TW201331168A - 作為甲醯基肽受體樣-1(fprl-1)受體調節劑的n-脲取代之胺基酸之醯胺衍生物 - Google Patents
作為甲醯基肽受體樣-1(fprl-1)受體調節劑的n-脲取代之胺基酸之醯胺衍生物 Download PDFInfo
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- TW201331168A TW201331168A TW101139839A TW101139839A TW201331168A TW 201331168 A TW201331168 A TW 201331168A TW 101139839 A TW101139839 A TW 101139839A TW 101139839 A TW101139839 A TW 101139839A TW 201331168 A TW201331168 A TW 201331168A
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- amino
- optionally substituted
- hydrogen
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- bromophenyl
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Abstract
本發明係關於N-脲取代之胺基酸的新穎醯胺衍生物、其製備方法、含有其之醫藥組合物及其作為醫藥(作為N-甲醯基肽受體樣-1(FPRL-1)受體之調節劑)的用途。
Description
本申請案主張2011年10月26日申請之美國臨時申請案第61/551,772號之權益,其以全文引用的方式併入本文中。
本發明係關於N-脲取代之胺基酸的新穎醯胺衍生物、其製備方法、含有其之醫藥組合物及其作為醫藥(作為N-甲醯基肽受體樣-1(FPRL-1)受體之調節劑)的用途。本發明特定言之係關於此等化合物及其醫藥組合物治療與N-甲醯基肽受體樣-1(FPRL-1)受體調節相關之病症的用途。
N-甲醯基肽受體樣-1(FPRL-1)受體為一種在發炎細胞(諸如單核細胞及嗜中性球)以及T細胞上表現的G蛋白偶聯受體且已顯示在發炎及人類病理學期間在白血球運輸中起到重要作用。FPRL-1為一種格外混雜之受體,其對一大批外源性及內源性配體,包括血清澱粉狀蛋白A(SAA)、趨化因子變體sCKβ8-1、人類神經保護肽、消炎性類花生酸脂氧素A4(anti-inflammatory eicosanoid lipoxin A4;LXA4)及糖皮質激素調節之蛋白質磷脂結合蛋白(annexin)A1起反應。FPRL-1在許多系統中轉導LXA4之消炎作用,但其亦可介導諸如SAA之肽之促炎性信號
傳導級聯。提出受體介導兩種相反作用之能力為由不同促效劑使用之不同受體域的結果(Parmentier,Marc等人,Cytokine & Growth Factor Reviews 17(2006)501-519)。
由LXA4或其類似物及由磷脂結合蛋白I蛋白質對FPRL-1之活化已顯示藉由促進炎症之主動消退來產生消炎活性,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細胞遷移,從而使凋亡細胞能夠以非炎性方式自發炎部位清除。此外,FPRL-1已顯示會抑制自然殺手(NK)細胞之細胞毒性且促進T細胞活化,此進一步有助於下調組織損傷性發炎信號。已在缺血再灌注、血管生成、皮膚發炎、化學療法誘發之禿髮、眼部發炎(諸如內毒素誘發之葡萄膜炎(uveitis))、角膜傷口癒合、上皮再形成等之實驗模型中顯示FPRL-1/LXA4相互作用為有益的。因此,FPRL-1代表一種用於開發用於發炎反應過度之疾病中之新穎治療劑的重要新穎促消退性分子目標。
JP 06172288揭示具有以下通式之苯丙胺酸衍生物之製備:
該等衍生物作為醯基-輔酶A:膽固醇醯基轉移酶衍生物之抑制劑,其適用於治療動脈硬化相關之各種疾病,
諸如心絞痛、心肌梗塞、暫時性缺血性痙攣、周邊血栓塞或阻塞。
Journal of Combinatorial Chemistry(2007),9(3),370-385教示一種與核苷肽類抗生素具有結構類似性之胸苷基二肽脲文庫:
WO 9965932揭示選擇性結合哺乳動物類鴉片(opioid)受體之四肽或類似物或擬肽物:
Helvetica Chimica Acta(1998),81(7),1254-1263教示異氰酸4-氯苯酯(1-氯-4-異氰酸酯基苯)加合物之合成及分光表徵,以胺基酸作為用於生物監測異氰酸酯暴露之潛在劑量計:
EP 457195揭示具有內皮素(endothelin)拮抗劑活性之
肽及包含其之醫藥組合物的製備:
Yingyong Huaxue(1990),7(1),1-9教示二肽及三肽甜味劑之結構-活性關係以及L-苯丙胺酸衍生物之結構-活性關係:
FR 2533210揭示作為合成甜味劑之L-苯丙胺酸衍生物:
WO2005047899揭示選擇性活化FPRL-1受體之由下列骨架表示之化合物:
已發現N-脲取代之胺基酸之一組醯胺衍生物,其為強力及選擇性FPRL-1調節劑。因此,本文所述之化合物適用於治療廣泛多種與FPRL-1受體調節相關之病症。如本文所用之術語「調節劑」包括(但不限於):受體促效劑、拮抗劑、反向促效劑、反向拮抗劑、部分促效劑和部分拮抗劑。
本發明描述式I化合物,其具有FPRL-1受體生物活性。因此,本發明化合物適用於醫學中,例如適用於治療患有藉由FPRL-1調節得以減輕之疾病及病狀之人類。
在一個態樣中,本發明提供一種由式I表示之化合物或其個別幾何異構體、個別對映異構體、個別非對映異構體、個別互變異構體、個別兩性離子或醫藥學上可接受之鹽:
其中:a為0或1;b為0、1、2、3或4;R1為視情況經取代之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、-NH2、-OH、-O(C1-8烷基),R2為視情況經取代之C1-8烷基、視情況經取代之C6-10芳基,R3為H、視情況經取代之C1-8烷基、鹵素、-COOH、-OH、-NH2、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、視情況經取代之C3-8環烯基;R4為H、視情況經取代之C1-8烷基、鹵素、-COOH、-OH、-NH2、-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、視情況經取代之C3-8環烯基;R5為視情況經取代之C1-8烷基、鹵素、-COOH、-OH、-NH2、-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、視情況經取代之C3-8環烯基;R6為H、視情況經取代之C1-8烷基、鹵素、-COOH、-OH、-NH2、-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、視情況經取代之C3-8環烯基;R7為H、視情況經取代之C1-8烷基、鹵素、-COOH、-OH、-NH2、-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、視情況經取代之C3-8環烯基;及以下化合物:
在另一態樣中,本發明提供一種由式II表示之化合物或其幾何異構體、對映異構體、非對映異構體、互變異構體、兩性離子、水合物、晶體形式、溶劑合物或醫藥學上可接受之鹽:
其中:a為1且b為0;a為0且b為1;a為1且b為1;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素、-CF3或-S(O)nR14;
n為0、1或2;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫、CF3或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;
其限制條件為:a).當a=1且b=0時,則:R9不為視情況經取代之苯甲基;且R11不為:
式II化合物不具有以下結構:
b).當a=0且b=1時,則:R1為OR13;且式II化合物不具有以下結構:
c).當a=1且b=1時,則:R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為1且b為0;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫、CF3或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且R11不為:
式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為1且b為0;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為-S(O)nR14;n為0、1或2;
R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫、CF3或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且R11不為:
式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為1且b為0;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為-CF3;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且R11不為:
式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為1且b為0;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且式II化合物不具有以下結構:
R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為0;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基;R3為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R4為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R7為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R8為氫或視情況經取代之C1-8烷基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;
R10為氫或視情況經取代之C1-8;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且式II化合物不具有以下結構:
R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為0;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;
R6為氫;R7為氫;R8為氫、視情況經取代之C1-8烷基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫或視情況經取代之C1-8烷基;其限制條件為:R9不為視情況經取代之苯甲基;且式II化合物不具有以下結構:
R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為0且b為1;
R1為-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之
C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫、CF3或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;且式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;
R3為氫、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為氫、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為鹵素;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a為氫、視情況經取代之C1-8烷基或視情況經取代之
C6-10芳基;R10a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;且式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基;R3為氫、視情況經取代之C1-8烷基、鹵素;R4為氫、視情況經取代之C1-8烷基、鹵素;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素;R7為氫、視情況經取代之C1-8烷基、鹵素;
R8為氫;R9為氫;R10為氫、視情況經取代之C1-8烷基;R9a為氫、視情況經取代之C1-8烷基;R10a為氫、視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;且R14為氫、CF3或視情況經取代之C1-8烷基;且式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素;R6為氫;R7為氫;R8為氫;
R9為氫;R10為氫或視情況經取代之C1-8烷基;R9a為氫或視情況經取代之C1-8烷基;R10a為氫或視情況經取代之C1-8烷基;且R13為氫;且式II化合物不具有以下結構:
在另一態樣中,本發明提供一種由式II表示之化合物,其中:a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素;R6為氫;R7為氫;R8為氫;R9為氫;
R10為氫或視情況經取代之C1-8烷基;R9a為視情況經取代之C1-8烷基;R10a為視情況經取代之C1-8烷基;且R13為氫。
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為1;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫或視情況經取代之C1-8烷基;且R15為氫或視情況經取代之C1-8烷基;且其限制條件為:彼R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為1;R1為視情況經取代之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為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、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為氫、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為鹵素;R6為氫、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為氫、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為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R9a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10a為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R15為氫或視情況經取代之C1-8烷基;且其限制條件為:彼R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為1;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫、視情況經取代之C1-8烷基、鹵素;R4為氫、視情況經取代之C1-8烷基、鹵素;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素;R7為氫、視情況經取代之C1-8烷基、鹵素;R8為氫;R9為氫、視情況經取代之C1-8烷基;R10為氫、視情況經取代之C1-8烷基;R9a為氫、視情況經取代之C1-8烷基;R10a為氫、視情況經取代之C1-8烷基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;
R14為氫或視情況經取代之C1-8烷基;且R15為氫或視情況經取代之C1-8烷基;其限制條件為:彼R11不為:
在另一態樣中,本發明提供一種由式II表示之化合物,其中a為1且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫;R4為氫;R5為鹵素;R6為氫;R7為氫;R8為氫;R9為氫;R10為氫;R9a為氫;R10a為氫;且
R13為氫或視情況經取代之C1-8烷基;且其限制條件為:彼R11不為:
如本文所用之術語「烷基」係指具有直鏈或分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置換。烷基可具有一或多個對掌中心。烷基可獨立地經鹵素原子、羥基、環烷基、胺基、雜環基、芳基、羧酸基、膦酸基、磺酸基、磷酸基、硝基、醯胺基、磺醯胺基取代。
如本文所用之術語「環烷基」係指源於飽和環烴之具有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取代:鹵素原子、磺醯基C1-8烷基、亞碸C1-8烷基、磺醯胺基、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。
如本文所用之術語「環烯基」係指源於飽和環烷基之具有3至8個碳原子之具有至少一個雙鍵的單價或二價基團。環烯基可為單環或多環。環烯基可獨立地經以下
取代:鹵素原子、磺醯基、亞碸基、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、烷基胺基、胺基、芳基、C3-8環烷基或羥基。
如本文所用之術語「鹵素」係指氯原子、溴原子、氟原子、碘原子。
如本文所用之術語「烯基」係指具有2至6個碳原子、源於飽和烷基、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置換。C2-6烯基可呈E或Z組態。烯基可經如上定義之烷基或經鹵素原子取代。
如本文所用之術語「炔基」係指具有2至6個碳原子、源於飽和烷基、具有至少一個參鍵之單價或二價烴基。炔基之一個亞甲基(-CH2-)可經氧、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置換。炔基可經如上定義之烷基或經鹵素原子取代。
如本文所用之術語「雜環」係指3至10員環,其可為芳族或非芳族,飽和或不飽和,含有至少一個雜於碳環結構中之選自氧、氮、硫之雜原子或其至少兩者之組合。雜環可雜有C=O;S及N雜原子可經氧化。雜環可為單環或多環。雜環部分可經以下取代:鹵素原子、磺醯基、亞碸基、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、烷基胺基、胺基、芳
基、C3-8環烷基或羥基。
如本文所用之術語「芳基」係指源於藉由移除一個氫原子由含有6至10個碳原子之環組成之芳族烴的有機部分。芳基可經以下取代:鹵素原子、磺醯基C1-6烷基、亞碸C1-6烷基、磺醯胺基、羧基環酸基、羧酸C1-6烷酯(酯)基、醯胺基、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、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。
如本文所用之術語「羥基」表示具有式「-OH」之基團。
如本文所用之術語「羰基」表示具有式「-C(O)-」之基團。
如本文所用之術語「酮」表示具有羰基連接於碳原子之有機化合物,諸如-(CO)Rx,其中Rx可為如上定義之烷基、芳基、環烷基、環烯基、雜環。
如本文所用之術語「胺」表示具有式「-NRxRy」之基團,其中Rx與Ry可相同或獨立地為如上定義之H、烷基、芳基、環烷基、環烯基、雜環。
如本文所用之術語「羧基」表示具有式「-C(O)O-」之基團。
如本文所用之術語「磺醯基」表示具有式「-SO2 -」之基團。
如本文所用之術語「硫酸酯」表示具有式「-O-S(O)2-O-」之基團。
如本文所用之術語「磺酸酯」表示具有式「-S(O)2-O-」
之基團。
如本文所用之術語「羧酸」表示具有式「-C(O)OH」之基團。
如本文所用之術語「硝基」表示具有式「-NO2」之基團。
如本文所用之術語「氰基」表示具有式「-CN」之基團。
如本文所用之術語「醯胺」表示具有式「-C(O)NRxRy」之基團,其中Rx與Ry可相同或獨立地為如上定義之H、烷基、芳基、環烷基、環烯基、雜環。
如本文所用之術語「磺醯胺」表示具有式「-S(O)2NRxRy」之基團,其中Rx與Ry可相同或獨立地為如上定義之H、烷基、芳基、環烷基、環烯基、雜環。
如本文所用之術語「亞碸」表示具有式「-S(O)-」之基團。
如本文所用之術語「膦酸」表示具有式「-P(O)(OH)2」之基團。
如本文所用之術語「磷酸」表示具有式「-OP(O)(OH)2」之基團。
如本文所用之術語「磺酸」表示具有式「-S(O)2OH」之基團。
如本文所用之式「H」表示氫原子。
如本文所用之式「O」表示氧原子。
如本文所用之式「N」表示氮原子。
如本文所用之式「S」表示硫原子。
本發明揭示以下化合物:{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-吲哚-3-基)丙醯基]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}乙酸第三丁酯;[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)胺基]乙酸;[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)胺基]乙酸第三丁酯;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸第三丁酯;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯基]胺基}乙酸;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)
丁醯基]胺基}乙酸第三丁酯;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;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}丙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;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;2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸第三丁酯;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)
戊醯基]胺基}乙酸第三丁酯;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸第三丁酯;{[(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-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2R)-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}-N-[2-(二甲基胺基)-2-側氧基乙基}-4-甲基戊醯胺;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸第三丁酯;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]
乙酸第三丁酯;[(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}-2,4-二甲基戊醯基)胺基]乙酸第三丁酯;(2S)-N-[(1S)-2-胺基-2-側氧基-1-苯基乙基]-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)-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}(苯基)乙酸第三丁酯;(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸第三丁酯;(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-{[(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-(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-羥基-2-甲基
丙基)-4-甲基戊醯胺;(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-{[(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-3-甲基丁酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴苯基)胺甲醯基]胺基}-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}丙酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(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-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸第三丁酯;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-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)-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-甲基戊醯基]胺基}乙酸;{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;(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-溴苯基)胺甲醯基]胺基}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}-4-甲基戊醯胺;{[(2S)-2-{[(4-溴苯基)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}-N-(2-羥基乙基)-4-甲基戊醯胺;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;{[(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-2-氟苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸第三丁酯;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-側氧基
丙基)戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-側氧基丙基)戊醯胺;{[(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-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸乙酯;{[(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-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)戊醯胺;(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;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸第三丁酯;(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-溴苯基)胺甲醯基]胺基}-N-(2-側氧基丙基)-3-苯基丙醯胺;(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基
