Synthesis and structure-activity relationship of 7-azaindole piperidine derivatives as CCR2 antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.10.061

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC₅₀ values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.

Full text of DOI:10.1016/j.bmcl.2008.10.061

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6468–6470
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationship of 7-azaindole piperidine
derivatives as CCR2 antagonists
*
Mingde Xia , Cuifen Hou, Duane DeMong, Scott Pollack, Meng Pan, Monica Singer,
Michele Matheis, William Murray, Druie Cavender, Michael Wachter
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and structure–activity relationship of a series of 7-azaindole piperidine derivatives are
described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC50 values in the
nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics
profile.
Received 16 September 2008
Revised 11 October 2008
Accepted 14 October 2008
Available online 17 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Chemokines
MCP-1
CCR2 antagonist
The monocyte chemoattractant protein-1 (MCP-1), a member of
the CC class of chemokines, mediates chemotaxis of monocytes to
inflammatory sites through interactions with its CC chemokine
receptor-2 (CCR2)1 and is implicated in various inflammatory dis-
eases.2–12 The therapeutic potential of CCR2 antagonists for pre-
venting and treating various pathological conditions (such as
cockroach allergen-induced asthma, atherosclerosis, rheumatoid
arthritis, and multiple sclerosis) has stimulated considerable inter-
est. Several series of CCR2 antagonists have already been described
in the literature.13–27 Recently, we disclosed both the phenyl pipe-
ridinyl derivatives as CCR2 antagonists with submicromolar bind-
ing affinity and the more potent carboxylic acid/alcohol analogs
with IC50 in the nanomolar range.28–30 We now in this communica-
tion report the identification of 7-azaindole piperidine derivatives
as potent CCR2 antagonists and present the synthesis and struc-
ture–activity relationship (SAR) studies.
Initial SAR studies on the CH2 linker between the two piperi-
dines revealed that carboxylic acid derivative 1d and hydroxy-
methyl derivative 1e showed a marked improvement in CCR2
binding affinity relative to the unsubstituted methylene, amide,
and ester analogs (Table 1). Hydroxy-methyl derivative was more
potent than carboxylic acid derivative. Therefore, we decided to
explore more SAR of the hydroxymethyl series. The synthesis of
carboxylic acid 1d is outlined in Scheme 1.
Compound 3-(3,4,5-trifluoro-phenyl)-acryloyl chloride (2) was
reacted with piperidin-4-yl-acetic acid ethyl ester to give {1-
[3,4,5-trifluoro-phenyl)acryloyl]-piperidin-4-yl}-acetic acid ethyl
ester (3), which was converted to a-bromo-acid 5 through bromin-
ation (LHMDS/TMSCl, Br2) and ester hydrolysis. Bromoacid 5 was
refluxed with 3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine in aceto-
nitrile to afford the carboxylic acid compound 1d.
When the carboxylic acid moiety was replaced with a hydroxyl-
methyl group the CCR2 binding affinity of the corresponding com-
pound was improved into single digital nanomolar region. Scheme
2 outlines the synthesis of alcohol analogs.
Boc-protected piperidin-4-yl-acetic acid ethyl ester 6 was con-
verted to
a-bromo-ester 7 through bromination (LHMDS/TMSCl,
Table 1
Functional group effect on CCR2 binding affinity
R
O
N
F
N
N
F
N
H
F
Compound
R
CCR2 IC50 (nM)
1a
1b
1c
1d
1e
CO2Et
H
CONH2
CO2H
CH2OH
1900
1300
960
17
* Corresponding author. Tel.: +1 609 409 3485; fax: +1 609 655 6930.
E-mail addresses: mxia@prdus.jnj.com, mingde_xia@hotmail.com (M. Xia).
7
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.061

