TW202115066A - 作為prmt5抑制劑的取代三環類化合物及其應用 - Google Patents
作為prmt5抑制劑的取代三環類化合物及其應用 Download PDFInfo
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- TW202115066A TW202115066A TW109135171A TW109135171A TW202115066A TW 202115066 A TW202115066 A TW 202115066A TW 109135171 A TW109135171 A TW 109135171A TW 109135171 A TW109135171 A TW 109135171A TW 202115066 A TW202115066 A TW 202115066A
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- alkyl
- alkylamino
- pharmaceutically acceptable
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- C07D471/04—Ortho-condensed systems
-
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Abstract
本發明屬於醫藥化學領域,關於一類作爲PRMT5抑制劑的取代三環類化合物及其應用,具體地,本發明提供式(A)所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,它們的製備方法以及含有這些化合物的藥物組合物和這些化合物或組合物用於治療PRMT5介導的疾病的用途。本發明化合物對PRMT5表現出顯著的抑制活性,
Description
本發明屬於醫藥化學領域,具體關於作爲PRMT5抑制劑的取代三環類化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,它們的製備方法以及含有這些化合物的藥物組合物和這些化合物或組合物用於治療PRMT5介導的疾病的用途。
DNA的修飾在觸發細胞生長和發育的不同階段的基因表現程序中具有核心作用,其中精胺酸甲基化在細胞進程中擔任重要角色,包括信號傳導,轉錄,RNA加工,DNA重組和修復。蛋白精胺酸甲基轉移酶(PRMTs)透過將甲基從S-腺苷甲硫胺酸(SAM)轉移到精胺酸的胍氮來催化特定精胺酸殘基的甲基化,根據催化精胺酸甲基化方式的不同,可將PRMTs分爲三類:I型(PRMT 1,2,3,4,6和8)催化單甲基化和不對稱二甲基化,II型(PRMT5和PRMT9)催化單甲基化和對稱二甲基化,而III型(PRMT7)僅進行單甲基化。
其中,PRMT5與甲基轉移酶複合體蛋白50(MEP50)特異性結合,可以對稱甲基化組蛋白H3和H4,並調節特定目標基因組的轉錄。PRMT5催化的組蛋白H3精胺酸8(R8)和H4R3對稱二甲基化已顯示抑制幾種腫瘤抑制基因的表現,例如抑癌基因7(ST7),視網膜母細胞瘤(RB)腫瘤抑制基因家族和受體O型蛋白質酪胺酸磷酸酶(PTPROt)。
除了甲基化組蛋白的能力外,PRMT5還能夠甲基化幾種重要的轉錄因子,使其在細胞調節的過程發揮重要作用。PRMT5可以甲基化p53並改變其DNA結合活性,從而引發p53控制的基因表現程序的變化。PRMT5還顯示甲基化N-MYC並改變其蛋白質穩定性以及增强其在神經母細胞瘤中的致癌活性。PRMT5還可直接甲基化轉錄因子,包括E2F-1和NF-κB/ p65,誘導其目標基因表現。PRMT5不僅可修飾核轉錄因子,還可甲基化細胞質蛋白如golgin,核糖體蛋白S10(RPS10)。因此,除了其直接調節其自身目標基因的能力之外,PRMT5還能夠透過關鍵轉錄因子的對稱甲基化間接影響全域基因表現,從而影響細胞生長,增殖和分化。
大量研究已經證實PRMT5在不同類型和侵襲性的癌症中過度表現,包括B細胞和T細胞淋巴瘤,轉移性黑色素瘤,神經母細胞瘤和成膠質細胞瘤,生殖細胞腫瘤,卵巢癌,鼻咽癌,乳腺癌,結腸直腸癌和胃癌。目前研究表明PRMT5在控制細胞生長和增殖中具有重要作用,並且其過表現促進細胞轉化。
癌細胞中增强的PRMT5表現與其目標腫瘤抑制基因的轉錄沉默相關。PRMT5能夠透過啓動子組蛋白H3R8和H4R3的甲基化以及透過修飾包括E2F1和NF-kB/p65的關鍵轉錄因子的特定精胺酸殘基引起全域染色質變化來促進癌細胞生長。PRMT5還會與程序性細胞死亡4(PDCD4)相互作用,使其在R110處變爲甲基化並且在MCF-7細胞中喪失其腫瘤抑制活性。總的來說,PRMT5過表現可能使其與生長促進蛋白和腫瘤抑制蛋白的相互作用,從而以有利於癌細胞生長,存活與轉移。
綜上所述,PRMT5抑制劑在治療腫瘤等相關疾病方面有著明確的機制,有很大潛力可以成爲腫瘤治療領域新的治療手段,因此,需要開發更安全、更有效的PRMT5抑制劑以滿足臨床需求。
本發明的一個目的是提供通式(A)所示的一類具有PRMT5抑制活性的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,,
其中,
Cy選自雜環基,所述雜環基可被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、烷基磺醯基、胺基醯基、烷基胺基醯基、雙烷基胺基、烯基、炔基、鹵代烷基醯基、羥基烷基醯基、環烷基醯基、雜環基醯基、環烷基、雜環基、芳基、雜芳基和氧代基團的基團取代。
本發明的另一個目的是提供製備本發明的通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥的方法。
本發明的再一個目的是提供包含本發明的通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥和可藥用載體的組合物,以及包含本發明的通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥和另一種或多種藥物的組合物。
本發明的又一個目的是提供本發明的通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥治療PRMT5介導的疾病的方法,以及本發明的通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥在製備用於治療PRMT5介導的疾病的藥物中的應用。
針對上述發明目的,本發明提供以下技術方案:
第一方面,本發明提供通式(A)所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,,
其中,
Cy選自雜環基,所述雜環基可被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、烷基磺醯基、胺基醯基、烷基胺基醯基、雙烷基胺基、烯基、炔基、鹵代烷基醯基、羥基烷基醯基、環烷基醯基、雜環基醯基、環烷基、雜環基、芳基、雜芳基和氧代基團的基團取代。
在一些較佳的實施方案中,本發明的化合物爲通式(A)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中:
Cy選自3-12元雜環基,所述3-12元雜環基可被一個或多個選自鹵素、羥基、C1-6
烷基、鹵代C1-6
烷基、羥基C1-6
烷基、C1-6
烷氧基、鹵代C1-6
烷氧基、羥基C1-6
烷氧基、硝基、羧基、氰基、胺基、單C1-6
烷基胺基、C1-6
烷基醯基胺基、C1-6
烷基醯基、C1-6
烷基磺醯基、胺基醯基、C1-6
烷基胺基醯基、雙C1-6
烷基胺基、C2-10
烯基、C2-10
炔基、鹵代C1-6
烷基醯基、羥基C1-6
烷基醯基、C3-12
環烷基醯基、3-12元雜環基醯基、C3-12
環烷基、3-12元雜環基、6-12元芳基、5-12元雜芳基和氧代基團的基團取代;
進一步較佳地,Cy選自3-10元雜環基,所述3-10元雜環基可被一個或多個選自鹵素、羥基、C1-3
烷基、鹵代C1-3
烷基、羥基C1-3
烷基、C1-3
烷氧基、鹵代C1-3
烷氧基、羥基C1-3
烷氧基、硝基、羧基、氰基、胺基、單C1-3
