Structure–Activity Relationship Study on Ligands Activating the Voltage‐Gated Potassium Channel K V 7.1

Figures

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  Figure 1. Distribution of KV7.1 in the human body. Created in https://BioRender.com.

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  Figure 2. Lead compound (R)‐L3 and envisaged structural modifications summarized in general formula 1.

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  Scheme 1. Synthesis of differently 2‐acylated anilines 4a–h. Reagents and reaction conditions: (a) 1. BCl3, AlCl3, xylene, 0°C then 144°C, 16 h; 2. H2O, 100°C, 40 min, 63%–91%. (b) 1. BCl3, AlCl3, xylene, 0°C then 144°C, 6 h; 2. 3 M HCl, 100°C, 1 h, 13%. (c) 1. 2‐methoxyaniline (3), PhBCl2, NEt3, CH2Cl2, −20°C, 30 min; 2. 2‐fluorobenzaldehyde, CH2Cl2, rt, 5 h; 3. 2 M NaOH, THF, rt, 1 h, 53%. (d) MnO2, CH2Cl2, THF, 40°C, 16 h, 93%.

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  Scheme 2. Synthesis of indol‐3‐ylmethyl substituted 1,4‐benzodiazepin‐2‐ones 8 and 9. Reagents and reaction conditions: (a) PCl3, CH2Cl2, 0°C, then rt, 16 h. (b) 1. Addition of 2‐aminoketones 4a–h, TFA, toluene, 60°C, 1 h; 2. Et3N, toluene 80°C, 1 h, 7%–53%. (c) 1. NaH, DMF, 0°C, 1 h; 2. CH3I, rt, 1 h, 42%–89%. (d) BBr3, CH2Cl2, rt, 3 h, 65% (8i), 55% (9i). The (S)‐configured enantiomers ent‐8b and ent‐9b were prepared analogously starting with Boc‐protected (S)‐configured tryptophan (ent‐6).

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  Scheme 3. Synthesis of benzyl substituted 1,4‐benzodiazepin‐2‐ones 12 and 13. Reagents and reaction conditions: (a) PCl3, CH2Cl2, 0°C, then rt, 16 h. (b) 1. Addition of 2‐aminoketones 4a and 4b, TFA, toluene, 60°C, 1 h; 2. Et3N, toluene 80°C, 1 h, 52%–67%. (c) 1. NaH, DMF, 0°C, 1 h; 2. CH3I, rt, 1 h, 73%. The (S)‐configured enantiomers ent‐12a and ent‐13a were prepared analogously starting with Boc‐protected (S)‐configured phenylalanine (ent‐10).

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  Scheme 4. Synthesis of 1,4‐benzodiazepine‐2‐ones 14–16 with various alky substituents in 1‐position, thioamide rac‐17 as well as triazole rac‐18. Reagents and reaction conditions: (a) 1. NaH, DMF, 0°C, 1 h; 2. ethyl methanesulfonate, 40°C, 1 h, 82%. (b) 1. NaH, DMF, 0°C, 1 h; 2. butyl methanesulfonate, 40°C, 1 h, 54%. (c) 1. NaH, DMF, 0°C, 1 h; 2. trifluoroethyl trifluoromethanesulfonate, rt, 40 min, 91% (d) Lawessons reagent, THF, reflux, 16 h, 73%. (e) AcNHNH2, butan‐1‐ol, reflux, 16 h, 35%.

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  Figure 3. Chiral HPLC chromatograms of 9b and ent‐9b. Top: racemic mixture of 9b and ent‐9b; bottom left: ent‐ 9b; bottom right: 9b. HPLC conditions: column: Daicel Chiralpak IA (l = 250 mm, d = 4.6 mm); eluent: iso‐hexane/iso‐propanol = 90:10; flow rate: 1.0 mL/min; detection λ = 254 nm. ent‐ 9b: 100.0% ee; 9b: 99.9% ee.

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  Figure 4. Chiral HPLC chromatograms of thioamides 17. Top: racemic mixture rac‐17; bottom left: (S)‐17; bottom right: (R)‐17. HPLC conditions: column: Daicel Chiralpak IA (l = 250 mm, d = 4.6 mm); eluent: iso‐hexane/iso‐propanol = 87:13; flow rate: 1.0 mL/min; detection λ = 254 nm. (S)‐17: > 99.9% ee; (R)‐17: > 99.9% ee.

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  Figure 5. Chiral HPLC chromatograms of triazoles 18. Top: racemic mixture rac‐18; bottom left: (S)‐18; bottom right: (R)‐18. HPLC conditions: column: Daicel Chiralpak IA (l = 250 mm, d = 4.6 mm); eluent: iso‐hexane/iso‐propanol = 87:13 + 0.05% Et2NH; flow rate: 1.0 mL/min; detection λ = 254 nm. (S)‐18: 100.0% ee; (R)‐18: 100.0% ee.

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  Figure 6. Activation of the KV7.1 channel by different concentrations of the 1,4‐benzodiazepines 8b, 9b, 9i, and (R)‐ 18.