11-(Pyridinylphenyl)steroids-A new class of mixed-profile progesterone agonists/antagonists

Article abstract of DOI:10.1016/j.bmc.2008.01.010

Recently, a new class (often referred to as SPRMs: selective progesterone receptor modulators) of progesterone receptor ligands with mixed agonist/antagonist properties has been described. Such compounds are envisaged, for example, as treatment for endome

Full text of DOI:10.1016/j.bmc.2008.01.010

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 2753–2763
11-(Pyridinylphenyl)steroids—A new class
of mixed-profile progesterone agonists/antagonists
a
a
a
a
Jos Rewinkel,a, Mark Enthoven, Irene Golstein, Marcel van der Rijst, Andre Scholten,
*
´
Martin van Tilborg,a Dirk de Weys,a Jeffry Wissea and Hans Hamersmab
aDepartment of Medicinal Chemistry, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands
bDepartment of Molecular Design and Informatics, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands
Received 14 September 2007; revised 28 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract—Recently, a new class (often referred to as SPRMs: selective progesterone receptor modulators) of progesterone receptor
ligands with mixed agonist/antagonist properties has been described. Such compounds are envisaged, for example, as treatment for
endometriosis, uterine fibroids, and leiomyomas. Existing SPRMs include Asoprisnil 1 and Uliprisnil acetate 2. In our hands, how-
ever, these compounds proved to have a predominantly or exclusively antagonistic in vitro profile, which may make this type of
compound less attractive, for example, as contraceptives. We therefore aimed at a class of mixed-profile compounds that would
show a more evenly balanced agonist/antagonist profile. A novel class of 11b-[4-(heteroaryl)phenyl]-substituted pregnanes was iden-
tified that displayed the desired balance. Contrary to known SPRMs, this novel class of MPP (mixed-profile progestagen) was found
to have a truly mixed activity, including a sizeable agonist component.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
referred to as selective progesterone receptor modula-
tors (SPRMs).4,5
In recent years, interest has grown in progestagenic com-
pounds that are neither full agonists nor full antagonists
towards the progesterone receptor (PR), but show a
mixed agonist/antagonist profile.1 These compounds
may be partial agonists/antagonists, or the agonist/antag-
onist balance may depend on tissue-specific factors that
are not yet fully understood.2 Thus, between full agonists
such as R 5020 and Org 2058 on one hand, and full antag-
onists such as Onapristone on the other hand there should
theoretically be a continuum of compounds of varying
partial activities, where the agonistic/antagonistic effica-
cies range from, say, 90% agonistic/10% antagonistic to
10% agonistic/90% antagonistic. Indeed, qualitative indi-
cations of such profiles have been discussed, for example,
based on the abortifacient activity.3
To date, most compounds described as SPRMs are ste-
roids (Fig. 1); notable examples are Asoprisnil 1 (J-867)
and related estra-4,9-dienes.6 SPRM activity has also
been claimed for Uliprisnil acetate (CDB-2914) 27 and
related compounds,8 as well as for derivatives of dexa-
methasone.9 In addition, non-steroidal SPRMs have
also been described.10–12
Various potential applications for SPRMs have been
mentioned,13 including treatment of leiomyomas14 and
of endometriosis.15 Such uses are assumed to be linked
to the antagonistic component of the SPRM profile.
We have, however, found that, in our hands, the in vitro
agonist/antagonist balance of most of the available
In recent years, compounds have been found for which
partial and/or mixed agonist/antagonist progesterone
activity has been described. Such compounds are often
HO
N
Me2N
O
OMe
OAc
OMe
Keywords: SPRM; Progestagens; Antiprogestagens; Progesterone rec-
eptor; Mixed profile.
O
O
2
1
*
Corresponding author. Tel.: +31 412 663668; fax: +31 412 662546;
e-mail: jos.rewinkel@organon.com
Figure 1. Steroidal SPRMs Asoprisnil (1) and Uliprisnil acetate (2).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.01.010

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J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
(steroidal) SPRMs is on the antagonist side; that is, in
the PRA and PRB assays the antagonistic effect is very
much larger than the agonistic one.16 Similar findings
have been reported in the literature17; these are also in
line with the observation that Asoprisnil induces an
antagonist conformation to PR.18
as the Suzuki, Stille or Negishi reactions. The general ac-
cess to (11b)-arylsteroids is the conjugate addition of
aryl-Grignard reagent, catalysed by copper(I) ions, to
5a,10a-epoxy-9,11-unsaturated steroids, and this reac-
tion was also applied to introduce the p-bromophenyl
group at position 11 of the steroids. As a consequence
of the chosen strategy the D-ring was modified at the
beginning of the synthetic route before the conjugate
addition at position 11 was applied.
For our ongoing programme, we sought mixed-profile
compounds for contraception. As mixed compounds,
they should in effect combine in a single chemical entity
the activities of a separate progesterone agonist and a
progesterone antagonist, a combination which in itself
has been demonstrated to be effective in principle. We
had, however, reason to believe19 that a considerable
agonistic component should be present in our com-
pounds. In addition, we sought to minimize the abortive
potential of the compounds.
The building block required for the preparation of the
17-spirocyclopentanone derivatives, 17,24-cyclo-19,21-
dinorchol-5(10),9(11)-diene-3,20-dione cyclic 1,2-etha-
nediyl acetal (6a), has been described in the literature.20
However, the 17-cyclopropylcarbonyl dienes 6b–f were
not described and a route to these dienes had to be ex-
plored and is depicted in Scheme 1. The readily avail-
able21 estradienedione monoacetal 7 was transformed
to enol triflate 8, which via a palladium(0) catalyzed
insertion gave amide 9. Nucleophilic substitution at
the amide by cyclopropyllithium yielded the versatile
building block 10. Using a conjugate addition at the
a,b-unsaturated ketone system a variety of substituents
could be introduced at position 16. When a copper-med-
iated conjugate addition of organomagnesium chlorides
in the presence of chlorotrimethylsilane was applied,22
this turned out to stereoselectively give the 16a isomer.
When a proton was introduced at position 16 by reac-
tion with lithium tri-sec-butylborohydride (L-selectride)
as the nucleophile, methyl iodide could be used as the
electrophile to yield the 17a-methyl substituent of 6d
stereoselectively.
Thus, we set out to find truly mixed-profile progestagens
(MPPs) where the agonistic and the antagonistic effica-
cies would be more comparable, that is where the ago-
nistic efficacy, unlike in SPRMs, would be at least
20%, and preferably between 40% and 60%. Also, the
agonistic and antagonistic activities should be compara-
ble with respect to both EC50s.
2. Chemistry
In our synthetic strategy we wanted to be able to intro-
duce a variety of heteroaryl groups in the last step.
Therefore, the synthetically versatile p-bromophenyl
group was desired at the 11-position in our final building
block 4 (Fig. 2). This bromide gave the opportunity to
introduce a variety of pyridinyl groups in the last step
via palladium-mediated cross-coupling reactions such
With the D-ring substitution pattern complete, we
turned our attention to the steps leading to introduction
of the 11b-aryl. Selective oxidation of diene 6a gave
R5
R3
R2
R3
R2
R3
R2
R3
R2
O
O
R4
O
O
Br
R1
R1
R1
R1
O
O
O
O
O
O
O
3
4
5
6
Figure 2. Synthetic strategy.
O
O
O
R
R2
c
d
R1
a
O
O
O
O
O
O
O
O
6b-e
10
8 R = OTf
9 R = CON(CH3)OCH3
7
b
b R1 = Me, R2 = H; c R1 = H, R2 = H; d R1 = H, R2 = Me; e R1 = Et, R2 = H; f R1 = CH=CH2, R2 = H
Scheme 1. Reagents and conditions: (a) i—LiHMDS, THF, ꢀ15 °C; ii—N-phenyl-bis(trifluoromethane-sulfonimide), 0 °C; (b) DMF, Et3N, PPh3,
MeN(OMe)HÆHCl, Pd(OAc)2, CO, 60 °C; (c) c-PrLi, Et2O, THF, 0 °C; (d) for 6b, e, f: R1MgCl, Cu(OAc)2, Me3SiCl, THF, 0 °C; for 6c: K-Selectride,
THF, ꢀ78 °C; for 6d; i—L-Selectride, DMPU, THF, ꢀ78 °C; ii—MeI; ꢀ30 °C.

