CN108024998A - 包含s1p受体调节剂的组合物 - Google Patents
包含s1p受体调节剂的组合物 Download PDFInfo
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- CN108024998A CN108024998A CN201680052675.8A CN201680052675A CN108024998A CN 108024998 A CN108024998 A CN 108024998A CN 201680052675 A CN201680052675 A CN 201680052675A CN 108024998 A CN108024998 A CN 108024998A
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Abstract
提供了包含S1P受体调节剂以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的组合物。所述组合物可用于治疗疾病,特别是炎症和免疫介导的疾病。
Description
技术领域
本公开涉及包含S1P受体调节剂的组合物,还涉及使用所述组合物治疗疾病的方法,特别是炎症和免疫介导的疾病。
背景技术
炎症
炎症是对损伤和感染的免疫应答。症状包括发红、发热、肿胀和疼痛。炎症的控制在再生和创伤愈合中是重要的,但是失控炎症可引起持久应答和损害性应答,从而导致慢性疾病。炎症可能是局部的或器官特异性的,或者可能会蔓延至全身,从而引起全身性疾病。
炎症部位过度表达促炎细胞素和像白细胞介素(IL1、IL6、IL17)、肿瘤坏死因子(TNFα)、诱导性氧化氮合酶(iNOS)、环氧合酶-2(COX-2)、髓过氧化物酶(MPO)和血管内皮生长因子(VEGF)这样的因子。这些细胞素和各因子参与免疫细胞的募集、免疫应答的改变、内皮屏障的破坏、分化的改变和炎症内的异常增殖模式。血管变得异常、膨胀、渗漏、弯曲,并且会出现积液和水肿。较远部位缺乏供血,并且产生组织缺氧,可能导致癌症发生。存在细胞存活模式的改变,并且会发生变性。
越来越多的科学数据表明炎症涉及几乎所有的疾病。源于炎症的多种疾病在各种身体器官系统中都是常见的,例如心血管疾病(即动脉粥样硬化、缺血性疾病、静脉疾病)、神经系统疾病(即多发性硬化、癫痫、ALS、神经病变)以及免疫介导的疾病(即类风湿性关节炎、哮喘、牛皮癣、特应性皮炎、痤疮、白斑病)。炎症在缺血性损伤、动脉粥样硬化损害(Galkina E.等人,Annu Rev Immunol,2009,27,165)和癌症肿瘤(Landskron G等人,JImmunolRes,2014,文章ID 149185,19页http://dx.doi.org/10.1155/2014/149185)中起根本作用。
S1P受体轴和炎症
S1P受体属于G蛋白偶联受体家族,广泛地在像免疫系统、神经系统和血管系统这样的主要器官系统中进行表达。存在5种称作鞘氨醇1-磷酸酯受体S1P1-5的受体,其共有的内源性配体S1P具有各种下游作用(Cooke等人,Annual Reportsin Medicinal Chemistry,2007,42,245-263页,以及其中的参考文献)。S1P受体,特别是1型受体S1P1,参与免疫应答、内皮屏障增强(Wilkerson B等人,J Biol Chem,2012,287卷,44645)、细胞保护(Rutherford C等人,Cell Death and Disease,2013,4,e927;doi:10.1038/cddis,455)、细胞分化、细胞动员/趋化性以及其它。
已知通过S1P受体的下游作用涉及mTOR调节和免疫调节(Liu G等人,NatImmunol,2010,11,1047)。已有文献详细记载S1P受体参与抑制STAT3(Garris C.S.等人,Nat Immunol,2013,14卷,1166),其为涉及炎症和癌症的已知靶点。众所周知S1P受体会调节疼痛(Welch S.P.等人,Biochem Pharmacol,2012,84,1551)。此外,S1P受体涉及干细胞趋化性(Kimura A.等人,Stem Cell,2007,25,115)和再生(Leronimakis等人,SkeletalMuscle,2013,3,20),并且S1P1轴参与神经保护(Asle R M等人,EXCLIJournal,2013,12,449)。S1P受体调节参与像TNFα、IL6、IL12、VEGF这样的细胞素的表达(Bolick D T等人,Arterioscler Thromb Vasc Biol,2005,25,976;Sanchez T,等人,JBiol Chem 2003,278(47),47281)。已经显示,S1P受体在像急性肺损伤、流感以及其它疾病这样的重病中进行主要参与。内皮细胞使得血管内层表达S1P受体,并且众所周知S1P1激动剂会增强血管屏障、防止血管渗漏、并增强血管系统的成熟化(McVerry B.J.等人,JCell Biochem,2004,92,1075;Allende M.L.等人,Blood,2003,102,3665;Paik J.等人,GenesDev,2004,18,2392;Garcia J.GN.等人,JClinInvest,2001,108(5),689)。S1P受体轴参与炎症和癌症(KunkelG.T.等人,Drug Discovery,2013,12,688)。
像类风湿性关节炎、关节疼痛、肌肉炎症、牛皮癣、皮炎、眼色素层炎和动脉粥样硬化这样的疾病会伴有炎症,以及像疼痛、瘙痒和变性这样的其它共有病状。S1P受体是炎性适应症中发生的多种病状的已知靶点。
多源性癌症具有各种常见病状,例如发炎、血管异常(血管泄露、新血管生成)、组织缺氧、异常分化、细胞从癌症原发位置的外渗和转移。S1P受体调节可在单独治疗中通过减轻炎症、屏障增强、避免转移和细胞分化来减轻各种癌症中存在的多种病状。据报道,S1P受体介导的细胞固定会产生固体实体,从而避免从癌症位点的细胞内渗(Feng H,CancerCell,2010,18(4),353-366)。
炎性反应为血管病的潜在原因,例如异常血管、渗漏和液体外渗以及血肿超多血管形成。神经变性、炎症和血管渗漏以及超多血管形成在黄斑变性、青光眼、视网膜病中是常见的。肺炎是像哮喘、慢性阻塞性肺病(COPD)、急性肺损伤和流感这样的各种肺部问题的首要原因。
心肌梗塞、脊髓损伤和缺血性损伤与重要器官的炎症、细胞死亡和功能受损相关。S1P受体调节可通过阻止炎症、防止细胞死亡(Schabbauer G.等人,Arterioscler ThrombVascBiol,2004,24,1963;Wang J.等人,Biomaterials,2015,62,76)、改进血液流动、吸引干细胞到损伤位点、分化和再生(Leronimakis等人,Skeletal Muscle,2013,3,20)来减轻病状。S1P受体调节剂的用途可延伸到肌肉、骨和其它器官的创伤愈合和再生,包括移植成功(LiaL等人,Cornea,2014,33(4),398)。
S1P受体调节能够解决人类、动物和其它物种的各种疾病中常见的多种病理学事件(图1)。
尽管以上所述S1P受体调节的发展,但是仍对改进的S1P受体调节剂(例如具有S1P受体亚型1活性的那些)、特别是包含S1P受体调节剂(其被配制成治疗特定状况)的组合物存在需要。
本说明书中所引用的任何现有出版物(或者从其中得到的信息)、或者已知的任何内容,都不是,也不应当看作是承认或接受或以任何形式建议现有出版物(或者从其中得到的信息)、或已知内容形成本说明书所涉及的所致力的领域内公知常识的一部分。
发明内容
在一个方面,提供了一种组合物,其包含至少一种S1P受体调节剂以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物。
所述至少一种S1P受体调节剂可以为式(I)化合物:
其中R1选自氢、氘、卤素、CN、CF3、-COOH、酰胺、磺酰胺、芳氧基、硝基和烷基链(C1-5),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基、环烷基(C3-7)和碳环中的一种或多种;
其中R2选自氢、氘、卤素、CN、CF3、烷基链(C1-4),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基或环烷基(C3-7)和碳环中的一种或多种;
其中R3选自氢、氘、卤素、烷基链(C1-7),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基或环烷基(C3-7)和碳环中的一种或多种;
其中R4选自氢、氘、卤素、CN、CF3、烷基链(C1-4),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基和环烷基(C3-7)中的一种或多种;
其中A是任选的,并且当存在时经选择由N取代一个或多个环碳原子;
