JP2016529306A - ジペプチジルペプチダーゼiインヒビターとしてのペプチジルニトリル化合物 - Google Patents
ジペプチジルペプチダーゼiインヒビターとしてのペプチジルニトリル化合物 Download PDFInfo
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- JP2016529306A JP2016529306A JP2016539571A JP2016539571A JP2016529306A JP 2016529306 A JP2016529306 A JP 2016529306A JP 2016539571 A JP2016539571 A JP 2016539571A JP 2016539571 A JP2016539571 A JP 2016539571A JP 2016529306 A JP2016529306 A JP 2016529306A
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Abstract
Description
本発明の目的は、炎症性疾患、ガンおよび感染症の治療に適した、ジペプチジルペプチダーゼIのインヒビターである新規な化合物を提供することである。さらなる目的は、該化合物が細胞ベースのDPPI阻害アッセイにおいて強力であり、良好な代謝安定性を有することである。
本発明は、式(I):
(I)
[式中、
X1は、
(ここで、yは、0、1、2、3、4、5、6、7または8を表す;
Zは、O(酸素)を表す;
yが1または2である場合、R1は、独立して、重水素、ハロゲン、ヒドロキシル、シアノ、オキソ(=O)、メルカプトまたはC1-3-アルキルを表し、ここで、C1-3-アルキルは、ハロゲン、ヒドロキシル、シアノおよびメルカプトから選択される少なくとも1つの置換基で任意に置換される;または
yが3、4、5、6、7または8を表す場合、R1は、重水素を表す)
を表す;
R2は、-C3-6-シクロアルキル、-C1-3-アルキル-C3-6-シクロアルキルまたは-C1-6-アルキルを表し、ここで、-C1-6-アルキルは、ヒドロキシル、シアノまたはアミノから選択される少なくとも1つの置換基で任意に置換される]
で示される化合物ならびにその医薬的に許容しうる塩、溶媒和物および水和物に関する。
すべての互変形態もまた、式(I)で示される化合物に包含され、このような互変異性体は、平衡状態で、または1つの形態が優勢な状態で存在する。
間欠的かつ持続的で、すべて重篤な、気管支、アレルギー性、内因性、外因性、運動誘発性、薬剤誘発性(アスピリンおよびNSAID誘発を含む)および塵埃誘発性喘息などの喘息、および気道過敏性の他の原因などの気道の閉塞性疾患;慢性閉塞性肺疾患(COPD);急性肺損傷;急性呼吸窮迫症候群;感染性および好酸球性気管支炎を含む気管支炎;肺気腫;気管支拡張症;嚢胞性線維症;α-1アンチトリプシン欠損症;サルコイドーシス;農夫肺および関連疾患;過敏性肺炎;特発性線維化性肺胞炎、特発性間質性肺炎、抗腫瘍療法ならびに結核およびアスペルギルス症および他の真菌感染症などの慢性感染症を悪化させる線維症などの肺線維症;肺移植の合併症;肺血管系の血管炎および血栓障害、および肺高血圧症;気道の炎症性および分泌状態に関連した慢性の咳、および医原性咳の治療などの鎮咳作用;薬物性鼻炎および血管運動性鼻炎などの急性および慢性鼻炎;神経性鼻炎(花粉症)などの多年性および季節性アレルギー性鼻炎;鼻ポリープ;風邪および呼吸器合胞体ウイルス、インフルエンザ、コロナウイルス(SARSを含む)およびアデノウイルスの感染などの急性ウイルス感染症;乾癬、アトピー性皮膚炎、接触性皮膚炎または他の湿疹性皮膚疾患および遅延型過敏症反応;植物性および光線皮膚炎;脂漏性皮膚炎;疱疹状皮膚炎、扁平苔癬;硬化性萎縮性苔癬;壊疽性膿皮症;皮膚サルコイド;円板状エリテマトーデス;天疱瘡;類天疱瘡;表皮水疱症;蕁麻疹;血管浮腫;血管炎;毒性紅斑;皮膚好酸球増加;円形脱毛症;男性型脱毛症;スイート症候群;ウェーバー・クリスチャン症候群;多形性紅斑;感染性および