Triazole oxytocin antagonists: Identification of aryl ether replacements for a biaryl substituent

Article abstract of DOI:10.1016/j.bmcl.2008.08.066

Several potent aryl ether/triazole oxytocin antagonists are described. The lead compound in this series had significantly improved aqueous solubility over related systems containing a biaryl substituent.

Full text of DOI:10.1016/j.bmcl.2008.08.066

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5242–5244
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triazole oxytocin antagonists: Identification of aryl ether replacements
for a biaryl substituent
*
Alan Brown , Lindsay Brown , T. Bruce Brown, Andrew Calabrese, Dave Ellis, Nicholas Puhalo,
Chris R. Smith à, Olga Wallacez, Lesa Watson
Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Several potent aryl ether/triazole oxytocin antagonists are described. The lead compound in this series
had significantly improved aqueous solubility over related systems containing a biaryl substituent.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 July 2008
Revised 18 August 2008
Accepted 18 August 2008
Available online 22 August 2008
This paper is dedicated to the memory of
Olga Wallace.
Keywords:
Oxytocin
Antagonist
Triazole
Solubility
Oxytocin (OT) is a nonapeptide hormone that acts on the OT
receptor, a seven-transmembrane (7TM) (Gq-coupled) receptor.
The OT receptor has no subtypes. It is, however, related to the vaso-
pressin receptors V1A, V1B and V2. OT antagonists have therapeutic
potential in areas such as pre-term labour,1 benign prostatic hyper-
plasia2 and sexual dysfunction.3 There is, as a result, significant
interest in the identification of potent, selective, orally bioavailable
OT antagonists.
We have recently disclosed 1 and 2, as potent, selective OT
antagonist with oral bioavailability in the rat.4
N
OMe
N
N
N
N
N
N
Me
N
N
N
NC
Me
N
OMe
N
2
F
Me
OT Ki 14 nM; MWt 413; clogP 1.7; L.E. 0.35
V1A Ki 4.3 μM; V1B >10 μM; V2 Ki > 10 μM
Aqueous solubility: 24 μg/ml at pH7.25
OMe
1
OT Ki 6 nM; MWt 376; clogP2.9; L.E. 0.41
V1A Ki 388 nM; V1B >10 μM; V2 Ki > 10 μM
Aqueous solubility: 6 μg/ml at pH7.45
In following up these compounds, one key issue we were keen
to address was the relatively low aqueous solubility6 typically seen
with biaryl triazoles in this series. Based on the assumption that
this low solubility was driven in part by the presence of a biaryl
substituent,7 we investigated a number of potential biaryl replace-
ments. Amongst these were a series of ether targets, 3, designed by
putative overlap of 1 and 2 with the previously disclosed8 OT
antagonist 4 (Fig. 1). Encouragingly, our first wave of targets of this
type contained a range of potent, highly ligand efficient9 OT
* Corresponding author. Tel./fax: +44 1304648240.
E-mail address: Alan.D.Brown@pfizer.com (A. Brown).
Present address: Organon Laboratories Ltd, A Part of Schering-Plough Corpora-
tion, Newhouse, Motherwell, UK.
Present address: Medicinal Chemistry, SGX Pharmaceuticals, Inc., 10505 Roselle
Street, San Diego, CA 92122, USA.
à
z
Deceased author.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.066

