Nonsteroidal progesterone receptor ligands (II); synthesis and SAR of new tetrahydrobenzindolone derivatives

Article abstract of DOI:10.1016/j.bmc.2006.03.022

The human progesterone receptor (PR) binding affinity and the PR agonistic or antagonistic potency of tetrahydronaphthofuranone derivatives were shown previously to be markedly influenced by substituents at the 6- and 7-positions. Here, we synthesized tet

Full text of DOI:10.1016/j.bmc.2006.03.022

Bioorganic & Medicinal Chemistry 14 (2006) 4862–4878
Nonsteroidal progesterone receptor ligands (II);
synthesis and SAR of new tetrahydrobenzindolone derivatives
Ken-ichi Kurihara,* Rie Shinei, Kiyoshi Tanabe, Yuji Tabata,
Yasushi Kurata, Shigeru Hoshiko and Tsuneo Okonogi
Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Received 25 January 2006; revised 13 March 2006; accepted 13 March 2006
Available online 31 March 2006
Abstract—The human progesterone receptor (PR) binding affinity and the PR agonistic or antagonistic potency of tetrahydronapht-
hofuranone derivatives were shown previously to be markedly influenced by substituents at the 6- and 7-positions. Here, we syn-
thesized tetrahydrobenzindolones possessing a lactam ring, which enabled us to modify the 6- and 7-positions more freely, since
tetrahydrobenzindolones are chemically more stable than tetrahydronaphthofuranones. The tetrahydrobenzindolone derivatives
generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. We also succeeded in separating
the agonistic and antagonistic activities by choosing suitable substituent groups at the 6- and/or 7-position(s) of the tetrahydrobenz-
indolone. The effects of representative agonists, 12c (CP8668), and 14a (CP8816), and a representative antagonist, 15f (CP8661),
were confirmed in in vivo tests. In this report, we mainly describe the synthesis and structure–activity relationships (SAR) of tetra-
hydrobenzindolone derivatives, as new nonsteroidal PR ligands.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
eton, and all the methyl groups at the C-4a and C-5 posi-
tions and hydroxyl groups at the C-6 and C-7 positions
have cis-configuration (Fig. 2). PF1092A and B have
highly selective affinity for human PR, but possess a non-
steroidal skeleton.9 We initially sought to identify
the minimal pharmacophore by totally synthetic
methods10,11 and then clarified the structure–activity
relationships (SAR) of tetrahydronaphthofuranone
derivatives.12 These compounds are good candidates for
new PR ligands that lack the side effects induced by steroi-
dal agents.
Various medicines that control the functions of steroid
hormones were developed in the 20th century and have
contributed greatly to medical care. Among them, pro-
gesterone receptor PR ligands have been used as contra-
ceptives (e.g., norethisterone) and to treat various
gynecological diseases and female sex hormone-depen-
dent tumors (e.g., medroxyprogesterone acetate
(MPA)).1 Furthermore, PR antagonists, such as Mife-
pristone (RU486),2 discovered in 1980s, contributed to
the great progress in understanding the PR functions
and are also used in clinical available for abortion. Since
the middle of 1990s, nonsteroidal PR ligands, such as
LG 100128, LG 120746, and RWJ 26819, were reported
and now Tanaproget,3–6 are on the clinical trial (Fig. 1).
During the above studies, we incidentally obtained a
small amount of compound (1) as a by-product during
an attempt to introduce a methylamino group at the
C-7 position of tetrahydronaphthofuranones. Com-
pound (1) has a new skeleton, tetrahydrobenzindolone,
containing a lactam ring, in place of the lactone ring
of tetrahydronaphthofuranone. Since a lactam ring is
generally more chemically stable than a lactone ring,
we compared the chemical stability of compounds (1)
and (2), especially in basic media. In alkaline solution
at pH 11.5, the 7a-methoxytetrahydrobenzindolone
compound (1) was sufficiently stable even after 24 h,
whereas the tetrahydronaphthofuranone compound (2)
was rapidly decomposed (Fig. 3).13
PF1092A, B, and C are new eremophilane-type sesquit-
erpenoids isolated from the fermentation broth of a rare
fungus, Penicillium oblatum, by a group at Meiji Seika
Kaisha.7,8 They have a tetrahydronaphthofuranone skel-
Keywords: Nonsteroidal progesterone receptor ligand; Tetrahydro-
benzindolone; Tetrahydronaphthofuranone; PF1092.
*
Corresponding author. Tel.: +81 45 541 2521; fax: +81 45 543
9771; e-mail: kenichi_kurihara@meiji.co.jp
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.03.022

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4863
Figure 1. Progesterone receptor ligands.
The C-7 acetoxy group of compound (5) was confirmed
to have a-configuration by comparison of the coupling
constants in the 1H NMR spectrum with those of
PF1902B having the 7b-configuration.
In our SAR study of the tetrahydronaphthofuranones as
candidate PR ligands, C-6 and C-7 were identified
as critical positions for the PR binding affinity and for
agonist and/or antagonist activities. Therefore, we
aimed towards transformation at the C-7 position of
tetrahydrobenzindolone in order to clarify the role of
the substituent at that position.
Figure 2. Structure of PF1092A, B, and C.
In view of this desirable feature of compound (1), we
investigated the synthesis and SAR of tetrahydrobenzin-
dolones in order to seek novel nonsteroidal PR agonists
and antagonists. In this paper, we describe in detail the
synthesis and SAR of tetrehydrobenzindolones as novel
nonsteroidal PR agonists and antagonists.
The 7-O-acetyl group of compound (5) was especially
reactive and was expected to be useful for introduction
of new substituents at the 7-position. For example,
treatment of compound (5) with alcohols (ROH) gave
7-O-alkyl compounds (1a, c–f), while the use of water
in place of alcohol readily afforded compound (1b).
2. Results and discussion
In order to obtain 7b-substituted compounds, we initial-
ly required the 7b-hydroxyl compound. First, the epoxy
compound was derived from compound (5) by treat-
ment with 1 N NaOH and then treatment with 1 N
HCl afforded the 7a- and 7b-hydroxyl compounds as a
mixture. The 7b-hydroxyl compound (6) was isolated
by silica gel column chromatography, but this diol (6)
was insufficiently stable and the yield was low.
2.1. Synthesis of the tetrahydrobenzindolone skeleton
from PF1092C
As shown in Scheme 1, the tetrahydrobenzindolone
compound (5) was synthesized by treatment of
PF1092C with methanesulfonyl chloride in the presence
of diisopropylethylamine, followed by one-pot sequen-
tial reactions of lactone opening and lactam closing with
methylamine, and SN20-type reaction with acetic acid.
The 7-deoxy compound (8) was next synthesized by
reduction of the 6-oxo precursor (7). This precursor
Figure 3. Structures of tetrahydrobenzindolone and tetrahydronaphthofuranone.

4864
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
Scheme 1. Reagents: (a)—(i) MsCl, i-Pr2NEt, CH2Cl2, (ii) MeNH2, THF; (b) AcOH, CH3CN; (c) R1OH or H2O, CH3CN; (d) 1N NaOH; (e) 1N
HCl; (f) p-TsOH, toluene; (g) NaBH4, MeOH.
(7) was obtained by treatment of compound (5) with p-
toluenesulfonic acid (p-TsOH). The oxo compound (7)
was considered to be formed from an enol intermediate
via elimination of the acetoxy group. Reduction of the
6-oxo precursor (7) with NaBH4 selectively afforded
the 6b-hydroxyl compound (8), but its stability was also
unsatisfactory.
of the relative binding affinity (RBA), that is, the ratio
obtained by dividing IC50 of progesterone (32 nM) by
IC50 of a test compound at the human progesterone
receptor (thus, a large value of RBA indicates high PR
binding affinity). The tetrahydrobenzindolone deriva-
tives showed substantially higher (2.4- to 21-fold) PR
binding affinity than the tetrahydronaphthofuranone
derivatives. Surprisingly, one of them (3c) showed 2.3-
fold higher PR-binding affinity than progesterone itself
(Table 1).
Thus, we established the basic synthetic route to tetrahy-
drobenzindolone and methods for its transformation at
the 7-position.
The improved chemical stability and high PR binding
affinity of the tetrahydrobenzindolone derivatives indi-
cated that they would be promising lead compounds.
We therefore started to search for new PR ligands based
on the tetrahydrobenzindolone skeleton.
2.2. Comparison of PR binding affinity of tetrahydro-
naphthofuranone and tetrahydrobenzindolone
To evaluate the PR binding affinity of the new skeleton,
tetrahydrobenzindolone, compared with that of the cor-
responding tetrahydronaphthofuranone, 6-O-acyl deriv-
atives (3a–e) were prepared from compound (1a) by
treatment with various acyl halides in the presence of
pyridine (Scheme 2).
2.3. Selection of lead compound
In the beginning of our SAR investigation, we started
with optimization of the substituent at the 1-position,
so the derivatives (10a–d) were synthesized in addition
to 3b and 3e. The derivatives (10a–d, 3b, and 3e), with
hydrogen, methyl, ethyl or benzyl at the 1-position, were
obtained by acylation of compound (9) in the same man-
ner as described for compound (1a) (Scheme 2).
The PR binding affinities of tetrahydrobenzindolone
derivatives (3a–e) and tetrahydronaphthofuranone
derivatives (4a–e) possessing the same substituent
groups at the 6- and 7-positions were compared in terms

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4865
Scheme 2. Reagents: (a) (i) MsCl, i-Pr2NEt, CH2Cl2; (ii) R1NH2, THF; (iii) AcOH, CH3CN; (iv) MeOH; (b) RCOCl or RCO2O, pyridine.
Table 1. Relative PR-binding affinities of the compounds
Compound
R1
RBAa
Compound
R2
RBAa
3a
3b
Me
Et
16
34
4a
4b
4c
4d
4e
Me
Et
5
4
3c
3d
Cyclopropyl
Thiophen-2-yl
Furan-2-yl
230
57
Cyclopropyl
Thiophen-2-yl
Furan-2-yl
11
10
40
3e
Progesterone
94
100
a Relative binding affinity (RBA) was calculated as follows: RBA = (IC50 of progesterone/IC50 of test compound) · 100.

4866
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
Table 2. Relative PR-binding affinities of the compounds
Table 3. Relative PR-binding affinities and LUC assay of the
compounds
Compound
R1
R2
RBAa
Compound
R1
R2
R3
RBAa
LUC assay
10a
3b
H
Et
Et
4
34
2
11a
11b
11c
11d
3b
H
HO
H
Et
Et
Me
Et
Et
Et
Et
Et
Et
17
178
59
12
34
20
13
8
c
Me
Et
H
c
10b
3e
Et
H
HO
H
N.T.b
Me
Et
Furan-2-yl
Furan-2-yl
Furan-2-yl
91
8
AcO
MeO
EtO
n-PrO
n-BuO
i-PrO
c
c
c
c
c
b
10c
10d
H
Benzyl
<5
11e
11f
11g
11h
H
a Relative binding affinity (RBA) was calculated as follows: RBA =
H
(IC50 of progesterone/IC50 of test compound) · 100.
H
H
6
a Relative binding affinity (RBA) was calculated as follows: RBA =
(IC50 of progesterone/IC50 of test compound) · 100.
b Not tested.
The methyl derivatives (3b, e) showed the highest PR
binding affinity among these compounds, and the bind-
ing affinity decreased as the side chain became larger.
Compound (10a), with hydrogen at the 1-position,
showed very low PR binding affinity. Thus, the methyl
group was selected for the 1-position (Table 2).
unsuitable, because of its insufficient chemical stability
and low yield, although the 7b-hydroxyl derivative
(11c) showed relatively satisfactory PR binding affinity.
On the other hand, the 7a-methoxytetrahydrobenzindo-
lone skeleton offers a good balance of high PR binding
affinity, good chemical stability, good yield, and ease
of derivatization. We therefore selected the 7a-meth-
oxy-1-methyl derivative (1a) as the preferred lead com-
pound, even though the 7a-hydroxyl derivative showed
higher PR binding affinity.
Next, to examine the SAR at the 7-position, we modified
the derivatives possessing a propionyl group at the 6-po-
sition by the method shown in Scheme 2 (except com-
pound (11c)).
The new derivatives were subjected not only to PR bind-
ing affinity assay, but also to an exogenous luciferase
(LUC) assay using a T47D human breast cancer cell line
to determine whether their activities were agonistic or
antagonistic.9 Agonistic activity represented the relative
activity to 1 nM progesterone as 100%. Antagonistic
activity represented the relative activity to 1 nM proges-
terone as 0%. A full agonist (i.e., progesterone) and a pure
antagonist (i.e., RU486) have 100% corresponding activ-
ity, whereas our derivatives generally did not show 100%
agonistic or antagonistic activity. We therefore classified
the derivatives into four types according to their pattern
of agonistic and antagonistic activities, as follows:
2.4. Screening of agonistic ligands
As most of the 6-O-propionyl derivatives were type-c
agonists in LUC assay, 6-O-acyl derivatives were syn-
thesized to clarify the role of acyl substituents at the 6-
position. The 6-O-acyl derivatives (3f–h) were prepared
from compound (1a) by treatment with various acyl ha-
lides in the presence of pyridine (Scheme 2).
The derivatives possessing the carbonyl group generally
showed high PR binding affinity. The cyclopropyl car-
bonyl derivative (3c) showed the highest affinity, while
the acetyl and cyclohexyl carbonyl derivatives (3a, 3f)
showed lower affinity. Moreover, they were type-c ago-
nists in LUC assay (Table 4).
Type a: agonist <10% and antagonist P90%,
Type b: agonist 11–25% and antagonist 75–89%,
Type c: agonist 26–74% and antagonist 74–26%,
Type d: agonist >75% and antagonist 625%.
To find compounds with superior agonistic activity, we
focused on the carbonyl group of 6-O-acyl derivatives.
The 6-O-carbamoyl derivatives (12a–f) were obtained
via 6-O-imidazolyl intermediates, which were generated
by treatment of compound (1a) with carbonyl diimidaz-
ole (CDI) in methylene chloride, followed by substitu-
tion of an appropriate amine. Further, the 6-propyl
carbamoyl derivatives (13a–e) and dialkyl carbamates
(14a–f) were similarly synthesized to study their SAR
(Scheme 3).
The 7-deoxy derivative (11a) did not show high PR bind-
ing affinity, whereas the 7b-hydroxyl derivative (11c)
showed high affinity. The 7a-hydroxyl derivative (11b)
showed the highest PR binding affinity. The 7a-methoxy
derivative (3b) showed relatively high PR binding affinity,
whereas among other 7a-alkyloxy derivatives (11e–h), the
PR binding affinity decreased with increasing size of the
alkyl moiety. In LUC assay, these compounds were gener-
ally classified as type-c agonists (Table 3).
In the selection of the lead compound, the 7-deoxy
derivative or 7b-hydroxyl derivative was regarded as
The series of 6-O-carbamoyl derivatives (12–14) showed
generally high PR binding affinity and had a type-c ago-

