Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitor

Article abstract of DOI:10.1248/cpb.49.1237

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazinone derivatives, containing a 4-(piperidino)pyridine group in place of guanidino and/or amidino groups, and discovered compound M55113 (30a: 4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]- methyl]piperazinone), as a potent inhibitor of FXa (IC₅₀=0.06 μM) with high selectivity for FXa over trypsin and thrombin.

Full text of DOI:10.1248/cpb.49.1237

October 2001
Chem. Pharm. Bull. 49(10) 1237—1244 (2001)
1237
Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as
Factor Xa Inhibitor
Hidemitsu NISHIDA,* Yutaka MIYAZAKI, Yoshihiro KITAMURA, Masayuki OHASHI,
Tomokazu MATSUSUE, Atsushi OKAMOTO, Yoshitaka HOSAKA, Shuhei OHNISHI, and
Hidenori MOCHIZUKI
Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 722, Jimba-aza-Uenohara, Gotemba,
Shizuoka 412–8524, Japan. Received January 25, 2001; accepted June 11, 2001
Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the
prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach
is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation
of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazi-
none derivatives, containing a 4-(piperidino)pyridine group in place of guanidino and/or amidino groups, and
discovered compound M55113 (30a: 4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
methyl]piperazinone), as a potent inhibitor of FXa (IC50؍0.06 mM) with high selectivity for FXa over trypsin and
thrombin.
Key words factor Xa inhibitor; 4-(piperidino)pyridine; structure–activity relationship; M55113
Regarding the prevention of blood coagulation, most re-
search in the past decade has been focused on thrombin inhi- and is nearly equal to that of amidinonaphthalene.
bition.1,2) More recently, inhibition of factor Xa (FXa), which
ii) The basicity of two nitrogen atoms in the piperazine
is directly responsible for prothrombin activation, has emerg- ring is reduced by the adjacent acyl and sulfonyl groups.
ed as an attractive target. iii) Due to a resonance structure of 4-dialkylaminopy-
i) The pKa value of 4-(piperidino)pyridine is about 12
FXa, which converts prothrombin to thrombin, holds a ridines, a 4-(piperidino)pyridine moiety in compound 3 is
central position in the coagulation cascade.3) One molecule thought to have a plane structure as well as the naphthalene
of FXa generates over 100 molecules of thrombin. Therefore, moiety in compounds 1 and 2.
inhibition of FXa may be more effective than inhibition of
To analyze the role of the carbonyl group in compound 3,
thrombin for the prevention of blood coagulation.4,5) In addi- the following compounds were synthesized and the in-
tion, a recent study by Harker et al.6) in a balloon model of hibitory activity of FXa in vitro was evaluated in our labora-
thrombosis showed that FXa inhibitors might have less tory.
bleeding risk than thrombin inhibitors.7)
In compound 4 the carbonyl group is removed and in com-
Most of the nonpeptide FXa inhibitors reported in the lit- pounds 5 and 6 the carbonyl group is replaced by a methyl-
erature are dibasic compounds. Nagahara et al.8,9) have re- ene group. In the present paper we wish to report the process
ported synthesis and evaluation of a series of bis(amidino)- of the above investigation.
derivatives, and through investigation compound DX-9065a
(1)10—14) was found to be a selective FXa inhibitor. Further, a
compound YM-60828 (2)15—20) which is closely related to 1
in terms of structure was found to have a more potent in-
hibitory effect on FXa.
A characteristic common to compounds 1 and 2 is having
two amidino groups in their molecules, and is considered the
presence of more than one such strongly basic group is seen
as an unfavorable element for adequate oral absorption and
the good pharmacokinetics necessary for oral antithrombotic
agents.
Based on these considerations, a compound (3) recently
reported by ZENECA Co.21) is of great interest in the follow-
ing points:
Fig. 1
To whom correspondence should be addressed. e-mail: hnishida@mochida.co.jp
© 2001 Pharmaceutical Society of Japan

1238
Vol. 49, No. 10
Chart 1. Synthesis of Compounds 4 and 5
Chart 3. Synthetic Route of 2-Substituted Piperazine Derivatives 23a—g
Chart 2. Synthesis of Compound 6 and General Synthesis of Sulfonamide
Derivatives 19a—l
Chemistry
Synthesis of compounds 4 and 5 was achieved as shown
in Chart 1. Compound 9, prepared by the reaction of 4-
piperidinone monohydrate hydrochloride (8) with (1E)-2-(4-
chlorophenyl) ethenesulfonyl chloride (7) under basic condi-
tions, was treated with 1-(4-pyridinyl)piperazine (10) in
methylene chloride (CH2Cl2) in the presence of sodium tri-
acetoxy borohydride (NaBH(OAc)3) to give desired com-
pound 4.22)
A similar reaction was adapted to the synthesis of com-
pound 5. Namely, 4-piperidinemethanol (11) was converted
to compound (12) by treatment with compound 7 and Swern
oxidation23) of compound 12 afforded the corresponding
aldehyde which condensed with compound 10 to give the de-
sired compound 5 in satisfactory yield.
Chart 4. Synthetic Route of 2-Piperazinone Derivatives 3a—e
accomplished according to the route shown in Chart 3.
Compound 21 was easily prepared by sulfonylation of 1-
(phenylmethyl)-2-piperazinecarboxylic acid ethyl ester (20)
with 6-chloro-2-naphthalenesulfonyl chloride (18f) under
traditional conditions. Debenzylation of compound 21 with
1-chloroethyl chloroformate afforded compound 22, and one
of the desired compounds (23a) was obtained by subsequent
reductive amination of compound 22 with the aldehyde 14.
Then, as shown in Chart 3, the conversion of compound 23a
to various derivatives (23b—g) was carried out. For example,
compound 23f was obtained by coupling reaction of com-
pound 23c with potassium ethyl malonate in the presence of
carbonyl diimidazole at room temperature and the resulting
mixture was heated to finish decarboxylation. Hydrolysis of
compound 23f in diluted hydrochloric acid gave the corre-
sponding acetyl compound (23g).
Synthesis of compound 6 and related sulfonamide deriva-
tives (19a—l) was shown in Chart 2.
Swern oxidation of 1-(4-pyridinyl)-4-piperidinemethanol
(13) which was obtained by the reaction of compound 11
with 4-chloropyridine gave the key intermediate carbalde-
hyde (14). Since the aldehyde tended to form a hydrate, the
crude 14 was treated with 1-piperazinecarboxylic acid 1,1-di-
methylethyl ester (15) under reductive conditions to give
compound 16. Deprotection of compound 16 in diethyl ether
in the presence of trifluoroacetic acid (TFA) and anisole
yielded compound 17, and the final compounds 6 and 19a—l
were obtained smoothly by the condensation with 7 or the
aromatic sulfonyl chlorides 18a—l in a similar manner to
that described in the synthesis of compounds 9 and 12.
Synthesis of piperazine derivatives containing a carbon
functional group at the 2-position of the piperazine ring was
Finally, synthesis of the corresponding 2-piperazinone de-
rivatives (30a—e) was carried out as shown in Chart 4.

