Small Molecules That Directly Activate Gi Proteins
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 20 6501
(m, 2H, CH2 piperidine), 2.64 (t, J ) 7.8 Hz, 2H, CH2CH2N),
3.20 (s, 3H, CH3N), 3.53-3.61 (m, 2H, CH2 piperidine), 4.08-
4.14 (m, 2H, CH2 piperidine). Anal. (C31H61IN2O2) C, H, N.
The cold solution was made alkaline with 10% NaOH and
extracted with CH2Cl2. Anhydrification and evaporation of the
solvent gave a mixture that was purified by column chroma-
tography with the eluent reported in Table 3 to give 33: 1H
NMR (CDCl3) δ 0.88 (t, J ) 6.6 Hz, 3H, CH3CH2), 1.18-1.32
(m, 24H, CH2-C), 1.35 (bs, 2H, NH2), 1.43-1.55 (m, 2H, CH2-
CH2-NH2), 1.63-1.74 (m, 3H, CH2 piperidine + CH), 1.86-
2.02 (m, 2H, CH2 piperidine), 2.38 (t, J ) 6.1 Hz, 2H,
CHCH2NH2), 2.47 (d, J ) 4.0 Hz, 2H, NCH2CH), 2.50-2.61
(m, 2H, CH2 piperidine), 2.78 (t, J ) 6.1 Hz, 2H, CH2CH2NH2),
2.83-2.95 (m, 4H, CH2 piperidine + NH2CH2C); 13C NMR
(CDCl3) δ 17.69 (q), 23.12 (t), 27.78 (t), 29.78 (t), 30.04 (t), 30.11
(t), 31.04 (t), 32.35 (t), 36.35 (d), 39.38 (t), 50.54 (t), 54.22 (t),
56.18 (t), 61.63 (t). Anal. (C23H49N3) C, H, N.
1-Methyl-1-pentadecyl-[4,4′]-bipiperidinium Chloride
(23). Two equivalents of 6 M HCl were added to 50 dissolved
in CH3CN. After 2 h at room temperature and 5 min at 60 °C,
the solution was made alkaline with 10% NaOH and extracted
with CH2Cl2. Anhydrification and evaporation of the solvent
gave 23 in 30% yield: mp 180-181 °C from anhydrous ether;
1H NMR (CDCl3) δ 0.88 (t, J ) 6.6 Hz, 3H, CH3CH2), 1.19-
1.31 (m, 24H, 12CH2C), 1.32-1.39 (m, 2H, CH2CH2N), 1.65-
1.89 (m, 12H, CH2 piperidine), 1.91-2.02 (m, 2H, CH2 piperi-
dine), 2.61 (t, J ) 7.7 Hz, 2H, CH2CH2N), 3.02-3.14 (m, 2H,
CH2 piperidine), 3.21 (s, 3H, CH3N), 3.32-3.43 (m, 2H, CH2
piperidine), 3.65 (bs, 1H, NH). Anal. (C26H53ClN2) C, H, N.
Using the same method and starting from 57, compound
58 was obtained and purified by flash chromatography.
(1-Benzyl-4-piperidinyl)tridecylamine (51). Two equiva-
lents of NEt3 and 1 equiv of bromotridecane were added to
4-amino-1-benzylpiperidine in CH3CN. After 3 h at reflux, the
solvent was removed, the residue made alkaline with 10%
NaOH, and the solution extracted with CH2Cl2. Anhydrifica-
tion and evaporation of the solvent gave a mixture from which
51 was purified by flash chromatography using the eluent
1-Pentadecyl-4-piperidinylamine (28). To 1 equiv of 48
in anhydrous MeOH were added molecular sieves (3 Å) (1 g of
derivative × 8 g of molecular sieves), 10 equiv of ammonium
acetate, and 1 equiv of NaBH3CN, under N2. After 24 h at room
temperature, the solvent was removed, 5 mL of H2O was
added, and the solution was adjusted at pH 2 with 6 N HCl.
