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3.74 (9H, m), 3.62 (3H, s), 5.64, 5.69 (each 0.5H, s), 7.20—7.42 (11H, m),
an amorphous. With 4 N hydrogen chloride in ethyl acetate, 6e was obtained
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8.06 (1H, d, Jϭ9.0 Hz), 8.37 (1H, s), 10.88 (1H, br s). IR (KBr) cmϪ1: 3300, as an amorphous (from diethyl ether). H-NMR (DMSO-d6) d: 1.16 (3H, t,
2930, 2650, 1740. Anal. Calcd for C32H40N4O3SCl2·H2O: C, 59.16; H, 6.52; Jϭ7.0 Hz), 1.63 (6H, s), 1.85—2.25 (6H, m), 2.80—3.10 (4H, m), 3.30—
N, 8.62. Found: C, 58.92; H, 6.76; N, 8.86.
6-[[4-[4-(Diphenylmethoxy)piperidino]butyl]amino][1,2,4]triazolo- (0.5H, s), 5.68 (0.5H, s), 7.20—7.40 (10H, m), 7.58—7.63 (1H, m), 8.03
[1,5-b]pyridazine (5g) To a solution of 3f (1.83 g, 5.41 mmol) and 1a
(1H, d, Jϭ10.5 Hz), 8.25 (1H, s), 10.97 (1H, br s). IR (KBr) cmϪ1: 3400,
(0.557 g, 3.60 mmol) in 1-butanol (30 ml) was added N-ethyldiisopropyl- 2930, 2640, 1730, 1600, 1510. Anal. Calcd for C34H45N5O3Cl2·H2O: C,
3.70 (5H, m), 3.09 (1.5H, s), 3.11 (1.5H, s), 4.11 (2H, q, Jϭ7.0 Hz), 5.63
amine (0.931 g, 7.20 mmol), and the mixture was refluxed for 14 h. After
cooling and evaporation of the solvent, the reaction mixture was diluted with
61.81; H, 7.17; N, 10.60. Found: C, 61.92; H, 7.47; N, 10.29.
Ethyl 1-[6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino]imi-
ice-cold water and extracted with ethyl acetate. The combined organic layer dazo[1,2-b]pyridazin-2-yl]cyclopropane-1-carboxylate Dihydrochloride
was washed with brine, dried, and concentrated. The residue was purified by (6i) From 3a and 2a was prepared the free base of 6i (50% yield) as an oil.
column chromatography on silica gel eluted with ethyl acetate–methanol– With 4 N hydrogen chloride in ethyl acetate, 6i was obtained as crystals, mp
triethylamine (45 : 5 : 1), and the desired fractions were concentrated. The re- 196—199 °C (from ethyl acetate). 1H-NMR (CDCl3) d: 1.28 (3H, t,
sulting crystals were collected, washed with diethyl ether, and dried to give Jϭ7.0 Hz), 1.72—2.46 (10H, m), 3.06—3.24 (4H, m), 3.40—3.56 (4H, m),
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0.149 g of 5g (36% yield), mp 102—104 °C. H-NMR (CDCl3) d: 1.63—
3.84—3.90 (1H, m), 4.22 (2H, q, Jϭ7.0 Hz), 5.44 (1H, s), 7.22—7.42 (11H,
2.06 (8H, m), 2.14—2.31 (2H, m), 2.41 (2H, t, Jϭ6.6 Hz), 2.74—2.88 (2H, m), 7.85 (1H, s), 8.05 (1H, br s), 8.07 (1H, d, Jϭ10.0 Hz), 11.34 (1H, br s).
m), 3.48—3.36 (2H, m), 3.40—3.60 (1H, m), 5.52 (1H, s), 6.07 (1H, br s), IR (KBr) cmϪ1: 3210, 3060, 2940, 2650, 1720, 1610, 1510. Anal. Calcd for
6.71 (1H, d, Jϭ9.6 Hz), 7.23—7.34 (10H, m), 7.71 (1H, d, Jϭ9.6 Hz), 8.16 C33H41N5O3Cl2·0.5H2O: C, 62.36; H, 6.66; N, 11.02. Found: C, 62.48; H,
(1H, s). IR (KBr) cmϪ1: 3290, 2940, 1630, 1590, 1500, 1450. Anal. Calcd 6.49; N, 11.18.
for C27H32N6O: C, 71.03; H, 7.06; N, 18.41. Found: C, 70.78; H, 6.77; N,
18.40.
