Synthesis of 4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]-quinolines derivatives as sorbitol dehydrogenase potential inhibitors

Article abstract of DOI:10.3987/com-02-9635

Synthesis of various quinolines, substituted in position 4 by [4-(N,N-dimethylsulfamoyl)piperazin-1-yl] group and in position 2 by different groups such as hydrogen, methyl, hydroxymethyl, formyl or carboxyl is described. Besides, we have synthesized derivatives of 8-hydroxyquinoline.

Full text of DOI:10.3987/com-02-9635

HETEROCYCLES, Vol. 60, No. 2, 2003
385
HETEROCYCLES, Vol. 60, No. 2, 2003, pp. 385 - 396
Received, 25th September, 2002, Accepted, 6th December, 2002, Published online, 16th December, 2002
SYNTHESIS OF 4-[4-(N,N-DIMETHYLSULFAMOYL (PIPERAZIN-1-YL)]-
QUINOLINES DERIVATIVES AS SORBITOL DEHYDROGENASE
POTENTIAL INHIBITORS
*
Didier Varlet, Eric Fourmaintraux, Patrick Depreux, and Daniel Lesieur
*
Institut de Chimie Pharmaceutique Albert Lespagnol, University of Lille 2, 3 rue
du Professeur Laguesse, 59006 Lille, France
Abstract - Synthesis of various quinolines, substituted in position 4 by [4-(N,N-
dimethylsulfamoyl)piperazin-1-yl] group and in position 2 by different groups
such as hydrogen, methyl, hydroxymethyl, formyl or carboxyl is described.
Besides, we have synthesized derivatives of 8-hydroxyquinoline.
INTRODUCTION
Diabetes is characterized by a sustained elevation of blood glucose. Glucose in excess follows the polyol
pathway and is reduced in sorbitol by the enzyme Aldose Reductase (AR) with the aid of the cofactor
1
,2
NADPH. This pathway is incriminated in the apparition of long-term diabetic complications
(
neuropathy, nephropathy, retinopathy, cataract, ...) by accumulation of sorbitol in the tissues. The
+
sorbitol may be then oxidized in fructose by Sorbitol Dehydrogenase (SDH), using the cofactor of NAD ,
according to a reversible reaction (Scheme 1).
AR
SDH
Glucose
Sorbitol
Fructose
NADPH, H+
NADP+
NAD+
NADH, H+
Scheme1
One of the most approaches, to protect vulnerable diabetic tissues from the detrimental elevated blood
glucose, has been to block excess glucose metabolism through the first step of polyol pathway via Aldose
3
,4
Reductase Inhibitors (ARIs).
Recently, excess glucose flux through the polyol pathway was proposed to create an imbalance in the
+
+
cytoplasmic redox status (increased free NADH/NAD ratio) because of rapid consumption of NAD
5
during oxidation of sorbitol to fructose by SDH. SDH inhibitors were shown to attenuate the diabetes-
+
5
induced increase in cytosolic NADPH / NAD ratio. CP-166572 and CP-470711 are reported as strong

386
HETEROCYCLES, Vol. 60, No. 2, 2003
6
,7
and specific inhibitors of SDH : SDH is a zinc-containing enzyme. It has been speculated that the
hydroxymethyl group serves as a strong ligand to the zinc atom, mimicking the hydroxymethyl group of
8
sorbitol (Scheme 2).
CH3
CH3
N SO N
N
N
N
N
N
2
N
CH3
N
CH3
CH3
CH3
OH
OH
HO
CP-166572
CP-470711
Cys44
His69
Zn
N
N
N SO N
2
N
O
H
Glu195
Scheme 2
9
In previous work, in order to obtain new compounds inhibiting SDH and to specify structure activity
relationships, we have described the synthesis of pyridinic derivatives potential inhibitors of SDH.
In order to obtain new compounds inhibiting SDH we describe here the synthesis of quinoline derivatives
substituted in position 4 by a dimethylsulfamoylpiperazinyl group and in position 2 by various
substituents.
CH3
CH3
CH3
CH3
N
N
N SO N
N
X
N
N SO N
2
2
N
HO
X = H, CH , CH OH, CHO, CO H
3
2
2
We have also synthesized derivatives of 8-hydroxyquinoline, known to complex metals.
CH3
CH3
CH3
N
N
N SO N
N
N
N SO N
2
2
N
CH3
HO
RO
R = H, CH3

