JP4777887B2 - 病気および状態の処置および防止のためのフロロ置換オメガカルボキシアリールジフェニル尿素 - Google Patents
病気および状態の処置および防止のためのフロロ置換オメガカルボキシアリールジフェニル尿素 Download PDFInfo
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- JP4777887B2 JP4777887B2 JP2006521221A JP2006521221A JP4777887B2 JP 4777887 B2 JP4777887 B2 JP 4777887B2 JP 2006521221 A JP2006521221 A JP 2006521221A JP 2006521221 A JP2006521221 A JP 2006521221A JP 4777887 B2 JP4777887 B2 JP 4777887B2
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- Transplantation (AREA)
Description
al.Immunol.Rev.1989,112,49;Taverne et al.Parasttol.Today 1996,12,290),Plasomdium falciparumマラリア(Perlmann et al.Infect.Immunit.1997,65,116)および脳マラリア(Rudin et al.Am.J.Pathol.1997,150,257),非インスリン依存性糖尿病(NIDDM;Stephens et al.J.Biol.Chem.1997,272,971;Ofei et al.Diabetes 1996,45,881),うっ血性心不全(Doyama et al.Int.J.Cardiol.1996,54,217;McMurray et al.Br.Heart J.1991,66,356),心臓病後損傷(Malkiel et al.Mol.Med.Today 1996,2,336),アテローム性動脈硬化症(Parums et al.J.Pathol.1996,179,A46),アルツハイマー病(Fagarasan et al.Brain Res.1996,723,231;Aisen et al.Gerontology 1997,43,143),急性脳炎(Ichiyama et al.J.Neural.1996,234,457),脳傷害(Cannon et al.Crit.Care Med.1992,20,1414;Hansbrogh et al.Surg.Clin.N.Am.1987,67,69;Marano et al,Surg.Gynecol.Obstetr.1990,170,32),多発性硬化症(M.S.;Coyle.Adv.Neuroimmunol.1996,6,143),Matusevicius et al.J.Neuroimmunol.1996,66,115),多発性硬化症における脱髄および稀突起膠細胞損失(Brosnan et al.Brain Pathol.1996,6,243),進行がん(Muc Wierzgon et al.J.Biol.Regulators Homeostatic Agents 1996,10,25),リンパ悪性腫瘍(Levy et al.Crit.Rev.Immunol.1996,16,31),膵臓炎(Exley et al.Gut 1992,33,1126),急性膵臓炎における全身合併症(Mckay et al.Br.J.Surg.1996,83,919),感染炎症およびがんにおける阻害された創傷治癒(Buck et al.Am.J.Pathol.1996,149,195),脊髄形成異常症候群(Raza et al.Int.J.Hematol.1996,63,265),全身エリテマトーデス(Maury et al.Arthritis Rheum.1989,32,146),胆汁性肝硬変(Miller et al.Am.J.Gasteroenterolog.1992,87,465),腸壊死(Sun et al.J.Clin.Invest.1988,81,1328),乾癬(Christophers Austr.J.Dermatol.1996,37,S4),放射線傷害(Redlick et
