Synthesis of 3,3-dialkyl-6-phenyl-imidazo-pyridinones designed as progestrone receptor modulator

Article abstract of DOI:10.1002/jhet.5570430540

When a known 2-[4-morpholino]-3-aryl-5-substituted thiophene, which showed moderate activity as a progesterone antagonist, was superimposed with a potent steroidal progesterone antagonist Org-33628, it showed a fair alignment in most parts of the molecule

Full text of DOI:10.1002/jhet.5570430540

Sep-Oct 2006
1391
Synthesis of Trisubstituted Thiophenes Designed as
Progesterone Receptor Modulator
Weiqin Jiang,* James J. Fiordeliso, Xin Chen, Zhihua Sui
Johnson & Johnson Pharmaceutical Research & Development L.L.C.,
1000 Route 202, Raritan, NJ 08869
Received February 8, 2006
N
O
O
N
S
R
N
O
When a known 2-[4-morpholino]-3-aryl-5-substituted thiophene, which showed moderate activity as a
progesterone antagonist, was superimposed with a potent steroidal progesterone antagonist Org-33628, it
showed a fair alignment in most parts of the molecules. According to the molecular modelling,
displacement of the morpholine oxygen atom in the thiophene derivative with a carbonyl group would
provide a better alignment with the C-3 carbonyl in Org-33628. Thus, a series of novel trisubstituted
thiophenes bearing a cyclic ketone moiety was synthesized. Although these compounds only showed weak
activities as progesterone receptor antagonists, all target compounds are novel and are fully characterized.
J. Heterocyclic Chem., 43, 1391 (2006).
Introduction.
Interestingly, when compound 1 was superimposed
with compound 2, using the automatic superimposition
program FlexS [5], it showed a fair alignment in most
parts of the molecules. The substituents at the 2- and 5-
positions in compound 1 together with the thiophene ring
spread out to mimic the steroid backbone in Org-33628,
while the 3-phenyl group mimics the C-11 phenyl group
in the steroid. The crystal structure of progesterone [6]
complexed with PR indicates that the C-3 carbonyl forms
hydrogen bonding directly or through two water
molecules with Gln 725 and Arg 766. This, together with
the C17-side chain carbonyl, forms the hydrogen-bonding
network between progesterone and its receptor. Close
examination of the aligned structures (Figure 2) provided
some hints for further structure modifications. For
example, displacement of the morpholine oxygen atom in
the thiophene derivatives with a carbonyl group would
provide better alignment with the C-3 carbonyl in Org-
33628.
Progesterone plays a central role in the regulation of
female reproduction [1]. Two main indications for the use
of progesterone receptor modulators (PRMs) are breast
cancer and fertility regulation. Compound 2, Org-33628
[2], is a highly selective progesterone receptor modulator
with respect to its anti-progestational and anti-glucocort-
icoidal activity. Recently, some non-steroidal compounds
[3] were identified as progesterone receptor (PR)
antagonists and also showed a high degree of selectivity
versus the antagonistic activity on glucocorticoid
receptors (GR).
In searching for non-steroidal progesterone receptor
antagonists [4], we found a known tri-substituted
thiophene to be weakly active in the PRM screening
program (Figure 1). When compound 1 was evaluated
for PR antagonist activity based on its ability to block
progesterone induced alkaline phosphatase in the
T47D human breast cancer cell line, it had an IC50 of
3200 nM.
This modification led us to synthesize a series of the
hitherto unknown tri-substituted thiophenes. We incor-
porated a pyridine ring in our designed structures in the
hope of increasing solubility to improve the physical and
chemical properties of the target molecules.
O
O
O
11
N
S
O
Results and Discussion.
1
3
2. Org-33628
O
Trisubstituted thiophenes are a common structural motif
in numerous biologically relevant targets [8].
