Compound and medical use thereof

a technology of propanoic acid and compound, which is applied in the field of(2s)2amino3(3, 4bis ((2(benzoyloxy)2methylpropanoyl) oxy) phenyl) propanoic acid, can solve the problems of cognitive impairment, difficult control of blood concentration, and pharmacokinetic problems of levodopa, so as to reduce the possibility of developing side effects such as dyskinesia, reduce drug complian

Inactive Publication Date: 2014-04-22
ONO PHARMA CO LTD
View PDF44 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0132](2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid, a salt thereof, or a solvate thereof (hereinafter, sometimes collectively abbreviated as “compound of the present invention”) is a levodopa prodrug that overcomes the pharmacokinetic problems of levodopa and can provide an effective blood concentration of levodopa in small number of doses. By taking the compound of the present invention in place of levodopa, an effective blood concentration of levodopa can be maintained for about 16 hours in two doses per day (at most three doses per day) in patients with Parkinson's disease and / or Parkinson's syndrome who took levodopa in the past, preferably patients with Parkinson's disease and / or Parkinson's syndrome who took levodopa in combination with a DCI in the past. Since the same efficacy can be obtained by dosing two times per day, also the drug compliance can be improved in patients who had to take a levodopa preparation in 6 to 12 doses per day.
[0133]Further, the compound of the present invention is a prodrug capable of providing an effective blood concentration (an effective plasma concentration: 0.4 to 1 μg / mL) of levodopa for a long period of time in humans, and reduces the possibility of developing side effects such as dyskinesia or wearing-off as much as possible by providing a flat blood concentration-time profile of levodopa.
[0134]In addition, the compound of the present invention is a drug which raises no concern about mutagenicity. The examination made by the inventors of the present invention revealed that among levodopa prodrugs, particularly some compounds showing long blood retention, there are not a few compounds confirmed to have mutagenicity in a mutagenicity assay using mammalian cells. However, since the compound of the present invention does not have mutagenicity, even in the case where a drug has to be taken over a period as long as several years or several decades such as Parkinson's disease and / or Parkinson's syndrome, patients can continue to take the drug without worrying.

Problems solved by technology

In addition, it is often the case that patients with Parkinson's disease also develop a cognitive impairment such as dementia.
However, levodopa has pharmacokinetic problems and also is one of the drugs whose blood concentration is difficult to be controlled at around an effective blood concentration.
Further, the absorption of levodopa is susceptible to the gastric residence time, the acidity of gastric acid, etc., and therefore is not stable.
As described above, since levodopa has pharmacokinetic problems that the absorption of levodopa is inconsistent, the blood retention time of levodopa is short, and the percentage of levodopa entered the central nervous system (brain uptake index) is low, levodopa is required to be taken 3 times or more per day, and some patients require to take levodopa as many as 12 times per day.
Moreover, levodopa also has a problem that the drug efficacy is gradually lost when several years have passed from the start of the treatment.
Due to this undesired property, even if a therapeutic effect is obtained by taking levodopa three times per day in a patient at present, after several years, the patient will have to take levodopa more than three times per day.
However, the half-life of levodopa in the blood does not change and is still about 1 hour or so even if a DCI is added, and therefore, from the viewpoint of maintaining the blood concentration of levodopa, there is nothing developed.
On the other hand, as for the administration of levodopa at a high dose, from the viewpoint of side effects, the implementation is not practical.
Among the patients who require levodopa, there are not a few patients who cannot take levodopa at a sufficient dose due to such side effects.
The problem that levodopa requires “large number of doses” is not improved even by using levodopa and an inhibitor of levodopa metabolism in combination or by changing the administration route of levodopa itself.
Further, side effects such as dyskinesia developed by frequent exposure to levodopa at a concentration exceeding the effective blood concentration are also problems which have been desired to be solved for patients who require levodopa.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-(Benzoyloxy)-2-methylpropanoic acid

[0371]

[0372]2-Hydroxyisobutyric acid (50 g) was dissolved in acetonitrile (480 mL). To this solution, pyridine (78 mL) was added, and then, benzoyl chloride (56 mL) was added thereto. The resulting solution was stirred at room temperature for 40 minutes. To the reaction mixture, 2 N hydrochloric acid (300 mL) was added to acidify the solution, and then, extraction was performed with ethyl acetate (400 mL×2). The organic layers were combined and dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was recrystallized from tert-butylmethyl ether / n-heptane, whereby the title compound (82 g, 82%) having the following physical properties was obtained.

