Indoles as Inhibitors of the Deacetylase SIRT1
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 8051
M in THF) was added dropwise to a solution of 2.2 mL of TFA
in 2.2 mL of dry THF and the mixture stirred for 5 min. A
solution of 10 (100 mg, 0.29 mmol) in 0.5 mL of THF was
added, and the mixture was stirred for 2.5 h at room temper-
ature. Water (15 mL) was added slowly, and the resulting
mixture was basified with 1 N NaOH to pH 10 and extracted
with DCM (3 × 50 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL), dried over Na2-
SO4, and evaporated in vacuo. The residue was purified by
silica gel column chromatography (10% MeOH in DCM) to give
74 mg (74%) of 6-chloro-2,3,4,4a,9,9a-hexahydro-1H-car-
bazole-1-carboxylic acid (1-phenylethyl)amide: LCMS tR
) 1.39 min; m/z ) 355 (100), 357 (35) (MH+).
The above amide intermediate was deprotected as for 1 to
give 26 mg (50%) of 13 as a white solid: 1H NMR (CD3OD) δ
1.04-1.23 (m, 2H), 1.28-1.48 (m, 1H), 1.71-1.84 (m, 4H),
2.61-2.69 (m, 1H), 2.91-3.01 (m, 1H), 3.97-4.01 (m, 1H), 6.65
(d, J ) 8.2 Hz, 1H), 6.95 (dd, J ) 8.2, 2.1 Hz, 1H), 7.04 (d, J
) 2.1 Hz, 1H); LCMS tR ) 0.97 min; m/z ) 251 (100), 253 (32)
(MH+), 234 (31), 236 (9).
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxyl-
ic Acid (Tetrahydropyran-2-yloxy)amide (14). To carboxy-
lic acid 8 (110 mg, 0.43 mmol) in 2 mL of DMF were added
triethylamine (90 µL, 0.65 mmol), O-THP-hydroxylamine (130
mg, 1.1 mmol), and EDC (100 mg, 0.52 mmol). The resulting
mixture was stirred overnight. Solvent was evaporated in
vacuo and the residual oil was dissolved in EtOAc (10 mL),
washed with 1 N HCl (3 × 10 mL), and dried over MgSO4.
The organic layer was evaporated in vacuo and the residue
was purified by silica gel column chromatography (EtOAc/
heptane 1:1) to give 15 mg (10%) of 14 as a light yellow oil:
1H NMR (CDCl3) δ 1.16-1.75 (m, 8H), 1.93-2.01 (m, 1H),
2.03-2.10 (m, 1H), 2.55-2.64 (m, 2H), 3.42-3.55 (m, 1H),
3.59-3.67 (m, 1H), 3.79-3.88 (m, 1H), 4.86-4.93 (m, 1H),
6.98-7.03 (m, 1H), 7.08-7.11 (m, 1H), 7.33-7.40 (m, 1H),
8.51-8.61 (m, 1H), 8.76-8.85 (m, 1H); LCMS tR ) 1.45 min;
m/z ) 371 (15), 373 (5) (M + Na+), 265 (22), 267 (8), 204 (100),
206 (34).
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-hydroxyam-
ic Acid (15). O-THP-hydroxamic acid 14 (15 mg, 0.04 mmol)
was dissolved in 1 mL of DCM, 4 N HCl in dioxane (20 µL,
0.08 mmol) was added, and the reaction mixture was stirred
at room temperature for 2 h. Solvent was evaporated in vacuo
and the residue was purified by silica gel column chromatog-
raphy (EtOAc/heptane 1:1) to give 10 mg (88%) of 15 as a
colorless oil: 1H NMR (CD3OD) δ 1.59-1.71 (m, 1H), 1.86-
2.01 (m, 3H), 2.58-2.65 (m, 2H), 3.55-3.60 (m, 1H), 6.90 (dd,
J ) 8.6, 2.0 Hz, 1H), 7.11 (d, J ) 8.6 Hz, 1H), 7.41 (d, J ) 2.0
Hz, 1H); LCMS tR ) 1.64 min; m/z ) 265 (100), 267 (32) (MH+).
