Journal of Medicinal Chemistry
ARTICLE
7.81 (m, 5H), 7.50 (m, 3H), 7.24 (m, 4H), 7.06 (d, 1H, J = 6.9 Hz), 3.44
(d, 1H, J = 11.4 Hz), 3.14 (m, 3H), 2.90 (m, 1H), 2.74 (d, 1H, J = 16.5
Hz), 2.53 (m, 3H), 1.61 (m, 2H), 0.97 (t, 3H, J = 7.2, 7.5 Hz). 13C NMR
(100 MHz, CDCl3): δ 147.1, 138.6, 134.0, 133.6, 131.8, 130.6, 128.7,
128.2, 127.7, 126.4, 126.1, 125.9, 125.7, 124.8, 122.4, 59.2, 56.5, 48.8,
34.9, 29.2, 19.5, 12.1. MS (ESI, [M þ H]þ): m/z 449. HRMS (ESI)
calcd for C30H29N2O2 449.2229, found 449.2226.
171.6, 147.1, 138.6, 135.8, 133.6, 130.6, 128.1, 127.7, 127.3, 125.9, 124.6,
122.0, 59.1, 56.4, 56.2, 48.7, 40.1, 38.4, 34.9, 34.5, 34.3, 29.2, 28.7, 24.3,
19.5, 12.0.
(6RR,30L)-(ꢀ)-11-[5-(1,2-Dithiolan-3-yl)pentyloxy]-N-n-propylnor-
aporphine (ꢀ)-15L. White oil (36 mg, 70%). [R]20 ꢀ32.0° (c 0.08,
D
DMSO). 1H NMR (300 MHz, CDC13): δ 7.72 (d, 1H, J = 7.8 Hz), 7.19
(m, 3H), 7.06 (d, 1H, J = 7.8 Hz), 7.00 (d, 1H, J = 8.1 Hz), 3.55 (m, 1H),
3.42 (dd, 1H, J = 13.5, 3.0 Hz), 3.06ꢀ3.21 (m, 5H), 2.90 (m, 1H), 2.75
(d, 1H, J = 15.9 Hz), 2.39ꢀ2.61 (m, 6H), 1.89 (m, 1H), 1.70 (m, 6H),
1.49 (m, 2H), 0.97 (t, 3H, J = 7.2, 7.5 Hz). 13C NMR (100 MHz,
CDC13): δ 171.6, 147.1, 138.6, 135.8, 133.6, 130.6, 128.1, 127.7, 127.3,
125.9, 124.6, 122.0, 59.1, 56.4, 56.2, 48.7, 40.1, 38.4, 34.9, 34.5, 34.3,
29.2, 28.7, 24.3, 19.5, 12.0.
(6RR,S)-N-n-Propylnoraporphin-11-yl Benzylcarbamate (()-13.
1
White oil (22 mg, 50%). H NMR (300 MHz, CDC13): δ 7.71 (d,
1H, J = 7.5 Hz), 7.32 (m, 4H), 7.22 (d, 1H, J = 7.5 Hz), 7.17 (m, 5H),
5.41 (s, 1H), 4.40 (d, 2H, J = 5.7 Hz), 3.44 (dd, 1H, J = 2.1, 13.5 Hz),
3.16 (m, 3H), 2.91 (m, 1H), 2.76 (d, 1H, J = 15.6 Hz), 2.53 (m, 3H),
1.61 (m, 2H), 0.97 (t, 3H, J = 7.2, 7.5 Hz). 13C NMR (100 MHz,
CDCl3): δ 154.3, 147.4, 138.4, 138.0, 135.7, 133.5, 130.7, 128.7, 128.1,
127.7, 127.6, 127.5, 127.3, 126.1, 125.7, 124.8, 122.4, 59.1, 56.5, 48.8,
45.2, 34.9, 29.2, 19.4, 12.1. MS (ESI, [Mþ]): m/z 412. HRMS (ESI)
calcd for C27H28N2O2 412.2150, found 412.2150.
(6RR)-11-Amino-N-n-propylnoraporphine (ꢀ)-17. To a solution of
triflate (ꢀ)-1646 (0.102 g, 0.25 mmol) in THF (10 mL) were added
Pd(OAc)2 (20 mg), rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (25
mg), benzophenone imine (69 μL, 0.37 mmol), Cs2CO3 (122 mg), and
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (20 mg)
under N2. The mixture was heated to 65ꢀ70 °C with stirring overnight.
The solvent was removed. The residue was diluted with CH2Cl2
(25 mL), washed with brine (15 mL), dried, and concentrated. The
crude product was purified by column chromatography (3:1 petroleum/
ethyl acetate, 1% of Et3N) to yield crude imine. To a solution of the
6RR-(ꢀ) isomer (ꢀ)-13. White oil (25 mg, 55%). [R]20 ꢀ36.5°
D
(c 2.00, CHCl3).
