Synthesis and enantioselective lipase-catalyzed kinetic resolution of methyl 6-(methoxycarbonyl-methyl)sulfanyl-1,4-dihydropyridine-3-carboxylates

Article abstract of DOI:10.1007/s10593-013-1263-8

A series of methyl 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridine-3- carboxylates as more lipophilic derivatives of biologically active 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylic acid esters has been prepared by alkylation of 6-thioxo-1,4-dihydropyridines with methyl bromoacetate. The kinetic resolution catalyzed by Candida antarctica lipase B (Novozym 435 ) has been investigated; the enantiomeric excess of the target products reached 70%. The experiments revealed that the 6- (methoxycarbonylmethyl)sulfanyl group is an essentially new activating group, which, being removed by five bonds from the chiral center, undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of racemic 1,4-dihydropyridines.

Full text of DOI:10.1007/s10593-013-1263-8

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
SYNTHESIS AND ENANTIOSELECTIVE LIPASE-CATALYZED
KINETIC RESOLUTION OF METHYL 6-(METHOXYCARBONYL-
METHYL)SULFANYL-1,4-DIHYDROPYRIDINE-3-CARBOXYLATES
1
1
1
1
Z. Andzans1,2 , A. Krauze , I. Adlere , L. Krasnova , and G. Duburs
*
A series of methyl 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridine-3-carboxylates as more
lipophilic derivatives of biologically active 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylic acid
esters has been prepared by alkylation of 6-thioxo-1,4-dihydropyridines with methyl bromoacetate. The
kinetic resolution catalyzed by Candida antarctica lipase B (Novozym 435®) has been investigated; the
enantiomeric excess of the target products reached 70%. The experiments revealed that the
6-(methoxycarbonylmethyl)sulfanyl group is an essentially new activating group, which, being removed
by five bonds from the chiral center, undergoes easy enzymatic hydrolysis and could be used for kinetic
resolution of racemic 1,4-dihydropyridines.
Keywords: dihydropyridines, Candida antarctica lipase B, enzymatic kinetic resolution.
1,4-Dihydropyridines (1,4-DHPs) are known as calcium channel effectors and antagonists. Many
cardiovascular drugs on their basis are currently in use in clinics or are still in different stages of development
[1-4]. The pharmacology of 1,4-DHPs is at the eve of a novel boom: academic interest is growing towards
pharmacological activities that are not related (or are only partially related) to their L-type calcium channel
antagonist properties: neurotropic (antiamnestic, anticonvulsant, neuroregulatory) [5], membrane protecting [6-
8], radioprotecting [9], analgesic [10], antidiabetic [11], antitumor [12], antitubercular [13], and anti-
inflammatory [14]; they are also used in gene transfection [15] and as uroselective agents for treatment of
benign prostatic hyperplasia [16]. Some 1,4-DHPs have also shown the ability to modulate N-type calcium
channels, and have been studied as anticonvulsants [17], stress protective agents [18], and cardiodepressants [19].
6-Alkylsulfanyl-substitued 1,4-DHPs display cardiovascular [20-24], hepatoprotective [25], antioxidant
[26], and antiradical [27] activities; however, these compounds are still insufficiently studied.
The enantiomers of chiral 1,4-DHPs usually differ in their biological activities and can even have an
opposite action profile [28-30]. Chemoenzymatic methods for preparation of optically pure drugs have a number
of advantages: they are simple, direct, efficient, mild, and cheap in case of repeated use of the enzyme.
Incorporation of an enzymatically labile functional group, which allows kinetic resolution of monocyclic
1,4-DHPs, has been used as a conventional technique for the last decade [30-32].
_______
*To whom correspondence should be addressed, e-mail: andzans@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
2The University of Latvia, 19 Raina Blvd., Riga LV-1586, Latvia; e-mail: zigmars.andzans@inbox.lv.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 454-460, March, 2013. Original
article submitted October 30, 2012.
0009-3122/13/4903-0421©2013 Springer Science+Business Media New York
421

The objective of this work was the preparation of enantiopure 1,4-DHPs containing the lipophilic
(methoxycarbonylmethyl)sulfanyl group at position 6. We expected that the enzymatic hydrolysis of this group
could promote kinetic resolution of the target 1,4-DHPs. The starting 4-aryl-5-cyano-3-methoxycarbonyl-
2-methyl-1,4-dihydropyridine-6-thiones 1a-c were prepared by a one-pot three-component condensation of the
methyl acetoacetate, aromatic aldehyde, and 2-cyanothioacetamide according to the previously described synthetic
protocol [33, 34].