HETEROCYCLES, Vol. 60, No. 2, 2003
387
RESULTS AND DISCUSSION
Compounds (1) and (2) were synthesized by substitution respectively of 4-chloroquinoline and 4-chloro-
9
quinaldine with piperazin-1-ylsulfonic acid dimethylamide (Scheme 3). The reaction was carried out
without solvent, at the melting point of the medium, with two equivalents of sulfamoylamide (60% yield
for 1 and 77% yield for 2).
CH3
H N
N SO2
2 eq.)
N
CH3
(
CH3
CH3
N
X
Cl
N
X
N
N SO N
2
fusion of the medium
1
: X = H
(60 %)
2
: X = CH3 (77 %)
Scheme 3
An attempt of substitution of 4-chloroquinaldine in refluxed toluene failed. A second attempt realized in
refluxed n-butanol gave (2) in only 17% yield while the 4-butoxyquinaldine was obtained with 66% yield
(Scheme 4).
CH3
CH3
H N
N SO2 N
(
1.1 eq.)
CH3
CH3
+
N
Cl
N
N
N SO N
N
O
2
NEt3
C H -n
n-Butanol at reflux
4
9
CH3
CH3
CH3
2
17%
6
6%
Scheme 4
The alcohol (5) was obtained in three steps from 4-chloroquinaldine, according to two ways.
1
0
In the first way, the methyl substituent was oxidized by action of selenium dioxide in refluxed dioxanne
to afford the aldehyde (3) (65% yield) which was reduced in alcohol (4) by action of sodium
1
1
borohydride in refluxed alcohol (75% yield). Substitution of the chlorine atom of compound (4) with
piperazin-1-ylsulfonic acid dimethylamide was then carried out without solvent, at melting point of the
medium, to furnish compound (5) (60% yield).
In the second way, the nucleophilic substitution was firstly realized (77% yield). The methyl group was
oxidized in aldehyde (6) (75% yield) wich was then reduced in alcohol (5) (90 % yield) in the same
conditions as described above.
Compound (5) was obtained with 52% overall yield in the second way versus 29% overall yield in the
first way (Scheme 5).

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HETEROCYCLES, Vol. 60, No. 2, 2003
Route 1
CH3
N SO2 N
Route 2
H N
(
overall yield : 29%)
(overall yield : 52%)
(2 eq.) CH
N
Cl
3
SeO2
fusion (140 °C)
CH3
7
7 %
6
5 %
CH3
N
N
N SO N
2
N
Cl
CH3
CH3
2
6
OHC 3
7
5 % SeO2
NaBH4 75 %
CH3
N
N
N SO N
2
CH3
N
Cl
OHC
4
90 %
HO
60 %
NaBH4
CH3
CH3
CH3
N SO N
H N
N SO2
N
N
N
2
fusion (110 °C)
CH3
5
HO
Scheme 5
The carboxylic acid (8) was firstly synthesized by substitution of the correspondent chloro acid (7) with
piperazin-1-ylsulfonic acid dimethylamide (30 % yield). All attempts to obtain compound (7) by
oxidation of 4-chloro-2-quinaldine with selenium dioxide failed because very numerous products were
formed and were difficult to separate. Compound (7) was finally obtained by oxidation of 4-chloro-2-
1
2
formylquinoline (3) using potassium permanganate at room temperature (55 % yield) (Scheme 6).
SeO2
dioxane /
N
Cl
CH3
CH3
HN
N SO2
fusion
N
CH3
CH3
KMnO4
rt
N
Cl
N
N
N SO N
2
30 %
CH3
HOOC
HOOC
8
55 %
7
N
Cl
3
OHC
Scheme 6

