Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors III. Effect of ring opening of piperazinone moiety on inhibition

Article abstract of DOI:10.1248/cpb.52.459

Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10-1/100) than that of M55113 and M55551 as FXa inhibitors.

Full text of DOI:10.1248/cpb.52.459

April 2004
Notes
Chem. Pharm. Bull. 52(4) 459—462 (2004)
459
Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as
Factor Xa Inhibitors1,2) III. Effect of Ring Opening of Piperazinone
Moiety on Inhibition
Hidemitsu NISHIDA,* Yutaka MIYAZAKI, Takafumi MUKAIHIRA, Hiroyasu SHIMADA, Kazuhiro SUZUKI,
Fumihiko SAITOH, Masashi MIZUNO, Tomokazu MATSUSUE, Atsushi OKAMOTO, Yoshitaka HOSAKA,
Miwa MATSUMOTO, Shuhei OHNISHI, and Hidenori MOCHIZUKI
Discovery Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412–8524,
Japan. Received November 5, 2003; accepted February 2, 2004
Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and
M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor
Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10—1/100) than that of M55113
and M55551 as FXa inhibitors.
Key words factor Xa inhibitor; 1-arylsulfonyl-3-piperazinone; M55551; structure–activity relationship
Recently, direct inhibition of factor Xa (FXa), which links place of the piperazine ring of M55113 and M55551. The
the intrinsic and extrinsic mechanisms in the blood coagula- present paper concerns the synthesis of such compounds to-
tion cascade,3—7) has emerged as an attractive strategy for the gether with their inhibition of FXa.
discovery of novel antithrombotic agents.8—11) In previous
papers,1,2) we reported the synthesis and biological activity of Chemistry
new compounds in a series of 1-arylsulfonyl-3-piperazinone
Synthesis of ethylenediamine derivative 9 corresponding
derivatives, and through this investigation M55113 (1) (IC50: to M55113 and M55551 was achieved as shown in Chart 1.
0.06 mM) and M55551 (2) (IC50: 0.006 mM) were confirmed to Compound 6, prepared by the reaction of N-tert-butoxycar-
be somewhat favorable as FXa inhibitors.
bonyl-1,2-diaminoethane hydrochloride (4) with 6-chloro-2-
In order to investigate the role played a piperazine moiety naphthalenesulfonyl chloride (5) under basic conditions, was
in these compounds, we focused on comparison of the activ- deprotected with trifluoroacetic acid (TFA) to yield com-
ity of compounds which have an ethylenediamine structure in pound 7. The condensation of 7 with 1-(4-pyridinyl)-4-
piperidinecarboxaldehyde (8) prepared by Swern oxidation12)
of the corresponding methanol yielded the desired ethylene-
diamine derivative 9 in the presence of reducing agent.13)
The route of synthesis of compound 13, which contains an
amide group on the ethylenediamine moiety of compound 9,
is shown in Chart 2. Compound 11, prepared by the reaction
Chart 1. Synthesis of Ethylenediamine Derivative 9
Chart 2. Synthesis of Glycine Derivative 13
To whom correspondence should be addressed. e-mail: hnishida@mochida.co.jp
© 2004 Pharmaceutical Society of Japan

460
Vol. 52, No. 4
Chart 3. Synthesis of 3-Aminoalanine Derivative 19 and 20
Table 1. FXa Inhibitory Activity of Compounds 1, 2, 3, 9, 13, 19 and 20
of glycine (10) with sulfonyl chloride 5 under basic condi-
tions, was treated with 1-(4-pyridinyl)-4-aminomethylpiperi-
dine (12), which was obtained by Mitsunobu reaction of the
corresponding methanol, in the presence of N,NЈ-dicyclo-
hexylcarbodiimide (DCC) and 1-hydroxybenzotriazole hy-
drate (HOBt) to yield the amide 13.
Compound
R
IC50 (mM)
Synthesis of (R)-3-aminoalanine derivative 19 was accom-
plished according to the route shown in Chart 3. Sulfonyla-
tion of ethyl ester 15 derived from (R)-3-amino-2-(benzyl-
oxycarbonylamino)propionic acid (14) with sulfonyl chloride
5 in CH2Cl2 in the presence of Et3N resulted in smooth for-
mation of the sulfonamide 16. Deprotection of 16 with
trimethylsilyl iodide (TMSI) in MeCN followed by reductive
condensation with 8 afforded compound 18. Hydrolysis of 18
in hydrochloric acid and acetic acid yielded the desired 3-
aminoalanine derivative 19. Starting from (S)-3-amino-2-
(benzyloxycarbonylamino)propionic acid, the method used to
synthesize compound 19 was repeated to obtain compound
20. Throughout the synthesis described above, no racemiza-
tion was observed.
1 (M55113)
0.060
2 (M55551)
0.006
0.079
3
9
3.27
0.80
0.60
1.76
13
19
20
Results and Discussion
The FXa inhibitory activities of these compounds were
measured by a method similar to that described in the pre-
ceding paper,1,2) and are listed in the Table 1 as IC50 values.
The following conclusions are derived from these data,
though they are still provisional.
bonyl and carboxyl groups favor interaction with FXa pro-
tein.
Finally, regarding the stereochemistry of carboxylic substi-
tution, it is clear that (R)-isomers have higher activity than
(S)-isomers in both the piperazine 2 and ethylenediamine 19
skeleton.
First, compared with the activity of compound 1
(M55113), those of compounds 9 and 13 are quite low. Simi-
larly, the activity of compound 19 was shown to be 1/100 that
of compound 2 (M55551). A similar difference in activity
was observed between 3 and 20. These data suggest that
rigidity of the central part of the molecules tested in this se-
ries may be an important factor for significantly FXa in-
hibitory activity.
These findings may be useful in guiding molecular design
in this field.
Second, when a carbonyl group or a carboxyl group was
introduced into the ethylenediamine skeleton (13, 19), activ-
ity clearly increased with activities of 13 and 19 four and five
Experimental
Melting points (mp) were determined by using METTLER FP82 hotstage
melting point apparatus and were uncorrected. Nuclear magnetic resonance
times that of 9, respectively. These findings suggest that car- (NMR) spectra were taken with JEOL JNM-EX270 FT-NMR or JEOL JNM-

April 2004
461
LA300 in CDCl3, dimethyl sulfoxide-d6 (DMSO-d6) or CD3OD using dried over dry Na2SO4. The solvent was evaporated under reduced pressure
tetramethylsilane as the internal reference. High-resolution mass spectra to yield compound 11 (820 mg, 89%) as colorless powder, mp 174—176 °C.
(HR-MS) were obtained using JEOL JMS-GCMATE. Infrared absorption
1H-NMR (270 MHz, DMSO-d6) d: 12.71—12.52 (1H, br, CO2H), 8.50—
spectra (IR) were run using HORIBA FT-720 FT-IR. High performance liq- 7.65 (7H, m, naphthyl and NH), 3.65 (2H, d, Jϭ5.9 Hz, NHCH2CO2H).
uid chromatographies (HPLC) were conducted by using Shimadzu LC-10A. IR (film) cmϪ1: 1702, 1324, 1153, 1108, 889, 827.
Optical rotations were measured with JASCO DIP-1000 digital polarimeter.
2-[(6-Chloro-2-naphthalenyl)sulfonyl]amino-N-[(1-(4-pyridinyl)-4-
Measurement of Factor Xa Inhibition The enzyme solution was piperidylmethyl]acetamide (13) A solution in CH2Cl2 (27 ml) of 1-(4-
mixed with a test compound dissolved at various concentrations in dimethyl pyridinyl)-4-aminomethylpiperidine (12) (350 mg, 1.83 mmol) was added
sulfoxide (DMSO). Synthetic substrate was added and incubated in a 20 mM
Tris–HCl buffer (pH 7.5) containing 0.13 M NaCl at 37 °C. The absorbance
dropwise to
a solution in THF (27 ml) of compound 11 (548 mg,
1.83 mmol). To the mixture, DCC (415 mg, 2.01 mmol) and HOBt (308 mg,
at 405 nm was measured continuously. The following enzyme and substrate 2.01 mmol) were added and the mixture was stirred at room temperature for
were used: human factor Xa (Enzyme Research Laboratories, Inc., 17 h under Ar. The reaction mixture was evaporated under reduced pressure.
