Non-imidazole heterocyclic histamine H3 receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00299-3

Continued exploration of the SAR around the lead imidazopyridine histamine H₃ antagonist 1 has led to the discovery of several related series of heterocyclic histamine H₃ antagonists. The synthesis and SAR of indolizine, indole and p

Full text of DOI:10.1016/S0960-894X(03)00299-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1767–1770
Non-imidazole Heterocyclic Histamine H3 Receptor Antagonists
Wenying Chai,* J. Guy Breitenbucher, Annette Kwok, Xiaobing Li, Victoria Wong,
Nicholas I. Carruthers, Timothy W. Lovenberg, Curt Mazur, Sandy J. Wilson,
Frank U. Axe and Todd K. Jones
Johnson & Johnson Pharmaceutical Research and Development L. L. C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 5 September 2002; accepted 25 February 2003
Abstract—Continued exploration of the SAR around the lead imidazopyridine histamine H3 antagonist 1 has led to the discovery
of several related series of heterocyclic histamine H3 antagonists. The synthesis and SAR of indolizine, indole and pyrazolopyridine
based compounds are now described.
# 2003 Elsevier Science Ltd. All rights reserved.
Histamine receptors are divided into four subtypes, H1,1
H2,2 H3,3 and H4,4 at which histamine exhibits distinct
pharmacological effects. Thus histamine plays a role in
the pathogenesis of allergic conditions via the H1
receptor and in gastric acid secretion via the H2 recep-
tor. H1 and H2 receptor antagonists have subsequently
proven effective for the treatment of allergic diseases
and gastric ulceration, respectively. The discovery of a
third histamine receptor, H3, by Arrang and co-
workers,3 stimulated extensive research which demon-
strated that the receptor is a presynaptic autoreceptor
on histaminergic neurons and a presynaptic hetero-
receptor on non-histamine containing neurons with
greatest densities in the central nervous system.5ꢀ9 Con-
sequently many applications have been proposed for H3
receptor ligands, particularly in the CNS and centrally
acting H3 antagonists may provide novel therapies for
neurological disorders such as epilepsy, sleeping dis-
turbances, arousal/vigilance, ADHD and cognition.10
recombinant human H3 receptor.12 This afforded a
potent and selective H3 antagonist 1 with good oral
bioavailability and blood–brain barrier penetration.
Following this discovery we sought to explore replace-
ments for the imidazopyridine nucleus which are the
subject of this Letter.
Results
Throughout the study, we chose to retain the piperi-
dinopropyloxyphenyl fragment which is optimal
according to our previous results.11 This piperi-
dinopropyloxyphenyl fragment is also present in the
potent non-imidazole H3 antagonists described by other
groups.13,14 Here, we only address replacements for the
imidazopyridine nucleus together with substitutions in
the heterocyclic and central phenyl rings. We first
turned our attention to removing one of the heterocyclic
ring nitrogens to afford indolizines and indoles. Thus
the parent indolizine 3 (Ki=13 nM) exhibited compar-
able activity to the corresponding imidazopyridine 2
(Ki=6 nM) (Table 1). A range of simple substitutions
were next examined. The attachment of a methyl group
was tolerated with the five-membered ring, but with the
six-membered ring, a reduction in affinity was observed.
This contrasts with the results11 for the imidazopyridine
where analogous substitutions were favorable and
suggests a slightly different receptor–ligand interaction
for the indolizines. Although substitution in the phenyl
ring led to reduced affinity (e.g., 14), introduction of
an additional substituent (e.g., 15) to impart a steric
Earlier, we described11 a series of imidazopyridines
identified via high throughput screening, utilizing the
*Corresponding author. Fax: +1-858-450-2049; e-mail: wchai@
prdus.jnj.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00299-3

