A new class of histamine H3-receptor antagonists: Synthesis and structure - Activity relationships of 7,8,9,10-Tetrahydro-6H-cyclohepta[b]quinolines

Article abstract of DOI:10.1016/S0960-894X(03)00356-1

The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H₃ receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H₃ receptor were discovered.

Full text of DOI:10.1016/S0960-894X(03)00356-1

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2131–2135
A New Class of Histamine H3-Receptor Antagonists: Synthesis
and Structure–Activity Relationships of 7,8,9,10-Tetrahydro-6H-
cyclohepta[b]quinolines
Sean C. Turner,* Timothy A. Esbenshade, Youssef L. Bennani and Arthur A. Hancock
Neuroscience Research, Global Pharmaceutical Research and Development,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 27 January 2003; revised 5 April 2003; accepted 9 April 2003
Abstract—The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H3 receptor are descri-
bed. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated.
Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described.
Several compounds with high affinity and selectivity for the H3 receptor were discovered.
# 2003 Elsevier Science Ltd. All rights reserved.
Histamine is believed to exert its pharmacological
effects in the CNS and periphery via the modulation of
at least four distinct G-protein coupled receptor sub-
types.1 The identification of the H1 and the H2 recep-
tors, and the subsequent determination of their
respective physiological roles, have allowed the devel-
opment of selective antagonists of these receptors with
therapeutic applications in the treatment of allergic
conditions (H1 mediated)2 and gastric ulcers (H2 medi-
ated).3 The histamine H3-receptor (H3R), first charac-
Many of the early approaches have focused on struc-
tural modification of the endogenous ligand, histamine,
and several very potent series of imidazole-containing
H3 antagonists have emerged, such as thioperamide,7
GT-2331,8 FUB 470,9 and ciproxifan.10 It has been
proposed that the basic imidazole moiety of these
ligands interacts with an active site aspartate.11 This has
prompted the search for other basic groups as replace-
ments for imidazole and a number of non-imidazole
H3R antagonists have recently been discovered, includ-
ing guanidine containing compounds such as JB 9806412
and tacrine derivatives.13 We have also focused on
developing non-imidazole H3R antagonists and have
recently published on several novel series.14
terized in 1983,4 was originally described as
a
presynaptic autoreceptor regulating the production and
release of histamine. Evidence has since accumulated
suggesting that H3R are also colocalized hetero-
receptors present on cholinergic, dopaminergic, nora-
drenergic, peptidergic and serotonergic neurons.5
Current pharmacological interest is focused on the
potential role for selective ligands of H3R in the treat-
ment of several diseases and neurological disorders, for
example, epilepsy, schizophrenia, obesity, arousal and
sleep disorders, memory and learning deficits, and Alz-
heimer’s disease.6
Following a high throughput screen of our internal
compound library, we identified an 11-amino cyclo-
heptaquinoline 1 as a ligand with high affinity for the H3
receptor. We synthesized a series of both amino ana-
logues and also alkyne bioisosteres (Fig. 1).
The synthetic strategy used to prepare both the 11-amino
and 11-alkynyl series is shown in Scheme 1. Heating
commercially available anthranilic acid and cyclohepta-
none afforded the tricycle 5.15 Halogenation of 5 was
accomplished by heating with POCl3 or POBr3. The
required amines were prepared by amination of N-3-
bromopropylphthalimide and subsequent cleavage of the
intermediate 10 with hydrazine to give the primary
The search for selective ligands for H3R has resulted in the
identification of several potent and selective inhibitors.
*Corresponding author. Tel.: +1-847-935-0404; fax: +1-847-935-
5466; e-mail: sean.turner@abbott.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00356-1

