CN105705484B - 作为甲酰肽受体调节剂的苯基氨基甲酸酯衍生物 - Google Patents
作为甲酰肽受体调节剂的苯基氨基甲酸酯衍生物 Download PDFInfo
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Abstract
本发明涉及N‑苯基氨基甲酸酯衍生物、用于制备它们的方法、含有它们的药物组合物以及它们以药物形式作为N‑甲酰肽2受体的调节剂的用途。
Description
相关申请的交叉引用
本申请要求2013年11月21日提交的美国临时专利申请号61/907,320的权益,所述美国临时专利申请的整个内容通过具体引用并入本文。
发明领域
本发明涉及N-苯基氨基甲酸酯衍生物、用于制备它们的方法、含有它们的药物组合物以及它们以药物形式作为N-甲酰肽2受体(FPR2)的调节剂的用途。本发明具体涉及这些化合物和它们的药物组合物治疗与FPR2调节相关的病症的用途。
发明背景
甲酰肽受体(FPR)家族属于七跨膜结构域G蛋白偶联受体(GPCR)家族。这个家族包括人中的3个成员,并且这个家族的一个成员FPR2(也称为FPRL-1、ALXA4)主要在诸如单核细胞和嗜中性白细胞的炎性细胞上以及在T细胞上表达,并且已显示在炎症和人病理学期间在白细胞运输中起关键作用(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是一种响应于一群结构不同的外源性和内源性配体的特别混杂的受体,其包括血清淀粉样蛋白A(SAA)、趋化因子变体sCKβ8-1、神经保护肽(humanin)、抗炎性类花生酸脂氧素A4(LXA4)和糖皮质激素调节的蛋白质膜联蛋白A1(Chiang N,Serhan CN,Dahlen,S,Drazen JM,Hay DWP,Rovati E,Shimizu T,Yokomizo T,Brink,C.The lipoxinreceptor ALX:Potent ligand-specific and stereoselective actions invivo.Pharmacological Reviews 2006;58:463-519)。已显示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,并且已显示其在炎症消退方面起关键作用(Dufton N,Perretti M.Therapeutic anti-inflammatory potential of formylpeptide receptor agonists.Pharamcology&Therapeutics 2010;127:175-188)。FPR2敲除小鼠在病情上显示炎症放大,如根据所述受体的生物作用所预期(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 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 annexin1FPR2/ALX anti-inflammatorysystem.FASEB 2012;26:1-13)。
已显示由脂氧素A4或其类似物以及由膜联蛋白(Annexin)I蛋白对FPR2的活化通过促进炎症的主动消退来产生抗炎活性,这涉及多形核嗜中性白细胞(PMN)的抑制和嗜酸性粒细胞的迁移,并且还刺激单核细胞的迁移,使来自炎症部位的凋亡细胞能够以非炎性方式清除(Gavins FNE,Hughes EL,Buss NAPS,Holloway PM,Getting SJ,BuckinghamJC.Leukocyte recruitment in the brain in sepsis:involvement of theannexin1FPR2/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 receptorexpression and internalization are critical for lipoxin A4and annexin-derivedpeptide-stimulated phagocytosis.FASEB 2010;24:4240-4249)。此外,已显示FPR2会抑制自然杀伤(NK)细胞毒性,并且促进T细胞的活化,这进一步有助于组织损伤炎性信号的下调。
已在皮肤炎症、血管生成、上皮迁移、水肿、脱发、缺血再灌注和眼部炎症(诸如内毒素诱导的葡萄膜炎和角膜伤口愈合)的实验模型中显示FPR2与LXA4和膜联蛋白的相互作用是有益的。(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.;Medeiros R,Rodrigues GB,Figueiredo CP,RodriguesEB,Grumman A Jr,Menezes-de-Lima O Jr,Passos GF,Calixto JB.Molecularmechanisms of topical anti-inflammatory effects of lipoxin A(4)in endotoxin-induced uveitis.Molecular Pharmacology 2008;74:154-161;Gronert K,MaheshwariN,Khan N,Hassan IR,Dunn M,Schwartzmann ML.A role for the mouse 12/15-lipoxygenase pathways in promoting epithelial wound healing and hostdefense.Journal of Biological Chemistry 2005;280:15267-15278;GronertK.Lipoxins in the eye and their role in wound healing.Prostaglandins,Leukotrienes and Essential fatty Acids.2005;73:221-229);Takano T,Fiore S,Maddox JF,Brady HR,Petasis NA,Serhan CN.Asprin-triggered 15-epi-lipoxin A4andLXA4stable analogues are potent inhibitors of acute inflammation:evidence foranti-inflammatory receptors.Journal of Experimental Medicine 1997;185:1693-1704.;Leoni G,Alam A,Neumann PA,Lambeth JD,Cheng G,McCoy J,Hilgarth RS,KunduK,Murthy N,Kusters D,Reutelingsperger C,Perretti M,Parkos CA,Neish AS,NusratA.Annexin A1,formyl peptide receptor,and NOX1orchestrate epithelialrepair.Journal of Clinical Investigation.2013;123:443-54;Leedom A,SullivanAB,Dong B,Lau D,Gronert K.Endogenous LXA4circuits are determinants ofpathological angiogenesis in response to chronic injury.American Journal ofPathology 2010;176:74-84;Tsuruki T,Takahata K,Yoshikawa M.Mechanism of theprotective effect of intraperitoneally administered agonists for formylpeptide receptors against chemotherapy-induced alopecia.Biosci BiotechnologyBiochemistry.2007;71:1198-202)。
脂氧素A4和其类似物的药物效用受天然聚烯烃天然产物的固有物理化学性质的阻碍。因此,FPR2的小分子抗炎性激动剂将在炎性病症,包括眼中的炎性病症中具有多种治疗益处。相较于具有IOP升高以及眼中伤口愈合延迟的明显副作用的更宽泛作用性抗炎剂,诸如类固醇或NSAID,选择性靶向FPR2也将具有副作用降低的益处。除了迁移到眼部组织的炎性细胞之外,FPR2还在角膜以及眼后部的眼部组织中表达。