October 2001
1239
When the aldehyde 14 was treated with N-(tert-butoxycar-
Finally, the structure–activity relationships (SARs) studies
bonyl)-1,2-diaminoethane in the presence of NaBH(OAc)3 in focused on the substitution to the 2-position of the piperazine
acetic acid (AcOH), a normal reductive amination product ring in compound 19f were carried out as follows. Based on
(24) was formed together with a considerable amount of a the results listed in Tables 1—3, for further development it
boron complex (25) in a ratio of about 1 : 2. The acylation of may be desirable to restrict the mobility of the lone pair on
24 with bromoacetyl chloride under basic conditions failed the N1 in the piperazine ring by the electron withdrawing ef-
to give the desired bromoacetamido derivative (26). In con- fect of an appropriate neighboring group.
trast, the reaction of the boron complex (25) under similar
Thus, the compounds containing an electron withdrawing
conditions afforded the bromoacetamido derivative (27) in substituent at the 2-position of the piperazine moiety (23a—
good yield, although the reason for these phenomena is not g) were evaluated for their FXa inhibitory activity. As listed
well understood. Deprotection of compound 27 with TFA in Table 4, except for the ethoxycarbonyl group (23a), sub-
and anisole was accompanied with removal of the boron moi- stituents at the 2-position have almost no effect on improve-
ety to give compound 28, which smoothly cyclized into the ment of the activity. However, it should be emphasized that
desired 2-piperazinone (29) under basic conditions. Com- the introduction of a carbonyl group instead of substituents
pounds 30a—e were obtained by sulfonation of compound was found to be the most effective (30a), and compound 30a
29 with several substituted naphthalenesulfonyl chlorides in is about 13 times more effective than compound 6. This find-
yields ranging from 13 to 31%.
ing suggests that extinguishing the basicity of N1 is a very
important factor for exhibition of FXa inhibitor.
Results and Discussion
In connection with this finding, replacement of the chloro
In comparison with compound 3, the FXa inhibitory activ- substituent on the naphthalene ring of compound 30a to
ity of compound 4 is remarkably low, while the activity of other substituents was investigated to prevent overlooking
compounds 5 and 6 is slightly less than that of compound 3 better compounds, but as shown in Table 5 no compound bet-
(Table 1). This fact seems to suggest that the whole molecu- ter than compound 30a could be found.
lar length is an important factor for the appearance of in-
hibitory activity of FXa and that the interaction of FXa with Conclusion
the carbonyl group in compound 3 is not strong. Further,
As described in this paper, through the modification of
compound 6 is 2 fold more active than compound 5, which piperazine derivatives, we accomplished a very active com-
means piperidine moiety is rather more favorable than piper-
azine moiety by the side of pyridine.
Table 2. FXa Inhibitory Activity of Compounds 19a—e
On the basis of this hypothesis, we decided to select com-
pound 6 as the lead substance to search for a more powerful
FXa inhibitor by optimization of the compound.
Compound
X
IC50 (mM)
Ͼ10
Next, the appropriateness of arylsulfonyl group on com-
pound 6 was investigated, because the bulkiness and co-pla-
narity of this group in the molecule is believed to be another
important factor of the interaction between tested compounds
and FXa. Among the compounds (19a—e) tested, naphtha-
lene-2-sulfonic acid (19b) and benzo[b]thiophene-2-sulfonic
acid (19d) derivatives were the most powerful inhibitors of
FXa, although all the compounds showed impaired activity
compared to compound 6. In addition, compound 19e, the
aza-analogue of compound 19d, ran counter to our expecta-
tion, probably due to the basicity of the nitrogen atom in a
thiazole ring.
19a
19b
19c
8.29
Ͼ10
19d
19e
3.95
Ͼ10
Table 3. FXa Inhibitory Activity of Compounds 19f—l
Then, according to the data shown in Table 2, the sub-
stituent effect of naphthyl and benzothienyl groups to the ac-
tivity was tested. The activity of compounds 19f—l together
with that of compound 6 is summarized in Table 3.
Compound
X
IC50 (mM)
19f
0.83
Table 1. FXa Inhibitory Activity of Compounds 3—6
19g
0.30
19h
19i
0.72
0.41
Compound
L
IC50 (mM)
3
0.21
19j
1.75
4
5
6
Ͼ10
1.74
0.83
19k
Ͼ10
19l
Ͼ10

1240
Vol. 49, No. 10
Table 4. FXa Inhibitory Activity and Anticoagulant Activity of Com- centrations in dimethyl sulfoxide (DMSO). Synthetic substrate was added
pounds 19f, 23a—g, and 30a
and incubated in a 20 mM Tris–HCl buffer (pH 7.5) containing 0.13 M NaCl
at 37 °C. The absorbance at 405 nm was measured continuously. The follow-
ing enzymes and substrates were used: human factor Xa (Enzyme Research
Laboratories, Inc., 0.019 U/ml) and S-2222 (Chromogenix AB, 0.4 mM);
human thrombin (Sigma Co., 0.09 U/ml) and S-2238 (Chromogenix AB,
0.2 mM); human trypsin (Athens Research and Technology, Inc., 15 ng/ml)
and S-2222 (Chromogenix AB, 0.4 mM). To calculate the inhibitory activity
of the test compound, the initial reaction velocity was compared with the
value for a control containing no test compound. The inhibitory activity of a
test compound was expressed as IC50.
Measurement of Anticoagulant Activity Activated partial thrombo-
plastin time (APTT) was measured with an automatic coagulometer (KC40,
Amelung Co.). Briefly, 1.5 ml of test compound diluted with DMSO at vari-
ous concentrations, 50 ml of normal human plasma and 50 ml of APTT
reagent (Dade Behring Inc.) were mixed and incubated for 2 min at 37 °C.
Then, 50 ml of 25 mM CaCl2 solution was added to the mixture to measure
clotting time. The concentration required to double the clotting time (CT2)
was calculated from each individual dose–response curve (nϭ1).
Compound
R
IC50 (mM)
CT2 (mM)
19f
23a
23b
23c
23d
23e
23f
23g
30a
–H
–CO2Et
–CH2OH
–CO2H
–CONH2
–CONMe2
–COCH2CO2Et
–COCH3
ϭO
0.83
0.13
0.23
0.70
0.47
0.54
0.52
0.42
0.06
20.7
2.98
3.29
46.0
17.1
12.3
14.0
8.15
1.04
1-[[(1E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-4-piperidinone (9) Tri-
ethylamine (Et3N, 0.7 ml, 5 mmol) and compound 7 (1.1 g, 4.6 mmol) pre-
pared by a documented method21) were added to a solution of compound 8
(0.5 g, 3.7 mmol) in dry CH2Cl2 (60 ml) and the mixture was stirred
overnight under Ar at room temperature. Water (30 ml) was added to the re-
action mixture. The mixture was extracted with CH2Cl2. The organic layer
was washed with water and brine, dried over dry sodium sulfate (Na2SO4)
and the solvent was evaporated under reduced pressure. The residue was pu-
rified by silica gel column chromatography (eluent; CH2Cl2) to give com-
pound 9 (500 mg, 36%). 1H-NMR (*DMSO-d6) d: 7.83—7.77 (2H, m),
7.55—7.38 (4H, m), 3.49 (4H, t, Jϭ6 Hz), 2.47 (4H, t, Jϭ6 Hz).
The concentration required to double the clotting time (CT2) was calculated from
each individual dose–response curve (nϭ1).
Table 5. FXa Inhibitory Activity and Anticoagulant Activity of Com-
pounds 30a—e
Compound
X
IC50 (mM)
CT2 (mM)
1-[[(1E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-4-[4-(4-pyridinyl)-1-
piperazinyl]piperidine (4) AcOH (0.18 ml) was added to a solution of
compound 9 (490 mg, 1.6 mmol) and compound 10 (254 mg, 1.55 mmol)
prepared by a documented method24) in dry CH2Cl2 (12 ml). The mixture
was stirred for 30 min under Ar at room temperature. To the stirred mixture,
NaBH(OAc)3 (660 mg, 3.1 mmol) was added and the mixture was stirred
overnight at room temperature. Water (10 ml) was added to the reaction mix-
ture. The mixture was rendered alkaline with 1 N sodium hydroxide solution
and was extracted with CH2Cl2. The organic layer was washed with water
and brine, dried over dry Na2SO4 and the solvent was evaporated under re-
duced pressure. The residue was purified by silica gel column chromatogra-
phy (eluents; CH2Cl2 : methanol (MeOH)ϭ95 : 5—90 : 10) to give compound
4 (290 mg, 42%). HR-MS m/z: Calcd for C22H27ClN4O2S: 446.1543. Found:
446.1555. 1H-NMR (*DMSO-d6) d: 8.20—8.10 (2H, m), 7.81 (2H, d,
Jϭ9 Hz), 7.52 (2H, d, Jϭ9 Hz), 7.46—7.30 (2H, m), 6.90—6.75 (2H, m),
3.65—3.55 (2H, m), 3.43—3.18 (4H, m), 2.75—2.62 (2H, m), 2.61—2.44
(4H, m), 2.44—2.31 (1H, m), 1.90—1.80 (2H, m), 1.58—1.40 (2H, m).
