JP2017537112A - キナーゼモジュレーターとしての重水素化トリアゾロピリダジン - Google Patents
キナーゼモジュレーターとしての重水素化トリアゾロピリダジン Download PDFInfo
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- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940004212 yondelis Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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Abstract
Description
代謝産物1:
代謝産物2:
代謝産物2の溶解性:
pH 4.84では0.001 mg/mlの溶解性、
pH 7.33では0.002 mg/mlの溶解性。
本発明の化合物は薬学的に許容可能な塩、特に薬学的に許容可能な酸付加塩の形態でも存在し得る。
式(I)の化合物が、特に塩の場合、その構造中に1つ又は複数の不斉炭素原子を有し得ることが当業者には認識される。本発明の範囲内に化合物の単一鏡像異性体形態、ラセミ混合物、及び鏡像異性体過剰率が見られる鏡像異性体の混合物が含まれることが意図される。
さらに、本発明の化合物は1つ若しくは複数の多形結晶形態を有するか、又は非晶質であり得る。そのように、これらの形態は本発明の範囲に含まれることが意図される。加えて、化合物は例えば水(すなわち水和物)又は通常の有機溶媒(例えばアルコール)とともに溶媒和物を形成し得る。本明細書で使用される場合、「溶媒和物」という用語は、本発明の化合物と1つ又は複数の溶媒分子との物理的会合を意味する。この物理的会合は様々な程度のイオン結合及び共有結合(水素結合を含む)を伴う。或る特定の例では、例えば1つ又は複数の溶媒分子が結晶性固体の結晶格子内に組み込まれる場合に、溶媒和物は単離することが可能である。「溶媒和物」という用語は、溶液相及び単離可能な溶媒和物の両方を包含することを意図したものである。好適な溶媒和物の非限定的な例としては、エタノレート、メタノレート等が挙げられる。本発明の範囲内には本発明の化合物の溶媒和物が含まれることが意図される。本発明の化合物の薬学的に許容可能な塩及びN-オキシドも溶媒和物を形成し得る。本発明の化合物の薬学的に許容可能な塩及びN-オキシドの溶媒和物も本発明の範囲内に含まれる。
式(I)の化合物は、重水素ガスの存在下、かつ好適な触媒、例えばパラジウム触媒、例えばパラジウム炭素10 %(10 % Pd/C)又はPt触媒等(パラジウム触媒、特にパラジウム炭素が好ましい)、好適な溶媒又は溶媒混合物、例えばメタノール、重水素化メタノール(d1-MeOD、d4-MeOD)、テトラヒドロフラン、N-メチル-2-ピロリドン(NMP)、又はそれらの混合物、例えばテトラヒドロフランとメタノールとの混合物若しくはテトラヒドロフランと重水素化メタノールとの混合物(後者が好ましい)、及び好適な塩基、例えばトリエチルアミン又は炭酸ナトリウム(Na2CO3)(後者が好ましい)の存在下での式(II)の中間体(式中、W1はクロロ、ブロモ又はヨードを表し、ヨードが好ましい)の還元的重水素化によって調製することができる。微量の水が水素源として作用する可能性があるため、触媒は乾燥させるのが好ましい。付加的に、触媒は触媒に結合した水素を除去するために重水素ガスで事前重水素化するのが好ましい。付加的に、触媒は触媒に結合した水素を除去するために洗浄するのが好ましい。溶媒混合物中の重水素化メタノールとテトラヒドロフランとのv:v比は好ましくは1:9〜1:2の範囲、好ましくは1:4である。
a)重水素ガスの存在下、かつ好適な触媒、好適な溶媒又は溶媒混合物、及び好適な塩基の存在下での式(II)の中間体(式中、W1はクロロ、ブロモ又はヨードを表す)の還元的重水素化、
b)式(III)の中間体(式中、W2は好適な脱離基を表す)と式(IV)の中間体(式中、Dは重水素を表す)とを、好適な溶媒の存在下で反応させること、
を特徴とする、方法に関する。
キャビネット乾燥機、85℃/100 mbar未満/24時間の適用、続いて85℃/1 mbar未満/24時間の適用
ガラスビーカーに塗布した湿式触媒(充填高さ5 mm未満、容器をティッシューで覆う)
