Arch. Pharm. Chem. Life Sci. 2006, 339, 182–192
Symmetrical Diamides and Diamines as Apoptosis Inducers
189
Table 5. IR and 1H-NMR data for selected compounds.
Ref.
1k
1m
2a
2f
IR [cm – 1
]
1H-NMR [J in Hz]
3305, 3072,
a) 1.55 ( brs, 4H, CH2); 3.30 ( brs, 4H, CH2); 7.50 (dd, J5-4 = 8, J5-6 = 6, 2H, H5, H59); 7.79 (d, J4-5 = 8, 2H, H4, H49); 8.34 (d, J6-5 = 6, 2H, H6, H69); 8.55 (s, 2H, H5,
3000 – 2850, 1636
3308, 3074, 2928,
2883, 1642
H59); 8.74 ( brs, 2H, NH, NH9).
a)
1.79 (q, J = 7, 2H, CH2); 3.32 (m, 4H, CH2); 7.55 (dd, J5-4 = 8, J5-6 = 6, 2H, H5, H59); 7.76 (d, J4-5 = 8, 2H, H4, H49); 8.34 (d, J6-5 = 6, 2H, H6, H69); 8.57 (s, 2H, H2,
H29); 8.75 (t, J = 5, 2H, NH, NH9).
3295, 3068,
a) 1.91 (q, J = 7, 2H, CH2); 3.45 (m, 4H, CH2); 7.68 (dd, J6-5 = 8, J6-7 = 8, 2H, H6, H69); 7.86 (dd, J7-6 = 8, J7-8 = 8, 2H, H7, H79); 8.07 (d, J5-6 = 8, 2H, H5, H59); 8.07
(d, J8-7 = 8, 2H, H8, H89); 8.81 (s, 2H, H4, H49); 8.89 (t, J = 5, 2H, NH, NH9); 9.28 (s, 2H, H2, H29).
3000 – 2900, 1634
3396, 3068, 2940,
1665
b)
3.84 (d, J = 6, 4H, CH2); 7.58 (dd, J6-5 = 8, J6-7 = 8, 2H, H6, H69); 7.72 (dd, J7-6 = 8, J7-8 = 8, 2H, H7, H79); 7.84 (d, J5-6 = 8, 2H, H5, H59); 8.07 (d, J8-7 = 8, 2H, H8, H89);
8.28 (d, 2H, H4, H49); 8.28 (d, 2H, H3, H39); 8.65 ( brs, 2H, NH, NH9).
3a
3c
3212, 3064, 1660
a) 1.64 ( brs, 4H, CH2); 3.38 ( brs, 4H, CH2); 4.41 (s, 6H, CH3); 8.25 (dd, J5-4 = 8, J5-6 = 5, 2H, H5, H59); 8.89 (d, J4-5 = 8, 2H, H4, H49); 9.09 (t, J = 5, 2H, NH, NH9);
9.09 (d, J6-5 = 5, 2H, H6, H69); 9.39 (s, 2H, H2, H29).
3262, 3040, 2952,
1660
3258, 3062, 1656
a) 1.89 (q, J = 7, 2H, CH2); 3.43 (m, 4H, CH2); 4.42 (s, 6H, CH3); 8.26 (dd, J5-4 = 8, J5-6 = 5, 2H, H5, H59); 8.89 (d, J4-5 = 8, 2H, H4, H49); 9.12 (t, J = 8, 2H, NH, NH9);
9.12 (d, J6-5 = 5, 2H, H6, H69); 9.40 (s, 2H, H2, H29).
4a
4c
a) 1.61 ( brs, 4H, CH2); 3.35 ( brs, 4H, CH2); 8.12 (dd, J5-4 = 8, J5-6 = 6, 2H, H5, H59); 8.61 (d, J4-5 = 8, 2H, H4, H49); 8.61 (s, 4H, NH2, NH29); 8.86 (d, J6-5 = 6, 2H, H6,
H69); 9.14 (s, 2H, H2, H29); 9.14 ( brs, 2H, NH, NH9).
