JP6889493B2 - 脳卒中からの回復のための方法および組成物 - Google Patents
脳卒中からの回復のための方法および組成物 Download PDFInfo
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- JP6889493B2 JP6889493B2 JP2018521382A JP2018521382A JP6889493B2 JP 6889493 B2 JP6889493 B2 JP 6889493B2 JP 2018521382 A JP2018521382 A JP 2018521382A JP 2018521382 A JP2018521382 A JP 2018521382A JP 6889493 B2 JP6889493 B2 JP 6889493B2
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Description
本出願は、その全体の内容が参照により本明細書に組み込まれる、2015年10月26日に出願された米国仮出願第62/246,574号の利益を主張する。
いくつかの実施形態では、本発明は、虚血損傷からの神経学的回復を促進するためのp38−αMAPK阻害剤を含む方法および組成物を含む。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
神経損傷を患う対象における機能の回復を促進する方法であって、VX−745を含む組成物を前記対象に投与するステップを含む、方法。
(項目2)
前記神経損傷が急性虚血発作に起因する、項目1に記載の方法。
(項目3)
前記脳卒中は血栓性脳卒中である、項目2に記載の方法。
(項目4)
前記脳卒中は塞栓性脳卒中である、項目2に記載の方法。
(項目5)
前記投与するステップが、脳卒中症状の発症の24時間以上後に開始される、項目2に記載の方法。
(項目6)
前記投与するステップが、脳卒中症状の発症の48時間以上後に開始される、項目2に記載の方法。
(項目7)
前記投与するステップが、脳卒中症状の発症の72時間以上後に開始される、項目2に記載の方法。
(項目8)
前記投与するステップが、一定の間隔でVX−745を含む組成物を投与することを含む、項目2に記載の方法。
(項目9)
前記一定の間隔は、週2回、週3回、毎日、1日2回、および8時間毎、からなる群から選択される、項目8に記載の方法。
(項目10)
前記投与するステップが経口投与するステップを含む、項目1に記載の方法。
(項目11)
対象における虚血損傷からの神経学的回復を促進する方法であって、VX−745を含む組成物を前記対象に投与することを含む、方法。
(項目12)
前記虚血損傷は脳卒中に起因する、項目11に記載の方法。
(項目13)
前記投与するステップが、脳卒中症状の発症の24時間以上後に開始される、項目12に記載の方法。
(項目14)
前記投与するステップが、脳卒中症状の発症の48時間以上後に開始される、項目12に記載の方法。
(項目15)
前記投与するステップが、脳卒中症状の発症の72時間以上後に開始される、項目12に記載の方法。
(項目16)
前記投与するステップが、一定の間隔でVX−745を含む組成物を投与することを含む、項目11に記載の方法。
(項目17)
前記投与するステップが経口投与を含む、項目11に記載の方法。
(項目18)
神経損傷を患う対象における機能の回復を促進する医薬組成物であって、治療上有効な量のVX−745および薬学的に許容可能な担体または賦形剤を含む、組成物。
(項目19)
神経損傷を患う対象における機能の回復を促進する方法における使用のための組成物であって、VX−745を含む、組成物。
(項目20)
神経損傷を患う対象における機能の回復を促進するための医薬品の製造における、VX−745を含む組成物の使用。
(項目21)
前記神経損傷が急性虚血発作に起因する、項目17から20のいずれかに記載の組成物または使用。
(項目22)
前記脳卒中は血栓性脳卒中である、項目21に記載の組成物または使用。
(項目23)
前記脳卒中は塞栓性脳卒中である、項目21に記載の組成物または使用。
(項目24)
前記組成物の投与が、脳卒中症状の発症の24時間以上後に開始される、項目21に記載の組成物または使用。
(項目25)
前記組成物の投与が、脳卒中症状の発症の48時間以上後に開始される、項目21に記載の組成物または使用。
(項目26)
前記組成物の投与が、脳卒中症状の発症の72時間以上後に開始される、項目21に記載の組成物または使用。
