4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5α-reductase. III

Article abstract of DOI:10.1248/cpb.49.799

A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop nonsteroidal inhibitors of steroid 5α-reductase, and the structure-activity relationships in this series were studied. We previously reported the structure-activity relationships in a series of indolebutyric acids as well as the discovery of the novel nonsteroidal 5α-reductase inhibitor, FK143. We have now made other modifications to this compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yllbutyric acid, which displays strong in vitro inhibitory activity against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound should be a useful agent for the treatment of benign prostatic hyperplasia.

Full text of DOI:10.1248/cpb.49.799

July 2001
Chem. Pharm. Bull. 49(7) 799—813 (2001)
799
4-(Benzoylindolizinyl)butyric Acids; Novel Nonsteroidal Inhibitors of
1)
a
Steroid 5 -Reductase. III.
Kozo SAWADA,* Satoshi OKADA,2) Akio KURODA, Shinya WATANABE, Yuki SAWADA, and
Hirokazu TANAKA
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 5–2–3 Tokodai, Tsukuba 300–2698, Japan.
Received December 11, 2000; accepted March 12, 2001
A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop
nonsteroidal inhibitors of steroid 5a-reductase, and the structure–activity relationships in this series were stud-
ied. We previously reported the structure–activity relationships in a series of indolebutyric acids as well as the
discovery of the novel nonsteroidal 5a-reductase inhibitor, FK143. We have now made other modifications to this
compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl
substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-
isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]butyric acid, which displays strong in vitro inhibitory activity
against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound
should be a useful agent for the treatment of benign prostatic hyperplasia.
Key words 5a-reductase inhibitor; FK687; benign prostatic hyperplasia; nonsteroidal
Benign prostatic hyperplasia (BPH) is a common disorder shown in Charts 1 and 2. Friedel–Crafts acylation of in-
in aging males. Approximately 50% to 75% of all males over dolizine was carried out with ethyl 3-(chloroformyl)propi-
the age of 50 are known to develop this condition.3) This dis- onate and aluminum chloride to obtain 1 and 2. The ketone 1
order is characterized by a progressive enlargement of the was reduced to 3 by a borane–tetrahydrofuran (THF) com-
prostate grand, leading to an increase in pressure on the ure- plex, and 3 was acylated with 3-nitrobenzoyl chloride to ob-
thra; it results in obstruction of urinary flow. In light of the tain 8. The catalytic reduction of 8 gave the amine 11, which
high incidence of this condition, it is obvious that some form was alkylated with bis(4-isobutylphenyl)chloromethane to
of chemical therapy would be of immense potential impor- afford 14. 17 was obtained by hydrolysis of the ester 14. The
tance in treating BPH.4)
indolizine derivative 18 was prepared from 2 in a similar
Steroid 5a-reductase enzymatically converts testosterone manner to 17 (Charts 1, 2). The imidazopyridine 19 was pre-
(T) into 5a-dihydrotestosterone (DHT), which is the most pared as shown in Charts 1 and 2. 1-Formylimidazo[1,5-
active agonist for androgen receptors.5) An accumulation of a]pyridine10) was treated with Wittig reagent to give the b,g-
DHT to high levels in the prostate gland or the skin is recog- unsaturated acid 5. Esterification and catalytic reduction of 5
nized as leading to various pathological conditions such as afforded 7, which was derived to 19 in a manner similar to
BPH, acne, female hirsutism, and male pattern baldness.4) 17. The imidazopyridine derivative 30 was prepared as
Therefore, therapy with a 5a-reductase inhibitor would be shown in Charts 3 and 4. The reaction of 2-picolylamine and
expected to lead to a decrease in DHT concentration within glutaric anhydride yielded 4-carbamylbutyric acid 20, which
the prostate gland or other tissues, and may be an extremely
useful agent for the treatment of BPH and other diseases.
Table 1. Inhibition of Human and Rat Prostate 5a-Reductase and the
Though many laboratories have investigated 5a-reductase
Growth of Ventral Prostate in the Castrated Young Rat Model by FK143 and
inhibitors,6,7) these efforts have predominantly concentrated
Finasteride
on compounds with a steroidal structure, for example finas-
In vitro IC50 (nM) In vivo (p.o.)a)
teride6a) (Table 1). However, due to the presence of a
Compd.
FK143
Structure
10 mg/kg
(%)
steroidal structure, there is the strong possibility of unwanted
side-effects.8) We previously reported1) the discovery of an
excellent nonsteroidal compound, FK143, 4-[3-[3-[[bis(4-
isobutylphenyl)methyl]amino]benzoyl]-1H-indol-1-yl]bu-
tyric acid (Table 1), which displays high in vitro inhibitory
activity against human prostatic 5a-reductase (IC50ϭ1.9 nM)
and in vivo inhibitory activity against the castrated young rat
model.9) In this model, the growth of ventral prostate was in-
duced by the subcutaneous injection of testosterone propi-
onate (TP) to castrated young rats and was reduced by ad-
ministration of the inhibitor. In order to obtain a more clini-
cally effective candidate, we have now investigated more ac-
tive compounds against this in vivo model. We employed two
types of modification, 1) altering the indole ring to other het-
rocyclic rings, and 2) changing the benzoyl substituent at the
3-position.
Human
1.9
Rat
4.2
46.1##
Finasteride
1.0
5.9
48.1##
a) In vivo effect of FK143 and finasteride on ventral prostate weight of castrated rats
(TP-treated). Prepubertal male rats were castrated, subcutaneously injected with
300 mg/kg of TP (except castrated control), and orally administered with drug suspen-
sion for 5 d. Data are expressed as percent reduction in prostate weight which was cal-
culated as follows: 100[(prostate weight of vehicleϩTP group)Ϫ(prostate weight of test
compϩTP group)]/[(prostate weight of vehicleϩTP group)Ϫ(prostate weight of cas-
##
trated control group)]. pϽ0.01 vs. Control Dunnett t-test meanϮS.E.
Chemistry The indolizine derivative 17 was prepared as
To whom correspondence should be addressed. e-mail: kouzo_sawada@po.fujisawa.co.jp
© 2001 Pharmaceutical Society of Japan

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Vol. 49, No. 7
Chart 1. Preparation of 3, 4 and 7
Chart 2. Preparation of Compouds 17—19
was treated with ethanol and camphorsulfonic acid (CSA) to nitrobenzoyl chloride to give 24, which was alkylated with
afford the ester 21. The imidazo[1,5-a]pyridine 22 was pre- ethyl 4-bromobutyrate to afford the ester 25. 25 was derived
pared by cyclization of 21 with phosphorus oxychloride, and to 31 in a manner similar to 30.
22 was acylated under Friedel–Crafts conditions with 3-ni-
The indole derivatives 39 and 40 were prepared as shown
trobenzoyl chloride to give 23. Hydrolysis of the ester moiety in Chart 6. Indole was acylated under Friedel–Crafts condi-
and reduction of the nitro group of 23 afforded the amine 28, tions to give 35a, b, which were alkylated with ethyl 4-bro-
which was alkylated with bis(4-isobutylphenyl)chloromethane mobutyrate to afford the ester 36a, b. Hydrolysis and the cat-
to obtain 30. The azaindole derivative 31 was prepared as alytic reduction of 36a, b afforded 38a, b, which were alky-
shown in Charts 3 and 4. 7-Azaindole was acylated with 3- lated with 1-(4-isobutylphenyl)ethyl bromide to obtain 39

July 2001
801
Chart 3. Preparation of 23 and 25
Chart 4. Preparation of 30 and 31
phenylborane ((ϩ)-DIP-chloride),11) under Mitsunobu condi-
tions, to give the S ethers 48a—d, which were hydrolyzed
with 1 N NaOH to afford 50a—d. 51a—d were prepared in a
similar manner to 50a—d. The indolizine derivatives 55b—f
were prepared as shown in Chart 9. The indolizinebutyric
acid ethyl ester 3 was acylated by 4-acetoxybenzoyl chloride
to afford 52, which was deacetylated to obtain the phenol 53.
O-Alkylation of 53 with the benzyl bromides 34b—f gave
54b—f, which were hydrolized with 1 N NaOH to afford
55b—f. The chiral indolizine derivatives FK687 and 59 were
prepared as shown in Chart 10. 56 was alkylated by the chiral
alcohol 46c under Mitsunobu conditions to give 57, which
was hydrolyzed by 1 N NaOH to afford FK687. 59 was ob-
and 40.
The indole derivatives 45a—g were prepared as shown in
Chart 7. Indole was acylated with 4-methoxybenzoyl chlo-
ride to give 41, which was alkylated with ethyl 4-bromobu-
tyrate to afford the ester 42. Demethylation of the methoxy
group of 42 was carried out with aluminum chloride and
ethanethiol to afford the phenol 43. O-Alkylation of 43 was
achieved with the benzyl bromides 34a—g and potassium
carbonate to obtain 44a—g, which were hydrolyzed to afford
45a—g. The chiral indole derivatives 50a—d and 51a—d
were prepared as shown in Chart 8. The phenol 43 was re-
acted with the chiral R alcohols 46a—d, obtained by reduc-
tion of the ketones 32a—d with (ϩ)-B-chlorodiisopinocam-

802
Vol. 49, No. 7
Chart 5. Preparation of 34a—g
Chart 6. Preparation of 39 and 40
Chart 7. Preparation of 45a—g
tained in a similar manner to FK687.
pounds were evaluated for their ability to inhibit human and
rat prostatic 5a-reductases, and inhibitory activities were ex-
pressed as the IC50 value. Two isozymes of human 5a-reduc-
Results and Discussion
Modification of the Indole Ring The prepared com- tase, type 1 and type 2, have been isolated,12) and the type 2

July 2001
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Chart 8. Preparation of 50a—d and 51a—d
Chart 9. Preparation of 55b—f
Chart 10. Preparation of FK687 and 59

804
Vol. 49, No. 7
Table 2. Inhibition of Human and Rat Prostate 5a-Reductase and the Growth of Ventral Prostate in the Castrated Young Rat Model by FK143, 60, 17—19,
30 and 31
In vitro IC50 (nM)
Human
In vivo (p.o.)a)
1 mg/kg (%)
Compd. No.
Structure
Rat
4.2
3.2
FK143
1.9
33.8###
8.3
60
17
18
38
75
N.T.b)
17.5##
22.7##
0.53
0.60
1.1
2.9
Ϫ9.8
11.7
19
30
31
15
5.3
5.0
1.5
N.T.b)
N.T.b)
N.T.b)
59
37
##
a) In vivo effect of FK143, 60, 17, 18, 19, 30, and 31 on ventral prostate weight of castrated rats (TP-treated). See the footnotes of Table 1. b) Not tested. pϽ0.01,
pϽ0.001 vs. Control Dunnett t-test meanϮS.E.
###
isozyme participates in the growth of the prostate. Since type ity against the human enzyme than FK143; the IC50 value of
2 isozyme is predominantly expressed in the prostate, we 17 was 0.53 nM and that of 18 was 0.60 nM. These com-
used the enzymes from the human and rat prostate for in pounds (17, 18) also displayed significant in vivo inhibitory
vitro assay. In vivo inhibitory activities of these compounds activity against the castrated young rat model (Table 2).
in the castrated young rat model were measured and ex- However, these inhibitory activities were not so potent, thus
pressed as a percentage of the reduction of ventral prostate other modifications were necessary to improve the in vivo in-
weight (Table 1).
hibitory activity.
Modification of the Benzoyl Substituent We next in-
We previously reported1) that FK143 displayed ten times
stronger in vitro inhibitory activity against human prostatic vestigated the benzoyl substituent on the indole moiety. We
5a-reductase than 60, 4-[1-[3-[[bis(4-isobutylphenyl)methyl]- considered that a bis(4-isobutylphenyl)methyl group was too
amino]benzoyl]-1H-indol-3-yl]butyric acid (Table 2), in lipophilic for in vivo inhibitory activity. Indeed, we previ-
which the two substituents on the indole ring are at opposite ously reported1) that compound 61, which has a 1-(4-
positions to those of FK143. This suggests that alteration of isobutylphenyl)ethyl group at the benzoyl substituent instead
the nucleus may lead to improvement of the in vitro in- of a bis(4-isobutylphenyl)methyl group, had strong in vivo
hibitory activity. Thus, we first exchanged the indole nucleus inhibitory activity in the castrated young rat model (Table 3).
of FK143 to other heterocyclic rings, such as indolizine (17, Thus, the 1-(4-isobutylphenyl)ethyl group was introduced to
18), imidazopyridine (19, 30) and azaindole (31), keeping the the benzoyl substituent of various indolebutyric acids (39,
substituents constant (Table 2). Among these compounds, the 40, 45a) (Table 3). Among these compounds, 45a had clearly
indolizine derivatives (17, 18) had stronger inhibitory activ- stronger in vivo inhibitory activity than FR143. However, re-

