TWI623315B - 3-[(3-{[4-(4-嗎啉基甲基)-1h-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1h-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及egfr tyr激酶抑制劑之新穎結合物 - Google Patents
3-[(3-{[4-(4-嗎啉基甲基)-1h-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1h-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及egfr tyr激酶抑制劑之新穎結合物 Download PDFInfo
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- TWI623315B TWI623315B TW105124215A TW105124215A TWI623315B TW I623315 B TWI623315 B TW I623315B TW 105124215 A TW105124215 A TW 105124215A TW 105124215 A TW105124215 A TW 105124215A TW I623315 B TWI623315 B TW I623315B
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- methyl
- methylene
- thiazolidine
- dione
- dihydro
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Classifications
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- A—HUMAN NECESSITIES
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本發明係關於式(I)之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮:
或其Z或E異構物及/或其與醫藥上可接受之酸或鹼之加成鹽,與人類表皮生長因子受體(EGFR)酪胺酸激酶抑制劑之結合物。本發明係關於一種藥劑。
Description
本發明係關於以下各項之新穎結合物:式(I)之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮:
或其Z或E異構物及/或其與醫藥上可接受之酸或鹼之加成鹽及人類表皮生長因子受體(EGFR)酪胺酸激酶抑制劑,其用於治療非小細胞肺癌、更尤其對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌。
非小細胞肺癌係當前世界上癌症死亡之主要原因(Goldstraw,P.、D.Ball、J.R.Jett、C.T.Le、E.Lim、A.G.Nicholson及F.A.
Shepherd,2011,Non-small-cell lung cancer:Lancet,v.378,no.9804,p.1727-1740;Jemal,A.、F.Bray、M.M.Center、J.Ferlay、E.Ward及D.Forman,2011,Global cancer statistics:CA Cancer J Clin,v.61,no.2,p.69-90)。在診斷時,大多數患者具有晚期病理學,其中1年存活率為30%且5年存活率為10%(U.S.National Institutes of Health,National Cancer Institute http://seer.cancer.gov/archive/csr/1975_2011/results_merged/topic_delaygraphs_overview.pdf;http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/survival/lung-cancer-survival-statistics)。EGFR基因之活化突變導致致癌基因成癮,換言之,癌細胞為了其生長及存活變得依賴於彼異常。此等突變在肺腺癌中時常發生,其中高加索患者中病例之15%且亞洲患者中病例之40%至50%(Shigematsu,H.等人,2005,Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers:J Natl Cancer Inst,v.97,no.5,p.339-346)。在具有EGFR基因突變之患者中,EGFR酪胺酸激酶抑制劑與化學療法相比顯著延遲疾病惡化且將其視為基準治療。目前市場上之治療尤其係第一代抑制劑吉非替尼(gefitinib)及厄洛替尼(erlotinib)及第二代抑制劑阿法替尼(afatinib),每一代均靶向EGFR之活化突變。不幸地,大多數患者在幾個月治療後藉助獲取能夠對EGFR酪胺酸激酶抑制劑產生抗性之其他遺傳及蛋白質變化而復發。已鑒定若干抗性機制,且尤其在大多數治療抗性之患者中發現EGFR受體之新突變(T790M:790位之蘇胺酸經甲硫胺酸取代)。對EGFR酪胺酸激酶抑制劑產生抗性之後,預後變得極差且向患者提供具有低有效率之化學療法。在此情形中,尋找用於非小細胞肺癌、且尤其對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌之新穎治療替代物以改良無惡化存活仍為目前之問題。特定而言,使對EGFR酪胺酸激酶抑制劑有抗性之患者重新敏感化構成需要探索之強
大治療策略。目前正開發特定作用於已獲得二次突變(例如T790M)之患者之第三代EGFR酪胺酸激酶抑制劑,且其似乎恢復治療活性。仍需要作用於除T790M突變外之抗性途徑及/或涉及其他細胞受體之其他替代物,且其已為患者期待許久且尤其可與第三代抑制劑結合。
在下文中且除非另有說明,否則「3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮」應理解為意指「3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及其Z或E異構物及/或與醫藥上可接受之酸或鹼之加成鹽」。
