TW202222314A - 神經鞘胺醇－１－磷酸受體促效劑的用途 - Google Patents
神經鞘胺醇－１－磷酸受體促效劑的用途 Download PDFInfo
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Abstract
本揭露係關於式1之化合物或其藥學上可接受之鹽用於預防或治療異位性皮膚炎之用途：
其中，X、R1、R2、R3、R4、R5和R6與本文所定義的相同。
Description
本揭露係關於使用式1之化合物或其藥學上可接受之鹽於預防或治療異位性皮膚炎的用途：
其中，X、R1、R2、R3、R4、R5和R6與本文所定義的相同。
神經鞘胺醇-1-磷酸(S1P)係經由細胞內神經醯胺途徑所產生，其中，神經醯胺為起始材料。神經醯胺是經由兩種途徑所產生的，第一種是從頭生物合成途徑。神經醯胺亦為藉由細胞中的神經鞘磷脂(一種細胞膜成分)所降解產生者。各組織中的S1P量係藉由兩種生物合成神經鞘胺醇激酶(SphK)和兩種可生物降解的S1P磷酸酶(S1P裂解酶和溶血磷脂磷酸酶)所調控。已知藉由神經鞘胺醇激酶磷酸化神經鞘胺醇所產生的S1P調
合不同細胞反應，例如細胞增殖、細胞骨架組織和遷移、黏附-和緊密之聯結等合體(adhesive and tight junction assembly)以及形體生成。S1P以與包括白蛋白的血漿蛋白質的結合形式存在於血漿中為高量級(100至1,000nM)，然在組織中則為低量級。
S1P與S1P受體(G蛋白偶聯受體)結合以顯示不同生物學功能。作為S1P受體亞型，迄今為止已知的S1P1至S1P5分別命名為內皮分化基因(EDG)受體1、5、3、6和8。S1P受體已參與在不同地生物學功能，例如白血球再循環、神經細胞增殖、形體變化、遷移、內皮功能、血管調節(vasoregulation)和心血管發育。
近年來，許多研究發現，經由這些受體的S1P訊號傳導過程在與多發性硬化相關的包括炎症反應和修復過程之系列反應中具有著重要作用，且一種非選擇性S1P1促效劑實際上已批准作為多發性硬化症之治療劑。S1P受體係廣泛表現在與多發性硬化症誘導相關的許多細胞中。特別地，S1P1受體在免疫系統中具有主要作用。S1P1受體主要表達於淋巴細胞表面，例如T細胞和B細胞，且對S1P作出反應從而參與淋巴細胞的再循環。正常情況下，體液中的S1P濃度較高於在淋巴組織中者，且因此淋巴細胞藉由S1P濃度的差異離開淋巴組織，會在輸出淋巴循環後，於體液中循環。然而，如果淋巴細胞中的S1P1受體被S1P1促效劑下調，則淋巴細胞不會從淋巴組織流出，導致造成中樞神經系統(CNS)發炎和組織損傷之自體侵襲性(autoaggressive)淋巴細胞之浸潤減少。結果，獲得對多發性硬化症的治療效果。芬戈莫德(Fingolimod)為一種非選擇性S1P1促效劑，已被批准作為治療多發性硬化症的口服藥。當其與S1P1受體結合而激
活時，該受體反效果地從淋巴細胞表面降解或內化，從而發揮功能性的S1P1拮抗作用。
關於這種S1P受體，國際專利案第WO 2014/129796號(公開日期：2014年8月28日)揭露有效於作為S1P受體促效劑之化合物。
同時，異位性皮膚炎是一種慢性復發性皮膚濕疹疾病，雖然至今病因尚未明確，有聲稱係起因於外部抗原的作用而使免疫相關因素反應過度所致。用於異位性皮膚炎之藥物主要有免疫壓制劑、外用類固醇、抗組織胺劑等。然而，這些藥物的使用存在副作用或對異位性皮膚炎改善的侷限性。因此，持續需要能夠更有效地預防或治療異位性皮膚炎的新藥。
本揭露之一目的為提供下式1之化合物或其藥學上可接受之鹽在預防或治療異位性皮膚炎之用途：
其中，X、R1、R2、R3、R4、R5和R6與本文所定義的相同。
本揭露提供了一種用於預防或治療異位性皮膚炎之藥物，其包含治療有效量的下式1之化合物或其藥學上可接受之鹽：
其中，
X為碳或氮；
