Synthesis of cyclopentapyridine and thienopyridine derivatives as potential calcium channel modulators

Article abstract of DOI:10.1055/s-0031-1299744

In this study, novel condensed 1,4-dihydropyridines bearing cyclopentanone (1-21) or tetrahydrothiophene-1,1-dioxide ring (22-42) with various ester substituents were synthesized via a modified Hantzsch reaction and their calcium channel modulator activities were investigated on isolated rat ileum and rat thoracic aorta. The introduction of a cyclopentanone ring fused to the 1,4-dihydropyridine nucleus and methyl, ethyl and allyl moieties to the ester group led to more active calcium modulators. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1299744

Original Article 167
Synthesis of Cyclopentapyridine and Thienopyridine
Derivatives as Potential Calcium Channel Modulators
Authors
M. G. Gündüz1, C. Şafak1, B. Kaygısız2, B. Ç. Koşar2, R. Şimşek1, K. Erol2, A. Linden3
Affiliations
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
2 Department of Pharmacology, Faculty of Medicine, Osman Gazi University, Eskişehir, Turkey
3 Institute of Organic Chemistry, University of Zurich Zurich, Switzerland
Key words
Abstract
▼
channel modulator activities were investigated
▶
● 1,4-Dihydropyridine
on isolated rat ileum and rat thoracic aorta. The
introduction of a cyclopentanone ring fused to
the 1,4-dihydropyridine nucleus and methyl,
ethyl and allyl moieties to the ester group led to
more active calcium modulators.
▶
● thienopyridine
In this study, novel condensed 1,4-dihydropy-
ridines bearing cyclopentanone (1–21) or tet-
rahydrothiophene-1,1-dioxide ring (22–42) with
various ester substituents were synthesized via
a modified Hantzsch reaction and their calcium
▶
● cyclopentapyridine
▶
● calcium channel modulator
Introduction
▼
receptor [13]. The phenyl ring is preferred as the
substituent at the C-4 position because of animal
toxicity observed with heteroaromatic rings [14].
Phenyl groups which possess one or more elec-
tron-withdrawing substituents at the ortho- or
meta-position are preferable to other groups
such as alkyls or phenyl groups having a substit-
uent at the para-position [15,16].
The aim of this work is to evaluate the influence
of cyclopentane or tetrahydrothiophene rings
fused to the DHP ring and that of various ester
groups in combination with 2 halogens attached
to the phenyl ring in the 1,4-DHP nucleus. The
compounds were synthesized and tested as race-
mates. The calcium modulator activities of the
compounds were assayed on isolated rat ileum
and rat thoracic aorta. Although compound 37
has been synthesized previously by Dodd and co-
workers [17], there is no data about its calcium
channel modulatory activity on ileum and aorta,
so it was also synthesized in this study.
Calcium ions play a critical role in various bio-
logical functions such as muscle contraction,
release of neurotransmitters and regulation of
neuronal excitability [1]. Calcium entry into the
cytosol is mediated by different types of calcium
channels with distinct physiological roles [2].
L-type channels are confined to cell bodies and
regulate contractions in muscle cells. Calcium
channel antagonists reversibly block Ca2+ influx
through L-type calcium channels [3]. 1,4-Dihy-
dropyridines (DHP), of which nifedipine is the
received 02.12.2011
accepted 19.12.2011
Bibliography
▶
prototype (● Fig. 1), are one of the known classes
DOI http://dx.doi.org/
10.1055/s-0031-1299744
Published online:
January 27, 2012
Arzneimittelforschung 2012;
62: 167–175
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0004-4172
of calcium antagonists, which are frequently
used for the treatment of cardiovascular diseases
like angina, hypertension and supraventricular
tachycardia [4–6].
Since the introduction of DHPs into clinical use,
many DHP analogs have been synthesized in
order to elucidate the structure-activity relation-
ships and to enhance calcium-modulating effects
[7]. It was reported that active derivatives could
be obtained by introducing the DHP structure
into condensed ring systems such as hexahydro-
quinolines, indenopyridines, acridines and furo-
quinolines [8–11]. C-3 and C-5 substituents
modulate activity and tissue selectivity and dif-
ferent substituents in these positions alter the
activity [12]. Studies of fused 1,4-DHPs, in which
one of the ester groups is immobilized, indicate
that at least one ester group must be cis to the
double bond of DHP for hydrogen bonding to the
Correspondence
M. G. Gündüz, MSc
Department of Pharmaceutical
Chemistry
Faculty of Pharmacy
Hacettepe University
Sihhiye
06100 Ankara
T u r k e y
Tel.: +90/312/3051 872
Fax: +90/312/3051 872
miyasegunduz@yahoo.com
Material and Methods
▼
Chemistry
General methods
All chemicals used in this study were purchased
from Aldrich and Fluka. Melting points were
determined on a Thomas Hoover Capillary Melt-
ing Point Apparatus and are uncorrected. Infra-
red spectra were recorded on a Perkin Elmer
FT-IR Spectrum BX. 1H-NMR, 13C-NMR DEPT and
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

168 Original Article
COSY spectra were obtained in dimethyl sulphoxide (DMSO)
pound and ammonium acetate in methanol, according to the
Hantzsch reaction.
solutions on a Varian Mercury 400, 400MHz High Performance
Digital FT-NMR Spectrometer. Chemical shifts are reported in
parts per million (ppm) relative to tetramethylsilane. The X-ray
crystallographic analysis was carried out on a Nonius Kappa CCD
area-detector diffractometer. Mass spectra were obtained on an
Agilent 5973 Network Mass Selective Detector by electron ioni-
zation. Elemental analyses were performed on a Leco CHNS-932
Elemental Analyzer. Purification by column chromatography
was performed on Merck silica gel 60 (0.040–0.063mm).
Alkyl 2-methyl-4-(2,3-disubstituted phenyl)-5-oxo-4,5,6,7-te-
trahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound
1–21): 1,3-Cyclopentanedione (0.001mol), 2,3-disubstituted
benzaldehyde (0.001mol), alkyl acetoacetate (0.001mol) and
ammonium acetate (0.005mol) were refluxed for 8h in 15mL
methanol. After the reaction was completed, either the reaction
mixture was poored into ice-water, the obtained precipitate was
filtered and crystallized from appropriate solvents or the solvent
(methanol) was removed via a rotary evaporator and the crude
product was then purified by column chromatography using
silica gel as the solid phase and a 7:3 mixture of ethyl acetate:
methanol as mobile phase.
Synthesis
The synthesis of tetrahydrothiophene-3-one-1,1-dioxide is
▶
shown in (● Fig. 2). Tetrahydrothiophen-3-one (0.1mol), triethyl
orthoformate (0.1mol), p-toluensulfonic acid (0.26mmol) and
2mL ethanol was stirred for 20h. The mixture was treated with
anhydrous sodium acetate (4mmol), sodium tungstate dehydrate
(0.00085mmol) and 28mL water. 28mL of a 35% solution of
hydrogen peroxide in water was added dropwise while keeping
the reaction cooled to 30°C. After stirring overnight at room
temperature, the resulting product was filtered and washed
with water to achieve 3,3-diethoxytetrahydrothiephene-1,1-
dione. The product was stirred in a mixture of HCl and water at
60 °C for 2h. The mixture was extracted with dichloromethane
(60mL). The dichloromethane layer was isolated and dried with
MgSO4, filtered and concentrated. The residue was crystallized
from ethanol to provide tetrahydrothiophene-3-one-1,1-diox-
ide [18].
Alkyl 5-methyl-7-(2,3-disubstituted phenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound
22–42): Tetrahydrothiophene-3-on-1,1-dioxide (0.001mol),
2,3-disubstituted benzaldehyde (0.001mol), alkyl acetoacetate
(0.001mol) and ammonium acetate (0.005mol) were refluxed
for 8h in 15mL methanol. The precipitate, which was obtained
after cooling the reaction mixture, was crystallized from meth-
anol.
Pharmacology
The calcium antagonistic activities of the compounds were
determined by the tests performed on isolated rat ileum and rat
thoracic aorta. All procedures involving animals and their care
were conducted in conformity with international laws and poli-
cies.
▶
The compounds 1–42 were prepared (● Fig. 3) by heating
1,3-cyclopentanedione or tetrahydrothiophene-3-one-1,1-diox-
ide, the aromatic aldehyde, the appropriate acetoacetate com-
All data are expressed as mean±standard error. The statistical
comparison between groups was performed using general linear
models, and p-values less than 0.005 were considered to be sta-
tistically significant.
Fig. 1 Nifedipine.
NO2
Studies on isolated rat ileum
COOCH3
H3COOC
H3C
Albino rats of either sex weighing 150–200g were used in phar-
macological studies. The animals were supplied from the
Laboratory Animal Production Center in the Department of
Pharmacology, School of Medicine, Osmangazi University,
Eskişehir, Turkey. The animals used in the test were fasted over-
night. After the animals were sacrificed by cervical dislocation,
N
H
CH3
Fig. 2 Synthesis of tetrahydrothiophene-3-one-
1,1-dioxide.
O
C2H5O
C2H5O
C2H5O
O
Triethyl orthoformate
TsOH
H2O2
Na2WO4, NaOAc
HCI
C2H5O
S
S
S
S
O
O
O
O
Fig. 3 Synthesis of the compounds 1–42.
Ar
X
COOR
CH3
O
O
X
CH3COONH4
+
+ ArCHO
CH3CCH2COR
N
H
O
X: CO (Compound 1-21), SO2 (Compound 22- 42)
Ar: 2,3-Difluorophenyl, 2-Fluoro-3-chlorophenyl, 2,3-Dichlorophenyl
R: CH3, C2H5, CH2CH2OCH3, CH2CH=CH2, CH2CH(CH3)2, C(CH3)3, CH2C6H5
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

Original Article 169
the ileum (10–15cm terminal portion) was immediately
removed, discarding the 5–8cm segment proximal to the ileo-
caecal junction. Segments 1.5–2cm long were mounted verti-
cally in a 10ml organ bath containing Tyrode solution of the
following composition (mmol/L): NaCl: 136.87, KCl: 2.68, CaCl2:
1.80, MgSO4: 0.81, NaH2PO4: 4.16, NaHCO3: 11.9, glucose: 5.55.
The bath contents were maintained at 37°C and aerated by 95%
O2 and 5% CO2. A tension of 2g was applied and isometric
recording was done by using an isometric transducer (FDT10-A)
May TDA95 Transducer Data Acquisition System (May, Commat,
Ankara, Turkey). The preparations were allowed to equilibrate
for 60min with regular washes every 15min. In order to check
the calcium antagonistic effects, contractions were induced
with barium chloride (4.10−3 mol/L, bath concentration). After
washing out, this process was repeated until the amplitude of
the contraction became constant. Investigations of the sub-
stances were performed using the single-dose technique. Bar-
ium chloride contractions were induced after addition of the
test substances dissolved in DMSO at 10−5 M concentration and
5min exposure time. Only one compound was tested in each
preparation [19].
1H-NMR (δ, DMSO-d6): 0.99 (3H; t; COOCH2CH3), 2.19–2.57 (4H;
m; H-6, H-7), 2.31 (3H; s; 2-CH3), 3.90 (2H; q; COOCH2CH3), 4.95
(1H; s; H-4), 6.92–7.16 (3H; m; Ar-H), 9.83 (H; s; N-H). 13C-NMR
(δ, DMSO-d6): 13.6, 18.6, 23.7, 30.7, 33.3, 59.0, 102.4, 114.4,
114.9, 124.2, 125.3, 136.5, 136.6, 146.7, 148.0, 164.2, 166.2,
200.5. MS (m/z): 333 [M]+. Anal. Calcd. for C18H17F2NO3: C, 64.86;
H, 5.14; N, 4.20. Found: C, 64.67; H, 4.55; N, 4.38.
2-Methoxyethyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-
tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound
3): P u r i fied via column chromatography. Yield: 46%. mp: 156 °C.
IR (ν, cm−1): 3268 (N-H), 1680 (C=O, ester), 1642 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.19–2.57 (4H; m; H-6, H-7), 2.31 (3H, s,
2-CH3), 3.15 (3H; s; OCH3), 3.31–3.38 (2H; m; CH2OCH3), 3.90–
4.02 (2H; m; CH2CH2OCH3), 4.95 (H; s; 4-H), 6.92–7.15 (3H; m;
Ar-H), 9.85 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.7, 23.7, 30.7,
33.3, 57.8, 62.3, 69.6, 102.1, 114.4, 115.0, 124.1, 125.3, 136.3,
145.7, 148.1, 150.5, 164.1, 166.2, 200.5. MS (m/z): 363 [M]+.
Anal. Calcd. for C19H19F2NO4: C, 62.81; H, 5.27; N, 3.85. Found: C,
62.16; H, 4.98; N, 3.98.
Allyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridine-3-carboxylate (Compound 4): C r y -
stallized from benzene/petroleum ether. Yield: 41%. mp: 183 °C.
IR (ν, cm−1): 3282 (N-H), 1686 (C=O, ester), 1640 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.14–2.57 (4H; m; H-6, H-7), 2.23 (3H; s;
2-CH3), 4.37 (H; dd; CH2A-CH=CH2), 4.43 (H; dd; CH2B-CH=CH2),
4.97 (H; dd; CH2CH=CH2A), 4.98 (H; s; 4-H), 5.04 (H; dd;
CH2CH=CH2B) 5.66–5.75 (H; m; CH=CH2), 6.93–7.15 (3H; m;
Ar-H), 9.86 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.8, 23.7, 30.7,
33.3, 63.7, 102.0, 114.7, 115.0, 116.8, 124.2, 125.2, 132.7, 136.3,
136.4, 145.4, 147.3, 164.1, 165.9, 200.5. MS (m/z): 345 [M]+.
Anal. Calcd. for C19H17F2NO3: C, 66.08; H, 4.96; N, 4.06. Found: C,
65.11; H, 4.60; N, 4.09.
Studies on rat thoracic artery
Rat thoracic artery preparations were also obtained from the
same animals, which were used for isolated rat ileum experi-
ments. Rings (3mm) were suspended in organ baths of 10mL
capacity which contained Tyrode solution. The bath contents
were maintained at 37°C and aerated by 95% O2 and 5% CO2. A
tension of 2g was applied. The preparations were allowed to
equilibrate for 60min with regular washes every 15min. In
order to check calcium antagonistic effects, contractions were
induced with 67mmol/L potassium chloride. After washing out,
this process was repeated until the amplitude of the contrac-
tions became constant. Investigations of the substances were
performed using a single-dose technique. Potassium chloride
contractions were induced after addition of the test substance
and 10min exposure time. During the administration of the
individual substances, the preparation was washed until the ini-
tial situation had been re-established and the potassium chlo-
ride contractions were induced. The isometric contractions
were recorded by an isometric transducer (FDT10-A) May TDA95
Transducer Data Acquisition System [20].
Isobutyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 5):
Crystallized from ethyl acetate/n-hexane. Yield: 52%. mp: 168°C.
IR (ν, cm−1): 3314 (N-H), 1690 (C=O, ester), 1646 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 0.67 (3H, d, COOCH2CHCH3), 0.73 (3H, d,
COO CH2CHCH3), 1.67–1.75 (H; m; CH(CH3)2), 2.15–2.55 (4H; m;
H-6, H-7), 2.33 (3H, s, 2-CH3), 3.63 (H; dd; CHACH(CH3)2), 3.71
(H; dd; CHBCH(CH3)2), 4.97 (H; s; 4-H), 6.93–7.17 (3H; m; Ar-H),
9.79 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.6, 18.8, 19.1, 23.6,
27.1, 30.6, 33.3, 69.3, 102.1, 114.4, 124.2, 125.1, 136.4, 145.3,
147.2, 148.2, 150.5, 164.0, 166.3, 200.4. MS (m/z): 360 [M-1]+.
Anal. Calcd. for C20H21F2NO3: C, 66.47; H, 5.86; N, 3.88. Found: C,
66.24; H, 5.86; N, 3.94.
Results
▼
Chemistry
Methyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridine-3-carboxylate (Compound 1): Puri-
fied via column chromatography. Yield: 45%. mp: 223 °C. IR (ν,
cm−1): 3288 (N-H), 1699 (C=O, ester), 1638 (C=O, ketone). 1H-NMR
(δ, DMSO-d6): 2.17–2.56 (4H; m; H-6, H-7), 2.27 (3H; s; 2-CH3), 3.40
(3H; s; COOCH3), 4.91 (1H; s; H-4), 6.89–7.15 (3H; m; Ar-H), 9.82 (H;
s; N-H). 13C-NMR (δ, DMSO-d6): 19.2, 24.2, 31.3, 33.8, 51.2, 102.8,
115.1, 124.7, 125.8, 136.7, 147.2, 148.6, 150.9, 151.1, 164.7, 167.3,
201.0. MS (m/z): 319 [M]+. Anal. Calcd. for C17H15F2NO3: C, 63.95; H,
4.73; N, 4.39. Found: C, 63.49; H, 4.61; N, 4.43.
