Triazole agonists of APJ receptors
A technology of tautomers and alkyl groups, applied in the field of triazole agonists of APJ receptors
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[0104] For convenience and for ease and clarity of reference when referring back to the various embodiments, the following embodiments are presented in numbered form.
[0105] 1. In a first embodiment, the present invention provides a compound of formula I or formula II:
[0106]
[0107] or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of said tautomer, a stereoisomer of any of the foregoing, or a mixture thereof,
[0108] in:
[0109] R 1 is unsubstituted pyridyl, pyridone or pyridine N-oxide, or is surrounded by 1, 2, 3 or 4 R 1a Substituent substituted pyridyl, pyridone or pyridine N-oxide;
[0110] R 1a independently in each case selected from -F, -Cl, -Br, -I, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Perhaloalkyl, -OH, -O-(C 1 -C 6 Alkyl), -O-(C 1 -C 6 haloalkyl), -O-(C 1 -C 6 perhaloalkyl), -C 2 -C 6 Alkenyl, -O-(C 1 -C 6 Alkyl)-OH, -O-(C 1 -C 6 Alkyl)-O-(C 1 -C 6 Alkyl), -O-(C ...
Embodiment 1
[1266] Example 1: Preparation of 2-isothiocyano-1,3-dimethoxybenzene.
[1267]
[1268] 2-Isothiocyano-1,3-dimethoxybenzene, Example 1.0. To a solution of 2,6-dimethoxyaniline (500 g, 3.25 mol, 1 equiv) in DCM (5.0 L) was added 2,6-lutidine (1.5 L, 13.0 mol, 4 equiv). The reaction mixture was cooled to 0°C (internal temperature) and CSCl was added dropwise 2 (374 mL, 4.88 mol, 1.5 equiv). The reaction mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was purified on silica gel to give the title compound 1.0,2-isothiocyano-1,3-dimethoxybenzene (1.06 g, 2.80 mol, 86%) as a white solid . LCMS (ESI cation) m / z: 196 (M+H) + . 1 HNMR (400MHz, CDCl 3 )δ7.16(t, J=8.48Hz, 1H), 6.55(d, J=8.48Hz, 2H), 3.90(s, 6H).
[1269] The compounds listed in the table below were synthesized according to the procedure in Example 1.0 using known starting materials as described.
[1270] Table 1
[1271]
Embodiment 13
[1272] Example 1.3: Preparation of 3-isothiocyano-1-methyl-1H-indole.
[1273]
[1274] (1-Methyl-1H-indol-3-yl)carbamate tert-butyl ester, Example 1.31: To 1-methylindole-3-carboxylic acid (commercially available from Sigma-Aldrich Corp, St. Louis , MO, USA) (10 g, 57.1 mmol) in THF (190 mL) was added sequentially with TEA (7.9 mL, 57.1 mmol) followed by diphenylphosphoryl azide (12.3 mL, 57.1 mmol). The reaction was stirred for 36 h, after which time the reaction was concentrated in vacuo and placed in tert-butanol (54.6 mL). The reaction was further stirred at 90°C over the weekend. After this time, water was added to the reaction and the mixture was extracted with EtOAc and concentrated in vacuo. The residue was purified on silica gel eluting with 0-30% EtOAc in hexanes to give 1.31 (7.1 g, 28.8 mmol, 51%). LCMS-ESI(+)m / z: 247.3(M+H) + .
[1275]
[1276] 1-Methyl-1H-indol-3-amine, Example 1.32: To a stirred solution of 1.31 (7.1 g, 28.8 mmol) in EtOAc (96 mL) w...
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