CN105007909A - 用于治疗眼部炎性疾病的甲酰基肽受体2激动剂的用途 - Google Patents
用于治疗眼部炎性疾病的甲酰基肽受体2激动剂的用途 Download PDFInfo
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Abstract
本发明涉及一种用于治疗需要此类治疗的受试者的眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种甲酰基肽受体2激动剂的药物组合物。
Description
相关申请
本申请要求2013年3月6日提交的美国临时专利申请序列号61/773,773的权益,所述美国临时专利申请的公开内容在此通过引用整体并入。
发明背景
1.发明领域
本发明涉及一种用于治疗需要此类治疗的受试者的眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种甲酰基肽受体2(FPR2)激动剂的药物组合物。
2.相关技术概述
甲酰基肽受体(FPR)家族不仅参与宿主对病原体的防御,而且还参与传感可提供细胞功能障碍信号的内部分子。这个家族在人类中包括3个成员,并且这个家族的一个成员FPR2(也称为FPRL-1、ALXA4)是主要在炎性细胞(如,单核细胞和嗜中性粒细胞)上以及在T细胞上表达的G蛋白偶联受体,并且已显示其在炎症和人体病理期间的白细胞运输中起着关键性作用(Chiang N,Serhan CN,Dahlen,S,DrazenJM,Hay DWP,Rovati E,Shimizu T,Yokomizo T,Brink,C.The lipoxinreceptor ALX:Potent ligand-specific and stereoselective actions in vivo.Pharmacological Reviews 2006;58:463-519)。FPR2是响应大量外源性和内源性配体的异常混杂的受体,所述配体包括血清淀粉样蛋白A(SAA)、趋化因子变体sCKβ8-1、神经保护肽humanin、抗炎性类二十烷酸脂氧素A4(LXA4)和糖皮质激素调节性蛋白膜联蛋白A1(Chiang N,Serhan CN,Dahlen,S,Drazen JM,Hay DWP,Rovati E,Shimizu T,Yokomizo T,Brink,C.The lipoxin receptor ALX:Potentligand-specific and stereoselective actions in vivo.PharmacologicalReviews 2006;58:463-519)。FPR2在多个系统中转导LXA4的抗炎效应,并且已显示其在炎症消退中起着关键作用(Dufton N,Perretti M.Therapeutic anti-inflammatory potential of formyl peptide receptoragonists.Pharmacology&Therapeutics 2010;127:175-188)。FPR2敲除小鼠在疾病状况中显示如通过所述受体的生物作用所预期的放大的炎症(Dufton N,Hannon R,BrancaleoneV,Dalli J,Patel HB,Gray M,D’Aquisto F,Buckingham JC,Perretti M,Flower RJ.Anti-inflammatoryrole of the murine formyl-peptide receptor 2:Ligand-specific effects onleukocyte responses and experimental inflammation.Journal ofImmunology 2010;184:2611-2619)。
通过脂氧素A4或其类似物以及通过膜联蛋白I蛋白激活FPR2已显示通过促进炎症的主动消退产生抗炎活性,所述主动消退涉及抑制多形核嗜中性粒细胞(PMN)和嗜酸性粒细胞迁移,并且显示还刺激单核细胞迁移,使得能够以非炎性方式从炎症部位清除凋亡细胞(Maderna P,Cottell DC,Toivonen T,Dufton N,Dalli J,Perretti M,Godson C.FPR2/ALX receptor expression and internalization are criticalfor lipoxin A4and annexin-derived peptide-stimulated phagocytosis.FASEB 2010;24:4240-4249;Reville K,Cream JK,Vivers S,DransfieldI,Godson C.lipoxin A4redistributes Mysoin IIA and Cdc42inmacrophages:Implications for phagocytosis of apoptotlc leukocytes.Journal of Immunology 2006;176:1878-1888)。另外,FPR2已显示抑制NK细胞毒性并且促进T细胞的激活,这进一步促成组织损害性炎症信号的下调。FPR2/LXA4相互作用已显示有益于缺血再灌注、血管生成、眼部炎症(如,内毒素诱导的葡萄膜炎)和角膜伤口愈合的实验模型(Serhan C.Resolution phase of inflammation:Novel endogenousanti-inflammatory and proresolving lipid mediators and pathways.Annualreviews of Immunology 2007;25:101-137;Medeiros R,Rodrigues GB,Figueiredo CP,Rodrigues EB,Grumman A Jr,Menezes-de-Lima O Jr,Passos GF.Calixto JB.Molecular mechanisms of topicalanti-inflammatory effects of lipoxin A(4)in endotoxin-induced uveitis.Molecular Pharmacology 2008;74:154-161;Gronert K,Maheshwari N,Khan N,Hassan IR,Dunn M,Schwartzmann ML.A role for the mouse12/15-lipoxygenase pathways in promoting epithelial wound healing andhost defense.Journal of Biological Chemistry 2005;280:15267-15278;Leedom A,Sullivan AB,Dong B,Lau D,Gronert K.Endogenous LXA4circuits are determinants of pathological angiogenesis in response tochronic injury.American Journal of Pathology 2010;176:74-84;GronertK.Lipoxins in the eye and their role in wound healing.Prostaglandins,Leukotrienes and Essential fatty Acids.2005;73:221-229)。天然的聚烯属天然产物的固有物理化学性质阻碍了脂氧素A4和其类似物的药学效用。因此,FPR2的小分子抗炎激动剂将在尤其是眼中的炎性病症中具有多种治疗益处。相比于具有升高的IOP和眼中伤口愈合延迟的显著副作用的更广泛作用的抗炎药,如类固醇或NSAID,选择性地靶向FPR2也将具有降低副作用的益处。除迁移至眼部组织中的炎性细胞之外,FPR2还在角膜以及还有眼后部中的眼部组织中表达。因此,FPR2代表了用于研发具有过度炎症反应的眼部疾病中的新型治疗剂的一种重要的新颖的促革命性(pro-resolutionary)的分子靶标。
发明概述
本发明涉及FPR2激动剂表现眼部抗炎活性与化学稳定性且适于眼部递送的能力。这些FPR2化合物对所述受体显示良好的效能,化合物亚类例示于下表中,并且重要的是,FPR2化合物是局部活性的,且因此其可以许多形式施用,所述形式包括但不限于滴眼剂。这些化合物还可直接施用或通过施加至眼部组织的局部药物递送装置施用,以及通过静脉内、肌肉内、鞘内、皮下、口服、玻璃体内或腹膜内施用。这些化合物将可用于治疗眼部炎性疾病,包括但不限于葡萄膜炎、干眼、角膜炎、过敏性眼病、感染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、葡萄膜炎、视网膜炎、和脉络膜炎,如急性多灶性鳞状色素上皮病变,贝切特氏病(Behcet’s disease)、手术后角膜创伤愈合、由激光引起的病状、由光动力疗法引起的病状、湿性和干性年龄相关性黄斑变性(ARMD)、影响眼后部的病状,如黄斑病变和视网膜变性,包括非渗出性年龄相关性黄斑变性、渗出性年龄相关性黄斑变性、脉络膜新血管生成、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、急性黄斑神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;鸟枪弹样视网膜脉络膜病变(birdshot retinochoroidopathy)、传染病(梅毒、莱姆病(lyme)、结核病、弓形体病)、中间葡萄膜炎(睫状体扁平部炎)、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼结节病、后巩膜炎、匐行性脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征;血管疾病/渗出性疾病,如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉微动脉瘤、柯氏病(Coat’disease)、旁中心凹毛细血管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、霜样分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病变、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科病状,如交感性眼炎、葡萄膜炎性视网膜疾病、视网膜脱离、外伤、由光动力疗法引起的病状、光凝固、手术期间的血流灌注不足、放射性视网膜病变和骨髓移植性视网膜病变;增生性疾病,如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的眼组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染相关的视网膜疾病、与HIV感染相关的脉络膜疾病、与HIV感染相关的葡萄膜炎疾病、病毒性视网膜炎、急性视网膜坏死、进行性外侧视网膜坏死、真菌性视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性神经视网膜炎和蝇蛆病;遗传性病症,如色素性视网膜炎、与视网膜营养不良相关的系统性病症、先天性静止性夜盲、锥体营养不良、斯特格氏病(Stargardt’s