JP7350337B2 - 神経障害の処置においてranタンパク質レベルを低下させるためのメトホルミンおよびそのアナログの使用 - Google Patents
神経障害の処置においてranタンパク質レベルを低下させるためのメトホルミンおよびそのアナログの使用 Download PDFInfo
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Description
本願は、2017年9月26日に出願された米国仮出願U.S.S.N.62/563,588に対する、35 U.S.C.§119(e)下における優先権を主張し、該仮出願は、本明細書において参考として援用される。
本開示は、国立衛生研究所(NIH)により付与された助成金番号NS04038O、NS058901およびNS098819下における政府の支援によりなされた。政府は、本発明において一定の権利を有する。
特定のリピート伸長(例えばCAGG、CCTG、GGGGCC、GGCCCC、CAGおよびCTG)の変異は、多数の様々な神経疾患(例えばC9ORFf72筋萎縮性側索硬化症(ALS)、またはC9ORFf72前頭側頭葉型認知症;筋強直性ジストロフィー1型(DM1)および筋強直性ジストロフィー2型(DM2);脊髄小脳失調症1、2、3、6、7、8、10、12、17、31および36型;球脊髄性筋萎縮症;歯状核赤核淡蒼球ルイ体萎縮症(DRPLA);ハンチントン病(HD);脆弱X振戦失調症候群(FXTAS));フックス角膜内皮ジストロフィー(FECD);ハンチントン病類縁症候群2型(HDL2);脆弱X症候群(FXS);7p11.2葉酸感受性脆弱部位FRA7Aに関係する障害;葉酸感受性脆弱部位2q11 FRA2Aに関係する障害;および脆弱XE症候群(FRAXE)に関連する。限定されないがC9ORF72 ALSまたはC9ORF72 FTD、FXTAS、HD、SCA8、DM1およびDM2を含む、漸増する疾患において、伸長変異は、複数のリーディングフレームにおいて起こり、古典的なAUG開始コドンを必要としない新規の型のタンパク質翻訳を受けることが示されている(Zu et al. 2011;Ash et al. 2013;Mori et al. 2013;Todd et al. 2013;Zu et al. 2013;Banez-Coronel et al. 2015;Cleary and Ranum 2017;Zu et al. 2017)。この型の翻訳は、Zuら(Zu et al. 2011)(PNAS 2011 108:260-265)により最初に記載され、リピート関連非ATG(RAN)翻訳と称され、産生されるタンパク質は、RANタンパク質と称される。RANタンパク質が毒性であり、多数の疾患に寄与するという証左は、漸増している(Cleary and Ranum 2017)。したがって、リピート伸長変異により引き起こされる神経疾患を処置するために、リピート関連非ATG(RAN)タンパク質のレベルを低下させる治療戦略を開発することは、重要である。
本明細書において記載されるのは、リピート関連非ATG(RAN)タンパク質に関連する神経疾患の処置のための組成物および方法である。いくつかの側面において、本開示はまた、タンパク質キナーゼR(PKR)の発現または活性を阻害することは、RANタンパク質翻訳を阻害するという認識に関する。本開示は、部分的に、リピート伸長(例えばCAGG、CCTG、GGGGCC、GGCCCC、CAGおよびCTG)の変異が、多数の様々な神経疾患(例えばC9ORFf72筋萎縮性側索硬化症(ALS)またはC9ORFf72前頭側頭葉型認知症;筋強直性ジストロフィー1型(DM1)および筋強直性ジストロフィー2型(DM2);脊髄小脳失調症1、2、3、6、7、8、10、12、17、31および36型;球脊髄性筋萎縮症;歯状核赤核淡蒼球ルイ体萎縮症(DRPLA);ハンチントン病(HD);フックス角膜内皮ジストロフィー(FECD);脆弱X振戦失調症候群(FXTAS);ハンチントン病類縁症候群2型(HDL2);脆弱X症候群(FXS);7p11.2葉酸感受性脆弱部位FRA7Aに関係する障害;葉酸感受性脆弱部位2q11 FRA2Aに関係する障害;および脆弱XE症候群(FRAXE))に関連するという発見に基づく。特に、4つのリピート関連非ATG翻訳タンパク質(RANタンパク質としてもまた言及される)-ポリアラニン、ポリセリン、ポリロイシン、およびポリシステイン(それぞれポリAla、ポリSer、ポリLeuおよびポリCys)-は、ハンチントン病(HD)を罹患する対象の脳、組織(例えば血液、脳脊髄液)および中枢神経系において蓄積する。