Design and synthesis of novel hydroxyalkylaminomethylchromones for their IL-5 inhibitory activity

Article abstract of DOI:10.1016/j.bmc.2010.05.028

A series of hydroxyalkylaminomethylchromone analogs 3 were prepared and evaluated as inhibitors of interleukin-5. The most active analog 3d inhibited interleukin-5 activity with an IC₅₀ of 17.5 μM. The structural requirements of chromone analog

Full text of DOI:10.1016/j.bmc.2010.05.028

Bioorganic & Medicinal Chemistry 18 (2010) 4625–4629
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of novel hydroxyalkylaminomethylchromones for their
IL-5 inhibitory activity
P. Thanigaimalai a, Ki-Cheul Lee a, Vinay K. Sharma a, Jun-Ho Yun b, Youngsoo Kim b, Sang-Hun Jung a,
*
a College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, Republic of Korea
b College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of hydroxyalkylaminomethylchromone analogs 3 were prepared and evaluated as inhibitors of
Received 14 April 2010
Revised 8 May 2010
Accepted 11 May 2010
Available online 15 May 2010
interleukin-5. The most active analog 3d inhibited interleukin-5 activity with an IC50 of 17.5 lM. The
structural requirements of chromone analogs possessing the inhibitory activity against IL-5 could be
summarized as: (i) the cyclohexylmethoxy group at 5th position of the A ring, (ii) the planarity of chro-
mone ring, (iii) hydrophobic unit around the B ring with hydroxyl functional group, (iv) the hydrophobic
unit which does not have to be a planar and (v) the length of carbon units between amino and hydroxyl
group is limited to two.
Keywords:
Hydroxyalkylaminomethylchromone
Inhibitors
Ó 2010 Elsevier Ltd. All rights reserved.
Interleukin-5
1. Introduction
Cys 66 residue in IL-5 have been identified as IL-5 antagonists.12
Noteworthy, sophoricoside (1a, 92.1% inhibition at 50
lM,
Inflammatory diseases consist of rheumatoid (arthritis), respi-
ratory (asthma), cutaneous (psoriasis) and inflammatory bowl
causes enormous toll on human health.1 It has been reported that
the eosinophil is recognized as a proinflammatory granulocyte in-
volved in various allergic reactions such as in bronchial asthma and
atopic dermatitis.2 Accumulating evidence suggests that eosino-
phil-activating cytokines, such as interleukin (IL-5), granulocyte
macrophage GSF (GM-GSF) and IL-3 are the key molecules impli-
cated in the pathway of inflammatory process associated with
eosinophils. However at present, IL-5 is the most predominant che-
mokine which has the capability of enhancing the activation, dif-
ferentiation, migration, expansion and survival of eosinophils.3–5
Thus IL-5 produced by activated Th2 lymphocytes plays a crucial
role in allergic disease.6,7 These eosinophils are a dominant cell
type in allergic reactions and this exquisite specificity makes inter-
leukin-5 as an excellent target for attenuating these responses
without profound interference with the overall immune system.
Glucocorticoids are the most potent agents to treat eosinophilic
inflammation and allergic diseases8 due to its tendency to suppress
the inflammatory genes expressing cytokines and inflammatory
enzyme.9 However; their utility is compromised by their metabolic
and endocrine side effects.
IC50 = 1.4 M) and its analogs isolated from Sophora japonica, a
l
plant of Leguminosae family, are identified as inhibitors of IL-5 bio-
activity.13 The activity of sophoricoside appears to be more potent
than budesonide (70.3% inhibition at 50 lM, IC50 = 26.8 lM),
which is used for the treatment of chronic asthma. Thus, a number
of isoflavonoid analogs of sophoricoside14,15 have been synthesized
and demonstrated to be novel inhibitors of IL-5.
Based on the above observation, the structure–activity relation-
ship of sophoricoside analogs 1a–d and 2a–b (Chart 1)10,11,14,15,18
inferred the necessity of planar chromen-4-one ring and a phenolic
hydroxyl group at 4th position on ring B. However, the exact role of
ring B in isoflavone analogs in inhibiting IL-5 has not been explored
clearly. In continuation of our effort to find more detailed struc-
ture–activity relationship (SAR) of isoflavones as IL-5 inhibitor,
we have designed and prepared a series of amino alcohol deriva-
tives of chromone 3a–p as shown in Chart 1 and evaluated their
inhibitory activity against interleukin-5.
2. Chemistry
The synthesis of title compound 3 was achieved by the reduc-
tive amination16,17 of 418 as shown in Scheme 1. Thus compound
4 was reacted with various amino alcohols 5 in ethanol at reflux
temperature to yield 6, which was then cooled to ambient condi-
tion and subsequently treated with sodium borohydride to obtain
the title compounds 3. The substituents of 3(a–p) are indicated in
Table 1.
Recently, some small organic compounds have shown to inhibit
the activity of IL-5. Chalcones10,11 and isothiazolones derived from
* Corresponding author. Tel.: +82 42 821 5939/823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.05.028

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P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4625–4629
R3
O
O
O
O
O
R1
O
O
R
R1
N
H
O
R2
3
1
2
1a: Sophoricoside R1,R2 = OH, R3 = OGlu
1b: R1 = benzyloxy, R2 = H, R3 = OH
1c: R1 = H, R2 = benzyloxy, R3 = OH
1d: R1 = cyclohexylmethoxy, R2 =H, R3 = OH
2a, R1 = 4-(OH)C6H4
2b, R1 = OH
3, R = substituents are
located in Table-1
Chart 1. Interleukin-5 inhibitors 1, 2 and hydroxyalkylaminomethylchromones 3.
Table 1
Structures and C log P values of 3(a–p)
O
O
O
O
O
O
C log Pa
R
Compd No.
R
(a)
N
H
R-NH2
5
O
4
3a
3.9589
6
OH
(b)
3b
4.2635
OH
O
O
R
N
3c
4.7913
5.8733
H
OH
OH
O
3
3d
Scheme 1. Synthesis of hydroxyalkylaminomethylchromones 3(a–p). Reagents and
conditions: (a) ethanol, reflux at 80–90 °C; (b) NaBH4, 10 min, rt. Note = substitu-
ents are located in Table 1.
3e
3f
4.6645
4.5835
3. Results and discussion
3.1. Pharmacology
O
3g
3h
3i
3.9975
5.0855
5.1881
OH
Inhibitory activity of the chromone analogs against IL-5 was
evaluated using the IL-5-dependent pro-B Y16 cell line according
to the known procedure.13 The cells were incubated with 3 units/
mL mIL-5 for 48 h in the presence or absence of sample, and then
cell metabolism was measured as an index of proliferation, using
2-(4-Iodophenyl)-3-(nitrophenyl)-5-(2,4-disulphophenyl)-2H tet-
razolium sodium salt (WST-1). Effect on the IL-5 bioassay by each
test compound is represented as inhibition% at 30 lM samples and
also IC50 values (Table 2). Data were collected from three indepen-
dent experiments.
O
3j
4.4185
OH
OH
OH
3k
3l
2.9143
3.2435
3.6355
3m
OH
3.2. Structure–activity relationship
OH
3n
3o
4.2813
3.6223
In our earlier work,10,11,13–15 we have emphasized on the impor-
tance of a hydrophobic unit at ring A (benzyloxy or cyclohexylmeth-
oxy), planarity of the chromone ring and the hydroxyl group on the
ring B for IL-5 inhibitory activity of isoflavones. We have also dem-
onstrated that a simple hydroxyl methyl (without ring B) chromone
OH
OH
3p
4.5503
analog 2b (85% inhibition at 30 lM, IC50 = 7.6 l
M)18 gave good inhi-
a
C log P values were calculated by Chem. draw version 9.0.
bition against IL-5 activity. However, the region around ring B was
not fully explored for the structure–activity relationship of isoflava-
nones. Thus, in the current article we have synthesized a series of
chromone derivatives 3a–p by fixing the cyclohexylmethoxy group
as a hydrophobic unit on ring A of chromone moiety. The principle is
obviously aimed for more effective binding at active site of IL-5 by
introducing the amino alcohol unit instead of ring B to get more
comparative SAR of these isoflavones.
This suggests that the hydroxyphenyl ring (ring B) of 2a can be re-
placed by hydroxyethylaminomethyl group to maintain the activ-
ity of isoflavanones. To confirm the optimum size of amino
alcohol moiety, we increased one carbon unit between amino
(NH) and hydroxyl (OH) function in 3a. As a result, complete loss
of activity was observed in analog 3b (30% inhibition at 30
lM,
In the first set of experiment, analog 3a (88% inhibition at
IC50 >50 M, C log P = 4.2635). This outcome supports that chain
l
30
lM, IC50 = 18.5
lM, C log P = 3.958) gave moderate inhibitory
length of amino alcohol plays a critical role in inhibitory activity
activity as compared to 2a (98% inhibition at 30
l
M, IC50 <3.0 M).
l
against IL-5.