0.019 U/ml) and S-2222 (Chromogenix AB, 0.4 mM). To calculate the in-
The residue was purified by silica gel column chromatography (eluents:
hibitory activity of the test compound, the initial reaction velocity was com- CH2Cl2 : MeOHϭ85 : 15—80 : 20) to give compound 13 (469 mg, 54%) as
pared with the value for a control containing no test compound. The in-
hibitory activity of a test compound was expressed as IC50.
colorless powder, mp 215—217 °C.
HR-MS m/z: Calcd for C23H2535ClN4O3S: 472.1336. Found: 472.1342. 1H-
N-(2-tert-Butoxycarbonylaminoethyl)-6-chloro-2-naphthalenesulfon- NMR (300 MHz, DMSO-d6) d: 8.50—6.67 (12H, m, naphthyl, pyridinyl and
amide (6) To a solution of N-(tert-butoxycarbonyl)ethylenediamine hy-
NH), 3.83—3.71 (2H, m, C2,6-H of piperidine), 3.50 (2H, br, COCH2NH),
drochloride (4) (310 mg, 1.92 mmol) in dry CH2Cl2 (15 ml), 6-chloro-2- 2.28—2.78 (2H, m, piperidine-CH2NH), 2.70—2.54 (2H, m, C2,6-H of
naphthalenesulfonyl chloride (5) (500 mg, 1.92 mmol) and Et3N (0.27 ml, piperidine), 1.56—0.83 (5H, m, C3,4,5-H of piperidine). 13C-NMR (75 MHz,
2.30 mmol) were added and the mixture was stirred overnight at room tem- DMSO-d6) d: 167.36 (HNCO), 154.15 (C4 of pyridine), 149.70 (C2,6 of pyri-
perature. Water (30 ml) was added to the reaction mixture and the mixture dine), 137.89—123.80 (10C, naphthyl), 108.26 (C3,5 of pyridine), 45.35 (C2,6
was extracted with CH2Cl2. The organic layer was washed with water and of piperidine), 45.08 (COCH2NH), 43.74 (piperidine-CH2NH), 35.47 (C4 of
brine and dried over dry Na2SO4. The solvent was evaporated under reduced piperidine), 28.40 (C3,5 of piperidine). IR (KBr) cmϪ1: 3153, 1664, 1604,
pressure. The residue was crystallized from hexane and Et2O to yield com- 1522, 1327, 1230, 1151.
pound 6 (738 mg, quant.) as colorless powder, mp 121—122 °C.
Ethyl (R)-3-Amino-2-(benzyloxycarbonylamino)propionate Hydro-
HR-MS m/z: Calcd for C17H2135ClN2O4S: 384.0910, Found: 384.0913. 1H- chloride (15) To a 20% (w/w) HCl–EtOH solution (1.5 l) under cooling
NMR (300 MHz, CDCl3) d: 8.42—7.54 (6H, m, naphthyl), 5.50—5.35 (1H, ice bath, (R)-3-amino-2-(benzyloxycarbonylamino)propionic acid (14)
br, NH), 4.90—4.75 (1H, br, NH), 3.29—3.19 (2H, m, BocNHCH2), 3.15—
(68.0 g, 0.28 mol) was added and the mixture was stirred overnight at room
temperature. The solvent was evaporated under reduced pressure and the
residue was crystallized with EtOAc and EtOH to yield compound 15
3.06 (2H, m, CH2NHSO2), 1.41 (9H, s, tBuOCO(Boc)). IR (film) cmϪ1
3383, 3267, 1682, 1508, 1319, 1132.