HETEROCYCLES, Vol. 60, No. 2, 2003
389
In a second way (Scheme 7), compound (8) was obtained in one step from compound (2) by oxidation of
the methyl group with two equivalents of selenium dioxide in hot dioxane (30 % yield).
SeO (2 eq.)
dioxane /
2
CH3
CH3
CH3
CH3
N
N
N SO N
N
N
N SO N
2
2
30 %
2
CH3
HOOC
8
Scheme 7
In order to increase this yield, we finally oxidized the formyl group of compound (6) by the mean of
potassium permanganate at room temperature (Scheme 8) in the same conditions as previously described
(32 % yield).
KMnO4
rt
CH3
CH3
CH3
CH3
N
N
N SO N
N
N
N SO N
2
2
32 %
6
8
OHC
HOOC
Scheme 8
8-Hydroxy- and 8-methoxyquinolines derivatives (compounds (9) and (11)) were synthesized from 4-
1
3
chloro-8-methoxyquinoline (Scheme 9).
N
Cl
BBr -Me S
3
2
CH O
or
3
CH3
CH3
BBr3 CH Cl /
;
2
2
HN
8 %
N SO2
fusion
N
5
CH3
CH3
CH3
N
N
N
N
N SO2
N
N SO2
N
CH3
CH O
HO
3
9
HBr or H SO
2
4
_
N
N
+
NH
X
CH O
3
X = Br or 1/2 SO4
Scheme 9

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HETEROCYCLES, Vol. 60, No. 2, 2003
The quinoline (9) was obtained by substitution of 8-methoxy-4-chloroquinoline with piperazin-1-
ylsulfonic acid dimethylamide, without solvent, at the fusion of the medium (58 % yield). We never
succeeded in the O-demethylation reaction. The use of boron tribromide-methyl sulfide complex or boron
1
4
tribromide in hot dichloromethane failed. Acid hydrolysis with bromohydric or sulfuric acid in hot
1
5
concentrated aqueous solution
did not give the compound (11), but the 8-methoxy-4-
piperazinylquinoline due to the hydrolysis of the sulfamoyl group.
Compound (11) was finally obtained from 8-methoxy-4-chloroquinoline by first the O-demethylation
using boron tribromide-methylsulfide complex followed by the substitution of the chlorine atom with
piperazin-1-ylsulfonic acid dimethylamide (35 % yield) (Scheme 10).
CH3
HN
N SO2
N
CH3
BBr3
CH Cl /
CH3
N
Cl
N
Cl
N
N
N SO N
2
2
2
fusion
35 %
CH3
6
0 %
CH O
HO
HO
3
1
1
1
0
Scheme 10
CONCLUSION
This paper reports the synthesis of new quinolines derivatives substituted in position 4 by a N,N-
dimethylsulfamoylpiperazin-1-yl group and in position 2 by various substituents such as hydrogen atom,
methyl, hydroxymethyl, formyl and hydroxycarbonyl groups (compounds (1), (2), (5), (6) and (8)). We
have also described the synthesis of original quinoline compounds : 8- methoxyquinoline (compound (9))
and 8-hydroxyquinoline (compound (11)) both substituted in position 4 by a N,N-dimethylsulfamoyl-
piperazin-1-yl group.
These compounds have been tested as sorbitol deshydrogenase potential inhibitors but were less potent
than the reference lead compound CP 166572.
All these test results confirm the importance of the two nitrogen atoms in the pyrimidinic cycle to obtain
a good interaction with the enzyme.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 297 spectrophotometer, using KBr tablets ; the waves
-1
1
numbers are expressed in cm . The H-NMR spectra were obtained on a Brücker AC 300P (300 MHz)
apparatus, with Me Si as the internal standard and with CDCl or DMSO-d as solvent ; the chemical
4
3
6

