5166 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Dressen et al.
eluant to afford 0.09 g (30%) of tert-butyl (1-(3-aminophenyl)-
piperidin-4-yl)methylcarbamate as an amber oil.
(1.4 mmol) of 2-chlorobenzoyl chloride, and 0.02 g (0.2 mmol) of
DMAP in 4.0 mL of methylene chloride was stirred at rt for 18 h.
The reaction mixture was adsorbed onto silica gel and chromato-
graphed using 1:1 EtOAc-hexanes to afford 0.45 g (91%) of
compound 48 as a clear, colorless, glassy solid. MS m/z 370.1 (M
+ H)+. 1H NMR (CDCl3) δ 8.67 (s, 1H), 7.75 (d, J ) 6.8 Hz, 1H),
7.48 (s, 5H), 7.34 (m, 3H), 4.37 (q, J ) 7.2 Hz, 2H), 1.38 (t, J )
7.2 Hz, 3H).
A solution of 0.09 g (0.3 mmol) of tert-butyl (1-(3-aminophenyl)-
piperidin-4-yl)methylcarbamate in 3.0 mL of neat TFA was stirred
at rt for 30 min. The TFA was then removed by rotary evaporation,
and the residue was concentrated in vacuo to afford 0.18 g of a
mixture of 3-(4-(aminomethyl)piperidin-1-yl)aniline and entrained
TFA. The aniline was coupled to carboxylic acid 12 as described
for compound 17. MS m/z 532.0 (M + H)+. 1H NMR (CD3OD) δ
8.28 (br, 1H), 7.63 (m, 2H), 7.56-7.42 (m, 3H), 6.22 (d, J ) 8.4
Hz, 1H), 6.10 (d, J ) 8.4 Hz, 1H), 3.97 (d, J ) 13.2 Hz, 2H), 3.33
(m, 2H), 3.11 (t, J ) 12.1 Hz, 2H), 1.94 (m, 3H), 1.40 (m, 2H).
N-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-4-bromo-5-[(2-chloroben-
zoyl)amino]-1H-pyrazole-3-carboxamide (21). Compound 21 was
prepared as described for compound 17 using carboxylic acid 12
and (S)-3-aminoquinuclidine dihydrochloride. MS m/z 451.9 (M
5-[[[2-Chlorophenyl]carbonyl]amino]-1-methyl-1H-pyrazole-
3-carboxylic Acid (49). A solution of 0.43 g (1.2 mmol) of ethyl
ester 48 and 0.25 g (6.0 mmol) of LiOH‚H2O in 4.0 mL of MeOH
and 1.0 mL of water was stirred at rt for 64 h. The reaction mixture
was concentrated by rotary evaporation and diluted with water. The
pH was lowered to 3 with 1 M HCl. A gray precipitate formed
that was triturated with ether and collected by filtration to afford
1
0.23 g (58%) of carboxylic acid 49. MS m/z 342.0 (M + H)+. H
1
+ H)+. H NMR (CDCl3) δ 8.35 (br, 1H), 7.89 (d, J ) 7.0 Hz,
NMR (CD3OD) δ 7.60-7.38 (m, 9H), 7.06 (s, 1H).
1H), 7.51-7.38 (m, 3H), 7.22 (d, J ) 7.3 Hz, 2H), 4.12 (m, 1H),
3.37 (dd, J ) 14.1, 9.7 Hz, 1H), 2.84 (m, 4H), 2.67 (dd, J ) 14.0,
4.5 Hz, 1H), 2.03 (m, 1H), 1.79-1.66 (m, 3H), 1.50-1.45 (m, 1H).
4-Bromo-5-[(2-chlorobenzoyl)amino]-N-[2-(1-methyl-4-pipe-
ridinyl)ethyl]-1H-pyrazole-3-carboxamide (22). Prepared as de-
scribed for compound 17 using carboxylic acid 12 and 1-methyl-
4-piperidineethanamine. MS m/z 468.0 (M + H)+. 1H NMR
(CDCl3) δ 7.98 (d, J ) 7.7 Hz, 1H), 7.54 (m, 2H), 7.50-7.43 (m,
1H), 7.22 (m, 1H), 3.49 (m, 3H), 2.81 (d, J ) 11.6 Hz, 2H), 2.24
(s, 3H), 1.89 (m, 2H), 1.69 (m, 2H), 1.57 (m, 2H), 1.29 (m, 4H).