Ar
O
Ar
O
H
O
CN
S
CN
S
Piperidine
MeO
Me
+
MeO
EtOH
room temp.,
0.5 h
N
H
1a–c
O H2N
Me
OMe
OH
Piperidine,
EtOH, 80°C, 1 h
Piperidine,
DMSO, 70°C, 0.5 h
Br
Br
O
O
O
Ar
O
Ar
CN
S
CN
S
MeO
MeO
Me
OMe
OH
Me
N
H
2a–c
N
H
3a–c
O
O
1–3 a Ar = Ph; b Ar = 2-ClC6H4; c Ar = 2-F2HCOC6H4
Alkylation of thiones 1a-c bearing several nucleophilic reaction centers (C-5, S, N atoms) under mild
reaction conditions with methyl bromoacetate proceeds preferably at the sulfur atom, giving methyl 4-aryl-
5-cyano-6-(methoxycarbonylmethyl)sulfanyl-2-methyl-1,4-dihydropyridine-3-carboxylates 2a-c. Carboxylic
acids 3a-c as references compounds for the investigation of enzyme-catalyzed hydrolysis were prepared by
alkylation of thiones 1a-c with bromoacetic acid in the presence of piperidine.
Enzymatic screening of the substrates 2a-c was performed in water-saturated diisopropyl ether (DIPE),
water-saturated tert-butyl methyl ether, and phosphate buffer pH 7.5, modified (or not) with 15% MeCN at 20
to 50°C by using protease P6 (Aspergillus melleus), acylase 30,000 (Aspergillus sp.), Candida rugosa lipase
(CRL), and Candida antarctica lipase B (CAL-B, Novozym 435®). In the case of methyl 6-(methoxycarbonyl-
methyl)sulfanyl-1,4-dihydropyridine-3-carboxylates 2a-c, protease P6 and acylase 30,000 were inactive.
CRL-catalyzed hydrolysis of the (methoxycarbonylmethyl)sulfanyl group in phosphate buffer was rather slow,
but Novozym 435® showed significant hydrolytic activity both in water-saturated DIPE and in phosphate buffer.
The kinetic resolution of methyl 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydro-pyridine-
3-carboxylates 2a-c in the presence of Novozym 435® was investigated in greater detail. As we have found, the
concentration of substrate in water-saturated DIPE had to be less than 0.01%, otherwise precipitation would take
place. To increase the solubility of methyl 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridine-
3-carboxylates 2a-c, 1–3% of dichloromethane (DCM) was added to the reaction mixture. It increased the
reaction rate but decreased the enantioselectivity.
The formed acid 4a-c and the remaining ester 5a-c were separated by column chromatography. The
yields and the enantiomeric excess (ee) of esters 5a-c were determined by HPLC equipped with Whelk O1 and
Lux Cellulose-2 (Table 1). The enantiomeric excess values ranged from 10 to 70%, depending on the
substituent at position 4. The reaction time is longer and the enantioselectivity is better at room temperature than
at 45°C.
422

O
Ar
O
Ar
CN
S
CN
S
H2O
MeO
Me
MeO
2a–c
+
Enzyme
OH
OMe
N
H
Me
N
H
O
O
(–)-4a–c
(+)-5a–c
O
Ph
CN
S
CH2N2
MeO
(–)-4a
CH2Cl2, room temp.
OMe
O
Me
N
H
(–)-6a
4, 5 a Ar = Ph; b Ar = 2-ClC6H4; c Ar = 2-F2HCOC6H4
TABLE 1. Reaction Conditions and Yields of Enzymatic Hydrolysis*
Sub-
strate
DCM–DIPE
ratio, v/v
Yield, %
ee of compound 5,
T, °C
Time, h
%
Compound 4
Compound 5
1:57
1:33
1:100
1:16
1:16
1:16
1:57
1:33
1:100
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
45
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
46
47
45
46
48
44
45
45
47
49
46
46
46
47
45
48
45
46
53
70
10
43
51
10
49
67
8
2a
2b
2c
2a
2b
2c
2a
2b
2c
45
45
_______
*Isolated yields and enantiomeric excess values were measured after
column chromatography.
