TWI748938B - 具抗腫瘤活性之化合物 - Google Patents
具抗腫瘤活性之化合物 Download PDFInfo
- Publication number
- TWI748938B TWI748938B TW105103940A TW105103940A TWI748938B TW I748938 B TWI748938 B TW I748938B TW 105103940 A TW105103940 A TW 105103940A TW 105103940 A TW105103940 A TW 105103940A TW I748938 B TWI748938 B TW I748938B
- Authority
- TW
- Taiwan
- Prior art keywords
- phenyl
- methyl
- ethoxymethyl
- azol
- amine
- Prior art date
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- 230000000259 anti-tumor effect Effects 0.000 title description 3
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- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 30
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- 239000001257 hydrogen Substances 0.000 claims description 60
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Abstract
Description
本發明涉及式(I)化合物或其藥學上可接受的鹽,所述化合物破壞、抑制或阻止細胞,特別是惡性細胞的生長或其向與各種人類和動物疾病有關的周圍組織中的擴散。
特別地,本發明涉及可用於治療與細胞增殖相關的疾病的化合物,所述疾病是例如造血癌症,包括淋巴瘤、白血病和多發性骨髓瘤;實體癌症,包括頭頸癌、黑色素瘤、腎癌、胃癌、肝癌、結腸直腸癌、胰腺癌、肺癌、神經元癌、骨癌、乳腺癌、卵巢癌和前列腺癌。
癌症是一大類可累及身體任何部位的疾病的總稱。癌症的一個定義性特徵是異常細胞的快速產生,所述異常細胞生長超過其通常界限,並且然後可侵入身體的鄰近部位並擴散到其它器官,後一過程被稱為轉移。轉移是癌症致死的主要原因。
癌症位列全世界發病率和死亡率的主要原因之中,在2012年約有1400萬新病例和820萬例癌症相關死亡。癌症死亡的最常見原因是肺癌(159萬例死亡)、肝癌(745000例死亡)、胃癌(723000例死亡)、結腸直腸癌(694000例死亡)、乳腺癌(521000例死亡)、食管癌(400000例死亡)。在男性中,2012年確診的癌症的5個最常見部位是肺癌、前列腺癌、結腸直腸癌、胃癌和肝癌。在女性中,確診的5個最常見部位是乳腺癌、結腸直腸癌、肺癌、子宮頸癌和胃癌。
新發病例的數量預計在未來二十年會增加約70%(世界癌症報告2014年,WHO)。
儘管對於作為癌症發展和進展的基礎的生物學以及癌症治療的潛在分子靶標的瞭解有了非凡的進步,但所有進入臨床開發的新型腫瘤學藥物中90%以上未取得銷售許可。許多藥物在開發後期(通常在第III期試驗中)因活性不足、缺乏對抗對這些藥物的抗藥性的策略、預想不到的安全性問題或者由於包括臨床試驗的結果混亂在內的原因難以測定功效而失敗。此外,對癌症生物學的增加的瞭解已表明,癌症是異質性疾病,這表明極有可能的是,有效的癌症治療將需要解決患者特異性分子缺陷和腫瘤微環境的各方面。
癌症的普遍發生和該疾病的高度異質性強調了對於用於治療惡性腫瘤的改進的抗癌方案的需要。一大組癌細胞系的最近使用正成為用於發現和評估潛在的新型抗癌劑的重要工具。事實上,一大組腫瘤衍生細胞系可概括新治療劑的基因型-反應關係,並且可能引起極大關注。
本發明提供用於治療與細胞增殖相關的疾病,例如造血癌症
或實體癌症的新型式(I)化合物。本發明的化合物對非常大的一組癌細胞系具有抗腫瘤活性。
式(I)化合物包含被A和B部分對位取代的6元芳基或雜芳基部分。包含被雜芳基和雜環基團間位取代的6元芳基或雜芳基部分的化合物公開於WO2013/014170中。WO2013/014170的化合物是酪胺酸激酶抑制劑,並且可用於治療增殖性疾病。令人驚訝的是,本發明的式(I)化合物不是酪胺酸激酶抑制劑,但具有抗增殖性質。因此,本發明的化合物提供與細胞增殖相關的疾病的新治療途徑。
根據一個實施方案,在式(I)化合物中,B是五元環雜芳基。
根據一個實施方案,B不選自1,2-二基、三唑並吡啶基或三唑基。根據一個實施方案,如果B是唑基,則A不是四唑基或四氫吡啶基。根據一個實施方案,如果B是噻唑基,則A不是咪唑基、三唑基、哌基、吡咯啶基、哌啶基或1,4-基。
根據一個實施方案,在式(I)化合物中,X是CH並且A是2-側氧基咪唑啶基或吡唑基。
根據一個實施方案,在本發明的化合物中,R3是氫。
根據一個實施方案,式(I)化合物具有如下文所定義的式(II)。
根據一個實施方案,式(I)化合物具有如下文所定義的式(III)。。
根據一個實施方案,在本發明的化合物中,R1是甲基,R2、R3和R5是氫並且R4是-CH2OC2H5。
根據一個實施方案,本發明的化合物選自:(5-甲氧基-2-甲基-苯基)-[5-(6-吡唑-1-基-吡啶-3-基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(3-甲氧基-4-吡唑-1-基-苯基)-唑-2-基]-胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-噻唑-4-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;4-甲基-N-(2-啉-4-基-乙基)-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苯甲醯胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(6-吡唑-1-基-吡啶-3-基)-唑-2-基]-胺;1-{4-[5-(5-乙氧基甲基-(2-甲基-苯基胺基))-[1,3,4]二唑-2-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-[1,3,4]二唑-2-基]-胺;1-{4-[5-(5-乙氧基甲基-(2-甲基-苯基胺基))-[1,2,4]噻二唑-3-基]-苯基}-咪
唑啶-2-酮;(5-甲氧基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;1-{4-[2-(5-甲氧基-2-甲基-苯基胺基)-噻唑-5-基]-苯基}-咪唑啶-2-酮;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-噻唑-5-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[4-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;{4-甲基-3-[4-(4-吡唑-1-基-苯基)-噻唑-2-基胺基]-苯基}-甲醇;1-{4-[2-(3-乙氧基甲基-(5-甲基-苯基胺基))-噻唑-4-基]-苯基}-咪唑啶-2-酮;1-{4-[2-(3-乙氧基甲基-(5-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;(3-乙氧基甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(3-乙氧基甲基-5-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(3,5-雙-(乙氧基甲基)-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(5-甲氧基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;[5-(2-胺基-乙氧基甲基)-2-甲基-苯基]-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;N-(2-{4-甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苄氧基}-乙基)-乙醯胺;2-{4-甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苄氧基}-乙醇;{4-甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苯基}-甲醇;{2-甲基-5-[(2-啉-4-基-乙基胺基)-甲基]-苯基}-[5-(4-吡唑-1-基-苯基)-
唑-2-基]-胺;[2-甲基-5-(2-啉-4-基-乙氧基)-苯基]-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;[5-(2-二甲基胺基-乙氧基)-2-甲基-苯基]-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;4,N-二甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苯甲醯胺;4-甲基-N-[2-(4-甲基-哌-1-基)-乙基]-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苯甲醯胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,4]三唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,3]三唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,3]三唑-2-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-咪唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-噻唑-2-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(3-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(4-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(5-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(3-甲氧基-吡唑-1-基)-苯基]-唑-2-基}-胺;
2-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-2,4-二氫-[1,2,4]三唑-3-酮;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-3-甲基-咪唑啶-2-酮;1-(2-胺基-乙基)-3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;N-[2-(3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-2-側氧基-咪唑啶-1-基)-乙基]-乙醯胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-吡咯啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡啶-2-基-苯基)-唑-2-基]-胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-1H-吡啶-2-酮;3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-1H-吡啶-2-酮(R)-1-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-5-甲基咪唑啶-2-酮4-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-5-甲基-2,4-二氫-3H-1,2,4-三唑-3-酮1-(4-(2-((3,5-雙(乙氧基甲基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮1-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-3-(2-甲氧基乙基)咪唑啶-2-酮
1-(5-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)吡啶-2-基)咪唑啶-2-酮1-(4-(2-((3-(乙氧基甲基)-5-(2-甲氧基乙氧基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮5-(4-(1H-吡唑-5-基)苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)唑-2-胺(R)-1-(5-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)吡啶-2-基)-5-甲基咪唑啶-2-酮1-(4-(2-((3-(乙氧基甲基)-5-(2-羥基乙氧基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮5-(4-(1H-吡唑-4-基)苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)唑-2-胺N-(5-(乙氧基甲基)-2-甲基苯基)-5-(4-(1-甲基-1H-吡唑-5-基)苯基)唑-2-胺4-(6-(1H-吡唑-1-基)吡啶-3-基)-N-(5-(乙氧基甲基)-2-甲基苯基)噻唑-2-胺1-(4-(2-((3-(乙氧基甲基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮1-(4-(2-((3-(乙氧基甲基)苯基)胺基)噻唑-4-基)苯基)咪唑啶-2-酮