工程2:TosCl(塩化トシル;4-メチルベンゼンスルホニルクロリド)、好適な塩基、例えばNaOAc(酢酸ナトリウム)等、及び好適な溶媒、例えばジクロロメタン等の存在下、続くLiOH、及び好適な溶媒、例えばアルコール、例えばメタノール等の存在下での反応。
工程3:NaI、(CF3SO2)2O(トリフリック(triflic)無水物;トリフルオロメタンスルホン酸無水物)の存在下、好適な溶媒、例えばアセトニトリル及びピリジン等の存在下。
出発物質4(400 g)(化合物A;国際公開第2007/075567号)、mCBA(メタクロロ過安息香酸)(1.2当量)及びジクロロメタン(10 V)(1 Vは出発物質1 kg当たり1リットルである)を室温で17時間混合した。混合物を飽和Na2CO3水溶液でpHが8超となるまで中和した。混合物を0.5時間撹拌した。混合物を濾過し、固体を水でpHが約7となるまで洗浄した。固体を真空下、室温で乾燥させた。収率:410 gの出発物質3。
出発物質3(410 g)、TosCl(塩化トシル;4-メチルベンゼンスルホニルクロリド)(2当量)及びジクロロメタン(20 V)(1 Vは出発物質1 kg当たり1リットルである)を混合した。NaOAc(4当量)を添加し、混合物を2時間撹拌した。溶媒を真空下で除去した。メタノールを添加した(20 V)。混合物を撹拌した。LiOH.H2Oを添加し(5当量)、混合物を室温で17時間撹拌した。混合物を濃縮して16 Vのメタノールを除去し、20 Vの水を添加した。混合物を濃HClでpHが約6となるまで中和した。混合物を0.5時間撹拌し、濾過した。固体を真空下、50℃で乾燥させた。固体を水(10 V)で0.5時間スラリー化した。混合物を濾過した。固体を真空下、50℃で乾燥させた。スラリー化工程及び乾燥工程を再度繰り返した。収率:375 gの出発物質2。
出発物質2(190 g)、ピリジン(1当量)及びアセトニトリル(10当量)を混合し、混合物を0℃未満に冷却した。(CF3SO2)2O(4当量)をゆっくりと滴加し、5℃を超えないように反応温度を制御した。添加後に混合物を20℃に加熱し、1時間撹拌した。反応混合物を0℃未満に冷却した。(CF3SO2)2O(1当量)を滴加した。NaI(7 V)(1 Vは出発物質1 kg当たり1リットルである)をゆっくりと添加し、5℃を超えないように反応温度を制御した。添加後に反応混合物を50℃に加熱し、50℃で17時間撹拌した。酢酸エチルを添加し、混合物を水、10 % Na2S2O3溶液、ブラインで洗浄した。有機層を無水Na2SO4で乾燥させ、ゲルクロマトグラフィーにより精製した。収率:98.5 gの出発物質1。
全収率=86 %
nブタノール(12 mL)中の中間体4(0.42 g、1.76 mmol)及び3,6-ジクロロピリダジン(0.788 g、5.3 mmol)の混合物を、130℃で2時間加熱した。混合物を室温に冷却し、蒸発乾固した。DCMを添加し、混合物を10 % K2CO3水溶液とともに撹拌した。有機層を抽出し、乾燥させ(MgSO4)、濾過し、蒸発乾固した。残渣(0.9 g)をシリカゲルクロマトグラフィー(40 gの不規則SiOH 35 μm〜40 μm、移動相:100 % DCMから95 % DCM 5 % CH3OH 0.1 % NH4OHへの勾配)によって精製した。純粋な画分を回収し、蒸発乾固して、0.385 gの中間体6を得た(66 %)。
機器 Bruker Avance 300
溶媒 CDCl3
サンプル調製 0.7 mlのCDCl3中10 mg〜25 mg、濾過
プローブヘッド 5 mm QNP 1H/13
パルスプログラム zg30
スキャン回数 16又は254
温度 29℃
緩和時間 4.6秒
化学シフト 1H-NMR予測によると、8.84ppmの化学シフトが予想される(ChemOffice)。積分及び予想化学シフトに基づいて、水素シグナルが8.9 ppm〜9.0 ppmの範囲で対応位置に割り当てられた。
機器 Bruker Avance III 500
溶媒 DMSO又はCDCl3
サンプル調製 0.7 mlのCDCl3又はDMSO中約4 mg
プローブヘッド 5 mm TXI Z-GRD(1H/13C/15N)
パルスプログラム zg30
スキャン回数 16
温度 22℃
緩和時間 1秒
化学シフト 積分及び化学シフトに基づいて9.02 ppmで測定される重水素/水素比。
機器 Agilent Chemstation 1100
カラム Agilent Eclipse Plus、C18 4.6×100 mm、3.5 um
