TW202333706A - N—羥基胞磷膽鹼(citicoline)化合物的醫藥用途 - Google Patents
N—羥基胞磷膽鹼(citicoline)化合物的醫藥用途 Download PDFInfo
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- TW202333706A TW202333706A TW111141670A TW111141670A TW202333706A TW 202333706 A TW202333706 A TW 202333706A TW 111141670 A TW111141670 A TW 111141670A TW 111141670 A TW111141670 A TW 111141670A TW 202333706 A TW202333706 A TW 202333706A
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P31/12—Antivirals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本發明係關於具有N
4-羥基胞苷部分之胞磷膽鹼(citicoline)類似物及其溶劑化物或醫藥上可接受之鹽之醫藥用途。該等化合物可用作用於治療(例如) Covid-19、人鼻病毒(HRV)、流感及呼吸道融合性病毒(RSV)之抗病毒藥物。
Description
本發明係關於具有N
4-羥基胞苷部分之胞磷膽鹼(citicoline)類似物之醫藥用途。此等類似物可用作用於治療(例如) Covid-19、人鼻病毒(HRV)、流感及呼吸道融合性病毒(RSV)之抗病毒藥物。
胞磷膽鹼(亦稱作胞苷二磷酸鹽-膽鹼(CDP-膽鹼)或胞苷5'-二膦基膽鹼)為自膽鹼生成磷脂醯膽鹼之中間體,自膽鹼生成磷脂醯膽鹼為細胞膜中之常見生物化學過程。胞磷膽鹼於人類及動物組織(特定言之器官)之細胞中天然產生。胞磷膽鹼係可作為膳食補充劑從市面上獲得。當用作膳食補充劑時,胞磷膽鹼於腸中水解成膽鹼及胞苷。一旦此等片段(即,膽鹼、胞苷)跨越血腦屏障,其即由磷脂醯膽鹼合成中之速率限制酶CTP-膦基膽鹼胞苷醯轉移酶重新組成胞磷膽鹼。胞磷膽鹼係水溶性,具有超過90%口服生物可利用率且於動物及人類中具有極低毒性譜。胞磷膽鹼作為活性成分(例如)於WO2004/006940中被描述為藥物誘導之神經病變之預防/補救。此等有利整體性質使胞磷膽鹼成為藥物開發之優異起點。然而,針對胞磷膽鹼尚未提及抗病毒活性。藉由將胞嘧啶部分之4-位置之氫用羥基置換,所得化合物顯示出人意料針對SARS-CoV-2之抗病毒活性,當與DHODH抑制劑組合時,其甚至可於協同行為中提高更多。
胞苷可在胞嘧啶之4-位置中之氮處經化學羥基化,以形成ß-D-N
4-羥基胞苷(NHC),亦稱作EIDD-1931。核糖之5'-位置中之異丁酸為EIDD-1931之前藥,稱作莫努皮拉韋(molnupiravir)或EIDD-2801。兩種化合物均為抗病毒藥物,其透過在病毒RNA複製期間引入複製錯誤來發揮其抗病毒作用(Nat. Struct. Mol. Biol. 2021;28:740)。目前開發莫努皮拉韋用於治療流感及批准用於治療Covid-19。當經口投與時,莫努皮拉韋水解成NHC,其隨後代謝成ß-D-N
4-羥基胞苷5′-三磷酸鹽(EIDD-2061)。在複製期間,病毒之RNA聚合酶將EIDD-2061併入新製備之RNA中代替使用真正胞苷。
反應圖1:莫努皮拉韋至活性代謝物NHC-TP之轉化
莫努皮拉韋之缺點為前藥必須首先水解成ß-D-N
4-羥基胞苷,然而其於人體中非活性,但是需要藉由宿主細胞激酶細胞內活化。此等酶經由單磷酸鹽及二磷酸鹽將核苷類似物轉化成最終活性核苷類似物三磷酸鹽。於此過程中至單磷酸鹽之轉化為速率限制步驟。
於本發明中,吾人藉由使用二磷酸鹽-膽鹼前藥(式(I))改善生物活化,其中ß-D-N
4-羥基胞苷5′-二磷酸鹽於膽鹼裂解後形成,從而繞過速率限制步驟。此外,吾人顯示式(I)之核苷類似物與莫努皮拉韋及NHC相比之出入意料的效果,例如,提高之滲透性,儘管低的溶解度(實例3)及歷時長時間段血漿中之NHC-DP及NHC-TP之高濃度(實例4)。此外,吾人描述根據式(I)之化合物自易得且便宜胞苷二磷酸鹽-膽鹼(CDP-膽鹼或胞磷膽鹼)之直截了當一步合成,該胞苷二磷酸鹽-膽鹼係作為膳食補充劑以醫藥等級品質銷售(實例1及實例2)。
本發明根據式(
I)之化合物為胞磷膽鹼之N
4-羥基類似物及以CAS號13186-92-0及13186-58-8見於SciFinder中及除了所述兩性離子未描述其他鹽。
對式(I)之唯一關聯參考為來自Abdelrahman等人之出版物(J. Sep. Sci. 2020;43:2981),其描述此化合物在胞磷膽鹼之氧化降解後之形成(使用3%過氧化氫)及其作為同時測定胞磷膽鹼及吡拉西坦(piracetam)之穩定性指示層析法之分析開發及驗證中之參考標準物的用途。
WO2019/113462 (Emory University)描述N
4-羥基胞苷及衍生物之製備及與之相關之抗病毒用途。該申請案描述N
4-羥基胞苷之許多不同酯前藥,包括莫努皮拉韋。
來自Emory University WO2017/156380及WO2016/106050之另外專利申請案亦描述N
4-羥基胞苷前藥之製備及與之相關之抗病毒用途。核糖部分之5'-O-位置亦可經寬範圍之殘基R
1(例如,單磷酸鹽、二磷酸鹽、三磷酸鹽)取代,該R
1可視情況經一或多個殘基R
20取代。此R
20提及許多基團,包括烷基。
ß-D-N
4-羥基胞苷5′-三磷酸鹽(NHC-TP,CAS號34973-27-8)及ß-D-N
4-羥基胞苷5′-二磷酸鹽(NHC-DP,CAS號39023-73-9)之游離酸係(例如)購自MedChemExpress。
若干先前專利申請案,例如,WO2002/100415 (Roche)或WO2016/100569 (Alios)提及二磷酸鹽部分,然而其不可經取代以產生酯。
本發明係關於具有N
4-羥基胞苷部分之胞磷膽鹼類似物之醫藥用途。此等類似物可用作用於治療(例如) Covid-19、人鼻病毒(HRV)、流感及呼吸道融合性病毒(RSV)之抗病毒藥物。
本發明之標的藉由下列實施例描述:
1.一種根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用作藥物。
2.如實施例1之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於預防及/或治療哺乳動物個體之由病毒感染引起之疾病,其中該病毒感染係由RNA病毒,諸如,例如,HIV、HCV、埃博拉(Ebola)、輪狀病毒、茲卡(Zika)病毒、小兒麻痺病毒、鼻病毒、A型肝炎病毒、麻疹病毒、腮腺炎病毒、RSV、狂犬病、拉薩(Lassa)病毒、漢坦病毒(hantavirus)或流感,特定言之單股RNA病毒,諸如HCoV-229E、HCoV-NL63或β冠狀病毒,諸如HCoV-OC43、SARS-CoV-1、HCoV-HKU1、MERS-CoV或SARS-CoV-2引起。
3.如實施例1或2之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於預防及/或治療人類之由利用冠狀病毒之病毒感染引起之疾病。
4.如實施例1至3中任一項之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於預防及/或治療疾病,其中該疾病係選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
5.如實施例1至4中任一項之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於預防及/或治療疾病,其中該預防及/或治療係與標準抗病毒療法(SAT)組合。
