Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.11.036

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H₃ ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.

Full text of DOI:10.1016/j.bmcl.2006.11.036

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1047–1051
Novel tetrahydroisoquinolines are histamine H3 antagonists
and serotonin reuptake inhibitors
Michael A. Letavic,a,* John M. Keith,a Jill A. Jablonowski,a Emily M. Stocking,a
Leslie A. Gomez,a Kiev S. Ly,a Jennifer M. Miller,a Ann J. Barbier,a,ꢀ
Pascal Bonaventure,a Jamin D. Boggs,a Sandy J. Wilson,a Kirsten L. Miller,a
Brian Lord,a Heather M. McAllister,a D. J. Tognarelli,a Jiejun Wu,a
Marta C. Abad,b Carsten Schubert,b Timothy W. Lovenberga and Nicholas I. Carruthersa
aJohnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
bJohnson & Johnson Pharmaceutical Research and Development, Exton, PA 19341, USA
Received 6 October 2006; revised 7 November 2006; accepted 10 November 2006
Available online 16 November 2006
Abstract—A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H3 ligands that also have serotonin reuptake
transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel
compounds are discussed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Depression is a major health issue that affects more than
340 million people worldwide.1 Many patients with
depressive disorders suffer cognitive impairment2 and fa-
tigue.3 Selective serotonin reuptake inhibitors (SSRIs)
including fluoxetine 1 and sertraline 2 are frequently
prescribed antidepressant drugs. However, SSRIs often
fail to improve the cognitive impairment and fatigue
that is often observed even as mood improves.4,5 Some
SSRIs even induce fatigue and excessive sleepiness.6,7
Attempts to improve the efficacy of SSRIs have included
co-administration of wake-promoting agents such as
modafinil 3.8 This drug, a molecule with an undeter-
mined mechanism of action,9 has been shown to im-
prove cognition and increase wakefulness.10,11
However, modafinil has not been widely prescribed, in
part because it is classified as a Schedule IV compound12
and is a cytochrome P450 inhibitor.13 Thus, alternative
agents with wake-promoting and/or cognitive improve-
ment activity might be useful for the treatment of
depression, particularly if these agents do not exhibit
stimulatory effects.
Cl
Cl
CF3
O
O
S
O
NH2
NH
HN
1
2
3
Histamine H3 receptor antagonists are known to im-
prove cognition14 and increase wakefulness15,16 in a
variety of animal models, without showing nonspecific
stimulant effects.17 This information led us to investigate
the attributes of combining an H3 antagonist with a
serotonin reuptake inhibitor as an improved treatment
for depression. As part of this effort, we combined
known H3 pharmacophores discovered earlier in these
laboratories with a serotonin reuptake transporter
(SERT) inhibitor pharmacophore to prepare a series
of tetrahydroisoquinolines that are H3 ligands with sero-
tonin reuptake inhibitor activity.
Keywords: Histamine; Histamine H3 antagonists; Serotonin; Serotonin
reuptake inhibitors; Tetrahydroisoquinolines.
*
Corresponding author. Tel.: +1 858 450 2302; e-mail:
mletavic@prdus.jnj.com
ꢀ
Present address: EnVivo Pharmaceuticals, 480 Arsenal Street,
Building 1, Watertown, MA 02472, USA.
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.036

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M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1047–1051
HO
(a, b)
H
N
(c)
H
O
N
O
HO
O
O
N
N
O
8
9
N
R1
5; hH3 Ki= 2.1 nM
4; hH3 Ki= 0.6 nM
OH
OH
R1
(d, e)
N
N
O
O
O
N
There have been numerous reports over the last few
years describing a wide variety of histamine H3 pharma-
cophores.18 We previously identified numerous potent
H3 ligands, including compounds 419 and 5.20
11
10
X
R1
N
High-throughput screening efforts in our laboratories
recently identified the previously described hexahydro-
pyrroloisoquinoline core 621 as a template having high
affinity for the serotonin transporter. This finding
prompted us to combine the core structure of 6 with
known histamine H3 pharmacophores to produce tetra-
hydroisoquinoline-based compounds 7. Our expectation
was that these new compounds would have high affinity
for the histamine H3 receptor while maintaining the high
affinity for SERT that was observed for compound 6.
