JP5680963B2 - 抗炎症性組成物 - Google Patents
抗炎症性組成物 Download PDFInfo
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- JP5680963B2 JP5680963B2 JP2010518744A JP2010518744A JP5680963B2 JP 5680963 B2 JP5680963 B2 JP 5680963B2 JP 2010518744 A JP2010518744 A JP 2010518744A JP 2010518744 A JP2010518744 A JP 2010518744A JP 5680963 B2 JP5680963 B2 JP 5680963B2
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Description
リーは、7員モノラクタム環を有する3−アミノ−カプロラクタムである(例えば国際公開第2005/053702号(WO2005/053702)及び国際公開第2006/016152号(WO2006/016152)を参照のこと)。しかしながら、さらに有用な抗炎症性化合物は同様に、異なる環サイズを有するその他の3−アミノラクタムからも生成されてきた(例えば国際公開第2006/134385号(WO2006/134385)を参照のこと)。ヘテロ原子及びビシクロラクタム環系の導入を含むラクタム環に対するその他の修飾も同様に、BSCI活性をもつ化合物を生み出す(例えば国際公開第2006/018609号(WO2006/018609)及び国際公開第2006/085096号(WO2006/085096)を参照のこと)。
− 自己免疫疾患例えば多発性硬化症、関節リウマチ、狼瘡、過敏性腸症候群、クローン病;
− 卒中、冠動脈疾患、心筋梗塞、不安定狭心症、アテローム性動脈硬化症又は脈管炎、例えばベーチェット症候群、巨細胞性動脈炎、リウマチ性多発性筋痛、ヴェグナー肉芽腫症、チャーグ・ストラウス症候群脈管炎、ヘノッポシェーンライン紫斑病及び川崎病;
− ウイルス感染又は複製、例えばポックスウイルス、ヘルペスウイルス(例えばHerpes virus samiri)、サイトメガロウイルス(CMV)、肝炎ウイルス又はレンチウイルス(HIVを含む)を含めたウイルスに起因する感染又はその複製;
− 喘息及びそれに関連する呼吸器疾患例えばアレルギー性鼻炎及びCOPD;
− 骨粗鬆症;(低骨密度);
− 腫瘍成長;
− 臓器移植拒否反応及び/又は臓器移植後臓器機能障害(例えば腎移植患者の場合);
− 高いTNF−αレベルを特徴とする疾患;
− 乾癬;
− 肥厚性瘢痕化(ケロイド形成)、一般又は婦人科外科手術後の癒着形成、肺線維症、肝線維症(アルコール性肝臓疾患を含む)又は特発性か又は糖尿病といった(糖尿病性ネフロパシー)基礎疾患の帰結としての腎臓の線維症を含めた、皮膚創傷及び他の線維性疾患;
− マラリア又は結核といったような細胞内寄生体に起因する疾患;
− 神経因性疼痛(例えば術後幻肢痛、肝炎後神経痛など)、
− アレルギー又は
− アルツハイマー病、
− ALS;
− 抗原誘発性想起応答、
− 免疫応答抑制。
一般式(I)又は(I’)の全ての化合物は、当業者にとって公知の一般的方法にしたがって容易に調製可能である。
「約」という用語は、考慮対象の値の前後の一定の範囲を意味する。本出願中で使用されている「約X」というのは、XからXの10%を減じたものからXにXの10%を加えたものまでの範囲を意味する。
化合物を、(静脈内経路を介して5%のDMSO中で体重1kgあたり1mgか又は、経口経路を介して1%のカルボキシメチルセルロース中で3mg/kgの)単回用量として3匹の成体ラットに(各化合物及び各投与経路について異なるラットを用いて)投与した。
経口経路を介して各化合物で処理された各ラットについての個々の濃度対時間グラフは、図1に示されている。これらの5つの構造的に多様なラクタムBSCIのうち、(IV)、(V)及び(I’)のみが感知され得る何らかの経口曝露を達成し、これらのうち(I’)がその他のものよりも実質的に優れている、ということは直ちに明らかである。
3匹のラットを平均した、各化合物についての単一の1コンパートメント薬物動態モデルからの、経口生物学的利用能(F,%)優性血漿半減期(t1/2、分)、クリアランス(ml/分/kg)、分布容量(Vss、L/kg)及び曝露(AUCO→無限、分、ng/ml)。*24分は、注入用量の95%超のクリアランスを説明する(V)についての優性半減期である;劣位t1/2βは110分であった。全てのケースにおいて、Cmaxは、30分以内で達成され、これは最適な吸収と一貫性あるものであった。