disease)和眼底黄色斑点症、贝斯特氏病(Best’s disease)、视网膜色素上皮图形营养不良(pattern dystrophy of the retinal pigmented epithelium)、X连锁视网膜劈裂症、索斯比氏眼底营养不良(Sorsby’s fundus dystrophy)、良性的同心性黄斑病变、比蒂氏结晶样营养不良(Bietti’s crystalline dystrophy)和弹性假黄色瘤;视网膜撕裂/视网膜裂孔,如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤,如与肿瘤相关的视网膜疾病、视网膜色素上皮的先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤和眼内淋巴瘤;以及影响眼后部的各种其它疾病,如点状内层脉络膜病变、急性后部多灶性鳞状色素上皮病变、近视性视网膜变性和急性视网膜色素上皮炎、手术后角膜炎症、眼睑炎、MGD、青光眼、分支静脉阻塞、贝斯特氏卵黄状黄斑变性(Best’s vitelliform macular degeneration)、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或视网膜色素上皮(RPE)的任何其它变性疾病。
在另一方面,这些化合物将可用于治疗与以下疾病相关的眼部炎性疾病:CNS病症(如阿尔茨海默氏病(Alzheimer’s disease))、关节炎、败血症、炎性肠病、恶病质、心绞痛、类风湿性关节炎和相关炎性病症、脱发、系统性炎性疾病(如中风)、冠状动脉疾病、阻塞性气道疾病、HIV介导的逆转录病毒感染、心血管病症(包括冠状动脉疾病)、神经炎症、神经性病症、疼痛和免疫性病症、哮喘、过敏性病症、炎症、系统性红斑狼疮。
附图简述
图1FPR2激动剂显示在内毒素诱导的大鼠葡萄膜炎模型中的强力抗炎活性。
图2FPR2激动剂显示在内毒素诱导的大鼠葡萄膜炎模型中的强力抗炎活性。
图3显示如通过化合物3{[(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}乙酸所例示的在角膜创伤的兔模型中的加速愈合和再上皮化。
发明详述
本发明涉及一种用于治疗需要此类治疗的受试者的眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种FPR2激动剂的药物组合物。
在另一方面,本发明提供至少一种FPR2激动剂用于制造用以治疗哺乳动物中由FPR2介导的眼部炎性疾病或病状的药物的用途。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/668,835中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/668,835中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/668,835中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
美国专利申请S.N.13/668,835中所公开的化合物由式I表示:
其中:
R1为仲丁基、C6-10芳基、-CH2-(C6-10)芳基、-CH2-杂环、C4-8环烷基或C3-8环烯基或杂环;
R2为卤素或甲基;
R3为卤素;
R4为H、甲基或卤素;
R5为OR6或NH2;
R6为H或C2-4烷基。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/523,579中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/523,579中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/523,579中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
美国专利申请S.N.13/523,579中所公开的化合物由式II表示:
其中:
a为1且b为0;
a为0且b为1;
a为1且b为1;
R1为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基、任选取代的C3-8环烯基、-NR11R12或-OR13;
R2为任选取代的C1-8烷基或任选取代的C6-10芳基;
R3为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R4为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R5为卤素、-CF3或一S(O)nR14;
n为0、1或2;
R6为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R7为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R8为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9a为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10a为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R11为氢或任选取代的C1-8烷基;
R12为氢或任选取代的C1-8烷基;
R13为氢或任选取代的C1-8烷基;
R14为氢、CF3或任选取代的C1-8烷基;
R15为氢或任选取代的C1-8烷基;
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/673,800中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/673,800中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/673,800中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
美国专利申请S.N.13/673,800中所公开的化合物由式III表示:
R1为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R2为卤素、任选取代的C1-8烷基、CF3、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R5一起形成任选取代的10元或11元多环;
R4为氢、任选取代的C1-8烷基、
任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R5一起形成螺单环或多环的、碳环或杂环的、饱和或不饱和的任选取代的5元至10元环;
R5为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R4一起形成螺单环或多环的、碳环或杂环的、饱和或不饱和的任选取代的5元至10元环,或与R3一起形成任选取代的5元或6元环;
R6为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、N02、NR13R14、CN、SR15或SO2R16;
R7为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R8为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R10为氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH;
R11为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R12为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R13为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R14为氢、任选取代的C6-10芳基、任选取代的C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基);
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R16为OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/765,527中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/765,527中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/765,527中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
美国专利申请S.N.13/765,527中所公开的化合物由式IV表示:
其中:
R1为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基、取代或未取代的杂环或取代或未取代的C6-10芳基,或与R2一起可形成任选取代的环丁基;
R2为异丙基,或与R3一起可形成取代或未取代的3元至6元环杂环,或与R1一起可形成任选取代的环丁基、环丙基;并且
