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K. Cho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4781–4785
N
R2
N
R4
O
R1
a
e or f
N
N
N
Boc
R3
H
4
5: R1 = OH, R2 = OMe, R3 = Boc
6: R1 = Ph, R2 = OMe, R3 = H
7: R1 = Ph, R2 = OH, R3 = Bn
8: R1 = Ph, R2 = Cl, R3 = Bn
9a: R4 = H
9b: R4 = Cl
b
c
d
Scheme 1. Synthesis of intermediates 6, 9a, and 9b. Reagents and conditions: (a) 5-bromo-2-methoxypyridine, n-BuLi, THF, ꢀ78 °C to rt, 12 h, quant.; (b) AlCl3, benzene,
CH2Cl2, 0 °C, 4 h, 72%; (c) (i) BnBr, TEA, MeCN, rt, 2 h, (ii) TMSCl, NaI, MeCN, reflux, 1 h, 90% over two steps; (d) POCl3, reflux, 3 d, 83%; (e) H2, 10 bar, 40 °C, H-cube, quant.; (f)
ACECl, CH2Cl2, rt, 1 h, then MeOH, reflux, 1 h, 53%.
R1
N
H
N
NH2
R2
c
d, e, f, or g
a or b
O
O
N
N
N
N
R3
H
Bn
Bn
11a: R1 = H
13a−d: R3 = Bn
10
12
h
11b: R1 = Me
14a−d: R3 = H
R2 =
N
N
O
N
NH
N
O
O
O
13a, 14a
13b, 14b
13c, 14c
13d, 14d
Scheme 2. Synthesis of intermediates 14a–d. Reagents and conditions: (a) H2, Pd(OH)2, MeOH, rt, 2 h, quant.; (b) (i) MeI, NaH, DMF, rt, 1 h, (ii) H2, Pd(OH)2, MeOH, rt, 2 h, 74%
over two steps; (c) 5 N HCl, reflux, 12 h, 68%; (d) (i) ClCO(CH2)4Br, TEA, CHCl3, rt, 2 h, (ii) NaH, DMF, rt, 1 h, 88% over 2 steps; (e) (i) ClCO2(CH2)3Cl, TEA, CHCl3, rt, 1 h, (ii) NaH,
DMF, rt, 1 h, 85% over two steps; (f) (i) Br(CH2)3NHBoc, K2CO3, DMF, 100 °C, 24 h, (ii) TMSOTf, 2,6-lutidine, CH2Cl2, rt, 2 h, (iii) di(N-succinimidyl) carbonate, DIEA, CHCl3, rt,
12 h, 39% over three steps; (g) glutaric dialdehyde, Zn(BH3CN)2, MeOH, rt, 12 h, 40%; (h) H2, Pd(OH)2, rt, 2 h, 90%.
or g as shown in Scheme 2. Deprotection of the benzyl group of
13a–d gave amines 14a–d.
COOH
R
a, b, c, d, e, or f
The preparation of intermediates 16a–f is outlined in Scheme 3.
Commercially available carboxylic acid 15 was coupled with pyr-
rolidine followed by removal of the Boc group of the resultant
amide to give amine 16a. Amines 16b and 16c were synthesized
in the same manner. Oxadiazole-containing piperidines 16d and
16e were prepared by coupling 15 with hydrazine followed by
thermal condensation of the resultant hydrazide with dimethyl-
formamide dimethylacetal (DMFDMA) or 1,1,1-triethoxyethane
and subsequent deprotection of the Boc group. Coupling of 15 with
AcNHNH2 and subsequent treatment with Lawesson’s reagent fol-
lowed by cleavage of the Boc group yielded desired amine 16f.
Synthesis of cyclohexanamine derivatives 1, 2a–o and 3a–j is
shown in Scheme 4. Compounds 6, 9a, 9b, 11a, 11b, 14a–d, 16a–
f, and commercially available 4,4-diphenylpiperidine (17) were
condensed with acid 18,15 followed by reductive amination with
the desired benzylamines to give the target compounds as a mix-
ture of diastereomers. Finally, the desired trans-isomers 1, 2a–o
and 3a–j were obtained by preparative reversed-phase HPLC.16,17
The cyclohexanamine compounds described herein were tested
in a [125I]PYY binding assay using LMtkꢀ cell membranes express-
ing human recombinant Y1 receptors.18 Selected compounds
were evaluated for hERG K+ channel inhibitory activity using the
N
N
Boc
15
H
16a: R = pyrrolidyl amide
16b: R =
Ν,Ν−dimethyl amide
16c: R = piperidyl amide
16d: R = 2-[1,3,4-oxadiazole]
16e: R = 2-[5-methyl-1,3,4-oxadiazole]
16f: R = 2-[5-methyl-1,3,4-thiadiazole]
Scheme 3. Synthesis of intermediates 16a–f. Reagents and conditions: (a) (i)
pyrrolidine, EDCIꢁHCl, HOBt, TEA, CHCl3, rt, 12 h, (ii) TMSOTf, 2,6-lutidine, CH2Cl2, rt,
2 h, 80%—quant. over two steps; (b) (i) 40% aq NHMe2, EDCIꢁHCl, HOBt, TEA, CHCl3,
rt, 12 h; (ii) TMSOTf, 2,6-lutidine, CH2Cl2, rt, 2 h, 96% over two steps; (c) (i)
piperidine, EDCIꢁHCl, HOBt, TEA, CHCl3, rt, 12 h; (ii) 4 N HCl, rt, 12 h, 70% over two
steps; (d) (i) CDI, CHCl3, 50 °C, 2 h, (ii) NH2NH2ꢁH2O, rt, 12 h; (iii) DMFDMA, cat.
TsOH, toluene, 100 °C, 12 h; (iv) TMSOTf, 2,6-lutidine, CHCl3, rt, 12 h, 19% over four
steps; (e) (i) CDI, CHCl3, 50 °C, 2 h, (ii) NH2NH2ꢁH2O, rt, 12 h; (iii) (EtO)3CMe, 170 °C,
microwave, 30 min; (iv) TMSOTf, 2,6-lutidine, CHCl3, rt, 12 h, 49% over four steps;
(f) (i) CDI, CHCl3, 50 °C, 2 h; (ii) AcNHNH2, 50 °C, 12 h; (iii) Lawesson’s reagent, THF,
reflux, 12 h; (iv) TMSOTf, 2,6-lutidine, CHCl3, rt, 12 h, 61% over four steps.
and chloro groups of 8 was achieved by hydrogenation using H-
cube14 to give amine 9a. Compound 8 was also converted to 9b
using 1-chloro-ethylchloroformate (ACECl).
The synthesis of intermediates 11a, 11b and 14a–d is illustrated
in Scheme 2. The benzyl group of commercially available amide 10
was cleaved by hydrogenation to give amine 11a. Methylation of
10 followed by removal of the benzyl group afforded 11b. The
amide group of 10 was hydrolyzed under acidic conditions to fur-
nish amine 12, which was converted to 13a–d by conditions d, e, f
[
35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl]-
3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]-
methanesulfonamide binding assay to assess QTc prolongation
liability.19 Inhibitory activity for hSERT was measured using the
[3H]imipramine binding assay.20
High-throughput screening of Merck sample collections against
the human Y1 receptor resulted in the identification of 1, which
has a Ki value of 7.4 nM.21 Compound 1 was found to have