JP2021528383A - Axl阻害剤として使用するためのピリドピリミジノン誘導体 - Google Patents
Axl阻害剤として使用するためのピリドピリミジノン誘導体 Download PDFInfo
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- JP2021528383A JP2021528383A JP2020567743A JP2020567743A JP2021528383A JP 2021528383 A JP2021528383 A JP 2021528383A JP 2020567743 A JP2020567743 A JP 2020567743A JP 2020567743 A JP2020567743 A JP 2020567743A JP 2021528383 A JP2021528383 A JP 2021528383A
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Images
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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Abstract
【選択図】 図1a
Description
(式中、
R1は、1つ又は2つのR3で任意選択で置換されている、C6〜C10アリール、C6〜C10アリールC1〜C6アルキル、C5〜C6シクロアルキル又はC5〜C6シクロアルキルメチルであり、
R3は、独立的に、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、又はトリフルオロメチルであり、
Xは、H、フルオロ、クロロ、ブロモ、ヨード、メチル、又はトリフルオロエチルであり、
Yは、クロロ、ブロモ、ヨード、C1〜C3アルキル、又はフェニルであり、
R2は、C3〜C6シクロアルキル又は4〜7員ヘテロシクロアルキルであり、該C3〜C6シクロアルキルは、炭素原子において1つ又は2つのR4で任意選択で置換されており、該4〜7員ヘテロシクロアルキルは、窒素、酸素、硫黄、スルホン及びスルホキシドからなる群から選択される1個又は2個のヘテロ原子を有し、炭素原子においてR4で又は窒素原子においてR5で任意選択で置換されており、
R4は、独立的に、ヒドロキシ、ヒドロキシC1〜C6アルキル、アミノ、アミノC1〜C6アルキル、−NH(−C1〜C3アルキル)、−N(−C1〜C3アルキル)2、C1〜C3アルキル又はハロであり、
R5は、H、C1〜C3アルキル又は−C(=O)(−C1〜C3アルキル)であり、該C1〜C3アルキルは、1〜3つのフルオロで任意選択で置換されている)
を提供する。
上に定義された式(I)の化合物又はその薬学的に許容できる塩、及び該化合物又は塩を含む医薬組成物は、Axl受容体チロシンキナーゼを阻害し、Axlによって媒介される疾患又は状態、例えば、細胞増殖性疾患、例えば複数の型のがん及び転移の処置に有用である。
(式中、
R1は、1つ又は2つのR3で任意選択で置換されている、C6〜C10アリール、C6〜C10アリールC1〜C6アルキル、C5〜C6シクロアルキル又はC5〜C6シクロアルキルメチルであり、
R3は、独立的に、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、又はトリフルオロメチルであり、
Xは、H、フルオロ、クロロ、ブロモ、ヨード、メチル、又はトリフルオロエチルであり、
Yは、クロロ、ブロモ、ヨード、C1〜C3アルキル、又はフェニルであり、
R2は、C3〜C6シクロアルキル又は4〜7員ヘテロシクロアルキルであり、該C3〜C6シクロアルキルは、炭素原子において1つ又は2つのR4で任意選択で置換されており、該4〜7員ヘテロシクロアルキルは、窒素、酸素、硫黄、スルホン、又はスルホキシドからなる群から選択される1個又は2個のヘテロ原子を有し、炭素原子においてR4で又は窒素原子においてR5で任意選択で置換されており、
R4は、独立的に、ヒドロキシ、ヒドロキシC1〜C6アルキル、アミノ、アミノC1〜C6アルキル、−NH(−C1〜C3アルキル)、−N(−C1〜C3アルキル)2、C1〜C3アルキル又はハロであり、
R5は、H、C1〜C3アルキル又は−C(=O)(−C1〜C3アルキル)であり、該C1〜C3アルキルは、1〜3つのフルオロで任意選択で置換されている)
を提供する。
(a)式(I)の化合物を薬学的に許容できる塩へと任意選択で変換すること、
(b)式(I)の化合物の塩形態を非塩形態に任意選択で変換すること、
(c)式(I)の化合物の非酸化形態を薬学的に許容できるN−オキシドへと任意選択で変換すること、
(d)式(I)の化合物の個々の異性体を異性体の混合物から任意選択で分割すること、