鉴于其强力的抗炎和促上皮修复作用,选择性靶向FPR2也将在皮肤伤口愈合方面具有益处。此外,已显示一些皮肤疾病具有异常LL37表达,所述LL37是一种已显示是FPR2的天然配体的促炎性抗菌肽。在慢性炎性疾病红斑痤疮中,LL37被高度表达,并且据信在发病机理方面起关键作用(Yamasaki K,Di Nardo A,Bardan A,Murakami M,Ohtake T,Coda A,Dorschner RA,Bonnart C,Descargues P,Hovnanian A,Morhenn VB,Gallo RL.Increasedserine protease activity and cathelicidin promotes skin inflammation inrosacea.Nature Medicine.2007;13:975-80)。
因此,FPR2代表一种重要的新型促消退性分子靶标,用于开发伴有过度炎性应答的疾病或病状的新型治疗剂。
发明概述
已发现一组是强力和选择性FPR2调节剂的N-苯基氨基甲酸酯衍生物。因此,本文所述的化合物适用于治疗多种与FPR2受体的调节相关的病症。如本文所用的术语“调节剂”包括但不限于:受体激动剂、拮抗剂、反向激动剂、反向拮抗剂、部分激动剂和部分拮抗剂。
本发明描述具有FPR2受体生物活性的式I化合物。因此,根据本发明的化合物可用于医学,例如用于治疗患有通过FPR2调节得以缓解的疾病和病状的人。
在一个方面,本发明提供一种由式I表示的化合物:
其中:
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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、-S(O)mR13、–C(O)R14或–OR15;
R2是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R3是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R4是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R5是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R6是H、任选取代的C1-8烷基、任选取代的杂环、-(CH2)pCOOH、-(CH2)p-NH2、-(CH2)p-OH、-(CH2)p-SH、-(CH2)p-CONH2、-(CH2)p-CONH2、-CH(OH)CH3、-(CH2)pSCH3、-(CH2)pNH-C(=NH)(NH2)或-CH2C6-10芳基,其中所述-C6-10芳基任选被取代;
R6a是H或任选取代的C1-8烷基;
R7是H或任选取代的C1-8烷基;
R8是H;
R9是H、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C6-10芳基或任选取代的C3-8环烯基;
R10是–(CH2)nOR16、–(CH2)nS(O)2OH、–(CH2)nC(O)R17、–(CH2)nOS(O)2OH、-(CH2)nNR18R19、-(CH2)nP(O)(OC1-6烷基)2、-(CH2)nP(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R11是H、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C6-10芳基或任选取代的C3-8环烯基;
R12是H、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C6-10芳基或任选取代的C3-8环烯基;
R13是H、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C6-10芳基、OH或任选取代的C3-8环烯基;
R14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C6-10芳基、任选取代的C3-8环烯基或–OR15;
R15是H或任选取代的C1-8烷基;
R16是H、-C(O)(C1-8烷基)或任选取代的C1-8烷基;
R17是OH、-OC1-8烷基或C1-8烷基;
R18选自由以下组成的组:H、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C6-10芳基、任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
R19选自由以下组成的组:H、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C6-10芳基、或任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
p是1、2或3;
n是0、1、2、3、4、5、6、7或8;并且
m是0、1或2;
其中
各C1-8烷基取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、C3-8环烷基、氨基、杂环、C6-10芳基、羧酸、膦酸、磺酸、磷酸、硝基、酰胺、磺酰胺、羧酸酯和酮;
各C3-8环烷基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、硝基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
各杂环取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
各C6-10芳基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、羧酸、羧酸C1-8烷基酯、酰胺、硝基、-OC1-6烷基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基和C3-8环烷基;并且
各C3-8环烯基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
本发明进一步提供一种选自由以下组成的组的化合物:
如本文所用的术语“烷基”是指具有直链或支链部分或其组合,并且含有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-)可被氧、硫、亚砜、-N(Rx)-(其中Rx是H、OH或任选取代的C1-8烷基)、羰基、羧基、磺酰基、硫酸酯基、磺酸酯基、酰胺、磺酰胺、二价C3-8环烷基、二价杂环或二价芳基置换。烷基可具有一个或多个手性中心。烷基可独立地被一个或多个卤素原子、羟基、-OC1-8烷基、环烷基、氨基、杂环基团、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、酯基团和/或酮基团取代。
如本文所用的术语“环烷基”是指源于饱和环烃的具有3至8个碳原子的单价或二价基团。环烷基可为单环或多环的。环烷基可独立地被一个或多个卤素原子、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺基团、硝基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、酮基团、烷基氨基、氨基、芳基、C3-8环烷基和/或羟基取代。
如本文所用的术语“环烯基”是指源于饱和环烷基的具有3至8个碳原子,具有至少一个双键的单价或二价基团。环烯基可为单环或多环的。环烯基可独立地被一个或多个卤素原子、磺酰基、亚砜基团、硝基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、酮基团、烷基氨基、氨基、芳基、C3-8环烷基和/或羟基取代。
如本文所用的术语“卤素”是指氟原子、氯原子、溴原子、碘原子。
如本文所用的术语“杂环”是指3至10元环,其可为芳族或非芳族的,饱和或不饱和的,含有打断碳环结构的至少一个选自氧、氮、硫的杂原子或其至少两者的组合。杂环可由C=O打断;S和N杂原子可被氧化。杂环可为单环或多环的。杂环部分可被一个或多个卤素原子、磺酰基、亚砜基团、硝基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、酮基团、烷基氨基、氨基、芳基、C3-8环烷基和/或羟基取代。
