Isoxazolopyrimidines as novel F508-CFTR correctors

Article abstract of DOI:10.1055/s-0029-1219781

Using a cell-based high-throughput screen, we identified isoxazolo[5,4-d]pyrimidines as novel small-molecule correctors of the cystic fibrosis mutant protein F508-CFTR. 22 Isoxazolo[5,4-d]pyrimidine analogues were synthesized and tested. Synthesis of the

Full text of DOI:10.1055/s-0029-1219781

LETTER
1063
Isoxazolopyrimidines as Novel DF508-CFTR Correctors
I
soxazolopyrimidi
u
nesas
N
ove
l
i
D
F508-CFT
R
J
Correcto
u
rs n Yu,a Baoxue Yang,b A. S. Verkman,*b Mark J. Kurth*a
a
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
Fax +1(530)7528995; E-mail: mjkurth@ucdavis.edu
Departments of Medicine and Physiology, University of California, San Francisco, CA 94143, USA
Fax +1(415)6653847; E-mail: alan.verkman@ucsf.edu
b
Received 10 December 2009
ing Laitonjam et al.,19 Badiger et al.,20 Wentrup et al.,21
Peinador et al.,22 and Sankyo Co., Ltd., Japan.23 Herein,
we report the synthesis and DF508-CFTR corrector activ-
ity of twenty-two novel isoxazolopyrimidines. To the best
Abstract: Using a cell-based high-throughput screen, we identified
isoxazolo[5,4-d]pyrimidines as novel small-molecule correctors of
the cystic fibrosis mutant protein DF508-CFTR. 22 Isoxazolo[5,4-
d]pyrimidine analogues were synthesized and tested. Synthesis of
the key intermediate, 5-amino-3-arylisoxazole-4-carboxamide, was of our knowledge, this is the first report of these heterocy-
accomplished by nitrile oxide cycloaddition to (2-amino-1-cyano-
2-oxoethyl)sodium. Formation of 3-arylisoxazolo-[5,4-d]pyrimi-
din-4(5H)-one and chlorination gave 4-chloro-3-arylisoxazolo[5,4-
cles as DF508-CFTR correctors.
Our synthetic route, illustrated in Scheme 1, began with
hydroximoyl chloride formation from aryl aldehyde 1 in
two steps in quantitative yield.24 Hydroximoyl chlorides
are well-established nitrile oxide precursors (via dehydro-
chlorination) that readily participate in 1,3-diploar cy-
d]pyrimidine. Finally, functionalization at C-4 of the pyrimidine
ring by nucleophilic substitution gave the targeted isoxazolo[5,4-
d]pyrimidines. Six of the reported analogues had low micromolar
potency for increasing halide transport in DF508-CFTR cells.
Key words: cystic fibrosis, DF508-CFTR, corrector, isoxazolo-
pyrimidine
cloadditions. Adapting
a
protocol reported by
Rajagopalan and Talaty,25 hydroximoyl chloride 3 was
dissolved in ethanol and added dropwise to an ethanol
suspension of (2-amino-1-cyano-2-oxoethyl)sodium to
produce 5-amino-3-arylisoxazole-4-carboxamide 4 (35–
89% yield). Next, carboxamide 4 and triethyl orthofor-
mate were dissolved in acetic anhydride, and the solution
was refluxed for 2.5 hours to give 3-isoxazolo[5,4-d]pyri-
midin-4(5H)-one 5 in 48–75% yield. Pyrimidinone 5 was
treated with phosphorous oxychloride (0.83 equiv) in dry
acetonitrile (alternatively, toluene can be used as solvent)
at reflux in the presence of N,N-dimethylaniline (2 equiv)
for 3 hours in a sealed tube under a N2 atmosphere to af-
ford 4-chloropyrimidine 6.26 The chlorination of 5a to 6a
was also attempted with excess phosphorous oxychloride
as described by Rajagopalan and Talaty.25 However, after
washing with water, only starting material 5a was recov-
ered suggesting that, under acidic conditions, water dis-
places the chloride to reverse the transformation (e.g., 6a
→ 5a). We also found that treating chloropyrimidine 6a
with 2,3-dimethylaniline under reflux in methanol for 24
