Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.12.100

A series of novel dopamine D₁ antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D₁ activity and more than 1000-fold selectivity over D₂.

Full text of DOI:10.1016/j.bmcl.2009.12.100

Bioorganic & Medicinal Chemistry Letters 20 (2010) 836–840
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of new SCH 39166 analogs as potent and selective dopamine
D1 receptor antagonists
a
a
a
a
a
Li Qiang a, , T. K. Sasikumar , Duane A. Burnett , Jing Su , Haiqun Tang , Yuanzan Ye ,
Robert D. Mazzola Jr. a, Zhaoning Zhu a, Brian A. McKittrick a, William J. Greenlee a, Ahmad Fawzi b,
Michelle Smith b, Hongtao Zhang b, Jean E. Lachowicz b
*
a Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of 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 dopamine D1 antagonists derived from functionalization of the D-ring of SCH 39166
were prepared. A number of these compounds displayed subnanomolar D1 activity and more than
1000-fold selectivity over D2. We found C-3 derivatization afforded compounds with superior overall pro-
file in comparison to the C-2 and C-4 derivatization. A number of highly potent D1 antagonists were dis-
covered which have excellent selectivity over other dopamine receptors and improved PK profile
compared to SCH 39166.
Received 13 October 2009
Revised 23 December 2009
Accepted 24 December 2009
Available online 4 January 2010
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
SCH 23390
SCH 39166
Dopamine antagonist
Ecopipam
Benzazepine
Obesity
Dopamine (DA) is a small-molecule neurotransmitter involved
in the regulation of several biological functions, including locomo-
tor activity, emotion, cognition, and neuroendocrine secretion.1
The actions of DA are mediated by five different receptor subtypes
classified into two families: D1-like (D1 and D5) and D2-like (D2, D3,
and D4).2 DA is the primary neurotransmitter in the reward path-
way and it has been reported that D1-like receptors play a role in
food intake in animal models.3a,3b Therefore, at the onset of these
studies, we believed a safe and efficacious D1 antagonist may have
therapeutic potential for the treatment of obesity in humans.4
The discovery of benzazepine 1 (SCH 23390), one of the first
highly potent and selective D1/D5 antagonists, represented a major
breakthrough in dopaminergic receptor research.5a,5b This com-
pound, however, could not be further developed as a drug due to
the poor oral absorption and short duration of action.6 The con-
formationally restricted analogue 2 (SCH 39166) was subsequently
discovered to have similar affinity and selectivity as a D1/D5 antag-
onist and improved overall pharmacologic profile.6,7 Compound 2,
also known as ecopipam, was developed as a potential treatment
for obesity and studied in phase III clinical trials.4,8 (Fig. 1)
ability.9a,9b Our goal was to discover a novel, highly potent and
selective dopamine D1/D5 antagonist with an improved PK profile.
A-ring modifications of SCH 39166 have been reported by W. Wu
et al.10 This present Letter describes the fuctionalization of the
D-ring of SCH 39166 with the emphasis on the exploration of the
C-3 and C-4 positions and complements the preceding Letter by
T. K. Sasikumar et al.11
Our initial efforts on SAR exploration of the bicyclic analog SCH
23390 investigated the modification of the pendent phenyl ring.
We started with optically pure compound 1.5a The phenolic group
was first protected by reacting with 4-nitrobenzoyl chloride. Sub-
sequent bromination12 of this protected intermediate 3 led to a
mixture of para-bromination product 4, ortho-bromination prod-
uct 5, and dibromination product 6, which could be carefully
Cl
Cl
A
B
N
N
HO
HO
C
SCH 39166 still retained some undesirable pharmacologic prop-
erties as a drug development candidate, such as low oral bioavail-
D
2
4
3
1 (SCH 23390)
2 (SCH 39166)
* Corresponding author. Tel.: +1 908 7404232; fax: +1 908 7407164.
E-mail address: li.qiang@merck.com (L. Qiang).
