis of type 6 N-(purin-2-
yl)benzenecarboxamides [15, 16]
+
+
To a solution of the appropriate benzoic acid (2.3 mmol) in 50
mL chloroform, 2 mL thionyl chloride was added at 758C. After 1
h, chloroform and thionyl chloride were removed in vacuo. The
residue was dissolved in 30 mL pyridine at 1008C and 0.4 g
(1.14 mmol) of the type 4 purin added. The mixture was stirred
for 30–60 min. After evaporation in vacuo the resulting brown
syrup was dissolved in 50 mL chloroform and washed with
NaOH (1N) three times. The organic phase was concentrated in
vacuo and purified by column chromatography. For the synth-
esis of 6c, 6d, and 7b the appropriate benzoyl chlorides were
commercially available.
hex+H], 91 (100) [C7H7 ], 56 (19), 41 (29), 30 (16) [CH2=NH2 ].
9-Phenylmethyl-N6-[3-((pyrrolidinyl)propyl]-9H-purin-2,6-
diamine 4b
From 0.5 g (1.92 mmol) of 2 and 0.9 g (7.03 mmol) 3-(pyrrolidi-
nyl)propylamine (method A), 12 h. Crystals (ethanol/water), mp.
1698C, yield 0.6 g (89%). – Anal. C19H25N7 (351.5). – IR (KBr): m =
3360 cm– 1; 3197; 2951; 2792; 1646; 1605; 1493; 1460; 1396;
1
1341; 1221; 1144; 787; 709; 646. – H-NMR/400 MHz ([D6]DMSO):
d (ppm) = 1.68–1.77 (m, 6H, pyrrH-3,4 and NHCH2CH2CH2), 2.44–
2.47 (m, 6H, pyrrH-2,5 and NHCH2CH2CH2), 3.44 (brs, 2H,
NHCH2CH2), 5.19 (s, 2H, CH2ph), 5.82 (brs, 2H, D2O exchange,
NH2), 7.21-7.35 (m, 6H, 1H, D2O exchange, ph and NH), 7.76 (s,
2H, purinH-8). – MS (EI, 1108C): m/z (%) = 351 (32) [M+9], 267 (26)
[M+9–CH2pyr], 254 (61) [M+9–CH2CH2pyrr+9H], 241 (16), 240 (11)
[M+9–CH2=CHCH2pyrr], 226 (14), 163 (14), 111 (15)
4-[9-Phenylmethyl-6-(3-(pyrrolidinyl)propylamino)-9H-
purin-2-ylaminocarbonyl]-benzoicacid methylester
semihydrate 6a
From 0.6 g (3.34 mmol) of terephthalic acid monomethylester
and 4b. Light brown crystals (SiO2; CH2Cl2/MeOH saturated with
NH3 9:1), mp. 70 8C, yield 0.3 g (51%). – Anal. C28H32N7O3.5
+
[CH2CH2CH2pyrr+9–H], 98 (15) [CH2CH2pyrr+9], 91 (86) [C7H7 ], 84
(100) [CH2=pyrr+], 42 (24).
1
(522.6). – H-NMR/400 MHz ([D6]DMSO: d (ppm) = 1.65 (s, 4H, pyrr-
3,4-H), 1.70 (m, 2H, CH2CH2CH2), 2.40 (m, 6H, pyrr2,5-H and
NHCH2CH2CH2), 3.39 (brs, after D2O exchange, 2H, NHCH2), 3.89
(s, 3H, CH3), 5.29 (s, 2H, CH2ph), 7.26–7.35 (m, 5H, ph), 7.89 (s,
1H, D2O exchange, NH), 7.93–7.97 (AA9BB9, J = 8.3 Hz, 2H, ph-3,5-
H), 8.02 (AA9BB9, J = 8.4 Hz, 2H, ph-2,6-H), 8.13 (s, 1H, purin-8-H),
10.59 (s, 1H, D2O exchange, CONH). – MS (70 eV, 250 8C): m/z (%)
N6-[3-(Cyclohexylamino)propyl]-9-phenylmethyl-7H-
purin-2,6-diamine 5a
From 0.5 g (1.92 mmol) of 3 and 4 mL 3-(cyclohexylamino)propy-
lamine (method B). Brownish bright crystals, mp. 149 8C, yield
0.5 g (69%). – Anal. C21H29N7 (379.5). – IR (KBr) m = 3457 cm– 1
;
+
= 514 (3) [M+9], 417 (17) [M+9–CH2CH2pyrr+H], 91 (56) [C7H7 ], 84
3390; 3294; 3147; 2927; 2853; 1600; 1574; 1483; 1451; 1384;
1293; 1234; 1235; 1189; 1123; 1031; 793; 731; 629. – 1H-NMR/
400 MHz ([D6]DMSO): d (ppm) = 0.87–0.96 (m, 2H, cyhexH-3a,5a),
1.02–1.18 (m, 3H, cyhexH-3e,5e,4a), 1.49–1.55 (m, 3H,
CH2CH2CH2 and cyhexH-4e), 1.61–1.65 (m, 2H, cyhexH-2e,6e),
(100) [CH2=pyrr+], 57 (30), 42 (57).
