M.H. Paulsen et al. / European Journal of Medicinal Chemistry 183 (2019) 111671
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J ¼ 4.5 Hz), 128.9 (d, J ¼ 8.6 Hz), 127.3, 127.1 (d, J ¼ 4.6 Hz), 126.4 (d,
55.6, 48.3, 46.8, 40.8, 40.5, 39.7. HRMS-ESI m/z: C
[MþH]þ calculated for 609.8694, found: 609.8719.
3-Amino-1-(2-aminoethylamino)-2,2-bis([3,5-
H Br4N3
19 24
J ¼ 1.9 Hz), 124.4 (d, J ¼ 2.7 Hz), 124.1 (d, J ¼ 15.9 Hz), 121.3 (d,
J ¼ 6.0 Hz), 120.6, 109.1 (d, J ¼ 20.1 Hz), 53.6, 42.9, 40.1, 38.2. HRMS-
ESI: C27H24F2N3O [MþH]þ calculated for 444.1882, found: 444.1883.
3-Amino-1-(2-aminoethylamino)-2,2-bis[(4-fluoro-1-naphthyl)
methyl]-1-propanone (2i). The nitrile 1i (0.11 mmol, 0.050 g, 1
equiv.) was dissolved in ZnCl2/NaBH4 reducing agent (1 mL) and
refluxed for 1.5 h. The reaction mixture was allowed to cool down to
r.t., quenched with water (0.1 mL) followed by 6 M aqueous HCl
(1 mL). A complex of a boron and 2i was detected by MS, which
dissociated on reflux of the mixture for 10 min (followed by MS).
The resulting solution was evaporated to dryness, the residue dis-
solved in MeOH and purified by C18 RP flash chromatography and
lyophilized to give the title derivative (2i) as light brown powder
bis(trifluoromethyl)phenyl]methyl) propane (3g). The nitrile 1g
(0.18 mmol, 0.104 g) and the reducing agent (2.7 mL) gave the title
derivative (3g) as clear crystals after purification (TFA-salt) (0.061 g,
37%). 1H NMR (400 MHz, Methanol-d4)
d
1H NMR (400 MHz,
Methanol-d4)
J ¼ 13.8 Hz, 2H), 2.93 (dAB, J ¼ 13.6 Hz, 2H), 2.87 (t, J ¼ 6.0 Hz, 2H),
2.74 (s, 2H). 13C NMR (101 MHz, Methanol-d4)
140.3, 132.9 (q,
d 7.92 (s, 2H), 7.88 (s, 4H), 3.10 (s, 4H), 3.04 (dAB,
d
J ¼ 33.1 Hz), 132.37e132.14 (m), 124.8 (q, J ¼ 272.0 Hz), 122.2 (h,
J ¼ 3.7 Hz), 55.9, 48.3 (overlap with solvent, confirmed by HSQC),
47.2, 40.8, 40.7, 40.0. HRMS-ESI m/z: C23H24F12N3 [MþH]þ calcu-
lated for 570.1774, found: 570.1766.
3-Amino-1-(2-aminoethylamino)-2,2-bis[(4-fluoro-1-naphthyl)
methyl]propane (3i). The nitrile 1i (0.33 mmol, 0.145 g) and the
reducing agent (3.0 mL) gave the title derivative (3i) as clear crys-
tals (TFA-salt) after purification (0.093 g, 36%). 1H NMR (400 MHz,
(0.038 g, 45%, TFA salt). 1H NMR (400 MHz, Methanol-d4)
d
8.17 (dd,
J ¼ 18.3, 8.2 Hz, 4H), 7.64 (dt, J ¼ 15.1, 7.0 Hz, 4H), 7.56e7.31 (m, 2H),
7.29e7.00 (m, 2H), 3.75 (dAB, J ¼ 15.1 Hz, 2H), 3.68 (dAB, J ¼ 15.1 Hz,
2H), 3.24 (t, J ¼ 6.4 Hz, 2H), 3.13 (s, 2H), 2.86 (t, J ¼ 6.4 Hz, 2H). 13
C
NMR (101 MHz, Methanol-d4)
d
176.7, 159.5 (d, J ¼ 250.9 Hz), 135.6
Methanol-d4)
d
8.14 (dt, J ¼ 6.3, 2.7 Hz, 2H), 8.05e7.89 (m, 2H), 7.58
(d, J ¼ 4.2 Hz), 129.4 (d, J ¼ 8.5 Hz), 129.0 (d, J ¼ 4.4 Hz), 128.5, 127.3
(d, J ¼ 1.9 Hz), 125.5 (d, J ¼ 2.6 Hz), 125.2 (d, J ¼ 15.9 Hz), 121.9 (d,
J ¼ 6.1 Hz), 109.8 (d, J ¼ 20.2 Hz), 51.6, 44.3, 40.4, 38.7, 36.9. m/z:
(dd, J ¼ 6.5, 3.1 Hz, 4H), 7.40 (t, J ¼ 6.7 Hz, 2H), 7.23 (td, J ¼ 9.2, 8.0,
2.3 Hz, 2H), 3.47e3.25 (m, 10H), 3.20 (s, 2H), 3.04 (t, J ¼ 5.9 Hz, 2H),
2.93 (s, 2H), 2.84 (t, J ¼ 5.6 Hz, 2H). 13C NMR (101 MHz, Methanol-
C
27H28F2N3O [MþH]þ calculated for 448.2195, found: 448.2194.
