3682 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9
Baur et al.
purged successively with nitrogen and hydrogen and then finally
pressurized to 0.05 bar above atmospheric pressure with hydro-
gen. After stirring at this hydrogen pressure for 1 h, the reaction
vessel was purged with nitrogen and the reaction mixture filtered
through celite and washed with methanol. The solvent was
removed in vacuo, and the resulting beige solid was triturated
with isohexane and compound 1a was collected by filtration and
dried under vacuum to give 245 mg yellow powder (20% yield).
HPLC/MS: > 95% purity; m/z 337 [(M þ H)þ 100%]. 1H NMR
(400 MHz, CDCl3): 2.72 (2H, br, dt, J = 15.3 CH2), 2.83 (2H, d,
J = 6.6, CH2), 3.15 (2H, m, CH2), 3.61 (1H, t, J = 6.7, CH), 5.11
(1H, m, CH), 6.61 (1H, d, J = 9.9, CH), 6.88 (1H, d, J = 8.2,
m, CH), 6.50 (1H, d, J=10.0, CH), 6.91(1H, s, Ar-H), 6.92(1H, s,
Ar-H), 6.93 (1H, d, J = 8.2, Ar-H), 7.08 (1H, d, J = 8.2, Ar-H),
8.18 (1H, d, J = 10.0, Ar-H). 13C NMR (100 MHz, DMSO):
13.86, 22.21, 31.68, 33.43, 38.98, 39.13, 55.63, 59.18, 68.98, 113.86,
117.01, 119.68, 121.54, 124.95, 125.00, 128.39, 131.28, 136.94,
137.75, 139.10, 139.15, 142.64, 160.74. HRMS: calculated for
(M þ H)þ, C28H37N2O3: 449.2804; found: 449.2806, tolerance
of 5 ppm. Analysis: Calcd for C28H37N2O3 0.7H2O (0.7 equiv of
3
water observed by 1HNMR):C, 72.92;H, 8.17;N, 6.07. Found:C,
72.61; H, 8.02; N, 6.01.
8-Hydroxy-5-[(R)-1-hydroxy-2-(5,6-dimethoxyindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1f). Prepared in an analogous fashion to
compound 1a. A reaction on a 1.4 mmol scale yielded 525 mg of
compound 1f asa yellowpowder (93%yield). HPLC/MS:>95%
purity; m/z 397 [(M þ H)þ, 100%]. 1H NMR (400 MHz, CDCl3):
