TWI821235B - 以ccr6或cxcr2之拮抗劑治療廣泛性膿疱型乾癬之方法 - Google Patents
以ccr6或cxcr2之拮抗劑治療廣泛性膿疱型乾癬之方法 Download PDFInfo
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- TWI821235B TWI821235B TW108100708A TW108100708A TWI821235B TW I821235 B TWI821235 B TW I821235B TW 108100708 A TW108100708 A TW 108100708A TW 108100708 A TW108100708 A TW 108100708A TW I821235 B TWI821235 B TW I821235B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
本發明尤其提供一種藉由投與有效量之趨化介素受體6 (CCR6)拮抗劑及/或C-X-C基元趨化介素受體2 (CXCR2)拮抗劑來治療廣泛性膿疱型乾癬(GPP)之方法。本發明亦提供一種調節有需要個體中失調IL-36信號傳導之方法,及減少有需要個體中嗜中性球、發炎性樹突狀細胞(iDC)及/或CD4 T細胞積聚之方法,該等方法包括投與有效量之趨化介素受體6 (CCR6)拮抗劑及/或C-X-C基元趨化介素受體2 (CXCR2)拮抗劑。在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
Description
廣泛性膿疱型乾癬(Generalized pustular psoriasis,GPP)係一種罕見疾病,對此疾病缺乏臨床研究且其治療及處理並無可普遍接受之循證準則(Benjegerdes等人Psoriasis ( Auckl )
2016;6:131-44.)。對較常見斑塊形式之乾癬有效之生物療法對GPP並無效(Benjegerdes等人Psoriasis ( Auckl )
2016;6:131-44,Mansouri等人Expert Opin Biol Ther
2013;13(12):1715-30),且尚未研發許多直接靶向GPP之所需治療(Mahil等人Semin Immunopathol
2016;38(1):11-27,Navarini等人 J Eur Acad Dermatol Venereol 2017;31(11):1792-9,Robinson等人 J Am Acad Dermatol 2012;67(2):279-88。
本發明解決對靶向且改善GPP症狀之有前景之療法之需求,且亦提供相關優勢。
本發明提供治療廣泛性膿疱型乾癬(GPP)、掌蹠乾癬(PPP)、急性廣泛性發疹性膿疱病(AGEP)、化膿性汗腺炎(HS)、疱疹樣皮炎及/或尋常天疱瘡之方法,該方法包含投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。
在另一態樣中,本文提供調節有需要個體中失調IL-36信號傳導之方法,該方法包含向個體投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。
在另一態樣中,本文提供減少有需要個體中嗜中性球、發炎性樹突狀細胞(iDC)及/或CD4 T細胞積聚之方法,該方法包含向個體投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。
在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
其中各變數在下文描述。
在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
其中各變數在下文描述。
在一些實施例中,CCR6及/或CXCR2拮抗劑係圖1中所示之化合物。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.129:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.123:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.136:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.138:
或其醫藥學上可接受之鹽。
相關申請案之交叉參考
本申請案主張根據35U.S.C.§119(e)之2018年1月8日申請之美國臨時申請案第62/614,927號及2018年8月7日申請之美國臨時申請案第62/715,503號之優先權,各者之揭示內容以全文引用之方式併入本文中。
綜述
廣泛性膿疱型乾癬(GPP)係罕見發炎性皮膚病症,其病因不同於較常見的斑塊型乾癬。GPP患者通常對典型用於斑塊型乾癬之治療劑不會有反應。先前已展示包括本文所揭示之化合物的CCR6及/或CXCR2之拮抗劑可改善斑塊型乾癬之模型中之炎症。出人意料地,本發明表明CCR6及/或CXCR2之拮抗劑可用以有效治療廣泛性膿疱型乾癬(GPP)。除治療GPP以外,諸如掌蹠乾癬(PPP)、急性廣泛性發疹性膿疱病(AGEP)、化膿性汗腺炎(HS)、疱疹樣皮炎及尋常天疱瘡之相關疾病亦可使用本文所述方法處理。
趨化介素導引之療法經設計以阻斷發炎性白細胞自周邊血液向組織中之遷移,因此阻止該等細胞參與及擴大任何現有的自體免疫性病變,由此使發炎性細胞介素環境消失。遺傳研究表明GPP與IL-36細胞介素軸之功能障礙強烈相關,且GPP之許多態樣可藉由皮內注射預先活化之IL-36α細胞介素在小鼠中再現。本發明表明浸潤注射IL-36α之小鼠皮膚的免疫細胞之組成明顯不同於浸潤經咪喹莫特(IMQ)處理之皮膚(一種Balb/c小鼠中之可接受的斑塊型乾癬模型)的彼等免疫細胞。本文所揭示之研究結果表明CCR6及CXCR2拮抗劑可構成治療GPP以及相關PPP、AGEP、HS、疱疹樣皮炎及尋常天疱瘡疾病之機理不同的治療性方法之新穎標靶類別。
縮寫及定義
除非另外指示,否則以下術語意欲具有以下闡述之含義。其他術語在整個說明書中在他處加以定義。
除非另外陳述,否則術語「烷基」本身或作為另一取代基之一部分意謂具有指定數量之碳原子之直鏈或分支鏈烴基(亦即C1 - 8
意謂一至八個碳)。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、正戊基、正己基、正庚基、正辛基及其類似烷基。
術語「環烷基」係指具有指定數目之環原子(例如C3 - 6
環烷基)且完全飽和或在環頂點之間具有不超過一個雙鍵的烴環。「環烷基」亦意指雙環及多環烴環,諸如雙環[2.2.1]庚烷、雙環[2.2.2]辛烷等。
術語「環雜烷基」係指具有指定數目之環頂點(或成員)且具有一至五個選自N、O及S之雜原子置換一至五個碳頂點,且其中氮及硫原子視情況經氧化,且氮原子視情況經四級銨化之環烷基環。環雜烷基可為單環、雙環或多環環系統。環雜烷基之非限制性實例包括吡咯啶、咪唑啶、吡唑啶、丁內醯胺、戊內醯胺、咪唑啶酮、乙內醯脲、二氧雜環戊烷、鄰苯二甲醯亞胺、哌啶、1,4-二噁烷、嗎啉、硫代嗎啉、硫代嗎啉-S-氧化物、硫代嗎啉-S,S-氧化物、哌嗪、哌喃、吡啶酮、3-吡咯啉、硫代哌喃、吡喃酮、四氫呋喃、四氫噻吩、啶及其類似基團。環雜烷基可經由環碳或雜原子連接至分子之其餘部分。
如本文所用,在本文所描述之任何化學結構中與單鍵、雙鍵或參鍵相交之波浪線「」表示單鍵、雙鍵或參鍵與分子之其餘部分之連接點。另外,延伸至環(例如苯環)之中心之鍵意謂指示在可用環頂點中之任一者處之連接。熟習此項技術者應理解顯示為連接至環之多個取代基將佔據提供穩定化合物且另外空間相容之環頂點。對於二價組分,表示意謂包括任一定向(正向或反向)。舉例而言,基團「-C(O)NH-」意謂包括在任一定向上之鍵:-C(O)NH-或-NHC(O)-,且類似地「-O-CH2
CH2
-」意謂包括-O-CH2
CH2
-與-CH2
CH2
-O-。
術語「烷氧基」、「烷基胺基」及「烷基硫基」(或硫代烷氧基)以其習知含義使用,且係指分別經由氧原子、胺基或硫原子連接至分子之其餘部分之彼等烷基。另外,對於二烷基胺基,烷基部分可相同或不同且亦可與其各自所連接之氮原子組合以形成3至7員環。因此,表示為二烷基胺基或-NRa
Rb
之基團意謂包括哌啶基、吡咯啶基、嗎啉基、氮雜環丁烷基及其類似基團。
除非另外陳述,否則術語「鹵基」或「鹵素」本身或作為另一取代基之一部分意謂氟、氯、溴或碘原子。另外,諸如「鹵烷基」之術語意謂包括單鹵烷基及多鹵烷基。舉例而言,術語「C1 - 4
鹵烷基」意謂包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基及其類似基團。
除非另外陳述,否則術語「芳基」意謂多不飽和,通常芳族之烴基,其可為單環或稠合在一起或共價連接之多個環(至多三個環)。芳基之非限制性實例包括苯基、萘基及聯苯。
術語「雜芳基」係指含有一至五個選自N、O及S之雜原子之芳基(或環),其中氮及硫原子視情況經氧化,且氮原子視情況經四級銨化。雜芳基可經由雜原子連接至分子之其餘部分。雜芳基之非限制性實例包括吡啶基、噠嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、㖕啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并異噁唑基、異苯并呋喃基、異吲哚基、吲哚嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、異喹啉基、異噻唑基、吡唑基、吲唑基、喋啶基、咪唑基、三唑基、四唑基、噁唑基、異噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基及其類似基團。雜芳基環之取代基可選自下文描述之可接受取代基之群。
在一些實施例中,以上術語(例如「烷基」、「芳基」及「雜芳基」)將視情況經取代。以下提供各類基團之所選取代基。
