Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disordersB
a technology of nitric oxide donor and reactive oxygen species, which is applied in the direction of biocide, drug composition, animal repellent, etc., can solve the problems of prolonged -agonist therapy and the tendency to increase the dosage of their medication, and the early development of tolerance to the drug is by far the most serious drawback of nitrate therapy
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example 1
Synthesis of 5-{2-[(1-Yloxyl-2,2,5,5-tetramethyl-pyrrolidin-3-ylmethyl)-amino]-1-S-nitroso-ethyl}-1,1,3,3-tetramethylisoindolin-2-yloxyl, hydrochloride, compound 1
[0247]
[0248]The compound in this example was synthesized as depicted in scheme 4 below:
Synthesis of Epoxide I:
[0249]The synthesis of epoxide I was performed as described in scheme 3.
2-Benzyl-1,1,3,3,-tetramethylisoindoline
[0250]To a solution of methyl Grignard reagent, prepared from methyl iodide (170 g, 1.2 mol) and magnesium turnings 930.4 g, 1.25 mol) in ether (700 ml) under nitrogen, was concentrated by slow distillation of solvent until the internal temperature reached 80° C. The residue was allowed to cool to 60° C., and a solution of N-benzylphthalimide (47.5 g, 0.2 mol) in toluene (600 ml) was added dropwise with stirring at a sufficient rate to maintain this temperature. When the addition was complete, solvent was distilled slowly from the mixture until the temperature reached 108-110° C. After being maintained at...
example 2
Synthesis of 5-(2-tert-Butylamino-1-S-nitroso-ethyl)-1,1,3,3-tetramethyl-isoindolin-2-yloxyl, compound 2
[0265]
[0266]This compound was prepared as described in the following scheme:
[0267]A mixture of tert-butylamine (10 mmol) and 1 ml of N,O-bis-(trimethylsilyl)-acetamide in 50 ml of DMSO was stirred under nitrogen for 30 minutes at room temperature. A solution of the thiirane (compound II) in 50 ml of DMSO was added and the solution was heated at 80° C. for 48 h. the mixture was cooled and the solvent was vacuum distilled (0.1 mm). The thiol-containing residue 2a was purified by column chromatography on neutral alumina eluting with ethylacetate:hexane (1:4). This compound 2a is dissolved in 10 ml of 8N HCl, stirred and cooled in an ice bath. Three mol equivalents of sodium nitrite is dissolved in distilled water and added dropwise to the reaction mixture. After 20 minutes, when most of the sodium nitrite was added, the title S-nitroso compound 2 separated as a pale orange powder. St...
example 3
Synthesis of 5-[1-Hydroxy-2-(2-S-nitroso-1-methyl-2,2-diphenyl-ethylamino)-ethyl]-1,1,3,3-tetramethyl-isoindoline-2-Yloxyl, compound 3
[0268]
[0269]This compound was synthesized as illustrated in the following scheme:
[0270]The amine utilized for this synthesis was synthesized as described in the following scheme:
[0271](S)-(−)-2-Amino-1,1-diphenyl-propan-1-ol was converted to (S)-(−)-2-amino-1,1-diphenyl-propane-1-thiol by refluxing in concentrated aqueous HBr with 4 mol equivalents of thiourea for 36 h. After cooling, the reaction mixture was neutralized with excess KOH and refluxed for 8 h under inert conditions (nitrogen). The product was extracted with ether and purified by column chromatography on neutral alumina (ethylacetate:hexane 1:3).
5-[1-Hydroxy-2-(2-S-nitroso-1-methyl-2,2-diphenyl-ethylamino)-ethyl]-1,1,3,3-tetramethyl-isoindoline-2-Yloxyl (compound 3)
[0272]A mixture of the amine thiol (10 mmol) and 1 ml of N,O-bis-(trimethylsilyl)-acetamide in 50 ml of DMSO was stirred und...
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