TWI640311B - 芳基喹啉衍生物作爲血管生成擬態抑制劑之新穎用途 - Google Patents
芳基喹啉衍生物作爲血管生成擬態抑制劑之新穎用途 Download PDFInfo
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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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Abstract
本發明揭示出一種芳基喹啉衍生物,其係使用在需要其之對象中來抑制血管生成擬態、治療特徵為異常的血管形態或功能及/或存在有血管生成擬態之疾病。在本發明的一個具體實例中,該化合物係使用來治療轉移性腫瘤、過度增生性或血管生成性疾病。在本發明的另一個具體實例中,該化合物之使用可結合使用額外的治療藥物,諸如抗癌劑、抗發炎藥、抗增殖劑、抗荷爾蒙劑或其任何組合。
Description
本發明係關於一種芳基喹啉衍生物的新穎用途;及更特別關於一種使用來抑制血管生成擬態及治療與迷管形態及功能相關及/或特徵為存在有血管生成擬態之疾病或症狀的芳基喹啉衍生物。
用語”血管生成擬態”描述為由高度侵入性及基因失調的腫瘤細胞形成流體輸導管道。已經描述出二種特殊的血管生成擬態型式。管狀型式的血管生成擬態可在形態學上與內襯內皮細胞的血管混淆。圖案狀基質型式的血管生成擬態在形態學或拓撲學上決不與血管類似。已經在這些圖案中鑑別出基質蛋白質,諸如板素、硫酸乙醯肝素(heparan sulfate)蛋白糖及膠原蛋白IV及VI。該圖案狀基質與血管交織。
已經在下列中鑑別出該圖案狀基質型式的血管生成擬態:葡萄膜、皮膚及黏液薄膜黑色瘤、炎性及導管型乳腺癌(ductal breast carcinoma)、卵巢及攝護腺癌、肺癌、腎
癌、肝細胞癌、間皮性肉瘤、膀胱癌、骨肉瘤、星細胞瘤、嗜鉻細胞瘤、結腸直腸癌、神經管胚細胞瘤、腺癌、食道基質瘤、妊娠性絨毛膜癌、膽囊癌、胃腸癌、喉癌、滑膜肉瘤(synoviosarcoma)、神經膠母細胞瘤、白血病及軟組織肉瘤,包括滑膜肉瘤、橫紋肌肉瘤、骨肉瘤、尤恩氏(Ewing)肉瘤及嗜鉻細胞瘤。
證據顯示出血管生成擬態在下列之侵襲性轉移中扮演一定角色:喉鱗狀細胞癌、肝細胞癌、腎細胞癌、乳房癌、卵巢癌、原發性膽囊癌、惡性食道基質癌、肝細胞癌、間皮性肉瘤及齒槽橫紋肌肉瘤。具有黑色素瘤顯示出VM的個體具有差的預後及較高的癌復發風險。可使用VM抑制劑來阻擋轉移或減慢腫瘤生長。因此,已經假定VM形成的拮抗劑可在抑制腫瘤生長及高度侵襲性轉移上具有有益的效應。
WO 2012/009519揭示出芳基及雜芳基喹啉衍生物之合成及抗癌活性。
在一個態樣中,本發明係關於如下式I、II、III或IV的化合物或其醫藥上可接受的鹽,其係使用在需要其之對象中抑制血管生成擬態:
其中R2’、R3’、R4’、R5’及R6’各自獨立地係H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、或(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;其中n係0-4的整數;Y係O或S;X係F、Cl或Br;及R8及R9各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y係如上述定義及m係0-4的整數;R2、R3、R4及R5各自獨立地係H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、(CH2)nN;或R4與R5一起係-Y(CH2)nY-;或R3與R4一起係-Y(CH2)nY-,其中n、Y、X、R8及R9係如上述定義;或R3係O-苄基;及R1及R1’各自獨立地係H、Li+、Na+、K+、Ca++、Mg++、
N+R8R9R10R11或苄基,其中R10及R11各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9係如上述定義。
在本發明的一個具體實例中,R2’、R3’、R4’、R5’及R6’全部係H;或R2’、R3’、R4’、R5’及R6’之一係F、OCH3或(CH2)nNR8R9,及其它係H,其中n、R8及R9係如上述定義。
在本發明的另一個具體實例中,R2、R3、R4及R5全部係H;或R2、R3、R4及R5之一係F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,及其它係H;或R2及R5係H,及R3與R4一起係-O(CH2)nO-,其中n、Y、R8及R9係如上述定義。
在本發明的另一個具體實例中,R1及R1’係H、Na+及/或K+。
在本發明的另一個具體實例中,R2及R5係H,及R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R5’全部係H,及R6’係F。
在本發明的另一個具體實例中,R2及R5係H,及R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R6’全部係H,及R5’係F。
在本發明的另一個具體實例中,R2、R3、R4及R5全部係H;及R2’、R3’、R4’、R5’及R6’全部係H。
