TW201446241A - 使用甲醯基肽受體2激動劑治療皮膚疾病 - Google Patents
使用甲醯基肽受體2激動劑治療皮膚疾病 Download PDFInfo
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- TW201446241A TW201446241A TW103107759A TW103107759A TW201446241A TW 201446241 A TW201446241 A TW 201446241A TW 103107759 A TW103107759 A TW 103107759A TW 103107759 A TW103107759 A TW 103107759A TW 201446241 A TW201446241 A TW 201446241A
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- amino
- bromophenyl
- optionally substituted
- alkyl
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Abstract
本發明係關於藉由局部或全身遞送,為需要治療之個體治療皮膚發炎及皮膚疾病的方法,其包括投與包含治療有效量之至少一種甲醯基肽受體2(FPR2)激動劑之醫藥組合物。
Description
本申請案主張於2013年3月06日提出申請的美國臨時專利申請案第61/773,778號之權益,該申請案揭示內容之全文以引用方式併入本文中。
本發明係關於藉由局部或全身遞送,為需要治療之個體治療皮膚發炎及皮膚疾病的方法,其包括投與包含治療有效量之至少一種甲醯基肽受體2(FPR2)激動劑之醫藥組合物。
甲醯基肽受體(FPR)家族屬於7個跨膜結構域G-蛋白偶聯受體(GPCR)家族。此家族在人類中包含3個成員,且此家族FPR2之一成員(亦稱為FPRL-1、ALXA4)主要在發炎性細胞(例如單核球及嗜中性球)以及T細胞上表現,並已顯示在發炎期間之白血球輸送及人類病理學中起關鍵作用(Chiang N、Serhan CN、Dahlen,S、Drazen JM、Hay DWP、Rovati E、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係因應眾多種結構不同之外源及內源配體之格外泛宿主性受體,該等配體包含血清類澱粉蛋白A(SAA)、趨化因子變體sCKβ8-1、神經保護肽humanin、抗發
炎類花生酸脂氧素A4(LXA4)及糖皮質素調節之蛋白質膜連蛋白A1(Chiang N、Serhan CN、Dahlen,S、Drazen JM、Hay DWP、Rovati E、Shimizu T、Yokomizo T、Brink,C.The lipoxin receptor ALX:Potent ligand-specific and stereoselective actions in vivo.Pharmacological Reviews 2006;58:463-519)。已顯示FPR2轉導許多系統中之花生四烯酸源性脂氧素A4(LXA4)之抗發炎效應,且已顯示在發炎之消退中起關鍵作用(Dufton N、Perretti M.Therapeutic anti-inflammatory potential of formyl peptide receptor agonists.Pharamcology & Therapeutics 2010;127:175-188)。FPR2基因敲除小鼠顯示如受體之生物作用所預期之疾病病況中之過度發炎(Dufton N、Hannon R、Brancaleone V、Dalli J、Patel HB、Gray M、D’Aquisto F、Buckingham JC、Perretti M、Flower RJ.Anti-inflammatory role of the murine formyl-peptide receptor 2:Ligand-specific effects on leukocyte responses and experimental inflammation.Journal of Immunology 2010;184:2611-2619.Gavins FNE、Hughes EL、Buss NAPS、Holloway PM、Getting SJ、Buckingham JC.Leukocyte recruitment in the brain in sepsis:involvement of the annexin 1 FPR2/ALX anti-inflammatory system.FASEB 2012;26:1-13)。
已顯示,脂氧素A4或其類似物及膜連蛋白I蛋白對FPR2之活化藉由促進發炎之主動消退來產生抗發炎活性,該主動消退涉及抑制多形核嗜中性球(PMN)及嗜酸性球遷移,且亦刺激單核球遷移,從而能夠以非炎性方式清除發炎位點之凋亡細胞(Gavins FNE、Hughes EL、Buss NAPS、Holloway PM、Getting SJ、Buckingham JC.Leukocyte recruitment in the brain in sepsis:involvement of the annexin 1 FPR2/ALX anti-inflammatory system.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 are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.FASEB 2010;24:4240-4249)。此外已顯示,FPR2抑制自然殺手(NK)細胞毒性且促進T細胞活化,此進一步有助於下調組織損傷發炎信號。已顯示FPR2與LXA4及膜連蛋白之相互作用在皮膚發炎、血管生成、上皮遷移、水腫、禿髮及角膜傷口癒合之實驗模型中有益。(Reville K、Cream JK、Vivers S、Dransfield I、Godson C.Lipoxin A4 redistributes Mysoin IIA and Cdc42 in macrophages:Implications for phagocytosis 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 of Immunology 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 are potent inhibitors of acute inflammation:evidence for anti-inflammatory receptors.Journal of Experimental Medicine 1997;185:1693-1704.;Leoni G、Alam A、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.Annexin A1,formyl peptide receptor,and NOX1 orchestrate epithelial repair.Journal of Clinical Investigation.2013;123:443-54;Leedom A、Sullivan AB、Dong B、Lau D、Gronert K.Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.American Journal of Pathology 2010;176:74-84;Tsuruki T、Takahata K、Yoshikawa M.Mechanism of the protective effect of intraperitoneally
administered agonists for formyl peptide receptors against chemotherapy-induced alopecia.Biosci Biotechnology Biochemistry.2007;71:1198-202)。
選擇性靶向FPR2亦將具有在皮膚傷口癒合中給予其有效抗發炎及促上皮修復作用之益處。此外,已顯示一些皮膚疾病具有LL37之異常表現,LL37係已顯示為FPR2之天然配體之促發炎抗菌肽。在慢性發炎性疾病酒渣鼻中,LL37高表現且認為其在發病機制方面起作用(Yamasaki K、Di Nardo A、Bardan A、Murakami M、Ohtake T、Coda A、Dorschner RA、Bonnart C、Descargues P、Hovnanian A、Morhenn VB、Gallo RL.Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nature Medicine.2007;13:975-80)。
本發明係關於藉由局部或全身遞送,為需要治療之個體治療皮膚發炎及皮膚疾病的方法,其包括投與包含治療有效量之至少一種甲醯基肽受體2(FPR2)激動劑之醫藥組合物。
鑒於LXA4-FPR2之抗發炎軸,提出FPR2激動劑可用於抑制LL-37介導之發炎性疾病,例如酒渣鼻。脂氧素A4及其類似物之醫藥應用受限於天然多烯烴天然產物之固有物理化學性質。因此,FPR2之小分子抗發炎激動劑將在發炎性病症、尤其在皮膚中具有眾多治療益處。FPR2在人類皮膚及其附屬物中廣泛表現。因此,FPR2代表用於研發具有過多發炎性反應之皮膚疾病之新治療劑之重要的新穎促消退分子靶。
本發明係關於FPR2激動劑展現皮膚抗發炎活性與化學穩定性及適於局部皮膚遞送之能力。該等FPR2化合物顯示針對受體之良好效能,重要的是,FPR2化合物在局部有活性,且因此可以許多形式來