烷基胺基、C1-3
烷基醯基胺基、C1-3
烷基醯基、C1-3
烷基磺醯基、胺基醯基、C1-3
烷基胺基醯基、雙C1-3
烷基胺基、C2-6
烯基、C2-6
炔基、鹵代C1-3
烷基醯基、羥基C1-3
烷基醯基、C3-8
環烷基醯基、3-8元雜環基醯基、C3-8
環烷基、3-8元雜環基、6-8元芳基、5-8元雜芳基和氧代基團的基團取代;
更進一步較佳地,Cy選自3-10元雜環基,其中所述雜環基進一步包含一個或多個N、O或S雜原子,且所述3-10元雜環基可被一個或多個選自鹵素、羥基、C1-3
烷基、鹵代C1-3
烷基、羥基C1-3
烷基、C1-3
烷氧基、鹵代C1-3
烷氧基、羥基C1-3
烷氧基、硝基、羧基、氰基、胺基、單C1-3
烷基胺基、C1-3
烷基醯基胺基、C1-3
烷基醯基、C1-3
烷基磺醯基、胺基醯基、C1-3
烷基胺基醯基、雙C1-3
烷基胺基、C2-6
烯基、C2-6
炔基、鹵代C1-3
烷基醯基、羥基C1-3
烷基醯基、C3-8
環烷基醯基、3-8元雜環基醯基、C3-8
環烷基、3-8元雜環基、6-8元芳基、5-8元雜芳基和氧代基團的基團取代。
在一些較佳的實施方案中,本發明提供通式(A)所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中通式(A)具有以下通式(I)的結構,,
其中,
X選自O、S、C(R1
)(R2
)和N(R3
),其中R1
、R2
、R3
各自獨立地選自氫、鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基,且R1
和R2
與它們所結合的碳原子一起形成雜環基,其中所述的雜環基任選被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基的基團取代;
m爲1、2、3或4;和
n爲0、1、2、3或4。
在一些較佳的實施方案中,本發明的化合物爲通式(I)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中:
R1
、R2
、R3
各自獨立地選自氫、鹵素、羥基、C1-6
烷基、鹵代C1-6
烷基、羥基C1-6
烷基、C1-6
烷氧基、鹵代C1-6
烷氧基、羥基C1-6
烷氧基、硝基、羧基、氰基、胺基、單C1-6
烷基胺基、C1-6
烷基醯基胺基、C1-6
烷基醯基、胺基醯基、C1-6
烷基胺基醯基、雙C1-6
烷基胺基和C3-12
環烷基;
進一步較佳地,R1
、R2
、R3
各自獨立地選自氫、鹵素、羥基、C1-3
烷基、鹵代C1-3
烷基、羥基C1-3
烷基、C1-3
烷氧基、鹵代C1-3
烷氧基、羥基C1-3
烷氧基、硝基、羧基、氰基、胺基、單C1-3
烷基胺基、C1-3
烷基醯基胺基、C1-3
烷基醯基、胺基醯基、C1-3
烷基胺基醯基、雙C1-3
烷基胺基和C3-8
環烷基;
更進一步較佳地,R1
、R2
、R3
各自獨立地選自氫、鹵素、羥基、甲基、乙基、丙基、異丙基、鹵代C1-3
烷基、羥基C1-3
烷基、C1-3
烷氧基、鹵代C1-3
烷氧基、羥基C1-3
烷氧基、硝基、羧基、氰基、胺基、單C1-3
烷基胺基、C1-3
烷基醯基胺基、C1-3
烷基醯基、胺基醯基、C1-3
烷基胺基醯基、雙C1-3
烷基胺基和C3-8
環烷基。
在一些較佳的實施方案中,本發明的化合物爲通式(I)的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中:
R1
和R2
與它們所結合的碳原子一起形成3元-8元雜環基,其中所述雜環基進一步包含一個或多個N、O或S雜原子,且所述雜環基任選被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基的基團取代;
進一步較佳地,R1
和R2
與它們所結合的碳原子一起形成3元-6元雜環基,其中所述雜環基進一步包含一個或多個N、O或S雜原子,且所述雜環基任選被一個或多個選自鹵素、羥基、C1-6
烷基、鹵代C1-6
烷基、羥基C1-6
烷基、C1-6
烷氧基、鹵代C1-6
烷氧基、羥基C1-6
烷氧基、硝基、羧基、氰基、胺基、單C1-6
烷基胺基、C1-6
烷基醯基胺基、C1-6
烷基醯基、胺基醯基、C1-6
烷基胺基醯基、雙C1-6
烷基胺基和C3-12
環烷基的基團取代;
更進一步較佳地,R1
和R2
與它們所結合的碳原子一起形成氮雜環丙基、氮雜環丁基、四氫吡咯基、呱啶基、二氫吡咯基、四氫吡啶基、吡唑烷基、二氫吡唑基、咪唑烷基、二氫咪唑基、吡唑基、二氫吡唑基、噁唑烷基、二氫噁唑基、噻唑烷基、二氫噻唑基、異噁唑烷基、二氫異噁唑基、異噻唑烷基、二氫異噻唑基、六氫嘧啶基、四氫嘧啶基、二氫嘧啶基、六氫噠嗪基、四氫噠嗪基、二氫噠嗪基、呱嗪基、四氫吡嗪基、二氫吡嗪基、嗎啉基、硫代嗎啉基或牛磺胺基,其中所述基團任選被一個或多個選自鹵素、羥基、C1-3
烷基、鹵代C1-3
烷基、羥基C1-3
烷基、C1-3
烷氧基、鹵代C1-3
烷氧基、羥基C1-3
烷氧基、硝基、羧基、氰基、胺基、單C1-3
烷基胺基、C1-3
烷基醯基胺基、C1-3
烷基醯基、胺基醯基、C1-3
烷基胺基醯基、雙C1-3
烷基胺基和C3-12
環烷基的基團取代。
另一方面,本發明提供本發明的通式(A)的化合物的製備方法,包括使式(1)的化合物和式(2)的化合物反應的步驟:,
其中,Cy具有通式(A)所述的定義,式(1)的化合物和式(2)的化合物爲市售化合物或可採用本領域技術人員慣用的其它技術手段進行合成。
第三方面,本發明提供藥物組合物,其包含本發明的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥。
在一些實施方案中,本發明提供本發明的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥及包含本發明的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥的藥物組合物,所述化合物或藥物組合物用於治療PRMT5介導的疾病。
在一些實施方案中,本發明提供藥物組合物,其包含本發明的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥和可藥用載體。
可以將本發明的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥與可藥用載體、稀釋劑或賦形劑混合製備成藥物製劑,以適合於經口或胃腸外給藥。給藥方法包括,但不限於皮內、肌內、腹膜內、靜脈內、皮下、鼻內和經口途徑。所述製劑可以透過任何途徑施用,例如透過輸注或推注,透過經上皮或皮膚黏膜(例如口腔黏膜或直腸等)吸收的途徑施用。給藥可以是全身的或局部的。經口施用製劑的實例包括固體或液體劑型,具體而言,包括片劑、丸劑、粒劑、粉劑、膠囊劑、糖漿、乳劑、混懸劑等。所述製劑可透過本領域已知的方法製備,且包含藥物製劑領域常規使用的載體、稀釋劑或賦形劑。
第四方面,本發明提供本發明式(A)、式(I)或(Ia)所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,或包含其的藥物組合物用於治療PRMT5介導的疾病的方法以及在製備治療PRMT5介導的疾病的藥物中的用途。
在一些較佳的實施方案中,本發明提供本發明式(A)、式(I)或(Ia)所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,或包含其的藥物組合物用於治療PRMT5介導的疾病的方法以及在製備治療PRMT5介導的疾病的藥物中的用途,其中所述的PRMT5介導的疾病包括但不限於:增殖性疾病、代謝疾病或血液疾病。在一些實施方案中,本發明所述的PRMT5介導的疾病爲癌症。
