JP2021513547A - ソベチロムの誘導体 - Google Patents
ソベチロムの誘導体 Download PDFInfo
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- JP2021513547A JP2021513547A JP2020543286A JP2020543286A JP2021513547A JP 2021513547 A JP2021513547 A JP 2021513547A JP 2020543286 A JP2020543286 A JP 2020543286A JP 2020543286 A JP2020543286 A JP 2020543286A JP 2021513547 A JP2021513547 A JP 2021513547A
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- disease
- compound according
- alkyl
- pharmaceutically acceptable
- demyelinating
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- 208000027765 speech disease Diseases 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004927 thianaphthalenyl group Chemical group S1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 150000004669 very long chain fatty acids Chemical class 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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Abstract
Description
甲状腺ホルモン(TH)は、発生の間のオリゴデンドロサイト分化及びミエリン形成の重要なシグナルであり、更に多発性硬化症(MS)の成人モデルでも再ミエリン化を刺激する(Calza L et al, Brain Res Revs48:339−346,2005(非特許文献1))。しかし、THは、慢性甲状腺機能亢進症に伴う心毒性及び骨脱灰を回避しながら再ミエリン化を達成することができる治療域が事実上存在しないことから、許容可能な長期療法ではない。いくつかの甲状腺ホルモン類似体は、甲状腺ホルモン応答性遺伝子を活性化しつつ、甲状腺ホルモン受容体の分子的及び生理学的特徴を活用することによってTHに関連する欠点を回避することができる(Malm J et al.Mini Rev Med Chem 7:79−86,2007(非特許文献2))。これらの受容体は、異種組織分布、及び重複するが異なる標的遺伝子セットを有する2つの主な形態で発現する(Yen PM,Physiol Rev81:1097−1142,2001(非特許文献3))。TRαは心臓、脳及び骨に多く、TRβは肝臓に多い(O’Shea PJ et al.Nucl Recept Signal4:e011,2006(非特許文献4))。
上述のように、本発明は、甲状腺ホルモン模倣化合物、及びそれを含む製品、ならびにその使用及び合成のための方法に関する。本発明のアミド化合物は、特異的加水分解酵素である脂肪酸アミド加水分解酵素(FAAH)(アミドを切断する)の基質として作用して、甲状腺ホルモン様物質を遊離させ得る。したがって、薬物へのプロドラッグ変換は、高レベルのFAAHを発現する組織(例えば、中枢神経系)で強化される。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩が、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R1及びR2は、それぞれ独立して、水素、−ORa、−NRaRb、アルキル、アルケニル、アルキニル、炭素環、炭素環アルキル、複素環または複素環アルキルであり、各アルキル、炭素環、炭素環アルキル、複素環または複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはアルキルであり;
ただし、R1が水素である場合で、かつ、X1及びX2の両方が臭素であるかまたはX1及びX2の両方が塩素である場合には、R2はメチルでない。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩が、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R1及びR2は、それぞれ独立して、水素、−ORa、−NRaRb、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環または3〜6員複素環アルキルであり、各C1〜C6アルキル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環または3〜6員複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Ra及び−S(O)2ORaの群から選択した1、2、3または4つの置換基で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはC1〜C6アルキルであり;
ただし、R1が水素である場合で、かつ、X1及びX2の両方が臭素であるかまたはX1及びX2の両方が塩素である場合には、R2はメチルでない。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩が、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、水素、−ORa、−NRaRb、アルキル、アルケニル、アルキニル、炭素環、炭素環アルキル、複素環、または複素環アルキルの群から選択され、各アルキル、炭素環、炭素環アルキル、複素環または複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはアルキルであり;
