On the synthesis of bioisosters of O-benzothiazolyloxybenzoic acids and evaluation as aldose reductase inhibitors

Article abstract of DOI:10.1002/ardp.200500119

In continuation of our attempts to develop novel aldose reductase inhibitors (ARIs), a number of compounds characterized by bioisosteric replacement of pharmacophors were prepared. On the one hand, the acidic function was formally replaced by an oxime or

Full text of DOI:10.1002/ardp.200500119

Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
DOI 10.1002/ardp.200500119
419
On the Synthesis of Bioisosters of O-Benzothiazolyl-
oxybenzoic Acids and Evaluation as Aldose
Reductase Inhibitors
Dietmar Rakowitz, Patric Muigg, Nicole Schröder, Barbara Matuszczak
Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
In continuation of our attempts to develop novel aldose reductase inhibitors (ARIs), a number of
compounds characterized by bioisosteric replacement of pharmacophors were prepared. On the one
hand, the acidic function was formally replaced by an oxime or a nitro group and on the other hand
the lipophilic substituent was modified. The results of the biological evaluation of these derivatives
enabled us to gain insight into structural features critical for the aldose reductase inhibition.
Keywords: Aldose reductase inhibitors; Enzyme inhibitors; Bioisosteric replacement; Diabetic complications
Received: April 12, 2005; Accepted: May 27, 2005
Introduction
restat, see Figure 1). The X-ray structure of aldose reductase
in complex with various inhibitors has indicated the pres-
ence of a hydrophobic pocket (’specificity pocket’) in the
target enzyme particularly suited for the above mentioned
substituents [4-8]. Furthermore, the latter subunit was
found to be effective for selectivity (i.e. differentiation be-
tween ALR 2 and the closely related enzyme aldehyde re-
ductase) [1].
Aldose reductase (EC 1.1.1.21, ALR 2) is a member of the
NADPH-dependent aldo-keto reductase family which re-
presents a super family of monomeric oxidoreductases.
ALR 2 is the first and rate-limiting enzyme in the polyol
pathway and catalyzes the reduction of glucose to sorbitol
with the associated oxidation of NADPH to NADPϩ. A
number of studies have suggested a correlation between the
increased polyol pathway activity and the occurrence of
chronic diabetic complications. Inhibiting aldose reductase
and thus preventing the entry of glucose in the polyol path-
way can decrease the damaging effects of late-onset diabetic
complications such as neuropathy, nephropathy, retinopa-
thy, and cataracts [1].
In several clinical studies the effects of aldose reductase in-
hibitors (ARIs), most notably Sorbinil, Tolrestat, Zopolres-
tat, and Zenarestat were demonstrated. However, these in-
hibitors were withdrawn from clinical trials due to lack of
high efficacy or toxicity. To date, the only drug launched on
the market is Epalrestat [2]. Another drug, AS-3201, has
recently entered phase III trials to study safety and efficacy
in the treatment of diabetic sensorimotor polyneuropathy
[3].
ARIs primarily contain either a carboxylic acid or an ionis-
able hydantoin group suggesting that both can interact in a
similar manner with the cationic site of the enzyme. More-
over, the potent inhibitors are characterized by a 5-trifluoro-
methylbenzothiazol-2-yl (e.g. Zopolrestat) or a 4-bromo-2-
fluorobenzyl residue (e.g. AS-3201, Minalrestat, and Zena-
Correspondence: Barbara Matuszczak, Leopold-Franzens-Uni-
versität, Institute of Pharmacy, Innrain 52a, Innsbruck A-6020,
Austria. Phone: ϩ43 512 507-5262, Fax: ϩ43 512 507-2940, e-mail:
barbara.matuszczak@uibk.ac.at
Figure 1. Aldose reductase inhibitors.