R3为氢、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-8环烷基、取代或未取代的C3-8环烯基、取代或未取代的杂环、取代或未取代的C6-10芳基,或与R2一起可形成取代或未取代的3元至6元环杂环。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用治疗有效量的包含至少一种如美国专利申请S.N.13/409,228中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/409,228中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/409,228中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
美国专利申请S.N.13/409,228中所公开的化合物由式V表示:
其中:
为单键或双键;
为单键或双键;
R1为H、卤素、-S(O)R10、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基、C3-8环烯基或羟基;
R2为H、卤素、-S(O)R10、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基、C3-8环烯基或羟基;
R3为H、卤素、-S(O)R10、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基、C3-8环烯基、C6-10芳基或羟基;
R4为H或C(O)R12;
R5为H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;
R6为H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;
Y为O或S;
X为O、NR或CH2;
Ra为C6-10芳基、杂芳基、C3-8环烷基、C3-8环烯基或H;
Rb为卤素;
c为0、1或2;
R7为H、卤素、-S(O)R10、-S(O)2R11、硝基、羟基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烯基或C3-8环烷基;
R8为H、卤素、-S(O)R10、-S(O)2R11、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烯基或C3-8环烷基;
R9为H、-S(O)2R11、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、C3-8环烯基或C3-8环烷基;
R10为-C1-6烷基、C3-8环烷基或C3-8环烯基;
R11为H、羟基、-C1-6烷基、C3-8环烷基或C3-8环烯基;
R12为H、羟基、-C1-6烷基、C3-8环烷基、C3-8环烯基、NR13R14或-OC1-6烷基;
R13为H、-C1-6烷基、C3-8环烷基、C3-8环烯基SO2R11或C(O)R15;
R14为H、-C1-6烷基、C3-8环烯基、芳基、杂环或C3-8环烷基;
R15为H、-C1-6烷基、C3-8环烯基或C3-8环烷基;并且
R为H、-C1-6烷基、C3-8环烯基或C3-8环烷基;
前提是:
当为双键时,则R5不存在;并且
当为双键时,R6不存在。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/370,472中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/370,472中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/370,472中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
如美国专利申请S.N.13/370,472中所公开的化合物由式VI表示:
其中:
A为C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R17为C1-6烷基或
B为C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R1为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R2为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R3为H、C1-6烷基或C3-8环烷基;
R4为H、C1-6烷基或C3-8环烷基;
R5a为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R5b为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R5c为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R5d为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R6为H、-S(O)2R11、-C1-6烷基、-(CH2)n NR13R14、-(CH2)m杂环、C(O)R12、NR13R14、C3-8环烷基、C6-10芳基或杂环;
R7为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R8为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R9为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
R10为H、卤素、-S(O)R15、-S(O)2R11、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、C(O)R12、NR13R14、C3-8环烷基或羟基;
X为O或S;
Y为O或S;
R11为H、羟基、-C1-6烷基、C3-8环烷基或NR13R14;
R12为H、羟基、-C1-6烷基、羟基、C3-8环烷基、NR13R14或-OC1-6烷基;
R13为H、-C1-6烷基、C3-8环烷基、SO2R11或C(O)R16;
R14为H、-C1-6烷基或C3-8环烷基;
R15为-C1-6烷基或C3-8环烷基;
R16为H、-C1-6烷基或C3-8环烷基;
n为1-4;并且
m为1-4。
在另一方面,本发明提供一种用于治疗眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种如美国专利申请S.N.13/863,934中所公开的FPR2激动剂的药物组合物,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/863,934中所公开的化合物用于制造用以治疗哺乳动物中由FPR2介导的眼部疾病或病状的药物的用途,前提是所述化合物对FPR2受体具有结合活性。
在另一方面,本发明提供至少一种如美国专利申请S.N.13/863,934中所公开的化合物用于治疗哺乳动物中由FPR2介导的眼部疾病或病状的用途,前提是所述化合物对FPR2受体具有结合活性。
如美国专利申请S.N.13/863,934中所公开的化合物由式VII表示:
式VII
其中:
n为0或1;
R1为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R2为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R3为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN、NO2、CF3、S(O)R15或S(O)2R16;
R4为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R5为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、SR11、-C(O)R12、CN或NO2;
R6为氢、取代或未取代的C1-8烷基、取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基、取代或未取代的C3-8环烯基或-CH2R19;
R7为取代或未取代的杂环、-SR11、-NR8R9、-N(H)C(O)N(H)S(O)2R19、-BR13R14、-S(O)R15、-C(O)N(H)(CN)、-C(O)N(H)S(O)2R19、-S(O)(N)(PO3H2)-、-S(O)2R16或-P(O)R17R18;
R8为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R9为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R10为氢或取代或未取代的C1-8烷基;
R11为氢、取代或未取代的C1-8烷基或-CF3;
R12为氢、取代或未取代的C1-8烷基、羟基、-OR24或-NR8R9;
R13为-OR22;
R14为-OR23;
R15为取代或未取代的C1-8烷基;
R16为取代或未取代的C1-8烷基、-NR8R9、-NHS(O)2R19或羟基;
R17为OR10或NR8R9;
R18为OR10或NR8R9;
R19为取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基或取代或未取代的C3-8环烯基;
R20为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R21为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R22为氢、取代或未取代的C1-8烷基,或与R23一起可形成环;
R23为氢、取代或未取代的C1-8烷基,或与R22一起可形成环;
R24为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基。
如本文所用的术语“烷基”是指具有直链或支链部分或其组合且含有1至8个碳原子的饱和的单价或二价烃部分。烷基的一个亚甲基(-CH2-)可被氧、硫、亚砜基、氮、羰基、羧基、磺酰基、硫酸酯、磺酸酯、酰胺、磺酰胺、二价C3-8环烷基、二价杂环基或二价芳基替代。烷基可具有一个或多个手性中心。烷基可独立地被卤素原子、羟基、环烷基、氨基、杂环基、芳基、羧酸基、膦酸基、磺酸基、磷酸基、硝基、酰胺基、磺酰胺基取代。
如本文所用的术语“环烷基”是指衍生自饱和环烃的3至8个碳原子的单价或二价基团。环烷基可为单环或多环的。环烷基可独立地被卤素原子、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺基、硝基、氰基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、-C2-6烯基、-C2-6炔基、酮基、烷基氨基、氨基、芳基、C3-8环烷基或羟基取代。