2.52 (2H, br, dd, J = 15.35 and 5.5, CH2), 2.78 (2H, m, CH2), 3.50
(2H, m, CH2), 3.51 (1H, t,J =6.7, CH), 3.77 (6H, s, 2ꢀ CH3) 5.50
(1H, dd, J = 3.64 and 3.82, CH), 6.50 (1H, d, J = 9.8, CH), 6.67
(2H, s, 2 ꢀ Ar-H), 6.81 (1H, d, J = 8.1, Ar-H), 7.56 (1H, d, J =
8.1, Ar-H), 8.03 (1H, d, J = 9.8, CH). 13C NMR (100 MHz,
CDCl3): 44.96, 61.23, 64.99, 74.64, 114.19, 114.24, 119.49, 122.63,
125.31, 127.13, 134.03, 138.71, 137.78, 142.51, 148.39, 153.35,
Ar-H), 7.11 (5H, m, 5 ꢀ Ar-H), 8.14 (1H, d, J = 9.9, CH). 13
C
NMR (100 MHz, CDCl3): 39.83, 55.34, 59.50, 69.48, 114.38,
118.00, 120.90, 121.32, 125.00, 126.95, 128.43, 130.34, 137.89,
141.35, 143.45, 162.63. Analysis: Calcd for C20H20N2O3 0.8H2O
3
(0.8 equiv of water observed by 1H NMR): C 68.48; H, 6.21; N,
7.99. Found: C, 68.56; H, 6.34; N, 8.04.
8-Hydroxy-5-[(R)-1-hydroxy-2-(5,6-dimethylindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1b). Prepared in an analogous fashion
to compound 1a. A reaction on a 0.33 mmol scale yielded 95 mg
of compound 1b as a yellow powder (80% yield). HPLC/MS:
> 95% purity; m/z 366 [(M þ H)þ, 100%]. 1H NMR (500 MHz,
DMSO): 2.15 (6H, s, 2 ꢀ CH3), 2.60 (2H, m, 2 ꢀ CH), 2.75 (2H,
m, CH2), 2.97 (2H, m, 2 ꢀ CH), 3.52 (1H, m, CH), 5.02 (1H, m,
CH), 6.51 (1H, d, J = 9.9, Ar-H), 6.93 (1H, s, Ar-H), 6.93 (1H, s,
Ar-H), 7.09 (1H, d, J = 8.1, Ar-H) 8.18 (1H, d, J = 9.9, CH)
10.6-9.7 (1H, s, br). 13C NMR (125 MHz, DMSO): 19.31, 38.84,
55.56, 59.18, 69.10, 113.85, 117.00, 119.64, 121.48, 125.42, 125.46,
128.36, 131.32, 133.59, 136.92, 139.04, 139.09, 142.56, 160.68.
166.36. Analysis: Calcd for C22H24N2O5 1.2H2O (1.2 equiv of
3
water observed by 1H NMR): C, 63.21; H, 6.37; N, 6.70. Found:
C, 62.92; H, 6.52; N, 6.63.
8-Hydroxy-5-[(R)-1-hydroxy-2-(4,7-diethylindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1g). Prepared in an analogous fashion
to compound 1a. A reaction on a 0.21 mmol scale yielded 70 mg of
compound 1g as a yellow powder (86% yield). HPLC/MS: > 95%
purity; m/z 393 (Mþ, 100%). 1H NMR (400 MHz, DMSO): 1.10
(6H, t, J = 7.6, 2ꢀ CH3), 2.49 (4H, m, 2 ꢀ CH3), 2.58 (2H, dt, J =
5.3, CH2), 2.82 (2H, d, J=6.1, CH2), 3.07(2H, m, CH2), 3.55 (1H,
t, J = 6.4, CH), 5.03 (1H, t, J = 5.4, CH), 6.51 (1H, d, J = 9.9,
CH), 6.89 (2H, s, 2 ꢀ Ar-H), 6.92 (1H, d, J = 8.1, Ar-H), 7.10 (1H,
Analysis: Calcd for C22H24N2O3 1.5H2O (1.5 equiv of water
observed by H NMR): C, 67.50, H, 6.95, N, 7.16. Found: C,
67.36, H, 6.79, N, 7.07.
3
1
8-Hydroxy-5-[(R)-1-hydroxy-2-(5,6-diethylindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1c). Prepared in an analogous fashion
to compound 1a. A reaction on a 0.75 mmol scale yielded 265 mg
of compound 1c as a whitesolid(83% yield). 1H NMR (400 MHz,
DMSO): 1.10 (t, 6H, J = 7.5, 2 ꢀ CH3), 2.51 (q, 4H, J = 7.5, 2 ꢀ
CH2), 2.53-2.62 (m, 2H, indanyl CH2), 2.68-2.76 (m, 2H,
CH2N), 2.90-3.03 (m, 2H, indanyl CH2), 3.48-3.55 (m, 1H,
indanyl CH), 4.97-5.04 (m, 1H, CHOH), 6.49 (d, 1H, J = 11.0,
Ar-H), 6.90 (d, 1H, J = 9.1, Ar-H), 6.91 (s, 2H, indanyl Ar-H),
7.07 (d, 1H, J = 9.1, Ar-H), 8.17 (d, 1H, J = 11.0, Ar-H). 13C
NMR (100 MHz, DMSO): 16.34, 25.54, 39.32, 39.50, 56.30,
59.88, 69.71, 114.56, 120.38, 122.13, 124.83, 124.88, 129.15,
131.71, 137.64, 139.65, 139.88, 139.94, 143.61, 161.39. HRMS
(m/z): [M þ H]þ (100%) calcd for C24H29N2O3, 393.2178; found,
393.2174 (error 1.0 ppm).
