JP2018535939A - Nash関連肝臓癌を治療するためのep4受容体拮抗薬の使用 - Google Patents
Nash関連肝臓癌を治療するためのep4受容体拮抗薬の使用 Download PDFInfo
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- JP2018535939A JP2018535939A JP2018516877A JP2018516877A JP2018535939A JP 2018535939 A JP2018535939 A JP 2018535939A JP 2018516877 A JP2018516877 A JP 2018516877A JP 2018516877 A JP2018516877 A JP 2018516877A JP 2018535939 A JP2018535939 A JP 2018535939A
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- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Description
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)。
[1]薬学的有効量のEP4拮抗薬を、その必要のあるヒトまたは動物に投与することを含む、NASH関連肝臓癌を治療する方法。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、[1]〜[3]のいずれか1つの方法。
その必要のあるヒトまたは動物において、抗腫瘍免疫機能を抑制するFoxp3+Treg細胞を減少させること、
その必要のあるヒトまたは動物において、CD8+/Treg存在比を増加させること、
その必要のあるヒトまたは動物において、活性化されたCD8+T細胞(CD69+細胞)を増加させること、および
その必要のあるヒトまたは動物において、CD8+T細胞のPD−1発現を低下させること、
からなる群から選択される、1以上の治療法であって、
薬学的有効量のEP4拮抗薬を、NASH関連肝臓癌の治療のために、その必要のあるヒトまたは動物に投与することを含む、治療法。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、[5]〜[7]のいずれか1つの方法。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、[9]または[10]の医薬組成物。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、[12]または[13]の使用。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、[15]または[16]の使用。
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)、
または薬学的に許容されるその塩である。
本発明の化合物には、その溶媒和物、錯体、多形体、プロドラッグ、異性体、同位体標識化合物も含まれる。
(i)本発明の化合物がカルボン酸官能基(−COOH)を含む場合、例えば、その水素を(C1〜C8)アルキルで置換することなどにより得られる、そのエステル、
(ii)本発明の化合物がアルコール官能基(−OH)を含む場合、例えば、その水素を(C1〜C6)アルカノイルオキシメチルで置換することなどにより得られる、そのエーテル、および
(iii)本発明の化合物が第一級または第二級アミノ官能基(−NH2または−NHR、ただしRはHではない)を含む場合、例えば、一方または両方の水素を(C1〜C10)アルカノイルで置換することなどにより得られる、そのアミド、
が挙げられる。
「EP4拮抗薬」とは、PGE2のΕΡ4受容体との相互作用により引き起こされる細胞のシグナル伝達を阻害または遮断する化合物を言う。ΕΡ4拮抗薬の例としては、IUPHARデータベースにΕΡ4受容体拮抗薬として列挙されている、ER−819762、MK−2894、MF498、ΟΝΟ−ΑΕ3−208、エバタネパグ(evatanepag)、ΟΝΟ−ΑΕ2−227、BGC201531、ΟΝΟ−ΑΕ3−240、GW627368およびΑΗ23848が挙げられるが、これらに限定はされない。化合物A、BおよびC、ならびに薬学的に許容されるその塩(本発明の化合物)もまた、EP4拮抗薬の例である。
化合物Aは、高脂肪食で誘発したNASH関連マウス肝臓癌モデルにおいて、肝臓癌の増殖を抑制した。
C57/BL6マウスは、日本クレア株式会社から購入した。Tlr2−/−マウス(C57/BL6)は、オリエンタル酵母工業株式会社から購入した。