ただし、X1及びX2の両方が臭素のとき、またはX1及びX2の両方が塩素のとき、R2はメチルでない。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩が、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、水素、−ORa、−NRaRb、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環、または3〜6員複素環アルキルの群から選択され、各C1〜C6アルキル、C2〜C6アルキニル、C2〜C6アルケニル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環または3〜6員複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Ra及び−S(O)2ORaの群から選択した1つ以上の置換基で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはC1〜C6アルキルであり;
ただし、X1及びX2の両方が臭素のとき、またはX1及びX2の両方が塩素のとき、R2はメチルでない。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩も、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、水素、−ORa、−NRaRb、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環、または3〜6員複素環アルキルの群から選択され、各C1〜C4アルキル、C3〜C6炭素環、C3〜C6炭素環アルキル、3〜6員複素環または3〜6員複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Ra及び−S(O)2ORaの群から選択した0、1、2、3または4つの置換基で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはC1〜C4アルキルであり;
ただし、X1及びX2の両方が臭素のとき、またはX1及びX2の両方が塩素のとき、R2はメチルでない。
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩も、提供され、
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、OH、−O−(C1〜C4アルキル)、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、−NH2、−NH(C1〜C4アルキル)、−N(C1〜C4アルキル)2、−(CH2)n−C3〜C6シクロアルキル、−(CH2)n−3〜6員複素環、−SO3H、−SO2−C1〜C4アルキル、及び
の群から選択され、
R2−O−(C1〜C4アルキル)、C1〜C4アルキル、−NH(C1〜C4アルキル)、−N(C1〜C4アルキル)2、−SO3H及び−SO2−C1〜C4アルキル基の中のC1〜C4アルキル基のそれぞれは、OH及びハロゲンから選択される0、1、2、3または4つの置換基によって置換され、
各例のnは、それぞれ独立して0、1、2及び3から選択される整数であり;
R3、R4及びR5は、それぞれ独立して水素、ハロゲン及びOHから選択される。
式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、OH、−O−(C1〜C3アルキル)、C1〜C3アルキル、C2〜C3アルケニル、C2〜C3アルキニル、−NH2、−NH(C1〜C3アルキル)、−N(C1〜C3アルキル)2、−(CH2)n−C3〜C6シクロアルキル、−(CH2)n−3〜6員複素環、−SO3H、−SO2−C1〜C3アルキル、及び
の群から選択され、
R2−O−(C1〜C3アルキル)、C1〜C3アルキル、−NH(C1〜C3アルキル)、−N(C1〜C3アルキル)2及び−SO2−C1〜C3アルキル基の中のC1〜C3アルキル基のそれぞれは、OH及びハロゲンから選択される0、1、2または3つの置換基によって置換され、
各例のnは、それぞれ独立して0、1、2及び3から選択される整数であり;
R3、R4及びR5は、それぞれ独立して水素、ハロゲン及びOHから選択される。
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、C1〜C4アルキル、C2〜C4アルケニル及びC2〜C4アルキニルの基から選択される。
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、−NH2、−NH(C1〜C4アルキル)及び−N(C1〜C4アルキル)2の基から選択される。
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、−(CH2)n−C3〜C6シクロアルキル及び−(CH2)n−3〜6員複素環の基から選択される。
X1及びX2は、それぞれ独立して塩素または臭素であり;
R2は、
であり、
各例のnは、それぞれ独立して0、1、2及び3から選択される整数であり;
R3、R4及びR5は、それぞれ独立して水素、ハロゲン及びOHから選択される。
