Cinnamylindoline derivatives: Synthesis and factor Xa (FXa) inhibitory activities

Article abstract of DOI:10.1248/cpb.55.1494

A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4- yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.

Full text of DOI:10.1248/cpb.55.1494

1494
Chem. Pharm. Bull. 55(10) 1494—1504 (2007)
Vol. 55, No. 10
Cinnamylindoline Derivatives: Synthesis and Factor Xa (FXa) Inhibitory
Activities1)
a
Tetsuji NOGUCHI, Naoki TANAKA ,b Toyoki NISHIMATA,b Riki GOTO,b Miho HAYAKAWA,a
*
Atsuhiro SUGIDACHI,c Taketoshi OGAWA,d Fumitoshi ASAI,c and Koichi FUJIMOTO
b,2)
a Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.; 1–16–13 Kitakasai, Edogawa-ku, Tokyo
134–8630, Japan: b Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.; c Biological Research
Laboratories II, Daiichi Sankyo Co., Ltd.; and d Biological Research Laboratories I, Daiichi Sankyo Co., Ltd.; 1–2–58
Hiromachi, Shinagawa-ku, Tokyo 140–8710, Japan.
Received June 21, 2007; accepted August 10, 2007; published online August 10, 2007
A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities
and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory
activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-
amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety ex-
hibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant ac-
tivities in vitro.
Key words factor Xa inhibitory activity; cinnamylindoline derivative; anticoagulant
In recent days, factor Xa (FXa) inhibitor attracts much at- against trypsin which belongs to a serine protease family. In
tention as a promising drug candidate for anticoagulation.3) general, compounds having selective inhibitory activity
FXa, a serine protease in the blood coagulation cascade,4) is against target enzyme were favorable as drug candidates be-
essential for the formation of thrombin. It plays an important cause of less possibility of unexpected adverse reaction.
role in the coagulation cascade at the convergent point of the From this viewpoint, we searched for a potent and selective
intrinsic and the extrinsic pathway. FXa inhibitor is expected FXa inhibitor.
to be a novel antithrombotic with potential for the treatment
Herein, we describe the synthesis and structure–activity
relationships (SARs) and FXa selectivity of these com-
and prevention of thromboembolic diseases.5,6)
In previous papers,7,8) we reported the syntheses and FXa pounds.
inhibitory activities of bisamidine compounds having indo-
line moiety in the center of the molecule. In these studies, Chemistry
we found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-
(E)-Substituted cinnamaldehyde intermediates 4a—e were
amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) synthesized as shown in Chart 1. 3-Cyanobenzaldehyde (3)
and ({(R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidi- was reacted with ylides to give corresponding substituted
nonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((R)-2) cinnamaldehyde 4a—c. Compound 3 and methyl acrylate (5)
exhibited potent FXa inhibitory activities (Fig. 1). However, were coupled to give cinnamate 6d having a methoxymethyl
these compounds also exhibited potent inhibitory activities group on the a-position. 3-Cyanoacetophenone (7) was re-
acted with an ylide to give cinnamate 6e having a methyl
group on the b-position. Compounds 6d and 6e were con-
verted to cinnamaldehydes 4d and 4e by 3 steps, respectively.
The syntheses of bisamidine derivatives (13a—e) are out-
lined in Chart 2. Cinnamaldehyde 4a—e were coupled with
compound 8a7) by tetrabutylammonium fluoride (TBAF) to
give the corresponding alcohols 9a—e.9) Nitro groups of al-
cohols 9a—e were converted to ethanesulfonylamino groups
Fig. 1. Structures of Naphthylindoline Derivatives
Chart 1
∗ To whom correspondence should be addressed. e-mail: noguchi.tetsuji.z8@daiichisankyo.co.jp
© 2007 Pharmaceutical Society of Japan

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1495
Chart 2
Chart 3
Chart 4
to give 11a—e. Intramolecular Mitsunobu reaction10) of respectively. Carboxylic acid 13j was synthesized from ester
11a—e with n-Bu3P and 1,1ꢀ-(azodicarbonyl)dipiperidine 13f by acid hydrolysis.
(ADDP) afforded 12a—e having indoline rings. 12a—e were
converted to desired bisamidine derivatives 13a—e by 3 13u) having substituents on aryl carbons of indoline are out-
steps. lined in Chart 4. Substituted nitrophenols 14 were coupled
The syntheses of bisamidine derivatives (13k—r, 13t,
The syntheses of bisamidine derivatives (13f, 13g, 13i, with N-protected piperidinol 15, followed by reaction with
13j) are outlined in Chart 3. After reaction of aniline 10a (trimethylsilylmethyl)magnesium chloride to give the corre-
with a sulfonyl chloride11) or acyl chlorides, resulting sulfon- sponding 2-substituted-3-trimethylsilylmethyl derivatives (8l,
amide 11f or amides 11g and 11h were cyclized by the same 8n, 8p, 8r) and/or 2-substituted-5-trimethylsilylmethyl deriv-
process described above to give indoline 12f—h. An acetoxy atives (8k, 8m, 8o, 8q, 8s).12) Compounds 8k—s were con-
group of indoline 12h was hydrolyzed to give alcohol 12i. In verted to cyclized compounds 12k—s by a similar method
a similar method described above, 12f, 12g and 12i were described in Chart 2. A 1,3-dioxolan-2-yl group of com-
converted to desired bisamidine derivatives 13f, 13g and 13i, pound 12s was converted to a carboxyl group (12t) by 2

1496
Vol. 55, No. 10
Chart 5
Chart 6
Table 1. FXa and Trypsin Inhibitory Activities of Cinnamyl Compound
13a and Naphthyl Compound 1
steps. Furthermore, 12t was converted to amide 12u in a
standard manner. Cyclized compounds 12k—r, 12t and 12u
were converted to desired bisamidine compounds 13k—r,
13t and 13u by a similar method described in Chart 2.
The syntheses of optically active (R)-13j and (S)-13j are
outlined in Chart 5. After oxidation of racemic alcohol 9a,
ketone 16 was subjected to enantioselective reduction13,14) by
using chiral prolinol ligand (R)-17 or (S)-17, followed by re-
duction of a nitro group to give optically pure aniline (S)-10a
and (R)-10a, respectively. Optically pure and stereochemi-
cally inversed bisamidines (R)-13j and (S)-13j were synthe-
sized from (S) and (R)-10a by the same method as their race-
mate, respectively.
IC50 (nM)
Compd.a)
L
Ratiob)
FXa
12
Trypsin
120
13a
1
10
11
52
4.7
The syntheses of 5-amidino-2-hydroxycinnamyl deriva-
tives (22a—c, 22f—h) are outlined in Chart 6. After treat-
ment of compound 18 with ylide, a hydroxyl group of result-
ing compound 19 was protected to give O-protected cin-
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
namaldehyde 20. Compound 20 was converted to cyclized only to enhance FXa inhibitory activity but to improve selec-
compounds (21a, 21c, 21d, 21e) by a similar method de- tivity over trypsin. From this viewpoint, we reexamined vari-
scribed in Chart 2. A methoxymethyl group of 21a was con- ous moieties of the indoline compound we have reported pre-
verted to a methyl group by 3 steps to give compound 21b. viously.7,8)
Cyclized compounds 21a—e were converted to desired com-
First, we focused on the naphthalene structure attached to
pounds 22a—e by a similar method described in Chart 2. an indoline ring (Table 1). We synthesized a cinnamyl com-
Furthermore, carboxylic acids 22f—h were synthesized from pound 13a, a ring-opening form of naphthalene, and tested
the corresponding esters 22c—e by acid hydrolysis.
its inhibitory activity against FXa and trypsin. Compound
13a exhibited potent FXa inhibitory activity even equal to
naphthyl compound 1. Moreover, 13a exhibited 10-fold en-
Results and Discussion
In vitro FXa and trypsin inhibitory activities of all com- hanced selectivity for FXa over trypsin. This selectivity was
pounds were evaluated and expressed as IC50 values. superior to that of naphthyl compound 1. According to this
As described above, we considered that it is important not result, cinnamyl moiety seemed to be appropriate as an alter-

October 2007
1497
Table 2. FXa and Trypsin Inhibitory Activities of Compounds 13a—e
Table 4. FXa and Trypsin Inhibitory Activities of Compounds 13f, 13k—
r, 13t and 13u
IC50 (nM)
Compd.a)
L
Ratiob)
IC50 (nM)
FXa
12
Trypsin
120
Compd.a)
R1
R2
Ratiob)
FXa
Trypsin
13a
13b
10
13k
13m
13o
13q
13t
13u
13l
13n
13p
13r
13f
H
H
H
H
H
H
Cl
F
CF3
Me
H
Cl
F
14
11
6.2
13
14
8.7
9.5
11
39
160
20
84
64
2.8
15
21
24
24
160
140
180
7.6
CF3
Me
CO2Et
CONH2
H
H
H
H
H
3.2
6.5
4.6
2.9
21
15
40
27
10
25
13c
13d
5.8
7.5
200
160
290
220
110
7.3
8.1
11
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
13e
49
130
2.7
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
improved. On the other hand, acetyl compound 13g showed
slightly less FXa inhibitory activity. An introduction of a hy-
droxyl group on the acetyl moiety (13i) resulted in similar
FXa inhibitory activity as 13a. However, 13i also exhibited
potent inhibitory activity against trypsin. These results were
also confirmed for the naphthylindoline derivatives,8) and
suggest that sulfonylacetic acid type structures are favorable
at this position.
Furthermore, the effects of the substituents on the indoline
ring (4- vs. 6-position) were examined (Table 4). Compounds
having a fluorine atom, a bioisoster of a hydrogen atom, on
the 4- (13n) or 6-position (13m) resulted in the same result
as non-substituted compound 13f. Compounds having a more
bulky group than a hydrogen atom (13k, 13o, 13q, 13t, 13u)
at the 6-position exhibited potent inhibitory activities against
both FXa and trypsin. On the other hand, compounds (13l,
13p, 13r) having a similar bulky group as above at the 4-po-
sition exhibited potent FXa inhibitory activity. Moreover, se-
lectivity over trypsin was improved compared to that of 13f.
These results suggest that an introduction at the 4- or 6-posi-
Table 3. FXa and Trypsin Inhibitory Activities of Compounds 13a, 13f,
13g, 13i and 13j
IC50 (nM)
Compd.a)
R
Ratiob)
FXa
Trypsin
13f
13j
13g
13i
13a
SO2CH2CO2Et
SO2CH2CO2H
COCH3
COCH2OH
SO2Et
11
9.4
17
11
12
110
160
190
65
10
17
11
5.9
10
120
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
native to naphthyl moiety.
To optimize this moiety, substituents were introduced on tion does not have an influence against FXa inhibitory activ-
the double bond and their effects were evaluated (Table 2). ity, but they do have a significant influence against trypsin in-
An introduction of a methyl or an ethyl group on the b-posi- hibitory activity. Furthermore, the bulkiness was important
tion of the cinnamyl moiety (13b, 13c) resulted in a decline for these activities, whereas the electron property (electron
of FXa inhibitory activity and selectivity compared to that of withdrawing/donating group) was not so important. From
13a. To examine the effect of an introduction of a polar sub- these results, it seemed that the 4-substitution is preferable to
stituent at this position, methoxymethylene compound 13d 6-substitution.
was synthesized and its inhibitory activity was evaluated.
All compounds discussed above are racemates having an
However, the activity was similar as those of 13b and 13c. asymmetric carbon atom at the 2-position of the indoline
On the other hand, compound 13e, having a methyl group on ring. We previously reported that the (R)-naphthylindoline
the a-position, exhibited much less inhibitory activity and derivative exhibited over 20 times higher FXa inhibitory ac-
selectivity. According to these results, a,b-non-substituted tivity than the corresponding (S)-isomer.7) Based on this re-
cinnamyl moiety seems to be more suitable.
sult, each of the enantiomers ((R)- and (S)-13j) of a cin-
Next, the effect of the substitution of the nitrogen atom of namylindoline derivative 13j was prepared and their FXa and
the indoline ring was examined (Table 3). Conversion of trypsin inhibitory activities were evaluated (Table 5). How-
ethanesulfonyl moiety of 13a into sulfonylacetic acid (13j) ever, to our surprise, the FXa inhibitory activities of (R)- and
and its ester form (13f) brought about similar FXa inhibitory (S)-13j were nearly equal. We thought that this result was
activities as 13a, but as for 13j, selectivity over trypsin was caused by the structural flexibility of cinnnamyl moiety. The

1498
Vol. 55, No. 10
Table 5. FXa and Trypsin Inhibitory Activities of Compounds (R)-13j,
(S)-13j and 13j
Table 7. FXa and Other Serine Protease Inhibitory Activities of Com-
pound 22f
Enzyme
IC50 (nM)
FXa
4.4
Trypsin
FIIa
Plasmin
1500
ꢁ100000
16000
IC50 (nM)
Compd.a)
2-position
Ratiob)
FXa
Trypsin
(R)-13j
(S)-13j
13j
R
S
RS
11
16
9.4
130
320
160
12
20
17
Table 8. In Vitro Anticoagulant Activities of Compounds 22f and (R)-2
Human CT2 (mM)a)
Compd.