乙基)-3-甲基戊醯胺;(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-甲基戊醯胺;(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基-N-(2-側氧基丙基)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,3S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴-2-氟苯基)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-溴苯基)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}乙酸第三丁酯;{[(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)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸第三丁酯;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-苯基丙醯胺;3-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}丙酸;3-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]
胺基}丙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}乙酸第三丁酯。在另一態樣中,本發明揭示以下化合物:{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯基]胺基}乙酸;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸第三丁酯;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;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}丙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;
{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;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;2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸第三丁酯;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸;
{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸第三丁酯;{[(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-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;(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;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸第三丁酯;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸第三丁酯;[(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}-2,4-二甲基戊醯基)胺基]乙酸第三丁酯;(2S)-N-[(1S)-2-胺基-2-側氧基-1-苯基乙基]-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)-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}(苯基)乙酸第三丁酯;(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸第三丁酯;(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-{[(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-(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-羥基-2-甲基丙基)-4-甲基戊醯胺;(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-{[(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-3-甲基丁酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴苯基)胺甲醯基]胺基}-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}丙酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(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-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸第三丁酯;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-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)-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-甲基戊醯基]胺基}乙酸;{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸第三丁酯;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸;
[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)胺基]乙酸第三丁酯;[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)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}乙酸第三丁酯;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-吲哚-3-基)丙醯基]胺基}乙酸。
一些式I及式II化合物及一些其中間物在其結構中具有至少一個不對稱中心。此不對稱中心可以R或S組態存在,該R及S記號與Pure Appli.Chem.(1976),45,11-13中所述之規則一致加以使用。
術語「醫藥學上可接受之鹽」係指保留以上鑒別之化合物之所要生物活性且展現最小或不展現非所要毒理學作用的鹽或複合物。本發明之「醫藥學上可接受之鹽」包括式I及式II化合物能夠形成之治療活性之無毒性鹼式鹽或酸式鹽形式。
以其游離鹼形式存在之式I及式II化合物之酸加成鹽形式可藉由用適當酸處理該游離鹼獲得,該適當酸諸如為無機酸,例如鹽酸、氫溴酸、硫酸、磷酸、硝酸及其類似物;或有機酸,諸如乙酸、羥基乙酸、丙酸、乳酸、丙酮酸、丙二酸、反丁烯二酸、順丁烯二酸、草酸、酒石酸、丁二酸、蘋果酸、抗壞血酸、苯甲酸、鞣酸(tannic acid)、帕莫酸(pamoic acid)、檸檬酸、甲基磺酸、乙烷
磺酸、苯磺酸、甲酸及其類似物(Handbook of Pharmaceutical Salts,P.Heinrich Stahal及Camille G.Wermuth(編),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
以其酸形式存在之式I及式II化合物之鹼加成鹽形式可藉由用適當鹼處理該酸獲得,該適當鹼諸如為無機鹼,例如氫氧化鈉、氫氧化鎂、氫氧化鉀、氫氧化鈣、氨及其類似物;或有機鹼,諸如L-精胺酸、乙醇胺、甜菜鹼、苯乍生(benzathine)、嗎啉及其類似物。(Handbook of Pharmaceutical Salts,P.Heinrich Stahal及Camille G.Wermuth(編),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
式I及式II化合物及其鹽可呈包括在本發明之範疇內之溶劑合物形式。此等溶劑合物包括例如水合物、醇化物及其類似物。
就本發明而言,除非特定提及特定異構形式,否則提及化合物意欲涵蓋呈其各個可能之異構形式之化合物及其混合物。
本發明化合物可以不同多晶型形式存在。儘管未在上式中明確指示,但此等形式意欲包括在本發明之範疇內。
本發明化合物經指示用於治療或預防可能存在涉及N-甲醯基肽受體樣-1受體之組分之病狀。
在另一實施例中,提供包括至少一種本發明化合物於醫藥學上可接受之載劑中之醫藥組合物。
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。
此等方法可例如藉由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進行。
N-甲醯基肽受體樣-1受體調節劑之治療效用為眼部發炎性疾病,包括(但不限於)濕性及乾性年齡相關之黃斑變性(ARMD)、葡萄膜炎、乾眼症、角膜炎、影響眼後部之過敏性眼疾病及病狀,諸如黃斑病變及視網膜變性,包括非滲出性年齡相關之黃斑變性、滲出性年齡相關之黃斑變性、脈絡膜新血管生成、糖尿病性視網膜病變(增生性)、早產兒視網膜病變(ROP)、急性黃斑視神經視網膜病變、中心性漿液性脈絡膜視網膜病變(central serous chorioretinopathy)、囊樣黃斑水腫及糖尿病性黃斑水腫;傳染性角膜炎、葡萄膜炎、皰疹性角膜炎、角膜血管生成、淋巴管生成、葡萄膜炎、視網膜炎及脈絡膜炎(諸如急性多灶性板狀色素上皮病變)、貝塞特氏病(Behcet's disease)、鳥槍彈樣視網膜脈絡膜病變(birdshot retinochoroidopathy)、傳染病(梅毒、萊姆病(lyme)、結核、弓漿蟲病(toxoplasmosis))、中間葡萄膜炎(扁平部睫狀體炎(pars planitis))、多灶性脈絡膜炎、多發性短暫性白點症候群(mewds)、眼部類肉瘤病、後鞏膜炎(posterior scleritis)、匐行性脈絡膜炎(serpiginous choroiditis)、視網膜下纖維化及葡萄膜炎症候群、伏格特-小柳-及原田症候群(Vogt-Koyanagi-and Harada syndrome);血管疾病/
