Syntheses and structure-activity relationship studies of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists

Article abstract of DOI:10.1016/j.bmcl.2003.12.101

Syntheses and structure-activity relationships of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists are described. Some of substituents on the piperidine ring that were investigated included a fused phenyl group, a

Full text of DOI:10.1016/j.bmcl.2003.12.101

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1795–1798
Syntheses and structure–activity relationship studies of
piperidine-substituted quinolones as nonpeptide gonadotropin
releasing hormone antagonists
Jinlong Jiang,a,* Robert J. DeVita,a Mark T. Goulet,a Matthew J. Wyvratt,a Jane-L. Lo,b
Ning Ren,b Joel B. Yudkovitz,b Jisong Cui,b Yi T. Yang,b Kang Chengb
and Susan P. Rohrerb
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Atherosclerosis and Endocrinology, Merck Research Laboratories, PO Box 2000,
Rahway, NJ 07065, USA
Received 11 September 2003; accepted 29 December 2003
Abstract—Syntheses and structure–activity relationships of piperidine-substituted quinolones as nonpeptide gonadotropin releasing
hormone antagonists are described. Some of substituents on the piperidine ring that were investigated included a fused phenyl
group, a (6R)-trifluoromethyl group, (6S) and (6R)-methyl group. This study showed that GnRH binding potency was tolerated by
a small group at the 6-position of the piperidine, and blocking the 6-position by a trifluoromethyl group reduced clearance rate and
increased oral bioavailability.
# 2004 Elsevier Ltd. All rights reserved.
Gonadotropin releasing hormone (GnRH) is a deca-
peptide released by the hypothalamus which binds to
GnRH receptors on pituitary. The activation of this
G-protein coupled receptor causes the release of lutei-
nizing hormone, which regulate gonadal steroid hor-
mone production.1c,d A variety of hormone disease
conditions such as prostate cancer and endometriosis
may be treated by suppression of the hypothalamic-
pituitary–gonadal axis.
tory also showed that N-substituents on the piperidine
ring could improve oral bioavailability but with reduced
binding and functional activity.1d The effect of sub-
stitution on other positions of the piperidine ring on
GnRH receptor binding and functional activity has not
been previously reported. Here we describe the synth-
eses and structure–activity relationships of substituents
on the piperidine ring in quinolone structure 1.
A series of recent reports from this laboratory describe
the syntheses and structure–activity relationships of
3-aryl quinolones 1 as nonpeptide GnRH antagonists.1
A cyclic amine moiety such as piperidine at the 4-position
of the quinolone was found to contribute significantly to
GnRH receptor binding affinity as demonstrated by the
comparison of the piperidine analogue 2 and much less
active pyridine compound 3. Compounds with the (S)-
configuration of cyclic amine at the 2-position were
more potent in GnRH receptor binding than those with
the R configuration.1c Previous work from this labora-
Scheme 1 outlines the preparation of quinolone analogues
1. 6-Nitro and 6-[N-(pyrimidin-6-yl)carboxamido]quin-
olones were prepared via the routes described in pre-
vious reports from this laboratory.1a,c,e Mitsunobu
reaction of quinolones 4 with pyridinyl-, quinoliny- or
isoquinolinylethanol followed by removal of the BOC
* Corresponding author. Tel.: +1-732-594-2119; fax: +1-732-594-
3220; e-mail: jinlong_jiang@merck.com
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.101

