Novel Antidiabetic and Hypolipidemic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3277
(2) DeFronzo, R. A.; Bonadonna, R. C.; Ferrannini, E. Diabetes Care
1992, 15, 318-368.
(s, 2 H), 7.06-7.7 (m, 9 H), 7.8 (s, 1 H); Mass m/z (relative
intensity) 613 (2.8), 157 (100). Anal. Calcd for C40H44N2O5S
(728.85): C, 65.86; H, 6.04; N, 3.84. Found: C, 65.85; H, 6.04;
N, 3.82.
(3) Gerich, J . E. Oral Hypoglycemic Agents. N. Engl. J . Med. 1989,
321, 1231-1245.
(4) (a) Goldman, J . M. Oral Hypoglycemic Agents: An Update of
Sulfonylureas. Drugs Today 1989, 25, 689-695. (b) Kolterman,
O. G.; Prince, M. J .; Olefsky, J . M. Insulin Resistance in Non-
Insulin Dependent Diabetes Mellitus: Impact of sulfonylureas
agents in vivo and in in vitro. Am. J . Med. 1983, 74 (Suppl. 1A),
82-101. (c) Bailey, C. J . Hypoglycemic and anti-hyperglycemic
drugs for the control of diabetes. Proc. Nutr. Soc. 1991, 50, 619-
630.
(5) (a) Holman, R. R.; Turner, R. C. Oral Agents and Insulin in the
treatment of Non-Insulin-Dependent Diabetes-Mellitus: Text Book
of Diabetes; Pickup, J . C., Williams, G., Eds.; Blackwell Scientific
Publications: London, 1991; p 462-476. (b) Ferrannini, E. The
Insulin Resistance Syndrome. Curr. Opin. Nephrol Hypertens.
1992, 1, 291-298.
5-[4-[N-[(2R/S)-6-Ben zyloxy-2,5,7,8-tetr am eth ylch r om an -
2-ylm et h yl]-(2S)-p yr r olid in e-2-m et h oxy]p h en ylm et h yl-
en e]th ia zolid in e-2,4-d ion e (15a ), Sod iu m Sa lt. To a solu-
tion of 5-[4-[N-[(2R/S)-6-benzyloxy-2,5,7,8-tetramethylchro-
man-2-ylmethyl]-(2S)-pyrrolidine-2-methoxy]phenylmethylene]-
thiazolidine-2,4-dione (15a ) (250 mg, 0.41 mmol) in dry Et2O
(15 mL) at room temperature was added NaOMe in MeOH
[prepared in situ by dissolving Na (13 mg, 0.57 mmol) in MeOH
(1 mL)]. The reaction mixture was stirred at room temperature
for 30 min, and the supernatant solvent was decanted. The
resulting solid was washed twice with Et2O (2 × 5 mL) and
dried over P2O5 under reduced pressure for 6 h to get the title
compound (235 mg, 65%) as a pale yellow solid: mp 245 °C;
(6) Sohda, T.; Mizuno, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.;
Kawanatsu, Y. Chem. Pharm. Bull. 1982, 30, 3563-3573 and
3580-3600.
27
[R]D ) -9.3 (c 0.82, CHCl3); IR νmax (KBr) 1676, 1601, 1557,
1
1509 cm-1; H NMR (CDCl3, 200 MHz) δ 1.15, 1.2 (2s, 3 H),
(7) (a) Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.;
Sohda, T. Studies on antidiabetic agents X: Synthesis and
biological activities of pioglitazone and related compounds.
Chem. Pharm. Bull. 1991, 39, 1440-1445. (b) Sohda, T.; Mizuno,
K.; Momose, Y.; Ikeda, H.; Fujita, T.; Meguro, K. Studies on
Antidiabetic Agents. 11. Novel Thiazolidinedione Derivatives as
Potent Hypoglycemic and Hypolipidemic Agents. J . Med. Chem.
1992, 35, 2617-2626. (c) Yoshioka, T.; Fujita, T.; Kanai, T.;
Aizawa, Y.; Kurumada, T.; Hasegawa, K.; Horikoshi, H. Studies
on Hindered Phenols and analogous. 1. Hypolipidemic Agents
with ability to Inhibit Lipid peroxidation. J . Med. Chem. 1989,
32, 421-428. (d) Clark, D. A.; Goldstein, S. W.; Volkmann, R.