Solvent was evaporated in vacuo and the residue was dissolved
in EtOAc (5 mL), washed with saturated NaHCO3 (2 × 5 mL),
and dried over Na2SO4. The organic layer was evaporated in
vacuo, and the residue was purified by silica gel column
chromatography (DCM/MeOH/NH4OH 97.5/2.5/0.1 to 90/10/
0.1) to give 10 mg (50%) of 20 as an off-white solid: 1H NMR
(CD3OD) δ 3.03-3.28 (m, 2H), 3.60-3.69 (m, 1H), 3.79-3.88
(m, 1H), 5.41 (s, 1H), 7.21 (dd, J ) 8.8, 2.1 Hz, 1H), 7.44 (d, J
) 8.8 Hz, 1H), 7.55 (brd, J ) 2.1 Hz, 1H); LCMS tR ) 1.43
min; m/z ) 250 (100), 252 (39) (MH+).
6-Bromo-2,3,4,9-tetrahydro-1H-â-carboline-1-carboxa-
mide (21) was prepared according to the method described
above for compound 20. Thus carboxylic acid 19 gave 23 mg
(45%) of 21 as an off-white solid: 1H NMR (CD3OD) δ 2.91-
3.10 (m, 2H), 3.48-3.59 (m, 1H), 3.68-3.77 (m, 1H), 5.29 (s,
1H), 7.23 (dd, J ) 8.5, 1.7 Hz, 1H), 7.29 (d, J ) 8.5 Hz, 1H),
7.61 (brd, J ) 1.7 Hz, 1H); LCMS tR ) 1.43 min; m/z ) 294
(98), 296 (100) (MH+).
2-Acetyl-6-chloro-2,3,4,9-tetrahydro-1H-â-carboline-1-
carboxylic Acid (22). Carboxylic acid 18 (250 mg, 1 mmol)
was dissolved in dioxane (5 mL). A solution of Na2CO3 (210
mg, 2 mmol) in water (5 mL) and acetic anhydride (186 µL, 2
mmol) were added, and the reaction mixture was stirred
overnight at room temperature. Solvent was evaporated in
vacuo, and the residue was dissolved in EtOAc (30 mL),
washed with 0.5 N HCl (15 mL), and dried over Na2SO4. The
EtOAc solution was evaporated in vacuo to give 160 mg (55%)
of 22 as a yellow oil, which was used without further purifica-
tion.
2-Acetyl-6-chloro-2,3,4,9-tetrahydro-1H-â-carboline-1-
carboxamide (23). Carboxylic acid 22 (50 mg, 0.17 mmol),
EDC (50 mg, 0.26 mmol), and HOBt (35 mg, 0.26 mmol) were
dissolved in DCM (2 mL), and the resulting mixture was
stirred for 1 h. NH4OH (0.24 mL, 28% in water) was added,
and the reaction mixture was stirred overnight. Solvent was
evaporated in vacuo, and the residue was dissolved in EtOAc
(3 mL), washed with water (2 × 2 mL), and dried over Na2-
SO4. The EtOAc solution was evaporated in vacuo and the
residue was purified by HPLC on a Hyperprep HS C18 column
(0.1% TFA in 20% aqueous acetonitrile to 0.1% TFA in
acetonitrile over 7.5 min) to give 8 mg (16%) of 23 as a colorless
oil: 1H NMR (CD3OD) δ 2.30 (s, 3H), 2.78-2.88 (m, 2H), 3.58-
3.69 (m, 1H), 4.17-4.28 (m, 1H), 6.01 (s, 1H), 7.06 (dd, J )
8.5, 2.0 Hz, 1H), 7.32 (d, J ) 8.5 Hz, 1H), 7.42 (brd, J ) 2.0
Hz, 1H); LCMS tR ) 1.15 min; m/z ) 292 (100), 294 (35) (MH+).
