Novel heterocyclic thyromimetics. Part 2

Article abstract of DOI:10.1016/j.bmcl.2007.04.085

Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocycles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined and fou

Full text of DOI:10.1016/j.bmcl.2007.04.085

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3992–3996
Novel heterocyclic thyromimetics. Part 2q
Helmut Haning,* Ulrich Mueller, Gunter Schmidt, Carsten Schmeck,
Verena Voehringer, Axel Kretschmer and Hilmar Bischoff
Bayer HealthCare AG, Bayer Schering Pharma Global Drug Discovery, D-42096 Wuppertal, Germany
Received 22 March 2007; revised 25 April 2007; accepted 25 April 2007
Available online 29 April 2007
Abstract—Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocy-
cles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined
and found to be mostly consistent with previously published thyromimetics. The lack of isoform selectivity demonstrated with
isoform-selective transient THR transfection assays has been confirmed by corresponding in vivo studies.
Ó 2007 Elsevier Ltd. All rights reserved.
Cardiovascular diseases continue to be the number one
cause of mortality in the western world. Aberrant lipo-
protein profiles have been well established as a risk fac-
tor contributing to the morbidity of these maladies. The
natural thyroid hormones (TH) T4 1 and T3 2 play an
important role in the regulation of multiple physiologi-
cal endpoints such as brain development, energy homeo-
stasis and control of cholesterol levels through
interaction with thyroid hormone receptors (THR),
members of the nuclear hormone receptor superfamily.
The different physiological functions of the thyroid hor-
mones are mediated by different receptor subtypes,
THRa and THRb, with distinct tissue distribution.
The natural hormones T4 and T3 cannot therapeutically
be used due to their cardiac side effects such as tachycar-
dia and arrhythmia. Molecules mimicking only the ben-
eficial effects of the thyroid hormones on these processes
and lacking their cardiac side effects potentially could
find therapeutic use in a number of conditions such as
obesity, atherosclerosis and dyslipidemia.
with the liver targeted conjugation of T3 with bile acid3
and demonstration of liver selective activity of L-94901
3 that can at least in part be attributed to liver selective
nucleic transport.4
Recently we have demonstrated that incorporation of
heterocycles into the biphenyl ether framework of the
natural hormones leads to a valuable addition in the
chemical diversity of synthetic thyromimetic agents
and can also form the basis for THRb selective
molecules.1
Since it has been demonstrated that changes either
in the outer ring of the biphenyl ether skeleton
"tail"
I
"head"
O
I
NH
N
O
I
NH2
Br
HO
COOH
O
NH2
COOH
R
Selective and therapeutically useful thyromimetic action
therefore can be based either on receptor selectivity or
specific tissue targeting. Over the last years great
improvements have been made in the design and under-
standing of THRb selective agonists.2 In addition the
concept of liver targeting has also been demonstrated
HO
Br
L-94901 3
R = I: T4
R = H: T3
1
2
Cl
3`
O
COOH
HO
KB 141 4
Figure 1. Thyroidhormones T4 1 and T3 2, L-94901 3, KB141 4.
HO
COOH
Cl
O
Keywords: Thyromimetics; Benzofuranes; Thiazinane-2,4-dione.
q
Ref. 1.
Corresponding author. Fax: +49 202 364160; e-mail: Helmut.
Haning@bayerhealthcare.com
GC 1 5
*
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.085