(e)式(I)の非誘導体化化合物を薬学的に許容できるプロドラッグ誘導体へと任意選択で変換すること、及び
(f)式(I)の化合物のプロドラッグ誘導体を非誘導体化形態に任意選択で変換すること。
1.試料を、室温で流速1.5mL/分で実行するZorbax Eclipse XDB−C18(3.5μm)逆相カラム(4.6×50mm)を備えたAgilent Technologies 6120 MSDシステムにかける。
2.移動相は、溶媒A(水/0.1%ギ酸)及び溶媒B(アセトニトリル/0.1%ギ酸):95%/5%〜0%/100%(A/B)を5分間使用する。
3.質量スペクトル(m/z)を、エレクトロスプレーイオン化(ESI)を使用して記録した。
4.イオン化データを最も近い整数に丸めた。
221. 4−((4−(ベンジルオキシ)フェニル)アミノ)−8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
222. 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−フェノキシフェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
223. 8−ブロモ−4−((4−(シクロペンチルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
224. 8−ブロモ−4−((4−(シクロヘキシルメトキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
225. 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−(p−トリルオキシ)フェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
226. 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−フェノキシフェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
227. 8−ブロモ−4−((4−(シクロペンチルメトキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
228. 8−ブロモ−4−((4−(シクロヘキシルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
229. 8−クロロ−4−((4−(シクロヘキシルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
230. 8−ブロモ−4−((4−(4−イソプロピルフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
231. 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−(p−トリルオキシ)フェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
232. 8−ブロモ−4−((4−(4−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
233. 8−ブロモ−4−((4−(シクロヘキシルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
234. 4−((4−(ベンジルオキシ)フェニル)アミノ)−8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
235. 8−ブロモ−4−((4−(シクロペンチルメトキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
236. 8−ブロモ−4−((4−(4−イソプロピルフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
237. 8−ブロモ−4−((4−(シクロペンチルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
238. 8−ブロモ−4−((4−(3−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
239. 8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−(o−トリルオキシ)フェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
240. 8−ブロモ−4−((4−(3−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
