JP2010528994A - アリールエーテルピリダジノン誘導体 - Google Patents
アリールエーテルピリダジノン誘導体 Download PDFInfo
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- JP2010528994A JP2010528994A JP2010509700A JP2010509700A JP2010528994A JP 2010528994 A JP2010528994 A JP 2010528994A JP 2010509700 A JP2010509700 A JP 2010509700A JP 2010509700 A JP2010509700 A JP 2010509700A JP 2010528994 A JP2010528994 A JP 2010528994A
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Abstract
Description
本発明は、有用な特性を有する新規な化合物、特に医薬を調製するために用いることができるものを見出す目的を有していた。
特に、本発明は、Metキナーゼによるシグナル伝達の阻害、調節および/または調整が作用を奏する化合物および化合物の使用に関する。
癌療法のための他のMetキナーゼ阻害剤は、J.G. Christensen et al.により、Cancer Res. 2003, 63(21), 7345-55に記載されている。
癌に対処するためのジヒドロピリダジノン類は、WO 03/037349 A1に記載されている。
免疫系の疾患、虚血性および炎症性疾患を処置するための他のピリダジン類は、EP 1 043 317 A1およびEP 1 061 077 A1から知られている。
EP 0 738 716 A2およびEP 0 711 759 B1には、殺真菌薬および殺虫剤としての他のジヒドロピリダジノン類およびピリダジノン類が記載されている。
他のピリダジノン類は、US 4,397,854において強心薬として記載されている。
特開昭57-95964号公報には、他のピリダジノン類が開示されている。
かつ/またはここで、1つまたは2つのCH2基は、O、S、SO、SO2および/またはCH=CH基により置き換えられていてもよい)、
あるいは、
3〜7個のC原子を有する環状アルキルを示し、
かつ/またはここで、1つまたは2つのCH2基は、O、S、SO、SO2、C≡Cおよび/またはCH=CH基により置き換えられていてもよい)、
あるいは、
3〜7個のC原子を有する環状アルキレンを示し、
R4、R5は、各々、互いに独立して、Hal、OR2、R2、CN、N(R2)2、NO2、COOR2、CON(R2)2、NR2COA、S(O)mA、NR2CON(R2)2またはCOAを示し、
Yは、Het2、NR2[C(R2)2]nHet2、NR2[C(R2)2]nN(R2)2、NR2[C(R2)2]nHet2A、OH、OR2、O[C(R2)2]nHet2、O[C(R2)2]nHet2NA2、C(=O)N(R2)2、C(=O)NAHet2またはC(=O)N(Het2)2を示し、
ここで、NH基は、N−COOAまたはN−COAにより置き換えられていてもよく、
mは、0、1または2を示し、
nは、1、2、3または4を示し、
pは、0、1、2、3または4を示す、
で表される化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物に関する。
薬学的に使用可能な誘導体の用語は、例えば、本発明の化合物の塩、およびまたいわゆるプロドラッグ化合物を意味するものと解釈される。
これらはまた、例えばInt. J. Pharm. 115, 61-67 (1995)に記載されているように、本発明の化合物の生分解性ポリマー誘導体を含む。
さらに、「治療的に有効な量」の表現は、この量を施与されていない対応する対象と比較して、以下の結果:
疾患、症候群、状態、愁訴、障害もしくは副作用の改善された処置、治癒、防止もしくは解消、またはまた疾患、愁訴もしくは障害の進行の低減
を有する量を示す。
「治療的に有効な量」の表現はまた、正常な生理学的機能を増大させるのに有効である量を包含する。
これらは、特に好ましくは、立体異性体化合物の混合物である。
a)式II
で表される化合物を、式III
R1−CHL−R2 III
式中、R1およびR2は、請求項1において示した意味を有し、
Lは、Cl、Br、Iまたは、遊離の、もしくは反応的に官能的に修飾されたOH基を示す、
で表される化合物と反応させ、
あるいは、
あるいは
c)これを、加溶媒分解剤または水素化分解剤で処理することにより、この機能的誘導体の1種から遊離させ、
かつ/または
式Iで表される塩基または酸を、この塩の1種に変換する
ことを特徴とする、前記方法に関する。
表現「カルバモイル」は「アミノカルボニル」を意味し、逆もまた同様である。
環状アルキル(シクロアルキル)は、好ましくはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルを意味する。
Ar1は、特に好ましくは、3位においてNR2COOAまたはOCON(R2)2により、極めて特に好ましくはNHCOOC2H5により置換されているフェニルを示す。
他の置換基とは関係なく、Het1およびHet3は、したがって、また、例えば、2,3−ジヒドロ−2−、−3−、−4−もしくは−5−フリル、2,5−ジヒドロ−2−、−3−、−4−もしくは−5−フリル、テトラヒドロ−2−もしくは−3−フリル、1,3−ジオキソラン−4−イル、テトラヒドロ−2−もしくは−3−チエニル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、2,5−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、1−、2−もしくは3−ピロリジニル、テトラヒドロ−1−、−2−もしくは−4−イミダゾリル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピラゾリル、テトラヒドロ−1−、−3−もしくは−4−ピラゾリル、1,4−ジヒドロ−1−、−2−、−3−もしくは−4−ピリジル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−もしくは−6−ピリジル、1−、2−、3−もしくは4−ピペリジニル、2−、3−もしくは4−モルホリニル、テトラヒドロ−2−、−3−もしくは−4−ピラニル、1,4−ジオキサニル、1,3−ジオキサン−2−、−4−もしくは−5−イル、ヘキサヒドロ−