H. Haning et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3992–3996
3993
(exemplified by analogues of KB 141 4 with diverse
substituents in the 30 position) or in the head group
(exemplified by GC 1 5) can lead to enhanced selectiv-
ity, we wanted to explore the incorporation of hetero-
cycles into the head group to expand the diversity in
thyromimetic scaffolds. This work expands on recent
disclosures in the field of bicyclic thyroid hormone
receptor agonists5 (Fig. 1).
The principal tolerance of the THR ligand binding
pocket to altered head groups has long been estab-
lished.6 In our studies we focused on benzofurans and
sulfur containing heterocycles as amino acid replace-
ments. The syntheses of our new heterocyclic thyromi-
metics are exemplified in Schemes 1–4. The syntheses
of the heterocyclic fragments used for the construction
of the biaryl ether framework are shown in Scheme 1.
R
b) or c)
HO
MeO
CHO
OH
a)
MeO
CO2Et
CO2Et
O
O
R
Br CO2Et
6
7
R = H 8a
R = Br 8b
d)
HO
HO
O
CO2Et
HO
OH
e)
Br
CO2Me
9
10
HO
O
O
HO
OH
f)
O
O
COOEt
Cl
12
Cl
CO2Et
11
13
Scheme 1. Synthesis of benzofuran fragments. Reagents and conditions: (a) K2CO3, DMF, 80 °C (33%); (b) BBr3, DCM, rt (39%); (c) i—BBr3,
DCM, rt (39%); ii—Br2, HOAc, 50 °C (21%); (d) i—ZnCl2 (1.7 equiv) n-heptane, reflux; ii—EtOH, concd H2SO4, reflux (6%); (e) concd H2SO4, rt
(87%); (f) i—0.1 N NaOH, reflux (69%); ii—H2SO4 (cat.), EtOH, reflux, 16 h (75%).
I+
R
R
BF4-
HO
R
O
R
MeO
CO2Et
CO2Et
2
O
O
MeO
a)
R = H 8a
R = Br 8b
R = H 14a
R = Br 14b
R1
c) or d)
b)
O
R1
O
14a
14b
CO2H
CO2H
O
R2O
O
HO
15
R1 = Br, R2 = Me 16
R1 = Br, R2 = H 17
R1 = Me, R2 = H 18
e)
I+
2
BF4-
MeO
CO2Et
HO
O
O
O
CO2H
HO
f)
19
10
I+
2
BF4-
MeO
HO
R
O
O
O
HO
g)
CO2Et
CO2H
13
R = H 20
R = iPr 21
Scheme 2. Synthesis of benzofuran thyromimetics. Reagents and conditions: (a) Cu bronze, NEt3, DCM, 0 °C–rt, 16h; (b) BBr3, DCM, ꢀ78 °C–rt
(10%); (c) EtOH, NaOH (90%); (d) i—BBr3, DCM, ꢀ78 °C–rt (90%); ii—EtOH, NaOH (85%); (e) i—Sn(Me)4, Pd(PPh3)4, Tol, reflux (46%); ii—
BBr3, DCM, ꢀ78 °C–rt (90%); iii—EtOH, NaOH (85%); (f) i—Cu bronze, DCM, NEt3 (17%); ii—AlCl3, DCM, rt, 6 h, EtSH (49%), iii—NaOH
(72%); (g) i—Cu bronze, DCM, NEt3 (42%); ii—AlCl3, DCM, rt, 6 h, EtSH (73%); iii—NaOH (72%) (yields refer to 21).

3994
H. Haning et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3992–3996
I+
MeO
2
Br
Br
BF4-
HO
Br
O
CO2Et
F
CO2Et
F
a)
O
O
MeO
Br
8b
22
Br
Br
O
O
c)
b)
O
O
CO2Et
CO2H
O
O
MeO
Br
HO
Br
24
23
F
Br
d)
O
HO
HO
CO2H
O
Br
25
Scheme 3. Synthesis of benzoyl thyromimetics. Reagents and conditions: (a) Cu bronze, NEt3, DCM, 0 °C–rt, 16 h (20%); (b) TiCl4, 4-F-
benzoylchloride (2.5 equiv), molsieves, DCM, rt (46%); (c) i—AlCl3, EtSH (16 equiv), DCM, rt (72%); ii—NaOH, EtOH, rt (84%); (d) NaBH4,
MeOH, 0 °C (92%).
I+
BF4-
MeO
2
HO
O
b)
S
a)
CHO
MeO
CHO
MeO
O
N
H
O
26
27
28
O
O
O
S
NH
+
O
MeO
O
S
NH
29
30
O
c)
d)
O
O
O
S
NH
O
HO
HO
O
S
NH
O
31
32
Scheme 4. Synthesis of thiazoline thyromimetics. Reagents and conditions: (a) Cu bronze, NEt3, DCM, 0 °C–rt, 16 h (93%); (b) 28, piperidine,
benzoic acid, Tol, reflux (62% 29, 12% 30); (c) i—BBr3, DCM, rt (26%); ii—Pd/C, H2 4 bar, dioxane (54%); (d) BBr3, DCM, rt (79%).
The benzofuran moieties 8, 10 and 13 were synthesized
either starting from the corresponding dihydroxy-benz-
aldehyde 6,7 from a substituted dihydrochinone 9 or fol-
lowing a sequence involving a coumarine rearrangement
(11–13).8
The bromine atoms adjacent to the biphenyl ether
bridge can be exchanged for methyl groups 18 using
Sn(Me)4.10 Deprotection of the phenol is typically
achieved with BBr3 or AlCl3/EtSH.
Incorporation of benzoyl type substituents in the
30-position is achieved via Friedel–Crafts acylation
(Scheme 3).
The synthesis of the benzofuran derivatives was
achieved via classical copper–bronze mediated coupling
reactions of the respective hydroxybenzofuran with
3-substituted bis-(4-methoxy-phenyl)iodonium-tetra-flu-
oroborates (Scheme 2).9
In addition to fused heterocyclic systems, we also inves-
tigated heterocycles attached via a spacer as substitutes

