(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4, 9-tetrahydro-1H-xanthen-1-one, a selective and orally active neuropeptide Y Y5 receptor antagonist

Article abstract of DOI:10.1021/jm8003587

(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4, 9-tetrahydro-1H-xanthen-1-one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The structure-activity relationship for this structural class was investigated and showed that limited substitution on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The C_max values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for (S)-1 was 0.34 in SD rats. In our acute D-Trp³⁴NPY-induced food intake model, both (S)-1 and (RS)-1 showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require sustained plasma exposure of (S)-1.

Full text of DOI:10.1021/jm8003587

J. Med. Chem. 2008, 51, 4765–4770
4765
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-
xanthen-1-one, a Selective and Orally Active Neuropeptide Y Y5 Receptor Antagonist
Nagaaki Sato,* Makoto Jitsuoka, Takunobu Shibata, Tomoko Hirohashi, Katsumasa Nonoshita, Minoru Moriya, Yuji Haga,
Aya Sakuraba, Makoto Ando, Tomoyuki Ohe, Hisashi Iwaasa, Akira Gomori, Akane Ishihara, Akio Kanatani, and
Takehiro Fukami
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan
ReceiVed March 31, 2008
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-
one ((S)-1) was identified as a selective and orally active neuropeptide Y Y5 receptor antagonist. The
structure-activity relationship for this structural class was investigated and showed that limited substitution
on the phenyl ring was tolerated and that modification of the 4,4-dimethyl group of the cyclohexenone and
the 3,3-dimethyl group of the xanthenone parts slightly improved potency. The plasma concentration-time
profile after oral administration of (S)-1 in Sprague-Dawley (SD) rats showed significant in vivo racemization
of (S)-1 and that (S)-1 is cleared much more quickly than (R)-1. The duration of (S)-1 in SD rats after oral
administration of (RS)-1 racemate was twice as long as that following oral administration of (S)-1. The Cmax
values of (S)-1 after administration of (S)-1 and (RS)-1 were comparable, and the brain to plasma ratio for
(S)-1 was 0.34 in SD rats. In our acute D-Trp34NPY-induced food intake model, both (S)-1 and (RS)-1
showed potent and dose-dependent efficacy. Therefore, the use of (RS)-1 is suitable for studies that require
sustained plasma exposure of (S)-1.
Introduction
NPYa is a highly conserved 36 amino acid peptide with
potent, centrally mediated orexigenic effects.1–4 Chronic ad-
ministration of NPY into the brain induces hyperphagia and
body weight gain.5,6 Concentrations of NPY and its mRNA in
the hypothalamus are markedly increased during food depriva-
tion and in some genetic models of obesity in rodents.7–11 In
addition, NPY-deficient ob/ob mice are less obese and have
Figure 1. Structure of (RS)-1.
reduced food intake when compared with ob/ob mice.12 These
data suggest that NPY may be a major regulator of physiological
feeding behavior. Five distinct types of G-protein-coupled NPY
receptors (Y1, Y2, Y4, Y5, and y6) have been cloned.13
Correlations between the in vitro function and the binding
activity of different peptide agonists and their potent stimulation
of food intake in rodent models resulted in the identification of
the Y5 receptor as a major feeding receptor.14 In addition, a
reduction in food intake induced by NPY and related peptides
in Y5 receptor deficient (Y5 -/-) mice was observed,15–17
thereby supporting the role of the Y5 receptor in food intake.
On the basis of these findings, the antagonism of the Y5 receptor
may have considerable therapeutic benefits in treating obesity.
A number of research groups have been interested in the Y5
receptor and have reported diverse structural classes of com-
pounds that target the Y5 receptor.18–26 Our laboratory has
demonstrated the potential for Y5 antagonism with the orally
active and selective Y5 antagonist, (RS)-9-(2-hydroxy-4,4-
dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahy-
dro-1H-xanthen-1-one ((RS)-1) (Figure 1),27–29 by showing that
chronic administration of (RS)-1 ameliorated diet-induced
obesity in mice by suppressing weight gain and adiposity while
(RS)-1 did not affect diet-induced obesity of Y5 deficient mice.
Scheme 1
Herein, we further elucidate the medicinal chemistry aspects
of this novel xanthene class of Y5 antagonists.