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
PT
APTT
22f
(R)-2
0.39
0.48
0.34
1.2
Table 6. FXa and Trypsin Inhibitory Activities of Compounds 22a—c,
22f—h, 13a and 13j
a) The concentration required to double clotting time.
tent FXa inhibitory activity and the enzyme selectivity. On
the other hand, the methoxy group of 22b makes it difficult
to interact with the S1 pocket of both FXa and trypsin, so
this caused a significant decline of inhibitory activity. Fur-
thermore, the replacement of the ethanesulfonyl group by a
carboxymethylsulfonyl group (and its ester form) gave the
most potent FXa inhibitory activity (22a vs. 22f and 22c).
Moreover, selectivity over trypsin of 22f was over 20 times
improved compared to that of 13j. However, 22g and 22h
with a chlorine atom at the 4- or 6-positon of the indoline
ring exhibited, despite the result shown in Table 4, lower FXa
inhibitory activities than that of non-substituted compound
22f.
IC50 (nM)
Compd.a)
R1
R2
R3
Ratiob)
FXa
Trypsin
22a
22b
22c
22f
22g
22h
13a
13j
Et
Et
OH
OMe
OH
OH
OH
OH
H
H
H
H
7.0
280
6.8
4.4
20
1300
2000
1900
1500
2600
1200
120
190
7.1
280
340
130
110
10
CH2CO2Et
CH2CO2H
CH2CO2H
CH2CO2H
Et
H
4-Cl
6-Cl
H
11
12
CH2CO2H
H
H
9.4
160
17
Compound 22f also exhibited good enzyme selectivity
over other serine proteases (Table 7). Therefore, compound
22f had the best profile in both the FXa inhibitory activity
and enzyme selectivity among all compounds we have syn-
a) All compounds were synthesized and evaluated as their hydrochlorides. b)
Ratio: the IC50 values for Trypsin vs. FXa (Trypsin/FXa).
structure of the cinnamyl group was less rigid than that of the thesized and tested.
naphthyl group, so it seemed that the difference of FXa in-
We evaluated the anticoagulant activity of 22f on both pro-
hibitory activity between (R)- and (S)-cinnamylindoline de- thrombin time (PT) and activated partial thromboplastin time
rivative was not observed. Moreover, from the synthetic as- (APTT) in human plasma (Table 8). CT2 values, the concen-
pect, selective synthesis of the one enantiomer needs more tration required to achieve 200% relative clotting time, of 22f
effort compared to that of its racemate. According to this re- were 0.39 mM (PT) and 0.34 mM (APTT), whereas those of
sult, we considered that it is suitable to develop our cin- naphthyl compound (R)-2 were 0.48 mM (PT) and 1.2 mM
namylindoline derivatives as a racemate.
(APTT), respectively. These results indicate that compound
The effect of the substituents on the benzene ring of the 22f has more potent in vitro anticoagulant activity than
cinnamyl moiety was examined (Table 6). Compound 22a, (R)-2.
having a hydroxyl group at the 2-position, exhibited more
In conclusion, we synthesized many cinnamylindoline de-
potent FXa inhibitory activity and much higher selectivity rivatives to find compounds having potent FXa inhibitory ac-
over trypsin than non-substituted compound 13a. However, tivities and selectivity over trypsin. As a result, we found that
compound 22b, having a methoxy group on the same posi- some novel derivatives having 2-hydroxycinnnamyl moieties
tion, showed much lower inhibitory activity. This result sug- showed high FXa inhibitory activities and selectivity over
gests that the hydroxyl group on this position is highly im- trypsin. Among them, (E)-2-{5-[1-(acetimidoyl)piperidin-4-
portant for both FXa inhibitory activity and selectivity over yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-
trypsin. From the X-ray crystallographic analysis, FXa has 1-ylsulfonyl}acetic acid (22f) exhibited potent FXa in-
an amino acid residue Ser 195 in its S1 pocket7,15) and Ser hibitory activity and good enzyme selectivity in vitro. Fur-
195 is located nearby the benzamidine moieties of FXa in- thermore, compound 22f exhibited potent in vitro anticoagu-
hibitors. We speculate that the hydroxyl group at the 2-posi- lant activity in human plasma, although oral anticoagulant
tion of the benzene ring makes a hydrogen bond with Ser activity remains to be determined. Our further synthetic ef-
195, whereas it makes a water-mediated hydrogen bond, a forts are in progress and the results will be disclosed in the
relatively indirect interaction, with Ser 195 in the S1 pocket next report.
of trypsin.16—19) It seems that this difference leads to both po-

October 2007
1499
Table 9. Elemental Analysis Data for Cinnamylindoline Derivatives 13 and 22
Analysis (%) Calcd (Found)
Compd.
Formula
C
H
N
Cl
S
F
13a
13b
13c
13d
13e
13f
C26H33N5O3S·2.0HCl·2.8H2O
C27H35N5O3S·2.4HCl·1.9H2O
C28H37N5O3S·2.1HCl·1.8H2O
C28H37N5O4S·2.0HCl·2.9H2O
C27H35N5O3S·2.0HCl·2.5H2O
C28H35N5O5S·2.0HCl·2.5H2O
C26H31N5O2·2.1HCl·2.5H2O
C26H31N5O3·2.0HCl·2.7H2O
C26H31N5O5S·2.4HCl·1.7H2O
C28H34ClN5O5S·1.9HCl·2.3H2O
C28H34ClN5O5S·2.1HCl·1.6H2O
C28H34FN5O5S·2.1HCl·1.4H2O
C28H34FN5O5S·1.7HCl·2.5H2O
C29H34F3N5O5S·2.1HCl·2.2H2O
C29H34F3N5O5S·2.3HCl·1.6H2O
C29H37N5O5S·2.1HCl·1.3H2O
C29H37N5O5S·2.1HCl·1.3H2O
C31H39N5O7S·2.0HCl·2.1H2O
C29H36N6O6S·2.4HCl·2.5H2O
C26H33N5O4S·2.0HCl·2.6H2O
C27H35N5O4S·2.1HCl·1.6H2O
C28H35N5O6S·2.0HCl·1.2H2O
C26H31N5O6S·2.5HCl·0.5H2O
C26H30ClN5O6S·1.9HCl·2.9H2O
C26H30ClN5O6S·2.0HCl·2.1H2O
50.45
(50.13)
51.36
(51.62)
53.16
(52.98)
50.58
(50.36)
51.67
(51.78)
50.07
(50.16)
55.06
(55.42)
53.55
(53.34)
48.51
(48.77)
48.12
(48.01)
48.49
(48.28)
49.94
(49.91)
49.55
(49.63)
47.21
(47.32)
47.43
(47.60)
52.17
(51.91)
52.17
(52.24)
50.56
(50.75)
47.76
(47.63)
49.46
(49.77)
51.39
(51.32)
50.79
(50.98)
48.66
(48.53)
44.77
(44.94)
45.47
6.61
(6.65)
6.58
(6.93)
6.80
(7.10)
6.79
(6.42)
6.75
(6.47)
6.30
(5.95)
6.77
(6.75)
6.64
(6.38)
5.76
(5.64)
5.84
(5.67)
5.71
(5.99)
5.82
(5.95)
6.04
(5.92)
5.53
(5.28)
5.42
(5.35)
6.30
(6.09)
6.30
(6.00)
6.19
(5.93)
6.00
(5.76)
6.42
(6.13)
6.44
(6.47)
5.69
(5.81)
5.42
(5.79)
5.45
(5.19)
5.31
11.31
(11.65)
11.09
(11.20)
11.07
(11.12)
10.53
(10.55)
11.16
(11.23)
10.43
(10.53)
12.35
(11.97)
12.01
(12.08)
10.88
(10.62)
10.02
(10.07)
10.10
(10.22)
10.40
(10.52)
10.32
(10.46)
9.49
(9.61)
9.54
(9.41)
10.49
(10.73)
10.49
(10.69)
9.51
(9.51)
11.52
(11.67)
11.09
(11.23)
11.10
(10.96)
10.58
(10.59)
10.91
(11.08)
10.04
(10.11)
10.20
11.45
(11.52
13.48
(13.12)
11.77
(11.48)
10.66
(10.66)
11.30
(11.12)
10.56
(10.46)
13.13
(12.99)
12.16
(12.39)
13.22
(13.10)
14.71
(14.70)
15.85
(15.83)
11.05
(11.16)
8.88
(8.73)
10.09
(10.01)
11.10
(11.22)
11.15
(11.44)
11.15
(11.15)
9.63
(9.55)
11.67
(11.68)
11.23
(11.02)
11.80
(11.89)
10.71
(10.69)
13.81
(13.46)
14.74
(14.90)
15.49
5.18
(5.22)
5.08
(5.02)
5.07
(5.36)
4.82
(4.91)
5.11
(5.28)
4.77
(4.66)
—
—
—
—
—
—
—
—
—
—
—
—
13g
13i
—
13j
4.98
(4.95)
4.59
(4.80)
4.62
(4.80)
4.76
(4.66)
4.72
(4.61)
4.35
(4.19)
4.37
(4.25)
4.80
(4.70)
4.80
(4.81)
4.35
(4.36)
4.40
(4.64)
5.08
(4.81)
5.08
(5.27)
4.84
(4.72)
5.00
(5.09)
4.60
(4.33)
4.67
13k
13l
13m
13n
13o
13p
13q
13r
13t
2.82
(2.67)
2.80
(2.58)
7.72
(7.76)
7.76
(7.76)
—
—
—
—
—
—
—
—
—
—
13u
22a
22b
22c
22f
22g
22h
(45.34)
(5.46)
(10.40)
(15.42)
(4.70)
Experimental
Jꢂ16.1 Hz), 7.58 (1H, t, Jꢂ7.8 Hz), 7.73 (1H, d, Jꢂ7.8 Hz), 7.81 (1H, d,
Jꢂ7.8 Hz), 7.84 (1H, s), 9.76 (1H, d, Jꢂ7.4 Hz).
1H-NMR spectra were obtained on a Varian Mercury 400 or Unity Inova
500 FT-NMR spectrometer and were reported as d values relative to Me4Si
Other derivatives (4b, 4c) were similarly prepared.
1
4b: 1H-NMR (CDCl3) d: 2.07 (3H, s), 7.25 (1H, s), 7.59 (1H, t,
Jꢂ7.8 Hz), 7.69 (1H, d, Jꢂ7.8 Hz), 7.74 (1H, d, Jꢂ7.8 Hz), 7.79 (1H, s),
9.63 (1H, s).
as the internal standard. Abbreviations of the H-NMR peak patterns are as
follows: bsꢂbroad singlet, sꢂsinglet, dꢂdoublet, ddꢂdouble doublet,
tꢂtriplet, dtꢂdouble triplet, qꢂquartet and mꢂmultiplet. Merck Silica gel
60 (230—400 mesh) was used in the column chromatography. Tetrahydrofu-
ran, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethylsulfox-
ide are abbreviated as THF, DMF, DMA and DMSO, respectively.
1
4c: H-NMR (CDCl3) d: 1.15 (3H, t, Jꢂ7.5 Hz), 2.52 (2H, q, Jꢂ7.5 Hz),
7.19 (1H, s), 7.59 (1H, t, Jꢂ7.8 Hz), 7.68—7.73 (2H, m), 7.75 (1H, s), 9.59
(1H, s).
(E)-3-Cyanocinnamaldehyde (4a) To a solution of 3-cyanobenzalde-
hyde 3 (4.50 g, 34.3 mmol) in toluene (200 ml) was added (triphenylphos-
phoranylidene)acetaldehyde (13.6 g, 44.7 mmol) and the mixture was stirred
at 70 °C for 4 h. The mixture was concentrated and the resulting residue was
chromatographed on a silica gel column (CH2Cl2) and then recrystallized
(toluene/hexane) to give 4a (3.09 g, 19.7 mmol, 57%) as pale yellow needles.
1H-NMR (CDCl3) d: 6.76 (1H, dd, Jꢂ7.4, 16.1 Hz), 7.46 (1H, d,
Methyl (E)-3-(3-Cyanophenyl)-2-(methoxymethyl)-2-propenoate (6d)
To a suspension of NaH (680 mg, 15.6 mmol, as a 55% w/w dispersion in
mineral oil) in THF (15 ml) was added MeOH (0.730 ml, 18.0 mmol) at 0 °C
and the mixture was stirred at room temperature for 30 min. 3-Cyanoben-
zaldehyde 3 (1.31 g, 9.99 mmol) and methyl acrylate 5 (1.35 ml, 15.0 mmol)
in THF (15 ml) was then added at 0 °C and the mixture was stirred at room
temperature for 2 h. The mixture was concentrated and the resulting residue

1500
Vol. 55, No. 10
Table 10. 1H-NMR Data for Cinnamylindoline Derivatives 13 and 22
Compd.
1H-NMR d (DMSO-d6)
13a 1.17 (3H, t, Jꢂ7.4 Hz), 1.63—1.83 (2H, m), 1.95—2.12 (2H, m), 2.30 (3H, s), 2.90 (1H, dd, Jꢂ2.2, 16.7 Hz), 3.02—3.13 (1H, m), 3.19—3.31
(1H, m), 3.44—3.88 (4H, m), 3.66 (1H, dd, Jꢂ9.9, 16.7 Hz), 4.56—4.67 (1H, m), 5.11—5.21 (1H, m), 6.58 (1H, dd, Jꢂ6.2, 15.8 Hz), 6.68
(1H, d, Jꢂ15.8 Hz), 6.87 (1H, dd, Jꢂ2.1, 8.8 Hz), 7.00 (1H, d, Jꢂ2.1 Hz), 7.24 (1H, d, Jꢂ8.8 Hz), 7.56 (1H, t, Jꢂ7.8 Hz), 7.70 (1H, d, Jꢂ7.8 Hz),
7.80 (1H, d, Jꢂ7.8 Hz), 7.93 (1H, s)
13b 1.19 (3H, t, Jꢂ7.4 Hz), 1.68—1.78 (2H, m), 1.84 (3H, s), 1.99—2.08 (2H, m), 2.31 (3H, s), 2.92 (1H, dd, Jꢂ3.4, 17.0 Hz), 3.05—3.29 (2H, m),
3.51—3.83 (4H, m), 3.67 (1H, dd, Jꢂ10.2, 17.0 Hz), 4.60—4.64 (1H, m), 5.06 (1H, dd, Jꢂ3.4, 10.2 Hz), 6.55 (1H, s), 6.86 (1H, dd, Jꢂ2.0,
8.8 Hz), 6.98 (1H, d, Jꢂ2.0 Hz), 7.24 (1H, d, Jꢂ8.8 Hz), 7.59—7.70 (4H, m)
13c 1.09 (3H, t, Jꢂ7.5 Hz), 1.18 (3H, t, Jꢂ7.4 Hz), 1.68—1.78 (2H, m), 2.00—2.08 (2H, m), 2.24 (1H, dt, Jꢂ7.5, 14.5 Hz), 2.29 (3H, s), 2.36 (1H,
dt, Jꢂ7.5, 14.5 Hz), 2.89 (1H, dd, Jꢂ2.2, 16.8 Hz), 3.04—3.33 (2H, m), 3.47—3.58 (2H, m), 3.70—3.84 (3H, m), 4.58—4.64 (1H, m), 5.09
(1H, dd, Jꢂ2.2, 10.3 Hz), 6.48 (1H, s), 6.87 (1H, dd, Jꢂ2.2, 8.8 Hz), 6.98 (1H, d, Jꢂ2.2 Hz), 7.27 (1H, d, Jꢂ8.8 Hz), 7.59—7.68 (4H, m)
13d 1.18 (3H, t, Jꢂ7.3 Hz), 1.69—1.88 (2H, m), 1.98—2.06 (2H, m), 2.29 (3H, s), 3.03—3.82 (8H, m), 3.20 (3H, s), 4.05 (1H, d, Jꢂ11.5 Hz),
4.09 (1H. d, Jꢂ11.5 Hz), 4.58—4.64 (1H, m), 5.19 (1H, dd, Jꢂ2.2, 10.2 Hz), 6.74 (1H, s), 6.86 (1H, dd, Jꢂ2.4, 8.8 Hz), 6.98 (1H, d, Jꢂ2.4 Hz),
7.27 (1H, d, Jꢂ8.8 Hz), 7.60—7.73 (4H, m)
13e 1.19 (3H, t, Jꢂ7.3 Hz), 1.67—1.80 (2H, m), 1.99—2.05 (2H, m), 2.18 (3H, s), 2.29 (3H, s), 2.79 (1H, dd, Jꢂ3.0, 16.8 Hz), 3.03—3.31 (2H, m),
3.49—3.59 (2H, m), 3.65—3.81 (3H, m), 4.59—4.63 (1H, m), 5.40 (1H, dt, Jꢂ3.0, 9.0 Hz), 6.08 (1H, d, Jꢂ9.0 Hz), 6.86 (1H, d, Jꢂ8.7 Hz),
6.99 (1H, s), 7.19 (1H, d, Jꢂ8.7 Hz), 7.57 (1H, t, Jꢂ7.8 Hz), 7.70 (1H, d, Jꢂ7.8 Hz), 7.79 (1H, d, Jꢂ7.8 Hz), 7.84 (1H, s)
13f 1.11 (3H, t, Jꢂ7.1 Hz), 1.64—1.83 (2H, m), 1.97—2.09 (2H, m), 2.29 (3H, s), 2.90 (1H, d, Jꢂ16.8 Hz), 3.45—3.62 (2H, m), 3.65—3.85 (2H, m),
3.67 (1H, dd, Jꢂ10.3, 16.8 Hz), 3.88—4.06 (2H, m), 4.28 (1H, d, Jꢂ14.0 Hz), 4.43 (1H, d, Jꢂ14.0 Hz), 4.58—4.67 (1H, m), 5.20—5.28 (1H, m),
6.58 (1H, dd, Jꢂ6.6, 15.9 Hz), 6.67 (1H, d, Jꢂ15.9 Hz), 6.89 (1H, dd, Jꢂ1.3, 8.9 Hz), 7.02 (1H, d, Jꢂ1.3 Hz), 7.24 (1H, d, Jꢂ8.9 Hz), 7.56
(1H, t, Jꢂ7.5 Hz), 7.69 (1H, d, Jꢂ7.5 Hz), 7.80 (1H, d, Jꢂ7.5 Hz), 7.91 (1H. s)
13g 1.65—1.82 (2H, m), 1.96—2.10 (2H, m), 2.16 (3H, s), 2.30 (3H, s), 2.88 (1H, d, Jꢂ16.5 Hz), 3.46—3.64 (3H, m), 3.68—3.87 (2H, m),
4.58—4.66 (1H, m), 5.23—5.31 (1H, m), 6.57 (2H, s), 6 84 (1H, d, Jꢂ9.2 Hz), 6.96 (1H, s), 7.55 (1H, t, Jꢂ7.8 Hz), 7.70 (1H, d, Jꢂ7.8 Hz),
7.79 (1H, d, Jꢂ7.8 Hz), 7.94 (1H, s), 7.99 (1H, d, Jꢂ9.2 Hz)
13i 1.65—1.82 (2H, m), 1.96—2.11 (2H, m), 2.30 (3H, s), 2.88 (1H, d, Jꢂ16.2 Hz), 3.45—3.63 (3H, m), 3.67—3.87 (2H, m), 3.96—4.11 (1H, m),
4.32—4.44 (1H, m), 4.58—4.67 (1H, m), 5.18—5.32 (1H, m), 6.50—6.62 (2H, m), 6.87 (1H, dd, Jꢂ2.1, 8.8 Hz), 6.98 (1H, d, Jꢂ2.1 Hz),
7.56 (1H, t, Jꢂ7.9 Hz), 7.70 (1H, d, Jꢂ7.9 Hz), 7.79 (1H, d, Jꢂ7.9 Hz), 7.92 (1H, s), 7.98—8.07 (1H, m)
13j 1.65—1.82 (2H, m), 1.97—2.01 (2H, m), 2.30 (3H, s), 2.88 (1H, d, Jꢂ16.0 Hz), 3.46—3.61 (2H, m), 3.65—3.86 (2H, m), 3.67 (1H, dd, Jꢂ10.1,
16.0 Hz), 4.01 (1H, d, Jꢂ14.2 Hz), 4.30 (1H, d, Jꢂ14.2 Hz), 4.58—4.67 (1H, m), 5.19—5.27 (1H, m), 6.59 (1H, dd, Jꢂ6.0, 15.8 Hz), 6.67
(1H, d, Jꢂ15.8 Hz), 6.89 (1H, dd, Jꢂ2.4, 8.8 Hz), 7.01 (1H, d, Jꢂ2.4 Hz), 7.24 (1H, d, Jꢂ8.8 Hz), 7.56 (1H, t, Jꢂ8.0 Hz), 7.69 (1H, d, Jꢂ8.0 Hz),
7.80 (1H, d, Jꢂ8.0 Hz), 7.92 (1H, s)
13k 1.11 (3H, t, Jꢂ7.1 Hz), 1.72—1.89 (2H, m), 1.96—2.11 (2H, m), 2.30 (3H, s), 2.92 (1H, dd, Jꢂ2.1, 16.9 Hz), 3.51—3.80 (4H, m), 3.67
(1H, dd, Jꢂ9.9, 16.9 Hz), 3.90—4.07 (2H, m), 4.44 (1H, d, Jꢂ14.3 Hz), 4.54 (1H, d, Jꢂ14.3 Hz), 4.68—4.77 (1H, m), 5.24—5.33 (1H, m),
6.59 (1H, dd, Jꢂ6.2, 15.8 Hz), 6.68 (1H, d, Jꢂ15.8 Hz), 7.33 (1H, s), 7.34 (1H, s), 7.57 (1H, t, Jꢂ7.9 Hz), 7.70 (1H, d, Jꢂ7.9 Hz), 7.81 (1H, d,
Jꢂ7.9 Hz), 7.92 (1H, s)
13l 1.10 (3H, t, Jꢂ7.1 Hz), 1.71—1.90 (2H, m), 1.96—2.14 (2H, m), 2.30 (3H, s), 2.95 (1H, dd, Jꢂ2.6, 16.8 Hz), 3.51—3.82 (4H, m), 3.69
(1H, dd, Jꢂ10.0, 16.8 Hz), 3.85—3.95 (1H, m), 3.98—4.08 (1H, m), 4.41 (1H, d, Jꢂ14.3 Hz), 4.50 (1H, d, Jꢂ14.3 Hz), 4.69—4.77 (1H, m),
5.27—5.35 (1H, m), 6.62 (1H, dd, Jꢂ5.9, 15.8 Hz), 6.69 (1H, d, Jꢂ15.8 Hz), 7.19 (1H, d, Jꢂ8.9 Hz), 7.23 (1H, d, Jꢂ8.9 Hz), 7.57 (1H, t,
Jꢂ8.0 Hz), 7.71 (1H, d, Jꢂ8.0 Hz), 7.81 (1H, d, Jꢂ8.0 Hz), 7.95 (1H, s)
13m 1.11 (3H, t, Jꢂ7.3 Hz), 1.66—1.85 (2H, m), 1.98—2.01 (2H, m), 2.30 (3H, s), 3.00 (1H, d, Jꢂ16.5 Hz), 3.47—3.61 (2H, m), 3.63—3.85 (3H, m),
3.89—4.08 (2H, m), 4.40 (1H, d, Jꢂ14.3 Hz), 4.50 (1H, d, Jꢂ14.3 Hz), 4.57—4.65 (1H, m), 5.29—5.36 (1H, m), 6.60 (1H, dd, Jꢂ6.3, 15.8 Hz),
6.70 (1H, d, Jꢂ15.8 Hz), 7.07 (1H, d, Jꢂ8.7 Hz), 7.19 (1H, t, Jꢂ8.7 Hz), 7.57 (1H, t, Jꢂ7.9 Hz), 7.70 (1H, d, Jꢂ7.9 Hz), 7.81 (1H, d, Jꢂ7.9 Hz),
7.93 (1H, s)
13n 1.12 (3H, t, Jꢂ7.1 Hz), 1.69—1.85 (2H, m), 1.97—2.10 (2H, m), 2.30 (3H, s), 2.90 (1H, d, Jꢂ15.3 Hz), 3.46—3.86 (5H, m), 3.90—4.08 (2H, m),
4.43 (1H, d, Jꢂ14.4 Hz), 4.54 (1H, d, Jꢂ14.4 Hz), 4.57—4.65 (1H, m), 5.24—5.32 (1H, m), 6.60 (1H, dd, Jꢂ6.2, 15.8 Hz), 6.68 (1H, d,
Jꢂ15.8 Hz), 7.14 (1H, d, Jꢂ11.6 Hz), 7.32 (1H, d, Jꢂ8.3 Hz), 7.57 (1H, t, Jꢂ7.8 Hz), 7.71 (1H, d, Jꢂ7.8 Hz), 7.80 (1H. d, Jꢂ7.8 Hz), 7.95
(1H, s)
13o 1.10 (3H, t, Jꢂ7.1 Hz), 1.74—1.86 (2H, m), 2.02—2.11 (2H, m), 2.31 (3H, s), 3.00 (1H, d, Jꢂ16.9 Hz), 3.56—3.70 (4H, m), 3.77 (1H, dd,
Jꢂ9.4, 16.9 Hz), 3.89—4.03 (2H, m), 4.49 (1H, d, Jꢂ13.0 Hz), 4.57 (1H, d, Jꢂ13.0 Hz), 4.88—4.90 (1H, m), 5.33 (1H, t, Jꢂ7.1 Hz), 6.61 (1H,
dd, Jꢂ6.1, 15.8 Hz), 6.69 (1H, d, Jꢂ15.8 Hz), 7.47 (1H, s), 7.50 (1H, s), 7.57 (1H, t, Jꢂ7.8 Hz), 7.72 (1H, d, Jꢂ7.8 Hz), 7.81 (1H, d, Jꢂ7.8 Hz),
7.96 (1H, s)
13p 1.09 (3H, t, Jꢂ7.1 Hz), 1.75—1.85 (2H, m), 2.01—2.12 (2H, m), 2.30 (3H, s), 3.10 (1H, d, Jꢂ18.1 Hz), 3.56—3.71 (4H, m), 3.80—4.06 (3H, m),
4.44 (1H, d, Jꢂ14.4 Hz), 4.53 (1H, d, Jꢂ14.4 Hz), 4.86—4.88 (1H, m), 5.26—5.34 (1H, m), 6.62 (1H, dd, Jꢂ6.1, 15.8 Hz), 6.68 (1H, d,
Jꢂ15.8 Hz), 7.29 (1H, d, Jꢂ9.2 Hz), 7.54 (1H, d, Jꢂ9.2 Hz), 7.57 (1H, t, Jꢂ7.8 Hz), 7.69 (1H, d, Jꢂ7.8 Hz), 7.81 (1H, d, Jꢂ7.8 Hz), 7.92 (1H, s)
13q 1.12 (3H, t, Jꢂ7.1 Hz), 1.70—1.85 (2H, m), 1.96—2.10 (2H, m), 2.17 (3H, s), 2.31 (3H, s), 2.87 (1H, d, Jꢂ15.6 Hz), 3.52—3.84 (5H, m),
3.90—4.08 (2H, m), 4.24 (1H, d, Jꢂ14.2 Hz), 4.43 (1H, d, Jꢂ14.2 Hz), 4.60—4.69 (1H, m), 5.18—5.26 (1H, m), 6.55 (1H, dd, Jꢂ6.2, 15.8 Hz),
6.66 (1H, d, Jꢂ15.8 Hz), 7.06 (1H, s), 7.16 (1H, s), 7.60 (1H, t, Jꢂ7.8 Hz), 7.68 (1H, d, Jꢂ7.8 Hz), 7.80 (1H. d, Jꢂ7.8 Hz), 7.87 (1H, s)
13r 1.11 (3H, t, Jꢂ7.1 Hz), 1.68—1.85 (2H, m), 1.93—2.13 (2H, m), 2.10 (3H, s), 2.32 (3H, s), 2.89 (1H, d, Jꢂ16.0 Hz), 3.46—3.84 (5H, m), 3.88—
4.09 (2H, m), 4.24 (1H, d, Jꢂ14.7 Hz), 4.42 (1H, d, Jꢂ14.7 Hz), 4.58—4.69 (1H, m), 5.20—5.30 (1H, m), 6.60 (1H, dd, Jꢂ6.1, 15.8 Hz), 6.68
(1H, d, Jꢂ15.8 Hz), 6.95 (1H, d, Jꢂ8.8 Hz), 7.11 (1H, d, Jꢂ8.8 Hz), 7.56 (1H, t, Jꢂ7.8 Hz), 7.73 (1H, d, Jꢂ7.8 Hz), 7.80 (1H, d, Jꢂ7.8 Hz), 7.96
(1H, s)
13t 1.11 (3H, t, Jꢂ7.2 Hz), 1.28 (3H, t, Jꢂ7.1 Hz), 1.81—1.86 (2H, m), 1.96—2.02 (2H, m), 2.30 (3H, s), 2.96 (1H, dd, Jꢂ1.8, 14.3 Hz), 3.62—3.77
(5H, m), 3.96—4.00 (2H, m), 4.27 (2H, q, Jꢂ7.2 Hz), 4.41 (1H. d, Jꢂ14.3 Hz), 4.51 (1H, d, Jꢂ14.3 Hz), 4.80—4.81 (1H, m), 5.29—5.30 (1H,
m), 6.58 (1H, dd, Jꢂ6.0, 15.8 Hz), 6.68 (1H, d, Jꢂ15.8 Hz), 7.32 (1H, s), 7.57 (1H, t, Jꢂ7.7 Hz), 7.61 (1H, s), 7.69 (1H, d, Jꢂ7.7 Hz), 7.81 (1H,
d, Jꢂ7.7 Hz), 7.91 (1H, s)
13u 1.12 (3H, t, Jꢂ7.1 Hz), 1.78—1.92 (2H, m), 2.00—2.10 (2H, m), 2.30 (3H, s), 2.95 (1H, d, Jꢂ17.0 Hz), 3.47—3.59 (2H, m), 3.69—3.75 (2H, m),
3.82—3.87 (1H, m), 3.96—4.05 (2H, m), 4.34 (1H, d, Jꢂ15.0 Hz), 4.48 (1H, d, Jꢂ15.0 Hz), 4.78—4.81 (1H, m), 5.26 (1H, t, Jꢂ6.9 Hz), 6.59
(1H, dd, Jꢂ6.0, 15.8 Hz), 6.68 (1H, d, Jꢂ15.8 Hz), 7.29 (1H, s), 7.57 (1H, t, Jꢂ7.9 Hz), 7.69 (1H, d, Jꢂ7.9 Hz), 7.71 (1H, s), 7.81 (1H, d,
Jꢂ7.9 Hz), 7.92 (1H, s)

October 2007
1501
Table 10. (Continued)
Compd.
1H-NMR d (DMSO-d6)
22a 1.17 (3H, t, Jꢂ7.4 Hz), 1.65—1.83 (2H, m), 1.96—2.11 (2H, m), 2.30 (3H, s), 2.86 (1H, dd, Jꢂ2.4, 17.0 Hz), 3.00—3.12 (1H, m), 3.19—3.30
(1H, m), 3.46—3.61 (2H, m), 3.65 (1H, dd, Jꢂ9.9, 17.0 Hz), 3.67—3.86 (2H, m), 4.57—4.66 (1H, m), 5.09—5.18 (1H, m), 6.52 (1H, dd, Jꢂ6.9,
16.0 Hz), 6 82 (1H, d, Jꢂ16.0 Hz), 6.86 (1H, dd, Jꢂ2.4, 8.8 Hz), 7.01 (1H, d, Jꢂ2.4 Hz), 7.06 (1H, d, Jꢂ8.6 Hz), 7.23 (1H, d, Jꢂ8.8 Hz), 7.62
(1H, dd, Jꢂ2.4, 8.6 Hz), 7.97 (1H, d, Jꢂ2.4 Hz)
22b 1.17 (3H, t, Jꢂ7.4 Hz), 1.64—1.82 (2H, m), 1.95—2.11 (2H, m), 2.30 (3H, s), 2.87 (1H, dd, Jꢂ2.4, 16.8 Hz), 3.00—3.12 (1H, m), 3.18—3.30
(1H, m), 3.44—3.87 (4H, m), 3.66 (1H, dd, Jꢂ10.0, 16.8 Hz), 3.92 (3H, s), 4.56—4.67 (1H, m), 5.11—5.20 (1H, m), 6.56 (1H, dd, Jꢂ7.0,
16.1 Hz), 6.85 (1H, d, Jꢂ16.1 Hz), 6.86 (1H, dd, Jꢂ2.3, 8.9 Hz), 7.00 (1H, d, Jꢂ2.3 Hz), 7.23 (1H, d, Jꢂ8.8 Hz), 7.24 (1H, d, Jꢂ8.9 Hz), 7.82
(1H, dd, Jꢂ2.4, 8.8 Hz), 8.05 (1H, d, Jꢂ2.4 Hz)
22c 1.10 (3H, t, Jꢂ7.1 Hz), 1.65—1.82 (2H, m), 1.96—2.10 (2H, m), 2.30 (3H, s), 2.87 (1H, d, Jꢂ16.4 Hz), 3.46—3.62 (2H, m), 3.67 (1H, dd,
Jꢂ9.6, 16.4 Hz), 3.68—3.85 (2H, m), 3.87—4.06 (2H, m), 4.26 (1H, d, Jꢂ14.1 Hz), 4.42 (1H, d, Jꢂ14.1 Hz), 4.60—4.67 (1H, m), 5.18—5.27
(1H, m), 6.53 (1H, dd, Jꢂ6.9, 15.8 Hz), 6.82 (1H, d, Jꢂ15.8 Hz), 6.89 (1H, dd, Jꢂ2.3, 8.8 Hz), 7.02 (1H, s), 7.08 (1H, d, Jꢂ8.6 Hz), 7.23
(1H, d, Jꢂ8.8 Hz), 7.64 (1H, d, Jꢂ8.6 Hz), 7.98 (1H, s)
22f 1.65—1.82 (2H, m), 1.96—2.10 (2H, m), 2.30 (3H, s), 2.85 (1H, d, Jꢂ15.8 Hz), 3.44—3.61 (2H, m), 3.66 (1H, dd, Jꢂ10.1, 15.8 Hz), 3.68—3.87
(2H, m), 4.02 (1H, d, Jꢂ14.2 Hz), 4.31 (1H, d, Jꢂ14.2 Hz), 4.58—4.67 (1H, m), 5.15—5.25 (1H, m), 6.53 (1H, dd, Jꢂ6.8, 15.9 Hz), 6.82
(1H, d, Jꢂ15.9 Hz), 6.88 (1H, dd, Jꢂ2.4, 8.8 Hz), 7.01 (1H, d, Jꢂ2.4 Hz), 7.08 (1H, d, Jꢂ8.6 Hz), 7.24 (1H, d, Jꢂ8.8 Hz), 7.63 (1H, dd, Jꢂ2.2,
8.6 Hz), 7.98 (1H, d, Jꢂ2.2 Hz)
22g 1.72—1.90 (2H, m), 1.96—2.13 (2H, m), 2.30 (3H, s), 2.87 (1H, d, Jꢂ16.4 Hz), 3.51—3.80 (4H, m), 3.68 (1H, dd, Jꢂ9.6, 16.4 Hz), 4.10
(1H, d, Jꢂ14.0 Hz), 4.32 (1H, d, Jꢂ14.0 Hz), 4.67—4.77 (1H, m), 5.25—5.33 (1H, m), 6.54 (1H, dd, Jꢂ6.9, 15.9 Hz), 6.84 (1H, d, Jꢂ15.9 Hz),
7.06 (1H, d, Jꢂ8.7 Hz), 7.17 (1H, d, Jꢂ8.8 Hz), 7.23 (1H, d, Jꢂ8.8 Hz), 7.62 (1H, dd, Jꢂ2.2, 8.7 Hz), 7.99 (1H, d, Jꢂ2.2 Hz)
22h 1.73—1.88 (2H, m), 1.97—2.11 (2H, m), 2.30 (3H, s), 2.87 (1H, dd, Jꢂ1.2, 16.7 Hz), 3.49—3.80 (5H, m), 4.14 (1H, d, Jꢂ14.2 Hz), 4.38
(1H, d, Jꢂ14.2 Hz), 4.68—4.76 (1H, m), 5.22—5.28 (1H, m), 6.53 (1H, dd, Jꢂ6.9, 15.7 Hz), 6.82 (1H, d, Jꢂ15.7 Hz), 7.05 (1H, d, Jꢂ8.7 Hz),
7.32 (2H, s), 7.62 (1H, dd, Jꢂ2.3, 8.7 Hz), 7.97 (1H, d, Jꢂ2.3 Hz)
was diluted with EtOAc. The organic layer was washed with H2O and brine.
The organic layer was dried and concentrated. The resulting residue was
chromatographed on a silica gel column (toluene/EtOAcꢂ20/1) to give 6d
(0.720 g, 3.11 mmol, 31%) as a colorless solid. H-NMR (CDCl3) d: 3.46
(3H, s), 3.88 (3H, s), 4.19 (2H, s), 7.55 (1H, t, Jꢂ7.8 Hz), 7.68 (1H, d,
Jꢂ7.8 Hz), 7.75 (1H, d, Jꢂ7.8 Hz), 7.84 (1H, s), 7.87 (1H, s).
Jꢂ7.8 Hz), 7.76 (1H, d, Jꢂ7.8 Hz), 7.81 (1H, d, Jꢂ7.8 Hz), 7.86 (1H, s),
10.24 (1H, d, Jꢂ7.5 Hz).
t-Butyl (E)-4-{3-[4-(3-Cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-nitro-
phenoxy}piperidine-1-carboxylate (9a) To a solution of (E)-3-cyanocin-
namaldehyde 4a (1.00 g, 6.36 mmol) and t-butyl 4-[4-nitro-3-(trimethylsilyl-
methyl)phenoxy]piperidine-1-carboxlate 8a (2.86 g, 7.00 mmol) in THF
(50 ml) was added a solution of TBAF monohydrate (0.180 g, 0.644 mmol)
in THF (10 ml) at ꢃ10 °C and the mixture was stirred at ꢃ10 °C for 1 h.
TBAF (75% in H2O, 1.19 g, 6.07 mmol) in THF (10 ml) was then added and
the mixture was stirred at ꢃ10 °C for 1 h. NH4Cl solution was added, and
the mixture was extracted with EtOAc. The organic layer was washed with
brine. The organic layer was dried and concentrated. The resulting residue
was chromatographed on a silica gel column (hexane/EtOAcꢂ1/1) to give
1
Ethyl (E)-3-(3-Cyanophenyl)-3-methylacrylate (6e) A solution of 3-
cyanoacetophenone 7 (2.90 g, 20.0 mmol) and (carbethoxymethylene)triph-
enylphosphorane (17.4 g, 49.9 mmol) in xylene (150 ml) was refluxed for 4 h
with stirring and the mixture was concentrated. The resulting residue was
chromatographed on a silica gel column (hexane/EtOAcꢂ4/1) to give 6e
(1.61 g, 7.48 mmol, 37%) as a yellow solid. 1H-NMR (CDCl3) d: 1.33 (3H, t,
Jꢂ7.1 Hz), 2.56 (3H, s), 4.23 (2H, q, Jꢂ7.1 Hz), 6.13 (1H, s), 7.50 (1H, t,
Jꢂ8.0 Hz), 7.64 (1H, d, Jꢂ8.0 Hz), 7.70 (1H, d, Jꢂ8.0 Hz), 7.75 (1H, s).
(E)-3-(3-Cyanophenyl)-2-(methoxymethyl)-2-propenal (4d) To a so-
lution of methyl (E)-3-(3-cyanophenyl)-2-(methoxymethyl)-2-propenoate 6d
(2.01 g, 8.69 mmol) in CH2Cl2 (20 ml) and hexane (50 ml) was added di-
isobutylaluminum hydride (DIBAL) (1.5 M in toluene, 6.70 ml, 10.1 mmol)
and i-Bu3Al (1.0 M in hexane, 10.0 ml, 10.0 mmol) at ꢃ78 °C and the mix-
ture was stirred for 30 min. After adding DIBAL (1.5 M in toluene, 6.70 ml,
10.1 mmol) and i-Bu3Al (1.0 M in hexane, 10.0 ml, 10.0 mmol) at ꢃ78 °C
and the mixture was stirred for 30 min. MeOH was added, and the mixture
was diluted with EtOAc and washed with 1 N HCl, H2O, NaHCO3 solution,
and brine. The organic layer was dried and concentrated. The resulting
residue was chromatographed on a silica gel column (hexane/EtOAcꢂ1/1)
to give a mixture of (E)- and (Z)-3-(3-formylphenyl)-2-(methoxymethyl)-2-
propen-1-ol. The mixture was dissolved in 1-methyl-2-pyrrolidinone (30 ml)
and the solution was added hydroxylamine hydrochloride (700 mg,
10.1 mmol). The mixture was stirred at 120 °C for 4 h. After cooling, the
mixture was diluted with EtOAc and washed with H2O, brine. The organic
layer was dried and concentrated. The resulting residue was chro-
matographed on a silica gel column (hexane/EtOAcꢂ1/1) to give (Z)-3-(3-
cyanophenyl)-2-(methoxymethyl)-2-propen-1-ol (850 mg, 4.18 mmol) as a
yellow solid. To a solution of (Z)-3-(3-cyanophenyl)-2-(methoxymethyl)-2-
propen-1-ol (850 mg, 4.18 mmol) in CH2Cl2 (10 ml) and hexane (10 ml) was
added MnO2 (5.00 g, 63.3 mmol) and the mixture was stirred at room tem-
perature for 4 h. After adding MnO2 (5.00 g, 63.3 mmol) and the mixture
was stirred at room temperature for 1 h. MnO2 was filtered away, and the fil-
trate was concentrated. The resulting residue was chromatographed on a sil-
ica gel column (hexane/EtOAcꢂ3/2) to give 4d (0.71 g, 3.53 mmol, 41%) as
1
9a (2.59 g, 5.25 mmol, 82%) as a pale yellow amorphous solid. H-NMR
(CDCl3) d: 1.48 (9H, s), 1.71—1.82 (2H, m), 1.85—1.98 (2H, m), 3.08 (1H,
dd, Jꢂ8.5, 13.4 Hz), 3.29—3.42 (2H, m), 3.43 (1H, dd, Jꢂ4.0, 13.4 Hz),
3.60—3.70 (2H, m), 4.54—4.62 (1H, m), 4.65—4.73 (1H, m), 6.41 (1H, dd,
Jꢂ5.8, 16.4 Hz), 6.63 (1H, d, Jꢂ16.4 Hz), 6.84—6.90 (2H, m), 7.44 (1H, t,
Jꢂ7.8 Hz), 7.53 (1H, d, Jꢂ7.8 Hz), 7.60 (1H, d, Jꢂ7.8 Hz), 7.65 (1H, s),
8.08 (1H, d, Jꢂ9.6 Hz).
t-Butyl (E)-4-{4-Amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-1-
yl]phenoxy}piperidine-1-carboxylate (10a) To a solution of t-butyl (E)-
4-{3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-nitrophenoxy}piperi-
dine-1-carboxylate 9a (2.49 g, 5.05 mmol) in AcOH (25 ml) was added zinc
powder (1.98 g, 30.3 mmol) and the mixture was stirred at room temperature
for 1 h. The mixture was filtered, and the filtrate was concentrated. The re-
sulting residue was diluted with EtOAc and washed with NaHCO3 solution
and brine. The organic layer was dried and concentrated. The resulting
residue was chromatographed on a silica gel column (hexane/EtOAcꢂ1/3)
1
to give 10a (1.39 g, 3.00 mmol, 59%) as a brown oil. H-NMR (CDCl3) d:
1.47 (9H, s), 1.62—1.74 (2H, m), 1.80—1.92 (2H, m), 2.82—2.87 (2H, m),
3.21—3.32 (2H, m), 3.62—3.73 (2H, m), 4.23—4.30 (1H, m), 4.58—4.65
(1H, m), 6.37 (1H, dd, Jꢂ5.9, 15.7 Hz), 6.62 (1H, d, Jꢂ15.7 Hz), 6.67—
6.71 (3H, m), 7.42 (1H, t, Jꢂ7.8 Hz), 7.52 (1H, d, Jꢂ7.8 Hz), 7.58 (1H, d,
Jꢂ7.8 Hz), 7.64 (1H, s).
t-Butyl (E)-4-{3-[4-(3-Cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-
[(ethanesulfonyl)amino]phenoxy}piperidine-1-carboxylate (11a) To
a
solution of t-butyl (E)-4-{4-amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-
1-yl]phenoxy}piperidine-1-carboxylate 10a (1.38 g, 2.98 mmol) in CH2Cl2
(15 ml) was added EtSO2Cl (0.340 ml, 3.59 mmol) and pyridine (0.290 ml,
3.59 mmol) and the mixture was stirred at room temperature for 4 h. H2O
was added, and the mixture was extracted with CH2Cl2. The organic layer
was washed with brine. The organic layer was dried and concentrated. The
resulting residue was chromatographed on a silica gel column (hexane/
EtOAcꢂ1/1) to give 11a (1.26 g, 2.27 mmol, 76%) as a yellow oil. 1H-NMR
1
a pale yellow solid. H-NMR (CDCl3) d: 3.45 (3H, s), 4.22 (2H, s), 7.47
(1H, s), 7.60 (1H, t, Jꢂ7.8 Hz), 7.74 (1H, d, Jꢂ7.8 Hz), 7.90 (1H, d,
Jꢂ7.8 Hz), 7.99 (1H, s), 9.67 (1H, s).
Another derivative (4e) was similarly prepared.
4e: 1H-NMR (CDCl3) d: 2.63 (3H, s), 6.41 (1H, d, Jꢂ7.5 Hz), 7.60 (1H, t,

1502
Vol. 55, No. 10
(CDCl3) d: 1.42 (3H, t, Jꢂ7.4 Hz), 1.47 (9H, s), 1.64—1.77 (2H, m), 1.81—
1.94 (2H, m), 2.98 (2H, d, Jꢂ6.3 Hz), 3.12 (2H, q, Jꢂ7.4 Hz), 3.24—3.36
(2H, m), 3.58—3.70 (2H, m), 4.35—4.44 (1H, m), 4.59—4.67 (1H, m), 6.34
(1H, dd, Jꢂ6.4, 16.0 Hz), 6.62 (1H, d, Jꢂ16.0 Hz), 6.75 (1H, d, Jꢂ2.9 Hz),
6.81 (1H, dd, Jꢂ2.9, 8.8 Hz), 7.40 (1H, d, Jꢂ8.8 Hz), 7.44 (1H, t, Jꢂ7.8 Hz),
7.55 (1H, d, Jꢂ7.8 Hz), 7.58 (1H, d, Jꢂ7.8 Hz), 7.63 (1H, s).
(9H, s), 1.67—1.80 (2H, m), 1.84—1.96 (2H, m), 2.86 (1H, dd, Jꢂ2.0,
16.1 Hz), 3.27—3.37 (2H, m), 3.63—3.78 (3H, m), 3.99 (1H, d, Jꢂ14.2 Hz),
4.03 (1H, d, Jꢂ14.2 Hz), 4.10—4.22 (2H, m), 4.35—4.43 (1H, m), 5.18—
5.25 (1H, m), 6.31 (1H, dd, Jꢂ6.8, 15.7 Hz), 6.67 (1H, d, Jꢂ15.7 Hz), 6.77
(1H, dd, Jꢂ2.5, 8.7 Hz), 6.81 (1H, d, Jꢂ2.5 Hz), 7.35 (1H, d, Jꢂ8.7 Hz),
7.40 (1H, t, Jꢂ7.8 Hz), 7.51 (1H, d, Jꢂ7.8 Hz), 7.58 (1H, d, Jꢂ7.8 Hz), 7.64
(E)-5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-cyanophenyl)- (1H, s).
ethen-1-yl]-1-(ethanesulfonyl)indoline (12a) To a solution of t-butyl (E)-
4-{3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-[(ethanesulfonyl)-
amino]phenoxy}piperidine-1-carboxylate 11a (1.20 g, 2.16 mmol) in THF
(30 ml) was added n-Bu3P (0.770 ml, 3.09 mmol) and ADDP (0.710 g,
2.81 mmol) in THF (10 ml) and the mixture was stirred at room temperature
Other derivatives (12g, 12h) were similarly prepared.
12g: H-NMR (CDCl3) d: 1.47 (9H, s), 1.68—1.79 (2H, m), 1.83—1.96
(2H, m), 2.24 (3H, s), 2.88 (1H, d, Jꢂ16.5 Hz), 3.27—3.37 (2H, m), 3.56—
3.74 (3H, m), 4.35—4.43 (1H, m), 4.96—5.05 (1H, m), 6.28 (1H, dd,
Jꢂ6.2, 15.9 Hz), 6.47 (1H, d, Jꢂ15.9 Hz), 6.76 (1H, s), 6.79 (1H, d,
1
for 3 h. NH4Cl solution was added, and the mixture was extracted with Jꢂ8.7 Hz), 7.41 (1H, t, Jꢂ7.7 Hz), 7.53 (2H, t, Jꢂ7.7 Hz), 7.62 (1H, s),
EtOAc. The organic layer was washed with brine. The organic layer was 8.14 (1H, d, Jꢂ8.7 Hz).