July 2001
805
Table 3. Inhibition of Human and Rat Prostate 5a-Reductase and the Growth of Ventral Prostate in the Castrated Young Rat Model by 61, 39, 40 and 45a
In vivo (%)a)
In vitro IC50 (nM)
Human
1.9
Compd. No.
Structure
Rat
4.2
3.2
1 mg/kg (p.o.)
FK143
33.8###
8.3
61
39
320
2.5
7.5
55.0###
14.4
89
20.8#
2.4
40
45
38
1.8
3.1
28.2#
20.8#
45a
44.6###
38.0###
#
##
###
a) In vivo effect of FK143, 61, 39, 40, and 45a on ventral prostate weight of castrated rats (TP-treated). See the footnotes of Table 1. pϽ0.1, pϽ0.01, pϽ0.001 vs. Con-
trol Dunnett t-test meanϮS.E.
Table 4. Inhibition of Human and Rat Prostate 5a-Reductase and the Growth of Ventral Prostate in the Castrated Young Rat Model by 45a—g
In vitro IC50 (nM)
In vivo (%)a)
Compd. No.
n
*
Human
Rat
3.2
1.0
0.32 mg/kg (p.o.)
45a
45b
45c
45d
45e
45f
0
1
2
3
4
5
6
RS
RS
RS
RS
RS
RS
RS
33
47
14
3.3
4.8
7.4
8.5
3.1
0.78
1.5
0.66
7.5
1.7
44.6###
60.4###
55.4##
52.7###
42.5##
Ϫ5.2
38.0###
46.7###
51.8##
29.3#
Ϫ3.2
Ϫ16.3
Ϫ7.5
50.0###
20.1
11.9
45g
7.7
Ϫ4.5
#
##
###
a) In vivo effect of 45a—g on ventral prostate weight of castrated rats (TP-treated). See the footnotes of Table 1. pϽ0.1, pϽ0.01, pϽ0.001 vs. Control Dunnett t-test
meanϮS.E.
garding in vitro inhibitory activity against the human en- metric center in the benzoyl moiety. Optical isomers often do
zyme, 45a was not so strong; its IC50 value was 38 nM. It was not have the same physiological activities, thus we compared
thus considered that a larger group was necessary at the the activities of both enantiomers (50a—d, 51a—d) (Table
benzoyl substituent for strong in vitro inhibitory activity 5). The S isomers of these compounds had stronger in vitro
against the human enzyme, and we introduced longer alkyl inhibitory activity against human and rat enzymes than the R
groups at the benzoyl substituent instead of the methyl isomers, and among them, 50d had the strongest inhibitory
group; i.e. 1-(4-isobutylphenyl)propyl, 1-(4-isobutylphenyl)- activity; its IC50 value was 4.8 nM against the human enzyme
butyl, 1-(4-isobutylphenyl)pentyl, and so on, were introduced and 0.8 nM against the rat enzyme. The in vivo inhibitory
instead of 1-(4-isobutylphenyl)ethyl (45b—g) (Table 4). As activity of 50d was also stronger than its R isomer, 51d.
expected, among these compounds, compounds with larger
Next, we introduced these benzoyl substituents to the in-
substituents (45d—g) had stronger in vitro inhibitory activi- dolizine moiety of 4-(indolizin-3-yl)butyric acid (55b—f)
ties against the human enzyme. On the other hand, the in vivo (Table 6). These indolizine derivatives showed the same ten-
inhibitory activities of compounds with smaller substituents dencies for in vitro inhibition as the indole derivatives, and
(45a—d) were stronger.
compounds with a larger substituent (55c—f) had stronger in
These compounds are racemic since they have an asym- vitro inhibitory activity against the human enzyme with

806
Vol. 49, No. 7
Table 5. Inhibition of Human and Rat Prostate 5a-Reductase and the Growth of Ventral Prostate in the Castrated Young Rat Model by 50a—d and 51a—d
In vitro IC50 (nM)
In vivo (%)a)
Compd. No.
n
ee (%)
*
Human
Rat
3.2
1.0
0.32 mg/kg (p.o.)
50a
50b
50c
50d
51a
51b
51c
51d
0
1
2
3
0
1
2
3
S
S
S
87.1
93.9
95.6
95.1
90.0
91.1
94.8
96.0
58
47
54
0.29
0.68
0.73
0.8
1.4
2.7
48.8##
54.1##
57.8###
70.6##
10.3
43.8#
50.3##
51.5##
49.4##
19.5
12.5
18.8
11.0
20.4
18.0
46.5###
9.0
S
4.8
R
R
R
R
440
470
490
4.4
36.1#
30.5##
20.3
23.4
23.5
14.7
1.3
1.8
62
#
##
###
a) In vivo effect of 50a—d and 51a—d on ventral prostate weight of castrated rats (TP-treated). See the footnotes of Table 1. pϽ0.1, pϽ0.01, pϽ0.001 vs. Control
Dunnett t-test meanϮS.E.
Table 6. Inhibition of Human and Rat Prostate 5a-Reductase and the Growth of Ventral Prostate in the Castrated Young Rat Model by 55b—f, 59 and
FK687
In vitro IC50 (nM)
In vivo (%)a)
Compd. No.
n
ee (%)
*
Human
Rat
3.2
1.0
0.32 mg/kg (p.o.)
55b
55c
55d
55e
55f
59
FK687
FK143
1
2
3
4
5
2
2
RS
RS
RS
RS
RS
R
12
3.6
5.0
3.4
5.3
120
4.6
1.9
0.55
2.2
1.8
1.6
6.4
1.2
1.7
4.2
47.6###
43.4###
45.7##
38.0##
10.3
47.2###
49.5###
17.3
10.5
13.4
Ϫ1.9
97.6
96.0
15.4
10.1
47.0##
8.3
2.4
S
60.1##
33.8###
42.6##
##
###
a) In vivo effect of 13b—f, 14, FK687 and FK143 on ventral prostate weight of castrated rats (TP-treated). See the footnotes of Table 1. pϽ0.01, pϽ0.001 vs. Control
Dunnett t-test meanϮS.E.
Experimental
nanomolar IC50 values. Amongst those compounds, 55c had
the strongest in vivo inhibitory activity. The S isomer of 55c,
FK687, had stronger in vitro inhibitory activity than the R
isomer (59); its IC50 value was 4.6 nM against the human en-
Chemistry Melting points were determined on a Thomas Hoover melt-
ing point apparatus and are uncorrected. Proton magnetic resonance (1H-
NMR) spectra were obtained on a Bruker AM200 (200 MHz) spectrometer,
and chemical shifts are reported in parts per million relative to tetramethylsi-
zyme. FK687 also had very strong in vivo inhibitory activity, lane (TMS) as an internal standard (TMS, d 0.00). Mass spectra (MS) were
obtained on a VG Platform. Optical rotations were obtained on a JASCO
and that activity was clearly stronger than that of FK143 in
the castrated young rat model.
DIP-370 operating at 589 nm. Enantiomeric excess (ee) was determined by
chiral HPLC on a Chiralpak AS (25 cmϫ4.6 mm) from Daicel.14)
Ethyl 4-(Indolizin-3-yl)-4-oxobutyrate (1) and Ethyl 4-(Indolizin-1-yl)-
Conclusions
4-oxobutyrate (2) To a mixture of ethyl 3-chloroformylpropionate (1.65 g,
10.0 mmol) and AlCl3 (1.78 g, 13.4 mmol) in CH2Cl2 (20 ml) was added a
solution of indolizine (977 mg, 7.97 mmol) in CH2Cl2 (5 ml) at room temper-
ature (r.t.) After being stirred for 1 h, the reaction was quenched by the addi-
tion of ice and the mixture was extracted with CHCl3. The extract was
washed with sat. NaHCO3 and brine, then dried over Na2SO4. After evapora-
tion of the solvent, the residue was chromatographed on silica gel (hexane :
We set out to produce 5a-reductase inhibitors with a non-
steroidal structure, beginning with the indole nucleus of
FK143. By introducing a benzoyl substituent with an (S)-1-
phenylbutoxy group and by changing the indole nucleous to
indolizine we have succeeded in producing the strongly ac-
tive compound, FK687, which displays high in vitro in-
hibitory activity against human prostatic 5a-reductase and,
significantly, very strong in vivo inhibitory activity against
the castrated young rat model. FK687 therefore has great po-
tential to be an extremely useful agent for the treatment of
BPH.13)
1
EtOAcϭ3 : 2) to give 1 (0.74 g, 37.9%) and 2 (0.26 g, 13.3%). 1: H-NMR
(CDCl3) d: 1.28 (3H, t, Jϭ7 Hz), 2.79 (2H, t, Jϭ7 Hz), 3.29 (2H, t,
Jϭ7 Hz), 4.18 (2H, q, Jϭ7 Hz), 6.51 (1H, d, Jϭ5 Hz), 6.84 (1H, dt, Jϭ2,
6 Hz), 7.12 (1H, m), 7.52 (1H, m), 7.58 (1H, d, Jϭ6 Hz), 9.83 (1H, dd, Jϭ2,
1
6 Hz). 2: H-NMR (CDCl3) d: 1.28 (3H, t, Jϭ7 Hz), 2.78 (2H, t, Jϭ7 Hz),
3.25 (2H, t, Jϭ7 Hz), 4.17 (2H, q, Jϭ7 Hz), 6.77 (1H, dt, Jϭ2, 7 Hz), 7.12
(1H, m), 7.22 (2H, m), 8.03 (1H, dt, Jϭ7, 2 Hz), 8.44 (1H, dt, Jϭ9, 2 Hz).
Ethyl 4-(Indolizin-3-yl)butyrate (3) To a solution of 1 (556 mg,

