CN107714683A - 用于治疗皮肤病的甲酰基肽受体2的激动剂的用途 - Google Patents
用于治疗皮肤病的甲酰基肽受体2的激动剂的用途 Download PDFInfo
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Abstract
本发明涉及在需要这种治疗的受试者中通过局部或全身递送来治疗皮肤炎症和皮肤疾病的方法,所述方法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。
Description
本申请是申请日为2014年3月4日、申请号为“201480011861.8”、发明名称为“用于治疗皮肤病的甲酰基肽受体2的激动剂的用途”的发明专利申请的分案申请。
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号 61/773,778的权益,其公开内容通过引用整体并入本文。
发明背景
1.发明背景
本发明涉及在需要这种治疗的受试者中通过局部或全身递送来治疗皮肤炎症和皮肤疾病的方法,所述方法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)家族属于七跨膜结构域G蛋白偶联受体 (GPCR)家族。该家族包括人类的3个成员,并且该家族FPR2的一个成员(还称为FPRL-1,ALXA4)主要在炎性细胞例如单核细胞和中性粒细胞以及T细胞上表达,并且已经显示在炎症和人类病理学过程的白血球运输中发挥关键作用(Chiang N,Serhan CN,Dahlen,S,Drazen JM,Hay DWP,RovatiE,Shimizu T,Yokomizo T,Brink,C.The lipoxin receptor ALX:Potent ligand-specific and stereoselective actions in vivo. Pharmacological Reviews 2006;58:463-519)。FPR2是响应于一组结构多样的外源性和内源性配体的特别混杂的受体,包括血清淀粉状蛋白A(SAA)、趋化因子变体sCKβ8-1、神经保护肽humanin、抗炎性类十二烷酸脂氧素A4(LXA4)和糖皮质激素调节的蛋白膜联蛋白 Al(Chiang N,Serhan CN,Dahlen,S,Drazen JM,Hay DWP,Rovati E, Shimizu T,Yokomizo T,Brink,C.The lipoxin receptorALX:Potent ligand-specific and stereoselective actions invivo.Pharmacological Reviews 2006;58:463-519)。已经显示FPR2在许多系统中转导花生四烯酸衍生的脂氧素A4(LXA4)的抗炎作用,并且已经显示其在炎症消退中的关键作用(Dufton N,Perretti M.Therapeutic anti-inflammatory potential of formylpeptide receptor agonists.Pharamcology& Therapeutics 2010;127:175-188)。如受体的生物作用所预期的,FPR2 敲除小鼠显示了在疾病状态下加重的炎症(Dufton N,HannonR, Brancaleone V,Dalli J,Patel HB,Gray M,D’Aquisto F,Buckingham JC, PerrettiM,Flower RJ.Anti-inflammatory role of the murine formyl-peptide receptor 2:Ligand-specific effects on leukocyte responses and experimentalinflammation.Journal of Immunology 2010;184: 2611-2619.Gavins FNE,Hughes EL,Buss NAPS,Holloway PM,Getting SJ,Buckingham JC.Leukocyte recruitment in thebrain in sepsis: involvement of the annexin1 FPR2/ALX anti-inflammatorysystem. FASEB 2012;26:1-13)。
已经显示脂氧素A4或其类似物和膜联蛋白I蛋白对FPR2的激活导致通过促进包括抑制多形核中性粒细胞(PMN)和嗜酸粒细胞迁移的炎症积极消退的抗炎活性,并且还刺激能够以非炎性方式从炎症部位清除凋亡细胞的单核细胞迁移(Gavins FNE,Hughes EL,Buss NAPS,Holloway PM,Getting SJ,Buckingham JC.Leukocyte recruitment in thebrain in sepsis:involvement of the annexin1 FPR2/ALX anti-inflammatorysystem.FASEB 2012;26:1-13,Maderna P, Cottell DC,Toivonen T,Dufton N,Dalli J,Perretti M,Godson C. FPR2/ALX receptor expression and internalization arecritical for lipoxin A4 and annexin-derived peptide-stimulatedphagocytosis.FASEB 2010;24:4240-4249)。此外,已经显示FPR2抑制天然杀伤细胞(NK)细胞毒性并促进T细胞活化,其进一步促进组织损伤炎性信号的下调。