TWI440462B - 包括甲胺蝶呤及二氫乳清酸脫氫酶抑制劑的組合 - Google Patents
包括甲胺蝶呤及二氫乳清酸脫氫酶抑制劑的組合 Download PDFInfo
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- TWI440462B TWI440462B TW098120322A TW98120322A TWI440462B TW I440462 B TWI440462 B TW I440462B TW 098120322 A TW098120322 A TW 098120322A TW 98120322 A TW98120322 A TW 98120322A TW I440462 B TWI440462 B TW I440462B
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- 239000008181 tonicity modifier Substances 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
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Description
本發明係關於甲胺蝶呤與DHODH抑制劑的新穎組合。所述組合適用於治療,預防或抑制已知易由甲胺蝶呤改善及/或易由二氫乳清酸脫氫酶(dihydroorotate dehydrogenase)之抑制得到改善的疾病及病症,諸如自體免疫疾病、免疫及發炎疾病、毀壞性骨病症、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及傳染性疾病。
甲胺蝶呤(Methotrexate,MTX)是影響許多細胞內嘌呤代謝途徑之抗代謝物及免疫調節劑。其有效降低類風濕性關節炎(rheumatoid arthritis,RA)之病徵及症狀以及減緩或停止放射線損傷。歸因於效力、投藥簡便性以及相對較低的成本,MTX已成為大多數患有RA之患者的第一線口服療法。在對MTX具有不完全反應之患者中,除MTX外亦添加另一疾病修飾抗風濕性藥物(disease modifying anti-rheumatic drug,DMARD)。因此,與MTX之組合療法在臨床實踐中越來越常見。
來氟米特(Leflunomide)是所述DMARD之實例。其於1998年9月獲准用於RA。已展示其減少疾病之病徵及症狀,抑制結構損傷(由X射線侵蝕及關節間隙變窄證明)以及提高身體功能。特立氟胺(Teriflunomide)是來氟米特之活性代謝物。
認為甲胺蝶呤主要對細胞代謝之嘌呤途徑起作用,而來氟米特影響嘧啶途徑。鑒於多種細胞內途徑受所述兩種藥物的影響,來氟米特與甲胺蝶呤之組合具有生物化學協同作用的潛能。實際上,已報導所述兩種藥劑之組合產生相當大的臨床改善(參見例如,Weinblatt ME等人,“Pharmacokinetics,safety,and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis
”.Arthritis Rheum1999
;42(7):1322-8及Kremer JM等人,“Concomitant Leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate”
.Ann.Intern.Med.,2002
;137,726-733)。
令人遺憾的是,甲胺蝶呤與來氟米特皆具有嚴重的副作用,尤其是肝毒性。甲胺蝶呤在長時期使用後可能引起致命的肝損傷,諸如纖維化及肝硬化。甲胺蝶呤治療期間通常可見肝酶增加。因此,服用MTX之患者的定期且仔細的監測是必要的,尤其當MTX與其他DMARD組合時。
來氟米特之最常報導的不良事件包含腹瀉、消化不良、皮疹、脫髮、高血壓及肝酶升高。肝毒性潛能特別相關,且必須對所有服用所述藥物之患者執行包含肝功能血液測試的定期實驗室測試。不推薦來氟米特用於有B型肝炎或C型肝炎感染或明顯肝功能損傷跡象之患者。
臨床試驗報導來氟米特加MTX組中經歷肝標誌物(以轉胺酶含量度量)增加之患者的數目顯著高於僅MTX組。來氟米特之產品資訊警告不要與甲胺蝶呤組合,依據在於所述組合療法會導致疊加或甚至協同的肝毒性。
雖然造成來氟米特且尤其其活性代謝物特立氟胺之肝毒性的機制尚不明確,但已將其歸因於作為二氫乳清酸脫氫酶(DHODH)之抑制劑的活性。因此,鑑別肝毒性為直接由DHODH抑制劑之作用機制產生的副作用,此阻礙該類化合物之發展。
吾人現已發現,與一般觀點相反,抑制DHODH不造成由來氟米特產生之肝損傷,且DHODH抑制劑尤其適合與甲胺蝶呤組合。
已知抑制DHODH會產生免疫抑制效應及抗增生效應。因此,DHODH抑制劑可在如RA之自體免疫、發炎性及增生性疾病的治療中用作免疫抑制劑及抗增生劑。
本發明是基於如下令人驚訝的研究結果:DHODH之抑制不與肝毒性相關,且因而由於無肝毒性潛能的DHODH抑制劑與RA治療中最常用的第一線藥物MTX的有利的可組合性,因此其代表對所述疾病之治療的重要貢獻。
吾人已開發小鼠肝毒性評定活體內模型,其中以欲使肝暴露最大的腹膜內途徑投與測試化合物。在所述模型中,來氟米特之活性代謝物特立氟胺展示血漿中轉胺酶及膽紅素之含量急劇增加,而DHODH抑制劑在相同模型中不展示任何血漿肝標誌物的增加,同時維持其對關節炎之效力。
因此,本發明針對一種組合產品,其包括(a)甲胺蝶呤及(b)DHODH抑制劑,尤其非肝毒性DHODH抑制劑。
在一較佳實施例中,DHODH抑制劑不是來氟米特或其任何活性代謝物。
DHODH抑制劑(b)最佳是式(I)化合物:
其中一個基團G1
表示氮原子或基團CRc
且另一個表示基團CRc
;G2
表示氮原子或基團CRd
;R1
表示選自以下各基的基團:氫原子、鹵素原子、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C3-8
