Derivatives of the κ-Opioid Antagonist GNTI
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5509
on either a Perkin-Elmer 782 Instrument or a Perkin-Elmer
RX 1 FT-IR Instrument. Anhydrous THF, DMF, DCM, and
MeOH were purchased from Aldrich. HPLC solvent grade
chloroform and MeOH were purchased from Merck. All other
solvents used were GPR grade, purchased from Merck or
Fisher Scientific. Chemicals were purchased from Aldrich,
Fluka, Lancaster, and Acros chemical companies.
Details are given for representative examples 10f and 15d .
Full experimental details for all compounds are provided as
Supporting Information.
and allowed to stir for 10 min at 0 °C. Trifluoroacetic acid (2
mL) was added and the solution allowed to warm to room
temperature. Stirring was continued for 12 h, after which the
solution was concentrated under reduced pressure. Washing
the resultant oil with diethyl ether afforded a precipitate that
could be isolated by vacuum filtration. Further purification
was achieved by recrystallization (methanol/diethyl ether) to
give 17-cyclopropylmethyl-6,7-didehydro-4,5R-epoxy-5′-(N′-4-
chlorobenzyl)guanidinyl-3,14-dihydroxyindolo[2′,3′:6,7]morphi-
nan (10f) as the bistrifluoroacetic acid salt (0.077 g, 0.09 mmol,
74%): mp 186-189 °C; Rf ) 0.13 [CH3OH/CH2Cl2/NH4OH (89:
10:1)]; IR νmax/cm (KBr) 3630-2475 (br, bonded OH and NH)
and 1678 (br, CdN, NH and NH2); 1H NMR (400 MHz, CD3OD)
δ 0.48-0.59 [m, 2H, NCH2CH(CHHCHH)], 0.73-0.91 [m, 2H,
NCH2CH(CHHCHH)], 1.09-1.22 [m, 1H, NCH2CH(CH2CH2)],
5.71 [s, 1H, C(5)H], 6.64 [d, J ) 8.2 Hz, 1H, C(1)H], 6.68 [d, J
) 8.2 Hz, 1H, C(2)H], 6.98-7.02 (m, 1H, ArH), and 7.28-7.46
[m, 6H, ArH]; 13C NMR (100.5 MHz, CD3OD) δ 3.5 [NCH2CH-
(CH2CH2)], 6.3 [NCH2CH(CH2CH2)], 6.9 [NCH2CH(CH2CH2)],
25.1 [C(10)], 29.7 [C(15)], 30.2 [C(8)], 45.3 [C(16)], 47.5
[quaternary C(13)], 48.0 (CH2Ph), 58.9 [C(18)], 63.6 [C(9)], 73.5
[quaternary C(14)], 84.8 [C(5)], 109.9 (Ar), 113.7 (Ar), 118.0
(Ar), 119.2 (Ar), 120.5 (Ar), 122.2 (Ar), 122.4 (Ar), 126.6 (Ar),
128.3 (Ar), 129.6 (Ar), 129.7 (Ar), 130.1 (Ar), 132.3 (Ar), 134.4
(Ar), 136.4 (Ar), 138.0 (Ar), 141.8 (Ar), 144.5 (Ar), and 157.5
(CdNH); FAB+MS m/z 596 [(M + 1)+, 100%]; HRMS (FAB)
m/z 596.2416 (M + 1)+, C34H35N5O3Cl requires 596.2428. Anal.
(C34H34N5O3Cl‚2TFA‚3H2O) C, H, N.
N-P r op yl-N′-cyclop r op ylm eth ylth iou r ea (12d ). Calcium
carbonate (1.97 g, 19.67 mmol) was dissolved in H2O (2 mL)
and added to a stirred solution of propylamine (1.16 g, 19.67
mmol) in CHCl3 (30 mL). Thiophosgene (4.52 g, 3 mL, 39.34
mmol) was added and the solution stirred at room temperature
for 24 h. The aqueous layer was washed with H2O and
concentrated to give propylisothiocyanate; Rf ) 0.72 [EtOAc/
hexane (1:1)]. Propylisothiocyanate (0.44 g, 4.38 mmol) was
then dissolved in acetone (15 mL) and added dropwise to
aminomethylcyclopropane (0.31 g, 4.38 mmol) in acetone (15
mL). The solution was refluxed gently for 3 h, concentrated,
and purified by column chromatography [hexane/EtOAc
(1:1)], providing the desired N-propyl-N′-cyclopropylmethyl-
thiourea (0.42 g, 2.44 mmol, 56%): Rf ) 0.38 [EtOAc/hexane
(1:1)]; 1H NMR (270 MHz, CDCl3) δ 0.21-0.30 [m, 2H, NCH2-
CH(CHHCHH)], 0.52-0.62 [m, 2H, NCH2CH(CHHCHH)], 0.97
(t, J ) 7.3 Hz, 3H, CH3), 1.02-1.13 [m, 1H, NCH2CH(CH2CH2)],
1.64 [q, J ) 7.3 Hz, 2H, CH2CH3), 3.30-3.41 [m, 4H, 2 ×
NCH2], and 6.24 [br s, 2H, 2 × NH]; 13C NMR (67.8 MHz,
CDCl3) δ 3.5 [NCH2CH(CH2CH2)] and [NCH2CH(CH2CH2)],
10.0 [NCH2CH(CH2CH2)], 11.3 (CH3), 22.1 (CH2CH3), 45.9
(NCH2), 49.4 (NCH2CH), and 181.0 (CdS); FAB+MS m/z 173
[(M + 1)+, 100%]; HRMS (FAB) m/z 173.1116 (M + 1)+,
C8H17N2S requires 173.1112.