241. 8−ブロモ−4−((4−(3,4−ジフルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
242. 8−ブロモ−4−((4−(4−クロロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
243. 8−ブロモ−4−((4−(3,5−ジフルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
244. 8−ブロモ−4−((4−(3−フルオロフェノキシ)−3−メチルフェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
245. 8−ブロモ−4−((3−フルオロ−4−フェノキシフェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
246. 8−ブロモ−4−((3−メチル−4−フェノキシフェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
247. 8−ブロモ−4−((3−フルオロ−4−(3−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩、
248. 8−ブロモ−2−(1−イソプロピルピペリジン−4−イルアミノ)−4−(4−フェノキシフェニルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、
249. 8−ブロモ−2−(1−エチルピペリジン−4−イルアミノ)−4−(4−フェノキシフェニルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン、及び
250. 8−ブロモ−4−(4−フェノキシフェニルアミノ)−2−(1−(2,2,2−トリフルオロエチル)ピペリジン−4−イルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン。
すべてのデータは、IC50値(Axl)の範囲で掲載されている。
各++++、+++、++及び+は、それぞれ、1〜10nM、11〜100nM、101〜1000nM、1001〜10000nMを示した。
上で得られた式(I)の化合物を、Axlキナーゼを阻害する能力を測定するためにアッセイした。Axlは、最近同定されたTYRO−3、Axl、MERTK(TAM)受容体チロシンキナーゼ(RTK)ファミリーに属する。成長停止特異的6(GAS6)タンパク質は、各TAMキナーゼに対する共通のリガンドとして働き、Axlに対して最も高い親和性を示す。GAS6が結合すると、Axlは、ホモ二量体化し、その後、細胞の増殖、遊走、浸潤、抗アポートシス、血管新生、転移、及び治療耐性に関与するいくつかの下流のシグナル伝達経路を誘発する。多種多様ながん細胞株及びとりわけ、乳がん、急性白血病、結腸直腸がん、肺がん、黒色腫、卵巣がん、又は前立腺がんを有する患者からのがん標本において、Axlの上方調節が報告されている。
上で得られた式(I)の化合物を、最初に、貯蔵のために100%DMSO(カルビオケム(CALBIOCHEM)(商標))で10mMに希釈し、キナーゼバッファー溶液として、1uM〜10uMの範囲の化合物濃度を生成した。化合物の連続希釈物を、96ウェルプレート(グライナーバイオサイエンス(GREINER BIOSCIENCES)(商標))に各6μLで分注した。切断されたヒトAxl(カルナバイオサイエンス(CARNA BIOSCIENCES)(商標))をキナーゼバッファーで希釈し、化合物溶液に添加し、室温で30分間プレインキュベートした。次に、ATP(テクノバ(TEKNOVA)(商標))及び基質溶液(パーキンエルマー(PerkinElmer)(商標)の提案された製造基質、例えば、Axlに対するユーライト(Ulight)(商標)−TKペプチド(パーキンエルマー(商標)))を化合物溶液及び酵素を含有するウェルに添加した(各12μL)。反応混合物を1時間インキュベートした。インキュベート後に、EDTA、水、及びLance検出バッファー(パーキンエルマー(商標))により作製された停止溶液を添加して(各12μL)、リン酸化を停止させた。停止溶液の添加及び5分の振盪後に、ユウロピウム標識抗体(パーキンエルマー(商標)の提案された製造基質、例えば、Axlに対するPT66)、水、及びLance検出バッファーを含有する検出溶液を反応混合物に添加し(12μL)、50分間再度インキュベートした。基質リン酸化は、検出溶液の添加及び50分のインキュベート後に測定された665nm発光の関数であった。