已经显示FPR2与LXA4和膜联蛋白相互作用在皮肤炎症、血管发生、上皮迁移、水肿、秃顶和角膜伤口愈合的实验模型中是有益的(Reville K,Cream JK,Vivers S,Dransfield I,Godson C.LipoxinA4redistributes Mysoin IIA and Cdc42in macrophages:Implications forphagocytosis of apoptotic leukocytes.Journal of Immunology 2006;176:1878-1888; Serhan C.Resolution phase of inflammation:Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.Annual reviews ofImmunology 2007;25:101-137.;Takano T,Fiore S,Maddox JF, Brady HR,Petasis NA,Serhan CN.Asprin-triggered 15-epi-lipoxin A4 and LXA4 stable analogues arepotent inhibitors of acute inflammation: evidence for anti-inflammatoryreceptors.Journal of Experimental Medicine 1997;185:1693-1704.;Leoni G,AlamA,Neumann PA, Lambeth JD,Cheng G,McCoy J,Hilgarth RS,Kundu K,Murthy N,Kusters D,Reutelingsperger C,Perretti M,Parkos CA,Neish AS,Nusrat A.AnnexinA1,formyl peptide receptor,and NOX1 orchestrate epithelial repair.Journal ofClinical Investigation.2013;123:443-54;Leedom A, Sullivan AB,Dong B,Lau D,Gronert K.Endogenous LXA4 circuits are determinants of pathologicalangiogenesis in response to chronic injury. American Journal of Pathology2010;176:74-84;Tsuruki T,Takahata K, Yoshikawa M.Mechanism of the protectiveeffect of intraperitoneally administered agonists for formyl peptidereceptors against chemotherapy-induced alopecia.Biosci BiotechnologyBiochemistry. 2007;71:1198-202)。
鉴于其潜在的抗炎和促上皮修复作用,选择性靶向FPR2还在皮肤伤口愈合中具有益处。此外,已经显示一些皮肤疾病具有LL37的异常表达,LL37是已经显示为FPR2的天然配体的促炎cathelicidin。在慢性炎性疾病红斑痤疮中,LL37高度表达并且被认为在致病中发挥关键作用(Yamasaki K,Di Nardo A,Bardan A,Murakami M,Ohtake T, Coda A,Dorschner RA,Bonnart C,Descargues P,Hovnanian A, Morhenn VB,GalloRL.Increased serine protease activity and cathelicidin promotes skininflammation in rosacea.Nature Medicine. 2007;13:975-80)。
发明简述
本发明涉及在需要这种治疗的受试者中通过局部或全身递送来治疗皮肤炎症和皮肤疾病的方法,所述方法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。
鉴于LXA4-FPR2的抗炎轴,我们提议FPR2激动剂用于抑制 LL-37介导的炎性疾病,例如红斑痤疮。脂氧素A4及其类似物的药物效用受到天然聚烯烃天然产物固有的理化性质妨碍。因此,FPR2 的小分子抗炎激动剂在特别是皮肤中的炎性疾患中具有多种治疗益处。FPR2广泛表达于人类皮肤及其附属物。因此,FPR2代表了用于开发具有过度炎性反应的皮肤疾病的新治疗剂的重要的新的促消退分子靶。
本发明涉及FPR2激动剂表现出具有化学稳定性并适合局部皮肤递送的皮肤抗炎活性的能力。这些FPR2化合物在受体处显示良好效价,并且重要的是,FPR2化合物是局部活性的,并且因此能够以许多形式施用,包括但不限于乳霜、洗剂、凝胶、溶液、喷雾剂和泡沫剂。这些化合物还可以IV、肌肉内、鞘内、皮下、口服或腹膜内施用。这些化合物用于治疗皮肤病,包括但不限于:红斑痤疮、爆发性红斑痤疮、晒伤、银屑病、绝经期相关的热潮红、热潮红相关的脸红、热潮红相关的红斑、睾丸切除术导致的热潮红、特异性皮炎、昆虫叮咬的红痒的治疗、光老化、脂溢性皮炎、痤疮、过敏性皮炎、面部毛细血管扩张(之前存在的小血管扩张)、血管扩张、肥大性酒渣鼻(具有滤泡性扩张的鼻子的过度生长)、痤疮样皮肤疹(可以渗出或结硬皮)、灼烧感或螫刺感、皮肤红斑、具有皮肤血管扩张的皮肤过兴奋、Lyell 综合征、Stevens-Johnson综合征、与痔疮相关的局部瘙痒和不适、痔疮、轻型多形红斑、重型多形红斑、结节性红斑、眼睛浮肿、荨麻疹、瘙痒症、紫癜、静脉曲张、接触性皮炎、特异性皮炎、钱币状皮炎、泛发型表皮脱落性皮炎、停滞性皮炎、单纯慢性苔藓、口周皮炎、须部假毛囊炎、环形肉芽肿、光化性角化病、基底细胞癌、鳞状细胞癌、湿疹、皮肤伤口愈合、肥大性瘢、瘢痕疙瘩、烧伤、红斑痤疮、特异性皮炎、痤疮、银屑病、脂溢性皮炎、光化性角化病、基底细胞癌、鳞状细胞癌、黑素瘤、病毒性疣、光老化、光损伤、黑斑病、炎症后色素沉着、其他色素沉着疾患、和秃顶(瘢痕化和非瘢痕化形式)。预期以下化合物在许多不同类型的皮肤疾病中具有治疗作用,但是已经示例证明了在小鼠皮肤伤口愈合模型(图1)中的加速伤口愈合活性,以及在小鼠(图2)和人类角质形成细胞(图2)中LL-37诱导炎症的减少。已经用以下三种FPR2激动剂示例了LL-37诱导的红斑痤疮小鼠模型中的抗炎活性:{[(2S)-2-{[(4-溴-2-氟代苯基)氨甲酰基]氨基}-4-甲基戊酰基]氨基}乙酸、{[(2S,3S)-2-{[(4-溴代苯基)氨甲酰基]氨基}-3-甲基戊酰基]氨基}乙酸、{[(2S)-2-{[(4-溴代苯基)氨甲酰基]氨基}-4-甲基戊酰基]氨基}乙酸。还已经证明了FPR2激动剂在皮肤施用之后的皮肤穿透(图3)。