在一些實施方案中,本發明所述的PRMT5介導的疾病包括但不限於:聽神經瘤、腺癌、腎上腺癌、肛門癌、血管肉瘤(例如,淋巴管肉瘤、淋巴管內皮肉瘤、血管肉瘤)、附件癌、良性單株性丙種球蛋白病、膽癌(例如,膽管癌)、膀胱癌、乳癌(例如,乳房腺癌、乳房乳頭狀癌、乳腺癌、乳房髓樣癌、三陰性乳腺癌)、腦癌(例如,腦膜瘤;神經膠質瘤,例如星形細胞瘤、少突神經膠質瘤;成神經管細胞瘤)、支氣管癌、類癌瘤、子宮頸癌(例如子宮頸腺癌)、絨毛膜癌、脊索瘤、顱咽管瘤、結腸直腸癌(例如,結腸癌、直腸癌、結腸直腸腺癌)、上皮癌、室管膜瘤、內皮肉瘤(例如,卡波西氏肉瘤(Kaposi's sarcoma)、多發性特發性出血性肉瘤)、子宮內膜癌(例如,子宮癌、子宮肉瘤)、食道癌(例如,食道腺癌、巴瑞特氏腺癌(Barrett’s adenocarinoma))、尤因肉瘤(Ewing sarcoma)、眼癌(例如,眼內黑色素瘤、成視網膜細胞瘤)、家族性嗜酸性粒細胞增多症、膽囊癌、胃癌(例如,胃腺癌)、胃腸道間質瘤(GIST)、頭頸部癌(例如,頭頸部鱗狀細胞癌、口腔癌(例如,口腔鱗狀細胞癌(OSCC)、咽喉癌(例如,喉癌、咽癌、鼻咽癌、口咽癌)、造血系統癌(例如,白血病,如急性淋巴細胞性白血病(ALL) (例如,B-細胞ALL、T-細胞ALL)、急性髓細胞性白血病(AML) (例如,B-細胞AML、T-細胞AML)、慢性粒細胞性白血病(CML) (例如,B-細胞CML、T-細胞CML)以及慢性淋巴細胞性白血病(CLL) (例如,B-細胞CLL、T-細胞CLL);淋巴瘤如何杰金淋巴瘤(HL) (例如,B-細胞HL、T-細胞HL)以及非何杰金淋巴瘤(NHL) (例如,B-細胞NHL,如彌漫性大細胞淋巴瘤(DLCL) (例如,彌漫性大B-細胞淋巴瘤(DLBCL))、濾泡性淋巴瘤、慢性淋巴細胞性白血病/小淋巴細胞性淋巴瘤(CLL/SLL)、套細胞淋巴瘤(MCL)、邊緣帶B-細胞淋巴瘤(例如,黏膜相關淋巴樣組織(MALT)淋巴瘤、結節邊緣帶B-細胞淋巴瘤、脾邊緣帶B-細胞淋巴瘤)、原發性縱隔B-細胞淋巴瘤、伯基特淋巴瘤(Burkittlymphoma)、淋巴漿細胞淋巴瘤(即,「沃爾丹斯特倫巨球蛋白血症(Waldenström’s macroglobulinemia)」)、毛細胞白血病(HCL)、免疫母細胞性大細胞淋巴瘤、前體B-成淋巴細胞性淋巴瘤以及原發性中樞神經系統(CNS)淋巴瘤;以及T-細胞NHL如前體T-成淋巴細胞性淋巴瘤/白血病、外周T-細胞淋巴瘤(PTCL) (例如,皮膚T-細胞淋巴瘤(CTCL) (例如,蕈樣真菌病(mycosis fungiodes)、西澤里症候群(Sezary syndrome))、血管免疫母細胞性T-細胞淋巴瘤、結節外天然殺手T-細胞淋巴瘤、腸病類型T-細胞淋巴瘤、皮下脂膜炎樣T-細胞淋巴瘤、間變性大細胞淋巴瘤);如上所描述的一種或多種白血病/淋巴瘤的混合物;以及多發性骨髓瘤(MM))、重鏈病(例如,α鏈病、γ鏈病、μ鏈病)、成血管細胞瘤、發炎肌纖維母細胞瘤、免疫細胞澱粉樣變性、腎癌(例如,腎母細胞瘤又稱韋爾姆斯氏瘤(Wilms’tumor)、腎細胞癌)、肝癌(例如,肝細胞癌(HCC)、惡性肝細胞瘤)、肺癌(例如,支氣管癌、小細胞肺癌(SCLC)、非小細胞肺癌(NSCLC)、肺腺癌)、平滑肌肉瘤(LMS)、肥大細胞增多症(例如,全身性肥大細胞增多症)、骨髓發育不良症候群(MDS)、間皮瘤、骨髓增殖性疾病(MPD) (例如,真性紅血球增多症(PV)、特發性血小板增多症(ET)、特發性骨髓外化生(AMM)又稱爲骨髓纖維變性(MF)、慢性特發性骨髓纖維變性、慢性骨髓性白血病(CML)、慢性嗜中性白血病(CNL)、嗜酸性白血球增多症候群(HES))、成神經細胞瘤、神經纖維瘤(例如,1型或2型多發性神經纖維瘤(NF)、許旺細胞瘤病(schwannomatosis))、神經內分泌癌(例如,胃腸胰腺神經內分泌腫瘤(GEP-NET)、類癌瘤)、骨肉瘤、卵巢癌(例如,囊腺癌、卵巢胚胎性癌、卵巢腺癌、卵巢透明細胞癌、卵巢漿液性囊腺癌)、乳頭狀腺癌、胰腺癌(例如,胰腺腺癌、管內乳頭狀黏液瘤(IPMN)、胰島細胞腫瘤)、陰莖癌(例如,陰莖和陰囊佩吉特氏病(Paget’s disease))、松果體瘤、原發性神經外胚層瘤(PNT)、前列腺癌(例如,前列腺腺癌)、直腸癌、橫紋肌肉瘤、唾液管癌、皮膚癌(例如,鱗狀細胞癌(SCC)、角化棘皮瘤(KA)、黑色素瘤、基底細胞癌(BCC))、小腸癌(例如,附件癌)、軟組織肉瘤(例如,惡性纖維組織細胞瘤(MFH)、脂肪肉瘤、惡性外周神經鞘瘤(MPNST)、軟骨肉瘤、纖維肉瘤、黏液肉瘤)、皮脂腺癌、汗腺癌、滑膜瘤、睪丸癌(例如,精原細胞瘤、睪丸胚胎性癌)、甲狀腺癌(例如,甲狀腺乳頭狀癌、乳頭狀甲狀腺癌(PTC)、髓樣甲狀腺癌)、尿道癌、陰道癌以及外陰癌(例如,外陰佩吉特氏病)、髓母細胞瘤、腺樣囊性癌、黑色素瘤、膠質母細胞癌。
在一些實施方案中,本發明所述的PRMT5介導的疾病包括代謝性病症如糖尿病或肥胖症。
在一些實施方案中,本發明所述的PRMT5介導的疾病包括血紅蛋白病如鐮狀細胞病或β-地中海貧血。
在一些實施方案中,本發明所述的PRMT5介導的疾病包括發炎和自身免疫性疾病。
在一些較佳的實施方案中,本發明提供本發明通式I所示的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,或包含其的藥物組合物用於治療PRMT5介導的疾病的方法以及在製備治療PRMT5介導的疾病的藥物中的用途,其中所述的PRMT5介導的疾病包括但不限於:乳腺癌、食道癌、膀胱癌、肺癌、造血系統癌、淋巴瘤、髓母細胞瘤、成神經管細胞瘤、直腸腺癌、結腸癌、胃癌、胰腺癌、肝癌、腺樣囊性癌、前列腺癌、肺癌、頭頸部鱗狀細胞癌、腦癌、肝細胞癌、黑色素瘤、少突神經膠質瘤、膠質母細胞癌、睪丸癌、卵巢透明細胞癌、卵巢漿液性囊腺癌、甲狀腺癌、多發性骨髓瘤(AML)、腎細胞癌、套細胞淋巴瘤、三陰性乳腺癌、非小細胞肺癌、血紅蛋白病、糖尿病和肥胖症。
術語定義
除非有相反陳述,在說明書和申請專利範圍中使用的術語具有下述含義。
本發明化合物中的「氫」、「碳」、「氧」包括其所有同位素。同位素應理解爲包括具有相同原子數但具有不同質量數的那些原子。舉例來說,氫的同位素包括氕、氚和氘,碳的同位素包括12
C、13
C和14
C,氧的同位素包括16
O和18
O等。
本發明的「異構體」是指原子組成及連接方式相同,而其三維空間排列不同的分子,包括但不限於非對映體,對映異構體,順反異構體,和它們的混合物,如外消旋混合物。很多有機化合物都以光學活性形式存在,即它們有能力旋轉平面偏振光的平面。在描述光學活性化合物時,前綴D、L或R、S用來表示分子手性中心的絕對構型。前綴D、L或(+)、(-)用來命名化合物平面偏振光旋轉的符號,(-)或L是指化合物是左旋的,前綴(+)或D是指化合物是右旋的。這些立體異構體的化學結構是相同的,但其立體結構不一樣。特定的立體異構體可以是對映體,異構體的混合物通常稱爲對映異構體混合物。50:50的對映體混合物被稱爲外消旋混合物或外消旋體,這可能導致化學反應過程中沒有立體選擇性或立體定向性。術語「外消旋混合物」和「外消旋體」是指等莫耳的兩個對映異構體的混合物,缺乏光學活性。
依據起始物料和方法的選擇,本發明化合物可以以可能的異構體中的一個或它們的混合物,例如外消旋體和非對應異構體混合物(這取決於不對稱碳原子的數量)的形式存在。光學活性的(R)-或(S)-異構體可使用手性合成子或手性試劑製備,或使用常規技術拆分。
所得的任何立體異構體的混合物可以依據組分物理化學性質上的差異被分離成純的或基本純的幾何異構體,對映異構體,非對映異構體,例如,透過色譜法和/或分步結晶法。
本發明的「鹵素」是指氟、氯、溴、碘。本發明的「鹵代」是指被氟、氯、溴或碘取代。
本發明的「烷基」指直鏈或支鏈的飽和脂肪烴基團,較佳含1至6個碳原子的直鏈或支鏈基團,進一步較佳含有1至3個碳原子的直鏈或支鏈基團,非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基等。烷基可以是取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上。
本發明的「羰基」、「醯基」均指-C(O)-。
本發明的「磺醯基」是指-S(O)2
-。
本發明的「磺醯胺基」是指-S(O)2
NH-。
本發明的「鹵代烷基」是指至少被一個鹵素取代的烷基。
本發明的「羥基烷基」是指至少被一個羥基取代的烷基。
本發明的「烷氧基」是指-O-烷基。烷氧基的非限制性實例包括:甲氧基、乙氧基、丙氧基、正丙氧基、異丙氧基、異丁氧基、仲丁氧基等。烷氧基可以是任選取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上。
本發明的「環烷基」是指環狀的飽和烴基。合適的環烷基可以爲取代或未取代的具有3-12個碳原子的單環、二環或三環飽和烴基,例如環丙基、環丁基、環戊基、環己基。