式(I)の化合物は、有用な薬理学的特性を示した。本明細書で使用される場合、阻害活性の効力(nM)を記載する方法は、表2に示す50%の阻害活性(IC50)の範囲である。参照化合物であるASP2215(ギルテリチニブ、Astellas)、R428(BGB324、BerGenBio)及びスタウロスポリン(汎キナーゼ阻害剤)をAxlに対して使用して、式(I)の化合物の阻害活性を判断した。
上で得られた式(I)の化合物を、Axl保有トリプルネガティブ乳がん細胞株(MDA−MB−231及びHs578T)及びAxl陰性乳がん細胞株(MCF7)の増殖の阻害に関する効果について試験した。Axlは、受容体チロシンキナーゼのTAM(TYRO3−Axl−MER)ファミリーのメンバーであり、活性化されると、腫瘍細胞の生存、増殖、遊走及び浸潤、血管新生、並びに腫瘍−宿主相互作用を増加させ得る。GAS6がAxlに結合すると、その後、Axlは、下流のシグナル伝達経路、例えばホスホイノシチド3キナーゼ(PI3K)、ラット肉腫(RAS)、及び細胞外シグナル調節キナーゼ(ERK)を活性化する。
上で得られた式(I)の化合物を、MDA−MB−231及びHs578T細胞に対する細胞生存性効果について試験した。細胞生存性アッセイのために、ヒトAxlを発現しているMDA−MB−231及びHs578T細胞をAmerican Type Culture Collection(ATCC、Manassas、VA)から入手した。MDA−MB−231及びHs578T細胞株を、鉄を補充した10%ウシ胎仔血清(BCS;ハイクローン(Hyclone)(商標))を含有するロズウェルパーク記念研究所(RPMI)培地(ハイクローン(HyClone)(商標))で維持した。細胞を96ウェル培養プレート中に細胞2×104個で播種し、次いで、連続希釈された化合物を添加した。37℃で72時間のインキュベート期間の後に、細胞生存性を、生細胞からのATPの定量化に基づくATPLite 1stepアッセイ(パーキンエルマー(商標))を使用して測定した。細胞増殖の最大阻害の50%のための濃度(GI50値)を、非線形回帰を使用して計算し、無処置対照細胞に対する処置細胞のルミネッセンス又は吸光度の50%低減に必要とされる濃度として定義した(プリズム(Prism)(商標)ソフトウェア)。
式(I)の代表的化合物のGI50阻害データを表3に示す。式(I)の化合物は、3μM未満のGI50値で細胞増殖の阻害を示した。特に、化合物237、8−ブロモ−4−((4−(シクロペンチルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩は、Axl保有乳がん細胞株において、参照化合物ASP2215及びR428が示す阻害レベルよりも大きい阻害レベルを示した。かかる強い抗腫瘍活性は、式(I)の化合物が、参照化合物及び先行技術(PCT出願番号国際出願PCT/US2010/054853)に記載されたアスタリスクによって示す化合物203よりも良好な治療的価値を有することを示唆している。
式(I)の化合物が転移の阻害に関する効果を示すか否かを試験するために、細胞の遊走及び浸潤挙動を、MDA−MB−231乳がん細胞株においてトランスウェル及びマトリゲル浸潤アッセイを使用して分析した。
上で得られた式(I)の化合物を、MDA−MB−231乳がん細胞株を使用して遊走及び浸潤アッセイにおいて試験した。細胞遊走は、トランスウェルアッセイ(BD Biosciences、CA、米国)によって実行した。簡潔には、無血清RPMI−1640中の細胞5×104個を、24ウェルプレートのウェルに挿入されたメンブレン(孔径8.0μm)に播種した。10%FBSを含有するRPMI−1640を各ウェルの下部チャンバーに添加した。24時間後に、上部チャンバー中の細胞を綿棒によって除去し、メンブレンの下側に達した細胞をクリスタルバイオレット(メチルアルコール中1%)で10分間固定し、染色した。フィルターの下側にある細胞(5フィールド/フィルター)を計数した。細胞浸潤アッセイは、細胞をメンブレンに播種する6時間前にマトリゲル(BD Biosciences、CA、米国)を各ウェルに添加したことを除き、同様に実施した。48時間後に、マトリゲル及び上部チャンバー中の残存する細胞を綿棒によって除去した。メンブレンの下面の細胞を上記のとおり固定し、染色した。化合物238及び参照化合物であるR428を、図1a〜1cに示すとおりにインキュベートした。データは、染色されたメンブレンの3つの独立したフィールドからの結果を代表するものである。
図1a〜1cに示すとおり、式(I)の代表的化合物238は、MDA−MB−231細胞の遊走及び浸潤能の低下を示し、参照化合物であるR428よりも優れている。興味深いことに、式(I)の代表的化合物238は、R428と比較して、0.03μMでも遊走及び浸潤を有意に阻害した。これらの結果は、MDA−MB−231細胞を使用して代表的化合物が非常に強力な抗転移活性を有することを示唆している。さらに、上で得られた式(I)の化合物は、例えば乳がんにおける侵襲性のAxl発現に関連する転移の治療選択肢を与える。
