Synthesis and aldose reductase inhibitory activities of novel O-substituted hydroxyphenylacetic acid derivatives

Article abstract of DOI:10.1002/ardp.200600024

In continuation of our work aimed towards the preparation of novel aldose reductase inhibitors, several O-substituted hydroxyphenylacetic acid derivatives were investigated. The highest inhibitory activity was found for compounds 7b and 7c bearing a cyclo

Full text of DOI:10.1002/ardp.200600024

Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
D. Rakowitz et al.
547
Full Paper
Synthesis and Aldose Reductase Inhibitory Activities of
Novel O-Substituted Hydroxyphenylacetic Acid Derivatives
Dietmar Rakowitz, Helga Angerer, and Barbara Matuszczak
Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
In continuation of our work aimed towards the preparation of novel aldose reductase inhibitors,
several O-substituted hydroxyphenylacetic acid derivatives were investigated. The highest inhibi-
tory activity was found for compounds 7b and 7c bearing a cyclohexylmethyl substituent. This
result demonstrates that within these series, this moiety is a useful surrogate for the 4-bromo-2-
fluorobenzyl residue which can be often found in potent aldose reductase inhibitors.
Keywords: Aldose reductase / Enzyme inhibitors / Inhibitor / Substituted phenylacetic acids /
Received: February 8, 2006; accepted: June 6, 2006
DOI 10.1002/ardp.200600024
Introduction
The number of people with diabetes mellitus is increas-
ing due to population growth, aging, urbanization, and
increasing prevalence of obesity and physical inactivity
[1]. Nevertheless, while prolonging life, antidiabetic ther-
apy does not prevent the occurrence of disabling compli-
cations such as neuropathy, nephropathy, retinopathy,
and cataracts. These problems arise from accumulation
of sorbitol which is formed in the polyol pathway cata-
lyzed by aldose reductase (EC 1.1.1.21, ALR 2). The latter is
Figure 1. Model of ARIs of type I (characterized by hydrophilic
activated due to saturation of hexokinase, the key
enzyme of the glycolytic pathway [2, 3]. These findings
have led to the development of numerous aldose reduc-
tase inhibitors (ARIs) which offer the possibility to pre-
vent or delay the occurrence of long-term complications.
However, to date none is currently marketed for world-
wide use due to lack of high efficacy and selectivity or
due to toxicity [4].
Using previously defined pharmacophore require-
ments [5–9], we have recently designed compounds of
type I (Fig. 1) as ARIs [10–12]. Modifications included the
spacers X and Y, the substituent R, and the lipophilic as
well as the hydrophilic (i.e. anionic) moieties. The latter
two represent the suggested pharmacophores.
and lipophilic pharmacophores) in the active site of the enzyme
(the most important amino acids are Trp20, Tyr48, His110, Trp111
Phe122, Leu300).
,
So far, out of these series, the 3- and 4-(4-bromo-2-fluoro-
benzyloxy)phenyl acetic acids II (IC50 = 20.9 lM) and III
(IC50 = 40.2 lM) emerged as the most potent aldose reduc-
tase inhibitors [12]. In order to get further insight into
structure-activity relationships, we now became inter-
ested in derivatives bearing different lipophilic moieties.
Results and discussion
The compounds 2 were prepared starting from 1a–c by
benzylation in the presence of potassium carbonate in
dry N,N-dimethylformamide. Whereas the use of phenyl-
ethyl bromide led to the desired compounds 3a–c,
employment of cyclohexylmethylbromide resulted in a
Correspondence: Dietmar Rakowitz, Leopold-Franzens-Universitꢀt, In-
stitute of Pharmacy, Innrain 52a, Innsbruck A-6020, Austria.
E-mail: barbara.matuszczak@uibk.ac.at
Fax: +43 512 507-2940
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

548
D. Rakowitz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Table 1. Aldose reductase inhibition data of compounds 5, II, and III.
Compound
Position
R9
Inhibition at 100 lM
IC50 (lM)*
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
5ba
5bb
5bc
5bd
5be
5bf
5bg
5bh
5bi
II**
5ca
5cb
5cc
5cd
5ce
5cf
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
H
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
4-Cl
4-OCH3
H
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
4-Cl
4-OCH3
4-Br-2F
H
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
4-Cl
4-OCH3
4-Br-2F
17%
42%
17%
15%
24%
58.6 (46.9–73.3)
32%
48%
28%
60.5 (58.8–62.3)
50.0 (35.6–70.4)
81.6 (60.3–110.3)
86.1 (85.3–86.9)
43.9 (34.2–56.4)
38.6 (29.7–50.1)
64.4 (52.2–79.4)
53.9 (40.0–72.2)
50.3 (48.2–52.7)
20.9 (18.0–24.3)
78.8 (66.4–93.6)
73.9 (73.3–74.6)
92.4 (83.8–101.9)
100.2 (99.3–101.1)
55.1 (50.0–60.8)
50.7 (48.1–53.5)
63.6 (56.9–71.1)
69.2 (49.7–96.5)
93.8 (77.3–113.7)
40.2 (38.3–42.1)
5cg
5ch
5ci
III**
Sorbinil
1.1 (1.0–1.2)
* IC50 values (95% CL).
** Data described in [12].
failure. However, 4a–c became accessible by reaction of This, however, is in accordance with the known impor-
1a–c with the corresponding iodo derivative. Finally, the tance of a negative charge for the interaction of aldose
esters were converted to the desired free carboxylic acids reductase inhibitors with the active site of the enzyme
5–7 by alkaline hydrolysis. Inhibitory activities of the [5–9]. Concerning the position of the lipophilic pattern
substituted phenylacetic acids 5aa–ci, 6a–c, and 7a–c on the benzene core, derivatives of the 3-hydroxy- and 4-
were evaluated in a spectrometric assay with D,L-glyceral- hydroxyphenylacetic acids are favourable to inhibition
dehyde as the substrate and NADPH as the cofactor.
of the enzyme compared to the corresponding 2-substi-
According to the in vitro results obtained (Tables 1 and tuted congeners. Additionally, in most cases the former
2), the substituted phenylacetic acids show satisfactory exhibit higher activity than the 4-isomers. Although no
but less inhibitory activity than the reference sorbinil. general structure-activity relationships can be given,
Hence, the following conclusions can be drawn: The pre- introduction of substituents on the aryl unit of the ben-
sence of an acidic proton appears to be an essential struc- zyl residue exhibits an effect on the inhibitory activity.
tural requisite since compounds devoid of any acidic pro- However, it can be seen that 3- and 4-fluoro are detrimen-
ton 2–4 do not show any or only poor inhibitory activity. tal whereas 2- and 3-trifluoromethyl substituents are ben-
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Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Novel Aldose Reductase Inhibitors
549
Table 2. Aldose reductase inhibition data of compounds 6 and 7.