本發明的「雜環基」是指具有1至4個環雜原子(其中每個雜原子獨立地選自氮、氧、硫、硼、磷以及矽)的3-至12-元非芳香族環系統的基團(「3-12元雜環基」)。在包含一個或多個氮原子的雜環基基團中,連接點可以是碳或氮原子,只要化合價許可。雜環基基團或者可以是單環的(「單環雜環基」)或者是融合的、橋聯的或螺的環系統(例如二環系統(又稱「二環雜環基」))並且可以是飽和的或可以是部分不飽和的。合適的雜環基包括但不限於呱啶基、氮雜環丁烷基、氮雜環丙烷基、四氫吡咯基、呱嗪基、二氫喹唑啉基、氧雜環丙基、氧雜環丁基、四氫呋喃基、四氫吡喃基、、、、、、、等。雜環基的每個實例可以是任選取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上。
本發明的「芳基」是指可以包含單環或稠合多環的芳香體系,較佳包含單環或稠合雙環的芳香體系,其含有6個至12個碳原子,較佳含有約6至約10個碳原子。合適的芳基包括但不限於苯基、萘基、蒽基、芴基、茚滿基。芳基可以是任選取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上。
本發明的「雜芳基」是指至少有一個碳原子被雜原子替代的芳基,較佳由5-12個原子構成(5-12元雜芳基),進一步較佳由5-10個原子組成(5-10元雜芳基),所述的雜原子爲O、S、N。所述雜芳基包括但不限於咪唑基、吡咯基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、異噁唑基、異噻唑基、噁二唑基、三唑基、四唑基、吲哚基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、異吲哚基、苯並吡唑基、苯並咪唑基、苯並呋喃基、苯並吡喃基、苯並噻吩基、苯並噁唑基、苯並噻唑基、苯並異噁唑基、苯並異噻唑基、喹啉基、異喹啉基、喹唑啉基、噌啉基、喹喔啉基、苯並噁嗪基、苯並噻嗪基、咪唑並吡啶基、嘧啶並吡唑基、嘧啶並咪唑基等。雜芳基可以是任選取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上。
本發明的「藥學上可接受的鹽」是指本發明化合物的鹽,這類鹽用於哺乳動物體內時具有安全性和有效性,且具有應有的生物活性。
本發明的「溶劑化物」在常規意義上是指溶質(如活性化合物、活性化合物的鹽)和溶劑(如水)組合形成的複合物。溶劑是指本領域的技術人員所知的或容易確定的溶劑。如果是水,則溶劑化物通常被稱作水合物,例如半水合物、一水合物、二水合物、三水合物或其替代量等。
具有化學式(A)的化合物的體內作用可以部分地由在給予具有化學式(A)的化合物之後在人體或動物體內形成的一種或多種代謝物來發揮。如上所述,具有化學式(A)的化合物的體內作用也可以經由前體化合物(「前藥」)代謝來發揮。本發明的「前藥」是指在生物體中的生理條件下,由於與酶、胃酸等反應而轉化成本發明化合物的化合物,即透過酶的氧化、還原、水解等轉化成本發明化合物的化合物和/或透過胃酸等的水解反應等轉化成本發明化合物的化合物等。
本發明的「結晶」是指其內部結構是在三維上規律地重複構成原子(或其集團)而形成的固體,有別於不具有這種規律的內部結構的無定形固體。
本發明的「藥物組合物」是指包含任何一種本發明所述的化合物,包括對應的異構體、前藥、溶劑化物、藥學上可接受的鹽或其化學的保護形式,和一種或多種可藥用載體和/或另一種或多種藥物的混合物。藥用組合物的目的是促進化合物對生物體的給藥。所述組合物通常用於製備治療和/或預防由一種或多種激酶介導的疾病的藥物。
本發明的「可藥用載體」是指對有機體不引起明顯刺激性和不干擾所給予化合物的生物活性和性質的載體,包含所有的溶劑、稀釋劑或其它賦形劑、分散劑、界面活性劑等滲劑、增稠劑或乳化劑、防腐劑、固體黏合劑、潤滑劑等。除非任何常規載體介質與本發明化合物不相容。可以作爲藥學上可接受的載體的一些實例包括,但不限於糖類,如乳糖、葡萄糖和蔗糖;澱粉,如玉米澱粉和馬鈴薯澱粉;纖維素及其衍生物,如羧甲基纖維素鈉、以及纖維素和乙酸纖維素;麥芽、明膠等。
本發明的「賦形劑」指加入到藥用組合物中以進一步促進給予化合物的惰性物質。賦形劑可以包括碳酸鈣、磷酸鈣、多種糖類和多種類型的澱粉、纖維素衍生物、明膠、植物油、聚乙二醇。
本發明的「PRMT5」可以是野生型PRMT5或PRMT5的任何突變體或變體,PRMT5的突變體或變體含有一個或多個突變(例如,保守取代)。
下面結合實施例對本發明作進一步詳細闡述,但本發明不限於這些實施例。以下實施例中使用的材料如無特殊說明均爲商購獲得。
實施例1:(R
)-7’-((1-乙醯基呱啶-4-基)胺基)-2’-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥基丙基)-2’,3’-二氫-1’H
-螺[環丙烷-1,4’-[2,6]萘啶]-1’-酮
將5-溴-2-氯異烟酸(10g,42.292 mmol)溶於甲醇中,在0℃下加入9.2 mL氯化亞碸(9.2 mL,126.8 mmol)。滴加完畢後,將反應液加熱至80℃,反應10小時後,LCMS監測反應完全,加入乙酸乙酯(200 mL),飽和碳酸鈉水溶液調至PH約8左右。分離有機相和水相後,水相用乙酸乙酯萃取3次,合併有機相用飽和氯化鈉洗一次,用無水硫酸鈉乾燥有機相後濃縮得到標題化合物。LC-MS m/z: [M+H]+
= 250.0, 252.0。
將5-溴-2-氯異烟酸甲酯(10g,51.8 mmol)和四(三苯基膦)鈀(4.6 g,3.98 mmol)加入到無水N
,N
-二甲基甲醯胺(DMF,25 mL)中。在氬氣保護下加入三甲基鋁(2 M甲苯溶液,51.9 mmol,25.95 mL),加入完畢後,將反應體系升溫至80℃反應並攪拌過夜。反應完全後,將反應液倒入冰水中(500 mL)淬滅,加入乙酸乙酯(500 mL)萃取。有機相用飽和氯化鈉水溶液水洗,無水硫酸鈉乾燥後減壓蒸去溶劑。柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 186.0。
將2-氯-5-甲基異烟酸甲酯(5.14 g,27.69 mmol)溶於四氯化碳(50 mL)中,加入N
-溴代丁二醯亞胺(4.93g,27.7 mmol),過氧化苯甲醯(1g,4.13 mmol),80℃下攪拌反應過夜。LCMS監測反應完全,減壓除去有機溶劑後,加入水和乙酸乙酯萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 264.0,266.1。
將5-(溴甲基)-2-氯異烟酸甲酯(5.29 g,20.1 mmol)溶於無水乙腈(35 mL)中,加入三甲基氰矽烷 (2.20 g,22.17 mmol),降溫至-10℃。在該反應液中緩慢滴加四丁基氟化銨(7.88 g,30.14 mmol),滴加完畢後升溫至0℃反應3小時。LCMS監測反應完全,反應液用矽藻土抽濾後,加水,用乙酸乙酯萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 211.0。
將2-氯-5-(氰基甲基)異烟酸甲酯(1.5 g,7.12 mmol)溶於無水二甲基亞碸(DMSO,25 mL)中,加入1,2-二溴乙烷(2.0 g,10.65 mmol),碳酸銫(4.64 g,14.24 mmol)。在N2
保護,70℃反應1個小時。LCMS監測反應完全後,冷卻至室溫,加水,用乙酸乙酯萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 237.0。
將2-氯-5-(1-氰基環丙基)異烟酸甲酯(0.1 g,0.38 mmol)溶於無水四氫呋喃(THF,3 mL)中,加入4-胺基呱啶-1-羧酸叔丁酯(114.1 mg,0.57 mmol),碳酸銫(247.6 mg,0.76 mmol),氯(2-二環己基膦基-2’,6’-二異丙基-1,1'-聯苯)[2-(2-胺基乙基苯基]鈀(II)(31.82 mg,0.04 mmol),N2
保護,70℃反應過夜。LCMS監測反應完全,加水,用乙酸乙酯萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 401.2.