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Table 7. NMR Data for 32a—g and 33a—g
Compd.
1H-NMR (CDCl3), d (ppm)
32a
32b
0.91 (6H, d, Jϭ7 Hz), 1.90 (1H, m), 2.53 (2H, d, Jϭ7 Hz), 7.23 (2H, d, Jϭ8 Hz), 7.88 (2H, d, Jϭ8 Hz)
0.92 (6H, d, Jϭ7 Hz), 1.21 (3H, d, Jϭ7 Hz), 1.90 (1H, m), 2.53 (2H, d, Jϭ7 Hz), 3.00 (3H, q, Jϭ7 Hz), 7.23 (2H, d, Jϭ8 Hz), 7.90
(2H, d, Jϭ8 Hz)
32c
32d
0.86—1.07 (9H, m), 1.67—2.01 (3H, m), 2.53 (2H, d, Jϭ7 Hz), 2.93 (3H, t, Jϭ7 Hz), 7.22 (2H, d, Jϭ8 Hz), 7.88 (2H, d, Jϭ8 Hz)
0.85—1.00 (9H, m), 1.31—1.51 (2H, m), 1.67—2.01 (3H, m), 2.53 (2H, d, Jϭ7 Hz), 2.95 (2H, t, Jϭ7 Hz), 7.22 (2H, d, Jϭ8 Hz),
7.88 (2H, d, Jϭ8 Hz)
32e
32f
0.84—0.98 (9H, m), 1.30—1.43 (4H, m), 1.60—2.01 (3H, m), 2.53 (2H, d, Jϭ7 Hz), 2.94 (2H, t, Jϭ7 Hz), 7.22 (2H, d, Jϭ8 Hz),
7.88 (2H, d, Jϭ8 Hz)
0.82—0.97 (9H, m), 1.18—1.47 (6H, m), 1.55—2.01 (3H, m), 2.53 (2H, d, Jϭ7 Hz), 2.94 (2H, t, Jϭ7 Hz), 7.22 (2H, d, Jϭ8 Hz),
7.88 (2H, d, Jϭ8 Hz)
32g
33a
33b
0.82—0.98 (9H, m), 1.20—1.46 (8H, m), 1.63—2.01 (3H, m), 2.53 (2H, d, Jϭ7 Hz), 2.95 (2H, t, Jϭ7 Hz), 7.22 (2H, d, Jϭ8 Hz),
7.88 (2H, d, Jϭ8 Hz)
0.85 (6H, d, Jϭ7 Hz), 1.30 (2H, d, Jϭ6 Hz), 1.80 (1H, m), 2.41 (2H, d, Jϭ7 Hz), 4.67 (1H, m), 7.08 (2H, d, Jϭ8 Hz), 7.23 (2H, d,
Jϭ8 Hz)
0.88 (6H, d, Jϭ7 Hz), 0.89 (3H, t, Jϭ7 Hz), 1.60—2.00 (3H, m), 2.47 (2H, d, Jϭ7 Hz), 4.57 (1H, t, Jϭ7 Hz), 7.13 (2H, d, Jϭ8 Hz),
7.25 (2H, d, Jϭ8 Hz)
33c
33d
0.86—0.98 (9H, m), 1.16—1.97 (5H, m), 2.47 (2H, d, Jϭ7 Hz), 4.63 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.26 (2H, d, Jϭ8 Hz)
0.82—0.95 (9H, m), 1.17—1.48 (4H, m), 1.60—1.97 (3H, m), 2.47 (2H, d, Jϭ7 Hz), 4.63 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.25 (2H, d, Jϭ8 Hz)
33e
33f
33g
0.83—0.96 (9H, m), 1.16—1.40 (6H, m), 1.60—1.96 (3H, m), 2.48 (2H, d, Jϭ7 Hz), 4.64 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.25 (2H, d, Jϭ8 Hz)
0.80—0.97 (9H, m), 1.16—1.50 (8H, m), 1.58—1.97 (3H, m), 2.47 (2H, d, Jϭ7 Hz), 4.63 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.25 (2H, d, Jϭ8 Hz)
0.80—0.97 (9H, m), 1.16—1.50 (10H, m), 1.60—1.97 (3H, m), 2.47 (2H, d, Jϭ7 Hz), 4.63 (1H, t, Jϭ7 Hz), 7.12 (2H, d, Jϭ8 Hz),
7.26 (2H, d, Jϭ8 Hz).
Table 8. NMR Data for Compounds 34a—g
Compd.
1H-NMR (CDCl3), d (ppm)
34a
34b
0.90 (6H, d, Jϭ7 Hz), 1.85 (1H, m), 2.04 (3H, d, Jϭ7 Hz), 2.40 (2H, d, Jϭ7 Hz), 5.22 (1H, q, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.34
(2H, d, Jϭ8 Hz)
0.90 (6H, d, Jϭ7 Hz), 1.01 (3H, t, Jϭ7 Hz), 1.70—2.00 (1H, m), 2.00—2.40 (2H, m), 2.45 (2H, d, Jϭ7 Hz), 4.89 (1H, t, Jϭ7 Hz),
7.11 (2H, d, Jϭ8 Hz), 7.30 (2H, d, Jϭ8 Hz)
34c
34d
0.84—1.00 (9H, m), 1.18—2.38 (5H, m), 2.46 (2H, d, Jϭ7 Hz), 4.99 (1H, t, Jϭ7 Hz), 7.10 (2H, d, Jϭ8 Hz), 7.30 (2H, d, Jϭ8 Hz)
0.80—0.94 (9H, m), 1.15—1.55 (4H, m), 1.60—1.97 (3H, m), 2.46 (2H, d, Jϭ7 Hz), 4.96 (1H, t, Jϭ7 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.29 (2H, d, Jϭ8 Hz)
34e
34f
34g
0.82—0.97 (9H, m), 1.20—1.60 (6H, m), 1.74—1.97 (1H, m), 2.00—2.38 (2H, m), 4.96 (1H, t, Jϭ7 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.29 (2H, d, Jϭ8 Hz)
0.81—0.97 (9H, m), 1.16—1.55 (8H, m), 1.73—1.98 (1H, m), 2.03—2.35 (2H, m), 4.96 (1H, t, Jϭ7 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.30 (2H, d, Jϭ8 Hz)
0.82—0.96 (9H, m), 1.18—1.55 (10H, m), 1.72—1.96 (1H, m), 2.08—2.30 (2H, m), 4.97 (1H, t, Jϭ7 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.30 (2H, d, Jϭ8 Hz)
18.1%). 1H-NMR (DMSO-d6) d: 3.20 (2H, dd, Jϭ2, 7 Hz), 6.32 (1H, dt,
Jϭ16, 7 Hz), 6.74 (1H, d, Jϭ16 Hz), 6.78 (1H, m), 7.65 (1H, d, Jϭ9 Hz),
8.27 (1H, d, Jϭ7 Hz), 8.33 (1H, s).
Ethyl trans-4-(Imidazo[1,5-a]pyridin-1-yl)-3-butenate (6) To a sus-
pension of 5 (1.91 g, 9.46 mmol) in EtOH (100 ml) was added CSA (2.4 g),
and the mixture was refluxed for 2 h, then water was removed by 3 Å molec-
ular sieves. After evaporation of the solvent, the residue was chro-
matographed on silica gel (EtOAc) to give 6 (1.20 g, 55.2%). 1H-NMR
(CDCl3) d: 1.28 (3H, t, Jϭ7 Hz), 3.30 (2H, dd, Jϭ2, 7 Hz), 4.18 (2H, q,
Jϭ7 Hz), 6.40—6.60 (2H, m), 6.65—6.80 (2H, m), 7.49 (1H, d, Jϭ9 Hz),
7.85 (1H, d, Jϭ7 Hz), 8.04 (1H, s).
Ethyl 4-(Imidazo[1,5-a]pyridin-1-yl)butyrate (7) To a solution of 6
(1.2 g, 5.22 mmol) in a mixture of dioxane (5 ml) and EtOH (5 ml) was
added 10% palladium on activated carbon (10% Pd–C) (200 mg), and the
mixture was hydrogenated under H2 (4 atm) for 2 h. After removal of the
catalyst by filtration, the filtrate was evaporated to give 7 (1.05 g, 86.7%) as
an oil. 1H-NMR (CDCl3) d: 1.24 (3H, t, Jϭ7 Hz), 2.10 (2H, m), 2.36 (2H, t,
Jϭ7 Hz), 2.94 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 6.50 (1H, dt, Jϭ2,
7 Hz), 6.63 (1H, m), 7.38 (1H, d, Jϭ9 Hz), 7.87 (1H, d, Jϭ7 Hz), 8.12 (1H,
s).
2.27 mmol) in THF (5 ml) was added a 1 M solution of borane in THF
(3.6 ml) at 0 °C. After being stirred for 10 min at r.t., the reaction was
quenched by the addition of aq. KH2PO4 at 0 °C, and the mixture was ex-
tracted with ether 2 times. The extracts were combined, washed with water,
sat. NaHCO3 and brine, and dried over Na2SO4. After evaporation of the sol-
vent, the residue was chromatographed on Al2O3 (hexane : CH2Cl2ϭ1 : 1) to
give 3 (294 mg, 56.1%). 1H-NMR (CDCl3) d: 1.26 (3H, t, Jϭ7 Hz), 2.08
(2H, m), 2.43 (2H, t, Jϭ7 Hz), 2.79 (2H, t, Jϭ7 Hz), 4.14 (2H, q, Jϭ7 Hz),
6.3—6.7 (4H, m), 7.37 (1H, dt, Jϭ9, 2 Hz), 7.78 (1H, dt, Jϭ6, 2 Hz).
Ethyl 4-(Indolizin-1-yl)butyrate (4) Yield: 56.0%. 1H-NMR (CDCl3)
d: 1.23 (3H, t, Jϭ7 Hz), 1.98 (2H, m), 2.34 (2H, t, Jϭ7 Hz), 2.79 (2H, t,
Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 6.37 (1H, dt, Jϭ2, 7 Hz), 6.56 (1H, m), 6.62
(1H, d, Jϭ3 Hz), 7.21 (1H, d, Jϭ3 Hz), 7.29 (1H, d, Jϭ9 Hz), 7.84 (1H, d,
Jϭ7 Hz).
trans-4-(Imidazo[1,5-a]pyridin-1-yl)-3-butenoic Acid (5) To a solu-
tion of (2-carboxyethyl)triphenylphosphonium chloride (6.87 g, 18.5 mmol)
in dimethylformamide (DMF) (20 ml) was added NaH (60% in mineral oil,
1.48 g, 37 mmol) at 20 °C. After 20 min, 1-formylimidazo[1,5-a]pyridine10)
(2.46 g, 16.8 mmol) was added, and the mixture was stirred at 30 °C for 1 h.
The reaction was quenched by the addition of ice and the mixture was made
acidic by 1 N HCl and extracted with EtOAc. The extract was washed with
brine, dried over Na2SO4 and evaporated in vacuo. The residue was chro-
matographed on silica gel (10% MeOH in CHCl3) to give 5 (613 mg,
Ethyl 4-[1-(4-Nitrobenzoyl)indolizin-3-yl]butyrate (8) To a solution
of 3-nitrobenzoyl chloride (314 mg, 1.69 mmol) in CH2Cl2 (20 ml) was
added AlCl3 (305 mg, 2.29 mmol) at room temperature (r.t.) After the reac-