附图简述
图1.FPR2激动剂显示冲击皮肤伤口的小鼠模型中有效的伤口愈合。
图2.FPR2激动剂阻断小鼠耳中LL-37诱导的炎症,在所有时间点与媒介物相比p<0.05。
图3.FPR2激动剂在体外人类皮肤穿透模型中的吸收。
发明详述
本发明涉及在需要这种治疗的受试者中治疗皮肤炎症和皮肤疾病的方法,所述方法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。
另一方面,本发明提供了至少一种FPR2激动剂在生产用于治疗哺乳动物的FPR2介导的皮肤炎症疾病或病症的药剂中的用途。
另一方面,本发明提供了治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/668,835中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/668,835中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/668,835中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/668,835中公开的化合物由式I表示:
其中:
R1是仲丁基、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是卤素或甲基;
R3是卤素;
R4是H、甲基或卤素;
R5是OR6或NH2;
R6是H或C2-4烷基。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/523,579中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/523,579中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/523,579中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/523,579中公开的化合物由式II表示:
其中:
a是1并且b是0;
a是0并且b是1;
a是1并且b是1;
R1是任选取代的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是任选取代的C1-8烷基或任选取代的C6-10芳基;
R3是氢、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是氢、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是卤素、-CF3或-S(O)nR14;
n是0、1或2;
R6是氢、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是氢、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是氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9是氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10是氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R9a是氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R10a是氢、任选取代的C1-8烷基或任选取代的C6-10芳基;
R11是氢或任选取代的C1-8烷基;
R12是氢或任选取代的C1-8烷基;
R13是氢或任选取代的C1-8烷基;
R14是氢、CF3或任选取代的C1-8烷基;
R15是氢或任选取代的C1-8烷基。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/673,800中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2 受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/673,800中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/673,800中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/673,800中公开的化合物由式III表示:
R1是卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、 CN、SR15或SO2R16;
R2是卤素、任选取代的C1-8烷基、CF3、OR9、C(O)R10、NO2、 NR13R14、CN、SR15或SO2R16;
R3是氢、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-或11-元多环;
R4是氢、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螺单环或多环、碳环或杂环、饱和或不饱和的5至10元环;
R5是氢、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R4一起形成任选取代的螺单环或多环、碳环或杂环、饱和或不饱和的5 至10元环,或与R3一起形成任选取代的5或6元环;
R6是卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、 CN、SR15或SO2R16;