如本文所用的术语“芳基”是指从由含有6至10个碳原子的环组成的芳族烃通过移除一个氢原子而衍生出的有机部分。芳基可被一个或多个卤素原子、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺基团、羧酸基团、羧酸C1-8烷基酯基团、酰胺基团、硝基、-OC1-6烷基、-SC1-8烷基、-C1-8烷基、酮基团、烷基氨基、氨基、C3-8环烷基和/或羟基取代。芳基可为单环或多环的。
如本文所用的术语“羟基”表示式“–OH”基团。
如本文所用的术语“羰基”表示式“-C(O)-”基团。
如本文所用的术语“酮”表示具有连接于碳原子的羰基的有机化合物,诸如–C(O)Rx,其中Rx可为如上定义的烷基、芳基、环烷基、环烯基或杂环。
如本文所用的术语“酯”表示具有连接于碳原子的羰基的有机化合物,诸如–C(O)ORx,其中Rx可为如上定义的烷基、芳基、环烷基、环烯基或杂环。
如本文所用的术语“胺”表示式“-NRxRy”的基团,其中Rx和Ry可相同或独立地为如上定义的H、烷基、芳基、环烷基、环烯基或杂环。
如本文所用的术语“羧基”表示式“-C(O)O-”的基团。
如本文所用的术语“磺酰基”表示式“-SO2-”的基团。
如本文所用的术语“硫酸酯基”表示式“-OS(O)2O-”的基团。
如本文所用的术语“磺酸酯基”表示式“-S(O)2O-”的基团。
如本文所用的术语“羧酸”表示式“-C(O)OH”的基团。
如本文所用的术语“硝基”表示式“–NO2”的基团。
如本文所用的术语“酰胺”表示式“-C(O)NRxRy”基团,其中Rx和Ry可相同或独立地为如上定义的H、烷基、芳基、环烷基、环烯基或杂环。
如本文所用的术语“磺酰胺”表示式“-S(O)2NRxRy”的基团,其中Rx和Ry可相同或独立地为如上定义的H、烷基、芳基、环烷基、环烯基或杂环。
如本文所用的术语“亚砜”表示式“-S(O)-”的基团。
如本文所用的术语“膦酸”表示式“-P(O)(OH)2”的基团。
如本文所用的术语“磷酸”表示式“-OP(O)(OH)2”的基团。
如本文所用的术语“磺酸”表示式“-S(O)2OH”的基团。
如本文所用的式“H”表示氢原子。
如本文所用的式“O”表示氧原子。
如本文所用的式“N”表示氮原子。
如本文所用的式“S”表示硫原子。
本发明的一些化合物是:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸叔丁酯;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)(甲基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}甲基)膦酸二乙酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}甲基)膦酸二乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸叔丁酯;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
乙酸2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-{甲基[2-(磺氧基)乙基]氨基}-1-氧代戊-2-基酯;
({(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)甲磺酸;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸叔丁酯;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
[4-(三氟甲基)苯基]氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
(4-溴苯基)氨基甲酸(1S)-1-[({2-[(叔丁氧基羰基)氨基]乙基}氨基)羰基]-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-苯甲基-2-氧代-2-[(1H-四唑-5-基甲基)氨基]乙酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸叔丁酯;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸;
(4-溴苯基)氨基甲酸(1S)-1-{[(2-氨基乙基)氨基]羰基}-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸;和
(4-溴苯基)氨基甲酸(1S)-1-{[(2-{[(二甲基氨基)磺酰基]氨基}乙基)氨基]羰基}-3-甲基丁酯。
本发明的其它化合物是:
(S)-2-(((4-溴苯基)氨基甲酰基)氧基)-4-甲基戊酸叔丁酯;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酸;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸叔丁酯;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸;
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸叔丁酯;和
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸。
一些式I化合物和一些它们的中间体在其结构中具有至少一个不对称中心。这个不对称中心可以R或S构型存在,所述R和S标记的使用与Pure Appl.Chem.(1976),45,11-13中所述的规则一致。
术语“药学上可接受的盐”是指保留以上鉴定的化合物的所需生物活性,并且展现最小或不展现非期望的毒理效应的盐或络合物。本发明的“药学上可接受的盐”包括式I化合物能够形成的治疗活性无毒碱或酸盐形式。
以其游离碱形式存在的式I化合物的酸加成盐形式可通过用适当酸处理游离碱获得,所述适当酸诸如无机酸,例如盐酸、氢溴酸、硫酸、磷酸、硝酸等;或有机酸,例如像乙酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、反丁烯二酸、顺丁烯二酸、草酸、酒石酸、丁二酸、苹果酸、抗坏血酸、苯甲酸、丹宁酸、扑酸(pamoic acid)、柠檬酸、甲基磺酸、乙磺酸、苯磺酸、甲酸等(Handbook of Pharmaceutical Salts,P.Heinrich Stahl和Camille G.Wermuth(编),Verlag Helvetica Chimica Acta-Zürich,2002,329-345)。
以其酸形式存在的式I化合物的碱加成盐形式可通过用适当碱处理酸获得,所述适当碱诸如无机碱,例如氢氧化钠、氢氧化镁、氢氧化钾、氢氧化钙、氨等;或有机碱,例如像L-精氨酸、乙醇胺、甜菜碱、苄星青霉素(benzathine)、吗啉等。(Handbook ofPharmaceutical Salts,P.Heinrich Stahl和Camille G.Wermuth(编),Verlag HelveticaChimica Acta-Zürich,2002,329-345)。
本发明化合物被指明用于治疗或预防其中可能存在涉及N-甲酰肽受体2的组分的病状。
在另一实施方案中,提供在药学上可接受的载体中包含至少一种本发明化合物的药物组合物。
在本发明的另一实施方案中,提供用于治疗与N-甲酰肽2受体的调节相关的病症的方法。
所述方法可例如通过向有需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来执行。