1-[[(1E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-4-piperidinemethanol
(12) Et3N (0.88 ml, 6.3 mmol) and compound 7 (1.03 g, 4.3 mmol) were
added to a solution of compound 11 (0.5 g, 4.3 mmol) prepared by a docu-
mented method25) in dry CH2Cl2 (10 ml) and the mixture was stirred for 4 h
under Ar at room temperature. Water (10 ml) was added to the reaction mix-
ture. The mixture was extracted with CH2Cl2. The organic layer was washed
with water and brine, dried over dry Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel column chro-
matography (eluents; CH2Cl2 : MeOHϭ99 : 1—97 : 3) to give compound 12
(180 mg, 13%). 1H-NMR (*DMSO-d6) d: 7.80 (2H, d, Jϭ9 Hz), 7.52 (2H, d,
Jϭ9 Hz), 7.38 (1H, d, Jϭ16 Hz), 7.33 (1H, d, Jϭ16 Hz), 4.54 (1H, t,
Jϭ5 Hz), 3.63—3.50 (2H, m), 3.28—3.21 (2H, m), 2.70—2.56 (2H, m),
1.80—1.35 (3H, m), 1.23—1.07 (2H, m).
30a
30b
30c
30d
30e
Cl
Br
CH3
OH
CN
0.06
0.10
0.90
9.08
12.8
1.04
1.79
8.57
69.6
93.6
The concentration required to double the clotting time (CT2) was calculated from
each individual dose–response curve (nϭ1).
Table 6. Selectivity of M55113 for FXa over Thrombin and Trypsin
Enzyme
IC50 (mM)
Selectivity (enzyme/FXa)
FXa
0.06
Ͼ100
Ͼ100
Thrombin
Trypsin
Ͼ3000
Ͼ3000
pound (30a-M55113) as FXa inhibitor using in vitro assay.
It should further be mentioned that M55113 showed clear
selectivity for FXa over related serine proteases: in particu-
lar, the compound is 3000 fold more selective for FXa than
for thrombin, as shown in Table 6.
Crystallization of a complex of M55113 with FXa has al-
ready been achieved in our laboratory, so the results of crys-
tal elucidation by X-ray analysis will be published in the near
future.
1-[[(1E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-4-[[4-(4-pyridinyl)-1-
piperazinyl]methyl]piperidine (5) A solution of oxalyl chloride (0.05 ml,
0.62 mmol) in dry CH2Cl2 (1.33 ml) was cooled to Ϫ78 °C under Ar. To the
cooled solution, a solution of dry DMSO (0.09 ml, 1.28 mmol) in dry
Experimental
Nuclear magnetic resonance (NMR) spectra were taken with JEOL JNM- CH2Cl2 (1.33 ml) was added dropwise over 20 min. Then, a solution of com-
EX270 FT-NMR (JEOL, Ltd.) or JEOL JNM-LA300 (JEOL, Ltd.) in CDCl3 pound 12 (150 mg, 0.47 mmol) in dry CH2Cl2 (1.33 ml) was added dropwise
or dimethyl sulfoxide-d6 (DMSO-d6) using tetramethylsilane as the internal over 20 min. The reaction mixture was stirred for 1 h at between Ϫ65 °C and
reference. Data measured by JEOL JNM-LA300 are marked with an aster- Ϫ60 °C. Then the mixture was cooled to Ϫ78 °C and Et3N (0.25 ml, 1.8
isk. The following abbreviations were used: sϭsinglet, dϭdoublet, ddϭdou- mmol) was added. The reaction mixture was allowed to stand at room tem-
ble doublet, dtϭdouble triplet, tϭtriplet, qϭquartet, mϭmultiplet and brϭ
broad. High-resolution mass spectra (HR-MS) were taken with JEOL JMS- CH2Cl2. The organic layer was washed with water and brine, dried over dry
GCMATE (JEOL, Ltd.).
Na2SO4 and the solvent was evaporated under reduced pressure. The result-
perature. Water (2 ml) was added and the mixture was extracted with
Measurement of Factor Xa, Thrombin and Trypsin Inhibition The ing residue was suspended in dry CH2Cl2 (2.0 ml) and compound 10 (42 mg,
enzyme solution was mixed with a test compound dissolved at various con- 0.25 mmol) and AcOH (0.02 ml) were added in that order. The mixture was

October 2001
1241
stirred at room temperature for 30 min under Ar, NaBH(OAc)3 (0.10 g,
6
to give compound 19a (15 mg, 41%). HR-MS m/z: Calcd for
0.47 mmol) was added and the mixture was stirred overnight at room tem- C27H32N4O2S: 476.2246. Found: 476.2241. 1H-NMR (*CDCl3) d: 8.25—
perature. Water was added to the reaction mixture, which was adjusted to pH
8.18 (2H, m), 7.83 (2H, d, Jϭ9 Hz), 7.74 (2H, d, Jϭ9 Hz), 7.66—7.58 (2H,
9 with 1 N sodium hydroxide solution and the mixture was extracted with m), 7.56—7.40 (3H, m), 6.65—6.57 (2H, m), 3.88—3.76 (2H, m), 3.16—
CH2Cl2. The organic layer was washed with water and brine, dried over dry 3.02 (4H, m), 2.86—2.71 (2H, m), 2.60—2.47 (4H, m), 2.21 (2H, d,
Na2SO4 and the solvent was evaporated under reduced pressure. The residue Jϭ7 Hz), 1.85—1.59 (3H, m), 1.30—1.08 (2H, m).
was purified by silica gel column chromatography (eluents; CH2Cl2 :
1-(2-Naphthalenylsulfonyl)-4-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-
MeOHϭ95 : 5) to give compound 5 (60 mg, 52%). HR-MS m/z: Calcd for piperazine (19b) Using 2-naphthalenesulfonyl chloride 18b (20 mg,
C23H29ClN4O2S: 460.1699. Found: 460.1701. 1H-NMR (*DMSO-d6) d: 0.08 mmol), synthesis was performed by the synthetic method of compound
8.17—8.11 (2H, m), 7.81 (2H, d, Jϭ9 Hz), 7.52 (2H, d, Jϭ9 Hz), 7.44—
6 to give compound 19b (24 mg, 61%). HR-MS m/z: Calcd for
7.29 (2H, m), 6.83—6.77 (2H, m), 3.63—3.52 (2H, m), 3.31—3.20 (4H, m), C25H30N4O2S: 450.2089. Found: 450.2099. 1H-NMR (*CDCl3) d: 8.36—
2.72—2.58 (2H, m), 2.47—2.37 (4H, m), 2.17 (2H, d, Jϭ7 Hz), 1.86—1.75 8.32 (1H, m), 8.20—8.11 (2H, m), 8.04—7.92 (3H, m), 7.76 (1H, dd,
(2H, m), 1.70—1.55 (1H, m), 1.25—1.05 (2H, m).