J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
2755
R3
R2
R3
R2
R3
R2
R3
R2
O
O
O
O
Br
Br
R1
R1
R1
R1
a
b
c
O
O
O
O
O
O
O
O
OH
e
6a-f
5a,b,d-f
11a,b,d-f
4a-f
11c
d
R1
R2
R3
HO
HO
HO
Br
a
b
c
d
e
f
H
Me
H
H
Et
-CH2CH2-
H
H
Me cyPr
H
cyPr
cyPr
a
b
O
O
O
O
O
O
O
OH
cyPr
cyPr
12
vinyl
H
14
13
Scheme 2. Reagents and conditions: (a) CH2Cl2, pyridine, 30% aq H2O2, trifluoracetophenone; (b) p-BrPhMgBr, THF, Cu(I)Cl, ꢀ40 °C; (c) MeOH,
aq H2SO4 or acetone, aq HCl; (d) Et2O, LiAlH4, 0 °C; (e) acetone, 4-methylmorpholine N-oxide.
epoxide 5a, which was treated with p-bromophenylmag-
R5
nesium bromide in the presence of copper(I) chloride to
give addition at position 11 without a need to protect the
ketone. Subsequent deketalisation and dehydration gave
3-keto-4,9-diene building block 4a.
R3
R2
R3
R2
O
Br
O
R4
R1
R1
O
O
The same overall synthetic strategy was chosen to pre-
pare 17-cyclopropylcarbonyl derivatives. The epoxida-
tion and conjugate addition of aryl-Grignard reagent
worked satisfyingly for the 17-spirocyclopentanone
derivatives (considering the 46% and 65% yields, respec-
tively, without using protection or a synthetic equivalent
of the ketone). Nonetheless, with the cyclopropylke-
tones both synthetic routes, that is without protection
or using the hydroxyl function as synthetic equivalent
of the ketone, were explored in parallel.
4a-f
3a-s
Scheme 3. Reagents and conditions: R5-R4-boronic acid, K2PO4,
Ph3As, water, dioxane, (PPh3)2PdCl2, 100 °C. See Table 1 for the
legend for R1–R5.
steps from diene 6b to compound 11b compared to the
26% yield over the five steps from diene 6c to compound
11c it was clear that the shortest route without protec-
tion of the ketone was the preferred one and this route
was applied to prepare building blocks 4d–f.
Without protection of the ketone, epoxidation of diene
6b worked well as illustrated by an 81% yield of impure
material containing 84% of the desired a-isomer 5b and
16% of the undesired b-isomer (Scheme 2). In addition,
the subsequent step, the copper(I) chloride catalysed
conjugate addition of p-bromophenylmagnesium bro-
mide to the mixture of epoxides, worked quite well with
a 77% isolated yield of compound 11b. Subsequent
deketalisation and dehydration produced 3-keto-4,9-
diene 4b in 66% yield, which could be used as versatile
building block in Suzuki reactions to introduce various
pyridinyl analogues.
Building blocks 4 were used in palladium-mediated
cross-coupling reactions to obtain a variety of 11-(pyrid-
inylphenyl)steroids (Scheme 3).
3. Results and discussion
For our compound design, we sought to combine in-
house expertise with literature data. Unfortunately,
much of the latter is conflicting with regard to the (com-
binations of) features that predispose a compound for a
mixed progestagenic profile.
In parallel the second route was explored starting from
diene 6c. First, the ketone was reduced to the hydroxyl
group in a quantitative yield; subsequent epoxidation
afforded 13 in a moderate yield. The next steps, cop-
per(I) chloride catalysed conjugate addition of p-brom-
ophenylmagnesium bromide followed by restoring the
ketone by oxidation of the hydroxyl of 14, produced
the desired 11c, and after deketalisation and dehydra-
tion building block 4c was obtained. The slightly diverse
substituents at position 17 make a direct comparison
difficult, but considering the 62% yield over the three
Our design started from the 17-spiromethylene-11b-[4-
(3-pyridinyl)phenyl] compound 1523 (Fig. 3). This com-
pound had been found (unpublished data) to combine
in vitro progesterone agonist and antagonist activity.
This result is in line with the observation1 that the
11b-biphenylyl compound 16 also has a mixed profile
(albeit predominantly antagonistic). Compounds with
a mixed profile should be orally applicable to be useful
in contraception. Since a biphenyl moiety is consider-

2756
J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
11b-pyridinylphenyl substituents had previously been
reported25,26 to have only antagonistic activity, we
decided to limit our further work to the pregnane series.
Our first two target compounds thus became 3a and 3b;
the latter was included because of indications in the lit-
erature that the basicity of nitrogen may influence the
agonistic/antagonistic properties.27 The methoxy substi-
tuent was placed in the 6-position, that is coaxially with
the pyridinylphenyl moiety, to avoid steric effects of
rotamers.
N
O
OH
O
O
16
15
O
Me2N
Me2N
O
As we had hoped, both our initial target compounds
3a and 3b did show a mixed profile (see Table 1),
but with the antagonistic component somewhat high-
er than we had aimed for (antagonistic efficacy:ago-
nistic efficacy ꢁ 3:1). We then turned our attention
from spiro compounds to the open-chain equivalents.
Within this series, a number of 21-substituted com-
pounds have been described which to some extent
have a mixed (MPP-like) profile.28 For stability con-
siderations, as well as for easier handling during
chemical manipulations elsewhere in the molecule,
we preferred to have a carbon substituent in position
21. To avoid the possibility to duplicate known mol-
ecules, for which dominantly antiprogestagenic activ-
ity could be expected, we decided to introduce the
cyclopropane moiety, which had received scant atten-
tion before.29,30
O
O
18
17
Figure 3. Starting points for the design of biphenyl-type compounds.
ably more lipophilic than a 4-(3-pyridinyl)phenyl moi-
ety, the latter one is more appealing from a pharmaco-
kinetic point of view. In addition, the basic pyridinyl
could give an opportunity for making salts in formula-
tion studies.
To investigate the influence of the pyridinylphenyl moi-
ety, we decided to combine this substituent with a 17-
spirocyclopentane moiety; earlier, it had been shown
that, for other 11b substituents, no appreciable change
in (anti)progestagenic activity was observed between
analogues of these two series. Thus, the antiprogesta-
genic IC50 for both 1716 and 1824 is more or less equiv-
alent at 0.2 nM. As 17-hydroxyestrane analogues with
Both compounds with a tertiary (3c, 3d) and with a qua-
ternary (3e) C17-carbon atom were prepared. These
three compounds also proved to have a sub-nanomolar
Table 1. Agonistic (EC50) and antagonistic (IC50) activity of substituted 11b-[4-(heteroaryl)phenyl]-19-norpregnanes 3 against PRB
Compound
EC50 (nM)
Eff
IC50 (nM)
Eff
R1
R2
R3
R4
R5
1
>100
>100
0.29
0.15
0.82
0.51
0.49
0.2
—
—
17
20
36
28
38
49
34
47
42
42
41
47
51
49
56
51
52
54
50
0.2
0.2
97
100
71
62
66
57
58
46
53
38
59
52
45
43
50
33
27
37
>27
35
24
b
—
—
—
—
—
—
—
—
H
OMe
a
—
—
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
0.33
0.55
0.75
0.43
0.13
0.27
0.6
H
–CH2CH2–
–CH2CH2–
a
H
a
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
d
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
cyPr
e
H
H
a
OMe
H
H
a
Me
Et
a
H
0.23
0.66
0.12
1.3
a
H
0.61
0.63
7.89
0.98
0.47
8.48
14.8
2.5
vinyl
Me
Et
a
H
a
OMe
OMe
OMe
Cl
3j
a
3k
3l
0.74
1.1
vinyl
Me
Me
Me
Me
Me
Me
Me
Me
c
a
a
3m
3n
3o
3p
3q
3r
3s
0.49
2.6
a
F
—
b
4
c
—
—
0.36
2.54
1.13
1
3.64
3.25
1.3
d
e
—
—
f
3.14
a
g
—
g
f
R5
N
N
N
N
N
N
N
N
Structure of the R4 substituent
N
N
Values are the average of at least two independent determinations. cyPr = cyclopropyl.