環烷基;R2
表示選自以下各基的基團:氫原子、鹵素原子、羥基、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷基、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷氧基以及可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C3-8
環烷基;Ra
、Rb
以及Rc
獨立地表示選自以下各基的基團:氫原子、鹵素原子、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷氧基;Rd
表示選自以下各基的基團:氫原子、鹵素原子、羥基、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷氧基以及可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C3-8
環烷氧基;基團G3
及G4
中之一個是氮原子且另一個是CH基團;M是氫原子或醫藥學上可接受之陽離子;其限制條件為當基團Ra
及Rb
中之至少一個表示氫原子且G2
是基團CRd
時,則Rd
表示選自以下各基之基團:可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C1-4
烷氧基、可視情況經1、2或3個選自鹵素原子及羥基的取代基取代之C3-8
環烷氧基;以及其醫藥學上可接受之鹽及N-氧化物。
如本文中所使用之術語烷基包含具有1至4個碳原子之視情況經取代之直鏈或支鏈烴基。烷基上之較佳取代基是鹵素原子及羥基,且更佳是鹵素原子。
實例包含甲基、乙基、正丙基、異丙基、正丁基、第二丁基以及第三丁基。
如本文中所使用之術語烷氧基包含具有1至4個碳原子之視情況經取代之直鏈或支鏈含氧基。烷氧基上之較佳取代基是鹵素原子及羥基,且更佳是鹵素原子。
實例包含甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基以及第三丁氧基。
如本文中所使用,術語環烷基包含飽和碳環基,且除非另作說明,否則環烷基通常具有3至8個碳原子。
實例包含環丙基、環丁基、環戊基、環己基以及環庚基。當環烷基具有2個或2個以上取代基時,取代基可相同或不同。環烷基上之較佳取代基是鹵素原子及羥基,且更佳是鹵素原子。
如本文中所使用,術語環烷氧基包含飽和含氧碳環基,且除非另作說明,否則環烷氧基通常具有3至8個碳原子。
實例包含環丙氧基、環丁氧基、環戊氧基、環已氧基以及環庚氧基。當環烷氧基具有2個或2個以上取代基時,取代基可相同或不同。環烷氧基上之較佳取代基是鹵素原子及羥基,且更佳是鹵素原子。
如本文中所使用,存在於本發明之一般結構中之一些原子、基團、部分、鏈或環「視情況經取代」。此意謂所述原子、基團、部分、鏈或環可未經取代或在任何位置經一或多個(例如1、2、3或4個)取代基取代,由此與未經取代之原子、基團、部分、鏈或環結合之氫原子被化學上可接受之原子、基團、部分、鏈或環置換。當存在兩個或兩個以上取代基時,各取代基可相同或不同。
如本文中所使用,術語鹵素原子包含氯、氟、溴或碘原子,通常包含氟、氯或溴原子,最佳包含溴或氟。當使用術語鹵作為前綴時,其具有相同含義。
M可以是氫原子或醫藥學上可接受之陽離子。當M是醫藥學上可接受之陽離子時,由式(I)表示的化合物另外可由下式(I*
)表示。
一些合適的經取代銨離子之實例是EtNH3 +
、Et2
NH2 +
、Et3
NH+
、(C6
H11
)2
NH2 +
、CH3
CH2
CH2
CH2
NH3 +
、PhCH2
NH3 +
以及(Ph)(PhCH2
)NH2 +
。常見四級銨離子之實例是N(CH3
)4 +
。
通常,M是氫原子或選自Li+
、Na+
、K+
、Ca2+
以及Mg2+
之醫藥學上可接受的陽離子。較佳,M是氫原子或選自Li+
、Na+
以及K+
之醫藥學上可接受的陽離子。更佳,M是氫原子或Li+
,且最佳,M是氫原子。
若式(1)之M是具有大於+1之電荷的醫藥學上可接受之陽離子,則存在其他陰離子來維持化合物之電中性。抗衡陰離子可以是如下文定義之陰離子X-或如上式(I*
)中表示之陰離子。
如本文中所使用,術語醫藥學上可接受之鹽包含與醫藥學上可接受之酸或鹼形成之鹽。醫藥學上可接受之酸包含無機酸,例如鹽酸、硫酸、磷酸、二磷酸、氫溴酸、氫碘酸以及硝酸;及有機酸、例如檸檬酸、反丁烯二酸、順丁烯二酸、蘋果酸、扁桃酸、抗壞血酸、草酸、丁二酸、酒石酸、苯甲酸、乙酸、甲烷磺酸、乙烷磺酸、苯磺酸、環己基胺基磺酸(cyclohexylsulfamic acid/cyclamic acid)或對甲苯磺酸。醫藥學上可接受之鹼包含鹼金屬(例如鈉或鉀)及鹼土金屬(例如鈣或鎂)氫氧化物及有機鹼,例如烷基胺、芳基烷基胺以及雜環胺。
根據本發明之其他較佳鹽是四級銨化合物,其中等量之陰離子(X-)與N原子之正電荷締合。X-可以是各種無機酸之陰離子,諸如氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根;或有機酸之陰離子,諸如乙酸根、順丁烯二酸根、反丁烯二酸根、檸檬酸根、草酸根、丁二酸根、酒石酸根、蘋果酸根、扁桃酸根、三氟乙酸根、甲烷磺酸根以及對甲苯磺酸根。X-較佳是選自氯離子、溴離子、碘離子、硫酸根、硝酸根、乙酸根、順丁烯二酸根、草酸根、丁二酸根或三氟乙酸根的陰離子。X-更佳是氯離子、溴離子、三氟乙酸根或甲烷磺酸根。
如本文中所使用,N-氧化物由存在於分子中的三級鹼性胺或亞胺使用適宜的氧化劑形成。
R1
通常選自由氫原子、溴原子以及氟原子、甲基、乙基、環丙基以及環丁基組成之族群。
G3
通常表示氮原子且G4
通常表示基團CH。
G3
通常表示基團CH且G4
通常表示氮原子。
G1
通常表示基團CRc
。
Rc
通常各自獨立地選自由氫原子、氟原子、氯原子以及C1-3
烷基組成之族群。
G2
通常表示基團CRd
。
Rd
通常選自由羥基、C1-3
烷氧基、2,2,2-三氟乙氧基以及C3-4
環烷氧基組成之族群。C1-3
烷氧基、2,2,2-三氟乙氧基以及C3-4
環烷氧基較佳。
Ra
通常選自由氟原子、甲基以及三氟甲氧基組成之族群。
Rb
通常選自由氫原子、氟原子以及氯原子組成之族群。
R2
通常選自由氫原子及鹵素原子組成之族群,較佳選自由氫原子及氟原子組成之族群。
通常,兩個基團G1
均表示C(Rc
)基團,G2
表示C(Rd
)基團,G2
較佳是選自C(OH)、C(OMe)以及C(OEt)的基團;Ra
是氟原子,Rb
選自由氫原子及氟原子組成之族群且R1
選自由氫原子、溴原子以及氟原子、甲基、乙基以及環丙基組成之族群;較佳地,兩個G1
均表示CH基團,G2
是選自C(OMe)及C(OEt)之基團;Ra
是氟原子,Rb
選自由氫原子及氟原子組成之族群且R1
選自由氫原子、溴原子以及氟原子、甲基、乙基以及環丙基組成之族群。
較佳地,Rc
是氫原子,Rd
是羥基或C1-3
烷氧基且R2
是氫原子;較佳地,Rc
是氫原子,Rd
是C1-3
烷氧基且R2
是氫原子。
較佳地,G3
表示氮原子,G4
表示基團CH且Rb
是氟原子,且較佳的是G3
表示基團CH、G4
表示氮原子之化合物。
更佳地,兩個基團G1
均表示C(Rc
)基團,G2
表示C(Rd
)基團,Ra
是氟原子,Rb
選自由氫原子及氟原子組成之族群且R1
選自由氫原子、溴原子以及氟原子、甲基、乙基以及環丙基組成之族群;較佳地,Rc
是氫原子,Rd
選自由C1-3
烷氧基及C3-4
環烷氧基組成之族群且R2
是氫原子。尤其較佳的是G3
表示氮原子、G4
表示基團CH且Rb
是氟原子之化合物及G3
表示基團CH、G4
表示氮原子之化合物。
DHODH抑制劑較佳是以下列表中之一個:1. 2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;2. 2-(3'-乙氧基-3-氟聯苯-4-基胺基)菸鹼酸;3. 2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;4. 2-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;5. 2-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;6. 2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;7. 2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸鹼酸;8. 2-(2',3-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;9. 2-(2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;10. 2-(3-氯-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;11. 2-(3-氯-3'-乙氧基聯苯-4-基胺基)菸鹼酸;12. 2-(3-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;13. 2-(3-氯-3'-甲氧基聯苯-4-基胺基)菸鹼酸;14. 2-(3'-(二氟甲氧基)-3-氟聯苯-4-基胺基)菸鹼酸;15. 2-(3'-環丁氧基-3-氟聯苯-4-基胺基)菸鹼酸;16. 2-(3-氟-3'-(2,2,2-三氟乙氧基)聯苯-4-基胺基)菸鹼酸;17. 2-(3'-環丁氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;18. 2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;19. 2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;20. 2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;21. 3-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸鹼酸鋰;22. 3-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸鹼酸鋰;23. 3-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸鹼酸鋰;24. 3-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)異菸鹼酸鋰;25. 2-(3'-乙氧基聯苯-4-基胺基)菸鹼酸;26. 2-(5-氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;27. 2-(2',3-二氟-5'-異丙氧基聯苯-4-基胺基)菸鹼酸;28. 2-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸;29. 2-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸鹼酸;30. 5-溴-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;31. 5-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;32. 5-溴-2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;33. 2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)-5-甲基菸鹼酸;34. 