Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders

1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)-1-((stearoyloxy)methyl)piperazin-1-ium iodide (Compound 1)

A. Formation of Acid Chloride

[0133]To a stirred suspension of stearic acid (20 g, 70.3 mmol) in dichloromethane (100 mL) was added oxalyl chloride (8.92 mL, 105.5 mmol). 1 drop dimethylformamide was added and the reaction stirred at room temperature for 3 hours. The solvent was removed in vacuo and the resulting product used in the next step without further purification.

[0134]1H-NMR (CDCl3) δ 2.87 (t, 2H), 1.65-1.70 (m, 2H), 1.20-1.40 (m, 28H), 0.87 (3H, t).

B. Formation of Chloromethyl Alkyl Ester

[0135]Paraformaldehyde (2.11 g, 70.3 mmol) and zinc chloride (258 mg) were added to the acid chloride prepared above and the reaction mixture was heated at 65° C. for 16 hours and then allowed to cool to room temperature. Dichloromethane (200 mL) and saturated aqueous NaHCO3 (70 mL) were added. The aqueous emulsion was extracted with dichloromethane (2×50 mL) and the comb

1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)-1-((palmitoyloxy)methyl)piperazin-1-ium iodide (Compound 2)

[0142]This compound was synthesized employing palmitoyl chloride. The product precipitated from the reaction mixture to give Compound 2 (1.23 g, endotherm peak in the DSC at 164° C.).

[0143]1H-NMR (CDCl3) δ 7.02-6.89 (3H, m), 6.67 (1H, dd), 6.35 (1H, s), 5.83 (2H, s), 5.32 (1H, s), 4.03-3.96 (2H, m), 3.79-3.71 (6H, m), 3.56 (3H, s), 2.52 (2H, t), 2.31 (3H, s), 1.64 (2H, t), 1.39-1.21 (24H, m), 0.87 (3H, t).

1-((butyryloxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (Compound 3)

[0144]This compound was synthesized employing butyryl chloride instead of stearyl chloride. The final precipitated from the reaction mixture to give Compound 3 (1.8 g, endotherm peak in the DSC at 203.2° C.).

[0145]1H-NMR (d6-DMSO) δ 6.77-6.88 (m, 3H), 6.65-6.69 (m, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.78-3.89 (m, 2H), 3.45-3.60 (m, 6H), 3.16 (s, 3H), 2.51 (t, 2H), 2.25 (s, 3H), 1.57 (st, 2H), 0.89 (t, 3H).