Pyrrolo(iso)quinoline derivatives as 5-HT2C receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2005.10.029

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT_2C receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and

Full text of DOI:10.1016/j.bmcl.2005.10.029

Bioorganic & Medicinal Chemistry Letters 16 (2006) 677–680
Pyrrolo(iso)quinoline derivatives as 5-HT2C receptor agonists
David R. Adams, Jonathan M. Bentley, Karen R. Benwell, Michael J. Bickerdike,
Corinna D. Bodkin, Ian A. Cliffe, Colin T. Dourish, Ashley R. George, Guy A. Kennett,
Antony R. Knight, Craig S. Malcolm, Howard L. Mansell,* Anil Misra, Kathleen Quirk,
Jonathan R. A. Roffey and Steven P. Vickers
Vernalis plc, Oakdene Court, 613 Reading Road, Winnersh, Wokingham, Berkshire RG41 5UA, UK
Received 19 August 2005; revised 7 October 2005; accepted 10 October 2005
Available online 27 October 2005
Abstract—A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT2C receptor agonists for
the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and
radioligand binding data for the compounds at 5-HT2 receptor subtypes are reported. The analogue which showed the highest
5-HT2C binding affinity (27, 1.6 nM) was found to be successful in reducing food intake in rats.
Ó 2005 Elsevier Ltd. All rights reserved.
The rising prevalence of obesity in the developed and
developing world carries an enormous financial burden.1
Obesity is a major risk factor in the development of such
conditions as cancer, coronary artery disease, dyslipida-
emia and hyperglycaemia. In the US, a recent survey has
suggested that 64% of adults are either overweight or
obese.2
development of compounds having improved selectivity
for 5-HT2C receptors over 5-HT2B receptors is consid-
ered a desirable objective.
NH2
HO
N
H
Cl
N
The non-selective 5-HT2C receptor agonist meta-chlor-
ophenylpiperazine (mCPP, 1) reduces food intake and
accelerates the appearance of the behavioural satiety se-
quence in rats.3,4 It also decreases food intake in normal
human volunteers5 and obese subjects.6 The anorectic
action of mCPP is absent in mutant mice lacking
the 5-HT2C receptor7 and is attenuated by the selective
5-HT2C receptor antagonist SB-242084 in rats.8
NH
1
2
NH2
O
F
N
H
N
Cl
3
4
The endogenous ligand 5-hydroxytryptamine (5-HT, 2)
is non-selective across 5-HT receptor subtypes. The con-
formationally restricted tryptamine 3 however is report-
ed to show selectivity for 5-HT2 receptors.9 In addition
to mCPP (1), the 1-(1-indolyl)-2-propylamine RO600175
(4) has been identified as a potent 5-HT2C receptor ago-
nist and is selective for 5-HT2C and 5-HT2B receptors.10
In the light of recent evidence11 that 5-HT2B agonism
might be associated with cardiac valvulopathy, the
NH2
In accordance with these literature leads, 1-(1-pyrrolo
(iso)quinolinyl)-2-propylamines such as 27–39 (Schemes
2 and 3) were proposed as conformationally restricted
targets for synthesis and evaluation as 5-HT2C receptor
agonists. It was reasoned that these novel targets might
retain the hydrogen bond accepting characteristics of the
oxygen atoms of 5-HT (2) and the conformationally
restricted tryptamine 3, the steric properties of 3, as well
as the electronic properties of the isotryptamine 4.
Keywords: Obesity; Serotonin; 5-HT2C; Agonist.
*
Corresponding author. Tel.: +44 1189 773133; fax: +44 1189
899300; e-mail: h.mansell@vernalis.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.029

678
D. R. Adams et al. / Bioorg. Med. Chem. Lett. 16 (2006) 677–680
Accordingly, a discovery research programme was initi-
ated to evaluate 1-(1-pyrrolo(iso)quinolinyl)-2-propyl-
amines as novel 5-HT2C receptor agonists for the
treatment of obesity.12
by nitration of 7- and 6-methylisoquinoline using potassi-
um nitrate in sulfuric acid.22 The precursor methyliso-
quinolines23 were prepared in two steps and in low
yields from m- and p-tolualdehyde by a modified24 Pom-
eranz–Fritsch reaction.25 The mixture of 5- and 7-methyl-
isoquinoline regioisomers obtained during the synthesis
of 7 was separated by recrystallisation from heptane.
In order to obtain a series of 1-(1-pyrrolo(iso)quinoli-
nyl)-2-propylamines 27–39, the synthesis of a selection
of pyrrolo(iso)quinolines (5–8 and 11) was undertaken.
The pyrrolo(iso)quinoline intermediates 5–8 and 11 were
transformed to the target (S)-N-unsubstituted indole
derivatives 27–31 as shown in Scheme 2.
