Imidazopyridazines as PAR1 inhibitors, production thereof, and use as medicaments
The technology of a kind of compound, mixture, is applied in new formula I compound: field
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Embodiment 1
[0191] N-{3-[2-(2,3-diethoxy-7-iminoimidazo[1,5-b]pyridazin-6-yl)acetyl]-5-pentafluorosulfanylphenyl }acetamide (which is trifluoroacetate)
[0192]
[0193] a) 3-nitro-5-pentafluorothiobenzoic acid
[0194]
[0195] 3-Pentafluorothiobenzoic acid (5.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at room temperature with dehumidification. Concentrated sulfuric acid (3ml) was then added, and the mixture was stirred at 75°C. After stirring at 75°C for 5 hours, additional sulfuric acid (1.5 ml) was added, and after stirring at 75°C for 2 hours, it was left to stand overnight. The mixture was then added to ice water and stirred for 2 hours. The precipitate formed was filtered off with suction and dried under high vacuum. 4.2 g of 3-pentafluorothio-5-nitrobenzoic acid are obtained. The mother liquor was extracted three times with dichloromethane, the combined dichloromethane phases were dried over magnesium sulfate and the solvent was concentrated, thus obtai...
Embodiment 2
[0231] 1-(3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl)-2-(7-imino-2,3-dimethoxyimidazo[1, 5-b]pyridazin-6-yl)ethanone (which is the trifluoroacetate salt)
[0232]
[0233] a) 3,4-dimethoxy-6-methylpyridazine-1-oxide
[0234] 3-Methoxy-6-methyl-4-nitropyridazine-1-oxide (1 g) was converted and worked up analogously to Example 1 g). No chromatographic separation of the crude product was necessary. The solvent used was methanol (30 ml), and the base used was sodium methoxide (30% strength in methanol, 1.1 ml). Yield: 900 mg. LC-MS Rt: 0.29 min, [M+H] + : 171.1.
[0235] b) ((5,6-dimethoxypyridazin-3-yl) methyl) methanesulfonate
[0236]
[0237] 3,4-Dimethoxy-6-methylpyridazine-1-oxide (880 mg) was converted into the title compound similarly to the sequence of Examples 1h) to 1i). Yield: 690 mg. LC-MS Rt: 0.71 min, [M+H] + : 249.0.
[0238] c) C-(5,6-dimethoxypyridazin-3-yl)methylamine trifluoroacetate
[0239]
[0240] ((5,6-dimethoxypyridazin-3-yl)methy...
Embodiment 3
[0247] 1-(3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl)-2-(2,3-diethoxy-7-iminoimidazo[1, 5-b]pyridazin-6-yl)ethanone (which is the trifluoroacetate salt)
[0248]
[0249] Similar to Example 1l), 2,3-diethoxyimidazo[1,5-b]pyridazin-7-ylamine trifluoroacetate [Example 1k), 15 mg] and 2-bromo- 1-(3-tert-Butyl-4-methoxy-5-(morpholin-4-yl)phenyl)ethanone (27 mg; prepared as described in WO 2004 / 078721 ) were reacted with each other, followed by processed and purified. 27 mg of the title compound were obtained. LC-MS Rt: 1.38 min, [M+H] + : 512.3.
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