Substituted bridged phenyl piperidines: Orally active growth hormone secretagogues

Article abstract of DOI:10.1016/S0960-894X(03)00261-0

A new series of growth hormone secretagogues have been discovered. The best compound, 26j, shows excellent ability to release growth hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.

Full text of DOI:10.1016/S0960-894X(03)00261-0

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1817–1820
Substituted Bridged Phenyl Piperidines: Orally Active Growth
Hormone Secretagogues
Zhijian Lu,a,* James R. Tata,a Kang Cheng,b Liente Wei,b Wanda W.-S. Chan,b
Bridget Butler,b Klaus D. Schleim,b Thomas M. Jacks,b Gerard Hickeyb
and Arthur A. Patchetta
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Biochemistry and Physiology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 10 October 2002; accepted 19 December 2002
Abstract—A new series of growth hormone secretagogues have been discovered. The best compound, 26j, shows excellent ability to
release growth hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.
# 2003 Elsevier Science Ltd. All rights reserved.
Small molecule growth hormone (GH) secretagogues
have been extensively studied in the past several years.
Research laboratories around the world have reported
rather diverse structures that act similarly in both ani-
mal models and human to release growth hormone.1
From Merck Research Laboratories several classes of
highly active small molecule GH secretagogues have
been reported. They include the biphenyl benzolactams,
such as 1;2 azaspiroindanes, represented by 2;3 spir-
oindanes, like 3;4 3,3-disubstituted piperidine class, like
4;5 and substituted phenyl piperazine series, compound
56 (Fig. 1). In this communication, we report a new
series of the substituted phenyl tropane containing
secretagogues in which the best compound displays
excellent in vitro activity and very good oral activity in
beagles.
with a-chloroethylchloroformate under reflux in
dichloroethane, followed by refluxing in MeOH. The
hydrochloride salt 10 was then coupled with different
amino acid blocks to provide the intermediates which
were deprotected to give final products (Scheme 4). The
synthesis is outlined in Scheme 1.
Exploration of substitutions at the phenyl ortho position
was also carried out based on the results from studies of
compounds 2, 3, and 5. The preparations of these ortho-
substituted intermediates are slightly different from the
above synthesis and they are described in Schemes 2 and
3.
Tropinone 6 was treated with KN(TMS)2 in THF at
ꢀ78 ꢁC, followed by traping with N-phenyl tri-
fluoromethanesulfonimide to give 14 in 75% yield.
Compound 14 was mixed with 2-MePhMgBr, CuI in
THF at 0 ꢁC toafford 15 in 94% yield. Reduction of 15
with Na/NH3 in THF at ꢀ78 ꢁC provided 16 in 82%
yield. Demethylation gave a hydrochloride salt of ortho-
methyl substituted phenyl intermediate 17 (Scheme 2).
Toprepare ester 22, the demethylation of 6 was carried
out first under the conditions described earlier. The
nitrogen atom was then protected with Boc2O togive 18
in 79% yield.
The synthesis of the non-substituted phenyl inter-
mediate 10 started from the commercially available tro-
pinone 6. Treatment of 6 with phenyllithium gave
hydroxy tropane 7 in 24% yield. Acidic dehydration of
7 afforded alkene 8 quantitatively.
Hydrogenation of 8 using Pd on carbon as catalyst in
EtOH at 1 atm provided 9 in excellent yield. Demethyl-
ation was accomplished in 95% yield by treatment of 9
Compound 18 was converted to vinyl triflate 19 (92%) and
vinyl tin 20 (72%). Stille coupling of 20 with ethyl 2-bro-
mobenzoate afforded 21 in 42% yield. Hydrogenation of
*Corresponding author. Tel.: +1-732-594-4392; fax: +1-732-594-
9473; e-mail: zhijian_lu@merck.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00261-0