al.J.Immunol.1996,157,1705),およびOKT3のようなモノクローナル抗体投与後の毒性(Brod et al.Neurology 1996,46,1633)を含む、多種類の炎症性および/または免疫調節病に関係している。
1990,4,21;Badley et al.J.Exp.Med.1997,185,55)を含む、感染病(レビュー;Beutler et al.Crit.Care Med.1993,21,5423;Degre,Biotherapy 1996,8,219)にも関連している。
(i)式Iの新規化合物、その塩、プロドラッグおよび代謝産物、
(ii)そのような化合物を含んでいる薬剤組成物および
(iii)単剤としてまたは細胞毒治療剤として、raf,VEGFR,PDGFR,flt−3およびp38によって仲介される病気および状態を処置するためのこの化合物および組成物の使用
を提供する。
本発明は、raf,VEGFR,PDGFR,p38,および/またはflt−3キナーゼが含まれる一以上の信号形質導入経路を変調することができる化合物を提供する。
リウマチ熱、骨吸収、閉経後骨粗しょう症、敗血症、グラム陰性敗血症、敗血症ショック、エンドトキシンショック、毒性ショック症候群、炎症応答症候群、炎症性腸病(クローン病および潰瘍性大腸炎)、ジャリッシューヘルクスハイマー反応、肺サルコイド−シス、アレルギー性呼吸器病、ケイ肺病、炭鉱労働者じん肺症、肺胞傷害、肝不全、急性炎症中の肝臓病、重症アルコール性肝炎、マラリア(Plasmodium falciparum マラリアおよび脳性マラリア)、非インスリン依存性真性糖尿病(NIDDM)、うつ血性心不全、心臓病後障害、動脈硬化、アルツハイマー病、急性脳炎、脳傷害、多発性硬化症(多発性硬化症における脱髄および稀突起細胞損失)、進行がん、悪性リンパ腫、膵臓炎、感染炎症およびがんにおける創傷治癒傷害、骨髄形成異常症候群、全身円板状エリテマトーデス、胆管硬変、腸壊死、放射線傷害/モノクローナル抗体投与後の毒性、ホスト対グラフト反応(虚血性灌流傷害および腎臓、肝臓、心臓および皮膚のアログラフト反応)、肺アログラフト拒絶反応(閉塞性気管支炎)、または股関節全置換による合併症;結核、消化器潰瘍病中のヘリコバクター・ピロリ感染、Tripanosoma cruzi感染から発生するチャガ病、大腸菌感染から生ずるシガ様トキシンの影響、スタフィロコッカス感染、メミンゴコッカス感染およびBorrelia burgdorferi,Treponema pallidum,サイトメガロウイルス、インフルエンザウイルス、Theiler’s脳脊髄炎ウイルス、およびヒト免疫不全ウイルス(HIV)からの感染よりなる群から選ばれた感染病;
乳頭腫、杯神経膠腫、カポジ肉腫、黒色腫、肺癌、頸部癌、膀こう癌、乳癌、大腸癌、甲状腺癌、胃癌、肝細胞カルチノーマ、白血病、リンパ腫、ホジキンス病、バーキッツ病、関節炎、リュウマチ性関節炎、糖尿性網膜炎、血管形成、狭窄、ステント内狭窄、血管移植狭窄、肺線維症、肝硬変、動脈硬化、糸状体腎炎、糖尿性腎炎、血栓性ミュアンギオパシー症候群、移植拒絶反応、乾癬、糖尿病、創傷治癒、炎症、神経退化病、高免疫障害、血管腫、筋心臓血管形成、冠および能併発脈管化、虚血症、角膜病、ルベオーシス、新脈管緑内障、未熟児斑退化網膜症、創傷治癒、潰瘍ヘリコバクター関連病、骨折、子宮内膜炎、糖尿状態、ネコ掻傷熱、甲状腺肥大、熱傷後の喘息または浮腫、外傷、慢性肺病、発作、ポリープ、嚢、滑膜炎、慢性およびアレルギー性炎症、卵巣高刺激症候群、肺および脳浮腫、ケロイド、線維症、硬変、手根トンネル症候群、成人呼吸窮迫症候群、腹水炎、眼状態、心脈管状態、クロウーフカセ(POEMS)病、クローン病、糸状体腎炎、変形性関節症、多発性硬化症、移植拒絶、ライム病、敗血症、フオンリツペルリンダウ病、天疱瘡、ページェト病、ポリ嚢腎臓病、ザルコイドーシス、咽頭炎、高粘度症候群、オスラー、ウエーバーレンジュ病、慢性閉塞性肺病、放射、低酸素症、前子かん、子宮内膜炎、ヘルペスシンプレックスによる感染、虚血性網膜炎、角膜血管形成、ヘルペスゾスター、ヒト免疫不全ウイルス、パラポツクスウイルス、プロトゾア、トキソプラスモシス、および腫瘍関連惨出および浮腫。