3-Cyano-N-[9-phenylmethyl-6-(3-(pyrrolidinyl)-
propylamino)-9H-purin-2-yl]benzenecarboxamide
2.21 (m, 1H, cyhexH-1), 2.34–2.38 (t,
J = 6.6 Hz, 2H,
NHCH2CH2CH2), 3.37 (m, 2H, NHCH2), 5.55 (26s, 4H, 2H, D2O
exchange, CH2ph and NH2), 6.21 (t, J = 5.4 Hz, 1H, D2O exchange,
NH2), 7.1 (d, J = 7.0 Hz, 2H, ph-H-2.6), 7.25–7.35 (m, 3H, phH-
3,4,5), 8.03 (s, 1H, purinH-8). – MS (EI, 508C): m/z (%) = 379 (25)
[M+9], 282 (33) [M+9–NHcyhex+H], 267 (43) [M+9–CH2NHcyhex],
254 (100) [M+9–CH2CH2NHcyhex+H), 241 (49) [M+9–CH2=
semihydrate 6b
From 0.5 g (3.4 mmol) of 3-cyanobenzoic acid and 4b. Light
brown crystals (SiO2; CH2Cl2/EtOH saturated with NH3 8:1), mp.
1048C, yield 0.3 g (54%). – Anal. C27H29N8O1.5 (489.6). – 1H-NMR/
400 MHz ([D6]DMSO): d (ppm) = 1.66 (s, 4H, pyrr3.4-H), 1.72–1.75
(m, 2H CH2CH2CH2), 2.41–2.45 (m, 6H, pyrr2,5-H and
NHCH2CH2CH2), 3.42 (brs, 2H, after D2O exchange, NHCH2), 5.31
(s, 2H, CH2ph), 7.27–7.36 (m, 5H, ph), 7.69 (dd, J = 7.8/7.8 Hz, 1H,
ph5-H), 7.91 (s, 1H, D2O exchange, NH), 8.01 (d, J = 7.7 Hz, 1H,
ph4-H), 8.15 (m, 2H, ph6-H) and purin8-H), 8.31 (s, 1H, ph2-H),
10.64 (s, 1H, D2O exchange, CONH). – MS (70 eV, 2508C): m/z (%) =
+
CHCH2NHcyhex+H], 177 (18), 91 (71) [C7H7 ], 56 (13), 41 (12), 30
+
(26) [CH2=NH2 ].
7-Phenylmethyl-N6-[3-(pyrrolidinyl)propyl]-7H-purin-2,6-
diamine 5b
+
480 (10) [M+9], 383 (77) [M+9–CH2CH2pyrr], 91 (73) [C7H7 ], 84 (100)
[CH2=pyrr+], 42 (17).
From 0.5 g (1.92 mmol) of 3 and 4 mL 3-(pyrrolidinyl)propyla-
mine (method B). Yellow crystals, mp. 1568C, yield 0.6 g (89%). –
Anal. C19H25N7 (351.5). – IR (KBr): m = 3339 cm– 1; 2959; 2826;
1615; 1574; 1480; 1445; 1392; 1371; 1293; 1207; 1150; 791; 728.
4-Methoxy-N-[9-phenylmethyl-6-(3-(pyrrolidinyl)propyl-
amino)-9H-purin-2-yl]benzenecarboxamide 6c
–
1H-NMR/400 MHz ([D6]DMSO): d (ppm) = 1.54–1.59 (m, 2H,
NHCH2CH2CH2), 1.63 (m, 4H, pyrrH-3,4), 2.23 (t, J = 7.0 Hz, 2H,
NHCH2CH2CH2), 2.33 (brs, 4H, pyrrH-2,5), 3.33–3.36 (t, J = 6.6 Hz,
2H, after D2O exchange, NHCH2), 5.57 (26s, 4H, 2H, D2O
exchange, CH2ph and NH2), 6.14 (t, J = 5.3 Hz, 1H, D2O exchange,
From 0.3 g (1.76 mmol) of 4-methoxybenzoyl chloride and 4b.