(f, g)
O
12
Scheme 1. Synthesis of 4-aryltetrahydroisoquinolines. Reagents and
conditions: (a) K2CO3, 3-bromopropan-1-ol, MeCN, reflux, 48 h, 90%,
(b) 40% aqueous MeNH2, MeOH, 0 ꢁC, then NaBH4, 0 ꢁC, 0.5 h, then
23 ꢁC 18 h, 100%, (c) (i-Pr)2NEt, 2-bromoacetophenones, THF, 23 ꢁC,
45 min, (d) MeSO3H, 60 ꢁC, 18 h, (e) NaCNBH3, MeOH, bromocresol
green, 23 ꢁC, 5 min, then 1.25 M MeOH Æ HCl, 0.5 h, typical yields 20–
60% for 3 steps, (f) MeSO2Cl, Et3N, DCM, 0 ꢁC to 23 ꢁC, 20 min, (g)
amine, Na2CO3, KI, n-BuOH, 50–80 ꢁC, 18 h, typical yields 20–50%
for two steps.
R1
reaction with an amine then gave the desired com-
pounds 12. Typical yields for the final steps were 20–
50%.
R
R
N
N
In several cases the racemic tetrahydroisoquinolines 12
were separated by chiral chromatography to provide
single enantiomers.23 As an example of this procedure,
Scheme 2 describes the preparation of compounds 13
and 14 as single diastereomers. In this case, (S)-3-meth-
ylmorpholine was used to prepare compounds 13 and
14. A single crystal X-ray structure was then obtained
for compound 1424 (Fig. 1), confirming the tetrahydro-
isoquinoline stereochemistry shown for this analog.
For ease of preparation on larger scale the enantiomers
of intermediates 11 (with R1 = 4-MeO–) could also be
separated by chiral chromatography and used to pre-
pare the desired tetrahydroisoquinolines as single enan-
N
O
7
6; rSERT Ki= 0.43 nM
We now report the SAR of a series of 4-aryltetrahydro-
isoquinolines 12. These compounds are substituted with
the previously described H3 pharmacophore 4 and ana-
logs of 4 with related cyclic amines attached at the 7-po-
sition of the isoquinoline ring. The compounds are
potent H3 antagonists and are high affinity serotonin
reuptake transporter ligands. We have recently reported
on the SAR of the amino substituents on the 7-alkoxy-
amino group of this class of compounds.22 This report
will focus on the biological properties of a variety of
4-aryl tetrahydroisoquinolines using the optimized
amine side chains reported earlier.
tiomers.
Chromatographic
separation
of
the
enantiomers of 11 gave (S)-11, which was converted to
both 14 and (+)-12c, confirming the (S) stereochemistry
for (+)-12c.
O
O
Compounds with the general structure 12 were prepared
as shown in Scheme 1. Thus, 3-hydroxybenzaldehyde (8)
was converted to 9 by reaction with 3-bromopropanol
followed by reductive amination with methylamine.
Due to the inherent instability of the intermediates,
the next three steps to form the tetrahydroisoquinoline
11 were performed without purification. The reaction
of 9 with various bromoacetophenones forms the amino
ketones 10, which were cyclized in the presence of
methanesulfonic acid and reduced to form the tetrahy-
droisoquinolines 11 in moderate yields. Activation of
the alcohol of 11 with methanesulfonyl chloride and
O
N
O
N
(a, b, c)
11
+
N
N
O
O
13
14
Scheme 2. Synthesis of 13 and 14. Reagents and conditions: (a)
MeSO2Cl, Et3N, DCM, 0 ꢁC to 23 ꢁC, 20 min, (b) (S)-3-methylmorph-
oline, Na2CO3, KI, n-BuOH, 75 ꢁC, 18 h, 37%, (c) chromatographic
separation.23

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1047–1051
1049
found to be antagonists. The substituent present on
the aryl ring (i.e., R1) has little effect on the affinity for
the human H3 receptor, however more dramatic differ-
ences in affinity are seen at the rat and human SERT
when changes are made to the aryl ring.