1−、−3−もしくは−4−ピリダジニル、ヘキサヒドロ−1−、−2−、−4−もしくは−5−ピリミジニル、1−、2−もしくは3−ピペラジニル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−、−6−、−7−もしくは−8−キノリル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−、−6−、−7−もしくは−8−イソキノリル、2−、3−、5−、6−、7−もしくは8−3,4−ジヒドロ−2H−ベンゾ−1,4−オキサジニル、さらに好ましくは、2,3−メチレンジオキシフェニル、3,4−メチレンジオキシフェニル、2,3−エチレンジオキシフェニル、3,4−エチレンジオキシフェニル、3,4−(ジフルオロメチレンジオキシ)フェニル、2,3−ジヒドロベンゾフラン−5−もしくは−6−イル、2,3−(2−オキソメチレンジオキシ)フェニルまたはまた3,4−ジヒドロ−2H−1,5−ベンゾジオキセピン−6−もしくは−7−イル、さらに好ましくは、2,3−ジヒドロベンゾフラニル、2,3−ジヒドロ−2−オキソフラニル、3,4−ジヒドロ−2−オキソ−1H−キナゾリニル、2,3−ジヒドロベンゾキサゾリル、2−オキソ−2,3−ジヒドロベンゾキサゾリル、2,3−ジヒドロベンズイミダゾリル、1,3−ジヒドロインドール、2−オキソ−1,3−ジヒドロインドールまたは2−オキソ−2,3−ジヒドロベンズイミダゾリルを示すことができる。
Het1は、特に好ましくは1,3−ジヒドロベンズイミダゾリル、ベンズオキサゾリル、インダゾリル、ベンズイミダゾリル、キノリニル、ジヒドロインドリルまたはインドリルを示し、この各々は、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されている。
Het3は、特に好ましくは、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい。
Het2は、特に好ましくは、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい。
R4、R5は、好ましくは、各々の場合において互いに独立して、HまたはHalを示す。
R2は、好ましくはH、メチル、エチル、プロピルまたはイソプロピルを示す。
Halは、好ましくは、F、ClまたはBr、しかしまたI、特に好ましくはFまたはClを示す。
式Iで表される化合物は、1つまたは2つ以上のキラル中心を有していてもよく、従って種々の立体異性体形態で存在し得る。式Iは、すべてのこれらの形態を包含する。
ここで、1〜7個のH原子は、Fおよび/またはClにより置き換えられていてもよく;
Ibにおいて、Alkは、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子は、F、Clおよび/またはBrにより置き換えられていてもよく;
Icにおいて、Ar1は、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示し;
Ieにおいて、Het1は、1,3−ジヒドロベンズイミダゾリル、ベンズオキサゾリル、インダゾリル、ベンズイミダゾリル、キノリニル、ジヒドロインドリルまたはインドリルを示し、この各々は、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されており;
Igにおいて、Het3は、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく;
Iiにおいて、Het2は、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく;
Ikにおいて、Xは、CHを示し;
Ilにおいて、Yは、Het2、N(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、ここでNH基は、N-COOAまたはN-COAにより置き換えられていてもよく;
R2は、HまたはAを示し、
R3は、Alk−YまたはHet3を示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
ここで、1〜7個のH原子は、Fおよび/またはClにより置き換えられていてもよく、
Alkは、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子は、F、Clおよび/またはBrにより置き換えられていてもよく、
Ar1は、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示し、
Het3は、1〜3個のNおよび/またはO原子を有し、非置換であるか、またはAおよび/または=O(カルボニル酸素)により単置換もしくは二置換されていてもよい、単環式または二環式の飽和複素環を示し、
Het2は、1〜2個のNおよび/またはO原子を有し、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、単環式の飽和複素環を示し、
Xは、CHを示し、
Yは、Het2、N(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、ここでNH基は、N−COOAまたはN−COAにより置き換えられていてもよく、
nは、1、2、3または4を示し;
R2は、HまたはAを示し、
R3は、Alk−YまたはHet3を示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
ここで、1〜7個のH原子は、Fおよび/またはClにより置き換えられていてもよく、
Alkは、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子は、F、Clおよび/またはBrにより置き換えられていてもよく、
Ar1は、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示し、
Het3は、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく、
Het2は、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々は、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく、
Xは、CHを示し、
Yは、Het2、NQ(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、ここでNH基は、N−COOAまたはN−COAにより置き換えられていてもよく、