Jϭ2,9 Hz), 7.72—7.60 (2H, m), 6.69—6.62 (2H, m), 3.93—3.82 (2H, m),
1-(4-Pyridinyl)-4-piperidinecarboxaldehyde (14) A solution of oxalyl 3.16—3.04 (4H, m), 2.98—2.78 (2H, m), 2.55—2.44 (4H, m), 2.19 (2H, d,
chloride (1.77 ml, 20 mmol) in dry CH2Cl2 (85 ml) was cooled to Ϫ78 °C Jϭ7 Hz), 1.86—1.63 (3H, m), 1.29—1.04 (2H, m).
under Ar. To the cooled solution, a solution of dry DMSO (3.25 ml,
46 mmol) in dry CH2Cl2 (85 ml) was added dropwise over 20 min. Then, a
1-(2-Benzofuranylsulfonyl)-4-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-
piperazine (19c) Using 2-benzofuransulfonyl chloride 18c (20 mg, 0.09
solution of compound 13 (3.0 g, 15 mmol) prepared by a documented mmol), synthesis was performed by the synthetic method of compound 6 to
method26) in dry CH2Cl2 (48 ml) and dry DMSO (48 ml) were added drop- give compound 19c (25 mg, 62%). HR-MS m/z: Calcd for C23H28N4O3S:
wise over 20 min. The reaction mixture was stirred at between Ϫ65 °C and 440.1882. Found: 440.1886. 1H-NMR (*CDCl3) d: 8.25—8.14 (2H, m),
Ϫ60 °C for 1 h, then cooled to Ϫ78 °C and Et3N (8.31 ml, 60 mmol) was 7.75—7.66 (1H, m), 7.61—7.33 (4H, m), 6.77—6.66 (2H, m), 4.00—3.88
added. The reaction mixture was allowed to stand at room temperature, (2H, m), 3.38—3.23 (4H, m), 3.05—2.90 (2H, m), 2.59—2.42 (4H, m), 2.22
water (200 ml) was added and the mixture was extracted with CH2Cl2. The (2H, d, Jϭ7 Hz), 1.93—1.71 (3H, m), 1.31—1.10 (2H, m).
organic layer was washed with water and brine, dried over dry Na2SO4 and
1-(Benzo[b]thien-2-ylsulfonyl)-4-[[1-(4-pyridinyl)-4-piperidinyl]-
the solvent was evaporated under reduced pressure. The resulting aldehyde methyl]piperazine (19d) Using 2-benzo[b]thiophenesulfonyl chloride 18d
14 was rather unstable and should be used in the next reaction without pu-
rification. MS m/z: 190 (Mϩ). 1H-NMR (*CDCl3) d: 9.56 (1H, s), 8.16—
(10 mg, 0.04 mmol), synthesis was performed by the synthetic method of
compound 6 to give compound 19d (24 mg, 12%). HR-MS m/z: Calcd for
7.99 (2H, m), 6.82—6.69 (2H, m), 3.83—3.71 (2H, m), 3.02—2.90 (2H, m), C23H28N4O2S2: 456.1653. Found: 456.1637. 1H-NMR (*CDCl3) d: 8.22—
2.61—2.45 (1H, m), 1.90—1.78 (2H, m), 1.52—1.36 (2H, m).
8.16 (2H, m), 7.95—7.86 (2H, m), 7.80 (1H, s), 7.56—7.46 (2H, m), 6.75—
4-[[1-(4-Pyridinyl)-4-piperidinyl]methyl]-1-piperazinecarboxylic Acid 6.68 (2H, m), 4.00—3.92 (2H, m), 3.25—3.13 (4H, m), 3.06—2.95 (2H, m),
1,1-Dimethylethyl Ester (16) A solution of compound 14 and compound 2.60—2.50 (4H, m), 2.23 (2H, d, Jϭ7 Hz), 1.93—1.72 (3H, m), 1.28—1.10
15 (3.19 g, 17 mmol) in dry CH2Cl2 (65 ml) containing AcOH (1.55 ml) was (2H, m).
stirred at room temperature for 30 min under Ar, NaBH(OAc)3 (6.61 g,
1-(2-Methylbenzothiazol-6-ylsulfonyl)-4-[[1-(4-pyridinyl)-4-piperidinyl]-
31 mmol) was added and the mixture was stirred overnight at room tempera- methyl]piperazine (19e) Using 2-methyl-6-benzothiazolesulfonyl chlo-
ture. Water (30 ml) was added to the reaction mixture, which was adjusted to ride 18e (10 mg, 0.04 mmol), synthesis was performed by the synthetic
pH 9 and the mixture was extracted with CH2Cl2. The organic layer was method of compound 6 to give compound 19e (8 mg, 42%). HR-MS m/z:
washed with water and brine, dried over dry Na2SO4 and the solvent was Calcd for C23H29N5O2S2: 471.1762. Found: 471.1743. 1H-NMR (*CDCl3) d:
evaporated under reduced pressure. The residue was purified by silica gel 8.31—8.13 (3H, m), 8.07 (1H, d, Jϭ9 Hz), 7.82 (1H, dd, Jϭ2,9 Hz), 6.66—
column chromatography (eluents; CH2Cl2 : MeOHϭ99 : 1) to give com- 6.53 (2H, m), 3.88—3.71 (2H, m), 3.14—2.96 (4H, m), 2.92 (3H, s), 2.85—
pound 16 (0.59 g, 10%). HR-MS m/z: Calcd for C20H32N4O2: 360.2525. 2.68 (2H, m), 2.61—2.39 (4H, m), 2.19 (2H, d, Jϭ7 Hz), 1.90—1.55 (3H,
Found: 360.2545. 1H-NMR (*CDCl3) d: 8.26—8.20 (2H, m), 6.68—6.62 m), 1.31—1.03 (2H, m).
(2H, m), 3.92—3.82 (2H, m), 3.46—3.37 (4H, m), 2.90—2.77 (2H, m),
2.40—2.31 (4H, m), 2.20 (2H, d, Jϭ7 Hz), 1.90—1.68 (3H, m), 1.46 (9H, methyl]piperazine (19f) Using 6-chloro-2-naphthalenesulfonyl chloride
s), 1.30—1.18 (2H, m). 18f (30 mg, 0.12 mmol), synthesis was performed by the synthetic method of
1-[(6-Chloro-2-naphthalenyl)sulfonyl]-4-[[1-(4-pyridinyl)-4-piperidinyl]-
1-[[1-(4-Pyridinyl)-4-piperidinyl]methyl]piperazine Mono(trifluoroac- compound 6 to give compound 19f (7 mg, 13%). HR-MS m/z: Calcd for
1
etate) (17) Anisole (2.23 ml) and TFA (17.2 ml) were added to the com- C25H29ClN4O2S: 484.1699. Found: 484.1706. H-NMR (*CDCl3) d: 8.32—
pound 16 (3.21 g, 8.9 mmol) at cooling with ice bath and the mixture was 8.29 (1H, m), 8.22—8.16 (2H, m), 8.01—7.86 (3H, m), 7.77 (1H, dd, Jϭ
stirred overnight at room temperature under Ar. Diethyl ether (200 ml) was 2,9 Hz), 7.58 (1H, dd, Jϭ2,9 Hz), 6.73—6.65 (2H, m), 3.97—3.84 (2H, m),
added to the reaction mixture and vigorous stirring followed. After standing, 3.16—2.88 (6H, m), 2.56—2.43 (4H, m), 2.19 (2H, d, Jϭ7 Hz), 1.90—1.67
the supernatant was removed by decantation and another 200 ml portion of (3H, m), 1.25—1.06 (2H, m).
diethyl ether was added; this procedure was repeated three times. Diethyl
1-[(6-Bromo-2-naphthalenyl)sulfonyl]-4-[[1-(4-pyridinyl)-4-piperidinyl]-
ether (200 ml) was added to the residue and the mixture was divided into methyl]piperazine (19g) Using 6-bromo-2-naphthalenesulfonyl chloride
1
fine particles, which were filtered to give compound 17 (3.24 g, 97%). H- 18g (20 mg, 0.07 mmol), synthesis was performed by the synthetic method
NMR (*DMSO-d6) d: 8.30—8.18 (2H, m), 7.25—7.17 (2H, m), 4.29—4.18
of compound 6 to give compound 19g (13 mg, 38%). HR-MS m/z: Calcd for
1
(2H, m), 4.00—3.35 (4H, m), 3.35—3.09 (6H, m), 2.50—2.40 (2H, m), C25H29BrN4O2S: 528.1194. Found: 528.1177. H-NMR (*CDCl3) d: 8.32—
2.12—1.98 (1H, m), 1.93—1.82 (2H, m), 1.23—1.06 (2H, m).
