Heterocyclic derivatives of 2-(3,5-dimethylphenyl)tryptamine as GnRH receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00133-0

A series of heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. The carbon tether length and heterocyclic ring attached to the amino group of 2-(3,5-dimethylphenyl)tr

Full text of DOI:10.1016/S0960-894X(01)00133-0

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1077–1080
Heterocyclic Derivatives of 2-(3,5-Dimethylphenyl)tryptamine
as GnRH Receptor Antagonists
Peter Lin,a,* Mamta Parikh,a Jane-Ling Lo,b Yi Tien Yang,b Kang Cheng,b
Roy G. Smith,b,y 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 heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin
releasing hormone receptor assay. The carbon tether length and heterocyclic ring attached to the amino group of 2-(3,5-dimethyl-
phenyl)tryptamine were varied. Several of these derivatives were potent GnRH antagonists with the most potent compound having
an IC50 of 16 nM. # 2001 Elsevier Science Ltd. All rights reserved.
The tryptamine-derived compound 1 (Fig. 1), has been
previously disclosed1,2 as a potent GnRH antagonist.
However, the phenol compound (1) may be prone to
conjugation and unwanted metabolic oxidation owing
to the presence of the phenolic group. This possible
metabolic liability prompted investigations to find suit-
able phenol surrogates. Our preceding paper3 described
one such study comprising tryptamine derivatives with
side chains having a terminal para-substituted benzene
ring (e.g., sulfonamide 2). In this Letter we report our
findings from a second study where the phenol ring is
replaced by a variety of heterocycles.
aromatic heterocyclic compounds, used a palladium(0)
alkynylation reaction as the key step in the sequence.
The preparation of a 2-pyridyl compound 20 is illus-
trative (Scheme 2). Reaction of 3-butyn-1-ol 16 and 2-
bromopyridine 17 in a Castro–Stevens reaction gave
acetylene 18. The carbon–carbon triple bond in 18 was
hydrogenated to give the saturated aliphatic chain pri-
mary alcohol. Swern oxidation of the alcohol afforded
Preparation of Compounds4
The compounds synthesized for this study were
prepared by two general routes. The first method3
involved a standard peptide amide bond formation
between 2-(3,5-dimethylphenyl)tryptamine 4 and a car-
boxylic acid 3 (Scheme 1). The resulting secondary
amides 5 were reduced with borane to give the corre-
sponding amines 6–15 that are described in Table 1. The
rat GnRH receptor binding data for compounds 6–15
are shown in Tables 3 and 4.
Figure 1. Two Merck tryptamine-derived GnRH receptor antagonists.
The second method, which was typically useful for the
preparation of some four- and five-carbon tethered
*Corresponding author. Tel.:+1-732-594-4646; fax: 1-732-594-5790;
e-mail: peter_lin@merck.com
yCurrent address: Hufffington Center for Aging, Baylor School of
Medicine, One Baylor Plaza (M-320), Houston, TX 77030, USA.
Scheme 1. Reagents and conditions: (a) EDC, HOBt, CH2Cl2, rt;
.
(b) BH3 THFcomplex, THF, reflux, followed by Me 2NCH2CH2OH,
reflux.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00133-0