R7是卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、 CN、SR15或SO2R16;
R8是卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R9是氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R10是氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH;
R11是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R12是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R13是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R14是氢、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是氢、任选取代的C1-8烷基或O(C1-8烷基);
R16是OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;
R17是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18是氢、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是氢、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是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21是氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n是1、2、3、4或5;
m是1、2、3、4或5。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/765,527中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2 受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/765,527中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/765,527中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/765,527中公开的化合物由式IV表示:
其中:
R1是氢、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R2一起可以形成任选取代的环丁基;
R2是异丙基或与R3一起可以形成取代或未取代的3至6元环杂环,或与R1一起可以形成任选取代的环丁基、环丙基;并且
R3是氢、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R2一起可以形成取代或未取代的3至6元环杂环。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/409,228中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2 受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/409,228中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/409,228中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
其中:
是单键或双键;
是单键或双键;
R1是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是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是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是H或C(O)R12;
R5是H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;
R6是H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;
Y是O或S;
X是O、NR或CH2;
Ra是C6-10芳基、杂芳基、C3-8环烷基、C3-8环烯基或H;
Rb是卤素;
c是0、1或2;
是
R7是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是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是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是-C1-6烷基、C3-8环烷基或C3-8环烯基;
R11是H、羟基、-C1-6烷基、C3-8环烷基或C3-8环烯基;
R12是H、羟基、-C1-6烷基、C3-8环烷基、C3-8环烯基、NR13R14或-OC1-6烷基;
R13是H、-C1-6烷基、C3-8环烷基、C3-8环烯基SO2R11或C(O)R15;
R14是H、-C1-6烷基、C3-8环烯基,芳基、杂环或C3-8环烷基;
R15是H、-C1-6烷基、C3-8环烯基或C3-8环烷基;并且
R是H、-C1-6烷基、C3-8环烯基或C3-8环烷基;
条件是
