Novel substituted 4-aminomethylpiperidines as potent and selective human β3-agonists. Part 2: Arylethanolaminomethylpiperidines

Article abstract of DOI:10.1016/S0960-894X(02)00608-X

The synthesis and SAR of a series of β₃ adrenoreceptor agonists based on a novel template derived from 4-aminomethylpiperidine coupled with a common pharmacophore, arylethylamine, is described. This combination led to the identification of human β₃ adrenoreceptor agonists with in vivo activity in a transgenic mouse model.

Full text of DOI:10.1016/S0960-894X(02)00608-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2963–2967
Novel Substituted 4-Aminomethylpiperidines as Potent
and Selective Human ꢀ3-Agonists. Part 2:
Arylethanolaminomethylpiperidines
Robert J. Steffan,a,* Mark A. Ashwell,a William R. Solvibile,a Edward Matelan,a
Elwood Largis,b Stella Han,b Jeffery Tilletb and Ruth Mulveyb
aChemical Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA
bCardiovascular/Metabolic Diseases, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA
Received 13 March 2002; accepted 1 July 2002
Abstract—The synthesis and SAR of a series of b3 adrenoreceptor agonists based on a novel template derived from 4-amino-
methylpiperidine coupled with a common pharmacophore, arylethylamine, is described. This combination led to the identification
of human b3 adrenoreceptor agonists with in vivo activity in a transgenic mouse model.
# 2002 Elsevier Science Ltd. All rights reserved.
Stimulation of b3 adrenoreceptors (AR), expressed on
the cell surface of adipocytes in brown and white adi-
pose tissue, is viewed as a potential treatment for obe-
sity and non-insulin-dependent diabetes mellitus.
Agonists1 of the b3-AR activate an intracellular signal-
ing process in which initiates lipolysis of triglycerides.
The resulting free fatty acids are processed by uncou-
pling protein (UCP) leading to thermogenesis.
Figure 1. The metabolically unstable arylmethoxy link-
age of the aryloxyaminomethylpiperidines was replaced
by a direct bond.
Variations to the aryl moiety and the R-group were
prepared to find the optimal substitutents for b3-AR
agonism while at the same time maintain the good
selectivity over the other b AR’s seen in the earlier aryl-
oxypropanolaminomethylpiperidines.1 The arylethano-
laminomethylpiperidines of Figure 1 were prepared by
reductive amination of a chiral arylethanolamine with a
4-formylpiperidine optimally substituted at the 1 posi-
tion (Scheme 1).
Early efforts by our group in the b3-AR agonist program
at Wyeth identified selective agonists to human b3-AR
which were based on a hybrid template of chiral aryloxy-
propanolamines, common to b-AR antagonists, and 4-
aminomethylpiperidines.2 These compounds were found
to be potent in vitro compounds to CHO cells transfected
with the human b3 adrenoreceptor. They were also selec-
tive over the other b-AR’s but showed low bioavailability
and metabolic cleavage of the aryl ether bond when incu-
bated with human microsomes in the presence of NADH.
The arylethanolamines were prepared as outlined in
Schemes 2–4. The 4-hydroxy-3-methansulfonamido-
phenyl analogue 4 was prepared starting from the opti-
mally substituted acetophenone 1. Chlorination with
benzyltrimethylammonium tetrachloroiodate3 gave
almost exclusively the monochlororinated intermediate
2. Selective reduction with borane in the presence of
(R)-2-methyl-CBS-oxazaborolidine4 in THF gave the
chiral alcohol 3. The chlorine was then converted to the
azide by treatment with sodium azide and sodium
iodide in DMF. Hydrogenation of the azide provided
the chiral phenethanolamine 4.
With the desire to prepare more metabolically stable ana-
logues and improve bioavailability, our recent synthetic
efforts have focused on modifying the aryloxy-
propanolaminomethylpiperidine template to the aryl-
ethanolaminomethylpiperidine template as shown in
The achiral indole 8 was prepared using literature con-
ditions5 from 5, obtained by Friedel–Crafts reaction of
*Corresponding author. Fax:+1-484-865-9398; e-mail: steffar@
wyeth.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00608-X