3-Amino-1-(2-aminoethylamino)-2,2-bis[(1-naphthyl)methyl]-1-
d4)
d
159.5 (d, J ¼ 251.1 Hz), 135.8 (d, J ¼ 4.2 Hz), 129.8 (d, J ¼ 8.4 Hz),
129.6 (d, J ¼ 4.8 Hz), 128.5, 127.4 (d, J ¼ 1.9 Hz), 125.47e125.20 (m),
125.4 (d, J ¼ 2.8 Hz), 122.1 (d, J ¼ 6.2 Hz), 109.9 (d, J ¼ 20.1 Hz), 56.5,
48.3, 47.7, 42.9, 39.8, 36.3. HRMS-ESI m/z: C27H30F2N3 [MþH]þ
calculated for 434.2402, found: 434.2420.
propanone (2j). One spoon of Raney-Nickel (approx. 5 g) was
transferred to a round bottomed flask, washed with MeOH
(3 ꢃ 15 mL) and EtOAc (3 ꢃ 15 mL) before addition of compound 1i
(0.114 g, 0.25 mmol) dissolved in EtOAc. Boc2O (0.224 g, 1.03 mmol,
4 equiv.) was added. The reaction was stirred for 18 h at 45 ꢂC with a
H2(g) containing balloon attached. The reaction mixture was cooled
to r.t. before the catalyst was filtered off through a pad of sand and
celite under N2, washed with brine, dried with Na2SO4, and evap-
orated to dryness. The Boc-protected intermediate was added
dioxane (4 mL), H2O (0.5 mL), and 4 M HCl/dioxane (2 mL) to yield
the crude HCl-salt. The product was purified by C18 RP flash chro-
Preparation of guanidine derivatives 4. Derivatives 4e, 4g, and 4i
were prepared using the following procedure: To a stirred solution
of the salt of 2e (HCl), 2g (HCl) or 2i (TFA) in THF, K2CO3 was added
followed by N,N0-Di-Boc-1H-pyrazole-1-carboxamidine. The reac-
tion was stirred at r.t. for 48e72 h. The reaction mixture was
concentrated, the crude product was dissolved in EtOAc and
washed with water and brine. The organic phase was dried over
Na2SO4, filtered and concentrated. The crude product was purified
by automated flash chromatography (EtOAc/Heptane) and the
resulting Boc-protected intermediate was deprotected with TFA
(1 mL) in CH2Cl2 (1:1) for 18 h. The reaction mixture was concen-
trated and the crude was purified by RP automated flash chroma-
tography (ACN/water 0,1% TFA) and lyophilized to yield the
guanylated product.
2,2-bis(3,5-dibromobenzyl)-3-guanidino-N-(2-guanidinoethyl)
propenamide (4e). The HCl salt of 2e (120 mg, 0.17 mmol, 1 equiv.)
was dissolved in THF (5 mL) and added K2CO3 (118 mg, 0.85 mmol,
5 equiv.) and N,N0-Di-Boc-1H-pyrazole-1-carboxamidine (221 mg, 4
equiv.) and stirred for 72 h. The reaction mixture was then treated
according to the general procedure to yield the title compound 4e
as a white powder (TFA-salt, 55 mg, 34%). 1H NMR (400 MHz,
matography. 1H NMR (400 MHz, Methanol-d4)
d 7.90e7.82 (m, 6H),
7.75 (d, J ¼ 1.7 Hz, 2H), 7.56e7.46 (m, 4H), 7.38 (dd, J ¼ 8.4, 1.8 Hz,
2H), 3.53 (t, J ¼ 6.5 Hz, 2H), 3.42 (d, J ¼ 14.2 Hz, 2H), 3.20 (d,
J ¼ 14.1 Hz, 2H), 3.12e3.08 (m, 4H). 13C NMR (101 MHz, Methanol-
d4) d 177.1, 134.8, 134.1, 134.0, 130.4, 129.4, 129.3, 128.7, 128.7, 127.5,
127.2, 51.0, 43.8, 41.4, 40.6, 38.7. HRMS-ESI m/z: C27H30N3O [MþH]þ
calculated for 412.2382, found: 412.2394.
