TW202342032A - 含有malt1抑制劑作為有效成分的癌治療劑 - Google Patents
含有malt1抑制劑作為有效成分的癌治療劑 Download PDFInfo
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Abstract
本發明關於一種MALT1抑制劑與細胞障礙性抗癌劑及/或分子標靶藥之組合,該MALT1抑制劑為說明書中記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物,該組合由於會發揮強的抗腫瘤效果,故有用於血液癌之治療。
Description
本揭示係有關用於治療血液癌之含有MALT1抑制劑作為有效成分之醫藥組成物。
於擔任細胞性免疫之主要的T細胞、B細胞中,T細胞受體訊息及B細胞受體訊息就其機能扮演重要之角色,此訊息傳遞異常會成為以癌或發炎性疾病為代表之種種疾病之原因。實際上,就癌之例子而言,已有報告藉由屬於難治性淋巴瘤之一的ATL(成人T細胞白血病/淋巴瘤)等源自T細胞之淋巴瘤的病患之基因分析,而於T細胞受體訊息/NF-κ B路徑確認到基因異常,此外,即使於DLBCL(瀰漫性大型B細胞淋巴瘤)及MCL(被套細胞淋巴瘤(mantle cell lymphoma))等其他B細胞淋巴瘤中,B細胞受體訊息路徑/NF-κ B路徑也持續性活化著。
此等T細胞及B細胞受體訊息滙合之CBM蛋白質複合體係由支架蛋白CARD11、轉接蛋白BCL10及具有副胱天蛋白酶(paracaspase)活性之MALT1(黏膜相關淋巴組織淋巴瘤易位蛋白1(Mucosa associated lymphoid tissue lympoma translocation protein 1))所構成。藉由T細胞受體訊息及B細胞受體訊息而促進
CBM蛋白質複合體形成,引導MALT1所具有之副胱天蛋白酶活性亢進,將轉錄因子NF-κ B活化。
因而,期待抑制MALT1活性之抑制劑能糾正因T細胞受體訊息或B細胞受體訊息異常所引起之MALT1活性亢進,並咸認其有用於作為起因於MALT1活性之癌或發炎性疾病等之預防或治療藥(參照非專利文獻1至3)。
於專利文獻1中揭示後述之式(I)表示之化合物具有MALT1抑制作用,而有用於作為癌治療藥(參照專利文獻1)。
[先前技術文獻]
[專利文獻]
[專利文獻1] 國際公開第2020/111087號
[非專利文獻]
[非專利文獻1] 臨床癌症研究(Clinical Cancer Research)、第19卷、第24號、6662-6668頁、2013年
[非專利文獻2] 細胞和分子生命科學(Cellular and Molecular Life Sciences)、第73卷、459-473頁、2016年
[非專利文獻3] 血液學當前觀點(Current Opinion in Hematology)、第23卷、第4號、402-409頁、2016年
本揭示之目的之一為發現有用於血液癌治療之藥劑之組合,並提供作為醫藥品。
本發明人等為了解決前述課題,發現藉由將下述式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物之MALT1抑制劑與抗癌劑之組合(以下,有時簡稱為本發明之組合),可解決前述課題。
因此,於某一態樣中,提供一種醫藥組成物,其係用於治療血液癌病患,並且含有會與抗癌劑組合使用之MALT1抑制劑作為有效成分,該MALT1抑制劑為下述式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物。
本發明之組合有用於血液癌治療。
除非有具體地指定,否則於本說明書中使用之用語具有與有機化學、醫學、藥學、分子生物學、微生物學等領域中之具有通常知識者通常可理解者相同之意義。以下記載一些針對本說明書中使用之用語之定義,惟,此等定義於本說明書中係優先於通常之理解。
於本說明書中,數值伴隨有「約」之用語時,意圖在於包含其值之±10%之範圍。例如「約10」為包含「9至11」者。數值之範圍包含兩端點間之所有數值及兩端點之數值。關於範圍之「約」係適用於其範圍之兩端點。因此,例如「約10至20」為包含「9至22」者。
(1)MALT1抑制劑
於一態樣中,本發明之組合中所使用之MALT1抑制劑為於專利文獻1(WO2020/111087)中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物(本說明書中,有時簡稱為「化合物(I)」);
(式中,
A表示
R1表示1)氫原子、2)鹵素原子、3)氰基、4)可經1至3個鹵素原子取代之C1-3烷基、5)C1-3烷氧基、6)C3-6環烷基或7)苯基;
R2表示1)氫原子或2)鹵素原子;
R3表示1)可經1至3個選自C1-3烷氧基、羥基及鹵素原子之取代基取代之C1-6烷基、2)可經1至3個選自C1-3烷基及鹵素原子之取代基取代之吡唑基、3)C3-6環烷基、4)經C1-3烷基而二取代之胺基或5)可經1至3個鹵素原子取代之苯基;
R4及R6表示1)氫原子、2)鹵素原子、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基及c)鹵素原子之取代基取代之C1-3烷基或4)可經1至3個鹵素原子取代之C1-3烷氧基;
R5、R7及R9表示1)可經1至3個C1-3烷氧基取代之C1-6烷基或2)可經1至3個鹵素原子取代之苯基;
R8表示C1-3烷基;
B表示下述1)至5)中之任一者,
1)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷氧基及d)三唑基之取代基取代之苯基,
2)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基及b)鹵素原子之取代基取代之C3-6環烷基,
3)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷基、d)可經1至3個選自鹵素原子及C1-3烷氧基之取代基取代之C1-3烷氧基、e)可經1至3個C1-3烷基取代之吡唑基、f)可經1至3個C1-3烷基取代之咪唑基、g)可經1至3個C1-3烷基取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基及鹵素原子之取代基取代、h)氮雜環丁烷基、i)吡咯啶酮基、j)可經1至3個C1-3烷基取代之四唑基、k)嘧啶基及l)唑基之取代基取代之吡啶基,
4)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基、b)可經1至3個鹵素原子取代C1-3之烷氧基、c)氰基及d)鹵素原子之取代基取代之吡唑基,
5)可經1至3個鹵素原子取代之咪唑并吡啶基)。
又,作為MALT1抑制劑之其他態樣可列舉WO2015/181747、WO2017/081641、WO2018/020474、WO2018/085247、WO2018/119036、WO2018/141749、WO2019/243965、WO2021/000855或WO2021/134004之國際公開說明書中記載之化合物。
本說明書中,「鹵素原子」可列舉例如氟、氯、溴、碘。
本說明書中,「C1-6烷基」可列舉例如甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、1-乙基丙基、己基、異己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2-乙基丁基。
本說明書中,「C3-6環烷基」可列舉例如環丙基、環丁基、環戊基、環己基。
本說明書中,「C1-3烷氧基」可列舉例如甲氧基、乙氧基、丙氧基、異丙氧基。
本說明書中,「經C1-3烷基而二取代之胺基」可列舉例如二甲基胺基、乙基甲基胺基、二乙基胺基、乙基丙基胺基、二丙基胺基。
本說明書中,「C1-3烷基」可列舉上述「C1-6烷基」中碳數為1至3個者。
以下,詳細敍述式(I)中之各符號之定義。
A表示
A較佳為
於本發明之一較佳之實施態樣中,A為
於本發明之其他較佳之實施態樣中,A為
。
R1表示1)氫原子、2)鹵素原子(例如氯原子、溴原子)、3)氰基、4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、5)C1-3烷氧基(例如甲氧基)、6)C3-6環烷基(例如環丙基)或7)苯基。
R1更佳為1)鹵素原子(例如氯原子)或2)C1-3烷基(例如甲基)。
R2表示1)氫原子或2)鹵素原子(例如氟原子、氯原子)。
R2較佳為氫原子。