808
Vol. 49, No. 7
Table 9. NMR Data for Compounds 44a—g
Compd.
1H-NMR (CDCl3), d (ppm)
44a
44b
44c
44d
44e
44f
0.90 (6H, d, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.67 (2H, d, Jϭ6 Hz), 1.85 (m, 2H), 2.18 (2H, quintet Jϭ7 Hz), 2.30 (2H, t, Jϭ7 Hz),
2.45 (2H, d, Jϭ7 Hz), 4.09 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.38 (1H, q, Jϭ6 Hz), 6.94 (2H, d, Jϭ9 Hz), 7.13 (2H, d, Jϭ9 Hz),
7.26—7.40 (5H, m), 7.54 (1H, s), 7.75 (2H, d, Jϭ9 Hz), 8.35 (1H, m)
0.89 (6H, d, Jϭ7 Hz), 1.02 (3H, t, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.70—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.09 (2H, q, Jϭ7 Hz),
4.23 (2H, t, Jϭ7 Hz), 5.09 (1H, t, Jϭ7 Hz), 6.93 (2H, d, Jϭ9 Hz), 7.12 (2H, d, Jϭ9 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s), 7.74 (2H,
d, Jϭ9 Hz), 8.30—8.40 (1H, m)
0.88 (6H, d, Jϭ7 Hz), 0.97 (3H, t, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.30—2.10 (7H, m), 2.10—2.40 (4H, m), 2.45 (2H, d, Jϭ7 Hz),
4.10 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.17 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45
(5H, m), 7.52 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.36 (1H, m)
0.80—1.00 (9H, m), 1.20 (3H, t, Jϭ7 Hz), 1.30—1.65 (4H, m), 1.75—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.10 (2H, q, Jϭ7 Hz),
4.23 (2H, t, Jϭ7 Hz), 5.15 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s),
7.74 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
0.80—0.95 (9H, m), 1.15—1.65 (9H, m), 1.70—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.09 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz),
5.14 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, Jϭ9 Hz),
8.30—8.40 (1H, m)
0.80—0.95 (9H, m), 1.15—1.65 (11H, m), 1.70—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.10 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz),
5.14 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, Jϭ9 Hz),
8.30—8.40 (1H, m)
44g
0.80—0.95 (9H, m), 1.15—1.65 (13H, m), 1.70—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.10 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz),
5.15 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s), 7.74 (2H, d, Jϭ9 Hz),
8.30—8.40 (1H, m)
Table 10. Spectral Data for Compounds 45a—g
Compd.
ESI-MS m/z:
496 (MϪH)Ϫ
1H-NMR (CDCl3), d (ppm)
45a
0.90 (6H, d, Jϭ7 Hz), 1.66 (3H, d, Jϭ6 Hz), 1.84 (1H, m), 2.20 (2H, t, Jϭ7 Hz), 2.38 (2H, t, Jϭ7 Hz), 2.45 (2H,
d, Jϭ7 Hz), 4.25 (2H, t, Jϭ7 Hz), 5.37 (1H, q, Jϭ6 Hz), 6.95 (2H, d, Jϭ9 Hz), 7.13 (2H, d, Jϭ9 Hz), 7.25—7.40
(5H, m), 7.75 (2H, d, Jϭ9 Hz), 8.32 (1H, m)
45b
45c
45d
45e
45f
510 (MϪH)Ϫ
524 (MϪH)Ϫ
538 (MϪH)Ϫ
552 (MϪH)Ϫ
566 (MϪH)Ϫ
580 (MϪH)Ϫ
0.88 (6H, d, Jϭ7 Hz), 1.00 (3H, t, Jϭ7 Hz), 1.70—2.30 (5H, m), 2.30—2.50 (4H, m), 4.24 (2H, t, Jϭ7 Hz), 5.09
(1H, t, Jϭ7 Hz), 6.73 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ9 Hz), 7.25—7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, Jϭ
9 Hz), 8.30—8.40 (1H, m)
0.88 (6H, d, Jϭ7 Hz), 0.96 (3H, t, Jϭ7 Hz), 1.20—2.30 (7H, m), 2.38 (2H, t, Jϭ7 Hz), 2.44 (2H, d, Jϭ7 Hz), 4.23
(2H, t, Jϭ7 Hz), 5.16 (1H, dd, Jϭ5, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53
(1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.33 (1H, m)
0.80—1.00 (9H, m), 1.25—1.60 (4H, m), 1.75—2.30 (5H, m), 2.37 (2H, d, Jϭ7 Hz), 2.43 (2H, d, Jϭ7 Hz), 4.24
(2H, t, Jϭ7 Hz), 5.14 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.54
(1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
0.80—0.95 (9H, m), 1.20—1.65 (6H, m), 1.70—2.30 (5H, m), 2.36 (2H, d, Jϭ7 Hz), 2.44 (2H, d, Jϭ7 Hz), 4.22
(2H, t, Jϭ7 Hz), 5.15 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.54
(1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
0.80—0.95 (9H, m), 1.15—1.65 (8H, m), 1.70—2.30 (5H, m), 2.32—2.50 (4H, m), 4.23 (2H, t, Jϭ7 Hz), 5.15
(1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d,
Jϭ9 Hz), 8.30—8.40 (1H, m)
0.80—0.95 (9H, m), 1.15—1.65 (10H, m), 1.70—2.28 (5H, m), 2.32—2.50 (4H, m), 4.24 (2H, t, Jϭ7 Hz), 5.15
1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d,
Jϭ9 Hz), 8.30—8.40 (1H, m)
45g
tion mixture was stirred at r.t. for 10 min, a solution of 3 (297 mg,
1.28 mmol) in CH2Cl2 (3 ml) was added thereto. After 1 h, the reaction was
quenched by the addition of ice and the mixture was extracted with CHCl3.
The extract was washed with water, sat. NaHCO3 and brine, and dried over
Na2SO4. After evaporation of the solvent, the residue was chromatographed
on silica gel (hexane : EtOAcϭ2 : 3) to give 8 (353 mg, 72.6%). 1H-NMR
(CDCl3) d: 1.23 (3H, t, Jϭ7 Hz), 2.08 (2H, m), 2.46 (2H, t, Jϭ7 Hz), 2.93
(2H, t, Jϭ7 Hz), 4.13 (2H, q, Jϭ7 Hz), 6.80 (1H, s), 6.98 (1H, dt, Jϭ1,
7 Hz), 7.30 (1H, m), 7.69 (1H, t, Jϭ8 Hz), 8.10 (1H, d, Jϭ7 Hz), 8.16 (1H,
m), 8.39 (1H, m), 8.53 (1H, dt, Jϭ9, 1 Hz), 8.57 (1H, m).
Ethyl 4-[3-(3-Nitrobenzoyl)indolizin-1-yl]butyrate (9) Yield: 72.0%.
1H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7 Hz), 2.01 (2H, m), 2.37 (2H, t,
Jϭ7 Hz), 2.81 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 7.02 (1H, dt, Jϭ2,
7 Hz), 7.11 (1H, s), 7.28 (1H, dt, Jϭ2, 8 Hz), 7.62 (1H, dt, Jϭ8, 2 Hz), 7.69
(1H, t, Jϭ7 Hz), 8.12 (1H, m), 8.38 (1H, m), 8.63 (1H, m), 9.98 (1H, d,
Jϭ7 Hz).
(2H, t, Jϭ7 Hz), 3.04 (2H, t, Jϭ7 Hz), 4.14 (2H, q, Jϭ7 Hz), 7.11 (1H, dt,
Jϭ7, 2 Hz), 7.28 (1H, m), 7.70 (1H, t, Jϭ8 Hz), 7.76 (1H, m), 8.51 (1H, m),
8.79 (1H, dt, Jϭ2, 8 Hz), 9.41 (1H, m), 9.89 (1H, dt, Jϭ7, 2 Hz).
Ethyl 4-[1-(4-Aminobenzoyl)indolizin-3-yl]butyrate (11) To a solu-
tion of 8 (350 mg, 0.921 mmol) in a mixture of dioxane (5 ml) and EtOH
(5 ml) was added 10% palladium on activated carbon (10% Pd–C) (210 mg),
and the mixture was hydrogenated under H2 (4 atm) for 4 h. After removal of
the catalyst by filtration, the filtrate was evaporated to give 11 (320 mg,
99.3%). 1H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7 Hz), 2.05 (2H, m), 2.43 (2H,
t, Jϭ7 Hz), 2.88 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 6.90 (1H, m), 6.91
(1H, s), 7.10—7.40 (5H, m), 8.10 (1H, d, Jϭ7 Hz), 8.48 (1H, dt, Jϭ8, 1 Hz).
Ethyl 4-[3-(3-Aminobenzoyl)indolizin-1-yl]butyrate (12) Yield: 100%.
1H-NMR (CDCl3) d: 1.23 (3H, t, Jϭ7 Hz), 1.98 (2H, m), 2.33 (2H, t,
Jϭ7 Hz), 2.78 (2H, t, Jϭ7 Hz), 4.25 (2H, q, Jϭ7 Hz), 6.80—7.00 (2H, m),
7.10—7.30 (6H, m), 7.54 (1H, dt, Jϭ8, 2 Hz), 9.94 (1H, d, Jϭ7 Hz).
Ethyl 4-[3-(3-Aminobenzoyl)imidazo[1,5-a]pyridin-1-yl]butyrate (13)
Yield: 96.1%. 1H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 2.17 (2H, m), 2.47
(2H, t, Jϭ7 Hz), 3.03 (2H, t, Jϭ7 Hz), 4.15 (2H, q, Jϭ7 Hz), 6.89 (1H, m),
Ethyl 4-[3-(3-Nitrobenzoyl)imidazo[1,5-a]pyridin-1-yl]butyrate (10)
Yield: 45.6%. 1H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 2.19 (2H, m), 2.48