Chemistry
Scheme 1 illustrates the general method for the preparation
of the xanthene derivatives 1-21.30,31 A mixture of a 1:2 ratio
of the salicylaldehyde 22 to the 1,3-cyclohexanedione 23 was
heated in aqueous acetic acid to give the desired xanthene
derivatives. The crystalline xanthene derivatives usually pre-
cipitated after cooling and dilution of the reaction mixture. 1,3-
Hexanediones 23 employed in the present study were either
commercially available or reported in the literature. Optical
resolution of (RS)-1 was initially performed by preparative
HPLC. Subsequently, the active isomer (S)-1 was resolved by
fractional crystallization. Fractional crystallization of the dia-
stereomeric salt of (RS)-1 with cinchonidine yielded >99.5%
ee of the active isomer (S)-1. The absolute stereochemistry of
* To whom correspondence should be addressed. Phone: 81-298-77-2004.
Fax: 81-298-77-2029. E-mail: nagaaki_sato@merck.com.
a Abbreviations: NPY, neuropeptide Y; P-gp, P-glycoprotein; SD rat,
Sprague-Dawley rat; SAR, structure-activity relationship; CHO, Chinese
hamster ovary; icv, intracerebroventricular.
10.1021/jm8003587 CCC: $40.75
2008 American Chemical Society
Published on Web 07/19/2008

4766 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Sato et al.
Table 1. Racemization of (S)-1 in Various Mediaa
Table 2. In Vitro Potency of Compounds 1-15 (Variation of the
Substituents on the Phenyl Ring)a
time
media
temp, °C 1 h
2 h
4 h
8 h
24 h
anhydrous acetnitrile
50% aqueous
25
25
>99.5 >99.5 >99.5 >99.5 >99.5
97.0
88.4
74.1
53.5
10.5
acetonitrile
H2O (suspension)
anhydrous methanol
25
25
99.1
81.7
98.3
65.0
98.0
47.5
94.9
27.9
83.5
2.8
a The values represent % enantioexcess.
binding affinity
(Ki, nM)b
[Ca2+]i response
(IC50, nM)c
compd
R
(S)-1 was unequivocally determined by means of X-ray crystal-
lography of the chinconidine salt of (S)-1. We tested (S)-1 for
its solution stability in terms of racemization. (S)-1 has an
indefinite shelf life in the solid state at -20 °C but is susceptible
to racemization in aqueous media (Table 1). (S)-1 was stable
in an anhydrous aprotic solvent such as acetonitrile at 25 °C
for up to 24 h, while fast racemization was observed in 50%
aqueous acetonitrile (10.5% ee after 24 h). Suspension of (S)-1
in H2O also induced racemization. The racemization in H2O
was much slower than that in 50% aqueous acetonitrile. The
racemization of (S)-1 was even faster in a protic organic solvent
such as anhydrous methanol. Thus, protic media are clearly
responsible for the racemization of (S)-1.
(RS)-1
(R)-1
(S)-1
2
3
4
5
6
7
8
H
H
H
8-OMe
7-OMe
6-OMe
5-OMe
7-Cl
6-Cl
5-Cl
7-F
6-F
5-F
6-Me
6-Et
6-OEt
6-Br
33 ( 6
61 ( 8
>1000
343 ( 78
14 ( 4
34 ( 5
d
>1000
d
d
d
d
590 ( 190
93 ( 19
2167 ( 203
197 ( 7
34 ( 0.3
71 ( 9
82 ( 15
d
d
9
81 ( 20
29 ( 7
10
11
12
13
14
15
63 ( 6
34 ( 2
73 ( 25
36 ( 7
111 ( 16
d
41 ( 2
d
833 ( 187
36 ( 1
81 ( 6
Results and Discussion
a The values represent the mean ( SE for n ) 3. b Human recombinant
Y5 receptors in LMtk- cells; [125I]PYY. See ref 27. c Antagonistic activities
(human recombinant Y5 receptors/Gqi5 in CHO cells) at 100 nM NPY
stimulation. d Not determined.
Structure-Activity Relationships. We screened our in-
house chemical collections for structurally diverse novel NPY
Y5 leads and identified 9-(2-hydroxy-4,4-dimethyl-6-oxo-1-
cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-
1-one ((RS)-1), which has a Ki value of 33 nM at the human
Y5 receptor and is selective over NPY receptor subtypes (IC50
> 10 µM for human Y1, Y2, and Y4). After resolution and
evaluation of the pure enantiomers, (S)-1 was identified as the
active isomer. Although racemization during the binding assay
was a concern, the binding affinity (Ki ) 14 nM) and
antagonistic activity (Ki ) 34 nM) of (S)-1 was about 2-fold
higher than that of (RS)-1 and therefore acceptable (Table 2).
The SAR turned out to be rather specific, and we were able to
achieve only slight improvement in binding affinity. Substitution
effects on the phenyl ring were examined initially (Table 2).