投與,包含(但不限於)乳霜、洗液、凝膠、溶液、噴霧及泡沫。該等化合物亦可經IV、肌內、鞘內、皮下、口服或腹膜內投與。該等化合物可用於治療皮膚疾病,包含(但不限於)酒渣鼻、猛爆性酒渣鼻、曬傷、牛皮癬、停經相關之熱潮紅、潮紅及與熱潮紅相關之充血、與熱潮紅相關之紅斑症、源自睪丸切除術、異位性皮炎、來自昆蟲叮咬之充血及瘙癢治療之熱潮紅、光老化、脂溢性皮炎、痤瘡、過敏性皮炎、面部毛細血管抗張(先前存在之小血管之抗張)、血管抗張症、肥大性酒渣鼻(鼻肥厚伴有濾泡抗張)、痤瘡樣皮膚疹(可滲出或結痂)、灼熱或刺痛感、皮膚紅斑症、伴有皮膚血管擴張之皮膚過動症、萊爾症候群(Lyell's syndrome)、史蒂芬強森症候群(Stevens-Johnson syndrome)、與痔瘡相關之局部瘙癢及不適、痔瘡、輕症多形性紅斑、重症多形性紅斑、結節性紅斑、眼部浮腫、蕁麻疹、瘙癢性皮炎、紫癜、靜脈曲張、接觸性皮炎、異位性皮炎、貨幣狀皮炎、泛發性表皮脫落性皮炎、鬱血性皮炎、慢性單純苔蘚、口周皮炎、鬍鬚假性毛囊炎、環狀肉芽腫、日光性角化症、基底細胞癌、鱗狀細胞癌、濕疹、皮膚傷口癒合、肥厚性瘢痕、瘢痕瘤、燒傷、酒渣鼻、異位性皮炎、痤瘡、牛皮癬、脂溢性皮炎、日光性角化症、基底細胞癌、鱗狀細胞癌、黑素瘤、病毒性疣、光老化、光損傷、黑皮病、發炎後色素沉著過度、其他色素沉著病症及禿髮(結瘢及非結瘢形式)。預期以下化合物將在許多不同類型之皮膚疾病中具有治療效應,但已藉由展示小鼠皮膚傷口癒合模型中之加速傷口癒合活性(圖1)及小鼠(圖2)及人類角質細胞(圖2)中之LL-37-誘導之發炎減輕來例示。LL-37-誘導之酒渣鼻小鼠模型中之抗發炎活性已使用三種FPR2激動劑來例示:{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸、{[(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸、{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸。
亦展示了FPR2激動劑在局部投與後之皮膚滲透(圖3)。
圖1 FPR2激動劑顯示小鼠穿孔皮膚傷口模型中之有效傷口癒合。
圖2 FPR2激動劑對媒劑在所有時間點下在小鼠耳朵中阻斷LL-37誘導之發炎(p<0.05)。
圖3. 活體外人類皮膚滲透模型中之FPR2激動劑之吸收。
本發明係關於為需要治療之個體治療皮膚發炎及皮膚疾病的方法,其包括投與包含治療有效量之至少一種甲醯基肽受體2(FPR2)激動劑之醫藥組合物。
在另一態樣中,本發明提供至少一種FPR2激動劑之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚發炎疾病或病況的藥劑。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/668,835中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/668,835中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況之藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/668,835中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
美國專利申請案S.N.13/668,835中所揭示之化合物係由式I表示:
其中:R1係第二丁基、C6-10芳基、-CH2-(C6-10)芳基、-CH2-雜環、C4-8環烷基或C3-8環烯基或雜環;R2係鹵素或甲基;R3係鹵素;R4係H、甲基或鹵素;R5係OR6或NH2;R6係H或C2-4烷基。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/523,579中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/523,579中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況的藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/523,579中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
美國專利申請案S.N.13/523,579中所揭示之化合物係由式II表
示:
其中:a為1且b為0;a為0且b為1;a為1且b為1;R1係視情況經取代之C1-8烷基、視情況經取代之C3-8環烷基、視情況經取代之雜環、視情況經取代之C3-8環烷基、視情況經取代之C6-10芳基、視情況經取代之C3-8環烯基、-NR11R12或-OR13;R2係視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3係氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12、NO2、視情況經取代之雜環、視情況經取代之C3-8環烷基、視情況經取代之C6-10芳基或視情況經取代之C3-8環烯基;R4係氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12、NO2、視情況經取代之雜環、視情況經取代之C3-8環烷基、視情況經取代之C6-10芳基或視情況經取代之C3-8環烯基;R5係鹵素、-CF3或-S(O)nR14;n為0、1或2;R6係氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12、NO2、視情況經取代之雜環、視情況經取代之C3-8環烷基、視情況經取代之C6-10芳基或視情況經取代之C3-8環烯基;
R7係氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12、NO2、視情況經取代之雜環、視情況經取代之C3-8環烷基、視情況經取代之C6-10芳基或視情況經取代之C3-8環烯基;R8係氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9係氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10係氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a係氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10a係氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11係氫或視情況經取代之C1-8烷基;R12係氫或視情況經取代之C1-8烷基;R13係氫或視情況經取代之C1-8烷基;R14係氫、CF3或視情況經取代之C1-8烷基;R15係氫或視情況經取代之C1-8烷基。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/673,800中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/673,800中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況之藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/673,800中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
美國專利申請案S.N.13/673,800中所揭示之化合物係由式III表示:
R1係鹵素、氫、視情況經取代之C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;R2係鹵素、視情況經取代之C1-8烷基、CF3、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;R3係氫、視情況經取代之C1-8烷基、視情況經取代之C3-8環烷基、視情況經取代之C3-8環烯基、視情況經取代之C6-10芳基、視情況經取代之雜環,或與R5一起形成視情況經取代之10或11員多環;
R4係氫、視情況經取代之C1-8烷基、、
、、、、、視情況經取代之C3-8環烷基、視情況經取代之C3-8環烯基、視情況經取代之C6-10芳基、視情況經取代之雜環,或與R5一起形成視情況經取代之螺單環或多環、碳環或雜環、飽和或不飽和5至10員環;R5係氫、視情況經取代之C1-8烷基、視情況經取代之C3-8環烷基、視情況經取代之C3-8環烯基、視情況經取代之C6-10芳基、視情況經取代之雜環,或與R4一起形成視情況經取代之螺單環或多環碳環或雜環、飽和或不飽和5至10員環,或與R3一起形成視情況經取代之5或6員環;R6係鹵素、氫、視情況經取代之C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;R7係鹵素、氫、視情況經取代之C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R8係鹵素、氫、視情況經取代之C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;R9係氫、C(O)(C1-8烷基)或視情況經取代之C1-8烷基;R10係氫、視情況經取代之C1-8烷基、O(C1-8烷基)、NR11R12或OH;R11係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R12係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R13係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R14係氫、視情況經取代之C6-10芳基、視情況經取代之C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基);R15係氫、視情況經取代之C1-8烷基或O(C1-8烷基);R16係OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;R17係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R18係氫、C(O)(C1-8烷基)、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R19係氫、C(O)(C1-8烷基)、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R20係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;R21係氫、視情況經取代之C6-10芳基或視情況經取代之C1-8烷基;n為1、2、3、4或5;m為1、2、3、4或5。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/765,527中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.