滲出性疾病,諸如視網膜動脈阻塞性疾病、中心性視網膜靜脈阻塞、囊樣黃斑部水腫、散播性血管內凝血症(disseminated intravascular coagulopathy)、分支視網膜靜脈阻塞、高血壓性眼底病變、眼部缺血性症候群、視網膜微動脈瘤(retinal arterial microaneurysms)、考特氏病(Coat's disease)、旁中心凹毛細血管擴張(parafoveal telangiectasis)、半視網膜靜脈阻塞、視乳頭靜脈炎(papillophlebitis)、中心性視網膜動脈阻塞、分支視網膜動脈阻塞、頸動脈疾病(CAD)、霜樣分支血管炎(frosted branch angiitis)、鐮狀細胞視網膜病變及其他血紅素病、血管樣條紋(angioid streak)、家族性滲出性玻璃體視網膜病變及伊爾斯病(Eales disease);創傷性/手術性病狀,諸如交感性眼炎(sympathetic ophthalmia)、葡萄膜炎性視網膜疾病、視網膜脫離、創傷、手術後角膜傷口癒合、由雷射引起之病狀、由光動力療法引起之病狀、光凝固、在手術期間之灌注不足、放射視網膜病變及骨髓移植視網膜病變;增生性病症,諸如增生性玻璃體視網膜病變及前膜、及增生性糖尿病性視網膜病變;感染性病症,諸如眼部組織胞漿菌病(ocular histoplasmosis)、眼部弓蛔蟲病、疑似眼部組織胞漿菌病症候群(POHS)、眼內炎(endophthalmitis)、弓漿蟲病、與HIV感染相關之視網膜疾病、與HIV感染相關之脈絡膜疾病、與HIV感染相關之葡萄膜炎性疾病、病毒性視網膜炎、急性視網膜壞死、進行性外部視網膜壞死、真菌性視網膜疾病、眼部梅毒、
眼部結核、彌漫性單側亞急性視神經網膜炎及蠅蛆病(myiasis);遺傳病症,諸如色素性視網膜炎(retinitis pigmentosa)、伴有視網膜營養不良之全身性病症、先天性靜止性夜盲症(congenital stationary night blindness)、錐體營養不良(cone dystrophies)、斯特格氏病(Stargardt's disease)及眼底黃色斑點症(fundus flavimaculatus)、貝斯特氏病(Best's disease)、視網膜色素上皮之圖案營養不良、X性聯視網膜分層剝離(X-linked retinoschisis)、索斯比氏眼底營養不良(Sorsby's fundus dystrophy)、良性同心黃斑病變(benign concentric maculopathy)、拜提氏結晶狀營養不良(Bietti's crystalline dystrophy)及彈性假黃瘤(pseudoxanthoma elasticum);視網膜撕裂/孔,諸如視網膜脫離、黃斑孔及巨大視網膜撕裂;腫瘤,諸如與腫瘤相關之視網膜疾病、先天性視網膜色素上皮肥大、後葡萄膜黑素瘤(posterior uveal melanoma)、脈絡膜血管瘤、脈絡膜骨瘤、脈絡膜轉移、視網膜及視網膜色素上皮之組合錯構瘤、視網膜母細胞瘤、眼底之血管增生性腫瘤、視網膜星形細胞瘤、及眼內淋巴腫瘤;及影響眼後部之其他雜項疾病,諸如點狀內部脈絡膜病變、急性後多灶性板狀色素上皮病變、近視性視網膜變性、及急性視網膜色素上皮炎、全身性發炎性疾病(諸如中風)、冠狀動脈疾病、阻塞性呼吸道疾病、HIV介導之逆轉錄病毒感染、心血管病症(包括冠狀動脈疾病)、神經發炎、神經病症、疼痛及免
疫病症、哮喘、過敏病症、發炎、全身性紅斑狼瘡、牛皮癬、CNS病症(諸如阿茲海默氏病(Alzheimer's disease))、關節炎、敗血症、發炎性腸病、惡病質(cachexia)、心絞痛、手術後角膜發炎、瞼炎、MGD、皮膚傷口癒合、燒傷、紅斑痤瘡(rosacea)、異位性皮炎、粉刺、牛皮癬、脂溢性皮炎(seborrheic dermatitis)、光化性角化病、病毒性疣、光老化性類風濕性關節炎及相關發炎性病症、禿髮、青光眼、分支靜脈阻塞、貝斯特氏卵黃狀黃斑變性、色素性視網膜炎、增生性玻璃體視網膜病變(PVR)、及光受體或RPE之任何其他退化性疾病(Perretti,Mauro等人,Pharmacology & Therapeutics 127(2010)175-188)。
此等化合物適用於治療患有一定範圍之藉由N-甲醯基肽受體樣-1受體調節來減輕之病狀及疾病的哺乳動物(包括人類):包括(但不限於)治療濕性及乾性年齡相關之黃斑變性(ARMD)、糖尿病性視網膜病變(增生性)、早產兒視網膜病變(ROP)、糖尿病性黃斑水腫、葡萄膜炎、視網膜靜脈阻塞、囊樣黃斑水腫、青光眼、分支靜脈阻塞、貝斯特氏卵黃狀黃斑變性、色素性視網膜炎、增生性玻璃體視網膜病變(PVR)、及光受體或RPE之任何其他退化性疾病。
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的方法。此等方法可例如藉由向有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
何組合或其醫藥學上可接受之鹽、水合物、溶劑合物、晶體形式及個別異構體、對映異構體及非對映異構體來進行。
本發明係關於式I及式II化合物或其醫藥學上可接受之鹽製造用於治療包括(但不限於)以下之眼部發炎性疾病之藥劑的用途:濕性及乾性年齡相關之黃斑變性(ARMD)、葡萄膜炎、乾眼症、角膜炎、影響眼後部之過敏性眼疾病及病狀,諸如黃斑病變及視網膜變性,包括非滲出性年齡相關之黃斑變性、滲出性年齡相關之黃斑變性、脈絡膜新血管生成、糖尿病性視網膜病變(增生性)、早產兒視網膜病變(ROP)、急性黃斑視神經視網膜病變、中心性漿液性脈絡膜視網膜病變、囊樣黃斑水腫及糖尿病性黃斑水腫;傳染性角膜炎、葡萄膜炎、皰疹性角膜炎、角膜血管生成、淋巴管生成、葡萄膜炎、視網膜炎及脈絡膜炎(諸如急性多灶性板狀色素上皮病變)、貝塞特氏病、鳥槍彈樣視網膜脈絡膜病變、傳染病(梅毒、萊姆病、結核、弓漿蟲病)、中間葡萄膜炎(扁平部睫狀體炎)、多灶性脈絡膜炎、多發性短暫性白點症候群(mewds)、眼部類肉瘤病、後鞏膜炎、匐行性脈絡膜炎、視網膜下纖維化及葡萄膜炎症候群、伏格特-小柳-及原田症候群;血管疾病/滲出性疾病,諸如視網膜動脈阻塞性疾病、中心性視網膜靜脈阻塞、囊樣黃斑水腫、散播性血管內凝血症、分支視網膜靜脈阻塞、高血壓性眼底病變、眼部缺血性症候群、視網膜微動脈瘤、考特氏病、旁中心凹
毛細血管擴張、半視網膜靜脈阻塞、視乳頭靜脈炎、中心性視網膜動脈阻塞、分支視網膜動脈阻塞、頸動脈疾病(CAD)、霜樣分支血管炎、鐮狀細胞視網膜病變及其他血紅素病、血管樣條紋、家族性滲出性玻璃體視網膜病變及伊爾斯病;創傷性/手術性病狀,諸如交感性眼炎、葡萄膜炎性視網膜疾病、視網膜脫離、創傷、手術後角膜傷口癒合、由雷射引起之病狀、由光動力療法引起之病狀、光凝固、在手術期間之灌注不足、放射視網膜病變及骨髓移植視網膜病變;增生性病症,諸如增生性玻璃體視網膜病變及前膜、及增生性糖尿病性視網膜病變;感染性病症,諸如眼部組織胞漿菌病、眼部弓蛔蟲病、疑似眼部組織胞漿菌病症候群(POHS)、眼內炎、弓漿蟲病、與HIV感染相關之視網膜疾病、與HIV感染相關之脈絡膜疾病、與HIV感染相關之葡萄膜炎性疾病、病毒性視網膜炎、急性視網膜壞死、進行性外部視網膜壞死、真菌性視網膜疾病、眼部梅毒、眼部結核、彌漫性單側亞急性視神經網膜炎及蠅蛆病;遺傳病症,諸如色素性視網膜炎、伴有視網膜營養不良之全身性病症、先天性靜止性夜盲症、錐體營養不良、斯特格氏病及眼底黃色斑點症、貝斯特氏病、視網膜色素上皮之圖案營養不良、X性聯視網膜分層剝離、索斯比氏眼底營養不良、良性同心黃斑病變、拜提氏結晶狀營養不良及彈性假黃瘤;視網膜撕裂/孔,諸如視網膜脫離、黃斑孔及巨大視網膜撕裂;腫瘤,諸如與腫瘤相關之視網膜疾病、先天性視
網膜色素上皮肥大、後葡萄膜黑素瘤、脈絡膜血管瘤、脈絡膜骨瘤、脈絡膜轉移、視網膜及視網膜色素上皮之組合錯構瘤、視網膜母細胞瘤、眼底之血管增生性腫瘤、視網膜星形細胞瘤、及眼內淋巴腫瘤;及影響眼後部之其他雜項疾病,諸如點狀內部脈絡膜病變、急性後多灶性板狀色素上皮病變、近視性視網膜變性、及急性視網膜色素上皮炎、全身性發炎性疾病(諸如中風)、冠狀動脈疾病、阻塞性呼吸道疾病、HIV介導之逆轉錄病毒感染、心血管病症(包括冠狀動脈疾病)、神經發炎、神經病症、疼痛及免疫病症、哮喘、過敏病症、發炎、全身性紅斑狼瘡、牛皮癬、CNS病症(諸如阿茲海默氏病)、關節炎、敗血症、發炎性腸病、惡病質、心絞痛、手術後角膜發炎、瞼炎、MGD、皮膚傷口癒合、燒傷、紅斑痤瘡、異位性皮炎、粉刺、牛皮癬、脂溢性皮炎、光化性角化病、病毒性疣、光老化性類風濕性關節炎及相關發炎性病症、禿髮、青光眼、分支靜脈阻塞、貝斯特氏卵黃狀黃斑變性、色素性視網膜炎、增生性玻璃體視網膜病變(PVR)、及光受體或RPF之任何其他退化性疾病。
在任何既定情況下欲投與之化合物之實際量均將由醫師在考慮相關事項下來確定,該等事項諸如為病狀嚴重性、患者年齡及重量、患者之一般身體狀況、病狀之病因及投藥途徑。
將向患者經口投與呈任何可接受形式之化合物,諸如錠劑、液體、膠囊、散劑及其類似物,或特定言之若患
者罹患噁心,則可能需要或必需其他途徑。此等其他途徑可無例外地包括經皮、非經腸、皮下、鼻內、經由植入支架、鞘內、玻璃體內、眼表面、眼後部、肌肉內、靜脈內及直腸內傳遞模式。另外,調配物可經設計以延遲活性化合物歷經一段既定時期之釋放,或仔細控制在療法之過程期間在既定時間釋放之藥物的量。