5-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;35. 2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸;36. 2-(3'-乙氧基-5-氟-2-甲基聯苯-4-基胺基)菸鹼酸;37. 2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸鹼酸;38. 2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)-5-甲基菸鹼酸;39. 5-環丙基-2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;40. 2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸鹼酸;41. 5-溴-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸鹼酸;42. 5-環丙基-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸鹼酸;43. 2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)-5-甲基菸鹼酸;44. 5-環丙基-2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸鹼酸;45. 2-(2',3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;46. 2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸鹼酸;47. 2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;48. 2-(3,5-二氟-2-甲基聯苯-4-基胺基)菸鹼酸;49. 5-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;50. 2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)-5-環丙基菸鹼酸;51. 5-氯-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;52. 5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;53. 2-(2,3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;54. 2-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸鹼酸;55. 2-(3,5-二氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸鹼酸;56. 2-(3,5-二氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;57. 2-(2'-氯-3,5-二氟-2-甲基聯苯-4-基胺基)菸鹼酸;58. 5-氯-2-(3,5-二氟聯苯-4-基胺基)菸鹼酸;59. 5-氯-2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸鹼酸;60. 2-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;61. 2-(3,5-二氟-2'-甲基聯苯-4-基胺基)菸鹼酸;62. 3-(3'-環丙氧基-3-氟聯苯-4-基胺基)異菸鹼酸;或其醫藥學上可接受之鹽或N-氧化物。
DHODH抑制劑更佳是以下化合物中之一個:2-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;2-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;3-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸鹼酸鋰;3-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸鹼酸鋰;3-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸鹼酸鋰;2-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸;5-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;5-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸;2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸鹼酸;2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸鹼酸;2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸;2-(3,5-二氟-2-甲基聯苯-4-基胺基)菸鹼酸;5-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸;2-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸鹼酸;2-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸;或其醫藥學上可接受之鹽或N-氧化物。DHODH抑制劑最佳是2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸、2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸、2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸、2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸或5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸鹼酸或其醫藥學上可接受之鹽或N-氧化物。
活性成分(a)及(b)較佳構成單一醫藥組合物之一部分。
更提供一種如上所描述的組合,其更包括(c)另一選自以下各物之化合物:(i)抗TNF-α單株抗體,諸如英利昔單抗(Infliximab)、塞妥珠單抗(Certolizumab pegol)、戈利木單抗(Golimumab)、阿達木單抗(Adalimumab)以及來自Applied Molecular Evolution之AME-527;(ii)TNF-α拮抗劑,諸如依那西普(Etanercept)、來那西普(Lenercept)、奧那西普(Onercept)以及培那西普(Pegsunercept);(iii)鈣調神經磷酸酶(Calcineurin)(PP-2B)抑制劑/INS表現抑制劑,諸如環孢素A(cyclosporine A)、他克莫司(Tacrolimus)及來自Isotechnika之ISA-247;(iv)IL-1受體拮抗劑,諸如阿那白滯素(Anakinra)及來自Amgen之AMG-719;(v)抗CD20單株抗體,諸如利妥昔單抗(Rituximab)、奧法姆單抗(Ofatumumab)、奧利珠單抗(Ocrelizumab)以及來自Trubion Pharmaceuticals之TRU-015;(vi)p38抑制劑,諸如AMG-548(來自Amgen)、ARRY-797(來自Array Biopharma)、乙二磺酸氯美噻唑(Chlormethiazole edisylate)、多拉莫德(Doramapimod)、PS-540446(來自BMS)、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553(所有均來自GlaxoSmithKline)、KC-706(來自Kemia)、LEO-1606、LEO-15520(所有均來自Leo)、SC-80036、SD-06(所有均來自Pfizer)、RWJ-67657(來自R.W.Johnson)、RO-3201195、RO-4402257(所有均來自Roche)、AVE-9940(來自Aventis)、SCIO-323、SCIO-469(所有均來自Scios)、TA-5493(來自Tanabe Seiyaku)以及VX-745及VX-702(所有均來自Vertex);(vii)NF-(NFKB)活化抑制劑,諸如柳氮磺吡啶(Sulfasalazine)及艾拉莫德(Iguratimod);(viii)二氫葉酸還原酶(dihydrofolate reductase,DHFR)抑制劑,諸如胺基蝶呤及來自Chelsea之CH-1504;(ix)Janus激酶(Janus kinase,JAK)抑制劑,諸如來自Pfizer之CP-690、CP-550及來自Incyte之INCB-18424;(x)MEK抑制劑,諸如來自Array之ARRY-162;(xi)神經鞘胺醇-1磷酸受體激動劑,諸如芬戈莫德(fingolimod)(Novartis);(xii)干擾素,包括干擾素β1a,諸如來自Biogen Idec之阿瓦克斯(Avonex)、來自CinnaGen之西努克斯(CinnoVex)以及來自Merck Serono之利比(Rebif);及干擾素β1b,諸如來自Schering之倍泰芬龍(Betaferon)及來自Berlex之倍泰瑟龍(Betaseron);(xiii)免疫調節劑,諸如來自Biogen Idec/Fu mapharm AG之BG-12(反丁烯二酸衍生物);(xiv)腺苷脫胺酶(Adenosine aminohydrolase)抑制劑,諸如來自Merck Serono之克拉屈濱(Cladribine)。
本發明更提供一種(a)甲胺蝶呤及(b)本發明之DHODH抑制劑之用途,其用於製備同時、分開或相繼用於治療易由二氫乳清酸脫氫酶之抑制得到改善的病理病狀或疾病的藥物。
DHODH抑制發揮作用之疾病或病症包含(但不限於)自體免疫疾病、免疫及發炎疾病、毀壞性骨病症、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及傳染性疾病。
可預防或治療之自體免疫疾病包含(但不限於)類風濕性關節炎、牛皮癬性關節炎、全身性紅斑狼瘡、多發性硬化、牛皮癬、強直性脊柱炎、韋格納肉芽腫病(Wegener's granulomatosis)、多關節炎性青少年特發性關節炎、諸如潰瘍性結腸炎及克羅恩氏病(Crohn's disease)之發炎性腸疾病、萊特氏症候群(Reiter's syndrome)、纖維肌痛以及1型糖尿病。
可預防或治療之免疫及發炎疾病包含(但不限於)哮喘、COPD、呼吸窘迫症候群、急性或慢性胰腺炎、移植物抗宿主疾病、慢性肉狀瘤病、移植排斥反應、接觸性皮炎、異位性皮炎、過敏性鼻炎、過敏性結膜炎、貝切特氏症候群(Behcet syndrome)、諸如結膜炎及葡萄膜炎之發炎性眼病。
可預防或治療之毀壞性骨病症包含(但不限於)骨質疏鬆症、骨關節炎以及多發性骨髓瘤相關骨病。
可預防或治療之惡性贅生性疾病包含(但不限於)前列腺癌、卵巢癌及腦癌。
可預防或治療之血管生成相關病症包含(但不限於)血管瘤、眼睛新血管生成、黃斑退化或糖尿病性視網膜病。
可預防或治療之病毒性疾病包含(但不限於)HIV感染、肝炎以及巨細胞病毒感染。
可預防或治療之傳染性疾病包含(但不限於)敗血症、敗血性休克、內毒素休克、革蘭氏陰性敗血症(Gram negative sepsis)、中毒性休克症候群、志賀氏菌病(Shigellosis)以及其他原蟲感染(諸如瘧疾)。
病理病狀或疾病較佳選自類風濕性關節炎、牛皮癬關節炎、強直性脊柱炎、多發性硬化、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病。病理病狀或疾病更佳是類風濕性關節炎、牛皮癬關節炎或牛皮癬。其最佳是類風濕性關節炎。
亦提供一種組合,其包括(a)諸如干擾素β1a或干擾素β1b之干擾素及(b)本發明之DHODH抑制劑,較佳式(I)DHODH抑制劑。
亦提供一種包括(a)諸如干擾素β1a或干擾素β1b之干擾素及(b)本發明之DHODH抑制劑、較佳式(I)DHODH抑制劑的組合的用途,其用於製備同時、分開或相繼用於治療多發性硬化之藥物。
亦提供一種產品,其包括(a)甲胺蝶呤及(b)本發明之DHODH抑制劑,作為同時、分開或相繼用於治療患有或易患如上所定義之病理病狀或疾病的人類或動物患者的組合製劑。所述產品可視情況更包括如上所定義之活性化合物(c)。
亦提供一種成套套組,其包括(b)本發明之DHODH抑制劑以及用於說明與(a)甲胺蝶呤組合用於同時、分開或相繼治療患有或易患如上所定義之病理病狀或疾病的人類或動物患者的說明書。所述套組可視情況更包括如上所定義之活性化合物(c)。
亦提供一種包裝,其包括(b)本發明之DHODH抑制劑及(a)甲胺蝶呤,其同時、分開或相繼用於治療如上所定義之病理病狀或疾病。所述包裝可視情況更包括如上所定義之活性化合物(c)。
亦提供一種(b)本發明之DHODH抑制劑的用途,其用於製備與(a)甲胺蝶呤組合用於治療如上所定義之病理病狀或疾病的藥物。
亦提供一種(a)甲胺蝶呤之用途,其用於製備與(b)本發明之DHODH抑制劑組合用於治療如上所定義之病理病狀或疾病的藥物。
亦提供一種如上所定義之用途,其中甲胺蝶呤(a)欲以涉及每週每公斤投與0.015至3毫克甲胺蝶呤的劑量方案投藥且DHODH抑制劑(b)欲以涉及每天每公斤投與0.03至30毫克DHODH抑制劑的劑量方案投藥。
藥物通常是用於治療患有或易患肝損傷或將由肝毒性加重之病狀的人類或動物患者。所述人類或動物患者更通常患有肝纖維化、肝炎(通常A型至G型肝炎)、肝硬化(通常由酗酒引起)或肝癌。
在本發明之一實施例中,組合、產品、成套套組或包裝包括(b)本發明之DHODH抑制劑及(a)甲胺蝶呤作為僅有的活性組分。
本發明研究發現本發明之DHODH抑制劑具有降低的肝副作用。因此,本發明亦提供一種如上所定義之本發明之DHODH抑制劑的用途,其用於製造供治療或預防患有或易患如上所定義之肝損傷或將由肝毒性加重之病狀的人類或動物患者的如上所定義之病理病狀或疾病的藥物。
亦提供一種治療患有或易患如上所定義之病理病狀或疾病之人類或動物患者的方法,所述方法包括向所述人類或動物患者同時、分開或相繼投與治療有效量之(a)甲胺蝶呤及(b)如上所定義之DHODH抑制劑。在所述方法中,較佳(a)甲胺蝶呤及(b)DHODH抑制劑是僅有的活性組分。
亦提供一種治療患有或易患如上所定義之病理病狀或疾病之人類或動物患者的方法,其中所述人類或動物患者患有或易患如上所定義之肝損傷或將由肝毒性加重之病狀,所述方法包括向所述人類或動物患者投與治療有效量之如上所定義之DHODH抑制劑。
亦提供一種如上所定義之組合,其用於治療如上所定義之病理病狀或疾病。
亦提供一種如上所定義之DHODH抑制劑,其用於治療患有或易患如上所定義之病理病狀或疾病之人類或動物患者,其中所述人類或動物患者患有或易患如上所定義之肝損傷或將由肝毒性加重之病狀。
本發明之組合中的活性化合物可視欲治療之病症之性質由任何合適途徑投與,例如經口(以糖漿、錠劑、膠囊、含片、控制釋放製劑、速溶製劑等形式);局部(以乳膏、軟膏、洗劑、鼻用噴霧或氣霧劑等形式);注射(皮下、真皮內、肌肉內、靜脈內等)或吸入(以乾粉、溶液、分散液等形式)。
組合中的活性化合物可在同一醫藥組合物中一起投與或以欲藉由相同或不同途徑分開、同時、相伴或相繼投藥之不同組合物投與。
本發明之組合適宜以單位劑型呈現且可由藥學技術熟知之任何方法製備。
適合經口投藥的本發明之組合可以如下形式呈現:各自含有預定量之活性成分的離散單元(諸如膠囊、扁囊劑或錠劑);散劑或顆粒劑;於水性液體或非水性液體中之溶液或懸浮液;或水包油型液體乳液或油包水型液體乳液。活性成分亦可以大丸劑、舐劑或糊劑形式呈現。
糖漿調配物通常將由化合物或鹽於液體載劑(例如乙醇、花生油、橄欖油、甘油或水)及調味劑或著色劑中之懸浮液或溶液組成。
當組合呈錠劑形式時,可使用常規用於製備固體調配物之任何醫藥載劑。所述載劑之實例包含硬脂酸鎂、滑石、明膠、阿拉伯膠(acacia)、硬脂酸、澱粉、乳糖以及蔗糖。
可藉由視情況與一或多種配合成分壓縮或模製製造錠劑。可藉由在合適機器中將視情況與黏合劑、潤滑劑(lubricant)、惰性稀釋劑、潤滑劑(lubricating agent)、表面活性劑或分散劑混合之呈自由流動形式(諸如粉狀物或顆粒物)之活性成分壓縮來製備壓縮錠劑。可藉由在合適機器中使經惰性液體稀釋劑潤濕之粉狀化合物的混合物模製來製造模製錠劑。可視情況將錠劑包衣或刻痕且可調配錠劑以提供其中之活性成分的緩慢或控制釋放。
當組合呈膠囊形式時,任何常規囊封均是合適的,例如於硬質明膠膠囊中使用上述載劑。當組合物呈軟質明膠膠囊形式時,可考慮常規用於製備分散液或懸浮液之任何醫藥載劑,例如水性膠、纖維素、矽酸鹽或油類,且可將其併入軟質明膠膠囊中。
組合可呈用於藉由吸入局部傳遞至肺之乾粉組合物形式。乾粉組合物可例如呈現於用於吸入器或吹入器中之例如明膠膠囊及藥匣或例如層壓鋁箔發泡包裝中。調配物通常含有本發明之化合物與諸如乳糖或澱粉之合適粉狀基質(載劑物質)的吸入用粉狀混合物。較佳使用乳糖。各膠囊或藥匣通常可含有2微克與150微克之間的各治療活性成分。或者,可呈現無賦形劑之活性成分。
可藉由使用諸如NovolizerSD2FL或Genuair之合適吸入器裝置進行吸入用調配物之封裝,所述裝置在以下專利申請案中描述:WO 97/000703、WO 03/000325以及WO 03/061742。
組合可呈用於經鼻傳遞之組合物的形式。用於經鼻傳遞之典型組合物包含以上所提及之用於吸入之組合物且更包含呈於諸如水之惰性媒劑中之溶液或懸浮液形式的可經鼻用泵投與之非加壓組合物,所述非加壓組合物視情況與諸如緩衝劑、抗微生物劑、張力調節劑以及黏度調節劑之習知賦形劑組合。
典型皮膚用及經皮調配物包括例如乳膏、軟膏、洗劑或糊劑之習知水性或非水性媒劑或呈藥用硬膏劑、貼片或膜形式。
組合較佳呈單位劑型,例如錠劑、膠囊或計量氣霧劑劑量,如此患者可投與單劑量。
實現治療效應所必需之各活性劑之量當然將隨特定活性劑、投藥途徑、所治療之個體以及所治療之特定病症或疾病而變化。
組合中的所有活性劑通常同時或以極靠近之時間投與。或者,一或兩種活性劑可在上午服用且其他活性劑當日稍後服用。或在另一方案中,一或兩種活性劑可每日服用兩次,且其他活性劑每日服用一次,與所進行之每天兩次給藥中之一次同時服用或分開服用。較佳至少兩種且更佳所有活性劑應同時一起服用。較佳至少兩種且更佳所有活性劑應以混合物形式投與。
本發明之藥物組合較佳欲以涉及投與(i)每週每公斤0.015至3毫克甲胺蝶呤、更佳每週每公斤0.07至0.7毫克甲胺蝶呤且最佳每週每公斤0.15至0.35毫克甲胺蝶呤及(ii)每天每公斤0.03至30毫克DHODH抑制劑、更佳每天每公斤0.07至14毫克DHODH抑制劑且最佳每天每公斤0.15至0.3毫克DHODH抑制劑的劑量方案投藥。
實例
實例1-人類DHODH活性抑制檢定
使用色原還原檢定(chromogen reduction assay)用2,6-二氯酚-靛基酚(2,6-dichlorophenol-indophenol,DCIP)研究DHODH活性及其抑制。受質氧化(二氫乳清酸,L-DHO)以及輔受質還原(輔酶Q,CoQ)與色原還原相關,因此酶促活性導致600奈米下之色原吸光度的損失。
在96孔板中培育酶提取物(8微升,約1.5微克人類蛋白質)。檢定混合物(200微升)含有於檢定緩衝液(100毫莫耳濃度HEPES(pH 8.0)、150毫莫耳濃度NaCl、10% Glicerol、0.05% Triton X-100)中的200微莫耳濃度CoQD、100微莫耳濃度L-DHO、120微莫耳濃度DCIP以及2微升測試化合物。將化合物溶解於DMSO中,儲備濃度為1毫莫耳濃度,且在10微莫耳濃度至1皮莫耳濃度不等之不同濃度下測試以計算IC50
(50%抑制所必需之抑制劑濃度)。
藉由添加酶啟動反應,且隨後在室溫下培育10分鐘,之後藉由使用標率儀器(Spectramax)計數600奈米下吸光度之降低來量測DCIP還原。
所有反應均一式兩份進行,且使用ABase軟體繪製確定各化合物之IC50
值的圖。
表1展示本發明之一些化合物(來自先前所指示之列表的化合物)在人類DHODH抑制檢定中的活性,展示所述化合物是有效的DHODH抑制劑。
實例2-降低的肝毒性
在瑞士小鼠(Swiss mice)中執行急性肝毒性檢定。動物接受媒劑或100毫克/公斤特立氟胺或本發明化合物(來自先前指示之列表的化合物)經由腹膜內途徑之單一投藥。24小時後,處死動物且測定血漿中肝標誌物AST(天冬胺酸轉胺酶)、ALT(丙胺酸轉胺酶)以及BIL(總膽紅素)的含量。
如由表2清楚可見,與媒劑治療小鼠相比,特立氟胺治療小鼠展示三個肝標誌物顯著增加,清楚指示高肝毒性,而根據本發明之DHODH抑制劑不引起所量測之任何參數的顯著增加。
實例3:本發明之組合產品在佐劑誘發關節炎中的效力檢定
在大鼠佐劑誘發關節炎模型(adjuvant-induced arthritis,AIA)中測試DHODH抑制劑化合物與甲胺蝶呤(每天每公斤0.05毫克)之組合在患有所創建疾病之動物中的效應(洽愈方案)。簡言之,將完全弗氏佐劑(Complete Freund Adjuvant,CFA)注射至維斯塔大鼠(Wistar rat)之左後腳掌中,且10天後,用器官充滿度量測器(plethysmometer)量測兩個後爪之腫脹。將兩個爪展現類似發炎程度之大鼠隨機分成治療組(每組n=7)。一天一次經口投與化合物,持續10天,且每隔一天測定爪體積直至第21天。
表3:化合物A(每天每公斤3毫克)、甲胺蝶呤(每天每公斤0.05毫克)以及其組合對關節炎大鼠之爪發炎之抑制的效應
結果以發炎的平均抑制表示,此是以誘發後10天與21天之間所包括的時間內右爪體積之曲線下面積(area under the curve,AUC)度量。每組之抑制百分比是相對於媒劑治療大鼠之值計算。結果是兩個獨立實驗之平均值,每個實驗每組具有5-6隻動物。表3之結果展示本發明之化合物A抑制大鼠中由實驗性關節炎引起之發炎。此外,共投與MTX及化合物A導致效力相對於單獨化合物A增加(34%),從而指示在經MTX治療之患者中投與所述化合物之可行性。
表4:特立氟胺(每天每公斤3毫克)、甲胺蝶呤(每天每公斤0.05毫克)以及其組合對關節炎大鼠之爪發炎之抑制的效應
結果以發炎的平均抑制表示,此是以誘發後10天與21天之間所包括的時間內右爪體積之曲線下面積(AUC)度量。每組之抑制百分比是相對於媒劑治療大鼠之值計算。結果是一個6隻動物之實驗的平均值。
共投與MTX及特立氟胺導致效力相對於單獨特立氟胺增加(9%)。
根據實驗結果,可推斷本發明之DHODH抑制劑化合物單獨以及與MTX(如特立氟胺)組合展示抗關節炎效應,但展示明顯減弱的肝毒性潛能,此使得本發明之組合,即(a)MTX及(b)本發明之DHODH抑制劑自安全概況觀點更具吸引力。
Claims (17)
- 一種組合,其包括(a)甲胺蝶呤及(b)二氫乳清酸脫氫酶抑制劑;其中該二氫乳清酸脫氫酶抑制劑係為2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸、2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸、2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸鹼酸、2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸鹼酸,或其醫藥學上可接受之鹽或N-氧化物。
- 如申請專利範圍第1項所述之組合,其中所述二氫乳清酸脫氫酶抑制劑係為2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸鹼酸或其醫藥學上可接受之鹽或N-氧化物。
- 如申請專利範圍第1項所述之組合,其特徵在於所述活性成分(a)及(b)構成單一醫藥組合物之一部分。
- 如申請專利範圍第1項所述之組合,其更包括(c)另一選自以下各物之化合物:(i)抗TNF-α單株抗體;(ii)TNF-α拮抗劑;(iii)鈣調神經磷酸酶(PP-2B)抑制劑/INS表現抑制劑;(iv)IL-1受體拮抗劑;(v)抗CD20單株抗體;(vi)p38抑制劑; (vii)NF-κB(NFKB)活化抑制劑;(viii)另一二氫葉酸還原酶(DHFR)抑制劑;(ix)Janus激酶(JAK)抑制劑;(x)MEK抑制劑;以及(xi)神經鞘胺醇-1磷酸受體激動劑;(xii)干擾素;(xiii)免疫調節劑;(xiv)腺苷脫胺酶抑制劑。
- 如申請專利範圍第4項所述之組合,其中:(i)所述抗TNF-α單株抗體係選自於英利昔單抗、塞妥珠單抗、戈利木單抗、阿達木單抗以及來自Applied Molecular Evolution之AME-527;(ii)所述TNF-α拮抗劑係選自於依那西普、來那西普、奧那西普以及培那西普;(iii)所述鈣調神經磷酸酶(PP-2B)抑制劑/INS表現抑制劑係選自於環孢素A、他克莫司及來自Isotechnika之ISA-247;(iv)所述IL-1受體拮抗劑係選自於阿那白滯素及來自Amgen之AMG-719;(v)所述抗CD20單株抗體係選自於利妥昔單抗、奧法姆單抗、奧利珠單抗以及來自Trubion Pharmaceuticals之TRU-015;(vi)所述p38抑制劑係選自於AMG-548、ARRY-797、 乙二磺酸氯美噻唑、多拉莫德、PS-540446、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553、KC-706、LEO-1606、LEO-15520、SC-80036、SD-06、RWJ-67657、RO-3201195、RO-4402257、AVE-9940、SCIO-323、SCIO-469、TA-5493以及VX-745及VX-702;(vii)所述NF-κB(NFKB)活化抑制劑係選自於柳氮磺吡啶及艾拉莫德;(viii)所述另一二氫葉酸還原酶(DHFR)抑制劑係選自於胺基蝶呤及來自Chelsea之CH-1504;(ix)所述Janus激酶(JAK)抑制劑係選自於來自Pfizer之CP-690、CP-550及來自Incyte之INCB-18424;(x)所述MEK抑制劑係為來自Array之ARRY-162;(xi)所述神經鞘胺醇-1磷酸受體激動劑係為芬戈莫德(Novartis);(xii)所述干擾素係選自於干擾素β1a及干擾素β1b;(xiii)所述免疫調節劑係為來自Biogen Idec/Fumapharm AG之BG-12(反丁烯二酸衍生物);(xiv)所述腺苷脫胺酶抑制劑係為來自Merck Serono之克拉屈濱。
- 一種(a)甲胺蝶呤及(b)如申請專利範圍第1項所定義之二氫乳清酸脫氫酶抑制劑於製備同時、分開或相繼用於治療易由二氫乳清酸脫氫酶之抑制得到改善的病理病狀或疾病的藥物之用途。
- 如申請專利範圍第6項所述之用途,其中所述病理病狀或疾病選自類風濕性關節炎、牛皮癬關節炎、強直性脊柱炎、多發性硬化、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病。
- 一種產品,其包括(a)甲胺蝶呤及(b)如申請專利範圍第1項所定義之二氫乳清酸脫氫酶抑制劑,其用作同時、分開或相繼用於治療患有或易患如申請專利範圍第6或7項所定義之病理病狀或疾病之人類或動物患者的組合製劑。
- 如申請專利範圍第8項所述之產品,其更包括如申請專利範圍第4或5項所定義之活性化合物(c)。
- 一種成套套組,其包括(b)如申請專利範圍第1項所定義之二氫乳清酸脫氫酶抑制劑與(a)甲胺蝶呤之組合,以及用於說明前述組合用於同時、分開或相繼治療患有或易患如申請專利範圍第6或7項所定義之病理病狀或疾病的人類或動物患者的說明書。
- 如申請專利範圍第10項所述之套組,其更包括如申請專利範圍第4或5項所定義之活性化合物(c)。
- 一種包裝,其包括(b)如申請專利範圍第1項所 定義之二氫乳清酸脫氫酶抑制劑及(a)甲胺蝶呤,其同時、分開或相繼用於治療如申請專利範圍第6或7項所定義之病理病狀或疾病。
- 如申請專利範圍第12項所述之包裝,其更包括如申請專利範圍第4或5項所定義之活性化合物(c)。
- 一種包括(a)甲胺蝶呤以及(b)如申請專利範圍第1項所定義之二氫乳清酸脫氫酶抑制劑之組合的用途,其用於製備供同時、分開或相繼用於治療易由二氫乳清酸脫氫酶之抑制得到改善的病理病狀或疾病的藥物;其中前述藥物係用於治療患有或易患肝損傷或將由肝毒性加重之病狀的人類或動物患者。
- 如申請專利範圍第14項所述之用途,其中所述病理病狀或疾病選自類風濕性關節炎、牛皮癬關節炎、強直性脊柱炎、多發性硬化、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病。
- 如申請專利範圍第14或15項所述之用途,其中所述將由肝毒性加重之病狀是肝纖維化、肝炎、肝硬化或肝癌。
- 如申請專利範圍第16項所述之用途,其中所述甲 胺蝶呤(a)欲以涉及每週每公斤投與0.015至3毫克甲胺蝶呤的劑量方案投藥且所述二氫乳清酸脫氫酶抑制劑(b)欲以涉及每天每公斤投與0.03至30毫克二氫乳清酸脫氫酶抑制劑的劑量方案投藥。
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