R3表示1)可經1至3個選自C1-3烷氧基(例如甲氧基)、羥基及鹵素原子(例如氟原子)之取代基取代之C1-6烷基(例如乙基、異丙基、第二丁基)、2)可經1至3個選自C1-3烷基(例如甲基)及鹵素原子(例如氯原子)之取代基取代之吡唑基(例如4-吡唑基)、3)C3-6環烷基(例如環丙基)、4)經C1-3烷基(例如甲基)而二取代之胺基或5)可經1至3個鹵素原子(例如氯原子)取代之苯基。
R3較佳為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基、異丙基)。
R4及R6表示1)氫原子、2)鹵素原子(例如氯原子)、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基(例如甲氧基)及c)鹵素原子(例如氟原子)之取代基取代之C1-3烷基(例如甲基、乙基)或4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基、乙氧基)。
R4較佳為1)鹵素原子(例如氯原子)或2)C1-3烷基(例如甲基)。
R6較佳為1)氫原子、2)鹵素原子(例如氯原子)、3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如甲氧基)。
R5、R7及R9表示1)可經1至3個C1-3烷氧基(例如甲氧基、乙氧基)取代之C1-6烷基(例如乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基。
R5較佳為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基)。
R7較佳為1)可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基。
R9較佳為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-3烷基(例如乙基)。
R8表示C1-3烷基(例如甲基)。
B表示下述1)至5)中之任一者,
1)可經1至3個選自a)鹵素原子(例如氟原子、氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及d)三唑基之取代基取代之苯基,
2)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)及b)鹵素原子(例如氟原子)之取代基取代之C3-6環烷基(例如環己基),
3)可經1至3個選自a)鹵素原子(例如氟原子、氯原子、溴原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個選自鹵素原子(例如氟原子)及C1-3烷氧基(例如甲氧基)之取代基取代之C1-3烷氧基(例如甲氧基、乙氧基)、e)可經1至3個C1-3烷基(例如甲基)取代之吡唑基、f)可經1至3個C1-3烷基(例如甲基)取代之咪唑基、g)可經1至3個C1-3烷基(例如甲基)取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基(例如甲氧基)及鹵素原子(例如氟原子)之取代基取代、h)氮雜環丁烷基、i)吡咯啶酮基、j)可
經1至3個C1-3烷基(例如甲基)取代之四唑基、k)嘧啶基及l)唑基之取代基取代之吡啶基,
4)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基、乙基、異丙基)、b)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)、c)氰基及d)鹵素原子(例如氯原子)之取代基取代之吡唑基,
5)可經1至3個鹵素原子(例如氯原子)取代之咪唑并吡啶基。
B較佳為可經1至3個選自a)鹵素原子(例如氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及e)三唑基之取代基取代之吡啶基。
化合物(I)之較佳例可列舉以下之化合物。又,下述較佳之[化合物I-1]至[化合物I-9]包含其鹽或其共晶體、水合物或溶劑合物。
[化合物I-1]
一種化合物(I),其中,
A為
R1為1)氫原子、2)鹵素原子(例如氯原子、溴原子)、3)氰基、4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、5)C1-3烷氧基(例如甲氧基)、6)C3-6環烷基(例如環丙基)或7)苯基;
R2為1)氫原子或2)鹵素原子(例如氟原子、氯原子);
R3為1)可經1至3個選自C1-3烷氧基(例如甲氧基)、羥基及鹵素原子(例如氟原子)之取代基取代之C1-6烷基(例如乙基、異丙基、第二丁基)、2)可經1至3個選自C1-3烷基(例如甲基)及鹵素原子(例如氯原子)之取代基取代之吡唑基(例如4-吡唑基)、3)C3-6環烷基(例如環丙基)、4)經C1-3烷基(例如甲基)而二取代之胺基或5)可經1至3個鹵素原子(例如氯原子)取代之苯基;
R4為1)氫原子、2)鹵素原子(例如氯原子)、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基(例如甲氧基)及c)鹵素原子(例如氟原子)之取代基取代之C1-3烷基(例如甲基、乙基)或4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基、乙氧基);
R5為1)可經1至3個C1-3烷氧基(例如甲氧基、乙氧基)取代之C1-6烷基(例如乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基;
R6為1)氫原子、2)鹵素原子(例如氯原子)、3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如乙氧基);
R7為1)可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基;
R8為C1-3烷基(例如甲基);
R9為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-3烷基(例如乙基);
B為下述1)至5)中之任一者,
1)可經1至3個選自a)鹵素原子(例如氟原子、氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及d)三唑基之取代基取代之苯基,
2)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)及b)鹵素原子(例如氟原子)之取代基取代之C3-6環烷基(例如環己基),
3)可經1至3個選自a)鹵素原子(例如氟原子、氯原子、溴原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個選自鹵素原子(例如氟原子)及C1-3烷氧基(例如甲氧基)之取代基取代之C1-3烷氧基(例如甲氧基、乙氧基)、e)可經1至3個C1-3烷基(例如甲基)取代之吡唑基、f)可經1至3個C1-3烷基(例如甲基)取代之咪唑基、g)可經1至3個C1-3烷基(例如甲基)取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基(例如甲氧基)及鹵素原子(例如氟原子)之取代基取代、h)氮雜環丁烷基、i)吡咯啶酮基、j)可經1至3個C1-3烷基(例如甲基)取代之四唑基、k)嘧啶基及l)唑基之取代基取代之吡啶基,
4)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基、乙基、異丙基)、b)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)、c)氰基及d)鹵素原子(例如氯原子)之取代基取代之吡唑基,
5)可經1至3個鹵素原子(例如氯原子)取代之咪唑并吡啶基。
[化合物I-2]
一種化合物(I),其中,
A為
R1為1)鹵素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R2為氫原子;
R3為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基、異丙基);
R4為1)鹵素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R5為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基);
B為可經1至3個選自a)鹵素原子(例如氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及e)三唑基之取代基取代之吡啶基;之化合物(I)。
[化合物I-3]
一種化合物(I),其中,
A為
R1為C1-3烷基(例如甲基);
R2為氫原子;