本發明進一步涉及包含本發明的化合物或其藥學上可接受的鹽以及至少一種藥學上可接受的賦形劑和/或載體的藥物組合物。
根據一個實施方案,所述藥物組合物包含本發明的化合物或其藥學上可接受的鹽作為唯一活性藥物成分。
根據一個實施方案,本發明的藥物組合物進一步包含另一種活性藥劑。
本發明還涉及包含本發明的化合物或其藥學上可接受的鹽
的醫藥品。
本發明進一步涉及本發明的化合物或其藥學上可接受的鹽用於治療血液病症和/或增殖性病症。
根據一個實施方案,所述血液病症選自淋巴瘤;白血病,例如急性骨髓性白血病(AML)、急性淋巴母細胞性白血病(ALL)、慢性淋巴性白血病(CLL)或慢性骨髓性白血病(CML);多發性骨髓瘤(MM);骨髓增生異常綜合征(MDS);以及骨髓增生異常伴骨髓纖維化。
根據一個實施方案,所述增殖性病症是癌症,例如頭頸癌、黑色素瘤、腎癌、胃癌、肝癌、結腸直腸癌、胰腺癌、肺癌、神經元癌、多形性膠質母細胞瘤、骨肉瘤、尤因肉瘤(Ewing sarcoma)、乳腺癌、卵巢癌或前列腺癌。
本發明還涉及包含本發明的化合物或其藥學上可接受的鹽以及另一種活性藥物成分的藥物組合物,其作為組合製劑用於在選自由血液病症和增殖性病症組成的群組的病症的治療中依序、同時或分開使用。
除非另有規定,否則本文所用的以下術語被定義如下。
除非另有說明,否則本文中未明確定義的取代基的命名藉由命名官能團的末端部分,隨後朝向連接點的相鄰官能團實現。例如,取代基”芳基烷基”是指基團(芳基)-(烷基)-。
如本文所用,術語”取代基”或”被取代的”是指化合物或基團上的氫基團被任何期望的基團替代,所述期望的基團在未受保護的形式下或者當使用保護基團保護時對於反應條件是基本上穩定的。較佳取代基的實例是在本文所公開的示例性化合物和實施方案中所示者,以及鹵素、如上文所定義的烷基或芳基、羥基、如上文所定義的烷氧基、硝基、硫醇基、雜環烷基、雜芳基、氰基、如上文所定義的環烷基,以及增溶基團、-NRR’、-NR-CO-R’、-CONRR’、-SO2NRR’基團,其中R和R’各自獨立地選自氫、烷基、環烷基、芳基、如上文所定義的雜環烷基或雜芳基。
如本文所用,術語”鹵素”是指氟、氯、溴或碘。
如本文所用,術語”烷基”是指具有1到10個碳原子,較佳1到6個碳原子,更佳1到4個碳原子的飽和直鏈或支鏈非環狀烴。代表性的飽和直鏈烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基和正癸基;而飽和支鏈烷基包括異丙基、二級丁基、異丁基、三級丁基、異戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基等。本發明的化合物中所包含的烷基可視需要被一個或多個取代基取代。
本發明的化合物中所包含的烷基可視需要被增溶基團取代。
如本文所用,術語”烷氧基”是指藉由氧原子連接到另一部分的如上文所定義的烷基。烷氧基的實例包括甲氧基、異丙氧基、乙氧基、三級丁氧基等。烷氧基可視需要被一個或多個取代基取代。本發明的化合物中所包含的烷氧基可視需要被增溶基團取代。
如本文所用,術語”雜環”統指雜環烷基和雜芳基。
如本文所用,術語”雜環烷基”是指具有至少一個選自O、N或S的雜原子並且具有2到11個碳原子的單環或多環基團,其可為飽和或不飽和的,但不為芳族的。雜環烷基的實例包括(但不限於):哌啶基、哌基、N-甲基哌基、2-側氧基哌基、2-側氧基哌啶基、2-側氧基吡咯啶基、4-哌啶酮基、吡咯啶基、乙內醯脲基(hydantoinyl)、戊內醯胺基(valerolactamyl)、氧基、氧呾基、四氫哌喃基、四氫噻喃基、2-側氧基咪唑啶基、四氫嘧啶基-2-酮、2-側氧基吡咯啶基、四氫氮茚基(tetrahydropyrindinyl)、四氫嘧啶基、四氫噻喃基碸基、四氫噻喃基亞碸基、啉基、硫代啉基、硫代啉基亞碸基、硫代啉基碸基、1,3-二氧戊環基、四氫呋喃基、二氫呋喃基-2-酮、四氫噻吩基和四氫-1,1-二側氧基噻吩基。典型地,單環雜環烷基具有3到7個成員。較佳的3到7元單環雜環烷基是具有5或6個環原子的那些基團。雜原子可被本領域普通技術人員已知的保護基團取代,例如,氮上的氫可被三級丁氧基羰基取代。此外,雜環烷基可視需要被一個或多個取代基取代。另外,雜環與另一基團的連接點可在雜環的碳原子或雜原子上。該定義中僅涵蓋這些被取代雜環基團的穩定異構體。
如本文所用,術語”雜芳基”或類似術語是指包含碳原子環成員以及一個或多個雜原子環成員(例如,氧、硫或氮)的單環或多環雜芳族環。典型地,雜芳基具有1到約5個雜原子環成員和1到約14個碳原子環成員。代表性雜芳基包括吡啶基、1-側氧基-吡啶基、呋喃基、苯並[1,3]間二氧雜環戊烯基、苯並[1,4]二氧雜環己烯基、噻吩基、吡咯基、唑基、二唑基、咪唑基、噻唑基、噻二唑基、異唑基、喹啉基、吡唑基、異噻唑基、嗒基、嘧啶基、吡基、三基、三唑基、噻二唑基、異喹啉基、吲唑基、苯並唑基、苯並呋喃基、吲基、咪唑並吡啶基、四唑基、苯並咪唑基、苯並噻唑基、苯並噻二唑基、苯並二唑基、吲哚基、四氫吲哚基、氮雜吲哚基、咪唑並吡啶基、喹唑啉基、嘌呤基、吡咯並[2,3]嘧啶基、吡唑並[3,4]嘧啶基、咪唑並[1,2-a]吡啶基和苯並(b)噻吩基。雜原子可被本領域普通技術人員已知的保護基團取代,例如,氮上的氫可被三級丁氧基羰基取代。另外,氮或硫雜原子環成員可被氧化。在一個實施方案中,雜芳族環選自5-8元單環雜芳基環。根據一個具體實施方案,雜芳基是5元環雜芳基。雜芳族環或雜芳基環與另一基團的連接點可在雜芳族環或雜芳基環的碳原子或雜原子上。
如本文所用,術語”芳基”是指包含碳原子和氫原子的單環或多環芳族基團。合適的芳基的實例包括但不限於苯基、甲苯基、蒽基、茀基、茚基、薁基和萘基,以及苯並稠合的碳環部分,例如5,6,7,8-四氫萘基。
術語”環烷基”是指含有指定數目環原子的飽和或部分不飽和的單環、稠合二環或橋接多環組合體。這包括經取代或未經取代的環烷基。例如,環烷基可以是C3-C10烷基,例如C3或C4烷基,特別是環丙基、
環丁基、環戊基、環己基、環庚基或環辛基等。
如本文所用,術語”增溶基團”是指與不包含該基團的類似化合物相比改善化合物在水或水溶液中的溶解性的基團。此類增溶基團的非限制性實例是在使用條件下電離以形成帶電荷部分的基團(例如,羧酸、磺酸、磷酸、胺等);包含永久電荷的基團(例如,四級銨基團);和/或雜原子或雜原子基團,例如O、S、N、NH、N-(CH2)zR、N-(CH2)z-C(O)R、N-(CH2)z-C(O)OR、N-(CH2)z-S(O)2R、N-(CH2)z-S(O)2OR、N-(CH2)z-C(O)NRR’,其中z是0到6範圍內的整數;R和R’各自獨立地選自氫;含有1到10個碳原子並且視需要被一個或多個例如鹵素(選自F、Cl、Br或I)、氧和氮的雜原子取代的烷基;以及含有1到10個碳原子的烷氧基;以及芳基和雜芳基。
在一些實施方案中,增溶基團是視需要包含1到5個取代基的雜環烷基,所述取代基本身可為增溶基團。
在一個具體實施方案中,增溶基團具有下式:
其中L選自由CH和N組成的群組;M選自由-CH(R)-、-CH2-、-O-、-S-、-NH-、-N(-(CH2)z-R)-、-N(-(CH2)z-C(O)R)-、-N(-(CH2)z-C(O)OR)-、
-N(-(CH2)z-S(O)2R)-、-N(-(CH2)z-S(O)2OR)-和-N(-(CH2)z-C(O)NRR’)-組成的群組,其中z是0到6範圍內的整數;R和R’各自獨立地選自氫;含有1到10個碳原子並且視需要被一個或多個例如鹵素(選自F、Cl、Br或I)、氧和氮的雜原子取代的烷基;以及含有1到10個碳原子的烷氧基;NRR’基團,其中R和R’各自獨立地選自氫;視需要被至少一個雜原子,特別是氧或氮取代的如上文所定義的烷基,所述雜原子視需要被含有1到10個碳的烷基取代,所述烷基視需要被取代;以及芳基和雜芳基,條件是L和M兩者不同時分別為CH和CH2。
在另一具體實施方案中,增溶基團選自由啉基、哌啶基、吡咯啶基、N-(C1-C6)烷基哌啶基(特別是N-甲基哌啶基和N-乙基哌啶基)、N-(4-哌啶基)哌啶基、4-(1-哌啶基)哌啶基、1-吡咯啶基哌啶基、4-啉基哌啶基、4-(N-甲基-1-哌基)哌啶基、哌基、N-(C1-C6)烷基哌基(特別是N-甲基哌基和N-乙基哌基)、N-(C3-C6)環烷基哌基(特別是N-環己基哌基)、吡咯啶基、N-(C1-C6)烷基吡咯啶基(特別是N-甲基吡咯啶基和N-乙基吡咯啶基)、二氮呯基、N-(C1-C6)烷基氮呯基(特別是N-甲基氮呯基和N-乙基氮呯基)、高哌基、N-甲基高哌基、N-乙基高哌基、咪唑基等組成的群組。
術語”溶劑合物”在本文中用於描述包含本發明的化合物以及一個或多個藥學上可接受的溶劑分子(例如乙醇)的分子複合物。當所述溶劑是水時,使用術語”水合物”。
術語”溶劑合物異構體”在本文中用於描述兩種或更多種包含本發明的化合物以及一個或多個藥學上可接受的溶劑分子(例如乙醇)的
分子複合物,其中所述複合物的不同之處在於相對於每個本發明的化合物分子的溶劑分子數目。當所述溶劑是水時,使用術語”水合物”。
術語”代謝物”在本文中用於描述經代謝從母體化合物的生化轉化產生的化合物。
本發明涉及能夠作為單一藥劑或與其它細胞毒性劑組合對一大組腫瘤細胞系顯示抗增殖活性的化合物。
在第一實施方案中,本發明的目的是式(I)化合物,其可表示物質的游離鹼形式或其藥學上可接受的鹽:
其中:R1、R2、R3、R4和R5各自獨立地選自:-氫;-雜環;-氰基;-CF3;-NRR’;-OH;-鹵素,較佳選自F、Cl、Br和I;-視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的
烷基;-視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的烷氧基;-CO-NRR’;-SO2-NRR’;-NR-CO-R’和-NR-SO2R’;其中R和R’各自獨立地選自氫、環烷基、雜環、增溶基團和視需要被一個或多個選自OR”、NR”R’”、NR”COR’”和增溶基團的基團取代的烷基;其中R”和R’”各自獨立地選自氫、烷基或環烷基;A是視需要被取代的雜環基團,較佳地,A是視需要被一個或多個選自以下的基團取代的雜環基團:鹵素、烷基、芳基、羥基、烷氧基、硝基、硫醇、雜環烷基、雜芳基、氰基、環烷基、增溶基團、-NRR’、-烷基-NRR’、-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和-SO2NRR’基團;其中R和R’各自獨立地選自氫、烷基、環烷基、芳基、雜環烷基和雜芳基;B是芳基或雜芳基;X是N或C-R6,其中R6選自氫、氰基、CF3、烷基和烷氧基。
根據一個實施方案,在式(I)化合物中,本發明涉及其中R3是氫的化合物。
或其藥學上可接受的鹽,其中:R1、R2和R4各自獨立地選自:氫;雜環;氰基;-CF3;-NRR’;-OH;鹵素,較佳選自F、Cl、Br和I;視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的烷基;視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的烷氧基;-CO-NRR’;-SO2-NRR’;-NR-CO-R’和-NR-SO2R’;其中R和R’各自獨立地選自氫、環烷基、雜環、增溶基團和視需要被一個或多個選自OR”、NR”R’”、NR”COR’”和增溶基團的基團取代的烷基;其中R”和R’”各自獨立地選自氫、烷基或環烷基;A選自視需要被取代的雜環基團,較佳的A是視需要被一個或多個選自以下的基團取代的雜環基團:鹵素、烷基、芳基、羥基、烷氧基、硝基、硫醇、雜環烷基、雜芳基、氰基、環烷基、增溶基團、-NRR’、-烷基-NRR’、-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和-SO2NRR’基團;其中R和R’各自獨立地選自氫、烷基、環烷基、芳基、雜環烷基和雜芳基;B是5元環雜芳基。
或其藥學上可接受的鹽,其中R1和R2各自獨立地選自:氫;雜環;氰基;-CF3;-NRR’;-OH;鹵素,較佳選自F、Cl、Br和I;視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的烷基;視需要被一個或多個選自雜環、NRR’、OR和增溶基團的基團取代的烷氧基;-CO-NRR’;-SO2-NRR’;-NR-CO-R’和-NR-SO2R’;其中R和R’各自獨立地選自氫、環烷基、雜環、增溶基團和視需要被一個或多個選自OR”、NR”R’”、NR”COR’”和增溶基團的基團取代的烷基;其中R”和R’”各自獨立地選自氫、烷基或環烷基;A選自視需要被取代的雜環基團,較佳地,A是視需要被一個或多個選自以下的基團取代的雜環基團:鹵素、烷基、芳基、羥基、烷氧基、硝基、硫醇、雜環烷基、雜芳基、氰基、環烷基、增溶基團、-NRR’、-烷基-NRR’、-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和-SO2NRR’基團;其中R和R’各自獨立地選自氫、烷基、環烷基、芳基、雜環烷基和雜芳基;B是5元環雜芳基。
根據一個具體實施方案,在本發明的化合物中,R1表示氫或烷基,較佳地,R1表示氫或C1-C3烷基,更佳地,R1表示氫、甲基、乙基或丙基,甚至更佳地,R1表示氫或甲基。根據另一具體實施方案,在本發明的化合物中,R1表示烷基,較佳地,R1表示C1-C3烷基,更佳地,R1
表示甲基、乙基或丙基,甚至更佳地,R1表示甲基。
根據一個具體實施方案,在本發明的化合物中,R2表示氫或視需要被烷氧基取代的烷基,較佳地,R2表示氫、甲基或-CH2-O-C2H5。根據另一具體實施方案,在本發明的化合物中,R2表示氫。
根據一個具體實施方案,在本發明的化合物中,R3表示氫。
根據一個具體實施方案,在本發明的化合物中,R4表示視需要被一個或多個選自NRR’和OR的基團取代的烷基;視需要被一個或多個選自NRR’和增溶基團的基團取代的烷氧基;或-CO-NRR’;其中R和R’各自獨立地選自氫和視需要被一個或多個選自OR”、NR”R’”、NR”COR’”和增溶基團的基團取代的烷基;其中R”和R’”各自獨立地選自氫或烷基。根據一個具體實施方案,在本發明的化合物中,R4表示被OR取代的烷基,其中R表示烷基;或者R4表示烷氧基;較佳地,R4表示-CH2-O-C2H5或-O-CH3。
根據一個具體實施方案,在本發明的化合物中,R5表示氫。
根據一個具體實施方案,在本發明的化合物中,R1表示烷基,R2表示氫,R3表示氫,R4表示被OR取代的烷基,其中R表示烷基;或者R4表示烷氧基;並且R5表示氫。根據一個具體實施方案,在本發明的化合物中,R1表示甲基,R2表示氫,R3表示氫,R4表示-CH2-O-C2H5或-O-CH3;並且R5表示氫。根據一個具體實施方案,在本發明的化合物中,R1是甲基,R2、R3和R5是氫並且R4是-CH2OC2H5。
根據一個具體實施方案,在本發明的化合物中,X表示N或C-R6,其中R6選自氫和烷氧基。根據一個具體實施方案,在本發明的化合物中,X表示N、CH或C(OCH3)。根據一個較佳實施方案,在本發明的
化合物中,X表示CH。
根據一個具體實施方案,在本發明的化合物中,A表示雜環烷基。或者,在本發明的化合物中,A表示雜芳基。根據一個具體實施方案,在本發明的化合物中,A表示三唑基、側氧基三唑基、咪唑基、側氧基咪唑啶基、吡唑基、吡啶基、側氧基吡啶基、噻唑基或側氧基吡咯啶基。根據一個具體實施方案,在本發明的化合物中,A表示2-側氧基咪唑啶基或吡唑基,更佳地,A表示2-側氧基咪唑啶基。
根據一個具體實施方案,在本發明的化合物中,A是被一個或多個選自以下的基團取代的雜環基團:鹵素、烷基、芳基、羥基、烷氧基、硝基、硫醇、雜環烷基、雜芳基、氰基、環烷基、增溶基團、-NRR’、-烷基-NRR’、-NR-CO-R’、-烷基-NR-CO-R’、-CONRR’和-SO2NRR’基團;其中R和R’各自獨立地選自氫、烷基、環烷基、芳基、雜環烷基和雜芳基。根據一個具體實施方案,在本發明的化合物中,A是被烷基、烷氧基、-烷基-NRR’或-烷基-NR-CO-R’取代的雜環基團,更佳地,A被甲基、甲氧基、-CH2-CH2-NH2或-CH2-CH2-NHCO-CH3取代。
根據一個具體實施方案,在本發明的化合物中,B表示芳基。或者,B表示雜芳基。根據一個具體實施方案,在本發明的化合物中,B表示5元環雜芳基。根據一個具體實施方案,在本發明的化合物中,B表示二唑基、唑基、噻二唑基或噻唑基,較佳地,B表示二唑基、唑基或噻唑基。根據一個具體實施方案,B不選自1,2-二基、三唑並吡啶基或三唑基。
根據一個具體實施方案,在本發明的化合物中,B表示唑
基或噻唑基。根據一個具體實施方案,如果B是唑基,則A不是四唑基或四氫吡啶基。根據一個具體實施方案,如果B是噻唑基,則A不是咪唑基、三唑基、哌基、吡咯啶基、哌啶基或1,4-基。
根據一個具體實施方案,在本發明的化合物中,X是CH並且A是2-側氧基咪唑啶基或吡唑基。
根據一個實施方案,在式(III)化合物中,R1和R2各自獨立地為氫或烷基(較佳地,C1-C3烷基,更佳地,甲基、乙基或丙基),A是2-側氧基咪唑啶基並且B是雜芳基。
在化合物中存在一個或多個手性中心的情況下,可存在對映異構體或非對映異構體的混合物。此類化合物可以對映異構體或非對映異構體純的形式作為外消旋混合物或富集一種或多種立體異構體的混合物用作藥物。要求保護的本發明的範圍描述此類化合物的外消旋形式以及單個對映異構體、非對映異構體,以及立體異構體富集的混合物。
手性化合物的單一立體異構體通常從光學純的前驅物製備,或者藉由色譜法,例如手性高壓液相色譜法(HPLC)分離對映異構體來製備。外消旋混合物也可藉由與適當反應性的手性化合物反應轉化為可分離的非對映異構體,以便藉由色譜法進行分離。或者,分離可藉由轉化為手性鹽來實現。例如,含有鹼性基團的外消旋手性化合物可與手性酸,例如蘋果酸形成非對映異構鹽。如此產生的非對映異構鹽的混合物可隨後藉
由分步結晶進行分離。藉由這些方法產生的純合成非對映異構體可隨後藉由本領域技術人員已知的經典化學方法轉化為期望的立體異構體。在本發明中,手性外消旋化合物可藉由手性HPLC在合適的手性固定相上用庚烷/乙醇的混合物或用純的醇(甲醇或乙醇)洗脫進行分離。立體異構體聚集體可藉由本領域技術人員已知的常規技術進行分離。參見例如Ernest L.Eliel的”Stereochemistry of Organic Compounds”(Wiley,New York,1994)。
式(I)化合物可以衍生自藥學上可接受的無機酸或有機酸的鹽的形式使用。除非另有說明,否則”藥學上可接受的鹽”是指藉由將式(I)化合物與酸或鹼組合製備的鹽,所述酸的陰離子或所述鹼的陽離子通常被認為適合人類食用。藥學上可接受的鹽由於其相對於母體化合物更大的水溶性而特別可用作本發明的方法的產物。對於在藥物中的使用,本發明的化合物的鹽是無毒性的”藥學上可接受的鹽”。涵蓋在術語”藥學上可接受的鹽”內的鹽是指本發明的化合物的無毒性的鹽,其通常藉由使游離鹼與合適的有機酸或無機酸反應來製備。本發明的化合物的合適的藥學上可接受的酸加成鹽在可能時包括衍生自以下酸的那些:無機酸,例如鹽酸、氫溴酸、氫氟酸、硼酸、氟硼酸、磷酸、偏磷酸、硝酸、碳酸、磺酸和硫酸;以及有機酸,例如乙酸、苯磺酸、苯甲酸、檸檬酸、乙磺酸、富馬酸、葡糖酸、乙醇酸、羥乙磺酸、乳酸、乳糖酸、馬來酸、蘋果酸、甲磺酸、三氟甲磺酸、琥珀酸、甲苯磺酸、酒石酸和三氟乙酸。合適的有機酸通常包括例如脂族、環脂族、芳族、芳脂族、雜環、羧酸和磺酸類的有機酸。合適的有機酸的具體實例包括乙酸鹽、三氟乙酸鹽、甲酸鹽、丙酸鹽、琥珀酸鹽、乙醇酸鹽、葡糖酸鹽、二葡糖酸鹽、乳酸鹽、蘋果酸鹽、酒石酸鹽、檸檬
酸鹽、抗壞血酸鹽、葡糖醛酸鹽、馬來酸鹽、富馬酸鹽、丙酮酸鹽、天冬胺酸鹽、麩胺酸鹽、苯甲酸鹽、鄰胺基苯甲酸、硬脂酸鹽、水楊酸鹽、對羥基苯甲酸鹽、苯乙酸鹽、杏仁酸鹽、雙羥萘酸鹽(embonate)(撲酸鹽(pamoate))、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、泛酸鹽、甲苯磺酸鹽、2-羥基乙磺酸鹽、對胺基苯磺酸鹽、環己基胺基磺酸鹽、β-羥基丁酸鹽、黏酸鹽、半乳糖醛酸鹽、己二酸鹽、藻酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、十二烷基硫酸鹽、葡庚糖酸鹽、甘油磷酸鹽、庚酸鹽、己酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、棕櫚酸鹽(palmoate)、果膠酸鹽、3-苯基丙酸鹽、苦味酸鹽、新戊酸鹽(pivalate)、硫氰酸鹽和十一烷酸鹽。此外,在本發明的化合物帶有酸性部分的情況下,其合適的藥學上可接受的鹽可包括鹼金屬鹽,即,鈉鹽或鉀鹽;鹼土金屬鹽,例如鈣鹽或鎂鹽;以及與合適的有機配體形成的鹽,例如季銨鹽。在另一實施方案中,鹼鹽由形成無毒性的鹽的鹼形成,包括鋁鹽、精胺酸鹽、苄星青黴素鹽(benzathine)、膽鹼鹽、二乙胺鹽、二乙醇胺鹽、甘胺酸鹽、離胺酸鹽、葡甲胺鹽、乙醇胺鹽、胺丁三醇鹽和鋅鹽。有機鹽可由二級胺鹽、三級胺鹽或四級胺鹽制得,例如胺丁三醇、二乙胺、N,N’-二苄基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普魯卡因(procaine)。鹼性含氮基團可用試劑四級銨化,所述試劑例如低級烷基(CrCe)鹵化物(例如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸鹽(即,二甲基、二乙基、二丁基和二戊基硫酸鹽)、長鏈鹵化物(例如,癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物)、芳烷基鹵化物(例如,苄基和苯乙基溴化物)以及其它。也可以形成酸和鹼的半
鹽,例如,半硫酸鹽和半鈣鹽。
用語”式(I)化合物”包括本文所公開的所有子式和具體實施方案。此外,除非另外說明,否則用語”式(I)化合物”包括所有形式的式(I)化合物,包括其水合物、溶劑合物異構體、結晶和非結晶形式、同晶型體、多晶型體和代謝物。例如,式(I)化合物或其藥學上可接受的鹽可以未溶劑化和溶劑化的形式存在。當溶劑或水緊密結合時,複合物會具有良好限定的與濕度無關的化學計量。然而,當溶劑或水微弱結合時,如在通道溶劑合物(channel solvate)和吸濕化合物中,水/溶劑含量將取決於濕度和乾燥條件。在此類情況下,非化學計量將成為常態。式(I)化合物的立體異構體包括本發明的化合物的順式和反式異構體、光學異構體例如R和S對映異構體、非對映異構體、幾何異構體、旋轉異構體、構形異構體和互變異構體,包括表現出一種以上類型的異構的化合物;以及其混合物(例如外消旋物和非對映異構體對)。除非另外說明,否則用語”式(I)化合物”包括化合物的互變異構形式。在結構異構體可經由低能量障壁互相轉化的情況下,可存在互變異構的異構(“互變異構”)。在含有例如亞胺基、酮基或肟基的本發明的化合物中,這可以採取質子互變異構的形式,或者在含有芳族部分的化合物中,這可以採取所謂的價互變異構的形式。由此得出結論,單一化合物可表現出一種以上類型的異構。呈固體和液體形式的互變異構體的不同比率取決於分子上的各個取代基以及用於分離化合物的特定結晶技術。
本發明還涉及包含如上文所描述的化合物的藥物組合物。
因此,本發明涉及包含至少一種本發明的化合物和可接受的
藥物賦形劑的藥物組合物。
根據一個實施方案,本發明涉及包含式(I)化合物或其藥學上可接受的鹽以及至少一種藥學上可接受的載體和/或賦形劑的藥物組合物。
如本領域技術人員已知的,可使用適於給藥方式的多種形式的賦形劑並且它們中的一些可促進活性分子的有效性,例如藉由促進釋放曲線從而使該活性分子總體上對於期望治療更有效來促進該有效性。
因此,本發明的藥物組合物能夠以多種形式給藥,例如作為可注射的、可粉化的或可攝取的形式給藥,例如經由肌內、靜脈內、皮下、皮內、口服、局部、直腸、陰道、眼、鼻、經皮或腸胃外途徑給藥。本發明顯著地涵蓋本發明的化合物用於製造組合物,特別是藥物組合物的用途。
此類醫藥品可呈適於口服給藥的藥物組合物形式,其可使用本領域內熟知的藥學上可接受的載體以合適劑量配製。此類載體使藥物組合物能夠被配製成片劑、丸劑、糖衣錠、膠囊、液體、凝膠劑、糖漿劑、漿液、混懸液等,以供患者攝入。除了活性成分外,這些藥物組合物還可含有合適的藥學上可接受的載體,所述載體包括促進活性化合物加工成可在藥學上使用的製劑的賦形劑和助劑。關於配製和給藥技術的其它細節可在Remington’s Pharmaceutical Sciences(Maack Publishing公司,Easton,Pa.)的最新版本中找到。
本發明的組合物也可採取用於局部給藥的藥物組合物或化妝品組合物的形式。
此類組合物可以下列形式提供:凝膠劑、糊劑、軟膏劑、霜劑、洗劑、液體混懸液、水-醇溶液或油性溶液,或者洗劑或漿液型分散體,
或者無水或親脂性凝膠劑,或者乳型液體或半固體稠度的乳劑,其藉由將脂肪相分散在水相中或反之獲得,或者霜劑或凝膠劑型的軟的半固體稠度的混懸液或乳劑,或者微乳、微囊劑、微粒或者離子和/或非離子型的囊泡分散體。這些組合物根據標準方法製備。
本發明的組合物可包含任何通常用於皮膚病學和化妝品中的成分。其可包含至少一種選自以下的成分:親水性或親脂性膠凝劑、親水性或親脂性活性劑、防腐劑、潤膚劑、黏度增強聚合物、保濕劑、表面活性劑、防腐劑、抗氧化劑、溶劑、芳香劑、填充劑、遮蔽劑、殺細菌劑、氣味吸收劑和色素。
作為可用於本發明的油,可提及礦物油(液體石蠟)、植物油(牛油樹脂的液體餾分、向日葵油)、動物油、合成油、矽油(環聚二甲基矽氧烷(cyclomethicone))和氟化油。脂肪醇、脂肪酸(硬脂酸)和蠟(石蠟、巴西棕櫚蠟、蜂蠟)也可用作脂肪物質。
可用於本發明的乳化劑包括例如硬脂酸甘油酯、聚山梨酯60和PEG-6/PEG-32/硬脂酸乙二醇酯混合物。
可用於本發明的親水性膠凝劑包括例如羧乙烯聚合物(卡波姆(carbomer))、丙烯酸共聚物例如丙烯酸酯/烷基丙烯酸酯共聚物、聚丙烯醯胺、多醣例如羥丙基纖維素、黏土和天然樹膠。可用於本發明的親脂性膠凝劑包括例如改性黏土例如有機皂土(bentone)、脂肪酸的金屬鹽例如硬脂酸鋁和疏水性二氧化矽,或者乙基纖維素和聚乙烯。
作為親水性活性劑,可使用蛋白質或蛋白質水解物、胺基酸、多元醇、脲、尿囊素、糖和糖衍生物、維生素、澱粉和植物提取物,
特別是蘆薈提取物。
作為親脂性活性劑,可使用視黃醇(維生素A)及其衍生物、生育酚(維生素E)及其衍生物、必需脂肪酸、神經醯胺和精油。這些試劑在使用時增加額外的保濕或皮膚軟化特徵。
另外,表面活性劑可以包含在組合物中,以便提供化合物的更深滲透,從而能夠作為單一藥劑或與其它細胞毒性劑組合對一大組腫瘤細胞系表現出抗增殖活性。
在預期成分中,本發明包括選自例如由以下組成的群組的滲透增強劑:礦物油、水、乙醇、三醋汀(triacetin)、甘油和丙二醇;選自例如由以下組成的群組的凝聚劑:聚異丁烯、聚乙酸乙烯酯和聚乙烯醇,以及增稠劑。
增強藥物的局部吸收的化學方法在本領域中是公知的。例如,具有滲透增強性質的化合物包括月桂基硫酸鈉(Dugard,P.H.和Sheuplein,R.J.,“Effects of Ionic Surfactants on the Permeability of Human Epidermis:An Electrometric Study”,J.Ivest.Dermatol.,第60卷,第263-69頁,1973)、月桂基氧化胺(Johnson等人,US 4,411,893)、月桂氮酮(Rajadhyaksha,US 4,405,616和3,989,816)和癸甲基亞碸(Sekura,D.L.和Scala,J.,“The Percutaneous Absorption of Alkylmethyl Sulfides”,Pharmacology of the Skin,Advances In Biology of Skin,(Appleton-Century Craft)第12卷,第257-69頁,1972)。已觀察到,增加兩性分子中的首基的極性會增加其滲透增強性質,但代價是增加其皮膚刺激性質(Cooper,E.R.和Berner,B.,“Interaction of Surfactants with Epidermal Tissues:Physiochemical Aspects”,Surfactant Science Series,第16卷,Reiger,M.M.編