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J. Jiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1795–1798
Scheme 3. Reagents and conditions: (f) (BOC)2O, DMAPcat. CH2Cl2,
20 ꢀC, 2 h; (g) LiAlH4, ether, 0 ꢀC, 2 h.
Treatment of compound 211b with s-butyllithium in
ether at À20 ꢀC followed by reaction with dimethylsul-
fate at À78 ꢀC provided compound 22 in ca. 50% yield.
The product thus obtained is exclusively the trans dia-
Scheme 1. Reagents and conditions: (a) DEAD, PPh3, THF, 20 ꢀC,
12 h; (b) TFA, CH2Cl2, anisolecat., 20 ꢀC, 2 h.
1
group afforded the final compounds 1. The R group in
quinolones of type 1 includes fused-phenyl, methyl,
ethyl, and trifluoromethyl groups.
stereomer based on H NMR spectrum (Scheme 4).
(2S)-(2-Hydroxyethyl)-(6R)-trifluoromethylpiperidine 28
was prepared from lactam triflate 24 that was dis-
covered in our laboratory (Scheme 5).4 Thus, reaction
of triflate 24 with PdCl2(PPh3)2 and propargyl alcohol
gave the coupled product 25. Subsequent hydrogenation
of the enamine double bond and the triple bond over
platinum oxide in toluene afforded a single diastereomer
26. Removal of one carbon unit from the 3-hydroxy-
propyl substituent via an elimination/ozonolysis strat-
egy followed by hydrogenation gave alcohol 28.
Scheme 2 shows the syntheses of (2-hydroxyethyl)-
piperidines, quinoline and isoquinolines. 5,6-Phenyl-
fused piperidine 8 was prepared as the (S)-enantiomer
from (S)-tetrahydroquinoline carboxylic acid via the
Arndt-Eistert homologation, followed by reduction of
the subsequently formed ester (eq 1). Alcohols 11, 14,
and 17 were synthesized by alkylation, followed by
reduction or hydrogenation and subsequently reduc-
tion, (eqs 2–4).
It is noteworthy that the earlier procedure of Munchhof
and Meyers2 failed to generate (2S)-(2-hydroxyethyl)-
(6R)-trifluoromethylpiperidine 28.5
The non-racemic 2-(methoxycarbonymethyl)-6-(S)-
methylpiperidine 18 was prepared following a procedure
of Munchhof and Meyers.2 Reduction of ester 18 with
lithium aluminum hydride followed by BOC-protection
afforded 19 (Scheme 3).
Compounds were evaluated for their ability to compete
with GnRH receptor agonist [125I]buserelin for binding
to the human GnRH receptor in the presence of 0.1%
BSA. In addition, functional antagonism in vitro was
determined via inhibition of GnRH-stimulated phos-
phatidyl inositol (PI) hydrolysis by cloned Chinese
hamster ovary (CHO) cells stably expressing the human
GnRH receptor.1c,d
In order to investigate the opposite steric effect of the 6-
(R)-methyl substituent on the GnRH binding affinity,
intermediate (2S)-(2-hydroxyethyl)-(6R)-methylpiperidine
23 was prepared by alkylation of the BOC-protected
piperidine following the procedure of Beak and Lee.3
Scheme 4. Reagents and conditions: (a) TBSCl, pyridine, CH2Cl2,
0–20 ꢀC, 12 h; (b) s-BuLi, TMEDA, À78 ꢀC to À18 ꢀC, 0.5 h;
(c) (MeO)2SO2, À78 ꢀC to À20 ꢀC, 4 h; (d) aq HF, 20 ꢀC, 12 h.
Scheme 2. Reagents and conditions: (a) ClCO2Bui, TEA, THF/ether,
0 C, 1 h; and excess ethereal CH2N2, 0 ꢀC, 3 h; (b) AgOBz (cat.), TEA,
MeOH; 0–20 ꢀC, 3 h; (c) LiAlH4, Et2O, 0 ꢀC, 2 h; (d) n-BuLi,
TMEDA, THF, À78 ꢀC, 0.5 h; (e) BrCH2CO2Et, THF, À78 ꢀC, 3 h;
(f) 2.2 equiv LDA, TMEDA, THF, À78 ꢀC, 1 h; (g) ClCOOEt, THF,
À78 to 20 ꢀC, 12 h; (h) PtO2 cat., H2 (45 psi), AcOH, 20 ꢀC, 12 h; (i)
(BOC)2O, CH2Cl2, 20 ꢀC, 5 h.
Scheme 5. Reagents and conditions. (d) PdCl2(PPh3)2, CuI, propargyl
alcohol, i-Pr2NH, THF, 20 ꢀC, 12 h; (e) PtO2 cat., H2 (50 psi), toluene,
18 h; (f) 2-cyanoseleno-nitrobenzene, BuPh3, THF, 0–20 ꢀC, 2 h; (g)
H2O2, 0–20 ꢀC; (h) O3, MeOH, –78 ꢀC, 15 min and Me2S, 20 ꢀC, 12 h;
(i) Pd(OH)2 cat., H2 (50 psi), EtOH, 20 ꢀC, 12 h.

J. Jiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1795–1798
1797
In order to investigate the effect of an aromatic ring
around the piperidine ring on the GnRH binding,
phenyl fused quinolined and isoquinolines 30–32 were
evaluated for the rat GnRH binding. In this series the
fused phenyl group at the 4,5-position (compound 30 in
Table 1) resulted in 7-fold loss of binding affinity at the
rat GnRH receptor as compared to the parent com-
pound 29. When the fused phenyl was moved closer to
the 2-hydroxyethyl group at the 2-position of the piper-
idine ring (31), binding affinity at the rat receptor was
reduced by more than 30-fold. In addition, moving the
fused phenyl away from the 2-position to 5,6-position of
the piperidine ring (32) also led to a big loss of the
binding affinity. These results indicated that a phenyl
group fused to the piperidine rings resulted in reduced
binding activity at the rat GnRH receptor.
Tolerability of the binding potency to substituents on
the piperidine ring was further investigated with analo-
gues containing a 3-, 5-, or 6-methyl group. The methyl
group at the 3- (35) or 5-position (34) resulted in a slight
reduction in binding affinity. In contrast, the 6-methyl
(33) and the 6-ethyl group (36) derivatives were equipo-
tent to 29. However, 6-(3-phenyl)propyl substituent led
to more than 20-fold reduced binding affinity as com-
pared to the parent compound 29.
Results from Table 1 showed that potency of the rat
GnRH binding was tolerated only by a small sub-
stituent at the 6-position of the piperidine ring. Based
on these results, study was focused on 6-substituted
analogues.
Table 2 lists quinolone-6-carboxamide compounds with
either a 6-methyl a 6-trifluoromethyl or a 6-ethyl sub-
stituted piperidine. Compounds with (6S)-methyl (40)
and (6R)-methyl (41) are both very potent antagonists
at the human GnRH receptor as compared to the par-
ent compound 38, suggesting that stereochemical con-
figuration at the 6-position of the piperidine ring has no
effect on either GnRH binding or functional activity.
(6R)-Trifluoromethyl group resulted in about 7-fold
reduction of binding and functional activity (compounds
43 vs 42). The trifluoromethylated compound 43 was
almost equipotent to the 6-ethyl substituted compound
Table 1. Inhibition of rat GnRH receptor binding by quinolones
with a 6-alkyl-substituted piperidine
Compd
R
rGnRH (IC50
10 nM
)
291b
Table 2. Inhibition of human GnRH receptor binding and PI turn-
over by quinolones with a 6-alkyl-substituted piperidine
30
70 nM
31
32
33
34
750 nM
Compd
R
R1
H
hGnTH
(IC50
PI Turn
(IC50
)
)
381e
0.9 nM
0.6 nM
0.5 nM
0.5 nM
0.3 nM
2 nM
5.0 nM
9.8 nM
8.7 nM
11.5 nM
2.2 nM
18 nM
—
85% inh.
@10.0 mM
39
Me
H
15 nM
63 nM
40
41
H
35
36
37
45 nM
18 nM
400 nM
421e
Me
Me
H
43
44
5.7 nM

