H. C. Smith et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1943–1946
1945
Table 2. Dose response assay results using AaEcRa
7. Hoppe, U. C.; Marban, E.; Johns, D. C. Molecular Therapy
2
8
Palli, S. R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14710.
000, 1, 159.
. Kumar, M. B.; Fujimoto, T.; Potter, D. W.; Deng, Q.;
b
c
EC50 (mM) /Rel Max FI
3
(X=H)
a
3b
(X=F)
3c
(X=Me)
9
2
. Wing, K. D.; Slawecki, R. A.; Carlson, G. R. Science 1988,
41, 470.
Z
a
H
1:12=0:07
1:73=0:76
5:40=0:19
10. Tice, C. M.; Hormann, R. E.; Thompson, C. S.; Friz, J.
L.; Cavanaugh, C. K.; Michelotti, E. L.; Garcia, J.; Nicolas,
E.; Albericio, F. Bioorg. Med. Chem. Lett. 2003, 13, 475.
d
d
d
e
b
c
d
e
2-F
2-Me
2-MeO
2-CF
3:00=0:28
3:19=0:50
33:30=0:01
10:99=0:32
33:30=0:01
8:71=0:04
1
1. Chaguturu, R.; Chiu, G.; Cruickshank, P.; Cullen, T.;
e
Dargar, R.; Dixson, J. Dungan, L.; Eldridge, R.; Halling, B.;
Henrie, R.; Peake, C.; Plummer, E.; Plummer, J.; Yuhas, D.
Presented by Cullen, T. at Changing AgroChem and AgBio-
tech R&D through Technology, IBC Agriculture, Biomole-
cular Symposium 23–24 September 1999, San Francisco, CA.
12. Dixson, J. A.; Eishenawy, Z. M.; Eldridge, J. R.; Dungan,
L. B.; Wowkun, J. S.; Wyle, M. J. ACS Mid Atlantic Regional
Meeting, Newark, DE, 15–16 May 2000.
3
33:30=0:04
f
3-F
3-Me
3-MeO
3-CF
0:75=0:44
d
0:99=0:57
1:36=0:55
1:48=0:98
1:00=0:93
3:00=0:27
33:30=0:01
33:30=0:01
1:84=0:47
g
h
i
0:70=0:15
1:21=0:42
3
j
k
l
4-Cl
4-Me
4-MeO
4-CF
3
0:98=0:43
0:99=0:42
1:43=0:44
1:18=0:64
0:64=0:70
0:87=0:67
1:14=0:87
0:92=0:63
2:15=0:39
5:00=0:26
5:32=0:09
4:41=0:23
1
3. Kakihana, M.; Kato, K.; Mori, M.; Yamashita, T. World
Patent 2001/76629; Chem. Abstr. 2001, 135, 313624.
4. Abe, H.; Nagata, M.; Hata, T. Japanese Patent
m
1
a
2002053557, 2002; Chem. Abstr. 2002, 136, 177981.
15. Forrest, T. P.; Dauphinee, G. A.; Miles, W. F. Can. J.
Chem. 1974, 52, 884.
See ref 23 for assay protocol.
Dose affording 50% of maximum transactivation.
Ratio of maximum level of gene expression of compound to max-
b
c
imum level of gene expression with 2.
d
16. Talukdar, S.; Chen, C.-T.; Fang, J.-M. J. Org. Chem.
Compound not made.
Compound not tested.
2
1
1
4
000, 65, 3148.
e
7. Preparation of cis-6-fluoro-2-methyl-4-(4-fluorophenylamino)-
,2,3,4-tetrahydroquinoline (6b): To a stirred solution of
-fluoroaniline (4b) (3.79 mL, 40.0 mmol) and benzotriazole
maximum fold induction. Library members derived
from 6c were much less effective than those derived
from 6a and 6b. Introduction of substituents at the
ortho position on the benzoyl ring reduced activity
compared to the parent compounds while substition at
the meta and para positions generally improved
(
0.95 g, 8.0 mmol, 0.2 equiv) in absolute ethanol (40 mL) was
added acetaldehyde (2.24 mL, 40.0mmol). The mixture was stir-
red at room temperature for 4 days. The solvent was removed
under reduced pressure. The oily crude product was taken up
in ether (175 mL), washed with 1% aq HCl (50 mL) and
immediately with saturated aqueous NaHCO
ether solution was dried over Na SO and the solvent was
removed under reduced pressure to leave an oily solid (2.93 g)
which was chromatographed on a 40-g silica cartridge eluted
sequentially with 0, 10, 20, 30, 40 and 50% ether in hexanes
(
(
(50 mL). The
3
potency. The meta-CF (3bi) and para-Cl compounds
3
2
4
(3bj) derived from difluorodiamine 6b were of particular
interest; however, none of the library compounds
equaled the potency of the standard ecdysone agonist
ligand 2, whose EC =0.44 mM in this assay.
