Triazolopyridazines 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
[1721] N-[3-[2-(6-ethoxy-3-imino-[1,2,4]triazolo[4,3-b]pyridazin-2-yl)acetyl]-5- (Pentafluorothio)phenyl]acetamide (which is the trifluoroacetate salt)
[1722]
[1723] a) 3-nitro-5-pentafluorothiobenzoic acid
[1724]
[1725]3-Pentafluorothiobenzoic acid (5.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at room temperature with the removal of moisture. Concentrated sulfuric acid (3ml) was then added, and the mixture was stirred at 75°C. After stirring at 75°C for 5 hours, sulfuric acid (1.5 ml) was added, and after stirring at 75°C for 2 hours, the mixture was allowed 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 is extracted 3 times with dichloromethane, the combined dichloromethane phases are dried over magnesium sulfate and the solvent is concentrate...
Embodiment 2
[1755] 2-(6-Chloro-3-imino-[1,2,4]triazolo[4,3-b]pyridazin-2-yl)-1-(3,5-di-tert-butyl-4 -Hydroxyphenyl)ethanone
[1756]
[1757] 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.001a; 30mg) was first added to DMF (3.5ml) at room temperature with stirring , 2-Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone (01.002; 58 mg) predissolved in DMF (0.5 ml) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then heated to 60 °C for 5 hours. After standing overnight, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (met. A). The pure product fractions were combined, acetonitrile removed under reduced pressure and lyophilized. 28 mg of the title compound were obtained. LC-MS rt: 1.28 min, [M+H] + : 416.1 (met.a).
[1758] Analogously to Example 2, the following compounds were obtained:
[1759]
Embodiment 5
[1761] 2-(6-ethoxy-3-imino-[1,2,4]triazolo[4,3-b]pyridazin-2-yl)-1-(4-methoxy-3- (Morpholin-4-yl)-5-trifluoromethylphenyl)ethanone trifluoroacetate
[1762]
[1763]6-Ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.001; 10mg) was first added to DMF (3.5ml ), add dropwise 2-bromo-1-(4-methoxy-3-(morpholin-4-yl)-5-trifluoromethylphenyl)ethanone dissolved in DMF (1.5ml) in advance (01.004; 21 mg). The reaction mixture was stirred at room temperature for 2 hours. After standing overnight, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (met. A). The pure product fractions were combined, acetonitrile removed under reduced pressure and lyophilized. The title compound (which was contaminated with the 1-substituted product) was purified using silica gel (dichloromethane / methanol gradient). The pure product fractions were dried, taken up in a small amount of acetonitrile / water + 0.05% TFA and lyophilized. 7 mg of the title c...
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