溶媒 A:水+0.1 % TFA;B:ACN+0.1 % TFA
勾配 10分で1 % Bから100 %、次いで100 % Bで2分間;ポストタイム(posttime):2分
流量 1.0 ml/分
検出:UV(220 nm)
温度 30℃
サンプル濃度 1.0 mlのMeOH中0.5 mgの生成物
注入量 1.0 μL
ランタイム 14分
保持時間:生成物2(式(I)の化合物):5.1分
以下の代表的なアッセイを行い、本発明の範囲内の化合物の生物活性を決定することができる。これらのアッセイは本発明を非限定的に説明するために与えられる。
アラマーブルーを用いた増殖アッセイ
細胞を96ウェルプレート内で180 μlの成長培地に播種した。成長曲線試験に応じて、1ウェル当たりの細胞の量は各細胞株で異なるものとした。細胞を37℃、加湿5 % CO2雰囲気のインキュベーター内で一晩インキュベートした。翌日、化合物プレートを調製し、4 μlの化合物を196 μlの予め加温した培地に添加した。20 μlのこの培地を180 μlの細胞に添加した。化合物を37℃、加湿5 % CO2雰囲気で添加した後、これを4日間インキュベートした。4日後に40 μlのアラマーブルー溶液を添加した。これを37℃、加湿5 % CO2雰囲気で4時間インキュベートした(細胞株に応じて、これを成長曲線試験において異なる時間のインキュベーション前に試験した)。4時後に蛍光を励起530 nm、発光590nmで測定した。対照(DMSO処理)の蛍光を100 %とみなし、化合物とともにインキュベートした細胞の蛍光を対照に対して%で算出した。そのようにして用量応答曲線を作成し、IC50を算出することができた。
Snu-5培地については、
50 μg/mlゲンタマイシン(Gentamycine)
ウエスタンブロット
細胞株:EBC-1及びSun-5
サンプルをSDS-PAGEにかけた。その後、ゲルをI-Blot装置(Invitrogen)にかけた。原理:電気的にタンパク質がPDVF膜に転写された。
一次抗体:
Cell Signaling technology #3077、抗pMet(Tyr1234/1235)ウサギmAb、1/2000
Cell Signaling technology #3127、抗Met(25H2)マウスmAb、1/1000
Sigma A1978、抗b-ActマウスmAb、1/30000
二次抗体:
Invitrogen #A21076、Alexa Fluor(商標) 680ヤギ抗ウサギIgG(H+L)、1/4000
Rockland #610-732-124、マウスIgG (H&L)抗体IRDye800(商標)、コンジュゲート、血清吸着済み(Pre-adsorbed)、1/4000
雄性ニュージーランドウサギ(Crl: KBL (NZW),Charles River,France)及び雌性ニュージーランドウサギ(NZW INRA A1077,Centre Lago)を使用した。1つの化合物(式(:formula)(I)の化合物及び化合物A)につき、1匹の雄性ウサギ及び2匹の雌性ウサギを平均体重2.6±0.2kgで使用した。完全な血漿濃度時間プロファイルを個々の動物の各々から得た。標準食及び水道水は自由摂取させた。式(I)の化合物及び化合物Aをどちらも、10%(w/v)SBE-B-CD(スルホブチルエーテル-β-シクロデキストリン)研究グレード(Captisol)溶液に最終濃度1 mg/mlで溶解した。化合物の溶解を容易にするためにHCl及びPVP K30を添加した。完全な溶解の後、NaOHを用いてpHを2.6/2.7とした。配合物は室温で保管し、光から保護し、調製日にLC-MS/MSにより定量的に分析した。配合物の安定性を投薬日に検査した。動物に、10mg/kgの最終用量が得られるように10 ml/kgで経口強制投薬した。投薬した個々の動物の各々から血液サンプルを経口投与の30分後、1時間後、2時間後、4時間後、7時間後及び24時間に採取した。血液を複数回のサンプリングにより外側耳静脈からMultivette(商標) 600 K3E管(Sarstedt)に回収した。サンプルを即座に融氷上に置き、4℃で10分間のおよそ1900×gでの遠心分離により血漿を得た。全てのサンプルを日光から遮蔽し、分析前に-18℃以下で保管した。血漿サンプルを化合物(I)、化合物A、代謝産物1、代謝産物2、N-デスメチル代謝産物3(N-デスメチル代謝産物4の曲線上で算出された)及びN-デスメチル代謝産物4について適格研究LC-MS/MS法を用いて分析した。本方法の主要分析性能(直線性、定量化の上限及び下限、正確さ及び精度)を、血漿濃度とともに報告した。血漿の定量化の下限(LLOQ)は全ての化合物について1.00 ng/mlとした。限定薬物動態分析をPhoenix(商標) Professional(Version 6.2.1)を用いて行った。lin/log補間を伴うlin/log台形公式を用いるノンコンパートメント(non-compartmental)分析を全てのデータについて用いた。