(Marcel Dekker公司)第195-210頁,1987)。
第二類化學增強劑通常稱為共溶劑。這些材料的局部吸收相對容易,並且藉由多種機制實現一些藥物的滲透增強。乙醇(Gale等人,美國專利第4,615,699號和Campbell等人,美國專利第4,460,372號和第4,379,454號)、二甲亞碸(US 3,740,420和US 3,743,727,以及US 4,575,515)和甘油衍生物(US 4,322,433)是已顯示增強各種化合物的吸收的能力的化合物的幾個例子。
本發明的藥物組合物還可預期用於以氣霧化製劑給藥以靶向患者的呼吸道部位。
用於遞送藥物製劑的氣霧化爆噴物(burst)的裝置和方法公開於US 5,906,202中。製劑較佳是溶液,例如水溶液、乙醇溶液、水/乙醇溶液、鹽水溶液、膠體混懸液和微晶混懸液。例如,氣霧化顆粒包含上文提及的活性成分和載體(例如,藥物活性呼吸藥物和載體),它們在將製劑擠壓通過噴嘴時形成,所述噴嘴較佳採取柔性多孔膜的形式。顆粒的尺寸足夠小,以使得在顆粒形成時它們仍然在空氣中懸浮足夠長的時間,從而使得患者可將顆粒吸入患者的肺中。
本發明包括描述於US 5,556,611中的系統:-液體氣體系統(在壓力容器中使用液化氣體作為拋射劑氣體,例如低沸點FCHC或丙烷、丁烷),-懸浮液氣霧劑(活性物質顆粒以固體形式懸浮在液體拋射劑相中),-加壓氣體系統(使用壓縮氣體,例如氮氣、二氧化碳、一氧化二氮或空氣)。
因此,根據本發明製備藥物製劑在於,將活性物質溶解或分散在合適的無毒性介質中,並將所述溶液或分散體霧化為氣霧劑,即非常細地分佈在載氣中。例如,採取氣霧劑拋射劑氣體包、泵氣霧劑或對於液體起霧和固體霧化自身已知的其它裝置的形式在技術上是可行的,其特別允許精確的單個劑量。
因此,本發明也涉及包含如上文所定義的化合物和這種製劑、較佳具有計量型劑量閥的氣霧劑裝置。
本發明的藥物組合物也可預期用於鼻內給藥。
在這方面,普通技術人員很容易鑒別出用於將化合物給藥到鼻黏膜表面的藥學上可接受的載體。這些載體描述於Arthur Osol編輯的”Remington’s Pharmaceutical ScienceS”第16版,1980中。
合適的載體的選擇取決於所設想的特定給藥類型。對於經由上呼吸道給藥,可將組合物配製為溶液,例如水或緩衝的或未緩衝的等滲鹽水,或者配製為混懸液,配製為滴劑或噴霧劑用於鼻內給藥。較佳地,此類溶液或混懸液相對於鼻分泌物是等滲的並且具有大致相同的pH,例如在約pH 4.0到約pH 7.4或pH 6.0到pH 7.0的範圍。緩衝劑應當是生理學上相容的,並且包括(僅作為實例)磷酸鹽緩衝液。例如,代表性鼻去充血劑被描述為緩衝到約6.2的pH(Remington’s,同上,在第1445頁)。當然,普通技術人員可以容易地確定用於鼻和/或上呼吸道給藥的無害水性載體的合適的鹽水含量和pH。
常見的鼻內載體包括黏度為例如約10到約3000cps、或約2500到6500cps或更大的鼻凝膠劑、霜劑、糊劑或軟膏劑,其也可用於提
供與鼻黏膜表面的更持久接觸。此類載體黏性製劑可基於(僅作為實例)烷基纖維素和/或本領域公知的其它高黏度的生物相容性載體(參見例如Remington’s,引用如上)。較佳的烷基纖維素是例如濃度範圍為每100ml載體約5mg到約1000mg或更多的甲基纖維素。甲基纖維素的更佳濃度為(僅作為實例)每100ml載體約25mg到約150mg。
也可包含其它成分,例如已知的防腐劑、著色劑、潤滑或黏性礦物質或植物油、香料、天然或合成植物提取物例如芳香油、以及保濕劑和黏度增強劑例如甘油,以為製劑提供額外的黏度、水分保持以及令人愉快的質地和氣味。對於本發明的溶液或混懸液的鼻腔給藥,各種裝置在本領域可用於產生滴劑、小滴和噴霧劑。
本發明的另一目的是製備包括滴管或噴霧裝置的預先測量的單位劑量分配器,所述滴管或噴霧裝置含有用於以滴劑或噴霧劑形式遞送的溶液或混懸液,所述單位劑量分配器含有一個或多個劑量的待給藥的藥物。本發明也包括試劑盒,所述試劑盒含有一個或多個單位脫水劑量的化合物,以及任何所需的鹽和/或緩衝劑、防腐劑、著色劑等,其備用於藉由添加合適量的水製備溶液或混懸液。
本發明的另一方面涉及所述化合物製備醫藥品的用途。特別地,本發明涉及包含本發明的化合物或其藥學上可接受的鹽的醫藥品。換句話說,本發明包括用於藉由抑制腫瘤細胞的增殖治療疾病的方法,其包括向需要此類治療的受試物件給藥有效量的至少一種如上文所定義的化合物。
有利地,本發明的化合物可以有效量使用。這些量通常包括
每天每千克體重0.1mg到2g本發明的化合物。
在另一方面,本發明涉及用於調節、調控和/或抑制細胞增殖的方法。所述方法包括向細胞給藥至少一種如上文所定義的式(I)化合物,例如式(II)或(III)的化合物,或其藥學上可接受的鹽。
本發明所公開的方法可用於治療受試物件的血液和/或增殖性疾病或病症。在一個具體實施方案中,所述疾病或病症是增殖性疾病或病症。在一個具體實施方案中,所述疾病或病症是血液疾病或病症。在一個具體實施方案中,所述疾病或病症是增殖性血液疾病或病症。在一個具體實施方案中,所述疾病是癌症。
在一個實施方案中,所述受試物件已被診斷為患有增殖性疾病或病症。在一個實施方案中,所述受試物件已被診斷為患有血液疾病或病症。
在一個實施方案中,本發明所公開的方法不誘導也不導致蛋白激酶的抑制。
已知與這些血液和增殖性疾病有關的疾病和病症包括例如:- 血液病症,例如淋巴瘤和白血病,包括非霍奇金淋巴瘤、彌漫性大B細胞淋巴瘤(DLBCL)、濾泡淋巴瘤(FL)、套細胞淋巴瘤(MCL)、B細胞慢性淋巴細胞白血病(B-CLL)/小淋巴細胞淋巴瘤(SLL)、沃爾登斯特倫巨球蛋白血症(Waldenstrom’s macroglbulinemia)(WM)、邊緣區淋巴瘤(MZL)、伯基特淋巴瘤(Burkitt lymphoma)和外周T細胞淋巴瘤(PTCL);以及多發性骨髓瘤(MM)、骨髓增生異常綜合征(MDS)、骨髓增生異常伴骨髓纖維化;- 增殖性疾病,例如肥大細胞增多症,包括色素性蕁麻疹(UP)、持久
斑疹性毛細管擴張(TMEP)、靜止性全身性肥大細胞增多症、攻擊性全身性肥大細胞增多症和白血病全身性肥大細胞增多症;- 增殖性疾病,例如實體腫瘤,包括頭頸癌、黑色素瘤、腎癌、胃癌、肝癌、結腸直腸癌、胰腺癌、肺癌、神經元癌、多形性膠質母細胞瘤、骨癌、骨肉瘤、尤因肉瘤、乳腺癌、卵巢癌、前列腺癌。
式(I)化合物例如式(II)或(III)的化合物或其藥學上可接受的鹽可用於治療如上文所公開的疾病或病症,例如血液病症和/或增殖性病症。增殖性病症可以是癌症。
在一個實施方案中,式(I)化合物例如式(II)或(III)的化合物或其藥學上可接受的鹽是用於治療如上文所公開的疾病或病症,例如血液和/或增殖性疾病或病症。在一個具體實施方案中,所述疾病或病症是增殖性疾病或病症。在一個具體實施方案中,所述疾病或病症是血液疾病或病症。在一個具體實施方案中,所述疾病或病症是增殖性血液疾病或病症。在一個具體實施方案中,所述疾病是癌症。
在一個具體實施方案中,式(I)化合物是用於調節、調控和/或抑制造血腫瘤細胞系增殖。在一個具體實施方案中,式(I)化合物是用於調節、調控和/或抑制實體腫瘤細胞系增殖。
在本發明所公開的方法中,式(I)化合物或其藥學上可接受的鹽可作為唯一活性藥物成分使用或與另一活性藥物成分組合使用。在一個實施方案中,式(I)化合物或其藥學上可接受的鹽作為唯一活性藥物成分使用。在一個實施方案中,式(I)化合物或其藥學上可接受的鹽與另一活性藥物成分組合使用。
本發明涉及用於預防或治療選自血液病症和增殖性病症的疾病或病症的方法,所述方法包括以足以提供治療效果的量向有此需要的人或動物受試物件同時或依序給藥至少一種式(I)化合物或其藥學上可接受的鹽與另一活性藥物成分的組合。
本發明涉及包含式(I)化合物例如式(II)或(III)的化合物或其藥學上可接受的鹽以及另一種活性藥劑的藥物組合物,其作為組合製劑用於在選自由血液病症和增殖性病症組成的群組的疾病或病症的治療中依序、同時或分開使用。
本發明涉及式(I)化合物例如式(II)或(III)的化合物或其藥學上可接受的鹽的用途,其視需要與另一種藥物活性劑組合用於製造用以治療選自由血液病症和增殖性病症組成的群組的疾病或病症的醫藥品。
儘管上文所公開的方法和用途針對式(I)化合物例如式(II)或(III)的化合物或其藥學上可接受的鹽,但只要技術上相容,它們都應理解為同樣針對包含所述化合物的藥物組合物。
本發明的化合物可藉由包括流程1-2中概述的方法在內的幾種方法來製備,其中除非進一步指出,否則取代基如上文式(I)中所定義。下文所述的合成方法僅僅是示例性的,並且本發明的化合物可藉由本領域普通技術人員瞭解的替代途徑來合成。
因此,胺基唑衍生物V的合成藉由以下方式進行:首先,使用Van Leusen等人(Tetrahedron Lett.,1972,23,2369)的方法(流程1),使芳族醛I與對甲苯磺醯基甲基異腈(TosMIC)反應,以製備相應的唑衍生物II。
非商業醛使用文獻方法引入醛基來製備,所述醛基是藉由使用有機金屬試劑和DMF而從相應的溴化芳族化合物獲得,或根據Frey等人(Tetrahedron Lett.,2001,39,6815)的方法從相應甲苯的氧化獲得,或從Bombrun等人(Tetrahedron Lett.,2005,36,6033)的方法中使用的反應獲得,所述反應使用溴甲基吡啶的二溴化隨後使用碳酸鈣水溶液水解。其次,這些化合物II然後藉由用合適的有機鹼進行唑部分的去質子化進一步官能化,並隨後使用親電氯化來製備2-氯唑化合物III。在合適的溶劑例如醇存在下,在升高的溫度下加熱下,經由苯胺化合物IV(其中R’是氫)的直接親核置換反應通常應得到最終的目標化合物V。化合物V還可以經由化合物IV(其中R’是乙醯基)和化合物III在氫化鈉存在下在合適的溶劑例如四氫呋喃或二甲基甲醯胺中的反應獲得(WO/2007/131953)。
胺基噻唑衍生物VIII的合成藉由以下方式進行:首先,使用Iwao等人(J.Org.Chem.2009,74,8143)所述的維悌希反應(Wittig reaction),使芳族醛I與(甲氧基甲基)三苯基氯化鏻反應,以製備相應的烯醇醚衍生物VI。其次,使用Zhao等人(Tetrahedron Lett.,2001,42,2101)的方法,用烯醇醚VI、硫脲衍生物VII和N-溴琥珀醯亞胺(NBS)進行環化。硫脲衍生物VII藉由使苯胺IX和硫氰酸銨反應來合成。
胺基噻唑衍生物XI的合成使用漢奇反應(Hantzsch reaction)藉由在鹼性條件下在合適的溶劑例如醇存在下,在升高的溫度下加熱下用
2-溴酮X和硫脲衍生物VII環化進行。
或者,式(I)化合物可根據下文流程2藉由銅或鈀偶聯反應,藉由使化合物XII和視需要被取代的雜環A-L反應製備,其中Y可以是I、Br或Cl,並且L是氫、硼酸、硼酸酯或三烷基甲錫烷基。本領域普通技術人員能夠認識到,化合物XII或者可根據上文流程1中概述的流程來製備。
現將藉由實施例對本發明進行說明,所述實施例代表目前較佳的實施方案,其構成本發明的一部分,但決不用於限制本發明的範圍。
A. 化合物的合成
藉由參考以下製備實施例更全面地瞭解本發明,但所述實施例不應被解釋為限制本發明的範圍。概要:使用的所有化學品均為商業試劑級產品。溶劑是無水商品級的,並且未經進一步純化即使用。反應進展藉由薄層色譜法使用預塗矽膠60F 254,Merck TLC板進行監測,所述板在UV光下視覺化。1H NMR譜中的多重性表示為單峰(s)、寬單峰(br s)、雙峰(d)、三重峰(t)、四重峰(q)和多重峰(m),並且NMR譜在Bruker 300或500MHz光譜儀上進行。
縮寫
A.1. 化合物001:
化合物001的合成方法
2-溴-5-(二溴甲基)吡啶(Ia)的製備
向2-溴-5-甲基-吡啶(3.000g,17.44mmol)於CCl4(30ml)中的
溶液中添加N-溴琥珀醯亞胺(6.829g,38.36mmol)和過氧化苯甲醯(506mg,2.09mmol)。將反應混合物在90℃下在黑暗條件下攪拌16小時。將反應混合物冷卻並添加PE。將所得固體過濾出來,並用另外的PE洗滌。將冷卻的混合物蒸發到乾燥,用水稀釋並用EtOAc萃取。將合併的有機物用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用10% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Ia(4.6g,80%)。1H NMR(500MHz,CDCl3)δ 8.46(d,J=2.6Hz,1H),7.87(dd,J=8.4,2.7Hz,1H),7.55(d,J=8.4Hz,1H),6.61(s,1H)。
6-溴菸醛(Ib)的製備
將中間體Ia(3.650g,11.07mmol)、碳酸鈣(2.437g,24.35mmol)於水(80ml)中的溶液在105℃下攪拌16小時。將冷卻的混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發,得到中間體Ib(1.890g,92%)。1H NMR(500MHz,CDCl3)δ 10.05(s,1H),8.78(d,J=2.2Hz,1H),7.98(dd,J=8.2,2.4Hz,1H),7.65(d,J=8.2Hz,1H)。
向中間體Ib(1.600g,8.60mmol)於MeOH(35ml)中的溶液中添加K2CO3(3.567g,25.80mmol)和TosMIC(2.015g,10.32mmol)。將反應混合
物在室溫下攪拌16小時。將冷卻的混合物蒸發到乾燥,用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Ic(1.371g,71%)。1H NMR(500MHz,CDCl3)δ 8.68(d,J=2.4Hz,1H),7.98(s,1H),7.78(dd,J=8.3,2.5Hz,1H),7.56(d,J=8.3Hz,1H),7.46(s,1H)。