其中L选自氢、氘、F、Cl、Br和烷基(C1-3);
其中G为选自以下之一的基团:
其中R选自H、COOH、烷基(C1-4)和羟基烷基(C1-4);
其中R’和R”独立地选自H和烷基(C1-4);
其中R”’选自OH、-OPO3H2和生理学上可接受的盐;
其中表示任选的桥连基团;
星号表示基团G在式(I)中的连接。
式(I)化合物可具有式(II):
其中R1、R2、R3、R4、A、L、R、R’和R”如上所定义。
式(I)或式(II)化合物可具有:
R1,其选自F、Cl、Br、CN、CF3、NO2、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、o-烯丙基、O-苄基和
R2,其选自H、氘、F、Cl、Br、CN、CF3、NO2、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
R3,其选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
R4,其选自H、氘、Me和Et;
R,其选自H、Me或-CH2OH;
R’,其选自H和Me;
R”,其选自H和Me;
L,其选自H、氘、Me和Cl;以及
A,其如上所定义。
式(I)或式(II)化合物可具有:
R1,其选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
R2为H;
R3,其选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
R4,其选自H、氘、Me和Et;
R,其选自H、Me或-CH2OH;
R’,其选自H和Me;
R”,其选自H和Me;
L为H;以及
A不存在。
式(I)化合物可具有式(III):
其中R1、R2、R3、R4、A、L、R和R’如上所定义。
式(I)化合物可具有式(III):
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2选自H、氘、F、Cl、Br、CN、CF3、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L选自H、氘、Me和Cl;并且
其中A如上所定义。
式(I)化合物可具有式(III):
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2为H;
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L为H;并且
其中A不存在。
类固醇可以是皮质类固醇。皮质类固醇可选自由以下组成的群组:阿氯米松、安西奈德、氯地米松、倍他米松、布地缩松、环索奈德、氯倍米松、去氢氯氟美松、氯可托龙、氯泼尼醇、可的伐唑、地夫可特、去氧皮质酮、羟泼尼缩松去羟米松、地塞米松、双氟拉松、双氟米松、二氟泼尼酯、氟氯洛龙、氟氢化可的松、氟氢缩松、氟米松、氟尼缩松、醋酸氟轻松、氟欣诺能、氟可丁、氟考龙、氯甲龙、氟培龙、氟替卡松、泼尼松、醛基缩松、氯氟舒松、卤米松、醋丙氢化可的松、丁丙氢化可的松、丁酸氢化可的松、氯替泼诺、甲羟松、甲泼尼松、甲泼尼龙、醋丙甲泼尼龙、糠酸莫米松、对氟米松、泼尼卡松、泼尼松、氢化泼尼松、泼尼立定、利美索龙、替可的松、氟烃氢化泼尼松和乌倍他松、其药学上可接受的盐、酯、溶剂化物、水合物和衍生物、及其混合物。
皮质类固醇可以是倍他米松。
阿片类药物可选自由以下组成的群组:阿芬太尼、烯丙罗定、阿法罗定、氨苄哌替啶、苄吗啡、贝齐米特、丁丙诺啡、布托啡诺、氯尼他秦、可待因、二氢脱氧吗啡、右旋摩拉胺、地佐辛、双胺丙酰胺、二乙酰吗啡、二氢可待因、二氢埃托啡、二氢吗啡、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、依他佐辛、依索庚嗪、乙甲噻丁、乙基吗啡、依托尼秦、埃托啡、芬太尼、海洛因、氢可酮、氢化二氢吗啡酮、羟基度冷丁、异美沙酮、凯托米、左啡诺、左芬啡烷、洛芬太尼、哌替啶、美普他酚、美他佐辛、美沙酮、米托本、吗啡、麦罗啡、纳布啡、那碎因碱、尼可吗啡、去甲左啡诺、去甲美沙酮、纳洛芬、去甲吗啡、诺匹哌酮、鸦片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、非那多松、非诺啡烷、非那佐辛、苯哌利定、匹米诺定、哌腈米特、普罗庚嗪、二甲哌替啶、丙哌利定、丙吡胺、丙氧吩、舒芬太尼、痛立定、曲马多、其药学上可接受的盐、溶剂化物、水合物和衍生物、及其混合物。
非甾体抗炎药可选自由以下组成的群组:阿司匹林、布洛芬、萘普生、双氯芬酸、Cox-2抑制剂、依托度酸、吲哚美辛、酪洛芬、吡罗昔康、folmetin、替诺昔康、美洛昔康、美洛昔康、甲芬那酸、异丁芬酸、酪洛芬、水杨酸甲酯、其药学上可接受的盐、溶剂化物、水合物和衍生物、及其混合物。
根据本公开的组合物可包含式(III)化合物以及皮质类固醇:
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2选自H、氘、F、Cl、Br、CN、CF3、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L选自H、氘、Me和Cl;并且
其中A如上所定义。
皮质类固醇可以是倍他米松。
还提供了一种通过给有此需要的对象施用有效量的根据本文公开的实施例中的任一个的组合物来治疗或预防炎症介导的疾病、免疫介导的疾病或疼痛的方法。
炎症介导的疾病或免疫介导的疾病可选自由以下组成的群组:牛皮癣、湿疹、白斑病、秃头症、类风湿性关节炎、骨关节炎、痛风、痔疮/痔疮、肺损伤、肝损伤、肾损伤、哮喘、慢性阻塞性肺病(COPD)、眼色素层炎、视网膜病、肾病、黄斑变性、青光眼、耳炎、过敏反应、败血症、流感、鼻炎和瘙痒症。
还提供了一种通过给有此需要的对象施用有效量的根据本文公开的实施例中的任一个的组合物来治疗或预防疼痛的方法。
疼痛可选自由以下组成的群组:关节疼痛、关节炎、痛风疼痛、背部疼痛、肌肉疼痛、肌肉疼痛、神经病变、神经痛、肌肉酸痛、运动损伤或创伤疼痛。
在本文公开的任一方法中,所述组合物可局部、口服、肠胃外、鼻内、经眼部或经直肠给药。
在本文公开的任一方法中,所述组合物可以为固体、贴片、粉末、液体、半固体、软膏、凝胶、喷剂、气雾剂、洗剂、片剂、胶囊、液体、溶液、混悬剂、乳剂或糖浆形式。
在本文公开的任一方法中,所述组合物可以是通过植入或注射或装置施用的缓释剂型(贮库制剂)。
在本文公开的任一方法中,所述组合物可与像小分子、生物制剂、抗病毒剂、抗菌剂、抗癌药或抗炎药这样的其它治疗活性化合物组合施用。
在一个实施例中,提供了一种通过给有此需要的对象施用有效量的包含式(III)化合物的组合物以及皮质类固醇来治疗或预防炎症介导的疾病、免疫介导的疾病或疼痛的方法:
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2选自H、氘、F、Cl、Br、CN、CF3、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L选自H、氘、Me和Cl;并且
其中A如上所定义。
皮质类固醇可以是倍他米松。
式(I)化合物的代表性实例包括(但不限于)以下:
S1P受体调节剂(例如式(I)化合物)可以为盐的形式。S1P受体调节剂(例如式(I)化合物)的盐可以是药学上可接受的。合适的药学上可接受的盐对于本领域技术人员而言是显而易见的,并且包括在JPharm Sci,1977,66,1-19中描述的那些,例如与无机酸(例如氢氯酸、氢溴酸、硫酸、硝酸或磷酸)和有机酸(例如琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸、甲磺酸或萘磺酸)形成的酸加成盐。某些S1P受体调节剂(例如式(I)化合物)可与一当量或多当量的酸形成酸加成盐。本公开在其范围内包括所有可能的化学计量和非化学计量的形式以及游离碱形式。
S1P受体调节剂(例如式(I)化合物)可制备成晶体或非晶体形式,并且如果制备成晶体形式,可任选地被水化或溶剂化。本公开在其范围内包括化学计量的水合物或溶剂化物,以及包含不同量的水和/或溶剂的化合物,以及所有的S1P受体调节剂(例如式(I)化合物)的盐、溶剂化物、水合物、复合物、多晶型物、前药、放射性标记的衍生物、立体异构体和光学异构体。
根据本公开的组合物可包含像药物赋形剂这样的各种递送运载体,包括稳定剂、载体或胶囊制剂。所述组合物可提供一种或多种S1P受体调节剂(例如式(I)化合物)、选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物和递送运载体之间的有利的协同效应。与单独的S1P受体调节剂(例如式(I)化合物)相比所述协同效应可改进治疗和/或预防和/或免疫疗法。