6.如實施例1至4中任一項之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於預防及/或治療疾病,其中該預防及/或治療係與DHODH抑制劑,及視情況與標準抗病毒療法(SAT)組合。
7.如實施例6之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其中於該組合中,該DHODH抑制劑由式(
II):
或其對映異構體、非對映異構體、互變異構體、前藥、溶劑化物或醫藥上可接受之鹽組成,其中
R
1及R
2係獨立地選自H及D;
R
3、R
4、R
5及R
6係獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
R
7、R
8、R
9及R
10獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
X係選自H、D、OH、OD、S(=O)
yR
11及OR
11;
R
11係選自C
1-4-烷基、C
3-4-環烷基及氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
y為0至2;
係選自5-員雜芳基、環戊烯基及雜環戊烯基,具有一或多個氫原子視情況經氘置換,
該A係未經取代或經獨立地選自由鹵素、CN、NO
2、側氧基、OH、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基、CO
2H及SO
3H組成之群之1至5個取代基取代,烷基中之一或多個氫原子視情況經氘置換;
限制條件為R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、X及/或A中之至少一個氫經氘置換。
8.如實施例7之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,其中於該組合中,該DHODH抑制劑係選自
或其溶劑化物或醫藥上可接受之鹽。
9.一種醫藥組合物,其包含如實施例1至8中任一項之用作藥物之式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,諸如錠劑、膠囊、顆粒、粉末、藥囊、可復水粉末、乾粉末吸入器及/或可咀嚼物。
10.如實施例9之醫藥組合物,其中該醫藥組合物進一步包含一或多種醫藥上可接受之載劑或賦形劑。
11.一種根據式(I)之化合物
,其可藉由使胞磷膽鹼或其鹽與羥胺或其鹽反應來獲得。
12.一種根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽,其用於治療選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應之疾病,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
13.一種根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽之用途,其用作藥物。
14.如實施例13之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽作為藥物的用途,其用於預防及/或治療哺乳動物個體之由病毒感染引起之疾病,其中該病毒感染係由RNA病毒,諸如,例如,HIV、HCV、埃博拉、輪狀病毒、茲卡病毒、小兒麻痺病毒、鼻病毒、A型肝炎病毒、麻疹病毒、腮腺炎病毒、RSV、狂犬病、拉薩病毒、漢坦病毒或流感,特定言之單股RNA病毒,諸如HCoV-229E、HCoV-NL63或β冠狀病毒,諸如HCoV-OC43、SARS-CoV-1、HCoV-HKU1、MERS-CoV或SARS-CoV-2引起。
15.如實施例13或14之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其用於預防及/或治療人類之由利用冠狀病毒之病毒感染引起之疾病。
16.如實施例13至15中任一項之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其用於預防及/或治療疾病,其中該疾病係選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
17.如請求項13至16中任一項之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其用於預防及/或治療疾病,其中該預防及/或治療係與標準抗病毒療法(SAT)組合。
18.如實施例13至16中任一項之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其用於預防及/或治療疾病,其中該預防及/或治療係與DHODH抑制劑,及視情況與標準抗病毒療法(SAT)組合。
19.如實施例18之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其中於該組合中,該DHODH抑制劑由式(
II):
或其對映異構體、非對映異構體、互變異構體、前藥、溶劑化物或醫藥上可接受之鹽組成,其中
R
1及R
2係獨立地選自H及D;
R
3、R
4、R
5及R
6係獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
R
7、R
8、R
9及R
10係獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
X係選自H、D、OH、OD、S(=O)
yR
11及OR
11;
R
11係選自C
1-4-烷基、C
3-4-環烷基及氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
y為0至2;
係選自5-員雜芳基、環戊烯基及雜環戊烯基,具有一或多個氫原子視情況經氘置換,
該A係未經取代或經獨立地選自由鹵素、CN、NO
2、側氧基、OH、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基、CO
2H及SO
3H組成之群之1至5個取代基取代,烷基中之一或多個氫原子視情況經氘置換;
限制條件為R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、X及/或A中之至少一個氫經氘置換。
20.如實施例19之根據式(
I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其中於該組合中,該DHODH抑制劑係選自
或其溶劑化物或醫藥上可接受之鹽。
21.如實施例13至20中任一項之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其中該(等)化合物係以適宜醫藥組合物,諸如錠劑、膠囊、顆粒、粉末、藥囊、可復水粉末、乾粉末吸入器及/或可咀嚼物提供。
22.如實施例21之根據式(
I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作藥物的用途,其中該醫藥組合物進一步包含一或多種醫藥上可接受之載劑或賦形劑。
23.一種根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽於治療選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應之疾病,特定言之該等疾病之中度至嚴重情況中的用途,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
