Journal of Medicinal Chemistry
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trans). Flash chromatography: 90/10 ethyl acetate/methanol, 0.15 g
(28%). H NMR (200 MHz, CDCl3): δ 1.38 (m, 1H), 1.90 (td, J =
MHz, DMSO): δ 1.62 (m, 1H), 2.24 (m, 1H), 2.62 (m, 1H), 2.83−
2.97 (m, 5H), 3.19−3.29 (m, 3H), 4.16 (pseudot, J = 5.0, 2H), 6.93−
7.00 (m, 3H), 7.13−7.38 (m, 12H); C28H29NO6 Anal. (C, H, N).
4.1.14. 5-({[2-(2-Methoxyphenoxy)ethyl]amino}methyl)-2,2-di-
phenylcyclopentan-1-one (14b) and Oxalate Salt (3b). The crude
extract was purified by flash chromatography on silica gel (20/80
cyclohexane/ethyl acetate) to give 0.75 g (36%) of the title compound.
1H NMR (200 MHz, CDCl3): δ 1.78 (m, 1H), 1.84 (bs, 1H), 2.23 (m,
1
9.7, 4.6, 1H), 2.00−2.17 (m, 2H), 2.18 (bs, 1H), 2.69−2.81 (m, 3H),
3.02 (m, 2H), 3.10 (dd, J = 4.4, 8.8, 1H), 3.78 (s, 3H), 4.08 (pseudot, J
= 5.0, 2H), 4.45 (d, J = 9.7, 1H) 6.83−6.98 (m, 4H) 7.09−7.45 (m,
10H). The free amine was transformed into the corresponding oxalate
salt which was crystallized from methanol to give compound 4b trans;
1
mp 182−186 °C. H NMR (200 MHz, DMSO): δ 1.50 (m, 1H),
1.80−2.20 (m, 3H), 2.66 (m, 1H), 2.95 (m, 3H), 3.07 (dd, J = 7.6,
12.2, 1H), 3.20 (dd, J = 4.3, 12.2, 1H), 3.27 (pseudot, J = 5.2, 2H),
3.75 (s, 3H), 4.15 (pseudot, J = 5.2, 2H), 4.33 (d, J = 9.5, 1H), 6.79−
7.06 (m, 4H), 7.06−7.39 (m, 10H); C29H33NO7 Anal. (C, H, N)
4.1.20. cis-5-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}-2,2-di-
phenylcyclopentan-1-ol (15c cis) and Oxalate salt (4c cis). Flash
1H), 2.40−3.15 (m, 5H), 3.0 (m, 2H), 3.84 (s, 3H), 4.09 (pseudot, J =
5.6, 2H), 6.83−6.99 (m, 4H), 7.14−7.34 (m, 10H). The free amine
was transformed into the corresponding oxalate salt which was
crystallized from methanol to give compound 3b; mp 143−145 °C. 1H
NMR (200 MHz, DMSO): δ 1.63 (m, 1H), 2.25 (m, 1H), 2.58 (m,
1H), 2.84−3.05 (m, 5H), 3.16−3.43 (m, 3H), 3.71 (s, 3H), 4.17
(pseudot, J = 5.0, 2H), 6.78−7.08 (m, 4H), 7.09−7.47 (m, 10H);
C29H31NO7 Anal. (C, H, N).
1
chromatography: 90/10 cyclohexane/ethyl acetate, 0.10 g (5%). H
NMR (200 MHz, CDCl3): δ 1.48 (m, 1H), 1.89 (m, 1H), 2.25 (m,
1H), 2.30−2.95(m, 9H), 3.13 (m, 4H), 3.82 (s, 3H), 5.08 (d, J = 4.4,
1H), 6.80−7.1 (m, 4H), 7.10−7.50 (m, 10H). The free amine was
transformed into the corresponding oxalate salt which was crystallized
4.1.15. 5-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}-2,2-diphe-
nylcyclopentan-1-one (14c) and Oxalate Salt (3c). The crude extract
was purified by flash chromatography on silica gel (80/20 cyclo-
1
1
from methanol to give compound 4c cis; mp 194−200 °C. H NMR
hexane/ethyl acetate) to give 0.31 g (35%) of the title compound. H
(200 MHz, DMSO): δ 1.59 (m, 1H), 1.89 (m, 1H), 2.22 (m, 1H),
2.42 (m, 1H), 2.78 (m, 1H), 2.85−3.30 (m, 12H), 3.77 (s, 3H), 4.91
(d, J = 4.2, 1H), 6.85−7.50 (m, 14H); C31H36N2O6 Anal. (C, H, N)
4.1.21. trans-5-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}-2,2-
diphenylcyclopentan-1-ol (15c trans) and Oxalate Salt (4c trans).