Compounds incorporating a 4-methoxy substituent (i.e.,
12a-c, 12f, 12v, 13, and 14) or a 4-thiomethyl substituent
(i.e., 12o-p and 12w-x) are generally high affinity SERT
ligands, both at the rat and the human transporter. The
least potent substituents for the human transporter in-
clude 2,5-diCl (12k) and 4-methylsulfone (12t). In sever-
al cases, data were obtained for individual enantiomers
(12c, 12p, and 12x). There is essentially no difference
in affinity for either enantiomer at rat or human SERT
or the human H3 receptor.
Figure 1. Crystal data for 14. C25H34N2O3, M = 410.55, Monoclinic,
with space group P21 and cell parameters, a = 5.9251, b = 15.3873,
3
˚
˚
c = 12.3147 A, b = 96.9246ꢁ, V = 1114.561 A , T = 123 K, Z = 1, l
(Cu-Ka) = 0.63 mm-1, F(000) = 444. 9046 reflections measured, 3018
unique (Rint = 0.0256), which were used in all calculation. R1 = 0.0204,
wR2 = 0.0564 (all data).
Compounds (+)-12p, (+)-12x, and 14 were also screened
in a panel of 50 receptor, ion channel, and transporter
assays including adenosine (A1, A2A, A3), adrenergic
(a1, a2, b1), angiotensin (AT1), dopamine (D1, D2), bra-
dykinin (B2), cholecystokinin (CCKA), galanin (GAL2),
melatonin (ML1), muscarinic (M1, M2, M3), neurotensin
(NT1), neurokinin (NK2, NK3), opiate (l, j, d), seroto-
nin (5-HT1A, 5-HT1B, 5-HT2A, 5-HT3, 5-HT5A, 5-HT6,
5-HT7), somatostatin, vasopressin (V1a), norepinephrine
transporter, dopamine transporter, and ion channels
(sodium, calcium, potassium, and chloride). The com-
pounds showed no affinity for the above receptors when
Human histamine H317, and rat and human SERT bind-
ing data25 for compounds 12–14 are shown in Table 1.
All of the compounds shown have optimized histamine
H3 pharmacophores22 and therefore all have relatively
high affinity for the histamine H3 receptor. Many of
the compounds were also tested for functional activity
at the human H3 receptor17 and all those tested were
Table 1. Binding data for the rat and human serotonin reuptake transporters25 and for the human H3 receptor17 for compounds 12, 13 and 14
R1
Rat SERT Ki (nM)a
Human SERT Ki (nM)a
Human H3 Ki (nM)a
Human H3 pA2
b
Compound
X
12a
12b
H2C–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
HFC–
O
4-MeO–
4-MeO-
4-MeO–
4-MeO–
3-MeO–
4-EtO–
4-MeO, 3-Cl
4-Cl
2.0 ( 0.7)
1.6 ( 0.6)
4.5 ( 1.3)
1.7 ( 0.3)
4.3 ( 1.1)