After evolution of gas had ceased, the solution was neutralized
with KOH, the salts were filtered off, and the solution was
extracted with CH2Cl2. Anhydrification and evaporation of the
solvent gave 28 pure: IR (Nujol) ν 3300-3400 (NH2) cm-1; 1H
NMR (CDCl3) δ 0.86 (t, J ) 6.9 Hz, 3H, CH3CH2), 1.15-1.39
(m, 26H, 12CH2C + CH2 piperidine), 1.39-1.55 (m, 2H,
CH2CH2N), 1.73-1.89 (m, 2H, CH2 piperidine), 1.89-2.07 (m,
2H, CH2N piperidine), 2.08 (bs, 2H, NH2), 2.29 (t, J ) 8.0 Hz,
2H, CH2CH2N), 2.56-2.73 (m, 1H, CH), 2.79-2.94 (m, 2H,
CH2N piperidine); 13C NMR (CDCl3) δ 14.56 (q, CH3), 23.12
(t, CH2), 27.58 (t, CH2), 28.15 (t, CH2), 29.78 (t, CH2), 30.02 (t,
CH2), 30.09 (t, CH2), 32.33 (t, CH2), 36.32 (t, CH2), 49.19 (d,
CH), 53.00 (t, CH2), 59.28 (t, CH2). Anal. (C20H42N2) C, H, N.
reported in Table 6: IR (neat) ν 3300 (NH) cm-1 1H NMR
;
(CDCl3) δ 0.89 (t, J ) 6.6 Hz, 3H, CH3CH2), 1.21-1.37 (m,
20H, 10CH2C), 1.37-1.57 (m, 4H, CH2CH2NH + CH2 piperi-
dine), 1.80-1.93 (m, 2H, CH2 piperidine), 1.93-2.09 (m, 2H,
CH2N), 2.39-2.53 (m, 1H, CH), 2.62 (t, J ) 7.3 Hz, 2H,
CH2CH2NH), 2.80-2.93 (m, 2H, CH2N), 3.50 (s, 2H, CH2Ph),
7.21-7.38 (m, 5H, CH aromatics). Anal. (C25H44N2) C, H, N.
Using the method described above, starting from ethyl
isonipecotate, 1-piperidone hydrochloride monohydrate,
1-nitrosopiperazine, 1-amino-4-benzylpiperazine, 30, and 6346
and using the proper bromoalkane or alkanoyl chloride,
compounds 48,39 52, 53, 59, 61, and 62 were obtained, which
were purified by flash chromatography using the eluent
reported in Table 6. Compounds 65 and 64 were purified by
column chromatography (eluent in Table 6), whereas com-
pounds 31a, 54, and 55 were obtained pure.
Using the same method, starting from 59, compound 29 was
obtained.
4-Pentadecylpiperazin-1-ylamine (34). Compound 61
(0.58 mmol) in 0.6 mL of H2O and 0.3 mL of MeOH cooled at
0 °C was added to 0.7 mmol of concentrated HCl and 1.5 mmol
of Zn. After a while, 3.2 mmol of concentrated HCl was added,
keeping the mixture for 30 min at room temperature. Finally,
the suspension was refluxed for 2 h. The mixture was then
basified with 50% NaOH and extracted with CH2Cl2. Anhy-
drification and evaporation of the solvent gave a mixture that
was purified by column chromatography with the eluent
reported in Table 4 to give 34: IR (Nujol) ν 3300-3600 (NH2)
In the same reaction of 30, when DMF was used instead of
CH3CN, compound 31b was obtained: IR (Nujol) ν 3300-3200
1
(NH), 1645 (NHCOH), 1633 (CONH) cm-1; H NMR (CDCl3)
δ 0.88 (t, J ) 6.8 Hz, 3H, CH3CH2), 1.20-1.37 (m, 24 H, 12
CH2C), 1.41-1.56 (m, 2H, CH2CH2N), 1.66-1.92 (m, 4H, 2CH2-
piperidine), 1.94-2.08 (m, 3H, CH2N + CH), 2.42 (t, J ) 6.3
Hz, 2H, NCH2CH2NH), 2.78-2.98 (m, 2H, CH2N), 3.18-3.26
(m, 2H, CH2NHCO), 3.28-3.41 (m, 2H, CH2NHCHO), 5.60 (bs,
1H, NH), 6.18 (bs, 1H, NH); 13C NMR (CDCl3) δ 14.48 (q, CH3),
23.12 (t, CH2), 27.34 (t, CH2), 29.38 (t, CH2), 29.73 (t, CH2),
29.78 (t, CH2), 30.11 (t, CH2), 32.33 (t, CH2), 35.04 (t, CH2),
39.72 (t, CH2), 39.85 (t, CH2), 43.75 (d, CH), 53.31 (t, CH2),
53.54 (t, CH2), 56.80 (t, CH2), 161.56 (d, CHO), 175.04 (s, CO).