Flash chromatography: 90/10 cyclohexane/ethyl acetate, 0.16 g (8%).
1H NMR (200 MHz, CDCl3): δ 1.33 (m, 1H), 1.95−2.20 (m, 3H),
NMR (200 MHz, CDCl3): δ 1.88 (m, 1H), 2.30 (m, 1H), 2.44 (dd, J =
9.1, 12.4 1H), 2.52−2.80 (m, 6H, H3a), 2.88 (m, 1H), 2.91 (dd, J =
3.6, 12.4, 1H), 3.04 (pseudot, J = 4.6, 4H), 3.86 (s, 3H), 6.84−7.05
(m, 4H), 7.18−7.36 (m, 10H). The free amine was transformed into
the corresponding oxalate salt which was crystallized from methanol to
give compound 3c; mp 131−139 °C. 1H NMR (200 MHz, DMSO): δ
1.67 (m, 1H), 2,27 (m, 1H), 2.58 (m, 1H), 2.62−3.25 (m, 14H), 3.77
(s, 3H), 6.87−6.98 (m, 4H), 7.12−7.38 (m, 10H); C31H34N2O6 Anal.
(C, H, N).
4.1.16. General Procedure for the Synthesis of Amines 15a cis
and trans, 15b trans, and 15c cis and trans. To a solution of the
appropriated ketone (14a or 14b or 14c) dissolved in the minimum of
ethanol, was added, dropwise, at 0 °C, a suspension of NaBH4 (1.5
equiv) in ethanol. The reaction mixture was allowed to stand 2−3 h at
rt and then was cooled to 0 °C and quenched with 0.1 N HCl. After
evaporation of the ethanol, the residue was basified to pH = 12 with a
saturated solution of NaHCO3 and extracted with CHCl3 (3×).
Evaporation of the solvent gave the desired cyclopentanol as oil.
Purification and diastereomeric separations were accomplished by flash
chromatography on silica gel.
2.50−2.90 (m, 8H), 3.08 (m, 4H), 3.85 (s, 3H), 4.43 (d, J = 8.9, 1H),
6.83−7.04 (m, 4H), 7.15−7.37 (m, 8H), 7.43−7.47 (m, 2H). The free
amine was transformed into the corresponding oxalate salt which was
crystallized from methanol to give compound 4c trans; mp 206−211
1
°C with dec. H NMR (200 MHz, DMSO): δ 1.49 (m, 1H), 1.85−
2.20 (m, 3H), 2.65 (m, 1H), 2.80−3.20 (m, 12H), 3.88 (s, 3H), 4.25
(d, J = 9.3, 1H), 6.85−7.00 (m, 4H), 7.10−7.40 (m, 10H);
C31H36N2O6 Anal. (C, H, N)
4.2. Modeling Studies. All the compounds isomers were built,
parametrized (Gasteiger−Huckel method), and energy minimized
within MOE using MMFF94 forcefield.28,29
Both the protonated and in the unprotonated forms were evaluated
for each structure.
Successively docking studies were performed, using the 5-HT1A
model previously built by us.12 Briefly, the protein model was derived
by the alignment of the 5-HT1A (P08908) fast sequence on the X-ray
coordinates of human β2 adrenoreceptor (2RH1), on the basis of the
Blosum62 matrix (MOE software). The gap regions between the
template and the target protein sequences, concerning 5-HT1A loop
domain, were built by means of the MOE loop library.