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

420
Matuszczak et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
Results and discussion
The target oximes 2a/b were prepared starting from the ap-
propriate hydroxybenzaldehyde by heteroarylation followed
by treatment with hydroxylamine hydrochloride in the pres-
ence of sodium acetate (Scheme 1). According to TLC and
1H-NMR spectroscopy, in both cases only one product was
isolated which could be determined as the E-isomer by
means of NOE difference spectroscopy. Inhibitory activities
of these compounds were evaluated in a spectrometric assay
with ,-glyceraldehyde as the substrate and NADPH as
the cofactor.
Figure 2. General structure of compounds of type I.
Recently, we have reported the synthesis and aldose-re-
ductase inhibition of a variety of benzothiazolyloxy substi-
tuted benzoic acid derivatives (i.e. compounds of type I with
n ϭ 0, see Figure 2). In this series, we have found that an
acidic moiety is necessary for enzyme inhibition. However,
no significant influence could be observed concerning the
position of the benzothiazolyloxy moiety at the benzoic acid
core. Furthermore, neither an additional substituent in the
benzene ring (e.g. hydroxy, methoxy, or carboxylic acid) nor
in the benzothiazolyl ring (e.g. 5-trifluoromethyl) showed
any effect [9].
According to the results obtained (Table 1), compounds
2a/b can be considered as aldose reductase inhibitors
(IC50 ϭ 44.9 µM and 38% at 50 µM, respectively). In con-
trast to the findings for the substituted benzoic acid deriva-
tives [9], in this class the substitution pattern possess an
influence on the biological activity. Moreover, considering
the bioisosteric potential, the results reveal that formal re-
placement of the carboxylic acid group by an oxime func-
tion potentiates the aldose reductase inhibition from 36%
at 117 µM for 3-[(5Ј-trifluoromethylbenzothiazol-2Ј-yl)-
oxy]benzoic acid 9 [9] to an IC50 value of 44.9 µM for 2a.
Whereas it is well demonstrated that an acidic moiety is
essential for interaction of the inhibitor with the aldose re-
ductase, these results surprisingly demonstrate that there is
no correlation between the enzyme inhibition and the
strength of acidity. Thus, we assume that the enhancement
of the biological activity results from steric effects. This ex-
planation is supported by results obtained from compounds
of type I with n > 0 and R3 ϭ H which will be presented in
a subsequent paper.
In the course of our ongoing studies devoted to the develop-
ment of novel aldose reductase inhibitors, we now focused
our attention on derivatives characterized by bioisosteric re-
placement of the carboxylic acid function by an oxime
group. In order to investigate this structural modification
on enzyme inhibition, only selected examples were prepared
since in the series of benzoic acid derivatives the position
of the benzothiazolyloxy moiety exhibited no influence on
biological activity.
Scheme 1. Synthesis of the target compounds.
(i): 1) K2CO3 in dry DMF, 2) 2-chloro-5-trifluoromethylbenzothiazole, rt. or: 1) K2CO3 in dry DMF, 2) (substituted) 4-bromobenzyl-
bromide, rt.; (ii): NH2OH·HCl, CH3COONa in dry EtOH, rt.; (iii): 1) 2N NaOH in EtOH, rt.; 2) HCl.
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Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
Table 1. Biological data.
