Substituted carbamoylmethylglycine derivatives as nep inhibitors
An inhibitor, ethylamino technology, applied in anti-inflammatory agents, metabolic diseases, drug combinations, etc., can solve problems such as short half-life
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Embodiment 1-1
[0316] Example 1-1: (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethyl Synthesis of ethyl amino]-propionate
[0317]
[0318] To (S)-3-(3'-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (4.0g, 10.84mmol) in Dichloromethane (60mL) and saturated NaHCO 3 To a suspension in aqueous solution (10 mL) was added triphosgene (1.90 g, 6.39 mmol). After stirring vigorously for 0.5 h, the reaction mixture was diluted with EtOAc and partially concentrated under reduced pressure. By adding saturated NaHCO 3 aqueous solution to quench excess triphosgene and stirred for 0.5 h. The mixture was extracted with EtOAc and washed with brine. use Na 2 SO 4 The organic layer was dried and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (50 mL). Triethylamine (1.93 mL, 13.8 mmol) and 5-amino-1H-tetrazole (1.18 g, 13.84 mmol) were added to the mixture at 0°C, and the reaction mixture was gradually w...
Embodiment 1-14
[0332] Example 1-14: (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethyl Oxy]-Ethyl propionate
[0333]
[0334] To (S)-3-(3'-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid (62mg, 0.165mmol ) in THF (5ml) was added 5-aminotetrazole (38.0mg, 0.447mmol), DIPEA (0.086ml, 0.494mmol), followed by 1,3-diisopropylcarbodiimide (0.060ml , 0.387mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched by brine and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. HPLC retention time = 0.99 min (condition C); MS (m+l) = 444.
Embodiment 2-1
[0335] Example 2-1: (S)-2-[(R)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethyl Amino]-propionate ethyl ester
[0336]
[0337] By reverse phase HPLC (Sunfire C-18 column, H containing 0.1% TFA 2 O / CH 3 CN) Separation of the cis isomer obtained by the method described in Example 1-1 to give (S)-2-[(R)-2-(3'-chloro-biphenyl-4-yl)-1 -(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester; 1 H NMR (400MHz, DMSO-d6) δ1.07 (t, 3H, J=7.1Hz), 1.12 (d, 3H, J=6.8Hz), 2.88 (dd, 1H, J=8.1, 13.6Hz), 3.04 (dd, 1H, J=6.1, 13.6Hz), 3.18-3.26(m, 1H), 3.69-3.78(m, 1H), 3.87-4.03(m, 2H), 7.35(d, 2H, J=8.1Hz ), 7.37-7.42 (m, 1H), 7.47 (dd, 1H, J=7.8, 7.8Hz), 7.58-7.65 (m, 3H), 7.68-7.72 (m, 1H); MS: m / z (MH + )443.
[0338] The following compounds were prepared using methods similar to Examples 1-1 and 2-1 and appropriate intermediates:
[0339]
[0340]
PUM
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