JP7497046B2 - Egfr二量体撹乱剤およびその使用 - Google Patents
Egfr二量体撹乱剤およびその使用 Download PDFInfo
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- JP7497046B2 JP7497046B2 JP2020544510A JP2020544510A JP7497046B2 JP 7497046 B2 JP7497046 B2 JP 7497046B2 JP 2020544510 A JP2020544510 A JP 2020544510A JP 2020544510 A JP2020544510 A JP 2020544510A JP 7497046 B2 JP7497046 B2 JP 7497046B2
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- triazaspiro
- cancer
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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Description
の化合物またはその薬学的に許容される塩を提供する。
Xは、O-C0~6アルキレン、S-C0~6アルキレン、またはNR3-C0~6アルキレンであり、当該アルキレンは、任意選択的に、独立して、ハロ、N(R3)2、およびOR3から選択される1~3個の基で置換され、
Yは、C0~6アルキレンであり、当該アルキレンは、任意選択的に、独立して、ハロ、N(R3)2およびOR3から選択される1~3個の基で置換され、
Aは、C6~10アリールまたはN、O、およびSから選択される1~4個のヘテロ原子を有する5~10員ヘテロアリールであり、当該アリールまたはヘテロアリールは、任意選択的に、1~3個のR4で置換され、
Bは、C6~10アリール、N、O、およびSから選択される1~4個のヘテロ原子を有する5~10員ヘテロアリール、3~8員シクロアルキル環、またはO、S、およびNから選択される1~3個の環ヘテロ原子を有する3~12員ヘテロシクロアルキルであり、当該アリール、ヘテロアリール、シクロアルキル、またはヘテロシクロアルキルは、任意選択的に、1~3個のR5で置換され、
各R1およびR2は、独立して、C1~6アルキルであるか、あるいはR1およびR2は、それらが結合している炭素原子と共に、4~8員シクロアルキルまたはヘテロシクロアルキル環を形成し、ヘテロシクロアルキル環は、O、S、およびNから選択される1個または2個の環ヘテロ原子を有し、当該シクロアルキル環またはヘテロシクロアルキル環は、任意選択的に、1~2個のR6で置換され、
各R3は、独立して、HまたはC1~6アルキルであり、
各R4およびR5は、独立して、C1~6アルキル、C1~6ハロアルキル、ハロ、またはC1~6アルコキシであり、
R6は、C1~6アルキル、C1~6ハロアルキル、(C=O)R3、(C=O)OR3、CON(R3)2、C0~3アルキレン-C3~8シクロアルキル、C0~3アルキレン-C6~10アリール、またはC0~3アルキレン-(N、O、およびSから選択される1~4個のヘテロ原子を有する5~10員ヘテロアリール)であり、アリールまたはヘテロアリールは、任意選択的に、1~3個のR5で置換される。)
の構造を有する化合物、またはその薬学的に許容される塩が本明細書で提供される。
本明細書で使用される場合、用語「アルキル」は、1~30個の炭素原子、例えば1~20個の炭素原子、または1~10個の炭素原子を含有する直鎖状および分枝状の飽和炭化水素基を指す。Cnという用語は、アルキル基が「n」個の炭素原子を有することを意味する。例えば、C4アルキルは、4個の炭素原子を有するアルキル基を指す。C1~C7アルキルとは、全範囲(例えば、1~7個の炭素原子)、ならびに全てのサブグループ(例えば、1~6、2~7、1~5、3~6、1、2、3、4、5、6、および7個の炭素原子)を包含する炭素原子数を有するアルキル基を指す。アルキル基の非限定的な例としては、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、sec-ブチル(2-メチルプロピル)、t-ブチル(1,1-ジメチルエチル)、3,3-ジメチルペンチル、および2-エチルヘキシルが挙げられる。別途指示されない限り、アルキル基は、非置換アルキル基または置換アルキル基であり得る。