如本文所用的术语“环烯基”是指具有至少一个双键的衍生自饱和环烷基的3至8个碳原子的单价或二价基团。环烯基可为单环或多环的。环烯基可独立地被卤素原子、磺酰基、亚砜基、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、酮基、烷基氨基、氨基、芳基、C3-8环烷基或羟基取代。
如本文所用的术语“卤素”是指氯原子、溴原子、氟原子、碘原子。
如本文所用的术语“烯基”是指具有至少一个双键、衍生自饱和烷基、具有2至6个碳原子的单价或二价烃基。烯基的一个亚甲基(-CH2-)可被氧、硫、亚砜基、氮、羰基、羧基、磺酰基、硫酸酯、磺酸酯、酰胺、磺酰胺、二价C3-8环烷基、二价杂环基或二价芳基替代。C2-6烯基可呈E或Z构型。烯基可被如上文所定义的烷基取代或被卤素原子取代。
如本文所用的术语“炔基”是指具有至少一个三键、衍生自饱和烷基、具有2至6个碳原子的单价或二价烃基。炔基的一个亚甲基(-CH2-)可被氧、硫、亚砜基、氮、羰基、羧基、磺酰基、硫酸酯、磺酸酯、酰胺、磺酰胺、二价C3-8环烷基、二价杂环基或二价芳基替代。炔基可被如上文所定义的烷基取代或被卤素原子取代。
如本文所用的术语“杂环”是指含有至少一个中断碳环结构的杂原子的可为芳香族或非芳香族的饱和或不饱和的3至10元环,所述杂原子选自氧、氮、硫或其至少两个的组合。所述杂环可被C=O中断;S和N杂原子可被氧化。杂环可为单环或多环的。杂环部分可被卤素原子、磺酰基、亚砜基、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-8烷基、-C2-6烯基、-C2-6炔基、酮基、烷基氨基、氨基、芳基、C3-8环烷基或羟基取代。
如本文所用的术语“芳基”是指通过去除一个氢原子从由含有6至10个碳原子的环组成的芳香族烃衍生的有机部分。芳基可被卤素原子、磺酰基C1-6烷基、亚砜C1-6烷基、磺酰胺基、环羧酸基(carboxcyclicacid group)、C1-6烷基羧酸(酯)基、酰胺基、硝基、氰基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基、-C2-6炔基、酮基、醛基、烷基氨基、氨基、芳基、C3-8环烷基或羟基取代。芳基可为单环或多环的。
如本文所用的术语“羟基”表示式“-OH”的基团。
如本文所用的术语“羰基”表示式“-C(O)-”的基团。
如本文所用的术语“酮”表示具有连接至碳原子的羰基的有机化合物,如-(CO)Rx,其中Rx可为如上文所定义的烷基、芳基、环烷基、环烯基、杂环。
如本文所用的术语“胺”表示式“-NRxRy”的基团,其中Rx和Ry可相同,或独立地为H、如上文所定义的烷基、芳基、环烷基、环烯基、杂环。
如本文所用的术语“羧基”表示式“-C(O)O-”的基团。
如本文所用的术语“磺酰基”表示式“-SO2”的基团。
如本文所用的术语“硫酸酯”表示式“-O-S(O)2-O-”的基团。
如本文所用的术语“磺酸酯”表示式“-S(O)2-O-”的基团。
如本文所用的术语“羧酸”表示式“-C(O)OH”的基团。
如本文所用的术语“硝基”表示式“-NO2”的基团。
如本文所用的术语“氰基”表示式“-CN”的基团。
如本文所用的术语“酰胺”表示式“-C(O)NRxRy”的基团,其中Rx和Ry可相同,或独立地为H、如上文所定义的烷基、芳基、环烷基、环烯基、杂环。
如本文所用的术语“磺酰胺”表示式“-S(O)2NRxRy”的基团,其中Rx和Ry可相同,或独立地为H、如上文所定义的烷基、芳基、环烷基、环烯基、杂环。
如本文所用的术语“亚砜”表示式“-S(O)-”的基团。
如本文所用的术语“膦酸”表示式“-P(O)(OH)2”的基团。
如本文所用的术语“磷酸”表示式“-OP(O)(OH)2”的基团。
如本文所用的术语“磺酸”表示式“-S(O)2OH”的基团。
如本文所用的式“H”表示氢原子。
如本文所用的式“O”表示氧原子。
如本文所用的式“N”表示氮原子。
如本文所用的式“S”表示硫原子。
在另一方面,FPR2激动剂为选自表1的化合物:
表1
US 2005/0137230A1和US 7820673公开了凝血因子Xa抑制剂并且可用于预防和/或治疗血栓栓塞性疾病和或治疗肿瘤。2-({[(4-氯苯基)氨基]羰基}氨基)-3-苯丙酸、(2S)-2-({[(4-甲氧基苯基)氨基]羰基}氨基)-3-苯丙酸、(2S)-3-苯基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氨基]丙酸、2-({[(4-碘苯基)氨基]羰基}氨基)-3-苯基丙酸甲酯、(2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸、(2R)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸是作为激活的凝血因子X(FXa)抑制剂的脲衍生物的合成中的中间体。
JP 63232846公开了在具有新颖的色谱手性固定相的HPLC柱上对N-(对溴苯基氨基甲酰基)衍生物((2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸、(2S,3S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-甲基戊酸、2-({[(4-溴苯基)氨基]羰基}氨基)-3-(1H-吲哚-3-基)丙酸、(2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-甲基丁酸)的拆分。
Journal of Chromatography(1987),404(1),117-22和Chromatographia(1987),23(10),727-30描述了在新颖的手性固定相上通过用水性移动相洗脱对对映异构蛋白氨基酸的对溴苯基氨基甲酰基衍生物((2R)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸、(2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸)的拆分。
Biochimica et Biophysica Acta,Nucleic Acids and Protein Synthesis(1972),272(4),667-71描述了对硝基苯基-氨基甲酰基-苯丙氨酰基tRNA的聚(尿苷酸)依赖性结合中的化合物(2S)-2-({[(4-硝基苯基)氨基]羰基}氨基)-3-苯丙酸)。
在另一方面,FPR2激动剂为选自表2的化合物:
表2
表2的化合物可购自Chemical Libraries,如Aurora FineChemicals。
在另一方面,FPR2激动剂为选自表3的化合物:
表3
表3的化合物可购自Chemical Libraries,如Chemical Block有限公司。
在本发明的又一实施方案中,提供用于治疗与FPR2调节相关的病症的方法。
此类方法可例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来进行。
FPR2的治疗效用为眼部炎性疾病,包括但不限于湿性和干性年龄相关性黄斑变性(ARMD)、葡萄膜炎、干眼、角膜炎、过敏性眼病和影响眼后部的病状,如黄斑病变和视网膜变性,包括非渗出性年龄相关性黄斑变性、渗出性年龄相关性黄斑变性、脉络膜新血管生成、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、急性黄斑神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;感染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、葡萄膜炎、视网膜炎、和脉络膜炎,如急性多灶性鳞状色素上皮病变,贝切特氏病、鸟枪弹样视网膜脉络膜病变、传染病(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体扁平部炎)、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼结节病、后巩膜炎、匐行性脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征;血管疾病/渗出性疾病,如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉微动脉瘤、柯氏病、旁中心凹毛细血管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、霜样分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病变、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科病状,如交感性眼炎、葡萄膜炎性视网膜疾病、视网膜脱离、外伤、手术后角膜创伤愈合、由激光引起的病状、由光动力疗法引起的病状、光凝固、手术期间的血流灌注不足、放射性视网膜病变和骨髓移植性视网膜病变;增生性病症,如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,如眼组织胞浆菌病、眼弓蛔虫病、推测的眼组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染相关的视网膜疾病、与HIV感染相关的脉络膜疾病、与HIV感染相关的葡萄膜炎疾病、病毒性视网膜炎、急性视网膜坏死、进行性外侧视网膜坏死、真菌性视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性神经视网膜炎和蝇蛆病;遗传性病症,如色素性视网膜炎、与视网膜营养不良相关的系统性病症、先天性静止性夜盲、锥体营养不良、斯特格氏病和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮图形营养不良、X连锁视网膜劈裂症、索斯比氏眼底营养不良、良性的同心性黄斑病变、比蒂氏结晶样营养不良和弹性假黄色瘤;视网膜撕裂/视网膜裂孔,如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤,如与肿瘤相关的视网膜疾病、视网膜色素上皮的先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤和眼内淋巴瘤;以及影响眼后部的各种其它疾病,如点状内层脉络膜病变、急性后部多灶性鳞状色素上皮病变、近视性视网膜变性和急性视网膜色素上皮炎,系统性炎性疾病,如中风,冠状动脉疾病、阻塞性气道疾病、HIV介导的逆转录病毒感染,心血管病症,包括冠状动脉疾病,神经炎症、神经性病症、疼痛和免疫性病症、哮喘、过敏性病症、炎症、系统性红斑狼疮、牛皮癣,CNS病症,如阿尔茨海默氏病,关节炎、败血症、炎性肠病、恶病质、心绞痛、手术后角膜炎症、眼睑炎、MGD、皮肤创伤愈合、烧伤、红斑痤疮、特应性皮炎、痤疮、牛皮癣、脂溢性皮炎、光化性角化病、病毒性疣、光老化性类风湿性关节炎和相关炎性病症、脱发、青光眼、分支静脉阻塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或RPE的任何其它变性疾病(Perretti,Mauro等,Pharmacology&Therapeutics 127(2010)175-188)。