Ethyl 1-[6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino]imi-
dazo[1,2-b]pyridazin-2-yl]cyclopentane-1-carboxylate Dihydrochloride
The following compounds, 5j, 5l and 5n, were prepared with a similar (6j) From 3a and 2b was prepared the free base of 6j (43% yield) as an oil.
procedure described for the preparation of 5g.
With 4 N hydrogen chloride in ethyl acetate, 6j was obtained as an amor-
6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino]-2-methyl[1,2,4]- phous (from diethyl ether). 1H-NMR (DMSO-d6) d: 1.15 (3H, t, Jϭ7.1 Hz),
triazolo[1,5-b]pyridazine (5j) From 3a and 1c was prepared 5j (59% 1.60—2.50 (10H, m), 2.80—3.76 (13H, m), 4.11 (2H, q, Jϭ7.1 Hz), 5.65
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yield) as crystals, mp 119—120 °C (from ethyl acetate–hexane). H-NMR (0.5H, s), 5.70 (0.5H, s), 7.19—7.44 (11H, m), 7.94 (0.5H, d, Jϭ9.4 Hz),
(CDCl3) d: 1.55—2.22 (8H, m), 2.51—2.56 (2H, m), 2.54 (3H, s), 2.80— 7.95 (0.5H, d, Jϭ10.0 Hz), 8.06 (1H, br s), 8.28 (0.5H, s), 8.29 (0.5H, s),
2.92 (2H, m), 3.42—3.52 (3H, m), 5.54 (1H, s), 6.59 (1H, d, Jϭ9.6 Hz), 10.75 (1H, br s). IR (KBr) cmϪ1: 3230, 3060, 2940, 2640, 1730, 1610, 1510.
6.99 (1H, br s), 7.26—7.36 (10H, m), 7.60 (1H, d, Jϭ9.6 Hz). IR (KBr) Anal. Calcd for C35H45N5O3Cl2·H2O: C, 62.49; H, 7.04; N, 10.41. Found: C,
cmϪ1: 3290, 2940, 1630, 1590, 1490, 1450. Anal. Calcd for C27H32N6O: C, 62.65; H, 7.22; N, 10.69.
71.03; H, 7.06; N, 18.41. Found: C, 70.91; H, 6.95; N, 18.18.
Ethyl 2-[6-[[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]amino]imi-
2-tert-Butyl-6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]-
dazo[1,2-b]pyridazin-2-yl]-2-methylpropionate Trihydrochloride (6f)
[1,2,4]triazolo[1,5-b]pyridazine Fumarate (5l) From 3a and 1d was pre- A mixture of 3b (1.31 g, 4.23 mmol) and 2d (0.567 g, 2.12 mmol) was stirred
pared the free base of 5l (43% yield). With fumaric acid, 5l was obtained as at 185 °C for 3 h. After cooling, the reaction mixture was diluted with an
an amorphous. 1H-NMR (CDCl3) d: 1.45 (9H, s), 1.92—2.25 (6H, m), aqueous solution of sodium hydrogen carbonate and extracted with ethyl ac-
3.00—3.40 (6H, m), 3.50—3.58 (2H, m), 3.74—3.84 (1H, m), 5.43 (1H, s),
etate. The organic layer was washed with brine, dried, and concentrated. The
residue was purified by column chromatography on silica gel eluted with
6.81 (2H, s), 6.90 (1H, d, Jϭ9.4 Hz), 7.25—7.32 (10H, m), 7.71 (1H, d,
Jϭ9.4 Hz). IR (KBr) cmϪ1: 3260, 2960, 1680, 1580, 1500. Anal. Calcd for ethyl acetate–methanol–triethylamine (50 : 5 : 1), and the desired fractions
C34H42N6O5·H2O·0.5Et2O: C, 64.55; H, 7.37; N, 12.55. Found: C, 64.79; H,
7.76; N, 12.44.
