JP2020515555A - 多発性硬化症の新規治療方法 - Google Patents
多発性硬化症の新規治療方法 Download PDFInfo
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- JP2020515555A JP2020515555A JP2019552879A JP2019552879A JP2020515555A JP 2020515555 A JP2020515555 A JP 2020515555A JP 2019552879 A JP2019552879 A JP 2019552879A JP 2019552879 A JP2019552879 A JP 2019552879A JP 2020515555 A JP2020515555 A JP 2020515555A
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- multiple sclerosis
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- 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
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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Abstract
Description
a)希釈剤、例えば、ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロース及び/又はグリシン;
b)潤滑剤、例えば、シリカ、タルカム、ステアリン酸若しくはそのマグネシウム塩若しくはカルシウム塩及び/又はポリエチレングリコール;錠剤の場合、さらに
c)結合剤、例えば、ケイ酸アルミニウムマグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロース、ナトリウムカルボキシメチルセルロース及び/又はポリビニルピロリドン;要望に応じて
d)崩壊剤、例えば、デンプン、寒天、アルギン酸若しくはそのナトリウム塩、又は発泡性混合物;並びに
e)吸収剤、着色剤、着香剤及び甘味料
の1つ又は複数と一緒に、活性成分を含む錠剤又はゼラチンカプセルである。
(1)経口プレドニゾン及び静脈内メチルプレドニゾロンなどのコルチコステロイド
(2)Avonex(登録商標)、Betaferon(登録商標)、Extavia(登録商標)、Plegridy(登録商標)又はRebif(登録商標)などのβインターフェロン
(3)オクレリズマブ(Ocrevus(登録商標))
(4)グラチラマー酢酸塩(Copaxone(登録商標))
(5)フマル酸ジメチル(Tecfidera(登録商標))
(6)フィンゴリモド(Gilenya(登録商標))
(7)テリフルノミド(Aubagio(登録商標))
(8)ナタリズマブ(Tysabri(登録商標))
(9)アレムツズマブ(Lemtrada(登録商標))又は
(10)ミトキサントロン。
以下に記載する実施例では、当技術分野で公知の方法を用いて、4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミドHCl塩を合成した。以下のアッセイ及び結果では、4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミドHCl塩は、BLZ945と呼ばれる、又は名付けられる。
以下に記載する試験は、ライセンス番号2711の下で、Swiss Cantonal Veterinary Authority of Basel City,Switzerlandにより承認された。マウス(C57BL/6J)は、Charles River Laboratories,Germanyからの市販のものを購入するか、又はNovartis Pharma AG飼育コロニー(8〜9週齢、雌)から取得した。動物は全て、実験開始前に7日間順応させ、IVCラック内に収容した(最大4匹/XJ型ケージ)。動物には不断給餌及び給水させた。動物をクプリゾンで5週間処置した。クプリゾン(ビス(シクロヘキサノン)オキサルジヒドラゾン、Sigma−Aldrich)は、Provimi Kliba AG,Switzerlandによりげっ歯動物用飼料ペレットに混合(0.2%w/w)した。クプリゾン後の動物の治療的処置は、169mg/kgのBLZ945、qd、p.o.10mg/kgと共に通常飼料で2週間にわたり実施した。BLZ945は、0.5%メチルセルロースの水溶液及び0.1%Tween−80から構成されるビヒクルを用いて調製した。最後のBLZ945投与から3時間後に死なせる前に、動物をリン酸緩衝生理食塩水(PBS)で経心腔的に灌流し、脳を単離し、4%パラホルムアルデヒド(PFA)中に4℃で48時間固定した。