Figure 1. Benzazepine D1 antagonists.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.100

L. Qiang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 836–840
837
separated by silica gel chromatography (Scheme 1). Compound 4
was used as a key intermediate to introduce different functional-
ities to this phenyl ring as part of our SAR exploration.13
An example of further SAR development using intermediate 4 is
shown in Scheme 2. The phenolic protecting group was first
exchanged to TBS via hydrolysis and silylation. Formylation was
accomplished by lithiation and trapping with DMF. Final function-
alizations were realized by reductive amination and/or capping
strategies. This effort led to a discovery of a series of highly potent
and selective D1/D5 antagonists. A number of representative exam-
ples are shown in Table 1. SAR result demonstrated that both
D1 affinity and selectivity over D2 were maintained or improved
with derivatization of the para-position with a high steric tolerance
for substitution.14
shown in Scheme 3. Additionally, C-2 and C-4 derivatization would
also be of high interest because they are in close proximity with
the C-3 position. For the regioselective functionalization of the
D-ring, we still faced the same challenge as we did for SCH 23390.
We used the optically pure SCH 39166 as our starting mate-
rial,15 protecting the phenolic group on the A-ring with a 4-nitro-
benzoyl group to afford the common intermediate 10. This
protected intermediate was used in all reactions for D-ring deriv-
atizations. A non-selective bromination was carried out and subse-
quent SAR development is reported in the preceding Letter.11
Chlorosulfonylation of intermediate 10 selectively functionalized
C-2 of the D-ring, but sulfonamides thus derived had low D1 activ-
ities.16 We next decided to try the nitration on the D-ring. A mild
nitration condition was used (Scheme 3) and we isolated all three
C-2, C-3, and C-4 regio isomers 11, 12, and 13 by HPLC in the ratio
of 1:1.4:4.17 The structures of the nitration products 11, 12, and 13
were assigned based on proton NOE data.
With this SAR information on SCH 23390 analogs in mind, we
moved on to explore the D-ring functionalization of the conforma-
tional restricted tetracyclic series focusing on the C-3 position, as
Cl
Cl
Cl
Cl
Cl
N
a
N
N
b
N
N
HO
PNBO
PNBO
PNBO
PNBO
+
+
Br
Br
Br
Br
1 (SCH 23390)
3
5
4
6
Scheme 1. Reagents and conditions: (a) 4-nitrobenzoyl chloride, TEA, CH2Cl2, rt, 98%; (b) Hg(OCOCF3)2, Br2, rt, 54% 4, 37% 5 and 5% 6.
Cl
Cl
Cl
N
N
Cl
TBSO
HO
N
N
a,b,c
d,e
f
TBSO
PNBO
R2
R2
N
R1
N
R1
OHC
Br
9
7
4
8
Scheme 2. Reagents and conditions: (a) NaOH, rt; (b)TBSCl, 88% for two steps; (c) n-BuLi, DMF, 95%; (d) Ti(OiPr)4, R1NH2, NaBH4; (e) RCOOH, EDCI, or RCOCl, DIEA, DMF or
RSO2Cl, pyridine or ROCOCl, DIEA, CH2Cl2 or RNCO, CH2Cl2 or RNCOCl, DIEA, DMF; (f) TBAF, rt, 95%.
Table 1
Dopamine binding properties for compounds 9a–g and 1
Cl
N
Cl
HO
N
HO
R2
N
R1
9a-g
1 (SCH 23390)
Compound
R1, R2
Kia (nM)
D1
D5
D2
D4
1
—
1.4
0.9
0.2
0.5
0.5
0.6
2
2.8
3.9
13
1000
2000
159
2000
6000
331
9a
9b
9c
9d
9e
9f
–C4H7, –H
>10,000
>10,000
>10,000
–C4H7, –COCH3
–C4H7, –SO2CH3
–CH3, –SO2CH3
–CH3, –SO2C6H5
–C6H5, –H
5.9
1.2
4331
2000
552
9g
–CH2C6H5, 2,4–F2C6H3
0.7
a
The standard error was 10%, and variability was less than twofold from assay to assay.

