Remote functionalization of SCH 39166: Discovery of potent and selective benzazepine dopamine D1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.12.094

A series of novel benzazepine derived dopamine D₁ antagonists have been discovered. These compounds are highly potent at D₁ and showed excellent selectivity over D₂ and D₄ receptors. SAR studies revealed that a

Full text of DOI:10.1016/j.bmcl.2009.12.094

Bioorganic & Medicinal Chemistry Letters 20 (2010) 832–835
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Remote functionalization of SCH 39166: Discovery of potent and selective
benzazepine dopamine D1 receptor antagonists
*
T. K. Sasikumar , Duane A. Burnett, William J. Greenlee, Michelle Smith, Ahmad Fawzi,
Hongtao Zhang, Jean E. Lachowicz
Department of Medicinal Chemistry and Metabolic Disorders, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel benzazepine derived dopamine D1 antagonists have been discovered. These compounds
are highly potent at D1 and showed excellent selectivity over D2 and D4 receptors. SAR studies revealed
that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2,
SCH 39166, leading to compounds with nanomolar potency at D1 and good selectivity over D2-like
receptors.
Received 13 October 2009
Revised 22 December 2009
Accepted 24 December 2009
Available online 4 January 2010
Published by Elsevier Ltd.
Keywords:
SCH 39166
Ecopipam
Benzazepine
Dopamine antagonist
Obesity
Dopamine (DA) receptors are a class of G protein-coupled
receptors that are prominent in the vertebrate central nervous sys-
tem. There are five subtypes of dopaminergic receptors have been
reported (D1–D5). These belong to two main subgroups, D1-like and
D2-like. The D1 like subgroup includes the D1 and D5 receptors,
while the D2-like subgroup includes the D2–D4 receptor sub-
types.1a,1b It has been well documented that dopamine D1 antago-
nism affects the dopamine reward system in the brain, eliminating
or reducing the dopamine mediated food-craving component of
eating.2 Thus an antagonist of dopamine D1 receptor might be use-
ful for the treatment of obesity and related disorders.
presented a challenge in generating high exposure multiples for
safety evaluation. A third generation compound would preferably
not have this liability. Introduction of catechol isosteres on the
A-ring of SCH 39166 was previously reported by our group as
one way to improve PK in the series.11 This present contribution
describes the remote functionalization of D-ring of SCH 39166
and further SAR development.
A large quantity of optically pure SCH 39166 (2) was available
in house and served as a convenient starting material for our SAR
studies.12 It had been reported that electrophilic reactions occur
at the alpha position of phenol in the A-ring.11 This undesired reac-
tivity was circumvented by deactivating the A-ring by the protec-
tion of phenolic group with a 4-nitrobenzoyl group. At first, we
decided to study bromination by use of various electrophilic bro-
minating agents. Conditions such as Br2/HCO2H, NBS, Br2/HOAc,
Hg(OAc)2/TFA/Br2 or Hg(OCOCF3)2/TFA/Br2 afforded either no
product or a complicated mixture of products. After much experi-
mentation, we have found that bromination of 3 on solid surface
(neutral alumina)13 gave mono-brominated products in about
50% isolated yields (4:5 = 1:2, and traces of 3-bromo derivative)
after deprotection of the phenolic group as described in Scheme
1.14 The structure of the bromination products were assigned
based on the proton NOE data. Initial analysis of the binding
properties of 4 and 5 in the dopamine D1 assay20 suggested that
compound 5 was more active (3–4-fold) than compound 4. Thus
we decided to focus on the SAR development at position 4 of the
D-ring of SCH 39166 (see Scheme 1 for numbering). Other electro-
philic substitution reactions such as nitration, chlorosulfonylation,
The discovery of SCH 23390 (1), a selective dopamine D1 antag-
onist, spurred a great amount of effort in the dopamine receptor re-
search.3 This compound is often used as a standard in dopamine
assay throughout pharmaceutical industry as well as in academic
laboratories. Later,
a conformationally restricted analog, SCH
39166 (2) was discovered.4 Several D1 antagonists have thus been
discovered such as 1a–e as shown in Figure 1.5–8 Compound 2 also
known as ecopipam, is a selective dopamine D1/D5 receptor antag-
onist that was in phase III clinical trials for treatment of obesity.9,10
The clinical results of ecopipam on obese humans revealed a signif-
icant dose dependent loss of body weight for patients on a low cal-
orie diet and drug therapy versus those on diet alone. Ecopipam is
better absorbed in humans than in animals, which initially
* Corresponding author. Tel.: +1 908 740 4373; fax: +1 908 740 7164.
