1924 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 10
Bavetsias et al.
isolated by filtration, washed with H2O, and dried in vacuo to
give the title compound 7b (0.066 g) as a solid: mp 184 °C; 1H
NMR (DMSO-d6) 2.0 (m, 4H, glu â-CH2), 2.3 (m, 5H, glu γ-CH2,
7-H), 2.35 (s, 3H, 2-CH3), 2.55 (m, 1H, 7-H), 3.0 (s, 1H,
CtCH), 3.05 (m, 1H, 8-H), 3.2 (m, 1H, 8-H), 3.85 (d, 1H,
CH2CtC), 4.1 (d, 1H, CH2CtC), 4.25 (2 d’s, 1H, glu R-CH),
4.4 (2 d’s, 1H, glu R-CH), 5.75 (t, 1H, 6-H), 7.05 (d, 2H, 3′,5′-
ArH), 7.5 (s, 1H, 9-H), 7.82 (d, 2H, 2′,6′-ArH), 7.85 (s, 1H, 5-H),
8.12 (d, 1H, CONH), 8.32 (d, 1H, CONH), 12.05 (s, 1H, N3-H);
MS (FAB, m/z) 654 (M + Na)+. Anal. (C32H33N5O9 3H2O) C,
H, N.
(d, J ) 7.3 Hz, 3H, CHCH3), 2.24 (m), 2.50 (m obscured) (4H,
CHCH2CH2 and 7-CH2), 2.33 (s, 3H, 2-CH3), 2.89-3.25 (m, 5H,
CHCH2CH2, 8-CH2 and CtCH), 3.96 (ABq, J ) 19.0 Hz, 2H,
CH2CtC), 4.18 (m, 1H, CHCH3), 4.46 (m, 1H, -C6H4-CON-
HCH), 5.21 (s, 2H, NCH2CONH), 5.76 (t, J ) 8.4 Hz, 6-CH),
7.01 (d, J ) 8.0 Hz, 2H, 3′,5′-ArH), 7.49 (s, 1H, 9-H), 7.78 (s,
1H, 5-H), 7.80 (d, J ) 8.6 Hz, 2H, 2′,6′-ArH), 8.44 (d, J ) 7.8
Hz, 1H, -C6H4-CONH), 8.86 (d, J ) 7.2 Hz, 1H, N-CH2CONH),
12.14 (s, 1H, N3-H); MS (FAB, m/z) 656 (M + H)+. Anal.
(C32H33N9O7‚1.5H2O) C, H, N.
(2S )-2-{N -{N -{4-[N -((6R S )-2-Me t h y l-4-o x o -3,4,7,8-
t e t r a h y d r o -6 H -c y c l o p e n t a [g ]q u i n a z o l i n -6 -y l )-N -
(p r op -2-yn yl)a m in o]ben zoyl}-L-γ-glu ta m yl}a m in o}-4-(1-
ca r boxyp r op ylltetr a zol-5-yl)bu tyr ic Acid (7f). The method
followed that used to prepare 7d but using 6f (0.094 g, 0.14
mmol) in MeOH (2 mL), 1 N aqueous NaOH (0.56 mL, 0.56
mmol), and H2O (2 mL). The title compound (7f) was obtained
as a white solid (0.070 g, 85%): mp 160 °C (softens); 1H NMR
(DMSO-d6) 1.95-2.31 (m), 2.50 (m obscured) (8H, CHCH2CH2,
CN4CH2CH2CH2 and 7-CH2), 2.33 (s, 3H, 2-CH3), 2.95-3.21
(m, 5H, CHCH2CH2, 8-CH2 and CtCH), 3.96 (ABq, J ) 19.44
Hz, 2H, CH2CtC), 4.34 (t, J ) 7.10 Hz, 2H, CN4CH2CH2), 4.47
(m, 1H, CHCH2CH2), 5.76 (t, J ) 7.9 Hz, 1H, 6-CH), 7.02 (d,
J ) 8.64 Hz, 2H, 3′,5′-ArH), 7.49 (s, 1H, 9-H), 7.79 (s, 1H, 5-H),
7.81 (d, J ) 8.87 Hz, 2H, 2′,6′-ArH), 8.43 (d, J ) 7.79 Hz, 1H,
CONH), 12.12 (s, 1H, N3-H); MS (FAB, m/z) 635 (M + Na)+.