2132
S. C. Turner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2131–2135
Figure 1.
amine 11.16 Reaction of 11 with the brominated tricycle
7 (lower yields were obtained using the chloro analogue)
in the presence of copper bronze and a catalytic quan-
tity of iodine, gave the desired 11-amino compounds 12.
Compounds 26 and 31 were prepared from 25 and 30,
respectively by TFA cleavage of the N-Boc group. The
4-thio cyclohexyl analogue 41 (Fig. 2) was obtained by
employing tetrahydrothiopyran-4-one in the initial for-
mation of the tricyclic core.
Figure 2.
to the mesylate. This can be aminated with a range of
primary and secondary amines in parallel fashion. A by-
product resulting from elimination of the mesylate is the
vinylogous alkyne 18, typically observed in yields of
12–20%. The cis alkene 39 was obtained by catalytic
reduction of 2 using Pd/C.
The alkynyl compounds were obtained by two approa-
ches. In Route A, 3-butynyl-p-toluenesulfonate was
treated with an amine to give the amino alkyne inter-
mediate 14. The Pd–Cu mediated coupling of 7 with the
alkyne 14, under mild conditions, was used to give the
acetylenic product 15. All attempts to employ the chloro
intermediate 6 in this coupling were unsuccessful. In the
more divergent Route B, the Pd coupling is conducted
using 1-butynol and the coupled product 17 is converted
Compounds were evaluated for H3 potency17 using a
radioligand assay measuring the inhibition of binding of
the agonist, [3H]-N-a-methyl histamine (RAMH), to rat
H3R using rat cortex homogenates. Functional antag-
onism was demonstrated by the compound’s inhibition
of the reversal of cAMP formation by RAMH. Affinity
for the human H3 was comparably determined with
receptors expressed in C-6 cells. Selectivity was assessed
against HEK cells expressing human H1 receptors
Scheme 1. Reagents and reaction conditions: (i) Xylene, 140 ꢀꢀC, 15 h (76%); (ii) POX3, reflux, 3 h (X=Cl, 76%; X=Br, 70%); (iii) K2CO3, DMF,
ꢀ
ꢀ
.
90 C, 4 h; (iv) N2H2 H2O, EtOH, 3 h; (v) Cu (s), I2 (cat), 180 C, 18 h; (vi) K2CO3, DMF, 80 C, 15 h; (vii) Pd(PPh3)2Cl2, CuI, Et3N, CH2Cl2, reflux,
22 h; (viii) Pd(PPh3)2Cl2, CuI, Et3N, CH2Cl2, reflux, 18 h; (65%); (ix) MeSO2Cl, Hunig’s base, CH2Cl2, 0 ꢀC–rt, 1 h; (x) R2NH, CH2Cl2, DMF,
70 ꢀC, 15 h.

S. C. Turner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2131–2135
2133
labeled with [3H]-mepyramine or human H2 receptors
labeled with [3H]-tiotidine.
(22 and 23) gives a moderate increase in potency and the
addition of a fused cyclopropyl group (26) is well toler-
ated, even with a bulky N-Boc group attached (25).
However, replacing the pyrrolidine ring with imidazole is
unfavorable (24). Incorporation of an N-Me piperazine
moiety (28) gave moderate potency but introduction of a
morpholine moiety (27) gave a further 12-fold reduction.
All attempts to incorporate the two N’s into a cyclic sys-
tem (29–31) were detrimental to activity.
SAR studies were conducted by varying the R sub-
stituent at the 11-position of the tricycle core (Table 1).
In the amine series, comparison of 19, 1 and 21 shows
that a 3 C linker between the two N’s is optimal. Acyla-
tion of the NH (20) results in a 50-fold drop in potency.
Constraint of the tertiary N into a five-membered ring
Table 1. Synthesis of 11-amino compounds and binding affinitiesa at human cloned H3 and rat cortical H3 receptors
Compdb
R
Method of preparation
A
Yield
44
Rat cortex H3-HR pKi
Human H3L pKi
1
7.66
8.01
19
20
21
22
23
24
25
26
27
28
29
30
31
A
—
A
A
A
A
A
—
A
A
A
A
—
526.83
7.32
85
<6
6.00
7.36
8.18
8.76
<6
31
7.41
39
7.74
43
8.60
30
<6
40
7.29
7.33
7.35
6.12
87
7.13
43
6.40
527.01
44
9
7.2
<6
<6
<6
<6
<6
<6
44
74
aValues are the mean of three or more experiments (SEM ꢁ0.2).
1
bSatisfactory H NMR, MS spectra and combustion analysis were obtained for all compounds.

