Journal of Medicinal Chemistry
Article
acylating reagent and a light-yellow powder was obtained in 50.0%
yield. The purity was 96% by HPLC analysis. RT = 5.3 min. 1H NMR
(DMSO-d6, 300 MHz): δ 10.12 (brs, 2H), 8.62 (brs, 2H), 8.10
(dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 2H), 8.03 (dd, J1 = 3.9 Hz, J2 = 1.5 Hz,
2H), 7.57 (d, J = 8.4 Hz, 4H), 7.37 (d, J = 8.7 Hz, 4H), 7.32 (dd, J1 =
3.9 Hz, J2 = 5.1 Hz, 2H), 7.28 (m, 2H), 7.26 (m, 2H), 7.20 (brd, J = 8.1
Hz, 2H), 4.98 (brs, 2H), 3.23 (s, 6H), 2.02 (s, 6H). 13C NMR
(DMSO-d6, 75 MHz,): δ 176.5, 168.8, 165.1, 159.5, 149.9, 142.0, 136.9,
136.5, 134.9, 131.7, 129.5, 128.6, 127.5, 121.6, 120.2, 118.3, 112.3, 64.9,
55.1, 52.0, 24.0. MS (ESI) m/z 983.0 [M + Na]+, 961.1 [M + H]+.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-propionamidobenzamido)-2,4-
bis(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-
1,3-dicarboxylic Acid (14). Compound 14 was prepared according to
the general procedure B above, in which propionyl chloride was used
as the acylating reagent, and a light-yellow powder was obtained in
50.0% yield. The purity was 96% by HPLC analysis. RT = 6.9 min. 1H
NMR (DMSO-d6, 400 MHz): δ 1.07 (t, J = 7.4 Hz, 6H), 2.35 (q, J =
7.4 Hz, 4H), 3.36 (s, 6H), 5.28 (s, 2H), 6.95 (brs, 4H), 7.26 (t, J = 4.6
Hz, 2H), 7.33 (s, 2H), 7.67 (brs, 8H), 7.93 (d, J = 2.9 Hz, 2H), 8.04
(d, J = 4.7 Hz, 2H), 10.24 (s, 2NH). MS (ESI) m/z 987.1 [M − H]−.
HRMS (ESI) m/z calcd for C50H43N4O14S2 [M − H]− 987.2217,
found 987.2211.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-butyramidobenzamido)-2,4-bis-
(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-1,3-
dicarboxylic Acid (15). Compound 15 was prepared according to the
general procedure B above, in which butyryl chloride was used as the
acylating reagent, and the light-yellow powder was obtained in 48%
yield. The purity was 96% by HPLC analysis. RT = 5.6 min. 1H NMR
(DMSO-d6, 400 MHz): δ 0.91 (t, J = 6.9 Hz, 6H), 1.58−1.63 (m, 4H),
2.31 (t, J = 7.1 Hz, 4H), 3.35 (s, 6H), 5.26 (s, 2H), 6.80 (s, 2H), 6.93
(brs, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 4.2 Hz, 2H), 7.67 (brs,
8H), 7.93 (d, J = 3.0 Hz, 2H), 8.04 (d, J = 5.0 Hz, 2H). 13C NMR
(DMSO-d6, 75 MHz): δ 176.1, 171.7, 165.2, 159.5, 150.0, 142.2,
136.6, 136.0, 134.9, 131.8, 129.3, 128.6, 127.6, 121.8, 120.2, 118.4,
112.1, 64.8, 55.1, 51.9, 35.0, 18.5, 13.6.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-isobutyramidobenzamido)-2,4-
bis(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-
1,3-dicarboxylic Acid (16). Compound 16 was prepared according to
the general procedure B above, in which isobutyryl chloride was used
as the acylating reagent, and a light-yellow powder was obtained in
40.0% yield. The purity was 96% by HPLC analysis. RT = 5.7 min. 1H
NMR (DMSO-d6, 400 MHz): δ 1.12 (d, J = 6.8 Hz, 12H), 2.60−2.65
(m, 2H), 3.77 (s, 6H), 4.62 (s, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.23 (s,
2H), 7.27 (d, J = 4.0 Hz, 2H), 7.63−7.64 (m, 2H), 7.85 (d, J = 8.7 Hz,
4H), 7.92 (d, J = 2.9 Hz, 2H), 8.02 (d, J = 8.8 Hz, 4H), 8.05 (d, J = 5.0
Hz, 2H), 10.28 (s, 2H). 13C NMR (DMSO-d6, 75 MHz): δ 175.1,
172.3, 166.3, 159.0, 149.7, 141.6, 137.2, 134.7, 133.1, 131.2, 128.7,
128.3, 127.7, 122.1, 121.7, 117.7, 112.0, 62.8, 54.4, 47.9, 34.5, 18.9.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-pivalamidobenzamido)-2,4-bis-
(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)cyclobutane-1,3-
dicarboxylic Acid (17). Compound 17 was prepared according to the
general procedure B above, in which pivaloyl chloride was used as the
acylating reagent, and a light-yellow powder was obtained in 45.0%
yield. The purity was 97% by HPLC analysis. RT = 5.6 min. 1H NMR
(DMSO-d6, 400 MHz) δ 1.23 (s, 18H), 3.38 (s, 6H), 5.39 (s, 2H),
6.90 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 7.70 (s, 2H), 7.26 (t,
J = 4.8 Hz, 2H), 7.66 (brs, 4H), 7.79 (d, J = 8.8 Hz, 4H), 7.93 (dd, J1 =
1.2 Hz, J2 = 3.8 Hz, 2H), 8.04 (dd, J1 = 1.2 Hz, J2 = 5.0 Hz, 2H), 9.56
(s, 2H). 13C NMR (DMSO-d6, 75 MHz): δ 176.9, 174.8, 165.1, 159.4,
150.0, 142.3, 137.4, 136.7, 135.3, 135.0, 131.7, 129.1, 128.6, 127.3,
121.9, 120.0, 119.5, 111.9, 64.5, 55.1, 52.1, 45.4, 27.1.
