TWI695718B - 前藥 - Google Patents
前藥 Download PDFInfo
- Publication number
- TWI695718B TWI695718B TW104120671A TW104120671A TWI695718B TW I695718 B TWI695718 B TW I695718B TW 104120671 A TW104120671 A TW 104120671A TW 104120671 A TW104120671 A TW 104120671A TW I695718 B TWI695718 B TW I695718B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- phosphate
- gemcitabine
- phenyl
- benzyloxy
- Prior art date
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- 229940002612 prodrug Drugs 0.000 title abstract description 6
- 239000000651 prodrug Substances 0.000 title abstract description 6
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 51
- 239000010452 phosphate Substances 0.000 claims abstract description 51
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 24
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 18
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Abstract
本發明係關於一種熟知腫瘤學藥物吉西他濱(gemcitabine)之單磷酸酯核苷酸之前藥。具體言之,當以單一磷酸酯非對映異構體形式存在時,本發明係關於吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯,且特定言之,本發明係關於(S)-磷酸酯非對映異構體,其相對於(R)-非對映異構體提供顯著及出人意料的溶解性增加。(S)-磷酸酯差向異構體亦比該(R)-非對映異構體優先溶解於環糊精溶液中。
Description
本發明係關於一種熟知腫瘤學藥物吉西他濱(gemcitabine)之單磷酸酯之前藥。具體言之,當以單一磷酸酯非對映異構體形式存在時,本發明係關於吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯,且特定言之,本發明係關於(S)-磷酸酯非對映異構體,其相對於(R)-非對映異構體提供顯著及出人意料的溶解性增加。(S)-磷酸酯非對映異構體亦比(R)-非對映異構體優先溶解於環糊精溶液中。
吉西他濱(1;以GemzarTM市售)為有效核苷腫瘤學藥物,其目前臨床上用於治療膀胱癌、乳癌、肺癌、卵巢癌及胰腺癌且尤其此等癌症之固體形式。
吉西他濱之臨床效用受多個固有及後天性抗性機制限制。在細胞水準下,抗性取決於三個參數:(i)用於活化成磷酸化部分所需之脫氧
胞苷激酶下調;(ii)核苷轉運子,尤其由癌細胞吸收所需的hENT1之表現減少;及(iii)催化酶,尤其降解吉西他濱之胞苷脫胺酶上調。
WO2005/012327描述一系列吉西他濱核苷酸前藥及相關核苷藥物分子。其中,吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)被識別為尤其有效化合物。此等前藥似乎避免許多限制吉西他濱效用之固有及後天性抗性機制(『Application of ProTide Technology to Gemcitabine:A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent(NUC-1031)in Clinical Development』;Slusarczyk等人;J.Med.Chem.;2014,57,1531-1542)。
NUC-1031 2製備為在磷酸酯中心處為差向異構的兩種非對映異構體之混合物。
不幸地,NUC-1031 2為極其親脂性的因此水溶性差(藉由計算:<0.1mg/mL),且已計算可電離部分、嘧啶氮及酚系羥基位於適合於非經腸投藥之pH範圍外之pKas。其基本上不溶於水,而不管鹽含量或pH,且此對用於以足夠高的劑量遞送前藥以有效治療之調配物之研發具有影響。其亦對將允許成本有效地製造NUC-1031之有效製造方法之研發具有影響。
本發明之某些具體實例之一目標為提供呈可調配為有效醫藥組成物形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)。
本發明之某些具體實例之一目標亦為提供一種可製備且儲存較長時間段之形式的吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)。
本發明之某些具體實例之一目標為提供呈比先前技術形式具有更高溶解性之形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)。