Compound
Position
R9
Inhibition at 100 lM
IC50 (lM)*
6a
6b
6c
7a
7b
7c
2
3
4
2
3
4
2-phenylethyl
2-phenylethyl
2-phenylethyl
cyclohexylmethyl
cyclohexylmethyl
cyclohexylmethyl
27%
43%
62.0 (56.5–68.1)
81.5 (66.1–100.6)
32.1 (23.1–44.5)
45.0 (44.1–45.9)
Sorbinil
1.1 (1.0 – 1.2)
* IC50 values (95% CL).
for aldose reductase inhibitors have been published
before. Based on these results, further modifications on
the nature of the lipophilic pharmacophore are in pro-
gress.
The authors wish to acknowledge Schlachthof Salzburg-Berg-
heim (Austria) (KR Ing. Sebastian Grießner and Mag. Erika
Sakoparnig) for providing calf lenses.
Scheme 1. Synthesis route for presented compounds 2–7.
Experimental
eficial. Formal introduction of a methylene group
between X and the lipophilic pharmacophore (i.e. phenyl-
ethyl, 6a–c) does not cause a significant change on the in
vitro activity. Surprisingly, the most intriguing result was
found in the case of cyclohexylmethyl substituted deriv-
atives 7a–c corresponding to a formal reduction of the
benzyl residue brought a 1.5-to 2-fold increase in inhibi-
tory activity [IC50 values: 32.1 lM (7b) versus 60.5 lM (5ba)
and 45.0 lM (7c) versus 78.8 lM (5ca)].
Chemistry
Melting points were determined with a Kofler hot-stage micro-
scope (C. Reichert, Vienna, Austria) and are uncorrected. Infra-
red spectra (KBr pellets) were recorded on a Mattson Galaxy Ser-
ies FTIR 3000 spectrophotometer (Mattson Instruments, Inc.,
Madison, WI, USA). Mass spectra were obtained on a Finnigan
MAT SSQ 7000 spectrometer (EI, 70 eV; Thermo Electron Cor-
poration, Bremen, Germany). The 1H-NMR spectra were recorded
in CDCl3 or DMSO-d6 solution in 5 mm tubes at 308C on a Varian
Gemini 200 spectrometer (199.98 MHz; Varian Inc., Palo Alto,
CA, USA) with the deuterium signal of the solvent as the lock
and TMS as internal standard. Chemical shifts are expressed in
parts per million. Reactions were monitored by TLC using Poly-
gramm SIL G/UV254 (Macherey-Nagel) plastic-backed plates
(0.25 mm layer thickness). The yields given are not optimized.
Light petroleum refers to the fraction of b.p. 40–608C. Elemental
analyses were performed by Mag. J. Theiner, “Mikroanalytisches
Laboratorium”, Faculty of Chemistry, University of Vienna, Aus-
tria, and the data for C and H are within l0.4% of the calculated
values.
Conclusions
In brief, we have discovered that the inhibitory activity of
compounds 7b and 7c is in the same range as those of
compounds II and III bearing a 4-bromo-2-fluorobenzyl
moiety. Thus, the cyclohexylmethyl side chain seems to
be a useful surrogate for the 4-bromo-2-fluorobenzyl resi-
due which can be often found in potent aldose reductase
inhibitors (e.g. zenarestat, ponalrestat, minalrestat, and
AS-3201 [4]). To our knowledge, no comparable findings
Compounds not listed were commercial samples of good
grade. Cyclohexylmethyl iodide was prepared starting from the
corresponding hydroxy compound according to [13] and [14].
The following compounds are already known but not tested as
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www.archpharm.com

