Novel Analogues of Anandamide
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5359
1H), 5.36 (m, 8H), 4.04 (m, 2H), 2.80 (m, 6H), 2.22-2.00 (m,
7H), 2.01 (m, 6H), 1.72 (m, 2H), 1.29 (m, 6H), 0.88 (t, J ) 6.73
Hz, 3H). Anal. (C23H35NO) C, H, N.
and 604 mg (2.31 mmol) of tetrabutylammonium fluoride in 5
mL of THF following the procedure for compound 22 to give
127 mg (0.54 mmol, 54.5% yield) of 23 as a colorless liquid:
Rf (50% EtOAc-petroleum ether) 0.12; 1H NMR (200 MHz,
CDCl3) δ 5.31-5.39 (m, 4H), 4.22 (t, J ) 9.38 Hz, 1H), 3.82 (t,
J ) 9.41 Hz, 2H), 2.77 (t, J ) 5.60 Hz, 2H), 2.27 (t, J ) 7.52
Hz, 2H), 2.00-2.06 (m, 4H), 1.62 (m, 2H), 1.30 (br s, 14H),
0.89 (t, J ) 6.48 Hz, 3H). Anal. (C20H35NO) C, H, N.
N-(2,2,2-Tr iflu or oeth yl)a r a ch id on a m id e (17). Arachi-
donic acid chloride was prepared from 50 mg (0.165 mmol) of
arachidonic acid as described under 13 and reacted with a
solution of 111.8 mg (0.825 mmol, 5 equiv) of 2,2,2-trifluoro-
ethylamine hydrochloride in 0.5 mL of pyridine. Reaction
mixture was stirred at room temperature for 30 min and
worked up in a similar manner to give 47.4 mg (75%) of the
title amide: Rf (35% ethyl ether-petroleum ether) 0.20; 1H
NMR (270 MHz, CDCl3) 5.60 (br s, 1H), 5.36 (m, 8H), 3.91 (m,
2H), 2.80 (m, 6H), 2.24 (t, J ) 7.39 Hz, 2H), 2.08 (m, 6H), 2.01
(m, 6H), 1.74 (m, 2H), 1.29 (m, 6H), 0.88 (t, J ) 6.56 Hz, 3H).
Anal. (C22H34F3NO) C, H, N.
2-(1-Ar a ch id on yl)-5(R)-m eth yloxa zolin e (24). The title
compound was prepared from 260 mg (0.72 mmol) of (R)-
methanandamide (4), 268 mg (1.54 mmol) of p-toluenesulfonyl
fluoride, and 604 mg (2.31 mmol) of tetrabutylammonium
fluoride in 5 mL of THF following the procedure for compound
22 to give 124 mg (0.36 mmol, 50.1% yield) of 24 as a colorless
1
liquid: Rf (50% EtOAc-petroleum ether) 0.34; H NMR (200
MHz, CDCl3) δ 5.23-5.46 (m, 8H), 4.31 (t, J ) 8.50 Hz, 1H),
4.06 (m, 1H), 3.74 (t, J ) 7.45 Hz, 1H), 2.74-2.84 (m, 6H),
2.28 (t, J ) 7.63 Hz, 2H), 2.01-2.19 (m, 4H), 1.63-1.78 (m,
2H), 1.30 (br s, 6H), 1.24 (d, J ) 6.34 Hz, 3H), 0.89 (t, J )
6.24 Hz, 3H). Anal. (C23H37NO) C, H, N.
N-(2-Hyd r oxyeth yl)lin olea m id e (18). The title amide
was prepared from 3.00 g (11.3 mmol) of linoleic acid and 6.90
g (113 mmol) of aminoethanol in benzene following the
procedure described for compound 6 to give 2.79 g (8.63 mmol,
76.6% yield) of a white solid: mp 38-39.5 °C; Rf (5% MeOH-
CH2Cl2) 0.24; 1H NMR (200 MHz, CDCl3) δ 6.00 (br s, 1H),
5.31-5.39 (m, 4H), 3.73 (t, J ) 4.68 Hz, 2H), 3.43 (td, J )
5.01 Hz, 5.09 Hz, 2H), 2.77 (t, J ) 5.45 Hz, 2H), 2.21 (t, J )
7.54 Hz, 2H), 2.03 (m, 4H), 1.67 (m, 2H), 1.31 (br s, 14H), 0.89
(t, J ) 6.30 Hz, 3H). Anal. (C20H37NO2) C, H, N.