7Tで作動するBiospec 70/30分光計(Bruker Medical Systems,Ettlingen,Germany)を用いて、測定を実施した。スキャナーの操作ソフトウエアは、Paravision 5.1(Bruker)であった。無線周波数励起及び検出のためのマウス脳円偏波コイル(Bruker,Model 1P T20063V3;内径23mm)を用いて、麻酔され、自発呼吸する動物から画像を収集し;その際、心臓又は呼吸同期のいずれも適用しなかった。箱の中への短時間の導入の後、ノーズコーンを介して投与する酸素中の1.5%イソフルラン(Abbott,Cham,Switzerland)を用いた麻酔に動物を維持した。MRIシグナル収集の間、Plexiglas製のクレードル内で動物を腹臥位に配置し、加熱パッドを用いて体温を37±1℃に保ち、呼吸をモニターした。
固定の後、エタノール系の増加による脱水によって、パラフィン包埋のために脳を処理した。SuperFrost+スライドガラスに載せた3μmパラフィン切片に対して、パラフィン切片の自動免疫組織化学を実施し、Discovery XT technology(Ventana/Roche Diagnostics)を用いて自動免疫染色した。手短には、切片を脱パラフィンし、再水和してから、CCl細胞馴化バッファーと一緒に加熱することにより抗原賦活化に付し、抗体希釈剤で希釈した一次抗体と一緒に室温で1〜3時間インキュベートし、抗体希釈物で希釈したそれぞれのビオチン化二次抗体と一緒にインキュベートし、DABMabキットと反応させた後、ヘマトキシリン(Hematoxylin)II及びBluing Agent試薬(Ventana/Roche Diagnostics)で対比染色した。石鹸を用いてスライドガラスを温水で洗浄してから、冷水の水道水ですすぐことにより石鹸を除去した後、脱水し、Pertexで包埋した。
一次抗体及び抗体希釈物:ウサギ抗マウスミエリン塩基性タンパク質(MBP,Dako A0623)、Ventana Antibody Diluent中1:1000、Dako Diluent(Dako S2022)中1:1500;ウサギ抗マウスGST−π(MBL 312)、Ventana Antibody Diluent中1:500、Dako Diluent(Dako S2022)中1:1000;ウサギ抗Iba1(Wako019−19741、50ug/100ul)、Ventana Antibody Diluent中1:500;ウサギ抗GFAP(Dako Z0334)、Ventana Antibody Diluent中1:5000;ウサギ抗マウスミエリン希突起膠細胞糖タンパク質(MOG、abcam ab32760)、Ventana Antibody Diluent中1:100、Dako Diluent(Dako S2022)中1:600。
組織染色した脳切片からの画像解析に基づくミクログリア/星状膠細胞数の定量評価のために、MS Visual Studio 2010及びMatrox MIL V9 libraries(Matrox Inc,Quebec,Canada)からの多数の機能に基づいて専有画像解析プラットフォーム(ASTORIA,Automated Stored Image Analysis)を開発した。
図1:クプリゾン中毒後2週間のBLZ945による治療的処置は、髄鞘形成増大を示すビヒクル対照と比較して、皮質及び線条体ではMRIコントラストを低減するが、脳梁では低減しない。様々な処置群の皮質(図1A)、線条体(図1B)及び脳梁(図1C)の磁気共鳴画像(MRI)コントラスト。MRIコントラストをビヒクル対照群(通常飼料)の絶対値に対して正規化する。これらの群は、通常飼料又はクプリゾン飼料(0.2%)で5週間処置した後、2週間の治療的処置のために通常飼料(ビヒクル又はBLZ945p.o.、qd、169mg/kg)に取り替えたマウスから構成される。様々な処置群について脳梁のMRIで磁化移動率(MTR)を測定する(図1D)。2つの異なる実験(グレー及び黒色)の個別の結果を示す。統計値:テューキーの多重比較検定(**:p<0.01、***:p<0.001、****:p<0.0001、n.s.:有意ではない)。
以下に記載する試験は、ライセンス番号2119の下、Swiss Cantonal Veterinary Authority of Basel City,Switzerlandにより承認された。
図8:実験的自己免疫性脳脊髄炎(EAE)マウスにおける治療的BLZ945処置は、疾患進行を変化させなかった。ミエリン希突起膠細胞糖タンパク質ペプチド免疫付与後の臨床スコアの評価により、全ての処置群で類似の疾患進行(図8A)、疾患発症/発生率(図8B)及び体重変化(図8C)が現れた。BLZ945処置は、免疫付与から14日後に開始し、14日間にわたって最大臨床スコア付近であった(グレイの陰影部)。実験は免疫付与から28日後に終了した。
