TW202220655A - 半胱天冬酶抑制劑於緩解或治療骨關節炎的用途 - Google Patents
半胱天冬酶抑制劑於緩解或治療骨關節炎的用途 Download PDFInfo
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Abstract
本發明係關於半胱天冬酶抑制劑於減輕或治療骨關節炎的用途。
Description
本發明係關於半胱天冬酶抑制劑於減輕或治療骨關節炎的用途。
半胱天冬酶係半胱氨酸蛋白酶,其係以α2β2四聚物形式存在。其中一者之半胱天冬酶-1(ICE)係一種細胞因子並參與將非活性的促介白素-1β(prointerleukin-1β)轉化為活性介白素-1β(interleukin-1β)。介白素-1包括介白素-1α和介白素-1β,這兩者均是在單核細胞中以31kDa之前驅物形式合成。只有促介白素-1β被ICE激活。將半胱天冬酶-1水解之位置為Asp27-Gly28以及Asp116-Ala117。後一位置之水解產生介白素-1β。介白素-1β據報導是引起炎症的重要介質。半胱天冬酶-1為1989年首次發現,在兩個獨立的研究小組中,藉由X光晶體學方法確定了其三維結構。
半胱天冬酶-3(CPP-32)因其作用或作用機製而被廣泛研究,並於1996年確定其三維結構。由促半胱天冬酶-3水解(P4)Asp-XX-Asp(P1)基序所激活的半胱天冬酶-3(果膠蛋白(apopain)),且已知受質包括聚(ADP-核糖)聚合酶、U1 70,000 Mr小胞核核糖核蛋白和460,000MrDNA依
賴性蛋白激酶的催化次體等。已經報導的半胱天冬酶-7的X光結構與半胱天冬酶-3非常相似。
半胱天冬酶-8和9存在於半胱天冬酶-3、6和7的上游,已知這些半胱天冬酶參與細胞凋亡級聯反應。於1999年確定半胱天冬酶-8的X光結構,特別是其抑制劑可有利地用於治療與細胞凋亡相關的疾病。
半胱天冬酶抑制劑是指抑制半胱天冬酶活性,從而控制半胱天冬酶活性引起的炎症、細胞凋亡等症狀之化合物。在半胱天冬酶抑制劑中,已知不可逆抑制劑顯示更有效的抑制活性,因其不可逆地使酶失活以控制細胞凋亡。已知癡呆、中風、糖尿病、胃潰瘍、缺血性心髒病等作為與半胱天冬酶相關的疾病。
骨關節炎是由關節軟骨和下層骨組織破壞引起的疾病,常見症狀是關節疼痛和僵硬。最初,只有在移動時才會感覺到疼痛,但隨著其變為慢性,疼痛會持續存在。迄今為止,尚無對骨關節炎的根本治療方法,且已經使用關節內類固醇鎮痛、口服或局部非甾體抗炎藥(NSAIDs)等作為對症治療。然而,在類固醇的情況下,其使用因影響身體新陳代謝之各種副作用而受到限制,如果反複使用,會逐漸產生對該效果的抵抗力。最近,一種類固醇的緩釋製劑已獲批准,但長期使用的安全性正在受到仔細監測。此外,在口服NSAID的情況下,其使用因胃腸道不良反應和心血管風險增加而受到限制。
因此,本發明的技術問題是提供一種緩解或治療骨關節炎之組成物──對此沒有根本的治療,只有緩解疼痛的對症治療──該組成物僅單次給藥即可顯示出長期的鎮痛作用以及改善軟骨功能和結構,而沒有副作用的風險或對一般使用的治療劑作用的抵抗力。
為解決上述技術問題,本發明提供一種單次給藥長效緩解或治療骨關節炎的醫藥組成物,其包含治療有效量之半胱天冬酶抑制劑和藥學上可接受的載體。
此外,本發明提供了一種長期緩解或治療骨關節炎之方法,包括將治療有效量的半胱天冬酶抑制劑以單次給藥方式給予有需要的受試者。
此外,本發明提供了半胱天冬酶抑制劑在藉由單次給藥長期緩解或治療骨關節炎中之用途。
下文將詳細說明本發明。
本發明提供一種單次給藥具有長效緩解或治療骨關節炎的醫藥組成物,其包含治療有效量的半胱天冬酶抑制劑以及藥學上可接受的載體。
半胱天冬酶抑制劑藉由干擾在細胞凋亡、壞死和炎症中起重要作用的半胱天冬酶的活性,作為肝細胞保護藥物或炎症相關疾病的治療劑而受到關注。本發明人藉由證實完成了本發明,當將半胱天冬酶抑制劑應用於骨關節炎時,其不僅可顯示長期鎮痛效果,且僅藉由單次給藥即可顯示改善軟骨結構的效果這一令人驚訝的結果。
根據本發明一實施例,半胱天冬酶抑制劑為選自尼沃卡桑(nivocasan)、IDN-1965、emricasan(恩里卡桑)、MX-1013、普拉納卡桑
(pralnacasan)、RU-36384、貝爾納卡桑(belnacasan)及其藥學上可接受之鹽,但不限於此。
尼沃卡桑是下式1之(R)-N-((2S,3S)-2-(氟甲基)-2-羥基-5-氧代四氫呋喃-3-基]-5-異丙基-3-(異喹啉-1-基)-4,5-二氫異噁唑-5-甲醯胺。
IDN-1965是下式2之3-[2(S)-(1,3-二甲基-1H-吲哚-2-基甲醯胺)-3-甲基丁醯胺]-5-氟-4-側氧戊酸。
恩里卡桑(IDN-6556)是N-(2-三級丁苯)-2-側氧甘胺醯-N-[1(S)-(羧甲基)-2-側氧-3-(2,3,5,6-四氟苯氧基)丙基]-L-丙胺醯胺。
MX-1013是下式4的N-(芐氧羰基)-L-纈胺醯基-DL-天冬胺醯氟甲烷。
普拉納卡桑是下式5的N-[2(R)-乙氧基-5-氧代四氫呋喃-3(S)-基]-9(S)-(1-異喹啉甲醯胺)-6,10-二側氧八氫-6H-噠嗪并[1,2-a][1,2]二氮呯-1(S)-甲醯胺。
RU-36384是下式6的3(S)-[9(S)-(1-異喹啉甲醯胺)-6,10-二側氧八氫-6H-噠嗪并[1,2-a][1,2]二氮呯-1(S)-基甲醯胺]-4-側氧丁酸。
貝爾納卡桑是下式7的N-(4-胺基-3-氯苯甲醯基)-3-甲基-L-纈胺醯基-N-[2(R)-乙氧基-5-氧代過氫呋喃-3(S)-基]-L-脯胺醯胺。
根據本發明的另一實施例,半胱天冬酶抑制劑為尼沃卡桑或其藥學上可接受之鹽。製備尼沃卡桑之方法在國際公開號WO2006/090997A1(公開日:2006年8月31日)中詳細描述,其藉由引用併入本文。
在本發明另一實施例中,尼沃卡桑的藥學上可接受之鹽的例子包括但不限於無機酸,如鹽酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸;有機碳酸,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;由磺酸形成的酸加成鹽,如甲磺酸、苯磺酸、對甲苯磺酸或萘磺酸。
根據本發明另一實施例,半胱天冬酶抑制劑為恩里卡桑或其藥學上可接受之鹽。
在根據本發明的另一個實施例中,長效作用是鎮痛或減輕疼痛的作用。
在根據本發明的另一實施例中,長效作用是軟骨結構改善作用。
本發明的化合物可配製為各種藥物給藥劑型。在本發明的醫藥組成物之製備中,考慮到所要製備之劑型,將活性成分──具體地,半胱天冬酶抑制劑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,本發明的醫藥組成物可根據需要配製為注射劑、口服製劑等。
在根據本發明的另一實施例中,醫藥組成物是注射製劑。在本發明中,可根據已知技術,藉由使用合適的分散劑、潤濕劑或懸浮劑來製備注射製劑──例如,用於注射的無菌水基或油基混懸劑。可用於此目的之溶劑包括水、林格氏溶液(ringer solution)和等滲透性的NaCl溶液,並且通常亦使用滅菌之固定化油作為溶劑或懸浮介質。任何非刺激性固定化油,包括甘油單酯和甘油二酯均可用於此目的,脂肪酸如油酸或聚山梨醇酯80(吐溫80(Tween 80))可用於注射製劑。
在根據本發明的另一實施例中,注射製劑為用於局部給藥
在根據本發明的另一實施例中,注射製劑為施用至關節腔中。
在根據本發明的另一實施例中,醫藥組成物的給藥效果可以持續很長時間──例如,1個月或更久、2個月或更久、3個月或更久、4個月或更久、5個月或更久,或6個月或更久。
在根據本發明的另一個實施例中,醫藥組成物的給藥間隔可以為4週或更久、5週或更久、6週或更久、7週或更久、8週或更久、9週或更久、10週或更久、11週或更久、12週或更久、13週或更久、14週或更久、15週或更久、16週或更久、17週或更久、18週或更久、19週或更久、20週或更久、21週或更久、22週或更久、23週或更久、24週或更久或25週或更久。
在根據本發明的另一實施例中,可製備醫藥組成物以用於對哺乳動物給藥。在根據本發明的另一實施例中,哺乳動物係人類。
在根據本發明的另一實施例中,個體受試者之「治療有效量」係指足以實現上述藥理作用──即如上所述之治療作用的量。化合物的量可根