P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4625–4629
4627
Table 2
these groups are highly participating in binding hydrophobic zone
of the putative receptor. This also supports that planarity is not
necessary for their effective inhibition around ring B of 1d.
Interleukin-5 inhibitory activity of 3(a–p)
Compd No.
Inhibitiona at 30
lM (%)
IC50
18.5
>50
25.7
17.3
>50
>30
28.5
>50
10.6
>50
27.3
3a
3b
3c
3d
3e
3f
3g
3h
88
30
72
93
32
43
50
4. Conclusion
On the basis of our previous18 and current studies, we can con-
clude that the structural requirements of chromones analogs for
their IL-5 activity should be considered as the following; (i) the
cyclohexylmethyl group at 5th position of the ring A for their
hydrophobic region,18 (ii) the planarity of chromone ring,18 (iii)
hydrophobic unit is must with hydroxyl functional group around
the ring B for activity and both should be inter-related to each
other (iv) the hydrophobic unit does not have to be a planar and
(v) the two methylene unit between amino and hydroxyl group
are important.
14
Sophoricoside
3i
3j
3k
3l
3m
3n
3o
79.1b
31
57
13
15
20
13
63
>50
>50
>50
>50
26.4
3p
65.0
26.2
26.2
Budesonide
70.2b
5. Materials and method
5.1. Chemistry
a
IC50 values are taken as a mean from three experiments.
Inhibition at 50 lM.
b
Melting points (mp) were determined on Electro thermal 1A
9100 MK2 apparatus and are uncorrected. All commercial chemicals
were used as obtained and all solvents were purified by the standard
procedures prior19 to use. Thin layer chromatography was per-
formed on E Merck Silica Gel GF-254 per-coated plates and the iden-
tification was done with UV light and colorization with 10%
phosphomolybdic acid spray followed by heating. Flash column
chromatography was performed with E Merck silica gel (230–
400 mesh). Infra red spectrum was recorded by using sample (neat
sample withoutsolvent or KBr) as such on FT-IR spectrum with Nico-
let—380 models. NMR spectra were measured against the peak of
tetramethylsilane by Varian Unity Inova 400 NMR (400 MHz) spec-
trometers. High resolution mass spectrum (HRMS) was recorded on
API2000 mass spectrometer (PE Sciex, Toronto, Canada).
Conversely, the analog 3c (72% inhibition at 30
lM,
IC50 <25.7 M, C log P = 4.7913) inserted with one methylene unit
l
between amino alcohol chain and phenyl group in 3a shows com-
parable activity to 3a. On the other hand, the replacement of phe-
nyl group of 3c with cyclohexyl moiety, as shown in 3d (93%
inhibition at 30 lM, IC50 <17.5 lM, C log P = 5.8733) led to
enhancement of activity. Thus the bulky hydrophobic group in this
region should be more important than the shape.
In order to explore the role of amino (–NH) group as hydrogen
bonding source, when we removed hydroxymethyl group from 3a,
there was a complete loss of activity in the resulting analogs 3e
(32% inhibition at 30
(43% inhibition at 30
l
M, IC50 >50
lM, C log P = 4.6645) and 3f
l
M, IC50 >30 M, C log P = 4.5835). This result
l
indicates that the alcoholic –OH group is very essential for the inhi-
bition than amino (–NH) group. However, introduction of phenolic
5.1.1. General synthetic procedure for the preparation of 3(a–d)
A solution of 3-formyl chromone 4(a–p) (1 mmol) in ethanol
(50 ml) was treated with appropriate amine 5 (1 equiv). The reac-
tion mixture was cooled to room temperature after stir at reflux
temperature for 4 h to obtain an intermediate 6 which was conse-
quently treated with sodium borohydride (2 mmol) portion wise
over a period of 10 min and allowed to stir for 2 h at the same con-
dition. The reaction mixture was concentrated, partitioned be-
tween water and ethylacetate. The organic layer was washed
with brine solution, dried over Na2SO4 and concentrated under re-
duced pressure to give a expected product. The purification was
done by flash silica gel chromatography.
hydroxyl group as shown in analogs 3g (55% inhibition at 30
IC50 = 28.5 M, C log P = 3.9975) and 3j (57% inhibition at 30
IC50 27.3
their levels are moderate. Such trend appears in the series of 3h
(14% inhibition at 30 M, IC50 >50 M, C log P = 5.0855), 3i (31%
inhibition at 30 M, IC50 >50 M, C log P = 5.1881) and 3j (57%
inhibition at 30 M, IC50 = 27.3 M, C log P = 4.4185). The more po-
lM,
l
lM,
lM, C log P = 4.4185) rejuvenates the activity, though
l
l
l
l
l
l
tent activity of 3a, 3c, and 3d than those of 3g and 3j implies that
the alcoholic hydroxyl is better than the phenolic one.