13/765,527中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況的藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/765,527中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
美國專利申請案S.N.13/765,527中所揭示之化合物係由式IV表示:
其中:R1係氫、鹵素、經取代或未經取代之C1-6烷基、經取代或未經取代之C2-6烯基、經取代或未經取代之C2-6炔基、經取代或未經取代之C3-8環烷基、經取代或未經取代之C3-8環烯基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基,或可與R2一起形成視情況經取代之環丁基;R2為異丙基,或可與R3一起形成經取代或未經取代之3至6員環雜環,或可與R1一起形成視情況經取代之環丁基、環丙基;且R3係氫、經取代或未經取代之C1-6烷基、經取代或未經取代之C2-6烯基、經取代或未經取代之C2-6炔基、經取代或未經取代之C3-8環烷基、經取代或未經取代之C3-8環烯基、經取代或未經取代之雜環、經取代或未經取代之C6-10芳基,或可與R2一起形成經取代或未經取代之
3至6員雜環。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與治療有效量之包括至少一種如美國專利申請案S.N.13/409,228中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/409,228中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況的藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/409,228中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
其中:「」係單鍵或雙鍵;「」係單鍵或雙鍵;R1係H、鹵素、-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環烷基、C3-8環烯基或羥基;R2係H、鹵素、-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環烷基、C3-8環烯基或羥基;R3係H、鹵素、-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環烷基、C3-8環烯基、C6-10芳基或羥基;R4係H或C(O)R12;R5係H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;R6係H、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、-C2-6烯基或-C2-6炔基;Y係O或S;X係O、NR或CH2;
Ra係C6-10芳基、、雜芳基、C3-8環烷基、C3-8環烯基或H;Rb係鹵素;c為0、1或2;係、、、或
R7係H、鹵素、-S(O)R10、-S(O)2R11、硝基、羥基、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環烯基或C3-8環烷基;R8係H、鹵素、-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環烯基或C3-8環烷基;R9係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環烯基或C3-8環烷基;R10係-C1-6烷基、C3-8環烷基或C3-8環烯基;R11係H、羥基、-C1-6烷基、C3-8環烷基或C3-8環烯基;R12係H、羥基、-C1-6烷基、C3-8環烷基、C3-8環烯基、NR13R14或-OC1-6烷基;R13係H、-C1-6烷基、C3-8環烷基、C3-8環烯基、SO2R11或C(O)R15;R14係H、-C1-6烷基、C3-8環烯基、芳基、雜環或C3-8環烷基;R15係H、-C1-6烷基、C3-8環烯基或C3-8環烷基;且R係H、-C1-6烷基、C3-8環烯基或C3-8環烷基;前提係當「」為雙鍵時,則R5及R6為空。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/370,472中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/370,472中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況的藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/370,472中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活
性。
如美國專利申請案S.N.13/370,472中所揭示之化合物係由式VI表示:
其中:A係C6-10芳基、雜環、C3-8環烷基或C3-8環烯基;
R17係C1-6烷基或;B係C6-10芳基、雜環、C3-8環烷基或C3-8環烯基;R1係H、鹵素、-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環烷基或羥基;R2係H、鹵素、-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環烷基或羥基;R3係H、C1-6烷基或C3-8環烷基;R4係H、C1-6烷基或C3-8環烷基;R5a係H、鹵素、-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環烷基或羥基;
R5b係H、鹵素、-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環烷基或羥基;R5c係H、鹵素、-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環烷基或羥基;R5d係H、鹵素、-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環烷基或羥基;R6係H、-S(O)2R11、-C1-6烷基、-(CH2)nNR13R14、-(CH2)m雜環、C(O)R12、NR13R14、C3-8環烷基、C6-10芳基或雜環;R7係H、鹵素、-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環烷基或羥基;R8係H、鹵素、-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環烷基或羥基;R9係H、鹵素、-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環烷基或羥基;R10係H、鹵素、-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環烷基或羥基;X係O或S;Y係O或S;R11係H、羥基、-C1-6烷基、C3-8環烷基或NR13R14;
R12係H、羥基、-C1-6烷基、羥基、C3-8環烷基、NR13R14或-OC1-6烷基;R13係H、-C1-6烷基、C3-8環烷基、SO2R11或C(O)R16;R14係H、-C1-6烷基或C3-8環烷基;R15係-C1-6烷基或C3-8環烷基;R16係H、-C1-6烷基或C3-8環烷基;n為1-4;且m為1-4。
在另一態樣中,本發明提供治療皮膚發炎性疾病之方法,其包括投與包含治療有效量之至少一種如美國專利申請案S.N.13/863,934中所揭示之FPR2激動劑的醫藥組合物,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/863,934中所揭示之化合物之用途,其用於製造用來治療哺乳動物中由FPR2介導之皮膚疾病或病況的藥劑,前提係該等化合物具有FPR2受體結合活性。
