SAR studies of novel 5-substituted 2-arylindoles as nonpeptidyl GnRH receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00708-3

The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported.

Full text of DOI:10.1016/S0960-894X(00)00708-3

Bioorganic & Medicinal Chemistry Letters 11 (2001) 515±517
SAR Studies of Novel 5-Substituted 2-Arylindoles as Nonpeptidyl
GnRH Receptor Antagonists
Lin Chu,a,* Jane-Ling Lo,b Yi-Tien Yang,b Kang Cheng,b Roy G. Smith,b
Michael H. Fisher,a Matthew J. Wyvratta and Mark T. Gouleta
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
bDepartment of Biochemistry and Physiology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
Received 24 October2000; accepted 6 December2000
AbstractÐThe discovery of the potency-enhancing e€ect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH
receptor antagonists led to the identi®cation of several analogues with high anities on the GnRH receptor. The syntheses and
SARs of these 5-substituted-2-arylindole analogues are reported. # 2001 Elsevier Science Ltd. All rights reserved.
In our previous letter,1 we discussed a novel class of
gonadotropin releasing hormone (GnRH) receptor
antagonists, the 2-arylindoles, and the initial structure±
activity studies, which concluded with a simpli®ed linker
between the phenol moiety and centeramine, and with
the optimized substituent, 3,5-dimethylphenyl, on the 2-
position of the indole (1). In this letter, we describe the
discovery of potency-enhancing 5-substitutions on the
indole core. The subsequent investigation of SARs led
to the identi®cation of several analogues with high
binding anities on the rat GnRH receptor.
selective bromination reaction. The 2-bromo compound
4 was coupled with 3,5-dimethylphenylboronic acid (5)
via a modi®ed Suzuki reaction2 to provide compound 6,
which was subsequently subjected to a series of pre-
viously reported transformations1 to a€ord the ®nal
target 9 in good yield.
The 5-benzyloxy analogue (10) was prepared following
the same sequence outlined in Scheme 1, starting with 5-
benzyloxytryptamine (11).
The commercially available 5-benzyloxytryptamine (11)
was also used as the building block fora variety of 5-
substituted analogues (Schemes 2 and 3). The phthalimide
12, prepared according to the synthetic scheme outlined
in Scheme 1, was fully deprotected with palladium cat-
alyzed hydrogenolysis followed by aqueous hydrazine to
provide tryptamine 13, which was subsequently coupled
with acid 14 to a€ord amide 15. Amide 15 was reduced
ꢀ
with BH3 THF and protected to give the advanced
5-Methoxytryptamine (2) was protected under the same
conditions described in our previous reports (Scheme
1).1,2 Bromination of phthalimide 3 with pyridine
hydrobromide perbromide a€orded the desired 2-bromo
compound 4 as the major product. Due to the electron-
donating nature of the 5-methoxy group, a small degree
of 2,6-dibromination was also observed in this normally
intermediate 16. The phenolic compound 16 was reacted
with triphosgene,3,4 followed by trapping with various
amines to a€ord carbamate compound 17, which was
then fully deprotected in one reaction with Pd(OH)2
catalyzed hydrogenolysis to give the ®nal target 18.
Care should be taken in the reaction of phenolic com-
pound 16 to avoid excess triphosgene and reaction time
so as to minimize reaction at the indole nitrogen.
When the amine (HNRR0) used in step h of Scheme 3
was piperazine, a large excess (ꢁ100 equiv) was used to
*Corresponding author. Tel.: +1-732-594-1125; fax: +1-732-594-5966;
e-mail: lin_chu@merck.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00708-3

