Modulators of Adrenomedullin
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 12 4073
N,N′-Bis(phenoxyacetyl)sebacic Dihydrazide (2n). From
sebacic dihydrazide (9.80 g, 42.61 mmol), phenoxyacetic acid
(12.95 g, 85.22 mmol), and POCl3 (52.32 g, 340.85 mmol) in
CH3CN (270 mL), 2n (4.99 g, 25%) was produced as a white
solid, mp 188-190 °C (EtOH).
General Procedure for the Preparation of Bisoxadia-
zoles 3j-n. To a stirred suspension of the corresponding
dihydrazide (1 equiv) in CH3CN was added a solution of POCl3
(8 equiv) in CH3CN dropwise over 30 min at room temperature.
The resulting mixture was heated at reflux temperature for 7
h. Then, the crude was cooled to room temperature and the
solvent was removed under reduced pressure. The obtained
residue was poured into ice-water and neutralized with
concentrated ammonium. After the mixture was stirred for one
night at room temperature, the resulting precipitate was
filtered off and purified by flash column chromatography on
sicila gel to give the corresponding oxadiazole.
justifying its behavior as outlier in the 3D-QSAR model
and the unexpected low affinity of this compound.
The SAR methodology employed has proved to be a
useful tool to elucidate some of the structural require-
ments to bind AM and to predict affinity. Similar work
on negative modulators of AM is in progress in our
laboratory.
Experimental Section
Small-Molecule Library. Compounds 1a-i were obtained
from the NCI’s small-molecule repository. The construction of
the library has been described15 and can be viewed at http://
cactus.nci.nih.gov/ncidb2. All compounds were provided diluted
in dimethyl sulfoxide (DMSO). NCI codes are 697165 for 1a,
697161 for 1b, 697164 for 1c, 697162 for 1d, 697163 for 1e,
697166 for 1f, 697169 for 1g, 697167 for 1h, and 697168 for
1i.
1,4-Bis(5-phenoxymethyl[1,3,4]oxadiazol-2-yl)butane
(3j). From 2j (2.50 g, 5.66 mmol) and POCl3 (6.95 g, 45.28
mmol) in CH3CN (35 mL), a white solid was produced. Flash
chromatography of the crude product using hexane-AcOEt
(1:1) as eluent gave 2j (1.75 g, 76%), mp 75-78 °C (EtOH). IR
General Methods. Melting points (uncorrected) were
determined on a Stuart Scientific SMP3 apparatus. Infrared
(IR) spectra were recorded with a Perkin-Elmer 1330 infrared
spectrophotometer. 1H and 13C NMR data were recorded on a
Bruker 300-AC instrument. Chemical shifts (δ) are expressed
in parts per million relative to internal tetramethylsilane;
coupling constants (J) are in hertz. Mass spectra were run on
a Bruker Esquire 3000 spectrometer. Elemental analyses (C,
H, N) were performed on a Perkin-Elmer 2400 CHN apparatus
at the Microanalyses Service of the University Complutense
of Madrid. Unless otherwise stated, all reported values are
within (0.4% of the theoretical compositions. Thin-layer
chromatography (TLC) was run on Merck silica gel 60 F-254
plates. Unless stated otherwise, starting materials used were
1
(KBr): 1600, 1570 cm-1. H NMR (CDCl3): δ 1.93 (4H, br s,
2CH2), 2.93 (4H, br s, 2CH2CNO), 5.24 (4H, s, 2CH2O), 7.02
(6H, m, ArH), 7.31 (4H, m, ArH). 13C NMR (CDCl3): δ 24.9,
25.4, 59.8, 114.8, 122.2, 129.7, 157.5, 162.6, 167.4. MS (ESI):
m/z 407 [M + H]+. Anal. (C22H22N4O4) C, H, N.
1,5-Bis(5-phenoxymethyl[1,3,4]oxadiazol-2-yl)pen-
tane (3k). From 2k (1.32 g, 2.89 mmol) and POCl3 (3.55 g,
23.13 mmol) in CH3CN (20 mL), a solid was produced. Flash
chromatography of the crude product using CH2Cl2-MeOH
(99:1) as eluent gave 3k (716 mg, 59%), mp 71-72 °C (EtOH).
1,6-Bis(5-phenoxymethyl[1,3,4]oxadiazol-2-yl)hex-
ane (3l). From 2l (3.60 g, 7.66 mmol) and POCl3 (9.40 g, 61.24
mmol) in CH3CN (50 mL), a white solid was produced. Flash
chromatography of the crude product using hexane-AcOEt
(1:1) as eluent gave 3l (920 mg, 28%), mp 57-60 °C (EtOH).
1,7-Bis(5-phenoxymethyl[1,3,4]oxadiazol-2-yl)hep-
tane (3m). From 2m (2.00 g, 4.13 mmol) and POCl3 (5.07 g,
33.03 mmol) in CH3CN (25 mL), an oil was produced. Flash
chromatography of the crude product using hexane-AcOEt
(1:1) as eluent gave 3m (1.17 g, 63%) as an oil, which
crystalized on standing to form a white solid, mp 48-52 °C
(EtOH).
1,8-Bis(5-phenoxymethyl[1,3,4]oxadiazol-2-yl)octane
(3n). From 2n (1.30 g, 2.61 mmol) and POCl3 (3.20 g, 20.85
mmol) in CH3CN (16 mL), a white solid was produced. Flash
chromatography of the crude product using toluene-AcOEt
(8:2) as eluent gave 3n (844 mg, 70%), mp 95-99 °C (EtOH).