当是双键时,则R5和R6是不存在。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/370,472中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2 受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/370,472中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/370,472中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/370,472中公开的化合物由式VI表示:
其中:
A是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R17是C1-6烷基或
B是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R1是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是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是H、C1-6烷基或C3-8环烷基;
R4是H、C1-6烷基或C3-8环烷基;
R5a是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是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是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是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是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是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是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是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是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是O或S;
Y是O或S;
R11是H、羟基、-C1-6烷基、C3-8环烷基或NR13R14;
R12是H、羟基、-C1-6烷基、羟基、C3-8环烷基、NR13R14或-OC1-6烷基;
R13是H、-C1-6烷基、C3-8环烷基、SO2R11或C(O)R16;
R14是H、-C1-6烷基或C3-8环烷基;
R15是-C1-6烷基或C3-8环烷基;
R16是H、-C1-6烷基或C3-8环烷基;
n是1-4;并且
m是1-4。
另一方面,本发明提供了用于治疗皮肤炎性疾病的方法,该方法包括施用包含治疗有效量的如美国专利申请S.N.13/863,934中公开的至少一种FPR2激动剂的药物组合物,条件是所述化合物在FPR2 受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/863,934中公开的至少一种化合物在生产用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的药剂中的用途,条件是所述化合物在FPR2受体处具有结合活性。
另一方面,本发明提供了如美国专利申请S.N.13/863,934中公开的至少一种化合物用于治疗哺乳动物的FPR2介导的皮肤疾病或病症的用途,条件是所述化合物在FPR2受体处具有结合活性。
美国专利申请S.N.13/863,934中公开的化合物由式VII表示:
其中:
n是0或1;
R1是氢、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是氢、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是氢、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是氢、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是氢、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是氢、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是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是氢、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是氢、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是氢或取代或未取代的C1-8烷基;
R11是氢、取代或未取代的C1-8烷基或-CF3;
R12是氢、取代或未取代的C1-8烷基、羟基、-OR24或-NR8R9;
R13是-OR22;
R14是-OR23;
R15是取代或未取代的C1-8烷基;
R16是取代或未取代的C1-8烷基、-NR8R9、-NHS(O)2R19或羟基;
R17是OR10或NR8R9;
R13是OR10或NR8R9;
R19是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是氢、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是氢、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是氢、取代或未取代的C1-8烷基,或与R23一起可以形成环;
R23是氢、取代或未取代的C1-8烷基,或与R22一起可以形成环;
R24是氢、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。