2134
S. C. Turner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2131–2135
As with the amine analogues, we see a pattern in the
alkyne series (Table 2) where the five- and six-membered
ring analogues are the most active (2 and 33). An inter-
esting stereochemical preference for the (S) enantiomer
is observed in the case of the 3-hydro-
xymethylpyrrolidines 37 and 38. The alkene derivative
39 was found to be of similar potency to its alkyne
counterpart. In Figure 2, we see that reduction of the
aromatic ring reduces potency (40) while the introduc-
tion of a thiocyclohexyl ring is better tolerated (41). The
most active amino analogues were much more potent
than the corresponding alkyne derivatives (e.g., 1 100-
fold >33) but this ratio drops to parity for weaker
analogues. The expansion of the cycloalkyl ring from
seven- to eight-membered (42) is detrimental to activity.
Table 3. Binding affinities of selected compounds at human H3, H1
and H2 receptors
Compd Human H3L Ki Human H1-HR Ki Human H2-HR Ki
(nM)
(nM)
(nM)
1
2
22
23
9.7
80
6.6
1.7
7696
1000
4085
15,733
10,131
1729
3781
3211
Values are the mean of four experiments.
In summary, we have identified a novel structural class
of H3 antagonists based upon a cycloheptaquinoline
core. Two series of compounds, bearing either an amino
substituent or an alkyne linker at the 11-position, were
shown to have moderate to high affinity and selectivity
for the H3 receptor.
A selection of the most potent compounds was also
evaluated for H3 selectivity with respect to the H1 and
H2 receptors (Table 3). The amino substituted ana-
logues were highly selective for H3: 600–6000-fold
selective over H1 and 500–1000-fold selective over H2.
The selectivity was markedly lower for the alkynyl ana-
logue 2 with 13- and 24-fold ratios, respectively.
References and Notes
1. (a) Leurs, R.; Watanabe, T.; Timmerman, H. Trends Phar-
macol. Sci. 2001, 22, 337. (b) Hough, B. L. Mol. Pharmacol.
2001, 59, 415. (c) Oda, T.; Morikawa, N.; Saito, Y.; Masuho,
Y.; Matsumoto, S. J. Biol. Chem. 2000, 275, 36781.
2. Kinsolving, C. R.; Munro, N. L.; Carr, A. A. Pharmacolo-
gist 1973, 15, 221.
Table 2. Synthesis of 11-alkynyl compounds and binding affinitiesa at
human cloned H3 and rat cortical H3 receptors
3. Black, J. W.; Duncan, W. A. M.; Durant, G. J.; Ganellin,
C. R.; Parsons, E. M. Nature 1972, 236, 385.
4. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Nature 1983,
302, 832.
5. Schlicker, E.; Kathmann, M. In The Histamine H3 Recep-
tor; A Target for New Drugs, 1st ed.; Leurs, R., Timmermman,
H., Eds.; Elsevier Science: Amsterdam, 1998; p 59.
6. (a) Tedford, C. E. In The Histamine H3 Receptor; A Target