J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
2757
activity for both agonistic and antagonistic activity to-
wards PR; overall, they are slightly more agonistic than
3a and 3b, as the antagonistic/agonistic ratio was im-
proved to ca 2:1.
Subsequently, we decided to investigate the influence of
a 16a substituent. Previous findings by Cook suggested31
that such a modification would turn the mixed 16a-
unsubstituted compounds into full agonists. Three sub-
stituents were introduced: methyl, ethyl and vinyl. As
can be observed from the results table, all these com-
pounds 3f–k have mixed profiles within the desired
boundaries, as had the unsubstituted analogues 3c and
3d.
In most cases observed, the 6-methoxy-3-pyridinyl ana-
logues have a similar progestagenic component in their
mixed profile relative to the unsubstituted analogues.
A case has been described before where the basicity of
a nitrogen group directly attached to the 4-position of
an 11b-phenyl group influences the agonistic or antago-
nistic activity of the compound; a lower basicity of the
nitrogen (as with substitution by fluorine) results in pre-
dominantly or exclusively agonistic compounds.27 How-
ever, in our series both the unsubstituted and the
methoxy-substituted pyridines (with a lower basicity)
clearly have an MPP profile. In addition, the two halo-
pyridines 3l and 3m still have a perfectly mixed profile.
Thus, in the pyridinylphenyl series basicity does not
materially influence the agonistic/antagonistic character.
Figure 4. The pyridinylphenyl moiety of compound 3f can be fitted
between helices 3 (yellow), 4/5 (blue) and 12 (red) without requiring
apparent dislocation. Superimposed (in white) are the corresponding
helices of PR containing progesterone (itself not shown).
In the literature, we found contradictory indications for
the influence of a 16a substituent on the progesterone
agonist/antagonist profile. In the 11b-dimethylamin-
ophenyl series, Cook reported32 that, for 17a-unsubsti-
tuted compounds, introduction of a 16a-ethyl group
switched the profile from mixed to agonistic. On the
other hand, the same group found33 that for 17a-acet-
oxy compounds, a 16a-ethyl group results in a mixed
agonist/antagonist profile. Our findings, however, give
no evidence of any influence of 16a-substitution in the
11b-pyridinylphenyl series.
produces clashes of the ligand with helix 12. This seems
to be confirmed by the recent findings17 that Asoprisnil
indeed causes a shift of the AF2 helix of PR. Our dock-
ing experiments, however, suggest that even an 11b-
biphenyl-type substituent can be accommodated be-
tween helices 3, 4/5 and 12, without causing serious dis-
location (see Fig. 4). Of the residues that are in closest
contact with the pyridinylphenyl substituent, only
˚
Finally, a number of alternative nitrogen heterocycles
were investigated. The resulting compounds all display
a mixed agonist/antagonist profile. Although there does
not appear to be a clear SAR, the most agonistic com-
pounds appear to be those with a clear maximum in
the negative electric potential in the region of the meta
and para atoms in the distal aryl ring (methoxypyridine
3i, fluoropyridine 3m and pyridazine 3p). The compound
which clearly lacks a centre of electronegativity in this
region, viz. the pyrimidine 3q, is also the one with the
highest antagonistic activity.
Met-909 has been shifted over ca 1.5 A. In addition,
there are indications that, under certain circumstances,
RU486 can indeed be accommodated in PR with helix
12 in the agonist position.35 Taken together, these obser-
vations seem to suggest that a receptor structure where
the AF2 helix has been shifted to an antagonistic confor-
mation17 is guided by ‘pull’ factors from corepressors
rather than by ‘push’ factors caused by steric influence
of and/or breaking helix–helix interactions by the ligand.
4. Conclusion
3.1. Docking
A series of 11b-[4-(heteroaryl)phenyl]pregnanes has
been identified with an MPP (mixed progesterone ago-
nist/antagonist) profile. Such compounds are promising
candidates for a variety of (gynaecological) indications.
However, additional vivo experiments are required to
determine what agonist/antagonist balance, which in
the series described ranges from 20% agonist/80% antag-
The results of the various heterocyclic substituents can-
not be readily related to the properties of the progester-
one receptor. Unfortunately, we have not been able to
date to obtain a crystal structure of one of our com-
pounds in PR. There have been claims34 that manual
docking of the antagonist RU 486 in the agonistic PR

2758
J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
onist to 70% agonist/30% antagonist efficacy, produces
the optimal effect.
1,4-dibromobenzene (3.2 g, 13 mmol) and a drop of 1,2-
dibromoethane in THF (15 mL) were added dropwise un-
der a nitrogen atmosphere while the temperature was kept
at 45 °C. After 2 h stirring at 45 °C this Grignard suspen-
sion was added to a cooled (ꢀ30 °C) solution of (5a,10a)-
17,24-cyclo-5,10-epoxy-19,21-dinorchol-9-ene- 3,20-dione
cyclic 1,2-ethanediyl acetal 5a (1.0 g, 2.6 mmol) and cop-
per(I) chloride (0.13 g, 1.3 mmol) in THF (25 mL) under
a nitrogen atmosphere while the temperature was kept at
ꢀ40 °C. The reaction mixture was stirred for 2 h while
the temperature rose to room temperature. A saturated
aqueous NH4Cl solution was added dropwise (exother-
mic). The organic layer was separated and the aqueous
layer was extracted three times with EtOAc. The combined
organic layers were washed with a saturated aqueous NaH-
CO3 solution and brine, dried (Na2SO4) and evaporated to
dryness. The crude product was purified by column chro-
matography (SiO2, heptane/EtOAc, 7/3 with a trace of
Et3N) to give compound 11a (0.92 g, 1.7 mmol, 65%
yield). 1H NMR: d 0.36 (s, 3H), 1.18–2.38 (m, 24H), 3.89–
4.06 (m, 4H), 4.25 (d, J = 7 Hz, 1H), 4.39 (s, 1H), 7.02–
7.06, (m, 2H), 7.32–7.36 (m, 2H).
5. Experimental
5.1. Chemical procedures
5.1.1. General. 1H NMR spectra were recorded on a
Bruker spectrometer (400 or 600 MHz) with deutero-
chloroform as the solvent. Chemical shifts are reported
as d values (parts per million) relative to tetramethylsil-
ane as the internal standard, and coupling constants are
expressed in Hertz. Melting points were obtained on a
Buchi Melting point B-545 apparatus and are uncor-
¨
rected. Thin layer chromatography was performed on
pre-coated Merck Silica gel 60 F254 plates and visualized
with UV light and/or with sulfuric acid in ethanol solu-
tion or the Usui reagent. Column chromatography was
performed on Merck Silica gel 60 (230–400 mesh or
400–600 mesh). HPLC purifications were performed
on Luna C18(2) column using water/acetonitrile as elu-
ent. High resolution TOF mass spectra were acquired
with an AB-Sciex QSTAR mass spectrometer equipped
with an electron-spray ion source applying the positive
ion mode (source voltage 4.5 kV). HRMS-a data were
obtained after calibration using reserpine and testoster-
one with a resolution of approximately 10,000 at m/z
500. HRMS-b data were obtained after calibration using
Agilent tuning mix prior to measurements with a resolu-
tion of approximately R = 8000 at m/z 500.
5.1.3.3. (11b)-11-(4-Bromophenyl)-17,24-cyclo-19,21-
dinorchola-4,9-diene-3,20-dione (4a).