Since the enantiomeric excess of carboxylic acids 4a-c could not be determined by the given HPLC
methods, acid (-)-4a was methylated with diazomethane, and the enantiomeric excess was measured for the
corresponding methyl (-)-6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridine-3-carboxylate (-)-6a, which
appeared to be 25%. The absolute configurations of the obtained enantioenriched esters 5a-c and 6a are still
unknown because we have not succeeded in growing crystals for X-ray structural analysis.
In conclusion, new methyl 6-(methoxycarbonylmethyl)sulfanyl-1,4-dihydropyridine-3-carboxylates as
more lipophilic derivatives of biologically active methyl 6-methylsulfanyl-1,4-dihydropyridine-3-carboxylates
have been prepared by alkylation of 1,4-dihydropyridine-6-thiolates with methyl bromoacetate, and their kinetic
resolution catalyzed by Candida antarctica lipase B has been investigated. Our experiments allowed us to
characterize 6-(methoxycarbonylmethyl)sulfanyl group as an essentially new activating group, which, being
removed by five bonds from the chiral center, could be used for the kinetic resolution of racemic 1,4-DHPs. The
stereoselectivity of the immobilized Candida antarctica lipase B under the studied conditions (water-saturated
DIPE, 25–45°C, excess of substrate with regard to lipase) towards the methyl 6-(methoxy-carbonyl-
methyl)sulfanyl-1,4-dihydropyridine-3-carboxylates was moderate.
423

EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 580 B spectrometer in nujol. H NMR spectrum of
1
1
13
compound 1c was recorded on a Varian Mercury 200BB spectrometer (200 MHz), H and C NMR spectra of
the remaining compounds were recorded on a Varian 400-MR spectrometer (400 and 100 MHz, respectively).
DMSO-d6 was used as solvent for compounds 3b,c, and CDCl3 for the remaining compounds. HMDSO was
used as internal standard ( 0.055 ppm). Mass spectral data were determined on an Acquity UPLC system
(Waters) connected to a micrOTOF-Q mass spectrometer operating in the ESI positive or negative ion mode on
an Acquity UPLC BEH C18 column (1.7 m, 2.150 mm) using gradient elution with MeCN–HCOOH (0.1%)
in water. The enantiomeric excesses were analyzed by HPLC on a Lux Cellulose-2 phase column (4 m,
4.6150 mm), eluent 0.1% AcOH in 2-PrOH–hexane, 50:50, flow rate 1 ml/min, detection at 254 nm. Elemental
analyses were determined on an EA 1106 elemental analyzer (Carlo Erba Instruments). Melting points were
determined on an OptiMelt system (SRS Stanford Research Systems). Optical rotation values were measured
with a Rudolph Research Analytical autopol VI automatic polarimeter. Thin-layer chromatography was
performed on 2020 cm silica gel TLC-PET F254 foils (Fluka). All reagents were purchased from Aldrich,
Acros, Fluka, or Merck and used without further purification.
Preparation of compound 1a was described in [33], compound 1b in [34], compounds 2a and 3a in [35].
Methyl 5-cyano-4-(2-difluoromethoxyphenyl)-2-methyl-6-thioxo-1,4,5,6-tetrahydropyridine-3-carb-
oxylate (1c). A mixture of 2-(difluoromethoxy)benzaldehyde (0.69 g, 4.0 mmol), methyl acetoacetate (0.46 g,
4.0 mmol), and piperidine (0.04 ml, 0.4 mmol) in EtOH (20 ml) was stirred for 5 min at room temperature. Then
2-cyanothioacetamide (0.40 g, 4.0 mmol) and piperidine (0.40 ml, 4.0 mmol) were added, and the reaction
mixture was stirred for 30 min. The resulting reaction mixture was acidified with 3 N hydrochloric acid in
EtOH (2.4 ml). The precipitate was separated by filtration and washed with cold (-10°C) MeOH (5 ml) and
water (20 ml). Yield 0.94 g (67%). Yellow powder; mp 121-122°C. IR spectrum, , cm-1: 3309 (N–H), 2198
(CN), 1714 (C=O). 1H NMR spectrum, , ppm (J, Hz): 2.45 (1.5H, s) and 2.53 (1.5H, s, 2-CH3 (cis- and trans-));
3.59 (1.5H, s) and 3.61 (1.5H, s, COOCH3 (cis- and trans-)); 4.11 (0.5H, d, J = 7.4) and 4.80 (0.5H, d, J = 1.8, H-5
(cis- and trans-)); 4.17 (0.5H, d, J = 7.4) and 5.00 (0.5H, d, J = 7.4, Н-4 (cis- and trans-)); 6.58 (1H, t, J = 73.2,
OCHF2); 6.84-7.30 (4Н, m, H Ar); 8.81 (1H, br. s, NH). Found, %: C 54.40; H 4.11; N 7.87. C16H14F2N2O3S.