ヘマトキシリン−エオシン染色と免疫蛍光分析を常法により行った(Yoshimotoら、Nature, 2013, 499:97-101)。
免疫細胞をマウス肝臓から得て、サイトカイン産生とフローサイトメトリーの解析を行った。
データの解析は、ウェルチ補正を伴う独立t検定(両側)またはマン・ホイットニー検定(両側)により行った。p値が0.05未満であれば有意差ありとした。「NS」は有意差がないことを示す。
このマウスモデルは、DMBA、すなわち7,12−ジメチルベンズ(a)アントラセンの投与と、高脂肪食(HFD)の給餌により発症させた(非特許文献15)。このマウスモデルでは、腫瘍組織中でEP4の発現が顕著にアップレギュレートされているが、他のPGE2受容体はアップレギュレートされていなかった。このことは、肥満誘発NASH関連肝腫瘍組織において、主にEP4がPGE2シグナル伝達に介在している可能性を示唆する。この実験において、30mg/kgの化合物Aを1日1回、マウスに19週齢から30週齢まで毎日投与した(図1)。対照として、別のマウス群にはビヒクルのみを投与し、活性成分は投与しなかった。化合物A投与マウスにおける肝細胞癌(HCC)の進行は、ビヒクル投与マウスと比較して、強く抑制された(図2および図3)。一方、化合物A投与が体重に影響を特に与えなかったことは注目に値する(図4)。
EP4拮抗薬である化合物Aは、肥満誘発NASH関連マウス肝臓癌モデルの増殖および進行を有意に抑制した。マウスモデルに化合物Aを投与すると、腫瘍組織中で、抗癌免疫反応に必須であるDCサブタイプの割合は増加し(CD103+)、細胞傷害性CD8+T細胞上のPD−1の発現は低下した。化合物Aを投与すると、腫瘍組織中の免疫抑制Treg細胞(Foxp3+)の割合も減少した。
化合物AをPD−1抗体と組み合わせると、HFD誘発NASH関連マウス肝臓癌モデルにおいて、化合物A単独よりも高い抗腫瘍効果を示すことが期待される。
実施例1と同じマウスモデルを用いて、HFD誘発NASH関連マウス肝臓癌モデルにおける、PD−1抗体と組み合わせた化合物Aの効果を試験することとした。したがって、化合物A処置群においてPD−1抗体を化合物Aとともに投与すること以外は、実施例1を繰り返す。
化合物AをPD−1抗体と組み合わせた治療は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、実施例1の化合物A投与マウスよりも高い抗腫瘍効果を示すことが期待される。
化合物Bの投与は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、肝臓癌の増殖を抑制することが期待される。
実施例1と同じマウスモデルを用いて、化合物Bの効果を試験することとした。すなわち、化合物Aの代わりに化合物Bを使用すること以外は、実施例1を繰り返す。
化合物Bによる治療は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、肝臓癌の増殖を抑制することが期待される。化合物Bは、実施例1の化合物Aと同様に、腫瘍組織における免疫細胞機能を制御することが期待される。
EP4拮抗薬である化合物Bは、実施例1における化合物Aの結果と同様に、NASH関連マウス肝臓癌モデルにおける増殖および進行を抑制することが期待される。化合物Bのマウスモデルへの投与は、腫瘍組織において、抗癌免疫反応に必須なDCサブタイプ(CD103+)の度数を増加させ、細胞傷害性CD8+T細胞上のPD−1の発現を低下させることが期待される。化合物Bの投与は、腫瘍組織中の免疫抑制Treg細胞(Foxp3+)の数を減少させることも期待される。
化合物BをPD−1抗体と組み合わせると、HFD誘発NASH関連マウス肝臓癌モデルにおいて、化合物B単独よりも高い抗腫瘍効果を示すことが期待される。
実施例3と同じマウスモデルを用いて、HFD誘発NASH関連マウス肝臓癌モデルにおける、PD−1抗体と組み合わせた化合物Bの効果を試験することとした。すなわち、化合物B投与群において、PD−1抗体を化合物Bとともに投与すること以外は、実施例3を繰り返す。
化合物BをPD−1抗体と組み合わせた治療は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、実施例3の化合物B投与マウスよりも高い抗腫瘍効果を示すことが期待される。
化合物C投与は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、肝臓癌の増殖を抑制することが期待される。
実施例1と同じマウスモデルを用いて、化合物Cの効果を試験することとした。すなわち、化合物Aの代わりに化合物Cを使用すること以外は、実施例1を繰り返す。
化合物Cによる治療は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、肝臓癌の増殖を抑制することが期待される。化合物Cは、実施例1の化合物Aと同様に、腫瘍組織における免疫細胞機能を制御することが期待される。
EP4拮抗薬である化合物Cは、実施例1における化合物Aの結果および実施例3における化合物Bの予想される結果と同様に、NASH関連マウス肝臓癌モデルにおける増殖および進行を抑制することが期待される。化合物Cのマウスモデルへの投与は、腫瘍組織において、抗癌免疫反応に必須なDCサブタイプ(CD103+)の度数を増加させ、細胞傷害性CD8+T細胞上のPD−1の発現を低下させることが期待される。化合物Cの投与は、腫瘍組織中の免疫抑制Treg細胞(Foxp3+)の数を減少させることも期待される。
化合物CをPD−1抗体と組み合わせると、HFD誘発NASH関連マウス肝臓癌モデルにおいて、化合物C単独よりも高い抗腫瘍効果を示すことが期待される。
実施例5と同じマウスモデルを用いて、HFD誘発NASH関連マウス肝臓癌モデルにおける、PD−1抗体と組み合わせた化合物Cの効果を試験することとした。すなわち、化合物C投与群において、PD−1抗体を化合物Cとともに投与すること以外は、実施例5を繰り返す。
化合物CをPD−1抗体と組み合わせた治療は、HFD誘発NASH関連マウス肝臓癌モデルにおいて、実施例5の化合物C投与マウスよりも高い抗腫瘍効果を示すことが期待される。
Claims (17)
- 薬学的有効量のEP4拮抗薬を、その必要のあるヒトまたは動物に投与することを含む、NASH関連肝臓癌を治療する方法。
- 薬学的有効量のEP4拮抗薬を、第2の活性薬剤、抗腫瘍療法またはその両方と組み合わせて投与することをさらに含む、請求項1に記載の方法。
- 第2の活性薬剤が免疫チェックポイント阻害剤またはPD−1阻害剤である、請求項2に記載の方法。
- EP4拮抗薬が、
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、請求項1〜3のいずれか一項に記載の方法。 - その必要のあるヒトまたは動物において、抗腫瘍免疫機能を活性化しうるDCであるCD103+DCを増加させること、
その必要のあるヒトまたは動物において、抗腫瘍免疫機能を抑制するFoxp3+Treg細胞を減少させること、
その必要のあるヒトまたは動物において、CD8+/Treg存在比を増加させること、
その必要のあるヒトまたは動物において、活性化されたCD8+T細胞(CD69+細胞)を増加させること、および
その必要のあるヒトまたは動物において、CD8+T細胞のPD−1発現を低下させること、
からなる群から選択される、1以上の治療法であって、
薬学的有効量のEP4拮抗薬を、NASH関連肝臓癌の治療のために、その必要のあるヒトまたは動物に投与することを含む、治療法。 - 薬学的有効量のEP4拮抗薬を、第2の活性薬剤、抗腫瘍療法またはその両方と組み合わせて投与することをさらに含む、請求項5に記載の方法。
- 第2の活性薬剤が免疫チェックポイント阻害剤またはPD−1阻害剤である、請求項5または6に記載の方法。
- EP4拮抗薬が、
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、請求項5〜7のいずれか一項に記載の方法。 - EP4拮抗薬と、薬学的に許容される添加剤、希釈剤または担体とを含む、NASH関連肝臓癌を治療するための医薬組成物。
- 第2の活性薬剤および/または抗腫瘍性抗生物質をさらに含む、請求項9に記載の医薬組成物。
- EP4拮抗薬が、
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、請求項9または10に記載の医薬組成物。 - ヒトまたは動物のNASH関連肝臓癌を治療するための、EP4拮抗薬または薬学的に許容されるその塩の使用。
- EP4拮抗薬を、第2の活性薬剤、抗腫瘍療法またはその両方と組み合わせて使用することを特徴とする、請求項12に記載の使用。
- EP4拮抗薬が、
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、請求項12または13に記載の使用。 - ヒトまたは動物のNASH関連肝臓癌を治療するための薬剤の製造における、EP4拮抗薬または薬学的に許容されるその塩の使用。
- EP4拮抗薬を、第2の活性薬剤、抗腫瘍療法またはその両方と組み合わせて使用することを特徴とする、請求項15に記載の使用。
- EP4拮抗薬が、
4−[(1S)−1−({[5−クロロ−2−(3−フルオロフェノキシ)ピリジン−3−イル]カルボニル}アミノ)エチル]安息香酸(化合物A)、
4−((1S)−1−{[5−クロロ−2−(4−フルオロフェノキシ)ベンゾイル]アミノ}エチル)安息香酸(化合物B)、および