Light yellow crystals (SiO2; CH2Cl2/EtOH saturated with NH3 8:2),
mp. 157 8C, yield 0.2 g (36%). – Anal. C27H31N7O2 (485.6). – 1H-
NMR/400 MHz ([D6]DMSO): d (ppm) = 1.66 (s, 4H, pyrr3.4-H), 1.75–
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K. Mꢀrschenz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
1.78 (tt, J = 6.8/6.8 Hz, 2H, CH2CH2CH2), 2.45 (m, 6H, pyrr2,5-H
and NHCH2CH2CH2), 3.47 (s, 2H, NHCH2), 3.83 (s, 3H, OCH3), 5.32
(s, 2H, CH2ph), 7.00 (AA'BB`, J = 8.8 Hz, 2H, ph3,5-H), 7.27–7.34
(m, 5H, ph), 7.87 (s, 1H, D2O exchange, NH), 7.92 (AA9BB9, J = 8.8
Hz, 2H, ph2.6-H), 8.13 (s, 1H, purin8-H), 10.22 (s, 1H, D2O
exchange, CONH). – MS (70 eV, 508C): m/z (%) = 485 (11) [M+9], 401
(21) [M+9–CH2pyrr], 388 (100) [M+9–CH2CH2pyrr+H], 135 (38), 91
4-[Morpholin-4-ylsulfonyl]-N-[9-phenylmethyl-6-(3-
(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6g
From 0.8 g (2.95 mmol) of 4-[morpholin-4-ylsulfonyl]benzoic
acid and 4b. Light yellow crystals (SiO2; CH2Cl2/EtOH saturated
with NH3 8.5:1.5), mp. 1068C, yield 0.4 g (58%).
– Anal.
C30H36N8O4S (604.7). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.65 (s, 4H, pyrr3,4-H), 1.70–1.74 (m, 2H, CH2CH2CH2), 2.40–2.45
(m, 6H, pyrr2,5-H and NHCH2CH2CH2), 2.90 (t, J = 4.5, 4H
morph3,5-H), 3.37 (brs, 2H, after D2O exchange, NHCH2) 3.64 (t, J
= 4.6 Hz, 4H, morph2,6-H), 5.29 (s, 2H, CH2ph), 7.27–7.37 (m, 5H,
ph), 7.82 (AA9BB9, J = 8.3 Hz, 2H, suph3,5-H), 7.91 (s, 1H, D2O
exchange, NH), 8.06 (AA9BB9, J = 7.7 Hz, 2H, suph2,6-H), 8.14 (s,
1H, purin8-H), 10.67 (s, 1H, D2O exchange, CONH). – MS (70 eV,
2508C): m/z (%) = 604 (4) [M+9], 520 (12), 507 (48) [M+9–
CH2CH2pyrr+H], 494 (11) [M+9–CH2=CHCH2pyrr+H], 110 (24), 91
+
(14) [C7H7 ], 84 (25) [CH2=pyrr+], 42 (14), 36 (33).
4-Chloro-N-[9-phenylmethyl-6-(3-(pyrrolidinyl)-
propylamino)-9H-purin-2-yl]benzenecarboxamide
semihydrate 6d
From 0.5 g (2.86 mmol) of 4-chlorobenzoyl chloride and 4b. Yel-
low crystals (SiO2; CH2Cl2/MeOH saturated with NH3 9:1), mp.
578C, yield 0.2 g (36%). – Anal. C26H29N7O1.5 (499.0). – 1H-NMR/
400 MHz ([D6]DMSO): d (ppm) = 1.66 (s, 4H, pyrr3,4-H), 1.72–1.76
(m, 2H, CH2CH2CH2), 2.41–2.46 (m, 6H, pyrr2,5-H and
NHCH2CH2CH2), 3.45 (brs, 2H, after D2O exchange, NHCH2), 5.31
(s, 2H, CH2ph), 7.27–7.36 (m, 5H, ph), 7.53 (AA9BB9, J = 8.5 Hz, 2H,
ph3,5-H), 7.90 (AA9BB9, J = 8.3 Hz, 2H, ph2,6-H), 8.14 (s, 1H, purin8-
H), 10.47 (s, 1H, D2O exchange, CONH). – MS (70 eV, 1808C): m/z
+
(67) [C7H7 ], 84 (100) [CH2=pyrr+], 56 (21), 42 (20), 28 (19).
3-[(4-Methyl)-piperazinylsulfonyl]-N-[9-phenylmethyl-6-
(3-(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6h
+
(%) = 489 (10) [M+9], 396 (85), 91 (73) [C7H7 ], 84 (100) [CH2=pyrr+],
From 0.6 g (2.11 mmol) of 3-[(4-methyl)piperazinylsulfonyl]ben-
zoic acid and 4b. Light yellow crystals (SiO2; CH2Cl2/EtOH satur-
ated with NH3 8.5:1.5), mp. 818C, yield 0.3 g (43%). – Anal.