在本發明的另一個具體實例中,R4係OCH3,及R2、R3及R5係H;及R5’係F,及R2’、R3’、R4’及R6’係H。
在本發明的另一個具體實例中,R2及R5係H,及R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R6’全部係
H,及R5’係OCH3。
在本發明的另一個具體實例中,該化合物係至少一種選自於由編號38、43、52、147、A6、B1、B3、C4及C6所組成之群的化合物。
在本發明的另一個具體實例中,該對象罹患特徵為異常的血管形態或功能及/或存在有血管生成擬態之疾病。
進一步在本發明的另一個具體實例中,該疾病係至少一種選自於由轉移性腫瘤、過度增生疾病、炎性疾病及眼科疾病所組成之群。
該轉移性腫瘤可係選自於由下列所組成之群的至少一種:黑色素瘤、卵巢癌、前列腺癌、腎細胞癌、尤恩氏肉瘤、乳房癌、神經內分泌系癌、甲狀腺癌、喉鱗狀細胞癌、肝細胞癌、葡萄膜黑色素瘤、皮膚黑色素瘤、口腔惡性黑色素瘤、絨毛膜癌、原發性膽囊癌、惡性食道基質癌、間皮性肉瘤、齒槽橫紋肌肉瘤、膀胱癌、骨肉瘤、星細胞瘤、嗜鉻細胞瘤、結腸直腸癌、神經管胚細胞瘤、腺癌、食道基質瘤、喉癌、白血病、滑膜肉瘤、神經膠母細胞瘤及胃腸癌。
該增生過度疾病可係至少一種選自於由下列所組成之群的疾病:牛皮癬性關節炎、類風濕性關節炎、狼瘡、反應性關節炎、索格倫氏(Sjogren’s)病、炎性腸病、皮肌炎、關節強硬性脊椎炎、幼年型類風濕性關節炎、痛風、炎性骨關節炎、假性痛風、類澱粉變性病、角質變性及角化病、糖尿病性視網膜病、子宮內膜異位、黃斑變性病、瘢瘤、疣、硬化、慢性炎性相關病症、增殖性玻璃體視網膜病變、早產
兒視網膜病、肉芽腫病、與器官或組織移殖相關的免疫過度增生、良性前列腺肥大及免疫增生疾病或病症。
該炎性疾病可係選自於由下列所組成之群的至少一種:尋常性痤瘡、阿茲海默氏(Alzheimer’s)症、關節炎、氣喘、動脈粥瘤硬化、自體免疫病、乳糜瀉、慢性前列腺炎、結腸炎、克隆氏(Crohn’s)病、皮膚炎、憩室炎、腎絲球腎炎、肝炎、發炎性腸道疾病、間質性膀胱炎、刺激性腸症候群、紅斑性狼瘡、腎炎、帕金森氏(Parkinson’s)病、骨盆腔發炎性疾病、類風濕性關節炎、肉狀瘤病、移植排斥、潰瘍性結腸炎及血管炎。
該眼科疾病可係選自於由下列所組成之群的至少一種:老年性黃斑部變性(AMD)、增生性糖尿病性視網膜病(PDR)、糖尿病性黃斑部水腫(DME)、中心性視網膜靜脈阻塞(CRVO)、新生血管性青光眼、角膜新生血管形成(沙眼)及翼狀胬肉。
在另一個態樣中,本發明係關於如下式Ia或Ib之化合物或其醫藥可接受的鹽,其係使用在需要其之對象中來抑制、減低及/或減輕血管生成擬態:
其中R2’、R3’、R4’、R5’、R6’各自獨立地係H、F、Cl、Br、(CH2)nCH3、
(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及其中R8及R9各自獨立地係H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各者係0至4的整數;R2、R3、R4及R5各自獨立地係H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9,(CH2)nNR8R9、(CH2)nN;或R4與R5一起為-O(CH2)nO-、或-S(CH2)nS-;或R3與R4一起係-O(CH2)nO-、或-S(CH2)nS-,其中n、R8及R9係如上述定義;或R3係O-苄基;或R5係OP=OOR1OR1’,及R1及R1’各自獨立地係H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9係如上述定義。
進一步在另一個態樣中,本發明係關於如下式(X)之化合物或其醫藥可接受的鹽,其係使用在需要其之對象中來抑制、減低及/或減輕血管生成擬態:
其中W係選自於由下列所組成之群的芳香基團:萘基、喹啉、
苯并呋喃基、苯并噻吩、蒽及式(Y)之經取代的苯:
及其中:R2’、R3’、R4’、R5’、R6’各自獨立地係H、F、Cl、Br、(CH2)nCH3、(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及其中R8及R9各自獨立地係H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各者係0至4的整數;R2、R3、R4及R5各自獨立地係H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9、(CH2)nN、(CH2)nNR8R9;R4與R5一起係-O(CH2)nO-、或-S(CH2)nS-;或R3與R4一起係-O(CH2)nO-、-S(CH2)nS-,其中n、R8及R9係如上述定義;或R3係O-苄基;或R5係OP=OOR1OR1’,及R1及R1’各自獨立地係H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9係如上述定義。
在本發明的一個具體實例中,所使用的化合物係至少一
種選自於由下列所組成之群的化合物:編號16-24、37-45、48-53、124-143、143a、143b、144、144a、144b、146-147、152-153、157-158、166-169及CHM-2133,如在表4中列出般。
再者,本發明係關於如上述定義的式I、II、III或IV、或式Ia或Ib、或式(X)之化合物或其醫藥上可接受的鹽的用途,其係使用來製造一用以在需要其之對象中抑制血管生成擬態的藥劑。
本發明亦關於一種用以抑制血管生成擬態的方法,其包括將一治療有效量之如上述定義的式I、II、III或IV、或式Ia或Ib、或式(X)之化合物給藥至需要其的對象。
如上述定義的式I、II、III或IV、或式Ia或Ib、或式(X)之化合物的使用可結合使用額外的治療藥物,其中該額外治療藥物係選自於由下列所組成之群的至少一種:抗癌劑、抗發炎藥、抗增殖劑、抗荷爾蒙劑及其任何組合。
將從下列較佳具體實例的說明且採用下列相關連的圖形明瞭這些及其它態樣,然而可在其中產生變化及修改而沒有離開本揭示的新穎概念之精神及範圍。伴隨的圖形闡明本發明之一或多個具體實例及與書面說明一起提供以解釋本發明之原理。只要有可能,遍及該圖形使用相同參考數字來指出具體實例之相同或類似元素。
圖1顯示出顯微照片,其闡明藉由TRX-818抑制在C8161侵襲性黑色素瘤細胞中之VM網絡形成。
圖2顯示出顯微照片,其闡明藉由TRX-818於濃度5至10nM下抑制在SK-MEL28癌細胞中之VM網絡形成。
圖3為典型的二進制影像,其闡明不同濃度的TRX-818在媒劑組中於細胞接合及小管長度之形成上的效應。
圖4顯示出顯微照片,其闡明藉由TRX-818M1抑制在C8161侵襲性黑色素瘤細胞中之VM網絡形成。
圖5顯示出顯微照片,其闡明藉由CHM2133抑制在C8161侵襲性黑色素瘤細胞中之VM網絡形成。
圖6A-D顯示出TRX-818在Notch 4 ICD、Nodal、CDH5及Eph A2之表現性上的效應。
圖7為相片,其闡明TRX-818在Pro-Nodal之蛋白質表現性上的效應。
圖8為相片,其闡明TRX-818在Smad之蛋白質表現性及磷酸化程度上的效應。
圖9顯示出在HCT-116結腸癌正位異種移植模型中,於腫瘤接種後第43天時,TRX-818在腫瘤體積上之效應。a:在50毫克/公斤QD組中,於研究終止前發現一隻動物死亡,及藉由β-分佈離群值分析偵測,一個資料點係離群值。b:在20毫克/公斤QOD組中,於研究終止前發現二隻動物死亡。c:在依立替康(irinotecan)50 Q4D組中,藉由β-分佈離群值分析偵測,一個資料點係離群值。對媒劑來說,*p<0.05;對媒劑來說,**p<0.01。
圖10顯示出在HCT-116結腸癌正位異種移植模型中,TRX-818於VM管道數目上之效應。對媒劑組來說,*p<0.05。圖11顯示出顯微照片,其闡明TRX-818結構類似化合物在侵襲性黑色素瘤細胞中於VM網絡形成上之效應。
本發明更特別以下列意欲僅作為闡明的實施例說明,因為將由熟習該項技術者明瞭許多在其中之修改及變化。現在,詳細地描述出本發明的多個具體實例。參照圖形,類似的數字遍及該等圖形指示出類似的組分。如在本文之描述中及遍及下列請求項所使用,除非上下文有明確指出,否則”一”、”一種”及”該”之意義包括複數個參考。同樣地,如在本文之描述中及遍及下列請求項所使用,除非上下文明確指出,否則”在...內”之意義包括”在...內”及”在...上”。再者,為了讀者方便,可在本專利說明書中使用標題或子標題,其應該在本發明之範圍上不具有影響。額外的是,下列更特別定義出在此專利說明書中所使用的某些用語。
在此專利說明書中,於本發明之上下文內所使用之用語及在每個用語所使用的特定上下文中,其通常具有其在技藝中的普通意義。使用來描述本發明的某些用語係在下列或在專利說明書別處中討論,以對從事者提供關於發明說
明之額外指導。將察知可以多於一種方式訴說相同事情。因此,可對本文所討論之任何一或多個用語使用另一種文字及同義字或強調任何特別意義,不論該用語是否於本文中闡述或討論。提供某些用語的同義字。在本專利說明書中的任何地方所使用之實施例,包括於本文中所討論的任何用語之實施例僅作為例證,及決不限制本發明或任何例示的用語之範圍及意義。同樣地,本發明不限於在此專利說明書中所提供的多個具體實例。
用語”血管生成擬態”描述由高度侵入性及基因失調的腫瘤細胞形成流體輸導管道。用語”轉移性腫瘤”指為已從源始位置蔓延至身體的其它部分之癌,包括血管及血管溝(vascular channels)的異常形成。不限於此,在本發明中的轉移性腫瘤包括涉及富血管性轉移(hypervascular metastasis)之腫瘤,例如,黑色素瘤、卵巢癌、前列腺癌、腎細胞癌、尤恩氏肉瘤、乳房癌、神經內分泌系癌、甲狀腺癌、喉鱗狀細胞癌、肝細胞癌、葡萄膜黑色素瘤、皮膚黑色素瘤、口腔惡性黑色素瘤、絨毛膜癌、原發性膽囊癌、惡性食道基質癌、間皮性肉瘤、齒槽橫紋肌肉瘤、膀胱癌、骨肉瘤、星細胞瘤、嗜鉻細胞瘤、結腸直腸癌、神經管胚細胞瘤、腺癌、食道基質瘤、喉癌、白血病、滑膜肉瘤、神經膠母細胞瘤及胃腸癌。
用語”增生過度疾病”指為細胞增生比正常組織生長更快速的任何疾病或病症。過度增生細胞係一種比正常細胞更快速增生的細胞。
用語”炎性疾病”指為特徵為炎性異常的症狀,及
包括尋常性痤瘡、阿茲海默氏病、關節炎、氣喘、動脈粥瘤硬化、自體免疫病、乳糜瀉、慢性前列腺炎、結腸炎、克隆氏病、皮膚炎、憩室炎、腎絲球腎炎、肝炎、發炎性腸道疾病、間質性膀胱炎、刺激性腸症候群、紅斑性狼瘡、腎炎、帕金森氏病、骨盆腔發炎性疾病、類風濕性關節炎、肉狀瘤病、移植排斥、潰瘍性結腸炎及血管炎,但不限於此。