3−[2−(4−{2−エチル−4,6−ジメチル−1H−イミダゾ[4,5−c]ピリジン−1−イル}フェニル)エチル]−1−[(4−メチルベンゼン)スルホニル]尿素(化合物C)
からなる群から選択される少なくとも1つの化合物、または薬学的に許容されるその塩である、請求項15または16に記載の使用。
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CN112292128A (zh) * | 2018-04-16 | 2021-01-29 | 阿瑞斯医疗有限公司 | Ep4抑制剂和其用途 |
CA3107023A1 (en) * | 2018-07-11 | 2020-01-16 | Arrys Therapeutics, Inc. | Ep4 inhibitors and synthesis thereof |
AU2020212111A1 (en) | 2019-01-22 | 2021-08-05 | Keythera (Suzhou) Pharmaceuticals Co. Ltd. | Compound for inhibiting PGE2/EP4 signaling transduction inhibiting, preparation method therefor, and medical uses thereof |
EP3722319A1 (en) | 2019-04-09 | 2020-10-14 | Rottapharm Biotech S.r.l. | Pharmaceutical combination of an ep4 antagonist and immune checkpoint inhibitors for the treatment of tumours |
CN110386941A (zh) * | 2019-08-15 | 2019-10-29 | 上海邦耀生物科技有限公司 | Ep4受体拮抗剂和pd-1抑制剂联合用于癌症的治疗 |
CN110680555B (zh) * | 2019-11-12 | 2021-06-01 | 重庆医药高等专科学校 | 一种裸鼠皮下成瘤装置 |
WO2021205367A1 (en) * | 2020-04-08 | 2021-10-14 | Askat Inc. | Use of ep4 receptor antagonists for the treatment of liver cancer, melanoma, lymphoma and leukemia |
CN113577267B (zh) * | 2021-09-06 | 2022-04-08 | 江西北正干细胞生物科技有限公司 | Nk细胞和抗体的药物组合物及其在治疗癌症中的用途 |
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KR20180064438A (ko) | 2018-06-14 |
CN108289960B (zh) | 2021-07-09 |
CA3000237C (en) | 2019-02-26 |
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RU2717331C2 (ru) | 2020-03-23 |
US10583129B2 (en) | 2020-03-10 |
US20190269663A1 (en) | 2019-09-05 |
MX2018005715A (es) | 2018-08-09 |
RU2018117891A (ru) | 2019-11-18 |
ES2729961T3 (es) | 2019-11-07 |
CA3000237A1 (en) | 2018-05-04 |
EP3344296B1 (en) | 2019-05-15 |
HK1253277A1 (zh) | 2019-06-14 |
CN108289960A (zh) | 2018-07-17 |
RU2018117891A3 (ja) | 2019-11-18 |
EP3344296A1 (en) | 2018-07-11 |
RU2020109376A (ru) | 2020-04-29 |
HK1251162B (zh) | 2020-01-17 |
WO2018084230A1 (en) | 2018-05-11 |
BR112018007947A2 (pt) | 2018-10-30 |
RU2020109376A3 (ja) | 2020-10-27 |
US10342785B2 (en) | 2019-07-09 |
JP6516341B2 (ja) | 2019-05-22 |
US20180125832A1 (en) | 2018-05-10 |
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