H. Haning et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3992–3996
3995
Table 1. EC50 data for compounds 15–33
for the amino acid head group in the natural hormones.
Syntheses are depicted in Scheme 4.
R1
R3
O
O
Condensation of the aromatic aldehyde 27 under basic
conditions gave the rearranged thiazinane-2,4-dione 30
as side product in addition to the desired product 29.
Compounds 29 and 31 are closely related to a series of
heterocyclic thyromimetics described by Ebisawa et al.
and later Hashimoto et al.11 and also Scanlan12 as po-
tent thyroid hormone receptor agonists. The corre-
R2
CO2H
R1
R3
Compound
R1
R2
EC50
(nM)
CO2H
CO2H
15
16
17
18
19
H
H
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
1000
O
O
O
O
i
sponding congener of 31 carrying two Pr-groups on
the inner ring 33 was synthesized from the correspond-
ing hydroxybenzaldehyde with the appropriate substitu-
tion pattern.
CO2H
CO2H
CO2H
Br
Br
Me
H
1000
7
Several SAR trends are apparent comparing the ana-
logues shown in Table 1. Potency was determined in a
HEP-G2 whole cell assay containing both receptor iso-
forms.1 As anticipated, substituents ortho to the central
ether bond on the inner ring are required for activity as
the derivative 15 is inactive.
Me
Me
H
110
5.1
H
O
O
CO2H
Hydrogen bond donor capacity on the outer ring is
also an essential component of these heterocyclic TR
agonists demonstrated by the inactivity of 16. Increas-
ing the steric bulk of the ortho substituents from H as
in 15 to methyl as in 18 to bromine as in 12 increases
the thyromimetic potency consistent with long estab-
lished trends in THR SAR and leads to potent single
digit nanomolar THR agonists in this benzofuran
series.
20
21
24
Me
Me
Br
H
H
H
H
1000
0.3
CO2H
O
i-Pr
CO2H
CO2H
F
210
O
A benzoyl substituent on the outer ring like in 24 is tol-
erated however with reduced activity compared to Pr-
i
O
F
derivative 17. Reduction of the carbonyl group in 24
to the corresponding alcohol 25 results in tenfold in-
creased potency; this SAR trend is also present in the
series of oxamic acid thyromimetics that spawned
CGS 26214.6a
CO2H
25
31
Br
H
H
22
O
HO
H
O
N
Me
i-Pr
0.08
O
Due to the relatively weak activity no attempt was made
on enantiomeric separation of the alcohol.
S
O
The regioisomeric benzofuran headgroup as represented
in the compounds 20 and 21 was investigated. The incor-
poration of a methylene spacer between the benzofuran
and the carboxylic acid leads to the highly potent subn-
anomolar THR ligand 21 (EC50 = 0.3 nM). A lipophilic
substituent like the iPr-group on the outer ring as in 21 is
required for activity since the unsubstituted derivative
20 exhibits only weak activity. In addition, a saturated
fused heterocycle was examined, also giving rise to a po-
tent THR agonist 19.
32
33
Me
H
H
i-Pr
i-Pr
0.06
70
NH
S
O
O
H
N
i-Pr
O
S
Unfortunately, none of the selected heterocyclic com-
pounds demonstrated selective activity for THR b.
In the series of non-fused agonists extremely potent
thyromimetics were found with 6- 31 as well as with
5-membered 32 heterocyclic moieties. The replacement
of the methyl groups in 32 on the inner ring by isopropyl
as in derivative 33 leads to a significant loss in activity.
In addition, thyromimetic activity was determined
in vivo for the ethyl ester of compound 21 which is read-
ily converted to the corresponding acid in vivo after oral
administration. Once daily oral treatment of NMRI
mice over a period of 7 days led to a non-linear dose
dependent reduction of cholesterol of 32–41% beginning
THR isoform selectivity was examined for the most po-
tent compounds 21, 31 and 32 using an isoform selective
transient transactivation assay as previously described.1