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1-acetylindoline with chloroacetylchloride. The diacyl-
N-benzyl compound 6 was deprotected with soduim
hydroxide to give the intermediate 7. Sequential oxida-
tion with manganese dioxide followed by hydrogenation
over palladium on carbon provided the arylethanola-
mine 8.
The synthesis of the intermediate 12, a related analogue
of 4, is outlined in Scheme 4. Selective reduction of 5
with borane in the presence of (R)-2-methyl-CBS-oxa-
zaborolidine4 in THF gave the chiral alcohol 9. Selective
nitration of 9 to give 10 was accomplished by reaction
with sodium nitrate in trifluoroacetic acid.6 Reduction
of the nitro group followed by sulfonylation with
methansulfonyl chloride gave 11. The chloro of 11 was
converted to the azide with sodium azide and reduced
by hydrogenation to provide the intermediate aryletha-
nolamine 12.
Figure 1. Aminomethylpiperidine template for development of b3
aderenoreceptor agonism.
A variety of benzenesulfonamides substituted with a
ureido function was prepared starting from the acetal of
4-formylpiperidine 13 as outlined in Scheme 5. Follow-
ing sulfonylation, the intermediate 14 could be function-
alized to the urea by reaction with triphosgene and a
second amine or by treatment with a substituted isocy-
anate to give 15. Deprotection was accomplished by
either treatment with TFA of formic acid. The resulting
formylpiperidine 16 was coupled with the intermediate
arylethanol amines by reductive amination to give
compounds represented by the template 17.
Scheme 1. (a) MeOH, HOAc, NaCNBH3, (10–60%).
In place of ureido substituents, benzene sulfonamides
substituted in the 4 posistion with heterocyles such as
indoles or pryazoles were prepared from the 4-F analogue
Scheme 2. (a) C6H5CH2N(CH3)3,+ ICl4ꢀ, 63%; (b) (R+)-2-methyl-
CBS-oxazolborolidin, borane, 95%, 99% ee; (c) NaN3, NaI, H2, Pd/C,
96%.
Scheme 5. (a) THF, DIEA, 90%; (b) triphosgene, RNH2 or RR1NH,
dioxane; (c) TFA (or HCOOH); (d) HOAc, NaCNBH3, 25–50% for
steps b and c.
Scheme 3. (a) NaOH, 90%; (b) MnO2, THF, 95%; (c) H2, 10% Pd/C,
ethanol, 25%.
Scheme 4. (a) (R)-2-methyl-CBS-oxazoborolidine, borane, 33%, 92%
ee; (b) NaNO3, TFA, 40%; (c) H2, Pd/C, 88%; (d) CH3SO2Cl, DIEA;
(e) NaN3, NaI, H2, Pd/C; (f) MnO2, 24% for steps d, e, and f.
Scheme 6. (a) THF, DIEA, 95%; (b) KH, ethyl pyrrole-4-carboxylate,
DMF 118 ꢁC; 18 h, 20%; (c) TFA (or HCOOH), 24%; (d) HOAc,
NaCNBH3,, MeOH, 30%; (e) NaOH aq, reflux, 65%.