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4867
Table 4. Relative PR-binding affinities and LUC assay of the
compounds
nistic profile in LUC assay. Compounds (12a, 12b, 12c,
13a, 14a, and 14f) in particular showed 1.1- to 1.9-fold
higher PR binding affinity than progesterone. Among
the series of 6-O-carbamoyl derivatives (12c, 13a–e),
the result for compound (12c), which showed the highest
PR binding affinity among the other derivatives, indicat-
ed that the best substituent at the 7-position of 6-O-car-
bamoyl derivatives was the a-methoxy group (Table 5).
Compound
R1
RBAa
LUC assay
Thus, we identified several new compounds with agonis-
tic activity in in vitro assay, that is, 3c, 12a, 12b, 12c,
13a, 14a, and 14f, based on the 7a-methoxytetrahydro-
benzindolone skeleton.
3a
3b
3c
3d
3e
3f
Me
Et
15
33
c
c
c
c
c
c
c
c
Cyclopropyl
Thiophen-2-yl
Furan-2-yl
Cyclohexanyl
Ph
230
56
91
17
2.5. Screening of antagonistic ligands
3g
3h
47
86
Pyridin-3-yl
In our previous study, the 6-hydroxyl group of tetrahy-
dronaphthofuranone could not be alkylated due to its
poor chemical stability under basic conditions, but it
a Relative binding affinity (RBA) was calculated as follows: RBA =
(IC50 of progesterone/IC50 of test compound) · 100.
Scheme 3. Reagents: (a) CDI, CH2Cl2; (b) various amines, THF; (c) n-PrNH2.

4868
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
Table 5. Relative PR-binding affinities and LUC assay of the
compounds
pound (15f), showed a type-b profile; compound (15f),
however, had a type-a profile (Table 6).
Interestingly, the derivatives (11h) and (13d), which pos-
sess a 7a-isopropyloxy group, showed a type-b profile in
LUC assay, although other derivatives were agonistic li-
gandswitha type-c profile (Tables 3and5). Wespeculated
that it might be possible to synthesize antagonistic PR
ligands by choosing an appropriate substituent at the
7-position.
Compound R1
R2
R3
RBAa LUC assay
To examine the substituent effect at the 7-position, the
7a-isopropyloxy derivatives (16a–e) were synthesized
by alkylation of compound (1f) (Scheme 4).
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
14f
MeO Me
MeO Et
MeO n-Pr
H
H
H
H
H
H
H
H
H
H
H
139
145
119
38
c
c
c
c
c
c
c
c
c
b
c
c
c
c
c
c
c
All the 7a-isopropyloxy derivatives obtained showed a
type-a profile in LUC assay, although they did not
always have high PR binding affinity (Table 6).
MeO Cyclopropyl
MeO Cyclohexanyl
MeO Benzyl
14
21
H
n-Pr
n-Pr
n-Pr
107
48
HO
EtO
78
11
Table 6. Relative PR-binding affinities and LUC assay of the
compounds
i-PrO n-Pr
i-BuO n-Pr
MeO Me
MeO Me
MeO Me
MeO Et
7
Me 188
Et
80
89
n-Pr
Et
43
59
MeO –(CH2)5–
MeO –(CH2)2O(CH2)2–
107
a Relative binding affinity (RBA) was calculated as follows: RBA =
Compound R1
R2
RBAa LUC assay
(IC50 of progesterone/IC50 of test compound) · 100.
15a
15b
15c
15d
15e
15f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
8
b
b
b
b
b
a
b
b
a
a
a
a
a
n-Pr
14
10
20
8
was possible to alkylate the hydroxyl group at the 6-po-
sition of the 7-methoxytetrahydrobenzindolone skele-
ton. Several kinds of 6-O-alkyl derivatives of
tetrahydrobenzindolone were synthesized, to investigate
the influence of the linkage at the 6-position. The 6-O-al-
kyl derivatives (15a–h) were obtained by treatment of
compound (1a) with alkyl halides in the presence of
sodium hydride (NaH) in DMF solution (Scheme 4).
CH2@CH2CH2–
n-Bu
(CH3)2CH(CH2)2–
15g
15h
16a
16b
16c
16d
16e
Cyclopropylmethyl 46
Benzyl
6
6
8
2
1
5
i-Pr Et
i-Pr n-Pr
i-Pr n-Bu
i-Pr (CH3)2CH(CH2)2–
i-Pr Cyclopropylmethyl
The PR binding affinities of the 6-O-alkyl derivatives
(15a–h) were generally lower than those of the 6-O-car-
bamoyl derivatives. All the derivatives, except for com-
a Relative binding affinity (RBA) was calculated as follows: RBA =
(IC50 of progesterone/IC50 of test compound) · 100.
Scheme 4. Reagents: (a) NaH, RX, DMF.

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4869
This result indicated that we would be able to separate
agonistic and antagonistic activities by choosing an
appropriate substituent at the 7-position.
yl-17b-hydroxy-17-[1-propynyl]estra-4,9-diene-3-one) was
purchased from Sigma. [1,2,6,7-3H(N)]Progesterone
(specific activity: 3848 GBq/mmol) was purchased from
NENTM Life Science Products.
2.6. In vivo study
4.1.2. Cell cultures. T47D human breast carcinoma cells
were purchased from the American Type Culture Col-
lection (ATCC). The T47D line was cultured in Dul-
becco’s modified Eagle’s medium (DMEM) containing
10% fetal bovine serum. This cell line was cultured at
37 ꢁC with 5% CO2.
In the selection of agonists, an endogenous alkaline-
phosphatase assay using T47D cell was employed as a
functional assay to evaluate the effects of compounds
on PR-dependent enzyme expression9 in addition to
LUC assay. We selected 12c (CP8668) and 14a
(CP8816) as agonists on the basis of the endogenous
alkaline-phosphatase assay. We examined their in vivo
effect using the Clauberg–McPhail assay, in which the
in vivo progestational activity is evaluated in terms of
4.1.3. PR binding assay. The measurements of the bind-
ing affinity of compounds for the PR were performed as
described earlier.9 Unless otherwise specified, the follow-
ing procedures were conducted at temperatures of 0–
4 ꢁC. Collected T47D cells were sonicated with a Bran-
son Sonifier 450 in a buffer consisting of 5 mM KH2PO4
(pH 7.4), 30% glycerol, 0.1% a-thioglycerol, and 25 lg/
ml leupeptin, followed by centrifugation at 100,000g
for 30 min. The resulting supernatant (cytosol) was
stored at ꢀ80 ꢁC prior to its use as a source of progester-
one receptors for the binding assays.
a
rabbit endometrial transformation.14,15 In the
Clauberg–McPhail assay, the compounds showed good
progestational activity after sc and po administration,
and their efficacy after sc administration was similar to
that of progesterone.14,15
To select antagonistic ligands, we also used the endoge-
nous alkaline-phosphatase assay. Compound 15f
(CP8661) was confirmed to possess pure PR antagonistic
activity in this assay, and in the Clauberg–McPhail
assay, it showed potent anti-progestational effects. This
compound was inactive in the agonist format of the rab-
bit endometrial transformation test at the same dosage.16
A reaction mixture (100 ll) containing 50 mM KH2PO4
(pH 7.4), 10% glycerol, 0.1% a-thioglycerol, 25 lg/ml
leupeptin, 1 mM EDTA, [1,2,6,7-3H(N)]progesterone
(final concentration of 1.4 nM), T47D cytosol (0.8 mg
protein/ml), and a test sample was incubated for 1 h at
4 ꢁC. After incubation, 100 ll of Dextran-coated char-
coal solution consisting of 0.5% Norit A (Nacalai
Tesque) and 0.05% Dextran T-70 (Pharmacia Fine
Chemicals) was added to the incubation mixture, and
incubation was continued for 10 min at 4 ꢁC. The mix-
ture was then centrifuged at 1800 rpm for 5 min. The
radioactivity of 100 ll of the supernatant was measured
in 2 ml of Aquasol-2 (Packard) with a liquid scintillation
counter (Beckman LS6500). Non-specific binding was
defined as the binding observed when 10 lM of cold
progesterone was added to the reaction mixture. Sig-
moid fitting curves of the results expressed as inhibitory
effects of the test compounds were obtained using Kale-
idaGraph software (Synergy Software). IC50 values were
determined from the sigmoid fitting curve parameters.
Relative binding affinity (RBA) was calculated by the
comparison of IC50 values of the test compounds and
progesterone.
The affinity of the agonistic ligands, 12c (CP8668) and
14a (CP8816), and the antagonistic ligand 15f
(CP8661) for other steroidal receptors was examined,
and these compounds exhibited selective affinity for
the progesterone receptor. The selectivity of 12c
(CP8668) and 14a (CP8816) was especially high.14–16
3. Conclusion
We have developed a new lead compound, tetrahydro-
benzindolone, possessing a lactam ring, which shows
sufficient stability for easy modification at the 6- and/
or 7-positions. We have investigated the SAR of tetrahy-
drobenzindolones as PR ligands. As representative
active compounds, we identified the 6-O-carbamoyl
derivatives 12c (CP8668) and 14a (CP8816) as agonists,
and the 6-O-alkyl derivative 15f (CP8661) as an antago-
nist by means of in vitro and in vivo assays. Our results
indicate that PR ligands with agonistic or antagonistic
activity, as required, can be derived from a tetrahydro-
benzindolone core structure by choosing an appropriate
linkage type and suitable substituents at the 6- and 7-po-
sitions. We expect that these compounds will be good
candidate drugs for the treatment of various PR-related
diseases.
4.1.4. Progesterone-dependent exogenous luciferase
expression assay. The progesterone-dependent modula-
tion of gene transcription was examined using the lucif-
erase assay with stable transfected T47D-pMAMneo-
LUC cells. The assay was performed as previously
described.9 In brief, the growth medium for T47D-
pMAMneo-LUC cells was replaced with phenol red-free
DMEM containing 5% fetal bovine serum treated with
dextran-coated charcoal. After 24 h of cultivation, the
cells were plated in 96-well plates at 50,000 cells/well.
After 8 h of cultivation, the test compounds were added
to each well to achieve the appropriate compound con-
centration. After 16 h of cultivation, 100 ll of Luc Lite
(Packard) solution was added to each well and mixed.
After 15 min of incubation at room temperature, lumi-
4. Experimental
4.1. Biological method
4.1.1. Materials. Progesterone was purchased from
Junsei Chemical. RU486 (11b-[4-dimethylamino]phen-