for New Drugs, 1st ed.; Leurs, R., Timmermman, H., Eds.;
Elsevier Science: Amsterdam, 1998; p 269. (b) Leurs, R., Vol-
linga, R. C., Timmerman, H. In Progress in Drug Research,
Jacker, E., Ed., Birkhausser: Basel, 1995; p 107.
7. Arrang, J.-M.; Garbarg, M.; Lancelot, J. C.; Lecomte,
J. M.; Pollard, H.; Robba, M.; Schunack, W.; Schwartz, J.-C.
Nature 1987, 327, 117.
8. Tedford, C. E.; Hoffmann, M.; Seyedi, N.; Maruyama, R.;
Levi, R.; Yates, S. L.; Ali, S. M.; Phillips, J. G. Eur. J. Phar-
macol. 1998, 351, 307.
9. Krause, M.; Ligneau, X.; Stark, H.; Garbarg, M.;
Schwartz, J.-C.; Schunack, W. J. Med. Chem. 1998, 41,
4171.
10. Ligneau, X.; Lin, J. S.; Vanni-Mercier, G.; Jouvet, M.;
Muir, J. L.; Ganellin, C. R.; Stark, H.; Elz, S.; Schunack, W.;
Schwartz, J.-C. J. Pharmacol. Exp. Ther. 1998, 287, 658.
11. De Esch, I. J.; Mills, J. E.; Perkins, T. D.; Romeo, G.;
Hoffmann, M.; Wieland, K.; Leurs, R.; Menge, W. M.;
Nederkoorn, P. H.; Dean, P. M.; Timmerman, H. J. J. Med.
Chem. 2001, 44, 1666.
12. Linney, I. D.; Buck, I. M.; Harper, E. A.; Kalindjian,
S. B.; Pether, M. J.; Shankley, N. P.; Watt, G. F.; Wright, P. T.
J. Med. Chem. 2000, 43, 2362.
13. Apelt, J.; Ligneau, X.; Pertz, H. H.; Arrang, J.-M.;
Ganellin, C. R.; Schwartz, J.-C.; Schunack, W.; Stark, H.
J. Med. Chem. 2002, 45, 1128.
Compd
R
Method of Yield Rat cortex Human
Preparation
H3-HR
pKi*
H3L
pKi*
2
B
B
59
29
77
50
38
19
37
41
99
6.39
6.16
6.19
<6
7.10
6.41
6.67
<6
32
33
34
35
36
37
38
39
C
C
C
C
C
C
—
<6
6.14
6.36
6.60
6.02
7.06
<6
6.21
<6
14. (a) Faghih, R.; Dwight, W.; Gentles, R. G.; Phelan, K.;
Esbenshade, T. A.; Ireland, L.; Miller, T.; Kang, C. H.; Fox,
G. B.; Gopalakrishnan, S.; Hancock, A. A.; Bennani, Y. L.
Bioorg. Med. Chem. Lett. 2002, 12, 2031. (b) Faghih, R.;
Dwight, W.; Black, L.; Liu, H.; Gentles, R. G.; Phelan, K.;
Esbenshade, T. A.; Ireland, L.; Miller, T.; Kang, C. H.;
6.56
aSee corresponding footnote for Table 1.

S. C. Turner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2131–2135
2135
Kreuger, K.; Fox, G. B.; Hancock, A. A.; Bennani,
Y. L. Bioorg. Med. Chem. Lett. 2002, 12, 2035. (c)
Vasudevan, A.; Connor, S. E.; Gentles, R. G.; Faghih, R.;
Liu, H.; Dwight, W.; Ireland, L.; Kang, C. H.; Esbenshade,
T. A.; Bennani, Y. L.; Hancock, A. A. Bioorg. Med. Chem.
Lett. 2002, 12, 3077. (d) Faghih, R.; Dwight, W.; Vasudevan,
A.; Dinges, J.; Connor, S. E.; Esbenshade, T. A.; Bennani,
Y. L.; Hancock, A. A. Bioorg. Med. Chem. Lett. 2002, 12,
3077.
15. Lee, C.-M. J. Med. Chem. 1968, 11, 388.
16. Baldwin, A. W.; Robinson, R. J. Chem. Soc. 1934, 1264.
17. Comparative pKi’s for reference standards ciproxifan and
thioperamide, respectively: human H3L 7.20 and 7.14; rat
cortex H3-HR 9.20 and 8.15.