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2965
Also prepared were indole-4-carboxylic acid and indole-
2-acetic acid by the route in Scheme 6.
In another series of compounds, the sulfonamide moiety
was replaced by a direct bond. Optimal substitution was
accomplished using the 4-COOH template 24 as shown
in Scheme 7. The intermediate 24 was obtained by first
reaction of 4-hydroxymethylpiperidine with ethyl 4-
fluorobenzoate at reflux in acetonitrile over potassium
carbonate to provide upon oxidation with IBX7 the
aldehyde 23. Following acetal formation, the acid moi-
ety of 24 was funtionalized to a variety of such as the
amides shown in template 26.
Full experimental details for the compounds in the
schemes reported above and following tables are avail-
able in the published patent application.8
A series of analogues was prepared to develop an SAR of a
variety of functional groups at the R and Ar positions of
Figure 1. The first series of compounds focused on ureido
substitutions previously identified in the aryloxypro-
panolaminomethylpiperidine series as an optimal sub-
stituion pattern. Aryl variations were minimal (Table 1).
Scheme 7. (a) K2CO3, CH3CN reflux, 50%; (b) IBX, DMSO, 50 ꢁC,
87%; (c) trimethylorthoformate, MeOH; (d) NaOH, 62% for steps b
and c; (e) DIEA, amino acid, THFC; (f) TFA, (25–28%) for steps e
and f; (g) HOAc, NaCNBH3, MeOH; (h) deprotection of R4.
19 as outlined in Scheme 6. The acetal of 4-formyl-
piperidine was sulfonylated with 4-fluorobenzenesulfonyl
chloride to provide the intermediate 18. The fluorine can
be smoothly substituted by the potassium salt of the
nitrogen heterocycle in DMF at 118ꢁC to provide the
intermediate 4-hetero analogues like 19.
When Ar was 4-hydroxy-3-methanesulfonylphenyl (17
c–e), all the compounds were were full agonists of the
b3-AR (IA’s from 0.93 to 1.0) with good potency
(EC50’s from 5 to 27 nM). The compounds however
showed little separation of activity from b2-AR.
Table 1. In vitro agonist activity at human b-AR’s for Ar and R variations of template 17
Compd
Ar
R
ꢀ-3 EC50 nM (IA)
ꢀ-1 EC50 nM (IA)
ꢀ-2 EC50 nM (IA)
17a
NHoctyl
iaa
ntb
nt
17b
17c
17d
17e
NHoctyl
ia
nt
nt
5 (0.93)
6 (1.0)
27 (093)
3160 (049)
730 (0.56)
6300 (1.21)
30 (0.73)
30 (0.7)
12 (0.89)
Octyl
b-AR agonist activities are expressed as EC50 values by a measurement of cAMP levels in CHO cells expressing human b-ARs intrinsic activity (IA)
was determined as the maximal response of the compound divided by the maximal response of isoproterenol at 10 mM.
aia=Inactive.
bnt=Not tested.

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R. J. Steffan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2963–2967
Table 2. In vitro agonist activity at human b-AR’s for R variations
Compd
R
ꢀ3 EC50 nM (IA)
ꢀ1 EC50 nM (IA)
ꢀ2 EC50nM (IA)
27
11 (0.96)
30 (0.86)
30 (0.81)
28
29
9 (1.0)
50 (1.0)
60 (0.76)
43 (0.93)
31 (1.2)
1000 (0.16)
520 (0.6)
10 (0.34)
20 (0.77)
30
NH(C¼O)Phe
See footnote for Table 1.
b3-AR knockout mice.9 Compound 17d showed an
increase in themogenesis of 10ꢂ5%.
Table 3. In vitro agonist activity at human b-AR’s for R variations
of template
In conclusion, development of SAR around the ary-
lethanolaminomethylpiperidine template of Figure 1
provided several in vitro potent compounds. Com-
pounds that contained the 4-hydroxy-3-methanesulfo-
nylphenyl moiety were most active with EC50’s in the 5–
45 nM range with full agonism to the b3-AR. Most of
these analogues had significant b2-AR agonism except
compounds 29 and the direct bond analogues 31–33. All
of the analogues prepared had weak antagonistic activ-
ity10 at b1-AR and b2-AR when compared to traditional
beta blockers such as propanolol. The Ki’s ranged from
240 nM for 27 and 6600 nM for the in vivo active 17d at
b1-AR and 180 nM for 27 to 140 nM for 17d at b2-AR.
The potent and selective agonists prepared have a
potential use as antiobesity and antihyperglycemic
agents in humans.
Compd
R
ꢀ3 EC50 nM (IA) ꢀ1 EC50 nM (IA) ꢀ2 (IA)
31
32
33
–(C¼O)Asp
–(C¼O)Phe
–(C¼O)Leu
6 (0.95)
31 (1.2)
10 (1.0)
580 (0.64)
520 (0.60)
1860 (0.68)
5 (0.34)
20,000 (0.77)
1000 (0.38)
See footnotes for Table 1.
The next series of analogues included benzenesulfon-
amides substituted with heterocycles and amino acids
combined with the optimal aryl group where Ar=4-
hydroxy-3-methansulfonylphenyl. These analogues
demonstrate some separation of activity between b3-AR
and b2-AR as shown in Table 2.
References and Notes
Compounds retained reasonable potency and agonistic
effects at the b3-AR. A reasonable separation of activ-
ity was also noted in compound 29 for both b1-AR and
b2-AR.
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The compounds prepared were also evaluated in vivo
using transgenic mice containing the human b3-AR and

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