Aryl sulfones as novel Bradykinin B1 receptor antagonists for treatment of chronic pain

Article abstract of DOI:10.1016/j.bmcl.2008.07.108

We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.

Full text of DOI:10.1016/j.bmcl.2008.07.108

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4764–4769
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Aryl sulfones as novel Bradykinin B1 receptor antagonists
for treatment of chronic pain
a
a
a
a
Kaustav Biswas a, , Toshihiro Aya , Wenyuan Qian , Tanya A. N. Peterkin , Jian Jeffrey Chen ,
Jason Human a, Randall W. Hungate a, Gondi Kumar b, Leyla Arik c, Dianna Lester-Zeiner a,
Gloria Biddlecome a, Barton H. Manning c, Hong Sun c, Hong Dong c, Ming Huang c, Richard Loeloff c,
Eileen J. Johnson c, Benny C. Askew a
*
a Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, MS 29-1-B, Thousand Oaks, CA 91320, USA
b Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
c Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker
region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to com-
pound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 13 July 2008
Revised 23 July 2008
Accepted 28 July 2008
Available online 31 July 2008
Keywords:
Bradykinin antagonist
Chronic pain
Aryl sulfone
The kinins, bradykinin (BK), kallidin (Lys-BK), and their des-
Arg[9/10] metabolites, are vasoactive peptides that are implicated
in the propagation of pain and inflammation. They are released in
response to tissue injury.1 They transmit their effects by activating
two G-protein coupled receptors termed the B1 and B2 receptors.
BK and Lys-BK preferentially bind to the constitutively expressed
B2 receptor, which after agonist stimulation is rapidly desensitized
and internalized. The B1 receptor, in contrast, is induced following
tissue injury and/or inflammation, and is preferentially activated
by the longer-lasting des-Arg[9/10] metabolites of BK and Lys-
BK.2 Preclinical studies suggest that the B2 receptor plays a signif-
icant role in acute pain processing, while the B1 receptor has been
implicated in establishing and maintaining the signaling for
chronic pain.3
induced diabetes, chronic constriction injury, and partial sciatic
nerve lesion.5
In addition to peptide antagonists, reports with small-molecule
antagonists have also offered corroboration of the role that the B1
receptor plays in chronic pain.6 These experiments have demon-
strated the efficacy of lead compounds in pain and/or biochemical
challenge models, such as inflammatory hyperalgesia, neuropathic
pain, spinal nociceptive reflex, and B1-mediated hypotension.
H
H
R2
N
N
H
R
ArSO2
N
S
O
X
O
O
R1
O
Recently, extensive preclinical research supporting the validity
of the B1 receptor as a target for treatment of chronic pain has been
published. Peptide antagonists of this receptor have been shown to
reverse neurogenic pain induced by capsaicin, and inflammatory
pain induced by UV irradiation, carrageenan, complete Freund’s
adjuvant, or bacterial lipopolysaccharide (LPS).4 Established hyper-
algesia has been shown to be reversed by synthetic peptide B1
antagonists in models of neuropathic pain like streptozotocin-
R
N
N
1, Ar = 2-Naphthyl, X = O, R = H
4, R1 and R2 = H/Aryl/OH/alkoxy
2, Ar = 2-Naphthyl, X = CH2, R = H
3, Ar = 3-CF3-Ph, X = O, R = F
* Corresponding author. Tel.: +1 805 447 4836; fax: +1 805 480 1337.
Figure 1. Lead arylsulfonamide-based bicyclic amine B1 antagonists and analogous
E-mail address: kbiswas@amgen.com (K. Biswas).
sulfones.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.108

K. Biswas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4764–4769
4765
These studies support the search for oral small-molecule B1 antag-
onists as therapy for chronic pain.
OMe
(a)
(b)
OEt
ArS
O
OH
O
Our initial investigations led to arylsulfonamide lead com-
pounds containing bicyclic amine carboxamide moieties (Fig. 1).7
Structure–activity relationship (SAR) studies on the initial leads 1
and 2 identified compound 3, which showed modest efficacy in
two rabbit in vivo models, a B1-mediated hypotension biochemical
challenge model and an efficacy model of inflammatory pain.8
While these sulfonamides were excellent proof-of-concept mole-
cules, we continued to seek analogs with improved pharmacoki-
netic and pharmacodynamic properties. In particular, we hoped
to address the high human and rat liver microsomal clearance ob-
served with these leads (see compound 2 in Table 1) by making
changes to the molecular framework of these compounds.