非感染性蜂巣炎;脂肪織炎;皮膚リンパ腫、非黒色腫皮膚ガンおよび他の形成異常病変;固定薬疹などの薬物誘発障害;眼瞼炎;多年性および春季アレルギー性結膜炎などの結膜炎;虹彩炎;前部および後部ブドウ膜炎;脈絡膜炎;網膜に影響を与える自己免疫、変性または炎症性障害;交感神経眼炎などの眼炎;サルコイドーシス;ウイルス、真菌および細菌などの感染症;敗血症;間質性および糸球体腎炎などの腎炎;腎炎症候群;急性および慢性(間質)膀胱炎およびハンナー潰瘍などの膀胱炎;急性および慢性尿道炎、前立腺炎、精巣上体炎、卵巣炎および卵管炎;外陰膣炎;ペイロニー病;勃起不全(男性と女性の両方);腎臓、心臓、肝臓、肺、骨髄、皮膚もしくは角膜の移植後または輸血後などの急性および慢性の影響;または慢性移植片対宿主病;関節リウマチ;過敏性腸症候群;炎症性腸疾患;痛風;偽痛風;アルツハイマー病;全身性エリテマトーデス;多発性硬化症;橋本甲状腺炎;バセドウ病;アジソン病;1型糖尿病などの糖尿病;特発性血小板減少性紫斑病;好酸球性筋膜炎;過1gE症候群;抗リン脂質抗体症候群およびセザリー症候群;好中球が関与するガン;前立腺ガン、乳ガン、肺ガン、卵巣ガン、膵臓ガン、腸ガンおよび結腸ガン、胃ガン、皮膚ガンおよび脳腫瘍などの一般的なガンの治療ならびに骨髄に影響を及ぼす悪性腫瘍(白血病など)およびホジキンおよび非ホジキンリンパ腫などのリンパ増殖系の治療;転移性疾患および腫瘍再発および腫瘍随伴症候群の予防および治療を含む;陰部疣贅、一般的ないぼ、足底いぼ、B型肝炎、C型肝炎、単純ヘルペスウイルス、伝染性軟属腫、痘瘡、ヒト免疫不全ウイルス(H1V)、ヒトパピローマウイルス(HPV)、サイトメガロウイルス(CMV)、水痘帯状疱疹ウイルス(VZV)、ライノウイルス、アデノウイルス、コロナウイルス、インフルエンザ、パラインフルエンザなどのウイルス性疾患;結核およびマイコバクテリウム・アビウム、ハンセン病などの細菌性疾患;マラリア、真菌性疾患、クラミジア、カンジダ、アスペルギルス、クリプトコッカス髄膜炎、ニューモニシスチス・カミイ、クリプトスポリジウム症、ヒストプラズマ症、トキソプラズマ症、トリパノソーマ感染およびリーシュマニア症などの他の感染性疾患;うっ血性心不全;アテローム性動脈硬化症;冠動脈疾患;心筋梗塞;再灌流傷害;腹部大動脈瘤(AAA);糖尿病性心筋症(DCM);高血圧症;末梢動脈疾患;心臓不整脈;脳卒中および心肥大。
態様1:式(I):
(I)
[ X1は、
(ここで、yは、0、1、2、3、4、5、6、7または8を表す;
Zは、O(酸素)を表す;
yが1または2である場合、R1は、独立して、重水素、ハロゲン、ヒドロキシル、シアノ、オキソ(=O)、メルカプトまたはC1-3-アルキルを表し、ここで、C1-3-アルキルは、ハロゲン、ヒドロキシル、シアノおよびメルカプトから選択される少なくとも1つの置換基で任意に置換される;または
yが3、4、5、6、7または8を表す場合、R1は、重水素を表す)
を表す;
R2は、-C3-6-シクロアルキル、-C1-3-アルキル-C3-6-シクロアルキルまたは-C1-6-アルキルを表し、ここで、-C1-6-アルキルは、ヒドロキシル、シアノまたはアミノから選択される少なくとも1つの置換基で任意に置換される]
で示される化合物ならびにその医薬的に許容しうる塩、溶媒和物および水和物。
細胞ベースのDPPI阻害アッセイ
本明細書に記載の化合物は、DPPIインヒビターであり、エラスターゼなどのDPPIによって活性化されるセリンペプチダーゼの活性を間接的に阻害する。下記の細胞ベースのアッセイを用いて、本発明化合物またはその他のDPPIインヒビターの生物活性を決定することができる。
このアッセイにより、DPPI特異的基質としてGly-Phe-パラニトロアニリドを用いて、本発明化合物のIC50値を決定することができる。
代謝安定性についての試験は、Absorption System、エクストン、ペンシルバニア 19341、USAによって行われた。
CYP2C9、CYP2D6およびCYP3A4酵素の阻害試験は、Absorption System、エクストン、ペンシルバニア 19341、USAによって、以下の手順にしたがって、行われた。