In the next set of experiment, we removed hydrophobic phenyl
group in 3a. The resulting compound 3k (13% inhibition at 30
lM,
IC50 >50 M, C log P = 2.9143) showed complete loss of activity,
l
even though it has the hydroxyl group. This was another important
result which implies that the hydrophobic side chain branched on
amino alcohol is critical for the activity. By increasing number of
methylene groups in amino alcohol as shown in 3l (one methylene
unit) and 3m (two methylene units) did not turn up with any inhi-
bition as indicated in 3b. Interestingly, the increment of the size of
alkyl group as a branch in 3k as in propyl analog 3n (13% inhibition
5.1.1.1. 5-(Cyclohexylmethoxy)-3-((2-hydroxy-1-phenylethyl-
amino)methyl)-4H-chromen-4-one (3a). Yield 52%; Yellow
crystal; mp 124–126 °C; IR(neat): 3403, 2924, 2853, 1645,
1593 cmÀ1
;
1H NMR (CDCl3) d 1.05–2.04 (m, 11H), 3.66 (t,
J = 6.8 Hz 1H), 3.68 (t, J = 6.8 Hz, 1H), 3.84 (d, J = 6.4 Hz, 2H), 4.41
(t, J = 6.0 Hz, 1H), 4.62 (s, 2H), 6.41 (d, J = 8.4 Hz, 1H), 6.54–6.61
(m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 7.21–7.37
(m, 4H). HRMS calcd for C25H29NO4 m/z 407.2097, found 407.2091.
at 30
inhibition at 30
analog 3p (65% inhibition at 30
l
M, IC50 >50
l
M, C log P = 4.2813), dimethyl analog 3o (63%
M, C log P = 3.6223) and tert-butyl
M, IC50 26.2 M, C log P = 4.5503)
lM, IC50 26.4
l
l
l
5.1.1.2. 5-(Cyclohexylmethoxy)-3-((3-hydroxy-1-phenylpropyla-
showed gradual increment in their inhibition. Thus, the bulky
hydrophobic group as a branch in amino ethanol is critical moiety
for the activity.
mino)methyl)-4H-chromen-4-one (3b). Yield 54%; viscous yel-
low solid; IR(neat): 3398, 2925, 1650, 1598 cmÀ1
;
1H NMR
(CDCl3) d 0.82–2.00 (m, 11H), 2.10 (q, J = 6.0 Hz, 2H), 3.67 (t,
J = 5.6 Hz, 2H), 3.84 (d, J = 6.0 Hz, 2H), 4.41 (t, J = 5.6 Hz, 1H), 4.60
(s, 2H), 6.49 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.20–7.40
(m, 7H). HRMS calcd for C26H31NO4 m/z 421.2253, found 421.2248.
Considering C log P values of 3a, 3c, 3n, 3o and 3p, it was ob-
served that increasing the hydrophobicity by introduction of
branched groups is not correlated to the activity but instead the
size of these groups is more important for the IL-5 inhibition. Thus,

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P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4625–4629
5.1.1.3. 5-(Cyclohexylmethoxy)-3-((1-hydroxy-3-phenylpropan-
IR(neat): 3403, 2925, 1650, 1597 cmÀ1 1H NMR (CDCl3) d 0.92–
;
2-ylamino)methyl)-4H-chromen-4-one (3c). Yield 48%; yellow
2.08 (m, 11H), 3.53 (t, J = 5.6 Hz, 2H), 3.67 (t, J = 5.6 Hz, 2H), 3.88
(d, J = 6.0 Hz, 2H), 4.82 (s, 2H), 6.38 (d, J = 8.0 Hz, 1H), 6.59 (d,
J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H). HRMS calcd
for C19H25NO4 m/z 331.1784, found 331.1779.
crystal; mp 123–125 °C; IR(neat): 3403, 2925, 1650, 1578 cmÀ1
;
1H NMR (CDCl3) d 1.08–2.05 (m, 11H), 2.51(d, J = 6.0 Hz, 1H),
2.72 (d, J = 6.0 Hz, 1H) 3.10 (m, 1H), 3.61–3.67 (m, 2H), 3.86 (d,
J = 6.0 Hz, 2H), 4.57 (s, 2H), 6.49–6.57 (m, 2H), 7.20–7.34 (m, 7H).
