JP2022505172A - カルバメート化合物の糖尿病性末梢神経障害又は化学療法剤誘発性末梢神経障害の予防、緩和又は治療のための使用 - Google Patents
カルバメート化合物の糖尿病性末梢神経障害又は化学療法剤誘発性末梢神経障害の予防、緩和又は治療のための使用 Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
(式中、R1及びR2は、それぞれ独立して、水素、ハロゲン、C1-C8アルキル、C1-C8ハロアルキル、C1-C8チオアルコキシ及びC1-C8アルコキシからなる群から選ばれ、A1及びA2の一つは、CHであり、他の一つはNである)
で示されるカルバメート化合物、又はその薬学的に許容可能な塩、溶媒和物又は水和物を含む、糖尿病性末梢神経障害又は化学療法剤誘発性末梢神経障害の予防、緩和又は治療用薬剤を提供する。
以下で、本願発明について、実施例を通じてより詳細に説明する。しかし、以下の実施例は、一つ以上の実施形態を例示的に説明することのみを意図しており、本発明の範囲を限定することを意図していない。
カルバミン酸(R)-1-(2-クロロフェニル)-2-テトラゾール-2-イル)エチルエステル(以下、「試験化合物」という)を国際公開番号WO2010/150946号の製造例50に記載された方法に従って製造した。
糖尿病及び糖尿病性末梢神経障害のモデルとして広く知られているストレプトゾトシン(STZ)誘発ラットモデルにより、試験化合物による糖尿病性末梢神経障害緩和効果を確認した。
雄ラット(Sprague-Dawley, 160-180g, Harlan Laboratories, Israel)を購入し、動物実験室で1週間以上馴化させた。実験動物は12時間の明暗周期、20~24℃の温度、40~60%の相対湿度に維持され、水と餌への自由なアクセスできるようにした。
痛みの程度は、Von Freyフィラメントを使用した離脱(回避反応)で評価した。機械的刺激は、up-down方法を使用して右後足に刺激を加え、回避反応を示す最小の曲げ力を足引っ込め閾値(paw withdrawal threshold)と定義した(J Neurosci Methods, 1994; 53 (1): 55-63)。まず、ラットを床から約35cmの高さに金網の底があるアクリルボックス(13×25×13cm3)に入れ、20分以上安定させた。様々な曲げ力(0.008、0.02、0.04、0.07、0.16、0.4、0.6、1.0、1.4、2.0、4.0、6.0、8.0、10.0、15.0、26.0、60.0、100、180及び300g)のVon Freyフィラメント中で、刺激は2.0gのフィラメントで開始した。足底表面に垂直方向に僅かに曲がる程度に刺激を加え、反応の有無に応じて、曲げ力を弱めたり強めたりするフィラメントでラットを刺激した。
この実験は、ストレプトゾトシン(STZ)により誘発されたラットの糖尿病性末梢神経障害性の痛みモデルにおいて、2種類の異なる用量(10mg/kg及び30mg/kg)での化合物治療の鎮痛効果を調査するために行われた。
1)試験化合物10mg/kgと30mg/kgのVon Freyテスト結果:
14日及び24日目にビヒクルを投与した群と比較して、ベースラインで陰性対照群の動物の回避反応を誘発するのに必要な平均曲げ力は、60.00±0.00gであった。実験14日目に、薬物投与前に、機械的異痛による離脱曲げ力(18.55±2.47g)が有意に低下し、実験24日目に、薬物投与前に、機械的異痛はまだ存在していた(23.00±5.35g)。
実験14日目に、陽性対照群投与前の18.15±2.07gの曲げ力をガバペンチン(150mg/kgIP)投与後51.85±4.91gに変更し、異痛誘発が有意に抑制されたことを示した。試験化合物(10mg/kgPO)投与後、投与前の18.23±2.66gの曲げ力を46.09±4.48gに変更し、異痛誘発が有意に抑制されたことを示した。試験化合物(30mg/kgPO)投与の場合、投与前の18.23±2.17gの曲げ力が投与後に50.23±3.89gに変更し、異痛誘発が有意に抑制されたことも示された。
本発明によれば、DPNのストレプトゾトシン誘発ラットモデルにおいて、異痛に対するDPN治療に使用される陽性対照群であるガバペンチンの最高用量(150mg/kg)と比較したとき、低用量の試験化合物(10mg/kg)は、陰性対照群と比較して約75%の痛み減少を示しており、これは、ガバペンチン150mg/kgと同様の効果である。このような結果か、ら試験化合物10mg/kg及び30mg/kgの投与は、機械的異痛の抑制に効果的であることが確認された。このことから、試験化合物の投与は糖尿病性末梢神経障害に有効であることが分かる。
実験動物
雄ラット(Sprague-Dawley, 160-180g, Harlan Laboratories, Israel)を購入し、動物実験室で1週間以上馴化させた。実験動物は12時間の明暗周期、20~24℃の温度、40~60%の相対湿度に維持され、水と餌への自由なアクセスできるようにした。
痛みの程度は、Von Freyフィラメントを使用した離脱(回避反応)で評価した。機械的刺激は、up-down方法を使用して右後足に刺激を加え、回避反応を示す最小の曲げ力を足引っ込め閾値(paw withdrawal threshold)と定義した(J Neurosci Methods, 1994; 53 (1): 55-63)。まず、ラットを床から約35cmの高さに金網の底があるアクリルボックス(13×25×13cm3)に入れ、20分以上安定させた。様々な曲げ力(0.008、0.02、0.04、0.07、0.16、0.4、0.6、1.0、1.4、2.0、4.0、6.0、8.0、10.0、15.0、26.0、60.0、100、180及び300g)のVon Freyフィラメント中で、刺激は2.0gのフィラメントで開始した。足底表面に垂直方向に僅かに曲がる程度に刺激を加え、反応の有無に応じて、曲げ力を弱めたり強めたりするフィラメントでラットを刺激した。
末梢神経障害を誘導するために、固形癌の治療に一般的に使用される抗癌剤であるタキソール(2mg/kg)を1、3、5、7及び9日目に0.5mL/kgの容量で腹腔内(IP)投与した。異痛の誘発を確認するために、Von Freyテストが使用しており、この研究では、後足の平均疼痛閾値が43g以下の動物のみを含めた。
ラットへのタキソール投与による疼痛誘発モデルは、広く知られた化学療法剤誘発性末梢神経障害のモデルである。1日、3日、5日、7日及び9日目にタキソールを投与することによる痛覚過敏の誘発は、薬物治療前のVon Freyテストによって確認されており、実験期間中の痛覚過敏状態の維持は、13日目及び14日目の薬物治療後の陰性対照群(ビヒクル投与群)のデータから確認された。
本試験の条件下で得られた結果及び生活習慣データに限定された結果を考慮すると、試験化合物(10mg/kg)用量での投与は、末梢神経障害モデルにおいて機械的異痛を抑制する傾向を示すことが確認され、試験化合物(30mg/kg)用量での投与は、タキソール誘発性末梢神経障害モデルにおいて機械的異痛の有意な抑制を示した。このことから、試験化合物の投与が化学療法剤誘発性末梢神経障害に有効であることが分かった。
各実験群は、一元配置分散分析とテューキーの検定(Prism(登録商標)GraphPad)を使用して、陰性対照群と比較した。
Claims (14)
- R1及びR2が、それぞれ独立して、水素、ハロゲン及びC1-C8アルキルからなる群から選ばれる、請求項1に記載の薬剤。
- 哺乳動物投与用である、請求項1~3のいずれか1項に記載の薬剤。
- 前記式(1)のカルバメート化合物の治療有効量が、遊離形態の1日1回投与に基づいて、50~500mgである、請求項1~3のいずれか1項に記載の薬剤。
- 前記糖尿病性末梢神経障害が、有痛性糖尿病性末梢神経障害、糖尿病性自律神経障害、又はその両方である、請求項1に記載の薬剤。
- 前記化学療法剤誘発性末梢神経障害が、白金系薬物、タキサン及びビンカアルカロイドからなる群から選ばれる1種またはそれ以上である化学療法剤によって引き起こされる、請求項1に記載の薬剤。
- R1及びR2が、それぞれ独立して、水素、ハロゲン及びC1-C8アルキルからなる群から選ばれる、請求項8に記載の医薬組成物。
- 哺乳動物投与用である、請求項8~10のいずれか1項に記載の医薬組成物。
- 前記式(1)のカルバメート化合物の治療有効量が、遊離形態の1日1回投与に基づいて、50~500mgである、請求項8~10のいずれか1項に記載の医薬組成物。
- 前記糖尿病性末梢神経障害が、有痛性糖尿病性末梢神経障害、糖尿病性自律神経障害、又はその両方である、請求項8に記載の医薬組成物。
- 前記化学療法剤誘発性末梢神経障害が、白金系薬物、タキサン及びビンカアルカロイドからなる群から選ばれる1種またはそれ以上である化学療法剤によって引き起こされる、請求項8に記載の医薬組成物。
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AU2019361856A1 (en) | 2021-05-06 |
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BR112021006586A2 (pt) | 2021-07-27 |
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