JP2016518443A - ピリミジン−4−イル)オキシ)−1h−インドール−1−カルボキサミド誘導体およびその使用 - Google Patents
ピリミジン−4−イル)オキシ)−1h−インドール−1−カルボキサミド誘導体およびその使用 Download PDFInfo
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- JP2016518443A JP2016518443A JP2016513490A JP2016513490A JP2016518443A JP 2016518443 A JP2016518443 A JP 2016518443A JP 2016513490 A JP2016513490 A JP 2016513490A JP 2016513490 A JP2016513490 A JP 2016513490A JP 2016518443 A JP2016518443 A JP 2016518443A
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- Prior art keywords
- methyl
- indole
- pyrimidin
- trifluoromethyl
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Plural Heterocyclic Compounds (AREA)
Abstract
Description
− ニトロンおよびオキシムの形成、
− ピリミジン−カルボン酸およびピリミジン−メタノールの形成、
− ピリミジン−アミド部分の形成、
− メチル−5−トリフルオロメチル−ピラゾール部分の脱メチル化、
− メチルアミノメチル−ピリミジン部分の脱メチル化。
− N−アセチル−システイン付加体の形成、
− N−アセチル化、
− 硫酸化、
− グルクロニド化
− インビトロ代謝反応およびインビボ代謝反応を介した、後述するさらなる特定の代謝物質の生成
を含む。
N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの特定の類縁体が今では同定されており、キャラクタリゼーションされてもいる。上記類縁体は、加齢性黄斑変性等の眼疾患の治療用として実現可能な新しい作用物質である。
したがって、本発明は、動物、ヒトおよび/またはインビトロ細胞アッセイにおけるN−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの代謝によって形成される、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの類縁体である、下記化合物に関する。
第1の実施形態から第70の実施形態までの同位体標識化合物は一般に、当業者に公知の慣例的な技法によって調製することもできるし、または、添付の実施例で記述された方法と同様の方法、およびこれまでに用いられた未標識試薬の代わりに適切な同位体標識試薬を用いる調製によっても調製することができる。
a)希釈剤、例えばラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロールおよび/またはグリシン;
b)滑沢剤、例えばシリカ、タルカム、ステアリン酸、ステアリン酸のマグネシウム塩もしくはカルシウム塩、および/またはポリエチレングリコールも含み、錠剤の場合にはさらに、
c)結合剤、例えばケイ酸アルミニウムマグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロール、ナトリウムカルボキシメチルセルロールおよび/またはポリビニルピロリドンも含み、望ましい場合には
d)崩壊剤、例えばデンプン、寒天、アルギン酸もしくはアルギン酸のナトリウム塩、または発泡性混合物;ならびに/または
e)吸収剤、着色料、香味料および甘味料
も含む、錠剤およびゼラチンカプセル剤である。
注射可能な特定の組成物は、等張性で水性の液剤または懸濁剤であり、坐剤は、有利には、脂肪乳剤または懸濁剤から調製される。前記組成物は、滅菌されていてもよく、ならびに/または、保存剤、安定剤、湿潤剤もしくは乳化剤、溶解促進剤、浸透圧調節用の塩および/またはバッファー等のアジュバントを含んでいてもよい。さらに、上記組成物はまた、治療用に有益な他の物質を含有していてもよい。前記組成物は、それぞれ慣例的な混合方法、顆粒化方法またはコーティング方法に従って調製され、約0.1〜75%の有効成分を含有し、または約1〜50%の有効成分を含有する。
a)線維芽細胞成長因子受容体(FGF−Rs)の活性を標的とし、低下させ、または阻害する化合物;
b)インスリン様成長因子I受容体(IGF−IR)の活性を標的とし、低下させ、または阻害する化合物、特に、IGF−IRを阻害する化合物、例としてWO02/092599で開示されている上述のような化合物;
c)Trk受容体チロシンキナーゼファミリーの活性を標的とし、低下させ、または阻害する化合物;
d)Axl受容体チロシンキナーゼファミリーの活性を標的とし、低下させ、または阻害する化合物;