R3為經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基、異丙基);
R4為1)鹵素原子(例如氯原子)或2)C1-3烷基(例如甲基);
R5為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基);
B為可經1至3個選自a)鹵素原子(例如氯原子)、b)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及d)三唑基之取代基取代之吡啶基。
[化合物I-4]
一種化合物(I),其中,
A為
R1為1)氫原子、2)鹵素原子(例如氯原子、溴原子)、3)氰基、4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、5)C1-3烷氧基(例如甲氧基)、6)C3-6環烷基(例如環丙基)或7)苯基;
R2為1)氫原子或2)鹵素原子(例如氟原子、氯原子);
R3為1)可經1至3個選自C1-3烷氧基(例如甲氧基)、羥基及鹵素原子(例如氟原子)之取代基取代之C1-6烷基(例如乙基、異丙基、第二丁基)、2)可經1至3個選自C1-3烷基(例如甲基)及鹵素原子(例如氯原子)之取代基取代之吡唑基(例如4-吡唑基)、3)C3-6環烷基(例如環丙基)、4)經C1-3烷基(例如甲基)而二取代之胺基或5)可經1至3個鹵素原子(例如氯原子)取代之苯基;
B為下述1)至4)中之任一者,
1)可經1至3個選自a)鹵素原子(例如氟原子、氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及d)三唑基之取代基取代之苯基,
2)可經1至3個選自a)鹵素原子(例如氯原子、溴原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)、e)可經1至3個C1-3烷基(例如甲基)取代之吡唑基、f)可經1至3個C1-3烷基(例如甲基)取代之咪唑基、g)可經1至3個C1-3烷基(例如甲基)取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基(例如甲氧基)及鹵素原子(例如氟原子)之取代基取代及h)唑基之取代基取代之吡啶基,
3)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、b)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)、c)氰基及d)鹵素原子(例如氯原子)之取代基取代之吡唑基,
4)可經1至3個鹵素原子(例如氯原子)取代之咪唑并吡啶基。
[化合物I-5]
一種化合物(I),其中,
A為
R4為1)氫原子、2)鹵素原子(例如氯原子)、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基(例如甲氧基)及c)鹵素原子(例如氟原子)之取代基取代之C1-3烷基(例如甲基、乙基)或4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基、乙氧基);
R5為1)可經1至3個C1-3烷氧基(例如甲氧基、乙氧基)取代之C1-6烷基(例如乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基;
B為下述1)至4)中之任一者,
1)可經1至3個鹵素原子(例如氟原子)取代之苯基,
2)可經1至3個選自a)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)及b)鹵素原子(例如氟原子)之取代基取代之C3-6環烷基(例如環己基),
3)可經1至3個選自a)鹵素原子(例如氟原子、氯原子、溴原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個選自鹵素原子(例如氟原子)及C1-3烷氧基(例如甲氧基)之取代基取代之C1-3烷氧基(例如甲氧基、乙氧基)、e)可經1至3個C1-3烷基(例如甲基)取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基(例如甲氧基)及鹵素原子(例如氟原子)之取代基取代、f)氮雜環丁烷基、g)吡咯啶酮基、h)可經1至3個選自C1-3烷基(例如甲基)之取代基取代之四唑基、i)嘧啶基及j)唑基之取代基取代之吡啶基,
4)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基、乙基、異丙基)取代之吡唑基。
[化合物I-6]
一種化合物(I),其中,
A為
R6為1)氫原子、2)鹵素原子(例如氯原子)、3)C1-3烷基(例如甲基)或4)C1-3烷氧基(例如乙氧基);
R7為1)可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-6烷基(例如乙基、異丙基)或2)可經1至3個鹵素原子(例如氯原子)取代之苯基;
B為
1)可經1至3個鹵素原子(例如氟原子)取代之苯基或
2)可經1至3個選自a)鹵素原子(例如氯原子)、b)氰基、c)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、d)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷氧基(例如甲氧基)及e)三唑基之取代基取代之吡啶基。
[化合物I-7]
一種化合物(I),其中,
A為
R8為C1-3烷基(例如甲基);
R9為可經1至3個C1-3烷氧基(例如甲氧基)取代之C1-3烷基(例如乙基);
B為可經1至3個選自a)鹵素原子(例如氯原子)、b)可經1至3個鹵素原子(例如氟原子)取代之C1-3烷基(例如甲基)、c)C1-3烷氧基(例如甲氧基)及d)三唑基之取代基取代之吡啶基。
[化合物I-8]
[化合物I-9]
式(I)表示之化合物之鹽較佳為藥理學上可容許之鹽,此種鹽可列舉例如無機鹼之鹽、有機鹼之鹽、無機酸之鹽、有機酸之鹽、鹼性或酸性胺基酸之鹽。
無機鹼之鹽之較佳例可列舉鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土金屬鹽;鋁鹽;銨鹽。
有機鹼之鹽之較佳例可列舉三甲胺、三乙胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、胺基丁三醇(Tromethamine;亦稱為三(羥甲基)甲基胺)、第三丁胺、環己胺、苯甲胺、二環己胺、N,N-二苯甲基乙二胺之鹽。
無機酸之鹽之較佳例可列舉氯化氫、溴化氫、硝酸、硫酸、磷酸之鹽。
有機酸之鹽之較佳例可列舉甲酸、乙酸、三氟乙酸、鄰苯二甲酸、富馬酸、草酸、酒石酸、馬來酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸之鹽。
鹼性胺基酸之鹽之較佳例可列舉精胺酸、賴胺酸、鳥胺酸之鹽。
酸性胺基酸之鹽之較佳例可列舉天門冬胺酸、麩胺酸之鹽。
化合物(I)可依照專利文獻1中記載之方法(例如參考例1至4、實施例1至9等)或WO2021/241611中記載之方法來製造。
化合物(I)含有光學異構體、立體異構體、位置異構體、旋轉異構體時,此等亦作為化合物(I)而被包含在內,並且可藉由本身公知之合成手法、分離手法而各別作為單品來獲得。例如當化合物(I)有光學異構體存在時,從該化合物分割之光學異構體亦被包含於化合物(I)。
此處,光學異構體可藉由本身公知之方法製造。
化合物(I)亦可為結晶。
化合物(I)之結晶(以下,有時亦簡稱為本發明之結晶)可藉由對化合物(I)應用本身公知之結晶化法,並結晶化而製造。
本發明之結晶之物理化學性質(例如熔點、溶解度、安定性)及生物學性質(例如體內動態(吸收性、分布、代謝、排泄)、藥效表現)優越,而期待有用於作為醫藥。
化合物(I)亦可為藥學上可容許之共結晶或共結晶鹽。此處,共結晶或共結晶鹽意指各自具有不同之物理特性(例如構造、熔點、熔解熱、吸濕性、溶解性及安定性),並且於室溫時由二種以上之獨特固體構成之結晶性物質。共結晶或共結晶鹽可依照本身公知之共結晶化法來製造。
化合物(I)可為水合物、非水合物、無溶劑合物、溶劑合物。
再者,將1H轉換為2H(D)而得之氘轉換體亦被包含於化合物(I)。
化合物(I)可由同位素(例如3H、13C、14C、18F、35S、125I)等來標記。經同位素標記或取代之化合物(I)可作為例如正電子發射斷層掃描(Positron Emission Tomography:PET)中使用之示蹤劑(PET示蹤劑)來使用,期待有用於醫療診斷等之領域。
化合物(I)亦可作為前驅藥使用。