試薬及び溶液(a)塩化トリエチルシリル、イミダゾール、DCM、0℃、95%、(b)(i)nBuLi、DIA/TMP、THF、−78℃、(ii)DMF、56〜67%、(c)tert−クロロアセテート、NaI、Cs2CO3、アセトン、60〜65℃、84〜88%、(d)NaI、NaOH、NaOCl、MeOH、H2O、87%、(e)MOMCl、TBAI、NaOH、DCM、H2O、81%、(f)(i)iPMgCl、THF、0℃〜RT、(ii)4、−78℃、54〜79%、(g)TFA、トリエチルシラン、DCM、0℃〜RT、58〜69%、(h)MeOH、H2SO4、NHR1R2、65℃〜RT。
THF(10mL)中の中間体9(250mg)溶液に、エチルアミン(3当量)、EDCI、HOBt及びジイソプロピルアミン(それぞれ1.5当量)を添加した。反応物を室温で一晩撹拌した。混合物を水(10mL)で希釈し、EtOAc(10mL*3)で抽出した。混合EtOAc相を、食塩水(10mL)で洗浄し、Na2SO4上で乾燥して、減圧下で濃縮して、分取HPLC(ACN/水は30/70〜85/15の範囲)で精製して、表題化合物を白色固体として得た。MS(ES−API)m/z396.0/398.0。
THF(10mL)中の中間体10(250mg)溶液に、エチルアミン(3当量)、EDCI、HOBt及びジイソプロピルアミン(それぞれ1.5当量)を添加した。反応物を室温で一晩撹拌した。混合物を水(10mL)で希釈し、EtOAc(10mL*3)で抽出した。混合EtOAc相を、食塩水(10mL)で洗浄し、Na2SO4上で乾燥して、減圧下で濃縮して、分取HPLC(ACN/水は30/70〜85/15の範囲)で精製して、表題化合物を白色固体として得た。MS(ES−API)m/z486.0。
組織分布スクリーニング
雄C57/BL6マウスの組織中濃度試験において、試験化合物は、濃度0.05mg/mLでNMP/solutol/PBS溶液として調製され、SC注射を介する標的用量0.100mg/kgで2mL/kg投与された。血漿、脳、肝臓及び他の選択した組織試料を、時点当たり3匹の動物の投与後1時間で採取した。上述のとおり、本発明のアミド化合物は、特異的加水分解酵素である脂肪酸アミド加水分解酵素(FAAH)(アミドを切断する)の基質として作用して、甲状腺ホルモン様物質を遊離させ得る。したがって、薬物へのプロドラッグ変換は、高レベルのFAAHを発現する組織(例えば、中枢神経系)で強化される。薬剤(変換したプロドラッグから)の組織ホモジネート及び血漿中濃度は、0.0200〜0.0500ng/mLまたは0.100〜0.500ng/gの定量下限でLC−MS/MSを使用して測定した。血漿に対する組織の濃縮比を測定し、表2で報告する。
更なる動物アッセイ
トランス活性化アッセイ
ヒト上皮腎臓細胞(HEK293)は、10%ウシ胎仔血清、50単位/mLペニシリン及び50μg/mLストレプトマイシンを含有するDubelcco改変イーグル4.5g/Lグルコース培地(高グルコースDMEM)にて、80%集密度になるまで増殖させる。細胞は、0.25%トリプシンでトリプシン処理され、それから高グルコースDMEMで5×105細胞/mLに希釈される。細胞は、5×104細胞/ウェルでCostar3917 96ウェルプレートに加えられ、そうして24時間37℃でインキュベートした。TR発現ベクター(全長TRα−CMVまたはTRβ−CMV)1.5μg、ホタルルシフェラーゼコード配列に連結された最小チミジンキナーゼプロモーターの上流にクローン化された4ヌクレオチドにより間隔の空いたDR4甲状腺ホルモン応答エレメント(TRE)直列反復配列(AGGTCAcaggAGGTCA)を含有するレポータープラスミド1.5μg、及びpRL−SV40構成Renillaルシフェラーゼレポータープラスミド0.75μgを、540μlのOptiMEMに希釈する。27μLのリポフェクタミン試薬を、540μLのOptiMEM中に希釈した。次にプラスミド及びリポフェクタミンの希釈液を混合して、そうして10分間RTでインキュベートする。そうして、混合物をOptiMEM4.29mLで希釈した。プレートは、1ウェル当たりマグネシウムまたは塩化カルシウムを含まないpH7.2のリン酸緩衝生理食塩水(PBS)100μLで洗浄した。トランスフェクション混合物を1ウェル当たり50μLで加えて、それから4時間37℃でインキュベートする。15mMのHEPES及び重炭酸塩、5mMのL−グルタミン、チャコール処理済みFBS、50単位/mLペニシリン及び50μg/mLストレプトマイシンを含有するフェノールレッド不含の改変DME/F−12ハム培地を50μL/ウェルで添加し、次いでプレートを37℃で20時間インキュベートした。薬物原液を、DMSO中の10mMで作製し、そうしてDME/F−12ハム中で1×濃度に連続希釈した。プレートを、1ウェル当たり100μLのPBS(pH7.2)で洗浄する。100μLの各薬物原液を3連でウェルに加えて、そうしてプレートを24時間37℃でインキュベートする。
実験プロトコルは、National Institutes of Health Guide for the Care and Use of Laboratory Animalsに準拠しており、Oregon Health & Science University Institutional Animal Care&Use Committeeによって承認された。8〜10週齢の野生型雄C57BL/6Jマウスを、気温湿度が制御された部屋で12時間の明暗サイクルにて飼育し、食物及び水を自由に摂取させた。
マウスに、9.14μmol/kgのGC−1、及び0.914、9.14、及び30.5μmol/kgの類似体を腹腔内(ip)に単回注射した。1時間で1用量につき3匹のマウスに対して安楽死を行い、組織及び血液を回収した。組織は直ちに凍結させ、そして血液は氷上で最低30分間維持してから7,500×Gで15分間遠心沈殿させた。血清(100μL)を採取し、試料が処理されるまで−80℃で組織と共に保存した。
