J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
3389
H
N
(R)-6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-
OMe
NH2
NH2
OMe
a
amine or (R)-7-(piperidin-1-ylmethyl)chroman-4-amine was cou-
pled with acid 45 gave the amides 25–35. Alternatively, acid 45
was coupled to (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-
yl)methanol to give the alcohol intermediate 46. It was oxidized
with MnO2 to give the aldehyde which was reductively aminated
with various amines to give the final compounds 36–46. Similarly
(R)-2-(4-methyl-3-oxo-1-tosylpiperazin-2-yl)acetic acid was pre-
pared and coupled with (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-
hydronaphthalen-1-amine to give compound 22.
An alternative chiral resolution based synthesis was developed
for arylsulfonylated oxopiperazine acetic acids (Scheme 3). The
racemic methyl 2-(3-oxopiperazin-2-yl)acetate 47 was prepared
from ethylenediamine and dimethyl maleate. Hydrolysis followed
by tosylation efficiently gave the racemic acid 50. Salt pairs were
formed from 50 and (R)-1-phenylethanamine. The (R)-oxopiper-
azine and (R) amine complex 52 was significantly less soluble
(16.5 mg/mL in MeOH, 28 °C) than the (S)-oxopiperazine and (R)
amine complex. The crystallized material (52) was obtained in
good ee (>98.5%). The complex 52 was treated with sulfuric acid
to afford the acid 53, which was recrystallized from methanol to
further improve the ee (>99.9%). Other arylsulfonylated oxopiper-
azine acetic acids were also similarly prepared with high ee %.
In summary, a series of highly potent B1 antagonists with im-
proved metabolic stability were identified. Based on in vitro po-
tency, protein binding, in vivo pharmacokinetics, and pre-clinical
animal safety assessment compound 17 was chosen for further
pre-clinical evaluation.
+
O
O
MeO
O
N
H
47
O
b
H
N
ClO2S
OLi
O2S
N
OH
O
c
N
H
O
O
N
H
O
H2N
48
50
Ph
d
O2S
N
O2S
N
+
+
H N
H N
3
OH
OH
3
+
O
Ph
Ph
O
N
H
O
51
N
H
O
52
e, f
O2S
N
OH
References and notes
O
N
H
O
53
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as mixture of 1:1 diastereomers. Compound 38 was sulfonylated
with various sulfonyl chlorides to give the ester 39. Basic hydroly-
sis of the ester 39 gave the corresponding acid 40. Coupling of
the acid 40 with (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-
hydronaphthalen-1-amine13 gave amides 4–16. Compounds 21,
23, and 24 were prepared similarly from the corresponding oxo-
piperazines: ethyl 2-(5,5-dimethyl-3-oxopiperazin-2-yl)acetate,15
ethyl 2-(2-methyl-3-oxopiperazin-2-yl)acetate,16 and ethyl 2-(5-
oxopiperazin-2-yl)acetate.17
Optically pure aryl sulfonylated 2-oxopiperazine acetic acids
were first prepared from the chiral aspartic acid derivative 41
(Scheme 2). Compound 41 was sulfonylated with aryl sulfonyl
chloride in THF/water in the presence of sodium carbonate to give
42. EDCI-mediated coupling of 42 with 2,2-dimethoxyethanamine
afforded amide 43. The p-toluenesulfonic acid (PTSA) catalyzed
cyclization of 43 gave the dehydrooxopiperazine 44. Sequential
reduction of the dehydrooxopiperazine double bond (Et3SiH/TFA)
followed by removal of the benzyl ester through hydrogenolysis
afforded 45 in high enantioselectivity (>99.5% ee).