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W. Chai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1767–1770
Table 1. Indolizine and aryl ring substituents, oxypropylpiperidine
terminus
Figure 1.
No.
Substituent
Ki (nM)
para to meta or ortho. We next prepared the indole
analogue 18 recognizing that the indole nucleus con-
tains a more acidic nitrogen than either the imidazo-
pyridine or the indolizine nucleus (the calculated proton
affinities of these heterocycles are in ref 16). In this case,
a significant reduction in affinity was observed,
although the sulfonamide intermediate 19 exhibited
high affinity (Fig. 1).
3
4
5
6
7
8
9
10
11
12
13
14
15
H
1-CH3
3-CH3
5-CH3
6-CH3
7-CH3
8-CH3
1-Ph
13 (ꢁ2.3)
16 (ꢁ2.6)
2 (ꢁ0.2)
46 (ꢁ13.1)
28 (ꢁ6.0)
40 (ꢁ7.4)
40 (ꢁ13.0)
40 (ꢁ6.2)
19 (ꢁ2.1)
5 (ꢁ1.6)
1-CH2CH3
3-CH2CH3
1-CH2CH2Ph
20-CH3
One additional heterocyclic system was also examined,
the pyrazolopyridine 20. In this case, the pyrazolopyri-
dine system exhibited similar affinity to that observed
for the imidazopyridine and indolizine system. The
potencies for the different heterocycles shown in Table 3
apparently reflect the basicities of the heterocycles and a
good correlation between their calculated proton affi-
nities and their binding affinities was observed.16
37 (ꢁ4.1)
152 (ꢁ33.4)
11 (ꢁ3.2)
20,1-di-CH3
Ki values for the human H3 receptor were determined in house and
calculated according to Cheng and Prusoff15 where Ki ¼
IC50=ð1 þ ½SŠ=KdÞ where [S]=0.8 nM and Kd=0.8 nM for [3H]-N-
methylhistamine. Values are means of three to seven experiments,
SEM is given in parentheses.
Table 2. Piperidinylpropoxy point of attachment
Synthesis
Syntheses of indolizine compounds (3–17) were accom-
plished according to the procedure outlined in Scheme 1
for the preparation of 3. 2-Picoline (21) was treated with
a-bromoacetophenone (22) providing the 2-phenyl indo-
lizine core 23. Demethylation of 23 gave 24 which was
condensed with 3-chloropropylpiperidine affording 3.
No.
Substituent
Ki (nM)
3
16
17
40
30
20
13 (ꢁ2.3)
308 (ꢁ34.1)
236 (ꢁ89.9)
The indole 19 was prepared according to Scheme 2.
Phenylacetylene 25 was prepared from benzaldehyde 26
via initial protection of the phenol followed by acetylene
formation17 using the Seyferth/Gilbert reagent.18 2-Iodo-
N-(methanesulfonyl)aniline 27 was obtained upon
treating 2-iodo-aniline 28 with methansulfonylchloride.
Palladium mediated coupling reaction19 of 27 with 25
afforded the appropriately substituted indole core 29.
Removal of the MEM (2-methoxyethoxymethyl) pro-
tecting group and alkylation of the free phenol under
Mitsunobu conditions20 gave protected indole 19 which
was converted to 18.
interaction between the indolizine and the phenyl ring
restored affinity. In the cases where a small substituent
was tolerated, larger substituents were examined (e.g.,
10–13) and found to be acceptable. However, no
improvement in potency was observed. The point of
attachment for the piperidinylpropoxy side chain was
also examined (Table 2) and a decrease in affinity was
observed as the point of attachment was moved from
Table 3. Heterocycle variations
No.
R
Ki (nM)
6 (ꢁ0.1)
No.
R
Ki (nM)
2
18
47 (ꢁ6.4)
3
13 (ꢁ2.3)
20
11 (ꢁ1.2)

W. Chai et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1767–1770
1769
Scheme 3. Reagents and conditions: (a) (i) HO3SONH2, H2O, reflux,
1 h; (ii) K2CO3; (iii) HI, 23%; (b) p-methoxybenzaldes, MeOH, reflux,
20 h; (c) I2, pyridine, 6 h, reflux, 10% (b and c two steps); (d) HBr/
HOAc, 100 ꢄC, 3 h, 80%; (e) NaOtBu/DMA, 3-chloropropylpiperi-
dine, 100 ꢄC, 16 h, 42%.
Scheme 1. Regents and conditions: (a) acetone, reflux, 1 h; (b) K2CO3/
H2O, 5 h, 99% (a and b two steps); (c) NaSEt/DMF, 100 ꢄC; or HBr/
HOAc, 100ꢄ C, 1 h; (d) NaOtBu/DMF, 3-chloropropylpiperidine,
100ꢄ C, 16 h, 93 or 90% (c and d two steps).
to be dictated by the basicity of the fused heterocycle.
Indolizine 3 was examined in more detail and exhibited
high selectivity with respect to a range of G-protein
coupled receptors, ion-channels and transporters.
(Inactive at concentrations below 500 nM). Its perme-
ability (Caco-2) is high (Papp=14.1 ꢂ 106 cm/s). In a
functional assay versus the human H3 receptor using
SKNMC cells stably transfected with the human H3
receptor 3 yielded a pA2=8.5. The rat pA2 was observed
to be 7.71. In contrast to imidazopyridine 1, indolizidine
3 exhibited less binding to human serum albumin, 50%
versus >90%, respectively. However whilst 3 showed a
very favorable potency, selectivity and pharmacokinetic
profile we were disappointed to observe rapid metabo-
lism when 3 was exposed to human liver microsomes
À
Á
t1=2 ꢃ 10 min . Therefore we chose to examine addi-
tional compounds and found that the introduction of an
alkyl group (e.g., 5) afforded a compound with superior
stability t1=2 ꢃ 54 min without loss of potency.
À
Á
In conclusion, the imidazopyridine nucleus of 2 may be
replaced by alternative fused heterocycles to afford
potent histamine H3 receptor antagonists that exhibit
favorable properties for further development as thera-
peutic agents.
Scheme 2. Regents and conditions: (a) NaH, DMF, 1 h, rt; MEMCl,
16 h, rt, 87%; (b) (MeO)2POC(N2)COMe, K2CO3, MeOH, 18 h, rt,
82%; (c) MsCl (2 equiv), TEA, CH2Cl2, 2 h, 0 ꢄC; KOH, 1:1 MeOH/
H2O, 1 h, rt, 74%; (d) Pd(PPh3)2Cl2, CuI, 4:1 DMF/TEA, 18 h, 80 ꢄC,
89%; (e) 2 N HCl, dioxane/MeOH, 1 h, rt, 81%; (f) DEAD, polymer-
supported PPh3, 3-hydroxypropylpiperidine, THF, 5 h, rt, 47%;
(g) KOH, 1:1:1 THF/MeOH/H2O, 12 h, rt, 20%.
References and Notes
Synthesis of pyrazolo[1,5-a]pyridine 20 was accom-
plished as shown in Scheme 3 using a published proce-
dure21 for the key ring construction sequence (30–33).
Picoline 30 was aminated to 31. Condensation of 31
with 4-methoxybenzaldhyde gave 32. Cyclisation of 32
then provided 2-phenyl-pyrazolo[1,5-a]pyridine 33.
Demethylation of 33 gave 34 which was alkylated with
3-chloropropylpiperidine to afford 20.
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