4870
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
nescence was measured using either the LUMIstar
(BMG Labtechnologies) luminometer or the ARVO
(Perkin-Elmer) luminometer.
J = 16.0 Hz, 4-H), 3.09 (3H, s, N-CH3), 3.43 (3H, s,
OCH3), 3.70 (1H, dd, J = 4.8, 1.9 Hz, 7-H), 3.91 (1H, br
s, 6-H), 5.74 (1H, s, 9-H), 5.82 (1H, d, J = 4.8 Hz, 8-H);
18
½aꢁ ꢀ584 (c 0.8, MeOH); mp 165–170 ꢁC; MS (EI) m/z
D
4.2. Chemistry
289 (M)+; HRMS (FAB) (C17H24O3N) calcd 290.1757,
obsd 290.1753.
Melting points were determined on a Yanagimoto micro-
melting point apparatus and are uncorrected. Optical rota-
tions were recorded on a JASCO DIP-370 polarimeter. 1H
NMR (300 MHz) spectra were recorded on a Varian Gem-
ini 300 spectrometer. Chemical shifts are reported in d val-
ue (ppm) with tetramethylsilane (TMS) as the internal
standard (NMR peak description: s, singlet; d, doublet; t,
triplet; q, quartet; sep, septet; m, multiplet; and br, broad
peak). Elemental analyses were within 0.4% of the theo-
retical values for the elements indicated, unless otherwise
noted. High-resolution mass spectra (HRMS) were ob-
tained on a JEOL JMS-700. All commercial reagents and
solvents were used as received. PF1092C was prepared
according to described procedure.7
4.2.3. (4aR,5R,6R,7R)-6-Acetoxy-7-methoxy-4a,5,6,7-tet-
rahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (3a).
To a solution of compound (1a) (20 mg = 0.07 mmol) in
pyridine (1 ml) was added acetyl chloride (15 ll =
0.21 mmol). The reaction mixture was stirred at room
temperature for 24 h. The mixture was concentrated, and
the residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3 and brine. The organic layer was dried
(MgSO4), filtered, and concentrated. Preparative TLC of
this residue provided 12 mg (53%) of the title compound
(3a) as a colorless solid: 1H NMR (CDCl3) d 1.08 (3H, s,
4a-CH3), 1.08 (3H, d, J = 7.2 Hz, 5-CH3), 1.86 (3H, d,
J = 1.9 Hz, 3-CH3), 2.06 (3H, s, OCOCH3), 2.08 (1H, dq,
J = 7.2, 2.8 Hz, 5-H), 2.12 (1H, br d, J = 15.9 Hz, 4-H),
2.79 (1H, d, J = 15.9 Hz, 4-H), 3.09 (3H, s,N-CH3),3.49
(3H, s, O-CH3), 3.60 (1H, dd, J = 4.8, 1.3 Hz, 7-H), 5.08
4.2.1. (4aR,5R,6R,7R)-7-Acetoxy-6-hydroxy-4a,5,6,7-tet-
rahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one
(5).
To a solution of PF1092C (200 mg = 0.76 mmol) in
CH2Cl2 (4 ml) were added methanesulfonyl chloride
(88 ll = 1.15 mmol) and diisopropylethylamine (266 ll =
1.53 mmol). The reaction was maintained at ꢀ15 ꢁC until
complete consumption of the starting material was ob-
served as determined by TLC analysis. The mixture was
washed with saturated NaHCO3 and brine. The organic
layer was dried (MgSO4), filtered, and concentrated. This
residue was used in the following step with no further puri-
fication. The residue was diluted in 2 M solution methyl-
amine in THF (2.29 ml) and stirred at room temperature
for 1 h. The solvent was removed under reduced pressure,
and the residue was used in the following step with no
further purification. To a solution of the residue
(100 mg = 0.36 mmol) in CH3CN(5 ml) was added acetic
acid (200 ll = 3.30 mmol). The mixture was stirred at
room temperature for 20 h. This mixture was washed with
saturated NaHCO3 and brine. The organic layer was dried
(MgSO4), filtered, and concentrated. Preparative TLC of
this residue provided 85 mg (74%) of the title compound
(1H, m, 6-H), 5.72 (1H, s, 9-H), 5.74 (1H, d, J = 4.8 Hz,
18
8-H); ½aꢁ ꢀ291 (c 1.0, MeOH); MS (EI) m/z 331 (M)+.
D
4.2.4. (4aR,5R,6R,7R)-6,7-Dihydroxy-4a,5,6,7-tetrahydro-
1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (1b). A solution
of compound (5) (100 mg = 0.32 mmol) in CH3CN (5 ml)–
H2O (5 ml) was stirred at room temperature for 20 h. The
solvent was removed under reduced pressure. Preparative
TLC of this residue provided 63 mg (71%) of the major
compound (1b) as a colorless solid and 10 mg (11%) of
1
the minor compound (6) as a colorless solid: H NMR
(CDCl3) d 1.11 (3H, s, 4a-CH3), 1.20 (3H, d, J = 7.2 Hz,
5-CH3), 1.86 (3H, d, J = 1.9 Hz, 3-CH3), 1.94 (1H, dq,
J = 7.2, 2.5 Hz, 5-H), 2.08 (1H, br d, J = 15.9 Hz, 4-H),
2.80 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.87
(1H, m, 6-H), 4.17 (1H, dd, J = 4.8, 1.9 Hz, 7-H), 5.73
20
D
(1H, s, 9-H), 5.80 (1H, d, J = 4.8 Hz, 8-H); ½aꢁ ꢀ455 (c
0.2, MeOH); MS (EI) m/z 275 (M)+.
4.2.5. (4aR,5R,6R,7S)-6,7-Dihydroxy-4a,5,6,7-tetrahydro-
1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (6). H NMR
1
1
(5) as a colorless solid: H NMR (CDCl3) d 1.14 (3H, s,
4a-CH3), 1.20 (3H, d, J = 7.2 Hz, 5-CH3), 1.88 (3H, d,
J = 2.0 Hz, 3-CH3), 1.90 (1H, dq, J = 7.2, 2.9 Hz, 5-H),
2.06 (3H, s, OCOCH3), 2.16 (1H, br d, J = 16.0 Hz, 4-H),
2.82 (1H, d, J = 16.0 Hz, 4-H), 3.10(3H, s, N-CH3), 3.84
(CDCl3) d 1.16 (3H, s, 4a-CH3), 1.21 (3H, d, J = 7.2 Hz,
5-CH3), 1.78 (1H, dq, J = 7.2, 2.5 Hz, 5-H), 1.85 (3H, d,
J = 1.9 Hz, 3-CH3), 2.08 (1H, br d, J = 15.9 Hz, 4-H),
2.78 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.98
(1H, m, 6-H), 4.39 (1H, m, 7-H), 5.67 (1H, br s, 8-H),
5.70 (1H, s, 9-H); MS (EI) m/z 275 (M)+.
(1H, m, 6-H), 5.20 (1H, dd, J = 4.8, 1.7 Hz, 7-H), 5.70
18
D
(1H, d, J = 4.8 Hz, 8-H), 5.75 (1H, s, 9-H); ½aꢁ ꢀ608 (c
1.0, MeOH); mp 50–55 ꢁC; MS (EI) m/z 317 (M)+; HRMS
(FAB) (C18H24O4N) calcd 318.1706, obsd 318.1710.
4.2.6. (4aR,5R)-6-Oxo-4a,5,6,7-tetrahydro-1,3,4a,5-tetram-
ethylbenz[f]indol-2(4H)-one (7). A solution of compound
(5) (20 mg = 0.07 mmol) in toluene (4 ml) was added
methanesulfonic acid (4.5 ll = 0.07 mmol). This mixture
was heated at reflux for 20 min. The reaction mixture was
cooled, and the mixture was washed with saturated
NaHCO3 and brine. The organic layer was dried (MgSO4),
filtered, and concentrated. Preparative TLC of this residue
provided 6 mg (36%) of the title compound (7) as a
colorless solid: 1H NMR (CDCl3) d 0.90 (3H, s, 4a-CH3),
1.15 (3H, d, J = 6.7 Hz, 5-CH3), 1.91 (3H, d, J = 2.2 Hz,
3-CH3), 2.45 (1H, br d, J = 15.9 Hz, 4-H), 2.77(1H, d,
4.2.2. (4aR,5R,6R,7R)-6-Hydroxy-7-methoxy-4a,5,6,7-tet-
rahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (1a). A
solution of compound (5) (100 mg = 0.32 mmol) in MeOH
(10 ml) was stirred at 50 ꢁC for 3 h. The solvent was re-
moved under reduced pressure. Preparative TLC of this
residue provided 90 mg (100%) of the title compound
(1a) as a colorless solid: 1H NMR (CDCl3) d 1.11 (3H, s,
4a-CH3), 1.19 (3H, d, J = 7.3 Hz, 5-CH3), 1.86 (3H, d,
J = 2.0 Hz, 3-CH3), 1.91 (1H, dq, J = 7.3, 2.6 Hz, 5-H),
2.13 (1H, br d, J = 16.0 Hz, 4-H), 2.78 (1H, d,

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4871
1
J = 15.9 Hz, 4-H), 2.82 (1H, q, J = 6.7 Hz, 5-H), 3.01 (1H,
dd, J = 23.3, 4.1 Hz, 7-H), 3.14 (3H, s, N-CH3), 3.17 (1H,
dd, J = 23.3, 4.1 Hz, 7-H), 5.77 (1H, br t, J = 4.1 Hz, 8-
H), 5.79 (1H, s, 9-H); MS (EI) m/z 257 (M)+.
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 0.83–1.04 (4H, m, OCO-cyclopropane), 1.09
(3H, d, J = 7.2 Hz, 5-CH3), 1.10 (3H, s, 4a-CH3), 1.57
(1H, m, OCO-cyclopropane), 1.87 (3H, d, J = 1.9 Hz, 3-
CH3), 2.07 (1H, dq, J = 7.2, 2.8 Hz, 5-H), 2.14 (1H, br
d, J = 15.9 Hz, 4-H), 2.80 (1H, d, J = 15.9 Hz, 4-H),
3.09 (3H, s, N-CH3), 3.49 (3H, s, OCH3), 3.60 (1H, dd,
4.2.7. (4aR,5R,6S)-6-Hydroxy-4a,5,6,7-tetrahydro-1,3,4a,5-
tetramethylbenz[f]indol-2(4H)-one (8). A solution of com-
pound (7) (215 mg = 0.84 mmol) in MeOH (4 ml) was
added sodium borohydride (63 mg = 1.67 mmol). The
reaction mixture was stirred at 0 ꢁC until complete con-
sumption of the starting material was observed as deter-
mined by TLC analysis. H2O was added to the reaction
mixture. The mixture was extracted with CH2Cl2 and
washed with brine. The organic layer was dried (MgSO4),
filtered, and concentrated. Preparative TLC of this residue
provided 190 mg (88%) of the title compound (8) as a col-
J = 4.7, 1.3 Hz, 7-H), 5.07 (1H, m, 6-H), 5.73 (1H, s, 9-
H), 5.75 (1H, d, J = 4.7 Hz, 8-H); ½aꢁ ꢀ196 (c 1.0,
20
D
MeOH); MS (EI) m/z 357 (M)+.
4.2.11. (4aR,5R,6R,7R)-7-Methoxy-4a,5,6,7-tetrahydro-1,3,
4a,5-tetramethyl-6-(2-thiophenecarbonyloxy)benz[f]indol-
2(4H)-one (3d). Reaction of 1a gave 3d in 89% yield as a
1
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 1.16 (3H, d, J = 7.2 Hz, 5-CH3), 1.22 (3H, s,
4a-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3), 2.17 (1H, dq,
J = 7.2, 2.8 Hz, 5-H), 2.18 (1H, br d, J = 15.9 Hz, 4-H),
2.83 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3),
3.55 (3H, s, OCH3), 3.76 (1H, br d, J = 4.8 Hz, 7-H),
5.27 (1H, m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d,
J = 4.8 Hz, 8-H), 7.10 (1H, dd, J = 4.9, 3.8 Hz,
1
orless solid: H NMR (CDCl3) d 1.14 (3H, s, 4a-CH3),
1.18 (3H, d, J = 7.0 Hz, 5-CH3), 1.74 (1H, dq, J = 7.0,
2.7 Hz, 5-H), 1.85 (3H, d, J = 2.0 Hz, 3-CH3), 2.09 (1H,
br d, J = 16.0 Hz, 4-H), 2.40 (1H, br dd, J = 20.5,
4.2 Hz, 7-H), 2.58 (1H, br ddd, J = 20.5, 4.2 Hz, 7-H),
2.71 (1H, d, J = 16.0 Hz, 4-H), 3.09 (3H, s, N-CH3),
4.01 (1H, m, 6-H), 5.68 (1H, br t, J = 4.2 Hz, 8-H), 5.74
(1H, s, 9-H); MS (EI) m/z 259 (M)+; HRMS (FAB)
(C16H22O2N) calcd 260.1651, obsd 260.1656.
OCOC4H3S), 7.55 (1H, dd, J = 4.9, 1.3 Hz, OCOC4H3S),
18
D
7.77 (1H, dd, J = 3.8, 1.3 Hz, OCOC4H3S); ½aꢁ +36 (c
1.0, MeOH); mp 148–153 ꢁC; MS (EI) m/z 399 (M)+.
4.2.8. (4aR,5R,6R,7R)-6,7-Dimethoxy-4a,5,6,7-tetrahydro-
1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (15a). A solution
of compound (1a) (20 mg = 0.07 mmol) in DMF (400 ll)
was gradually added 60% sodium hydride (NaH)
(7 mg = 0.18 mmol) under ice cooling. Methyl iodide
(22 ll = 0.35 mmol) was added into the mixture after foam-
ing subsided. The reaction mixture was stirred at room tem-
perature for 2 h. H2O was gradually added to the reaction
mixture. The mixture was extracted with CH2Cl2 and
washed with brine. The organic layer was dried (MgSO4), fil-
tered, and concentrated. Preparative TLC of this residue
provided 13 mg (62%) of the title compound (15a) as a col-
4.2.12. (4aR,5R,6R,7R)-6-(2-Furancarbonyloxy)-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (3e). Reaction of 1a gave 3e in 75% yield as a
1
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 1.15 (3H, d, J = 7.2 Hz, 5-CH3), 1.21 (3 H,
s, 4a-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3), 2.17 (1H,
dq, J = 7.2, 2.8 Hz, 5-H), 2.17 (1H, br d, J = 15.9 Hz,
4-H), 2.83 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-
CH3), 3.54 (3H, s, O-CH3), 3.73 (1H, dd, J = 4.8,
1.3 Hz, 7-H), 5.30 (1H, m, 6-H), 5.75 (1H, s, 9-H),
5.77 (1H, d, J = 4.8 Hz, 8-H), 6.49 (1H, dd, J = 3.5,
1.7 Hz, OCOC4H3O), 7.10 (1H, dd, J = 3.5, 0.8 Hz,
1
orless oil: H NMR (CDCl3) d 1.05 (3H, s, 4a-CH3), 1.16
OCOC4H3O), 7.57 (1H, dd, J = 1.7, 0.8 Hz, OCO-
18
D
(3H, d, J = 7.1 Hz, 5-CH3), 1.85 (3H, d, J = 2.0 Hz, 3-
CH3), 1.89 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.09 (1H, br d,
J = 15.9 Hz, 4-H), 2.77 (1H, d, J = 15.9 Hz, 4-H), 3.08
(3H, s, N-CH3), 3.28 (1H, m, 6-H), 3.40 (3H, s, O-CH3),
C4H3O); ½aꢁ 0 (c 1.0, MeOH); mp 155–158 ꢁC; MS
(FAB) m/z 384 (M+H)+.
4.2.13. (4aR,5R,6R,7R)-6-(2-Cyclohexylcarbonyloxy)-7-
methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]-
indol-2(4H)-one (3f). Reaction of 1a gave 3b in 52% yield
3.43 (3H, s, OCH3), 3.74 (1H, dd, J = 4.8, 1.4 Hz, 7-H),
18
D
5.72 (1H, s, 9-H), 5.81 (1H, d, J = 4.8 Hz, 8-H); ½aꢁ ꢀ340
(c 1.0, MeOH); MS (EI) m/z 303 (M)+.
as a colorless solid by a similar procedure to 3f: H
1
NMR (CDCl3) d 1.06 (3H, d, J = 7.2 Hz, 5-CH3), 1.09
(3H, s, 4a-CH3), 1.14–1.66 (11H, m, OCO-cyclohexane),
1.85 (3H, d, J = 1.9 Hz, 3-CH3), 2.07 (1H, dq, J = 7.2,
2.8 Hz, 5-H), 2.13 (1H, br d, J = 15.9 Hz, 4-H), 2.28
(1H, m, OCO-cyclohexane), 2.77 (1 H, d, J = 15.9 Hz,
4-H), 3.08 (3 H, s, N-CH3), 3.48 (3 H, s, OCH3), 3.53
(1 H, dd, J = 4.8, 1.3 Hz, 7-H), 5.06 (1H, m, 6-H),
4.2.9. (4aR,5R,6R,7R)-7-Methoxy-6-propionyloxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (3b).
Reaction of 1a gave 3b in 30% yield as a colorless solid by
1
a similar procedure to 3a: H NMR (CDCl3) d 1.08 (3H,
d, J = 7.2 Hz, 5-CH3), 1.09 (3H, s, 4a-CH3), 1.14 (3H, t,
J = 7.5 Hz, OCOCH2CH3), 1.87 (3H, d, J = 1.9 Hz, 3-
CH3), 2.08 (1H, dq, J = 7.2, 2.8 Hz, 5-H), 2.13 (1H, br d,
J = 15.9 Hz, 4-H), 2.34 (2H, q, J = 7.5 Hz, OCOCH2CH3),
2.79 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.50
(3H, s, OCH3), 3.60 (1H, dd, J = 4.8, 1.3 Hz, 7-H), 5.09
5.72 (1H, s, 9-H), 5.73 (1H, br d, J = 4.8 Hz, 8-H);
½aꢁ
18
D
ꢀ152 (c 2.0, MeOH); MS (FAB) m/z 400
(M+H)+; HRMS (FAB) (C24H34O4N) calcd 400.2488,
obsd 400.2514.
(1H, m, 6-H), 5.73 (1H, s, 9-H), 5.75 (1H, d, J = 4.8 Hz, 8-
18
H); ½aꢁ ꢀ280 (c 0.6, MeOH); MS (FAB) m/z 346 (M+H)+.
4.2.14. (4aR,5R,6R,7R)-6-Benzoyloxy-7-methoxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (3g).
Reaction of 1a gave 3g in 87% yield as a colorless solid by
a similar procedure to 3a: H NMR (CDCl3) d 1.17 (3H,
d, J = 7.2 Hz, 5-CH3), 1.25 (3H, s, 4a-CH3), 1.89 (3H, d,
D
4.2.10. (4aR,5R,6R,7R)-6-Cyclopropylcarbonyloxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (3c). Reaction of 1a gave 3c in 100% yield as a
1

