JP2012508179A - プロテインキナーゼモジュレーターとしてのイミダゾロチアゾール化合物 - Google Patents
プロテインキナーゼモジュレーターとしてのイミダゾロチアゾール化合物 Download PDFInfo
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- JP2012508179A JP2012508179A JP2011534916A JP2011534916A JP2012508179A JP 2012508179 A JP2012508179 A JP 2012508179A JP 2011534916 A JP2011534916 A JP 2011534916A JP 2011534916 A JP2011534916 A JP 2011534916A JP 2012508179 A JP2012508179 A JP 2012508179A
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Abstract
【選択図】図1
Description
本出願は、「イミダゾロチアゾール化合物及びそれらの使用方法(Imidazolothiazole Compounds And Methods Of Use Thereof)」と題する2008年11月6日出願の米国特許仮出願第61/112,146号に基づく優先権を主張する。参照により上記参照出願の開示をその全体で本明細書に組み込む。
疾患を治療するための小分子化合物、組成物及び方法が提供される。提供される化合物は、キナーゼなどの酵素の活性に関するモジュレーターであり、酵素活性に関連した疾患又は障害、或いはそれらの1種以上の症状を治療、予防及び/又は改善するのに役立つ。
プロテインキナーゼ(PK)は、タンパク質のチロシン、セリン及びトレオニン残基上のヒドロキシ基のリン酸化を触媒する酵素である。プロテインキナーゼ、及び特にプロテインキナーゼの中の受容体型タンパク質チロシンキナーゼ(RTK)ファミリーは、主として増殖因子の受容体として機能を発揮し、且つ細胞周期、細胞増殖、細胞分化及び細胞死などのいくつかの細胞機能を調節するシグナル伝達経路中で中心的な役割を演じる。受容体型タンパク質チロシンキナーゼ(RPTK)の異常な又は過剰な活性或いは活性調節不全が、良性及び悪性の増殖性障害及び炎症性障害、並びに免疫系の不適切な活性化に由来し、例えば自己免疫疾患を引き起こす免疫系障害を含む、多くの疾患状態で観察されている。
いくつかの実施態様において、キナーゼの活性、結合又は細胞内分布を調節するための、医学的治療で使用するための化合物、医薬組成物及び方法が提供される。一実施態様において、本明細書で提供される化合物は、下記式を有するか、又はそれらの医薬として許容し得る塩、溶媒和物、水和物若しくはプロドラッグである:
i)R1及びR2は各々、-CH3、及び-CH2OHから選択され;かつ、R3は、-CH3、-CH(OH)2、-CHO、-CH2OH、
ii)R1、R2及びR3は各々、-CH3及び-COOHから選択される;から選択され、かつ
R4は:
(A.定義)
別途に定義しない限り、本明細書中で使用されるすべての技術及び科学用語は、当業者が通常的に理解しているのと同様の意味を有する。すべての特許、出願、公開出願及びその他の刊行物は、参照によりその全体で組み込まれる。本明細書中の1つの用語に対して複数の定義が存在する場合には、特記しない限り本セクションの定義が優先する。
一実施態様において、本明細書で提供される化合物は、下記式を有するか、又はそれらの医薬として許容し得る塩、溶媒和物、水和物若しくはプロドラッグである:
i)R1及びR2は各々、-CH3、及び-CH2OHから選択され;かつ、R3は、-CH3、-CH(OH)2、-CH2OH、
ii)R1、R2及びR3は各々、-CH3及び-COOHから選択される;から選択され、かつ、
R4は:
i)R1、R2若しくはR3の少なくとも1つが-CH3以外である場合に、R4は、
ii)R1、R2若しくはR3が各々-CH3である場合に、R4は、
i)R1及びR2は各々、-CH3、又は-CH2OHから選択され;かつ、R3は、-CH3、-CH(OH)2、-CH2OH、及び
ii)R1、R2及びR3は各々、-CH3及び-COOHから選択される;から選択され、かつ、
R4は:
i)R1、R2若しくはR3の少なくとも1つが-CH3以外である場合に、R4は、
ii)R1、R2及びR3が各々-CH3である場合に、R4は、
本明細書で提供される化合物は、当業者に明らかな任意の方法により調製されるか、単離されるか、又は入手することができる。調製方法の例は、下記実施例において詳細に説明されている。化合物IAは、米国特許公開第2007/0232604号に記載された方法により調製されることができる。
いくつかの実施態様において、本明細書で提供されるのは、本明細書で提供される化合物を活性成分として含有する医薬組成物である。一実施態様において、医薬組成物は、化合物I-1、I-1a、I-1b、I-2、I-3、I-4、I-5、I-6、I-7又はI-8を精製された形態で含有する。
経口用の医薬剤形は、固形、ゲル又は液体である。固形の剤形は、錠剤、カプセル、顆粒剤、及びバルク散剤である。経口用錠剤の種類には、圧縮、チュアブルロゼンジ、及び腸溶性コーティング、糖コーティング又はフィルムコーティングが可能な錠剤が含まれる。カプセルは、硬質又は軟質ゼラチンカプセルでよく、一方、顆粒剤及び散剤は、当業者に公知の他の成分と組合せた非発泡性又は発泡性形態で提供できる。
本明細書では、皮下、筋内又は静脈内のいずれかでの注射によって概略的に特徴付けられる非経口投与も想定される。注射剤は、液状の溶液又は懸濁液、注射に先立って液体中に溶解又は懸濁するのに適した固形形態として、又はエマルジョンとして通常の形態で調製できる。適切な賦形剤は、例えば、水、生理食塩水、デキストロース、グリセロール又はエタノールである。更に、所望の場合、投与される医薬組成物は、湿潤剤及び乳化剤、pH緩衝剤、安定剤、溶解性増強剤などの少量の非毒性補助物質、並びに例えば、酢酸ナトリウム、モノラウリン酸ソルビタン、オレイン酸トリエタノールアミン及びシクロデキストリンなどのこのような薬剤を含むこともできる。一実施態様において、組成物は、賦形剤としてヒドロキシプロピル-β-シクロデキストリン(HPBCD)を用いた水性溶液として投与される。一実施態様において、水性溶液は、約1%〜約50%のHPBCDを含有する。一実施態様において、水性溶液は、約1%、3%、5%、10%又は約20%のHPBCDを含有する。