本発明は、1以上の本発明の化合物を含む医薬組成物にも関する。これらの組成物はそれを必要とする患者へ投与することによって所望の薬理効果を達成するために利用される。本発明の目的のための患者は特定の状態および疾病のための処置を含むヒトを含む哺乳類である。それ故本発明は、薬学的に許容し得る担体と、本発明の化合物およびそれらの塩よりなる医薬組成物を含む。薬学的に許容し得る担体は、好ましくは担体に帰すべき副作用が活性成分の有益な効果を損なわないように、活性成分の有効活性と矛盾しない濃度において無毒性でありかつ患者に対して無害の担体である。化合物の薬学的に有効量は、好ましくは処置されている特定の状態に結果を産むまたは影響する量である。本発明の化合物は、薬学的に許容し得る担体と共に、即時、遅延および時間放出製剤を含む有効な慣用の投与単位形において経口、非経口、局所、経鼻、経眼、光学的、舌下、経直腸、経膣等により投与することができる。
アルカリ化剤(非限定的な例は、アンモニア溶液、炭酸アンモニウム、ジエタノールアミン、モノエタノールアミン、水酸化カリウム、ホウ酸ナトリウム、炭酸ナトリウム、水酸化ナトリウム、トリエタノールアミン、トロールアミンを含む);
吸着剤(非限定的な例は、粉末セルロースおよび活性炭を含む);
エアゾル噴射剤(非限定的な例は、二酸化炭素、CCl2F2,F2ClC−CClF2およびCClF3);
空気置換剤(非限定的な例は、窒素およびアルゴンを含む);
抗カビ保存剤(非限定な例は、安息香酸、ブチルパラベン、エチルパラベン、メチルパラベン、プロピルパラベン、安息香酸ナトリウムを含む);
抗微生物保存剤(非限定的な例は、塩化ベンズアルコニウム、塩化ベンゼトニウム、ベンジルアルコール、塩化セチルピリジニム、クロロブタノール、フェノール、フェニルエチルアルコール、硝酸フェニル水銀、およびメチロサールを含む);
抗酸化剤(非限定的な例は、アスコルビン酸、アスコルビルパルミテート、ブチル化ヒドロキシアニソール、ブチル化ヒドロキシトルエン、次亜リン酸、モノチオグリセロール、没食子酸プロピル、アスコルビン酸ナトリウム、重亜硫酸ナトリウム、ナトリウムホルムアルデヒドスルホキシレート、メタ重亜硫酸ナトリウムを含む);
結合物質(非限定的な例は、ブロック共重合体、天然および合成ゴム、ポリアクリレート、ポリウレタン、シリコーン、ポリシロキサン、スチレンブタジエン共重合体を含む);
緩衝剤(非限定な例は、メタリン酸カリウム、リン酸二カリウム、酢酸ナトリウム、無水クエン酸ナトリウム、クエン酸ナトリウム二水和物を含む);
担持剤(非限定的な例は、アカシアシロップ、芳香シロップ、芳香エリキサー、チェリーシロップ、ココアシロップ、オレンジシロップ、シロップ、コーンオイル、鉱油、落花生油、ゴマ油、静菌塩化ナトリウム注射液、注射用静菌水を含む);
キレート剤(非限定的な例は、エデト酸ジナトリウムおよびエデト酸を含む);
着色剤(非限定的な例は、FD & CレッドNo.3,FD & CレッドNo.20,FD & CイエローNo.6,FD & CブルーNo.2,D & CグリーンNo.5,D & CオレンジNo.5,D & CレッドNo.8,カラメル、赤色酸化鉄を含む);
乳化剤(非限定的な例は、アカシア、セトマクロゴール、セチルアルコール、グリセリルモノステアレート、レシチン、ソルビタンモノオレエート、ポリオキシエチレン50モノステアレートを含む);
カプセル化剤(非限定的な例は、ゼラチンおよびセルロースアセテートフタレートを含む);
香味剤(非限定的な例は、アニス油、シナモン油、ココア、メンソール、オレンジ油、ペパーミント油、バニリンを含む);
調湿剤(非限定的な例は、グリセロール、プロピレン、グリコール、ソルビトールを含む);
オイル(非限定的な例は、アラキス油、鉱油、オリーブ油、グリセリンを含む);
軟膏基剤(非限定的な例は、ラノリン、親水性軟膏、ポリエチレングリコール軟膏、ペテロラタム、親水性ペトロラタム、白色軟膏、黄色軟膏、ローズウォーター軟膏を含む);