hours in the presence of K2CO3 failed to deliver isoxazol-
opyrimidine 7 (4-chloro- → 4-hydroxypyrimidine oc-
curred instead). Fortunately, target molecules 7–26 were
obtained by refluxing an isopropanol solution of 6 with
the appropriate aniline (2 equiv) in the presence of a cata-
lytic amount of HCl gas.27
Cystic fibrosis (CF) is a relatively common inherited dis-
ease caused by mutations in the CF transmembrane con-
ductance regulator protein (CFTR). The most common
CFTR mutation, deletion of phenylalanine at residue 508,
DF508, results in a defective CFTR protein that fails to
traffic to the plasma membrane and fails to activate as a
chloride channel.1–3 As a consequence a viscous mucus
accumulates in the lung, which promotes bacterial growth
and progressive deterioration of lung function.4,5 Al-
though CF patient care has improved considerably, there
is no cure for CF. While available CF-relevant drugs tar-
get the various symptoms of CF, many current studies are
focused on the discovery of compounds that restore nor-
mal DF508-CFTR processing, which are called correc-
tors.6–14
Using screening methods we developed to discover bithi-
azoles as the first DF508-CFTR correctors,14 we screened
a new collection of 50,000 diverse, drug-like small mole-
cules (from Chemdiv Inc., San Diego CA). The goal was
to identify new corrector scaffolds as potential drug can-
didates. Screening and secondary verification studies in-
dicated isoxazolopyrimidines as DF508-CFTR correctors.
Fused pyrimidines have broad-ranging biological activi-
ties, including antibacterial,15 CRF (corticotropin-releas-
ing factor) antagonist,16 antimalarial,17 and antitumor
activities.18 While isoxazolopyrimidines are not well stud-
ied, pyrimidine-based synthesis and application studies
have been the focus of numerous research groups, includ-
Twenty isoxazolo[5,4-d]pyrimidine analogues (7–26)
were synthesized using the method outlined in Scheme 1
by varying R1 (four inputs) and R2 (five inputs). DF508-
CFTR corrector data for six active compounds are sum-
marized in Table 1. Compounds were tested using a cell-
based fluorimetry assay of iodide influx as described pre-
viously.30 Corrector activity of each compound was veri-
fied by the lack of compound effect on FRT-null cells (not
expressing DF508-CFTR) and by inhibition of the in-
SYNLETT 2010, No. 7, pp 1063–1066
x
x.
x
x.
2
0
1
0
Advanced online publication: 17.03.2010
DOI: 10.1055/s-0029-1219781; Art ID: S13609ST
© Georg Thieme Verlag Stuttgart · New York

1064
G. J. Yu et al.
LETTER
OH
OH
O
N
N
R1
R1
R1
H
Cl
H
a
b
c
1a: 4-F 1c: 3-Cl
1b: 4-Cl 1d: 2-OMe
2a: 4-F 2c: 3-Cl
2b: 4-Cl 2d: 2-OMe
3a: 4-F 3c: 3-Cl
3b: 4-Cl 3d: 2-OMe
O
N
O
O
N
N
R1
R1
R1
N
NH2
NH2
N
e
d
N
N
Cl
O
O
H
5a: 4-F 5c: 3-Cl
5b: 4-Cl 5d: 2-OMe
4a: 4-F 4c: 3-Cl
4b: 4-Cl 4d: 2-OMe
6a: 4-F 6c: 3-Cl
6b: 4-Cl 6d: 2-OMe
R1
R2
R1
R2
f
2,3-diMe
3-OMe
2-Me
2,3-diMe
3-OMe
2-Me
7
8
9
10
11
12
13
14
15
16
4-F
17 3-Cl
18
19
20
21
O
N
R1
N
3-Me
3-Me
3,4-[1,3]dioxole
2,3-diMe
3-OMe
2-Me
3-Me
3,4-[1,3]dioxole
3,4-[1,3]dioxole
2,3-diMe
3-OMe
2-Me
3-Me
3,4-[1,3]dioxole
N
4-Cl
2-OMe
22
23
24
25
26
HN
7–26
R2
Scheme 1 Reagents: (a) NH2OH·HCl, H2O–EtOH–THF, NaOAc, 66–100%; (b) NCS, DMF–MeCl, Et3N, pyridine (cat.), 60–95%; (c) i) 2-
cyanoacetamide, NaOEt, EtOH, ii) 3, EtOH, 35–89%; (d) triethyl orthoformate, Ac2O, reflux, 2.5 h, 48–75%; (e) POCl3 (0.83 equiv), N,N-
dimethylaniline (2 equiv), Et3N·HCl (2 equiv), MeCN, reflux under N2, sealed tube, 2.5 h, 83–92%; (f) 2,3-dimethylaniline, i-PrOH, HCl (gas),
30–76%.