4872
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
J = 1.9 Hz, 3-CH3), 2.20 (1H, br d, J = 15.9 Hz, 4-H), 2.21
(1H, dq, J = 7.2, 2.8 Hz, 5-H), 2.85 (1H, d, J = 15.9 Hz, 4-
H), 3.11 (3H, s, N-CH3), 3.57 (3H, s, OCH3), 3.75 (1H,
dd, J = 4.7, 1.3 Hz, 7-H), 5.36 (1H, m, 6-H), 5.76 (1H, s,
5.29 (1H, br s, 6-H), 5.75 (1H, s, 9-H), 5.76 (1H, d,
J = 4.8 Hz, 8-H), 6.49 (1H, dd, J = 3.5, 1.7 Hz, OCO-
C4H3O), 7.11 (1 H, dd, J = 3.5, 0.8 Hz, OCOC4H3O),
18
D
7.57 (1H, dd, J = 1.7, 0.8 Hz, OCOC4H3O); ½aꢁ ꢀ17 (c
9-H), 5.79 (1H, d, J = 4.7 Hz, 8-H), 7.40–8.00 (5H, m,
1.0, MeOH); MS (EI) m/z 397 (M)+.
20
D
OCOC6H5); ½aꢁ +12 (c 1.0, MeOH); MS (FAB) m/z 394
(M+H)+.
4.2.19. (4aR,5R,6R,7R)-1-Benzyl-6-(2-furancarbonyloxy)-7-
methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-
2(4H)-one (10d). Reaction of PF1092C with PhCH2NH2
gave 9c in 32% by a similar procedure to 5. Reaction of
9c gave 10d in 100% yield as a colorless solid by a similar
procedure to 3a: 1H NMR (CDCl3) d 1.14 (3H, d,
J = 7.1 Hz, 5-CH3), 1.19 (3H, s, 4a-CH3), 1.93 (3H, d,
J = 1.8 Hz, 3-CH3), 2.14 (1H, dq, J = 7.1, 2.8 Hz, 5-H),
2.19 (1H, br d, J = 15.9 Hz, 4-H), 2.85 (1H, d,
J = 15.9 Hz, 4-H), 3.52 (3H, s, OCH3), 3.68 (1H, dd,
J = 4.7, 1.1 Hz, 7-H), 4.69 (1H, d, J = 15.9 Hz, N-
CH2C6H5), 4.91 (1H, d, J = 15.9 Hz, N-CH2C6H5), 5.27
(1H, m, 6-H), 5.65 (1H, s, 9-H), 5.66 (1H, d, J = 4.8 Hz,
8-H), 6.49 (1H, dd, J = 3.5, 1.7 Hz, OCOC4H3O), 7.09
(1H, dd, J = 3.5, 0.8 Hz, OCOC4H3O), 7.17–7.32 (5H,
4.2.15. (4aR,5R,6R,7R)-7-Methoxy-6-(3-pyridinecarbonyl-
oxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (3h). Reaction of 1a gave 3h in 54% yield as a
1
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 1.17 (3H, d, J = 7.1 Hz, 5-CH3), 1.23 (3H, s,
4a-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3), 2.20 (1H, br
d, J = 15.9 Hz, 4-H), 2.23 (1H, dq, J = 7.1, 2.8 Hz, 5-H),
2.85 (1H, d, J = 15.9 Hz, 4-H), 3.11 (3H, s, N-CH3), 3.57
(3H, s, OCH3), 3.76 (1H, dd, J = 4.7, 1.4 Hz, 7-H), 5.38
(1H, m, 6-H), 5.75 (1H, s, 9-H), 5.78 (1H, d, J = 4.7 Hz,
20
D
8-H), 7.40–8.76(4H, m, OCOC5H4N); ½aꢁ ꢀ7 (c 1.0,
MeOH); MS (EI) m/z 363 (M)+.
4.2.16.
(4aR,5R,6R,7R)-7-methoxy-6-propionyloxy-4a,5,
m, N-CH2C6H5), 7.56 (1H, dd, J = 1.7, 0.8 Hz, OCO-
20
C4H3O); ½aꢁ ꢀ30 (c 1.0, MeOH); MS (EI) m/z 459 (M)+.
6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one (10a).
Reaction of PF1092C with NH3 gave 9a in 16% by a similar
procedure to 5. Reaction of 9a gave 10a in 74% yield as a col-
orless solid by a similar procedure to 3a:1HNMR(CDCl3)d
1.10 (3H, d, J = 7.3 Hz, 5-CH3), 1.12 (3H, s, 4a-CH3), 1.16
(3H, t, J = 7.5 Hz, OCOCH2CH3), 1.89 (3H, d, J =
1.9 Hz, 3-CH3), 2.08 (1H, dq, J = 7.3, 2.7 Hz, 5-H), 2.17
(1H, br d, J = 15.9 Hz, 4-H), 2.35 (2H, q, J = 7.5 Hz,
OCOCH2CH3), 2.81 (1H, d, J = 15.9 Hz, 4-H), 3.51 (3H,
s, OCH3), 3.60 (1H, dd, J = 4.8, 1.7 Hz, 7-H), 3.61 (2H, m,
N-CH2CH3), 5.11 (1H, m, 6-H), 5.73 (1H, d, J = 4.8 Hz,
8-H), 5.84 (1H, s, 9-H); MS (FAB) m/z332 (M+H)+;HRMS
(FAB) (C19H26O4N) calcd 332.1862, obsd 332.1852.
D
4.2.20. (4aR,5R,6S)-6-Propionyloxy-4a,5,6,7-tetrahydro-
1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11a). Reac-
tion of 8 gave 11a in 58% yield as a colorless solid by
a similar procedure to 3a: 1H NMR (CDCl3) d 1.07
(3H, d, J = 7.0 Hz, 5-CH3), 1.11 (3H, t, J = 7.5 Hz,
OCOCH2CH3), 1.13 (3H, s, 4a-CH3), 1.87 (3H, d,
J = 2.0 Hz, 3-CH3), 1.88 (1H, dq, J = 7.0, 2.7 Hz, 5-
H), 2.11 (1H, br d, J = 16.0 Hz, 4-H), 2.31 (2H, q,
J = 7.5 Hz, OCOCH2CH3), 2.52 (1H, br dd, J = 20.5,
4.2 Hz, 7-H), 2.72 (1H, br ddd, J = 20.5, 4.2Hz, 7-H),
2.78 (1H, d, J = 16.0 Hz, 4-H), 3.09 (3H, s, N-CH3),
5.13 (1H, m, 6-H), 5.63 (1H, br t, J = 4.2 Hz, 8-H),
5.73 (1H, s, 9-H); MS (EI) m/z 315 (M)+.
4.2.17. (4aR,5R,6R,7R)-1-Ethyl-7-methoxy-6-propionyloxy-
4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-2(4H)-one
(10b). Reaction of PF1092C with EtNH2 gave 9b in 47%
by a similar procedure to 5. Reaction of 9b gave 10b in
30% yield as a colorless solid by a similar procedure to
3a: 1H NMR (CDCl3) d 1.08 (3H, d, J = 7.3 Hz,
5-CH3), 1.09 (3H, s, 4a-CH3), 1.14 (3H, t, J = 7.5 Hz,
OCOCH2CH3), 1.15 (3H, t, J = 7.2 Hz, N-CH2CH3),
1.86 (3H, d, J = 1.9 Hz, 3-CH3), 2.08 (1H, dq, J = 7.3,
2.7 Hz, 5-H), 2.14 (1H, br d, J = 15.9 Hz, 4-H), 2.34
(2H, q, J = 7.5 Hz, OCOCH2CH3), 2.80 (1H, d,
J = 15.9 Hz, 4-H), 3.50 (3H, s, OCH3), 3.60 (1H, dd,
J = 4.8, 1.7 Hz, 7-H), 3.61 (2H, m, N-CH2CH3), 5.09
4.2.21. (4aR,5R,6R,7R)-7-Hydroxy-6-propionyloxy-4a,5,6, 7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11b).
A solution of 1b (200 mg = 0.73 mmol) in DMF (10 ml)
were added t-butyldimethylsilyl chloride (TBDMSCl) (650
mg = 4.31 mmol) and imidazole (500 mg = 7.34 mmol).
The reaction mixture was stirred at room temperature for
15 h. The reaction mixture was dissolved in AcOEt and
washed with saturated NaHCO3 and brine. The organic layer
was dried (MgSO4), filtered, and concentrated. Flash column
chromatography on silica gel of this residue provided
(282 mg, 100%) of the 7-O-TBDMS-compound. To a solu-
tion of 7-O-TBDMS-compound (25 mg = 0.06 mmol) in
CH2Cl2 (1 ml) were added propionyl chloride (28 ll =
0.28 mmol) and pyridine (52 ll = 0.64 mmol). The reaction
mixture was stirred at room temperature for 17 h. The mix-
ture was washed with saturated NaHCO3 and brine. The
organic layer was dried (MgSO4), filtered, and concentrated.
This residue was used in the following step with no further
purification. The residue was diluted in THF (1 ml) and
added 1 M solution of tetrabutylammonium fluoride
(TBAF)inTHF (50 ll =0.05 mmol). Themixturewasstirred
at room temperature for 2 h. The reaction mixture was
dissolved in AcOEt and washed with brine. The organic layer
was dried (MgSO4), filtered, and concentrated. Preparative
TLC of this residue provided 1.4 mg (34%) of the title
(1H, m, 6-H), 5.73 (1H, s, 9-H), 5.74 (1H, d, J = 4.8 Hz,
18
8-H); ½aꢁ ꢀ228 (c 1.0, MeOH); MS (EI) m/z 359 (M)+.
D
4.2.18. (4aR,5R,6R,7R)-1-Ethyl-6-(2-furancarbonyloxy)-7-
methoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylbenz[f]indol-
2(4H)-one (10c). Reaction of 9b gave 10c in 85% yield as a
1
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 1.15 (3H, d, J = 7.3 Hz, 5-CH3), 1.16 (3H, t,
J = 7.2 Hz, N-CH2CH3), 1.87 (3H, d, J = 1.9 Hz, 3-
CH3), 1.21 (3H, s, 4a-CH3), 2.17 (1H, dq, J = 7.3,
2.7 Hz, 5-H), 2.18 (1 H, br d, J = 15.9 Hz, 4-H), 2.83
(1H, d, J = 15.9 Hz, 4-H), 3.55 (3H, s, OCH3), 3.59 (1H,
dq, J = 7.0, 7.2 Hz, N-CH2CH3), 3.66 (1H, dq, J = 7.0,
7.2 Hz, N-CH2CH3), 3.73 (1H, br d, J = 4.8 Hz, 7-H),

