TWI694087B - 多黏桿菌素衍生物及其用途 - Google Patents
多黏桿菌素衍生物及其用途 Download PDFInfo
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- TWI694087B TWI694087B TW105101251A TW105101251A TWI694087B TW I694087 B TWI694087 B TW I694087B TW 105101251 A TW105101251 A TW 105101251A TW 105101251 A TW105101251 A TW 105101251A TW I694087 B TWI694087 B TW I694087B
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- polymyxin
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- 108010040201 Polymyxins Proteins 0.000 title abstract description 38
- 241000894006 Bacteria Species 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 7
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 41
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
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- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 claims description 5
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- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 claims description 5
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- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 claims description 4
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Abstract
本發明係有關式(I)之多黏桿菌素衍生物
及其醫藥上可接受之鹽類。本發明進一步有關其等在治療一細菌感染,特別是革蘭氏陰性菌引起之感染上的用途。
Description
本發明係有關多黏桿菌素衍生物及其用途,以治療革蘭氏陰性菌引起之感染。
敗血性感染每年造成215,000以上的美國人死亡。據估計,每年有750,000美國人感染嚴重敗血症,且其中29%死亡。敗血症死亡佔美國所有死亡病例的9%。美國人的敗血症死亡率與心肌梗塞相同,甚至高於交通事故。
每年有二至三百萬美國人發生院內感染,且該些感染者中有10%演變成敗血症。該些病患中有90,000人以上死於院內感染敗血症。
大腸桿菌(Escherichia coli)及克留氏肺炎桿菌(Klebsiella pneumoniae)兩者為革蘭氏陰性菌,導致幾乎40%之所有社區型敗血性感染(community-acquired septic infections)及幾乎三分之一之所有醫療保健相關敗血性感染。在所有革蘭氏陰性敗血性感染中,其致病率約60至75%。其他敗血性感染之革蘭氏陰性病原體包括鮑氏靜止
桿菌(Acinetobacter baumannii)及綠膿桿菌(Pseudomonas aeruginosa)。總之,革蘭氏陰性菌導致40%以上之所有敗血性感染,且該些細菌之多者係極端多重抗藥性。
多黏桿菌素係一密切相關之抗生素物質族群,其由多黏芽孢桿菌(Paenibacillus polymyxa)及相關病原體菌株產生。該些陽離子性藥物係相對簡單之胜肽,其中分子量約1000。多黏桿菌素,如多黏桿菌素B,係十胜肽抗生素,亦即其由十個(10)胺基醯基殘基組成。其為殺菌劑,且尤其有效抑制革蘭氏陰性菌,如大腸桿菌及其他類型之腸桿菌科(Enterobacteriaceae)、假單胞菌屬(Pseudomonas)、鮑氏靜止桿菌(A.baumannii)等等。然而,多黏桿菌素具嚴重不良影響,包括腎毒性及神經毒性。因此,這些藥物侷限於治療劑之用途,係因全身毒性高。
極端多重抗藥性革蘭氏陰性菌之大流行,現已迫使臨床醫師恢復以多黏桿菌素作為嚴重感染之最後一線治療,儘管多黏桿菌素具腎毒性。多黏桿菌素之腎毒性可使治療變得複雜,或甚至必須終止。據此,必須權衡腎毒性風險對病人存活效益之影響。根據近來研究,多黏桿菌素B及黏菌素(colistin)(自黏菌素甲烷磺酸酯游離出)之腎毒性比率由10%至30%間變化,但於所選材料中,黏菌素之比率可高達43至48%,而多黏桿菌素B之比率則高達55%。據此,個別差異係高(Vaara,M.2013,New derivatives of polymyxins,Journal of Antimicrobial Chemotherapy 2013,68:1213-9)。現有數據顯示情況甚至更糟,顯示在病危患者,
當前劑量療法較不理想,且導致血清濃度過低。因此,臨床醫師會建議使用更大劑量,但其進一步增加腎毒性。
因此,本發明之目的係提供多黏桿菌素衍生物,以有效對抗革蘭氏陰性菌且具降低之腎毒性。本發明之目的係藉多黏桿菌素衍生物及其醫藥上可接受之鹽類且藉其用途而實現,其特徵在於那些在獨立請求項中所陳述者。
本發明之較佳具體例係於附屬請求項中揭示。
以下,本發明將藉較佳具體例並參考隨文檢附之圖示來更詳盡地說明,其中:圖1顯示以多黏桿菌素B(PMB)、NAB739、或NAB815處理前(第-7/-8天)及期間(第2-8天)之S-BUN(mg/dL)(每組3隻動物,IV,TID);圖2顯示以多黏桿菌素B(PMB)、NAB739、或NAB815處理前(第-7/-8天)及期間(第2-8天)之S-Crea(mg/dL)(每組3隻動物,IV,TID);圖3顯示以多黏桿菌素B(PMB)、NAB739、或NAB815處理前(第-7/-8天)及期間(第2-8天)之U-NAG(U/L)/U-Crea(mg/dL)比x 10(每組3隻動物,IV,TID);圖4顯示以多黏桿菌素B(PMB)、NAB739、或NAB815處理前(第-7/-8天)及期間(第2-8天)之U-GGT(U/L)/U-Crea(mg/dL)比(每組3隻動物,IV,TID)。
