Synthesis and biological activity of phenoxyphenyl oxamic acid derivatives related to L-Thyronine

Article abstract of DOI:10.1016/S0960-894X(00)00309-7

The synthesis of substituted phenoxyphenyl oxamic acid derivatives related to L-thyronine (L-T₃) is described. The in vitro and in vivo cholesterol lowering and cardiovascular effects of these compounds are presented and discussed. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00309-7

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1661±1663
Synthesis and Biological Activity of Phenoxyphenyl Oxamic
Acid Derivatives Related to L-Thyronine
James L. Stanton,* Edna Cahill, Ronald Dotson, Jenny Tan, Hollis C. Tomaselli,
Jong M. Wasvary, Zouhair F. Stephan and Ronald E. Steele
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research,
556 Morris Avenue, Summit, NJ 07901, USA
Received 11 April 2000; accepted 19 May 2000
AbstractÐThe synthesis of substituted phenoxyphenyl oxamic acid derivatives related to l-thyronine (l-T3) is described. The in
vitro and in vivo cholesterol lowering and cardiovascular e€ects of these compounds are presented and discussed. # 2000 Elsevier
Science Ltd. All rights reserved.
Triiodothyronine (l-T3) 1 and related analogues have
been shown to lower cholesterol levels in animal models1
and man.2 This property results from the action of thy-
roid hormone on its liver nuclear receptors to stimulate
the synthesis of low density lipoprotein (LDL) receptors3
as well as the synthesis of several lipolytic enzymes.4
However, these agents are not used therapeutically due
to adverse cardiac side e€ects, which arise either directly
by acting on cardiac receptors or indirectly through an
increase in metabolic rate.5 Recently we described a
series of diaryl ether containing oxamic acid derivatives
such as 2 that shows a large separation between lipid
Chemistry Results
lowering activity and cardiovascular side e€ects and
selectivity for activation of thyroid hormone b receptor
(TRb) compared to TRa.6 As previously shown, these
compounds have an unusual structure±activity pro®le in
that replacement of the 3,5-diiodo groups with methyl
groups resulted in comparable or enhanced potency and
improved in vivo activity. In the previous report,6a inves-
tigation of the structure±activity pro®le at the 30-position
was limited. Herein we report the results of the synthesis
and testing of a variety of 30-alkyl and 30-aryl derivatives 3.
Compounds 3d and 3f±3j were prepared as described in
Scheme 1. Nucleophilic aromatic substitution reaction
of iodophenol 6 with p-chloronitrobenzene 7 led to the
key diphenyl ether derivative 8. Suzuki coupling7 of 8
with arylboronic acids (9) produced the 30-aryl analogues
10. Demethylation of 10 with boron tribromide fol-
lowed by nitro group reduction generated the phenols
11. Reaction of 11 with dimethyl oxalate led to the cor-
responding oxamate esters, which underwent alkaline
hydrolysis to yield the ®nal compounds 3. The 30-phenyl-
40-deshydroxy analogue 5 was prepared analogously
starting with the reaction of commercially available 3-
phenylphenol with 7, followed by nitro group reduction,
treatment with dimethyl oxalate and alkaline hydrolysis.
Compounds 3a±c and 3e were prepared from the starting
hydroquinones 12 as shown in Scheme 2. Selective pro-
tection of the less hindered hydroxyl group with t-butyl-
dimethylchlorosilane, followed by methylation of the
*Corresponding author. Tel.: +1-908-277-7968; fax: +1-908-277-
2405; e-mail: james.stanton@pharma.novartis.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00309-7