以下に記載する試験は、ライセンス番号2711の下で、Swiss Cantonal Veterinary Authority of Basel City,Switzerlandにより承認された。マウス(C57BL/6J)は、Charles River Laboratories,Germanyから市販のものを購入するか、又はNovartis Pharma AG飼育コロニー(8〜9週齢、雌)から取得した。動物は全て、実験開始前に7日間順応させ、IVCラック内に収容した(最大4匹/XJ型ケージ)。動物は、不断給餌及び給水させた。動物をクプリゾンで5週間処置した。クプリゾン(ビス(シクロヘキサノン)オキサルジヒドラゾン、Sigma−Aldrich)は、Provimi Kliba AG,Switzerlandにより、げっ歯動物用飼料ペレットに混合(0.2%w/w)した。クプリゾン後の動物の治療的処置は、20及び60mg/kgのBLZ945を含む通常飼料を用い、qd、p.o.10mg/kgで2週間にわたり実施した。BLZ945は、0.5%メチルセルロースの水溶液及び0.1%Tween−80から構成されるビヒクルを用いて調製した。最後のBLZ945投与から3時間後に死なせる前に、動物をリン酸緩衝生理食塩水(PBS)で経心腔的に灌流し、脳を単離し、4%パラホルムアルデヒド(PFA)中に4℃で48時間固定した。
7Tで作動するBiospec 70/30分光計(Bruker Medical Systems,Ettlingen,Germany)を用いて、測定を実施した。スキャナーの操作ソフトウエアは、Paravision 5.1(Bruker)であった。無線周波数励起及び検出のためのマウス脳円偏波コイル(Bruker,Model 1P T20063V3;内径23mm)を用いて、麻酔され、自発呼吸する動物から画像を収集し;心臓又は呼吸同期のいずれも適用しなかった。箱の中への短時間の導入の後、ノーズコーンを介して投与する酸素中1.5%イソフルラン(Abbott,Cham,Switzerland)を用いた麻酔に動物を維持した。MRIシグナル収集の間、Plexiglas製のクレードル内で動物を腹臥位に配置し、加熱パッドを用いて体温を37±1℃に保ち、呼吸をモニターした。
改変タンパク質沈殿方法に基づいてサンプル調製及び分析を行った後、検出のために質量分析法と組み合わせた液体クロマトグラフィー分離を実施した。20%CH3OHを0.20g/mLの最終濃度まで添加することにより、gentleMACS(商標)Dissociator(Milteniy Biotec,♯130−093−235)中で小脳を均質化した。さらなる調製のために、血液−EDTAサンプルを直接使用した。既知量のBLZ945(0.02〜62.5μg/mL)を含むブランク血液及びブランク脳ホモジネートを添加することにより、較正、クオリティーコントロール、リカバリーコントロールサンプルを調製した。検体決定のために、ラベタロール(Labetalol)塩酸塩(Sigma−Aldrich,♯L1011)を一般的な内部標準(IS)として使用した。10μLの較正標準、クオリティーコントロール、リカバリーコントロール、及び不明サンプルのアリコートを0.75mlの96ウェル−Loborack(Vitaris AG,♯51004BC−MIC)に移し、3μLのIS混合物(50%CH3CN中2.5μg/mL)を各試験管に添加した。血液及び脳マトリックスからのタンパク質沈殿及び抽出のために、200μlのCH3CNを添加した。10分間のボルテックスの後、サンプルを3220gで、4℃にて15分間遠心分離した。50μlの上層を1.2mL 96ディープウェルプレート(Thermo Scientific,♯AB−0787)に移した。
固定の後、エタノール系の増加による脱水によって、パラフィン包埋のために脳を処理した。SuperFrost+スライドガラス(Thermo Fisher Scientific)に載せた3μmパラフィン切片に対して、パラフィン切片の自動免疫組織化学を実施した後、Discovery XT technology(Ventana,Roche Diagnostics)を用いて、自動免疫染色した。切片を脱パラフィン、再水和し、抗体に応じて26〜68分間CCl細胞馴化バッファーと一緒に加熱することにより抗原賦活化に付し、抗体希釈剤(Ventana)で希釈した一次抗体と一緒に室温で、抗体に応じて1〜3時間インキュベートし、抗体希釈物で希釈したそれぞれのビオチン化二次抗体と一緒にインキュベートし、DABMabキットと反応させた後、ヘマトキシリンII及びBluing試薬(Ventana)で対比染色した。石鹸を用い、スライドガラスを温水で洗浄してから、冷水の水道水ですすぐことにより石鹸を除去した後、脱水し、Pertexで包埋した。