516
L. Chu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 515±517
Scheme 1. Reagents and conditions: (a) N-carbethoxyphthalimide,
THF, re¯ux; (b) pyridine hydrobromide perbromide, THF/CHCl3; (c)
3,5-dimethylphenylboronic acid (5), Na2CO3, LiCl, Pd(PPh3)4, tolu-
ene/EtOH (1:1), re¯ux, 1.25 h; (d) hydrazine in H2O, THF/EtOH,
overnight; (e) 4-(4-hydroxyphenyl)butyric acid (8),1 HOBT, EDAC,
DMF/CH2Cl2; (f) BH3ꢀ THF, THF, re¯ux, 3 h; (g) N,N-dimethyl-
ethanolamine, MeOH/THF, re¯ux, 3 h.
Scheme 3. Reagents and conditions: (a) BnBr, NaH, DMF; (b)
NaOH, MeOH/H2O; (c) 13, HOBT, EDAC, CH2Cl2; (d) BH3ꢀ THF,
re¯ux; (e) N,N-dimethylethanolamine, MeOH/THF, re¯ux; (f) CbzCl,
Hunig's base, CH2Cl2, À78 ꢂC; (g) triphosgene, pyridine, CH2Cl2,
0 ꢂC, 30 min; (h) HNRR0; (i) Pd(OH)2, H2, AcOH, MeOH, THF.
Scheme 4. Reagents and conditions: (a) R00X, Et3N, CH2Cl2; (b)
Pd(OH)2, H2, AcOH, MeOH/THF.
Scheme 2. Reagents and conditions: (a) 10% Pd on carbon, H2
(1 atm), EtOAc, 2 days; (b) hydrazine in H2O, THF/EtOH, overnight.
Table 1.
avoid over reaction on the remote nitrogen of the
piperazinyl group. This remote nitrogen would later
serve as an excellent handle for functionalizations to
provide a wide range of analogues 20 (Scheme 4).
The observation that the 5-methoxy analogue
9
(IC50=40 nM)5 was slightly more active than our pre-
vious lead compound 1 (IC50=50 nM), togetherwith
the fact that the substantially sized benzyloxy group in
analogue 10 (IC50=100 nM) did not render the com-
pound much less active than 1, which lacked any 5-
substitution, prompted us to further investigate various
5-substituents on the indole. Table 1 lists selected ana-
logues and theirbinding anities on the art GnRH
receptor.
NRR0
Analogue
IC50 (nM)
MeHNÀ
Me2N
EtHN
PrHNÀ
21
22
23
24
30
30
16
30
25
26
32
20
Although many di€erent carbamates (21±26) had similar
activities, none of them was particularly outstanding.
However, upon further investigation, we discovered that
functionalized piperazinyl compounds, especially
27
100

L. Chu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 515±517
517
Table 2.
The initial structure±activity relationship studies on the
5-position of the indole core of the novel 2-arylindoles
as nonpeptidyl GnRH receptor antagonists led to the
discovery of sulfonylated piperazinyl carbamate groups
as potency-enhancing pharmacophores. The most
potent compound in this series, analogue 35, exhibited a
13-fold increase in rat GnRH binding activity relative to
compound 1, which lacked any 5-substitution. Further
progress in this area will be reported in the near future.
R00
Analogue
IC50 (nM)
25
Acknowledgements
MeÐ
28
The authors would like to thank Dr. L. Colwell and Ms.
A. Bernick for providing mass spectrometry support.
29
30
31
32
33
30
15
30
27
32
References and Notes
1. Chu, L.; Hutchins, J. E.; Weber, A. E.; Lo, J.-L.; Yang, Y.-
T.; Cheng, K.; Smith, R. G.; Fisher, M. H.; Wyvratt, M. J.;
Goulet, M. T. Bioorg. Med. Chem. Lett 2001, 11, 509.
2. Chu, L.; Fisher, M. H.; Goulet, M. T.; Wyvratt, M. J.
Tetrahedron Lett. 1997, 38, 3871 and references cited therein.
3. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987,
26, 894.
4. Larock, R. C.; Lee, N. H. Tetrahedron Lett. 1991, 32, 6315.
5. Crude membranes prepared from rat pituitary glands were
the GnRH receptor source and [125I]buserelin (a peptidyl
GnRH analogue) was used as the radio-labeled ligand. The
competitive binding was conducted in a Tris±HCl based bu€er
at 4 ꢂC for 90 min. The activities are presented as the IC50 for
the inhibition of [125I]buserelin binding to the receptors. A
similar assay is described in ref 6 using a di€erent radioligand.
6. Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto,
H.; Hayase, Y.; Sasaki, S.; Furuya, S.; Suzuki, N.; Okubo, S.;
Ogi, K.; Endo, S.; Onda, H.; Fujino, M. J. Med. Chem. 1998,
41, 4190.
MeO2SÀ
EtO2SÀ
iPrO2SÀ
PrO2S
34
35
36
37
6
4
7
12
sulfonylated ones (34±37), exhibited potent binding
activities (Table 2). In particular, the ethyl sulfonyl
analogue 35 was shown to be 13-fold more active than
ourprevious lead compound 1.