Prodrug Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use
a transmembrane conductance regulator and protein technology, applied in the field of prodrug compounds, can solve the problems of low blood exposure and high pill burden, and achieve the effect of improving exposur
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example 1
(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol
Step 1: 3-Amino-5-(4-trifluoromethoxy-phenylsulfanyl)-pyridine-2-carboxylic acid
[0272]A solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (CAS: 870997-85-6, 3.26 g, 15 mmol), 4-(trifluoromethoxy)benzene-1-thiol (CAS: 169685-29-4, 3.5 g, 18 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.22 mL, 15 mmol) was prepared in N,N-dimethylacetamide (15 mL). The mixture was heated at 140° C. for 45 minutes in a microwave reactor. The mixture was diluted with a mixture of 1% acetic acid in water. A suspension was obtained that was subsequently filtered. The collected solid was washed with a 1% acetic acid / water mixture and washed with petroleum ether. After drying in a vacuum oven, the title compound was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J=2.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.48-7.44 (m, 2H), 6.99 (d, J=2.0 Hz, 1H).
Step 2: 3-Amino-5-(4-trifluoromethoxy-benzenesulfonyl)-pyrid...
example 2
(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl (dimethylamino)acetate
[0281](5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol (1.5 g), N,N-dimethylglycine hydrochloride (1.5 eq.), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.7 eq.) and 4-(dimethylamino) pyridine (0.25 eq.) were combined and suspended in dichloromethane (30 mL). The suspension was stirred at room temperature. Analysis after 1 hour showed 2.5% starting material, and 97.5% title compound. Additional 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.2 eq.) and dichloromethane (15 mL) were added and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (60 mL) was added and the layers were separated. The organic layer was washed with saturated NH4Cl solution (60 mL), dried over Na2SO4, filtered and concentrated to provide the title compound (93% y...
example 3
(5-{3-amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methyl 3-(dimethylamino)propanoate
[0282](5-{3-Amino-5-[4-(trifluoromethoxy)benzene-1-sulfonyl]pyridin-2-yl}-1,3,4-oxadiazol-2-yl)methanol (1.5 g), N,N-dimethyl-β-alanine hydrochloride (1.1 eq.), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.7 eq.) and 4-(dimethylamino) pyridine (0.25 eq.) were combined and suspended in dichloromethane (30 mL). The mixture was stirred at room temperature. Analysis of the reaction mixture after 1 hour showed 3.5% starting material left, and 95.9% title compound. 1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.2 eq.) and dichloromethane (15 mL) were added and the reaction mixture was stirred at room temperature overnight. A saturated aqueous Na2CO3 solution (60 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated NH4Cl solution (60 mL), dried over Na2SO4, filtered and concentrated to ...
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