New 2-amino-thiazole-4-acetamides with antiplatelet activity

Article abstract of DOI:10.1002/ardp.200700046

In the Born test, 23 title compounds were synthesized and investigated for their antiplatelet activities against collagen, ADP, adrenaline, and platelet-activating factor (PAF) as inducers of the aggregation. Using collagen, three compounds with IC₅₀ values below 10 μM were found (3a, 3b, 3c) and 15 compounds with IC₅₀ values between 10 and 100 μM were determined. In general, a cyclohexylamino rest on an 4-carboxamide moiety is a pre-requisite for this pharmacological activity. A clear dependence from the substituent R¹ in the structural element Y is observed. The same is true for the spacer n in the 4-carboxamide substituent. Compound 3e showed strong ADP-antagonistic effects (IC₅₀ = 2.2 nM); 3c antagonized adrenaline (IC₅₀ = 2.8 nM), while 3n was highly effective against platelet-activating factor (IC₅₀ = 0.2 μM).

Full text of DOI:10.1002/ardp.200700046

Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
K. Rehse and T. Baselt
645
Full Paper
New 2-Amino-thiazole-4-acetamides with Antiplatelet Activity
Klaus Rehse and Tobias Baselt
Institut fꢀr Pharmazie, Freie Universitꢁt Berlin, Berlin, Germany
In the Born test, 23 title compounds were synthesized and investigated for their antiplatelet
activities against collagen, ADP, adrenaline, and platelet-activating factor (PAF) as inducers of
the aggregation. Using collagen, three compounds with IC50 values below 10 lM were found (3a,
3b, 3c) and 15 compounds with IC50 values between 10 and 100 lM were determined. In general,
a cyclohexylamino rest on an 4-carboxamide moiety is a pre-requisite for this pharmacological
activity. A clear dependence from the substituent R1 in the structural element Y is observed. The
same is true for the spacer n in the 4-carboxamide substituent. Compound 3e showed strong
ADP-antagonistic effects (IC50 = 2.2 nM); 3c antagonized adrenaline (IC50 = 2.8 nM), while 3n was
highly effective against platelet-activating factor (IC50 = 0.2 lM).
Keywords: ADP / Antiplatelet properties / Born test with Adrenaline / PAF / Thiazole acetamides /
Received: October 4, 2007; accepted: February 26, 2008
DOI 10.1002/ardp.200700046
Introduction
In a number of publications, we have shown that the sub-
stitution of heterocycles rich in nitrogen-like purines [1],
indazoles [2], triazoles [3], oxadiazoles [4], imidazoles [5],
pyrimidocinnolines [6], or phthalazines [7] with a carbox-
amide partial structure, a hydrophobic moiety and basic
groups leads to a wide variety of compounds with anti-
platelet activities in micromolar concentrations. In this
paper, we wish to report a number of thiazole derivatives
fulfilling these structural requirements and, conse-
quently, were promising to show remarkable antiplatelet
activities.
Results and discussion
For X, Y, R1, R2 and n see Table 1.
Chemistry
Scheme 1. Synthesis of 2-amino-thiazole-4-acetamides (type-3).
The synthesis of the title 2-amino-thiazole-4-acetamides
is summarized in Scheme 1. Starting material is the com-
mercially available 2-amino-thiazol-4-acetic acid ethyl-
ester 1. This compound is converted with sulfonic acid
chlorides (X = SO2) or carboxylic acid chlorides (X = CO) to
the corresponding sulfonamide or carboxamide deriv-
atives of type 2. The substituent Y was phenyl, 2-naphthyl,
phenylalkyl, or cyclohexyl. The rest R1 is 4-H, 4-F, 4Cl, 3-
Cl, 2-Cl, 3,4-Cl2, 2,4-Cl2, 4-Br, 4-I, 4-CH3, or 4-phenyl. The
Correspondence: Prof. Dr. Klaus Rehse, Pharmazeutisches Institut –
Freie Universitꢁt Berlin, Kꢂnigin-Luise-Str. 2 + 4, D-14195 Berlin, Ger-
many.
E-mail: rehiwer@zedat.fu-berlin.de
Fax: +49 30 304 29 25
Abbreviation: platelet-activating factor (PAF)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
Table 1. Antiplatelet activity of 3a–w in the Born test with collagen as inducer.
Compound
R1
Y
X
n
R2
IC50 (lM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
2k
3l
3m
3n
3o
3p
3q
3r
3s
4-F
4-Cl
4-F
4-phenyl
4-Cl
2-Cl
–
4-I
H
H
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
cyclohexyl
phenyl
phenylCH2
phenyl(CH2)2
phenyl
2-naphthyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
SO2
SO2
CO
SO2
SO2
SO2
CO
CO
CO
CO
CO
SO2
CO
SO2
CO
SO2
CO
SO2
SO2
SO2
CO
3
5
3
3
2
3
3
3
3
3
–
3
3
3
3
3
3
3
3
6
3
4
3
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
–
cyclohexyl
cyclohexyl
-CH2-cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
1
6
9
14
15
19
19
21
22
22
26
28
33
36
44
46
53
57
100
126
137
204
282
4-phenyl
–
4-Cl
4-Cl
4-Br
3-Cl
4-phenyl
4-Cl
4-I
4-Cl
H
4-Cl
H
phenyl
phenyl
phenyl
phenyl
3t
3u
3v
3w
SO2
SO2
phenyl
successful synthesis is indicated in the 1H-NMR spectrum 2k, showed antiplatelet activity (IC50 = 26 lM). We sup-
by the shift of the NH2-Signal from 6.87 ppm to 12.3–12.8 pose that this is due to the high lipophilicity of the
(NHSO2) or 12.0–13.0 ppm (NHCO). The 5-H thiazole pro- biphenyl group which had turned out to be favorable in
ton is shifted from 6.30 to 6.6–6.7 ppm (sulfonamides) or other heterocycles [3, 4]. The additional introduction of a
to 6.95–7.1 ppm (carboxamides). Aminolysis of type 2 suitable basic function which yielded compound 3q
esters with suitable primary amines yielded the desired leads, however, to decreased activity (3q: IC50 = 53 lM). In
test compounds of type 3. Some of them were obtained contrast in the corresponding sulfonamide 2d (IC50
=
by aminolysis with twofold primary diamines followed 212 lM), the same procedure leads to the highly active
by reductive alkylation with cyclohexanone and sodium- compound 3d (IC50 = 14 lM). The same is true for all other
triacetoxy boron hydride. The number of methylene compounds for which the introduction of a cyclohexyl-
groups varied from n = 2–6. For R2 a variety of alkyl, alky- (methyl)-aminoalkyl rest in 4-position is a prerequisite
loxy, or carboxylic acid groups were used. Surprisingly, for pharmacological activity.
however, all pharmacologically active compounds were
substituted by a cyclohexyl- or cyclohexylmethyl group; influence on the antiplatelet activity. If R1 is hydrogen,
The substituent R1 in the phenyl group has a decisive
consequently, we will only discuss these substances here.
only small effects are seen (3w: X = SO2, IC50 = 282 lM; 3u:
X = CO, IC50 = 137 lM). If R1 is fluorine in 4-position, the
most active compound 3a (X = SO2) is obtained showing
Biology
Due to the limited space of the paper, only compounds an IC50 = 1 lM. If X is CO (see 3c) high activity (IC50 = 9 lM)
which showed an inhibition of the platelet aggregation is still observed. If, however, there are one or two methyl-
in the Born test [8] (induced by collagen) with an IC50 ene groups between the phenyl ring and the CO group
below 300 lM were included in the discussion. For the (see 3i and 3j, respectively), no fluorine substitution is
same reason, only for these compounds the synthetic needed for a remarkable effect of 22 lM in each case. If Y
and analytical data are given in the experimental part. is 2-naphthyl (see 3l), also no further substituent R1 is nec-
The full set of data can be found in the PhD thesis of T. essary for an activity of 28 lM. If the phenyl group is
Baselt [9]. To identify the favorable structural elements, a replaced by a cyclohexyl moiety (compare 3u: 137 lM
ranking of the substances was performed according to with 3g: 19 lM), a strong increase in activity is seen. If R1
their IC50 values. This is shown in Table 1. Unexpectedly, is a chlorine atom (n = 3 and Y = SO2 held constant) a
already one type (ester 2), i.e. the biphenylcarboxamide decrease of the IC50 from 4-Cl (3r: 57 lM) via 3-Cl (3p:
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Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
2-Amino-thiazole-4-acetamides with Antiplatelet Activity
647
Figure 1. Most active platelet-aggre-
gation inhibitors in each class of het-
erocycles.
46 lM) to 2-Cl (3f: 19 lM) is observed. A 4-Br or 4-I substi- (33 lM), and 3w (282 lM) vs 3u (137 lM), it is just the
tution (3o: 44 lM, 3h: 21 lM, 3s: 100 lM) results active other way round.
compounds as well.