C9ORF72 ALSまたはC9ORF72 FTDにおいて、ジペプチドRANタンパク質(例えばポリGlyPro(GP)、ポリGlyAla(GA)、ポリGlyArg(GR)、ポリProAla(PA))を有するRANタンパク質は、患者の脳、血液および他の組織において蓄積することが示されている。同様に、ホモポリマーかつテトラペプチドであるRANタンパク質は、脆弱X振戦失調症候群(FXTAS)、筋強直性ジストロフィー1型(DM1)および筋強直性ジストロフィー2型(DM2)を有する患者において見出されている。Zu et al., PNAS 2011からの結果に基づいて、RANタンパク質はまた、限定されないが脊髄小脳失調症1、2、3、6、7、8、10、12、17、31および36型;球脊髄性筋萎縮症(SBMA);歯状核赤核淡蒼球ルイ体萎縮症(DRPLA);およびフックス角膜内皮ジストロフィーを含む、CAG・CTGリピート伸長により引き起こされた疾患を有する患者において蓄積することが予測される。RANタンパク質は、HD、C9ORF72 ALS、C9ORF72 FTD、DM1、DM2、FXTAS、SCA8;ハンチントン病類縁症候群2型(HDL2);脆弱X症候群(FXS);7p11.2葉酸感受性脆弱部位FRA7Aに関係する障害;葉酸感受性脆弱部位2q11 FRA2Aに関係する障害;および脆弱XE症候群(FRAXE);またはマイクロサテライトリピート伸長変異により引き起こされる他の疾患を有するか、これらを発症するリスクがある対象からの、生物学的試料(例えば血液、血清、組織、または脳脊髄液(CSF))において検出され得る。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、式中、R2A、R3、R4、R6およびR7は、本明細書において定義されるとおりである。
、またはその薬学的に受入可能な塩、溶媒和物、水和物、互変異性体、立体異性体、誘導体もしくはプロドラッグの治療有効量を投与することを含む。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、式中、R2’、R3、R4’、R6およびR7は、本明細書において定義されるとおりである。
ならびにその薬学的に受入可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体的に濃縮された誘導体およびプロドラッグが挙げられる。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、式中、R4A、R8およびR9は、本明細書において定義されるとおりである。
ならびにその薬学的に受入可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体的に濃縮された誘導体およびプロドラッグが挙げられる。
特定の官能基および化学用語の定義は、以下により詳細に記載される。化学元素は、元素周期表、CASバージョン、Handbook of Chemistry and Physics、第75版、内表紙に従って同定され、特定の官能基は、本明細書において一般的に定義される。さらに、有機化学の一般的原理、ならびに特定の官能部分および反応性は、Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March’s Advanced Organic Chemistry、第5版、John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;およびCarruthers, Some Modern Methods of Organic Synthesis、第3版、Cambridge University Press, Cambridge, 1987において記載される。本開示は、本明細書において記載される置換基の例示的なリストによりどのような様式においても限定されることを意図しない。
は、C3炭化水素鎖である。ある範囲の値が用いられる場合(例えばC1-6炭化水素鎖)、当該範囲の意味は、本明細書において記載されるとおりである。炭化水素鎖は、飽和していてもよい(例えば-(CH2)4-)。炭化水素鎖はまた、不飽和であってもよく、炭化水素鎖中のいずれかの場所において、1つ以上のC=Cおよび/またはC≡C結合を含んでもよい。例えば、-CH=CH-(CH2)2-、-CH2-C≡C-CH2-、および-C≡C-CH=CH-は、全て、置換されていない不飽和の炭化水素鎖の例である。ある態様において、炭化水素鎖は、置換されていない(例えば-(CH2)4-)。ある態様において、炭化水素鎖は、置換されている(例えば-CH(C2H5)-および-CF2-)。炭化水素鎖上の任意の2つの置換基は、連結して、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、または任意に置換されたヘテロアリール環を形成してもよい。例えば、