A solution of
H2SO4 (75 lL) in water (0.55 mL) was added to a solution
of acetal 11a (0.92 g, 1.7 mmol) in methanol (18.4 mL).
After stirring this solution for 30 min at room tempera-
ture, water (20 mL) was added. The solids were isolated
to give dione 4a (0.75 g, 1.6 mmol, 92% yield). 1H
NMR: d 0.42 (s, 3H), 1.28–2.76 (m, 22H), 4.36 (d,
J = 7 Hz, 1H), 5.79 (s, 1H), 6.98–7.02 (m, 2H), 7.35–
7.40 (m, 2H).
5.1.2. Abbreviations. DMF, N,N-dimethylformamide;
EtOAc, ethyl acetate; Et3N, triethylamine; HPLC, high
performance liquid chromatography; LCMS, liquid
chromatography/mass spectrometry; mp, melting point;
SiO2, silicon dioxide (silica gel); THF, tetrahydrofuran.
5.1.3.4. (11b)-11-[4-(3-Pyridinyl)phenyl]-17,24-cyclo-
19,21-dinorchola-4,9-diene-3,20-dione (3a). 0.15 g (0.31
mmol) of dione 4a, 3-pyridinylboronic acid 1,3-propane-
diol cyclic ester (0.14 g, 0.85 mmol), potassium phosphate
5.1.3. Synthesis of (11b)-11-[4-(3-pyridinyl)phenyl]-17,24-
cyclo-19,21-dinorchola-4,9-diene-3,20-dione (3a)
5.1.3.1. (5a,10a)-17,24-cyclo-5,10-Epoxy-19,21-dinor-
chol-9-ene-3,20-dione cyclic 1,2-ethanediyl acetal (5a). To
(78 mg,
0.46 mmol),
bis(triphenylphosphine)palla-
dium(II) chloride (7 mg, 0.012 mmol) and triphenylarsine
(7 mg, 0.027 mmol) were dissolved in a mixture of diox-
ane (7 mL) and water (1.2 mL) under a nitrogen atmo-
sphere. The reaction mixture was stirred for 3 h at
100 °C and then cooled to room temperature. Water
was added and the mixture was extracted twice with
EtOAc. The combined organic layers were washed with
brine, dried (MgSO4) and evaporated to dryness. Purifi-
cation by column chromatography (SiO2, heptane/
EtOAc 1/1) gave title compound 3a (100 mg, 0.21 mmol,
67% yield). 1H NMR: d 0.47 (s, 3H), 1.24–2.82 (m, 22H),
4.48 (d, J = 7 Hz, 1H), 5.80 (s, 1H), 7.23–7.27 (m, 2H),
7.35 (dd, J = 8 and 4 Hz, 1H), 7.46–7.51 (m, 2H), 7.84
(dt, J = 8 and 1 Hz, 1H), 8.58 (dd, J = 4 and 1 Hz, 1H),
8.82 (d, J = 1 Hz, 1H). HRMS-a m/z calcd 478.2746,
obsd 478.2740.
a
stirred solution of 17,24-cyclo-19,21-dinorchol-
5(10),9(11)-diene-3,20-dione cyclic 1,2-ethanediyl ace-
tal20 (35.1 g, 95 mmol) in a mixture of dichloromethane
(615 mL), pyridine(3.3 mL, 42 mmol), trifluoroacetophe-
none (10.4 mL, 74 mmol) and hydrogen peroxide (30% in
water, 147 mL) were added. The resulting two-phase sys-
tem was vigorously stirred at ambient temperature for
42 h. The organic layer was separated and the aqueous
layer was extracted twice with dichloromethane. The
combined organic layers were washed twice with a satu-
rated aqueous Na2S2O3 solution, washed with brine,
dried (Na2SO4) and evaporated to dryness. The crude
product was purified by column chromatography (SiO2,
heptane/EtOAc, gradient 8/2 to 7/3) to give the title epox-
ide (16.7 g, 43 mmol, 46% yield). 1H NMR: d 0.74 (s, 3H),
1.13–2.50 (m, 24H), 3.85–3.98 (m, 4H), 6.00–6.04 (m, 1H).
5.1.4. Synthesis of (11b)-11-[4-(6-methoxypyridin-3-yl)phe-
nyl]-17,24-cyclo-19,21-dinorchola-4,9-diene-3,20-dione (3b).
Using the method described for compound 3a treatment of
dione 4a (0.15 g, 0.31 mmol) with 6-methoxy-3-pyr-
idinylboronic acid (82 mg, 0.53 mmol) followed by purifi-
cation by column chromatography (SiO2, gradient
heptane/EtOAc 7/3 to 1/1) gave the crude product. Addi-
5.1.3.2. (5a,11b)-11-(4-Bromophenyl)-17,24-cyclo-19,21-
dinorchola-4,9-diene-5-hydroxy-3,20-dione cyclic 1,2-etha-
nediyl acetal (11a). A grain of iodine was added to magne-
sium (0.32 g, 13 mmol) and heated for 1 min. A solution of

J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
2759
tional purification by HPLC (Luna C18(2)) and lyophilisa-
tion yielded compound 3b (99 mg, 0.19 mmol, 62% yield).
1H NMR: d 0.47 (s, 3H), 1.25–2.81 (m, 22H), 3.98 (s, 3H),
4.46 (d, J = 7 Hz, 1H), 5.80 (s, 1 H), 6.80 (d, J = 9 Hz,
1H), 7.18–7.22 (m, 2H), 7.40–7.44 (m, 2H), 7.75 (dd,
J = 9 and 2 Hz, 1H), 8.36 (d, J = 2 Hz, 1H). HRMS-a m/z
calcd 508.2851, obsd 508.2826.
lowed by water. The organic layer was separated and
the aqueous layer was extracted three times with EtOAc.
The combined organic layers were washed with brine,
dried (Na2SO4) and evaporated to dryness. The crude
product was purified by column chromatography (SiO2,
heptane/EtOAc, 4/1) to give compound 10 (33.9 g,
1
93 mmol, 67% yield). H NMR: d 0.82–2.67 (m, 24H),
3.99 (s, 4H), 5.59 (m, 1H), 6.88 (m, 1H).
5.1.5. Synthesis of (11b,17b)-17-cyclopropylcarbonyl-11-
[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (3c)
5.1.5.4.
(17b)-17-(Cyclopropylcarbonyl)estra-5(10),
5.1.5.1. 17-[[(Trifluoromethyl)sulfonyl]oxy]estra-5(10),
9(11),16-trien-3-one cyclic 1,2-ethanediyl acetal (8). Lith-
ium hexamethyldisilazane (1M in THF, 478 mL,
478 mmol) was added to THF (1 L) and cooled to
ꢀ40 °C under a nitrogen atmosphere. A solution of
mono-acetal 7 (50 g, 159 mmol) in dry THF (500 mL)
was added dropwise while the reaction temperatureslowly
rose to ꢀ15 °C. After stirring for 30 min at ꢀ15 °C, N-phe-
nyl-bis(trifluoromethanesulfonimide) (62.5 g, 175 mmol)
was added batchwise and the reaction mixture was stirred
for 3 h at 0 °C. A saturated aqueous NaHCO3 solution
was added dropwise (exothermic) followed by water.
The organic layer was separated and the aqueous layer
was extracted three times with EtOAc. The combined or-
ganic layers were washed with brine, dried (Na2SO4) and
evaporated to dryness. The crude product was purified by
column chromatography (SiO2, heptane/EtOAc, 4/1) to
give compound 8 (90.1 g, 159 mmol, 100% yield, still con-
taining some solvent). 1H NMR: d 0.91 (s, 3H), 1.20–2.55
(m, 16H), 3.98 (s, 4H), 5.52 (m, 1H), 5.59 (m, 1H).
