9
24
J . Org. Chem. 1996, 61, 924-928
Ap p r oa ch es to Com bin a tor ia l Syn th esis of Heter ocycles: A
Solid -P h a se Syn th esis of 1,4-Dih yd r op yr id in es
Mikhail F. Gordeev,* Dinesh V. Patel, and Eric M. Gordon
Affymax Research Institute, 3410 Central Expressway, Santa Clara, California 95051
Received September 18, 1995X
N-Immobilized enamino esters 2 derived from amine-functionalized PAL or Rink polystyrene resins
react with preformed 2-arylidene â-keto esters or directly with â-keto esters and aldehydes to afford,
upon trifluoroacetic acid cleavage, 1,4-dihydropyridine (DHP) derivatives in good yields. The
mechanism of this transformation on solid support has been studied using 13C NMR and IR
spectroscopies. This new solid-phase synthesis has been applied to the preparation of several
bioactive DHPs and is designed to be amenable to the “split and pool” protocol for combinatorial
library synthesis.
In tr od u ction
Combinatorial chemistry has recently emerged as a
tion of combinatorial libraries. In this communication,
we report our findings toward the development of a
general method for the solid-phase synthesis of 1,4-
dihydropyridines (DHPs).
1
powerful tool for drug discovery. While methods for the
generation of combinatorial libraries of peptides and
oligonucleotides are now well established, preparation of
libraries of small organic molecules remains a relatively
unexplored and rapidly evolving area of research.2 Sig-
nificantly, it is this aspect of combinatorial chemistry
which may hold the most promise for efficient discovery
of nonpeptidic drug candidates. An important feature
of combinatorial chemistry is the synthesis of compounds
on solid supports, allowing Furka’s3 “split and pool”
methodology to be employed for library construction.
Thus, a challenging prerequisite to combinatorial drug
The DHP nucleus is common to numerous bioactive
compounds which include various vasodilator, antihy-
pertensive, bronchodilator, antiatherosclerotic, hepato-
protective, antitumor, antimutagenic, geroprotective, and
antidiabetic agents.5 DHPs have found commercial util-
ity as calcium channel blockers, as exemplified by
6
a
therapeutic agents such as Nifedipine (7a ), Nitren-
dipine (7b),6b and Nimodipine (7c). Second-generation
calcium antagonists include DHP derivatives with im-
proved bioavailability, tissue selectivity, and/or stability,
6c
1
(4) For early ground-breaking reviews on solid-phase synthesis of
organic molecules, see (a) Crowley, J . I.; Rapoport, H. J . Org. Chem.
discovery is to develop solid-phase syntheses of biologi-
4
cally active molecules on solid supports and to explore
1
976, 9, 135. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327. (c)
the utility of such synthetic methodologies for prepara-
Frechet, J . M. J . Tetrahedron 1981, 37, 663. (d) Mathur, N. G.;
Narang, C. K. Polymers as Aids in Organic Synthesis; Academic
Press: New York, 1980. (e) Frechet, J . M. J . Tetrahedron 1981, 37,
663. (f) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557. For
some early examples of organic syntheses using polymeric support,
see also: (g) Patchornik, A.; Kraus, M. A. J . Am. Chem. Soc. 1970, 92,
7587. (h) Camps, F.; Castells, M. J .; Ferrando, M. J .; Font, J .
Tetrahedron Lett. 1971, 12, 1713.
(5) For reviews, see e.g.: (a) Godfraind, T.; Miller, R.; Wibo, M.
Pharmacol. Rev. 1986, 38, 321. (b) J anis, R. A.; Silver, P. J .; Triggle,
D. J . Adv. Drug Res. 1987, 16, 309. (c) Sausins, A.; Duburs, G.
Heterocycles 1988, 27, 269. (d) Mager, P. P.; Coburn, R. A.; Solo, A.
J .; Triggle, D. J .; Rothe, H. Drug Des. Discovery 1992, 8, 273. (e)
Mannhold, R.; J ablonka, B.; Voigdt, W.; Schoenafinger, K.; Schraven,
E. J . Med. Chem. 1992, 27, 229. (f) Gaudio, A. C.; Korolkovas, A.;
Takahata, Y. J . Pharm. Sci. 1994, 83, 1110.
(6) (a) Bossert, F.; Vater, W. U.S. Patent 3,485,847, Dec 23, 1969.
(b) Meyer, V. H.; Bossert, F.; Wehinger, K.; Stoepel, K.; Vater, W.
Arzneim.-Forsch. 1981, 31, 407. (c) Meyer, V. H.; Bossert, F.; Vater,
W.; Stoepel, K. U.S. Patent 3,799,934, March 26, 1974. (d) Galiano,
A. Drugs Fut. 1995, 20, 231. (e) Alajarin, R.; Vaquero, J . J .; Alvarez-
Builla, J .; Pastor, M.; Sunkel, C.; de Casa-J uana, M. F.; Priego, J .;
Statkow, P. R.; Sanz-Aparicio, J . Tetrahedron: Asymmetry 1993, 4,
617. (f) Alajarin, R.; Alvarez-Builla, J .; Vaquero, J . J .; Sunkel, C.; de
Casa-J uana, M. F.; Statkow, P. R.; Sanz-Aparicio, J .; Fonseka, I. J .
Med. Chem. 1995, 38, 830. (g) Sannita, W. A.; Busico, S.; Di Bon, G.;
Ferrari, A.; Riela, S. Int. J . Clin. Pharmacol. Res. 1993, 13, 281. (h)
Uehar, Y.; Kawabata, Y.; Ohshima, N.; Hirawa, N.; Takada, S.;
Numabe, A.; Nagata, T.; Goto, A.; Yagi, S.; Omata, M. J . Cardiovasc.
