Tetrahydroisoquinolines as MCH-R1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.06.055

A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.

Full text of DOI:10.1016/j.bmcl.2006.06.055

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4917–4921
Tetrahydroisoquinolines as MCH-R1 antagonists
T. K. Sasikumar,* L. Qiang, W.-L. Wu, D. A. Burnett, W. J. Greenlee, K. O’Neill,
B. E. Hawes, M. van Heek and M. Graziano
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 16 May 2006; revised 14 June 2006; accepted 14 June 2006
Available online 7 July 2006
Abstract—A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide com-
pounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly
potent compounds 12d and 12g displayed excellent rat pk.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin concentrating hormone (MCH) is a 19-mem-
bered neuropeptide that is found in the lateral hypothala-
mus and regulates food intake.1,2 There is evidence for
involvement of MCH in feeding and obesity.3 One of
the major findings is that hypothalamic MCH peptide lev-
els increase during fasting in ob/ob and WT mice. ICV
administration of MCH or analogs stimulates feeding in
rodents and MCHÀ/À mice are hypophagic and leaner
than WT mice but otherwise healthy.4 MCH receptor
knock-out mice are lean, hypophagic, hyperactive, have
reduced fat mass, have increased metabolic rate, and they
are resistant to diet-induced obesity (DIO). Evidence
from knock-outs suggests an MCH receptor antagonist
should be beneficial for treatment of obesity and related
disorders.5,6 Several classes of small molecule MCH-R1
antagonists have recently been disclosed.7–12
Ar1
Ar1
O
O
H
N
Ar2
N
Ar2
N
H
N
H
N
R
N
R
I
III
Ar1
Ar1
O
O
H
N
Ar2
N
Ar2
N
H
N
H
N
R
II
N
R
IV
Figure 1. Design of tetrahydroisoquinoline MCH antagonists
III and IV.
Recently we found compounds of the types I and II are
potent and selective MCH-R1 antagonists useful for the
treatment of metabolic diseases.13 Compounds of this
piperidine glycineamide series had been hindered by mod-
erate pharmacological properties primarily due to the
amide hydrolysis. In order to minimize these issues, we
designed constrained analogs III and IV as shown in
Figure 1. This restriction would better define the active
binding conformations and mask the glycineamide
structure. Since the free basic N–H is tied back to the aro-
matic ring, we anticipated less metabolism among these
tetrahydroisoquinoline (THQ) structures (III and IV).
The synthesis of various spirocyclic as well as 2-substitut-
ed tetrahydroisoquinoline structures and structure–activ-
ity relationships (SARs) are described in this paper.
The spirocyclic tetrahydroisoquinoline compound 2 was
synthesized from 3-methoxyphenethylamine 1 by Pictet–
Spengler cyclization.14 During this reaction, the tert-but-
oxy carbonyl group was hydrolyzed. The methyl group
was removed by the reaction of BBr3 and the Boc group
was re-introduced in good yield. The phenol was con-
verted to the triflate and Suzuki coupling reaction on
this intermediate afforded the biaryl compound 3.15
N-Alkylation using methylbromoacetate gave com-
pound 4. Sodium hydride or trimethylaluminum medi-
ated displacement of methyl ester with aromatic
anilines afforded the corresponding amides in moderate
Keywords: Melanin concentrating hormone; Tetrahydroisoquinolines.
*
Corresponding author. Tel.: +1 908 740 4373; fax: +1 908 740
7164; e-mail: thavalakulamgar.sasikumar@spcorp.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.055