In summary, a 4-fluorophenylsulfonylamino rest in 2-
With R1 = 4-Cl, the influence of the spacer n was investi- position of the thiazoles combined with a cylohexylami-
gated. Comparison of 3b (n = 5, IC50 = 6 lM) with 3e (n = 2, nopropyl acetamide in 4-position exhibits the strongest
IC50 = 15 lM) and 3r (n = 3, IC50 = 57 lM) shows that the antiplatelet activity with an IC50 = 1 lM against collagen
number of methylene groups has a strong influence on as inducer of the aggregation.
the activity. Surprisingly, for n = 4 (3v: 204 lM) and n = 6
(3t: 126 lM) only small activities could be observed.
To compare structure and activity of the thiazole deriv-
atives 3 with the other heterocycles already investigated,
The question whether sulfonamides or carboxamides we have compiled the most effective inhibitory com-
are the superior class of compounds should be answered pound of each series in Fig. 1 (3–11).
by comparing pairs of compounds which only differ with
Concerning the activity, there is an obvious difference
respect to this structural element. This is possible with between compounds 4–8 (IC50 = 65 to 160 lM) and 9–11
five pairs of compounds; see Table 1. Comparison of 3a (2.5 to 3 lM). The latter compounds are joined by the thia-
(1 lM) with 3c (9 lM) and 3d (14 lM) with 3q (53 lM) sug- zole 3a with an IC50 = 1 lM. The reason for this difference
gests an advantage for sulfonamides. Unfortunately, is the basic substituent. Since Steege [5] discovered the
with the pairs 3s (100 lM) vs 3h (21 lM), 3r (57 lM) vs 3m enormous influence of the 3-cyclohexylaminopropyl-
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648
K. Rehse and T. Baselt
Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
Table 2. Selected compounds for the investigation of other
inducers than collagen in the platelet aggregation.
moiety in the imidazole derivatives 9, the way for getting
strong antiplatelet activity was opened (see 10 and 3a).
The purine derivative 11, however, shows that the pyrrol
Compound Collagen
ADP
Adrenaline PAF
moiety can substitute the cyclohexylamino rest (IC50
=
IC50 (lM)
IC50 (lM)
IC50 (lM)
IC50 (lM)
3 lM). In this case, the cyclohexylamino compound
reached rang two with an IC50 = 17 lM [1]. The carboxa-
mide structure of 11 corresponds to the sulfonamide
group in 9 or 3a. In conclusion, the differentiation by the
heterocyclic moiety in 9–11 is small provided that the
heterocyclic system is rich in nitrogen and combined
with the most suitable basic substituent.
The same is true for the upper compounds of Fig. 1,
where the N,N-dimethylaminopropyl-group (4, 5, 6, 7, 8)
had been taken for the basic substituent. The (most effec-
tive) hydrophobic substituent in 6, 7, and 8 is 4,49-
biphenyl. These three compounds show nearly the same
antiplatelet activity despite different heterocycles.
The indazole 4 and the phthalazine 5 even exhibit
nearly the same antiplatelet activity, which is equal to
acetylsalicylic acid (175 lM). When the indazole 4 is sub-
stituted by a fluorine atom in 2-position of the benzyl
group, a slight improvement (85 lM) is obtained. The
structure of 3a finally and surprisingly shows that a thia-
zole is a sufficient frame for the two substituents needed
for strong antiplatelet activity. A special hydrophobic
substitution seems not to be necessary.
To get a more complete idea concerning the mecha-
nism of action, the effects using other inducers of the pla-
telet aggregation were investigated with selected com-
pounds.
The criteria-of-choice were: (i) High activity against col-
lagen (3a, 3b, 3c, 3e); (ii) influence of the spacer n (3e, 3r,
3v, 3b, 3t) (n = 2-6); (iii) exchange of R1 = 4-Cl against 4-F
(3a / 3r); (iv) exchange of X = SO2 against CO (3a, 3c, 3m,
3r); (v) an example for Y = 2-naphthyl (3l): (vi) an example
for Y = phenylethyl (3j); (vii) an example for R2 = cyclohex-
ylmethyl (3n).
3a
3b
3c
3e
3j
1
6
9
27
31
43
0.0022
0.82
39
11
26
106
0.9
0.0053
0.0027
0.44
0.0028
1.1
14
22
0.59
106
14
0.53
53
40
53
42
106
58
3
12
0.2
106
106
15
15
22
28
33
36
57
126
204
3l
3m
3n
3r
3t
3v
the ADP antagonism is nearly lost (see 3r). Altogether, the
spacer n plays a crucial role in ADP-mediated platelet
aggregation.
Contrary to the collagen-induced aggregation, the
exchange of chlorine by fluorine in R1 has only a small
effect [3r (106 lM) 1 3a (27 lM)]. The exchange of X = SO2
against X = CO (3r = 106 lM; 3m = 11 lM) increases the
activity tenfold, while the same procedure in 3a (27 lM)
gives 3c with similar activity. The Y-part phenylethyl is
accepted (see 3j = 0.82 lM) while the naphthyl group pro-
vides only small activity (see 3l = 39 lM). The cylohexyl-
methyl group instead of cyclohexyl as R2 is a possibility
(3r: 106 lM; 3n: 26 lM).
The influence of the selected compounds on the aggre-
gation induced by adrenaline shows a different pattern
of activity. Concerning the spacer, similar effects are
found for 3e: n = 2 (1.1 lM), 3b: n = 5 (0.44 lM), and 3t: n =
6 (0.53 lM). Medium distances 3r: n = 3, (14 lM) and 3v:
n= 4 (53 lM) generate smaller activities. Altogether, a
dependence of the effects from the number of methylene
groups is seen. If 3r is slightly modified by exchange of R1
= 4-Cl against R1 = 4-F, a dramatic increase in activity by
more than three orders of magnitude is observed (3a:
2.7 nM) which stresses the importance of a highly electro-
negative rest in R1. Instead of X = SO2 the rest X = CO is as
well accepted as compound 3c (2.8 nM) is showing. R2 =
cyclohexylmethyl is less suitable as the comparison of 3r
(14 lM) with 3n (106 lM) indicates.
The results obtained with the inducers adenosinedi-
phosphate (ADP), adrenaline, or PAF are summarized in
Table 2. The results with collagen are added once more
for better comparison.
Considering firstly the influence of the spacer (n = 2–6)
on ADP-induced platelet aggregation this can be achieved
by R1 YX = 4-Cl-phenyl-SO2 held constant for the row 3e
(IC50 = 2.2 nM, n = 2), 3v (5.3 nM, n = 4), 3t (0.9 lM, n = 6),
3b (31 lM, n = 5), and 3r (106 lM, n = 3). It is obvious that
two or four methylene groups between the sulfonamide
and the nitrogen function are most suitable and show
inhibitory effects in the lower nanomolar range. By
enlarging the spacer to five or six methylene groups, a
decrease in activity by three orders of magnitude is
observed. The same is even more evident for n = 3 where
This is in strong contrast to the influence on PAF-
induced aggregation where 3n is the most powerful
inhibitor with an IC50 = 200 nM. The naphthyl derivative
3l follows with an IC50 = 3 lM which is one order of mag-
nitude weaker but still tenfold stronger than all other
compounds so that 3n and 3l probably can by classified
as rather specific PAF antagonists.
The authors have declared no conflict of interest.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
2-Amino-thiazole-4-acetamides with Antiplatelet Activity
649
2-[[(4-Iodophenyl)carbonyl]amino]-1,3-thiazol-4-yl-acetic
acid ethylester 2h
From 1.9 g (10.2 mmol) 1 and 2.7 g (10.2 mmol) 4-iodobenzoic
acid chloride. Light beige crystals, m.p. 1198C, yield 2.7 g (63%).
Experimental
Chemistry
M.p. (uncorr.), Linstrꢀm (Bꢁhler, Tꢁbingen Germany). – Elemen-
tary analysis, Elementar Vario EL-IR (Elementaranalysen Sys-
teme, Hanau, Germany), ATI Mattson Genesis Serie FTIR (Unicam
1
2-[(Phenylacetyl)amino]-1,3-thiazol-4-yl-acetic acid
Analytische Systeme, Kassel, Germany). – H-NMR: Bruker DPX
400 in [d6]DMSO (Bruker, Bioscience, USA).
ethylester 2i
From 1.9 g (10.2 mmol) 1 and 1.6 g 2-phenylacetic acid chloride.
Light yellow crystals, m.p. 90–928C, yield 2.1 g (68%).
General procedure for the synthesis of type-2 acylesters
The corresponding acid chloride (10 mmol) was dissolved in
10 mL pyridine while the mixture was cooled with ice. 10 mmol
of 1 were slowly added and heated for 10 min at 1208C. Then the
mixture was poured on 400 mL ice water. The solution was acidi-
fied with hydrochloric acid to pH 2. Meanwhile, an oily product
separated and crystallized. The crystals were sucked off and
recrystallized from ethanol (sulfonamides) or ethanol / water
(80 : 20, v/v) (carboxamides). The purity of the products was con-
firmed by elementary analysis within the usual (l 0.4%) limits.
The full set of IR, NMR, and MS data is given in the PhD thesis of
Baselt [9].