在本發明之另一實施例中,提供包括至少一種本發明化合物於其醫藥學上可接受之載劑中之醫藥組合物。片語「醫藥學上可接受」意謂載劑、稀釋劑或賦形劑必須可與調配物之其他成分相容且不對其接受者有害。
本發明之醫藥組合物可以固體、溶液、乳液、分散液、貼片、膠束、脂質體及其類似物形式使用,其中所得組合物含有一或多種作為活性成分之本發明化合物與適於經腸或非經腸施用之有機或無機載劑或賦形劑混合。本發明化合物可例如與常用於錠劑、丸粒、膠囊、栓劑、溶液、乳液、懸浮液及任何其他適用形式醫藥學上可接受之無毒載劑組合。可使用之載劑包括葡萄糖、乳糖、阿拉伯膠、明膠、甘露糖醇、澱粉糊、三矽酸鎂、滑石、玉米澱粉、角蛋白(keratin)、膠態二氧化矽、馬鈴薯澱粉、尿素、中鏈長度三酸甘油酯、聚葡萄糖、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狀況產生所要作用之量包括在醫藥組合物中。
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、片劑、口含錠、水性或油性懸浮液、可分散散劑或顆粒劑、乳液、硬質或軟質膠囊、或糖漿或酏劑形式。意欲供經口使用之組合物可根據此項技術中已知之用於製造醫藥組合物之任何方法製備且此等組合物可含有一或多種選自由甜味劑,諸如蔗糖、乳糖或糖精;調味劑,諸如胡椒薄荷、冬青油或櫻桃油;著色劑及防腐劑組成之群之試劑以提供醫藥學上精緻且可口之製劑。亦可藉由已知方法製造含有本發明化合物與醫藥學上可接受之無毒賦形劑混合之錠劑。所用賦形劑可為例如(1)惰性稀釋劑,諸如碳酸鈣、乳糖、磷酸鈣或磷酸鈉;(2)粒化劑及崩解劑,諸如玉米澱粉、馬鈴薯澱粉或海藻酸;(3)黏合劑,諸如黃蓍膠、玉米澱粉、明膠或阿拉伯膠;及(4)潤滑劑,諸如硬脂酸鎂、硬脂酸或滑石。錠劑可不經包覆或其可藉由已知技術包覆以延遲在胃腸道中之崩解及吸收且藉此提供歷經較長時期之持續作用。舉例而言,可採用延時物質,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情況下,供經口使用之調配物可呈硬質明膠膠囊形式,其中本發明化合物與惰性固體稀釋劑,例如碳酸鈣、磷酸鈣或高嶺土混合。其亦可呈軟質明膠膠囊形式,其中本發明化合物與水或油介質,例如花生油、液體石蠟或橄欖油混合。
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合分散劑或濕潤劑及懸浮劑加以調配。無菌可注射製劑亦可為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,例如呈於1,3-丁二醇中之溶液形式。無菌不揮發性油習用作溶劑或懸浮介質。出於此目的,可採用任何溫和不揮發性油,包括合成單酸甘油酯或二酸甘油酯、脂肪酸(包括油酸)、天然存在之植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成脂肪媒劑(如油酸乙酯或其類似物)。必要時可併有緩衝劑、防腐劑、抗氧化劑及其類似物。
本發明化合物亦可以用於經直腸投與藥物之栓劑形式投與。此等組合物可藉由混合本發明化合物與在常溫下為固體,但在直腸腔中液化及/或溶解以釋放藥物之適合非刺激性賦形劑(諸如可可脂、聚乙二醇之合成甘油酯)來製備。
因為個別個體之症狀嚴重性可呈現廣泛變化且各藥物具有其獨特治療特徵,所以對各個體採用之確切投藥模式及劑量留給從業者來判斷。
本文所述之化合物及醫藥組合物在哺乳動物(包括人類)中適用作用於治療疾病及/或減輕病狀之藥劑,該等疾病及/或病狀對用N-甲醯基肽受體樣-1(FPRL-1)受體之促效劑或功能性拮抗劑進行之治療起反應。因此,在本發明之其他實施例中,提供治療與N-甲醯基肽受體樣-1(FPRL-1)受體之調節相關之病症的方法。此等方法可例如藉由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進行。如本文所用,術語「治療有效量」意謂將引發有需要之個體之由研究人員、獸醫、醫學醫生或其他臨床醫師所尋求之生物或醫學反應之醫藥組合物的量。在一些實施例中,有需要之個體為哺乳動物。在一些實施例中,哺乳動物為人類。
本發明亦係關於製備式I化合物之方法。本發明之式I化合物可以與如由熟習合成有機化學技術者所瞭解之習知方法類似之方式製備。以下闡述之合成流程1說明可如何製備本發明化合物。
如流程1中所述製備式I化合物。如流程2中所述製備式II化合物。一般而言,使胺基酸之第三丁酯衍生物與經取代之苯基異氰酸酯反應以產生苯基脲衍生物。接著在酸性條件下移除第三丁酯保護基以得到胺基酸脲。接著藉由在胺存在下用活化試劑,諸如1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺(EDCI)及羥基苯并三唑(HOBt)處理化合物,或藉由熟習此項技術者已知之其他方法使羧酸基轉化成醯胺。在此階段,熟習此項技術者應瞭解屬於本發明之範疇之許多其他化合物可藉由進行各種常見化學反應來製備。某些特定化學轉化之詳情提供於實例中。
熟習此項技術者將能夠常規地修改及/或改適下列流程以合成由式I或式II涵蓋之任何本發明化合物。
應瞭解上文一般性描述及下文【實施方式】僅具有例示性及說明性且不限制所主張之本發明。除非另外特定陳述,否則如本文所用,單數之使用包括複數。
熟習此項技術者將顯而易知,一些本發明化合物可含有一或多個不對稱中心,以致化合物可以對映異構形式以及非對映異構形式存在。除非另外特定指示,否則本發明之範疇包括所有對映異構體、非對映異構體及外消旋混合物。一些本發明化合物可與醫藥學上可接受之酸或鹼形成鹽,且本文所述之化合物之此等醫藥學上可接受之鹽亦在本發明之範疇內。
本發明包括所有醫藥學上可接受之同位素增濃化合物。任何本發明化合物均可含有一或多個增濃或不同於天然比率之同位素原子,諸如氘2H(或D)替代氫1H(或H)或使用13C增濃物質替代12C及其類似物。類似取代可用於N、O及S。使用同位素可有助於本發明之分析態樣以及治療態樣。舉例而言,使用氘可藉由改變本發明化合物之代謝(速率)來增加活體內半衰期。此等化合物可依照所述製備,藉由使用同位素增濃試劑來製備。
下列實例僅用於說明目的且不意欲,亦不應被解釋為以任何方式限制本發明。熟習此項技術者應瞭解可在不超出本發明之精神或範疇下對下列實例作出變化及修改。
如將為熟習此項技術者所顯而易知,個別異構形式可藉由以習知方式分離其混合物獲得。舉例而言,在非對映異構異構體之情況下,可採用層析分離。
用12.5版ACD產生化合物名稱。一般而言,根據下列方法對化合物進行表徵,NMR光譜係在300 MHz Varian或600 MHz Varian上記錄且在室溫下獲得。以ppm給出參照內部TMS或溶劑信號之化學位移。
合成未經描述之所有試劑、溶劑、催化劑皆購自化學品供應商,諸如Sigma Aldrich、Fluka、Bio-Blocks、Combi-blocks、TCI、VWR、Lancaster、Oakwood、Trans World Chemical、Alfa、Fisher、Maybridge、Frontier、Matrix、Ukrorgsynth、Toronto、Ryan Scientific、SiliCycle、Anaspec、Syn Chem、Chem-Impex、MIC-scientific,Ltd;然而,一些已知中間物係根據公開程序製備。
除非另外指示,否則本發明化合物通常藉由中壓液相層析純化。
下列縮寫用於實例中:Et3N 三乙胺
CH2Cl2 二氯甲烷
CDCl3 氘化氯仿
MeOH 甲醇
CD3OD 氘化甲醇
Na2SO4 硫酸鈉
DMF N,N二甲基甲醯胺
EDCI 1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺
HOBt 羥基苯并三唑
THF 四氫呋喃
ClCO2Et 氯甲酸乙酯
NH3 氨
下列合成流程說明可如何製備本發明化合物。熟習此項技術者將能夠常規地修改及/或改適下列流程以合成由式II涵蓋之任何本發明化合物。
在25℃下向L-苯基-丙胺酸第三丁酯鹽酸鹽(100 mg,0.41 mmol)及6 mL二氯甲烷之溶液中添加異氰酸4-溴-苯酯(81 mg,0.41 mmol)及三乙胺(62 mg,0.62 mmol)。在25℃下攪拌所得混合物30分鐘。濃縮混合物且殘餘物藉由使用乙酸乙酯:己烷(20:80)進行中壓液相矽膠層析來純化以產生呈白色固體狀之中間物1。
1H NMR(CDCl3,300MHz)δ:7.20-7.35(m,5H),7.13-7.20(m,2H),7.01-7.10(m,2H),6.79(br.s.,NH),5.52(br.s.,NH),4.70(t,J=6.2 Hz,1H),2.91(ddd,J=
19.0 Hz,J=6.0 Hz,2H),1.47(m,9H)。
以與實例1中針對中間物1所述之程序類似之方式,以適當胺基酸為起始物自相應胺基酸製備中間物2、3及4。結果以下描述於表1中。
在25℃下攪拌中間物1(60 mg,0.15 mmol)及0.5 mL甲酸之溶液3小時。所得混合物用水(1 mL)淬滅,接著用乙酸乙酯萃取。有機層用水、鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下濃縮濾液。殘餘物用二氯甲烷:己烷(1:1)沖洗4次以產生呈白色固體狀之中間物5。
1H NMR(丙酮-d6,300MHz)δ:8.29(s,NH),7.40-7.50(m,2H),7.32-7.40(m,2H),7.18-7.31(m,5H),5.98(d,J=7.9 Hz,NH),4.67(m,1H),3.02(ddd,J=19.0 Hz,J=6.0 Hz,2H)。
以與實例2中針對中間物5所述之程序類似之方式自相應脲衍生物製備中間物6、7及8以及化合物1至6。結果以下描述於表2中。