A
Figure 1. The structures of compound 1 and 2.
convenient synthesis, designed to rapidly assemble this

1392
W. Jiang, J. J. Fiordeliso, X. Chen, Z. Sui
Vol 43
motif, is presented in this paper. Thus, a four-step
synthetic pathway to novel trisubstituted thiophenes
bearing a cyclic ketone is shown in Scheme 1.
primary amine bearing alkyl chain or aromatic group,
secondary amine bearing dialkyl chains or diaryl groups
or aryl and alkyl groups. Consistent with literature
reports for similar systems, the reaction proceeds
smoothly in high yield and can be carried out on
multigram scale. Condensation of thioamide 12 with
ethyl orthoformate followed by imine formation with
morpholine gave the key intermediate 3-amino
thioacrylamide 13. By allowing 13 and 14 to react in a
stoichiometric manner using a polar solvent, such as
acetonitrile or methanol, a 1-benzoyl methylmercapto-
substituted vinamidinium salt of the structure 15
(shown in Scheme 3) is generated. The salt 15, can be
converted in situ by addition of a suitable base, such as
triethylamine or sodium methoxide, under reflux, into
the 5-benzoyl substituted 2-aminothiophene derivative
16. As demonstrated with a series of different ꢀ-bromo
ketones 14, this heterocyclisation reaction gives low to
moderate yield (20 – 40%) of products bearing
structure 17.
Figure 2. Compound 1 was flexibly aligned onto compound 2, using
program FlexS. Compound 1 is shown in green, Org-33628 in gray.
Sulfur is shown in yellow and oxygen in red.
A proposed mechanism for thiophene formation is
shown in Scheme 2. Thus, the 3-amino thioacrylamide 13
condenses with ꢁ-bromoketone 14 to generate iminium
In order to access the substrate type designed from
molecular modeling, and to make the synthetic route
more amenable to a large number of compounds, we
utilized the Willgerodt-Kindler (W-K) reaction [7] to
generate thioacetamides 12 in one step. Thus, the
ketone 10 was reacted with sulfur and the high boiling
point cyclic amine 11 in the presence of a catalytic
amount of acid under heat to generate the
salt 15.
Proton abstraction in compound 15 and
intramolecular cyclization reaction with iminium ion
provided a dihydrothiophene core 16. Dehydroamination
of compound 16 resulted in compound 17. At this point,
it is uncertain whether the reaction proceeds via a
carbanion intermediate (E1cb, AxhDH + DN) or via the
concerted loss of a proton and the amine (E2, ANDEDN)
upon the base attack. Due to the electronegativity of
carbonyl group and electron negativity of nitrogen on
morpholinyl group, it is more likely that the reaction went
through E1cb mechanism [9]. Due to the stoichiometric
amount of HBr generated in the reaction, ketal group in
compound 13 was cleaved. The resulting ketone may
thioacetamide 12.
Although W-K reaction was
discovered for a while, there are still a lot of room for
detailed mechanism, as seen in reference 7a and 7c.
The hallmark of the W-K reaction is its cleanliness,
ease of purification, and tolerance of different
functionalities. Amines can range from ammonium,
Scheme 1
O
O
N
O
O
N
ii
N
Br
i
+
N
54%
N
N
R
O
86%
S
O
S
14
10
13
12
O
N
N
O
O
iii
20% - 40%
N
S
iv
50% - 80%
N
S
R
O
R
O
O
17
18
i) p-TSA, S8, 1,4-dioxa-8-aza-spiro[4.5]decane 11, 120oC; ii) HC(OEt)3, morpholine, 160oC; iii) Et3N, 65oC, iv) p-TSA, reflux in acetone.
Synthetic route for compound 17 and 18.

Sep-Oct 2006
Synthesis of Trisubstituted Thiophenes Designed
as Progestrone Receptor Modulator
1393
Scheme 2
N
O
N
O
O
N
Et3N, 65oC,
20% - 40%
+
Br
N
S
O
N
O
13
S
14
O
O
17
Br-
HN
O
O
O
N
N
N
N+
N
S
N
O
O
O
H+
O
S
O
H
O
16
15
Proposed mechanism of formation of compound 17 from compound 13 and 14.
compete with the major reaction pathway, thus leading to
a decrease in yield for formation of compound 17.
This is in consistency with our observation that the
reactions of thioacrylamides without ketal functionality,
such as 19, proceed with higher yields (shown in Scheme
3), to generate thiophene 21.
Both thiophene 17 and 18 were evaluated for PR
antagonist activity based on their ability to block
progesterone induced alkaline phosphatase in the human
breast cancer cell line (T47D) [4c]. On the contrary to the
predictions by molecular modeling, both of compound 17
and 18 showed very weak activities as progesterone
Scheme 3
N
O
O
N
O
O
Et3N, 65oC
N
Br
+
N
S
R
N
O
S
20
19
21
R
a. R = 3,4-di-chloro, 87%
b. R = 4-NO2, 55%
Yields for compound 21.