N-甲酰肽2受体调节剂的治疗效用是眼部炎性疾病和病状,包括但不限于湿性和干性年龄相关性黄斑变性(ARMD)、葡萄膜炎、干眼症、角膜炎、影响眼后部的过敏性眼疾病和病状,诸如黄斑病变和视网膜变性,包括非渗出性年龄相关性黄斑变性、渗出性年龄相关性黄斑变性、脉络膜新血管生成、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变(central serouschorioretinopathy)、囊样黄斑水肿和糖尿病性黄斑水肿;传染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、视网膜炎、脉络膜炎(诸如急性多灶性鳞状色素上皮病变)、贝切特氏病(Behcet’s disease)、鸟枪弹样视网膜脉络膜病变(birdshotretinochoroidopathy)、传染性(梅毒、莱姆病(lyme)、结核、弓浆虫病(toxoplasmosis))、中间葡萄膜炎(睫状体平坦部炎(pars planitis))、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼部结节病、后巩膜炎(posterior scleritis)、匐行性脉络膜炎(serpiginouschoroiditis)、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-and Harada综合征;血管疾病/渗出性疾病,诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血症(disseminated intravascular coagulopathy)、视网膜分支静脉阻塞、高血压性眼底变化、眼部缺血性综合征、视网膜动脉微动脉瘤(retinal arterialmicroaneurysms)、柯氏症(Coat’s disease)、旁中心凹毛细血管扩张(parafovealtelangiectasis)、半侧视网膜静脉阻塞、视乳头静脉炎(papillophlebitis)、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎(frosted branchangiitis)、镰状细胞视网膜病变和其它血红蛋白病、血管样条纹(angioid streak)、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎(Eales disease);创伤性/手术性病状,诸如交感性眼炎(sympathetic ophthalmia)、葡萄膜炎性视网膜疾病、视网膜脱离、创伤、手术后角膜伤口愈合、白内障手术后炎症、由激光引起的病状、由光动力疗法、光凝固、手术期间的灌注不足引起的病状、放射性视网膜病变和骨髓移植视网膜病变;增生性病症,诸如增生性玻璃体视网膜病变和视网膜前膜以及增生性糖尿病性视网膜病变;传染性病症,诸如眼部组织胞浆菌病(ocular histoplasmosis)、眼部弓蛔虫病、疑似眼部组织胞浆菌病综合征(POHS)、眼内炎(endophthalmitis)、弓浆虫病、与HIV感染相关的视网膜疾病、与HIV感染相关的脉络膜疾病、与HIV感染相关的葡萄膜炎性疾病、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌性视网膜疾病、眼部梅毒、眼部结核、弥漫性单侧亚急性视神经网膜炎和蝇蛆病(myiasis);遗传病症,诸如色素性视网膜炎(retinitispigmentosa)、与视网膜营养不良相关的全身性病症、先天性静止性夜盲症(congenitalstationary night blindness)、锥细胞营养不良(cone dystrophies)、斯特格氏病(Stargardt’s disease)和眼底黄色斑点症(fundus flavimaculatus)、贝斯特氏病(Best’s disease)、视网膜色素上皮的图形营养不良、伴X染色体的视网膜分层剥离(X-linkedretinoschisis)、Sorsby眼底营养不良(Sorsby’s fundus dystrophy)、良性同心性黄斑病变(benign concentric maculopathy)、Bietti结晶状营养不良(Bietti’s crystallinedystrophy)和弹性假黄瘤(pseudoxanthoma elasticum);视网膜撕裂/裂孔,诸如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤,诸如与肿瘤相关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑素瘤(posterior uveal melanoma)、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底的血管增生性肿瘤、视网膜星形细胞瘤和眼内淋巴肿瘤;以及影响眼后部的各种其它疾病,诸如点状内层脉络膜病变、急性后部多灶性鳞状色素上皮病变、近视性视网膜变性和急性视网膜色素上皮炎、全身性炎性疾病(诸如中风)、冠状动脉疾病、阻塞性气道疾病、HIV介导的逆转录病毒性感染、心血管病症(包括冠状动脉疾病)、神经炎症、神经学病症、疼痛和免疫病症、哮喘、变态反应性病症、炎症、全身性红斑狼疮、牛皮癣、CNS病症(诸如阿尔茨海默氏病(Alzheimer’s disease))、关节炎、败血症、炎性肠病、恶病质(cachexia)、心绞痛、手术后角膜炎症、睑炎、睑腺功能障碍;皮肤炎症和皮肤疾病,包括但不限于皮肤伤口愈合、肥厚性瘢痕、疤痕疙瘩、烧伤、红斑痤疮、异位性皮炎、粉刺、牛皮癣、脂溢性皮炎(seborrheicdermatitis)、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、炎性后色素沉着过度、色素沉着病症、脱发,结疤和非结疤形式;病毒性疣、光老化性类风湿性关节炎和相关炎性病症、脱发、青光眼、静脉分支阻塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或RPE的任何其它退行性疾病(Perretti,Mauro等Pharmacology&Therapeutics 127(2010)175-188)。
本发明化合物适用于治疗患有一系列的通过N-甲酰肽2受体调节而缓解的病状和疾病的哺乳动物,包括人,包括但不限于治疗湿性和干性年龄相关性黄斑变性(ARMD)、干眼症、角膜炎、过敏性眼病、传染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、视网膜炎、脉络膜炎、急性多灶性鳞状色素上皮病变、贝切特氏病、手术后角膜伤口愈合、白内障手术后炎症、葡萄膜炎、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、糖尿病性黄斑水肿、视网膜静脉阻塞、囊样黄斑水肿、青光眼、静脉分支阻塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或RPE的任何其它退行性疾病;以及皮肤炎症和皮肤疾病,包括但不限于皮肤伤口愈合、肥厚性瘢痕、疤痕疙瘩、烧伤、红斑痤疮、异位性皮炎、粉刺、牛皮癣、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、炎性后色素沉着过度、色素沉着病症、脱发,结疤和非结疤形式。
在本发明的另一实施方案中,提供用于治疗与FPR2受体的调节相关的病症的方法。所述方法可例如通过向有需要的受试者施用治疗有效量的至少一种本发明化合物或其任何组合或其药学上可接受的盐、个别对映异构体和/或非对映异构体来执行。
本发明涉及式I化合物或其药学上可接受的盐用于制造用以治疗包括但不限于以下的眼部炎性疾病的药剂的用途:湿性和干性年龄相关性黄斑变性(ARMD)、葡萄膜炎、干眼症、角膜炎、影响眼后部的过敏性眼疾病和病状,诸如黄斑病变和视网膜变性,包括非渗出性年龄相关性黄斑变性、渗出性年龄相关性黄斑变性、脉络膜新血管生成、糖尿病性视网膜病变(增生性)、早产儿视网膜病变(ROP)、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;传染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、葡萄膜炎、视网膜炎和脉络膜炎(诸如急性多灶性鳞状色素上皮病变)、贝切特氏病、鸟枪弹样视网膜脉络膜病变、传染性(梅毒、莱姆病、结核、弓浆虫病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼部结节病、后巩膜炎、匐行性脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-andHarada综合征;血管疾病/渗出性疾病,诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血症、视网膜分支静脉阻塞、高血压性眼底变化、眼部缺血性综合征、视网膜动脉微动脉瘤、柯氏症、旁中心凹毛细血管扩张、半侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状细胞视网膜病变和其它血红蛋白病、血管样条纹、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