O. Familiar et al. / European Journal of Medicinal Chemistry 45 (2010) 5910e5918
5917
ꢀ
the mixture was heated at 80 C until total solubilization of
127.2 (Ar), 141.0 (C6), 150.8, 152.4 (C2, CO), 164.2 (C4). Anal. Calc. for
$2H O: C: 56.57; H: 6.25; N: 17.36.; found: C: 56.43; H:
6.40; N: 17.10.
thymine. Then, NaI (73 mg, 0.5 mmol) and a solution of the cor-
responding halide 21e23 (1.0 mmol) in CH
The reaction was kept at 80 C for 8 h. The mixture was filtered and
the isolated solid contained the target compound. The filtrate was
treated with a solution of sodium bisulphite (10 mL) and extracted
C
19
H
20
N
5
O
3
2
3
CN (4 mL) were added.
ꢀ
4.2.4. (Z)-8-Acetamido-1-(4-(thymin-1-yl)but-2-enyl)-5,6-
dihydro-1H-imidazo[4,5,1-ij]quinolin-2(4H)-one (27)
with ethyl acetate (25 mL). The organic layer was dried over MgSO
4
,
According to the general procedure, thymine (46 mg,
0.36 mmol) reacted with 23 (77 mg, 0.24 mmol). The reaction was
allowed to reach rt and filtered to afford 95 mg (96%) of 27 as
filtered, and evaporated. The residue obtained was purified by
column chromatography. The yields given include the amount
obtained from the isolated solid together with that obtained after
column chromatography.
ꢀ
a yellow solid. Mp: 288e289 C (CH
3
CN); MS (ES): m/z 410
), 2.00 (s, 3H, CH ),
), 3.72 (t, 2H, J ¼ 5.5 Hz,
), 4.56 (t, 2H, J ¼ 4.5 Hz, CH ), 5.61
(m, 2H, CH]CH), 6.96 (s, 1H, H-6), 7.34 (s, 1H, Ar), 7.58 (s, 1H, Ar),
þ
1
[M þ 1] ; H NMR (CDCl
.05 (m, 2H, CH
), 2.74 (t, 2H, J ¼ 5.9 Hz, CH
CH
), 4.50 (t, 2H, J ¼ 4.8 Hz, CH
3
)
d
: 1.76 (s, 3H, 5-CH
3
3
2
2
2
4.2.1. (Z)-1-(4-(Thymin-1-yl)but-2-enyl)-5,6-dihydro-1H-imidazo
2
2
2
[4,5,1-ij]quinolin-2(4H)-one (24)
13
According to the general procedure, thymine (91 mg,
9.80 (br s, 1H, NH), 11.30 (br s, 1H, NH); C NMR (CDCl
CH ), 23.8 (CH ), 21.5, 23.1, 37.4, 43.7 (CH ), 108.8(C5),128.3, 131.2
(CH]CH), 98.1, 110.0, 118.9, 122.1, 126.6, 127.7 (Ar), 150.8 (C2), 152.4
(CO), 164.2 (C4), 167.6 (CO). Anal. Calc. for C21 : C: 61.60; H:
5.66; N: 17.10; found: C: 61.54; H: 5.60; N: 17.08.
3
) d: 11.8 (5-
0
.72 mmol) reacted with the chloride 21 (95 mg, 0.36 mmol). After
purification by flash column chromatography HPFC (CH Cl /MeOH,
0:1), 110 mg (87%) of 24 were obtained as a white solid. Mp:
3
3
2
2
2
4
23 5 4
H N O
ꢀ
þ 1
2
11e212 C (CH
CDCl : 1.92 (s, 3H, 5-CH
J ¼ 6.1 Hz, CH ), 3.87 (t, 2H, J ¼ 5.9 Hz, CH
m, 1H, CH]CH), 5.81 (m, 1H, CH]CH), 6.81 (m, 3H, Ar), 7.36 (s, 1H,
2
Cl
2
/MeOH); MS (APCI): m/z 353 [M þ 1] ; H NMR
), 2.13 (m, 2H, CH ), 2.87 (t, 2H,
), 4.60 (m, 4H, CH ), 5.67
(
3
)
d
3
2
2
2
2
4.2.5. (Z)-8-Amino-1-(4-(thymin-1-yl)but-2-enyl)-5,6-dihydro-
1H-imidazo[4,5,1-ij]quinolin-2(4H)-one (28)
A solution of 27 (90 mg, 0.22 mmol) in a mixture of dioxane (9 mL)
and1.6MofHCl(2mL)wasrefluxedfor 7h. Aftercooling,themixture
(
13
H-6), 8.26 (br s, 1H, NH). C NMR (CDCl
7.6, 39.0, 44.2 (CH ), 110.0 (C5), 127.3, 128.4 (CH]CH), 105.2, 119.6,
19.8,120.9,126.4,127.1 (Ar),140.4 (C6),150.9 (C2),153.1 (CO),164.2
C4). Anal. Calc. for C19 : C: 64.76; H: 5.72; N: 15.90; found:
C: 64.71; H: 6.10; N: 15.72.