、細胞毒性についての試験は、Cyprotex Discovery Ltd.15 ビーチ・レイン、マックルズフィールド、チェシャー、SK10 2DR、UKによって行なわれた。
PZ1025
(S)-tert-ブチル 1-アミノ-3-(4-ブロモフェニル)-1-オキソプロパン-2-イルカルバメート(1)
DCM(400 mL)中の(S)-3-(4-ブロモフェニル)-2-(tert-ブトキシカルボニルアミノ)プロパン酸(20.0 g、58.3 mol)の溶液を氷水浴で冷却し、DMTMM(24.2 g、87.5 mol)を加えた。混合物を、0℃にて1時間攪拌した後、25% NH3-H2O(6 g、87.5 mol)を加えた。反応混合物を室温に暖め、12時間攪拌した。混合物を酢酸エチルで3回抽出し、合わせた有機層を食塩水で洗浄し、無水Na2SO4で乾燥し、濃縮して、化合物1(19.0 g、収率95%)を白色固体で得た。
無水ピリジン(150 mL)中の化合物1(14.73 g、43 mmol)の溶液を氷水浴で冷却し、POCl3(8 mL、77.4 mmol)を30分間にわたって滴下した。反応混合物を0℃にて2時間攪拌し、次いで、室温に暖め、一夜攪拌した。混合物を氷水浴で処置し、酢酸エチルで抽出した。合わせた有機層を1 M HCl溶液、飽和水性NaHCO3および食塩水でそれぞれ洗浄した。有機層を無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(石油エーテル/EtOAc=50:1〜10:1)によって精製して、化合物2(9.67 g、収率69.3%)を白色固体で得た。
DMF(400 mL)中の1-ブロモ-4-(ブロモメチル)ベンゼン(78.0 g、0.312 mol)およびK2CO3(86.1 g、0.624 mol)の混合物に、1-メチルピペラジン(37.4 g、0.374 mol)を滴下し、反応混合物を室温にて4時間攪拌した。混合物に水(1500 mL)を注ぎいれ、次いで、EtOAcで3回抽出した。合わせた抽出物を食塩水で洗浄し、無水Na2SO4で乾燥し、濃縮して、化合物3(50.0 g、収率59.5%)を黄色油状物で得た。
1,4-ジオキサン(500 mL)中の化合物3(35.0 g、130 mmol)の攪拌溶液に、室温にて酢酸カリウム(38.3 g、390 mmol)およびピナコラトジボロン(33.0 g、130 mmol)を加えた。混合物を真空にし、窒素で再充填した(3回)。Pd(dppf)Cl2(3.0 g、1.3 mmol)を加え、反応混合物を窒素下110℃にて12時間攪拌した。混合物を室温に冷却し、固体をろ去した。ろ液を濃縮し、残渣を酢酸エチルおよび水で希釈した。有機層を無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=50:1〜10:1)によって精製して、化合物4(37.0 g、収率90%)を褐色固体で得た。
1,4-ジオキサン(200 mL)中の化合物4(5.0 g、15.4 mmol)および化合物2(4.4 g、14.0 mmol)の攪拌溶液に、炭酸ナトリウム(3.7 g、35 mmol)を加えた。混合物を真空にし、窒素で再充填した(3回)。Pd(dppf)Cl2(0.5 g、0.22 mmol)を加え、反応混合物を窒素下90℃にて12時間攪拌した。混合物を室温に冷却し、固体をろ去した。ろ液を濃縮し、残渣を酢酸エチルおよび水で希釈した。有機層を無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=50:1〜10:1)によって精製して、化合物5(3.4 g、収率50.7%)を褐色固体で得た。
化合物5(1.0 g、2.3 mmol)を88% HCOOH(20 mL)に溶解し、反応混合物を室温にて12時間攪拌した。飽和水性NaHCO3を滴下し、得られる混合物をDCMで抽出した。合わせた抽出物を食塩水で洗浄し、無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=100:1〜20:1)によって精製して、化合物6(300 mg、収率38%)を白色固体で得た。