这些化合物可用于治疗患有通过FPR2调节减轻的一系列病状和疾病的哺乳动物(包括人类):包括但不限于治疗湿性和干性年龄相关性黄斑变性(ARMD)、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、糖尿病性黄斑水肿、葡萄膜炎、干眼、视网膜静脉阻塞、囊样黄斑水肿、青光眼、分支静脉阻塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或RPE的任何其它变性疾病。
在本发明的再一实施方案中,提供用于治疗与FPRL-1受体调节相关的病症的方法。此类方法可例如通过向有此需要的受试者施用治疗有效量的至少一种本发明化合物或其任何组合或其药学上可接受的盐、水合物、溶剂合物、晶体形式和单个异构体、对映异构体和非对映异构体来进行。
在任何给定情况下化合物的实际施用量将由医师考虑如以下的相关情况来确定:病状的严重性、患者的年龄和体重、患者的一般身体状况、病状的病因和施用途径。
患者将以如片剂、液体、胶囊剂、粉末等的任何可接受的形式口服施用化合物,或其它途径可为合乎需要的或必需的,特别是如果患者出现恶心的情况。此类其它途径可毫无例外地包括经皮、胃肠外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼局部、眼后部、肌肉内、静脉内和直肠内递送模式。另外,制剂可被设计成在给定时期内延迟释放活性化合物,或小心地控制在治疗过程期间在给定时间所释放药物的量。
在本发明的另一实施方案中,提供在药学上可接受的载体中包括至少一种本发明化合物的药物组合物。短语″药学上可接受的″意指载体、稀释剂或赋形剂必须与制剂的其它成分相容并且不对其接受者有害。
本发明的药物组合物可以固体、溶液、乳剂、分散剂、贴片、胶束、脂质体等形式使用,其中所得组合物含有与适于肠道或胃肠外应用的有机或无机载体或赋形剂混合的作为活性成分的一种或多种本发明化合物。本发明化合物可例如与用于片剂、丸剂、胶囊剂、栓剂、溶液、乳剂、混悬剂和适合使用的任何其它形式的通常无毒的药学上可接受的载体组合。可使用的载体包括葡萄糖、乳糖、阿拉伯胶、明胶、甘露糖醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶态二氧化硅、马铃薯淀粉、脲、中等链长甘油三酯、右旋糖酐和适用于制造呈固体、半固体或液体形式的制剂的其它载体。另外,可使用助剂、稳定剂、增稠剂和着色剂以及芳香剂。本发明化合物以足以对过程或疾病状况产生所需效果的量被包含在药物组合物中。
含有本发明化合物的药物组合物可呈适于口服使用的形式,例如呈片剂、锭剂、糖锭、水性或油性混悬剂、可分散性粉末或颗粒、乳剂、硬胶囊剂或软胶囊剂或糖浆剂或酏剂形式。旨在用于口服使用的组合物可根据本领域中已知用于制造药物组合物的任何方法来制备,并且此类组合物可以含有一种或多种选自由以下组成的组的试剂:甜味剂,如蔗糖、乳糖或糖精;调味剂,如薄荷油、冬青油或樱桃油;着色剂和防腐剂,以提供药学上精美并且可口的制剂。含有与无毒的药学上可接受的赋形剂混合的本发明化合物的片剂也可通过已知方法制造。所使用的赋形剂可为例如(1)惰性稀释剂,如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)造粒剂和崩解剂,如玉米淀粉、马铃薯淀粉或海藻酸;(3)粘合剂,如黄蓍胶、玉米淀粉、明胶或阿拉伯胶;和(4)润滑剂,如硬脂酸镁、硬脂酸或滑石。片剂可未经包衣或它们可通过已知技术包衣以延迟崩解和在胃肠道中的吸收,并且由此在较长时期内提供持续作用。例如,可采用延时材料,如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,用于口服使用的制剂可呈硬明胶胶囊剂形式,其中本发明化合物与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合。它们还可呈软明胶胶囊剂形式,其中本发明化合物与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
含有本发明化合物的药物组合物可呈适于局部使用的形式,例如呈油性混悬剂形式,呈水性液体或非水性液体中的溶液或混悬剂形式,或呈水包油或油包水液体乳剂形式。
药物组合物可通过组合治疗有效量的至少一种作为活性成分的根据本发明的化合物或其药学上可接受的盐与常规的眼科上可接受的药物赋形剂并且通过制备适于局部眼部使用的单位剂量来制备。液体制剂中的治疗有效量通常为约0.001%(w/v)与约5%(w/v)之间,优选约0.001%(w/v)至约2.0%(w/v)。
对于眼部施加来说,优选地使用生理盐水溶液作为主要媒介物来制备溶液。此类眼用溶液的pH值应当优选地利用适当的缓冲液系统维持在4.5与8.0之间,中性pH是优选的,但并非必不可少的。所述制剂还可含有常规的药学上可接受的防腐剂、稳定剂和表面活性剂。
可用于本发明药物组合物中的优选的防腐剂包括但不限于苯扎氯铵、氯丁醇、硫柳汞(thimerosal)、醋酸苯汞和硝酸苯汞。优选的表面活性剂为例如Tween 80。同样,多种优选的媒介物可用于本发明的眼用制剂中。这些媒介物包括但不限于聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊洛沙姆(poloxamer)、羧甲基纤维素、羟乙基纤维素、环糊精和纯化水。
可根据需要或在方便时添加张力调节剂。它们包括但不限于盐(特别是氯化钠、氯化钾)、甘露糖醇和甘油或任何其它合适的眼科上可接受的张力调节剂。
可使用用于调节pH值的多种缓冲液和手段,只要所得到的制剂为眼科上可接受的。因此,缓冲液包括乙酸盐缓冲液、柠檬酸盐缓冲液、磷酸盐缓冲液和硼酸盐缓冲液。可根据需要使用酸或碱来调节这些制剂的pH值。
以类似方式,用于本发明中的眼科上可接受的抗氧化剂包括但不限于偏亚硫酸氢钠、硫代硫酸钠、乙酰半胱氨酸、丁基化羟基苯甲醚和丁基化羟基甲苯。
可包括在眼用制剂中的其它赋形剂组分为螯合剂。优选的螯合剂为乙二胺四乙酸二钠,尽管还可使用其它螯合剂代替乙二胺四乙酸二钠或还可结合乙二胺四乙酸二钠使用其它螯合剂。
成分通常以如下量使用:
本发明活性化合物的实际剂量取决于具体化合物以及待治疗的病状;适当剂量的选择完全在本领域技术人员的知识范围内。
方便地将本发明的眼用制剂以适于计量施加的形式包装,例如包装在配备有点滴器的容器中,以便于施加至眼。适于逐滴施加的容器通常由合适的惰性无毒塑料材料制成,且通常含有约0.5ml至约15ml之间的溶液。一个包装可含有一个或多个单位剂量。尤其地,通常在含有高达约10单位剂量、优选高达约5单位剂量的不可再密封的容器中配制无防腐剂的溶液,其中典型的单位剂量为1至约8滴,优选1至约3滴。一滴的体积通常为约20-35μl。
药物组合物可呈无菌可注射混悬剂形式。此混悬剂可根据已知方法使用合适的分散剂或润湿剂以及悬浮剂来配制。无菌可注射制剂还可为无毒的胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬剂,例如,呈1,3-丁二醇溶液形式。常规地采用无菌的不挥发性油作为溶剂或悬浮介质。出于此目的,可采用任何温和的不挥发性油,包括合成的单或二甘油酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成的脂肪媒介物(如油酸乙酯)等。可根据需要并入缓冲液、防腐剂、抗氧化剂等。
本发明的化合物还可以用于药物的直肠施用的栓剂形式施用。这些组合物可通过混合本发明化合物与合适的无刺激性的赋形剂来制备,所述赋形剂如可可脂、合成的聚乙二醇甘油酯,其在常温下为固体,但在直肠腔内液化和/或溶解以释放药物。
因为个别受试者可在症状严重性方面呈现很大的不同,并且每种药物具有其独特的治疗特征,所以每个受试者所采用的精确施用模式和剂量由从业医师的判断来决定。
本文所述的化合物和药物组合物可用作哺乳动物(包括人类)的药剂,用于治疗对通过FPR2的激动剂或功能性拮抗剂进行治疗有响应的疾病和/或减轻对通过FPR2的激动剂或功能性拮抗剂进行治疗有响应的病状。因此,在本发明的其它实施方案中,提供用于治疗与FPR2调节相关的病症的方法。此类方法可例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来进行。如本文所用的术语″治疗有效量″意指研究人员、兽医、医生或其他临床医师所寻求的将引起有此需要的受试者出现生物学或医学反应的药物组合物的量。在一些实施方案中,有此需要的受试者为哺乳动物。在一些实施方案中,哺乳动物为人类。
材料和方法
预期FPR2激动剂将在许多不同类型的眼部炎症中具有显著作用,但已通过在内毒素诱导的大鼠葡萄膜炎中证实抗炎活性来例示(图1和2)。此模型中的抗炎活性已利用表4中所述的FPR2激动剂来例示。
FLIPR:利用了稳定地表达人类FPR2受体的HEK-Gα16细胞。在使用前一天以每孔18,000个细胞的密度将细胞平铺至384孔聚-D-赖氨酸涂覆板中。生长培养基为补充有10%胎牛血清(FBS)、1%抗生素-抗真菌剂、50μg/ml潮霉素和400μg/ml遗传霉素的DMEM培养基。在实验当天,用补充有20mM HEPES(HBSS/hepes缓冲液)的汉克斯氏平衡盐溶液(Hank's Balanced Salt Solution)将细胞洗涤两次。然后将细胞用在HBSS/Hepes缓冲液中稀释的2μM Fluo-4染料加载并且在37℃下孵育40分钟。在将细胞板置于FLIPR(荧光成像板读数器(Fluorometric Imaging Plate Reader),Molecular Devices)中之前,通过将板洗涤4次来去除细胞外染料。将配体在HBSS/Hepes缓冲液中稀释并且准备于384孔微板中。以相对荧光单位获得Ca+2反应的数据。
表4