近來,多數致力於開發耐受性更佳之多黏桿菌素衍生物。發明人先前已顯示,PCT/FI2007/050441(其完整內容及揭示在此併入本案以作為參考資料)揭示之化合物具顯著抗菌作用,且適於治療革蘭氏陰性菌造成之感染。此外,發明人建議,該些化合物皆攜帶僅三個(3)正電荷,比攜帶五個(5)正電荷之化合物毒性低,且發明人亦有其初步證據(Vaara M.et al.Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents.Antimicrob Agents Chemother 2008,52:3229-36;Vaara M.and Vaara T.Polymyxin derivatives and uses thereof.2010.U.S.Patent 7,807,637;Vaara M.Polymyxins and their novel derivatives.Curr Opin Microbiol 2010;13:574-81;Mingeot-Leclercq M.-P.Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells.Peptides 2012;35:248-52;Vaara M.and Vaara T.The novel polymyxin derivative NAB739 is remarkably less cytotoxic than polymyxin B and colistin to human kidney proximal tubular cells.Int J Antimicrob Chemother 2013,41:292-3;Vaara,M.2013,New derivatives of polymyxins,Journal of Antimicrobial Chemotherapy 2013,68:1213-9)。
儘管該些化合物,如NAB739,對革蘭氏陰性菌具良好抗菌活性,理想的是,嘗試以可靠及明確方式開發
更具耐受性之衍生物。
目前,驚訝發現,本文定義之專一性多黏桿菌素衍生物對革蘭氏陰性菌展現所需之高抗菌功效而未有不可接受之腎毒性。
在美國專利申請號2006004185中,CB-182,804(一與多黏桿菌素B相同之分子,但攜帶2-氯苯基胺基羰基以作為連接至N端之脂肪醯基部分)的開發(亦參見Quale J.et al.,Activity of polymyxin B and the novel polymyxin analogue CB-182,804 against contemporary Gram-negative pathogens in New York City,Microb Drug Resist 2012,13:574-81)於2010年終止。Dap-3多黏桿菌素類似物與多黏桿菌素B於犬腎毒性研究中未有充分差異(Magee T.V.et al.,Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections,J.Med.Chem.2013,56:5079-5093)。兩方案包含僅具五個正電荷之化合物。Kern及同事亦有嘗試(Keirstead N,Early prediction of polymyxin-induced nephrotoxicity with next generation urinary kidney injury biomarkers,Toxicol Sci 2014,137:278-91);未有詳盡或任何進一步進展公開。
專利申請號WO/2013/072695揭示超過30個多黏桿菌素九胜肽,每一者攜帶至少四個正電荷。其中數者對人類近端腎小管上皮細胞(human renal proximal tubule epithelial cell;hRPTEC)株HK-2之細胞毒性低於多黏桿菌
素B及黏菌素。此外,於7天之大鼠研究中,其中三者之尿液血清胱蛋白C(cystatin C)、白蛋白、及NAG濃度增加幅度低於同等劑量之黏菌素。
專利申請號WO/2014/188178接續WO/2013/072695所述工作。如標題「polymyxin derivatives and their use in combination therapy together with different antibiotics」所指,主要重點為其他抗生素活性之增強作用,該抗生素如先前專利申請案之多黏桿菌素衍生物雷發平(rifampin)及數個新穎衍生物。該等新穎衍生物中之一些(範例衍生物44、46、及48)在R3(根據多黏桿菌素常用圖解進行胺基醯基殘基之編號,亦即多黏桿菌素B之N端第一個殘基編號為R1)攜帶DSer。其中一者(衍生物46)僅攜帶三個正電荷。其係NAB739類似物,其餘者皆相同但終端部分攜帶2-環己基-2-羥基乙醯基(ethanoyl)(亦稱作2-環己基-2-羥基乙醯基(acetyl)),而NAB739攜帶辛醯基(octanoyl)。總之,該申請案揭示約100個衍生物,其中除了上述衍生物範例46以外,皆攜帶4-6個正電荷。所有衍生物具與多黏桿菌素B相同之環七胜肽部分,但衍生物範例19、30、31、及32除外,其環七胜肽部分與多黏桿菌素E的相同,以及衍生物範例50除外,其環七胜肽部分與多黏桿菌素S的相同。該衍生物之多者對人類近端腎小管上皮細胞(hRPTEC)株HK-2之細胞毒性低於多黏桿菌素B及黏菌素。此外,於7天之大鼠研究中,其中三者(範例衍生物1、4、及10)之尿液血清胱蛋白C、白蛋白、及NAG濃度增
加幅度低於同等劑量之黏菌素。於申請案中提出,N端基團內存在胺基官能基可減少腎毒性。然而,於眾所周知之腎毒性多黏桿菌素B及黏菌素中,R1確實攜帶游離胺基。申請案亦提出,N端之羥基及/或雜環基可具類似之毒性降低功效。
尋找臨床相關腎毒性模型具有挑戰性。Magee T.V.等人於2013年(參見上述)顯示,多黏桿菌素衍生物5x,其中R3為二胺基丙醯基(而非二胺基丁醯基)且一相對極性之6-側氧基-1-苯基-1,6-二氫吡啶-3-羰基作為脂肪醯基取代基,對人類近端腎小管上皮細胞(hRPTEC)之細胞毒性明顯低於多黏桿菌素B。此外,於7天之大鼠研究中,5x之腎毒性低於多黏桿菌素B。由於該些成果鼓舞,作者進行7天之犬研究。於該研究中,5x僅稍微有利於腎毒性結果。作者的結論是,5x於大鼠腎病變之耐受性優於多黏桿菌素B,但此優勢於犬未出現,顯示hRPTEC試驗無法預測該物種之腎毒性。