エタノール/水(1:1、100 mL)中のジヒドロ-2H-ピラン-4(3H)-オン(5.0 g、50 mmol)および(NH4)2CO3(24.5 g、255 mmol)の懸濁液に、シアン化ナトリウム(2.5 g、51 mmol)を加えた。反応混合物を50℃にて12時間加熱し、次いで、80℃に加熱して、過剰の(NH4)2CO3を分解した。エタノールを除去し、水酸化ナトリウム(8.16 g、0.76 mmol)を加えた。反応混合物を一夜還流し、次いで、室温に冷却した。2 N HCl溶液で混合物をpH=10に調節し、Boc2O(11.1 g、51 mmol)およびアセトニトリル(50 mL)を加えた。反応混合物を室温にて一夜攪拌し、酢酸エチルを加えた。2 N HCl溶液で得られる混合物をpH=3-4に注意深く調節し、有機層を分離し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=100:1)によって精製して、化合物7(3.0 g、3ステップで収率24%)を白色固体で得た。
氷水浴中のDCM(90 mL)中の化合物6(4.5 g、13.51 mmol)の溶液に、DMTMM(7.5 g、27 mmol)を加えた。混合物を0℃にて0.5時間攪拌し、化合物7(4-(tert-ブトキシカルボニルアミノ)テトラヒドロ-2H-ピラン-4-カルボン酸(4.0 g、16.22 mmol)を加えた。反応混合物を室温に暖め、12時間攪拌した。混合物をEtOAcで3回抽出し、合わせた有機層を食塩水で洗浄し、無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=20:1)によって精製して、化合物Boc-PZ1025(6.3 g、収率83.1%)を明黄色固体で得た。
88% HCOOH(150 ml)中のBoc-PZ1025(8.5 g、15.16 mmol)の溶液を室温にて3時間攪拌した。混合物に飽和水性NaOH(200 mL)を注ぎいれ、得られる混合物をDCMで2回抽出した。有機層をあわせ、食塩水で洗浄し、無水Na2SO4で乾燥し、濃縮した。残渣をシリカゲル上のフラッシュカラムクロマトグラフィー(DCM/MeOH=40:1〜20:1)によって精製して、化合物PZ1025(3.9 g、55.9%収率)を白色固体で得た。1H NMR(300 MHz、CDCl3):δ 8.25(d、1H、J=9.0 Hz)、7.61-7.53(m、4H)、7.42-7.33(m、4H)、5.14(m、1H)、3.95-3.85(m、2H)、3.67-3.62(m、2H)、3.60-3.57(m、2H)、3.16(d、J=6.9 Hz、2H)、2.56(m、8H)、2.35(s、3H)、2.32-2.18(m、2H)、1.33(m、1H)、1.21(m、1H);MS(ESI):m/z 446.4 [M+H]+。
比較例A:WO2012119941との比較
下記の表1は、PZ1025(実施例1)とWO2012119941の実施例1とを比較する。WO2012119941(PZ1024)の実施例1と本発明化合物(PZ1025)との間の差異は、PZ1025における酸素 対 PZ1024における炭素である。表に示すように、PZ1025とPZ1024 (WO2012119941の実施例1)の効力は、ほとんど同じである。
図1および2は、細胞毒性に関してPZ1025(実施例1)とWO2012119941の実施例1(PZ1024)とを比較する。図1は、24時間(図1A)および48時間(図1B)の時点で分析された化合物PZ1025を示す。図2は、24時間(図2A)および48時間(図2B)の時点で分析された化合物PZ1024を示す。各ケースにおいて水平軸は、μMである。
下記の表2は、PZ1025(実施例1)とWO2010128324の実施例29とを比較する。WO2010128324(PZ1032)の実施例29は、フェニルとピペラジニル環との間の架橋部分がメチレンの代わりにスルホニルであることにおいて、本発明化合物(PZ1025)と相異する(下記の表2の構造を参照)。表2に示すように、細胞ベースのDPPI阻害アッセイにおいて測定されたPZ1025およびPZ1032の効力は、ほとんど同じである。