在密封管中,向中間體Ic(1.000g,4.44mmol)於無水甲苯(6mL)中的溶液中相繼添加吡唑(454mg,6.66mmol)、碳酸鉀(1.228g,8.88mmol)、外消旋-反式-N,N’-二甲基環己烷-1,2-二胺(137μL,0.89mmol)和碘化亞銅(42mg,0.22mmol)。將反應混合物在110℃下攪拌3天。將冷卻的混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Id(817mg,87%)。1H NMR(300MHz,DMSO-d 6 )δ 8.85(d,J=2.3Hz,1H),8.65(dd,J=2.6,0.5Hz,1H),8.55(s,1H),8.31(dd,J=8.6,2.3Hz,1H),8.02(dd,J=8.6,0.7Hz,1H),7.87(d,J=1.6Hz,1H),7.84(s,1H),6.61(dd,J=2.6,1.7Hz,1H)。
在-78℃下,歷時10min向中間體Id(817mg,3.85mmol)於無水THF(26ml)中的攪拌溶液中逐滴添加LiHMDS於無水THF(4.23ml,4.23mmol)中的溶液。將反應混合物在-78℃下攪拌30min。然後,添加C2Cl6(1.094g,4.62mmol),並將反應混合物在室溫下攪拌16小時。將混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Ie(736mg,78%)。1H NMR(300MHz,DMSO-d 6 )δ 8.81(d,J=2.2Hz,1H),8.65(d,J=2.6Hz,1H),8.27(dd,J=8.6,2.3Hz,1H),8.02(d,J=8.7Hz,1H),7.92(s,1H),7.87(d,J=0.8Hz,1H),6.72-6.55(m,1H)。
N-(5-甲氧基-2-甲基苯基)乙醯胺(If)的製備
在0℃下,向5-甲氧基-2-甲基-苯基胺(4.000g,29.16mmol)於無水DCM(60ml)中的溶液中相繼逐滴添加無水Et3N(12.2ml,87.48mmol)和乙醯氯(4.2ml,58.32mmol)。將反應混合物在室溫下攪拌2小時。將混合物用水稀釋並用DCM萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用40-60% EtOAc/環己烷作為洗脫劑進行純化,得到中間體If(4.952g,95%)。1H NMR
(300MHz,CDCl3)δ 7.49(d,J=2.2Hz,1H),7.05(d,J=8.4Hz,2H),6.63(dd,J=8.3,2.3Hz,1H),3.77(s,3H),2.18(s,3H),2.17(s,3H)。
在0℃下,向氫化鈉於礦物油中的60%分散液(162mg,4.06mmol)於無水DMF(5ml)中的溶液中逐滴添加中間體If(363mg,2.03mmol)於無水DMF(5ml)中的溶液。將反應混合物在室溫下攪拌1小時,並在0℃下逐滴添加中間體Ie(500mg,2.03mmol)於無水DMF(5ml)中的溶液。將反應混合物在0℃下攪拌3小時。將混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用飽和NaHCO3溶液(3次)、水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用10-30% EtOAc/環己烷作為洗脫劑進行純化,得到001(480mg,68%)。1H NMR(300MHz,DMSO-d 6 )δ 9.38(s,1H),8.68(d,J=2.1Hz,1H),8.62(d,J=2.4Hz,1H),8.12(dd,J=8.6,2.3Hz,1H),7.99(d,J=8.6Hz,1H),7.84(s,1H),7.59(s,2H),7.09(d,J=8.3Hz,1H),6.66-6.51(m,2H),3.73(s,3H),2.23(s,3H)。
A.2. 化合物002:
化合物002的合成方法
3-甲氧基-4-硝基苯甲醛(IIa)的製備
向3-羥基-4-硝基苯甲醛(2.000g,11.98mmol)於DMF(24ml)中的溶液中添加K2CO3(1.687g,12.22mmol)和碘甲烷(1.52ml,24.44mmol)。將反應混合物在室溫下攪拌4小時。將混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用飽和NaHCO3溶液(3次)、水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發,得到中間體IIa(2.137g,98%)。1H NMR(500MHz,CDCl3)δ 10.06(s,1H),7.93(d,J=8.1Hz,1H),7.60(s,1H),7.54(dd,J=8.1,1.4Hz,1H),4.04(s,3H)。
如上文對於中間體Ic一樣從中間體IIa製備,以得到中間體
IIb(2.708g,100%)。1H NMR(500MHz,CDCl3)δ 8.00(s,1H),7.95(d,J=8.4Hz,1H),7.52(s,1H),7.35(d,J=1.5Hz,1H),7.31(dd,J=8.4,1.7Hz,1H),4.05(s,3H)。
向中間體IIb(2.708g,12.30mmol)於EtOH/DCM(104/46ml)中的溶液中添加SnCl2.2H2O(13.875g,61.50mmol)和濃HCl(10ml)。將反應混合物在室溫下攪拌16小時。添加水,並添加NaOH水溶液(2.5M),直至達到鹼性pH。將粗產物用DCM萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-40% EtOAc/環己烷作為洗脫劑進行純化,得到中間體IIc(1.972g,84%)。1H NMR(500MHz,DMSO-d 6 )δ 8.26(s,1H),7.37(s,1H),7.10(d,J=1.8Hz,1H),7.06(dd,J=8.0,1.8Hz,1H),6.68(d,J=8.1Hz,1H),5.07(s,2H),3.83(s,3H)。
在0℃下,向中間體IIc(1.972g,10.37mmol)於6N HCl(25ml)中的懸浮液中逐滴添加NaNO2(787mg,11.47mmol)於H2O(10ml)中的溶液。將反應混合物在0℃下攪拌15min。然後,添加SnCl2.2H2O(6.784g,30.07mmol),並將反應混合物在0℃下攪拌2小時。添加2.5N NaOH溶液,直至
達到鹼性pH,並將粗產物用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發,得到中間體IId(1.834g,86%)。1H NMR(500MHz,DMSO-d 6 )δ 8.27(s,1H),7.41(s,1H),7.20(dd,J=8.2,1.7Hz,1H),7.10(d,J=1.7Hz,1H),7.05(d,J=8.2Hz,1H),6.29(s,1H),4.05(s,2H),3.31(s,3H)。
向中間體IId(1.834g,8.94mmol)於EtOH(30ml)中的懸浮液中添加丙二醛二甲縮醛(1.63ml,9.84mmol)和濃HCl(1ml)。將反應混合物在70℃下攪拌2小時。將冷卻的混合物蒸發到乾燥,用飽和NaHCO3溶液稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體IIe(1.380g,64%)。1H NMR(500MHz,CDCl3)δ 8.12(d,J=2.1Hz,1H),7.94(s,1H),7.85(d,J=8.3Hz,1H),7.72(d,J=1.4Hz,1H),7.40(s,1H),7.36(dd,J=8.3,1.8Hz,1H),7.32(d,J=1.7Hz,1H),6.46-6.43(m,1H),3.97(s,3H)。
如上文對於中間體Ie一樣從中間體IIe製備,隨後使用0-20% EtOAc/環己烷作為洗脫劑進行矽膠色譜法處理,得到中間體IIf(1.380g,88%)。1H NMR(500MHz,CDCl3)δ 8.13(d,J=2.5Hz,1H),7.86(d,J=8.3Hz,1H),7.72(d,J=1.6Hz,1H),7.33(s,1H),7.30(dd,J=8.3,1.8Hz,1H),7.24(d,J=1.7Hz,1H),6.48-6.42(m,1H),3.98(s,3H)。
向中間體IIe(300mg,1.09mmol)於無水iPrOH(2ml)中的溶液中添加中間體IIg(171mg,1.04mmol)和HCl於乙醚中的溶液(220μl,0.22mmol)。將反應混合物在90℃下攪拌16小時。將冷卻的混合物蒸發到乾燥,用水稀釋並用EtOAc萃取兩次。將合併的有機物用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-40% EtOAc/環己烷作為洗脫劑進行純化,得到中間體002(230mg,55%)。1H NMR(500MHz,DMSO-d 6 )δ 9.33(s,1H),8.20(d,J=2.3Hz,1H),7.85(s,1H),7.74-7.66(m,2H),7.55(s,1H),7.39(d,J=1.6Hz,1H),7.29(dd,J=8.3,1.7Hz,1H),7.18(d,J=7.7Hz,1H),6.95(dd,J=7.6,1.2Hz,1H),6.52-6.45(m,1H),4.43(s,2H),3.95(s,3H),3.49(q,J=7.0Hz,2H),2.30(s,3H),1.16(t,J=7.0Hz,3H)。
(IIg)的合成方法
4-乙氧基甲基-1-甲基-2-硝基-苯(IIh)的製備
向乙醇鈉於無水乙醇中的溶液(75mL,246.42mmol)中添加4-氯甲基-1-甲基-2-硝基-苯(15.000g,82.14mol)。將反應混合物在室溫下攪拌16小時。添加水,並在減壓下移除乙醇。將粗產物用DCM萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體IIh(15.364g,96%)。1H NMR(300MHz,CDCl3)δ 7.95(d,J=1.0Hz,1H),7.48(dd,J=7.8,1.5Hz,1H),7.31(d,J=7.9Hz,1H),4.52(s,2H),3.56(q,J=7.0Hz,2H),2.58(s,3H),1.26(t,J=7.0Hz,3H)。
5-乙氧基甲基-2-甲基-苯基胺(IIg)的製備
在0℃下,向中間體IIh(15.364g,78.70mmol)於乙醇(500ml)中的溶液中相繼地逐滴添加Pd/C(5.405g,0.33重量%)和單水合肼(10.7mL,
212.49mmol)。將反應混合物在80℃下攪拌2小時。然後,將熱混合物過濾藉由celite®墊,並用乙醇洗滌。將濾液濃縮以得到中間體IIg(13.779g,100%)。1H NMR(500MHz,CDCl3)δ 7.01(d,J=7.4Hz,1H),6.68(s,1H),6.67(d,J=7.6Hz,1H),4.41(s,2H),3.59(s,2H),3.51(q,J=7.0Hz,2H),2.15(s,3H),1.23(t,J=7.0Hz,3H)。
A.3. 化合物003:
化合物003的合成方法
1-(5-(乙氧基甲基)-2-甲基苯基)硫脲(IIIa)的製備
在室溫下,向硫氰酸鉀(2.534g,33.29mmol)於丙酮(35ml)中的溶液中逐滴添加苯甲醯氯溶液(3.5ml,30.26mmol)。將反應混合物在50℃
下攪拌15分鐘。然後,添加中間體IIg(5.000g,30.26mmol)於丙酮(15ml)中的溶液,並將反應混合物在50℃下攪拌15分鐘。添加水,並將固體過濾,用另外的水和乙醚洗滌,得到白色固體。將白色固體與碳酸鉀(7.946g,57.49mmol)於MeOH(27ml)中的溶液在室溫下攪拌3小時。在減壓下移除甲醇,並將固體用水和乙醚洗滌,得到中間體IIIa(5.800g,78%)。1H NMR(500MHz,DMSO-d 6 )δ 9.20(s,1H),7.21(d,J=7.7Hz,1H),7.14(s,1H),7.10(d,J=7.7Hz,1H),4.40(s,2H),3.47(q,J=7.0Hz,2H),2.17(s,3H),1.14(t,J=7.0Hz,3H)。
4-(4-溴苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)噻唑-2-胺(IIIb)的製備
向2,4’-二溴苯乙酮(1.500g,5.39mmol)於EtOH(54ml)中的溶液中添加中間體IIIa(1.211g,5.39mmol)和碳酸氫鉀(1,621g,16.02mmol)。將反應混合物在80℃下攪拌16小時。將冷卻的混合物蒸發到乾燥,用水稀釋並用EtOAc萃取兩次。將合併的有機物用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體IIIb(2.000g,92%)。1H NMR(500MHz,DMSO-d 6 )δ 9.37(s,1H),8.01(s,1H),7.82(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),7.35(s,1H),7.18(d,J=7.7Hz,1H),6.95(d,J=7.7Hz,1H),4.44(s,2H),3.50(q,J=7.0Hz,2H),2.27(s,3H),1.16(t,J=7.0Hz,3H)。
1-{4-[2-(5-乙氧基甲基-2-甲基-苯基胺基)-噻唑-4-基]-苯基}-咪唑啶-2-酮(003)的製備