C31H39N9O3S (617.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.65 (s, 4H, pyrr3,4-H), 1.72 (m, 2H, CH2CH2CH2), 2.12 (s, 3H, CH3),
2.32 (s, 4H, mepipera3,5-H), 2.41–2.46 (m, 6H, pyrr2,5-H and
NHCH2CH2CH2), 2.86 (s, 4H, mepipera2,6-H), 3.43 (brs, 2H, after
D2O exchange, NHCH2), 5.29 (s, 2H, CH2ph), 7.26–7.36 (m, 5H,
ph), 7.74-7.78 (dd, J = 7.8 Hz, 1H, suph5-H), 7.87–7.92 (m, 2H, 1H,
D2O exchange, NH and suph4-H), 8.09–8.19 (m, 3H, suph2,6-H
and purin8-H), 10.77 (s, 1H, D2O exchange, CONH). – MS (70 eV,
55 (14), 42 (21).
3-[Pyrrolidinylsulfonyl]-N-[9-phenylmethyl-6-(3-
(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6e
From 0.8 g (3.13 mmol) of 4-[pyrrolidinylsulfonyl]benzoic acid
and 4b. Light yellow crystals (SiO2; CH2Cl2/MeOH saturated with
NH3 9:1), mp. 858C, yield 0.5 g (75%). – Anal. C30H36N8O3S (588.7).
–
1H-NMR/400 MHz ([D6]DMSO): d (ppm) = 1.58–1,61 (m, 4H,
2108C): m/z (%) = 617 (1) [M+9], 254 (16). 99 (45), 91 (32) [C7H7 ], 84
pyrr3,4-H), 1.66 (s, 4H, pyrr3,4-H), 1.73 (m, 2H, CH2CH2CH2), 2.44
(m, 6H, pyrr2,5-H and NHCH2CH2CH2), 3.11 (s, 4H, SO2pyrr2,5-H),
3.39 (brs, 2H, after D2O exchange, NHCH2), 5.31 (s, 2H, CH2ph),
7.27–7.36 (m, 5H, ph), 7.73–7.77 (dd, J = 7.8/7.8 Hz, 1H, suph5-
H), 7.93–7.98 (m, 2H, 1H, D2O exchange, NH and suph4-H), 8.15–
8.19 (m, 3H, suph2,6-H and purin8-H), 10.78 (s, 1H, D2O
exchange, CONH). – MS (70 eV, 80 8C): m/z (%) = 588 (11) [M+9],
504 (21), 491 (70) [M+9CH2pyrr+H], 478 (17) [M+9–CH2=
+
(100) [CH2pyrr+], 56 (19), 42 (17).
3-[4-Pyrimidin-2-yl)-piperazinylsulfonyl]-N-[9-
phenylmethyl-6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6i
From 0.9 g (2.58 mmol) of 3-[4-pyrimidin-2-yl)piperazinylsulfo-
nyl]benzoic acid and 4b. Brown crystals (SiO2; CH2Cl2/EtOH satur-
ated with NH3 8: 2), mp. 988C, yield 0.3 g (39%). – Anal.
+
CHCH2pyrr+H], 358 (19), 110 (22), 91 (100) [C7H7 ], 84 (96)
[CH2=pyrr+], 70 (24), 42 (42).
1
C34H39N11O3S (681.8). – H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.63 (s, 4H, pyrr3,4-H), 1.72 (m, 2H, CH2CH2CH2), 2.40–2.45 (s, 6H,
pyrr2,5-H and NHCH2CH2CH2), 2.96 (m, 4H, pipera3,5-H), 3.43
(brs, 2H, after D2O exchange, NHCH2), 3.81 (s, 4H, mepipera2,6-
H), 5.29 (s, 2H, CH2ph), 6.64 (dd, J = 4.8 Hz, 1H, pyrim5-H), 7.26–
7.34 (m, 5H, ph), 7.72–7.76 (dd, J = 7.8 Hz, 1H, suph5-H), 7.90 (m,
2H, 1H, after D2O exchange, NH and suph4-H), 8.14–8.18 (m, 3H,
suph2,6-H) and purin8-H), 8.33 (d, J = 4.7 Hz, 2H, pyrim4,6-H),
10.75 (s, 1H, D2O exchange, CONH). – MS (70 eV, 608C): m/z (%) =
3-[Morpholin-4-ylsulfonyl]-N-[9-phenylmethyl-6-(3-
(pyrrolidinyl)propylamino)-9H-purin-2-yl]-
benzenecarboxamide 6f
From 0.8 g (2.95 mmol) of 3-[morpholin-4-ylsulfonyl]benzoic
acid and 4b. Light yellow crystals (SiO2; CH2Cl2/EtOH saturated
with NH3 8.5:1.5), mp. 858C, yield 0.5 g (73%).
– Anal.
