Y. Mori et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7677–7682
7681
19
(a)
(b), (c), (d), (e)
(f), (g), (h)
(i), (j)
18
20
21
22
(k), (l)
(m), (n)
(o), (p)
fumaric acid
23
24
25
7-17
Scheme 1. Synthetic pathway leading to (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides 7–17. Reagents and conditions: (a) 19,
CH3OH, THF, ꢀ20 °C, 1 d, 69%, 94% ee; (b) diphenylphosphoryl azide, Et3N, toluene, allyl alcohol, 90 °C, 15 h, 90%; (c) TFA, CH2Cl2, r.t., 1 h; (d) NsCl, Et3N, CH2Cl2, r.t., 1 h, 75% (2
steps); (e) (PPh3)4Pd, morpholine, THF, r.t., 1 h, 81%; (f) isobutylaldehyde, CH2Cl2, r.t., 2 h; (g) N-chlorosuccinimide, CH2Cl2, r.t., 2 h; (h) CH3OH, 60 °C, 18 h, 49% (3 steps); (i)
conc. HCl aq., CH2Cl2, 40 °C, 4 h; (j) SOCl2, CH3OH, r.t., 1 h, 68% (2 steps); (k) 2-chloroaniline, AcOH, toluene, 110 °C, 2 h, then NaBH(OAc)3, r.t., 6 h, 76%; (l) bromoacetyl
bromide, Et3N, CH2Cl2, 0 °C, then 40 °C, 5 h, 66%; (m) 1N NaOH aq., CH3OH, 50 °C, 0.5 h, quant.; (n) amine (R-NH2), HBTU, diisopropylethylamine, DMF, r.t., 5 h; (o) PhSH,
Cs2CO3, CH3CN, r.t., 1.5 h; (p) fumaric acid, CH3OH, r.t., 1 min.
3. (a) Zaman, M. A.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug Disc. 2002, 1, 621; (b)
aldimine. Treatment of the a-chloro aldimine with methanol gave
Schmieder, R. E.; Hilgers, K. F.; Schlaich, M. P.; Schmidt, B. M. W. Lancet 2007,
369, 1208.
4. Hershey, J. C.; Steiner, B.; Fischli, W.; Feuerstein, G. Drug Discovery Today:
Therapeutic Strategies 2005, 2, 181.
the rearranged product 22 via the ring opening of the correspond-
ing aziridine intermediate.20 The dimethyl acetal and methyl ester
in 22 were hydrolyzed with concentrated hydrochloric acid, then
esterification of the carboxylic acid with thionyl chloride and
methanol provided aldehyde 23. The aldehyde 23 was converted
into ketopiperazine 24 by reductive amination with 2-chloroani-
line and subsequent ring formation with bromoacetyl bromide.
The condensation of various amines21 and carboxylic acid resulting
from the hydrolysis of compound 24 afforded the amides 25. Final-
ly, removal of the N-Ns groups, then addition of fumaric acid gave
compounds 7–17 as fumarate salts.
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N.-C.; Rasetti, V.; Rügar, H.; Göschke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.;
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4832.
In summary, we have described the design and discovery of
(3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-
yl]piperidine-3-carboxamides as new types of renin inhibitors by
using X-ray crystal structure analysis. The application of the con-
0
0
cept of using interactions with both S1 and S2 pockets resulted
in an improvement of the renin inhibitory activities. The most po-
tent compound 15 demonstrated 45% oral bioavailability in SD rat
and was orally efficacious in a dTG rat model of hypertension. From
these encouraging results, we selected compound 15 as a new lead
compound. Further optimization to acquire a more promising com-
pound is under investigation. These results will be reported in due
course.
9. Nakamura, Y.; Fujimoto, T.; Ogawa, Y.; Sugita, C.; Miyazaki, S.; Tamaki, K.;
Takahashi, M.; Matsui, Y.; Nagayama, T.; Manabe, K.; Mizuno, M.; Masubuchi,
N.; Chiba, K.; Nishi, T. ACS Med. Chem. Lett. 2012, 3, 754.
10. Märki, H. P.; Binggeli, A.; Bittner, B.; Bohner-Lang, V.; Breu, V.; Bur, D.;
Coassolo, Ph.; Clozel, J. P.; D’Arcy, A.; Doebeli, H.; Fischli, W.; Funk, Ch.;
Foricher, J.; Giller, T.; Grüninger, F.; Guenzi, A.; Güller, R.; Hartung, T.; Hirth, G.;
Jenny, Ch.; Kansy, M.; Klinkhammer, U.; Lave, T.; Lohri, B.; Luft, F. C.; Mervaala,
E. M.; Müller, D. N.; Müller, M.; Montavon, F.; Oefner, Ch.; Qiu, C.; Reichel, A.;
Sanwald-Ducray, P.; Scalone, M.; Schleimer, M.; Schmid, R.; Stadler, H.; Treiber,
A.; Valdenaire, O.; Vieira, E.; Waldmeier, P.; Wiegand-Chou, R.; Wilhelm, M.;
Wostl, W.; Zell, M.; Zell, R. Il Farmaco 2001, 56, 21.
Acknowledgments
We thank Dr. Masao Yoshida, Dr. Kazuki Mori, Dr. Mitsuhiro
Iwamoto, Sayaka Suzuki, Dr. Akifumi Kurata, Dr. Makoto Mizuno,
Masumi Ueno and Mina Nishi for their technical assistance and
helpful discussions.
ˇ
11. Bezençon, O.; Bur, D.; Weller, T.; Richard-Bildstein, S.; Remen, L.; Sifferlen, T.;
Corminboeuf, O.; Grisostomi, C.; Boss, C.; Prade, L.; Delahaye, S.; Treiber, A.;
Strickner, P.; Binkert, C.; Hess, P.; Steiner, B.; Fischli, W. J. Med. Chem. 2009, 52,
3689.
12. (a) Oefner, C.; Binggeli, A.; Breu, V.; Bur, D.; Clozel, J.-P.; D’Arcy, A.; Dorn, A.;
Fischli, W.; Grüninger, F.; Güller, R.; Hirth, G.; Märki, H. P.; Mathews, S.; Müller,
M.; Ridley, R. G.; Stadler, H.; Vieira, E.; Wilhelm, M.; Winkler, F. K.; Wostl, W.
Chem. Biol. 1999, 6, 127; (b) Vieira, E.; Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.;
Güller, R.; Hirth, G.; Märki, H. P.; Müller, M.; Oefner, C.; Scalone, M.; Stadler, H.;
Wilhelm, M.; Wostl, W. Bioorg. Med. Chem. Lett. 1999, 9, 1397.
13. Assays were performed with the same procedure described by in Ref. 9. Assay
results are the average of at least two replicates.
References and notes
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2. MacGregor, G. A.; Markandu, N. D.; Roulston, J. E.; Jones, J. C.; Morton, J. J.
Nature 1981, 291, 329.