9(11)-dien-3-one cyclic 1,2-ethanediyl acetal (6c). K-select-
ride (1 M in THF, 12.1 mL, 12.1 mmol) was added drop-
wise to a cooled solution (ꢀ78 °C) of compound 10 (3.7 g,
10.0 mmol) in THF (105 mL) under a nitrogen atmo-
sphere while the reaction temperature was kept below
ꢀ70 °C. After stirring this solution for 20 min, a saturated
aqueous Na2SO4 solution was added dropwise followed
by water. The organic layer was separated and the aque-
ous layer was extracted three times with EtOAc. The com-
bined organic layers were washed with brine, dried
(Na2SO4) and evaporated to dryness. The crude product
was purified by column chromatography (SiO2, hep-
tane/EtOAc, 4/1) to give compound 6c (2.1 g, 5.8 mmol,
57% yield). 1H NMR: d 0.59 (s, 3H), 0.80–2.59 (m,
23H), 2.86 (t, J = 9 Hz, 1H), 3.99 (s, 4H), 5.55–5.60 (m,
1H).
5.1.5.5. (17b)-17-(Cyclopropylhydroxymethyl)estra-
5(10),9(11)-dien-3-one cyclic 1,2-ethanediyl acetal (12).
A solution of compound 6c (2.1 g, 5.8 mmol) in diethyl
ether (54 mL) was added slowly to a cooled (0 °C) sus-
pension of lithium aluminium hydride (262 mg,
6.9 mmol) in diethyl ether (36 mL) under a nitrogen
atmosphere. After 1 h stirring at 0 °C a saturated aque-
ous Na2SO4 solution was added until the grey colour
disappeared. Solid Na2SO4 was added and the mixture
was filtered, washed with EtOAc and the filtrate evap-
orated to dryness to give cyclic compound 12 (2.2 g,
5.8 mmol, >100% yield, product still contained some
5.1.5.2. N-Methoxy-N-methyl-3,3-[1,2-ethanediylbis-
(oxy)]oxo-estra-5(10),9(11),16-triene-17-carboxamide (9).
Triethylamine (221 mL, 1.59 mol), triphenylphosphine
(6.67 g, 25 mmol) and N,O-dimethylhydroxylamine.HCl
(82.2 g, 843 mmol) were added to a solution of compound
8 (70.9 g, 159 mmol) in DMF (1.5 L). Carbon monoxide
was passed through the solution for 10 min, then palla-
dium(II)acetate (2.86 g, 12.7 mmol) was added and the
reaction mixture was stirred overnight at 60 °C under a
CO atmosphere. The reaction mixture was poured into a
saturated aqueous NH4Cl solution and extracted three
times with EtOAc. The combined organic layers were
washed with brine, dried (Na2SO4) and evaporated to dry-
ness. The crude product was purified by column chroma-
tography (SiO2, heptane/EtOAc, 2/1) to give compound 9
(59.7 g, 139 mmol, 87% yield, still containing some sol-
vent). 1H NMR: d 0.97 (s, 3H), 1.25–2.58 (m, 16H), 3.25
(s, 3H), 3.62 (s, 3H), 3.99 (s, 4H), 5.58 (m, 1H), 6.41 (m,
1H).
1
EtOAc). H NMR: d 0.20–0.59 (m, 4H), 0.70 (s, 3H),
0.82–2.59 (m, 21H), 2.85 (dt, J = 9 and 4 Hz, 1H),
3.99 (s, 4H), 5.53–5.58 (m, 1H).
5.1.5.6.
(5a,11b,17b)-11-(4-Bromophenyl)-17-(cyclo-
propylhydroxymethyl)-5-hydroxyestr-9-en-3-one cyclic 1,2-
ethanediyl acetal (14). Following the procedures described
to prepare compounds 5a and 11a, acetal 12 was trans-
formed to the title compound 14 (26% yield). 1H NMR: d
0.12–0.57 (m, 7H), 0.79–0.89 (m, 1H), 1.10–2.12 (m,
17H), 2.27–2.40 (m, 2H), 2.65–2.76 (m, 2H), 3.88–4.03
(m, 4H), 4.14 (d, J = 7 Hz, 1H), 4.34 (s, 1H), 7.08–7.13
(m, 2H), 7.32–7.36 (m, 2H).
5.1.5.3. 17-(Cyclopropylcarbonyl)estra-5(10),9(11),16-
trien-3-one cyclic 1,2-ethanediyl acetal (10). A solution of
cyclopropyl bromide (22.3 mL, 278 mmol) in diethyl
ether (20 mL) was slowly added to a cooled suspension
(0 °C) of crushed lithium (5.8 g, 834 mmol) in ether
(380 mL) (exothermic) under a nitrogen atmosphere.
The reaction mixture was stirred for 90 min while the tem-
perature rose to room temperature. The solution of this
lithiate was slowly added to a cooled solution (0 °C) of
compound 9 (59.7 g, 139 mmol) in THF (260 mL). After
stirring this mixture for 2 h at 0 °C, a saturated aqueous
NH4Cl solution was added dropwise (exothermic) fol-
5.1.5.7. (5a,11b,17b)-11-(4-Bromophenyl)-17-(cyclo-
propylcarbonyl)-5-hydroxyestr-9-en-3-one cyclic 1,2-eth-
anediyl acetal (11c). To a solution of compound 14
(726 mg, 1.3 mmol) in acetone (25 mL), 4-methylmor-
pholine N-oxide (438 mg, 3.7 mmol) and tetra-N-propyl-
ammonium perruthenate (VII) (28 mg, 0.08 mmol) were
added and the reaction mixture was stirred for 2 h at
room temperature under a nitrogen atmosphere. Silica
and heptane (14 mL) were added and the mixture was
stirred for 1 h, then filtered through dicalite and washed

2760
J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
properly with EtOAc. The filtrate was evaporated to
dryness to give compound 11c (732 mg, 1.3 mmol,
100% yield). 1NMR: d 0.21 (s, 3H), 0.80–2.39 (m,
22H), 2.66–2.74 (m, 2H), 3.88–4.05 (m, 4H), 4.23 (d,
J = 7 Hz, 1H), 4.37 (s, 1H), 7.06–7.10 (m, 2H), 7.34–
7.38 (m, 2H).
rated in vacuo. The crude product was purified by column
chromatography (SiO2, heptane/EtOAc = 9/1, v/v) to
give compound 6d (255 mg 0.67 mmol, 49% yield).
NMR: d 0.67 (s, 3H), 0.78–2.72 (m, 27H), 1.23 (s, 3H),
3.96–4.02 (m, 4H), 5.57–5.61 (m, 1H).
1
5.1.7.2. (11b,17b)-17-Cyclopropylcarbonyl-17-methyl-
11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (3e). Com-
pound 6d was transformed to crude 3e using the proce-
dures described in experiments 5.1.3.1, 5.1.3.2, 5.1.5.8
and 5.1.3.4. Purification by HPLC (Luna C18(2)) fol-
lowed by lyophilisation gave the title compound. (19 %
yield over these four steps). 1NMR: d 0.42 (s, 3H), 0.80–
2.82 (m, 24H), 2.28 (s, 3H), 4.48 (d, J = 8 Hz, 1H), 5.80
(s, 1H), 7.30 (d, J = 8 Hz, 1H), 7.34 (dd, J = 4 and 8 Hz,
1H), 7.50 (d, J = 8 Hz, 1H), 7.85 (dt, J = 2 and 8 Hz,
1H), 8.57 (dd, J = 2 and 4 Hz, 1H), 8.84 (d, J = 2 Hz,
1H). HRMS-b m/z calcd 492.2903, obsd 492.2842.
5.1.5.8. (11b,17b)-11-(4-Bromophenyl)-17-cyclopropyl-
carbonylestra-4,9-dien-3-one (4c). 3 N Hydrochloric acid
(2 mL, 6 mmol) was added to a solution of compound
11c (0.73 g, 1.35 mmol) in acetone (25 mL). After stirring
this solution for 15 min at room temperature, brine was
added and the reaction mixture extracted with EtOAc.
The combined organic layers were washed with brine,
dried (Na2SO4) and evaporated to dryness. The crude
product was purified by column chromatography (SiO2,
heptane/EtOAc, 2/1) to give 4c (0.45 g, 65% yield).