nは、1、2、3または4を示す;
ならびに、これらの薬学的に使用可能な誘導体、塩、溶媒和物、互変異性体および立体異性体であり、すべての比率でのこれらの混合物を含む。
用いる式IIで表されるピリダジノン類は、商業的に入手できない場合には、一般的にW. J. Coates, A. McKillop, Synthesis, 1993, 334-342の方法により調製する。
式IIIで表される化合物において、Lは、好ましくはCl、Br、Iまたは遊離の、もしくは反応的に修飾されたOH基、例えば1〜6個のC原子を有する活性化エステル、イミダゾリドまたはアルキルスルホニルオキシ(好ましくはメチルスルホニルオキシもしくはトリフルオロメチルスルホニルオキシ)または6〜10個のC原子を有するアリールスルホニルオキシ(好ましくはフェニルもしくはp−トリルスルホニルオキシ)を示す。
アルカリもしくはアルカリ土類金属水酸化物、炭酸塩もしくは重炭酸塩、またはアルカリもしくはアルカリ土類金属、好ましくはカリウム、ナトリウム、カルシウムもしくはセシウムの弱酸の他の塩を加えることがまた、好ましい場合がある。
用いる条件に依存して、反応時間は数分〜14日であり、反応温度は約−30℃〜140℃、通常−10℃〜90℃、特に約0℃〜約70℃である。
特に好ましいのは、アセトニトリル、ジクロロメタンおよび/またはDMFである。
Pbf(ペンタメチルベンゾフラニル)基を用いて、Argを保護する。これを、例えばジクロロメタン中のTFAを用いて切断して除去する。
本発明の前述の化合物を、これらの最終的な非塩形態で用いることができる。一方、本発明はまた、これらの化合物を、当該分野において知られている手順により、種々の有機および無機酸類および塩基類から誘導し得るこれらの薬学的に許容し得る塩の形態で用いることを包含する。式Iで表される化合物の薬学的に許容し得る塩形態は、大部分、慣用的な方法により調製される。式Iで表される化合物がカルボキシル基を含む場合には、この好適な塩の1種を、当該化合物を好適な塩基と反応させて対応する塩基付加塩を得ることにより、生成することができる。このような塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウム;アルカリ金属アルコキシド類、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに種々の有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンである。
特に好ましいのは、塩酸塩、二塩酸塩、臭化水素酸塩、マレイン酸塩、メシル酸塩、リン酸塩、硫酸塩およびコハク酸塩である。
局所的投与用に適合された医薬化合物を、軟膏、クリーム、懸濁液、ローション、散剤、溶液、ペースト、ゲル、スプレー、エアゾールまたは油として処方することができる。
口における局所的適用のために適合された医薬処方物は、薬用キャンデー、トローチおよび洗口剤を包含する。
直腸内投与のために適合された医薬処方物を、坐剤または浣腸剤の形態で投与することができる。
膣内投与のために適合された医薬処方物を、膣坐薬、タンポン、クリーム、ゲル、ペースト、発泡体またはスプレー処方物として投与することができる。
(a)式Iで表される化合物および/または、その薬学的に使用可能な誘導体、溶媒和物および立体異性体(すべての比率でのこの混合物を含む)の有効量、
ならびに
(b)さらなる医薬活性成分の有効量
の個別のパックからなる、セット(キット)に関する。
本発明の化合物は、哺乳類のための、特にヒトのための、チロシンキナーゼにより誘発された疾患の処置における医薬活性成分として適する。これらの疾患には、固形腫瘍、眼性血管新生(糖尿病性網膜症、年齢により誘発された黄斑変性症など)および炎症(乾癬、関節リウマチなど)の成長を促進する腫瘍細胞、病理学的血管新生(または血管形成)の増殖が含まれる。
血管形成が関係するこのような疾患は、眼の疾患、例えば網膜血管化、糖尿病性網膜症、年齢により誘発された黄斑変性症などである。
眼の疾患、例えば糖尿病性網膜症および年齢により誘発された黄斑変性症を処置または防止するための方法は、同様に本発明の一部である。炎症性疾患、例えば関節リウマチ、乾癬、接触性皮膚炎および遅延型過敏症応答の処置または防止、ならびに骨肉腫、骨関節炎およびくる病からの骨の病態の処置または防止のための使用もまた、同様に本発明の範囲内にある。
したがって、本発明は、式Iで表される化合物ならびにこれらの薬学的に使用可能な誘導体、溶媒和物および立体異性体、すべての比率でのこれらの混合物の、キナーゼシグナル伝達の阻害、調節および/または調整が作用を奏する疾患を処置するための医薬を調製するための使用に関する。
好ましいのは、式Iで表される化合物ならびにこれらの薬学的に使用可能な誘導体、溶媒和物および立体異性体、すべての比率でのこれらの混合物の、請求項1に記載の化合物によりチロシンキナーゼを阻害することによって影響される疾患を処置するための医薬を調製するための使用である。
特に好ましいのは、疾患が固形腫瘍である疾患を処置するための使用である。
固形腫瘍はさらに、好ましくは肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、結腸癌および乳癌の群から選択される。
例に記載する式Iで表される化合物を、以下に記載するアッセイにより試験し、キナーゼ阻害活性を有することを見出した。他のアッセイは、文献から知られており、当業者が容易に行うことができた(例えば、Dhanabalら、Cancer Res. 59:189-197; Xinら、J. Biol. Chem. 274:9116-9121; Sheuら、Anticancer Res. 18:4435-4441; Ausprunkら、Dev. Biol. 38:237-248; Gimbroneら、J. Natl. Cancer Inst. 52:413-427; Nicosiaら、In Vitro 18:538- 549を参照)。
製造者のデータ(Met、活性、upstate、カタログNo.14-526)に従って、Metキナーゼを、バキュロウイルス発現ベクター中の「N末端6Hisタグ化」組換えヒトタンパク質として、昆虫細胞(Sf21; S. frugiperda)におけるタンパク質産生およびその後のアフィニティークロマトグラフィー精製のために発現させる。