1662
J. L. Stanton et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1661±1663
Scheme 1. Synthesis of 30±aryl derivatives 3d±j. R is de®ned in Table 1. Reagents: (a) NaH, DMF, 120 ꢀC; (b) RB(OH)2 (9), PdCl2(dppf), K3PO4,
DME; (c) BBr3; (d) H2, 10% Pd/C, EtOH or H2NNH2, 10% Pd/C, EtOH; (e) Dimethyl oxalate, 120ꢀC; (f) NaOH.
Table 1. In vitro competitive binding to the L-T3 receptor of intact
nuclei
Compound
R
IC50(nM)a
1
2
1.1
0.19b
5.4
0.25
2.2
iPr
Me
Et
c-C6H11
Ph
o-CI-C6H4
m-CI-C6H4
m-F-C6H4
m-CF3-C6-H4
p-CF3-C6H4
p-Me-C6H4
c-C6H11
c-C6H11
3a
3b
3c
3d
3e
3f
3g
3h
3i
Scheme 2. Synthesis of intermediates for 3a±c and 3e. R is de®ned in
Table 1. Reagents: (a) Me3CSi(Me)2Cl; (b) Me2SO4, K2CO3; (c) 6 N
HCl; (d) 7, NaH.
1.9
0.17
0.64
1.9
0.92
14
9.0
2.0
1.9
32
more hindered hydroxyl group and de-silylation produced
the phenols 13. Reaction of 13 with 4-chloro-3,5-dime-
thylnitrobenzene 7 generated 10, which was elaborated to
the ®nal compounds as outlined in Scheme 1.
3j
4a
4b
5
The sulfur containing analogues 4a and 4b were prepared
as described in Scheme 3. Nucleophilic aromatic sub-
stitution reaction of 2-cyclohexyl-4-mercaptophenol
(14)8 with 7 led to thioether 15. Hydrogenation of nitro
compound 15 produced the intermediate aniline, which
was condensed with dimethyl oxalate to yield 16. Alkaline
hydrolysis of 15 led to thioether product 4a. Sulfone 4b
was prepared by MCPBA oxidation of the intermediate
oxamate ester, followed by alkaline hydrolysis.
aThe IC50 value is the concentration of compound which inhibits 50%
of bound [125I]-l-T3 at the rat hepatic l-T3 receptor as previously
described and represents the mean of two or more assays using 6 to 8
concentrations of compound per assay. See ref 6.
bSee ref 6.
were more active than the methyl analogue (3a), which is
consistent with the structure±activity pro®le of previously
reported l-T3 analogues.9,10
Biological Results
The cyclohexyl analogue (3c) had anity comparable to
the phenyl analogue (3d), with IC50's of 2.2 and 1.9 nM
respectively. The o-chlorophenyl analogue (3e, 0.17 nM)
was the most active compound in the series, the meta-
substituted analogues 3f±h showed good activity (0.64±
Compounds 3a±j, 4a,b and 5 were tested in vitro for com-
petitive binding to the l-T3 receptor of intact rat liver
nuclei and the results are summarized in Table 1. Among
the 30-alkyl derivatives, the ethyl (3b) and isopropyl (2)
Scheme 3. Synthesis of sulfur analogues 4a and 4b. Reagents: (a) 7, NaH, DMF; (b) H2, 10% Pd/C; (c) Dimethyl oxalate, 120 ꢀC; (d) NaOH; (e) mCPBA.