単回経口用量(1%のCMC中3mg/kg)の各化合物に曝露されたラットから代謝ケージ内で24時間にわたり尿を収集した。その後プールした尿試料を、前述の実施例1で記述されたものと同じLC−MS条件を用いて、フルスキャン質量スペクトル分析に付した。次にプロダクトイオンのさらなるMS−MS分析を実施し、公に入手可能な代謝産物IDデータベースから、可能性ある断片化/転位を割当てた。
検出された濃度の順位で、検出された代謝産物が、分析された5つの化合物について図2で示されている。ここで使用される方法が必然的に網羅的でなく、ここで適用された方法について検出限界を下回るさらなる(特に微量の)代謝産物も同様に存在し得るという点に留意することが重要である。一般に、注射された用量の10%以上を占める代謝産物が、ここで使用される方法によって(必ずしも構造的に同定されはしないものの)検出されるものと仮定することができる。
確率の高い遺伝毒性を評価するために、5つの化合物を標準的AMES試験に付した。S9ラット肝臓ミクロソーム代謝系の存在下及び不在下で(最高5mg/mlまでの)5つの濃度を用いて各々の化合物でS. Typhinuriumの3つのHis−栄養要求性菌株(TA102、TA98及びTA100)を処置した。次に、微量His最小培地上に平板固定することによって、復帰突然変異体コロニーの数を決定した。
5つの化合物の一般薬理を、特異的標的受容体に対してと同様、多くが標的受容体と構造的に関連づけられる多種多様なその他の受容体に対して評価した。標的受容体に対する特異的結合は、[3H]−BN83250の結合に対する競合により評価された(BN83250は、(S)−3−(2’,2’−ジメチルドデカノイルアミノ)−カプロラクタム(Foxら、J. Med Chem. 第200;4813号);867〜74頁)、すなわちここで開示されているラクタムBSCIと同じ標的受容体に結合するものとして知られている薬剤である)。非標的受容体に対する結合は、当該技術分野において周知であるその他の受容体のための様々な特異的放射性リガンドの結合に対する競合によって評価された。
本発明の化合物の生物学的活性は、ボイデンチャンバ及び関連するトランスウェル遊走検定、アガロース下遊走検定及び直接視覚化チャンバたとえばダン・チャンバーを含めた(ただしこれらに限定されない)広範な試験管内での白血球遊走の機能的検定のいずれかを用いて実証可能である。
トランスウェル遊走システムは、Neuroprobe, Gaithersburg, MD, USAが製造している。使用される平板は、Chemo TxTM平板(Neuroprobe 101−8)及び30μlの透明平板(Neuroprobe MP30)である。
ケモカインによって誘発される白血球遊走を特異的に遮断する能力について、本発明の化合物を試験するために以下の手順を使用する:
THP−1細胞のMCP−1誘発型遊走を阻害する化合物(I’)についての典型的用量応答曲線が、特に高い(すなわち<1nM)効力をもつものとして知られているその他の選択されたラクタムBSCIについての比較可能な用量応答曲線と合わせて、図6に示されている。ED50値として表現されている、化合物(I’)対様々なケモカイン及び非ケモカイン化学誘引物質の効力は、表6に示され、先に記述したその他のラクタムBSCIと比較されている。
我々は、先に開示されたBSCI(例えばFoxら、J Med Chem. 2002年;第45号(2):360〜70頁; Foxら、J Med Chem. 2005年;第48号(3):867〜74頁参照)の生体内での全身的抗炎症性特性を実証するために、亜致死LPS誘発型内毒素血症検定を使用した。この検定において、マウスには、細菌内毒素(LPS)を用いて非特異的炎症性抗原投与が与えられ、(正常な条件下の血液からは基本的に存在しないものの広範囲の炎症性刺激に応答して急速に上昇する)中心的炎症性サイトカインTNF−αの血清レベルによって全身性炎症性応答の程度が測定される。このモデルはそれ自体がいずれかのヒト炎症性疾患条件に特に近いモデルではないにせよ、TNFαが非常に数多くの疾患(関節リウマチ、自己免疫疾患、クローン病、アテローム性動脈硬化症、喘息その他多数を含む)において重要であることがわかっているために、このモデルが選択された。したがって、このような広範囲の疾病を治療するために、TNF−αの産生を抑制する薬剤がすでに臨床的に使用されている(例えばEnbrelTM及びその他の抗TNF−α抗体製品)。したがってこのモデルにおけるTNF−α抑制活性の実証は、広範囲の疾患において、臨床的に有用な抗炎症性効果を充分予測させるものである。