2-[[(2-Phenylethyl)carbonyl]amino]-1,3-thiazol-4-yl-acetic
acid ethylester 2j
From 1.9 g (10.2 mmol) 1 and 1.7 g 2-phenylethanecarboxylic
acid chloride. Light yellow crystals, m.p. 848C, yield 2.25 g (69%).
2-[[1,19-(Biphenyl-4-yl)carbonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2k
From 1.9 g (10.2 mmol) 1 and 2.0 g biphenyl-4-carboxylic acid
chloride. Light beige crystals, m.p. 191–1948C, yield 3.0 g (73%).
Compounds 2a, 2b, 2d, 2f, and 2p have already been described
in the literature [10, 11].
2-[(2-Naphthylsulfonyl)amino]-1,3-thiazol-4-yl-acetic acid
ethylester 2l
2-[[(4-Fluorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-
From 1.9 g (10.2 mmol) 1 and 2.3 g 2-naphthylsulfonic acid
chloride. Light beige crystals, m.p. 159–1608C, yield 2.75 g
(71%).
acetic acid ethylester 2a
From 1.9 g (10.2 mmol) 1 and 2.0 g 4-fluorophenylsulfonic acid
chloride. Beige crystals, m.p. 1228C, yield 2.5 g (71%).
2-[[(4-Chlorophenyl)carbonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2m
From 1.9 g (10.2 mmol) 1 and 1.8 g (10.2 mmol) 4-chlorophenyl-
carboxylic acid chloride. Light beige crystals, m.p. 1308C, yield
2.6 g (79%).
2-[[(4-Chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2b
From 1.9 g (10.2 mmol) 1 and 2.15 g 4-chlorophenylsulfonic acid
chloride. Light beige crystals, m.p. 1738C, yield 2.9 g (79%).
2-[[(4-Fluorophenyl)carbonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2c
From 1.9 g (10.2 mmol) 1 and 1.62 g (10.2 mmol) 4-fluorobenzoic
acid chloride. Light beige crystals, m.p. 104–1078C (decomp.),
yield 2.1 g (67%).
2-[[(4-Bromophenyl)carbonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2o
From 1.9 g (10.2 mmol) 1 and 2.2 g (10.2 mmol) 4-bromophenyl-
carboxylic acid chloride. Light beige crystals, m.p. 119–1218C,
yield 2.45 g (65%).
2-[[1,19-(Biphenyl-4-yl)sulfonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2d
From 1.9 g (10.2 mmol) 1 and 2.6 g biphenyl-4-sulfonic acid
chloride. Light beige crystals, m.p. 1728C, yield 2.6 g (63%).
2-[[(3-Chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2p
From 1.9 g (10.2 mmol) 1 and 2.15 g 3-chlorophenylcarboxylic
acid chloride. Light red crystals, m.p. 143–1448C, yield 2.15 g
(60%).
2-[[(2-Chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-
acetic acid ethylester 2f
2-[[(4-Iodophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetic
From 1.9 g (10.2 mmol) 1 and 2.15 g 2-chlorophenylsulfonic acid
chloride. Light brown crystals, m.p. 1728C, yield 2.7 g (74%).
acid ethylester 2s
From 1.9 g (10.2 mmol) 1 and 3.1 g 4-iodophenylsulfonic acid
chloride. Light beige crystals, m.p. 1628C, yield 3.8 g (83%).
2-[(Cyclohexylcarbonyl)amino]-1,3-thiazol-4-yl-acetic
acid ethylester 2g
From 1.9 g (10.2 mmol) 1 and 1.5 g cyclohexylcarboxylic acid
chloride. Needles, m.p. 1888C, yield 2.4 g (80%).
2-Benzoylamino-1,3-thiazol-4-yl-acetic acid ethylester 2u
From 1.9 g (10.2 mmol) 1 and 1.44 g benzoylchloride. Crystals,
m.p. 92–958C, yield 1.8 g (60%).
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650
K. Rehse and T. Baselt
Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
2-Phenylsulfonylamino-1,3-thiazol-4-yl-acetic acid
N-[5-(Cyclohexylamino)pentyl]-2-[[(4-
ethylester 2w
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
From 1.9 g (10.2 mmol) 1 and 1.8 g phenylsulfonic acid chloride.
Light beige crystals, m.p. 1298C, yield 2.65 g (80%).
hydrochloride hydrate 3b
From 2b and 1,5-pentanediamine (first step) and cyclohexanone
(second step) by procedure B. Crystals, m.p. 1968C, yield 15%
(both steps). – Anal. C22H32Cl2N4O3S2 (535.55). – IR (KBr): m =
3434 cm– 1; 3300; 3086; 2939; 2860; 2820; 1654; (CO); 1611;
1582; 1533; 1476; 1454; 1429; 1393; 1376; 1351; 1310 (SO2);
General procedure for the synthesis of 2-acylamino-1,3-
thiazol-4-yl-acetamides (see type-3 in Scheme 1)
Procedure A: The suitable type-2 acetic acid ethylester (10 mmol)
is suspended in the desired diamine (at least 50 mmol) and kept
1.5 h at 1208C or at 708C overnight. Then, the mixture is diluted
with ethylene, diethylene, or triethylene glycol (about 80 mL).
Now, the solvent and the excess of the diamine are removed in
vacuo at 1 mm Hg. The temperature should not exceed 1308C.
A 1: The residue is mixed with water (708C). The crystals
formed are sucked off and recrystallized from a small amount of
methanol.
A 2: The residue is mixed with ethanol and 3 mL isopropanolic
HCl are added. The mixture is concentrated and mixed with eth-
ylacetate / methanol (3 : 1). A precipitate of crystals forms and is
sucked off. If necessary, the crystals are purified by column chro-
matography or recrystallization with the solvent stated.
1273; 1174; 1146 (SO2); 1089; 1012.
–
1HNMR / 400 MHz
([d6]DMSO): d (ppm) = 1.07–1.13 (m, 1H, 4a-chex-H), 1.17–1.32
(m, 6H, 2a, 3a, 5a, 6a-chex-H, CONHCH2CH2CH2), 1.38-1.48 (m,
2H, CONH(CH2)3CH2), 1.50–1.67 (m, 3H, CONHCH2CH2, 4e-chex-
H), 1.75 (m, 2H, 3e, 5e-chex-H), 2.01 (m, 2H, 2e, 6echexH), 2.84
(brs, 2H, CH2CH2N+H2-chex), 2.93 (brs, 1H, 1-chex-H), 3.04 (dt, J =
6.2/6.2 Hz, 2H, CONHCH2CH2), 3.39 (s, 2H, thia-CH2, visible after
CF3COOD exchange), 6.55 (s, 1H, thiaH), 7.61 (“d”, J = 8.5 Hz, 2H,
3,5-ph-H), 7.80 (“d”, J = 8.4 Hz, 2H, 2,6-ph-H), 8.10 (t, J = 5.0 Hz, 1H,
D2O exchange, CONHCH2), 8.57 (brs, 2H, D2O exchange, -N+H2-
chex), 12.78 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV,
2108C): M/z (%) = 498 (27) [M+9], 455 (49), 413 (12), 398 (24), 287
(13), 314 (28), 323 (57), 288 (28), 224 (19), 191 (16), 175 (27), 124
(57), 112 (100), 98 (50), 84 (58), 56 (49), 30 (42).
Procedure B (3b, 3e, 3t, 3v): When the suitable diamine (n = 2,
4, 5, 6) was not commercially available or the purification of the
type-3 compound was difficult, these complications could be cir-
cumvented by procedure B via type-3 compounds with R2 = H.
The aminolysis follows procedure A. Then, these compounds
were transformed by reductive alkylation with cyclohexanone
and sodiumtriacetoxy boron hydride to the test compounds of
Table 1 (R2 = cyclohexyl). The reductive alkylation is described
below. The intermediate primary aminoalkylamide 3 (R2 = H,
10 mmol) and 10 mmol cyclohexanone get dissolved in 35 mL
dry 1,2-dichloroethane, 10 mL dry methanol, 2 mL acetic acid,
and 4 mL DMSO. Then, 14 mmol NaBH(OAc)3 are added and the
mixture is stirred under nitrogen at r.t. When the reaction is
completed (TLC control), the mixture is poured into 2 N HCl,
twice extracted with ether, and brought to pH 8. After extraction
with dichloromethane / methanol (1 : 1), the organic layer is
dried with Na2SO4, acidified with 3 mL isopropanolic HCl, and
the solvent removed. The crystallizing hydrochloride is sus-
pended in ethylacetate / methanol (3 : 1) and sucked off.