1NMR: d 0.27 (s, 3H), 0.83–2.83 (m, 22H), 4.34 (d,
J = 7 Hz, 1H), 5.79 (s, 1H), 7.02–7.07 (m, 2H), 7.37–
7.42 (m, 2H).
5.1.8. Synthesis of (11b,16a,17b)-17-cyclopropylcarbonyl-
16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one
(3f)
5.1.5.9. (11b,17b)-17-Cyclopropylcarbonyl-11-[4-(3-
pyridinyl)phenyl]estra-4,9-dien-3-one (3c). Compound 4c
was transformed into crude title compound using the pro-
cedure described for the preparation of compound 3a.
Purification by preparative LCMS followed by lyophilisa-
5.1.8.1. (16a,17b)-17-(Cyclopropylcarbonyl)-16-meth-
ylestra-5(10),9(11)-dien-3-one cyclic 1,2-ethanediyl acetal
(6b). Methylmagnesium chloride (3 M in THF, 92.6 mL,
278 mmol) was added to a stirred and cooled solution
(0 °C) of copper(II)acetate (1.7 g, 9.3 mmol) in THF
(1 L) under a nitrogen atmosphere. A solution of com-
pound 10 (33.9 g, 93 mmol) and trimethylsilyl chloride
(58.5 mL, 463 mmol) in THF (500 mL) was added drop-
wise while the temperature was kept at 0 °C. After 1 h an-
other equivalent of methylmagnesium chloride was added
dropwise and stirring was continued for 30 min at 0 °C. A
saturated aqueous NH4Cl solution was added dropwise
followed by water. The organic layer was separated and
the aqueous layer was extracted three times with EtOAc.
The combined organic layers were washed with brine,
dried (Na2SO4) and evaporated to dryness to give com-
pound 6b (32.9 g, 86 mmol, 93% yield). 1H NMR: d 0.61
(s, 3H), 0.80–2.79 (m, 26H), 3.99 (s, 4H), 5.55 (m, 1H).
1
tion gave 3c (66% yield). NMR (400 MHz, CDCl3): d
0.32 (s, 3H), 0.84–2.82 (m, 21H), 2.92 (d, J = 13 Hz,
1H), 4.46 (d, J = 7 Hz, 1H), 5.80 (s, 1H), 7.27–7.32 (m,
2H), 7.34 (dd, J = 8 and 5 Hz, 1H), 7.49–7.54 (m, 2H),
7.86 (dt, J = 8 and 1 Hz, 1H), 8.58 (d, J = 5 Hz, 1H),
8.84 (d, J = 1 Hz, 1H). HRMS-a m/z calcd 478.2746, obsd
478.2743.
5.1.6. Synthesis of (11b,17b)-17-cyclopropylcarbonyl-11-[4-
(6-methoxypyridin-3-yl)phenyl]estra-4,9-dien-3-one (3d).
Compound 4c was transformed into crude title compound
using the procedure described in experiment 5.1.3.4 for
compound 3a using 6-methoxy-3-pyridinylboronic acid
as reagent. Purification by preparative LCMS followed
by lyophilisation gave the title compound. (60% yield).
1NMR: d 0.32 (s, 3H), 0.83–2.81 (m, 21H), 2.91 (d,
J = 13 Hz, 1H), 3.98 (s, 3H), 4.44 (d, J = 7 Hz, 1H), 5.80
(s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.22–7.26 (m, 2H), 7.42–
7.46 (m, 2H), 7.77 (dd, J = 8 and 2 Hz, 1H), 8.37 (d, J =
2 Hz, 1H). HRMS-a m/z calcd 508.2851, obsd 508.2822.
5.1.8.2.
(11b,16a,17b)-17-Cyclopropylcarbonyl-16-
methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (3f).
Compound 6b was transformed into crude title com-
pound using the procedures described in experiments
5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4. Purification by col-
umn chromatography (SiO2, heptane/EtOAc, gradient
2/1 to 1/2) and subsequently crystallisation from acetoni-
trile/water gave compound 3f (22% yield over these four
5.1.7. Synthesis of (11b,17b)-17-cyclopropylcarbonyl-17-
methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (3e)
5.1.7.1. (17b)-17-(Cyclopropylcarbonyl)-17-methyles-
tra-5(10),9(11)-dien-3-one cyclic 1,2-ethanediyl acetal
(6d). L-selectride (3.0 mL, 3.0 mmol, 1 M in THF) was
slowly added to a cooled (ꢀ78 °C) and stirred solution
of compound 10 (500 mg, 1.4 mmol) and 1,3-dimethyl-
1
steps), mp 206 °C. H NMR: d 0.35 (s, 3H), 0.86–2.86
(m, 24H), 4.46 (d, J = 8 Hz, 1H), 5.80 (s, 1 H), 7.26–7.29
(m, 2H), 7.35 (dd, J = 10 and 6 Hz, 1H), 7.49–7.53 (m,
2H), 7.86 (dt, J = 10 and 4 Hz, 1H), 8.57 (dd, J = 6 and
4 Hz, 1H), 8.84 (d, J = 4 Hz, 1H). HRMS-a m/z calcd
492.2902, obsd 492.2928.
3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(0.33 mL,
2.7 mmol) in dry THF (20 mL) under a nitrogen atmo-
sphere. After 1 h at ꢀ78 °C methyl iodide (1.7 mL,
27 mmol) was added. The reaction mixture was stirred
for an additional 1.5 h while the temperature raised to
ꢀ30 °C. The reaction mixture was poured into water
and extracted with EtOAc. The combined organic layers
were washed with a saturated aqueous NaHCO3 solution
and brine, dried (MgSO4) and the solvents were evapo-
5.1.9. Synthesis of (11b,16a,17b)-17-cyclopropylcarbonyl-
16-ethyl-11-[4-(3-pyridinyl)phenyl]-estra-4,9-dien-3-one (3g)
5.1.9.1. (16a,17b)-17-(Cyclopropylcarbonyl)-16-ethyl-
estra-5(10),9(11)-dien-3-one cyclic 1,2-ethanediyl acetal
(6e). Reaction of compound 10 and ethylmagnesium
chloride according to the procedure described for com-
pound 6b in experiment 5.1.8.1 afforded the title com-

J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
2761
1
pound (87% yield). H NMR: d 0.60 (s, 3H), 0.80–2.64
(m, 28H), 3.99 (s, 4H), 5.54–5.58 (m, 1H).
5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4. using 6-methoxy-3-
pyridinylboronic acid in the last step. Purification by col-
umn chromatography gave compound 3j (14% yield over
four steps). d 0.35 (s, 3H), 0.82 (t, J = 8 Hz, 3H), 0.85–0.99
(m, 4H), 1.07–1.13 (m, 1H), 1.25–1.34 (m, 2H), 1.41–2.84
(m, 16H), 3.98 (s, 3H), 4.44 (d, J = 7 Hz, 1H), 5.80 (s, 1H),
6.80 (d, J = 8 Hz, 1H), 7.21–7.25 (m, 2H), 7.42–7.46 (m,
2H), 7.77 (dd, J = 8 and 2 Hz, 1H), 8.37 (d, J = 2 Hz, 1H).
