JP2020530477A - Nr4a1リガンド、医薬組成物、及び関連する使用方法 - Google Patents
Nr4a1リガンド、医薬組成物、及び関連する使用方法 Download PDFInfo
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Description
本出願は、内容が参照により本明細書に組み込まれている、2017年8月10日に出願した米国出願第62/543761号の利益を主張するものである。
式中、
R1、R2、R1'、及びR2'は、それぞれ独立して、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、及び1個から約10個の炭素原子を含む分枝状アルキル基からなる群から選択され、
R3、R4、R5、R6、R3'、R4'、R5'、及びR6'は、それぞれ独立して、水素、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、及びニトロ基からなる群から選択され、
R7は、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むシクロアルキル基、及びアリール基からなる群から選択され、
R8、R9、R10、R11、及びR12は、独立して、H、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、1個から約10個の炭素原子を含むハロアルキル基、ニトロ基、ヒドロキシル基、及び1個から約10個の炭素原子を含むハロアルコキシ基からなる群から選択され、
R8、R9、R10、R11、及びR12のうちの少なくとも1つはOHであり、
R10がOHであるとき、R8、R9、R10、R11、及びR12のうちの少なくとも1つは水素でない。
一態様において、本開示は、NR4A1リガンドである化合物を提供する。本明細書において更に記載するように、特定の実施形態において、4-、3-及び2-ヒドロキシフェニルC-DIM類似体を骨格として使用して、癌及び他の疾患に対して強力な活性を示すNR4A1リガンドの第二世代の合成及び最終的な開発を調べるが、ここで、NR4A1は代謝性及び神経疾患等の潜在的治療標的である。
式中、
R1、R2、R1'、及びR2'は、それぞれ独立して、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、及び1個から約10個の炭素原子を含む分枝状アルキル基からなる群から選択され、
R3、R4、R5、R6、R3'、R4'、R5'、及びR6'は、それぞれ独立して、水素、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、及びニトロ基からなる群から選択され、
R7は、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むシクロアルキル基、及びアリール基からなる群から選択され、
R8、R9、R10、R11、及びR12は、独立して、H、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、1個から約10個の炭素原子を含むハロアルキル基、ニトロ基、ヒドロキシル基、及び1個から約10個の炭素原子を含むハロアルコキシ基からなる群から選択され、
R8、R9、R10、R11、及びR12のうちの少なくとも1つはOHであり、
R10がOHであるとき、R8、R9、R10、R11、及びR12のうちの少なくとも1つは水素でない。
幾つかの実施形態において、R8はOHである。特定の場合には、このようなリガンドは、中心のフェニル基のOH基の置換に起因して、本明細書中、「2-ヒドロキシ」及び/又は「2-OH」と称する。特定の該実施形態において、R9、R10、R11、及びR12は、それぞれHである。特定の他の実施形態において、R9、R10、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。一実施形態において、R10はOCH3である。一実施形態において、R11は、CH3、OCH3、及びCF3からなる群から選択される。一実施形態において、R9及びR11はBrである。
幾つかの実施形態において、R9はOHである。特定の場合には、このようなリガンドは、中心のフェニル基のOH基の置換に起因して、本明細書中、「3-ヒドロキシ」及び/又は「3-OH」と称する。特定の該実施形態において、R8、R10、R11、及びR12は、それぞれHである。特定の他の実施形態において、R8、R10、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。特定の実施形態において、R8はハロゲンである。
幾つかの実施形態において、R10はOHである。特定の場合には、このようなリガンドは、中心のフェニル基のOH基の置換に起因して、本明細書中、「4-ヒドロキシ」及び/又は「4-OH」と称する。特定の該実施形態において、R8、R9、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。特定の他の実施形態において、R9はハロゲンであり、R11はH、ハロゲン、及びOCH3からなる群から選択される。