浸透促進剤(経皮送達)(非限定的な例は、モノまたはポリヒドロキシアルコール、モノまたは多価アルコール、飽和または不飽和脂肪アルコール、飽和または不飽和脂肪エステル、飽和または不飽和ジカルボン酸、精油、ホスフェチジル誘導体、セファリン、テルペン、アミド、エーテル、ケトンおよび尿素を含む);
可塑剤(非限定的な例は、フタル酸ジエチルおよびグリセロールを含む);
溶媒(非限定的な例は、エタノール、コーンオイル、綿実油、グリセロール、イソプロパノール、鉱油、オレイン酸、落花生油、精製水、注射用水、注射用無菌水、洗浄のための無菌水を含む);
硬化剤(非限定的な例は、セチルアルコール、セチルエステルワックス、微結晶ワックス、パラフィン、ステアリルアルコール、白ロウ、黄色ロウを含む);
界面活性剤(非限定的な例は、塩化ベンゼトニウム、ノノキシノール10、オキシトキシリノール9、ポリソルベート80、ラウリル硫酸ナトリウム、ソルビタンモノパルミテートを含む);
懸濁剤(非限定的な例は、寒天、ベントナイト、カルボマー、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カオリン、メチルセルロース、トラガントガム、ビーガムを含む);
甘味剤(非限定的な例は、アスパルテーム、デキストロース、グリセロール、マンニトール、プロピレングリコール、サッカリンナトリウム、ソルビトール、ショ糖を含む);
錠剤抗粘着剤(非限定的な例は、ステアリン酸マグネシウム、タルクを含む);
錠剤バインダー(非限定的な例は、アカシア、アルギン酸、カルボキシメチルセルロースナトリウム、圧縮性糖、エチルセルロース、ゼラチン、液体グルコース、メチルセルロース、非架橋ポリビニルピロリドン、プレゼラチン化デンプンを含む);
錠剤およびカプセル希釈剤(非限定的な例は、二塩基性リン酸カルシウム、カオリン、乳糖、マンニトール、微結晶セルロース、粉末セルロース、沈降性炭酸カルシウム、炭酸ナトリウム、リン酸ナトリウム、ソルビトール、デンプンを含む);
錠剤コーティング剤(非限定的な例は、液体グルコース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、セルロースアセテートフタレート、シエラックを含む);
錠剤直打賦形剤(非限定的な例は、二塩基性リン酸カルシムウムを含む);
錠剤崩壊剤(非限定的な例は、アルギン酸、カルボキメチルセルロースカルシウム、微結晶セルロース、ポラクリンカリウム、架橋ポリビニルピロリドン、アルギン酸ナトリウム、デンプングリコール酸ナトリウム、デンプンを含む);
錠剤滑剤(非限定的な例は、コロイド状シリカ、コーンスターチおよびタルクを含む);
錠剤滑沢剤(非限定的な例は、ステアリン酸カルシウム、ステアリン酸マグネシウム、鉱油、ステアリン酸、ステアリン酸亜鉛を含む);
錠剤/カプセル不透明化剤(非限定な例は、二酸化チタンを含む);
錠剤研磨剤(非限定的な例は、カルナウバロウ、シロロウを含む);
濃化剤(非限定的な例は、蜜ロウ、セチルアルコール、パラフィンを含む);
浸透圧調節剤(非限定的な例は、デキストロース、塩化ナトリウムを含む);
増粘剤(非限定的な例は、アルギン酸、ベントナイト、カルボマー、カルボキシメチルセルロースナトリウム、メチルセルロース、ポリビニルピロリドン、アルギン酸ナトリウム、トラガントガムを含む);そして
湿潤剤(非限定的な例は、ペプタデカエチレンオキシセタノール、レシチン、ソルビトールモノオレエート、ポリオキシエチレンソルビトールモノオレエート、ポリオキシエチレンステアレートを含む)
本発明の所望の水不溶性化合物 50mg/ml
カルボキシメチルセルロースナトリウム 5mg/ml
TWEEN80 4mg/ml
塩化ナトリウム 9mg/ml
ベンジルアルコール 9mg/ml