838
L. Qiang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 836–840
To quickly explore the SAR from these intermediates, we uti-
low D1 affinity.18 Both C-3 and C-4 derivatization afforded com-
pounds with high D1 affinity. A large number of compounds from
these two series showed single digit nanomolar or lower D1 affin-
ity. In addition, C-3 derivatization generated compounds with
excellent selectivity over D2, often greater than 1000-fold. C-4
modification, however, only afforded compounds with moderate
selectivity over D2. Selected binding results from the libraries of
these two isomers are listed in Table 2.
The profile of one of the representative compounds 17c from C-
3 series is shown in Figure 2. This compound not only had subn-
anomolar D1 affinity, but also demonstrated almost 10-fold
improvement of selectivity over D2, D4, and D5 compared to SCH
lized a high-throughput synthesis strategy, since compounds 11,
12, and 13 are ideal for solid-phase library synthesis. The example
of compound 12 being coupled with Wang resin and subsequent
library synthesis is described in Scheme 4. After Mitsunobu attach-
ment to the resin, the nitro group was selectively reduced using
SnCl2 to afford aniline 15. Our derivatization of the C-3 aniline in-
cluded sulfonylation, acylation, urea formation and carbamate for-
mation. The reductive alkylation did not give a satisfactory result,
instead, we used the amide intermediate 18 followed by borane
reduction to make these compounds as described in Scheme 5.
The final products could be cleaved from the resin using 30% TFA
in dichloromethane. This high-throughput synthetic strategy
turned out to be a very efficient way to allow us to quickly access
a thorough SAR. Twelve focused libraries with a total number of
three hundred compounds were accomplished in a short period
of time. All compounds were evaluated by LCMS and those with
a purity of >70% were then submitted for biological evaluation.
In a similar manner, we investigated the SAR of all three regioi-
somers. Derivatization on C-2 position generally gave moderate to
39166. Both 5HT2a and a2a receptor selectivity also improved over
SCH 39166. More interestingly, we saw a significant improvement
of PK and oral bioavailability, a major goal for our program. To this
end, rapid rat AUC19 improved more than 10-fold to 2486 ng/ml h
and oral bioavailability increased to 29%.
In summary, we discovered a practical method to functionalize
the D-ring of SCH 39166 which provided access to functionaliza-
tion of C-2, C-3, and C-4 positions. We have utilized a parallel
Cl
Cl
Cl
Cl
Cl
a
b,c
N
N
N
A
B
+
+
N
N
HO
HO
HO
HO
PNBO
C
D
2
O2N
4
2
4
3
3
NO2
O2N
2 (SCH 39166)
10
13
12
11
1
:
1.4
:
4
Scheme 3. Reagents and conditions: (a) 4-nitrobenzoyl chloride, TEA, CH2Cl2, rt, 98%; (b) BF4NO2, MeCN, rt, 12 h; (c) LiOH, THF–H2O, rt, 56% for combined isomers after two
steps. After HPLC separation, the ratio of isomers 11, 12, and 13 is 1:1.4:4.
Cl
Cl
Cl
Cl
N
N
N
N
a
c
b
OH
O
O
O
HO
+
Wang resin
HN
O2N
H2N
O2N
R
12
14
15
16
Cl
HO
N
d
HN
R
17
Scheme 4. Reagents and conditions: (a) PPh3, 1,1’-(azodicarbonyl)dipiperidine, THF/CH2Cl2, rt, 12 h; (b) SnCl2Á2H2O, DIEA, DMF, rt, 24 h; (c) RCOOH, DIC, HOBT, DMAP, NMP
or RCOCl, DIEA, DMF or RSO2Cl, pyridine or ROCOCl, DIEA, CH2Cl2 or RNCO, CH2Cl2 or RNCOCl, DIEA, DMF; (d) 30% TFA/ CH2Cl2, rt, 15 min.
