Uroselective R1-Adrenoceptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2685
solid: mp 112.2-112.5 °C; IR 3436, 1682, 1641, 1597 cm-1
;
Et3N (0.41 mL, 2.84 mmol), cooled to 0 °C, and treated with
MsCl (0.21 mL, 2.52 mmol). After 0.5 h, the solution was
partitioned between aqueous NaHCO3 and CH2Cl2, dried (Na2-
SO4), concentrated, and subjected to 24f (700 mg, 2.69 mmol),
NaI (165 mg, 1.1 mmol), and K2CO3 (400 mg, 2.9 mmol) in
DMF (22 mL) at 40 °C for 18 h. The ester was isolated by
standard extraction and SGC (eluant: 3:2 hexanes:EtOAc, tr.
Et3N) as a foam (650 mg, 1.2 mmol, ca. 55%) and partially
characterized: 1H NMR δ 1.41 (t, 3 H, J ) 7.2 Hz), 1.97 (quin,
2 H, J ) 6.9 Hz), 2.51-2.68 (m, 6 H), 3.03-3.10 (m, 4 H), 3.85
(q, 2 H, J ) 5.7 Hz), 4.40 (dq, 4 H, J ) 7.2, 8.4 Hz), 6.87-7.07
(m, 4 H), 7.26 (dd, 1 H, J ) 7.7, 8.4 Hz), 7.77 (dd, 1 H, J ) 1.2,
7.5 Hz), 8.17 (dd, 1 H, J ) 1.2, 8.7 Hz), 9.20 (s, 1 H), 9.27
(broad t, 1 H, J ) 5.1 Hz). The foam (650 mg, 1.2 mmol) was
dissolved in MeOH (10 mL) and treated with KOH (270 mg,
4.8 mmol) and water (1 mL). The solution was heated to 40
°C for 16 h, allowed to cool, and treated with HCl (10 mL, 1 M
Et2O, 10 mmol). White solids formed and were collected and
dried in vacuo (6 h, 50 °C). They were suspended in DMF (15
mL), treated with CDI (215 mg, 1.32 mmol), and stirred at 60
°C for 2 h, at which time, i-Pr2NEt (1.0 mL, 6.0 mmol) and
Me2NH‚HCl (145 mg, 1.8 mmol) were added and heating
continued for 2.6 d. The resulting suspension was concen-
trated in vacuo and partitioned between aqueous NaHCO3 and
CH2Cl2 (5 × 20 mL), dried (Na2SO4), and concentrated. The
title compound was isolated by SGC (eluant 2% MeOH/CH2-
Cl2, trace Et3N) as a foam (405 mg, 63%) and formed a solid
1H NMR δ 1.33 (t, 3 H, J ) 7.2 Hz), 1.39 (t, 3 H, J ) 7.2 Hz),
4.26 (q, 2 H, J ) 7.2 Hz), 4.36 (q, 2 H, J ) 7.2 Hz), 6.88 (dt, 1
H, J ) 1.2, 7.5 Hz), 7.22 (dd, 1 H, J ) 1.5, 8.1 Hz), 7.39 (dt, 1
H, J ) 1.5, 8.4 Hz), 7.84 (dd, 1 H, J ) 1.5, 7.8 Hz), 8.44 (d, 1
H, J ) 13.2 Hz), 11.09 (d, 1 H, J ) 12.9 Hz); MS m/z 389 (M+),
343 (M+ loss of OEt). The adduct (3.76 g, 9.7 mmol) was
treated with (i-Pr)2NEt (2.0 mL, 11.6 mmol) and POCl3 (6.8
mL, 73 mmol) and heated to reflux in xylenes (35 mL). After
14 h, the dark mixture was distilled to ca. 10 mL of residue,
cooled to rt, poured into ice, extracted with Et2O (5 × 30 mL),
washed with saturated NaHCO3 and then brine, and stored
over Na2SO4. Ethyl 4-chloro-8-iodoquinoline-3-carboxamide
was obtained following SGC (eluant: 8:1 hexanes:EtOAc) as
tan powder (2.304 g, 66%): mp 81.5-82.9 °C; 1H NMR δ 1.46
(t, 3 H, J ) 7.2 Hz), 4.51 (q, 2 H, J ) 7.2 Hz), 7.42 (t, 1 H, J
) 7.5 Hz), 8.43 (dd, 1 H, J ) 1.2, 8.1 Hz), 8.46 (dd, 1H, J )
0.9, 7.2 Hz), 9.31 (s, 1 H); MS m/z 363 (M+ with 37Cl), 361 (M+
with 35Cl), 318 (M+ with 37Cl loss of OEt), 316 (M+ with 35Cl
loss of OEt). Anal. (C12H9ClINO2) C, H, N. The ester (2.72
g, 7.5 mmol) was dissolved in DME (35 mL), treated with
NaOH (900 mg, 23 mmol), dissolved in 7 mL of water, and
heated to reflux for 40 min. Upon cooling, the solution was
treated with HOAc (3.0 mL, 53 mmol), solids formed, and the
volatiles were removed by the aid of toluene azeotrope (3 ×
25 mL). The resulting white solids were treated with (COCl)2
[(0.98 mL, 11.25 mmol), DCE (15 mL), 80 °C, 2 h] and Me2NH
[(12 mL, 24 mmol, 2 M THF), -10 °C, 0.5 h]. The title
compound was obtained following aqueous workup and SGC
(eluant: 3:2 hexanes:EtOAc) as a waxy solid (985 mg, 2.7
mmol, 36%): 1H NMR δ 2.93 (s, 3 H), 3.23 (s, 3 H), 7.41 (t, 1
H, J ) 7.5 Hz), 8.29 (dd, 1H, J ) 1.2, 8.4 Hz), 8.43 (dd, 1 H,
J ) 1.2, 7.5 Hz), 8.86 (s, 1 H); MS m/z 362 (M+ with 37Cl), 360
(M+ with 35Cl), 318 (M+ with 37Cl loss of NMe2), 316 (M+ with
35Cl loss of NMe2).