在另一態樣中,本發明提供至少一種如美國專利申請案S.N.13/863,934中所揭示之化合物之用途,其用於治療哺乳動物中由FPR2介導之皮膚疾病或病況,前提係該等化合物具有FPR2受體結合活性。
如美國專利申請案S.N.13/863,934中所揭示之化合物係由式VII表示:
其中:n為0或1;R1係氫、經取代或未經取代之C1-8烷基、鹵素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21-SR11、-C(O)R12、CN或NO2;R2係氫、經取代或未經取代之C1-8烷基、鹵素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;R3係氫、經取代或未經取代之C1-8烷基、鹵素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN、NO2、CF3、S(O)R15或S(O)2R16;R4係氫、經取代或未經取代之C1-8烷基、鹵素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、-SR11、-C(O)R12、CN或NO2;R5係氫、經取代或未經取代之C1-8烷基、鹵素、-NR8R9、-NC(O)R20、-OR10、-OC(O)R21、SR11、-C(O)R12、CN或NC2;R6係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之雜環、經取代或未經取代之C3-8環烷基、經取代或未經取代之C6-10芳基、經取代或未經取代之C3-8環烯基或-CH2R19;R7係經取代或未經取代之雜環、-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係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之C3-8
環烷基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基;R9係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之C3-8環烷基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基;R10係氫或經取代或未經取代之C1-8烷基;R11係氫、經取代或未經取代之C1-8烷基或-CF3;R12係氫、經取代或未經取代之C1-8烷基、羥基、-OR24或-NR8R9;R13係-OR22;R14係-OR23;R15係經取代或未經取代之C1-8烷基;R16係經取代或未經取代之C1-8烷基、-NR8R9、-NHS(O)2R19或羥基;R17係OR10或NR8R9;R18係OR10或NR8R9;R19係經取代或未經取代之雜環、經取代或未經取代之C3-8環烷基、經取代或未經取代之C6-10芳基或經取代或未經取代之C3-8環烯基;R20係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之C3-8環烷基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基;R21係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之C3-8環烷基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基;R22係氫、經取代或未經取代之C1-8烷基,或可與R23一起形成
環;R23係氫、經取代或未經取代之C1-8烷基,或可與R22一起形成環;R24係氫、經取代或未經取代之C1-8烷基、經取代或未經取代之C3-8環烷基、經取代或未經取代之雜環或經取代或未經取代之C6-10芳基。
如本文所使用,術語「烷基」係指具有直鏈或具支鏈部分或其組合且含有1至8個碳原子之飽和、單價或二價烴部分。烷基之一個亞甲基(-CH2-)可經以下各項置換:氧、硫、亞碸、氮、羰基、羧基、磺醯基、硫酸酯、磺酸酯、醯胺、磺醯胺、二價C3-8環烷基、二價雜環或二價芳基。烷基可具有一或多個對掌性中心。烷基可獨立地經以下各項取代:鹵素原子、羥基、環烷基、胺基、雜環基團、芳基、羧酸基團、膦酸基團、磺酸基團、磷酸基團、硝基、醯胺基團、磺醯胺基團。
如本文所使用,術語「環烷基」係指源自飽和環狀烴之3至8個碳原子之單價或二價基團。環烷基可為單環或多環。環烷基可獨立地經以下各項取代:鹵素原子、磺醯基C1-8烷基、亞碸C1-8烷基、磺醯胺基團、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。
如本文所使用,術語「環烯基」係指源自飽和環烷基、具有至少一個雙鍵之3至8個碳原子之單價或二價基團。環烯基可為單環或多環。環烯基可獨立地經以下各項取代:鹵素原子、磺醯基、亞碸基團、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。
如本文所使用,術語「鹵素」係指氯、溴、氟、碘原子。
如本文所使用,術語「烯基」係指具有2至6個碳原子、源自飽
和烷基、具有至少一個雙鍵之單價或二價烴基。烯基之一個亞甲基(-CH2-)可經以下各項置換:氧、硫、亞碸、氮、羰基、羧基、磺醯基、硫酸酯、磺酸酯、醯胺、磺醯胺、二價C3-8環烷基、二價雜環或二價芳基。C2-6烯基可呈E或Z構型。烯基可經如上文所定義之烷基取代或經鹵素原子取代。
如本文所使用,術語「炔基」係指具有2至6個碳原子、源自飽和烷基、具有至少一個三鍵之單價或二價烴基。炔基之一個亞甲基(-CH2-)可經以下各項置換:氧、硫、亞碸、氮、羰基、羧基、磺醯基、硫酸酯、磺酸酯、醯胺、磺醯胺、二價C3-8環烷基、二價雜環或二價芳基。炔基可經如上文所定義之烷基取代或經鹵素原子取代。
如本文所使用,術語「雜環」係指3至10員環,其可為芳香族或非芳香族、飽和或不飽和,其含有至少一個選自氧、氮、硫或其至少兩者之組合之雜原子從而使碳環結構中斷。雜環可經C=O中斷;S及N雜原子可經氧化。雜環可為單環或多環。雜環部分可經以下各項取代:鹵素原子、磺醯基、亞碸基團、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。
如本文所使用,術語「芳基」係指藉由移除一個氫原子自由含有6至10個碳原子之環組成之芳香族烴衍生之有機部分。芳基可經以下各項取代:鹵素原子、磺醯基C1-6烷基、亞碸C1-6烷基、磺醯胺基團、羧酸基團、羧酸C1-6烷基酯(酯)基團、醯胺基團、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。芳基可為單環或多環。
如本文所使用,術語「羥基」表示式「-OH」基團。
如本文所使用,術語「羰基」表示式「-C(O)-」基團。
如本文所使用,術語「酮」表示具有連接至碳原子之羰基之有機化合物,例如-(CO)Rx,其中Rx可為如上文所定義之烷基、芳基、環烷基、環烯基、雜環。
如本文所使用,術語「胺」表示式「-NRxRy」基團,其中Rx與Ry可相同或獨立地係H、如上文所定義之烷基、芳基、環烷基、環烯基、雜環。
如本文所使用,術語「羧基」表示式「-C(O)O-」基團。
如本文所使用,術語「磺醯基」表示式「-SO2 -」基團。
如本文所使用,術語「硫酸酯」表示式「-O-S(O)2-O-」基團。
如本文所使用,術語「磺酸酯」表示式「-S(O)2-O-」基團。
如本文所使用,術語「羧酸」表示式「-C(O)OH」基團。
如本文所使用,術語「硝基」表示式「-NO2」基團。
如本文所使用,術語「氰基」表示式「-CN」基團。
如本文所使用,術語「醯胺」表示式「-C(O)NRxRy」基團,其中Rx與Ry可相同或獨立地係H、如上文所定義之烷基、芳基、環烷基、環烯基、雜環。
如本文所使用,術語「磺醯胺」表示式「-S(O)2NRxRy」基團,其中Rx與Ry可相同或獨立地係H、如上文所定義之烷基、芳基、環烷基、環烯基、雜環。
如本文所使用,術語「亞碸」表示式「-S(O)-」基團。
如本文所使用,術語「膦酸」表示式「-P(O)(OH)2」基團。
如本文所使用,術語「磷酸」表示式「-OP(O)(OH)2_基團。
如本文所使用,術語「磺酸」表示式「-S(O)2OH」基團。
如本文所使用,式「H」表示氫原子。
如本文所使用,式「O」表示氧原子。