e)c−Met受容体の活性を標的とし、低下させ、または阻害する化合物;
f)タンパク質キナーゼC(PKC)およびセリン/チロシンキナーゼのRafファミリーのメンバー、MEK、SRC、JAK、FAK、PDKおよびRas/MAPKファミリーメンバーのメンバー、もしくはPI(3)キナーゼファミリーのメンバー、もしくはPI(3)キナーゼ関連キナーゼファミリーのメンバー、ならびに/または、サイクリン依存性キナーゼファミリー(CDK)のメンバーの活性を標的とし、低下させ、または阻害する化合物、特にUS5,093,330で開示されている上述のようなスタウロスポリン誘導体、例えばミドスタウリン(さらなる化合物の例には、例えばUCN−01、サフィンゴール、BAY43−9006、Bryostatin1、Perifosine;Ilmofosine;RO318220およびRO320432;GO6976;Isis3521;LY333531/LY379196;WO00/09495で開示されたイソキノリン化合物等のイソキノリン化合物;FTIs;PD184352またはQAN697(P13K阻害剤)が挙げられる。);
g)タンパク質−チロシンキナーゼの活性を標的とし、低下させ、または阻害する化合物、例としてイマチニブメシル酸塩(GLIVEC/GLEEVEC)またはチルホスチン等
を含める。(チルホスチンは、好ましくは、低分子量(Mr<1500)化合物または薬学的に許容されるその塩であり、特には、ベンジリデンマロニトリルの部類またはS−アリールベンゼンマリニトリルもしくは二基質キノリン類(bisubstrate quinoline)の部類の化合物から選択される化合物であり、より特定的には、Tyrphostin A23/RG−50810;AG99;Tyrphostin AG213;Tyrphostin AG1748;Tyrphostin AG490;Tyrphostin B44;Tyrphostin B44(+)鏡像異性体;Tyrphostin AG555;AG494;Tyrphostin AG556、AG957およびアダホスチン(4−{[(2,5−ジヒドロキシフェニル)メチル]アミノ}安息香酸アダマンチルエステル;NSC680410、アダホスチン)からなる群より選択される任意の化合物である。);ならびに
h)受容体チロシンキナーゼ(ホモ二量体状態またはヘテロ二量体状態のEGF−R、ErbB2、ErbB3、ErbB4)の上皮成長因子ファミリーの活性を標的とし、低下させ、または阻害する化合物、例として上皮成長因子受容体ファミリーの活性を標的とし、低下させ、または阻害する化合物は特に、EGF受容体チロシンキナーゼファミリーのメンバー、例えばEGF受容体、ErbB2、ErbB3およびErbB4を阻害し、またはEGFもしくはEGF関連リガンドに結合する化合物、タンパク質または抗体であり、特には、WO97/02266(例えば、実施例39の化合物)で具体的に概略を開示されている、またはEP0564409、WO99/03854、EP0520722、EP0566226、EP0787722、EP0837063、US5,747,498、WO98/10767、WO97/30034、WO97/49688、WO97/38983、ならびに特にWO96/30347(例えば、CP358774として公知の化合物)、WO96/33980(例えば、化合物ZD1839)およびWO95/03283(例えば、化合物ZM105180)で具体的に概略を開示されている、上述のような化合物、タンパク質またはモノクローナル抗体であり;例えば、トラツズマブ(HERCEPTIN)、セツキシマブ、Iressa、エルロチニブ(Tarceva(商標))、CI−1033、EKB−569、GW−2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3またはE7.6.3、およびWO03/013541で開示されている7H−ピロロ−[2,3−d]ピリミジン誘導体である。
本明細書で使用されるとき、「多形」は、同じ化学組成を有するが、結晶を形成している分子、原子および/またはイオンの空間的配列が異なっている、結晶形態を指す。
本明細書で使用されるとき、ある形態に関して使用されている場合の「実質的に純粋な」とは、当該化合物の重量に基づいて、90重量%超の純度、91重量%超の純度、92重量%超の純度、93重量%超の純度、94重量%超の純度、95重量%超の純度、96重量%超の純度、97重量%超の純度、98重量%超の純度および99重量%超の純度の純度を含め、約100重量%に等しい純度も同様に含めて、90重量%超の純度のN−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドを有する、化合物を意味する。残存の材料は、化合物の他の形態、ならびに/または、化合物の調製から発生する反応不純物および/もしくは加工不純物を含む。例えば、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの結晶形態は、この結晶形態が、当技術分野において現時点で公知になっていて一般に受け入れられてもいる手段によって測定して90重量%超の純度を有するのならば、実質的に純粋と考えることができ、ここで、残存している10重量%未満の材料は、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの他の形態、ならびに/または反応不純物および/もしくは加工不純物を含む。