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Z. Lu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1817–1820
Figure 1. Some highly active GH secretagogues.
Scheme 3. (a) a-Chloroethyl chloroformate, dichloroethane, reflux;
MeOH, reflux; Boc2O, NaOH, i-PrOH, rt, 79%; (b) KN(TMS)2, THF,
ꢀ78 ꢁC; (CF3–SO2)2NPh, ꢀ78 ꢁC, 92%; (c) (Me3Sn)2, LiCl, (Ph3P)4Pd,
THF, reflux, 72%; (d) 2-BrPhCO2Et, (Ph3P)4Pd, toluene, reflux, 42%;
(e) Pd/C, H2, MeOH, 97%; (f) recrystallization from hexane/EtOAc at
0 ꢁC (g) HCl/dioxane, 100%.
21 gave a 1:1 mixture of 22 (97%) which was separated
toisomer 22a and 22b via flash column and recrystalli-
zation7 (Scheme 3). The crystal structure of 22a was
determined by X-ray crystallography. 22a and 22b were
deprotected using HCl in dioxane to give 23a and 23b
quantitatively.
Scheme 1. (a) PhLi, ether, 0 ꢁC!rt, 24%; (b) 48% HBr, 75 ꢁC, 100%;
(c) H2, Pd/C, EtOH, 96%; (d) a-chloroethyl chloroformate, dichloro-
ethane, reflux; MeOH, reflux, 95%.
Conversion of intermediates 10, 17, 23a, and 23b into
the final secretagogues was accomplished via standard
peptide coupling/deprotection reactions as shown in
Scheme 4. The acids were prepared in one additional
step by basic hydrolysis of esters, and the amide was
made by EDC coupling of ethyl amine with the corre-
sponding acid.
All the compounds were evaluated for their ability to
release growth hormone in the rat pituitary cell assay.8
Methyl substituted and non-substituted phenyl amines
10 and 17 were used as a 1:1 mixture of cis/trans iso-
mers. Each of these compounds (26a–d) were moder-
ately potent. Separation of the cis and trans isomers of
Scheme 2. (a) KN(TMS)2, THF, ꢀ78 ꢁC; (CF3–SO2)2NPh, ꢀ78 ꢁC,
75%; (b) 2-MePhMgBr, CuI, THF, 0 ꢁC, 94%; (c) Na/NH3, THF,
ꢀ78 ꢁC, 82%; (d) a-chloroethyl chloroformate, dichloroethane, reflux;
MeOH, reflux.

Z. Lu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1817–1820
1819
Table 1. SAR of bridged substituted phenyl piperidines and A com-
parison to compound 2
Compd 26
R
X
*
EC50 (nM)
a
b
c
d
e
f
g
h
i
Phenylpropyl
3-Indolylmethyl
Phenylpropyl
3-Indolylmetyhyl
Phenylpropyl
Phenylpropyl
Phenylpropyl
Phenylpropyl
Phenylpropyl
Phenylpropyl
H
H
Me
Me
cis+trans
cis+trans
cis+trans
cis+trans
cis+trans
cis
cis
trans
trans
cis
24
62.8
78.4
33.2
90
CO2Et
CO2Et
CO2H
CO2Et
CO2H
CONHEt
48
9.6
324
>500
1.3
j
2
1.0
Data from the rat pituitary cell assay. The results are from a single
experiment. All EC50 are normalized against standards, compound 1
(EC50=60 nM).
after 3 h. The in vivo data was comparable to that of
compound 2.
In summary, a new class of potent bridged substituted
phenyl-piperidine GH secretagogues has been reported.
The best compound, 26j, is not only highly potent in the
rat pituitary cell assay but also orally active at low dose
in dogs to release growth hormone.
Acknowledgements
We would like to thank Amy Bernick for mass spectro-
metry support, and Dr. Richard Ball and Ms. Nancy
Tsou for X-ray crystallography.
References and Notes
Scheme 4. (a) Amino acid, EDC, HOBT, 4-methyl morpholine, rt, 50–
90%; (b) HCl in EtOAc, rt, 100%; (c) BocNHC(Me)2COOH, EDC,
HOBT, 4-methyl morpholine, CH2Cl2, rt, 50–85%; (d) HCl in diox-
ane, rt, 60–80%; (e) NaOH/MeOH/H2O, 96%; (f) EtNH2, EDC,
HOBT, N-methylmorpholine, CH2Cl2, 71%.
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1820
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