烷基之視情況選用之取代基(包括彼等通常稱為伸烷基、烯基、炔基及環烷基之基團)可為選自以下之多種基團:鹵素、-OR'、-NR'R''、-SR'、-SiR'R''R'''、-OC(O)R'、-C(O)R'、-CO2
R'、-CONR'R''、-OC(O)NR'R''、-NR''C(O)R'、-NR'-C(O)NR''R'''、-NR''C(O)2
R'、-NH-C(NH2
)=NH、-NR'C(NH2
)=NH、-NH-C(NH2
)=NR'、-S(O)R'、-S(O)2
R'、-S(O)2
NR'R''、-NR'S(O)2
R''、-CN及-NO2
,其數目在零至(2m'+1)範圍內,其中m'係此類基團中碳原子之總數。R'、R''及R'''各自獨立地指氫、未經取代之C1 - 8
烷基、未經取代之芳基、經1至3個鹵素取代之芳基、未經取代之C1 - 8
烷基、C1 - 8
烷氧基或C1 - 8
硫代烷氧基或未經取代之芳基-C1 - 4
烷基。當R'及R''連接至同一氮原子時,其可與氮原子組合以形成3員、4員、5員、6員或7員環。舉例而言,-NR'R''意謂包括1-吡咯啶基及4-嗎啉基。
類似地,芳基及雜芳基之視情況選用之取代基不同且一般選自以下各者:-鹵素、-OR'、-OC(O)R'、-NR'R''、-SR'、-R'、-CN、-NO2
、-CO2
R'、-CONR'R''、-C(O)R'、-OC(O)NR'R''、-NR''C(O)R'、-NR''C(O)2
R'、-NR'-C(O)NR''R'''、-NH-C(NH2
)=NH、-NR'C(NH2
)=NH、-NH-C(NH2
)=NR'、-S(O)R'、-S(O)2
R'、-S(O)2
NR'R''、-NR'S(O)2
R''、-N3
、全氟(C1
-C4
)烷氧基及全氟(C1
-C4
)烷基,其數目在零至芳族環系統上開放價數之總數範圍內;且其中R'、R''及R'''獨立地選自氫、C1 - 8
烷基、C1 - 8
鹵烷基、C3 - 6
環烷基、C2 - 8
烯基及C2 - 8
炔基。其他適合的取代基包括藉由1至4個碳原子之伸烷基繫鏈連接於環原子之以上芳基取代基中之各者。
芳基或雜芳基環之相鄰原子上的取代基中之兩者可視情況經式-T-C(O)-(CH2
)q
-U-之取代基置換,其中T及U獨立地係-NH-、-O-、-CH2
-或單鍵,且q係0至2之整數。或者,芳基或雜芳基環之相鄰原子上的取代基中之兩者可視情況經式-A-(CH2
)r
-B-之取代基置換,其中A及B獨立地係-CH2
-、-O-、-NH-、-S-、-S(O)-、-S(O)2 -
、-S(O)2
NR'-或單鍵,且r係1至3之整數。由此形成之新穎環之單鍵中之一者可視情況經雙鍵置換。或者,芳基或雜芳基環之相鄰原子上之取代基中之兩者可視情況經式-(CH2
)s
-X-(CH2
)t
-之取代基置換,其中s及t獨立地係0至3之整數,且X係-O-、-NR'-、-S-、-S(O)-、-S(O)2
-或-S(O)2
NR'-。-NR'-及-S(O)2
NR'-中之取代基R'係選自氫或未經取代之C1 - 6
烷基。
如本文所用,術語「雜原子」意謂包括氧(O)、氮(N)、硫(S)及矽(Si)。
當任何變數(例如R1
或Ra
)在任何化合物或取代基中出現一次以上時,其在每次出現時之定義獨立於其在其他每次出現時之定義。另外,取代基及/或變數之組合僅在此類組合產生穩定化合物時為容許的。
術語「醫藥學上可接受之鹽」意謂包括視本文中所述之化合物上所存在之特定取代基而定,利用相對無毒之酸或鹼製備之活性化合物的鹽。當本發明化合物含有相對酸性官能基時,可藉由使此類化合物之中性形式與足夠量之所需鹼在無溶劑下或在適合的惰性溶劑中接觸來獲得鹼加成鹽。自醫藥學上可接受之無機鹼衍生的鹽之實例包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、亞錳鹽、鉀鹽、鈉鹽、鋅鹽及其類似鹽。衍生自醫藥學上可接受之有機鹼的鹽包括一級、二級及三級胺之鹽,包括經取代之胺、環狀胺、天然產生之胺及其類似物,諸如精胺酸、甜菜鹼、咖啡因、膽鹼、N,N'-二苯甲基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺、葡糖胺、組胺酸、海卓胺、異丙胺、離胺酸、甲基葡糖胺、嗎啉、哌嗪、哌啶、多元胺樹脂、普魯卡因(procaine)、嘌呤、可可豆鹼、三乙胺、三甲胺、三丙胺、緩血酸胺及其類似物。當本發明之化合物含有相對鹼性的官能基時,酸加成鹽可藉由使此類結合物的中性形式與足夠量之所需酸在無溶劑下或在適合的惰性溶劑中接觸來獲得。醫藥學上可接受之酸加成鹽之實例包括衍生自無機酸之彼等酸加成鹽,該等無機酸如鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及其類似物;以及衍生自相對無毒性有機酸之鹽,該等有機酸如乙酸、丙酸、異丁酸、丙二酸、苯甲酸、丁二酸、辛二酸、反丁烯二酸、杏仁酸、鄰苯二甲酸、苯磺酸、對甲苯基磺酸、檸檬酸、酒石酸、甲磺酸及其類似物。亦包括諸如精胺酸及其類似酸之胺基酸的鹽,及如葡糖醛酸或半乳糖醛酸及其類似物之有機酸的鹽(參見例如Berge, S.M.等人, 「Pharmaceutical Salts」,Journal of Pharmaceutical Science
,1977
,66
, 1-19)。本發明之某些特定化合物含有允許化合物轉化成鹼加成鹽或酸加成鹽之鹼性與酸性官能基。
化合物之中性形式可藉由使鹽與鹼或酸接觸且以習知方式分離母體化合物而再生。化合物之母體形式與各種鹽形式的不同之處在於某些物理特性,諸如在極性溶劑中之溶解性,但出於本發明之目的,在其他方面,鹽等效於化合物之母體形式。
除鹽形式以外,本發明提供呈前藥形式之化合物。本文所述之化合物之前藥為容易在生理條件下經歷化學變化以提供本發明化合物之彼等化合物。另外,前藥可藉由化學方法或生物化學方法在離體環境中轉化成本發明化合物。舉例而言,當前藥與適合的酶或化學試劑一起置於經皮貼片儲集層中時,其可緩慢轉化成本發明化合物。
某些本發明化合物可以未溶劑化形式及溶劑化形式(包括水合形式)存在。一般而言,溶劑化形式等效於未溶劑化形式,且意欲包涵於本發明範疇內。本發明之某些化合物可以多種結晶形式或非晶形式存在。一般來說,所有物理形式皆等同地用於本發明涵蓋之用途且意欲在本發明範疇內。
某些本發明化合物具有不對稱碳原子(光學中心)或雙鍵;外消旋體、非對映異構體、幾何異構體、區位異構體及個別異構體(例如個別對映異構體)均意欲涵蓋於本發明之範疇內。當顯示立體化學描述時,其意指存在異構體中之一者且實質上不含其他異構體之化合物。『實質上不含』另一異構體指示兩種異構體之至少80/20比率,更佳90/10或95/5或更高。在一些實施例中,異構體中之一者將以至少99%之量存在。
本發明化合物亦可在構成此類化合物之原子中之一或多者處含有非天然比例之原子同位素。非天然比例之同位素可定義為在於自然界中發現之量至由100%所討論之原子組成之量的範圍內。舉例而言,化合物可併入有放射性同位素,諸如氚(3
H)、碘-125 (125
I)或碳-14 (14
C);或非放射性同位素,諸如氘(2
H)或碳-13 (13
C)。此等同位素變體可為在本申請案內他處描述之彼等者提供額外效用。舉例而言,本發明化合物之同位素變體可發現額外效用,包括(但不限於)作為診斷及/或成像試劑或作為細胞毒性/輻射毒性治療劑。另外,本發明化合物之同位素變體可具有改變之藥物動力學及藥效學特徵,其可有助於治療期間增強之安全性、耐受性或功效。本發明化合物之所有同位素變體無論是否具放射性均意欲涵蓋於本發明之範疇內。
術語「患者」或「個體(subject)」可互換使用且係指人類或非人類動物(例如哺乳動物)。
術語「投與(administration/administer)」及其類似術語在其應用於例如個體、細胞、組織、器官或生物流體時係指使例如CCR6及/或CXCR2之拮抗劑、包含其之醫藥組合物或診斷劑與個體、細胞、組織、器官或生物流體接觸。在細胞之情況下,投與包括使試劑與細胞接觸(例如活體外或離體),以及使試劑與流體接觸,其中該流體與細胞接觸。
術語「治療(treat/treating/treatment)」及其類似術語係指在疾病、病症或病狀或其症狀已經診斷、觀測及其類似者之後起始以便暫時或永久地消除、減輕、抑制、緩解或改善折磨個體之疾病、病症或病狀之根本病因中之至少一者或與折磨個體之疾病、病症、病狀相關之症狀中之至少一者的作用過程(諸如投與CCR6及/或CXCR2之拮抗劑或包含其之醫藥組合物)。因此,治療包括抑制(例如阻止疾病、病症或病狀或與其相關之臨床症狀之發展或進一步發展)活動性疾病。
如本文所用,術語「需要治療」係指由醫師或其他照護者作出的個體需要或將受益於治療之判斷。此判斷係基於在醫師或照護者之專門知識範圍內的多種因素作出。
術語「預防(prevent/preventing/prevention)」及其類似術語係指一般在個體易患特定疾病、病症或病狀之情況下,以暫時或永久地預防、遏制、抑制或減輕個體罹患疾病、病症、病狀或其類似者之風險(如藉由例如臨床症狀之不存在確定)或延遲其發作之方式起始(例如在疾病、病症、病狀或其症狀發作之前)的作用過程(諸如投與CCR6及/或CXCR2之拮抗劑或包含其之醫藥組合物)。在某些情況下,術語亦指減緩疾病、病症或病狀發展或抑制其發展成有害或者不希望的病況。
如本文所用,術語「需要預防」係指由醫師或其他照護者作出的個體需要或將受益於預防性護理之判斷。此判斷係基於在醫師或照護者之專門知識範圍內的多種因素作出。
片語「治療有效量」係指向個體投與單獨或作為醫藥組合物之一部分且呈單一劑量或作為一系列劑量之一部分的藥劑,其呈當向個體投與時能夠對疾病、病症或病狀之任何症狀、態樣或特徵具有任何可偵測的積極效果之量。治療有效量可藉由量測相關生理效果確定,且其可結合給藥方案及個體病狀之診斷分析及其類似者進行調整。舉例而言,投與後特定時間之CCR6及/或CXCR2之拮抗劑(或例如其代謝物)之血清含量量測可指示是否已使用治療有效量。
片語「呈影響變化之足夠量」意謂在投與特定療法之前(例如基線水準)及之後在量測之指示物含量之間存在可偵測差異。指示物包括任何客觀參數(例如血清濃度)或主觀參數(例如個體之健康感覺)。