担体 用語「担体」は、(例えば、生物活性を有する)作用物質の安定性および/または活性を有意に妨害することなく活性薬剤(例えば、p38αMAPK阻害剤)を含有する組成物に組み込むことができる化学成分を指す。特定の実施形態では、用語「担体」は、薬学的に許容可能な担体を指す。本明細書の例示的な担体は水である。
p38−αMAPK阻害剤
いくつかの実施形態では、p38−αMAPK阻害剤はp38−αMAPKに選択的に結合する。選択的p38−αMAPK阻害剤は、p38−βMAPK、p38−γMAPKおよびp38−δMAPKよりもp38−αMAPKに対する親和性が大きい。いくつかの実施形態では、選択的p38−αMAPK阻害剤は、p38−βMAPK、p38−γMAPK、またはp38−δMAPKのいずれかよりも、p38−αMAPKに対して少なくとも5、10、20、30または50倍高い親和性を有する。
いくつかの実施形態において、p38−αMAPK阻害剤は、p38−αMAPKの触媒部位に結合する。いくつかの実施形態において、p38−αMAPK阻害剤は、アデノシン三リン酸(ATP)のアデニン環に結合し、ATP結合を競合的に阻害する。いくつかの実施形態では、p38−αMAPK阻害剤はカルボニル基を含み、p38−αMAPKのMet109とGly110アミノ酸残基との間でペプチドの反転を誘導する。いくつかの実施形態では、p38−αMAPK阻害剤は、p38−αMAPKのアミノ酸残基Met109と水素結合を形成する。いくつかの実施形態において、p38−αMAPK阻害剤は、上記の特性の1つ以上または全てを有する。
環Aは、フェニル;窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環;窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する6〜10員飽和又は部分不飽和二環式複素環;並びに、窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する7〜10員二環式ヘテロアリール環;から選択される任意に置換された環であり、
L1は、共有結合または任意に置換された直鎖または分岐鎖の二価のC1−6炭化水素鎖であり、式中、1つ以上のメチレン単位は、−NR−、−O−、−S−、−C(O)−、またはフェニレン;窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する3〜8員飽和または部分不飽和単環式複素環;窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環;窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する6〜10員飽和又は部分不飽和二環式複素環;並びに、窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する7〜10員二環式ヘテロアリール環;から選択される任意に置換された二価の環で、任意に置換されていてもよく、
各Rは、独立して、水素、または、C1−6脂肪族;3〜8員飽和または部分不飽和単環式炭素環式環;フェニル;8〜10員二環式アリール環;窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する3〜8員飽和または部分不飽和単環式複素環;窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環;窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する6〜10員飽和又は部分不飽和二環式複素環;並びに、窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する7〜10員二環式ヘテロアリール環;から選択される任意に置換された基であり、
Rxは、独立して、R、ハロゲン、−NR2、OR、または、フェニル、窒素、酸素および硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環;窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する6〜10員飽和または部分不飽和二環式複素環;並びに、窒素、酸素及び硫黄から独立して選択される1〜5個のヘテロ原子を有する7〜10員二環式ヘテロアリール環;から選択される任意に置換された環である。