2.7 ( 1.5)
5.3 ( 1.8)
16 ( 7)
5.1 ( 0.8)
2.9 ( 1.8)
9.3 ( 0.4)
2.7 ( 0.4)
4.3 ( 1.8)
4.7 ( 0.4)
5.7 ( 2.0)
11 ( 1)
2.0 ( 0.0)
2.0 ( 0.5)
3.8 ( 1.1)
4.0 ( 1.3)
2.0 ( 0.0)
7.3 ( 2.4)
9.7 ( 1.6)
8.3 ( 1.1)
3 ( 0.0)
9.22
8.58
8.44
8.89
9.07
(À)-12c
(+)-12c
12d
12e
12f
8.21
8.86
12g
12h
3-Cl
2-Cl
14 ( 7)
17 ( 8)
24 ( 4)
18 ( 4)
12i
12j
5.6 ( 3.1)
31 ( 13)
9.3 ( 0.8)
3.3 ( 0.9)
18 ( 3)
3,4-di-Cl
2,5-di-Cl
H
8.3 ( 3.5)
120 ( 52)
13 ( 4)
21 ( 2)
107 ( 26)
46 ( 7)
7.48
8.34
9.14
12k
12l
12m
12n
4-F3C–
3-F3C–
4-MeS–
4-MeS–
4-MeS–
4-NC–
14 ( 7)
30 ( 9)
8.6 ( 1.5)
15 ( 5)
11 ( 0)
17 ( 10)
15 ( 4)
12o
2.3 ( 0.4)
5.0 ( 1.2)
2.0 ( 0.0)
7.8 ( 2.7)
4.4 ( 1.4)
36 ( 14)
22 ( 8)
8.8 ( 6.0)
4.2 ( 0.6)
2.0 ( 0.7)
16 ( 2)
8.21
8.10
(À)-12p
(+)-12p
12q
6.5 ( 3.1)
3.5 ( 1.4)
8.3 ( 2.0)
46 ( 7)
8.85
12r
12s
4-Me–
13 ( 3)
34 ( 3)
4-F3CS–
4-MeS(O)2–
4-F2HCO–
4-MeO–
4-MeS–
4-MeS–
4-MeS–
12t
12u
135 ( 39)
4.3 ( 1.8)
6.5 ( 2.0)
6.2 ( 1.6)
5.2 ( 2.2)
3.8 ( 0.4)
13 ( 5)
2.0 ( 0.0)
10 ( 2)
9.28
8.36
8.64
3.0 ( 1.9)
4.8 ( 0.7)
4.0 ( 1.2)
3.0 ( 0.7)
2.3 ( 0.9)
6.0 ( 0.7)
5.0 ( 1.7)
2.9( 0.6)
12v
12w
3.8 ( 0.9)
13 ( 1)
10 ( 1)
O
(À)-12x
(+)-12x
13
O
O
11 ( 3)
8.05
8.53
9.05
6.9 ( 1.3)
5.6 ( 0.3)
7300 ( 1100)
14
Fluoxetine 1
13 ( 3)
2.2 ( 0.6)
a Values are the means of at least three experiments in triplicate, standard error of the mean is in parentheses.
b The result of a single experiment.

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M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1047–1051
Table 2. Binding data for human NET and DAT26
References and notes
Compound
Human NET Ki (nM)a
Human DAT Ki (nM)a
1. Jane-Llopis, E.; Hosman, C.; Jenkins, R.; Anderson, P.
Br. J. Psychiatry; J. Mental Sci. 2003, 183, 384.
2. Quraishi, S.; Frangou, S. J. Affect. Dis. 2002, 72, 209.
3. Tylee, A.; Gastpar, M.; Lepine, J. P.; Mendlewicz, J. Int.
Clin. Psychopharmacol. 1999, 14, 139.
4. Nierenberg, A. A.; Keefe, B. R.; Leslie, V. C.; Alpert, J.
E.; Pava, J. A.; Worthington, J. J., 3rd; Rosenbaum, J. F.;
Fava, M. J. Clin. Psychiatry 1999, 60, 221.
(+)-12p
(+)-12x
14
118 ( 32)
106 ( 33)
121 ( 56)
46 ( 23)
29 ( 2)
102 ( 16)
a Values are the means of at least three experiments in triplicate,
standard error of the mean is in parentheses.
5. Fava, G. A.; Fabbri, S.; Sonino, N. Prog. Neuro-Psycho-
pharmacol. Biol. Psychiatry 2002, 26, 1019.