Substitution with a methoxy group (2-5) did not enhance
binding affinity; only the 6-methoxy derivative 4 was tolerated,
whereas a dramatic decrease in activity was observed for the
5- and 8-methoxy derivatives 2 and 5. Regarding the chloro
derivatives 6-8, both the 5- and 6-chloro derivatives 7 and 8
were tolerated. The fluoro derivatives 10-12 showed the same
trend as the chloro derivatives. These results clearly suggest
that substitution at the 7 and 8 positions should be avoided.
The 5-position seems also to be sensitive to the size of the
substituent, based on the markedly decreased potency of the
5-methoxy derivative 5. Variations of the 6-substituent were
therefore examined (12-15) but provided no clues for improv-
ing binding affinity. The significantly decreased potency of the
ethoxy derivative 14 indicates that this phenyl site is extremely
sensitive to the steric bulkiness of the substituents. We then
focused on the 4,4-dimethyl group of the cyclohexenone and
the 3,3-dimethyl group of the xanthenone parts (Table 3).
Removing the methyl groups, as in 16 and 17, resulted in a
decrease in binding affinity. The diethyl derivative 18 was
equiactive to (RS)-1. The cyclobutyl derivative 19 showed a
slightly higher affinity than (RS)-1, whereas enlargement of the
ring size, as in 20 and 21, did not enhance binding affinity.
The antagonistic activities of selected potent derivatives were
determined by measuring the ability of the antagonists to inhibit
Table 3. In Vitro Potency of Compounds 16-21a
binding affinity
[Ca2+
]
i
compds
R1, R2
(Ki, nM)b
response (IC50, nM)c
(RS)-1
16
17
18
19
20
21
R1 ) R2 ) Me
R1 ) R2 ) H
R1 ) Me, R2 ) H 193 ( 20
R1 ) R2 ) Et
-(CH2)3-
-(CH2)4-
-(CH2)5-
33 ( 6
>1000
61 ( 8
d
d
20 ( 2
14 ( 3
17 ( 2
24 ( 4
90 ( 16
45 ( 7
58 ( 2
109 ( 7
a The values represent the mean ( SE for n ) 3. b Human recombinant
Y5 receptors in LMtk- cells; [125I]PYY. See ref 27. c Antagonistic activities
(human recombinant Y5 receptors/Gqi5 in CHO cells) at 100 nM NPY
stimulation. d Not determined.
NPY-induced [Ca2+]i increase in LMtk- cells expressing the
recombinant human Y5 receptor. In this [Ca2+]i functional assay,
all the tested compounds showed potent antagonistic activities
(Tables 2 and 3). We decided to employ 1 for in vivo concept
studies on the basis of its potent functional activity. (RS)-1 had
excellent selectivity with respect to other NPY receptors and
to 130 diverse selection of unrelated binding sites (IC50 > 10
µM for all the binding sites tested).
Pharmacokinetics and Brain Penetration of 1. Plasma
concentration-time profiles after oral administration of (S)-1
in SD rats were evaluated. Plasma levels of both enantiomers
were monitored because in vivo racemization was speculated
on the basis of the in vitro racemization study. In vivo
racemization of (S)-1 was indeed observed (Figure 2). It was
subsequently found that the duration of (S)-1 was extended when

A Xanthen-1-one as Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4767
Figure 4. Effect of (RS)-1 (a) and (S)-1 (b) on D-Trp34NPY-induced
food intake in SD rats. Significant differences with respect to controls
are indicated by an asterisk (/, P < 0.05). The data shown are expressed
as the mean ( SE. The graphs show the cumulative food intake in SD
rats for 2 h after icv injection of D-Trp34NPY. n ) 8 rats/group.
Figure 2. Plasma concentration-time profiles of (S)-1 and (R)-1 after
oral dosing of 10 mg/kg of (S)-1 in SD rats. The reported data are
generated after 10 mg/kg po doses in n ) 3 animals/dose.
Food Intake Inhibition of (S)-1 and (RS)-1. Prior to
evaluation of in vivo efficacy, the effect of (RS)-1 on gross
behavior in mice was investigated. Oral administration of (RS)-1
at a dose of 150 mg/kg caused no treatment-related changes in
psychomotor activities, motor activities, muscle tone, central
nerves system excitation, autonomic responses, and reflexes. No
deaths occurred at any time after the administration. Thus, this
agent was proven not to cause adverse effects at least up to
150 mg/kg oral dosing. In our D-Trp34NPY-induced food intake
model, Y5 antagonists are typically dosed 2 h prior to icv dosing
of D-Trp34NPY in SD rats to ensure sufficient distribution of
the antagonists, and food intake of the rats is measured
subsequently for 2 h. Since the Tmax value of (S)-1 after the
administration of (S)-1 is short (Tmax ) 0.5 h), (S)-1 was instead
dosed 1 h prior to icv dosing of D-Trp34NPY. In the event, the
differences in the duration of (S)-1 were not critical in this acute
model, and (RS)-1 and (S)-1 showed almost identical potent and
dose-dependent food intake inhibition (Figure 4). We recently
reported the antiobese effects of chronic treatment with (RS)-1
on diet-induced obese mice.29 In this chronic study, we
employed racemate (RS)-1, since sustained plasma exposure was
required to obtain sustained receptor occupancy and maximum
efficacy in this chronic model.