Anal. (C24H47N3O2) C, H, N.
1
cm-1; H NMR (CDCl3) δ 0.89 (t, J ) 6.9 Hz, 3H, CH3CH2),
1.16-1.38 (m, 24H, 12CH2C), 1.40-1.64 (m, 2H, CH2CH2N),
1.58 (bs, 2H, NH2), 2.31 (t, J ) 8.0 Hz, 2H, CH2CH2N), 2.36-
2.48 (m, 4H, 2CH2 piperazine), 2.91 (t, J ) 5.1 Hz, 4H, 2CH2
piperazine); 13C NMR (CDCl3) δ 14.56 (q, CH3), 23.12 (t, CH2),
27.11 (t, CH2), 28.05 (t, CH2), 29.78 (t, CH2), 30.02 (t, CH2),
30.09 (t, CH2), 32.33 (t, CH2), 46.45 (t, CH2), 55.02 (t, CH2),
59.90 (t, CH2). Anal. (C19H41N3) C, H, N.
With the same method, starting from 62, compound 35 was
obtained. Both compounds were transformed into the hydro-
chlorides as described before.
1-Benzylpiperidine-4-carboxylic acid pentadecyl-
amide (57). To N-benzylisonipecotic acid 5641 (0.55 g; 2.1
mmol) in CHCl3, cooled to 0 °C and under nitrogen was added
0.39 mL (5.4 mmol) of NEt3 and 3.1 mL (3.2 mmol) of ethyl
chloroformate. After 1 h, pentadecylamine (0.73 g; 3.2 mmol)
in a few milliliters of CHCl3 was added, and the mixture was
kept at room temperature for 20 min. The solution was then
basified with NaHCO3 and extracted with CH2Cl2. Anhydri-
fication and evaporation of the solvent gave a residue that was
purified by chromatography using eluent A, to give 57 (yield
56%): mp 47-50 °C; IR (Nujol) ν 3307 (NHCO), 1640 (CONH)
Pentadecylpiperazin-1-ylamine (36). Five equivalents of
HCOONH4 and 0.5 equiv of 10% Pd/C were added to a solution
of 64 in anhydrous MeOH under N2. The mixture was refluxed
for 8 h, then the carbon was filtered off and the solution was
evaporated. The residue was made alkaline with 10% NaOH
and extracted with CH2Cl2. Anhydrification and evaporation
of the solvent afforded 36 pure: IR (Nujol) ν 3200-3400 (NH)
1
cm-1; H NMR (CDCl3) δ 0.88 (t, J ) 6.6 Hz, 3H, CH3CH2),
1.17-1.40 (m, 24H, 12CH2C), 1.40-1.59 (m, 2H, CH2CH2NH),
1.67-1.91 (m, 4H, 2CH2 piperidine), 1.91-2.18 (m, 3H, CH2N
+ CH), 2.86-3.00 (m, 2H, CH2N), 3.23 (m, 2H, CH2CH2NH),
3.49 (s, 2H, CH2Ph), 5.57 (bt, 1H, NH), 7.20-7.39 (m, 5H, CH
aromatics). Anal. (C28H48N2O) C, H, N.
1
cm-1; H NMR (CDCl3) δ 0.88 (t, J ) 6.6 Hz, 3H, CH3CH2),
1.13-1.38 (m, 24H, 12CH2C), 1.40-1.63 (m, 3H, CH2CH2N +
NH), 2.30 (t, J ) 7.9 Hz, 2H, CH2CH2N), 2.36-2.49 (m, 4H,
2CH2NH piperazine), 2.89 (t, J ) 5.1 Hz, 4H, 2CH2NNH); 13
C
[1-(2-Aminoethyl)-4-piperidylmethyl]pentadecyl-
amine (33). Borane methyl sulfide complex (2 M in THF; 2.2
mmol) was added to 31a (0.75 mmol) in THF anhydrous at
reflux under nitrogen. After 1 h, the solution was treated with
4.9 mmol of 6 M HCl and maintained at reflux for 30 min.
NMR (CDCl3) δ 14.56 (q, CH3), 23.12 (t, CH2), 27.09 (t, CH2),
28.07 (t, CH2), 29.78 (t, CH2), 30.02 (t, CH2), 30.09 (t, CH2),
32.33 (t, CH2), 46.48 (t, CH2), 55.04 (t, CH2), 59.92 (t, CH2).
Anal. (C19H41N3) C, H, N.