As shown in Scheme 2, deprotection of ketal group in
compound 17 under acidic conditions afforded final
product 18. In order to maximize the coverage of the
parameter space with fewest compounds, we selected
various aryl substituents of ꢀ-bromo-aryl ketone 14 based
on the Topliss Tree principle [10]. We also included an
alkyl bromoketone for SAR purpose (see compound 18i).
The yields of compound 18 are listed in Table 1. All of
the heterocyclic ketones 17 and 18 described here are new
antagonists. At the present time, we do not have any
explanations. From the modeling result, the modification
of benzoyl group at 5-position on thiophene ring to
introduce more rigidity to the molecule might be helpful.
In summary, we have prepared a series of novel
trisubstituted thiophenes bearing a cyclohexyl ketone side
chain. Although these compounds only showed weak
activities as progesterone receptor antagonists, the
molecular modelling work and the synthetic methodology
are highly useful for the design and synthesis of additional
compounds.
The structures were unambiguously
confirmed by 1HNMR, MS, elemental analysis and
HRMS.
substituted thiophene derivatives.
Potentially, these
compounds can be further derivatized, owing to their

1394
W. Jiang, J. J. Fiordeliso, X. Chen, Z. Sui
Vol 43
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-
pyridin-4-yl-propenethione (13).
reactive carbonyl moiety, to other pharmaceutically useful
thiophenes.
Table 1
Physical and Analytical Data of Compounds 18a – 18i
R
Comp
Molecular
Formula
HR
Calc’d
MS
Found
Anal.
Calc’d
Yield
(%)
%
Found
Ph
18a
18b
18c
63
69
74
C21H18N2O2S
C21H17FN2O2S
C21H17ClN2O2S
363.1167
381.1073
397.0777
363.1168
381.1080
397.0767
C
H
N
4-F-ph
4-Cl-ph
63.55
63.29
4.32
4.20
7.06
7.06
2-MeO-ph
3,5-di-CF3-ph
4-NO2-ph
3-MeO-ph
3-Br-ph
18d
18e
18f
48
33
47
73
71
C22H20N2O3S
C23H16F6N2O2S
C21H17N3O4S
C22H20N2O3S
C21H17ClN2O2S
393.1273
499.0915
408.1018
393.1273
441.0272
393.1289
499.0914
408.1024
393.1280
441.0263
18g
18h
57.15
57.48
64.94
64.16
3.88
3.93
5.77
5.77
6.35
5.97
8.91
8.52
Et
18i
60
C17H18N2O2S
315.1167
315.1171
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethane-
thione (20.0 g, 72.0 mmol), HC(OEt)3 (21.3 g, 144 mol),
morpholine (48.0 g, 55.0 mmol) was stirred at 125 ºC for 4 h.
The solvent and excess reagent were distilled out at 100 ºC
under house vacuum. The residue formed a yellow solid. After
30 min at 0 ºC, the solid was collected, washed with water (10
mL) and dried overnight under air suction to provide the product
(20.0 g, 54 %). 1H NMR (CDCl3) ꢁ 8.3 – 8.4 (m, 2H), 7.0 –7.1
(m, 2H), 6.40 (s, 1H), 4.6 – 4.7 (m, 1H), 4.3 – 4.4 (m, 1H), 3.8 –
4.0 (m, 4H), 3.5 – 3.7 (m, 6H), 3.50 (s, 4H), 3.2 – 3.4 (m, 2H),
2.1 – 2.2 (m, 1H), 1.7 – 1.6 (m, 2H); MS (m/z): 376 (MH+).
EXPERIMENTAL
General Information for Chemistry.
NMR spectra were obtained at 400 MHz and 300 MHz on a
Bruker AVANCE300 and AVANCE400 spectrometer.