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxyl-
ic Acid (24).39 4-Chlorophenylhydrazine hydrochloride (240
mg, 1.34 mmol) and cyclohexanone-3-carboxylic acid (200 mg,
1.41 mmol) were added to AcOH (4 mL). The resulting mixture
was stirred at room temperature for 1 h and then refluxed for
5 h. Ice water (10 mL) was added, and the mixture was cooled
at 0 °C. The precipitate was filtered and recrystallized from
EtOH to yield 48 mg (14%) of 24 as white crystals: 1H NMR
(DMSO-d6) δ 1.76-1.87 (m, 1H), 2.09-2.19 (m, 1H), 2.54-2.66
(m, 1H), 2.67-2.83 (m, 1H), 2.86-2.93 (m, 1H), 2.83-2.89 (m,
2H), 6.97 (dd, J ) 8.2, 2.0 Hz, 1H), 7.26 (d, J ) 8.2 Hz, 1H),
7.36 (brd, J ) 2.0 Hz, 1H), 10.93 (bs, 1H), 12.33 (m, 1H); LCMS
tR ) 1.39 min; m/z ) 250 (100), 252 (31) (MH+).
6-Bromo-2,3,4,9-tetrahydro-1H-carbazole-2-carboxyl-
ic acid (25) was prepared according to the method described
above for compound 24. Thus, 4-bromophenylhydrazine hy-
drochloride gave 350 mg (89%) of 25 as a white solid: 1H NMR
(DMSO-d6) δ 1.73-1.84 (m, 1H), 2.10-2.16 (m, 1H), 2.52-2.58
(m, 1H), 2.61-2.68 (m, 1H), 2.72-2.81 (m, 1H), 2.83-2.89 (m,
2H), 7.03 (dd, J ) 8.1, 1.9 Hz, 1H), 7.18 (d, J ) 8.1 Hz, 1H),
7.44 (brd, J ) 1.9 Hz, 1H), 10.91 (bs, 1H), 12.27 (m, 1H); LCMS
tR ) 1.49 min; m/z ) 294 (100), 296 (99) (MH+).
6-Chloro-2,3,4,9-tetrahydro-1H-â-carboline-1-carboxy-
lic Acid (18).38 A solution of glyoxylic acid (110 mg, 1.2 mmol)
in water (1 mL) followed by 1 N KOH (1 mL) was added
dropwise to a suspension of 16 (210 mg, 1.07 mmol) in 5:1
water/dioxane (15 mL). The reaction mixture was stirred at
room temperature overnight. The precipitate was filtered,
washed with water, and dried in a vacuum oven to give 63
mg (23%) of 18 as an off-white powder: 1H NMR (DMSO-d6)
δ 2.74-2.86 (m,1H), 2.87-2.97 (m, 1H), 3.23-3.43 (m, 2H),
4.70 (s, 1H), 7.03 (dd, J ) 2.0, 8.6 Hz, 1H), 7.43 (brd, J ) 2.0
Hz, 1H), 7.46 (d, J ) 8.6 Hz, 1H), 8.81-9.20 (m, 1H), 10.97
(bs, 1H).
6-Bromo-2,3,4,9-tetrahydro-1H-â-carboline-1-carboxy-
lic acid (19) was prepared according to the method described
above for compound 18. Thus indole 17 gave 210 mg (67%) of
19 as an off-white solid: 1H NMR (DMSO-d6) δ 2.77-2.89 (m,
2H), 3.28-3.49 (m, 2H), 4.72 (s, 1H), 7.15 (dd, J ) 8.6, 1.9 Hz,
1H), 7.43 (d, J ) 8.6 Hz, 1H), 7.58 (d, J ) 1.9 Hz, 1H), 10.98
(bs, 1H).
6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxam-
ide (26). EDC (44 mg, 0.23 mmol) was added to a suspension
of 24 (48 mg, 0.19 mmol) and HOBt (31 mg, 0.23 mmol) in
DCM (5 mL) at 0 °C and the mixture was stirred for 5 min.
S-R-Methylbenzylamine (30 µL, 0.23 mmol) was added and the
reaction mixture was stirred overnight at room temperature.
Appearance of product was monitored by TLC (Rf ) 0.30,
6-Chloro-2,3,4,9-tetrahydro-1H-â-carboline-1-carboxa-
mide (20). Carboxylic acid 18 (20 mg, 0.08 mmol) was
dissolved in 4:1 DCM/DMF (2 mL), and PyAOP (50 mg, 0.1
mmol) was added. After stirring of the reaction mixture for
30 min, 30% aqueous NH4OH (20 µL) was added, and the
resulting mixture was stirred at room temperature overnight.