また、本明細書中で注目すべきは、溶液、エマルジョン及びその他の混合物として投与するために再構成できる凍結乾燥粉末である。それらの粉末を固体又はゲルとして再構成し、製剤することもできる。
局所用混合物は、局部及び全身投与について説明したと同様に調製される。生じる混合物は、溶液、懸濁液、エマルジョンなどでよく、クリーム、ゲル、軟膏、エマルジョン、溶液、エリキシル剤、ローション、懸濁液、チンキ、ペースト、発泡剤、エアロゾル、灌注剤、スプレー、坐薬、包帯、皮膚パッチ又は局所投与に適したその他の任意の製剤として製剤される。
本明細書では、局所適用、経皮パッチ及び直腸投与などのその他の投与経路も想定される。
本明細書中で提供される活性成分は、制御された放出手段によって又は当業者に周知の送達デバイスによって投与できる。例には、限定はされないが、米国特許第3845770号;3916899号;3536809号;3598123号;及び、4008719号、5674533号、5059595号、5591767号、5120548号、5073543号、5639476号、5354556号、5639480号、5733566号、5739108号、5891474号、5922356号、5972891号、5980945号、5993855号、6045830号、6087324号、6113943号、6197350号、6248363号、6264970号、6267981号、6376461号、6419961号、6589548号、6613358号、6699500号及び6740634号に記載の例が含まれ、そのそれぞれを参照により本明細書に組み込む。このような剤形を使用して、様々な比率の所望の放出プロフィールを提供するために、例えば、ヒドロプロピルメチルセルロース、その他のポリマーマトリックス、ゲル、透過膜、浸透系、多層コーティング、微小粒子、リポソーム、微小球又はこれらの組合せを使用する、1種以上の活性成分の遅延又は制御放出を提供できる。本明細書中で提供される活性成分と一緒に使用するために、本明細書に記載の製剤を含む当業者に公知の適切な制御放出製剤を容易に選択できる。
本明細書中で提供される化合物又は医薬として許容し得るその誘導体は、治療されるべき対象の特定の組織、受容体又は身体のその他の区域を標的にして製剤することもできる。多くのこのような標的化法は、当業者に周知である。本明細書では、本組成物中で使用するために、すべてのこのような標的化法を意図している。標的化法の非制限的例については、例えば、米国特許第6316652号、6274552号、6271359号、6253872号、6139865号、6131570号、6120751号、6071495号、6060082号、6048736号、6039975号、6004534号、5985307号、5972366号、5900252号、5840674号、5759542号及び5709874号を参照されたい。
化合物を試験して、キナーゼの活性を選択的に調節する生物学的活性を所持する化合物を同定するためには、標準的な生理学的、薬理学的及び生化学的方法を利用できる。
本明細書では、プロテインキナーゼ活性によって介在される若しくは影響される疾患又は障害、或いはプロテインキナーゼの活性により介在される若しくは影響される疾患又は障害の1つ以上の症状を治療、予防又は改善するために、開示される化合物及び組成物、或いはその医薬として許容し得る塩、溶媒和物、又は水和物を使用する方法も提供される(Krause及びVan Ettenの論文、N Engl J Med, 353(2):172-187 (2005);Blume-Jensen及びHunterの論文、Nature, 411(17):355-365 (2001);及びPlowmanらの論文、DN&P, 7:334-339(1994)参照)。上記の説明と密接に関連して、このような疾患又は障害には、限定はされないが、次のものが含まれる。
1)a)Kit介在性癌腫、腺癌、扁平上皮癌、腺扁平上皮癌、奇形癌、頭部及び頚部癌、脳癌、頭蓋内癌、PDGFR介在性神経膠芽腫を含む神経膠芽腫、PDGFR介在性多形性神経膠芽腫を含む多形性神経膠芽腫、神経芽細胞腫、喉頭癌、RET介在性MENSを含む多発性内分泌腺腫2A及び2B(MENS 2A及びMENS 2B)、散発性及び家族性髄様甲状腺癌を含む甲状腺癌、乳頭状甲状腺癌、任意のRET介在性甲状腺癌を含む副甲状腺癌、濾胞状甲状腺癌、未分化甲状腺癌、気管支カルチノイド、燕麦細胞癌、肺癌、flt-3及び/又はKit介在性小細胞肺癌を含む小細胞肺癌、胃(stomach)/胃(gastric)癌、消化管癌、Kit介在性GIST及びPDGFRα介在性GISTを含む消化管間質性腫瘍(gastrointestinal stromal tumor)(GIST)、結腸癌、結腸直腸癌、膵癌、膵島細胞癌、肝(hepatic)/肝臓(liver)癌、肝臓への転移、膀胱癌、PDGFR介在性腎細胞癌を含む腎細胞癌、尿生殖器管の癌、Kit介在性及び/又はPDGFR介在性卵巣癌を含む卵巣癌、CSF-1R介在性子宮内膜癌を含む子宮内膜癌、子宮頚癌、Flt-3介在性及び/又はPDGFR介在性乳癌を含む乳癌、Kit介在性前立腺癌を含む前立腺癌、Kit介在性胚細胞腫瘍を含む胚細胞腫瘍、Kit介在性セミノーマを含むセミノーマ、Kit介在性未分化胚細胞腫を含む未分化胚細胞腫、PDGFR介在性黒色腫を含む黒色腫、CSF-1R-介在性骨転移を含む骨への転移、VEGFR介在性腫瘍を含む転移性腫瘍、間質性腫瘍、神経内分泌腫瘍、VEGFR介在性腫瘍血管新生を含む腫瘍血管新生、混合中胚葉腫瘍を含む、癌腫;
b)PDGFR介在性肉腫、骨肉腫、骨原性肉腫、骨癌、PDGFR介在性及び/又はCSF-1R-介在性神経膠腫を含む神経膠腫、星状細胞腫、VEGFR介在性血管腫瘍を含む血管腫瘍、カポジ肉腫、癌肉腫、VEGFR3介在性血管肉腫を含む血管肉腫、VEGFR3介在性リンパ管肉腫を含むリンパ管肉腫を含む、肉腫;
c)骨髄腫、白血病、骨髄増殖性疾患、flt-3介在性及び/又はKIT介在性及び/又はCSF-1R介在性急性骨髄性白血病を含む急性骨髄性白血病(AML)、Flt-3介在性及び/又はPDGFR介在性慢性骨髄性白血病を含む慢性骨髄性白血病(CML)、Flt-3介在性骨髄異形成白血病を含む骨髄異形成白血病、Flt-3介在性及び/又はKit介在性骨髄異形成症候群を含む骨髄異形成症候群、PDGFR介在性HESを含む特発性好酸球増加症候群(HES)、PDGFR介在性CELを含む慢性好酸球性白血病(CEL)、慢性骨髄単球性白血病(CMML)、Kit介在性肥満細胞白血病を含む肥満細胞白血病、又はKit介在性全身性肥満細胞症を含む全身性肥満細胞症;並びに