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T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4917–4921
yields.16 The Boc deprotection was achieved by trifluo-
roacetic acid and the reductive alkylation using a wide
variety of aldehydes and ketones under standard
reaction conditions furnished the final target
compounds 5a–q in good yields (Scheme 1).
Next, we turned our attention to the alterations of the
aromatic amide group in order to optimize the right-
hand side of the molecule. Deprotection of 4 followed
by reductive alkylation and subsequent amidation using
various anilines furnished compounds 6a–j (Scheme 2).
As seen from Table 2, 3,5-dichlorophenyl glycineamide
compound 5f still has the best MCH-R1 binding affinity
(Ki = 15 nM). Other aromatic amides such as 3-Cl-4-F-
phenyl 6d and 3-CF3-4-F-phenyl 6h also showed a sim-
ilar binding profile. We decided to keep the 3,5-dichlor-
ophenyl group as a constant in the further development
of SAR in the THQ series.
The MCH-R1 affinities of several representative spirocy-
clic glycineamide compounds containing modifications
on the piperidine nitrogen are shown in Table 1. A wide
range of alkyl substitutions on the piperidine nitrogen is
tolerated. The cyclopropylmethyl 5f, cyclopentyl 5g,
cyclobutyl 5i, and cycloheptyl 5j were the best among
the several other compounds prepared. Acylations and
sulfonylations of the piperidine nitrogen completely
eliminate the MCH-R1 binding affinity (5n–q).
After having examined the binding affinity of spirocyclic
compounds, we began looking into the homologated
tetrahydroisoquinoline structures represented by IV
(Fig. 1). Compound of this type was prepared according
to Scheme 3. At first we decided to study the biaryl SAR
in detail. Pictet–Spengler cyclization of 1 with N-cyclo-
pentylpiperidine-4-carboxaldehyde afforded compound
7. Initial trials of this cyclization reaction using phos-
phoric acid gave mixture of products. However, cycliza-
tion reaction in boiling TFA gave 7 in 60% yield.
Further modifications of 7 according to Scheme 3 affor-
ded compounds 10a–p (Table 3).
MeO
NC
b-e
MeO
NH
a
NH
NH
2
N
1
2
3
H
N
Boc
NC
NC
g-i
O
O
N
N
Ar
f
O
N
H
N
Boc
N
R
4
5a-q
Scheme 1. Reagents and conditions: (a) N-Boc-piperidone, H3PO4,
90 °C; (b) BBr3, CH2Cl2; (c) Boc2O; (d) PhNTf2, CH2Cl2; (e) 3-CN-
phenylboronic acid, Pd(PPh3)4, Na2CO3, Tol/MeOH, 90 °C; (f)
BrCH2COOMe, K2CO3, CH3CN; (g) 3,5-di-Cl-aniline, NaH, THF;
(h) TFA, CH2Cl2; (i) RCHO, NaBH(OAc)3, CH2Cl2.
NC
NC
a-c
O
O
N
N
Ar
O
N
H
N
N
4
6a-j
Boc
Table 1. MCH-R1 binding affinities of spirocyclic THQs (5a–q)
Cl
Scheme 2. Reagents and conditions: (a) TFA, CH2Cl2; (b) RCHO,
NaBH(OAc)3, CH2Cl2; (c) Ar-NH2, NaH, THF.
NC
O
N
N
Cl
H
Table 2. MCH-R1 binding affinities of spirocyclic THQs (6a–i)
N
R
(5a-q)
NC
O
Compound
R
h-MCH-R1
Kia (nM)
N
Ar
N
H
5a
5b
5c
5d
5e
5f
Boc
H
>1000
59
38
N
Methyl
Ethyl
Isopropyl
(6a-i)
38
29
Compound
Ar
h-MCH-R1
Kia (nM)
Cyclopropylmethyl
Cyclopentyl
15
16
5g
5h
5i
5f
3,5-Dichlorophenyl
3,5-Difluorophenyl
3,4-Dichlorophenyl
3-CF3-4-Cl-phenyl
3-Cl-4-F-phenyl
4-Cl-phenyl
15
63
1-Hydroxyethyl
Cyclobutyl
Cycloheptyl
41
13
6a
6b
6c
6d
6e
6f
138
119
24
5j
11
34
5k
5l
1-Tetrahydro-3-thienyl
1-Tetrahydropyran-4-yl
3-Furanylmethyl
Acetyl
16
36
138
45
5m
5n
5o
5p
5q
3-Cl-phenyl
823
>1000
>1000
>1000
6g
6h
6i
3,4-Difluorophenyl
3-CF3-4-F-phenyl
3-CF3-5-F-phenyl
35
25
Methylsulfonyl
1-Dimethylaminosulfonyl
1-Ethylaminosulfonyl
54
a Values are means of three experiments. Variability around the mean
value was <5%.
a Values are means of three experiments. Variability around the mean
value was <5%.