Calculated, %: C 54.54; H 4.00; N 7.95.
Methyl 4-(2-chlorophenyl)-5-cyano-6-(methoxycarbonylmethyl)sulfanyl-2-methyl-1,4-dihydropyridine-
3-carboxylate (2b). A mixture of thione 1b (0.32 g, 1.0 mmol) and piperidine (0.10 ml, 1.0 mmol) in EtOH
(20 ml) was stirred for 10 min at room temperature. Then methyl bromoacetate (0.12 ml, 1.3 mmol) was added,
and the reaction mixture was stirred at 80°C for 1 h. The precipitate was separated by filtration and washed with
cold (-10°C) MeOH (5 ml) and water (20 ml). Yield 0.35 g (90%). White powder; mp 159-161°C. IR spectrum,
1
, cm-1: 3309 (N–H), 2198 (CN), 1714 (C=O). H NMR spectrum, , ppm (J, Hz): 2.35 (3H, s, 2-CH3); 3.54
(2H, AB system, J = 16.0, SCH2); 3.54 (3H, s, 3-COOCH3); 3.78 (3H, s, CH2COOCH3); 5.24 (1H, s, H-4);
7.00-7.30 (4H, m, H Ar); 8.51 (1H, s, NH). 13C NMR spectrum, δ, ppm: 19.3 (2-CH3); 34.7 (SCH2); 39.2 (C-4);
51.2 (CH2COOCH3); 53.7 (3-COOCH3); 90.9 (C-3); 101.3 (C-5); 117.9 (CN); 127.4 (C Ar); 128.4 (C Ar);
129.7 (C Ar); 130.2 (C Ar); 132.3 (C Ar); 141.9 (C Ar); 145.4 (C-6); 145.5 (C-2); 167.0 (3-COOCH3); 173.1
(CH2COOCH3). Mass spectrum, m/z (Irel, %): 393 [M+H]+ (100), 281 [M-Ar]+ (47). Found, %: C 55.23; H 4.21;
N 7.02. C18H17ClN2O4S. Calculated, %: C 55.03; H 4.36; N 7.13.
Methyl 5-Cyano-4-(2-difluoromethoxyphenyl)-6-(methoxycarbonylmethyl)sulfanyl-2-methyl-1,4-di-
hydropyridine-3-carboxylate (2c). Compound 2c was prepared in the same manner as compound 2b using
thione 1c instead of thione 1b. Yield 0.32 g (76%). Mp 180-181°C. IR spectrum, , cm-1: 3309 (N–H), 2198
1
(CN), 1714 (C=O). H NMR spectrum, , ppm (J, Hz): 2.35 (3H, s, 2-CH3); 3.50 (3H, s, 3-COOCH3); 3.51
(2H, AB system, J = 16.0, SCH2); 3.78 (3H, s, CH2COOCH3); 5.00 (1H, s, H-4); 6.48 (1H, dd, J = 73.2, J = 2.7,
OCHF2); 7.00-7.30 (4H, m, H Ar); 8.36 (1H, s, NH). 13C NMR spectrum, δ, ppm: 19.4 (2-CH3); 34.7 (SCH2);
37.2 (C-4); 51.1 (CH2COOCH3); 53.7 (3-COOCH3); 90.5 (C-3); 100.6 (C-5); 116.6 (t, J = 259.2, OCHF2);
424

118.1 (CN); 125.7 (C Ar); 128.4 (C Ar); 130.3 (C Ar); 132.3 (C Ar); 135.4 (C Ar); 142.0 (C Ar); 145.6 (C-6);
148.8 (C-2); 167.1 (3-COOCH3); 173.0 (CH2COOCH3). Mass spectrum, m/z (Irel, %): 447 [M+Na]+ (100), 425
[M+H]+ (35), 296 [M-Ar]+ (53). Found C 53.64; H 4.42; N 6.55. C19H18F2N2O5S. Calculated, %: C 53.77;
H 4.27; N 6.60.