3214, 3072, 1655
a) 1.94 (q, J = 6, 2H, CH2); 3.48 (t, J = 6, 4H, CH2); 8.02 (dd, J5-4 = 8, J5-6 = 6, 2H, H5, H59); 8.58 (d, J4-5 = 8, 2H, H4, H49); 8.80 (d, J6-5 = 6, 2H, H6, H69); 9.06 (s, 2H,
H2, H29).
5c
3414, 3053, 3000 – b) 2.19 (q, J = 6, 2H, CH2); 3.82 (m, 4H, CH2); 7.77 – 7.99 (dd, 2H, H6, H69); 7.77 – 7.99 (dd, 2H, H7, H79); 7.77 – 7.99 (d, 2H, H5, H59); 7.77 – 7.99 (d, 2H, H8,
2900, 1656
H89); 8.53 (d, J4-3 = 8, 2H, H4, H49); 8.75 (d, J3-4 = 8, 2H, H3, H39); 11.83 ( brs, 2H, NH, NH9).
6a
3400, 3290, 3100 – c) 1.62 ( brs, 4H, CH2); 3.14 ( brs, 2H, CH2); 7.02 (dd, J6-5 = 8, J6-7 = 8, 2H, H6, H69); 7.10 (s, 2H, H3, H39); 7.16 (dd, J5-4 = 8, J5-6 = 8, 2H, H5, H59); 7.41 (d, J4-5 = 8,
3000, 3000 – 2900, 2H, H4, H49); 7.59 (d, J7-6 = 8, 2H, H7, H79); 8.50 (t, J = 5, 2H, NH, NH9 amide); 11.53 (s, 2H, NH, NH9 indole).
1623
7
3150 – 3000, 3000 – d) 2.57 ( brs, 8H, CH2); 3.68 (s, 4H, CH2); 7.12 (dd, J5-4 = 8, J5-6 = 5, 2H, H5, H59); 7.39 (d, J3-4 = 8 2H, H3, H39); 7.62 (dd, J4-3 = 8, J4-5 = 8, 2H, H4, H49); 8.54 (d, J6-5
=
2750
3254, 3100 – 3000, b) 3.15 ( brs, 4H, CH2-pyridine); 3.96 ( brs, 4H, CH2-N); 7.11 ( brs, 1H, H6 pyridopyrimidine); 7.19 (dd, J5-4 = 8, J5-6 = 5, 2H, H5, H59 pyridine); 7.23 (d, J3-4 = 8,
3000 – 2900 2H, H3, H39 pyridine); 7.56 ( brs, 1H, H5 pyridopyrimidine); 7.64 (dd, J4-3 = 8, J4-5 = 8, 2H, H4, H49 pyridine); 8.54 ( brs, 1H, H7 pyridopyrimidine); 8.57 (d,
6-5 = 5, 2H, H6, H69 pyridine); 7.00 – 7.92-8.29 – 8.71 (dd- brs- brs- brs, 2H, NH, NH9)
3415, 3300, 3100 – b) 3.01 (t, 2H, CH2-indole); 3.10 (t, 2H, CH2-indole); 3.74 (m, 2H, CH2-N); 3.85 (m, 2H, CH2-N); 6.86 (dd, J5-4 = 8, J5-6 = 8, 1H, H5 indole); 6.97 (dd, J59-49 = 8, J59-69
5, 2H, H6, H69).
8a
J
8b
8d
3000, 3000 – 2900
= 8, 1H, H59 indole); 7.03 ( brs, 1H, H6 pyridopyrimidine); 7.03 ( brs, 2H, H6, H69 indole); 7.14 ( brs, 1H, H29 indole); 7.19 ( brs, 1H, H2 indole); 7.33 (d, J5-6
= 8, 1H, H5 pyridopyrimidine); 7.35 (d, J7-6 = 8, 2H, H7, H79 indole); 7.57 (d, J4-5 = 8, 2H, H4, H49 indole); 8.63 (d, J7-6 = 5, 1H, H7 pyridopyrimidine); 10.80 (
brs, 2H, NH, NH9 indole); 7.96 – 8.40 – 8.52 – 9.55 ( brs, 3H, NH, NH‘,HCl).