化合物(I)之前驅藥為於生體內之生理條件下藉由以酵素或胃酸等所進行之反應而轉換為化合物(I)之化合物,亦即,酵素上引起氧化、還原、水解等而轉換為化合物(I)之化合物、藉由胃酸等引起水解等而轉換為化合物(I)之化合物。
化合物(I)之前驅藥可列舉:化合物(I)之胺基經醯化、烷基化或磷酸化而成之化合物(例如化合物(I)之胺基經二十烷醯化、丙胺醯化、戊基胺基羰基化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧基羰基化、四氫呋喃基化、吡咯啶基甲基化、新戊醯氧基甲基化或第三丁基化而成之化合物);化合物(I)之羥基經醯化、烷基化、磷酸化或硼酸化而成之化合物(例如化合物(I)之羥基經乙醯化、棕櫚醯
化、丙醯化、新戊醯化、琥珀醯化、富馬醯化、丙胺醯化或二甲基胺基甲基羰基化而成之化合物);化合物(I)之羧基經酯化或醯胺化而成之化合物(例如化合物(I)之羧基經乙酯化、苯酯化、羧基甲酯化、二甲基胺基甲酯化、新戊醯氧基甲酯化、乙氧基羰基氧基乙酯化、酞基(phthalidyl)酯化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲酯化、環己基氧基羰基乙酯化或甲基醯胺化而成之化合物)等。此等化合物可從化合物(I)藉由本身公知之方法而製造。
又,化合物(I)之前驅藥可為如廣川書店1990年刊「醫藥品之開發」第7卷「分子設計」163至198頁中記載般的於生理條件下會轉換為化合物(I)者。
於本揭示中,前驅藥亦可形成鹽,此種鹽可列舉前述之作為式(I)表示之化合物之鹽所例示者。
本發明之組合中使用之MALT1抑制劑可直接或調配藥理學上可容許之載體而作成醫藥,並於哺乳動物(較佳為人類)經口或非經口投予。
該醫藥之劑型可因應所組合之「抗癌劑」之種類或投予形態而適當選擇,能以例如錠劑(例如糖衣錠、膜衣錠、舌下錠、口頰錠、口腔內速崩錠)等經口劑、例如注射劑、點滴劑等非經口劑之形態投予。又,該醫藥可藉由製劑技術領域中通常使用之公知之製造方法(例如日本藥典中記載之方法)而製造。
於本揭示中,藥理學上可容許之載體可列舉製劑領域中通常使用之賦形劑、黏合劑、崩解劑、潤滑劑、甜味劑、界面活性劑、懸浮化劑、乳化劑、著色劑、保存劑、芳香劑、矯味劑、安定劑、黏稠劑等添加劑。
賦形劑之例可列舉乳糖、白糖、葡萄糖、澱粉、蔗糖、微結晶纖維素、甘草粉、甘露醇、碳酸氫鈉、磷酸鈣、硫酸鈣。
黏合劑之例可列舉5至10重量%澱粉糊液、10至20重量%阿拉伯樹膠液或明膠液、1至5重量%黃蓍膠液、羧基甲基纖維素液、海藻酸鈉液、甘油。
崩解劑之例可列舉澱粉、碳酸鈣。
潤滑劑之例可列舉硬脂酸鎂、硬脂酸、硬脂酸鈣、精製滑石粉。
甜味劑之例可列舉葡萄糖、果糖、轉化糖、山梨糖醇、木糖醇、甘油、單糖漿。
界面活性劑之例可列舉月桂基硫酸鈉、聚山梨糖醇酯80、山梨糖醇酐單脂肪酸酯、聚乙二醇40硬脂酸酯。
懸浮化劑之例可列舉阿拉伯樹膠、海藻酸鈉、羧基甲基纖維素鈉、甲基纖維素、膨潤土。
乳化劑之例可列舉阿拉伯樹膠、黃蓍膠、明膠、聚山梨糖醇酯80。
本發明之組合中使用之MALT1抑制劑之投予量係依化合物之種類、年齡、體重、症狀(病患之狀態)、治療效果、投予方法、投予路徑、處理時間等而異,能以會帶來最適合之所期望之效果的方式調整。
例如,關於本發明之組合中使用之MALT1抑制劑之1日投予量,於以癌的治療為目的而對病患經口投予時,成人(體重約60kg)每日之投予量以MALT1抑制劑(例如化合物(I))而言為約0.5至約2000mg,較佳為約1至約1000mg,更佳為約3至約300mg,再佳為約10至約200mg,可將此等以1次或分成2至3次投予。
(2)抗癌劑
於本揭示中,抗癌劑意指為了治療血液癌而投予之抗癌劑。抗癌劑若為為了治療血液癌而投予之抗癌劑即可,無特別限定,可列舉例如細胞障礙性抗癌劑、分子標靶藥、嵌合抗原受體(CAR)表現T細胞(CAR-T細胞)。
於本揭示中,細胞障礙性抗癌劑意指具有藉由抑制癌細胞之DNA合成或細胞分裂等而對癌細胞造成障礙之作用之抗癌劑。
細胞障礙性抗癌劑之例可列舉烷基化劑、抗癌性抗生素、代謝拮抗藥、植物生物鹼、免疫調節藥、鉑製劑及類固醇。
烷基化劑之例可列舉:異環磷醯胺(Ifosfamide)、環磷醯胺(Cyclophosphamide)、達卡巴仁(Dacarbazine)、白消安(Busulfan)、丙卡巴肼(Procarbazine)、苯達莫司汀(Bendamustine)、美法侖(Melphalan)、雷莫司汀(Ranimustine)、卡莫司汀(Carmustine)、苯丁酸氮芥(Chlorambucil)、洛莫司汀(Lomustine)、氮芥(Mechlorethamine)、尼莫司汀(Nimustine)、卡波醌(Carboquone)或噻替哌(Thiotepa)。
抗癌性抗生素之例可列舉:艾達黴素(Idarubicin)、泛艾黴素(Epirubicin)、道諾黴素(Daunorubicin)、多柔比星(Doxorubicin)、吡柔比星(Pirarubicin)、博來黴素(Bleomycin)、米托蒽醌(Mitoxantrone)、阿克拉比星(Aclarubicin)、絲裂黴素C(Mitomycin C)、阿柔比星(Aclacinon)、淨司他丁斯酯(Zinostatin stimalamer)、新抑癌素(Neocarzinostatin)或培洛黴素(Peplomycin)。
代謝拮抗藥之例可列舉:阿扎胞苷(Azacitidine)、依諾他濱(Enocitabine)、克拉屈濱(Cladribine)、吉西他濱(Gemcitabine)、阿糖胞苷(Cytarabine)、硫鳥嘌呤(Thioguanine)、奈拉濱(Nelarabine)、羥基脲(Hydroxyurea)、氟達拉濱(Fludarabine)、噴司他丁(Pentostatin)、胺甲喋呤(Methotrexate)、培美曲塞(Pemetrexed)、巰基嘌
呤(Mercaptopurine)、地西他濱(Decitabine)、瓜地西他濱(Guadecitabine)、CPX-351、氯法拉濱(Clofarabine)、羥基尿素(Hydroxycarbamide)、卡培他濱(Capecitabine)、卡莫氟(Carmofur)、替加氟(Tegafur)、TS-1、去氧氟尿苷(Doxifluridine)、氟尿嘧啶(Fluorouracil)。
植物生物鹼之例可列舉:愛萊諾迪肯(Irinotecan)、依託泊苷(Etoposide)、索布佐生(Sobuzoxane)、長春新鹼(Vincristine)、長春地辛(Vindesine)、長春花鹼(Vinblastine)、多西紫杉醇(Docetaxel)、諾吉替康(Nogitecan)、紫杉醇(Paclitaxel)或長春瑞濱(Vinorelbine)。
免疫調節藥之例可列舉:沙利竇邁(Thalidomide)、來那度胺(Lenalidomide)或泊馬度胺(Pomalidomide)。
鉑製劑之例可列舉:卡鉑(Carboplatin)、順鉑(Cisplatin)、奈達鉑(Nedaplatin)或奧沙利鉑(Oxaliplatin)。
類固醇之例可列舉潑尼松龍(Prednisolone)。
於本揭示中,細胞障礙性抗癌劑較佳為環磷醯胺、多柔比星、長春新鹼、苯達莫司汀、愛萊諾迪肯、潑尼松龍、來那度胺。
於本揭示中,分子標靶藥意指將與癌細胞之增殖、浸潤、轉移相關之分子作為標靶之抗癌劑。
用於治療血液癌之分子標靶藥可列舉例如:選自由CD20、CD30、CD33、CD38、CD47、CD52、CD70、CD79、PD-1、PD-L1、ABL、AXL、蛋白酶體(Proteasome)、CCR4、JAK、CXCR4、BET、Bcl-2、HDAC、FLT3、LSD1、MDM2、IDH1、IDH2、Btk、IRAK4、PI3K、PKC、SYK、mTOR、Akt、MEK、EZH2、
PLK、HSP90、XPO1、SMO及NEDD8所構成之群組之分子之抑制劑。以下列舉分子標靶藥之例,惟分子標靶藥不限定於此等。
用於治療血液癌之分子標靶藥之例可列舉:抗CD20抗體、抗CD30抗體藥物複合體、抗CD33抗體、抗CD38抗體、抗CD47抗體、抗CD52抗體、抗CD70抗體、抗CD79抗體藥物複合體、抗PD-1抗體、抗PD-L1抗體、ABL抑制劑、AXL抑制劑、蛋白酶體抑制劑、抗CCR4抗體、JAK抑制劑、CXCR4拮抗藥、BET抑制劑、Bcl-2抑制劑、HDAC抑制劑、FLT3抑制劑、LSD1抑制劑、MDM2抑制劑、IDH1抑制劑、IDH2抑制劑、Btk抑制劑、PI3K抑制劑、PKC抑制劑、SYK抑制劑、mTOR抑制劑、Akt抑制劑、MEK抑制劑、EZH2抑制劑、PLK抑制劑、HSP90抑制劑、XPO1抑制劑、SMO抑制劑、NEDD8抑制劑、Btk分解誘導藥、IRAK4分解誘導藥、IRAK4抑制劑、CDK4/6抑制劑及類視色素(Retinoid)。