Anal. (C31H32N8O6‚1.2H2O) C, H, N.
N-{N-{4-[N-((6RS)-2-Met h yl-4-oxo-3,4,7,8-t et r a h yd r o-
6H-cyclop en ta [g]qu in a zolin -6-yl)-N-(p r op -2-yn yl)a m in o]-
ben zoyl}-L-γ-glu ta m yl}-D-a la n in e (7c). The method followed
that used to prepare 7a but using 6c (0.138 g, 0.2 mmol) and
TFA (7 mL). After acidification the precipitated white solid
was collected by filtration, washed with H2O (∼5 mL), and
dried in vacuo over P2O5 to afford the title compound 7c as a
1
white solid: mp 185 °C (dec); H NMR (DMSO-d6) 1.23 (d, J
) 7.3 Hz, 3H, ala-CH3), 1.83-2.28 (m, 6H, glu â-CH2, glu
γ-CH2 and 7-CH2), 2.33 (s, 3H, 2-CH3), 2.97, 3.15 (2 × m, 3H,
8-CH2 and CtCH), 3.96 (ABq, J ) 19.0 Hz, 2H, CH2CtC),
4.18 (m (obscured), 1H, ala R-CH), 4.35 (m, 1H, glu R-CH),
5.76 (t, J ) 7.9 Hz, 1H, 6-CH), 7.02 (d, J ) 8.9 Hz, 2H, 3′,5′-
ArH), 7.49 (s, 1H, 9-H), 7.81 (d, J ) 8.5 Hz, 3H, 2′,6′-ArH and
5-H), 8.17 (d, J ) 7.0 Hz, 1H, ala NH), 8.33 (d, J ) 7.4 Hz,
1H, glu NH), 12.10 (s, 1H, N3-H); MS (FAB, m/z) 574 (M +
H)+. Anal. (C30H31N5O7‚1.5H2O) C, H, N.
(2S )-2-{N -{N -{4-[N -((6R S )-2-Me t h y l-4-o x o -3,4,7,8-
t et r a h yd r o-6H -cyclop en t a [g]q u in a zolin -6-yl)-N-(p r op -
2-yn yl)a m in o]b e n zoyl}-L-γ-glu t a m yl}a m in o}-4-(1-ca r -
boxym et h ylt et r a zol-5-yl)bu t yr ic Acid (7h ). The method
followed that used to prepare 7d but using 6h (0.120 g, 0.16
mmol) in MeOH (3.2 mL) and 1 N aqueous NaOH (0.96 mL,
0.96 mmol). The title compound 7h was obtained as a white
solid (0.090 g, 79%): mp 176 °C (dec); 1H NMR (DMSO-d6)
1.80-2.27 (m), 2.50 (m obscured) (8H, 2 × CHCH2CH2,
CHCH2CH2CONH and 7-CH2), 2.34 (s, 3H, 2-CH3), 2.87 (t, J
) 7.8 Hz, 2H, CHCH2CH2), 2.94-3.20 (m, 3H, 8-CH2 and
CtCH), 3.96 (ABq, J ) 18.3 Hz, 2H, CH2CtC), 4.35 (m, 2H,
2 × CHCH2CH2), 5.35 (s, 2H, N-CH2CO2Me), 5.75 (t, J ) 7.6
Hz, 1H, 6-H), 7.01 (d, J ) 8.8 Hz, 2H, 3′,5′-ArH), 7.49 (s, 1H,
9-H), 7.80 (s, 1H, 5-H), 7.82 (d, J ) 6.8 Hz, 1H, 2′,6′-ArH),
8.24 (d, J ) 7.8 Hz) and 8.34 (d, J ) 7.7 Hz) (2H, 2 × CONH),
12.09 (s, 1H, N3-H); MS (FAB, m/z) 714 (M + H)+. Anal.