d)そのいずれもFlt-3介在性及び/又はPDGFR介在性でよい、リンパ腫、リンパ組織増殖性疾患、急性リンパ芽球性白血病(ALL)、B細胞急性リンパ芽球性白血病、T細胞急性リンパ芽球性白血病、ナチュラルキラー(NK)細胞白血病、B細胞リンパ腫、T細胞リンパ腫、及びナチュラルキラー(NK)細胞リンパ腫、CSF-1R-介在性及びflt-3介在性ランゲルハンス細胞組織球症を含むランゲルハンス細胞組織球症、肥満細胞腫瘍及び肥満細胞症;
2)非悪性増殖性疾患、すなわち、PDGFR介在性アテローム性動脈硬化症を含むアテローム性動脈硬化症、PDGFR介在性再狭窄を含む血管形成術に続く再狭窄、及びその両方がPDGFR介在性でよい閉塞性細気管支炎及び特発性骨髄線維症などの線維増殖性障害;
3)flt-3介在性及び/又はCSF-1R介在性である前記疾患のいずれかを含む、免疫機能不全に関連した炎症性疾患又は障害、免疫不全、免疫調節、自己免疫疾患、組織移植拒絶、移植片対宿主病、創傷治癒、腎臓疾患、多発性硬化症、甲状腺炎、1型糖尿病、サルコイドーシス、アレルギー性鼻炎、クローン病及び潰瘍性大腸炎(UC)を含む炎症性腸疾患、全身性紅斑性狼瘡(SLE)、関節炎、変形性関節炎、関節リウマチ、骨粗鬆症、喘息及び慢性閉塞性肺疾患(COPD);並びに
4)ウイルス又は細菌性病原体により媒介される感染性疾患、及びKIT介在性敗血症を含む敗血症。
1)PDGFRα、PDGFRβ、CSF-1R、Kit及びFlt3を含む、血小板由来増殖因子受容体(PDGFR)サブファミリー;
2)VEGFR1(Flt1)、VEGFR2(KDR又はFlk1)及びVEGFR3(Flt4)を含む、血管内皮増殖因子(VEGF)受容体サブファミリー;
3)Ret;
4)HER(EGFR)サブファミリー;
5)FGFRサブファミリー;
6)HGFR(Met)サブファミリー;
7)Ab1タンパク質チロシンサブファミリー;
8)Src、Yes1、Fyn、Lyn、Lck、Blk、Hck、Fgr及びYrkを含むSrcサブファミリー;
9)Frk、Btk、Csk、Ab1、Syk、Fes、Fps、Fak、Jak及びAck(及びそれらのそれぞれのサブファミリー);
10)前立腺由来sterile20、sterile11及びsterile7からなる群から選択されるキナーゼ;
11)camキナーゼサブファミリー(カルモジュリン調節性キナーゼ及び関連キナーゼ);
12)AGCサブファミリー;及び
13)CMGCサブファミリー(cdk、mapキナーゼ、グリコーゲンシンテターゼキナーゼ及びclk)。
更に当業者は、本明細書中で提供される化合物は、これらの化合物を含有する医薬組成物及び製剤を含め、前記の状態及び疾患を治療するための多様な併用療法で使用できることを理解するであろう。従って、本明細書では、本明細書中で提供される化合物、その医薬として許容し得る塩、溶媒和物又は水和物を、本明細書に記載の疾患/状態を治療するためのその他の活性医薬と組合せて使用することも意図される。
(実施例1:ラット、サル及びヒト肝ミクロソーム画分における化合物IAのインビトロ代謝動態)
化合物IAの代謝安定性を、マウス、ラット、イヌ、カニクイザル(Cynomolgus monkey)、及びヒトミクロソームにおいて測定した。
(ミクロソーム安定性:)
被験化合物(1μM)を、プールした肝ミクロソームと一緒にインキュベーションした。アリコートを0、5、15、30、及び60分の時点で採取し、内部標準(IS)を含有するACNの2倍量で直ちにクエンチした。この試料を抽出し、LC-MS/MSにより分析した。
(試薬)
0.5M KPO4、pH7.4(GAL-PAC, Sigma社936-4GP)又は1M KH2PO4+1M K2HPO4(19mL 1M一塩基物(Sigma社P8709)+89mL 1M二塩基物(Sigma社P8584)+100mL H2O);0.065M MgCl2、6H2O(Sigma社M-0250)(1.33g+100mL H2O);10mM NADPH(4Na)(8.33mg/mL) (Sigma社N7785);NADPH再生系溶液A:NADP(Sigma社N0505)(2g+10mL H2O)+グルコース-6-リン酸塩(Sigma社G7250)(2g+10mL H2O)、及び溶液B:グルコース-6-リン酸デヒドロゲナーゼ(Sigma社G6378)(14単位/ml)。
2又は15mLのプラスチックキャップ付きチューブを使用し、化合物溶液及びミクロソーム希釈物を作製し(混合物1及び2);20mLのシンチレーションバイアルをNADPH(混合物3)に使用し;取り外し可能なウェルである2mLの96ウェルプレートを、37℃でのプレートのインキュベーションに使用し;2mL NUNC 96ウェルプレートを受け取りプレート(receiving plate)に使用した。
ピーク面積比(化合物ピーク面積/内部標準ピーク面積)を、時間=0分データを用いる100%に対して標準化し、かつ残存する化合物割合の自然対数(ln)を、時間に対してプロットした。直線の勾配を線形フィッティングを用い決定し、かつ消失速度定数を算出した。
消失速度定数(k)=(−勾配)
代謝試験のために、化合物IAは、以下の点を除き、ミクロソームの安定性に関して説明されたものと同様の条件でインキュベーションした。被験化合物濃度は、タンパク質濃度(1μM)の増加に伴い、10μMまで増大した。インキュベーション時間は、60分間であった。
いくつかの種(マウス(ロットBDS)、ラット(ロットLMO)、イヌ(ロットLQU)、及びカニクイサル(ロットDIS))のプールされた肝ミクロソームは、In Vitro Technologies社から購入した。プールされたヒト肝ミクロソーム(男性及び女性)は、BD Gentest社(ロット23)から購入した。ミクロソームは、使用前は-80℃で貯蔵した。
これらの試料は、以下に説明された下記LC法を用いて分析した:
カラム:Prodigy 150×2;5μm
30分勾配(溶媒A=0.05%ギ酸、B=アセトニトリル+0.05%ギ酸)