6. Beasley, C. M., Jr.; Koke, S. C.; Nilsson, M. E.; Gonzales,
J. S. Clin. Ther. 2000, 22, 1319.
Table 3. Rat pharmacokinetics after intravenous and oral
administration
Compound Clp
(mL/min/kg)
Vss (L/kg) t1/2 (h) %F Brain
Cmax
7. Zajecka, J. M. J. Clin. Psychiatry 2000 (Suppl. 2), 20.
8. Thase, M. E.; Fava, M.; DeBattista, C.; Arora, S.;
Hughes, R. J. CNS Spectr. 2006, 93.
(lM)a
9. Saper, C. B.; Scammell, T. E. Sleep 2004, 27, 11.
10. Turner, D. C.; Clark, L.; Dowson, J.; Robbins, T. W.;
Sahakian, B. J. Biol. Psychiatry 2004, 55, 1031.
11. Turner, D. C.; Clark, L.; Pomarol-Clotet, E.; McKenna,
P.; Robbins, T. W.; Sahakian, B. J. Neuropsychopharma-
cology 2004, 29, 1363.
12b
(+)-12c
12e
32.3
5.1
19.9
15.5
9.6
13.3
16.0
10.3
9.9
13
6
21.8
29.9
18.5
14.0
18.1
1.5
11
21
38
5
(+)-12p
(+)-12x
14
2.4
9.6
5.1
6.8
6.6
9.0
12. Jasinski, D. R.; Kovacevic-Ristanovic, R. Clin. Neuro-
pharmacol. 2000, 23, 149.
a Brain Cmax following oral administration of 10 mg/kg test compound.
13. Robertson, P., Jr.; Hellriegel, E. T. Clin. Pharmacokinet.
2003, 42, 123.
14. Witkin, J. M.; Nelson, D. L. Pharmacol. Ther. 2004, 103,
1.
15. Monti, J. M.; Jantos, H.; Boussard, M.; Altier, H.;
Orellana, C.; Olivera, S. Eur. J. Pharmacol. 1991, 205, 283.
16. Monti, J. M.; Jantos, H.; Ponzoni, A.; Monti, D.
Neuropsychopharmacology 1996, 15, 31.
17. Barbier, A. J.; Berridge, C.; Dugovic, C.; Laposky, A. D.;
Wilson, S. J.; Boggs, J.; Aluisio, L.; Lord, B.; Mazur, C.;
Pudiak, C. M.; Langlois, X.; Xiao, W.; Apodaca, R.;
Carruthers, N. I.; Lovenberg, T. W. Br. J. Pharmacol.
2004, 143, 649.
18. Letavic, M. A.; Barbier, A. J.; Dvorak, C. A.; Carruthers,
N. I. Prog. Med. Chem. 2006, 44, 181.
19. Apodaca, R.; Dvorak, C. A.; Xiao, W.; Barbier, A. J.;
Boggs, J. D.; Wilson, S. J.; Lovenberg, T. W.; Carruthers,
N. I. J. Med. Chem. 2003, 46, 3938.
20. Dvorak, C. A.; Apodaca, R.; Barbier, A. J.; Berridge, C.
W.; Wilson, S. J.; Boggs, J. D.; Xiao, W.; Lovenberg, T.
W.; Carruthers, N. I. J. Med. Chem. 2005, 48, 2229.
21. Maryanoff, B. E.; Vaught, J. L.; Shank, R. P.; McComsey,
D. F.; Costanzo, M. J.; Nortey, S. O. J. Med. Chem. 1990,
33, 2793.
22. Keith, J. M., Gomez, L. A.; Letavic, M. A.; Ly, K. S.;
Jablonowski, J. A.; Seierstad, M.; Barbier A. J.; Wilson, S.
J.; Boggs, J. D.; Frazer, I. C.; Mazur, C.; Lovenberg, T.
W.; Carruthers, N. I. Bioorg. Med. Chem. Lett, in press.
23. Chromatographic conditions. Preparative; AD-H column
(Chiral Technologies) (21 · 250 mm). Mobile phase; (A)
0.2% Et3N in i-PrOH and (B) CO2 eluted at 7.56 mL/min
A/30 g/min B at 25 ꢁC at a back-pressure of 100 bar.