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4917–4921
4919
Cl
MeO
MeO
a
O
MeO
N
NH
N
H
Cl
b
NH2
1
7
8
N
N
Cl
Cl
HO
c
Ar
O
O
N
N
N
Cl
N
Cl
H
H
d,e
N
N
10a-p
9
Scheme 3. Reagents and conditions: (a) N-cyclopentylpiperidine-4-carboxaldehyde, TFA, reflux; (b) BrCH2CONHAr, K2CO3, CH3CN; (c) BBr3,
CH2Cl2; (d) PhNTf2, CH2Cl2; (e) ArB(OH)2, Pd(PPh3)4, Na2CO3, Tol/MeOH.
Table 4. MCH-R1 binding affinities of THQs (12a–q)
Table 3. MCH-R1 binding affinities of THQs (10a–p)
Cl
Cl
Ar
O
NC
O
N
N
Cl
Cl
N
N
H
H
N
N
R
(12a-q)
(10a-p)
Compound
R
h-MCH-R1
Kia (nM)
Compound
Ar
h-MCH-R1
Kia (nM)
12a
12b
12c
12d
12e
12f
12g
12h
12i
H
Methyl
26
22
10a
10b
10c
10d
10e
10f
10g
10h
10i
3-CN-phenyl
Phenyl
11
168
108
73
Phenylmethyl
5-(OH)-1-pentyl
Cycloheptyl
24
6.8
9.7
68
4-CN-phenyl
3-F-phenyl
3-Cl-phenyl
N-Methylpiperidinyl
1-Tetrahydropyran-4-yl
1-Tetrahydro-3-thienyl
3-Furanylmethyl
2-MeO-phenylmethyl
Cyclopropylmethyl
Cyclobutyl
43
95
6.4
7.0
14
3-MeO-phenyl
3-CF3-phenyl
3-CF3O-phenyl
3-CHO-phenyl
3,6-Di-Cl-phenyl
8-Quinolinyl
4-Pyridyl
191
77
12j
16
77
87
12k
12l
9.3
15
10j
10k
10l
799
24
12m
12n
12o
12p
12q
Phenylpropyl
Isopropyl
69
35
10m
10n
10o
10p
3-Pyridyl
23
46
Cyclohexyl
Acetyl
Methanesulfonyl
10
3-(1H-Imidazol-2-yl)phenyl
1H-Pyrrol-2-yl
3-Thienyl
927
718
455
115
a Values are means of three experiments. Variability around the mean
value was <5%.
a Values are means of three experiments. Variability around the mean
value was <5%.
As evidenced from Table 3, the biaryl portion of the
molecule is less tolerant of substitutions. 3-Cyanophenyl
moiety is still the best substitution in the biaryl region of
the molecule. Groups like 3- and 4-pyridyls are tolerated
to some extent (10l and 10m). Heterocyclic substitutions
such as 2-pyrrolyl 10o and quinolyl 10k reduce the bind-
ing affinity by 40- to 70-fold. 3-Chlorophenyl substitu-
tion 10e afforded a 4-fold decrease in potency relative
to 3-cyanophenyl.
Cl
MeO
NC
O
MeO
N
NH
N
H
Cl
a
b-g
NH
2
1
11
12a-q
N
N
R
Bn
Scheme 4. Reagents and conditions: (a) N-benzylpiperidine-4-carbox-
aldehyde, TFA, reflux; (b) BrCH2CONHAr, K2CO3, CH3CN; (c)
BBr3, CH2Cl2; (d) PhNTf2, CH2Cl2; (e) ArB(OH)2, Pd(PPh3)4,
Na2CO3, Tol/MeOH; (f) chloroethylchloroformate, CH2Cl2; (g)
RCHO, NaBH(OAc)3, CH2Cl2.
The piperidine nitrogen SAR was studied according
to Scheme 4. Pictet–Spengler cyclization of 1 with

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T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4917–4921
F
Cl
Cl
NC
N
Cl
NC
N
N
N
N
N
H
H
N
N
13, MCH-R1 Ki = 133 nM
14, MCH-R1 Ki = 84 nM
Figure 2. Benzimidazole compounds 13 and 14.
Table 5. PK data for selected compounds
formationally restricted analogs are better MCH-R1
antagonists with improved pharmacokinetic profiles.
Further in vivo results will be reported in due course.
Compound
h-MCH-R1
Kia (nM)
Rat PK (10 mpk, po)b
AUC (ng h/mL)
5g
10a
12d
12g
12h
16
11
6.8
6.4
7
332
910
In summary, we have undertaken a three-point modifi-
cation of our tetrahydroisoquinoline (THQ) core struc-
tures and generated a number of selective MCH-R1
antagonists. Both spirocyclic as well as homologated
tetrahydroisquinolines followed a similar SAR trend.
We have shown that the basic nitrogen of the piperidine
moiety is very important for high affinity binding. Phar-
macokinetic studies confirmed an enhanced profile rela-
tive to non-THQ analogs.
1636
1244
499
a Values are means of three experiments. Variability around the mean
value was <5%.
b See Ref. 17 for procedure.
N-benzylpiperidine-4-carboxaldehyde afforded com-
pound 11. N-Alkylation of 11 followed by demethyla-
tion, triflation, and Suzuki coupling produced the
biaryl compound, and subsequent debenzylation and
reductive alkylations using various aldehydes and
ketones gave compounds 12a–q (Scheme 4).
Acknowledgment
We thank Dr. John Clader for helpful discussions.
References and notes
The SAR of the MCH-R1 binding of several tetrahydro-
isoquinoline structures with substitutions on the piperi-
dine nitrogen is summarized in Table 4. Generally
reductive alkylation products showed excellent MCH-
R1 binding affinity. Compounds such as hydroxypentyl
12d (Ki 6.8 nM), tetrahydropyranyl 12g (Ki = 6.4 nM),
tetrahydrothienyl 12h (Ki = 7.0 nM), and cyclopropyl
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compounds in this series. Other modifications to the
piperidine nitrogen, including acylation, sulfonylation,
and urea formation, resulted in inactive compounds.
These results indicate that the basic nitrogens both in
chemotypes III and IV are very important for MCH-R1
binding affinity. In most of the cases, the MCH-R1
SAR for chemotypes IV parallels that for chemotype III.
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