2758 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
Quan et al.
(DMSO-d6): δ 3.12-3.37 (m, 2H); 3.59 (s, 3H); 3.78-4.08 (m,
2H); 7.41 (bs, 2H); 7.50-7.76 (m, 5H); 7.86 (d, 1H); 7.97-8.10
(m, 3H); 8.22 (m, 1H); 8.98 (d, 1H); 9.10 (s, 2H); 9.38 (s, 2H);
10.42 (s, 1H). Anal. (C25H24N6O6S‚2TFA‚0.5H2O) C, H, N.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[5-[2′-(a m in osu lfon yl)p h en yl]-2-p yr id in yl]a m i-
n o]ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic
Acid Sa lt (() (30). MS (ES+): 537.3 (M + H)+. 1H NMR
(DMSO-d6): δ 3.22-3.45 (m, 2H); 3.62 (s, 3H); 3.80-4.13 (m,
2H); 7.38 (d, 1H); 7.42 (bs, 2H); 7.58-7.60 (m, 3H); 7.86 (d,
1H); 7.96 (d, 1H); 8.08 (m, 2H); 8.15 (s, 1H); 8.32 (s, 1H); 9.35
(s, 2H); 9.52 (s, 2H); 9.80 (s, 1H). Anal. (C25H24N6O6S‚TFA‚
2H2O) C, H, N.
5-Isoxa zolea cetic Acid , 3-[3-(a m in oim in om eth yl)p h e-
n yl]-5-[[[5-[2′-(a m in osu lfon yl)p h en yl]-2-p yr im id in yl]a m i-
n o]ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic
Acid Sa lt (() (31). MS (ES+): 538.2 (M + H)+. 1H NMR
(DMSO-d6): δ 3.20-3.40 (m, 2H); 3.60 (s, 3H); 3.78-4.08 (m,
2H); 7.38 (d, 1H); 7.42 (bs, 2H); 7.58-7.60 (m, 3H); 7.86 (d,
1H); 8.00-8.10 (m, 3H); 8.62 (s, 2H);9.02 (s, 2H); 9.38 (s, 2H);
10.06 (s, 1H). Anal. (C24H23N7O6S‚1.3TFA‚0.8H2O) C, H, N.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[2′-(am in osu lfon yl)[1,1′-biph en yl]-4-yl]am in o]car -
bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic Acid
Sa lt (+) (32). Optical rotation +51° (acetonitrile, 0.100 g/mL,
25 °C); >99% ee. MS (ES+): 536.2 (M + H)+. 1H NMR (DMSO-
d6): δ 3.10-3.22 (m, 2H); 3.58 (s, 3H); 3.78-4.05 (m, 2H);
7.17-7.34 (m, 6H); 7.48-7.61 (m, 2H); 7.64-7.75 (m, 2H); 7.85
(d, 1H); 7.98 (d, 1H); 8.05 (m, 2H); 9.13 (s, 2H); 9.40 (s, 2H);
10.05 (s, 1H). High-resolution MS (C26H25N5O6S): calcd,
536.1638; found, 536.1598. HPLC purity 96%.
Acid Sa lt (-) (37). Optical rotation -59.64° (acetonitrile,
0.166 g/mL, 25 °C); 99% ee. MS (ES+): 537.3 (M + H)+. 1H
NMR (DMSO-d6): δ 3.22-3.45 (m, 2H); 3.60 (s, 3H); 3.80-
4.15 (m, 2H); 7.38 (d, 1H); 7.42 (bs, 2H); 7.58-7.60 (m, 3H);
7.86 (d, 1H); 7.96 (d, 1H); 8.08 (m, 2H); 8.15 (s, 1H); 8.32 (s,
1H); 9.35 (s, 2H); 9.52 (s, 2H); 9.80 (s, 1H). High-resolution
MS (C25H24N6O6S): calcd, 537.1556; found, 537.1548. HPLC
purity 98%.
Ack n ow led gm en t. We thank D. McCall, J . M.
Luettgen, S. Spitz, R. Bernard, E. Crain, and C. Watson
for their technical assistance. We would also like to
thank A. M. Blum, N. C. Caputo, and A. J . Mical for
the chiral separations.
Refer en ces
(1) This work was partially presented at the 215th ACS National
Meeting: Quan, M. L. Design and Synthesis of Isoxazoline
Derivatives as Factor Xa Inhibitors. 215th ACS National Meet-
ing, Dallas, TX, March 29-April 2, 1998; Abstract 202.
(2) Ripka, W. C.; Vlasuk, G. P. Antithrombotics/Serine Proteases.
In Annual Reports in Medicinal Chemistry: Bristol, J . A., Ed.;
Academic Press: New York, 1997; Vol. 32, pp 71-89.
(3) Davre, E. W.; Fujikawa, K.; Kisiel, W. The Coagulation Cas-
cade: Initiation, Maintenance and Regulation. Biochemistry
1991, 30, 10363-10370.
(4) Elodi, S.; Varadi, K. Optimization of Conditions for the Catalytic
Effect of the Factor IXa-Factor VIII Complex: Probable Role of
the Complex in the Amplication of Blood Coagulation. Thromb.
Res. 1979, 15, 617-629.
(5) Harker, L. A.; Hanson, S. R.; Kelly, A. B. Antithrombotic
Strategies Targeting Thrombin Activities, Thrombin Receptors
and Thrombin Generation. Thromb. Haemostasis 1997, 78, 736-
741.
(6) Tidwell, R. R.; Webster, W. P.; Shaver, S. R.; Geratz, J . D.
Strategies for Anticoagulation with Synthetic Protease Inhibi-
tors. Xa Inhibitors Versus Thrombin Inhibitors. Thromb. Res.
1980, 19, 339-349.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[2′-(am in osu lfon yl)[1,1′-biph en yl]-4-yl]am in o]car -
bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic Acid
Sa lt (-) (33). Optical rotation -63.2° (acetonitrile, 0.242 g/mL,
1
25 °C); >98% ee. MS (ES+) 536.2 (M + H)+. H NMR (DMSO-
d6): δ 3.25 (m, 2H); 3.60 (s, 3H); 3.92-4.03 (m, 2H); 7.22 (bs,
2H); 7.35 (m, 5H); 7.58 (m, 2H); 7.76 (m, 3H); 7.91 (d, 1H);
8.05 (d, 1H); 8.09 (m, 2H); 9.08 (s, 2H); 9.42 (s, 2H); 10.10 (s,
1H). Anal. (C26H25N5O6S‚TFA) C, H, N.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[5-[2′-(a m in osu lfon yl)p h en yl]-2-p yr im id in yl]a m i-
n o]ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic
Acid Sa lt (+) (34). Optical rotation +49.38° (acetonitrile,
0.162 g/mL, 25 °C); 95% ee. MS (ES+): 538.2 (M + H)+. 1H
NMR (DMSO-d6): δ 3.28-3.45 (m, 2H); 3.65 (s, 3H); 3.80-
4.10 (m, 2H); 7.44 (m, 1H); 7.52 (bs, 2H); 7.58-7.64 (m, 3H);
7.92 (d, 1H); 8.03-8.15 (m, 3H); 8.68 (s, 2H); 9.13 (s, 2H); 9.44
(s, 2H); 10.12 (s, 1H). Anal. (C24H23N7O6S‚1.3TFA‚1H2O) C,
H, N.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[5-[2-(a m in osu lfon yl)p h en yl]-2-p yr im id in yl]a m i-
n o]ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic
Acid Sa lt (-) (35, SF 324). Optical rotation -47.01° (aceto-
nitrile, 0.134 g/mL, 25 °C); 95% ee. MS (ES+): 538.2 (M + H)+.
1H NMR (DMSO-d6): δ 3.28-3.45 (m, 2H); 3.65 (s, 3H); 3.80-
4.10 (m, 2H); 7.44 (m, 1H); 7.52 (bs, 2H); 7.58-7.64 (m, 3H);
7.92 (d, 1H); 8.03-8.15 (m, 3H); 8.68 (s, 2H); 9.13 (s, 2H); 9.44
(s, 2H); 10.12 (s, 1H). Anal. (C24H23N7O6S‚1TFA‚0.5H2O) C,
H, N.
5-Isoxa zolea cetic Acid , 3-[3-(a m in oim in om eth yl)p h e-
n yl]-5-[[[5-[2-(a m in osu lfon yl)p h en yl]-2-p yr id in yl]a m in o]-
ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic
Acid Sa lt (+) (36). Optical rotation +53.15° (acetonitrile,
0.222 g/mL, 25 °C); 84% ee. MS (ES+): 537.3 (M + H)+. 1H
NMR (DMSO-d6): δ 3.22-3.45 (m, 2H); 3.60 (s, 3H); 3.80-
4.15 (m, 2H); 7.38 (d, 1H); 7.42 (bs, 2H); 7.58-7.60 (m, 3H);
7.86 (d, 1H); 7.96 (d, 1H); 8.08 (m, 2H); 8.15 (s, 1H); 8.32 (s,
1H); 9.35 (s, 2H); 9.52 (s, 2H); 9.80 (s, 1H). High-resolution
MS (C25H24N6O6S): calcd, 537.1556; found, 537.1559. HPLC
purity 98%.