Bioisostere of O-Benzothiazolyloxybenzoic acids as ARIs
421
Compound
R
ORЈ
Position
RЉ
Enzyme inhibition at concentration
or IC50 value (95% CL)
2a
2b
CH(ϭNOH)
CH(ϭNOH)
3
4
H
H
44.9 µM (33.5Ϫ60.2)
38% at 50 µM
3
NO2
3
2
3
4
3
H
H
26% at 50 µM
0% at 100 µM
7% at 100 µM
0% at 100 µM
30% at 100 µM
5a
5b
5c
5d
COOH
COOH
COOH
COOH
H
3-OCH3
5-COOH
5e
5f
COOH
COOH
2
3
4
3
3
4
H
H
0% at 100 µM
3% at 100 µM
5g
5h
7a
7b
COOH
3-OCH3
5-COOH
H
26% at 100 µM
26% at 100 µM
40% at 50 µM
COOH
CH(ϭNOH)
CH(ϭNOH)
H
46% at 50 µM
8
NO2
3
3
H
H
31.9 µM (28.8Ϫ35.2)
9 [9]
COOH
36% at 117 µM
Sorbinil (used as the reference)
1.2 µM (0.8Ϫ1.6)
In order to get further insight into structural features criti-
cal for aldose reductase inhibition, compound 3 became an
object of interest, too. This target compound is charac-
terized by bioisosteric replacement of the carboxylate anion
of the deprotonated 9 by a nitro function. Despite the lack
of an acidic function, such a compound should interact di-
rectly with the cationic site of the enzyme. This consider-
ation may be supported by molecular docking experiments
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422
Matuszczak et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
recently published by Rastelli et al. [10]. The desired 3 was
prepared by reaction of 3-nitrophenol with 2-chloro-5-tri-
fluoromethylbenzothiazole in the presence of potassium
carbonate in dry N,N-dimethylformamide (Scheme 1).
Quantitatively, this structural modification does not result
in a substantial enhancement of enzyme inhibition (26% at
50 µM versus 36% at 117 µM for 9).
increase in activity (26% at 50 µM versus IC50 value of 31.9
µM for 8).
Conclusion
In continuation of our attempts to develop aldose reductase
inhibitors, a number of bioisosters of recently reported
benzothiazolyloxy-substituted benzoic acids were synthe-
sized and tested for their biological activity. The findings
described above allowed us to gain knowledge of structural
features critical for the enzyme inhibition. Based on these
results, we intend to expand the modifications within this
class of compounds.
It is well known from the literature that introduction of a
(substituted) benzothiazolyl or a (substituted) benzyl moi-
ety leads to increased aldose reductase inhibition [1, 2]. Be-
sides, we became interested in formal replacement of the
lipophilic residue. This structural modification was planed
for the oximes 2a/b, the nitro analogue 3, and for some of
the recently published benzoic acid derivatives [9].
The derivatives with substituted benzyloxy subunit became
accessible by reaction of the appropriate phenols (methyl
hydroxybenzoates, hydroxybenzaldehydes, or 3-nitrophenol,
respectively) with 4-bromobenzylbromide or 4-bromo-2-
fluorobenzylbromide in the presence of base. Subsequently,
alkaline hydrolysis of the benzoic acid derivatives 4aϪh or
treatment of the aldehydes 6a/b with hydroxylamine led to
our desired compounds 5aϪh and 7a/b, respectively
(Scheme 1). The structures of these novel compounds were
confirmed by elemental analyses, IR, and NMR spec-
troscopy as well as MS data.
Experimental
Chemistry
Melting points were determined with a Kofler hot-stage microscope
(Reichert, Vienna; Austria) and are uncorrected. Infrared spectra
(KBr pellets) were recorded on a Mattson Galaxy Series FTIR 3000
spectrophotometer (Mattson, Instruments, Inc., Madison, WI,
USA). Mass spectra were obtained on a Finnigan MAT SSQ 7000
spectrometer (EI, 70 eV or CI, 200 eV, reactant gas: methane)
(Thermo Electron. Corporation, Bremen, Germany). All NMR
spectra were recorded in DMSO-d6 or CDCl3 solution in 5 mm
tubes at 30°C on a Varian Gemini 200 spectrometer (199.98 MHz
for 1H; 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 Polygram SIL G/UV254 (Macherey-Nagel, Düren,
Germany) plastic-backed plates (0.25 mm layer thickness). The
yields given are not optimized. Light petroleum refers to the frac-
tion of bp. 40Ϫ60°C. Elemental analyses were performed by Mag.
J. Theiner, ‘Mikroanalytisches Laboratorium’, Faculty of Chemistry,
University of Vienna, Austria.
In the class of benzoic acids, the formal exchange of the
benzothiazolyl substituent turned out not to be beneficial.
