New Non-Peptide G Protein Activators
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19 3137
(equimolar amount) in 10-20 mL of dry THF was added, and
the mixture was stirred overnight at ambient temperature.
The solvent was removed in vacuo, and the residue was
dissolved in CH2Cl2, extracted with saturated NaHCO3 (3×),
10% acetic acid (3×), water (3×), dried over Na2SO4, and
evaporated under reduced pressure. The resulting amino acid
amides were deprotected by the following methods.
BOC Gr ou p : A solution of BOC-protected amino acid
amides (3-11 mmol) in 15-25 mL of 1 N HCl was refluxed
for 2 h and evaporated to dryness in vacuo. The residue was
dissolved in 10-15 mL of water, alkalized with 2 N NaOH
(pH 13), and extracted with CH2Cl2. The organic layer was
dried over Na2SO4 and evaporated to dryness under reduced
pressure.
P h t Gr ou p : To a solution of phthalimido-protected amino
acid amides (3-5.3 mmol) in 10-20 mL of EtOH was added
hydrazine hydrate (1.1 equiv). After 1 h the mixture was
acidified with 10 mL of 1 N HCl and refluxed for 2 h. The
precipitate was separated, and the solution was alkalized with
2 N NaOH, extracted with CH2Cl2/2-propanol (3:1), dried over
Na2SO4, and evaporated to dryness under reduced pressure.
NO2 Gr ou p : A solution of nitro-protected arginine amide
(0.60 g, 1.5 mmol) in 30 mL of MeOH, 10 mL of acetic acid,
and 10% Pd/C (0.06 g) was stirred under hydrogen (1 bar) for
48 h. The mixture was filtered through Celite and washed
with MeOH, and the solvent was evaporated under reduced
pressure.
The deprotected alkyl amino acid amides or the nitroargi-
nine derivative was purified by rotatory chromatography
[eluent: CH2Cl2/MeOH (gradient from 19:1 to 15:1), ammonia
atmosphere] and recrystallized from EtOH/Et2O as a free base
(20, 22), hydrochloride (11), or hydrogen maleate (15-17, 23,
27, 29).
mixture was stirred overnight. The precipitated urea was
removed, and the solvent was evaporated under reduced
pressure. Then 100 mL of CH2Cl2 was added, and the solution
was subsequently washed with 50 mL of 5% K2CO3, 50 mL of
2 N citric acid, and 50 mL of water and dried over Na2SO4.
Evaporation of the solvent gave the BOC-protected product.
A solution of 10 mL of trifluoroacetic acid in 10 mL of CH2Cl2
was added to the residue and stirred for 0.5 h. Evaporation
of the solvent under reduced pressure, dissolving of the residue
in 2 mL of EtOH, and dilution with 200 mL of Et2O gave the
crude product after cooling (-20 °C). Recrystallization in
EtOH/Et2O gave 19 as the trifluoroacetate (yield 2.10 g,
48%): mp 97-98 °C; 1H NMR (DMSO-d6) δ 8.42 (br*, 1H, NH),
8.19 (br*, 3H, NH3+), 7.44 (br*, 1H, NH2), 6.92 (br*, 1H, NH2),
3.74 (t, J ) 6.2 Hz, 1H, CH), 3.20-3.00 (m, 2H, CH2), 2.20-
2.00 (m, 2H, CH2), 2.00-1.80 (m, 2H, CH2), 1.50-1.30 (m, 2H,
CH2), 1.30-1.10 (m, 18H, 9 CH2), 0.86 (t, J ) 6.3 Hz, 3H, CH3);
MS m/ z (FAB+) 314 ([M + H]+, 33), 297 (33), 296 (24), 186
.
(20), 101 (31), 84 (100). Anal. (C17H35N3O2 0.9CF3COOH) C,
H, N.