[0373]TLC (Rf value): 0.37 (ethyl acetate)

[0374]NMR (300 MHz, CDCl3): δ 8.20-9.40 (br, 1H), 8.01-8.06 (m, 2H), 7.53-7.59 (m, 1H), 7.40-7.46 (m, 2H), 1.73 (s, 6H)

example 2

(2S)-Benzyl 2-((tert-butoxycarbonyl)amino)-3-(3,4-dihydroxyphenyl)propanoate

[0375]

[0376]To (S)-3,4-dihydroxyphenylalanine (L-DOPA, 10.0 g), purified water (30 mL) was added under an argon atmosphere to form a suspension. To this solution, triethylamine (14.2 mL) was added, and then, a solution of di-tert-butyl-dicarbonate (Boc2O, 13.3 g) in tetrahydrofuran (30 mL) was added thereto at room temperature. The resulting solution was stirred at room temperature for 14 hours. To the reaction mixture, 2 N hydrochloric acid (61 mL) was added under ice-cooling to acidify the solution, and then, extraction was performed with ethyl acetate (200 mL×2). The organic layers were combined and washed with a saturated aqueous solution of sodium chloride (200 mL), and then dried over magnesium sulfate. After magnesium sulfate was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue was used in the subsequent step without purification.

[0377]TLC (Rf value): 0...

example 3

(2S)-((4-(3-Benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl-1,2-phenylene)bis(oxy))bis(2-methyl-1-oxopropan-2,1-diyl)dibenzoate

[0381]

[0382]To the compound (90.7 g) produced in Example 1, toluene (227 mL) was added to form a suspension. To this solution, N,N-dimethylformamide (0.8 mL) was added under an argon atmosphere, and then, thionyl chloride (38.2 mL) was added thereto. The reaction mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue, toluene (170 mL) was added, and the resulting solution was concentrated under reduced pressure. This procedure was repeated twice, whereby an acid chloride was obtained.

[0383]The compound (76.7 g) produced in Example 2 was dissolved in acetonitrile (100 mL) under an argon atmosphere. To this solution, triethylamine (83 mL) was added under ice-cooling, and subsequently, the acid chloride produced by the previous reaction was added thereto ov...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
melting pointaaaaaaaaaa
Login to view more

Abstract

Provided is a levodopa prodrug that overcomes the problems attributed to the blood kinetics of levodopa such as large number of doses and the incidence of side effects due to frequent dosing. (2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid, a salt thereof, or a solvate thereof is a levodopa prodrug, and provides a flat blood concentration-time profile of levodopa through oral administration, and therefore is useful as a preventive and / or therapeutic agent for Parkinson's disease and / or Parkinson's syndrome that overcomes the problems associated with pharmaceutical preparations of levodopa.

Description

TECHNICAL FIELD[0001]The present invention relates to (2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid, a salt thereof, or a solvate thereof, and crystalline forms thereof, which is useful for prevention and / or treatment of Parkinson's disease and / or Parkinson's syndrome.BACKGROUND ART[0002]Parkinson's disease is one of the representative neurodegenerative diseases in the elderly caused by degeneration or loss of Dopamine neurons and is designated as a specified disease (intractable disease). The prevalence of Parkinson's disease is considered to be 100 to 300 people per 100,000 of the population, and the clinical symptoms can be roughly divided into motor symptoms and non-motor symptoms. As the motor symptoms, extrapyramidal symptoms such as tremor, akinesia, rigidity, and postural instability are observed, and among these, three symptoms: tremor, akinesia, and rigidity are known as three main characteristic features of Parkinson's disease.[0003]O...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(United States)
IPC IPC(8): A01N37/34A61K31/275A01N37/12A01N37/44A61K31/195C07C229/00A61K31/198C07C229/36
CPCA61K31/198C07C229/36
Inventor KOKUBO, MASAYAYANO, KOJI
Owner ONO PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap