JPWO2020014144A5

JPWO2020014144A5 -

Info

Publication number: JPWO2020014144A5
Application number: JP2021500423A
Authority: JP
Publication date: 2022-07-14

Description

ＰＫ分析。５ｇの薬物動態分析はＥｘｐｌｏｒａＢｉｏｌａｂｓにより実施された。１２匹のＣ５７ＢＬ／６（６匹の雄、６匹の雌）マウスに５ｇを１０ｍｇ／ｋｇで静脈内注射により投与した。注射後の２分ならびに０．０８、０．２５、０．５、１、２、８および２４時間の時点で血液サンプルを採取した。生物分析はＩｎｔｅｇｒａｔｅｄＡｎａｌｙｔｉｃａｌＳｏｌｕｔｉｏｎｓにより実施され、島津ＶＰシリーズ１０システムＬＣによる処理およびそれに続くＡｐｐｌｉｅｄＢｉｏｓｙｓｔｅｍｓ／ＭＤＳＳＣＩＥＸＡＰＩ３０００トリプル四重極質量分析計での質量分析により行われた。動物の管理および使用を含む全ての手順は、ＥｘｐｌｏｒａＢｉｏＬａｂｓにおいて、ＩＡＣＵＣにより承認された。
一態様において、本発明は以下を提供する。
[項目１]
式（Ｉ）

（式中、
ＸはＮまたはＣＨである；
Ｒ ^１はシアノまたはチアゾリルである；
Ｒ ^２は２－フラニルである；
Ｒ ^３はｐ－Ｃ６Ｈ４－ＣＯＮＨ２である）
を含む化合物。
[項目２]
Ｒ ^１がチアゾリルである、項目１記載の化合物。
[項目３]
式（Ｉ）

（式中、
ＸはＮまたはＣＨである；
Ｒ ^１はシアノまたはチアゾリルである；
Ｒ ^２は２－フラニルである；
Ｒ ^３はｐ－Ｃ６Ｈ４－ＣＯＮＨ２である）
の化合物の有効量を含む医薬組成物。
[項目４]
Ｒ ^１がチアゾリルである、項目３記載の医薬組成物。
[項目５]
式（Ｉ）

（式中、
ＸはＮまたはＣＨである；
Ｒ ^１はシアノまたはチアゾリルである；
Ｒ ^２は２－フラニルである；
Ｒ ^３はｐ－Ｃ６Ｈ４－ＣＯＮＨ２である）
を含む組成物の有効量を投与することを含む、癌適応症の治療方法。
[項目６]
Ｒ ^１がチアゾリルである、項目４記載の方法。
[項目７]
項目１記載の化合物の有効量または有効濃度とＭＹＣを接触させることを含む、ＭＹＣ－ＭＡＸ二量体化の抑制方法。
[項目８]
項目１記載の化合物の有効量または有効濃度とＭＹＣを接触させることを含む、ＭＹＣによる転写活性化の抑制方法。
[項目９]
項目１記載の化合物の有効量または有効濃度とＭＹＣを接触させることを含む、ＭＹＣ誘導性細胞増殖の抑制方法。 PK analysis. Pharmacokinetic analysis of 5 g was performed by Explora Biolabs. Twelve C57BL / 6 (6 males, 6 females) mice were administered 5 g by intravenous injection at 10 mg / kg. Blood samples were taken 2 minutes after injection and at 0.08, 0.25, 0.5, 1, 2, 8 and 24 hours. Bioanalysis was performed by Integrated Analytical Solutions and was performed by processing with the Shimadzu VP Series 10 System LC followed by mass spectrometry with the Applied Biosystems / MDS SCIEX API 3000 Triple Quadrupole Mass Spectrometer. All procedures, including animal management and use, were approved by IACUC at Explora BioLabs.
In one aspect, the invention provides:
[Item 1]
Equation (I)

(During the ceremony,
X is N or CH;
R ¹ is cyano or thiazolyl;
R ² is 2-franil;
R3 is p ^- C6H4-CONH2)
Compounds containing.
[Item 2]
The compound according to item 1, wherein R ¹ is thiazolyl.
[Item 3]
Equation (I)

(During the ceremony,
X is N or CH;
R ¹ is cyano or thiazolyl;
R ² is 2-franil;
R3 is p ^- C6H4-CONH2)
A pharmaceutical composition comprising an effective amount of the compound of.
[Item 4]
The pharmaceutical composition according to item 3, wherein R ¹ is thiazolyl.
[Item 5]
Equation (I)

(During the ceremony,
X is N or CH;
R ¹ is cyano or thiazolyl;
R ² is 2-franil;
R3 is p ^- C6H4-CONH2)
A method of treating a cancer indication, comprising administering an effective amount of the composition comprising.
[Item 6]
The method according to item 4, wherein R ¹ is thiazolyl.
[Item 7]
A method for suppressing MYC-MAX dimerization, which comprises contacting MYC with an effective amount or concentration of the compound according to item 1.
[Item 8]
A method for suppressing transcriptional activation by MYC, which comprises contacting MYC with an effective amount or concentration of the compound according to item 1.
[Item 9]
A method for suppressing MYC-induced cell proliferation, which comprises contacting MYC with an effective amount or concentration of the compound according to item 1.

Claims

Equation (I)

(During the ceremony,
X is N or CH;
R ¹ is cyano or thiazolyl;
R ² is 2-franil;
R ³ is p-C ₆ H ₄ -CONH ₂ )
Compounds containing.

The compound according to claim 1, wherein R ¹ is thiazolyl.

Equation (I)

(During the ceremony,
X is N or CH;
R ¹ is cyano or thiazolyl;
R ² is 2-franil;
R ³ is p-C ₆ H ₄ -CONH ₂ )
A pharmaceutical composition comprising an effective amount of the compound of.

The pharmaceutical composition according to claim 3, wherein R ¹ is thiazolyl.

The pharmaceutical composition according to claim 3 or 4, for use in the treatment of cancer indications.

A composition for use in suppressing MYC-MAX dimerization , comprising the compound according to claim 1.

A composition comprising the compound according to claim 1 for use in suppressing transcriptional activation by MYC.

A composition for use in suppressing MYC-induced cell proliferation , comprising the compound according to claim 1.