乳房4T1同系in vivoがんモデルにおいて式(I)の化合物が抗腫瘍活性を示すか否かを試験するために、式(I)の化合物を以下のとおり試験した。
上で得られた式(I)の化合物を、マウス乳房4T1がん細胞を使用して同系モデルにおいて試験した。4T1細胞を、10%FBS(Invitrogen、カタログ番号10438−026)、及び1%ペニシリンストレプトマイシン(Thermo Fisher Scientific、カタログ番号15140−122)を補充したRPMI1640培地(Sigma、カタログ番号R6504)中で成長させた。細胞を、70〜80%コンフルエンスに達した時点で、トリプシン処理によって収穫した。細胞接種の1日前に、BALB/Cマウスの右脇腹の体毛を、ヘアトリマーを使用して除毛した。翌日に、注射部位周辺の皮膚領域を、消毒用アルコールで穏やかに拭くことによって消毒した。同種移植片を確立するために、細胞を無血清培地に懸濁し、マトリゲルと1:1で混合して、細胞1×106個/100μLを得た。マトリゲルに懸濁した細胞を、24ゲージ針(BD Precision Glide針、0.55mm×25mm、参照番号302805)に取り付けた1mL BDシリンジを使用して皮下移植した。マウスを腫瘍体積に基づいてランダム化し、1群当たり6匹のマウスを割り当てた。腫瘍移植片を、細胞接種の概ね5日後に、触知可能になった時点で測定した。動物にビヒクル対照又は化合物238(QD、30mg/kg/日)を1日1回14日間経口投与した。経口投与のためのビヒクルは、50mMクエン酸バッファー(pH3.0)中の10%スルホブチルエーテルβ−シクロデキストリンナトリウム(SBECD)からなる。腫瘍成長阻害(TGI)を以下のとおり計算した:%TGI=[1−(処置TV最終−処置TV初期)/(対照TV最終−対照TV初期)]*100
本研究の目的は、乳房4T1同系腫瘍モデルにおける化合物238単独の抗腫瘍効能を試験することであった。すべての処置は、ビヒクル対照と比較して、異常の臨床徴候及び動物体重の有意な変化が存在しなかったことから、忍容性が良好であった。15日目に、処置群番号2(化合物238)の平均腫瘍体積は、669±60mm3であり、59%の腫瘍成長阻害(TGI)を生じた(図2aを参照)。全体として、これらの結果は、BALB/Cマウスにおける免疫応答性4T1同系腫瘍モデルにおいて化合物238が良好な抗腫瘍活性を示すことを示唆している。
興味深いことに、免疫不全マウスにおいては30mg/kg/日の化合物238の抗腫瘍効果は存在せず(図2bを参照)、化合物238が免疫応答を直接増加させることによって腫瘍成長を抑制できることを示している。
B16F10肺及びCT−26腹膜転移モデルにおいて式(I)の化合物が抗がん転移活性を示すか否かを試験するために、式(I)の化合物を以下のとおり試験した。
上で得られた式(I)の化合物を、マウスB16F10黒色腫及びCT26−ルシフェラーゼ結腸がん細胞を使用して転移モデルにおいて試験した。両方の細胞を、10%FBS(Invitrogen、カタログ番号10438−026)、及び1%ペニシリンストレプトマイシン(Thermo Fisher Scientific、カタログ番号15140−122)を補充したRPMI1640培地(Sigma、カタログ番号R6504)中で成長させた。70〜80%コンフルエンスに達した時点で、トリプシン処理によって細胞株を収穫した。細胞接種の1日前に、C57BL/6マウスをSPF基準に従う無病原体条件(室温、湿度40〜60%)下で維持し、延世大学校のABMRCに収容した。転移を確立するために、B16F10細胞(細胞1×106個/マウス、n=3/群)を無血清培地に懸濁し、24ゲージ針(BD Precision Glide針、0.55mm×25mm、参照番号302805)に取り付けた1mL BDシリンジを使用して尾静脈に静脈内注射した。CT−26−ルシフェラーゼ細胞(細胞1×104個/マウス、n=5/群)を、30mg/kg/日の化合物226の24時間の前処置後に、腹腔内に植え付けた。
本研究の目的は、B16F10肺及びCT−26腹膜転移モデルに対する化合物226の予防効果を評価することであった。化合物226の処置は、ビヒクル対照と比較して、異常の臨床徴候が存在しなかったことから、忍容性が良好であった。CT26転移モデルにおいて、9日目に、ビヒクル群におけるマウス2匹が死亡しているのが発見された。B16F10転移モデルにおいて、経口の30mg/kg/日の化合物226は、すべての肉眼的肺標本における黒色区域として示される肺転移を劇的に阻害し、腫瘍結節は存在しなかった(図3a〜3cを参照)。CT−26腹膜転移モデルにおいて、化合物226の処置は、腹腔におけるルミネッセンス強度を大幅に低減した。加えて、ビヒクル群におけるマウスは、CT26−ルシフェラーゼ細胞植付け後9日目から死亡し始めたのに対し、化合物226(QD、30mg/kg/日)で処置されたマウスは、処置期間の間生存していた(図4a及び4bを参照)。したがって、これらの結果は、式(I)の化合物226がAxl陽性がん患者における転移を予防する治療的可能性を有することを示唆している。
