JP2018501314A - ジアリールメチリデンピペリジン誘導体およびデルタオピオイド受容体アゴニストとしてそれらの使用 - Google Patents
ジアリールメチリデンピペリジン誘導体およびデルタオピオイド受容体アゴニストとしてそれらの使用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Dppf=(ジフェニルホスフィノ)フェロセン
HATU=1−[ビス(ジメチルアミノ)メチレン] −1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム−3−オキシドヘキサフルオロホスフェート
本発明は、以下の実施例によって例証される。
インビトロ
δ−オピオイド受容体(DOR)は、アデニリルシクラーゼ活性を阻害し、K+チャネルを開き、Ca2+チャネルを遮断する阻害性Gタンパク質(Gi/o)に結合する。それらはまた、アゴニスト依存的な方法で、β−アレスチン2に結合し、脱感作をもたらし、およびMAPキナ−ゼ(ERK)リン酸化反応に結合することができる。
cAMP測定は、DiscoveRx cAMP Hunter(商標)アッセイキットを用いて、増加するアゴニスト濃度に暴露されたδ−オピオイド発現CHO細胞において行われ、β−アレスチンの補充はDiscoveRx Pathunter(登録商標)キットを使用して、アゴニスト濃度が増加している状態で測定される。μおよびκオピオイド受容体の選択は、整理番号1392及び2071(Cerep Le Bois L’eveque、86600 Celle L’evescault、France)からのCerep cAMP評価を用いて行われる。
慢性疼痛 セルツァーモデル
セルツァーアセスメントは、慢性疼痛を評価するために用いられる。 30匹の雄CD1マウス(29から37g)がこの研究に含まれる。マウスはCharles−River社から入手し、標準的な飼料および水を自由に与え、24から25℃で、ペーチ大学のthe Animal Facility of the Department of Pharmacology and Pharmacotherapyに保管した。すべての実験手順は、Animal Protectionに関するハンガリー議会の1998/XXVIIIActおよびConsideration Decree of Scientific Procedures of Animal Experiments(243/1988)に従って実施され、ヘルシンキ宣言の勧告を遵守した。研究は、the Ethical Codex of Animal Experimentsに基づいて、ペ−チ大学の動物研究に関するthe Ethics Committeeによって承認され、ライセンスが与えられた(ライセンス番号:BA 02/2000−11−2006)。条件付け測定後、3つの信頼できる制御機械的侵害受容閾値が3日間連続してすべてのマウスについて判定され、手術がその後に行われる。神経結紮後の7日目に、機械的侵害受容閾値を判定し、腹腔内に薬物投与した前及び15分後、注射前と注射後の閾値の差を観察する。最小で30%の注射前痛覚過敏性を有するマウスのみがこの研究に含まれる。
ラットを、1リットル/分の流速の酸素中で2.5%イソフルラン(Abbott、Maidenhead、UK)を用いて麻酔する。左脚を剃毛し、外科的に準備する。内側の側副靱帯が露出し、その一部が除去されて半月板が露出する。半月板は、最も幅が狭い点で厚さにわたって切断される。次いで、結合組織層および皮膚を、それぞれコーティングされたVicryl8−0および4−0縫合糸(Ethicon、Livingstone、UK)で閉じる。疼痛による行動は実験結果の尺度となるため、術後の鎮痛薬は投与しない。模擬手術を受けた動物は、半月板が切断されないことを除いて、同一の手順を受ける。左(同側)膝および右(対側)膝にかかる体重分布に対する治療の効果は、インキャパシタンスメーター(an incapacitance meter)(Linton Instruments UK)を用いて評価される。後肢重量分布の変化は、右対側対照肢と左同側処置肢との体重量の差を左右の脚の体重×100の合計で割ったものとして定義される。機械的刺激に対する後肢を引っ込める閾値は、アップダウン法を用いて較正されたvon Freyモノフィラメントを用いて測定される。実験動物は、実験の開始前に少なくとも2つの機会において順応させられている。
ベースライン行動の疼痛測定は、モデル導入前の0日目、次いで14日目、28日目、35日目、および49日目に行われる。
λ−カラギーナン(100μL、生理食塩水中2%;Sigma、Poole、UK)をラット後肢の足底面に注射する。カラギーナンを注射し、後脚をひっこめる反応を記録した後、機械的刺激(8−100g von Freyモノフィラメント)を10分間間隔で180分間末梢受容野に(昇順で)適用する。後足の周の長さは、中足レベルで足の周りに輪をかけた縫合糸を用いて測定され、そっと締め付けられる。次に、糸を開いて、最も近いミリメートルまで測定される。測定はカラギーナン注射前に行われ、その後60分間隔で測定する。
協調動作(ロータロッド);ロータロッドアセスメントは、一般的な協調動作(co−ordinator behavior)を評価するために使用される。それは、マウスを3日間訓練するロ−タロッド装置(Ugo Basile)上のパフォーマンスによって評価され、この装置で各マウスは24rpmまでの速度で回転するロッド上に2分間マウスを置くことからなる1日当たり4回の訓練試験を受け、ロータロッドから発泡ゴムパッディング上に落下するレイテンシが測定され、マウスが落ちていない場合、2分後に試験が終了する。
オープンフィールド動作;オープンフィールドアセスメントは、一般的な社会的行動を評価するために使用される。実験動物は標準オープンフィールドアリーナ内に置かれ、動作がコンピュータトラッキング(Ethovision)によって1日あたり最大2時間モニタリングされる。移動全体が測定され、アリーナの中央部にいた時間および後脚で立っていた時間が、不安を感じているような行動の指標となるであろう。
Claims (9)
- 疼痛状態に用いられる、請求項1から4のいずれか1つに記載の式(I)の化合物。
- 前記疼痛状態が急性疼痛を指す、請求項5に記載の式(I)の化合物。
- 前記疼痛状態が慢性疼痛を指す、請求項5に記載の式(I)の化合物。
- 前記疼痛状態が、変形性関節症または線維筋痛症によって引き起こされる痛みなどの慢性関節痛を指す、請求項7に記載の式(I)の化合物。
- 有効成分として請求項1から4に記載の少なくとも1つの式(I)の化合物またはその生理学的に許容可能な塩を、薬学的に許容可能な担体と一緒に含む医薬組成物。
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HUE050241T2 (hu) | 2020-11-30 |
EP3233825B1 (en) | 2020-04-29 |
AU2015363757A1 (en) | 2017-08-03 |
CN107531670A (zh) | 2018-01-02 |
AU2015363757B2 (en) | 2019-11-14 |
LT3233825T (lt) | 2020-08-10 |
CN107531670B (zh) | 2020-12-15 |
CA2970256C (en) | 2022-03-29 |
ES2808667T3 (es) | 2021-03-01 |
EP3233825A1 (en) | 2017-10-25 |
HRP20201050T1 (hr) | 2020-10-30 |
JP6691135B2 (ja) | 2020-04-28 |
US10118921B2 (en) | 2018-11-06 |
PT3233825T (pt) | 2020-07-15 |
DK3233825T3 (da) | 2020-06-29 |
SI3233825T1 (sl) | 2020-10-30 |
EP3233825A4 (en) | 2018-08-15 |
PL3233825T3 (pl) | 2020-11-02 |
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