M. Xia et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6468–6470
6469
H
N
N
O
O
Br
O
Br
O
Cl
O
HO
O
N
HO
O
N
N
N
(iv)
O
(ii)
(iii)
(i)
O
O
1e
N
F
F
O
F
F
F
F
F
F
F
F
F
F
F
1d
4
5
2
3
F
F
Scheme 1. Synthesis of carboxylic acid 1d. Reagents and conditions: (i) Piperidin-4-ylacetic acid ethyl ester, TEA, 75%; (ii) LiHMDS, TMSCl, À78 °C, then Br2, 60%; (iii) LiOH,
98%; (iv) 3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine, CH3CN, TEA, reflux, 38%.
CO2Et
(iii)
COOEt
COOEt
N
Boc
(i)
(ii)
N
N
N
Boc
N
Boc
Br
N
H
8
6
7
O
CH2OH
CH2OH
R1
(iv)
N
N
Boc
X
N
N
N
N
N
H
N
H
9
1e, 10a-c
Scheme 2. Synthesis of alcohol analogs. Reagent and conditions: (i) LHMDS, TMSCl, À78 °C, then Br2, 82%; (ii) 3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine, CH3CN, N(i-Pr)2Et,
reflux, 44%; (iii) LAH, 0 °C, 95%; (iv) a—TFA; b—ArCH@CHCOCl, or ArNCO, 22–87%.
Br2). Compound 7 was then refluxed with 3-piperidin-4-yl-1H-pyr-
rolo[2,3-b]pyridine in acetonitrile to afford ester 8, which was
reduced to alcohol 9 with lithium aluminum hydride. Alcohol 9
was converted to the target compounds 1e and 10a–c via deprotec-
tion of the Boc group with TFA, and acylation with appropriate acid
chloride or isocyanate.
The 7-azaindole piperidine series showed similar SAR with that
of the previously reported indole piperidine series,29,30 but was
found to have improved solubility. Table 2 lists CCR2 membrane
binding affinities for the most potent analogs. Halogen substitution
on the 3-, 4-, or 5-position of the cinnamoyl phenyl ring was pre-
ferred. The urea-containing compound 10c also possessed signifi-
cant affinity for the CCR2.
Compounds 1e and 10a–c were initially prepared as their race-
mates. In order to determine if there was a difference in binding
affinity between the two enantiomers of 10a, the (S) enantiomer
was prepared from the chiral chloro-acid 11 through the synthetic
route outlined in Scheme 3.
Compound 11 was refluxed with 3-piperidin-4-yl-1H-pyrrol-
o[2,3-b]pyridine in acetonitrile to give the amino acid 12, which
was converted to ester 13 with (trimethylsilyl)diazomethane. Ester
13 was reduced to alcohol 14 with LAH. Alcohol 14 was converted
to the target compound 15 via removal of the Boc group with TFA,
and acylation with appropriate acid chloride.
Compound 15 possessed an hCCR2 membrane binding IC50 of
4 nM and was selected for further evaluation. During the CYP450
study (using cDNA expressed human enzymes), it showed rela-
tively clean profile with IC50s of >40
2C19, 13.3 for 2D6, 25.2 for 3A4(BFC), >40
3A4(BQ) and 20.6 M for 3A4 (DBF). The bioavailability of com-
l
M for 1A2, 27.1
l
M for
Table 2
lM
lM
lM for
CCR2 binding affinities of alcohol analogs
l
HOH2C
pound 15 in rats was 36% with po (Cmax 341 ng/ml, T1/2 5.6 h) at
O
10 mg/kg dosage (vehicle 20% HPBCD in water).
N
N
In summary, a series of 7-azaindole piperidine derivatives have
been synthesized and the carboxylic acid 1d and alcohol 1e have
been identified as potent CCR2 antagonists. Those compounds
were found to possess significantly higher affinity for the human
CCR2 receptor than the ester 1a, amide 1c, and unsubstituted ana-
log 1b. Alcohol analogs 1e, 10a, and 10b showed IC50 values in the
nanomolar range. Compound 15 showed reasonable P450 and
pharmacokinetics profiles. Further studies in this series that ad-
dress pharmacology profile will be reported in due course.
R1
X
N
N
H
Compound
X
R1
CCR2 IC50 (nM)
1e
CH@CH
CH@CH
CH@CH
NH
3,4,5-TriF
3,5-DiF
3,4-DiCl
3,4-DiCl
7
6
6
10a
10b
10c
14

6470
M. Xia et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6468–6470
H
N
H
N
H
N
H
N
N
N
N
N
OH
Cl
O
N
N
(i)
N
(ii)
O
O
(iv)
N
(iii)
O
HO
HO
HO
N
N
N
O
O
N
N
O
O
O
O
O
O
O
F
F
14
11
12
13
15
Scheme 3. Synthesis of chiral alcohol. Reagents and conditions: (i) 3-Piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine, CH3CN, Na2CO3, reflux; (ii) TMSCHN2, MeOH, 22% for two
steps; (iii) LAH, 0 °C, 97%; (iv) a—TFA; b—3-(3,5-difluoro-phenyl)-acryloyl chloride, 50%.
17. Butora, G.; Jiao, R.; Parsons, W. H.; Vicario, P. P.; Jin, H.; Ayala, J. M.; Cascieri, M.
Acknowledgment
A.; Yang, L. Bioorg. Med. Chem. Lett. 2007, 17, 3636.
18. Yang, L.; Butora, G.; Jiao, R. X.; Pasternak, A.; Zhou, C.; Parsons, W. H.; Mills, S.
We thank Dr. Marlon Zhong for the synthetic method of chiral
starting material.
G.; Vicario, P. P.; Ayala, J. M.; Cascieri, M. A.; MacCoss, M. J. Med. Chem. 2007, 50,
2609.
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M.; Vicario, P. P.; Patel, S. R.; Wisniewski, T.; DeMartino, J. A.; Vernier, J. Bioorg.
Med. Chem. Lett. 2007, 17, 807.
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