N
H
N
H
N
N
Thus, reaction of the pyrrolo(iso)quinolines 5–8, 11 with
sodium hydride and (R)-propylene oxide gave the (R)-
alcohols 12–16, which were converted via their methane-
sulfonate ester derivatives 17–21 to the (S)-azides 22–26.
Catalytic hydrogenation of 22–26 then gave the target
primary amines 27–31.26
5
6
N
H
N
H
N
N
Finally, in order to explore structure–activity relation-
ships around the nitrogen atom of the 2-propylamine
unit, a small series of N-alkyl derivatives were prepared
from 27 using solution-phase parallel reductive amina-
tion reactions (Scheme 3).
8
7
For example, 1H-pyrrolo[2,3-f]quinoline 5 was prepared
by the Bartoli reaction of 5-nitroquinoline with excess
vinylmagnesium bromide.13 The 5-chloro analogue 11
of 5 was initially prepared in the same way in low yield
from 8-chloro-5-nitroquinoline, the latter being made by
nitration of 8-chloroquinoline.
This entailed imine formation, reduction with polymer
supported borohydride, the use of polymer-supported
5-Chloro-1H-pyrrolo[2,3-f]quinoline (11) was later pre-
pared in a more efficient manner using the Leimgru-
ber–Batcho reaction (Scheme 1).14
O
H
X
X
Me
Accordingly 8-chloro-6-methyl-5-nitroquinoline (9)15
was treated with N,N-dimethylformamide, dimethyl
acetal and pyrrolidine to give the nitroenamine 10, which
underwent reductive cyclisation to give the chloroquino-
line 11. The Leimgruber–Batcho reaction was also ap-
plied in analogous fashion to 6-methyl-5-nitroquinoline
to provide an improved synthesis of 5 (in 69% overall
yield).16 This procedure was additionally employed in
the synthesis of 1H-pyrrolo[3,2-h]quinoline (6)16–18 from
7-methyl-8-nitroquinoline, and in the synthesis of the pyr-
rolo(iso)quinolines 719 and 820,21 from the appropriately
substituted methylnitroisoquinolines. The requisite meth-
ylnitroisoquinolines were obtained in quantitative yield
NaH
THF
N
N
H
N
N
OH
12, 14 - 16 X = H
13 X = Cl
5 - 8 X = H
11 X = Cl
MeSO2Cl
Et3N, CH2Cl2
17, 19 - 21 X = H
OMs
18
X = Cl
NaN3 DMF
70 o
C
PtO2
X
X
H2
EtOH
N
N
N
N
NH2
N3
DMF-DMA
C4H8NH
Cl
N
Cl
27, 29 - 31 X = H
28 X = Cl
22, 24 - 26 X = H
23 X = Cl
DMF
N
NO2
N
NO2
110 o
C
Scheme 2. Synthesis of (S)-1-(1-pyrrolo(iso)quinolinyl)-2-propylam-
ines 27–31 (see Table 1).
10
9
Fe
AcOH
EtOH
(55%)
(i) - (vi)
N
N
N
N
Cl
N
NH2
NHR
N
H
27
32 - 39
Scheme 3. Synthesis of (S)-N-alkyl-1-(1-pyrrolo[2,3-f]quinolinyl)-2-
propylamine derivatives 32–39 (see Table 1). Reagents: (i) RCHO,
MeOH; (ii) PS–BH4; (iii) PS–4-BnOC6H4CHO, CH2Cl2; (iv) filtration;
(v) SCX-2, MeOH; (vi) NH3, 2 M in MeOH.
11
Scheme 1. Synthesis of 5-chloro-1H-pyrrolo[2,3-f]quinoline 11.