用いる試験プレートは、Perkin Elmer製の96ウェルのFlashplate(登録商標)マイクロタイタープレート(カタログNo. SMP200)である。以下に記載するキナーゼ反応の成分を、アッセイプレート中にピペットする。Metキナーゼおよび基質ポリAla−Glu−Lys−Tyr(pAGLT、6:2:5:1)を、試験物質の存在下および不存在下で、100μlの合計容積において、放射性標識33P−ATPと共に、3時間室温にてインキュベートする。反応を、150μlの60mMのEDTA溶液を用いて終了させる。室温でさらに30分間インキュベートした後に、上清を、吸引しながら濾別し、ウェルを、各々の回において200μlの0.9%NaCl溶液で3回洗浄する。結合した放射性の測定を、シンチレーション測定器(Topcount NXT, Perkin-Elmer)により行う。
30μlのアッセイ緩衝液
10μlの10%のDMSOを含むアッセイ緩衝液中の試験するべき物質
10μlのATP(最終濃度1μM、0.35μCiの冷33P−ATP)
50μlのアッセイ緩衝液中のMetキナーゼ/基質混合物;(10ngの酵素/ウェル、50ngのpAGLT/ウェル)
−アッセイ緩衝液:
50mMのHEPES
3mMの塩化マグネシウム
3μMのオルトバナジウム酸ナトリウム
3mMの塩化マンガン(II)
1mMのジチオトレイトール(DTT)
pH=7.5(水酸化ナトリウムを用いて調整)
60mMのTitriplex III(EDTA)
−33P−ATP:Perkin-Elmer;
−Metキナーゼ:Upstate, カタログNo. 14-526, Stock1μg/10μl;比活性954U/mg;
−ポリ−Ala−Glu−Lys−Tyr、6:2:5:1:SigmaカタログNo. P1152
実験手順:雌のBalb/Cマウス(ブリーダー:Charles River Wiga)は、到着時に5週齢であった。これらを、7日間本発明者らの維持条件に順応させた。その後、各々のマウスに、100μlのPBS(Ca++およびMg++を含まない)中の400万個のTPR−Met/NIH3T3細胞を、骨盤領域に皮下注射した。5日後、各々の群の9匹のマウスが、110μl(範囲:55〜165)の平均腫瘍容積を有するように動物を3つの群に無作為に分けた。100μlのビヒクル(0.25%のメチルセルロース/100mMの酢酸緩衝液、pH5.5)を、毎日対照群に投与し、ビヒクル(容積は同様に100μl/動物であった)に溶解した200mg/kgの「A56」または「A91」を、各々の場合において胃管により、毎日処置群に投与した。9日後、対照は、1530μlの平均容積を有しており、実験を終了した。
維持条件:ケージあたり4匹または5匹の動物、市販のマウスフード(Sniff)で飼育した。
化合物「A56」および「A91」は、顕著な抗腫瘍作用を有する。
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレーイオン化)(M+H)+
APCI−MS(大気圧化学的イオン化−質量分析法)(M+H)+。
質量分析法(MS):EI(電子衝撃イオン化)M+
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレーイオン化)(M+H)+
APCI−MS(大気圧化学的イオン化−質量分析法)(M+H)+。
方法A:勾配:4.5分/流:3ml/分、99:01〜0:100
水+0.1%(容積)のTFA:アセトニトリル+0.1%(容積)のTFA
0.0〜0.5分:99:01
0.5〜3.5分:99:01→0:100
3.5〜4.5分:0:100
カラム:Chromolith SpeedROD RP18e 50-4.6
波長:220nm
水+0.1%(容積)のTFA:アセトニトリル+0.1%(容積)のTFA
0.0〜0.2分:99:01
0.2〜3.8分:99:01→0:100
3.8〜4.2分:0:100
カラム:Chromolith Performance RP18e;長さ100mm、内径3mm波長:220nm
滞留時間Rt.、単位[分]。
出発化合物の調製
一般的作業手順1(GWP1):
収量:41.8g、ESI 211;Rt.=1.95分(方法A)。
当該物質を、さらに精製せずにさらに反応させる。
収量:11.1g、ESI 211;Rt.=1.99分(方法A)。
当該物質を、さらに精製せずにさらに反応させる。
収量:12.9g、ESI 227;Rt.=2.44分(方法B)。
当該物質を、さらに精製せずにさらに反応させる。
収量:16.4g、ESI 289(M−Boc+H);Rt.=3.19分(方法A)。生成物を、さらに精製せずにさらに反応させる。
収量:5.0g(ベージュ色固体);ESI 289;Rt.=2.67分(方法A)。
収量:17g、茶色油;ESI 303;Rt.=3.21分(方法A)。
収量:67.7g、油、これは結晶化してベージュ色固体を生成する;ESI 196;Rt.=1.98分(方法B)。
収量:6.4g、黄色固体;ESI 366;Rt.=2.56分(方法A)。生成物を、さらに精製せずにさらに反応させる。
収量:4.2g、ベージュ色固体;ESI 366;Rt.=2.59分(方法A)。
当該物質を、さらに精製せずにさらに反応させる。
収量:3.8g、ベージュ色固体;ESI 404;Rt.=3.18分(方法B)。生成物を、さらに精製せずにさらに反応させる。
A:塩基性アルコール類との反応:
混合物を、1NのHClを用いて中和する。混合物を蒸発乾固させ、残留物を酢酸エチル(1mmolのアルコールあたり100ml)に懸濁させ、飽和炭酸水素ナトリウム溶液(1mmolのアルコールあたり20ml)および飽和炭酸水素ナトリウム/塩化ナトリウム溶液(1:1、1mmolのアルコールあたり20ml)で抽出する。有機相を、2NのHCl(1mmolのアルコールあたり30ml)で2回抽出する。水性相を、固体の炭酸水素ナトリウムを用いて注意深く中和し、2×50mlの酢酸エチルで抽出する。有機相を硫酸ナトリウムで乾燥し、蒸発させ、残留物を分取HPLCにより精製する。
反応溶液を、氷水(1mmolのアルコールあたり50ml)中に注入する。水性相を、2×酢酸エチル(1mmolのアルコールあたり50ml)で抽出し、有機相を半飽和(semi-saturated)塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥する。溶媒を蒸留により除去し、残留物を分取HPLCにより精製する。
tert−ブチルオキシカルボニル保護基のアミノ基からの除去
BOCで保護された化合物を、ジクロロメタンに溶解し、10〜20当量のトリフルオロ酢酸を加える。反応物を、室温にて1〜20時間撹拌する(反応をHPLCによりモニタリングする)。反応混合物を蒸発させ、真空中で乾燥する。粗生成物を−所要に応じて−分取HPLCにより精製する。