from HBr/EtOH: mp 185-192 °C; IR 3430, 2955, 1635 cm-1
;
1H NMR δ 2.19 (quin, 2 H, J ) 5.7 Hz), 3.02-3.32 (m with 2
predominant s, 12 H), 3.41-3.70 (m, 6 H), 4.73 (q, 2 H, J )
9.0 Hz), 6.98-7.11 (m, 4 H), 7.76 (t, 1 H, J ) 8.7 Hz), 8.19 (d,
1 H, J ) 7.8 Hz), 8.45 (s, 1 H), 8.74 (d, 1 H, J ) 8.4 Hz), 9.28
(broad s, 1 H); 13C NMR δ 23.0 (t), 34.8 (q), 38.6 (q), 42.1 (t),
46.9 (t), 51.3 (t), 53.1 (t), 65.0 (t, J ) 34 Hz), 109.6 (s), 114.8
(d), 118.8 (d), 119.7 (s), 122.9 (d), 123.2 (d), 123.4 (d), 124.0 (q,
J ) 142 Hz), 126.9 (d), 133.6 (d), 134.1 (s), 139.9 (d),143.1 (s),
149.4 (s), 152.7 (s), 165.2 (s); MS m/z 551 (M+ with 37Cl), 549
(M+ with 35Cl), 321, 319. Anal. (C27H31F3ClN5O2‚(HBr)2‚
(H2O)2.5) C, N; H: calcd, 5.06; found, 4.60.
N,N-Dim eth yl-4-ch lor o-8-cya n oqu in olin e-3-ca r boxa m -
id e (35). Following the report of Piers16 as modified for 14vi,
34 (2.3 g, 6.4 mmol) was treated with 12-crown-4 (0.1 mL, 0.64
mmol), LiCN (12.7 mmol), and [Ph3P]4Pd (910 mg, 0.8 mmol)
in benzene (60 mL) at rt for 10 d and gave 35 (280 mg, 1.08
mmol) as a powder: mp 194-200 °C; 1H NMR δ 2.95 (s, 3 H),
3.24 (s, 3 H), 7.79 (dd, 1 H, J ) 7.2, 8.7 Hz), 8.24 (dd, 1 H, J
) 1.2, 7.2 Hz), 8.54 (dd, 1 H, J ) 1.2, 8.7 Hz), 8.94 (s, 1 H);
MS m/z 260 (M+ with 37Cl), 258 (M+ with 35Cl), 217 (M+ with
37Cl loss of NMe2), 215 (M+ with 35Cl loss of NMe2).
N-Meth yl-4-ch lor o-1,3-d im eth yl-1H-p yr a zolo[3,4-b]p y-
r id in e-5-ca r boxylic a cid (36) was prepared from 4-chloro-
1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride28
(1.38 g, 4.9 mmol), Et3N (2.4 mL, 17.2 mmol), and MeNH2 (0.42
mL, 40% aqueous, 5.4 mmol) in THF (10 mL) at -10 °C and
obtained as a white powder (247 mg, 1.03 mmol, 20%): mp
219.7-221.2 °C; 1H NMR δ 2.73 (s, 3 H), 3.08 (d, 3 H, J ) 4.8
Hz), 4.07 (s, 3 H), 6.05 (broad s, 1 H), 8.74 (s, 1 H); MS m/z
240 (M+ with 37Cl), 238 (M+ with 35Cl), 210 (M+ with 37Cl loss
of NHMe), 208 (M+ with 35Cl loss of NHMe).
N,N-Dim eth yl-4-[[3-[4-[2-(2,2,2-tr iflu or oeth oxy)ph en yl]-
piper azin -1-yl]pr opyl]am in o]qu in olin e-3-car boxam ide h y-
d r ob r om id e (30f′): mp 120 °C dec. Anal. (C27H32F3N5O2‚
(HBr)2.5) C, H, N.