D. R. Adams et al. / Bioorg. Med. Chem. Lett. 16 (2006) 677–680
679
Table 1. 5-HT2 receptor subtype functional efficacy, potency and binding for 1, 2, 4 and 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines 27–39
Compound
Substituent(s)
Percentage relative efficacy (EC50, nM)a
Binding affinity (nM)a
b
b
b
c
d
d
h5-HT2A
h5-HT2B
h5-HT2C
Ki h5-HT2A
Ki h5-HT2B
Ki h5-HT2C
1 (mCPP)
2 (5-HT)
41% (75)
98% (11)
33% (>1000) 83% (26)
54
14
32
12
9
6.9
2.3
1.6
2.4
27
101% (1.5)
71% (4.3)
65% (1.1)
61% (2.1)
60% (45)
67% (62)
99% (1.7)
93% (18)
99% (2.9)
101% (6.9)
39% (97)
98% (73)
93% (297)
99% (52)
98% (42)
95% (74)
86% (200)
88% (348)
92% (257)
77% (551)
87% (219)
4 (RO600175)
27 (VER-2692) Pyrrolo[2,3-f]quinolinyl
72% (131)
88% (32)
5-Chloropyrrolo[2,3-f]quinolinyl 85% (36)
38
31
5.1
12
28
29
30
31
32
33
34
35
36
37
38
39
29
18
Pyrrolo[3,2-h]quinolinyl
Pyrrolo[3,2-h]isoquinolinyl
Pyrrolo[2,3-f]isoquinolinyl
N-(2-Naphthyl)methyl
N-(3,4-Methylenedioxy)benzyl
N-(2-Chloro)benzyl
N-Benzyl
41% (446)
67% (473)
229
230
1041
181
398
674
842
927
1158
1568
1681
115
210
778
136
138
380
515
624
455
883
739
37
72
63% (>1000) 70% (152)
56% (222)
69% (359)
58% (638)
76% (27)
71% (20)
72% (44)
16
16
39
77
39% (>1000) 70% (97)
32% (>1000) 67% (128)
N-(Cyclohexyl)methyl
N-Allyl
78
86
54% (777)
70% (91)
N-(2-Methoxy)benzyl
N-(2-Methyl)benzyl
24% (>1000) 41% (462)
49% (>1000) 64% (128)
168
171
a Relative efficacy, EC50 and Ki values are the mean of two determinations run at 11 different concentrations. Each experiment was carried out in
triplicate. Standard errors were within 20% of the mean.
b Efficacy relative to 10 lM 5-HT (100%).
c Displacement of [125I]DOI.
d Displacement of [3H]5-HT.
4-benzyloxybenzaldehyde as a scavenger resin for
unreacted 27 and catch-release purification with SCX-2
cartridges. The N-allyl derivative 37 was made by alkyl-
ation with allyl bromide.
using dexfenfluramine as a positive control.29 Animals
treated 3 mg/kg with either compound 27 or dexfenflur-
amine significantly reduced food intake 4 h after food
presentation when compared to vehicle treated animals
using the analysis of variance test and DunnettÕs post
hoc test. The anorectic effect of compound 27 was
dose-dependently blocked by pre-treatment with the
selective 5-HT2C receptor antagonist SB-242084, indi-
cating a 5-HT2C receptor mediated effect.
The target 2-propylamines 27–39 were screened for
,
functional activity at recombinant human 5-HT2A
5-HT2B and 5-HT2C receptors expressed in CHO cells
using a Fluorometric Imaging Plate Reader (FLIPR)
(Table 1). The maximum fluorescent signal was mea-
sured and compared with the response produced by
10 lM 5-HT (defined as 100%).27 The compounds were
then compared in radioligand binding assays using
recombinant human 5-HT2A, 5-HT2B and 5-HT2C
receptors expressed in mammalian cell lines.28
In conclusion, a series of 1-(1-pyrrolo(iso)quinolinyl)-2-
propylamines and selected N-alkyl derivatives has been
synthesised and subjected to pharmacological evaluation.
Compound 27 (VER-2692) was shown to be a potent
5-HT2C receptor agonist and reduced feeding in rats.
Thus, the 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines
27–39 have potential for use in therapy as anti-obesity
agents.
The 2-propylamines 27–39 were potent partial or full
agonists at 5-HT2C receptors. In binding studies, all of
the compounds 27–39 had greater selectivity for
5-HT2C receptors over 5-HT2B receptors than
RO600175 (4) (2.2-fold). Compounds 27–39 also had
greater selectivity for 5-HT2C receptors over both
5-HT2A and 5-HT2B receptors than mCPP (1) (6.0-
and 3.6-fold, respectively). Compounds 27 and 28 also
had higher binding affinities for 5-HT2C receptors than
both mCPP (1) and 5-HT (2). With the exception of
compound 29, compounds 27–39 showed a broadly sim-
ilar percentage relative efficacy profile to RO600175 (4).
Compounds 27–39 did, however, show less functional
selectivity than 4 for 5-HT2B receptors over 5-HT2C
receptors (EC50 ratios of 1.2- to 3.3-fold vs 4.2-fold).
Finally, the N-alkyl analogues 32–39 retained the bind-
ing and functional selectivities of their precursor 27, but
the binding affinities and functional potencies were
significantly reduced.
Acknowledgments
We thank K. Heatherington, T. V. Haymes and their
team for analytical support.
References and notes
1. Carek, P. J.; Dickerson, L. M. Drugs 1999, 57, 883.
2. National Center for Health Statistics, US Centers for
Disease Control and Prevention (http://www.cdc.gov/
nchs/).
3. Kennett, G. A.; Curzon, G. Psychopharmacology 1988, 96,
93.
4. Kitchener, S. J.; Dourish, C. T. Psychopharmacology 1994,
113, 369.
5. Walsh, A. E. S.; Smith, K. A.; Oldman, A. D.; Williams,
C.; Goodall, E. M.; Cowen, P. J. Psychopharmacology
1994, 116, 120.