如本文所使用,式「N」表示氮原子。
如本文所使用,式「S」表示硫原子。
在另一態樣中,FPR2激動劑係選自表1之化合物:
US 2005/0137230 A1及US 7820673揭示凝血因子Xa之抑制劑且可
用於預防及/或治療血栓栓塞性疾病及或治療腫瘤。2-({[(4-氯苯基)胺基]羰基}胺基)-3-苯基丙酸、(2S)-2-({[(4-甲氧基苯基)胺基]羰基}胺基)-3-苯基丙酸、(2S)-3-苯基-2-[({[4-(三氟甲基)苯基]胺基}羰基)胺基]丙酸、2-({[(4-碘苯基)胺基]羰基}胺基)-3-苯基丙酸甲酯、(2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸、(2R)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸係合成脲衍生物之中間體作為經活化之凝血因子X(FXa)抑制劑。
JP 63232846揭示在HPLC管柱上使用新穎層析對掌性固定相對N-(對-溴苯基胺甲醯基)衍生物((2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸、(2S,3S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-甲基戊酸、2-({[(4-溴苯基)胺基]羰基}胺基)-3-(1H-吲哚-3-基)丙酸、(2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-甲基丁酸)之拆分。
Journal of Chromatography(1987),404(1),117-22及Chromatographia(1987),23(10),727-30闡述在新穎對掌性固定相上藉由使用水性流動相溶析對鏡像異構蛋白質胺基酸((2R)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸、(2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸)之對-溴苯基胺甲醯基衍生物之拆分。
Biochimica et Biophysica Acta,Nucleic Acids and Protein Synthesis(1972),272(4),667-71闡述對硝基苯基-胺甲醯基-苯基丙胺醯基tRNA之聚(尿苷酸)依賴性結合中之化合物(2S)-2-({[(4-硝基苯基)胺基]羰基}胺基)-3-苯基丙酸)。
在另一態樣中,FPR2激動劑係選自表2之化合物:
表2之化合物可自Chemical Libraries(例如Aurora Fine Chemicals)購得。
在另一態樣中,FPR2激動劑係選自表3之化合物:
表3化合物可自Chemical Libraries(例如Chemical Block有限公司)購得。
在本發明之另一實施例中,提供治療與N-甲醯基肽受體樣1受體之調節相關之病症的方法。
該等方法可藉由例如向有需要之個體投與含有治療有效量之至少一種本發明化合物之醫藥組合物來實施。
N-甲醯基肽受體樣-1受體調節劑之治療應用為皮膚發炎及疾病,包含(但不限於)皮膚傷口癒合、肥厚性瘢痕、瘢痕瘤、燒傷、酒渣鼻、異位性皮炎、痤瘡、牛皮癬、脂溢性皮炎、日光性角化症、基底細胞癌、鱗狀細胞癌、黑素瘤、病毒性疣、光老化、光損傷、黑皮病、發炎後色素沉著過度、其他色素沉著病症及禿髮(結瘢及非結瘢形式)。
該等化合物可用於治療患有可藉由調節N-甲醯基肽受體樣-1受體而緩解之一系列病況及疾病之哺乳動物(包括人類):皮膚發炎及疾病,包括(但不限於)皮膚傷口癒合、肥厚性瘢痕、瘢痕瘤、燒傷、酒渣鼻、異位性皮炎、痤瘡、牛皮癬、脂溢性皮炎、日光性角化症、基底細胞癌、鱗狀細胞癌、黑素瘤、病毒性疣、光老化、光損傷、黑皮病、發炎後色素沉著過度、其他色素沉著病症及禿髮(結瘢及非結瘢形式)。
在本發明之另一實施例中,提供治療與FPRL-1受體之調節相關
之病症之方法。該等方法可藉由例如向有此需要之個體投與治療有效量之至少一種本發明化合物或其任何組合、或其醫藥上可接受之鹽、水合物、溶劑合物、晶體形式及個別異構體、鏡像異構體及非鏡像異構體來實施。
在任一指定情形下欲投與之化合物之實際量將由醫師考慮相關情況來決定,例如病況之嚴重程度、患者之年齡及體重、患者之一般身體狀況、病況之原因及投藥途徑。
該化合物將呈任何可接受之形式向患者經口投與,例如錠劑、液體、膠囊、粉末及諸如此類,或尤其在患者出現噁心時,可能需要或必要有其他途徑。該等其他途徑可包括(但不限於)經皮、非經腸、皮下、鼻內、經由植入支架、鞘內、玻璃體內、局部投藥至眼部、眼後部、肌內、靜脈內及直腸內遞送模式。此外,調配物可經過設計,以便讓活性化合物在指定時間期間延緩釋放,或在療程期間之指定時間點小心控制藥物之釋放量。
在本發明之另一實施例中,提供一種醫藥組合物,其在其醫藥上可接受之載劑中包含至少一種本發明化合物。片語「醫藥上可接受」意指載劑、稀釋劑或賦形劑必須與調配物之其他成份相容且對其接受者無害。
本發明之醫藥組合物可呈下列形式使用:固體、溶液、乳液、分散液、貼片、膠束、脂質體及諸如此類,其中所得組合物含有一或多種作為活性成份之本發明化合物與適於腸內或非經腸施加之有機或無機載劑或賦形劑之混合物。本發明化合物可與例如一般無毒、醫藥上可接受之載劑組合用於錠劑、丸劑、膠囊、栓劑、溶液、乳液、懸浮液及適於使用之任何其他形式。可使用之載劑包含葡萄糖、乳糖、阿拉伯膠、明膠、甘露醇、澱粉糊、三矽酸鎂、滑石、玉米澱粉、角蛋白、膠質二氧化矽、馬鈴薯澱粉、脲、中等鏈長三酸甘油酯、葡聚
糖及適用於製造呈固體、半固體或液體形式之製劑之其他載劑。此外,可使用助劑、穩定劑、增稠劑及著色劑以及香料。本發明化合物以足以對過程或疾病病況產生期望效應之量包含於醫藥組合物中。
含有本發明化合物之醫藥組合物可呈適於經口使用之形式,例如呈錠劑、口含劑、菱形錠錠、水性或油性懸浮液、可分散粉末或顆粒、乳液、硬或軟膠囊或糖漿或酏劑形式。意欲口服使用之組合物可根據業內已知用於製造醫藥組合物之任一方法來製備,且該等組合物可含有一或多種選自由甜味劑(例如蔗糖、乳糖或糖精)、矯味劑(例如薄荷、冬青油或月桂櫻油)、著色劑及防腐劑組成之群的藥劑,以提供醫藥上美觀且可口之製劑。亦可藉由已知方法來製造含有本發明化合物與無毒醫藥上可接受之賦形劑之混合物的錠劑。所使用之賦形劑可為例如(1)惰性賦形劑,例如碳酸鈣、乳糖、磷酸鈣或磷酸鈉;(2)造粒及崩解劑,例如玉米澱粉、馬鈴薯澱粉或海藻酸;(3)黏合劑,例如黃蓍膠、玉米澱粉、明膠或阿拉伯膠,及(4)潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。錠劑可無包衣或其可藉由已知技術包衣以延遲在胃腸道中之崩解及吸收並由此提供持續較長時間之作用。例如,可採用諸如甘油單硬脂酸酯或甘油二硬脂酸酯等延時材料。
在一些情形下,用於口服使用之調配物可呈硬明膠膠囊形式,其中混合本發明化合物與惰性固體賦形劑(例如,碳酸鈣、磷酸鈣或高嶺土(kaolin))。其亦可呈軟明膠膠囊形式,其中混合本發明化合物與水或油介質(例如,花生油、液體石蠟或橄欖油)。
含有本發明化合物之醫藥組合物可呈適於局部使用之形式,例如,呈油性懸浮液、於水性液體或非水性液體中之溶液或懸浮液或水包油或油包水液體乳液形式。
該等醫藥組合物可呈無菌可注射懸浮液形式。此懸浮液可根據已知方法使用適宜分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑
亦可為含於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如,呈含於1,3-丁二醇中之溶液形式。通常採用無菌不揮發性油作為溶劑或懸浮介質。出於此目的,可採用任何溫和不揮發性油,包括合成性單酸或二酸甘油酯、脂肪酸(包括油酸)、天然植物油(如:芝麻油、椰子油、花生油、棉籽油等)或合成性脂肪媒劑(如:油酸乙酯或諸如此類)。可視需要納入緩衝劑、防腐劑、抗氧化劑及諸如此類。
本發明化合物亦可呈栓劑形式投與,用於經直腸投與藥物。該等組合物可藉由混合本發明化合物與適宜非刺激性賦形劑(如:可可油、聚乙二醇之合成甘油酯)來製備,其在常溫下為固體,但於直腸腔中液化及/或溶解以釋放藥物。
由於個別個體之症狀嚴重程度可能有很大變化,且每一藥物具有其獨特的治療特徵,因此將由從業醫師來決定每一個體之精確投與模式及劑量。
