JP2018523644A - アルコール乱用の治療におけるγ−ヒドロキシ酪酸の選択されたアミドおよびその使用 - Google Patents
アルコール乱用の治療におけるγ−ヒドロキシ酪酸の選択されたアミドおよびその使用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
Description
式(I)の化合物の調製(ACGET61と称する)
サルデーニャ(Sardinian)のアルコール嗜好(sP)ラットにおける式(I)の化合物(ACGET61と称する)の抗アルコールプロファイル
サルデーニャのアルコール嗜好(sP)ラットにおけるACGET61の抗アルコールプロファイル
サルデーニャのアルコール嗜好(sP)ラットは、高いエタノール嗜好および消費に関して世界中で選択的に交配された少数のラット系統のうちの1つを表し(Colomboら、2006)、異なる種のアルコール飲料の評価について検証される多くの実験手順において利用されている。これらの実験手順はアルコール摂取の維持、およびアルコールのオペラント自己投与を含む。
この手順において、sPラットを、アルコール(10%v/v)と水との間の2つのボトルの自由選択のレジメンに曝露した。この条件下で、アルコール溶液を含有するボトルと水を含有するボトルとの間で、約6g/kg/日のアルコールを自発的に消費し、約90%のアルコールを嗜好する動物を選択できる。この手順はヒトアルコール依存症の能動的な飲料段階の有益な実験モデルを構成し;このモデルに曝露したsPラットのアルコール摂取は、ヒトアルコール依存症におけるアルコールの欲求および消費を低減させる、GHB、ナルトレキソンおよびバクロフェンなどの薬物によって低減されることが見出され、このモデルの予測妥当性が実証された。
これらの手順において、sPラットに、レバーを押すことによってアルコールまたはスクロースを自己投与する訓練をし、アルコールを得るのに必要とされる仕事の量(レバーを押すこと)を、強化、一定比率(FR)または累進比率(PR)の単一のスケジュールの目的に応じて変化させた。
ACGET61 100mg/kgは、図2に示されるように、強化のFR4スケジュールに曝露したsPラットにおけるアルコールの強化特性に対する選択的な低減効果を与え、30分の時間におけるレバー応答の総数ならびにアルコール摂取(g/kg)およびスクロース摂取(ml/kg)の量を報告する。具体的には、図2は、sPラットにおけるアルコールのFR4オペラント自己投与に対するACGET61の効果を示す。レバー押しの数およびアルコールまたはスクロース摂取の量を報告した。*ビヒクル処置群に対してp<0.05。
ACGET61 50および100mg/kgは、PRに曝露したsPラットにおいてレバー押しの数、およびアルコールに対するブレークポイントの両方を低減させ、効果がアルコールに特異的でなかった場合でさえ、化合物は図3に証明されるようにスクロースに対する応答も低減させることができる。具体的には、図3は、aPラットにおけるアルコールのPRオペラント自己投与に対するACGET61の効果を示す。アルコールまたはスクロースに対するレバー押しおよびブレークポイントの数を報告した。*ビヒクル処置群に対してp<0.05および**ビヒクル処置群に対してp<0.01。
特に、GET73は、PRに曝露し、50mg/kgで投与したsPラットにおけるスクロース摂取の有意な低減を除いて、同じモデルにおいていずれの効果も実証しなかった(比較のために本明細書以下の表1を参照のこと)。
おそらく、代謝型グルタミン酸受容体サブタイプ5(mGluR5)の複雑な調節によりラット海馬においてアミノ酸作動性(aminoacidergic)神経伝達に影響を及ぼす、GET73について得られた以前の結果に基づいて(Beggiatoら、2013;Ferraroら、2011、2013)、位置異性体ACGET61を、異なる実験条件においてGABAおよびグルタミン酸レベルを測定することによって海馬スライスにおいてインビトロで評価した。
GABAおよびグルタミン酸の基礎放出に対する効果は、ACGET61(10および100μM)によって与えられなかった。
KCl刺激性海馬スライスにおけるACGET61(10pM〜10μM)の効果を調べることを目的としたさらなる研究を実施した。
mGluR5アゴニストCHPGとのACGET61の相互作用をKCl刺激性海馬スライスにおいて調べた。ACGET61 300pM(それ自体で効果がない濃度)の灌流媒体への添加は、図5に示されるようにCHPGによって与えられるK+誘発性グルタミン酸流出の増加に少なくとも部分的に対抗できた。具体的には、図5は、KCl刺激性海馬スライス−K+誘発性グルタミン酸流出である。グルタミン酸流出の増加に対するACGET61 300pMの効果はCHPG 100μMによって誘導された。**対照に対してp<0.01;〇ACGET61+CHPGに対してp<0.05。
アルコールの神経毒作用は動物およびヒトの両方において十分に確立されており、海馬は特にアルコールの有害作用に感受性がある脳領域を表す。異なる前臨床モデルがアルコールの神経毒作用を研究するために利用されている。これらのモデルの1つは、器官型海馬培養物をアルコールに曝露することで構成され、それは、細胞生存率の低減、および活性酸素種(ROS)の増加を含む、様々な効果を与える。
エタノールへの曝露は、対照細胞培養値に対する吸光度値の有意な減少(p<0.01)によって示されるように細胞生存率の減少を誘導した。慢性エタノール曝露の1時間前および間に加えたACGET61 0.1、1および10μMはエタノール誘導性損傷を阻止し、細胞生存率は対照群に対して有意に異ならなかったが、エタノール群に対して有意に異なった(p<0.05)。ACGET61(0.01〜10μM)はそれ自体でエタノールに曝露しなかった海馬細胞培養物において細胞生存率に影響を与えなかった。対照培養物中で測定したニューロン生存率のパーセンテージとして表した結果を図6に示す。具体的には、図6は、エタノール(EtOH;75mM、4日)に曝露した海馬細胞培養物における細胞生存率に対するACGET61の効果を示す。**対照に対してp<0.01;〇EtOH 75mMに対してp<0.05。