3.0g(13.3mmol)の6−(3,4,5−トリフルオロフェニル)−2H−ピリダジン−3−オンおよび4.8g(14.4mmol)の炭酸セシウムを、250mlのDMFに懸濁させ、3.0g(13.3mmol)の5−(ブロモメチル)2,1,3−ベンゾチアジアゾールを加え、混合物を室温にて撹拌する。15時間後、110mlの水を反応混合物に加え、これを次に室温にて2時間撹拌する。生成した沈殿物を吸引により濾別し、水で洗浄し、真空中で乾燥する。
収量:4.1g(淡い茶色の残留物);ESI 375;Rt=3.32分(方法B)。
3.5g(9.4mmol)の2−ベンゾ−1,2,5−チアジアゾール−5−イルメチル−6−(3,4,5−トリフルオロフェニル)−2H−ピリダジン−3−オンを、35mlのTHFに溶解し、水素雰囲気下でオートクレーブ中で30℃にて2barの圧力下で、2gのラネーNi(70%、水湿潤)で水素化する。17時間後、さらに3gのラネーNi(70%、水湿潤)を加え、混合物を、35℃にて2barの圧力下でさらに16時間水素化する。触媒を濾別し、洗浄し、濾液を蒸発乾固させる。
収量:3.1g、黄色固体;ESI 341;Rt=2.37分(方法B)。
1g(2.89mmol)の2−(3,4−ジアミノベンジル)−6−(3,4,5−トリフルオロフェニル)−2H−ピリダジン−3−オンを、10mlのTHFに溶解し、702mg(4.33mmol)の1,1’−カルボニルジイミダゾール(CDI)を加え、混合物を室温にて撹拌する。15時間後、生成した沈殿物を吸引により濾別し、THFで洗浄し、真空中で乾燥する。
収量:1.04g、淡黄色固体;ESI 373;Rt=2.65分(方法B)。
126μl(1.08mmol)の3−(ジメチルアミノ)−1−プロパノールを、20mlのDMFに溶解し、64.5mg(1.61mmol)のパラフィン油(60%)中のNaHを窒素の下で加え、混合物を室温にて撹拌する。10分後、200mg(0.54mmol)の5−[6−オキソ−3−(3,4,5−トリフルオロフェニル)−6H−ピリダジン−1−イルメチル]−1,3−ジヒドロベンズイミダゾール−2−オンを加え、混合物を室温にて窒素雰囲気下で撹拌する。反応を、HPLCによりモニタリングする。3時間後、反応は終了する。混合物を、1NのHClを用いて中和する。混合物を蒸発乾固させ、残留物を100mlの酢酸エチル、20mlの飽和炭酸水素ナトリウム溶液および10mlの飽和塩化ナトリウム溶液に懸濁させる。不溶性沈殿物を吸引により濾別し、残留物を分取HPLCにより精製する。
収量:22mgの「A55」、トリフルオロ酢酸塩、白色固体として;ESI 456;Rt.=2.08分(方法B)。
収量:41mgの「A56」、白色固体として;ESI 511;Rt.=1.97分(方法B)。
収量:42mgの「A57」、トリフルオロ酢酸塩、白色固体として;ESI 499;Rt.=1.86分(方法B)。
例A:注射バイアル
100gの式Iで表される活性成分および5gのリン酸水素二ナトリウムを3lの2回蒸留水に溶解した溶液を、2N塩酸を用いてpH6.5に調整し、滅菌濾過し、注射バイアル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々の注射バイアルは、5mgの活性成分を含む。
20gの式Iで表される活性成分の100gの大豆レシチンおよび1400gのココアバターとの混合物を、溶融し、型中に注入し、放冷する。各々の座剤は、20mgの活性成分を含む。
1gの式Iで表される活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから、940mlの2回蒸留水中に溶液を調製する。pHを6.8に調整し、溶液を1lにし、放射線により滅菌する。この溶液を、点眼剤の形態で用いることができる。
500mgの式Iで表される活性成分を、99.5gのワセリンと、無菌条件下で混合する。
1kgの式Iで表される活性成分、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方法で圧縮して、錠剤を得、各々の錠剤が10mgの活性成分を含むようにする。
例Eと同様にして、錠剤を圧縮し、次に、慣用の方法で、スクロース、ジャガイモデンプン、タルク、トラガカントおよび染料の被膜で被覆する。
2kgの式Iで表される活性成分を、硬質ゼラチンカプセル中に、慣用の方法で導入して、各々のカプセルが20mgの活性成分を含むようにする。
1kgの式Iで表される活性成分を60lの2回蒸留水に溶解した溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々のアンプルは、10mgの活性成分を含む。
Claims (29)
- 式I
R1は、Ar1またはHet1を示し、
R2は、HまたはAを示し、
R3は、−Alk−YまたはHet3を示し、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキル(ここで、1〜7個のH原子は、F、Clおよび/またはBrにより置き換えられていてもよく、
かつ/またはここで、1つまたは2つのCH2基は、O、S、SO、SO2および/またはCH=CH基により置き換えられていてもよい)、
あるいは、
3〜7個のC原子を有する環状アルキルを示し、
Alkは、1〜10個のC原子を有する非分枝状または分枝状アルキレン(ここで、1〜7個のH原子は、OH、F、Clおよび/またはBrにより置き換えられていてもよく、
かつ/またはここで、1つまたは2つのCH2基は、O、S、SO、SO2、C≡Cおよび/またはCH=CH基により置き換えられていてもよい)、
あるいは、
3〜7個のC原子を有する環状アルキレンを示し、
Ar1は、フェニル、ナフチルまたはビフェニルを示し、この各々は、Hal、A、OR2、N(R2)2、SR2、NO2、CN、COOR2、CON(R2)2、NR2COA、NR2SO2A、SO2N(R2)2、S(O)mA、CO−Het2、Het2、O[C(R2)2]nN(R2)、OCON(R2)2、O[C(R2)2]nHet2、NR2COOA、NR2COO[C(R2)2]nN(R2)2、NR2COO[C(R2)2]pHet2、OCONR2[C(R2)2]nN(R2)2、OCONR2[C(R2)2]nHet2、CHOおよび/またはCOAにより単置換、二置換または三置換されており、