如本文使用的术语“烷基”指具有直链或支链部分或其组合并且包含1至8个碳原子的饱和、单价或二价烃部分。烷基的一个亚甲基 (-CH2-)基团可以被氧、硫、亚砜、氮、羰基、羧基、磺酰基、硫酸根、磺酸根、酰胺、磺酰胺、二价C3-8环烷基、二价杂环或二价芳基替代。烷基可以具有一个或多个手性中心。烷基可以独立地经卤素原子、羟基、环烷基、氨基、杂环基、芳基、羧酸基团、膦酸基团、磺酸基团、磷酸基团、硝基、酰胺基团、磺酰胺基团取代。
如本文使用的,术语“环烷基”指衍生自饱和环烃的3至8个碳原子的单价或二价基团。环烷基可以是单环或多环的。环烷基可以独立地被卤素原子、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺基团、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。
如本文使用的,术语“环烯基”指衍生自饱和环烷基的具有至少一个双键的3至8个碳原子的单价或二价基团。环烯基可以是单环或多环的。环烯基可以独立地被卤素原子、磺酰基、亚砜基团、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。
如本文使用的,术语“卤素”指氯、溴、氟、碘的原子。
如本文使用的,术语“烯基”指衍生自饱和烷基的具有至少一个双键的具有2至6个碳原子的单价或二价烃自由基。烯基的一个亚甲基(-CH2-)基团可以被氧、硫、亚砜、氮、羰基、羧基、磺酰基、硫酸根、磺酸根、酰胺、磺酰胺、二价C3-8环烷基、二价杂环或二价芳基替代。C2-6烯基可以是E或Z构型。烯基可以被如上定义的烷基或被卤素原子取代。
如本文使用的,术语“炔基”指衍生自饱和烷基的具有至少一个三键的具有2至6个碳原子的单价或二价烃自由基。炔基的一个亚甲基(-CH2-)基团可以被氧、硫、亚砜、氮、羰基、羧基、磺酰基、硫酸根、磺酸根、酰胺、磺酰胺、二价C3-8环烷基、二价杂环或二价芳基替代。炔基可以被如上定义的烷基或被卤素原子取代。
如本文使用的,术语“杂环”指可以是芳香族或非芳香族、饱和或不饱和的、包含中断碳环结构的选自氧、氮、硫或其至少两个的组合的至少一个杂原子的3至10元环。杂环可以被C=O中断;S和N 杂原子可以是氧化的。杂环可以是单环或多环的。杂环部分可以经卤素原子、磺酰基、亚砜基团、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。
如本文使用的,术语“芳基”指通过去除一个氢原子而从包含6 至10个碳原子的环组成的芳香烃衍生的有机部分。芳基可以经卤素原子、磺酰基C1-6烷基、亚砜C1-6烷基、磺酰胺基团、羧酸基团、 C1-6烷基羧酸酯(酯)基团、酰胺基团、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、烷基氨基、氨基、芳基、C3-8环烷基或羟基取代。芳基可以是单环或多环的。
如本文使用的,术语“羟基”代表式“-OH”基团。
如本文使用的,术语“羰基”代表式“-C(O)-”基团。
如本文使用的,术语“酮”代表具有与碳原子连接的羰基的有机化合物,例如-(CO)Rx,其中Rx可以是如上定义的烷基、芳基、环烷基、环烯基、杂环。
如本文使用的,术语“胺”代表式“-NRxRy”基团,其中Rx和 Ry可以相同或独立为H、如上定义的烷基、芳基、环烷基、环烯基、杂环。
如本文使用的,术语“羧基”代表式“-C(O)O-”基团。
如本文使用的,术语“磺酰基”代表式“-SO2 -”基团。
如本文使用的,术语“硫酸根”代表式“-O-S(O)2-O-”基团。
如本文使用的,术语“磺酸根”代表式“-S(O)2-O-”基团。
如本文使用的,术语“羧酸”代表式“-C(O)OH”基团。
如本文使用的,术语“硝基”代表式“-NO2”基团。
如本文使用的,术语“氰基”代表式“-CN”基团。
如本文使用的,术语“酰胺”代表式“-C(O)NRxRy”基团,其中 Rx和Ry可以相同或独立为H、如上定义的烷基、芳基、环烷基、环烯基、杂环。
如本文使用的,术语“磺酰胺”代表式“-S(O)2NRxRy”基团,其中Rx和Ry可以相同或独立为H、如上定义的烷基、芳基、环烷基、环烯基、杂环。
如本文使用的,术语“亚砜”代表式“-S(O)-”基团。
如本文使用的,术语“膦酸”代表式“-P(O)(OH)2”基团。
如本文使用的,术语“磷酸”代表式“-OP(O)(OH)2”基团。
如本文使用的,术语“磺酸”代表式“-S(O)2OH”基团。
如本文使用的,式“H”代表氢原子。
如本文使用的,式“O”代表氧原子。
如本文使用的,式“N”代表氮原子。
如本文使用的,式“S”代表硫原子。
另一方面,FPR2的激动剂是选自表1的化合物:
表1
US 2005/0137230 A1和US 7820673公开了凝血因子Xa的抑制剂,并且可以用于预防和/或治疗血栓栓塞性疾病和或治疗肿瘤。2-({[(4- 氯代苯基)氨基]羰基}氨基)-3-苯基丙酸、(2S)-2-({[(4-甲氧基苯基)氨基] 羰基}氨基)-3-苯基丙酸、(2S)-3-苯基-2-[({[4-(三氟代甲基)苯基]氨基} 羰基)氨基]丙酸、2-({[(4-碘代苯基)氨基]羰基}氨基)-3-苯基丙酸甲酯、 (2S)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3-苯基丙酸、(2R)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3-苯基丙酸是合成作为活化的凝血因子X(FXa) 抑制剂的脲衍生物的中间体。
JP 63232846公开了N-(对溴代苯基氨甲酰基)衍生物((2S)-2-({[(4- 溴代苯基)氨基]羰基}氨基)-3-苯基丙酸、(2S,3S)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3-甲基戊酸、2-({[(4-溴代苯基)氨基]羰基}氨基)-3-(1H- 吲哚-3-基)丙酸、(2S)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3-甲基丁酸) 在具有新的色谱手性固定相的HPLC柱上的拆分。