前記した障害の処置に有用な化合物を評価するための既知の標準的研究室技術を基にして、標準的毒性試験および哺乳動物において上で同定した状態の処置のための標準的薬理学的アッセイにより、およびこれらの結果をこれら状態を処置するために使用される既知の医薬の結果と比較することにより、本発明の化合物の有効投与量はそれぞれの所望の適応症の処置のために容易に決定することができる。これらの状態の一つの処置において投与すべき有効成分の量は、特定の化合物および採用した投与ユニット、投与モード、処置の期間、処置される患者の年令と性、および処置される状態の性格および程度のような配慮に従って広く変動することができる。
本発明の化合物は単剤として、または合剤が許容できない副作用を発生させない場合一以上の他の薬剤との合剤として投与することができる。これは癌のような高増殖病の処置のために特に適切であり得る。この場合、本発明の化合物は既知の細胞毒剤、信号形質導入阻害剤、または他の抗癌剤、それにそれらの混合物または合剤と組合せることができる。
(1)どちらの剤単独の投与に比較して、腫瘍成長の減少または腫瘍排除においてより良い有効性を与える;
(2)投与される化学療法剤のより少ない量の投与を提供する;
(3)単一剤化学療法およびいくつかの他の併用療法で観察されるよりも、少ない有害薬理学的合併症をもって患者が良く耐えられる化学療法処置を提供する;
(4)哺乳類、特にヒトにおいて異なる癌タイプのより広いスペクトルを処置することを提供する;
(5)処置した患者の間でより高い応答を提供する;
(6)標準的化学療法処置に比較して、処置した患者の中でより長い生存時間を提供する;
(7)腫瘍進行のためより長い時間を提供する;および/または
(8)他の抗癌剤組合せが拮抗的効果を産む既知の場合に比較して、単独で使用した剤と少なくとも同等に良好な有効性および耐薬性結果を与える。
HPLC 高速液体クロマトグラフィー
MS 質量スペクトル分析
ES エレクトロスプレー
DMSO ジメチルスルホキシド
NMR 核磁気共鳴スペクトル分析
TLC 薄層クロマトグラフィー
rt 室温
遊離塩基として実施例1の化合物(2.0g)を無水テトラヒドロフラン(15ml)に溶かし、そして4M HCl/ジオキサン(過剰)を加えた。次に溶液を真空濃縮し、灰白色固体2.32gを得た。この粗製塩を熱エタノール(125ml)に溶かし、活性炭を加えて15分間還流加熱した。熱い懸濁液をセライトパッドを通して濾過し、室温へ冷却した。フラスコを一夜フリーザー中に入れた。結晶性固体を吸引濾過し、エタノール、次にヘキサンで洗い風乾した。母液は濃縮し、一夜結晶化(フリーザー中)を許容した。固体の2回目のクロップを集め、1回目のクロップと合併した。無色の塩を2日間60℃で真空オーブン中で乾燥した。得られた塩酸塩の収量は1.72g(79%)であった。m.p.215℃
計算値 実施値
C 48.57 48.68
H 3.11 2.76
N 10.79 10.60
Cl 13.65 13.63
F 14.63 14.88
遊離塩基として実施例1の化合物(2.25g)をエタノール(100ml)に溶かし、メタンスルホン酸のストック溶液(過剰)を加えた。溶液を次に減圧濃縮し、黄色オイルを得た。エタノールを加え、濃縮を繰り返した灰白色固体2.41gを得た。粗製塩を熱エタノール(〜125ml)に溶かし、徐々に冷却化して結晶化させた。室温へ達した後、フラスコを一夜フリーザー中へ置いた。無色結晶性物質を吸引濾過により集め、フィルターケーキをエタノール、次にヘキサンで洗い風乾して物質2.05gを得た。これを一夜60℃で真空オーブン中で乾燥した。m.p.231℃
計算値 実施値
C 45.64 45.34
H 3.31 3.08
N 9.68 9.44
Cl 6.12 6.08
F 13.13 13.42
S 5.54 5.59
遊離塩基として実施例1の化合物(2.25g)をエタノール(50ml)に懸濁し、エタノール(50ml)中のベンゼンスルホン酸(0.737g)を加えた。混合物を激しくかきまぜながら加熱した。すべての固体が溶解し、赤色溶液を与えた。この溶液を室温へ冷やし、フラスコを引掻いた。結晶生成を達成するのは困難で、いくらかの種晶が発見され、これを溶液へ加え、一夜フリーザー中へ置いた。フラスコ中に灰褐色の固体が生成し、この物質を砕き、そして吸引濾過により集めた。固体をエタノール、次にヘキサンで洗い、風乾した。秤量した生成物は2.06gであり、収率は69%であった。m.p.213℃