Tert-butyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 6):
Crystallized from ethyl acetate/n-hexane. Yield: 48%. mp: 196°C.
IR (ν, cm−1): 3302 (N-H), 1696 (C=O, ester), 1632 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 1.16 (9H; s; COOC(CH3)3), 2.12–2.52 (4H;
m; H-6, H-7), 2.24 (3H; s; 2-CH3), 4.88 (H; s; 4-H), 6.89–7.34
(3H; m; Ar-H), 9.67 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.9,
23.9, 24.0, 24.1, 28.0, 31.5, 33.7, 79.4, 104.3, 115.0, 124.6, 125.8,
136.9, 145.9, 146.1, 148.6, 150.9, 164.5, 166.2, 200.9. MS (m/z):
360 [M-1]+. Anal. Calcd. for C20H21F2NO3: C, 66.47; H, 5.86; N,
3.88. Found: C, 66.40; H, 5.80; N, 3.85.
Ethyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 2):
Purified via column chromatography. Yield: 60%. mp: 211 °C’dir.
IR (ν, cm−1): 3275 (N-H), 1698 (C=O, ester), 1634 (C=O, ketone).
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

170 Original Article
Benzyl 2-methyl-4-(2,3-difluorophenyl)-5-oxo-4,5,6,7-tetrahydro-
Anal. Calcd. for C19H17ClFNO3: C, 63.08; H, 4.74; N, 3.87. Found:
C, 62.97; H, 4.89; N, 3.90.
1H-cyclopenta[b]pyridine-3-carboxylate (Compound 7): C r y -
stallized from ethyl acetate/n-hexane. Yield: 54%. mp: 202 °C. IR
(ν, cm−1): 3260 (N-H), 1695 (C=O, ester), 1630 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.19–2.57 (4H; m; H-6, H-7), 2.33 (3H; s;
2-CH3), 4.93, 5.02 (1H, AB system, JAB =12.8Hz, COOCH2C6H5),
4.99 (1H; s; H-4), 6.90–7.27 (8H; m; Ar-H), 9.77 (H; s; N-H). 13C-
NMR (δ, DMSO-d6): 18.8, 23.7, 30.7, 33.3, 64.7, 101.8, 114.5,
115.0, 124.1, 125.2, 127.4, 127.6, 128.1, 136.2, 145.4, 145.6,
147.5, 147.9, 148.1, 150.5, 164.0, 166.1, 200.5. MS (m/z): 395
[M]+. Anal. Calcd. for C23H19F2NO3: C, 69.87; H, 4.84; N, 3.54.
Found: C, 69.25; H, 4.77; N, 3.61.
Isobutyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-tetra-
hydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 12):
Purified via column chromatography. Yield: 56%. mp: 163 °C. IR
(ν, cm−1): 3254 (N-H), 1697 (C=O, ester), 1628 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 0.65 (3H; d; COOCH2CHCH3), 0.72 (3H;
d; COO CH2CHCH3), 1.66–1.74 (H; m; CH(CH3)2), 2.14–2.57 (4H;
m; H-6, H-7), 2.33 (3H; s; 2-CH3), 3.60 (H; dd; CH2 ACH(CH3)2),
3.71 (H; dd; CH2BCH(CH3)2), 4.95 (H; s; 4-H), 7.07–7.33 (3H; m;
Ar-H), 9.86 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.5, 18.6, 18.8,
23.7, 27.1, 31.1, 33.3, 69.4, 102.1, 115.0, 119.3, 125.0, 129.0,
135.9, 147.3, 152.8, 155.3, 164.1, 166.3, 200.4. MS (m/z): 377
[M]+. Anal. Calcd. for C20H21ClFNO3: C, 63.58; H, 5.60; N, 3.71.
Found: C, 63.63; H, 5.41; N, 3.81.
Methyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-tet-
rahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 8):
Purified via column chromatography. Yield: 52%. mp: 245 °C. IR
(ν, cm−1): 3268 (N-H), 1709 (C=O, ester), 1634 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.20–2.59 (4H; m; H-6, H-7), 2.30 (3H; s;
2-CH3), 3.44 (3H; s; COOCH3), 4.93 (1H; s; H-4), 7.06–7.34 (3H;
m; Ar-H), 9.85 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.7, 23.7,
31.5, 33.3, 50.6, 102.3, 114.8, 119.2, 124.9, 128.1, 129.2, 135.6,
146.8, 155.5, 164.3, 166.8, 200.5. MS (m/z): 334 [M-1]+. Anal.
Calcd. for C17H15ClFNO3: C, 60.81; H, 4.50; N, 4.17. Found: C,
60.13; H, 4.66; N, 4.29.
Tert-butyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-
tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate
(Com-
pound 13): Crystallized from ethyl acetate/n-hexane. Yield:
49%. mp: 207 °C. IR (ν, cm−1): 3266 (N-H), 1696 (C=O, ester),
1631 (C=O, ketone). 1H-NMR (δ, DMSO-d6): 1.16 (9H; s;
COOC(CH3)3), 2.12–2.52 (4H; m; H-6, H-7), 2.24 (3H; s; 2-CH3),
4.88 (H; s; 4-H), 7.07–7.32 (3H; m; Ar-H), 9.63 (H; s; N-H). 13C-
NMR (δ, DMSO-d6): 18.9, 24.1, 24.3, 24.5, 28.0, 32.0, 33.7, 79.4,
104.4, 115.0, 119.5, 125.4, 128.3, 129.7, 136.4, 146.2, 153.3,
155.8, 166.2, 165.9, 200.7. MS (m/z): 377 [M]+. Anal. Calcd. for
C20H21ClFNO3: C, 63.58; H, 5.60; N, 3.71. Found: C, 63.27; H,
5.22; N, 3.84.
Ethyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 9): Puri-
fied via column chromatography. Yield: 64%. mp: 239 °C. IR (ν,
cm−1): 3272 (N-H), 1698 (C=O, ester), 1632 (C=O, ketone). 1H-
NMR (δ, DMSO-d6): 0.98 (3H; t; COOCH2CH3), 2.20–2.58 (4H; m;
H-6, H-7), 2.30 (3H; s; 2-CH3), 3.87 (2H; q; COOCH2CH3), 4.94
(1H; s; H-4), 7.06–7.34 (3H; m; Ar-H), 9.84 (H; s; N-H). 13C-NMR
(δ, DMSO-d6): 13.6, 18.6, 23.7, 31.2, 33.3, 59.0, 102.4, 114.9,
119.1, 124.9, 129.2, 135.9, 146.7, 152.9, 155.4, 164.2, 166.2,
200.5. MS (m/z): 349 [M]+. Anal. Calcd. for C18H17ClFNO3: C,
61.81; H, 4.90; N, 4.00. Found: C, 61.37; H, 5.10; N, 4.11.
Benzyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-tet-
rahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 14):
Crystallized from ethyl acetate. Yield: 48%. mp: 172 °C. IR (ν, cm−1):
3261 (N-H), 1699 (C=O, ester), 1633 (C=O, ketone). 1H-NMR (δ,
DMSO-d6): 2.19–2.56 (4H; m; H-6, H-7), 2.32 (3H; s; 2-CH3),
4.89, 4.99 (1H, AB system, JAB =13.2Hz, COOCH2C6H5), 4.95 (1H;
s; H-4), 7.00–7.36 (8H; m; Ar-H), 9.88 (H; s; N-H). 13C-NMR (δ,
DMSO-d6): 19.3, 24.2, 31.9, 33.8, 65.3, 102.4, 115.5, 119.8, 125.4,
127.9, 128.1, 128.5, 128.6, 129.6, 135.9, 136.1, 136.8, 148.1,
153.5, 155.9, 164.7, 166.6, 200.1. MS (m/z): 411 [M]+. Anal.
Calcd. for C23H19ClFNO3: C, 67.07; H, 4.65; N, 3.40. Found: C,
66.67; H, 4.67; N, 3.40.