HRMS calcd for C26H31NO4 m/z 421.2253, found 421.2249.
5.1.1.12. 5-(Cyclohexylmethoxy)-3-((3-hydroxypropylamino)-
methyl)-4H-chromen-4-one (3l). Yield 59%; yellow crystal; mp
5.1.1.4. 3-((1-Cyclohexyl-3-hydroxypropan-2-ylamino)methyl)-
5-(cyclohexylmethoxy)-4H-chromen-4-one (3d). Yield 45%;
yellow crystal; mp 103–105 °C; IR(neat): 3408, 2922, 1650,
110–112 °C; IR(neat): 3390, 2924, 1650, 1597 cmÀ1 1H NMR
;
(CDCl3) d 1.04–2.04 (m, 13H), 3.34 (t, J = 5.6 Hz, 2H), 3.63 (t,
J = 5.6 Hz, 2H), 3.85 (d, J = 6.0 Hz, 2H), 4.67 (s, 2H), 6.51 (d,
J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 7.37
(s, 1H). HRMS calcd for C20H27NO4 m/z 345.1940, found 345.1931.
1597 cmÀ1 1H NMR (CDCl3) d 0.81–1.98 (m, 24H), 2.98 (m, 1H),
;
3.45 (d, J = 6.0 Hz, 1H), 3.68 (d, J = 5.6 Hz, 1H), 3.87 (d, J = 5.6 Hz,
2H), 4.62 (s, 2H), 5.20 (s, 1H), 6.45 (d, J = 8.0 Hz), 6.61 (d,
J = 8.0 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 7.32 (s, 1H). HRMS calcd
for C26H37NO4 m/z 427.2723, found 427.2718.
5.1.1.13. 5-(Cyclohexylmethoxy)-3-((5-hydroxypentylamino)-
methyl)-4H-chromen-4-one (3m). Yield 44%; viscus yellow oil;
IR(neat): 3398, 2924, 1650, 1598, 1453 cmÀ1 1H NMR (CDCl3) d
;
5.1.1.5. 3-((Benzylamino)methyl)-5-(cyclohexylmethoxy)-4H-
chromen-4-one (3e). Yield 54%; colorless crystal; mp 115–
1.03–2.04 (m, 17H), 3.31 (t, J = 6.0 Hz. 2H), 3.70 (t, J = 5.6 Hz, 2H),
3.85 (d, J = 5.6 Hz, 2H), 4.69 (s, 2H), 6.49 (d, J = 8.0 Hz, 1H), 6.71
(d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.38 (s, 1H). HRMS calcd
for C22H31NO4 m/z 373.2253, found 373.2245.
117 °C; IR(neat): 2410, 2925, 1650, 1598, 1579 cmÀ1 1H NMR
;
(CDCl3) d 0.82–2.01 (m, 11H), 3.87 (d, J = 6.0 Hz, 2H), 4.40 (s, 2H),
4.62 (s, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 7.17
(t, J = 8.4 Hz, 1H), 7.21–7.38 (m, 6H). HRMS calcd for C24H27NO3
m/z 377.1991, found 377.1984.
5.1.1.14. 5-(Cyclohexylmethoxy)-3-((1-hydroxypentan-2-ylami-
no)methyl)-4H-chromen-4-one (3n). Yield 59%; viscus yellow
oil; IR(neat): 3409, 2923, 1650, 1578, 1455 cmÀ1 1H NMR (CDCl3)
;
5.1.1.6.
methyl)-4H-chromen-4-one (3f). Yield 50%; yellow crystal; mp
96–98 °C; IR(neat): 3403, 2922, 1650, 1598, 1579 cmÀ1 1H NMR
(CDCl3) d 0.80–2.00 (m, 11H), 3.86 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H),
4.39 (s, 2H), 4.60 (s, 2H), 6.45–6.51 (m, 2H), 6.82 (d, J = 8.0 Hz,
2H), 6.98 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.4 Hz, 1H), 7.38 (s, 1H).
HRMS calcd for C25H29NO4 m/z 407.2097, found 407.2092.