エタノール曝露は、ローダミン123の蛍光発光によって測定して、ROS生成の有意な増加を誘導した(p<0.001)。
医薬組成物
N−[(2−トリフルオロメチル)ベンジル]−4−メトキシブチルアミド(ACGET61) 50mg
微結晶性セルロース(適切な崩壊剤として) 60mg
タルク(潤滑剤として) 10mg
ラウリル硫酸ナトリウム(界面活性剤として) 5mg
リン酸カルシウム(凝集剤−希釈剤として) 200mg
炭酸マグネシウム(希釈剤−結合剤として) 100mg
医薬組成物
N−[(2−トリフルオロメチル)ベンジル]−4−メトキシブチルアミド(ACGET61) 150mg
トウモロコシデンプン(適切な崩壊剤として) 100mg
ベヘン酸グリセリル(潤滑剤として) 10mg
ポリソルベート(界面活性剤として) 10mg
炭酸マグネシウム(希釈剤−結合剤として) 150mg
ラクトース(希釈剤として) 150mg
フィルムコーティング/修飾放出を有する医薬組成物
N−[(2−トリフルオロメチル)ベンジル]−4−メトキシブチルアミド(ACGET61) 500mg
微結晶性セルロース(適切な崩壊剤として) 200mg
クロスポビドン(抗凝集剤として) 50mg
デンプン(希釈剤−崩壊剤として) 50mg
コロイド状シリカ(乾燥剤として) 10mg
ステアリン酸マグネシウム(潤滑剤として) 10mg
ヒプロメロース(コーティング剤として) 50mg
マクロゴール(可塑剤として) 10mg
二酸化チタン(染料として) 10mg
Claims (12)
- 式(I)の化合物:
- 式(I)の化合物を調製する方法であって、以下の反応スキーム
- 前記反応がNH4Clに基づいた触媒の存在下で実施される、請求項2に記載の方法。
- NH4Clが試薬R1の重量に対して8〜12重量%の量で加えられる、請求項3に記載の方法。
- 試薬R1およびR2が等モルである、請求項2〜4のいずれか一項に記載の方法。
- 前記反応が120〜170℃の温度で実施される、請求項2〜5のいずれか一項に記載の方法。
- 試薬4−メトキシ酪酸メチルR2が、以下の反応スキーム:
- 医薬として使用するための以下の式を有する化合物
- 薬物依存症の予防および/または治療における使用のための式(I)を有する化合物
- 強硬症、睡眠発作、不眠症、閉塞性睡眠時無呼吸症候群、鬱病、不安症、統合失調症に関連する不眠症、過剰な鎮静作用、本態性振戦、慢性疲労症候群、慢性的な不眠症または有害物質からの神経防護作用から選択される障害の予防または治療における請求項9に記載の使用のための化合物。
- アルコール乱用、アルコール依存症、アルコール使用障害の予防または治療における請求項9に記載の使用のための化合物。
- 好ましくは50〜500mgの量で、請求項1に記載の式(I)の化合物と、薬学的に許容可能な担体とを含む医薬組成物。
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PCT/EP2016/068517 WO2017021438A1 (en) | 2015-08-04 | 2016-08-03 | SELECTED AMIDE OF γ -HYDROXYBUTYRIC ACID AND USES THEREOF IN THE TREATMENT OF ALCOHOL MISUSE |
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BR112018002245A2 (pt) | 2018-09-18 |
PH12018550008A1 (en) | 2018-07-09 |
US10336687B2 (en) | 2019-07-02 |
EA033769B9 (ru) | 2020-04-10 |
EP3331853A1 (en) | 2018-06-13 |
AU2016302869B2 (en) | 2020-10-22 |
IL257314B (en) | 2020-04-30 |
EA201890419A1 (ru) | 2018-07-31 |
PT3331853T (pt) | 2020-02-25 |
GEP20207107B (en) | 2020-05-11 |
CL2018000282A1 (es) | 2018-07-13 |
ZA201801402B (en) | 2019-01-30 |
KR20180066033A (ko) | 2018-06-18 |
CN108026029A (zh) | 2018-05-11 |
IL257314A (en) | 2018-03-29 |
CA2994599C (en) | 2023-08-29 |
WO2017021438A1 (en) | 2017-02-09 |
EA033769B1 (ru) | 2019-11-22 |
EP3331853B1 (en) | 2019-12-11 |
MY185942A (en) | 2021-06-14 |
MX2018001239A (es) | 2018-07-06 |
DK3331853T3 (da) | 2020-03-16 |
CA2994599A1 (en) | 2017-02-09 |
ITUB20152860A1 (it) | 2017-02-04 |
JP6832336B2 (ja) | 2021-02-24 |
AU2016302869A1 (en) | 2018-03-15 |
ES2776628T3 (es) | 2020-07-31 |
UA121994C2 (uk) | 2020-08-25 |
PL3331853T3 (pl) | 2020-06-15 |
GEAP202014717A (en) | 2020-01-27 |
CO2018002428A2 (es) | 2018-07-10 |
CN108026029B (zh) | 2020-12-04 |
US20180230086A1 (en) | 2018-08-16 |
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