JP2009510097A - Vla−4によって媒介される白血球接着を阻害するピリミジニルアミド化合物 - Google Patents
Vla−4によって媒介される白血球接着を阻害するピリミジニルアミド化合物 Download PDFInfo
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Abstract
Description
本出願は、同時継続中の米国仮特許出願第60/722,358号(2005年9月29日出願)に対する、米国特許法第119条(e)の下の優先権を主張する。この米国出願は、その全体が、本明細書中で参考として援用される。
本発明は、白血球接着、特にα4インテグリン(ここで、α4インテグリンは好ましくはVLA−4である)によって媒介される白血球接着を阻害する化合物に関する。本発明はまた、このような化合物を含む医薬組成物、ならびに、本発明の化合物または医薬組成物を用いる、例えば炎症などの治療方法に関する。
以下の刊行物は、上付き数字として本願に引用されている。
1 HemlerおよびTakada,欧州特許出願公開第330,506号(1989年8月30日公開)
2 Elices,ら,Cell,60:577584(1990)
3 Springer,Nature,346:425434(1990)
4 Osborn,Cell,62:36(1990)
5 Vedder,ら,Surgery,106:509(1989)
6 Pretolani,ら,J.Exp.Med.,180:795(1994)
7 Abraham,ら,J.Clin.Invest.,93:776(1994)
8 Mulligan,ら,J.Immunology,150:2407(1993)
9 Cybulsky,ら,Science,251:788(1991)
10 Li,ら,Arterioscler.Thromb.,13:197(1993)
11 Sasseville,ら,Am.J.Path.,144:27(1994)
12 Yang,ら,Proc.Nat.Acad.Science(USA),90:10494(1993)
13 Burkly,ら,Diabetes,43:529(1994)
14 Baron,ら,J.Clin.Invest.,93:1700(1994)
15 Hamann,ら,J.Immunology,152:3238(1994)
16 Yednock,ら,Nature,356:63(1992)
17 Baron,ら,J.Exp.Med.,177:57(1993)
18 vanDinther−Janssen,ら,J.Immunology,147:4207(1991)
19 vanDinther−Janssen,ら,Annals.RheumaticDis.,52:672(1993)
20 Elices,ら,J.Clin.Invest.,93:405(1994)
21 Postigo,ら,J.Clin.Invest.,89:1445(1991)
22 Paul,ら,Transpl.Proceed.,25:813(1993)
23 Okarhara,ら,Can.Res.,54:3233(1994)
24 Paavonen,ら,Int.J.Can.,58:298(1994)
25 Schadendorf,ら,J.Path.,170:429(1993)
26 Bao,ら,Diff.,52:239(1993)
27 Lauri,ら,BritishJ.Cancer,68:862(1993)
28 Kawaguchi,ら,JapaneseJ.CancerRes.,83:1304(1992)
29 Konradi,ら,PCT/US00/01686(2000年1月21日出願)
上記のすべての刊行物は、それぞれの個々の刊行物の内容が具体的かつ個別にその全体が引用により援用されるよう記載されたのと同じ程度まで、その全体が引用により援用される。
HemlerおよびTakada1(特許文献1)によって最初に同定されたVLA−4(α4β1インテグリンおよびCD49d/CD29とも呼ばれる)は、細胞表面レセプターのβ1インテグリンファミリーのメンバーである。その各々は、2つのサブユニット、α鎖およびβ鎖を含んでいる。VLA−4は、α4鎖およびβ1鎖を含有する。少なくとも9つのβ1インテグリンが存在し、これらはすべて同じβ1鎖を共有し、それぞれ異なるα鎖を有する。これらの9つのレセプターはすべて、種々の細胞マトリックス分子の異なる補体(例えば、フィブロネクチン、ラミニン、およびコラーゲン)に結合する。例えば、VLA−4は、フィブロネクチンに結合する。VLA−4はまた、内皮細胞および他の細胞によって発現される非マトリックス分子にも結合する。これらの非マトリックス分子としてはVCAM−1が挙げられるが、これは、培養物中のサイトカイン活性化ヒト臍静脈内皮細胞上で発現される。VLA−4の別のエピトープは、フィブロネクチン結合活性およびVCAM−1結合活性を担っており、各活性は、独立して阻害されることが明らかになっている2(非特許文献1)。
本発明は、VLA−4媒介性疾患を治療するための化合物、その薬学的に許容可能な塩、その組成物、その合成、および方法を提供する。
R1は、C1〜C4アルキル、C1〜C4ハロアルキル、ヘテロアリールおよび−N(R5)(R6)からなる群から選択され、ここで、R5およびR6は、水素、C1〜C4アルキルからなる群から独立して選択されるか、R5およびR6は、それらにペンダントしている窒素原子と一緒になって複素環を形成しており;
R2は、C1〜C4アルキル、C2〜C4アルケニル、およびC2〜C4アルキニルからなる群から選択され;