24.一種治療或預防哺乳動物個體之由病毒感染引起之疾病之方法,其中該病毒感染係由RNA病毒,諸如,例如,HIV、HCV、埃博拉、輪狀病毒、茲卡病毒、小兒麻痺病毒、鼻病毒、A型肝炎病毒、麻疹病毒、腮腺炎病毒、RSV、狂犬病、拉薩病毒、漢坦病毒或流感,特定言之單股RNA病毒,諸如HCoV-229E、HCoV-NL63或β冠狀病毒,諸如HCoV-OC43、SARS-CoV-1、HCoV-HKU1、MERS-CoV或SARS-CoV-2引起,該方法包括包括向需要此治療或預防之患者投與治療上或預防上有效量之根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽。
25.如實施例24之方法,其中該疾病係由人類之由利用冠狀病毒之病毒感染引起。
26.如實施例24或25之方法,其中該疾病係選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
27.如實施例24至26中任一項之方法,其中該預防及/或治療係與標準抗病毒療法(SAT)組合。
28.如實施例24至26中任一項之方法,其中該預防及/或治療係與DHODH抑制劑,及視情況與標準抗病毒療法(SAT)組合。
29.如實施例28之方法,其中於該組合中,該DHODH抑制劑由式(
II):
或其對映異構體、非對映異構體、互變異構體、前藥、溶劑化物或醫藥上可接受之鹽組成,其中
R
1及R
2係獨立地選自H及D;
R
3、R
4、R
5及R
6係獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
R
7、R
8、R
9及R
10係獨立地選自H、D、鹵素、CN、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
X係選自H、D、OH、OD、S(=O)
yR
11及OR
11;
R
11係選自C
1-4-烷基、C
3-4-環烷基及氟-C
1-4-烷基,烷基中之一或多個氫原子視情況經氘置換;
y為0至2;
係選自5-員雜芳基、環戊烯基及雜環戊烯基,具有一或多個氫原子視情況經氘置換,
該A係未經取代或經獨立地選自由鹵素、CN、NO
2、側氧基、OH、C
1-4-烷基、O-C
1-4-烷基、氟-C
1-4-烷基及O-氟-C
1-4-烷基、CO
2H及SO
3H組成之群之1至5個取代基取代,烷基中之一或多個氫原子視情況經氘置換;
限制條件為R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、X及/或A中之至少一個氫經氘置換。
30.如實施例29之方法,其中於該組合中,該DHODH抑制劑係選自
或其溶劑化物或醫藥上可接受之鹽。
31.一種治療選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應之疾病,特定言之該等疾病之中度至嚴重情況之方法,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴),該方法包括向需要此治療或預防之患者投與治療上或預防上有效量之根據式(
I)之化合物:
。
本發明進一步關於根據式(
I)之化合物:
或其互變異構體、溶劑化物或醫藥上可接受之鹽於製造如以上實施例中任一項中所定義之藥物中的用途。
定義及特定實施例
與根據式(I)之化合物組合之DHODH抑制劑係選自維多迪莫司(vidofludimus)、維多迪莫司鈣(IMU-838)、特立氟胺(teriflunomide)、來氟米特(leflunomide)、依沃司他(emvododstat) (PTC299)、布喹那(brequinar)、法如司他(farudostat) (ASLAN003)、PP-001、RP7214、奧魯司他(orludodstat) (BAY2402234)、JNJ-74856665、AG-636、MEDS433或根據式(
II)之化合物,其已描述於臨時申請案EP21167690中。較佳地,該DHODH抑制劑為根據式(II)之化合物。更佳地,該DHODH抑制劑係選自
或其溶劑化物或醫藥上可接受之鹽。
用於標準抗病毒療法(SAT)中之可與式(I)化合物組合單獨投與、共同投與或於相同醫藥組合物中之其他治療劑之實例包括(但不限於):
(1)蛋白酶抑制劑(例如,PF-07304814、PF-00835231、尼瑪特韋(nirmatrelvir)、洛匹那韋(lopinavir)或利托那韋(ritonavir));
(2)聚合酶抑制劑(例如,吉西他濱(gemcitabine));
(3)變構聚合酶抑制劑;
(4)干擾素α-2a,其可經聚乙二醇化或以其他方式修改,及/或利巴韋林(ribavirin);
(5)非受質基抑制劑;
(6)螺旋酶抑制劑;
(7)引物酶-螺旋酶抑制劑(例如,普瑞利韋(pritelivir));
(8)反義寡脫氧核苷酸(S-ODN);
(9)適體;
(10)抗核酶核糖酶;
(11) iRNA,包括microRNA及SiRNA;
(12)抗體,針對病毒之部分抗體或域抗體;
(13)誘導宿主抗體反應之病毒抗原或部分抗原;
(14)含NOD-、LRR-及pyrin域之蛋白3 (NLRP3);
(15)抗冠狀病毒疫苗療法;
(16) RNA複製調節劑;或
(17)神經胺酸酶抑制劑;
(18)麩胺醯基-脯胺醯基-tRNA合成酶抑制劑(例如,鹵夫酮(halofuginone));
(19)平衡核苷轉運蛋白(ENT)抑制劑(例如,雙嘧達莫(dipyridamole));或
(20)其他核苷類似物/RNA複製調節劑(例如,莫努皮拉韋、比尼布韋(bemnifosbuvir))。
本文中提供之任何式或結構亦意欲表示同位素標記原子。可併入本發明之化合物中之同位素之實例包括氫之另外同位素(即,氘或氚),以及碳、氮、氧、磷、氟及氯之同位素,諸如(但不限於)
11C、
13C、
14C、
15N、
18F、
31P、
32P、
35S、
36Cl及
125I。本發明進一步包括併入放射性同位素(諸如
3H、
13C及
14C)之各種同位素標記化合物。此等同位素標記化合物可用於代謝研究、反應動力學研究、偵測或造影技術(諸如正電子發射斷層掃描術(PET)或單光子發射電腦斷層掃描術(SPECT)),包含患者之藥物或受質組織分佈分析或放射性治療中。
本發明之化合物部分經受互變異構。例如,若於環中含有氮原子之雜芳族基團經與該氮原子相鄰之碳原子上之羥基或胺基取代,則下列互變異構可出現:
術語「醫藥上可接受之鹽」係指自醫藥上可接受之無毒鹼(包括無機鹼及有機鹼)製備之鹽。因此,含有酸性基團之本發明之化合物可在此等群上存在及可根據本發明(例如)作為鹼金屬鹽、鹼土金屬鹽或銨鹽使用。此等鹽之更精確實例包括鈉鹽、鉀鹽、鈣鹽、鎂鹽或與氨水或有機胺(諸如,例如,乙胺、乙醇胺、三乙醇胺或胺基酸)之鹽。各自鹽可藉由熟習此項技術者已知之慣用方法,如(例如)藉由使此等於溶劑或分散劑中與有機或無機鹼接觸,或藉由與其他鹽陽離子交換來獲得。本發明亦包含本發明化合物之所有鹽,由於低生理相容性,其不直接適用於醫藥,但是其可(例如)作為化學反應或製備醫藥上可接受之鹽之中間體使用。
另外,本發明之化合物可以溶劑化物(諸如包含作為溶劑化水之彼等)或醫藥上可接受之溶劑化物(諸如醇,特定言之乙醇)之形式存在。溶劑之化學計量或非化學計量量藉由非共價分子間力約束。當溶劑為水時,該「溶劑化物」為「水合物」。應瞭解,此外,「醫藥上可接受之鹽」可視情況含有「溶劑化物」。
術語「有效量」意欲包括當投與時,足以防止正在治療之病症、疾病或病狀之症狀中之一或多者之發展或在一定程度上減輕症狀中之一或多者之化合物的量。術語「有效量」亦係指正在由研究者、獸醫、醫生或臨床醫師尋求之足以引起細胞、組織、系統、動物或人類之生物或醫學反應之化合物的量。