本發明之某些具體實例之一目標為提供在磷處呈單一非對映異構體形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)。
本發明之某些具體實例滿足一些或所有上述目標。
本發明之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯較佳具有與吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯(NUC-1031;2)實質上相同的活性。然而,若以此形式使用其存在製造或治療益處,則其可能具有稍微較低活性但具有如本說明書中所描述之其他益處。
根據本發明,提供吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3:
或其醫藥學上可接受之鹽或溶劑合物。較佳地,吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3呈實質上非對映異構純形式。
本發明者已發現兩種非對映異構體之溶解性的出人意料且顯著的差異。(S)-差向異構體3在多種極性有機溶劑與水之混合物中具有足夠溶解性,使得其適合於作為治療劑調配及投予。(R)-差向異構體4實質上不溶於大多數所量測之溶劑混合物中。此溶解性之顯著差異先前未被識別且(S)-差向異構體之此特性的潛在益處尚未被識別。在多種所測試之溶劑混合物中,(S)-差向異構體與(R)-差向異構體之間的溶解性差異超過100倍。
出人意料地,(S)-差向異構體亦比(R)-差向異構體優先溶解於環糊精溶液中。其他吉西他濱磷酸酯衍生物尚未觀測到此現象。
在本發明之第二態樣中提供一種醫藥調配物,其包含非對映異構純度大於約90%之吉西他濱[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3或其醫藥學上可接受之鹽或溶劑合物;及至少一種醫藥學上可接受之賦形劑。
該調配物可用於非經腸,例如靜脈內、皮下或肌內投藥。較佳地,該調配物用於靜脈內投藥。
該調配物可為視情況亦包含極性有機溶劑之水性調配物。在非經腸(例如靜脈內)投藥之情況下,調配物較佳亦包含極性有機溶劑。
調配物亦可包含環糊精。
在本發明之第三態樣中提供吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3或其醫藥學上可接受之鹽或溶劑合物,其用於醫療用途。
在本發明之第四態樣中提供吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3或其醫藥學上可接受之鹽或溶劑合物,其用於治療癌症。
在本發明之第五態樣中提供吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3或其醫藥學上可接受之鹽或溶劑合物,其用於製造用於治療癌症之醫藥品。
在本發明之第六態樣中提供一種治療癌症之方法,該方法包含向有需要之個體投予治療有效量之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3或其醫藥學上可接受之鹽或溶劑合物。
溶劑合物將通常為水合物。因此,吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯可呈鹽或水合物形式。吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯可能不呈鹽及/或溶劑合物(例如水合物)形式。較佳地,其呈自由鹼形式。
吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯之非對映異構純度可大於約90%。其非對映異構純度可大於95%、98%、99%或甚至99.5%。『實質上非對映性純(Substantially diastereomerically pure)』出於本發明的目的定義為大於約90%之非對映異構純度。
癌症可為選自以下各者之癌症:胰腺癌、乳癌、卵巢癌、膀胱癌、結腸直腸癌、肺癌、膀胱癌、前列腺癌、膽管癌、腎癌、子宮頸癌、胸腺癌、原發灶(primary origin)不明之癌症。癌症亦可為淋巴瘤或白血病。
在本發明之第七態樣中提供一種提供呈實質上非對映異構純形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯之至少一種非對映異構體的方法,該方法包含以下步驟:獲得吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4與吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3之混合物;使該混合物經受分離技術;及分離後,分離呈實質上非對映異構純形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4及/或吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3。
在本發明之第八態樣中提供一種提供呈實質上非對映異構純形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯之至少一種非對映異構體的方法,該方法包含以下步驟:獲得3'-保護之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4與3'-保護之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3之混合物;使該混合物經受分離技術;分離後,分離呈實質上非對映異構純形式之3'-保護之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4及/或3'-保護之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3;
自分離非對映異構體中之一者或兩者移除3'-保護基,提供呈實質上非對映異構純形式之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4及/或吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3。
3'-保護之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯為吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-磷酸酯之衍生物,其中3-羥基之特徵在於羥基保護基。所討論之保護基必須可乾淨地移除。例示性保護基包括矽烷基保護基(例如第三丁基二甲基矽烷基及三乙基矽烷基),在該情況下,可使用選自TFA、HF、氟矽酸及四丁基氟化銨之試劑移除保護基。替代性保護基將為碳酸酯基(例如碳酸第三丁酯),在該情況下,可使用布朗斯特酸(Bronsted acid)(例如TFA)或路易斯酸(Lewis acid)(例如ZnBr2)移除保護基。
分離技術可為層析,例如管柱層析、製備型薄層層析或製備型HPLC。當分離技術為製備型HPLC時,其可使用例如包含直鏈澱粉三(3,5-二甲苯基胺基甲酸酯)之手性管柱的手性管柱進行。適用於本發明方法之手性管柱之一實例為Chiralpak ADTM;其固定相由其上已物理塗佈直鏈澱粉三(3,5-二甲苯基胺基甲酸酯)之20μm二氧化矽支撐件組成。
分離技術可選擇性溶解於環糊精溶液中。此技術涉及使混合物與環糊精溶液接觸,使得一個差向異構體優先於另一差向異構體溶解於環糊精溶液中,且隨後分離環糊精溶液與未溶解固體。環糊精溶液可為環糊精水溶液。可藉由過濾達成溶液與固體之分離。
本發明亦提供吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4:
或其醫藥學上可接受之鹽或溶劑合物。本發明亦提供一種醫藥調配物,其包含非對映異構純度大於約90%之吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯4或其醫藥學上可接受之鹽或溶劑合物及醫藥學上可接受之賦形劑;以及化合物4之醫療用途及使用化合物4之治療方法。(R)-差向異構體之此等態樣對應於在上文所描述之本發明之第三態樣至第六態樣中關於化合物3所描述之彼等態樣。吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯可呈實質上非對映異構純形式。吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯可能不為鹽及/或溶劑合物(例如水合物)。較佳地,其以自由鹼形式存在。
已展示R-差向異構體自人類肝細胞的固有清除率之半衰期為s-差向異構體之彼半衰期的四倍。與R-異構體相關之較長半衰期應導致S-異構體之不同藥物動力學及藥效學特徵。此特徵可能意謂與在S-差向異構體之情況下相比,R-異構體在暴露於R-差向異構體之血漿及較大組織中將達成延長循環。特定言之,可能預期其更穩定朝向代謝,且具有較不快速代謝達成Cmax。其在一定程度上可充當混合物之緩慢釋放形式,尤其與更快速代謝之單一S-異構體相比時。Cmax可較低但AUC可能較高,考慮到較大及較長時間暴露於蛋白。此長時間暴露於R-差向異構體可允許實質
上延長腫瘤暴露於R-差向異構體且可導致較大療效,其中肝中之首關代謝減少將導致較高藥物濃度。此不同特性亦可允許靶向特定腫瘤,其中較長PK特徵可導致在難以進入的脈管較差之腫瘤位點處之較大療效。長時間暴露於R-差向異構體可經由更多細胞週期階段(包括細胞分裂)確保活性代謝物之適當藥物濃度。
在下文中參考附圖進一步描述本發明之具體實例,其中:圖1展示藉由HPLC使用Chiralpak AD管柱及正庚烷/lPA梯度溶劑系統來分離化合物3與化合物4之層析。
圖2展示如藉由x射線繞射確定之化合物4之結構。
圖3展示如藉由x射線繞射確定之化合物3之結構。
圖4展示在以1:2.3莫耳比添加HP-β-CD之後NUC-1031異構混合物(3.12mM)之31P-NMR光譜(202MHz,D2O)。
圖5展示在以1:2.3莫耳比添加HP-β-CD之後MeOH(A)於H2O中之NUC-1031(3.12mM)之HPLC跡線。
在本說明書通篇中,術語S-差向異構體或S-非對映異構體係指吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯。同樣,在本說明書通篇中,術語R-差向異構體或R-非對映異構體係指吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(R)-磷酸酯。
本發明化合物可用於人體之治療。其可用於動物體之治療。特定言之,本發明化合物可用於治療諸如家畜之商業動物。替代地,本發
明化合物可用於治療諸如貓、狗等之伴侶動物。
本發明化合物可以醫藥學上可接受之鹽形式獲得、儲存及/或投予。適合的醫藥學上可接受之鹽包括(但不限於)醫藥學上可接受無機酸,諸如鹽酸、硫酸、磷酸、硝酸、碳酸、硼酸、胺磺酸及氫溴酸之鹽;或醫藥學上可接受有機酸,諸如乙酸、丙酸、丁酸、酒石酸、順丁烯二酸、羥基順丁烯二酸、反丁烯二酸、蘋果酸、檸檬酸、乳酸、黏液酸、葡萄糖酸、苯甲酸、丁二酸、草酸、苯乙酸、甲磺酸、甲苯磺酸、苯磺酸、柳酸、磺胺酸、天冬胺酸、麩胺酸、依地酸、硬脂酸、棕櫚酸、油酸、月桂酸、泛酸、鞣酸、抗壞血酸及戊酸之鹽。適合鹼鹽由形成無毒鹽之鹼形成。實例包括鋁、精胺酸、苄星青黴素、鈣、膽鹼、二乙胺、二乙醇胺、甘胺酸、離胺酸、鎂、葡甲胺、乙醇胺、鉀、鈉、緩血酸胺及鋅之鹽。亦可形成酸及鹼之半鹽,例如半硫酸鹽及半鈣鹽。
本發明化合物可以單晶形或以晶形之混合物形式存在或其可為非晶形。因此,欲用於醫藥用途之本發明化合物可以結晶或非晶形產品形式投予。其可藉由諸如沈澱、結晶、冷凍乾燥或噴霧乾燥或蒸發乾燥之方法以例如固體塞、粉末或膜形式獲得。微波或射頻乾燥可用於此目的。
對於上文所提及之本發明化合物,所投予之劑量將當然隨所用化合物、投藥模式、所需治療及所指示病症而變化。舉例而言,若本發明化合物為非經腸投予,則本發明化合物之劑量可在0.1g/m2至5g/m2範圍內,例如0.5g/m2至2g/m2。根據熟知醫學原理,本發明化合物之用於治療目的之劑量大小將自然地根據病狀之性質及嚴重程度、動物或患者之年齡及性別及投藥途徑而變化。
預計本發明化合物之劑量、給藥頻率及治療持續時間視調配物及患者之臨床適應症、年齡及共同罹病之醫學病狀而不同。
本發明化合物或其醫藥學上可接受之鹽可獨立地使用但一般將以醫藥組成物形式投予,其中本發明化合物或其醫藥學上可接受之鹽與醫藥學上可接受之佐劑、稀釋劑或載劑結合。用於選擇及製備適合醫藥調配物之習知程序描述於例如「Pharmaceuticals-The Science of Dosage Form Designs」,M.E.Aulton,Churchill Livingstone,1988中。
視本發明化合物之投藥模式而定,用於投予本發明化合物之醫藥組成物將較佳包含0.05%w至99%w(重量百分比)本發明化合物,更佳0.05%w至80%w本發明化合物,再更佳0.10%w至70%w本發明化合物,且甚至更佳0.10%w至50%w本發明化合物,所有重量百分比均以總組成物計。
對於口服投藥,本發明化合物可與以下各者摻合:佐劑或載劑,例如乳糖、蔗糖、山梨糖醇、甘露糖醇;澱粉,例如馬鈴薯澱粉、玉米澱粉或支鏈澱粉;纖維素衍生物;黏合劑,例如明膠或聚乙烯吡咯啶酮;及/或潤滑劑,例如硬脂酸鎂、硬脂酸鈣、聚乙二醇、蠟、石蠟及其類似物,且隨後壓縮成錠劑。若需要包衣錠劑,則可用可含有例如阿拉伯膠(gum arabic)、明膠、滑石及二氧化鈦之濃縮糖溶液包覆如上文所描述製備之內核。替代地,可用溶解於易揮發性有機溶劑中之適合聚合物包覆錠劑。
對於軟明膠膠囊之製備,可使本發明化合物與例如植物油或聚乙二醇摻合。硬明膠膠囊可含有使用用於錠劑之上文所提及之任一種賦形劑的化合物之顆粒。亦可將本發明化合物之液體或半固體調配物填充至
硬明膠膠囊中。
口服施用之液體製劑可呈糖漿或懸浮液形式,例如含有本發明化合物,其餘為糖及乙醇、水、甘油與丙二醇之混合物之溶液。視情況,此類液體製劑可含有著色劑、調味劑、甜味劑(諸如糖精)、防腐劑及/或羧甲基纖維素(作為增稠劑)或熟習此項技術者已知之其他賦形劑。
對於非經腸(例如靜脈內)投藥,本發明化合物可以無菌水溶液或油性溶液形式投予。本發明化合物為極親脂性的。因此,水性調配物通常將亦含有醫藥學上可接受之極性有機溶劑。
已展示環糊精發現在藥物遞送方面之廣泛應用(Rasheed等人,Sci.Pharm.,2008,76,567-598)。環糊精為環狀寡醣之一族。其充當『分子籠』,其包封藥物分子且改變彼等藥物分子之特性(諸如溶解性)。環糊精包含(α-1,4)-連接之α-D-葡萄哌喃糖單元。環糊精可含有6、7或8個葡萄哌喃糖單元(分別命名為α-環糊精、β-環糊精及γ-環糊精)。醫藥調配物中所用之環糊精通常為β-環糊精。可用C1-C6經取代或未經取代之烷基使側羥基烷基化。環糊精之實例為α-環糊精、β-環糊精、γ-環糊精、2-羥丙基-β-環糊精(HP-β-CD)、磺基丁醚β-環糊精鈉鹽、部分甲基化β-環糊精。
根據熟知醫學原理,本發明化合物之用於治療目的之劑量大小將自然地根據病狀之性質及嚴重程度、動物或患者之年齡及性別及投藥途徑而變化。
預計本發明化合物之劑量、給藥頻率及治療持續時間視調配物及患者之臨床適應症、年齡及共同罹病之醫學病狀而不同。
本發明亦包括所有醫藥學上可接受之經同位素標記之形式的化合物3或化合物4,其中一個或多個原子經具有相同原子數但原子質量或質量數不同於通常在自然界中發現的主要同位素之原子質量或質量數之原子置換。
適合於包括在本發明化合物中之同位素之實例包括氫同位素,諸如2H及3H;碳同位素,諸如11C、13C及14C;氯同位素,諸如36Cl;氟同位素,諸如18F;碘同位素,諸如123I及125I;氮同位素,諸如13N及15N;氧同位素,諸如15O、17O及18O;磷同位素,諸如32P;及硫同位素,諸如35S。
某些經同位素標記之化合物(例如併有放射性同位素之彼等化合物)適用於藥物及/或受質組織分佈研究。放射性同位素氚(亦即3H)及碳-14(亦即14C)鑒於其併入之簡易性及即用之偵測手段而尤其適用於此目的。
經諸如氘(亦即2H)之較重同位素取代可提供由較大代謝穩定性產生之某些治療優勢,例如活體內半衰期增加或劑量需求降低,因此在某些情況下可較佳。
經正電子發射同位素(諸如11C、18F、15O及13N)取代可適用於正電子發射斷層攝影術(Positron Emission Topography;PET)研究以檢查受質受體佔有率。
經同位素標記之化合物一般可藉由熟習此項技術者已知之習知技術或藉由類似於使用適當經同位素標記之試劑替代先前所用的非標記試劑來描述之製程的製程來製備。
用於治療癌症之治療方法或化合物除本發明化合物之外可
涉及習知手術或放射線療法或化學療法。此類化學療法可包括投予一種或多種其他活性劑。
當作為本發明之治療方法之一部分投予另一活性劑時,此類組合治療可藉助於同時、依次或各別給予治療之個別組分而達成。此類組合產品採用上文所描述之治療有效劑量範圍內之本發明化合物及一種或多種批准劑量範圍內之其他醫藥學活性劑。
因此,本發明之醫藥調配物可包含另一活性劑。
一種或多種其他活性劑可為以下類別之抗腫瘤劑中之一或多者:(i)抗增殖/抗腫瘤藥物及其組合,諸如烷基化劑(例如環磷醯胺、氮芥、苯達莫司汀(bendamustin)、美法侖(melphalan)、苯丁酸氮芥、白消安(busulphan)、替莫唑胺(temozolamide)及亞硝基脲);抗代謝物(例如吉西他濱及抗葉酸劑,諸如氟嘧啶(如5-氟尿嘧啶及喃氟啶)、雷替曲塞(raltitrexed)、甲胺喋呤、培美曲塞(pemetrexed)、胞嘧啶阿拉伯糖苷(cytosine arabinoside)及羥基脲);抗生素(例如蒽環黴素,如阿德力黴素(adriamycin)、博萊黴素(bleomycin)、小紅莓(doxorubicin)、柔紅黴素(daunomycin)、表阿黴素(epirubicin)、艾達黴素(idarubicin)、絲裂黴素-C(mitomycin-C)、更生黴素(dactinomycin)及光神黴素(mithramycin));抗有絲分裂劑(例如長春花生物鹼(vinca alkaloid),如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞賓(vinorelbine)及類紫杉醇(taxoid)(如紫杉醇(taxol))及克癌易(taxotere)及保羅激酶(polokinase)抑制劑);蛋白酶體抑制劑,例如卡非佐米(carfilzomib)及硼替佐米
(bortezomib);干擾素療法;及拓撲異構酶抑制劑(例如表鬼臼毒素,如依託泊苷(etoposide)及替尼泊苷(teniposide)、安吖啶(amsacrine)、拓朴替康(topotecan)、米托蒽醌(mitoxantrone)及喜樹鹼(camptothecin));(ii)細胞生長抑制劑,諸如抗雌激素(例如他莫昔芬(tamoxifen)、氟維司群(fulvestrant)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、曲洛昔芬(droloxifene)及艾多昔芬(iodoxyfene))、抗雄激素(例如比卡魯胺(bicalutamide)、氟他米特(flutamide)、尼魯米特(nilutamide)及乙酸環丙孕酮)、LHRH拮抗劑或LHRH促效劑(例如戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)及布舍瑞林(buserelin))、孕激素(例如乙酸甲地孕酮)、芳香酶抑制劑(例如阿那曲唑(anastrozole)、來曲唑(letrozole)、維拉唑(vorazole)及依西美坦(exemestane))及5 α-還原酶抑制劑(諸如非那雄安(finasteride));(iii)抗侵襲劑,例如達沙替尼(dasatinib)及伯舒替尼(bosutinib)(SKI-606);及金屬蛋白酶抑制劑;尿激酶纖維蛋白溶酶原活化物受體功能抑制劑或肝素酶抗體;(iv)生長因子功能抑制劑:例如此類抑制劑包括生長因子抗體及生長因子受體抗體,例如抗erbB2抗體曲妥珠單抗(trastuzumab)[HerceptinTM]、抗EGFR抗體帕尼單抗(panitumumab)、抗erbB1抗體西妥昔單抗(cetuximab),酪胺酸激酶抑制劑,例如表皮生長因子家族抑制劑(例如EGFR家族酪胺酸激酶抑制劑,諸如吉非替尼(gefitinib)、埃羅替尼(erlotinib)及6-丙烯醯胺基-N-(3-氯-4-氟苯基)-7-(3-嗎啉基丙氧基)-喹唑啉-4-胺(CI 1033),erbB2酪胺酸激酶抑制劑,諸如拉帕替尼(lapatinib));肝細胞生長
因子家族抑制劑;胰島素生長因子家族抑制劑;細胞凋亡之蛋白調節因子調節劑(例如Bcl-2抑制劑);血小板衍生生長因子家族抑制劑,諸如伊馬替尼(imatinib)及/或尼羅替尼(nilotinib)(AMN107);絲胺酸/蘇胺酸激酶抑制劑(例如Ras/Raf信號傳導抑制劑,諸如法呢基(farnesyl)轉移酶抑制劑,例如索拉非尼(sorafenib)、替吡法尼(tipifarnib)及洛那法尼(lonafarnib)),細胞信號傳導通過MEK及/或AKT激酶之抑制劑、c-套組抑制劑、abl激酶抑制劑、PI3激酶抑制劑、Plt3激酶抑制劑、CSF-1R激酶抑制劑、IGF受體激酶抑制劑;極光激酶抑制劑及週期素依賴性激酶抑制劑(諸如CDK2及/或CDK4抑制劑);(v)抗血管生成劑,諸如抑制血管內皮生長因子之效果的彼等抗血管生成劑,例如抗血管內皮細胞生長因子抗體貝伐單抗(bevacizumab)(AvastinTM);撒利度胺(thalidomide);來那度胺(lenalidomide);及例如VEGF受體酪胺酸激酶抑制劑,諸如凡德他尼(vandetanib)、凡塔藍尼(vatalanib)、舒尼替尼(sunitinib)、阿西替尼(axitinib)及帕唑帕尼(pazopanib);(vi)基因療法,包括例如置換諸如異常p53或異常BRCA1或BRCA2之異常基因之方法;(vii)免疫療法,包括例如抗體療法,諸如阿侖單抗(alemtuzumab)、利妥昔單抗(rituximab)、替伊莫單抗(ibritumomab tiuxetan)(Zevalin®)及奧法木單抗(ofatumumab);干擾素,諸如干擾素α;介白素,諸如IL-2(阿地介白素(aldesleukin));介白素抑制劑,例如IRAK4抑制劑;包括預防性及治療疫苗之癌症疫苗,諸如HPV疫苗,例如加德西(Gardasil)、卉妍康
(Cervarix)、奧克非格(Oncophage)及西普亮塞-T(Sipuleucel-T)(Provenge);及toll樣受體調節劑,例如TLR-7或TLR-9促效劑;及(viii)細胞毒素劑,例如氟達拉濱(fludaribine)(氟達拉(fludara))、克拉屈濱(cladribine)、噴司他丁(pentostatin)(NipentTM);(ix)類固醇,諸如皮質類固醇,包括糖皮質激素及鹽皮質激素,例如阿可羅米松(aclometasone)、二丙酸阿可羅米松、醛固酮、安西縮松(amcinonide)、倍氯米松(beclomethasone)、二丙酸倍氯米松、倍他米松(betamethasone)、二丙酸倍他米松、倍他米松磷酸鈉、戊酸倍他米松、布地奈德(budesonide)、氯倍他松(clobetasone)、丁酸氯倍他松、丙酸氯倍他索(clobetasol propionate)、氯潑尼醇(cloprednol)、可的松(cortisone)、乙酸可的松、可的伐唑(cortivazol)、脫氧皮質酮(deoxycortone)、地奈德(desonide)、去羥米松(desoximetasone)、地塞米松(dexamethasone)、地塞米松磷酸鈉、異菸酸地塞米松、二氟可妥龍(difluorocortolone)、氟氯奈德(fluclorolone)、氟米松(flumethasone)、氟尼縮松(flunisolide)、氟輕松(fluocinolone)、丙酮化氟新龍(fluocinolone acetonide)、醋酸氟輕松(fluocinonide)、氟考丁酯(fluocortin butyl)、氟可的松、氟可妥龍、己酸氟可龍(fluocortolone caproate)、特戊酸氟可龍、氟米龍(fluorometholone)、氟潑尼定(fluprednidene)、乙酸氟潑尼定、氟氫縮松(flurandrenolone)、氟替卡松(fluticasone)、丙酸氟替卡松、哈西奈德(halcinonide)、氫化可的松(hydrocortisone)、乙酸氫化可的松、丁酸氫化可的松、醋丙酸氫化可的松、丙丁酸氫化可的松、戊酸氫化可的松、艾可米松(icomethasone)、醋丁艾可米松(icomethasone enbutate)、甲潑尼松(meprednisone)、甲潑尼龍
(methylprednisolone)、莫米松帕拉米松(mometasone paramethasone)、糠酸莫米松單水合物、潑尼卡酯(prednicarbate)、潑尼松龍(prednisolone)、潑尼松(prednisone)、替可的松(tixocortol)、特戊酸替可的松、曲安西龍(triamcinolone)、曲安奈德(triamcinolone acetonide)、曲安西龍醇及其各別醫藥學上可接受之衍生物。可使用類固醇之組合,例如此段中所提及之兩種或多於兩種類固醇之組合;(x)靶向療法,例如PI3Kd抑制劑,例如艾代拉利司(idelalisib)及哌立福辛(perifosine)。
一種或多種其他活性劑亦可為抗生素。
在本說明書之描述及申請專利範圍通篇中,詞語「包含」及「含有」及其變化形式意謂「包括(但不限於)」,且其不意欲(且不)排除其他部分、添加劑、組分、整體或步驟。在本說明書之描述及申請專利範圍通篇中,除非上下文另有要求,否則單數涵蓋複數。特定言之,當使用不定冠詞時,除非上下文另有要求,否則本說明書應理解為考慮複數以及單數。
結合本發明之特定態樣、具體實例或實施例描述之特徵、整體、特性、化合物、化學部分或基團應理解為適用於本文所描述之任何其他態樣、具體實例或實施例,除非與其不相容。本說明書中所揭示之所有特徵(包括任何隨附申請專利範圍、摘要及圖式)及/或如此揭示之任何方法或製程之所有步驟可以任何組合形式組合,此類特徵及/或步驟中之至少一些相互排斥之組合除外。本發明不限於任何前述具體實例之細節。本發明延伸至本說明書(包括任何隨附申請專利範圍、摘要及圖式)中所揭示
之特徵之任何新穎特徵或任何新穎組合,或延伸至如此揭示之任何方法或製程之步驟的任何新穎步驟或任何新穎組合。
將讀者之注意力導引至結合本申請案與本說明書同時或先於本說明書申請且對公眾查閱本說明書開放之所有論文及文件,且所有此類論文及文件之內容均以引用的方式併入本文中。
實施例1
藉由HPLC在以下條件下分離(R)異構體與(S)異構體:
設備:具有DAD偵測器之按捷倫(Agilent)1200TM系列
流動速率:1.0mL/min
管柱:Chiralpak ADTM;250×4.6mm ID(正相)
溫度:環境
粒度:20μm
饋料:溶解於MeOH中;10g/L
溶劑:正庚烷/IPA 10->50%IPA
層析圖展示於圖1中。在8.6min洗提(S)-差向異構體且在10.3分鐘洗提(R)-差向異構體。
特性化方法及材料:質子(1H)、碳(13C)、磷(31P)及氟(19F)
NMR光譜在25℃下記錄於Bruker Avance 500光譜儀上。光譜自動校準至氘化溶劑峰且所有13C NMR及31P NMR為質子去耦。藉由HPLC分析使用Varian Polaris C18-A(10μM)作為分析管柱在35min內用100/0至0/100之H2O/MeOH梯度洗提來驗證最終化合物之純度>95%。HPLC分析由Varian Prostar(LC工作站-Varian prostar 335 LC偵測器)進行。
2'-脫氧-2',2'-二氟-D-胞苷-5'-O-[苯基(苯甲氧基-L-丙胺醯基)]-(S)-磷酸酯3
(ES+)m/z,實驗值:(M+Na+)603.14。C25H27F2N4O8NaP要求:(M+)580.47。
31P NMR(202MHz,MeOD):δP 3.66
1H NMR(500MHz,MeOD):δH 7.58(d,J=7.5Hz,1H,H-6),7.38-7.32(m,7H,ArH),7.26-7.20(m,3H,ArH),6.24(t,J=7.5Hz,1H,H-1'),5.84(d,J=7.5Hz,1H,H-5),5.20(AB系統,J AB=12.0Hz,2H,OCH 2Ph),4.46-4.43(m,1H,H-5'),4.36-4.31(m,1H,H-5'),4.25-4.19(m,1H,H-3'),4.07-4.00(m,2H,H-4',CHCH3),1.38(d,J=7.2Hz,3H,CHCH 3)。
19F NMR(470MHz,MeOD):δF-118.0(d,J=241Hz,F),-120.24(寬d,J=241Hz,F)。
13C NMR(125MHz,MeOD):δC 174.61(d,3 J C-P=5.0Hz,C=O,酯),167.63(C-NH2),157.74(C=O鹼),152.10(d,2 J C-P=7.0Hz,C-Ar),142.40(CH-鹼),137.22(C-Ar),130.90,129.63,129.39,129.32,126.32(CH-Ar),124.51(d,1 J C-F=257HZ,CF2),121.47,121.43(CH-Ar),96.67(CH-鹼),85.92(寬信號,C-1'),80.31(C-4'),71.27(明顯t, 2 J C-F=23.7Hz,C-3'),68.03(OCH2Ph),65.73(d,2 J C-P=5.30Hz,C-5'),51.66(CHCH3),20.42(d, 3 J C-P=6.25Hz,CHCH3)。
逆相HPLC,在35min內用100/0至0/100之H2O/MeOH洗提,展示在t R=22.53min之情況下非對映異構體之一個峰。
2'-脫氧-2',2'-二氟-D-胞苷-5'-O-[苯基(苯甲氧基-L-丙胺醯基)]-(R)-磷酸酯4。
(ES+)m/z,實驗值:(M+Na+)603.14。C25H27F2N4O8NaP要求:(M+)580.47。
31P NMR(202MHz,MeOD):δP 3.83
1H NMR(500MHz,MeOD):δH 7.56(d,J=7.5Hz,1H,H-6),7.38-7.31(m,7H,ArH),7.23-7.19(m,3H,ArH),6.26(t,J=7.5Hz,1H,H-1'),5.88(d,J=7.5Hz,1H,H-5),5.20(s,2H,OCH 2Ph),4.49-4.46(m,1H,H-5'),4.38-4.34(m,1H,H-5'),4.23-4.17(m,1H,H-3'),4.07-4.01(m,2H,H-4',CHCH3),1.38(d,J=7.2Hz,3H,CHCH 3)。
19F NMR(470MHz,MeOD):δF-118.3(d,J=241Hz,F),-120.38(寬d,J=241Hz,F)。
13C NMR(125MHz,MeOD):δC 174.65(d,3 J C-P=5.0Hz,C=O,酯),167.65(C-NH2),157.75(C=O鹼),152.10(d,2 J C-P=7.0Hz,C-Ar),142.28(CH-鹼),137.50(C-Ar),130.86,129.63,129.40,129.32,126.31(CH-Ar),124.50(d,1 J C-F=257Hz,CF2),121.44,121.40(CH-Ar),96.67(CH-鹼),85.90(寬信號,C-1'),80.27(C-4'),71.30(明顯t, 2 J C-F=23.7Hz,C-3'),68.02(OCH2Ph),65.50(C-5'),51.83(CHCH3),20.22(d,3 J C-P=7.5Hz,CHCH3)。
逆相HPLC,在35min內用100/0至0/100之H2O/MeOH洗提,展示在t R=21.87min之情況下非對映異構體之一個峰。
亦獲得兩種異構體之X射線繞射資料且所得影像展示於圖2及圖3中。相應繞射資料及方法提供於以下表1至表4中。
實施例2
在一系列醫藥學上可接受之溶劑系統中確定NUC-1031之溶解性及其非對映異構體。所採用之協定如下:製備小體積1-2mL之各溶劑系統且添加所討論之化合物之重量。將溶液攪拌大約4小時且隨後過濾0.45μL膜。隨後藉由HPLC分析確定所討論之化合物在濾液中之濃度。
基於用於治療胰腺癌之吉西他濱劑量計劃表,NUC-1031之分子量調節劑量將為約3200mg,以輸液形式每週給予一次。作為所需溶解性水準之指示,取500mL輸液體積之概念上目標,所需的NUC-1031在輸液流體中之溶解性將>6mg/ml。然而,此溶解性水準僅為一指示且低於其之溶解性仍可提供有效療法。
如自表6可見,(R)-差向異構體4實質上不溶於極性有機溶劑於水中之10%混合物中。另一方面,(S)-差向異構體3展示顯著改良之溶解性。在極性有機溶劑於水中之50%混合物中,(S)-差向異構體3可比(R)-差向異構體4超過100倍更可溶。(S)-差向異構體可因此提供潛在極方便且有效之療法。