本発明化合物は、特に、カルボキサミド部分に隣接するテトラヒドロ-ピラニル環特徴とする。WO 2012/119941は、カルボキサミド部分に隣接する架橋または縮合酸素含有飽和環系を含む異なる構造を説明する(57頁の第4の化合物および58頁の第5の化合物を参照)。これらの2つの化合物を利用可能にする合成経路はなく、したがって、生物試験は行われていない。
Claims (13)
- 式(I):
(I)
[ X1は、
(ここで、yは、0、1、2、3、4、5、6、7または8を表す;
Zは、O(酸素)を表す;
yが1または2である場合、R1は、独立して、重水素、ハロゲン、ヒドロキシル、シアノ、オキソ(=O)、メルカプトまたはC1-3-アルキルを表し、ここで、C1-3-アルキルは、ハロゲン、ヒドロキシル、シアノおよびメルカプトから選択される少なくとも1つの置換基で任意に置換される;または
yが3、4、5、6、7または8を表す場合、R1は、重水素を表す)
を表す;
R2は、-C3-6-シクロアルキル、-C1-3-アルキル-C3-6-シクロアルキルまたは-C1-6-アルキルを表し、ここで、-C1-6-アルキルは、ヒドロキシル、シアノまたはアミノから選択される少なくとも1つの置換基で任意に置換される]
で示される化合物ならびにその医薬的に許容しうる塩、溶媒和物および水和物。 - R2が、-C1-6-アルキルであり、ここで、-C1-6-アルキルは、ヒドロキシル、シアノまたはアミノから選択される少なくとも1つの置換基で任意に置換される、請求項1に記載の化合物。
- R2が、-C1-6-アルキル、好ましくは-C1-3-アルキル、より好ましくはメチル-、エチル-またはプロピル-である、請求項1または3のいずれか1つに記載の化合物。
- yが、0、1、2、3または4、たとえば0または1、好ましくは0を表す、請求項1、3または4のいずれか1つに記載の化合物
- 請求項1〜5のいずれか1つに記載の式(I)で示される化合物またはその医薬的に許容しうる塩ならびに少なくとも1つの医薬的に許容しうるアジュバント、担体または希釈剤を含む医薬組成物。
- 医薬としての使用のための請求項1〜5のいずれか1つに記載の化合物または請求項6に記載の組成物。
- 喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、急性肺傷害、急性呼吸窮迫症候群、鬱血性心不全、アテローム性動脈硬化症、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、炎症性腸疾患、乾癬、関節リウマチ、多発性硬化症、マラリア、アルツハイマー病または敗血症を治療するための請求項1〜5のいずれか1つに記載の化合物または請求項6に記載の組成物。
- 喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、鬱血性心不全、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、関節リウマチまたは敗血症を治療するための請求項1〜5のいずれか1つに記載の化合物または請求項6に記載の組成物。
- 喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、急性肺傷害、急性呼吸窮迫症候群、鬱血性心不全、アテローム性動脈硬化症、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、炎症性腸疾患、乾癬、関節リウマチ、多発性硬化症、マラリア、アルツハイマー病または敗血症から選ばれる病状の治療方法であって、
薬剤的有効量の請求項1〜5のいずれか1つに記載の化合物または請求項6に記載の組成物を投与することを含む方法。 - 病状が、喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、鬱血性心不全、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、関節リウマチまたは敗血症から選ばれる、請求項10に記載の方法。