血清試料を室温まで温め、2.99μMの内部標準(D6−GC−1)10μLをそれに添加した。アセトニトリル(500μL)を加え、試料を20秒間ボルテックスした。試料を次に10,000×Gで15分間、4℃にて遠心分離した。次に、上清の90%をガラス試験管に移し、speedvacを用いて45℃で1.5時間濃縮した。乾燥した試料を400μLの50:50のACN:H2Oに溶解させ、20秒間ボルテックスした。得られた混合物をエッペンドルフ管に移し、10,000×Gで15分間遠心した。上清を0.22μMの遠心フィルターで濾過し、LCMS/MS分析に供した。検量線は、T3、GC−1または類似体を注射していない8〜10週齢のマウスの血清100μLを用いて作成した。濾過後、試料を6つのバイアルに分けた以外は、まったく同じ処理を行った。GC−1、JD−20及びJD−21は、(0.1pg/μL、1pg/μL、10pg/μL、100pg/μL、及び1000pg/μL)の各化合物の最終濃度/マトリックスを作製するために、6つのバイアルのうちの5つに加えた。
脳試料を室温に温め、5GoldSpec1/8クロム鋼球(Applied Industrial Technologies)と共にホモジナイザー管に移した。得られた管を秤量し、次いで1mLのH2Oを添加し、続いて10μLの2.99μMの内部標準(D6−ソベチロム)を添加した。管をBead Bugで30秒間ホモジナイズし、次いで3mLのACNを含むFalcon(登録商標)チューブに移した。1ml体積のACNを用いてホモジナイザー管を洗浄した。次いで、その溶液をFalcon(登録商標)管に戻した。試料を45℃で4時間スピードバックを用いてガラス管に濃縮した以外は、上記の血清処理と同じ方法を用いて試料を処理した。
マウスにビヒクル(1:1食塩水/DMSO)、0.305μmol/kgのT3、9.14μmol/kgのGC−1、及び0.914、9.14、及び30.5μmol/kgの類似体を腹腔内(ip)に単回注射した。2時間で1用量につき3匹のマウスで安楽死を行い、組織を採取した。qPCR分析のために採取された脳組織を、Trizol試薬及びPureLink RNAミニキットを用いたRNA抽出のためのプロトコルに従って、オプションのDNase処理工程中にQiagen RNase−free DNaseキットを用いて処理した。1μgの抽出RNAを用いて、Qiagen QuantiTect Reverse Transcriptionキットを使用した逆転写(RT)反応によりcDNAを合成した。DNA混入は、RT酵素の添加のない1つの試料を複製することによって制御された。Hairless(Hr)遺伝子の発現は、Qiagen製QuantiTect SYBR green PCRキットを用いてQPCRにより測定した。Hairlessのプライマー配列(順方向:CCAAGTCTGGGCCAAGTTTG、逆方向:TGTCCTTGGTCCGATTGGAA)は、Barca−Mayo19により以前に記載された。鋳型cDNAを、qPCR反応でのRT試薬の干渉を最小限にするために2倍希釈した。グリセルアルデヒド−3−リン酸脱水素酵素(GAPDH)は、試料間の正規化に使用されるハウスキーピング遺伝子であった。Hr遺伝子発現の相対的差異を調べるために、比較CT法を用いて、単回投与試験のデータ解析を行った。用量反応試験のためのデータ解析はGraphPad Prism v.4aを使用して行われ、シグモイド用量反応モデルでEC50値±SEMを求めた。
1H NMRは、Bruker400で行った。すべての1H NMRは、NMR溶媒の参照ピーク(D6−アセトン、CDCl3)に対して較正した。無水テトラヒドロフラン(THF)及びジメチルホルムアミド(DMF)は、Seca Solvent Systemから入手した。使用した他の溶媒はすべてSigma−AldrichまたはFisherから購入した。最終化合物の純度分析では、HPLCにより95%超であると決定された。HPLC分析は、Agilent Eclipse PlusC18 5μMカラム(4.6×250mm)を用いたVarian ProStar HPLCで、15分間にわたって10%〜95%アセトニトリル(0.1%TFA)の勾配で行った。
[本発明1001]
式(I)
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩であって、式中、
X 1 及びX 2 は、それぞれ独立して塩素または臭素であり;
R 1 及びR 2 は、それぞれ独立して、水素、−OR a 、−NR a R b 、C 1 〜C 6 アルキル、C 2 〜C 6 アルケニル、C 2 〜C 6 アルキニル、C 3 〜C 6 炭素環、C 3 〜C 6 炭素環アルキル、C 3 〜C 6 複素環またはC 3 〜C 6 複素環アルキルであり、各C 1 〜C 6 アルキル、C 3 〜C 6 炭素環、C 3 〜C 6 炭素環アルキル、C 3 〜C 6 複素環またはC 3 〜C 6 複素環アルキルは、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよく;
各R a 及びR b は、それぞれ独立して水素またはC 1 〜C 6 アルキルであり;
ただし、R 1 が水素である場合で、かつ、X 1 及びX 2 の両方が臭素であるかまたはX 1 及びX 2 の両方が塩素である場合には、R 2 はメチルでない、前記化合物。
[本発明1002]
X 1 及びX 2 が両方とも塩素である、本発明1001の化合物。
[本発明1003]
X 1 及びX 2 が両方とも臭素である、本発明1001の化合物。
[本発明1004]
X 1 が塩素であり、X 2 が臭素である、本発明1001の化合物。
[本発明1005]
X 1 が臭素であり、X 2 が塩素である、本発明1001の化合物。
[本発明1006]
R 1 が水素である、本発明1001〜1005のいずれかの化合物。
[本発明1007]
R 2 が水素である、本発明1001、1002、1003、1004、1005及び1006のいずれかの化合物。
[本発明1008]
R 2 が−OR a である、本発明1001、1002、1003、1004、1005及び1006のいずれかの化合物。