Figure 3. Plasma concentration-time profiles of (S)-1 and (R)-1 after
oral dosing of 10 mg/kg of (RS)-1 in SD rats. The reported data are
generated after 10 mg/kg po doses in n ) 3 animals/dose.
(RS)-1 was administered (Figure 3). After oral administration
of 10 mg/kg (RS)-1 in SD rats, the initial concentration of (S)-1
was lower than that of (R)-1, reflecting the first-pass clearance
Summary
(9S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1) was
identified as a selective and orally active neuropeptide Y5
receptor antagonist. The plasma concentration-time profile after
oral administration of (S)-1 in SD rats showed significant in
vivo racemization of (S)-1 and that (S)-1 is cleared much more
quickly than (R)-1. The duration of (S)-1 in SD rats after oral
administration of racemate (RS)-1 was found to be about 2 times
longer than that after administration of (S)-1. In our acute
D-Trp34NPY-induced food intake model, both (S)-1 and (RS)-1
showed potent and dose-dependent efficacy. The use of (RS)-1
is suitable for studies that require sustained plasma exposure
and receptor occupancy of (S)-1.
of each enantiomer; nevertheless, the half-life of (S)-1 (t1/2
)
5.2 h) was 2 times longer than that after administration of (S)-1
(t1/2 ) 2.7 h), probably because of the steady supply of (S)-1
from the abundant levels of (R)-1. This difference in clearance
might be partly due to the binding of the enantiomers to plasma
proteins. Indeed, rapidly cleared (S)-1 has a higher free fraction
(27% free) than (R)-1 (10% free) in rat plasma.32 Additional
experiments are needed to fully understand this observation,
and a detailed account will be reported in due course. The brain
to plasma ratio of (S)-1 in SD rats 1 h following oral dosing of
10 mg/kg (S)-1 was determined to be 0.34. Interestingly, the
brain to plasma ratio for (R)-1 was 0.10, which is one-third of
the ratio for (S)-1. It is noted that (RS)-1 is not a substrate for
P-gp (the transcellular transport ratio (B-to-A/A-to-B ratio) for
(RS)-1 was 1.0), suggesting that P-gp mediated transport is not
involved in the brain penetration of 1.32 Hence, this 3-fold
difference in the brain to plasma ratio between (R)-1 and (S)-1
is considered to be a consequence of the 3-fold difference in
the free fraction in rat plasma between (R)-1 and (S)-1.
Experimental Section
General. Nuclear magnetic resonance spectra were recorded on
Varian Gemini 200, 300, and JEOL JNM-A500 spectrometers in
the indicated solvents. Chemical shifts are reported in parts per
million (δ unit) relative to tetramethylsilane. Melting points were
recorded on a Yanaco MP-S3 model melting point apparatus and
are uncorrected. Electrospray ionization (ESI) mass spectra were

4768 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Sato et al.
recorded on micromass Quattro II and Q-Toff-2 instruments.
Elemental analyses were performed on CE instruments EA 1108
automatic elemental analyzer and are within 0.4% of theoretical
values otherwise noted. Flash chromatography was performed with
Merck silica gel 60 (230-400 mesh). Air- and/or moisture-sensitive
reactions were carried out in commercially available anhydrous
solvents under an atmosphere of nitrogen. All reagents were
obtained from commercial suppliers and were used without further
purification.
(2H, m), 6.89 (1H, m), 10.41 (1H, brs); MS (ESI+) m/z [M + H]+
397. Anal. (C24H28O5) C, H, N.
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-5-methoxy-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (5). White solid, mp
217-222 °C; 1H NMR (CDCl3) δ 0.99 (3H, s), 1.00 (3H, s), 1.03
(3H, s), 1.12 (3H, s), 1.93 (1H, d, J ) 16.2 Hz), 2.00 (1H, d, J )
16.2 Hz), 2.33 (2H, s), 2.37 (2H, s), 2.55 (1H, d, J ) 17.7 Hz),
2.68 (1H, d, J ) 17.7 Hz), 3.89 (3H, s), 4.66 (1H, s), 6.59 (1H, dd,
J ) 1.2, 7.5 Hz), 6.76 (1H, dd, J ) 1.2, 7.5 Hz), 6.94 (1H, t, J )
7.5 Hz), 10.42 (1H, brs); MS (ESI+) m/z [M + H]+ 397. Anal.
(C24H28O5) C, H, N.