E-mail addresses: sasikumartk@yahoo.com, thavalakulamgar.sasikumar@
merck.com (T.K. Sasikumar).
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.12.094

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 832–835
833
Cl
Cl
Cl
Cl
N
O
N
O
N
N
HO
HO
HO
HO
1
1a
1b
2
(SCH 39166)
(SCH 23390)
(NNC-112)
(NNC-756)
Cl
Cl
Cl
N
N
N
N
HO
HO
HO
O
N
H
Cl
(BTS-73947)
O
(BW-737C89)
R
1c
1d
1e
SCH 39166 analogs
(LE-300)
Figure 1. Representative D1 antagonists (1, 2, 1a–e).
Cl
Cl
Cl
Cl
+
HO
a
b,c
A
B
4
N
N
N
N
HO
O
HO
C
1
O
2
D
—O
Br
2
4
N+
3
Br
O
2 (SCH 39166)
3
4
(1:2)
5
Scheme 1. Reagents and conditions: (a) 4-Nitrobenzoyl chloride, TEA, CH2Cl2, rt, 98%; (b) Br2/Al2O3, rt, 72%; (c) KOH, THF–H2O, rt, 51%.
Cl
Cl
Table 1
a
b
5b R = CN
5d R = CO2H
5e R = OH
N
N
Dopamine binding properties for compounds 2, 5, 6, 5a–f
HO
HO
Cl
c
N
d
HO
5f R =
N
Br
R
O
5
5b, 5d, 5e, 5f
R
Scheme 2. Reagents and conditions: (a) Zn(CN)2, Pd2(dba)3, DPPF, DMFÁH2O, 88%;
(b) NaH, THF then n-BuLi, THF, À78 °C, then diethyl carbonate, THF, À78 °C, 88%,
then LiOH, THF–H2O, 70 °C, 76%; (c) NaOH, CuSO4, H2O, 135 °C, 41%; (d) pyrrolid-
inone, Cu powder, K2CO3, DMF, 150 °C, 25%.
2, 5, 6, 5a-f
Compd
R
Kia (nM)
D2
D1
D5
D4
2
5
6
–H
–Br
–CHO
–CH2OH
–CN
–CO2Me
–CO2H
–OH
1.2
3
2.6
2
2.8
2.3
38
0.6
3.1
2.0
7.5
3.3
7.4
89
3.7
na
1.4
26.9
980
1693
1371
1647
1328
923
420
440
1370
5520
10,000
5972
6281
10,000
4830
na
and formylation were carried out and those results are reported in
the following Letter by L. Qiang et al. To that end, compound 5 was
converted to 5b–f by protocols described in the literature (Scheme
2).15–18 The phenolic group of the 4-Br-derivative 5 was protected
with a TBS group followed by lithiation and DMF addition to pro-
vide aldehyde 6 that was condensed with various O-substituted
hydroxyl amines to give oxime analogs 7a–d. The intermediate 5
was also used for the standard Suzuki coupling reactions as de-
scribed in Scheme 3.19
5ab
5b
5cc
5d
5e
5f
3987
10,000
Pyrrolidine-2-one
na = not available.
a
The standard error was 10%, and variability was less than twofold from assay to
assay.