2-Methoxyethyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-
4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate
(Compound 10): P u r i fied via column chromatography. Yield:
51%. mp: 158°C. IR (ν, cm−1): 3319 (N-H), 1696 (C=O, ester),
1
1637 (C=O, ketone). H-NMR (δ, DMSO-d6): 2.12–2.57 (4H; m;
H-6, H-7), 2.31 (3H, s, 2-CH3), 3.15 (3H; s; OCH3), 3.31–3.42 (2H;
m; CH2OCH3), 3.91–4.02 (2H; m; CH2CH2OCH3), 4.95 (H; s; 4-H),
6.92–7.17 (3H; m; Ar-H), 9.85 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 19.2, 24.2, 31.9, 36.4, 58.4, 64.8, 70.1, 102.6, 115.4, 125.3,
128.5, 129.7, 131.8, 136.1, 147.7, 153.6, 156.1,166.7, 200.5. MS
(m/z): 379 [M]+. Anal. Calcd. for C19H19ClFNO4: C, 60.08; H, 5.04;
N, 3.69. Found: C, 59.99; H, 4.99; N, 3.73.
Methyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 15):
Crystallized from ethyl acetate/n-hexane. Yield: 62%. mp: 216 °C.
IR (ν, cm−1): 3294 (N-H), 1741 (C=O, ester), 1640 (C=O gerilim,
ketone). 1H-NMR (δ, DMSO-d6): 2.10–2.57 (4H; m; H-6, H-7),
2.29 (3H; s; 2-CH3), 3.41 (3H; s; COOCH3), 5.17 (1H; s; H-4),
7.14–7.37 (3H; m; Ar-H), 9.76 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 19.0, 23.7, 33.2, 36.4, 51.0, 103.1, 115.6, 127.8, 128.3, 129.8,
130.5, 131.2, 146.5, 147.0, 164.0, 166.8, 200.4. DEPT-135 (δ,
DMSO-d6): 19.0 (CH3), 23.7 (CH2), 33.2 (CH2), 36.4 (CH), 51.0
(CH3), 128.3 (CH), 129.8 (CH), 130.5 (CH). MS (m/z): 351 [M-1]+.
Anal. Calcd. for C17H15Cl2NO3: C, 57.97; H, 4.29; N, 3.98. Found:
C, 57.91; H, 4.24; N, 3.90.
Allyl 2-methyl-4-(2-fluoro-3-chlorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 11):
Purified via column chromatography. Yield: 49%. mp: 194 °C. IR
(ν, cm−1): 3265 (N-H), 1740 (C=O, ester), 1712 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.15–2.58 (4H; m; H-6, H-7), 2.32 (3H; s;
2-CH3), 4.36 (H; dd; CH2 A-CH=CH2), 4.25 (H; dd; CH2B-CH=CH2),
4.96 (H; s; 4-H), 4.99 (H; dd; CH2CH=CH2 A), 5.05 (H; dd;
CH2CH=CH2B), 5.65–5.76 (H; m; CH=CH2), 7.06–7.33 (3H; m;
Ar-H), 9.85 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.8, 23.7, 31.3,
33.3, 63.7, 102.1, 117.0, 119.2, 124.9, 128.0, 129.1, 132.6, 135.7,
147.3, 153.0, 155.4, 164.2, 165.9, 200.5. MS (m/z): 361 [M]+.
Ethyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridine-3-carboxylate (Compound 16): C r y s -
tallized from ethyl acetate. Yield: 56%. mp: 206 °C. IR (ν, cm−1):
3380 (N-H), 1675 (C=O, ester), 1639 (C=O, ketone). 1H-NMR (δ,
DMSO-d6): 0.93 (3H; t; COOCH2CH3), 2.14–2.56 (4H; m; H-6,
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

Original Article 171
H-7), 2.29 (3H; s; 2-CH3), 3.85 (2H; q; COOCH2CH3), 5.71 (1H; s;
H-4), 7.15–7.38 (3H; m; Ar-H), 9.80 (H; s; N-H). 13C-NMR (δ,
DMSO-d6): 14.2, 19.1, 24.2, 33.7, 36.5, 59.4, 103.8, 116.0, 128.3,
128.8, 129.8, 130.7, 131.7, 147.0, 147.6, 164.4, 166.8, 200.8. MS
(m/z): 366 [M]+. Anal. Calcd. for C18H17Cl2NO3: C, 59.03; H, 4.68;
N, 3.82. Found: C, 59.87; H, 4.56; N, 3.74.
Benzyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetrahy-
dro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 21):
Crystallized from benzene/petroleum ether. Yield: 58%. mp: 129 °C.
IR (ν, cm−1): 3257 (N-H), 1698 (C=O, ester), 1632 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.11–2.56 (4H; m; H-6, H-7), 2.30 (3H; s;
2-CH3), 4.87, 4.99 (1H, AB system, JAB =12.8Hz, COOCH2C6H5),
5.20 (1H; s; H-4), 6.96–7.35 (8H; m; Ar-H), 9.79 (H; s; N-H). 13C-
NMR (δ, DMSO-d6): 19.3, 24.2, 33.7, 36.4, 65.1, 103.3, 116.2,
127.9, 128.0, 128.2, 128.4, 128.5, 128.7, 129.8, 130.7, 131.9,
132.8, 136.9, 147.4, 147.9. 165.4, 166.6, 200.8. MS (m/z): 427
[M-1]+. Anal. Calcd. for C23H19Cl2NO3: C, 64.50; H, 4.47; N, 3.27.
Found: C, 64.96; H, 4.27; N, 3.24.
2-Methoxyethyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-
tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound
17): Crystallized from benzene/petroleum ether. Yield: 58%.
mp: 153 °C. IR (ν, cm−1): 3263 (N-H), 1676 (C=O ester), 1637
(C=O, ketone). 1H-NMR (δ, DMSO-d6): 2.12–2.56 (4H; m; H-6,
H-7), 2.30 (3H, s, 2-CH3), 3.12 (3H; s; OCH3), 3.26–3.34 (2H; m;
CH2OCH3), 3.89–3.98 (2H; m; CH2CH2OCH3), 5.16 (H; s; 4-H),
7.15–7.37 (3H; m; Ar-H), 9.90 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 18.7, 23.7, 33.3, 36.0, 57.8, 62.2, 69.5, 102.9, 115.5, 127.7,
127.9, 128.2, 129.4, 130.1, 131.3, 146.8, 147.0, 166.3, 200.3. MS
(m/z): 396 [M]+. Anal. Calcd. for C19H19Cl2NO4: C, 57.59; H, 4.83;
N, 3.53. Found: C, 57.70; H, 4.68; N, 3.43.
Methyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 22): Y i e l d :
61%. mp: 264 °C. IR (ν, cm−1): 3337 (N-H), 1683 (C=O), 1303,
1166 (S=O). 1H-NMR (δ, DMSO-d6): 2.28 (3H; s; 5-CH3), 2.78 (H;
ddd; H-3A), 2.85 (H; ddd; H-3B), 3.26 (H; ddd; H-2A), 3.31 (H;
ddd; H-2B), 3.44 (3H; s; COOCH3), 5.14 (1H; s; H-7), 6.69–7.22
(3H; m; Ar-H), 9.50 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 19.2,
23.2, 30.2, 49.2, 51.3, 99.7, 112.0, 115.7, 124.9, 125.4, 135.8,
142.7, 145.9, 148.3, 151.1, 167.0. MS (m/z): 354 [M-1]+. Anal.
Calcd. for C16H15F2NO4S: C, 54.08; H, 4.25; N, 3.94; S, 9.02. Found:
C, 53.89; H, 4.26; N, 4.43; S, 9.18.
Allyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridine-3-carboxylate (Compound 18): C r y s -
tallized from ethyl acetate/n-hexane. Yield: 44%. mp: 192 °C. IR
(ν, cm−1): 3315 (N-H), 1711 (C=O, ester), 1640 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 2.10–2.55 (4H; m; H-6, H-7), 2.29 (3H; s;
2-CH3), 4.32 (H; dd; CH2 A-CH=CH2), 4.39 (H; dd; CH2B-CH=CH2),
4.89 (H; dd; CH2CH=CH2 A), 4.98 (H; dd; CH2CH=CH2B), 5.17 (H;
s; 4-H), 5.60–5.69 (H; m; CH=CH2), 7.14–7.35 (3H; m; Ar-H),
9.78 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.5, 23.7, 33.2, 36.7,
79.1, 104.8, 114.7, 127.6, 127.8, 128.2, 129.4, 130.3, 131.3, 132.1,
145.0, 146.6, 164.1, 165.9, 200.2. MS (m/z): 377 [M-1]+. Anal.
Calcd. for C19H17Cl2NO3: C, 60.33; H, 4.53; N, 3.70. Found: C,
60.13; H, 4.38; N, 3.83.
Ethyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 23):
Yield: 75%. mp: 273 °C. IR (ν, cm−1): 3333 (N-H), 1686 (C=O),
1252, 1135 (S=O). 1H-NMR (δ, DMSO-d6): 0.99 (3H; t;
COOCH2CH3), 2.28 (3H; s; 5-CH3), 2.77 (H; ddd; H-3A), 2.84 (H;
ddd; H-3B), 3.26 (H; ddd; H-2A), 3.32 (H; ddd; H-2B), 3.85 (H; dq;
COOCH2A-CH3), 3.92 (H; dq; COOCH2B-CH3) 5.15 (H; s; H-7),
6.97–7.22 (3H; m; Ar-H), 9.48 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 14.2, 19.1, 23.2, 30.1, 49.1, 59.6, 99.9, 112.0, 115.6, 115.8,
125.0, 125.5, 135.9, 136.1, 142.6, 148.2, 166.4. MS (m/z): 368
[M-1]+. Anal. Calcd. for C17H17F2NO4S : C, 55.28; H, 4.64; N, 3.79;
S, 8.68. Found: C, 54.96; H, 4.26; N, 3.94; S, 8.65.
Isobutyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetra-
hydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 19):
Crystallized from ethyl acetate. Yield: 63%. mp: 234 °C. IR (ν, cm−1):
3306 (N-H), 1699 (C=O, ester), 1638 (C=O, ketone). 1H-NMR (δ,
DMSO-d6): 0.58 (3H; d; COOCH2CHCH3), 0.69 (3H; d; COO
CH2CHCH3), 1.68–1.76 (H; m; CH(CH3)2), 2.14–2.55 (4H; m; H-6,
H-7), 2.32 (3H; s; 2-CH3), 3.58 (H; dd; CH2 ACH(CH3)2), 3.70 (H;
dd; CH2BCH(CH3)2), 5.17 (H; s; 4-H), 7.16–7.37 (3H; m; Ar-H),
9.78 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.6, 18.8, 20.7, 23.7,
27.0, 33.3, 35.9, 69.3, 103.1, 115.7, 127.8, 127.9, 129.1, 130.1,
131.4, 147.0, 147.1, 163.9, 166.4, 200.3. MS (m/z): 393 [M-1]+.
Anal. Calcd. for C20H21Cl2NO3: C, 60.92; H, 5.37; N, 3.55. Found:
C, 60.94; H, 5.07; N, 3.69.
2-Methoxyethyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetra-
hydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Com-
pound 24): Yield: 57. mp: 239 °C’dir. IR (ν, cm−1): 3343 (N-H),
1665 (C=O), 1279, 1096 (S=O). 1H-NMR (δ, DMSO-d6): 2.11 (H;
ddd; H-3A), 2.28 (3H; s; 5-CH3), 2.43 (H; ddd; H-3B), 3.02 (3H; s;
OCH3), 3.08 (H; ddd; H-2A), 3.21–3.35 (2H; m; CH2OCH3), 3.39
(H; ddd; H-2B), 3.78 (H; ddd; CH2 ACH2OCH3), 3.93 (H; ddd;
CH2BCH2OCH3), 4.59 (H; s; 7-H), 5.89 (H; s; N-H), 6.96–7.44 (3H;
m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.2, 33.8, 34.2, 48.6, 57.8,
65.9, 70.0, 82.5, 99.3, 111.7, 115.9, 123.8, 126.8, 133.0, 142.1,
148.4, 153.6, 166.4. MS (m/z): 398 [M-1]+. Anal. Calcd. for
C18H19F2NO5S: C, 54.13; H, 4.79; N, 3.51; S, 8.03. Found: C, 54.40;
H, 4.55; N, 3.55; S, 7.89.
Tert-butyl 2-methyl-4-(2,3-dichlorophenyl)-5-oxo-4,5,6,7-tetra-
hydro-1H-cyclopenta[b]pyridine-3-carboxylate (Compound 20):
Crystallized from ethyl acetate/n-hexane. Yield: 54%. mp: 193 °C.
IR (ν, cm−1): 3276 (N-H), 1697 (C=O, ester), 1634 (C=O, ketone).
1H-NMR (δ, DMSO-d6): 1.14 (9H; s; COOC(CH3)3), 2.11–2.51 (4H;
m; H-6, H-7), 2.21 (3H; s; 2-CH3), 5.08 (H; s; 4-H), 7.14–7.39
(3H; m; Ar-H), 9.66 (H; s; N-H). 13C-NMR (δ, DMSO-d6): 18.7,
23.5, 23.6, 23.7, 33.3, 35.9, 38.8, 63.7, 103.2, 115.6, 127.8, 127.9,
129.3, 130.2, 131.3, 132.7, 147.0, 163.9, 165.9, 200.4. MS (m/z):
394 [M]+. Anal. Calcd. for C20H21Cl2NO3: C, 60.92; H, 5.37; N,
3.55. Found: C, 60.84; H, 5.47; N, 3.59.
Allyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 25):
Yield: 64%. mp: 240 °C. IR (ν, cm−1): 3339 (N-H), 1666 (C=O),
gerilim), 1288, 1132 (S=O). 1H-NMR (δ, DMSO-d6): 2.12 (H;
ddd; H-3A), 2.29 (3H; s; 5-CH3), 2.40 (H; ddd; H-3B), 3.08 (H;
ddd; H-2A), 3.40 (H; ddd; H-2B), 4.37 (H; dd; CH2 ACH=CH2), 4.42
(H; dd; CH2BCH=CH2), 4.94 (H; dd; CH2CH=CH2A), 5.02 (H; dd;
CH2CH=CH2B), 5.18 (H; s; 7-H), 5.66–5.73 (H; m; CH=CH2),
6.69–7.49 (3H; m; Ar-H), 9.53 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 20.8, 30.1, 34.3, 49.2, 64.3, 83.0, 99.8, 115.7, 117.3, 124.2,
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

172 Original Article
125.4, 127.3, 129.6, 135.8, 142.5, 148.6, 150.2, 166.0. MS (m/z):
COOCH2A-CH3), 3.87 (H; dq; COOCH2B-CH3) 5.12 (H; s; H-7),
7.04–7.43 (3H; m; Ar-H), 9.51 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 14.1, 20.7, 30.6, 34.6, 51.0, 59.6, 81.1, 90.8, 112.0, 129.4,
133.1, 135.4, 142.6, 148.2, 154.0, 156.5, 166.9. EI-MS (m/z): 385
[M]+. Anal. Calcd. for C17H17ClFNO4S : C, 52.92; H, 4.44; N, 3.63;
S, 8.31. Found: C, 52.22; H, 4.61; N, 3.81; S, 8.42.
381 [M]+. Anal. Calcd. for C18H17F2NO4S: C, 56.69; H, 4.49; N,
3.67; S, 8.41. Found: C, 57.08; H, 4.45; N, 3.72; S, 8.45.
Isobutyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 26):
Yield: 68%. mp: 264 °C. IR (ν, cm−1): 3364 (N-H), 1683 (C=O),
1245, 1084 (S=O). 1H-NMR (δ, DMSO-d6): 0.55 (3H; d;
COOCHCH3), 0.58 (3H; d; COOCHCH3), 1.48–1.57 (H; m;
CH(CH3)2), 2.13 (H; ddd; H-3A), 2.32 (3H; s; 5-CH3), 2.46 (H; ddd;
H-3B), 3.03 (H; ddd; H-2A), 3.37 (H; ddd; H-2B), 3.49 (H; dd;
CH2ACH(CH3)2), 3.65 (H; dd; CH2BCH(CH3)2), 4.62 (H; s; 7-H),
5.88 (H; s; N-H), 7.01–7.45 (3H; m; Ar-H). 13C-NMR (δ, DMSO-
d6): 18.9, 19.0, 20.7, 27.6, 34.3, 34.7, 49.2, 69.9, 83.0, 99.9, 115.7,
124.0, 125.2, 127.3, 133.6, 142.5, 148.8, 154.1, 166.8. MS (m/z):
397 [M]+. Anal. Calcd. for C19H21F2NO4S: C, 57.42; H, 5.33; N,
3.52; S, 8.07. Found: C, 57.06; H, 4.94; N, 3.57; S, 8.34.
