JP2015535839A - ウイルス感染を治療するための1,2,4−トリアジン誘導体 - Google Patents
ウイルス感染を治療するための1,2,4−トリアジン誘導体 Download PDFInfo
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- JP2015535839A JP2015535839A JP2015533635A JP2015533635A JP2015535839A JP 2015535839 A JP2015535839 A JP 2015535839A JP 2015533635 A JP2015533635 A JP 2015533635A JP 2015533635 A JP2015533635 A JP 2015533635A JP 2015535839 A JP2015535839 A JP 2015535839A
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- alkyl
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- carboxylic acid
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- heteroarylalkyl
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
R1は、C1〜6アルキル、アリールアルキル、又はヘテロアリールアルキルであり、これらのそれぞれは、ハロゲン、ヒドロキシル、アミノ、C1〜6アルキル、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、C1〜6アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、複素環、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよい。
2の調製
全ての化合物を、以下のLC−MS法に従うLC−MSによって特徴付けした。
0.343mL/分の流速を有するWaters Acquity BEH(架橋エチルシロキサン/シリカハイブリッド)C18カラム(1.7μm、2.1×100mm)の逆相UPLC。2つの移動相(移動相A:95%の7mM酢酸アンモニウム/5%のアセトニトリル;移動相B:100%のアセトニトリル)を使用して、84.2%のA及び15.8%のB(0.49分間保持)から10.5%のA及び89.5%のBの勾配条件に2.18分で動作させ、1.94分間保持し、0.73分で最初の条件に戻し、0.73分間保持した。2μLの注入体積を使用した。コーン電圧は、正及び負イオン化モードで20Vであった。質量スペクトルを、0.1秒の走査間遅延を使用して0.2秒で100から1000まで走査して取得した。
(生物学的アッセイの説明)
TLR7及びTLR8の活性の評価
ヒトTLR7及び/又はTLR8を活性化させる化合物の能力を、TLR7又はTLR8発現ベクター及びNFKB−lucレポーター構築で一時的にトランスフェクトされたHEK293細胞を使用する細胞レポーターアッセイ(cellular reporter assay)で評価した。
IFN−Iを誘起する化合物の可能性を、PBMCからの調節された媒体によるインターフェロン活性化応答配列(ISRE)の活性化を測定することによって評価した。配列GAAACTGAAACTのISRE配列は、STAT1−STAT2−IRF9転写因子に高い応答性を有し、その受容体IFNAR(Clontech、PT3372−5W)にIFN−Iが結合した際に活性化される。Clontech(ref.631913)からのプラスミドpISRE−Lucは、5コピーのこのISRE配列、続けて蛍ルシフェラーゼORFを含有する。pISRE−Lucで安定にトランスフェクトされたHEK297細胞株(HEK−ISREluc)を、調節されたPBMC細胞培養媒体のプロファイルに定着させた。
Claims (9)
- 式(I)の化合物、又は医薬的に許容可能なその塩、互変異性体、溶媒和物、若しくは多形:
R1は、C1〜6アルキル、アリールアルキル、又はヘテロアリールアルキルであり、これらのそれぞれは、ハロゲン、ヒドロキシル、アミノ、C1〜6アルキル、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、C1〜6アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、複素環、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよく、
R2は、ハロゲン、ヒドロキシル、アミノ、C1〜3アルキル、C1〜3アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、アリール、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよいC1〜8アルキルである。 - R2が、ブチル又はペンチルであり、
R1が、C1〜6アルキル、アリールアルキル、又はヘテロアリールアルキルであり、これらのそれぞれは、ハロゲン、ヒドロキシル、アミノ、C1〜6アルキル、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、C1〜6アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、複素環、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよい、
請求項1に記載の化合物。 - R2がヒドロキシルで置換されたC1〜8アルキルであり、R1が置換又は非置換のアリールアルキル基である、請求項1に記載の化合物。
- R1がCH3であり、
R2が、ハロゲン、ヒドロキシル、アミノ、C1〜3アルキル、C1〜3アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、アリール、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよいC1〜8アルキルである、
請求項1に記載の化合物。 - R1がヘテロアリールアルキルであり、
R2が、ハロゲン、ヒドロキシル、アミノ、C1〜3アルキル、C1〜3アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、ジ−(C1〜6)アルキルアミノ、C1〜6アルキルアミノ、アリール、ヘテロアリール、ヘテロアリールアルキル、又はニトリルから独立に選択される1つ以上の置換基で場合によって置換されていてもよいC1〜8アルキルである、
請求項1に記載の化合物。 - 請求項1から6のいずれか一項に記載の式(I)の化合物、又はその医薬的に許容可能な塩、互変異性体、溶媒和物、若しくは多形を、1つ以上の医薬的に許容可能な賦形剤、希釈剤、又は担体と一緒に含む、医薬組成物。
- 医薬として使用するための、請求項1から6のいずれか一項に記載の式(I)の化合物、又はその医薬的に許容可能な塩、互変異性体、溶媒和物、若しくは多形、或いは請求項7に記載の医薬組成物。
- TLR7及び/又はTLR8の調節が含まれる疾患の治療において使用するための、請求項1から6のいずれか一項に記載の式(I)の化合物、又はその医薬的に許容可能な塩、互変異性体、溶媒和物、若しくは多形、或いは請求項7に記載の医薬組成物。
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PCT/EP2013/070488 WO2014053516A1 (en) | 2012-10-01 | 2013-10-01 | 1,2,4-triazine derivatives for the treatment of viral infections. |
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JP2019530692A (ja) * | 2016-09-29 | 2019-10-24 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | ウイルス感染症および他の疾患を処置するためのピリミジンプロドラッグ |
JP7274415B2 (ja) | 2016-09-29 | 2023-05-16 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | ウイルス感染症および他の疾患を処置するためのピリミジンプロドラッグ |
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