一次抗体は、下記の通りである:ウサギ抗Iba1(Wako 019−19741、50μg/100μl)1:500;ウサギ抗GFAP(Dako Z0334)1:5000。
組織染色した脳切片からの画像解析に基づくミクログリア/星状膠細胞数の定量評価のために、MS Visual Studio 2010及びMatrox MIL V9 libraries(Matrox Inc,Quebec,Canada)からの多数の機能に基づいて専有画像解析プラットフォーム(ASTORIA,Automated Stored Image Analysis)を開発した。
図9:クプリゾン中毒後2週間のBLZ945による治療的処置は、髄鞘形成増大を示すビヒクル対照と比較して、皮質及び線条体ではMRIコントラストを低減するが、脳梁では低減しない。様々な処置群の皮質(図9A)、線条体(図9B)及び脳梁(図9C)の磁気共鳴画像(MRI)コントラスト。MRIコントラストを、ビヒクル対照群(通常飼料)の絶対値に対して正規化する。これらの群は、通常飼料又はクプリゾン飼料(0.2%)で5週間処置した後、2週間の治療的処置のために通常飼料(ビヒクル又はBLZ945p.o.、qd、20及び60mg/kg)に取り替えたマウスから構成される。平均±SEM。統計値:ホルム・シダック(Holm Sidak)の多重比較検定(**:p<0.01、**:p<0.005)。
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Claims (20)
- 多発性硬化症の治療方法であって、有効量の式(I):
- 前記被験者が、霊長類である、請求項1に記載の方法。
- 前記被験者が、ヒトである、請求項2に記載の方法。
- 前記式(I)の化合物が、遊離塩基として投与される、請求項1〜3のいずれか1項に記載の方法。
- 前記薬学的に許容される塩が、HClである、請求項1〜3のいずれか1項に記載の方法。
- 前記多発性硬化症が、初回発作状態である、請求項1〜3のいずれか1項に記載の方法。
- 前記多発性硬化症が、再発寛解型多発性硬化症である、請求項1〜3のいずれか1項に記載の方法。
- 前記多発性硬化症が、一次性進行型多発性硬化症又は二次性進行型多発性硬化症である、請求項1〜3のいずれか1項に記載の方法。
- 多発性硬化症の治療が必要なヒトへの4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩の投与を含む、多発性硬化症の治療方法であって、4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩が、1日当たり約250mg〜約350mgの用量で投与される方法。
- 前記用量が、1日当たり約275mg〜約325mgである、請求項9に記載の方法。
- 前記用量が、1日当たり約300mgである、請求項10に記載の方法。
- 4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩を連続して4〜6日間投与した後、−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩の投与を停止する、請求項9〜11のいずれか1項に記載の方法。
- 4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩を連続して4日間投与した後、4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩の投与を停止する、請求項12に記載の方法。
- 4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩の投与は、前期ヒトが、多発性硬化症を有すると最初に診断されたとき開始する、請求項12又は13に記載の方法。
- 有効量の4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩を別の治療薬と組み合わせて、それを必要とする被験者に投与することを含む、多発性硬化症の治療方法。
- 4−(2−((1R,2R)−2−ヒドロキシシクロヘキシルアミノ)ベンゾチアゾール−6−イルオキシ)−N−メチルピコリンアミド又はその薬学的に許容される塩が個別に、又は他の薬剤と同じ若しくは異なる投与経路により投与される、請求項15に記載の方法。
- 前記他の治療薬が、コルチコステロイド、βインターフェロン、オクレリズマブ、グラチラマー酢酸塩、フマル酸ジメチル、フィンゴリモド、テリフルノミド、ナタリズマブ、アレムツズマブ又はミトキサントロンである、請求項16に記載の方法。
- 多発性硬化症の治療における式(I):
- 多発性硬化症の治療における使用のための式(I):
- 治療法が、多発性硬化症から選択される疾患である、請求項11に記載の使用。
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