Catecholamine carbamate prodrugs for use in the treatment of parkinson s disease
An amino acid and carbamoyl technology, applied in the field of catecholamine carbamate prodrugs for the treatment of Parkinson's disease, can solve the problems of not disclosing catecholamine prodrugs and the like
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[0437] Preparation of Compounds of the Invention
[0438] Compounds of formula (Id) can be prepared by the methods described below as well as synthetic methods known in the art of organic chemistry or modifications familiar to those of ordinary skill in the art. The starting materials used herein are either commercially available or can be obtained by conventional methods known in the art, as described in standard reference books (e.g. "Compendium of Organic Synthetic Methods [Compendium of Organic Synthetic Methods], Volumes I-XII" (Western Published by Wiley-Interscience (Wiley-Interscience)). Preferred methods include, but are not limited to, those described below.
[0439] These schemes are representative of methods that can be used to synthesize compounds of the invention. They are not intended to limit the scope of the invention in any way.
[0440] Abbreviated List of Compounds
[0441] BF 3 -OEt 2 : Boron trifluoride ether
[0442] BnBr: benzyl bromide
[0443]...
example 1
[0585] Example 1: Transformation of Compounds of the Invention in Human Plasma
[0586] Frozen human plasma was thawed and then centrifuged at 3200 xg for 5 minutes to remove debris. The pH of the supernatant was then measured and adjusted to 7.4±0.1 by adding 1% phosphoric acid or 1N sodium hydroxide. 2 μL of dosing solution (50 μM for test compound and 100 μM (propantheline bromide) for positive control) was mixed with 98 μL blank plasma to obtain a final concentration of 1 μM test compound and 2 μM positive control. The mixture was incubated at 37°C in a water bath and samples were taken from the incubation at predetermined time points of 0, 0.5, 1, 2, 4 and 6 hours (in duplicate). At each respective time point 10 μL inhibitor and 20 μL ascorbic acid and 2 μL formic acid (20%) were added, and then 400 μL “stop solution” (200 ng / mL tolbutamide in 50% ACN / MeOH plus 200 ng / mL mL labetalol) to precipitate protein. The material was mixed well and thereafter centrifuged at 4...
example 2
[0589] Example 2: 5-HT2B Agonist Activity and Binding Assays
[0590] 5-HT2B agonist activity assay
[0591] The effects of compounds (I), (Ia) and (Ib) on human 5- Assessment of agonist activity of the HT2B receptor. Briefly, in transfected CHO cells, the human 5-HT2B receptor was expressed. Suspend the cells in a solution containing 10mM Hepes / NaOH (pH 7.4), 4.2mM KCl, 146mM NaCl, 1mM CaCl 2 , 0.5mM MgCl2, 5.5mM glucose and 50mM LiCl in buffer, then distributed in microplates at a density of 4100 cells / well, and in the presence of buffer (basal control), test compound or reference agonist, Incubate at 37°C for 30 min. For stimulated control measurements, individual assay wells contained 1 [mu]M 5-HT. After incubation, cells were lysed and a fluorescent acceptor (fluorophenyl D2-labeled IP1) and a fluorescent donor (anti-IP1 antibody labeled with europium cryptate) were added. After 60 min at room temperature, the fluorescence shift was measured using a microplate rea...
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