Linear Tachykinin NK2 Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4803
under stirring for 12 h. The precipitate was filtered and washed
with dichloromethane, giving a first crop of 10a as the free base
(0.09 g, 0.17 mmol, 30% yield). HPLC: (B) 10.8 min, 99%. MS
(ESI) m/z: 509.3 (MH+). 1H NMR (500 MHz, DMSO-d6): δ (ppm)
9.02 (t, J ) 5.8 Hz, 1H), 8.23 (d, J ) 8.3 Hz, 1H), 8.10 (s, 1H),
8.02 (d, J ) 7.5 Hz, 1H), 8.00 (d, J ) 7.1 Hz, 1H), 7.92 (t, J ) 5.6
Hz, 1H), 7.48-7.42 (m, J ) 7.5 Hz, 2H), 7.25-7.15 (m, 5H), 4.46
(m, 1H), 4.19 (m, 4H), 3.93 (dd, J ) 16.3/6.0 Hz, 1H), 3.80 (dd,
J ) 16.3/5.8 Hz, 1H), 3.18-3.01 (m, 2H), 2.98 (dd, J ) 13.7-5.4
Hz, 1H), 2.81 (dd, J ) 13.7-8.9 Hz, 1H), 2.28 (m, 4H), 2.20 (t,
7.2 Hz, 1H), 1.50 (m, 2H).
(ppm) 8.14 (s, 1H), 8.11-7.97 (m, 2H), 7.59-7.42 (m, 2H), 2.18-
1.68 (m, 8H). 13C NMR (200 MHz, DMSO-d6): δ (ppm) 182.6 (s,
1C), 157 (s, 1C), 142.2 (s, 1C), 140.4 (s, 1C), 131.1 (d, 1H), 129.9
(s, 1C), 129.0 (D, 1C), 127.4 (d, 1C), 127.2 (d, 1C), 124.7 (d, 1C),
76.5 (s, 1C), 39.8 (t, 2C), 27.1 (t, 2C).
2-(R)-Amino-N-(3-hydroxypropyl)-3-phenylpropionamide (18).
Z-D-Phe-OSu 17 (5 g, 13 mmol) was dissolved in dimethoxyethane
(DME, 50 mL), and the solution was treated with 1-amino-3-
propanol (0.76 mL, 13 mmol) in DME (10 mL) and triethylamine
(1.74 mL, 0.14 mmol). The turbid mixture was stirred for 2 h and
then was diluted with water (100 mL), and the solution was
extracted with ethyl acetate (2 × 50 mL). The combined extracts
were dried over Na2SO4, and the solvent wasremoved under reduced
pressure to give a waxy solid, which was further washed with
cyclohexane. Drying by suction gave 4.05 g (11.7 mmol, 90% yield)
of a white solid. HPLC: (A) 3.48 min. MS (ESI) m/z: 357.2 (MH+).
1H NMR (200 MHz, DMSO-d6): δ (ppm) 7.94 (broad t, J ) 5.3
Hz, 1H), 7.46 (broad d, J ) 8.6 Hz, 1H), 7.35-7.10 (m, 10H),
4.93 (s, 2H), 4.4 (t, J ) 5.3 Hz, 1H), 4.16 (ddd, H ), 10, 8.6, 4.7
Hz, 1H), 3.4-3.3 (m, 2H), 3.14-3.00 (m, 2H), 3.92 (dd, J ) 13.6,
4.7 Hz, 1H), 2.72 (dd, 13.5, 8.6 Hz, 1H), 1.6-1.44 (m, 2H). The
Z-protected derivative (4.18 g, 11.7 mmol) was dissolved in
methanol (50 mL), and 1 N HCl (15 mL, 15 mmol) was added.
