J TT-608: A New Class of Antidiabetic Agent
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 27 5425
sodium sulfate and concentrated. The crude product was
crystallized from ethyl acetate/hexane, followed by recrystal-
lization from aqueous methanol to give 4-(trans-4-methylcy-
clohexyl)-4-oxobutyric acid 7 as a white solid (19.7 g, 48%):
biological response to compound 7 and the strict struc-
tural specificity of the active compound may indicate
the existence of a specific binding site and a related
system that modulates the response of pancreatic â-cells
to glucose. Further studies on compound 7 may help to
elucidate the mechanism by which â-cells respond to
glucose and the relationship between this mechanism
and type 2 diabetes.
1
mp 100.4-101.2 °C; H NMR (300 MHz, CDCl3) δ 0.88-1.02
(2H, m), 0.89 (3H, d, J ) 6.5 Hz), 1.26-1.43 (1H, m), 1.36 (2H,
dq, J ) 3.3 and 12.7 Hz), 1.78 (2H, dd, J ) 3.3 and 13.5 Hz),
1.89 (2H, m), 2.31 (1H, tt, J ) 3.3 and 12.7 Hz), 2.62 (2H, t, J
) 6.3 Hz), 2.76 (2H, t, J ) 6.3 Hz). Anal. (C11H18O3) C, H.
4-Cycloh exyl-4-oxobu tyr ic Acid (1): mp 73.8-74.9 °C;
1H NMR (300 MHz, CDCl3) δ 1.17-1.43 (5H, m), 1.64-1.69
(1H, m), 1.77-1.88 (4H, m), 2.31-2.40 (1H, m), 2.62 (2H, t, J
) 6.2 Hz), 2.75 (2H, t, J ) 6.2 Hz); MS (FAB) m/z 185 (M +
H)+. HRMS calcd for C10H17O3, 185.1178; found, 185.1183.
Anal. (C10H16O3) C, H.
Exp er im en ta l Section
Ch em istr y. Melting points were obtained with a Yanagi-
moto micro melting point apparatus or a Mettler-Toledo FP62
melting point instrument and are uncorrected. Elemental
analysis was performed with a Perkin-Elmer 2400 Series II
CHNS/O analyzer, and all values were within (0.4% of the
calculated values. FAB mass spectra were recorded on a
Finnigan TSQ 700 spectrometer. High-resolution mass spectra
4-Cyclop en tyl-4-oxobu tyr ic Acid (2): mp 79.8 °C; 1H
NMR (300 MHz, CDCl3) δ 1.53-1.88 (8H, m), 2.63 (2H, t, J )
7.0 Hz), 2.77 (2H, t, J ) 7.0 Hz), 2.90 (1H, quintet, J ) 8.0
Hz); MS (FAB) m/z 171 (M + H)+. HRMS calcd for C9H15O3,
171.1021; found, 171.1011. Anal. (C9H14O3) C, H.
4-Cycloh ep tyl-4-oxobu tyr ic Acid (3): mp 48.7 °C; 1H
NMR (300 MHz, DMSO-d6) δ 1.43-1.82 (12H, m), 2.38 (2H, t,
J ) 6.4 Hz), 2.53-2.62 (1H, m), 2.68 (2H, t, J ) 6.4 Hz), 2.68
(2H, t, J ) 6.4 Hz), 12.03 (1H, br s); MS (FAB) m/z 199 (M +
H)+. HRMS calcd for C11H19O3, 199.1334; found, 199.1327.
Anal. (C11H18O3) C, H.
1
were obtained with a J EOL SX 102A spectrometer. H NMR
spectra were recorded on a J EOL J NM-A300W, Bruker AMX
300, or Bruker ARX 400 spectrometer in a solution of either
CDCl3, CD3OD, or DMSO-d6, using tetramethylsilane as the
internal standard. Chemical shifts are expressed as δ (ppm)
values for protons relative to the internal standard; all
compounds gave spectra consistent with their assigned struc-
tures.