本明細書に開示される化合物は、市販の出発物質、文献で知られている化合物を使用して、または容易に調製された中間体から、当業者に既知のまたは本明細書の教示に照らした標準的な合成方法および手順を採用することによって、様々な方法で調製することができる。本明細書に開示される化合物の合成は、一般に、実施例の節に記載されている合成スキームに従い、特定の所望の置換基を変更することにより達成することができる。
本明細書に記載の化合物(例えば、式(I)の化合物、またはその薬学的に許容される塩)、および薬学的に許容される賦形剤を含む医学的製剤がさらに提供される。
本明細書に記載の化合物は、EGFRを調節することができる。一部の実施形態では、化合物は、EGFRの二量体化を阻害する。様々な実施形態では、化合物は、EGFRの分解を誘導する。
アセトアミド7Aを使用して、一般手順Aに従った。粗生成物を、10%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.31(d,J=2.29 Hz,1H),7.74-7.86(m,5H),6.78(d,J=8.87 Hz,1H),4.14(s,2H),3.79(s,3H),2.50-2.67(m,4H),2.24(s,3H),1.55-1.75(m,4H);MS(ESI+m/z 503.10,ESI-m/z 501.10);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.56。
アセトアミド7Bを使用して、一般手順Aに従った。粗生成物を、10%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.63(s,1H),8.10(br d,J=9.15 Hz,1H),7.85(q,J=8.23 Hz,4H),7.53(d,J=8.60 Hz,1H),4.24(s,2H),2.56-2.81(m,4H),2.27(br s,3H),1.55-1.85(m,4H);MS(ESI+m/z 507.95,ESI-m/z 505.95);TLC:(95:5:0.5,DCM:MeOH:NH4OH)Rf=0.17。
アセトアミド7Cを使用して、一般手順Aに従った。粗生成物を、10%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.89(br s,1H),8.95(s,1H),8.67(s,1H),7.96(br d,J=8.33 Hz,1H),7.92(br d,J=8.33 Hz,1H),7.78-7.87(m,4H),7.52-7.72(m,2H),4.29(s,2H),2.43-2.52(m,4 H),2.18(br s,3H),1.55-1.85(m,4H);MS(ESI+m/z 523.05,ESI-m/z 521.00);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.47。
アセトアミド7Dを使用して、一般手順Aに従った。粗生成物を、13%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.41(br d,J=6.13 Hz,2H),7.78(q,J=8.51 Hz,4H),7.52(d,J=6.04 Hz,2H),4.18(s,2H),2.50-2.73(m,4 H),2.19(br s,3H),1.28-1.91(m,4H);MS(ESI+m/z 473.05,ESI-m/z 471.05);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.24。
アセトアミド7Eを使用して、一般手順Aに従った。一般手順Aにおけるワークアップ手順に従って、カラム精製なしで標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ8.04(br d,J=7.78 Hz,1H),7.78(q,J=8.63 Hz,4H),3.89(s,2H),3.45-3.55(m,1H),2.50-2.71(m,4 H),2.29(s,3H),1.58-1.80(m,7H),1.51(br d,J=12.44 Hz,1H),1.05-1.28(m,6 H);MS(ESI+m/z 478.90,ESI-m/z 476.90);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.60。