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P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1077–1080
aldehyde 19. A reductive alkylation reaction between
tryptamine1 4 and aldehyde 19 afforded the desired sec-
ondary amine product 20, along with the tertiary amine
sideproduct resulting from a second reductive amina-
tion. Other tryptamines (21–26, Table 2) were prepared
using a similar protocol to that described in Scheme 2.
The GnRH receptor binding data for compounds 21–26
are shown in Tables 3 and 4.
a similar reaction sequence to that shown in Scheme 2.
Hydrolysis of amide 33 gave the 2-aminopyridine 34.
The 2-pyridyl methanesulfonamide 35 was obtained
from amine 34 by using a three-step reaction sequence
comprising t-butoxycarbonyl protection (BOC-protec-
tion) of the secondary amine followed by methane-
sulfonamide formation and then BOC-deprotection.
The compounds listed in Tables 1 and 2 were evaluated
in a rat GnRH receptor binding assay according to
The a-methoxypyridine analogue 29 and a-pyridone 30
were synthesized as described in Scheme 3. 2,5-Dibro-
mopyridine 27 was reacted with sodium methoxide in
dimethylformamide (DMF) to give the 5-bromo-2-meth-
oxy pyridine. The bromopyridine 28 was transformed
into 2-methoxypyridine 29 using the reaction sequence
described in Scheme 2. Reaction of methoxypyridine 29
with boron tribromide afforded the a-pyridone 30.
The three 2-aminopyridine derived analogues 33–35
were prepared from 2-amino-5-bromopyridine (31)
according to Scheme 4. Acetylation in the presence of
pyridine in THFgave the acetamide 32 from which the
N-acetylated 2-aminopyridine 33 was obtained through
Table 1. 2-Arylindole derivatives prepared from secondary amides by
borane reduction
Scheme 2. Reagents and conditions: (a) Pd(PPh3)4, LiCl, CuCl, NEt3,
bromide 17, 80 ꢀC; (b) H2, PtO2, EtOH, rt; (c) oxalyl chloride, DMSO,
NEt3, CH2Cl2, ꢁ78 ꢀC to rt; (d) NaCNBH3, MgSO4, anhyd MeOH,
0 ꢀC.
Table 3. Rat GnRH receptor binding IC50 values for the three pyri-
dine isomers with different tether lengths
Compound
n
Heterocycle
6
7
8
9
10
11
12
13
14
15
1
1
1
2
2
2
3
3
4
4
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
Isomer
Chain length
4-Pyridyl
4-Imidazolyl
7-(1,2,3,4-Tetrahydro)-1,8-napthyridyl
n=1
n=2
n=3
n=4
n=5
2-pyridyl
3-pyridyl
4-pyridyl
6a
>10 mMb
7
4 500 nM
8
9 000 nM
9
20
450 nM
21
40 nM
22
16 nM
2 170 nM
10
200 nM
11
160 nM
12
23
50 nM
24
200 nM
13
210 nM
150 nM
Table 2. 2-Arylindole derivatives prepared by reductive amination
aThe number in bold (e.g., 6) refers to the compound number.
bRat GnRH receptor binding assay IC50 values (nM or mM).
Table 4. Rat GnRH receptor binding IC50 values for different
heterocyclic systems and a four-carbon tether
Compd
n
Heterocycle
20
21
22
23
24
25
26
29
30
33
34
35
4
4
4
5
5
4
4
4
4
4
4
4
2-Pyridyl
3-Pyridyl
4-Pyridyl
3-Pyridyl
4-Pyridyl
Compound
Rat GnRH receptor binding
IC50 (nM)
14
15
25
26
29
30
33
34
35
450
1260
270
36
90
57
120
41
45
5-Pyrimidinyl
3-Quinolinyl
5-(2-MeO)-Pyridyl
5-Pyrid-2-onyl
5-(2-AcNH)-Pyridyl
5-(2-Amino)pyridyl-
5-(2-MsNH)-Pyridyl