Q1を構成する環は、1〜4個の置換基で置換されており、その各々は、ハロ;NR’2、OR’、CO2R’、もしくはCONR’2で任意に置換されたC1−C3アルキル;NR’2、OR’、CO2R’、もしくはCONR’2で任意に置換されたO−(Cl−C3)−アルキル;NR’2;OCF3;CF3;NO2;CO2R’;CONHR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;または、N=CH−N(R’)2、から独立して選択される。
Q2を構成する環は、4個までの置換基で置換されていてもよく、その各々は、ハロ;NR’2、OR’、CO2R’、S(O2)N(R’)2、N=CH−N(R’)2、R3、またはCONR’2で任意に置換されたC1−C3直鎖または分岐アルキル;O−(C1−C3)−アルキル;NR’2、OR’、CO2R’、S(O2)N(R’)2、N=CH−N(R’)2、R3、またはCONR’2で任意に置換されたO−(C1−C3)−アルキル;NR’2;OCF3;CF3;NO2;CO2R’;CONHR’;R3;OR3;NHR3;SR3;C(O)R3;C(O)N(R’)R3;C(O)OR3;SR’;S(O2)N(R’)2;SCF3;N=CH−N(R’)2;またはCN、から独立して選択される。
R’は、水素、(C1−C3)−アルキル;(C2−C3)−アルケニルまたはアルキニル;フェニルまたはハロ、メトキシ、シアノ、ニトロ、アミノ、ヒドロキシ、メチルまたはエチルから独立して選択される1〜3個の置換基で置換されたフェニルから選択される。
R3は、5〜6員の芳香族炭素環式または複素環式環系から選択される。
R4は、N(R’)2、OR’、CO2R’、CON(R’)2、もしくはSO2N(R2)2で任意に置換された(C1−C4)−−アルキル、または、N(R’)2、OR’、CO2R’、CON(R’)2、もしくはSO2N(R2)2で任意に置換された5〜6員炭素環式または複素環式環系である。
Xは、−S−、−O−、−S(O2)−、−S(O)−、−S(O2)−N(R2)−、−N(R2)−S(O2)−、−N(R2)−C(O)O−、−O−C(O)−N(R2)、−C(O)−、−C(O)O−、−O−C(O)−、−C(O)−N(R2)−、−N(R2)−C(O)−、−N(R2)−C(R2)2−、または−C(OR2)2−から選択される。
各Rは、水素、−R2、−N(R2)2、−OR2、SR2、−C(O)−N(R2)2、−S(O2)、−N(R2)2,または−C(O)−OR2から独立して選択され、式中、2つの隣接するRは、任意で互いに結合し、それぞれ結合しているYと一緒になって、4〜8員の炭素環または複素環を形成する。
2つのR成分がそれぞれ結合しているY成分と一緒に環を形成する場合、各未融合R成分からの末端水素が失われることは当業者には明らかであろう。例えば、2つのR成分を一緒に結合することによって環構造が形成される場合(一方は−NH−CH3であり、他方は−CH2−CH3である)、各R成分上の一方の末端水素(太字で示す)は失われる。従って、環構造の得られる部分は、式−NH−CH2−CH2−CH2−を有する。
R2は、水素、(C1−C3)−アルキルまたは(C2−C3)アルケニルから選択され、任意に−N(R’)2、−OR’、SR’、−C(O)−N(R’)2、−S(O2)−N(R’)2、−C(O)−OR’、またはR3で置換される。
YはNまたはCであり;
Aは、存在する場合は、NまたはCRであり、
Nは0または1であり、
R1は、水素、(C1−C3)アルキル、OH、またはO−(C1−C3)−アルキルから選択される。R1がOHである場合、得られた阻害剤は互変異性化して式:
VX−745
脳卒中
脳卒中からの回復
回復を促進するP38MAPK阻害
本発明の方法
医薬組成物
投薬
併用療法
この実施例は、脳卒中のラットモデルにおいて、機能的な感覚運動回復を高めるVX−745化合物による遅延治療の有効性を示す。この試験のエンドポイントには、mNSSスコア(Neuroscore)、ステッピングテスト(ST)、ボディスイングテスト(BSW)、前肢配置テスト(FLP)、体重測定および脳採取が含まれた。
実験的試験設計
人道的なエンドポイント
試験開始定義
準備と麻酔
動物
動物を以下のように分類した:
グループ1M:3日目(1日目が脳卒中手術の日)から42日目(PO強制飼養を介して)にビヒクルを1日2回投与した20のtMCAO動物
グループ2M:3日目(1日目は脳卒中手術の日)から42日目(PO胃管栄養法による)までVX−745(1.5mg/kg)で1日2回治療した22のtMCAO動物