R3およびR4は、独立してC1〜C3アルキルであるか、R3およびR4は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物;またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
R7は、C1〜C4アルキル、C1〜C4ハロアルキルまたはヘテロアリールであり;
R8は、C1〜C4アルキルであり;
R9およびR10は、独立してC1〜C3アルキルであるか、R9およびR10は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物、またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
R11およびR12は、独立してC1〜C4アルキルであるか、R11およびR12は、これらにペンダントしている窒素原子と一緒になって複素環を形成しており;
R13は、C1〜C4アルキルであり;
R14およびR15は、独立してC1〜C3アルキルであるか、R14およびR15は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物;またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
上記のように、本発明は、白血球接着、特に、少なくとも部分的にα4インテグリン(好ましくは、VLA−4)により媒介される白血球接着を阻害する化合物に関する。しかし、本発明をさらに詳細に記述する前に、まず、以下の用語を定義する。
特に明記しない限り、本明細書および請求項で用いている以下の用語は、以下に示す意味を有する:
本明細書中で使用する「アルキル」とは、特に定義しない限り、好ましくは1個〜4個の炭素原子、より好ましくは1〜3個の炭素原子を有する直鎖、分枝鎖および環式のアルキル基を意味する。この用語は、メチル、エチル、n−プロピル、イソ−プロピル、n−ブチル、イソ−ブチル、sec−ブチル、t−ブチル、シクロプロピル、シクロブチルおよびメチレン−シクロプロピルなどの基が例として挙げられる。
(1)その疾患を予防すること、すなわち、その疾患に曝され得るか感染し易いが、未だその疾患の症状を経験しないか示さない哺乳動物において、その疾患の臨床症状を発症させないようにすること;
(2)その疾患を阻止すること、すなわち、その疾患またはその臨床症状の発症を抑えるか少なくすること;または
(3)その疾患を軽減すること、すなわち、その疾患またはその臨床症状の退縮を起こすこと。
R1は、C1〜C4アルキル、C1〜C4ハロアルキル、ヘテロアリールおよび−N(R5)(R6)からなる群から選択され、ここで、R5およびR6は、水素、C1〜C4アルキルからなる群から独立して選択されるか、R5およびR6は、それらにペンダントしている窒素と一緒になって複素環を形成しており;
R2は、C1〜C4アルキル、C2〜C4アルケニル、およびC2〜C4アルキニルからなる群から選択され;
R3およびR4は、独立してC1〜C3アルキルであるか、R3およびR4は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物;またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
R7は、C1〜C4アルキル、C1〜C4ハロアルキルまたはヘテロアリールであり;
R8は、C1〜C4アルキルであり;
R9およびR10は、独立してC1〜C3アルキルであるか、R9およびR10は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物;またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
R11およびR12は、独立してC1〜C4アルキルであるか、R11およびR12は、それにペンダントしている窒素原子と一緒になって複素環を形成しており;
R13はC1〜C4アルキルであり;
R14およびR15は、独立してC1〜C3アルキルであるか、R14およびR15は、それにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物;またはその薬学的に許容可能な塩、エステルもしくはプロドラッグを提供する。
N−[2−ジエチルアミノ−5−{N−エチル−N−(トリフルオロアセチル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(イソ−プロピルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(ピペリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(N−エチル−N−イソ−プロピルアミノカルボニル)アミノ}−ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(3−チアピロリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−トリフルオロメチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;および
N−[2−ジエチルアミノ−5−{N−エチル−N−フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
または薬学的に許容可能なその塩、エステルもしくはプロドラッグを含んでいる。
本発明の化合物は、以下の一般法および手順を使用して、容易に入手できる出発物質から調製できる。典型的または好ましい工程の条件(すなわち、反応温度、回数、反応成分のモル比、溶媒、圧力など)が記載されている場合、特段の記載がない限り、別の工程条件も使用可能であることは理解されよう。最適な反応条件は、使用する特定の反応成分または溶媒によって変動し得るが、当業者であれば、慣用の最適化手順により、このような条件は決定することができる。
