JP6923522B2 - ケモカイン受容体のモジュレーター - Google Patents
ケモカイン受容体のモジュレーター Download PDFInfo
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- JP6923522B2 JP6923522B2 JP2018526119A JP2018526119A JP6923522B2 JP 6923522 B2 JP6923522 B2 JP 6923522B2 JP 2018526119 A JP2018526119 A JP 2018526119A JP 2018526119 A JP2018526119 A JP 2018526119A JP 6923522 B2 JP6923522 B2 JP 6923522B2
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Description
連邦政府の支援による研究及び開発によりなされた発明の権利に関する声明
コンパクトディスクにより提出された「配列リスト」、表、又はコンピュータプログラムのリストなどの参照
本発明は、式(A)、(A1)、(A2)、(I)、及び(Ia1)の化合物が、CCR6受容体及び/又はCXCR2受容体の強力なアンタゴニストとして作用するという発見に由来する。これらの化合物はインビボの抗炎症活性を有し、優れた薬物動態特性を有する。従って本明細書で提供される化合物は、CCR6媒介疾患及び/又はCXCR2媒介疾患の治療のための医薬組成物として、方法として、及びCCR6及び/又はCXCR2アンタゴニストの同定のためのアッセイにおける対照として有用である。
特に別の指定がなければ、以下の用語は以下に示す意味を有することが意図される。他の用語は、本明細書の別のところで定義される。
「
式(I)を有する化合物:
Bは、フラニル、オキサゾリル、フェニル、ピリジル、ピリミジニル、及びピラジニルからなる群から選択され、その各々は、ハロゲン、CN、C1-4アルキル、C1-4アルコキシ、及びC1-4ハロアルキルからなる群から独立して選択されるR1a、R1b、及びR2で場合により置換され;
R3は、H及びDから選択されるメンバーであり;
R4は、H、C1-8アルキル、及びYから選択されるメンバーであり;ここで、C1-8アルキルは、ハロゲン、−CN、−CO2Ra、−CONRaRb、−C(O)Ra、OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、及びYで場合により置換され、ここで、各Ra及びRbは、水素、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから独立して選択され、Rcは、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから選択され、Yは、ハロゲン、−CN、−C1-4アルキル、−C1-4アルコキシ、−C1-4ヒドロキシアルキル、−C1-4ハロアルキル、OCF3、−CO2Ra、−CONRaRb、−C(O)Ra,−OC(O)NRaRb,−NRaC(O)Rb,−CH2CO2Raから選択される1〜4個の置換基で場合により置換される5員若しくは6員のアリール又はヘテロアリール基であり;
R5a及びR5bは、それぞれ独立して、H、ハロゲン、C1-4アルキル、C1-4アルコキシ、CO2H、及びCNから選択されるメンバーであり;
R6a及びR6bは、それぞれ独立して、H、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから選択されるメンバーであり;又は、場合によりR6a及びR6bは一緒になってオキソ(=O)を形成し;そして
添字nは1又は2である。
Bは、フラニル、チオフェニル、オキサゾリル、フェニル、ピリジル、ピリミジニル、及びピラジニルからなる群から選択され、その各々は、ハロゲン、CN、C1-4アルキル、C1-4アルコキシ、及びC1-4ハロアルキルから成る群から独立して選択される、R1a、R1b、及びR2により場合により置換され;
R3は、H及びDからなる群から選択されるメンバーであり;
R4は、H、C1-8アルキル、OH、−NRaRb、−C1-4アルコキシ、及びYからなる群から選択されるメンバーであり;ここで、C1-8アルキルは、ハロゲン、−CN、−CO2Ra、−CONRaRb、−C(O)Ra、OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、及びYで場合により置換され、ここでYは、4〜8員のシクロへテロアルキル基、又は3〜8員のシクロアルキル基、又は5員若しくは6員のアリール又はヘテロアリール基であり、そのいずれも、ハロゲン、オキソ、−CN、−C1-6アルキル、−C1-6アルコキシ、−C1-6ヒドロキシアルキル、−C1-6ハロアルキル、O−C1-6ハロアルキル、−C1-4アルキル−O−C1-4アルキル、−C1-6アルキル−NRaRb、−C1-6アルキル−CO2H、−C1-6アルキル−CO2Ra、−C1-6アルキル−CONRaRb、−C1-6アルキル−C(O)Ra、−C1-6アルキル−OC(O)NRaRb、−C1-6アルキル−NRaC(O)Rb、−C1-6アルキル−NRaC(O)2Rc、−C1-6アルキル−NRaC(O)NRaRb、−C1-6アルキル−ORa、−C1-6アルキル−S(O)2NRaRb、−C1-6アルキル−NRaS(O)2Rb、−CO2Ra、−CONRaRb、C(O)Ra、−OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、−CH2CO2Raから選択される1〜4個の置換基で場合により置換され;各Ra及びRbは、水素、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから独立して選択され、RcはC1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから選択され。ここで4〜8員のシクロヘテロアルキル基及び3〜8員のシクロアルキル基は、さらにオキソで場合により置換されていてもよく;
R5a及びR5bはそれぞれ、H、ハロゲン、C1-4アルキル、−C1-4ハロアルキル、O−C1-4ハロアルキル、C1-4アルコキシ、CO2H、及びCNからなる群から独立して選択されるメンバーであり;
R6a及びR6bはそれぞれ、H、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルからなる群から独立して選択されるメンバーであり;又は、場合によりR6a及びR6bは、一緒になってオキソ(=O)、又は4〜6員のシクロへテロアルキル基、又は3〜6員のシクロアルキル基を形成し;
R7は、メチル、エチル、及びC1-2ハロアルキルからなる群から選択されるメンバーであり;そして
下付き文字nは1又は2である]、
又はその医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体が提供される。
又はその医薬的に許容し得る塩、溶媒和物、又は水和物が提供される。
以下の実施例におけるスキームは、本発明のいくつかの化合物にアクセスするために従うことができる特定の合成経路を提供する。他の経路又は以下に示す経路の改変は、当業者には容易に明らかであり、本発明の範囲内である。
さらに、上記で提供される化合物に加えて、ヒト及び動物におけるCCR6及び/又はCXCR2活性を調節するための組成物は、典型的には、薬学的担体又は希釈剤を含有する。
1つの態様において本発明は、CCR6媒介性症状若しくは疾患及び/又はCXCR2媒介性症状若しくは疾患を治療又は予防する方法であって、そのような症状又は疾患を有する被験体に、本発明のいずれかの化合物の治療有効量を投与することにより治療する方法を提供する。本方法で使用するのに好ましい化合物は、好適な実施態様として上に提供された化合物、並びに以下の実施例で具体的に例示され、本明細書において特定の構造を有する化合物である。本明細書において「被験体」は、特に限定されるものではないが、霊長類(例えば、ヒト)、ウシ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、ラット、マウスなどを含む哺乳類のような動物を含むと定義される。好適な実施態様において、対象はヒトである。
本開示の化合物は、単独で、又は1つ以上の他の薬物と一緒に供給することができる。可能性のある組み合わせパートナーは、追加の抗血管新生因子、及び/又は化学療法剤(例えば、細胞傷害剤)、又は放射線、癌ワクチン、免疫調節剤、チェックポイント阻害剤、抗血管剤、シグナル伝達阻害剤、抗増殖剤、アポトーシス誘導物質、アルキル化剤、ニトロソ尿素剤、代謝拮抗剤、抗癌性抗生物質、植物由来アルカロイド、トポイソメラーゼ阻害剤、ホルモン剤、ホルモン拮抗剤、アロマターゼ阻害剤、P−糖タンパク質阻害剤、白金錯体誘導体、抗線維剤、放射線療法、放射線治療薬、及び遺伝子発現調節剤を含む。
ラゴン、ピリドキサミン、コルチコトロピン、INT−767、エパルレスタット、トピロスタット、SER−150−DN、ピルフェニドン、VEGFR−1 mAb、AKB−9778、PF−489791、SHP−627、CS−3150、イミダプリル、ペリンドプリル、カプトプリル、エナラプリル、リシノプリル、ゾフェノプリル、リシノプリル、キナプリル、ベナゼプリル、トランドラプリル、シラザプリル、フォシノプリル、ラミプリル、バルドキソロンメチル、イルベサルタン+プロパゲマニウム、GKT−831、MT−3995、TAK−648、TAK−272、GS−4997、DW−1029M、ASP−8232、VPI−2690B、DM−199、レイン、PHN−033、GLY−230、及びサプロプテリン、スロデキシド、リリルマブ、IPH−4102、IPH−2101、IMP−321、BMS−986016、MGD−013、LAG−525、ヅルバルマブ、モナリズマブ、MCLA−134、MBG−453、CA−170、AUPM−170、AUPM−170、AUPM−327、レスミノスタット、イピリムマブ、BGB−A317、トレメリムマブ、REGN−2810、AZD−5069、マシチニブ、ビニメチニブ、トラメチニブ、ルキソリチニブ、ダブラフェニブ、リナクロチド、イピリムマブ、アパチニブ、ニンテダニブ、カボザンチニブ、パゾパニブ、ベリノスタット、パニツムマブ、グアデシタビン、ビスモードジブ、ベムラフェニブ、ダサチニブ、トレメリムマブ、ベバシズマブ、オキサリプラチン、アフリベルセプト、バンデタニブ、エベロリムス、サリドマイド、ベリパリブ、エンコラフェニブ、ナパブカシン、アルペリジブ、アキチニブ、セジラニブ、ネチツムマブ、ラムシルマブ、イロフルベン、トリフルリジン+チピラシル、ドナフェニブ、パクリチニブ、ペキサスチモジン、デパシレプベク、チバンチニブ、GNR−011、タラポルフィン、ピクリデノソン、デシタビン、ガニトマブ、パノビノスタット、リンタトリモド、ポルマコキシブ、レボフォリネート、ファミチニブ、ボツムマブ、チボザニブ、エンチノスタット、プリチデプシン、レフィトリモド、OSE−2101、ビテスペン、TroVax、ブロモクリプチン、ミドスタウイン、フォスブレブリン、フルキンチニブ、ガネテスピブ、ブリバニブ、アンロチニブ、L19−TNF−アルファ、ラコツモマブ、ノバフェロン、ラルチトレキセド、エンザスタウリン、GM−CT−01、アルシツモマブ、デニロイキンジフチトクス、ベキサロテン、ボリノスタット、ロミデプシン、プララトレキサート、プレドニゾン、プレドニゾロン、又はそれらの任意の組み合わせが挙げられる。
用語「キット」及び「医薬キット」は、1つ以上の適切な容器に、1つ以上の医薬組成物、及びそれらの使用説明書を含む市販のキット又はパッケージを指す。1つの実施態様において、式(A)、(A1)、(A2)、(I)、又は(Ia1)の化合物又はその医薬的に許容し得る塩と、その投与のための説明書を含むキットが提供される。1つの実施態様において、式(A)、(A1)、(A2)、(I)、又は(Ia1)の化合物又はその医薬的に許容し得る塩を、1つ以上(例えば、1、2、3、1若しくは2、又は1〜3)の追加の治療薬、及びそれらの投与のための説明書と、組み合わせて含むキットが提供される。
本実施態様はまた、本発明の化合物又はその医薬的に許容し得る塩の調製に有用なプロセス及び中間体に関する。
HPLC、高圧液体クロマトグラフィー;DMF、ジメチルホルムアミド;TFA、トリフルオロ酢酸;THF、テトラヒドロフラン;EtOAc、酢酸エチル;BOC2O、ジ−tertブチルジカーボネート又はBOC無水物;HPLC、高圧液体クロマトグラフィー;DIPEA、ジイソプロピルエチルアミン;HBTU、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロリン酸;dppf、1,1’−ビス(ジフェニルホスフィノ)フェロセン;Pd2(dba)3、トリス(ジベンジリデンアセトン)ジパラジウム(0);DIPEA、ジイソプロピルエチルアミン;DMP、フタル酸ジメチル;Me、メチル;Et、エチル;DCM、ジクロロメタン。
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生物学的実施例1
