Journal of Medicinal Chemistry
Article
35.1, 32.1, 31.6, 31.4, 28.8, 22.4, 22.3, 11.5, 11.3. Analytical RP-HPLC
tR = 5.52 min, purity >99% (method C).
general procedure A. Compound 18a (20 mg, 46 μmol, 1.1 equiv)
was added to a solution of 2-(2-((tert-butoxycarbonyl)amino)-
ethoxy)acetic acid (10 mg, 46 μmol, 1.0 equiv), BOP (30 mg, 68
μmol, 1.50 equiv), and DIPEA (32 mL, 182 μmol, 4.0 equiv) in DMF
(1 mL). Purification by flash column chromatography using a gradient
of 97:3 to 96:4 DCM/MeOH gave the title compound as colorless oil,
which slightly solidified upon cooling (10 mg, 36%). LC/MS m/z
calcd for C31H50N7O7 [MH]+: 632.20, found 632.40 tR = 3.53 min
(method A). HRMS (TOF ES+) calcd for C31H50N7O7 632.3766,
found 632.3781; calcd for C31H50N7O7Na 654.3586, found 654.3601.
1H NMR (CDCl3) δ 11.86 (s, 1H), 7.38 (s, 1H), 6.57 (s, 1H), 5.46
(s, 1H), 4.09 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.96 (s,
2H), 3.57 (t, J = 5.0 Hz, 2H), 3.47−3.41 (m, 4H), 3.40−3.33 (m,
2H), 2.09−2.01 (m, 6H), 1.92−1.85 (m, 6H), 1.79 (h, J = 6.9 Hz,
2H), 1.69 (h, J = 6.9 Hz, 2H), 1.45 (s, 9H), 0.95 (t, J = 7.5 Hz, 6H).
13C NMR (CDCl3) δ 178.5, 171.1, 156.4, 155.5, 151.2, 106.9, 79.7,
tert-Butyl(2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl) bicyclo[2.2.2]octane-1-carboxamido)ethyl)carbamate
(17a). Following general procedure A, to a solution of (2,6-dioxo-
1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl) bicyclo [2.2.2] octane-
1-carboxylic acid (compound 16 from Kiesman et al.)59 (80 mg, 206
μmol, 1.0 equiv), tert-butyl (2-aminoethyl) carbamate (33 mg, 206
μmol, 1.0 equiv), and BOP (137 mg, 309 μmol, 1.50 equiv) in dry
DMF (2 mL) was added DIPEA (143 μL, 824 μmol, 4.0 equiv).
Purification by flash column chromatography using a gradient of 97:3
to 96:4 DCM/MeOH gave the title compound as off-white solid (85
mg, 78%). LC/MS m/z calcd for C27H43N6O5 [MH]+: 531.30, found
1
531.30 tR = 3.61 min (method A). H NMR (CDCl3) δ 11.67 (br s,
1H), 6.53 (br s, 1H), 4.90 (br s, 1H), 4.09 (t, J = 6.3 Hz, 2H), 4.02 (t,
J = 6.6 Hz, 2H), 3.37−3.26 (m, 4H), 2.08−2.01 (m, 6H), 1.93−1.87
(m, 6H), 1.80 (h, J = 6.5 Hz, 2H), 1.70 (h, J = 6.5 Hz, 2H), 1.45 (s,
9H), 0.96 (t, J = 7.5 Hz, 6H). 13C NMR (CDCl3) δ 176.1, 155.5,
152.2, 151.3, 148.9, 106.9, 30.2, 28.5, 21.5, 11.6, 11.3.
70.4, 69.5, 43.3, 40.7, 39.9, 39.0, 33.9, 30.1, 29.8, 28.6, 28.5, 21.5,
21.5, 11.6, 11.3. Analytical RP-HPLC tR = 5.87 min, purity >97%
(method C).