結晶形態は、種々の方法によって調製することができ、例えば、適切な溶媒からの結晶化または再結晶、昇華、溶融物からの成長、別の相から固相への転移、超臨界流体からの結晶化、およびジェット噴霧が挙げられる。溶媒混合物からの結晶形態の結晶化または再結晶のための技法には、例えば溶媒の蒸発、溶媒混合物の温度低下、結晶形態の分子および/または塩の過飽和溶媒混合物への結晶接種処理、溶媒混合物の凍結乾燥、ならびに溶媒混合物への逆溶剤(逆溶媒)の添加が挙げられる。処理能力の高い結晶化技法を用いて、多形を含めた結晶形態を調製してもよい。
当業者ならば、採用される測定条件に依存する測定誤差を伴ってX線回折パターンが得られ得る点については、理解されよう。特に、X線回折パターンの強度が、採用される測定条件に応じて増減し得る点については、一般に公知である。相対強度もまた、実験条件に応じて変動し得、したがって、強度の正確な桁を考慮すべきではないという点については、さらに理解すべきである。さらに、慣例的なX線回折パターンに関する回折角度の測定誤差は、典型的には約5%以下であり、こうした測定誤差の度合いは、上記回折角度につきものであるとして考慮すべきである。この結果、本発明の結晶形態が、本明細書で開示されている添付の図面中に示されたX線回折パターンと完全に同一なX線回折パターンをもたらす結晶形態に限定されない点については、理解すべきである。添付の図面中で開示されたX線回折パターンと実質的に同一のX線回折パターンを提供する、あらゆる結晶形態は、本発明の範囲に含まれる。X線回折パターンの実質的同一性を確認する能力は、当業者の範囲に含まれる。
結晶形態を試験するために使用したDSC機器は、TA Instrument(登録商標)Differential Scanning Calorimetryモデル2910、TA Instruments(登録商標)Modulated Differential Scanning Calorimetryモデル2920、またはTA Instruments(登録商標)Modulated Differential Scanning CalorimetryモデルQ1000であった。DSCセル/試料チャンバーを、100ml/minの超高純度窒素ガスによってパージした。上記機器を、高純度のインジウムによって較正した。こうした方法によって測定される試料温度の精度は、約±1℃以内であり、融解熱は、約±5%の相対誤差に収めて測定することができる。試料を、むき出しのアルミニウムDSC皿に入れて、空の基準皿に対比させて測定した。約2〜6mgの試料粉末を皿の底部に置き、軽めにたたいて潰して、皿と接触させた。試料の重量は、100分の1ミリグラムまで精密に測定して記録した。上記機器は、25℃から300℃の間の温度範囲において、1分当たり10℃で昇温するようにプログラムしておいた。
結晶形態を試験するために使用したTGA機器は、TA Instruments.RTM.High Resolution Thermogravimetric Analyzer Q500またはTA Instruments.RTM.High Resolution Thermogravimetric Analyzer 2950であった。15〜20ミリグラムの試料を、25℃から約300℃の間の温度範囲において、1分当たり10℃の加熱速度で分析した。
略語
ACN アセトニトリル
app 見掛けの
aq 水溶液
atm 雰囲気
ATP アデノシン5’−三リン酸
BOC ターシャリーブチルカルボキシ
BOP (ベンゾトリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート
br ブロード
BSA ウシ血清アルブミン
d 二重項
DBU 1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン
DCE 1,2−ジクロロエタン
dd 二重項の二重項
DCM ジクロロメタン
DIEA ジイソプロピルエチルアミン
DMAP 4,4−ジメチルアミノピリジン
DME 1,4−ジメトキシエタン
DMF N,N−ジメチルホルムアミド
DMP デス−マーチン試薬、1,1,1−トリアセトキシ−1,1−ジヒドロ−1,2−ベンゾヨードキソール−3(1H)−オン
DMSO ジメチルスルホキシド
DTT ジチオトレイトール
EDTA エチレンジアミンテトラ酢酸
ESI エレクトロスプレーイオン化
EtOAc 酢酸エチル
FCC フラッシュカラムクロマトグラフィー
g グラム
g(イタリック体) 重力加速度定数
GSH グルタチオン
h 時間
HATU 2−(1H−7−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェートメタンアミニウム
HBTU 1−[ビス(ジメチルアミノ)メチレン]−1H−ベンゾトリアゾリウムヘキサフルオロホスフェート(1−)3−オキシド
HOBt 1−ヒドロキシ−7−アザベンゾトリアゾール
HPLC 高速液体クロマトグラフィー
IR 赤外分光法
LCMS 液体クロマトグラフィー結合質量分析法
LTMP リチウム2,2’,6,6’−テトラメチルピペリジン
M モル
m 多重項
MeOH メタノール
min 分
mL ミリリットル
mmol ミリモル
MS 質量分析法
MsOH メタンスルホン酸
m/z 質量電荷比
N 標準
NADPH β−ニコチンアミドジヌクレオチドリン酸(還元済み形態)
NMR 核磁気共鳴
Pd/C パラジウム炭素
ppm パーツパーミリオン
PyBOP ベンゾトリアゾール−1−イルオキシトリピロリジノホスホニウムヘキサフルオロホスフェート
rac ラセミ
rt 室温
Rt 保持時間
s 一重項
sat 飽和
SFC 超臨界流体クロマトグラフィー
t 三重項
TBSCl tert−ブチルジメチルシリルクロリド
TFA トリフルオロ酢酸
THF テトラヒドロフラン
UDPGA ウリジン5’−ジホスホ−α−D−グルクロン酸
a) 5−(6−(ベンジルオキシメチル)ピリミジン−4−イルオキシ)−N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−1H−インドール−1−カルボキサミド
インビトロプロトコル
[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドを、雄性Sprague−Dawleyラット、ニュージーランドホワイト種雄性ウサギ、雄性カニクイザルおよびヒト(男性と女性とが混在)に由来した肝細胞を用いて、10μmol/Lの濃度で6hインキュベートした。ヒト肝臓ミクロソームを用いて、10μmol/Lの[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドのインキュベーションも同様に1h実施した。インキュベート対象物を、放射能検出を用いたHPLCによって分析した。代謝物質構造をLC−MSによってキャラクタリゼーションした。
冷凍保存肝細胞を解凍した後、生細胞を、HepatoZYME細胞培養培地(Gibco Invitrogen)中で遠心分離によって富化した。こうした富化を目的として、細胞は、37℃の温かい45mLのHepatoZYMEに添加し、室温において50gで5min遠心分離した。死細胞含有の上清を廃棄し、ペレット内の細胞をHepatoZYMEに再懸濁させた。
N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドの追加インキュベーションを、放射性標識の代謝安定性を評価するために別途実施した。インキュベーションは、先述したように実施したが、サル肝細胞には新たなバッチ(SZH)を使用した。0時間、2時間、4時間および6時間の時点において、50μLのアリコート(4つとも同一の試料)を、10mLのRialuma(Lumac、The Netherlands)が入った20mLZinsser製バイアル内にピペットで直接移した。追加の50μLのアリコート(4つとも同一の試料)を空の20mLZinsser製バイアル内にピペットで移し、このバイアル内で試料を終夜乾燥させた後、試料を10mLのRialumaと混合し、放射能測定用に60分超音波処理した。
この研究においては、表3に記載の市販ヒト肝臓ミクロソームを使用した。ロットを、供給業者による様々な酵素の活性に関してキャラクタリゼーションした(データは図示されていないが、ファイルに保持されている。)。ミクロソームを、ドライアイスによって受け止め、使用するまで−80℃で貯蔵した。
代謝物質プロファイル用のミクロソームインキュベーションを、10μmol/Lの[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミド(約50%放射性標識済み)において実施し、このとき、1つの時点を用いて調査した(60min)。インキュベーションを、0.1mol/Lのリン酸ナトリウムバッファー pH7.4の中において37℃で実施した。インキュベーションカクテル中の最終濃度はミクロソームタンパク質1mg当たりにおいて、4mmol/LのUDPGA(Sigma−Aldrich)、1mmol/Lのβ−NADPH(Sigma−Aldrich)、5mmol/LのMgCl2、および60μgのアラメチシン(Sigma−Aldrich)。上記の系を、10minインキュベートしておいた後、試験化合物を添加して、アラメチシンによる細孔形成を可能にした。代謝反応を、[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドの添加によって開始し、二倍量の氷冷したアセトニトリルの添加によって終結させた。試料は、分析まで−20℃で貯蔵した。ミクロソームの非存在下における対照インキュベーションを実施して、インキュベーション混合物中での[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドの化学的安定性を60minにわたって測定した。