計算値 実施値
C 50.59 50.24
H 3.30 3.50
N 8.74 8.54
Cl 5.53 5.63
F 11.86 11.79
S 5.00 5.16
c−RAF生化学アッセイは、Lckキナーゼによって活性化(ホスホリル化)したc−Raf酵素で実施された。Lck−活性化c−Raf(Lck−Raf)は、Sf9昆虫細胞中にポリヘドリンプロモーターのコントロール下にGST−c−Raf(アミノ酸302からアミノ酸684まで)とLck(全長)を発現するバキュロウイルスで同時感染させることによって生産した。両方のバキュロウイルスは2.5の感染倍数で使用し、そして細胞は感染後48時間で収穫した。
ここでTib=(阻害剤ありのカウント/分)−(バックグラント)
Ti=(阻害剤なしのカウント/分)−(バックグラント)
本発明化合物は、このアッセイにおいてrafキナーゼの強力な阻害を示した。
精製し、His−標識したp38α2(E.Coli中に発現)をMMK−6により高比活性へインビトロで活性化した。マイクロタイターフォーマットを使用し、すべての反応はアッセイパッファー(25mM HEPES 7.4,20mM MgCl2,150mM NaCl)中に活性化p38α2の0.05μg/ウエルとミエリン塩基性タンパク10μg/ウエルを得るように希釈された試薬で100μL体積において実施された。テスト化合物(水中10%DMSO溶液5μL)が調製され、そして5nMから2.5μMまでの最終濃度をカバーするように希釈された。キナーゼアッセイはウエルあたりコールドATP 10μMおよび〔γ−33P〕ATP0.2μCi(200−400dpm/pmolATP)最終濃度を与えるようにATPカクテル25μLの添加によって開始された。プレートを32℃において35分間インキュベートし、反応を1N HCl水溶液の7μLで停止した。サンプルはTomTec1295ハーベスター(Wallac,Inc.)を用いてP30フィルターマット(Wallac,Inc.)上に収穫され、そしてLKB 1205ベータプレート液体シンチレーションカウンター(Wallac,Inc.)中でカウントされた。陰性対照は基質プラスATP単独を含んでいた。
SW1353細胞アッセイ:細胞(ヒトコンドロ肉腫)が96ウエルプレート中に接種(1000細胞/100μL DMEM10%FCS/ウエル)され、そして一夜インキュベートされた。培地置換後、細胞はテスト化合物へ37℃において1時間曝露され、その時ヒトIL−1(1ng/ml,Endogen,Woburn,WA)と、組換えヒトTNFα(10ng/ml)が添加された。培養物は37℃で48時間インキュベートされ、次に上清IL−6値がELISAによって決定される。本発明の化合物はp38キナーゼの有意な阻害を示す。
レーザーフローサイトメトリープラットフォームを使用する96−ウエルホスホ−ERK(pERK)イムノアッセイは、細胞ライン中のベーサルpERKの阻害を測定するために確立された。MDA−MB−231細胞を完全成育培地中、96−ウエルマイクロタイタープレート中で50,000細胞/ウエルにおいてプレートした。ベーサルpERK1/2阻害に対するテスト化合物の効果のため、プレート翌日にMDA−MB−231細胞を0.1%BSAを有するDMEMへ移し、0.1%DMSO中3μMないし12nMの最終濃度へ1:3希釈した。細胞をテスト化合物と2時間インキュベートし、洗浄し、Bio−Plex全細胞溶解バッファーAに溶解した。サンプルはバッファーB1:1(v/v)で希釈し、アッセイプレートへ直接移すか、または処理するまで−80℃で凍結した。希釈したMDA−MB−231溶解物の50μLを抗ERK1/2抗体を接合した5ミクロンBio−Plexビーズ約2000と一夜シエカー上で室温でインキュベートした。翌日、ビオチニル化ホスホERK1/2サンドイッチイノムアッセイを実施し、ビーズを各インキュベーションの間3回洗い、次に現像剤としてPE−ストレプトアビジン50μLを使用した。pERK1/2の相対的蛍光単位が高感度において25ビーズをBio−Plexフローセル(プローブ)でカウントすることによって検出された。IC50が最大として未処理細胞をそしてバックグランドとして細胞なし(ビーズのみ)を用いて計算された。本発明化合物はこのアッセイにおいて有意な阻害を示す。