Chemical shifts are reported in ppm downfield from TMS as an
internal standard. Thin-layer chromatography was carried out
using 2.5 ꢀ 7.5 ꢀcm silica gel 60 (250 μM layer) plates with UV
detection. Magnesium sulfate was employed to dry organic
extracts prior to concentration by rotary evaporation. Flash
chromatography was done using EM science silical gel 60 (230 -
400 mesh). Standard solvents from J. T. Baker were used as
received. Anhydrous solvents from J. T. Baker or Aldrich and
all other commercially available reagents were used without
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-phenyl-methanone (17a).
A mixture of 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-mor-
pholin-4-yl-2-pyridin-4-yl-propenethione (374.5 mg, 1.00 mmol),
2-bromo-1-(4-nitro-phenyl)-ethanone (374.5 mg, 1.00 mmol), 2-
bromo-1-phenyl-ethanone (199.0 mg, 1.00 mmol), and triethyl-
amine (0.140 mL, 1.00 mmol) in methanol (10.0 mL) was
heated for 1.5 h at 65 °C. The temperature was increased to 75
°C and heated for 3 h then stirred overnight at room temperature.
Water (50.0 mL) and ethyl acetate (50.0 mL) were added. The
aqueous layer was extracted twice with ethyl acetate (50.0 mL).
The organic extracts were washed with brine, dried, filtered, and
evaporated. The crude material was purified by prep TLC
eluting with 2% methanol/dichloromethane. The product was
obtained as a yellow solid (114 mg, 28.0%). 1H NMR (CDCl3)
ꢁ 8.5 – 8.4 (m, 2H), 7.8 – 7.7 (m, 2H), 7.6 – 7.4 (m, 6H), 4.01 (s,
4H), 3.3 – 3.2 (m, 4H), 1.9 – 1.7 (m, 4H); MS (m/z): 407 (MH+);
further purification.
Microanalysis was carried out by
Quantitative Technologies Inc., Whitehouse, NJ. Mass spectra
were obtained on a Hewlett-Packard 5989A quadrupole mass
spectrometer. Silica gel (E. Merck, 230 - 400 mesh) was used
for all flash chromatography. Thin-layer chromatography was
performed on Analtech silica gel GF prescored plates (250 μm).
HPLC analysis was carried on Agilent 1100 Series LC/MSD
equipment.
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-pyridin-4-yl-ethane-
thione (12).
1-Pyridin-4-yl-ethanone (12.1 g, 0.10 mol), sulfur (3.36 g,
0.105 mol) and 1,4-dioxa-8-aza-spiro[4.5]decane were mixed
with p-toluene sulfonic acid (0.50 g, 2.8 mmol) and heated to
120 °C for 3 h. The slurry was poured into MeOH (50 mL). A
bright yellow solid precipitated out. This was collected by
filtration and washed with another 20 mL of MeOH. The solid
was dried to provide the product (24.0 g, 86.3 %). 1H NMR
(CD3OD) ꢁ 8.4 – 8.3 (m, 2H), 7.3 – 7.4 (m, 2H), 4.4 – 4.3 (m,
4H), 4.0 – 3.9 (m, 4H), 3.8 – 3.9 (m, 2H), 1.7 – 1.9 (m, 2H), 1.4
–1.5 (m, 2H); MS (m/z): 279 (MH+).
HRMS:
407.1436.
calc’d MH+ for C23H22N2O3S 407.1429; found
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-(4-fluoro-phenyl)-methanone (17b).
The title product was prepared in 33% yield according to the
procedure described for compound 17a using 1-(1,4-dioxa-8-
aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propen-

Sep-Oct 2006
Synthesis of Trisubstituted Thiophenes Designed
as Progestrone Receptor Modulator
1395
ethione and 2-bromo-1-(4-fluoro-phenyl)-ethanone as starting
material. 1H NMR (CDCl3) ꢀ 8.61 (dd, J = 1.5, 4.6 Hz, 2H), 7.9 –
7.8 (m, 2H), 7.6 – 7.5 (m, 3H), 7.2 – 7.1 (m, 2H), 4.0 (s, 4H), 3.23
(t, J = 5.7 Hz, 4H), 1.83 (t, J = 5.7 Hz, 4H); MS (m/z): 425 (MH+).
trifluoromethyl-phenyl)-2-bromo-ethanone as starting material.
1H NMR (CDCl3) ꢀ 8.6 – 8.5 (m, 2H), 7.9 – 7.3 (m, 7H), 3.94
(s, 4H), 3.3 – 3.2 (m, 4H), 1.8 – 1.7 (m, 4H); MS (m/z): 485, 487
(MH+); HRMS: calc’d MH+ for C23H21BrN2O3S 485.0534; found
485.0514.