Almost no change of enzyme inhibition was found for the
derivatives with isophthalic acid subunit (5d and 5h) as well
as for 5g, however, (nearly) complete loss of the aldose re-
ductase inhibitory activity (at 100 µM) resulted in all other
cases. Moreover, in the case of the oximes, this modification
was found to be detrimental (3-substituted) or did not lead
to a significant change in activity (4-substituted). On the
other hand, starting from 3-(5-trifluoromethylbenzothiazol-
2-yloxy)nitrobenzene 3 formal replacement of the heteroaryl
subunit by 4-bromo-2-fluorobenzyl resulted in a remarkable
2-Chloro-5-trifluoromethylbenzothiazol was readily available by re-
action of 2-chloro-5-trifluoromethylaniline with carbon disulfide in
the presence of sodium hydride to give 5-trifluoromethyl-2-mercap-
tobenzothiazol [11], which was subsequently chlorinated with
sulfuryl chloride in analogy to literature [12]. 4-Bromo-2-fluoro-
benzylbromide was synthesized by radical bromination of 4-bromo-
Table 2. General procedure data for O-substitution (compounds 1, 3, 4, 6, and 8).
R
RЈ
Equivalents
hydroxy derivative
batch size
reaction condition
RЈ-X
base
CHO
NO2
5-CF3-benzothiazol-2-yl
4-Br-2-F-benzyl
8.19 mmol
2.05 mmol
50°C
1.1
1.1
2.0
1.0
2.2
rt.
5-CF3-benzothiazol-2-yl
4-Br-2-F-benzyl
1.80 mmol
0.72 mmol
rt.
rt.
1.0
1.0
2.2
4.0
COOCH3
4-Br-benzyl
4-Br-2-F-benzyl
4.00 mmol
1.87 mmol
rt.
rt.
rt.; room temperature
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Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
Table 3. Data of compounds 1Ϫ8.
Bioisostere of O-Benzothiazolyloxybenzoic acids as ARIs
423
Compound
1a
R
RЈ† Position RЉ
of ORЈ
Solvent‡
Yield
Formula§
Spectroscopic Data$
MS
Mp.
CHO
A
3
H
DIPE
62%
92Ϫ94°C
C15H8F3NO2S
IR 1697 cmϪ1 (CϭO)
(m/z) 323 (Mϩ)
1H-NMR (CDCl3) δ 10.06 (s, 1H, CHO),
8.00Ϫ7.99 (m, 1H, ArH), 7.95Ϫ7.93 (m,
1H, ArH), 7.88Ϫ7.81 (m, 2H, ArH),
7.71Ϫ7.65 (m, 2H, ArH), 7.58Ϫ7.53 (m,
1H, ArH)
1b
2a
CHO
A
A
4
3
H
H
DIPE
56%
93Ϫ95°C
C15H8F3NO2S
IR 1695 cmϪ1 (CϭO)
(m/z) 323 (Mϩ)
1H-NMR (CDCl3) δ 10.05 (s, 1H, CHO),
8.05Ϫ7.98 (m, 3H, ArH), 7.85 (d, J ϭ 8.4