1-[[(1E)-2-(4-Chlorophenyl)ethenyl]sulfonyl]-4-[[1-(4-pyridinyl)-4-
8.28 (1H, m), 8.23—8.18 (2H, m), 8.11 (1H, d, Jϭ2 Hz), 7.90 (1H, d,
Jϭ9 Hz), 7.85 (1H, d, Jϭ9 Hz), 7.78 (1H, dd, Jϭ2,9 Hz), 7.71 (1H, dd, Jϭ
piperidinyl]methyl]piperazine (6) Et3N (0.09 ml, 0.65 mmol) and com- 2,9 Hz), 6.62—6.57 (2H, m), 3.88—3.74 (2H, m), 3.18—2.99 (4H, m),
pound 7 (15.6 mg, 0.06 mmol) were added to a suspension in CH2Cl2 2.88—2.70 (2H, m), 2.59—2.42 (4H, m), 2.18 (2H, d, Jϭ7 Hz), 1.81—1.57
(1.0 ml) of compound 17 (47 mg, 0.12 mmol). The mixture was stirred (3H, m), 1.35—1.04 (2H, m).
overnight at room temperature under Ar. Water (2 ml) was added to the reac-
1-[(5-Fluorobenzo[b]thien-2-yl)sulfonyl]-4-[[1-(4-pyridinyl)-4-
tion mixture, the mixture was rendered alkaline with 1 N sodium hydroxide piperidinyl]methyl]piperazine (19h) Using 5-fluoro-2-benzo[b]thiophen-
solution and was extracted with CH2Cl2. The organic layer was washed with sulfonyl chloride 18h (10 mg, 0.04 mmol), synthesis was performed by the
water and brine, dried over dry Na2SO4 and the solvent was evaporated synthetic method of compound 6 to give compound 19h (15 mg, 82%). HR-
under reduced pressure. The residue was purified by silica gel column chro- MS m/z: Calcd for C23H27FN4O2S2: 474.1559. Found: 474.1553. 1H-NMR
matography (eluents; CH2Cl2 : MeOHϭ95 : 5—90 : 10) to give compound 6
(*DMSO-d6) d: 8.21 (1H, dd, Jϭ5,8 Hz), 8.14—8.08 (2H, m), 8.04 (1H, s),
(13 mg, 47%). HR-MS m/z: Calcd for C23H29ClN4O2S: 460.1699. Found: 7.94—7.87 (1H, m), 7.51 (1H, dt, Jϭ3,9 Hz), 6.91—6.83 (2H, m), 4.03—
1
460.1709. H-NMR (*CDCl3) d: 8.26—8.17 (2H, m), 7.47—7.37 (5H, m), 3.87 (2H, m), 3.14—2.97 (4H, m), 2.95—2.78 (2H, m), 2.57—2.49 (4H, m),
6.73—6.62 (3H, m), 3.93—3.80 (2H, m), 3.30—3.16 (4H, m), 2.89—2.75
(2H, m), 2.60—2.47 (4H, m), 2.24 (2H, d, Jϭ7 Hz), 1.89—1.65 (3H, m),
1.30—1.13 (2H, m).
2.15 (2H, d, Jϭ7 Hz), 1.85—1.62 (3H, m), 1.12—0.93 (2H, m).
1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]piperazine (19i) Using 6-chloro-2-benzo[b]thiophen-
1-([1,1؅-Biphenyl]-4-ylsulfonyl)-4-[[1-(4-pyridinyl)-4-piperidinyl]- sulfonyl chloride 18i (10 mg, 0.04 mmol), synthesis was performed by the
methyl]piperazine (19a) Using 4-biphenylsulfonyl chloride 18a (20 mg, synthetic method of compound 6 to give compound 19i (2 mg, 8%). HR-MS
0.08 mmol), synthesis was performed by the synthetic method of compound m/z: Calcd for C23H27ClN4O2S2: 490.1264. Found: 490.1272. 1H-NMR

1242
Vol. 49, No. 10
(1H, s), 8.26—8.15 (2H, m), 7.98—7.88 (3H, m), 7.80—7.74 (1H, m),
7.63—7.56 (1H, m), 6.63—6.56 (2H, m), 4.25—4.10 (2H, m), 3.85—3.76
(2H, m), 3.63—3.52 (1H, m), 3.37—3.18 (3H, m), 3.07—2.99 (1H, m),
2.94—2.84 (1H, m), 2.82—2.70 (2H, m), 2.62—2.46 (2H, m), 2.37—2.27
(1H, m), 1.80—1.54 (3H, m), 1.34—1.23 (3H, m), 1.20—1.03 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
methyl]-2-piperazinemethanol (23b) A solution in CH2Cl2 (3 ml) of
compound 23a (9 mg, 0.016 mmol) was cooled to Ϫ78 °C. To the cooled so-
lution, 24 ml of diisobutyl aluminum hydride (as 1.5 M toluene solution) was
added dropwise. The reaction mixture was stirred to room temperature, satu-
rated ammonium chloride was added and the mixture was extracted with
CH2Cl2. The organic layer was washed with brine, dried over dry Na2SO4
and the solvent was evaporated under reduced pressure. The residue was pu-
rified by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ
95 : 5) to give compound 23b (3 mg, 30%). 1H-NMR (CDCl3) *d: 8.31 (1H,
s), 8.20—8.16 (2H, m), 7.97—7.88 (3H, m), 7.80—7.74 (1H, m), 7.62—
7.55 (1H, m), 6.68—6.62 (2H, m), 3.95—3.79 (3H, m), 3.66—3.55 (1H, m),
3.36—3.30 (2H, m), 3.06—2.78 (5H, m), 2.65—2.40 (3H, m), 2.25—2.14
(1H, m), 1.89—1.70 (3H, m), 1.30—1.10 (2H, m).
(*CDCl3) d: 8.25—8.17 (2H, m), 7.90—7.80 (2H, m), 7.76 (1H, s), 7.48—
7.42 (1H, m), 6.67—6.59 (2H, m), 3.90—3.78 (2H, m), 3.23—3.11 (4H, m),
2.85—2.74 (2H, m), 2.60—2.48 (4H, m), 2.21 (2H, d, Jϭ7 Hz), 1.85—1.53
(3H, m), 1.30—1.09 (2H, m).
1-[(6-Methoxybenzo[b]thien-2-yl)sulfonyl]-4-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]piperazine (19j) Using 6-methoxy-2-benzo[b]thio-
phenesulfonyl chloride 18j (10 mg, 0.04 mmol), synthesis was performed by
the synthetic method of compound 6 to give compound 19j (2 mg, 11%).
HR-MS m/z: Calcd for C24H30N4O3S2: 486.1759. Found: 486.1734. 1H-NMR
(*CDCl3) d: 8.24—8.18 (2H, m), 7.77 (1H, d, Jϭ9 Hz), 7.71 (1H, s), 7.29
(1H, d, Jϭ2 Hz), 7.09 (1H, dd, Jϭ2,9 Hz), 6.65—6.59 (2H, m), 3.91 (3H, s),
3.89—3.78 (2H, m), 3.24—3.06 (4H, m), 2.85—2.72 (2H, m), 2.58—2.44
(4H, m), 2.21 (2H, d, Jϭ7 Hz), 1.85—1.56 (3H, m), 1.35—1.08 (2H, m).