アセトアミド7Fを使用して、一般手順Aに従った。粗生成物を、10%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ8.15(br d,J=6.77 Hz,1H),7.79(q,J=8.42 Hz,4H),3.92-4.01(m,1H),3.91(s,2H),2.50-2.71(m,4 H),2.32(s,3H),1.58-1.82(m,8H),1.45-1.54(m,2H),1.38(td,J=6.27,12.35 Hz,2H);MS(ESI+m/z 464.10,ESI-m/z 462.15);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.62。
アセトアミド7Gを使用して、一般手順Aに従った。粗生成物を、10%メタノール/ジクロロメタン溶液で溶出が起こるフラッシュクロマトグラフィーにより精製して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ8.65(br t,J=5.81 Hz,1H),7.73-7.82(m,4H),7.17-7.30(m,5H),4.27(d,J=5.95 Hz,2H),3.99(s,2H),2.50-2.73(m,5 H),2.28(s,3H),1.66(br s,3H);MS(ESI+m/z 486.00,ESI-m/z 484.10);TLC:(90:10:0.5,DCM:MeOH:NH4OH)Rf=0.59。
tert-ブチル2-(4-メトキシフェニル)-3-オキソ-1,4,8-トリアザスピロ[4.5]デカ-1-エン-8-カルボキシレートの溶液、無水DMF中の1に、水素化ナトリウム(2当量)を添加した。反応混合物を、40℃に30分間加温した。次に、2-クロロ-N-(3-クロロ-4-メトキシフェニル)アセトアミド塩酸塩、2(1.76当量)を、反応混合物に添加した。反応混合物を40℃に保ち、N2の流下で攪拌した。5時間後、TLCは出発物質が残留していることを示したが、反応を精製した。粗反応混合物を、室温に冷却し、次いでシリカ上に装填した。ドライロードされた材料を、ドライロードカラムに入れて、充填した。ドライロードカラムを、事前に平衡化した(ヘプタン中1%の酢酸エチル)シリカカラムの上に配置した。粗生成物を、ヘプタン中1~100%の酢酸エチルの勾配で溶出するフラッシュクロマトグラフィーを使用して精製した。所望の画分(50%の酢酸エチルで溶出)を収集し、減圧下で濃縮して、標題化合物を得た。1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.46(d,J=8.97 Hz,2H),7.55(d,J=2.56 Hz,1H),7.27-7.39(m,1H),6.99(d,J=8.97 Hz,2H),6.84(d,J=8.87 Hz,1H),4.01-4.22(m,2H),3.88(s,3H),3.86(s,3H),3.39(m,2H),2.21(dt,J=4.80,12.69Hz,2H),1.50(s,9H),1.19-1.40(m,4H);MS(ESI+m/z 501,ESI-m/z 556.15);TLC:(50:50 EA:HEP)Rf=0.21。
3の溶液、無水ジオキサン中のtert-ブチル4-(2-((3-クロロ-4-メトキシフェニル)アミノ)-2-オキソエチル)-2-(4-メトキシフェニル)-3-オキソ-1,4,8-トリアザスピロ[4.5]デカ-1-エン-8-カルボキシレートに、ジオキサン中の4MのHCl(3.3当量)を添加した。1時間後、TLCで反応が観察されなかったため、ジオキサン(3.3当量)中の4MのHClの追加部分を追加した。1時間後、新しいスポット(ベースライン)が観察されたが、出発物質が残留していた。ジオキサン(3.3当量)中の4MのHClの追加部分を添加し、反応混合物を、40℃で一晩撹拌した。一晩、反応混合物中に黄色沈殿が形成された。固体をフリット漏斗で濾過し、過剰のジオキサンですすいだ。固体をバイアルに移し、減圧下で乾燥して、標題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.22(br d,J=9.70 Hz,1H),8.93(br d,J=10.70 Hz,1H),8.39(d,J=8.97 Hz,2H),7.78(d,J=2.47 Hz,1H),7.45(dd,J=2.52,9.01Hz,1H),7.07-7.14(m,3H),4.98(br s,2H),4.25(s,2H),3.84(s,3H),3.81(s,3H),3.39-3.48(m,2H),3.25-3.39(m,2H),1.55(br d,J=13.45Hz,2H);MS(ESI+m/z 457.10,ESI-m/z 455.10);TLC:(95:5:0.5,DCM:MeOH:NH4OH)Rf=0.03。