在25℃下向中間物5(80 mg,0.22 mmol)及2 mL無水DMF之溶液中添加EDCI(64 mg,0.33 mmol)、HOBt(45 mg,0.33 mmol)、甘胺酸第三丁酯(44 mg,0.33 mmol)及N-甲基嗎啉(44 mg,0.44 mmol)。在25℃下攪拌所得混合物12小時。混合物用水(1 mL)淬滅,且產物用乙酸乙酯(20 mL)萃取。分離各層,且有機層用水、鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下濃縮濾液。所得產物藉由使用乙酸乙酯:己烷(40:60)進行中壓液相矽膠層析來純化以產生呈白色固體狀之化合物7。
1H NMR(CDCl3,300MHz)δ:7.18-7.35(m,7H),7.03(d,J=8.5 Hz,2H),6.85(br.s.,1H),4.69(t,J=7.5 Hz,1H),3.74-3.96(m,2H),2.98-3.19(m,2H),1.42(s,9H)。
以與實例3中針對化合物7所述之程序類似之方式自
相應脲衍生物製備化合物8至27及中間物9。結果以下描述於表3中。
在-78℃下在氬氣下向化合物11(50 mg,0.13 mmol)及5 mL無水四氫呋喃之溶液中添加三乙胺(24 mg,0.17 mmol)及氯甲酸乙酯(17 mg,0.16 mmol)。在-78℃下攪拌混合物30分鐘,接著將氨氣鼓泡入反應燒瓶中持續1分鐘。在25℃下攪拌所得混合物2小時。反應用水(1 mL)淬滅,且殘餘物用乙酸乙酯(20 mL)萃取。分離各層,且有機層用水、鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下濃縮濾液。所得產物藉由使用溶離劑甲醇:二氯甲烷(10:90)進行中壓矽膠層析來純化以產生呈白色固體狀之化合物28。
1H NMR(CD3OD,300MHz)δ:7.33-7.40(m,2H),7.26-7.33(m,2H),4.05(d,J=6.7 Hz,1H),3.85(q,J=
17.0 Hz,2H),1.78-1.91(m,1H),1.54-1.69(m,1H),1.16-1.33(m,1H),0.99(d,J=6.7 Hz,3H),0.92-0.98(m,3H)。
以與實例4中針對化合物28所述之程序類似之方式自相應酸衍生物製備化合物29至85以及中間物10至35。
式II化合物之生物活性闡述於下表5中。於(F12、10% FBS、1% PSA、400 μg/ml遺傳黴素(geneticin)及50 μg/ml潮黴素(hygromycin))中培養穩定表現FPRL1之CHO-G α 16細胞且於(高葡萄糖DMEM、10%FBS、1%PSA、400 μg/ml遺傳黴素及50 μg/ml潮黴素)中培養穩定表現FPR1之HEK-Gqi5細胞。一般而言,在實驗前一天,將每孔18,000個細胞接種於384孔透明底部聚d-離胺酸塗佈之盤中。次日在FLIPRTetra上分析篩檢化合物誘導之鈣活性。使用EP3及MultiPROBE機器人液體處理系統以384孔微盤製備藥物盤。在介於0.61 nM至10,000 nM之範圍的濃度下測試化合物。結果表示為EC50(nM)及功效值。
表5
Claims (15)
- 一種由式II表示之化合物、其對映異構體、非對映異構體、互變異構體、水合物、溶劑合物或其醫藥學上可接受之鹽,
- 如申請專利範圍第1項之化合物,其中:a為1且b為0。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0;且R5為-S(O)nR14。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0;且R5為-CF3。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0;且R5為鹵素。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0; R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基;R3為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R4為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R7為氫、視情況經取代之C1-8烷基、鹵素、-COOR15、-OR13、-NR11R12;R8為氫或視情況經取代之C1-8烷基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫或視情況經取代之C1-8;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫或視情況經取代之C1-8烷基;且R15為氫或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13; R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫;R7為氫;R8為氫、視情況經取代之C1-8烷基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;且R14為氫或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其中:a為1且b為0;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素;R6為氫;R7為氫; R8為氫、視情況經取代之C1-8烷基;R9為氫、視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R10為氫、視情況經取代之C1-8烷基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;且R13為氫或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其中:a為0且b為1。
- 如申請專利範圍第1項之化合物,其中:a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基;R3為氫、視情況經取代之C1-8烷基、鹵素;R4為氫、視情況經取代之C1-8烷基、鹵素;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素;R7為氫、視情況經取代之C1-8烷基、鹵素;R8為氫;R9為氫;R10為氫、視情況經取代之C1-8烷基;R9a為氫、視情況經取代之C1-8烷基;R10a為氫、視情況經取代之C1-8烷基; R13為氫或視情況經取代之C1-8烷基;且R14為氫、CF3或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其中:a為0且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基;R3為氫或鹵素;R4為氫;R5為鹵素;R6為氫;R7為氫;R8為氫;R9為氫;R10為氫或視情況經取代之C1-8烷基;R9a為氫或視情況經取代之C1-8烷基;R10a為氫或視情況經取代之C1-8烷基;且R13為氫。
- 如申請專利範圍第1項之化合物,其中:a為1且b為1。
- 如申請專利範圍第1項之化合物,其中:a為1且b為1;R1為視情況經取代之C1-8烷基、-NR11R12或-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基; R3為氫、視情況經取代之C1-8烷基、鹵素;R4為氫、視情況經取代之C1-8烷基、鹵素;R5為鹵素、-CF3或-S(O)nR14;n為0、1或2;R6為氫、視情況經取代之C1-8烷基、鹵素;R7為氫、視情況經取代之C1-8烷基、鹵素;R8為氫;R9為氫、視情況經取代之C1-8烷基;R10為氫、視情況經取代之C1-8烷基;R9a為氫、視情況經取代之C1-8烷基;R10a為氫、視情況經取代之C1-8烷基;R11為氫或視情況經取代之C1-8烷基;R12為氫或視情況經取代之C1-8烷基;R13為氫或視情況經取代之C1-8烷基;R14為氫或視情況經取代之C1-8烷基;且R15為氫或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其中:a為1且b為1;R1為-OR13;R2為視情況經取代之C1-8烷基或視情況經取代之C6-10芳基;R3為氫;R4為氫;R5為鹵素; R6為氫;R7為氫;R8為氫;R9為氫;R10為氫;R9a為氫;R10a為氫;且R13為氫或視情況經取代之C1-8烷基。
- 如申請專利範圍第1項之化合物,其選自:{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-吲哚-3-基)丙醯基]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}乙酸第三丁酯;[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)胺基]乙酸;[(4-胺基-2-{[(4-溴苯基)胺甲醯基]胺基}-4-側氧基丁醯基)胺基]乙酸第三丁酯;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸;2-{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-2-甲基丙酸第三丁酯;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯基]胺基}乙酸;{[2-{[(4-溴苯基)胺甲醯基]胺基}-3-(1H-咪唑-4-基)丙醯 基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-(甲基磺醯基)丁醯基]胺基}乙酸第三丁酯;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;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}丙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基亞磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;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;2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基] 