Pyridine carboxamides as 11-beta-hsd1 inhibitors
A compound, the technology of trifluoromethyl, used in the preparation of medicines for inhibiting 11βHSD1 in warm-blooded animals, and the field of preparing the compounds
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[0602] 2.i.a Preparation of calibration and QC samples:
[0603] 1. Prepare the standard solution as follows:
[0604]
[0605] 2. Transfer 50 μl of blank plasma to a well of a 1 ml 96-well plate (shallow well).
[0606] 3. Transfer 5 μl of each standard solution to other wells of the plate.
[0607] 4. Add 50 [mu]l blank plasma to each of these wells.
[0608] 5. To generate QC samples, add 3 aliquots of 5 μl of 100 ng / ml, 1000 ng / ml and 10,000 ng / ml standard solutions to the plate (3 QC samples for each concentration).
[0609] 6. Add 50 [mu]l blank plasma to each of these samples.
[0610] 7. Transfer 50 μl of each PK sample to a 1 ml 96-well plate.
[0611] 8. Add 5 μl methanol (-compound) to each PK sample.
[0612] 9. Ensure that all doses of formulation are well mixed by vortexing.
[0613] 10. Dilute intravenous (IV) and oral (PO) formulations of desired concentration to 10 μg / ml in methanol. (eg, to prepare a formulation with a desired concentration of 2 mg / ml...
Embodiment 1
[0693] 2-[(3R)-1-[5-(Cyclohexylcarbamoyl)-6-propylthio-pyridin-2-yl]-3-piperidinyl]acetic acid
[0694]
[0695] 6-Chloro-N-cyclohexyl-2-propylthio-pyridine-3-carboxamide (Intermediate 2, 1.88g, 6.03mmol), (R)-3-piperidineacetate methyl ester hydrochloride (1.17 g, 6.03mmol), K 2 CO 3 (2.50 g, 18.08 mmol) and nitrile were mixed in a microwave tube and stirred at 170°C for 2 hours. The mixture turned from a poorly soluble white mixture to an orange solution. The reaction was stopped, and most of the butyronitrile was evaporated under reduced pressure. After adding water (20 mL), the product was extracted with EtOAc (2 x 40 mL), washed with brine (10 mL), washed over MgSO 4 Drying, filtration and evaporation under reduced pressure gave an orange oil which was purified by flash column chromatography (SiO 2 , elution gradient: 0%-50%, hexanes: EtOAc), the title compound was obtained as a pale yellow oil which crystallized to give a white solid (1.44 g, 55%).
[0696] Th...
Embodiment 111
[0855] (1R, 5S, 6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)pyridine-2- Base)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid
[0856]
[0857] Lithium hydroxide monohydrate (102 mg, 2.44 mmol) was added to (1R,5S,6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine Stirred solution of -1-carbonyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid methyl ester (400mg, 0.81mmol) and methanol (5ml) / water (2ml) middle. The resulting solution was stirred at ambient temperature for 24 hours. After removing most of the organic solvent in vacuo, the resulting solution was acidified with 1N citric acid. The resulting suspension was extracted with EtOAc (3x 30ml). The combined organic layers were washed successively with HCl solution (pH 3, 30ml), saturated brine (30ml), and dried (MgSO 4 ), filtered and evaporated to give (1R,5S,6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)pyridine-2 -yl)-3-azabicyclo[3.1.0]hexane-6-...
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