4の溶液、メタノール中のN-(3-クロロ-4-メトキシフェニル)-2-(3-(4-メトキシフェニル)-2-オキソ-1,4,8-トリアザスピロ[4.5]デカ-3-エン-1-イル)アセトアミド塩酸塩に、ホルムアルデヒド水溶液(37重量%溶液、7当量)を添加した。反応混合物を5分間撹拌し、次いでトリアセトキシボロヒドリド(3当量)を添加した。反応混合物を室温で一晩撹拌した。翌朝、TLC(95:5:0.5、DCM:MeOH:NH4OH)で、新しいより高いスポットRfを伴って、反応が完了したこと示した。粗反応物を分液漏斗に注いだ。分液漏斗にジクロロメタンを添加した。有機層を飽和NaHCO3水溶液(1x)、続いてブライン(1x)で洗浄した。有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で濃縮して、表題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.34(d,J=8.97 Hz,2H),7.74(d,J=2.47 Hz,1H),7.39(dd,J=2.56,8.97Hz,1H),7.03-7.12(m,3H),4.24(s,2H),3.81(s,3H),3.80(s,3H),2.78(br s,2H),2.29(br s,3H),2.15-2.26(m,2H)1.13-1.33(m,3H);MS(ESI+m/z 471.10);TLC:(95:5:0.5,DCM:MeOH:NH4OH)Rf=0.23。
実施例12~14-化合物10、11、および12の合成
tert-ブチル2-(4-メトキシフェニル)-3-オキソ-1,4,8-トリアザスピロ[4.5]デカ-1-エン-8-カルボキシラートの溶液、無水THF中の1、にローソン試薬(1当量)を添加した。反応混合物を室温で48時間撹拌した後、粗生成物をフラッシュクロマトグラフィーにより精製した。粗反応混合物をシリカ上にドライロードした。ドライロードされた材料をドライロードカラムに入れ、充填した。ドライロードカラムを、事前に平衡化した(ヘプタン中2%の酢酸エチル)シリカカラムの上に配置した。粗生成物を、ヘプタン中の2~100%の酢酸エチルの勾配で溶出するフラッシュクロマトグラフィーを使用して精製した。所望の画分(50%の酢酸エチルでの溶出)を収集し、減圧下で濃縮して、粗固形物を得た。固体をヘプタン、ジクロロメタン、および酢酸エチルの混合物(3:2:1 v/v)で粉砕し、フリット漏斗で濾過して、9 tert-ブチル2-(4-メトキシフェニル)-3-チオキソ-1,4,8-トリアザスピロ[4.5]デカ-1-エン-8-カルボキシレートを得た。MS(ESI+m/z 376.9,ESI-m/z 374.9);TLC:(95:0.5:0.5,DCM:MeOH:NH4OH)Rf=0.68。
10の溶液、無水ジオキサン中のtert-ブチル 2-(4-メトキシフェニル)-3-((2-((6-メトキシピリジン-3-イル)アミノ)-2-オキソエチル)チオ)-1,4,8-トリアザスピロ[4.5]デカ-1,3-ジエン-8-カルボキシレートに、ジオキサン中の4MのHCl(3当量)を添加した。2時間後、TLCで出発物質は観察されず、新しいスポット(ベースライン)が形成された。反応混合物中に黄色沈殿が形成された。固体をフリット漏斗で濾過し、過剰のジオキサンですすいだ。固体が不純であったため、最小量のジクロロメタンを使用してシリカカラム上に装填した。ジクロロメタン中のメタノールの勾配(0~15%)を使用して、フラッシュクロマトグラフィーを介して生成物を溶出した。生成物画分を減圧下で濃縮して、表題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.45-8.60(br s,1H),8.25-8.43(m,1H),7.85-7.93(m,3H),7.12(d,J=8.87 Hz,2H),6.80(d,J=8.78 Hz,2H),4.18(s,2H),3.84(s,3H),3.81(s,3H),3.22-3.56(m,4H),1.84-2.01(m,2H),1.60-1.75(m,2H);MS(ESI+m/z 440.10,ESI-m/z 438.10);TLC:(50:50,EA:Hep)Rf=0.25。