7-Chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (6). White solid, 237-238 °C;
1H NMR (CDCl3) δ 1.02 (9H, s), 1.13 (3H, s), 1.98 (2H, s),
2.30-2.65 (6H, m), 4.60 (1H, s), 6.92-7.01 (2H, m), 7.09-7.14
(1H, m), 10.41 (1H, brs); MS (ESI+) m/z [M + H]+ 401. Anal.
(C23H25ClO4) C, H, N.
(RS)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((RS)-1). A mixture
of salicylaldehyde (7.56 mL, 0.07 mol) and dimedone (20.0 g, 0.14
mol) in 140 mL of acetic acid and 140 mL of H2O were heated to
reflux for 1.5 h. The mixture was cooled to room temperature, and
the resulting precipitate was collected, washed with ethanol, and
vacuum-dried to give 23.2 g (89%) of the title compound: White
solid, mp 208-210 °C; 1H NMR (CDCl3) δ 0.99 (6H, s), 1.03
(3H, s), 1.12 (3H, s), 1.92 (1H, d, J ) 16.6 Hz), 1.99 (1H, d, J )
16.6 Hz), 2.33 (2H, s), 2.37 (2H, s), 2.47 (1H, d, J ) 17.7 Hz),
2.57 (1H, d, J ) 17.7 Hz), 4.66 (1H, s), 7.00-7.04 (3H, m),
7.13-7.18 (1H, m), 10.46 (1H, brs); MS (ESI+) m/z [M + H]+
367; HRMS (ESI+) m/z [M + H]+ 367.1934 (C23H27O4 requires
367.1909). Anal. (C23H26O4) C, H, N.
6-Chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (7). White solid, mp 198-199
1
°C; H NMR (CDCl3) δ 0.98 (6H, s), 1.01 (3H, s), 1.12 (3H, s),
1.93 (1H, d, J ) 16.5 Hz), 2.00 (1H, d, J ) 16.5 Hz), 2.33 (2H, s),
2.37 (2H, s), 2.46 (1H, d, J ) 17.8 Hz), 2.58 (1H, d, J ) 17.8 Hz),
4.60 (1H, s), 6.91 (1H, d, J ) 8.2 Hz), 6.98 (1H, dd, J ) 2.0, 8.2
Hz), 7.03 (1H, d, J ) 2.0 Hz), 10.39 (1H, brs); MS (ESI+) m/z [M
+ H]+ 401. Anal. (C23H25ClO4) C, H, N.
(S)-9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ((S)-1). A mixture of
(RS)-1 (7 g, 19.1 mmol) and cinchonidine (5.62 g, 19.1 mmol) in
490 mL of acetonitrile was heated to reflux until the mixture became
clear. The mixture was cooled and gently stirred at room temper-
ature for 3 days. The precipitate was collected to give 8.34 g of
the S isomer rich cinchonidine salt. The salt was recrystallized from
490 mL of hot acetonitrile to give 6.85 g of (S)-1 cinchonidine
salt. The optically pure salt was suspended in a mixture of 300 mL
of ethyl acetate and 200 mL of 10% citric acid, and the mixture
was stirred until the layers became clear. The layers were separated,
and the organic layer was washed with 10% citric acid and brine,
dried over sodium sulfate, and concentrated. The residue was
crystallized from hot ethyl acetate and heptane to give 2.23 g of
the title compound. The ee was determined to be >99.9% by chiral
HPLC analysis (DAICEL CHIRALCEL OD-RH, 150 mm × 4.6
mm i.d., 50:50 H2O/CH3CN; 1.0 mL/min, 230 nm; (S)-1, tR ) 4.69
min, (R)-1, tR ) 7.07 min): White solid, mp 213-215 °C; [R]D25
+185° (c 1.0, CHCl3).
5-Chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (8). White solid, mp 217-222
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.04 (3H, s), 1.15 (3H, s),
1.95 (1H, d, J ) 18.0 Hz), 2.01 (1H, d, J ) 18.0 Hz), 2.35 (2H, s),
2.38 (2H, s), 2.67 (1H, d, J ) 18.0 Hz), 2.70 (1H, d, J ) 18.0 Hz),
4.66 (1H, s), 6.89-6.95 (2H, m), 7.21 (1H, d, J ) 7.3 Hz), 10.38
(1H, brs); MS (ESI+) m/z [M + H]+ 401. Anal. (C23H25ClO4) C,
H, N.