医薬品として使用する場合、本発明の化合物は、通常、医薬組成物の形態で投与される。これらの組成物は、種々の経路(経口経路、直腸経路、経皮経路、皮下経路、静脈内経路、筋肉内経路および鼻内経路を含む)により投与することができる。これらの化合物は、注射用組成物および経口用組成物として有効である。このような組成物は、医薬品分野で周知の方法で調製され、また少なくとも1種の活性化合物を含有する。
以下の成分を含有する硬質ゼラチンカプセル剤を調製する:
成分 量(mg/カプセル)
活性成分 30.0
デンプン 305.0
ステアリン酸マグネシウム 5.0
上記成分を混合し、340mgの量で硬質ゼラチンカプセルに充填する。
以下の成分を使用して、錠剤製剤を調製する:
成分 量(mg/錠剤)
活性成分 25.0
微結晶セルロース 200.0
コロイド状二酸化ケイ素 10.0
ステアリン酸 5.0
これらの成分をブレンドし、圧縮して錠剤(各々、240mg重量)を形成する。
以下の成分を含有する乾燥粉末吸入剤製剤を調製する:
成分 重量%
活性成分 5
ラクトース 95
活性成分をラクトースと混合し、混合物を乾燥粉末吸入器に加える。
以下のようにして、錠剤(各々、30mgの活性成分を含有する)を調製する:
成分 量(mg/錠剤)
活性成分 30.0mg
デンプン 45.0mg
微結晶セルロース 35.0mg
ポリビニルピロリドン 4.0mg(滅菌水中10%水溶液として)
カルボキシメチルデンプンナトリウム 4.5mg
ステアリン酸マグネシウム 0.5mg
タルク 1.0mg
活性成分、デンプンおよびセルロースをNo.20メッシュU.S.篩に通し、十分に混合する。得られた粉末にポリビニルピロリドンの溶液を混合し、次いで、これを16メッシュU.S.篩に通す。このように製造した顆粒を50〜60℃で乾燥し、16メッシュU.S.篩に通す。次いで、この顆粒に、No.30メッシュU.S.篩に予め通したカルボキシメチルデンプンナトリウム、ステアリン酸マグネシウムおよびタルクを加え、これらを混合後、錠剤機で圧縮して錠剤(各々、120mg重量)を得る。
以下のようにして、カプセル剤(各々、40mgの薬剤を含有)を作製する:
成分 量(mg/カプセル)
活性成分 40.0mg
デンプン 109.0mg
ステアリン酸マグネシウム 1.0mg
全量 150.0mg
活性成分、デンプンおよびステアリン酸マグネシウムをブレンドし、No.20メッシュU.S.篩に通し、150mgの量で硬質ゼラチンカプセルに充填する。
以下のようにして、坐剤(各々、25mgの活性成分を含有)を製造する:
成分 量
活性成分 25mg
飽和脂肪酸グリセリド 2,000mg
活性成分をNo.60メッシュU.S.篩に通し、飽和脂肪酸グリセリド(これは、必要最低限の熱を使用して、予め融解しておいた)に懸濁させる。次いで、この混合物を、名目容量2.0gの坐剤金型に注ぎ、冷却させる。
以下のようにして、懸濁液(各々、5.0ml用量当たり、50mgの薬剤を含有)を製造する:
成分 量
活性成分 50.0mg
キサンタンガム 4.0mg
カルボキシメチルセルロース
ナトリウム(11%)
微結晶セルロース(89%)50.0mg
スクロース 1.75g
安息香酸ナトリウム 10.0mg
香料および着色料 q.v.
精製水 5.0mlまで
活性成分、スクロースおよびキサンタンガムをブレンドし、No.10メッシュU.S.篩に通し、次いで、微結晶セルロースおよびカルボキシメチルセルロースナトリウムの予め製造しておいた水溶液と混合する。安息香酸ナトリウム、香料および着色料を一部の水で希釈し、撹拌しながら加える。次いで、十分な水を加えて、必要な容量を製造する。
成分 量(mg/カプセル)
活性成分 15.0mg
デンプン 407.0mg
ステアリン酸マグネシウム 3.0mg
全量 425.0mg
活性成分、デンプンおよびステアリン酸マグネシウムをブレンドし、No.20メッシュU.S.篩に通し、425mgの量で硬質ゼラチンに充填する。
以下のようにして、皮下製剤を調製することができる:
成分 量
活性成分 5.0mg
トウモロコシ油 1.0mL
(製剤実施例10)
以下のようにして、局所製剤を調製することができる:
成分 量
活性成分 1〜10g
乳化ワックス 30g
液状パラフィン 20g
白色軟質パラフィン 100gまで
白色軟質パラフィンを溶融するまで加熱する。この液状パラフィンおよび乳化ワックスを混合し、溶解するまで撹拌する。活性成分を加え、分散するまで撹拌を継続する。次いで、混合物を固化するまで冷却する。
以下のようにして、静脈内投与製剤を調製することができる:
成分 量
活性成分 250mg
等張性生理食塩水 1000mL
本発明の方法で使用される他の好ましい製剤は、経皮送達器具(「パッチ」)を使用する。このような経皮パッチは、本発明の化合物を制御した量で連続または不連続的に注入するために使用することができる。薬剤を送達するための経皮パッチの構造および使用については、当技術分野で周知である。例えば、米国特許第5,023,252号(1991年6月11日発行、その内容は、引用により本明細書に援用するものとする)を参照されたい。このようなパッチは、薬剤を連続送達、脈動送達またはオンデマンド送達するように構成することができる。
最も一般的な脱髄疾患は多発性硬化症であるが、多くの他の代謝障害および炎症障害も、不完全または異常な有髄化をもたらす。MSは慢性の神経疾患であり、これは、成人期の初期に現れ、多くの症例では著しい障害まで進行する。米国だけでも、MSは約350,000症例存在する。外傷を除いて、MSは、成人期の初期から中期における神経障害の最も多い原因である。