11の溶液、95:5のジクロロメタン:メタノール中の2-((3-(4-メトキシフェニル)-1,4,8-トリアザスピロ[4.5]デカ-1,3-ジエン-2-イル)チオ)-N-(6-メトキシピリジン-3-イル)アセトアミド塩酸塩に、ホルムアルデヒド水溶液(37重量%の溶液、7当量)を添加した。反応混合物を1時間撹拌し、次いでトリアセトキシボロヒドリド(3当量)を添加した。反応混合物を室温で一晩撹拌した。翌朝、TLC(95:5:0.5、DCM:MeOH:NH4OH)は、新しいより高いRfスポットを伴って、反応が完了したことを示した。粗反応物を分液漏斗に注いだ。分液漏斗にジクロロメタンと水を添加した。有機層を分離し、ブラインで洗浄した(1x)。有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で濃縮して、粗生成物を得た。粗生成物が不純であったため、最小量のジクロロメタンを使用してシリカカラム上に装填した。ジクロロメタン中のメタノールの勾配(0~10%)を使用して、フラッシュクロマトグラフィーを介して生成物を溶出した。生成物画分を減圧下で濃縮して、表題化合物を得た。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.35(d,J=2.38 Hz,1H),7.85-7.91(m,3H),7.12(d,J=8.02 Hz,2H),6.81(d,J=9.06 Hz,1H),4.16(s,2H),3.85(s,3H),3.82(s,3H),2.53-2.81(m,4H),2.15-2.40(m,2H),1.92(s,3H),1.50-1.80(m,2H);MS(ESI+m/z 454.10,ESI-m/z 452.10);TLC:(95:5:0.5,DCM:MeOH:NH4OH)Rf=0.22。
化合物33a 2-((3-(4-ブロモフェニル)-8-イソプロピル-1,4,8-トリアザスピロ[4.5]デカ-1,3-ジエン-2-イル)チオ)-N-(キノリン-3-イル)アセトアミド。1H NMR(400 MHz,DMSO-d6)δ10.81(s,1H),8.97-8.90(m,1H),8.00-7.95(m,1H),7.95-7.90(m,1H),7.89-7.83(m,2H),7.83-7.77(m,2H),7.71-7.63(m,1H),7.62-7.55(m,1H),4.26(s,2H),2.73-2.60(m,4H),1.88-1.71(m,2H),1.62-1.40(m,2H),0.90(s,3H),0.88(s,3H)。
メチルアミノ(4-フルオロフェニル)アセテートHClを28%の水酸化アンモニウム(5mL/g)溶液中で96時間撹拌すると、2-アミノ-2-(4-フルオロフェニル)アセトアミドが白色沈殿として生成され、これを濾過して収集し、さらに精製することなく使用した。エタノール(0.1M)中の2-アミノ-2-(4-フルオロフェニル)アセトアミド(1当量)の溶液に、tert-ブチル4-オキソ-1-ピペリジンカルボキシレート(1当量)を添加し、反応混合物を加熱して12時間還流した。反応混合物を室温に冷却し、減圧下で濃縮した。得られた残留物をDCM(0.1M)に溶解し、N-ブロモスクシンイミド(1当量)を添加した。反応混合物を8時間撹拌し、飽和重炭酸ナトリウムを添加した。得られた混合物をDCMで抽出した。有機物を乾燥させ、濃縮し、FCC(ヘキサン中0~100%のEtOAc)で精製して、tert-ブチ2-(4-フルオロフェニル)-3-オキソ-1,4,8-トリアザスピロ[4.5]デカ-1-エン-8-カルボキシレートを提供した。1H NMR(400 MHz,DMSO-d6)δ10.28(s,1H),8.48-8.37(m,2H),7.41-7.31(m,2H),3.71-3.50(m,4H),1.79-1.69(m,2H),1.68-1.56(m,2H),1.44(s,9H)。
実施例44-精製されたEGFRキナーゼドメインとディスラプチンとの間の相互作用
WT-EGFRキナーゼドメイン(aa696~1022、活性キナーゼ)を発現させ、SF9昆虫細胞から精製した。100ngの純粋なEGFRをビオチン結合ディスラプチンとインキュベートし、結合したEGFRをクエン酸バッファーで洗浄した後、CaptAvidinビーズを使用して捕獲した。この相互作用の特異性は、この反応をビオチン化されていないディスラプチンの量を増やしながら共インキュベートすることによって確認した。結合したEGFRタンパク質をLaemmliバッファーで遊離し、SDS-PAGEで分離した。ディスラプチン結合EGFRは、ImageJソフトウェアを使用して定量化し、ブロットの下に表示した。非標識(cold)ディスラプチンによるディスラプチン-EGFR結合の競合阻害は、ディスラプチンがEGFRに直接結合することを示す(図2Bを参照)。