550
D. Rakowitz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Table 3a. Physicochemical data of compounds of type 2a.
No
R9 Formula
(MW)
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
2aa
C6H5 C17H18O3
(270.33)
71% cc with CH2Cl2 followed
by recryst. from EtOH colorless
crystals mp 32–338C
1733
270
7.44–7.20 (m, 7H, phenyl-H), 6.97–6.90 (m,
2H, phenyl-H), 5.08 (s, 2H, OCH2), 4.10 (q, J = 7.1
Hz, 2H, OCH2CH3), 3.67 (s, 2H, CH2), 1.19 (t, J =
7.1 Hz, 3H, OCH2CH3)
2ab
2ac
2ad
2-F(C6H4) C17H17FO3
(288.32)
86% recryst. from EtOH
colorless crystals
mp 56–578C
1731
288
7.56–7.48 (m, 1H, phenyl-H), 7.36–6.92 (m,
7H, phenyl-H), 5.15 (s, 2H, OCH2), 4.11 (q, J = 7.1
Hz, 2H, OCH2CH3), 3.67 (s, 2H, CH2), 1.19 (t, J =
7.1 Hz, 3H, OCH2CH3)
7.39–7.13 (m, 5H, phenyl-H), 7.04–6.87 (m,
3H, phenyl-H), 5.08 (s, 2H, OCH2), 4.13 (q, J = 7.2
Hz, 2H, OCH2CH3), 3.68 (s, 2H, CH2), 1.21 (t, J =
7.2 Hz, 3H, OCH2CH3)
7.42–7.35 (m, 2H, phenyl-H), 7.29–7.20 (m,
2H, phenyl-H), 7.11–6.89 (m, 4H, phenyl-H),
5.04 (s, 2H, OCH2), 4.10 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.65 (s, 2H, CH2), 1.19 (t, J = 7.1 Hz,
3H, OCH2CH3)
3-F(C6H4) C17H17FO3
(288.32)
88% recryst. from EtOH
colorless crystals
mp 38–408C
1733
288
4-F(C6H4) C17H17FO3
(288.32)
43% cc with CH2Cl2
colorless oil
1735
288
2ae
2-CF3(C6H4) C18H17F3O3
(338.33)
59% recryst. from EtOH
colorless crystals
mp 38–418C
1722
338
7.79–7.67 (m, 2H, phenyl-H), 7.60–7.53 (m,
1H, phenyl-H), 7.44–7.37 (m, 1H, phenyl-H),
7.28–7.19 (m, 2H, phenyl-H), 7.00–6.84 (m,
2H, phenyl-H), 5.30 (s, 2H, OCH2), 4.13 (q, J = 7.2
Hz, 2H, OCH2CH3), 3.71 (s, 2H, CH2), 1.21 (t, J =
7.2 Hz, 3H, OCH2CH3)
2af
3-CF3(C6H4) C18H17F3O3
(338.33)
39% recryst. from EtOH
colorless crystals
mp 54–568C
1729
338
7.70–7.46 (m, 4H, phenyl-H), 7.31–7.22 (m,
2H, phenyl-H), 7.00–6.89 (m, 2H, phenyl-H),
5.13 (s, 2H, OCH2), 4.11 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.68 (s, 2H, CH2), 1.19 (t, J = 7.1 Hz,
3H, OCH2CH3)
2ag
4-CF3(C6H4) C18H17F3O3
(338.33)
72% recryst. from EtOH
colorless crystals
mp 93–948C
1725
338
7.64 (9d9, J = 8.4 Hz, 2H, phenyl-H), 7.54 (d, J =
8.4 Hz, 2H, phenyl-H), 7.29–7.21 (m, 2H, phe-
nyl-H), 7.00–6.87 (m, 2H, phenyl-H), 5.14 (s,
2H, OCH2), 4.11 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.68 (s, 2H, CH2), 1.20 (t, J = 7.1 Hz, 3H,
OCH2CH3)
2ah
2ai
4-Cl(C6H4) C17H17ClO3
(304.78)
56% recryst. from EtOH
colorless crystals
mp 44–518C
1725
304/306
7.35 (s, 4H, phenyl-H), 7.28–7.20 (m, 2H, phe-
nyl-H), 6.98–6.87 (m, 2H, phenyl-H), 5.04 (s,
2H, OCH2), 4.10 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.66 (s, 2H, CH2), 1.20 (t, J = 7.1 Hz, 3H,
OCH2CH3)
7.36–7.19 (m, 4H, phenyl-H), 6.96–6.87 (m,
4H, phenyl-H), 5.01 (s, 2H, OCH2), 4.10 (q, J = 7.1
Hz, 2H, OCH2CH3), 3.82 (s, 3H, OCH3), 3.65 (s,
2H, CH2), 1.19 (t, J = 7.1 Hz, 3H, OCH2CH3)
4-OCH3(C6H4) C18H20O4
(300.36)
59% cc with CH2Cl2
colorless oil
1728
300
cc = column chromatography
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Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Novel Aldose Reductase Inhibitors
551
Table 3b. Physicochemical data of compounds of type 2b.
No
R9 Formula
(MW)
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
2bb
2-F(C6H4) C17H17FO3
(288.32)
75% cc with CH2Cl2
colorless oil
1734
288
7.56–7.47 (m, 1H, phenyl-H), 7.37–7.04 (m,
4H, phenyl-H), 6.93–6.88 (m, 3H, phenyl-H),
5.13 (s, 2H, OCH2), 4.15 (q, J = 7.2 Hz, 2H,
OCH2CH3), 3.59 (s, 2H, CH2), 1.25 (t, J = 7.2 Hz,
3H, OCH2CH3)
2bc
2bd
3-F(C6H4) C17H17FO3
(288.32)
86% cc with CH2Cl2
colorless oil
1733
288
7.40–7.13 (m, 4H, phenyl-H), 7.05–6.84 (m,
4H, phenyl-H), 5.05 (s, 2H, OCH2), 4.15 (q, J = 7.2
Hz, 2H, OCH2CH3), 3.58 (s, 2H, CH2), 1.25 (t, J =
7.2 Hz, 3H, OCH2CH3)
4-F(C6H4) C17H17FO3
(288.32)
61% cc with CH2Cl2
colorless oil
1733
288
7.44–7.37 (m, 2H, phenyl-H), 7.28–7.20 (m,
1H, phenyl-H), 7.12–7.01 (m, 2H, phenyl-H),
6.91–6.84 (m, 3H, phenyl-H), 5.01 (s, 2H,
OCH2), 4.15 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.58 (s,
2H, CH2), 1.25 (t, J = 7.2 Hz, 3H, OCH2CH3)
7.77–7.68 (m, 2H, phenyl-H), 7.61–7.53 (m,
1H, phenyl-H), 7.45–7.38 (m, 1H, phenyl-H),
7.29–7.21 (m, 1H, phenyl-H), 6.92–6.84 (m,
3H, phenyl-H), 5.27 (s, 2H, OCH2), 4.15 (q, J = 7.2
Hz, 2H, OCH2CH3), 3.59 (s, 2H, CH2), 1.25 (t, J =
7.2 Hz, 3H, OCH2CH3)
2be
2-CF3(C6H4) C18H17F3O3
(338.33)
80% cc with CH2Cl2
colorless oil
1735
338
2bf
2bg
2bh
2bi
3-CF3(C6H4) C18H17F3O3
(338.33)
83% cc with CH2Cl2
colorless oil
1735
338
7.71–7.47 (m, 4H, phenyl-H), 7.30–7.22 (m,
1H, phenyl-H), 6.93–6.86 (m, 3H, phenyl-H),
5.11 (s, 2H, OCH2), 4.15 (q, J = 7.2 Hz, 2H,
OCH2CH3), 3.60 (s, 2H, CH2), 1.25 (t, J = 7.2 Hz,
3H, OCH2CH3)
7.65 (d, J = 8.4 Hz, 2H, phenyl-H), 7.55 (d, J = 8.4
Hz, 2H, phenyl-H), 7.29–7.21 (m, 1H, phenyl-
H), 6.92–6.84 (m, 3H, phenyl-H), 5.12 (s, 2H,
OCH2), 4.15 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.59 (s,
2H, CH2), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3)
7.35 (s, 4H, phenyl-H), 7.28–7.19 (m, 1H, phe-
nyl-H), 6.92–6.82 (m, 3H, phenyl-H), 5.02 (s,
2H, OCH2), 4.15 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.58 (s, 2H, CH2), 1.25 (t, J = 7.1 Hz, 3H,
OCH2CH3)
4-CF3(C6H4) C18H17F3O3
(338.33)
87% cc with CH2Cl2
colorless oil
1735
338
4-Cl(C6H4) C17H17ClO3
(304.78)
60% cc with CH2Cl2
colorless oil
1735
304/306
4-OCH3(C6H4) C18H20O4
(300.36)
66% cc with CH2Cl2
colorless oil
1737
300
7.39–7.20 (m, 3H, phenyl-H), 6.95–6.85 (m,
5H, phenyl-H), 4.98 (s, 2H, OCH2), 4.15 (q, J = 7.1
Hz, 2H, OCH2CH3), 3.82 (s, 3H, OCH3), 3.58 (s,
2H, CH2), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3)
cc = column chromatography
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Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Table 3c. Physicochemical data of compounds of type 2c.