抗CD20抗體之例可列舉奧法木單抗(Ofatumumab)、利妥昔單抗(Rituximab)、烏妥昔單抗(Ublituximab)或阿托珠單抗(Obinutuzumab)。
抗CD30抗體藥物複合體之例可列舉維布妥昔單抗(Brentuximab Vedotin)。
抗CD33抗體之例可列舉吉妥珠單抗(Gemtuzumab)或吉妥珠單抗奧佐米星(Gemtuzumab ozogamicin)。
抗CD38抗體之例可列舉達雷妥尤單抗(Daratumumab)或伊沙妥昔單抗(Isatuximab)。
抗CD52抗體之例可列舉阿崙單抗(Alemtuzumab)。
抗CD70抗體之例可列舉古妥珠單抗(Cusatuzumab)。
抗CD79抗體藥物複合體之例可列舉維泊洛妥珠單抗(Polatuzumab vedotin)。
ABL抑制劑之例可列舉伊馬替尼(Imatinib)、達沙替尼(Dasatinib)或尼洛替尼(Nilotinib)。
AXL抑制劑之例可列舉ONO-7475或貝生替尼(Bemcentinib)。
蛋白酶體抑制劑之例可列舉硼替佐米(Bortezomib)或卡非佐米(Carfilzomib)。
抗CCR4抗體之例可列舉莫格利珠單抗(Mogamulizumab)。
JAK抑制劑之例可列舉魯索利替尼(Ruxolitinib)。
CXCR4拮抗藥之例可列舉AMD3100、BMS-936564、BL-8040、多西帕司他鈉(Dociparstat sodium)或LY2624587(CXCR4抑制抗體)。
BET抑制劑之例可列舉OTX015、GSK525762、RVX-208、BMS-986158、PLX51107、CPI-0610、TEN-010、INCB054329、ABBV075或GS-5829。
Bcl-2抑制劑之例可列舉維奈托克(Venetoclax)、ABT-263、GX15-070或AT-101。
HDAC抑制劑之例可列舉妥西司他(Tucidinostat)、普拉諾他(Pracinostat)、伏立諾他(Vorinostat)、羅米地辛(Romidepsin)、帕比司他(Panobinostat)、貝利司他(Belinostat)、恩替諾特(Entinostat)或西達本胺(Chidamide)。
FLT3抑制劑之例可列舉吉瑞替尼(Gilteritinib)、米哚妥林(Midostaurin)、索拉非尼(Sorafenib)、普納替尼(Ponatinib)、克雷諾拉尼(Crenolanib)、坦度替尼(Tandutinib)、舒尼替尼(Sunitinib)、奎扎替尼(Quizartinib)或帕克替尼(Pacritinib)。
LSD1抑制劑之例可列舉GSK-2879552、INCB-59872或ORY-1001。
MDM2抑制劑之例可列舉伊達努素(Idasanutlin)、SAR405838、DS-3032b、RG7112、HDM201、MK4828、AMG-232或ALRN-6924。
IDH1抑制劑之例可列舉艾伏尼布(Ivosidenib)。
IDH2抑制劑之例可列舉恩西地平(Enasidenib)。
Btk抑制劑之例可列舉依魯替尼(Ibrutinib)、替拉魯替尼(Tirabrutinib)、斯貝魯替尼(Spebrutinib)、阿卡替尼(Acalabrutinib)、依弗魯替尼(Evobrutinib)、菲那魯替尼(Fenebrutinib)、普瑟替尼(Poseltinib)、維卡替尼(Vecabrutinib)、澤布替尼(Zanubrutinib)、布瑞替尼(Branebrutinib)、PRN-1008、BMS-986142、LOU-064、M-7583、AC-058、DTRMWXHS-12、TAS-5315、TAK-020、ARQ-531、BMS-935177、PCI-45292、PRN-2246、SHR-1459、ABBV-105、CT-1530、ICP022、LOXO-305、JNJ-64264681或HWH-486。
PI3K抑制劑之例可列舉艾代拉利西布(Idelalisib;亦稱為艾代拉里斯)、度維利塞(Duvelisib)、阿培利司(Alpelisib)、庫潘尼西(Copanlisib)、厄布利塞(Umbralisib)、匹克昔布(Pictilisib)、布帕尼西(Buparlisib)、達克利司(Dactolisib)、匹拉昔布(pilaralisib)、塔西利司(Taselisib)、PX866、CH5132799、ZSTK474、SF1126、MLN1117、阿匹托西布(Apitolisib)、吉達昔布(Gedatolisib)、帕沙利西布(Paxalisib)、必米昔布(Bimiralisib)、薩莫昔布(Samotolisib)、沃塔昔布(Voxtalisib)、BKM120、GDC-0941或贊德利西布(Zandelisib)。
PKC抑制劑之例可列舉恩扎妥林(Enzastaurin)、索曲妥林(Sotrastaurin)、魯伯斯塔(Ruboxistaurin)、星形孢菌素(Staurosporine)、米哚妥林(Midostaurin)。
SYK抑制劑之例可列舉福他替尼(Fostamatinib)、恩妥替尼(Entospletinib)、賽度替尼(Cerdulatinib)、GS-9876、TAK-659或PRT062607。
mTOR抑制劑之例可列舉西羅莫司(Sirolimus)、替西羅莫司(Temsirolimus)、依維莫司(Everolimus)、地磷莫司(Ridaforolimus)、沙帕色替(Sapanisertib)、維妥色替(Vistusertib)、MLN0128、CC-223或RapaLink-1。
Akt抑制劑之例可列舉MK-2206、TAS-117、優普色替(Uprosertib)、卡匹色替(Capivasertib)或帕他色替(Ipatasertib)。
MEK抑制劑之例可列舉曲美替尼(Trametinib)、司美替尼(Selumetinib)或考比替尼(Cobimetinib)。
EZH2抑制劑之例可列舉他澤司他(Tazemetostat)。
PLK抑制劑之例可列舉伏拉塞替(Volasertib)、GSK461364、瑞格色替(Rigosertib)、BI2536、HMN-176、NMS-P937、CYC-140或RO3280。
HSP90抑制劑之例可列舉甘內特斯比(Ganetespib)。
XPO1抑制劑可列舉塞利尼索(Selinexor)。
SMO抑制劑之例可列舉格拉吉布(Glasdegib)、維莫吉布(Vismodegib)或索尼吉布(Sonidegib)。
NEDD8抑制劑之例可列舉佩沃塔特(Pevonedistat)。
Btk分解誘導藥之例可列舉NX-2127、NX-5948或BGB-16673。
IRAK4抑制劑之例可列舉CA-4948、GS-5718、BAY-1834845或PF-06650833。
CDK4/6抑制劑之例可列舉帕博西利(Palbociclib)、阿貝西利(Abemaciclib)、瑞博西利(Ribociclib)或迪那西利(Dinaciclib)。
類視色素之例可列舉貝沙羅汀(Bexarotene)。
於本揭示中,嵌合抗原受體(CAR)表現T細胞意指使將癌細胞表面所表現之分子作為標靶之嵌合抗原受體(CAR)表現之T細胞(CAR-T細胞)。
CAR-T細胞之例可列舉替沙來塞(Tisagenlecleucel)、阿基侖賽(Axicabtagene ciloleucel)、Brexucabtagene autoleucel(KTE-X19)、利基邁侖賽(Lisocabtagene maraleucel)或艾基維侖賽(Idecabtagene vicleucel)。
將此等抗癌劑中之任1種或任意之複數種與本發明之MALT1抑制劑組合,可用於血液癌治療。
本發明之組合中使用之抗癌劑之投予量係依年齡、體重、症狀、治療效果、投予方法、處理時間等而異,能以會帶來最適合之所期望之效果的方式調整。所使用之抗癌劑已經應用於臨床時,可參照臨床用量。
本發明之組合中使用之抗癌劑可直接或調配藥理學上可容許之載體而作成醫藥,並於哺乳動物(較佳為人類)以經口或非經口投予。
該醫藥之劑型可因應所組合之「MALT1抑制劑」之種類或投予形態而適當選擇,能以例如錠劑(例如糖衣錠、膜衣錠、舌下錠、口頰錠、口腔內速崩錠)等經口劑,例如注射劑、點滴劑等非經口劑之形態投予。又,該醫藥可藉由製劑技術領域中通常使用之公知之製造方法(例如日本藥典中記載之方法)而製造。更具體之態樣可參照前述之針對MALT1抑制劑所述者。又,所使用之抗癌劑已經應用於臨床時,可參照其劑型。
[毒性]
本發明之組合之毒性足夠地低,可作為醫藥品而安全地使用。
[於醫藥品之應用]