d, J = 8.1, Ar-H), 8.19 (d, J = 9.9, CH), 10.31 (1H, s, br, OH). 13
C
NMR (100 MHz, DMSO): 14.86, 25.95, 37.35, 58.43, 94.89,
114.25, 117.35, 120.11, 122.03, 126.11, 128.78, 136.95, 137.17,
139.55, 143.09, 161.07. Analysis: Calcd for C24H28N2O3 1.2H2O
3
(1.2 equiv of water observed by 1H NMR): C, 69.61; H, 7.40; N,
6.76. Found: C, 69.77; H, 7.46; N, 6.70.
Acknowledgment. We thank Brian Everatt for analytical
support, Grety Rihs and Hansrudolf Walter for performing
the X-ray structural analysis, and Reiner Aichholz, Wolfgang
Blum, Matthias Kittelmann, and Kurt Laumen for performing
metabolite identification studies.
Supporting Information Available: Experimental procedures
for the synthesis of the aminoindans 3b-g and the ethanolamine
derivatives 4a-g, characterizing data for the whole sequence
leading to indacaterol 1c, HPLC methods for CHIIAM and %
HSA binding determinations, methods for pKa and plasma
protein binding determinations, details of the single-crystal
X-ray structure determination for 1c, pharmacokinetic data for
1c compared to formoterol, procedures for the isolation and
determination of the β2-adrenoceptor activity of the phenolic
glucuronide of 1c, and time versus inhibition of contraction plots
from the electrically stimulated superfused guinea-pig tracheal-
strip assays with aminoindan derivatives 1a-g, and the reference
β2-adrenoceptor agonists. This material is available free of charge
8-Hydroxy-5-[(R)-1-hydroxy-2-(5,6-di-n-propylindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1d). Prepared in an analogous fashion to
compound 1a. A reaction on a 5 mmol scale yielded 460 mg of
compound 1d as a yellow powder (21% yield). HPLC/MS: > 95%
purity; m/z 422 [(M þ H)þ, 100%]. 1H NMR (400 MHz, DMSO):
0.94 (6H, t, J = 7.3, 2 ꢀ CH3), 1.50 (4H, q, J = 7.5, 2 ꢀ CH2), 2.48
(4H, m, 2 ꢀ CH2), 2.58 (2H, dt, J = 15.6 and 5.4, CH2), 2.74 (2H,
m, CH2), 2.99 (2H, m, CH2), 3.53 (1H, m, CH), 5.01 (1H, t, J =
5.4, CH), 6.50 (1H, d, J = 9.9, CH), 6.92 (3H, m, 3 ꢀ Ar-H),
7.08 (1H, d, J = 8.2, Ar-H) 8.19 (1H, d, J = 9.9, Ar-H). 13C NMR
(100 MHz, DMSO): 14.43, 24.59, 34.47, 42.18, 55.71, 59.41, 69.07,
114.24, 117.39, 120.07, 121.94, 125.33, 128.73, 137.26, 138.07,
139.27, 139.32, 143.02, 161.13. Analysis: Calcd for C26H32N2O3
1.2H2O (1.2 equiv of water observed by 1H NMR): C, 70.63; H,
7.84; N, 6.34. Found: C, 70.48; H, 7.89; 6.46.
3
8-Hydroxy-5-[(R)-1-hydroxy-2-(5,6-di-n-butylindan-2-ylamino)-
ethyl]-1H-quinolin-2-one (1e). Prepared in an analogous fashion to
compound 1a. A reaction on a 0.22 mmol scale yielded 56 mg of
compound 1e as a yellow solid (58% yield). 1H NMR (400 MHz,
DMSO): 0.90 (6H, t, J = 7.3, 2 ꢀ CH3), 1.34 (4H, m, 2 ꢀ CH2),
1.47 (4H, m, 2 ꢀ CH2), 2.48 (4H, m, 2 ꢀ CH2), 2.58 (2H, m, CH2),
2.74 (2H, m, CH2), 2.97 (2H, m, CH2), 3.51 (1H, m, CH), 5.02 (1H,
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