/手术性病状,诸如交感性眼炎、葡萄膜炎性视网膜疾病、视网膜脱离、创伤、手术后角膜伤口愈合、白内障手术后炎症、湿性和干性年龄相关性黄斑变性(ARMD)、由激光引起的病状、由光动力疗法、光凝固、手术期间的灌注不足引起的病状、放射性视网膜病变和骨髓移植视网膜病变;增生性病症,诸如增生性玻璃体视网膜病变和视网膜前膜以及增生性糖尿病性视网膜病变;传染性病症,诸如眼部组织胞浆菌病、眼部弓蛔虫病、疑似眼部组织胞浆菌病综合征(POHS)、眼内炎、弓浆虫病、与HIV感染相关的视网膜疾病、与HIV感染相关的脉络膜疾病、与HIV感染相关的葡萄膜炎性疾病、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌性视网膜疾病、眼部梅毒、眼部结核、弥漫性单侧亚急性视神经网膜炎和蝇蛆病;遗传病症,诸如色素性视网膜炎、与视网膜营养不良相关的全身性病症、先天性静止性夜盲症、锥细胞营养不良、斯特格氏病和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、伴X染色体的视网膜分层剥离、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶状营养不良和弹性假黄瘤;视网膜撕裂/裂孔,诸如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤,诸如与肿瘤相关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底的血管增生性肿瘤、视网膜星形细胞瘤和眼内淋巴肿瘤;以及影响眼后部的各种其它疾病,诸如点状内层脉络膜病变、急性后部多灶性鳞状色素上皮病变、近视性视网膜变性和急性视网膜色素上皮炎、全身性炎性疾病(诸如中风)、冠状动脉疾病、阻塞性气道疾病、HIV介导的逆转录病毒性感染、心血管病症(包括冠状动脉疾病)、神经炎症、神经学病症、疼痛和免疫病症、哮喘、变态反应性病症、炎症、全身性红斑狼疮、CNS病症(诸如阿尔茨海默氏病)、关节炎、败血症、炎性肠病、恶病质、心绞痛、手术后角膜炎症、睑炎、睑腺功能障碍、病毒性疣、光老化性类风湿性关节炎和相关炎性病症、脱发、青光眼、静脉分支阻塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和光感受器或RPE的任何其它退化性疾病;皮肤炎症和皮肤疾病,包括但不限于皮肤伤口愈合、肥厚性瘢痕、疤痕疙瘩、烧伤、红斑痤疮、异位性皮炎、粉刺、牛皮癣、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、炎性后色素沉着过度、色素沉着病症、脱发,结疤和非结疤形式。
在任何给定情况下待施用的化合物的实际量都将由医师考虑相关情况而确定,诸如病状的严重性、患者的年龄和体重、患者的一般身体状况、病状的原因和施用途径。
将以任何可接受形式向患者口服施用所述化合物,所述形式诸如片剂、液体、胶囊、粉末等,或其它途径可为合乎需要或必要的,特别是患者出现恶心的情况。所述其它途径可无例外地包括经皮、肠胃外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼局部、眼后部、肌肉内、静脉内和直肠内递送模式。另外,可对制剂进行设计以在给定时间段内延迟活性化合物的释放,或仔细地控制在治疗过程期间于给定时间释放的药物量。
在本发明的另一实施方案中,提供在其药学上可接受的载体中包含至少一种本发明化合物的药物组合物。短语“药学上可接受”意指载体、稀释剂或赋形剂必须可与制剂的其它成分相容,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、分散液、贴片、胶束、脂质体等形式使用,其中所得组合物含有作为活性成分的与适于肠内或肠胃外施加的有机或无机载体或赋形剂掺混的一种或多种本发明化合物。本发明化合物可例如与通常无毒、药学上可接受的用于片剂、丸粒、胶囊、栓剂、溶液、乳液、混悬液和适于使用的任何其它形式的载体组合。可使用的载体包括葡萄糖、乳糖、阿拉伯树胶、明胶、甘露糖醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白(keratin)、胶体二氧化硅、马铃薯淀粉、脲、中等链长甘油三酯、右旋糖苷以及其它适用于制造呈固体、半固体或液体形式的制剂的载体。此外,可使用助剂、稳定剂、增稠剂和着色剂以及芳香剂。本发明化合物以足以对过程或疾病状况产生所需效果的量包含在药物组合物中。
含有本发明化合物的药物组合物可呈适于口服使用的形式,例如呈片剂、锭剂、糖锭、水性或油性混悬液、可分散粉末或颗粒剂、乳液、硬质或软质胶囊、或糖浆或酏剂形式。意图供口服使用的组合物可根据本领域中已知的用于制造药物组合物的任何方法制备,并且所述组合物可含有一种或多种选自由以下组成的组的试剂:甜味剂,诸如蔗糖、乳糖或糖精;调味剂,诸如胡椒薄荷、冬青油或樱桃油;着色剂和防腐剂,以提供药学上精致且适口的制剂。也可通过已知方法制造含有与无毒药学上可接受的赋形剂掺混的本发明化合物的片剂。所用赋形剂可为例如(1)惰性稀释剂,诸如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)粒化剂和崩解剂,诸如玉米淀粉、马铃薯淀粉或海藻酸;(3)粘合剂,诸如黄蓍胶、玉米淀粉、明胶或阿拉伯胶;以及(4)润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可为未包衣的,或它们可通过已知技术包衣以延迟在胃肠道中的崩解和吸收,并且由此在较长时期内提供持续作用。举例来说,可采用延时物质,诸如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,供口服使用的制剂可呈硬明胶胶囊形式,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。它们也可呈软明胶胶囊形式,其中本发明化合物与水或油介质,例如花生油、液体石蜡或橄榄油混合。
含有本发明化合物的药物组合物可呈适于局部使用的形式,例如呈油性混悬液形式,呈于水性液体或非水性液体中的溶液或混悬液形式,或呈水包油或油包水液体乳液形式。可通过组合作为活性成分的治疗有效量的至少一种根据本发明的化合物或其药学上可接受的盐与常规眼科可接受的药物赋形剂,以及通过制备适于眼局部使用的单位剂量来制备药物组合物。在液体制剂中,治疗有效量通常在约0.0001至约5%(w/v),优选约0.001至约2.0%(w/v)之间。
对于眼科施加,优选使用生理盐水溶液作为主要媒介物来制备溶液。所述眼科溶液的pH应优选用适当缓冲体系维持在4.5与8.0之间,其中中性pH是优选但非必需的。制剂也可含有常规药学上可接受的防腐剂、稳定剂和表面活性剂。可用于本发明的药物组合物中的优选防腐剂包括但不限于氯化苯甲烃铵、氯丁醇、硫柳汞、乙酸苯汞和硝酸苯汞。优选的表面活性剂是,例如,吐温80。同样,各种优选媒介物可用于本发明的眼科制剂中。这些媒介物包括但不限于聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊洛沙姆(poloxamer)、羧甲基纤维素、羟乙基纤维素、环糊精和纯化水。
需要或适宜时可添加张力调节剂。它们包括但不限于盐(特别是氯化钠、氯化钾)、甘露糖醇和甘油,或任何其它适合的眼科可接受的张力调节剂。
可使用用于调节pH的各种缓冲剂和手段,只要所得制剂是眼科可接受的即可。因此,缓冲剂包括乙酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂和硼酸盐缓冲剂。可根据需要使用酸或碱调节这些制剂的pH。
以类似方式,用于本发明中的眼科可接受的抗氧化剂包括但不限于焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁基化羟基苯甲醚和丁基化羟基甲苯。
可包含在眼科制剂中的其它赋形剂组分是螯合剂。优选螯合剂是依地酸二钠(edentate disodium),但其它螯合剂也可替代它或与它联合使用。
各成分通常以以下量使用:
本发明的活性化合物的实际剂量取决于具体化合物和待治疗的病状;对适当剂量的选择是熟练技术人员所熟知的。
本发明的眼科制剂以适于计量施加的形式适宜地包装,诸如包装在配备有滴管的容器中,以方便向眼部施加。适于逐滴施加的容器通常由适合的惰性、无毒塑料材料制得,并且通常含有约0.5与约15ml之间的溶液。一个包装可含有一个或多个单位剂量。尤其是不含防腐剂的溶液通常在不可再密封的容器中配制,所述容器含有多达约10个,优选多达约5个单位剂量,其中典型单位剂量是1至约8滴,优选是1至约3滴。1滴的体积通常是约20-35微升。