Het1、Het3は、各々、互いに独立して、1〜4個のN、Oおよび/またはS原子を有し、非置換であるか、またはHal、A、OR2、(CH2)pN(R2)2、(CH2)pN(R2)Het2、(CH2)pN(R2)CO−R2、(CH2)pN(R2)CO−Het2、SR2、NO2、CN、(CH2)pCOOR2、(CH2)pCON(R2)2、(CH2)pCONR2Het2、O[C(R2)2]nN(R2)、O[C(R2)2]nHet2、NHCOOA、NHCOO[C(R2)2]nN(R2)2、NHCOO[C(R2)2]nHet2、OCONH[C(R2)2]nN(R2)2、OCONH[C(R2)2]nHet2、NR2SO2A、SO2N(R2)2、S(O)mA、CO−Het2、CHO、COA、=S、=NH、=NA、オキシ(−O−)および/または=O(カルボニル酸素)により単置換、二置換または三置換されていてもよい、単環式、二環式または三環式の、飽和、不飽和または芳香族複素環を示し、
Het2は、1〜2個のNおよび/またはO原子を有し、A、OA、OH、Halおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、単環式の飽和または芳香族複素環を示し、
R4、R5は、各々、互いに独立して、Hal、OR2、R2、CN、N(R2)2、NO2、COOR2、CON(R2)2、NR2COA、S(O)mA、NR2CON(R2)2またはCOAを示し、
Xは、CHまたはNを示し、
Yは、Het2、N(R2)2、NR2[C(R2)2]nHet2、NR2[C(R2)2]nN(R2)2、NR2[C(R2)2]nHet2A、OH、OR2、O[C(R2)2]nHet2、O[C(R2)2]nHet2NA2、C(=O)N(R2)2、C(=O)NAHet2またはC(=O)N(Het2)2を示し、
ここで、NH基は、N−COOAまたはN−COAにより置き換えられていてもよく、
Halは、F、Cl、BrまたはIを示し、
mは、0、1または2を示し、
nは、1、2、3または4を示し、
pは、0、1、2、3または4を示す、
で表される化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Aが、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
ここで、1〜7個のH原子が、Fおよび/またはClにより置き換えられていてもよい、
請求項1に記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Alkが、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子が、F、Clおよび/またはBrにより置き換えられていてもよい、
請求項1または2に記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Ar1が、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示す、
請求項1〜3のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het1が、1〜3個のNおよび/またはO原子を有し、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されていてもよい、単環式または二環式の不飽和または芳香族複素環を示す、
請求項1〜4のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het1が、1,3−ジヒドロベンズイミダゾリル、ベンズオキサゾリル、インダゾリル、ベンズイミダゾリル、キノリニル、ジヒドロインドリルまたはインドリルを示し、この各々が、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されている、
請求項1〜5のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het3が、1〜3個のNおよび/またはO原子を有し、非置換であるか、またはAおよび/または=O(カルボニル酸素)により単置換もしくは二置換されていてもよい、単環式または二環式の飽和複素環を示す、
請求項1〜6のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het3が、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々が、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、
請求項1〜7のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het2が、1〜2個のNおよび/またはO原子を有し、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、単環式の飽和複素環を示す、
請求項1〜8のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Het2が、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々が、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、
請求項1〜9のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - R4、R5が、各々、互いに独立して、HまたはHalを示す、
請求項1〜10のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - XがCHを示す、
請求項1〜11のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - Yが、Het2、N(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、
ここで、NH基が、N−COOAまたはN−COAにより置き換えられていてもよい、
請求項1〜12のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - R1が、Ar1またはHet1を示し、
R2が、HまたはAを示し、
R3が、Alk−YまたはHet3を示し、
Aが、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
ここで、1〜7個のH原子が、Fおよび/またはClにより置き換えられていてもよく、
Alkが、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子が、F、Clおよび/またはBrにより置き換えられていてもよく、
Ar1が、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示し、