C30H36N8O4S (604.7). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.65 (s, 4H, pyrr3,4-H), 1.72 (m, 2H, CH2CH2CH2), 2.41–2.46 (m,
6H, pyrr2,5-H and NHCH2CH2CH2), 2.84 (s, 4H morph3,5-H), 3.41
(brs, 2H, after exchange, NHCH2) 3.59 (s, 4H, morph2,6-H), 5.30 (s,
2H, CH2ph), 7.26–7.36 (m, 5H, ph), 7.76-7.80 (dd, J = 7.8 Hz, 1H,
suph5-H), 7.88-7.93 (m, 3H, 1H, D2O exchange, NH and suph4-H),
8.10–8.21 (m, 3H, suph2,6-H) and purin8-H), 10.77 (s, 1H, D2O
exchange, CONH). – MS (70 eV, 210 8C): m/z (%) = 504 (11) [M+9],
520 (18), 507 (77) [M+9–CH2CH2pyrr+H], 494 (11) [M+9–
+
681 (1) [M+9], 254 (30), 163 (66) [piperapyrim+9] 91 (43) [C7H7 ], 84
(100) [CH2pyrr+], 56 (28), 42 (17), 28 (20).
3-[N-(Phenylmethyl)aminosulfonyl]-N-[9-phenylmethyl-6-
(3-(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6j
From 0.6 g (2.1 mmol) of 3-[4-phenylmethyl)aminosulfonyl]ben-
zoic acid and 4b. Light brown crystals (SiO2; CH2Cl2/EtOH satur-
ated with NH3 9: 1), mp. 1048C, yield 0.2 g (42%). – Anal.
+
CH2=CHCH2pyrr+H], 358 (14), 110 (21), 98 (16), 91 (64) [C7H7 ], 84
(100) [CH2=pyrr+], 56 (15), 42 (14), 28 (20).
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Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
New Antiplatelet Purines
121
C33H36N8O3S (624.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.65 (s, 4H, pyrr3,4-H), 1.68–1.72 (m, 2H, CH2CH2CH2), 2.39–2.45
(m, 6H, pyrr2,5-H and NHCH2CH2CH2), 3.41 (brs, 2H, after D2O
exchange, NHCH2), 3.96 (s, 2H, NHCH2ph), 5.31 (s, 2H, CH2ph),
7.21-7.36 (m, 10H, 2xph), 7.68 (dd, J = 7.8 Hz, 1H, suph5-H), 7.94
(d, J = 8.0 Hz, 1H, suph4-H), 8.10 (d, J = 7.7 Hz, 1H, suph6-H), 8.14
(s, 1H, purin8-H), 8.26 (s, 1H, suph2-H), 10.66 (s, 1H, D2O
exchange, CONH). – MS (70 eV, 808C): m/z (%) = 624 (1) [M+9], 527
10.63 (brs, 1H, D2O exchange, CONH). – MS (70 eV, 1808C): m/z
(%) = 592 (2) [M+9], 495 (28) [M+9–CH2CH2pyrr+H], 351 (20), 267
+
(18), 254 (31), 91 (72) [C7H7 ], 84 (100) [CH2=pyrr+], 42 (20), 28 (52).
3-[N-(3-Methoxypropyl)aminosulfonyl]-N-[9-
phenylmethyl-6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-
yl]benzenecarboxamide 6n
From 0.8 g (2.93 mmol) of 3-[N-(3-methoxypropyl)aminosulfonyl]-
benzoic acid and 4b. Light yellow crystals (SiO2; CH2Cl2/EtOH
saturated with NH3 8:2), mp. 678C, yield 0.3 g (43%). – Anal.
C30H38N8O4S (606.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.54–1.61 (tt, J = 6.9/6.9 Hz, 2H, CH2CH2CH2OCH3), 1.66 (s, 4H,
pyrr3,4-H), 1.74 (m 2H, CH2CH2CH2), 2.42–2.47 (m, 6H, pyrr2,5-H
+
(28) [M+9–CH2CH2pyrr+H], 91 (91) [C7H7 ], 84 (100) [CH2=pyrr+], 28
(25).
3-[N,N-Diethylaminosulfonyl]-N-[9-phenylmethyl-6-(3-
(pyrrolidinyl)propylamino)-9H-purin-2-yl]benzene-
carboxamide 6k
From 0.5 g (1.94 mmol) of 3-[N,N-diethylaminosulfonyl]benzoic
acid and 4b. Light yellow crystals (SiO2; CH2Cl2/EtOH saturated
and NHCH2CH2CH2), 2.88–2.91 (dt,
J = 6.6/6.6 Hz, 2H,
NHCH2CH2OCH3), 3.15 (s, 3H, OCH3), 3.24–3.27 (t, J = 6.2 Hz, 2H,
after D2O exchange, NHCH2CH2OCH3), 3.41 (brs, 2H, after D2O
exchange, NHCH2), 5.31 (s, 2H, CH2ph), 7.27–7.37 (m, 5H, ph),
7.68–7.72 (m, 2H, 1H after D2O exchange, suph5-H and NH),
7.91–7.95 (m, 2H, 1H, after D2O exchange, suph4-H), 8.11–8.15
(m, 2H, suph6-H and purin8-H), 8.24 (s, 1H, suph2-H), 10.69 (s,
1H, after D2O exchange, CONH). – MS (70 eV, 1008C): m/z (%) =
606 (3) [M+9], 509 (27) [M+9–CH2CH2pyrr+H], 254 (21), 91 (70),)
with NH3 8.5:1.5), mp. 658C, yield 0.5 g (75%).