先天性代謝障害には、フェニルケトン尿症(PKU)および他のアミノ酸尿症、テイ−サックス病、ニーマン−ピック病、ゴーシェ病、ハーラー症候群、クラッベ病、および下記でさらに詳述するように発達中の鞘に強い影響を及ぼす他の白質萎縮症が含まれる。
患者に脱髄化をもたらす様々な慢性免疫多発性神経障害が存在する。この症状を発症する年齢は、症状によって変わる。これらの疾患に対する標準的治療は存在し、本明細書に記載の組成物および化合物と組み合わせることができる。あるいは、本明細書に記載の組成物および化合物を単独で使用することもできる。既存の標準的治療としては、以下のものが挙げられる:
一定の薬剤および放射線は、対象に脱髄化を誘発し得る。脱髄化の原因である薬剤は、これらに限定されるものではないが、クロロキン、FK506、ペルヘキシリン、プロカインアミドおよびジメルジンが挙げられる。
脱髄化をもたらすさらなる遺伝性症候群/疾患としては、コケーン症候群、先天性ミエリン形成減少、ファーバー病、異染色性脳白質ジストロフィー、ペリツェウス−メルツバッヘル病、レフサム病、プリオン関連疾患およびサラ病が挙げられる。
Å=オングストローム
br s=ブロード1重項
BSA=ウシ血清アルブミン
d=2重項
dd=2重項の2重項
dq=4重項の2重項
dsextet=6重項の2重項
DMF=ジメチルホルムアミド
EDTA=エチレンジアミン四酢酸
EtOAc=酢酸エチル
EM=発光波長(nm)
EX=励起波長(nm)
g=グラム
HBSS=ハンクス平衡塩類溶液
HEPES=4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
HPLC=高速液体クロマトグラフィー
hrsまたはh=時間
in.=インチ
i−PrOH=イソプロパノール
kg=キログラム
L=リットル
LC/MS=液体クロマトグラフィー/質量分光法
m=多重項
m2=平方メートル
M=モル
mbar=ミリバール
mg=ミリグラム
MHz=メガヘルツ
min.=分
mL=ミリリットル
mm=ミリメートル
mM=ミリモル
mmol=ミリモル
mOsm=ミリオスモル
m/z=質量対電荷比
N=正常
ng=ナノグラム
nm=ナノメーター
NMR=核磁気共鳴
PBS=リン酸緩衝生理食塩水
PBS++=カルシウムとマグネシウムを含むPBS
ppm=百万分率
psi=1平方インチ当たりのポンド
q=4重項
Rf=保持係数(物質から移動した距離/溶媒前端から移動した距離の比)
rpm=1分当たりの回転数
rt=室温
s=1重項
t=3重項
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
TLC=薄層クロマトグラフィー
UV=紫外線
wt/wt=重量/重量の比
w/v=重量/容積の比
μg=マイクログラム
μm=ミクロン
μM=マイクロモル
一般法。フラッシュクロマトグラフィーは、800gのKP−Silシリカカートリッジを使用し、Biotage Flash 75Lを用いて行った(32〜63μM、60Å、500〜550m2/g)。Rfは、EM Sciences Silica Gel 60 F(254)、順相用の250μM厚プレートを使用した分析用TLCについての報告である。NMRスペクトルは、Varian Gemini 300 MHzスペクトロメーター上に記録した(1Hスペクトルに関しては300MHz、13Cのスペクトルに関しては75MHz)。分析用HPLCは、Phenomenex Luna、3μm、C−18、30×4.6mmカラムを備えたAgilent 1100 Series HPLC上で行った。検出器は210nmUVであった。溶媒は、水に溶解の0.1%TFAおよびアセトニトリルに溶解の0.1%TFAであった。標準流速は1.5mL/分であった。また、標準分析法では、2.33分かけて20%のCH3CNから70%のCH3CNに溶媒勾配を変えた。第2の別法の流速は2mL/分であり、勾配は、1.75分かけて20%のCH3CNから70%のCH3CNに変えた。第3の方法の流速は1.5ml/分であり、溶媒の組成は10分かけて20%のCH3CNから70%のCH3CNに変化させ、2分間70%で保持し、次いで1分間かけて95%までランピングし、2分間95%で保持した。LC/MSは、(化学イオン化として他に特に示さない限り)エレクトロスプレーイオン化法を行う、Series 1100 MSDを備えたAgilent 1100 Series HPLCで行った。カラムおよび条件は、フリースタンディングHPLCに合わせた。アミド類の1H NMRは、一般的には回転異性体を示し、いくつかのピークの積分値はフラクショナルプロトン値で報告している。
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製。
1H NMR(CDCl3,300MHz)δ,ppm:7.80(見かけd,1H),7.18(見かけd,AA’XX’,2H),7.03(見かけdd,AA’XX’,2H),5.00(見かけd,1H),4.80(見かけdq,1H),3.95(見かけd六重線,1H),3.4−3.7(m,8.5H),3.0−3.3(m,3H),2.78(六重線,0.7H),1.93(AA’BB’,4H),1.38(見かけd,9H),1.24−1.05(m,9H).1H NMRは、ほとんどのピークのダブリングにより明らかなように回転異性体を示す。
13CNMR(CDCl3,75MHz)δ,ppm:166.5,166.3,155.6,152.7,150.9,146.0,145.9,128.7,128.3,125.44,125.39,117.18,77.66,(72.82,72.28,71.97−CDCl3),50.23,49.74,41.72,41.64,40.16,39.90,37.28,32.60,32.44,23.24,23.17,21.05,20.23,8.50,8.47,7.32。