O
12
11
OMe
(c)
ArSO2
OH
(d)
ArSO2
OR
O
OR
O
13a: R = H
14a: R = H
14b: R = Me
13b: R = Me
H
N
ArSO2
(e)
OR
O
In designing alternative B1 antagonists toward these goals, we
sought to introduce small, polar groups in the linker region in com-
bination with searching for replacements for the lipophilic aryl
ring of the b-arylglycine core. These investigations, we hoped,
would ameliorate the observed oxidative instability in microsomal
preparations. Modifying the sulfonamide in compounds 1–3 to the
corresponding sulfone moiety (substitution of the N–H unit by a
CH2 fragment) would allow the replacement of the core aryl ring
with groups like hydroxyl and ether groups, compounds previously
unattainable due to unstable aminal-like structures. Hence, as part
of this SAR study, we decided to prepare sulfones of the general
structure 4 (Fig. 1). Herein, we report on the identification and
optimization of aryl sulfone-based B1 antagonists, which led to
lead compounds with improved efficacy compared to sulfonamide
3 in animal models for evaluation of in vivo activity.
15a: R = H
15b: R = Me
N
Ar = 2-Naphthyl
Scheme 2. Reagents and conditions: (a) 2-naphthalenethiol, K2CO3, MeOH, 82%; (b)
OxoneÒ, methanol, water, 0 °C–rt, 92%; (c) MeI, NaH, DMF, 0 °C, 76%; (d) LiOH, THF,
water, 98% for 14a, 99% for 14b; (e) (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-
hydronaphthalen-1-amine, EDCI, HOBt, DMF, 68% for 15a, 80% for 15b.
rane ethyl ester 11 was treated with sodium 2-naphthalenethiolate
in methanol, resulting in ring-opened alcohol 12. Oxidation affor-
ded sulfone 13a. The alcohol was converted to the methyl ether
with iodomethane for analog 13b. The corresponding esters were
deprotected and individually coupled to (R)-6-(piperidin-1-yl-
methyl)-1,2,3,4-tetrahydronaphthalen-1-amine in the usual man-
ner, affording the desired final compounds.
The diastereomeric alcohol 16 was prepared from intermediate
13a. Oxidation of the alcohol to a ketone, reduction to the racemic
alcohol with sodium borohydride, and chiral separation with SFC
afforded the enantiomer ent-13a, which was then converted to
the final compound in a sequence similar to Scheme 2.
The compounds that were synthesized as part of this study are
shown in Tables 1 and 2, and their preparations are described in
Schemes 1–3.9 Scheme 1 outlines the synthesis of the sulfone
analog of sulfonamide 2, compound 9. Tetrahydrofuran 6 was
obtained from aniline (5) via conversion to the diazonium salt,
Pd(0)-mediated Heck reaction with dihydrofuran and trapping
with methanol.10 Jones oxidation gave lactone 7, reaction of which
with 2-naphthalenethiolate sodium salt afforded sulfide 8. Oxida-
tion with OxoneÒ and amide bond formation with (R)-6-(piperi-
Diastereomeric hydroxyl analogs 17 and 18a were prepared via
the lactone ring-opening procedure outlined in Scheme 1, from
corresponding commercially available chiral hydroxy-butyrolac-
din-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine11
the final compound 9. Compound 10 was synthesized from
rolactone using a similar protocol.
gave
-buty-
c
Scheme 2 illustrates the synthesis of the hydroxyl and methyl
ether analogs 15a and 15b. The commercially available chiral oxi-
O
O
O
OH
(a)
(c)
(b)
O
O
O
OH
O
O
O
OMe
NH2
O
(c)
(b)
O
ArSO2
(a)
ArS
O
O
21
19
20
5
6
7
O
OH
H
H
H
O
N
N
N
(d) ArSO2
ArSO2
(d)
OH
O
OH
O
ArS
O
ArSO2
O
N
N
N
23
22
Ar = 2-Naphthyl
9, Ar = 2-Naphthyl
8, Ar = 2-Naphthyl
Scheme 1. Reagents and conditions: (a) sodium nitrite, 1 M HCl, 0 °C, then
dihydrofuran, Pd(OAc)2, MeOH, 71%;9 (b) Jones reagent, acetone, 91%; (c) 2-
naphthalenethiol, NaH, DMF, 0 °C, then 7, 100 °C, 91%; (d) (i) OxoneÒ, MeOH,
dioxane, water, 88%; (ii) (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphtha-
len-1-amine, EDCI, HOBt, DMF, 75%.