N-Dod ecyl L-Lysin e Am id e (24) a n d N-Dod ecyl D-
Lysin e Am id e (25). To a solution of dodecylamine (1.63 g,
8.8 mmol, or 1.17 g, 6.3 mmol) in 80 mL of CH2Cl2 were added
90 mL of water and a solution of BOC-L-Lys(BOC)-OH (9) (3.07
g, 8.8 mmol) or BOC-D-Lys(BOC)-OH (10) (2.18 g, 6.3 mmol)
in 10 mL of CH2Cl2. Finely powdered HOBT (1.19 g, 8.8 mmol,
or 0.85 g, 6.3 mmol) was added, and the mixture was cooled
down to 0 °C. Then EDC (1.87 g, 9.7 mmol, or 1.33 g, 6.9
mmol) was added, and the temperature was kept at 0 °C for 3
h. The ice bath was removed, and the mixture was stirred
for 24 h at ambient temperature. To the reaction mixture was
added 50 mL of 1 N HCl, and the organic phase was separated,
subsequently washed with 50 mL of 0.5 N HCl, 40 mL of brine,
40 mL of 1 N NaHCO3 (2×), and 30 mL of brine (2×), and
dried over Na2SO4. Evaporation of the solvent under reduced
pressure gave 4.24 g of oil. The oil was dissolved in 50 mL of
CH2Cl2, and 50 mL of 5-6 N HCl in 2-propanol was added
and stirred for 24 h. Evaporation of the solvent and recrys-
tallization of the residue from EtOH/Et2O gave 24 and 25 as
dihydrochlorides (yield 1.50 g, 44%, or 0.91 g, 37%): mp 105-
106 or 106-107 °C.
N-Dod ecyl L-lysin e a m id e (24): 1H NMR (DMSO-d6) δ
8.58 (t*, J ) 5.4 Hz, 1H, NH), 8.26 (br*, 3H, NH3+), 8.02 (br*,
3H, NH3+), 3.73 (t, J ) 6.1 Hz, 1H, CH), 3.20-3.00 (m, 2H,
CH2), 2.80-2.70 (m, 2H, CH2), 1.80-1.70 (m, 2H, CH2), 1.50-
1.10 (m, 22H, 11 CH2), 0.86 (t, J ) 6.7 Hz, 3H, CH3); MS m/ z
(FAB+) 627 ([2M + H]+, 1), 314 ([M + H]+, 28), 297 (3), 295
(3), 242 (2), 186 (15), 184 (4), 129 (4), 112 (5), 84 (100), 55 (49),
43 (72). Anal. (C18H39N3O‚2.3HCl) C, H, N.
N-Dod ecyl D-lysin e a m id e (25): 1H NMR (DMSO-d6) δ
8.60 (t*, J ) 5.4 Hz, 1H, NH), 8.26 (br*, 3H, NH3+), 8.05 (br*,
3H, NH3+), 3.73 (t, J ) 6.2 Hz, 1H, CH), 3.20-3.00 (m, 2H,
CH2), 2.80-2.70 (m, 2H, CH2), 1.80-1.70 (m, 2H, CH2), 1.50-
1.10 (m, 22H, 11 CH2), 0.86 (t, J ) 6.6 Hz, 3H, CH3); MS m/ z
(FAB+) 627 ([2M + H]+, 1), 314 ([M + H]+, 36), 297 (3), 295
(4), 242 (3), 186 (41), 184 (7), 129 (3), 112 (2), 84 (90), 55 (60),
43 (100). Anal. (C18H39N3O.2.2HCl) C, H, N.
Alk yl-Su bstitu ted Di- a n d Tr ia m in es 12, 18, 21, 26, 28,
a n d 30. A solution of the amino acid amides (11, 17, 20, 24,
27, 29) (0.5-2.1 mmol) in 10 mL of dry THF was added to a
suspension of LiAlH4 (2 equiv; 4 equiv for 12 and 21) in 20-
50 mL of dry THF (activated via stirring for 30 min under
reflux). The mixture was refluxed for 6-10 h under argon
atmosphere. The LiAlH4 was hydrolyzed with 1 N NaOH, and
the organic layer was decanted. The inorganic pulp was
washed three times with 40 mL of THF, and the THF phase
was dried over Na2SO4 and evaporated under reduced pres-
sure. The resulting oil was purified by rotatory chromatog-
raphy [eluent: CH2Cl2/MeOH (2.5:1), ammonia atmosphere]
and recrystallized as a free base (21) or the hydrogen maleate.