:
N-(2-Aminoethyl)-6-chloro-2-naphthalenesulfonamide (7) Anisole (75.0 g, 87%) as white powder, mp 136—137 °C.
(0.49 ml) and TFA (3.8 ml) were added to compound 6 (0.75 g, 1.95 mmol)
at cooling with ice bath and the mixture was stirred for 2 h at room tempera-
HR-MS m/z: Calcd for C13H18N2O4: 266.1266, Found: 266.1277. 1H-
NMR (300 MHz, DMSO-d6) d: 8.27 (2H, br s, NH2), 7.92 (1H, d, Jϭ8.3 Hz,
ture. Et2O (5 ml) was added to the reaction mixture. After vigorous stirring NH), 7.45—7.30 (5H, m, phenyl), 5.07 (2H, s, PhCH2O), 4.45—4.35 (1H,
and followed standing, the supernatant was removed by decantation and an- m, CH), 4.13 (2H, q, Jϭ7.1 Hz, CO2CH2CH3), 3.21 (1H, dd, Jϭ4.6, 13.0 Hz,
other 5 ml portion of Et2O was added. This procedure was repeated three NH2CH2), 3.06 (1H, dd, Jϭ9.5, 13.0 Hz, NH2CH2), 1.19 (3H, t, Jϭ7.1 Hz,
times. The residue was crystallized from CH2Cl2 to give compound 7 CO2CH2CH3). IR (KBr) cmϪ1: 1720, 1527, 1461, 1305, 1261, 1224, 1025.
(0.21 g, 38%) as colorless powder, mp 147—148 °C.
[a]D26ϭϩ37.1° (cϭ1.000, MeOH).
Ethyl (R)-2-(Benzyloxycarbonyl)amino-3-[(6-chloro-2-naphthalenyl-
HR-MS m/z: Calcd for C12H1335ClN2O2S: 284.0386, Found: 284.0395. 1H-
NMR (300 MHz, CDCl3) d: 8.45—7.54 (6H, m, naphthyl), 3.07—2.95 (2H, sulfonyl)amino]propionate (16) To a solution of 6-chloro-2-naphthalene-
m, CH2NHSO2), 3.15—3.06 (2H, m, NH2CH2). IR (film) cmϪ1: 3257, 1473, sulfonyl chloride (5) (52.5 g, 0.20 mol) in dry CH2Cl2 (1130 ml), compound
1317, 1149, 1080, 474.
15 (60.9 g, 0.20 mmol) and Et3N (56.1 ml, 0.4 mol) were added and the mix-
6-Chloro-N-[2-[[1-(4-pyridinyl)-4-piperidinyl]methyl]aminoethyl]-2-
ture was stirred at room temperature for three days under Ar. Water (700 ml)
naphthalenesulfonamide (9) A solution of 1-(4-pyridinyl)-4-piperidine- was added to the reaction mixture and the mixture was extracted with
carbaldehyde (8) (150 mg, 0.79 mmol) and compound (200 mg, CH2Cl2. The organic layer was washed with water and brine and dried over
0.70 mmol) in dry CH2Cl2 (3 ml) containing AcOH (0.07 ml) was stirred at dry Na2SO4. The solvent was evaporated under reduced pressure. The
room temperature for 30 min under Ar. To the solution, NaBH(OAc)3 residue was crystallized with hexane and Et2O to yield compound 16
(298 mg, 1.4 mmol) was added and the mixture was stirred overnight at (97.7 g, 97%) as white powder, mp 96—97 °C.
7
room temperature. Water (5 ml) was added to the reaction mixture, which
was adjusted to pH 9 with 1 N NaOH and the mixture was extracted with
HR-MS m/z: Calcd for C23H2335ClN2O6S: 490.0965, Found: 490.0946. 1H-
NMR (300 MHz, CDCl3) d: 8.41—7.26 (11H, m, naphthyl and phenyl),
CH2Cl2. The organic layer was washed with water and brine and dried over 5.72—5.62 (1H, m, NH), 5.35—5.24 (1H, m, NH), 5.12—4.97 (2H, m,
dry Na2SO4. The solvent was evaporated under reduced pressure. The PhCH2O), 4.42—4.33 (1H, m, CHCH2), 4.26—4.08 (2H, m, CO2CH2CH3),
residue was purified by silica gel column chromatography (eluents: 3.53—3.36 (2H, m, CHCH2NHSO2), 1.23 (3H, t, Jϭ7.2 Hz, CO2CH2CH3).