No
R9 Formula
(MW)
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
2cb
2-F(C6H4) C16H15FO3
(274.29)
73% recryst. from dipe/lp
colorless crystals
mp 29–328C
1728
274
7.54–7.46 (m, 1H, phenyl-H), 7.37–7.03 (m,
5H, phenyl-H), 6.98–6.91 (m, 2H, phenyl-H),
5.12 (s, 2H, OCH2), 3.69 (s, 3H, OCH3), 3.57 (s,
2H, CH2)
2cc
3-F(C6H4) C16H15FO3
(274.29)
97% cc with CH2Cl2
colorless oil
1737
274
7.39–7.12 (m, 5H, phenyl-H), 7.05–6.89 (m,
3H, phenyl-H), 5.04 (s, 2H, OCH2), 3.68 (s, 3H,
OCH3), 3.56 (s, 2H, CH2)
2cd
4-F(C6H4) C16H15FO3
(274.29)
76% recryst. from EtOH
colorless crystals
mp 42–478C
1734
274
7.43–7.36 (m, 2H, phenyl-H), 7.23–7.16 (m,
2H, phenyl-H), 7.11–7.02 (m, 2H, phenyl-H),
6.95–6.88 (m, 2H, phenyl-H), 5.00 (s, 2H,
OCH2), 3.69 (s, 3H, OCH3), 3.57 (s, 2H, CH2)
7.76–7.67 (m, 2H, phenyl-H), 7.59–7.52 (m,
1H, phenyl-H), 7.45–7.37 (m, 1H, phenyl-H),
7.24–7.17 (m, 2H, phenyl-H), 6.96–6.88 (m,
2H, phenyl-H), 5.26 (s, 2H, OCH2), 3.69 (s, 3H,
OCH3), 3.57 (s, 2H, CH2)
2ce
2-CF3(C6H4) C17H15F3O3
(324.30)
83% cc with CH2Cl2
colorless oil
1740
324
2cf
3-CF3(C6H4) C17H15F3O3
(324.30)
73% cc with CH2Cl2
colorless oil
1737
324
7.70–7.46 (m, 4H, phenyl-H), 7.24–7.18 (m,
2H, phenyl-H), 6.97–6.89 (m, 2H, phenyl-H),
5.10 (s, 2H, OCH2), 3.69 (s, 3H, OCH3) 3.58 (s,
2H, CH2)
2cg
4-CF3(C6H4) C17H15F3O3
(324.30)
84% recryst. from EtOH
colorless crystals
mp 75–828C
1728
324
7.64 (d, J = 8.1 Hz, 2H, phenyl-H), 7.54 (d, J = 8.1
Hz, 2H, phenyl-H), 7.24–7.17 (m, 2H, phenyl-
H), 6.95–6.88 (m, 2H, phenyl-H), 5.11 (s, 2H,
OCH2), 3.69 (s, 3H, OCH3), 3.57 (s, 2H, CH2)
7.35 (s, 4H, phenyl-H), 7.23–7.16 (m, 2H, phe-
nyl-H), 6.94–6.87 (m, 2H, phenyl-H), 5.01 (s,
2H, OCH2), 3.68 (s, 3H, OCH3), 3.56 (s, 2H, CH2)
7.35 (9d9, J = 8.8 Hz, 2H, phenyl-H), 7.19 (9d9 J =
8.8 Hz, 2H, phenyl-H), 6.94–6.89 (m, 4H, phe-
nyl-H), 4.97 (s, 2H, OCH2), 3.81 (s, 3H, OCH3),
3.68 (s, 3H, COOCH3), 3.56 (s, 2H, CH2)
2ch
2ci
4-Cl(C6H4) C16H15ClO3
(290.75)
74% recryst. from EtOH
colorless crystals
mp 53–588C
55% recryst. from EtOH
colorless crystals
mp 54–608C
1734
290/292
4-OCH3(C6H4) C17H18O4
(286.33)
1740
286
cc = column chromatography; dipe = diisopropyl ether; lp = light petroleum.
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Novel Aldose Reductase Inhibitors
553
Table 3d. Physicochemical data of compounds of type 3 and 4.