3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係癌細胞遷移之強效抑制劑,其尤其可用於治療癌症且尤其轉移性實體腫瘤。其描述於專利申請案WO2011/015728及WO2015/004395。
根據本發明,已在先利用EGFR酪胺酸激酶抑制劑治療之動物模型中顯示3-{[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基]甲基}-1,3-噻唑啶-2,4-二酮之效應可以去除對此一抑制劑之抗性。
由此等效應可以設想使用3-{[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基]甲基}-1,3-噻唑啶-2,4-二酮與EGFR酪胺酸激酶抑制劑之結合物治療非小細胞肺癌,尤其用於儘管經過治療但仍觀察到疾病惡化或復發之患者中之非小細胞肺癌。
更尤其在本發明之結合物中,3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係呈Z異構物形式。
較佳在本發明之結合物中,3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-
二酮係呈鹽形式,尤其鹽酸鹽或甲磺酸鹽之形式。
仍更有利地,本發明之結合物包括3-[((3Z)-3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽。
在本發明之EGFR酪胺酸激酶抑制劑中,可提及第一代及第二代抑制劑厄洛替尼、吉非替尼及阿法替尼,及第三代抑制劑AZD9291(奧斯替尼(osimertinib))或羅西替尼(rociletinib)。
根據有利實施例,本發明結合物之EGFR酪胺酸激酶抑制劑係式(II)之N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺或厄洛替尼:
或其與醫藥上可接受之酸或鹼之加成鹽且尤其其鹽酸鹽。
根據另一有利實施例,本發明結合物之EGFR酪胺酸激酶抑制劑係式(III)之N-(3-氯-4-氟-苯基)-7-甲氧基-6-(3-嗎啉-4-基丙氧基)喹唑啉-4-胺或吉非替尼:
或其與醫藥上可接受之酸或鹼之加成鹽。
較佳地,本發明之結合物包括3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯
-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之Z異構物或其醫藥上可接受之鹽及吉非替尼或其醫藥上可接受之鹽。
仍更尤其地,本發明係關於3-[((3Z)-3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽及吉非替尼或其醫藥上可接受之鹽之結合物。
本發明亦係關於醫藥組合物,其包括3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及EGFR酪胺酸激酶抑制劑之結合物與一或多種醫藥上可接受之賦形劑組合。
本發明亦係關於該等醫藥組合物在治療非小細胞肺癌、更尤其對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌中之用途。
在本發明之醫藥組合物中,更尤其可提及適於經口、非經腸、肌內及靜脈內、經皮或透皮、經鼻、經直腸、經舌、經眼睛或呼吸途徑投與之彼等且更尤其地錠劑、糖衣藥丸、舌下錠劑、明膠膠囊、直腸給藥劑型(glossette)、膠囊、菱形錠劑、可注射製劑、氣溶膠、滴眼或滴鼻劑、栓劑、乳膏、軟膏劑、皮膚用凝膠等。
在較佳實施例中,3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係以經口形式投與。
除3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及EGFR酪胺酸激酶抑制劑外,本發明之醫藥組合物包括一或多種選自以下之賦形劑或載劑:稀釋劑、潤滑劑、黏合劑、崩解劑、穩定劑、防腐劑、吸收劑、著色劑、甜味劑、矯味劑等。
可提及而不意味著任何限制之實例包含:
- 稀釋劑:乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素、丙三醇;- 潤滑劑:二氧化矽、滑石、硬脂酸及其鎂與鈣鹽、聚乙二醇;- 黏合劑:矽酸鋁及矽酸鎂、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及聚乙烯吡咯啶酮;- 崩解劑:瓊脂、海藻酸及其鈉鹽、泡騰混合物。
結合物之各化合物可同時或依序投與。相應之醫藥組合物可允許活性成份立即或延遲釋放。此外,結合物之各化合物可呈兩種分開的醫藥組合物之形式(各包含其中一種活性成份)或另一選擇為呈單一醫藥組合物之形式(其中混合活性成份)投與。
所用劑量根據患者之性別、年齡及體重、投與途徑、癌症之性質及任何相關治療而變化,且在以下範圍內:每天投與300mg至1500mg3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之游離鹼等效物,且更佳地每天400mg至800mg游離鹼等效物,且仍更尤其地每天500mg至600mg游離鹼等效物。EGFR酪胺酸激酶抑制劑之劑量將等於當其單獨投與時所用之劑量或更少。舉例而言,在吉非替尼之情形中,所投與劑量係每天250mg。對厄洛替尼而言,所投與劑量係每天25mg至150mg。
1000個含有100mg游離鹼等效物3-[3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽,Z異構物之錠劑................................121g
羥乙酸澱粉鈉................................................................20g
玉米澱粉.............................................................133g
乳糖單水合物..............................................................357g
硬脂酸鎂....................................................................6.7g
二氧化矽....................................................................1.3g
