Top > Search of International Patents > LEVODOPA DERIVATIVE AND USE THEREOF

LEVODOPA DERIVATIVE AND USE THEREOF

Foreign code F200010234
File No. (S2019-0223-N0)
Posted date Oct 29, 2020
Country WIPO
International application number 2020JP004494
International publication number WO2020166473
Date of international filing Feb 6, 2020
Date of international publication Aug 20, 2020
Priority data
  • P2019-022895 (Feb 12, 2019) JP
Title LEVODOPA DERIVATIVE AND USE THEREOF
Abstract [Problem] To provide a medicine in which problems associated with the use of L-DOPA in treating Parkinson's disease, for example, poor retentivity in blood are improved.
[Solution] By incorporating L-DOPA in the form of a block copolymer [PEG-b-poly(3,4-hydroxy protected L-DOPA)] into a carrier, the retentivity of the medicine in blood is significantly improved.
Outline of related art and contending technology BACKGROUND ART
A disease in which the number of dopamine cells in the brain is reduced by gene mutation, dopamine, a neurotransmitter, is not sufficiently produced, and symptoms such as muscle solidification and tremor appear is sometimes abbreviated as Parkinson's disease (or less, PD, and). (Non-Patent Document 1), where L-dopa, which is a precursor of dopamine and is capable of passing through the blood-brain barrier (BBB), is used as PD therapeutic agent (levodopa), which is a mechanism for limiting substance exchange between blood and brain tissue fluid.
L-dopa (3,4-dihydroxy-L-phenylalanine or levodopa) is extremely excellent in that it is highly effective at the early stage of treatment, has little side effects, and is inexpensive, while it is a drawback that the half-life is the largest. In the latter stage of treatment, dopamine retention of dopamine neurons decreases with progress of primary disease, and the treatment area becomes narrower. As a result, adjustment of dosage becomes difficult due to low blood retention of L-dopa, and a wearable off phenomenon in which improvement and deterioration of symptoms are repeated in a day or dyskinesia due to excessive administration is observed.
In order to overcome such a problem, there are some reports aiming at improving retention of L-dopa in blood using (Patent Document 1) or nanoparticles of prodrugs of L-dopa such as esterification or L-dopa, for example, esters or peptides of L-dopa. As the latter, for example, nanoparticles in which PLGA is supported extend the half-life of L-dopa in blood, and (Non-Patent Document 3), and (Non-Patent Document 4) in which micelles in which chitosan is an outer shell and dopamine is supported by a core can penetrate into the brain together with micelles by loosening tight junction of BBB by chitosan. However, in the nanoparticles, it is possible to cause unexpected leakage of L-dopa due to its weak binding force, and in the latter, it is suggested that blood toxins and the like can be simultaneously transferred into the brain due to loosening of tight junction.
There are few reports on effective parkinson's disease in order to treat L-dopa. L-dopa easily causes oxidative polymerization in the atmosphere to produce a melanin-like viscous black substance, and therefore is applied as a surface modifier. however, the bond of L-dopa cannot be decomposed in vivo because of its strong carbon-carbons, and is difficult to use as a prodrug. On the other hand, there is a report example in which L-dopa is polymerized by a peptide bond degradable by an enzyme in vivo and used as a bioadhesive, but side reactions due to oxidative polymerization during synthesis are not considered. Therefore, there is also a method of protecting the two hydroxyl groups with acetyl groups in advance in order to prevent oxidative polymerization during the reaction, but the use of hydrogen chloride causes danger.
Scope of claims (In Japanese)[請求項1]
 次式(I)及び(II)で表されるブロック共重合体。

 上式中、各変動可能な略号は次のとおりである。
 上式中、
 Aは、非置換または置換C 1-C 12アルキルを表し、置換されている場合の置換基は、ホルミル基、式R R CH-基を表し、ここで、R およびR は独立してC 1-C 4アルコキシまたはR とR は一緒になって-OCH 2CH 2O-、-O(CH 23O-もしくは-O(CH 24O-を表す。
 L 1及びL 2は、それぞれ独立して連結基を表す。
 R 1及びR 2は、それぞれ独立して保護基を表す。
 Y 1は水素原子、ハロゲン若しくはC 1-C 6-アルキルオキシ若しくは置換フェニル若しくはパーフルオロ基で置換されていてもよいC 1-C 20-アルキルカルボニル、ベンゾイル基を表す。Y 2はヒドロキシル、ハロゲン若しくはC 1-C 6-アルコキシ若しくは置換フェニル若しくはパーフルオロ基で置換されていてもよいC 1-C 20-アルキルオキシ、ベンジルオキシ基を表す。
mは2~100の整数を表し、nは4~1,000の整数を表す。

[請求項2]
 請求項1に記載の共重合体であって、L 1の連結基は単結合、-(CH 2)a-NH-、-(CH 2)a-O-、-S-又は-Ph-を表し、L 2の連結基はカルボニル、-(CH 2)a-C(O)-、-C(O)-(CH 2)a-C(O)-、-PhC(O)-又は-Ph-NH-を表し、ここで、aは1~6の整数であり、R 1及びR 2の保護基は、それぞれ独立して、ハロゲン若しくはC 1-C 6-アルキルオキシ若しくは置換フェニルで置換されていてもよいC 1-C 6-アルキルカルボニルを表す、共重合体。

[請求項3]
 請求項1又は2に記載の共重合体であって、式(I)で表される、共重合体。

[請求項4]
 請求項1~3のいずれかに記載の共重合体を含有するナノミセル。

[請求項5]
 請求項1~3のいずれかに記載の共重合体又は請求項4のナノミセルを有効成分として含んでなるパーキンソン病の予防又は治療用製剤。

[請求項6]
 請求項5に記載のパーキンソン病の予防又は治療用製剤であって、さらなる有効成分として、L-ドーパ脱炭酸酵素阻害薬、モノアミン酸化酵素B(MAO-B)阻害薬、カテコール-O-メチル基転移酵素(COMT)阻害薬、ノルアドレナリン増強薬、アデノシンA 2A受容体刺激薬、L-ドーパ及び/又はドーパミン拮抗薬、ドーパミンD2受容体遮断薬から選ばれる少なく1種を含む、製剤。

[請求項7]
 パーキンソン病の予防又は治療に使用するための請求項1~3のいずれかの共重合体。

[請求項8]
 パーキンソン病の予防又は治療に使用するための請求項4のナノミセル。

[請求項9]
 投与を必要とする被検体に予防又は治療に有効量の請求項1の共重合体を投与するステップを含んでなるパーキンソン病の予防又は治療方法。

[請求項10]
 投与を必要とする被検体(subject)に予防又は治療に有効量の請求項4のナノミセルを投与するステップを含んでなるパーキンソン病の予防又は治療方法。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF TSUKUBA
  • Inventor
  • NAGASAKI, Yukio
  • SATO, Yuna
  • VONG, Binh Long
  • CHONPATHOMPIKUNLERT, Pennapa
  • HUTAMEKALIN, Pilaiwanwadee
  • TAKAHASHI, Reita
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN WS ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
Please contact us by E-mail or facsimile if you have any interests on this patent.

PAGE TOP

close
close
close
close
close
close