1-[(3-Nitrobenzo[b]thien-2-yl)sulfonyl]-4-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]piperazine (19k) Using 3-nitro-2-benzo[b]thiophene-
sulfonyl chloride 18k (20 mg, 0.07 mmol), synthesis was performed by the
1
synthetic method of compound 6 to give compound 19k (16mg, 44%). H-
NMR (*CDCl3) d: 8.48—8.40 (1H, m), 8.38—8.17 (2H, m), 7.60—7.22
(3H, m), 6.74—6.64 (2H, m), 4.00—3.85 (2H, m), 3.60—3.44 (4H, m),
2.98—2.82 (2H, m), 2.75—2.61 (4H, m), 2.31 (2H, d, Jϭ7 Hz), 1.97—1.50
(3H, m), 1.40—1.16 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic acid (23c) To a solution in
MeOH (4 ml) of compound 23a (240 mg, 0.43 mmol), 2 N of sodium hydrox-
ide solution (0.86 ml) was added and the mixture was stirred at 40 °C for 2 h.
The reaction mixture was concentrated under reduced pressure, the residue
was dissolved in water (20 ml) and the mixture rendered acidic with AcOH.
The supernatant was removed by decantation and the residue was dissolved
in MeOH, dried over dry Na2SO4 and the solvent was evaporated under re-
duced pressure. The residue was crystallized with diethyl ether to yield com-
pound 23c (219 mg, 96%). HR-MS m/z: Calcd for C26H29ClN4O4S:
1-[[1-(4-Pyridinyl)-4-piperidinyl]methyl]-4-[[3-(trifluoromethyl)-
benzo[b]thien-2-yl]sulfonyl]piperazine (19l) Using 3-(trifluoromethyl)-
2-benzo[b]thiophenesulfonyl chloride 18l (10 mg, 0.03 mmol), synthesis was
performed by the synthetic method of compound 6 to give compound 19l
(4 mg, 23%). HR-MS m/z: Calcd for C24H27F3N4O2S2: 524.1527. Found:
1
524.1524. H-NMR (*CDCl3) d: 8.25—8.17 (2H, m), 8.14—8.07 (1H, m),
7.93—7.86 (1H, m), 7.62—7.53 (2H, m), 6.71—6.63 (2H, m), 3.95—3.84
(2H, m), 3.47—3.35 (4H, m), 2.94—2.80 (2H, m), 2.60—2.49 (4H, m), 2.24
(2H, d, Jϭ7 Hz), 1.91—1.67 (3H, m), 1.35—1.12 (2H, m).
1
528.1598. Found: 528.1543. H-NMR (DMSO-d6) *d: 8.51 (1H, s), 8.34—
8.02 (5H, m), 7.87—7.68 (2H, m), 6.82—6.68 (2H, m), 3.95—3.74 (2H, m),
3.57—2.20 (11H, m), 1.78—1.52 (3H, m), 1.07—0.82 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-(phenylmethyl)-2-piperazinecar-
boxylic Acid Ethyl Ester (21) Et3N (6.2 ml, 45 mmol) was added to a so-
lution in CH2Cl2 (70 ml) of compound 20 (3.7 g, 15 mmol) prepared by a
documented method.27) To this was added a solution of compound 18f (4.3 g,
16 mmol) in CH2Cl2 (40 ml) under cooling with ice. After stirring the reac-
tion mixture overnight at room temperature, water (50 ml) was added and the
mixture was extracted with CH2Cl2. The organic layer was washed with
brine, dried over dry Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
(eluents; hexane : ethyl acetate (AcOEt)ϭ90 : 10—80 : 20) to give compound
21 (6.4g, 85%). 1H-NMR (*CDCl3) d: 8.29 (1H, s), 7.94—7.87 (3H, m),
7.78—7.73 (1H, m), 7.61—7.55 (1H, m), 7.33—7.18 (5H, m), 4.27—4.11
(2H, m), 3.88 (1H, d, Jϭ13 Hz), 3.61 (1H, d, Jϭ13 Hz), 3.57—3.47 (1H, m),
3.42—3.36 (1H, m), 3.26—3.08 (3H, m), 2.98—2.88 (1H, m), 2.52—2.43
(1H, m), 1.30 (3H, t, Jϭ7 Hz).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-2-piperazinecarboxylic Acid Ethyl
Ester (22) To a solution in dichloroethane (70 ml) of compound 21 (6.4 g,
14 mmol), 1-chloroethyl chloroformate (3.7 ml, 34 mmol) was added and the
mixture was heated under reflux for 24 h and concentrated under reduced
pressure. MeOH (60 ml) was added to the residue and the reaction mixture
was heated under reflux for 2 h. This mixture was concentrated under re-
duced pressure and the residue was neutralized with 1 N sodium hydroxide
solution and extracted with AcOEt. The organic layer was washed with
water and brine, dried over dry Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel column chro-
matography (eluents; hexane : AcOEtϭ67 : 33 and AcOEt : Et3Nϭ99.9 : 0.1)
to give compound 22 (4.1 g, 79%). 1H-NMR (CDCl3) d: 8.32 (1H, s), 7.96—
7.88 (3H, m), 7.80—7.75 (1H, m), 7.58 (1H, dd, Jϭ2,9 Hz), 4.25—4.15
(2H, m), 3.79—3.72 (1H, m), 3.58 (1H, dd, Jϭ3,9 Hz), 3.47—3.39 (1H, m),
3.16—3.06 (1H, m), 2.96—2.63 (3H, m), 1.32—1.25 (3H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
methyl]-2-piperazinecarboxylic Acid Ethyl Ester (23a) A crude product
14 obtained by Swern oxidation using compound 13 (2.0 g, 10 mmol) was
suspended in dry CH2Cl2 (20 ml). To the suspension, a solution in dry
CH2Cl2 (30 ml) of compound 22 (2.0 g, 5.2 mmol) and AcOH (1.0 ml) were
added in that order. After stirring the reaction mixture at room temperature
for 30 min under Ar, NaBH(OAc)3 (2.2 g, 10 mmol) was added and the mix-
ture was stirred overnight at room temperature. The reaction mixture was
poured into water (50 ml), adjusted to pH 9 and was extracted with CH2Cl2.