tert-Butyl(3-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl)bicyclo[2.2.2]octane-1-carboxamido)propyl)carbamate
(17b). The synthesis of the title compound 17b was carried out as
described for xanthine (17a), following general procedure A. To a
stirred solution of (2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl) bicyclo [2.2.2] octane-1-carboxylic acid (compound 16
from Kiesman et al.) (110 mg, 283 μmol, 1 equiv), tert-butyl (3-
aminopropyl) carbamate (49 mg, 283 μmol, 1.0 equiv), and BOP
(188 mg, 425 μmol, 1.50 equiv) in dry DMF (2 mL) was added
DIPEA (197 μL, 1.13 μmol, 4.0 equiv). Purification by flash column
chromatography using a gradient of 97:3 to 96:4 DCM/MeOH gave
the title pure compound as an off-white solid (132 mg, 86%). LC/MS
m/z calcd for C28H45N6O5 [MH]+: 545.30, found 545.40 tR = 3.66
tert-Butyl(3-((2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl)bicyclo[2.2.2]octane-1-carboxamido)ethyl)amino)-3-
oxopropyl)carbamate (21). Compound 18a (22 mg, 53 μmol, 1.0
equiv) was reacted with Boc-β-Ala-OH (10 mg, 53 μmol, 1.0 equiv)
in the presence of BOP (35 mg, 79 μmol, 1.50 equiv) and DIPEA (37
μL, 211 μmol, 4.0 equiv) in DMF (2 mL) according to general
procedure A. Purification by flash column chromatography using a
gradient of 97:3 to 96:4 DCM/MeOH gave the title compound as
colorless oil, which slightly solidified upon cooling (12 mg, 38%). LC/
MS m/z calcd for C30H48N7O6 [MH]+: 602.20, found 602.40 tR
=
1
3.48 min (method A). H NMR (CD3OD) δ 4.07 (t, J = 6.9, 2H),
3.95 (t, J = 6.9, 2H), 3.32 (s, 2H), 3.30 (s, 4H), 2.37 (t, J = 6.8 Hz,
2H), 2.05−1.98 (m, 6H), 1.95−1.87 (m, 6H), 1.77 (h, J = 7.5, 2H),
1.66 (h, J = 7.5, 2H), 1.45 (s, 9H), 0.96 (t, J = 7.4, 6H).
1
min (method A). H NMR (CDCl3) δ 12.20 (br s, 1H), 6.55 (br s,
1H), 4.91 (br s, 1H), 4.08 (t, J = 6.9, Hz, 2H), 4.02 (t, J = 6.2 Hz,
2H), 3.30 (q, J = 4.6 Hz, 2H), 3.16 (q, J = 4.6 Hz, 2H), 2.10−2.04
(m, 6H), 1.94−1.88 (m, 6H), 1.78 (h, J = 6.5 Hz, 2H), 1.70 (h, J =
6.5 Hz, 2H), 1.62−1.54 (m, 2H), 1.43 (s, 9H), 0.95 (t, J = 7.0 Hz,
6H). 13C NMR (CDCl3) δ 177.6, 161.4, 156.9, 155.6, 151.2, 149.0,
107.0, 79.6, 45.3, 43.2, 39.1, 36.9, 35.6, 33.9, 30.2, 28.5, 21.5, 11.6,
11.3.
tert-Butyl(3-((3-((2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-
1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxamido)ethyl)amino)-3-
oxopropyl)amino)-3-oxopropyl)carbamate (25a). Compound 21
(12 mg, 1.0 equiv) was treated with 4 M HCl in dioxane following
general procedure B to yield the corresponding 3-((2-(4-(2,6-dioxo-
1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-
carboxamido)ethyl)amino)-3-oxopropan-1-aminium chloride inter-
mediate (9 mg, quantitative), which was used for the next step
without any further purification. The synthesis of the title compound
25a was carried out as described for 8-bicyclo[2.2.2]octylxanthine 21,
treating the 3-((2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-
purin-8-yl)bicyclo[2.2.2]octane-1-carboxamido)ethyl)amino)-3-oxo-
propan-1-aminium chloride intermediate (5 mg, 1.10 equiv) with
DIPEA (31 μL, 186 μmol, 10.0 equiv), Boc-β-Ala-OH (4 mg, 19
μmol, 1.0 equiv), and BOP (12 mg, 28 μmol, 1.50 equiv) in DMF (1
mL). Purification by flash column chromatography using a gradient of
