2-(3,5-Dimethylphenyl)tryptamine derivatives that bind to the GnRH receptor

Article abstract of DOI:10.1016/S0960-894X(01)00134-2

A series of 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. Some para-substituents on the 4-phenylbutyl side chain attached to the tryptamine nitrogen led to compounds with po

Full text of DOI:10.1016/S0960-894X(01)00134-2

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1073–1076
2-(3,5-Dimethylphenyl)tryptamine Derivatives
That Bind to the GnRH Receptor
Peter Lin,a,* Dominick Marino,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, USA
bDepartment of Biochemistry & Physiology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 11 December 2000; accepted 23 February 2001
Abstract—A series of 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing
hormone receptor assay. Some para-substituents on the 4-phenylbutyl side chain attached to the tryptamine nitrogen led to com-
pounds with potent GnRHreceptor binding. The study has helped define structural requirements for GnRHreceptor binding for
the 2-aryltryptamine GnRHantagonists. # 2001 Elsevier Science Ltd. All rights reserved.
Since Schally’s initial discovery1,2 in 1971 of the deca-
peptide gonadotropin releasing hormone (GnRH),
(synonymous with luteinizing hormone-releasing hor-
mone—LHRH), much is now known as to how this
peptide functions in mammalian biochemistry.3À5
GnRHwhen released from the hypothalamus leads to
stimulation of the GnRHreceptor, a G-protein coupled
receptor, located on gonadotrophes in the pituitary
gland. The stimulated gonadotrophes, in turn release
follicle stimulating hormone (FSH) and luteinizing hor-
mone (LH), which interact with the tissues of the
reproductive system. Several medical conditions6 related
to reproductive health that are likely to benefit from
GnRHantagonist therapy are endometriosis, pre-
cocious puberty, and breast and prostate cancer.
seen in patients receiving peptidyl GnRHagonist ther-
apy and secondly, the potential with a small drug
molecule for oral administration. In 1998, Takeda
described peptidomimetic compounds that bind to the
GnRHreceptor that are based on thieno[2,3- b]pyridin-
4-one9 (e.g., 1). Some quinolone-10À14 (e.g., 2) and 2-
aryltryptamine-derived15,16 (e.g., 3) GnRHantagonist
compounds have been reported by Merck authors in the
past 18 months (Fig. 1).
This Letter focuses on some phenol ring replacements of
the Merck 2-arylindole GnRHantagonist 3. Our inves-
tigations on phenol surrogates have helped increase our
In recent years effort has been directed toward finding
drugs effective as GnRHantagonists. Several peptidyl 7,8
GnRHagonist and antagonist compounds are now
known. GnRHpeptidyl agonists have been approved
for clinical use for some time and two peptide antago-
nists, Ganirelix (AntagonTM) and Cetrorelix (Cetro-
tide1), are now currently available for clinical use in
humans. More recently, attention has switched to find-
ing nonpeptidyl GnRHantagonists. The advantages of
using a nonpeptide GnRHantagonist drug are firstly,
avoidance of the initial ‘flare-up’ condition that is often
*Corresponding author.Tel.:+1-732-594-4646; fax: +1-732-594-5790;
e-mail: peter_lin@merck.com
Figure 1. GnRHreceptor antagonists recently reported by Takeda
and by Merck.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00134-2