A Rep r esen ta tive P r oced u r e for Ta r get P r ep a r a tion
in Sch em e 6. 4-[[3-[4-[4-F lu or o-2-(oxa zol-2-yl)p h en yl]-
p ip er a zin -1-yl]p r op yl]a m in o]-1,3-d im eth yl-1H-p yr a zolo-
[3,4-b]p yr id in e-5-ca r b oxylic Acid Dim et h yla m id e, Ox-
a la te (37y). Piperazine 24y (300 mg, 1.21 mmol) was ho-
mologated to its aminopropyl derivative 43y [N-(3-bromopro-
pyl)phthalimide (358 mg, 1.33 mmol), K2CO3 (200 mg, 1.45
mmol), DMF (10 mL), then SGC and N2H4‚H2O (0.5 mL, 0.82
mmol) in boiling EtOH (15 mL)] as described for Scheme 1.
Crude 43y was treated with 37 (190 mg, 0.69 mmol) and K2-
CO3 (114 mg, 0.83 mmol) in xylene (10 mL) and heated to 120
°C for 16 h. The desired 37y was obtained following SGC
(eluant: 3% MeOH/CH2Cl2, 211 mg, 59%) and formed a solid
with oxalic acid/EtOAc/MeOH: mp 88-96 °C; 1H NMR δ 1.93
(quin, 2 H, J ) 6.7 Hz), 2.64 (s, 3 H), 2.88 (t, 2 H, J ) 7.0 Hz),
2.97-3.29 (m with predominant s, 16 H), 3.84 (s, 3 H), 5.97
(broad s, 1 H), 7.21-7.36 (m, 2 H), 7.41 (d, 1 H, J ) 0.9 Hz),
7.89 (s, 1 H), 8.22 (d, 1 H, J ) 0.9 Hz); 13C NMR δ 15.3 (q),
24.7 (t), 32.9 (q), 41.6 (t), 50.0 (t), 51.8 (t), 53.9 (t), 103.5 (s),
107.3 (s), 116.4 (d, J ) 24.7 Hz), 117.7 (d, J ) 21.7 Hz), 121.9
(d, J ) 8.3 Hz), 122.3 (d, J ) 8.5 Hz), 128.3 (d), 138.9 (s), 140.0
(d), 146.4 (s), 146.6 (s), 149.1 (d), 151.8 (s), 157.3 (d, J ) 240
N,N-Dim eth yl-4-ch lor o-1,3-d im eth yl-1H-p yr a zolo[3,4-
b]p yr id in e-5-ca r boxylic a cid (37) was prepared from 4-chlo-
ro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chlo-
ride28 (4.81 g, 19.7 mmol), Et3N (7 mL, 50 mmol), Me2NH‚HCl
(1.77 g, 21.7 mmol) in DCE (25 mL) at -10 °C and obtained
1
as a white solid (3.15 g, 63%): mp 143.3-143.8 °C; H NMR
δ 2.73 (s, 3 H), 2.93 (s, 3 H), 3.20 (s, 3 H), 4.08 (s, 3 H), 8.36
(s, 1 H); 13C NMR δ 14.4 (q), 33.9 (q), 34.9 (q), 38.3 (q), 112.5
(s), 135.0 (s), 141.1 (s), 147.5 (d), 151.5 (s), 167.0 (s); MS m/z
254 (M+ with 37Cl), 252 (M+ with 35Cl), 210 (M+ with 37Cl loss
of CONMe2), 208. Anal. (C11H13ClN4O) C, H, N.
Hz), 163.5 (s), 169.5 (s). Anal. (C27H33FN8O2‚C2H2O4‚(H2O)0.2
C, H, N.
)
A Rep r esen ta tive P r oced u r e for Ta r get P r ep a r a tion
in Sch em e 6. N,N-Dim eth yl-8-ch lor o-4-[[3-[4-[2-(2,2,2-tr i-
flu or oeth oxy)p h en yl]p ip er a zin -1-yl]p r op yl]a m in o]qu in -
olin e-3-ca r boxa m id e Hyd r obr om id e (30f). A toluene (15
mL) suspension of ethyl 4,8-dichloroquinoline-3-carboxylate
(982 mg, 3.64 mmol), K2CO3 (550 mg, 3.9 mmol), and 3-amino-
1-propanol (0.29 mL, 3.8 mmol) was heated to reflux for 3.5
h. The mixture was filtered hot, the filter cake was washed
with EtOAc, and the filtrate was concentrated. Some of the
resulting powder (650 mg) was dissolved in CH2Cl2 (9 mL) and
4-[[3-[4-(4-Flu or o-2-m eth oxyph en yl)piper azin -1-yl]pr o-
p yl]a m in o]-8-m eth ylqu in olin e-3-ca r boxylic a cid d im e-
th yla m id e h yd r obr om id e (33t): mp 174-180 °C. Anal.
(C27H34FN5O2‚(HBr)3‚H2O) C, H; N: calcd, 9.45; found, 8.99.
4-[[3-[4-(4-Flu or o-2-m eth oxyph en yl)piper azin -1-yl]pr o-
p yl]a m in o]-8-cya n oqu in olin e-3-ca r boxylic a cid d im eth -
yla m id e oxa la te (35t): mp 118-133 °C. Anal. (C27H31
-
FN6O2‚(C2H2O4)1.5) C, H, N.
4-[[3-[4-(4-Flu or o-2-m eth oxyph en yl)piper azin -1-yl]pr o-