如本文中所用,術語「個體」係指動物王國之任何成員,包括人類。於一些實施例中,「個體」係指在任何發育階段之人類。於一些實施例中,「個體」係指人類患者。於一些實施例中,「個體」係指非人類動物。於一些實施例中,該非人類動物為哺乳動物(例如,嚙齒動物、小鼠、大鼠、兔、猴、犬、貓、綿羊、牛、靈長類動物或豬)。於一個實施例中,個體包括(但不限於)哺乳動物、鳥、爬行動物、兩棲動物、魚或蠕蟲。於一些實施例中,個體可為轉殖基因動物、經遺傳工程改造之動物或純系。
如本文中所用,術語「治療(treating/treatment)」包括(但不限於)產生接受者之健康狀態之有益變化之方法及操作。該等變化可係主觀或客觀及可係指特徵,諸如正在治療之病毒感染之症狀或徵兆。該術語亦包含預防接受者之狀態之惡化。如本文中所用,治療亦包括向具有病毒感染或有變得病毒感染之風險之個體單獨或與另外治療劑組合投與式(I)化合物。
如本文中所用,術語「投與」包括與向患者提供一定量之本文中所述之化合物(例如,式(I)化合物)相關聯之活動。投與包括向有需要患者提供本文中所闡述之組合物之單位劑量。投與包括提供有效量之化合物(例如,式(I)化合物)持續特定時間段,例如,約1、2、3、4、5、6、7、8、9、10、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31天或更多天,或以特定順序,例如,投與式(I)化合物,接著投與一或多種抗病毒藥物,或反之亦然。
如本文中所用,術語「共同投與」包括兩種或更多種結構上不同化合物之依序或同時投與。例如,兩種或更多種結構上不同醫藥活性化合物可藉由投與含有兩種或更多種結構上不同活性醫藥活性化合物之適用於口服投與之醫藥組合物來共同投與。作為另一實例,兩種或更多種結構上不同化合物可藉由投與一種化合物及然後投與另一種化合物來共同投與。於一些實例中,經共同投與之化合物係藉由相同途徑投與。於其他實例中,經共同投與之化合物係經由不同途徑投與。例如,一種化合物可經口投與,及另一種化合物可經由靜脈內或腹膜內注射(例如)依序或同時投與。
式(I)化合物或視情況另外治療劑可與關於意欲投與形式及與習知醫藥實踐一致適宜選擇之適宜醫藥稀釋劑、擴展劑、賦形劑或載劑(本文中統稱作醫藥上可接受之載劑)混合投與。單元可以適用於口服投與之形式。式(I)化合物或視情況另外治療劑可單獨投與,但是一般與醫藥上可接受之載劑混合及以錠劑或膠囊、脂質體或呈聚集粉末之形式共同投與。適宜固體載劑之實例包括乳糖、蔗糖、明膠及瓊脂。膠囊或錠劑可容易調配及可製備易於吞食或咀嚼;其他固體形式包括顆粒及散裝粉末。錠劑可含有適宜黏合劑、潤滑劑、稀釋劑、崩解劑、著色劑、調味劑、流動誘導劑及熔化劑。
組合物可進一步包含一或多種醫藥上可接受之另外成分,諸如明礬、穩定劑、抗微生物劑、緩衝劑、著色劑、調味劑、佐劑及類似者。
組合物可呈以習知方式調配之錠劑或***錠之形式。例如,用於口服投與之錠劑及膠囊可含有習知賦形劑,包括(但不限於)黏合劑、填料、潤滑劑、崩解劑及潤濕劑。黏合劑包括(但不限於)糖漿、***膠、明膠、山梨醇、黃蓍膠、澱粉黏液及聚乙烯吡咯啶酮。填料包括(但不限於)乳糖、糖、微晶纖維素、玉米澱粉、磷酸鈣及山梨醇。潤滑劑包括(但不限於)硬脂酸鎂、硬脂酸、滑石、聚乙二醇及二氧化矽。崩解劑包括(但不限於)馬鈴薯澱粉及澱粉乙醇酸鈉。潤濕劑包括(但不限於)月桂基硫酸鈉。錠劑可根據此項技術中熟知之方法包覆。
組合物亦可為液體調配物,包括(但不限於)水性或油性懸浮液、溶液、乳液、漿液及酏劑。該等組合物亦可經調配成乾產品用於在使用之前與水或其他適宜媒劑構成,此等液體製劑可含有添加劑,包括(但不限於)懸浮劑、乳化劑、非水性媒劑及防腐劑。懸浮劑包括(但不限於)山梨醇漿液、甲基纖維素、葡萄糖/糖漿、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁明膠及氫化食用脂肪。乳化劑包括(但不限於)卵磷脂、脫水山梨糖醇單油酸酯及***膠。非水性媒劑包括(但不限於)食用油、檸檬油、分級椰子油、油酯、丙二醇及乙醇。防腐劑包括(但不限於)對羥基苯甲酸甲酯或對羥基苯甲酸丙酯及山梨酸。
如本文中所用,病毒感染,尤其急性病毒感染係選自冠狀病毒感染、SARS-CoV-2 (COVID-19)、SARS、流行性感冒/流感(及禽流感)、HIV/愛滋病、水痘(Varicella)、巨細胞病毒、革登熱(Dengue Fever)、德國麻疹(Rubella)、手足口病、漢坦病毒感染、肝炎之所有形式、拉薩熱(Lassa fever)、馬爾堡(Marburg)病毒感染、麻疹、腦膜炎、MERS-CoV、腮腺炎、諾如病毒(norovirus)感染、單純疱疹病毒感染、天花、猴痘、輪狀病毒感染、埃博拉病毒、小兒麻痺病毒感染、鼻病毒感染、副充氣病毒(parainflunenzavirus)感染、RSV感染、HCMV感染及巴納病毒(bannavirus)感染。較佳為SARS-CoV-2 (COVID-19)、流行性感冒/流感、鼻病毒及呼吸道融合性病毒(RSV)感染。更佳為SARS-CoV-2 (COVID-19)、流行性感冒/流感及鼻病毒感染,最佳為SARS-CoV-2 (COVID-19)。應瞭解,亦覆蓋病毒(例如,SARS-CoV-2)之突變形式。
病毒,尤其SARS-CoV-2正在不斷突變,其可增加毒力及傳播率。病毒之藥物抗性變異體可於利用抗病毒劑之延長之治療後出現。藥物抗性可藉由編碼用於病毒複製之酶之基因之突變發生。藥物針對RNA病毒感染之功效於某些情況下可藉由投與化合物與誘導不同突變或通過與主要藥物不同路徑作用之另一種及甚至可能兩種或三種其他抗病毒化合物組合或交替來延長、增強或恢復。已知病毒之變異體可係指如與已知病毒相比,於病毒基因組中攜帶一或多個核苷酸突變,例如至少1、2、3、4、5、6、7、8、9、10、15、20、30、40、60、100、200、300個或甚至更多個核苷酸突變之病毒。突變可係指核苷酸缺失、***或置換。於一些情況下,變異體可具有不同於已知病毒之基因組之至多50%、40%、30%、20%、10%、5%、4%、3%、2%或1%之病毒基因組。
於本發明之特定實施例中,根據式(I)之化合物係用作藥物及/或用於療法中。於本發明之更特定實施例中,該療法為預防及/或治療哺乳動物個體之由病毒感染引起之疾病。於本發明之甚至更特定實施例中,該疾病由RNA病毒,諸如,例如HIV、HCV、埃博拉、輪狀病毒、茲卡病毒、小兒麻痺病毒、鼻病毒、A型肝炎病毒、麻疹病毒、腮腺炎病毒、RSV、狂犬病、拉薩病毒、漢坦病毒或流感,特定言之單股RNA病毒,諸如HCoV-229E、HCoV-NL63或β冠狀病毒,諸如HCoV-OC43、SARS-CoV-1、HCoV-HKU1、MERS-CoV或SARS-CoV-2引起。於本發明之甚至更特定實施例中,該疾病由SARS-CoV-2、鼻病毒、RSV及流感病毒引起。於本發明之最特定實施例中,該疾病由SARS-CoV-2引起。
於本發明之其他特定實施例中,根據式(I)之化合物係用作藥物及/或用於療法中。於本發明之更特定實施例中,該療法為預防及/或治療哺乳動物個體之由病毒感染引起之疾病。於本發明之甚至更特定實施例中,該疾病係選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。於本發明之甚至更特定實施例中,該疾病為COVID-19、病毒性流感、呼吸道疾病及急性呼吸道疾病。於本發明之最特定實施例中,該疾病為COVID-19。
於本發明之其他特定實施例中,根據式(I)之化合物係與標準抗病毒療法(SAT)組合用作藥物。於本發明之更特定實施例中,此組合係與DHODH抑制劑,及視情況與標準抗病毒療法(SAT)。於本發明之更特定實施例中,該DHODH抑制劑係選自維多迪莫司、維多迪莫司鈣(IMU-838)、特立氟胺、來氟米特、依沃司他(PTC299)、布喹那、法如司他(ASLAN003)、PP-001、RP7214、奧魯司他(BAY2402234)、JNJ-74856665、AG-636、MEDS433。於本發明之同等更特定實施例中,該DHODH抑制劑由式(II)組成。
於本發明之其他特定實施例中,根據式(I)之化合物係藉由使胞磷膽鹼或其鹽與羥胺或其鹽反應來製備。於本發明之更特定實施例中,根據式(I)之化合物係藉由使胞磷膽鹼或其鹽與羥胺游離鹼、硫酸羥胺或鹽酸羥胺反應來製備。於本發明之甚至更特定實施例中,根據式(I)之化合物係藉由使胞磷膽鹼或其鹽與1至6當量之硫酸羥胺或鹽酸羥胺反應來製備。
實驗部分
N
4-羥基部分進入胞苷衍生物之引入已例如藉由Paymode等人之描述(Org. Process Res. Dev. 2021;25:1822),使用硫酸羥胺於水中在升高之溫度下進行或藉由Purohit等人(J. Med. Chem. 2012;55:9988)或Vasudevan等人之描述(Chem. Commun. 2020;56:13363),使用乙酸羥銨於水中在37℃至40℃下在pH 5.5至6.0下進行。
實驗章節
比較例:胞磷膽鹼鈉(C1)
胞磷膽鹼鈉(CAS: 33818-15-4)係購自例如:MedChemExpress (Art.-Nr.: HY-B0739A)且具有下列分析資料:
1H-NMR (400 MHz, D
2O) δ 7.84 (d, J = 7.6 Hz, 1H), 6.01 (d, J = 7.6 Hz, 1H), 5.89 (d, J = 4.0 Hz, 1H), 4.30-4.06 (m, 7H), 3.59-3.57 (m, 2H), 3.12 (s, 9H)。針對[C
14H
27N
4O
11P
2 +] [M]
+計算的ESI-MS
m/z:489.1;實測值:489.0。
實例1:
2-(((((((2
R,3
S,4
R,5
R)-3,4-二羥基-5-(4-(羥胺基)-2-側氧基嘧啶-1(2
H)-基)四氫呋喃-2-基)甲氧基)(羥基)膦醯基)氧基)氧負離子基膦醯基)氧基)-
N,
N,
N-三甲基乙-1-銨單鈉鹽(1)
向含於EtOH (5 mL)中之胞磷膽鹼鈉(200 mg,392 µmol)之懸浮液中添加5N水性鹽酸羥胺,直至將溶液調整至pH = 5至6。將混合物在37℃下攪拌8天,同時間歇添加5N水性鹽酸羥胺,以維持pH值。LCMS分析指示大多數起始物質消耗。在減壓下移除溶劑及將殘留物藉由層析法使用二乙胺基乙基(DEAE) Sephadex A-25 (CAS 12609-80-2) (100 mM碳酸氫三乙基銨/H
2O,梯度自0/1至3/7,20 mL/min,UV偵測254 nm)純化。溶離份之凍乾得到所需產物之三乙基銨鹽。將所製備之三乙基銨鹽溶解於水中及通過離子交換管柱(Amberlite IR120鈉形式)溶離。合併含有產物之溶離份及凍乾,以得到呈灰白色固體之化合物1 (60.4 mg,24%)。
1H-NMR (400 MHz, D
2O) δ 7.08 (d, J = 8.4 Hz, 1H), 5.87-5.84 (m, 1H), 5.73 (d, J = 8.4 Hz, 1H), 4.30-4.21 (m, 4H), 4.14-4.13 (m, 1H), 4.08-4.03 (m, 2H), 3.59-3.57 (m, 2H), 3.12 (s, 9H)。針對[C
14H
27N
4O
12P
2 +] [M]
+計算的ESI-MS
m/z:505.1;實測值:505.0。元素分析:
實測值:C: 26.19% H: 5.99% N: 8.68%
計算值:C: 26.14% H: 5.95% N: 8.71%針對C
14H
25N
4NaO
12P
2• 6.5 H
2O
實例2:
2-(((((((2
R,3
S,4
R,5
R)-3,4-二羥基-5-(4-(羥胺基)-2-側氧基嘧啶-1(2
H)-基)四氫呋喃-2-基)甲氧基)(羥基)膦醯基)氧基)氧負離子基膦醯基)氧基)-
N,
N,
N-三甲基乙-1-銨三乙基銨鹽
(2) 在38℃下,向含於H
2O (100 mL)中之胞磷膽鹼(10.0 g)之溶液中添加鹽酸羥胺(2.8 g,2 eq.)。將混合物在38℃下攪拌5天。添加另一批次之鹽酸羥胺(2.6 g,50%含於水中,2 eq.)及將反應混合物在38℃下再攪拌2天。添加第三批次之鹽酸羥胺(2.6 g,50%含於水中,2 eq.)及將反應混合物在38℃下再攪拌2天。將混合物在減壓下濃縮及用MeOH (30 mL)洗滌,以得到粗產物。將所得粗製物溶解於H
2O中及直接藉由製備型HPLC (管柱:Phenomenex Luna C
18250 mm x 100 mm x 10 µm;流動相:[水(20 mM碳酸氫三乙基銨)-ACN];B%:0%至5%,20 min)純化,以得到呈白色固體之純化合物
2(1.0 g,7.3%,呈1.65 TEA鹽)。HPLC:214 nm:98.52%純度;254 nm:99.87%純度;260 nm:>99.9%純度。
實例3:溶解度、logD及Caco-2滲透性
實例1及比較例(參見反應圖1)之水性溶解度(於PBS,pH 7.4中-目錄參考:435;於模擬腸液中-目錄參考:2062及於模擬胃液中-目錄參考:2061)、分配係數(logD,正辛醇/PBS,pH 7.4;目錄參考:417)及滲透性(Caco-2,pH 6.5/7.4;目錄參考:3318及3320)係在Eurofins下根據其標準程序量測及提供下列結果:
化合物 I.D. | 客戶化合物 I.D. | 測試 濃度 | 偵測 波長 | 溶解度 (µM) | 層析法 純度 (%) | 標示 | ||
第一次 | 第二次 | 平均值 | ||||||
水性溶解度 (PBS , pH 7.4) | ||||||||
100060338-1 | 實例 1 | 2.0E-04 M | 230 nm | 14.20 | 14.42 | 14.3 | 100 | |
100060338-2 | NHC | 2.0E-04 M | 230 nm | 349.99 | 362.05 | 200 | 100 | ADJ |
100060338-3 | 莫 努皮拉韋 | 2.0E-04 M | 230 nm | 246.79 | 290.52 | 200 | 100 | ADJ |
100060338-4 | NHC-DP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
100060338-5 | NHC-TP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
水性溶解度 ( 模擬腸液 ) | ||||||||
100060338-1 | 實例 1 | 2.0E-04 M | 230 nm | 13.87 | 18.29 | 16.1 | 100 | |
100060338-2 | NHC | 2.0E-04 M | 230 nm | 244.66 | 263.52 | 200 | 100 | ADJ |
100060338-3 | 莫 努皮拉韋 | 2.0E-04 M | 230 nm | 301.69 | 328.92 | 200 | 100 | ADJ |
100060338-4 | NHC-DP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
100060338-5 | NHC-TP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
水性溶解度 ( 模擬胃液 ) | ||||||||
100060338-1 | 實例 1 | 2.0E-04 M | 230 nm | <1 | <1 | <1 | 100 | BQA |
100060338-2 | NHC | 2.0E-04 M | 230 nm | 275.19 | 210.58 | 200 | 100 | ADJ |
100060338-3 | 莫 努皮拉韋 | 2.0E-04 M | 230 nm | 257.79 | 292.76 | 200 | 100 | ADJ |
100060338-4 | NHC-DP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
100060338-5 | NHC-TP | 2.0E-04 M | 205 nm | - | - | - | - | ND |
ADJ:經調整。當觀測的平均溶解度大於200 µM時,將平均值調整至最大分析濃度,其為200 µM。ND:未偵測。BQA:低於定量極限。 |
化合物 I.D. | 客戶化合物 I.D. | 測試 濃度 | logD | 標示 |
分配 係數 (log D , 正辛醇 /PBS , pH 7.4) | ||||
100060338-1 | 實例 1 | 1.0E-04 M | 0.52 | |
100060338-2 | NHC | 1.0E-04 M | 1.12 | |
100060338-3 | 莫 努皮拉韋 | 1.0E-04 M | 0.39 | |
100060338-4 | NHC-DP | 1.0E-04 M | 0.12 | |
100060338-5 | NHC-TP | 1.0E-04 M | - | ND |
ND:未偵測。 |
化合物 I.D. | 客戶 化合物 I.D. | 測試 濃度 | 滲透性 (10 -6cm/s) | 標示 | 回收 百分比 (%) | ||||
第 1 次 | 第 2 次 | 平均值 | 第 1 次 | 第 2 次 | 平均值 | ||||
A-B 滲透性 (Caco-2 , pH 6.5/7.4) | |||||||||
100060338-1 | 實例 1 | 1.0E-05 M | 36.15 | 30.68 | 33.4 | 121 | 115 | 118 | |
100060338-2 | NHC | 1.0E-05 M | 0.55 | 0.34 | 0.4 | 77 | 73 | 75 | |
100060338-3 | 莫 努皮拉韋 | 1.0E-05 M | 0.19 | 0.13 | 0.2 | 70 | 71 | 71 | |
100060338-4 | NHC-DP | 1.0E-05 M | 0.07 | 0.06 | <0.07 | BLQ | 8 | 7 | 7 |
100060338-5 | NHC-TP | 1.0E-05 M | - | - | - | ND | - | - | - |
B-A 滲透性 (Caco-2 , pH 6.5/7.4) | |||||||||
100060338-1 | 實例 1 | 1.0E-05 M | 26.15 | 21.17 | 23.7 | 91 | 83 | 87 | |
100060338-2 | NHC | 1.0E-05 M | 0.27 | 0.30 | 0.3 | 83 | 87 | 85 | |
100060338-3 | 莫 努皮拉韋 | 1.0E-05 M | 0.26 | 0.27 | 0.3 | 90 | 89 | 89 | |
100060338-4 | NHC-DP | 1.0E-05 M | 0.03 | 0.02 | <0.03 | BLQ | 64 | 72 | 68 |
100060338-5 | NHC-TP | 1.0E-05 M | - | - | - | ND | - | - | - |
BLQ:低於定量極限。測試化合物於供體樣品中良好偵測,但是於接受者樣品中未偵測。測試化合物於接受者樣品中之濃度係低於定量極限。 ND:未偵測。測試化合物於分析矩陣中不可靠偵測。 |
結論:雖然根據logD,實例1與莫努皮拉韋及NHC相比具有相似親脂性,但是於PBS、模擬腸液及模擬胃液中之水性溶解度更糟糕(即,實際上不溶)。NHC及莫努皮拉韋之溶解度係在分析之量測極限以上,及的確,針對莫努皮拉韋,於水中121 mM (39.7 mg/mL)之高溶解度已於由人用藥品委員會(Committee for Medicinal Products for Human Use/CHMP)發表之使用莫努皮拉韋治療COVID-19之評估報告中提及:
www.ema.europa.eu/en/documents/referral/lagevrio-also-known-molnupiravir-mk-4482-covid-19-article-53-procedure-assessment-report_en.pdf
針對NHC,於水中58 mM (15 mg/mL)之高溶解度已在輕微升溫後提及:www.cellsignal.com/products/activators-inhibitors/beta-d-n4-hydroxycytidine/81178
然而,兩性離子實例1之滲透性與莫努皮拉韋、NHC及NHC-DP相比提高約兩個數量級,允許類別II (低溶解度,高滲透性)之有益生物醫藥分離。
實例 4 :小鼠藥物動力學本研究旨在測定實例2及其代謝物(NHC、NHC-MP、NHC-DP及NHC-TP)於向雌性C57BL/6小鼠(體重20至21 g)單次劑量口服投與96.5 µmol/kg後於血液中之藥物動力學參數。自球後靜脈叢獲得血液樣本至Li-肝素管(Minivette POCT, SARSTEDT)中。用於製備劑量調配物之媒劑為PBS。藉由Pharmacelsus GmbH, Germany之高解析度LC-MS分析樣本。
於口服投與96.5 µmol/kg實例2後,於所有血液樣本中未發現測試條項(低於14.4 nM之定量下限)。代謝物NHC-DP於給藥4小時後達到923 ± 138 nM之最大血液濃度及其代謝物NHC-TP於給藥4小時後達到611 ± 100 nM之最大血液濃度。消除半衰期及AUC
(0-inf)於兩種代謝物中不可計算。此外,其代謝物NHC-MP於給藥30分鐘後達到274 ± 41.4 nM之最大血液濃度。消除半衰期為7.3 h及AUC
(0-inf)為1624 nM*h。代謝物NHC於給藥30分鐘後達到4239 ± 902 nM之最大血液濃度。消除半衰期為1.7 h及AUC
(0-inf)為5761 nM*h。
結論:圖2顯示NHC、NHC-PM、NHC-DP及NHC-TP各自歷時測試時間段之血液濃度。雖然給藥之實例2之前藥不可偵測,但是磷酸化NHC類似物之持續濃度歷時長時間段存在,強調速率限制步驟可利用實例2成功繞過。
實例50:
步驟 1 :2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯胺(
50a)
向含於1,4-二噁烷(30 mL)中之4-溴-2-氟苯胺(4.00 g,21.1 mmol)之溶液中添加雙(頻哪醇根基)二硼(5.38 g,21.2 mmol)、KOAc (6.23 g,63.5 mmol)及Pd(dppf)Cl
2(776 mg,1.1 mmol)。然後將混合物在90℃下加熱1小時,冷卻至室溫,過濾,濃縮及藉由FCC (PE:EA = 8:1)純化,以得到呈白色固體之化合物50a。
步驟 2 :3-氟-3'-(甲氧基-
d3)-[1,1'-聯苯]-4-胺(50b)
向含於1,4-二噁烷(10 mL)及H
2O (1 mL)中之化合物50a (800 mg,3.37 mmol)之溶液中添加1-溴-3-(甲氧基-
d3)苯(638 mg,3.36 mmol)、Na
2CO
3(1.07 g,10.1 mmol)及Pd(dppf)Cl
2(124 mg,0.17 mmol)及然後將混合物在90℃下加熱2小時,冷卻至室溫,過濾,濃縮及藉由FCC (PE:EA = 10:1)純化,以得到呈油之化合物50b。
步驟 3 :2-((3-氟-3'-(甲氧基-