7-Fluoro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (9). White solid, mp 201-206
1
°C; H NMR (CDCl3) δ 1.00 (3H, s), 1.01 (3H, s), 1.02 (3H, s),
1.13 (3H, s), 1.98 (2H, s), 2.33 (2H, s), 2.35 (1H, d, J ) 12.8 Hz),
2.41 (1H, d, J ) 12.8 Hz), 2.47 (1H, d, J ) 17.1 Hz), 2.57 (1H, d,
J ) 17.1 Hz), 4.63 (1H, s), 6.70 (1H, m), 6.83 (1H, m), 6.95 (1H,
m), 10.38 (1H, brs); MS (ESI+) m/z [M + H]+ 385. Anal.
(C23H25FO4) C, H, N.
6-Fluoro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (10). White solid, mp 238-239
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-8-methoxy-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (2). 2-Hydroxy-6-
methoxybenzaldehyde (447 mg, 2.94 mmol) and dimedone (824
mmol, 5.88 mmol) in 3 mL of acetic acid and 6 mL of H2O were
heated to 100 °C for 1 h and cooled to room temperature. The
mixture was diluted with H2O and the resulting precipitate was
collected to give 607 mg (52%) of the title compound: White solid,
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.02 (3H, s), 1.28 (3H, s),
1.92 (1H, d, J ) 17.0 Hz), 2.02 (1H, d, J ) 17.0 Hz), 2.33 (2H, s),
2.37 (2H, s), 2.47 (1H, d, J ) 17.5 Hz), 2.59 (1H, d, J ) 17.5 Hz),
4.61 (1H, s), 6.71 (1H, dd, J ) 2.7, 8.2 Hz), 6.75 (1H, dt, J ) 2.2,
9.2 Hz), 6.92 (1H, dd, J ) 5.9, 7.7 Hz), 10.39 (1H, brs); MS (ESI+)
m/z [M + H]+ 385. Anal. (C23H25FO4 ·0.3H2O) C, H, N.
5-Fluoro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (11). White solid, mp 205-209
1
mp 189-193 °C; H NMR (CDCl3) δ 0.94 (3H, s), 0.98 (3H, s),
1.02 (3H, s), 1.11 (3H, s), 1.91 (1H, d, J ) 16.7 Hz), 2.00 (1H, d,
J ) 16.7 Hz), 2.32 (2H, s), 2.34 (2H, s), 2.45 (1H, dd, J ) 1.1,
17.5 Hz), 2.59 (1H, d, J ) 17.5 Hz), 3.74 (3H, s), 4.74 (1H, s),
6.55 (1H, dd, J ) 0.9, 8.3 Hz), 6.69 (1H, dd, J ) 0.9, 8.3 Hz),
7.13 (1H, t, J ) 8.3 Hz), 10.25 (1H, brs); MS (ESI+) m/z [M +
H]+ 397. Anal. (C24H28O5) C, H, N.
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.03 (3H, s), 1.13 (3H, s),
1.93 (1H, d, J ) 17.1 Hz), 2.01 (1H, d, J ) 17.1 Hz), 2.34 (2H, s),
2.38 (2H, s), 2.53 (1H, d, J ) 17.8 Hz), 2.66 (1H, d, J ) 17.8 Hz),
4.66 (1H, s), 6.76 (1H, m), 6.95 (2H, m), 10.36 (1H, brs); MS
(ESI+) m/z [M + H]+ 385. Anal. (C23H25FO4) C, H, N.
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3,6-trimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (12). White solid, mp 192-195
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-7-methoxy-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (3). White solid, mp
217-221 °C; 1H NMR (CDCl3) δ 1.00 (3H, s), 1.02 (6H, s), 1.12
(3H, s), 1.94 (1H, d, J ) 17.0 Hz), 2.01 (1H, d, J ) 17.0 Hz), 2.32
(2H, s), 2.38 (2H, s), 2.46 (1H, d, J ) 17.8 Hz), 2.59 (1H, d, J )
17.8 Hz), 3.70 (3H, s), 4.64 (1H, s), 6.50 (1H, d, J ) 3.0 Hz), 6.69
(1H, dd, J ) 3.0, 8.9 Hz), 6.95 (1H, d, J ) 8.9 Hz), 10.57 (1H,
brs); MS (ESI+) m/z [M + H]+ 397. Anal. (C24H28O5) C, H, N.