N-[3-(Cyclohexylamino)propyl]-2-[[(4-
fluorophenyl)carbonyl]amino]-1,3-thiazol-4-yl-acetamide
dihydrochloride 3c
From 2.5 g (8.1 mmol) 2c and 4.0 g N-cyclohexylpropane-1,3-dia-
mine, procedure A2. Crystals, m.p. 200–2058C, yield 0.95 g
(24%). – Anal. C21H29Cl2FN4O2S (491.45). – IR (KBr): m = 3411 cm– 1
;
3326; 3247; 3058; 2939; 2859; 2818; 2787; 2739; 2546; 2429;
1681 (CO); 1661 (CO); 1598; 1556; 1528; 1456; 1414; 1369; 1316;
1300; 1274; 1236; 1190; 1163; 1132; 1089; 1046; 1033; 1013. –
1H–NMR / 400 MHz ([d6]DMSO): (ppm) = 1.00–1.09 (m, 1H, 4a-
chex-H), 1.13–1.41 (m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.55 (m, 1H, 4e-
chex-H, 1.71 (m, 2H, 3e, 5e-chex-H), 1.83 (tt, J = 7.0/7.0 Hz, 2H,
CONHCH2CH2), 2.0 (m, 2H, 2e, 6e-chex-H), 2.87 (brs, 3H, 1-chex-H,
CONHCH2CH2CH2), 3.17 (dt, J = 6.2/6.2 Hz, 2H, CONHCH2CH2),
3.56 (s, 2H, thia-CH2), 7.02 (s, 1H, thia-H), 7.39 (dd, J = 8.8/8.8 Hz,
2H, 3,5-ph-H), 8.18–8.21 (m, 2H, 2,6-ph-H), 8.37 (t, J = 5.7 Hz, 1H,
D2O exchange, CONHCH2), 9.02 (brs, 2H, D2O exchange, -N+H2-
chex), 12.73 (brs, 1H, D2O exchange, thia-NHCO). – MS (70 eV,
2208C): m/z (%) = 418 (23) [M+9], 376 (810), 375 (45), 321 (32), 320
(18), 307 (14), 280 (49), 262 (41), 236 (13), 139 (10), 123 (100), 112
(24), 98 (41), 95 (24), 56 (17), 30 (20).
N-[3-(Cyclohexylamino)propyl]-2-[[(4-
fluorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
semihydrate 3a
From 2.5 g (7.26 mmol) 2a and 4.0 g N-cyclohexyl-1,3-propanedi-
amine, procedure A2, column chromatography (CHCl3 / CH3OH
saturated with NH3 = 3 : 1). Crystals, m.p. 182–1878C, yield
0.21 g (6%). – Anal. C20H28FN4O3.5S2 (454.58). – IR (KBr): m =
3434 cm1; 3096; 3067; 2938; 2859; 2554; 2454; 1648 (CO); 1591;
1539; 1492; 1454; 1353; 1326; 1297; 1257 (SO2); 1234; 1155; 1138
(SO2); 1086; 1045; 1021. – 1H-NMR / 400 MHz ([d6]DMSO): d (ppm)
= 1.03–1.12 (m, 1H, 4a-chex-H), 1.16–1.33 (m, 4H, 2a, 3a, 5a, 6a-
chex-H), 1.58 (m, 1H, 4e-chex-H), 1.72-1.81 (m, 4H, 3e, 5e-chex-H,
CONHCH2CH2CH2), 1.99 (m, 2H, 2e, 6e-chex-H), 2.88 (brs, 3H,
2-[-(1,19-Biphenyl-4-yl)sulfonyl]amino-1,3-thiazol-4-yl-N-
[3-(cyclohexylamino)propyl]-acetamide 3d
From 2.5 g 2d and 4.0 g N-cyclohexylpropane-1,3-diamine, proce-
dure A1. Light yellow powder, m.p. 1628C, yield 0.22 g (7%). –
Anal. C26H32N4O3S2 (512.69). – IR (KBr): m = 3392 cm– 1; 3060; 3029;
2933; 2857; 1650 (CO); 1595; 1450; 1348; 1271 (SO2); 1256; 1133
(SO2); 1089; 1024; 1006. – 1H-NMR / 400 MHz ([d6]DMSO): d (ppm)
= 1.03–1.11 (m, 1H, 4a-chex-H), 1.14–1.33 (m, 4H, 2a, 3a, 5a, 6a-
chex-H), 1.56 (m, 1H, 4e-chex-H), 1.60–1.77 (m, 4H, 3e, 5e-chex-H,
CONHCH2-CH2), 1.92 (m, 2H, 2e, 6e-chex-H), 2.90 (t, J = 7.4 Hz, 2H,
CONHCH2CH2CH2), 2.97–3.05 (m, 1H, 1-chex-H), 3.14 (dt, J = 6.1/
6.1 Hz, 1H, CONHCH2CH2), 3.21 (s, 2H, thia-CH2), 6.19 (s, 1H, thia-
H), 7.38 (t, J = 7.6 Hz, 1H, 49biph-H), 7.47 (t, J = 7.6 Hz, 2H, 39,59-
biph-H), 7.62-7.71 (m, 4H, 3, 5, 29, 69-biph.–H), 7.81 (d, J = 8.2 Hz,
2H, 2,6-biph-H), 8.17 (t, J = 5.8 Hz, 1H, D2O exchange, CONHCH2),
1chex-H, CONHCH2CH2CH2), 3.13 (dt, 2H,
J = 6.2/6.2 Hz,
CONHCH2), 3.40 (s, 2H, thiaCH2), 6.58 (s, 1H, thia-H), 7.56 (“d”, J =
8.4 Hz, 2H, 3,5 ph-H), 7.92 (“d”, J = 8.4 Hz, 2H, 2,6 ph-H), 8.34 (t, J =
5.6 Hz, 1H, D2O exchange, CONH), 8.77 (brs, D2O exchange, NH-
chex), 12.84 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV,
2208C): m/z (%) = 454 (23) [M+9], 411 (36), 316 (19), 295 (21), 198
(15), 175 (47), 159 (61), 112 (72), 95 (100), 56 (41).
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
2-Amino-thiazole-4-acetamides with Antiplatelet Activity
651
12.9 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV, 2208C): m/
z (%) = 512 (2) [M+9], 330 (23), 266 (51), 233 (32), 217 (19), 153 (100),
112 (19), 56 (52).
CONHCH2CH2CH2), 3.15 (dt, J = 6.2/6.2 Hz, CONHCH2CH3), 3.47 (s,
2H, thia-CH2), 6.88 (s, 1H, thia-H), 8.26 (t, J = 5.6 Hz, 1H, D2O
exchange, CONHCH2), 8.85 (brs, 2H, D2O exchange, -N+H2-chex),
12.06 (brs, 1H, D2O exchange, thia-NHCO). – MS (70 eV, 2108C):
m/z (%) = 406 (46) [M+9], 363 (100), 323 (30), 309 (73), 295 (14), 268
(81), 250 (40), 224 (11), 140 (16), 98 (11).
N-[2-(Cyclohexylamino)ethyl]-2-[[(4-
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
hydrochloride 3e
N-[3-(Cyclohexylamino)propyl]-2-[(4-
From 2b and 1,2-ethanediamine (1st step) and cyclohexanone
(2nd step) by procedure B. Crystals, m.p. 172–1758C, yield 35%
(both steps). – Anal. C19H26Cl2N4O3S2 (493.47). – IR(KBr): m =
3413 cm– 1; 3248; 3216; 3071; 2939; 2859; 2816; 2654; 2432;
1663 (CO); 1609; 1581; 1533; 1476; 1453; 1424; 1393; 1351; 1310
(SO2); 1174; 1146 (SO2); 1088; 1025; 1012. – 1H-NMR / 400 MHz
([d6]DMSO): d (ppm) = 1.07–1.13 (m, 1H, 4a-chex-H), 1.11.35 (m,
4H, 2a, 3a, 5a, 6a-chex-H), 1.59 (m, 1H, 4e-chex-H), 1.74 (m, 2H, 3e,
5e-chex-H), 2.00 (m, 2H, 2e, 6e-chex-H), 2.97 (brs, 3H, 1-chex-H,
CONHCH2CH2), 3.39 (t, J = 5.9 Hz, 2H, CONHCH2-CH2, visible after
D2O exchange), 3.43 (s, 2H, thia-CH2), 6.59 (s, 1H, thia-H), 7.61
(“d”, J = 8.1 Hz, 2H, 3,5-ph-H), 7.79 (“d”, J = 8.1 Hz, 2H, 2,6-ph-H),
8.40 (t, J = 5,4 Hz, 1H, D2O exchange, CONHCH2), 8.75 (brs, 2H,
D2O exchange, CON+H2CH2), 12.80 (brs, 1H, D2O exchange, thia-
NHSO2). – MS (70 eV, 2108C): m/z (%) = 456 (3) [M+9], 438 (39), 263
(44), 231 (14), 223 (15), 191 (21), 175 (23), 166 (58), 123 (100), 112
(53), 55 (19), 36 (64).
iodophenylcarbonyl)amino]-1,3-thiazol-4-yl-acetamide
dihydrochloride 3h
From 2.5 g (6 mmol) 2h and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 198–2018C, yield 1.1 g
(30%). – Anal. C21H29Cl2IN4O2S. – IR (KBr): m = 3411 cm– 1; 3248;
3123; 3057; 2938; 2857; 2793; 2371; 1679 (CO); 1587; 1556; 1482;
1453; 1397; 1368; 1353; 1316; 1302; 1264; 1189; 1095; 1058;
1
1033; 1007. – H-NMR /400 MHz ([d6]DMSO): d (ppm) = 1.00–1.07
(m, 1H, 4a-chex-H), 1.13–1.33 (m, 4H, 2a, 3a, 5a, 6achexH), 1.56
(m, 1H, 4e-chex-H), 1.71 (m, 2H, 3e, 5e-chex-H), 1.81 (tt, J = 7.0/
7.0 Hz, 2H, CONHCH2-CH2-CH2), 1.99 (m, 2H, 2e, 6e-chex-H), 2.86
(brs, 3H, 1-chex-H, CONHCH2CH2CH2), 3.16 (dt, J = 6.2/6.2 Hz, 2H,
CONHCH2CH2), 3.55 (s, 2H, thia-CH2), 7.02 (s, 1H, thia-H), 7.76
(“d”, J = 8.5 Hz, 2H, 3,5-ph-H), 8.04 (“d”, J = 8.5 Hz, 2H, 2,6phH),
8.33 (t, J = 5.7 Hz, 1H, D2O exchange, CONHCH2), 8.95 (brs, 2H,
D2O exchange, N+H2chex), 12.76 (brs, 1H, D2O exchange, thia-
NHCO). – MS (70 eV, 2208C): m/z (%) = 526 (23) [M+9], 483 (54), 443
(11), 429 (41), 415 (17), 388 (59), 369 (42), 344 (12), 231 (100), 203
(25), 112 (38), 98 (66), 76 (34), 56 (29), 30 (25).