No
3a
R
Position R9 Formula (MW) Yield Purification
IR (cm– 1
MS
)
1H-NMR (CDCl3)
Properties
C2H5
2
CH2C6H5 C18H20O3 33% cc with CH2Cl2
(284.36) + lp (1/1) colorless oil
1734
284
7.32–7.14 (m, 7H, phenyl-H), 6.94–6.82 (m,
2H, phenyl-H), 4.17 (t, J = 6.8 Hz, 2H, OCH2CH2),
4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.59 (s, 2H,
CH2), 3.08 (t, J = 6.8 Hz, 2H, OCH2CH2), 1.25 (t, J
= 7.1 Hz, 3H, OCH2CH3)
3b
C2H5
3
CH2C6H5 C18H20O3 11% cc with CH2Cl2
(284.36) colorless oil
1734
284
7.36–7.17 (m, 6H, phenyl-H), 6.87–6.77 (m,
3H, phenyl-H), 4.17 (t, J = 7.1 Hz, 2H, OCH2CH2),
4.14 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.56 (s, 2H,
CH2), 3.09 (t, J = 7.1 Hz, 2H, OCH2CH2), 1.24 (t, J
= 7.2 Hz, 3H, OCH2CH3)
3c
4a
CH3
4
2
CH2C6H5 C17H18O3 41% cc with CH2Cl2
1736
270
7.35–7.14 (m, 7H, phenyl-H), 6.88–6.82 (m,
2H, phenyl-H), 4.16 (t, J = 7.2 Hz, 2H, OCH2CH2),
3.67 (s, 3H, OCH3), 3.55 (s, 2H, CH2), 3.09 (t, J =
7.2 Hz, 2H, OCH2CH2)
(270.33)
colorless oil
C2H5
C6H11C17H24O3
(276.38)
43% cc with CH2Cl2
+ lp (1/1)
1733
276
7.26–7.16 (m, 2H, phenyl-H), 6.90 (dd, J = 0.9
Hz, J = 7.6 Hz, 1H, phenyl H), 6.83 (d, J = 7.6 Hz,
1H, phenyl H), 4.14 (q, J = 7.0 Hz, 2H, OCH2CH3),
3.75 (d, J = 5.8 Hz, 2H, OCH2C6H11), 3.61 (s, 2H,
CH2), 1.87–1.69 (m, 6H, alkyl-H), 1.39–0.98 (m,
5H, alkyl-H), 1.25 (t, J = 7.0 Hz, 3H, OCH2CH3)
7.25–7.17 (m, 1H, phenyl-H), 6.86–6.77 (m,
3H, phenyl-H), 4.15 (q, J = 7.2 Hz, 2H, OCH2CH3),
3.74 (d, J = 6.2 Hz, 2H, OCH2C6H11), 3.57 (s, 2H,
CH2), 1.90–1.68 (m, 6H, alkyl-H), 1.40–0.96 (m,
5H, alkyl-H), 1.26 (t, J = 7.2 Hz, 3H, OCH2CH3)
7.17 (d, J = 8.4 Hz, 2H, phenyl-H), 6.87–6.80 (m,
2H, phenyl-H), 3.73 (d, J = 5.8 Hz, 2H, OCH2-
C6H11), 3.68 (s, 3H, OCH3), 3.55 (s, 2H, CH2),
1.89–1.72 (m, 6H, alkyl-H), 1.39–0.95 (m, 5H,
alkyl-H)
colorless oil
4b
4c
C2H5
CH3
3
4
C6H11C17H24O3
(276.38)
24% cc with CH2Cl2
+ lp (1/1)
1734
276
colorless oil
C6H11C16H22O3
(262.35)
22% cc with CH2Cl2
+ lp (1/1)
1728
262
colorless oil
cc = column chromatography; lp = light petroleum
aldose reductase inhibitors: ethyl 3-benzyloxyphenyl acetate
2ba [15], methyl 4-benzyloxyphenyl acetate 2ca [16], the benzyl-
oxyphenyl acetic acids 5aa, 5ba, 5ca [17] and (4-cyclohexylmethy-
loxy)phenyl acetic acid 7c [18]. Moreover, 5ah [CAS: 52804-00-9],
5ce [CAS: 574005-40-6], 5cf [CAS: 574005-41-7], 5ci [CAS: 76968-
91-7], and 6a [19] were published as intermediates; however, no
spectroscopic as well as analytical data are given.
the mixture was poured into cold water, the mixture was acidi-
fied with 2N HCl and the product was extracted exhaustively
with diethyl ether or dichloromethane, respectively. The
organic layer was washed successively with 2N NaOH, water and
brine, dried over anhydrous sodium sulphate, and evaporated to
dryness. The residue thus obtained was purified as described in
Tables 3a–d.
General procedure for the O-substitution to prepare
General procedure for the synthesis of phenylacetic acids
compounds of type 2–4
of type 5–7
Powdered potassium carbonate (4 equiv., 11.1mmol) was added
to a solution of the appropriate compound 1 (2 equiv.,
5.55 mmol) in 10 mL of dry N,N-dimethylformamide under
atmosphere of nitrogen. After stirring for 30 min at room tem-
perature, one equivalent of the appropriate aralkyl halide or
cyclohexylmethyl iodide, respectively, was added and stirring
was continued until TLC indicated no further conversion. Then,
A solution of the appropriate ester 2–4 in 10 mL of ethanol was
treated with 2N NaOH (1.4 equivalents) and stirred overnight at
room temperature. The solvent was then evaporated, the residue
treated with a small amount of water and the pH adjusted to 5
with 2N HCl. The mixture thus obtained was extracted with
ethyl acetate, the organic layer was washed successively with
water and brine, dried over anhydrous sodium sulphate, and
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554
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Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Table 4a. Physicochemical data of compounds of type 5a.