Hz, 1H, ArH), 7.63Ϫ7.55 (m, 3H, ArH)
CH(ϭNOH)
Et2O/LP
24%
153Ϫ155°C
C15H9F3N2O2S
IR 3178 cmϪ1 (OH), 1616 cmϪ1 (CϭN)
(m/z) 339 (Mϩ1ϩ) 1H-NMR (CDCl3) δ 8.15 (s, 1H, CH),
8.00 (s, 1H, OH), 7.80 (d, J ϭ 8.4 Hz,
1H, ArH), 7.65 (“d”, J ϭ 1.6 Hz, 1H,
ArH), 7.55Ϫ7.37 (m, 5H, ArH)
2b
CH(ϭNOH)
A
A
4
3
H
H
DIPE
41%
C15H9F3N2O2S·
0.1 DIPE
IR 3266 cmϪ1 (OH), 1614 cmϪ1 (CϭN)
1H-NMR (CDCl3) δ 8.16 (s, 1H, CH),
142Ϫ144°C (m/z) 339 (Mϩ1ϩ) 8.00 (br s, 1H, OH), 7.81 (d, J ϭ 8.4 Hz,
1H, ArH), 7.73Ϫ7.66 (m, 2H, ArH), 7.54
(dd, J ϭ 1.8 Hz, J ϭ 8.4 Hz, 1H, ArH),
7.45Ϫ7.38 (m, 2H, ArH), 7.36 (s, 1H,
ArH)
3
NO2
DIPE/LP
47%
142Ϫ144°C
C14H7F3N2O3S
IR 1523 cmϪ1 (C-NO2)
(m/z) 340 (Mϩ)
1H-NMR (CDCl3) δ 8.35Ϫ8.33 (m, 1H,
ArH), 8.24Ϫ8.18 (m, 1H, ArH),
8.01Ϫ7.99 (m, 1H, ArH), 7.86 (d, J ϭ 8.4
Hz, 1H, ArH), 7.82Ϫ7.76 (m, 1H, ArH),
7.71Ϫ7.63 (m, 1H, ArH), 7.58 (dd, J ϭ
1.8 Hz, J ϭ 8.4 Hz, 1H, ArH)
4a
4b
COOCH3
COOCH3
B
B
2
3
H
H
DIPE
59%
70Ϫ71°C
C15H13BrO3
IR 1718 cmϪ1 (CϭO)
(m/z) 320 (Mϩ)
1H-NMR (CDCl3) δ 7.83 (dd, J ϭ 1.8 Hz,
J ϭ 7.6 Hz, 1H, ArH), 7.54-7.36 (m, 5H,
ArH), 7.05Ϫ6.96 (m, 2H, ArH), 5.13 (s,
2H, CH2), 3.90 (s, 3H, OCH3)
DIPE
95%
75Ϫ78°C
C15H13BrO3
IR 1716 cmϪ1 (CϭO)
(m/z) 320 (Mϩ)
1H-NMR (CDCl3) δ 7.68Ϫ7.62 (m, 2H,
ArH), 7.55Ϫ7.49 (m, 2H, ArH),
7.39Ϫ7.29 (m, 3H, ArH), 7.17Ϫ7.11 (m,
1H, ArH), 5.06 (s, 2H, CH2), 3.91 (s, 3H,
OCH3)
4c
4d
COOCH3
COOCH3
B
B
4
3
3-OCH3
DIPE/EA C16H15BrO4
95%
113Ϫ115°C
IR 1700 cmϪ1 (CϭO)
(m/z) 350 (Mϩ)
1H-NMR (CDCl3) δ 7.61 (dd, J ϭ 2.0 Hz,
J ϭ 8.3 Hz, 1H, ArH), 7.57 (d, J ϭ 2.0
Hz, 1H, ArH), 7.52Ϫ7.44 (m, 2H, ArH),
7.33Ϫ7.26 (m, 2H, ArH), 6.86 (d, J ϭ 8.3
Hz, 1H, ArH), 5.15 (s, 2H, CH2), 3.93 (s,
3H, OCH3), 3.90 (s, 3H, OCH3)
5-COOCH3 DIPE/EA C17H15BrO5
IR 1725 cmϪ1 (CϭO)
88%
124Ϫ128°C
(m/z) 378 (Mϩ)
1H-NMR (CDCl3) δ 8.31Ϫ8.29 (m, 1H,
ArH), 7.81 (d, J ϭ 1.6 Hz, 2H, ArH),
7.55Ϫ7.51 (m, 2H, ArH), 7.34Ϫ7.30 (m,
2H, ArH), 5.10 (s, 2H, CH2), 3.94 (s, 6H,
2 ϫ OCH3)
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424
Matuszczak et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
Table 3. (continued).
Compound
4e
R
RЈ† Position RЉ
of ORЈ
Solvent‡
Yield
Formula§
Spectroscopic Data$
MS
Mp.