9-(2-Hydroxy-4,4-dimethyl-6-oxocyclohexyl)-6-methoxy-3,3-di-
methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (4). White solid, mp
177-181 °C; 1H NMR (CDCl3) δ 0.98 (3H, s), 0.99 (3H, s), 1.02
(3H, s), 1.12 (3H, s), 1.92 (1H, d, J ) 16.0 Hz), 1.99 (1H, d, J )
16.0 Hz), 2.33 (2H, s), 2.36 (2H, s), 2.46 (1H, d, J ) 17.5 Hz),
2.59 (1H, d, J ) 17.5 Hz), 3.77 (3H, s), 4.61 (1H, s), 6.56-6.62
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.03 (3H, s), 1.12 (3H, s),
1.92 (1H, d, J ) 17.1 Hz), 2.00 (1H, d, J ) 17.1 Hz), 2.29 (3H, s),
2.32 (2H, s), 2.37 (2H, s), 2.45 (1H, d, J ) 17.0 Hz), 2.60 (1H, d,
J ) 17.0 Hz), 4.63 (1H, s), 6.80-6.90 (3H, m), 10.35 (1H, brs);
MS (ESI+) m/z [M + H]+ 381. Anal. (C24H28O4) C, H, N.
6-Ethyl-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimeth-
yl-2,3,4,9-tetrahydro-1H-xanthen-1-one (13). White solid, mp
167-171 °C; 1H NMR (CDCl3) δ 0.99 (3H, s), 1.00 (3H, s), 1.03
(3H, s), 1.12 (3H, s), 1.22 (3H, t, J ) 7.6 Hz), 1.92 (1H, d, J )
17.1 Hz), 1.99 (1H, d, J ) 17.1 Hz), 2.32 (2H, s), 2.37 (2H, s),
2.45 (1H, d, J ) 17.0 Hz), 2.59 (1H, d, J ) 17.0 Hz), 2.60 (2H, q,
J ) 7.6 Hz), 4.63 (1H, s), 6.82-6.92 (3H, m), 10.38 (1H, brs);
MS (ESI+) m/z [M + H]+ 395. Anal. (C25H30O4) C, H, N.

A Xanthen-1-one as Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4769
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6-Ethoxy-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one(14).Whitesolid,mp176.0-176.2
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.02 (3H, s), 1.12 (3H, s),
1.39 (3H, t, J ) 6.9 Hz), 1.92 (1H, d, J ) 17.0 Hz), 1.99 (1H, d,
J ) 17.0 Hz), 2.32 (2H, s), 2.36 (2H, s), 2.46 (1H, d, J ) 18.0
Hz), 2.59 (1H, d, J ) 18.0 Hz), 3.98 (2H, q, J ) 6.9 Hz), 4.60
(1H, s), 6.52-6.60 (2H, m), 6.87 (1H, d, J ) 9.3 Hz), 10.38 (1H,
brs); MS (ESI+) m/z [M + H]+ 411. Anal. (C25H30O5) C, H, N.
6-Bromo-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohexyl)-3,3-dimethyl-
2,3,4,9-tetrahydro-1H-xanthen-1-one (15). White solid, mp 205-208
1
°C; H NMR (CDCl3) δ 0.99 (6H, s), 1.02 (3H, s), 1.12 (3H, s),
1.93 (1H, d, J ) 16.5 Hz), 2.00 (1H, d, J ) 16.5 Hz), 2.33 (2H, s),
2.37 (2H, s), 2.46 (1H, d, J ) 17.7 Hz), 2.59 (1H, d, J ) 17.7 Hz),
4.59 (1H, s), 6.87 (1H, d, J ) 9.0 Hz), 7.13 (1H, d, J ) 9.0 Hz),
7.19 (1H, s), 10.38 (1H, brs); MS (ESI+) m/z [M + H]+ 445. Anal.
(C23H25BrO4) C, H, N.
9-(2-Hydroxy-6-oxocyclohexyl)-2,3,4,9-tetrahydro-1H-xanthen-
1-one (16). White solid, mp 215-219 °C; 1H NMR (CDCl3) δ
1.50-2.20 (7H, m), 2.36-2.68 (4H, s), 2.71-2.84 (1H, m), 4.64
(1H, s), 6.98-7.09 (3H, m), 7.10-7.20 (1H, m), 10.80 (1H, brs);
MS (ESI+) m/z [M + H]+ 311. Anal. (C19H18O4) C, H, N.
9-(2-Hydroxy-4-methyl-6-oxocyclohexyl)-3-methyl-2,3,4,9-tet-
rahydro-1H-xanthen-1-one (17). White solid, mp 166-171 °C; 1H
NMR (CDCl3) δ 1.01 (0.9H, d, J ) 5.7 Hz), 1.02 (2.1H, d, J )
5.8 Hz), 1.13 (3H, d, J ) 6.3 Hz), 1.87-2.52 (8H, m), 2.60-2.74
(2H, m), 4.50 (0.3H, d, J ) 2.6 Hz), 4.52 (0.7H, d, J ) 2.6 Hz),
6.75 (1H, m), 6,87 (1H, m), 7.03 (1H, m), 10.35 (1H, brs); MS
(ESI+) m/z [M + H]+ 339. Anal. (C21H22O4) C, H, N.