(R)-N-(1-Meth yl-2-h yd r oxyeth yl)lin olea m id e (19). This
amide was prepared from 1.00 g (3.76 mmol) of linoleic acid
and 1.41 g (18.8 mmol) of (R)-(-)-2-amino-1-propanol in
benzene following the procedure described for compound 6 to
give 1.07 g (3.17 mmol, 84.5% yield) of 19 as a colorless
liquid: Rf (5% MeOH-CH2Cl2) 0.21; 1H NMR (200 MHz,
CDCl3) δ 5.90 (br s, 1 H), 5.22-5.45 (m, 4H), 3.99-4.07 (m,
1H), 3.47-3.66 (m, 3H), 2.77 (t, J ) 5.58 Hz, 2H), 2.18 (t, J )
7.50 Hz, 2H), 2.00-2.06 (m, 4H), 1.58-1.65 (m, 2H), 1.30 (br
s, 14H), 0.89 (t, J ) 6.07 Hz, 3H). Anal. (C21H39NO2) C, H,
N.
N-(2-Hyd r oxyeth yl)olea m id e (20). Reaction of 3.00 g
(10.6 mmol) of oleic acid and 6.50 g (106 mmol) of aminoethanol
in benzene following the procedure described for compound 6
gave 2.88 g (8.86 mmol, 83.6% yield) of 20 as a white solid:
mp 60-61 °C; Rf (5% MeOH-CH2Cl2) 0.28; 1H NMR (200 MHz,
CDCl3) δ 6.34 (br s, 1H), 5.34 (m, 2H), 3.70 (t, J ) 4.54 Hz,
2H), 3.56 (br s, 1H), 3.41 (m, 2H), 2.20 (t, J ) 7.20 Hz, 2H),
2.00 (m, 4H), 1.69 (m, 2H), 1.30 (br s, 20H), 0.88 (t, J ) 6.00
Hz, 3H). Anal. (C20H39NO2) C, H, N.
(R)-N-(1-Meth yl-2-h ydr oxyeth yl)oleam ide (21). The title
compound was prepared from 1.00 g (3.54 mmol) of oleic acid
and 1.33 g (17.5 mmol) of (R)-(-)-2-amino-1-propanol in
benzene following the procedure described for compound 6 to
give 860 mg (2.53 mmol, 71.6% yield) of a white solid: mp 43-
44 °C; Rf (5% MeOH-CH2Cl2) 0.23; 1H NMR (200 MHz, CDCl3)
δ 5.83 (br s, 1H), 5.22-5.45 (m, 4H), 3.99-4.07 (m, 1H), 3.54-
3.67 (m, 2H), 3.37 (br s, 1H), 2.77 (t, J ) 5.58 Hz, 2H), 2.18 (t,
J ) 6.90 Hz, 2H), 2.00-2.06 (m, 4H), 1.58-1.65 (m, 2H), 1.30
(br s, 14H), 0.88 (t, J ) 6.04 Hz, 3H). Anal. (C21H41NO2) C,
H, N.
Ar a ch id on yla m in e (27). To a magnetically stirred solu-
tion of 50 mg (0.17 mmol) of arachidonyl alcohol in 1 mL of
pyridine was added 29.2 mg (0.255 mmol) of mesyl chloride
at 0 °C. After stirring for 5 h, the reaction mixture was poured
into 2 mL of cold water and extracted with diethyl ether (2 ×
4 mL). The combined ether extracts were washed with 1 N
sulfuric acid and saturated sodium bicarbonate solution and
evaporated in vacuo. The crude mesylate was dissolved in 2
mL of anhydrous DMF, and then a solution of 6.5 mg (0.85
mmol) of sodium azide in 4 mL of anhydrous DMF was added
at room temperature. The reaction mixture was heated at 90
°C for 24 h behind a safety shield. The mixture was cooled to
room temperature, inorganic material was filtered off, and the
filtrate was poured into 1 mL of cold water. Extraction with
diethyl ether (2 × 6 mL), drying (MgSO4), and evaporation
gave an oily residue which was chromatographed on silica gel
(petroleum ether) to afford 39 mg (73%) of arachidonyl azide
as a colorless oil: 1H NMR (200 MHz, CDCl3) δ 5.38 (m, 8H),
3.27 (t, J ) 6 Hz, 2H), 2.81 (m, 6H), 2.11-2.01 (m, 4H), 1.62
(m, 2H), 1.48-1.25 (m, 6H), 0.89 (t, J ) 7 Hz, 3H).