Methyl 6-(Carboxymethyl)sulfanyl-4-(2-chlorophenyl)-5-cyano-2-methyl-1,4-dihydropyridine-3-carb-
oxylate (3b). A mixture of thione 1b (0.32 g, 1.0 mmol) and piperidine (0.1 ml, 1.0 mmol) in DMSO (20 ml) was
stirred for 10 min at room temperature. Then bromoacetic acid (0.14 g, 1.0 mmol) was added, and the reaction
mixture was stirred at 70°C for 30 min. The resulting mixture was diluted with water (30 ml) and extracted with
EtOAc (330 ml). The combined organic extracts were evaporated and crystallized from CH2Cl2. The precipitate
was separated by filtration and washed with cold (-10°C) MeOH (5 ml) and water (20 ml). Yield 0.33 g (87%).
White powder; mp 165-167°C. IR spectrum, , cm-1: 3225 (N–H), 3175 (O–H), 2216 (CN), 1685 (C=O). 1H NMR
spectrum, , ppm (J, Hz): 2.30 (3H, s, 2-CH3); 3.44 (3H, s, COOCH3); 3.81 (2H, AB system, J = 15.6, SCH2); 5.07
(1H, s, H-4); 7.17-7.39 (4H, m, H Ar); 9.59 (1H, s, NH). 13C NMR spectrum, δ, ppm: 18.5 (2-CH3); 34.7 (SCH2);
39.2 (C-4); 53.7 (3-COOCH3); 90.0 (C-3); 101.3 (C-5); 118.9 (CN); 127.2 (C Ar); 128.3 (C Ar); 129.5 (C Ar);
130.2 (C Ar); 132.1 (C Ar); 141.7 (C Ar); 145.4 (C-6) 145.5 (C-2); 166.9 (3-COOCH3); 172.8 (CH2COOH). Mass
spectrum, m/z (Irel, %): 401 [M+Na]+ (21), 379 [M+H]+ (100), 267 [M-Ar]+ (68). Found, %: C 53.80; H 3.81; N 7.22.
C17H15ClN2O4S. Calculated, %: C 53.90; H 3.99; N 7.39.
Methyl 6-(Carboxymethyl)sulfanyl-5-cyano-4-(2-difluoromethoxyphenyl)-2-methyl-1,4-dihydro-
pyridine-3-carboxylate (3c). Compound 3c was prepared in the same manner as compound 3b using thione 1c
instead of thione 1b. Yield 0.33 g (81%). Mp 122-124°C. IR spectrum, , cm-1: 3225 (N–H), 3175 (O–H), 2216
(CN), 1685 (C=O). 1H NMR spectrum, , ppm (J, Hz): 2.29 (3H, s, 2-CH3); 3.45 (3H, s, COOCH3); 3.80 (2H,
AB system, J = 15.6, SCH2); 4.90 (1H, s, H-4); 6.58 (1H, t, J = 73.9, OCHF2); 7.08-7.31 (4H, m, H Ar); 9.50
(1H, s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 19.3 (2-CH3); 34.7 (SCH2); 37.1 (C-4); 53.7 (3-COOCH3);
90.5 (C-3); 100.4 (C-5); 118.1 (CN); 116.3 (t, J = 259.2, OCHF2); 125.5 (C Ar); 128.3 (C Ar); 130.1 (C Ar);
132.2 (C Ar); 135.4 (C Ar); 141.9 (C Ar); 145.4 (C-6); 148.7 (C-2); 167.0 (3-COOCH3); 173.0 (CH2COOH).
Mass spectrum, m/z (Irel, %): 433 [M+Na]+ (85), 411 [M+H]+ (100), 267 [M-Ar]+ (24). Found, %: C 52.40; H 3.82;
N 6.73. C18H16F2N2O5S. Calculated, %: C 52.68; H 3.93; N 6.83.
Preparative Hydrolysis of Esters 2a-c Catalyzed by Candida antarctica Lipase B (CAL-B,
Novozym 435®) (General Method). To a solution of ester 2a–c (1 mmol) in dichloromethane (2 ml), an
appropriate amount of diisopropylether was added to reach the desired solvent ratio, as mentioned in Table 1.