N-[3-(Cyclohexylamino)propyl]-2-[[(2-
chlorophenyl)sulfonyl]amino]-1,3-thiazolyl-4-yl-
acetamide hydrochloride 3f
From 2.5 g (7 mmol) 2f and 4.0 g N-cyclohexylpropane-1,3-dia-
N-[3-(Cyclohexylamino)propyl]-2-[(phenylacetyl)amino]-
1,3-thiazol-4-yl-acetamide hydrochloride hydrate 3i
From 2.5 g (8 mmol) 2i and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 130–1378C, yield 0.6 g
mine by procedure A2. Crystals, m.p. 172–1768C, yield 0.4 g
(11%). – Anal. C20H29Cl2N4O3S2 (507.50). – IR (KBr): m = 3370 cm– 1
;
3274; 3066; 2939; 2859; 2818; 2791; 2564; 2505; 2453; 1650 (CO);
1607; 1527; 1453; 1434; 1375; 1354; 1312 (SO2); 1297; 1252;
(15%). – Anal. C23H33ClN4O3S (469.04). – IR (KBr): m = 3381 cm– 1
;
1
3247; 3030; 2940; 2858; 2544; 2433; 1651 (CO); 1543; 1453; 1312;
1274; 1190; 1143; 1087; 1031. – 1H-NMR / 400 MHz ([d6]DMSO): d
(ppm) = 1.05–1.10 (m, 1H, 4achex-H), 1.14–1.28 (m, 4H, 2a, 3a,
5a, 6a-chex-H), 1.57 (m, 1H, 4e-chex-H), 1.70–1.77 (m, 4H, 3e, 5e-
chex-H, CONHCH2CH2CH2), 1.95 (m, 2H, 2e, 6e-chex-H), 2.77 (brs,
3H, 1chexH, CONHCH2CH2CH2), 3.15 (dt, J = 6.4/6.4 Hz, 2H,
CONHCH2-CH2), 3.47 (s, 2H, thiaCH2), 3.75 (s, 2H, COCH2-ph), 6.89
(s, 1H, thia-H), 7.23–7.33 (m, 5H, ph-H), 8.19 (t, J = 5.7 Hz, 1H, D2O
exchange, CONHCH2), 8.54 (brs, 2H, D2O exchange, -N+H2-chex),
12.35 (brs, 1H D2O exchange, thia-NHCO). – MS (70 eV, 2008C):
m/z (%) = 414 (52) [M+9], 371 (86), 32 (26), 317 (100), 303 (32), 289
(14), 276 (95), 259 (34), 258 (73), 231 (17), 158 (13), 140 (52), 112
(54), 98 (89), 91 (88), 56 (48), 55 (41), 30 (91).
1193; 1148 (SO2); 1129; 1108; 1046; 1018. – H-NMR / 400 MHz
([d6]DMSO): d (ppm) = 1.05–1.13 (m, 1H, 4a-chex-H), 1.17–1.32
(m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.59 (m, 1H, 4e-chex-H), 1.73–1.80
(m, 4H, 3e, 5echex-H, CONHCH2CH2CH2), 1.99 (m, 2H, 2e, 6e-chex-
H), 2.89 (brs, 3H, 1-chex-H, CONHCH2CH2CH2), 3.41 (s, 2H, thia-
CH2), 6.57 (s, 1H, thia-H), 7.49–7.55 (m, 1H, 5phH), 7.57–7.62 (m,
2H, 3, 4-ph-H), 8.05 (“d”, J = 7.1 Hz, 6-ph-H), 8.28 (t, J = 5,6 Hz, 1H,
D2O exchange, CONHCH2), 8.62 (brs, 2H, D2O exchange –N+H2-
chex), 12.84 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV,
2208C): m/z (%) = 470 (23) [M+9], 427 (43), 295 (46), 253 (12), 190
(18), 175 (13), 155 (44), 112 (100), 138 (29), 98 (49), 56 (95).
N-[(3-Cyclohexylamino)propyl]-2-
[(cyclohexylcarbonyl)amino]-1,3-thiazol-4-yl-acetamide
dihydrochloride 3g
From 2.5 g (7.5 mmol) 2g and 4.0 g N-cyclohexyl-propane-1,3-dia-
N-[3-(Cyclohexylamino)propyl]-2-[[(2-
phenylethyl)carbonyl]amino]-1,3-thiazol-4-yl-acetamide
dihydrochloride 3j
From 2.5 g (8 mmol) 2f and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 197 2058C, yield 1.5 g
(49%). – Anal. C21H36Cl2N4O2S (479.51). – IR (KBr): m = 3405 cm– 1
;
3253; 3058; 2935; 2856; 2810; 2431; 2364; 1708 (CO); 1657 (CO);
1601; 1551; 1451; 1386; 1348; 1334; 1302; 1302; 1258; 1212;
1189; 1162; 1123; 1077; 1046; 1032. – 1H-NMR / 400 MHz
([d6]DMSO): d (ppm) = 1.05–1.11 (m, 1H, 4a-chex-H-amino), 1.15-
1.32 (m, 7H, 2a, 3a, 5a, 6a, chex-H-amino, 4a-chex-H-CO, 3a, 5a-
chex-H-CO), 1.351.43 (m, 2H, 2a, 6a-chex-H-CO), 1.56–1.65 (m,
2H, 4e-chex-H-amino, 4echexHCO), 1.72–1.83 (m, 8H, 2e, 3e, 5e,
6e-chex-H-amino, 3e, 5e-chex-H-CO, CONHCH2CH2), 1.98 (m, 2H,
mine by procedure A2. Crystals, m.p. 197–2058C, yield 0.6 g
(15%). – Anal. C23H34Cl2N4O2S (501.51). – IR (KBr): m = 3408 cm– 1
;
3282; 3059; 3024; 2938; 2858; 2814; 2436; 2370; 1713; 1713 (CO);
1644 (CO); 1592; 1547; 1497; 1453; 1420; 1380; 1353; 1301; 1263;
1
1206; 1187; 1142; 1077; 1044; 1030; 1004. – H-NMR / 400 MHz
([d6]DMSO); d (ppm) = 1.12–1.17 (m, 1H, 4a-chex-H), 1.21–1.38
(m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.64 (m, 1H, 4e-chex-H), 1.77–1.84
(m, 4H, 3e, 5e-chex-H, CONH-CH2CH2CH2), 2.02 (m, 2H, 2e, 6e-
chex-H), 2.79 (t, J = 7.7 Hz, 2H, COCH2CH2-ph), 2.93–3.09 (m, 5H,
2e,
6e-chex-H-CO),
2.86
(brs,
3H,
1-chex-H-amino,
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www.archpharm.com

652
K. Rehse and T. Baselt
Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
COCH2-CH2-ph, 1-chex-H, CONHCH2CH2CH2), 3.19 (dt, J = 6.3/
6.3 Hz, 2H, CONHCH2CH2CH2), 3.52 (s, 2H, thia-CH2), 6.94 (s, 1H,
thia-H), 7.237.36 (m, 5H, ph-H), 8.26 (t, J = 5.7 Hz, 1H, D2O
exchange, CONHCH2), 8.68 (brs, D2O exchange, 2H, N+H2-chex),
12.10 (brs, D2O exchange, 1H, thia-NHCO). – MS (70 eV, 2208C):
m/z (%) = 484 (22) [M+9], 428 (45), 385 (88), 345 (20), 331 (89), 317
(27), 290 (92), 272 (60), 246 (21), 198 (17), 158 (22), 139 (62), 112
(51), 105 (58), 98 (67), 91 (100), 80 (26), 56 (65), 41 (44), 30 (68).