雄性及び雌性ウサギにおける10 mg/kgの化合物(I)の単回経口投与後の式(I)の化合物及びその代謝産物の基本薬物動態パラメーター。化合物Aも検出された(不純物)。
*ND:未決定
**MRT:平均滞留時間(時間)
**MRT:平均滞留時間(時間)
代謝産物2:
N-デスメチル代謝産物3:
これを親チャイニーズハムスター卵巣(CHO)細胞又はOCT2で安定にトランスフェクトしたCHO細胞を使用して試験した。14C-メトホルミンをOCT2基質として使用した。
化合物の配合
必要に応じて、適当な化学及び放射活性濃度を得るために非放射標識化合物と放射標識化合物とを混合した。ストック溶液(200倍)を下記表に指定される溶媒を使用して調製した。適当な溶媒対照を含めた。試験項目並びに必要とされる全ての参照及び阻害化合物を下記表に述べる。
T=-24時間
親CHO細胞及びCHO OCT2細胞をどちらも24ウェルプレート(1 mL/ウェル、400000細胞/ウェル)内でCHO培養培地に播種した。
輸送実験を、pH 7.4の10 mM HEPESを添加したハンクス平衡塩溶液+Ca,+Mg(HBSS+/+)中で行った。全ての培地を細胞に添加し、プレートを37℃に維持した。
データを1分間の1 mgのタンパク質当たりの対照(溶媒対照=DMSO)に対するパーセンテージとしてピコモル量で表す。Sigmaplotを用いてIC50値を算出した。
14C-メトホルミン(OCT2基質)の取込みは、親細胞と比較してOCT2トランスフェクトCHO細胞においてはるかに高かった(7.39倍及び17.2倍)。この取込みは陽性対照阻害剤である300 μMキニジンによって阻害された(85.5%及び100 %)。これらのデータから、使用されるアッセイ条件がOCT2依存性輸送に対する試験化合物の阻害効果の研究に効率的に働くことが示される。
式(I)の化合物の細胞毒性を、親CHO及びCHOOCT2細胞の両方において100 μMで決定した。また、1 % Triton-X100条件を陽性対照の細胞毒性試薬として含めた。1分間のインキュベーション後に、上清を吸引し、乾燥細胞を1 mL HBSS+/++10 mM Hepes(pH 7.4)で2回洗浄した(37℃)。バッファーの吸引後に、HBSS+/++10 mM Hepes(pH 7.4)中10倍希釈のPrestoBlue(商標)Viability Reagent(Life Technologies)を添加し、プレートを37℃で60分間インキュベートし、光から保護した。各ウェルを黒色96ウェルプレートにサンプリングし(150 μL)、蛍光を測定した(励起:560 nm/12 nm帯域幅(bandwidth)、発光:590 nm/12 nm帯域幅)。
式(I)の化合物については、100 μMで細胞毒性効果は観察されなかった。陽性対照の細胞毒性試薬であるTriton X 100の1 %溶液を用いると、生存能力は劇的に低下した(下記表を参照されたい)。これにより考え得る阻害効果が細胞生存能力の喪失に関連しないことが示される。
本発明の別の態様では、本発明の化合物はc-Met活性を含むチロシンキナーゼの活性若しくは発現を阻害する、c-Met活性を含むキナーゼの活性若しくは発現を低減する、細胞若しくは対象におけるc-Metの発現をモジュレートする、又は対象におけるc-Metキナーゼの活性若しくは発現に関連する障害を治療するために使用することができる。c-Met活性の阻害はc-Met発現を間接的にモジュレートすると考えられる。
*)N-(3,5-ジメトキシフェニル)-N'-(1-メチルエチル)-N-[3-(1-メチル-1H-ピラゾール-4-イル)キノキサリン-6-イル]エタン-1,2-ジアミン(化合物X)は、以下の式によって表される。
ポリペプチドである血管内皮成長因子(VEGF)はin vitroで内皮細胞に分裂促進的であり、in vivoで血管新生応答を刺激する。VEGFは不適切な血管新生にも関連付けられている。VEGFR(複数の場合もある)はタンパク質チロシンキナーゼ(PTK)である。PTKは細胞機能に関与するタンパク質中の特定のチロシン残基のリン酸化を触媒し、ひいては細胞の成長、生存及び分化を調節する。