將2-((1-(叔丁氧基羰基)呱啶-4-基)胺基)-5-(1-氰基環丙基)異烟酸甲酯(162 mg,0.405 mmol)溶於無水二氯甲烷(4 mL)中,冰浴至0℃緩慢滴加三氟乙酸(0.4 mL,5.38 mmol),滴加完畢後撤去冰浴,室溫攪拌過夜。減壓蒸去有機溶劑後,加入無水二氯甲烷(5 mL)。在該溶液中加入N
,N
-二異丙基乙胺至pH爲7-8後再補加N
,N
-二異丙基乙胺(52.3 mg,0.405 mmol),並加入乙酸酐(49.0 mg,0.48 mmol),室溫攪拌2小時。LCMS監測反應完全後,在反應液中加水淬滅後,並用二氯甲烷萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,濃縮後得到標題化合物。LC-MS m/z: [M+H]+
= 343.2。
將2-((1-乙醯基呱啶-4-基)胺基)-5-(1-氰基環丙基)異烟酸甲酯(311.0 mg,0.91 mmol)溶於甲醇中,冰浴至0℃加入六水合二氯化鈷(865.4 mg,3.64 mmol),分批緩慢加入硼氫化鈉(207.26 mg,5.48 mmol),0℃下攪拌0.5小時後常溫攪拌1小時。LCMS監測反應未完全,反應液加入飽和氯化銨水溶液淬滅後,乙酸乙酯萃取,有機相用飽和氯化鈉洗2次,無水硫酸鈉乾燥,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 315.2
步驟9: (R
)-7’-((1-乙醯基呱啶-4-基)胺基)-2’-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥基丙基)-2’,3’-二氫-1’H
-螺[環丙烷-1,4’-[2,6]萘啶]-1’-酮的製備
將7’-((1-乙醯基呱啶-4-基)胺基)-2’,3’-二氫-1’H
-螺[環丙烷-1,4’-[2,6]萘啶]-1’-酮(45 mg,0.175 mmol)溶於無水DMF(5 mL)中,在氮氣保護下降溫至0℃並緩慢加入NaH(11.45 mg,0.48 mmol),0.5小時後加入(R
)-2-(環氧乙烷-2-基甲基)-1,2,3,4-四氫異喹啉(32.53 mg,0.172 mmol),室溫攪拌過夜。LCMS監測反應未完全,補加10 mg NaH,33 mg (R
)-2-(環氧乙烷-2-基甲基)-1,2,3,4-四氫異喹啉,繼續反應2小時。LCMS監測反應完全,減壓蒸去有機溶劑,柱層析分離得標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 8.12-8.23 (m, 1H), 7.10-7.16 (m, 4H), 6.65-6.80 (m, 1H), 5.50-5.60 (m, 1H), 4.72 (s, 1H), 4.12-4.25 (m, 1H), 3.94-4.10 (m, 1H), 3.71-3.87 (m, 2H), 3.62 (s, 2H), 3.42-3.54 (m, 2H), 3.36-3.41 (m, 1H), 3.11-3.25 (m, 2H), 2.75-2.94 (m, 3H), 2.65-2.80 (m, 2H), 2.36-2.48 (m, 2H), 2.05 (s, 3H), 1.80-2.00 (m, 2H), 1.15-1.36 (m, 2H), 0.80-0.97 (m, 4H). LC-MS m/z: [M+H]+
= 504.3.
實施例2:(R
)-7’-((2-乙醯基-2-氮雜螺[3.3]庚-6-基)胺基)-2’-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2’,3’-二氫-1’H
-螺[環丙烷-1,4’-[2,6]萘啶]-1’-酮
製備方法同實施例1的製備方法,不同的是將實施例1步驟6中的4-胺基呱啶-1-羧酸叔丁酯替換成6-胺基-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯,得標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 7.71 (s, 1H), 7.00-7.15 (m, 4H), 6.87 (m, 1H), 4.78 (s, 1H), 4.16 (s, 1H), 4.04-4.10 (m, 3H), 3.88 (m, 1H), 3.70-3.80 (m, 3H), 3.61-3.63 (m, 2H), 2.80-2.83 (m, 2H), 2.70-2.72 (m, 2H), 2.18-2.20 (m, 1H), 1.98-2.02 (m, 4H), 1.72 (s, 3H), 1.24-1.30 (m, 4H), 0.94-1.0 (m, 4H). LC-MS m/z: [M+H]+
= 516.3.
按照本發明實施例1的合成方法,利用不同市售原料合成實施例3-9的化合物,這些化合物的表徵參數如表1所示:
實施例10:(R
)-7'-((2-乙醯基-2-氮雜螺[3.3]庚-6-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮
將氫化鈉(4.46 g,111 mmol)置於三頸瓶中,0℃下加入20 mL無水N
,N
-二甲基甲醯胺,攪拌5 min,緩慢加入2-(氰基甲基)苯甲酸甲酯(7.80 g,44.6 mmol)的N
,N
-二甲基甲醯胺溶液(80 mL),0℃下攪拌30 min,然後緩慢滴加1,2-二溴乙烷(10.0 g,53.5 mmol),滴畢後移至室溫反應2 h。反應完全後,加入20 mL飽和氯化銨溶液淬滅,乙酸乙酯(30 mL × 3)萃取,合併有機相,水洗(10 mL × 2),飽和食鹽水洗,經無水硫酸鈉乾燥,減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=202.
將2-(1-氰基環丙基)苯甲酸甲酯(13.3 g,66.1 mmol) 溶解於150 mL無水乙醇中,加入六水合氯化鈷(31.5 g,132 mmol),0℃下分批加入硼氫化鈉(7.54 g,198 mmol),移至室溫反應1 h後80℃反應2 h。反應完全後,抽濾,濾液減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=174.
將2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(6.33 g,36.6 mmol)溶解於冰浴下冷卻的濃硫酸(30 mL)中,-10℃下分批加入硝酸鉀(3.69 g,36.6 mmol),移至室溫反應1 h。反應完全後,倒入冰水中,有固體析出,抽濾,濾餅乾燥得到標題化合物。LC-MS m/z: [M+H]+
=219.
將7'-硝基-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(300 mg,1.38 mmol)溶解於10 mL DMSO中,加入碳酸銫(900 mg,2.75 mmol)後室溫攪拌0.5h,加入(R
)-2-(環氧乙烷-2-基甲基)-1,2,3,4-四氫異喹啉(520 mg,2.75 mmol),100℃反應3h。反應完全後,加入水50 mL,乙酸乙酯(30 mL × 3)萃取,無水硫酸鈉乾燥,減壓蒸除溶劑,經柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 408.
將(R
)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-7'-硝基-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(500 mg,1.23 mmol),還原鐵粉(274 mg,4.9 mmol),氯化銨(260 mg,4.90 mmol),加入10 mL乙醇和2 mL水的混合溶液中,75℃反應2h。反應完全後,過濾,濾液減壓蒸除溶劑,加入二氯甲烷20 mL,過濾,濾液減壓蒸除溶劑,得到標題化合物。LC-MS m/z: [M+H]+
= 378.
步驟6:(R
)-6-((2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-1'-氧代-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-7'-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯的製備
將(R
)-7'-胺基-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(200 mg,0.526 mmol),6-氧代-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯(65.06 mg,0.582 mmol)溶解於5 mL甲醇中,加入一滴冰醋酸,室溫攪拌0.5 h,冰浴滴加吡啶硼烷(74.0 mg,0.796 mmol),室溫攪拌0.5 h。反應完全後,減壓蒸除溶劑,經柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
= 573.
步驟7: (R
)-7'-((2-氮雜螺[3.3]庚-6-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮的製備
將(R
)-6-((2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-1'-氧代-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-7'-基)胺基)-2-氮雜螺[3.3]庚烷-2-羧酸叔丁酯(180 mg,0.315 mmol)溶解於10 mL 氯化氫甲醇(4.0 mol/L)溶液中,室溫攪拌0.5h。反應完全後,減壓蒸除溶劑,得到標題化合物。LC-MS m/z: [M+H]+
= 473.
步驟8: (R
)-7'-((2-乙醯基-2-氮雜螺[3.3]庚-6-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮的製備
將(R)-7'-((2-氮雜螺[3.3]庚-6-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(140 mg,0.297 mmol)加入10 mL二氯甲烷中,加入三乙胺至溶液呈弱鹼性,完全溶解後,加入醋酸酐(61.0 mg,0.593 mmol),室溫攪拌15 min。反應完全後,減壓蒸除溶劑,柱層析分離得標題化合物。1
H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.31 (m, 1H), 7.14-7.12 (m, 4H), 7.06-7.00 (m, 1H), 4.25-4.23 (m, 1H), 4.05-3.83 (m, 5H), 3.70-3.61 (m, 2H), 3.45-3.37 (m, 2H), 3.05-2.90 (m, 4H), 2.87-2.72 (m, 2H), 2.02-1.98 (m, 2H), 1.93 (s, 3H), 1.84-1.81 (m, 1H), 1.79-1.76 (m, 3H), 1.34-1.02 (m, 4H). LC-MS m/z: [M+HCO2 -
]-
= 559.
參照WO2014/100719 (PCT/US2013/077235)中化合物208公開的方法製備上式代表的化合物A,並透過氫譜和質譜鑒定。
比較例2:(R
)-7'-((1-乙醯基呱啶-4-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥基丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(化合物B)
將氫化鈉(4.46 g,111 mmol)置於三頸瓶中,0℃下加入20 mL無水N
,N
-二甲基甲醯胺,攪拌5 min,緩慢加入2-(氰基甲基)苯甲酸甲酯(7.80 g,44.6 mmol)的N
,N
-二甲基甲醯胺溶液(80 mL),0℃下攪拌30 min,然後緩慢滴加1,2-二溴乙烷(10.0 g,53.5 mmol),滴畢後移至室溫反應2 h。反應完全後,加入20 mL飽和氯化銨溶液淬滅,乙酸乙酯(30 mL × 3)萃取,合併有機相,水洗(10 mL × 2),飽和食鹽水洗,經無水硫酸鈉乾燥,減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=202.
將2-(1-氰基環丙基)苯甲酸甲酯(13.3 g,66.1 mmol) 溶解於150 mL無水乙醇中,加入六水合氯化鈷(31.5 g,132 mmol),0℃下分批加入硼氫化鈉(7.54 g,198 mmol),移至室溫反應1 h後80℃反應2 h。反應完全後,抽濾,濾液減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=174.