1023; 1010. – 1H-NMR / 400 MHz ([d6]DMSO): d (ppm) = 0.89–0.97
(m, 2H, 2a, 6a-chex-H), 1.11–1.24 (m, 3H, 3a, 4a, 5a-chex-H),
1.53–1.85 (m, 8H, 1e, 2e, 3e, 4e, 5e, 6e-chex-H,
CONHCH2CH2CH2), 2.70 (brs, 2H, NH2CH2-chex), 2.86 (brs, 2H,
CONHCH2CH2CH2), 3.12 (dt, J = 6.2/6.2 Hz, 2H, CONHCH2CH2),
3.40 (s, 2H, thia-CH2), 6.57 (s, 1H, thia-H), 7.61 (“d”, J = 8.5 Hz, 2H,
3,5ph-H), 7.80 (“d”, J = 8.4 Hz, 2H, 2,6-ph-H), 8.26 (t, J = 5.5 Hz, D2O
exchange, 1H, CONHCH2CH2CH2), 8.46 (brs, 2H, D2O exchange, -
N+H2-chex), 12.80 (brs, 1H, D2O exchange, thia-NHSO2). – MS
(70 eV, 2208C): m/z (%) = 484 (34) [M+9], 468 (74), 401 (55), 358 (10),
227 (23), 191 (13), 175 (17), 113 (29), 111 (27), 36 (100), 28 (52).
N-[3-(Cyclohexylamino)propyl]-2-[(2-
naphthylsulfonyl)amino]-1,3-thiazol-4-yl-acetamide
hydrochloride 3l
From 2.5 g (6 mmol) 2l and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 212–2138C, yield 2.9 g
(80%). – Anal. C24H31ClN4O3S2 (523.11). – IR (KBr): m = 3401 cm– 1
;
N-[3-(Cyclohexylamino)propyl]-2-[[(4-
bromophenyl)carbonyl]amino]-1,3-thiazol-4-yl- acetamide
dihydrochloride 3o
2163; 3056; 2938; 2858; 2448; 1648 (CO); 1608; 1593; 1524; 1454;
1
1424; 1346; 1309; 1264 (SO2); 1146 (SO2); 1073; 1022. – H-NMR /
400 MHz ([d6]DMSO): d (ppm) = 1.07–1.16 (m, 1H, 4a-chex-H),
1.20-1.36 (m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.62 (m, 1H, 4e-chex-H),
1.77–1.84 (m, 4H, 3e, 5e-chex-H, CONHCH2-CH2), 2.03 (m, 2H, 2e,
6echex-H), 2.93 (brs, 3H, 1-chex-H, CONHCH2CH2CH2), 3.18 (dt, J =
6.2/6.2 Hz, 2H, CONHCH2), 3.44 (s, 2H, thia-CH2), 6.61 (s, 1H, thia-
H), 7.69–7.76 (m, 2H, 6,7-naph-H), 7.86 (“d”, J = 8.6 Hz, 1H, 5-
naph-H), 8.07 (“d”, J = 7.9 Hz, 1H, 8-naph-H), 8.13 (“d”, J = 8.7 Hz,
1H, 4-naph-H), 8.22 (“d”, J = 7.6 Hz, 1H, 3-naph-H), 8.34 (t, J =
5.4 Hz, 1H, D2O exchange, CONHCH2), 8.52 (s, 1H, 1-naph-H), 8.69
(brs, 2H, D2O exchange, N+H2-chex), 12.82 (brs, 1H, D2O exchange,
thia-NH-SO2). – MS (70 eV, 2408C): m/z (%) = 486 (6) [M+9], 443 (10),
348 (10), 295 (11), 261 (10), 207 (59), 191 (10), 160 (28), 127 (100),
98 (26), 56 (54), 41 (14).
From 2.5 g 2o and 4.0 g N-cyclohexyl-propane-1,3-diamine by
procedure A2. Crystals, m.p. 203–2048C, yield 0.95 g (25%). –
Anal. C21H29BrCl2N4O2S (552.36). – IR (KBr): m = 3347 cm– 1; 3247;
3053; 3023; 2937; 2858; 2819; 2792; 2546; 2434; 1686 (CO); 1648
(CO); 1590; 1556; 1486; 1456; 1400; 1366; 1317; 1303; 1269;
1243; 1187; 1160; 1160; 1098; 1071; 1046; 1033; 1010. – 1H-NMR
/ 400 MHz ([d6]DMSO): d (ppm) = 1.00–1.09 (m, 1H, 4achex-H),
1.13–1.33 (m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.55 (m, 1H, 4e-chex-H),
1.71 (m, 2H, 3e, 5e-chex-H), 1.81 (tt, J = 7.0/7.0 Hz, 2H,
CONHCH2CH2CH2), 1.99 (m, 2H, 2e, 6echex-H), 2.86 (m, 2H, 1-
chex-H, CONHCH2-CH2-CH2), 3.16 (dt,
J = 6.2/6.2 Hz, 2H,
CONHCH2CH2), 3.54 (s, 2H, thia-CH2), 7.01 (s, 1H, thia-H), 7.86
(“d”, J = 8.4 Hz, 2H, 3,5ph-H), 7.93 (“d”, J = 8.3 Hz, 2H, 2,6-ph-H),
8.33 (t, J = 5.6 Hz, D2O exchange, 1H, CONHCH2CH2CH2), 8.95
(brs, D2O exchange, 2H, -N+H2-chex), 12.75 (brs, D2O exchange,
1H, thia-NHCO). – MS (70 eV, 1008C): m/z (%) = 480/478 (23) [M+9],
437/435 (50), 383/381 (31), 380 (17), 367 (14), 342/340 (50), 325/
323 (20), 322 (38), 295 (19), 261 (34), 185/183 (100), 179 (14), 155
(24), 139 (19), 112 (46), 98 (86), 56 (33), 30 (29).
N-[3-(Cyclohexylamino)propyl]-2-[[(4-
chlorophenyl)carbonyl]amino]-1,3-thiazol-4-yl-acetamide
dihydrochloride 3m
From 2.5 g 2m and 4.0 g N-cyclohexyl-propane-1,3-diamine by
procedure A2. – Crystals, m.p. 2278C, yield 1.3 g (36%). – Anal.
C21H29Cl3N4O2S (507.90). – IR (KBr): m = 3428 cm1; 3256; 3058;
3025; 2938; 2818; 2550; 2435; 1685 (CO); 1648 (CO); 1594; 1556;
1490; 1455; 1404; 1367; 1316; 1301; 1291; 1270; 1243; 1187;
1
1162; 1098; 1045; 1033; 1013. – HNMR / 400 MHz ([d6]DMSO): d
N-[3-(Cyclohexylamino)propyl]-2-[[(3-
chlorophenylsulfonyl)]amino]-1,3-thiazol-4-yl- acetamide
monohydrate 3p
(ppm) = 1.03–1.09 (m, 1H, 4a-chex-H), 1.13–1.32 (m, 4H, 2a, 3a,
5a, 6a-chex-H), 1.56 (m, 1H, 4e-chex-H), 1.71 (m, 2H, 3e, 5e-chexH),
1.81 (tt, J = 7.1/7.1 Hz, 2H, CONHCH2CH2CH2), 1.98 (m, 2H, 2e, 6e-
chex-H), 2.86 (brs, 3H, 1chexH, CONHCH2CH2CH2), 3.16 (dt, J =
6.1/6.1 Hz, 2H, CONHCH2CH2CH2), 3.54 (s, 2H, thia-CH2), 7.01 (s,
1H, thia-H), 7.62 (“d”, J = 8.5 Hz, 2H, 3,5-ph-H), 8.12 (“d”, J =
8.5 Hz, 2H, 2,6-ph-H), 8.31 (t, J = 5.1 Hz, D2O exchange, 1H,
CONHCH2CH2CH2), 8.88 (brs, D2O exchange, 2H, -N+H2-chex),
12.58 (brs, D2O exchange, 1H, thia-NHCO). – MS (70 eV, 2008C):
m/z (%) = 434 (20) [M+9], 391 (40), 337 (27), 336 (15), 323 (11), 296
(42), 280 (17), 252 (11), 139 (100), 112 (33), 98 (64), 56 (31), 30 (39).
From 2.5 g (6.9 mmol) 2p and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2, column chromatography (chloroform /
methanol saturated with NH3 = 4 : 1). Crystals, m.p. 132–1378C,
yield 0.1 g (3%). – Anal. C20H29ClN4O4S2 (489.05). – IR (KBr): m =
3420 cm– 1; 3064; 2938; 2859; 1648 (CO); 1540; 1456; 1408; 1354;
1326; 1259 (SO2); 1140 (SO2); 1106; 1079; 1021. – 1HNMR /
400 MHz ([d6]DMSO): d (ppm) = 1.04–1.12 (m, 1H, 4a-chex-H),
1.16–1.32 (m, 4H, 2a, 3a, 5a, 6a-chex-H), 1,57 (m, 1H, 4e-chex-H),
1.72–1.80 (m, 4H, 3e, 5echex-H, CONH-CH2-CH2-CH2), 1.99 (m, 2H,
2e, 6e-chex-H), 2.89 (brs, 3H, 1-chex-H, CONHCH2CH2-CH2), 3,13
(dt, J = 6.3/6.3 Hz, 2H, CONH-CH2-CH2), 3.41 (s, 2H, thiaCH2), 6.59
(s, 1H, thia-H), 7.59 (dd, J = 8.2 Hz, 1H, 5-ph-H), 7.67-7.90 (m, 1H,
4ph-H), 7.75–7.77 (m, 2H, 2,6-ph-H), 8.31 (t, J = 5.4 Hz, D2O
exchange, 1H, CONH-CH2), 8.67 (brs, 2H, D2O exchange, -N+H2-
chex), 12.87 (brs, D2O exchange, 1H, thia-NH-SO2). – MS (70 eV,
2008C): m/z (%) = 470 (61) [M+9], 427 (94), 372 (19), 332 (40), 295
(59), 253 (11), 191 (52), 190 (35), 175 (31), 139 (19), 127 (47), 111
(100), 98 (42), 74 (28), 56 (44).