試験化合物および条件
DMSO中の[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドの10mmol/Lのストック溶液を、ミクロソームインキュベーションおよび肝細胞インキュベーションのために使用した。
すべての種に対する代謝物質プロファイルは、肝細胞を用いて6hのインキュベーション時間で実施し、一方、ヒト肝臓ミクロソームに対する代謝物質プロファイルは、1hのインキュベーション時間で実施した。
肝細胞インキュベーションのために、[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドを、10μmol/Lの初期濃度において、1mL当たり約1×106個の生存肝細胞を含んだ血清不含培地(HepatoZYME)中でインキュベートした。
インキュベーション期間の終了時には、インキュベーション懸濁液のアリコート500μLを、二倍量の氷冷したアセトニトリルと混合して、酵素反応を停止させた。混合物をボルテックス混合し、次いで、タンパク質の沈殿を完了させる分析まで少なくとも4時間の間−20℃で貯蔵した。次いで、各試料を解凍し、10000gで10min遠心分離し、続いて上清S1を取り除いた。上清S1を、試料濃縮装置を用いて蒸発させ、さらなる使用まで−20℃で貯蔵した。HPLCへの注入前に、濃縮済み試料を移動相Aで希釈した。
放射能を、Liquid Scintillation Analyzer(モデルTriCarb2200CA、Packard Inst.)によって測定した。インキュベーション混合物のアリコート(50μL)を、10〜15mLのシンチレーションカクテル(Rialuma)の添加後に測定した。可溶化したペレットを、17.5mLのシンチレーションカクテル(IrgaSafe Plus、Zinsser analytic、Frankfurt、Germany)の添加後に測定した。
[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミド(10μmol/L)を用いたインキュベーション中では、ラット、ウサギ、サルおよびヒトに由来した肝細胞の生存可能性(合計細胞に対する生細胞の%)は、初期の70〜93%から6時間後には8〜42%まで低下した。生存可能性の低下率は、(ヒト≒サル)<ラット<ウサギという順番に従っていた。本化合物の非存在下における対照インキュベーションでは、6時間後に4〜21%という、いくらか低下した生存可能性が示された。
本研究において使用された[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドストック溶液を、オンライン式放射能検出を用いたHPLCによって分析した。放射化学的純度は、99.6%であった。すべての不純物の総計は、0.4%を占めていた。肝細胞または肝臓ミクロソームの非存在下における[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドの対照インキュベーションにより、インキュベーション媒体中でのインキュベーションの間における本化合物の安定性を確認した。
動物
動物ライセンス番号
No.18、Kantonales Veterinaramt Basel
種、系統、性別
ラット、Wistar(Han:WIST、アルビノ)、雄性ラット、Brown Norway(Bn/Crl、色素沈着済み)、雄
供給業者
Han:WIST:Harlan、Th Netherlands Bn/Crl:Janvier、France
水/給餌
研究の間を通して、水道水およびNAFAGペレットNo.890(Eberle NAFAG AG、Gossau、Switzerland)を自由に摂取可能
環境条件
22±2℃
試験製剤は、投与日に新たに調製した。原薬を10%N−メチルピロリドン(NMP)、70%単分散PEG200(テトラ−エチレングリコール)および20%水溶液状の0.9%NaCl溶液に溶解させた。化合物10mgに対して、1グラムのNMPを添加して化合物を溶解させ、次いで、7gのPEG200および2gの0.9%NaClを、合計で10gになるまで引き続き添加した。
投与溶液(1g/kg)を、酸素/イソフルラン(ホレン)混合物(97/3、v/v)の吸入によって麻酔したすべてのラットの大腿静脈にボーラスとして投与した。名目用量は、1mg/kgであった。
血液試料を舌下から収集した。試料収集のために、ラットを、酸素/イソフルラン(ホレン)混合物(97/3、v/v)の吸入によって麻酔した。舌下静脈を、微細針を用いて穿孔し、必要な血液をK3−EDTAバイアル内に収集した。出血は、傷に綿棒を押し当てることによって10〜15s以内に止めた。ラットは、試料収集の度に約2〜3minの間無意識状態にしておいた。