– Anal.
C30H38N8O3S (590.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.02 (t, J = 7.1 Hz, 6H, 26CH3), 1.65 (s, 4H, pyrr3,4-H), 1.72 (m, 2H,
CH2CH2CH2), 2.40–2.44 (m, 6H, pyrr2,5-H and NHCH2CH2CH2),
3.10–3.15 (q, J = 6.9 Hz, 4H, SO2N(CH2CH3)2), 3.39 (brs, 2H, after
D2O exchange, NHCH2), 5.30 (s, 2H, CH2ph), 7.29–7.36 (m, 5H,
ph), 7.69–7.73 (dd, J = 7.8/7.8 Hz, 1H, suph5-H), 7.95 (d, J = 7.7 Hz,
2H, 1H after D2O exchange, suph4-H), 8.14 (m, 3H, suph2,6-H and
purin8-H), 10.75 (s, 1H, D2O exchange, CONH). – MS ([+]-FAB,
DMSO/m-NO2-C6H4OH): m/z (%) = 591 (45) [M+9+H], 110 (46), 105
[C7H7 ], 84 (100) [CH2=pyrr+], 42 (21), 30 (26), 28 (25).
+
4-[N-(3-Methoxypropyl)aminosulfonyl]-N-[9-phenyl-
methyl-6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-
+
(22), 91 (69) [C7H7 ], 84 (100) [CH2=pyrr+], 55 (16).
yl]benzenecarboxamide semihydrate 6o
From 0.8 g (2.93 mmol) of 4-[N-(3-methoxypropyl)aminosulfonyl]-
benzoic acid. Yellow crystals (SiO2; CH2Cl2/EtOH saturated with
3-[N-(2-Methoxyethyl)aminosulfonyl]-N-[9-phenylmethyl-
6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-yl]benzene-
carboxamide semihydrate 6l
NH3 8:2), mp. 838C, yield 0.2 g (28%). – Anal. C30H39N8O4.5
S
(615.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) = 1.56–1.61 (tt, J
= 6.8/6.8 Hz, 2H, CH2CH2CH2OCH3), 1.66 (s, 4H, pyrr2,4-H), 1.72 (m
2H, CH2CH2CH2), 2.43–2.47 (m, 6H, pyrr2,5-H and NHCH2
CH2CH2), 2.79–2.84 (dt, J = 6.7/6.7 Hz, 2H, NHCH2CH2OCH3), 3.15
(s, 3H, OCH3), 3.27-3.32 (t, J = 6.1 Hz, 2H, after D2O exchange,
NHCH2CH2CH2OCH3), 3.42 (s, 2H, after D2O exchange, NHCH2),
5.30 (s, 2H, CH2ph), 7.28–7.37 (m, 5H, ph), 7.74–7.77 (t, J = 5.8
Hz, 1H, D2O exchange, NH), 7.85 (AA9BB9, J = 8.4 Hz, 2H, suph3,5-
H), 7.92 (s, 1H, D2O exchange, NH), 8.02 (AA'BB`, J = 8.1 Hz, 2H,
suph2,6-H), 8.15 (s, 1H, purin8-H), 10.64 (s, 1H, D2O exchange,
CONH). – MS (70 eV, 408C): m/z (%) = 606 (3) [M+9], 509 (24) [M+9–
From 0.8 g (3.09 mmol) of 3-[N-(2-methoxyethyl)aminosulfonyl]-
benzoic acid and 4b. Light brown crystals (SiO2; CH2Cl2/EtOH
saturated with NH3 8:2), mp. 738C, yield 0.1 g (15%). – Anal.
1
C29H37N8O4.5S (601.7). – H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.65 (s, 4H, pyrr3,4-H), 1.74 (m, 2H, CH2CH2CH2), 2.41–2.46 (m,
6H, pyrr2,5-H and NHCH2CH2CH2), 2.88–2.91 (t, J = 5.6 Hz, 2H,
NHCH2CH2OCH3), 3.14 (s, 3H, OCH3), 3.27 (t, J = 5.6 Hz, 2H, after
D2O exchange, NHCH2CH2OCH3), 3.41 (brs, 2H NHCH2), 5.31 (s,
2H, CH2ph), 7.27–7.36 (m, 5H, ph), 7.67–7.71 (dd, J = 7.8 Hz, 1H,
suph5-H), 7.91–7.96 (m, 2H, 1H after D2O exchange, suph4-H),
8.10–8.15 (m, 2H, suph6-H and purin8-H), 8.25 (s, 1H, suph2-H),
10.68 (s, 1H, D2O exchange, CONH). – MS (70 eV, 1308C): m/z (%) =
592 (6) [M+9], 495 (48) [M+9–CH2CH2pyrr+H], 254 (18), 91 (59)
+
CH2CH2pyrr+H], 351 (30), 267 (24), 254 (50), 91 (81) [C7H7 ], 84
(100) [CH2=pyrr+], 42 (22).