術語「小分子」係指分子量小於約10 kDa,小於約2 kDa,或小於約1 kDa之化合物。小分子包括(但不限於)無機分子、有機分子、含有無機組分之有機分子、包含放射性原子之分子及合成分子。治療學上,與大分子相比,小分子更易滲透過細胞、不易降解,且不大可能引發免疫反應。
術語「抑制劑」及「拮抗劑」或「活化劑」及「促效劑」分別係指例如用於活化例如配位體、受體、輔因子、基因、細胞、組織或器官之抑制或活化分子。抑制劑係減少、阻斷、防止、延遲活化、不活化、脫敏或下調例如基因、蛋白質、配體、受體或細胞之分子。活化劑係增加、活化、促進、增強活化、敏化或上調例如基因、蛋白質、配體、受體或細胞之分子。抑制劑亦可定義為降低、阻斷或不活化組成活性之分子。「促效劑」係與標靶相互作用以引起或促進標靶活化增加之分子。「拮抗劑」係對抗促效劑之作用的分子。拮抗劑防止、降低、抑制或抵消促效劑之活性,且拮抗劑亦可防止、抑制或減輕標靶(例如標靶受體)之固有活性,甚至當不存在經鑑定促效劑時亦如此。
術語「調節(modulate/modulation)」及其類似術語係指分子(例如活化劑或抑制劑)直接或間接增加或降低CCR6及/或CXCR2之功能或活性之能力。調節劑可單獨起作用,或其可使用輔因子,例如蛋白質、金屬離子或小分子。
分子之「活性」可描述或指分子與受體之結合;催化活性;刺激基因表現或細胞信號傳導、分化或成熟之能力;抗原活性;其他分子活性之調節;及其類似情況等等。
如本文所使用,「相當的」、「相當的活性」、「與…相當的活性」、「相當的效果」、「與…相當的效果」以及其類似術語為可以定量及/或定性方面而言之相對術語。術語之含義通常視其使用之上下文而定。舉例而言,均活化受體之兩種藥劑可自定性觀點視為具有類似效果,但若如在技術接受之分析(例如劑量反應分析)或技術接受之動物模型中所測定,一種藥劑僅能夠達到另一藥劑之活性之20%,則兩種藥劑可自定量觀點視為缺乏類似效果。當將一種結果與另一結果(例如一種結果與參考標準)比較時,「相當的」通常(儘管未必總是)意謂一種結果與參考標準偏差小於35%、小於30%、小於25%、小於20%、小於15%、小於10%、小於7%、小於5%、小於4%、小於3%、小於2%或小於1%。在特定實施例中,若一個結果與參考標準偏差小於15%、小於10%或小於5%,則其與參考標準相當。舉例而言(但不限制),活性或效果可指功效、穩定性、溶解性或免疫原性。
「實質上純」指示組分佔組合物之總含量之大於約50%,且通常組合物之總含量之大於約60%。更通常,「實質上純」係指其中總組合物之至少75%、至少85%、至少90%或更多係所關注組分之組合物。在一些情況下,所關注組分佔組合物總含量之大於約90%或大於約95%。
實施例之詳細描述
使用方法
本文提供使用趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑來防止、降低或維持白血球積聚(諸如嗜中性球、發炎性樹突狀細胞(iDC)及/或CD4 T細胞積聚)、處理及調節與IL-36失調相關之疾病及治療諸如廣泛性膿疱型乾癬(GPP)、掌蹠乾癬(PPP)、急性廣泛性發疹性膿疱病(AGEP)、化膿性汗腺炎(HS)、疱疹樣皮炎及尋常天疱瘡之疾病之方法。如本文所述,本發明表明趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑有效調節通常在經歷IL-36失調之個體中觀察到之白血球遷移。投與趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)有效改善此等個體中之炎症。
因此,在一個態樣中,本發明提供治療選自廣泛性膿疱型乾癬(GPP)、掌蹠乾癬(PPP)、急性廣泛性發疹性膿疱病(AGEP)、化膿性汗腺炎(HS)、疱疹樣皮炎或尋常天疱瘡之疾病或病狀之方法,該方法包含投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。
在一些實施例中,疾病或病狀係廣泛性膿疱型乾癬(GPP)。在一些實施例中,疾病或病狀係掌蹠乾癬(PPP)。在一些實施例中,疾病或病狀係急性廣泛性發疹性膿疱病(AGEP)。在一些實施例中,疾病或病狀係化膿性汗腺炎(HS)。在一些實施例中,疾病或病狀係疱疹樣皮炎。在一些實施例中,疾病或病狀係尋常天疱瘡。
在另一態樣中,本文提供調節有需要個體之失調IL-36信號傳導之方法,該方法包含向個體投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。
在另一態樣中,本文提供減少有需要個體之嗜中性球、發炎性樹突狀細胞(iDC)及/或CD4 T細胞積聚之方法,其包含向個體投與有效量之趨化介素受體6 (CCR6)及/或C-X-C基元趨化介素受體2 (CXCR2)之拮抗劑。CCR6 及 / 或 CXCR2 之拮抗劑
在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
其中
B選自由以下組成之群:呋喃基、噻吩基、噁唑基、苯基、吡啶基、嘧啶基及吡嗪基,其各自視情況經R1a
、R1b
及R2
取代,該R1a
、R1b
及R2
獨立地選自由以下組成之群:鹵素、CN、C1 - 4
烷基、C1 - 4
烷氧基及C1 - 4
鹵烷基;
R3
係選自由H及D組成之群的成員;
R4
係選自由以下組成之群的成員:H、C1 - 8
烷基、OH、-NRa
Rb
、-C1 - 4
烷氧基及Y;其中C1 - 8
烷基視情況經以下取代:鹵素、-CN、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
及Y,其中Y係4員至8員環雜烷基或3員至8員環烷基或5員或6員芳基或雜芳基,其中任一者視情況經1至四個選自以下之取代基取代:鹵素、側氧基、-CN、-C1 - 6
烷基、-C1 - 6
烷氧基、-C1 - 6
羥烷基、-C1 - 6
鹵烷基、O-C1 - 6
鹵烷基、-C1 - 4
烷基-O-C1 - 4
烷基、-C1 - 6
烷基-NRa
Rb
、-C1 - 6
烷基-CO2
H、-C1 - 6
烷基-CO2
Ra
、-C1 - 6
烷基-CONRa
Rb
、-C1 - 6
烷基-C(O)Ra
、-C1 - 6
烷基-OC(O)NRa
Rb
、-C1 - 6
烷基-NRa
C(O)Rb
、-C1 - 6
烷基-NRa
C(O)2
Rc
、-C1 - 6
烷基-NRa
C(O)NRa
Rb
、-C1 - 6
烷基-ORa
、-C1 - 6
烷基-S(O)2
NRa
Rb
、-C1 - 6
烷基-NRa
S(O)2
Rb
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
、-CH2
CO2
Ra
;各Ra
及Rb
獨立地選自氫、C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基,且Rc
選自C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基;且其中4員至8員環雜烷基及3員至8員環烷基可另外視情況經側氧基取代;
R5a
及R5b
各自係獨立地選自由以下組成之群的成員:H、鹵素、C1 - 4
烷基、-C1 - 4
鹵烷基、O-C1 - 4
鹵烷基、C1 - 4
烷氧基、CO2
H及CN;
R6a
及R6b
各自係獨立地選自由以下組成之群的成員:H、C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基;或R6a
及R6b
視情況結合在一起形成側氧基(=O)或4員至6員環雜烷基或3員至6員環烷基;
R7
係選自由以下組成之群的成員:甲基、乙基及C1 - 2
鹵烷基;及
下標n係1或2;
或其任何醫藥學上可接受之鹽、溶劑合物、水合物、N-氧化物、互變異構體或旋轉異構體。
在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
或其任何鹽、溶劑合物、水合物、N-氧化物、互變異構體或旋轉異構體,其中
B選自由以下組成之群:呋喃基、噁唑基、苯基、吡啶基、嘧啶基及吡嗪基,其各自視情況經R1a
、R1b
及R2
取代,該R1a
、R1b
及R2
獨立地選自由以下組成之群:鹵素、CN、C1 - 4
烷基、C1 - 4
烷氧基及C1 - 4
鹵烷基;
R3
係選自H及D之成員;
R4
係選自H、C1 - 8
烷基及Y之成員;其中C1 - 8
烷基視情況經以下取代:鹵素、-CN、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、OC(O)NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)2
Rc
、-NRa
C(O)NRa
Rb
、-NRa
Rb
、-ORa
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
及Y,其中各Ra
及Rb
獨立地選自氫、C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基,Rc
選自C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基,且Y係5員或6員芳基或雜芳基,其視情況經一至四個選自以下之取代基取代:鹵素、-CN、-C1 - 4
烷基、-C1 - 4
烷氧基、-C1 - 4
羥烷基、-C1 - 4
鹵烷基、OCF3
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-CH2
CO2
Ra
;
R5a
及R5b
各自係獨立地選自以下之成員:H、鹵素、C1 - 4
烷基、C1 - 4
烷氧基、CO2
H及CN;
R6a
及R6a
各自係獨立地選自以下之成員:H、C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基;或R6a
及R6b