Scheme 3. Reagents and conditions: (a) 2-naphthalenethiol, NaH, DMF, 0 °C, then
19, 80 °C, 91%; (b) OxoneÒ, methanol, water, 94%; (c) (R)-6-(piperidin-1-ylmethyl)-
1,2,3,4-tetrahydronaphthalen-1-amine, EDCI, HOBt, DMF, 69%; (d) HCl (4.0 M in
dioxane), methanol, 100%.

4766
K. Biswas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4764–4769
tones. Methyl ether analog 18b was prepared from iodomethane-
mediated alkylation of the corresponding hydroxyl analog inter-
mediate obtained during the synthesis of 18a.
Finally, the synthesis of diol 23 is shown in Scheme 3. Ring
opening of the commercially available erythronolactone ketal 19
with 2-naphthalenethiolate anion afforded acid 20. Oxidation to
the sulfone, peptide bond formation, and ketal deprotection with
dilute hydrochloric acid afforded the final compound.
The compounds synthesized as part of this study were tested in
a human B1 receptor binding assay and a human B1 agonist-in-
duced aqueorin-based calcium flux assay in Chinese hamster ovary
cells.7 This discussion is focused on the binding assay data,
although similar trends were seen in the functional assay. SAR of
the linker region is described in Table 1. Initially, sulfonamide 2
was compared to the corresponding sulfone analog 9. Encourag-
ingly, the resulting modest sixfold loss in binding affinity showed
that the N–H moiety was not an absolute requirement for binding.
The high metabolic clearance in human liver microsomal assays,
however, remained with the modification to compound 9. To fur-
The diol compounds shown in Table 2 (compounds 24–32) were
prepared by the method outlined in Scheme 3 using corresponding
commercially available aryl thiols in the first step.
Table 1
SAR of linker region: hB1 binding and functional assay data
O
S
H
Linker
N
O
O
N
Compound
Linker
hB1
HLM (lL/min/mg)
RLM (lL/min/mg)
a
Binding Kia (nM)
Aqn IC50 (nM)
H
N
2
0.24 0.03
5.5 0.7
919
572
Ph
9
1.5
13.7 2.5
74.8 9.3
48.9 7.9
107 21
744
50
167
100
100
ND
Ph
10
15a
16
59.9
41.4 9.5
100
112
ND
OH
OH
OH
17
19.1
30.8 2.8
50.6 7.0
16.8 5.6
79 21
100
100
274
216
100
143
50
OH
18a
15b
18b
23
23.5 5.0
6.4 0.5
169 56
1.7 0.7
316
237
186
OMe
OMe
OH
4.0 0.3
OH
HLM, RLM n = 1. ND, not determined.
a
Values reported are an average of at least 3 determinations with the SEM, unless otherwise noted (values without SEM represent the average of 2 determinations).

K. Biswas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4764–4769
4767
Table 2
SAR of aryl region: human and rabbit B1 Ki and IC50 data
OH
H
Ar
N
S
O
O
OH
O
N
a
Compound
Ar
hB1
Rabbit B1 Aqn IC50 (nM)
HLM (
lL/min/mg)
RLM (lL/min/mg)
a
Binding Kia (nM)
Aqn IC50 (nM)
23
24
25
26
27
28
29
30
31
32
2-Naphth
Ph
2-CF3-Ph
3-CF3-Ph
4-CF3-Ph
3-Cl-Ph
4-Me-Ph
4-tBu-Ph
3,4-di-Cl-Ph
2,3-di-Cl-Ph
1.7 0.7
565 86
43.8 4.4
4.1 0.4
48.4 9.7
54.4 10.7
138 26
15.8
4.0 0.3
977
297.2
4.3 1.0
44.9
39.2 12.2
84.2 9.5
4.5 0.8
17.1 4.5
9.9
20.0 1.8
ND
ND
11.2 1.9
210
85.9 7.8
ND
25.3 6.2
20.3 3.8
141
100
319
ND
100
50
180
50
296
100
214
186
50
ND
50
50
139
50
50
193
50
16.9
12.7 3.1
HLM, RLM n = 1. ND, not determined.