July 2001
809
Table 11. NMR Data for Compounds 46a—d, 47a—d, 48a—d and 49a—d
Compd.
1H-NMR (CDCl3), d (ppm)
46a, 47a
0.90 (6H, d, Jϭ7 Hz), 1.51 (1H, d, Jϭ7 Hz), 1.81 (1H, m), 2.47 (2H, d, Jϭ7 Hz), 4.88 (1H, q, Jϭ7 Hz), 7.13 (2H, d, Jϭ8 Hz), 7.28
(2H, d, Jϭ8 Hz)
46b, 47b
46c, 47c
46d, 47d
0.85—1.00 (9H, m), 1.60—1.90 (4H, m), 2.47 (2H, d, Jϭ7 Hz), 4.57 (1H, t, Jϭ7 Hz), 7.12 (2H, d, Jϭ8 Hz), 7.26 (2H, d, Jϭ8 Hz)
0.86—0.98 (9H, m), 1.16—1.97 (5H, m), 2.47 (2H, d, Jϭ7 Hz), 4.65 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.26 (2H, d, Jϭ8 Hz)
0.82—0.95 (9H, m), 1.17—1.48 (4H, m), 1.60—1.97 (3H, m), 2.47 (2H, d, Jϭ7 Hz), 4.63 (1H, t, Jϭ7 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.25 (2H, d, Jϭ8 Hz)
48a, 49a
48b, 49b
48c, 49c
48d, 49d
0.88 (6H, d, Jϭ7 Hz), 1.21 (3H, t, Jϭ7 Hz), 1.67 (3H, d, Jϭ7 Hz), 1.85 (1H, m), 2.10—2.40 (4H, m), 2.46 (2H, d, Jϭ7 Hz), 4.11 (2H,
q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.39 (1H, q, Jϭ7 Hz), 6.94 (2H, d, Jϭ9 Hz), 7.12 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H, m), 7.53 (1H,
s), 7.75 (2H, d, Jϭ9 Hz), 8.36 (1H, m)
0.89 (6H, d, Jϭ7 Hz), 1.02 (3H, t, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.70—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz), 4.09 (2H, q, Jϭ7 Hz),
4.23 (2H, t, Jϭ7 Hz), 5.09 (1H, t, Jϭ7 Hz), 6.93 (2H, d, Jϭ9 Hz), 7.12 (2H, d, Jϭ9 Hz), 7.20—7.45 (5H, m), 7.53 (1H, s), 7.74 (2H,
d, Jϭ9 Hz), 8.30—8.40 (1H, m)
0.88 (6H, d, Jϭ7 Hz), 0.97 (3H, t, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.30—2.10 (7H, m), 2.10—2.40 (4H, m), 2.45 (2H, d, Jϭ7 Hz),
4.10 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.16 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H,
m), 7.52 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.36 (1H, m)
0.89 (6H, d, Jϭ7 Hz), 0.80—0.95 (3H, m), 1.20 (3H, t, Jϭ7 Hz), 1.30—1.65 (4H, m), 1.75—2.35 (7H, m), 2.45 (2H, d, Jϭ7 Hz),
4.10 (2H, q, Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.15 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz), 7.20—7.45 (5H,
m), 7.53 (1H, s), 7.74 (2H, d, Jϭ9 Hz), 8.34 (1H, m)
Table 12. Spectral Data for Compounds 50a—d and 51a—d
Compd.
[a]2D5
ESI-MS m/z:
1H-NMR (CDCl3), d (ppm)
50a
Ϫ56.1°
(cϭ0.5, CHCl3)
496 (MϪH)Ϫ 0.90 (6H, d, Jϭ7 Hz), 1.66 (3H, d, Jϭ6 Hz), 1.84 (1H, m), 2.20 (2H, t, Jϭ7 Hz), 2.38 (2H, t, Jϭ7 Hz),
2.45 (2H, d, Jϭ7 Hz), 4.25 (2H, t, Jϭ7 Hz), 5.37 (1H, q, Jϭ6 Hz), 6.95 (2H, d, Jϭ9 Hz), 7.13 (2H, d,
Jϭ9 Hz), 7.25—7.40 (5H, m), 7.75 (2H, d, Jϭ9 Hz), 8.32 (1H, m)
50b
50c
50d
51a
51b
51c
51d
Ϫ71.2°
(cϭ0.5, CHCl3)
510 (MϪH)Ϫ 0.88 (6H, d, Jϭ7 Hz), 1.00 (3H, t, Jϭ7 Hz), 1.70—2.30 (5H, m), 2.30—2.50 (4H, m), 4.24 (2H, t,
Jϭ7 Hz), 5.09 (1H, t, Jϭ7 Hz), 6.73 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ9 Hz), 7.25—7.45 (5H, m), 7.53
(1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
Ϫ66.8°
(cϭ0.5, CHCl3)
524 (MϪH)Ϫ 0.88 (6H, d, Jϭ7 Hz), 0.96 (3H, t, Jϭ7 Hz), 1.20—2.30 (7H, m), 2.38 (2H, t, Jϭ7 Hz), 2.44 (2H, d,
Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.16 (1H, dd, Jϭ5, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.20—7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.33 (1H, m)
Ϫ59.6°
(cϭ0.5, CHCl3)
538 (MϪH)Ϫ 0.80—1.00 (9H, m), 1.25—1.60 (4H, m), 1.75—2.30 (5H, m), 2.37 (2H, d, Jϭ7 Hz), 2.43 (2H, d,
Jϭ7 Hz), 4.24 (2H, t, Jϭ7 Hz), 5.14 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.20—7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
ϩ60.3°
(cϭ0.5, CHCl3)
496 (MϪH)Ϫ 0.90 (6H, d, Jϭ7 Hz), 1.66 (3H, d, Jϭ6 Hz), 1.84 (1H, m), 2.20 (2H, t, Jϭ7 Hz), 2.38 (2H, t, Jϭ7 Hz),
2.45 (2H, d, Jϭ7 Hz), 4.25 (2H, t, Jϭ7 Hz), 5.37 (1H, q, Jϭ6 Hz), 6.95 (2H, d, Jϭ9 Hz), 7.13 (2H, d
Jϭ9 Hz), 7.25—7.40 (5H, m), 7.75 (2H, d, Jϭ9 Hz), 8.32 (1H, m)
ϩ70.2°
(cϭ0.5, CHCl3)
510 (MϪH)Ϫ 0.88 (6H, d, Jϭ7 Hz), 1.00 (3H, t, Jϭ7 Hz), 1.70—2.30 (5H, m), 2.30—2.50 (4H, m), 4.24 (2H, t,
Jϭ7 Hz), 5.09 (1H, t, Jϭ7 Hz), 6.73 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ9 Hz), 7.25—7.45 (5H, m), 7.53
(1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
ϩ65.3°
(cϭ0.5, CHCl3)
524 (MϪH)Ϫ 0.88 (6H, d, Jϭ7 Hz), 0.96 (3H, t, Jϭ7 Hz), 1.20—2.30 (7H, m), 2.38 (2H, t, Jϭ7 Hz), 2.44 (2H, d,
Jϭ7 Hz), 4.23 (2H, t, Jϭ7 Hz), 5.16 (1H, dd, Jϭ5, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.11 (2H, d, Jϭ8 Hz),
7.20—7.45 (5H, m), 7.53 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.33 (1H, m)
ϩ62.4°
(cϭ0.5, CHCl3)
538 (MϪH)Ϫ 0.80—1.00 (9H, m), 1.25—1.60 (4H, m), 1.75—2.30 (5H, m), 2.37 (2H, d, Jϭ7 Hz), 2.43 (2H, d,
Jϭ7 Hz), 4.24 (2H, t, Jϭ7 Hz), 5.14 (1H, dd, Jϭ2, 7 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.10 (2H, d, Jϭ8 Hz),
7.20—7.45 (5H, m), 7.54 (1H, s), 7.73 (2H, d, Jϭ9 Hz), 8.30—8.40 (1H, m)
Table 13. NMR Data for Compounds 54b—f
Compd.
1H-NMR (CDCl3), d (ppm)
54b
54c
0.88 (6H, d, Jϭ7 Hz), 1.01 (3H, t, Jϭ7 Hz), 1.24 (3H, t, Jϭ7 Hz), 1.72—2.17 (5H, m), 2.35—2.50 (4H, m), 2.87 (2H, t, Jϭ7 Hz),
4.12 (2H, q, Jϭ7 Hz), 5.10 (1H, t, Jϭ7 Hz), 6.79—6.97 (4H, m), 7.07—7.32 (5H, m), 7.73 (2H, d, Jϭ9 Hz), 7.96 (1H, d, Jϭ7 Hz),
8.44 (1H, d, Jϭ9 Hz)
0.80—1.05 (9H, m), 1.24 (3H, t, Jϭ7 Hz), 1.30—1.65 (2H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m), 2.87 (2H, t, Jϭ7 Hz), 4.12
(2H, q, Jϭ7 Hz), 5.17 (1H, dd, Jϭ2, 7 Hz), 6.80—6.94 (4H, m), 7.05—7.30 (5H, m), 7.72 (2H, d, Jϭ9 Hz), 7.98 (1H, d, Jϭ7 Hz),
8.44 (1H, d, Jϭ9 Hz)
54d
54e
54f
0.80—1.00 (9H, m), 1.20—1.65 (7H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 5.15
(1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H, m), 7.73 (2H, d, Jϭ9 Hz), 7.99 (1H, d, Jϭ7 Hz), 8.44 (1H, d, Jϭ9 Hz)
0.80—0.95 (9H, m), 1.26—1.65 (9H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m), 2.87 (2H, t, Jϭ7 Hz), 4.13 (2H, q, Jϭ7 Hz), 5.15
(1H, dd, Jϭ2, 7 Hz), 6.80—6.97 (4H, m), 7.07—7.31 (5H, m), 7.72 (2H, d, Jϭ9 Hz), 7.98 (1H, d, Jϭ7 Hz), 8.43 (1H, d, Jϭ9 Hz)
0.80—1.00 (9H, m), 1.20—1.65 (11H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 5.15
(1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H, m), 7.74 (2H, d, Jϭ9 Hz), 7.98 (1H, d, Jϭ7 Hz), 8.43 (1H, d, Jϭ9 Hz)