在密封管中,向IIIb(500mg,1.29mmol)於無水二(7mL)中的溶液中相繼添加2-咪唑啶酮(556mg,6.45mmol)、碳酸銫(1.052g,3.23mmol)、Xantphos(75mg,0.13mmol)。將反應混合物用氮氣脫氣20分鐘,然後添加Pd2(dba)3(35mg,0.04mmo1)。然後,將反應混合物在110℃下攪拌16小時。將冷卻的混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用60-90% EtOAc/環己烷作為洗脫劑進行純化,得到中間體003(260mg,52%)。1H NMR(500MHz,DMSO-d 6 )δ 9.29(s,1H),8.05(s,1H),7.81(d,J=8.8Hz,2H),7.58(d,J=8.9Hz,2H),7.18(d,J=7.7Hz,1H),7.12(s,1H),6.96(s,1H),6.93(d,J=7.7Hz,1H),4.44(s,2H),3.91-3.83(m,2H),3.50(q,J=7.0Hz,2H),3.45-3.37(m,2H),2.27(s,3H),1.17(t,J=7.0Hz,3H)。
A.4. 化合物004:
化合物004的合成方法
(E/Z)-1-(4-(2-甲氧基乙烯基)苯基)-1H-吡唑(IVa)的製備
在0℃下,向(甲氧基甲基)三鏻氯化物(5.973g,17.43mmol)於無水THF(40mL)中的溶液中逐滴添加n-BuLi於無水THF中的溶液(4.7mL,11.62mmol)。將反應混合物在室溫下攪拌1小時。然後,在0℃下逐滴添加4-(1H-吡唑-1-基)苯甲醛(1.000g,5.81mmol)於無水THF(20mL)中的溶液。將反應混合物在室溫下攪拌16小時。將冷卻的混合物用飽和NH4Cl溶液稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-20% EtOAc/環己烷作為洗脫劑進行純化,得到中間體(E/Z)50/50 IVa(758mg,65%)。1H NMR(500MHz,CDCl3)δ 7.90(d,J=2.4Hz,1H),7.88(d,J=2.4Hz,1H),7.71(s,2H),7.65(d,J=8.8Hz,2H),7.62-7.56(m,4H),7.30(d,J=8.5Hz,2H),7.07(d,J=13.0Hz,1H),6.47-6.43(m,2H),6.17(d,J=7.0Hz,1H),5.83(d,J=13.0Hz,1H),5.24(d,J=7.0Hz,1H),3.80(s,3H),3.70(s,3H)。
5-(4-(1H-吡唑-1-基)苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)噻唑-2-胺(004)的製備
向中間體IVa(200mg,1.00mmol)於二/水(1/1mL)中的溶
液中添加N-溴琥珀醯亞胺(196mg,1.10mmol)。將反應混合物在室溫下攪拌1小時。然後,添加中間體IIIa(224mg,1.00mmol),並將反應混合物在80℃下攪拌16小時。將冷卻的混合物用飽和NH4Cl溶液稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用0-30% EtOAc/環己烷作為洗脫劑進行純化,得到中間體004(270mg,69%)。1H NMR(500MHz,DMSO-d 6 )δ 9.42(s,1H),8.50(d,J=2.4Hz,1H),7.83(d,J=8.7Hz,2H),7.79(s,1H),7.75(d,J=1.6Hz,1H),7.67(s,1H),7.60(d,J=8.7Hz,2H),7.20(d,J=7.7Hz,1H),6.98(d,J=7.7Hz,1H),6.60-6.52(m,1H),4.42(s,2H),3.48(q,J=7.0Hz,2H),2.27(s,3H),1.15(t,J=7.0Hz,3H)。
A.5. 化合物005:
化合物005的合成方法
如上文對於中間體Ic一樣從4-(1H-吡唑-1-基)苯甲醛製備,隨後使用40% EtOAc/環己烷作為洗脫劑進行矽膠色譜法處理,得到中間體Va(23.637g,96%)。1H NMR(500MHz,CDCl3)δ 7.97(d,J=2.5Hz,1H),7.93(s,1H),7.78(d,J=8.9Hz,2H),7.76-7.72(m,3H),7.38(s,1H),7.26(s,1H),6.54-6.47(m,1H)。
如上文對於中間體Ie一樣從中間體Va製備,隨後使用30%EtOAc/環己烷作為洗脫劑進行矽膠色譜法處理,得到中間體Vb(7g,100%)。1H NMR(500MHz,CDCl3)δ 7.97(d,J=2.5Hz,1H),7.78(d,J=8.9Hz,2H),7.75(d,J=1.5Hz,1H),7.68(d,J=8.8Hz,2H),7.31(s,1H),6.53-6.46(m,1H)。
(Vc)的合成方法
4-甲基-3-硝基苯甲酸三級丁酯(Vf)的製備
在0℃下,向4-甲基-3-硝基苯甲酸(6.000g,33.12mmol)於無水DCM中的溶液中相繼添加DMAP(404mg,3.312mmol)、t-BuOH(2.946g,27.602mmol)和DCC(8.200g,27.602mmol)。將反應混合物在室溫下攪拌48小時。然後,將反應混合物過濾,用另外的DCM洗滌,並將濾液濃縮。最終產物藉由矽膠色譜法使用0-20% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Vf(6.793g,86%)。1H NMR(300MHz,CDCl3)δ 8.51(d,J=1.6Hz,1H),8.08(dd,J=8.0,1.7Hz,1H),7.40(d,J=8.0Hz,1H),2.64(s,3H),1.60(s,9H)。
3-胺基-4-甲基苯甲酸三級丁酯(Vg)的製備
向中間體Vf(6.793g,28.64mmol)於EtOH(60ml)中的用氮氣脫氣的溶液中添加Pd/C(1.200g)和環己烯(60ml)。將反應混合物在80℃下攪拌16小時。將反應混合物過濾藉由Celite®墊,用另外的EtOH洗滌,並將濾液濃縮以得到中間體Vg(6.200g,100%)。1H NMR(300MHz,CDCl3)δ 7.32(d,J=7.8Hz,1H),7.29(s,1H),7.07(d,J=7.8Hz,1H),3.68(s,2H),2.20(s,3H),1.57(s,9H)。
3-乙醯胺基-4-甲基苯甲酸三級丁酯(Vc)的製備
如上文對於中間體If一樣從中間體Vg製備,隨後藉由矽膠色譜法使用25-40% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Vc(6.296g,84%)。1H NMR(300MHz,CDCl3)δ 8.17(s,1H),7.71(d,J=7.7Hz,1H),7.21(d,J=8.0Hz,2H),2.27(s,3H),2.19(s,3H),1.57(s,9H)。
如上文對於001一樣從中間體Vb和Vc製備,隨後藉由矽膠色譜法使用10-40% EtOAc/環己烷作為洗脫劑進行純化,得到中間體Vf(1.100g,65%)。1H NMR(300MHz,DMSO-d 6 )δ 9.47(s,1H),8.54(d,J=2.3Hz,1H),8.51(d,J=1.5Hz,1H),7.92(d,J=8.8Hz,2H),7.76(d,J=1.5Hz,1H),7.70(d,J=8.8Hz,2H),7.53(d,J=1.6Hz,1H),7.50(s,1H),7.32(d,J=7.9Hz,1H),6.59-6.52(m,1H),2.36(s,3H),1.54(s,9H)。
向中間體Vd(1.100g,2.64mmol)於DCM(13ml)中的溶液中逐滴添加TFA(2.7ml)。將反應混合物在室溫下攪拌16小時。將反應混合物濃縮,將固體在Et2O中研磨並過濾,得到中間體Ve(1.200g,96%)。1H NMR(300MHz,DMSO-d 6 )δ 9.55(s,1H),8.57(d,J=1.3Hz,1H),8.54(d,J=2.4Hz,1H),7.93(d,J=8.7Hz,2H),7.76(d,J=1.6Hz,1H),7.71(d,J=8.7Hz,2H),7.57(dd,J=7.8,1.5Hz,1H),7.53(s,1H),7.33(d,J=7.9Hz,1H),6.62-6.48(m,1H),2.37(s,3H)。
向中間體Ve(200mg,0.42mmol)於無水DMF(2ml)中的溶液中相繼添加HOBt(83mg,0.61mmol)、EDCI(159mg,0.83mmol)、Et3N(464μl,6.32mmol)和2-啉基乙胺(72μl,0.55mmol)。將反應混合物在室溫下攪拌16小時。將混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用飽和NaHCO3溶液(3次)、水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。
最終產物藉由矽膠色譜法使用0-20% MeOH/EtOAC作為洗脫劑進行純化,得到005(165mg,83%)。1H NMR(300MHz,DMSO-d 6 )δ 9.41(s,1H),8.54(d,J=2.4Hz,1H),8.32(s,1H),8.29(d,J=5.7Hz,1H),7.92(d,J=8.8Hz,2H),7.76(d,J=1.6Hz,1H),7.69(d,J=8.7Hz,2H),7.47(s,1H),7.45(dd,J=7.9,1.7Hz,1H),7.28(d,J=7.9Hz,1H),6.59-6.53(m,1H),3.61-3.52(m,4H),3.42-3.33(m,2H),2.47(m,2H),2.42(m,4H),2.34(s,3H)。
A.6. 化合物006:
化合物006的合成方法
如上文對於中間體Ic一樣從4-溴苯甲醛製備,以得到中間體VIa(15.000g,95%)。1H NMR(300MHz,CDCl3)δ 7.92(s,1H),7.56(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.36(s,1H)。
如上文對於中間體Ie一樣從中間體VIa製備,隨後使用5% EtOAc/環己烷作為洗脫劑進行矽膠色譜法處理,得到中間體VIb(9.000g,98%)。1H NMR(300MHz,CDCl3)δ 7.57(d,J=8.6Hz,2H),7.46(d,J=8.6Hz,2H),7.29(s,1H)。
如上文對於002一樣從中間體VIb和IIg製備,隨後使用0-20% EtOAc/環己烷作為洗脫劑進行矽膠色譜法處理,得到中間體VIc(4.234g,68%)。1H NMR(300MHz,DMSO-d 6 )δ 9.32(s,1H),7.79(s,1H),7.61(d,J=8.6Hz,2H),7.50(d,J=9.9Hz,3H),7.16(d,J=7.7Hz,1H),6.93(d,J=7.6Hz,1H),4.40(s,2H),3.47(q,J=7.0Hz,2H),2.27(s,3H),1.14(t,J=7.0Hz,3H)。
在密封管中,向VIc(500mg,1.29mmol)於無水二(7mL)中的溶液中相繼添加2-咪唑啶酮(556mg,6.45mmol)、碳酸銫(1.052g,3.23
mmol)、Xantphos(75mg,0.13mmol)。將反應混合物用氮氣脫氣20分鐘,然後添加Pd2(dba)3(35mg,0.04mmol)。然後,將反應混合物在110℃下攪拌16小時。將冷卻的混合物用水稀釋並用EtOAc萃取兩次。將合併的有機物用水、飽和NaCl溶液洗滌,用MgSO4乾燥,過濾並蒸發。最終產物藉由矽膠色譜法使用10-50% EtOAc/環己烷作為洗脫劑進行純化,得到中間體006(260mg,52%)。1H NMR(500MHz,DMSO-d 6 )δ 9.16(s,1H),7.84(s,1H),7.63(d,J=8.9Hz,2H),7.52(d,J=8.8Hz,2H),7.28(s,1H),7.16(d,J=7.7Hz,1H),7.00(s,1H),6.93(d,J=7.6Hz,1H),4.42(s,2H),3.91-3.85(m,2H),3.48(q,J=7.0Hz,2H),3.45-3.38(m,2H),2.28(s,3H),1.15(t,J=7.0Hz,3H)。
A.7. 化合物007-064:
表1的化合物007-050根據上文所述的方法和一般合成程式來合成。
B. 藥理學實施例-抗腫瘤活性
B.1. 引言:
截至20世紀80年代中期,已在全球範圍內建立許多腫瘤細胞系,並且許多細胞系可從儲存庫,例如美國典型培養物保藏中心(American Type Culture Collection)獲得。在20世紀80年代後期,開發了”美國國家癌症研究所60種人腫瘤細胞系抗癌藥物篩選(US National Cancer Institute 60 human tumor cell line anticancer drug screen)”(NCI60)作為針對生長抑制活性篩選化合物的工具。NCI60由代表9種癌症類型的60種人腫瘤細胞系組成,一直是研究團體的化合物評估資源(Sharma等人,Nature Reviews,2010,10,241;Shoemaker,Nature Reviews,2006,6,813)。
這種高通量的基於細胞的分析方法對於幾種藥劑的發現至關重要,所述幾種藥劑後來被發現表現出治療活性。NCI60對目前的化學療法的最顯著貢獻或許是於2003年被FDA批准的蛋白酶體抑制劑硼替佐米(Bortezomib)的開發。
儘管這種方法用於評估藥物功效的生理學相關性和有用性仍然存在爭議,但大多數研究者同意,其仍然是用於鑒別和表徵可潛在地在癌症患者中產生臨床益處的藥劑的最好工具。
針對一組代表17種癌症類型的約34種人腫瘤細胞系對式(I)化合物進行測試,所述類型即白血病(由1種細胞系代表)、淋巴瘤(4種細胞系)、骨髓瘤(1種細胞系)、結腸直腸癌(2種細胞系)、頭頸癌(3種細胞系)、肺癌(3種細胞系)、黑色素瘤(2種細胞系)、胰腺癌(2種細胞系)、前列腺癌(2種細胞系)、卵巢癌(2種細胞系)、乳腺癌(2種細胞系)、腎癌(2種細胞系)、胃癌(2種細胞系)、肝癌(2種細胞系)、膠質母細胞瘤(2種細胞系)、骨肉瘤(1種細胞系)、尤因肉瘤(1種細胞系)。
B.2. 方法:
化合物的基於細胞的增殖篩選