No
R9 Formula
(MW)
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
5ab
2-F(C6H4) C15H13FO3
(260.27)
60% recryst. from dipe colorless 1706
crystals mp 107–1138C 260
7.51–7.43 (m, 1H, phenyl-H), 7.33–6.93 (m,
7H, phenyl-H), 5.15 (s, 2H, OCH2), 3.71 (s, 2H,
CH2)
5ac
5ad
3-F(C6H4) C15H13FO3
(260.27)
4-F(C6H4) C15H13FO3
(260.27)
55% recryst. from dipe colorless 1713
7.36–6.88 (m, 8H, phenyl-H), 5.08 (s, 2H,
OCH2), 3.73 (s, 2H, CH2)
7.38–7.20 (m, 4H, phenyl-H), 7.06–6.89 (m,
4H, phenyl-H), 5.03 (s, 2H, OCH2), 3.70 (s, 2H,
CH2)
crystals mp 85–908C
260
1710
260
54% recryst. from dipe/lp
colorless crystals mp 76–848C
5ae
5af
5ag
2-CF3(C6H4) C16H13F3O3
(310.27)
63% recryst. from dipe/lp color- 1718
less crystals mp 100–1078C 310
7.72–7.64 (m, 2H, phenyl-H), 7.53–7.21 (m,
4H, phenyl-H), 7.00–6.83 (m, 2H, phenyl-H),
5.26 (s, 2H, OCH2), 3.74 (s, 2H, CH2)
7.66–7.21 (m, 6H, phenyl-H), 7.00–6.88 (m,
2H, phenyl-H), 5.11 (s, 2H, OCH2), 3.72 (s, 2H,
CH2)
7.59 (d, J = 8.2 Hz, 2H, phenyl-H), 7.48 (d, J = 8.2
Hz, 2H, phenyl-H), 7.31–7.22 (m, 2H, phenyl-
H), 7.01–6.86 (m, 2H, phenyl-H), 5.11 (s, 2H,
OCH2), 3.72 (s, 2H, CH2)
3-CF3(C6H4) C16H13F3O3
(310.27)
34% recryst. from dipe colorless 1718
crystals mp 96–1028C 310
4-CF3(C6H4) C16H13F3O3
(310.27)
66% recryst. from dipe colorless 1710
crystals mp 109–1158C 310
5ah
5ai
4-Cl(C6H4) C15H13ClO3
(276.72)
86% recryst. from dipe/lp color- 1714
less crystals mp 90–1008C 276/278
7.30 (s, 4H, phenyl-H), 7.26–7.20 (m, 2H, phe-
nyl-H), 6.99–6.87 (m, 2H, phenyl-H), 5.03 (s,
2H, OCH2), 3.70 (s, 2H, CH2)
7.33–7.20 (m, 4H, phenyl-H), 6.97–6.85 (m,
4H, phenyl-H), 5.00 (s, 2H, OCH2), 3.78 (s, 3H,
OCH3), 3.69 (s, 2H, CH2)
4-OCH3(C6H4) C16H16O4
(272.30)
73% recryst. from dipe colorless 1710
crystals mp 128–1328C 272
dipe = diisopropyl ether; lp = light petroleum
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www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Novel Aldose Reductase Inhibitors
555
Table 4b. Physicochemical data of compounds of type 5b.
No
R9
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
Formula (MW)
5bb
5bc
5bd
2-F(C6H4) C15H13FO3
(260.27)
52% recryst. from dipe colorless 1700
crystals mp 99–1048C 260
7.54–7.46 (m, 1H, phenyl-H), 7.37–7.03 (m,
4H, phenyl-H), 6.93–6.88 (m, 3H, phenyl-H),
5.13 (s, 2H, OCH2), 3.63 (s, 2H, CH2)
7.40–7.13 (m, 4H, phenyl-H), 7.05–6.86 (m,
4H, phenyl-H), 5.05 (s, 2H, OCH2), 3.63 (s, 2H,
CH2)
7.43–7.36 (m, 2H, phenyl-H), 7.29–7.21 (m,
1H, phenyl-H), 7.10–7.02 (m, 2H, phenyl-H),
6.91–6.87 (m, 3H, phenyl-H), 5.01 (s, 2H,
OCH2), 3.62 (s, 2H, CH2)
3-F(C6H4) C15H13FO3
(260.27)
66% recryst. from dipe colorless 1696
crystals mp 90–968C 260
4-F(C6H4) C15H13FO3
(260.27)
68% recryst. from dipe colorless 1700
crystals mp 124–1298C 260
5be
2-CF3(C6H4) C16H13F3O3
(310.27)
39% recryst. from dipe colorless 1700
crystals mp 93–998C 310
7.77–7.67 (m, 2H, phenyl-H), 7.60–7.52 (m,
1H, phenyl-H), 7.44–7.37 (m, 1H, phenyl-H),
7.30–7.22 (m, 1H, phenyl-H), 6.92–6.85 (m,
3H, phenyl-H), 5.26 (s, 2H, OCH2), 3.63 (s, 2H,
CH2)
5bf
3-CF3(C6H4) C16H13F3O3
(310.27)
54% recryst. from dipe colorless 1700
crystals mp 93–1018C 310
7.70 (s, 1H, phenyl-H), 7.63–7.45 (m, 3H, phe-
nyl-H), 7.31–7.22 (m, 1H, phenyl-H), 6.93–6.87
(m, 3H, phenyl-H), 5.10 (s, 2H, OCH2), 3.63 (s,
2H, CH2)
5bg
4-CF3(C6H4) C16H13F3O3
(310.27)
42% recryst. from dipe colorless 1700
crystals mp 97–1028C 310
7.64 (d, J = 8.8 Hz, 2H, phenyl-H), 7.54 (d, J = 8.8
Hz, 2H, phenyl-H), 7.30–7.22 (m, 1H, phenyl-
H), 6.92–6.86 (m, 3H, phenyl-H), 5.11 (s, 2H,
OCH2), 3.63 (s, 2H, CH2)
5bh
5bi
4-Cl(C6H4) C15H13ClO3
(276.72)
65% recryst. from dipe colorless 1696
crystals mp 115–1248C 276/278
7.35 (s, 4H, phenyl-H), 7.29–7.21 (m, 1H, phe-
nyl-H), 6.91–6.84 (m, 3H, phenyl-H), 5.02 (s,
2H, OCH2), 3.62 (s, 2H, CH2)
7.38–7.31 (m, 2H, phenyl-H), 7.28–7.20 (m,
1H, phenyl-H), 6.94–6.85 (m, 5H, phenyl-H),
4.97 (s, 2H, OCH2), 3.81 (s, 3H, OCH3), 3.62 (s,
2H, CH2)
4-OCH3(C6H4) C16H16O4
(272.30)