Table 1 IC50 and Vmax Data for Active Isoxazolopyrimidinesa
creased iodide influx by the thiazolidinone CFTR inhibi-
tor CFTRinh-172. Compound 7 exhibited a greater Vmax
value than s-cis locked bithiazole 27 reported in our earli-
er studies.14 Compounds 10–14 also had comparable cor-
rector activities (Table 1). An SAR trend is observed
when the location of substituent R on the phenyl ring of
the isoxazole portion of the molecule is varied. For in-
stance, when R1 = 3-Cl or 2-OMe, corrector activity is di-
minished. Of the isoxazolopyrimidines tested, only those
with a para substituent on the isoxazole phenyl moiety (4-
F and 4-Cl) were active. This dramatic change in corrector
activity in the 4-F or 4-Cl versus the 3-Cl or 2-OMe sug-
gests that the aldehyde reagent employed in Scheme 1 is
best fixed as 4-chloro- or 4-fluorobenzaldehyde. When R2
is fixed as 2,3-dimethyl (e.g., employing 3,4-dimethyla-
niline in Scheme 1), isoxazolopyrimidines 7 and 12 had
comparable IC50 values, although the Vmax of 7 is much
larger. The best IC50 value was obtained when 3-methoxy-
aniline (13) was employed.
O
N
N
S
R1
HN
O
N
S
N
N
HN
Cl
HN
7,10–14
27
R2
MeO
Compound R1
R2
IC50 mM
3.9
Vmax mM/s
161
7
10
11
12
13
14
4-F
2,3-diMe
3-Me
4-F
4-F
5.8
113
3,4-[1,3]dioxole
2,3-diMe
3-OMe
5.7
90
4-Cl
4-Cl
4-Cl
3.9
109
3.2
100
2-Me
6.9
103
The hydrogen bond donor/acceptor profile of these isox-
azolopyrimidines was then considered. For example, we
investigated changing the NH of isoxazolopyrimidine 7 to
an NMe (Figure 1; 28 was prepared by N-methylating 7
with iodomethane in methanol + NaH). We also modified
7 (starting from 6a) by replacing the 2,3-dimethylaniline
moiety with a 3-methylpyridin-2-amine moiety to give
analogue 29. When comparing the LogP values of com-
pound 7, 28, and 29 (Figure 1), there is no significant dif-
ference between 7 and 28, while 29 has a lower LogP
value (7: LogP 5.4813; 28: LogP 5.7171; 29: LogP
4.3731; data generated with ChemPropPro 8.03). Unfor-
a For comparison, IC50 and Vmax of reference compound corr-4a11
were 0.92 mM and 152 mM/s.
tunately, isoxazolopyrimidines 28 and 29 showed little
corrector activity compared to 7.
In summary, a collection of 4-aniline substituted deriva-
tives of isoxazole[5,4-d]pyrimidines was synthesized.