Pharmacol. 1994, 23, 970. (i) Nakagawa, T.; Yamauchi, Y.; Kondo,
S.; Fuji, M.; Yokoo, N. J pn. J . Pharmacol. 1994, 64 (Suppl. 1); Abstr.
P-260. (j) Boer, R.; Gekeler, V. Drugs Fut. 1995, 20, 499. (k) Bristolol,
J ames A., Ed. In Annu. Rep. Med. Chem. 1992, 27, 330. (l) Bristolol,
J ames A., Ed. In Annu. Rep. Med. Chem. 1992, 27, 322. (m) Schramm,
M.; Thomas, G.; Towart, R.; Franckowiak, G. Nature 1983, 303, 535.
(n) Sunkel, C. E.; de Casa-J uana, M. F.; Santos, L.; Garcia, A. G.;
Artaljero, C. R.; Vilaroya, M.; Gonzalez-Morales, M. A.; Lopez, M. G.;
Cillero, J .; Alonso, S.; Priego, J . G. J . Med. Chem. 1992, 35, 2407. (o)
Vo, D.; Matowe, W. C.; Ramesh, M.; Iqbal, M.; Wolowyk, M. W.;
Howlett, S. E.; Knaus, E. E. J . Med. Chem. 1995, 38, 2851. (p) Klusa,
V. Drugs Fut. 1995, 20, 135. (r) Cooper, K.; Fray, M. J .; Parry, M. J .
J . Med. Chem. 1992, 35, 3115.
X
Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) For reviews on the use of combinatorial technology for drug
discovery, see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor,
S. P. A.; Gordon, E. M. J . Med. Chem. 1994, 37, 1233. (b) Gordon, E.
M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.; Gallop, M. A. J . Med.
Chem. 1994, 37, 1385. (c) Moos, W. H.; Green, G. D.; Pavia, M. R.
Recent Advances in Generation of Molecular Diversity. In Annual
Reports in Medicinal Chemistry; Bristol, J . A., Ed.; Academic Press,
Inc.: San Diego, CA, 1993; Vol. 28, pp 315-324. (d) Ecker, D. J .;
Crooke, S. T. Biotechnology 1995, 13, 351. (e) Terrett, N. K.; Gardner,
M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51,
8
135. For some recent examples, see: (e) Virgilio, A. A.; Ellman, J .
A. J . Am. Chem. Soc. 1994, 116, 11580. (f) Pei, Y.; Moos, W. H.
Tetrahedron Lett. 1994, 35, 5825. (g) Singh, J .; Allen, M. P.; Ator, M.
A.; Gainor, J . A.; Whipple, D. A.; Solowiej, J . E.; Treasurywala, A. M.;
Morgan, B. A.; Gordon, T. D.; Upson, D. A. J . Med. Chem. 1995, 38,
2
17. (h) Freier, S. M.; Konings, D. A. M.; Wyatt, J . R.; Ecker, D. J . J .
Med. Chem. 1995, 38, 344. (g) Baldwin, J . J .; Burbaum, J . J .;
Henderson, I.; Ohlmeyer, M. H. J . J . Am. Chem. Soc. 1995, 117, 5588.
(
2) (a) Bunin, B. A.; Ellman, J . A. J . Am. Chem. Soc. 1992, 114,
1
0997. (b) Kurth, M. J .; Randall, L. A. A.; Chen, C.; Melander, C.;
Miller, R. B.; McAlister, K.; Reitz, G.; Kang, R.; Nakatsu, T.; Green,
C. J . Org. Chem. 1994, 59, 5862. (c) Yu, K.-L.; Deshpande, M. S.; Vyas,
D. M. Tetrahedron Lett. 1994, 35, 8919. (d) Backes, B. J .; Ellman, J .
A. J . Am. Chem. Soc. 1994, 116, 11171. (e) Patek, M.; Drake, B.; Lebl,
M. Tetrahedron Lett. 1994, 35, 9169. (f) Smith, P. W.; Lai, J . Y. Q.;
Whittington, A. R.; Cox, B.; Houston, J . G.; Stylli, C. H.; Banks, M.
N.; Tiller, P. R. Bioorg. Med. Chem. Lett. 1994, 4, 2821. (g) Kick, E.
K.; Ellman, J . A. J . Med. Chem. 1995, 38, 1427. (h) Holmes, C. P.;
J ones, D. G. J . Org. Chem. 1995, 60, 2318. (i) Campbell, D. A.; Bermak,
J . C.; Burkoth, T. S.; Patel, D. V. J . Am. Chem. Soc. 1995, 117, 5381.
(
j) Murphy, M. M.; Schullek, J . R.; Gordon, E. M.; Gallop, M. A. J .
Am. Chem. Soc. 1995, 117, 5381.
3) (a) Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. 14th
International Congress of Biochemistry, Prague, Czechoslovakia, J uly
0-15, 1988; W. de Gruyter: Berlin/New York, 1989; Vol. 5, p 47
abstract). (c) Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Int. J .
(
1
(
Pept. Protein Res. 1991, 37, 487. (d) Sebestyen, F.; Dibo, G.; Kovacs,
A.; Furka, A. Bioorg. Med. Chem. Lett. 1993, 3, 413.
0
022-3263/96/1961-0924$12.00/0 © 1996 American Chemical Society