據受試者的狀況和嚴重程度、給藥方式和待治療受試者的年齡而變化,但可由所屬技術領域中具有通常知識者根據其知識來確定。
在根據本發明的另一實施例中,基於游離鹼基形式,可將尼沃卡桑以1至50mg之劑量施用於人。在根據本發明的另一實施例中,可將尼沃卡桑基於游離鹼基形式以1mg或以上、2mg或以上、3mg或以上、4mg或以上、5mg或以上、6mg或以上、7mg或以上、8mg或以上、9mg或以上、10mg或以上、11mg或以上、12mg或以上、13mg或以上、14mg或以上、15mg或以上、16mg或以上、17mg或以上、18mg或以上、19mg或以上、20mg或以上、30mg或以下、31mg或以下、32mg或以下、33mg或以下、34mg或以下、35mg或以下、36mg或以下、37mg或以下、38mg或以下、39mg或39以下、40mg或以下、41mg或以下、42mg或以下、43mg或以下、44mg或以下、45mg或以下、46mg或以下、47mg或以下、48mg或以下、49mg或以下、50mg或以下或其組合之劑量對人類給藥。
在本發明中,「醫藥組成物(pharmaceutical composition)」除了本發明的有效成分外,亦可包括其他成分,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。
在本文中,「載體(carrier)」是指有助於將化合物添加至細胞或組織中之化合物。例如,二甲亞碸(DMSO)是一種一般載體,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(diluent)」是指不僅穩定生物活性形式而且在溶解化合物的溶劑中稀釋之化合物。緩衝液中的溶解鹽用作該領域之稀釋
劑。一般使用之緩衝液是模擬體液中鹽形式之磷酸鹽緩衝鹽水。由於緩衝溶液可以在低濃度下控制溶液的pH值,緩衝稀釋劑幾乎不會改變化合物的生物活性。
在本文中,「藥學上可接受的(pharmaceutically acceptable)」是指不損害化合物的生物活性和物理性質的性質。
在本文中,術語「減輕(alleviation)」是指完全或部分地改善疾病和/或其伴隨症狀。
在本文中,術語「治療(treatment)」用於表示阻止、延遲或改善表現出疾病症狀的受試者的疾病進展。
本發明之醫藥組成物可有效減輕或治療骨關節炎,沒有副作用的風險,並顯示出改善軟骨功能和結構以及僅需單次給藥即可長期鎮痛之效果對效果,而不會產生耐藥性。具體而言,在注射劑具有高侵入性和受試者感覺到的劇烈疼痛或不適的情況下,本發明之醫藥組成物──其中單次給藥可顯示長期骨關節炎緩解或治療功效,因此給藥間隔可長至例如12週或更久時間──可減輕患者的痛苦並節省成本。
圖1為測量THP-1細胞對LPS/奈及利亞菌素(nigericin)誘導的IL-1β分泌的抑制效果圖。
圖2為測量人源周邊血液單核細胞對LPS誘導的IL-1β分泌抑制效果之結果圖。
圖3為測量人源軟骨細胞中TNF-α對細胞凋亡的預防效果的結果圖。
圖4為顯示在骨關節炎動物模型中測量關節內施用尼沃卡桑後改善步行能力之功效的結果圖。
圖5為與尼沃卡桑相比,在骨關節炎動物模型中單次關節內施用恩里卡桑後測量改善步行能力之功效的結果圖。
圖6為藉由MRI評估在骨關節炎動物模型中單次關節內給藥後尼沃卡桑和恩里卡桑對關節結構之影響的結果圖。
圖7為在骨關節炎動物模型中屍檢後對關節影響的組織病理學評估的結果圖。
在下文中,藉由以下實例更詳細地解釋本發明。然而,必須理解的是,本發明的保護範圍並不限於這些實例。
實例1:在THP-1細胞中對LPS/奈及利亞菌素誘導的IL-1β分泌的抑制作用
為了評估尼沃卡桑的炎症阻斷作用,在脂多醣(LPS)/奈及利亞菌素處理誘導炎症的條件下,測量THP-1細胞中的IL-1β分泌。在LPS處理前一天,將THP-1細胞以2.5×105細胞/孔(24孔板)接種於RPMI-1640培養基中,並用0.5μM佛波醇12-肉荳蔻酸13-乙酸酯(PMA)處理,以用於隔夜培養期間的巨噬細胞分化。接著用Opti-MEM培養基更換培養基,並將細胞與LPS 100ng/ml(用於促-IL-1β上調之第一個炎症信號)孵育24小時。然後將細