・ IFN−g−PE(e Bioscience Rat IgG1, Cat. Code. 12-7311-82,100μg)又は、
・ Il−4−PE(e Bioscience Rat IgG1, Cat. Code. 12-7041-82,100μg)又は、
・ イソタイプ対照(Rat IgG2b-FITC, e Bioscience Cat. Code 11-4031及びRat IgG1-PE, e Bioscience Cat. Code 12-4301の混合物)。
その後、細胞を洗浄し(PBS/BSA/サポニンで2回、そして次にサポニン無しでPBS/BSAで洗浄し膜閉鎖を可能にする)、ダルベッコのPBS中に再懸濁させていつでもフローサイトメトリ分析できる状態にした。
その他のアシルアミノラクタムBSCIに比べて、(特にその薬物動態に関して)驚くほど優れた薬剤学的特性を有するものとして化合物(I)を同定した上で、次に我々は、それを先に開示された大部分の構造的に類似する類似体と直接比較した。
残念なことに、(VI)は、溶媒を保持する傾向をもつロウ質固体であった。溶媒を含まない(VI)の調製物を得ることは困難であったが、これは何週間にもわたる相当な乾燥の後に最終的に達成された。しかしながら、この試料は、先の化合物の静脈内投薬のためのビヒクルとして使用された生理食塩水中の5%DMSO内では全く不溶であった。結果として、静脈内投薬に適した溶液を調製するために全く異なるビヒクルを用いる必要があった。静脈内投薬のため、50%のPEG400/20%のソルトール(Solutol)/30%の生理食塩水中に化合物(VI)を溶解させた。(VI)を含む全ての化合物を、経口投薬のため、生理食塩水中の1%のカルボキシメチルセルロース中に懸濁(又は溶解)させた。異なるビヒクルを用いて実験間の経口生物学的利用能を比較することは一般に推奨されないが(ビヒクルが、化合物の腸管吸収に著しい影響を与える可能性があるため)、それでもビヒクルの選択が、(I)といったその他の化合物と比べた(VI)の静脈内注射後の実際の半減期に著しい影響を及ぼす確率は非常に低い。
化合物(I’)のより優れたADME特性を同定するプロセスにおいて、我々は、試験管内でBSCIとしてサブナノモル効力をもつ様々な異なるアシルアミノラクタムの薬物動態を分析した。その結果、我々は、この構造的空間の内部で分子のためのADME特性を変調させる因子についての幾分かの洞察力を得たものと期待できると思われる。したがって我々は、この実験を用いて、(I’)のものと可能なかぎり同じようなADME特性をもつ先に開示された構造的部類の中から第2のアシルアミノラクタムBSCI化合物を選択しようと試みた。
単純な1コンパートメント薬物動態モデルのパラメータは表8に示されている。以上の表1からの化合物(I’)についてのデータが、比較のために示されている。クリアランス率が20倍超高く、検出可能な経口生物学的利用能が全く無いことから、化合物(VIII)が(I’)よりも著しく劣っていることは明白である。
化合物(I’)は、予想外の著しく優れたADME特性を有することが示された(実施例1を参照のこと)。この化合物は、(アミドリンカーとの環接合部において)非対称の炭素原子を有し、その結果2つの立体異性体の形すなわち、(I’)と呼ばれる(S)−光学異性体及び(R)−(I)と呼ばれる反対の(R)−光学異性体の形で存在する。
単純な1コンパートメント薬物動態モデルのパラメータは表9に示されている。以上の表1からの化合物(I’)についてのデータが、比較のために示されている。(R)−(I)が、大体において(I’)の予想外に優れたADME特性を共有していることは明白である。(I’)の場合と同様に、(R)−(I)は本質的に、量的には経口生物学的利用能を有し、これまでに試験された次善の化合物よりも5倍超高い3mg/kgでの単一経口用量にしたがって曝露を達成する(実施例1中の化合物(V)を参照;表1)。
Claims (12)