特定の態様において、本開示は、治療有効量の本開示の化合物を、薬学的に許容される担体並びに任意選択の他の治療及び/又は予防成分と共に含む医薬組成物を提供する。
別の態様において、本開示は、細胞中のNR4A1活性を調節する方法であって、本明細書に記載の化合物又は医薬組成物を細胞に投与することを含む方法を提供する。
式中、
R1、R2、R1'、及びR2'は、それぞれ独立して、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、及び1個から約10個の炭素原子を含む分枝状アルキル基からなる群から選択され、
R3、R4、R5、R6、R3'、R4'、R5'、及びR6'は、それぞれ独立して、水素、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、及びニトロ基からなる群から選択され、
R7は、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むシクロアルキル基、及びアリール基からなる群から選択され、
R8、R9、R10、R11、及びR12は、独立して、H、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、1個から約10個の炭素原子を含むハロアルキル基、ニトロ基、ヒドロキシル基、及び1個から約10個の炭素原子を含むハロアルコキシ基からなる群から選択され、
R8、R9、R10、R11、及びR12のうちの少なくとも1つはOHであり、
R10がOHであるとき、R8、R9、R11、及びR12のうちの少なくとも1つは水素でない。
一実施形態において、R10はOHである。特定の該実施形態において、R8、R9、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。特定の他の実施形態において、R9はハロゲンであり、R11はH、ハロゲン、及びOCH3からなる群から選択される。
一実施形態において、R9はOHである。特定の該実施形態において、R8、R10、R11、及びR12は、それぞれHである。特定の他の実施形態において、R8、R10、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。特定の実施形態において、R8はハロゲンである。
一実施形態において、R8はOHである。特定の該実施形態において、R9、R10、R11、及びR12は、それぞれHである。特定の他の実施形態において、R9、R10、R11、及びR12は、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される。一実施形態において、R10はOCH3である。一実施形態において、R11はCH3、OCH3、及びCF3からなる群から選択される。一実施形態において、R9及びR11はBrである。
別の態様において、本開示は、NR4A1活性の調節によって治療可能な個人における疾患又は状態を治療する方法であって、治療に有効な量の本明細書に記載の化合物又は医薬組成物を個人に投与することを含む方法を提供する。
以下は、NR4A1と結合する本開示の実施形態による化合物の説明である。
以下は、本開示の実施形態による化合物の構造-活性相関の説明である。
以下は、表面プラズモン共鳴(SPR)を使用した、本開示の実施形態による化合物のNR4A1との結合の説明である。
本開示の実施形態による化合物によるオステオポンチン(OPN)の発現の誘導を示す。
以下は、本開示の実施形態による3-ヒドロキシ及び2-ヒドロキシ化合物によって結合するNR4A1の説明である。
2-及び3-ヒドロキシC-DIM類似体で得られた結果は、特定の実施形態において、これらが、親4-ヒドロキシ参照標準物質より強力なNR4A1アンタゴニストだったことを実証した。したがって、幾つかの2-及び3-ヒドロキシDIMの置換類似体を合成し、トランス活性化アッセイにおけるそれらの活性を調べた。その上、2-ヒドロキシ類似体では、本発明者らは、それらの遺伝子誘導(SERPINB5及びGADD45α)(図17参照)及び抑制(β1-インテグリン及びTXNDC5)(図16参照)に与える機能的効果も調べた。
核内受容体に対するリガンドは、遺伝子発現の活性化及び抑制の両方を行い、これらの効果は細胞背景に特異的である。本発明者らの初期研究は、β1-インテグリン及びTXNDC5等の発癌促進遺伝子を下方制御するNR4A1アンタゴニストのC-DIMに集中していたが、C-DIMは、癌細胞中の腫瘍抑制遺伝子発現も誘導する。
以下は、インビボ及びインビトロ両方のアッセイにおける本開示の実施形態によるより活性のDIM-4-OH類似体3種の説明である。
以下は、本開示の実施形態による化合物で処置した細胞によるグルコース取り込みの説明である。
以下は、本開示の実施形態による化合物で処置した、高脂肪食で維持されたマウスの説明である。
Claims (33)
- 次式:
(式中、
R1、R2、R1'、及びR2'が、それぞれ独立して、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、及び1個から約10個の炭素原子を含む分枝状アルキル基からなる群から選択され、