CH2Cl2 : MeOHϭ95 : 5—80 : 20) to give compound 9 (148 mg, 46%) as col- IR (KBr) cmϪ1
:
3261, 1730, 1713, 1527, 1336, 1157. [a]D27ϭϩ10.7°
(cϭ1.000, MeOH).
Ethyl (R)-2-Amino-3-[(6-chloro-2-naphthalenylsulfonyl)amino]propi-
orless powder, mp 150—153 °C.
HR-MS m/z: Calcd for C23H2735ClN4O2S: 458.1543, Found: 458.1535. 1H-
NMR (270 MHz, CDCl3) d: 8.43—6.57 (10H, m, naphthyl and pyridinyl), onate (17) To a solution in MeCN (460 ml) of compound 16 (28.2 g,
3.86—3.74 (2H, m, C2,6-H of piperidine), 3.12—3.01 (2H, m, CH2NHSO2), 57.4 mmol), TMSI (20.4 ml, 143.6 mmol) was added under cooling with ice.
2.83—2.62 (2H, m, NHCH2CH2NHSO2), 2.83—2.62 (2H, m, C2,6-H of
After stirring the mixture at the same temperature for 20 min, 2 N HCl
piperidine), 2.34 (2H, d, Jϭ6.8 Hz, piperidine-CH2NH), 1.77—1.03 (5H, m, (220 ml) was added and the reaction mixture was washed with hexane. The
C3,4,5-H of piperidine). 13C-NMR (75 MHz, CDCl3) d: 154.64 (C4 of pyri- mixture was neutralized by sat. aq. NaHCO3 and was extracted with EtOAc.
dine), 149.69 (C2,6 of pyridine), 137.15—123.47 (10C, naphthyl), 108.21 The organic layer was washed with water and brine and dried over dry
(C3,5 of pyridine), 54.66 (piperidine-CH2NH), 48.24 (NHCH2CH2NHSO2), Na2SO4. The solvent was evaporated under reduced pressure to give com-
46.35 (C2,6 of piperidine), 42.32 (NHCH2CH2NHSO2), 36.11 (C4 of piperi- pound 17 (20.0 g, 98%) as brown amorphous.
dine), 29.36 (C3,5 of piperidine). IR (film) cmϪ1: 1599, 1325, 1157, 1080,
694.
N-[(6-Chloro-2-naphthalenyl)sulfonyl]glycine (11) To a solution of
HR-MS m/z: Calcd for C15H1735ClN2O4S: 356.0597, Found: 356.0564. 1H-
NMR (300 MHz, CDCl3) d: 8.44—7.53 (6H, m, naphthyl), 4.20—4.07 (2H,
m, CO2CH2CH3), 3.61 (1H, dd, Jϭ4.6, 7.2 Hz, CHCH2), 3.36 (1H, dd,
glycine (10) (276 mg, 3.68 mmol) and K2CO3 (508 mg, 3.68 mmol) in H2O Jϭ4.6, 12.8 Hz, CHCH2NHSO2), 3.07 (1H, dd, Jϭ7.2, 12.8 Hz,
(8 ml), 6-chloro-2-naphthalenesulfonyl chloride (5) (800 mg, 3.06 mmol) CHCH2NHSO2), 1.23 (3H, t, Jϭ7.2 Hz, CO2CH2CH3). IR (KBr) cmϪ1: 3224,
and PhMe (1.0 ml) were added and the mixture was refluxed for 90 min. The 1734, 1620, 1329, 1155, 1078. [a]D26ϭϪ22.6° (cϭ1.000, MeOH).