Het1が、1〜3個のNおよび/またはO原子を有し、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されていてもよい、単環式または二環式の不飽和または芳香族複素環を示し、
Het3が、1〜3個のNおよび/またはO原子を有し、非置換であるか、またはAおよび/または=O(カルボニル酸素)により単置換もしくは二置換されていてもよい、単環式または二環式の飽和複素環を示し、
Het2が、1〜2個のNおよび/またはO原子を有し、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよい、単環式の飽和複素環を示し、
R4、R5が、各々、互いに独立して、HまたはHalを示し、
Xが、CHを示し、
Yが、Het2、N(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、ここでNH基が、N−COOAまたはN−COAにより置き換えられていてもよく、
nが、1、2、3または4を示す、
請求項1〜13のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - R1が、Ar1またはHet1を示し、
R2が、HまたはAを示し、
R3が、Alk−YまたはHet3を示し、
Aが、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
ここで、1〜7個のH原子が、Fおよび/またはClにより置き換えられていてもよく、
Alkが、1〜8個のC原子を有する非分枝状または分枝状アルキレンを示し、
ここで、1〜7個のH原子は、F、Clおよび/またはBrにより置き換えられていてもよく、
Ar1が、NR2COOAまたはOCON(R2)2により単置換されているフェニルを示し、
Het1が、1,3−ジヒドロベンズイミダゾリル、ベンズオキサゾリル、インダゾリル、ベンズイミダゾリル、キノリニル、ジヒドロインドリルまたはインドリルを示し、この各々は、非置換であるか、またはA、NH2、OR2および/または=O(カルボニル酸素)により単置換もしくは二置換されており、
Het3が、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々が、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく、
Het2が、ピペリジニル、ピロリジニル、ピペラジニルまたはモルホリニルを示し、この各々が、Aおよび/または=O(カルボニル酸素)により単置換または二置換されていてもよく、
R4、R5が、各々、互いに独立して、HまたはHalを示し、
Xが、CHを示し、
Yが、Het2、Y(R2)2、NR2[C(R2)2]nN(R2)2またはC(=O)N(R2)2を示し、ここでNH基が、N−COOAまたはN−COAにより置き換えられていてもよく、
nが、1、2、3または4を示す、
請求項1〜14のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物、塩、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物。 - 請求項1〜16に記載の式Iで表される化合物、または、これらの薬学的に使用可能な誘導体、塩、溶媒和物、互変異性体もしくは立体異性体の製造方法であって、
a)式II
で表される化合物を、式III
R1−CHL−R2 III
式中、R1およびR2は、請求項1において示した意味を有し、
Lは、Cl、Br、Iまたは、遊離の、もしくは反応的に官能的に修飾されたOH基を示す、
で表される化合物と反応させ、
あるいは、
b)ラジカルR1および/またはR3を他のラジカルR1および/またはR3に、アミノ基または水酸基をアシル化、アルキル化またはエーテル化することにより変換し、
あるいは
c)これを、加溶媒分解剤または水素化分解剤で処理することにより、この機能的誘導体の1種から遊離させ、
かつ/または
式Iで表される塩基または酸を、この塩の1種に変換する
ことを特徴とする、前記方法。 - 請求項1〜16のいずれかに記載の式Iで表される少なくとも1種の化合物、および/または、これらの薬学的に使用可能な誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物、ならびに、任意に賦形剤および/または補助剤を含む、医薬。
- 請求項1〜16のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、またはすべての比率でのこれらの混合物の、キナーゼシグナル伝達の阻害、調節および/または調整が作用を奏する疾患の処置のための医薬の製造のための使用。
- 請求項1〜16のいずれかに記載の化合物、または、これらの薬学的に使用可能な誘導体、溶媒和物もしくは立体異性体、またはすべての比率でのこれらの混合物の、
請求項1〜16のいずれかに記載の化合物によるチロシンキナーゼの阻害により影響される疾患の処置のための医薬の製造のための、請求項19に記載の使用。 - 請求項1〜16のいずれかに記載の化合物によるMetキナーゼの阻害により影響される疾患の処置のための医薬の製造のための、請求項19に記載の使用。
- 処置するべき疾患が固形腫瘍である、請求項20または21に記載の使用。
- 固形腫瘍が、扁平上皮、膀胱、胃、腎臓、頭頸部、食道、子宮頸部、甲状腺、腸、肝臓、脳、前立腺、尿生殖路、リンパ系、胃、喉頭および/または肺の腫瘍の群に由来する、請求項22に記載の使用。
- 固形腫瘍が、単球性白血病、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫および乳癌の群に由来する、請求項22に記載の使用。
- 固形腫瘍が、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、結腸癌および乳癌の群に由来する、請求項23に記載の使用。
- 処置するべき疾患が血液および免疫系の腫瘍である、請求項20または21に記載の使用。
- 腫瘍が、急性脊髄性白血病、慢性脊髄性白血病、急性リンパ性白血病および/または慢性リンパ性白血病の群に由来する、請求項26に記載の使用。
- 請求項1〜16のいずれかに記載の式Iで表される少なくとも1種の化合物および/または、これらの薬学的に使用可能な誘導体、溶媒和物もしくは立体異性体、またはすべての比率でのこれらの混合物、ならびに少なくとも1種の他の医薬活性成分を含む、医薬。
- (a)請求項1〜16のいずれかに記載の式Iで表される化合物および/または、これらの薬学的に使用可能な誘導体、溶媒和物、塩もしくは立体異性体、またはすべての比率でのこれらの混合物の有効量、