Then Novozym 435® (≥10,000 U/g, 0.4 g) was added, and the reaction mixture was stirred (300 rpm) at the
appropriate temperature. Probe samples (10-20 l) were taken with syringe every 10-20 min, diluted with 75%
aq. MeCN solution (1 ml), and analyzed by HPLC. The reaction was stopped when ~50% of acid 4a-c was
formed (HPLC). Blank reactions without enzyme showed no conversion of substrate. Then the enzyme was
filtered off, the filtrate was evaporated under reduced pressure at 50°C to dryness and the residue was separated
by flash chromatography to give acids 4a-c and esters 5a-c, which were analyzed by HPLC. The spectral
characteristics of optically active acids 4a-c and esters 5a-c correspond to that of the corresponding racemates
3a-c and 2a-c.
Methyl
6-(Carboxymethyl)sulfanyl-5-cyano-2-methyl-4-phenyl-1,4-dihydropyridine-3-carb-
oxylate ((-)-4a). Yield 0.16 g (46%). Mp 122-123°C. []D20 -2.9° (c 1, MeOH).
Methyl 5-Cyano-6-(methoxycarbonylmethyl)sulfanyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carb-
oxylate ((+)-5a). Yield 0.18 g (49%). Mp 160-161°C. []D20 +55.1° (c 1, MeOH).
Methyl 5-Cyano-6-(methoxycarbonylmethyl)sulfanyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carb-
oxylate ((-)-6a). A mixture of acid (-)-4a (0.1 g, 0.3 mmol), 0.5 M diazomethane solution in Et2O (1.0 ml), and
CH2Cl2 (7 ml) was stirred for 10 min at room temperature. The precipitate was separated by filtration and
washed with cold (-10°C) MeOH (5 ml) and water (20 ml). Yield 0.10 g (97%). White powder; mp 159-161°C.
[]D20 -19.2° (c 1, MeOH). IR spectrum, , cm-1: 3309 (N–H), 2198 (CN), 1714 (C=O). 1H NMR spectrum, ,
425

ppm (J, Hz): 2.35 (3H, s, 2-CH3); 3.50 (3H, s, 3-COOCH3); 3.51 (2H, AB system, J = 16.0, SCH2); 3.78 (3H, s,
CH2COOCH3); 5.24 (1H, s, H-4); 7.06-7.28 (5H, m, H Ph); 8.37 (1H, s, NH). 13C NMR spectrum, δ, ppm: 19.4
(2-CH3); 34.8 (SCH2); 42.4 (C-4); 51.2 (CH2COOCH3); 53.7 (3-COOCH3); 91.5 (C-3); 101.5 (C-5); 118.5
(CN); 127.2 (C Ph); 127.3 (C Ph); 128.7 (C Ph); 141.5 (C Ph); 144.3 (C-6); 145.0 (C-2); 167.2 (3-COOCH3);
173.0 (CH2COOCH3). Mass spectrum, m/z (Irel, %): 359 [M+H]+ (100), 281 [M-Ph]+ (61). Found, %: C 60.22;
H 5.11; N 7.86. C18H18N2O4S. Calculated, %: C 60.32; H 5.06; N 7.82.
This
work
was
supported
by
European
Regional
Development
Fund
project
2010/0227/2DP/2.1.1.1.0/10/APIA/VIAA/072.
REFERENCES
1.
P. Ioan, E. Carosati, M. Micucci, G. Cruciani, F. Broccatelli, B. S. Zhorov, A. Chiarini, and R. Budriesi,
Curr. Med. Chem., 18, 4901 (2011).
2.
3.
4.
5.
6.
D. J. Triggle, Biochem. Pharmacol., 74, 1 (2007).
G. Derosa and P. Maffioli, Expert Rev. Cardiovasc. Ther., 9, 1499 (2011).
R. R. Wenzel, Drugs, 65, 29 (2005).
V. Klusa, Drugs Future, 20, 135 (1995).
C. Napoli, S. Salomone, T. Godfraind, W. Palinski, D. M. Capuzzi, G. Palumbo, F. P. D'Armiento,
R. Donzelli, F. de Nigris, R. L. Capizzi, M. Mancini, J. S. Gonnella, and A. Bianchi, Stroke, 30, 1907
(1999).
7.
8.
9.