(4-Chloro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-
pyridin-4-yl-thiophen-2-yl]-methanone (17c)
1-[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thio-
phen-2-yl]-1-one (17i).
The title product was prepared in 29% yield according to the
procedure described for compound 17a using 1-(1,4-dioxa-8-
azaspiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propene-
thione (374.5 mg, 1.00 mmol), 2-bromo-1-(4-chloro-phenyl)-
ethanone (233.0 mg, 1.00 mmol) as starting material. 1H NMR
(CDCl3) ꢀ 8.6 – 8.5 (m, 2H), 7.8 – 7.7 (m, 2H), 7.5 – 7.4 (m,
5H), 3.98 (s, 1H), 3.24 (t, J = 5.7 Hz, 4H), 1.83 (t, J = 5.8 Hz,
4H); MS (m/z): 441 (MH+); HRMS: calc’d MH+ for
C23H21ClN2O3S 441.1039; found 441.1025.
The title product was prepared in 22% yield as a white solid
according to the procedure described for compound 17a using
1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-
4-yl-propenethione (374.5 mg, 1.00 mmol), 1-bromo-butan-2-
one (90%, 0.11 mL, 1.00 mmol) as starting material. 1H NMR
(CDCl3) ꢀ 8.62 (dd, J = 1.5, 4.6 Hz, 2H), 7.65 (s, 1H), 7.55 (dd,
J = 1.5, 4.6 Hz, 2H), 3.97 (s, 4H), 3.17 (t, J = 5.7 Hz, 4H), 2.85
(q, J = 7.4 Hz, 2H), 1.82 (t, J = 5.7 Hz, 4H), 1.23 (t, J = 7.4 Hz,
3H); MS (m/z): 359 (MH+); HRMS:
C19H22N2O3S 359.1429; found 359.1420.
calc’d MH+ for
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-(2-methoxy-phenyl)-methanone (17d).
1-(5-Benzoyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one
(18a).
The title product was prepared in 23% yield according to the
procedure described for compound 17a using 1-(2-methoxy-
phenyl)-2-bromo-ethanone as starting material. 1H NMR
(CDCl3) ꢀ 8.6 – 8.5 (m, 2H), 7.4 – 7.3 (m, 7H), 7.0 – 6.9 (m,
2H), 3.95 (s, 4H), 3.2 – 3.1 (m, 4H), 1.9 – 1.8 (m, 4H); MS
(m/z): 437 (MH+); HRMS: calc’d MH+ for C24H24N2O4S
437.1535; found 437.1541.
A
solution of [5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-
pyridin-4-yl-thiophen-2-yl]-phenyl-methanone (39.5 mg, 0.0970
mmol), p-toluenesulfonic acid monohydrate (37.0 mg, 0.194
mmol, 2 eq.), acetone (2 mL), and water (1 mL) was heated to
reflux overnight. The solution was diluted with 1 M sodium
carbonate solution and was extracted twice with ethyl acetate.
The organic extracts were washed with brine, dried, filtered, and
purified by column chromatography to provide the product as
yellow solid (22.0 mg, 63%). 1H NMR (CDCl3) ꢀ 8.6 – 8.5 (m,
2H), 7.8 – 7.4 (m, 8H), 3.5 – 3.4 (m, 4H), 2.5 – 2.4 (m, 4H). MS
(m/z): 363 (MH+), 385 (MNa+); HRMS: calc’d MH+ for
C21H18N2O2S 363.1167; found 363.1168.
(3,5-Bis-trifluoromethyl-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]-
dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone (17e).
The title product was prepared in 18% yield according to the
procedure described for compound 17a using 1-(3,5-bis-
trifluoromethyl-phenyl)-2-bromo-ethanone as starting material.
1H NMR (CDCl3) ꢀ 8.6 – 7.4 (m, 7H), 3.95 (s, 4H), 3.3 – 3.2 (m,
4H), 1.9 – 1.8 (m, 4H); MS (m/z): 543 (MH+); HRMS: calc’d
MH+ for C25H20F6N2O3S 543.1177; found 543.1157.
1-[5-(4-Fluoro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-
4-one (18b).