可使根据本公开的组合物适合局部使用或针对性地使用,例如局部、耳朵、眼睛、鼻、口服、肠胃外、直肠给药,并因此可以是这样的组合物形式:其中S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物作为活性物质存在,作为单独的活性物质,或者在各种组合物中与其它活性和非活性成分/赋形剂(例如(不限于)软膏、凝胶、水凝胶、溶液、滴剂、局部贴片、经皮贴片、局部液体制剂、喷剂、气雾剂、片剂、胶囊、口服液体制剂、粉末、细粒、锭剂、控释颗粒(包括微粒、脂质体、纳米乳剂、聚合物、微海绵或富勒烯)、可注射或可注入溶液或混悬剂或栓剂及其它)组合存在。
将根据本公开的组合物针对性地施用或应用到受影响区域可能比曝露于全身更有利。这可以使得S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物被针对性地和期望地曝露于病变部分,同时又避免由于不必要地曝露于健康器官而可能产生潜在的副作用。例如牛皮癣或特应性皮炎(湿疹)的皮肤损害可通过将根据本公开的组合物直接施用到损害处接受所需要的S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的曝露,而全身治疗可能不会获得足够的S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物对损害处的治疗曝露,而曝露于其它非针对性的器官的则可能会导致不良作用。
根据本公开的组合物可以是缓释组合物,并且可容许S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的缓慢释放。该释放可来自于植入物,其在受影响部分(例如、炎症、缺血性损伤、癌症、肿瘤、动脉粥样硬化病变)的外围中或处可具有所期望的治疗水平的S1P受体调节剂(例如式(I)化合物),并且相关的全身浓度较低。该方法可增加总的治疗窗口,否则通过全身治疗这也许是不可能的。因此,提供了一种通过给有需要的对象局部施用有效量的根据本公开的组合物来治疗炎症、缺血性损伤、癌症、肿瘤、或动脉粥样硬化病变的方法。所述组合物可以是缓释组合物。
根据本公开的组合物可以为像液体、半固体或固体这样的各种形式,并且可以为像溶液、软膏、凝胶、糊剂、洗剂、泡沫、受控降解聚合物、贴片这样的各种组合物类型,包含像式(I)化合物这样的S1P受体调节剂以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物。这些各种剂型可用来针对性地施用式(I)化合物,以通过直接施用来治疗像皮肤、眼睛、耳朵、鼻、嘴、直肠、肛门或肺这样的身体部位的适应症;通过缓释剂型治疗肠胃器官的适应症;通过植入物或注射来治疗内脏器官的适应症。因此,提供了通过给有需要的对象施用有效量的根据本公开的组合物通过直接施用来治疗像皮肤、眼睛、耳朵、鼻、嘴、直肠、肛门或肺这样的身体部位的适应症、通过缓释剂型治疗肠胃器官的适应症、通过植入物或注射来治疗内脏器官的适应症的方法。
炎症适应症经常与感染相关。提供了具有像抗菌剂、抗病毒剂或抗真菌剂这样的抗感染剂或抗病原体剂的S1P受体调节剂(例如式(I)化合物)和选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的组合物,其可用来治疗像(例如)湿疹和痤疮形式这样的适应症。因此,提供了通过将有效量的根据本公开的组合物与像抗菌剂、抗病毒剂或抗真菌剂这样的抗感染剂或抗病原体剂一起组合施用到有需要的对象来治疗像湿疹或痤疮这样的适应症的方法。
可通过添加S1P受体调节剂恢复类固醇耐受性(Tsuji T.等人,Biol Pharm Bull,2012,35(8),13149)。S1P受体调节还对癌症中它莫西芬耐受性的产生具有影响(Watson C等人,Am J Pathol,2010,177(5),2205)。因此提供了具有像(但不限于)免疫调节剂、抗癌剂、抗菌剂、抗病毒剂、抗真菌剂、疼痛调节剂这样的其它类型的药物的包含S1P受体调节剂(例如式(I)化合物)和选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的组合物。
提供了通过给有需要的对象局部施用有效量的根据本公开的组合物来治疗组织缺氧(例如癌症远端部位的组织缺氧)的方法。
移植排斥经常伴随有炎症(Lutz等人,J Inflamm(Lond),2010,7,27;Liang J等人,Cornea,2014,33(4),398)。S1P受体调节参与免疫耐受性和血管修正,并且局部给药和最佳曝露是一种用于成功移植的有前途的方法,不管是否使用其它免疫调节剂。因此,提供了通过给有需要的对象施用有效量的根据本公开的组合物来治疗移植排斥的方法。
S1P受体调节可产生有效且适当的应答,包括从对感染(Pinschewer D.D.等人,Neurology,2011,76(副刊3):S15-S19)或癌症(Marcus等人,Blood,2011,118(4),975)的免疫作用到免疫耐受(Liu G.等人,J Immunol,2014,192;Yoshida Y.等人,Biol PharmBull,2011,34(6),933)和移植成功。因此S1P受体调节可能广泛用于抑制或促进免疫应答。这是令人惊讶的,并且可能需要适当模式的给药和具有式(I)化合物的组合物来获得期望的效果。
还提供了包含S1P受体调节剂(例如式(I)化合物)和选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物以及像抗体这样的高度特异性的蛋白、肽、或分子的组合物。所述组合物可用来被针对性地递送到身体的特定区域或器官。
根据本公开的组合物可以是局部用组合物。局部用组合物可以是像(不限于)洗剂和溶液这样的液体制剂、像(不限于)软膏、凝胶、泡沫或霜、喷剂和气雾剂这样的半固体制剂、或像(不限于)局部贴片这样的固体制剂的形式。局部递送系统还可包括气溶胶泡沫、脂质体、纳米乳剂、聚合物、微海绵或富勒烯(Pharma Innovation,2012,1(9),18-31)。局部用组合物可包含皮肤渗透增强剂。皮肤渗透增强剂的实例包括(但不限于):短链醇,例如乙醇和异丙醇;长链醇,例如正癸醇、己醇、十二烷醇、肉豆蔻醇、辛醇、辛基十二烷醇、油醇;环酰胺,例如氮酮;酯,例如乙酸乙酯、水杨酸辛酯、帕地马酯O、油酸乙酯、甘油单油酸酯、甘油单癸酸酯、甘油三辛酸酯、十四烷酸异丙酯、棕榈酸异丙酯、丙二醇单月桂酸酯、或丙二醇单辛酸酯;脂肪酸,例如月桂酸、亚油酸、肉豆蔻酸、油酸、棕榈酸、硬脂酸或异硬脂酸;二醇,例如二丙二醇、丙二醇、1,2-丁基二醇或1,3-丁基二醇;吡咯酮,例如N-甲基-2-吡咯酮、或2-吡咯酮;亚砜,例如癸基甲基亚砜或二甲基亚砜;阴离子表面活性剂,例如十二烷基硫酸钠;阳离子表面活性剂,例如烷基二甲基苄基卤化铵、烷基三甲基卤化铵、烷基吡啶卤化物;非离子表面活性剂,例如Brij 36T或Tween 80;单萜,例如丁子香酚、d-柠檬烯、薄荷醇、薄荷酮;倍半萜,例如双三醇或neridol。
包含S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的本公开的组合物可包含其它成分,例如像(不限于)DMSO、聚乙烯基吡咯烷酮(PVP)、月桂酸甘油酯、乳酸月桂酯、气溶胶、EUDRAGIT(其可溶于溶剂中(例如乙醇、丙醇或异丙醇))这样的增溶剂或渗透增强剂。可加入粘合剂并混合以得到均匀混合物。可将该均匀混合物浇注到释放层(例如硅酮或含氟聚合物涂覆的聚酯膜)上并干燥。
用于口服给药的根据本公开的局部用组合物、片剂和胶囊可以为单位剂量形式,并且可包含常规赋形剂,例如粘合剂(例如预凝胶玉米淀粉、聚乙烯吡咯酮、羟基乙基或羟基丙基甲基纤维素);填料(例如乳糖、微晶纤维素或磷酸氢钙);片剂润滑剂(例如硬脂酸镁、滑石或硅石);崩解剂(例如马铃薯淀粉或淀粉羟乙酸钠);以及可接受的润湿剂(例如十二烷基硫酸钠)。片剂可根据普通药学实践中众所周知的方法进行包衣。片剂可以是缓释的,并在像胃或肠这样的特定器官中释放以递送S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物。
本公开的局部和口服液体组合物可以为水性或油性混悬剂、溶液、乳剂、糖浆或酏剂形式,或者可以为用来在使用前与水或其它合适运载体重建的干燥产物形式。此类液体制剂可包含常规添加剂,例如悬浮剂(例如山梨醇糖浆、纤维素衍生物或氢化可食用脂肪)、乳化剂(例如卯磷脂或阿拉伯胶)、非水性运载体(其可包括可食用油,例如杏仁油、油状酯、乙醇或分级植物油)、防腐剂(例如对羟基苯甲酸甲酯或丙酯或山梨酸)、以及(适当时如果需要的话)常规调味剂或着色剂、缓冲盐和甜味剂。用于局部和口服给药的制剂可被合适地配制,以获得S1P受体调节剂(例如式(I)化合物)和选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的控释。