COOCH3
C
C
C
2
3
4
H
DIPE
95%
72Ϫ74°C
C15H12BrFO3
IR 1720 cmϪ1 (CϭO)
(m/z) 338 (Mϩ) 1H-NMR (CDCl3) δ 7.84 (dd, J ϭ 1.7 Hz,
J ϭ 7.9 Hz, 1H, ArH), 7.66Ϫ7.24 (m, 4H,
ArH), 7.07Ϫ7.00 (m, 2H, ArH), 5.18 (s,
2H, CH2), 3.90 (s, 3H, OCH3)
4f
COOCH3
COOCH3
H
DIPE
99%
102Ϫ104°C
C15H12BrFO3
IR 1716 cmϪ1 (CϭO)
(m/z) 338 (Mϩ) 1H-NMR (CDCl3) δ 7.69Ϫ7.64 (m, 2H,
ArH), 7.44Ϫ7.26 (m, 4H, ArH),
7.18Ϫ7.11 (m, 1H, ArH), 5.12 (s, 2H,
CH2), 3.92 (s, 3H, OCH3)
4g
3-OCH3
DIPE
96%
108Ϫ115°C
C16H14BrFO4
IR 1716 cmϪ1 (CϭO)
(m/z) 368 (Mϩ) 1H-NMR (CDCl3) δ 7.63 (dd, J ϭ 1.7 Hz,
J ϭ 8.4 Hz, 1H, ArH), 7.57 (d, J ϭ 1.7
Hz, 1H, ArH), 7.44Ϫ7.26 (m, 3H, ArH),
6.90 (d, J ϭ 8.4 Hz, 1H, ArH), 5.20 (s,
2H, CH2), 3.93 (s, 3H, OCH3), 3.89 (s,
3H, OCH3)
4h
5a
COOCH3
COOH
C
B
3
2
5-COOCH3 DIPE/EA
95%
C17H14BrFO5
IR 1725 cmϪ1 (CϭO)
(m/z) 396 (Mϩ) 1H-NMR (CDCl3) δ 8.32Ϫ8.31 (m, 1H,
ArH), 7.83 (d, J ϭ 1.4 Hz, 2H, ArH),
7.44Ϫ7.28 (m, 3H, ArH), 5.15 (s, 2H,
CH2), 3.94 (s, 6H, 2 ϫ OCH3)
125Ϫ129°C
H
DIPE
94%
116Ϫ117°C
C14H11BrO3
IR 1700 cmϪ1 (CϭO)
(m/z) 306 (Mϩ) 1H-NMR (DMSO-d6) δ 7.64 (dd, J ϭ 1.8
Hz, J ϭ 7.6 Hz, 1H, ArH), 7.60Ϫ7.55 (m,
2H, ArH), 7.51Ϫ7.43 (m, 3H, ArH), 7.16
(d, J ϭ 7.6 Hz, 1H, ArH), 7.04Ϫ6.96 (m,
1H, ArH), 5.17 (s, 2H, CH2)
5b
5c
5d
COOH
COOH
COOH
B
B
B
3
4
3
H
DIPE/EA
96%
182Ϫ183°C
C14H11BrO3
IR 1685 cmϪ1 (CϭO)
(m/z) 306 (Mϩ) 1H-NMR (DMSO-d6) δ 7.61Ϫ7.37 (m,
7H, ArH), 7.27Ϫ7.22 (m, 1H, ArH), 5.14
(s, 2H, CH2)
3-OCH3
5-COOH
THF/EA
94%
224Ϫ225°C
C15H13BrO4
IR 1684 cmϪ1 (CϭO)
(m/z) 336 (Mϩ) 1H-NMR (DMSO-d6) δ 7.61Ϫ7.38 (m,
6H, ArH), 7.10 (d, J ϭ 8.4 Hz, 1H, ArH),
5.14 (s, 2H, CH2), 3.80 (s, 3H, OCH3)
THF/EA
97%
114Ϫ116°C
C15H11BrO5
IR 1685 cmϪ1 (CϭO)
(m/z) 350 (Mϩ) 1H-NMR (DMSO-d6) δ 8.09Ϫ8.07 (m,
1H, ArH), 7.72 (d, J ϭ 1.2 Hz, 2H, ArH),
7.61Ϫ7.57 (m, 2H, ArH), 7.45Ϫ7.41 (m,
2H, ArH), 5.22 (s, 2H, CH2)
5e
COOH
C
2
H
DIPE
89%
135Ϫ137°C
C14H10BrFO3
IR 1702 cmϪ1 (CϭO)
(m/z) 324 (Mϩ) 1H-NMR (DMSO-d6) δ 7.68Ϫ7.43 (m,
5H, ArH), 7.21 (d, J ϭ 8.0 Hz, 1H, ArH),