4.1.17. cis-5-{[(2-Phenoxyethyl)amino]methyl}-2,2-diphenylcyclo-
pentan-1-ol (15a cis) and Oxalate Salt (4a cis). Flash chromatog-
1
raphy: 90/10 ethyl acetate/methanol. 0,15 g (26%). H NMR (200
MHz, CDCl3): δ 1.66 (m, 1H), 1.86 (m, 1H), 1.93 (m, 1H), 2.05 (bs,
1H), 2.38 (m, 1H), 2.61 (dd, J = 8.2, 11.4, 1H), 2.70 (m, 2H), 2.91
(dd, J = 4.4, 11.4, 1H) 2.98 (m, 2H), 4.05 (pseudo t, J = 5.1, 2H), 5.02
(d, J = 4.7, 1H), 6.87−6.99 (m, 3H), 7.03−7.47 (m, 12H). The free
amine was transformed into the corresponding oxalate salt which was
crystallized from methanol to give compound 4a cis; mp 200−203 °C.
1H NMR (200 MHz, DMSO): δ 1.53 (m, 1H), 1.84 (m, 1H), 2.22 (m,
1H), 2.40 (m, 2H), 2.79 (m, 2H), 2.97 (dd, J = 6.8, 12.3, 1H), 3.18
(dd, J = 7.5, 12.3, 1H), 3.32 (pseudot, J = 5.2, 2H), 4.20 (pseudot, J =
5.2, 2H), 4.92 (d, J = 3.5, 1H), 6.89−7.49 (m, 15H); C28H31NO6 Anal.
(C, H, N)
4.1.18. trans-5-{[(2-Phenoxyethyl)amino]methyl}-2,2-diphenylcy-
clopentan-1-ol (15a trans) and Oxalate Salt (4a trans). Flash
chromatography: 90/10 ethyl acetate/methanol, 0.24 g (42%). 1H
NMR (200 MHz, CDCl3): δ 1.38 (m, 1H), 1.80- 2.18 (m, 3H), 2.22
(bs, 1H), 2.68- 2.90 (m, 3H), 2.98 (pseudot, J = 4.7, 2H), 3.09 (dd, J =
4.3, 11.4, 1H), 4.05 (pseudot, J = 4.7, 2H), 4.44 (d, J = 9.5, 1H), 6.74−
6.99 (m, 3H), 7.04−7.47 (m, 12H). The free amine was transformed
into the corresponding oxalate salt which was crystallized from
methanol to give compound 4a trans; mp 189−194 °C. 1H NMR (200
MHz, DMSO): δ 1.49 (m, 1H), 1.82- 2.23 (m, 3H), 2.40 (m, 2H),
2.64 (m, 2H), 3.02 (dd, J = 8.3, 12.0, 1H), 3.19 (dd, J = 4.5, 12.0, 1H),
3.27 (pseudot, J = 5.1 2H), 4.19 (pseudot, J = 5.1, 2H), 4.33 (d, J =
9.3, 1H), 6.88−7.03 (m, 3H), 7.04−7.38 (m, 12H); C28H31NO6, Anal.
(C, H, N).
The putative 5-HT1A receptor binding site was determined starting
from the fact that, for the ligand activity, formation of a polar
interaction between the ligand and Asp116 is necessary.30−32 Thus, the
MOE tool SiteFinder was employed to identify the proper protein
pocket, including Asp116 and those residues highlighted by the
rhodopsin-based homology modeling studies developed by Nowak.27
Each isomer was docked into the 5-HT1A putative ligand binding
site, by means of the Surflex docking module implemented in Sybyl-
X1.0. Then, for all the compounds, the best docking geometries
(selected on the basis of the SurFlex scoring functions) were refined
by ligand−receptor complex energy minimization (CHARMM27) by
means of the MOE software. To verify the reliability of the derived
docking poses, the obtained 5-HT1A/cis conformer and 5-HT1A/trans
conformer complexes were further investigated by docking calculations
(10 run), using MOE-Dock (Genetic algorithm; applied on the poses
already located into the putative 5-HT1A receptor). The conformers
showing lower energy scoring functions and rmsd values (respect to
the starting poses) were selected as the most stable and allowed us to
identify the most probable enantiomers with 5-HT1A. At this step, for
all compounds bearing a tertiary amino group (piperazine derivatives),
the protonated conformers showed to be the most probable (by means
of lower values of energy scoring functions). This result may be
explained by an H-bond interaction between the protonated
4.1.19. trans-5-({[2-(2-Methoxyphenoxy)ethyl]amino}methyl)-
2,2-diphenylcyclopentan-1-ol (15b trans) and Oxalate Salt (4b
33
dx.doi.org/10.1021/jm200421e | J. Med. Chem. 2012, 55, 23−36