JP2020509062A - 2−(置換フェニルヘテロ)芳香族カルボン酸系fto阻害剤、その製造方法およびその使用 - Google Patents
2−(置換フェニルヘテロ)芳香族カルボン酸系fto阻害剤、その製造方法およびその使用 Download PDFInfo
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- JP2020509062A JP2020509062A JP2019548071A JP2019548071A JP2020509062A JP 2020509062 A JP2020509062 A JP 2020509062A JP 2019548071 A JP2019548071 A JP 2019548071A JP 2019548071 A JP2019548071 A JP 2019548071A JP 2020509062 A JP2020509062 A JP 2020509062A
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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Abstract
Description
上記のように、本分野では、特異的にFTOを標的とする小分子阻害剤を開発し、そして関連疾患の治療・研究に使用することが切望されている。
本発明の第一の側面では、以下のような式(I)で表される化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグを提供する。
A1、A2、A3、A4はそれぞれ独立にCR'またはNである。
Yは置換または無置換のC6-C12アリール基、置換または無置換の3-12員複素環基からなる群から選ばれる。
本発明の第二の側面では、以下のような式(I)で表される化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグを提供する。
Xはカルボキシ基、置換または無置換のC2-C12エステル基、置換または無置換のアミド基、置換または無置換の5-9員複素環基のような構造を有する。
Yは置換または無置換のC6-C12アリール基、置換または無置換の3-12員複素環基からなる群から選ばれる。
もう一つの好適な例において、Yは無置換のフェニル基ではない。
もう一つの好適な例において、前記のXは下記式で表される構造を有する。
もう一つの好適な例において、前記のYは以下の群から選ばれる。
もう一つの好適な例において、Ra、Rb、Rc、Rdはそれぞれ独立にH、F、Cl、OH、メチル基、メトキシ基からなる群から選ばれる。
もう一つの好適な例において、RaおよびRbはそれぞれ独立にHであるか、RcおよびRdはそれぞれ独立にHである。
もう一つの好適な例において、RaとRbは同様である。
もう一つの好適な例において、RcとRdは同様である。
一つの好適な例において、A2、A3はそれぞれ独立にCR'である。
もう一つの好適な例において、前記のX基およびY基は具体的な実施例における化合物の相応する基である。
もう一つの好適な例において、前記のR、R1、R2、R3、R4、R5、R6は具体的な実施例における化合物の相応する基である。
もう一つの好適な例において、前記の式I化合物は化合物1-88から選ばれる。
もう一つの好適な例において、前記の薬学的に許容される塩は無機酸塩、有機酸塩、無機塩基塩、または有機塩基塩である。
もう一つの好適な例において、前記の薬学的に許容される塩はアルカリ金属塩、好ましくはリチウム塩、ナトリウム塩またはカリウム塩である。
(a) FTOタンパク質の活性または発現量に関連する疾患を治療する薬物の製造、
(b) FTOタンパク質活性選択的阻害剤の製造、
(c) 体外における FTOタンパク質の活性に対する非治療的な阻害、および/または
(d) FTOの活性または発現量に関連する疾患の治療。
もう一つの好適な例において、FTOの活性または発現量に関連する疾患を治療する場合、前記の式I化合物は第二の治療剤と併用される。
もう一つの好適な例において、前記の薬物組成物はさらに第二の治療剤を含む。
本発明の第五の側面では、式6化合物の製造方法であって、以下の工程を含む方法を提供する:
もう一つの好適な例において、前記のカップリング試薬はY-B(OH)2である。
本発明者は長期間にわたって深く研究したところ、式(I)で表される1種類の化合物は効率的に、高選択性でFTOタンパク質の活性を抑制し、既存のFTO阻害剤と比べ、その活性が顕著に向上したことを見出した。上記の知見に基づき、発明者らは本発明を完成させた。
用語
用語「ハロゲン」とは、F、Cl、BrおよびIをいう。
本発明は、下記式(I)で表される化合物、およびその薬学的に許容される塩およびそのプロドラッグを提供する。
A1、A2、A3、A4はそれぞれ独立にCR'またはNである。
