D. Maciejewska et al. / European Journal of Medicinal Chemistry 48 (2012) 164e173
171
C-50), 127.3 (C-200, C-600), 129.5 (C-300, C-500), 133.2 (C-400), 139.0 (C-
100), 149.5 (C-2, C-20), 151.8 (C-1, C-10). C26H25N3O6S (507.57 g/mol):
calcd. (%): C ¼ 61.53, H ¼ 4.96, N ¼ 8.28, S ¼ 6.32; found (%):
C ¼ 61.28, H ¼ 5.14, N ¼ 8.51, S ¼ 6.12.
solid was filtered, washed with water and dried at room temp. After
recrystalisation from ethanol, a white solid of 15a was obtained
(50%). M.p. ¼ 106.5e108.0 ꢁC 1H (299.86 MHz, CDCl3)
d in ppm: 2.23
(s; 3H; H-13), 3.71 (t; J ¼ 6.0 Hz, 4H; H-9, H-90), 3.78 (s; 6H; H-10, H-
100), 4.30 (t; J ¼ 6.0 Hz; 4H; H-8, H-80), 6.87 (d; J ¼ 8.4 Hz; 2H; H-6,
H-60), 7.04 (d; J ¼ 1.8 Hz; 2H; H-3, H-30), 7.24 (dd; J1 ¼ 8.4 Hz
J2 ¼ 1.8 Hz; 2H; H-5. H-50), 7.48 (broad s; 1H; NH-11), 7.58e7.61 (m;
2H; H-300, H-500), 7.75e7.78 (m; 2H; H-200, H-600). 13C NMR
4.2.1.15. N,N-Bis[2(4-amidino-2-methoxyphenoxy)ethyl]benzenesulfo-
namidedihydrochloride (12). Ethanol was evaporated in vacuo to give
a yellow solid of 12 (Yield: 78). M.p. ¼ 166.0e170.0 ꢁC 1H NMR
(299.87 MHz, DMSO-d6)
d
in ppm: 3.68 (t; J ¼ 5.7 Hz; 4H; H-9, H-90),
(75.40 MHz, CDCl3) d
in ppm: 24.9 (C-13), 49.7 (H-9, H-90), 56.2 (C-
3.79 (s, 6H; H-10, H-100), 4.28 (t; J ¼ 5.7 Hz; 4H; H-8, H-80), 7.14 (d;
J ¼ 8.1 Hz; 2H; H-6, H-60), 7.49e7.52 (m; 4H; H-3, H-5, H-30, H-50),
7.56e7.61 (m; 2H; H-300, H-500), 7.65e7.70 (m; 1H; H-400), 7.88e7.91
(m; 2H; H-200, H-600), 8.98 (broad s; 4H; 2 ꢀ 2NH), 9.28 (broad s; 4H;
10, C-100), 68.3 (C-8, C-80), 104.6 (C-4, C-40), 112.8 (C-6, C-60), 114.5
(C-3, C-30),119.3 (C-7, C-70),119.5 (C-300, C-500),126.5 (C-5, C-50),128.6
(C-200, C-600),133.9 (C-100),142.3 (C-400),149.6 (C-2, C-20),151.9 (C-1, C-
10), 168.8 (C-12). C28H28N4O7S (564.62 g/mol): calcd. (%): C ¼ 59.56,
H ¼ 5.00, N ¼ 9.92, S ¼ 5.68; found (%): C ¼ 59.48, H ¼ 4.87,
N ¼ 10.06, S ¼ 5.79.
2 ꢀ 2NH). 13C NMR (75.40 MHz, DMSO-d6)
d
in ppm: 48.4 (C-9, C-90),
55.9 (C-10, C-100), 67.6 (C-8, C-80), 111.4 (C-3, C-30), 112.2 (C-6, C-60),
119.6 (C-4, C-40), 121.8 (C-5, C-50), 126.9 (C-200, C-600), 129.5 (C-300, C-
500),133.1 (C-400), 138.5 (C-100),148.5 (C-2, C-20),152.0 (C-1, C-10),164.5
(C-7, C-70). C26H31N5O6S ꢀ 2HCl ꢀ 3½H2O (677.62 g/mol): calcd. (%):
C ¼ 46.08, H ¼ 5.90, N ¼ 10.33, S ¼ 4.73; found (%): 46.08, H ¼ 5.80,
N ¼ 10.25, S ¼ 4.68.