Methyl 6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino][1,2,4]-
were concentrated. The free base of 6f (1.07 mmol, 50% yield) was dis-
solved in ethanol, and addition of 4 N hydrogen chloride in ethyl acetate
(0.80 ml, 3.21 mmol) to the solution was followed by concentration. The
triazolo[1,5-b]pyridazine-2-carboxylate (5n) From 3a and 1e (in N,N-di- residue was crystallized from ethanol, washed with ethanol–ethyl acetate,
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methylformamide, at 80 °C) was prepared 5n (75% yield) as crystals, mp and dried to give 0.502 g of 6f, mp 190—193 °C. H-NMR (DMSO-d6) d:
93—96 °C (from ethanol–ethyl acetate). 1H-NMR (CDCl3) d: 1.64—1.86
1.18 (3H, t, Jϭ7.1 Hz), 1.63 (6H, s), 2.00—2.18 (2H, m), 2.80—3.80 (13H,
(4H, m), 1.92—2.06 (2H, m), 2.08—2.26 (2H, m), 2.56 (2H, t, Jϭ5.5 Hz), m), 4.13 (2H, q, Jϭ7.1 Hz), 5.02 (1H, br s), 7.24—7.41 (8H, m), 7.60—7.76
2.82—2.94 (2H, m), 3.42—3.56 (3H, m), 4.03 (3H, s), 5.54 (1H, s), 6.71 (5H, m), 7.98 (1H, d, Jϭ9.6 Hz), 8.09 (1H, br s), 8.23 (1H, s). IR (KBr)
(1H, d, Jϭ9.6 Hz), 7.22—7.38 (10H, m), 7.64 (1H, br s), 7.72 (1H, d, cmϪ1: 3460, 3250, 2980, 2500, 1730, 1610, 1510. Anal. Calcd for
Jϭ9.6 Hz). IR (KBr) cmϪ1: 2950, 1740. Anal. Calcd for C28H32N6O3· C32H43N6O2Cl3·H2O: C, 57.50; H, 6.79; N, 12.58. Found: C, 57.27; H, 6.52;
0.5H2O: C, 65.99; H, 6.53; N, 16.49. Found: C, 65.69; H, 6.28; N, 16.58.
Ethyl 2-[6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino]imi-
N, 12.55.
The following compounds, 6g, 6h, 6k, 6l and 6m, were prepared with a
dazo[1,2-b]pyridazin-2-yl]-2-methylpropionate Difumarate (6a) A so- similar procedure described for the preparation of 6f.