は、全て、炭化水素鎖の例である。対照的に、ある態様において、
は、本明細書において記載される炭化水素鎖の範囲内ではない。
または、炭素原子上の2つのジェミナルな水素は、基=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb、または=NORccで置き換えられている;
Raaの各々の場合は、独立して、C1-10アルキル、C1-10パーハロアルキル、C2-10アルケニル、C2-10アルキニル、ヘテロC1-10アルキル、ヘテロC2-10アルケニル、ヘテロC2-10アルキニル、C3-10カルボシクリル、3~14員のヘテロシクリル、C6-14アリール、および5~14員のヘテロアリールから選択されるか、または、2つのRaa基は、連結して、3~14員のヘテロシクリルまたは5~14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換されている;
Rbbの各々の場合は、独立して、水素、-OH、-ORaa、-N(Rcc)2、-CN、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、-P(=O)(Raa)2、-P(=O)(ORcc)2、-P(=O)(N(Rcc)2)2、C1-10アルキル、C1-10パーハロアルキル、C2-10アルケニル、C2-10アルキニル、ヘテロC1-10アルキル、ヘテロC2-10アルケニル、ヘテロC2-10アルキニル、C3-10カルボシクリル、3~14員のヘテロシクリル、C6-14アリール、および5~14員のヘテロアリールから選択されるか、または、2つのRbb基は、連結して、3~14員のヘテロシクリルまたは5~14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換されており;ここで、X-は、対イオンである;
Rccの各々の場合は、独立して、水素、C1-10アルキル、C1-10パーハロアルキル、C2-10アルケニル、C2-10アルキニル、ヘテロC1-10アルキル、ヘテロC2-10アルケニル、ヘテロC2-10アルキニル、C3-10カルボシクリル、3~14員のヘテロシクリル、C6-14アリール、および5~14員のヘテロアリールから選択されるか、または、2つのRcc基は、連結して、3~14員のヘテロシクリルまたは5~14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換されている;
Rddの各々の場合は、独立して、ハロゲン、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(=O)Ree、-CO2H、-CO2Ree、-OC(=O)Ree、-OCO2Ree、-C(=O)N(Rff)2、-OC(=O)N(Rff)2、-NRffC(=O)Ree、-NRffCO2Ree、-NRffC(=O)N(Rff)2、-C(=NRff)ORee、-OC(=NRff)Ree、-OC(=NRff)ORee、-C(=NRff)N(Rff)2、-OC(=NRff)N(Rff)2、-NRffC(=NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(=O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(=S)N(Rff)2、-C(=O)SRee、-C(=S)SRee、-SC(=S)SRee、-P(=O)(ORee)2、-P(=O)(Ree)2、-OP(=O)(Ree)2、-OP(=O)(ORee)2、C1-6アルキル、C1-6パーハロアルキル、C2-6アルケニル、C2-6アルキニル、ヘテロC1-6アルキル、ヘテロC2-6アルケニル、ヘテロC2-6アルキニル、C3-10カルボシクリル、3~10員のヘテロシクリル、C6-10アリール、5~10員のヘテロアリールから選択され、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRgg基で置換されているか、または、2つのジェミナルなRdd置換基は、連結されて、=Oまたは=Sを形成してもよく;ここで、X-は、対イオンである;