药物组合物可呈无菌可注射混悬液形式。该混悬液可根据已知方法,使用适合的分散剂或湿润剂和助悬剂配制。无菌可注射制剂也可为于无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如为于1,3-丁二醇中的溶液。无菌、不挥发性油常规用作溶剂或混悬介质。出于这个目的,可采用任何温和不挥发性油,包括合成的甘油单酯或甘油二酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成的脂肪媒介物(如油酸乙酯)等。可根据需要并入缓冲剂、防腐剂、抗氧化剂等。
本发明化合物也可以用于经直肠施用药物的栓剂形式施用。这些组合物可通过将本发明化合物与适合的非刺激性赋形剂(诸如可可脂、聚乙二醇的合成甘油酯)混合来制备,所述赋形剂在常温下是固体,但在直肠腔中液化和/或溶解以释放药物。
因为个体受试者在症状的严重性方面可表现出巨大的变化,并且各药物具有其独特的治疗特征,所以对各受试者采用的精确施用模式和剂量留给从业者来判断。
本文所述的化合物和药物组合物适合作为哺乳动物(包括人)中用于治疗疾病和/或缓解病状的药剂,所述疾病和/或病状对通过N-甲酰肽2受体的激动剂或功能性拮抗剂进行的治疗有反应。因此,在本发明的其它实施方案中,提供用于治疗与N-甲酰肽2受体的调节相关的病症的方法。所述方法可例如通过向有需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来执行。如本文所用,术语“治疗有效量”意指研究人员、兽医、医生或其它临床医师所寻求的将引发有需要的受试者出现生物或医学应答的药物组合物的量。在一些实施方案中,有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。
本发明还涉及用于制备式I化合物的方法。根据本发明的式I化合物可以与合成有机化学领域技术人员所了解的常规方法类似的方式制备。
以下阐述的合成流程1说明可如何制备根据本发明的化合物。本领域技术人员将能够以常规方式修改和/或改动以下流程以合成由式I涵盖的任何本发明化合物或它们的合成前体。
流程1
如流程1中所描绘制备式I化合物。一般来说,使α-羟基羧酸的叔丁酯衍生物与取代的异氰酸苯酯反应以产生苯基氨基甲酸酯衍生物。接着在酸性条件下移除叔丁酯保护基以产生苯基氨基甲酸酯乙酸衍生物。接着通过在胺的存在下用诸如1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)和羟基苯并三唑(HOBt)的活化试剂处理化合物,或通过为本领域技术人员所知的其它方法来使羧酸基团转化成酰胺。
以下缩写用于一般流程中以及实施例中:
Et3N 三乙胺
CD3OD 氘化甲醇
Na2SO4 硫酸钠
DMF N,N二甲基甲酰胺
EDCI/EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
HOBt 羟基苯并三唑
THF 四氢呋喃
TMS 四甲基硅烷
EtOAc 乙酸乙酯
HCO2H 甲酸
DMAP 4-二甲基氨基吡啶
DCC N,N'-二环己基碳二亚胺
HATU 六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-1,2,3-
三唑并[4,5-b]吡啶鎓3-氧化物
DIEPA N,N-二异丙基乙胺
HCl 盐酸
在这个阶段,本领域技术人员将了解归入本发明的范围的许多其它化合物可通过进行各种常见化学反应来制备。某些特定化学转化的细节提供于实施例中。
附图
图1显示式I的结构。
发明详述
应了解上文一般性描述与下文详细描述均仅为示例性和说明性的,并且不限制所要求保护的本发明。除非另外明确陈述,否则如本文所用,单数的使用包括复数。
本领域技术人员将显而易见的是一些本发明化合物可含有一个或多个不对称中心,以致化合物可以对映异构形式以及非对映异构形式存在。除非另外明确指示,否则本发明的范围包括所有对映异构体、非对映异构体和外消旋混合物。一些本发明化合物可与药学上可接受的酸或碱形成盐,并且本文所述的化合物的所述药学上可接受的盐也在本发明的范围内。
本发明包括所有药学上可接受的同位素富集的化合物。任何本发明化合物都可含有富集的或不同于天然比例的一个或多个同位素原子,诸如氘2H(或D)替代氢1H(或H)或使用富含13C的材料替代12C等。类似取代可用于N、O和S。同位素的使用可有助于本发明的分析以及治疗方面。举例来说,氘的使用可通过改变本发明化合物的代谢(速率)来增加体内半衰期。这些化合物可依照通过使用同位素富集的试剂描述的制备方法来制备。
以下实施例仅出于说明目的,并且它们不意图也不应被解释为以任何方式限制本发明。本领域技术人员将了解可在不超出本发明的精神或范围的情况下对以下实施例进行变化和修改。
在实施方案(1)中,提供一种由式I表示的化合物:
其中:
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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、-S(O)mR13、–C(O)R14或–OR15;
R2是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R3是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R4是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R5是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R6是H、任选取代的C1-8烷基、任选取代的杂环、-(CH2)pCOOH、-(CH2)p-NH2、-(CH2)p-OH、-(CH2)p-SH、-(CH2)p-CONH2、-(CH2)p-CONH2、-CH(OH)CH3、-(CH2)pSCH3、-(CH2)pNH-C(=NH)(NH2)或-CH2C6-10芳基,其中所述-C6-10芳基任选被取代;
R6a是H或任选取代的C1-8烷基;
R7是H或任选取代的C1-8烷基;
R8是H;
R9是H、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C6-10芳基或任选取代的C3-8环烯基;
R10是–(CH2)nOR16、–(CH2)nS(O)2OH、–(CH2)nC(O)R17、–(CH2)nOS(O)2OH、-(CH2)nNR18R19、-(CH2)nP(O)(OC1-6烷基)2、-(CH2)nP(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R11是H、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C6-10芳基或任选取代的C3-8环烯基;
R12是H、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C6-10芳基或任选取代的C3-8环烯基;
R13是H、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C6-10芳基、OH或任选取代的C3-8环烯基;
R14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C6-10芳基、任选取代的C3-8环烯基或–OR15;
R15是H或任选取代的C1-8烷基;
R16是H、-C(O)(C1-8烷基)或任选取代的C1-8烷基;
R17是OH、-OC1-8烷基或C1-8烷基;
R18选自由以下组成的组:H、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C6-10芳基、任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
R19选自由以下组成的组:H、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C6-10芳基、或任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
p是1、2或3;
n是0、1、2、3、4、5、6、7或8;并且
m是0、1或2;
其中