4T1自然転移モデルにおいて式(I)の化合物がマウス抗PD−1抗体との組合せ効果を示すか否かを試験するために、式(I)の化合物を以下のとおり試験した。
上で得られた式(I)の化合物を、マウス4T1乳がん細胞を使用して自然転移モデルにおいて試験した。4T1細胞を、10%FBS(Invitrogen、カタログ番号10438−026)、及び1%ペニシリンストレプトマイシン(Thermo Fisher Scientific、カタログ番号15140−122)を補充したRPMI1640培地(Sigma、カタログ番号R6504)中で成長させた。70〜80%コンフルエンスに達した時点で、トリプシン処理によって細胞株を収穫した。細胞接種の1日前に、BALB/Cマウスの右脇腹の体毛を、ヘアトリマーを使用して除毛した。翌日に、注射部位周辺の皮膚領域を、消毒用アルコールで穏やかに拭くことによって消毒した。同種移植片を確立するために、BALB/c雌マウス(7週齢)に、5×106個の同系4T1細胞を乳腺内に同所移植した。平均腫瘍体積が1500mm3に達した時点でマウスを屠殺した。
BALB/c雌マウス(7週齢)に、5×106個の同系4T1細胞を乳腺内に同所移植した。腫瘍が概ね50mm3のサイズに達した時点で、マウスをビヒクル、抗PD−1抗体(100mg 2回/週)、式(I)の化合物226(30mg/kg/日)又は式(I)の化合物226及び抗PD−1抗体の組合せのいずれかで4週間処置した。マウスを28日目に屠殺し、結節を計数することによって、肺転移を評価した。肺への転移は、化合物226単独によって有意に減少し、抗PD1抗体と化合物226との組合せは、化合物226処置単独と比較して、腫瘍結節のより高度な低減を増強した(図5a〜5cを参照)。抗PD−1抗体で処置された群は、肺転移に対して顕著な効能を示さなかった。化合物226は、総転移性負荷及びより大型の転移の数(中型+大型転移、直径≧5mm;図5cを参照)の両方を有意に抑制した。原発部位での腫瘍成長に関して、化合物226単独及び組合せ群は、群間で効能差が存在しない腫瘍成長の阻害を示しており、組合せ効果が転移性腫瘍に対して働き、原発腫瘍に対しては働かないことを示唆している(図6を参照)。まとめると、これらの結果は、式(I)の化合物226が転移処置における免疫腫瘍学用途のために高い可能性を示すことを示唆している。
Claims (15)
- Axlによって媒介される疾患又は状態の処置のためのAxl阻害剤としての、式(I)によって表される化合物又はその薬学的に許容できる塩の使用:
(式中、
R1は、1つ又は2つのR3で任意選択で置換されている、C6〜C10アリール、C6〜C10アリールC1〜C6アルキル、C5〜C6シクロアルキル又はC5〜C6シクロアルキルメチルであり、
R3は、独立的に、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、又はトリフルオロメチルであり、
Xは、H、フルオロ、クロロ、ブロモ、ヨード、メチル、又はトリフルオロエチルであり、
Yは、クロロ、ブロモ、ヨード、C1〜C3アルキル、又はフェニルであり、
R2は、C3〜C6シクロアルキル又は4〜7員ヘテロシクロアルキルであり、前記C3〜C6シクロアルキルは、炭素原子において1つ又は2つのR4で任意選択で置換されており、前記4〜7員ヘテロシクロアルキルは、窒素、酸素、硫黄、スルホン及びスルホキシドからなる群から選択される1個又は2個のヘテロ原子を有し、炭素原子においてR4で又は窒素原子においてR5で任意選択で置換されており、
R4は、独立的に、ヒドロキシ、ヒドロキシC1〜C6アルキル、アミノ、アミノC1〜C6アルキル、−NH(−C1〜C3アルキル)、−N(−C1〜C3アルキル)2、C1〜C3アルキル又はハロであり、
R5は、H、C1〜C3アルキル又は−C(=O)(−C1〜C3アルキル)であり、前記C1〜C3アルキルは、1〜3つのフルオロで任意選択で置換されている)。 - R1が、1つ又は2つのR3で任意選択で置換されている、フェニル、ベンジル、シクロペンチル、シクロヘキシル、シクロペンチルメチル、又はシクロヘキシルメチルであり、R3が、独立的に、フルオロ、クロロ、ブロモ、ヨード、C1〜C6アルキル、又はトリフルオロメチルである、請求項1に記載の使用。
- R2が、窒素原子においてR5で置換されているピペリジニル又はピロリジニルであり、R5が、H、C1〜C3アルキル又は−C(=O)(−C1〜C3アルキル)である、請求項1に記載の使用。