The synthetic protocol outlined in Scheme 1 is suitable to
high-volume combinatorial analogue generation. The six
isoxazolopyrimidine-fused heterocycles listed in Table 1
demonstrate corrector activity with low micromolar po-
tency. Isoxazolopyrimidines might thus serve as novel
Synlett 2010, No. 7, 1063–1066 © Thieme Stuttgart · New York

LETTER
Isoxazolopyrimidines as Novel DF508-CFTR Correctors
1065
MeCN was removed in vacuo. The resulting residue was subjected
to flash column chromatography purification (hexane–EtOAc =
9:1) to provide 6a as off-white crystals (480 mg, 92%).29c Pyrim-
idines 6b–d were prepared following analogous procedures.
O
O
N
N
N
N
7
F
F
N
N
MeN
HN
N-(2,3-Dimethylphenyl)-3-(4-fluorophenyl)-4,5-dihydroisox-
azolo[5,4-d]pyrimidin-4-amine (7)
N
Me
Me
6a
A mixture of 6a (111 mg, 0.443 mmol), 2,3-dimethylbenzenamine
(108 mL, 0.885 mmol), and catalytic HCl (g) in 2-PrOH (2 mL) was
sealed in a tube and refluxed overnight. Cooling on ice produced
white crystals which were collected by filtration and washed with
cold 2-PrOH to afford 7 (112 mg, 76%).29d Isoxazolopyrimidines 8–
26 and 29 were prepared following analogous procedures.
Me
28
29
Figure 1 N-Methyl and pyridyl analogues of 7
correctors to probe defective DF508-CFTR cellular pro-
cessing and for further preclinical development.
N-(2,3-dimethylphenyl)-3-(4-fluorophenyl)-4,5-dihydroisox-
azolo[5,4-d]pyrimidin-4-amine (28)
To a solution of 7 (95 mg, 0.284 mmol) in DMF (3 mL) was added
60% NaH (26 mg, 0.643 mmol) in mineral oil. The suspension was
stirred at r.t. for 30 min; MeI (40 mL, 0.643 mmol) was added and
the mixture stirred at r.t. overnight. The resulting mixture was
washed with H2O (3 × 10 mL), extracted with EtOAc (10 mL),
washed with brine, dried over anhyd Na2SO4, and filtered. Removal
of EtOAc afforded crude 28 which was subjected to flash chroma-
tography (hexanes–EtOAc = 9:1 → 4:1) to deliver pure 28 (58 mg,
61%).29e
4-Fluorobenzaldehyde Oxime (2a)
To a stirred solution of hydroxylamine·HCl (1.85 g, 26.6 mmol) in
THF–EtOH–H2O (30 mL:75 mL:15 mL) was added 4-fluoro-
benzaldehyde (1a, 3.0 g, 24.2 mmol), and the mixture was stirred at
r.t. for 25 min at which time EtOH and THF were removed in vacuo.
The residue was extracted with Et2O (3 × 30), washed with brine,
dried over anhyd Na2SO4, and filtered. Evaporation of the solvent
afforded 2a (3.36 g, 100%), which was used in the next step without
further purification. 1H NMR matches the literature data;28 ESI-MS:
m/z = 139.99 [M + H]+. Oximes 2b–d were prepared following anal-
ogous procedures with or without NaOAc.
Acknowledgement
The authors thank the Tara K. Telford Fund for Cystic Fibrosis Re-
search at UC Davis, the National Institutes of Health (DK072517,
GM076151, and HL073856), and the National Science Foundation
[CHE-0910870; and CHE-0443516, CHE-0449845, and CHE-
9808183 for NMR spectrometers] for their generous support.
4-Fluoro-N-hydroxybenzimidoyl Chloride (3a)
To a stirred solution of NCS (3.55 g, 26.6 mmol) in DMF–CH2Cl2
(20 mL:120 mL) was added dropwise a CH2Cl2 (120 mL) solution
of pyridine (200 mL, 2.42 mmol), Et3N (3.37 mL, 24.2 mmol), and
4-fluorobenzaldehyde oxime (2a: 3.36 g, 24.2 mmol). The solution
was stirred at r.t. for 12 h at which time it was washed with H2O
(5 × 100 mL) and concentrated to afford 3a (4.2 g, 100%). 1H NMR
matches the literature data.28 Hydroximoyl chloride 3b–d were pre-
pared following analogous procedures.