尿および糞便を、グループ2およびグループ5aの各ラットから定量的に収集した。尿をドライアイスにより収集した。糞便を室温で収集した。毎回の尿収集後、収集バイアルを3〜5mLの水ですすぎ洗いし、この水も各尿試料に添加した。各尿試料(各約0.05g)のアリコート2つを取り除き、秤量し、放射能測定用に処理した。残存の尿は、IDDによる分析まで約−80℃で貯蔵した。各糞便試料を秤量し、1%カルボキシメチルセルロール水溶液(糞便重量の約10倍)を添加し、続いて、回転ナイフ式ホモジナイザー(Polytron)を用いて均一化した。各糞便ホモジネート(それぞれ2〜3g)のアリコート3つを取り除き、秤量し、CO2捕集後の放射能測定用に処理した。残存の糞便ホモジネートは、IDDによる分析まで約−20℃で貯蔵した。
インビボCO2捕集
グループ5aに属する2匹のラット1aおよび2aを、改造した代謝ガラスケージ内で48h飼育した。捕集された合計14CO2の放射能を、エタノールアミン:メタノール(1:10)およびメタノールという2つの捕集媒体中で、試料採取計画に従って各ラットから測定した。
糞便ホモジネート入りのバイアルを、気流(2.1〜3.6mL/min)下に維持されたチャンバー内で開いた。上記気流を、それぞれエタノールアミン:メタノール(1:10)およびメタノールという捕集媒体が入っている連接した2つのフラスコの中にバブリングした。こうした媒体を放射能測定用に処理した。
生体試料(血液、血漿、尿、糞便および死骸)およびその他の試料(投与溶液、ケージ洗液、捕集溶液)のアリコートにおける放射能を、Packard Instr.製の2500TR液体シンチレーションカウンターを用いてLSCによって測定した。クエンチング補正のために、外部標準法を使用した。クエンチング補正曲線を、密封済み標準物質(Packard Instr.)によって確立した。バックグラウンド値を、各マトリックスのブランク試料を用いて、試料の各バッチについて得た。LODは、バックグラウンド値の1.8倍と規定していた。すべての放射能測定は、秤量済み試料を用いて実施した。
生体試料中の放射能含量、および代謝物質パターン用の試料調製後の放射能の回収を、液体シンチレーション計数によって次の通りに測定した:均一な試料(血漿、尿、糞便、抽出物)を、10〜20mLのIrgasafe Plus液体シンチレーションカクテル(Perkin Elmer)が入っている20mL帯電防止型ポリエチレンバイアル(Packard BioScience、Groningen、The Netherlands)内で直接測定した。不均一試料(糞便、ペレット)を、0.5〜2mLのSolvable(Perkin−Elmer)/イソプロパノール(1:1、v/v)の混合物中に可溶化した。完全な溶解の後、試料を塩酸で中和し、液体シンチレーション計数のために15〜20mLのRialuma液体シンチレーションカクテル(Zinsser Analytic Maidenhead、Berkshire、UK)と混合した。0〜48hにおける糞便プール中の放射能を、CO2捕集方法を用いて測定した。試料を、クエンチング補正用の外部標準比の方法を用いて、LSCカウンターモデルTri−Carb(Packard Instruments、Meriden、CT、USA)内で14C放射能について評価した。
代謝物質パターン分析のために、血漿プール(1つの時点および1匹のラット毎に3μLから15μLまでの範囲になっている、同一の体積)を、i.v.投与後にある後続の時点(0.083h、0.5h、1h、4h、8hおよび24h)(n=4/試料採取)用に調製した。血漿試料を、放射能検出を用いたHPLC分析に直接使用した。HPLCへの注入前に、参照用化合物と230μL溶媒Aとを含有する20μLの混合物を添加した。放射能のHPLC回収を、0.5hおよび8hの血漿プール(n=4)を用いた代表的な別個の試行によって、測定した。回収は、それぞれ93.4%から106.2%の間の範囲であった。したがって、放射能の回収は、完全であることが示された。
LC設備
バイナリー型キャピラリーポンプモデルG1376A、脱気装置モデルG1379A、および、標準的な13μLフローセルモデルG1315−60012付きのUV/VISダイオードアレイ検出器モデルG1315Bを備え付けた、HPLCシステムモデル1100(Agilent Technologies)。UVスペクトルは、200〜800nmの範囲で監視した。HPLCシステム用の処理ソフトウェアは、LC3D、Rev.B.04.02用のAgilent ChemStationであった。
ACE3 C18 Guard Cartridge、内径15mm×4.6mm、Art.ACE−111−0103GD(ACT、Aberdeen、Scotland)。
分析カラム
ACE3 C18、3μm、内径150mm×4.6mm、Art.ACE−111〜1546(ACT)
カラム条件
カラムチラーモデル7955(Jones Chromatography Ltd.、Hengoed、Mid.Glamorgan、U.K.)内にある40℃のサーモスタット
注入量
最大250μLの量を、HTS PALオートサンプラー(CTC、Zwingen、Switzerland)を用いて500μL試料ループに注入した。