Cl
Cl
Cl
Cl
N
N
N
N
O
O
HO
c
a
b
O
O
NH
18
NH
19
NH
20
H2N
R
R
R
15
Scheme 5. Reagents and conditions: (a) RCOOH, DIC, HOBT, DMAP, NMP or RCOCl, DIEA, DMF; (b) BH3ÁTHF; (c) 30% TFA/CH2Cl2, rt, 15 min.

L. Qiang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 836–840
839
Table 2
Dopamine binding properties for compounds 17a–f, 21a–f and 2
Cl
Cl
Cl
N
N
N
HO
HO
HO
R
N
HN
R
H
17a-f
21a-f
Kia (nM)
2 (SCH 39166)
R
Compd
Compd
Kia (nM)
D1
D5
D2
D4
D1
D5
D2
D4
—
–H
–COC3H5
–SO2CH3
–SO2CH2CH3
–CONHCH2CH3
–CONH-2,6-Cl2C6H3
–CO2CH2CH3
2
1.2
7
2.0
8.3
980
5515
>10,000
17a
17b
17c
17d
17e
17f
17g
5400
>10,000
3000
3300
6000
1093
3900
21a
21b
21c
21d
21e
21f
2.8
5.7
4.7
5.8
2.4
7.1
2.3
7.0
2100
>10,000
2.3
0.5
0.7
1.5
0.7
1.4
2137
1000
618
900
566
5.8
5.6
7.1
>10,000
>10,000
>10,000
3.3
>10,000
21g
500
a
The standard error was 10%, and variability was less than twofold from assay to assay.
References and notes
Cl
N
Cl
1. 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.
HO
N
HO
2. Kebabian, J.; Calne, D. B. Nature 1979, 277, 93.
3. (a) Sutton, M.; Beninger, R. Psychopharmacology 1999, 144, 95; (b) Hoebel, B.;
Hernandez, L.; Schwartz, D.; Mark, G.; Hunter, G. Ann. N. Y. Acad. Sci. 1989, 575,
171.
4. Astrup, A.; Greenway, F. L.; Ling, W.; Pedicone, L.; Lachowicz, J.; Strader, C. D.;
Kwan, R. Obesity 2007, 15, 1717.
5. (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.
6. Barnett, A.; McQuade, R. D.; Tedford, C. Neurochem. Int. Suppl. 1992, 20, 119S.
7. Berger, J. G.; Chang, W. K.; Clader, J. W.; Hou, D.; Chipkin, R. E.; Mcphail, A. T. J.
Med. Chem. 1989, 32, 1913.
8. McQuade, R. D.; Duffy, R. A.; Coffin, V. L.; Chipkin, R. E.; Barnett, A. J. Pharmacol.
Exper. Ther. 1991, 257, 42.
9. (a) Tedford, C. E.; Coffin, V. L.; Ruperto, V.; Cohen, M.; McQuade, R. D.; Johnson,
R.; Kim, H.-K.; Lin, C.-C. Psychophamacology 1993, 113, 199; (b) Tedford, C. E.;
Ruperto, V.; Coffin, V. L.; Cohen, M.; Libonati, M.; Barnett, A. Drug Dev. Res.
1992, 26, 389.
10. 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.
11. Sasikumar, T. K.; Burnett, D. A.; Greenlee, W. J.; Smith, M.; Fawzi, A.; Zhang, H.;
Lachowicz, J. E. Bioorg. Med. Chem. Lett. preceding paper.
HN
O
O
S
2 (SCH 39166)
17c
D
1 Ki = 0.5 nM
D1 Ki = 1.2 nM
D2/D1 = 816.7
D2/D1 = 6000
D4/D1 > 20000
D4/D1 = 4595
D5/D1 = 11.6
D5/D1 = 1.7
5HT2a/D1 =1300
α2a/D1=3600
5HT2a/D1 =70
α2a/D1=630
Rat AUC = 2486 ng/mL.hr
rat bioavailability 29%
Rat AUC = 156 ng/mL.hr
rat bioavailability 0.6%
Figure 2. Discovery of compound 17c with improved profile compared to SCH
39166.