63% recryst. from dipe colorless 1700
crystals mp 125–1328C 272
dipe = diisopropyl ether
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556
D. Rakowitz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Table 4c. Physicochemical data of compounds of type 5c.
No
R9
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR
Formula (MW)
5cb
5cc
5cd
2-F(C6H4)
C15H13FO3 (260.27)
50% recryst. from dipe colorless 1700
crystals mp 106–1098C 260
(CDCl3) 7.53–7.45 (m, 1H, phenyl-H), 7.36–
7.02 (m, 5H, phenyl-H), 6.95 (9d9, J = 8.8 Hz, 2H,
phenyl-H), 5.12 (s, 2H, OCH2), 3.59 (s, 2H, CH2)
(CDCl3) 7.39–7.12 (m, 5H, phenyl-H), 7.05–
6.88 (m, 3H, phenyl-H), 5.04 (s, 2H, OCH2), 3.59
(s, 2H, CH2)
(CDCl3) 7.42–7.35 (m, 2H, phenyl-H), 7.24–
7.16 (m, 2H, phenyl-H), 7.12–7.00 (m, 2H, phe-
nyl-H), 6.95–6.88 (m, 2H, phenyl-H), 5.00 (s,
2H, OCH2), 3.58 (s, 2H, CH2)
3-F(C6H4)
C15H13FO3 (260.27)
65% recryst. from dipe colorless 1684
crystals mp 98–1038C 260
4-F(C6H4)
C15H13FO360.2 H2O
(263.87)
47% recryst. from dipe colorless 1684
crystals mp 128–1308C 260
5ce
5cf
2-CF3(C6H4)
C16H13F3O3 (310.27)
56% recryst. from dipe colorless 1700
(CDCl3) 7.75–7.67 (m, 2H, phenyl-H), 7.59–
7.52 (m, 1H, phenyl-H), 7.45–7.37 (m, 1H, phe-
nyl-H), 7.21 (9d9, J = 8.4 Hz, 2H, phenyl-H), 6.96–
6.89 (m, 2H, phenyl-H), 5.26 (s, 2H, OCH2), 3.59
(s, 2H, CH2)
(CDCl3) 7.69 (9s9, 1H, phenyl-H), 7.63–7.46 (m,
3H, phenyl-H), 7.27–7.18 (m, 2H, phenyl-H),
6.97–6.90 (m, 2H, phenyl-H), 5.09 (s, 2H,
OCH2), 3.59 (s, 2H, CH2)
crystals mp 94–998C
310
3-CF3(C6H4)
C16H13F3O3 (310.27)
54% recryst. from dipe/lp
colorless crystals mp 77–808C
1700
310
5cg
5ch
5ci
4-CF3(C6H4)
C16H13F3O3 (310.27)
46% recryst. from dipe colorless 1706
crystals mp 104–1108C 310
(CDCl3) 7.66–7.52 (m, 4H, phenyl-H), 7.21 (d, J=
8.0 Hz, 2H, phenyl-H), 6.92 (d, J = 8.0 Hz, 2H,
phenyl-H), 5.11 (s, 2H, OCH2), 3.59 (s, 2H, CH2)
(CDCl3) 7.35 (s, 4H, phenyl-H), 7.19 (9d9, J = 8.4
Hz, 2H, phenyl-H), 6.91 (9d9, J = 8.4 Hz, 2H, phe-
nyl-H), 5.01 (s, 2H, OCH2), 3.58 (s, 2H, CH2)
(DMSO-d6) 7.35 (d, J = 8.4 Hz, 2H, phenyl-H),
7.14 (d, J = 8.8 Hz, 2H, phenyl-H), 6.95–6.89 (m,
2H, phenyl-H), 6.91 (d, J = 8.4 Hz, 2H, phenyl-
H), 4.98 (s, 2H, OCH2), 3.74 (s, 3H, OCH3), 3.46
(s, 2H, CH2)
4-Cl(C6H4)
C15H13ClO3 (276.72)
65% recryst. from dipe colorless 1700
crystals mp 144–1578C
276/278
4-OCH3(C6H4)
C16H16O4 (272.30)
77% recryst. from ea/THF
colorless crystals
1710
272
mp 148–1658C
dipe = diisopropyl ether; ea = ethyl acetate; lp = light petroleum
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Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
Novel Aldose Reductase Inhibitors
557
Table 4d. Physicochemical data of compounds of type 6 and 7.
No
6a
Position
R9
Yield Purification
Properties
IR (cm– 1
MS
)
1H-NMR (CDCl3)
Formula (MW)
2
CH2C6H5
C16H16O3 (256.30)
19% recryst. from dipe/lp
colorless crystals
mp 69–758C
1700
256
7.31–7.16 (m, 7H, phenyl-H), 6.95–6.84 (m,
2H, phenyl-H), 4.19 (t, J = 6.8 Hz, 2H, OCH2CH2),
3.63 (s, 2H, CH2), 3.08 (t, J = 6.8 Hz, 2H,
OCH2CH2)
6b
6c
7a
7b
7c
3
4
2
3
4
CH2C6H5
C16H16O3 (256.30)
12% recryst. from dipe/lp
colorless crystals
mp 96–1048C
1700
256
7.36–7.18 (m, 6H, phenyl-H), 6.87–6.78 (m,
3H, phenyl-H), 4.17 (t, J = 7.1 Hz, 2H, OCH2CH2),
3.60 (s, 2H, CH2), 3.09 (t, J = 7.1 Hz, 2H,
OCH2CH2)
7.35–7.15 (m, 7H, phenyl-H), 6.85 (9d9, J = 8.8
Hz, 2H, phenyl-H), 4.16 (t, J = 7.2 Hz, 2H,
OCH2CH2), 3.57 (s, 2H, CH2), 3.09 (t, J = 7.2 Hz,
2H, OCH2CH2)
7.28–7.16 (m, 2H, phenyl-H), 6.94–6.83 (m,
2H, phenyl-H), 3.77 (d, J = 5.8 Hz, 2H, OCH2),
3.66 (s, 2H, CH2), 1.86–1.71 (m, 6H, alkyl-H),
1.32–0.82 (m, 5H, alkyl-H)
7.23–7.18 (m, 1H, phenyl-H), 6.86–6.78 (m,
3H, phenyl-H), 3.74 (d, J = 6.2 Hz, 2H, OCH2),
3.61 (s, 2H, CH2), 1.89–1.73 (m, 6H, alkyl-H),
1.43–0.95 (m, 5H, alkyl-H)
CH2C6H5
C16H16O3 (256.30)
15% recryst. from dipe/lp
colorless crystals
mp 85–918C
1700
256
C6H11
C15H20O360.3 H2O
(253.73)
24% recryst. from lp
colorless crystals
mp 58–608C
1700
248
C6H11
C15H20O3
(248.32)
19% recryst. from dipe/lp
colorless crystals
mp 75–808C
1700
248
C6H11
C15H20O360.2 H2O
(251.93)
28% recryst. from dipe
colorless crystals
mp 95–1038C
1700
248
7.17 (9d9, J = 8.8 Hz, 2H, phenyl-H), 6.84 (9d9, J =
8.8 Hz, 2H, phenyl-H), 3.73 (d, J = 5.8 Hz, 2H,
OCH2), 3.57 (s, 2H, CH2), 1.88–1.72 (m, 6H, al-
kyl-H), 1.39-0.94 (m, 5H, alkyl-H)
dipe = diisopropyl ether; lp = light petroleum; compound 7c has been already described in [18].