810
Vol. 49, No. 7
Table 14. Spectral Data for Compounds 55b—f
Compd.
ESI-MS m/z:
496 (MϪH)Ϫ
1H-NMR (CDCl3), d (ppm)
55b
0.88 (6H, d, Jϭ7 Hz), 1.01 (3H, t, Jϭ7 Hz), 1.72—2.17 (5H, m), 2.40—2.55 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 5.08
(1H, t, Jϭ7 Hz), 6.79—6.98 (4H, m), 7.07—7.32 (5H, m), 7.73 (2H, d, Jϭ9 Hz), 7.94 (1H, d, Jϭ7 Hz), 8.42 (1H,
d, Jϭ9 Hz)
55c
55d
55e
55f
510 (MϪH)Ϫ
524 (MϪH)Ϫ
538 (MϪH)Ϫ
552 (MϪH)Ϫ
0.80—1.05 (9H, m), 1.30—1.65 (2H, m), 1.70—2.15 (5H, m), 2.40—2.55 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 5.16
(1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H, m), 7.72 (2H, d, Jϭ9 Hz), 7.96 (1H, d, Jϭ7 Hz), 8.42
(1H, d, Jϭ9 Hz)
0.80—1.00 (9H, m), 1.20—1.65 (7H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 4.12
(2H, q, Jϭ7 Hz), 5.15 (1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H, m), 7.73 (2H, d, Jϭ9 Hz), 7.99
(1H, d, Jϭ7 Hz), 8.44 (1H, d, Jϭ9 Hz)
0.80—0.95 (9H, m), 1.23—1.65 (6H, m), 1.70—2.15 (5H, m), 2.38—2.55 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 5.14
(1H, dd, Jϭ2, 7 Hz), 6.78—6.97 (4H, m), 7.05—7.30 (5H, m), 7.72 (2H, d, Jϭ9 Hz), 7.94 (1H, d, Jϭ7 Hz), 8.43
(1H, d, Jϭ9 Hz)
0.80—1.00 (9H, m), 1.20—1.65 (8H, m), 1.70—2.15 (5H, m), 2.40—2.55 (4H, m), 2.89 (2H, t, Jϭ7 Hz), 5.15
(1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H, m), 7.73 (2H, d, Jϭ9 Hz), 7.95 (1H, d, Jϭ7 Hz), 8.43
(1H, d, Jϭ9 Hz)
7.01 (1H, dt, Jϭ2, 7 Hz), 7.16 (1H, m), 7.29 (1H, t, Jϭ8 Hz), 7.60—7.90
(3H, m), 9.92 (1H, dt, Jϭ7, 2 Hz).
d, Jϭ9 Hz), 9.59 (1H, d, Jϭ9 Hz). ESI-MS m/z: 600 (MϪH)Ϫ.
4-[N-(2-Pyridylmethyl)carbamoyl]butyric Acid (20) To a solution of
Ethyl 4-[1-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]indolizin- 2-(aminomethyl)pyridine (1.74 g, 15.9 mmol) in pyridine (5 ml) was added
3-yl]butyrate (14) To a solution of 11 (320 mg, 0.913 mmol) in CH2Cl2
(10 ml) were added chlorobis(4-isobutylphenyl)methane (340 mg, 1.07 mmol)
glutaric anhydride (1.84 g, 16.1 mmol) at r.t., and the mixture was stirred for
2 h. The resulting solid was treated with CH2Cl2 and the crystals were fil-
and iso-Pr2NEt (0.22 ml) at r.t. After being stirred overnight at r.t., the reac- tered to give 20 (3.38 g, 95.8%). 1H-NMR (DMSO-d6) d: 1.55 (2H, m),
tion mixture was evaporated and the residue was partitioned between ether 2.15—2.30 (4H, m), 4.32 (2H, d, Jϭ6 Hz), 7.15—7.30 (2H, m), 7.75 (1H,
and 0.1 N HCl. The organic layer was washed with water and brine, then dt, Jϭ2, 8 Hz), 8.35—8.55 (2H, m).
dried over Na2SO4. After evaporation of the solvent, the residue was chro-
Ethyl 4-[N-(2-Pyridylmethyl)carbamoyl]butyrate (21) Following the
matographed on silica gel (CH2Cl2 : EtOAcϭ20 : 1) to give 14 (279 mg, procedure described above for 6, 21 (3.22 g, 84.7%) was prepared from 20
1
1
48.6%) as a pale yellow amorphous solid. H-NMR (CDCl3) d: 0.92 (12H,
(3.38 g). H-NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 2.01 (2H, m), 2.30—
d, Jϭ7 Hz), 1.28 (3H, t, Jϭ7 Hz), 1.87 (2H, m), 2.08 (2H, m), 2.40—2.55
2.50 (4H, m), 4.13 (2H, q, Jϭ7 Hz), 4.59 (2H, d, Jϭ2 Hz), 6.95 (1H, m),
(6H, m), 2.88 (2H, t, Jϭ7 Hz), 4.25 (2H, q, Jϭ7 Hz), 5.56 (1H, s), 6.70 (1H, 7.20—7.40 (2H, m), 7.75 (1H, dt, Jϭ1, 7 Hz), 8.57 (1H, m).
m), 6.86 (1H, s), 6.90 (1H, dt, Jϭ1, 7 Hz), 7.00—7.40 (12H, m), 8.02 (1H,
d, Jϭ7 Hz), 8.50 (1H, d, Jϭ9 Hz).
Ethyl 4-[3-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]indolizin-1-
Ethyl 4-(Imidazo[1,5-a]pyridin-3-yl)butyrate (22) A mixture of 21
(692 mg, 2.76 mmol) and POCl3 (1.4 ml) in benzene (5 ml) was refluxed for
5 h. The reaction was quenched by the addition of the water, and the mixture
yl]butyrate (15) Yield: 48.0%. 1H-NMR (CDCl3) d: 0.87 (12H, d, was made basic by sat. NaHCO3 and extracted with ether. The extract was
Jϭ7 Hz), 1.22 (3H, t, Jϭ7 Hz), 1.70—2.05 (4H, m), 2.32 (2H, t, Jϭ7 Hz), washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue
2.43 (4H, d, Jϭ7 Hz), 2.73 (2H, t, Jϭ7 Hz), 4.10 (2H, q, Jϭ7 Hz), 5.52 (1H, was chromatographed on silica gel (EtOAc) to give 22 (638 mg, 93.9%). 1H-
s), 6.68 (1H, m), 6.88 (1H, dt, Jϭ2, 7 Hz), 7.00—7.30 (13H, m), 7.52 (1H, NMR (CDCl3) d: 1.25 (3H, t, Jϭ7 Hz), 2.26 (2H, m), 2.48 (2H, t, Jϭ7 Hz),
dt, Jϭ8, 2 Hz), 9.92 (1H, d, Jϭ7 Hz).
3.11 (2H, t, Jϭ7 Hz), 4.14 (2H, q, Jϭ7 Hz), 6.55—6.80 (2H, m), 7.48 (1H,
s), 7.43 (1H, dt, Jϭ9, 2 Hz), 7.88 (1H, dd, Jϭ2, 7 Hz).
Ethyl 4-[1-(3-Nitrobenzoyl)imidazo[1,5-a]pyridin-3-yl]butyrate (23)
Following the procedure described above for 8, 23 (240 mg, 38.4%) was pre-
Ethyl 4-[3-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]imidazo-
[1,5-a]pyridin-1-yl]butyrate (16) Yield: 46.0%. 1H-NMR (CDCl3) d:
0.85 (12H, d, Jϭ7 Hz), 1.20 (3H, t, Jϭ7 Hz), 1.81 (2H, m), 2.03 (2H, m),
2.32 (2H, t, Jϭ7 Hz), 2.41 (4H, d, Jϭ7 Hz), 3.04 (2H, t, Jϭ7 Hz), 4.08 (2H, pared from 22 (405 mg). 1H-NMR (CDCl3) d: 1.27 (3H, t, Jϭ7 Hz), 2.24
q, Jϭ7 Hz ), 5.51 (1H, s), 6.80—7.20 (4H, m), 7.06 (4H, d, Jϭ8 Hz), 7.28 (2H, m), 2.59 (2H, t, Jϭ7 Hz), 3.14 (2H, t, Jϭ7 Hz), 4.16 (2H, q, Jϭ7 Hz),
(4H, d, Jϭ8 Hz), 7.43 (1H, t, Jϭ9 Hz), 7.52 (1H, t, Jϭ9 Hz), 7.79 (1H, t, 6.99 (1H, dt, Jϭ2, 7 Hz), 7.32 (1H, m), 7.68 (1H, t, Jϭ8 Hz), 8.16 (1H, m),
Jϭ9 Hz), 7.92 (1H, s), 8.43 (1H, d, Jϭ9 Hz), 9.60 (1H, d, Jϭ9 Hz).
4-[1-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]indolizin-3-
yl]butyric Acid (17) To a solution of 14 (279 mg, 0.443 mmol) in EtOH
(10 ml) was added 4 N NaOH (0.44 ml). After being stirred at 40 °C for 1 h,
8.38 (1H, m), 8.55 (1H, dt, Jϭ2, 8 Hz), 8.72 (1H, m), 9.43 (1H, m).
3-(3-Nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridine (24) Following the pro-
cedure described above for 8, 24 (430 mg, 19.0%) was prepared from 1H-
pyrrolo[2,3-b]pyridine (1.0 g) and 3-nitrobenzoyl chloride (1.88 g). 1H-NMR
the reaction mixture was evaporated in vacuo, then an aq. solution of (DMSO-d6) d: 7.36 (1H, dd, Jϭ5, 8 Hz), 7.87 (1H, t, Jϭ7 Hz), 8.26 (1H, d,
KH2PO4 (300 mg) and 1 N HCl (26 ml) were added. The mixture was ex-
tracted with EtOAc and the extract was dried over Na2SO4. After evapora-
Jϭ7 Hz), 8.35—8.66 (5H, m).
Ethyl 4-[3-(3-Nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]butyrate (25)
tion of the solvent, the residue was chromatographed on silica gel (EtOAc) A mixture of 24 (400 mg, 1.43 mmol), ethyl 4-bromobutyrate (0.257 ml,
to give 17 (229 mg, 86.0%). 1H-NMR CDCl3) d: 0.87 (12H, d, Jϭ7 Hz), 1.80 mmol) and K2CO3 (620 mg, 4.49 mmol) in DMF (10 ml) was stirred at
1.83 (2H, m), 2.22 (2H, m), 2.40—2.50 (6H, m), 2.85 (2H, t, Jϭ7 Hz), 5.51 50 °C for 4 h. The reaction mixture was partitioned between EtOAc and
(1H, s), 6.69 (1H, m), 6.82 (1H, s), 6.84 (1H, dt, Jϭ1, 7 Hz), 7.00—7.30
water. The organic layer was washed with water and brine, dried over
(12H, m), 7.94 (1H, d, Jϭ7 Hz), 8.46 (1H, d, Jϭ9 Hz). Electrospray ioniza- MgSO4 and evaporated in vacuo. The residue was chromatographed on silica
tion (ESI)-MS m/z: 599 (MϪH)Ϫ.
4-[3-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]indolizin-1-
gel (EtOAc : hexaneϭ1 : 4) to give 25 (480 mg, 83.9%). 1H-NMR (CDCl3) d:
1.20 (3H, t, Jϭ8 Hz), 2.20—2.44 (2H, m), 2.38 (2H, t, Jϭ8 Hz), 4.08 (2H,
yl]butyric Acid (18) Yield: 86.0%. 1H-NMR (CDCl3) d: 0.86 (12H, d, q, Jϭ8 Hz), 4.48 (2H, t, Jϭ8 Hz), 7.35 (1H, dd, Jϭ5, 8 Hz), 7.73 (1H, s),
Jϭ7 Hz), 1.70—2.05 (4H, m), 2.38 (2H, t, Jϭ7 Hz), 2.43 (4H, d, Jϭ7 Hz), 7.74 (1H, t, Jϭ7 Hz), 8.18 (1H, dd, Jϭ1, 7 Hz), 8.40—8.52 (2H, m) , 8.65—
2.76 (2H, t, Jϭ7 Hz), 5.52 (1H, s), 6.71 (1H, m), 6.88 (1H, dt, Jϭ2, 7 Hz), 8.72 (2H, m).
7.00—7.30 (13H, m), 7.49 (1H, dt, Jϭ8, 2 Hz), 9.91 (1H, d, Jϭ7 Hz). ESI-
4-[1-(3-Nitrobenzoyl)imidazo[1,5-a]pyridin-3-yl]butyric Acid (26)
To a solution of 23 (719 mg, 1.89 mmol) in EtOH (10 ml) was added 4 N
MS m/z: 599 (MϪH)Ϫ.
4-[3-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]imidazo[1,5- NaOH (1.9 ml). After being refluxed for 40 min, the reaction mixture was
a]pyridin-1-yl]butyric Acid (19) Yield: 73.3%. 1H-NMR (CDCl3) d: 0.85
(12H, d, Jϭ7 Hz), 1.82 (2H, m), 2.05 (2H, m), 2.40 (2H, t, Jϭ7 Hz), 2.42
evaporated in vacuo, and the resulting aqueous solution was made acidic
with sat. KH2PO4. The mixture was extracted with EtOAc and the extract
(4H, d, Jϭ7 Hz), 3.06 (2H, t, Jϭ7 Hz), 5.51 (1H, s), 6.68 (1H, m), 7.08 (4H, was washed with brine, then dried over Na2SO4. Evaporation of the solvent
1
d, Jϭ8 Hz), 7.10—7.30 (3H, m), 7.25 (4H, d, Jϭ7 Hz), 7.42 (1H, t, gave 26 (638 mg, 95.8%). H-NMR (DMSO-d6) d: 2.05 (2H, m), 2.48 (2H,
Jϭ9 Hz), 7.51 (1H, t, Jϭ9 Hz), 7.78 (1H, t, Jϭ9 Hz), 7.92 (1H, s), 8.41 (1H, t, Jϭ7 Hz), 3.13 (2H, t, Jϭ7 Hz), 7.17 (1H, dt, Jϭ2, 7 Hz), 7.52 (1H, dd,