3
)
d: 12.3 (5-CH
3
), 21.8, 23.8,
3
1
(
2
was filtered and the filtrated was treated with a solution 30% NH
(5 mL) and extracted with CH Cl (30 mL). The organic phase was
driedover MgSO , filtered, andevaporated. The residue obtained was
purified by CCTLC in the Chromatotron (CH
3
H
20
N
4
O
3
2
2
4
2
Cl
2
/Acetone,1:2) to yield
ꢀ
4
.2.2. (þ/ꢂ)(Z)-5-Acetamido-1-(4-(thymin-1-yl)but-2-enyl)-5,6-
71 mg (88%) of 28 as a light brown solid. Mp: 247e249 C. MS (ES): m/
þ
1
dihydro-1H-imidazo[4,5,1-ij]quinolin-2(4H)-one (25)
z 368 [M þ 1] ; H NMR (DMSO ꢂ d
J¼ 5.0Hz,CH ), 2.80(t, 2H,J¼ 5.0Hz, CH
4.51 (d, 2H, J ¼ 4.7 Hz, CH ), 4.64 (d, 2H, J ¼ 4.5 Hz, CH
CH]CH), 6.72 (s, 1H, H-6), 6.84 (s, 1H, Ar), 7.61 (s, 1H, Ar), 9.99 (br s,
6
)
d
: 1.76 (s, 3H, 5-CH
), 3.75(t,2H,J¼5.0Hz,CH
), 5.62 (m, 2H,
3
), 2.01 (t, 2H,
According to the general procedure, thymine (154 mg,
2
2
2
),
1
.22 mmol) reacted with the chloride 22 (229 mg, 0.72 mmol). After
purification by column chromatography flash HPFC (CH Cl /MeOH,
0:1) 241 mg (82%) of 25 were obtained as a yellow amorphous
2
2
2
2
1
3
1
2H, NH
21.8, 21.9, 23.7, 38.4, 44.6 (CH
128.0, 128.7, 128.8 (Ar, CH]CH), 141.6 (C-6), 151.5 (C-2), 153.1 (CO),
164.9(C-4),167.6(CO).Anal. Calc. forC19 :C:62.11;H:5.76;N:
19.06; found: C: 62.03; H: 5.69; N: 18.98.
2
), 11.28 (br s, 1H, NH); C NMR (DMSO ꢂ d
6 3
) d: 12.6 (5-CH ),
þ
1
solid. MS (ES): m/z 410 [M þ 1] ; H NMR (DMSO ꢂ d
H, 5-CH ), 1.78 (s, 3H, CH
), 2.79 (dd, 1H, J ¼ 16.1, 6.4 Hz, CH
), 3.60 (dd, 1H, J ¼ 12.2, 6.3 Hz, CH
), 4.29 (m, 1H, CH), 4.49 (d, 2H,
), 4.61 (d, 2H, J ¼ 4.9 Hz, CH ), 5.61 (m, 2H, CH]CH),
6
)
d
: 1.75 (s,
), 2.97
),
2
), 109.6 (C-5), 101.3, 101.4, 114.3, 120.7,
3
3
3
2
(
3
dd, 1H, J ¼ 16.8, 4.3 Hz, CH
2
2
21 5 3
H N O
.85 (dd, 1H, J ¼ 12.2, 3.9 Hz, CH
2
J ¼ 5.2 Hz, CH
2
2
6
.85 (d, 1H, J ¼ 7.5 Hz, Ar), 6.93 (t, 1H, J ¼ 7.5 Hz, Ar), 7.02 (d, 1H,
4.3. Synthesis of 5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2-ij]
quinolin-2,2-dioxide derivatives
J ¼ 7.4 Hz, Ar), 7.59 (s, 1H, H-6), 8.06 (d, 1H, J ¼ 6.9 Hz, NHAc), 11.30
(
2
br s, 1H, NH); 13C NMR (DMSO ꢂ d
6 3 3
) d: 12.5 (5-CH ), 22.8 (CH ),
9.5, 38.1, 43.1, 44.5 (CH
2
), 42.8 (CH), 127.8, 128.9 (CH]CH), 109.5
4.3.1. 1-[(Z)-4-Chlorobut-2-enyl]-5,6-dihydro-1H,4H-1,2,5-
thiadiazolo[4,3,2-ij]quinolin-2,2-dioxide (30)
(
1
C
C5), 106.6, 117.4, 120.5, 121.6, 125.8, 127.4 (Ar), 141.6 (C6), 151.3,
53.1 (C2, CO), 164.9 (C4), 170.6 (COCH ). Anal. Calc. for
O: C: 59.01; H: 5.90; N: 16.38; found: C: 58.72; H:
3
Compound 29 [26] (179 mg, 0.85 mmol) reacted with (Z)-1,4-
dichloro-2-butene (0.15 mL, 1.45 mmol) for 4 h, as described for the
synthesis of 21. The final residue was purified by flash column
chromatography (hexane/ethyl acetate, 2:1) to yield 116 mg (46%)
21
23
H N
5
O
4
$H
2
6
.25; N: 16.06.