(7) Stu¨rzebecher, J .; Markwardt, F.; Walsmann, P. Synthetic Inhibi-
tors of Serine Proteinases XIV. Inhibition of Factor Xa by
Derivatives of Benzamidine. Thromb. Res. 1976, 9, 637-646.
(8) Stu¨rzebecher, J .; Markwardt, F.; Walsmann, P. Synthetic Inhibi-
tors of Serine Proteinases XXIII. Inhibition of Factor Xa by
Diamidines. Thromb. Res. 1980, 17, 545-548.
(9) Nagahara, T.; Yukoyama, Y.; Inamura, K.; Katakura, S.; Ko-
moriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. Dibasic
(amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagu-
lation Factor Xa Inhibitors. J . Med. Chem. 1994, 37, 1200-1207.
(10) Nagahara, T.; Yukoyama, Y.; Inamura, K.; Katakura, S.; Ko-
moriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. Design,
Synthesis and Biological Activities of Orally Active Coagulation
Factor Xa Inhibitors. Eur. J . Med. Chem. 1995, 30, 139s.
(11) Sato, K.; Kawasaki, T.; Taniuchi, Y.; Hisamichi, N.; Koshio, H.;
Matsumoto, Y. YM-60828, a Novel Factor Xa Inhibitor: Separa-
tion of its Antithrombotic Effects from its Prolongation of
Bleeding Time. Eur. J . Pharmacol. 1997, 339, 141-146.
(12) Taniuchi, Y.; Sakai, Y.; Hisamichi, N.; Kayama, M.; Mano, Y.;
Sato, K.; Hirayama, F.; Koshio, H.; Matsumoto, Y.; Kawasaki,
T. Biochemical and Pharmacological Characterization of YM-
60828, a Newly Synthesized and Orally Active Inhibitor of
Human Factor Xa. Thromb. Haemostasis 1998, 79, 543-548.
(13) Sato, K.; Kawasaki, T.; Hisamichi, N.; Taniuchi, Y.; Hirayama,
F.; Koshio, H.; Matsumoto, Y. Antithrombotic Effects of YM-
60828, a Newly Synthesized Factor Xa Inhibitor, in Rat Throm-
bosis Model and its Effects on Bleeding Time. Br. J . Pharmacol.
1998, 123, 92-96.
(14) Maduskuie, T. P., J r.; McNamara, K. J .; Ru, Y.; Knabb, R. M.;
Stouten, P. F. W. Rational Design and Synthesis of Novel, Potent
Bis-Phenylamidine Carboxylate Factor Xa Inhibitors. J . Med.
Chem. 1998, 41, 53-62.
(15) Quan, M. L.; Pruitt, J . R.; Ellis, C. D.; Liauw, A. Y.; Galemmo,
R. A., J r.; Stouten, P. F. W.; Wityak, J .; Knabb, R. M.; Thoolen,
M. J .; Wong, P. C.; Wexler, R. R. Design and Synthesis of
Isoxazoline Derivatives as Factor Xa Inhibitors. Bioorg. Med.
Chem. Lett. 1997, 7, 2813-2818.
(16) Wong, P. C.; Crain, E. J ., J r.; Nguan, O.; Watson, C. A.;
Racanelli, A. Antithrombotic Actions of Selective Inhibitors of
Blood Coagulation Factor Xa in Rat Models of Thrombosis.
Thromb. Res. 1996, 83, 117-126.
(17) Boykin, D. W.; Kumar, A.; Hall, J . E.; Bender, B. C.; Tidwell, R.
R. Anti-Pneumocystis Activity of Bis-amidoximes and Bis-o-
alkylamidoximes Prodrugs. Bioorg. Med. Chem. Lett. 1996, 6,
3017-3020.
5-Isoxa zolea cetic Acid , 3-[3-(Am in oim in om eth yl)p h e-
n yl]-5-[[[5-[2-(a m in osu lfon yl)p h en yl]-2-p yr id in yl]a m in o]-
ca r bon yl]-4,5-d ih yd r o-, Meth yl Ester , Tr iflu or oa cetic