针对肠胃外给药,可使用S1P受体调节剂(例如式(I)化合物或其药学上可接受的盐)、选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物、以及无菌运载体来制备液体单位剂量形式。用于注射的制剂可以使用S1P受体调节剂(例如式(I)化合物)或其药学上可接受的衍生物和无菌运载体并任选地添加有防腐剂的单位剂量形式(例如在安瓶中或多剂量中)提供。组合物可采用像油状或水性运载体中的混悬剂、溶液或乳剂这样的形式,并且可包含像悬浮剂、稳定剂和/或分散剂这样的配制剂。或者,活性成分可以为用于在使用前与合适的运载体(例如无菌无热原水)配制的粉末形式。取决于所用运载体和浓度,化合物可被悬浮于或溶于运载体中。在制备溶液时,可将化合物溶解用于注射并在过滤灭菌后装入合适的小瓶中或安瓶中并密封。有利地,可将像局部麻醉剂、防腐剂和缓冲剂这样的佐剂溶于运载体中。为了增强稳定性,可在装到小瓶中之后将组合物冷冻并在真空下除去水。可以基本上相同的方式制备肠胃外混悬剂,除了化合物悬浮在运载体中而不是溶于其中,并且不能通过过滤进行灭菌。可在悬浮于无菌运载体中之前通过曝露于环氧乙烷对化合物进行灭菌。有利地,可将表面活性剂或润湿剂包括到组合物中,以便于化合物的均匀分布。
洗剂可使用水性或油性基质来配制,并且还可包含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂、或着色剂。滴剂可使用水性或非水性基质来配制,还包含一种或多种分散剂、稳定剂、增溶剂或悬浮剂。它们还可包含防腐剂。
S1P受体调节剂(例如式(I)化合物)或其药学上可接受的盐、以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物还可被配制成(例如)包含常规栓剂基质(例如可可脂或其它甘油酯)的直肠用组合物,比如栓剂或滞留型灌肠剂。
S1P受体调节剂(例如式(I)化合物)或其药学上可接受的盐、以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物还可被配制成贮库制剂。此类长效制剂可通过植入(例如皮下或肌内,原位,在炎性和/或损伤部位的外围)或通过肌内注射施用。因此,例如,S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物可使用合适的聚合材料或疏水性材料(例如配制成可接受的油中的乳剂)或离子交换树脂配制,或者配制成低溶性衍生物,例如配制成低溶性盐。
对于作为控释颗粒的制剂,所需量的S1P受体调节剂(例如式(I)化合物)以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物可用聚合物,特别是可生物降解聚合物进行处理,所述可生物降解聚合物进行体内酶降解或非酶降解或两者同时进行,产生生物相容的、毒理学上安全的副产物,其通过正常的代谢途径被进一步除去。此类可生物降解聚合物的选择包括(例如)聚乳酸-羟基乙酸共聚物(PLGA)、聚酸酐、聚已酸丙酯(PCL)、复合糖(透明质酸、壳聚糖)和无机物(羟磷灰石)。为了更好地进行递送,将S1P调节剂(包括式(I)化合物)与选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物结合的制剂,与各种类型的聚酯与聚乙二醇(PEG)的嵌段共聚物。PLGA/PEG嵌段共聚物作为二嵌段(PLGA-PEG),或者具有ABA(PLGA-PEG-PLGA)和BAB(PEG-PLGA-PEG)的三嵌段分子。这些药物递送策略可避免令人不便地外科插入大的移植物,并且可生物降解的和生物相容的可注射PLGA颗粒(微球体、微胶囊、纳米胶囊、纳米微球体)可用于控释剂型。PLGA颗粒可包含S1P调节剂,包括单独的式(I)化合物,或者与其它治疗相关药物组合的式(I)化合物。活性成分可通过扩散穿过聚合物屏障、或通过聚合物材料的蚀解、或通过扩散和蚀解两种机制的组合从聚合器件释放。PLGA可容易地加工和制造成各种形式和尺寸。PLGA应具有生物相容性、药物兼容性、合适的生物降解动力学和力学性能标准。
对于鼻内给药,式(I)化合物或其药学上可接受的盐、以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物可配制成通过合适计量或单位剂量的装置施用的溶液,或者另外配制成使用合适的递送装置施用的具有合适载体的粉末混合物。因此可将式(I)化合物或其药学上可接受的盐、以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物配制用于口服、口腔、肠胃外、局部(包括眼和鼻)、贮库或直肠给药,或者配制成适合通过吸入或吹入(通过嘴或鼻)给药的形式。
式(I)化合物或其药学上可接受的盐以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物可被配制成软膏、霜、凝胶、洗剂、阴道栓剂、气雾剂或滴剂(例如滴眼剂、滴耳剂或滴鼻剂)形式用于局部给药。软膏和霜可(例如)使用水性或油性基质并加入合适的增稠剂和/或胶凝剂来配制。用来施用到眼睛的软膏可使用无菌组分以无菌方式制造。
根据本公开的组合物取决于给药方法可包含以重量计0.001%到99%、优选以重量计0.001到60%、更优选以重量计0.01到25%的S1P受体调节剂(例如式(I)化合物)。用于治疗以上所述疾病的S1P受体的剂量将会以通常方式随着疾病严重程度、患者重量、以及其它类似因素而改变。但是,作为一般性指导合适的单位剂量可以是0.001到10000mg、1.0到500mg、或1.0到200mg式(I)化合物,并且此类单位剂量可每天施用一次以上,例如每天两次或三次或更多次。
根据本公开的组合物取决于给药方法可包含以重量计0.001%到99%、优选以重量计0.01到25%的选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物。用于治疗以上所述疾病的选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的剂量将会以通常方式随着疾病严重程度、患者重量、以及其它类似因素而改变。但是,作为一般性指导合适的单位剂量可以是0.05到10000mg、1.0到500mg、或1.0到200mg选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物,并且此类单位剂量可每天施用一次以上,例如每天两次或三次或更多次。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以0.001到25wt.%的量存在于根据本公开的组合物中,并且类固醇以0.005到2wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计SIP受体调节剂(例如式(I)化合物)可以1到3wt.%的量存在于根据本公开的组合物中,并且类固醇以0.01到0.05wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以1.0或1.5或2.0或2.5或3.0或3.5或4.0或4.5或5.0wt.%的量存在于根据本公开的组合物中,并且倍他米松以0.005或0.01或0.02或0.03或0.04或0.05或0.06或0.07或0.08或0.09或0.10wt.%的量存在于根据本公开的组合物中。
在个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以1.0到3.0wt.%的量存在于根据本公开的组合物中,并且倍他米松以0.01到0.05wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以0.001到25wt.%的量存在于根据本公开的组合物中,并且阿片类药物以0.01到20wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以0.001到25wt.%的量存在于根据本公开的组合物中,并且非甾体抗炎药(NSAID)以0.1到20wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以0.5或1.0或1.5或2.0或2.5或3.0wt.%的量存在于根据本公开的组合物中,并且布洛芬或双氯芬酸以0.5或1.0或1.5或2.0或2.5或3.0wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以1到3wt.%的量存在于根据本公开的组合物中,并且布洛芬或双氯芬酸以1wt.%到4wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以2wt.%的量存在于根据本公开的组合物中,并且布洛芬或双氯芬酸以2wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以2到3wt.%的量存在于根据本公开的组合物中,并且辣椒素以0.01到2.5wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以2或3或4wt.%的量存在于根据本公开的组合物中,并且辣椒素以0.025或0.5或1wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以2到3wt.%的量存在于根据本公开的组合物中,并且利多卡因以0.5到10wt.%的量存在于根据本公开的组合物中。