本文所闡述之化合物及醫藥組合物可作為哺乳動物(包括人類)之藥劑,用於治療及/或緩解對N-甲醯基肽受體樣-1(FPRL-1)受體之激動劑或功能性拮抗劑之治療有反應之疾病及/或病況。因此,在本發明之另一實施例中,提供治療與調節N-甲醯基肽受體樣-1(FPRL-1)受體相關之病症的方法。該等方法可藉由例如向有此需要之個體投與含有治療有效量之至少一種本發明化合物之醫藥組合物來實施。如本文所使用,術語「治療有效量」意指可對有此需要之個體誘發研究者、獸醫、醫師或其他臨床醫師所尋求生物或醫學反應時之醫藥組合物之量。在一些實施例中,該有此需要之個體為哺乳動物。在一些實施例中,該哺乳動物為人類。
預期FPR2激動劑將在許多不同類型之皮膚發炎中具有顯著效
應,但已藉由展示小鼠穿孔皮膚傷口模型中之傷口癒合例子來證實(圖2)。此模型中之抗發炎活性已利用表4中所闡述之FPR2激動劑舉例說明。
FLIPR:利用穩定表現人類FPR2受體之HEK-Gα16細胞。在使用前一天將細胞以18,000個細胞/孔之密度平鋪於384孔已塗覆聚-D-離胺酸之分析板中。生長培養基係補充10%胎牛血清(FBS)、1%抗生素-抗黴菌劑、50μg/ml潮黴素及400μg/ml遺傳黴素之DMEM培養基。在實驗當天,用補充有20mM HEPES(HBSS/hepes緩衝液)之漢克氏平衡鹽溶液(Hank’s Balanced Salt Solution)將細胞洗滌兩次。然後使用於HBSS/Hepes緩衝液中稀釋之2μM Fluo-4對細胞添加染料,且在37℃下培育40分鐘。藉由將細胞板洗滌四次移除細胞外染料,然後將板置於FLIPR(螢光成像板讀取器,Molecular Devices)中。取配體於HBSS/Hepes緩衝液中稀釋且於384孔微量板中製備。獲得Ca+2反應之數據,以相對螢光單位表示。
免疫組織化學:使用利用特異性針對FPR2之抗體之螢光免疫組織化學來確定在正常人類皮膚中之定位。使用以1:200稀釋之抗FPR2抗體(Abcam)來檢測FPR2蛋白。
皮膚傷口癒合模型:使用5隻稱重24-28g之ICR雄性小鼠之群。在研究期間,將所測試動物圈養於個別籠中。在六巴比妥鹽(90mg/kg,i.p.)麻醉下,將每一動物之肩及背部區域剃毛。施加鋒利穿孔機(ID 12mm)以移除包含肉膜(panniculus carnosus)及黏附組織之皮膚。在第1、3、5、7、9及11天藉由使用Image-ProPlus(Media Cybernetics,4.5.0.29版)量測示蹤至透明塑膠板上之傷口區域。在皮膚穿孔後每天一次投與測試物質及媒劑(安慰劑,20μL/小鼠)局部(TOP),總共連續10天。經局部給予於0.5% CMC/PBS(pH 7.4)中之CGS-21680陽性對照作為相同方案。計算傷口閉合百分數(%),且使用Graph-Prism(Graph Software USA)藉由線性回歸分析傷口半閉合時間(CT50)。施加單因子ANOVA然後進行鄧奈特測試(Dunnett’s test)來比較每一測試時間點下之治療組與媒劑組。在P<0.05時之差別視為顯著。
LL37-誘導之小鼠酒渣鼻模型:在投藥之前,使用異氟烷
(isofluorane)將動物輕微麻醉且使用數位卡尺(Mitutoyo 293-340)進行基線右耳及左耳厚度量測。在t=-1hr時,使用異氟烷將動物輕微麻醉以允許將10μL於由PBS:乙醇(50:50)組成之媒劑中調配之FPR2激動劑或媒劑對照局部施加(背側)至兩耳。在t=0hr時,再將小鼠麻醉。在耳厚度量測後,將20μL LL-37(100μM)注射至右耳中,同時將PBS注射至左耳中。在t=3及6小時時進行額外耳厚度量測。在最後時間點後,藉由CO2吸入使小鼠安樂死且收集耳以供其他分析。
活體外人類皮膚滲透模型:簡言之,將來自兩個供體之分層(split-thickness)人類腹部皮膚(約0.50mm)區段包埋於流通型擴散細胞(PermeGear)中。將FPR2激動劑以10μL之劑量施加至0.64cm2之表面積(n=7/化合物)。將PBS以約42μL/min之恆定流速泵送至皮膚下方。在1、3、6、12及24hr時收集受體液樣品且藉由LC/MS/MS分析。
Claims (11)
- 一種甲醯基肽受體2(FPR2)激動劑之用途,其係製備用於治療皮膚發炎及皮膚疾病的藥劑,其中該藥劑係用於局部或全身遞送。
- 如請求項1之用途,其中該等皮膚發炎及皮膚疾病係選自:皮膚傷口癒合、肥厚性瘢痕、瘢痕瘤、燒傷、酒渣鼻、異位性皮炎、痤瘡、牛皮癬、脂溢性皮炎、日光性角化症、基底細胞癌、鱗狀細胞癌、黑素瘤、病毒性疣、光老化、光損傷、黑皮病、發炎後色素沉著過度、色素沉著病症、結瘢及非結瘢形式之禿髮。
- 如請求項1之用途,其中該FPR2激動劑係由式I表示:
- 如請求項3之用途,其中該FPR2激動劑係選自:(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基戊酸; (2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊酸;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊酸;(2S)-2-{[(4-碘苯基)胺甲醯基]胺基}-4-甲基戊酸;及(2S)-4-甲基-2-({[4-(甲基硫基)苯基]胺甲醯基}胺基)戊酸。
- 如請求項1之用途,其中該FPR2激動劑係由式II表示:
- 如請求項5之用途,其中該FPR2激動劑係選自:{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸;{[(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸; (2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基戊酸;2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸;{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸;2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-側氧基氮雜環庚-3-基)-3-苯基丙醯胺;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}乙酸;3-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}丙酸;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-苯基丙醯胺;{[(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸;(2S,3S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯胺;(2S,3S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴-2-氟芳基)胺甲醯基]胺基}-3-甲基戊醯胺;(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基-N-(2-側氧基丙基)戊醯胺;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-側氧基丙基)-3-苯基丙醯胺;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-苯 基丙醯胺;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸甲酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸丙-2-基酯;{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-4-甲基戊醯胺;(2S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基-N-(2-側氧基丙基)戊醯胺;(2S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯胺;(2S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}戊醯胺;(2S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基-N-(2-側氧基丙基)戊醯胺;(2S)-2-{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-3-甲基丁酸; (2S)-N-[(2S)-1-胺基-3-甲基-1-側氧基丁-2-基]-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基-2-甲基丙基)-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(1,3-二羥基丙-2-基)-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2,3-二羥基丙基)-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-[(2R)-1-羥基丙-2-基]-4-甲基戊醯胺;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸第三丁基酯;(2s)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸;(2S)-N-[(2S)-1-胺基-1-側氧基戊-2-基]-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(2S)-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}(苯基)乙酸;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基-N-(1H-四唑-5-基甲基)戊醯胺;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2,4-二甲基戊醯基)胺基]乙酸;(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-[(3-羥基-1,2-噁唑-5-基)甲基]-4-甲基戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-[2-(二甲基胺基)-2-側氧 基乙基]-4-甲基戊醯胺;{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基硫基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;(2S)-4-甲基-N-(1H-四唑-5-基甲基)-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯胺;2-甲基-2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}丙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基硫基)丁醯基]胺基}乙酸;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-吲哚-3-基)丙醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基](甲基)胺基}乙酸第三丁基酯;及{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基](甲基)胺基}乙酸。
- 如請求項1之用途,其中該FPR2激動劑係由式III表示:
- 如請求項7之用途,其中該FPR2激動劑係選自:1-(4-溴苯基)-3-[4-乙基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-[4-乙基-2,5-二側氧基-4-(丙-2-基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-(4,4-二乙基-2,5-二側氧基咪唑啶-1-基)脲;1-(4-溴-2-氟苯基)-3-(4,4-二乙基-2,5-二側氧基咪唑啶-1-基)脲; 1-(4-溴苯基)-3-(2,4-二側氧基-1,3-二氮雜螺[4.5]癸-3-基)脲;1-(4-溴苯基)-3-[4-甲基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-[4-甲基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]脲;1-(4-溴-2-氟苯基)-3-[4-乙基-2,5-二側氧基-4-(丙-2-基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-[2,5-二側氧基-4,4-二(丙-2-基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-(4,4-二環丙基-2,5-二側氧基咪唑啶-1-基)脲;1-(4-溴苯基)-3-[4-乙基-2,5-二側氧基-4-(丙-2-基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-[4-乙基-2,5-二側氧基-4-(丙-2-基)咪唑啶-1-基]脲;1-(4-溴-2-氟苯基)-3-[4-乙基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]脲;1-(4-溴苯基)-3-{4-[2-(呋喃-2-基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(4-氟苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(3-氟苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(4-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-甲基-2,5-二側氧基-4-[2-(噻吩-2-基)乙基]咪唑啶-1-基}脲; 1-(4-溴-2-氟苯基)-3-{4-[2-(4-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-甲基-4-[2-(5-甲基呋喃-2-基)乙基]-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴-2-氟苯基)-3-{4-[2-(3-氟-4-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(3-氟-4-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴-2-氟苯基)-3-{4-[2-(2-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴-2-氟苯基)-3-{4-[2-(3-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(3-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-{4-[2-(2-羥基苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;1-(4-溴苯基)-3-[4-(羥基甲基)-2,5-二側氧基-4-(丙-2-基)咪唑啶-1-基]脲;2-[1-{[(4-溴苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]-N-(2-羥基乙基)乙醯胺;2-[2-(1-{[(4-溴苯基)胺甲醯基]胺基}-4-乙基-2,5-二側氧基咪唑啶-4-基)乙基]苯甲酸甲酯;2-[1-{[(4-溴苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]-N-(1,3-二羥基丙-2-基)乙醯胺;2-[2-(1-{[(4-溴苯基)胺甲醯基]胺基}-4-乙基-2,5-二側氧基咪唑啶-4-基)乙基]苯甲酸; 