於相同實驗室之另一研究中(Burt D.等人,Application of emerging biomarkers of acute kidney injury in development of kidney-sparing polypeptide-based antibiotics.Drug Chem Toxicol.2014;37:204-12),多黏桿菌素B於犬及猴引發快速發生S-Crea及BUN反應,但未出現在大鼠。作者的結論是,大鼠缺乏反應可能肇因於物種專一性多黏桿菌素B反應及腎生理差異。化合物5x未包括於此研究中。由於S-Crea及BUN為臨床治療時非常重要之腎毒性標記,
動物模型如犬或猴預期將比齧齒類模型更可靠,以預測人類腎毒性。
因此,體外hRPTEC試驗及體內大鼠研究,雖有其吸引人之處,可能誤導產生令人信服之結果,而無法於更接近人類之動物模型重複該結果。
NAB815及其先前描述之參考化合物NAB739落入多黏桿菌素類別,其僅攜帶三個(3)正電荷。於此所示,兩者對石蟹獼猴(cynomolgus monkeys)之腎毒性明顯低於多黏桿菌素B。此外,NAB815之腎毒性甚至比NAB739的更低。所有動物對其皆具耐受性。病患對多黏桿菌素B及黏菌素反應之異質性具臨床顯著性,係因一些病患似乎對腎毒性效應比其他人更脆弱。由相同高劑量(36mg/kg/d)之NAB739及NAB815誘發之型態學研究結果之組織病理學比較顯示,NAB815具較不嚴重之腎病理改變。據此,NAB815明顯優於NAB739。雖不希望受限於理論,此可能係因電荷分佈差異。NAB739之七胜肽環攜帶三個正電荷,而NAB815之七胜肽環僅攜帶二個正電荷。因此,NAB815之七胜肽環不像習知多黏桿菌素之任一者。
於相同發明人之先前專利申請案(PCT/FI2007/050441)及公開文獻中(Vaara M.et al.2008.Novel Polymyxin Derivatives Carrying Only Three Positive Charges Are Effective Antibacterial Agents.Antimicrob Agents Chemother 52:3229-3236;Vaara,M.,T.Vaara.2010.Structure-activity studies on novel polymyxin derivatives that
carry only three positive charges.Peptides 31:2318-2321),所有分子之環部分具二個正電荷且尾端部分具一個正電荷(NAB715、NAB716、及NAB717),係同一主題之不同變化。該尾端部分之一正電荷係位於R3位置,且該環部分之二個正電荷係於三潛在位置R5、R8、及R9之間轉移。於三個組合之間(正電荷位於R5 & R8、位於R5 & R9、及位於R8 & R9),僅一者(R5 & R9)顯示活性,然而,其明顯低於最佳化合物(NAB739及NAB737),其中環部分具所有三個正電荷(位於R5 & R8 & R9)。
於設計本專利申請案之化合物(NAB815)上,採用完全不同之方法。於尾端部分,該二羥基(由於Thr及DThr分別在R2及R3)係保留,且正電荷置於R1(而非R3)。結果令人驚訝,可保留高抗菌活性,而三個僅正電荷之一者位於尾端部分。先前之專利申請案及後續之公開文獻並未揭示任何具全長尾端(R1、R2、及R3)且一正電荷於其上之化合物。
相當顯著地,本文亦顯示,NAB815以非常顯著之程度排泄至石蟹獼猴尿液中,而多黏桿菌素B之排泄幾乎為零。這對於源自尿道之嚴重感染之治療具優勢。
根據本發明,提供具式(I)之化合物:
其中R1為Dab;R2為Thr;R3為DThr;R4為Dab;R5為Dab;R6為DPhe;R7為Leu;R8為Abu;R9為Dab;R10為Thr;以及R(FA)為辛醯基;以及其醫藥上可接受之鹽類。
本發明化合物包含環七胜肽部分R4-R10,且一
側鏈連接至N端胺基醯基殘基R4。該側鏈由R(FA)-三胜肽(R1-R3)殘基組成。R(FA)係辛醯基殘基(OA)連接至三胜肽側鏈N端胺基酸殘基之α-胺基。
特別是,R1-R10代表胺基酸序列Dab-Thr-DThr-cy[Dab-Dab-DPhe-Leu-Abu-Dab-Thr-],亦即SEQ ID NO.1。因此,本發明化合物係OA-Dab-Thr-DThr-cy[Dab-Dab-DPhe-Leu-Abu-Dab-Thr-],亦即OA-SEQ ID NO.1,或其醫藥上可接受之鹽類。
式(I)化合物呈現高抗菌活性,且於投予時顯示僅局部或無不希望之腎毒性作用,其如下列所論之示例性藥理學測試結果所示。
本文使用之縮寫:Dab係指α,γ-二胺基正丁醯基,亦即2,4-二胺基丁醯基;Abu係指2-胺基丁醯基;Thr係指L-蘇胺酸;DThr係指D-蘇胺酸;DPhe係指D-苯丙胺酸;Leu係指L-白胺酸;以及OA係指辛醯基。
「醫藥上可接受」乙詞代表適用於製備一般安全、無毒、及無生物學或其他不良之醫藥組成物,且包括適用於獸醫用途及人類醫藥用途兩者。
「醫藥上可接受之鹽類」乙詞係指具酸及鹼之鹽類,其習知無毒且常用於醫藥文獻。此類鹽類之範例係酸加成鹽類,其係藉使用醫藥上可接受之無毒酸,如鹽酸、硝酸、硫酸、磷酸、草酸、延胡索酸、馬來酸、琥珀酸、乙酸、檸檬酸、抗壞血酸、馬來酸、苯甲酸、酒石酸、碳酸、及其類似物,而形成。典型上,用於形成醫藥上可接
受之鹽類之酸為硫酸。
本文使用之「包含」或「含有」表示後續所述設定可能但毋須包括其他元件。