ならびに
(b)さらなる医薬活性成分の有効量
の個別のパックからなる、セット(キット)。
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2007
- 2007-06-01 DE DE102007025717A patent/DE102007025717A1/de not_active Withdrawn
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2008
- 2008-05-02 CN CN200880018485XA patent/CN101678214B/zh not_active Expired - Fee Related
- 2008-05-02 DK DK08749296.3T patent/DK2152370T3/da active
- 2008-05-02 EP EP08749296A patent/EP2152370B1/de not_active Not-in-force
- 2008-05-02 PT PT08749296T patent/PT2152370E/pt unknown
- 2008-05-02 KR KR1020097027511A patent/KR20100027182A/ko not_active Application Discontinuation
- 2008-05-02 EA EA200901603A patent/EA200901603A1/ru unknown
- 2008-05-02 CA CA2688517A patent/CA2688517C/en active Active
- 2008-05-02 WO PCT/EP2008/003549 patent/WO2008145242A1/de active Application Filing
- 2008-05-02 AU AU2008255327A patent/AU2008255327B2/en not_active Ceased
- 2008-05-02 JP JP2010509700A patent/JP5385262B2/ja not_active Expired - Fee Related
- 2008-05-02 ES ES08749296T patent/ES2367152T3/es active Active
- 2008-05-02 US US12/602,284 patent/US8445489B2/en active Active
- 2008-05-02 MX MX2009012709A patent/MX2009012709A/es active IP Right Grant
- 2008-05-02 PL PL08749296T patent/PL2152370T3/pl unknown
- 2008-05-02 AT AT08749296T patent/ATE515289T1/de active
- 2008-05-02 BR BRPI0812295-4A2A patent/BRPI0812295A2/pt not_active IP Right Cessation
- 2008-05-30 AR ARP080102270A patent/AR066769A1/es unknown
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2009
- 2009-11-26 IL IL202373A patent/IL202373A/en active IP Right Grant
- 2009-12-18 ZA ZA200909055A patent/ZA200909055B/xx unknown
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Cited By (2)
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JP2016508505A (ja) * | 2013-02-07 | 2016-03-22 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | ピリダジノン−アミド誘導体 |
US12012395B2 (en) | 2018-11-06 | 2024-06-18 | Edgewise Therapeutics, Inc. | Pyridazinone compounds and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
EP2152370A1 (de) | 2010-02-17 |
DK2152370T3 (da) | 2011-08-15 |
JP5385262B2 (ja) | 2014-01-08 |
EA200901603A1 (ru) | 2010-06-30 |
ZA200909055B (en) | 2010-09-29 |
MX2009012709A (es) | 2009-12-08 |
KR20100027182A (ko) | 2010-03-10 |
US8445489B2 (en) | 2013-05-21 |
WO2008145242A1 (de) | 2008-12-04 |
IL202373A0 (en) | 2011-08-01 |
PT2152370E (pt) | 2011-10-11 |
IL202373A (en) | 2015-05-31 |
EP2152370B1 (de) | 2011-07-06 |
DE102007025717A1 (de) | 2008-12-11 |
CN101678214B (zh) | 2013-06-19 |
AR066769A1 (es) | 2009-09-09 |
ES2367152T3 (es) | 2011-10-28 |
US20100179149A1 (en) | 2010-07-15 |
CA2688517C (en) | 2015-08-18 |
CN101678214A (zh) | 2010-03-24 |
BRPI0812295A2 (pt) | 2014-11-25 |
PL2152370T3 (pl) | 2011-10-31 |
CA2688517A1 (en) | 2008-12-04 |
AU2008255327A1 (en) | 2008-12-04 |
ATE515289T1 (de) | 2011-07-15 |
AU2008255327B2 (en) | 2014-02-27 |
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