胺基}-2-甲基丙酸第三丁酯;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸;({(2S)-4-甲基-2-[({4-[(三氟甲基)磺醯基]苯基}胺甲醯基)胺基]戊醯基}胺基)乙酸第三丁酯;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸;{[(2S)-4-甲基-2-({[4-(甲基磺醯基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸;{[(2R)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸{[(2R,3R)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸第三丁酯;{[(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-(三氟甲基)苯基]胺甲醯基}胺基)戊醯基]胺基}乙酸第三丁酯;{[(2R)-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}-N-[2-(二甲基胺 基)-2-側氧基乙基]-4-甲基戊醯胺;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-甲基丙醯基)胺基]乙酸第三丁酯;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸;[(2-{[(4-溴苯基)胺甲醯基]胺基}-2-乙基丁醯基)胺基]乙酸第三丁酯;[(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}-2,4-二甲基戊醯基)胺基]乙酸第三丁酯;(2S)-N-[(1S)-2-胺基-2-側氧基-1-苯基乙基]-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)-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}(苯基)乙酸第三丁酯;(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}戊酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊 醯基]胺基}戊酸第三丁酯;(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-{[(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-(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-羥基-2-甲基丙基)-4-甲基戊醯胺;(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-{[(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)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}-3-甲基丁酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴苯基)胺甲醯基]胺基}-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}丙酸;(2S)-2-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}丙酸第三丁酯;(2S)-N-[(2S)-1-胺基-1-側氧基丙-2-基]-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯胺;(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-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基1胺基}丙酸第三丁酯;(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-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)-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-甲基戊醯基]胺基}乙酸;{[(2S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;(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-溴苯基)胺甲醯基]胺基}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}-4-甲基戊醯胺;{[(2S)-2-{[(4-溴苯基)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}-N-(2-羥基乙基)-4- 甲基戊醯胺;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-4-甲基戊醯基]胺基}乙酸第三丁酯;{[(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-2-氟苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸第三丁酯;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-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)戊醯胺;{[(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-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸乙酯;{[(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-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)戊醯胺;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)戊醯胺;(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;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}戊醯基]胺基}乙酸第三丁酯;(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-溴苯基)胺甲醯基]胺基}-N-(2-側氧基丙基)-3-苯基丙醯胺;(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-甲基戊醯胺;(2S,3S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-甲基戊醯胺;(2S,3S)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基-N-(2-側氧基丙基)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,3S)-N-(2-胺基-2-側氧基乙基)-2-{[(4-溴-2-氟苯基)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-溴苯基)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}乙酸第三丁酯;{[(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)-2-{[(4-溴-2-氟苯基)胺甲醯基]胺基}-3-甲基戊醯基]胺基}乙酸第三丁酯;(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-N-(2-羥基乙基)-3-苯基丙醯胺;3-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}丙酸;3-{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}丙酸第三丁酯;{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}乙酸;及{[(2S)-2-{[(4-溴苯基)胺甲醯基]胺基}-3-苯基丙醯基]胺基}乙酸第三丁酯。
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JP6496728B2 (ja) * | 2013-11-21 | 2019-04-03 | アラーガン、インコーポレイテッドAllergan,Incorporated | ホルミルペプチド受容体の調節因子としてのカルバミン酸フェニル誘導体 |
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