如於本文中使用,用語”眼科疾病”包括老年性黃斑部變性(AMD)、增生性糖尿病性視網膜病(PDR)、糖尿病性黃斑部水腫(DME)、中心性視網膜靜脈阻塞(CRVO)、新生血管性青光眼、角膜新生血管形成(沙眼)及翼狀胬肉,但不限於此。
當於本文中使用時,”抗血管生成劑”指為一種試管內或活體內抑制血管生成、阻擋血管生長或破壞/移除血管生成的脈管之化合物或組成物。該抗血管生成劑的實施例包括VEGF/VEGFR、PDGF/PDEGFR抑制劑、類固醇、激酶抑制劑、沙利竇邁艾妥可那唑(itraconazole)羧基醯胺三唑、TNP-470 CM101、IFN-α、IL-12、血小板因子-4、蘇拉明、SU5416、凝血酶致敏蛋白(thrombospondin)、軟骨取得的血管生成抑制因子、母質金屬蛋白酶抑制劑、安吉歐史達丁(angiostatin)、英多史達丁(endostatin)、2-甲氧基雌二醇(methoxyestradiol)、替可加蘭(tecogalan)、四硫鉬酸鹽、凝血酶致敏蛋白、催乳激素、αvβ3抑制劑、三羧胺基喹啉(linomide)、他喹莫德(tasquinimod)。
用語”化學療劑”及”抗癌劑”可互換。”抗癌劑”指
為抑制癌細胞生長或造成癌細胞死亡的試劑。該化學療劑之實施例包括烷基化試劑,諸如噻替派(thiotepa)及環磷醯胺(cyclosphosphamide);磺酸烷酯,諸如二甲磺酸丁酯(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);吖類,諸如苯佐替哌(benzodopa)、卡波醌、美妥替哌(meturedopa)及烏瑞替哌(uredopa);伸乙基亞胺類(ethylenimines)及甲基蜜胺類(methylamelamines),包括六甲蜜胺(altreamine)、三伸乙基蜜胺、三伸乙基磷醯胺(trietylenephosphoramide)、三伸乙基硫代磷醯胺(triethylenethiophosphaoramide)及三羥甲基蜜胺(trimethylolomelamine);氮芥類諸,如苯丁酸氮芥、萘氮芥、氯磷醯胺(cholophosphamide)、雌二醇氮芥、異環磷酸胺、甲氮芥、氧化甲氮芥鹽酸、苯丙胺酸氮芥、新氮芥(novembichin)、膽固醇苯乙酸氮芥(phenesterine)、松龍苯芥(prednimustine)、氯乙環磷醯胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲類(nitrosureas),諸如卡莫司汀(carmustine)、吡葡亞硝脲(chlorozotocin)、福塔氮芥(fotemustine)、環己亞硝脲、尼氮芥、雷尼氮芥(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysins)、放線菌素、氨茴黴素(authramycin)、氮絲胺酸、博萊黴素、放線菌素C、卡奇黴素(calicheamicin)、卡拉比星(carabicin)、洋紅黴素(carminomycin)、嗜癌素(carzinophilin)、色黴素、更生黴素(dactinomycin)、柔毛黴素、地托比星(detorubicin)、6-重氮-5-側氧-L-正白胺酸、阿黴素(doxorubicin)、表阿黴素
(epirubicin)、依索比星(esorubicin)、去甲氧柔紅黴素(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素、派來黴素(peplomycin)、甲基絲裂黴素(potfiromycin)、嘌呤黴素、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黴黑素、鏈黴亞硝基素、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、新製癌菌素、佐柔比星(zorubicin);抗代謝物,諸如胺基甲基葉酸及5-氟尿嘧啶(5-FU);葉酸類似物,諸如二甲葉酸(denopterin)、胺基甲基葉酸、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉賓(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤;嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-硫唑脲嘧啶、卡莫氟(carmofur)、阿糖胞苷、二脫氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、5-氟脫氧尿苷;雄性激素,諸如二甲睪酮(calusterone)、屈他雄酮(dromostanolone)丙酸鹽、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪丸內脂(testolactone);抗腎上腺,諸如胺基苯乙哌啶酮、氯苯二氯乙烷、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺(aldophosphamide)醣苷;胺乙醯丙酸;安吖啶(amsacrine);貝斯曲布昔(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);得福安(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾福敏(elformithine);依利醋銨(elliptinium acetate);乙環氧啶(etoglucid);硝酸鎵;羥基脲;
香菇糖;氯尼達明(lonidamine);丙脒腙(mitoguazone);米托山聰(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴脫史達丁(pentostatin);蛋胺氮芥(phenamet);吡喃阿黴素(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;普魯卞肼;PSK.RTM.;雷佐生(razoxane);西佐糖(sizofiran);螺旋鍺;細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2’,2”-三氯三乙基胺;烏拉坦(urethan);長春地辛;達卡巴仁(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇;二溴矛醇(mitolactol);哌泊溴烷(pipobroman);加胞苷(gacytosine);阿拉伯糖苷(”Ara-C”);環磷醯胺;噻替派(thiotepa);紫杉醇類(taxanes),例如,太平洋紫杉醇(paclitaxel)及歐洲紫杉醇(docetaxel);苯丁酸氮芥;吉西他賓(gemcitabine);6-硫鳥嘌呤;巰基嘌呤;胺基甲基葉酸;鉑類似物,諸如順氯氨鉑及卡鉑(carboplatin);長春鹼;鉑;鬼臼乙叉(VP-16);異環磷酸胺;絲裂黴素C;米托山聰(mitoxantrone);長春新鹼;長春瑞賓(vinorelbine);溫諾平(navelbine);諾凡酮(novantrone);鬼臼噻吩;柔毛黴素(daunomycin);胺蝶呤;截瘤達(xeloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);視黃酸;埃斯波黴素(esperamicins);卡培他濱(capecitabine);及上述任何之醫藥可接受的鹽、酸或衍生物。在此定義中亦包括抗荷爾蒙劑,其作用以調節或抑制荷爾蒙在腫瘤上的作用,諸如抗雌激素,包括例如泰莫西芬(tamoxifen)、拉樂西芬(raloxifene)、抑制4(5)-咪唑類的芳香
環轉化酶(aromatase)、4-羥基他莫昔芬(hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY 117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(弗瑞斯(Fareston));及抗雄性激素,諸如氟硝丁醯胺、尼魯米特(niluamide)、比卡魯胺(bicalutamide)、柳菩林(leuprolide)及夠蛇林(goserelin);及上述任何之醫藥可接受的鹽、酸或衍生物。
用語”芳基”指為6至20個碳原子具有單環(例如,苯基)或多重稠和(并合)環之不飽和芳香族碳環基團,其中至少一個環係芳香族(例如,萘基、二氫菲基、茀基或蒽基)。較佳的芳基包括苯基、萘基及其類似基團。該芳基可選擇性係二價基團,因此提供伸芳基。
該芳基可選擇性以一或多個下列基團取代:烷基、烯基、烷氧基、鹵基、鹵烷基、羥基、羥烷基、芳基、雜芳基、雜環、環烷基、烷醯基、烷氧基羰基、胺基、亞胺基、烷基胺基、醯基胺基、硝基、三氟甲基、三氟甲氧基、羧基、羧基烷基、酮基、噻基、烷硫基、烷基亞碸基、烷基碸基、氰基、乙醯胺基、乙醯氧基、乙醯基、苯醯胺基、苯亞碸基、苯磺醯胺基、苯磺醯基、苯磺醯基胺基、苄醯基、苄醯基胺基、苄醯氧基、苄基、苄氧基、苄氧基羰基、苄硫基、胺甲醯基、胺基甲酸酯、異氰酸基、胺磺醯基、胺亞磺醯基、亞磺酸基、磺基、磺基胺基、硫磺基、NR<x>R<y>及/或COOR<x>,其中每個R<x>及R<y>各自獨立地係H、烷基、烯基、芳基、雜芳基、雜環、環烷基或羥基。
用語化合物的”衍生物或類似物”指為經化學修
改的化合物,其中該化學修改發生在該化合物的一或多個官能基處,及當存在時,在芳香族、脂環族或雜環結構上。但是,預計該衍生物或類似物保留衍生出其之化合物的藥物活性。
多種組分的濃度、量等等遍及本揭示經常以範圍形式顯現。以範圍形式描述全然為了方便及簡潔,應該不解釋為在所主張的發明範圍內無彈性限制。此外,範圍的描述應該視為具有在該範圍內之特別揭示出的全部可能次範圍和各別數值。例如,範圍之描述諸如1%至8%應該視為具有特別揭示出的次範圍,諸如1%至7%、2%至8%、2%至6%、3%至6%、4%至8%、3%至8%等等,和在其範圍內的各別數值,諸如2%、5%、7%等等。此架構適用在遍及本揭示的全部上下文中而不管範圍幅度。
於本文中描述出的化合物係揭示在WO 2012/009519中,其全文於此以參考方式併入本文。
用語”進行治療”或”治療”指為將有效量的治療藥物給藥至需要其之對象,其目的為治癒、減輕、解除、補救、改善或防止疾病、其症狀、或朝向其之體質。此對象可由保健專家根據任何合適的診斷方法之結果鑑別出。
”有效量”指為在接受治療的對象上授予治療效應所需要之活性試劑的量。如由熟習該項技術者了解,該有效劑量將依給藥途徑、賦形劑使用及與其它治療性處理共使用的可能性而變化。
QD×28意謂著動物一天服用一次28天。QOD×7
意謂著動物每隔一天服用共7次劑量。Q4Dx3意謂著動物每4天服用一次總共3次劑量。
用語”MED”指為”最小有效劑量”。
由U.S.Department of Health and Human Services Food and Drug Administration出版之”Guidance for Industry and Reviews Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers”揭示出可藉由從下列式計算獲得”人類當量劑量”:HED=動物劑量以毫克/公斤計x(動物重量以公斤計/人類重量以公斤計)0.33。
本發明係關於一種芳基喹啉衍生物的新穎用途;及更特別關於一種芳基喹啉衍生物,其使用在需要其之對象中來抑制血管生成擬態及治療與迷管形態及功能相關及/或特徵為存在有血管生成擬態之疾病或症狀。特別是,本發明係關於一種使用來治療特徵為存在有血管擬態網絡之高度轉移性腫瘤、過度增生疾病、炎性疾病及眼科疾病的芳基喹啉衍生物。
本發明可與其它抗轉移性腫瘤治療法組合,或與用以提高抗血管生成、化學治療或免疫治療劑在治療腫瘤細胞或其它增殖性疾病之高度侵襲性轉移性蔓延上的治療效應之治療法組合進行施加。
不意欲限制本發明的範圍,下列提供根據本發明
之具體實例的範例性儀器、設備、方法及其相關結果。要注意的是,為了讀者方便可在實施例中使用標題或子標題,但其決不應該限制本發明之範圍。再者,於本文中提出及揭示出某些理論;但是,它們決不應該限制本發明之範圍,不論它們是正確或錯誤,只要本發明係根據本發明實施而不考慮作用的任何特別理論或方法。
如下製備TRX-818(磷酸2-(3-氟苯基)-6-甲氧基-4-側氧-1,4-二氫喹啉-5-基酯)之溶液。稱出呈鈉鹽形式的TRX-818之重量,將其溶解在無菌組織培養水中以預先製備10mM貯存溶液。然後,將該貯存溶液分裝及貯存冷凍,直到使用。解凍該貯存溶液的新鮮液份,及使用細胞培養媒質進行一系列稀釋以在試驗當天製備最後操作溶液。
將侵襲性人類黑色素瘤(C8161或SK-MEL28;1x105)細胞播種進三維聚合的MATRIGELTM(75微升)中用於VM網絡分析。在細胞附著後之5或24小時處,以0.5、1、5、
10、25或50或100nM的TRX-818處理C8161或SK-MEL28細胞24小時。將另一組黑色素瘤細胞播種到塑膠碟上,及在使用Guava Nexin Assay(Millipore,USA)決定C8161或SK-MEL28細胞之細胞生存能力前,處理相同的時間量。
使用配備有環境艙的共焦雷射掃描式顯微鏡取得VM網絡影像以追蹤癌細胞對測試化合物之反應。然後,數位化該影像及隨後使用Angiosys軟體分析。每個樣品分析四個影像來定量接合數目及VM形成之總小管長度。變化係以相對於媒劑對照的百分比呈現。使用無菌去離子水(組織培養等級)作為媒劑對照。
在C8161或SK-MEL28癌細胞中,VM網絡形成受濃度5至10nM的TRX-818抑制(圖1及2)。全部TRX-818測試濃度皆明顯減少VM形成所需的細胞接合數目及總小管長度形成(圖3)。5nM的TRX-818達成最大細胞接合減少(43%減少),然而50nM的TRX-818達成最大總小管長度減少(48%減少)。這些結果總整理在表1中,及建議TRX-818在濃度10nM下藉由破壞細胞-細胞及/或細胞-基質交互作用來抑制VM網絡形成,其中該交互作用可先於TRX-818在癌細胞中的抗增殖性活性。表1顯示出TRX-818在細胞接合數目及總小管長度上相對於對照之效應。資料以減少百分比對媒劑組呈現。
對實施例化合物TRX-818M1及CHM-2133進行類似的研究。圖解結果各別顯示在圖4及5中。
為了決定TRX-818是否藉由改變VM的必需蛋白質程度來減低VM網絡形成,使用qRT-PCR決定其在Nodal、Notch4、VE-鈣黏附素(cadherin)(CDHE5)或肝配蛋白(ephrin)受體A2(Eph A2)表現性上的效應。以10nM的TRX-818處理2x106個侵襲性人類黑色素瘤(C8161)細胞8、24、48或72小時。使用無菌去離子水(組織培養等級)作為媒劑。
在8小時處理後,Notch4細胞內區段(Notch 4 ICD)及Nodal的mRNA程度各別減少75%及80%,與對照組比較。在72小時處理後,Notch4 ICD及Nodal的mRNA程度各別保持在對照細胞之50%及70%(圖6A-D)。在8小時處理(10nM)後,CDH5的mRNA程度減少70%,與對照組比較。在72小時連續曝露至10nM的TRX-818後,CDH5的mRNA
程度保持在對照細胞之50%(圖6A-D)。這些結果建議TRX-818藉由抑制Notch、Nodal及CDHE5,但不是Eph A2的mRNA表現性來減低VM網絡形成。
為了進一步了解TRX-818如何改變VM網絡形成所需要的發信途徑,使用免疫油墨鑑定分析法來決定Pro-Nodal、Smad2及磷酸化的Smad2(P-Smad2)之蛋白質程度。在研究當天,如於實施例1中所描述般製備TRX-818。以10nM的TRX-818處理或不處理(對照)C8161細胞1、4、8及24小時。藉由免疫油墨鑑定分析法來分析Nodal及總Smad2、及P-Smad2的蛋白質表現性。於10nM的TRX-818存在下,將5x106個侵襲性人類黑色素瘤(C8161)細胞播種到塑膠碟上,及收集總蛋白質用於分析。為了定量Nodal及P-Smad2的蛋白質程度,各別使用40微克及25微克的總蛋白質用於SDS-PAGE及免疫油墨鑑定法。使用β-肌動蛋白的蛋白質程度來標準化以保證相等的蛋白質負載。