The benzazepine derivatives 5–8 were tested for their binding
to dopamine receptors.20 The 4-bromo derivative 5 was active at
D1 (Ki = 3 nM) and D5 (Ki = 7.5 nM) and relatively inactive at D2
b
c
Compound 5a was obtained by the reduction of 6 using sodium borohydride.
Compound 5c was obtained by lithiation followed by dimethyl carbonate
addition.
Cl
Cl
Cl
Cl
N
N
N
N
a-c
e
d
HO
HO
HO
HO
N
CHO
Br
Ar
OR
5
7a-e
6
8a-l
Scheme 3. Reagents and conditions: (a) TBSCl, TEA, CH2Cl2, rt; (b) n-BuLi, THF, À78 °C, DMF; (c) TBAF, THF, rt, 50% for three steps; (d) H2N–OR.HCl, Py, 70 °C, 60–70%; (e)
ArB(OH)2, Pd(PPh3)4, Na2CO3, MeOH–Tol, 90 °C, 60–80%.

834
T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 832–835
Table 2
Table 4
Dopamine binding properties for compounds 7a–e
PK profiles of selected compoundsa
Cl
Compd Rat PK (10 mg/kg po) AUC0–6 h (h
156
76
lg/mL) Cmax (ng/mL) Tmax (h)
N
2
8g
72
18
90
43
0.5
2
2
HO
8j
353
75
8k
0.5
N
a
Data are from pooled samples from two mice in cassette-accelerated rapid rat
protocol as described in Ref. 21.
7a-e
OR
Kia (nM)
D2
Compd
R
D1
D5
D4
position
4 such as, 2-thienyl (D1 Ki = 0.9 nM), pyridinyl (D1
7a
7b
7c
7d
7e
H
Me
Et
Bn
Ph
1.6
4.4
1.8
0.2
1.0
3.3
22
10
2.5
2.1
882
483
217
69
4370
7506
5886
8344
10,000
Ki = 0.3 nM), and indolyl (D1 Ki = 0.6 nM) were also potent D1 com-
pounds (8j–l). It was observed that the introduction of some func-
tional groups at the para position of pendant phenyl ring resulted
in significant D2 activity (compounds 8h and 8l).
124
a
The standard error was 10%, and variability was less than twofold from assay to
Having achieved the required dopamine D1 potency, several
compounds were selected for pharmacokinetic investigations in
rat. The PK profiles are shown in Table 4.21 The historic compound,
SCH 39166 showed a reasonable pharmacokinetic profile, however
introduction of 2-thienyl group at position 4 in the D-ring of 2
considerably increased the AUC and Cmax (8j). On the other hand,
4-methoxy phenyl or 4-pyridinyl substitution (compounds 8g
and 8k) did not improve the pharmacokinetic profile.
In summary we have achieved a large number of extremely po-
tent dopamine D1 antagonists based on the SCH 39166 scaffold. A
highly substitutable sweet spot was discovered for optimizing
overall compound properties. Compound 8j showed a modestly
improved pharmacokinetic profile. Further efforts in this series
were discontinued as results from long term clinical trials of ecopi-
pam revealed untoward mechanism-based side effects.10b
assay.
and D4. A wide variety of functional groups such as –CHO, –CH2OH,
–CN, –CO2Me, –OH and pyrrolidine-2-one were well tolerated at 4-
position of the D-ring as shown in Table 1 (Ki ranges from 0.6 to
3.1 nM). All these analogs showed remarkable selectivity over the
D2-like receptors. The free carboxylic acid functionality was less
tolerated than the corresponding methyl ester group. Structurally
similar compounds showed lower single digit nanomolar activity
in a functional FLIPR assay (Kb value), confirming dopamine D1
antagonism in this series.
The oxime analogs (7a–e) were also generally well tolerated in
the benzazepine series as shown in Table 2. The O-benzyl oxime
compound 7d is the most potent in this series with a D1 Ki of
0.2 nM, however affinity at the D2 receptor was notably higher.