悪性腫瘍は無制御の細胞増殖によるものである。細胞成長は成長促進因子と成長阻害因子との間の微妙なバランスによって制御される。正常組織においては、これらの因子の産生及び活性は、器官の正常な完全性及び機能を維持する制御及び調節されて成長する分化細胞をもたらす。悪性細胞はこの制御を回避し、自然のバランスが(様々な機構によって)乱され、無秩序となり、異常な細胞成長が生じる。腫瘍発生において重要な成長因子は、細胞表面チロシンキナーゼ受容体(PDGFR)を介してシグナル伝達を行い、成長、増殖及び分化を含む様々な細胞機能を刺激するペプチド成長因子のファミリーを含む血小板由来成長因子(PDGF)である。
*)インテダニブ(Intedanib)
*)抗体又は関連化合物、例えばHGS1036/FP-1039;MFGR1877S;AV-370;GP369/AV-396b;HuGAL-FR21;モノクローナル抗体(BAY1179470、RG-7444)等
Compound A 化合物A
Compound offormula (I) 式(I)の化合物
Total Met 全Met
β-Actin β-アクチン
pMet proteinlevels normalized to actin in EBC-1 cells after treatment with compounds 化合物による処理後にEBC-1細胞中のアクチンに対して正規化したpMetタンパク質レベル
actin アクチン
Westernblotting for Snu-5. Cells incubated with the compounds at indicated doses for24h Snu-5のウエスタンブロット法。指定用量の化合物とともに24時間インキュベートした細胞
pMet proteinlevels normalized to actin in Snu-5 cells after treatment with compounds 化合物による処理後にSnu-5細胞中のアクチンに対して正規化したpMetタンパク質レベル
signal シグナル
concentrationcompound 化合物の濃度
Claims (17)
- 式(I):
- 前記化合物が、
- キノリンの2位(D位)における重水素含量が少なくとも93 %である、請求項1又は2に記載の化合物。
- キノリンの2位(D位)における重水素含量が少なくとも95 %である、請求項3に記載の化合物。
- キノリンの2位(D位)における重水素含量が少なくとも98 %である、請求項4に記載の化合物。
- 薬剤として使用される、請求項1〜5のいずれか一項に記載の化合物。
- 癌の治療のための、請求項1〜5のいずれか一項に記載の化合物。
- 細胞増殖性障害の治療のための、請求項1〜5のいずれか一項に記載の化合物。
- 薬学的に許容可能な担体と、活性成分として治療有効量の請求項1〜5のいずれか一項に記載の化合物とをを含む医薬組成物。
- 請求項1に記載の化合物を調製する方法であって、
重水素ガスの存在下かつ好適な触媒、好適な溶媒又は溶媒混合物、及び好適な塩基の存在下での式(II)の中間体(式中、W1はクロロ、ブロモ又はヨードを表す)の還元的重水素化、
又は所望に応じて、式(I)の化合物を酸処理によって治療的に活性な非毒性の酸付加塩へと変換すること、若しくは反対に、酸付加塩形態をアルカリ処理によって遊離塩基へと変換すること、若しくは所望に応じて、その溶媒和物又はN-オキシド形態を調製すること、
を特徴とする、方法。 - 癌の治療に使用される、請求項1〜5のいずれか一項に記載の化合物。
- 細胞増殖性障害の治療に使用される、請求項1〜5のいずれか一項に記載の化合物。
- 請求項1〜5のいずれか一項に記載の化合物と別の化学療法剤との組合せ。
- 前記化学療法剤がキナーゼ阻害剤である、請求項13に記載の組合せ。
- 前記キナーゼ阻害剤がFGFR阻害剤である、請求項14に記載の組合せ。
- 前記化学療法剤が白金含有抗癌薬である、請求項13に記載の組合せ。
- 対象におけるc-Metのキナーゼ活性を低減する方法であって、請求項1〜5のいずれか一項に記載の化合物を該対象に投与する工程を含む、方法。
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