N-[[(3-Cyclohexylmethyl)amino]propyl]-2-[[(4-
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
hydrochloride 3n
From 2b and 1,3-propanediamine (1st step) and cyclohexane
aldehyde (2nd step) by procedure B. Crystals, m.p. 179–1818C,
yield 15% (both steps). – Anal. C21H29Cl2N4O3S2 (521.52). – IR
(KBr): m = 3306 cm– 1; 3087; 2958; 2087; 1919; 1638 (CO); 1581;
1536; 1454; 1392; 1324; 1281 (SO2); 1261; 1174; 1131 (SO2); 1087;
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Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
2-Amino-thiazole-4-acetamides with Antiplatelet Activity
653
2208C): m/z (%) = 562 (26) [M+9], 519 (38), 424 (26), 407 (14), 380
(11), 295 (36), 283 (100), 267 (37), 203 (15), 139 (25), 112 (38), 98
(52), 56 (54).
N-[(3-Cyclohexylamino)propyl]-2-[[(1,19-biphenyl-4-
yl)carbonyl]amino]-1,3-thiazol-4-yl- acetamide 3q
From 2.5 g (7 mmol) 2k and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A1. Light yellow powder, m.p. 156–1578C,
yield 0.2 g (7%). – Anal. C27H32N4O2S (476.63). – IR (KBr): m =
3419 cm– 1; 3251; 3059; 2939; 2859; 2818; 1680 (CO); 1606; 1554;
1512; 1489; 1450; 1408; 1371; 1324; 1302; 1277; 1240; 1203;
N-(6-Cyclohexylaminohexyl-2-[(4-
chlorophenylsulfonyl)amino]-1,3-thiazol-4-yl)-acetamide
hydrochloride 3t
1
1163; 1127; 1092; 1050; 1007. – HNMR / 400 MHz ([d6]DMSO): d
From 2b and 1,6-hexanediamine (first step) and cyclohexanone
(second step) by procedure B. Crystals, m.p. 190–1918C, yield
35% (both steps). – Anal. C23H34Cl2N4O3S2 (549.15). – IR (KBr): m =
3417 cm– 1; 3081; 2938; 2859; 2819; 1655 (CO); 1533; 1476; 1455;
1429; 1393; 1376; 1353; 1307 (SO2); 1274; 1172; 1145 (SO2); 1088;
(ppm) = 1.03–1.12 (m, 1H, 4a-chex-H), 1.12–1.36 (m, 4H, 2a, 3a,
5a, 6a-chex-H), 1.56 (m, 1H, 4e-chex-H), 1,71 (m, 2H, 3e, 5e-chex-
H), 1.77 (tt, J = 6.9/6.9 Hz, 2H, CONHCH2CH2-CH2), 1.96 (m, 2H, 2e,
6e-chex-H), 2.88 (brs, 3H, 1chexH, CONHCH2CH2CH2), 3.18 (dt, J =
6.3/6.3 Hz, 2H, CONHCH2CH2CH2), 3.55 (s, 2H, thia-CH2), 7.00 (s,
1H, thia-H), 7.44 (t, J = 7.6 Hz, 1H, 49-biph-H), 7.52 (dd, J = 7.6/
7.6 Hz, 2H, 39,59biphH), 7.77 (d, J = 7.4 Hz, 2H, 29,69-biph-H), 7.85
(d, J = 8.4 Hz, 2H, 3,5-biph-H), 8.20 (d, J = 8.3 Hz, 2H, 2,6-biph-H),
8.24 (t, J = 5.5 Hz, D2O exchange, 1H, CONH-CH2), 8.57 (brs, D2O
exchange, 1H, NH-chex-H), 12.69 (brs, D2O exchange, 1H,
thiaNHCO). – MS (70 eV, 2208C): m/z (%) = 476 (10) [M+9], 433 (15),
379 (18), 338 (21), 320 (17), 294 (10), 181 (100), 152 (40), 98 (12),
36 (27).
1
1011. – H-NMR / 400 MHz ([d6]DMSO): d (ppm) = 1.07–1.13 (m,
1H, 4a-chex-H), 1.17–1.34 (m, 8H, 2a, 3a, 5a, 6achex-H,
CONHCH2CH2CH2CH2), 1.36-1.43 (m, 2H, CH2CH2N+H2-chex),
1.53–1.67 (m, 3H, CONHCH2CH2CH2, 4e-chex-H), 1.75 (m, 2H, 3e,
5e-chex-H), 2.02 (m, 2H, 2e, 6echexH), 2.84 (brs, 2H, CH2CH2N+H2-
chex), 2.93 (brs, 1H, 1-chex-H), 3.03 (dt,
J = 6.4/6.4 Hz,
CONHCH2CH2), 3.39 (s, 2H, thia-CH2, visible after addition of
CF3COOD), 6.55 (s, 1H, thia-H), 7.61 (“d”, J = 8.6 Hz, 2H, 3,5-ph-H),
7.80 (“d”, J = 8.5 Hz, 2H, 2,6-ph-H), 8.11 (t, J = 5.5 Hz, 1H, D2O
exchange, CONHCH2), 8.68 (brs, 2H, D2O exchange, N+H2chex),
12.79 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV, 2208C):
m/z (%) = 512 (34) [M+9], 469 (71), 412 (12), 401 (12), 337 (84), 314
(12), 226 (16), 175 (12), 168 (21), 156 (29), 138 (18), 112 (100), 98
(56), 56 (25), 28 (18).
N-[3-(Cyclohexylamino)-propyl-2-[[(4-
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl- acetamide
hydrochloride 3r
From 2.5 g (7 mmol) 2b and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A1. Crystals, m.p. 1918C, yield 0.4 g (12%). –
Anal. C20H28Cl2N4O3S2 (507.50). – IR (KBr): m = 3363 cm– 1; 3267;
3084; 2939; 2859; 2818; 1649 (CO); 1607; 1529; 1475; 1455; 1424;
N-(3-Cyclohexylaminopropyl)-2-phenylcarbonylamino-
1,3-thiazol-4-yl-acetamide dihydrochloride 3u
1
1393; 1352; 1316 (SO2); 1174; 1146 (SO2); 1088; 1025; 1011. – H-
From 2,5 g (8.6 mmol) 2u and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 217–2218C, yield 0.5 (10%).
– Anal. C21H30Cl2N4O2S (472.15). – IR (KBr): m = 3425 cm– 1; 3251;
3060; 2938; 2858; 2795; 2544; 2434; 2362; 2340; 1683 (CO); 1650
(CO); 1597; 1552; 1450; 1370; 1303; 1277; 1243; 1189; 1145;
NMR / 400 MHz ([d6]DMSO): d (ppm) = 1.06–1.12 (m, 1H, 4a-chex-
H), 1.16–1.31 (m, 4H, 2a, 3a, 5a, 6achexH), 1.59 (m, 1H, 4e-chex-
H), 1.73–1.81 (m, 4H, 3e, 5e-chex-H, CONHCH2CH2CH2), 1.98 (m,
2H, 2e, 6e-chex-H), 2.88 (brs, 3H, 1-chex-H, CONHCH2CH2-CH2),
3.13 (dt, J = 6.3/6.3 Hz, 2H, CONH-CH2-CH2), 3.39 (s, 2H, thia-CH2),
6.57 (s, 1H, thia-H), 7.61 (“d”, J = 8.6 Hz, 3,5-ph-H), 7.80 (“d”, J =
8.6 Hz, 2H, 2,6-ph-H), 8.28 (t, J = 5.6 Hz, D2O exchange, 1H, CONH-
CH2), 8.60 (brs, 2H, D2O exchange, N+H2chex-H), 12.49 (brs, 1H,
D2O exchange, thia-NHSO2). – MS (70 eV, 2208C): m/z (%) = 470
(14) [M+9], 427 (26), 332 (17), 295 (26), 188 (10), 277 (11), 261 (17),
219 (12), 191 (36), 175 (47), 113 (65), 112 (100), 98 (42), 75 (43), 56
(58).