Reeの各々の場合は、独立して、C1-6アルキル、C1-6パーハロアルキル、C2-6アルケニル、C2-6アルキニル、ヘテロC1-6アルキル、ヘテロC2-6アルケニル、ヘテロC2-6アルキニル、C3-10カルボシクリル、C6-10アリール、3~10員のヘテロシクリル、および3~10員のヘテロアリールから選択され、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRgg基で置換されている;
Rffの各々の場合は、独立して、水素、C1-6アルキル、C1-6パーハロアルキル、C2-6アルケニル、C2-6アルキニル、ヘテロC1-6アルキル、ヘテロC2-6アルケニル、ヘテロC2-6アルキニル、C3-10カルボシクリル、3~10員のヘテロシクリル、C6-10アリールおよび5~10員のヘテロアリールから選択されるか、または2つのRff基は、連結して、3~10員のヘテロシクリルまたは5~10員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRgg基で置換されている;ならびに、
Rggの各々の場合は、独立して、ハロゲン、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6アルキル、-ON(C1-6アルキル)2、-N(C1-6アルキル)2、-N(C1-6アルキル)3 +X-、-NH(C1-6アルキル)2 +X-、-NH2(C1-6アルキル)+X-、-NH3 +X-、-N(OC1-6アルキル)(C1-6アルキル)、-N(OH)(C1-6アルキル)、-NH(OH)、-SH、-SC1-6アルキル、-SS(C1-6アルキル)、-C(=O)(C1-6アルキル)、-CO2H、-CO2(C1-6アルキル)、-OC(=O)(C1-6アルキル)、-OCO2(C1-6アルキル)、-C(=O)NH2、-C(=O)N(C1-6アルキル)2、-OC(=O)NH(C1-6アルキル)、-NHC(=O)(C1-6アルキル)、-N(C1-6アルキル)C(=O)(C1-6アルキル)、-NHCO2(C1-6アルキル)、-NHC(=O)N(C1-6アルキル)2、-NHC(=O)NH(C1-6アルキル)、-NHC(=O)NH2、-C(=NH)O(C1-6アルキル)、-OC(=NH)(C1-6アルキル)、-OC(=NH)OC1-6アルキル、-C(=NH)N(C1-6アルキル)2、-C(=NH)NH(C1-6アルキル)、-C(=NH)NH2、-OC(=NH)N(C1-6アルキル)2、-OC(NH)NH(C1-6アルキル)、-OC(NH)NH2、-NHC(NH)N(C1-6アルキル)2、-NHC(=NH)NH2、-NHSO2(C1-6アルキル)、-SO2N(C1-6アルキル)2、-SO2NH(C1-6アルキル)、-SO2NH2、-SO2C1-6アルキル、-SO2OC1-6アルキル、-OSO2C1-6アルキル、-SOC1-6アルキル、-Si(C1-6アルキル)3、-OSi(C1-6アルキル)3、-C(=S)N(C1-6アルキル)2、C(=S)NH(C1-6アルキル)、C(=S)NH2、-C(=O)S(C1-6アルキル)、-C(=S)SC1-6アルキル、-SC(=S)SC1-6アルキル、-P(=O)(OC1-6アルキル)2、-P(=O)(C1-6アルキル)2、-OP(=O)(C1-6アルキル)2、-OP(=O)(OC1-6アルキル)2、C1-6アルキル、C1-6パーハロアルキル、C2-6アルケニル、C2-6アルキニル、ヘテロC1-6アルキル、ヘテロC2-6アルケニル、ヘテロC2-6アルキニル、C3-10カルボシクリル、C6-10アリール、3~10員のヘテロシクリル、5~10員のヘテロアリールであるか;または、2つのジェミナルなRgg置換基は、連結されて、=Oまたは=Sを形成してもよく;ここで、X-は、対イオンである。
本発明は、それを必要とする対象においてリピート伸長に関連する神経疾患を処置および/または予防するために式(I)、(II)、(III)、(III-A)および(III-B)の化合物(例えばメトホルミン、ブホルミン、フェンホルミン)を使用するための、組成物、方法、使用およびキットを提供する。メトホルミンは、RAN翻訳を阻害するために用いられる。ある態様において、処置されるべき神経疾患は、リピート伸長に関連する。ある態様において、神経疾患は、RANタンパク質翻訳を受けるリピート伸長変異に関連する。ある態様において、神経疾患は、RANタンパク質の発現に関連する。
本開示はまた、式(I)、(II)、(III)、(III-A)または(III-B)の化合物(例えばメトホルミン)および任意に薬学的に受入可能な賦形剤を含む、医薬組成物を提供する。ある態様において、医薬組成物は、式(I)、(II)、(III)、(III-A)または(III-B)の化合物(例えばメトホルミン)、またはその薬学的に受入可能な塩、および薬学的に受入可能な賦形剤を含む。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、