クロマトグラフィー後、流出物を約1:20の比に分割した。少ない方の量は、エレクトロスプレーLC−MSインターフェース内に誘導した。多い方の部分は、UV検出用に使用し、続いてオンライン式放射能検出用にも使用した。
フローセルモデルZ−500−5(Berthold Technologies)を備え付けたHPLC放射能モニターモデルLB513を使用した。このようにして、流出物を、3mL/minの流量で、Rialuma液体シンチレーション混合物(Perkin Elmer)と混合した。クロマトグラムを、RadioStarソフトウェア(Berthold)を用いて評価した。
移動相
A: 10mMギ酸アンモニウム+ギ酸1mL/L;pH=3.58
B: アセトニトリル+ギ酸1mL/L
流量
1000μL/min
グラジエント
0〜5min:10%B;5〜50min:10〜60%B;50〜55min:60〜100%B;55〜60min:100%B
MS設備
MassLynxバージョン4.1により動作する飛行時間(PremierのQ−T)式質量分析装置(Waters、Manchester、UK)。
コーン電圧
30V
コリジョンエネルギー
コリジョンセル内の分子のフラグメント化のために、15〜35eVのコリジョンエネルギーを適用した
脱溶媒ガス
窒素
イオン化モード
陽イオンモードのエレクトロスプレー、Zスプレーインターフェースには、LockSpray(商標)を選択肢として用いてもよい。
精密質量測定
LockSprayインターフェースの参照チャンネルは、5μL/minの流量において、50/50/0.1(v/v/v)のアセトニトリル/水/ギ酸の混合物中のロイシン−エンケファリン(200pg/μL)の溶液によって動作する。参照チャンネルからのデータ取得中、コーン電圧を40Vに設定し、コリジョンエネルギーを5eVに設定した。
温度
ソースブロック:100℃;脱溶媒:200℃
[14C]N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドのエレクトロスプレー質量スペクトルでは、プロトン化済み無欠失分子イオンM+H+(m/z446)、および、鍵となる2つの主要なフラグメントイオンA(m/z255)およびフラグメントイオンB(m/z212)が示された。それほどではないが、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミドは、エーテルのところでフラグメント化して、フラグメントC(m/z122)をもたらす。他のフラグメントは、構造への割り当てへの有用性が劣っている。顕著な標識度(約50%)のために、14C標識を含むフラグメントイオンを質量スペクトルにより観察できたが、提案の構造と合致していた。
メカニカルスターラー、窒素導入アダプター、温度計、滴下漏斗および冷却浴を備え付けた5L4ツ口丸底フラスコ内に、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミド(76.8g、172.4mmol)およびエタノール(1.5L)を入れた。白色スラリーを20℃で30min撹拌し、1N(157ml、157mmol)のHClを迅速に添加した(pH=5)。さらなる量のHClを添加して(2g)、pHを4に低下させた。得られた白色懸濁液を23で2h撹拌し、MTBE(1.5L)で希釈した。二相混合物を0〜5℃に冷却し、この温度で3h撹拌した。固体を吸引ろ過によって単離し、冷たいMTBE(2×30mL)で洗浄し、真空オーブン内において55〜60℃で乾燥させると、N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−(6−((メチルアミノ)メチル)ピリミジン−4−イルオキシ)−1H−インドール−1−カルボキサミド塩酸塩(66.9g、81%)がタン色固体として生じた。
N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドのHCl塩の結晶形態Bを、上記実施例5と同じ手順を用いて入手した。形態Bは、形態Aに再び転化することになる一時的な形態である。
結晶性N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミドの単結晶型多形が、このようにして確認され、形態Aと同定された。多形は、P1スペース基を有する三斜晶型結晶である。形態Aが、蒸発方法によってメタノール、THF、アセトン、エタノール、アセトニトリル、塩化メチレンの溶液から結晶化すると、1mg/mLの濃度で多形Aが生じた。結晶性N−(1−メチル−5−(トリフルオロメチル)−1H−ピラゾール−3−イル)−5−((6−((メチルアミノ)メチル)ピリミジン−4−イル)オキシ)−1H−インドール−1−カルボキサミド多形Aもまた、>5mg/mLの濃度になっている結晶16を利用して、上記に列記されたすべての上記溶媒中において、加熱/冷却サイクル処理によって調製した。