Analytical; AD-H column (4.6 · 250 mm). Mobile phase;
(A) 0.2% Et3N in i-PrOH and (B) CO2 eluted at 30% A/
70% B at 2 mL/min at 25 ꢁC at a back-pressure of 100 bar.
The analytical Rf’s; (À)-12p (5.3 min), (+)-12p (8.4 min);
(À)-12x (5.4 min), (+)-12x (8.3 min); 13 (4.1 min), 14
(7.2 min). Measured optical rotations (as the HCl salts in
MeOH); (À)-12 c [a]589 À0.74 (c = 11.1 mg/mL), (+)-12 c
[a]589 +0.73 (c = 9.36 mg/mL), (À)-12p [a]589 À13.9
(c = 9.36 mg/mL), (+)-12p [a]589 +12.51 (c = 9.27 mg/
mL), (À)-12x [a]589 À9.11 (c = 10.1 mg/mL), (+)-12x
[a]589 +9.89 (c = 10.8 mg/mL), 13 [a]589 +14.5
(c = 11.2 mg/mL), 14 [a]589 +14.0 (c = 11.1 mg/mL).
tested at 1 lM with the exception of the norepinephrine
transporter (NET) and the dopamine transporter
(DAT). In-house testing confirmed these compounds
do have affinity for the human NET and DAT26, and
showed that the compounds are moderately selective
for the serotonin transporter over NET and DAT
(Table 2).
Rat pharmacokinetic data (Table 3) were obtained
for several of the more interesting compounds on
Table 1. The compounds have moderate clearance
and high volumes of distribution resulting in rela-
tively long half-lives in rat. Compounds (+)-12p
and (+)-12x have the highest bioavailability in rat
(21% and 38%, respectively). Compounds (+)-12p
and (+)-12x also show high exposure in the brain
following oral administration. Ex vivo receptor occu-
pancy data were obtained for select compounds
from Table 3. As examples, compounds (+)-12x
and 14 showed 100% receptor occupancy in the
rat brain at both the SERT and H3 receptor follow-
ing subcutaneous administration of a 0.3 mg/kg dose
(corresponding to brain concentrations of 0.67 and
0.88 lM, respectively). In addition, compound (+)-
12p had an ED50 of 0.1 mg/kg (corresponding to a
brain concentration of 0.13 lM) for the serotonin
transporter and an ED50 of 0.05 mg/kg at the H3
receptor as measured by receptor occupancy. De-
tailed pharmacological characterization of the more
interesting compounds in this series will be the sub-
ject of future disclosures.
In conclusion, we have designed and prepared a new
class of potent histamine H3 antagonists with SERT
inhibitor activity. The pharmacokinetic properties of
these compounds should allow for thorough pre-clinical
evaluation of the utility of histamine H3 antagonists
with reuptake inhibitor activity.

M. A. Letavic et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1047–1051
1051
24. Crystallographic details of 14 have been deposited at the
CCDC and allocated the deposition number CCDC
623130. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
25. Carruthers, N. I.; Gomez, L. A.; Jablonowski, J. A.;
Keith, J. M.; Letavic, M. A.; Ly, K. S.; Miller, J. M. B.;
Stocking, E. M.; Wolin, R. L. PCT Int. Appl. 2006, WO
2006066197 A1.
the human norepinephrine transporter, incubated with
5.4 nM [3H]-nisoxetine plus/minus test compounds for
60 min on ice, and harvested by rapid filtration.
Nonspecific binding was defined in the presence of
10 lM desipramine. Human DAT: Membranes were
prepared from Chinese hamster ovary (CHO) cells
expressing the human dopamine transporter, and
incubated on ice with 10.9 nM [3H]-WIN 35,428 for
2 h, and harvested by rapid filtration. Nonspecific
binding was determined in the presence of 10 lM
GBR-12909.
26. Human NET: Membranes were prepared from
MDCK (Madin-Darby Canine Kidney) expressing