a
Values reported are an average of at least 3 determinations with the SEM, unless otherwise noted (values without SEM represent the average of 2 determinations).
ther address this metabolism, we began exploring variations in the
linker region. We decided to replace the phenyl moiety with select
polar functional groups to test the hypothesis that improving
polarity might reduce oxidative metabolism. To establish this
SAR, the 2-naphthyl sulfone and the tetralin benzylic amine moie-
ties were kept unchanged.
We established in vivo models in rabbits since these B1 antag-
onists are not potent at the rodent B1 receptors, but show cross-
reactivity with the rabbit.8 In order to examine the in vivo efficacy
of our leads, we sought to optimize the SAR for compounds which
show potency at both the human and rabbit B1 receptors. Thus, we
also obtained rabbit B1 IC50s from a functional assay to establish
the corresponding SAR at the rabbit receptor. Compound 23 was
examined initially, and it was shown to be a potent antagonist
(rabbit B1 IC50 = 20 nM). Consequently, we next explored the SAR
of the aryl region in compound 23 to identify analogs of the lipo-
philic naphthyl domain that while maintaining potency might
show further improvements in pharmacokinetic or pharmacody-
namic parameters (vide supra). The B1 binding and functional assay
data are shown in Table 2.
The phenyl sulfone 24 lost potency, with hB1 Ki = 565 nM. Sub-
stitution with lipophilic functional groups on the aryl ring, how-
ever, improved the hB1 binding affinity. First, we synthesized the
2-, 3-, and 4-trifluoromethyl substituted phenyl sulfones (com-
pounds 25–27). The 3-trifluoromethylphenyl sulfone 26 was most
potent, with hB1 Ki = 4.1 nM. The corresponding 3-chlorophenyl
analog 28 was 30-fold less potent than 23, with hB1 Ki = 54.4 nM.
The 4-tolyl analog 29 lost potency, while the 4-tert-butylphenyl
sulfone 30 was ninefold less potent than 23 (hB1 Ki = 15.8 nM).
The di-chlorophenyl substituted analogs 31 and 32 were similar
in potencies, with Kis of 16.9 and 12.7 nM, respectively.
Compound 10, with the unsubstituted 3-carbon linker, lost
affinity, with Ki = 59.9 nM. The (S)-hydroxyl analog of 9, com-
pound 15a, exhibited a Ki = 41.4 nM, while the corresponding
(R)-hydroxyl analog 16 had a Ki = 100 nM. Moving the hydroxyl
group one carbon towards the amide carbonyl moiety afforded
compounds 17 and 18a, which had hB1 Kis of 19.0 and
23.5 nM, respectively. The methoxy analog of 15a, compound
15b, was only fourfold less potent than 9 (Ki = 6.4 nM), while
the methylated analog of 18a, compound 18b, was less potent
(Ki = 169 nM). Examination of the liver microsomal assay data
showed that while the hydroxyl compounds (15a, 17, and 18a)
possessed improved stability, both methoxy analogs, compounds
15b and 18b, were susceptible to greater metabolism. Finally,
incorporation of both hydroxyl groups in the same molecule in
the 2R, 3S-configuration afforded compound 23, which restored
binding affinity equivalent to analog 9. In terms of metabolic
profiling of these analogs, a general trend emerged indicating
that the hydroxyl group modification conferred the most advan-
tage with regard to stability in liver microsomal assays. This im-
proved metabolic stability, together with the potent binding
affinity, directed us toward further optimization of compound
23.