對腫瘤細胞系進行基於細胞的CellTiter-Blue存活/增殖測定(Promega G8080)。將總共1 x 104個細胞/孔/50μL接種在96孔盤中。藉由添加0到10μM範圍的1/10系列稀釋的2倍藥物溶液開始處理。使細胞在37℃下生長48小時,然後在37℃下用10μl/孔的Promega CellTiter-Bleue試劑培育4小時。所形成的試鹵靈染料的量使用掃描多孔式分光光度計(OPTIMA,BMG labtech,France)藉由其在590nm下的螢光發射進行定量。沒有細胞的空
白孔用作分光光度計的背景對照。
所測試的細胞系的實例
A375、A4513、A498、A549、ACHN、AGS、BT20、BXPC3、CALU6、CLS354、DLD1、DU145、H1299、HCT116、HEP2、HEPG2、HGC27、HL60、HUT78、KARPAS299、MDAMB231、MELWO、MESSA、OPM2、PANC1、PC3、PLCPRF5、REC1、RL、SW579、TOV112D、U118、U2OS、U87MG。
B.3. 結果:
式(I)化合物的抗腫瘤活性
上表2中給出的IC50表示為:
+:IC50>1000nM
N.D.:未測定
上表3中給出的IC50表示為:
+:IC50>1000nM
N.D.:未測定
諸位發明人觀察到本發明的式(I)化合物種類對以上所列的細胞系的非常有效的抗增殖效果。表2和3中所列出的化合物充分代表式(I)化合物種類。
C. 不存在蛋白激酶抑制
進行體外激酶分析,以便證實本發明的化合物不存在蛋白激酶抑制。
DiscoveRx(Ambit Biosciences)開發了用於針對大量人類激酶(456種激酶)篩選化合物的高通量系統(KINOMEscanTM)。
在1μM的濃度下對本發明的化合物進行篩選,並且初步篩選結合相互作用的結果報告為對照的百分比(% Ctrl),其中較小的數字表
示較強的命中。DMSO用作陰性對照(100% Ctrl),而高親和性的化合物用作陽性對照(0% Ctrl)。%Ctrl計算如下:
選擇性得分或S得分是化合物選擇性的定量量度。它通過將化合物所結合的激酶的數目除以所測試的不同激酶的總數(不包括突變變體)來計算。S(10)=(%Ctrl<10的激酶的數目)/(所測試的激酶的數目),S(1)=(%Ctrl<1的激酶的數目)/(所測試的激酶的數目)。
作為實例,化合物003、006和033的S得分示於下表中。
本發明的化合物,尤其是如上文所示的化合物003、006和033不能有效地與所測試的456種激酶相互作用。剩餘的弱的激酶抑制活性不能解釋所觀察到的抗增殖作用,因為化合物沒有共同的激酶靶酶(化合物003和033),並且在無激酶抑制下仍表現出抗增殖活性(化合物006)。
Claims (15)
- 一種式(I)化合物或其藥學上可接受的鹽,
- 根據申請專利範圍第1項所述的化合物或其藥學上可接受的鹽,其 中X是CH並且A是2-側氧基咪唑啶基或吡唑基。
- 根據申請專利範圍第1項所述的化合物或其藥學上可接受的鹽,其係以下所示式(II)化合物或其藥學上可接受的鹽:
- 根據申請專利範圍第1項所述的化合物或其藥學上可接受的鹽,其 係以下所示式(III)化合物或其藥學上可接受的鹽:
- 根據申請專利範圍第1項所述的化合物或其藥學上可接受的鹽,其中R1是甲基,R2、R3和R5是氫並且R4是-CH2OC2H5。
- 根據申請專利範圍第1項所述的化合物或其藥學上可接受的鹽,其選自:(5-甲氧基-2-甲基-苯基)-[5-(6-吡唑-1-基-吡啶-3-基)-唑-2-基]-胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-噻唑-4-基]-苯基}-咪唑啶-2-酮; (5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基苯基)-[5-(6-吡唑-1-基-吡啶-3-基)-唑-2-基]-胺;1-{4-[5-(5-乙氧基甲基-(2-甲基-苯基胺基))-[1,3,4]二唑-2-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-[1,3,4]二唑-2-基]-胺;1-{4-[5-(5-乙氧基甲基-(2-甲基-苯基胺基))-[1,2,4]噻二唑-3-基]-苯基}-咪唑啶-2-酮;(5-甲氧基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;1-{4-[2-(5-甲氧基-2-甲基-苯基胺基)-噻唑-5-基]-苯基}-咪唑啶-2-酮;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-噻唑-5-基]-苯基}-咪唑啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[4-(4-吡唑-1-基-苯基)-噻唑-2-基]-胺;{4-甲基-3-[4-(4-吡唑-1-基-苯基)-噻唑-2-基胺基]-苯基}-甲醇;1-{4-[2-(3-乙氧基甲基-(5-甲基-苯基胺基))-噻唑-4-基]-苯基}-咪唑啶-2-酮;1-{4-[2-(3-乙氧基甲基-(5-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;(3-乙氧基甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(3-乙氧基甲基-5-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺; (3,5-雙-(乙氧基甲基)-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(5-甲氧基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;[5-(2-胺基-乙氧基甲基)-2-甲基-苯基]-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;2-{4-甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苄氧基}-乙醇;{4-甲基-3-[5-(4-吡唑-1-基-苯基)-唑-2-基胺基]-苯基}-甲醇;[5-(2-二甲基胺基-乙氧基)-2-甲基-苯基]-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,4]三唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,3]三唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-[1,2,3]三唑-2-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-咪唑-1-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-噻唑-2-基-苯基)-唑-2-基]-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(3-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(4-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(5-甲基-吡唑-1-基)-苯基]-唑-2-基}-胺;(5-乙氧基甲基-2-甲基-苯基)-{5-[4-(3-甲氧基-吡唑-1-基)-苯基]-唑-2-基}-胺; 2-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-2,4-二氫-[1,2,4]三唑-3-酮;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-3-甲基-咪唑啶-2-酮;1-(2-胺基-乙基)-3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-咪唑啶-2-酮;N-[2-(3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-2-側氧基-咪唑啶-1-基)-乙基]-乙醯胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-吡咯啶-2-酮;(5-乙氧基甲基-2-甲基-苯基)-[5-(4-吡啶-2-基-苯基)-唑-2-基]-胺;1-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-1H-吡啶-2-酮;3-{4-[2-(5-乙氧基甲基-(2-甲基-苯基胺基))-唑-5-基]-苯基}-1H-吡啶-2-酮;(R)-1-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-5-甲基咪唑啶-2-酮;4-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-5-甲基-2,4-二氫-3H-1,2,4-三唑-3-酮;1-(4-(2-((3,5-雙(乙氧基甲基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮;1-(4-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)苯基)-3-(2-甲氧基乙基)咪唑啶-2-酮; 1-(5-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)吡啶-2-基)咪唑啶-2-酮;1-(4-(2-((3-(乙氧基甲基)-5-(2-甲氧基乙氧基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮;5-(4-(1H-吡唑-5-基)苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)唑-2-胺;(R)-1-(5-(2-((5-(乙氧基甲基)-2-甲基苯基)胺基)唑-5-基)吡啶-2-基)-5-甲基咪唑啶-2-酮;1-(4-(2-((3-(乙氧基甲基)-5-(2-羥基乙氧基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮;5-(4-(1H-吡唑-4-基)苯基)-N-(5-(乙氧基甲基)-2-甲基苯基)唑-2-胺;N-(5-(乙氧基甲基)-2-甲基苯基)-5-(4-(1-甲基-1H-吡唑-5-基)苯基)唑-2-胺;4-(6-(1H-吡唑-1-基)吡啶-3-基)-N-(5-(乙氧基甲基)-2-甲基苯基)噻唑-2-胺;1-(4-(2-((3-(乙氧基甲基)苯基)胺基)唑-5-基)苯基)咪唑啶-2-酮;以及1-(4-(2-((3-(乙氧基甲基)苯基)胺基)噻唑-4-基)苯基)咪唑啶-2-酮。
- 一種藥物組合物,其包含根據申請專利範圍第1項至第6項中任一項所述的化合物以及至少一種藥學上可接受的賦形劑和/或載體。
- 根據申請專利範圍第7項所述的藥物組合物,其包含根據申請專利範圍第1項至第6項中任一項所述的化合物作為唯一活性藥物成分。
- 根據申請專利範圍第7項所述的藥物組合物,其進一步包含另一種活性藥劑。
- 一種醫藥品,其包含根據申請專利範圍第1項至第6項中任一項所 述的化合物。
- 一種根據申請專利範圍第1項至第6項中任一項所述的化合物於製備用於治療血液病症和/或增殖性病症之醫藥品之用途。
- 根據申請專利範圍第11項所述的用途,其中所述血液病症選自淋巴瘤;白血病;多發性骨髓瘤(MM);骨髓增生異常綜合征(MDS);以及骨髓增生異常伴骨髓纖維化。
- 根據申請專利範圍第12項所述的用途,其中,所述白血病是選自急性骨髓性白血病(AML)、急性淋巴母細胞性白血病(ALL)、慢性淋巴性白血病(CLL)或慢性骨髓性白血病(CML)。
- 根據申請專利範圍第11項所述的用途,其中所述增殖性病症是癌症。
- 根據申請專利範圍第14項所述的用途,其中所述癌症是選自頭頸癌、黑色素瘤、腎癌、胃癌、肝癌、結腸直腸癌、胰腺癌、肺癌、神經元癌、多形性膠質母細胞瘤、骨肉瘤、尤因肉瘤(Ewing sarcoma)、乳腺癌、卵巢癌及前列腺癌。
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Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018106643A1 (en) * | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
CN109467531A (zh) * | 2017-09-08 | 2019-03-15 | 沈阳科创化学品有限公司 | 一种取代吡啶二羧酸衍生物的制备方法 |
CN112225733B (zh) * | 2020-11-25 | 2022-12-09 | 湖南科技大学 | 一种含1,3,4-噻二唑吡啶-2-酮衍生物的制备方法和作为抗癌药物的应用 |
Family Cites Families (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US810665A (en) * | 1905-10-10 | 1906-01-23 | Joseph Mlada | Mold for butter. |
US1346834A (en) * | 1918-08-17 | 1920-07-20 | Charles E Mcmanus | Resilient rod |
US3740420A (en) | 1967-11-28 | 1973-06-19 | Crown Zellerbach Corp | Pharmaceutical compositions with dimethyl sulfoxide |