試料を、3工程プロセスを用いて解析した。最初に、親ピークからの全てのLC-MS/MSフラグメントを同定した。第二に、2つの対照及び活性インキュベーションからのクロマトグラムを比較し、非CYP-介在性ピークを除外した。最後に、分子量及びフラグメンテーション産物を比較することにより、全ての代謝産物ピークを分析し、最も起こり得る変換、そして可能であるならば、親分子上のどの部分で変換が生じるかを決定した。
化合物IAは、マウス、ラット、及びヒトミクロソームインキュベーションにおいて、低い固有クリアランスを明らかにした。クリアランスは、イヌミクロソームにおいて中程度であり、かつカニクイサルミクロソームにおいて高かった。同様に代謝回転は、ミクロソームの安定性データと一致した。従って、化合物IAの回転は、ヒト及びラット肝ミクロソームにおいて非常に低く、イヌミクロソームにおいて中程度であり、かつカニクイサルミクロソームにおいて高かった。
(試験手順及び方法)
組織試料調製は、本実施例において肝組織について説明されている。同様の手順を腎試料の試験に使用した。
LCパラメータ:
モデル:SPD-10Avp
実行時間:30.00
波長(Ch1): 298nm
ランプ:D2
極性:陽性
時間プログラム:(勾配)
溶媒A:水中0.05%ギ酸
溶媒B:アセトニトリル中0.05%ギ酸
極性:陽性
スキャンモード:N/A
イオン源:ターボスプレー
分解能Q1:低
分解能Q3:低
強度閾値:0.00 cps
セトリング時間:0.0000msec
MRポーズ:5.0070msec
MCA:なし
ステップサイズ:0.00amu
CUR:15.00
IS:5200.00
TEM:500.00
GS1:50.00
GS2:50.00
ihe:オン
CAD:8.00
DP 96.00
EP 10.00
CE 41.00
CXP 12.00
スキャン型:ニュートラルロス(NL)
極性:陽性
スキャンモード:プロファイル
イオン源:ターボスプレー
ロスオブ(Loss Of):140.00amu
分解能Q1:低
分解能Q3:低
強度閾値:0.00cps
セトリング時間:0.0000msec
MRポーズ:5.0070msec
MCA:なし
センター/幅:なし
ステップサイズ:0.10amu
CUR: 40.00
IS:4500.00
TEM:550.00
GS1:60.00
GS2:60.00
ihe:オン
CAD:12.00
DP 96.00
EP 10.00
CE 41.00
CXP 12.00
スキャン型:プリカーサーイオン(Prec)
極性:陽性
スキャンモード:プロファイル
イオン源:ターボスプレー
プリカーサーオブ(Precursor Of):114.18amu
分解能Q1:低
分解能Q3:低
強度閾値:0.00cps
セトリング時間:0.0000msec
MRポーズ:5.0070msec
MCA:なし
センター/幅:なし
ステップサイズ:0.10amu
CUR:40.00
IS:4500.00
TEM:550.00
GS1:60.00
GS2:60.00
ihe:オン
CAD:12.00
DP 96.00
EP 10.00
CE 61.00
CXP 6.00
(尿分析)
下記ストック液を、分析に使用した。
A1. DMSO中ストック2mg/mL(遊離塩基)
A2. DMSO中ストック0.1mg/mL(2mg/mLストック50μL+950μL DMSO)
1.標準:1000ng/mL(0.1mg/mL溶液(前記A2)10μL+尿990μL)。直ちにボルテックス。
2. QC 800ng/mL(0.1mg/mL溶液(前記A2)8μL+尿992μL)。直ちにボルテックス。
1. 600μL希釈液(対照尿)をウェルA2-12、B2-B4、及びB6-12へピペッティング。
2. 600μL STD 1000をウェルA1へピペッティング。
3. 600μL QC 800をウェルB1及びB5へピペッティング。
4. 標準−STD+尿の1:1希釈で、STD 500、250、125、62.5、31.25、15.6、7.8ng/mLを作製(すなわち、STD500に関して、ウェルA2においてSTD1000の600μLを、対照尿600μLへ添加、など)。注記:連続希釈液のみウェルA9に入れる。ウェルA10-A12はブランク尿である。
5. QC−QC+尿の1:3(4倍)希釈で、QC 200ng/mL、QC 50ng/mL、及びQC 12.5ng/mLを作製(すなわち、QC200に関して、ウェルB2及びB6においてQC 800の200μLを、対照尿600μLに添加)。注記:QC希釈液のみウェルB8に入れる。ウェルB9-B12はブランク尿である。
1. 列A及びB(標準曲線、QC、及びブランク尿)から500μLを、新たな96ウェルプレートへ移す。
2. 患者試料(群)500μLを、列C-Hに必要に応じ添加し、残りのウェルには水500μLを添加する。
3. 内部標準(アセトニトリル中AC012168又は現行の(current)DMPK標準25ng/mL)100μLを、各ウェルに添加する。混合する。
Biotage Isolute C18(EC) 25mg 96ウェルプレートを下記のように調製した。
1. メタノール5μL/ウェルを添加する。プレートを1分間静置させ、その後短時間(5〜10秒間)真空(<127mmHg(5" Hg))を用い、メタノールを除去する。
2. 水250μL/ウェルを添加する。プレートを1分間静置させ、その後短時間真空を用い、水を除去する。
1. 調製されたプレートに、内部標準を含有する試料(標準曲線、QC、患者試料など)250μLを加える。未使用のウェルに水250μLを添加する。
2. 試料を1分間静置させ、その後短時間真空下で尿を除去する。
3. 試料を水250μL/ウェルで洗浄する。試料を1分間静置させ、その後短時間真空下で水を除去する。
4. 化合物IAを、メタノールによる2×250μL洗浄を用いて溶出する。1回目の洗浄に関して、メタノールを250μL/ウェルで添加する。1分間静置させ、溶出液を短時間真空下で収集する。2回目の洗浄に関して、メタノール250μL/ウェルを添加し、4分間静置させる(洗浄1からの収集プレートは依然適所にある)。4分後、短時間真空を適用する。
モデル:SPD-10Avp
波長(Ch1):254nm
ランプ:D2
極性:陽性
ピリオッド1 実験1:
スキャン型:MRM (MRM)
極性:陽性
スキャンモード:N/A
イオン源:ターボスプレー
分解能Q1:低
分解能Q3:低
強度閾値:0.00cps
セトリング時間:0.0000msec
MRポーズ:5.0070msec
MCA:なし
ステップサイズ:0.00amu