The substrate was then hydrogenated in the presence of 10% Pd/C
(0.452 g) under normal pressure. After 2 h, a check by TLC (ethyl
acetate/hexane, 80/20) indicated that some precursor still remained
as a higher running spot, so additional catalyst (0.22 g) was added
and the hydrogenation continued for another 2 h, with the reaction
then left to stand overnight. The mixture was then filtered off
through a pad of Celite, and the filtrate was evaporated down under
reduced pressure. The residue was treated with saturated sodium
bicarbonate solution (100 mL) and lyophilized. The lyophilized
product was taken up in methanol and the suspension filtered off
to remove insoluble sodium salts. The resulting filtrate was
evaporated down, and the remaining solid residue was washed with
diethyl ether. This gave 18 (2.91 g, quantitative yield) as a white
solid. 1H NMR (200 MHz, DMSO-d6): δ (ppm) 7.9-7.73 (m, 1H),
7.35-7.07 (m, 1H), 4.50-4.30 (m, 1H, CHR), 3.47-3.21 (m, 2H),
3.18-3.04 (m, 2H), 2.90 (component of ABX spin system, dd, Japp
) 13.3, 5.2 Hz, 1H), 2.60 (component of ABX spin system, dd,
Japp ) 13.3, 8.1 Hz, 1H), 1.73 (broad s, 2H), 1.57-1.42 (m, 2H).
Benzo[b]thiophene-2-carboxylic Acid {1-[1-(3-Hydroxypro-
pylcarbamoyl)-2-(R)-phenylethylcarbamoyl]cyclopentyl}-
amide (19). The oxazolone 16 (1 g, 3.7 mmol) was dissolved in
DMF (40 mL), and 18 (1.11 g, 5.6 mmol) added. The mixture was
stirred at room temperature for 24 h. After this time the mixture
was diluted with ethyl acetate (150 mL) and the solution washed
with water (3 × 50 mL) and saturated sodium bicarbonate (2 × 50
mL). The organic extract was dried over sodium carbonate to give
1.51 g (83% yield) of material (19) as a foamy solid. HPLC: (C)
3.73 min, 94% purity. MS (ESI) m/z: 492.1 (MH+). 1H NMR (500
MHz, DMSO-d6) δ (ppm) 8.88 (s, 1H), 8.30 (s, 1H), 8.04 (m, 1H),
7.98 (m, 1H), 7.83 (d, J ) 8.3 Hz, 1H), 7.51 (t, J ) 5.6 Hz, 1H),
7.46 (m, 2H), 7.11 - 7.19 (m, 5H), 4.44 (m, 1H), 4.39 (t, J ) 5.2
Hz, 1H), 3.43 (m, 2H), 3.2-3.0 (m, 3H), 2.83 (dd, J ) 13.9, 10.6
Hz, 1H), 2.22 (m, 1H), 1.9-1.4 (m, 9H).
In a similar way, 10b-e were obtained. Starting from 5f,g by
simple coupling with 9, 10f,g were obtained.
Products 12a-c and 14a-h were similarly obtained from the
common precursor 11 (see Scheme 2).
General Procedure for the Obtainment of Ureas 13a-g. 1-[3-
(4-Bromophenyl)ureido]cyclopentanecarboxylic Acid [1-(R)-(3-
Morpholin-4-yl-propylcarbamoyl)-2-phenylethyl]amide Triflu-
oroacetate (13a). To a freshly prepared solution of 1-aminocyclopen-
tanecarboxylic acid [1-(3-morpholin-4-ylpropylcarbamoyl)-2-
phenylethyl]amide (11) (0.189 mmol) (obtained with the same
methodology used for 5a using 1-aminocyclopentanecarboxylic acid
in dichloromethane), 4-bromophenyl isocyanate (37 mg, 0.187
mmol) was added, and the solution was heated at 40 °C for 3 h
and then left at room temperature overnight. The solvent was then
removed under reduced pressure, and the crude was purified through
preparative HPLC (Jupiter column C18, 300 Å, 250 mm × 21.20
mm, 15 µm, H2O + 0.1% TFA, CH3CN + 0.1% TFA, gradient
20-80% CH3CN in 40 min), obtaining 13a as a trifluoroacetate
(52.5 mg, 0.07 mmol, 40% yield). HPLC: (B) 12.2 min, 99%. MS
1
(ESI) m/z: 603.3 pattern for 1 Br (MH+). H NMR (500 MHz,
DMSO-d6): δ (ppm) 9.52 (broad s, 1H), 8.88 (s, 1H), 7.96 (d, J )
8.4 Hz, 1H), 7.89 (t, J ) 5.6 Hz, 1H), 7.44 (d, J ) 8.8 Hz, 2H),
7.36 (d, J ) 8.8 Hz, 2H), 7.23-7.14 (m, 5H), 6.77 (s, 1H), 4.39
(m, 1H), 3.96 (d, J ) 12.3 Hz, 2H), 3.62 (t, J ) 12.3 Hz, 2H),
3.24 (m, 1H), 3.19 (dd, J ) 13.9, 3.9 Hz, 1H), 3.1-2.95 (m, 3H),
2.91 (dd, J ) 13.9, 10.9 Hz, 1H), 2.14 (m, 1H), 1.79 (m, 2H),
1.67-1.50 (m, 7H).