4.2.1.19. N,N-Bis[2(4-amidino-2-methoxyphenoxy)ethyl]-4-acetami-
dobenzenesulfonamide (15). A light yellow solid of 15 was obtained
(Yield: 72%). M.p. ¼ 262.0e264.0 ꢁC 1H (299.86 MHz, DMSO-d6)
d in
ppm: 2.09 (s; 3H; H-13), 3.65 (t; J ¼ 5.7 Hz; 4H; H-9. H-90), 3.80 (s;
6H; H-10, H-100), 4.26 (t; J ¼ 5.7 Hz; 4H; H-8, H-80), 7.12 (d;
J ¼ 8.7 Hz; 2H; H-6, H-60), 7.46e7.52 (m; 4H; H-3, H-5, H-30, H-50),
7.75e7.81 (m; 4H; H-200, H-300, H-500, H-600), 9.03 (broad s; 4H;
2 ꢀ 2NH), 9.32 (broad s; 4H; 2 ꢀ 2NH), 10.54 (s; 1H; NH-11). 13C
4.2.1.16. N,N-Bis[2(4-cyano-2,6-dimethoxyphenoxy)ethyl]benzene-
sulfonamide (13a). 3,5-dimethoxy-4-hydroxybenzonitrile (1.79 g,
10 mmol), N,N-bis(2-chloroethyl)benzenesulfonamide (1.41 g,
5 mmol), anhydrous K2CO3 (2.76 g, 20 mmol) and N-methyl-2-
pyrrolidone (30 ml) were heated at 120 ꢁC for 3 h while stirring
(progress of the reaction was followed by TLC) and then poured into
ice water (250 ml). The resultant solid was filtered, washed with
water and dried at 60 ꢁC. Recrystalisation from a large volume of
ethanol gave a white solid of 13a (Yield: 64%). M.p. ¼ 194e195 ꢁC.
NMR (75.40 MHz, DMSO-d6)
d
in ppm: 23.7 (C-13), 47.9 (C-9, C-90),
55.5 (C-10, C-100), 67.2 (C-8, C-80), 111.0 (C-3, C-30), 111.8 (C-6, C-60),
118.3 (C-300, C500), 119.2 (C-4, C-40), 121.4 (C-5, C-50), 127.7 (C-200, C-
600), 131.7 (C-100), 143.0 (C-400), 148.1 (C-2, C-20), 151.6 (C-1, C-10),
164.2 (C-7, C-70), 168.7 (C-12). C28H34N6O7S ꢀ 2HCl ꢀ 1½H2O
(698.60 g/mol): calcd. (%): C ¼ 48.14, H ¼ 5.64, N ¼ 12.02, S ¼ 4.59;
found (%): C ¼ 48.13, H ¼ 5.71, N ¼ 11.72, S ¼ 4.31.
1H NMR (299.86 MHz, CDCl3)
d
in ppm: 3.71 (t; J ¼ 8.0 Hz, 4H; H-9,
H-90), 3.80 (s; 12H; H-10, H-100), 4.22 (t; J ¼ 8.0 Hz, 4H; H-8, H-80),
6.82 (s; 4H; H-3, H-5, H-30, H-50), 7.44e7.48 (m; 2H; H-300, H-500),
7.52e7.57 (m; 1H; H-400), 7.83e7.85 (m; 2H; H-200, H-600). 13C NMR
4.2.2. General procedure for synthesis of bisnitriles 17ae20a
A solution of an appropriate aliphatic diamine (10 mmol) in
dichloromethane (30 mL) and triethylamine (2.8 mL) was added
dropwise to a stirred, ice cooled solution of 4-cyanobenzoyl chlo-
ride (3.31 g, 20 mmol) in dichloromethane (30 mL). The reaction
mixture was stirred at room temperature for 12 h (progress of the
reaction was followed by TLC), then the solvent was evaporated
under reduced pressure and the residue was washed with 1 M
NaHCO3, 1 M HCl and water, then dried over anhydrous CaCl2.
Analytical samples were obtained after recrystalisation from
DMSO-water mixtures (50e90 % DMSO).
(75.40 MHz, CDCl3)
d
in ppm: 49.2 (C-9, C-90), 56.4 (C-10, C-100),
72.4 (C-8, C-80),107.1 (C-4, C-40),109.5 (C-3, C-5, C-30, C-50),119.0 (C-
7, C-70), 127.4 (C-200, C-600), 129.2 (C-300, C-500), 132.7 (C-400), 140.1 (C-
100), 141.4 (C-1, C-10), 153.7 (C-2, C-6, C-20, C-60). C28H29N3O8S
(567.62 g/mol): calcd. (%): C ¼ 59.25, H ¼ 5.15, N ¼ 7.40, S ¼ 5.65;
found (%): C ¼ 59.06, H ¼ 5.23, N ¼ 7.16, S ¼ 5.89.
4.2.1.17. N,N-Bis[2(4-amidino-2,6-dimethoxyphenoxy)ethyl]-benzene-
sulfonamide (13). The solvent was evaporated in vacuo and the
resultant brown solid was recrystalised from a small amount of
ethanol to give
a
light brown solid of 13 (Yield: 51%).