パラメータ表(ピリオッド1 実験1)
CUR:15.00
IS:5200.00
TEM:500.00
GS1:50.00
GS2:50.00
ihe:オン
CAD:8.00
DP 96.00
EP 10.00
CE 41.00
CXP 12.00
ピリオッド1 実験2:
スキャン型:エンハンスドプロダクトイオン(EPI)
極性:陽性
スキャンモード:プロファイル
イオン源:ターボスプレー
サムへのスキャン数:1
プロダクトオブ:30.00amu
分解能Q1:ユニット
スキャン速度:4000amu/秒
強度閾値:0.00cps
セトリング時間:0.0000msec
MRポーズ:5.0070msec
Q0トラッピング:あり
MCA:なし
センター/幅:なし
LIT充填時間:20.00msec
Q3エントリーバリヤ:8.00V
ステップサイズ:0.12amu
パラメータ表(ピリオッド1 実験2)
CUR:15.00
CAD:高
IS:5200.00
TEM:500.00
GS1:50.00
GS2:50.00
ihe:オン
DP 96.00
CES 17.00
CE 57.00
時間プログラム:(勾配)
溶媒A:水中0.05%ギ酸
溶媒B:アセトニトリル中0.05%ギ酸
ヒト血漿試料を、化合物IAが60mg及び90mgコホートで投与された患者2名から採取した。血漿試料を、コホート別に一緒にし、次にアセトニトリルで抽出した。これらの試料を、Sciex 4000 Q-Trap LC/MS/MSシステム上で分析した。標準の予想される代謝産物及び推定外代謝産物を、多重反応モニタリング(MRM)、プレカーサーイオン(PCI、m/z=114、421、及び130)、及びコンスタントニュートラルロス(CNL、m=140及び156)MSトランジションの組合せを用いてスキャンした。これらの異なるスキャンは、化合物IAの推定代謝産物のかなり包括的概要を提供する。
血漿試料を、コホート別に一緒にした:60mg及び90mgコホートで各患者から25μL。一緒にした試料及びブランクヒト血漿を、アセトニトリル200μLで抽出し、ボルテックスし、20分間遠心させた。得られる上清を、Sciex 4000 Q-Trap LC/MS/MSシステムにおいて、注入20μLで、30分間LC勾配を用いて分析した。チューニング条件は、親分子について最適化した。プロトコール及びスキャン条件は、以下に説明している。
LCパラメータ:
モデル:SPD-10Avp
実行時間:30.00
波長(Ch1):254nm
ランプ:D2
極性:陽性
時間プログラム:(勾配)
溶媒A:水中0.05%ギ酸
溶媒B:アセトニトリル中0.05%ギ酸
(手順A:2-アミノ-6-ヒドロキシベンゾチアゾールの調製)
2. このフラスコに、48%臭化水素酸(14L, 123.16mol, 13.10当量)を充填した。加熱を開始し、2-アミノ-6-メトキシベンゾチアゾール(1.7Kg, 9.4mol, 1.00当量)を、10分間にわたり攪拌しながら添加した。
3. 反応混合物の加熱を継続し、還流し、およそ5時間維持した(≧107℃)。この反応混合物は、75℃〜85℃の間で、透明な溶液に変わった。
4. この反応の進行は、出発材料が認められなくなるまで、TLCによりモニタリングした[5%メタノール/ジクロロメタン;Rf(生成物)=0.35;Rf(出発材料)=0.40]。TLC分析のための試料の調製については、反応混合物アリコート〜0.5mLを水〜0.5mLにより透明な溶液として希釈し、酢酸ナトリウムによりpH〜5へと中和し、ジクロロメタン1mLにより抽出し;その有機層をスポットした。
5. この反応混合物を、〜20℃に冷却した(一晩)。白色固形物が沈殿した。この固形物をポリプロピレンフィルター上で濾過し、加圧し、固形物から可能な限り多くの臭化水素酸を除去した。
6. わずかに湿った粗生成物を、温(50℃)水(5L)に溶解した。透明な溶液を濾過し、存在する不溶性の物質を除去した。固形物を50℃の水で洗浄し、次に濾過したものを10℃に冷却した。
7. 冷却した濾液を、激しく攪拌しながら、酢酸ナトリウム(〜1.0Kg)によりpH4.5〜5.5に中和した。粘稠な白色固形物が沈殿した。この固形物を濾過により収集し、冷(〜10℃3f)水(2×1.0L)により洗浄し、風乾した。
8. 湿った粗生成物を、温(50℃)イソプロパノール(3L)中で短時間でスラリー化し、低温室(〜5℃)内で一晩放置させた。固形物を濾過により収集し、メチルtert-ブチルエーテル(2×500mL)により洗浄した。
9. 固形物を、一晩真空炉において(<30mmHg)30℃で乾燥した(第一ロット)。
10. 第二収穫物:有機濾液を総容積1.0Lまで収集し、10℃に冷却し、濾過により帯黄白色固形物を収集した。
11. この固形物を、一晩真空炉において(<30mmHg)30℃で乾燥した(第二ロット)。
第一ロット:
収量:1068g(68%)、白色固形物。
HPLC:99.4%(面積)
1H NMR:立体配座解析(conforms)(300MHz, DMSO)
第二ロット:
収量:497g(32%)、帯黄白色固形物。
HPLC:99.8%(面積)
全体の収量:1565g(99%)
(手順B:2-(4-ニトロフェニル)イミダゾ[2,1-b]ベンゾチアゾール-7-オール(2)の調製)
2. このフラスコに、2-アミノ-6-ヒドロキシベンゾチアゾール(1068g, 6.43mol, 1.0当量)及びエタノール(200pf, 32.0L)を充填し、この懸濁液を10分間攪拌した。
3. 2-ブロモ-4-ニトロアセトフェノン(1667g, 6.49mol, 1.01当量)を一気に添加した。
4. この反応混合物を還流加熱した(78℃)。還流をおよそ25時間継続し、黄色懸濁液を生じた。
5. この反応の進行は、TLCによりモニタリングした:[20%メタノール/酢酸エチル;Rf(生成物)=0.85;Rf(出発材料)=0.30]。TLCは、24時間の還流後、出発材料が〜50%であることを示した。
テトラブチルアンモニウムヨージド(10g)を添加し、更に12時間還流を継続したところ、TLCは、出発材料の〜50%が依然存在することを示した。カップリングは、チアゾール及びアミンの両方で生じるように見えた。
6. 反応混合物を、0〜5℃に冷却した。固形物を濾過により収集し、黄色固形物をエタノール200pf(2×1.0L)及びジエチルエーテル(2×1.5L)により洗浄した。
7. 固形物を、真空炉(<10mmHg)において40℃で乾燥した。