US3743727A (en) | 1970-11-16 | 1973-07-03 | Crown Zellerbach Corp | Enhancing tissue penetration of certain antimicrobial agents with dimethyl sulfoxide |
US4405616A (en) | 1975-06-19 | 1983-09-20 | Nelson Research & Development Company | Penetration enhancers for transdermal drug delivery of systemic agents |
US3989816A (en) | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
CA1163561A (en) | 1979-11-06 | 1984-03-13 | Cyril Boroda | Preparation containing nitroglycerine and optionally other medicaments and preparation thereof |
US4460372A (en) | 1981-02-17 | 1984-07-17 | Alza Corporation | Percutaneous absorption enhancer dispenser for use in coadministering drug and percutaneous absorption enhancer |
US4379454A (en) | 1981-02-17 | 1983-04-12 | Alza Corporation | Dosage for coadministering drug and percutaneous absorption enhancer |
US4411893A (en) | 1981-08-14 | 1983-10-25 | Minnesota Mining And Manufacturing Company | Topical medicament preparations |
CA1236029A (en) | 1984-05-14 | 1988-05-03 | Edmund Sandborn | Pharmaceutical solutions comprising dimethyl sulfoxide |
US4615699A (en) | 1985-05-03 | 1986-10-07 | Alza Corporation | Transdermal delivery system for delivering nitroglycerin at high transdermal fluxes |
DE3815221C2 (de) | 1988-05-04 | 1995-06-29 | Gradinger F Hermes Pharma | Verwendung einer Retinol- und/oder Retinsäureester enthaltenden pharmazeutischen Zubereitung zur Inhalation zur Einwirkung auf die Schleimhäute des Tracheo-Bronchialtraktes einschließlich der Lungenalveolen |
GB9622363D0 (en) | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
US5906202A (en) | 1996-11-21 | 1999-05-25 | Aradigm Corporation | Device and method for directing aerosolized mist to a specific area of the respiratory tract |
US6448272B1 (en) * | 1998-12-07 | 2002-09-10 | Smithkline Beecham Corporation | Myt1 kinase inhibitors |
JP4216947B2 (ja) * | 1999-05-18 | 2009-01-28 | 三井化学株式会社 | アミン化合物 |
CN100491374C (zh) * | 2002-08-02 | 2009-05-27 | Ab科学公司 | 2-(3-氨基芳基)氨基-4-芳基-噻唑及其作为c-kit抑制剂的应用 |
US8450302B2 (en) * | 2002-08-02 | 2013-05-28 | Ab Science | 2-(3-aminoaryl) amino-4-aryl-thiazoles and their use as c-kit inhibitors |
CA2525547C (en) * | 2003-05-14 | 2012-07-03 | Torreypines Therapeutics, Inc. | Compounds and uses thereof in modulating amyloid beta |
EP1684750B1 (en) * | 2003-10-23 | 2010-04-28 | AB Science | 2-aminoaryloxazole compounds as tyrosine kinase inhibitors |
US20090196912A1 (en) * | 2004-07-30 | 2009-08-06 | Gpc Botech Ag | Pyridinylamines |
CA2578122A1 (en) | 2004-08-27 | 2006-03-02 | Gpc Biotech Ag | Pyrimidine derivatives |
WO2006106437A2 (en) * | 2005-04-04 | 2006-10-12 | Ab Science | Substituted oxazole derivatives and their use as tyrosine kinase inhibitors |
US8088806B2 (en) * | 2005-05-09 | 2012-01-03 | Achillion Pharmaceuticals, Inc. | Thiazole compounds and methods of use |
JP5214096B2 (ja) * | 2005-06-17 | 2013-06-19 | 富士フイルムファインケミカルズ株式会社 | 新規なビピリジン誘導体 |
US20080207572A1 (en) * | 2005-07-14 | 2008-08-28 | Ab Science | Use of Dual C-Kit/Fgfr3 Inhibitors for Treating Multiple Myeloma |
CA2617394C (en) * | 2005-09-13 | 2014-06-03 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
GB0524436D0 (en) * | 2005-11-30 | 2006-01-11 | Novartis Ag | Organic compounds |
ES2375576T3 (es) * | 2006-03-31 | 2012-03-02 | Novartis Ag | Derivados del �?cido (4-(4-[6-(trifluorometil-piridin-3-ilamino)-heteroarilo con contenido de n]-fenil)-ciclohexil)-acético y sus usos farmacéuticos. |
JO3019B1 (ar) * | 2006-04-19 | 2016-09-05 | Janssen Pharmaceutica Nv | ثلاثي مستبدل 4،2،1-ثلاثي زولات |
WO2007131953A1 (en) | 2006-05-12 | 2007-11-22 | Ab Science | A new process for the synthesis of 2-aminoxazole compounds |
FR2901273B1 (fr) * | 2006-05-19 | 2010-12-24 | Anaconda Pharma | Inhibiteurs du virus du papillome humain et les compositions pharmaceutiques les contenant |
MX2009007302A (es) * | 2007-01-23 | 2009-07-15 | Palau Pharma Sa | Derivados de purina. |
MX2009008921A (es) * | 2007-02-22 | 2009-08-28 | Irm Llc | Derivados de tiazole en la forma de moduladores de receptores acoplados por proteina g. |
GB0709031D0 (en) * | 2007-05-10 | 2007-06-20 | Sareum Ltd | Pharmaceutical compounds |
CA2730010A1 (en) * | 2008-07-09 | 2010-01-14 | Merck Sharp & Dohme Corp. | Inhibitors of janus kinases |
JP2012180281A (ja) * | 2009-06-29 | 2012-09-20 | Dainippon Sumitomo Pharma Co Ltd | 新規オキサジアゾール誘導体 |
WO2011006903A1 (en) * | 2009-07-15 | 2011-01-20 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Substituted triazole and imidazole derivatives as gamma secretase modulators |
EP2499282B1 (en) * | 2009-11-09 | 2015-04-22 | NeuroGenetic Pharmaceuticals, Inc. | Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor |
ES2539170T3 (es) * | 2010-01-12 | 2015-06-26 | Ab Science | Inhibidores de quinasas de oxazol |
GB201012105D0 (en) | 2010-07-19 | 2010-09-01 | Domainex Ltd | Novel pyrimidine compounds |
EP2616443A1 (en) * | 2010-09-14 | 2013-07-24 | Exelixis, Inc. | Phtalazine derivatives as jak1 inhibitors |
US20120129843A1 (en) * | 2010-11-18 | 2012-05-24 | Yan Zhang | Pyridyl-thiazolyl inhibitors of pro-matrix metalloproteinase activation |
US20120302569A1 (en) * | 2011-05-25 | 2012-11-29 | Paul Francis Jackson | Phenyl-thiazolyl inhibitors of pro-matrix metalloproteinase activation |
EP2714667B1 (en) * | 2011-05-27 | 2020-11-25 | Laxman S. DESAI | Aminooxazole inhibitors of cyclin dependent kinases |
EP2736904B1 (en) * | 2011-07-27 | 2016-03-16 | AB Science | Oxazole and thiazole derivatives as selective protein kinase inhibitors (c-kit) |
KR101896035B1 (ko) * | 2011-08-23 | 2018-09-07 | 덕산네오룩스 주식회사 | 유기전기소자용 신규 화합물, 이를 이용하는 유기전기소자 및 그 단말 |
CN103436048B (zh) * | 2013-08-08 | 2014-12-03 | 陕西师范大学 | 硫脲供体双桥链有机染料及其应用 |
US20150045353A1 (en) * | 2013-08-09 | 2015-02-12 | Neurogenetic Pharmaceuticals, Inc. | Formulations containing gamma secretase modulators, methods for preparation and delivery thereof |
RU2016139031A (ru) * | 2014-03-24 | 2018-04-25 | Аб Сьянс | Производные оксазола, замещенные диазаспироалкалоном, в качестве ингибиторов тирозинкиназы селезенки |
EP3144307A1 (en) * | 2015-09-18 | 2017-03-22 | AB Science | Novel oxazole derivatives that inhibit syk |
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