實施例3
為評估(R)-差向異構體及(S)-差向異構體溶解於環糊精中之差異性,在D2O中用HP-β-CD處理後,記錄NUC-1031異構體混合物之31P NMR光譜。
NMR研究。在25℃下於Bruker Avance 500MHz光譜儀上記錄1H NMR(500MHz)及31P NMR(202MHz)。以相對於內部D2O(δ 4.9 1H NMR)或外部85%H3PO4(δ 0.00 31P NMR)之百萬分率(ppm)引述化學位移(δ)。HPLC研究及NMR研究均在室溫下進行。
HPLC研究。使用ThermoScientific系統進行分析型高效液相層析(HPLC)分析。在1mL/min流動速率下且在280nm偵測波長下在30min內於用90/10至0/100之H2O/CH3CN洗提之SCIENTIFIC Hypersil Gold C18,5
μ,150×4.6mm上進行反相HPLC分析。在此等條件下分別在13.58min觀測(S)-差向異構體3且在13.44min觀測(R)-差向異構體4之NUC-1031差向異構體(溶解於MeOH中)之滯留時間(圖5A)。
稱重2.36mg NUC-1031異構體混合物(1:1.1之(S):(R))且轉移至NMR管中。隨後將13.3mg HP-β-CD溶解於1.3mL氧化氘中且此為添加至NMR管中之溶液(1:2.3莫耳比之NUC1031:HP-β-CD)(註釋:並非所有固體溶解於該溶液中)。
31P NMR光譜展示HP-β-CD能夠增強NUC-1031(S)-差向異構體3(4.14Hz)相對於(R)-差向異構體(4.00Hz)之溶解性,其中所觀測到的呈溶解狀態之(S)-差向異構體與(R)-差向異構體之比率為6.6:1,即支持(S)-差向異構體(圖4)。
藉由添加0.5mL水(1.15mg/mL)將來自NMR研究之0.5mL D2O溶液稀釋至1mL。將20μL此溶液注入HPLC中。
經稀釋之NMR樣品之HPLC分析證實(S)-差向異構體3比(R)-差向異構體4更好地溶解於溶液中,其中所觀測到的呈溶解狀態之(S)-差向異構體與(R)-差向異構體之比率為5:1,即支持(S)-差向異構體,與NMR資料廣泛一致(圖5B)。
藉由另一吉西他濱磷酸酯衍生物進行之類似研究未展示彼衍生物之(S)-差向異構體與(R)-差向異構體溶解於環糊精溶液中之間的差異。
實施例4
大多數藥物之清除率及生物可用性強烈受其在肝中之首關代謝影響。
有可能藉由用冷凍保存肝細胞培育化合物且測定培育混合物中之測試化合物之初始量與最終量來估計試管內相對肝「代謝穩定性」。
以下程序為使用合併的人類冷凍保存肝細胞懸浮液之HPLC-MS/MS分析。
分析矩陣
人類肝細胞:10個混合性別及合併物
最終細胞密度:每毫升1百萬(106)個可存活細胞
實驗方案
將合併之冷凍保存肝細胞解凍,洗滌且再懸浮於克雷布斯-赫斯萊特(Krebs-Heinslet)緩衝劑(pH 7.3)中。藉由添加測試化合物(1μM最終濃度)至細胞懸浮液中且以100μL最終體積於平底96孔板上在37℃/5%CO2下分別培育0分鐘及120分鐘來起始反應。藉由添加100μL乙腈至培育混合物中使反應停止。隨後輕輕地混合樣品且簡言之於板振盪器上完全轉移至0.8mL V底96孔板,且在室溫下在2550 xg下離心15分鐘。將各上清液(150μL)轉移至清潔群集管中,隨後於熱電三重四極系統上進行HPLC-MS/MS分析。
修改此分析以用於半衰期確定。在此情況下,取樣時間點為0分鐘、30分鐘、60分鐘、90分鐘及120分鐘。
參考化合物
四種參考化合物(1μM)與測試化合物同時測試。普萘洛爾(Propranolol)在人類肝細胞之情況下相對穩定,然而弗拉西泮(flurazepam)、納洛酮(naloxone)及特非那定(terfenadine)在人類肝細胞
之情況下相對不穩定。
分析方法
使用所選擇之反應監測(SRM)經由(RP)HPLC-MS/MS分析樣品。HPLC條件由具有自動取樣器之HP1100二元泵、C-12混合模式2×20mm管柱及梯度組成。
資料分析
藉由HPLC-MS/MS記錄對應於測試化合物之峰面積。表示為剩餘測試化合物之百分比之代謝穩定性係藉由比較在2小時與時間零點時測試化合物之峰面積來計算。在半衰期測定之情況下,假定一級動力學,根據剩餘測試化合物(%)與時間之對數曲線之初始線性範圍之斜率估計半衰期。
結果展示於表7中。
Claims (11)
- 如申請專利範圍第1項或第2項之用途,其中該癌症係胰腺癌。
- 如申請專利範圍第1項或第2項之用途,其中該癌症係卵巢癌。
- 如申請專利範圍第1項或第2項之用途,其中該癌症係膽管癌。
- 如申請專利範圍第1項或第2項之用途,其中該醫藥品包含環糊精。
- 如申請專利範圍第1項或第2項之用途,其中該醫藥品用於口服投藥。
- 如申請專利範圍第1項或第2項之用途,其中該醫藥品用於靜脈內投藥。
- 如申請專利範圍第8項之用途,其中該醫藥品為亦包含極性有機溶劑之水性調配物。
- 如申請專利範圍第1項或第2項之用途,其中該吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3之非對映異構純度係在90%至99.5%的範圍。
- 如申請專利範圍第10項之用途,其中該吉西他濱-[苯基-苯甲醯氧基-L-丙胺醯基)]-(S)-磷酸酯3之非對映異構純度係在大於95%至99.5%的範圍。
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