[本発明1009]
R 2 が−NR a R b である、本発明1001、1002、1003、1004、1005及び1006のいずれかの化合物。
[本発明1010]
R 1 及びR 2 がアルキルである、本発明1001〜1005のいずれかの化合物。
[本発明1011]
R 2 がアルキルである、本発明1001、1002、1003、1004、1005及び1006のいずれかの化合物。
[本発明1012]
前記アルキルが、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、分岐鎖ペンチル、n−ヘキシルまたは分岐鎖ヘキシルである、本発明1011の化合物。
[本発明1013]
R 2 がアルケニルまたはアルキニルである、本発明1001、1002、1003、1004、1005及び1006のいずれかの化合物。
[本発明1014]
R 2 がプロペニルである、本発明1001、1002、1003、1004、1005、1006及び1013のいずれかの化合物。
[本発明1015]
R 2 がプロピニルである、本発明1001、1002、1003、1004、1005、1006及び1013のいずれかの化合物。
[本発明1016]
R 2 が、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されているアルキルである、本発明1001〜1006のいずれかの化合物。
[本発明1017]
R 2 が、C 3 〜C 6 炭素環またはC 3 〜C 6 炭素環アルキルであり、それぞれが、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよい、本発明1001〜1006のいずれかの化合物。
[本発明1018]
R 2 が、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよいC 3 〜C 6 シクロアルキルである、本発明1017の化合物。
[本発明1019]
R 2 が、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよいアリールである、本発明1017の化合物。
[本発明1020]
R 2 が、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよいC 3 〜C 6 炭素環アルキルである、本発明1017の化合物。
[本発明1021]
R 2 が、3〜6員複素環または3〜6員複素環アルキルであり、それぞれが、ハロ、シアノ、−OR a 、−NR a R b 、−S(O) 2 R a または−S(O) 2 OR a のうちの1つ以上で置換されていてもよい、本発明1001〜1006のいずれかの化合物。
[本発明1022]
構造
を有する、本発明1001の化合物。
[本発明1023]
本発明1001〜1022のいずれかの化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩の薬学的に有効な量と、1つ以上の薬学的に許容される担体とを含む、医薬組成物。
[本発明1024]
神経変性疾患を有する対象を治療する方法であって、本発明1001〜1022のいずれかの化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または本発明1023の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
[本発明1025]
前記神経変性疾患が脱髄疾患である、本発明1024の方法。
[本発明1026]
前記神経変性疾患がX連鎖副腎白質ジストロフィーまたは多発性硬化症である、本発明1024または1025の方法。
[本発明1027]
前記神経変性疾患が、急性散在性脳脊髄炎、急性出血性白質脳炎、成人レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害、デビック病、びまん性ミエリン破壊硬化症、ギラン−バレー症候群、特発性炎症性脱髄疾患、乳児レフサム病、クラッベ病、レーベル遺伝性視神経症、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー、多巣性運動神経障害、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病、腓骨筋萎縮症、進行性多巣性白質脳症、横断性脊髄炎、熱帯性痙性麻痺、van der Knaap疾患、X連鎖副腎白質ジストロフィー、またはツェルウェガー症候群である、本発明1024〜1026のいずれかの方法。
[本発明1028]
アルツハイマー病を有する対象を治療する方法であって、本発明1001〜1022のいずれかの化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または本発明1023の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
[本発明1029]
急性散在性脳脊髄炎(ADEM)、急性出血性白質脳炎(AHLまたはAHLE)、成人レフサム病、乳児レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症(CPM)、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害(CIDP)、デビック病、びまん性ミエリン破壊硬化症、脳脊髄炎、ギラン‐バレー症候群、特発性炎症性脱髄疾患(IIDD)、クラッベ病、レーベル遺伝性視神経症、白質ジストロフィー、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー(MLD)、多巣性運動神経障害(MMN)、多発性硬化症(MS)、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病(PMD)、進行性多巣性白質脳症(PML)、熱帯性痙性麻痺(TSP)、X連鎖副腎白質ジストロフィー(X−ALD、ALDまたはX連鎖ALD)、またはツェルウェガー症候群を有する対象を治療する方法であって、本発明1001〜1022のいずれかの化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または本発明1023の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
