JP2022116144A - 糖尿病性末梢神経障害の治療のためのhdac阻害剤 - Google Patents
糖尿病性末梢神経障害の治療のためのhdac阻害剤 Download PDFInfo
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/42—One nitrogen atom
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Abstract
Description
以下に、本明細書で使用される様々な用語の定義を列挙する。これらの定義は、具体例で制限の断りがない限り、個別又は集団の一部として明細書及び特許請求の範囲全体において使用される用語に適用する。
一つの態様において、本明細書においては、対象に治療有効量のHDAC6阻害剤を投与することを含む、それを必要とする対象における糖尿病性末梢神経障害の治療又は予防のための方法が提供される。
Rxは、H及びC1-6-アルキルから選択される;
Ryは、H及びC1-6-アルキルから選択される;
又は、Rx及びRyは、それぞれが結合する炭素と一緒に、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチルを形成し;
各RAは、独立してC1-6-アルキル、C1-6-アルコキシ、ハロ、OH又はハロアルキルであり;
mは0、1又は2である。
Rx及びRyは、それぞれが結合する炭素と一緒に、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチルを形成し;
各RAは、独立してC1-6-アルキル、C1-6-アルコキシ、ハロ、OH又はハロアルキルであり;
mは0、1又は2である。
環Bは、OH、ハロ又はC1-6-アルキルで置換された又は置換されていないアリール又はヘテロアリールであり;
R1は、OH、ハロ又はC1-6-アルキルで置換された又は置換されていないアリール又はヘテロアリールであり;
Rは、H又はC1-6-アルキルである。
HDAC6(ヒストンデアセチラーゼ6)阻害剤は、血液癌及びCNS疾患の動物モデルにおいて有効性を示す。本願においては、糖尿病性末梢神経障害の治療又は予防のために、HDAC6阻害剤の使用が提供される。
また、本願は、対象において、糖尿病性末梢神経障害を治療する又は予防するためのHDAC6阻害剤を提供する。一つの実施形態において、HDAC6阻害剤はHDAC6特異的阻害剤である。
他の態様において、本発明は、本願で提供される任意の化合物又はその薬学的に許容される塩を、薬学的に許容される担体と共に含み、糖尿病性末梢神経障害の治療又は予防に使用するための医薬組成物を提供する。
本出願を通して列挙したすべての文献(引用文献、登録特許、公開特許公報及び同時係属中の特許出願を含む)の全文は、参照することにより組み入れられたものとする。別段の記載がある場合を除き、明細書で使用される技術用語及び科学用語は全て当業者に一般に公知な意味と一致する。
当業者は、単なる日常的な実験によって、明細書に記載した発明の具体的な実施形態の多くの均等物を認識しまたは確認することができるであろう。そのような均等物は以下の特許請求の範囲によって包含されることが意図されている。
MeOH/DCM(6/2ml)中のエチル2-(2-メトキシ-5-(トリフルオロメチル)ベンジルアミノ)ピリミジン-5-カルボキシレート(100mg、0.28mmol)の混合物に対して、NH2OH(0.5ml)を添加し、次いでNaOH溶液(MeoH中で飽和、1ml)を0°Cで滴下した。混合物を0°Cで3時間撹拌した。TLCで反応が完了したと判断された後、混合物を濃縮しMeOHとDCMを除去し、pH6~7付近まで酸性化し、prep-TLCで精製し、所望の生成物である化合物3を白色固体として得た(30mg、31%)。LCMS: m/z = 343 (M+H)+. 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.99 (s, 1H), 8.61 (d, J = 17.4 Hz, 2H), 8.22 (t, J = 6.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 3.91 (s, 3H)。
化合物1、2及び3を、一般的な疼痛DPNのモデルであるストレプトゾトシン誘導性糖尿病ラット(STZラット)において、神経障害の回復能について試験した。両方の化合物が、STZラットにおいて、用量依存的に接触性アロディニアを反転させ、痛覚閾値を正常レベル付近まで回復させた。化合物1の場合、例えば、薬物治療の停止後でさえも痛覚閾値における薬物のプラスの効果がみられ、このことはDPNにおけるHDAC6阻害剤の進行抑制効果を示している。
後根神経節ニューロン(DRGN: dorsal root ganglion neuron)を化合物2で24時間処置し、全細胞抽出物をウエスタンブロットで分析した。化合物2は、用量依存的にチューブリンのアセチル化の増大を誘導した。DRGNにおいて、最も少ないヒストンアセチル化の増大が観察されたのは、1μMまでの化合物2に対する応答においてである。化合物2は、ラットDRGNの全細胞溶解物においてチューブリン高アセチル化を誘導する(図3A)。
処置後4時間の間、1時間ごとにテールフリック試験を実施した。化合物1又は2をテールフリック試験前4日間にわたってラットに投与した(BID群)。あるいは、化合物1又は2を試験の1時間前にラットに単回投与した(QD群)。
代謝ストレスは、糖尿病に関連する多くの病態の根底にある。Freemanら (Freeman, O.J., Unwin, R.D., Dowsey, A.W., Begley, P., Ali, S., Hollywood, K.A., Rustogi, N., Petersen, R.S., Dunn, W.B., Cooper, G.J.S., Gardiner, N.J. (2016) “Metabolic Dysfunction is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy” Diabetes 65) は、ストレプトゾトシンで処置して高血糖を誘導したラットにおいて、坐骨神経における代謝産物の変化が神経因性疼痛の増加と関連することを示した。
Claims (21)
- 対象において、糖尿病性末梢神経障害の治療又は予防において使用するための、HDAC6阻害剤。
- HDAC6特異的阻害剤である、請求項1に記載のHDAC6阻害剤。
- 治療有効量のHDAC6阻害剤を対象に投与することを含み、それを必要とする対象において糖尿病性末梢神経障害を治療又は予防するための方法。
- HDAC6阻害剤が特異的HDAC6阻害剤である、請求項14に記載の方法。
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