Hz, 4H), 7.94 (dd, J1 = 1.2 Hz, J2 = 3.7 Hz, 2H), 8.04 (dd, J1 = 1.1 Hz,
J2 = 4.9 Hz, 2H), 9.33 (s, 2NH). 13C NMR (DMSO-d6, 75 MHz): δ
176.2, 174.5, 164.9, 159.4, 149.9, 142.2, 136.6, 136.2, 134.9, 131.7,
129.3, 128.6, 127.3, 121.8, 120.0, 119.4, 112.0, 64.6, 55.1, 51.7, 45.6,
41.1, 36.0, 27.6.
( 1 , 2 - c i s - 2 , 3 - c i s - 3 , 4 - c i s ) - 1 , 3 - B i s ( 4 - ( 2 - b e n z y l o x y ) -
acetamidobenzamido)-2,4-bis(3-methoxy-4-(thiophene-2-
carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic Acid (19). Com-
pound 19 was prepared according to the general procedure B above, in
which benzyloxyacetyl chloride was used as the acylating reagent, and a
light-yellow powder was obtained in 40.0% yield. The purity was 96%
by HPLC analysis. RT = 5.7 min. 1H NMR (CD3Cl, 400 MHz): δ 3.35
(s, 6H), 4.12 (s, 4H), 4.62 (s, 4H), 6.95 (d, J = 8.0 Hz, 2H), 7.02 (d,
J = 8.0 Hz, 2H), 7.21 (s, 2H), 7.26 (t, J = 3.9 Hz, 2H), 7.31 (t, J = 7.0
Hz, 4H), 7.37 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 7.2 Hz, 4H), 7.71 (d, J =
8.0 Hz, 4H), 7.75 (d, J = 8.2 Hz, 4H), 7.94 (d, J = 4.0 Hz, 2H), 8.03
(d, J = 4.8 Hz, 2H), 10.09 (s, 2NH). 13C NMR (DMSO-d6, 75 MHz):
δ 176.0, 168.5, 165.2, 159.5, 150.1, 141.4, 137.7, 136.9, 136.2, 134.9,
131.8, 129.9, 128.6, 128.3, 127.9, 127.7, 127.6, 122.0, 120.5, 119.2,
112.5, 72.2, 69.5, 64.9, 55.2, 51.8.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-(2-chloroacetamido)-
benzamido)-2,4-bis(3-methoxy-4-(thiophene-2-carbonyloxy)-
phenyl)cyclobutane-1,3-dicarboxylic Acid (20). Compound 20 was
prepared according to the general procedure B above, in which 2-
chloroacetyl chloride was used as the acylating reagent, and a light-
yellow powder was obtained in 35.0% yield. The purity was 97% by
1
HPLC analysis. RT = 5.7 min. H NMR (DMSO-d6, 400 MHz): δ
3.76 (s, 6H), 4.31 (s, 4H), 4.63 (s, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.23
(dd, J1 = 1.7 Hz, J2 = 6.0 Hz, 2H), 7.25 (t, J = 4.8 Hz, 2H), 7.61 (d, J =
1.6 Hz, 2H), 7.82 (d, J = 8.7 Hz, 4H), 7.91 (dd, J1 = 1.2 Hz, J2 = 3.7
Hz, 2H), 8.04 (d, J = 1.8 Hz, 2H), 8.06 (d, J = 7.0 Hz, 4H), 10.73 (s,
2H). 13C NMR (DMSO-d6, 75 MHz): δ 172.8, 168.6, 166.9, 165.0,
159.5, 150.2, 141.1, 137.8, 135.2, 133.6, 131.7, 130.2, 128.8, 128.3,
122.6, 122.2, 118.6, 112.6, 63.3, 55.0, 48.5, 45.7, 43.6.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-(phenylacetamido)benzamido)-
2,4-bis(3-methoxy-4-(thiophene-2-carbonyloxy)phenyl)-
cyclobutane-1,3-dicarboxylic Acid (21). Compound 21 was prepared
according to the general procedure B above, in which phenylacetyl
chloride was used as the acylating reagent, and a light-yellow powder
was obtained in 35.0% yield. The purity was 98% by HPLC analysis.