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-(4-nitro-phenyl)-methanone (17f).
The title product was prepared in 69% yield according to the
procedure described for compound 18a using [5-(1,4-dioxa-8-
aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(4-fluoro-
The title product was prepared in 18% yield according to the
procedure described for compound 17a using 1-(1,4-dioxa-8-
aza-spiro[4.5]dec-8-yl)-3-morpholin-4-yl-2-pyridin-4-yl-propen-
ethione (374.5 mg, 1.00 mmol), 2-bromo-1-(4-nitro-phenyl)-
ethanone (244 mg, 1.00 mmol) as starting materials. 1H NMR
(CDCl3) ꢀ 8.61 (dd, J = 1.6, 4.5 Hz, 2H), 8.4 – 8.3 (m, 2H), 8.0 –
7.9 (m, 2H), 7.5 – 7.4 (m, 3H), 3.99 (s, 4H), 3.27 (t, J = 5.7 Hz,
4H), 1.83 (t, J = 5.7 Hz, 4H); MS (m/e): 452 (MH+); HRMS:
calc’d MH+ for C23H21N3O5S 452.1280; found 452.1286
1
phenyl)-methanone as starting material. H NMR (CDCl3) ꢀ 8.6
– 7.1 (m, 9H), 3.4 – 3.3 (m, 4H), 2.6 – 2.5 (m, 4H); MS (m/z):
413 (MNa+), 379 (MH-); HRMS: calc’d MH+ for C21H17FN2O2S
381.1073; found 381.1080.
1-[5-(4-Chloro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-
4-one (18c).
The title product was prepared in 74% yield according to the
procedure described for compound 18a using (4-chloro-phenyl)-
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-methanone as starting material. 1H NMR (CDCl3) ꢀ 8.7 –
7.4 (m, 9H), 3.5 – 3.4 (m, 4H), 2.6 – 2.5 (m, 4H); MS (m/z): 397
(MH+), 395 (MH-); HRMS: calc’d MH+ for C21H17ClN2O2S
397.0777; found 397.0767.
[5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-(3-methoxy-phenyl)-methanone (17g).
The title product was prepared in 24% yield as a yellow solid
according to the procedure described for compound 17a using 2-
bromo-1-(3-methoxy-phenyl)-ethanone as starting material. 1H
NMR (CDCl3) ꢀ 8.7 – 8.6 (m, 2H), 7.6 – 7.1 (m, 7H), 3.95 (s,
4H), 3.3 – 3.2 (m, 4H), 1.8 – 1.6 (m, 4H); MS (m/z): 437 (MH+);
HRMS: calc’d MH+ for C24H24N2O4S 437.1535; found 437.1534.
Anal. Calc’d for C21H17ClN2O2S: C, 63.55; H, 4.32; N, 7.06.
Found , C, 63.29; H, 4.20; N, 7.06.
1-[5-(2-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piper-
idin-4-one (18d).
(3-Bromo-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-
pyridin-4-yl-thiophen-2-yl]-methanone (17h).
The title product was prepared in 48% yield as a yellow solid
according to the procedure described for compound 18a using
(2-methoxy-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-
The title product was prepared in 25% yield according to the
procedure described for compound 17a using 1-(3,5-bis-

1396
W. Jiang, J. J. Fiordeliso, X. Chen, Z. Sui
Vol 43
pyridin-4-yl-thiophen-2-yl]-methanone as starting material. 1H
NMR (CDCl3) ꢀ 8.6 – 7.0 (m, 9H), 3.80 (s, 3H), 3.5 – 3.4 (m,
4H), 2.6 – 2.5 (m, 4H); MS (m/z): 393 (MH+), 391 (MH-);
HRMS: calc’d MH+ for C22H20N2O3S 393.1273; found 393.1289.
Acknowledgement.
The authors are thankful to Dr. Terry Hughes for helpful
discussion and input.
1-[5-(3,5-Bis-trifluoromethyl-benzoyl)-3-pyridin-4-yl-thiophen-
2-yl]-piperidin-4-one (18e).
REFERENCES AND NOTES
The title product was prepared in 33% yield as a yellow solid
according to the procedure described for compound 18a using
(3,5-bis-trifluoromethyl-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-
8-yl)-4-pyridin-4-yl-thiophen-2-yl]-methanone as starting material.