(C34H35N9O9‚1.5H2O) C, H, N.
(2S)-2-[4-[N-((6RS)-2-Meth yl-4-oxo-3,4,7,8-tetr a h yd r o-
6H-cyclop en ta [g]qu in a zolin -6-yl)-N-(p r op -2-yn yl)a m in o]-
ben zam ido]-4-(2-car boxym eth yltetr azol-5-yl)bu tyr ic Acid
(7d ). To a suspension of 6d (0.079 g, 0.13 mmol) in MeOH (2
mL) was slowly added 1 N aqueous NaOH (0.52 mL, 0.5 mmol)
followed by H2O (2 mL). The resulting clear solution was
stirred at room temperature for 2.5 h, and then more 1 N
NaOH (0.2 mL) was added. Stirring was continued at room
temperature for 1 h, then the reaction mixture was diluted
with H2O (5 mL), and the solution was acidified to pH ∼4 with
1 N HCl. The white precipitate was collected by filtration,
washed with water, and dried in vacuo over P2O5 to afford the
title compound 7d as a white solid (0.063 g, 84%): mp 173 °C
(dec); 1H NMR (DMSO-d6) 2.10-2.30 (m) and 2.50 (m obscured)
(4H, CHCH2CH2 and 7-CH2), 2.33 (s, 3H, 2-CH3), 2.90-3.20
(m, 5H, CHCH2CH2, 8-CH2 and CtCH), 3.97 (ABq, J ) 18.8
Hz, 2H, CH2CtC), 4.43 (m, 1H, CHCH2CH2), 5.62 (s, 2H,
N-CH2CO2H), 5.76 (t, J ) 7.9 Hz, 1H, 6-CH), 7.03 (d, J ) 8.22
Hz, 2H, 3′,5′-ArH), 7.49 (s, 1H, 9-H), 7.82 (d, J ) 8.2 Hz, 3H,
5-H and 2′,6′-ArH), 8.44 (d, J ) 9.0 Hz, 1H, CONH), 12.14 (s,
1H, N3-H); MS (FAB, m/z) 607 (M + Na)+. Anal. (C29H28N8O6‚
1.8H2O) C, H, N.
(2S)-2-{4-[N-(6RS)-2-Met h yl-4-oxo-3,4,7,8-t et r a h yd r o-
6H-cyclop en a [g]qu in a zolin -6-yl)-N-(p r op -2-yn yl)a m in o]-
b en za m id o}-5-(1H -1,2,4-t r ia zol-3-ylsu lfon yl)p en t a n oic
Acid (7i). The method followed that used to prepare 7d but
using 6i (0.038 g, 0.06 mmol) in MeOH (1 mL), 1 N aqueous
NaOH (0.15 mL, 0.15 mmol), and H2O (1 mL). The title
compound 7i was obtained as a white solid (0.021 g, 57%): mp
180 °C (dec); 1H NMR (DMSO-d6) 1.60-2.00, 2.20 (2 × m),
2.50 (m obscured) (6H, 3-CH2 and 4-CH2 and 7-CH2), 2.34 (s,
3H, 2-CH3), 2.90-3.23 (m, 3H, 7-CH2 and CtCH) 3.40 (m, 2H,
CH2SO2-), 3.96 (ABq, J ) 18.53 Hz, 2H, CH2CtC), 4.32 (m,
1H, 2-CH), 5.76 (t, J ) 7.2 Hz, 6-CH), 7.02 (d, J ) 8.3 Hz, 2H,
3′,5′-ArH), 7.49 (s, 1H, 9-H), 7.77 (d, J ) 8.9 Hz, 2H, 2′, 6′-
ArH), 7.80 (s, 2H, 5-H), 8.32 (d, J ) 7.7 Hz, 1H, CONH), 8.87
(2S)-2-[4-[N-((6RS)-2-Meth yl-4-oxo-3,4,7,8-tetr a h yd r o-