1H NMR(CDCl3,300MHz)δ,ppm:7.58(見かけd,1H),7.35−6.90(見かけABABXと重複,6H),6.45(見かけd,1H),5.25(見かけd,1H),4.85(見かけdq,1H),4.05(見かけ八重線,1H),3.7−3.4(m,8H),3.0−3.3(m,2.5H),2.90(六重線,0.5H),1.93(AA’BB’,4H),1.38(見かけd,9H),1.24−1.05(m,9H).1H NMRは、ほとんどのピークの合わせによって明らかなように、回転異性体を示す。
1H NMR(CD3OD,300MHz)δ,ppm:7.65(s,0.55H),7.45(s,0.45H),7.38(m,2H),7.25(d,1.3H),7.18(d,1H),7.05(d,1.2H),6.90(d,1H),6.55(s,0.55H),6.22(広幅s,0.45H),4.9−4.8残存溶媒ピークが試料と重なっている,4.10(見かけ七重線,1.1H),3.7(m,3.3H),3.58(m,7H),3.45−2.9(m,6H),2.78(見かけ六重線,0.7H),1.90(AA’BB’,4.5H),1.85(m,3.16H),1.23−1.0(m,10.3H)。
13CNMR(CD3OD,75MHz)δ,ppm:169.6,169.2,160.8,153.9,153.6148.8,145.8,145.2,145.1,140.7,140.5,138.0,137.9,130.3,130.2,124.7,124.6,116.5,116.4,116.2,116.1,106.9,106.6,105.1,105.0,62.4,50.7,50.1,41.0,37.9,37.2,30.5,20.2,20.0,19.4,6.9,6.8,6.1,5.9。
(S)−2−(2−(ジエチルアミノ)−5−(N−エチル−2,2,2−トリフルオロアセトアミド)ピリミジン−4−イルアミノ)−3−(4−(ピロリジン−1−カルボキシロイルオキシ)フェニル)プロパン酸の調製
HPLC/MS:MH+=567.1。
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
ステップ1:
HPLC/MS:MH+=637.2。
HPLC/MS:MH+=581.2。
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
ステップ1:
HPLC/MS:MH+=637.2。
HPLC/MS:MH+=581.2。
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
ステップ1:
HPLC/MS:MH+=621.3。
HPLC/MS:MH+=565.2。
N−[2−ジエチルアミノ−5−{N−エチル−N−(t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
ステップ1:
HPLC/MS:MH+=611.3。
HPLC/MS:MH+=555.2。
N−[2−ジエチルアミノ−5−{N−エチル−N−(イソ−プロピルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
ステップ1:
HPLC/MS:MH+=597.3。
HPLC/MS:MH+=541.3。
ピリミジニル尿素を調製するための一般法。
HPLC/MS:MH+=589.0。
N−[2−ジエチルアミノ−5−{N−エチル−N−(ピペリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
HPLC/MS:MH+=582.3。
N−[2−ジエチルアミノ−5−{N−エチル−N−(N−エチル−N−イソ−プロピルアミノカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
HPLC/MS:MH+=584.4。
N−[2−ジエチルアミノ−5−{N−エチル−N−(3−チアピロリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニンの調製
HPLC/MS:MH+=586.2。
α4β1インテグリン接着アッセイ:ヒト血漿フィブロネクチンに対するJurkat(商標)細胞接着
手順
96ウェルプレート(Costar 3590 EIAプレート)を、10μg/mLの濃度で4℃のヒトフィブロネクチン(Gibco/BRL、カタログ番号33016−023)で一晩コートした。次いで、このプレートを、生理食塩水中のウシ血清アルブミン(BSA;0.3%)の溶液でブロックした。Jurkat(商標)細胞(対数期増殖で維持したもの)を、製造業者の指示書に従ってCalcein AMで標識し、Hepes/生理食塩水/BSA中で2×106細胞/mLの濃度に懸濁した。次いで、細胞を、室温で30分間、試験化合物およびコントロール化合物に曝露し、その後、フィブロネクチン被覆プレートの個々のウェルに移した。接着は37℃で35分間行った。次いで、ウェルを、新鮮な生理食塩水を用いて穏やかに吸引およびピペッティングすることによって洗浄した。残存接着細胞に関する蛍光を、EX485/EM530で蛍光プレートリーダーを使用して定量した。
ヒト血漿フィブロネクチンへの細胞接着。候補化合物のα4β1への結合を決定するためのインビトロ飽和アッセイ
以下は、実験的自己免疫脳脊髄炎(「EAE」)モデル(次の実施例に記する)または他のインビボモデルにおいて化合物が活性であるために必要とされる血漿レベルを決定するためのインビトロアッセイを記載する。