CXCR2活性のリガンド結合アッセイ
生物学的実施例2
CXCR2活性の遊走/走化性アッセイ
生物学的実施例3
CCR6活性の遊走/走化性アッセイ
生物学的実施例4
乾癬のIL−23誘発耳腫脹モデルにおけるインビボ有効性
生物学的実施例5
イミキモド(imiquimod)誘発乾癬様モデルにおけるインビボ有効性
Claims (40)
- 式(A)を有する化合物:
Bは、フラニル、チオフェニル、オキサゾリル、フェニル、ピリジル、ピリミジニル、及びピラジニルからなる群から選択され、その各々は、ハロゲン、CN、C1-4アルキル、C1-4アルコキシ、及びC1-4ハロアルキル成る群から独立して選択されるR1a、R1b、及びR2により場合により置換され;
R3は、H及びDからなる群から選択されるメンバーであり;
R4は、H、C1-8アルキル、OH、−NRaRb、−C1-4アルコキシ、及びYからなる群から選択されるメンバーであり;ここで、C1-8アルキルは、ハロゲン、−CN、−CO2Ra、−CONRaRb、−C(O)Ra、−OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、及びYで場合により置換され、ここでYは、4〜8員のシクロへテロアルキル基、又は3〜8員のシクロアルキル基、又は5員若しくは6員のアリール又はヘテロアリール基であり、そのいずれも、ハロゲン、オキソ、−CN、−C1-6アルキル、−C1-6アルコキシ、−C1-6ヒドロキシアルキル、−C1-6ハロアルキル、O−C1-6ハロアルキル、−C1-4アルキル−O−C1-4アルキル、−C1-6アルキル−NRaRb、−C1-6アルキル−CO2H、−C1-6アルキル−CO2Ra、−C1-6アルキル−CONRaRb、−C1-6アルキル−C(O)Ra、−C1-6アルキル−OC(O)NRaRb、−C1-6アルキル−NRaC(O)Rb、−C1-6アルキル−NRaC(O)2Rc、−C1-6アルキル−NRaC(O)NRaRb、−C1-6アルキル−ORa、−C1-6アルキル−S(O)2NRaRb、−C1-6アルキル−NRaS(O)2Rb、−CO2Ra、−CONRaRb、−C(O)Ra、−OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、−CH2CO2Raから選択される1〜4個の置換基で場合により置換され;各Ra及びRbは、水素、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから独立して選択され、RcはC1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから選択され。ここで4〜8員のシクロヘテロアルキル基及び3〜8員のシクロアルキル基は、さらにオキソで場合により置換されていてもよく;
R5a及びR5bはそれぞれ、H、ハロゲン、C1-4アルキル、−C1-4ハロアルキル、O−C1-4ハロアルキル、C1-4アルコキシ、CO2H、及びCNからなる群から独立して選択されるメンバーであり;
R6a及びR6bはそれぞれ、H、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルからなる群から独立して選択されるメンバーであり;又は、場合によりR6a及びR6bは、一緒になってオキソ(=O)、又は4〜6員のシクロへテロアルキル基、又は3〜6員のシクロアルキル基を形成し;
R7は、メチル、エチル、及びC1-2ハロアルキルからなる群から選択されるメンバーであり;そして
下付き文字nは1又は2である]、
又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。 - 式(I)を有する請求項1に記載の化合物:
Bは、フラニル、オキサゾリル、フェニル、ピリジル、ピリミジニル、及びピラジニルからなる群から選択され、その各々は、ハロゲン、CN、C1-4アルキル、C1-4アルコキシ、及びC1-4ハロアルキルからなる群から独立して選択されるR1a、R1b、及びR2で場合により置換され;
R3は、H及びDから成る群から選択されるメンバーであり;