1H NMR (CDCl3) ꢀ 8.7 – 7.4 (m, 8H), 3.6 – 3.5 (m, 4H), 2.7 –
2.6 (m, 4H); MS (m/z): 499 (MH+), 497 (MH); HRMS: calc’d
MH+ for C23H16F6N2O2S 499.0915; found 499.0914.
*
Corresponding author: e-mail wjiang1@prdus.jnj.com
[1a] K. Chwalisz, M. C. Perez, D. DeManno, C. Winkel, G.
Schubert and W. Elger, Endocrine Reviews, 26, 423-438 (2005); [b]
K.Chwalisz, D. DeManno, R. Garg, L. Larsen, C. Mattia-Goldberg and
T. Stickler, Seminars in Reproductive Medicine, 22, 113 (2004); [c] R.
Lahoud and R. F. Harrison,
DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G.
Schubert and K. Chwalisz, Steroids, 68, 1019 (2003).
Endometriosis, 203 (2004); [d] D.
[2] For Org-33628, see [a] P. M. Verbost, R. G. J. M. Hanssen, G.
H. V. Korver and T. M. T. Mulders, Seminars in Reproductive Medicine,
23, 101 (2005); [b] H. J. Kloosterboer, G. H. Deckers, W. G. E. J.
Schoonen, R. G. J. M. Hanssen, U. M. Rose, P. M. Verbost, J. G. Hsiu, R.
F. Williams and G. D. Hodgen, Steroids, 65, 733 (2000); [c] G. Teutsch
and D. Philibert, Human Reproduction 9, suppl. 1, 12 (1994).
[3] For reviews on non-steroidal progesterone receptor
modulator, see: [a] P. Zhang, A. Fensome, J. Wrobel, R. Winneker and
Z. Zhang, Expert Opin. Ther. Patents, 13, 1839 (2003) and references
1-[5-(4-Nitro-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-
4-one (18f).
The title product was prepared in 47% yield as a yellow solid
according to the procedure described for compound 18a using
(4-nitro-phenyl)-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-
4-yl-thiophen-2-yl]-methanone as starting material. 1H NMR
(CDCl3) ꢀ 8.6 – 6.9 (m, 9H), 3.3 – 3.2 (m, 4H), 2.7 – 2.6 (m,
4H); MS (m/z): 408 (MH+), 407 (MH-); HRMS: calc’d MH+ for
C21H17N3O4S 408.1018; found 408.1024.
therein; [b] G. F. Allan and Z. Sui,
Mini-Reviews in Medicinal
Chemistry, 5, 701 (2005); [c] R. C. Buijsman, P. H. H. Hermkens, R.
D. van Rijn, H. T. Stock and N. M. Teerhuis, Current Medicinal
Chemistry, 12, 1017 (2005).
1-[5-(3-Methoxy-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piper-
idin-4-one (18g).
[4] For non-steroidal PR antagonists, see: [a] D. G. Jones, X.
Liang, E. L. Stewart, ; R. A. Noe, L. S. Kallander, K. P. Madauss, S. P.
Williams, S. K. Thompson, D. W. Gray and W. J. Hoekstra, Bioorg.
Med. Chem. Lett., 15, 3203 (2005); [b] A. Fensome, R. Bender, J.
Cohen, M. A. Collins, V. A. Mackner, L. L. Miller, J. W. Ullrich, R.
Winneker, J. Wrobel, P. Zhang, Z. Zhang and Y. Zhu, Bioorg. Med.
Chem. Lett., 12, 3487 (2002); [c] P. Zhang, E. A. Terefenko, A.
Fensome, J. Wrobel, R. Winneker, S. Lundeen, K. B. Marschke and Z.
Zhang, J. Med. Chem., 45, 4379 (2002); [d] P. Zhang, E. A. Terefenko,
J. Wrobel, Z. Zhang, Y. Zhu, J. Cohen, K. B. Marschke and D. Mais,
Bioorg. Med. Chem. Lett., 11, 2747 (2001); [e] L. Zhi, C. M. Tegly, B.
Pio, S. J. West, K. B. Marschke, D. E. Mais and T. K. Jones, Bioorg.
Med. Chem. Lett., 10, 415 (2000); [f] L. G. Hamann, D. T. Winn, C. L.