式中:
の各々の場合は、結合価が許容する限り、単結合または二重結合であり;
R2Aの各々の場合は、独立して、水素、任意に置換されたアシル、任意に置換されたアルキル、または窒素保護基であり;
R3は、水素、任意に置換されたアルキル、または窒素保護基であり;
R4の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキルもしくは窒素保護基であるか、もしくは不在であり;または任意に、R4の1つの場合は、R3および介在原子と一緒になって、任意に置換された5~7員のヘテロ環式環を形成する;
または任意に、R4の1つの場合が、R3および介在原子と一緒になって、任意に置換された5~7員のヘテロ環式環を形成する場合、部分-N(R6)3の窒素と部分-C(NR4)2の炭素を連結する
は、結合価が許容する限り、二重結合であり;
R6の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基であるか、もしくは不在であり;ならびに、
R7は、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基または不在である。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグであり、式中:
R2Aの各々の場合は、独立して、水素、任意に置換されたアルキル、または窒素保護基である。
またはその薬学的に受入可能な塩、溶媒和物、水和物、互変異性体、立体異性体、誘導体もしくはプロドラッグの治療有効量を投与することを含む。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、
式中:
の各々の場合は、結合価が許容する限り、単結合または二重結合であり;
R2’は、水素、ハロゲン、または-N(R2A)2であり;
R2Aの各々の場合は、独立して、水素、任意に置換されたアシル、任意に置換されたアルキル、または窒素保護基であり;
R3は、水素、任意に置換されたアルキル、または窒素保護基であり;
R4’は、水素、-N(R4)2、または、
であり;
R4の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキルもしくは窒素保護基であるか、もしくは不在であり;または任意に、R4’が-N(R4)2である場合、R4の1つの場合は、R3および介在原子と一緒になって、任意に置換された5~7員のヘテロ環式環を形成し;
R4Aの各々の場合は、独立して、水素、任意に置換されたアルキル、または窒素保護基であり;
R6の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基であるか、もしくは不在であり;ならびに、
R7は、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基であるか、もしくは不在である。
の各々の場合は、結合価が許容する限り、単結合または二重結合である。ある態様において、
の少なくとも1つの場合は、単結合である。ある態様において、
の少なくとも1つの場合は、二重結合である。
のものである。ある態様において、R2Aの少なくとも1つの場合は、任意に置換されたn-プロピルである。ある態様において、R2Aの少なくとも1つの場合は、置換されていないn-プロピルである。ある態様において、R2Aの少なくとも1つの場合は、窒素保護基(例えばベンジル(Bn)、t-ブチルカルボネート(BOCまたはBoc)、ベンジルカルバメート(Cbz)、9-フルオレニルメチルカルボネート(Fmoc)、トリフルオロアセチル、トリフェニルメチル、アセチル、またはp-トルエンスルホンアミド(Ts))である。
であり、R4の各々の場合は、独立して、水素または任意に置換されたアルキルである。ある態様において、R4’は、
である。ある態様において、R4は、本明細書において定義されるとおりである。