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J. Jiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1795–1798
Table 3. Clearance rate and oral bioavailability of compounds 42
and 43
References and notes
1. (a) DeVita, R. J.; Hollings, D. D.; Goulet, M. T.; Wyv-
ratt, M. J., Jr.; Fisher, M. H.; Lo, J.; Yang, Y. T.; Cheng,
K.; Smith, R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2615.
(b) DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J., Jr.;
Fisher, M. H.; Lo, J.; Yang, Y. T.; Cheng, K.; Smith,
R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2621. (c) DeVita,
R. J.; Walsh, T. F.; Young, J. R.; Jiang, J.; Ujjainwalla,
F.; Toupence, R. B.; Parikh, M.; Huang, S. X.; Fair, J. A.;
Goulet, M. T.; Wyvratt, M. J.; Lo, J.; Ren, N.; Yudko-
vitz, J. B.; Yang, Y. T.; Cheng, K.; Cui, J.; Mount, G.;
Rohrer, S. P.; Schaeffer, J. M.; Rhodes, L.; Drisko, J. E.;
McGowan, E.; MacIntyre, D. E.; Vincent, S.; Carlin,
J. R.; Cameron, J.; Smith, R. G. J. Med. Chem. 2001, 44,
917. (d) Walsh, T. F.; Toupence, R. B.; Young, J. R.;
Huabg, S. X.; DeVita, R. J.; Hollings, D. D.; Goulet,
M. T.; Wyvratt, M. J., Jr.; Fisher, M. H.; Lo, J.; Cui, J.;
Ren, N.; Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Smith,
R. G. Bioorg. Med. Chem. Lett. 2000, 10, 443. (e) Young,
J. R.; Huang, S. X.; Chen, I.; Ren, N.; Walsh, T. F.;
DeVita, R. J.; Hollings, D. D.; Wyvratt, M. J., Jr.; Goulet,
M. T.; Ren, N.; Lo, J.; Yang, Y. T.; Yudkovitz, J. B.;
Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett. 2000,
10, 1723.
Compd
Clearance rate in dog
(mL/Kg/min)
F% in dog
42
43
36.8
21.6
4.4
14.6
44 in binding, although 2-(2-hydroxyethyl)-6-trifluoro-
methyl piperidine is about one thousand-fold less basic
than piperidine (pKa=ꢁ9 for piperidine versus pKa=5.6
for 2-(2-hydroxyethyl)-6-trifluoromethyl) piperidine 286).
Therefore, basicity of the cyclic amine has no significant
effect on the GnRH binding affinity.
Although the previously reported compound 42, with-
out 6-substituent, was still the most active GnRH bind-
ing, it showed low oral bioavailability and high
clearance in dogs. Considering that the high clearance
might relate to metabolism at the 6-position of the
piperidine, pharmacokinetic properties in dog of 6-tri-
fluoromethyl piperidine derivative 43 were evaluated
and compared to the parent compound 42. Indeed, the
6-trifluoromethyl group increased the oral bio-avail-
ability (F%) by 3-fold and reduced the clearance rate
by about 2-fold (Table 3).
2. Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995,
117, 5399.
3. Beak, P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578.
4. Jiang, J.; DeVita, J. R.; Doss, G. A.; Goulet, M. T.;
Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593.
5. In attempts to apply the procedure of Munchhof and
Meyers to preparation of compound 28, intermediate 46
was not detected by 1H NMR, and only compound 47
was isolated. Intermediate 46 was presumably hydrolyzed
by a trace amount of water in methyl a-bromoacetate.
In conclusion, we have synthesized a variety of novel
quinolone analogues with substituted piperidines. SAR
studies indicated that adding a substituent on the
piperidine ring did not enhance GnRH binding affinity
or functional activity, although installing a relatively
small substituent at the 6-position was tolerated. Basicity
of the cyclic amine and stereochemical configuration of
substituents at the 6-position of the piperidine had no
significant affect on potency of the GnRH receptor
binding. Comparison of the pharmacokinetic results of
trifluoromethyl substituted antagonist 43 with those of
the parent compound 42 showed that modification of
the piperidine could improve oral bioavailability.
6. We thank Dorothy Levorse for testing basicity of com-
pound 2-(2-hydroxyethyl)-6-trifluoromethylpiperidine (28).