R3、R4、R5、R6、R3'、R4'、R5'、及びR6'が、それぞれ独立して、水素、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、及びニトロ基からなる群から選択され、
R7が、水素、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むシクロアルキル基、及びアリール基からなる群から選択され、
R8、R9、R10、R11、及びR12が、独立して、H、ハロゲン、1個から約10個の炭素原子を含む直鎖状アルキル基、1個から約10個の炭素原子を含む分枝状アルキル基、1個から約10個の炭素原子を含むアルコキシ基、1個から約10個の炭素原子を含むハロアルキル基、ニトロ基、ヒドロキシル基、及び1個から約10個の炭素原子を含むハロアルコキシ基からなる群から選択され、
R8、R9、R10、R11、及びR12のうちの少なくとも1つがOHであり、
R10がOHであるとき、R8、R9、R11、及びR12のうちの少なくとも1つが水素でない)。 - R8がOHである、請求項1に記載の化合物。
- R9、R10、R11、及びR12がそれぞれHである、請求項2に記載の化合物。
- R9、R10、R11、及びR12が、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される、請求項2に記載の化合物。
- R10がOCH3である、請求項2に記載の化合物。
- R11が、CH3、OCH3、CF3からなる群から選択される、請求項2に記載の化合物。
- R9及びR11がBrである、請求項2に記載の化合物。
-
- R9がOHである、請求項1に記載の化合物。
- R8、R10、R11、及びR12が、それぞれHである、請求項9に記載の化合物。
- R8、R10、R11、及びR12が、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される、請求項9に記載の化合物。
- R8がハロゲンである、請求項9に記載の化合物。
-
- R10がOHである、請求項1に記載の化合物。
- R8、R9、R11、及びR12が、独立して、ハロゲン、CH3、OCCl3、CF3、t-ブチル、OCH3、OH、C6H5、及びCNからなる群から選択される、請求項14に記載の化合物。
- R9がハロゲンであり、R11がH、ハロゲン、及びOCH3からなる群から選択される、請求項14に記載の化合物。
-
- 治療有効量の請求項1から17のいずれか一項に記載の化合物、又はその塩、及び薬学的に許容される担体を含む医薬組成物。
- 核内受容体サブファミリー4グループAメンバー1(NR4A1)活性を調節することによって治療可能な個人における疾患又は状態を治療する方法であって、治療有効量の請求項1から17のいずれか一項に記載の化合物、若しくはその塩、又は請求項18に記載の医薬組成物を個人に投与する工程を含む方法。
- 疾患又は条件が、癌、血栓症、大腸炎、クローン病、炎症性腸疾患、多発性硬化症、関節リウマチ免疫抑制障害、関節炎、喘息、卒中、再狭窄、鼻炎、糖尿病、及び骨粗しょう症からなる群から選択される、請求項19に記載の方法。
- 癌が、膵臓癌、乳癌、大腸癌、横紋筋肉腫、及び肺癌からなる群から選択される、請求項20に記載の方法。
- NR4A1活性の調節が、β1-インテグリン、TXNDC5、スルビビン、EFGR、PAX3-FOX01A、及びこれらの組み合わせからなる群から選択されるタンパク質の下方制御を誘導する、請求項19に記載の方法。
- NR4A1活性の調節が、SERPINB5、GADD45α、及びこれらの組み合わせからなる群から選択されるタンパク質の上方制御を誘導する、請求項19に記載の方法。
- 疾患が糖尿病であり、NR4A1活性の調節が、個人におけるグルコース取り込みを誘導する、請求項20に記載の方法。
- NR4A1活性の調節が、GLUT-4及びRab4の上方制御並びにAMPKのリン酸化を誘導する、請求項24に記載の方法。
- 投与が、局所投与、経口投与、静脈注射、腹腔内注射、筋肉注射、鼻腔内投与、経皮投与、直腸投与、又はこれらの組み合わせを含む、請求項19に記載の方法。
- 細胞中のNR4A1活性を調節する方法であって、請求項1から17のいずれか一項に記載の化合物、若しくはその塩、又は請求項18に記載の医薬組成物を細胞に投与する工程を含む方法。
- 細胞中のNR4A1活性の調節が、細胞中の機能的NR4A1のレベルを低減する工程を含む、請求項27に記載の方法。
- 細胞が、癌細胞である、請求項27に記載の方法。
- 細胞を、インビトロで化合物又は医薬組成物と接触させる、請求項27に記載の方法。
- 有効量の化合物又は医薬組成物を対象に投与することによって、細胞をインビボで化合物又は医薬組成物と接触させる、請求項27に記載の方法。
- NR4A1活性の調節が、β1-インテグリン、TXNDC5、スルビビン、EFGR、PAX3-FOX01A、及びこれらの組み合わせからなる群から選択されるタンパク質の下方制御を誘導する、請求項27に記載の方法。
- NR4A1活性の調節が、SERPINB5、GADD45α、及びこれらの組み合わせからなる群から選択されるタンパク質の上方制御を誘導する、請求項27に記載の方法。
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