7.07Ϫ7.00 (m, 1H, ArH), 5.19 (s, 2H,
CH2)
5f
COOH
COOH
C
C
3
4
H
DIPE
90%
155Ϫ157°C
C14H10BrFO3
IR 1685 cmϪ1 (CϭO)
(m/z) 324 (Mϩ) 1H-NMR (DMSO-d6) δ 7.63Ϫ7.38 (m,
6H, ArH), 7.29Ϫ7.23 (m, 1H, ArH), 5.17
(s, 2H, CH2)
5g
3-OCH3
DIPE/EA
98%
194Ϫ196°C
C15H12BrFO4
IR 1685 cmϪ1 (CϭO)
(m/z) 354 (Mϩ) 1H-NMR (DMSO-d6) δ 7.63Ϫ7.44 (m,
5H, ArH), 7.16 (d, J ϭ 8.4 Hz, 1H, ArH),
5.16 (s, 2H, CH2), 3.79 (s, 3H, OCH3)
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Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
Table 3. (continued).
Bioisostere of O-Benzothiazolyloxybenzoic acids as ARIs
425
Compound
5h
R
RЈ† Position RЉ
of ORЈ
Solvent‡
Yield
Formula§
Spectroscopic Data$
MS
Mp.
COOH
C
3
5-COOH
DIPE/EA
98%
292Ϫ300°C
C15H10BrFO5
IR 1698 cmϪ1 (CϭO)
(m/z) 368 (Mϩ) 1H-NMR (DMSO-d6) δ 8.11Ϫ8.09 (m,
1H, ArH), 7.73 (d, J ϭ 1.2 Hz, 2H, ArH),
7.64Ϫ7.44 (m, 3H, ArH), 5.25 (s, 2H,
CH2)
6a
6b
CHO
CHO
C
C
3
4
H
H
DIPE
43%
72Ϫ74°C
C14H10BrFO2
IR 1702 cmϪ1 (CϭO)
(m/z) 308 (Mϩ) 1H-NMR (CDCl3) δ 9.99 (s, 1H, CHO),
7.53Ϫ7.21 (m, 7H, ArH), 5.14 (s, 2H,
CH2)
DIPE
73Ϫ77°C
C14H10BrFO2
IR 1689 cmϪ1 (CϭO)
(m/z) 308 (Mϩ) 1H-NMR (CDCl3) δ 9.90 (s, 1H, CHO),
7.89Ϫ7.82 (m, 2H, ArH), 7.42Ϫ7.29 (m,
3H, ArH), 7.11Ϫ7.04 (m, 2H, ArH), 5.16
(s, 2H, CH2)
7a
7b
CH(ϭNOH)
CH(ϭNOH)
NO2
C
C
C
3
4
3
H
H
H
DIPE/LP
45%
C14H11BrFNO2 IR 3201 cmϪ1 (OH), 1604 cmϪ1 (CϭN)
(m/z) 324
1H-NMR (CDCl3) δ 8.10 (s, 1H, CH),
7.44Ϫ7.22 (m, 6H, ArH, OH), 7.16 (d,
J ϭ 7.8 Hz, 1H, ArH), 7.02Ϫ6.96 (m, 1H,
ArH), 5.10 (s, 2H, CH2)
107Ϫ110°C (Mϩ1ϩ)
DIPE/LP
36%
93Ϫ95°C
C14H11BrFNO2 IR 3251 cmϪ1 (OH), 1604 cmϪ1 (CϭN)
(m/z) 324
1H-NMR (CDCl3) δ 8.08 (s, 1H, CH),
7.56Ϫ7.49 (m, 2H, ArH), 7.42Ϫ7.26 (m,
4H, ArH, OH), 7.00Ϫ6.93 (m, 2H, ArH),
5.10 (s, 2H, CH2)
(Mϩ1ϩ)
8
DIPE
21%
69Ϫ70°C
C13H9BrFNO3
IR 1533 cmϪ1 (C-NO2)
(m/z) 325 (Mϩ) 1H-NMR (CDCl3) δ 7.90Ϫ7.82 (m, 2H,
ArH), 7.50Ϫ7.30 (m, 5H, ArH), 5.15 (s,
2H, CH2)
†
The following abbreviations are used: A: 5-trifluoromethylbenzothiazol-2-yl; B: 4-bromobenzyl; C: 4-bromo-2-fluorobenzyl.