- 喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、急性肺傷害、急性呼吸窮迫症候群、鬱血性心不全、アテローム性動脈硬化症、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、炎症性腸疾患、乾癬、関節リウマチ、多発性硬化症、マラリア、アルツハイマー病または敗血症の治療のための医薬の製造のための請求項1〜5のいずれか1つに記載の化合物または請求項6に記載の組成物の使用。
- 医薬が、喘息、慢性閉塞性肺疾患、気管支拡張症、嚢胞性線維症、α-1アンチトリプシン欠損症、鬱血性心不全、心筋梗塞、再灌流障害、腹部大動脈瘤、糖尿病性心筋症、痛風、偽痛風、呼吸器合胞体ウイルス感染症、関節リウマチまたは敗血症の治療のための医薬である請求項12に記載の使用。
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WO2010142985A1 (en) * | 2009-06-10 | 2010-12-16 | Astrazeneca Ab | Substituted n-[1-cyano-2-(phenyl)ethyl]piperidin-2-ylcarboxmide compounds 761 |
WO2011154677A1 (en) | 2010-06-09 | 2011-12-15 | Astrazeneca Ab | Substituted n-[1-cyano-2-(phenyl)ethyl] 1-aminocycloalk-1-ylcarboxamide compounds - 760 |
WO2012130299A1 (en) | 2011-03-30 | 2012-10-04 | Prozymex A/S | Peptidase inhibitors |
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JP2012526093A (ja) * | 2009-05-07 | 2012-10-25 | アストラゼネカ・アクチエボラーグ | 置換1−シアノエチルヘテロシクリルカルボキサミド化合物750 |
WO2012119941A1 (en) * | 2011-03-04 | 2012-09-13 | Prozymex A/S | Peptidyl nitrilcompounds as peptidase inhibitors |
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CA2923484C (en) | 2022-09-06 |
US9856228B2 (en) | 2018-01-02 |
DK3044214T3 (da) | 2017-11-13 |
NZ718128A (en) | 2021-04-30 |
CN105612149A (zh) | 2016-05-25 |
WO2015032943A1 (en) | 2015-03-12 |
EP3044214A1 (en) | 2016-07-20 |
JP6408008B2 (ja) | 2018-10-17 |
EA029030B1 (ru) | 2018-01-31 |
WO2015032945A1 (en) | 2015-03-12 |
SG11201601150WA (en) | 2016-03-30 |
AU2014317048A1 (en) | 2016-04-07 |
CA2923484A1 (en) | 2015-03-12 |
EA201690561A1 (ru) | 2016-07-29 |
EP3044214B1 (en) | 2017-08-09 |
AU2014317048B2 (en) | 2018-05-10 |
US20160207900A1 (en) | 2016-07-21 |
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