バイオアベイラビリティを決定するためのカセット投薬および血清分析
経口バイオアベイラビリティを、ラットにカセット(すなわち、投薬溶液当たり6種の化合物の混合物)を投薬することによりスクリーニングした。このカセットは、合計用量10mg/kgにつき5種の試験物質および標準化合物を含んでいる。各化合物/試験物質を、等モル量の1N NaOHでナトリウム塩に変換し、2mg/mLにて水に溶解する。そのカセットを、等容量のそれぞれ6つの溶液を混合することによって調製する。カセット投薬溶液を十分に混合し、次いで、そのpHを7.5〜9に調節する。その投薬溶液を、研究の前日に調製し、室温にて一晩撹拌する。
喘息モデル
α4β1インテグリンによって媒介される炎症疾患としては、例えば、好酸球流入、気道過剰応答および慢性喘息と一緒に起こる閉塞が挙げられる。以下は、喘息の治療において使用するための本発明の化合物のインビボ効果の研究に使用した喘息の動物モデルを記載する。
これは、Chapmanら、Am J.Resp.Crit.Care Med、153〜4頁、A219(1996年)およびChapmanら、Am.J.Resp.Crit Care Med、155巻、4号、A881(1997年)(これは両方とも引用によりその全体を本明細書に援用するものとする)により記載されている手順に従う。
化合物をまた、Kungら、Am J.Respir.Cell Mol.Biol.、13巻:360〜365頁、(1995年)およびSchneiderら、(1999年)、Am J.Respir.Cell Mol.Biol.20巻:448〜457頁、(1999年)(これらはそれぞれ、引用にによりその全体を本明細書に援用するものとする)により記載されている手順の後に、急性肺炎症のマウスモデルにおいて評価する。雌性Black/6マウス(8〜12週齡)を、20μgのova(Grade 4、Sigma)および2mgの注射用ミョウバン(Pierce)を含む0.2mL ova/ミョウバン混合物の腹腔内注射(i.p.)により1日目に感作させる。追加免疫注射を14日目に投与する。28日目および29日目に、20分間、エアロゾル化1%ova(0.9%生理食塩水中)でマウスにチャレンジする。マウスを安楽死させ、気管支洗浄液サンプル(3mL)を30日目(最初のチャレンジの48時間後)に回収する。好酸球を、FACs/FITC染色法により定量する。本発明の化合物を、0.5%カルボキシメチルセルロースおよび2%Tween80懸濁液に処方し、アレルゲンであるオボアルブミンに感作させたマウスに経口投与する。能動的に感作したC57BL/6マウスの気道におけるアレルゲン誘導性白血球蓄積を阻害した化合物を、このモデルにおいて活性があるものとみなした。
このモデルは、Abrahamら、J.Clin,Invest、93巻:776〜787頁(1994年)およびAbrahamら、Am J.Respir Crit Care Med、156巻:696〜703頁(1997年)(これらは両方とも、引用によりその全体を本明細書に援用するものとする)により記載されている手順に従う。本発明の化合物を、Ascaris suum抗原に過敏性のヒツジへ静脈内投与(生理食塩水溶液)、経口投与(2%Tween80、0.5%カルボキシメチルセルロース)、およびエアロゾル投与することにより評価する。早期の抗原誘導性気管支応答を減少させ、かつ/または遅延相の気道応答をブロックする(例えば、抗原誘導性後期応答および気道過剰応答(「AHR」)に対する防御効果を有する)化合物を、このモデルにおいて活性があるものとみなす。
30.0mg/mLの濃度で0.5%重炭酸ナトリウム/生理食塩水(w/v)に溶解した候補化合物の溶液を以下の手順を用いて調製する:
A.0.5%重炭酸ナトリウム/生理食塩水保存溶液の調製:100.0mL
1.0.5gの重炭酸ナトリウムを100mL容量のメスフラスコに加える。
2.約90.0mLの生理食塩水を加え、溶解するまで超音波処理する。
3.生理食塩水で100.0mLまで満たし、完全に混合する。
1.0.300gの候補化合物を10.0mL容量のメスフラスコに加える。
2.約9.7mLの0.5%重炭酸ナトリウム/生理食塩水保存溶液を加える。
3.候補化合物が完全に溶解するまで超音波処理する。
4.0.5%重炭酸ナトリウム/生理食塩水保存溶液で10.0mLまで満たし、完全に混合する。
C57B6マウスにおける10日間の毒性試験
10日間の試験を、雌C57B6マウスに対して本発明の化合物の毒性を評価するために行う。この化合物を、5段階の投薬レベル(0(ビヒクルコントロール)、10、30、100、300および1000mg/kg(mpk))にて、各々の投薬レベルで5匹のマウスを用いて胃管栄養法によって投与する。すべてのレベルについての投与容量は10mL/kgであった。投薬溶液または懸濁液を、0.5%カルボキシメチルセルロース(CMC)中2%Tween80で調製し、新しい投薬溶液または懸濁液を、2〜3日おきに調製する。生態観察には、体重(試験日:1、2、3、5、7、8および11日目)、毎日のケージの外からの臨床的観察(1〜2回/日)ならびに周期的(試験日:1、2および9日目)機能的観察バッテリーを含む。
ラットにおけるアジュバント誘導性関節炎
アジュバント誘導性関節炎(「AIA」)は、関節リウマチ(RA)の研究において有用な動物モデルであるが、これは、Lewisラットの尾の基部において結核菌(M.tuberculosis)を注入することにより誘導される。注射の後10日間〜15日間の間、動物には重篤な進行性のリウマチが発症する。