R4は、H、C1-8アルキル、及びYから成る群から選択されるメンバーであり;ここで、C1-8アルキルは、ハロゲン、−CN、−CO2Ra、−CONRaRb、−C(O)Ra、OC(O)NRaRb、−NRaC(O)Rb、−NRaC(O)2Rc、−NRaC(O)NRaRb、−NRaRb、−ORa、−S(O)2NRaRb、−NRaS(O)2Rb、及びYで場合により置換され、ここで、Yは、ハロゲン、−CN、−C1-4アルキル、−C1-4アルコキシ、−C1-4ヒドロキシアルキル、−C1-4ハロアルキル、OCF3、−CO2Ra、−CONRaRb、−C(O)Ra,−OC(O)NRaRb,−NRaC(O)Rb,−CH2CO2Raから選択される1〜4個の置換基を有する5員若しくは6員のアリール又はヘテロアリール基であり;各Ra及びRbは、水素、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから独立して選択され、Rcは、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから選択され;
R5a及びR5bは、それぞれ独立して、H、ハロゲン、C1-4アルキル、C1-4アルコキシ、CO2H、及びCNから成る群から選択されるメンバーであり;
R6a及びR6bは、それぞれ独立して、H、C1-4アルキル、C1-4ヒドロキシアルキル、及びC1-4ハロアルキルから成る群から選択されるメンバーであり;又は、場合によりR6a及びR6bは一緒になってオキソ(=O)を形成し;そして
添字nは1又は2である]、
又はその任意の塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。 - Bが、フラニル又はオキサゾリルであり、その各々は、ハロゲン、CN、C1-4アルキル、C1-4アルコキシ、及びC1-4ハロアルキルからなる群から独立して選択されるR1a及びR1bで場合により置換される、請求項1又は2のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- Bが、CH3又はClであるR1aで置換され、及びCH3であるR1bで場合により置換されたフラニルである、請求項5に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R3がHである、請求項1〜6のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R5a及びR5bのそれぞれが、H、CH3、Cl、及びFからなる群から独立して選択される、請求項1〜7のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R6a及びR6bのそれぞれが、H及びC1-2アルキルからなる群から独立して選択される、請求項1〜10のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R4が、H、C1-3アルキル、又はYであり、ここで、C1-3アルキルはテトラゾリル又はテトラゾロニルで置換されており、テトラゾリル又はテトラゾロニルは、C1-6アルキル、C1-6ヒドロキシアルキル、又はC1-4アルキル−O−C1-4アルキルで場合により置換されており、Yは、ピリジニル、ピラゾリル、及びフェニルからなる群から選択され、ピリジニル、ピラゾリル、及びフェニルは、その各々が−C1-4アルキル、−C1-4アルコキシ、及び−CO2Hから独立して選択される1〜3個の置換基を有する、請求項1又は請求項3〜13のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R7が、メチル、エチル、及びCF3からなる群から選択される、請求項1又は請求項3〜15のいずれか1項に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R1aはCH3であり;R1bは存在しないか又はCH3であり;R3はH又はDであり;R4はHであり;R5bはH、F、Me、又はCl、又はBrであり;R5bはH又はFであり;R6a及びR6bはそれぞれHであり;R7はメチル又はエチルである、請求項17に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R3を有する炭素原子において他の異性体を実質的に含まない、請求項17に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- R4がYである、請求項17に記載の化合物、又はその任意の医薬的に許容し得る塩、溶媒和物、水和物、N−オキシド、互変異性体、又は回転異性体。