A.; Eggler, J . F.; Holland, G. F.; Hulin, B.; Stevenson, R. W.;
Kreutter, D. K.; Gibbs, E. M.; Krupp, M. N. Merrigan, P.;
Kelbaugh, P. L.; Andrews, E. G.; Tickner, D. L.; Suleske, R. T.;
Lamphere, C. H.; Rajeckas, F. J .; Kappeler, W. H.; McDermott,
R. E. Hutson, N. J .; J ohnson, M. R. Substituted Dihydroben-
zopyran and Dihydrobenzofuran Thiazolidine-2,4-diones and
Hypoglycemic Agents. J . Med. Chem. 1991, 34, 319-325. (e)
Lohray, B. B.; Bhushan, V.; Rao, P. B.; Madhavan, G. R.; Murali,
N.; Rao, K. N.; Reddy, K. A.; Rajesh, B. M.; Reddy, P. G.;
Chakrabarti, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett. 1997,
7, 785.
(8) Fujita, T.; Sugiyama, Y.; Taketomi, S.; Sohda, T.; Kawamastsu,
Y.; Iwatsuka, H.; Suzuoki, Z. Reduction of Insulin Resistance
in Obese and/or Diabetic Animals by 5-[4-(1-Methylcyclohexyl
methoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878, U, 63287,
Ciglitazone), a New Antidiabetic Agent. Diabetes 1983, 32, 804-
810.
(9) (a) Williams, D. G.; Deldar, A.; J ordan, W. H.; Gries, C.; Long,
G. G.; Dimarchi, R. D. Subchronic Toxicity of the Thiazolidinedi-
one, Tanabe 174, in Rat and Dog. Diabetes 1993, 42 (Suppl. 1),
59A (abstr. 186). (b) Deldar, A.; William, G.; Stevenes, C.
Pathogenesis of Thiazolidinedione induced haemotoxocity in the
dog. Diabetes 1993, 42 (Suppl. 1) 57A (abstr. 179).
2.05, 2.1, 2.15 (3s, 9 H), 1.5-3.6 (complex, 13 H), 3.8 (m, 1 H),
4.0 (m, 1 H), 4.6 (s, 2 H), 7.0 (m, 2 H), 7.5 (m, 8 H); Mass m/z
(relative intensity) 614 (1.6), 301 (100).
5-[4-[N-[(2R/S)-6-Ben zyloxy-2,5,7,8-tetr am eth ylch r om an -
2-ylm eth yl]-(2S)-p yr r olid in e-2-m eth oxy]p h en ylm eth yl]-
th ia zolid in e-2,4-d ion e (20a ), Ma lea te. The title compound
(0.28 g, 94%) was prepared as a pale yellow solid from 5-[4-
[N-[(2R/S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethyl]-
(2S)-pyrrolidine-2-methoxy]phenylmethyl]thiazolidine-2,4-di-
one (20a ) (0.25 g, 0.41 mmol) and maleic acid (47 mg, 0.41
mmol) by a procedure analogous to that described above for
27
15a -maleate: mp 180 °C; [R]D ) +19.4 (c 0.66, CHCl3); IR
ν
max (KBr) 3429, 1752, 1700 cm-1; 1H NMR (CDCl3, 200 MHz)
δ 1.2, 1.25 (2s, 3 H), 2.0, 2.05, 2.1 (3s, 9 H), 1.5-4.5 (complex,
17 H), 4.6 (s, 2 H), 4.9 (m, 1 H), 6.1 (s, 2 H), 6.9 (m, 2 H), 7.2
(m, 2 H), 7.5 (m, 5 H), 12.1 (bs, 1 H, exchangeable with D2O);
Mass m/z (relative intensity) 615 (8.8), 392 (100). Anal. Calcd
for C40H46N2O9S (730.8): C, 65.68; H, 6.29; N, 3.83. Found:
C, 65.69; H, 6.27; N, 3.85.
5-[4-[N-[(2R/S)-6-Ben zyloxy-2,5,7,8-tetr am eth ylch r om an -
2-ylm eth yl]-(2S)-p yr r olid in e-2-m eth oxy]p h en ylm eth yl]-
th ia zolid in e-2,4-d ion e (20a ), Hyd r och lor id e. To a solution
of 5-[4-[N-[(2R/S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-
ylmethyl]-(2S)-pyrrolidine-2-methoxy] phenylmethyl]thiazoli-
dine-2,4-dione (20a ) (0.2 g, 0.33 mmol) in Et2O (10 mL) at 0
°C was bubbled HCl gas for 30 min. The resulting solution
was stirred for an additional 30 min, the supernatant liquid
was decanted, and the resulting solid was washed with Et2O
(2 × 5 mL) and dried under reduced pressure over P2O5 for 6
h to get the title compound (0.18 g, 86%) as a pale yellow
(10) Matsumoto, K.; Miyake, S. Yano, M.; Ueki, Y.; Tominaga, Y.
Increase of Lipoprotein (a) with Troglitazone. Lancet 1997, 350,
1748-1749. See also Scrip 1997, 2282, 21 and Scrip 1997, 2292,
20.