lution of 3a (6.49 g, 20.0 mmol) and 2d (2.68 g, 10.0 mmol) in N-methyl-2-
Ethyl 2-[6-[[3-[4-[Bis(4-fluorophenyl)methoxy]piperidino]propyl]-
pyrrolidinone (13.4 ml) was stirred at 191—195 °C under nitrogen gas for amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate Difumarate
4.5 h. After cooling, the reaction mixture was diluted with aqueous solution (6g) From 3c and 2d was prepared the free base of 6g (43% yield) as an
of sodium hydrogen carbonate and extracted with ethyl acetate. The com- oil. With fumaric acid, 6g was obtained as crystals, mp 159—161 °C (from
bined organic layer was washed with water and concentrated. The residue acetone). 1H-NMR (DMSO-d6) d: 1.11 (3H, t, Jϭ7.1 Hz), 1.50 (6H, s),
was purified by column chromatography on silica gel eluted with ethyl ac- 1.56—2.00 (6H, m), 2.38—2.70 (4H, m), 2.82—3.00 (2H, m), 3.14—3.30
etate–methanol–triethylamine (100 : 5 : 1), and the desired fractions were (2H, m), 3.36—3.50 (1H, m), 4.02 (2H, q, Jϭ7.1 Hz), 5.69 (1H, s), 6.59
concentrated to give the free base of 5.14 g of 6a (65% yield). The free base (1H, d, Jϭ9.7 Hz), 6.60 (4H, s), 6.96 (1H, br s), 7.12—7.21 (4H, m), 7.36—
of 6a (5.14 g, 9.22 mmol) and fumaric acid (2.15 g, 18.5 mmol) was dis- 7.43 (4H, m), 7.61 (1H, d, Jϭ9.7 Hz), 7.65 (1H, s). IR (KBr) cmϪ1: 3350,
solved in ethanol, and the solvent was evaporated. The residue was crystal- 2920, 2500, 1870, 1740, 1590, 1580, 1500. Anal. Calcd for C41H47N5O11F2·
lized from acetone, followed by drying to give 5.69 g of 6a, mp 126—
128 °C. 1H-NMR (DMSO-d6) d: 1.12 (3H, t, Jϭ7.1 Hz), 1.51 (6H, s),
1.65—2.04 (6H, m), 2.54—2.82 (4H, m), 2.94—3.08 (2H, m), 3.16—3.28
0.5H2O: C, 59.13; H, 5.81; N, 8.41. Found: C, 58.94; H, 5.84; N, 8.34.
Ethyl 2-[6-[[3-[4-(Hydroxydiphenylmethyl)piperidino]propyl]amino]-
imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate Dihydrochloride (6h)
(2H, m), 3.44—3.58 (1H, m), 4.03 (2H, q, Jϭ7.1 Hz), 5.64 (1H, s), 6.60 From 3d and 2d was prepared (at 160 °C) the free base of 6h (51% yield).
(4H, s), 6.58 (1H, d, Jϭ9.7 Hz), 6.98 (1H, br s), 7.19—7.42 (10H, m), 7.59
With 4 N hydrogen chloride in ethyl acetate, 6h was obtained as an amor-
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(1H, d, Jϭ9.7 Hz), 7.62 (1H, s). IR (KBr) cmϪ1: 3240, 2960, 2880, 2650, phous: H-NMR (CDCl3) d: 1.24 (3H, t, Jϭ7.0 Hz), 1.76 (6H, s), 2.05—
1730, 1570, 1490. Anal. Calcd for C41H49N5O11: C, 62.50; H, 6.27; N, 8.89. 3.90 (15H, m), 4.20 (2H, q, Jϭ7.0 Hz), 7.05—8.35 (13H, m), 10.80 (1H,
Found: C, 62.28; H, 6.15; N, 8.97.
The following compounds, 6e, 6i and 6j, were prepared with a similar C33H43N5O3Cl2·H2O·Et2O: C, 61.49; H, 7.37; N, 10.24. Found: C, 61.47; H,
br s). IR (KBr) cmϪ1: 3220, 2900, 1730, 1610, 1510. Anal. Calcd for
procedure described for the preparation of 6a.
7.36; N, 9.87.
Ethyl 2-[6-[N-[3-[4-(Diphenylmethoxy)piperidino]propyl]methyl-
amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate Dihydrochlo-
ride (6e) From 3e and 2d was prepared the free base of 6e (53% yield) as 6k (66% yield) as crystals, mp 105—108 °C (from diethyl ether). H-NMR
2-[6-[[3-[4-(Diphenylmethoxy)piperidino]propyl]amino]imidazo[1,2-
b]pyridazin-2-yl]-2-methylpropanol (6k) From 3a and 2e was prepared
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