F. Pooley, C. M. Tegley, S. J. West, L. J. Farmer, L. Zhi, J. P. Edwards,
K. B. Marschke, D. E. Mais, M. E. Goldman and T. K. Jones, Bioorg.
Med. Chem. Lett., 8, 2731 (1998); [g] C. L. F. Pooley, J. P. Edwards, M.
E. Goldman, M.-W. Wang, K. B. Marschke, D. L. Crombie and T. K.
Jones, J. Med. Chem., 41, 3461 (1998).
The title product was prepared in 73% yield according to the
procedure described for compound 18a using [5-(1,4-dioxa-8-
aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-(3-methoxy-
phenyl)-methanone as starting material. 1H NMR (CDCl3) ꢀ 8.7
(m, 2H), 7.5 – 7.1 (m, 9H), 3.5 – 3.4 (m, 4H), 2.7 – 2.6 (m, 4H);
MS (m/z): 393 (MH+), 391 (MH-); HRMS: calc’d MH+ for
C22H20N2O3S 393.1273; found 393.1280.
1-[5-(3-Bromo-benzoyl)-3-pyridin-4-yl-thiophen-2-yl]-piperidin-
4-one (18h).
The title product was prepared in 71% yield according to the
procedure described for compound 18a using (3-bromo-phenyl)-
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-methanone as starting material. 1H NMR (CDCl3) ꢀ 8.7 –
8.6 (m, 2H), 7.9 – 7.4 (m, 7H), 3.4 – 3.3 (m, 4H), 2.7 – 2.6 (m,
2H); MS (m/z): 441 (MH+), 439 (MH-); HRMS: calc’d MH+ for
C21H17BrN2O2S 441.0272; found 441.0263.
[5] For modeling, see: [a] FlexS, version 1.9, Tripos Associates,
Inc., St. Louis, MO, 2002; [b] C. Lemmen, T. Lengauer and G. Klebe,
J. Med. Chem., 41, 4502 (1998).
Anal. Calc’d for C21H17BrNzO2S: C, 57.15; H, 3.88; N, 6.35.
Found , C, 57.48; H, 3.93; N, 5.97.
[6] S. P. Williams and P. B. Sigler Nature, 393, 392 (1998).
[7] For Willgerodt-Kindler reaction reviews, see [a] G. Purrello,
Heterocycles, 65, 411 (2005); [b] H. R. Darabi and K. Aghapoor,
European Symposium on Organic Chemistry, 13th, Cavtat-Dubrovnik,
Croatia, Sept. 10-15, 2003, pp 25-28; [c] E. V. Brown, Synthesis, 358
(1975). For similar compounds, not using Willgerodt-Kindler reaction,
see [d]A. Noack, H. Hartmann, Tetrahedron, 58, 2137 (2002).
[8] For recent publication utilizing Willgerodt-Kindler reaction,
see A. D. Pillai, P. D. Rathod, F. P. Xavier, K. K. Vasu, H. Padh and V.
Sudarsanam, Bioorg. Med. Chem., 12, 4667 (2004).
1-(5-Propionyl-3-pyridin-4-yl-thiophen-2-yl)-piperidin-4-one (18i).
The title product was prepared in 60% yield as a white solid
according to the procedure described for compound 18a using 1-
[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-
2-yl]-propan-1-one as starting material. 1H NMR (CDCl3) ꢀ
8.7 – 8.6 (m, 2H), 7.6 – 7.5 (m, 2H), 3.5 – 3.4 (m, 4H), 3.0 – 2.9
(m, 2H), 2.6 – 2.5 (m, 2H), 1.3 – 1.2 (m, 3H); MS (m/z): 315
(MH+), 313 (MH-); HRMS: calc’d MH+ for C17H18N2O2S
315.1167; found 315.1171.
[9] For E1cb reaction, see S. Alunni, F. D. Angelis, L. Ottavi, M.
Papavasileiou and F. Tarantelli, J. Am. Chem. Soc., 127, 15151 (2005).
Anal. Calc’d for C17H18N2O2S, C, 64.94; H, 5.77; N, 8.91.
Found , C, 64.16; H, 5.77; N, 8.52.
[10]
J. G. Topliss, J. Med. Chem., 15, 1006 (1972).