は、結合価が許容する限り、二重結合である。ある態様において、R4の少なくとも1つの場合は、水素である。ある態様において、R4の両方の場合は、水素である。ある態様において、R4の少なくとも1つの場合は、重水素である。ある態様において、R4の両方の場合は、重水素である。ある態様において、R4の少なくとも1つの場合は、任意に置換されたアルキル(例えば置換された、または置換されていないC1-6アルキル)である。ある態様において、R4の少なくとも1つの場合は、任意に置換されたC1-6アルキルである。ある態様において、R4の少なくとも1つの場合は、置換されていないC1-6アルキルである。ある態様において、R4の少なくとも1つの場合は、置換されていないメチルまたは置換されていないエチルである。ある態様において、R4の少なくとも1つの場合は、任意に置換されたメチルである。ある態様において、R4の少なくとも1つの場合は、-CH2(D)である。ある態様において、R4の少なくとも1つの場合は、置換されていないメチルである。ある態様において、R4の2つの場合は、置換されていないメチルである。ある態様において、R4の少なくとも1つの場合は、-CD3である。ある態様において、R4の両方の場合は、-CD3である。ある態様において、R4の少なくとも1つの場合は、置換されていないエチルである。ある態様において、R4の少なくとも1つの場合は、窒素保護基(例えばベンジル(Bn)、t-ブチルカルボネート(BOCまたはBoc)、ベンジルカルバメート(Cbz)、9-フルオレニルメチルカルボネート(Fmoc)、トリフルオロアセチル、トリフェニルメチル、アセチル、またはp-トルエンスルホンアミド(Ts))である。ある態様において、R4の1つの場合は、R3および介在原子と一緒になって、任意に置換された6員のヘテロ環式環を形成する。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、R4の1つの場合が、R3および介在原子と一緒になって、任意に置換された6員のヘテロ環式環を形成する場合、部分-N(R6)3の窒素と部分-C(NR4)2の炭素を連結する
は、二重結合である。ある態様において、式(I)の化合物は、式:
のものである。
は、式:
のものである。ある態様において、R6の少なくとも1つの場合は、置換されていないC1-6アルキルである。ある態様において、R6の少なくとも1つの場合は、置換されていないメチルまたは置換されていないエチルである。ある態様において、R6の少なくとも1つの場合は、任意に置換されたメチルである。ある態様において、R6の少なくとも1つの場合は、-CH2(D)である。ある態様において、R6の少なくとも1つの場合は、置換されていないメチルである。ある態様において、R6の2つの場合は、置換されていないメチルである。ある態様において、R6の少なくとも1つの場合は、-(C-11)H3または-(C-13)H3である。ある態様において、R6の少なくとも1つの場合は、-(C-11)H3である。ある態様において、R6の少なくとも1つの場合は、-(C-13)H3である。ある態様において、R6の少なくとも1つの場合は、-CD3である。ある態様において、R6の両方の場合は、-CD3である。ある態様において、R6の少なくとも1つの場合は、置換されていないエチルである。ある態様において、R6の少なくとも1つの場合は、窒素保護基(例えばベンジル(Bn)、t-ブチルカルボネート(BOCまたはBoc)、ベンジルカルバメート(Cbz)、9-フルオレニルメチルカルボネート(Fmoc)、トリフルオロアセチル、トリフェニルメチル、アセチル、またはp-トルエンスルホンアミド(Ts))である。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグであって、式中:
xは、0または1であり;
R10は、ハロゲン、任意に置換されたアルキル、-NH2、-NH(任意に置換されたアルキル)、または-N(任意に置換されたアルキル)2である。
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。ある態様において、式(I)の化合物は、式:
のものである。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグであって、式中:
xは、0または1であり;および
R10は、ハロゲン、任意に置換されたアルキル、-NH2、-NH(任意に置換されたアルキル)、または-N(任意に置換されたアルキル)2である。
のもの、またはその薬学的に受入可能な塩である。ある態様において、式(II)の化合物は、式:
のものである。ある態様において、式(II)の化合物は、式:
のもの、またはその薬学的に受入可能な塩である。ある態様において、式(II)の化合物は、式:
のもの、またはその薬学的に受入可能な塩である。
のものであり、式中:
R5は、任意に置換されたアシル、非置換のアルキル、非置換のカルボシクリル、または任意に置換されたアリールであり;
R5Aの各々の場合は、独立して、-O(任意に置換されたアルキル)、-OH、-NH2、-NH(任意に置換されたアルキル)、または-N(任意に置換されたアルキル)2であり;ならびに、