視情況結合在一起形成側氧基(=O);及
下標n係1或2。
在一些實施例中,CCR6及/或CXCR2拮抗劑具有下式:
其中R1a
選自CH3
及Cl;R1b
係H或係CH3
;R3
係H或D;R4
係H或Y;R5a
及R5b
各自獨立地選自H、F、Cl、Br及CH3
;R6a
及R6b
各自獨立地選自H及CH3
;且R7
係甲基或乙基;或其醫藥學上可接受之鹽、溶劑合物或水合物。
在一些實施例中,R1a
係CH3
;R1b
不存在或係CH3
;R3
係H或D;R4
係H;R5a
係H、F、Me或Cl或Br;R5b
係H或F;R6a
及R6b
各自係H;且R7
係甲基或乙基;或其醫藥學上可接受之鹽、溶劑合物或水合物。
在一些實施例中,化合物在下帶有R3
之碳原子處實質上不含其他異構體。
在一些實施例中,R4
係Y。
在一些實施例中,提供式(A2)化合物:
其中R1a
選自CH3
及Cl;R1b
係H或CH3
;R3
係H或D;R4a
及R4b
係獨立地選自鹵素、-CN、-C1 - 4
烷基、-C1 - 4
烷氧基、-C1 - 4
羥烷基、-C1 - 4
鹵烷基、OCF3
、-CO2
Ra
、-CONRa
Rb
、-C(O)Ra
、-OC(O)NRa
Rb
、-NRa
C(O)Rb
、-CH2
CO2
Ra
,且Ra
及Rb
獨立地選自氫、C1 - 4
烷基、C1 - 4
羥烷基及C1 - 4
鹵烷基;R5a
及R5b
各自獨立地選自H、F、Cl、Br及CH3
;R6a
及R6b
各自獨立地選自H及CH3
;且R7
選自由以下組成之群:甲基、乙基及C1 - 2
鹵烷基;或其醫藥學上可接受之鹽、溶劑合物或水合物。
在一些實施例中,提供一種化合物或其醫藥學上可接受之鹽,其選自由以下組成之群: 。
在一些實施例中,提供一種化合物或其醫藥學上可接受之鹽,其選自由以下組成之群: 。
在一些實施例中,提供一種化合物或其醫藥學上可接受之鹽,其選自由以下組成之群: 。
在一些所選實施例中,提供式(I)化合物,其選自圖1中之彼等化合物。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.129:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.123:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.136:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑係化合物1.138:
或其醫藥學上可接受之鹽。
在一些實施例中,CCR6及/或CXCR2拮抗劑選自源自ChemoCentryx之2016年11月17日申請之申請案第15/353,889號的美國專利案第9,834,545號中所揭示之化合物或醫藥組合物,出於所有目的將其內容併入本文中。
醫藥組合物
除上文所述之化合物以外,用於調節人類及動物中之CCR6及/或CXCR2活性的組合物將典型地含有醫藥載劑或稀釋劑。
如本文所用,術語「組合物」意欲涵蓋包含指定量之指定成分的產物,以及直接或間接由指定量之指定成分之組合產生的任何產物。「醫藥學上可接受之」意謂可與調配物之其他成分相容且對其接受者無害的載劑、稀釋劑或賦形劑。
用於投與本發明化合物之醫藥組合物宜可以單位劑型呈現且可藉由藥劑學及藥物遞送技術中熟知之方法中之任一者製備。所有方法均包括使活性成分與構成一或多種附屬成分之載劑結合的步驟。一般而言,藉由使活性成分與液體載劑或細粉狀固體載劑或兩者均勻且緊密地結合,且接著必要時使產物成形為所需調配物,來製備醫藥組合物。在醫藥組合物中,活性目標化合物之包括量足以對疾病之過程或病狀起所需作用。
含有活性成分之醫藥組合物可呈適用於口服使用之形式,例如作為錠劑、糖衣錠、口含錠、水性或油性懸浮液、可分散散劑或顆粒、如美國專利第6,451,339號中所描述之乳液及自身乳化劑、硬膠囊或軟膠囊、糖漿劑、酏劑、溶液、口腔貼片、經口凝膠、口嚼錠、咀嚼錠、發泡散劑及發泡錠劑。意欲用於經口使用之組合物可根據用於製造醫藥組合物之此項技術已知之任何方法製備,且此類組合物可含有一或多種選自由以下組成之群的藥劑:甜味劑、調味劑、著色劑、抗氧化劑及防腐劑以便提供醫藥學上精緻且可口之製劑。錠劑含有與醫藥學上可接受之無毒賦形劑摻合的活性成分,該等賦形劑適用於製造錠劑。此等賦形劑可為例如惰性稀釋劑,諸如纖維素、二氧化矽、氧化鋁、碳酸鈣、碳酸鈉、葡萄糖、甘露糖醇、山梨糖醇、乳糖、磷酸鈣或磷酸鈉;粒化劑及崩解劑,例如玉米澱粉或海藻酸;結合劑,例如PVP、纖維素、PEG、澱粉、明膠或阿拉伯膠;及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。錠劑可不包覆包衣或其可藉由已知技術包覆包衣(腸溶或以其他方式)以延遲在胃腸道中之崩解及吸收,且由此經較長時間段提供持續作用。舉例而言,可採用時間延遲材料,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。其亦可藉由美國專利第4,256,108號;第4,166,452號;及第4,265,874號中所述之技術包覆包衣以形成用於控制釋放之滲透性治療錠劑。
用於經口使用之調配物亦可以硬明膠膠囊形式呈現,其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合;或以軟明膠膠囊形式呈現,其中活性成分與水或油狀介質(例如花生油、液體石蠟或橄欖油)混合。另外,乳液可用非水可混溶成分(諸如油)製備且用界面活性劑(諸如單二酸甘油酯、PEG酯及其類似物)穩定化。
水性懸浮液含有與適用於製造水性懸浮液之賦形劑摻合的活性材料。此類賦形劑係懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥基丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及阿拉伯膠;分散劑或潤濕劑可為天然產生之磷脂,例如卵磷脂,或環氧烷與脂肪酸之縮合產物,例如聚氧乙烯硬脂酸酯,或氧化乙烯與長鏈脂族醇之縮合產物,例如十七伸乙基氧基十六醇,或氧化乙烯與衍生自脂肪酸及己糖醇之偏酯之縮合產物,諸如聚氧乙烯山梨糖醇單油酸酯,或氧化乙烯與衍生自脂肪酸及己糖醇酐之偏酯之縮合產物,例如聚乙烯脫水山梨糖醇單油酸酯。水性懸浮液亦可含有一或多種防腐劑,例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯;一或多種著色劑;一或多種調味劑;及一或多種甜味劑,諸如蔗糖或糖精。
油性懸浮液可藉由使活性成分懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)中或礦物油(諸如液體石蠟)中來調配。油性懸浮液可含有增稠劑,例如蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑(諸如上述彼等甜味劑)及調味劑,以提供可口之經口製劑。此等組合物可藉由添加抗氧化劑(諸如抗壞血酸)來保存。
適用於藉由添加水製備水性懸浮液之可分散散劑及顆粒提供活性成分與分散劑或潤濕劑、懸浮劑及一或多種防腐劑之摻合物。適合的分散劑或潤濕劑及懸浮劑藉由上文已提及之藥劑例示。亦可存在其他賦形劑,例如甜味劑、調味劑及著色劑。
本發明醫藥組合物亦可呈水包油乳液形式。油相可為植物油,例如橄欖油或花生油;或礦物油,例如液體石蠟,或此等之混合物。適合的乳化劑可為天然產生之膠狀物,例如阿拉伯膠或黃蓍膠;天然產生之磷脂,例如大豆、卵磷脂;及衍生自脂肪酸及己醣醇酐之酯或偏酯,例如脫水山梨糖醇單油酸酯;及該等偏酯與氧化乙烯之縮合產物,例如聚氧乙烯脫水山梨糖醇單油酸酯。乳液亦可含有甜味劑及調味劑。
糖漿及酏劑可用例如丙三醇、丙二醇、山梨糖醇或蔗糖之甜味劑來調配。此類調配物亦可含有緩和劑、防腐劑、調味劑及/或著色劑。經口溶液可與例如環糊精、PEG及界面活性劑組合製備。
醫藥組合物可呈無菌可注射水性或油性懸浮液形式。此懸浮液可根據已知技術使用上文已提及之彼等適合的分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑亦可為非經腸可接受之無毒稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如呈1,3-丁二醇中之溶液的形式。在可接受之媒劑及溶劑中,可採用的有水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外,無菌非揮發性油習知地用作溶劑或懸浮介質。出於此目的,可採用任何溫和的不揮發性油,包括合成之單甘油酯或二甘油酯。另外,脂肪酸(諸如油酸)用於製備可注射劑。
本發明化合物亦可以用於直腸投與藥物之栓劑形式投與。此等組合物可藉由將藥物與適合的無刺激性賦形劑混合來製備,該賦形劑在常溫下係固體但在直腸溫度下係液體且因此在直腸中熔融以釋放藥物。此類材料包括可可脂及聚乙二醇。另外,化合物可藉助於溶液或軟膏經由眼部遞送來投與。再者,本文所述化合物之經皮遞送可藉助於離子導入貼片及其類似物實現。對於表面使用,可採用含有本發明化合物之乳膏、軟膏、凝膠劑、溶液或懸浮液等。如本文所用,表面應用亦意謂包括使用漱口水及漱口劑。
本發明化合物可經調配以放置於醫療裝置中,醫療裝置可包括多種習知移植物、支架(包括支架移植物)、導管、膨脹體、筐或可部署或永久地植入體腔內的其他裝置中之任一者。作為特定實例,期望具有可將本發明化合物遞送至已藉由介入技術治療之身體區域的裝置及方法。
在例示性實施例中,本發明化合物可放置於醫療裝置(諸如支架)中,且傳遞至治療部位用於治療身體之一部分。