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4873
1
compound (11 b) as a colorless solid: H NMR (CDCl3) d
1.10 (3H, s, 4a-CH3), 1.11 (3H, d, J = 7.1 Hz, 5-CH3), 1.15
(3H, t, J = 7.6 Hz, OCOCH2CH3), 1.89 (3H, d, J = 2.0 Hz,
3-CH3), 2.16 (1H, br d, J = 15.0 Hz, 4-H), 2.16 (1H, dq,
J = 7.1, 3.1 Hz, 5-H), 2.35 (1H, q, J = 7.6 Hz, OCOCH2
CH3), 2.36 (1H, q, J = 7.6 Hz, OCOCH2CH3), 2.82 (1H, d,
J = 15.0 Hz, 4-H), 3.12 (3H, s, N-CH3), 4.14 (1H, dd,
J = 4.6, 1.2 Hz, 7-H), 4.96 (1H, m, 6-H), 5.74 (1H, s, 9-H),
5.77 (1H, d, J = 4.6 Hz, 8-H); MS (TSP) m/z 332 (M+H)+.
(3H, s, N-CH3), 3.53 (1H, dt, J = 9.4, 6.5 Hz, OCH2CH2
CH3), 3.67 (1H, m, 7-H), 3.70 (1H, dt, J = 9.4, 6.5 Hz,
OCH2CH2CH3), 5.05 (1H, m, 6-H), 5.71 (1H, s, 9-H), 5.72
(1H, d, J = 4.8 Hz, 8-H); MS (FAB) m/z 374 (M+H)+;
HRMS (FAB) (C22H32O4N) calcd 374.2331, obsd 374.2309.
4.2.26. (4aR,5R,6R,7R)-7-Butoxy-6-propionyloxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11g).
Reaction of 5 with BuOH gave 1e in 85% by a similar
n
procedure to 1a. Reaction of 1e gave 11g in 42% yield as
a colorless solid by a similar procedure to 3a: H NMR
1
4.2.22. (4aR,5R,6R,7S)-7-Acetoxy-6-hydroxy-4a,5,6,7-tet-
rahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11c).
Reaction of 6 gave 11c in 42% yield as a colorless solid
(CDCl3) d 0.90 (3H, t, J = 7.2 Hz, OCH2CH2CH2CH3),
1.07 (3H, d, J = 7.3 Hz, 5-CH3), 1.08 (3H, s, 4a-CH3), 1.13
(3H, t, J = 7.5 Hz, OCOCH2CH3), 1.36 (2H, m, OCH2
CH2CH2CH3), 1.54 (2H, m, OCH2CH2CH2CH3), 1.85
(3H, d, J = 2.0 Hz, 3-CH3), 2.09 (1H, dq, J = 7.3, 2.6 Hz, 5-
H), 2.15 (1H, br d, J = 16.0 Hz, 4-H), 2.32 (1H, q,
J = 7.5 Hz, OCOCH2CH3), 2.33 (1H, q, J = 7.5 Hz,
OCOCH2CH3), 2.79 (1H, d, J = 16.0 Hz, 4-H), 3.08 (3H, s,
N-CH3), 3.57 (1H, dt, J = 6.4, 9.4 Hz, OCH2CH2CH2CH3),
3.66 (1H, dd, J = 5.2, 1.4 Hz, 7-H), 3.76 (1H, dt, J = 6.4,
9.4 Hz, OCH2CH2CH2CH3), 5.05 (1H, br s, 6-H), 5.71
(1H, s, 9-H), 5.72 (1H, d, J = 4.8 Hz, 8-H); MS (FAB)
m/z 388 (M+H)+; HRMS (FAB) (C23H34O4N) calcd
388.2488, obsd 388.2494.
1
by a similar procedure to 11b: H NMR (CDCl3) d 1.11
(3H, d, J = 7.2 Hz, 5-CH3), 1.15 (3H, s, 4a-CH3), 1.88
(3H, d, J = 1.9 Hz, 3-CH3), 1.99 (1 H, dq, J = 7.2, 2.5 Hz,
5-H), 2.12 (1H, br d, J = 15.9 Hz, 4-H), 2.15 (3H, s,
COCH3), 2.81 (1H, d, J = 15.9 Hz, 4-H), 3.12 (3H, s,
N-CH3), 4.56 (1H, m, 7-H), 5.30 (1H, m, 6-H), 5.60 (1H,
s, 8-H), 5.74 (1H, s, 9-H); MS (EI) m/z 317 (M)+; HRMS
(FAB) (C13H24O6N3) calcd 318.1665, obsd 318.1694.
4.2.23. (4aR,5R,6R,7R)-7-Acetoxy-6-propionyloxy-4a,5,6,
7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11d).
Reaction of 5 gave 11d in 30% yield as a colorless solid by
a similar procedure to 3a: 1H NMR (CDCl3) d 1.09 (3H, d,
J = 7.2 Hz, 5-CH3), 1.11 (3H, s, 4a-CH3), 1.14 (3H, t,
J = 7.6 Hz, OCOCH2CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3),
2.05 (3H, s, OCOCH3), 2.10 (1H, dq, J = 7.2, 2.8 Hz, 5-H),
2.17 (1H, br d, J = 15.9 Hz, 4-H), 2.34 (2H, q, J = 7.6 Hz,
OCOCH2CH3), 2.83 (1H, d, J = 15.9 Hz, 4-H), 3.10 (3H, s,
4.2.27. (4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propionyl-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (11h). Reaction of 5 with PrOH gave 1f in
i
85% by a similar procedure to 1a. Reaction of 1f gave
11h in 31% yield as a colorless solid by a similar proce-
dure to 3a: 1H NMR (CDCl3) d 1.08 (3H, d, J = 7.1 Hz,
5-CH3), 1.09 (3H, s, 4a-CH3), 1.14 (3H, t, J = 7.6 Hz,
OCOCH2CH3), 1.16 (3H, d, J = 6.1 Hz, OCH(CH3)2),
1.19 (3H, d, J = 6.1 Hz, OCH(CH3)2), 1.86 (3H, d,
J = 1.9 Hz, 3-CH3), 2.13 (1H, dq, J = 7.1, 2.7 Hz, 5-
H), 2.16 (1H, br d, J = 15.9 Hz, 4-H), 2.34 (2H, q,
J = 7.6 Hz, OCOCH2CH3), 2.78 (1H, d, J = 15.9 Hz,
4-H), 3.08 (3H, s, N-CH3), 3.75 (1H, dd, J = 4.8,
1.4 Hz, 7-H), 3.97 (1H, sep, J = 6.1 Hz, OCH(CH3)2),
N-CH3), 5.08 (1H, m, 6-H), 5.13 (1H, dd, J = 4.7, 1.6 Hz, 7-
20
H), 5.73 (1H, s, 9-H), 5.76 (1H, d, J = 4.7 Hz, 8-H); ½aꢁ
D
ꢀ291 (c 1.0, MeOH); MS (FAB) m/z 374 (M+H)+.
4.2.24. (4aR,5R,6R,7R)-7-Ethoxy-6-propionyloxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11e).
Reaction of 5 with EtOH gave 1c in 85% by a similar
procedure to 1a. Reaction of 1c gave 11e in 44% yield as a
1
colorless solid by a similar procedure to 3a: H NMR
(CDCl3) d 1.08 (3H, d, J = 7.1 Hz, 5-CH3), 1.09 (3H, s,
4a-CH3), 1.13 (3H, t, J = 7.5 Hz, OCOCH2CH3), 1.20
(3H, t, J = 7.0 Hz, OCH2CH3), 1.86 (3H, d, J = 1.9 Hz, 3-
CH3), 2.11 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.15 (1H, br d,
J = 15.9 Hz, 4-H), 2.33 (2H, q, J = 7.5 Hz, OCOCH2CH3),
2.78 (1H, d, J = 15.9 Hz, 4-H), 3.09 (3H, s, N-CH3), 3.62
(1H, dq, J = 7.0, 2.4 Hz, OCH2CH3), 3.68 (1H, dd, J =
4.8, 1.5 Hz, 7-H), 3.83 (1H, dq, J = 7.0, 2.4 Hz, OCH2CH3),
4.96 (1H, m, 6-H), 5.67 (1H, d, J = 4.8 Hz, 8-H), 5.72
28
D
(1H, s, 9-H); ½aꢁ ꢀ304 (c 0.5, MeOH); MS (FAB) m/z
374 (M+H)+.
4.2.28. (4aR,5R,6R,7R)-7-Methoxy-6-methylcarbamoyl-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (12a). A solution of 1a (100 mg = 0.35 mmol)
in CH2Cl2 (3 ml) was added 1,10-carbonyldiimidazole
(204 mg = 1.26 mmol). The reaction mixture was stirred
at room temperature for 17 h. The reaction mixture was
added CH2Cl2 and washed with brine. The organic layer
was dried (MgSO4), filtered, and concentrated. The
organic layer was dried (MgSO4), filtered, and concen-
trated. This residue was used in the following step with
no further purification. The residue was diluted in tolu-
ene and added 1 M methylamine of THF solution
(0.7 ml). The reaction mixture was stirred at room tem-
perature until complete consumption of the starting
material was observed as determined by TLC analysis.
The mixture was washed with brine. The organic layer
was dried (MgSO4), filtered, and concentrated. Prepara-
tive TLC of this residue provided 103 mg (85%) of the
title compound (12a) as a colorless solid: 1H NMR
5.06 (1H, m, 6-H), 5.72 (1H, s, 9-H), 5.73 (1H, d, J = 4.8 Hz,
18
D
8-H); ½aꢁ ꢀ267 (c 1.0, MeOH); MS (EI) m/z 359 (M)+.
4.2.25. (4aR,5R,6R,7R)-6-Propionyloxy-7-propoxy-4a,5,6,
7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (11f).
Reaction of 5 with PrOH gave 1d in 85% by a similar
n
procedure to 1a. Reaction of 1d gave 11f in 59% yield as
a colorless solid by a similar procedure to 3a: H NMR
1
(CDCl3) d 0.91 (3H, t, J = 7.5, OCH2CH2CH3), 1.07 (3H,
d, J = 7.3 Hz, 5-CH3), 1.08 (3H, s, 4a-CH3), 1.13 (3H, t,
J = 7.5 Hz, OCOCH2CH3), 1.57 (2H, sep, J = 7.2 Hz,
OCH2CH2CH3), 1.85 (3H, d, J = 2.0 Hz, 3-CH3), 2.09 (1H,
dq, J = 7.3, 2.6 Hz, 5-H), 2.15 (1H, br d, J = 16.0 Hz, 4-H),
2.32 (1H, q, J = 7.5, OCOCH2CH3), 2.33 (1H, q, J =
7.5 Hz, OCOCH2CH3), 2.77 (1H, d, J = 16.0 Hz, 4-H), 3.07