nは、0、1、2、3または4である。
のものである。
のものであり、少なくとも1つの炭素原子は、C-13である。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグである。ある態様において、式(I)の化合物は、式:
のもの(メトホルミン)、またはその薬学的に受入可能な塩である。ある態様において、式(I)の化合物は、式:
のもの(ブホルミン)、またはその薬学的に受入可能な塩である。ある態様において、式(I)の化合物は、式:
のもの(フェンホルミン)、またはその薬学的に受入可能な塩である。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグである。
の化合物、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグの治療有効量を投与することを含み、式中:
R4Aの各々の場合は、独立して、水素、任意に置換されたアルキル、窒素保護基、または-CNであり;
R8の各々の場合は、独立して、水素、任意に置換されたアルキル、または窒素保護基であり;ならびに
R9は、水素、任意に置換されたアルキル、-CN、または窒素保護基である。
のもの、またはその薬学的に受入可能な塩、共結晶、互変異性体、立体異性体、溶媒和物、水和物、多形、同位体的に濃縮された誘導体もしくはプロドラッグである。
本開示がより完全に理解され得るために、以下の例を記載する。本願において記載される例は、本明細書において提供される組成物および方法を説明するために提供され、決して、それらの範囲を限定するものとして解釈されるべきではない。
メトホルミンを、CAG、CCTGまたはGGGGCCリピート伸長モチーフを含むコンストラクトで遺伝子導入されたHEK293T細胞におけるRANタンパク質翻訳に対する、その効果について評価した。遺伝子導入されたHEK293T細胞を、メトホルミンで処置した。図1Aにおいて示される多様なリピート伸長コンストラクトで遺伝子導入されたHEK293T細胞からのタンパク質ライセートに対して、タンパク質ブロットを行った。図1Bにおいて、KMQとラベルされたレーンは、以下を示す:RANポリ-Ser-Flag、RANポリ-Ala-HA、ATGで開始されるポリGln-Myc。図1Bにおいて、KMQとラベルされたレーンは、CAGリピート伸長のすぐ5’側にメチオニンをコードするATGを有し、ポリGlnリーディングフレーム中に位置する。KKQとラベルされたレーンは、AUG開始コドンなしでCAG伸長を含むKKQベクターを示し、以下を示す:RANポリSer-Flag、RANポリAla-HA、RANポリGln-Myc。これらのコンストラクトは、これらのリピート伸長全体にわたり発現されるATGにより開始されるポリ-Glnならびに非ATG開始RANタンパク質(ポリ-Gln、ポリ-Leu-Pro-Ala-Cysおよびポリ-Gly-Pro)のC末端領域中に組み込まれるエピトープタグを含む。CCTGとラベルされたレーンは、以下のRANタンパク質を発現する:RANポリLPAC-Flag、RANポリLPAC-HA、RANポリLPAC-Myc。G4C2とラベルされたレーンは、以下のRANタンパク質を検出するように設計される:RANポリGP-Flag、RANポリGR-HA、RANポリGA-Myc。図1Bにおけるタンパク質ブロットは、以下のRANタンパク質:3つ全てのリーディングフレームにおけるポリ-LPAC(ポリ-ロイシン-プロリン-アラニン-システイン)、ポリ-Ala、およびポリ-GP(ポリグリシン-プロリン)のRANタンパク質レベルの低下を示す。図1Bは、メトホルミンが、例示的なリピート伸長コンストラクトで遺伝子導入された細胞において、RANタンパク質蓄積を阻害することを示す。
メトホルミンを、メトホルミンC9ORF72による処置の前後にC9ORF72伸長陽性研究対象の末梢血から抽出されたタンパク質において、in vivoで検出されたグリシン-プロリン(GP)RANタンパク質の定常状態レベルに対するその効果について評価した。これらのレベルを、ヒト研究対象において、メトホルミン(1日あたり500mgまたは1000mgの塩酸メトホルミン持続放出錠剤)を、対象の主治医により処方された様々な用量において投与した前後に測定した。C9ORF72リピート伸長を有する単一のヒト対象から採取された血液試料において、前処置レベルと比較して、グリシン-プロリン(GP)RANタンパク質レベルの用量依存的低下が観察された。500または1000mg/日のメトホルミンによる処置の後、10~30日の間の複数の時点において、末梢血から単離された白血球からのタンパク質ライセートにおいて、GPレベルを測定した。多重比較のための補正の後で、*p<0.05、***p<0.001。図2は、メトホルミンが、in vivoで、C9ORF72の発現により生成されるRANタンパク質のレベルを低下させることを示す。