The 3-trifluoromethylphenyl sulfone 26 was the most potent on
rabbit B1 receptor as well (IC50 = 11.2 nM). Compounds 23, 30, and
31 also had rabbit IC50s in the 20–25 nM range.12
Table 3
Pharmacokinetic parameters of compounds 23 and 26
Compound
Rat in vivo PK
Cla (L/h/kg)
Human PPB (%)
Rabbit PPB (%)
Fb (%)
a
a
t1/2 (h)
Vss (L/kg)
23
26
2.99
4.74
4.6
7.3
6.0
27.9
14
18
97.54
71.79
95.26
78.38
t1/2 = half-life, Cl = clearance, Vss = volume of distribution, F = oral bioavailability, PPB = plasma protein binding.
a
Sprague–Dawley rats dosed i.v. at 3 mg/kg in 100% water/methanesulfonic acid (pH 3.0).
Sprague–Dawley rats dosed p.o. (same dose and formulation).
b

4768
K. Biswas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4764–4769
Figure 2. (A) Compound 23 and (B) compound 26 reduce DAK-induced hypotension. For details, see Ref. 8. The x-axis shows the measured plasma concentration of the
compound. In this study, the plasma IC50 for compound 23 is 2500 nM (CI95% 1277–5010 nM, R2 = 0.6616), while that for compound 26 is 127 nM (CI95% 34–459 nM,
R
2 = 0.8191).
Pharmacokinetic parameters of the compounds with highest
Figure 2, both compounds, injected subcutaneously (s.c.), reversed
this hypotension effect in a dose-dependent fashion, with plasma
IC50s of 2500 nM (compound 23) and 127 nM (compound 26).
Interestingly, both compounds are more potent in this model than
our previously described lead compound, sulfonamide 3.14
In a model of inflammatory pain, mechanical hyperalgesia was
induced in the rabbit hind paw using local injection of carrageenan.
Systemic (s.c.) injection of either compound reversed hyperalgesia
when administered 2 h after carrageenan (Fig. 3).15 Compound 26
was more efficacious, with a plasma EC50 = 402 nM, while com-
pound 23 exhibited a plasma EC50 = 3600 nM. This rank order of
the two compounds parallels the results found in the biochemical
challenge model. In addition, both sulfones were also more effica-
cious than sulfonamide 3, which showed a maximal reversal of
45.5% at a 10 mg/kg dose. The higher efficacy seen with 26 might
perhaps be attributable to the higher free fraction of drug present,
compared to 23.
In summary, we report the identification of aryl sulfone-based
B1 antagonists. The replacement of the sulfonamide N–H fragment
with a CH2 unit allowed the introduction of polar replacements of
the lipophilic core aryl group in 1–3, where it was found that incor-
poration of hydroxyl groups leads to the largest benefit in attenu-
ating metabolic instability. SAR of the linker region led to selection
of the (2R,3S)-2,3-dihydroxy-butanamide moiety (compound 23)
hB1 binding affinity, compounds 23 and 26, were profiled next.
These data are shown in Table 3. In rats, compound 23 had a
half-life of 3 h, high clearance, and low oral bioavailability of
14%. Similarly, compound 26 had a half-life of 4.7 h, high clearance,
and oral bioavailability of 18%. As seen in Table 2, both compounds
showed lower susceptibility to metabolism in liver microsomes,
suggesting other mechanisms for the high rat in vivo clearance.
One major difference emerged in plasma protein binding, with
the 3-trifluoromethyl analog 26 being less bound in both human
and rabbit plasma (in vivo models were developed in rabbits, see
below). This encouraging finding was next examined in context
of in vivo activity of these compounds.
We tested compounds 23 and 26 in two rabbit pharmacody-
namic models described previously.8 In the first biochemical chal-
lenge model, administration of LPS upregulates B1 receptors, and
B1 agonists (e.g., DAK: des-Arg10-Kallidin) induce a hypotensive re-
sponse.13 This effect can be reversed with B1 antagonists.8 Rabbits
were treated with five different doses of compounds, followed by
repeat administration of the agonist DAK at two different time
points (30 and 75 min). Blood samples were collected prior to
the DAK administrations to obtain plasma concentrations of each
compound, which were correlated with the hypotensive responses,
thus generating two data points for each dose (Fig. 2). As seen in
Figure 3. Antinociceptive effects of test compounds 23 and 26 in a rabbit inflammatory pain model (carrageenan-induced mechanical hyperalgesia). Plasma levels of both
compounds are also included for each dose. The vehicle was 20% CaptisolÒ in water. *P < 0.05, **P < 0.01, one-factor ANOVA followed by Dunnett’s post hoc multiple
comparison test, as compared with the vehicle (s.c.) group.