在一个实施例中,以组合物的总重计S1P受体调节剂(例如式(I)化合物)可以2到3wt.%的量存在于根据本公开的组合物中,并且利多卡因以1到5wt.%的量存在于根据本公开的组合物中。
在公开组合物中某个量的式(I)化合物的以上所述任一实施例中,式(I)化合物可以是式(III)化合物:
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2选自H、氘、F、Cl、Br、CN、CF3、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L选自H、氘、Me和Cl;并且
其中A如上所定义。
式(I)化合物或其药学上可接受的盐可以组合制剂使用。例如,式(I)化合物可与像(不限于)环孢菌素A、甲胺喋呤、类固醇、皮质类固醇、非甾体抗炎药、炎性细胞素抑制剂、激酶抑制剂(例如JAK激酶)、免疫调节剂(包括生物制剂)、抗病毒剂(包括但不限于阿昔洛韦、5-氟脲嘧啶、更昔洛韦、伐昔洛韦、阿糖腺苷或齐多夫定和广谱抗病毒剂(FrontMicrobiol,2015;6:517))、抗生素(包括但不限于阿莫西林、头孢洛林、粘杆菌素、达托霉素、厄他培南、磷霉素、盘尼西林、雷帕霉素或替加环素)、或抗真菌剂(包括但不限于两性霉素、脂质体两性霉素B、氟康唑、氟胞嘧锭、米卡芬净、泊沙康唑和伏立康唑)这样的其它治疗活性化合物组合使用。
式(I)化合物或其药学上可接受的盐可与像阿片类药物、皮质类固醇、非甾体抗炎药、吗啡、芬太尼、曲马多、美沙酮、羟考酮、吲哚美辛、双氯芬酸、布洛芬、萘普生、塞来昔布、阿米替林、去甲阿密替林、地昔帕明、氟西汀、帕罗西汀、度洛西汀/文拉法、那密浓、加巴喷丁、环苯扎林、巴氯芬、氯胺酮、酪洛芬、可乐宁、维拉帕米这样的其它治疗活性化合物组合使用。
包含式(I)化合物或其药学上可接受的盐以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的各种组合物可与其它赋形剂组合使用,并且/或者各活性成分可随着像软膏、凝胶或洗剂这样的制剂被涂覆并散布在像(不限于)皮肤损害(牛皮癣、湿疹)、创伤这样的受影响部分;并且/或者被吸入以曝露于发生在(但不限于)肺炎、慢性阻塞性肺病(COPD)或哮喘中的肺部受影响部分的表面;并且/或者作为控释装置被施用或移植到像(但不限于)动脉粥样硬化病变、癌症肿瘤、缺血性损伤或移植物这样的受影响部分的外围中或处;并且/或者作为控释装置被施用或移植到需要愈合和/或再生(包括但不限于骨再生、肌肉再生、缺血性损伤部位、创伤处的愈合/再生)的受影响部分的外围中或处。
根据本公开的组合物可以为滴眼剂形式。该滴剂可用来治疗像(但不限于)眼睛发炎、疼痛、视网膜病、黄斑变性、眼色素层炎和青光眼这样的眼睛疾病。
根据本公开的组合物可以为滴鼻剂形式。该滴剂可用来治疗像(但不限于)鼻部发炎、鼻充血、鼻炎、鼻息肉、鼻窦炎、疼痛、偏头痛和头痛这样的适应症。
根据本公开的组合物可以为滴耳剂形式。该滴剂可用来治疗像(但不限于)耳炎、耳部湿疹、耳部牛皮癣、疼痛、慢性溃疡、创伤、感染和耳神经再生这样的耳部疾病。
根据本公开的组合物可以为吸入剂形式。该吸入剂可用来治疗像(但不限于)肺炎、急性肺损伤、哮喘、COPD和肺部动脉高血压这样的肺病。
根据本公开的组合物可用来治疗像(但不限于)牛皮癣、湿疹、皮炎、蜂窝织炎、光化性角化病、痤疮、皮肤T细胞淋巴瘤、基底细胞癌、黑素瘤、白斑病、创伤、瘙痒、疼痛、秃头症和皮肤疼痛这样的皮肤病。
根据本公开的组合物可用来治疗像(但不限于)关节发炎、关节炎、类风湿性关节炎、痛风和骨关节炎这样的关节问题。
根据本公开的组合物可用来治疗像(但不限于)缺血性损伤、脊髓损伤、运动员损伤、肌肉损伤和肌肉痛性痉挛、肌肉疼痛、肌痛、或背部疼痛这样的损伤。组合物可作为局部涂覆、局部递送、或植入被施用到损伤/炎症部位的外围中或处。
根据本公开的组合物可用来治疗像(但不限于)痔疮、血管异常和炎症、血管病变、慢性创伤或腿溃疡这样的血管问题。
根据本公开的组合物可用来治疗像(但不限于)神经痛、伤害性疼痛、神经性疼痛、炎性疼痛、创伤疼痛、紧张性头痛、疱疹神经痛、肌肉疼痛、关节疼痛、背部疼痛、创伤疼痛、运动损伤疼痛和其它疼痛这样的疼痛。
根据本公开的组合物可用来治疗像(但不限于)肠炎、脉管异常、创伤、溃疡、溃疡性结肠炎和克罗恩氏病这样的肠胃问题。
根据本公开的组合物可用来治疗动脉粥样硬化损害。可将组合物施用到损害外围中或处。
根据本公开的组合物可用来治疗癌症。可将组合物施用到像癌症肿瘤这样的癌症的外围中或处。
根据本公开的组合物可用于骨再生、肌肉再生、上皮细胞溃疡治疗、创伤愈合、治疗性血管生成和坏疽治疗。
根据本公开的组合物可用于像(但不限于)角膜移植、肾脏移植和肝脏移植这样的移植目的,。
根据本公开的组合物可用来治疗像(但不限于)肾脏(肾病)、前列腺(前列腺炎)、尿道(炎症)、胰脏(胰腺炎)、结肠(结肠炎)、肝脏(肝病)、深层组织(神经病变、炎症、变性)这样的内脏器官的炎症和/或血管异常、溃疡、创伤和缺血性损伤。可将制剂施用到受影响区域的外围中或处。
在整个该说明书中,术语“包含(comprises)”或“包含(comprising)”或由此产生的表述变体的使用应被看作表明存在所陈述的特征、整数、步骤或组分,但并不排除存在或添加未具体提到的一个或多个其它特征、整数、步骤、组分或其群组。
附图说明
图1显示各种S1P受体调节剂通路。
图2显示口服AKP给药对BALB/c小鼠中二硝基氟苯(DNFB)诱导的迟发型过敏反应(DTH)的体内影响。
图3显示佛波酯介导的刺激性接触性皮炎小鼠模型中AKP(一种式(I)化合物)、倍他米松或组合的局部效能。
图4显示牛皮癣研究中AKP(一种式(I)化合物)的临床效果。
具体实施方式
应理解,在公开和描述本发明组合物和/或方法之前,除非另外指出,否则本发明并不限于特定的组合物、组分、设计、方法等,因为它们可能会有所变化,除非另外表明。还应理解,本文使用的术语仅用于描述特定实施例的目的,并不旨在进行限制。
实例
实例1
鞘胺醇-1-磷酸酯(S1P)受体的活性
式(I)化合物显示S1P受体活性,特别是1型受体激动活性。S1P1测试系统是结合到表达S1P1人类受体的CHOK1细胞的细胞膜中的GTP伽马-S35。在这些受体上对化合物进行测试并产生浓度-效果(剂量响应)曲线。该分析提供各化合物相对于S1P的效能(Emax)和效力(EC50),并在S1P1受体上展示<2nM的EC50。式(I)化合物降解S1P1受体的倾向性较低。
实例2
抗炎活性
当在LPS刺激的巨噬细胞(RAW细胞)上测试时式(I)化合物显示附加抗炎活性。促炎细胞素和因子在炎症、癌症和其它适应症中被过度表达。众所周知脂多糖在单核细胞(RAW细胞)中会诱导各种促炎因子,并评估化合物对LPS刺激的细胞的效能,以评估对肿瘤坏死因子(TNFα)、白细胞介素(IL1β、IL6)、以及像诱导性氧化氮合酶(iNOS)、COX-2和血管内皮生长因子(VEGF)这样的因子的抑制。当在1到5μM的范围内体外使用时,式(I)化合物(AKP)显著地抑制多种促炎细胞素和因子(包括通透性因子)。
实例3
免疫介导的皮肤发炎模型中的效能
代表性的式I化合物的制剂已经在迟发型过敏反应(DTH)反应模型中显示出有有效性。DTH是细胞介导的免疫的表达,并且在许多炎性疾病(包括炎性皮肤适应症)的病状和慢性化中起主要作用。最典型的DTH现象之一是接触性超敏反应,其特征在于肿胀和增加组织水平的细胞素。接触性超敏反应(CHS)是响应于皮肤敏感和反应性半抗原刺激而产生的T细胞介导的免疫反应,所述反应性半抗原能够直接与可溶的和细胞相关的蛋白结合,并在自身MHC产物的情况下被T细胞识别。识别皮肤中的抗原-蛋白复合物的细胞是郎格罕氏细胞(LC)。局部应用过敏原之后,郎格罕氏细胞(LC),诱导皮肤中的免疫应答的主要的抗原呈递细胞(APC),显示表面MHCII类分子的增强表达,并开始从皮肤移动到区域淋巴结(特异性淋巴细胞活化被认为在其中发生)。第二次与半抗原接触之后,T细胞首先聚集到组织中,然后被抗原呈递细胞活化,从而产生介导局部炎症的细胞素。髓过氧化物酶(MPO)是一种仅存在于嗜中性粒细胞颗粒中的酶,其通常用作粒细胞浸润指标。
作为口服治疗的AKP(一种式(I)化合物)的效果在BALB/c小鼠中的二硝基氟苯(DNFB)诱导的迟发型过敏反应(DTH)中进行评估。将总共18只雌性BALB/c小鼠随机分为2组,第1组:经AKP的运载体治疗的DTH(N=9);第2组:经AKP-11治疗的DTH,每日2次,剂量为3mg/Kg(N=9)。DTH的诱导如下进行:在第0天和第1天,将刮净的小鼠腹部皮肤用25μL0.5%的丙酮/橄榄油(4∶1)中的DNFB致敏。在第5天,用20μL0.3%的DNFB刺激小鼠右耳的每侧。作为对照,第1组小鼠施用等量的运载体。在刺激之前和刺激24h之后用千分尺测量耳朵厚度。刺激24h之后测量耳朵重量。处死时,收集右耳样品并用于组织MPO活性。
DNFB诱导显著的耳朵水肿响应,这被耳朵厚度和耳壳重量的显著增加证实。施用AKP显著减小耳朵厚度和耳朵重量,包括MPO活性。
图2在BALB/c小鼠中口服施用AKP对二硝基氟苯(DNFB)诱导的迟发型过敏反应(DTH)的体内效果。
实例4
炎性皮肤疾病模型中的局部效能
代表性的式(I)化合物的制剂在佛波酯介导的炎症中显示出有效性。局部施用佛波酯会刺激蛋白激酶C(PKC)、COX、LOX的活性、自由基的形成(包括调节TNF-α产生的介体的合成)。整个过程介导如炎性皮肤疾病(例如牛皮癣、湿疹及其它)中所观察到的炎症和细胞增生。
AKP(一种式(I)化合物)的局部效能在佛波酯介导的刺激性接触性皮炎模型中测定。将24只动物(瑞士白化病小鼠)分成4组(G1-4),每组6只;G1(经对照和运载体治疗)、G2(经PMA刺激和运载体治疗)、G3(经PMA刺激和氯倍米松治疗)和G4(经PMA刺激和AKP治疗)。局部施用AKP(3%的制剂;或者作为DMSO溶液)显示出对耳炎的显著抑制(>40%;p<0.05)。式(I)化合物在减轻炎症上显示与类固醇(倍他米松)的协同效应。单独的式(I)化合物或类固醇(倍他米松)显示类似的和显著的效能并使耳朵肿胀(炎症)减小30%(p>0.05)。如图3(在佛波酯介导的刺激性接触性皮炎小鼠模型中AKP、倍他米松或组合的局部效能)所示,该组合使耳朵肿胀(炎症)减小43%(p>0.001)。
尽管通过局部施用AKP(式(I)化合物)非常有效,但是它并未改变血液中的淋巴细胞计数。
皮质类固醇涉及各种副作用,例如皮肤萎缩、延迟创伤愈合、肌肉萎缩/肌肉病变、真皮萎缩、骨质疏松、骨坏死、青光眼、疼痛、愈合中断(《涉及肾上腺糖皮质激素副作用的机制(mechanisms involved in the side effects of glucocorticoids)》,Heike Schacke等人,Pharmacol Therap,2002,96,23-43)、肺萎缩(《类固醇诱导的肌肉病变及其对呼吸道疾病的重要性:再发现的已知疾病(Steroid-induced myopathy and its significanceto respiratory disease:a known disease rediscovered)》,P.N.R.Dekhuijzen,M.Decramer,EurRespirJ 1992,5,997-1003)。
一个S1P受体介导的机制(特别是S1P1)涉及骨再生(《通过从明胶水凝胶双重释放巨噬细胞募集剂和富血小板血浆增强骨再生(Enhancement ofbone regeneration bydual release ofa macrophage recruitment agent and platelet-rich plasma fromgelatinhydrogels)》,Yang-HeeKim等人,Biomaterials,2014,35(1),214-224)、肌肉愈合(《增加的鞘胺醇-1-磷酸酯会改进急性损伤的mdx小鼠中的肌肉再生(Increasedsphingosine-1-phosphate improves muscle regeneration in acutely injured mdxmice)》,Nicholas Ieronimakis等人,Ieronimakis等人,SkeletalMuscle 2013,3:20)、神经元再生(《响应于PC12细胞中的氧化应激S1P1受体的活化调控PI3K/Akt/FoxO3a通道(Activation of S1P1Receptor Regulates PI3K/Akt/FoxO3a Pathway in Response toOxidative Stressin PC12 Cells)》,Safarian等人,J Mol Neurosci,2015,56,177)、疼痛减轻(《通过阻断S1P/S1PR1轴阻断并反转硼替佐米诱导的神经性疼痛(Bortezomib-induced neuropathic pain is blocked and reversed by blocking the S1P/S1PR1axis)》;Stockstill等人,JPain,2014,15(4),S60)。
尽管存在AKP(式I化合物)与皮质类固醇的协同效应以增强效能;但是考虑到AKP作为S1P1激动剂抵消皮质类固醇的不良作用(皮肤萎缩、延迟创伤愈合、肌肉萎缩/肌肉病变、真皮萎缩、骨质疏松、骨坏死、青光眼、疼痛、愈合中断),AKP与皮质类固醇组合会有另外的优点。这些组合可用于皮肤病适应症(牛皮癣、湿疹、痤疮等)、关节炎相关适应症(类风湿性关节炎、痛风、骨关节炎、牛皮癣性关节炎等)、肺相关适应症(哮喘、COPD等)、以及眼睛相关适应症(青光眼、视网膜病等)、脊髓损伤、以及其它损伤。
实例5
I期临床研究中局部使用的临床效果
代表性的式(I)化合物的制剂在牛皮癣患者中显示出有效性和安全性。在临床研究中,对健康志愿者和具有轻度到中度牛皮癣的牛皮癣患者每天进行治疗,进行28天。在该局部研究中无严重不良作用,并且AKP在血液中不明显。测量局部牛皮癣严重性指数(LPSI)并记录显著的有效性(>40%;p=0.0016;图4)。图4显示AKP的临床效果。
式(I)化合物具有经证实的S1P受体活性和其它抗炎效果。因此,包含式(I)化合物以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物的组合物可用于宽范围的适应症中,所述适应症需要适合此类病状或适应症的各种制剂具有宽范围的活性以处理不同的病状。这些适应症可具有一种或多种病理学因子,例如过度表达促炎细胞素和因子和/或异常免疫应答的炎症部位,并且/或者血管在疾病部位是异常的,并且/或者VEGF被过度表达。
实例6
3%w/w的式(I)S1P1激动剂游离碱软膏组合物,用于局部使用。
将凡士林(30.8g)和Gelucire 50/13球粒(4g)的混合物在~70℃下熔融并搅拌,直到均匀为止(~15min)。在剧烈搅拌下向其中加入式(I)化合物游离碱(1.2g)在无水DMSO(4m1)中的溶液。该混合物冷却到室温,得到浑浊软膏(40g),其包含3%(w/w)的式(I)化合物游离碱。
实例7
3%w/w的式(I)HCl盐凝胶组合物,用于局部使用。
制备H2O(4.85g)、丙二醇(4.85g)和CELLOSIZE PCG 10(0.3g)的溶液。将该混合物在室温下搅拌过夜,得到透明的粘稠凝胶(10g)。将该凝胶(6g)与EtOH(4g)混合,并将所得混合物在~70℃下搅拌2h。立即向其中加入溶于无水DMSO(3g)中的式(I)化合物的盐酸盐(0.45g),并加入EtOH,得到最终质量15g。将所得混合物在~70℃下搅拌1小时,得到具有优异的稳定性和可铺展性的透明的无色凝胶。
实例8
3%w/w的式(I)甲磺酸盐凝胶组合物,用于局部使用。
当用实例7的式(I)化合物的盐酸盐替代式(I)化合物的甲磺酸盐时,同样的方法得到标题组合物。
实例9
3%的式(I)甲磺酸盐液体组合物,用于局部使用。
将式(I)化合物的甲磺酸盐(0.3g)溶于50%的含水DMSO中(4g),并用EtOH将其稀释到10g,得到无色液体状标题制剂(10g)。
实例10
具有聚乙烯吡咯酮(PVP)的1%的式(I)HCl盐液体组合物,用于局部使用。
将式(I)化合物的HCl盐(0.05g)溶于80%的含水EtOH中(4.45ml)。向其中加入聚乙烯PVP(0.5g),并在室温下搅拌该混合物,直到完全均匀为止(~1h),得到一稳定的无色溶液,其在涂覆到皮肤上之后形成薄膜。
实例11
0.5%的式(I)甲磺酸盐无菌水溶液,用于注射/液体口服制剂/滴眼剂和滴耳剂给药。
通过注射器向具有式(I)化合物的甲磺酸盐(0.005g)的无菌容器中加入无菌等渗溶液(1ml),并在室温下通过摇晃搅拌所得混合物,直到均匀为止,其可用于注射、滴眼剂或滴耳剂或口服。
实例12
式(I)的局部贴片制剂。
可将式(I)化合物和其它成分(包括像(不限于)DMSO、聚乙烯基吡咯烷酮(PVP)、月桂酸甘油酯、乳酸月桂酯、气溶胶、EUDRAGIT这样的增溶剂或渗透增强剂)溶于溶剂(乙醇、丙醇、异丙醇)中。加入粘合剂并混合,直到均匀为止。可将该均匀浆液在最佳温度下浇注到释放层(硅酮或含氟聚合物涂覆的聚酯膜)上并干燥。
实例13
3%w/w的式(I)S1P1激动剂游离碱与1%的烟酰胺和2%的维他命E的软膏组合物,用于局部使用。
将无水DMSO(2ml)中的式(I)化合物的游离碱(0.6g)、烟酰胺(0.2g)、维他命E(d异构体;0.4g)、Gelucire 50/13球粒(2g)、Polysorb 20(0.6g)在~55℃下搅拌,直到均匀为止(~30min)。加入熔融凡士林,使得最终重量为20g。将其在~50℃下剧烈搅拌15min,冷却至室温,得到灰白色软膏。
实例14
3%w/w的式(I)S1P1激动剂游离碱和0.05%w/w的倍他米松的软膏组合物,用于局部使用。
将凡士林(30.78g)和Gelucire 50/13球粒(4g)的混合物在~70℃下熔融并搅拌,直到均匀为止(~15min)。在剧烈搅拌下向其中加入式(I)化合物游离碱(1.2g)和倍他米松(0.02g)在无水DMSO(4g)中的溶液。让该混合物冷却至室温,得到浑浊软膏(40g),其包含3%(w/w)的式(I)化合物游离碱和0.05%的倍他米松。