MはCR'2、NH、OまたはSからなる群から選ばれる。R'はH、ハロゲン原子、カルボニル基(=O)、カルボキシ基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C1-C6アルコキシカルボニル基、置換または無置換のC1-C6アシルアミノ基、C2-C12エステル基、あるいは置換または無置換のC1-C10アルキル基からなる群から選ばれる。
Yは置換または無置換のC6-C12アリール基、置換または無置換の3-12員複素環基からなる群から選ばれる。
本発明化合物は、優れたFTOタンパク質に対する抑制活性を有するため、本発明化合物およびその各種の結晶型、薬学的に許容される無機・有機塩、水和物もしくは溶媒和物、並びに本発明化合物を主要活性成分として含有する薬物組成物はFTOの活性または発現量に関連する疾患の治療、予防および緩和に有用である。既存技術によれば、本発明の化合物は、肥満、代謝症候群(metabolic syndrome、MS)、2型糖尿病(Type 2 diabetes、T2D)、アルツハイマー病、乳癌、小細胞肺癌、ヒト骨髄横紋筋肉腫、膵臓癌、悪性神経膠芽細胞脳腫などの癌のような疾患の治療に使用することができる。
これらの不活性希釈剤の他、組成物は助剤、たとえば、湿潤剤、乳化剤、懸濁剤、甘味料、矯味剤や香料を含んでもよい。
本発明化合物は、単独で投与してもよいし、あるいは他の薬学的に許容される化合物と併用して投与してもよい。
(1) 本発明は非常に低い濃度(IC50値は通常30μM未満である)でFTOタンパク質の活性を抑制することができる、斬新な脱メチル化酵素FTO阻害剤を提供する。
(2) 前記のFTO阻害剤は優れた安全性を有する。
(4) 前記のFTO阻害剤は細胞レベルでFTO選択性を有する。
(5) 前記のFTO阻害剤は血漿安定性を有する。
(6) 本発明のFTOタンパク質活性阻害剤はマウスモデルにおいて優れた薬物動態学的効果が現れる。
実験における実験試薬は主に中国国薬グループ、sigma社および上海生工社から購入された。
2-(置換フェニルヘテロ)芳香族カルボン酸系化合物15および化合物25の製造
化合物25の合成は、下記図に示すように、o-ヨード安息香酸および4-ブロモ-2,6-ジクロロアニリンを出発原料とし、無水酢酸銅およびN-メチルモルホリンの作用においてウルマンカップリングをさせ、エステル化、鈴木カップリング反応を経て、加水分解して化合物15が得られたが、これに基づいてヒドロキサム酸化して化合物25が得られた。
ほかのピリジン、ピラジン母核の2-(置換フェニルヘテロ)芳香族カルボン酸系化合物を実施例1に類似する合成方法によって、相応する出発原料で製造した。
ニッケルカラムアフィニティークロマトグラフィーによって精製して高純度のFTOタンパク質を得た。
FTO酵素活性抑制反応系は、50 mM Tris・HCl、pH 7.5、0.3μM FTO、1 μM 39nt-m6Aで修飾された二本鎖DNA、300μM 2OG、280μM (NH4)2Fe(SO4)2、2 mM L-アスコルビン酸および異なる濃度の化合物で、室温で2hインキュベートした後、65℃でゆっくり加熱して不活性化させ、1μM 39ntのアンチセンス鎖DNAをアニーリングして二本鎖にした。8μlの反応液を取り、メチル化に敏感な酵素DpnIIで二本鎖基質を酵素切断し、酵素切断されたサンプルを15%非変性ポリアクリルアミド電気泳動によって検出し、Gel-Redで染色した後、ゲルイメージングシステムで撮影し、得られたバンドに対してグレイスケールによる抑制率の読み取りを行った。
化合物(濃度50 μM)のFTOに対する体外抑制率:
以下は一般式(I)で表される2-(置換フェニルヘテロ)芳香族カルボン酸およびその誘導体系阻害剤のにおける固形腫瘍のヒト小細胞肺癌細胞系(SCLC-21H)、ヒト骨髄横紋筋肉腫細胞系(RH30)および膵臓癌細胞系(KP3)に対する細胞毒性の研究である。
化合物の活性(濃度50 μMにおける細胞抑制率)のまとめ:
Claims (15)
- 下記式(I)で表される化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
A1、A2、A3、A4はそれぞれ独立にCR'またはNである。
MはCR'2、NH、OまたはSからなる群から選ばれる。R'はH、ハロゲン原子、カルボニル基(=O)、カルボキシ基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C1-C6アルコキシカルボニル基、置換または無置換のC1-C6アシルアミノ基、C2-C12エステル基、あるいは置換または無置換のC1-C10アルキル基からなる群から選ばれる。
Xはカルボキシ基、ヒドロキサム酸基、置換または無置換のC2-C12エステル基、置換または無置換のアミド基、置換または無置換の3-12員複素環基のような構造を有する。