+
[C7H7 ], 84 (100) [CH2=pyrr+], 42 (17), 28 (16).
3-[N,N-bis-(2-Methoxyethyl)aminosulfonyl]-N-[9-phenyl-
methyl-6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-yl]-
benzenecarboxamide 6p
From 0.6 g (1.89 mmol) of 3-[N,N-bis(3-methoxyethyl)aminosulfo-
nyl]benzoic acid and 4b. Crystals (SiO2; CH2Cl2/EtOH saturated
4-[N-(2-Methoxyethyl)aminosulfonyl]-N-[9-phenylmethyl-
6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-yl]benzene-
carboxamide 6m
From 0.8 g (3.09 mmol) of 4-[N-(2-methoxyethyl)aminosulfonyl]-
benzoic acid and 4b. Light brown crystals (SiO2; CH2Cl2/EtOH
saturated with NH3 8: 2), mp. 738C, yield 0.1 g (15%). – Anal.
C29H36N8O4S (592.7). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.66 (s, 4H, pyrr3,4-H), 1.73 (m, 2H, CH2CH2CH2), 2.44 (m, 6H,
pyrr2,5-H and NHCH2CH2CH2), 2.88–2.91 (dt, J = 5.5/5.5 Hz, 2H,
NHCH2CH2OCH3), 3.15 (s, 3H, OCH3), 3.30–3.33 (t, J = 5.4 Hz, 2H,
after D2O exchange, NHCH2CH2OCH3), 3.40 (brs, 2H, after D2O
exchange, NHCH2), 5.33 (s, 2H, CH2ph), 7.31–7.36 (m, 5H, ph),
7.86–7.91 (m, 4H, 2H, after D2O exchange, suph3,5-H and 2xNH),
8.02 (AA9BB9, J = 8.1 Hz, 2H, suph2,6-H), 8.14 (s, 1H, purin8-H),
with NH3 8,5:1,5), mp. 678C, yield 0.4 g (54%).
– Anal.
C32H42N8O5S (650.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.85 (s, 4H, pyrr3,4-H), 1.94 (m, 2H, CH2CH2CH2), 2.64 (m, 6H,
pyrr2,5-H and NHCH2CH2CH2), 3.37 (s, 6H, 26OCH3), 3.30–3.33
(m, 4H, after D2O exchange, N(CH2CH2OCH3)2), 3.40–3.43 (m, 6H,
after D2O exchange, NHCH2 and N(CH2CH2OCH3)2), 5.50 (s, 2H,
CH2ph), 7.46–7.53 (m, 5H, ph), 7.88–7.92 (dd, J = 7.8/7.8 Hz, 1H,
suph5-H), 8.11 (s, 1H, D2O exchange, NH), 8.18 (d, J = 7.9 Hz, 1H,
suph4-H), 8.34 (m, 2H, suph6-H and purin 8-H), 8.43 (s, 1H, suph2-
H), 10.94 (s, 1H, D2O exchange, CONH). – MS (70 eV, 808C): m/z
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122
K. Mꢀrschenz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 115–122
(%) = 650 (5) [M+9], 553 (40) [M+9–CH2CH2pyrr+H], 254 (17), 91 (89),
Biology
[C7H7 ], 84 (100) [CH2=pyrr+], 42 (25), 28 (49).
+
The Born test was carried out as reported in detail recently in
this journal [4].
4-[N,N-bis-(2-Methoxyethyl)aminosulfonyl]-N-[9-phenyl-
methyl-6-(3-(pyrrolidinyl)propylamino)-9H-purin-2-yl]-
benzenecarboxamide semihydrate 6q
References
From 0.8 g (2.52 mmol) of 4-[N,N-bis(2-methoxyethyl)aminosulfo-
nyl]benzoic acid and 4b. Light brown crystals (SiO2; CH2Cl2/EtOH
saturated with NH3 8:2), mp. 758C, yield 0.3 g (40%). – Anal.