DIPE: diisopropyl ether; LP: light petroleum; EA: ethyl acetate; THF: tetrahydrofurane.
All compounds tested and the carboxylic esters of 4 were analyzed for C, H, N. Analytical results obtained for these elements were wi-
thin 0.4% of the theoretical values.
‡
§
$
In the NMR spectra of compounds 5 (in DMSO-d6) no signal could be detected for the carboxylic acid proton(s).
2-fluorotoluene with N-bromosuccinimide and a catalytic amount
of azobisisobutyronitrile in CCl4 as described in the literature [13].
and evaporated to dryness. The residue thus obtained was purified
by recrystallization (Table 3).
General procedure for the O-substitution to prepare compounds of
General procedure for the synthesis of the oximes 2a/b and 7a/b
type 1, 3, 4, 6, and 8
A solution of one equivalent of the appropriate aldehyde derivative
(1a/b: 3.71 mmol, 6a/b: 0.81 mmol) in dry ethanol was treated with
three equivalents of hydroxylamine hydrochloride and four equiva-
lents of sodium acetate and the reaction mixture was stirred at room
temperature until TLC indicated no further conversion. Then, the
solvent was removed in vacuo and the residue was treated with a
small amount of water. After neutralisation, the aqueous phase was
extracted exhaustively with ethyl acetate and the organic layer was
then washed with water and brine, dried over anhydrous sodium
sulfate, and evaporated to dryness under reduced pressure. The
resulting product was purified by recrystallization (Table 3).
Powdered potassium carbonate was added to a solution of the
hydroxy derivative in dry N,N-dimethylformamide under an atmos-
phere of nitrogen. After stirring for 30 minutes at room temperature,
the appropriate ar(alk)yl halide (2-chloro-5-trifluoromethylbenzo-
thiazole, 4-bromobenzylbromide, or 4-bromo-2-fluorobenzylbro-
mide) was added and stirring was continued until TLC indicated no
further conversion (further information, Table 2). Then, the mixture
was poured into cold 2N HCl and the product was extracted
exhaustively with diethyl ether. The organic layer was washed with
2N NaOH, water, and brine, dried over anhydrous sodium sulfate
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

426
Matuszczak et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 419−426
General procedure for the synthesis of the carboxylic acids of type 5
Acknowledgments
A solution of the appropriate ester 4 (0.76Ϫ1.56 mmol) in ethanol
was treated with 2N NaOH (1.1 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 reaction mixture was extracted with ethyl acetate,
the organic layer washed with water and brine, dried over anhydrous
sodium sulfate, and evaporated to dryness under reduced pressure.
The crystals thus obtained were purified by recrystallization
(Table 3).
The authors wish to acknowledge ‘Metzgerei Otto Steiner’,
Stans/Tirol (Austria) for providing calf lenses.
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 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim