TWI830262B - 克立咪唑(clemizole)化合物於預防及治療肝癌之用途 - Google Patents
克立咪唑(clemizole)化合物於預防及治療肝癌之用途 Download PDFInfo
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- TWI830262B TWI830262B TW111123545A TW111123545A TWI830262B TW I830262 B TWI830262 B TW I830262B TW 111123545 A TW111123545 A TW 111123545A TW 111123545 A TW111123545 A TW 111123545A TW I830262 B TWI830262 B TW I830262B
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- clemizole
- liver
- compound
- inflammation
- chloroquine
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- CJXAEXPPLWQRFR-UHFFFAOYSA-N clemizole Chemical class C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2N=C1CN1CCCC1 CJXAEXPPLWQRFR-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 238000011282 treatment Methods 0.000 title claims abstract description 38
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- 206010061218 Inflammation Diseases 0.000 claims description 18
- 230000004054 inflammatory process Effects 0.000 claims description 18
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 15
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- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 6
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本文揭示使用R-氯喹(R-chloroquine)或克立咪唑(clemizole)或R-氯喹及克立咪唑之組合以治療需要其之個體之方法。用途包含治療個體中發炎病況、治療肝癌或降低罹患肝癌之風險之方法。用途亦包含治療個體中非酒精性脂肪性肝炎之方法。
Description
本發明係關於醫學領域,且更特定而言係關於某些化合物用於治療及預防發炎及癌症病況(具體而言是肝臟)之用途。
發炎及癌症病況之治療及預防代表廣泛地未滿足之醫學需求。肝之發炎病況(例如非酒精性脂肪性肝炎(NASH))尤其需要經改良療法。若不治療,則NASH及其他發炎性肝病症(例如由病毒感染引起者)可導致肝細胞癌。本發明藉由提供用於治療及/或預防下文所述發炎及/或癌症病況之方法來解決該等需要。
本文揭示包括向有需要之個體投與有效量之克立咪唑(clemizole)及/或氯喹(cholorquine)或其類似物之方法。在本發明之一些態樣中,向個體投與R-氯喹、克立咪唑或R-氯喹與克立咪唑之組合。
在本發明之一些態樣中,個體患有發炎病況。
在本發明之其他態樣中,個體患有發炎肝病況。在本發明之一些態樣中,個體患有非酒精性脂肪性肝炎,且其中此方法進一步包括治療非酒精性脂肪性肝炎。在一些態樣中,此方法減輕肝之小葉發炎。在其他態樣中,此方法減輕肝癌之風險。在本發明之再其他態樣中,個體患有肝癌,且其中此方法進一步包括治療肝癌。
在本發明之一些態樣中,向患有非酒精性脂肪性肝炎之個體投與克立咪唑及/或R-氯喹。在其他態樣中,向個體投與克立咪唑或R-氯喹使得血漿丙胺酸胺基轉移酶之含量與媒劑對照相比減少。在其他態樣中,向個體投與克立咪唑及/或R-氯喹使得非酒精性脂肪肝疾病活動性評分降低,如藉由肝組織之組織學分析所測定。在一些態樣中,投與克立咪唑及/或R-氯喹使得脂肪變性減輕。在其他態樣中,投與克立咪唑及/或R-氯喹使得肝細胞氣球樣變減輕。在再其他態樣中,投與克立咪唑及/或R-氯喹使得肝小葉發炎減輕。
在本發明之一些態樣中,向個體投與克立咪唑及/或R-氯喹以降低罹患肝癌之風險。在本發明之其他態樣中,個體經診斷患有非酒精性脂肪性肝炎。在本發明之其他態樣中,向患有肝癌之個體投與克立咪唑及/或R-氯喹。在再其他態樣中,克立咪唑及/或R-氯喹之投與使得個體之腫瘤負荷減輕或個體之存活增加。
在本發明之一些態樣中,向個體投與0.5 mg/kg至50 mg/kg之克立咪唑。在一些態樣中,每日一次、每日兩次或每日三次投與克立咪唑。在其他態樣中,每日投與克立咪唑達1週、2週、3週、4週、5週、6週或更多週。
在本發明之一些態樣中,向個體投與0.5 mg/kg至50 mg/kg之R-氯喹。在其他態樣中,每日一次、每隔一天一次或每週一次投與R-氯喹。在一些態樣中,投與R-氯喹達1週、2週、3週、4週、5週、6週或更多週。在再其他態樣中,在治療之前兩天每日以雙倍負荷劑量投與R-氯喹,隨後以單一劑量(即雙倍負荷劑量之一半)用於剩餘治療。
優點及效用簡言之且如下文更詳細闡述,本文闡述使用克立咪唑及/或R-氯喹治療非酒精性脂肪性肝炎或減輕肝癌之風險或嚴重性之組合物及方法。此方法之優點包含(但不限於)與未利用克立咪唑及/或R-氯喹治療患者相比,當患者利用克立咪唑及/或R-氯喹治療時,減輕患有發炎病況之個體之發炎、減輕肝之小葉發炎、改良肝功能及降低肝癌罹患或進展之風險。
定義除非另有說明,否則申請專利範圍及說明書中所用之術語係如下文所述來定義。
術語「治療」係指在治療疾病狀態(例如由發炎肝病況導致之疾病狀態)中之任何治療有益結果,包含預防、減輕嚴重性或進展、緩解或治癒該疾病狀態。
術語「原位」係指在自活生物體分離而正生長(例如於組織培養基中生長)之活細胞中發生之過程。
術語「活體內」係指在活生物體中發生之過程。
如本文所用術語「哺乳動物」包含人類及非人類二者,且包含(但不限於)人類、非人類靈長類、犬類、貓、鼠類、牛、馬及豬。
術語「有效量」意指足以產生期望效應之量,例如足以預防肝癌或減少個體中肝癌之量的量。
術語「個體」係指細胞、人類及非人類動物。
術語「治療有效量」係有效改善疾病症狀之量。治療有效量可係「預防有效量」,此乃因預防可視為療法。
術語「投與」係指將本發明之藥劑引入至宿主中。藥劑之一較佳投與途徑係經口投與。另一較佳途徑係靜脈內投與。然而,可使用任何投與途徑,例如局部、皮下、經腹膜、動脈內、吸入、經陰道、經直腸、經鼻、引入至腦脊液中或滴注至身體腔室中。
術語「媒劑對照」廣泛地指活性成分投與其中之任何惰性介質,其包含(但不限於)用於活性成分之溶劑、載劑或黏合劑。
術語「氘化類似物」係指本發明化合物之經改質形式或類似物,其中化合物含有至少一個氘代同位素。
術語「克立咪唑代謝物」係指克立咪唑代謝物化合物M1、M12及M14,如本申請案之圖2中所述。
術語「R-氯喹代謝物」係指氯喹之代謝物化合物,如本申請案之圖6中所述。
術語「R-羥基氯喹代謝物」係指羥基氯喹之代謝物化合物,如本申請案之圖7中所述。
術語「抗NASH藥劑」係指用於治療非酒精性脂肪性肝炎或與非酒精性脂肪性肝炎相關之病況之藥物或化合物,其包含(但不限於) FXR促效劑(例如奧貝膽酸(obeticholic acid)及PX-104)、LOXL2抑制劑(例如西妥珠單抗(Simtuzumab))、半胱天冬酶蛋白酶抑制劑(例如恩利卡生(Emricasan)及二十碳五烯酸乙酯)、半胱胺重酒石酸氫鹽(例如普若雅思比(Procysbi)或RP103)、半乳糖凝集素-3抑制劑(例如GR-MD-02及LJPC-1010)、CCR2及CCR5途徑抑制劑(例如賽瑞韋若克(Cenicriviroc))、PPAR促效劑(例如GFT505、DUR-928、薩格列紮(Saroglitazar)及吡格列酮(Pioglitazone))、半胱胺酸消耗劑(例如RP103)、SGLT-2抑制劑(例如依碳酸瑞格列淨(remogliflozin etabonate))、GLP-1 (例如利拉魯肽(liraglutide))、膽汁酸(熊去氧膽酸)、合成脂肪酸及膽汁酸偶聯物(例如,阿蘭姆秋(Aramchol))、去乙醯化酶刺激劑(例如MB12066)、細胞凋亡信號調控激酶1 (ASK1)抑制劑(例如GS-4997)及免疫調節劑(例如IMM124E)。
如本文所用,術語「發炎病況」係指由發炎細胞介素或涉及發炎之細胞直接導致之醫學問題。發炎病況包含(但不限於)非酒精性脂肪性肝炎、關節炎,其中發炎細胞介素破壞並導致滑膜中之病灶及關節軟骨及骨之破壞;腎衰竭,其中發炎細胞介素限制循環並損害腎元;狼瘡,其中發炎細胞介素誘導自體免疫攻擊;氣喘,其中發炎細胞介素閉合呼吸道;牛皮癬,其中發炎細胞介素誘導皮膚炎;胰臟炎,其中發炎細胞介素誘導胰臟細胞損傷;過敏,其中發炎細胞介素誘導自體免疫反應;纖維化,其中發炎細胞介素導致受損傷之組織;手術併發症,其中發炎細胞介素阻止癒合;貧血,其中發炎細胞介素干擾紅血球生成素生成;及纖維肌痛,其中在纖維肌痛患者中發炎細胞介素升高。與慢性發炎相關之其他疾病包含癌症,其由慢性發炎導致;心臟病發作,其中慢性發炎促使冠狀動脈粥樣硬化;阿茲海默氏病(Alzheimer's disease),其中慢性發炎破壞腦細胞;充血性心臟衰竭,其中慢性發炎導致心臟肌肉虛耗;中風,其中慢性發炎促進血栓栓塞性事件;及主動脈瓣狹窄,其中慢性發炎損害心臟瓣膜。動脈粥樣硬化、骨質疏鬆症、帕金森氏病(Parkinson's disease)、感染、發炎性腸疾病(包含羅恩氏病(Crohn's disease)及潰瘍性結腸炎)以及多發性硬化(典型的自體免疫發炎相關疾病)亦與發炎有關。一些疾病在晚期階段可危及生命。若干方法可用於治療該等發炎疾病;然而,結果通常並不令人滿意,如藉由缺乏功效及與其相關之藥物相關副作用所證明。
如本文所用,術語「非酒精性脂肪肝疾病活動性評分」係指肝組織之組織學檢查結果,其中已針對脂肪變性、肝細胞氣球樣變及/或小葉發炎對組織進行檢查。
如本文所用,術語「肝癌」係指肝之過度增生性疾病,包含(但不限於)肝細胞癌、纖維板層肝細胞癌、膽管癌、血管肉瘤、繼發性或轉移性肝癌及肝母細胞瘤。
如本文所用,術語「化學治療劑」係指可用於治療疾病(例如癌症)之化合物。本發明之化學治療劑可包含任何適宜化學療法藥物或化學療法藥物之組合(例如混合物(cocktail))。實例性化學療法劑包含(但不限於)烷基化劑、鉑、抗代謝物、蒽環類(anthracyclines)、紫杉烷、喜樹鹼(camptothecins)、亞硝基脲、EGFR抑制劑、抗生素、HER2/neu抑制劑、血管生成抑制劑、激酶抑制劑(例如索拉菲尼(sorafenib))、蛋白酶體抑制劑、免疫療法、激素療法、光動力療法、癌症疫苗、組織蛋白去乙醯酶抑制劑、神經脂質調節劑、寡聚物、其他未分類化學療法藥物及其組合。有效對抗癌症之實例性化學治療劑亦包含(但不限於)柔紅黴素(daunorubicin)、放線菌素(dactinomycin)、多柔比星(doxorubicin)、博來黴素(bleomycin)、絲裂黴素(mitomycin)、氮芥(nitrogen mustard)、氮芥苯丁酸(chlorambucil)、美法侖(melphalan)、環磷醯胺、6-巰基嘌呤、6-硫鳥嘌呤、阿糖胞苷(CA)、5-氟尿嘧啶(5-FU)、氟尿苷(5-FUdR)、胺甲喋呤(MTX)、秋水仙鹼、泰素帝(taxotere)、長春新鹼(vincristine)、長春花鹼(vinblastine)、依託泊苷(etoposide)、替尼泊苷(teniposide)、順鉑及己烯雌酚(DES)。
術語「醫藥上可接受之賦形劑」、「醫藥上可接受之稀釋劑」、「醫藥上可接受之載劑」或「醫藥上可接受之佐劑」意指可用於製備醫藥組合物且通常安全、無毒且生物學上或其他方面均合意之賦形劑、稀釋劑、載劑及/或佐劑,且包含對於獸醫用途及/或人類醫藥用途可接受之賦形劑、稀釋劑、載劑及佐劑。說明書及申請專利範圍中所用之「醫藥上可接受之賦形劑、稀釋劑、載劑及/或佐劑」包含該等賦形劑、稀釋劑、載劑及佐劑中之一或多者。
「醫藥上可接受之鹽」係指彼等保留游離鹼之生物有效性及視情況其他性質且藉由與以下無機或有機酸反應獲得之鹽:例如氫氯酸、氫溴酸、硫酸、硝酸、磷酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、柳酸、蘋果酸、馬來酸、琥珀酸、酒石酸、檸檬酸及諸如此類。術語「醫藥上可接受之鹽」亦係指可與游離氯喹鹼組合之化合物(例如磷酸鹽及磷酸氫鹽)。
在所揭示藥劑之實施例形成鹽之情形中,該等鹽係在本發明之範圍內。應瞭解,除非另有說明,否則本文對式中之任一者之藥劑的提及包含提及其鹽。如本文所用,術語「鹽」表示與無機及/或有機酸及鹼形成之酸性及/或鹼性鹽。此外,當藥劑含有鹼性部分及酸性部分二者時,可形成兩性離子(「內鹽」)且包含在本文所用之術語「鹽」內。醫藥上可接受(例如無毒、生理學上可接受)之鹽係較佳的,但亦可使用其他鹽,例如在製備期間可採用之分離或純化步驟中。
如本文所用術語「醫藥組合物」意欲涵蓋適於投與個體(例如哺乳動物、尤其人類)之組合物。通常,「醫藥組合物」係無菌的,且較佳不含能夠在個體內引發不期望反應之污染物。
術語「前藥」係指在活體內轉化成生物學上活性形式之藥劑之無活性前體。本發明之化合物包含R-氯喹及克立咪唑之改質形式、氘化克立咪唑或克立咪唑代謝物,該等用作前藥。可用於產生前藥之本發明化合物之改質實例包含(但不限於)酯、糖苷(糖衍生物)之添加或其他無毒化學基團之添加或去除,該等基團在代謝期間在活體內經酶促方式改變(例如磷酸化、去磷酸化、去烷基化、脫羥基或糖衍生物之改質)。前藥通常係有用的,此乃因在一些情況下,其可較母體化合物更易於投與。例如,其可藉由經口投與供生物利用,而母體化合物則不行。前藥亦可在醫藥組合物中具有優於母體藥物之經改良溶解度。前藥可藉由多種機制轉化成母體藥物,包含酶促過程及代謝水解。
縮寫此申請案中所用之縮寫包含如下:
必須指出,除非上下文另有明確說明,否則說明書及隨附申請專利範圍中所用之單數形式「一(a, an)」及「該(the)」均包含複數個指示物。
化合物A = R-氯喹及S-氯喹之外消旋混合物
化合物B = R-氯喹
化合物C = S-氯喹
化合物D =克立咪唑
ALT =丙胺酸胺基轉移酶
HE =蘇木素及伊紅
HFD =高脂肪飼料
NAFLD =非酒精性脂肪肝疾病
NASH =非酒精性脂肪性肝炎
SD =標凖偏差
SPF =無特定病原體
STZ =鏈佐黴素
本發明化合物R-氯喹之式及合成R-氯喹之製程闡述於圖1中。或者,R-氯喹有市售且可購自Chemical Entities of Biological Interest (ChEBI™);(目錄號,CHEBI:48811)。
克立咪唑及主要人類(M1、M6)及齧齒類動物(M12、M14)克立咪唑代謝物之結構顯示於圖2中。克立咪唑鹽酸鹽係購自APExBIO™ (目錄編號3316)。
在人類肝中,克立咪唑主要轉化成中間體A,有若干CYP450酶(CYP3A4、CYP2C19或CYP2D6)可將其氧化成M1。在CYP2C9或CYP1A2存在下生成M2,但其無法產生M1。Cyp2C9似乎係M4之唯一來源,M4係人類中之次要代謝物。在人類肝中最豐富表現之CYP450酶CYP3A4介導此藥物生物轉變反應之大部分。CYP3A4活性之抑制劑利托那韋(ritonavir)活體外抑制克立咪唑代謝之能力表明在人類中CYP3A4在克立咪唑代謝中發揮主要作用。相比之下,不同類型(CYP2C樣)之芳香族氧化反應在齧齒類動物肝中藉助克立咪唑代謝之優勢路徑產生在齧齒類動物中佔優勢之代謝物(M12、M14及M15)。
克立咪唑鹽酸鹽之合成克立咪唑鹽酸鹽係購自APExBIO™ (目錄編號3316)。圖3闡述用於克立咪唑之優良製造規範(GMP)生產之合成方案。在某些實施例中,克立咪唑之氘化類似物可藉由用氘化吡咯啶取代吡咯啶起始材料來產生。吡咯啶-2,2,5,5-d
4可購自©CDN Isotopes, Inc. (產品號D-5946)。完全經取代之吡咯啶(吡咯啶-2,2,3,3,4,4,5,5-d
8)可購自©CDN Isotopes, Inc. (產品號D-3532)。
R- 氯喹之合成如圖1所述,(R)-(-)-氯喹係藉由使(R)-(-)-4-胺基-1-(二乙基胺基)戊烷與已知4,7-二氯喹啉進行縮合作用製備而成。(R)-(-)-4-胺基-1-(二乙基胺基)戊烷製備如下:經由與已知(D)-(-)-苦杏仁酸形成鹽來分解已知外消旋4-胺基-1-(二乙基胺基)戊烷,並藉由結晶作用分離兩種鏡像異構物之(D)-(-)-苦杏仁酸鹽。
(R)-(-)-4- 胺基 -1-( 二乙基胺基 ) 戊烷之製備向(D)-(-)-苦杏仁酸(100g,658 mmol)於350 mL乙醇中之溶液中緩慢添加外消旋4-胺基-1-(二乙基胺基)戊烷(98 g,658 mmol)。混合物以標題化合物之(D)-(-)-苦杏仁酸鹽晶體加晶種,且靜置過夜後,藉由過濾收集所得固體並用冰冷乙醇快速洗滌兩次,以得到呈白色晶體之標題化合物之(D)-(-)-苦杏仁酸鹽(批次1)。將母液濃縮直到觀察到混濁,然後再加熱直到得到均質溶液為止。加晶種並靜置過夜後,藉由過濾收集所得固體並用冰冷乙醇快速洗滌兩次,以得到呈白色晶體之第二批所期望的鹽(批次2)。將兩個鹽批次(批次1及2)組合以得到總共44 g標題化合物之(D)-(-)-苦杏仁酸鹽。將上述製程重複4次。將多個批次之標題化合物之(D)-(-)-苦杏仁酸鹽(總共150 g)組合,且然後利用加熱及音波使其溶解於乙醇中。使溶液加晶種且靜置過夜後,藉由過濾收集所得固體並用冰冷乙醇快速洗滌兩次,以得到標題化合物之(D)-(-)-苦杏仁酸鹽(重結晶批次1)。將母液濃縮且利用加熱及音波使殘餘物溶解於乙醇中。然後使溶液加晶種且靜置過夜後,藉由過濾收集所得固體以得到第二批標題化合物之(D)-(-)-苦杏仁酸鹽(重結晶批次2)。將母液濃縮且利用加熱及音波使殘餘物溶解於乙醇中。然後使溶液加晶種且靜置過夜後,藉由過濾收集所得固體以得到第三批標題化合物之(D)-(-)-苦杏仁酸鹽(重結晶批次3)。將三個重結晶批次(重結晶批次1、2及3)組合並在真空中乾燥以得到總共100 g之標題化合物之(D)-(-)-苦杏仁酸鹽,[α]
D = -56.2 (1%於水中)。將此鹽懸浮於二氯甲烷中並用1 M氫氧化鈉溶液洗滌三次。將有機層乾燥(Na
2SO
4)並在真空中濃縮以得到標題化合物,其直接用於下一步驟。
(R)-(-)- 氯喹之製備將來自以上之粗製(R)-(-)-4-胺基-1-(二乙基胺基)戊烷(約45 g,285 mmol,1.00當量)、4,7-二氯喹啉(56 g,285 mmol,1.00當量)及苯酚(53.6 g,570 mmol,2.0當量)之混合物加熱至120℃並保持18 h,然後冷卻至室溫並用二氯甲烷稀釋。利用1.5 M氫氧化鈉溶液洗滌所得混合物且洗滌液利用二氯甲烷反萃取。利用1 M氫氯酸萃取合併之有機層。水性萃取物利用飽和碳酸鈉溶液鹼化至pH 12並用二氯甲烷萃取。將有機萃取物乾燥(Na
2SO
4)並在真空中濃縮。然後藉由管柱層析(矽膠,利用2.5% 7N NNH
3/MeOH溶析)純化殘餘物以得到42.8 g之標題化合物,[α]
D =-101.3 (1%於乙醇中)。
藉由將42.8 g (133 mmol)之標題化合物於乙醇中之溶液加熱至90℃並保持15 min並逐滴添加2當量(314 g,267 mmol)之85%磷酸將此材料轉化成其磷酸氫鹽。將所得懸浮液在回流下(90℃)加熱1 h且然後冷卻至室溫後,藉由過濾收集固體,用乙醇及二乙醚洗滌且在真空中乾燥以得到68 g (R)-(-)-氯喹磷酸氫鹽,[α]
D =-82.96 (2.1%於水中)。
1H NMR (甲醇-
d4): δ 8.59 (d,
J= 9.2 Hz, 1H), 8.36 (d,
J= 6.8 Hz, 1H), 7.92 (s, 1H), 7.61 (d,
J= 9.2 Hz, 1H), 6.89 (d,
J= 7.2 Hz, 1H), 4.05–4.14 (m, 1H), 3.07–3.17 (m, 6H), 1.73–1.96 (m, 4H), 1.39–1.41 (m, 3H)及1.27–1.31 (m, 6H)
R- 羥基氯喹之合成及純化鏡像異構物(R)及(S)羥基氯喹之合成及純化製程充分闡述於Blaney, P.等人「A Practical Synthesis of the Enantiomers of Hydroxychloroquine,」 Tetrahedron: Asymmetry, 1994, pp. 1815-1822, 第5卷。下文包含此製程之概述。
如圖6所示,外消旋二胺
rac-2係藉由其與S(+)苦杏仁酸之鹽之結晶來拆分。隨後與4,7二氯喹啉偶合得到S(+)-羥基氯喹((S)-la)。類似地,使用苦杏仁酸之相反鏡像異構物得到(R)-2及R(-)-羥基氯喹((R)-la)。(R)-2及(S)-2之拆分涉及其非鏡像異構物苦杏仁酸鹽自異丙醇之結晶。使用0.5莫耳當量之S(+)-苦杏仁酸並在45℃下利用純非鏡像異構物使混合物加晶種,在單次結晶後回收67%之(S)-3,其非鏡像異構過量(d.e.)為92%。隨後,(S)-3或(R)-3經水解成相應二胺(S)-2或(R)-2。比率及產率係在不考慮(S)-2或(R)-2中存在可變數量(高達10%)之水的情況下計算。
S(+)-5-[N- 乙基 -N-(2- 羥基乙基 ) 胺基 ]-2- 戊胺 ((S)-2) 之製備將rac-2 (200g,1.15 mol)於2-丙醇(350 ml)中之溶液添加至(+)-苦杏仁酸(87.4g, 0.575 mol)於2-丙醇(500 ml)中之溶液中。添加額外2-丙醇以使總體積達900 ml並將溶液在室溫下攪拌過夜。過濾得到白色晶體(235g),將其自2-丙醇重結晶兩次(分別1800 ml及1600 ml),以得到呈白色晶體之(S)-3 (145.4g)。將固體懸浮於35%氫氧化鈉水溶液(350 ml)中並用第三丁基甲基醚(5 x 600 ml)萃取。將萃取物組合,乾燥(MgSO
4)並濃縮以得到呈無色油狀物之(S)-2 (55.5g, 55%)。
1H NMR (CDCl3) δ 0.98 (3H, t, J = 7.1 Hz), 1.025 (3H, d, J = 6.3 Hz), 1.25-1.35 (2H, m), 1.35-1.55 (2H,m),約 1.9(3H,brs), 2.42(2H,t,J=7.3Hz), 2.51 (2H,q,J=7.1Hz), 2.54(2H,t,J=5.5Hz), 2.85(1H,tq,J = 6.3 5.2 Hz), 3.50 (2H, t, J = 5.5 Hz); MS (CI,氨) 175 ([MH]+). C
9H
22N
2O之HRMS計算值:175.181039; 試驗值:175.180493。
R(-)-5-[N- 乙基 -N-(2- 羥基乙基 ) 胺基 ]-2- 戊胺 ((R)-2) 之製備將來自上述第一次結晶之母液濃縮。將殘餘物懸浮於35%氫氧化鈉水溶液(250 ml)中並用第三丁基甲基醚(5 x 550 ml)萃取。合併之萃取物經乾燥(MgSO
4)並濃縮以得到黃色油狀物(70.6g)。將此再溶解於2-丙醇(200 ml)中並添加至(-)-苦杏仁酸(64.00 g,0.421 mol)於2-丙醇(300 ml)中之溶液。添加額外2-丙醇使總體積達600 ml並將溶液在室溫下攪拌過夜。過濾得到白色晶體(111 g),使其自2-丙醇重結晶兩次(分別1100 ml及800 ml)得到呈白色晶體之(R)-3 (77.2 g)。
1H NMR DMSO-d
6) δ 0.92 (3H, t), 1.09 (3H, d), 1.35-1.55 (4H, m), 2.3-2.55 (6H, m), 3.03 (1H, tq).3.43 (2H, t), 4.48 (IH, s), 7.1-7.25 (3H, m), 7.39 (2H, dd).將(R)-3懸浮於35%氫氧化鈉水溶液(200 ml)中並用第三丁基甲基醚(5 x 400ml)萃取。將萃取物合併,乾燥(MgSO
4)並濃縮以得到呈無色油狀物之(R)-2 (29.3g,29%)。
1NMR (CDC13) δ 0.97 (3H, t,
J= 7.1 Hz), 1.025 (3H, d,
J= 6.3 Hz), 1.25-1.35 (2H, m), 135- 1.5 (2H, m), 約2.1 (3H,br s), 2.41 (2H,t.
J=7.3Hz), 2.51 (2H, q
,J=7.1Hz), 2.53 (2H, t,
J= 5.5Hz), 2.85 (1H, tq,
J=6.35.2Hz), 3.49 (2H, t,
J=5.5Hz);C
9H
22N
2O之HRMS (CI,氨)計算值:175.181039;試驗值:175.180390。
S(+)- 羥基氯喹 ((S)-la) 之製備在125℃下將(S)-2 (55.47 g, 0.32 mol)、4,7-二氯喹啉(63.03 g, 0.32 mol)及二異丙基乙胺(63.9 ml, 0.37 mol)之混合物在回流下在氮氣氣氛中加熱四天。冷卻後,將混合物轉移至分液漏斗中並使用1M氫氧化鈉水溶液(500 ml)及二氯甲烷(500 ml)。分離有機相並利用二氯甲烷(2 x 500 ml)再萃取水相。將有機相合併,乾燥(MgSO
4)並濃縮以得到黃色油狀物(116 g),將其在矽膠上於95:3:2二氯甲烷:三乙胺:甲醇中層析,以得到呈淺黃色油狀物之(S)-la
(73 g, 78%)。或者,將粗產物在氧化鋁上於2:2:1丙酮:己烷:甲醇中層析,得到呈無色油狀物之(S)-la。
1H NMR (CDC1
3) δ 0.99 (3H, t,
J= 7 Hz, CH
2CH
3), 1.285 (3H, d,
J= 6 Hz, CHCH
3), 1.45-1.85 (4H, m), 2.35-2.75 (6H, m), 3.4-3.95 (3H, m), 5.18 (1H,br d,
J=8Hz,NH), 6.37 (1H, d,
J=6Hz, 3-H), 7.28 (1H, dd,
J o= 9 Hz,
J m= 2 Hz, 6-H), 7.74 (1H, d,
J= 9 Hz, 5-H), 7.91 (1H, d,
J= 2 Hz, 8-H), 8.465 (1H,d,
J= 6 Hz, 2-H);
13C NMR (CDCl
3) 11.5 (CH
2CH
3), 20.2 (CH-CH
3), 23.9 (CH
2CH
2CH
2N), 34.2 (CH
2CH
2CH
2N).47.5 (CH
2CH
3), 48.3 (CH), 53.1 (CH
2H
2CH
2N), 54.9 (CH
2CH
2OH), 58.5 (CH
2CH
2OH), 99.0 (C3), 117.2 (C4a), 121.3 (C6), 125.0 (C8), 128.4 (C5), 134.7 (C7), 149.1 (C4), 151.65 (C2); MS (EI, 70EV) 337,335 (15, 44%, M
+), 306,304 (20, 62%, [M-CH
2OH]
+), 247 (81%), 102 (100%); C
18H
26ClN
3O之HRMS計算值: 335.176440;實驗值: 335.175518。
R(- 羥基氯喹 ((R)-la) 之製備在135℃下將(R)-2 (29.34 g, 0.168 mol)、4,7-二氯喹啉(33.34 g, 0.168 mol)及二異丙基乙胺(33.8 ml, 0.194 mol)之混合物在回流下在氮氣氣氛中加熱三天。如針對(S)-la所述處理及純化得到呈淺黃色油狀物之(R)-la (39.8 g,
84%)。
可選純化:將粗製(R)-la (18.7 g)溶解於鹽酸(1M,50 ml)中並用乙酸乙酯(2 x 50 ml)洗滌以去除2,7-二氯喹啉。利用1 M氫氧化鈉水溶液中和至pH 7.5後,利用乙酸乙酯(2 x 50 ml)再次洗滌水相,然後與活性炭一起攪拌過夜。藉助矽藻土過濾後,將混合物鹼化至pH 12並用乙酸乙酯(4 x 50 ml)萃取。將萃取物組合,乾燥(MgSO
4)並濃縮以得到呈淺黃色油狀物之(R)-la。
1H NMR (CDCl
3) δ0.99 (3H, t).1.285 (3H, d), 1.45-1.85 (4H, m), 2.35-2.75 (6H, m), 3.4-3.95 (3H, m), 5.18 (1H, brd), 6.37 (1H, d), 7.28 (IH, dd), 7.74 (1H, d), 7.91 (1H, d), 8.465 (1H, d);
13C NMR (CDCl
3) δ 11.5, 20.2, 23.9, 34.2, 47.5, 48.3, 53.1, 54.9, 58.5, 99.0, 117.2, 121.3,125.0, 128.4, 134.7, 149.1, 151.65; MS (熱噴霧) 338,336([MH]+);在247處之主要碎片離子(100%, [M-EtNHCH
2CH
2OH]
+), 158。
用於分析 (R)-2 及 (S)-2 之鏡像異構物純度之程序經完全解析之(R)-2或(S)-2在區域6中具有[α]
D。測定鏡像異構物純度之可靠方法涉及(R)-2及(S)-2之非鏡像異構物衍生物之
1H-NMR。添加1莫耳當量之(R)-α-甲氧基-α-三氟甲基苯乙酸(MTPA)至(R)-2及(S)-2之氯仿溶液之結果導致兩種非鏡像異構物中之H
a所致之共振加寬並移至更高頻率,同時過量MTPA形成非鏡像異構物鹽,其中H
a及H
b所致之共振改變位置。在後一種情形下,由於兩個非鏡像異構物之H
b使得共振之間存在大的分離。此技術允許檢測低至1%之次要鏡像異構物。此表明單質子化獲得以假環形式存在之物質,而雙質子化物質係以非環形式存在。類似地,在非鏡像異構物樟腦磺醯胺之
1H NMR光譜中,由二胺部分之末端甲基所致之共振甚至在低場強亦完全解析。經解析二胺(R)-2及(S)-2至羥基氯喹之鏡像異構物(R)-la及(S)-la之轉化涉及在二異丙基乙胺存在下將(R)-2及(S)-2與4,7-二氯喹啉一起加熱。針對兩個鏡像異構物之最佳條件不同:在135℃下,(S)-2始終比(R)-2更易於降解,且相應地轉化較不完全。藉由酸-鹼萃取實施(R)-la及(S)-la之大規模純化。在低於pH 5下,自水相去除過量二氯喹啉,且藉由在pH 7與pH 8之間進一步萃取去除剩餘雜質,隨後木炭處理水相以去除痕量高度著色之材料。在高於pH 8 (最方便pH為12左右)下,萃取純羥基氯喹。(R)-1a及(S)-1a二者均係油狀物,且在儲存期間需要保護其免於光,否則產生黃色。純化後,藉由用磷酸(2莫耳當量)處理將鏡像異構物(R)-1a及(S)-1a轉化成雙(磷酸二氫鹽)鹽((R)-b及((S)-1b)。在三乙胺自前述層析步驟保留之情形中,藉由與丙酮一起研磨將此去除以留下易潮解水合物。將磷酸(19.7 ml, 0.29 mol)添加至(S)-la (43.4 g, 0.144 mol),同時冰冷卻以緩和反應。將所得膠狀物在丙酮下碾磨並將所得易潮解固體快速過濾,立即懸浮於新鮮丙酮(200 ml)中,然後攪拌過夜。藉由在乙醇懸浮液中加熱脫水獲得易碎的白色固體。快速過濾獲得白色粉末,立即將其轉移至含有乙醇(200 ml)之燒瓶中。將所得懸浮液回流四天,然後過濾,並用乙醇洗滌固體。在真空中乾燥至恆定重量後,(S)-1b之產量係52.6 g (69%)。將(R)-1a以類似方式轉化成雙(磷酸二氫鹽)鹽。無水樣品及單水合物二者均在192℃熔融,該溫度實質上高於外消旋物所報導之熔點168℃至170℃。鏡像異構物產生實質上且可再現之旋轉,且可藉由HPLC使用對掌性AGP固定相檢測低至0.5%之次要鏡像異構物。因此,旋光測定及HPLC二者均適於測定鏡像異構物之光學純度。硫酸羥基氯喹亦有市售,且可購自3B Scientific Corporation™ (目錄編號DR001622)。
使用方法本發明亦涵蓋治療發炎病況、脂肪性肝炎及發炎相關肝癌之方法。本發明之該等方法包含向有需要之個體投與治療有效量之克立咪唑及/或R-氯喹。
本發明亦提供用於治療發炎病況之方法,其包括向個體投與一或多種化合物或包括本發明之一或多種化合物及醫藥上可接受之媒劑之組合物。本發明亦提供與目前臨床中所用之抗發炎治療組合用於治療或預防發炎病況之方法。抗發炎治療之實例包含(但不限於)非類固醇抗發炎藥物,例如阿斯匹林(aspirin)、布洛芬(ibuprofen)及萘普生(naproxen);皮質類固醇;抗發炎生物活性化合物,例如白花丹素(plumbagin);或免疫選擇性抗發炎衍生物。
本發明提供用於治療非酒精性脂肪性肝炎之方法,其包括向個體投與一或多種化合物或包括本發明之一或多種化合物及醫藥上可接受之媒劑之組合物。如本文所用,術語「非酒精性脂肪性肝炎」係指以肝臟發炎與肝中之併發脂肪累積為特徵之肝病。本發明亦提供與目前臨床中用於治療通常與非酒精性脂肪性肝炎相關之病況(例如,代謝症候群及/或糖尿病)所用之治療組合用於治療非酒精性脂肪性肝炎之方法。治療代謝症候群及/或糖尿病之非限制性實例包含降低胰島素抗性、膽固醇及甘油三酯之治療。降低胰島素抗性之治療實例包含但(不限於)二甲雙胍、噻唑啶二酮、吡格列酮及羅格列酮(rosiglitazone)。高膽固醇血症之治療實例包含(但不限於)他汀(statin)、膽汁酸螯合劑、膽固醇吸收抑制劑、纖維酸衍生物或菸鹼酸。
本發明提供治療或預防肝癌之方法,其包括向個體投與一或多種化合物或包括本發明之一或多種化合物及醫藥上可接受之媒劑之組合物。如本文所用,術語「肝癌」係指肝之過度增生性疾病,包含(但不限於)肝細胞癌、纖維板層肝細胞癌、膽管癌、血管肉瘤、繼發性或轉移性肝癌及肝母細胞瘤。本發明亦提供與目前臨床中用於治療或預防肝癌所用之治療(包含但不限於化學治療劑)組合用於治療或預防肝癌之方法。
本發明之醫藥組合物可將本發明之克立咪唑及R-氯喹調配於醫藥組合物中。此等組合物除克立咪唑及/或R-氯喹之外可包括醫藥上可接受之賦形劑、載劑、緩衝劑、穩定劑或熟習此項技術者熟知之其他材料。該等材料應無毒且不應干擾活性成分之效力。載劑或其他材料之確切性質可取決於投與途徑,例如經口、靜脈內、經皮膚或皮下、經鼻、肌內、腹膜腔內途徑。
用於經口投與之醫藥組合物可呈錠劑、膠囊、粉末或液體形式。錠劑可包含固體載劑,例如明膠或佐劑。液體醫藥組合物通常包含液體載劑,例如水、石油、動物或植物油、礦物油或合成油。可包含生理鹽水溶液、右旋糖或其他糖溶液或二醇(例如乙二醇、丙二醇或聚乙二醇)。
對於靜脈內、經皮膚或皮下注射或病痛位點處之注射,活性成分將呈非經腸可接受之水溶液形式,其無熱原且具有適宜pH、等滲性及穩定性。熟習此項技術者完全能夠使用(例如)等滲媒劑(例如氯化鈉注射液、林格氏注射液(Ringer's Injection)、乳酸林格氏注射液)來製備適宜溶液。可視需要包含防腐劑、穩定劑、緩衝劑、抗氧化劑及/或其他添加劑。
給予個體之本發明小分子有用化合物較佳以「治療有效量」或「預防有效量」(視情況而定,但預防可視為療法)投與,此足以顯示對個體之益處。所投與之實際量及投與速率及時程將取決於所治療病況之性質及嚴重性。治療處方(例如劑量決定等)在普通醫師及其他醫師之責任內,且通常慮及所治療病症、個體患者之狀況、遞送位點、投與方法及醫師已知之其他因素。上述技術及方案之實例可在Remington's Pharmaceutical Sciences, 第16版, Osol, A. (編輯), 1980中找到。
組合物可單獨投與或以同時或依序方式與其他治療組合投與,端視所欲治療的病況而定。
實例以下係用於實施本發明之特定實施例之實例。實例僅出於說明之目的提供,且非欲以任何方式限制本發明之範圍。已努力確保所用數值(例如量、溫度等)之精確性,但當然應容許一些實驗誤差及偏差。
除非另有說明,否則本發明之實踐將採用熟習此項技術者所知之蛋白質化學、生物化學、重組DNA技術及藥理學之習用方法。該等技術全面解釋於文獻中。參見例如T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook等人, Molecular Cloning: A Laboratory Manual (第2版, 1989); Methods In Enzymology (S. Colowick及N. Kaplan編輯, Academic Press, Inc.); Remington's Pharmaceutical Sciences, 第18版(Easton, Pennsylvania: Mack Publishing Company, 1990); Carey及Sundberg,Advanced Organic Chemistry第3版. (Plenum Press)卷A及B (1992)。
本文中未直接定義之任何術語應理解為具有如本發明技術內所理解之通常與其相關之意義。本文討論某些術語以在闡述本發明態樣之組合物、裝置、方法及諸如此類及如何製造或使用其之方面為醫師提供額外導引。應瞭解,相同事物可以多於一種方式來表達。因此,本文所討論術語中之任一或多者可使用替代性語言及同義詞。對於術語在本文中是否詳細闡述或討論而言並不重要。提供一些同義詞或可取代方法、材料及諸如此類。除非另有明確說明,否則一個或幾個同義詞或等效物之陳述並不排除其他同義詞或等效物之使用。實例(包含術語之實例)之使用僅出於說明性目的且並不限制本文中本發明態樣之範圍及意義。
方法 非酒精性脂肪性肝炎之誘發55隻雄性小鼠出生2天後以單一皮下方式注射200 µg鏈佐黴素(STZ, Sigma-Aldrich, USA)溶液及在4週齡後飼餵高脂肪飼料(HFD, 57 kcal%脂肪, 目錄編號HFD32, CLEA Japan, Inc., Japan)以誘發NASH。以下將藉由此方法誘發具有NASH之小鼠稱為NASH小鼠。
醫藥組合物及藥物投與路徑化合物A、B、C、D及媒劑係以每公斤5 mL之體積量經口投與。
化合物A包括R-氯喹及S-氯喹之外消旋混合物。
化合物B包括R-氯喹。化合物C包括S-氯喹。
化合物D包括克立咪唑。將所有測試化合物稱重並溶解於媒劑(5% DMSO/水)中。
藥物之治療劑量前兩天以258 mg/kg之劑量經口投與化合物A、B及C,且此後129 mg/kg每日一次投與。以89 mg/kg之劑量每日兩次經口投與化合物D。下表1是治療時間表的概要。
表 1 :研究組之治療時間表
*258 mg/kg:僅前2天。
動物自Japan SLC, Inc. (Shizuoka, Japan)獲得C57BL/6小鼠(妊娠14天,雌性)。研究中所使用的所有動物係根據日本藥理學會動物使用指南(Japanese Pharmacological Society Guidelines for Animal Use)圈養並照料。
全血之血漿取樣及量測及血漿生物化學在6週齡(投藥前)、7週齡及8週齡時利用抗凝血劑(Novo-heparin, Mochida Pharmaceutical, Japan)自頜下出血收集非禁食血液至聚丙烯管中。將所收集血液樣品離心並收集上清液作為肝素化血漿。
使用LIFE CHECK (EIDIA Co. Ltd., Japan)量測全血中之非禁食血糖。藉由FUJI DRI-CHEM 7000 (Fujifilm Corporation, Japan)量測血漿ALT。
組織病理學分析對於HE染色,自預固定於布安溶液(Bouin’s solution)中之肝組織的石蠟塊切割切片並用Lillie-Mayer之蘇木素(Muto Pure Chemicals Co., Ltd., Japan)及伊紅溶液(Wako Pure Chemical Industries)染色。根據Kleiner準則(Kleiner DE.等人,Hepatology, 2005;41:1313)計算NAFLD活動性評分(NAS)。為可視化膠原沈積,使用苦味酸-天狼星紅(picro-Sirius red)溶液(Waldeck, Germany)對經布安固定之肝切片染色。
為定量分析纖維化面積,使用數位相機(DFC280; Leica, Germany)在200倍放大率下在肝之中央靜脈周圍捕獲天狼星紅染色切片之亮視野影像,且使用ImageJ軟體(National Institute of Health, USA)量測5個視野/切片之陽性面積。
肝之宏觀分析量測肝表面上所形成之宏觀可視化之腫瘤結節之數量。量測肝表面上所形成之宏觀可視化腫瘤結節之最大直徑。
統計學測試使用GraphPad Prism 4 (GraphPad Software Inc., USA)上之Bonferroni多重比較測試實施統計學分析。
P值< 0.05視為統計學上顯著。
實例 1 : S- 氯喹之投與導致具有 NASH 之小鼠之肝重量及體重均減輕。所有組之體重在治療時段期間無明顯變化(表2)。媒劑組與所有化合物組間之平均體重無顯著差異。在治療時段期間,小鼠在第9週之前死亡如下:在所有組中,11隻小鼠中之1隻死亡。
在處死之日,化合物C組顯著降低平均體重(表2)。在處死之日,媒劑組與化合物A、化合物B及化合物D組間之平均體重無顯著差異。
化合物C組顯著降低平均肝重量(表2)。在處死之日,媒劑組與化合物A、化合物B及化合物D組間之平均肝重量無顯著差異。在處死之日,媒劑組與化合物A、化合物B、化合物C及化合物D組間之平均肝重量與體重比率無顯著差異。
表 2. NASH 小鼠之體重及肝重量
實例 2 :在 NASH 小鼠中投與氯喹或克立咪唑之小鼠全血生物化學 。在研究時段期間,媒劑組與化合物A、化合物B、化合物C及化合物D組間之全血血糖含量無顯著差異。在處死之日,量測媒劑組與化合物A、化合物B、化合物C及化合物D組間之血漿ALT含量(表3)。
表 3. 經測試化合物治療之 NASH 小鼠之 ALT 含量。
實例 3 :在 經 R- 氯喹或克立咪唑治療之 NASH 小鼠中觀察到 NAFLD 活動性評分降低。對來自經測試化合物治療之小鼠之肝組織切片實施蘇木素及伊紅染色,並計算NAFLD活動性評分(表4)。化合物B及化合物D組與媒劑組相比顯示NAS之顯著降低。
表 4 : 經測試化合物治療之 NASH 小鼠之 NAFLD 活動性評分
實例 4 : 在 NASH 小鼠中投與測試化合物不影響肝之纖維化面積。對測試化合物治療之NASH小鼠之肝切片實施肝天狼星紅染色(表5)。在處死時,媒劑組與化合物A、化合物B、化合物C及化合物D組間之纖維化面積無顯著差異。
表 5 : 投與測試化合物之 NASH 小鼠之肝之纖維化面積。
實例 5 : 投與測試化合物之具有經 NASH 誘發之肝細胞癌之小鼠之體重及肝重量。所有研究組之體重在治療時段期間無明顯變化(表6)。媒劑組與所有化合物組間之平均體重無顯著差異(表6)。在治療時段期間,小鼠在第18週之前死亡如下:在媒劑及化合物D組中,4隻小鼠中的1隻死亡。在化合物B及化合物C組中,4隻小鼠中的2隻死亡。在化合物A組中,4隻小鼠中的3隻死亡。平均值±SD顯示於表6中。
表 6. 經 測試化合物治療之 NASH 誘發之 HCC 小鼠之器官重量及肝重量與體重之比率
實例 6 : 在具有肝細胞癌之小鼠中投與克立咪唑減少肝腫瘤直徑及腫瘤結節之數量。量測肝表面上所形成之宏觀可視化腫瘤結節之數量。量測肝表面上所形成之宏觀可視化腫瘤結節之最大直徑(圖7)。在媒劑組中,所有存活小鼠(n=3)在肝表面上均顯示可視化腫瘤結節。在化合物D (克立咪唑)組中,觀察到3隻存活小鼠中的2隻在肝表面上不存在可視化腫瘤結節(圖8)。平均值±SD顯示於表7中。
表 7. 經 測試化合物治療之具有 HCC 之小鼠之可視化腫瘤結節之最大直徑。
實例 7 : 利用克立咪唑治療患有肝細胞癌 (HCC) 之人類患者。執行IIa期開放標籤先導性研究以測試每日三次向患有肝細胞癌(HCC)之個體(等待肝移植或具有不可切除性病灶)經口給予200 mg與400 mg與500 mg克立咪唑鹽酸鹽之安全性、耐受性、藥物動力學及藥效學活性。整個研究治療多達40名患者。以下闡述兩名患有肝細胞癌之患者之初始臨床結果,該兩名患者投與200 mg克立咪唑達3個月或5個月。
患者 #1 概述 :患者#1係70歲男子,經診斷患有在慢性肝炎B誘發之肝硬化情況下之HCC。診斷係藉由動態肝臟CT確定。患者#1已於2011年接受針對HCC之射頻燒灼治療,但治療後經歷疾病進展。患者#1亦於2015年4月至5月及2015年6月接受三個療程之動脈化療栓塞(TACE)。患者#1在HCC進展之前展現穩定之疾病達約5個月之時段。然後患者開始克立咪唑治療,每日三次經口投與200 mg克立咪唑。克立咪唑治療3個月後,患者經歷追蹤動態肝臟CT成像,且預計在不存在任何療法之情況下腫瘤大小將顯著增加時,HCC保持穩定。彼時,患者感覺良好,無抱怨或副作用。
患者 #2 概述 :患者#2係77歲男子,經診斷患有在慢性肝炎B誘發之肝硬化情況下之多灶性HCC。診斷係藉由動態肝臟磁共振成像確定。患者#2已經索拉菲尼治療失敗及/或對索拉菲尼治療不耐受並展現治療後疾病進展。患者#2然後開始克立咪唑治療,每日三次經口投與200 mg克立咪唑。克立咪唑治療5個月後,患者經歷追蹤動態肝臟磁共振成像,且預計在不存在任何療法之情況下腫瘤大小將顯著增加時,HCC保持穩定。彼時,患者感覺非常好,無抱怨或副作用。
儘管迄今為止治療少量患者,但利用所用低劑量克立咪唑(即,在隨後患者中200 mg對高達500 mg)觀察到之功效及耐受性本身令人極為興奮,尤其當與針對HCC之唯一經批准療法索拉菲尼相比時。在索拉菲尼2期研究(Abou-Alpha等人Journal Clinical Oncology 2006, 24(26): 4293-4300)中,中位進展時間(TTP)係4.2個月。毒性包含超過40%之腹瀉、超過30%之手足皮膚反應及30%之疲勞,包含等級3/4之藥物相關毒性,例如疲勞(9.5%)、腹瀉(8.0%)及手足皮膚反應(5.1%)。在索拉菲尼3期研究(Llovet等人NEJM 2008;359:378-90)中,索拉菲尼組之中位放射性進展時間為5.5個月,且安慰劑組之中位放射性進展時間為2.8個月。索拉菲尼組之治療相關不良事件之總發生率係80%。此等本質上主要係胃腸、全身性或皮膚病學事件(嚴重性為等級1或2)、以及低磷酸鹽血症(11%之等級3)及血小板減少症(4%之等級3或4)。
儘管已特別地參考實施例及各種替代性實施例顯示及闡述本發明,但熟習此項技術者將理解,可在不背離本發明之精神及範疇之情形下做出形式及細節之各種改變。
出於全部目的,本說明書之主體內所引用之所有參考文獻、發佈之專利及專利申請案均以整體引用的方式併入本文中。
組 | 小鼠數量 | 小鼠 | 測試物質 | 劑量 (mg/kg) | 體積 (mL/kg) | 方案 | 處死 (9週) | 處死 (18週) |
1 | 11 | STAM | 媒劑 | - | 5 | 經口,每日一次, 6週- 18週 | 6 | 4 |
2 | 11 | STAM | 化合物A (R-氯喹及S-氯喹) | 258* 129 | 5 | 經口,每日一次, 6週- 18週 | 6 | 4 |
3 | 11 | STAM | 化合物B (R-氯喹) | 258* 129 | 5 | 經口,每日一次, 6週- 18週 | 6 | 4 |
4 | 11 | STAM | 化合物C (S-氯喹) | 258* 129 | 5 | 經口,每日一次, 6週- 18週 | 6 | 4 |
5 | 11 | STAM | 化合物D (克立咪唑) | 89 | 5 | 經口,每日兩次, 6週- 18週 | 6 | 4 |
參數 (平均值±SD) | 媒劑 (n=6) | 化合物A (n=6) | 化合物B (n=6) | 化合物C (n=6) | 化合物D (n=6) |
體重(g) | 16.9 ±2.1 | 15.0 ±1.9 | 14.5 ±2.4 | 13.7 ± 1.3 | 15.5 ± 1.5 |
肝重量(mg) | 1082 ± 130 | 1045±243 | 934 ± 135 | 810 ± 77 | 1047 ± 76 |
肝重與體重比率(%) | 6.5 ± 0.9 | 7.0 ± 1.4 | 6.5 ± 0.4 | 5.9 ± 0.4 | 6.8 ± 0.4 |
參數 (平均值± SD) | 媒劑(n=6) | 化合物A (n=6) | 化合物B (n=6) | 化合物C (n=6) | 化合物D (n=6) |
血漿ALT (U/L) | 22 ± 11 | 21 ± 13 | 14 ±6 | 9 ± 3 | 18 ± 10 |
組 | n | 評分 | NAS (平均值±SD) | |||||||||||
脂肪變性 | 小葉發炎 | 肝細胞氣球樣變 | ||||||||||||
0 | 1 | 2 | 3 | 0 | 1 | 2 | 3 | 0 | 1 | 2 | ||||
媒劑 | 6 | - | 4 | 2 | - | - | - | 4 | 2 | - | - | 6 | 5.7±0.8 | |
化合物A | 6 | 1 | 5 | - | - | - | - | 1 | 5 | - | 3 | 3 | 5.2±0.8 | |
化合物B | 6 | 1 | 5 | - | - | - | 2 | 4 | - | - | 1 | 5 | 4.3±0.5 | |
化合物C | 6 | - | 6 | - | - | - | - | 4 | 2 | - | - | 6 | 5.3±0.5 | |
化合物D | 6 | 1 | 5 | - | - | - | 4 | 1 | 1 | - | - | 6 | 4.3±1.0 |
NAS分量之定義 | ||
項目 | 評分 | 範圍 |
脂肪變性 | 0 | <5% |
1 | 5-33% | |
2 | >33-66% | |
3 | >66% | |
肝細胞氣球樣變 | 0 | 無 |
1 | 較少氣球狀細胞 | |
2 | 許多細胞/突出氣球狀 | |
肝小葉發炎 | 0 | 無病灶 |
1 | <2病灶/200x | |
2 | 2-4病灶/200x | |
3 | >-4病灶/200x |
參數 (平均值± SD) | 媒劑 (n=6) | 化合物A (n=6) | 化合物B (n=6) | 化合物C (n=6) | 化合物D (n=6) |
天狼星紅陽性面積(%) | 1.13 ± 0.17 | 0.87 ± 0.23 | 0.78 ±0.35 | 0.90 ± 0.44 | 0.95 ± 0.39 |
參數 (平均值±SD) | 媒劑 (n=3) | 化合物A (n=1) | 化合物B (n=2) | 化合物C (n=2) | 化合物D (n=3) |
體重(g) | 24.6 ±2.1 | 17.5 ±0.0 | 20.4 ±0.3 | 17.9 ± 2.8 | 18.8 ± 3.8 |
肝重量(mg) | 2059 ± 667 | 1443±0 | 1616 ± 635 | 1353 ± 178 | 1710 ± 113 |
肝重量與體重之比率(%) | 8.3 ± 2.5 | 8.2 ± 0.0 | 7.9 ± 3.0 | 7.6 ± 0.1 | 6.3 ± 0.8 |
參數 (平均值±SD) | 媒劑 (n=3) | 化合物A (n=1) | 化合物B (n=2) | 化合物C (n=2) | 化合物D (n=3) |
結節數量 | 3.0 ±2.0 | 2.0 ±0.0 | 2.0 ±1.4 | 1.5 ± 2.1 | 0.3 ± 0.6 |
結節之最大直徑(mm) | 7.3 ± 6.5 | 6.1 ±0 | 11.1 ± 7.0 | 3.5 ± 5.0 | 0.7 ± 1.2 |
參照以下闡述及附圖,本發明之該等及其他特徵、態樣以及優點將變得更好理解,其中:
圖 1 :圖解說明合成R-氯喹之製程方案。
圖 2 :顯示克立咪唑及克立咪唑代謝物之化學結構。
圖 3 :圖3圖解說明用於克立咪唑之優良製造規範(GMP)合成之合成方案。
圖 4 :顯示氯喹代謝物之化學結構。
圖 5:顯示羥基氯喹(rac-1)及R-羥基氯喹(R)-1之化學結構。
圖 6 :圖解說明合成羥基氯喹之鏡像異構物之製程方案。
圖 7:顯示羥基氯喹代謝物之化學結構。
圖 8:顯示小鼠肝之代表性影像,其繪示用克立咪唑(化合物D)治療之小鼠中腫瘤形成之抑制。
Claims (16)
- 如請求項1之用途,其中該有效量係每日、每日兩次或每日三次200至500mg。
- 如請求項1或2之用途,其中投與克立咪唑、該克立咪唑之氘化類似物或該克立咪唑代謝物達6週或更多週。
- 如請求項1或2之用途,其中該藥劑導致發炎之減輕、肝之小葉發炎之減輕、肝功能之改良、或肝癌發展或進展之風險之降低。
- 如請求項1或2之用途,其中該藥劑係調配為經口及/或靜脈內投與。
- 如請求項1或2之用途,其中該發炎之特徵係在於與正常健康對照群相關的含量相比,該個體的血清或血漿中丙胺酸胺基轉移酶的血清或血漿含量提高。
- 如請求項1或2之用途,其中該個體中之發炎係小葉發炎,其特徵在於組織學樣品中的多個浸潤免疫細胞病灶。
- 如請求項1或2之用途,其中該個體中之發炎係藉由自肝活體組織切片獲得的樣品檢查來診斷的。
- 如請求項1或2之用途,其中該個體中之發炎係經超音波、電腦斷層掃描、磁共振成像、血液測試或包括超極化13C-NMR光譜之NMR光譜診斷。
- 如請求項1或2之用途,其中該治療顯著減少個體的丙胺酸胺基轉移 酶血清或血漿含量。
- 如請求項1或2之用途,其中該個體為胰島素抵抗且係經投與有效量之可增加該個體中胰島素敏感性的藥劑,其係選自二甲雙胍(metformin)、噻唑啶二酮(thiazolidinedione)、吡格列酮(pioglitazone)或羅格列酮(rosiglitazone)。
- 如請求項1或2之用途,其中該個體係經投與有效量之可降低該個體中膽固醇及/或高甘油三酯的藥劑,其係選自他汀(statin)、膽汁酸螯合劑、膽固醇吸收抑制劑、纖維酸衍生物或菸鹼酸。
- 如請求項1或2之用途,其中該藥劑進一步包含有效量之下列一或多者或與有效量之下列一或多者共同使用:CYP3A4抑制劑、第二抗發炎劑、R-氯喹代謝物、R-羥基氯喹、R-羥基氯喹之氘化類似物、或R-羥基氯喹代謝物、及抗NASH藥劑。
- 如請求項13之用途,其中該CYP3A4抑制劑為利托那韋(ritonavir)或可比司他(cobicistat)。
- 如請求項13之用途,其中該第二抗發炎劑包含阿斯匹林(aspirin)、布洛芬(ibuprofen)、萘普生(naproxen)、皮質類固醇、白花丹素(plumbagin)、或免疫選擇性抗發炎衍生物。
- 如請求項13之用途,其中該抗NASH藥劑為FXR促效劑、LOXL2抑制劑、半胱天冬酶蛋白酶抑制劑、半胱胺重酒石酸氫鹽、半乳糖凝集素-3抑制劑、CCR2及CCR5途徑抑制劑、半胱胺酸消耗劑、SGLT-2抑制劑、GLP-1、膽汁酸、合成脂肪酸及膽汁酸偶聯物、去乙醯化酶刺激劑(Sirtuin stimulant)、免疫調節劑、或PPAR促效劑。
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