In a similar way, products 13b-g were obtained.
General Procedure for the Obtainment of 21a-h. 1-[(Benzo-
[b]thiophene-2-carbonyl)amino]cyclopentanecarboxylic Acid (15).
To a stirred suspension of 6a (10 g, 77.5 mmol) in dichloromethane
(500 mL), BSA (35 mL, 140 mmol) was added. After 1.5 h the
solution was clear and a solution of 9 in dichloromethane (200 mL)
was added dropwise in 1.5 h. The resulting opalescent solution was
kept at room temperature overnight and then evaporated to dryness.
The residue was treated with K2CO3 (5% aqueous) and extracted
with ethyl acetate. The aqueous phase was acidified with 10% HCl
until complete precipitation of the carboxylic acid, which was
filtered and recrystallized from acetonitrile to obtain yellowish
crystals of 15 (17 g + 2 g (second crop), 66 mmol, 85% yield).
1
HPLC: (C) 3.51 min. H NMR (200 MHz, DMSO-d6): δ (ppm)
12.3 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 8.05-7.9 (m, 2H), 7.50-
7.37 (m, 2H), 2.23-1.97 (m, 4H), 1.82-1.61 (m, 4H). 13C NMR
(200 MHz, DMSO-d6): δ (ppm) 175 (s, 1C), 161.45 (s, 1C), 140.1
(s, 1C), 139.7 (s, 1C), 139.1 (s, 1C), 126.1 (d, 1C), 125.3 (d, 1C),
125.0 (d, 1C), 124.8 (d, 1C), 122.65 (d, 1C), 65.6 (s, 1C), 36.3 (t,
2C), 24.1 (t, 2C).
4-[2-({1-[(Benzo[b]thiophene-2-carbonyl)amino]cyclopentane-
carbonyl}amino)-3-(R)-phenylpropionylamino]propanal (20).
The alcohol 19 (2.10 g, 4.26 mmol) was partially dissolved in
dichloromethane/THF (40 mL/30 mL), and Dess-Martin periodi-
nane (1.99 g, 4.72 mmol) in dichloromethane (15 mL) was added
at room temperature. The turbid reaction mixture was left to stir
for 2 h at room temperature, after which the mixture was poured
into a saturated solution of sodium bicarbonate (50 mL) in which
sodium thiosulphate (10.6 g) had been dissolved. The phases were
shaken and separated. The aqueous fraction was then extracted
further with chloroform (50 mL), and the combined organic extracts
were dried over sodium sulfate. The solvent was removed under
reduced pressure to give an oil, which was triturated with diethyl
ether. The resulting solid was filtered off by suction to give 2.07 g
(99% yield) of 20 as a pale-yellow amorphous solid. HPLC: (C)
2-Benzo[b]thiophen-2-yl-3-oxa-1-azaspiro[4.4]non-1-en-4-
one (16). A partial suspension of 15 (16 g, 55 mmol) in THF (500
mL) was treated with EDC‚HCl (12.7 g, 66 mmol) and 30 mL of
DIPEA. After the mixture was stirred for 2 h at room temperature,
10 mmol of EDC‚HCl and DIPEA were added. After an additional
3 h, the solvent was evaporated and the residue was dissolved in 1
L of ethyl acetate and washed with 10% aqueous citric acid solution
and water. The organic phase was dried over Na2SO4, filtered, and
evaporated to dryness. The formed white needles were suspended
in a small amount of ethyl acetate and filtered to give 13 g of 16
(48 mmol, 88% yield), another crop was obtained by a second
filtration from the mother liquor (1 g). HPLC: (C) 4.97 min, 95%
1
purity, presence of 15 (4%). H NMR (200 MHz, DMSO-d6): δ