References and Notes
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5-Amino-3-(4-fluorophenyl)isoxazole-4-carboxamide (4a)
A freshly prepared NaOEt in EtOH solution, made at r.t. from Na
metal (977 mg, 42.5 mmol) in abs. EtOH (150 mL), was added to a
stirred solution of 2-cyanoacetamide (3.57 g, 42.5 mmol) in abs.
EtOH (50 mL) at 50 °C. To the resulting clear solution cooled to 0
°C was added dropwise a solution of hydroximoyl chloride 3a (7.38
g, 42.5 mmol) in abs. EtOH (100 mL). The resulting suspension was
stirred at r.t. for 30 min and then refluxed overnight. EtOH was re-
moved in vacuo, and the resulting residue was washed with H2O and
recrystallized from MeOH to yield 4a as light yellow crystals (2.91
g, 31%).29a Carboxamides 4b–d were prepared following analogous
procedures.
(5) Verkman, A. S.; Song, Y.; Thiagarajah, J. R. Am. J. Physiol.
Cell Physiol. 2003, 284, C2.
(6) Van Goor, F.; Hadida, S.; Grootenhuis, P. D.; Burton, B.;
Cao, D.; Neuberger, T.; Turnbull, A.; Singh, A.; Joubran, J.;
Hazlewood, A.; Zhou, J.; McCartney, J.; Arumugam, V.;
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3-(4-Fluorophenyl)isoxazolo[5,4-d]pyrimidin-4(5H)-one (5a)
A mixture of 4a (2.88 g, 13 mmol), triethyl orthoformate (2.16 mL,
13 mmol), and Ac2O (15 mL) was refluxed overnight. The solution
was cooled on ice, and the resulting precipitate was collected by fil-
tration, washed with H2O, and air dried to yield 5a as an off white
powder (2.05 g, 68%).29b Pyrimidinones 5b–d were prepared fol-
lowing analogous procedures refluxing for from 2.5–12 h.
(8) Van Goor, F.; Straley, K. S.; Cao, D.; González, J.; Hadida,
S.; Hazlewood, A.; Joubran, J.; Knapp, T.; Makings, L. R.;
Miller, M.; Neuberger, T.; Olson, E.; Panchenko, V.; Rader,
J.; Singh, A.; Stack, J. H.; Tung, R.; Grootenhuis, P. D.;
Negulescu, P. Am. J. Physiol. 2006, 290, L1117.
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Moran, O.; Galietta, L. J. V.; Verkman, A. S. J. Clin. Invest.
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4-Chloro-3-(4-fluorophenyl)-4,5-dihydroisoxazolo[5, 4-d]pyri-
midine (6a)
POCl3 (167 mL, 1.79 mmol) was added to a solution of 5a (0.54 g,
2.16 mmol), N,N-dimethylaniline (411 mL, 3.24 mmol), and
Et3N·HCl (0.6 g, 4.33 mmol) in dry MeCN (1.7 mL) under N2 in a
sealable tube. The mixture was refluxed for 3 h, cooled, and the
(12) Pedemonte, N.; Sonawane, N. D.; Taddei, A.; Hu, J.;
Zegarra-Moran, O.; Suen, Y. F.; Robins, L. I.; Dicus, C. W.;
Synlett 2010, No. 7, 1063–1066 © Thieme Stuttgart · New York

1066
G. J. Yu et al.
LETTER
Willenbring, D.; Nantz, M. H.; Kurth, M. J.; Galietta, L. J.
V.; Verkman, A. S. Mol. Pharmacol. 2005, 67, 1797.