4.2.2.1. N,N0-propane-1,3-diylbis(4-cyanobenzamide) (17a). A white
solid of 17a was obtained (Yield: 94%). M.p. ¼ 212.5e213.5 ꢁC 1H
M.p. ¼ 207.5e210.0 ꢁC (decomp). 1H NMR (299.86 MHz, DMSO-d6)
d
in ppm: 3.62 (t; J ¼ 5.7 Hz; 4H; H-9, H-90), 3.81 (s; 12H; H-10, H-
NMR (400.13 MHz, DMSO-d6)
d
in ppm: 1.81 (quintet; J ¼ 6.8; 2H;
100), 4.08 (t; J ¼ 5.7 Hz; 4H; H-8, H-80), 7.21 (s; 4H; H-3, H-5, H-30, H-
50), 7.56e7.61 (m; 2H; H-300, H-500), 7.63e7.68 (m; 1H; H-400),
7.79e7.82 (m; 2H; H-200, H-600), 9.11 (broad s; 4H; 2 ꢀ 2NH), 9.39
H-11), 3.34 (quartet; J ¼ 6.3 Hz; 4H; H-10, H-100), 7.97 (m; 8H; H-2,
H-3, H-5, H-6, H-20, H-30, H-50, H-60), 8.73 (m; 2H; H-9, H-90). 13C
NMR (100.62 MHz, DMSO-d6)
d in ppm: 28.8 (C-11), 37.3 (C-10, C-
(broad s; 4H; 2 ꢀ 2NH). 13C NMR (75.40 MHz, DMSO-d6)
d
in ppm:
100), 113.5 (C-4, C-40), 118.3 (C-7, C-70), 128.0 (C-2, C-6, C-20, C-60),
132.4 (C-3, C-5, C-30, C-50), 138.5 (C-1, C-10), 164.8 (C-8, C-80).
C19H16N4O2 ꢀ 0.75H2O (345.87 g/mol). Calcd. (%) C ¼ 65.99;
H ¼ 5.07; N ¼ 16.21; found (%): C ¼ 66.05; H ¼ 4.84; N ¼ 16.00.
48.3 (C-9, C-90), 56.3 (C-10, C-100), 71.4 (C-8, C-80), 105.8 (C-3, C-5, C-
30, C-50), 122.5 (C-4, C-40), 126.8 (C-200, C-600), 129.3 (C-300, C-500), 132.8
(C-400),139.2 (C-100), 140.5 (C-1, C-10),152.6 (C-2, C-6, C-20, C-60),164.7
(C-7, C-70). C28H35N5O8S ꢀ 2HCl ꢀ 2H2O (710.64 g/mol): calcd. (%):
C ¼ 47.33, H ¼ 5.82, N ¼ 9.86, S ¼ 4.51; found (%): C ¼ 47.48, H ¼ 6.11,
N ¼ 9.66, S ¼ 4.60.
4.2.2.2. N,N0-propane-1,3-diylbis(4-amidinobenzamide)
dihydro-
chloride (17). A beige solid of 17 was obtained (Yield: 37%).
M.p. ¼ 302.5e304.5 ꢁC 1H NMR (400.13 MHz, DMSO-d6)
d in ppm:
4.2.1.18. N,N-Bis[2(4-cyano-2-methoxyphenoxy)ethyl]-4-acetamido-
benzenesulfonamide (15a). 3-methoxy-4-hydroxybenzonitrile (1.49
g, 10 mmol), N,N-bis(2-chloroethyl)-4-acethyloaminobenzenesul-
fonamide(1.69 g, 5 mmol), and anhydrous K2CO3 (3.46 g, 25 mmol)
in N-methyl-2-pyrrolidone (20 ml) were stirred together at130 ꢁC
for 7 h (progress of the reaction was followed by TLC). The hot
reaction mixture was poured into ice water (250 ml), the resultant
1.82 (quintet; J ¼ 6.3; 2H; H-11), 3.38 (quartet; J ¼ 6.2 Hz; 4H; H-10,
H-100), 7.95 (d; J ¼ 8.4 Hz; 4H; H-3, H-5, H-30, H-50), 8.12 (d;
J ¼ 8.4 Hz; 4H; H-2, H-6, H-20, H-60), 9.09 (t; J ¼ 5.6 Hz; 2H; H-9, H-
90), 9.40 (s; 4H; H-7, H-70), 9.58 (s; 4H; H-7, H-70). 13C NMR
(100.62 MHz, DMSO-d6)
d
in ppm: 28.8 (C-11), 37.0 (C-10, C-100),
127.6 (C-2, C-6, C-20, C-60), 128.2 (C-3, C-5, C-30, C-50), 130.2 (C-4, C-
40), 138.9 (C-1, C-10), 164.9 (C-8, C-80), 165.2 (C-7, C-70).