General Procedure for the Preparation of Bistriazoles
1j-n. A mixture of the corresponding bisoxadiazole and an
excess of benzylamine was heated at 150 °C for 30 h under
argon. The reaction mixture was cooled to room temperature,
and CH2Cl2 (25 mL) was added. The solution was washed with
10% aqueous HCl, saturated aqueous NaHCO3, and brine. The
extract was dried (MgSO4), filtered, and evaporated to dryness,
and the obtained crude product was purified by flash column
chromatography on silica.
1
high-grade commercial products. Complete H and 13C NMR,
IR, MS, and elemental analysis data are given in the Sup-
porting Information.
General Procedure for the Preparation of Dihy-
drazides 2j-n. To a stirred suspension of either adipic,
pimelic, suberic, azelaic, or sebacic dihydrazide (1 equiv) and
phenoxyacetic acid (2 equiv) in CH3CN was added a solution
of POCl3 (8 equiv) in CH3CN dropwise over 30 min at room
temperature. The reaction mixture was heated at reflux
temperature until the solution became clear and then for 30
additional minutes. Then, the crude was cooled to room
temperature and the solvent was removed under reduced
pressure. The obtained residue was poured into ice-water and
neutralized with concentrated ammonium. After the mixture
was stirred for one night at room temperature, the resulting
precipitate was filtered off and recrystallized from absolute
EtOH.
N,N′-Bis(phenoxyacetyl)adipic Dihydrazide (2j). From
adipic dihydrazide (5.00 g, 28.73 mmol), phenoxyacetic acid
(8.73 g, 57.46 mmol), and POCl3 (35.30 g, 229.97 mmol) in CH3-
CN (70 mL), 2j (2.00 g, 16%) was produced as a white solid,
mp 237-239 °C (EtOH). IR (KBr): 3420, 3250, 1700, 1660
1
cm-1. H NMR (DMSO-d6): δ 1.54 (4H, br s, 2CH2), 2.50 (4H,
br s, 2CH2CO), 4.58 (4H, s, 2OCH2CO), 6.97 (6H, m, ArH),
7.30 (4H, t, J ) 7.9, ArH), 9.83 (2H, s, 2NH), 10.08 (2H, s,
2NH). 13C NMR (DMSO-d6): δ 24.6, 32.9, 65.9, 114.7, 121.2,
129.4, 157.7, 166.6, 170.9. MS (ESI): m/z 465 [M + Na]+.
N,N′-Bis(phenoxyacetyl)pimelic Dihydrazide (2k). From
pimelic dihydrazide (14.53 g, 77.29 mmol), phenoxyacetic acid
(23.50 g, 154.60 mmol), and POCl3 (94.90 g, 618.24 mmol) in
CH3CN (180 mL), 2k (8.10 g, 23%) was produced as a white
solid, mp 198-200 °C (EtOH).
1,4-Bis(4-benzyl-5-phenoxymethyl[1,2,4]triazol-3-yl)-
butane (1j). From 3j (200 mg, 0.49 mmol) and benzylamine
(3 mL, 27.48 mmol) and after flash chromatography of the
crude product using CHCl3-MeOH (95:5) as eluent, 1j (84 mg,
30%) was produced as a white solid, mp 190-192 °C (EtOH).
1
IR (KBr): 1600, 1590 cm-1. H NMR (CDCl3): δ 1.72 (4H, br
s, 2CH2), 2.53 (4H, br s, 2CH2CN2), 5.08 (4H, s, 2CH2N), 5.13
(4H, s, 2CH2O), 6.86 (10H, m, ArH), 7.20 (10H, m, ArH). 13C
NMR (CDCl3): δ 24.5, 26.1, 47.0, 60.6, 114.6, 121.8, 126.3,
128.3, 129.1, 129.6, 134.6, 150.8, 155.9, 157.5. MS (ESI): m/z
585 [M + H]+. Anal. (C36H36N6O2) C, H, N.
1,5-Bis(4-benzyl-5-phenoxymethyl[1,2,4]triazol-3-yl)-
pentane (1k). From 3k (100 mg, 0.24 mmol) and benzylamine
(1 mL, 9.16 mmol) and after flash chromatography of the crude
product using CHCl3-MeOH (94:6) as eluent, 1k (31 mg, 22%)
was produced as a white solid, mp 94-97 °C (EtOH).
N,N′-Bis(phenoxyacetyl)suberic Dihydrazide (2l). From
suberic dihydrazide (5.00 g, 24.75 mmol), phenoxyacetic acid
(7.52 g, 49.47 mmol), and POCl3 (30.39 g, 197.98 mmol) in CH3-
CN (60 mL), 2l (4.15 g, 36%) was produced as a white solid,
mp 202-204 °C (EtOH).
N,N′-Bis(phenoxyacetyl)azelaic Dihydrazide (2m). From
azelaic dihydrazide (5.00 g, 23.15 mmol), phenoxyacetic acid
(7.03 g, 46.25 mmol), and POCl3 (28.43 g, 185.21 mmol) in CH3-
CN (70 mL), 2m (2.47 g, 23%) was produced as a white solid,
mp 172-175 °C (EtOH).