就藉由本發明之組合或屬於MALT1抑制劑之化合物(I)而進行治療之血液癌而言,無特別限定,可列舉例如:多發性骨髓瘤、白血病(例如急性骨髓性白血病、急性淋巴球性白血病、慢性淋巴性白血病)、惡性淋巴瘤(例如B細胞淋巴瘤(例如伯基特淋巴瘤(Burkitt lymphoma)、AIDS關連性淋巴瘤、邊緣體B細胞淋巴瘤、瀰漫性大型B細胞淋巴瘤、原發性滲出液淋巴瘤、淋巴瘤樣肉芽腫病、濾胞性淋巴瘤、B細胞慢性淋巴性白血病、B細胞前淋巴性白血病、淋巴漿細胞
性白血病/華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、漿細胞瘤、被套細胞淋巴瘤、縱隔大型B細胞淋巴瘤、血管內大型B細胞淋巴瘤、毛細胞白血病)、T細胞淋巴瘤(例如成人T細胞白血病/淋巴瘤、皮膚T細胞淋巴瘤、末梢性T細胞淋巴瘤、血管免疫母細胞性T細胞淋巴瘤、間變性大細胞淋巴瘤、結外性NK/T細胞淋巴瘤)、慢性骨髓增殖性疾病等)、霍奇金病、原發部位不明癌。
就一態樣而言,本發明之組合亦可應用於轉移性癌之治療或轉移之抑制。
就一態樣而言,本發明之組合係抑制再發。
於本發明中,治療意指產生了延長無惡化生存期間(PFS)、延長全生存期間(OS)、延長無病生存期間(DFS)、延長無進行期間(TTP)、延長無事件生存期間(EFS)、延長無再發生存期間(RFS)、減少癌細胞數、降低腫瘤大小、抑制(延遲或停止)腫瘤成長、抑制(延遲或停止)腫瘤轉移、抑制(防止或延遲)再發及緩和與癌有關之一個或複數個症狀中之至少一種的效果。
於本揭示中,「組合投予」包含相同或不同劑型之化合物的同時投予或是化合物各別投予(例如逐次投予)。更具體而言,能以在一個製劑中調配有所有成分之調配劑之形態來投予、或可採用製作成各別之製劑並投予之形態。此製作成各別之製劑並投予之情形,包含同時投予及以時間差所進行之投予。又,以時間差所進行之投予可先投予MALT1抑制劑,後投予抗癌劑,亦可先投予抗癌劑,後投予MALT1抑制劑。各自之投予方法可相同亦可不同。
於本揭示中,本發明之組合可為了(1)補齊及/或增強治療效果、(2)改善動態/吸收、減少投予量及/或(3)減輕副作用,而更與其他之藥物(例如公知之癌治療劑)組合投予。
於本發明之組合中,MALT1抑制劑與抗癌劑之調配比可依投予對象、投予路徑、對象疾病、症狀、藥劑之具體組合等而適當選擇。例如當投予對象為人類時,相對於MALT1抑制劑1重量份,使用0.01至100重量份的抗癌劑即可。
本案提供例如下述之實施態樣。可列舉:
[1]一種血液癌治療劑,含有會與細胞障礙性抗癌劑及/或分子標靶藥組合投予之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物,
(式中,
A表示
R1表示1)氫原子、2)鹵素原子、3)氰基、4)可經1至3個鹵素原子取代之C1-3烷基、5)C1-3烷氧基、6)C3-6環烷基或7)苯基;
R2表示1)氫原子或2)鹵素原子;
R3表示1)可經1至3個選自C1-3烷氧基、羥基及鹵素原子之取代基取代之C1-6烷基、2)可經1至3個選自C1-3烷基及鹵素原子之取代基取代之吡唑基、3)C3-6環烷基、4)經C1-3烷基而二取代之胺基或5)可經1至3個鹵素原子取代之苯基;
R4及R6表示1)氫原子、2)鹵素原子、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基及c)鹵素原子之取代基取代之C1-3烷基或4)可經1至3個鹵素原子取代之C1-3烷氧基;
R5、R7及R9表示1)可經1至3個C1-3烷氧基取代之C1-6烷基或2)可經1至3個鹵素原子取代之苯基;
R8表示C1-3烷基;
B為下述1)至5)中之任一者,
1)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷氧基及d)三唑基之取代基取代之苯基,
2)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基及b)鹵素原子之取代基取代之C3-6環烷基,
3)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷基、d)可經1至3個選自鹵素原子及C1-3烷氧基之取代基取代之C1-3烷氧基、e)可經1至3個C1-3烷基取代之吡唑基、f)可經1至3個C1-3烷基取代之咪唑基、g)可經1至3個之C1-3烷基取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基及鹵素原子之取代基取代、h)氮雜環丁烷基、i)吡咯啶酮基、j)可經1至3個C1-3烷基取代之四唑基、k)嘧啶基及l)唑基之取代基取代之吡啶基,
4)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基、b)可經1至3個鹵素原子取代C1-3之烷氧基、c)氰基及d)鹵素原子之取代基取代之吡唑基,
5)可經1至3個鹵素原子取代之咪唑并吡啶基)。
[2]一種血液癌治療劑,含有會與前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合投予之細胞障礙性抗癌劑及/或分子標靶藥。
[3]如前述[1]或[2]所述之血液癌治療劑,其中,式(I)表示之化合物為
[4]如前述[1]至[3]中任1項所述之血液癌治療劑,其中,式(I)表示之化合物為(S)-N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-N’-(8-(1-甲氧基乙基)-2-甲基咪唑并[1,2-b]嗒-7-基)尿素。
[5]如前述[1]至[3]中任1項所述之血液癌治療劑,其中,式(I)表示之化合物為(S)-N-(6-氯-4-(1-甲氧基乙基)-1,5-啶-3-基)-N’-(6-(2H-1,2,3-三唑-2-基)-5-(三氟甲基)吡啶-3-基)尿素。
[6]如前述[1]至[5]中任1項所述之血液癌治療劑,其中,細胞障礙性抗癌劑為選自由環磷醯胺(Cyclophosphamide)、多柔比星(Doxorubicin)、長春新鹼(Vincristine)、苯達莫司汀(Bendamustine)、愛萊諾迪肯(Irinotecan)、潑尼松龍(Prednisolone)及來那度胺(Lenalidomide)所構成之群組中之一種以上。
[7]如前述[1]至[5]中任1項所述之血液癌治療劑,其中,分子標靶藥為選自由抗CD20抗體、抗CD30抗體藥物複合體、抗CD33抗體、抗CD38抗體、抗CD47抗體、抗CD52抗體、抗CD70抗體、抗CD79抗體藥物複合體、抗PD-1抗體、抗PD-L1抗體、ABL抑制劑、AXL抑制劑、蛋白酶體抑制劑、抗CCR4抗體、JAK抑制劑、CXCR4拮抗藥、BET抑制劑、Bcl-2抑制劑、HDAC抑制劑、FLT3抑制劑、LSD1抑制劑、MDM2抑制劑、IDH1抑制劑、IDH2抑制劑、Btk抑制劑、PI3K抑制劑、PKC抑制劑、SYK抑制劑、mTOR抑制劑、Akt抑制劑、MEK抑制劑、EZH2抑制劑、PLK抑制劑、HSP90抑制劑、XPO1抑制劑、
SMO抑制劑、NEDD8抑制劑、Btk分解誘導藥、IRAK4分解誘導藥、IRAK4抑制劑、CDK4/6抑制劑及類視色素所構成之群組中之一種以上。
[8]如前述[1]至[7]中任1項所述之血液癌治療劑,其中,分子標靶藥為Btk抑制劑,Btk抑制劑為選自由依魯替尼(Ibrutinib)、替拉魯替尼(Tirabrutinib)、斯貝魯替尼(Spebrutinib)、阿卡替尼(Acalabrutinib)、依弗魯替尼(Evobrutinib)、普瑟替尼(Poseltinib)、菲那魯替尼(Fenebrutinib)、維卡替尼(Vecabrutinib)、澤布替尼(Zanubrutinib)、PRN-1008、BMS-986142、LOXO-305、ARQ-531及此等之鹽所構成之群組中之一種以上。
[9]如前述[1]至[8]中任1項所述之血液癌治療劑,其中,Btk抑制劑為依魯替尼或其鹽。
[10]如前述[1]至[8]中任1項所述之血液癌治療劑,其中,Btk抑制劑為選自由替拉魯替尼、阿卡替尼、澤布替尼、LOXO-305、ARQ-531及此等之鹽所構成之群組中之一種以上。
[11]如前述[1]至[10]中任1項所述之血液癌治療劑,其中,血液癌為多發性骨髓瘤、白血病、惡性淋巴瘤、T細胞淋巴瘤、霍奇金病或原發部位不明癌。
[12]一種醫藥(血液癌治療劑),為由將前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與細胞障礙性抗癌劑及/或分子標靶藥組合而成者。
[13]一種醫藥(血液癌治療劑),為將前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與細胞障礙性抗癌劑及/或分子標靶藥組合,且被分別或同時投予者。