July 2001
811
procedure described above for 26, 37a (1.28 g, 86.0%) was prepared from
36a (1.60 g). 1H-NMR (CD3Cl : CD3ODϭ1 : 1) d: 2.10 (2H, m), 2.35 (2H, t,
Jϭ7 Hz), 4.30 (2H, t, Jϭ7 Hz), 7.30—7.55 (3H, m), 7.60 (1H, s), 7.72 (1H,
t, Jϭ8 Hz), 8.16 (1H, dd, Jϭ2, 8 Hz), 8.31—8.48 (2H, m), 8.65 (1H, d,
Jϭ2 Hz).
4-[3-(4-Nitrobenzoyl)-1H-indol-1-yl]butyric Acid (37b) Yield: 93.2%.
1H-NMR (CD3Cl : CD3ODϭ1 : 1) d: 1.80—2.00 (2H, m), 2.15 (2H, t,
Jϭ7 Hz), 4.12 (2H, t, Jϭ7 Hz), 7.10—7.25 (2H, m), 7.45—7.55 (1H, m),
7.81 (1H, s), 7.85 (2H, d, Jϭ8 Hz), 8.10—8.15 (1H, m), 8.18 (2H, d,
Jϭ8 Hz).
Jϭ7, 9 Hz), 7.84 (1H, t, Jϭ8 Hz), 8.30—8.50 (2H, m), 8.59 (1H, d,
Jϭ7 Hz), 8.78 (1H, m) , 9.28 (1H, m).
4-[3-(3-Nitrobenzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]butyric Acid (27)
Yield: 98.9%. 1H-NMR (DMSO-d6) d: 2.00—2.40 (2H, m), 2.26 (2H, t,
Jϭ8 Hz), 4.38 (2H, t, Jϭ8 Hz), 7.38 (1H, dd, Jϭ5, 8 Hz), 7.88 (1H, t,
Jϭ8 Hz), 8.28 (1H, dd, Jϭ2, 8 Hz), 8.42 (1H, s), 8.44—8.56 (3H, m), 8.58
(1H, dd, Jϭ2, 8 Hz).
4-[1-(3-Aminobenzoyl)imidazo[1,5-a]pyridin-3-yl]butyric Acid (28)
Following the procedure described above for 11, 28 (86 mg, 100%) was pre-
1
pared from 26 (93 mg). H-NMR (CDCl3 : CD3ODϭ1 : 1) d: 2.23 (2H, m),
4-[3-(3-Aminobenzoyl)-1H-indol-1-yl]butyric Acid (38a) Following
the procedure described above for 11, 38a (982 mg, 89.0%) was prepared
from 37a (1.20 g). 1H-NMR (CDCl3 : CD3ODϭ1 : 1) d: 2.15—2.45 (4H, m),
4.32 (2H, t, Jϭ7 Hz), 6.97 (1H, m), 7.15—7.60 (6H, m), 7.72 (1H, s), 8.45
(1H, m).
4-[3-(4-Aminobenzoyl)-1H-indol-1-yl]butyric Acid (38b) Yield:
71.2%. 1H-NMR (CDCl3 : CD3ODϭ1 : 1) d: 2.20 (2H, quintet, Jϭ7 Hz),
2.33 (2H, t, Jϭ7 Hz), 4.36 (2H, t, Jϭ7 Hz), 6.75 (2H, d, Jϭ8 Hz), 7.20—
7.40 (2H, m), 7.50 (1H, dd, Jϭ2, 8 Hz), 7.65—7.80 (1H, m), 7.70 (2H, d,
Jϭ8 Hz), 8.25 (1H, dd, Jϭ2, 8 Hz).
4-[3-[3-[[1-(4-Isobutylphenyl)ethyl]amino]benzoyl]-1H-indol-1-yl]bu-
tyric Acid (39) Following the procedure described above for 30, 39
(420 mg, 43.5%) was prepared from 38a (600 mg). 1H-NMR (CDCl3) d:
0.90 (6H, d, Jϭ7 Hz), 1.51 (3H, d, Jϭ7 Hz), 1.70—2.00 (1H, m), 2.10—
2.30 (2H, m), 2.35 (1H, m), 2.43 (2H, d, Jϭ7 Hz), 4.20 (2H, m), 4.52 (1H, q,
Jϭ7 Hz), 6.67 (1H, d, Jϭ8 Hz), 7.00—7.40 (10H, m), 7.45 (1H, s), 8.43
(1H, m). ESI-MS m/z: 495 (MϪH).
4-[3-[4-[[1-(4-Isobutylphenyl)ethyl]amino]benzoyl]-1H-indol-1-yl]bu-
tyric Acid (40) Yield: 33.3%. 1H-NMR (CDCl3) d: 0.87 (6H, d, Jϭ7 Hz),
1.60 (3H, d, Jϭ7 Hz), 1.70—2.00 (1H, m), 2.35 (2H, m), 2.45 (2H, d,
Jϭ7 Hz), 4.23 (2H, m), 4.56 (1H, q, Jϭ7 Hz), 6.50—6.70 (2H, m), 7.10
(2H, d, Jϭ8 Hz), 7.20—7.50 (5H, m), 7.51 (1H, s), 7.70 (2H, d, Jϭ8 Hz),
8.30 (1H, m). ESI-MS m/z: 495 (MϪH)Ϫ.
3-(4-Methoxybenzoyl)-1H-indole (41) Following the procedure de-
scribed above for 8, 41 (8.38 g, 78.4%) was prepared from indole (5.0 g) and
4-methoxybenzoyl chloride (7.29 g). mp 203—205 °C. 1H-NMR (CDCl3) d:
3.70 (2H, s), 6.93 (2H, d, Jϭ8 Hz), 7.00—7.19 (2H, m), 7.30—7.44 (1H,
m), 7.67 (2H, d, Jϭ8 Hz), 7.31 (1H, s), 8.02—8.15 (1H, m).
Ethyl 4-[3-(4-Methoxybenzoyl)-1H-indol-1-yl]butyrate (42) A mix-
ture of 41 (4.0 g, 15.9 mmol), ethyl 4-bromobutyrate (3.42 g, 17.5 mmol) and
K2CO3 (6.60 g, 47.8 mmol) in DMF (60 ml) was stirred at 20 °C for 14 h.
The mixture was partitioned between EtOAc and 1 N HCl, and the organic
layer was washed with water and brine, then dried over MgSO4. After evapo-
ration of the solvent, the residue was chromatographed on silica gel (CHCl3)
to give 42 (5.81 g, 100%) as an orange oil. 1H-NMR (CDCl3) d: 1.20 (3H, t,
Jϭ7 Hz), 2.08—2.38 (4H, m), 3.38 (3H, s), 4.10 (2H, q, Jϭ7 Hz), 4.23 (2H,
t, Jϭ7 Hz), 6.99 (2H, d, Jϭ8 Hz), 7.28—7.48 (3H, m), 7.58 (1H, s), 7.85
(2H, d, Jϭ8 Hz), 8.32—8.45 (1H, m).
2.56 (2H, t, Jϭ7 Hz), 3.13 (2H, t, Jϭ7 Hz), 6.96 (1H, m), 7.05—7.50 (3H,
m), 7.80 (1H, m), 7.92 (1H, m), 8.13 (1H, m), 8.42 (1H, d, Jϭ9 Hz).
4-[3-(3-Aminobenzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]butyric Acid (29)
Yield: 100%. 1H-NMR (CDCl3 : CD3ODϭ1 : 1) d: 2.20—2.32 (2H, m), 2.38
(2H, t, Jϭ8 Hz), 4.42 (2H, t, Jϭ8 Hz), 6.90—7.40 (5H, m), 7.86 (1H, s),
8.40 (1H, dd, Jϭ1, 5 Hz), 8.65 (1H, dd, Jϭ1, 8 Hz).
4-[1-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]imidazo[1,5-
a]pyridin-3-yl]butyric Acid (30) To a solution of 28 (93 mg, 0.288 mmol)
in CH2Cl2 (6 ml) were added chlorobis(4-isobutyphenyl)methane (109 mg,
0.35 mmol) and iso-Pr2NEt (0.12 ml) at r.t. After stirring overnight at r.t., the
reaction mixture was evaporated and partitioned between EtOAc and 0.1 N
HCl. The organic layer was washed with water and brine, and dried over
Na2SO4. After evaporation of the solvent, the residue was purified by thin
layer silica gel chromatography (EtOAc) to give 30 (77 mg, 44.5%). 1H-
NMR (CDCl3) d: 0.84 (12H, d, Jϭ7 Hz), 1.81 (2H, m), 2.18 (2H, m), 2.52
(4H, d, Jϭ7 Hz), 2.54 (2H, t, Jϭ7 Hz), 3.10 (2H, t, Jϭ7 Hz), 5.52 (1H, s),
6.70—6.90 (2H, m), 7.00—7.85 (10H, m), 7.60—7.70 (2H, m), 7.98 (1H, d,
Jϭ7 Hz), 8.40 (1H, d, J ϭ8 Hz). ESI-MS m/z: 600 (MϪH)Ϫ.
4-[3-[3-[[Bis(4-isobutylphenyl)methyl]amino]benzoyl]-1H-pyrrolo[2,3-
b]pyridin-1-yl]butyric Acid (31) Yield: 54.4%. 1H-NMR (CDCl3) d: 0.87
(12H, d, Jϭ8 Hz), 1.72—1.95 (2H, m), 2.14—2.28 (2H, m), 2.38 (2H, d,
Jϭ8 Hz), 2.42 (4H, d, Jϭ8 Hz), 4.36 (2H, t, Jϭ8 Hz), 5.51 (1H, s), 6.74 (1H,
dd, Jϭ2, 8 Hz), 7.00—7.34 (12H, m), 7.60 (1H, s), 8.40 (1H, dd, Jϭ2,
5 Hz), 8.68 (1H, dd, Jϭ2, 8 Hz). ESI-MS m/z: 600 (MϪH)Ϫ.
4-Isobutylacetophenone (32a) Acetyl chloride (6.43 g, 81.9 mmol) was
added to a suspension of AlCl3 (10.9 g, 81.9 mmol) in CH2Cl2 (100 ml) at
0 °C. After the mixture was stirred at 0 °C for 30 min, isobutylbenzene (10 g,
74.6 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the mixture was
poured into a mixture of CH2Cl2 and ice water. The organic layer was sepa-
rated, washed with water and brine, and dried over MgSO4. After evapora-
tion of the solvent, the residue was distilled (96 °C/0.8 mmHg) to give 32a
(12.1 g, 92.1%) as an oil.
1-(4-isobutylphenyl)-1-ethanol (33a) NaBH4 (2.58 g, 68.3 mmol) was
added to a solution of 32a (10 g, 56.8 mmol) in methanol (100 ml) at 0 °C.
The mixture was stirred for 1 h at r.t. and poured into ice water. The mixture
was acidified with 6 N HCl to pH 3 and extracted with ether. The extract was
washed with water and brine, then dried over MgSO4. Evaporation of the
solvent afforded 33a (10.1 g, 99.9%) as a colorless oil.
Ethyl 4-[3-(4-Hydroxybenzoyl)-1H-indol-1-yl]butyrate (43) AlCl3
(3.29 g, 24.7 mmol) was added to a solution of 42 (3.0 g, 8.21 mmol) in a
mixture of CH2Cl2 (10 ml) and ethanethiol (10 ml) at 0 °C. After being
stirred at 20 °C for 1 h, the mixture was cooled to 0 °C, and AlCl3 (1.64 g,
12.3 mmol) and ethanethiol (5 ml) were added. The mixture was stirred at
20 °C for 30 min and evaporated in vacuo. 1 N HCl was added to the residue
and the mixture was extracted with EtOAc 2 times. The extracts were com-
bined, washed with water and brine, and dried over MgSO4. After evapora-
tion of the solvent, the residue was crystallized (EtOAc–hexane) to obtain 43
(2.41 g, 83.5%) as colorless crystals, mp 129—131 °C. 1H-NMR (CDCl3) d:
1.20 (3H, t, Jϭ7 Hz), 2.08—2.40 (4H, m), 4.10 (2H, q, Jϭ7 Hz), 4.25 (2H,
t, Jϭ7 Hz), 6.91 (2H, d, Jϭ8 Hz), 7.25—7.50 (3H, m), 7.60 (1H, s), 7.75
(2H, d, Jϭ8 Hz), 8.30—8.42 (1H, m).
Ethyl (؎)-4-[3-[4-[[1-(4-Isobutylphenyl)ethyl]oxy]benzoyl]-1H-indol-
1-yl]butyrate (44a) A mixture of 43 (0.50 g, 1.42 mmol), 34a (0.35 g,
1.57 mmol) and K2CO3 (0.59 g, 4.27 mmol) in DMF (10 ml) was stirred
overnight at r.t. The precipitates were filtered off and the filtrate was evapo-
rated in vacuo. The residue was partitioned between EtOAc and 0.5 N HCl,
and the organic layer was washed with water and brine, and dried over
MgSO4. After evaporation of the solvent, the residue was purified by silica
gel column chromatography (EtOAc : hexaneϭ1 : 4) to give 44a (520 mg,
71.4%) as an oil.
1-Bromo-1-(4-isobutylphenyl)ethane (34a) To a mixture of 33a (20.2
g, 113 mmol) and CBr4 (75.25 g, 227 mmol) in THF (250 ml) was added
PPh3 (59.5 g, 227 mmol) at 0 °C, and the mixture was stirred at r.t. for 5 h.
The precipitate was removed by filtration and the filtrate was evaporated in
vacuo. The residue was triturated with hexane and the precipitate was fil-
tered off. The filtrate was evaporated in vacuo and the residue was distilled
(77—80 °C/0.3 mmHg) to give 34a (17.4 g, 63.7%) as a colorless oil.
3-(3-Nitrobenzoyl)-1H-indole (35a) Following the procedure described
1
above for 8, 35a (495 mg, 43.6%) was prepared from indole (500 mg). H-
NMR (CDCl3 : CD3ODϭ1 : 1) d: 7.21—7.35 (2H, m), 7.42—7.55 (1H, m),
7.68—7.79 (2H, m), 8.13 (1H, dd, Jϭ1, 8 Hz), 8.24—8.35 (1H, m), 8.40
(1H, dd, Jϭ1, 8 Hz).
3-(4-Nitrobenzoyl)-1H-indole (35b) Yield: 34.3%. 1H-NMR (CDCl3 :
CD3ODϭ1 : 1) d: 7.20—7.45 (2H, m), 7.50—7.60 (2H, m), 7.72 (2H, d,
Jϭ8 Hz), 8.20—8.30 (1H, m), 8.31 (2H, d, Jϭ8 Hz).
Ethyl 4-[3-(3-Nitrobenzoyl)-1H-indol-1-yl]butyrate (36a) Following
the procedure described above for 25, 36a (630 mg, 90.0%) was prepared
1
from 35a (490 mg). H-NMR (CDCl3) d: 1.20 (3H, t, Jϭ7 Hz), 2.12—2.40
(4H, m), 4.10 (2H, q, Jϭ7 Hz), 4.30 (2H, t, Jϭ7 Hz), 7.30—7.50 (3H, m),
7.58 (1H, s), 7.70 (1H, t, Jϭ8 Hz), 8.27 (1H, dd, Jϭ1, 8 Hz), 8.35—8.48
(2H, m), 8.68 (1H, d, Jϭ1 Hz).
Ethyl 4-[3-(4-Nitrobenzoyl)-1H-indol-1-yl]butyrate (36b) Yield:
83.9%. 1H-NMR (CDCl3) d: 1.20 (3H, t, Jϭ7 Hz), 2.20—2.40 (4H, m), 4.10
(2H, q, Jϭ7 Hz), 4.27 (2H, t, Jϭ7 Hz), 7.35—7.50 (3H, m), 7.52 (1H, s),
7.95 (1H, t, Jϭ8 Hz), 8.35 (2H, d, Jϭ8 Hz), 8.40—8.50 (1H, m).
4-[3-(3-Nitrobenzoyl)-1H-indol-1-yl]butyric Acid (37a) Following the
(؎)-4-[3-[4-[[1-(4-Isobutylphenyl)ethyl]oxy]benzoyl-1H-indol-1-yl]bu-
tyric Acid (45a) To a solution of 44a (500 mg, 0.949 mmol) in THF (3 ml)
were added 1 N NaOH (1.5 ml) and MeOH (1.5 ml), and the mixture was
stirred at r.t. for 4 h. The mixture was diluted with water and washed with