4874
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
(CDCl3) d 0.97 (3H, s, 4a-CH3), 1.10 (3H, d, J = 7.1 Hz,
5-CH3), 1.84 (3H, br s, 3-CH3), 2.03 (1H, dq, J = 7.1,
2.6 Hz, 5-H), 2.11 (1H, br d, J = 16.3 Hz, 4-H), 2.77
(1H, d, J = 16.3 Hz, 4-H), 2.82 (3H, d, J = 4.7 Hz,
OCONHCH3), 3.06 (3H, s, N-CH3), 3.51 (3H, s,
OCH3), 3.67 (1H, br d, J = 4.8 Hz, 7-H), 4.97 (1H, m,
6-H), 5.11 (1H, m, OCONHCH3), 5.70 (1H, s, 9-H),
5.75 (1H, d, J = 4.8 Hz, 8-H); MS (FAB) m/z 347
(M+H)+; HRMS (FAB) (C19H27O4N2) calcd 347.1971,
obsd 347.1977.
1.88 (3H, d, J = 1.9 Hz, 3-CH3), 2.07 (1H, dq, J = 7.2,
3.0 Hz, 5-H), 2.14 (1H, br d, J = 16.1 Hz, 4-H), 2.80
(1H, d, J = 16.1 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.50
(1H, m, OCONHC6H11), 3.53 (3H, s, OCH3), 3.70 (1H,
br d, J = 4.9 Hz, 7-H), 4.97 (1H, m, 6-H), 5.73 (1H, s, 9-
H), 5.77 (1H, d, J = 4.8 Hz, 8-H); MS (FAB) m/z 415
(M+H)+; HRMS (FAB) (C24H35O4N2) calcd 415.2596,
obsd 415.2600.
4.2.33. (4aR,5R,6R,7R)-6-Benzylcarbamoyloxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (12f). Reaction of 1a gave 12f in 64% yield
4.2.29. (4aR,5R,6R,7R)-6-Ethylcarbamoyloxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (12b). Reaction of 1a gave 12b in 97% yield as a
1
as a colorless solid by a similar procedure to 12a: H
NMR (CDCl3) d 1.03 (3H, s, 4a-CH3), 1.14 (3H, d, J =
7.1 Hz, 5-CH3), 1.86 (3H, d, J = 1.7 Hz, 3-CH3), 2.08
(1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.13 (1H, br d, J =
15.7 Hz, 4-H), 2.79 (1H, d, J = 15.7 Hz, 4-H), 3.08 (3H,
s, N-CH3), 3.54 (3H, s, OCH3), 3.72 (1H, br d,
J = 4.6 Hz, 7-H), 4.40 (2H, m, OCONHCH2C6H5), 5.04
(1H, m, 6-H), 5.16 (1H, m, OCONHCH2C6H5), 5.72
(1H, s, 9-H), 5.77 (1H, d, J = 4.6 Hz, 8-H), 7.27-7.35
(5H, m, OCONHCH2C6H5); MS (FAB) m/z 423
(M+H)+; HRMS (FAB) (C25H31O4N2) calcd 423.2284,
obsd 423.2291.
1
colorless solid by a similar procedure to 12a: H NMR
(CDCl3) d 1.02 (3H, s, 4a-CH3), 1.12 (3H, d, J = 7.1 Hz,
5-CH3), 1.16 (3H, t, J = 6.9 Hz, OCONHCH2CH3),
1.86 (3H, br s, 3-CH3), 2.05 (1H, dq, J = 7.1, 1.9 Hz, 5-
H), 2.13 (1H, br d, J = 16.0 Hz, 4-H), 2.79 (1H, d,
J = 16.0 Hz, 4-H), 3.08 (3H, s, N-CH3), 3.25 (2H, br q,
J = 6.9 Hz, OCONHCH2CH3), 3.52 (3H, s, OCH3),
3.69 (1H, br d, J = 4.7 Hz, 7-H), 4.49 (1H, m,
OCONHCH2CH3), 4.97 (1H, m, 6-H), 5.72 (1H, s, 9-
H), 5.76 (1H, d, J = 4.7 Hz, 8-H); MS (FAB) m/z 361
(M+H)+.
4.2.34. (4aR,5R,6S)-6-Propylcarbamoyloxy-4a,5,6,7-tetra-
hydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (13a).
Reaction of 9b gave 13a in 74% yield as a colorless solid
4.2.30. (4aR,5R,6R,7R)-7-Methoxy-6-propylcarbamoyloxy-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (12c). Reaction of 1a gave 12c in 88% yield as a
1
by a similar procedure to 12a: H NMR (CDCl3) d 0.91
1
colorless solid by a similar procedure to 12a: H NMR
(3H, t, J = 7.1 Hz, OCONHCH2CH2CH3), 1.03 (3H, s,
4a-CH3), 1.09 (3H, d, J = 7.0 Hz, 5-CH3), 1.53 (2H, seq,
J = 7.1 Hz, OCONHCH2CH2CH3), 1.83 (1H, br q,
J = 6.9 Hz, 5-H), 1.85 (3H, br s, 3-CH3), 2.10 (1H, br d,
J = 16.0 Hz, 4-H), 2.45 (1H, dd, J = 20.4, 4.5 Hz, 7-H),
2.56 (1H, br dd, J = 20.4, 4.5 Hz, 7-H), 2.77 (1H, d,
J = 16.0 Hz, 4-H), 3.08 (3H, s, N-CH3), 3.14 (2H, br dt,
J = 7.1 Hz, OCONHCH2CH2CH3), 4.99 (1H, m,
OCONHCH2CH2CH3), 5.04 (1H, m, 6-H), 5.65 (1H, m,
8-H), 5.71 (1H, s, 9-H); MS (FAB) m/z 343 (MꢀH)+.
(CDCl3) d 0.92 (3H, t, J = 7.2 Hz, OCONHCH2
CH2CH3), 0.99 (3H, s, 4a-CH3), 1.11 (3H, d, J = 6.8 Hz,
5-CH3), 1.54 (2H, seq, J = 7.2 Hz, OCONHCH2CH2
CH3), 1.85 (3H, br s, 3-CH3), 2.04 (1H, dq, J = 6.8,
1.9 Hz, 5-H), 2.11 (1H, br d, J = 16.3 Hz, 4-H), 2.77
(1H, d, J = 16.3 Hz, 4-H), 3.06 (3H, s, N-CH3), 3.15
(2H, br dt, J = 7.2 Hz, OCONHCH2CH2CH3), 3.51
(3H, s, OCH3), 3.67 (1H, br d, J = 4.9 Hz, 7-H), 4.97
(1H, m, 6-H), 5.08 (1H, m, OCONHCH2CH2CH3), 5.71
(1H, s, 9-H), 5.75 (1H, d, J = 4.9 Hz, 8-H); MS (FAB)
m/z 375 (M+H)+; HRMS (FAB) (C21H30O4N2 Na) calcd
397.2103, obsd 397.2074.
4.2.35. (4aR,5R,6R,7R)-7-Hydroxy-6-propylcarbamoyl-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (13b). Reaction of 1b gave 7-O-TBDMS-com-
pound by a procedure to 11b. Reaction of 7-O-TBDMS-
compound gave 13b in 34% by a similar procedure to
12a, followed by deprotection of the TBDMS group
with TBAF: 1H NMR (CDCl3) d 0.92 (3H, t,
J = 7.3 Hz, OCONHCH2CH2CH3), 1.04 (3H, s, 4a-
CH3), 1.12 (3H, d, J = 7.0 Hz, 5-CH3), 1.53 (2H, seq,
J = 7.3 Hz, OCONHCH2CH2CH3), 1.88 (3H, br s, 3-
CH3), 2.14 (1H, dq, J = 7.0, 2.8 Hz, 5-H), 2.15 (1H, br
d, J = 16.3 Hz, 4-H), 2.80 (1H, d, J = 16.3 Hz, 4-H),
3.10 (3H, s, N-CH3), 3.15 (2H, br dt, J = 7.3 Hz,
OCONHCH2CH2CH3), 4.21 (1H, m, 7-H), 4.83 (1H,
m, 6-H), 4.83 (1H, m, OCONHCH2CH2CH3), 5.74
(1H, s, 9-H), 5.78 (1H, d, J = 4.5 Hz, 8-H); MS (FAB)
m/z 361 (M+H)+; HRMS (FAB) (C20H29O4N2) calcd
361.2128, obsd 361.2122.
4.2.31. (4aR,5R,6R,7R)-6-Cyclopropylcarbamoyloxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (12d). Reaction of 1a gave 12d in 68% yield
1
as a colorless solid by a similar procedure to 12a: H
NMR (CDCl3) d 0.52–0.74 (4H, m, OCONHC3H5),
1.00–1.22 (6H, m, 4a-CH3, 5-CH3), 1.87 (3H, d, J =
1.7 Hz, 3-CH3), 2.10 (1H, m, 5-H), 2.14 (1H, br d, J =
15.9 Hz, 4-H), 2.61 (1H, m, OCONHC3H5), 2.80 (1H, d,
J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.54 (3H, s,
OCH3), 3.71 (1H, br d, J = 4.4 Hz, 7-H), 5.00 (1H, m,
6-H,), 5.73 (1H, s, 9-H), 5.76 (1H, d, J = 4.4 Hz, 8-H);
MS (FAB) m/z 373 (M+H)+; HRMS (FAB)
(C21H29O4N2) calcd 373.2121, obsd 373.2124.
4.2.32. (4aR,5R,6R,7R)-6-Cyclohexylcarbamoyloxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (12e). Reaction of 1a gave 12e in 52% yield
4.2.36. (4aR,5R,6R,7R)-7-Ethoxy-6-propylcarbamoyloxy-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (13c). Reaction of 1c gave 13c in 56% yield as a
1
as a colorless solid by a similar procedure to 12a: H
NMR (CDCl3) d 1.08 (3H, s, 4a-CH3), 1.14 (3H, d, J =
7.2 Hz, 5-CH3), 1.10–2.10 (11H, m, OCONHC6H11),
1
colorless solid by a similar procedure to 12a: H NMR

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4875
(CDCl3) d 0.92 (3H, t, J = 7.1 Hz, OCONHCH2CH2CH3),
1.01 (3H, s, 4a-CH3), 1.11 (3H, d, J = 7.2 Hz, 5-CH3), 1.21
(3H, t, J = 7.0 Hz, OCH2CH3), 1.54 (2H, seq, J = 7.1 Hz,
OCONHCH2CH2CH3), 1.85 (3H, br s, 3-CH3), 2.08 (1H,
dq, J = 7.2, 2.6 Hz, 5-H), 2.14 (1H, br d, J = 15.8 Hz,
4-H), 2.77 (1H, d, J = 15.8 Hz, 4-H), 3.07 (3H, s, N-CH3),
3.16 (2H, br dt, J = 7.1 Hz, OCONHCH2CH2CH3), 3.64
(1H, dq, J = 9.4, 7.0 Hz, OCH2CH3), 3.77 (1H, br d,
J = 4.9 Hz, 7-H), 3.87 (1H, dq, J = 9.4, 7.0 Hz, OCH2CH3),
4.99 (1H, m, OCONHCH2CH2CH3), 4.95 (1H, m, 6-H),
5.74 (1H, d, J = 4.9 Hz, 8-H), 5.71 (1H, s, 9-H); MS
(FAB) m/z 389 (M+H)+; HRMS (FAB) (C22H33O4N2)
calcd 389.2441, obsd 389.2425.
3.11 (3H, s, N-CH3), 3.55 (3H, s, OCH3), 3.71 (1H, br
d, J = 4.8 Hz, 7-H), 4.98 (1H, m, 6-H), 5.74 (1H, s, 9-
H), 5.76 (1H, d, J = 4.8 Hz, 8-H); MS (FAB) m/z 361
(M+H)+; HRMS (FAB) (C20H29O4N2) calcd 361.2127,
obsd 361.2123.
4.2.40. (4aR,5R,6R,7R)-7-Methoxy-6-(N-ethyl-N-meth-
ylcarbamoyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetrameth-
ylbenz[f]indol-2(4H)-one (14b). Reaction of 1a gave 14b
in 54% yield as a colorless solid by a similar procedure
1
to 12a: H NMR (CDCl3) d 1.06 (3H, t, OCO(CH3)N
(CH2CH3)), 1.10 (3H, s, 4a-CH3), 1.14 (3H, d, J =
7.1 Hz, 5-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3), 2.10
(1H, dq, J = 7.1, 2.6 Hz, 5-H), 2.16 (1H, br d, J =
16.3 Hz, 4-H), 2.81 (1H, d, J = 16.3 Hz, 4-H), 2.83 and
2.93 (3H, s, OCO(CH3)N(CH2CH3)), 3.28 (2H, m,
OCO(CH3)N(CH2CH3)), 3.11 (3H, s, N-CH3), 3.55
(3H, s, OCH3), 3.70 (1H, br s, 7-H), 4.99 (1H, br s, 6-
H), 5.74 (1H, s, 9-H), 5.77 (1H, d, J = 4.8 Hz, 8-H);
MS (FAB) m/z 375 (M+H)+, HRMS (FAB) (C21H31
O4N2) calcd 375.2284, obsd 375.2276.
4.2.37. (4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propylcar-
bamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz-
[f]indol-2(4H)-one (13d). Reaction of 1f gave 13d in 43%
yield as a colorless solid by a similar procedure to
12a: 1H NMR (CDCl3) d 0.93 (3H, t, J = 7.3 Hz,
OCONHCH2 CH2CH3), 1.03 (3H, s, 4a-CH3), 1.12 (3H,
d, J = 7.0 Hz, 5-CH3), 1.18 (3H, d, J = 6.5 Hz, OCH
(CH3)2), 1.21 (3H, d, J = 6.5 Hz, OCH(CH3)2), 1.55
(2H, seq, J = 7.3 Hz, OCONHCH2CH2CH3), 1.86 (3H,
br s, 3-CH3), 2.12 (1H, br q, J = 7.1 Hz, 5-H), 2.16 (1H,
br d, J = 16.6 Hz, 4-H), 2.78 (1H, d, J = 16.6 Hz, 4-H),
3.08 (3H, s, N-CH3), 3.16 (2H, br dt, J = 7.3 Hz,
OCONHCH2CH2 CH3), 3.84 (1H, m, 7-H), 4.03 (1H,
sep, J = 6.5 Hz, OCH(CH3)2), 4.09 (1H, m, OCONHCH2
CH2CH3), 4.86 (1H, m, 6-H), 5.69 (1H, d, J = 4.5 Hz, 8-
H), 5.72 (1H, s, 9-H); MS (FAB) m/z 403 (M+H)+; HRMS
(FAB) (C23H35O4N2) calcd 403.2596, obsd 403.2599.
4.2.41. (4aR,5R,6R,7R)-7-Methoxy-6-(N-methyl-N-pro-
pylcarbamoyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetra-
methylbenz[f]indol-2(4H)-one (14c). Reaction of 1a
gave 14c in 52% yield as a colorless solid by a similar
procedure to 12a:1H NMR (CDCl3) d 0.80 & 0.88
(3H, each t, OCO(CH3)N(CH2CH2CH3)), 1.09 (3H, s,
4a-CH3), 1.13 (3H, d, J = 7.1 Hz, 5-CH3), 1.51 (2H, m,
OCO(CH3) N(CH2CH2CH3)), 1.87 (3H, d, J = 1.9 Hz,
3-CH3), 2.09 (1H, dq, J = 7.1, 2.6 Hz, 5-H), 2.15 (1H, br
d, J = 16.3 Hz, 4-H), 2.81 (1H, d, J = 16.3 Hz, 4-H),
2.82 and 2.92 (3H, each s, OCO(CH3)N(CH2CH2CH3)),
3.09 (3H, s, N-CH3), 3.18 (2H, m, OCO(CH3)N(CH2CH2
CH3)), 3.18 (2H, m, OCO(CH3)N(CH2CH3)), 3.55 (3H, s,
OCH3), 3.68 (1H, m, 7-H), 4.98 (1H, br s, 6-H), 5.73 (1H,
s, 9-H), 5.74 (1H, d, J = 4.8 Hz, 8-H); MS (FAB) m/z 389
(M+H)+; HRMS (FAB) (C22H33O4N2) calcd 389.2440,
obsd 389.2435.
4.2.38. (4aR,5R,6R,7R)-7-(2-Methyl-1-propoxy)-6-pro-
pylcarbamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetrameth-
ylbenz[f]indol-2(4H)-one (13e). Reaction of 5 gave 1g in
52% by a similar procedure to 1a. Reaction of 1g
gave 13e in 34% yield as a colorless solid by a similar pro-
cedure to 12a: 1H NMR (CDCl3) d0.91 (3H, d, J = 6.6 Hz,
OCH2 CH(CH3)2), 0.92 (3H, d, J = 6.6 Hz, OCH2CH
(CH3)2), 0.95 (3H, t, J = 7.0 Hz, OCONHCH2CH2CH3),
1.03 (3H, s, 4a-CH3), 1.12 (1H, m, OCH2CH(CH3)2), 1.12
(3H, d, J = 7.0 Hz, 5-CH3), 1.55 (2H, seq, J = 7.0 Hz,
OCONHCH2CH2CH3), 1.87 (3H, br s, 3-CH3), 2.09
(1H, dq, J = 7.0, 2.3 Hz, 5-H), 2.16 (1H, br d, J =
16.2 Hz, 4-H), 2.79 (1H, d, J = 16.2 Hz, 4-H), 3.09 (3H,
s, N-CH3), 3.17 (2H, br dt, J = 7.0 Hz, OCONHCH2CH2
CH3), 3.40 (3H, dd, J = 9.2, 6.8 Hz, OCH2CH(CH3)2),
3.53 (3H, dd, J = 9.2, 6.8 Hz, OCH2CH(CH3)2), 3.76
(1H, br d, J = 4.7 Hz, 7-H), 4.89 (1H, m, OCONHCH2
CH2CH3), 4.95 (1H, m, 6-H), 5.74 (1H, s, 9-H), 5.77
(1H, d, J = 4.7 Hz, 8-H); MS (FAB) m/z 417 (M+H)+;
HRMS (FAB) (C24H37O4N2) calcd 417.2753, obsd
417.2756.
4.2.42.
(4aR,5R,6R,7R)-6-(N,N-Diethylcarbamoyloxy)-7-
methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (14d). Reaction of 1a gave 14d in 70% yield as a
colorless solid by a similar procedure to 12a: H NMR
1
(CDCl3) d 1.07–1.17 (6H, m, OCON(CH2CH3)2), 1.10 (3H,
s, 4a- CH3), 1.16 (3H, d, J = 7.2 Hz, 5-CH3), 1.88 (3H, d,
J = 1.7 Hz, 3-CH3), 2.12 (1H, dq, J = 7.2, 3.0 Hz, 5-H), 2.17
(1H, br d, J = 15.9 Hz, 4-H), 2.82 (1H, d, J = 15.9 Hz, 4-H),
3.11 (3H, s, N-CH3), 3.18–3.53 (4H, m, OCON(CH2CH3)2),
3.55 (3H, s, OCH3), 3.70 (1H, br d, J = 4.7 Hz, 7-H), 5.00
(1H, m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J = 4.7 Hz, 8-
H); MS (FAB) m/z 387 (M+H)+; HRMS (FAB)
(C22H33O4N2) calcd 389.2440, obsd 389.2435.
4.2.39. (4aR,5R,6R,7R)-7-Methoxy-6-N,N-dimethylcar-
bamoyloxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz-
[f]indol-2(4H)-one (14a). Reaction of 1a gave 14a in 82%
yield as a colorless solid by a similar procedure to 12a:
1H NMR (CDCl3) d 1.11 (3H, s, 4a-CH3), 1.14 (3H, d,
J = 7.1 Hz, 5-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-CH3),
2.10 (1H, dq, J = 7.1, 2.6 Hz, 5-H), 2.16 (1H, br d,
J = 16.3 Hz, 4-H), 2.82 (1H, d, J = 16.3 Hz, 4-H), 2.86
(3H, s, OCON(CH3)2), 2.95 (3H, s, OCON(CH3)2),
4.2.43.
(4aR,5R,6R,7R)-7-Methoxy-6-(piperidin-1-ylcarba-
moyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (14e). Reaction of 1a gave 14e in 85% yield as a
colorless solid by a similar procedure to 12a: H NMR
(CDCl3) d 1.10 (3H, s, 4a-CH3), 1.14 (3H, d, J = 7.2 Hz, 5-
CH3), 1.49–1.59 (6H, m, OCOC5H10N), 1.88 (3H, d,
J = 1.9 Hz, 3-CH3), 2.10 (1H, dq, J = 7.2, 3.0 Hz, 5-H), 2.16
(1H, br d, J = 16.1 Hz, 4-H), 2.82 (1H, d, J = 16.1 Hz, 4-H),
3.11 (3H, s, N-CH3), 3.32–3.47 (4H, m, OCOC5H10N), 3.55
1