このアッセイは、TR−FRETフォーマット中の96ウエルオパックプレート(Costar3915)中で実施された。反応条件は以下のとおり。10μM ATP,25nMポリGT−ビオチン、2nM En標識ホスホ−Try Ab,10nM APC,7nM Flk−1(キナーゼドメイン)、1%DMSO,30mM HEPES pH7.5,10mM MgCl2,0.1mM EDTA,0.015%BRU,0.1mg/ml BSA,0.1%メルカプトエタノール。反応は酵素の添加により開始される。各ウエル中の最終容積は100μLである。プレートは、反応開始後約1.5ないし2.0時間においてパーキンエルマービクターVマルチラベルカウンター上で615および665nmの両方において読まれる。信号は各ウエルあたり比:(665nm/615nm)*10000として計算される。本発明化合物は有意なVEGFR−2キナーゼ阻害を示す。
このアッセイは96ウエルブラックプレート(Costar3915)中にフォーマット化された。以下の試薬(およびそれらのソース)が使用された。ユーロピウム標識抗ホスフォチロシン抗体pY20およびストレプトアビジン−APC;ポリGT−ビオチン、およびDRT中のマウスPDGFR。反応条件は以下のとおり。1nMマウスPDGFRがアッセイバッファー(50mM HEPES pH7.5,10mM MgCl2,0.1mM EDTA,0.015% BRIJ 35,0.1mg/mL BSA,0.1%メルカプトエタノール)中、20μM ATP,7nMポリGT−ビオチン、1nM pY20抗体、5nMストレプトアビジン−APCおよび1% DMSOと混合される。各ウエル中の最終反応容積は100μLである。90分後10μL/ウエルの5μMスタウロスポリンを添加して反応を停止する。反応停止約1時間後、プレートはPerkin Elmer VictorVマルチラベルカウンター上615および665nmにおいて読取られる。信号は各ウエルについて比:(665nm/615nm)×1000として計算される。本発明化合物はPDGFRキナーゼの有意な阻害を示す。
ヒト乳癌細胞(MDA MB−231,NCI)が10%熱不活性化FBSを補給した標準成長培地(DMEM)中で加湿インキュベーター中5%CO2(vol/vol)中37℃で培養された。細胞は96ウエル培養皿中90μL成長培地中3000細胞/ウエルの密度にプレートされた。Toh CTG値を決定するため、プレート24時間後CellTiter−Gloルミネセント試薬の100μLが各ウエルへ加えられ、室温で30分インキュベートされた。Wallac Victor II機器上で発光が記録された。CellTiter−Glo試薬は細胞溶解をもたらし、存在する細胞の数に正比例する、存在するATPの量に比例するルミネセント信号を発生した。
ここで、T72h test=テスト化合物の存在下72時間におけるATP依存ルミネセンス
T72h ctr1=テスト化合物なしの72時間におけるATP依存ルミネセンス
Toh=時間ゼロにおけるATP依存ルミネセンス
本発明化合物はこのアッセイを用いて増殖の有意な阻害を示す。
100K P3−P6大動脈SMCが標準的細胞技術を用いて12ウエルクラスターの各ウエルへSGM−2の100μL/ウエルにおいてプレートされた。翌日細胞を100μL D−PBS(Gibco)で1回リンスし、0.1%BSA(シグマ、CatA9576)で500μL SBM(平滑筋細胞ベーサル培地)中で一夜餓えさせた。化合物はDMSO中に10μMないし1nMまで10倍希釈ステップにおいて希釈された。流し中で急速に反転することによって古い培地を除去し、次に各希釈液の100μLを細胞の対応するウエルへ37℃において1時間加えた。次に細胞を10ng/mLのPDGF BBリガンドで37℃において7分間刺激した。培地を傾斜し、プロテアーゼ阻害剤錠(完全、EDTAなし)と0.2mM Naバナデートを含む等張溶解バッファーを加えた。細胞は冷室内で−4℃において15分間溶解される。