N-n-Propylnoraporphin-11-yl Carboxylic Esters (()-14, (()-15,
(ꢀ)-15, (ꢀ)-15D, and (ꢀ)-15L. To a solution of 11-hydroxy-N-n-
propylnoraporphine (ꢀ)-6 or (()-6 (30 mg, 0.11 mmol), an appropriate
acid (0.13 mmol), and a catalytic amount of DMAP in anhydrous CH2Cl2
(8 mL) under N2 was added EDCI (42 mg, 0.22 mmol) at room
temperature. The reaction mixture was stirred overnight and then diluted
with CH2Cl2 (20 mL) and H2O (15 mL). The organic layer was
separated, washed with brine (15 mL), dried over anhydrous Na2SO4,
and evaporated. The residue was purified by silica gel chromatography
(4:1 petroleum/ethyl acetate, 1% Et3N) to give a pure oily product, which
was then converted into the hydrochloride salt with HCl ether (1 M).
(6RR,S)-11-[2-(Phenylthio)acetyloxy]-N-n-propylnoraporphine
(()-14. Yellow oil (21 mg, 53%). 1H NMR (300 MHz, CDC13): δ 7.68
(d, 1H, J = 7.5 Hz), 7.43 (m, 2H), 7.23 (m, 5H), 7.08 (m, 2H), 6.92 (m,
1H), 3.89 (d, 1H, J = 15.3 Hz), 3.81 (d, 1H, J = 15.3 Hz), 3.41 (dd, 1H,
J = 3.3, 13.2 Hz), 3.12 (m, 3H), 2.90 (m, 1H), 2.76 (d, 1H, J = 15.6 Hz),
2.51 (m, 3H), 1.62 (m, 2H), 0.97 (t, 3H, J = 7.2, 7.5 Hz). 13C NMR (100
MHz, CDC13): δ 167.9, 147.1, 138.7, 135.8, 134.6, 133.7, 130.3, 130.2,
129.1, 128.3, 127.7, 127.3, 127.2, 126. 2, 124.8, 121.7, 59.2, 56.5, 48.8,
37.1, 34.9, 29.3, 19.5, 12.0. MS (ESI, [Mþ]): m/z 429. HRMS (ESI)
calcd for C27H27NSO2 429.1762, found 429.1761.
crude imine in 10 mL of methanol were added NH2OH HCl (35 mg,
3
0.50 mmol) and anhydrous NaOAc (61 mg, 0.75 mmol). The mixture
was stirred overnight at room temperature. The solvent was removed.
The residue was diluted with a 0.1 M NaOH solution (10 mL) and
extracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic layer was
washed with brine (20 mL) and dried over anhydrous Na2SO4, and the
solvent was evaporated. The residue was purified by column chroma-
tography eluting with a 3:1 petroleum/ethyl acetate mixture (with 1%
Et3N) to give amine (ꢀ)-17 as yellow oil (31 mg, 46% for two steps).
1
[R]20 ꢀ142.0° (c 0.75, CHCl3). ee 99.93%. H NMR (300 MHz,
D
CDC13): δ 7.89 (d, 1H, J = 7.8 Hz), 7.23 (t, 1H, J = 8.1 Hz), 7.04 (t, 2H,
J = 7.8, 9.3 Hz), 6.71 (dd, 2H, J = 7.5, 10.8 Hz), 4.06 (s, 2H), 3.33 (dd,
1H, J = 2.1, 11.1 Hz), 3.18 (m, 3H), 2.91 (m, 1H), 2.77 (d, 1H, J = 17.1
Hz), 2.48 (m, 3H), 1.62 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): δ 143.2, 138.0, 136.0, 133.9, 132.7, 127.9, 127.1,
126.0, 123.0, 120.3, 118.5, 115.8, 59.8, 56.6, 48.9, 35.5, 29.3, 19.6, 12.1.
MS (ESI, [Mþ]): m/z 278. HRMS (ESI) calcd for C19H22N2 278.1783,
found 278.1774.
(6RR,S)-11-[5-(1,2-Dithiolan-3-yl)pentyloxy]-N-n-propylnorapor-
phine (()-15. White oil (40 mg, 78%). 1H NMR: δ 7.73 (d, 1H, J = 7.5
Hz), 7.20 (m, 3H), 7.07 (d, 1H, J = 7.5 Hz), 7.01 (d, 1H, J = 7.8 Hz), 3.54
(m, 1H), 3.43 (dd, 1H, J = 13.8, 2.7 Hz), 3.07ꢀ3.20 (m, 5H), 2.89 (m,
1H), 2.75 (d, 1H, J = 16.5 Hz), 2.38ꢀ2.62 (m, 6H), 1.89 (m, 1H), 1.69
(m, 6H), 1.49 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz).