3270, 3124, 3100 – b) 1.59 ( brs, 4H, CH2); 1.97 (m, 4H, CH2); 2.94 ( brs, 4H, CH2); 3.00 ( brs, 4H, CH2-NH-CH2); 3.63 ( brs, 4H, CH2-NH-pyridopyrimidine); 7.60 (dd, J6-5 = 8, J6-7
3000, 2986, 2950,
2838
= 4, 2H, H6, H69); 8.35 ( brs, 4H, NH-HI); 8.65 (s, 2H, H2, H29); 8.68 (d, J5-6 = 8, 2H, H5, H59); 8.79 ( brs, 2H, NH-pyridopyrimidine, NH9-pyridopyrimidine);
9.01 (d, J7-6 = 4, 2H, H7, H79).
a)
b)
c)
d)
200 MHz, DMSO-d6.
400 MHz, DMSO-d6.
200 MHz, CDCl3.
400 MHz, CDCl3.
Strasbourg, France). The spectroscopic properties of the most
active compounds are summarised in Table 5.
mine (12.6 mmol) and triethylamine (3.50 mL, 25.2 mmol) in
dry chloroform and the mixture was stirred at room tempera-
ture for 1 h. The mixture was then heated under reflux for 5 h.
The solvent was removed and the residue was suspended in
water (100 mL). The resulting solid was filtered off, washed with
water and recrystallized.
General procedures for N,N9-alkyl-diyldinicotinamides
and related compounds
Method A, for compounds 1a–g
A solution of nicotinic acid (1a–f) or isonicotinic acid (1g)
(4.00 g, 32.5 mmol) in thionyl chloride (15-20 mL) was stirred
and heated under reflux for 2 h. The solvent was removed and
the residue was suspended in dry chloroform (30 mL). Triethyla-
mine was then added (4.52 mL, 32.5 mmol). The resulting solu-
tion was added dropwise at room temperature over 1 h to a mix-
ture of the appropriate diamine (16.2 mmol) and triethylamine
(4.52 mL, 32.5 mmol) in dry chloroform. After completion of the
addition, the mixture was heated under reflux for 5 h. The sol-
vent was removed and the resulting residue was subjected to the
purification method described below for each compound.
Method C, for compounds 1k–n
A solution of nicotinic acid N-oxide (4.00 g, 28.7 mmol) in thio-
nyl chloride (15–20 mL) was stirred and heated under reflux for
3 h. The solvent was removed under reduced pressure. The resi-
due was suspended in dry chloroform (30 mL) and triethylamine
was added (4.00 mL, 28.7 mmol). The resulting solution was
added dropwise to a mixture of the appropriate diamine
(14.4 mmol) and triethylamine (4.00 mL, 28.7 mmol) in dry
chloroform and the mixture was stirred at room temperature
for 1 h. The mixture was then heated under reflux for 5 h. The
solvent was removed and the resulting residue was subjected to
the purification method described for each compound.
Method B, for compounds 1h–j
A solution of 6-chloronicotinic (1h) and (1i) or 2-chloronicotinic
acid (1j) (4.00 g, 25.2 mmol) in thionyl chloride (15–20 mL) was
stirred and heated under reflux for 2 h. The solvent was removed
and the residue was suspended in dry chloroform (30 mL).
Triethylamine was then added (3.50 mL, 25.2 mmol). This solu-
tion was added dropwise to a mixture of the appropriate dia-
General procedure for N,N9-alkyl-diyldiquinoline-
carboxamide and related 2a–f
A solution of 3-quinolinic acid (2a–c) or 2-quinolinic acid (2d–f)
(2.00 g, 11.5 mmol) and thionyl chloride (15–20 mL) in dry
chloroform (50 mL) was stirred and heated under reflux for 2 h.
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