胞用PBS洗滌兩次,並在Opti-MEM培養基中用尼沃卡桑或DMSO處理30分鐘,隨後與5μM奈及利亞菌素和1mM ATP孵育1小時以激活炎性體(NLRP3激活和IL-1β分泌)。藉由使用R&D Systems Quantikine人類IL-1β(偵測極限:7.8pg/ml)測量細胞培養基中分泌的IL-1β,結果如圖1所示。從圖1中可以看出,其已證實尼沃卡桑以劑量依賴性方式抑制THP-1細胞中LPS/奈及利亞菌素誘導的IL-1β分泌。
實例2:在人源PBMC中對LPS誘導的IL-1β分泌的抑制作用
藉由測量LPS誘導的IL-1β分泌來評估尼沃卡桑對人類周邊血液單核細胞(PBMC)炎症小體激活之抑製作用。將新鮮分離的PBMC以2.5×105細胞/孔(24孔板)接種於RPMI-1640培養基中,並用尼沃卡桑或DMSO處理30分鐘,然後與100ng/ml LPS孵育24小時以誘導炎症。藉由ELISA(R&D Systems Quantikine人類IL-1β;偵測極限:7.8pg/ml)測量PBMC上清液中IL-1β的水平,結果如圖2所示。從圖2中可以看出,其已證實尼沃卡桑以劑量依賴性方式抑制LPS誘導的PBMC之IL-1β分泌,在0.3μM時顯示出最大作用。
實例3:對人源軟骨細胞中TNF-α誘導的細胞凋亡的保護作用
在人類軟骨細胞中評估了尼沃卡桑對TNF-α誘導的細胞凋亡的保護作用。將人類正常軟骨細胞以1×105細胞/孔(膠原包被的24孔板)接種於軟骨細胞培養基(Prigrow IV培養基,Applied Biological Materials Inc.)中並孵育過夜。細胞用尼沃卡桑或DMSO處理30分鐘,隨後與10ng/ml人類重組TNF-α和1μg/ml放線菌素D孵育18小時以誘導細胞凋亡。使用細胞死亡檢測
ELISA試劑盒測量細胞凋亡,結果如圖3所示。從圖3中可以看出,其已證實尼沃卡桑以劑量依賴性方式阻止TNF-α誘導的人軟骨細胞凋亡。
實例4:骨關節炎動物模型步行能力改善效果評價
比格犬購自Orient Bio,且健康動物經過一週的檢疫循環後用於實驗。
前交叉韌帶橫斷加內側半月板切除術後恢復1週後,每天強制運動30分鐘,誘發骨關節炎。誘發骨關節炎的手術在動物雙膝脫毛後麻醉下進行。用聚維酮和70%乙醇對切口部位進行廣泛消毒後,切開右膝皮膚。藉由鈍性解剖周圍組織,暴露股骨遠端的關節面。在內側關節面上創建一個器械入口,切除半月板和前交叉韌帶。藉由使用4-0尼龍縫合線進行傷口閉合。在左膝的情況下,僅橫斷前交叉韌帶。對於正常(假)組的動物,切開並縫合雙膝,未切除半月板或前交叉韌帶。手術後服用抗生素和鎮痛藥7天。從手術後第7天,每天強制運動30分鐘,直到施用受試物質的前一天。
用於評價骨關節炎動物疼痛狀態和功能水平的步行能力評估按照Pashuck等人提出的方法進行。(Troy D.Pashuck et al.,J Orthop Res,2016,34(10):1772-1779),並記錄表1中的跛行評分直至實驗結束。
當骨關節炎誘發的比格犬跛足評分達到平均3.5或更高時,將狗分成每組5隻狗之組,每組平均值一致。藉由在單次關節內給藥後每週兩次評估跛足評分來測量尼沃卡桑在骨關節炎動物模型中的功效。藉由將0.1、0.3、1、3或10mg受試物質溶解在1mL含有0.4%(重量比)聚山梨醇酯80(吐溫80)和0至25mM NaOH溶液,且最終pH值為7.0至7.4。將0.1、0.3、1、3和10mg/膝劑量的培養基或尼沃卡桑溶液給藥至每隻動物的關節腔中。麻醉動物後,使用C型臂(Siemens)將尼沃卡桑注射液注入右膝關節腔。
對骨關節炎動物模型中單次關節內給藥提高尼沃卡桑步行能力的療效進行評估,每週進行兩次,持續3個月,結果如圖4所示。從圖4中可以看出,其已證實尼沃卡桑以劑量依賴的方式顯示出改善步行能力的功效,該功效持續長達3個月。
在前交叉韌帶橫斷與內側半月板切除術後恢復1週後每天強迫運動30分鐘誘發的骨關節炎狗模型中,如圖5所示,單次關節內給藥10mg恩里卡桑,一種泛半胱天冬酶抑制劑,顯示出與10毫克尼沃卡桑相似的步行能力改善。
實例5:MRI對骨關節炎動物模型中關節結構影響的評價
在前交叉韌帶橫斷術與內側半月板切除術後每天強迫運動誘發骨關節炎的比格犬模型中,藉由在單次關節內給藥之前和之後3個月對關節進行MRI(SIGNA Pioneer 3.0T MR,GE Healthcare Co.,USA)評估對關節結構的影響。根據Hunter等人提出的方法評估試驗物質對關節結構的影響。(DavidJ.Hunteretal.,OsteoarthritisandCartilage2011,19,990-1002)如表2所示。
在骨關節炎動物模型中,單次關節內給藥前後的3個月比較MRI時,尼沃卡桑和恩里卡桑,泛半胱天冬酶抑制劑,顯示骨髓病變和滑膜炎有所改善。
實例6:骨關節炎動物模型中對關節影響的組織病理學評價
在前交叉韌帶橫斷加內側半月板切除術後每日強迫運動誘發骨關節炎的比格犬模型中,在單次關節內給藥後3個月進行屍檢,收集並固定關節。固定後的組織進行脫礦、修整、脫水、石蠟包埋、切片等一般組織處理,製備組織病理學檢查標本,隨後進行蘇木精伊紅和番紅染色。使用光學顯微鏡(Olympus BX53,日本)觀察組織病理學變化。
根據Cook等人提出的方法,藉由比較組間評分進行組織病理學評估,如表3至表8所示(Cook et al.,Osteoarthritis Cartilage.2010;18 Suppl 3:S66-S79),結果如圖7所示。
從圖7中可以看出,在單次關節內給藥尼沃卡桑後3個月,藉由屍檢收集的關節的組織病理學評估證實劑量相關的組織病理學改善。
從實例4至6的上述結果證實,即使單次給藥,無需重複給藥或緩釋製劑,尼沃卡桑不僅能有效提高步行能力,這反映出至少3個月或更久時間的長期鎮痛效果,且因其抗炎作用,亦能有效改善軟骨結構。
Claims (20)
- 一種用於減輕或治療骨關節炎之醫藥組成物,該醫藥組成物單次給藥具有長效作用,其包含治療有效量之半胱天冬酶抑制劑以及藥學上可接受之載體。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該半胱天冬酶抑制劑選自尼沃卡桑、IDN-1965、恩里卡桑、MX-1013、普拉納卡桑、RU-36384、貝爾納卡桑及其藥學上可接受之鹽。
- 如請求項2所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該半胱天冬酶抑制劑為尼沃卡桑或其藥學上可接受之鹽。
- 如請求項2所述之用於減輕或治療骨關節炎的醫藥組成物,其中,該尼沃卡桑之藥學上可接受之鹽選自鹽酸、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。
- 如請求項2所述的用於緩解或治療骨關節炎之醫藥組成物,其中,該半胱天冬酶抑制劑為恩里卡桑或其藥學上可接受之鹽。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該長效作用為鎮痛或減輕疼痛的作用。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該長效作用是軟骨結構改善作用。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其為注射劑。
- 如請求項8所述之用於減輕或治療骨關節炎的醫藥組成物,其中,該注射劑係用於局部給藥。
- 如請求項9所述之用於減輕或治療骨關節炎的醫藥組成物,其中,該注射劑為施用至關節腔內。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該給藥效果持續1個月或更久。
- 如請求項11所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該給藥效果持續3個月或更久。
- 如請求項12所述之用於緩解或治療骨關節炎之醫藥組成物,其中,該給藥效果持續6個月或更久。
- 如請求項1所述之用於緩解或治療骨關節炎之醫藥組成物,其係以4週或以更久間隔給藥。
- 如請求項14所述之用於緩解或治療骨關節炎之醫藥組成物,其係以8週或更久之間隔給藥。
- 如請求項15所述之用於減輕或治療骨關節炎的醫藥組成物,其係以12週或更久之間隔給藥。
- 如請求項16所述之用於減輕或治療骨關節炎的醫藥組成物,其係以24週或更久之間隔給藥。
- 如請求項1所述之用於減輕或治療骨關節炎的醫藥組成物,其係用於對哺乳動物給藥。
- 如請求項18所述之用於減輕或治療骨關節炎的醫藥組成物,其中,該哺乳動物係人類。
- 如請求項3所述之用於減輕或治療骨關節炎的醫藥組成物,其中,該尼沃卡桑基於游離鹼基形式,以1至50mg之劑量對人類給藥。
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US (1) | US20230310412A1 (zh) |
EP (1) | EP4173622A4 (zh) |
JP (1) | JP2023537012A (zh) |
KR (1) | KR20220017851A (zh) |
CN (1) | CN116113413A (zh) |
AU (1) | AU2021321068A1 (zh) |
BR (1) | BR112022026725A2 (zh) |
CA (1) | CA3185212A1 (zh) |
MX (1) | MX2023000230A (zh) |
TW (1) | TW202220655A (zh) |
WO (1) | WO2022030987A1 (zh) |
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AR026748A1 (es) * | 1999-12-08 | 2003-02-26 | Vertex Pharma | Un compuesto inhibidor de caspasas, una composicion farmaceutica que lo comprende, un metodo para la sintesis del mismo y un compuesto intermediario paradicha sintesis |
US7411000B2 (en) * | 2001-03-15 | 2008-08-12 | The Scripps Research Institute | Process of inhibiting cell death in injured cartilage |
KR100774999B1 (ko) | 2005-02-26 | 2007-11-09 | 주식회사 엘지생명과학 | 이소옥사졸린 유도체 및 그의 제조 방법 |
GB201213968D0 (en) * | 2012-08-06 | 2012-09-19 | Isis Innovation | Prevention and treatment of osteoarthritis |
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- 2021-08-04 KR KR1020210102476A patent/KR20220017851A/ko not_active Application Discontinuation
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CA3185212A1 (en) | 2022-02-10 |
MX2023000230A (es) | 2023-02-09 |
US20230310412A1 (en) | 2023-10-05 |
BR112022026725A2 (pt) | 2023-02-14 |
AU2021321068A1 (en) | 2023-02-02 |
EP4173622A1 (en) | 2023-05-03 |
JP2023537012A (ja) | 2023-08-30 |
CN116113413A (zh) | 2023-05-12 |
WO2022030987A1 (ko) | 2022-02-10 |
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