溶解物をエッペンドルフ管へ入れ、それへアガロース接合抗PDGFR−β抗体15μLを加え(Santa Cruz,sc−339)、4℃で一夜インキュベートする。翌日ビーズをPBSの50ボリュームで3回リンスし、1×LDSサンプルバッファー(Invitrogen)中5分間沸騰する。サンプルを3−8%勾配トリス−アセテートゲル(Invitrogen)を通し、ニトロセルロース上へ移した。膜は、ブロッキングバッファー(1:1000希釈)中抗ホスホPDGFR−β中1時間インキュベートする前に、1%BSA/TBS−T中で1時間ブロックした。TBS−T中で3回洗った後、膜をヤギ抗ウサギHRP IgG(Amersham,1:25000希釈)中で1時間インキュベートした。ECL基質の添加前にもう3回の洗浄が続いた。膜をハイパーフィルムECLへ露出した。その後膜を剥がし、トータルPDGFR−βについて抗PDGFR−β(Santa Cruz)で再プローブした。
mPDGFR mVEGFR2 p38
IC50,nM IC50,nM IC50,nM
実施例1 83 5.5 24
細胞中のpERK 増殖 pPDGFR
(MDA−MB231)(MDA−MB231)(AoSMC)
IC50,nM IC50,nM IC50,nM
実施例1 22 600 43.5
Claims (8)
- a)塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、トリフロロメタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸(トシレート塩)、1−ナフタレンスルホン酸、2−ナフタレンスルホン酸、酢酸、トリフロロ酢酸、リンゴ酸、酒石酸、クエン酸、乳酸、シュウ酸、コハク酸、フマル酸、マレイン酸、安息香酸、サリチル酸、フェニル酢酸、またはマンデル酸である有機酸または無機酸の塩基塩;または
b)アルカリ金属カチオン、アルカリ土類金属カチオン、アンモニウムカチオン、脂肪族置換アンモニウムカチオン、または芳香族置換アンモニウムカチオンを含有する有機または無機塩基の酸塩;
である請求項1の化合物の薬学的に許容し得る塩。 - 4−{4−〔3−(4−クロロ−3−トリフルオロメチルフェニル)−ウレイド〕−3−フルオロフェノキシ}ピリジン−2−カルボン酸メチルアミド、またはその塩である化合物。
- 塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、トリフロロメタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸(トシレート塩)、1−ナフタレンスルホン酸、2−ナフタレンスルホン酸、酢酸、トリフロロ酢酸、リンゴ酸、酒石酸、クエン酸、乳酸、シュウ酸、コハク酸、フマル酸、マレイン酸、安息香酸、サリチル酸、フェニル酢酸、またはマンデル酸である有機酸の塩基塩である請求項3の化合物の薬学的に許容し得る塩。
- N−(4−クロロ−3−(トリフルオロメチル)フェニル)−N’−2−フルオロ−(4−(2−N−メチルカルバモイル)−4−ピリジルオキシ)フェニル)尿素の塩酸塩、ベンゼンスルホン酸塩、またはメタンスルホン酸塩である化合物。
- 請求項1に記載の式(I)において、1以上の尿素窒素原子および/またはピリジン窒素原子がN−オキシド型である化合物。
- 請求項1に記載の化合物において、メチルアミド官能基は脱メチル化され、1以上の尿素窒素がヒドロキシ基によって置換され、および/またはピリジン窒素がN−オキシド型である化合物。
- 4−{4−〔3−(4−クロロ−3−トリフロロメチルフェニル)ウレイド〕−3−フロロフェノキシ}ピリジン−2−カルボン酸アミド;
4−{4−〔3−(4−クロロ−3−トリフロロメチルフェニル)ウレイド〕−3−フロロフェノキシ}−1−ヒドロキシピリジン−2−カルボン酸メチルアミド;または
4−{4−〔3−(4−クロロ−3−トリフロロメチルフェニル)ウレイド〕−3−フロロフェノキシ}−1−ヒドロキシピリジン−2−カルボン酸アミド;
から選ばれた請求項6または請求項7の化合物。
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