將2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(6.33 g,36.6 mmol)溶解於冰浴下冷卻的濃硫酸(30 mL)中,-10℃下分批加入硝酸鉀(3.69 g,36.6 mmol),移至室溫反應1 h。反應完全後,倒入冰水中,有固體析出,抽濾,濾餅乾燥得到標題化合物。LC-MS m/z: [M+H]+
=219.
將7'-硝基-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(4.57 g,210 mmol) 溶解於40 mL 乙醇和10 mL水的混合溶劑中,加入鐵粉(2.93 g,52.4 mmol),氯化銨(3.33 g,62.9 mmol),80℃反應2 h。反應完全後,抽濾,濾液減壓濃縮,二氯甲烷(30 mL × 3)萃取,合併有機相,經無水硫酸鈉乾燥,減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=189.
將7'-胺基-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(1.55 g,8.24 mmol),1-乙醯基-4-呱啶酮(1.16 g,8.24 mmol)溶解於20 mL甲醇中,加入冰醋酸(0.472 mL,8.24 mmol),室溫反應2 h。然後0℃下緩慢滴加硼烷吡啶絡合物(1.24 mL,12.4 mmol),移至室溫2 h。反應完全後,用飽和碳酸氫鈉溶液調pH至鹼性,二氯甲烷(20 mL × 3)萃取,合併有機相,經無水硫酸鈉乾燥,減壓蒸除溶劑,柱層析分離得到標題化合物。LC-MS m/z: [M+H]+
=314.
步驟6:(R
)-7'-((1-乙醯基呱啶-4-基)胺基)-2'-(3-(3,4-二氫異喹啉-2(1H
)-基)-2-羥基丙基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮 (化合物B)的製備
將7'-((1-乙醯基呱啶-4-基)胺基)-2',3'-二氫-1'H
-螺[環丙烷-1,4'-異喹啉]-1'-酮(1.56 g,4.98 mmol) 溶解於10 mL無水N
,N
-二甲基甲醯胺溶液中,0℃下分批加入氫化鈉(0.299 g,7.48 mmol),攪拌30 min,加入(R
)-2-(環氧乙烷-2-基甲基)-1,2,3,4-四氫異喹啉(0.942 g,4.98 mmol)的N
,N
-二甲基甲醯胺溶液(5 mL),移至室溫反應過夜。反應完全後,加入8 mL飽和氯化銨溶液淬滅,減壓蒸除溶劑,經柱層析分離,經prep-HPLC(製備液相)製備分離得到標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 7.16-7.23 (m, 1H), 7.05-7.16 (m, 3H), 6.99-7.05 (m, 1H), 6.65-6.77 (m, 2H), 5.57 (d, 1H), 4.75 (s, 1H), 4.19 (d, 1H), 3.94-4.10 (m, 1H), 3.71-3.87 (m, 2H), 3.62 (s, 2H), 3.42-3.54 (m, 2H), 3.34-3.41 (m, 1H), 3.11-3.25 (m, 2H), 2.75-2.94 (m, 3H), 2.62-2.74 (m, 2H), 2.36-2.48 (m, 2H), 2.00 (s, 3H), 1.79-1.96 (m, 2H), 1.12-1.36 (m, 2H), 0.75-0.97 (m, 4H). LC-MS m/z: [M+H]+
=503.
實驗例1 化合物體外激酶活性評價
1. 實驗材料
化合物:以上實施例製備的本發明的化合物,每個化合物用DMSO配製成10 mM母液,最終稀釋爲10個濃度進行檢測,終濃度爲10000.00 nM、3333.33 nM、1111.11 nM、370.37 nM、123.46 nM、41.15 nM、13.72 nM、4.57 nM、1.52 nM、0.51 nM。
試劑與耗材:PRMT5,購自於Active Motif公司,貨號爲31921;多肽基質H4(1-21)S1ac,購自於吉爾生化(上海)有限公司,貨號爲342095;[3
H]-SAM,購自於PerkinElmer公司,貨號爲NET155V001MC;SAM,購自於Sigma,貨號爲A7007-100MG;SAH,購自於Sigma公司,貨號爲A9384-25MG;DTT,購自於生工生物工程(上海)股份有限公司,貨號爲A620058-0005。Corning-3657,購自於Corning公司,貨號爲3657;Echo Qualified 384-Well,購自於Labcyte公司,貨號爲P-05525;FlashPlate,購自於Perkin Elmer,貨號爲SMP410J001PK。
儀器:閃爍計數儀,購自於PerkinElmer公司,型號爲MicroBeta2;超音波納升液體處理系統,購自於Labcyte公司,型號爲Echo 550。
2. 實驗方法
2.1. 反應緩衝液和反應終止液配製:1倍反應緩衝液體成分爲10 mM Tris-HCl,pH 8.0;0.01% Tween-20;1 mM DTT。反應終止液成分爲125 μM的3
H-SAM溶液。
2.2 化合物配製
2.2.1 化合物稀釋
化合物用100% DMSO溶解成10 mM母液,再將化合物在Echo384孔盤上稀釋到所需要的濃度。
2.2.2 轉移化合物到384反應盤
用Echo550儀器從上述稀釋好Echo384孔盤中轉移250 nL化合物到384孔反應盤中。
2.3 酶學反應
2.3.1 配製1.67倍酶溶液
將PRMT5加入1倍反應緩衝液,形成1.67倍酶溶液。
2.3.2 配製2.5倍的基質溶液
將多肽基質和[3
H]-SAM加入1倍反應緩衝液,形成2.5倍基質溶液(終濃度分別爲100 nM和250 nM)。
2.3.3 向384孔盤中加入酶溶液
向384孔反應盤孔中加入15 μL的1.67倍酶溶液。對於無酶活性對照孔,用15 μL 的1倍反應緩衝液替代酶溶液。1000 rpm離心1 min,室溫下孵育15分鐘。
2.3.4 向384孔盤中加入基質溶液啓動酶學反應
向384孔反應盤每孔中加入10 μL的2.5倍基質溶液。1000 rpm離心1 min。25℃反應60分鐘。
2.3.5 酶學反應的終止
向384孔反應盤每孔中加入5 μL的反應終止液終止反應。從試驗盤中每孔取25 μL轉移到Flashplate中,在室溫下放置1 h。然後用0.1%的Tween-20溶液洗Flashpate盤3次。
2.4 MicroBeta 2讀取數據
2.4 抑制率計算
從Microbeta 2上複製數據。把數據轉化成抑制率數據。其中最大值是指DMSO對照的轉化率,最小值是指無酶活性對照的轉化率。抑制率(%) = (最大值-樣本值)/(最大值-最小值)×100%。
將數據導入GraphPad,並使用「log(inhibitor) vs. response -- Variable slope」進行曲線擬合,得到IC50
。部分化合物的IC50
結果見表2。
表2
酶型 受試化合物 | IC50 (nM) |
PRMT5 | |
實施例1 | 32.66 |
實施例2 | 49.70 |
實施例10 | 2659 |
實驗例2 化合物體外細胞活性評價
1. 實驗材料
受試化合物:以上實施例製備的本發明的化合物,每個化合物用DMSO配製成10 mM母液,最終稀釋爲8個濃度進行檢測,Z-138細胞實驗的化合物終濃度爲33333.00 nM、6666.60 nM、1333.32 nM、266.66 nM、53.33 nM、10.67 nM、2.13 nM、0.43 nM,MDA-MB-468和NCI-H358細胞實驗化合物終濃度爲50000 nM、10000 nM、2000 nM、400 nM、80 nM、16 nM、3.2 nM、0.64 nM。
人套細胞淋巴瘤細胞Z-138、三陰性乳腺癌細胞MDA-MB-468、人非小細胞肺癌細胞NCI-H358購於美國典型培養物保藏中心(ATCC)。
試劑:Iscove's Modified Dulbecco's Medium(IMEM培養基),貨號爲ATCC 30-2005;Leibovitz's L-15 Medium(L-15培養基),貨號爲Gibco 11415-064;1640培養基,貨號爲Gibco 22400089;馬血清,貨號爲Gibco 16050122;Fetal Bovine Serum,貨號爲Gibco 10099-141;青鏈黴素,貨號爲Gibco 15140-122;丙酮酸鈉,貨號爲Gibco 11360070;CellTiter-Glo Luminescent Cell Viability Assay,貨號爲Promega G7571。CCK-8增殖抑制檢測套組,貨號爲KeyGEN KGA317。
2. 實驗方法
2.1 細胞復甦:
2.1.1 Z-138細胞復甦:從液氮罐中取出Z-138細胞凍存管置於37℃水浴鍋中,輕輕搖動使其儘快解凍。解凍後取出凍存管,用酒精棉球消毒後旋開蓋子,吸出細胞液注入離心管,並加入1 mL含10%馬血清的完全培養基,混勻後置於離心機中,1000 rpm,離心5 min。之後棄上清液,加入完全培養基反覆吹打至細胞完全吹散、重新懸浮。以適宜濃度接種於培養皿中。置37℃,5% CO2
、95%潮濕空氣的CO2
培養箱中培養。
2.1.2 MDA-MB-468細胞復甦:從液氮罐中取出MDA-MB-468細胞凍存管置於37℃水浴鍋中,輕輕搖動使其儘快解凍。解凍後取出凍存管,用酒精棉球消毒後旋開蓋子,吸出細胞液注入離心管,並加入1 mL含10% FBS的L-15培養基,混勻後置於離心機中,1000 rpm,離心5 min。之後棄上清液,加入完全培養基反覆吹打至細胞完全吹散、重新懸浮。以適宜濃度接種於培養皿中。置37℃,95%潮濕空氣的無CO2
培養箱中培養。
2.1.3 NCI-H358細胞復甦:從液氮罐中取出NCI-H358細胞凍存管置於37℃水浴鍋中,輕輕搖動使其儘快解凍。解凍後取出凍存管,用酒精棉球消毒後旋開蓋子,吸出細胞液注入離心管,並加入1 mL含10% FBS的1640培養基,混勻後置於離心機中,1000 rpm,離心5 min。之後棄上清液,加入完全培養基反覆吹打至細胞完全吹散、重新懸浮。以適宜濃度接種於培養皿中。置37℃,5% CO2
,95%潮濕空氣的CO2
培養箱中培養。
2.2細胞培養和繼代:
2.2.1 Z-138細胞培養和繼代:細胞生長至約80-90%,將培養基(IMDM培養基+10%馬血清 +1%青鏈黴素)轉移至15 mL離心管中,1000 rpm,離心5 min。去除上清液,用完全培養基重新懸浮細胞,按所需密度接種於培養皿中,置於37℃、5% CO2
、95%潮濕空氣的培養箱中培養,視細胞生長情况每2-3天補一次培養液或進行繼代。
2.2.2 MDA-MB-468細胞培養和繼代:細胞生長至約80-90%,將培養基(Leibovitz's L-15 Medium 培養基+10% FBS +1%青鏈黴素)轉移至15 mL離心管中,1000 rpm,離心5 min。去除上清液,用完全培養基重新懸浮細胞,按所需密度接種於培養皿中,置於37℃、95%潮濕空氣的無CO2
培養箱中培養,視細胞生長情况每2-3天換一次培養液或進行繼代。
2.2.3 NCI-H358細胞培養和繼代:細胞生長至約80-90%,將培養基(1640培養基+10% FBS+1%青鏈黴素+1 mM丙酮酸鈉)轉移至15 mL離心管中,1000 rpm,離心5 min。去除上清液,用完全培養基重新懸浮細胞,按所需密度接種於培養皿中,置於37℃、5% CO2
、95%潮濕空氣的CO2
培養箱中培養,視細胞生長情况每2-3天換一次培養液或進行繼代。
2.3 實驗步驟:
實驗第一天:
Z-138細胞繼代後以1000個/孔的密度重新懸浮於完全培養基中,接種於96孔培養盤內:96孔盤最外面一圈36個孔以200 μL PBS填充,以防邊緣培養基蒸發較快導致內部盤孔的培養條件差異過大;內部60個孔的最左列爲空白孔,不加細胞,以等體積的PBS填充;其餘的54個孔以排槍進行細胞鋪板,每孔爲含對應細胞的100 μL培養基,鋪盤完成後,拍打96孔盤使細胞均勻懸浮,放入5% CO2
培養箱內37℃培養24 h。
MDA-MB-468細胞繼代後以對應的密度重新懸浮於完全培養基中,2000個/孔,接種於96孔培養盤內:細胞外面一圈以200 μL PBS填充,以防邊緣培養基蒸發較快導致內部盤孔的培養條件差異過大;內部60個孔的最左列爲空白孔,不加細胞,以等體積的PBS填充;其餘的54個孔以排槍進行細胞鋪盤,每孔100 μL,放入無CO2
培養箱內37℃培養24 h。
NCI-H358細胞繼代後以對應的密度重新懸浮於完全培養基中,1000個/孔,接種於96孔培養盤內:細胞外面一圈以200 μL PBS填充,以防邊緣培養基蒸發較快導致內部盤孔的培養條件差異過大;內部60個孔的最左列爲空白孔,不加細胞,以等體積的PBS填充;其餘的54個孔以排槍進行細胞鋪盤,每孔100 μL,放入5% CO2
培養箱內37℃培養24 h。
實驗第二天:
Z-138細胞在原培養基(100 μL)的基礎上,加入50 μL的(3×)藥物,每個濃度組設置兩個複孔,繼續放入CO2
培養箱培養7天。化合物配製如下:提前稱取化合物1-2 mg,使用DMSO配置成10 mM母液。使用完全培養基稀釋藥物,藥物終濃度以33333.00 nM爲起始最高濃度,按1:4梯度依序稀釋至7個濃度梯度:6666.60 nM、1333.32 nM、266.66 nM、53.33 nM、10.67 nM、2.13 nM、0.43 nM。①取10 mM的母液1:4稀釋成對應的藥液,共8個濃度(10 μL母液+40 μL DMSO);②取5 μL①的藥物加入的495 μL完全培養基,配製成對應的濃度(3×)(稀釋100倍)。
MDA-MB-468細胞在原培養基(100 μL)的基礎上,加入100 μL的(2×)藥物,每個濃度組設置兩個複孔,繼續放入無CO2
培養箱培養7天。化合物配製如下:提前稱取化合物1-2 mg,使用DMSO配置成10 mM母液。使用完全培養基稀釋藥物,藥物終濃度以50000 nM爲起始最高濃度,按1:4梯度依序稀釋至7個濃度梯度:50000 nM、10000 nM、2000 nM、400 nM、80 nM、16 nM、3.2 nM、0.64 nM。①取10 mM的母液1:4稀釋成對應的藥液,共8個濃度(10 μL藥液+40 μL DMSO);②取5 μL①的藥物加入的495 μL完全培養基,配製成對應的濃度(2×)(稀釋100倍)。
NCI-H358細胞在原培養基(100 μL)的基礎上,加入100 μL的(2×)藥物,每個濃度組設置兩個複孔,繼續放入5% CO2
培養箱培養7天。化合物配製如下:提前稱取化合物1-2 mg,使用DMSO配置成10 mM母液。使用完全培養基稀釋藥物,藥物終濃度以50000 nM爲起始最高濃度,按1:4梯度依序稀釋至7個濃度梯度:50000 nM、10000 nM、2000 nM、400 nM、80 nM、16 nM、3.2 nM、0.64 nM。①取10 mM的母液1:4稀釋成對應的藥液,共8個濃度(10 μL藥液+40 μL DMSO);②取5 μL①的藥物加入的495 μL完全培養基,配製成對應的濃度(2×)(稀釋100倍)。
實驗第八天:
Z-138細胞在藥物處理7天後,提前30 min將CellTiter-Glo Luminescent Cell Viabillity Assay取出,平衡至室溫。空白孔將PBS吸棄,加入150 μL的完全培養基,然後空白孔、給藥孔和DMSO孔都加入75 μL的 Celltiter-Glo reagent,室溫震盪2 min。繼續室溫孵育10 min後,每孔各吸取180 μL轉移至不透明白板,去除氣泡後,檢測化學發光信號,震盪,Read進樣檢測條件爲500 ms。根據酵素免疫分析測讀儀導出的A.U.值,計算每個孔相對於溶劑對照孔的抑制率:Inhibition (%) = 100 - (A.U.實驗孔
–A.U.空白孔
) / (A.U.溶劑對照孔
- A.U.空白孔
) * 100。根據不同藥物濃度及其所對應的抑制率,使用GraghPad 5.0軟體進行IC50
曲線繪製,分析數據,得出最終IC50
值,實驗結果見表3。
MDA-MB-468和NCI-H358細胞藥物處理7天後吸棄孔內培養基,加入100 μL已加入CCK-8的完全培養基(CCK-8:完全培養基=1:10),第一豎排PBS作爲空白對照孔,同步加入100 μL的CCK-8,然後放入培養箱培養40min-2h左右,根據CCK-8的顯色深淺決定最佳檢測時間(DMSO組的OD值在1.0左右最佳)。待CCK-8顯色至橙色,並且出現肉眼可分辨的一定梯度,將96孔盤從培養箱中取出,置於室溫中平衡5-10分鐘;打開酵素免疫分析測讀儀軟體,調整好檢測參數,檢測450 nm處的吸光度(OD值);將培養盤的蓋子取下,直接將培養盤水平放置於盤槽內,開始讀數;讀數完成後,保存程式,導出數據,關閉軟體和電腦。根據酵素免疫分析測讀儀導出的OD值,計算每個孔相對於溶劑對照孔的抑制率:Inhibition (%) = 100 - (OD實驗孔
–OD空白孔
) / (OD溶劑對照孔
-OD空白孔
) * 100。根據不同藥物濃度及其所對應的抑制率,使用GraghPad 5.0軟體進行IC50
曲線繪製,分析數據,得出最終IC50
值,實驗結果見表3。
表3
細胞種類 受試化合物 | IC50 (nM) | ||
Z-138細胞 | MDA-MB-468細胞 | NCI-H358細胞 | |
實施例1 | 3.07 | 11.57 | 8.90 |