96:4 to 94:6 DCM/MeOH gave the title compound as colorless oil,
which solidified upon cooling (8 mg, 67%). LC/MS m/z calcd for
C33H53N8O7 [MH]+: 673.20, found 673.40 tR = 3.42 min (method
A). HRMS (TOF ES+) calcd for C33H53N8O7 673.4032, found
tert-Butyl(1-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl)bicyclo[2.2.2]octan-1-yl)-1,6-dioxo-8,11-dioxa-2,5-dia-
zatridecan-13-yl)carbamate (19). Following general procedure B,
compound 17a (85 mg, 206 μmol, 1.0 equiv) was treated with 4 M
HCl in dioxane (1 mL) to afford compound 18a (68 mg,
quantitative) as HCl salt, which was used in the next step without
further purification. LC/MS m/z calcd for C22H35N6O3 [MH]+:
431.34, found 431.30 tR = 3.10 min. Compound 19 was synthesized
according to general procedure A, reacting a solution of compound
18a (25 mg, 57 μmol, 1.1 equiv) in DMF (0.5 mL) with 2,2-dimethyl-
4-oxo-3,8,11-trioxa-5-azatridecan-13-oic acid (15 mg, 57 μmol, 1.0
equiv), DIPEA (40 mL, 228 μmol, 4.0 equiv), and BOP (38 mg, 85
μmol, 1.50 equiv). Purification by flash column chromatography using
a gradient of 98:2 to 96:4 DCM/MeOH gave the title compound as
colorless oil (15 mg, 38%). LC/MS m/z calcd for C33H54N7O8
[MH]+: 676.20, found 676.40 tR = 3.50 min (method A). HRMS
(TOF ES+) calcd for C33H54N7O8 676.4028, found 676.4045; calcd
for C33H54N7O8Na 698.3848, found 698.3869. 1H NMR (CD3OD) δ
4.07 (t, J = 6.9, Hz, 2H), 4.01 (s, 2H), 3.95 (t, J = 7.1 Hz, 2H), 3.72−
3.66 (m, 4H), 3.56 (t, J = 5.7 Hz, 2H), 3.41−3.37 (m, 2H), 3.37−
3.34 (m, 2H), 3.27 (td, J = 5.7, 4.4 Hz, 2H), 2.05−1.98 (m, 6H),
1.93−1.86 (m, 6H), 1.79 (h, J = 7.3 Hz, 2H), 1.65 (h, J = 7.3 Hz,
2H), 1.44 (s, 9H), 0.96 (t, J = 7.4, 6.3 Hz, 6H). 13C NMR (CD3OD)
δ 180.5, 173.3, 160.9, 156.0, 152.9, 151.6, 149.5, 108.2, 80.1, 72.0,
71.3, 71.2, 71.1, 49.6, 45.9, 43.8, 41.3, 40.5, 40.5, 40.1, 39.7, 34.9,
31.0, 29.2, 28.8, 22.4, 22.3, 11.5, 11.4. Analytical RP-HPLC tR = 5.85
min, purity >99% (method C).
1
673.4043; calcd for C33H52N8O7Na 695.3851, found 695.3866. H
NMR (CD3OD) δ 4.07 (t, J = 6.3 Hz, 2H), 3.95 (t, J = 5.7 Hz, 2H),
3.45 (t, J = 6.8 Hz, 2H), 3.30 (s, 4H), 2.38 (t, J = 6.8 Hz, 4H), 2.04−
1.98 (m, 6H), 1.93−1.87 (m, 6H), 1.77 (h, J = 7.4 Hz, 2H), 1.66 (h, J
= 6.4 Hz, 2H), 1.43 (s, 9H), 0.96 (t, J = 7.2 Hz, 6H). 13C NMR
(CD3OD) δ 179.1, 172.9, 161.5, 160.8, 151.5, 95.1, 78.7, 46.8, 42.5,
39.1, 38.7, 35.7, 35.5, 33.6, 33.6, 33.3, 29.6, 27.8, 27.4, 20.9, 20.9,
10.1, 9.9. Analytical RP-HPLC tR = 5.58 min, purity >97% (method
C).
Methyl 3-(4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl) bicyclo[2.2.2]octane-1-carboxamido)propanoate (26).
To a solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-
purin-8-yl)bicyclo[2.2.2]octane-1-carboxylic acid (compound 16
from Kiesman et al.) (80 mg, 206 μmol, 1.0 equiv) in DMF (1
mL) were added DIPEA (0.143 mL, 824 μmol, 4.0 equiv), β-Ala-
methyl ester (29 mg, 206 μmol, 1.0 equiv), and BOP (136 mg, 309
μmol, 1.50 equiv). The resulting mixture was stirred at rt. for 1 h.
tert-Butyl(2-(2-((2-(4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-
1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxamido)ethyl)amino)-2-
oxoethoxy)ethyl)carbamate (20). The synthesis of 20 was carried
out as described for 8-bicyclo[2.2.2]octylxanthine 19, following
P
J. Med. Chem. XXXX, XXX, XXX−XXX