þ
4
.2.3. (þ/ꢂ)(Z)-5-Amino-1-(4-(thymin-1-yl)but-2-enyl)-5,6-
of 30 as colourless oil. MS (ES, positive mode): m/z 229 [M þ 1] ,
1
dihydro-1H-imidazo[4,5,1-ij]quinolin-2(4H)-one (26)
with a Cl isotopic pattern; H NMR (CDCl
3
)
d
: 2.18 (m, 2H, CH
2
), 2.76
A solution of 25 (40 mg, 0.12 mmol) in a mixture of dioxane
(t, 2H, J ¼ 6.2 Hz, CH
J ¼ 7.7 Hz, CH ), 4.39 (d, 2H, J ¼ 6.5 Hz, CH
5.91 (m, 1H, CH]CH), 6.59e6.89 (m, 3H, Ar); C NMR (CDCl
21.7, 23.8, 38.7, 40.0, 41.2 (CH ), 128.9, 130.2 (CH]CH), 106.9, 120.4,
121.6, 121.9, 126.6, 128.4 (Ar).
2
), 3.68 (t, 2H, J ¼ 5.7 Hz, CH
2
), 4.22 (d, 2H,
), 5.81 (m, 1H, CH]CH),
(
4 mL) and 1.6 M of HCl (1 mL) was refluxed for 7 h. After cooling,
the mixture was filtered and the filtrated was treated with a solu-
tion of 30% NH (5 mL) and CH Cl (30 mL). The organic phase was
dried over MgSO , filtered, and evaporated. The residue obtained
was purified by flash column chromatography HPFC (CH Cl
MeOH, 10:1) to yield 37 mg (83%) of 26 as a white amorphous solid.
2
2
13
3
) d:
3
2
2
2
4
2
2
/
4.3.2. 1-[(Z)-(4-(Thymin-1-yl)but-2-enyl)]-5,6-dihydro-1H,4H-
1,2,5-thiadiazolo[4,3,2-ij]quinolin-2,2-dioxide (31)
The halide 30 (110 mg, 0.36 mmol) was made to react with
thymine (79 mg, 0.63 mmol) as already described in the general
procedure. The final residue was purified by flash column chro-
þ
1
MS (ES): m/z 377 [M þ 1] ; H NMR (DMSO ꢂ d
CH ), 2.97 (dd, 1H, J ¼ 16.8,
), 2.90 (dd, 1H, J ¼ 16.8, 5.8 Hz, CH
.3 Hz, CH ), 3.96 (m, 2H, CH ), 4.00 (m, 1H, CH ), 4.49 (d, 2H,
J ¼ 5.2 Hz, CH ), 4.62 (d, 2H, J ¼ 4.9 Hz, CH ), 5.60 (m, 2H, CH]CH),
.89 (d, 1H, J ¼ 7.5 Hz, Ar), 6.97 (t, 1H, J ¼ 7.6 Hz, Ar), 7.05 (d, 1H,
6
) d: 1.75 (s, 3H, 5-
3
2
4
2
2
2
2
2
6
matography HPFC (CH
2
Cl
2
/MeOH, 40:1) to yield 110 mg (79%) of 31
13
ꢀ
J ¼ 7.6 Hz, Ar), 7.60 (s, 1H, H-6), 11.30 (br s, 1H, NH); C NMR
DMSO ꢂ d : 11.9 (5-CH ), 28.9, 37.7, 41.9, 44.0 (CH ), 43.9 (CH),
08.9 (C5), 127.6, 128.5 (CH]CH), 106.3, 115.3, 119.7, 121.1, 125.4,
as a yellow solid. Mp: 289e290 C (CH
2
Cl
: 1.74 (s, 3H, 5-CH
), 3.58 (t, 2H, J ¼ 5.4 Hz, CH
2
/MeOH); MS (ES): m/z
), 2.05 (m,
),
þ
1
(
1
6
)
d
3
2
389 [M þ 1] ; H NMR (DMSO ꢂ d
6
)
d
3
2H, CH
2
), 2.71 (t, 2H, J ¼ 6.1 Hz, CH
2
2