- R5が、メチル、エチル、トリフルオロエチル、又はi−プロピルである、請求項1に記載の使用。
- R3が、独立的に、クロロ又はフルオロである、請求項1に記載の使用。
- Yが、ブロモである、請求項1に記載の使用。
- Xが、フルオロ又はメチルである、請求項1に記載の使用。
- 前記式(I)の化合物又はその薬学的に許容できる塩が、8−ブロモ−2−((1−メチルピペリジン−4−イル)アミノ)−4−((4−フェノキシフェニル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩である、請求項1に記載の使用。
- 前記式(I)の化合物又はその薬学的に許容できる塩が、8−ブロモ−4−((4−(シクロペンチルオキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩;又は8−ブロモ−4−((4−(3−フルオロフェノキシ)フェニル)アミノ)−2−((1−メチルピペリジン−4−イル)アミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン塩酸塩である、請求項1に記載の使用。
- 前記式(I)の化合物が、その立体異性体を含む、請求項1に記載の使用。
- Axlによって媒介される疾患又は状態の処置のための医薬を調製するための、請求項1に記載の式(I)の化合物又はその薬学的に許容できる塩の使用。
- 前記疾患又は状態が、Axlによって媒介される複数の型のがんである、請求項1又は11に記載の使用。
- 前記疾患又は状態が、急性リンパ芽球性白血病、急性骨髄白血病、副腎皮質癌、エイズ関連がん、エイズ関連リンパ腫、肛門がん、虫垂がん、星細胞腫、非定型奇形腫様/ラブドイド腫瘍、基底細胞癌、胆管がん、膀胱がん、骨がん、骨肉腫及び悪性線維性組織球腫、脳幹神経膠腫、脳腫瘍、中枢神経系非定型奇形腫様/ラブドイド腫瘍、星細胞腫、頭蓋咽頭腫、上衣芽腫、上衣腫、髄芽腫、髄上皮腫、中間分化型松果体実質腫瘍、テント上原始神経外胚葉性腫瘍及び松果体芽細胞腫、脳及び脊髄腫瘍、乳がん、気管支腫瘍、バーキットリンパ腫、カルチノイド腫瘍、消化管がん、中枢神経系リンパ腫、子宮頸がん、脊索腫、慢性リンパ性白血病、慢性骨髄性白血病、慢性骨髄増殖性障害、結腸がん、結腸直腸がん、頭蓋咽頭腫、皮膚T細胞リンパ腫、菌状息肉症、セザリー症候群、子宮内膜がん、上衣芽腫、上衣腫、食道がん、感覚神経芽腫、ユーイング肉腫ファミリー腫瘍、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、肝外胆管がん、眼球内黒色腫、網膜芽細胞腫、胆嚢がん、胃のがん、消化管カルチノイド腫瘍、消化管間質腫瘍、消化管間質細胞腫瘍、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、卵巣胚細胞腫瘍、妊娠性絨毛性腫瘍、神経膠腫、毛様細胞白血病、頭頸部がん、心臓がん、肝細胞がん、組織球症、ホジキンリンパ腫、下咽頭がん、眼球内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎細胞がん、腎臓がん、ランゲルハンス細胞組織球症、喉頭がん、急性リンパ芽球性白血病、急性骨髄白血病、慢性リンパ性白血病、慢性骨髄性白血病、白血病、口唇及び口腔前庭がん、肝臓がん、肺がん、非小細胞肺がん、小細胞肺がん、エイズ関連リンパ腫、バーキットリンパ腫、皮膚T細胞リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、原発性中枢神経系リンパ腫、マクログロブリン血症、骨の悪性線維性組織球腫及び骨肉腫、髄芽腫、髄上皮腫、黒色腫、眼球内黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮がん、口がん、多発性内分泌新形成症候群、多発性骨髄腫、形質細胞新生物、骨髄異形成症候群、骨髄異形成/骨髄増殖性新生物、骨髄性白血病、骨髄白血病、骨髄増殖性障害、鼻腔及び副鼻腔がん、上咽頭がん、神経芽腫、非ホジキンリンパ腫、非小細胞肺がん、口腔がん、口腔前庭がん、中咽頭がん、骨肉腫及び骨の悪性線維性組織球腫、卵巣がん、卵巣上皮がん、卵巣胚細胞腫瘍、低悪性度卵巣腫瘍、膵がん、乳頭腫症、副甲状腺がん、陰茎がん、咽頭がん、松果体芽細胞腫及びテント上原始神経外胚葉性腫瘍、下垂体腫瘍、胸膜肺芽腫、妊娠及び乳がん、前立腺がん、直腸がん、腎細胞がん、移行細胞がん、気道がん、網膜芽細胞腫、横紋筋肉腫、唾液腺がん、肉腫、ユーイング肉腫、カポジ肉腫、子宮肉腫、非黒色腫皮膚がん、黒色腫皮膚がん、皮膚癌、小細胞肺がん、小腸がん、軟部組織肉腫、扁平上皮癌、頸部扁平上皮がん、胃がん、テント上原始神経外胚葉性腫瘍、T細胞リンパ腫、精巣がん、咽喉がん、胸腺腫及び胸腺癌、甲状腺がん、腎盂及び尿管の移行細胞がん、絨毛性腫瘍、妊娠期がん、尿管及び腎盂がん、移行細胞がん、尿道がん、子宮がん、子宮内膜がん、子宮肉腫、膣がん、外陰がん、ワルデンストロームマクログロブリン血症、又はウィルムス腫瘍である、請求項1又は11に記載の使用。