100 mL of each) to afford a ca. 1:1 mixture of 5b and 6b
1.03 g, 18%). A second chromatography on a 40-g silica gel
5
0
cartridge eluted sequentially with 0, 5, 10, 15, 20, 25, 30, 40
and 50% ether in hexanes (100 mL of each) afforded, in order
of elution, 5b (0.30 g, 5%) as an oil, a mixture of 5b and 6b
(0.34 g, 6%) as an oily solid and 6b (0.23 g, 4%) as a beige
We have described the synthesis and SAR of a first
generation optimization library of cis-1-benzoyl-1,2,3,4-
tetrahydroquinolines of general structure 3. These com-
pounds are promising leads for use as inducers in systems
to control gene expression based on AaEcR.
solid. trans-6-fluoro-2-methyl-4-(4-fluorophenylamino)-1,2,3,4-
1
tetrahydroquinoline (5b): H NMR (CDCl
J=6.2 Hz, 3H), 1.56 (m, 1H), 2.12 (m, 1H), 3.38 (m, 1H), 3.78
3
) d 1.22 (d,
(
br s, 2H), 4.43 (br s, 1H), 6.47 (m, 1H), 6.57 (m, 2H), 6.80 (m,
9
1
13
1
NMR (CDCl
H), 6.92 (m, 3H); F NMR (CDCl ) d À127.9, À128.2;
C
3
Acknowledgements
3
) d 22.0, 34.9, 42.6, 49.5, 113.7, 115.5, 115.9,
1
3
16.3, 116.4, 122.1, 141.3, 142.6, 154.7, 156.6. IR (CDCl )
3
427 cm . MS (EI) m/z 274, 164, 148. cis-6-fluoro-2-methyl-4-
This work was supported in part by NIST Advanced
Technology Project Grant 70NANB0H3012.
À1
(
4-fluorophenyl amino)-1,2,3,4-tetrahydroquinoline (6b): Mp.
ꢁ
1
1
20–122 C. H NMR (CDCl ) d 1.22 (d, J=6.3 Hz, 3H), 1.44
3
(
1H), 6.58 (m, 2H), 6.73 (m, 1H), 6.88 (m, 2H), 7.11 (m, 1H);
F NMR (CDCl ) d-127.3,-128.0; C NMR (CDCl ) d 22.4,
3 3
m, 1H), 2.29 (m, 1H), 3.55 (m, 3H), 4.67 (m, 1H), 6.42 (m,
References and Notes
1
9
13
1
. Laudet, V.; Gronemeyer, H. In The Nuclear Receptor Facts
Book; Academic Press: San Diego, CA, 2002; pp 181–191.
37.5, 47.2, 51.1, 113.3, 114.2, 114.7, 114.9, 115.8, 124.6, 141.2,
À1
143.8, 154.9, 156.8. IR (CDCl ) 3419 cm . MS (EI) m/z 274,
164, 148. Anal. calcd for C H F N : C, 70.06; H, 5.88; F,
16 16 2 2
3
2
3
. Riddiford, L. M.; Truman, J. W. Am. Zool. 1993, 33, 340.
. Dhadialla, T. S.; Carlson, G. R.; Le, D. P. Ann. Rev.
13.85; N, 10.21. Found: C, 70.08; H, 5.67; N, 10.16.
18. Funabashi, M.; Iwakaw, M.; Yoshimura, J. Bull. Soc.
Chem. Jpn. 1969, 42, 2885.
19. Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119,
4882.
20. Preparation of cis-2,6-dimethyl-1-(4-methoxy benzoyl)-4-
Entomology 1998, 43, 545.
. Christopherson, K. S.; Mark, M. R.; Bajaj, V.; Godowski,
P. J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 6314.
. Suhr, S. T.; Gil, E. B.; Senut, M.-C.; Gage, F. H. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 7999.
. Martinez, A.; Sparks, C.; Hart, C. A.; Thompson, J.; Jep-
son, I. The Plant Journal 1999, 19, 97.
4
5
6
(4-methylphenylamino)-1,2,3,4-tetrahydro quinoline (3cl) To a
À1
vial was added PS-NMM resin (400 mg, 1.87 mmol g
,