HETEROCYCLES, Vol. 60, No. 2, 2003
391
shifts are reported in ppm of Me Si in δ units ; coupling constants are expressed in Hz. Melting points
4
were determined using a Büchi SMP-535 apparatus and are uncorrected. Elemental analysis were
determined by the CNRS center of analysis in Vernaison (France).
General procedure for nucleophilic substitution (1, 2, 5, 8, 9 and 11) :
4-Chloroquinoline derivatives (1 mmol) and N,N-dimethylsulfamoylpiperazine (0.289 g, 2 mmol) were
heated until the appropriate temperature. The mixture was stirred until the corresponding 4-
chloroquinoline derivatives disappeared and then, cooled. Water was added and the mixture was extracted
with ethyl acetate. The combined organic layer were washed with water and dried over anhydrous
magnesium sulfate. The solvent was removed in vacuo and the residue was purified either by silica gel
column chromatography using an appropriate eluent and / or by recrystallization with a suitable solvent
(Table 1).
-1
4
-[4-(N,N-Dimethylsulfamoyl)piperazin-1-yl]quinoline (1) : IR 2815, 1590 and 1580, 1330 and 1140 cm .
1
H-NMR (300 MHz, DMSO-d ) δ : 2.85 (s, 6H), 3.13-3.31 (m, 4H), 3.38-3.56 (m, 4H), 7.03 (d, J=5.0
6
Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H),
8.72 (d, J=5.0 Hz, 1H). Anal. Calcd for C H N O S : C, 56.23; H, 6.29; N, 17.49. Found; C, 56.19; H,
15 20 4 2
6.39; N, 17.52.
-1
2
-Methyl-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (2) : IR 2800, 1570, 1330 and 1140 cm .
1
H-NMR (300 MHz, DMSO-d
H), 6.90 (s, 1H), 7.51 (t, J=8.2 Hz, 1H), 7.64 (t, J=8.2 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 8.02 (d, J=8.2
Hz, 1H). Anal. Calcd for C H N O S : C, 57.46; H, 6.63; N, 16.75. Found; C, 57.35; H, 6.80; N, 16.88.
6
) δ : 2.61 (s, 3H), 2.85 (s, 6H), 3.20 (t, J=4.5 Hz, 4H), 3.49 (t, J=4.5 Hz,
4
1
6
22
4
2
2-Hydroxymethyl-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (5) : IR 3260, 2900, 1590, 1330
-1 1
and 1150 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.85 (s, 6H), 3.11-3.31 (m, 4H), 3.36-3.57 (m, 4H),
6
4.65 (s, 2H), 5.60 (s, 1H), 7.21 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz,
1
H), 8.05 (d, J=7.8 Hz, 1H). Anal. Calcd for C H N O S : C, 54.84; H, 6.33; N, 15.99. Found; C, 54.66;
1
6
22
4
3
H, 6.42; N, 15.78.
2-Carboxy-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (8) : IR 2960-2800, 1640, 1580, 1330
-1 1
and 1140 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.83 (s, 6H), 3.24 (m, 4H), 3.45 (m, 4H), 7.37-7.83
6
(
m, 3H), 8.00 (m, 1H), 8.30 (m, 1H), 8.79 (s, 1H). Anal. Calcd for C H N O S : C, 52.73; H, 5.53; N,
16 20 4 4
15.37. Found; C, 52.43; H, 5.72; N, 15.29.

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HETEROCYCLES, Vol. 60, No. 2, 2003
8
1
4
-Methoxy-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (9) : IR 2960-2820, 1600 and 1580,
-1 1
330 and 1145 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.84 (s, 6H), 3.15-3.23 (m, 4H), 3.40-3.48 (m,
6
H), 3.93 (s, 3H), 7.05 (d, J=5.0 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.59 (d,
J=7.5 Hz, 1H), 8.65 (d, J=5.0 Hz, 1H). Anal. Calcd for C H N O S : C, 54.84; H, 6.33; N, 15.99.
1
6
22
4
3
Found; C, 54.73; H, 6.39; N, 16.06.
8
1
7
5
-Hydroxy-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (11) : IR 3380-3140, 1600, 1340 and
-1 1
140 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.85 (s, 6H), 3.17-3.29 (m, 4H), 3.39-3.51 (m, 4H), 6.96-
6
.12 (m, 2H), 7.33-7.51 (m, 2H), 8.66 (d, J=4.8 Hz, 1H), 9.65 (s, 1H). Anal. Calcd for C H N O S : C,
1
5
20
4
3
3.56; H, 5.99; N, 16.65. Found; C, 53.22; H, 5.85; N, 16.42.
Y
CH3
CH3
N
X
N
N SO2 N
Compound
X
Y
Yield (%)
Recristallization solvent
Mp (°C)
169-171
Reaction
Temperature (°C)
Reaction
Time (h)
1
1
-H
-H
60 %
140
ethanol-water (1-1)
2
5
8
9
- CH
3
-H
-H
77 %
ethanol-water (1-1)
147-149
190-191
240-242
177-179
185-187
140
110
110
80
1
0.1
0.5
2
-CH
2
OH
60 %
ethanol-water (1-1)
-COOH
-H
-H
30 %
ethanol-water (95-5)
-OCH
3
83 %
Dioxanne
11
-H
-OH
35 %
130
4
Toluene-cyclohexane (1-2)
Table 1 : Reactions conditions and physical properties of dimethylaminosulfamoylpiperazinyl quinolines.
General procedure for the oxidation of methyl in aldehyde in quinaldine derivatives (3 and 6) :
Quinaldine derivatives (5.6 mmol) was dissolved in dioxane (60 mL). Selenium dioxide (0.74 g, 6.9 mmol)
was added and the mixture refluxed under nitrogen (Table 2). The reaction medium was cooled, filtered
on celite and the filtrate evaporated under reduced pressure. The obtained residue was recrystallized.