以10nM的TRX-818處理C8161細胞一小時在Nodal蛋白質表現性上產生4%減少(對Pro-Nodal進行偵測,與對照細胞比較)。四至八小時處理在蛋白質程度上產生28%減少,同時24小時處理在Pro-Nodal的蛋白質程度上產生63%減少(圖7)。二十四小時處理亦減低Smad-2的磷酸化程度(圖8)。這些結果建議TRX-818藉由減少在C8161細胞中的Nodal
及磷醯基-Smad2之蛋白質程度來減低VM網絡形成,如總整理在表2中,其顯示出TRX-818在Smad蛋白質程度及其磷酸化上的效應之總整理。
TRX-818一起採用減少必需蛋白質之轉錄、轉譯表現性及轉譯後修改來抑制在侵襲性黑色素瘤細胞中的VM網絡形成。首先,TRX-818明顯減低Nodal、Notch4 ICD及VE-鈣黏附素(CDH5)的mRNA程度。其次,TRX-818減低Nodal前驅物Pro-Nodal的蛋白質表現性;及Smad2的磷酸化。這些結果建議TRX-818可有效防止用於VM網絡形成之上游至下游發信途徑。
使用HCT-116正位異種移植模型檢驗TRX-818在高度轉移性結腸腫瘤HCT-116之腫瘤生長及VM形成上的
抑制效應。使用接種HCT116結腸癌細胞株的正位異種移植人類結腸癌模型,藉由免疫組織化學染色(IHC)評估TRX-818在血管或血管似的(血管生成擬態,VM)網絡形成上之效應。
在此研究中設定六組(十隻老鼠/組)。於此:群組1,提供20毫克/公斤的TRX-818作為口服給藥;群組2,提供50毫克/公斤的TRX-818作為口服給藥;群組3,提供100毫克/公斤的TRX-818作為口服給藥;群組4,提供20毫克/公斤的TRX-818作為靜脈內注射;群組5,提供50毫克/公斤的依立替康作為腹膜內注射;群組6,媒劑組。G1、G2、G3及G6的劑量計劃表為QD×28,及對G4來說為QOD×7。監視體重用於安全性評估。在一生研究結束時測量腫瘤尺寸及腫瘤重量。在用於抗腫瘤效應評估的研究終止時,計算腫瘤生長抑制百分比(TGI%)。研究老鼠的平均體重,其在第1天時係~20克及在研究結束(第42天)時減少至~17-19克。
在28天服用結束時,在該研究中,於腫瘤及肺切除前,使用CO2麻醉(1分鐘)接著頸椎脫臼法讓老鼠安樂死。首先,進行下腹正中切口及切除及收集含有原發腫瘤的結腸。在安樂死後,於3分鐘內完成腫瘤收集。在固定前,以PBS沖洗組織以移除血液。
以在顯微鏡下之5倍光場(200x)為基準,在每組中,於每個樣品的全斷面上計數含有CD31+/紅血球(RBC)+或CD31-/RBC+的管道數目,及計數含有CD31正或負染色的血管數目。血管網由CD31+/RBC+染色表示,然而VM網絡由CD31-/RBC+染色表示,因為該VM形成係與血管內皮細胞各
自獨立。由不知情(blinded)、客觀的觀測者進行評分。
在HCT-116正位人類結腸癌異種移植模型(Ortho)中,於50毫克/公斤下的TRX-818明顯減少腫瘤體積49%,與媒劑組比較(圖9)。口服給藥的TRX-818之MED係50毫克/公斤。
在群組3(TRX-818 100毫克/公斤QD×28,口服)及群組5(依立替康50毫克/公斤Q4D×3,腹膜內)二者中,含有CD31-/RBC+的平均管道數目明顯減少,與在媒劑組中者比較(圖10)。CD31-表示血管生成擬態(VM)形成之形成。這些結果建議化合物TRX-818作為單一試劑在抑制HCT116腫瘤細胞形成血管生成擬態結構上闡明出有益的效應。表3顯示出在正位HCT116人類結腸癌異種移植模型中的VM管道(CD31-/RBC+)數目。
使用類似於在實施例1中的方式製備TRX-818M1(2-(3-氟苯基)-6-甲氧基-4-側氧-1,4-二氫喹啉-5-基)之溶液,除了使用TRX-818M1置換呈鈉鹽形式的TRX-818外。
如在實施例1中所揭示般,播種侵襲性人類黑色素瘤(C8161,7.5x104)細胞。以0.3、1或5nM的TRX-818M1處理C8161細胞4小時或24小時。將另一組黑色素瘤細胞播種到塑膠碟上及在決定C8161細胞之細胞生存能力前,處理相同的時間量。
全部的TRX-818M1測試濃度皆抑制在C8161癌細胞中之VM網絡形成(圖4)。TRX-818M1顯露出係一種在皮莫耳濃度(~0.3nM)下有效之強效性血管破壞劑(vascular disrupting agents)。在該nM範圍內,較高的濃度引發細胞死亡。
使用類似於在實施例1及5中的方式製備CHM-2133(2-(2-氟苯基)-6,7-伸甲基二氧基喹啉-4-酮)之溶液。全部的CHM-2133測試濃度皆抑制在C8161癌細胞中之VM網絡形成(圖5)。CHM-2133顯露出係一種在皮莫耳濃度(~0.3nM)下有效之強效性血管破壞劑。
根據在美國專利案號8524740中所揭示之方法合成顯示於表4的化合物16-24、37-45、48-53、124-143、143a、143b、144、144a、144b、146-147、152-153、157-158、166-169。使用如在實施例1中所描述的方法測試其在抑制於侵襲性黑色素瘤細胞中的血管生成擬態網絡形成上之效應。
使用如在實施例2中所描述之方法檢驗顯示在表4中的化合物其於VM蛋白質之mRNA程度上的效應。