N−[2−ジエチルアミノ−5−{N−エチル−N−(トリフルオロアセチル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(イソ−プロピルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(ピペリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(N−エチル−N−イソ−プロピルアミノカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(3−チアピロリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−トリフルオロメチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;および
N−[2−ジエチルアミノ−5−{N−エチル−N−フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル。
Claims (40)
- 式I:
R1は、C1〜C4アルキル、C1〜C4ハロアルキル、ヘテロアリールおよび−NR5R6からなる群から選択され、ここで、R5およびR6は、水素およびC1〜C4アルキルからなる群から独立して選択されるか、R5およびR6は、それらにペンダントしている窒素原子と一緒になって複素環を形成しており;
R2は、C1〜C4アルキル、C2〜C4アルケニル、およびC2〜C4アルキニルからなる群から選択され;
R3およびR4は、独立してC1〜C3アルキルであるか、R3およびR4は、これらにペンダントしている窒素原子と一緒になって複素環を形成している)
の化合物、またはその薬学的に許容可能な塩、エステルもしくはプロドラッグ。 - −OC(O)NR3R4基がフェニル環のパラ位にある、請求項1に記載の化合物。
- R3およびR4がそれらにペンダントしている窒素原子と一緒になって複素環を形成している、請求項2に記載の化合物。
- 前記複素環がピロリジニルである、請求項3に記載の化合物。
- R2がC1〜C4アルキルである、請求項4に記載の化合物。
- R2がエチルである、請求項5に記載の化合物。
- −OC(O)NR9R10基がフェニル環のパラ位にある、請求項7に記載の化合物。
- R9およびR10がそれらにペンダントしている窒素原子と一緒になって複素環を形成している、請求項8に記載の化合物。
- 前記複素環がピロリジニルである、請求項9に記載の化合物。
- R8がC1〜C4アルキルである、請求項10に記載の化合物。
- R8がエチルである、請求項11に記載の化合物。
- R7がC1〜C4アルキルである、請求項12に記載の化合物。
- R7がイソプロピルおよびt−ブチルからなる群から選択される、請求項13に記載の化合物。
- R7がC1〜C4ハロアルキルである、請求項12に記載の化合物。
- R7がトリフルオロメチルである、請求項15に記載の化合物。
- R7がヘテロアリールである、請求項12に記載の化合物。
- R7がフラン−2−イル、フラン−3−イル、チエン−2−イルおよびチエン−3−イルからなる群から選択される、請求項17に記載の化合物。
- −OC(O)NR14R15基がフェニル環のパラ位にある、請求項19に記載の化合物。
- R14およびR15がそれらにペンダントしている窒素原子と一緒になって複素環を形成している、請求項20に記載の化合物。
- 前記複素環がピロリジニルである、請求項21に記載の化合物。
- R13がC1〜C4アルキルである、請求項22に記載の化合物。
- R13がエチルである、請求項23に記載の化合物。
- R11およびR12が独立してC1〜C4アルキルである、請求項24に記載の化合物。
- R11がエチルであり、R12がイソプロピルである、請求項25に記載の化合物。
- R11およびR12がそれらにペンダントしている窒素原子と一緒になって複素環を形成している、請求項24に記載の化合物。
- 前記複素環がピペリジン−1−イルおよび3−チアピロリジン−1−イルからなる群から選択される、請求項27に記載の化合物。
- N−[2−ジエチルアミノ−5−{N−エチル−N−(トリフルオロアセチル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(イソ−プロピルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(ピペリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(N−エチル−N−イソ−プロピルアミノカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン;
N−[2−ジエチルアミノ−5−{N−エチル−N−(3−チアピロリジン−1−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}フェニルアラニン
N−[2−ジエチルアミノ−5−{N−エチル−N−(チエン−2−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−トリフルオロメチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
N−[2−ジエチルアミノ−5−{N−エチル−N−t−ブチルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;および
N−[2−ジエチルアミノ−5−{N−エチル−N−フラン−3−イルカルボニル)アミノ}ピリミジン−4−イル]−L−4’−{(ピロリジン−1−イル)カルボニルオキシ}−フェニルアラニンt−ブチルエステル;
からなる群から選択される化合物、またはその薬学的に許容可能な塩、エステルもしくはプロドラッグ。 - 薬学的に許容可能な担体と、治療有効量の請求項1から29のいずれか一項に記載の1種または複数の化合物とを含む医薬組成物。