Preparation of triamine derivatives 3. Derivatives 3d, 3e, 3g, and
3i were prepared in accordance to the procedure for nitrile
reduction of 2i with ZnCl2/NaBH4, but with 24 h reaction time [32].
3-Amino-1-(2-aminoethylamino)-2,2-bis[(o-bromophenyl)
methyl]propane (3d). The nitrile 1d (0.985 mmol, 0.455 g) and the
ZnCl2/NaBH4 reducing agent (7.0 mL) gave the title derivative (3d)
as clear crystals (HCl-salt) after purification by C18 RP flash chro-
matography with acetonitrile/water and lyophilized with aq. HCl
Methanol-d4)
d
7.67 (t, J ¼ 1.7 Hz, 2H), 7.32 (d, J ¼ 1.7 Hz, 4H),
3.45e3.39 (m, 2H), 3.37e3.32 (m, 2H), 3.21 (dAB, J ¼ 14.0 Hz, 2H),
(0.123 g, 22%). 1H NMR (600 MHz, DMSO‑d6)
d 10.04 (s, 2H), 8.66 (s,
3.10 (s, 2H), 2.91 (dAB J ¼ 14.1 Hz, 2H). 13C NMR (101 MHz, Meth-
3H), 8.44 (s, 3H), 7.66 (d, J ¼ 8.1 Hz, 2H), 7.51 (d, J ¼ 7.6 Hz, 2H), 7.43
(t, J ¼ 7.6 Hz, 2H), 7.26 (t, J ¼ 7.8 Hz, 2H), 3.39 (s*, 2H), 3.36(s*, 2H),
3.31 (d*, J ¼ 14.6 Hz, 2H), 3.25 (d*, J ¼ 14.9 Hz, 2H), 2,97 (s*, 2H), 2.91
(s*, 2H). * Extensive line broadening due to conformational ex-
anol-d4) d 175.6, 158.9, 158.9, 141.4, 134.0, 133.0, 124.0, 52.6, 43.8,
42.1, 41.3, 40.1. HRMS-ESI m/z: [MþH]þ calculated for
79
C
H
Br4N7Oþ 707.8926, found: 707.8947.
21 26
2,2-bis(3,5-bis(trifluoromethyl)benzyl)-3-guanidino-N-(2-
guanidinoethyl)propenamide (4g). The HCl salt of 2g (34 mg,
change. 13C NMR (151 MHz, DMSO‑d6)
d
134.8, 133.3, 133.0, 129.4,
128.0, 125.9, 50.2, 46.3, 42.4, 41.3, 36.2, 35.2. HRMS-ESI m/z:
0.052 mmol, 1 equiv.) was dissolved in THF (3 mL) and added K2CO3
79
C
H
19 26
Br2N3 [MþH]þ calculated for 454.0486, found: 454.0495.
(35 mg, 0.25 mmol, 5
equiv.) and N,N0-Di-Boc-1H-pyrazole-1-
3-Amino-1-(2-aminoethylamino)-2,2-bis[(3,5-dibromophenyl)
carboxamidine (66 mg, 0.21 mmol, 4 equiv.) and stirred for 72 h.
The reaction mixture was then treated according to the general
procedure to yield the title compound 4e as a white powder (TFA-
methyl]propane (3e). The nitrile 1e (0.33 mmol, 0.205 g) and the
reducing agent (3.0 mL) gave the title derivative (3e) as clear
crystals after purification (TFA-salt) (0.068 g, 22%). 1H NMR
salt, 17 mg, 37%). 1H NMR (400 MHz, Methanol-d4)
d 7.91 (s, 2H),
(400 MHz, Methanol-d4)
J ¼ 6.4 Hz, 2H), 3.06 (s, 2H), 2.96 (t, J ¼ 6.4 Hz, 2H), 2.88e2.68 (m,
6H). 13C NMR (101 MHz, Methanol-d4)
141.4, 134.0, 133.7, 124.1,
d
7.69 (s, 2H), 7.44 (s, 4H), 3.15 (t,
7.75 (s, 4H), 3.49 (dAB
,
J ¼ 14.2 Hz, 2H), 3.41e3.35 (m, 2H),
3.34e3.32 (m, 2H), 3.19 (dAB, J ¼ 14.2 Hz, 2H), 3.08 (s, 2H). 13C NMR
d
(101 MHz, Methanol-d4)
d
175.0, 162.9 (q, J ¼ 35.6 Hz, TFA), 159.1,