NCI-H1975細胞を10μMのディスラプチンで1時間処理し、さらにEGF(30ng/ml)で30分、およびスベリン酸ジサクシンイミジル(DSS、150μM)で30分処理して、相互作用するタンパク質を架橋した。溶解物を調製し、抗EGFR抗体でイムノブロットした。(図3Aを参照)。
NCI-H1975異種移植を有するマウスに、1日目と2日目にディスラプチン(10mg/kg、腹腔内)を注射した。3日目に腫瘍を除去し、イムノブロット用に準備した(図3Bを参照)。2日連続の(月曜日と火曜日)ディスラプチンの注射(10mg/kg、i.p.)を伴う2週間の処置後、NCI-H1975異種移植に対するディスラプチンの効果を評価した。各処置条件について、腫瘍体積をプロットした。スクランブルペプチドを対照として使用した(図3Cを参照)。処置の2週間後、腫瘍を免疫染色することによって、腫瘍組織学、EGFR発現、および分裂指数(Ki-67スコアによる測定)に対する処置の長期効果を評価した(図3Dを参照)。
ディスラプチンは、TKI(エルロチニブ)耐性NCI-H1975異種移植モデルに対して有効であることが示された(図3A~図3Dを参照)(14)。しかしながら、不良なPK、およびペプチド薬の開発上のその他の課題のため、同様の作用メカニズムを有するが、優れた薬物動態の小分子を開発するための創薬プログラムを実施した(図4A~図4Dを参照)。活性EGFR二量体の界面に基づいて、仮想スクリーニング、商用ライブラリの取得、およびカスタム合成を使用して、プレリード化合物95(C95)および67(C67)を含む一連の新規分子を開発した(図4A~図4Dを参照)。これらのプレリード分子はどちらも、エルロチニブ耐性NCI-H1975異種移植モデルに対して、インビボで活性である。EGFR二量体阻害のインビボ活性を試験するために、TKI耐性NCI-H1975 EGFRレポーター細胞を使用した。これらの腫瘍異種移植片では、EGFR活性の減少時に、生物発光が誘導される(47)。100mg/kgのC95を1回注射すると、EGFRレポーターが2.5倍誘導され、48時間持続した(図9を参照)。EGFRレベルの低下に対するC95処置の効果が、生物発光の変化と相関することが確認された。これらのデータは、EGFRの分解を誘導することができる薬剤が、TKI耐性腫瘍に有効であり得ることを示す。
化合物8CがEGFR上の同じ結合部位に対して競合するかどうかを決定するために、ビオチン-ディスラプチン-アビジン結合ビーズを、化合物8Cの存在下または非存在下で、37℃で15分間精製EGFRとインキュベートした。アガロースビーズを遠沈し、クエン酸バッファーで洗浄することによって非特異的タンパク質を除去した。結合したタンパク質をLaemmliバッファーで遊離し、SDS-PAGEで分離した。化合物8Cによるディスラプチン-EGFR結合の競合阻害は、この分子が同様なメカニズムで作用すること示唆する(図5Aを参照)。
化合物8Cの選択性を試験するために、オシメルチニブ耐性肺癌細胞株(PC9-AZRおよびHCC827-AZR)を、正常な肺線維芽細胞(MRC5)と共に、様々な濃度で処理し、細胞生存をクローン原性生存アッセイを使用して決定した(以下の図7Aおよび表3を参照)。これらの予備データは、化合物8Cが、EGFRにより駆動される癌細胞を選択的に死滅させることを示唆する。化合物8Cへの応答が、EGF誘導二量体化およびEGFR分解の阻害と相関するかどうかを決定した。このため、PC9-AZR細胞を1μMの化合物8Cで1時間処理し、さらにEGF(30ng/ml)で30分、スベリン酸ジサクシンイミジル(DSS、150μM)で30分処理して、相互作用するタンパク質を架橋した。溶解物を調製し、抗EGFR抗体でイムノブロットした。図7Bは、1μMの化合物8CがEGFRの二量体化を阻害し、EGFRの分解を誘導できることを示す。全体として、これらの結果は、Ba/F3細胞からの発見を裏付けるものである。
RKO、UM10B、UM1、MCR5、およびUMCC92細胞における処理時の細胞の生存率を、製造元のプロトコ-ルに従ってCellTiter-Blue(登録商標)試薬によって評価した。手短に、10,000個の細胞を96穴プレートに4連で播種した。播種1日後、細胞を濃度範囲(0.1~30マイクロモル)で処理した。処理3日後、細胞をCellTiter-Blue(登録商標)試薬と4時間インキュベートした。生存細胞のみが、酸化還元色素(レサズリン)を蛍光産物(レゾルフィン)に変換する。蛍光の発光(励起560nm)を、590nmで測定した。IC50値は、590nmでの蛍光による測定で、ビヒクル処理対照と比較して、細胞増殖を50パーセント阻害するのに必要な化合物の平均濃度として計算された。結果を、以下の表3および表4に提示する。