1
dried and concentrated. The resulting residue was chromatographed on a sil-
ica gel column (hexane/EtOAcꢂ11/9) to give 12a (1.05 g, 1.95 mmol, 90%)
as a colorless amorphous solid. 1H-NMR (CDCl3) d: 1.35 (3H, t, Jꢂ7.4 Hz),
1.47 (9H, s), 1.67—1.78 (2H, m), 1.84—1.96 (2H, m), 2.89 (1H, dd, Jꢂ2.8,
16.5 Hz), 2.98—3.13 (2H, m), 3.27—3.36 (2H, m), 3.58 (1H, dd, Jꢂ9.8,
12h: H-NMR (CDCl3) d: 1.47 (9H, s), 1.66—1.79 (2H, m), 1.83—1.97
(2H, m), 2.20 (3H, s), 2.92 (1H, d, Jꢂ16.1 Hz), 3.25—3.38 (2H, m), 3.54—
3.75 (3H, m), 4.36—4.45 (1H, m), 4.69 (1H, d, Jꢂ14.6 Hz), 4.90 (1H, d,
Jꢂ14.6 Hz), 4.98—5.11 (1H, m), 6.28 (1H, dd, Jꢂ5.6, 15.8 Hz), 6.55 (1H,
d, Jꢂ15.8 Hz), 6.75—6.82 (2H, m), 7.41 (1H, t, Jꢂ7.7 Hz), 7.53 (1H, d,
16.5 Hz), 3.64—3.74 (2H, m), 4.34—4.42 (1H, m), 5.05—5.12 (1H, m), Jꢂ7.7 Hz), 7.56 (1H, d, Jꢂ7.7 Hz), 7.63 (1H, s), 8.08—8.17 (1H, m).
6.30 (1H, dd, Jꢂ6.9, 15.6 Hz), 6.69 (1H, d, Jꢂ15.6 Hz), 6.75—6.82 (2H,
m), 7.33 (1H, d, Jꢂ8.6 Hz), 7.40 (1H, t, Jꢂ7.8 Hz), 7.51 (1H, d, Jꢂ7.8 Hz),
7.58 (1H, d, Jꢂ7.8 Hz), 7.64 (1H, s).
(E)-5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-cyanophenyl)-
ethen-1-yl]-1-(hydroxyacetyl)indoline (12i) To solution of (E)-1-
(acetoxyacetyl)-5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-
a
(E)-5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidinophenyl)- cyanophenyl)ethen-1-yl]indoline 12h (813 mg, 1.49 mmol) in MeOH (12 ml)
ethen-1-yl]-1-(ethanesulfonyl)indoline Dihydrochloride (13a) HCl gas was added K2CO3 (51 mg, 0.37 mmol) at 0 °C. The mixture was stirred at
was bubbled through a solution of (E)-5-[1-(t-butoxycarbonyl)piperidin-4- room temperature for 1 h. The mixture was concentrated and the resulting
yloxy]-2-[2-(3-cyanophenyl)ethen-1-yl]-1-(ethanesulfonyl)indoline 12a residue was diluted with EtOAc. The organic layer was washed with H2O,
(970 mg, 1.80 mmol) in CH2Cl2 (12 ml) and EtOH (12 ml) at 0 °C. Then the
mixture was stirred at room temperature for 7 h and concentrated. The re-
sulting residue was dissolved in EtOH (21 ml) and the solution was treated 12i (478 mg, 0.949 mmol, 64%) as a pale yellow oil. H-NMR (CDCl3) d:
with NH4Cl (174 mg, 3.25 mmol) and NH3 solution (0.360 ml, 5.92 mmol).
brine. The organic layer was dried and concentrated. The resulting residue
was chromatographed on a silica gel column (hexane/EtOAcꢂ2/3) to give
1
1.47 (9H, s), 1.68—1.80 (2H, m), 1.86—1.97 (2H, m), 2.92 (1H, d,
The mixture was allowed to stand overnight at room temperature and con- Jꢂ15.8 Hz), 3.28—3.38 (2H, m), 3.55—3.75 (3H, m), 4.20—4.27 (1H, m),
centrated. The resulting residue was purified by reverse-phase HPLC (YMC- 4.30—4.46 (2H, m), 4.84—4.92 (1H, m), 6.24 (1H, dd, Jꢂ7.1, 15.9 Hz),
pack ODS, YMC, H2O/MeCNꢂ17/3) to give (E)-2-[2-(3-amidinophenyl)- 6.48 (1H, d, Jꢂ15.9 Hz), 6.77—6.88 (2H, m), 7.42 (1H, t, Jꢂ8.0 Hz), 7.54
ethen-1-yl]-1-(ethanesulfonyl)-5-(piperidin-4-yloxy)indoline (684 mg, 1.50 (2H, d, Jꢂ8.0 Hz), 7.61 (1H, s), 8.13 (1H, d, Jꢂ8.5 Hz).
mmol, 83%) as an amorphous solid. This solid (481 mg, 1.06 mmol) was
dissolved in EtOH (12 ml) and treated with ethyl acetimidate hydrochloride phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate Dihydrochloride (13f)
(288 mg, 2.33 mmol) and Et3N (0.490 ml, 3.53 mmol). The mixture was Ethyl (E)-2-{5-[1-(t-buthoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-cyano-
stirred overnight at room temperature. Ethyl acetimidate hydrochloride phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate 12f was converted into 13f
Ethyl (E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidino-
(65 mg, 0.53 mmol) and Et3N (0.074 ml, 0.53 mmol) was added, and the
mixture was stirred for 3 h. The mixture was concentrated and the resulting
residue was purified by reverse-phase HPLC (YMC-pack ODS, YMC,
H2O/MeCNꢂ4/1) to give the free base of 13a (430 mg, 0.867 mmol) as an
amorphous solid. This solid was dissolved in MeOH (8 ml) and treated with
4 N HCl in dioxane (0.640 ml, 2.56 mmol). The mixture was concentrated
and the resulting residue was lyophilized to give 13a (411 mg, 0.723 mmol,
68%) as a colorless amorphous solid.
by the similar procedure as that for 13a. 13f was obtained (61%, 3 steps) as
a colorless amorphous solid.
Other derivatives (13g, 13i) were similarly prepared.
(E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidinophenyl)-
ethen-1-yl]indolin-1-ylsulfonyl}acetic Acid Dihydrochloride (13j) A so-
lution of ethyl (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidino-
phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate dihydrochloride 13f (248 mg,
0.448 mmol) in 4 N HCl (12 ml) was stirred at 80 °C for 1.5 h. The mixture
was concentrated and the resulting residue was purified by reverse-phase
Other derivatives (13b—e) were similarly prepared.
t-Butyl (E)-4-{3-[4-(3-Cyanophenyl)-2-hydroxy-3-buten-1-yl]-4- HPLC (YMC-pack ODS, YMC, H2O/MeCNꢂ87/13) to give the free base of
[(ethoxycarbonylmethlysulfonyl)amino]phenoxy}piperidine-1-carboxy- 13j as an amorphous solid. This solid was dissolved in 1 N HCl (7 ml) and
late (11f) To a solution of t-butyl (E)-4-{4-amino-3-[4-(3-cyanophenyl)-2- the mixture was concentrated. The resulting residue was lyophilized to give
hydroxy-3-buten-1-yl]phenoxy}piperidine-1-carboxylate 10a (1.50 g, 3.24
13j (226 mg, 0.378 mmol, 84%) as a colorless amorphous solid.
mmol) in CH2Cl2 (25 ml) was added ethoxycarbonylmethylsulfonyl chloride
t-Butyl 4-[2-Chloro-4-nitro-5-(trimethylsilylmethyl)phenoxy]piperi-
(664 mg, 3.56 mmol) in CH2Cl2 (10 ml) at ꢃ10 °C and the mixture was dine-1-carboxylate (8k) and t-Butyl 4-[2-Chloro-4-nitro-3-(trimethylsi-
stirred for 1 h. Pyridine (0.290 ml, 3.59 mmol) was added, and the mixture
lylmethyl)phenoxy]piperidine-1-carboxylate (8l) To a solution of 2-
was stirred for 1.5 h. Ethoxycarbonylmethylsulfonyl chloride (664 mg, chloro-4-nitrophenol 14 (R4ꢂCl) (2.36 g, 13.6 mmol), t-butyl 4-hydroxyp-
3.56 mmol) in CH2Cl2 (2 ml) was added, and the mixture was stirred for iperidine-1-carboxylate 15 (3.32 g, 16.5 mmol) and PPh3 (5.11 g, 19.5 mmol)
0.5 h. NaHCO3 solution was added, and the mixture was extracted with in CH2Cl2 (60 ml) was added DEAD (3.10 ml, 19.7 mmol) at 0 °C and the
CH2Cl2. The organic layer was washed with brine. The organic layer was mixture was stirred at room temperature for 18 h. The mixture was concen-
dried and concentrated. The resulting residue was chromatographed on a sil- trated and the resulting residue was chromatographed on a silica gel column
ica gel column (hexane/EtOAcꢂ1/1) to give 11f (576 mg, 0.938 mmol, 29%)
as a yellow oil. H-NMR (CDCl3) d: 1.31 (3H, t, Jꢂ7.1 Hz), 1.47 (9H, s),
1.65—1.77 (2H, m), 1.81—1.95 (2H, m), 3.02—3.14 (2H, m), 3.25—3.36 36.2 mmol) was dissolved in THF (200 ml) and treated with (trimethylsilyl-
(hexane/EtOAcꢂ5/2) to give t-butyl 4-(2-chloro-4-nitro)phenoxypiperidine-
1-carboxylate (3.90 g, 10.9 mmol) as a pale yellow solid. This solid (12.90 g,
1
(2H, m), 3.59—3.72 (2H, m), 4.01 (1H, d, Jꢂ14.7 Hz), 4.05 (1H, d,
methyl)magnesium chloride (1.0 M in Et2O, 40.0 ml, 40.0 mmol) slowly at
Jꢂ14.7 Hz), 4.26 (2H, q, Jꢂ7.1 Hz), 4.38—4.46 (1H, m), 4.61—4.68 (1H, ꢃ25 °C and the mixture was stirred at ꢃ10 °C for 1 h. DDQ (10.21 g,
m), 6.36 (1H, dd, Jꢂ6.4, 15.9 Hz), 6.63 (1H, d, Jꢂ15.9 Hz), 6.78 (1H, d,
Jꢂ2.8 Hz), 6.81 (1H, dd, Jꢂ2.8, 8.7 Hz), 7.44 (1H, t, Jꢂ7.8 Hz), 7.48 (1H,
d, Jꢂ8.7 Hz), 7.54 (1H, d, Jꢂ7.8 Hz), 7.58 (1H, d, Jꢂ7.8 Hz), 7.63 (1H, s).
45.0 mmol) in THF (30 ml) was added slowly, and the mixture was stirred at
ꢃ10 °C for 2 h. NH4Cl solution was added, and the mixture was extracted
with EtOAc. The organic layer was washed with brine. The organic layer
Ethyl (E)-2-{5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-cyano- was dried and concentrated. The resulting residue was chromatographed on
phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate (12f) t-Butyl (E)-4-{3- a silica gel column (hexane/EtOAcꢂ4/1) to give 8k (4.40 g, 9.93 mmol,
[4-(3-cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-[(ethoxycarbonylmethlysul- 22%) as a yellow oil and 8l (7.04 g, 15.9 mmol, 35%) as a yellow oil.
1
fonyl)amino]phenoxy}piperidine-1-carboxylate 11f was converted into 12f
by the same procedure as that for 12a. 12f was obtained (86%) as a pale yel- 2.64 (2H, s), 3.43—3.65 (4H, m), 4.60—4.68 (1H, m), 6.56 (1H, s), 8.16
low amorphous solid. 1H-NMR (CDCl3) d: 1.26 (3H, t, Jꢂ7.1 Hz), 1.47
(1H, s).
