Cardioprotective delta opioid receptor agonists and methods of using same
a technology of delta opioid receptor and agonist, which is applied in the field of compositions and methods of treating cardioprotection, can solve the problems of physical reduction of blood supply, difficult or impractical for most patients, and many patients are not physically capable of reaching the level of cardiac output required
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example 1
4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl} benzoic acid
[0065]
[0066]A solution of 3-bromophenol (400 g, 2.31 mol), tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole (346 g, 5.08 mol) in 5000 mL of dichloromethane was stirred overnight at room temperature. The reaction solution was poured into 2000 mL of water and the layers were separated. The organic layer was washed with 1N aqueous sodium hydroxide solution (3×1500 mL) and water (2×1500 mL) before passing through a pad of silica gel (400 g, silica 60, 230-400 mesh). The silica gel was washed with dichloromethane (2×500 mL), the filtrates were combined and the solvent removed under reduced pressure to give 669 g (98.4%) of 3-bromophenoxy-tert-butyldimethylsilane as a clear pale yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 7.1 (m, 2H); 7.0 (br s, 1H); 6.75 (m, 1H); 1.0 (s, 9H); 0.2 (s, 6H).
[0067]3-tert-Butyldimethylsilyloxyphenylmagnesium bromide was formed by the...
example 2
4-{(2R,5S)-4-[(S)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl}benzoic acid
[0075]
[0076]4-Carboxybenzaldehyde (100 g, 666 mmol) was weighed in a 2000 mL, 3-necked, round bottom flask and stirred under nitrogen in 1200 mL of toluene. Thionyl chloride (53.5 mL, 733 mmol) was added to the mixture, followed by the addition of 0.15 mL of dimethylformamide. A reflux condenser fitted with a calcium chloride drying tube was placed on the flask. The reaction was placed in an oil bath and heated at a bath temperature maintained below 120° C. The mixture was allowed to reflux for 1 hour after a clear solution was obtained and then cooled to room temperature. The solution was diluted with anhydrous toluene, and all volatiles were removed under vacuum.
[0077]The crude acid chloride was dissolved in 1500 mL of dry tetrahydrofuran and cooled in an ice / water bath. Diethylamine (173 mL, 1.67 mol, 2.5 equivalents) was added dropwise via an addition funnel. The clo...
example 3
3-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl} benzoic acid
[0087]
[0088]4-{(R)-(2S,5R)-4-Allyl-2,5-dimethyl-piperazin-1-yl)-[3-(tert-butyldimethylsilanyloxy)-phenyl]methyl}-N,N-diethylbenzamide (11.00 g, 20.0 mmol, Example 2) was dissolved in 40 mL of dry acetonitrile and tetraethylammonium fluoride dihydrate (5.56 g, 30.00 mmol) was added and stirred overnight. The reaction solution was concentrated to dryness, the residue was dissolved in 40 mL of ethyl acetate and washed with 2% aqueous NaHCO3 solution (3×40 mL) and water (40 mL). The organic layer was dried over sodium sulfate and evaporated to give 4-{(R)-(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)[3-hydroxyphenyl]methyl}-N,N-diethylbenzamide (10.30 g) as a yellow amorphous solid.
[0089]The allyl group was removed using Pd(dba)2 / DPPB in the presence of thiosalicylic acid by the method of Genet as discussed in Example 1. The reaction was concentrated and the residue was pour...
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