4876
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
18
D
(3H, s, OCH3), 3.72 (1H, dd, J = 4.8, 1.2 Hz, 7-H), 5.02 (1H,
m, 6-H), 5.75 (1H, s, 9-H), 5.77 (1H, d, J = 4.8 Hz, 8-H);
MS (FAB) m/z 401 (M+H)+; HRMS (FAB) (C23H33O4N2)
calcd 401.2440, obsd 401.2436.
J = 4.8 Hz, 8-H), 5.89 (1H, m, OCH2CH@CH2); ½aꢁ
ꢀ272 (c 1.0, MeOH); MS (EI) m/z 329 (M)+.
4.2.48. (4aR,5R,6R,7R)-6-Butoxy-7-methoxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (15e).
Reaction of 1a gave 15e in 31% yield as a colorless oil by
a similar procedure to 15a: 1H NMR (CDCl3) d 0.91
(3H, t, J = 7.3 Hz, OCH2CH2CH2CH3), 1.08 (3H, s, 4a-
CH3), 1.16 (3H, d, J = 7.2 Hz, 5-CH3), 1.38 (2H, m,
OCH2CH2CH2 CH3), 1.54 (2H, m, OCH2CH2CH2CH3),
1.87 (3H, d, J = 2.0 Hz, 3-CH3), 1.89 (1H, dq, J = 7.2,
2.7 Hz, 5-H), 2.11 (1H, br d, J = 15.9 Hz, 4-H), 2.78 (1H,
d, J = 15.9 Hz, 4-H), 3.10 (3H, s, N-CH3), 3.36 (1H, dt,
J = 9.0, 6.3 Hz, OCH2CH2CH2CH3), 3.38 (1H, m, 6-H),
3.44 (3H, s, OCH3), 3.62 (1H, dt, J = 9.0, 6.3 Hz,
OCH2CH2CH2CH3), 3.72 (1H, br d, J = 4.4 Hz, 7-H),
5.74 (1H, s, 9-H), 5.82 (1H, d, J = 4.4 Hz, 8-H); MS
(TSP) m/z 346 (M+H)+.
4.2.44. (4aR,5R,6R,7R)-7-Methoxy-6-(morpholin-4-yl-
carbamoyloxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethyl-
benz[f]indol-2(4H)-one (14f). Reaction of 1a gave 14f in
74% yield as a colorless solid by a similar procedure to
1
12a: H NMR (CDCl3) d 1.07 (3H, s, 4a-CH3), 1.14
(3H, d, J = 7.1 Hz, 5-CH3), 1.88 (3H, d, J = 1.9 Hz, 3-
CH3), 2.12 (1H, dq, J = 7.1, 3.0 Hz, 5-H), 2.17 (1H, br
d, J = 15.8 Hz, 4-H), 2.82 (1H, d, J = 15.8 Hz, 4-H),
3.11 (3H, s, N-CH3), 3.40–3.66 (8H, m, OCOC4H8NO),
3.54 (3H, s, OCH3), 3.71 (1H, br d, J = 4.8 Hz, 7-H),
5.04 (1H, m, 6-H), 5.74 (1H, s, 9-H), 5.77 (1H, d,
J = 4.8 Hz, 8-H); MS (FAB) m/z 403 (M+H)+; HRMS
(FAB) (C22H31O5N2) calcd 403.2233, obsd 403.2234.
4.2.45. (4aR,5R,6R,7R)-6-Ethoxy-7-methoxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one
(15b). Reaction of 1a gave 15b in 36% yield as a colorless
4.2.49.
(4aR,5R,6R,7R)-7-Methoxy-6-(3-methylbutoxy)-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (15f). Reaction of 1a gave 15f in 19% yield as a
colorless oil by a similar procedure to 15a: H NMR
1
1
oil by a similar procedure to 15a: H NMR (CDCl3) d
1.06 (3H, s, 4a-CH3), 1.14 (3H, d, J = 7.1 Hz, 5-CH3),
1.17 (3H, t, J = 7.0 Hz, OCH2CH3), 1.85 (3H, d,
J = 2.0 Hz, 3-CH3), 1.87 (1H, dq, J = 7.1, 2.8 Hz, 5-
H), 2.09 (1H, br d, J = 15.9 Hz, 4-H), 2.77 (1H, d,
J = 15.9 Hz, 4-H), 3.08 (3H, s, N-CH3), 3.38 (1H, m,
6-H), 3.42 (1H, dq, J = 7.0, 2.3 Hz, OCH2CH3), 3.42
(3H, s, O-CH3), 3.66 (1H, dq, J = 7.0, 2.3 Hz,
(CDCl3) d 0.88 (3H, d, J = 6.7 Hz, OCH2CH2CH(CH3)2),
0.88 (3H, d, J = 6.7 Hz, OCH2CH2CH(CH3)2), 1.06 (3H,
s, 4a-CH3), 1.14 (3H, d, J = 7.1 Hz,5-CH3), 1.43 (2H, m,
OCH2CH2CH (CH3)2), 1.70 (1H, m, OCH2CH2CH
(CH3)2), 1.86 (3H, d, J = 1.9 Hz, 3-CH3), 1.87 (1H, dq,
J = 7.1, 2.8 Hz, 5-H), 2.09 (1H, br d, J = 15.9 Hz, 4-H),
2.77 (1H, d, J = 15.9 Hz, 4-H), 3.08 (3H, s, N-CH3),
3.36 (1H, m, 6-H), 3.36 (1H, dt, J = 9.1, 6.3 Hz,
OCH2CH2 CH(CH3)2), 3.43 (3H, s, OCH3), 3.63 (1H,
dt, J = 9.1, 6.3 Hz, OCH2CH2 CH(CH3)2), 3.71 (1H, dd,
OCH2CH3), 3.70 (1H, dd, J = 4.8, 1.4 Hz, 7-H), 5.72
18
D
(1H, s, 9-H), 5.81 (1H, d, J = 4.8 Hz, 8-H); ½aꢁ ꢀ300
(c 1.0, MeOH); MS (EI) m/z 317 (M)+.
J = 4.7, 1.4 Hz, 7-H), 5.72 (1H, s, 9-H), 5.81 (1H, d,
20
D
4.2.46. (4aR,5R,6R,7R)-7-Methoxy-6-propoxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one
(15c). Reaction of 1a gave 15c in 24% yield as a colorless
J = 4.7 Hz, 8-H); ½aꢁ ꢀ157 (c 1.0, MeOH); MS (EI) m/z
359 (M)+; HRMS (FAB) (C22H34O3N) calcd 360.2538,
obsd 360.2540.
1
oil by a similar procedure to 15a: H NMR (CDCl3) d
0.91 (3H, t, J = 6.4 Hz, OCH2CH2CH3), 1.07 (3H, s,
4a-CH3), 1.14 (3H, d, J = 7.1 Hz, 5-CH3), 1.55 (2H,
seq, J = 6.4 Hz, OCH2CH2CH3), 1.85 (3H, d,
J = 2.0 Hz, 3-CH3), 1.87 (1H, dq, J = 7.1, 2.8 Hz, 5-
H), 2.09 (1H, br d, J = 15.9 Hz, 4-H), 2.77 (1H, d,
J = 15.9 Hz, 4-H), 3.08 (3H, s, N-CH3), 3.30 (1H, dt,
J = 9.0, 6.4 Hz, OCH2CH2CH3), 3.37 (1H, m, 6-H),
3.42 (3H, s, OCH3), 3.57 (1H, dt, J = 9.0, 6.4 Hz,
4.2.50. (4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-meth-
oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (15g). Reaction of 1a gave 15g in 40% yield as
1
a colorless oil by a similar procedure to 15a: H NMR
(CDCl3) d 0.20-0.48 (4H, m, OCH2C3H5), 1.02 (1H,m,
OCH2C3H5), 1.09 (3H, s, 4a-CH3), 1.16 (3H, d,
J = 7.1 Hz, 5-CH3), 1.86 (3H, d, J = 1.9 Hz, 3-CH3),
1.88 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.10 (1H, br d, J =
15.9 Hz, 4-H), 2.78 (1H, d, J = 15.9 Hz, 4-H), 3.09 (3H,
s, N-CH3), 3.27 (1H, dd, J = 10.1, 6.4 Hz, OCH2C3H5),
3.42 (3H, s, OCH3), 3.43 (1H, m, 6-H), 3.46 (1H, dd,
J = 10.1, 6.4 Hz, OCH2C3H5), 3.71 (1H, dd, J = 4.7,
OCH2CH2CH3), 3.70 (1H, dd, J = 4.8, 1.4 Hz, 7-H),
18
5.72 (1H, s, 9-H), 5.80 (1H, d, J = 4.8 Hz, 8-H); ½aꢁ
D
ꢀ309 (c 1.0, MeOH); MS (EI) m/z 331 (M)+.
4.2.47. (4aR,5R,6R,7R)-7-Methoxy-6-(2-propenyloxy)-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (15d). Reaction of 1a gave 15d in 69% yield as a
1.4 Hz, 7-H), 5.73 (1H, s, 9-H), 5.82 (1H, d, J = 4.7 Hz,
20
8-H); ½aꢁ ꢀ264 (c 1.0, MeOH); MS (EI) m/z 343 (M)+.
D
1
colorless oil by a similar procedure to 15a: H NMR
(CDCl3)
4.2.51. (4aR,5R,6R,7R)-6-Benzyloxy-7-methoxy-4a,5,6,7-
tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one (15h).
Reaction of 1a gave 15h in 70% yield as a colorless oil by a
similar procedure to 15a: 1H NMR (CDCl3) d 1.13 (3H, s,
4a-CH3), 1.14 (3H, d, J = 7.1 Hz, 5-CH3), 1.86 (3H, d,
J = 2.0 Hz, 3-CH3), 1.92 (1H, dq, J = 7.1, 2.8 Hz, 5-H),
2.11 (1H, br d, J = 15.9 Hz, 4-H), 2.78 (1H, d, J = 15.9 Hz,
4-H), 3.09 (3H, s, N-CH3), 3.40 (3H, s, OCH3), 3.55 (1H,
m, 6-H), 3.78 (1H, dd, J = 4.8, 1.4 Hz, 7-H), 4.51 (1H, d,
J = 12.0 Hz, OCH2C6H5), 4.69 (1H, d, J = 12.0 Hz,
d 1.08 (3H, s, 4a-CH3), 1.15 (3H, d,
J = 7.1 Hz, 5-CH3), 1.85 (3H, d, J = 2.0 Hz, 3-CH3),
1.90 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.10 (1H, br d,
J = 15.9 Hz, 4-H), 2.78 (1H, d, J = 15.9 Hz, 4-H), 3.08
(3H, s, N-CH3), 3.41 (3H, s, OCH3), 3.46 (1H, m,
6-H), 3.72 (1H, dd, J = 4.8, 1.4 Hz, 7-H), 3.94 (1H,
ddt, J = 13.1, 5.6, 1.5 Hz, OCH2CH@CH2), 4.15 (1H,
ddt, J = 13.1, 5.6, 1.5 Hz, OCH2CH@CH2), 5.20 (2H,
m, OCH2CH@CH2), 5.72 (1H, s, 9-H), 5.80 (1H, d,