[本発明1030]
神経変性疾患の治療において使用するための、本発明1001〜1022のいずれかの化合物もしくはその薬学的に許容される塩または本発明1023の医薬組成物。
[本発明1031]
前記神経変性疾患が脱髄疾患である、本発明1030の化合物もしくはその薬学的に許容される塩または医薬組成物。
[本発明1032]
前記神経変性疾患がX連鎖副腎白質ジストロフィーまたは多発性硬化症である、本発明1030または1031の化合物もしくはその薬学的に許容される塩または医薬組成物。
[本発明1033]
前記神経変性疾患が、急性散在性脳脊髄炎、急性出血性白質脳炎、成人レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害、デビック病、びまん性ミエリン破壊硬化症、ギラン−バレー症候群、特発性炎症性脱髄疾患、乳児レフサム病、クラッベ病、レーベル遺伝性視神経症、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー、多巣性運動神経障害、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病、腓骨筋萎縮症、進行性多巣性白質脳症、横断性脊髄炎、熱帯性痙性麻痺、van der Knaap疾患、X連鎖副腎白質ジストロフィー、またはツェルウェガー症候群である、本発明1030の化合物もしくはその薬学的に許容される塩または医薬組成物。
[本発明1034]
アルツハイマー病の治療において使用するための、本発明1001〜1022のいずれかの化合物もしくはその薬学的に許容される塩または本発明1023の医薬組成物。
[本発明1035]
急性散在性脳脊髄炎(ADEM)、急性出血性白質脳炎(AHLまたはAHLE)、成人レフサム病、乳児レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症(CPM)、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害(CIDP)、デビック病、びまん性ミエリン破壊硬化症、脳脊髄炎、ギラン‐バレー症候群、特発性炎症性脱髄疾患(IIDD)、クラッベ病、レーベル遺伝性視神経症、白質ジストロフィー、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー(MLD)、多巣性運動神経障害(MMN)、多発性硬化症(MS)、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病(PMD)、進行性多巣性白質脳症(PML)、熱帯性痙性麻痺(TSP)、X連鎖副腎白質ジストロフィー(X−ALD、ALDまたはX連鎖ALD)、またはツェルウェガー症候群の治療において使用するための、本発明1001〜1022のいずれかの化合物もしくはその薬学的に許容される塩または本発明1023の医薬組成物。
[本発明1036]
医薬の製造における、本発明1001〜1022のいずれかの化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩の使用。
更なる動物アッセイ
トランス活性化アッセイ
ヒト上皮腎臓細胞(HEK293)は、10%ウシ胎仔血清、50単位/mLペニシリン及び50μg/mLストレプトマイシンを含有するDubelcco改変イーグル4.5g/Lグルコース培地(高グルコースDMEM)にて、80%集密度になるまで増殖させる。細胞は、0.25%トリプシンでトリプシン処理され、それから高グルコースDMEMで5×105細胞/mLに希釈される。細胞は、5×104細胞/ウェルでCostar3917 96ウェルプレートに加えられ、そうして24時間37℃でインキュベートした。TR発現ベクター(全長TRα−CMVまたはTRβ−CMV)1.5μg、ホタルルシフェラーゼコード配列に連結された最小チミジンキナーゼプロモーターの上流にクローン化された4ヌクレオチドにより間隔の空いたDR4甲状腺ホルモン応答エレメント(TRE)直列反復配列(AGGTCAcaggAGGTCA(配列番号1))を含有するレポータープラスミド1.5μg、及びpRL−SV40構成Renillaルシフェラーゼレポータープラスミド0.75μgを、540μlのOptiMEMに希釈する。27μLのリポフェクタミン試薬を、540μLのOptiMEM中に希釈した。次にプラスミド及びリポフェクタミンの希釈液を混合して、そうして10分間RTでインキュベートする。そうして、混合物をOptiMEM4.29mLで希釈した。プレートは、1ウェル当たりマグネシウムまたは塩化カルシウムを含まないpH7.2のリン酸緩衝生理食塩水(PBS)100μLで洗浄した。トランスフェクション混合物を1ウェル当たり50μLで加えて、それから4時間37℃でインキュベートする。15mMのHEPES及び重炭酸塩、5mMのL−グルタミン、チャコール処理済みFBS、50単位/mLペニシリン及び50μg/mLストレプトマイシンを含有するフェノールレッド不含の改変DME/F−12ハム培地を50μL/ウェルで添加し、次いでプレートを37℃で20時間インキュベートした。薬物原液を、DMSO中の10mMで作製し、そうしてDME/F−12ハム中で1×濃度に連続希釈した。プレートを、1ウェル当たり100μLのPBS(pH7.2)で洗浄する。100μLの各薬物原液を3連でウェルに加えて、そうしてプレートを24時間37℃でインキュベートする。