一般的なアッセイ設定を、液体取り扱い用ロボットにより室温で運転した。50nLの化合物または対照溶液が入ったアッセイプレートに、4.5μLのATP混合物(20mM Tris−HCl pH7.4、1mMのDTT、0.025% Tween20、0.01mM Na3VO4、10mM MgCl2、1mM MnCl2および4μM ATP)を1ウェル毎に添加した。続いて、4.5μLの酵素−基質混合物(20mM Tris−HCl pH7.4、1mM DTT、0.025% Tween20、0.01mM Na3VO4、10mM MgCl2、1mM MnCl2、0.5%BSA、100nM フルオレセイン標識ポリ(EAY)および0.76nM KDR(GST−KDR(807−1356)、内部で生成された組み換えタンパク質)を添加した。
Claims (9)
- 請求項1または2に記載の代謝物質またはその塩、および少なくとも1種の薬学的に許容される賦形剤を含む、医薬製剤。
- 患者の眼内血管新生性疾患を治療する方法であって、請求項1または2に記載の代謝物質またはその塩を、療法を必要としている前記患者に投与するステップを含む方法。
- タンパク質キナーゼ、特にタンパク質チロシンキナーゼに媒介される対象の疾患または障害、より特定的にはVEGF−R受容体依存性疾患の治療のための、請求項1または2のいずれか一項に記載の代謝物質またはその塩の使用。
- タンパク質キナーゼ、特にタンパク質チロシンキナーゼ、さらに特にVEGF−R受容体の異常活性を特徴とする、対象の障害または疾患の治療のための、請求項1または2のいずれか一項に記載の代謝物質の使用。
- 対象のVEGF−R活性を阻害する方法であって、治療有効量の請求項1または2のいずれか一項に記載の代謝物質を前記対象に投与することを含む方法。
- VEGF−Rに媒介される対象の障害または疾患を治療する方法であって、治療有効量の請求項1または2のいずれか一項に記載の代謝物質を前記対象に投与することを含む方法。
- 前記疾患が、AMDまたは糖尿病網膜症である、請求項8に記載の方法。
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- 2014-05-14 US US14/277,313 patent/US20150018376A1/en not_active Abandoned
- 2014-05-16 BR BR112015028551A patent/BR112015028551A2/pt not_active IP Right Cessation
- 2014-05-16 CN CN201480040394.1A patent/CN105452241B/zh not_active Expired - Fee Related
- 2014-05-16 ES ES14728655T patent/ES2699776T3/es active Active
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- 2014-05-16 JP JP2016513490A patent/JP2016518443A/ja active Pending
- 2014-05-16 EA EA201592190A patent/EA201592190A1/ru unknown
- 2014-05-16 US US14/891,674 patent/US9604969B2/en not_active Expired - Fee Related
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- 2014-05-16 WO PCT/IB2014/061484 patent/WO2014184778A1/en active Application Filing
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AU2014266867A1 (en) | 2015-12-03 |
US9604969B2 (en) | 2017-03-28 |
KR20160010522A (ko) | 2016-01-27 |
US20150018376A1 (en) | 2015-01-15 |
AR096322A1 (es) | 2015-12-23 |
CA2912130A1 (en) | 2014-11-20 |
MX2015015845A (es) | 2016-06-29 |
CN105452241A (zh) | 2016-03-30 |
BR112015028551A2 (pt) | 2017-07-25 |
AU2014266867B2 (en) | 2017-07-13 |
EP2997022B1 (en) | 2018-08-29 |
US20160115156A1 (en) | 2016-04-28 |
EP2997022A1 (en) | 2016-03-23 |
ES2699776T3 (es) | 2019-02-12 |
CN105452241B (zh) | 2018-01-05 |
WO2014184778A1 (en) | 2014-11-20 |
EA201592190A1 (ru) | 2016-04-29 |
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