K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
4877
OCH2C6H5), 5.72 (1H, s, 9-H), 5.80 (1H, d, J = 4.8 Hz, 8-H),
J = 6.0 Hz, OCH(CH3)2), 1.19 (3H, d, J = 6.0 Hz,
OCH(CH3)2), 1.43 (2H, m, OCH2CH2CH(CH3)2), 1.70
(1H, m, OCH2CH2 CH(CH3)2), 1.85 (3H, d, J = 1.9 Hz,
3-CH3), 1.92 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.11 (1H, br d,
J = 15.9 Hz, 4-H), 2.75 (1H, d, J = 15.9 Hz, 4-H), 3.07
(3H, s, N-CH3), 3.27 (1H, m, 6-H), 3.34 (1H, dt, J = 9.1,
6.3 Hz, OCH2CH2CH (CH3)2), 3.62 (1H, dt, J = 9.1,
6.3 Hz, OCH2CH2CH(CH3)2), 3.75 (1H, sep, J = 6.0 Hz,
18
D
7.25–7.37 (5H, m, OCH2C6H5); ½aꢁ ꢀ198 (c 1.0, MeOH);
MS (EI) m/z 379 (M)+.
4.2.52. (4aR,5R,6R,7R)-6-Ethoxy-7-(1-methylethoxy)-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (16a). Reaction of 1f gave 16a in 49% yield as a
colorless oil by a similar procedure to 3a: 1H NMR
(CDCl3)
d
1.07 (3H, s, 4a-CH3), 1.15 (3H, d,
OCH(CH3)2), 3.85 (1H, dd, J = 5.2, 1.4 Hz, 7-H), 5.71
20
D
J = 7.1 Hz, 5-CH3), 1.18 (3H, t, J = 7.0 Hz, OCH2CH3),
1.19 (3H, d, J = 6.0 Hz, OCH(CH3)2), 1.19 (3H, d,
J = 6.0 Hz, OCH(CH3)2), 1.86 (3H, d, J = 2.0 Hz, 3-
CH3), 1.93 (1H, dq, J = 7.1, 2.7 Hz, 5-H), 2.12 (1H, br
d, J = 15.9 Hz, 4-H), 2.77 (1H, d, J = 15.9 Hz, 4-H),
3.08 (3H, s, N-CH3), 3.30 (1H, m, 6-H), 3.40 (1H, dq,
J = 9.2, 7.0 Hz, OCH2CH3), 3.67 (1H, dq, J = 9.2,
7.0 Hz, OCH2CH3), 3.86 (1H, br d, J = 4.1 Hz, 7-H),
3.75 (1H, sep, J = 6.0 Hz, OCH(CH3)2), 5.72 (1H, s, 9-
H), 5.73 (1H, d, J = 4.1 Hz, 8-H); MS (EI) m/z 345 (M)+.
(1H, d, J = 5.2 Hz, 8-H), 5.71 (1H, s, 9-H); ½aꢁ ꢀ289
(c 1.0, MeOH); MS (EI) m/z 387 (M)+; HRMS
(FAB) (C24H38O3N) calcd 388.2852, obsd 388.2881.
4.2.56. (4aR,5R,6R,7R)-6-Cyclopropylmethoxy-7-(1-methy-
lethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]in-
dol-2(4H)-one (16e). Reaction of1fgave16e in22% yield as
1
a colorless oil by a similar procedure to 3a: H NMR
(CDCl3) d 0.10–0.54 (4H, m, OCH2C3H5), 1.00 (1H, m,
OCH2C3H5), 1.07 (3H, s, 4a-CH3), 1.15 (3H, d,
J = 7.1 Hz, 5-CH3), 1.17 (3H, d, J = 6.0 Hz, OCH(CH3)2),
1.18 (3H, d, J = 6.0 Hz, OCH(CH3)2), 1.85 (3H, d, J =
1.9 Hz, 3-CH3), 1.92 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.11
(1H, br d, J = 15.9 Hz, 4-H), 2.76 (1H, d, J = 15.9 Hz, 4-
H), 3.07 (3H, s, N-CH3), 3.23 (1H, dd, J = 10.2, 6.6 Hz,
OCH2C3H5), 3.33 (1H, m, 6-H), 3.47 (1H, dd, J = 10.2,
6.6 Hz, OCH2C3H5), 3.73 (1H, sep, J = 6.0 Hz, OCH
4.2.53.
(4aR,5R,6R,7R)-7-(1-Methylethoxy)-6-propoxy-
4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (16b). Reaction of 1f gave 16b in 34% yield as a
colorless oil by a similar procedure to 3a: 1H NMR
(CDCl3) d 0.92 (3H, t, J = 7.4 Hz, OCH2CH2CH3), 1.08
(3H, s, 4a-CH3), 1.16 (3H, d, J = 7.1 Hz, 5-CH3), 1.19
(3H, d, J = 6.1 Hz, OCH(CH3)2), 1.20 (3H, d, J = 6.1 Hz,
OCH (CH3)2), 1.57 (2H, m, OCH2CH2CH3), 1.86 (3H, d,
J = 1.9 Hz, 3-CH3), 1.94 (1H, dq, J = 7.1, 2.7 Hz, 5-H),
2.12 (1H, br d, J = 15.9 Hz, 4-H), 2.77 (1H, d, J =
15.9 Hz, 4-H), 3.09 (3H, s, N-CH3), 3.29 (1H, dt, J = 8.8,
6.4 Hz, OCH2CH2CH3), 3.29 (1H, m, 6-H), 3.58 (1H, dt,
J = 8.8, 6.4 Hz, OCH2CH2CH3), 3.87 (1H, dd, J = 5.2,
1.3 Hz, 7-H), 3.76 (1H, sep, J = 6.1 Hz, OCH(CH3)2),
5.72 (1H, d, J = 5.2 Hz, 8-H), 5.73 (1H, s, 9-H); MS (EI)
m/z 359 (M)+.
(CH3)2), 3.84 (1H, dd, J = 5.2, 1.4 Hz, 7-H), 5.71 (1H, s,
20
D
9-H), 5.72 (1H, d, J = 5.2 Hz, 8-H); ½aꢁ ꢀ515 (c 1.0,
MeOH); MS (EI) m/z 371 (M)+; HRMS (FAB)
(C23H34O3N) calcd 372.2539, obsd 372.2533.
Acknowledgments
We thank Ms. Y. Iizuka for PR binding results. We also
grateful to Ms. S. Miki and Ms. Miyara for mass spec-
tral analyses.
4.2.54. (4aR,5R,6R,7R)-6-Butoxy-7-(1-methylethoxy)-4a,
5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-
one (16c). Reaction of 1f gave 16c in 19% yield as a
colorless oil by a similar procedure to 3a: 1H NMR
(CDCl3) d 0.10 (3H, t, J = 7.2 Hz, OCH2CH2CH2CH3),
1.05 (3H, s, 4a-CH3), 1.14 (3H, d, J = 7.1 Hz, 5-CH3),
1.18 (3H, d, J = 6.0 Hz, OCH(CH3)2), 1.19 (3H, d, J =
6.0 Hz, OCH(CH3)2), 1.37 (2H, m, OCH2CH2CH2CH3),
1.52 (2H, m, OCH2CH2CH2CH3), 1.85 (3H, d, J =
1.9 Hz, 3-CH3), 1.92 (1H, dq, J = 7.1, 2.8 Hz, 5-H), 2.11
(1H, br d, J = 15.9 Hz, 4-H), 2.75 (1H, d, J = 15.9 Hz,
4-H), 3.07 (3H, s, N-CH3), 3.27 (1H, m, 6-H), 3.32 (1H,
dt, J = 8.9, 6.2 Hz, OCH2CH2CH2CH3), 3.60 (1H, dt,
J = 8.9, 6.2 Hz, OCH2CH2CH2CH3), 3.75 (1H, sep,
J = 6.0 Hz, OCH(CH3)2), 3.85 (1H, dd, J = 5.2, 1.4 Hz,
References and notes
1. Pasqualini, J. R. J. Steroid Biochem. Mol. Biol. 1996, 59,
357–363.
2. Spitz, I. M.; Bardin, C. W. Contraception 1993, 48, 403–444.
3. Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.;
Ianiro, T.; Mais, D. E.; Torres, A.; Goldman, M. E. Mol.
Pharmacol. 1995, 47, 630–635.
4. Pooley, C. L. F.; Edwards, J. P.; Goldman, M. E.; Wang,
M. W.; Marschke, K. B.; Crombie, D. L.; Jones, T. K.
J. Med. Chem. 1998, 41, 3461–3466.
5. Palmer, S.; Campen, C. A.; Allan, G. F.; Rybczynski, P.;
Haynes-Johnson, D.; Hutchins, A.; Kraft, P.; Kiddoe, M.; Lai,
M. T.; Lombardi, E.; Pedersen, P.; Hodgen, G.; Combs, D. W.
J. Steroid Biochem. Mol. Biol. 2000, 75, 33–42.
6. Zang, Z.; Olland, A. M.; Zhu, Y.; Cohen, J.; Berrodin, T.;
Chippari, S.; Appavu, C.; Li, S.; Wilhem, J.; Chopra, R.;
Fensome, A.; Zhang, P.; Wrobel, J.; Unwalla, R. J.;
Lyttle, C. R.; Winneker, R. C. J. Biol. Chem. 2005, 280,
28468–28475.
7. Tabata, Y.; Miike, N.; Hatsu, M.; Kurata, Y.; Yaguchi,
T.; Someya, A.; Miyadoh, S.; Hoshiko, S.; Tsuruoka, T.;
Omoto, S. J. Antibiot. 1997, 50, 304–308.
7-H), 5.71 (1H, d, J = 5.2 Hz, 8-H), 5.71 (1H, s, 9-H);
20
½aꢁ ꢀ308 (c 1.0, MeOH); MS (EI) m/z 373 (M)+; HRMS
D
(FAB) (C23H36O3N) calcd 374.2695, obsd 374.2702.
4.2.55. (4aR,5R,6R,7R)-6-(3-Methylbutoxy)-7-(1-methyl-
ethoxy)-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-
2(4H)-one (16d). Reaction of 1f gave 16d in 11% yield
1
as a colorless oil by a similar procedure to 3a: H NMR
(CDCl3) d 0.87 (3H, d, J = 6.6 Hz, OCH2CH2CH(CH3)2),
0.88 (3H, d, J = 6.6 Hz, OCH2CH2CH(CH3)2), 1.05 (3H, s,
4a-CH3), 1.14 (3H, d, J = 7.1 Hz, 5-CH3), 1.18 (3H, d,
8. Tabata, Y.; Hatsu, M.; Kurata, Y.; Miyajima, K.; Tani,
M.; Sasaki, T.; Kodama, Y.; Tsuruoka, T.; Omoto, S.
J. Antibiot. 1997, 50, 309–313.

4878
K. Kurihara et al. / Bioorg. Med. Chem. 14 (2006) 4862–4878
9. Tabata, Y.; Iizuka, Y.; Kashiwa, J.; Takei Masuda, N.;
14. Tabata, Y.; Iizuka, Y.; Shinei, R.; Kurihara, K.; Okonogi,
T.; Hoshiko, S.; Kurata, Y. Eur. J. Pharmacol. 2003, 461,
73–78.
15. Kurata, Y.; Tabata, Y.; Shinei, R.; Iizuka, Y.; Takei, M.
N.; Kurihara, K.; Okonogi, T.; Hoshiko, S. J. Pharmacol.
Exp. Ther. 2005, 313, 916–920.
Shinei, R.; Kurihara, K.; Okonogi, T.; Hoshiko, S.;
Kurata, Y. Eur. J. Pharmacol. 2001, 430, 159–165.
10. Kurihara, K.; Tanabe, K.; Shinei, R.; Okonogi, T.;
Ohtsuka, Y.; Omoto, S.; Yasuda, S.; Tatsuta, K.
J. Antibiot. 1997, 50, 360–362.
11. Kurihara, K.; Tanabe, K.; Yamamoto, Y.; Shinei, R.; Ajito,
K.; Okonogi, T. Bioorg. Med. Chem. Lett. 1999, 9, 1837–1842.
12. Shinei, R.; Kurihara, K.; Tanabe, K.; Tabata, Y.; Kurata,
Y.; Hoshiko, S.; Okonogi, T. Bioorg. Med. Chem. 2006,
14, in press.
16. Tabata, Y.; Iizuka, Y.; Takei, M. N.; Shinei, R.; Kurihara,
K.; Okonogi, T.; Hoshiko, S.; Kurata, Y. J. Steroid
Biochem. Mol. Biol. 2002, 82, 217–223.
13. Figure of Stability at pH 11.5.
100
1
2
75
50
25
0
time (hrs)
0
4
8
12
16
20
24