マウスにビヒクル(1:1食塩水/DMSO)、0.305μmol/kgのT3、9.14μmol/kgのGC−1、及び0.914、9.14、及び30.5μmol/kgの類似体を腹腔内(ip)に単回注射した。2時間で1用量につき3匹のマウスで安楽死を行い、組織を採取した。qPCR分析のために採取された脳組織を、Trizol試薬及びPureLink RNAミニキットを用いたRNA抽出のためのプロトコルに従って、オプションのDNase処理工程中にQiagen RNase−free DNaseキットを用いて処理した。1μgの抽出RNAを用いて、Qiagen QuantiTect Reverse Transcriptionキットを使用した逆転写(RT)反応によりcDNAを合成した。DNA混入は、RT酵素の添加のない1つの試料を複製することによって制御された。Hairless(Hr)遺伝子の発現は、Qiagen製QuantiTect SYBR green PCRキットを用いてQPCRにより測定した。Hairlessのプライマー配列(順方向:CCAAGTCTGGGCCAAGTTTG(配列番号2)、逆方向:TGTCCTTGGTCCGATTGGAA(配列番号3))は、Barca−Mayo19により以前に記載された。鋳型cDNAを、qPCR反応でのRT試薬の干渉を最小限にするために2倍希釈した。グリセルアルデヒド−3−リン酸脱水素酵素(GAPDH)は、試料間の正規化に使用されるハウスキーピング遺伝子であった。Hr遺伝子発現の相対的差異を調べるために、比較CT法を用いて、単回投与試験のデータ解析を行った。用量反応試験のためのデータ解析はGraphPad Prism v.4aを使用して行われ、シグモイド用量反応モデルでEC50値±SEMを求めた。
Claims (36)
- 式(I)
の構造を有する化合物、またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩であって、式中、
X1及びX2は、それぞれ独立して塩素または臭素であり;
R1及びR2は、それぞれ独立して、水素、−ORa、−NRaRb、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C6炭素環、C3〜C6炭素環アルキル、C3〜C6複素環またはC3〜C6複素環アルキルであり、各C1〜C6アルキル、C3〜C6炭素環、C3〜C6炭素環アルキル、C3〜C6複素環またはC3〜C6複素環アルキルは、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよく;
各Ra及びRbは、それぞれ独立して水素またはC1〜C6アルキルであり;
ただし、R1が水素である場合で、かつ、X1及びX2の両方が臭素であるかまたはX1及びX2の両方が塩素である場合には、R2はメチルでない、前記化合物。 - X1及びX2が両方とも塩素である、請求項1に記載の化合物。
- X1及びX2が両方とも臭素である、請求項1に記載の化合物。
- X1が塩素であり、X2が臭素である、請求項1に記載の化合物。
- X1が臭素であり、X2が塩素である、請求項1に記載の化合物。
- R1が水素である、請求項1〜5のいずれか一項に記載の化合物。
- R2が水素である、請求項1、2、3、4、5及び6のいずれか一項に記載の化合物。
- R2が−ORaである、請求項1、2、3、4、5及び6のいずれか一項に記載の化合物。
- R2が−NRaRbである、請求項1、2、3、4、5及び6のいずれか一項に記載の化合物。
- R1及びR2がアルキルである、請求項1〜5のいずれか一項に記載の化合物。
- R2がアルキルである、請求項1、2、3、4、5及び6のいずれか一項に記載の化合物。
- 前記アルキルが、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、分岐鎖ペンチル、n−ヘキシルまたは分岐鎖ヘキシルである、請求項11に記載の化合物。
- R2がアルケニルまたはアルキニルである、請求項1、2、3、4、5及び6のいずれか一項に記載の化合物。
- R2がプロペニルである、請求項1、2、3、4、5、6及び13のいずれか一項に記載の化合物。
- R2がプロピニルである、請求項1、2、3、4、5、6及び13のいずれか一項に記載の化合物。
- R2が、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されているアルキルである、請求項1〜6のいずれか一項に記載の化合物。
- R2が、C3〜C6炭素環またはC3〜C6炭素環アルキルであり、それぞれが、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよい、請求項1〜6のいずれか一項に記載の化合物。
- R2が、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよいC3〜C6シクロアルキルである、請求項17に記載の化合物。
- R2が、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよいアリールである、請求項17に記載の化合物。
- R2が、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよいC3〜C6炭素環アルキルである、請求項17に記載の化合物。
- R2が、3〜6員複素環または3〜6員複素環アルキルであり、それぞれが、ハロ、シアノ、−ORa、−NRaRb、−S(O)2Raまたは−S(O)2ORaのうちの1つ以上で置換されていてもよい、請求項1〜6のいずれか一項に記載の化合物。
- 請求項1〜22のいずれか一項に記載の化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩の薬学的に有効な量と、1つ以上の薬学的に許容される担体とを含む、医薬組成物。
- 神経変性疾患を有する対象を治療する方法であって、請求項1〜22のいずれか一項に記載の化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または請求項23に記載の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