- 式(A2)を有する、請求項1に記載の化合物:
又はその医薬的に許容し得る塩、溶媒和物、又は水和物。 - 請求項1〜27のいずれか1項に記載の化合物を含む医薬組成物。
- 1種以上の追加の治療薬をさらに含む、請求項28に記載の医薬組成物。
- 前記1種以上の追加の治療薬が、細胞傷害性化学療法、抗癌若しくは抗腫瘍ワクチン、抗免疫サイトカイン療法、免疫サイトカイン療法、キメラ抗原受容体(CAR)T細胞受容体、遺伝子導入療法、チェックポイント阻害剤、コルチコステロイド、レチノイド様薬剤、抗新生物剤、及びインターフェロン類似体から成る群から選択される、請求項29に記載の医薬組成物。
- 請求項29に記載の医薬組成物であって、前記1種以上の追加の治療薬が、TNFアルファリガンド阻害剤、TNF結合剤、IL−1リガンド阻害剤、IL−6リガンド阻害剤、IL−8リガンド阻害剤、IL−17アンタゴニスト、TNFアンタゴニスト、レチノイン酸受容体ガンマアンタゴニスト、IL−17Aリガンド阻害剤、IL−17Fリガンド阻害剤、スフィンゴシン−1−リン酸受容体−1アンタゴニスト、スフィンゴシン−1−リン酸受容体−1モジュレーター、IL−12アンタゴニスト、IL−23アンタゴニスト、II型TNF受容体モジュレーター、IL−23A阻害剤、PDE4阻害剤、JAKチロシンキナーゼ阻害剤、Jak1チロシンキナーゼ阻害剤、Jak3チロシンキナーゼ阻害剤、レチノン酸受容体アゴニスト、スフィンゴシン−1−リン酸受容体−1モジュレーター、又はTLR−7アンタゴニスト、TLR−8アンタゴニスト、TLR−9アンタゴニスト、IL−8アンタゴニスト、及びCTLA−4(CD152)、PD−1(CD279)、PDL−1(CD274)、TIM−3、LAG−3(CD223)、VISTA、KIR、NKG2A、BTLA、PD−1H、TIGIT、CD96,4−1BB(CD137)、4−IBBL(CD137L)、GARP、CSF−1R、A2AR、CD73、CD47、トリプトファン2,3−ジオキシゲナーゼ(TDO)、又はインドールアミン2,3−ジオキシゲナーゼ(IDO)の活性を阻害する薬剤、及びOX40、GITR、4−1BB、ICOS、STING、又はCD40のアゴニストから成る群から選択される、上記医薬組成物。
- 治療を必要とする被験体のCXCR2及び/又はCCR6媒介性疾患若しくは症状を治療する医薬組成物であって、請求項1〜27のいずれか1項に記載の化合物又はその医薬的に許容し得る塩の有効量を含む、上記医薬組成物。
- 前記疾患又は症状は急性又は慢性の炎症性障害である、請求項32に記載の医薬組成物。
- 前記急性又は慢性の炎症性障害が、乾癬、ドライアイ疾患、アテローム性動脈硬化症、円板状エリテマトーデス、関節リウマチ、狼瘡、放射線誘発線維性肺疾患、自己免疫性水疱性皮膚症(AIBD)、慢性閉塞性肺疾患、又はオゾン誘導性気道炎症である、請求項33に記載の医薬組成物。
- 請求項32に記載の医薬組成物であって、前記疾患が、皮膚T細胞リンパ腫、非ホジキンリンパ腫、菌状息肉腫、パジェット様細網症、セザリー症候群、肉芽腫様弛緩皮膚、リンパ腫様丘疹症、慢性苔癬状粃糠疹、急性痘瘡状苔癬状粃糠疹、CD30+皮膚T細胞リンパ腫、続発性皮膚CD30+大細胞リンパ腫、非菌状息肉腫CD30皮膚大T細胞リンパ腫、多形性T細胞リンパ腫、レナートリンパ腫、皮下T細胞リンパ腫、血管中心リンパ腫、芽球性NK細胞リンパ腫、B細胞リンパ腫、ホジキンリンパ腫(HL)、頭頸部腫瘍;扁平上皮癌、横紋筋肉腫、ルイス肺癌(LLC)、非小細胞肺癌、食道扁平上皮癌、食道腺癌、腎細胞癌(RCC)、結腸直腸癌(CRC)、急性骨髄性白血病(AML)、乳癌、胃癌、前立腺小細胞神経内分泌癌(SCNC)、肝臓癌、膠芽細胞腫、肝臓癌、口腔扁平上皮癌、膵臓癌、甲状腺乳頭癌、肝内胆管癌、肝細胞癌、骨癌、転移、及び鼻咽頭癌から成る群から選択される癌である、上記医薬組成物。
- 前記化合物が、単独で又は1種以上の他の抗癌療法と組合せて使用される、請求項35に記載の医薬組成物。
- 請求項36に記載の医薬組成物であって、前記化合物が、細胞傷害性化学療法、抗癌ワクチン、抗腫瘍ワクチン、抗免疫サイトカイン療法、免疫サイトカイン療法、チェックポイント阻害剤、キメラ抗原受容体(CAR)T細胞受容体、遺伝子導入療法の1種以上と組合せて使用される、上記医薬組成物。