A. Brown et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5242–5244
5243
antagonists, as illustrated by compounds 5–8 (Fig. 2). These com-
pounds typically had good to excellent selectivity over the related
vasopressin receptors.10 One of these compounds, 6, was crysta-
N
N
N
N
N
Me
OMe
Me
N
Me
N
lised5 and shown to have an aqueous solubility of 170
lg/ml at
EtO
EtO
pH 7.4, a 28-fold improvement over biaryl 1, to which it has a sim-
ilar lipophilicity.
N
OMe
OMe
Subsequent modification of the right-hand side substituent in
lead 5 then yielded several sub 100 nM OT antagonists such as
compounds 9–11 (Fig. 3). Interestingly V1A selectivity was some-
what reduced in these systems, with the 2-triazole substituent ,
as exemplified by 9, routinely yielding compounds with (approxi-
mately) balanced activity versus OT and V1A. However, small ether
substituents, as exemplified by 10 and 11, resulted in an increase
in OT potency whilst allowing good V1A and V2 selectivity to be
maintained. One of these, compound 11, was also crystalised5
and fully profiled.
6: OT Ki 102 nM
1A Ki 3.8 μM
5: OT Ki 143 nM
1A Ki > 10 μM
V2 Ki > 10 μM
V
V
V2 Ki > 10 μM
clogP 2.7
N
N
N
N
OMe
Cl
OMe
CF3
EtO
N
N
EtO
Despite its increased clogP, 11 also had significantly improved
aqueous solubility over that measured for related biaryl analogues,
as represented by compounds 1 and 2. Compound 11 also had rea-
sonable in vitro metabolic stability,11 and wide ligand profiling
N
N
OMe
OMe
8: OT Ki 114 nM
1A Ki 2.9 μM
V2 Ki > 10 μM
showed no significant activity (<30% binding at <1 lM) across a
7: OT Ki 190 nM
1A > 10 μM
V2 Ki > 10 μM
V
range (>70) of receptors and enzymes. Furthermore, with a ligand
efficiency of 0.4, compound 11 represents one of the most ligand
efficient OT antagonists reported to date.
V
Figure 2. Initial aryl ethers and their OT activity.
N
OEt
N
Me
N
N
N
N
N
N
N
Me
EtO
Me
O
EtO
N
N
N
OMe
N
EtO
N
N
OMe
11
OMe
OMe
OT Ki 28 nM; MWt 367; clogP3.2; L.E. 0.40
V1A Ki 549 nM; V1B > 10 μM; V2 Ki > 10μM
Aqueous solubility: 344 μg/ml at pH7.45
10: OT Ki 19 nM
1A Ki 1.7 μM
9: OT Ki 45 nM
1A Ki 214 nM
V2 Ki 1 μM
V
V
V2 Ki 6.4 μM
N
N
The preparation of compound 11 is described in Scheme 1.
Commercially available 4-hydroxy-3-methylbenzoic acid was con-
verted to benzoic hydrazide 12. Acylation with chloroacetylchlo-
ride followed by POCl3 catalysed cyclisation furnished
OEt
Me
EtO
N
N
OMe
11: OT Ki 28 nM
H
OMe
N
N
O
N
V1A 594 nM
N
H
N
SO
N
V2 Ki > 10μM
2 N
N
N
O
O
Figure 3. OT antagonists with modified right-hand side substituents.
N
NC
Me
OMe
2: OT Ki 14 nM
4: OT Ki 6 nM
X
chloromethyloxazole 13 which was in turn converted to the corre-
sponding hydroxylmethyloxazole via its acetate ester. Acid
catalysed reaction with 5-amino-2-methoxypyridine then gave
triazole 14, a key project intermediate. Compound 14 was con-
verted to ether 11 following activation with methane sulphonyl
chloride and subsequent reaction with sodium ethoxide.12
In summary, we have utilized overlap of known OT antago-
nists to identify aryl ether left-hand side substituents as
replacements for biaryl substituents. One such compound, 11,
had significantly improved aqueous solubility and is a selective
and potent OT antagonist. Further work in this area will be re-
ported in due course.
R'
N
N
N
N
substituent
RO
R
Me
3
N
OMe
R = Ar, EtO-
X = -SO2- or C of triazole ring
Figure 1. Putative overlap of OT antagonists 2 and 4, illustrating possible use of
ethoxyphenyl substituent as a biaryl replacement in targets 3.