6H-cyclop en ta [g]qu in a zolin -6-yl)-N-(p r op -2-yn yl)a m in o]-
ben zam ido]-4-(1-car boxym eth yltetr azol-5-yl)bu tyr ic Acid
(7e). The method followed that used to prepare 7d but using
6e (0.080 g, 0.13 mmol) in MeOH (2 mL), 1 N aqueous NaOH
(0.52 mL, 0.52 mmol), and H2O (2 mL). The title compound
7e was obtained as a white solid (0.060 g, 80%): mp 179 °C
1
(dec); H NMR (DMSO-d6) 2.10-2.30 (m), 2.50 (m obscured)
(4H, CHCH2CH2 and 7-CH2), 2.33 (s, 3H, 2-CH3), 2.90-3.22
(m, 5H, CHCH2CH2, 8-CH2 and CtCH), 3.97 (ABq, J ) 19.8
Hz, 2H, CH2CtC), 4.51 (m, 1H, CHCH2CH2), 5.38 (s, 2H,
N-CH2CO2H), 5.76 (t, J ) 7.7 Hz, 1H, 6-CH), 7.02 (d, J ) 8.8
Hz, 2H, 3′,5′-ArH), 7.49 (s, 1H, 9-H), 7.79 (s, 1H, 5-H), 7.81
(d, J ) 8.89 Hz, 2H, 2′,6′-ArH), 8.46 (d, J ) 7.86 Hz, 1H,
CONH), 12.14 (s, 1H, N3-H); MS (FAB, m/z) 607 (M + Na)+.
Anal. (C29H28N8O6‚1.5H2O) C, H, N.
(s, 1H, NdCH); MS (FAB, m/z) 604 (M + H)+. Anal. (C29H29
N7O6S‚1.5H2O) C, H, N.
-
(4R )-4-{N -{N -{4-[N -((6R S )-2-Me t h y l-4-o x o -3,4,7,8-
t et r a h yd r o-6H -cyclop en t a [g]q u in a zolin -6-yl)-N-(p r op -
2-yn yl)a m in o]b en zoyl}-L-γ-glu t a m yl}a m in o}-4-(5-t et r a -
zolyl)bu tyr ic Acid (7j). TFA (9 mL) was added dropwise
during 8 min to a stirred, cooled (ice-water bath) suspension
of 6j (0.080 g, 0.10 mmol) in H2O (3.75 mL). The resulting
solution was protected from light and allowed to come to room
temperature. After 3.5 h, further TFA (9 mL) was added, and
after a further 1 h the solution was evaporated. TFA (3 × 5
mL) was added to the residue and evaporated. A solution of
the final residue in aqueous NaOH solution (0.5 M; 5 mL) was
filtered and acidified to pH 4 with 1 M HCl while stirring and
cooling in ice. The resulting precipitate was isolated by
(2S)-2-{4-[N-(6RS)-2-Met h yl-4-oxo-3,4,7,8-t et r a h yd r o-
6H-cyclop en ta [g]qu in a zolin -6-yl)-N-(p r op -2-yn yl)a m in o]-
ben za m id o}-4-{1-[((1R)-1-(ca r boxy)eth yl)ca r ba m oylm e-
th yl]tetr a zol-5-yl}bu tyr ic Acid (7g). The method followed
that used to prepare 7d but using 6g (0.085 g, 0.12 mmol) in
MeOH (2.0 mL), 1 N aqueous NaOH (0.5 mL, 0.5 mmol), and
H2O (1 mL). The title compound 7g was obtained as a white
solid (0.062 g, 77%): mp 182-189 °C; 1H NMR (DMSO-d6) 1.27