[14]一種癌治療方法,包含將有效量之前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與有效量之細胞障礙性抗癌劑及/或分子標靶藥分別或同時投予於需要血液癌治療之病患。
[15]一種血液癌治療方法,該血液癌治療方法包含將有效量之前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物投予於需要血液癌治療之病患,且該血液癌治療方法更包含投予有效量之細胞障礙性抗癌劑及/或分子標靶藥。
[16]一種血液癌治療方法,該血液癌治療方法包含將有效量之細胞障礙性抗癌劑及/或分子標靶藥投予於需要血液癌治療之病患,且該血液癌治療方法更包含投予有效量之前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物。
[17]一種如前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物,其係與細胞障礙性抗癌劑及/或分子標靶藥組合而用於血液癌治療。
[18]一種細胞障礙性抗癌劑及/或分子標靶藥,其係與前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合而用於血液癌治療。
[19]一種前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物之使用,係用於製造血液癌治療劑,其中該血液癌治療劑係與細胞障礙性抗癌劑及/或分子標靶藥組合投予。
[20]一種細胞障礙性抗癌劑及/或分子標靶藥之使用,係用於製造血液癌治療劑,其中該血液癌治療劑係與前述[1]所述之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合投予
等態樣。
本說明書中引用之所有文獻係藉由明確顯示出處而引用作為本說明書之一部分。
上述之說明全都皆為非限定性,本發明在不超出後述專利申請範圍中所定義者、其技術思想之範圍下,可作各種變更。以下,藉由實施例而將本發明作更詳細之說明,惟本發明不限定於此等實施例。
[實施例]
以下,呈示實施例而將本發明加以具體地說明,惟本發明不限定於此等。
生物學上的實施例1:評估對於人類B細胞淋巴瘤細胞株,藉由將化合物A與Btk抑制劑併用而得之對於細胞生存率之併用效果(試管內)
[操作]
(1)細胞之培養
使用依魯替尼作為Btk抑制劑,於試管內評估其與化合物A之對於細胞生存率之併用效果。於本評估試驗中,使用將人類CD79突變陽性瀰漫性大型B細胞淋巴瘤細胞株2種利用含有20%滅活小牛血清及0.5mmol/L單硫代甘油(Monothioglycerol)之Iscove改良Dulbecco培養基於5%CO2、37℃之條件下培養而得者。
(2)細胞生存性評估
將人類CD79突變陽性瀰漫性大型B細胞淋巴瘤細胞株2種(1250個/90μL或1000個/90μL)播種於96孔盤之各孔後,迅速地以成為各種之最終濃度之方式添加只有DMSO或含有化合物A(0.3nM、1nM、3nM、10nM、30nM、100nM、
300nM、1000nM及3000nM)、依魯替尼(0.3nM、1nM、3nM、10nM及30nM)或兩藥劑(前述濃度之組合)之培養基10μL。從添加起培養6日後進行以下之細胞生存率之評估。
藉由使用CellTiter-Glo測定細胞內三磷酸腺苷(ATP),而進行由各處理所致之細胞生存率之評估。亦即,於各孔添加每1孔100μL之CellTiter-Glo液,於室溫保溫15分鐘後測定化學發光。從所獲得之數據算出各組合之平均值,將只經DMSO處理之細胞之發光強度作為100%,而製作各藥劑於單獨或併用時之細胞生存率之濃度反應曲線。
(3)數據分析
使用中位數效應分析軟體CalcuSyn 2.0(CalcuSyn,Inc.製造),來決定對於各藥劑之半數抑制濃度(IC50)。接著,決定藥劑之組合濃度之合併指數(combination index;CI)(藉由酶調控的進展(Advances in enzymeregulation)、第22卷、1984年、27-55頁記載之方法而進行)。又,CI值為用於判定併用效果之強度而通常使用之指標,且表示表2所記載之意義。
[結果]
表1表示於各細胞株之藉由化合物A與依魯替尼之併用處置所得之抗腫瘤作用之評估結果。將化合物A與依魯替尼併用處置時之CI之中央值都未達1,而顯示協同作用(synergistic effect)。
生物學上的實施例2:評估對於人類B細胞淋巴瘤細胞株,藉由化合物A與Btk抑制劑併用而得之抗腫瘤作用之併用效果(體內)
[操作]
(1)細胞之培養
使用人類CD79突變陽性瀰漫性大型B細胞淋巴瘤細胞株。細胞係使用含有20%滅活小牛血清及0.5mmol/L單硫代甘油之Iscove改良Dulbecco培養基,於5%CO2、37℃之條件下進行繼代培養。
(2)評估於小鼠皮下移植模型之抗腫瘤作用
將細胞懸浮於HBSS:基質膠(Matrigel)=1:1,於7週齡之雌性NOG小鼠之腹部皮下以1x106細胞/隻進行皮下移植。腫瘤體積之測定係使用游標卡尺,並以腫瘤體積=(腫瘤長徑×腫瘤短徑×腫瘤短徑)/2之計算式算出。當腫瘤體積達到約120mm3之時間點以每1群6隻而分成4群實施。化合物A係以10mg/kg之用量1日2次,經口投予21日,依魯替尼係以10mg/kg之用量1日1次,經口投予21日。又,對於併用投予群係經口投予化合物A 10mg/kg及依魯替尼10mg/kg。對於對照群係經口投予0.5%甲基纖維素溶液。分組後每週實施2次之腫瘤體積之測定。抗腫瘤效果之指標使用T/C(%)。
T/C(%)=(藥物投予群之腫瘤體積之變化量)/(對照群之腫瘤體積之變化量)x100
(3)數據分析
關於各群之投予期間之腫瘤體積變化量,藉由EZR(ver.1.54)軟體之雙因子變異數分析之統計手法來分析化合物A與依魯替尼之併用抗腫瘤效果。
[結果]
表3表示於人類CD79突變陽性瀰漫性大型B細胞淋巴瘤細胞株之由化合物A與依魯替尼之單劑及併用投予而得之抗腫瘤作用之評估結果。當將化合物A與依魯替尼併用投予時之交互作用為有顯著性(p=0.001543),確認了藉由併用而顯示抗腫瘤作用之協同作用。
生物學上的實施例3:評估對於人類B細胞淋巴瘤細胞株,藉由化合物A與Btk抑制劑或Bcl-2抑制劑併用而得之抗腫瘤作用(試管內)
[操作]
(1)細胞之培養
使用人類CD79突變陽性及CARD11突變陽性瀰漫性大型B細胞淋巴瘤細胞株及人類被套細胞淋巴瘤細胞株。細胞係使用含有10或20%滅活胎牛血清之RPMI1640(以下,稱為培養基),於5%CO2、37℃之條件下進行繼代培養。
(2)細胞生存性評估
將已懸浮於培養基之細胞以每1孔1250、2500或5000cells/100μL之密度播種於96孔盤。使用Tecan數位分注器D300e(Tecan),添加介質或最終濃度之1000倍濃度之化合物A及Btk抑制劑或Bcl-2抑制劑,於5%CO2、37℃之條件下培養6日。化合物A之處置濃度設為10、30或100nmol/L,Btk抑制劑及Bcl-2抑制劑之處置濃度各別設定在0.3至300nmol/L或0.003至10nmol/L之間。培養結束後使用細胞計數套組-8(Cell Counting Kit-8)(DOJINDO公司製造),依照套組之步驟而測定生存之細胞數。
(3)數據分析
以將介質處置群設為100%而得之相對值之形式算出各化合物處置群之細胞增殖抑制率(%)。使用所算出之細胞增殖抑制率(%),而算出於酶調控的進展(Advances in enzyme regulation)、第22卷、1984年、27-55頁所記載之合併指數(CI)值,分析各化合物之併用效果。又,CI值為用於判定併用效果之強度而通常使用之指標,且表示上述表2所記載之意義。
[結果]
表4及表5表示於各細胞株之藉由化合物A與Btk抑制劑(替拉魯替尼(Tirabrutinib)、阿卡替尼(Acalabrutinib)、澤布替尼(Zanubrutinib)、LOXO-305、ARQ-531)或Bcl-2抑制劑(維奈托克(Venetoclax))之併用處置所得之抗腫瘤作用之評估結果(CI值)。化合物A與Btk抑制劑或Bcl-2抑制劑併用處置時之CI之中央值都未達1,而顯示相加或協同作用。
從以上之結果確認了化合物A與Btk抑制劑或Bcl-2抑制劑之併用會發揮強的抗腫瘤效果。
生物學上的實施例4:評估對於人類B細胞淋巴瘤細胞株,藉由化合物A與各抗癌劑併用而得之抗腫瘤作用(試管內)
[操作]
(1)細胞之培養
使用人類CD79突變陽性瀰漫性大型B細胞淋巴瘤細胞株及人類被套細胞淋巴瘤細胞株。細胞係使用含有10%滅活胎牛血清之RPMI1640(以下,稱為培養基),於5%CO2、37℃之條件下進行繼代培養。
(2)細胞生存性評估