N-(2,6-Dia m in oh exyl)h exa d ecyla m in e (30): 1H NMR
(DMSO-d6) δ 6.05 (s, 6H, 6 Mal-H), 3.34 (m, 1H, CH), 3.08-
2.70 (m, 6H, 3 N-CH2), 1.54 (m, 6H, 3 N-CH2-CH2), 1.24 (m,
28H, 14 CH2), 0.84 (t, J ) 7.0 Hz, 3H, CH3); MS m/ z (FAB+)
356 ([M + H]+, 13), 98 (81), 96 (20), 84 (51), 82 (18), 81 (25),
N-Hexa d ecyl L-lysin e a m id e (29): 1H NMR (DMSO-d6) δ
8.35 (br*, 2H, NH2), 6.02 (s, 4H, 4 Mal-H), 3.66 (m, 1H, CH),
3.10 (m, 2H, N-CH2), 2.74 (m, 2H, N-CH2), 1.66-1.42 (m, 6H,
3 CH2), 1.24 (br, 28H, 14 CH2), 0.84 (t, J ) 6.9 Hz, 3H, CH3);
MS m/ z (FAB+) 370 ([M + H]+, 6), 84 (100), 82 (20), 55 (46),
43 (57), 41 (67), 30, (48). Anal. (C22H47N3O‚2C4H4O4‚1.5H2O)
C, H, N.
N-Dod ecyl Glycylglycin e Am id e (13). A solution of
dodecylamine (3.71 g, 20.0 mmol), Gly-Gly(Z)-OH (2) (5.33 g,
20.0 mmol), and HOBT (2.97 g, 22.0 mmol) in 150 mL of dry
THF was cooled to 0 °C, and DCC (4.54 g, 22.0 mmol) in 10
mL of THF was added. The mixture was stirred at 0 °C for 1
h. Then the temperature was raised to ambient temperature,
and the mixture was stirred overnight; 150 mL of EtOAc and
150 mL of MeCN were added. The mixture was heated to
reflux and filtered hot by gentle suction. The solution was
cooled to ambient temperature, and the precipitate was
isolated (6.68 g of crude product). The crude product (1.00 g)
was dissolved in 100 mL of MeOH, ammonium formate (0.60
g) and 10% Pd/C (0.20 g) were added, and the mixture was
stirred for 12 h. The solution was filtered through Celite, the
carbon was washed with MeOH, and the solvent was evapo-
rated under reduced pressure. To the residue was added 50
mL of 1 N NaOH, and the solution was extracted with 50 mL
of CH2Cl2 (3×). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The residue was dissolved
in the minimum amount of EtOH, acidified with 5-6 N HCl
in 2-propanol; afterwards 50 mL of Et2O was added, and the
precipitate (0.40 g) was isolated. Recrystallization from EtOH/
Et2O gave 13 as the hydrochloride (yield 0.25 g, 25%): mp
1
176-180 °C; H NMR (DMSO-d6) δ 8.59 (br*, 1H, NH), 7.96
(br*, 3H, NH3+), 3.75 (d, J ) 5.7 Hz, 2H, CH2), 3.58 (s, 2H,
CH2), 3.10-3.00 (m, 2H, CH2), 1.40-1.30 (m, 2H, CH2), 1.30-
0.90 (m, 18H, 9 CH2), 0.86 (t, J ) 6.7 Hz, 3H, CH3); MS m/ z
(FAB+) 300 ([M + H]+, 11), 243 (22), 186 (22), 55 (46), 41 (75),
30 (100). Anal. (C16H33N3O2‚HCl) C, H, N.
N-Dod ecyl L-Glu ta m in e Am id e (19). To a solution of
dodecylamine (1.90 g, 10.2 mmol) and BOC-L-Gln-OH (6) (2.5
g, 10.2 mmol) in 40 mL of dry THF was added HOBT (1.52 g,
11.2 mmol), and the solution was cooled to 0 °C. Then a
solution of DCC (2.31 g, 11.2 mmol) in 10 mL of THF was
added. Stirring at 0 °C was continued for 1 h, then the
temperature was raised to ambient temperature, and the