1,3-Bis-ter t-bu toxycar bon yl-1-(4′-ch lor oben zyl)-2-m eth -
yl-2-th iop seu d ou r ea (8b). To 1,3-bis-tert-butoxycarbonyl-2-
methyl-2-thiopseudourea (7) (2 g, 6.90 mmol) in dry DMF (20
mL) in an ice-bath was added NaH (60% in oil, 0.334 g, 8.36
mmol), and the mixture stirred for 1 h. 4-Chlorobenzyl bromide
(1.56 g, 7.60 mmol) was added, and the mixture stirred at room
temperature for a further 12 h. Water (30 mL) was added and
the mixture extracted with ethyl acetate (3×). The combined
organic layers were washed with brine (2×), dried (Na2SO4),
and concentrated to give crude 8b. Column chromatography
[hexane/EtOAc (9:2)] provided pure 8b (2.21 g, 5.33 mmol,
77%): Rf ) 0.42 [hexane/EtOAc (9:2)];1H NMR (400 MHz,
CDCl3) δ 1.36 [s, 9H, C(CH3)3], 1.47 [s, 9H, C(CH3)3], 2.24 (s,
3H, SCH3), 4.68 (s, 2H, CH2), and 7.24 (s, 4H, ArH); 13C NMR
(100.5 MHz, CDCl3) δ 16.0 (SCH3), 28.3 [C(CH3)3], 28.4
[C(CH3)3], 52.0 (CH2), 82.0 [C(CH3)3], 83.1 [C(CH3)3], 128.7 (Ar),
129.4 (Ar), 133.4 (quaternary Ar), 136.0 (quaternary Ar), 151.9
(CdO), 157.9 (CdO), and 162.7 (CdN); FAB+MS m/z 415
[(M + 1)+, 30%] and 259 (65); HRMS (FAB) m/z 415.1439
(M + 1)+, C19H28N2O4SCl requires 415.1458.
17-Cyclopr opylm eth yl-6,7-d id eh yd r o-4,5r-ep oxy-5′-bis-
ter t-bu toxyca r bon yl-(N′-4-ch lor oben zyl)gu a n id in yl-3,14-
d ih yd r oxyin d olo[2′,3′:6,7]m or p h in a n (9f). 1,3-Bis-tert-
butoxycarbonyl-1-(4′-chlorobenzyl-2-methyl-2-thiopseudo-
urea (8b) (0.243 g, 0.59 mmol), 5′-amino-17-cyclopropylmethyl-
6,7-didehydro-4,5R-epoxy-3,14-dihydroxyindolo[2′,3′:6,7]mor-
phinan (6a ) (0.126 g, 0.29 mmol), HgCl2 (0.079 g, 0.29 mmol),
triethylamine (0.059 g, 0.082 mL, 0.59 mmol), and DMF (10
mL) were stirred at 50 °C for 24 h. The solution was
subsequently filtered and sodium bicarbonate (30 mL) added.