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P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1073–1076
knowledge of the structure–activity relationships (SAR)
for the 2-arylindole class of nonpeptide GnRH
antagonists.
derivatives 12 and 13. Also, the two corresponding
methyl- and ethyl-sulfonylureas (14 and 15) were syn-
thesized. Thus, the aniline 9 was reacted with two
mono-alkylsulfamoyl chlorides in the presence of tri-
ethylamine. Removal of the BOC-group as described
above gave the sulfonyl ureas 14 and 15. Various
sulfonamide derivatives (16–19 R3=Me; Et; i-Pr and
Ph, respectively, in Scheme 3) were obtained by reacting
the aniline 9 with the appropriate sulfonyl chloride in
the presence of triethylamine at 0 ꢀC. The sulfonamide
products were isolated and subsequent removal of the
BOC group by the usual method led to the target com-
pounds 16–19.
Preparation of Compounds17
In this study, side chains were attached to the trypta-
mine nitrogen of the 2-arylindole core 5 using the reac-
tion sequence shown in Scheme 1. Thus, a 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and
1-hydroxybenzotriazole (HOBt) mediated amide bond
formation between an appropriate para-substituted
phenylbutyric acid 4 and the tryptamine 5 afforded
amides 6. These amides 6 were reduced with borane–
The four-carbon tethered sulfonamide 25 was prepared
as shown in Scheme 4. Protection of 3-butyn-1-ol, 20,
using t-butyldiphenylsilyl chloride (TBDPS-Cl) and
imidazole gave the TBDPS-ether. A palladium(0) cata-
lyzed reaction between this silyl ether with the t-butyl
sulfonamide bromide 21 in triethylamine provided the
acetylene 22. Treatment of silyl ether 22 with tetra-
butylammonium fluoride (TBAF) in THF followed by
hydrogenation of the carbon–carbon triple bond using
Adams’ catalyst (PtO2) gave the alcohol 23. A chro-
mium trioxide on Celite1 oxidation of alcohol 23 to the
aldehyde and a subsequent sodium chlorite oxidation
afforded the acid 24. The tryptamine 5 was reacted with
acid 24 to give amide 25 as described above. The pri-
mary sulfonamide 26 was obtained from amide 25 after
.
tetrahydrofuran (BH3 THF) complex to give the corre-
sponding secondary amines 7 and 8. Protection of tryp-
tamine 8 as its t-butoxycarbonyl (BOC) derivative
(Scheme 2) followed by catalytic hydrogenation using
platinum(IV) oxide led smoothly to the aniline 9. The
latter served as a key intermediate for the synthesis of
the amine derivatives depicted in Scheme 3.
The parent aniline analogue 10 was obtained by treat-
ment of aniline 9 with trifluoroacetic acid (TFA) in the
presence of anisole. This TFA–anisole treatment for
removing BOC-groups was used effectively to reveal the
secondary amine nitrogen from other intermediates
described below. Acetylation of the aniline 9 followed
by TFA promoted deprotection gave the acetanilide 11.
The two urea compounds 12 and 13 were prepared by
reacting aniline 9 with methyl isocyanate and ethyl iso-
cyanate, respectively. The intermediary BOC-containing
adducts were individually treated with the usual BOC-
deprotection conditions to give the 2-aryltryptamine
.
a BH3 THF reduction and treatment with TFA and
anisole.
The various compounds listed in Table 1 containing
phenol surrogates of compound 3 were evaluated. The
compounds were all evaluated in a rat GnRHreceptor
binding assay and in two cases a human GnRHreceptor
Scheme 1. Reagents and conditions: (a) EDC, HOBt, tryptamine 5,
.
CH2Cl2, rt; (b) BH3 THF complex, THF, reflux.
Scheme 3. Reagents and conditions: (a) TFA, anisole, dry CH2Cl2, rt;
(b) CH3COCl, pyridine, CH2Cl2, rt; (c) R1NCO, NEt3, CH2Cl2, rt; (d)
R2NHSO2Cl, NEt3, CH2Cl2, rt; (e) R3SO2Cl, NEt3, CH2Cl2, 0 ꢀC.
Scheme 2. Reagents and conditions: (a) (BOC)2O, NEt3, CH2Cl2, rt;
(b) H2 (1 atm), cat. PtO2, EtOH, rt.