HETEROCYCLES, Vol. 60, No. 2, 2003
393
-
1 1
4
5
7
-Chloro-2-formylquinoline (3) : IR 1710 and 1570 cm . H-NMR (80 MHz, DMSO-d
6
) δ 7.80-8.45 (M,
H), 10.10 (s, 1H). Anal. Calcd for C H NOCl : C, 62.68; H, 3.16; N, 7.31. Found; C, 62.94; H, 3.35; N,
1
0
6
.08.
2-Formyl-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (6) : IR 2990-2800, 1690, 1560, 1330 and
-1 1
1
150 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.86 (s, 6H), 3.24-3.41 (m, 4H), 3.45-3.63 (m 4H), 7.42
6
(s, 2H), 7.73 (t, J=7.0 Hz, 1H), 7.87 (t, J=7.0 Hz, 1H), 8.17 (d, J=7.0 Hz, 1H), 8.19 (d, J=7.0 Hz, 1H),
10.07 (s, 1H). Anal. Calcd for C H N O S : C, 55.16; H, 5.79; N, 16.08. Found; C, 54.97; H, 5.76; N,
16 20 4 3
16.04.
N
X
OHC
Compound
X
Yield (%)
Recrystallization solvent
Mp (°C)
136-139
Reaction
Time (h)
2.5
3
-Cl
65 %
cyclohexane
6
CH3
CH3
55 %
183-186
1
N
N SO N
Toluene-cyclohexane (4-1)
2
Table 2
General procedure for reduction of aldehyde (4 and 5) :
To the corresponding 2-formylquinoline derivatives (3 or 6) (1.6 mmol) dissolved in ethanol (6 mL), was
added sodium borohydride (0.031 g, 0.8 mmol). The reaction medium was refluxed for the appropriate
time (Table 3), cooled and alcohol was evaporated under reduced pressure. Water (10 mL) was added and
the aqueous layer extracted with ethyl acetate. The organic layer was dried (magnesium sulfate),
evaporated and the obtained product recrystallized.
-1 1
4
-Chloro-2-hydroxymethylquinoline (4) : IR 3160 and 1580 cm . H-NMR (80 MHz, DMSO-d ) δ : 4.70
6
(s, 2H), 5.75 (s, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.85 (t, J=8.0 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H),
8.20 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.72 (d, J=5.0 Hz, 1H). Anal. Calcd for C H NCl : C,
11 10
68.94; H, 5.26; N, 7.31. Found; C, 68.71; H, 5.47; N, 7.01.

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HETEROCYCLES, Vol. 60, No. 2, 2003
2-Hydroxymethyl-4-[4-(N,N-dimethylsulfamoyl)piperazin-1-yl]quinoline (5) : IR 3260, 2900, 1590, 1330
-1 1
and 1150 cm . H-NMR (300 MHz, DMSO-d ) δ : 2.85 (s, 6H), 3.21 (m, 4H), 3.46 (m, 4H), 4.65 (s, 2H),
6
5.60 (s, 1H), 7.21 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.05 (d,
J=7.8 Hz, 1H). Anal. Calcd for C H N O S : C, 54.84; H, 6.33; N, 15.99. Found; C, 54.66; H, 6.42; N,
1
6
22
4
3
15.78.
N
X
HO
Compound
X
Yield (%)
Recrystallization solvent
Mp (°C)
103-106
190-192
Reaction
Time (h)
2
4
5
-Cl
75 %
cyclohexane
90 %
CH3
CH3
0.5
N
N SO N
ethanol-water (1-1)
2
Table 3
General procedure for aldehyde oxidation in carboxylic acid derivatives (7 and 8) :
To the suitable 2-formylquinoline derivative ( or ) (2.6 mmol) dissolved in acetone (18 mL), was added
3
6
dropwise a solution of potassium permanganate (0.711 g, 4.5 mmol) in acetone (5 mL). The reaction
medium was stirred at rt for 2 h, filtrated and poured in hot water (15 mL). The mixture was then stirred,
filtrated and acidified with 0.5 M hydrochloric acid. The formed precipitate was filtrated, dried and
recrystallized (Table 4).
-1 1
2-Carboxy-4-chloroquinoline (
6
7) : IR 3300-3020, 1710 and 1580 cm . H-NMR (300 MHz, DMSO-d ) δ
7
.86 (t, J=7.5 Hz, 1H), 8.00 (t, J=7.5 Hz, 1H), 8.22 (m, 3H), 13.69 (s, 1H). Anal. Calcd for C H NO Cl :
1
0
6
2
C, 57.85; H, 2.91; N, 6.75. Found; C, 57.59; H, 2.98; N, 6.54.
2
-Carboxy-4-[4-(N,N-dimethylsulfamoyl) piperazin-1-yl]quinoline (
8
) : IR 2960-2800, 1640, 1580, 1330
2.83 (s, 6H), 3.32 (m, 4H), 3.54 (m, 4H), 7.55 (m, 3H),
.00 (m, 1H), 8.30 (m, 1H), 8.79 (s, 1H). Anal. Calcd for C H N O S : C, 52.73; H, 5.53; N, 15.37.
-1 1
and 1140 cm . H-NMR (300 MHz, DMSO-d )
δ
6
8
1
6
20
4
4
Found; C, 52.43; H, 5.72; N, 15.29.