本發明之化合物可抑制生長或使臨床上重要之革蘭氏陰性菌對抗菌劑敏感。該革蘭氏陰性菌可為彼等隸屬於不動菌屬(Acinetobacter)、產氣單胞菌屬(Aeromonas)、產鹼桿菌屬(Alcaligenes)、博德氏桿菌屬(Bordetella)、布蘭漢氏菌屬(Branhamella)、曲狀桿菌屬(Campylobacter)、檸檬酸桿菌屬(Citrobacter)、腸桿菌屬(Enterobacter)、大腸桿菌屬(Escherichia)、弗朗西斯氏菌屬(Francisella)、細梭菌屬(Fusobacterium)、嗜血桿菌屬(Haemophilus)、螺桿菌屬(Helicobacter)、克留氏菌屬(Klebsiella)、軍團菌屬(Legionella)、摩拉克氏菌屬(Moraxella)、巴斯德桿菌屬(Pasteurella)、鄰單胞菌屬(Plesiomonas)、假單胞菌屬(Pseudomonas)、沙門氏桿菌屬(Salmonella)、鋸桿菌屬(Serratia)、志賀桿菌屬(Shigella)、及耶氏桿菌屬(Yersinia)等物種之屬者。該細菌可為,例如,大腸桿菌(Escherichia coli)、克留氏肺炎桿菌(Klebsiella pneumoniae)、產酸克雷伯氏菌(Klebsiella oxytoca)、陰溝腸桿菌(Enterobacter cloacae)、產氣腸桿菌(Enterobacter aerogenes)、其他腸桿菌屬物種、弗氏檸檬酸桿菌(Citrobacter freundii)、綠膿桿菌(Pseudomonas aeruginosa)、其他假單胞菌屬物種、鮑氏靜止桿菌(Acinetobacter baumannii)、及許多其他非發酵型革蘭氏陰
性菌物種。該細菌亦包括幽門螺旋桿菌(Helicobacter pylori),及其他臨床上重要之革蘭氏陰性菌。特別是,該革蘭氏陰性菌係選自於由大腸桿菌、克留氏肺炎桿菌、產酸克雷伯氏菌、陰溝腸桿菌、弗氏檸檬酸桿菌、綠膿桿菌、及鮑氏靜止桿菌所組成之族群,較佳地該革蘭氏陰性菌係選自於由大腸桿菌、克留氏肺炎桿菌、綠膿桿菌、及鮑氏靜止桿菌所組成之族群。
以本發明化合物治療之細菌感染包括,例如,菌血症、敗血症、皮膚與軟組織感染、肺炎、腦膜炎、腹膜後區(pelveoperitoneal region)感染、異物感染、血液病患發燒、靜脈線或其他導管、管路、及/或裝置相關聯之感染、胃腸道、眼、或耳之感染、淺表皮膚感染、及潛在有害細菌導致之胃腸道、黏膜、及/或皮膚之移生(colonization)。
本發明化合物可用於治療細菌感染及/或細菌感染性疾病,特別是該些革蘭氏陰性菌所致者。發炎性疾病及病症之範例包括但不侷限於,嚴重醫院獲得性感染、免疫功能低下病患感染、器官移植病患感染、加護病房(ICU)感染、燒傷嚴重感染、嚴重社區獲得性感染、囊腫纖維化病患感染、及多重抗性革蘭氏陰性菌所致之感染。
據此,本發明提供一治療細菌感染之方法,特別是革蘭氏陰性菌所致之感染,包含投予本文定義之化合物或本文定義之醫藥組成物至有需求之病患。
本發明化合物可於每日投劑範圍內投予一有效
量,該範圍約1mg/kg至約300mg/kg,較佳地介於3mg/kg至100mg/kg體重之間。本發明化合物可以單一每日投劑量投予,或可以總每日投劑量分成每日二、三、或四次劑量投予。
「一有效量」係指一化合物量賦予治療個體治療功效。治療功效可為客觀(亦即以一些測試或標記測定)或主觀(亦即個體對功效產生指示或感覺該功效)。此類治療不一定完全改善疾病狀況。此外,此類治療或預防可用於結合其他常規治療,以減少本領域技術人員習知之病況。
本發明化合物最佳地係單獨使用或結合其他活性成分,特別是其他抗菌劑。該其他活性成分可同時或以任何順序結合本發明化合物投予。該抗菌劑可選自於由克拉黴素(clarithromycin)、亞藥索黴素(azithromycin)、紅黴素及其他巨環內酯類(macrolides)、酮內酯類(ketolides)、氟酮內酯類(fluoroketolides)、克林達黴素(clindamycin)及其他林可醯胺類(lincosamines)、鏈黴殺陽素(streptogramins)、雷發平、利福布丁(rifabutin)、利福拉齊(rifalazil)及其他利福黴素類(rifamycins)、梭鏈孢酸(fusidic acid)、莫匹羅星(mupirocin)、唑烷酮類(oxazolidinones)、萬古黴素、達巴萬星(dalbavancin)、特拉萬星(telavancin)、奧利萬星(oritavancin)及其他醣胜肽抗生素、氟喹啉酮類(fluoroquinolones)、枯草桿菌素(bacitracin)、四環黴素及氟四環素衍生物、β內醯胺(betalactam)抗生素、新生黴素(novobiocin)、截短側耳素
(pleuromutilins)、葉酸鹽合成抑製劑、去甲醯酶(deformylase)抑製劑、及細菌輸出幫浦抑製劑所組成之族群。特別是,該抗菌劑可選自於由克拉黴素、亞藥索黴素、紅黴素、泰利黴素(telithromycin)、索利黴素(solithromycin)、克林達黴素、鏈黴殺陽素結合物奎奴普丁-達福普汀(quinupristin-dalfopristin)、邇喏哇四環素(eravacycline)、米諾四環素(minocycline)、奧瑪四環素(omadacycline)、雷發平、利福布丁、利福拉齊、梭鏈孢酸、莫匹羅星、唑烷酮類泰地唑胺(tedizolid)及利奈唑胺(linezolid)、萬古黴素、達巴萬星、奧利萬星、特拉萬星、氟喹啉酮類莫西沙星(moxifloxacin)、德拉沙星(delafloxacin)及阿法諾沙星(avarafloxacin)、及葉酸鹽合成抑製劑甲氧芣啶(trimetoprim)所組成之族群。
本發明化合物可以各途徑投予,例如,非經口、皮下、靜脈、關節內、鞘內、肌肉、腹腔、及藉皮內注射、及經由透皮、直腸、頰、口腔黏膜、鼻、眼路線、及經由吸入、及經由植入。
一含有以本發明化合物作為活性成分之醫藥組成物,可進一步包括醫藥上可接受之添加劑,如醫藥上可接受之載體及/或賦形劑,其促進活性化合物加工為可用於醫藥之製劑。適用之醫藥組成物可包含以本發明化合物結合一或多個其他活性成分,特別是前述之抗菌劑。化合物可配製成適用之組成物;適用之投予形式包括例如,溶液、分散液、懸浮液、粉劑、膠囊劑、片劑、丸劑、控釋
膠囊、控釋片劑、及控釋丸劑。
本發明化合物可藉本領域習知之方法製備。下列範例說明式(I)化合物之製備。
NAB815具結構式辛醯基-αDab-Thr-DThr-[環-α,γDab-αDab-DPhe-Leu-Abu-αDab-Thr],其中位於R10之羧基端Thr經由其羧基連接至位於R4之2,4-二胺基丁酸殘基(Dab)之4-胺基,且其相對分子質量為1175.44,可由如常規固相化學合成,係使用前述用於其他多黏桿菌素衍生物之方法,如NAB739(美國專利號7,807,637)。C端胺基酸係商業上購得,其係預先連接至固相,且當以酸切斷樹脂時,產生C端羧酸。
保護策略係使用三級別之正交保護:暫時性Fmoc保護α-胺基功能;保護Dab殘基之γ-胺基,其涉及酸切割階段期間基團經移除後之環化作用;以及半永久性保護以於環化反應發生時覆蓋反應性側鏈功能。自樹脂切割胜肽後,C端羧酸係與位於R4之二胺基丁酸殘基(Dab)之γ-胺基反應,以形成環胜肽。於環化步驟後,移除半永久性保護基,產生NAB胜肽。