d3)-[1,1'-聯苯]-4-基)胺甲醯基)環戊-1-烯-1-甲酸(50)
將含於DCM (2.5 mL)中之化合物50b (120 mg,545 µmol)及1-環戊烯-1,2-二甲酸酐(74 mg,540 µmol)之溶液在40℃下加熱4小時。將混合物過濾及將濾餅用MeCN (2 × 2 mL)洗滌。將固體於真空中乾燥,以得到呈淺黃色固體之化合物50
。 1H-NMR (400 MHz, DMSO-
d6) δ 13.04 (br s, 1H), 10.58 (s, 1H), 8.07 (t, J = 8.4 Hz, 1H), 7.63 (d, J = 12.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.27-7.23 (m, 2H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 2.80 (br s, 2H), 2.69 (br s, 2H), 1.93-1.85 (m, 2H)。LCMS (ESI): m/z 359.0 (M+H)
+。
實例51:
步驟 1 :2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯胺(51a)
向含於1,4-二噁烷(100 mL)中之4-溴-2,6-二氟苯胺(10 g,48 mmol)之溶液中添加雙(頻哪醇根基)二硼(12.8 g,50.4 mmol)、CH
3COOK (14.1 g,144 mmol)及Pd(dppf)Cl
2(1.0 g,2.40 mmol)。將混合物在90℃下在N
2下攪拌2小時,冷卻至室溫,濃縮及藉由FCC (PE:EA = 10:1)純化,以得到呈黃色固體之化合物51a。
步驟 2 :3,5-二氟-3'-(甲氧基-
d3)-[1,1'-聯苯]-4-胺(51b)
向含於1,4-二噁烷(50 mL)及H
2O (5 mL)中之化合物51a (4.5 g,13.3 mmol)之溶液中添加1-溴-3-(甲氧基-
d3)苯(3.34 g,13.3 mmol)、Na
2CO
3(5.61 g,39.4 mmol)及Pd(dppf)Cl
2(400 mg,0.67 mmol)。將混合物在90℃下在N
2下攪拌2小時,冷卻至室溫,濃縮及藉由FCC (PE:EA = 10:1)純化,以得到呈黃色固體之化合物51b。LCMS (ESI): m/z 239.1 (M+H)
+。
步驟 3 :2-((3,5-二氟-3'-(甲氧基-d3)-[1,1'-聯苯]-4-基)胺甲醯基)環戊-1-烯-1-甲酸(51)
向含於DCM (20 mL)中之化合物51b (3.40 g,14.3 mmol)之溶液中添加1-環戊烯-1,2-二甲酸酐(1.90 g,14.3 mmol),然後將混合物在室溫下攪拌2小時。將混合物過濾及將濾餅用MeCN洗滌。將固體於真空中乾燥,以得到呈白色固體之化合物
51。
1H-NMR (500 MHz, DMSO-
d6) δ 12.95 (br s, 1H), 10.13 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.32-2.83 (m, 2H), 6.99 (dd, J = 1.8, 8.3 Hz, 1H), 2.81-2.79 (m, 2H), 2.69-2.66 (m, 2H), 1.97-1.89 (m, 2H)。LCMS (ESI): m/z 377.3 (M+H)
+。
實例99:人類DHODH抑制分析
hDHODH之活體外抑制係使用
N-端截短之重組hDHODH酶量測,如
J. Med. Chem.2006;49:1239中所述。簡言之,以約0.2 AU/min之平均斜率用作陽性對照(例如,不含有抑制劑)之方式調整hDHODH濃度。標準分析混合物含有60 µM 2,6-二氯吲哚苯酚、50 µM癸基泛醌及100 µM二氫乳清酸鹽。添加含有或不含有至少六種不同濃度之化合物之hDHODH酶及於50 mM TrisHCl、150 mM KCl及0.1% Triton X-100中在pH 8.0及30℃下進行量測。藉由添加二氫乳清酸鹽開始反應,及在600 nm下量測吸光度2分鐘。對於測定IC
50值,一式三份記錄各數據點。對於測定抑制常數K
i,測定DHO及癸基泛醌之K
M值。之後,化合物依其IC
50值,於DMSO中稀釋成一系列稀釋度。該稀釋度為:0 x IC
50、¼ x IC
50、½ x IC
50、1 x IC
50、2 x IC
50、4 x IC
50。此外,將DHO及癸基泛醌之受質濃度於另外系列稀釋度中改變成 ¼ x K
M、½ x K
M、1 x K
M、2 x K
M、4 x K
M,其中單獨量測DHO及癸基泛醌。一式兩份記錄各數據點。
本發明之實例之K
i值係於非氘化匹配對(來自WO2003/006425之實例C26)之範圍內:
實例編號 | K i(DHO) [nM] | K i(癸基泛醌) [nM] |
C26 | 592 | 245 |
50 | 521 | 234 |
如上所示,氘化類似物50之DHODH抑制與非氘化匹配對(來自WO2003/006425之實例C26)相比不受影響,然而微粒體穩定性提高。
實例100:對SARS-CoV-2之抗病毒活性
病毒複製(YFP)及細胞存活率分析已述於
Pathogens2021;10:1076中及提供下列結果:
實例編號 | EC 50 | CC 50 | SI |
C1 | >50 µM | >100 µM | 不活躍 |
1 | <10 µM | >100 µM | >10 |
50 | <10 µM | >100 µM | >10 |
51 | <20 µM | >100 µM | >5 |
與胞磷膽鹼(C1)相反,其類似物1顯示針對SARS-CoV-2之抗病毒活性。此外,DHODH抑制劑50及51顯示相似抗病毒活性。
實例101:與DHODH抑制劑對SARS-CoV-2之協同抗病毒活性
化合物
1與DHODH抑制劑
50一起之協同效能
藉由病毒複製抑制分析法評估組合藥物之方法已於
Pathogens2021;10:1076中公開。將Caco-2細胞於96孔板中以25000個細胞/孔培養,利用SARS‐CoV‐2 d6‐YFP,依0.003之MOI感染,及利用實例50、實例1或藥物之組合處理,以單一化合物之各自4 × EC
50濃度開始。病毒複製係在感染後(p.i.)30小時藉由固定細胞中之病毒驅動之YFP表現之定量螢光偵測來測定。透過病毒編碼之YFP報導子表現所量測之病毒複製之抑制型態係以四重覆測定(平均值±SD)之條形圖呈現。組合藥物評估係藉由使用如
Int. J. Mol. Sci.2021;22:575中所述之CompuSyn演算法計算。
代表性實驗示於圖1中。化合物1顯示當與實例50之DHODH抑制劑組合時,對SARS-CoV-2之協同抗病毒效應。
實例102:對HRV-14、流感A及RSV之抗病毒活性
與國家衛生研究院(National Institute of Health/NIH)合作,測試核苷類似物實例1針對人類鼻病毒-14 (HRV-14)、流感A及呼吸道融合性病毒(RSV) A2之抗病毒活性。針對HRV-14使用HeLa細胞,針對流感A使用MDCK細胞及針對RSV A2使用MA-104細胞。將細胞用實例1之連續log10稀釋液處理及隨後用人類鼻病毒14 (HRV-14)、流感A (H1N1,California/07/2009)或RSV A2感染。藉由線性回歸測定EC
50濃度及藉由中性紅測定CC
50濃度。針對實例1,獲得下列量測值:
病毒 | EC 50 | CC 50 | SI |
HRV-14 | 4.7 µM | >25 µM | >5.8 |
流感A | 4.8 µM | 25 µM | 5.2 |
RSV A2 | 1.1 µM | 2.4 µM | 2.2 |