The crude azide was reduced to the title amine as follows.
To a magnetically stirred solution of 132 mg (0.43 mmol) of
arachidonyl azide in 3 mL of dry diethyl ether was added 0.43
mL of a 1.0 M solution of lithium aluminum hydride (0.43
mmol) in THF dropwise at room temperature. The reaction
mixture was refluxed for 3 h and then quenched with wet
diethyl ether. The white suspension was filtered, and the
filtrate was evaporated to dryness. Chromatography on silica
gel (10-50% MeOH in dichloromethane) gave 65 mg (51%) of
arachidonylamine as a colorless oil: TLC (EtOAc) Rf 1.50; 1H
NMR (200 MHz, CDCl3) δ 5.38 (m, 8H), 2.82 (m, 6H), 2.70 (t,
J ) 6.6 Hz, 2H), 2.08 (m, 4H), 1.40 (m, 4H), 1.26 (m, 6H), 0.89
(t, J ) 6.4 Hz, 3H). Anal. (C20H35N) C, H, N.
N-(3-Hyd r oxyp r op ion yl)a r a ch id on yla m in e (25). To a
magnetically stirred solution of 48 mg (0.17 mmol) of arachi-
donylamine in 2 mL of anhydrous dichloromethane was added
58 µL of a 2.0 M solution of trimethylaluminum (0.17 mmol)
in hexane at room temperature. The mixture was stirred for
20 min, and then 12.24 mg (0.17 mmol) of â-propiolactone was
added. The reaction mixture was refluxed for 6 h, quenched
with 1 N HCl, and extracted with dichloromethane. The crude
product was purified by column chromatography on silica gel
(50-80% ethyl acetate in dichloromethane) to afford 51 mg
(83%) of the title compound as an oil: TLC (EtOAc) Rf 0.26;
1H NMR (200 MHz, CDCl3) δ 5.35 (m, 8H), 3.85 (q, J ) 5.4
Hz, 2H), 3.25 (q, J ) 5.4 Hz, 2H), 2.84 (m, 6H), 2.66 (t, J )
6.8 Hz, 2H), 2.05 (m, 4H), 1.57 (m, 2H), 1.35 (m, 6H) 0.89 (t,
J ) 6.5 Hz, 3H). Anal. (C23H39NO2) C, H, N.
N-(2-Acetoxya cetyl)a r a ch id on yla m in e (26). To a mag-
netically stirred solution of 75 mg (0.26 mmol) of arachidonyl-
amine in 2 mL of dry dichloromethane was added 40 µL (0.37
mmol) of acetoxyacetyl chloride at room temperature, and the
mixture was stirred for 1 h. Excess acetoxyacetyl chloride was
destroyed by adding 50 µL of water, solvents were evaporated,
2-(1-Oleyl)oxa zolin e (22). To a magnetically stirred solu-
tion of 604 mg (2.31 mmol) of tetrabutylammonium fluoride
in 5 mL of THF was added a mixture of 268 mg (1.54 mmol)
of p-toluenesulfonyl fluoride and 250 mg (0.77 mmol) of N-(2-
hydroxyethyl)oleylamide (20) in 5 mL of THF at room tem-
perature. After stirring at reflux for 2 h, the reaction mixture
was filtered through a pad of Celite. The filtrate was collected
and evaporated in vacuo, and the residue was chromato-
graphed on silica gel (10% EtOAc-petroleum ether) to give
114 mg (0.37 mmol, 48.0% yield) of 22 as a colorless liquid:
Rf (50% EtOAc-petroleum ether) 0.12; 1H NMR (200 MHz,
CDCl3) δ 5.32-5.37 (m, 2H), 4.22 (t, J ) 9.51 Hz, 2H), 3.82 (t,
J ) 9.34 Hz, 2H), 2.27 (t, J ) 7.52 Hz, 2H), 2.01 (d, J ) 5.27
Hz, 4H), 1.59-1.66 (m, 2H), 1.31 (br s, 20H), 0.89 (t, J ) 6.24
Hz, 3H). Anal. (C20H37NO) C, H, N.
2-(1-Lin oleyl)oxa zolin e (23). This compound was pre-
pared from 250 mg (0.77 mmol) of N-(2-hydroxyethyl)linole-
amide (18), 268 mg (1.54 mmol) of p-toluenesulfonyl fluoride,