Highly potent dopamine D1 antagonists were obtained by the
introduction of an aromatic group at the 4-position of the D-ring
of 2. Almost every aromatic group was well tolerated as shown
in Table 3. Simple phenyl substitution afforded subnanomolar
compound 8a (D1 Ki = 0.2 nM). Similar results were obtained by
introducing various substitutions (electron withdrawing or donat-
ing) on the pendant phenyl ring (8b–i). Heterocyclic rings at
References and notes
1. (a) Kebabian, J.; Calne, D. B. Nature 1979, 277, 93; (b) Claudi, F.; Stefano, A. D.;
Napolitani, F.; Cingolani, G. M.; Giorgioni, G.; Fontenla, J. A.; Montenegro, G. Y.;
Rivas, M. E.; Rosa, E.; Michelotto, B.; Orlando, G.; Brunetti, L. J. Med. Chem. 2000,
43, 599.
2. Coffin, V. L. WO Patent 19990301, 1999.
3. (a) Gold, E. H.; Chang, W. K. U.S. Patent 4284555, 1981.; (b) Iorio, L. C.; Barnett,
A.; Leitz, F. H.; Houser, V. P.; Korduba, C. A. Pharmacology 1983, 226, 462.
4. Berger, J. G.; Chang, W. K.; Clader, J. W.; Hou, D.; Chipkin, R. E.; Mcphail, A. T. J.
Med. Chem. 1989, 32, 1913.
5. Andersen, P. H.; Gronvald, F. C.; Hohlweg, R.; Hansen, L. B.; Guddal, E.;
Braestrup, C.; Nielsen, E. B. Eur. J. Pharmacol. 1992, 219, 45.
6. Riddall, D. R. Eur. J. Pharmacol. 1992, 210, 279.
7. Kozlik, A.; Sargent, B. J.; Needham, P. L. WO Patent 9313073, 1993.
8. Witt, T.; Hock, F. J.; Lehmann, J. J. Med. Chem. 2000, 43, 2079.
9. McQuade, R. D.; Duffy, R. A.; Coffin, V. L.; Chipkin, R. E.; Barnett, A. J. Pharmacol.
Exp. Ther. 1991, 257, 42.
10. (a) Coffin, V.; Glue, P. W. WO Patent 9921540, 1999.; (b) Astrup, A.; Greenway,
F. L.; Ling, W.; Pedicone, L.; Lachowicz, J.; Strader, C. D.; Kwan, R. Obesity 2007,
15, 1717.
Table 3
Dopamine binding properties for compounds 8a–l
Cl
N
HO
11. Wu, W.-L.; Burnett, D. A.; Spring, R.; Greenlee, W. J.; Smith, M.; Favreau, L.;
Fawzi, A.; Zhang, H.; Lachowicz, J. E. J. Med. Chem. 2005, 48, 680.
12. Gala, D.; Dahanukar, V. H.; Eckert, J. M.; Lucas, B. S.; Schumacher, D. P.;
Zavialov, I. A.; Buholzer, P.; Kubisch, P.; Mergelsberg, I.; Scherer, D. Org. Process
Res. Dev. 2004, 8, 754.
Ar
8a-l
Compd
Ar
Kia (nM)
D2
D1
D5
D4
13. Ranu, B. C.; Sarkar, D. C.; Chakraborty, R. Synth. Commun. 1992, 22, 1095.
14. A typical experimental method is given below: Compound 3 (5 g, 10.8 mmol) was
mixed with 10 g of neutral alumina (chromatography grade, 50–200 micron).