- ヒトまたは動物対象に請求項30に記載の医薬組成物を投与することを含む、ヒトまたは動物対象のα4インテグリン媒介性疾患の治療方法。
- 前記α4インテグリンがVLA−4である、請求項31に記載の方法。
- 前記疾患が、喘息、アルツハイマー病、アテローム性動脈硬化、エイズ認知症、糖尿病、急性若年性糖尿病、炎症性腸疾患、潰瘍性大腸炎、クローン病、多発性硬化症、関節炎、関節リウマチ、組織移植、腫瘍転移、脳膜炎、脳炎、卒中、脳外傷、腎炎、網膜炎、アトピー性皮膚炎、乾癬、心筋虚血症、急性白血球媒介性肺損傷、および成人呼吸窮迫症候群からなる群から選択される、請求項31に記載の方法。
- 前記疾患が炎症性疾患である、請求項31に記載の方法。
- 前記炎症性疾患が、結節性紅斑、アレルギー性結膜炎、視神経炎、ブドウ膜炎、アレルギー性鼻炎、強直性脊椎炎、乾癬性関節炎、血管炎、ライター症候群、全身性エリテマトーデス、進行性全身性硬化症、多発性筋炎、皮膚筋炎、ウェグナー肉芽腫症、大動脈炎、サルコイドーシス、リンパ球減少症、側頭動脈炎、心膜炎、心筋炎、鬱血性心不全、結節性多発性動脈炎、過敏性症候群、アレルギー、好酸球増加症候群、チャーグ・ストラウス症候群、慢性閉塞性肺疾患、過敏性肺臓炎、活動性慢性肝炎、間質性膀胱炎、自己免疫内分泌不全、原発性胆汁性肝硬変、自己免疫再生不良性貧血、慢性持続性肝炎および甲状腺炎からなる群から選択される、請求項34に記載の方法。
- α4インテグリン媒介性疾患を治療するための薬剤の製造のための、請求項32に記載の医薬組成物の使用。
- 前記α4インテグリンがVLA−4である、請求項38に記載の使用。
- 前記疾患が、喘息、アルツハイマー病、アテローム性動脈硬化、エイズ認知症、糖尿病、急性若年性糖尿病、炎症性腸疾患、潰瘍性大腸炎、クローン病、多発性硬化症、関節炎、関節リウマチ、組織移植、腫瘍転移、脳膜炎、脳炎、卒中、脳外傷、腎炎、網膜炎、アトピー性皮膚炎、乾癬、心筋虚血症、急性白血球媒介性肺損傷、および成人呼吸窮迫症候群からなる群から選択される、請求項38に記載の使用。
- 前記疾患が炎症性疾患である、請求項38に記載の使用。
- 前記炎症性疾患が、結節性紅斑、アレルギー性結膜炎、視神経炎、ブドウ膜炎、アレルギー性鼻炎、強直性脊椎炎、乾癬性関節炎、血管炎、ライター症候群、全身性エリテマトーデス、進行性全身性硬化症、多発性筋炎、皮膚筋炎、ヴェグナー肉芽腫症、大動脈炎、サルコイドーシス、リンパ球減少症、側頭動脈炎、心膜炎、心筋炎、鬱血性心不全、結節性多発性動脈炎、過敏性症候群、アレルギー、好酸球増加症候群、チャーグ・ストラウス症候群、慢性閉塞性肺疾患、過敏性肺臓炎、活動性慢性肝炎、間質性膀胱炎、自己免疫内分泌不全、原発性胆汁性肝硬変、自己免疫再生不良性貧血、慢性持続性肝炎、および甲状腺炎からなる群から選択される、請求項40に記載の使用。
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PCT/US2006/038009 WO2007041270A1 (en) | 2005-09-29 | 2006-09-28 | Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by vla-4 |
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US7763632B2 (en) | 2010-07-27 |
IL190084A0 (en) | 2008-08-07 |
NZ567270A (en) | 2011-06-30 |
CA2624450A1 (en) | 2007-04-12 |
ATE493405T1 (de) | 2011-01-15 |
CN101273034A (zh) | 2008-09-24 |
US20090192181A1 (en) | 2009-07-30 |
NO20082002L (no) | 2008-06-03 |
EA200800975A1 (ru) | 2008-08-29 |
AU2006297220A1 (en) | 2007-04-12 |
JP5101512B2 (ja) | 2012-12-19 |
EA015388B1 (ru) | 2011-08-30 |
DK1940826T3 (da) | 2011-04-18 |
ZA200803280B (en) | 2009-11-25 |
AU2006297220C1 (en) | 2012-11-29 |
AU2006297220B8 (en) | 2013-01-31 |
BRPI0616687A2 (pt) | 2011-06-28 |
US20070142416A1 (en) | 2007-06-21 |
EP1940826B1 (en) | 2010-12-29 |
DE602006019296D1 (de) | 2011-02-10 |
CA2624450C (en) | 2014-02-04 |
ZA200906610B (en) | 2011-05-25 |
AU2006297220B2 (en) | 2012-04-26 |
KR20080059268A (ko) | 2008-06-26 |
US7511052B2 (en) | 2009-03-31 |
EP1940826A1 (en) | 2008-07-09 |
CN101273034B (zh) | 2011-07-27 |
WO2007041270A1 (en) | 2007-04-12 |
IL190084A (en) | 2013-05-30 |
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