聚維酮(Povidone)........................................................46.6g
使用允許量測抗腫瘤化合物之抗增殖能力之細胞活力測試。所選細胞株係細胞株HCC827,一種其依賴於EGFR而存活之非小細胞肺癌細胞株。所用參數係IC50,換言之與未經治療之對照細胞相比,抑制50%之細胞增殖之產品濃度。在實驗前2天以適當密度將細胞接種(150μl)於96孔板之孔中。一行含有代表100%增殖之未經治療之對照細胞。其他行與測試產物一起培育達4次倍增時間。EGFR酪胺酸激酶抑制劑厄洛替尼對細胞株HCC827細胞活力之半數抑制濃度係10nM。對厄洛替尼之獲得性抗性係藉由使細胞株HCC827慢性暴露於厄洛替尼產生:將細胞暴露於培養基中1μM劑量之厄洛替尼直至倍增時間穩定為止,換言之約2個月。厄洛替尼對抗性細胞株HCC827之細胞活力之半數抑制濃度高約1000倍,為11.5μM。然後將抗性細胞暴露於100nM濃度之3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽濃度與增加之劑量的厄洛替尼之組合。3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽自身對活力無影響。在組合中,厄洛替尼對抗性細胞株HCC827之半數抑制濃度恢復至3.8nM之大約對非抗性細胞株HCC827之半數抑制濃度。
此結果表明3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮能夠在對EGFR酪胺酸激酶抑制劑具有抗性之非小肺癌細胞細胞株中恢復對此
一抑制劑之敏感性。
將活體外呈現厄洛替尼抗性之細胞株HCC827(一種非小細胞肺細胞株)以5.106個細胞/小鼠之量在皮下位置處移植於雌性SCID小鼠上。當腫瘤體積達到約200mm3時,將腫瘤隨機分派至多個組,每組八隻小鼠。利用50mg/kg劑量之化合物A(3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽)及12.5mg/kg劑量之厄洛替尼(分別地,載劑=乙酸銨/HEC及PEG300/乙醇/水緩衝液)之每日治療係經口投與19天之時期,如由下文圖1上之三角形所指示。使用游標卡尺每週兩至三次量測腫瘤體積。將具有四分位距之中值腫瘤體積記錄於圖表上。
在d19治療結束時,利用化合物本身治療後之生長抑制如下:厄洛替尼為65%且3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽(化合物A)為83%。當兩種化合物組合使用時,腫瘤完全消退,且此消退一旦治療停止後隨時間持續直至d30。所觀察到兩種產品間之協同在研究期間係統計上顯著的(p<0.001)。
患有非小細胞肺癌之患者對利用EGFR酪胺酸激酶抑制劑(吉非替尼、厄洛替尼、阿法替尼、奧斯替尼或羅西替尼)之治療產生抗性且對治療不再敏感,且疾病惡化。
正進行概念驗證研究以證實臨床前研究中所觀察到之結果且表明3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮能夠使患有非小細胞肺癌且已變得抗性之患者恢復對EGFR抑制劑、在此情形下吉非替尼之敏感性。患者係根據其分子譜包含在內。此研究包含I期,其中目的係
評估耐受譜並確定用於繼續研發之推薦劑量。將包含約20名患者。在此期間,患者將在28天週期中以每天400mg、500mg或600mg游離鹼等效物3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之劑量與每天250mg之吉非替尼組合治療。治療將維持直至疾病惡化為止。在此期結束時,將起始II期,目的係評估3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及吉非替尼之組合之活性。此II期將包含約150名患者。將每2個月評估腫瘤。患者將在28天週期中以I期中所界定的推薦劑量之3-[(3-{[4-(4-嗎啉基-甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮與每天250mg之吉非替尼組合治療。
圖1:每日利用50mg/kg之劑量之化合物A、12.5mg/kg之劑量之厄洛替尼、及同時利用相同劑量之化合物A與厄洛替尼二者進行治療,其中治療係經口投與(分別使用載劑=乙酸銨/HEC及PEG300/乙醇/水緩衝液)歷時19天。
Claims (12)
- 如請求項1之結合物,其中3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係以Z異構物形式使用。
- 如請求項1或2之結合物,其中3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係以鹽酸鹽形式使用。
- 如請求項1或2之結合物,其中3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮係以甲磺酸鹽形式使用。
- 如請求項1或2之結合物,其中該EGFR酪胺酸激酶抑制劑係吉非替尼(gefitinib)或厄洛替尼(erlotinib)。
- 如請求項1或2之結合物,其用於治療非小細胞肺癌。
- 如請求項1或2之結合物,其用於治療對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌。
- 一種醫藥組合物,其包括作為活性成份之如請求項1至7中任一項之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮或其Z或E異構物或其與醫藥上可接受之酸或鹼之加成鹽與EGFR酪胺酸激酶抑制劑之結合物,與一或多種醫藥上可接受之賦形劑之組合。
- 如請求項8之醫藥組合物,其用於治療非小細胞肺癌。
- 如請求項9之醫藥組合物,其用於治療對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌。
- 一種如請求項1至7中任一項之結合物之用途,其用於製備用於治療非小細胞肺癌之藥劑。
- 一種如請求項1至7中任一項之結合物之用途,其用於製備用於治療對EGFR酪胺酸激酶抑制劑有抗性之患者之非小細胞肺癌之藥劑。
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