2-Methoxythyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-
tetrahydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide
(Compound 31): Yield: 64%. mp: 189 °C. IR (ν, cm−1): 3332
(N-H), 1665 (C=O), 1284, 1125 (S=O gerilim). 1H-NMR (δ,
DMSO-d6): 2.12 (H; ddd; H-3A), 2.28 (3H; s; 5-CH3), 2.42 (H;
ddd; H-3B), 3.01 (3H; s; OCH3), 3.08 (H; ddd; H-2A), 3.21–3.27
(2H; m; CH2OCH3), 3.38 (H; ddd; H-2B), 3.78 (H; ddd;
CH2 ACH2OCH3), 3.93 (H; ddd; CH2BCH2OCH3), 4.57 (H; s; 7-H),
5.88 (H; s; N-H), 7.02–7.38 (3H; m; Ar-H). 13C-NMR (δ, DMSO-
d6): 20.7, 29.0, 34.6, 51.2, 58.3, 66.3, 70.5, 81.1, 90.5, 119.5,
124.7, 128.6, 129.5, 129.8, 133.0, 150.3, 154.2,166.9. EI-MS
(m/z): 415 [M]+. Anal. Calcd. for C18H19ClFNO5S: C, 51.99; H,
4.61; N, 3.37; S, 7.71. Found: C, 51.10; H, 4.54; N, 3.49; S, 7.89.
Tert-butyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 27):
Yield: 58%. mp: 259 °C. IR (ν, cm−1): 3368 (N-H), 1684 (C=O),
1304, 1133 (S=O). 1H-NMR (δ, DMSO-d6): 1.09 (9H; s;
COOC(CH3)3), 2.12 (H; ddd; H-3A), 2.26 (3H; s; 5-CH3), 2.44 (H;
ddd; H-3B), 3.06 (H; ddd; H-2A), 3.39 (H; ddd; H-2B), 4.53 (H; s;
7-H), 5.89 (H; s; N-H), 6.99–7.27 (3H; m; Ar-H). 13C-NMR (δ,
DMSO-d6): 20.5, 28.2, 28.4, 28.7, 30.3, 34.5, 49.1, 80.9, 92.6,
101.2, 115.6, 124.9, 126.0, 134.3, 136.1, 142.4, 147.3, 153.0,
166.5. MS (m/z): 397 [M]+. Anal. Calcd. for C19H21F2NO4S: C,
57.42; H, 5.33; N, 3.52; S, 8.07. Found: C, 57.16; H, 5.28; N, 3.77;
S, 8.63.
Allyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 32):
Yield: 58%. mp: 232°C’dir. IR (ν, cm−1): 3335 (N-H), 1699 (C=O),
1
1281, 1129 (S=O). H-NMR (δ, DMSO-d6): 2.13 (H; ddd; H-3A),
2.34 (3H; s; 5-CH3), 2.44 (H; ddd; H-3B), 3.03 (H; ddd; H-2A),
3.39 (H; ddd; H-2B), 4.27 (H; dd; CH2 ACH=CH2), 4.35 (H; dd;
CH2BCH=CH2), 4.75 (H; s; 7-H), 4.84 (H; dd; CH2CH=CH2A), 4.93
(H; dd; CH2CH=CH2B) 5.57–5.65 (H; m; CH=CH2), 5.86 (H; s;
N-H) 7.22–7.57 (3H; m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.8,
30.6, 34.2, 51.0, 66.3, 83.0, 99.6, 119.6, 124.8, 125.6, 128.7, 129.3,
132.7, 133.8, 148.8, 150.3, 154.5, 166.5. EI-MS (m/z): 397 [M]+.
Anal. Calcd. for C18H17ClFNO4S : C, 54.34; H, 4.31; N, 3.52; S, 8.06.
Found: C, 54.03; H, 4.53; N, 3.71; S, 8.55.
Benzyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 28): Yield:
67%. mp: 237 °C’dir. IR (ν, cm−1): 3341 (N-H), aromatik), 1665
(C=O), 1288, 1131 (S=O). 1H-NMR (δ, DMSO-d6): 2.14 (H; ddd;
H-3A), 2.33 (3H; s; 5-CH3), 2.46 (H; ddd; H-3B), 3.05 (H; ddd;
H-2A), 3.39 (H; ddd; H-2B), 4.65 (H; s; 7-H), 4.77, 4.98 (1H, AB
system, JAB =13.2Hz, COOCH2C6H5), 5.94 (H; s; N-H) 6.81–7.55
(8H; m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.8, 28.6, 34.7, 51.0,
66.4, 81.2, 90.1, 115.3, 115.5, 124.1, 125.8, 127.2, 127.7, 128.4,
128.6, 133.5, 133.6, 137.4, 143.6, 149.9, 154.6, 166.6. MS (m/z):
430 [M-1]+. Anal. Calcd. for C22H19F2NO4S: C, 61.24; H, 4.44; N,
3.25; S, 7.43. Found: C, 61.52; H, 4.56; N, 3.29; S, 7.31.
Isobutyl5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 33):
Yield: 66%. mp: 243°C’dir. IR (ν, cm−1): 3339 (N-H), 1683 (C=O),
1304, 1132 (S=O). 1H-NMR (δ, DMSO-d6): 0.52 (3H; d;
COOCHCH3), 0.56 (3H; d; COOCHCH3), 1.48–1.55 (H; m;
CH(CH3)2), 2.11 (H; ddd; H-3A), 2.31 (3H; s; 5-CH3), 2.44 (H; ddd;
H-3B), 3.02 (H; ddd; H-2A), 3.38 (H; ddd; H-2B), 3.47 (H; dd;
CH2ACH(CH3)2), 3.62 (H; dd; CH2BCH(CH3)2), 4.58 (H; s; 7-H),
5.86 (H; s; N-H), 7.05–7.44 (3H; m; Ar-H). 13C-NMR (δ, DMSO-
d6): 18.9, 19.0, 20.7, 27.7, 34.2, 34.7, 49.2, 69.9, 83.0, 90.2, 112.2,
124.8, 125.7, 128.6, 129.5, 131.1, 142.5, 156.5, 166.8. MS (m/z):
413 [M]+. Anal. Calcd. for C19H21ClFNO4S : C, 55.14; H, 5.11; N,
3.38; S, 7.75. Found: C, 55.38; H, 4.51; N, 3.57; S, 7.27.
Methyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 29):
Yield: 59%. mp:245 °C. IR (ν, cm−1): 3346 (N-H), 1663 (C=O),
1
1303, 1128 (S=O). H-NMR (δ, DMSO-d6): 2.27 (3H; s; 5-CH3),
2.78 (H; ddd; H-3A), 2.85 (H; ddd; H-3B), 3.25 (H; ddd; H-2A),
3.33 (H; ddd; H-2B), 3.43 (3H; s; COOCH3), 5.13 (1H; s; H-7),
7.08–7.37 (3H; m; Ar-H), 9.51 (H; s; N-H). 13C-NMR (δ, DMSO-
d6): 19.2, 23.2, 30.9, 49.2, 51.3, 99.7, 112.0, 119.7, 125.6, 129.2,
134.9, 135.1, 142.7, 148.3, 156.0, 167.0. EI-MS (m/z): 370 [M-1]+.
Anal. Calcd. for C16H15ClFNO4S: C, 51.69; H, 4.07; N, 3.77; S, 8.62.
Found: C, 51.91; H, 3.74; N, 3.89; S, 8.45.
Tert-butyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetra-
hydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Com-
pound 34): Yield: 70%. mp: 241°C’dir. IR (ν, cm−1): 3340
1
(N-H), 1689 (C=O), 1304, 1132 (S=O). H-NMR (δ, DMSO-d6):
1.05 (9H; s; COOC(CH3)3), 2.10 (H; ddd; H-3A), 2.23 (3H; s;
5-CH3), 2.42 (H; ddd; H-3B), 3.06 (H; ddd; H-2A), 3.38 (H; ddd;
H-2B), 4.49 (H; s; 7-H), 5.86 (H; s; N-H), 7.05–7.40 (3H; m; Ar-H).
13C-NMR (δ, DMSO-d6): 20.0, 27.5, 27.6, 27.7, 30.3, 34.0, 48.5,
80.4, 92.1, 99.1, 124.4, 125.2, 128.4, 129.2, 130.6, 133.3, 149.8,
156.0, 166.0. MS (m/z): 413 [M]+. Anal. Calcd. for C19H21ClFNO4S :
C, 55.14; H, 5.11; N, 3.38; S, 7.75. Found: C, 55.17; H, 4.95; N,
3.61; S, 7.05.
Ethyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 30):
Yield: 56%. mp: 239 °C. IR (ν, cm−1): 3348 (N-H), 1663 (C=O),
1287, 1127 (S=O). 1H-NMR (δ, DMSO-d6): 0.97 (3H; t;
COOCH2CH3), 2.12 (H; ddd; H-3A), 2.28 (3H; s; 5-CH3), 2.45 (H;
ddd; H-3B), 3.03 (H; ddd; H-2A), 3.37 (H; ddd; H-2B), 3.74 (H; dq;
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

Original Article 173
N-H), 7.22–7.57 (3H; m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.8,
Benzyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 35):
Yield: 72%. mp: 208°C. IR (ν, cm−1): 3348 (N-H), 1664 (C=O),
30.5, 34.1, 51.0, 65.5, 91.0, 100.1, 115.7, 127.6, 128.8, 129.8,
130.5, 131.7, 133.7, 139.3, 150.4, 154.4, 166.5. EI-MS (m/z): 413
[M-1]+. Anal. Calcd. for C18H17Cl2NO4S : C, 52.18; H, 4.14; N, 3.38;
S, 7.74. Found: C, 52.29; H, 4.26; N, 3.43; S, 7.72.
1
1303, 1130 (S=O). H-NMR (δ, DMSO-d6): 2.12 (H; ddd; H-3A),
2.33 (3H; s; 5-CH3), 2.43 (H; ddd; H-3B), 3.04 (H; ddd; H-2A),
3.38 (H; ddd; H-2B), 4.61 (H; s; 7-H), 4.74, 4.94 (1H, AB system,
JAB =13.2Hz, COOCH2C6H5), 5.90 (H; s; N-H), 6.77–7.54 (8H; m;
Ar-H). 13C-NMR (δ, DMSO-d6): 20.8, 29.0, 34.7, 49.2, 66.8, 83.0,
89.9, 124.9, 125.6, 127.7, 128.1, 128.6, 129.1, 129.6, 131.1, 132.8,
133.0, 136.7, 137.4, 142.5, 156.5, 166.6. EI-MS (m/z): 447 [M]+.
Anal. Calcd. for C22H19ClFNO4S : C, 58.99; H, 4.28; N, 3.13; S, 7.16.
Found: C, 58.12; H, 4.43; N, 3.34; S, 7.73.
Isobutyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 40):
Yield: 58%. mp: 244 °C. IR (ν, cm−1): 3345 (N-H), 1663 (C=O),
1302, 1128 (S=O). 1H-NMR (δ, DMSO-d6): 0.52 (3H; d;
COOCHCH3), 0.56 (3H; d; COOCHCH3), 1.47–1.54 (H; m;
CH(CH3)2), 2.12 (H; ddd; H-3A), 2.30 (3H; s; 5-CH3), 2.44 (H; ddd;
H-3B), 3.04 (H; ddd; H-2A), 3.39 (H; ddd; H-2B), 3.48 (H; dd;
CH2ACH(CH3)2), 3.61 (H; dd; CH2BCH(CH3)2), 4.73 (H; s; 7-H),
5.84 (H; s; N-H), 7.22–7.47 (3H; m; Ar-H). 13C-NMR (δ, DMSO-
d6): 18.9, 19.0, 20.6, 27.7, 34.1, 34.8, 51.1, 68.9, 81.3, 91.1, 127.6,
128.7, 129.5, 130.5, 131.8, 133.2, 143.5, 154.1, 166.9. EI-MS
(m/z): 429 [M-1]+. Anal. Calcd. for C19H21Cl2NO4S : C, 53.03; H,
4.92; N, 3.25; S, 7.45. Found: C, 53.19; H, 4.89; N, 3.35; S, 7.79.
Methyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 36): Yield:
48%. mp: 230 °C. IR (ν, cm−1): 3373 (N-H), 1660 (C=O), 1299,
1127 (S=O). 1H-NMR (δ, DMSO-d6): 2.11 (H, ddd, H-3A), 2.32
(3H; s; 5-CH3), 2.42 (H, ddd, H-3B), 3.01 (H, ddd, H-2A), 3.34 (3H;
s; COOCH3), 3.40 (H, ddd, H-2B), 4.69 (1H; s; H-7), 5.82 (H; s;
N-H), 7.18–7.46(3H; m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.8,
34.2, 34.8, 50.7, 51.1, 81.5, 91.2, 127.7, 128.8, 129.4, 129.8, 130.5,
131.8, 143.2, 153.9, 167.6. DEPT-135 (δ, DMSO-d6): 20.8 (CH3),
34.2 (CH), 34.8 (CH2), 50.7 (CH2), 51.1 (CH3), 127.7 (CH), 128.8
(CH),129.4 (CH). EI-MS (m/z): 388 [M]+. Anal. Calcd. for
C16H15Cl2NO4S: C, 49.50; H, 3.89; N, 3.61; S, 8.26. Found: C,
49.10; H, 4.15; N, 3.62; S, 8.01.
Tert-butyl 5-methyl-(2,3-dichlorophenyl)-2,3,4,7-tetrahydro-
thieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 41):
Yield: 58%. mp: 248 °C. IR (ν, cm−1): 3344 (N-H), 1689 (C=O),
1364, 1156 (S=O). 1H-NMR (δ, DMSO-d6): 1.06 (9H; s;
COOC(CH3)3), 2.11 (H; ddd; H-3A), 2.28 (3H; s; 5-CH3), 2.44 (H;
ddd; H-3B), 3.06 (H; ddd; H-2A), 3.37 (H; ddd; H-2B), 4.65 (H; s;
7-H), 5.75 (H; s; N-H), 7.19–7.47 (3H; m; Ar-H). 13C-NMR (δ,
DMSO-d6): 19.8, 27.5, 27.6, 27.7, 30.0, 34.1, 48.5, 80.6, 92.9,
101.9, 121.1, 128.0, 129.1, 130.8, 131.2, 131.4, 143.8, 152.6,166.1.
EI-MS (m/z): 429 [M-1]+. Anal. Calcd. for C19H21Cl2NO4S : C,
53.03; H, 4.92; N, 3.25; S, 7.45. Found: C, 53.38; H, 4.74; N, 3.35;
S, 7.79.
Ethyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 37): Yield:
53%. mp: 228 °C. IR (ν, cm−1): 3369 (N-H), 1660 (C=O), 1299,
1
1093 (S=O). H-NMR (δ, DMSO-d6): 0.81 (3H; t; COOCH2CH3),
2.12 (H; ddd; H-3A), 2.31 (3H; s; 5-CH3), 2.44 (H; ddd; H-3B),
3.03 (H; ddd; H-2A), 3.36 (H; ddd; H-2B), 3.71 (H; dq; COOCH2A
-
Benzyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 42): Yield:
55%. mp: 214 °C. IR (ν, cm−1): 3359 (N-H), 1661 (C=O), 1300,
1178 (S=O). 1H-NMR (δ, DMSO-d6): 2.13 (H; ddd; H-3A), 2.35
(3H; s; 5-CH3), 2.44 (H; ddd; H-3B), 3.04 (H,; ddd; H-2A), 3.39 (H;
ddd; H-2B), 4.73, 4,94 (1H, AB system, JAB =12.8Hz, COOCH2C6H5),
4.75 (H; s; 7-H), 5.88 (H; s; N-H), 6.77–7.56 (8H; m; Ar-H). 13C-
NMR (δ, DMSO-d6): 20.7, 34.1, 34.7, 51.1, 64.3, 81.3, 90.9, 127.0,
127.7, 128.4, 128.8, 129.5, 129.9, 130.6, 130.8, 131.2, 131.9,
132.3, 137.3, 143.4, 154.7, 166.6. EI-MS (m/z): 464 [M]+. Anal.
Calcd. for C22H19Cl2NO4S : C, 56.90; H, 4.12; N, 3.02; S, 6.90.
Found: C, 56.06; H, 4.43; N, 3.10; S, 6.95.
CH3), 3.82 (H; dq; COOCH2B-CH3) 4.72 (H; s; H-7), 5.86 (H; s;
N-H), 7.22–7.47 (3H; m; Ar-H). 13C-NMR (δ, DMSO-d6): 14.3,
20.6, 30.5, 34.3, 51.1, 58.5, 81.3, 91.8, 127.6, 128.6, 129.5, 130.5,
131.6, 131.9, 143.7, 153.7, 167.0. EI-MS (m/z): 401 [M-1]+. Anal.
Calcd. for C17H17Cl2NO4S: C, 50.76; H, 4.26; N, 3.48; S, 7.97.
Found: C, 50.98; H, 4.22; N, 3.53; S, 8.03.