8k: H-NMR (CDCl3) d: 0.02 (9H, s), 1.48 (9H, s), 1.79—1.98 (4H, m),

October 2007
1503
1
8l: H-NMR (CDCl3) d: 0.06 (9H, s), 1.48 (9H, s), 1.82—1.98 (4H, m),
(1H, m), 6.80 (1H, d, Jꢂ2.7 Hz), 6.92 (1H, dd, Jꢂ2.7, 9.2 Hz), 6.94 (1H, d,
Jꢂ16.1 Hz), 7.54 (1H, t, Jꢂ7.9 Hz), 7.63 (1H, d, Jꢂ16.1 Hz), 7.69 (1H, d,
Jꢂ7.9 Hz), 7.80 (1H, d, Jꢂ7.9 Hz), 7.86 (1H, s), 8.22 (1H, d, Jꢂ9.2 Hz).
t-Butyl (S)-(E)-4-{4-Amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-
1-yl]phenoxy}piperidine-1-carboxylate ((S)-10a) To a solution of (R)-
a,a-diphenyl-2-pyrrolidinemethanol (R)-17 (665 mg, 2.62 mmol) in THF
(30 ml) was added trimethoxyborane (409 mg, 3.94 mmol) in THF (5 ml) and
the mixture was stirred at room temperature for 1 h. Borane-dimethylsulfide
complex (2.0 M in THF, 2.62 ml, 5.24 mmol) and t-butyl (E)-4-{3-[4-(3-
cyanophenyl)-2-oxo-3-buten-1-yl]-4-nitrophenoxy}piperidine-1-carboxylate
16 (1.29 g, 2.62 mmol) in THF (25 ml) was added, and the mixture was
stirred at room temperature for 1.5 h. NH4Cl solution was added, and the
mixture was extracted with EtOAc. The organic layer was washed with
brine. The organic layer was dried and concentrated. The resulting residue
was chromatographed on a silica gel column (hexane/EtOAcꢂ1/1) to give t-
butyl (S)-(E)-4-{3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-nitrophe-
noxy}piperidine-1-carboxylate (963 mg, 1.95 mmol, 74%) as a colorless
amorphous solid. To a solution of this solid in AcOH (15 ml) was added zinc
powder (762 mg, 11.7 mmol) and the mixture was stirred at room tempera-
ture for 1 h. Zinc powder (762 mg, 11.7 mmol) was added, and the mixture
was stirred at room temperature for 1 h. The mixture was filtered, and the fil-
trate was concentrated. The resulting residue was diluted with EtOAc and
washed with NaHCO3 solution and brine. The organic layer was dried and
concentrated. The resulting residue was chromatographed on a silica gel col-
umn (hexane/EtOAcꢂ1/3) and then purified by chiral HPLC (Daicel Chiral-
cel OD, Daicel Chemical Industries Ltd., hexane/i-PrOHꢂ7/3) to give (S)-
10a (432 mg, 0.932 mmol, 48%, ꢁ99% ee) as a yellow oil. [a]D ꢄ46.1° (cꢂ
0.43, MeOH).
(R)-(E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidino-
phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic Acid Dihydrochloride ((R)-
13j) t-Butyl (S)-(E)-4-{4-amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-
1-yl]phenoxy}piperidine-1-carboxylate (S)-10a was converted into (R)-13j
by the same procedure as that for racemate 13j. (R)-13j was obtained (10%,
6 steps) as a colorless amorphous solid. [a]D ꢃ13.6° (cꢂ0.29, MeOH).
t-Butyl (R)-(E)-4-{4-Amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-
1-yl]phenoxy}piperidine-1-carboxylate ((R)-10a) t-Butyl (E)-4-{3-[4-(3-
cyanophenyl)-2-oxo-3-buten-1-yl]-4-nitrophenoxy}piperidine-1-carboxylate
16 was converted into (R)-10a by the same procedure as that for (S)-10a.
(S)-a,a-Diphenyl-2-pyrrolidinemethanol (S)-17 was used instead of (R)-17.
(R)-10a was obtained (17%, 2 steps, ꢁ99% ee) as a brown amorphous solid.
[a]D ꢃ43.6° (cꢂ1.02, MeOH).
2.84 (2H, s), 3.48—3.66 (4H, m), 4.64—4.75 (1H, m), 6.76 (1H, d,
Jꢂ9.2 Hz), 7.91 (1H, d, Jꢂ9.2 Hz).
Ethyl (E)-2-{5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-6-chloro-2-[2-
(3-cyanophenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate (12k) t-Butyl 4-
[2-chloro-4-nitro-5-(trimethylsilylmethyl)phenoxy]piperidine-1-carboxylate
8k was converted into 12k by the same procedure as that for 12a. 12k was
obtained (8%, 4 steps) as a pale yellow oil. 1H-NMR (CDCl3) d: 1.28 (3H, t,
Jꢂ7.4 Hz), 1.47 (9H, s), 1.76—1.95 (4H, m), 2.85 (1H, dd, Jꢂ1.8, 16.2 Hz),
3.36—3.47 (2H, m), 3.63—3.77 (3H, m), 4.05 (2H, s), 4.10—4.22 (2H, m),
4.39—4.48 (1H, m), 5.19—5.27 (1H, m), 6.30 (1H, dd, Jꢂ6.8, 15.4 Hz),
6.67 (1H, d, Jꢂ15.4 Hz), 6.87 (1H, s), 7.41 (1H, t, Jꢂ7.8 Hz), 7.49 (1H, s),
7.52 (1H, d, Jꢂ7.8 Hz), 7.58 (1H, d, Jꢂ7.8 Hz), 7.65 (1H, s).
Other derivatives (12l—s) were similarly prepared.
Ethyl (E)-2-{5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-6-carboxy-2-
[2-(3-cyanophenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate (12t) To a so-
lution of ethyl (E)-2-{5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-[2-(3-
cyanophenyl)ethen-1-yl]-6-(1,3-dioxolan-2-yl)indolin-1-ylsulfonyl}acetate
12s (850 mg, 1.27 mmol) in acetone (40 ml) and H2O (10 ml) was added p-
TsOH monohydrate (80 mg, 0.42 mmol) and the mixture was stirred at room
temperature for 30 min. NaHCO3 solution was added, and the mixture was
concentrated. The resulting residue was extracted with EtOAc and the or-
ganic layer was washed with brine. The organic layer was dried and concen-
trated to give Ethyl (E)-2-{5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-[2-
(3-cyanophenyl)ethen-1-yl]-6-formylindolin-1-ylsulfonyl}acetate (780 mg)
as a yellow amorphous solid. This solid (770 mg, 1.23 mmol) and 2-methyl-
2-butene (8.00 ml, 75.5 mmol) was dissolved in t-BuOH (80 ml) and treated
with NaClO2 (1.03 g, 11.4 mmol) and NaH2PO4 (1.37 g, 11.4 mmol) in H2O
(12 ml) slowly. The mixture was stirred at room temperature for 0.5 h and
concentrated. The resulting residue was extracted with EtOAc. The organic
layer was washed with NaHCO3 solution and brine. The organic layer was
dried and concentrated to give 12t (920 mg, quant.) as a yellow amorphous
solid. 1H-NMR (CDCl3) d: 1.29 (3H, t, Jꢂ7.2 Hz), 1.47 (9H, s), 1.81—1.86
(2H, m), 2.04—2.11 (2H, m), 2.94 (1H, dd, Jꢂ2.3, 17.0 Hz), 3.26 (2H, t,
Jꢂ10.3 Hz), 3.79—3.86 (3H, m), 4.07 (2H, s), 4.11—4.24 (2H, m), 4.66—
4.68 (1H, m), 5.28 (1H, t, Jꢂ6.8 Hz), 6.30 (1H, dd, Jꢂ6.8, 15.7 Hz), 6.68
(1H, d, Jꢂ15.7 Hz), 6.99 (1H, s), 7.41 (1H, t, Jꢂ7.7 Hz), 7.52 (1H, d,
Jꢂ7.7 Hz), 7.58 (1H, d, Jꢂ7.7 Hz), 7.65 (1H, s), 8.13 (1H, s).
Ethyl (E)-2-{5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-6-carbamoyl-
2-[2-(3-cyanophenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate (12u) To a
solution of ethyl (E)-2-{5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-6-car-
boxy-2-[2-(3-cyanophenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate 12t (460
mg, 0.719 mmol) in CH2Cl2 (10 ml) was added Et3N (0.120 ml, 0.866 mmol)
and ClCO2i-Pr (0.110 ml, 0.966 mmol) and the mixture was stirred at room
temperature for 30 min. NH3 solution (0.090 ml, 1.5 mmol) was added, and
the mixture was stirred at room temperature for 30 min. The mixture was ex-
tracted with EtOAc and the organic layer was washed with H2O and brine.
The organic layer was dried and concentrated. The resulting residue was
chromatographed on a silica gel column (EtOAc) to give 12u (380 mg,
(S)-(E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidino-
phenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic Acid Dihydrochloride ((S)-
13j) t-Butyl (R)-(E)-4-{4-amino-3-[4-(3-cyanophenyl)-2-hydroxy-3-buten-
1-yl]phenoxy}piperidine-1-carboxylate (R)-10a was converted into (S)-13j
by the same procedure as that for racemate 13j. (S)-13j was obtained (9%, 6
steps) as a yellow amorphous solid. [a]D ꢄ16.1° (cꢂ0.99, MeOH).
5-Cyano-2-(methoxymethoxy)cinnamaldehyde (20) To a solution of
5-cyano-2-hydroxybenzaldehyde 18 (2.08 g, 14.1 mmol) in toluene (60 ml)
was added (triphenylphosphoranylidene)acetaldehyde (4.52 g, 14.9 mmol)
and the mixture was stirred at 70 °C for 1.5 h. The mixture was concentrated
and the resulting residue was chromatographed on a silica gel column
(hexane/EtOAcꢂ1/1) to give 5-cyano-2-hydroxycinnamaldehyde 19 (1.65 g,
9.53 mmol) as a colorless solid. To a solution of this solid (1.63 g,
9.41 mmol) in DMA (30 ml) was added methoxymethylchloride (0.850 ml,
11.2 mmol) and Et3N (1.57 ml, 11.3 mmol) at 0 °C and the mixture was
stirred at room temperature for 5 h. Methoxymethylchloride (0.210 mmol,
2.76 mmol) and Et3N (0.390 ml, 2.81 mmol) were added, and the mixture
was stirred for 2 h. Brine was added, and the mixture was extracted with
EtOAc. The organic layer was washed with brine. The organic layer was
dried and concentrated. The resulting residue was chromatographed on a sil-
ica gel column (hexane/EtOAcꢂ17/3) to give 20 (1.86 g, 8.56 mmol, 61%)
1
0.595 mmol, 83%) as a brown amorphous solid. H-NMR (CDCl3) d: 1.29
(3H, t, Jꢂ7.2 Hz), 1.47 (9H, s), 1.73—1.83 (2H, m), 1.99—2.08 (2H, m),
2.90 (1H, dd, Jꢂ2.4, 16.8 Hz), 3.25 (2H, t, Jꢂ10.5 Hz), 3.77—3.84 (3H, m),
4.05 (1H, d, Jꢂ14.4 Hz), 4.08 (1H, d, Jꢂ14.4 Hz), 4.10—4.24 (2H, m),
4.55—4.59 (1H, m), 5.27 (1H, t, Jꢂ7.0 Hz), 6.29 (1H, dd, Jꢂ6.6, 15.7 Hz),
6.67 (1H, d, Jꢂ15.7 Hz), 6.92 (1H, s), 7.40 (1H, t, Jꢂ7.8 Hz), 7.51 (1H, d,
Jꢂ7.8 Hz), 7.57 (1H, d, Jꢂ7.8 Hz), 7.65 (1H, s), 8.18 (1H, s).
Ethyl (E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(3-amidino-
phenyl)ethen-1-yl]-6-chloroindolin-1-ylsulfonyl}acetate Dihydrochloride
(13k) Ethyl (E)-2-{5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-6-chloro-2-
[2-(3-cyanophenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate 12k was con-
verted into 13k by the same procedure as that for 13a. 13k was obtained
(50%, 3 steps) as a colorless amorphous solid.
1
Other derivatives (13l—r, 13t, 13u) were similarly prepared.
as a colorless solid. H-NMR (CDCl3) d: 3.52 (3H, s), 5.36 (2H, s), 6.80
t-Butyl (E)-4-{3-[4-(3-Cyanophenyl)-2-oxo-3-buten-1-yl]-4-nitrophe-
noxy}piperidine-1-carboxylate (16) To a solution of t-butyl (E)-4-{3-[4-
(3-cyanophenyl)-2-hydroxy-3-buten-1-yl]-4-nitrophenoxy}piperidine-1-car-
boxylate 9a (2.55 g, 5.17 mmol) in CH2Cl2 (50 ml) was added pyridinium
chlorochromate (PCC) (1.45 g, 6.73 mmol) at 0 °C and the mixture was
stirred overnight at room temperature. The mixture was filtered, and the fil-
trate was washed with H2O and brine. The organic layer was dried and con-
centrated. The resulting residue was chromatographed on a silica gel column
(CH2Cl2/EtOAcꢂ4/1) to give 16 (1.79 g, 3.64 mmol, 70%) as a colorless
(1H, dd, Jꢂ7.6, 16.2 Hz), 7.30 (1H, d, Jꢂ8.7 Hz), 7.66 (1H, dd, Jꢂ2.1,
8.7 Hz), 7.75 (1H, d, Jꢂ16.2 Hz), 7.84 (1H, d, Jꢂ2.1 Hz), 9.74 (1H, d,
Jꢂ7.6 Hz).