各C1-8烷基取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、C3-8环烷基、氨基、杂环、C6-10芳基、羧酸、膦酸、磺酸、磷酸、硝基、酰胺、磺酰胺、羧酸酯和酮;
各C3-8环烷基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、硝基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
各杂环取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
各C6-10芳基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、羧酸、羧酸C1-8烷基酯、酰胺、硝基、-OC1-6烷基、-SC1-8烷基、-C1-8烷基、酮、烷基氨基、氨基和C3-8环烷基;并且
各C3-8环烯基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、酮、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(2)中,提供一种根据实施方案(1)的化合物,其中:
n是0或1;
R10是-(CH2)nOR16、-(CH2)nC(O)R17、-(CH2)nS(O)2OH、-(CH2)nNR18R19、-(CH2)n-P(O)(OC1-6烷基)2、-(CH2)n-P(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R16是H或-C(O)(C1-8烷基);
R17是OH或-OC1-8烷基;
R18是H;并且
R19选自由以下组成的组:H、-C(O)R17和-S(O)2N(C1-8烷基)2;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(3)中,提供一种根据实施方案(1)或(2)中任一个的化合物,其中R9是H。
在实施方案(4)中,提供一种根据实施方案(1)至(3)中任一个的化合物,其中:
R6是H、任选取代的C1-8烷基或-CH2-C6-10芳基,其中所述C1-6芳基任选被取代;并且
R6a是H;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(5)中,提供一种根据实施方案(1)至(4)中任一个的化合物,其中R7是H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(6)中,提供一种根据实施方案(1)至(5)中任一个的化合物,其中R1选自卤素、氟化C1-8烷基和全氟化C1-8烷基;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(7)中,提供一种根据实施方案(1)至(6)中任一个的化合物,其中R2、R3、R4和R5各自是H;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(8)中,提供一种根据实施方案(1)至(7)中任一个的化合物,其中R10是任选取代的杂环,其中所述杂环选自咪唑、三唑、四唑、噁唑和噻唑;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(9)中,提供一种根据实施方案(1)至(8)中任一个的化合物,其中:
n是0或1;
R1选自卤素、氟化C1-8烷基和全氟化C1-8烷基;
R2、R3、R4和R5各自是H;
R6是H、任选取代的C1-8烷基或-CH2C6-10芳基,其中所述C6-10芳基任选被取代;
R6a是H;
R9是H;
R10是-(CH2)nOR16、-(CH2)nC(O)R17、-(CH2)n-S(O)2OH、-(CH2)nNR18R19、-(CH2)n-P(O)(OC1-6烷基)2、-(CH2)n-P(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R16是H或-C(O)(C1-8烷基);
R17是OH或-OC1-8烷基;
R18是H;并且
R19选自由以下组成的组:H、-C(O)R17和-S(O)2N(C1-8烷基)2;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(10)中,提供一种根据实施方案(1)至(9)中任一个的化合物,其中-CH2-C6-10芳基是任选取代的苯甲基。
在实施方案(11)中,提供一种根据实施方案(1)至(10)中任一个的化合物,其中:
各C1-8烷基独立地选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基;并且
R7是H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
或其对映异构体、非对映异构体或互变异构体;
或上述各物中任一个的药学上可接受的盐。
在实施方案(12)中,提供一种选自由以下组成的组的化合物:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸叔丁酯;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)(甲基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}甲基)膦酸二乙酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}甲基)膦酸二乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸叔丁酯;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
乙酸2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-{甲基[2-(磺氧基)乙基]氨基}-1-氧代戊-2-基酯;
({(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)甲磺酸;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸叔丁酯;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
[4-(三氟甲基)苯基]氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
(4-溴苯基)氨基甲酸(1S)-1-[({2-[(叔丁氧基羰基)氨基]乙基}氨基)羰基]-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-苯甲基-2-氧代-2-[(1H-四唑-5-基甲基)氨基]乙酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸叔丁酯;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸;
(4-溴苯基)氨基甲酸(1S)-1-{[(2-氨基乙基)氨基]羰基}-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸;和
(4-溴苯基)氨基甲酸(1S)-1-{[(2-{[(二甲基氨基)磺酰基]氨基}乙基)氨基]羰基}-3-甲基丁酯;
及其对映异构体、非对映异构体和互变异构体;
以及上述各物中任一个的盐,包括药学上可接受的盐。
在实施方案(13)中,提供一种选自由以下组成的组的化合物:
(S)-2-(((4-溴苯基)氨基甲酰基)氧基)-4-甲基戊酸叔丁酯;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酸;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸叔丁酯;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸;
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸叔丁酯;和
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸;
及其对映异构体、非对映异构体和互变异构体;
以及上述各物的盐。
在实施方案(14)中,提供一种药物组合物,其包含作为活性成分的治疗有效量的根据实施方案(1)至(13)中任一个的化合物,以及药学上可接受的佐剂、稀释剂或载体。