5-(Cyclohexylmethoxy)-3-((4-methoxybenzylamino)-
d 0.88–2.07 (m, 18H), 3.10 (m, 1H), 3.42 (d, J = 5.6 Hz, 1H), 3.70 (d,
J = 5.6 Hz, 1H), 3.88 (d, J = 6.0 Hz, 2H), 4.56 (s, 2H), 6.44–5.53 (m,
2H), 7.20 (t, J = 8.4 Hz, 1H), 7.36 (s, 1H). HRMS calcd for
C22H31NO4 m/z 373.2253, found 373.2248.
;
5.1.1.15.
5-(Cyclohexylmethoxy)-3-((1-hydroxy-2-methylpro-
pan-2-ylamino)methyl)-4H-chromen-4-one (3o). Yield 55%;
yellow crystal; mp 93–95 °C; IR(neat): 3381, 2924, 1647,
5.1.1.7. 5-(Cyclohexylmethoxy)-3-((4-hydroxybenzylamino)methyl)-
1581 cmÀ1 1H NMR (CDCl3) d 0.82–2.01 (m, 17H), 3.72 (s, 2H),
;
4H-chromen-4-one (3g). Yield 48%; yellow crystal; mp 121–
3.87 (d, J = 6.0 Hz, 2H), 4.54 (s, 2H), 6.46–6.55 (m, 2H), 7.23 (t,
J = 8.0 Hz, 1H), 7.38 (s, 1H). HRMS calcd for C21H29NO4 m/z
359.2097, found 359.2093.
123 °C; IR(neat): 3381, 2926, 1650, 1598, 1578 cmÀ1 1H NMR
;
(CDCl3) d 0.84–2.03 (m, 11H), 3.90 (d, J = 5.6 Hz, 2H), 4.42 (s, 2H),
4.58 (s, 2H), 6.46 (d, J = 8.0 Hz, 1H), 6.57–6.81 (m, 3H), 7.01–7.16
(m, 3H), 7.37 (s, 1H). 10.9 (s, 1H). HRMS calcd for C24H27NO4 m/z
393.1940, found 393.1933.
5.1.1.16. 5-(Cyclohexylmethoxy)-3-((1-hydroxy-3,3-dimethylb-
utan-2-ylamino)methyl)-4H- chromen-4-one (3p). Yield 50%;
Yellow crystal; mp 70–71 °C; IR(neat): 3402, 2925, 2855, 1646,
5.1.1.8. 5-(Cyclohexylmethoxy)-3-((phenylamino)methyl)-4H-
chromen-4-one (3h). Yield 57%; viscous yellow oil; IR(neat):
1595 cmÀ1 1H NMR (CDCl3) d 0.95 (s, 6H), 1.07–2.04 (m, 11H),
;
2.80 (m, 1H), 3.56 (m, 1H), 3.85 (d, J = 5.6 Hz, 2H), 4.14 (m, 1H),
4.62 (q, 1H), 6.43–6.57 (m, 2H), 7.19 (t, J = 8.4 Hz, 1H), 7.26 (s,
1H). HRMS calcd for C23H33NO4 m/z 387.2410, found 387.2403.
3410, 2922, 1650, 1597 cmÀ1 1H NMR (CDCl3) d 1.06–2.01 (m,
;
11H), 3.88 (d, J = 6.0 Hz, 2H), 4.77 (s, 2H), 6.44 (d, J = 8.4 Hz, 1H),
6.57 (d, J = 8.4 Hz, 1H), 7.10–7.33 (m, 7H). HRMS calcd for
C23H25NO3 m/z 363.1834, found 363.1831.
Acknowledgment
5.1.1.9.
methyl)-4H-chromen-4-one (3i). Yield 45%; yellow crystal; mp
121–123 °C; IR(neat): 3410, 2922, 1650, 1580 cmÀ1 1H NMR
(CDCl3) d 1.02–2.00 (m, 11H), 3.86 (d, J = 6.0 Hz, 2H), 3.93 (s, 3H),
4.57 (s, 2H), 6.45 (d, J = 8.0 Hz, 2H), 6.51–6.78 (m, 3H), 6.96 (d,
J = 8.0 Hz, 2H), 7.21 (t, J = 8.4 Hz, 1H), 7.33 (s, 1H). HRMS calcd
for C24H27NO4 m/z 393.1940, found 393.1936.
5-(Cyclohexylmethoxy)-3-((4-methoxyphenylamino)-
This work was supported by Priority Research Centers Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0093815).
;
References and notes
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;
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(CDCl3) d 1.02–2.00 (m, 11H), 3.87 (d, J = 6.0 Hz, 2H), 4.80 (s, 2H),
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P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4625–4629
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