evaporated to dryness under reduced pressure. The residue thus
obtained was purified as described in the Tables 4a–d.
sium phosphate buffer pH 6.8, 0.38 M ammonium sulfate,
0.11 mM NADPH and 4.7 mM D,L-glyceraldehyde as substrate in a
final volume of 1.5 mL. All inhibitors were dissolved in DMSO.
The final concentration of DMSO in the reaction mixture was
1%. To correct for the nonenzymatic oxidation of NADPH, the
rate of NADPH oxidation in the presence of all the components
except the substrate was subtracted from each experimental
rate. Each dose-effect curve was generated using at least three
concentrations of inhibitor causing an inhibition between 20
and 80%. Each concentration was tested in duplicate and IC50
values as well as the 95% confidence limits (95% CL) were
obtained by using CalcuSyn software [21] for dose effect analysis.
Aldose reductase inhibitory assay
NADPH, D,L-glyceraldehyde, and dithiothreitol (DTT) were pur-
chased from Sigma Chemical Co. DEAE-cellulose (DE-52) was
obtained from Whatman. Sorbinil was a gift from Prof. Dr. Luca
Costantino, University of Modena (Italy) and was used as stan-
dard [IC50 = 1.1 (l 0.1) lM]. All other chemicals were commercial
samples of good grade. Calf lenses for the isolation of ALR 2 were
obtained locally from freshly slaughtered animals. The enzyme
was purified by a chromatographic procedure as previously
described [20]. Briefly, ALR 2 was released by carving the capsule
and the frozen lenses were suspended in potassium phosphate
buffer pH 7 containing 5 mM DTT and stirred in an ice-cold bath
for 2 h. The suspension was centrifuged at 4000 rpm at 48C for
30 min and the supernatant was subjected to ion exchange chro-
matography on DE-52. Enzyme activity was assayed spectropho-
tometrically on a Cecil Super Aurius CE 3041 spectrophotometer
(Cecil Instruments, Cambridge, England) by measuring the
decrease in absorption of NADPH at 340 nm which accompanies
the oxidation of NADPH catalysed by ALR 2. The assay was per-
formed at 378C in a reaction mixture containing 0.25 M potas-
References
[1] S. Wild, G. Roglic, A. Green, R. Sicree, H. King, Diabetes
care 2004, 27, 1047–1053.
[2] S. Suzen, E. Buyukbingol, Curr. Med. Chem. 2003, 10,
1329–1352.
[3] L. G. Humber, Prog. Med. Chem. 1987, 24, 299–343.
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

558
D. Rakowitz et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 547–558
[4] S. Miyamoto, Exp. Opin. Ther. Patents 2002, 12, 621–631.
[13] A. P. Krapcho, R. G. Johanson, J. Org. Chem. 1971, 36, 146–
156.
[5] E. I. Howard, R. Sanishvili, R. E. Cachau, A. Mitschler, et
al., Proteins 2004, 55, 792–804.
[14] P. J. Kropp, N. J. Pienta, J. Org. Chem. 1983, 48, 2084–2090.
[6] T. Kinoshita, H. Miyake, T. Fujii, S. Takakura, T. Goto,
[15] G. Guanti, L. Banfi, R. Riva, Tetrahedron 1994, 50, 11945–
Acta Cryst. 2002, D58, 622–626.
11966.
[7] A. Podjarny, R. E. Cachau, T. Schneider, M. Van Zandt, A.
[16] W. Wasikiewicz, G. Rokicki, J. Kielkiewicz, E. F. Paulus, V.
Joachimiak, Cell. Mol. Life Sci. 2004, 61, 763–773.
Bohmer, Monatsh. Chem. 1997, 128, 863–879.
[8] A. Urzhumtsev, F. Tete-Favier, A. Mitschler, J. Barbanton,
[17] E. Mannekens, D. Tourwꢁ, W. D. Lubell, Synthesis 2000, 9,
et al., Structure (London) 1997, 5, 601–612.
1214–1216.
[9] D. K. Wilson, I. Tarle, J. M. Petrash, F. A. Quiocho, Proc.
Natl. Acad. Sci. USA 1993, 90, 9847–9851.
[18] M. Kuchar, B. Brunova, Z. Roubal, J. Schlanger, O. Neme-
cek, Collect. Czech. Chem. Commun. 1980, 45, 1401–1409.
[10] D. Rakowitz, B. Hennig, M. Nagano, S. Steger, et al., Arch.
Pharm. Chem. Life Sci. 2005, 338, 411–418.
[19] A. Nakazato, K. Ohta, Y. Sekiguchi, S. Okuyama, et al., J.
Med. Chem. 1999, 42, 1076–1087.
[11] D. Rakowitz, P. Muigg, N. Schrꢀder, B. Matuszczak, Arch.
Pharm. Chem. Life Sci. 2005, 338, 419–426.
[20] L. Costantino, G. Rastelli, K. Vescovini, G. Cignarella, et
al., J. Med. Chem. 1996, 39, 4396–4405.
[12] D. Rakowitz, A. Gmeiner, N. Schrꢀder, B. Matuszczak,
[21] T.-C. Chou, M. P. Hayball, 1996 CalcuSyn software version
Eur. J. Pharm. Sci. 2006, 27, 188–193.
1.1.1., Biosoft, Cambridge, UK.
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com