薬剤を腹腔内注射により投与する短期PK研究により、化合物8Cは血漿から急速に除去されるという事実にもかかわらず、化合物8Cが選択的に腫瘍に蓄積することが明らかになった(図8Aおよび図8Bを参照)。腫瘍で達成された化合物8Cのピーク濃度(7時間以上で69.7±15.68μM)は、TKI耐性腫瘍細胞の99%を死滅させるのに必要な濃度よりもはるかに高い。PC9-AZR、およびHCC827-AZRのIC50およびIC90の範囲は、約1.5~約4μMである(図7Aを参照)。興味深いことに、ピーク血漿濃度が、30分間で5.4±1.5μMであった。化合物8Cの血漿中の半減期は7.96時間であるが、腫瘍での半減期は24時間よりもはるかに長かった(図8Aを参照)。急速な全身クリアランスにもかかわらず、腫瘍への遷延した薬物蓄積は、治療的使用に理想的である。24時間の時点のデータは、薬剤が連日投与に好適であることを示す。腹腔内注射された腫瘍における化合物8Cの選択的蓄積を観察した後、化合物8Cが経口で利用可能であるかどうかが決定された。経口投与の場合、短時間の超音波処理後、化合物8Cを、PBS(v/v)中の20%のtween80に処方した。マウスは、強制経口投与により、100mg/kgが投与された。7時間、15時間および24時間での腫瘍および血漿サンプル中の化合物8Cの濃度が決定され、図8Bにプロットされている。
このアプローチは、化合物C95で検証された。手短に、腫瘍が約100mm3のサイズに達したら、マウスを撮像し、基底生物発光および異なる時点でのプレリード化合物95の効果を得た(図9Aを参照)。生物発光の変化を定量化してプロットした(図9Bを参照)。最後に、EGFRタンパク質レベルに対する処置の効果を、処置の48時間後に、イムノブロットによって確認した。
UMSCC74B(約100mm2)を有するヌードマウスを(30mg/kg、毎日1週間)またはビヒクル(PBS中の5%のDMSO)で処置した。各群は、少なくとも5匹のマウスを有した。腫瘍体積および体重を週3~4回記録し、平均腫瘍体積の経時変化をプロットした。処置中の体重の平均減少は、10%未満であった。エラーバーは、平均値の標準誤差を表す。
オシメルチニブ耐性EGFR駆動性腫瘍に対する化合物8Cの活性を試験するために、以前に報告されたように、Ba/F3-AZR細胞(L858R+T790M+C797S-EGFR)を使用して、腹水腫瘍モデルが開発された(65)。500万個のBA/F3-AZR細胞を、6週齢の雌ヌードマウスに腹腔内注射した。マウスは腹水腫瘍を発症し、平均生存期間は20日間であった。オシメルチニブと比較した化合物8Cの有効性を試験するために、注射した15匹のマウスにBa/F3-AZR細胞を注射した。腫瘍細胞の注射18日後、マウスを3つの群に無作為化した。マウスを、ビヒクル、単回経口用量が30mg/kgのオシメルチニブ、または腹腔内注射を介する30mg/kgの化合物8Cで処置した。マウスの健康状態を監視し、ULAM末期ガイドラインに従ってマウスを安楽死させた。腫瘍負荷が高くなった後に処置が開始されたが、化合物8Cの30mg/kgの単回投与で、オシメルチニブ処置群と比較して、これらのマウスの寿命が延びた。ビヒクル対照群とオシメルチニブ処置群との間に違いは認められなかった。オシメルチニブと化合物8Cとの間の差は、ログランク検定を使用して計算された(p=0.072)。標的に対する処置の効果を試験するために、処置前、処置後18時間、および24時間に、1匹のマウスから腫瘍細胞を収集した。細胞をPBSで洗浄し、図3に記載のように処理した。図11に与えられるイムノブロットの結果は、EGFR、pEGFRおよび他の分子に対する処理の効果を示す。
C57BL6マウスを使用して、1日30mg/kgの用量で1週間の安全性に関する予備試験を行った。処置の間、マウス6匹の群の健康全般と体重を監視した。処置の1週間後、3.5±2.4%の体重のわずかな減少が観察されたが、処置を中止して2日後、マウスは完全に体重を回復した。
化合物8Cの活性は、国立癌研究所で標準NCI 60スクリーニングプロトコ-ルを使用して、60種類の異なるヒト腫瘍細胞株に対して試験された。上位成績の細胞株について、成長阻害のパーセントを以下の表5に示す。
6週齢のKCマウスを、強制経口投与により、化合物8Cで処置した(30mg/kg体重、毎日)。化合物8Cが投与されなかった対照マウスと比較して、PanInレベルに対する結果としての効果が観察された。化合物8Cで処置されたマウスは、図13に示すように、膵管病変の一種であるPanIn(膵上皮内腫瘍)の発症傾向が有意に低下した。