(R)-4-Bromo-5-(2-chlorobenzamido)-N-(2-oxoazepan-3-yl)-
1H-pyrazole-3-carboxamide (24). Compound 24 was prepared as
described for compound 17 using carboxylic acid 12 and (R)-3-
Supporting Information Available: Mass and 1H NMR
characterization of compounds 23, 29-45, and 52-55 and purity
determinations. This material is available free of charge via the
References
(1) Marceau, F. Kinin B1 receptors: A review. Immunopharmacology
1995, 30, 1-26.
(2) Bouthillier, J.; Beblois, D.; Marceau, F. Studies on the induction of
pharmacological responses to des-Arg9-bradykinin in vitro and in
vivo. Br. J. Pharmacol. 1987, 92, 257-264.
(3) Ferreira, J.; Beirith, A.; Mori, M. A. S.; Araujo, R. C.; Bader, M.;
Pesquero, J. B.; Calixto, J. B. Reduced nerve injury-induced
neuropathic pain in kinin B1 receptor knock-out mice. J. Neurosci.
2005, 25, 2405-2412.
(4) Pesquero, J. B.; Araujo, R. C.; Heppenstall, P. A.; Stucky, C. L.:
Silva, J. A. Jr.; Walther, T: Oliveira, S. M.; Pesquero, J. L.; Paiva,
A. C. M.; Calixto, J. B.; Lewin, G. R.; Bader, M. Hypoalgesia and
altered inflammatory responses in mice lacking kinin B1 receptors.
Proc. Natl. Acad. Sci. U.S.A. 2000, 14, 8140.
(5) Wood, M. R.; Kim, J. J.; Han, W.; Dorsey, B. D.; Homnick, C. F.;
DiPardo, R. M.; Kuduk, S. D.; MacNeil, T.; Murphy, K. L.; Lis, E.
V.; Ransom, R. W.; Stump, G. L.; Lynch, J. J.; O’Malley, S. S.;
Miller, P. J.; Chen, T-B.; Harrell, C. M.; Chang, R. S. L.; Sandhu,
P.; Ellis, J. D.; Bondiskey, P. J.; Pettibone, D. J.; Freidinger, R. M.;
Bock, M. G. Benzodiazepines as potent and selective bradykinin B1
antagonists. J. Med. Chem. 2003, 46, 1803-1806.
(6) Gougat, J.; Ferrari, B.; Sarran, L.; Planchenault, C.; Poncelet, M.;
Maruani, J.; Alonso, R.; Cudennec, A.; Croci, T.; Guagnini, F.;
Urban-Szabo, K.; Martinolle, J-P.; Soubrie, P.; Finance, O.; Le Fur,
G. SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-{[(6-meth-
oxy-2-naphthyl)sulfonyl]amino}propanoyl)amino]-3-(4-{[2R,6S)-2,6-
dimethylpiperidinyl]methyl}phenyl)-N-isopropyl-N-methylpropana-
mide hydrochloride], a new nonpeptide antagonist of the bradykinin
B1 receptor: Biochemical and pharmacological characterization. J.
Pharmacol. Exp. Ther. 2004, 309, 661-669.
1
amino-azepan-2-one. MS m/z 454.0 (M + H)+. H NMR (CD3-
OD) δ 7.65 (m, 1H), 7.40-7.52 (m, 3H), 5.48 (s, 3H), 4.72 (d, J
) 9.9 Hz, 1H), 3.31 (m, 2H), 2.25-1.95 (m, 2H), 1.82-1.95 (m,
2H), 1.60 (m, 1H), 1.45 (m, 1H).
4-Bromo-5-[(2-chlorobenzoyl)amino]-N-[(1R)-1-phenylethyl]-
1H-pyrazole-3-carboxamide (25). Compound 25 was prepared as
described for compound 17 using carboxylic acid 12 and (R)-R-
methylbenzylamine. MS m/z 448.9 (M + H)+. 1H NMR (CD3OD)
δ 7.61 (d, J ) 7.1 Hz, 1H), 7.37 (m, 8H), 5.19 (q, J ) 7.1 Hz,
1H), 1.55 (d, J ) 7.1 Hz, 1H).
4-Bromo-5-[(2-chlorobenzoyl)amino]-N-4-pyridinyl-1H-pyra-
zole-3-carboxamide (26). Compound 26 was prepared as described
for compound 17 using carboxylic acid 12 and 4-aminopyrdine.
MS m/z 421.9 (M + H)+. 1H NMR (DMSO-d6) δ 8.63 (d, J ) 7.1
Hz, 2H), 8.17 (m, 2H), 7.55 (m, 4H).
