Methods of treating factor VIIa-associated conditions with compounds having an amine nucleus
a technology of compound and nucleus, which is applied in the direction of biocide, drug composition, cardiovascular disorder, etc., can solve the problems of inability to carry out normal function, so as to achieve the effect of inhibiting the activity of factor viia
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example 1
Part J. Example 1
[0233] To a solution of compound 1D (0.180 g, 0.50 mmol) in 2 mL of dioxane was added compound 1I (220 mg of crude mixture, 1 mmol) followed by triphenylphosphine (0.140 g, 0.53 mmol). The reaction mixture was placed in an oil bath preheated to 80° C. and stirred for 2 hour, then cooled to rt and the solvent was evaporated. The residue was treated for 1 h at rt with a 1:1 mixture of TFA and DCM, and the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL), loaded onto an SCX cartridge (CUBX1HL, 500 mg cartridge, United Chemical Technologies, Bristol Pa., USA) which was washed with MeOH (3 mL). The title compound was eluted from the cartridge with a 2.0 M solution of ammonia in MeOH (3 mL) and purified by preparative reverse phase HPLC to yield 0.070 g of an orange oil. (LC / MS retention time=2.93 min.; MH+=435, Column: Phenominex 4.6 mm×50 mm, Solvent A=10% MeOH, 90% H2O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H2O, 10 mM NH4Ac, Flow...
examples 2-29
[0234]
[0235] Compounds having the above formula, wherein the group R has the values listed in Table 1, were prepared following the procedure set forth above for Example 1, using appropriately-substituted aryl or heteroaryl amine in place of 5-(4-Amino-2-methoxyphenyl)oxazole 1H.
TABLE 1HPLCtimeHPLCEx.R(min)MethodMH+22.57c387.333.11c429.343.17c443.3252.61c404.2963.26b443.2373.02b438.1582.68b405.2192.44b405.21102.75b420.21112.67b404.21123.02b387.21132.7b408.18141.93b377.16152.08b403.22162.92b444.19173.21a453.81183.11a431.98192.86a433.95203.12a418213.12a418222.65a403.02232.88a417.03242.79a415.01252.68b421.23262.99b495.18272.05b377.2283.12b471.2291.87b393.17
HPLC Conditions for Table 1:
a Column: Phenominex 4.6 × 5.0 mm. Solvent A = 10% MeOH, 90% H2O, 10 mM NH4Ac; Solvent B = 90% MeOH, 10% H2O, 10 mM NH4Ac. Flow rate: 4 mL / min. Gradient: 4 min 0% B-100% B.
b Column: Phenominex ODS 4.6 × 5.0 mm. Solvent A = 10% MeOH, 90% H2O, 0.1% TFA; Solvent B = 90% MeOH, 10% H2O, 0.1% TFA: Flow rate: ...
examples 30-48
[0236] Compounds having the formulae set forth in Table 2, were prepared following the same or similar procedures to those set forth above for Examples 1-29, and / or in the general schemes previously set forth herein. In the compounds shown in Table 2, the terminal nitrogen atom on the right-hand side is intended to designate NH2 and the central nitrogen atom NH. These compounds are useful in the inventive methods of inhibiting Factor VIIa.
TABLE 2Ex.Structure30313233343536373839404142434445464748
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