Journal of Chromatography(1987),404(1),117-22和 Chromatographia(1987),23(10),727-30描述了对映体蛋白氨基酸的对溴代苯基氨甲酰基衍生物((2R)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3- 苯基丙酸、(2S)-2-({[(4-溴代苯基)氨基]羰基}氨基)-3-苯基丙酸)在新的手性固定相上通过用含水流动相洗脱的拆分。
Biochimica et Biophysica Acta,Nucleic Acids and Protein Synthesis(1972),272(4),667-71描述了在对硝基苯基-氨甲酰基-苯基丙氨酰tRNA的多聚(尿嘧啶核苷酸)依赖性结合中的化合物 (2S)-2-({[(4-硝基苯基)氨基]羰基}氨基)-3-苯基丙酸)。
另一方面,FPR2激动剂是选自表2的化合物:
表2
表2的化合物可获自化学文库例如Aurora Fine Chemicals。
另一方面,FPR2激动剂是选自表3的化合物:
表3
表3化合物可获自化学文库,例如Chemical Block Ltd。
在本发明的另一实施方案中,提供了用于治疗与N-甲酰基肽受体样-1受体调节相关的疾患的方法。
例如,此类方法可以通过给有相应需要的受试者施用包含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。
N-甲酰基肽受体样-1受体调节剂的治疗效用是皮肤炎症和疾病,包括但不限于皮肤伤口愈合、肥大性瘢、瘢痕疙瘩、烧伤、红斑痤疮、特异性皮炎、痤疮、银屑病、脂溢性皮炎、光化性角化病、基底细胞癌、鳞状细胞癌、黑素瘤、病毒性疣、光老化、光损伤、黑斑病、炎症后色素沉着、其他色素沉着疾患、和秃顶(瘢痕化和非瘢痕化形式)。
这些化合物用于治疗具有受N-甲酰基肽受体样-1受体调节缓解的一系列病症和疾病的哺乳动物(包括人):皮肤炎症和疾病,包括但不限于皮肤伤口愈合、肥大性瘢、瘢痕疙瘩、烧伤、红斑痤疮、特异性皮炎、痤疮、银屑病、脂溢性皮炎、光化性角化病、基底细胞癌、鳞状细胞癌、黑素瘤、病毒性疣、光老化、光损伤、黑斑病、炎症后色素沉着、其他色素沉着疾患和秃顶(瘢痕化和非瘢痕化形式)。
在本发明的另一实施方案中,提供了用于治疗与FPRL-1受体调节相关的疾患的方法。例如,此类方法可以通过给有相应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意组合或其药学上可接受的盐、水合物、溶剂化物、结晶形式和个体异构体、对映体和非对映体来进行。
在任何给定案例中施用的化合物的实际量将通过医师考虑相关情况来确定,所述相关情况例如病症严重度、患者年龄和体重、患者一般身体状况、病症原因和施用途径。
可以任何可接受的形式给患者口服施用化合物,所述形式例如片剂、液体、胶囊、粉末等,或者其他途径可能是希望或必要的,特别是如果患者受累于恶心。所述其他途径可以无例外地包括经皮、胃肠外、皮下、鼻内、经由植入支架、鞘内、玻璃体内、局部至眼睛、向后至眼睛、肌内、静脉内和直肠内递送方式。此外,可以设计制剂以延迟活性化合物经给定时段的释放,或者小心控制治疗期间给定时间释放的药量。
在本发明的另一实施方案中,提供了包括在药学上可接受的载体中的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”表示载体、稀释剂或赋形剂必须与制剂的其他成分相容,并且对其接受者无害。
本发明的药物组合物可以固体、溶液、乳液、分散体、贴片、胶束、脂质体等形式使用,其中得到的组合物包含与适合肠内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。本发明化合物可以例如与用于片剂、丸剂、胶囊、栓剂、溶液、乳液、悬液和适合使用的任何其他形式的常用非毒性药学上可接受的载体组合。可以使用的载体包括葡萄糖、乳糖、阿拉伯树胶、明胶、甘露醇、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、中链长的甘油三酯、右旋糖酐和适用于生产固体、半固体或液体形式制剂的其他载体。此外,可以使用辅助剂、稳定剂、增稠剂和着色剂和香料。本发明化合物以足以在过程或疾病状态时产生所需作用的量包括在药物组合物中。
包含本发明化合物的药物组合物可以是适合口服使用的形式,例如作为片剂、锭剂、糖锭、水性或油性混悬液、可分散粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂。可以根据本领域已知用于生产药物组合物的任何方法来制备预期口服使用的组合物,并且此类组合物可以包含选自由以下组成的组的一种或多种剂以提供药学上精巧且适口的制剂:增甜剂例如蔗糖、乳糖或糖精,调味剂例如薄荷、冬绿树或樱桃油,着色剂和防腐剂。包含与非毒性药学上可接受的赋形剂混合的本发明化合物的片剂还可以通过已知方法生产。使用的赋形剂可以是例如(1)惰性稀释剂,例如碳酸钙、乳糖、磷酸钙或磷酸钠;(2) 制粒剂和分散剂,例如玉米淀粉、马铃薯淀粉或藻酸;(3)结合剂,例如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶,和(4)润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者它们可以通过已知技术包衣以延迟在胃肠道中的分解和吸收,从而提供经更长时段的持续作用。例如,可以采用时间延迟材料,例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以是硬明胶胶囊形式,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。它们还可以是软明胶胶囊形式,其中本发明化合物与水或油介质例如花生油、液体石蜡或榄橄油混合。
包含本发明化合物的药物组合物可以是适合局部使用的形式,例如作为油性混悬液、作为在水液体或非水液体中的溶液或混悬液、或作为水包油或油包水液体乳液。