4-(1-Meth ylcycloh exyl)-4-oxobu tyr ic Acid (4): mp 66.8-
67.2 °C; 1H NMR (300 MHz, CDCl3) δ 1.10 (3H, s), 1.26-1.41
(8H, m), 1.93-2.00 (2H, m), 2.62 (2H, t, J ) 6.0 Hz), 2.81 (2H,
t, J ) 6.0 Hz); MS (FAB) m/z 199 (M + H)+. HRMS calcd for
Di-ter t-bu tyl 2-(eth oxyca bon ylm eth yl)m a lon a te (20).
A solution of di-tert-butyl malonate (96.6 g, 447 mmol) in
anhydrous tetrahydrofuran (150 mL) was added to a suspen-
sion of sodium hydride (18 g, 450 mmol, 60% dispersion) in
anhydrous tetrahydrofuran (500 mL) at room temperature.
When evolution of hydrogen ceased, a solution of ethyl bro-
moacetate (57.2 g, 343 mmol) in anhydrous tetrahydrofuran
(250 mL) was added, and the mixture was stirred for 4 h. Then
the mixture was poured into saturated aqueous ammonium
chloride (500 mL) and extracted with ethyl acetate (200 mL
× 2). The combined extract was washed with brine (500 mL),
dried over sodium sulfate, and concentrated. The residue was
C
11H19O3, 199.1334; found, 199.1321. Anal. (C11H18O3) C, H.
4-(2-Meth ylcycloh exyl)-4-oxobu tyr ic Acid (5): mp 70.4-
70.6 °C; 1H NMR (300 MHz, CDCl3) δ 0.81 (3H, d, J ) 6.5
Hz), 0.94-1.03 (1H, m), 1.18-1.35 (3H, m), 1.63-1.82 (5H,
m), 2.08-2.17 (1H, m), 2.59-2.63 (2H, m), 2.67-2.71 (1H, m),
2.78-2.89 (1H, m); MS (FAB) m/z 199 (M + H)+. HRMS calcd
for C11H19O3, 199.1334; found, 199.1340. Anal. (C11H18O3) C,
H.
4-(3-Meth ylcycloh exyl)-4-oxobu tyr ic Acid (6): mp 56.0-
57.0 °C; 1H NMR (300 MHz, CDCl3) δ 0.80-1.06 (2H, m), 0.92
(3H, d, J ) 6.6 Hz), 1.21-1.49 (3H, m), 1.66-1.72 (1H, m),
1.79-1.89 (3H, m), 2.34-2.47 (1H, m), 2.62 (2H, t, J ) 6.6
Hz), 2.76 (2H, t, J ) 6.6 Hz); MS (FAB) m/z 199 (M + H)+.
HRMS calcd for C11H19O3, 199.1334; found, 199.1340. Anal.
(C11H18O3) C, H.
1
distilled to give 20 (69.8 g, 67%): bp0.8 115 °C; H NMR (300
MHz, CDCl3) δ 1.25 (3H, t, J ) 6.9 Hz), 1.46 (18H, s), 1.81
(2H, d, J ) 7.3 Hz), 3.64 (1H, t, J ) 7.3 Hz), 4.15 (2H, q, J )
7.1 Hz); MS (FAB) m/z 303 (M + H)+. HRMS calcd for
C
15H27O6, 303.1808; found, 303.1809.
4-Oxobu tyr ic Acid s (1-7 a n d 9-11). A typical run (7 in
Table 1) was as follows. A solution of 20 (68.3 g, 226 mmol) in
anhydrous tetrahydrofuran (642 mL) was added to a suspen-
sion of sodium hydride (9.49 g, 237 mmol, 60% dispersion) in
anhydrous tetrahydrofuran (100 mL) at room temperature.