歩行分析。電動トレッドミルの透明なベルトの下からの高速ビデオカメラにより、マウスの下側のデジタルビデオ画像を撮影した(DigiGait(商標)Imaging system、Mouse Specific)。モーターの速度を14cm/sに設定して、各々のマウスに1分間にわたりトレッドミル区画を探索させ、次いで、ビデオ録画のためにモーター速度を24cm/sまで増大させた。マウスがカメラから一定の相対的位置により直線的に歩いたビデオ録画のみを、分析のために用いた。各々の足からのデータを、DigiGait自動歩行分析ソフトウェア(Mouse Specifics)により分析した。
請求の範囲において、「a」、「an」および「the」などの冠詞は、逆であることが示されない限り、または文脈から別段に明らかでない限り、1つ、または1つより多くを意味し得る。群の1つ以上のメンバーの間で「or」を含む請求項または記載は、逆であることが示されない限り、または文脈から別段に明らかでない限り、群のメンバーのうちの1つ、1つより多く、または全てが、所与の生成物またはプロセスにおいて存在するか、使用されるか、または他に関係がある場合に、満たされるとみなされる。本発明は、群の正確に1つのメンバーが、所与の生成物またはプロセスにおいて存在するか、使用されるか、または別段に関係がある態様を含む。本発明は、群のメンバーのうちの1つより多くまたは全てが、所与の生成物またはプロセスにおいて存在するか、使用されるか、または別段に関係がある態様を含む。
Claims (10)
- それを必要とする対象においてリピート伸長に関連する神経疾患を処置するための医薬組成物であって、式(I):
式中:
R2Aの各々の場合は、独立して、水素、任意に置換されたアシル、任意に置換されたアルキル、または窒素保護基であり;
R3は、水素、任意に置換されたアルキル、または窒素保護基であり;
R4の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキルもしくは窒素保護基であるか、もしくは不在であり;
R6の各々の場合は、独立して、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基であるか、もしくは不在であり;ならびに
R7は、結合価が許容する限り、水素、任意に置換されたアルキル、窒素保護基であるか、もしくは不在であり;
リピート伸長に関連する神経疾患は、筋萎縮性側索硬化症(ALS);前頭側頭葉型認知症(FTD);脊髄小脳失調症;フックス角膜内皮ジストロフィー;球脊髄性筋萎縮症;歯状核赤核淡蒼球ルイ体萎縮症;脆弱X振戦失調症候群(FXTAS);または脆弱XE症候群(FRAXE)である、
前記医薬組成物。 - 化合物が、式(I-A):
R2Aの各々の場合は、独立して、水素、任意に置換されたアルキル、または窒素保護基である、
請求項1に記載の医薬組成物。 - 化合物が、式:
請求項1または2に記載の医薬組成物。 - (a)R2Aの少なくとも1つの場合が、水素であるか、
(b)R2Aの少なくとも1つの場合が、任意に置換されたC1-6アルキルであるか、または
(c)R2Aの少なくとも1つの場合が、置換されていないメチルまたは置換されていないエチルである、請求項1~3のいずれか一項に記載の医薬組成物。 - (a)R3が、水素であるか、または
(b)R3が、任意に置換されたC1-6アルキルである、請求項1~4のいずれか一項に記載の医薬組成物。 - (a)R6の少なくとも1つの場合が、水素であるか、
(b)R6の少なくとも1つの場合が、任意に置換されたC1-6アルキルであるか、または
(c)R6の少なくとも1つの場合が、置換されていないメチルである、
請求項1~5のいずれか一項に記載の医薬組成物。 - R7が、任意に置換されたC1-6アルキルである、
請求項1および3~6のいずれか一項に記載の医薬組成物。 - 化合物が、式:
請求項1に記載の医薬組成物。 - 化合物が、式:
- 脊髄小脳失調症が、脊髄小脳失調症1型、脊髄小脳失調症2型、脊髄小脳失調症3型、脊髄小脳失調症8型、脊髄小脳失調症6型、脊髄小脳失調症7型、脊髄小脳失調症10型、脊髄小脳失調症12型、脊髄小脳失調症17型、脊髄小脳失調症31型、または脊髄小脳失調症36型である、
請求項1~9のいずれか一項に記載の医薬組成物。
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