K. Biswas et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4764–4769
4769
Okamoto, H.; Nara, Y.; Matsuzaki, S.; Hoka, S.; Majima, M. Inflamm. Res.
2003, 52, 164; (h) Gabra, B. H.; Merino, V. F.; Bader, M.; Pesquero, J. B.;
Sirois, P. Regulatory Peptides 2005, 127, 245.
for further exploration of the aryl region. The 3-trifluoromethyl-
phenyl group (compound 26) emerged as a potent replacement
for the naphthyl moiety, in terms of activity at both the human
and rabbit B1 receptors. Both compounds showed activity in two
rabbit in vivo models, and are more potent than our previously de-
scribed lead, sulfonamide 3. Compound 26 is more efficacious in
both the rabbit blood pressure model and the carrageenan-induced
mechanical hyperalgesia pain model, suggesting the possible role
of greater unbound drug concentration.
6. For
a recent review, see: Chen, J. J.; Biswas, K.. In Progress in Medicinal
Chemistry; Lawton, G., Witty, D. R., Eds.; Elsevier, 2008; Vol. 46, p 173. and
references therein.
7. D’Amico, D. C.; Aya, T.; Human, J.; Fotsch, C.; Chen, J. J.; Biswas, K.; Riahi, B.;
Norman, M. H.; Willoughby, C. A.; Hungate, R.; Reider, P. J.; Biddlecome, G.;
Lester-Ziener, D.; Van Staden, C.; Johnson, E.; Kamassah, A.; Arik, L.; Wang, J.;
Viswanadhan, V. N.; Groneberg, R. D.; Zhan, J.; Suzuki, H.; Toro, A.; Mareska, D.
A.; Clarke, D. E.; Harvey, D. M.; Burgess, L. E.; Laird, E. R.; Askew, B.; Ng, G. J.
Med. Chem. 2007, 50, 607.
8. Biswas, K.; Li, A.; Chen, J. J.; D’Amico, D. C.; Fotsch, C.; Han, N.; Human, J.; Liu,
Q.; Norman, M. H.; Riahi, B.; Yuan, C.; Suzuki, H.; Mareska, D. A.; Zhan, J.;
Clarke, D. E.; Toro, A.; Groneberg, R. D.; Burgess, L. E.; Lester-Zeiner, D.;
Biddlecome, G.; Manning, B. H.; Arik, L.; Dong, H.; Huang, M.; Kamassah, A.;
Loeloff, R.; Sun, H.; Hsieh, F.-Y.; Kumar, G.; Ng, G. Y.; Hungate, R. W.; Askew, B.
C.; Johnson, E. J. Med. Chem. 2007, 50, 2200.
9. These compounds were characterized by 1H NMR and MS, and their purity was
determined to be greater than 95% by HPLC.
10. Mehta, G.; Sengupta, S. Tetrahedron Lett. 1996, 37, 8625.
Acknowledgment
The authors thank Dr. Jennifer R. Allen and Dr. Christopher
Fotsch for critical reading of this letter.
References and notes
11. Obtained from (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol
(tetralin amino alcohol) in 4 steps by (i) t-Boc protection of the amine, (ii)
oxidation of alcohol to aldehyde by manganese dioxide, (iii) reductive
amination with piperidine and (iv) t-Boc deprotection by HCl. For the
tetralin amino alcohol, see: Fotsch, C.; Biddlecome, G.; Biswas, K.; Chen, J. J.;
D’Amico, D. C.; Groneberg, R. D.; Han, N.; Hsieh, F.-Y.; Kamassah, A.; Kumar,
G.; Lester-Zeiner, D.; Liu, Q.; Mareska, D. A.; Riahi, B. B.; Wang, Y.-J. J.; Yang,
K.; Zhan, J.; Zhu, J.; Johnson, E.; Ng, G.; Askew, B. C. Bioorg. Med. Chem. Lett.
2006, 16, 2071.
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