1
1089; 1029. – H-NMR / 400 MHz ([d6]DMSO): d (ppm) = 1.00–1.09
(m, 1H, 4a-chex-H), 1.13–1.30 (m, 4H, 2a, 3a, 5a, 6achex-H), 1.55
(m, 1H, 4e-chex-H), 1.71 (m, 2H, 3e, 5e-chex-H), 1.79 (tt, J = 7.1/
7.1 Hz, 2H, CONHCH2CH2CH2), 1.97 (m, 2H, 2e, 6e-chex-H), 2.87
(brs, 3H, 1-chex-H, CONHCH2CH2CH2), 3.17 (dt, J = 6.3 Hz, 2H,
CONHCH2CH2CH2), 3.54 (s, 2H, thiaCH2), 6.99 (s, 1H, thia-H), 7.54
(dd, J = 7.6 Hz, 2H, 3,5-ph-H), 7.63 (t, J = 7.3 Hz, 1H, 4-ph-H), 8.10
(d, J = 7.8 Hz, 2H, 2,6-ph-H), 8.24 (t, J = 5.7 Hz, 1H, D2O exchange,
CONHCH2), 8.73 (brs, 2H, D2O exchange, N+H2-chex), 12.6 (brs,
1H, D2O exchange, thiaNHCO). – MS (70 eV, 2008C): m/z (%) = 400
(25) [M+9], 357 (39), 303 (39), 289 (15), 262 (46), 245 (24), 244 (51),
217 (10), 112 (20), 105 (100), 98 (38), 77 (38), 56 (23), 38 (22), 35
(68), 30 (42).
N-[3-(Cyclohexylamino)propyl]-2-[[(4-
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
hydrochloride 3s
From 2.5 g (5 mmol) 2s and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2. Crystals, m.p. 2108C, yield 1.2 g (28%). –
Anal. C20H28ClIN4O3S2 (598.95). – IR (KBr): m = 3432 cm– 1; 3276;
3086; 2938; 2858; 2816; 2454; 1649 (CO); 1607; 1567; 1529; 1454;
1434; 1382; 1352; 1314 (SO2); 1268; 1181; 1147; (SO2); 1085;
1054; 1024; 1004. – 1HNMR / 400 MHz ([d6]DMSO): d (ppm) =
1.03–1.12 (m, 1H, 4a-chex-H), 1.16–1.33 (m, 4H, 2a, 3a, 5a, 6a-
chex-H), 1.58 (m, 1H, 4e-chex-H), 1.72–1.81 (m, 4H, 3e, 5e-chex-H,
CONHCH2CH2), 1.99 (m, 2H, 2e, 6e-chex-H), 2.88 (brs, 3H, 1-chex-
H, CONHCH2CH2CH2), 3.13 (dt, J = 6.2/6.2 Hz, 2H, CONHCH2CH2),
3.40 (s, 2H, thia-CH2), 6.58 (s, 1H, thia-H), 7.56 (“d”, J = 8.4 Hz, 2H,
3,5-ph-H), 7.92 (“d”, J = 8.4 Hz, 2H, 2,6-ph-H), 8.34 (t, J = 5.6 Hz,
D2O exchange, 1H, CONHCH2), 8.77 (brs, 2H, D2O exchange, N+H2-
chex-H), 12.84 (brs, 1H, D2O exchange, thia-NHSO2). – MS (70 eV,
N-(4-Cyclohexylamino-butyl)-2-[[(4-
chlorophenyl)sulfonyl]amino]-1,3-thiazol-4-yl-acetamide
hydrochloride 3v
From 2b and 1,4-butanediamine (first step) and cyclohexanone
(second step) by procedure B. Crystals, m.p. 186–1878C, yield
50% (both steps). – Anal. C21H30Cl2N4O3S2 (521.53). – IR (KBr): m =
3329 cm– 1; 3086; 2939; 2861; 2801; 2556; 2506; 2432; 2046;
1910; 1655 (CO); 1609; 1582; 1533; 1475; 1453; 1453; 1423; 1393;
1377; 1352; 1318 (SO2); 1174; 1146 (SO2); 1089; 1055; 1023; 1012.
1
– H-NMR / 400 MHz ([d6]DMSO): d (ppm) = 1.07–1.13 (m, 1H, 4a-
chex-H), 1.17-1.32 (m, 4H, 2a, 3a, 5a, 6a-chex-H), 1.43–1.48 (m,
2H, CONHCH2CH2CH2CH2), 1.53–1.64 (m, 3H, CONHCH2CH2CH2,
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654
K. Rehse and T. Baselt
Arch. Pharm. Chem. Life Sci. 2008, 341, 645–654
4e-chex-H), 1.74 (m, 2H, 3e, 5e-chex-H), 2.00 (m, 2H, 2e, 6e-chex-
H), 2.87 (brs, 3H, 1-chex-H, CH2-CH2N+H2-chex), 3.06 (dt, J = 6.3 Hz,
2H, CONHCH2CH2), 3.38 (s, 2H, thia-CH2), 6.56 (s, 1H, thia-H), 7.61
(“d”, J = 8.6 Hz, 2H, 3,5-ph-H), 7.80 (“d”, J = 8.6 Hz, 2H, 2,6-ph-H),
8.16 (brs, 1H, D2O exchange, CONHCH2), 8.57 (brs, 2H, D2O
exchange, N+H2-chex), 1.78 (brs, 1H, D2O exchange, thia-NHCO).
Biology
The Born test was carried out as recently reported in detail in
this journal [8].
– MS (70 eV, 2208C): m/z (%) = 484 (48) [M+9], 441 (100), 384 (45), References
373 (25), 314 (28), 309 (76), 210 (26), 175 (16), 123 (100), 112 (67),
110 (47), 98 (46), 70 (61), 56 (56), 36 (39), 28 (64).
[1] K. Mꢂrschenz, K. Rehse, Arch. Pharm. Chem. Life Sci. 2006,
339, 115–122.
[2] A. K. Yildiz, K. Rehse, J.-P. Stasch, E. Bischoff, Arch. Pharm.
Pharm. Med. Chem. 2004, 337, 311–316.
N-[(3-Cyclohexylamino)propyl]-2-(phenylsulfonylamino)-
1,3-thiazol-4-yl-acetamide hydrate 3w
[3] A. Cwiklicki, K. Rehse, Arch. Pharm. Pharm. Med. Chem.
2004, 337, 156–163.
From 2.5 g (6 mmol) 2w and 4.0 g N-cyclohexyl-propane-1,3-dia-
mine by procedure A2, column chromatography (chloroform /
methanol saturated with NH3 = 85 : 15). Crystals, m.p. 1478C,
[4] K. Bethge, H. H. Pertz, K. Rehse, Arch. Pharm. Chem. Life Sci.
2005, 338, 78–86.
yield 0,3 g (10%). – Anal. C20H30N4O2S2. – IR (KBr): m = 3411 cm– 1
;
[5] K. Rehse, J. Steege, Arch. Pharm. Chem. Life Sci. 2005, 338,
3062; 2938; 2859; 2169; 1648 (CO); 1538; 1456; 1326; 1257 (SO2);
1
539–547.
1131 (SO2); 1087; 1017. – H-NMR / 400 MHz ([d6]DMSO): d (ppm)
[6] K. Rehse, H. Gonska, Arch. Pharm. Chem. Life Sci. 2005, 338,
= 1.03–1.09 (m, 1H, 4a-chex-H-), 1.13–1.30 (m, 4H, 2a, 3a, 5a,
6achex-H), 1.55 (m, 1H, 4e-chex-H), 1.71 (m, 2H, 3e, 5e-chex-H),
1.79 (tt, J = 7.0/7.0 Hz, 2H, CONHCH2CH2CH2), 1.97 (m, 2H, 2e, 6e-
chex-H), 2.87 (brs, 3H, 1-chex-H, CONHCH2CH2CH2), 3.17 (dt, J =
6.4/6.4 Hz, 2H, CONHCH2CH2), 3.54 (s, 2H, thia-CH2), 7.00 (s, 2H,
thia-H), 7.54 (dd, J = 7.6/7.6 Hz, 2H, 3,5-ph-H), 7.64 (t, J = 7.3 Hz,
1H, 4-ph-H), 8.10 (“d”, J = 7.1 Hz, 2H, 2,6-ph-H), 8.25 (t, J = 5.7 Hz,
1H, D2O exchange, CONHCH2CH2CH2), 8.71 (brs, 2H, D2O
exchange, N+H2-chex), 12.6 (brs, 1H, D2O exchange, thia-NHSO2.
– MS (70 eV, 2108C): m/z (%) = 436 (18) [M+9], 393 (39), 295 (25), 280
(13), 198 (13), 141 (35), 112 (44), 77 (100).
590–597.
[7] M. Johnsen, K. Rehse, H. Pertz, J.-P. Stasch, E. Bischhoff,
Arch. Pharm. Med. Chem. 2003, 336, 1–7.
[8] K. Bethge, H. H. Pertz, K. Rehse, Arch. Pharm. Chem. Life Sci.
2005, 338, 78–86.
[9] T. Baselt, PhD thesis, Freie Universitꢂt Berlin 2006.
[10] C. Nilsson, C. Dreifeldt, PCT WO 2004/112782 A1.
[11] T. Barf, R. Emond, G. Kurz, J. Vallgarda, et al., Biovitrum
AB, PCT WO 03/043999 A1, 2003.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com