R1為氫或烷基；
R2為氫、烷基、鹵素、CN、CF3或COCF3；
R3和R4各自獨立地為氫、烷基、鹵素、鹵烷基或烷氧烷基；
R5為氫、烷基或鹵素；
R6為
；
R7為氫或烷基；和
m和n各自獨立地為0、1、2或3。
此外，本揭露提供用於預防或治療異位性皮膚炎之醫藥組成物，其包含治療有效量的式1之化合物或其藥學上可接受之鹽以及藥學上可接受之載體。
此外，本揭露提供了一種預防或治療異位性皮膚炎的方法，包含向有需要的個體給藥治療有效量的式1之化合物或其藥學上可接受之鹽。
此外，本揭露提供式1之化合物或其藥學上可接受之鹽用於預防或治療異位性皮膚炎的用途。
本揭露詳細地描述於下文。
根據本揭露的一方面，提供一種用於預防或治療異位性皮膚炎之藥物，其包含治療有效量的式1之化合物或其藥學上可接受之鹽。
根據本揭露的另一方面，提供一種用於預防或治療異位性皮膚炎之醫藥組成物，其包含治療有效量的式1之化合物或其藥學上可接受之鹽以及藥學上可接受之載體。
式1之化合物的製備方法在國際專利案第WO 2014/129796A1號中有詳細描述，該文獻以引用方式併入本文。
在根據本揭露的一實施例中，式1中
X為C或N；
R1為氫或C1-C5烷基；
R2為氫、C1-C5烷基、鹵素、CN、CF3或COCF3；
R3和R4各自獨立地為氫、C1-C5烷基、鹵素、鹵-C1-C5烷基或C1-C5烷氧基-C1-C5烷基；
R5為氫、C1-C5烷基或鹵素；
R6為
；
R7為氫或C1-C5烷基；以及
m和n各自獨立地為0、1、2或3。
在根據本揭露的另一個實施例中，式1之化合物是下式2之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸：
在根據本揭露的另一實施例中，藥學上可接受之鹽包括，例如，酸加成鹽，其由含有藥學上可接受之陰離子的無毒酸加成鹽所形成，例如無機酸，如鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸；有機酸，如酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸；或磺酸，如甲磺酸、苯磺酸、對甲苯磺酸或萘磺酸，但不限於此。
在根據本揭露的另一實施例中，個別個體的「治療有效量」是指足以實現上述藥理作用--即，如上所述的治療作用的量。化合物的量可根據個體的狀況和嚴重程度、給藥方式和待治療個體的年齡而變化，但可由所屬技術領域中具有通常知識者根據其知識來決定。
在根據本揭露的另一實施例中，根據給藥頻率和強度，式1之化合物的治療有效量通常在例如每天約0.1至500毫克之範圍。成人肌
內或靜脈內給藥的通常每日劑量在每天約0.1至300毫克之範圍，其可以分開的單位劑量給藥。一些患者需要更高的每日劑量。
在本揭露中，「醫藥組成物」除了本揭露的有效成分外，亦可包括其他成分，例如載體、稀釋劑、賦形劑等。因此，如有需要，醫藥組成物可包括藥學上可接受之載體、稀釋劑、賦形劑或其組合。該醫藥組成物有助於將化合物給藥至體內。化合物給藥的各種方法包括但不限於口服、注射、霧劑、腸胃外和局部給藥。
在本文中，「載體」是指促進化合物添加至細胞或組織中之化合物。例如，二甲基亞碸(DMSO)是一種一般載體，其有助於將許多有機化合物給藥至活細胞或組織中。
在本文中，「稀釋劑」是指不僅穩定生物活性形式且在溶劑中稀釋以溶解化合物之化合物。緩衝液中的溶解鹽為用作該領域之稀釋劑。一般使用的緩衝液是模擬體液中鹽形式之磷酸鹽緩衝鹽水。由於緩衝溶液可在低濃度調控溶液之pH值，緩衝稀釋劑難以改變化合物之生物活性。
在本文中，「藥學上可接受之」是指不損害化合物的生物活性和物理性質之性質。
本揭露的化合物可以配製為各種藥物給藥劑型。在本揭露之醫藥組成物的製備中，考慮到要製備的劑型，將活性成分--具體地，式1之化合物或其藥學上可接受之鹽--與選定的藥學上可接受之載體混合。例如，本揭露之醫藥組成物可根據需要配製為注射劑、口服製劑等。
本揭露之化合物可使用已知之藥物載體和賦形劑藉由一般方法配製，並插入至單元或複數個單元容器。製劑可為油或水性溶劑中的
溶液、懸浮液或乳液，並且包括一般分散劑、懸浮劑或穩定劑。此外，該化合物可為例如在使用前溶解於滅菌無熱原水中的乾粉形式。本揭露之化合物可藉由使用一般栓劑基質如可可脂或其他甘油酯配製成栓劑。用於口服給藥之固體形式包括膠囊、片劑、丸劑、粉劑和顆粒劑。較佳為膠囊劑和片劑。片劑和丸劑較佳為經腸衣被覆。固體形式是藉由將本揭露之化合物與至少一種載體混合製備而成，該載體選自惰性稀釋劑如蔗糖、乳糖或澱粉，潤滑劑如硬脂酸鎂、崩解劑、黏合劑等。此外，其可配製為經皮劑型--例如，作為洗劑、軟膏、凝膠、乳膏、貼劑或噴霧劑。
在本文中，術語「預防」是指減少或消除感染疾病的可能性。
在本文中，術語「治療」是用於意指阻止、延遲或改善表現出疾病症狀之個體的疾病進展。
本揭露之藥物或醫藥組成物可有效預防或治療異位性皮膚炎。
圖1為異位性皮膚炎動物模型之誘導過程示意圖。
圖2為在異位性皮膚炎動物模型中給藥測試物質後耳朵厚度減少之測量結果。
圖3為在異位性皮膚炎動物模型中給藥測試物質後耳朵重量減少之測量結果。
圖4為在異位性皮膚炎動物模型中給藥測試物質後IgE的血液量級降低之測量結果。
圖5為在異位性皮膚炎動物模型中給藥測試物質後表皮厚度減少之測量結果。
圖6為在異位性皮膚炎動物模型中給藥測試物質後肥大細胞蓄積減少之測量結果。
圖7為在異位性皮膚炎動物模型中與作為比較化合物的依曲莫德(etrasimod)進行比較的結果。
在下文中，藉由以下實例更詳細地解釋本揭露。然而，必須理解的是，本揭露的保護範圍並不限於實例。
製備例：1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸的之合成
根據國際專利案第WO2014/129796A1號之實例153中揭露之方法製備1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸(以下簡稱為「測試化合物」)。
實例1：異位性皮膚炎動物模型的誘導
藉由使用
唑啉酮(oxazolone)在小鼠(Balb/c)中誘導異位性皮膚炎之動物模型。將
唑啉酮的第一個致敏日設為第0天，從第7天開始每天一次口服或經皮給藥。當
唑啉酮的施用日期和藥物的給藥日期重疊時，在施用
唑啉酮約6小時後給藥藥物。
對於所有小鼠，在第一次施用
唑啉酮前一天去除腹毛。接著，藉由使用4：1比例之丙酮/玉米油製備1%或0.2%
唑啉酮，並以如表1和圖1所示之相同劑量和排程，對經刮除的小鼠腹部和雙耳進行致敏和誘導。
[表1]
實例2：用於口服給藥的物質之製備
如下表2所示，藉由使用0.5%甲基纖維素，為給藥劑量各自製備測試物質(測試化合物和地塞松(dexamethasone)作為陽性對照組)。至於測試化合物，其係考慮到HCl鹽形式來製備。將測試物質溶解於0.5%甲基纖維素中，接著進行超音波處理。如未完全溶解，則以懸浮液狀態給藥。
實例3：用於經皮(局部)給藥的物質之製備
將其以0.1%(w/v)之濃度溶解於溶液(PEG400：100%乙醇=1：1)中來製備測試物質藉。將5毫升PEG400加入至10毫克測試物質中並進行超音波處理。當其溶解到一定程度時，將5毫升100%乙醇加入並進行超音波處理以使其完全溶解。此外，每天製備及使用新鮮的媒劑和測試物質。
[表2]
實例4：測量結果
耳朵厚度的減小是在給藥測試物質後第14天和第21天測量，且結果示於表3和圖2。在給藥測試物質後第21天，於屍檢後測量耳朵重量的減少，且結果示於表3和圖3。在給藥測試物質後第21天，測量IgE血液量級的降低，且結果示於表3和圖4。此外，在給藥測試物質後第21天，測量耳朵組織表皮厚度和肥大細胞蓄積的減少，且結果示於表3、圖5和圖6。
[表3]