支架已用作治療劑(即藥物)之遞送媒介物。血管內支架一般永久地植入冠狀動脈或周邊血管中。支架設計包括美國專利第4,733,655 (Palmaz)號、第4,800,882 (Gianturco)號或第4,886,062 (Wiktor)號之彼等支架設計。此類設計包括金屬與聚合支架,以及自身擴展及膨脹體擴展支架。支架亦可用於在與脈管接觸之部位遞送藥物,如美國專利第5,102,417號(Palmaz)號及國際專利申請案第WO 91/12779號(Medtronic Inc.)及第WO 90/13332號(雪松-西奈醫療中心(Cedars-Sanai Medical Center))、美國專利第5,419,760號(Narciso, Jr.)及美國專利第5,429,634號(Narciso, Jr.)中所揭示。支架亦已用以將病毒遞送至用於基因遞送之管腔壁,如美國專利案第5,833,651號(Donovan等人)中所揭示。
在一個實施例中,可在形成針對醫療裝置(諸如支架)之生物相容性塗層期間將抑制劑與聚合物組合物一起併入。由此等組分產生之塗層通常係均勻的且可用於塗佈許多經設計用於植入之裝置。
聚合物可視所需釋放速率或所需聚合物穩定程度而定為生物穩定聚合物或生物可吸收聚合物,但生物可吸收聚合物通常對此實施例較佳,因為與生物穩定聚合物不同,其不會在植入後長期存在以引起任何不良長期局部反應。可使用之生物可吸收聚合物包括(但不限於)聚(L-乳酸)、聚己內酯、聚乙交酯(PGA)、聚(丙交酯-共-乙交酯) (PLLA/PGA)、聚(羥基丁酸酯)、聚(羥基丁酸酯-共-戊酸酯)、聚二氧環己酮、聚原酸酯、聚酸酐、聚(乙醇酸)、聚(D-乳酸)、聚(L-乳酸)、聚(D,L-乳酸)、聚(D,L-丙交酯) (PLA)、聚(L-丙交酯) (PLLA)、聚(乙醇酸-共-碳酸三亞甲酯) (PGA/PTMC)、聚氧化乙烯(PEO)、聚二氧環己酮(PDS)、聚磷酸酯、聚磷酸酯胺基甲酸酯、聚(胺基酸)、氰基丙烯酸酯、聚聚(碳酸三亞甲酯)、聚(亞胺基碳酸酯)、共聚(醚-酯) (例如PEO/PLA)、聚乙二酸烷二酯、聚磷氮烯及生物分子,諸如纖維蛋白、血纖維蛋白原、纖維素、澱粉、膠原蛋白及玻尿酸、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯、水凝膠之交聯或兩親性嵌段共聚物及此項技術中已知的其他適合的生物可吸收聚合物。同樣,可使用具有相對低慢性組織反應之生物穩定聚合物,諸如聚胺基甲酸酯、聚矽氧及聚酯,且亦可使用在醫療裝置上可溶解及固化或聚合的其他聚合物,諸如聚烯烴、聚異丁烯及乙烯-α-烯烴共聚物;丙烯酸系聚合物及共聚物、乙烯基鹵化物聚合物及共聚物,諸如聚氯乙烯;聚乙烯吡咯啶酮;聚乙烯醚,諸如聚乙烯甲基醚;聚偏二乙烯鹵化物,諸如聚偏二氟乙烯及聚偏二氯乙烯;聚丙烯腈、聚乙烯酮;聚乙烯芳族物,諸如聚苯乙烯;聚乙烯酯,諸如聚乙酸乙烯酯;乙烯基單體彼此及與烯烴之共聚物,諸如乙烯-甲基丙烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS樹脂及乙烯-乙酸乙烯酯共聚物;哌喃共聚物;聚羥基-丙基-甲基丙烯醯胺-酚;聚羥乙基-天冬醯胺-酚;經軟脂醯基殘基取代之聚氧化乙烯-聚離胺酸;聚醯胺,諸如Nylon 66及聚己內醯胺;醇酸樹脂、聚碳酸酯;聚甲醛;聚醯亞胺;聚醚;環氧樹脂、聚胺基甲酸酯;人造絲;人造絲-三乙酸酯;纖維素、乙酸纖維素、丁酸纖維素;乙酸丁酸纖維素;塞璐芬(cellophane);硝酸纖維素;丙酸纖維素;纖維素醚;及羧甲基纖維素。
聚合物及半透性聚合物基質可形成為成型物品,諸如瓣膜、支架、導管、輔具及其類似物。
在本發明之一個實施例中,本發明之抑制劑與形成為支架或支架移植物裝置之聚合物或半透性聚合物基質偶合。
通常,聚合物藉由旋轉塗覆、浸漬或噴塗施用於可植入裝置之表面。出於此目的,亦可利用此項技術中已知的額外方法。噴塗方法包含傳統方法以及使用噴墨型施配器之微沈積技術。另外,聚合物可使用光圖案化沈積於可植入裝置上以將聚合物僅置放於裝置之特定部分上。裝置之此塗層在裝置周圍提供均勻的層,致使可改良多種分析物經裝置塗層之擴散。
在本發明之較佳實施例中,將抑制劑調配成可自聚合物塗層釋放至放置醫療裝置之環境中。較佳地,抑制劑使用涉及聚合物載劑或層之若干熟知技術中之至少一者以控制方式經長時間範圍(例如幾個月)釋放,以控制溶離。先前在美國專利申請案20040243225A1中描述一些此等技術。
此外,如例如美國專利案第6,770,729號中所述,可操縱聚合物組合物之試劑及反應條件以使得可控制自聚合物塗層釋放抑制劑。舉例而言,可調節一或多個聚合物塗層之擴散係數以控制抑制劑自聚合物塗層之釋放。在此主題之變化形式中,可控制一或多個聚合物塗層之擴散係數來調節置放醫療裝置之環境中存在之分析物(例如促進聚合物之一些部分分解或水解之分析物)進入聚合物組合物內之一或多種組分中(及例如由此調節抑制劑自聚合物塗層之釋放)之能力。本發明之又一實施例包括具有複數個聚合物塗層之裝置,所述塗層各自具有複數個擴散係數。在本發明之此類實施例中,可藉由複數個聚合物塗層調節抑制劑自聚合物塗層之釋放。
在本發明之又一實施例中,抑制劑自聚合物塗層之釋放藉由調節聚合物組合物之特性中之一或多者來控制,諸如一或多種內源性或外源性化合物之存在,或者聚合物組合物之pH值。舉例而言,某些聚合物組合物可經設計成因應聚合物組合物之pH降低而釋放抑制劑。或者,某些聚合物組合物可經設計成因應過氧化氫之存在而釋放出抑制劑。
在一些實施例中,提高包含本發明化合物之醫藥組合物。在一些實施例中,醫藥組合物進一步包含一或多種額外治療劑。在一些實施例中,一或多種額外治療劑選自由以下組成之群:細胞毒性化學療法、抗癌或抗腫瘤疫苗、抗免疫細胞介素療法、免疫細胞介素療法、嵌合抗原受體(CAR)T細胞受體、基因轉移療法、檢查點抑制劑、皮質類固醇、類視黃素樣藥劑、抗腫瘤藥及干擾素類似物。在一些實施例中,一或多種額外治療劑選自由以下組成之群:TNF α配體抑制劑、TNF結合劑、IL-1配體抑制劑;IL-6配體抑制劑、IL-8配體抑制劑;IL-17拮抗劑、鈣調神經磷酸酶抑制劑、TNF拮抗劑、視黃酸受體γ拮抗劑、IL-17A配體抑制劑;IL-17F配體抑制劑、RIP-1激酶抑制劑、神經鞘胺醇-1-磷酸酯受體-1拮抗劑、神經鞘胺醇-1-磷酸酯受體-1調節劑、ρ相關蛋白激酶2抑制劑、IL-12拮抗劑;IL-23拮抗劑、II型TNF受體調節劑、IL-23A抑制劑、PDE 4抑制劑、JAK酪胺酸激酶抑制劑、Jak1酪胺酸激酶抑制劑;Jak3酪胺酸激酶抑制劑、組織胺H1受體拮抗劑、視黃酸受體促效劑、膜銅胺氧化酶抑制劑、PI3K調節劑、磷酸肌醇-3激酶δ抑制劑、粒線體10 kDa熱衝擊蛋白質刺激劑、腺苷A3受體促效劑、半乳糖凝集素-3抑制劑、F1F0 ATP合成酶調節劑、GM-CSF配體抑制劑、維生素D3受體促效劑、糖皮質激素促效劑、組織胺H4受體拮抗劑、CCR3趨化激素拮抗劑、伊紅趨素配體抑制劑、神經鞘胺醇-1-磷酸酯受體-1調節劑、磷脂酶A2抑制劑、PDE 4抑制劑、白蛋白調節劑、TLR-7拮抗劑、TLR-8拮抗劑、TLR-9拮抗劑、CD40配體受體拮抗劑、Src酪胺酸激酶抑制劑、微管蛋白結合劑、介白素-1 α配體抑制劑、組蛋白脫乙醯基酶-1抑制劑、組蛋白脫乙醯基酶-2抑制劑、組蛋白脫乙醯基酶-3抑制劑、組蛋白脫乙醯基酶-6抑制劑、核苷逆轉錄酶抑制劑、核因子κ B抑制劑、STAT-3抑制劑、副甲狀腺激素配體抑制劑;維生素D3受體促效劑、T細胞表面糖蛋白CD28刺激劑、組織胺H4受體拮抗劑、TGF β促效劑、P-選擇蛋白糖蛋白配體-1刺激劑、DHFR抑制劑、視黃酸受體γ調節劑、胞溶質磷脂酶A2抑制劑、類視黃素X受體調節劑、β-連環蛋白抑制劑、CREB結合蛋白抑制劑、TrkA受體拮抗劑、T細胞分化抗原CD6抑制劑、ADP核糖基環化酶-1抑制劑、介白素-1β配體調節劑;胰島素受體底物-1抑制劑、DHFR抑制劑、IL-8拮抗劑、阻斷CTLA-4 (CD152)、PD-1 (CD279)、PDL-1 (CD274)、TIM-3、LAG-3 (CD223)、VISTA、KIR、NKG2A、BTLA、PD-1H、TIGIT、CD96、4-1BB (CD137)、4-1BBL (CD137L)、GARP、CSF-1R、A2AR、CD73、CD47、色胺酸2,3-雙加氧酶(TDO)或吲哚胺2,3二加氧酶 (IDO)之活性的藥物及OX40、GITR、4-1BB、ICOS、STING或CD40之促效劑。
投與方法
一般而言,本文所提供之治療方法包含向患者投與有效量之一或多種本文所提供之化合物。在一較佳實施例中,本發明化合物較佳經口或表面向患者(例如人類)投與。治療方案可視所用化合物而變化。一般而言,每天2次之給藥方案更佳,其中一天一次給藥尤其較佳。然而,應理解,任何特定患者之特定劑量及治療方案將視多種因素而定,包括所採用之特定化合物之活性、年齡、體重、一般健康狀況、性別、飲食、投與時間、投與途徑、分泌速率、藥物組合(亦即向患者投與之其他藥物)及經歷療法之特定疾病之嚴重程度以及開處方醫師之判斷。一般而言,使用足以提供有效療法之最小劑量較佳。一般可針對治療有效性,使用適用於所治療或預防之病狀之醫學或獸醫學準則,來監測患者。
本發明之化合物及組合物可藉由經口、非經腸(例如肌肉內、腹膜內、靜脈內、ICV、腦池內注射或輸注、皮下注射或植入)、吸入、經鼻、經陰道、經直腸、舌下或表面投與途徑投與,且可以含有習知無毒醫藥學上可接受之載劑、佐劑及媒劑(適於各投與途徑)之適合的劑量單元調配物形式單獨或一起調配。本發明亦涵蓋投與呈儲槽式調配物形式之本發明之化合物及組合物。
約為每天約0.1 mg至約100 mg/公斤體重之劑量適用於治療或預防涉及病原性CCR6及/或CXCR2活性之病狀(每天每人類患者約0.5 mg至約7 g)。較佳地,劑量將為每天約0.01 mg/kg至約25 mg/kg;更佳每天約0.05 mg/kg至約10 mg/kg。適合的劑量可為約每天0.01 mg/kg至25 mg/kg,每天約0.05 mg/kg至10 mg/kg,或每天約0.1 mg/kg至5 mg/kg。在此範圍內,劑量可為每天0.005至0.05,0.05至0.5,0.5至5.0,或5.0至50 mg/kg。對於口服投與而言,組合物較佳以錠劑形式提供,該等錠劑含有1.0毫克至1000毫克活性成分,特定言之1.0毫克、5.0毫克、10.0毫克、15.0毫克、20.0毫克、25.0毫克、50.0毫克、75.0毫克、100.0毫克、150.0毫克、200.0毫克、250.0毫克、300.0毫克、400.0毫克、500.0毫克、600.0毫克、750.0毫克、800.0毫克、900.0毫克及1000.0毫克活性成分以達成對待治療患者之劑量的症狀調節。化合物可按每天1至4次、較佳每天一次或兩次之方案投與。
可與載劑材料組合產生單一劑型之活性成分之量將視所治療之主體及特定投與模式而變化。單位劑型將一般含有約1 mg至約500 mg之間的活性成分。對於經口、經皮、靜脈內或皮下投與之化合物,較佳的是投與足夠量之化合物以達到5 ng (奈克)/mL-10 μg (微克)/mL血清之血清濃度,更佳應投與足夠的化合物以達到20 ng-1 μg/ml血清之血清濃度,最佳應投與足夠的化合物以達到50 ng/ml-200 ng/ml血清之血清濃度。
然而,應理解,可改變任何特定患者之特定劑量水準及給藥頻率且將視多種因素而定,包括所採用之特定化合物之活性、該化合物之代謝穩定性及作用時長、年齡、體重、遺傳特徵、一般健康狀況、性別、飲食、投與模式及時間、分泌速率、藥物組合、特定病狀之嚴重程度及經歷療法之主體。
I. 實例實例 1 : IL36 介導之皮膚炎症需要經由趨化介素受體 CCR6 之 信號傳導
廣泛性膿疱型乾癬(GPP)係罕見發炎性皮膚病症,其病因不同於較常見的斑塊型乾癬。GPP患者通常並不對通常用於斑塊型乾癬之治療劑有反應。遺傳證據表明GPP起因於IL-36/IL36Ra/IL36R信號傳導軸之功能障礙,且GPP之許多態樣可經由皮內(ID)注射預先活化之IL36在小鼠中再現。吾人已使用此ID
-IL36模型以研究積聚於GPP皮膚內之白血球群體。在先前研究中,吾人報導小分子CCR6拮抗劑化合物1.129改善斑塊型乾癬之表面咪喹莫特誘導之模型中之炎症。CCR6拮抗作用防止此模型中分泌IL17之γδ T (γδT17)之積聚,其似乎為化合物1.129緩解疾病之機制。在本發明研究中吾人已發現,γδT17細胞並不積聚於IL36發炎皮膚中。實際上,習知CD4+
αβ T細胞群體積聚在此模型中。化合物1.129降低IL36誘導之炎症,同時阻止此CD4+
αβ T細胞群體積聚。因此,儘管不同T細胞群體與各模型相關,但炎症皆藉由CCR6拮抗作用與CXCR2拮抗作用改善。此等研究結果表明CCR6可構成GPP療法之機理不同之方法的新穎標靶。實例 2 : 抑制趨化介素受體及配體相互作用逆轉 IL - 36 誘導之炎症 材料及方法
對於趨化介素受體抑制劑活性之活體外測定,將化合物1.136溶解於DMSO中以產生10 mM之儲備液濃縮物,將該儲備液濃縮物進一步用趨化性遷移緩衝劑(HBSS、1% BSA、1% HEPES)稀釋以產生100 nM至0.01 nM範圍內之10點抑制劑梯度。接著進行遷移分析,該分析係使用ChemoTx盤(Neuroprobe,Gaithersburg MD)測定在100%小鼠血清因應rmCCL20之CCR6活性或因應rmCXCL1之CXCR2活性,且用CyQuant (Thermo Fisher)藉由螢光染色經遷移細胞進行評估。
Balb/c小鼠購自Jackson Laboratories (Bar Harbor,Maine)且根據國家研究委員會實驗室動物管理及使用指南(the Guide and Use of Laboratory Animals of the National Research Council)中所述之準則圈養於ChemoCentryx動物設備。所有研究均由ChemoCentryx機構動物護理及使用委員會(Institutional Animal Care and Use Committee)批准。
對於活體內給藥,除非另外說明,否則在研究之第0天開始,小鼠皮下給藥90 mg/kg之化合物1.136每天一次(皮下,每天一次,於1% HPMC中)。活體內劑量根據活體外效能及小鼠對單次劑量之藥物動力學反應來預計。已確定完全覆蓋梯度感測化學引誘劑受體之最小拮抗劑濃度(處於谷值)與IC90
濃度相對應(Schall, T. J.及A. E. Proudfoot. 2011. Overcoming hurdles in developing successful drugs targeting chemokine receptors.Nat Rev Immunol
11: 355-363)。對於CCR6抑制,100%血清中之化合物1.136之IC90
係45 ng/ml,且對於CXCR2抑制係145 ng/ml。表1中展示30、60及90 mg/kg之化合物1.136在活體內達成之實際谷值濃度。
表1:給藥90、60、30 mg/kg於1% HPM中之化合物1.136之動物在谷值(亦即最終給藥(第5天)後24小時)所量測之平均值±s.d.電漿濃度
IL-36誘導之耳部增厚之小鼠模型。8週齡Balb/c小鼠之右耳每天接受皮內注射重組鼠類IL-36α (每小鼠150 μg,調配於PBS中,BioLegend)持續5天。對左耳皮內注射PBS作為對照。在研究開始之前及整個研究中每天使用數位測微計量測耳部厚度。如先前所述執行乾癬狀皮膚炎之咪喹莫特模型(Campbell J等人J Immunol .
2017;199(9):3129-36.,van der Fits等人J Immunol
2009;182(9):5836-45)。簡言之,每天將5%咪喹莫特(Fougera®
)施用於Balb/c小鼠之刮毛及脫毛之背部,長達4天。施用凡士林(Vaseline)來處理對照小鼠。以0至4之等級獨立地評估紅斑、脫屑及皮膚增厚,其中0 = 無疾病;1 = 輕微疾病;2 = 中度疾病;3 = 顯著疾病;4 = 極顯著疾病(Campbell J等人J Immunol .
2017;199(9):3129-36,van der Fits等人J Immunol
2009;182(9):5836-45)。在研究結束時切下來自小鼠之背部之皮膚且加工以用於流式細胞測量術分析,
白細胞之流式細胞測量術。在37℃下在攪拌下於膠原蛋白酶A及1 U/ml DNAse I中消化耳部或切下之皮膚樣品30分鐘。接著自皮膚移出細胞,經由70 μM篩網過濾,洗滌且再懸浮於FACS緩衝劑(具有10%FBS之PBS)中以進行分析。
直接結合之單株抗體來自R&D Systems (Minneapolis, MN)、BioLegend (San Diego, CA)或eBioscience/ThermoFisher (San Diego, CA)。於AlexaFluor488中之CD45.2 (104)、於PE中之Ly6C (HK1.4)、於Per CP-Cy5.5中之CD90.2 (30-H12)、於PE-Cy7中之TCRVγ4 (UC3-10A6)、於APC中之TCRβ (H57-597)、於APC-eFluor-780中之CD4 (GK1.5)、於BV-421中之TCRγδ (GL3)、LIVE/DEAD可固定淺綠色 染色劑(Molecular Probes, Eugene, OR)、於BV650中之CD11c (N418)、於BV711中之Ly6G (1A4)及於BV785中之CD11b (M1/70)。使用Fortessa (BD Biosciences)細胞計數器獲得流式細胞測量術數據且使用FlowJo 10.2版分析。
提取自發炎皮膚之白細胞之流式細胞測量術示於圖 5
中,且圖 11
包括一組未結合的單株抗體(或其同型匹配對照),之後為適當的結合APC多株(FAB)2
(Jackson ImmunoResearch, West Grove, PA, USA)。此等未結合試劑包括來自R&D Systems之抗CCR6 (140706)(Minneapolis, MN)及來自Biolegend之抗CXCR2 (SA044G4)(San Diego, CA),所有均係大鼠IgG2a。抗譜系標記CD103、CD11c、FLT3、CD205及F4/80之未結合MAb均獲自Biolegend。在用未結合單株及APC多株染色之後,在用直接結合物染色之前用10%小鼠、10%倉鼠及10%大鼠血清(Jackson ImmunoResearch)阻斷細胞。
每小鼠每天一次腹膜內給藥200-500 μg小鼠抗IL-17RA (R&D Systems)作為陽性對照。認為每小鼠每天給藥200 μg/ml完全屬於此治療之最大活性之平穩段內(圖 6A
)。
對皮膚中趨化介素蛋白質濃度之多重分析。將皮內IL-36α處理4天之後收集之耳部組織於含有蛋白酶抑制劑(Roche)之冷PBS中均質化,接著離心以移除碎片。使用多重分析套組根據製造商說明書(R&D systems)分析可溶性溶離份且經MagPix (Luminex)分析儀讀取。組織趨化介素之濃度針對使用標準布拉福分析(standard Bradford assay)量測之各樣品之總蛋白含量標準化。
對於蘇木精及曙紅(H&E)染色,最初將耳部組織固定於多聚甲醛中以進行石蠟包埋。樣品藉由標準程序處理。將表皮厚度量測為使用Photoshop CS4軟體(Adobe®)沿H&E染色之耳部切片之長度之中間三分之一(含有病變之區域)獲得之7個量測值之平均值
藉由Mann Whitney計算使用GraphPad Prism 6.0軟體測定統計顯著性。結果及論述
在獲自兩個鼠類乾癬模型之發炎皮膚內比較發炎性細胞群體。對於斑塊型乾癬,使用公認咪喹莫特(IMQ)模型(van der Fits等人J Immunol
2009;182(9):5836-45),其中每天將TLR 7/8促效劑IMQ施用於脫毛皮膚之表面。對於GPP,使用每天向耳部皮膚內注射活化之小鼠IL-36α。
在處理4天之後,流式細胞測量術展示在兩種模型之間自皮膚分離之發炎性細胞浸潤(如圖 2
中所示閘控)明顯不同。IMQ處理產生較大嗜中性球群體(圖 3A
及圖 3C
),然而活化之IL-36α產生幾乎等數目之T細胞、嗜中性球及Ly6Chi
/Ly6G-
骨髓細胞(圖 3B
及圖 3C
)。來自各模型之T細胞群體亦高度相異圖 3 D
);具有顯著γδT17 (Vγ4+
)群體之IMQ處理之皮膚(具有水平條帶之灰色條柱)(如先前所觀察(Cai等人Immunity
2011;35(4):596-610,Campbell J等人J Immunol .
2017;199(9):3129-36.))及來自注射IL-36α之皮膚的T細胞(具有對角斜條帶之灰色條柱)幾乎全部由CD4+
「習知」αβ T細胞組成。
由IL-36誘導之骨髓皮膚群體表現骨髓與樹突狀細胞之標記特徵之組合(圖 11
)。此等細胞表現CD103、CD11c及F4/80。其並不表現Flt3,一種經典樹突狀細胞(cDC)之診斷性標記,其亦不表現CD205 (DEC205)(圖 11
)。根據此免疫表型及此等細胞在有效發炎之皮膚內之位置,咸信此等細胞係源自單核細胞之發炎性樹突狀細胞(iDC) (Merad等人Annu Rev Immunol
2013;31:563-604.)且係指其以原樣用於此點。
吾人觀察到在皮膚中藉由用IL-36α處理CCL20及CXCR2之趨化介素配體顯著增加(圖 4
),與先前研究一致。(Campbell, J. J., K. Ebsworth, L. S. Ertl, J. P. McMahon, D. Newland, Y. Wang, S. Liu, Z. Miao, T. Dang, P. Zhang, I. F. Charo, R. Singh及T. J. Schall. 2017. IL-17-Secreting gammadelta T Cells Are Completely Dependent upon CCR6 for Homing to Inflamed Skin.J Immunol
199: 3129-3136,及van der Fits, L., S. Mourits, J. S. Voerman, M. Kant, L. Boon, J. D. Laman, F. Cornelissen, A. M. Mus, E. Florencia, E. P. Prens及E. Lubberts. 2009. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.J Immunol
182: 5836-5845。) 吾人使用流式細胞測量術檢查包含因應IL-36積聚之大多數CD45+浸潤的三個白血球亞型中之各者之CCR6及CXCR2表現(圖 5
)。關於此等三個白血球亞型,僅嗜中性球之CXCR2表現量大於同型對照染色(圖 5B
,左欄)。少數iDC及大多數CD4 T細胞表現CCR6 (圖 5A
,右欄)。
CCR6及CXCR2配體在發炎皮膚中之突出伴隨著藉由IL-36α誘導之子組之此等兩種受體之表現促使吾等評定CCR6/CXCR2拮抗劑在阻止此等細胞在皮膚內積聚之功效(且由此改善IL-36α誘導之皮膚炎症)。化合物1.136係具有約440之分子量及10 nM (對於小鼠CCR6)及20 nM (對於小鼠CXCR2)之IC50
的小分子,如藉由100%血清中趨化性之活體外抑制所評定。下表提供關於化合物1.136活體外抑制之其他資訊。
表2:化合物1.136之活體外活性 a
mCCR6轉染之BaF3細胞對血清中之mCCL20之趨化性之IC50
。b
小鼠骨髓細胞對血漿中之mCXCL1之趨化性之IC50
。c
小鼠WEHI-274.1細胞對血清中之mCCL3之趨化性之IC50
。d
小鼠骨髓細胞對血清中之mCCL2之趨化性之IC50
。e
mCCR4轉染之BaF3細胞對血清中之mCCL22之趨化性之A2
。f
mCCR5轉染之BaF3細胞對血清中之mCCL5之趨化性之IC50
。g
小鼠脾細胞對血清中之mCCL19之趨化性之IC50
。h
小鼠胸腺細胞對血清中之mCCL25之趨化性之IC50
。i
小鼠BaF3-WT對血清中之mCXCL12之趨化性之IC50
。
在每天4次皮內注射單獨PBS(陰性對照)或於PBS中之活化IL-36α之後吾人量測耳部厚度(圖 6
)。PBS處理之耳部之平均厚度係約2.5 mm,IL-36α處理之耳部厚度(約5.0 mm,圖 6A
)之一般。每天一次皮下給藥化合物1.136 (在小鼠背部,遠離IL-36處理之耳部處),且實現IL-36誘導之耳部增厚之劑量依賴性減小(圖 6A
)。時程顯示在第二天處理之後化合物1.136之作用明顯(圖 6B
及圖 7A
)。
吾人接下來比較化合物1.136之有效性與α-IL-17RA單株抗體之有效性(每小鼠每天一次腹膜內給藥200或500 μg)。抗IL-17RA處理有效減小IL-36誘導之耳部腫脹(圖 6A
),但有效性顯著低於90 mg/kg劑量之化合物1.136。在第二天處理之後飽和劑量之抗IL-17RA MAb與90 mg/kg之化合物1.136之間的有效性差別顯而易見(圖 6B
(亦參見關於500μg/小鼠/天之抗IL-17RA MAb處理與此MAb之同型匹配對照之直接比較之圖 7B
))。
吾人接下來檢測在每天4次用PBS(對照)或活化之IL-36α處理之後獲取之小鼠耳部之切片以用於量測表皮厚度(圖 8A
、圖 8B
及圖 9
)。與圖 6
中所示之耳部腫脹之直接量測一致,相對於PBS處理之耳部,在IL-36α處理之耳部中表皮增厚顯而易見(圖 9A
)。投與化合物1.136或抗IL-17RA顯著減小IL-36α介導之表皮厚度(圖 9B
)。
投與化合物1.136減小IL-36α誘導之真皮、表皮及總體皮膚厚度(圖 8 C
)。另外,角質層保持完整且白血球浸潤減少。給藥抗IL-17RA亦對IL-36處理之皮膚具有有益作用(圖 8D
)。
吾人接下來藉由流式細胞測量術評定化合物1.136對積聚於IL-36處理之皮膚內發炎性細胞子組之作用(圖 10
)。在每天4次耳部注射IL-36α及用化合物1.136或α-IL-17RA MAb處理之後自皮膚分離免疫細胞。吾人發現化合物1.136顯著減少CD4+
T細胞、嗜中性球及發炎性iDC之積聚。相反,α-IL-17RA並不減少CD4+
T細胞之積聚,但對嗜中性球及iDC具有與化合物1.136類似之作用。
膿疱型乾癬係包含若干亞型之罕見皮膚病症,包括廣泛性及局部性形式(Benjegerdes等人Psoriasis ( Auckl )
2016;6:131-44,Mahil等人Semin Immunopathol
2016;38(1):11-27,Navarini等人J Eur Acad Dermatol Venereol
2017;31(11):1792-9.)。廣泛性形成(GPP)伴隨明顯發病率,且在一些情況下伴隨死亡率(Borges-Costa等人Am J Clin Dermatol
2011;12(4):271-6.)。IL - 36RN
基因中之功能損失型突變常見於GPP患者中,尤其不併發斑塊型乾癬之症狀之彼等GPP患者中(Marrakchi等人N Engl J Med
2011;365(7):620-8.)。IL - 36RN
基因編碼稱為IL-36受體拮抗劑(IL-36RA)之蛋白質。在健康個體中,IL-36RA與活化之IL36α、β及/或γ細胞介素競爭以結合至IL36受體(IL-36R),從而為此蛋白質提供有助於保持體內平衡之抗炎特性。IL-36RA之異常結構及功能致使發炎性細胞介素及趨化介素之分泌失調(Marrakchi等人N Engl J Med
2011;365(7):620-8.)。在本文中,吾人報導CCR6/CXCR2之小分子拮抗劑比抗IL-17療法更有效地減小將活化之IL-36α直接皮內注射至小鼠皮膚中後之皮膚厚度及白血球浸潤。
GPP之特徵在於膿包及紅斑型斑塊之普遍爆發。在急性變型中,患者通常看起來全身性不適,因為膿包之急劇爆發伴隨著疼痛及發熱。危及生命之白血球增多症、電解質異常、低白蛋白血症及肝酶升高亦可出現於急性變型中(Benjegerdes等人Psoriasis ( Auckl )
2016;6:131-44)。不存在認可之用於GPP之治療。由於此疾病罕見發生,故不存在評定對治療之反應之標準化方法。關於治療結果之資料主要由回溯性研究、病例報導及專家觀點組成(Benjegerdes等人Psoriasis ( Auckl )
2016;6:131-44,Robinson等人J Am Acad Dermatol
2012;67(2):279-88.)。
GPP之當前治療涉及全身性不適之彼等患者之支持性護理,之後係控制皮膚疾病之醫藥治療(Robinson等人J Am Acad Dermatol
2012;67(2):279-88.)。慢性緩慢發展疾病通常藉由經口類視黃素或甲胺喋呤處理。急性疾病用環孢靈或抗TNFα生物製品中之一者治療。此等治療均不高度有效,且所有均具有副作用(Robinson等人 J Am Acad Dermatol 2012;67(2):279-88.)。因此,對新穎治療及用於GPP處理之新穎臨床靶標之臨床需求尚未得以滿足。
除積聚於IL-36處理之皮膚中之T細胞及嗜中性球以外,此模型亦產生大量吾人咸信為iDC之骨髓細胞。此後一群體表現DC與巨噬細胞之標記。因為此等細胞並不表現FLT3/CD135,所以吾人咸信其源自單核球而非經典DC。先前已表明來自人類血液之單核細胞源DC表現高表現量之IL-36R (Foster等人J Immunol
2014;192(12):6053-61.)。若證明來自小鼠皮膚之iDC具有與人類血液單核細胞源DC類似之特性,則此等細胞可為用於本發明研究中之模型中IL-36誘導之炎症的重要調節劑。
吾人使用IL36α模型以比較化合物1.136化合物之有效性與α-IL-17RA MAb之有效性。在臨床中通常使用針對IL-17軸之生物製品作為GPP之第二線治療(Imafuku等人J Dermatol
2016;43(9):1011-7.)。吾人發現90 mg/kg劑量之化合物1.136比α-IL-17RA (500 mg/小鼠/天)顯著更有效地減小耳部腫脹(圖 8
)。儘管α-IL-17RA治療顯著減少嗜中性球及iDC於皮膚中之積聚,但不影響CD4+
αβ T細胞計數。因此,高於α-IL-17RA之抗炎效應的化合物1.136之額外抗炎效應密切對應於CD4+
αβ T細胞減少。
總之,吾人已展示由活化之IL-36α皮膚注射產生之炎症涉及嗜中性球、iDC及CD4 T細胞積聚,其與GPP患者中所見類似。CCR6及CXCR2藉由化合物1.136之選擇性抑制會減少所有三種此等發炎性細胞類型,且改善皮膚炎症。IL-17軸之阻斷逆轉嗜中性球及iDC而非CD4 T細胞在皮膚中之積聚。化合物1.136係比此IL-36α誘導之乾癬模型中所評定之飽和濃度之α-IL-17RA單株抗體更有效的治療劑。此等研究結果表明CCR6/CXCR2拮抗作用可構成新穎標靶類別、及藉由特定作用於可能介導疾病之發炎性細胞來治療IL-36細胞介素軸失調(如在GPP中)之機理不同的治療性方法。
儘管出於清楚理解之目的已藉助於說明及實例相當詳細地描述前述發明,但熟習此項技術者應瞭解,可在所附申請專利範圍之範疇內實踐某些改變及修改。此外,本文中所提供之各參考文獻係以全文引用的方式併入本文中,其引用的程度如同個別地將各參考文獻以引用的方式併入一般。當本申請案與本文所提供之參考文獻之間存在衝突時,應以本申請案為準。
圖 1A
-1AJ
提供本文所述之化合物之特定結構。
圖 2A
-D
展示用以鑑別自如圖3、圖5及圖10中所論述之IL-36處理之皮膚分離之iDC、嗜中性球及CD4+
αβ T細胞之閘控流程。首先在活CD45+
群體上閘控細胞,之後進行Thy-1相對於CD11b閘控(圖A
)。圈於左下角中之細胞在Ly6C相對於Ly6G上閘控以鑑別iDCs及嗜中性球(圖B
)。圈於圖A之左上角中之細胞接著在TCRαβ相對於TCRγδ上閘控(圖C
)。圈於圖C中之細胞在CD8α相對於CD4上閘控以鑑別CD4+
αβ T細胞(圖D
)。
圖 3A - D
展示在斑塊型乾癬之咪喹莫特模型及GPP之IL-36模型中產生之明顯不同的發炎性細胞皮膚浸潤。圖A
及B
展示在用IMQ ( A ,
具有水平條帶之灰色條柱)或IL-36α
( B
,具有對角斜條帶之灰色條柱)每天四次治療之後自小鼠皮膚分離之每公克之細胞數。黑色條柱指示自經對照處理之皮膚分離之每公克之細胞數,該對照對於咪喹莫特實驗( A
)係表面凡士林(VAS)及對於IL-36實驗( B
)係皮內PBS。圖C
展示經IL-36處理相對於經咪喹莫特處理之皮膚內之白血球子組之相對圖像:在個別實驗之中進行比較。計算5個個別咪喹莫特實驗及7個個別IL-36實驗之總活CD45+
浸潤之T細胞、嗜中性球及iDC之百分比,各實驗利用至少5隻個別小鼠。展示此等實驗之平均值(及SEM)之平均。圖D
展示在用咪喹莫特(具有水平條帶之灰色條柱)或IL-36α
(具有對角斜條帶之灰色條柱)處理之後自小鼠皮膚分離之表現指定免疫表型之T細胞的百分比。各條柱指示來自單個實驗之十隻小鼠之平均值及SEM,表示重複至少5次。所有所示群體首先閘控為活(AQUA-活/死陰性)及CD45+
。對於圖A及B,T細胞閘控為表現TCRβ或TCRγδ之Thy-1+
/CD11b-
細胞。Ly6G+
及Ly6Chi
/Ly6G-
細胞在Thy-1-
/CD11b+
群體內閘控。對於圖C,指定群體中之各者計算為表現TCRβ或TCRγδ之總Thy-1+
/CD11b-
群體之百分比。
圖 4A - B
展示對CCL20及CXCL2蛋白質之多重分析表明在每天4次皮內注射IL-36α之後兩種蛋白質明顯增加。CCL20蛋白質含量繪製於圖A中;CXCL2蛋白質含量繪製於圖B中。
圖 5A
-C
展示藉由因應皮內IL-36α注射而積聚於皮膚中之白細胞表現CCR6及CXCR2。將自20隻小鼠之經IL-36處理之耳部分離之細胞混合且用未結合之特異性MAb (如上文各欄所指示)或同型匹配對照,之後使用標準程序用第二階段MAb染色。未結合第二階段用正常小鼠、大鼠及倉鼠血清,之後用直接標記之單株抗體阻斷。對各細胞類型進行閘控指示各列之左邊:骨髓細胞係圖A;嗜中性球係圖B;且CD4 T細胞係圖C
。比同型匹配對照更亮之細胞之百分比若大於5%,則指示於流式細胞測量術曲線內。混合細胞之染色表示4次重複實驗。
圖 6A
-B
展示化合物1.136改善注射IL-36α之耳部的發炎性腫脹。圖A
繪製在IL-36α誘導之GPP模型期間每天給藥指定劑量之化合物1.136(或α-IL-17RA)之小鼠之耳部厚度。在處理4天之後藉由測徑規量測耳部厚度。圖B,(A)中所示之實驗之耳部厚度的時程,比較90 mg/kg劑量之化合物1.136與α-IL-17RA。每數據點十隻小鼠。來自Mann-Whitney等級次序測試之統計資料。注意:滴定實驗展示在每天每隻小鼠200 μg下α-IL-17RA對平穩段之作用,且此實驗中之小鼠每天每隻小鼠給藥500 μg (數據未示出)。n . s .
,不明顯,p
<.05*,p
<.0005***,p
<.0001****。
圖 7A
-B
展示耳部厚度數據。圖A
展示圖6 A
中所示之化合物1.136之滴定時程。圖B
展示IL-36α發炎皮膚之抗IL-17RA處理之同型匹配對照。如本文中所述,藉由每天皮內注射PBS或活化之IL-36α使各群組中五隻小鼠之耳朵發炎。一些群組亦接受每天腹膜內注射500 μg/小鼠之抗IL-17RA或500 μg/小鼠之抗IL-17RA MAb之大鼠IgG2a同型匹配陰性對照。Mann-Whitney等級次序測試在第3、4及5天抗IL-17RA MAb與其同型匹配對照之作用之間建立顯著性。*p
< 0.05,**p
< 0.01。儘管在200 μg/小鼠/天之劑量下抗IL17RA之作用達至飽和(與圖3中之500 μg/小鼠/天相比),但在500 mg/kg/天下,將抗IL-17RA與其同型匹配對照相比,表明作用並非甚至此等極高含量下之同型之非特異性作用。
圖 8A - D
展示化合物1.136基本上改良注射IL-36α之耳部之組織結構。在90 mg/kg之IL-36α或PBS處理4天之後自處死之小鼠獲得耳部(圖A係PBS +媒劑;圖B係IL-36 +媒劑)。在處理期間,小鼠每天給藥1% HPMC (化合物1.136之媒劑;圖A
及B
)、於媒劑中之化合物1.136 (圖C
)或抗IL17RA (圖D
)。使用標準FFPE技術將耳部固定且包埋,切片且使用標準蘇木精及曙紅(H&E)染色技術染色。所示切片表示來自五個不同耳部之至少五個不同部分。
圖 9A
-B
展示化合物1.136基本上降低注射活化之IL-36α之耳部之表皮厚度。圖A
頂部列展示在每天4次IL-36α注射之後耳部之整體寬度之切片。圖A
第二列展示較高放大倍率之聚焦於病變區域之頂部影像。圖A
三及四列展示來自經化合物1.136處理之IL-36α處理小鼠耳部及注射PBS而非IL-36α之小鼠耳部的病變區域。黑色條柱指示圖B中所圖示之所有切片進行7次個別表皮厚度量測之各次的位置。圖B係各處理組之8隻小鼠的耳部厚度量測。各點表示1隻小鼠之耳部的7次表皮厚度量測之平均值。在每天4次活化之IL-36α (或PBS)處理之後自處死之小鼠獲得耳部。在處理期間,小鼠每天皮下給藥1% HPMC (媒劑),皮下給藥90 mg/kg/天之於媒劑中之化合物1.136,或腹膜內給藥200 μg/小鼠/天之於PBS中之抗IL17RA。使用標準FFPE技術將耳部固定且包埋,切片且使用標準蘇木精及曙紅(H&E)染色技術染色。所示切片表示來自八個不同耳部之至少五個不同部分。來自Mann-Whitney等級次序測試之統計資料p
< 0.05*。
圖 10A
-C
展示化合物1.136顯著降低CD4 T細胞(圖A
)、嗜中性球(圖B
)及發炎性樹突狀細胞(圖C
)在IL-36處理之皮膚內之積聚。在每天4次IL-36α (或PBS對照)處理之後自處死之小鼠獲得耳部。注射IL-36α之小鼠單獨接受媒劑、化合物1.136 (90 mg/kg/天,在背部皮下)或α-IL-17RA (200 μg/小鼠/天,腹膜內)。藉由Mann-Whitney等級次序測試進行統計分析。一個實驗展示為每組具有10隻小鼠且表示重複3次。n . s .
,不明顯,p<.005**,p<.0001****。
圖 11A - E
展示在皮內IL-36α注射之後積聚於皮膚中之Ly6Chi
骨髓細胞之特徵。在每天四次IL-36α注射之後自20個耳部分離細胞,接著混合且用未結合特異性MAb (如各圖內所指示,淺灰色曲線)或同型匹配對照(深灰色曲線),之後使用標準程序用抗Ig第二階段多株Ab染色。未結合之第二階段用正常小鼠、大鼠及倉鼠血清,之後用直接結合之MAb阻斷。圖A
使用CD103特異性MAb;圖B
使用Flt3特異性MAb;圖C
使用CD205特異性MAb;圖D
使用CD11c特異性MAb;且圖E
使用F4/80特異性MAb。骨髓細胞如圖5 A
中般閘控。所示混合細胞之染色表示3次重複實驗。
Claims (9)
- 如請求項1之用途,其中R1a為CH3。
- 如請求項1或2之用途,其中R5b為H或F。
- 如請求項1或2之用途,其中R6a及R6b各自為H。
- 如請求項1或2項之用途,其中該藥劑投與至人類個體。
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