reaction mixture was adjusted to pH 1 with 3 N HCl and the mixture was ex-
Ethyl (R)-3-[(6-Chloro-2-naphthalenyl)sulfonyl]amino-2-[1-(4-
tracted with EtOAc. The organic layer was washed with water and brine and pyridinyl)-4-piperidinylmethylamino]propionate (18) A solution of 1-

462
Vol. 52, No. 4
dine), 61.16 (CHCH2NHSO2), 52.20 (piperidine-CH2NH), 47.22 (C2,6 of
piperidine), 42.05 (CHCH2NHSO2), 34.27 (C4 of piperidine), 30.20 (C3,5 of
piperidine). IR (KBr) cmϪ1: 3435, 3068, 2925, 1741, 1645, 1547, 1331,
1157. [a]D28ϭϩ21.2° (cϭ1.000, MeOH).
(S)-3-[(6-Chloro-2-naphthalenyl)sulfonyl]amino-2-[1-(4-pyridinyl)-4-
piperidinylmethylamino]propionic Acid Dihydrochloride (20) Using
(S)-3-Amino-2-(benzyloxycarbonylamino)propionic acid, the method of
synthesis in above was repeated to yield the title compound as colorless
amorphous.
The optical purity of this compound was measured by HPLC [CHIRAL-
PAKTM AD-H (Daicel Chemical Industries, Ltd.); hexane : EtOH : TFA : di-
ethylamineϭ70 : 30 : 0.1 : 0.1], and it was found to be 98.3% e.e. [a]D27ϭ
Ϫ21.9° (cϭ1.000, MeOH).
(4-pyridinyl)-4-piperidinecarbaldehyde (8) (2.63 g, 14 mmol) and compound
17 (5.0 g, 14 mmol) in dry CH2Cl2 (117 ml) containing AcOH (1.67 ml) were
stirred at room temperature for 50 min under Ar. To the reaction mixture,
NaBH(OAc)3 (7.42 g, 35 mmol) was added and the mixture was stirred
overnight at room temperature. Water (200 ml) was added to the reaction
mixture, which was adjusted to pH 7 by sat. aq. NaHCO3 and the mixture
was extracted with CH2Cl2. The organic layer was washed with water and
brine and dried over dry Na2SO4. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
(eluents: CH2Cl2 : MeOHϭ95 : 5—80 : 20) to give compound 18 (3.96 g,
53%) as colorless amorphous.
HR-MS m/z: Calcd for C26H3135ClN4O4S: 530.1754. Found: 530.1762. 1H-
NMR (CDCl3) d: 8.43—6.61 (10H, m, naphthyl and pyridinyl), 5.40—5.25
(1H, m, NH), 4.20—4.03 (2H, m, CO2CH2CH3), 3.90—3.79 (2H, m, C2,6-H
of piperidine), 3.32 (1H, dd, Jϭ4.6, 11.9 Hz, CHCH2NHSO2), 3.25 (1H, dd,
Jϭ4.6, 7.1 Hz, CHCH2NHSO2), 2.99 (1H, dd, Jϭ7.1, 11.9 Hz,
CHCH2NHSO2), 2.85—2.72 (2H, m, C2,6-H of piperidine), 2.47 (1H, dd,
Jϭ6.6, 11.3 Hz, piperidine-CH2NH), 2.20 (1H, dd, Jϭ6.6, 11.3 Hz, piperi-
dine-CH2NH), 1.82—1.08 (5H, m, C3,4,5-H of piperidine), 1.22 (3H, t,
Jϭ7.2 Hz, CO2CH2CH3). 13C-NMR (75 MHz, CDCl3) d: 172.43
(CO2CH2CH3), 154.66 (C4 of pyridine), 150.06 (C2,6 of pyridine), 137.20—
123.51 (10C, naphthyl), 108.32 (C3,5 of pyridine), 61.50 (CO2CH2CH3),
60.49 (CHCH2NHSO2), 53.54 (piperidine-CH2NH), 46.17 (C2 or C6 of
piperidine), 46.13 (C2 or C6 of piperidine), 44.43 (CHCH2NHSO2), 36.45
(C4 of piperidine), 29.45 (C3 or C5 of piperidine), 29.34 (C3 or C5 of piperi-
dine), 14.16 (CO2CH2CH3). IR (KBr) cmϪ1: 2929, 1732, 1599, 1329, 1157,
1078. [a]D27ϭϩ15.3° (cϭ1.000, MeOH).