P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1073–1076
1075
binding assay, according to the methods described pre-
viously.10,12 The IC50 values obtained are also shown in
Table 1.
Our initial attempts at replacement of the phenolic
hydroxyl 3 by a fluorine atom (7, IC50=300 nM) resul-
ted in significant loss of receptor binding affinity to the
rat GnRHreceptor relative to the phenol
3
The GnRHantagonist 3 is a phenol derivative. From
some other work, conjugation and metabolism of phe-
nol derivatives had been observed. Thus, this phenol of
3 may be a liability if it is retained in later designs of the
2-arylindole series of GnRHantagonists. The possibility
of metabolism or conjugation of the phenol ring pro-
vided the impetus to study phenol ring surrogates.
(IC50=27 nM). This observation probably implicated
the need for a hydrogen bond donor group, as well as
polarity for significant binding on the GnRHreceptor.
On that basis, poor receptor binding affinity was
observed with
a
para-nitro phenyl group (8,
IC50=500 nM). The simple aniline 10 (IC50=300 nM)
and the acetanilide18 11 (IC50=200 nM) both of which
are capable of acting as a hydrogen bond donor also
showed poor receptor binding affinity to the rat GnRH
receptor. Therefore, some derivatives of the aniline with
pKa <15 were evaluated.18 To our delight, the next
series of analogues, the methylurea 12 (IC50=48 nM)
and ethylurea 13 (IC50=28 nM) did achieve comparable
receptor binding affinity to the phenol 3 as did the two
sulfonyl ureas 14 (IC50=47 nM) and 15 (IC50=40 nM).
Therefore, we were gratified to find that urea and sul-
fonylurea derivatives 12–15 did act as phenol surrogates
of compound 3.
The series of sulfonamides 16–19 was also of interest.
The methanesulfonamide 16 (IC50=7 nM) was 4-fold
more potent in binding than the phenol 3. The methane-
sulfonamide 16 was also more potent (IC50=170 nM for
16 vs IC50=357 nM for 3) at the human GnRHrecep-
tor. Other nonpeptide GnRHantagonists have also
shown differences in their binding affinities toward the
9,13
rat and human forms of the GnRHreceptor.
We
speculate that the 10-fold difference in binding between
the rat and human GnRHreceptor is due to receptor
homology which is approximately 90% conserved.19
Sterically more demanding ethyl-, isopropyl-, and ben-
zene-sulfonamide groups were less potent and had IC50
values in the range 200–300 nM at the rat GnRH
receptor. The ‘reversed’ primary sulfonamide 26 also
showed potent binding affinity (IC50=36 nM) to the rat
receptor, comparable to that of the phenol analogue 3,
but less potent than the methanesulfonamide 16. Fur-
ther studies were made in search of other phenol surro-
gates. One such study on heterocyclic ring replacements20
of the phenol is described in the following Letter.
Scheme 4. Reagents and conditions: (a) t-BuPh2SiCl, imidazole,
CH2Cl2, rt; (b) Pd(PPh3)4, LiCl, CuCl, NEt3, bromide 21, 80 ꢀC; (c)
TBAF, THF, rt; (d) H2, cat. PtO2, EtOH, rt; (e) CrO3 on Celite1
CH2Cl2, rt; (f) NaClO2, sulfamic acid, THF, H2O, rt; (g) tryptamine 5,
,
.
EDC, HOBt, CH2Cl2, rt; (h) BH3 THF complex, THF, reflux; (i)
TFA, anisole, rt.
Table 1. GnRHbinding IC 50 values for the rat and human receptors
Based on the IC50 values presented in Table 1, some
para-substituted benzene derivatives (e.g., compounds
12–17 and 26) may indeed turn out to be valuable
alternative structural motifs for substitution of the phe-
nol ring of 3 that circumvent the metabolism problem
associated with the phenol ring system. One such
compound, methanesulfonamide 16, appears to be a
suitable, more potent replacement for the phenol
containing GnRHantagonist 3.
Compound
X
Rat GnRH
receptor
binding
Human GnRH
receptor
binding
IC50, nM
IC50, nM
3
7
8
-OH27
-F
-NO2
357
300
500
300
200
48
28
47
40
7
10
11
12
13
14
15
16
17
18
19
26
-NH2
-NHCOMe
-NHCONHMe
-NHCONHEt
-NHSO2NHMe
-NHSO2NHEt
-NHSO2Me
-NHSO2Et
-NHSO2iPr
-NHSO2Ph
-SO2NH2
Acknowledgements
The authors are indebted to Dr. Eric E. Allen for help-
ful discussions relating to the preparation of the pri-
mary sulfonamide analogue 26 and to Ms. Amy Bernick
and Dr. Lawrence Colwell for help with mass spectro-
scopic analysis of our compounds. Our gratitude to
170
200
220
300
36

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P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1073–1076
Robert Frankshun, Joseph Leone and Mark Levorse
who supplied us with synthetic intermediates used
throughout the course of this study. Insightful discus-
sions with Ralph Mosley of the molecular modeling
group are graciously recognized. Helpful discussions
with Drs. Robert DeVita, Feroze Ujjainwalla and
Jonathan Young in the preparation of this manuscript
are also gratefully acknowledged.
11. DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Fisher,
M. H.; Lo, J.-L.; Yang, Y. T.; Cheng, K.; Smith, R. G. Bioorg.
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Jr.; Fisher, M. H.; Lo, J.-L.; Ren, N.; Yudkovitz, J. B.; Yang,
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Fair, J. A.; Goulet, M. T.; Wyvratt, M. J.; Lo, J.-L.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Cui, J.; Mount, G.;
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References and Notes
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17. All of the final products and intermediates described in
this paper have been fully characterized by thin-layer chro-
matography, MS and by 1HNMR spectroscopy.
18. Note added in proof: Calculated pKa values obtained
from the ACD/pKa DB (version 4.50) computer program
obtained from Advanced Chemistry Development Inc. are: 4-
Me-C6H4-NHCOMe (15.13Æ0.7); 4-MeC6H4-NHCONHMe
(14.24Æ0.46); 4-MeC6H4-SO2NH2 (10.20Æ0.10); 4-MeC6H4-
OH(10.21 Æ0.13); 4-MeC6H4-NHSO2Me (9.71Æ0.50); 4-
+
MeC6H4-NHSO2NHMe
(5.04Æ0.10).
(8.13Æ0.50);
4-MeC6H4-NH3
19. Work relating to receptor sequences from the Biochem-
istry and Physiology department at Merck will be disclosed in
due course.
20. For a related study concerned with heterocyclic rings as
phenol surrogates see: Lin, P.; Parikh, M.; 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,
1077.
10. DeVita, R. J.; Hollings, D. D.; Goulet, M. T.; Wyvratt,
M. J.; Fisher, M. H.; Lo, J.-L.; Yang, Y. T.; Cheng, K.; Smith,
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