D. Tirzite, J. Koronova, and A. Plotniece, Biochem. Mol. Biol. Int., 45, 849 (1998).
A. Velēna, J. Zilbers, and G. Duburs, Cell Biochem. Funct., 17, 237 (1999).
E. V. Ivanov, T. V. Ponamarjova, G. N. Merkushev, I. K. Romanovich, G. J. Dubur, E. A. Bisenieks,
J. R. Uldrikis, and J. J. Poikans, Radiats. Biol., Radioekol., 44, 550 (2004).
S. Gullapalli and P. Ramarao, Neuropharmacology, 42, 467 (2002).
J. Briede, D. Daija, M. Stivrina, and G. Duburs, Cell Biochem. Funct., 17, 89 (1999).
R. Boer and V. Gekeler, Drugs Future, 20, 499 (1995).
G. A. Wächter, M. C. Davis, A. R. Martin, and S. G. Franzblau, J. Med. Chem., 41, 2436 (1998).
S. Bahekar and D. Shinde, Acta Pharm., 52, 281 (2002).
Z. Hyvönen, A. Plotniece, I. Reine, B. Chekavichus, G. Duburs, and A. Urtti, Biochim. Biophys. Acta,
1509, 451 (2000).
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
B. Kenny, S. Ballard, J. Blagg, and D. Fox, J. Med. Chem., 40, 1293 (1997).
J. M. Tusell, S. Barrón, and J. Seratosa, Brain Res., 622, 99 (1993).
L. M. Tarasenko, K. S. Neporada, and V. Klusha, Bull. Exp. Biol. Med., 133, 369 (2002).
R. Budriesi, P. Ioan, A. Locatelli, S. Cosconati, A. Leoni, M. P. Ugenti, A. Andreani, R. Di Toro,
A. Bedini, S. Spampinato, L. Marinelli, E. Novellino, and A. Chiarini, J. Med. Chem., 51, 1592 (2008).
A. Krauze, L. Baumane, L. Sile, L. Cernova, M. Vilums, R. Vitolina, G. Duburs, and J. Stradins, Khim.
Geterotsikl. Soedin., 1022 (2004). [Chem. Heterocycl. Compd., 40, 876 (2004)].
A. A. Krauze, R. O. Vitolina, M. R. Romanova, and G. Y. Dubur. Khim.-Farm. Zh., 22, 955 (1988).
K. Schreiber and L. Melvin, WO Pat. Appl. 042478.
20.
21.
22.
23.
A. Krauze, J. Pelcers, R. Vitolina, M. Selga, I. Petersone, Z. Kalme, A. Kimenis, and G. Duburs, WO
Pat. Appl. 003529.
24.
25.
K. Schreiber and L. Melvin, US Pat. Appl. 7485653.
A. A. Krauze, A. G. Odynets, A. A. Verreva, S. K. Germane, A. N. Kozhukhov, and G. Y. Dubur,
Pharm. Chem. J., 25, 477 (1991).
426

26.
27.
28.
I. E. Kirule, A. A. Krauze, A. H. Velena, D. Y. Antipova, G. Y. Arnitsane, I. A. Vutsina, and
G. Y. Dubur, Pharm. Chem. J., 26, 865 (1992).
D. Tirzite, A. Krauze, A. Zubareva, G. Tirzitis, and G. Duburs, Khim. Geterotsikl. Soedin., 902 (2002).
[Chem. Heterocycl. Compd., 38, 795 (2002)].
D. Vo, W. C. Matowe, M. Ramesh, N. Iqbal, M. W. Wolowyk, S. E. Howlett, and E. E. Knauss, J. Med.
Chem., 38, 2851 (1995).
29.
30.
31.
32.
33.
J. Young, US Pat. Appl. 5834496.
A. Sobolev, M. C. R. Franssen, G. Duburs, and A. de Groot, Biocatal. Biotransform., 22, 231 (2004).
S. Marchalín, M. Chudík, V. Mastihuba, and B. Decroix, Heterocycles, 48, 1943 (1998).
K. Achiwa and T. Kato, Curr. Org. Chem., 3, 77 (1999).
A. A. Krauze, Y. E. Pelcher, Z. A. Kalme, and G. Y. Duburs, Khim. Geterotsikl. Soedin., 935 (1984).
[Chem. Heterocycl. Compd., 20, 1400 (1984).]
34.
35.
L. Bekere, A. Krauze, I. Sestakova, I. Domraceva, Z. Andzans, and G. Duburs, Latv. J. Chem., 2, 146
(2010).
A. Krauze, L. Sīle, L. Chernova, Z. Andzans, and G. Duburs, Heterocycl. Commun., 15, 297 (2009).
427