The solution was extracted with ethyl acetate and the organic
layer washed successively with water and brine, dried (Na2-
SO4), filtered, and concentrated under reduced pressure to give
the crude product mixture, which was purified by column
chromatography-gradient elution (CH2Cl2) until unreacted 8b
had been removed then [CH3OH/CH2Cl2/NH4OH (10:89:1)],
affording 17-cyclopropylmethyl-6,7-didehydro-4,5R-epoxy-5′-
bis-tert-butoxycarbonyl-(N′-4-chlorobenzyl)guanidinyl-3,14-di-
hydroxyindolo[2′,3′:6,7]morphinan (0.103 g, 0.13 mmol, 44%):
Rf ) 0.47 [CH3OH/CH2Cl2/NH4OH (89:10:1)]; 1H NMR (400
MHz, CDCl3) δ 0.16-0.27 [m, 2H, NCH2CH(CHHCHH)],
0.56-0.68 [m, 2H, NCH2CH(CHHCHH)], 0.88-1.00 [m, 1H,
NCH2CH(CH2CH2)], 1.37 [s, 9H, C(CH3)3], 1.43 [s, 9H, C(CH3)3],
5.60 [s, 1H, C(5)H], 6.55 [d, J ) 8.2 Hz, 1H, C(1)H], 6.59 [d, J
) 8.2 Hz, 1H, C(2)H], 6.70 (s, 1H, C(4′)H], 6.78 [d, J ) 8.6 Hz,
1H, C(6′)H], 7.21 [d, J ) 8.6 Hz, 1H, C(7′)H], and 7.25-7.48
[m, 4H, ArH]; 13C NMR (100.5 MHz, CDCl3) δ 3.4 [NCH2CH-
(CH2CH2)], 3.9 [NCH2CH(CH2CH2)], 9.2 [NCH2CH(CH2CH2)],
22.9 [C(10)], 27.2 [C(CH3)3], 27.6 [C(15)], 27.7 [C(CH3)3], 28.4
[C(8)], 43.5 [C(16)], 47.6 (CH2Ph), 47.9 [quaternary C(13)], 59.1
[C(18)], 61.8 [C(9)], 72.3 [quaternary C(14)], 79.7 [C(CH3)3],
82.6 [C(CH3)3], 84.3 [C(5)], 110.2 (Ar), 111.2 (Ar), 112.0 (Ar),
116.6 (Ar), 118.1 (Ar), 118.4 (Ar), 124.2 (Ar), 126.3 (Ar), 127.8
(Ar), 128.2 (Ar), 129.9 (Ar), 130.1 (Ar), 130.2 (Ar), 130.4 (Ar),
132.8 (Ar), 135.1 (Ar), 135.3 (Ar), 139.0 (Ar), 142.6 (CdO) and
162.7 (CdN); FAB+MS m/z 796 [(M + 1)+, 100%], 696 (20),
and 596 (30); HRMS (FAB) m/z 796.3463 (M + 1)+, C44H51N5O7-
Cl requires 796.3477.
N-ter t-Bu toxyca r bon yl-N-p r op yl-N′-cyclop r op ylm eth -
ylth iou r ea (13d). N-Propyl-N′-cyclopropylmethylthiourea (12d)
(0.41 g, 2.38 mmol) was added to NaH (0.19 g, 60% in oil, 4.75
mmol) in THF (40 mL) at 0 °C and stirred for 10 min. (tert-
Butoxycarbonyl)2O (0.60 g, 2.73 mmol) was added and the
mixture stirred at room temperature for 12 h before addition
of 10% NaOH and stirring for 20 min. The organic layer was
then separated and the aqueous layer further extracted with
EtOAc. The combined organic layers were concentrated and
subsequently treated with hexane, which caused unreacted
starting material to precipitate out. The solid was removed
by filtration and the filtrate subsequently purified by column
chromotography [EtOAc/hexane (1:3)], yielding the N-tert-
butoxycarbonyl-N-propyl,N′-cyclopropylmethylthiourea (0.30 g,
1.09 mmol, 46%): Rf ) 0.66 [EtOAc/hexane (1:3)]; 1H NMR
(400 MHz, CDCl3) δ 0.22-0.49 [m, 4H, NCH2CH(CHHCHH)
and NCH2CH(CHHCHH)], 0.51-0.57 [m, 1H, NCH2CH(CH2-
CH2)], 0.88 (t, J ) 7.4 Hz, 3H, CH3), 1.51 [s, 9H, C(CH3)3],
1.65 [q, J ) 7.4 Hz, 2H, CH2CH3], 3.39-3.60 (m, 2H, NHCH2),
4.16-4.30 (m, 2H, CONCH2), and 10.86 (br s, 1H, NH); 13C
NMR (100.5 MHz, CDCl3) δ 4.0 [NCH2CH(CH2CH2)], 4.1
[NCH2CH(CH2CH2)], 11.0 [NCH2CH(CH2CH2)], 11.7 (CH3),
17-Cyclopr opylm eth yl-6,7-dideh yd r o-4,5r-ep oxy-5′-(N′-
4-c h lo r o b e n z y l)g u a n i d i n y l-3,14-d i h y d r o x y i n d o lo -
[2′,3′:6,7]m or p h in a n (10f). 17-Cyclopropylmethyl-6,7-dide-
hydro-4,5R-epoxy-5′-bis-tert-butoxycarbonyl-(N′-4-chloro-
benzyl)guanidinyl-3,14-dihydroxyindolo[2′,3′:6,7]morphinan (9f)
(0.100 g, 0.13 mmol) was dissolved in dichloromethane (4 mL)