免疫组织化学:使用利用对FPR2具有特异性的抗体进行的显色的DAB免疫组织化学来确定在正常人类、灵长类动物和大鼠眼中的位置。以1∶200的稀释度使用抗-FPR2抗体(Abcam)在所有物种中检测FPR2蛋白。
大鼠中内毒素诱导的葡萄膜炎:葡萄膜炎为人类的有害的眼部炎性病状。前葡萄膜炎为复发性炎性疾病并且可具有潜在的致盲后果。人们对于该疾病的致病机理知之甚少,且所用的抗炎疗法是非特异性的并且与显著的并发症相关。动物模型对于理解该疾病和测试新颖疗法至关重要。足跖中单一低剂量的脂多糖(LPS)诱导大鼠的前葡萄膜炎。称为内毒素诱导的葡萄膜炎的这个模型充当了人类前葡萄膜炎的有用范例。从Charles River Laboratory购得雄性Lewis大鼠(260±25克)。向大鼠足跖注射(后左侧)100μl的1mg/ml LPS(List BiologicalLabs)溶液(于无菌0.9%盐水中)。在由七水合磷酸氢二钠盐、CMC和无菌水组成的媒介物中配制测试化合物。在LPS后2小时经局部(0.1-1%)或皮下(10mg/kg)给予化合物。在注射LPS后24小时杀死动物。收集房水并且进行分析以确定炎性细胞计数和总蛋白浓度。
兔的碱灼伤:角膜上皮在角膜功能和完整性的维持中起重要作用。持续性角膜上皮缺损引起角膜混浊、新血管生成、细菌感染和视力丧失。角膜上皮愈合是涉及对损伤的炎性反应、细胞增殖和迁移的复杂过程。角膜损伤的动物模型均可用于测试新的抗炎性和促创伤愈合疗法。用克他命(Ketamine)/赛拉嗪(Xylazine)(35/5mg/kg)经皮下且用丙美卡因(proparacaine)(0.5%)经局部将称重在2.1kg与2.5kg之间的新西兰白兔全身性地麻醉。用含有1.0N NaOH的NaOH饱和滤纸诱导一只眼中的角膜上皮创伤持续30秒。用无菌PBS对眼进行冲洗。通过用10%荧光素钠(Science Lab Com)进行荧光素染色和裂隙灯照相术来确认角膜创伤。在上述媒介物中配制测试化合物。对于初始研究来说,每天三次局部给予化合物。使用Image J软件进行角膜创伤面积的定量,其中追踪荧光染色绿色部分并且将其转化成总像素。
预期下面的化合物将在许多不同类型的眼部炎症中具有显著作用,但已通过在内毒素诱导的大鼠葡萄膜炎中证实抗炎活性来例示(图1和2)。此模型中的抗炎活性已利用以下的FPR2激动剂来例示:
在此模型中,所述化合物显示阻断嗜中性粒细胞和蛋白浸润至前房中的强抗炎活性。另外,FPR2激动剂显示在角膜创伤的小鼠模型中的加速愈合和再上皮化,如通过(图3)中的化合物{[(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}乙酸所例示。这些数据证实FPR2激动剂是适于在不同的眼部炎症模型中供眼部使用的强力且有效的抗炎剂。
Claims (11)
1.一种治疗需要此类治疗的受试者的眼部炎性疾病的方法,其包括施用包含治疗有效量的至少一种甲酰基肽受体2激动剂的药物组合物。
2.根据权利要求1所述的方法,其中所述眼部炎性疾病选自:葡萄膜炎、干眼、角膜炎、过敏性眼病、感染性角膜炎、葡萄膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、视网膜炎、脉络膜炎、急性多灶性鳞状色素上皮病变、贝切特氏病、手术后角膜创伤愈合、湿性和干性年龄相关性黄斑变性(ARMD),。
3.根据权利要求1所述的方法,其中所述FPR2激动剂由式I表示:
其中:
R1为仲丁基、C6-10芳基、-CH2-(C6-10)芳基、-CH2-杂环、C4-8环烷基或C3-8环烯基或杂环;
R2为卤素或甲基;
R3为卤素;
R4为H、甲基或卤素;
R5为OR6或NH2;并且
R6为H或C2-4烷基。
4.根据权利要求3所述的方法,其中所述FPR2激动剂选自:
(2S,3S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-3-甲基戊酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酸;
(2S)-2-{[(4-碘苯基)氨基甲酰基]氨基}-4-甲基戊酸;和
(2S)-4-甲基-2-({[4-(甲基硫烷基)苯基]氨基甲酰基}氨基)戊酸。
5.根据权利要求1所述的方法,其中所述FPR2激动剂由式II表示:
其中:
a为1且b为0;
a为0且b为1;
a为1且b为1;
R1为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基、任选取代的C3-8环烯基、-NR11R12或-OR13;
R2为任选取代的C1-8烷基或任选取代的C6-10芳基;
R3为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R4为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R5为卤素、-CF3或-S(O)nR14;
n为0、1或2;
R6为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R7为氢、任选取代的C1-8烷基、卤素、-COOR15、-OR13、-NR11R12、NO2、任选取代的杂环、任选取代的C3-8环烷基、任选取代的C6-10芳基或任选取代的C3-8环烯基;
R8为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9a为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10a为氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R11为氢或任选取代的C1-8烷基;
R12为氢或任选取代的C1-8烷基;
R13为氢或任选取代的C1-8烷基;
R14为氢、CF3或任选取代的C1-8烷基;并且
R15为氢或任选取代的C1-8烷基。
6.根据权利要求5所述的方法,其中所述FPR2激动剂选自:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}乙酸;
{[(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}乙酸;
(2S,3S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-3-甲基戊酸;
2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}-2-甲基丙酸;
{[(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}乙酸;
2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2-氧代氮杂环庚烷-3-基)-3-苯基丙酰胺;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-苯基丙酰基]氨基}乙酸;
3-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-苯基丙酰基]氨基}丙酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2-羟基乙基)-3-苯基丙酰胺;
{[(2S,3S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}乙酸;
(2S,3S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰胺;
(2S,3S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-3-甲基戊酰胺;
(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基-N-(2-氧代丙基)戊酰胺;
(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-N-(2-氧代丙基)-3-苯基丙酰胺;
(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-N-(2-羟基乙基)-3-苯基丙酰胺;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}乙酸甲酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}乙酸丙-2-基酯;
{[(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}戊酰基]氨基}乙酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2-羟基乙基)-4-甲基戊酰胺;
(2S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基-N-(2-氧代丙基)戊酰胺;
(2S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰胺;
(2S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}戊酰胺;
(2S)-N-(2-氨基-2-氧代乙基)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-4-甲基戊酰胺;
(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-4-甲基-N-(2-氧代丙基)戊酰胺;
(2S)-2-{[(2S)-2-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}丙酸;
(2S)-2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}丙酸;
(2S)-2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}-3-甲基丁酸;
(2S)-N-[(2S)-1-氨基-3-甲基-1-氧代丁-2-基]-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2-羟基-2-甲基丙基)-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(1,3-二羟基丙-2-基)-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2,3-二羟基丙基)-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-[(2R)-1-羟基丙-2-基]-4-甲基戊酰胺;