P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1077–1080
1079
literature methods.5,6 We looked first at different carbon
tether length linking the pyridine ring and tryptamine
nitrogen and surveyed which of the isomeric forms of
pyridine was intrinsically more potent. The IC50 values
obtained from the biological assay are presented in
Table 3.
With the results of the preliminary study in hand, fur-
ther examples of heterocyclic phenol mimetics of GnRH
antagonist 1 were evaluated with the potency enhancing
saturated four-carbon chain tether. Weak activity was
observed in the 7-(1,2,3,4-tetrahydro)-1,8-napthyridyl
analogue 15 (IC50=1260 nM). The 5-pyrimidyl analo-
gue 25 (IC50=270 nM) and the 4-imidazolyl analogue
14 (IC50=450 nM), had reduced potency. The 3-quino-
lyl analogue (26, IC50=36 nM) had comparable potency
to the 3-pyridyl analogue (21, IC50=40 nM) implying
that the extra aromatic ring apparently contributed little
towards rat GnRH receptor binding.
From this study, we found that one-carbon tether com-
pounds (6, 7, and 8) were weakly active and 2-pyridyl
derivatives (6, 9, and 20) were much less active than their 3-
and 4-pyridyl counterparts (7, 10, 21, and 8, 11, 22,
respectively). For a 3-pyridyl system, moderate activity
was achieved with tethers of two or three atoms length (10
and 12) while an approximately 5-fold increase in potency
was seen when the tether was lengthened (21, n=4 and 23,
n=5). In the 4-pyridyl series, the receptor binding activity
with tether lengths of n=2, 3 or 5 (11, IC50=160 nM; 13,
IC50=210 nM; and 24, IC50=150nM) were essentially
comparable. However, a sharp distinction was seen with a
four-carbon tether. The most active analogue was the 4-
pyridyl analogue attached with a four-carbon tether, 22,
(IC50=16 nM) at the rat GnRH receptor. This IC50 value
is similar to the affinity shown by the initial phenol lead
compound 1 (IC50=27 nM). Overall, tether lengths of
approximately three to five carbons are well tolerated
with a clear preference for a four-carbon linkage in the
4-pyridyl series. The ranking of the pyridine isomers with
respect to potency is: 4-pyridylꢂ3-pyridyl>2-pyridyl.
We speculated that combination of either a hydroxyl1 or
a methanesulfonamide3 group with a 3-pyridyl ring
might have potency advantages. The pyridone 30 and
the sulfonamide 35 were tested on the rat GnRH recep-
tor binding assay. The two compounds, 30 and 35, had
respectable binding affinities to the rat GnRH receptor
(IC50=57 and 45 nM, respectively) that were compar-
able to phenol 1. The desired additive effect of combin-
ing a pyridine ring system with a phenol or with a
sulfonamide group that was anticipated was not
observed. Intriguingly, two 3-pyridyl intermediates 29
(IC50=90 nM) and 33 (IC50=120 nM) were potent
compounds and the basic 2-amino-3-pyridyl analogue
34 (IC50=41 nM) had comparable potency to the phe-
nol 1. We speculate that under our assay conditions
(pHꢂ7) weakly acidic groups7 such as a phenol, a sul-
fonamide or a 2-aminopyridine group are partially pro-
tonated and can act as hydrogen bond donors
interacting with the receptor binding pocket. We hypo-
thesize that the pyridines7 indirectly act as hydrogen
bond donors through the potentiation of an associated
water molecule.
Indeed, the phenol ring of indole antagonist 1 can be
replaced by a heterocyclic ring. The rat GnRH antago-
nist compounds 6–12 and 20–24 helped to establish
optimum tether lengths and position of the nitrogen in
the pyridine ring is preferred. The 3- and 4-pyridyl sub-
stitutions were favored over the 2-pyridyl. A single atom
tether length generally resulted in weaker receptor
binding potency than longer tether lengths. Of these
compounds, analogue 22, which features a four-carbon
tether and a 4-pyridine ring system, had a rat GnRH
receptor binding IC50=16 nM, which is between that of
the phenol 1 and the methanesulfonamide 2, previously
reported.1,3 The ‘hybrid compounds’ 30 and 34 did not
have the anticipated increases in potency relative to the
phenol 1 and sulfonamide 2. Other heterocyclic ring sys-
tems may be substituted for the simple 3- and 4-pyridyl
systems without loss of potency (viz. 26, 29, 33, and 34).
Scheme 3. Reagents and conditions: (a) NaOMe, DMF, 100 ꢀC;
(b) BBr3, CH2Cl2, ꢁ78 ꢀC to rt.
Acknowledgements
We are indebted to Ms. Amy Bernick and Dr. Lawrence
Colwell for help with mass spectroscopic analysis of our
compounds. Useful and perceptive discussions with
Ralph Mosley, a member of the molecular modeling
group, is also amicably acknowledged here. Our thanks
to Robert Frankshun, Joseph Leone, Judy Pisano and
Scheme 4. Reagents and conditions: (a) Ac2O, pyridine, THF, rt;
(b) NaOH, MeOH 45 ꢀC; (c) (BOC)2O, NEt3, CH2Cl2, rt; (d) MsCl,
NEt3, CH2Cl2, 0 ꢀC; (e) TFA, anisole, CH2Cl2, 0 ꢀC to rt.

1080
P. Lin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1077–1080
Mark Levorse who supplied us with synthetic inter-
mediates used throughout the course of this study.
Useful discussions with Drs. Robert DeVita, Jonathan
Young and Feroze Ujjainwalla concerning the work
described here are also gratefully acknowledged.
4. All of the final products and intermediates described in this
paper have been fully characterized by thin-layer chromato-
graphy, MS and by H NMR spectroscopy.
5. DeVita, R. J.; Hollings, D. D.; Goulet, M. T.; Wyvratt, M.
J.; Fisher, M. H.; Lo, J.-L.; Yang, Y. T.; Cheng, K.; Smith, R.
G. Bioorg. Med. Chem. Lett. 1999, 9, 2615
1
6. Walsh, T. F.; Toupence, R. B.; Young, J. R.; Huang, S. X.;
Ujjainwalla, F.; DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.,
Jr.; Fisher, M. H.; Lo, J.-L.; Ren, N.; Yudkovitz, J. B.; Yang,
Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett. 2000,
10, 443
7. Note added in proof: Calculated pKa values obtained from
the ACD/pKa DB (version 4.50) computer program obtained
from Advanced Chemistry Development Inc. The values
obtained are: 4-methylphenol (10.21ꢃ0.13); N-(4-methylphe-
nyl)methanesulfonamide (9.71ꢃ0.5); 2-amino-4-methylpyr-
idinium ion (7.38ꢃ0.11); 4-methylpyridinium ion (5.94ꢃ0.1);
4-methylanilinium ion (5.04ꢃ0.1).
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.; 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, 515.
3. Lin, P.; Marino, D.; 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, 1073.