- 請求項36に記載の医薬組成物であって、前記1種以上の他の抗癌療法が、CTLA−4(CD152)、PD−1(CD279)、PDL−1(CD274)、TIM−3、LAG−3(CD223)、VISTA、KIR、NKG2A、BTLA、PD−1H、TIGIT、CD96,4−1BB(CD137)、4−1BBL(CD137L)、GARP、CSF−1R、A2AR、CD73、CD47、トリプトファン2,3−ジオキシゲナーゼ(TDO)、又はインドールアミン2,3ジオキシゲナーゼ(IDO)の活性をブロックする薬剤、及びOX40、GITR、4−1BB、ICOS、STING、又はCD40のアゴニストから成る群から選択される、上記医薬組成物。
- 前記化合物が、単独で又は1種以上の他の治療薬と組合せて使用される、請求項34に記載の医薬組成物。
- 請求項39に記載の医薬組成物であって、前記化合物が、コルチコステロイド、レチノイド様薬剤、抗新生物薬、及びインターフェロン類縁体、TNFアルファリガンド阻害剤、TNF結合剤、IL−1リガンド阻害剤;IL−6リガンド阻害剤、IL−8リガンド阻害剤、IL−17アンタゴニスト、TNFアンタゴニスト、レチノイン酸受容体ガンマアンタゴニスト、IL−17Aリガンド阻害剤、IL−17Fリガンド阻害剤、スフィンゴシン−1−リン酸受容体−1アンタゴニスト、スフィンゴシン−1−リン酸受容体−1モジュレーター、IL−12アンタゴニスト;IL−23アンタゴニスト、II型TNF受容体モジュレーター、IL−23A阻害剤、PDE4阻害剤、JAKチロシンキナーゼ阻害剤、Jak1チロシンキナーゼ阻害剤;Jak3チロシンキナーゼ阻害剤、レチノイン酸受容体アゴニスト、スフィンゴシン−1−リン酸受容体−1モジュレーター、TLR−7アンタゴニスト、TLR−8アンタゴニスト、TLR−9アンタゴニスト、又はIL−8アンタゴニストの1種以上と組合せて使用される、上記医薬組成物。
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EA201891209A1 (ru) | 2018-12-28 |
BR112018009880A2 (pt) | 2018-11-13 |
KR20180100116A (ko) | 2018-09-07 |
US10988464B2 (en) | 2021-04-27 |
EP3383386A4 (en) | 2019-07-03 |
MX2018006150A (es) | 2019-05-27 |
EA035666B1 (ru) | 2020-07-23 |
CA3005656A1 (en) | 2017-05-26 |
US20180141934A1 (en) | 2018-05-24 |
IL259342A (en) | 2018-07-31 |
US10336736B2 (en) | 2019-07-02 |
MA43382A (fr) | 2018-10-10 |
US20200039969A1 (en) | 2020-02-06 |
US9834545B2 (en) | 2017-12-05 |
CN108697684A (zh) | 2018-10-23 |
TWI734715B (zh) | 2021-08-01 |
EP3383386A1 (en) | 2018-10-10 |
US20170144997A1 (en) | 2017-05-25 |
SG11201804133PA (en) | 2018-06-28 |
IL259342B (en) | 2021-09-30 |
WO2017087607A1 (en) | 2017-05-26 |
TW201720817A (zh) | 2017-06-16 |
EP3383386B1 (en) | 2024-02-14 |
US11820759B2 (en) | 2023-11-21 |
EP3383386B8 (en) | 2024-03-20 |
US20220009912A1 (en) | 2022-01-13 |
AU2016357413A1 (en) | 2018-06-14 |
NZ742809A (en) | 2022-09-30 |
PH12018501096A1 (en) | 2018-12-17 |
JP2018538266A (ja) | 2018-12-27 |
AU2016357413B2 (en) | 2021-03-04 |
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