When evolution of hydrogen ceased, a solution of 4-methylcy-
clohexanecarbonyl chloride (36.3 g, 226 mmol) in anhydrous
tetrahydrofuran (250 mL) was added, and the mixture was
stirred for 2 h. Then the mixture was poured into saturated
aqueous ammonium chloride (500 mL) and extracted with
ethyl acetate (200 mL × 2). The combined extract was washed
with brine (500 mL), dried over sodium sulfate, and concen-
trated to a crude residue. p-Toluenesulfonic acid monohydrate
(4.08 g, 21.4 mmol) was added to a solution of the product (91.5
g, 215 mmol) in toluene (914 mL), and the mixture was
refluxed for 2 h. After cooling to room temperature, the mixture
was washed with saturated aqueous sodium hydrogencarbon-
ate (300 mL) and water (300 mL). The organic layer was dried
over sodium sulfate and concentrated to give ethyl 4-(4-
methylcyclohexyl)-4-oxobutyrate as an oil (46.7 g, 92%): 1H
NMR (300 MHz, CDCl3) δ 0.88-0.98 (2H, m), 0.89 (3H, d, J )
6.5 Hz), 1.22 (3H, t, J ) 7.3 Hz), 1.25-1.43 (3H, m), 1.74-
1.80 (2H, m), 1.86-1.92 (2H, m), 2.32 (1H, tt, J ) 3.3 and 12.7
Hz), 2.56 (2H, t, J ) 6.5 Hz), 2.75 (2H, t, J ) 6.6 Hz), 4.12
(2H, q, J ) 7.4 Hz). To a solution of the oil (46.7 g, 206 mmol)
in ethanol (500 mL) was added 1 N aqueous sodium hydroxide
(226.7 mL), and the mixture was stirred at room temperature
for 12 h. Then the mixture was acidified with 1 N hydrochloric
acid, and the solvent was removed under a vacuum. The
residue was dissolved in ethyl acetate (500 mL) and washed
with brine (200 mL), after which the solution was dried over
4-(4,4-Dim eth ylcycloh exyl)-4-oxobu tyr ic Acid (9). 4,4-
Dimethyl-cyclohexanecarbonyl chloride, which was a starting
material for 9, was prepared by the reported method13: mp
1
50.0 °C; H NMR (300 MHz, CDCl3) δ 0.89 (3H, s), 0.92 (3H,
s), 1.20 (2H, dt, J ) 3.8 and 13.1 Hz), 1.43-1.63 (4H, m), 1.68-
1.74 (2H, m), 2.29 (1H, tt, J ) 3.4 and 12.1 Hz), 2.62 (2H, t, J
) 6.3 Hz), 2.77 (2H, t, J ) 6.3 Hz); MS (FAB) m/z 213 (M +
H)+. HRMS calcd for C12H21O3, 213.1491; found, 213.1483.
Anal. (C12H20O3) C, H.
4-(tr a n s-4-Eth ylcycloh exyl)-4-oxobu tyr ic Acid (10): mp
103.0-104.0 °C; 1H NMR (300 MHz, CDCl3) δ 0.85-0.97 (2H,
m), 0.88 (3H, t, J ) 7.4 Hz), 1.03-1.41 (5H, m), 1.82-1.93 (4H,
m), 2.32 (1H, tt, J ) 3.3 and 12.2 Hz), 2.62 (2H, t, J ) 6.6 Hz),
2.76 (2H, t, J ) 6.6 Hz). Anal. (C12H20O3) C, H.
4-(tr a n s-4-P r op ylcycloh exyl)-4-oxob u t yr ic Acid (11):
1
mp 109.7-113.5 °C; H NMR (300 MHz, CDCl3) δ 0.85-0.99
(2H, m), 0.88 (3H, t, J ) 7.1 Hz), 1.15-1.40 (7H, m), 1.80-
1.94 (4H, m), 2.32 (1H, tt, J ) 3.3 and 12.7 Hz), 2.62 (2H, t, J
) 6.5 Hz), 2.76 (2H, t, J ) 6.6 Hz); MS (FAB) m/z 227 (M +
H)+. HRMS calcd for C13H23O3, 227.1647; found, 227.1646.
Anal. (C13H22O3) C, H.
Ben zyl 4-(cis-4-Meth ylcycloh exyl)-4-oxobu tyr a te (24).
Benzyl bromide (10.8 g, 63.2 mmol) and sodium hydrogencar-
bonate (5.31 g) were added to a solution of 22, which was
obtained from the mother liquor after separating trans isomer
7 by crystallization in N,N-dimethylformamide (100 mL). The
mixture was stirred for 12 h and then evaporated under a
vacuum. The residue was dissolved in ethyl acetate (100 mL)
and washed with saturated aqueous sodium hydrogencarbon-