(6RR)-(ꢀ)-N-n-Propylnoraporphin-11-yl Carboxamides (ꢀ)-18
and (ꢀ)-19. To a solution of 11-amino-N-n-propylnoraporphine (ꢀ)-
17 (29 mg, 0.1 mmol), an appropriate acid (0.12 mmol), and a catalytic
amount of DMAP in anhydrous CH2Cl2 (8 mL) under N2 was added
EDCI (38 mg, 0.2 mmol) at room temperature. The reaction mixture
was stirred overnight and then diluted with CH2Cl2 (20 mL) and H2O
(10 mL). The organic layer was separated, washed with brine (10 mL),
dried over anhydrous Na2SO4, and evaporated. The residue was purified
by silica gel chromatography (2:1 petroleum/ethyl acetate, 1% of Et3N)
to give pure oily products (ꢀ)-18 and (ꢀ)-19.
6RR isomer (ꢀ)-15. White oil (35 mg, 70%). [R]20D ꢀ140.2° (c 0.85,
1
CHCl3). H NMR (600 MHz, CDC13): δ 7.71 (d, 1H, J = 7.8 Hz),
7.14ꢀ7.24 (m, 3H), 7.06 (d, 1H, J = 7.2 Hz), 6.99 (d, 1H, J = 7.8 Hz),
3.53 (m, 1H), 3.42 (d, 1H, J = 13.2 Hz), 3.06ꢀ3.18 (m, 5H), 2.89 (m,
1H), 2.74 (d, 1H, J = 16.2 Hz), 2.38ꢀ2.62 (m, 6H), 1.87 (m, 1H),
1.54ꢀ1.76 (m, 6H), 1.39ꢀ1.53 (m, 2H), 0.96 (t, 3H, J = 7.2 Hz). 13C
NMR (100 MHz, CDC13): δ 171.6, 147.1, 138.6, 135.8, 133.6, 130.6,
128.1, 127.7, 127.3, 125.9, 124.6, 122.0, 59.1, 56.4, 56.2, 48.7, 40.1, 38.4,
34.9, 34.5, 34.3, 29.2, 28.7, 24.3, 19.5, 12.0. MS (ESI): m/z 467 (Mþ).
Anal. Calcd for C24H33NO2S2 0.9HCl 0.1H2O: C, 64.33; H, 6.86; N,
(6RR)-N-n-Propylnoraporphin-11-yl Butyramide (ꢀ)-18. Yellow oil
(20 mg, 56%). [R]20 ꢀ50.2° (c 0.95, CHCl3). 1H NMR (300 MHz,
D
CDC13): δ 8.08 (d, 1H, J = 8.4 Hz), 7.56 (d, 2H, J = 7.8 Hz), 7.21 (d, 1H,
J = 8.4 Hz), 7.09 (t, 2H, J = 7.5, 7.8 Hz), 3.26 (dd, 1H, J = 3.0, 13.2 Hz),
3.14 (m, 3H), 2.91 (m, 1H), 2.77 (d, 1H, J = 16.2 Hz), 2.48 (m, 3H),
2.32 (m, 2H), 1.75 (m, 2H), 1.60 (m, 2H), 0.98 (m, 6H). 13C NMR (100
MHz, CDCl3): δ 171.1, 137.7, 136.9, 134.6, 133.5, 131.3, 128.1, 127.8,
126.1, 125.3, 124.3, 123.6, 122.1, 59.6, 56.5, 48.7, 39.8, 35.4, 29.3, 19.6,
18.9, 13.8, 12.0. MS (ESI, [Mþ]): m/z 348. HRMS calcd for
C23H28ON2 348.2202, found 348.2194.
3
3
2.78. Found: C, 64.36; H, 6.86; N, 2.60. Mp: 172ꢀ174 °C (HCl salt).
(6RR,30D)-(ꢀ)-11-[5-(1,2-Dithiolan-3-yl)pentyloxy]-N-n-propylnor-
aporphine (ꢀ)-15D. White oil (38 mg, 74%). [R]20D ꢀ18.0° (c 0.07,
DMSO). 1H NMR (300 MHz, CDC13): δ 7.73 (d, 1H, J = 7.8 Hz), 7.19
(m, 3H), 7.07 (d, 1H, J = 7.5 Hz), 7.00 (d, 1H, J = 7.5 Hz), 3.53 (m, 1H),
3.44 (d, 1H, J = 12.3 Hz), 3.05ꢀ3.21 (m, 5H), 2.91 (m, 1H), 2.75 (d, 1H,
J = 16.2 Hz), 2.38ꢀ2.65 (m, 6H), 1.89 (m, 1H), 1.70 (m, 6H), 1.48 (m,
2H), 0.97 (t, 3H, J = 7.2, 7.5 Hz). 13C NMR (100 MHz, CDC13): δ
(6RR)-5-(1,2-Dithiolan-3-yl)-N-(N-n-propylnoraporphin-11-yl)
pentanamide (ꢀ)-19. Yellow oil (17 mg, 37%). [R]20 ꢀ14.6°
D
(c 0.70, CHCl3). 1H NMR (300 MHz, CDC13): δ 8.07 (d, 1H,
4333
dx.doi.org/10.1021/jm200347t |J. Med. Chem. 2011, 54, 4324–4338