5.1.9.2. (11b,16a,17b)-17-Cyclopropylcarbonyl-16-ethyl-
11-[4-(3-pyridinyl)phenyl]-estra-4,9-dien-3-one (3g). Com-
pound 6e was transformed into crude title compound using
the procedures described in experiments 5.1.3.1, 5.1.3.2,
5.1.5.8 and 5.1.3.4. Purification by preparative LCMS fol-
lowed by lyophilisation gave the title compound. (22 % yield
1
over these four steps). H NMR: d 0.35 (s, 3H), 0.82 (t,
5.1.13. Synthesis of (11b,16a,17b)-17-(cyclopropylcarbon-
yl)-16-ethenyl-11-[4-(6-methoxypyridin-3-yl)phenyl]estra-
4,9-dien-3-one (3k). Compound 6f was transformed into
crude title compound using the procedures described in
experiments 5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4 (using 6-
methoxy-3-pyridinylboronic acid in the last step). Purifi-
cation by crystallisation from heptane gave compound
J = 7 Hz, 3H), 0.87–0.98 (m, 3H), 1.07–1.14 (m, 1H),
1.25–1.34 (m, 2H), 1.41–1.64 (m, 5H), 1.91–1.99 (m, 1H),
2.03–2.11 (m, 1H), 2.24–2.85 (m, 10H), 4.46 (d, J = 7 Hz,
1H), 5.80 (s, 1H), 7.25–7.30 (m, 2H), 7.35 (dd, J = 7 and
5 Hz, 1H), 7.48–7.53 (m, 2H), 7.46 (dt, J = 8 and 1 Hz,
1H), 8.57 (dd, J = 5 and 1 Hz, 1H), 8.84 (d, J = 3 Hz, 1H).
HRMS-a m/z calcd 506.3059, obsd 506.2685.
1
3k. (24 % yield over these four steps), mp 197 °C. H
NMR: d 0.39 (s, 3H), 0.84–2.87 (m, 20H), 3.26–3.34 (m,
1H), 3.98 (s, 3H), 4.45 (d, J = 7 Hz, 1H), 4.88 (d,
J = 11 Hz, 1H), 4.95 (d, J = 16 Hz, 1H), 5.70–5.81 (m,
2 H), 6.81 (d, J = 8 Hz, 1 H), 7.23 (d, J = 8 Hz, 2H),
7.45 (d, J = 8 Hz, 2H), 7.77 (dd, J = 8 and 3 Hz, 1H),
8.37 (d, J = 3 Hz, 1H). HRMS-a m/z calcd 534.3008, obsd
534.3014.
5.1.10. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-ethenyl-11-[4-(3-pyridinyl)phenyl]-estra-4,9-dien-3-
one (3h)
5.1.10.1. (16a,17b)-17-(Cyclopropylcarbonyl)-16-ethe-
nylestra-5(10),9(11)-dien-3-one cyclic 1,2-ethanediyl acetal
(6f). Reaction of compound 10 and vinylmagnesium chlo-
rideaccordingtotheproceduredescribedforcompound6b
in experiment 5.1.8.1 afforded the title compound (48%
yield). 1H NMR: d 0.63 (s, 3H), 0.80–2.66 (m, 21H), 2.71
(d, J = 9 Hz, 1H), 3.30–3.39 (m, 1H), 3.99 (s, 4H), 4.84–
4.97 (m, 2H), 5.54–5.58 (m, 1H), 5.71–5.81 (m, 1H).
5.1.14. Synthesis of (11b,16a,17b)-11-[4-(6-chloropyridin-
3-yl)phenyl]-17-cyclopropylcarbonyl-16-methylestra-4,9-
dien-3-one (3l). Compound 6d was transformed into
compound 4b using the procedures described in experi-
ments 5.1.3.1, 5.1.3.2 and 5.1.5.8. To prepare the title
compound from compound 4b and 6-chloro-3-pyr-
idinylboronic acid the procedure described in experi-
ment 5.1.3.4 was slightly modified. The reaction
mixture was heated for 4 h and an additional two equiv-
alents of 6-chloro-3-pyridinylboronic acid were added in
four portions. Purification by LCMS followed by lyo-
philisation gave the product (4% yield over these four
5.1.10.2. (11b,16a,17b)-17-Cyclopropylcarbonyl-16-
ethenyl-11-[4-(3-pyridinyl)phenyl]-estra-4,9-dien-3-one (3h).
Compound 6f was transformed into crude title compound
using the procedures described in experiments 5.1.3.1,
5.1.3.2, 5.1.5.8 and 5.1.3.4. Purification by preparative
LCMS followed by lyophilisation gave the title compound.
(15% yield over these four steps). 1H NMR: d 0.38 (s, 3H),
0.84–0.99 (m, 3H), 1.08–1.15 (m, 1H), 1.46–2.88 (m, 16H),
3.26–3.35 (m, 1H), 4.47 (d, J = 7 Hz, 1H), 4.86–4.97 (m,
2 H), 5.70–5.79 (m, 1H), 5.81 (s, 1H), 7.26–7.30 (m, 2H),
7.35 (dd, J = 8 and 5 Hz, 1H), 7.49–7.53 (m, 2H), 7.86 (dt,
J = 8 and 1 Hz, 1H), 8.58 (dd, J = 5 and 1 Hz, 1H), 8.84
(d, J = 1 Hz, 1H). HRMS-a m/z calcd 504.2902, obsd
504.2873.
1
steps). H NMR: d 0.34 (s, 3H), 0.84–2.84 (m, 24H),
4.45 (d, J = 7 Hz, 1H), 5.80 (s, 1H), 7.25–7.30 (m, 2H),
7.38 (d, J = 8 Hz, 1H), 7.45–7.49 (m, 2H), 7.82 (dd,
J = 8 and 3 Hz, 1H), 8.59 (d, J = 3 Hz, 1H). HRMS-b
m/z calcd 526.2513, obsd 526.2510.
5.1.15. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-11-[4-(6-fluoropyridin-3-yl)phenyl]-16-methylestra-4,9-
dien-3-one (3m). Compound 6b was transformed into
crude title compound using the procedures described
in experiments 5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4 and
using 6-fluoro-3-pyridinylboronic acid in the last step.
Purification by LCMS followed by lyophilisation gave
product 3m (10% yield over these four steps). 1H
NMR: d 0.34 (s, 3H), 0.80–2.85 (m, 24H), 4.45 (d,
J = 7 Hz, 1H), 5.80 (s, 1H), 7.00 (dd, J = 8 and 3 Hz,
1H), 7.25–7.29 (m, 2H), 7.44–7.48 (m, 2H), 7.95 (dt,
J = 8 and 3 Hz, 1H), 8.41 (d, J = 3 Hz, 1H). HRMS-b
m/z calcd 510.2808, obsd 510.2811.
5.1.11. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-11-[4-(6-methoxypyridin-3-yl)phenyl]-16-methylestra-
4,9-dien-3-one (3i). Reaction of compound 4b and 6-meth-
oxy-3-pyridinylboronic acid using the procedure de-
scribed in experiment 5.1.3.4 gave compound 3i (54%
yield). 1H NMR: d 0.35 (s, 3H), 0.84–0.99 (m, 6H),
1.08–1.15 (m, 1H), 1.33–1.39 (m, 1H), 1.45–1.54 (m,
1H), 1.62–1.70 (m, 2H), 1.91–1.97 (m, 1H), 2.01–2.08
(m, 1H), 2.24–2.53 (m, 6H), 2.58–2.64 (m, 2H), 2.68–
2.85 (m, 3H), 3.98 (s, 3H), 4.44 (d, J = 8 Hz, 1H), 5.80
(s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.23 (d, J = 7 Hz, 2H),
7.44 (d, J = 7 Hz, 2H), 7.75–7.79 (m, 1H), 8.36–8.38 (m,
1H).
5.1.16. Synthesis of (11b,16a,17b)-17-cyclopropylcarbonyl-
16-methyl-11-[4-(2-pyridinyl)phenyl]estra-4,9-dien-3-one (3n).
Compound 6d was transformed into compound 4b using
the procedures described in experiments 5.1.3.1, 5.1.3.2
and 5.1.5.8. To a solution of compound 4b (200 mg,
0.41 mmol) in THF (4 mL) under a nitrogen atmosphere
5.1.12. Synthesis of (11b,16a,17b)-17-cyclopropylcarbonyl-
16-ethyl-11-[4-(6-methoxypyridin-3-yl)phenyl]-estra-4,9-dien-
3-one (3j). Compound 6e was transformed into crude title
compound using the procedures described in experiments

2762
J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
were added (PPh3)2PdCl2 (4 mg, 0.006 mmol), ferrocene pal-
ladium dichloride (6 mg, 0.009 mmol) and 2-pyridinylzinc
bromide (2 mL, 1.0 mmol). The reaction mixture was stirred
for 5 h at 60 °C and then cooled to room temperature. A sat-
urated aqueous NH4Cl solution was added and the mixture
was extracted three times with dichloromethane. The com-
bined organic layers were dried through a phase separation
filter and evaporated to dryness. Purification by HPLC
(Luna C18(2)) followed by lyophilisation gave compound
J = 3 and 1 Hz, 1H). HRMS-b m/z calcd 493.2855, obsd
493.2766.