實例103:與DHODH抑制劑組合對HRV-14及RSV之抗病毒活性
此外,進行利用DHODH抑制劑實例50及核苷類似物實例1之活體外組合分析(AP2B)以研究針對RSV及HRV-14之抗病毒活性。針對兩種病毒,於將兩種化合物組合後存在抗病毒活性之提高。
RSV :將MA-104細胞以單藥療法利用實例50或實例1之連續稀釋液,或25 µM實例50與實例1之連續稀釋液之組合處理及然後用RSV A2感染。藉由終點滴定測定病毒濃度(CCID
50)及得到下列結果:
RSV 病毒效價 - *CCID 50/mL (Log10) | |||
濃度(µM) | 實例 50 | 實例 1 | 實例 1+ 25 µM 實例 50 |
25 | <0.7 | 3.5 | <0.7 |
7.9 | 2.0 | 3.5 | <0.7 |
2.5 | 2.0 | 3.5 | <0.7 |
0.79 | 3.5 | 4.0 | <0.7 |
0.25 | 3.5 | 4.0 | <0.7 |
0.079 | 3.5 | 3.5 | <0.7 |
0.025 | 3.7 | 4.0 | <0.7 |
0.0079 | 3.7 | 4.5 | <0.7 |
*CCID 50= 50%細胞培養物感染劑量 | 4.0 (病毒對照) |
HRV-14:將HeLa細胞以單藥療法利用實例50或實例1之連續稀釋液,或25 µM實例50與實例1之連續稀釋液之組合處理及然後用HRV-14感染。藉由終點滴定測定病毒濃度(CCID
50)及得到下列結果:
HRV-14 病毒效價 - *CCID 50/mL (Log10) | |||
濃度(µM) | 實例 50 | 實例 1 | 實例 1+ 25 µM 實例 50 |
25 | 3.5 | 3.5 | <0.7 |
7.9 | 4.0 | 4.7 | <0.7 |
2.5 | 7.0 | 6.0 | <0.7 |
0.79 | 6.7 | 6.7 | 3.7 |
0.25 | 6.7 | 7.0 | 3.5 |
0.079 | 7.0 | 6.7 | 4.0 |
0.025 | 6.7 | 6.7 | 3.7 |
0.0079 | 6.7 | 6.7 | 4.5 |
*CCID 50= 50%細胞培養物感染劑量 | 6.7 (病毒對照) |
結論:DHODH抑制劑與實例1之組合顯示亦對人類鼻病毒-14 (HRV-14)及呼吸道融合性病毒(RSV)之協同行為。
圖1描述實驗之代表性結果,其中實例1與DHODH抑制劑組合。資料顯示在不同劑量下對SARS-CoV-2之協同抗病毒效應。
圖2描述NHC及其磷酸化衍生物於小鼠中於給藥實例2之後之血液含量。
Claims (12)
- 一種根據式(I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽的用途, 其用作製造藥物。
- 如請求項1之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作製造藥物的用途,其用於預防及/或治療哺乳動物個體之由病毒感染引起之疾病,其中該病毒感染係由RNA病毒,諸如,例如,HIV、HCV、埃博拉(Ebola)、輪狀病毒、茲卡(Zika)病毒、小兒麻痺病毒、鼻病毒、A型肝炎病毒、麻疹病毒、腮腺炎病毒、RSV、狂犬病、拉薩(Lassa)病毒、漢坦病毒(hantavirus)或流感,特定言之單股RNA病毒,諸如HCoV-229E、HCoV-NL63或β冠狀病毒,諸如HCoV-OC43、SARS-CoV-1、HCoV-HKU1、MERS-CoV或SARS-CoV-2引起。
- 如請求項1或2之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作製造藥物的用途,其用於預防及/或治療人類之由利用冠狀病毒之病毒感染引起之疾病。
- 如請求項1或2之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作製造藥物的用途,其用於預防及/或治療疾病,其中該疾病係選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
- 如請求項1或2之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作製造藥物的用途,其用於預防及/或治療疾病,其中該預防及/或治療係與標準抗病毒療法(SAT)組合。
- 如請求項1或2之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽用作製造藥物的用途,其用於預防及/或治療疾病之藥物,其中該預防及/或治療係與DHODH抑制劑,及視情況與標準抗病毒療法(SAT)組合。
- 如請求項6之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽的用途,其中於該組合中,該DHODH抑制劑由式(II): 或其對映異構體、非對映異構體、互變異構體、前藥、溶劑化物或醫藥上可接受之鹽組成,其中 R 1及R 2係獨立地選自H及D; R 3、R 4、R 5及R 6係獨立地選自H、D、鹵素、CN、C 1-4-烷基、O-C 1-4-烷基、氟-C 1-4-烷基及O-氟-C 1-4-烷基,烷基中之一或多個氫原子視情況經氘置換; R 7、R 8、R 9及R 10係獨立地選自H、D、鹵素、CN、C 1-4-烷基、O-C 1-4-烷基、氟-C 1-4-烷基及O-氟-C 1-4-烷基,烷基中之一或多個氫原子視情況經氘置換; X係選自H、D、OH、OD、S(=O) yR 11及OR 11; R 11係選自C 1-4-烷基、C 3-4-環烷基及氟-C 1-4-烷基,烷基中之一或多個氫原子視情況經氘置換; y為0至2; 係選自5-員雜芳基、環戊烯基及雜環戊烯基,具有一或多個氫原子視情況經氘置換, 該A係未經取代或經獨立地選自由鹵素、CN、NO 2、側氧基、OH、C 1-4-烷基、O-C 1-4-烷基、氟-C 1-4-烷基及O-氟-C 1-4-烷基、CO 2H及SO 3H組成之群之1至5個取代基取代,烷基中之一或多個氫原子視情況經氘置換; 限制條件為R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、X及/或A中之至少一個氫經氘置換。
- 如請求項7之式(I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽的用途,其中於該組合中,該DHODH抑制劑係選自 或其溶劑化物或醫藥上可接受之鹽。
- 一種醫藥組合物的用途,其包含如請求項1所定義之式( I)化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽,諸如錠劑、膠囊、顆粒、粉末、藥囊、可復水粉末、乾粉末吸入器及/或可咀嚼物。
- 如請求項9之醫藥組合物的用途,其中該醫藥組合物進一步包含一或多種醫藥上可接受之載劑或賦形劑。
- 一種根據式(I)之化合物 ,其可藉由使胞磷膽鹼或其鹽與羥胺或其鹽反應來獲得。
- 一種根據式(I)之化合物或其互變異構體、溶劑化物或醫藥上可接受之鹽的用途, 其用作製造藥物以治療選自AIDS、肝炎、埃博拉、小兒麻痺、腹瀉、麻疹、腮腺炎、狂犬病、拉薩熱、病毒性流感、呼吸道疾病、急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應之疾病,特定言之該等疾病之中度至嚴重情況,且其中該疾病較佳地選自由SARS-CoV-2,特定言之COVID-19引起之疾病,諸如急性呼吸道疾病、膿毒症、急性呼吸窘迫症候群、長COVID及不良免疫反應(諸如細胞激素風暴)。
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