収量:930g(46%)、黄色固形物。
HPLC:99.5%(面積)
1H NMR:立体配座解析(300MHz, DMSO)
(手順C:7-(2-モルホリン-4-イル-エトキシ)-2-(4-ニトロフェニル)イミダゾ[2,1-b]ベンゾチアゾール(3)の調製)
2. このフラスコに、2-(4-ニトロフェニル)イミダゾ[2,1-b]ベンゾチアゾール-7-オール(1.770Kg)、N,N-ジメチルホルムアミド(18.0L)、4-(2-クロロエチル)モルホリン塩酸塩(2.751Kg)、炭酸カリウム(2.360Kg)及びテトラブチルアンモニウムヨージド(0.130Kg)を攪拌しながら充填した。
3. 生じた黄色懸濁液を、90℃〜95℃に加熱し、この温度でおよそ5時間維持した。
4. この反応を、出発材料が認められなくなるまで、TLCによりモニタリングした(20%メタノール/酢酸エチル;Rf(生成物)=0.15;Rf(出発材料)=0.85)。
5. 反応混合物を〜10℃に冷却し、黄色固形物を、ポリプロピレンフィルターパッド上での濾過により収集した。固形物を、水(2×5L)でスラリー化し、濾過した。
6. 湿った粗生成物を、アセトン(5L)中でスラリー化し、濾過し、かつ固形物をアセトン(2×1.5L)ですすいだ。
7. 固形物を、真空炉(<10mmHg)内で45℃で乾燥した。
収量:2.300Kg(95%)、黄色固形物。
TLC:Rf=0.15(20%メタノール/EtOAc)
HPLC:95.7%(面積)
1H NMR:立体配座解析(300MHz, DMSO)
2. この反応容器を、窒素(3×50psi)及び水素(2×50psi)でパージし、加圧下で短時間攪拌し、その後通気した。
3. オートクレーブを、水素(150psi)により加圧した。
4. この混合物を攪拌し、必要に応じ再加圧し、水素圧を150psiで24時間以上維持した。
5. この反応の進行は、TLCによりモニタリングした[10%メタノール/クロロホルム+水酸化アンモニウム1滴;Rf(生成物)0.20;Rf(7-(2-モルホリン-4-イル-エトキシ)-2-(4-ニトロフェニル)イミダゾ[2,1-b]ベンゾチアゾール)0.80]。TLCが出発材料が存在しないことを示した時点で、反応は完了し、典型的には150psiで24時間攪拌した後であった。水素添加は、150psiで、最低4時間、又は7-(2-モルホリン-4-イル-エトキシ)-2-(4-ニトロフェニル)イミダゾ[2,1-b]ベンゾチアゾールが依然存在する場合は完了するまで、継続した。
6. 反応混合物を、ガラスファイバーフィルターを装着しその上に紙フィルターを備えたブフナー漏斗を通して濾過した。あらゆる未反応の出発材料を、触媒と一緒に除去した。
7. 濾液を、総容積0.5Lまで濃縮し、残渣をメチルtert-ブチルエーテル(0.5L)により摩砕した。得られた固形物を濾過により収集し、メチルtert-ブチルエーテル(0.3L)により洗浄した。
8. 第二の収穫物:前記濾液を濃縮乾固し、残渣をメチルtert-ブチルエーテル(2L)により希釈した。得られた固形物を、濾過により収集し、メチルtert-ブチルエーテル(0.5L)により洗浄した。
9. 固形物を真空炉(<10mmHg)において25℃で乾燥した。
収量:510g(95%)、ベージュ色固形物。
TLC:Rf 0.2(10%メタノール/クロロホルム及び水酸化アンモニウム1滴)
HPLC:99.0%(面積)
1H NMR:(立体配座解析)(300MHz, DMSO)
化合物I-1のヒト代謝酵素CYP3A4、CYP2C9、CYP2D4、CYP2C19及びCYP1A2を阻害する能力を、ヒト肝ミクロソームにおいて集合的に認められたこれらの酵素を使用し評価した。被験化合物I-1は、DMSO又はアセトニトリル中の溶液として調製し、96-ウェルプレート(Nunc社)において、第一カラムに0.2%DMSO(又は2%アセトニトリル)中最終アッセイ濃度40μMで、2つ組み列で播種し、列を下に進むにつれ連続して2倍希釈した。表8に列記した所与のCYP酵素の既知の選択的阻害薬を、好適な陽性対照として選択した。各CYP酵素阻害アッセイに関して、好適な酵素-基質混合物を調製し、各CYP酵素アッセイに関して表8に示した好適な基質の量を含む、最終アッセイ濃度75mM KPO4/pH7.4、6.5mM MgCl2、0.25mg/mLプールした男性及び女性ヒト肝ミクロソーム(CellzDirect社、ロットHMMC-PL020)を供した。この酵素−基質混合物を、カラム1から10に添加し、カラム11は基質を欠く酵素溶液の陰性対照として使用した。その後NADPH-非依存性非-CYP-介在性代謝を検出するために、NADPHをインキュベーション期間後に添加する1列を除き、全ての列にNADPH(Calbiochem社)の溶液を添加した。プレートを、短時間ボルテックスし、37℃の水浴中で20分間振盪させた。酵素活性は、3:1アセトニトリル/H2O+0.05%ギ酸及び表8において各CYP阻害アッセイに関して示された好適な内部標準を含有する停止液を用いて終結させた。その後NADPHを第一のカラムに添加し、プレートをボルテックスし、その後3600rpmで10分間遠心した。ウェルを0.05%ギ酸を含むアセトニトリル/水で1:1に更に希釈し、その後表8に列記された対応するCYP代謝産物の形成をLC-MSにより検出した。IC50値は、係数を1に固定したHill式により作製した曲線から得た。各CYP酵素に関する化合物I-1のIC50値は、表8に示し、これは所与のCYP酵素活性を50%阻害するのに必要な化合物I-1の量を表している。
癌細胞の生存率及び増殖は、様々なレドックス酵素による、レサズリン-含有色素CTB(Cell Titer Blue(登録商標), Promega社#G8081)の高蛍光レソルフィンへの還元を測定する蛍光アッセイを用いて測定し、ここで代謝活性は細胞生存度の測定と見なされる。
(試験デザイン)
ラットに、化合物I-1を投与量1mg/kgで静脈内に又は投与量10mg/kgで経口のいずれかで投与した。血液試料を、24時間の時間経過にわたり採取した。血漿を、化合物I-1について分析し、その薬物動態パラメータを決定した。