HETEROCYCLES, Vol. 60, No. 2, 2003
395
N
X
HO C
2
Compound
X
Yield (%)
Recrystallization solvent
Mp (°C)
160-162
Reaction
Time (h)
2
7
-Cl
55 %
acetonitrile
CH3
CH3
8
32 %
ethanol-water (95-5)
240-242
2
N
N SO N
2
Table 4.
REFERENCES
1
2
3
. D. R. Tomlinson, E. J. Stevens, and L. Diemel, Trends Pharmacol. Sci., 1994, 15, 293.
. P. F. Kador, Med. Res. Rev., 1988, 8, 325.
. D. T. Fong, F. K. Lee, Z. T. Song, N. A. Calcutta, L. W. Lee, S. S. M. Chung, and S. K. Chung,
Diabetes, 1998, 47, 961.
4
. P. J. Oates and B. L. Mylari, Exp. Opin. Invest. Drugs, 1999, 8, 2098.
. J. R. Williamson, K. Chang, M. Frangos, K. S. Hasan, Y. Ido, T. Kawamura, J. R. Nyengaard, M. Van
Den Eden, C. Kilo, and R. G. Tilton, Diabetes, 1994, 44, 801.
5
6
. B. L. Mylari, P. J. Oates, D. A. Beebe, N. S. Brackett, J. B. Coutcher, M. S. Dina, and W. J.
Zembrowski, J. Med. Chem., 2001, 44, 2695.
7
. M. Y. Chu-Moyer, W. E. Ballinger, D. A. Beebe, R. Berger, J. B. Coutcher, W. W. Day, J. Li, B. L.
Mylari, P. J. Oates, and R. M. Weekly, J. Med. Chem., 2002, 45, 511.
. N. E. Cameron, M. A. Basso, and T. C. Hohman, Diabetologia, 1997, 40, 271.
. D. Varlet, E. Fourmaintraux, P. Depreux, and D. Lesieur, Heterocycles, 2000, 53, 797.
0. Krief, Hevesi ‘Organoselenium Chemistry’, Springer : New York, 776, 1988.
1. S. W. Chaikin and W. G. Brown, J. Am. Chem. Soc., 1949, 71, 122.
2. A. Ashimori, T. Ono, T. Uchida, Y. Ohtaki, C. Fukaya, M. Watanabe, and K. Yokoyama, Chem.
Pharm. Bull., 1990, 38, 2446.
8
9
1
1
1
13. 4-Chloro-8-methoxyquinoline was prepared in five steps from ortho-anisidine : C. C. Price and R.
Roberts, J. Am. Chem. Soc., 1946, 68, 1204.

396
HETEROCYCLES, Vol. 60, No. 2, 2003
14. R. M. Bartholow and E. J. Walaszek, J. Med. Chem., 1976, 19, 189.
1
5. P. Depreux, D. Lesieur, H. Ait Mansour, P. Morgan, H. Edward Howell, P. Renard, D. H. Caignard,
B. Pfeiffer, P. Delagrange, B. Guardiola, S. Yous, A. Demarque, G. Adam, and J . Andrieux, J. Med.
Chem., 1994, 37, 3231.