2-[2-(1-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-乙基-2,5-二側氧基咪唑啶-4-基)乙基]苯甲酸;3-({[1-{[(4-溴苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]乙醯基}胺基)丙酸;2-[1-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]-N-(2-羥基乙基)乙醯胺;2-{2-[1-{[(4-溴苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]乙基}苯甲酸;[2-({[1-{[(4-溴苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]乙醯基}胺基)乙基]膦酸二乙酯;3-{[(4-溴苯基)胺甲醯基]胺基}-2,4-二側氧基-1,3-二氮雜螺[4.5]癸烷-8-甲酸乙酯;1-(4-溴苯基)-3-{4-[2-(2-氟苯基)乙基]-4-甲基-2,5-二側氧基咪唑啶-1-基}脲;及3-({[1-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-2,5-二側氧基-4-(丙-2-基)咪唑啶-4-基]乙醯基}胺基)丙酸。
- 如請求項1之用途,其中該FPR2激動劑係由式VII表示:
- 如請求項9之用途,其中該FPR2激動劑係選自:{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸; 2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-側氧基氮雜環庚-3-基)-3-苯基丙醯胺;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}甲基)膦酸氫乙酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}甲基)膦酸二乙酯;({[(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}甲基)膦酸二乙酯;({[(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}甲基)膦酸氫乙酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}甲基)膦酸二乙酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}甲基)膦酸二乙酯;(2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙基)膦酸二乙酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}甲基)膦酸氫乙酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}甲基)膦酸二丙-2-基酯;({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}甲基)膦酸氫乙酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}甲烷磺酸;氫{[(2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基)胺基]甲基}膦酸丙-2-基酯; ({[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}甲基)膦酸二丙-2-基酯;({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}甲基)膦酸二乙酯;({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}甲基)膦酸氫乙酯;{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}甲烷磺酸;及({[(2S)-4-甲基-2-({[4-(甲基硫基)苯基]胺甲醯基}胺基)戊醯基]胺基}甲基)膦酸二乙酯。
- 如請求項1之用途,其中該FPR2激動劑係選自:2-({[(4-氯苯基)胺基]羰基}胺基)-3-苯基丙酸;(2S)-2-({[(4-甲氧基苯基)胺基]羰基}胺基)-3-苯基丙酸;(2S)-3-苯基-2-[({[4-(三氟甲基)苯基]胺基}羰基)胺基]丙酸;(2S)-2-({[(3,4-二氯苯基)胺基]羰基}胺基)-3-苯基丙酸;(2S)-2-({[(4-硝基苯基)胺基]羰基}胺基)-3-苯基丙酸;3-苯基-2-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]丙酸;2-({[(3,4-二甲氧基苯基)胺基]羰基}胺基)-3-苯基丙酸;2-({[(4-碘苯基)胺基]羰基}胺基)-3-苯基丙酸甲酯;(2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸;(2R)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-苯基丙酸;3-苯基-2-{[(吡啶-3-基胺基)羰基]胺基}丙酸;(2S,3S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-甲基戊酸;(2S)-({[(4-溴苯基)胺基]羰基}胺基)(苯基)乙酸;2-({[(4-溴苯基)胺基]羰基}胺基)-3-(1H-吲哚-3-基)丙酸;(2S)-2-({[(4-溴苯基)胺基]羰基}胺基)-3-甲基丁酸; (2S)-2-({[(4-溴-2-氟苯基)胺基]羰基}胺基)-3-甲基丁酸;1-(4-氯苯基)-3-(2,4-二側氧基-1,3-二氮雜螺[4,5]癸-3-基)脲;1-(4-氯苯基)-3-(4-乙基-4-甲基-2,5-二側氧基咪唑啶-1-基)脲;1-[4-甲基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]-3-苯基脲;1-(8-甲基-2,4-二側氧基-1,3-二氮雜螺[4,5]癸-3-基)-3-(對甲苯基)脲;1-(2-氟苯基)-3-[4-甲基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]脲;N-(4-溴苯基)-2-(4,4-二甲基-2,5-二側氧基咪唑啶-1-基)乙醯胺;N-(4-溴苯基)-2-(4,4-二乙基-2,5-二側氧基咪唑啶-1-基)乙醯胺;N-(4-溴苯基)-2-(2,4-二側氧基-1,3-二氮雜螺[4.4]壬-3-基)乙醯胺;N-(4-溴苯基)-2-(2,5-二側氧基-4,4-二丙基咪唑啶-1-基)乙醯胺;N-(4-溴苯基)-2-(4-乙基-2,5-二側氧基-4-苯基咪唑啶-1-基)乙醯胺;N-(4-溴苯基)-2-(4-環丙基-4-甲基-2,5-二側氧基咪唑啶-1-基)乙醯胺;N-(4-溴苯基)-2-(2,4-二側氧基-1,3-二氮雜螺[4.6]十一碳烷-3-基)乙醯胺;N-(4-溴苯基)-2-(4-乙基-4-甲基-2,5-二側氧基咪唑啶-1-基)乙醯胺;N-(4-氯苯基)-2-(4,4-二乙基-2,5-二側氧基咪唑啶-1-基)乙醯 胺;2-(4,4-二乙基-2,5-二側氧基咪唑啶-1-基)-N-(4-氟苯基)乙醯胺;N-(4-溴苯基)-2-[4-甲基-2,5-二側氧基-4-(2-苯基乙基)咪唑啶-1-基]乙醯胺;N-(4-溴苯基)-1,3,3a,4,7,7a-六氫-1,3-二側氧基-4,7-橋亞甲基-2H-異吲哚-2-乙醯胺;及N-(4-溴苯基)-1,3,3a,4,7,7a-六氫-1,3-二側氧基-2H-異吲哚-2-乙醯胺。
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