- 請求項1〜10のいずれか一項に記載の式(I)の化合物又はその薬学的に許容できる塩を、薬学的に許容できる担体、希釈剤、アジュバント又は賦形剤と組み合わせて含む医薬組成物。
- Axlによって媒介される疾患又は状態の処置のための、請求項1〜10のいずれか一項に記載の式(I)の化合物又はその薬学的に許容できる塩を活性成分として含む医薬組成物。
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JP2013509438A (ja) * | 2009-10-29 | 2013-03-14 | ジェノスコ | キナーゼ阻害剤 |
JP2015510942A (ja) * | 2012-03-22 | 2015-04-13 | ジェノスコ | 置換ピリドピリミジン化合物およびflt3阻害剤としてのこれらの使用 |
WO2017214433A1 (en) * | 2016-06-09 | 2017-12-14 | Seattle Genetics, Inc. | Combinations of pbd-based antibody drug conjugates with flt3 inhibitors |
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RS49779B (sr) * | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
EP2897950A1 (en) * | 2012-09-18 | 2015-07-29 | Ziarco Pharma Ltd | 2-(2-aminocyclohexyl)amino-pyrimidine-5-carboxamides as spleen tyrosine kinasei(syk) inhibitors |
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WO2017059280A1 (en) * | 2015-10-02 | 2017-04-06 | The University Of North Carolina At Chapel Hill | Novel pan-tam inhibitors and mer/axl dual inhibitors |
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JP2013509438A (ja) * | 2009-10-29 | 2013-03-14 | ジェノスコ | キナーゼ阻害剤 |
JP2015510942A (ja) * | 2012-03-22 | 2015-04-13 | ジェノスコ | 置換ピリドピリミジン化合物およびflt3阻害剤としてのこれらの使用 |
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CA3103160A1 (en) | 2020-01-02 |
WO2020004938A1 (en) | 2020-01-02 |
KR20210014212A (ko) | 2021-02-08 |
US20210275532A1 (en) | 2021-09-09 |
ZA202100140B (en) | 2022-07-27 |
IL279593A (en) | 2021-03-01 |
CA3103160C (en) | 2023-03-07 |
CN112351985B (zh) | 2023-12-15 |
CL2020003340A1 (es) | 2021-04-23 |
AU2019292207B2 (en) | 2022-06-30 |
EP3814350A1 (en) | 2021-05-05 |
EP3814350A4 (en) | 2022-05-04 |
BR112020026641A2 (pt) | 2021-03-30 |
SG11202013029UA (en) | 2021-01-28 |
EA202190125A1 (ru) | 2021-05-24 |
JP7200453B2 (ja) | 2023-01-10 |
CN112351985A (zh) | 2021-02-09 |
AU2019292207A1 (en) | 2021-02-18 |
MX2020013805A (es) | 2021-03-09 |
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