Ethyl (E)-2-(5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-2-{2-[5-cyano-
2-(methoxymethoxy)phenyl]ethen-1-yl}indolin-1-ylsulfonyl)acetate (21c)
5-Cyano-2-(methoxymethoxy)cinnamaldehyde 20 was converted into 21c by
the similar procedure as that for 12a. 21c was obtained (15%, 4 steps) as a
colorless amorphous solid. 1H-NMR (CDCl3) d: 1.26 (3H, t, Jꢂ7.1 Hz),
1.47 (9H, s), 1.68—1.79 (2H, m), 1.85—1.95 (2H, m), 2.87 (1H, dd, Jꢂ2.1,
16.3 Hz), 3.28—3.38 (2H, m), 3.47 (3H, s), 3.64—3.77 (3H, m), 3.98 (1H,
d, Jꢂ14.1 Hz), 4.03 (1H, d, Jꢂ14.1 Hz), 4.09—4.20 (2H, m), 4.34—4.42
1
solid. H-NMR (CDCl3) d: 1.48 (9H, s), 1.73—1.86 (2H, m), 1.90—2.02
(2H, m), 3.30—3.44 (2H, m), 3.61—3.75 (2H, m), 4.35 (2H, s), 4.57—4.64

1504
Vol. 55, No. 10
Research Laboratories, Inc., IN, U.S.A.) and S-2238 (4 mM, Daiichi Pure
Chemical, Japan); human plasmin (8 mg, Enzyme Research Laboratories,
Inc., IN, U.S.A.) and S-2251 (4 mM, Daiichi Pure Chemical, Japan).
Coagulation Assay Citrated blood samples were collected from healthy
male volunteers (Japan SLC). Platelet-poor plasma was prepared by cen-
trifugation at 2000ꢅg for 10 min and stored at ꢃ20 °C until use. Plasma
clotting times were determined using a COAGMASTER II (Sankyo, Japan).
Prothrombin time (PT) and activated partial thromboplastin time (APTT)
were measured using Simplastin Excel (Organon Teknika, NC, U.S.A.) and
Platelin LS (Organon Teknika, NC, U.S.A.), respectively. Coagulation times
for each compound were compared with coagulation times measured using a
distilled water control. Each measurement was performed three times. The
concentration required to double the clotting time (CT2) was estimated by
linear regression analysis using two data points, the two mean values of the
concentrations closest to the predicted 2-fold PT.
(1H, m), 5.17—5.24 (1H, m), 5.25 (2H, s), 6.29 (1H, dd, Jꢂ7.4, 15.9 Hz),
6.77 (1H, dd, Jꢂ2.5, 8.7 Hz), 6.81 (1H, d, Jꢂ2.5 Hz), 6.96 (1H, d,
Jꢂ15.9 Hz), 7.14 (1H, d, Jꢂ8.6 Hz), 7.34 (1H, d, Jꢂ8.7 Hz), 7.47 (1H, dd,
Jꢂ2.1, 8.6 Hz), 7.69 (1H, d, Jꢂ2.1 Hz).
Other derivatives (21a, 21d, 21e) were similarly prepared.
(E)-5-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]-2-[2-(5-cyano-2-
methoxyphenyl)ethen-1-yl]-1-(ethanesulfonyl)indoline (21b) To a solu-
tion of (E)-5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-{2-[5-cyano-2-
(methoxymethoxy)phenyl]ethen-1-yl}-1-(ethanesulfonyl)indoline 21a (530
mg, 0.887 mmol) in EtOAc (5 ml) was added 4 N HCl in EtOAc (5 ml) at
0 °C and the mixture was stirred at room temperature for 4 h. The mixture
was concentrated to give monohydrochloride of (E)-2-[2-(5-cyano-2-
hydroxyphenyl)ethen-1-yl]-1-(ethanesulfonyl)-5-(piperidin-4-yloxy)indoline
(514 mg) as a pale brown oil. To a solution of this oil (514 mg) in acetone
(10 ml) and H2O (10 ml) was added Boc2O (203 mg, 0.930 mmol) and
NaHCO3 (82.0 mg, 0.976 mmol) at 0 °C and the mixture was stirred at room
temperature for 5 h. The mixture was concentrated and the resulting residue
was extracted with EtOAc. The organic layer was washed with NH4Cl solu-
tion and brine. The organic layer was dried and concentrated. The resulting
residue was chromatographed on a silica gel column (hexane/EtOAcꢂ2/3)
to give (E)-5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-[2-(5-cyano-2-hy-
droxyphenyl)ethen-1-yl]-1-(ethanesulfonyl)indoline (472 mg, 0.852 mmol)
as a colorless oil. To a solution of this oil (452 mg, 0.816 mmol) in benzene
(16 ml) and MeOH (4 ml) was added (trimethylsilyl)diazomethane (2.0 M in
hexane, 1.22 ml, 2.44 mmol) and the mixture was stirred at room tempera-
ture for 0.5 h. The mixture was concentrated and the resulting residue was
chromatographed on a silica gel column (hexane/EtOAcꢂ1/1) to give 21b
(448 mg, 0.789 mmol, 93%) as a colorless oil. 1H-NMR (CDCl3) d: 1.36
(3H, t, Jꢂ7.4 Hz), 1.47 (9H, s), 1.67—1.79 (2H, m), 1.83—1.96 (2H, m),
2.89 (1H, dd, Jꢂ2.7, 16.4 Hz), 2.98—3.14 (2H, m), 3.26—3.39 (2H, m),
3.57 (1H, dd, Jꢂ9.7, 16.4 Hz), 3.63—3.75 (2H, m), 3.89 (3H, s), 4.33—4.42
(1H, m), 5.04—5.12 (1H, m), 6.30 (1H, dd, Jꢂ7.5, 16.0 Hz), 6.76 (1H, dd,
Jꢂ2.4, 8.7 Hz), 6.79 (1H, d, Jꢂ2.4 Hz), 6.90 (1H, d, Jꢂ8.6 Hz), 6.93 (1H, d,
Jꢂ16.0 Hz), 7.31 (1H, d, Jꢂ8.7 Hz), 7.51 (1H, dd, Jꢂ2.0, 8.6 Hz), 7.65 (1H,
d, Jꢂ2.0 Hz).
Acknowledgments We wish to thank Ms. Naoko Suzuki and Ms. Yumi-
ko Fujisawa for their expert technical assistance, and Dr. Ken-ichi Otsuguro
for his helpful discussions.
References and Notes
1) Fujimoto K., Asai F., Tanaka N., JP Patent 2002-088080 (2002).
2) Present address: General Administration Department, Daiichi Sankyo
Business Associe Co., Ltd.; 1–8 Nihonbashikomicho, Chuo-ku, Tokyo
103–8541, Japan.
3) Kaiser B., Hauptmann J., Cardiovasc. Drug Rev., 12, 225—236
(1994).
4) Davie E. W., Fujisawa K., Kisiel W., Biochemistry, 30, 10363—10370
(1991).
5) Hara T., Yokoyama A., Tanabe K., Ishihara H., Iwamoto M., Thromb.
Haemostasis, 74, 635—639 (1995).
6) Sato K., Kawasaki T., Hisamichi N., Taniuchi Y., Hirayama F., Koshio
H., Matsumoto Y., Br. J. Pharmacol., 123, 92—96 (1998).
7) Noguchi T., Tanaka N., Nishimata T., Goto R., Hayakawa M., Sugi-
dachi A., Ogawa T., Asai F., Matsui Y., Fujimoto K., Chem. Pharm.
Bull., 54, 163—174 (2006).
8) Noguchi T., Tanaka N., Nishimata T., Goto R., Hayakawa M., Sugi-
dachi A., Ogawa T., Asai F., Ozeki T., Fujimoto K., Chem. Pharm.
Bull., 55, 393—402 (2007).
Ethyl (E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-
hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetate Dihydrochloride
(22c) Ethyl (E)-2-(5-[1-(t-butoxycarbonyl)piperidin-4-yloxy]-2-{2-[5-
cyano-2-(methoxymethoxy)phenyl]ethen-1-yl}indolin-1-ylsulfonyl)acetate
21c was converted into 22c by the similar procedure as that for 13a. 22c was
obtained (23%, 3 steps) as a pink amorphous solid.
9) Bartoli G., Bosco M., Caretti D., Dalpozzo R., Todesco P. E., J. Org.
Chem., 52, 4381—4384 (1987).
10) Tsunoda T., Yamamiya Y., Ito S., Tetrahedron Lett., 34, 1639—1642
(1993).
11) Oliver J. E., DeMilo A. B., Synthesis, 1975, 321—322 (1975).
12) Bartoli G., Bosco M., Dalpozzo R., Todesco P. E., J. Org. Chem., 51,
3694—3696 (1986).
13) Corey E. J., Bakshi R. K., Shibata S., Chen C. P., Singh V. K., J. Am.
Chem. Soc., 109, 7925—7926 (1987).
14) Wallbaum S., Martens J., Tetrahedron Asymmetry, 3, 1475—1504
(1992).
Other derivatives (22a, 22b, 22d, 22e) were similarly prepared.
(E)-2-{5-[1-(Acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-
hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic Acid Dihydrochlo-
ride (22f) A solution of dihydrochloride of ethyl (E)-2-{5-[1-(acetimi-
doyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]in-
dolin-1-ylsulfonyl}acetate 22c (223 mg, 0.347 mmol) in 1 N HCl (10 ml) was
stirred at 80 °C for 7.5 h. The mixture was concentrated and the resulting
residue was purified by reverse-phase HPLC (YMC-pack ODS, YMC,
H2O/MeCNꢂ9/1) to give the free base of 22f as an amorphous solid. This
solid was dissolved in 1 N HCl (10 ml) and the mixture was concentrated to
give 22f (143 mg, 0.247 mmol, 67%) as a pale brown amorphous solid.
Other derivatives (22g, 22h) were similarly prepared.
15) Brandstetter H., Kuhne A., Bode W., Huber R., von der Saal W.,
Wirthensohn K., Engh R. A., J. Biol. Chem., 271, 29988—29992
(1996).
16) Adler M., Davey D. D., Phillips G. B., Kim S.-H., Jancarik J., Rumen-
nik G., Light D. R., Whitlow M., Biochemistry, 39, 12534—12542
(2000).
17) Maignan S., Guilloteau J.-P., Pouzieux S., Choi-Sledeski Y. M., Becker
M. R., Klein S. I., Ewing W. R., Pauls H. W., Spada A. P., Mikol V., J.
Med. Chem., 43, 3226—3232 (2000).
18) Phillips G., Guilford W. J., Buckman B. O., Davey D. D., Eagen K. A.,
Koovakkat S., Liang A., McCarrick M., Mohan R., Ng H. P., Pinkerton
M., Subramanyam B., Ho E., Trinh L., Whitlow M., Wu S., Xu W.,
Morrissey M. M., J. Med. Chem., 45, 2484—2493 (2002).
19) Willardsen J. A., Dudley D. A., Cody W. L., Chi L., McClanahan T. B.,
Mertz T. E., Potoczak R. E., Narasimhan L. S., Holland D. R., Rapun-
dalo S. T., Edmunds J. J., J. Med. Chem., 47, 4089—4099 (2004).
Biology. Anti-FXa, Trypsin, FIIa and Plasmin Assay The hydroly-
sis of chromogenic substrates was assayed by continuously measuring ab-
sorbance at 405 nm at 37 °C with a microplate reader (SPECTRA max
PLUS 384, Molecular Devices, CA, U.S.A.). Reaction mixtures (90 ml) were
prepared in 96-well plates containing enzyme and compounds in reaction
buffer (50 mM Tris–HCl–150 mM NaCl, pH 8.4, as for plasmin: pH 7.4). Re-
actions were initiated by the addition of 10 ml of substrate and monitored for
5 min. The concentration required to inhibit enzyme activity by 50% (IC50)
was estimated from dose–response curves. Enzyme and substrate were used
as follows: human FXa (0.5 IU, Enzyme Research Laboratories, Inc., IN,
U.S.A.) and S-2222 (4 mM, Daiichi Pure Chemical, Japan); human trypsin
(750 mU, Athens Research & Tech., Inc., GA, U.S.A.) and S-2222 (4 mM,
Daiichi Pure Chemical, Japan); human alpha thrombin (1.25NIH u, Enzyme