- 前記炎症性疾患が、自己免疫疾患、血管障害、ウイルス感染又は複製、喘息、骨粗鬆症(低骨密度)、腫瘍成長、臓器移植拒否反応及び/又は臓器移植後臓器機能障害、乾癬、皮膚創傷、細胞内寄生体に起因する疾患、神経因性疼痛、アレルギー、アルツハイマー病、免疫応答抑制、関節リウマチ、多発性硬化症、ALS、線維症、婦人科手術又は外科手術後の癒着形成を含む癒着形成、アレルギー性鼻炎、慢性閉塞性肺疾患、及び糖尿病性ネフロパシーを含むネフロパシーからなる群から選択される、請求項1又は2に記載の式(I)又は(I’)の化合物の使用。
- 前記炎症性疾患が、喘息、アレルギー性鼻炎又は慢性閉塞性肺疾患である、請求項7に記載の式(I)又は(I’)の化合物の使用。
- 前記炎症性疾患が、婦人科手術又は外科手術後の癒着形成である、請求項7に記載の式(I)又は(I’)の化合物の使用。
- 前記炎症性疾患が、糖尿病性ネフロパシーを含むネフロパシーである、請求項7に記載の式(I)又は(I’)の化合物の使用。
- 前記疾患が、自己免疫疾患、血管障害、ウイルス感染又は複製、喘息、骨粗鬆症(低骨密度)、腫瘍成長、臓器移植拒否反応及び/又は臓器移植後臓器機能障害、乾癬、皮膚創傷、細胞内寄生体に起因する疾患、神経因性疼痛、アレルギー、アルツハイマー病、免疫応答抑制、関節リウマチ、多発性硬化症、ALS、線維症、婦人科手術又は外科手術後の癒着形成を含む癒着形成、アレルギー性鼻炎、慢性閉塞性肺疾患、及び糖尿病性ネフロパシーを含むネフロパシーからなる群から選択される、請求項11に記載の医薬組成物。
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- 2008-08-01 ES ES08776116.9T patent/ES2478243T3/es active Active
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Publication number | Publication date |
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EP2185151B1 (en) | 2014-04-09 |
GB2452696B (en) | 2009-09-23 |
US8853200B2 (en) | 2014-10-07 |
RU2010103320A (ru) | 2011-09-10 |
RU2483730C2 (ru) | 2013-06-10 |
CN102973562B (zh) | 2014-12-24 |
CN101801377B (zh) | 2013-01-02 |
MX2010001243A (es) | 2010-03-11 |
US20150141460A1 (en) | 2015-05-21 |
ZA201000667B (en) | 2010-09-29 |
US20100324089A1 (en) | 2010-12-23 |
KR20100043258A (ko) | 2010-04-28 |
CN102973562A (zh) | 2013-03-20 |
SI2185151T1 (sl) | 2014-08-29 |
NZ583503A (en) | 2011-05-27 |
GB2452696A (en) | 2009-03-18 |
EP2572716A1 (en) | 2013-03-27 |
ES2478243T3 (es) | 2014-07-21 |
DK2185151T3 (da) | 2014-07-14 |
HRP20140647T1 (hr) | 2014-09-26 |
BRPI0815003A2 (pt) | 2015-03-03 |
AU2008281570C1 (en) | 2013-06-06 |
JP2010535186A (ja) | 2010-11-18 |
GB0715068D0 (en) | 2007-09-12 |
EP2185151A1 (en) | 2010-05-19 |
CN101801377A (zh) | 2010-08-11 |
PT2185151E (pt) | 2014-07-18 |
WO2009016390A1 (en) | 2009-02-05 |
CY1115384T1 (el) | 2017-01-04 |
CA2695257A1 (en) | 2009-02-05 |
AU2008281570B2 (en) | 2012-10-25 |
PL2185151T3 (pl) | 2014-09-30 |
AU2008281570A1 (en) | 2009-02-05 |
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