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9-(4,4-Diethyl-2-hydroxy-6-oxocyclohexyl)-3,3-diethyl-2,3,4,9-tet-
rahydro-1H-xanthen-1-one (18).33 White solid, mp 165-168 °C;
1H NMR (CDCl3) δ 0.70-0.90 (12H, m), 1.23-1.49 (4H, m), 1.93
(1H, d, J ) 15.0 Hz), 2.01 (1H, d, J ) 15.0 Hz), 2.33-2.67 (6H,
m), 4.63 (1H, s), 6.99 (2H, m), 7.14 (1H, m), 10.43 (1H, brs); MS
(ESI+) m/z [M + H]+ 423. Anal. (C27H34O4) C, H, N.
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(18) (a) Galiano, S.; Erviti, O.; Pe´rez, S.; Moreno, A.; Juanenea, L.;
Aldana, I.; Monge, A. Synthesis of New Thiophene and Benzo[b-
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Bioorg. Med. Chem. Lett. 2004, 14, 597–599. (b) Juanenea, L.;
Galiano, S.; Erviti, O.; Moreno, A.; Pe´rez, S.; Aldana, I.; Monge, A.
Synthesis and Evaluation of New Hydrazide Derivatives as Neuropep-
tide Y Y5 Receptor Antagonists for the Treatment of Obesity. Bioorg.
Med. Chem. 2004, 12, 4717–4723.
(19) Rueeger, H.; Gerspacher, M.; Buehlmayer, P.; Rigollier, P.; Yamagu-
chi, Y.; Schmidlin, T.; Whitebread, S.; Nuesslein-Hildesheim, B.; Nick,
H.; Cricione, L. Discovery and SAR of Potent, Orally Available and
Brain-Penetrable 5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen- and
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9′-(6-Hydroxy-8-oxospiro[3.5]non-7-yl)-4′,9′-dihydrospiro[cy-
clobutane-1,3′-xanthen]-1′(2′H)-one (19).34 White solid, mp 181-184
1
°C; H NMR (CDCl3) δ 1.66-1.96 (12H, m), 2.04 (1H, d, J )
12.0 Hz), 2.29 (1H, d, J ) 12.0 Hz), 2.43-2.71 (5H, m), 2.89
(1H, d, J ) 12.0 Hz), 4.59 (1H, s), 6.90 (1H, d, J ) 6.0 Hz), 6.98
(1H, t, J ) 6.0 Hz), 7.02 (1H, d, J ) 6.0 Hz), 7.15 (1H, t, J ) 6.0
Hz), 10.60 (1H, brs); MS (ESI+) m/z [M + H]+ 391. Anal.
(C25H26O4) C, H, N.
9′-(7-Hydroxy-9-oxospiro[4.5]dec-8-yl)-4′,9′-dihydrospiro[cyclo-
pentane-1,3′-xanthen]-1′(2′H)-one (20). White solid, mp 203-205
1
°C; H NMR (CDCl3) δ 1.32-1.67 (16H, m), 2.00 (1H, d, J )
16.5 Hz), 2.09 (1H, d, J ) 16.5 Hz), 2.44 (2H, s), 2.47 (2H, s),
2.56 (1H, d, J ) 17.8 Hz), 2.62 (1H, d, J ) 17.8 Hz), 4.63 (1H, s),
6.97-7.04 (3H, m), 7.15 (1H, m), 10.56 (1H, brs); MS (ESI+)
m/z [M + H]+ 419. Anal. (C27H30O4) C, H, N.
9′-(2-Hydroxy-4-oxospiro[5.5]undec-3-yl)-4′,9′-dihydrospiro[cy-
clohexane-1,3′-xanthen]-1′(2′H)-one (21). White solid (recrystallized
from methanol), mp 185-188 °C; 1H NMR (CDCl3) δ 1.20-1.60
(20H, m), 1.92-2.09 (2H, m), 2.32-2.73 (6H, m), 4.63 (1H, s),
6.96-7.03 (3H, m), 7.15 (1H, m), 10.48 (1H, brs); MS (ESI+)
·
m/z [M + H]+ 447. Anal. (C29H34O4 0.1MeOH) C, H, N.
Acknowledgment. We thank Drs. Keiko Miura and Hisaki
Kojima for all the X-ray crystallography work.
Supporting Information Available: Procedures for pharmaco-
kinetic and D-Trp34NPY induced food intake studies, X-ray
crystallography data, and a table of elemental analysis data for the
target compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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F.; Dezube, M. Synthesis and Structure Activity Relationship of
Guanidines as NPY Y5 Antagonists. Bioorg. Med. Chem. 2004, 12,
2691–2708.
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