5244
A. Brown et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5242–5244
N
N
Me
Me
CONHNH2
O
Me
HO
COOH
d,e
Cl
a,b,c
EtO
EtO
13
12
f,g
N
N
N
N
N
O
N
Me
Me
Me
N
N
i,j
h
OEt
OH
OH
EtO
EtO
EtO
N
N
OMe
OMe
14
11
Scheme 1. Reagents and conditions: (a) MeOH/cH2SO4, 88%; (b) EtI/K2CO3/DMF/rt, 82%; (c) NH2NH2:H2O/MeOH/reflux, 70%; (d) ClCH2COCl/N-methylmorpholine/DCM, 90%;
(e) POCl3 reflux, 68%; (f) KOAc/DMF/rt, 96%; (g) Na2CO3/MeOH/H2O/60 °C/97%; (h) 5-amino-2-methoxypyridine/toluene/p-TsOH/reflux, 69%; (i) CH3SO2Cl/Me3N:HCl/DCM/
TEA, 42%; (j) Na metal/EtOH/50 °C/54%.
7. For an example of solubility increasing with replacement of
a biaryl
Acknowledgment
substituent, see: (a) Neff, D. K.; Lee-Dutra, A.; Blevitt, J. M.; Axe, F. U.; Hack,
M. D.; Buma, J. C.; Rynberg, R.; Brunmark, A.; Karlsson, L.; Breitenbucher, J. G.
Bioorg. Med. Chem. Lett. 2007, 17, 6467; b Examination of the crystal packing in
small molecule X-ray structures of a range of biaryls in this series (including 1
and 2) revealed a range of quite different stacking interactions involving the
biaryl substituent(s). We are therefore unable to offer a unifying explanation
for the poor solubility of biaryl compounds of this type. However, our general
We acknowledge the contributions of the following co-workers:
Mark Lewis, Simon Pegg and Nicola Robinson.
References and notes
experience in this programme has been that replacement of
substituent with a range of alternative substituents generally resulted in a
significant jump in aqueous solubility for given lipophilicity. Data for
a biaryl
1. Gullam, J. E.; Chatterjee, J.; Thornton, S. Drug Discov. Today: Ther. Strateg. 2005,
2, 47.
2. Tiwari, A.; Nanda, K.; Chugh, A. Expert Opin. Investig. Drugs 2005, 14, 1359.
3. See, for example, WO 2005028452, and the references therein.
4. Brown, A.; Brown, L.; Ellis, D.; Puhalo, N.; Smith, C.; Wallace, O.; Watson, L.
Bioorg. Med. Chem. Lett. 2008, 18, 4278.
5. (a) All solubilities described in this paper were measured on fully crystalline
material.; (b) All in vitro biological data reported herein represents functional
antagonism, as measured against the corresponding cloned human receptor in
a cell based b lactamase reporter assay using technology licensed from Rhoto
Pharmaceuticals.
a
additional bioisosteres will be disclosed in forthcoming publications.
8. Quattropani, A.; Dorbais, J., et al J. Med. Chem. 2005, 48, 7882.
9. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 430.
10. All of the compounds herein described had no significant binding (<20%) to the
V1B receptor at 10
11. Profiling of 11 in an in vitro Human Liver Microsome assay gave a Clint of
12 l/min/mg. In house experience suggested that this value was consistent
lM.
l
with good to moderate stability towards Cytochrome P450 oxidation.
12. Spectroscopic data for compound 11 as follows: 1H NMR (CDCl3, 400 MHz) d
1.20 (t, 3H), 1.40 (t, 3H), 2.20 (s, 3H), 3.50 (q, 2H), 4.00 (m, 5H), 4.50 (s, 2H),
6.70 (d, 1H), 6.80 (d, 1H), 7.10 (d, 1H), 7.40 (s, 1H), 7.50 (d, 1H), 8.20 (s, 1H).
Mass Spectroscopy (APCI+): m/z 369 [MH+].
6. For a discussion on the solubility requirements of biotherapeutics, see Lipinski,
C. A. J. Pharmacol. Toxicol. Methods 2000, 44, 235.