The organic layer was washed with water and brine, dried over dry Na2SO4
and the solvent was evaporated under reduced pressure. The residue was pu-
rified by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ
98 : 2—90 : 10) to yield compound 23a (2.6 g, 45%). HR-MS m/z: Calcd for
C28H33ClN4O4S: 556.1911. Found: 556.1867. 1H-NMR (CDCl3) *d: 8.31
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxamide (23d) To a solution in dry
dimethylformamide (0.5 ml) of compound 23c (50 mg, 0.09 mmol), 4-di-
methylaminopyridine (in a catalytic amount) and carbonyl diimidazole
(17 mg, 0.1 mmol) were added in that order and the mixture was stirred at
room temperature for 1 h. The reaction mixture was poured into 27% aque-
ous ammonia (1 ml) and stirred at room temperature for 2 h. The reaction
mixture was extracted with AcOEt and the organic layer was washed with
water and brine, dried over dry Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was crystallized with diethyl ether to
give compound 23d (21 mg, 42%). HR-MS m/z: Calcd for C26H30ClN5O3S:
527.1758. Found: 527.1730. 1H-NMR (CDCl3) *d: 8.32 (1H, s), 8.28—8.17
(2H, m), 8.00—7.89 (3H, m), 7.85—7.75 (1H, m), 7.67—7.57 (1H, m),
6.65—6.56 (2H, m), 6.33—6.25 (1H, m), 5.39—5.32 (1H, m), 3.91—3.75
(2H, m), 3.75—3.65 (1H, m), 3.65—3.52 (1H, m), 3.14—2.99 (2H, m),
2.87—2.62 (4H, m), 2.46—2.31 (2H, m), 2.29—2.16 (1H, m), 1.91—1.53
(3H, m), 1.32—1.04 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-N,N-dimethyl-1-[[1-(4-pyridinyl)-
4-piperidinyl]methyl]-2-piperazinecarboxamide (23e) To a solution in
dry dimethylformamide (0.5 ml) of compound 23c (50 mg, 0.09 mmol), 4-di-
methylaminopyridine (in a catalytic amount) and carbonyl diimidazole
(17 mg, 0.1 mmol) were added in that order and the mixture was stirred at
room temperature for 1 h. The reaction mixture was poured into 50% di-
methylamine solution (1 ml) and stirred at room temperature for 2 h. The re-
action mixture was extracted with AcOEt and the organic layer was washed
with water and brine, dried over dry Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was crystallized with diethyl ether to
give compound 23e (21 mg, 40%). HR-MS m/z: Calcd for C28H34ClN5O3S:
555.2070. Found: 555.2068. 1H-NMR (CDCl3) *d: 8.29 (1H, s), 8.31—8.03
(2H, m), 8.03—7.82 (3H, m), 7.82—7.69 (1H, m), 7.57 (1H, dd, Jϭ2,9 Hz),
6.74—6.50 (2H, m), 3.95—3.75 (2H, m), 3.65 (2H, d, Jϭ11 Hz), 3.60—
3.43 (1H, m), 3.28—2.40 (6H, m), 3.15 (3H, s), 2.94 (3H, s), 2.26 (1H, dd,
Jϭ9,12 Hz), 2.12—1.97 (1H, m), 1.87 (1H, d, Jϭ13 Hz), 1.80—1.55 (2H,
m), 1.35—1.02 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-b-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinepropanoic Acid Ethyl Ester (23f) To a
solution in dry dimethylformamide (0.5 ml) of compound 23c (50 mg,
9.4 mmol), 4-dimethylaminopyridine (in a catalytic amount) and carbonyl
diimidazole (17 mg, 0.1 mmol) were added in that order and the mixture was
stirred at room temperature for 2 h. To the stirred mixture, a solution pre-
pared by stirring potassium ethyl malonate (40 mg, 0.23 mmol), magnesium
chloride (27 mg, 0.29 mmol) and Et3N (33 ml, 0.23 mmol) in dry acetonitrile

October 2001
1243
(0.5 ml) for 2 h was added and the resulting mixture was stirred at room tem-
perature for 2 h, then at 40—60 °C for 3 h. To the reaction mixture, 1 N HCl
1-[[1-(4-Pyridinyl)-4-piperidinyl]methyl]piperazinone (29) To a solu-
tion in dry dimethylformamide (20 ml) of a portion of compound 28 (0.46 g,
was added until a pH of 2 was reached. After stirring for 10 min, the mixture 0.65 mmol), Et3N (1.43 ml, 10 mmol) was added under cooling with ice
was neutralized with saturated sodium hydrogen carbonate and was ex- water; the mixture was stirred at the same temperature for 1 h, then at room
tracted with AcOEt. The organic layer was washed with water and brine, temperature for another 1 h. The solvent was evaporated under reduced pres-
dried over dry Na2SO4 and the solvent was evaporated under reduced pres- sure and the residue was used in the next reaction without purification. HR-
sure to give compound 23f (40 mg, 76%). 1H-NMR (CDCl3) *d: 8.37—8.27 MS m/z: Calcd for C15H22N4O: 274.1793. Found: 274.1767. 1H-NMR
(1H, m), 8.26—8.15 (2H, m), 8.00—7.92 (3H, m), 7.81—7.71 (1H, m), (*CDCl3) d: 8.24—8.20 (2H, m), 6.67—6.63 (2H, m), 3.96—3.86 (2H, m),
7.64—7.53 (1H, m), 6.66—6.53 (2H, m), 4.26—4.10 (2H, m), 3.90—3.34
(5H, m), 3.33—1.94 (10H, m), 1.90—1.57 (3H, m), 1.35—0.94 (5H, m).
2-Acetyl-4-[(6-chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]piperazine (23g) A solution in 1 N HCl (1 ml) of
3.55 (2H, s), 3.40—3.26 (4H, m), 3.14—3.06 (2H, m), 2.92—2.81 (2H, m),
2.10—1.94 (1H, m), 1.90—1.72 (2H, m), 1.42—1.24 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
methyl]piperazinone (30a) The crude product of compound 29 was sus-
compound 23f (35 mg, 0.06 mmol) was stirred at 60—70 °C for 2 h. The re- pended in dry CH2Cl2 (34 ml), to the suspension, Et3N (0.72 ml, 5.2 mmol)
action mixture was rendered alkaline and was extracted with AcOEt. The or- and a solution of 6-chloro-2-naphthalensulfonyl chloride (245 mg, 0.94
ganic layer was washed with water and brine, dried over dry Na2SO4 and the mmol) in dry CH2Cl2 (5 ml) were added in that order, and the mixture was
solvent was evaporated under reduced pressure to yield compound 23g
stirred overnight at room temperature under Ar. Water (30 ml) was added to
(31 mg, 99%). HR-MS m/z: Calcd for C27H31ClN4O3S: 526.1805. Found: the reaction mixture, which was adjusted to pH 9 with 1 N sodium hydroxide
1
526.1843. H-NMR (CDCl3) *d: 8.38—8.14 (3H, m), 8.00—7.84 (3H, m), solution and the mixture was extracted with CH2Cl2. The organic layer was
7.81—7.69 (1H, m), 7.64—7.54 (1H, m), 6.66—6.51 (2H, m), 3.89—3.24
washed with water and brine, dried over dry Na2SO4 and the solvent was
(2H, m), 3.38—2.92 (6H, m), 2.84—2.67 (2H, m), 2.50—2.11 (3H, m), 2.18 evaporated under reduced pressure. The residue was purified by silica gel
(3H, s), 1.89—1.56 (3H, m), 1.36—1.00 (2H, m).
column chromatography (eluents; CH2Cl2 : MeOHϭ99 : 1—95 : 5) to give
compound 30a (130 mg, 28%). HR-MS m/z: Calcd for C25H27ClN4O3S:
498.1492. Found: 498.1494. 1H-NMR (*CDCl3) d: 8.29 (1H, s), 8.20—8.11
4-[N-[2-(tert-Butoxycarbonylamino)ethyl]aminomethyl]-1-(4-pyridyl)-
piperidine (24) and 4-[N-[2-(tert-Butoxycarbonylamino)ethyl]aminomethyl]-
1-(4-pyridyl)piperidine Boron Complex (25) [Unpurified]28) A crude (2H, m), 7.91—7.83 (3H, m), 7.73 (1H, dd, Jϭ2,9 Hz), 7.55 (1H, dd,
product obtained from compound 14 (3.0 g, 15.7 mmol) by Swern oxidation Jϭ2,9 Hz), 6.57—6.50 (2H, m), 3.78—3.68 (4H, m), 3.40—3.30 (4H, m),
was suspended in dry CH2Cl2 (13 ml). To the suspension, N-(tert-butoxycar-
3.17 (2H, d, Jϭ8 Hz), 2.74—2.60 (2H, m), 1.90—1.70 (1H, m), 1.60—1.48
bonyl)-1,2-diaminoethane (0.54 g, 3.2 mmol) and AcOH (0.31 ml) were (2H, m), 1.28—1.07 (2H, m).
added in that order. After stirring the resulting mixture at room temperature
4-[(6-Bromo-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
for 30 min under Ar, NaBH(OAc)3 (1.33 g, 6.3 mmol) was added and the methyl]piperazinone (30b) Using 6-bromo-2-naphthalenesulfonyl chlo-
mixture was stirred overnight at room temperature. Water (10 ml) was added ride (22.3 mg, 0.07 mmol), synthesis was performed by the synthetic method
to the reaction mixture, the mixture was adjusted to pH 9 with 1 N sodium of compound 30a to give compound 30b (12 mg, 32%). HR-MS m/z: Calcd
hydroxide solution, and was extracted with CH2Cl2. The organic layer was for C25H27BrN4O3S: 542.0987. Found: 542.1022. 1H-NMR (*CDCl3) d:
washed with water and brine, dried over dry Na2SO4 and the solvent was 8.37—8.34 (1H, m), 8.26—8.19 (2H, m), 8.16—8.11 (1H, m), 7.93 (1H, d,
evaporated at reduced pressure. Compound 24 (0.25 g, 23%) was obtained Jϭ9 Hz), 7.88 (1H, d, Jϭ9 Hz), 7.80 (1H, dd, Jϭ2,9 Hz), 7.75 (1H, dd,
by silica gel column chromatography of the residue (eluents; CH2Cl2 : Jϭ2,9 Hz), 6.66—6.59 (2H, m), 3.89—3.77 (2H, m), 3.80 (2H, s), 3.49—
MeOHϭ99 : 1) together with unpurified 25 (0.62 g, 40%).
3.38 (4H, m), 3.25 (2H, d, Jϭ7 Hz), 2.84—2.72 (2H, m), 1.99—1.83 (1H,
Compound 24: 1H-NMR (CDCl3) d: 8.24—8.18 (2H, m), 6.68—6.62 m), 1.68—1.57 (2H, m), 1.35—1.17 (2H, m).
(2H, m), 5.03—4.98 (1H, br), 3.95—3.83 (2H, m), 3.29—3.12 (2H, m),
2.90—2.78 (2H, m), 2.73 (2H, t, Jϭ6 Hz), 2.53 (2H, d, Jϭ7 Hz), 1.97—1.65
(3H, m), 1.45 (9H, s), 1.33—1.16 (2H, m).
4-[(6-Methyl-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
methyl]piperazinone (30c) Using 6-methyl-2-naphthalenesulfonyl chlo-
ride (41 mg, 0.17 mmol), synthesis was performed by the synthetic method
Compound 25: 1H-NMR (CDCl3) d: 8.22—8.14 (2H, m), 6.73—6.64 of compound 30a to yield compound 30c (14 mg, 17%). HR-MS m/z: Calcd
(2H, m), 4.93—4.78 (1H, br), 4.20—3.92 (2H, m), 3.29—3.12 (2H, m),
3.12—2.98 (2H, m), 2.73 (2H, t, Jϭ6 Hz), 2.54 (2H, d, Jϭ7 Hz), 2.03 (6H,
s), 1.99—1.72 (3H, m), 1.45 (9H, s), 1.33—1.15 (2H, m).
for C26H30N4O3S: 478.2038. Found: 478.2031. 1H-NMR (*CDCl3) d: 8.35—
8.32 (1H, m), 8.26—8.19 (2H, m), 7.94—7.88 (2H, m), 7.77—7.70 (2H, m),
7.54—7.48 (1H, m), 6.65—6.58 (2H, m), 3.86—3.76 (4H, m), 3.48—3.37
(4H, m), 3.27—3.21 (2H, m), 2.83—2.70 (2H, m), 2.59 (3H, s), 1.97—1.81
Compound 25: 11B-NMR (CDCl3) d: Ϫ18.9 (br).
2-Bromo-N-[2-(tert-butoxycarbonylamino)ethyl]-N-[[1-(4-pyridinyl)- (1H, m), 1.66—1.56 (2H, m), 1.29—1.16 (2H, m).
4-piperidinyl]methyl] Acetamide Boron Complex (27) [Unpurified]28)
4-[(6-Hydroxy-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
Et3N (0.28 ml, 2.0 mmol) was added to a solution in dry CH2Cl2 (5 ml) of a methyl]piperazinone (30d) Using 6-hydroxy-2-naphthalenesulfonyl chlo-
portion of compound 25 (0.6 g, 1.25 mmol). To the mixture, a solution of ride (20 mg, 0.08 mmol), synthesis was performed by the synthetic method
bromoacetyl chloride (0.31 g, 2.0 mmol) in dry CH2Cl2 (5 ml) was added of compound 30a to yield compound 30d (7.4 mg, 19%). HR-MS m/z: Calcd
dropwise under cooling with ice water and the mixture was stirred at room for C25H28N4O4S: 480.1831. Found: 480.1834. 1H-NMR (*CDCl3) d: 8.30—
temperature for 2 h under Ar. Ice water (10 ml) was added to the reaction 8.24 (1H, m), 8.13—8.05 (2H, m), 7.92—7.86 (1H, m), 7.84—7.78 (1H, m),
mixture and the mixture was extracted with CH2Cl2. The organic layer was 7.72—7.65 (1H, m), 7.32—7.20 (2H, m), 6.70—6.61 (2H, m), 3.93—3.74
washed with water and brine, dried over dry Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was isolated by silica gel 1.96—1.82 (1H, m), 1.60—1.50 (2H, m), 1.35—1.10 (2H, m).
column chromatography (eluents; CH2Cl2 : MeOHϭ99 : 1) to give com- 4-[(6-Cyano-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-
(4H, m), 3.49—3.36 (4H, m), 3.28—3.19 (2H, m), 2.85—2.61 (2H, m),
1
pound 27 (0.61 g, 81%). H-NMR (*CDCl3) d: 8.26—8.15 (2H, m), 6.75— methyl]piperazinone (30e) Using 6-cyano-2-naphthalenesulfonyl chlo-
6.65 (2H, m), 4.95—4.73 (1H, m), 4.18—3.84 (4H, m), 3.56—3.45 (2H, m), ride (43 mg, 0.15 mmol), synthesis was performed by the synthetic method
3.37—3.21 (4H, m), 3.13—2.99 (2H, m), 2.25—2.10 (1H, m), 2.04 (6H, s),
of compound 30a to yield compound 30e (11 mg, 15%). HR-MS m/z: Calcd
1.92—1.77 (2H, m), 1.44 (9H, s), 1.39—1.19 (2H, m). 11B-NMR (CDCl3) d: for C26H27N5O3S: 489.1834. Found: 489.1868. 1H-NMR (*CDCl3) d: 8.45—
Ϫ18.8 (br).
8.43 (1H, m), 8.37—8.34 (1H, m), 8.26—8.21 (2H, m), 8.14—8.09 (2H, m),
7.94—7.88 (1H, m), 7.84—7.79 (1H, m), 6.65—6.60 (2H, m), 3.92—3.79
(4H, m), 3.54—3.40 (4H, m), 3.30—3.24 (2H, m), 2.88—2.75 (2H, m),
N-(2-Aminoethyl)-2-bromo-N-[[1-(4-pyridinyl)-4-piperidinyl]methyl]
Acetamide Tri(trifluoroacetate) (28) To a portion of compound 27
(0.54 g, 0.89 mmol), anisole (0.29 g) and TFA (2.3 ml) were added under 2.00—1.50 (3H, m), 1.37—1.16 (2H, m).
cooling with ice water and the mixture was stirred at room temperature for
1.5 h under Ar. Diethyl ether (50 ml) was added and the reaction mixture was
Acknowledgment The authors thank Emeritus Professor Hiroshi Ya-
stirred vigorously. After standing, the supernatant was removed by decanta- manaka of Tohoku University for his encouragement and helpful discussions
tion and another 50 ml of diethyl ether was added; this procedure was re- throughout this study.
peated three times. Diethyl ether (50 ml) was added to the residue and the
mixture was divided into fine particles, which were filtered to give com- References
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(2H, m), 3.29—2.87 (6H, m), 2.15—1.96 (1H, m), 1.78—1.63 (2H, m),
1.32—1.04 (2H, m).
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