药物组合物可以是无菌注射混悬液的形式。该混悬液可以使用适当的分散剂或润湿剂和悬浮剂根据已知方法配制。无菌注射制剂还可以是在非毒性胃肠外可接受的稀释剂或溶剂中的无菌注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。无菌固定油常规用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的单甘油酯或二甘油酯、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,或者合成的脂肪媒介物如油酸乙酯等。可以按需要加入缓冲剂、防腐剂、抗氧化剂等。
还可以用于直肠施用药物的栓剂形式施用本发明化合物。可以通过将本发明化合物与适当的非刺激性赋形剂混合来制备,所述非刺激性赋形剂例如可可脂、聚乙二醇的合成甘油酯,其在常温下是固体,但在直肠腔内液化和/或溶解以释放药物。
由于个体受试者可以在症状严重度方面存在许多差异,并且每种药物具有其独特的治疗特征,每个受试者采用的精确的施用方式和剂量由专业人员判断。
本文描述的化合物和药物组合物用作包括人在内的哺乳动物中的药剂,用于治疗疾病和/或缓解病症,其响应于N-甲酰基肽受体样 -1(FPRL-1)受体的激动剂或功能拈抗剂的治疗。因此,在本发明的其他实施方案中,提供了用于治疗与N-甲酰基肽受体样-1(FPRL-1)受体调节相关的疾患的方法。例如,此类方法可以通过给有相应需要的受试者施用包含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。如本文使用的,术语“治疗有效量”表示将在有相应需要的受试者中引发研究者、兽医、医学博士或其他临床医生所寻求的生物或医学响应的药物组合物的量。在一些实施方案中,有相应需要的受试者是哺乳动物。在一些实施方案中,哺乳动物是人。
材料和方法
预期FPR2激动剂在许多不同类型的皮肤炎症中具有显著作用,但是已经示例证明了在冲击皮肤伤口的小鼠模型中的伤口愈合(图2)。已经用表4描述的FPR2激动剂示例说明了该模型中的抗炎活性。
FLIPR:利用了稳定表达人类FPR2受体的HEK-Gα16细胞。在使用前一天,将细胞以每孔18,000个细胞的密度铺板到384孔聚D- 赖氨酸涂布板。生长培养基是补充有10%胎牛血清(FBS)、1%抗生素 -抗霉菌、50μg/ml潮霉素和400μg/ml遗传霉素的DMEM培养基。在实验当天,细胞用补充有20mM HEPES(HBSS/hepes缓冲液)的汉克斯平衡盐溶液洗涤两次。然后细胞用HBSS/Hepes缓冲液中稀释的2μM Fluo-4加载染料并在37℃下孵育40分钟。在将板放入FLIPR(荧光成像读板器,Molecular Devices)之前,通过洗涤细胞板来去除细胞外染料。将配体在HBSS/Hepes缓冲液中稀释并在384孔微量滴定板中制备。以相对荧光单位获得Ca+2响应数据。
表4
免疫组织化学:利用特异性针对FPR2的抗体的荧光免疫组织化学来确定在正常人类皮肤中的定位。以1∶200稀释使用抗FPR2抗体(Abcam)来检测FPR2蛋白。
皮肤伤口愈合模型:使用体重24-28g的5ICR雄性小鼠组。研究期间,将测试动物圈养在个体笼子里。环已烯巴比妥(90mg/kg,i.p.) 麻醉下,给每只动物的肩部和背部区域剃毛。应用尖锐冲头(ID 12mm) 以去除皮肤,包括肉膜(panniculus carnosus)和粘附组织。在第1、 3、5、7、9和11天,通过使用Image-ProPlus(Media Cybernetics,版本4.5.0.29)测量印在清洁塑料片上的伤口面积。在皮肤冲击后每天一次局部(TOP)施用测试物质和媒介物(安慰剂,20μL/小鼠),持续总共连续10天。以相同方案局部给予0.5% CMC/PBS,pH 7.4中的 CGS-21680的阳性对照。计算伤口的百分比闭合(%),并使用 Graph-Prism(GraphSoftware USA)通过线性回归分析伤口半闭合时间 (CT50)。应用单向ANOVA、随后Dunnett检验,用于比较每个测量时间点的治疗组和媒介物组。在P<0.05时认为差异是显著的。
小鼠中LL37诱导的红斑痤疮模型:在给药之前,用异荧烷轻微麻醉动物,并且用数字卡尺(Mitutoyo 293-340)进行基线右耳和左耳厚度的测量。在t=-1小时,用异荧烷轻微麻醉动物以允许向两个耳朵局部应用(背面)在由PBS∶乙醇(50∶50)组成的媒介物或媒介物对照中配制10μL FPR2激动剂。在t=0小时,再次麻醉小鼠。在耳厚度测量之后,将20uL LL-37(100μM)注射进入右耳,同时将PBS注射进入左耳。在t=3和6小时进行额外的耳厚度测量。在最后一个时间点,通过CO2吸入处死小鼠并收集耳朵供额外分析。
体外人类皮肤穿透模型:简言之,将来自两个供体的刃厚人类腹部皮肤(~0.50mm)切片固定于流经扩散池(PermeGear)。将FPR2激动剂以10μL的剂量应用至0.64cm2的表面积(每个化合物n=7)。将PBS 以~42μL/min的恒定流速泵入皮肤之下。在1、3、6、12和24小时收集受体流体样品并通过LC/MS/MS分析。
Claims (4)
1.一种用于治疗皮肤炎症和/或皮肤疾病的药物组合物,其包含式I的化合物或其药学上可接受的盐:
其中:
R1是仲丁基、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是卤素或甲基;
R3是卤素;
R4是H、甲基或卤素;
R5是OR6或NH2;并且
R6是H或C2-4烷基;
或者所述组合物包含选自以下的化合物或其药学上可接受的盐:
2.如权利要求1所述的药物组合物,其中所述式I的化合物选自:
3.如权利要求1所述的药物组合物,其中所述化合物为:
4.如权利要求1-3中任一项所述的药物组合物,其中所述皮肤炎症和/或皮肤疾病选自:皮肤伤口愈合、肥大性瘢、瘢痕疙瘩、烧伤、红斑痤疮、特异性皮炎、痤疮、银屑病、脂溢性皮炎、光化性角化病、基底细胞癌、鳞状细胞癌、黑素瘤、病毒性疣、光老化、光损伤、黑斑病、炎症后色素沉着、色素沉着疾患、秃顶、瘢痕化和非瘢痕化形式。
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