27
solid: mp 230 °C; [R]D ) -9.5 (c 1.0, CHCl3); IR νmax (KBr)
1
3425, 1751, 1697 cm-1; H NMR (CDCl3, 200 MHz) δ 1.3, 1.4
(11) (a) Fujiwara, T.; Yoshioka, S.; Yoshioka, T.; Ushiyama, I.;
Horikoshi, H. Characterization of New Oral Antidiabetic Agent
CS-045. Diabetes 1988, 37, 1549-1558. (b) Hulin, B.; Clark, D.
A.; Goldstein, S. W.; McDermott, R. E.; Dambek, P. J .; Kappeler,
W. H.; Lamphere, C. H.; Lewis.; D. M.; Rizzi, J . P. Novel
Thiazolidine-2,4-diones as Potent Euglycemic Agents. J . Med.
Chem. 1992, 35, 1853-1864. (c) Cantello, B. C. C.; Cawthorne,
M. A.; Haigh, D.; Hindley, R. M.; Smith, S. A.; Thurlby, P. L.
The Synthesis of BRL-49653 - A Novel and Potent antihyper-
glycemic agent. Bioorg. Med. Chem. Lett. 1994, 4, 1181-1184.
(d) Cantello, B. C. C.; Cawthorne, M. A.; Cottam, G. P.; Duff, P.
T.; Haigh, D.; Hindley, R. M.; Lister, C. A.; Smith, S. A.; Thurlby,
P. L. [(ω-(Heterocyclylamino)alkoxy]-benzyl]-2,4-thiazolidinedi-
ones as potent antihyperglycemic agents. J . Med. Chem. 1994,
37, 3977-3985. (e) Hulin, B.; McCarthy, P. A.; Gibbs, E. M. The
Glitazone Family of Antidiabetic Agents. Curr. Pharm. Des.
1996, 2, 85-102.
(12) For nonthiazolidinedione-like agents; see: (a) Kees, K. L.;
Cheeseman, R. S.; Prozialeck, D. H.; Steiner, K. E. Perfluoro-
N-[4-(1H-tetrazol-5-ylmethyl) phenyl] alkanamides. A New Class
of Oral Antidiabetic Agents. J . Med. Chem. 1989, 32, 11-13.
(b) Kees, K. L.; Fitzgerald, J . J ., J r.; Steiner, K. E.; Mattes, J .
F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New Potent
Antihyperglycemic Agents in db/db mice: Synthesis and struc-
ture Activity Relationship Studies of 4-substituted benzyl (tri-
fluoromethyl) pyrazoles and Pyrazolones. J . Med. Chem. 1996,
39, 3920-3928. (c) Hulin, B.; Newton, L. S.; Lewis, D. M.;
Genereux, P. E.; Gibbs, E. M.; Clark, D. A. Hypoglycemic Activity
(2s, 3 H), 2.0, 2.05, 2.2 (3s, 9 H), 1.5-4.5 (complex, 17 H), 4.6
(s, 2 H), 4.9 (m, 1 H), 6.9 (m, 2 H), 7.2 (m, 2H), 7.5 (m, 5 H),
9.8 (bs, 1 H, exchangeable with D2O), 12.1 (bs, 1 H, exchange-
able with D2O); Mass m/z (relative intensity) 615 (19), 224
(100). Anal. Calcd for C36H43ClN2O5S (650.5): C, 66.41; H, 6.61;
N, 4.30. Found: C, 66.39; H, 6.62; N, 4.30.
5-[4-[N-[(2R/S)-6-Ben zyloxy-2,5,7,8-tetr am eth ylch r om an -
2-ylm eth yl]-(2S)-p yr r olid in e-2-m eth oxy]p h en ylm eth yl]-
th ia zolid in e-2,4-d ion e (20a ), Sod iu m Sa lt. The title com-
pound (0.27 g, 75%) was prepared as a white solid from 5-[4-
[N-[(2R/S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethyl]-
(2S)-pyrrolidine-2-methoxy]phenylmethyl]thiazolidine-2,4-
dione (20a ) (0.35 g, 0.57 mmol) and Na (19 mg, 0.83 m mol) in
MeOH (1 mL) by a procedure analogous to that described
27
above for 15a -sodium salt: mp 191 °C; [R]D ) -23.1 (c 1.0,
1
CHCl3); IR νmax (KBr) 1665, 1563 cm-1; H NMR (CDCl3, 200
MHz) δ 1.05, 1.25 (2s, 3 H), 2.0 (s, 3 H), 2.1 (s, 6 H), 1.4-4.0
(complex, 17 H), 4.1 (m, 1 H), 4.6 (s, 2 H), 6.8 (m, 2 H), 7.1 (m,
2 H), 7.5 (m, 5 H); Mass m/z (relative intensity) 558 (3.1), 301
(100).
Refer en ces
(1) Porte, D., J r.; Schwartz, M. W. Diabetes complications: Why is
Glucose Potentially Toxic? Science 1996, 27, 699-700.