N-[(1S)-2-Amino-2-oxo-1-phenylethyl]-4-bromo-5-[(2-chlo-
robenzoyl)amino]-1H-pyrazole-3-carboxamide (27). Compound
27 was prepared as described for compound 17 using carboxylic
acid 12 and (S)-R-aminobenzeneacetamide. MS m/z 475.9 (M +
1
H)+. H NMR (DMSO-d6) δ 7.88 (s, 1H), 7.60-7.47 (m, 9H),
7.40-7.28 (m, 3H), 5.53 (bs, 2H).
(7) Fox, A.; Kaur, S.; Li, B.; Panesar, M.; Saha, U.; Davis, C.; Dragoni,
I.; Colley, S.; Ritchie, T.; Bevan, S.; Burgess, G.; McIntyre, P.
Antihyperalgesic activity of a novel nonpeptide bradykinin B1
receptor antagonist in transgenic mice expressing the human B1
receptor. Br. J. Pharmacol. 2005, 144(7), 889-899.
5-[(2-Chlorobenzoyl)amino]-N-[2-[1-(4-pyridinyl)-4-piperidi-
nyl]ethyl]-1H-pyrazole-3-carboxamide (28). Compound 28 was
prepared as described for compound 17 using carboxylic acid 11.
1
MS m/z 453.1 (M + H)+. H NMR (DMSO-d6) δ 13.14 (s, 1H),
(8) (a) Beyreuther, B.; Hahn, M.; Kallus, C.; Kruger, J.; Meier, H.;
Reissmuller, E.; Telan, L.; Wittka-Nopper, R.; Kroll, M. Tetrahyd-
roquinoxalines acting as bradykinin antagonists, their preparation,
and their therapeutic use. WO 2003007958, 2003. (b) Grant, F.;
Bartulis, S.; Brogley, L.; Dappen, M. S.; Kasar, R.; Khan, A.; Neitzel,
M.; Pleiss, M. A.; Thorsett, E. D.; Tucker, J.; Ye, M.; Hawkinson,
J. Preparation of sulfonylquinoxalone acetamide derivatives and
related compounds as bradykinin antagonists. WO 2003093245, 2003.
(c) Su, D.-S.; Markowitz, M. K.; DiPardo, R. M.; Murphy, K. L.;
Harrell, C. M.; O’Malley, S. S.; Ransom, R. W.; Chang, R. S. L.;
Ha, S.; Hess, F. J.; Pettibone, D. J.; Mason, G. S.; Boyce, S.;
Freidinger, R. M.; Bock, M. G. Discovery of a Potent, nonpeptide
bradykinin B1 receptor antagonist. J. Am. Chem. Soc. 2003, 125,
7516-7517.
11.06 (s, 1H), 8.54 (s, 1H), 8.11 (d, J ) 6.0 Hz, 2H), 7.40-7.56
(m, 4H), 6.80 (d, J ) 6.0 Hz, 2H), 3.92 (m, 2H), 3.33 (m, 2H),
2.76 (m, 2H), 1.80 (m, 2H), 1.59 (m, 1H), 1.51 (m, 2H), 1.14 (m,
2H).
5-Amino-1-phenyl-1H-pyrazole-3-carboxylic Acid Ethyl Ester
(47). A suspension of 1.01 g (6.2 mmol) of 3-cyano-2-oxo-propionic
acid ethyl ester sodium salt and 1.08 g (7.5 mmol) of phenylhy-
drazine hydrochloride in 25 mL of ethanol was stirred and refluxed
for 64 h. The reaction mixture was cooled to rt and filtered through
Celite, and the solvent was removed by rotary evaporation. The
product was isolated by flash chromatography on silica gel using
1:1 EtOAc-hexanes as eluant to afford 0.93 g (65%) of compound
47 as a rust-colored solid.
(9) Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman, A. F.;
Mukhin, A. G.; Horti, A. G. Synthesis, structure-activity relationship,
and evaluation of SR141716 analogues: Development of central
cannabinoid receptor ligands with lower lipophilicity. J. Med. Chem.
2003, 46, 642-645.
5-[[[2-Chlorophenyl]carbonyl]amino]-1-methyl-1H-pyrazole-
3-carboxylic Acid Ethyl Ester (48). A solution of 0.31 g (1.3
mmol) of ethyl ester 47, 0.17 mL (2.1 mmol) of pyridine, 0.18 g