2-Methoxythyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetra-
hydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Com-
pound 38): Yield: 41%. mp: 196 °C. IR (ν, cm−1): 3345 (N-H),
1663 (C=O), 1355, 1129 (S=O). 1H-NMR (δ, DMSO-d6): 2.12 (H,
ddd, H-3A), 2.32 (3H, s, 5-CH3), 2.44 (H, ddd, H-3B), 3.02 (3H; s;
OCH3), 3.08 (H, ddd, H-2A), 3.21–3.29 (2H; m; CH2OCH3), 3.40
(H, ddd, H-2B), 3.78 (H; ddd; CH2A CH2OCH3), 3.92 (H; ddd;
CH2BCH2OCH3), 4.73 (H; s; 7-H), 5.86 (H; s; N-H), 7.20–7.48 (3H;
m; Ar-H). 13C-NMR (δ, DMSO-d6): 20.6, 34.3, 34.7, 48.9, 58.3,
65.6, 70.5, 91.4, 100.1, 127.5, 128.6, 129.8, 130.5, 131.6, 139.3,
143.5, 154.1, 166.9. EI-MS (m/z): 432 [M]+. Anal. Calcd. for
C18H19Cl2NO5S: C, 50.01; H, 4.43; N, 3.24; S, 7.42. Found: C,
50.22; H, 4.50; N, 3.31; S, 7.92.
Pharmacology
The relaxant effects of the compounds and nicardipine on iso-
lated rat ileum, on rat thoracic artery and the half maximal
effective concentration (EC50) of the selected compounds are
▶
given in● Table 1, 2.
Discussion
▼
Allyl 5-methyl-7-(2,3-dichlorophenyl)-2,3,4,7-tetrahydrothieno-
[3,2-b]pyridine-6-carboxylate-1,1-dioxide (Compound 39): Yield:
47%. mp: 188 °C. IR (ν, cm−1): 3342 (N-H), 1664 (C=O), 1303,
1129 (S=O). 1H-NMR (δ, DMSO-d6): 2.13 (H; ddd; H-3A), 2.34
(3H; s; 5-CH3), 2.44 (H; ddd; H-3B), 3.03 (H; ddd; H-2A), 3.39 (H;
ddd; H-2B), 4.27 (H; dd; CH2 ACH=CH2), 4.35 (H; dd;
CH2BCH=CH2), 4.75 (H; s; 7-H), 4.84 (H; dd; CH2CH=CH2A), 4.93
(H; dd; CH2CH=CH2B) 5.57–5.65 (H; m; CH=CH2), 5.86 (H; s;
In this work a series of condensed 1,4-dihydropyridines were
prepared via modified Hantzsch reaction. The structures of the
compounds were elucidated by IR, 1H-NMR, 13C-NMR, DEPT,
COSY and mass spectra. Elemental analysis results were
within±0.4% of theoretical values for all compounds. Their cal-
cium channel modulator activities were investigated on isolated
rat ileum and thoracic aorta.
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

174 Original Article
Table 1 Relaxant effects of the synthesized compounds and nicardipine (10−5 mol/L).
Compound
Inhibition % a
Inhibition % b
Compound
Inhibition % a
Inhibition % b
1
2
89.00±13.05
93.50±8.67
4.18±1.53*
3.77±0.99*
–
22
78.67±23.14
88.00±15.60
0
3.08±1.74*
23
2.80±1.82*
3
47.00±23.07 *
58.50±14.27*
48.83±8.04 *
27.50±10.75*
99.17±2.04
24
–
4
3.42±1.31*
–
25
80.12±9.55
7.68±2.38
5
26
47.40±16.00*
45.60±14.66 *
65.83±15.68 *
91.40±12.88
89.40±11.22
26.25±19.92 *
88.33±16.26
39.83±11.90*
52.20±20.00*
40.60±16.47*
82.67±15.98
75.83±21.70
48.67±11.53 *
60.33±19.17 *
73.83±16.20 *
37.83±15.54 *
37.60±10.79 *
93.30±7.42
–
6
–
27
–
7
2.15±1.42 *
3.42±0.97*
2.12±1.60 *
–
28
4.96±1.39*
8
77.00±21.37
53.00±17.58 *
47.80±18.66 *
100.00±0
29
0
9
30
0
10
11
12
13
14
15
16
17
18
19
20
21
31
–
1.83±1.13*
2.73±1.19*
–
32
3.82±2.11*
100.00±0
33
0
43.50±11.90 *
61.60±28.95*
96.83±4.99
34
3.30±2.71*
3.08±0.78*
5.38±1.78
4.62±2.77*
1.72±0.90*
3.10±1.25*
5.02±1.36*
2.60±1.54*
2.98±0.74*
9.13±3.83
35
–
36
0
84.33±23.35
76.67±19.79
67.40±27.29 *
88.00±14.35
54.50±26.40*
66.50±22.00*
93.30±7.42
37
1.55±0.9*
38
0
39
4.88±2.89
40
0
41
0
42
3.21±2.04*
9.13±3.83
Nicardipine
Nicardipine
a
Studies on isolated rat ileum precontracted with barium chloride (4×10−3 M)
b Studies on rat thoracic artery precontracted with potassium chloride (67mmol/L)
*p<0.05, compared with control responses (n=6)
Table 2. E C 50 values of the synthesized compounds and nicardipine on
isolated rat ileum.
Fig. 4 The molecular
structure of compound
14.
C13
C14
C11
C12
C15
C20
Compound
EC50
C19
C18
1
0.34±0.17×10−7
2.66±1.53×10−7
0.14±0.08×10−7
1.32±0.35×10−7
2.88±1.67×10−7
4.63±2.98×10−7
6.22±4.78×10−7
0.85±0.68×10−7
0.55±0.33×10−7
8.12±1.94×10−7
7.66±4.46×10−7
4.25±2.72×10−7
2.17±1.46×10−7
0.90±0.60×10−7
4.00±1.27×10−6
4.27±1.85×10−7
1.33±0.34×10−7
*
*
C11
C16
C21
2
F1
C10
7
C22
C17
11
O2
C9
O5
C4
12
C5
C3
C4a
O1
15
16
C2
C6
19
C8
C7a
N1
C7
23
*
25
28
29
30
32
is an interaction between the methylene groups of the cyclopen-
tanone ring. The mass spectra of the compounds were recorded
via the electron ionization technique. The molecular ion peak
(M+) or the M-1 peak due to the aromatisation of the DHP ring to
the pyridine analogue were seen in the spectra of compounds.
Cleavage of the ester groups and phenyl rings from the parent
molecule are the next most observed fragmentations.
36
39
Nicardipine
*p< 0.05, compared with control responses
In the IR spectra, characteristic N-H, C=O (ester), C=O (ketone)
and S=O stretching bonds were observed. In the 1H-NMR, while
the protons of the cyclohexanone ring were at 2.10–2.59 ppm as
multiplet, each proton of the tetrahydrothiophene ring was
observed at 2.10–3.40ppm seperately and as doublet of doublet
of doublets (ddd). The methyl and methine protons on the DHP
ring were seen at 2.21–2.35 ppm and 4.69–5.71ppm, respec-
tively. The protons, which are on the aromatic rings, were seen
at 6.69–7.57ppm. The N-H signals were observed at either 5.75–
5.94ppm or 9.48–9.90ppm as singlets. In the 13C-NMR spectra
the number of the signals fitted exactly the number of carbon
atoms. The COSY spectrum of Compound 15 indicates that there
The structure of the compound 14 was also confirmed by an
X-ray crystal structure analysis (● Fig. 4). A detailed description
▶
of the structure has been presented in [21]. It was founded that,
1,4-DHP ring has very shallow boat conformation, whereas the
oxocyclopentene ring is planar and there is an intermolecular
N-H…….O hydrogen bond between the amine group and the car-
bonyl O atom of the oxocyclopentene ring of a neighbouring
molecule.
On isolated rat ileum strips precontracted with barium chloride
(4×10−3 M) compounds 2, 7, 11, 12 and 15 are more active than
the standard compound, nicardipine, at 10−5 M concentration
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175

Original Article 175
References
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Acknowledgements
▼
This study was supported by Hacettepe University, Scientific
Research and Development Office (Project No: 1713) and The
Scientific and Technological Research Council of Turkey-National
Scholarship Programme for PhD Students.
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Conflict of Interest
▼
All authors of the article declare no conflict of interest.
Gündüz MG et al. Synthesis of Cyclopentapyridine and… Arzneimittelforschung 2012; 62: 167–175