- 前記神経変性疾患が脱髄疾患である、請求項24に記載の方法。
- 前記神経変性疾患がX連鎖副腎白質ジストロフィーまたは多発性硬化症である、請求項24または25に記載の方法。
- 前記神経変性疾患が、急性散在性脳脊髄炎、急性出血性白質脳炎、成人レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害、デビック病、びまん性ミエリン破壊硬化症、ギラン−バレー症候群、特発性炎症性脱髄疾患、乳児レフサム病、クラッベ病、レーベル遺伝性視神経症、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー、多巣性運動神経障害、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病、腓骨筋萎縮症、進行性多巣性白質脳症、横断性脊髄炎、熱帯性痙性麻痺、van der Knaap疾患、X連鎖副腎白質ジストロフィー、またはツェルウェガー症候群である、請求項24〜26のいずれか一項に記載の方法。
- アルツハイマー病を有する対象を治療する方法であって、請求項1〜22のいずれか一項に記載の化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または請求項23に記載の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
- 急性散在性脳脊髄炎(ADEM)、急性出血性白質脳炎(AHLまたはAHLE)、成人レフサム病、乳児レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症(CPM)、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害(CIDP)、デビック病、びまん性ミエリン破壊硬化症、脳脊髄炎、ギラン‐バレー症候群、特発性炎症性脱髄疾患(IIDD)、クラッベ病、レーベル遺伝性視神経症、白質ジストロフィー、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー(MLD)、多巣性運動神経障害(MMN)、多発性硬化症(MS)、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病(PMD)、進行性多巣性白質脳症(PML)、熱帯性痙性麻痺(TSP)、X連鎖副腎白質ジストロフィー(X−ALD、ALDまたはX連鎖ALD)、またはツェルウェガー症候群を有する対象を治療する方法であって、請求項1〜22のいずれか一項に記載の化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩または請求項23に記載の医薬組成物の薬学的に有効な量を前記対象に投与する工程を含む、前記方法。
- 神経変性疾患の治療において使用するための、請求項1〜22のいずれか一項に記載の化合物もしくはその薬学的に許容される塩または請求項23に記載の医薬組成物。
- 前記神経変性疾患が脱髄疾患である、請求項30に記載の化合物もしくはその薬学的に許容される塩または医薬組成物。
- 前記神経変性疾患がX連鎖副腎白質ジストロフィーまたは多発性硬化症である、請求項30または31に記載の化合物もしくはその薬学的に許容される塩または医薬組成物。
- 前記神経変性疾患が、急性散在性脳脊髄炎、急性出血性白質脳炎、成人レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害、デビック病、びまん性ミエリン破壊硬化症、ギラン−バレー症候群、特発性炎症性脱髄疾患、乳児レフサム病、クラッベ病、レーベル遺伝性視神経症、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー、多巣性運動神経障害、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病、腓骨筋萎縮症、進行性多巣性白質脳症、横断性脊髄炎、熱帯性痙性麻痺、van der Knaap疾患、X連鎖副腎白質ジストロフィー、またはツェルウェガー症候群である、請求項30に記載の化合物もしくはその薬学的に許容される塩または医薬組成物。
- アルツハイマー病の治療において使用するための、請求項1〜22のいずれか一項に記載の化合物もしくはその薬学的に許容される塩または請求項23に記載の医薬組成物。
- 急性散在性脳脊髄炎(ADEM)、急性出血性白質脳炎(AHLまたはAHLE)、成人レフサム病、乳児レフサム病、アレキサンダー病、アルツハイマー病、バロ同心円硬化症、カナバン病、橋中心髄鞘崩壊症(CPM)、脳性麻痺、脳腱黄色腫症、慢性炎症性脱髄性多発神経障害(CIDP)、デビック病、びまん性ミエリン破壊硬化症、脳脊髄炎、ギラン‐バレー症候群、特発性炎症性脱髄疾患(IIDD)、クラッベ病、レーベル遺伝性視神経症、白質ジストロフィー、マールブルグ多発性硬化症、マルキアファーヴァ−ビニャミ病、異染性白質ジストロフィー(MLD)、多巣性運動神経障害(MMN)、多発性硬化症(MS)、パラプロテイン血症性脱髄性多発神経障害、ペリツェウス−メルツバッハー病(PMD)、進行性多巣性白質脳症(PML)、熱帯性痙性麻痺(TSP)、X連鎖副腎白質ジストロフィー(X−ALD、ALDまたはX連鎖ALD)、またはツェルウェガー症候群の治療において使用するための、請求項1〜22のいずれか一項に記載の化合物もしくはその薬学的に許容される塩または請求項23に記載の医薬組成物。
- 医薬の製造における、請求項1〜22のいずれか一項に記載の化合物またはその薬学的に許容される異性体、ラセミ体、水和物、溶媒和物、同位体もしくは塩の使用。
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