Yは置換または無置換のC6-C12アリール基、置換または無置換の3-12員複素環基からなる群から選ばれる。
Ra、Rb、Rc、Rdはそれぞれ独立にH、ハロゲン、-OH、CN、NO2、NH2、置換または無置換のC1-C6アルキル基、置換または無置換のC1-C6アルコキシ基からなる群から選ばれる。
前記の置換とは基における一つまたは複数の水素原子がハロゲン原子、カルボニル基(=O)、カルボキシ基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C1-C6アルコキシカルボニル基、C1-C6アシルアミノ基、C2-C12エステル基、置換または無置換のC1-C10アルキル基、置換または無置換のC2-C10アルケニル基、置換または無置換のC2-C10アルキニル基、置換または無置換のC6-C10アリール基、あるいは置換または無置換の5員または6員ヘテロアリール基、3-12員複素環基、3-12員シクロアルキル基、好ましくはC1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基またはC1-C6アルキルアミノ基からなる群から選ばれる置換基で置換されることをいう。ここで、前記の置換または無置換のC1-C10アルキル基、置換または無置換のC6-C10アリール基あるいは5員または6員ヘテロアリール基の置換基はハロゲン原子、カルボニル基(=O)、ヒドロキシ基、カルボキシ基、C1-C6アルコキシカルボニル基、アミノ基、C1-C6アシルアミノ基、ニトロ基、シアノ基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C6-C10アリール基あるいは5員または6員ヘテロアリール基、3-12員複素環基、3-12員シクロアルキル基、好ましくはハロゲン原子、C1-C6アルコキシカルボニル基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基またはフェニル基、5-6員複素環基からなる群から選ばれる。) - 下記式(I)で表される化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
Xはカルボキシ基、置換または無置換のC2-C12エステル基、置換または無置換のアミド基、置換または無置換の5-9員複素環基のような構造を有する。
Yは置換または無置換のC6-C12アリール基、置換または無置換の3-12員複素環基からなる群から選ばれる。
前記の置換とは基における一つまたは複数の水素原子がハロゲン原子、カルボニル基(=O)、カルボキシ基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C1-C6アルコキシカルボニル基、C1-C6アシルアミノ基、置換または無置換のC1-C10アルキル基、置換または無置換のC6-C10アリール基あるいは5員または6員ヘテロアリール基、好ましくはC1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基またはC1-C6アルキルアミノ基からなる群から選ばれる置換基で置換されることをいう。ここで、前記の置換または無置換のC1-C10アルキル基、置換または無置換のC6-C10アリール基あるいは5員または6員ヘテロアリール基の置換基はハロゲン原子、カルボニル基(=O)、ヒドロキシ基、カルボキシ基、C1-C6アルコキシカルボニル基、アミノ基、C1-C6アシルアミノ基、ニトロ基、シアノ基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C6-C10アリール基あるいは5員または6員ヘテロアリール基、好ましくはハロゲン原子、C1-C6アルコキシカルボニル基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基またはフェニル基からなる群から選ばれる。) - 前記のXは下記式で表される構造を有することを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
Yは置換または無置換のベンゼン、置換または無置換のピリジン、置換または無置換のピリミジン、置換または無置換のピリダジン、置換または無置換のテトラジン、置換または無置換のトリアジン、置換または無置換のピロール、置換または無置換のチオフェン、置換または無置換のフラン、置換または無置換のテトラゾール、置換または無置換のトリアゾール、置換または無置換のイミダゾール、置換または無置換のチアゾール、置換または無置換のオキサゾール、置換または無置換のピラゾール、置換または無置換のイソチアゾール、置換または無置換のイソオキサゾール、置換または無置換のオキサジアゾール、置換または無置換のチアジアゾール、置換または無置換のナフタレン、置換または無置換のインドール、置換または無置換のインダゾール、置換または無置換のキノリン、置換または無置換のイソキノリン、置換または無置換のベンゾフラン、置換または無置換のベンゾチオフェン、置換または無置換のベンゾイミダゾール、置換または無置換のベンゾオキサゾール、置換または無置換のベンゾチアゾール、置換または無置換のベンゾイソチアゾール、置換または無置換のベンゾイソオキサゾール、置換または無置換のベンゾトリアゾール、置換または無置換のモルホリン、置換または無置換のジヒドロピペリジン、置換または無置換のチオモルホリン、置換または無置換のピペリジン、置換または無置換のピペラジン、置換または無置換のテトラヒドロピラン、置換または無置換のジヒドロピラン、置換または無置換のピロリン、置換または無置換のテトラヒドロチオフェン、置換または無置換のテトラヒドロフラン、置換または無置換のオキセタン、置換または無置換のチエタン、置換または無置換のアゼチジンである。) - 前記のYは以下の群から選ばれることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
ここで、置換基はハロゲン原子、カルボニル基(=O)、カルボキシ基、ヒドロキシ基、アミノ基、ニトロ基、シアノ基、C1-C6アルコキシカルボニル基、C1-C6アシルアミノ基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基、C1-C6アルキルアミノ基、C6-C10アリール基あるいは5員または6員ヘテロアリール基、好ましくはハロゲン原子、C1-C6アルコキシカルボニル基、C1-C6アルキル基、C1-C6ハロアルキル基、C1-C6アルコキシ基またはフェニル基から選ばれる。) - Ra、Rb、Rc、Rdはそれぞれ独立にH、F、Cl、OH、メチル基、メトキシ基からなる群から選ばれることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
- A2、A3はそれぞれ独立にCR'であることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
- 前記の式I化合物は以下の群から選ばれることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ:
- 前記の薬学的に許容される塩は無機酸塩、有機酸塩、無機塩基塩、または有機塩基塩からなる群から選ばれることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
- 前記の薬学的に許容される塩はアルカリ金属塩、好ましくはリチウム塩、ナトリウム塩またはカリウム塩であることを特徴とする請求項1に記載の化合物、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグ。
- 請求項1に記載の式I化合物およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグの使用であって、以下の群から選ばれる用途に使用されることを特徴とする使用:
(a) FTOタンパク質の活性または発現量に関連する疾患を治療する薬物の製造、
(b) FTOタンパク質活性選択的阻害剤の製造、
(c) 体外における FTOタンパク質の活性に対する非治療的な阻害、および/または
(d) FTOの活性または発現量に関連する疾患の治療。 - 前記の疾患は、肥満、代謝症候群(metabolic syndrome、MS)、2型糖尿病(Type 2 diabetes、T2D)、アルツハイマー病、乳癌、小細胞肺癌、ヒト骨髄横紋筋肉腫、膵臓癌、悪性神経膠芽細胞脳腫などの癌からなる群から選ばれることを特徴とする請求項10に記載の使用。
- (i)治療有効量の式I化合物、またはその薬学的に許容される塩、およびその薬学的に許容される塩、水和物、溶媒和物またはプロドラッグと、(ii)薬学的に許容される担体とを含むことを特徴とする薬物組成物。
- 前記の薬物組成物はさらに第二の治療剤を含むことを特徴とする請求項12に記載の薬物組成物。
- FTOタンパク質の活性を抑制する方法であって、抑制対象に、抑制有効量の請求項1に記載の式I化合物またはその薬学的に許容される塩を施用する工程、あるいは抑制対象に、抑制有効量の請求項12に記載の薬物組成物を施用する工程を含むことを特徴とする方法。
- 以下の工程を含むことを特徴とする式I化合物の製造方法:
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WO2018157843A1 (zh) | 2018-09-07 |
WO2018157842A1 (zh) | 2018-09-07 |
CN108530310A (zh) | 2018-09-14 |
CN108524482A (zh) | 2018-09-14 |
US20200079727A1 (en) | 2020-03-12 |
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