Acknowledgments The authors thank Emeritus Professor Hiroshi Ya-
manaka of Tohoku University for his encouragement and helpful discussions
throughout this study.
References and Notes
1) Part 3 in the series of studies on 1-arylsulfonyl-3-piperazinone deriva-
tives as factor Xa inhibitor; Part 1: Nishida H., Miyazaki Y., Kitamura
Y., Ohashi M., Matsusue T., Okamoto A., Hosaka Y., Ohnishi S.,
Mochizuki H., Chem. Pharm. Bull., 49, 1237—1244 (2001).
2) Part 2: Nishida H., Miyazaki Y., Mukaihira T., Saitoh F., Fukui M.,
Harada K., Itoh M., Muraoka A., Matsusue T., Okamoto A., Hosaka
Y., Matsumoto M., Ohnishi S., Mochizuki H., Chem. Pharm. Bull., 50,
1187—1194 (2002).
(R)-3-[(6-Chloro-2-naphthalenyl)sulfonyl]amino-2-[1-(4-pyridinyl)-4-
piperidinylmethylamino]propionic Acid Dihydrochloride (19) To a so-
lution in AcOH (5.0 ml) of compound 18 (500 mg, 0.94 mmol), c. HCl
(5.0 ml) was added and the mixture was heated under reflux for 3.5 h. The
reaction mixture was concentrated under reduced pressure to give compound
19 (540 mg, quant.) as brown amorphous.
3) Davie E. W., Fujikawa K., Kisiel W., Biochemistry, 30, 10363—10370
(1991).
4) Mann K. G., Nesheim M. E., Church W. R., Haley P., Krishnaswamy
S., Blood, 76, 1—16 (1990).
5) Rosenberg J. S., Beeler D. L., Rosenberg R. D., J. Biol. Chem., 250,
1607—1617 (1995).
The optical purity of this compound was measured by HPLC [CHIRAL-
PAKTM AD-H (Daicel Chemical Industries, Ltd.); hexane : EtOH : TFA :
Et2NHϭ70 : 30 : 0.1 : 0.1], and it was found to be 94.1% ee.
6) Harker L. A., Hanson S. R., Kelly A. B., Thromb. Haemost., 78, 736—
741 (1997).
7) Elodi S., Varadi K., Thromb. Res., 15, 617—629 (1979).
8) Fevig J. M., Wexler R. R., Ann. Rep. Med. Chem., 34, 81—100 (1999)
9) Sanderson P. E. J., Med. Res. Rev., 19, 179—197 (1999).
10) Hauptmann J., Sturzebecher J., Thromb. Res., 93, 203—241 (1999).
11) Weitz J. I., Hirsh J., Chest., 119, 95S—107S (2001).
12) Mancuso A. J., Swern D., Synthesis, 1981, 165—185 (1981).
13) Merck & Co., Inc., WO 97/36592 (1997).
1H-NMR (300 MHz, CD3OD) d: 8.53—7.16 (10H, m, naphthyl and
pyridinyl), 4.40—4.28 (2H, m, C2,6-H of piperidine), 4.21—4.14 (1H, m,
CHCH2NHSO2), 3.65—3.01 (6H, dd, CHCH2NHSO2, C2,6-H of piperidine
and piperidine-CH2NH), 2.41—1.34 (5H, m, C3,4,5-H of piperidine). 13C-
NMR (75 MHz, CD3OD) d: 168.71 (CO2H), 158.20 (C4 of pyridine), 140.59
(C2,6 of pyridine), 138.05—124.60 (10C, naphthyl), 108.73 (C3,5 of pyri-