予めカテーテル留置した(頚静脈)雄のSprague-Dawleyラット(230〜300g)を、Charles River社(ホリスター、CA)から入手し、これらを配達後試験開始前に少なくとも3日間、Rabbit and Rodent Diagnostic Associates(サンディエゴ、CA)の飼育室において馴化した。ラットは、静脈内又は経口投薬前に一晩絶食させた。静脈内投薬に関して、化合物I-1は、PEG400:H2O(注射用水)3:1溶液中に溶解し、投与量1mg/kgで投与した。経口投薬に関して、化合物I-1は、22%ヒドロキシプロピル-β-シクロデキストリン(HPBCD)溶液に溶解し、かつ投与量10mg/kgで投与した。血液を、抗凝固薬としてK3EDTAを使用し、投与後5分(IVのみ)、15分、30分、1時間、2時間、4時間、6時間、及び24時間後に採取し、かつ血漿を化合物I-1の分析用に収集した。
化合物I-1の薬物動態パラメータは、WinNonlin v5.2(Pharsight社、マウンテンビュー、CA)のノンコンパートメントモデルを用い、各動物の血漿濃度−時間プロファイルを基に算出した。
試薬:1×等張PBS(Mediatech社、ヘルンドン、VA);96ウェル平衡透析装置(Harvard Apparatus社、ホリストン、MA)、及び注目種の動物血漿。
被験化合物1μM溶液を、等張PBS及び等張PBS中10%動物血漿の両方中に調製した。
試料、較正標準及び定量対照標準の50μlを、内部標準25ng/mlを含有するアセトニトリル100μlで抽出した。
移動相A=水中0.05%ギ酸
移動相B=アセトニトリル中0.05%ギ酸
1.6ml/分で、0.2〜0.8分間に、5%〜90%のBの勾配で溶出。
10%血漿中の非結合画分を算出した。Fu(10%)=1−((PC-PF)/PC)
10%血漿値を100%へ変換した。Fu(100%)=Fu10%/(10−9*Fu10%)。
本明細書において使用される競合結合アッセイは、Fabianらの論文、Nature Biotechnology, 23(3):329-336(2005)に記載されているように開発し、バリデーションしかつ実行した。キナーゼは、T7ファージへの融合物として作製されるか(Fabianらの論文、又はWO04/015142を参照されたい)、あるいはキナーゼはHEK-293細胞において発現され、引き続きPCR検出のためにDNAでタグづけされた(WO08/005310を参照されたい)。結合アッセイに関して、ストレプトアビジンでコートされた磁気ビーズを、ビオチニル化された親和性リガンドにより、室温で30分間処理し、親和性樹脂を作製した。リガンド化されたビーズは、過剰なビオチンによりブロックし、かつブロック緩衝液(SeaBlock(Pierce社)、1%BSA、0.05%Tween 20、1mM DTT)により洗浄し、未結合のリガンドを除去し、かつ非特異的結合を減少した。結合反応は、1×結合緩衝液(20%SeaBlock、0.17×PBS、0.05%Tween 20、6mM DTT)中で、キナーゼ、リガンド化された親和性ビーズ、及び被験化合物により組み立てた。被験化合物は、DMSO中100×ストック液として調製し、かつ水性環境に直ちに希釈した。DMSOを、被験化合物を欠いている対照アッセイに添加した。一次スクリーニング相互作用を、ポリプロピレン製384-ウェルプレートにおいて、最終容積34μLで実行し、他方でKd決定を、ポリスチレン製96-ウェルプレートにおいて最終容積135μLで実行した。これらのアッセイプレートを、室温で、結合反応が平衡に到達するのに十分な時間である1時間振盪しながらインキュベーションし、かつ親和性ビーズを、過剰な洗浄緩衝液(1×PBS、0.05%Tween 20)により洗浄し、未結合のタンパク質を除去した。その後ビーズを、溶出緩衝液(1×PBS、0.05%Tween 20、2μMビオチニル化されない親和性リガンド)中で再浮遊させ、かつ室温で30分間振盪しながらインキュベーションした。溶出液中のキナーゼ濃度を、定量的PCRにより測定した。各キナーゼを、各化合物に対し個別に試験した。Kdは、11の連続3倍希釈を用い決定した。
本試験の目的は、化合物I-1が、CYPアイソフォーム3A4、2C19及び2C8の時間依存型阻害剤であるかどうかを決定することであった。
本試験は、ヒトCYPアイソフォーム3A4、2C19及び2C8に関する阻害定数KIを決定し、かつ阻害の型(競合的、非競合的、又は不競合的)を特徴付けるためにデザインした。
本アッセイの目的は、有害な心臓事象の基となる最も一般的な機序である、hERG心カリウムイオンチャネルの阻害を判定することである。この電流は、心筋細胞再分極にとって重要であり、かつQT間隔を延長する薬物の共通の標的である。従って本試験における被験物質は、hERGチャネルを阻害するそれらの能力について判定することを特徴とした。イオンチャネル活性は、hERG mRNAを発現している安定してトランスフェクションされたチャイニーズハムスター卵巣(CHO)細胞株を用いて測定した。
外液:2mM CaCl2;2mM MgCl2;4mM KCl;150mM NaCl;10mMグルコース;10mM HEPES;310-320mOsm;pH7.4(1M NaOHで調節)。
内液:140mM KCl;10mM MgCl2;6mM EGTA;5mM HEPES-Na;5mM ATP-Mg;300-320mOsm;pH7.25(1M KOHで調節)。
本試験は、化合物I-1の水性及び界面活性剤への溶解度を得、かつMDR1-MDCK細胞モデルシステムにおける化合物I-1の基質及び阻害剤を流出させる能力を特徴付けるために行った。阻害剤試験に関して、ジゴキシンの二方向輸送に対する化合物I-1の作用を評価した。
DMSOストックのアリコートを、pH7.4の、25mM HEPES(HBSS)を含有するハンクス平衡塩溶液又は0.05%ポリソルベート80を含有するHBSSのいずれかに移し、溶質及び2.5%DMSO中標的濃度250μMとした。この溶液を室温で一晩平衡とした後、濾過し、試料を更に希釈することなく、高速勾配HPLCにより溶質濃度を決定した。UV/VIS/MS検出を、1、5、10、50、100及び250μM分析標準を参照し使用した。これらの分析標準は、10mM試料ストック10μlを50:50(v/v)アセトニトリル/水190μlに希釈することにより作製した中間体ストック液500μMから調製した。この溶液のアリコートを、0.4、2、4、20、40、及び100μlの量で、96ウェルプレートへ2つ組みで移し、アセトニトリル/水で総容積200μlとし、次にこのプレートをフォイルシートで密封し加熱した。試料濾過の前に、フィルターを、試料600μlによりプライミングし、可能性のある吸着の問題点を解決した。両方の試料の反復を、プライミングしたフィルターを通じて収集した。2つ組みでの測定を全ての場合において行った。