实例15
2%w/w的式(I)HCl盐和1%的双氯芬酸的凝胶组合物,用于局部使用。
制备H2O(4.85g)、丙二醇(4.85g)和CELLOSIZE PCG10(0.3g)的溶液。将该混合物在室温下搅拌过夜,得到透明的粘稠凝胶(10g)。将该凝胶(6g)与EtOH(3.9g)混合,并且将所得混合物在~70℃下搅拌2h。立即向其中加入式(I)化合物的盐酸盐(0.3g)和双氯芬酸(0.15g)溶于无水DMSO(4.5g)中的混合物,并加入EtOH,最终质量达到15g。将所得混合物在~70℃下搅拌1小时,得到具有优异稳定性和铺展性的透明无色凝胶状标题产物。
实例16
2%w/w的式(I)HCl盐和0.12%的吗啡盐酸盐的凝胶组合物,用于局部使用。
当用实例15的双氯芬酸盐酸盐替代吗啡盐酸盐(18mg)时,同样的方法得到标题组合物。
应理解,尽管本公开结合其具体实施例进行了描述,但是以上说明旨在说明而不是限制本公开的范围。其它方面、优势、及变型对于本公开所属领域的技术人员而言将会是显而易见的。因此,给出以下实例是为了为本领域技术人员提供如何制备和使用所公开的组合物的充分公开和描述,而并非旨在对本公开的范围进行限制。
为了简明起见,本文中仅仅明确公开了某些数值范围。但是,从任何下限开始的范围可与任何上限组合以列出未明确提及的范围,并且从任何下限开始的范围可与任何其它下限组合以列出未明确提及的范围,以同样方式,从任何上限开始的范围可与任何其它上限结合以列出未明确提及的范围。
所有引用的文件对于所有允许这种并入的司法管辖通过引用完全并入本文,并且达到此类公开与本公开的描述相一致的程度。
Claims (29)
1.一种组合物,其包含至少一种S1P受体调节剂以及选自由类固醇、阿片类药物和非甾体抗炎药组成的群组的一种或多种的至少一种化合物。
2.根据权利要求1所述的组合物,其中所述至少一种S1P受体调节剂为式(I)化合物:
其中R1选自氢、氘、卤素、CN、CF3、-COOH、酰胺、磺酰胺、芳氧基、硝基和烷基链(C1-5),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基、环烷基(C3-7)和碳环中的一种或多种;
其中R2选自氢、氘、卤素、CN、CF3、烷基链(C1-4),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基或环烷基(C3-7)和碳环中的一种或多种;
其中R3选自氢、氘、卤素、烷基链(C1-7),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基或环烷基(C3-7)和碳环中的一种或多种;
其中R4选自氢、氘、卤素、CN、CF3、烷基链(C1-4),所述烷基链任选地包含氘、O、S、NR’(R’=H、烷基、环烷基)、卤素、重键、杂环、芳基和环烷基(C3-7)中的一种或多种;
其中A为任选的,并且当存在时经选择由N取代一个或多个环碳原子;
其中L选自氢、氘、F、Cl、Br和烷基(C1-3);
其中G为选自以下之一的基团:
其中R选自H、COOH、烷基(C1-4)和羟基烷基(C1-4);
其中R’和R”独立地选自H和烷基(C1-4);
其中R”’选自OH、-OPO3H2和生理学上可接受的盐;
其中表示任选的桥连基团;
星号表示基团G在式(I)中的连接。
3.根据权利要求2所述的组合物,其中所述式(I)化合物具有式(II):
其中R1、R2、R3、R4、A、L、R、R’和R”如权利要求2所定义。
4.根据权利要求2所述的组合物,其中在式(II)化合物中:
R1选自F、Cl、Br、CN、CF3、NO2、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
R2选自H、氘、F、Cl、Br、CN、CF3、NO2、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
R4选自H、氘、Me和Et;
R选自H、Me或-CH2OH;
R’选自H和Me;
R”选自H和Me;
L选自H、氘、Me和Cl;并且
A如权利要求2所定义。
5.根据权利要求2所述的组合物,其中在所述式(I)化合物中:
R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
R2为H;
R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
R4选自H、氘、Me和Et;
R选自H、Me或-CH2OH;
R’选自H和Me;
R”选自H和Me;
L为H;并且
A不存在。
6.根据权利要求3所述的组合物,其中所述式(I)化合物具有式(III):
其中R1、R2、R3、R4、A、L、R和R’如权利要求2所定义。
7.根据权利要求3所述的组合物,其中所述式(I)化合物具有式(III):
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2选自H、氘、F、Cl、Br、CN、CF3、Me、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L选自H、氘、Me和Cl;并且
其中A如权利要求2所定义。
8.根据权利要求3所述的组合物,其中所述式(I)化合物具有式(III):
其中R1选自F、Cl、Br、CN、CF3、Me、NO2、OMe、OEt、OPr、O-iPr、O-异丁基、O-异戊基、O-环戊基、O-烯丙基、O-苄基和
其中R2为H;
其中R3选自H、氘、Pr、丁基、OMe、OEt、OPr、OiPr、O-异丁基、O-异戊基、O-丁基、O-戊基、O-环戊基、O-烯丙基、O-苄基和
其中R4选自H、氘、Me和Et;
其中R选自H、Me或-CH2OH;
其中R’选自H和Me;
其中L为H;并且
其中A不存在。
9.根据权利要求1到8中任一项所述的组合物,其中所述类固醇为皮质类固醇。
10.根据权利要求9所述的组合物,其中所述皮质类固醇选自由以下组成的群组:阿氯米松、安西奈德、氯地米松、倍他米松、布地缩松、环索奈德、氯倍米松、去氢氯氟美松、氯可托龙、氯泼尼醇、可的伐唑、地夫可特、去氧皮质酮、羟泼尼缩松去羟米松、地塞米松、双氟拉松、双氟米松、二氟泼尼酯、氟氯洛龙、氟氢化可的松、氟氢缩松、氟米松、氟尼缩松、醋酸氟轻松、氟欣诺能、氟可丁、氟考龙、氯甲龙、氟培龙、氟替卡松、泼尼松、醛基缩松、氯氟舒松、卤米松、醋丙氢化可的松、丁丙氢化可的松、丁酸氢化可的松、氯替泼诺、甲羟松、甲泼尼松、甲泼尼龙、醋丙甲泼尼龙、糠酸莫米松、对氟米松、泼尼卡松、泼尼松、氢化泼尼松、泼尼立定、利美索龙、替可的松、氟烃氢化泼尼松和乌倍他松、其药学上可接受的盐、酯、溶剂化物、水合物和衍生物、及其混合物。
11.根据权利要求10所述的组合物,其中所述皮质类固醇为倍他米松。
12.根据权利要求1到11中任一项所述的组合物,其中所述阿片类药物选自由以下组成的群组:阿芬太尼、烯丙罗定、阿法罗定、氨苄哌替啶、苄吗啡、贝齐米特、丁丙诺啡、布托啡诺、氯尼他秦、可待因、二氢脱氧吗啡、右旋摩拉胺、地佐辛、双胺丙酰胺、二乙酰吗啡、二氢可待因、二氢埃托啡、二氢吗啡、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、依他佐辛、依索庚嗪、乙甲噻丁、乙基吗啡、依托尼秦、埃托啡、芬太尼、海洛因、氢可酮、氢化二氢吗啡酮、羟基度冷丁、异美沙酮、凯托米、左啡诺、左芬啡烷、洛芬太尼、哌替啶、美普他酚、美他佐辛、美沙酮、米托本、吗啡、麦罗啡、纳布啡、那碎因碱、尼可吗啡、去甲左啡诺、去甲美沙酮、纳洛芬、去甲吗啡、诺匹哌酮、鸦片、羟考酮、羟吗啡酮、阿片全碱、喷他佐辛、非那多松、非诺啡烷、非那佐辛、苯哌利定、匹米诺定、哌腈米特、普罗庚嗪、二甲哌替啶、丙哌利定、丙吡胺、丙氧吩、舒芬太尼、痛立定、曲马多、其药学上可接受的盐、溶剂化物、水合物和衍生物、及其混合物。
13.根据权利要求1到12中任一项所述的组合物,其中所述非甾体抗炎药选自由以下组成的群组:阿司匹林、布洛芬、萘普生、双氯芬酸、Cox-2抑制剂、依托度酸、吲哚美辛、酪洛芬、吡罗昔康、folmetin、替诺昔康、美洛昔康、美洛昔康、甲芬那酸、异丁芬酸、酪洛芬、其药学上可接受的盐、溶剂化物、水合物和衍生物、及其混合物。
14.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以0.001wt.%到25wt.%的量存在于所述组合物中,并且所述类固醇以0.005wt.%到2wt.%的量存在于所述组合物中。
15.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以0.001wt.%到25wt.%的量存在于所述组合物中,并且所述倍他米松以0.005wt.%到2wt.%的量存在于所述组合物中。
16.根据权利要求1到15中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以1wt.%到3wt.%的量存在于所述组合物中,并且倍他米松以0.01wt.%到0.05wt.%的量存在于所述组合物中。
17.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以0.001wt.%到25wt.%的量存在于所述组合物中,并且所述阿片类药物以0.01wt.%到20wt.%的量存在于所述组合物中。
18.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体凋节剂以0.001wt.%到25wt.%的量存在于所述组合物中,并且所述非甾体抗炎药(NSAID)以0.1wt.%到20wt.%的量存在于所述组合物中。
19.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以2wt.%到3wt.%的量存在于所述组合物中,并且布洛芬或双氯芬酸以1wt.%到2wt.%的量存在于所述组合物中。
20.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以2wt.%到3wt.%的量存在于所述组合物中,并且辣椒素以0.01wt.%到2.5wt.%的量存在于所述组合物中。
21.根据权利要求1到13中任一项所述的组合物,其中以所述组合物的总重计所述S1P受体调节剂以2wt.%到3wt.%的量存在于所述组合物中,并且利多卡因以0.5wt.%到10wt.%的量存在于所述组合物中。
22.一种通过给有此需要的对象施用有效量的根据权利要求1到21中任一项所述的组合物来治疗或预防炎症介导的疾病、免疫介导的疾病或疼痛的方法。
23.根据权利要求22所述的方法,其中所述炎症介导的疾病或免疫介导的疾病选自由以下组成的群组:牛皮癣、湿疹、白斑病、秃头症、类风湿性关节炎、骨关节炎、痛风、中风、痔疮/痔疮、肺损伤、肝损伤、急性肾损伤、哮喘、慢性阻塞性肺病(COPD)、眼色素层炎、视网膜病、肾病、黄斑变性、青光眼、耳炎、过敏反应、败血症、流感、鼻炎和瘙痒症。
24.一种通过给有此需要的对象施用有效量的根据权利要求1到21中任一项所述的组合物来治疗或预防疼痛的方法。
25.根据权利要求24所述的方法,其中所述疼痛选自由以下组成的群组:关节疼痛、关节炎、痛风疼痛、背部疼痛、肌肉疼痛、神经病变、神经疾病、运动损伤疼痛或创伤疼痛。
26.根据权利要求22到25中任一项所述的方法,其中所述组合物经局部、口服、经皮、肠胃外、鼻内、经眼部或经直肠给药。
27.根据权利要求22到26中任一项所述的方法,其中所述组合物为固体、贴片、粉末、液体、半固体、软膏、凝胶、喷剂、气雾剂、洗剂、片剂、胶囊、液体、溶液、混悬剂、乳剂或糖浆形式。
28.根据权利要求22到27中任一项所述的方法,其中所述组合物为通过植入或注射或装置施用的缓释剂型(贮库制剂)。
29.根据权利要求22到28中任一项所述的方法,其中所述组合物与像小分子、生物制剂、抗病毒剂、抗菌剂、抗癌药或其它抗炎药这样的其它治疗活性化合物组合施用。
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EP2344484A1 (en) * | 2008-10-17 | 2011-07-20 | Akaal Pharma Pty Ltd | S1p receptors modulators and their use thereof |
WO2014063199A1 (en) * | 2012-10-26 | 2014-05-01 | Akaal Pharma Pty Ltd | Organic compounds |
US20150045332A1 (en) * | 2012-03-26 | 2015-02-12 | Rolf E. Swenson | Novel Sphingosine 1-Phosphate Receptor Antagonists |
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WO2003020313A1 (fr) * | 2001-09-04 | 2003-03-13 | Ono Pharmaceutical Co., Ltd. | Medicaments contre les maladies respiratoires renfermant un agent de regulation du recepteur de la sphingosine-1-phosphate |
TWI322008B (en) * | 2003-01-31 | 2010-03-21 | Kaneka Corp | Fatigue improving agent including reduced coenzyme q10 |
WO2012015758A2 (en) * | 2010-07-30 | 2012-02-02 | Saint Louis University | Methods of treating pain |
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2016
- 2016-08-11 RU RU2018108109A patent/RU2018108109A/ru not_active Application Discontinuation
- 2016-08-11 MA MA042625A patent/MA42625A/fr unknown
- 2016-08-11 JP JP2018526972A patent/JP2018527406A/ja not_active Withdrawn
- 2016-08-11 CN CN201680052675.8A patent/CN108024998A/zh active Pending
- 2016-08-11 US US15/751,709 patent/US20180228778A1/en not_active Abandoned
- 2016-08-11 EP EP16834321.8A patent/EP3334428A4/en not_active Withdrawn
- 2016-08-11 CA CA2993621A patent/CA2993621A1/en not_active Abandoned
- 2016-08-11 AU AU2016305496A patent/AU2016305496A1/en not_active Abandoned
- 2016-08-11 KR KR1020187005158A patent/KR20180035840A/ko unknown
- 2016-08-11 WO PCT/AU2016/050732 patent/WO2017024355A1/en active Application Filing
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2018
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2344484A1 (en) * | 2008-10-17 | 2011-07-20 | Akaal Pharma Pty Ltd | S1p receptors modulators and their use thereof |
US20150045332A1 (en) * | 2012-03-26 | 2015-02-12 | Rolf E. Swenson | Novel Sphingosine 1-Phosphate Receptor Antagonists |
WO2014063199A1 (en) * | 2012-10-26 | 2014-05-01 | Akaal Pharma Pty Ltd | Organic compounds |
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US20180228778A1 (en) | 2018-08-16 |
JP2018527406A (ja) | 2018-09-20 |
RU2018108109A3 (zh) | 2020-01-17 |
WO2017024355A1 (en) | 2017-02-16 |
MA42625A (fr) | 2018-06-20 |
CA2993621A1 (en) | 2017-02-16 |
KR20180035840A (ko) | 2018-04-06 |
RU2018108109A (ru) | 2019-09-12 |
HK1254769A1 (zh) | 2019-07-26 |
EP3334428A4 (en) | 2019-07-17 |
EP3334428A1 (en) | 2018-06-20 |
AU2016305496A1 (en) | 2018-03-08 |
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