(2S)-2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}戊酸叔丁酯;
(2S)-2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}戊酸
(2S)-N-[(2S)-1-氨基-1-氧代戊-2-基]-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰胺;
(2S)-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}(苯基)乙酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基-N-(1H-四唑-5-基甲基)戊酰胺;
[(2-{[(4-溴苯基)氨基甲酰基]氨基}-2,4-二甲基戊酰基)氨基]乙酸;
(2-{[(4-溴苯基)氨基甲酰基]氨基}-2-乙基丁酰基)氨基]乙酸;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-[(3-羟基-1,2-噁唑-5-基)甲基]-4-甲基戊酰胺;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-N-[2-(二甲基氨基)-2-氧代乙基]-4-甲基戊酰胺;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰基]氨基}乙酸;
{[(2S)-4-甲基-2-({[4-(甲基硫烷基)苯基]氨基甲酰基}氨基)戊酰基]氨基}乙酸;
(2S)-4-甲基-N-(1H-四唑-5-基甲基)-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰胺;
2-甲基-2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰基]氨基}丙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-(甲基硫烷基)丁酰基]氨基}乙酸;
{[2-{[(4-溴苯基)氨基甲酰基]氨基}-3-(1H-吲哚-3-基)丙酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基](甲基)氨基}乙酸叔丁酯;和
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基](甲基)氨基}乙酸。
7.根据权利要求1所述的方法,其中所述FPR2激动剂由式III表示:
R1为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R2为卤素、任选取代的C1-8烷基、CF3、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R5一起形成任选取代的10元或11元多环;
R4为氢、任选取代的C1-8烷基、
任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R5一起形成螺单环或多环的、碳环或杂环的、饱和或不饱和的任选取代的5元至10元环;
R5为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,或与R4一起形成螺单环或多环的、碳环或杂环的、饱和或不饱和的任选取代的5元至10元环,或与R3一起形成任选取代的5元或6元环;
R6为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R7为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R8为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R10为氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH;
R11为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R12为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R13为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R14为氢、任选取代的C6-10芳基、任选取代的C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基);
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R16为OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5。
8.根据权利要求7所述的方法,其中所述FPR2激动剂选自:
1-(4-溴苯基)-3-[4-乙基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-[4-乙基-2,5-二氧代-4-(丙-2-基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-溴苯基)-3-[4-甲基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-[4-甲基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]脲;
1-(4-溴-2-氟苯基)-3-[4-乙基-2,5-二氧代-4-(丙-2-基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-[2,5-二氧代-4,4-二(丙-2-基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-(4,4-二环丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-[4-乙基-2,5-二氧代-4-(丙-2-基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-[4-乙基-2,5-二氧代-4-(丙-2-基)咪唑烷-1-基]脲;
1-(4-溴-2-氟苯基)-3-[4-乙基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]脲;
1-(4-溴苯基)-3-{4-[2-(呋喃-2-基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(4-氟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(3-氟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(4-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-甲基-2,5-二氧代-4-[2-(噻吩-2-基)乙基]咪唑烷-1-基}脲;
1-(4-溴-2-氟苯基)-3-{4-[2-(4-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-甲基-4-[2-(5-甲基呋喃-2-基)乙基]-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴-2-氟苯基)-3-{4-[2-(3-氟-4-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(3-氟-4-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴-2-氟苯基)-3-{4-[2-(2-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴-2-氟苯基)-3-{4-[2-(3-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(3-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-{4-[2-(2-羟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;
1-(4-溴苯基)-3-[4-(羟基甲基)-2,5-二氧代-4-(丙-2-基)咪唑烷-1-基]脲;
2-[1-{[(4-溴苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]-N-(2-羟基乙基)乙酰胺;
2-[2-(1-{[(4-溴苯基)氨基甲酰基]氨基}-4-乙基-2,5-二氧代咪唑烷-4-基)乙基]苯甲酸甲酯;
2-[1-{[(4-溴苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]-N-(1,3-二羟基丙-2-基)乙酰胺;
2-[2-(1-{[(4-溴苯基)氨基甲酰基]氨基}-4-乙基-2,5-二氧代咪唑烷-4-基)乙基]苯甲酸;
2-[2-(1-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-4-乙基-2,5-二氧代咪唑烷-4-基)乙基]苯甲酸;
3-({[1-{[(4-溴苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]乙酰基}氨基)丙酸;
2-[1-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]-N-(2-羟基乙基)乙酰胺;
2-{2-[1-{[(4-溴苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]乙基}苯甲酸;
[2-({[1-{[(4-溴苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]乙酰基}氨基)乙基]膦酸二乙酯;
3-{[(4-溴苯基)氨基甲酰基]氨基}-2,4-二氧代-1,3-二氮杂螺[4.5]癸烷-8-羧酸乙酯;
1-(4-溴苯基)-3-{4-[2-(2-氟苯基)乙基]-4-甲基-2,5-二氧代咪唑烷-1-基}脲;和