MHz, CDCl3): d = 175.19, 165.60, 164.12, 158.07, 157.03,
156.72, 132.17, 132.11, 122.57, 116.39, 116.24, 110.62,
77.37, 77.16, 76.95. (d) Compound 7: 1H NMR (600 MHz,
CDCl3): d = 8.59 (s, 1 H), 7.85–7.69 (m, 2 H), 7.45 (d,
J = 7.9 Hz, 1 H), 7.38–7.29 (m, 2 H), 7.16 (t, J = 7.7 Hz, 1
H), 7.10 (d, J = 7.5 Hz, 1 H), 6.81 (br s, 1 H), 2.31 (s, 3 H),
2.03 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 176.12,
165.31, 163.63, 159.45, 157.18, 156.18, 138.28, 134.79,
131.06, 130.70, 130.64, 128.85, 126.29, 124.84, 123.31,
117.45, 117.30, 95.73, 20.71, 14.21. ESI-MS: m/z = 335.10
[M + H]+. (e) Compound 28: 1H NMR (600 MHz, CDCl3):
d = 8.67 (s, 1 H), 6.79 (m, 7 H), 6.56 (br s, 1 H), 3.35 (s, 3
H), 2.00 (s, 2 H), 1.96 (s, 3 H). 13C NMR (150 MHz, CDCl3):
d = 176.07, 163.97, 162.25, 160.25, 157.52, 144.82, 139.36,
133.03, 130.43, 129.88, 127.08, 123.56, 114.55, 96.77,
40.97, 20.28, 15.68. ESI-MS: m/z = 349.12 [M + H]+.
(30) General Procedure for Bioassays – D508-CFTR
Corrector Activity Assay
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Assays were performed by utilizing FRT epithelial cells
stably coexpressing human DF508-CFTR and the high-
sensitivity halide-sensing fluorescent protein YFP-H148Q/
I152L used as described previously.11 Cells were grown at
37 °C (95% air/5% CO2) for 24 h and then incubated for 16–
20 h with 50 mL of medium containing the test compound. At
the time of the assay, cells were washed with PBS and then
incubated with PBS containing forskolin (20 mM) and
genistein (50 mM) for 20 min. Measurements were carried
out using FLUOstar fluorescence plate readers (Optima;
BMG LABTECH Gmbh), each equipped with 500 10 nm
excitation and 535 15 nm emission filters (Chroma
Technology Corp.). Each well was assayed individually for
I– influx by recording fluorescence continuously (200 ms per
point) for 2 s (baseline) and then for 12 s after rapid (<1 s)
addition of 165 mL PBS in which 137 mM Cl– was replaced
by I–. I– influx was computed by fitting the final 11.5 s of the
data to an exponential for extrapolation of initial slope All
experiments contained negative control (DMSO vehicle)
and positive control corr-4a11 ({N-[2-(5-chloro-2-meth-
oxyphenylamino)-4¢-methyl-4,5¢-bithiazol-2¢-yl]benz-
amide}). Background I– influx (from DMSO control) was
subtracted to report the increase in I– influx in Table 1.
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(29) Representative Spectral Data (a) Compound 4a: 1H NMR
(600 MHz, DMSO): d = 7.65 (br s, 2 H), 7.63–7.58 (m, 2 H),
7.38–7.32 (m, 2 H). 13C NMR (15 MHz, DMSO): d =
171.70, 164.11, 163.85, 162.22, 159.78, 131.09, 131.04,
125.46, 125.44, 115.93, 115.79, 86.79. ESI-MS: m/z =
222.08 [M + H]+. (b) Compound 5a: 1H NMR (300 MHz,
DMSO): d = 13.17 (br s, 1 H), 8.46 (s, 1 H), 8.38 (m, 2 H),
7.42 (m, 2 H). ESI-MS: m/z = 232.06 [M + H]+.
(c) Compound 6a: 1H NMR (600 MHz, CDCl3): d = 9.02 (s,
1 H), 7.92–7.77 (m, 2 H), 7.28 (m, 2 H). 13C NMR (150
Synlett 2010, No. 7, 1063–1066 © Thieme Stuttgart · New York

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