812
Vol. 49, No. 7
1
ether. The aqueous layer was acidified with 1 N HCl and extracted with
EtOAc. The extract was washed with water and brine, dried over MgSO4,
and evaporated in vacuo. The residue was purified by silica gel chro-
matograpy with 5% MeOH in CHCl3 to give 45a (466 mg, 98.6%) as an oil.
yl]butyrate (58) Yield: 60.5% as an oil. H-NMR (CDCl3) d: 0.80—1.05
(9H, m), 1.24 (3H, t, Jϭ7 Hz), 1.30—1.65 (2H, m), 1.70—2.15 (5H, m),
2.35—2.50 (4H, m), 2.87 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 5.17 (1H,
dd, Jϭ2, 7 Hz), 6.80—6.94 (4H, m), 7.05—7.30 (5H, m), 7.72 (2H, d,
Jϭ9 Hz), 7.98 (1H, d, Jϭ7 Hz), 8.44 (1H, d, Jϭ9 Hz).
(R)-1-(4-Isobutylphenyl)ethanol (46a)
A solution of 32a (1.86 g,
10.6 mmol) in THF was added to a solution of (ϩ)-DIP-chloride (3.90 g,
12.1 mmol) in THF (8 ml) at Ϫ20 °C. After being stirred at the same temper-
ature for 3.5 h, the mixture was quenched by acetaldehyde (0.2 ml) and evap-
orated in vacuo. The residue was dissolved in ether (40 ml), and di-
ethanolamine (2.5 ml) was added to the solution, then the mixture was
stirred for 2 h. The precipitates were filtered and washed with ether. The fil-
trate and washings were combined and evaporated, and the residue was chro-
matographed on silica gel (CH2Cl2) to give 46a (616 mg, 39.0%).
[a]2D2ϭϩ27.8° (cϭ1, MeOH).
(S)-4-[1-[4-[[1-(4-Isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]bu-
tyric Acid (FK687) Following the procedure described above for 45a,
FK687 (36.1 g, 75.9%, 97.6 ee)14) was prepared from 57 (48.6 g) as a pow-
der, mp 94.5—96.5 °C. 1H-NMR (CDCl3) d: 0.80—1.05 (9H, m), 1.30—
1.65 (2H, m), 1.70—2.15 (5H, m), 2.40—2.55 (4H, m), 2.88 (2H, t,
Jϭ7 Hz), 5.16 (1H, dd, Jϭ2, 7 Hz), 6.80—6.95 (4H, m), 7.05—7.30 (5H,
m), 7.72 (2H, d, Jϭ9 Hz), 7.96 (1H, d, Jϭ7 Hz), 8.42 (1H, d, Jϭ9 Hz). [a]2D5
Ϫ82.8° (cϭ1.0, CHCl3). ESI-MS m/z: 524 (MϪH)Ϫ.
(R)-4-[1-[4-[[1-(4-Isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]bu-
1
tyric Acid (59) Yield: 84.1%, 96.0% ee14) as a powder. H-NMR (CDCl3)
(S)-1-(4-Isobutylphenyl)ethanol (47a) Following the procedure de-
scribed above for 46a, 47a (1.69 g, 84.0%) was prepared from 4-isobutylace-
tophenone (2.0 g, 11.4 mmol) and (Ϫ)-DIP-chloride (4.39 g, 13.7 mmol) as
an oil. [a]2D2ϭϪ30.6° (cϭ1, MeOH). (Ref. [a]2D0ϭϪ30° (cϭ1, MeOH)).15)
Ethyl (S)-4-[3-[4-[[1-(4-Isobutylphenyl)ethyl]oxy]benzoyl-1H-indol-1-
yl]butyrate (48a) To a mixture of 43 (375 mg, 1.03 mmol), 46a (200 mg,
1.12 mmol) and triphenylphosphine (294 mg, 1.12 mmol), in a mixture of
THF (2 ml) and toluene (8 ml), was added diethyl azodicarboxylate (DEAD)
(0.177 ml, 1.12 mmol) at Ϫ20 °C under N2. The mixture was stirred at
Ϫ20 °C for 1 h and AcOH (0.05 ml) was added. The mixture was warmed up
to 20 °C and the solvent was evaporated off. The residue was partitioned be-
tween EtOAc and water and the organic layer was washed with water and
brine, dried over MgSO4, and evaporated. The residue was chromatographed
on silica gel (EtOAc : hexaneϭ1 : 2) to give 48a (349 mg, 63.7%) as an oil.
(S)-4-[3-[4-[[1-(4-Isobutylphenyl)ethyl]oxy]benzoyl-1H-indol-1-yl]bu-
tyric Acid (49a) Following the procedure described above for 45a, 50a
(270 mg, 83.0%, 87.1% ee)14) was prepared from 48a (345 mg) as a powder.
Ethyl 4-[1-(4-Acetoxybenzoyl)indolizin-3-yl]butyrate (52) 4-Ace-
toxybenzoyl chloride (53.6 g, 269 mmol) was added to a suspension of AlCl3
(36.5 g, 723 mmol) in CH2Cl2 (500 ml). After the mixture was stirred for
20 min at r.t., a solution of 3 (57.8 g, 250 mmol) in CH2Cl2 (50 ml) was
added. The mixture was stirred for 2 h at r.t., and the solvent was evaporated
off. The residue was partitioned between EtOAc and water. The organic
layer was separated and 3-(dimethylamino)propylamine (20 ml) was added.
The mixture was stirred for 15 min and washed with 1 N HCl, water, sat.
NaHCO3, and brine, successively, and dried over MgSO4. After evaporation
of the solvent, the crystalline residue was washed with diisopropyl ether
d: 0.80—1.05 (9H, m), 1.30—1.65 (2H, m), 1.70—2.15 (5H, m), 2.40—
2.55 (4H, m), 2.88 (2H, t, Jϭ7 Hz), 5.16 (1H, dd, Jϭ2, 7 Hz), 6.80—6.95
(4H, m), 7.05—7.30 (5H, m), 7.72 (2H, d, Jϭ9 Hz), 7.96 (1H, d, Jϭ7 Hz),
8.42 (1H, d, Jϭ9 Hz). [a]2D5 ϩ79.8° (cϭ0.5, CHCl3). ESI-MS m/z: 524
(MϪH)Ϫ.
Biological Data Preparation of Prostatic Enzyme: Rat ventral prostates,
removed from 10—20 week old male Wistar rats, dissected free of their cap-
sules, were washed with saline, and stored at Ϫ80 °C. Human prostatic tis-
sues from BPH patients who received transurethral prostatectomy were
kindly provided by Dr M. Tachibana at Keio University Hospital, and stored
at Ϫ80 °C. Prostatic enzyme fractions were prepared as previously described
in the literature.16) Frozen tissues were thawed on ice and minced with scis-
sors. Unless specified, all of the following procedures were carried out at
4 °C. The tissues were homogenized with a Polytron homogenizer in 3—4
tissue volumes of medium A (0.32 M sucrose, 0.1 mM dithiothreitol (DTT),
and 20 mM sodium phosphate buffer, pH 6.5). The homogenates were cen-
trifuged at 1500 g for 20 min, and the nuclear membrane fractions were pre-
cipitated. The pellets were then resuspended in medium A and filtered with
gauze. The suspension (3—10 mg/ml) was stored at Ϫ80 °C until use.
5a-Reductase Assay: 5a-Reductase activities were assayed as previously
described in the literature.17) The reaction mixture contained in a final vol-
ume of 200 ml: 1 mM DTT, 40 mM of sodium phosphate buffer, 0.1 mM
NADPH, 2 nM [1,2,6,7-3H]T, and the rat prostatic enzyme fraction. The
amount of the prostatic enzyme fraction was adjusted to set the rate of con-
version of T into DHT at around 30% at pH 6.5. The reaction, in duplicate,
was started by adding the enzyme fraction, followed by incubation at 37 °C
for 60 min, and stopped by mixing it with 200—300 ml of ethyl acetate con-
taining cold 500 mg/ml T and 300 mg/ml of DHT as UV markers (245 nm for
T, 305 nm for DHT). 50 ml of ethyl acetate was spotted on Kieselgel 60 F254
plates, and T and DHT were chromatographed using ethyl acetate: cyclo-
hexane (1 : 1) as the developing solvent. The plate was air dried, sprayed
with primuline solution (10 mg/400 ml in acetone: water (4 : 1)), and the T
and DHT were located under UV light. Androgen containing areas were cut
and the strips soaked in 5 ml of aquasol-2. Radioactivities were counted in a
scintillation counter.
1
(IPE) to give 52 (36.5 g, 37.2%) as a yellow powder. H-NMR (CDCl3) d:
1.25 (3H, t, Jϭ7 Hz), 2.00—2.20 (2H, m), 2.35 (3H, s), 2.43 (2H, t,
Jϭ7 Hz), 2.90 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 6.85—7.00 (2H, m),
7.15—7.30 (1H, m), 7.25 (2H, d, Jϭ8 Hz), 7.88 (2H, d, Jϭ8 Hz), 8.03 (1H,
d, Jϭ7 Hz), 8.52 (1H, d, Jϭ9 Hz).
Ethyl 4-[1-(4-Hydroxybenzoyl)indolizin-3-yl]butyrate (53) NaH (60%
dispersion in mineral oil, 4.38 g, 110 mmol) was added to an ice cooled solu-
tion of 52 (36.1 g, 91.9 mmol) in a mixture of EtOH (200 ml) and THF
(200 ml). The mixture was stirred for 20 min at 0 °C and the solvent was
evaporated off. The residue was poured into a mixture of dil. HCl and ice,
then extracted with 10% MeOH in CHCl3. The extract was washed with sat.
NaHCO3 and brine, then dried over MgSO4. After evaporation of the sol-
vent, the crystalline residue was washed with EtOAc and ether to give 53
(29.3 g, 90.9%) as a yellow powder. 1H-NMR (CDCl3) d: 1.25 (3H, t,
Jϭ7 Hz), 2.00—2.20 (2H, m), 2.45 (2H, t, Jϭ7 Hz), 2.89 (2H, t, Jϭ7 Hz),
4.15 (2H, q, Jϭ7 Hz), 6.80—7.00 (4H, m), 7.18 (1H, t, Jϭ9 Hz), 7.78 (2H,
d, Jϭ8.5 Hz), 8.00 (1H, d, Jϭ5.5 Hz), 8.50 (1H, d, Jϭ9 Hz).
Ethyl (؎)-4-[1-[4-[1-(4-Isobutylphenyl)propyloxy]benzoyl]indolizin-3-
yl]butyrate (54b) Following the procedure described above for 48a, 54b
(80 mg, 87.5%) was prepared from 53 (53 mg) and 34b (53 mg, 0.27 mmol)
as an oil.
(؎)-4-[1-[4-[[1-(4-Isobutylphenyl)propyl]oxy]benzoyl]indolizin-3-
yl]butyric Acid (55b) Following the procedure described above for 45a,
55b (64 mg, 91.3%) was prepared from 54b (74 mg).
Effects in Castrated Young Rats: Four-week-old prepubertal male Wistar
rats were anesthetized by pentobarbital and castrated. From the incised ab-
domen vas deferens, the testicular artery and vein were fastened and the
testes were cut out.18) After 3 d, oral administration of 5 ml/kg of drug solu-
tion was started once daily for 5 consecutive days. Drugs were dissolved in
sesame oil. 300 mg/kg of TP in sesame oil was subcutaneously injected to
the rats at the same time as the drug administration. Rats were sacrificed
with CO2 gas about 6 h after the last dosing, and ventral prostates and semi-
nal vesicles were removed and weighed.
References and Notes
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(48.6 g, 56.2%) was prepared from 56 (55 g, 157 mmol) and 46c (32.3 g,
1
157 mmol) as an oil. H-NMR (CDCl3) d: 0.80—1.05 (9H, m), 1.24 (3H, t,
Jϭ7 Hz), 1.30—1.65 (2H, m), 1.70—2.15 (5H, m), 2.35—2.50 (4H, m),
2.87 (2H, t, Jϭ7 Hz), 4.12 (2H, q, Jϭ7 Hz), 5.17 (1H, dd, Jϭ2, 7 Hz),
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