據此,胺基酸之α-胺基功能係由茀基甲氧基羰基(Fmoc)保護,且每一循環以含20%哌啶之二甲基甲醯胺(DMF)移除Fmoc。涉及環化作用之胺基酸,亦即位於R4之Dab,係由第三丁氧基羰基(tBoc)保護,其係一酸不穩定基
團,並於切割步驟中移除。具功能性側鏈基團之胺基酸係由酸切割階段呈現安定之基團,亦即芐基伸氧基羰基(Z),保護。胺基酸D-苯丙胺酸及白胺酸自然毋須側鏈保護。胺基端未經保護,使其於醯化作用程序中直接反應。
合成步驟係於商用自動化合成儀進行,其以0-(6-氯苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(HCTU)作為活化劑。
購得之胺基酸已由標準供應商進行保護。自樹脂移除胜肽,其係藉室溫下反應於95%三氟乙酸及5%水之溶液2小時,以產生部分經保護之產物。所得胜肽以乙醚沈澱。
所使用之環化作用混合物為苯并三唑-1-基伸氧基-參-吡咯啶鏻六氟磷酸酯(PyBop)、N-羥基苯并三唑(HoBt)、及N-甲基啉(NMM),其莫耳過剩分別為2、2、及4。將胜肽溶於二甲基甲醯胺,加入環化混合物,並使其反應2小時。藉加入冰冷乙醚,沈澱經環化、保護之胜肽。以水清洗胜肽,移除任何殘餘之PyBop。
藉催化脫氫作用,移除剩餘之側鏈保護基團(Z)。將胜肽溶於乙酸-甲醇-水(5:4:1),其係於氫氣環境及鈀木炭催化劑存在下進行。
胜肽係以逆相層析法純化,其使用常規梯度乙腈:水:三氟乙酸。產物以凍乾法乾燥。
NAB815係轉換為其硫酸酯。產物為白色凍乾物。其於溶液中(1mg/mL溶於水)之外觀為澄清且無色。當以ESI-MS鑑定時,m為1175.4u(平均質量)。
下列範例之提供,係以說明方式證實本發明,且不應視為侷限本發明之範疇。此外,試驗之化合物濃度係示例性,且不應視為侷限。本領域之技術人員可以本領域習知方法定義醫藥上相關濃度。所有動物實驗之進行皆根據倫理標準及適當機構動物照護與使用準則。
化學物質來源:NAB815硫酸酯(批號1051607;純度98.8%,HPLC分析)且NAB739硫酸酯具結構式辛醯基-Thr-DSer-[環-α,γDab-αDab-DPhe-Leu-αDab-αDab-Thr],亦即OA-SEQ ID 2(批號1049851,純度,97.3%,藉由HPLC)。多黏桿菌素B硫酸酯係購自Sigma-Aldrich,St.Louis,MO,USA(目錄編號P0972,批號BCBF8382V;純度,89.3%)。
以三重複完成最小抑制濃度(MIC)試驗,其係使用CLSI標準方法及Müller-Hinton II培養液,如Clinical and Laboratory Standards Institute,2012之說明(Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically.Approved standard,Ninth edition.CLSI document M07-A9.Clinical and Laboratory Standards Institute,Wayne,PA.)。起始接種體(5 x 105CFU/mL)係製自含5%羊血之胰蛋白酶大豆瓊脂上之隔夜培養物。微滴定盤
係於35℃下培養20小時,於該點時,可肉眼判讀。進行協同研究,係以多黏桿菌素衍生物結合雷發平,其係此類抗菌劑之模型化合物,其中革蘭氏陰性菌之完整外膜可作為滲透屏障。
表1顯示MIC值(μg/mL),亦即多黏桿菌素B、參考化合物(NAB739)、及本發明化合物(NAB815),單獨及結合固定濃度之雷發平(0.25μg/mL)*,之抗菌活性;包括多黏桿菌素敏感性及多黏桿菌素非敏感性菌株兩者。
多黏桿菌素敏感性菌株大腸桿菌、克留氏肺炎桿菌、及不動菌屬之NAB815之MICs係等同或非常接近NAB739與多黏桿菌素B。多黏桿菌素B對綠膿桿菌及三菌株(其對多黏桿菌素B之敏感性降低)之二者(克留氏肺炎桿菌JM109及鮑氏靜止桿菌CMI417)之活性優於NAB815及NAB739。
所有三胜肽之次抑菌濃度(subinhibitory concentration)明顯增強雷發平之活性(表1)。於1μg/mL時,NAB815減少雷發平對克留氏肺炎桿菌ATCC 43816之MIC,自16μg/mL至0.25μg/mL(亦即,因數值64),且對大腸桿菌ATCC 25922及大腸桿菌JMI3328,自8μg/mL至0.25μg/mL(亦即,因數值32)。很重要的是,多黏桿菌素敏感性下降之菌株,對NAB815與雷發平之結合活性亦敏感。NAB739取得非常類似之結果。對於綠膿桿菌,NAB815與NAB739兩者與雷發平缺乏任何顯著協同活性。
結論為,NAB815與NAB739之抗菌活性相同或彼此非常接近,其不僅是在單獨時,亦出現於存在雷發平時。
以石蟹獼猴進行體內毒性及毒物動力學研究。執行動物研究之實驗室係經實驗動物管理評估及認證協會
(Association for Assessment and Accreditation of Laboratory Animal Care,AAALAC)認可,其具實驗動物福祉辦公室(Office of Laboratory Animal Welfare,OLAW)頒發之動物福祉保證(Animal Welfare Assurance),其註冊在美國農業部(USDA),並具實驗動物照護及使用委員會(Institutional Animal Care and Use Committee,IACUC),負責實驗室動物人為照護及用途之相關應用法規及規則之合法性。
將稚嫩雌性石蟹獼猴置於研究室中適應28天,期間各動物植入一永久留置型股導管,以允許連續靜脈輸注。於開始投劑前,動物之術後恢復期至少2週。
化學物質來源如下:NAB815硫酸酯(批號1051607;純度98.8%,HPLC分析,以及批號1054308;純度98.4%,HPLC分析)及NAB739硫酸酯(批號1049851,純度97.3%,HPLC分析)。多黏桿菌素B硫酸酯係購自Sigma-Aldrich(目錄編號P0972,批號BCBF8382V)。每天使用時,將適量之NAB739、NAB815、或多黏桿菌素B秤重,並溶解於適當體積之無菌鹽液,以製備各測試件儲液及陽性對照組。儲液製備物採行一校正因數,以計算各測試件之純度及硫酸酯含量。據此,劑量(如36mg/kg/d)係指純之胜肽於其游離鹼而非硫酸酯形式時之劑量。
劑量如下:多黏桿菌素B 18mg/kg/d(第1組)、多黏桿菌素B 24mg/kg/d(第2組)、NAB739 24mg/kg/d(第3組)、NAB739 36mg/kg/d(第4組)、NAB815 24mg/kg/d(第5組)、NAB815 36mg/kg/d(第6組)。各研究組包括三隻動
物。
為期七天,動物每天三次(TID)靜脈(IV)輸注投劑1小時(±10分鐘),間隔8±0.5小時,其中劑量體積為10mL/kg。將初始投劑日定為研究第1天,隨後幾天連續編號。初始投劑日前之天數亦連續編號,其最終日定為第-1天。
於設定時間評估下列參數:臨床觀察、體重、臨床病理學(血液學、凝血、血清化學、尿液分析包括尿液沉積及尿液化學)、毒物動力學(血漿及尿液)及解剖病理學(腎臟)。一旦動物計畫外犧牲,於犧牲日取得樣本。
於屍體剖驗當天,動物以克他明(ketamine)麻醉、秤重、及靜脈注射戊巴比妥(pentobarbital)與苯妥英(phenytoin)溶液麻醉,之後放血(exsanguinations)。
於第8天進行存活動物之最終剖驗。多黏桿菌素B組於第4天進行計畫外剖驗,其中一隻動物接受18mg/kg/d(第1組)且二隻動物接受24mg/kg/d(第2組),以及於第5天進行計畫外剖驗,其中二隻動物接受18mg/kg/d(第1組)。NAB739組之一隻動物於第5天亦進行計畫外剖驗,其係接受36mg/kg/d(第4組)。
於剖驗時,記錄大體觀察結果及器官重量,並收集特定組織。以腎臟切片進行組織病理學分析,其係以蘇木精與曙紅(hematoxylin and eosin;H&E)染色。
用於毒物動力學(TK)研究之血漿及尿液濃度,係於蛋白質沈澱後以液相層析連接質譜儀測定。樣本(100μL)混合於內標準品溶液,其溶於水:甲酸(99:1 v/v;50mL)。
隨後,將600μL之乙腈:甲酸(100:1)加入。培養盤以3200rpm離心5分鐘。利用Tomtec Quadra96,將450μL等分試樣移至新的96孔培養盤,並於40℃之氮氣下乾燥。隨後,將200μL之水:甲醇:甲酸(85:15:1 1 v/v)加入,且密封培養盤以進行LC-MS/MS注射。LC-MS系統由Waters Acquity液相層析連接Thermo Scientific TSQ Quantitative三重四極桿MS組成,其於陽離子模式離子化。將各樣本(20μL)注入Waters Acquity BEH Shield RP18管柱(2.1 x 50mm;1.7μm),其於50℃下平衡。移動相A為85:15:1 v/v水:甲醇:甲酸。移動相B為50:50:1 v/v乙腈:甲醇:甲酸。
表2顯示適於量化所有化合物之梯度。
表3顯示各化合物之質量轉變及滯留時間。
以(1/濃度平方)線性擬合廻歸分析多黏桿菌素B之校正標準反應之尖峰面積比,其中以黏菌素作為內標準品。針對NAB739及NAB815,以(1/濃度平方)二次擬合廻歸分析校正標準反應之尖峰面積(未使用內標準品)。
根據發展期間分析物於濃度範圍內之行為,選擇廻歸模型。
毒物動力學分析係以WinNonlin Phoenix 6.3版軟體進行(Pharsight,Cary,NC)。針對血漿TK,使用房室靜脈輸注模式(noncompartmental IV infusion model)。
圖中顯示動物於處理前及相同動物於接受多黏桿菌素B、NAB739、或NAB815後,血尿素氮(S-BUN;圖1)及血肌酐(S-Crea;圖2)之濃度,兩者為腎臟損傷之血液標記物。圖中亦顯示該些動物之尿液N-乙醯基-β-D-葡萄糖苷酶/尿液肌酐比(U-NAG/Crea;圖3)及尿液γ-麩胺醯轉化酶/尿液肌酐比(U-GGT/Crea;圖4),兩者為腎臟損傷之尿液生物標記物。利用Olympus Analyzer(OA)及修正之賈菲法
(Jaffe method)測定S-Crea及U-Crea,而S-BUN則利用OA與尿素酶/L-麩胺酸脫氫酶。以OA/酵素法測定U-NAG,且以OA與麩胺醯基羧基對硝基醯胺苯IFCC(glutamyl-carboxy-p-nitroanilide IFCC)測定U-GGT。於圖1至4,「*」代表動物因嚴重腎毒性影響,必須進行安樂死。
結論為,NAB815明顯具有比NAB739更好的耐受性。一隻接受NAB739 36mg/kg/d之動物因嚴重腎毒性影響,必須進行安樂死。於此動物,所有四標記物數值皆明顯升高。於另一接受NAB739 36mg/kg/d之動物,兩尿液生物標記物數值皆明顯升高。相反地,NAB815動物之四參數值僅輕微升高,且毋須進行計畫外剖驗。
於24mg/kg/d之劑量,一接受NAB739之動物S-Crea明顯增加。接受同等劑量NAB815之動物未有參數升高情況。
如預期,多黏桿菌素B明顯有毒。二隻接受多黏桿菌素B 24mg/kg/d之動物及所有三隻接受多黏桿菌素B 18mg/kg/d之動物,必須進行安樂死。於所有六隻動物,S-BUN、S-Crea、及U-GGT/Crea皆明顯增加。該動物中有五隻U-NAG/Crea明顯增加。
相同高劑量(36mg/kg/d)之NAB739與NAB815所誘發之型態結果之組織病理學比較顯示NAB815之腎病理變化較不嚴重。記錄各動物之下列腎病理學參數:腎小管嗜鹼性(再生)、腎小管退化/壞死、浸潤(單核及/或混合之發炎細胞)、腎小管擴張、及腎小管圓柱(tubular casts)。各參
數評分如下:等級代碼=0:無明顯發現;1:最低;2:輕度;3:中等;4:明顯。明顯發現僅出現在安樂死之NAB739處理動物,如下:明顯腎小管退化/壞死及明顯存在腎小管圓柱。NAB739處理動物有二參數具中等發現。NAB815處理動物之二者僅一參數具中等發現。第三隻NAB815處理動物無超過最低或輕度之發現。據此,相對於該些NAB739處理動物之觀察結果,NAB815處理動物具較不嚴重之組織變化。
輸注8mg/kg之NAB815後,時間0h至8h之濃度-時間下面積(AUCs 0-8h,hr*μg/mL),於第1天測定時為102(SD=5),且於第7天測定時為110(SD=12)。輸注同等劑量(8mg/kg)之NAB739後,其相對應之值為108(SD=2)及137(SD=2)。輸注同等劑量(8mg/mL)之多黏桿菌素B後,於第1天測定時,其值為112(SD=5)。據此,三化合物之AUC值彼此非常接近。
值得注意的是,輸注後8小時內,有非常顯著部分之NAB815劑量排泄至尿液中(0-8h之回收率)。輸注8mg/kg之NAB815後,0-8h之回收率(各動物所得百分比)高達投劑量之38%、55%、及88%。NAB739之相對應回收率高達20%、91%、及92%,且多黏桿菌素B為1%、2%、及2%。NAB815與NAB739之尿液中濃度極高。於輸注8mg/kg之NAB815後,0-4h或4-8h之樣本(各動物所得濃度)發現濃度高達175、225、及260μg/mL。NAB739之相對應濃度為80、140、及155μg/mL,且多黏桿菌素B為7、9、及15μg/mL。
總結,NAB815之腎毒性明顯低於NAB739。兩化合物之AUC彼此非常接近。兩者以非常顯著之程度排泄至尿液,使得尿液中濃度非常高。
數據係源自範例3所述之石蟹獼猴研究,其中胜肽係以1小時靜脈輸注方式每日投予三次。血漿及尿液中胜肽濃度之測定如範例3所示。
當胜肽以36mg/kg/d投劑時,NAB815之第1天及第7天AUCs(hr*μg/ml)分別為153(SD,32)及205(SD,56)。NAB739之相對應值為239(SD,9)及302(無SD,動物數,2)。於此劑量,三隻動物於第1天之NAB815尿液回收率(0-8h之尿液收集)為14.3%、20.9%、及36.3%,且於第7天為33.9%、40.5%、及41.9%。NAB739於第1天之相對應值為15.4%、20.4%、及26.4%,且於第7天為30.6%及55.8%(僅二隻動物)。此外,三動物於第1天之NAB815尿液濃度(μg/ml,0-8h之尿液收集)為114、173、及265,且於第7天為17、62、及149。NAB739於第1天之相對應值為33、82、及92,且於第7天為268及348(僅二隻動物)。
本研究使用64隻遠親雜交且體重28-32公克之OF-1雌性小鼠(Charles River,France)以及一種製作第1型繖毛(fimbriae)之臨床分離物,大腸桿菌C175-94(血清型O8:K48:H4)。胜肽為NAB815(批號1054308)及多黏桿菌素B(Sigma-Aldrich,批次BCBF8382V)。研究係於丹麥哥本哈
根Statens Serum Institut進行。
研究開始前三天及研究期間,小鼠自由攝取5%葡萄糖液作為飲用水。
於第0天,輕按腹部,自膀胱移除尿液。隨後,以約0.15ml之舒泰(Zoletil)混合物皮下注射麻醉小鼠。含細菌懸浮液之聚乙烯導管注射器(Becton Dickison)經由尿道插入膀胱,並將50μl之細菌接種物緩慢注入膀胱。隨後,將小鼠置於籠中。小鼠留置於暖櫃中並監視,直到完全清醒。
於測量菌落形成單位(CFUs)後,接種物經測定含有9.38 log10CFU/ml,相對應於8.08 log10CFU/小鼠。
於感染後第1天及第2天,小鼠每日二次皮下處理含NAB815、多黏桿菌素B、或載具(0.9% NaCl)之溶液(0.2ml)。處理組別(各組六隻小鼠)如下:載具對照組;NAB815,0.25mg/kg/劑量;NAB815,0.5mg/kg/劑量;NAB815,1mg/kg/劑量;NAB815,2mg/kg/劑量;多黏桿菌素B,0.25mg/kg/劑量;多黏桿菌素B,0.5mg/kg/劑量;多黏桿菌素B,1mg/kg/劑量;以及多黏桿菌素B,2mg/kg/劑量。此外,以一組作為預處理對照組,以於感染後開始第1天治療之前,協助評估感染如何進行。
於感染後第1、2、及3天,取樣尿液以進行菌落計數。於感染後第1天(預處理對照組)及感染後第3天(所有其他組別),尿液取樣後,以頸椎脫位(cervical dislocation)方式犧牲小鼠,並以無菌方式取出膀胱及腎臟。將膀胱及
腎臟保存於-80℃,之後分別於0.5及1ml鹽液中均質化。
於取樣後2-3小時內立即測定尿液中CFUs。將冷凍之器官解凍,並於組織研磨機(tissue lyser)中以鋼珠均質化。所有樣本、尿液、腎臟、及膀胱係以鹽液進行10倍稀釋,並以二重複方式將20-μl樣本點施加於血液瓊脂培養盤。此外,將未經稀釋之尿液樣本(2-100μl,取決於尿液量)塗佈於個別之瓊脂培養盤,以測定菌落計數之最低可能檢測程度。所有瓊脂培養盤皆培養於35℃環境空氣中18-22h。
當以感染後第1天之預處理對照組之程度相較於第3天開始處理二天後之程度,處理1與2mg/kg/劑量之NAB815造成明顯減少尿中CFU程度(分別為**p<0.01及*p<0.05(ANNOVA Dunnett's多重比較檢定))。相反地,載具對照組、接受0.25與0.5mg/kg/劑量之NAB815組、及任何多黏桿菌素B組之相對應程度間未發現顯著差異。
處理NAB815顯示,膀胱及腎臟之CFUs具劑量反應趨勢,而處理多黏桿菌素B未顯示任何劑量反應趨勢。
於所有處理0.25-2mg/kg/劑量之NAB815之24隻小鼠中,有8隻小鼠之尿液及20隻小鼠之腎臟細菌程度低於檢測極限,而處理多黏桿菌素B之小鼠之相對應數值分別為1與10。
本領域之技術人員將顯見的是,隨著技術進步,本發明概念可以各種方式實現。本發明及其實施例並未侷限於上述範例,但可於所揭露之範疇內變化。
<110> 北方抗體科技公司
<120> 多黏桿菌素衍生物及其用途
<140> TW 105101251
<141> 2016-01-15
<150> FN 20155027
<151> 2015-01-15
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 細菌
<220>
<221> 不確定
<222> (1)..(1)
<223> Dbu
<220>
<221> 不確定
<222> (3)..(3)
<223> d-Thr
<220>
<221> 不確定
<222> (4)..(5)
<223> Dbu
<220>
<221> 不確定
<222> (6)..(6)
<223> d-Phe
<220>
<221> 不確定
<222> (8)..(8)
<223> Abu
<220>
<221> 不確定
<222> (9)..(9)
<223> Dbu
Claims (8)
- 一種醫藥組成物,其包含一抗菌有效量之如請求項1之化合物或其醫藥上可接受之鹽類,及至少一醫藥上可接受之載體及/或賦形劑。
- 如請求項2之醫藥組成物,其更包含一或多種抗菌劑。
- 如請求項3之醫藥組成物,其中該一或多種抗菌劑係選自於由下列所組成之族群:克拉黴素(clarithromycin)、亞藥索黴素(azithromycin)、紅黴素及其他巨環內酯類(macrolides)、酮內酯類(ketolides)、氟酮內酯類(fluoroketolides)、克林達黴素(clindamycin)及其他林可醯胺類(lincosamines)、鏈黴殺陽素(streptogramins)、雷發平(rifampin)、利福布丁(rifabutin)、利福拉齊(rifalazil)及其他利福黴素類(rifamycins)、梭鏈孢酸(fusidic acid)、莫匹羅星(mupirocin)、唑烷酮類(oxazolidinones)、萬古黴素、達巴萬星(dalbavancin)、特拉萬星(telavancin)、奧利萬星(oritavancin)及其他醣胜肽抗生素、氟喹啉酮類(fluoroquinolones)、枯草桿菌素(bacitracin)、四環黴素及氟四環素衍生物、β內醯胺(betalactam)抗生素、新生黴素(novobiocin)、截短側耳素(pleuromutilins)、葉酸鹽合成抑製劑、去甲醯酶(deformylase)抑製劑、及細菌輸出幫浦(bacterial efflux pump)抑製劑。
- 如請求項4之醫藥組成物,其中該抗菌劑係選自於由下列所組成之族群:克拉黴素、亞藥索黴素、紅黴素、泰 利黴素(telithromycin)、索利黴素(solithromycin)、克林達黴素、鏈黴殺陽素結合物奎奴普丁-達福普汀(quinupristin-dalfopristin)、邇喏哇四環素(eravacycline)、米諾四環素(minocycline)、奧瑪四環素(omadacycline)、雷發平、利福布丁、利福拉齊、梭鏈孢酸、莫匹羅星、唑烷酮類泰地唑胺(tedizolid)及利奈唑胺(linezolid)、萬古黴素、達巴萬星、奧利萬星、特拉萬星、氟喹啉酮類莫西沙星(moxifloxacin)、德拉沙星(delafloxacin)及阿法諾沙星(avarafloxacin)、及葉酸鹽合成抑製劑甲氧芐啶(trimetoprim)。
- 一種如請求項1之化合物或其醫藥上可接受之鹽類或如請求項2至5中任一項之醫藥組成物於製備藥劑之用途,該藥劑用於治療細菌感染。
- 如請求項6之用途,其中該細菌感染為革蘭氏陰性菌所引起。
- 如請求項7之用途,其中該革蘭氏陰性菌係選自於由大腸桿菌(Escherichia coli)、克留氏肺炎桿菌(Klebsiella pneumoniae)、產酸克雷伯氏菌(Klebsiella oxytoca)、陰溝腸桿菌(Enterobacter cloacae)、弗氏檸檬酸桿菌(Citrobacter freundii)、綠膿桿菌(Pseudomonas aeruginosa)、及鮑氏靜止桿菌(Acinetobacter baumannii)所組成之族群。
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FI20085469A0 (fi) * | 2008-02-08 | 2008-05-16 | Northern Antibiotics Oy | Polymyksiinijohdannaiset, joissa on lyhyt rasvahappohäntä, ja niiden käyttöjä |
AU2012338571B2 (en) | 2011-11-18 | 2016-06-16 | New Pharma Licence Holdings Limited | Polymyxin derivatives |
MX360905B (es) * | 2013-01-11 | 2018-11-21 | Xellia Pharmaceuticals Aps | Polimixinas, composiciones, metodos de preparacion y metodos de uso. |
RU2730012C2 (ru) | 2013-05-22 | 2020-08-14 | Сперо Терапьютикс, Инк. | Производные полимиксина и их применение в комбинированной терапии совместно с различными антибиотиками |
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2015
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008017734A1 (en) * | 2006-08-11 | 2008-02-14 | Northern Antibiotics Oy | Polymyxin derivatives and uses thereof |
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CN107207569B (zh) | 2020-11-03 |
TW201630930A (zh) | 2016-09-01 |
CN107207569A (zh) | 2017-09-26 |
KR20170102005A (ko) | 2017-09-06 |
IL253457A0 (en) | 2017-09-28 |
SG11201705125UA (en) | 2017-07-28 |
JP6471236B2 (ja) | 2019-02-13 |
RU2675819C1 (ru) | 2018-12-25 |
CA2972743A1 (en) | 2016-07-21 |
DK3045469T3 (en) | 2018-03-05 |
EP3045469B1 (en) | 2017-11-29 |
BR112017014670A2 (pt) | 2018-03-13 |
IL253457B (en) | 2019-10-31 |
MX2017009094A (es) | 2018-03-01 |
HRP20180180T1 (hr) | 2018-03-09 |
JP2018505868A (ja) | 2018-03-01 |
EP3045469A1 (en) | 2016-07-20 |
FI20155027A (fi) | 2016-07-15 |
PT3045469T (pt) | 2018-02-08 |
AU2016207942A1 (en) | 2017-08-10 |
HUE035778T2 (hu) | 2018-08-28 |
FI126143B (en) | 2016-07-15 |
KR102020886B1 (ko) | 2019-09-16 |
NO3045469T3 (zh) | 2018-04-28 |
AU2016207942B2 (en) | 2018-05-10 |
CA2972743C (en) | 2020-06-09 |
ES2656562T3 (es) | 2018-02-27 |
WO2016113470A1 (en) | 2016-07-21 |
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