頭頸部腫瘍細胞株であるUMSCC74Bのマウス異種移植片を、強制経口投与により化合物8Cで処置した(30mg/kg体重、週2回)。化合物8Cが投与されなかった対照マウス、およびセツキシマブが投与された対照マウスと比較して、腫瘍体積に対する結果としての効果が観察された。図14に示すように、化合物8Cで処置したマウスでは、両方の対照と比較して、腫瘍体積の有意な減少を示した。
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Claims (17)
- 式(I):
Xは、O-C0~6アルキレン、S-C0~6アルキレン、またはNR3-C0~6アルキレンであり、前記アルキレンは、任意選択的に、独立して、ハロ、N(R3)2、およびOR3-から選択される1~3個の基で置換され、
Yは、C0~6アルキレンであり、前記アルキレンは、任意選択的に、独立して、ハロ、N(R3)2およびOR3から選択される1~3個の基で置換され、
Aは、C6~10アリールまたはN、O、およびSから選択される1~4個のヘテロ原子を有する5~10員ヘテロアリールであり、前記アリールまたはヘテロアリールは、任意選択的に、1~3個のR4で置換され、
Bは、キノリニルであり、
R1およびR2は、各々独立して、C1~6アルキルであるか、あるいはR1およびR2は、それらが結合している炭素原子と共に4~8員シクロアルキルまたはヘテロシクロアルキル環を形成し、ヘテロシクロアルキル環は、O、S、およびNから選択される1個または2個の環ヘテロ原子を有し、前記シクロアルキル環またはヘテロシクロアルキル環は、任意選択的に、1~2個のR6で置換され、
各R3は、独立して、HまたはC1~6アルキルであり、
各R4およびR5は、独立して、C1~6アルキル、C1~6ハロアルキル、ハロ、またはC1~6アルコキシであり、
R6は、C1~6アルキル、C1~6ハロアルキル、(C=O)R3、(C=O)OR3、CON(R3)2、C0~3アルキレン-C3~8シクロアルキル、C0~3アルキレン-C6~10アリール、またはC0~3アルキレン-(N、O、およびSから選択される1~4個のヘテロ原子を有する5~10員ヘテロアリール)であり、前記アリールまたはヘテロアリールは、任意選択的に、1~3個のR5で置換される。)
の構造を有する化合物、またはその薬学的に許容される塩。 - R1およびR2が、それらが結合している炭素原子と共に、1~2個のR6で置換されてもよい、4~8員シクロアルキルまたはヘテロシクロアルキル環を形成する、請求項1に記載の化合物または塩。
- R1およびR2が、それらが結合している炭素原子と共に、次の構造:
- R6が、C1~6アルキルである、請求項2または3に記載の化合物または塩。
- Aが、1~3個のR4で置換されてもよい、C6~10アリールである、請求項1~4のいずれか1項に記載の化合物または塩。
- Aが、1~3個のR4で置換されてもよい、フェニルである、請求項5に記載の化合物または塩。
- Aが、1つのR4で置換されている、請求項1~6のいずれか1項に記載の化合物または塩。
- Aが、次の構造:
- 少なくとも1つのR4が、ハロである、請求項1~8のいずれか1項に記載の化合物または塩。
- Xが、O-C0~6アルキレンまたはS-C0~6アルキレンである、請求項1~9のいずれか1項に記載の化合物または塩。
- Xが、S-C0~6アルキレンである、請求項10に記載の化合物または塩。
- Yが、C0~2アルキレンである、請求項1~11のいずれか1項に記載の化合物または塩。
- Xが、NR3-CH2、O-CH2-、またはS-CH2-であり、Yが存在しない、請求項12に記載の化合物。
- R3が、Hである、請求項1~13のいずれか1項に記載の化合物または塩。
- 化合物8C、33a、33b、33c、33d、33e、33f、33g、33h、33i、33j、33k、33l、34a、34b、34c、34d、34e、34f、35a、35b、35c、35d、35e、35f、35g、35h、および35iから選択される化合物、またはその薬学的に許容される塩。
- 化合物8Cである請求項15に記載の化合物、またはその薬学的に許容される塩。
- 治療有効量の請求項1~16のいずれか1項に記載の化合物または塩を含む、癌を治療するための医薬組成物。
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