使用如在實施例3中所描述的方法檢驗顯示在表4中之化合物其於Nodal及Smad蛋白質程度上的效應。
使用如在實施例4中所描述的HCT-116正位人類結腸癌異種移植模型檢驗顯示於表4中的化合物其效應。
測試TRX-818 MI(即,化合物編號38)結構類似化合物其在抑制血管生成擬態上的效應。將侵襲性人類黑色素瘤(SK-MEL-28,來自ATCC®;7.5x104/毫升媒質)細胞播種到三維聚合塗佈MATRIGELTM的24井板上。在細胞播種18小時後,形成VM網絡。然後,以負對照(未處理及經DMSO處理的對照)、正對照(100nM的TRX-818M1)或每種100nM測試化合物置換該媒質。在0小時、5小時及24小時處理後觀察VM網絡形成。
已發現TRX-818結構類似化合物在VM網絡形成上顯示出抑制效應。以化合物TRX-818M1(正對照,化合物
38)、43、52、147、A6、B1、B3、C4及C6在100nM下處理之SK-MEL28細胞(人類黑色素瘤細胞株)顯示出在處理後5小時中度失去VM網絡,如與負對照(未處理及經DMSO處理的對照)比較;及在處理後24小時顯著失去VM網絡(圖11)。要注意的是,雖然該測試化合物在濃度100nM下抑制VM網絡形成,其對SK-MEL-28細胞具略微的細胞毒性。
本發明不限於如所闡明的特別形式,及其未離開本發明的精神及範圍之全部修改係在如附加的請求項所定義之範圍內。選擇及描述出具體實例及實施例以解釋本發明之
原理及其可實行的應用,以便能夠讓其它熟練技藝人士使用本發明及多個具體實例,及多種修改如係適合於特別考慮到的用途。將由熟習該項技術者明瞭涉及本發明而沒有離開其精神及範圍之可替代的具體實例。在本發明的說明中引用及討論一些參考,其可包括專利、專利申請案及多種公告。此等參考之引用及/或討論僅提供闡明本發明之說明及不准許任何此參考係於本文中所描述的發明之”先前技藝”。在本專利說明書中所引用及討論的全部參考其全文以參考之方式併入本文至與如每篇參考各別以參考方式併入本文相同的程度。
Claims (11)
- 一種式IV之化合物或其醫藥上可接受的鹽之用途,其係使用來製造一用以在需要其之對象中抑制與轉移性腫瘤相關的血管生成擬態的藥劑:其中R2’、R3’、R4’、R5’及R6’係全部為H,或R2’、R3’、R4’、R5’及R6’中之一係F、OCH3或(CH2)nNR8R9,及其它係H;其中n係0-4的整數;及R8及R9各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n係如上述定義,m係0-4的整數;Y係O或S;R2、R3及R4各自獨立地係H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、(CH2)nN;或R3與R4一起係-Y(CH2)nY-,其中n、Y、R8及R9係如上述定義;X係F、Cl或Br;或R3係O-苄基;及R1及R1’各自獨立地係H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自獨立地係H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9係如上述定義。
- 如請求項1之用途,其中R2、R3及R4全部係H;或R2、R3及R4之一係F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,及其它係H;或R2係H且R3與R4一起係-O(CH2)nO-,其中n、Y、R8及R9係如在請求項1中所定義。
- 如請求項1之用途,其中R1及R1’係H、Na+及/或K+。
- 如請求項2之用途,其中R2係H且R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R5’全部係H;及R6’係F。
- 如請求項2之用途,其中R2係H且R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R6’全部係H;及R5’係F。
- 如請求項2之用途,其中R2、R3及R4全部係H;及R2’、R3’、R4’、R5’及R6’全部係H。
- 如請求項2之用途,其中R4係OCH3;及R2及R3係H;及R5’係F;及R2’、R3’、R4’及R6’係H。
- 如請求項2之用途,其中R2係H且R3與R4一起係-O(CH2)O-;及R2’、R3’、R4’及R6’全部係H;及R5’係OCH3。
- 如請求項1之用途,其中該轉移性腫瘤係選自於由下列所組成之群的至少一種:黑色素瘤、卵巢癌、前列腺癌、腎細胞癌、尤恩氏肉瘤、乳房癌、神經內分泌系癌、甲狀腺癌、喉鱗狀細胞癌、肝細胞癌、葡萄膜黑色素瘤、皮膚黑色素瘤、口腔惡性黑色素瘤、絨毛膜癌、原發性膽囊癌、惡性食道基質癌、間皮性肉瘤、齒槽橫紋肌肉瘤、膀胱癌、骨肉瘤、星細胞瘤、嗜鉻細胞瘤、結腸直腸癌、神經管胚細胞瘤、腺癌、食道基質瘤、喉癌、白血病、滑膜肉瘤、神經膠母細胞瘤及胃腸癌。
- 如請求項1之用途,其中該轉移性腫瘤係葡萄膜黑色素瘤、皮膚黑色素瘤、口腔惡性黑色素瘤或結腸直腸癌。
- 如請求項1至10之任一項的用途,其中該藥劑與選自於由下列所組成之群的額外治療藥物一起使用:抗癌劑、抗發炎藥、抗增殖劑、抗荷爾蒙劑及其任何組合。
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