MDR1-MDCK細胞は、24-ウェルプレートにおいて1μmフィルター上で5〜10日間集密になるまで増殖した。DMSO溶質ストックのアリコートを、25mM HEPES+〜0.05%PS80を含有するハンクス平衡塩溶液(HBSS)pH7.4に希釈し、溶質濃度0.5、1.5又は5.0μMとした。アッセイ試料中のDMSO最終濃度は、0.5μM濃度に関しての0.005%から5μM濃度に関して0.05%までの範囲であった。この濃度範囲のDMSOは、単層又は輸送特性に影響を及ぼさないことは既に示されている。溶質を含有するドナー溶液を、透過性拡散装置の先端又は基底外側のいずれかのチャンバーへ移した。レシーバー溶液は、25mM HEPES+0.05%PS80を含有するハンクス平衡塩溶液(HBSS)pH7.4からなる。レシーバー溶液全てを20分インターバルで除去し、手作業で新鮮な緩衝液と交換した。各試料採取インターバルの間に輸送された溶質の濃度を、HPLC/UV/MSにより決定した。投薬溶液(dosing solution)の連続希釈から、標準曲線を作製した。D0は、450μl HBSSで希釈したドナーウェルからの投薬溶液の50μlアリコートであった。この標準曲線は、投薬溶液の連続希釈(1:10、1:25、1:50、1:100、1:500及び1:1000)から作製した。透過性係数は、下記式を用い、各試料採取インターバルについて算出した。
Claims (31)
- 式Iの化合物、又はそれらの医薬として許容し得る塩、溶媒和物、水和物若しくはプロドラッグ:
i)R1及びR2は各々、-CH3、及び-CH2OHから選択され;かつ、R3は、-CH3、-CH(OH)2、-CHO、-CH2OH、
ii)R1、R2及びR3は各々、-CH3及び-COOHから選択される;から選択され、かつ
R4は:
- 請求項1又は2記載の化合物の水和物。
- 請求項1又は2記載の化合物のプロドラッグ。
- 前記化合物が、精製された化合物である、請求項1〜4のいずれか1項記載の化合物。
- 固形である、請求項1〜5のいずれか1項記載の化合物。
- 請求項1〜6のいずれか1項記載の化合物の治療的有効量及び医薬として許容し得る担体、賦形剤又は希釈剤を含有する医薬組成物。
- 化学療法薬、抗増殖薬、抗炎症薬、免疫調節薬、免疫抑制薬又は制吐薬から選択される第二の治療薬を更に含有する、請求項8記載の組成物。
- 請求項1〜6のいずれか1項記載の化合物の治療的有効量を患者へ投与することを含む、患者における増殖性疾患の治療方法。
- 前記増殖性疾患が、癌である、請求項9記載の方法。
- 前記癌が、白血病である、請求項10記載の方法。
- 前記白血病が、急性骨髄性白血病である、請求項11記載の方法。
- 前記白血病が、再発した又は不応性である、請求項11又は12記載の方法。
- 前記白血病が、薬剤抵抗性白血病である、請求項11又は12記載の方法。
- 前記癌が、薬剤抵抗性癌である、請求項10記載の方法。
- 前記薬剤抵抗性癌が、イマチニブ、スニチニブ、ゲフィチニブ、エルロチニブ、ニロチニブ、ダサチニブ、ラパチニブ又はソラフェニブに対し抵抗性である、請求項15記載の方法。
- 前記薬剤抵抗性白血病が、FLT3キナーゼ阻害薬に対し抵抗性である、請求項14記載の方法。
- 前記薬剤抵抗性白血病が、PKC 412、MLN 578、CEP-701、CT 53518、CT-53608、CT-52923、D-64406、D-65476、AGL-2033、AG1295、AG1296、KN-1022、PKC-412、SU5416、SU5614、SU11248、L-00021649、又はCHIR-258に対し抵抗性である、請求項14記載の方法。
- 前記薬剤抵抗性白血病である哺乳動物が、構成的に活性化されたFLT3変異を有する、請求項17〜18のいずれか1項記載の方法。
- 前記対象に第二の治療薬の治療的有効量を投与することを更に含む、請求項9〜19のいずれか1項記載の方法。
- 前記第二の治療薬が、抗癌剤である、請求項20記載の方法。
- 前記抗癌剤が、アドリアマイシン、ブスルファン、シタラビン、シクロホスファミド、デキサメタゾン、フルダラビン、フルオロウラシル、ヒドロキシ尿素、インターフェロン、オブリメルセン、白金誘導体、タキソール、トポテカン、及びビンクリスチンからなる群から選択される、請求項21記載の方法。
- 前記抗癌剤が、PKC 412、MLN 578、CEP-701、CT 53518、CT-53608、CT-52923、D-64406、D-65476、AGL-2033、AG1295、AG1296、KN-1022、PKC-412、SU5416、SU5614、SU11248、L-00021649、及びCHIR-258からなる群から選択されるFLT3キナーゼ阻害薬である、請求項22記載の方法。
- 前記癌が、固形腫瘍である、請求項10記載の方法。
- 前記癌が、膀胱癌、乳癌、子宮頸癌、CNS癌、結腸癌、食道癌、頭頸部癌、肝癌、肺癌、鼻咽腔癌、神経内分泌癌、卵巣癌、膵癌、前立腺癌、腎癌、唾液腺癌、小細胞肺癌、皮膚癌、胃癌、精巣癌、甲状腺癌、子宮癌、又は血液悪性腫瘍である、請求項24記載の方法。
- 請求項1〜6のいずれか1項記載の化合物の治療的有効量を患者へ投与することを含む、患者における自己免疫疾患の治療方法。
- 前記自己免疫疾患が、関節リウマチ、狼瘡又は多発性硬化症、甲状腺炎、1型糖尿病、サルコイドーシス、炎症性腸疾患、クローン病又は全身性狼瘡である、請求項26記載の方法。
- 請求項1〜6のいずれか1項記載の化合物の治療的有効量を患者へ投与することを含む、患者における炎症疾患の治療方法。
- 前記疾患が、FLT3-介在性疾患、KIT-介在性疾患、RET-介在性疾患、PDGFR-介在性疾患、VEGFR-介在性疾患又はCSF-1R-介在性疾患である、請求項28記載の方法。
- 前記疾患が、FLT3-介在性疾患、KIT-介在性疾患、RET-介在性疾患、PDGFR-介在性疾患、VEGFR-介在性疾患又はCSF-1R-介在性疾患である、請求項26記載の方法。
- 前記疾患が、FLT3-介在性疾患、KIT-介在性疾患、RET-介在性疾患、PDGFR-介在性疾患、VEGFR-介在性疾患又はCSF-1R-介在性疾患である、請求項9記載の方法。
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