グループ3M:3日目(1日目が脳卒中手術の日)から42日目(PO胃管栄養法を介して)までVX−745(4.5mg/kg)で1日2回治療した21のtMCAO動物
実験手順
一過性中大脳動脈閉塞(tMCAO)
試験アイテムの投与
治療、手術、および行動テストのタイムテーブル
投与前の行動習慣試験
前肢配置試験(0−12):
ウィスカー配置(0−2);
視覚的な配置(前方(0−2)、後方(0−2)
触覚配置(背側(0−2)、側方(0−2)
固有感覚配置(0−2)。
サンプル採取と屠殺
IL−1β分析
データ分析
結果
死亡率と臨床徴候
体重モニタリング
神経学的症状試験スコア(ニューロスコア)
ステッピングテストのスコア
前肢配置試験のスコア
ボディスイングテストのスコア
IL−1β ELISA
ディスカッション
均等と適用範囲
Claims (27)
- 神経損傷を患う対象における機能の回復を促進するための、VX−745を含む組成物であって、前記神経損傷は脳卒中に起因し、前記組成物の前記対象への投与は脳卒中症状の発症の24時間以上後に開始されることを特徴とする、組成物。
- 前記神経損傷が急性虚血発作に起因する、請求項1に記載の組成物。
- 前記脳卒中は血栓性脳卒中である、請求項2に記載の組成物。
- 前記脳卒中は塞栓性脳卒中である、請求項2に記載の組成物。
- 前記組成物の前記投与が、脳卒中症状の発症の48時間以上後に開始されることを特徴とする、請求項1に記載の組成物。
- 前記組成物の前記投与が、脳卒中症状の発症の72時間以上後に開始されることを特徴とする、請求項1に記載の組成物。
- 前記組成物が、一定の間隔で投与されることを特徴とする、請求項1に記載の組成物。
- 前記一定の間隔は、週2回、週3回、毎日、1日2回、および8時間毎、からなる群から選択される、請求項7に記載の組成物。
- 前記組成物が経口投与されることを特徴とする、請求項1に記載の組成物。
- 対象における虚血損傷からの神経学的回復を促進するための、VX−745を含む組成物であって、前記虚血損傷は脳卒中に起因し、前記組成物の前記対象への投与は脳卒中症状の発症の24時間以上後に開始されることを特徴とする、組成物。
- 前記組成物の前記投与が、脳卒中症状の発症の48時間以上後に開始されることを特徴とする、請求項10に記載の組成物。
- 前記組成物の前記投与が、脳卒中症状の発症の72時間以上後に開始されることを特徴とする、請求項10に記載の組成物。
- 前記組成物が、一定の間隔で投与されることを特徴とする、請求項10に記載の組成物。
- 前記組成物が経口投与されることを特徴とする、請求項10に記載の組成物。
- 神経損傷を患う対象における機能の回復を促進する医薬組成物であって、前記神経損傷は脳卒中に起因し、前記組成物は治療上有効な量のVX−745および薬学的に許容可能な担体または賦形剤を含み、前記組成物の投与は脳卒中症状の発症の24時間以上後に開始されることを特徴とする、組成物。
- 神経損傷を患う対象における機能の回復を促進する方法における使用のための組成物であって、前記神経損傷は脳卒中に起因し、前記組成物はVX−745を含み、前記組成物の投与は脳卒中症状の発症の24時間以上後に開始されることを特徴とする、組成物。
- 神経損傷を患う対象における機能の回復を促進するための医薬品の製造における、VX−745を含む組成物の使用であって、前記神経損傷は脳卒中に起因し、前記医薬品の投与は脳卒中症状の発症の24時間以上後に開始されることを特徴とする、使用。
- 前記神経損傷が急性虚血発作に起因する、請求項15もしくは16に記載の組成物。
- 前記脳卒中は血栓性脳卒中である、請求項18に記載の組成物。
- 前記脳卒中は塞栓性脳卒中である、請求項18に記載の組成物。
- 前記組成物の投与が、脳卒中症状の発症の48時間以上後に開始されることを特徴とする、請求項15もしくは16に記載の組成物。
- 前記組成物の投与が、脳卒中症状の発症の72時間以上後に開始されることを特徴とする、請求項15もしくは16に記載の組成物。
- 前記神経損傷が急性虚血発作に起因する、請求項17に記載の使用。
- 前記脳卒中は血栓性脳卒中である、請求項23に記載の使用。
- 前記脳卒中は塞栓性脳卒中である、請求項23に記載の使用。
- 前記医薬品の投与が、脳卒中症状の発症の48時間以上後に開始されることを特徴とする、請求項17に記載の使用。
- 前記医薬品の投与が、脳卒中症状の発症の72時間以上後に開始されることを特徴とする、請求項17に記載の使用。
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