Selected compounds were tested for their ability to
decrease food consumption in 23 h food-deprived rats

680
D. R. Adams et al. / Bioorg. Med. Chem. Lett. 16 (2006) 677–680
6. Sargent, P. A.; Sharpley, A. L.; Williams, C.; Goodall, E.
M.; Cowen, P. J. Psychopharmacology 1997, 133, 309.
20. Govindachari, T. R.; Rajappa, S.; Susarsanam, V. Indian
J. Chem. 1966, 4, 118.
7. Tecott, L. H.; Sun, L. M.; Akana, S. F.; Strack, A. M.;
Lowenstein, D. H.; Dallman, M. F.; Julius, D. Nature
1995, 374, 542.
21. Ferlin, M. G.; Chiarelotto, G.; Basadonna, O.; Gia, O.;
Mobilio, S.; Baccichetti, F.; Carlassare, F. Farmaco 1989,
44, 1141.
8. Kennett, G. A.; Wood, M. D.; Bright, F.; Trail, B.; Riley,
G.; Holland, V.; Avenell, K. Y.; Stean, T.; Upton, N.;
Bromidge, S.; Forbes, I. T.; Brown, A. M.; Middlemiss, D.
N.; Blackburn, T. P. Neuropharmacology 1997, 36, 609.
9. Macor, J. E.; Fox, C. B.; Johnson, C.; Koe, B. K.; Lebel,
L. A.; Zorn, S. H. J. Med. Chem. 1992, 35, 3625.
10. Bo¨s, M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.; Sleight, A.
J.; Wichmann, J.; Widmer, U. J. Med. Chem. 1997, 40, 2762.
11. Rothman, R. B.; Baumann, M. H.; Savage, J. E.; Rauser,
L.; McBride, A.; Hufeisen, S. J.; Roth, B. L. Circulation
2000, 102, 2836.
12. Adams, D. R.; Bentley, J. M.; Roffey, J. R. A.; Bodkin, C.
D.; Mansell, H. L.; George, A. R.; Cliffe, I. A. Patent
Appl. WO 0012502, 2000; Chem. Abstr. 2000, 132,
194301.
13. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
Tetrahedron Lett. 1989, 30, 2129.
14. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214.
15. Neely, T. A.; Capps, J. D. J. Am. Chem. Soc. 1955, 77,
182.
16. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
2004, 2, 160.
17. Ferlin, M. G.; Chiarelotto, G.; Baccichetti, F.; Carlassare,
F.; Toniolo, L.; Bordin, F. Farmaco 1992, 47, 1513.
18. Vlachou, M.; Tsotinis, A.; Kelland, L. R.; Thurston, D. E.
Heterocycles 2002, 57, 129.
22. A typical procedure for the nitration of 6- and 7-
methylisoquinoline is as follows: Sulfuric acid (3 mL)
was cooled to 0 °C and treated portionwise with the
methylisoquinoline (1 mmol) and potassium nitrate
(1.2 mmol). The solution was stirred for 1 h, poured onto
ice/water (15 mL) and basified with ammonium hydroxide.
The required methylnitroisoquinoline was isolated by
filtration or extraction, recrystallising from ethanol, if
necessary.
23. Miller, R. B.; Frincke, J. M. J. Org. Chem. 1980, 45, 5312.
24. Bondinelli, W. E.; Chapin, F. W.; Girard, G. R.; Kaiser,
C.; Krog, A. J.; Pavloff, A. M.; Schwartz, M. S.; Silvestri,
J. S.; Vaidya, P. D.; Lam, B. L.; Wellman, G. R.;
Pendleton, R. G. J. Med. Chem. 1980, 23, 506.
25. Brown, E. V. J. Org. Chem. 1977, 42, 3208.
26. The optical purity of compound 27 was determined by
chiral HPLC as 99.2% (CHIRALPAK AD, hexane/2-
propanol, 9:1; tr, 13.8 min).
27. Porter, R. H. P.; Benwell, K. R.; Lamb, H.; Malcolm, C.
S.; Allen, N. H.; Revell, D. F.; Adams, D. R.; Sheardown,
M. J. Br. J. Pharmacol. 1999, 128, 13.
28. 5-HT2A: (a) McKenna, D. J.; Peroutka, S. J. J. Neurosci.
1989, 9/10, 3482; 5-HT2B: (b) Schmuck, K.; Ullmer, C.;
Engels, P.; Lubbert, H. FEBS Lett. 1994, 342, 85; 5-HT2C
:
(c) Hoyer, D.; Engel, G.; Kalkman, H. O. Eur. J.
Pharmacol. 1985, 118, 13.
19. Govindachari, T. R.; Susarsanam, V. Indian J. Chem.
1971, 9, 402.
29. Vickers, S. P.; Dourish, C. T.; Kennett, G. A. Neurophar-
macology 2001, 41, 200.