C32H43N8O5.5S (659.8). – 1H-NMR/400 MHz ([D6]DMSO): d (ppm) =
1.70 (s, 4H, pyrr3,4-H), 1.76–1.80 (m, 2H, CH2CH2CH2), 2.57 (m,
6H, pyrr2,5-H and NHCH2CH2CH2), 3.19 (s, 6H, 26OCH3), 3.38 (m,
4H, after D2O exchange, N(CH2CH2OCH3)2), 3.44 (m, 6H, after D2O
exchange, NHCH2 and N(CH2CH2OCH3)2), 5.31 (s, 2H, CH2ph),
7.27–7.37 (m, 5H, ph), 7.89–7.93 (m, 3H, 2H after D2O exchange,
suph3,5-H and NH), 8.04 (AA9BB9, J = 8.3 Hz, 2H, suph2,6-H), 8.16
(s, 1H, purin8-H), 10.69 (s, 1H, D2O exchange, CONH). – MS (70
eV, 808C): m/z (%) = 650 (19) [M+9], 553 (50) [M+9–CH2CH2pyrr+H],
[1] K. Mꢁrschenz, PhD thesis, Freie Universitꢁt Berlin, Ger-
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+
272 (27), 254 (14), 91 (57) [C7H7 ], 84 (100) [CH2=pyrr+], 56 (28), 42
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590–597.
[6a] M. Johnsen, K. Rehse, H. Pertz, J.-P. Stasch, E. Bischhoff,
N-[6-[3-Cyclohexylamino)-propylamino]-9-phenylmethyl-
Arch. Pharm. Med. Chem. 2003, 336, 1–7.
9H-purin-2-yl]-3-cyanobenzenecarboxamide hydrate 7b
From 0.16 g (0.97 mmol) of 3-cyanobenzoic acid and 0.19 g
(0.5 mmol) and 4a. Light yellow crystals (SiO2; CH2Cl2/EtOH satur-
ated with NH3 7.5:1), mp. 1088C, yield 0.20 g (76%). – Anal.
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1
C29H32N8O.H2O (508.6). – H-NMR/400 MHz ([D6]DMSO): d (ppm) =
5625–5638.
1.0–1.2 (m, 5H, cyhex-H2a,3a,4a,5a,6a), 1.55 (m, 1H, cyhex-H4e),
1.63 (m, 2H, cyhex-H3e,5e), 1.75 (m, 2H, –CH2-CH2 –CH2), 1.83 (m,
2H, cyhex-H2e,6e), 2.41 (m, 1H, cyhex-H1a), 2.65 (dt, J = 6/6 Hz, 2-
H, –CH2-NH-cyhex), 3.35 (brs, 2H, NH, D2O exchange), 3.5 (brs,
2H, CH2-NH-purin), 5.33 (s, 2H, CH2-ph), 7.3 (m, 5H, ph), 7.7 (dd, J
= 8/8 Hz, 1H, H-5), 8.03 (d, J = 8 Hz, 1H, H-4), 8.17 (m, 2H, H-2,6),
8.32 (s, 1H, purinH-8). – MS (EI, 1908C): m/z (%) = 508 (9) [M+9], 383
(61), 370 (42), 242 (44), 130 (51), 112 (33), 91 (100).
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N-[9-Phenylmethyl-6-[3-(pyrrolidinyl)propylamino]-9H-
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purin-2-yl]furane-2-carboxamide-semihydrate 8
From 0.4 g (3.08 mmol) of furane-2-carboxylicacid chloride and
0.4 g (1.14 mmol) and 4b. Light brown crystals (SiO2; CH2Cl2/
EtOH saturated with NH3 8:2), mp. 658C, yield 0.1 g (19%). –
Anal. C24H28N7O2,5 (454.5). – IR (KBr): d = 3421 cm– 1; 2958; 2797;
1693; 1620; 1517; 1464; 1384; 1260; 1165; 724. 1H-NMR/400 MHz
([D6]DMSO): d (ppm) = 1.68 (brs, 4H, pyrrH-3,4), 1.75–1.82 (tt, J =
7.0/7.0 Hz, 2H, CH2CH2CH2), 2.45 (m, 6H, pyrrH-2,5 and
NHCH2CH2CH2), 3.50 (brs, 2H, NHCH2), 5.32 (s, 2H, CH2ph), 6.67
(m, 1H, furaneH-4), 7.28–7.35 (m, 5H, ph), 7.42 (d, J = 3.4 Hz, 1H,
furaneH-5), 7.90 (s, 1H, furaneH-3), 7.93 (brs, 1H, D2O exchange,
NH), 8.15 (s, 1H, purinH-8), 10.10 (s, 1H, D2O exchange, CONH). –
MS (EI, 408C): m/z (%) = 445 (14) [M+9], 361 (25) [M+9–CH2pyrr], 348
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Soroko, J. Med. Chem. 1988, 31, 606–612.
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North, J. Med. Chem. 1983, 26, 1164–1168.
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Med. Chem. 1966, 9, 373–377.
+
(100) [M+9–CH2CH2pyrr+H], 91 (40) [C7H7 ], 84 (34) [CH2=pyrr+], 28
(28).
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