1
RT = 5.4 min. H NMR (DMSO-d6, 400 MHz): δ 3.56 (s, 4H), 3.63
(s, 6H), 4.98 (s, 2H), 7.25−7.32 (m, 18H), 7.39 (d, J = 8.5 Hz, 4H),
7.60 (d, J = 8.5 Hz, 4H), 8.02 (d, J = 3.6 Hz, 2H), 8.09 (d, J = 4.2 Hz,
2H), 8.62 (s, 2H), 10.40 (s, 2H). MS (ESI) m/z 1111.2 [M − H]−.
General Procedure C for Compounds 22−25. Compound 3 (0.16
g, 0.15 mmol) was dissolved in 6 mL of dichloromethane and cooled
in iced bath. Trifluoroacetic acid (0.6 mL) was added to the solution
and was stirred at room temperature for 2 h. The solvent was removed
in vacuo, and the residue was dissolved in the mixture of 2 mL of
dichloromethane and 3 drops of DMF. Isothiocyanate or isocyanate
(0.33 mmol) was added to the solution and stirred for 2 days at 50 °C.
After removal of the solvent in vacuo, the residue was purified on silica
gel column to afford the product.
( 1 , 2 - c i s - 2 , 3 - c i s - 3 , 4 - c i s ) - 1 , 3 - B i s ( 4 - ( 3 - m e t h y l ) -
thioureidobenzamido)-2,4-bis(3-methoxy-4-(thiophene-2-
carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic Acid (22). Com-
pound 22 was prepared according to the general procedure C above,
in which isothiocyanatomethane was used as the reagent (yield:
1
30.0%). The purity was 96% by HPLC analysis. RT = 5.5 min. H
NMR (DMSO-d6, 300 MHz): δ 2.84 (d, J = 3.3 Hz, 6H), 3.39 (s, 6H),
5.25 (s, 2H), 6.92−6.93 (m, 4H), 7.23 (t, J = 4.5 Hz, 2H), 7.36 (s,
2H), 7.57 (d, J = 7.5 Hz, 4H), 7.73 (d, J = 9.0 Hz, 4H), 7.92 (brs, 2H),
8.00 (d, J = 4.8 Hz, 2H), 10.36 (brs, 2H), 11.96 (brs, 2H). MS (ESI)
m/z 1021.1 [M − H]−. HRMS (ESI) m/z calcd for C48H41N6O12S4
[M − H]− 1021.1665, found 1021.1707.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis(4-(3-naphthalen-1-yl)-
thioureidobenzamido)-2,4-bis(3-methoxy-4-(thiophene-2-
carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic Acid (23). Com-
pound 23 was prepared according to the general procedure C above,
in which 1-isothiocyanatonaphthalene was used as the reagent (yield:
32.0%). The purity was 96% by HPLC analysis. RT = 5.6 min.
(1,2-cis-2,3-cis-3,4-cis)-1,3-Bis((4-((1-adamantane)carbonyl)-
amino)benzamido)-2,4-bis(3-methoxy-4-(thiophene-2-
carbonyloxy)phenyl)cyclobutane-1,3-dicarboxylic Acid (18). Com-
pound 18 was prepared according to the general procedure B above, in
which 1-adamantanecarbonyl chloride was used as the acylating
reagent, and a light-yellow powder was obtained in 42.0% yield. The
1
purity was 96% by HPLC analysis. RT = 5.6 min. H NMR (CD3Cl,
400 MHz): δ 1.71 (brs, 12H), 1.92 (brs, 12H), 2.02 (brs, 6H), 3.31 (s,
6H), 5.20 (s, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H),
7.17 (brs, 2H), 7.26 (t, J = 5.0 Hz, 2H), 7.67 (brs, 4H), 7.75 (d, J = 8.4
262
dx.doi.org/10.1021/jm201150j | J. Med. Chem. 2012, 55, 250−267