5.1.19. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-methyl-11-[4-(pyrimidin-2-yl)phenyl]estra-4,9-dien-
3-one (3q). According to the procedure described for
compound 3p in experiment 5.1.18 compound 4b and
2-tributylstannylpyrimidine were heated for 4 h at
110 °C to give the title compound (17% yield). 1H
NMR: d 0.32 (s, 3H), 0.83–2.87 (m, 24H), 4.47 (d,
J = 7.0 Hz, 1H), 5.80 (s, 1H), 7.18 (t, J = 4.7 Hz, 1H),
7.28–7.31 (m, 2H), 8.32–8.35 (m, 2H), 8.79 (d,
J = 4.7 Hz, 2H).
1
3n (80 mg, 0.16 mmol, 40% yield from 4b). H NMR: d
0.33 (s, 3H), 0.80–2.87 (m, 24H), 4.46 (d, J = 7 Hz, 1H),
5.80 (s, 1H), 7.20–7.23 (m, 1H), 7.25–7.29 (m, 2H), 7.68–
7.77 (m, 2H), 7.89–7.92 (m, 2H), 8.67 (dt, J = 5 and 1 Hz,
1H). m/z calcd 492.2902, obsd 492.2897.
5.1.20. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-methyl-11-[4-(pyrazin-2-yl)phenyl]estra-4,9-dien-3-
one (3r). According to the procedure described for com-
pound 3p in experiment 5.1.18, compound 4b and 2-tri-
butylstannylpyrazine were heated in a microwave at
135 °C (150 W, 25 min) to give the title compound (35%
5.1.17. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-methyl-11-[4-(4-pyridinyl)phenyl]estra-4,9-dien-3-one
(3o). Compound 6b was transformed into crude title
compound using the procedures described in experi-
ments 5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4 using 4-pyr-
idinylboronic acid in the last step. Purification by
HPLC (Luna C18(2)) followed by crystallisation (aceto-
1
yield). H NMR: d 0.33 (s, 3H), 0.84–2.86 (m, 24H),
4.47 (d, J = 7 Hz, 1H), 5.81 (s, 1H), 7.30–7.34 (m, 2H),
7.92–7.96 (m, 2H), 8.49 (d, J = 3 Hz, 1H), 8.61 (dd,
J = 3 and 1 Hz, 1H), 9.01 (d, J = 1 Hz, 1H). HRMS-b
m/z calcd 493.2855, obsd 493.2829.
1
nitrile/water) gave the product (18% yield). H NMR: d
0.33 (s, 3H), 0.84–2.85 (m, 24H), 4.46 (d, J = 7 Hz, 1H),
5.81 (s, 1H), 7.26–7.30 (m, 2H), 7.48–7.50 (m, 2H), 7.55–
7.59 (m, 2H), 8.63–8.65 (m, 2H). HRMS-b m/z calcd
492.2903, obsd 492.2844.
5.1.21. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-methyl-11-[4-(3-quinolidinyl)phenyl]estra-4,9-dien-
3-one (3s). Compound 6b was transformed into crude title
compound using the procedures described in experiments
5.1.3.1, 5.1.3.2, 5.1.5.8 and 5.1.3.4 and 6-using quinoline-
3-boronic acid pinacolate and heating for 3 h in the last
step. Purification by LCMS followed by lyophilisation
gave the title compound (8% yield). 1H NMR: d 0.38 (s,
3H), 0.78–2.89 (m, 24H), 4.49 (d, J = 7 Hz, 1H), 5.81 (s,
1H), 7.30–7.34 (m, 2H), 7.58 (dt, J = 7 and 1 Hz, 1H),
7.63–7.67 (m, 2H), 7.72 (dt, J = 8 and 1 Hz, 1H), 7.87
(dd, J = 8 and 1 Hz, 1H), 8.13 (d, J = 8 Hz, 1H), 8.29 (d,
J = 3 Hz, 1H), 9.17 (d, J = 3 Hz, 1H). HRMS-b m/z calcd
542.3059, obsd 542.3012.
5.1.18. Synthesis of (11b,16a,17b)-17-cyclopropylcarbon-
yl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-
3-one (3p). n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in
hexane) was added dropwise to a cooled (0 °C) solu-
tion of diisopropylamine (0.97 mL, 6.9 mmol) in THF
(2 mL) under a nitrogen atmosphere. After stirring
for 30 min the reaction mixture was cooled to
ꢀ78 °C and
a
solution of pyridazine (452 lL,
6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol)
were added simultaneously while the temperature was
kept below ꢀ 70 °C. The reaction mixture was stirred
for 2 h at ꢀ78 °C; subsequently, a saturated aqueous
NH4Cl solution was added and the reaction mixture
was extracted three times with EtOAc. The combined
organic layers were dried (MgSO4) and evaporated to
dryness. The crude product was purified by LCMS to
give tributylstannylpyridazine (197 mg, 0.53 mmol, 8%
yield).36
5.2. Biological testing
The progestagenic activity of the compounds (EC50 and
intrinsic agonistic activity) was determined in an in vitro
bioassay of Chinese hamster ovary (CHO) cells as de-
scribed before.37 The efficacy is expressed as the percent-
age of the effect of the agonist (16a)-16-ethyl-21-
This stannylpyridazine (183 mg, 0.49 mmol), compound
4b (100 mg, 0.20 mmol, prepared according to the pro-
cedures described in experiments 5.1.3.1, 5.1.3.2 and
5.1.5.8) and bis(triphenylphosphine)palladium(II) chlo-
ride (3 mg, 0.004 mmol) were dissolved in dioxane
(3 mL) under a nitrogen atmosphere. The reaction mix-
ture was stirred overnight at 110 °C and then cooled to
room temperature. Water was added and the mixture
was extracted three times with dichloromethane. The
combined organic layers were dried through a phase
separate filter and evaporated to dryness. Purification
by LCMS followed by lyophilisation gave compound
3p (78 mg, 0.16 mmol, 79% yield from compound 4b).
1H NMR: d 0.33 (s, 3H), 0.85–2.84 (m, 26H), 4.48 (d,
J = 7 Hz, 1H), 5.81 (s, 1H), 7.33–7.37 (m, 2H), 7.60–
7.64 (m, 3H), 9.21 (dd, J = 5 and 1 Hz, 1H), 9.46 (dd,
hydroxy-19-norpregn-4-ene-3,20-dione
(Org
2058)
which was set to 100%.
The antiprogestagenic activity (IC50) was determined in a
setting comparable to the agonistic assay described
above, by the inhibition of the transactivation via the pro-
gesterone receptor-B of the enzyme luciferase in the pres-
ence of 0.1 nM of the inducer Org 2058. The efficacy of the
antagonistic effect was expressed relative to the effect, set
to 100%, of the antagonist Org 31710 ((6b,11b,17b)-11-[4-
(dimethylamino)phenyl]-40,50-dihydro-6-methylspiro[estra-
4,9-diene-17,20(30H)-furan]-3-one).
Data are the average of at least two independent
determinations.

J. Rewinkel et al. / Bioorg. Med. Chem. 16 (2008) 2753–2763
2763
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Eur. Patent 443,957, 1991; Chem. Abstr. 1991, 115,
232605.
Acknowledgments
We thank Dr. C. Kuil and Mr. T.-W. Lam for determin-
ing the in vivo activity data.
21. Gebhard, R.; van der Voort, H.; Schuts, W.; Schoonen,
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