12. Barnett, J. R.; Andrew, L. J.; Keefer, R. M. J. Am. Chem. Soc. 1972, 94, 6129.
13. Similar but more limited SAR efforts were also explored with intermediate 5.
14. Fluorescent ligands with high affinity for D1 receptor based on SCH 23390 have
been reported earlier. See: Monsma, F. J.; Barton, A. C.; Kang, H. C.; Brassard, D.
L.; Haugland, R. P.; Sibley, D. R. J. Neuochem. 1989, 52, 1641.
15. 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.
16. A typical experimental method is given below: Compound 10 (0.17 g, 0.37 mmol)
was dissolved in dichloromethane (5 ml) and cooled to 0 °C under atmosphere
of nitrogen. Chlorosulfonic acid (2 ml, excess) was added dropwise to this
solution. The reaction was then raised to room temperature and stirred for 3 h.
The reaction was quenched with ice water and light brown solid was
precipitated out from the solution. The liquid was descanted and the
resulting solid was dried by forming the azeotropic solution with toluene.
The crude solid material was redissolved in acetonitrile and added amines
(excess amount) dropwise. The reaction mixture was left to stir at room
temperature over night. Saturated ammonium chloride solution was used to
quench the reaction followed by extraction with dichloromethane. The final
product was isolated by preparative TLC with the yield ranging from 20–50%.
17. A typical experimental method is given below: To a solution of compound 10
(2.0 g, 4.3 mmol) in 30 ml acetonitrile was added BF4NO2 (1.6 g, 12.9 mmol)
and the reaction mixture was left to stir for 3 h. The reaction was then
synthetic strategy to quickly develop SAR of all three different
regions of D-ring. Functionalization of the C-3 position produced
a series of sulfonamido D1 antagonists with high affinity, high
selectivity, and in some cases improved PK. Compound 17c was
discovered to have excellent affinity, selectivity, and PK as com-
pared to SCH 39166. Further efforts in this series were discontin-
ued as results from long term clinical trials of ecopipam revealed
untoward mechanism-based side effects.4
Acknowledgments
The authors gratefully acknowledge Dr. Michael Czarniecki for
his support of this work, Dr. Tze-Ming Chan’s group for NOE anal-
ysis, Emily C. Luk for LCMS analytical support, Lisa Broske for ani-
mal dosing and Dr. Sam Wainhaus and Neeta Juvekar for mass
spectrometric analysis. We also thank Robert Budich for the ACS
nomenclature of all the compounds.

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L. Qiang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 836–840
quenched with water and neutralized with saturated sodium bicarbonate
19. 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.
solution. This mixture was extracted with dichloromethane and the solvent
was evaporated under vacuum. The residue was redissovled in
tetrahydrofuran/water solution (3:1), treated with 1 N LiOH aqueous solution
and stir at room temperature for 3 h. The reaction mixture was then quenched
with acetic acid, extracted with dichloromethane and dried with sodium
sulfate. The solvent was evaporated and the resulting crude material was
passed through a short silicon gel column to remove baseline material. The
mixture was then purified by HPLC (silica gel column, eluting solvent 95% ethyl
acetate/hexane, 0.25% triethylamine) to give three regioisomers.
18. Formylation of 39166 followed by reductive amination were used to generate a
small library of C-2 aminomethyl substituted SCH 39166 analogs. For several of
these analogs, D2/D1 selectivity was reversed due to decreased D1 affinity and
increased D2 affinity. Two examples are shown as below:
Cl
Cl
N
N
HO
HO
D1 Ki = 152 nM
D2 Ki = 1.3 nM
D1/D2 = 117
D1 Ki = 225 nM
D2 Ki = 26 nM
D1/D2 = 8.7
N
N
N
N
ii
i