J. L. Stanton et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1661±1663
Table 2. E€ects in vivo on cardiovascular activity in rats after 7 days treatment
Per cent di€erence from vehicle treated controls
1663
Compound
Dose
Heart weight
Heart rate
% of initial developed tension
At 20 pulses/min
At 40 pulses/min
1
3c
3d
100 mg/kg
25 mg/kg
25 mg/kg
+38.9a
+4.4
3.1
+52.5a
+6.3
8.5
+18.2a
+7.6a
+3.7
+12.7a
+12.6a
0.7
ap<0.05 versus vehicle according to Student's t-test.
1.9 nM) and the para-substituted derivatives 3i,j were
the least active (14 and 9.0 nM), suggesting that the
binding subsite is not deep enough to optimally accom-
modate para substituents. The 40-deshydroxy analogue
5 was substantially less active than the corresponding
4-hydroxy compound 3d.
properties needed for potent in vitro activity and the
desired in vivo pro®le.
Acknowledgements
The authors wish to thank Drs. Cynthia Fink and Paivi
Kukkola for helpful discussions and Ms. Fatima DeSousa
for the preparation of this manuscript.
Replacement of the diaryl ether oxygen in 3c with sulfur
(4a) or sulfonyl (4b) led to comparable anity consistent
with earlier reported studies.9
References and Notes
Compounds 3a±j, 4a,b and 5 were tested in hypercholes-
terolemic rats at 20 mg/kg po for 7 days as described
previously.6 The rats were made hypercholesterolemic
by maintaining them ad libitum on a water and high cho-
lesterol diet containing 1.5% cholesterol and 0.5% cholic
acid. Only compounds 3c and 3d showed signi®cant
reduction in cholesterol (42 and 49%, respectively)
relative to control animals. This activity is comparable
to the results previously found for 2, which at 25 mg/kg po
lowered cholesterol by 54%.6a Compounds 3c and 3d were
next tested for cardiovascular side e€ects. Previously it
was found that the cardiovascular e€ects normally attri-
butable to excess exposure of thyroid hormone, such as
increased heart weight, chronotropy and inotropy,
could be reproduced in rats.6d To test for the lack of
cardiac e€ects, atrial heart rate, atrial tension and heart
weight were determined after administration of the
compounds to rats at 25 mg/kg po for 7 days as pre-
viously described.6 Although 3c had signi®cant cardio-
vascular activity, 3d showed no e€ects (Table 2). By
comparison, l-T3(1) produces cardiovascular e€ects at
a dose of 100 mg/kg.6
1. (a) Engelken, S. F.; Eaton, R. P. Atherosclerosis 1981, 38,
177. (b) Cuthbertson, W. F. J.; Elcoate, P. V.; Ireland, D. M.;
Mills, D. C. B.; Shearley, P. J. Endocrinol. 1960, 21, 45.
2. (a) Boyd, G. S.; Oliver, M. F. J. Endocrinol. 1960, 21, 33.
(b) Hansson, P.; Valdemarsson, S.; Nilsson-Ehle, P. Horm.
Metabol. Res. 1983, 15, 449. (c) The Coronary Drug Project
Research Group, The Coronary Drug Project. J. Am. Med.
Assoc. 1972, 222, 996.
3. Scarabottolo, L.; Trezzi, E.; Roma, P.; Catapano, A. L.
Atherosclerosis 1986, 59, 329.
4. (a) Ridgeway, N. D.; Dolphin, P. J. J. Lipid Res. 1985, 26,
1300. (b) Kuusi, T.; Taskinen, M.; Kikkila, E. J. Clin. Endocrinol.
1988, 66, 51. (c) Hulsmann, W. C.; Oerlemans, M. C.; Geelhoed-
Mieras, M. M. Biochem. Biophys. Res. Comm. 1977, 79, 784.
5. Klein, I. Am. J. Med. 1990, 88, 631.
6. (a) Yokoyama, N.; Walker, G. N.; Main, A. J.; Stanton, J.
L.; Morrissey, M. M.; Boehm, C.; Engle, A.; Neubert, A. D.;
Wasvary, J. M.; Stephan, Z. F.; Steele, R. E. J. Med. Chem.
1995, 38, 695. (b) Taylor, A.H.; Stephan, Z. F.; Steele, R. E.;
Wong, N. C. Mol. Pharmacol. 1997, 52, 542. (c) Stephan, Z.
F.; Yurachek, E. C.; Sharif, R.; Wasvary, J. M.; Leonards, K.
S.; Hu, C.-W.; Hintze, T. H.; Steele, R. E. Atherosclerosis
1996, 126, 53. (d) Stephan, Z. F.; Yurachek, E. C.; Sharif, R.;
Wasvary, J. M.; Steele, R. E.; Howes, C. Biochem. Pharmacol.
1992, 43, 1969.
Thus compound 3d was found to have the desired bio-
logical pro®le, showing potent lipid lowering e€ects and
no cardiovascular side e€ects with over a 1000-fold
separation between the two e€ects. The 30-phenyl analo-
gues described here extend the structure±activity pro®le
of the oxamic acid series of thyrominetics beyond the
7. Miyauri, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
8. Reifschneider, W. US Patent 3674857 (1972); Chem. Abstr.
1972, 77, 101154y.
9. Dietrich, S. W.; Bolger, M. B.; Kollman, P. A.; Jorgensen,
E. C. J. Med. Chem. 1977, 20, 863.
previously reported 30-benzyl and benzoyl derivatives
6a
10. Leeson, P. D.; Ellis, D. E.; Emmett, J. C.; Shah, V. P.;
Showell, G. A. J. Med. Chem. 1988, 31, 37.
and provide additional insights into the structural