從表3和圖2至圖6可以看出，在
唑啉酮誘導的異位性皮膚炎動物模型中，與地塞松(陽性對照組)相比，測試化合物以劑量依賴性方式顯示出優異的效果。由這些結果證實，本揭露之化合物可用作預防或治療異位性皮膚炎之藥物。
實例5：對比實驗
為了與另一種S1P受體促效劑進行比較，依曲莫德(2-[(3R)-7-[[4-環戊基-3-(三氟甲基)苯基」甲氧基]-1,2,3,4-四氫環戊烷[b]吲哚-3-基]乙酸)，以與實例4相同之方式測量耳朵厚度的減少、耳朵重量的減少、IgE的血液量級、上皮厚度和肥大細胞蓄積，且結果示於表4和圖7中。
[表4]
從表4和圖7可以看出，與比較化合物依曲莫德相比，即使在較低劑量下，測試化合物也表現出相同或更好的效果。從這些結果可以預期，藉由給予相同劑量以獲得更好的療效或給予較低劑量以達到特定的療效量級，可以將全身暴露引起的副作用降至最低。此外，藉由對GIRKs(G蛋白偶聯內向整流鉀離子通道)的低親和力，可預期在副作用方面具有優勢，GIRKs可藉由S1P受體促效劑誘導心跳遲緩(brachycardia)。
Claims (8)
- 一種用於預防或治療異位性皮膚炎之藥物，包含治療有效量的下式1之化合物或其藥學上可接受之鹽：
其中，X為碳或氮；R1為氫或烷基；R2為氫、烷基、鹵素、CN、CF3或COCF3；R3和R4各自獨立地為氫、烷基、鹵素、鹵烷基或烷氧烷基；R5為氫、烷基或鹵素；R6為；
R7為氫或烷基；以及m和n各自獨立地為0、1、2或3。 - 如請求項1所述的用於預防或治療異位性皮膚炎之藥物，其中，X為C或N；R1為氫或C1-C5烷基；R2為氫、C1-C5烷基、鹵素、CN、CF3或COCF3；R3和R4各自獨立地為氫、C1-C5烷基、鹵素、鹵-C1-C5烷基或C1-C5烷氧基-C1-C5烷基；R5為氫、C1-C5烷基或鹵素；R6為；
R7為氫或C1-C5烷基；以及m和n各自獨立地為0、1、2或3。 - 如請求項1所述的用於預防或治療異位性皮膚炎之藥物，其中，式1之化合物為下式2之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸：
- 如請求項1所述的用於預防或治療異位性皮膚炎之藥物，其中，該藥學上可接受之鹽選自由鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸以及萘磺酸所組成之群組。
- 一種用於預防或治療異位性皮膚炎之醫藥組成物，包含治療有效量的下式1之化合物或其藥學上可接受之鹽，以及藥學上可接受之載體：
其中，X為碳或氮；R1為氫或烷基；R2為氫、烷基、鹵素、CN、CF3或COCF3；R3和R4各自獨立地為氫、烷基、鹵素、鹵烷基或烷氧烷基；R5為氫、烷基或鹵素；R6為；
R7為氫或烷基；以及m和n各自獨立地為0、1、2或3。 - 如請求項5所述的用於預防或治療異位性皮膚炎之醫藥組成物，其中，X為C或N；R1為氫或C1-C5烷基；R2為氫、C1-C5烷基、鹵素、CN、CF3或COCF3；R3和R4各自獨立地為氫、C1-C5烷基、鹵素、鹵-C1-C5烷基或C1-C5烷氧基-C1-C5烷基；R5為氫、C1-C5烷基或鹵素；R6為；
R7為氫或C1-C5烷基；以及m和n各自獨立地為0、1、2或3。 - 如請求項5所述的用於預防或治療異位性皮膚炎之醫藥組成物，其中，式1之化合物為下式2之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸：
- 如請求項5所述的用於預防或治療異位性皮膚炎之醫藥組成物，其中，該藥學上可接受之鹽選自由鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸以及萘磺酸所組成之群組。
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