3-({[1-{[(4-溴-2-氟苯基)氨基甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]乙酰基}氨基)丙酸。
9.根据权利要求1所述的方法,其中所述FPR2激动剂由式VII表示:
其中:
n为0或1;
R1为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R2为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R3为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN、NO2、CF3、S(O)R15或S(O)2R16;
R4为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;
R5为氢、取代或未取代的C1-8烷基、卤素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、SR11、-C(O)R12、CN或NO2;
R6为氢、取代或未取代的C1-8烷基、取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基、取代或未取代的C3-8环烯基或-CH2R19;
R7为取代或未取代的杂环、-SR11、-NR8R9、-N(H)C(O)N(H)S(O)2R19、-BR13R14、-S(O)R15、-C(O)N(H)(CN)、-C(O)N(H)S(O)2R19、-S(O)(N)(PO3H2)-、-S(O)2R16或-P(O)R17R18;
R8为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R9为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R10为氢或取代或未取代的C1-8烷基;
R11为氢、取代或未取代的C1-8烷基或-CF3;
R12为氢、取代或未取代的C1-8烷基、羟基、-OR24或-NR8R9;
R13为-OR22;
R14为-OR23;
R15为取代或未取代的C1-8烷基;
R16为取代或未取代的C1-8烷基、-NR8R9、-NHS(O)2R19或羟基;
R17为OR10或NR8R9;
R18为OR10或NR8R9;
R19为取代或未取代的杂环、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基或取代或未取代的C3-8环烯基;
R20为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R21为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基;
R22为氢、取代或未取代的C1-8烷基,或与R23一起可形成环;
R23为氢、取代或未取代的C1-8烷基,或与R22一起可形成环;
R24为氢、取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的杂环或取代或未取代的C6-10芳基。
10.根据权利要求9所述的方法,其中所述FPR2激动剂选自:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}乙酸;
2-{[(4-溴苯基)氨基甲酰基]氨基}-N-(2-氧代氮杂环庚烷-3-基)-3-苯基丙酰胺;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}甲基)膦酸氢乙酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}甲基)膦酸二乙酯;
({[(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}甲基)膦酸二乙酯;
({[(2S,3S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-甲基戊酰基]氨基}甲基)膦酸氢乙酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}甲基)膦酸二乙酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-苯基丙酰基]氨基}甲基)膦酸二乙酯;
(2-{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}乙基)膦酸二乙酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}甲基)膦酸氢乙酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基]氨基}甲基)膦酸二丙-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-3-苯基丙酰基]氨基}甲基)膦酸氢乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}甲磺酸;
{[(2-{[(4-溴苯基)氨基甲酰基]氨基}戊酰基)氨基]甲基}膦酸氢丙-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氨基}-4-甲基戊酰基]氨基}甲基)膦酸二丙-2-基酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰基]氨基}甲基)膦酸二乙酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰基]氨基}甲基)膦酸氢乙酯;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氨基)戊酰基]氨基}甲磺酸;和
({[(2S)-4-甲基-2-({[4-(甲基硫烷基)苯基]氨基甲酰基}氨基)戊酰基]氨基}甲基)膦酸二乙酯。
11.根据权利要求1所述的方法,其中所述FPR2激动剂选自:
2-({[(4-氯苯基)氨基]羰基}氨基)-3-苯丙酸;
(2S)-2-({[(4-甲氧基苯基)氨基]羰基}氨基)-3-苯丙酸;
(2S)-3-苯基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氨基]丙酸;
(2S)-2-({[(3,4-二氯苯基)氨基]羰基}氨基)-3-苯丙酸;
(2S)-2-({[(4-硝基苯基)氨基]羰基}氨基)-3-苯丙酸;
3-苯基-2-[({[4-(三氟甲氧基)苯基]氨基}羰基)氨基]丙酸;
2-({[(3,4-二甲氧基苯基)氨基]羰基}氨基)-3-苯丙酸;
2-({[(4-碘苯基)氨基]羰基}氨基)-3-苯基丙酸甲酯;
(2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸;
(2R)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-苯丙酸;
3-苯基-2-{[(吡啶-3-基氨基)羰基]氨基}丙酸;
(2S,3S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-甲基戊酸;
(2S)-({[(4-溴苯基)氨基]羰基}氨基)(苯基)乙酸;
2-({[(4-溴苯基)氨基]羰基}氨基)-3-(1H-吲哚-3-基)丙酸;
(2S)-2-({[(4-溴苯基)氨基]羰基}氨基)-3-甲基丁酸;
(2S)-2-({[(4-溴-2-氟苯基)氨基]羰基}氨基)-3-甲基丁酸;
1-(4-氯苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4,5]癸-3-基)脲;
1-(4-氯苯基)-3-(4-乙基-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-[4-甲基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]-3-苯基脲;
1-(8-甲基-2,4-二氧代-1,3-二氮杂螺[4,5]癸-3-基)-3-(对-甲苯基)脲;
1-(2-氟苯基)-3-[4-甲基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]脲;
N-(4-溴苯基)-2-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)乙酰胺;
N-(4-溴苯基)-2-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)乙酰胺;
N-(4-溴苯基)-2-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)乙酰胺
N-(4-溴苯基)-2-(2,5-二氧代-4,4-二丙基咪唑烷-1-基)乙酰胺;
N-(4-溴苯基)-2-(4-乙基-2,5-二氧代-4-苯基咪唑烷-1-基)乙酰胺;
N-(4-溴苯基)-2-(4-环丙基-4-甲基-2,5-二氧代咪唑烷-1-基)乙酰胺;
N-(4-溴苯基)-2-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)乙酰胺
N-(4-溴苯基)-2-(4-乙基-4-甲基-2,5-二氧代咪唑烷-1-基)乙酰胺;
N-(4-氯苯基)-2-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)乙酰胺;
2-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)-N-(4-氟苯基)乙酰胺;
N-(4-溴苯基)-2-[4-甲基-2,5-二氧代-4-(2-苯基乙基)咪唑烷-1-基]乙酰胺;
N-(4-溴苯基)-2-(2,4-二氧代-1,3-二氮杂螺[4.6]十一烷-3-基)乙酰胺
N-(4-溴苯基)-1,3,3a,4,7,7a-六氢-1,3-二氧代-4,7-亚甲基-2H-异吲哚-2-乙酰胺;和
N-(4-溴苯基)-1,3,3a,4,7,7a-六氢-1,3-二氧代-2H-异吲哚-2-乙酰胺。
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CN107814773A (zh) * | 2017-11-13 | 2018-03-20 | 西安交通大学 | 含有喹唑啉酮的二芳基脲类化合物及其制备方法和应用 |
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