實施例2 | 2.20 | 7.35 | 5.02 |
化合物A | 19.49 | 116.00 | 73.20 |
化合物B | 4.33 | 41.28 | 15.35 |
從以上實驗可以看出,本發明的化合物對人套細胞淋巴瘤細胞Z-138、三陰性乳腺癌細胞MDA-MB-468、人非小細胞肺癌細胞NCI-H358均表現出了良好的抑制活性,非常有希望成爲淋巴瘤、三陰性乳腺癌、非小細胞肺癌治療劑。
實驗例3 電生理手動膜片鉗檢測化合物對hERG鉀通道的作用
hERG鉀離子通道是藥物安全篩查的標準。hERG鉀離子通道被阻滯會導致心臟中毒和心室複極延長,嚴重時可能會導致猝死。具有hERG鉀通道抑制作用的藥物可能是臨床用藥的潛在禍患。因此,化合物對hERG鉀離子通道抑制作用弱則安全性高。藥物導致的QT間期延長與致命性室性心律失常和猝死的危險性增加有關。
1實驗材料
主要試劑:青黴素-鏈黴素溶液(100×)、DMEM/F12購自Gibco公司;胎牛血清購自PAA公司;DMSO、EGTA、MgATP購自Sigma公司;KCl、CaCl2
·2H2
O、MgCl2
·6H2
O、NaCl購自Sinopharm公司;葡萄糖購自General-reagent公司;HEPES購自Solarbio公司;奎尼丁購自aladdin公司。
儀器:TI-S-FLU顯微鏡購自Nikon公司;SMZ-140/143顯微鏡購自Motic公司;EPC-10放大器、Patchmaster V2X60購自HEKA公司;TMC-36防震台購自TMC公司;MP-225、MPC-200操控器、ROE-200微操縱儀、P-97電極拉制儀購自Sutter公司;VC3-8PP灌流給藥系統購自ALA公司。
2實驗方法
測試溶劑配製:細胞外液配製(mM):137 NaCl、4 KCl、1.8 CaCl2
、1 MgCl2
、10葡萄糖和10 HEPES(pH 7.4);細胞內液配製(mM):130 KCl、1 MgCl2
、5 EGTA、5 MgATP和10 HEPES(pH 7.2);陰性對照配製:細胞外液+0.3% DMSO;陽性對照:奎尼丁。
化合物處理:稱取化合物溶解於DMSO中,配製10 mM母液,用DMSO稀釋母液成次級母液,濃度爲3.3,1.1,0.37,0.12 mM。取母液和次級母液各90 μL稀釋至30 mL細胞外液中,用於電生理檢測。化合物的終濃度爲30,10,3.3,1.1,0.37 μM,DMSO的終濃度爲3:1000。
穩定轉染細胞培養:細胞株來源於過表現hERG 鉀離子通道HEK-293 細胞,是在紐約大學醫學院Mohamed Boutjdir 博士實驗室提供技術支持後科瑞斯生物與之合作建立並驗證。細胞在37℃、5 % CO2
培養箱中培養。當細胞密度達培養皿80 %時,先用磷酸鹽緩衝液(PBS)預清洗,然後用胰蛋白酶/ EDTA 消化細胞2-3 min,加入細胞培養基停止消化,輕輕把細胞吹下來並轉移到離心管中,1000 rpm* 3min,上清液棄置,加入細胞培養基,輕輕吹打將細胞混勻,隨後轉移到培養皿中進行繼代培養,或將細胞滴於圓形玻片之上並置於培養皿中待細胞貼壁用於實驗。
細胞培養基組成:DMEM、15 %胎牛血清和1% 100× 青黴素-鏈黴素。
電生理手動膜片鉗系統實驗:將穩定轉染的細胞接種於玻片上,細胞密度低於50%,培養過夜。將實驗用細胞轉移到一個嵌於倒置顯微鏡平臺的約1 mL 的浴槽中,灌流細胞外液,灌流速度爲2.7 mL/min。穩定5 分鐘後即可開始實驗。採用HEKA EPC-10 膜片鉗放大器和PATCHMASTER 採集系統記錄膜電流。所有實驗均在室溫(22-24℃)下完成。實驗中使用P-97 微電極拉制儀拉直電極(BF150-110-10)。電極內徑爲1-1.5 mm,充滿內液後的入水電阻爲2-4 MΩ。hERG 鉀通道的電生理刺激方案,是首先將膜電壓鉗制在-80 mV,給予細胞持續2 s、+20 mV 電壓刺激,啟動hERG 鉀通道,再複極化至-50 mV、持續5 s,産生外向尾電流,刺激頻率每15 s 一次。電流值爲尾電流的峰值。實驗中採用全細胞記錄模式記錄通道電流。首先灌流細胞外液(大約每分鐘2 mL)並持續記錄,並等待電流穩定(5分鐘內電流衰減(Run-Down)小於5 %),此時尾電流峰值即爲對照電流值。接著灌流含待測藥物的細胞外液並持續記錄直到藥物對hERG電流的抑制作用到達穩定狀態,此時尾電流峰值即爲加藥後電流值。穩定狀態的標準以最近的連續3個電流記錄線是否重合來判斷。達到穩定態勢以後如果以細胞外液灌流沖洗後hERG 電流回復或接近加藥物之前的大小,則可以繼續灌流測試其它濃度或藥物。30 μM奎尼丁被用於實驗中作爲陽性對照以保證所使用的細胞反應正常。
3參數分析和數據分析統計
本研究透過測量對照組與藥物處理組的電流最大值,計算處理組最大電流值所占對照組最大電流值的比率,評估待測化合物在測試濃度下對hERG鉀離子通道的作用效果(Mean±SE)。
實驗數據使用PATCHMASTER V2X60採集,並採用Origin 8.5軟體以及Microsoft Excel進行分析和統計。實驗結果見表4。
表4
受試化合物 | hERG IC50 (μM) |
實施例1 | 5.24 |
實施例2 | 15.07 |
化合物B | 2.71 |
從以上實驗可以看出,本發明實施例1和2的化合物對hERG鉀通道抑制作用輕,對心臟的毒性低,優於化合物B。
此外,化合物B在離體心臟實驗中表現出顯著延長QT間期,而本發明實施例1和2的化合物在離體心臟實驗中顯示對QT間期無影響。本發明的化合物具有更好的心臟安全性。
儘管以上已經對本發明作了詳細描述,但是本領域技術人員理解,在不偏離本發明的精神和範圍的前提下可以對本發明進行各種修改和改變。本發明的權利範圍並不限於上文所作的詳細描述,而應歸屬於申請專利範圍。
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Claims (10)
- 如請求項1所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中通式(A)具有以下通式(I)的結構,, 其中, X選自O、S、C(R1 )(R2 )和N(R3 ),其中R1 、R2 、R3 各自獨立地選自氫、鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基,且R1 和R2 與它們所結合的碳原子一起形成雜環基,其中所述的雜環基任選被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基的基團取代; m爲1、2、3或4;和 n爲0、1、2、3或4。
- 如請求項2所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥, 其中R1 、R2 、R3 各自獨立地選自氫、鹵素、羥基、C1-6 烷基、鹵代C1-6 烷基、羥基C1-6 烷基、C1-6 烷氧基、鹵代C1-6 烷氧基、羥基C1-6 烷氧基、硝基、羧基、氰基、胺基、單C1-6 烷基胺基、C1-6 烷基醯基胺基、C1-6 烷基醯基、胺基醯基、C1-6 烷基胺基醯基、雙C1-6 烷基胺基和C3-12 環烷基。
- 如請求項2-3中之任一項所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中R1 和R2 與它們所結合的碳原子一起形成3元-8元雜環基,其中所述雜環基進一步包含一個或多個N、O或S雜原子,且所述雜環基任選被一個或多個選自鹵素、羥基、烷基、鹵代烷基、羥基烷基、烷氧基、鹵代烷氧基、羥基烷氧基、硝基、羧基、氰基、胺基、單烷基胺基、烷基醯基胺基、烷基醯基、胺基醯基、烷基胺基醯基、雙烷基胺基和環烷基的基團取代。
- 如請求項2-4中之任一項所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥,其中R1 和R2 與它們所結合的碳原子一起形成3元-6元雜環基,其中所述雜環基進一步包含一個或多個N、O或S雜原子,且所述雜環基任選被一個或多個選自鹵素、羥基、C1-6 烷基、鹵代C1-6 烷基、羥基C1-6 烷基、C1-6 烷氧基、鹵代C1-6 烷氧基、羥基C1-6 烷氧基、硝基、羧基、氰基、胺基、單C1-6 烷基胺基、C1-6 烷基醯基胺基、C1-6 烷基醯基、胺基醯基、C1-6 烷基胺基醯基、雙C1-6 烷基胺基和C3-12 環烷基的基團取代。
- 一種藥物組合物,其包含如請求項1至8中之任一項所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥和可藥用載體。
- 一種如請求項1-8中之任一項所述的化合物或其異構體、藥學上可接受的鹽、溶劑化物、結晶或前藥或如請求項所述的藥物組合物在製備用於治療PRMT5介導的疾病的藥物中的應用。
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