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H. Haning et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3992–3996
at a dose of 0.1 mg/kg.13 On the other hand, a pro-
nounced increase of the heart weight of 12–27% could
be demonstrated for this compound in a dose dependent
manner beginning at 0.1 mg/kg in a mouse model for
cardiac effects,14 thus confirming the lack of in vitro
selectivity.
R. J.; Webb, P.; Apriletti, J. W.; Scanlan, T. S. J. Steroid
Biochem. Mol. Biol. 2001, 76, 31.
3. Stephan, Z. F.; Yurachek, E. C.; Sharif, R.; Wasvary, J.
M.; Stele, R. E.; Howes, C. Biochem. Pharmacol. 1992, 43,
1969.
4. (a) Underwood, A. H.; Emmett, J. C.; Ellis, D.; Flynn, S.
B.; Leeson, P. D.; Benson, G. M.; Novelli, R.; Pearce, N.
J.; Shah, V. P. Nature 1986, 324, 425; (b) Ichikawa, K.;
Miyamoto, T.; Kakizawa, T.; Suzuki, S.; Kaneko, A.;
Mori, J.; Hara, M.; Kumagai, M.; Takeda, T.; Hashizume,
K. J. Endocrinol. 2000, 165, 391.
5. Garcia Collazo, A. M.; Koehler, K. F.; Garg, N.;
Fa¨rnegardh, M.; Husman, B.; Ye, L.; Lunggren, J.;
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In conclusion we have expanded the chemical diversity
of potent thyromimetic agents with heterocyclic substit-
uents in the head group. Picomolar agonists have been
synthesized and their selective isoform activation has
been determined. The lack of isoform selectivity has
been confirmed with corresponding in vivo studies dem-
onstrating thyromimetic activity on cholesterol homeo-
stasis as well as on cardiac function in a similar dose
range.
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13. NMRI mice (8–10 animals per group) were orally
treated once daily by gavage (vehicle: solutol/ethanol/
water 10:10:80) with doses of 0.1, 0.3, 1.0 and 3.0 mg/kg
with the ethyl ester of compound 21 over a period of 7
days. At the end of the study blood was retroorbitally
collected and serum cholesterol and triglyceride concen-
tration levels were enzymatically determined using
commercially available test kits (Boehringer Mannheim,
Germany) and an autoanalyzer (EPOS 5060, Eppendorf
Gera¨tebau, Hamburg, Germany). Serum cholesterol
reductions of 32%, 34%, 39% and 41% versus control
were determined.
14. C57BL/6J mice (10-12 animals per group) were orally
treated once daily by gavage (vehicle: solutol/ethanol/
water 10:10:80) with doses of 0.1, 0.3 and 3.0 mg/kg with
the ethyl ester of compound 21 over a period of 11 days.
At the end of the study heart rate was determined using a
computerized non-invasive tail cuff system (TSE Systems
GmbH, Bad Homburg, Germany). Animals were sacri-
ficed and heart weight was determined. Increases in heart
weight of 12%, 17% and 27% were determined,
respectively.