將已懸浮於培養基之細胞以每1孔2500或5000cells/100μL之密度播種於96孔盤。使用Tecan數位分注器D300e(Tecan),添加介質或最終濃度之1000倍濃度之化合物A及各種抗癌劑,於5%CO2、37℃之條件下培養6日。化合物A之處置濃度設為3、10、30或100nmol/L,抗癌劑之處置濃度係參考各抗癌劑的單劑時之抗腫瘤效果而設定在0.178至10000nmol/L之間。培養結束後使用細胞計數套組-8(DOJINDO公司製造),依照套組之步驟而測定生存之細胞數。
(3)數據分析
以將介質處置群設為100%而得之相對值之形式算出各化合物處置群之細胞增殖抑制率(%)。使用所算出之細胞增殖抑制率(%),而算出於酶調控的進展(Advances in enzyme regulation)、第22卷、1984年、27-55頁所記載之合併指數(CI)值,分析各化合物之併用效果。又,CI值為用於判定併用效果之強度而通常使用之指標,且表示上述表2所記載之意義。
[結果]
表6表示於各細胞株之藉由化合物A與各抗癌劑之併用處置所得之抗腫瘤作用之評估結果(CI值)。將化合物A與抗癌劑併用處置時之CI之中央值大致為未達1,而與任一種抗癌劑都顯示相加或協同作用。
[產業上之可利用性]
本發明之組合由於發揮強的抗腫瘤效果,故有用於作為血液癌治療劑。
本專利申請案將於日本提出專利申請之日本特願2022-015169(申請日:2022年2月2日)作為基礎,並且其內容全被包含於本說明書中。
Claims (20)
- 一種血液癌治療劑,含有會與細胞障礙性抗癌劑及/或分子標靶藥組合投予之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物,式中,A表示R1表示1)氫原子、2)鹵素原子、3)氰基、4)可經1至3個鹵素原子取代之C1-3烷基、5)C1-3烷氧基、6)C3-6環烷基或7)苯基;R2表示1)氫原子或2)鹵素原子;R3表示1)可經1至3個選自C1-3烷氧基、羥基及鹵素原子之取代基取代之C1-6烷基、2)可經1至3個選自C1-3烷基及鹵素原子之取代基取代之吡唑基、3)C3-6環烷基、4)經C1-3烷基而二取代之胺基或5)可經1至3個鹵素原子取代之苯基;R4及R6表示1)氫原子、2)鹵素原子、3)可經1至3個選自a)羥基、b)可經4-甲氧基苯基取代之C1-3烷氧基及c)鹵素原子之取代基取代之C1-3烷基或4)可經1至3個鹵素原子取代之C1-3烷氧基;R5、R7及R9表示1)可經1至3個C1-3烷氧基取代之C1-6烷基或2)可經1至3個鹵素原子取代之苯基;R8表示C1-3烷基;B為下述1)至5)中之任一者,1)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷氧基及d)三唑基之取代基取代之苯基,2)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基及b)鹵素原子之取代基取代之C3-6環烷基,3)可經1至3個選自a)鹵素原子、b)氰基、c)可經1至3個鹵素原子取代之C1-3烷基、d)可經1至3個選自鹵素原子及C1-3烷氧基之取代基取代之C1-3烷氧基、e)可經1至3個C1-3烷基取代之吡唑基、f)可經1至3個C1-3烷基取代之咪唑基、g)可經1至3個C1-3烷基取代之三唑基,其中該C1-3烷基可經1至3個選自C1-3烷氧基及鹵素原子之取代基取代、h)氮雜環丁烷基、i)吡嗒啶酮基、j)可經1至3個C1-3烷基取代之四唑基、k)嘧啶基及l)唑基之取代基取代之吡啶基,4)可經1至3個選自a)可經1至3個鹵素原子取代之C1-3烷基、b)可經1至3個鹵素原子取代C1-3之烷氧基、c)氰基及d)鹵素原子之取代基取代之吡唑基,5)可經1至3個鹵素原子取代之咪唑并吡啶基。
- 一種血液癌治療劑,含有會與請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合投予之細胞障礙性抗癌劑及/或分子標靶藥。
- 如請求項1或2所述之血液癌治療劑,其中,式(I)表示之化合物為:
- 如請求項1或2所述之血液癌治療劑,其中,細胞障礙性抗癌劑為選自由環磷醯胺(Cyclophosphamide)、多柔比星(Doxorubicin)、長春新鹼(Vincristine)、苯達莫司汀(Bendamustine)、愛萊諾迪肯(Irinotecan)、潑尼松龍(Prednisolone)及來那度胺(Lenalidomide)所構成之群組中之一種以上。
- 如請求項1或2所述之血液癌治療劑,其中,分子標靶藥為選自由抗CD20抗體、抗CD30抗體藥物複合體、抗CD33抗體、抗CD38抗體、抗CD47抗體、抗CD52抗體、抗CD70抗體、抗CD79抗體藥物複合體、抗PD-1抗體、抗PD-L1抗體、ABL抑制劑、AXL抑制劑、蛋白酶體抑制劑、抗CCR4抗體、JAK抑制劑、CXCR4拮抗藥、BET抑制劑、Bcl-2抑制劑、HDAC抑制劑、FLT3抑制劑、LSD1抑制劑、MDM2抑制劑、IDH1抑制劑、IDH2抑制劑、Btk抑制劑、PI3K抑制劑、PKC抑制劑、SYK抑制劑、mTOR抑制劑、Akt抑制劑、MEK抑制劑、EZH2抑制劑、PLK抑制劑、HSP90抑制劑、XPO1抑制劑、SMO抑制劑、NEDD8抑制劑、Btk分解誘導藥、IRAK4分解誘導藥、IRAK4抑制劑、CDK4/6抑制劑及類視色素所構成之群組中之一種以上。
- 如請求項7所述之血液癌治療劑,其中,分子標靶藥為Btk抑制劑,Btk抑制劑為選自由依魯替尼(Ibrutinib)、替拉魯替尼(Tirabrutinib)、斯貝魯替尼(Spebrutinib)、阿卡替尼(Acalabrutinib)、依弗魯替尼(Evobrutinib)、普瑟替尼(Poseltinib)、菲那魯替尼(Fenebrutinib)、維卡替尼(Vecabrutinib)、澤布替尼(Zanubrutinib)、PRN-1008、BMS-986142、LOXO-305、ARQ-531及此等之鹽所構成之群組中之一種以上。
- 如請求項8所述之血液癌治療劑,其中,Btk抑制劑為依魯替尼或其鹽。
- 如請求項8所述之血液癌治療劑,其中,Btk抑制劑為選自由替拉魯替尼、阿卡替尼、澤布替尼、LOXO-305、ARQ-531及此等之鹽所構成之群組中之一種以上。
- 如請求項1或2所述之血液癌治療劑,其中,血液癌為多發性骨髓瘤、白血病、惡性淋巴瘤、T細胞淋巴瘤、霍奇金病或原發部位不明癌。
- 一種醫藥,為由將請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與細胞障礙性抗癌劑及/或分子標靶藥組合而成者。
- 一種醫藥,為將請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與細胞障礙性抗癌劑及/或分子標靶藥組合,且被分別或同時投予者。
- 一種血癌治療方法,包含將有效量之請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物與有效量之細胞障礙性抗癌劑及/或分子標靶藥分別或同時投予於需要血液癌治療之病患。
- 一種血液癌治療方法,該血液癌治療方法包含將有效量之請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物投予於需要血液癌治療之病患,且該血液癌治療方法更包含投予有效量之細胞障礙性抗癌劑及/或分子標靶藥。
- 一種血液癌治療方法,該血液癌治療方法包含將有效量之細胞障礙性抗癌劑及/或分子標靶藥投予於需要血液癌治療之病患,且該血液癌治療方法更包含投予有效量之請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物。
- 一種請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物,其係與細胞障礙性抗癌劑及/或分子標靶藥組合而用於血液癌治療。
- 一種細胞障礙性抗癌劑及/或分子標靶藥,其係與請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合而用於血液癌治療。
- 一種請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物之使用,係用於製造血液癌治療劑,其中該血液癌治療劑係與細胞障礙性抗癌劑及/或分子標靶藥組合投予。
- 一種細胞障礙性抗癌劑及/或分子標靶藥之使用,係用於製造血液癌治療劑,其中該血液癌治療劑係與請求項1中所記載之式(I)表示之化合物或其鹽、或其共晶體、水合物或溶劑合物組合投予。
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