In a separate bottle, bromine (17.27 g, 10 equiv) was mixed with 10 g of
alumina. The above mixtures were shaken together for 30 minutes and charged
onto a small silica gel column. The excess bromine was eluted with hexane
followed by dichloromethane. The column was eluted with 5% methanol/
dichloromethane to get the bromination products (4.2 g). This was redissolved
in 50 mL of THF–H2O (9:1) and treated with 15 mL 1 N KOH. The mixture was
stirred for 4 h, then neutralized with acetic acid. The contents were poured into
a satd NaHCO3/dichloromethane mixture and extracted with dichloromethane.
The solvent was removed in vacuo and the products were isolated by silica gel
chromatography eluting with 50% acetone/hexane. The products were further
purified by repeated crystallization from ethanol. This purification method
8a
8b
8c
8d
8e
8f
8g
8h
8i
Ph
3-F–Ph
3-CN–Ph
0.2
0.4
0.6
0.6
2.3
0.9
0.7
0.7
0.7
0.9
0.3
0.6
na
na
3.4
4.7
na
na
6.2
na
79
223
na
na
10,000
10,000
na
na
10,000
na
584
618
1612
312
550
12
89
93
756
51
3-NO2–Ph
3-OCF3–Ph
3,5-di-F–Ph
4-OMe–Ph
4-NMe2–Ph
4-CH2OH–Ph
2-Thienyl
4-Pyridinyl
1H-Indol-5-yl
na
na
8j
8k
8l
1.9
10.5
na
10,000
5060
na
gave 1.2 g of compound
5 and 0.5 g of compound 4: ES-MS: calcd for
C19H20BrClNO+ = 392.04, 394.04; found = 394.1 (M+1)+.
na = not available.
a
The standard error was 10%, and variability was less than twofold from assay to
assay.
15. Compound 5b was prepared according to the following reference Maligres, P.
E.; Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 8193.

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 832–835
835
16. Compound 5c and 5d were prepared according to the following reference
Banwell, M. G.; Bonadio, A.; Turner, K. A.; Ireland, N. K.; Mackay, M. F. Aust. J.
Chem. 1993, 46, 325.
17. Compound 5e was prepared according to the following references: (a) Weller,
D. D.; Stirchak, E. P. J. Org. Chem. 1983, 48, 4873; (b) Ellis, J. E.; Lenger, S. R.
Synth. Commun. 1998, 1517.
18. Compound 5f was prepared according to the following reference Aebischer, E.;
Bacher, E.; Demnitz, F. W. J.; Keller, T. H.; Kurzmeyer, M.; Ortiz, M. L.; Pombo-
Villar, E.; Weber, H.-P. Heterocycles 1998, 48, 2225.
19. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 513.
20. Ltk- cells stably expressing D1 and D2 receptors at a density of 4–7 pmol/mg
protein were lysed in hypotonic buffer and centrifuged at 48,000g. Membrane
pellets were frozen and stored at À80 °C for use in binding assays. Receptor
affinities were determined by equilibrium binding experiments in which
bound and free radioligand were separated by rapid filtration, and bound
counts were quantified by liquid scintillation counting. For D1 binding, the
radioligand was [3H] SCH 23390 (0.3 nM), and nonspecific binding was defined
by addition of 10 M unlabeled SCH 23390. For D2 binding, the radioligand was
[3H] methylspiperone (0.5 nM) and nonspecific binding was defined using
10
Prism, in which curves fit a one-site competition model with a Hill Slope equal
to or approximately 1. Mean Ki values from four separate determinations are
reported. The SEM was below 15% in each case.
l
lM (À)-sulpride. Competition binding data was analyzed using Graphpad
21. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.;
Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E. Rapid Commun. Mass
Spectrom. 2001, 15, 335. Data are from pooled samples from two mice in
cassette-accelerated rapid rat protocol as described in the above reference.
Briefly, two male Sprauge–Dawley rats were dosed orally at
a dose of
10 mg/kg. Blood samples were collected at different time points and
analyzed according to Ref. 21. Compound plasma levels for individual
animals used to calculate PK parameters were generally with 25% of
average values.