在实施方案(15)中,提供一种治疗需要所述治疗的受试者的眼部炎性疾病或病状的方法,所述方法包括向所述受试者施用药物组合物,其包含治疗有效量的根据实施方案(1)至(13)中任一个的化合物。
在实施方案(16)中,提供根据实施方案(15)的方法,其中所述眼部炎性疾病或病状选自:葡萄膜炎、干眼症、角膜炎、过敏性眼病、传染性角膜炎、疱疹性角膜炎、角膜血管生成、淋巴管生成、视网膜炎、脉络膜炎、急性多灶性鳞状色素上皮病变、贝切特氏病、手术后角膜伤口愈合、白内障手术后炎症、湿性和干性年龄相关性黄斑变性(ARMD)。
在实施方案(17)中,提供一种治疗需要所述治疗的受试者的皮肤炎症或皮肤疾病的方法,所述方法包括向所述受试者施用药物组合物,其包含治疗有效量的根据实施方案(1)至(13)中任一个的化合物。
在实施方案(18)中,提供根据实施方案(17)的方法,其中所述皮肤炎症或疾病选自:皮肤伤口愈合、肥厚性瘢痕、疤痕疙瘩、烧伤、红斑痤疮、异位性皮炎、粉刺、牛皮癣、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、炎性后色素沉着过度、色素沉着病症和脱发(结疤和非结疤形式)。
如将为本领域技术人员所显而易见,个别非对映异构形式可通过以常规方式分离其混合物来获得;可采用色谱分离。
化合物名称用ACDLabs版本12.5生成。用于实施例中的一些中间体和试剂名称用诸如Chem Bio Draw Ultra版本12.0或来自MDL ISIS Draw 2.5SP1的Auto Nom 2000的软件生成。
一般来说,化合物的表征根据以下方法进行。NMR光谱在300或600MHz Varian NMR光谱仪上记录,并且在室温下获取。参考内部TMS或溶剂信号以ppm给出化学位移。大多数式I化合物以旋转异构体形式获得。
所有未描述其合成的试剂、溶剂、催化剂都购自化学品供应商,诸如SigmaAldrich、Fluka、Bio-Blocks、Combi-blocks、TCI、VWR、Lancaster、Oakwood、Trans WorldChemical、Alfa、Fisher、Maybridge、Frontier、Matrix、Ukrorgsynth、Toronto、RyanScientific、SiliCycle、Anaspec、Syn Chem、Chem-Impex、MIC-scientific、Ltd;然而,一些已知中间体则根据已公开的程序来制备。
除非另外指示,否则本发明化合物通常通过中压液相色谱法纯化。
实施例1
中间体1
(S)-2-(((4-溴苯基)氨基甲酰基)氧基)-4-甲基戊酸叔丁酯
在25℃下向(2S)-2-羟基-4-甲基-戊酸、1,1-二甲基乙酯(1.10g,5.85mmol)和25mL二氯甲烷的溶液中添加异氰酸4-溴-苯酯(1.15g,5.85mmol)和三乙胺(1.22mL,8.78mmol)。在25℃下搅拌所得混合物4小时。浓缩混合物,并且通过中压液相色谱法,在硅胶上使用乙酸乙酯:己烷(8:92)纯化残余物以产生呈粘稠油状的中间体1。
1H NMR(CD3OD,300MHz)δ:7.33-7.47(m,4H),4.87(m,1H),1.56-1.91(m,1H),1.47(s,9H),0.93-1.04(m,6H)。
中间体2
(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基甲酰基}氧基]戊酸叔丁酯
以与实施例1中对于中间体1所述的程序类似的方式由相应α-羟基羧酸酯制备中间体2。中间体2以白色固体形式获得;1H NMR(CD3OD,300MHz)δ:7.52-7.67(m,4H),4.89(m,1H),1.71-1.92(m,2H),1.58-1.70(m,1H),1.47(s,9H),0.98(t,J=6.2Hz,6H)。
实施例2
中间体3
(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酸
在25℃下搅拌中间体1(1.53g,3.98mmol)和20mL甲酸的溶液5小时。所得混合物用水(20mL)淬灭,接着用乙酸乙酯萃取。有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。残余物用二氯甲烷:己烷(1:9)冲洗4次以产生呈白色固体状的中间体3;1HNMR(CD3OD,300MHz)δ:7.33-7.45(m,4H),4.94-5.04(m,1H),1.73-1.95(m,2H),1.63-1.73(m,1H),0.98(dd,J=6.6,3.7Hz,6H)。
中间体4
(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基甲酰基}氧基]戊酸
以与实施例2中对于中间体3所述的程序类似的方式由相应氨基甲酸酯衍生物制备中间体4。中间体4以白色固体形式获得;1H NMR(CD3OD,300MHz)δ:7.60-7.66(m,2H),7.53-7.59(m,2H),5.02(dd,J=9.2,3.7Hz,1H),1.76-1.91(m,2H),1.66-1.75(m,1H),0.99(dd,J=6.3,3.4Hz,6H)。
实施例3
化合物1
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸叔丁酯
在25℃下向中间体3(300mg,0.911mmol)和12mL无水DMF的溶液中添加EDCI(262mg,1.37mmol)、HOBt(185mg,1.37mmol)、甘氨酸叔丁酯(179mg,1.37mmol)和N-甲基吗啉(184mg,1.82mmol)。在25℃下搅拌所得混合物12小时。混合物用水(5mL)淬灭,并且产物用乙酸乙酯(40mL)萃取。分离各层,并且有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。通过中压液相色谱法,在硅胶上使用乙酸乙酯:己烷(1:4)纯化所得产物以产生呈白色固体状的化合物1;1H NMR(CD3OD,300MHz)δ:7.34-7.46(m,4H),5.10(dd,J=9.5,4.0Hz,1H),3.75-3.94(m,2H),1.73-1.92(m,2H),1.60-1.72(m,1H),1.45(s,9H),0.99(s,3H),0.97(s,3H)。
以与实施例3中对于化合物1所述的程序类似的方式,由相应氨基甲酸酯衍生物制备化合物2、3、4、5、6、7和8。具体来说,化合物3、4、7和8由中间体3制备,并且化合物2、5和6由中间体4制备。化合物2、3、4、5、6、7和8以白色固体形式获得;它们的特征描述于以下表1中。
表1
实施例4
化合物9
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸叔丁酯
在25℃下搅拌中间体3(170mg,0.52mmol)、DCC(106mg,0.52mmol)和14mL无水二氯甲烷的溶液12小时。过滤混合物。滤液用10%HCl(5mL)淬灭,并且产物用乙酸乙酯(20mL)萃取。分离各层,并且有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。通过中压液相色谱法,在硅胶上使用乙酸乙酯:己烷(15:85)纯化所得产物以产生呈白色固体状的化合物9;1H NMR(CD3OD,300MHz)δ:7.30-7.47(m,4H),5.39(d,J=11.1Hz,1H),4.19(d,J=17.0Hz,1H),3.75(d,J=17.0Hz,1H),3.38(t,J=7.5Hz,2H),1.66-1.95(m,3H),1.52-1.64(m,2H),1.44(s,9H),0.91-1.07(m,9H)。
以与实施例4中对于化合物9所述的程序类似的方式由相应氨基甲酸酯衍生物制备化合物10、11、12、13、14、15、16和17。具体来说,化合物10、11、14和16由中间体3制备,并且化合物12、13、15和17由中间体4制备。化合物10、11、12、13、14、15、16和17各自以白色固体形式获得;它们的特征描述于以下表2中。
表2
实施例5
化合物18
乙酸2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酯
在25℃下搅拌化合物6(50mg,0.14mmol)、4mL无水THF和乙酸酐(0.014mL,0.15mmol)的溶液1小时。浓缩混合物,并且通过中压液相色谱法,在硅胶上使用乙酸乙酯:己烷(4:6)纯化所得产物以产生呈澄清油状的化合物18;1H NMR(CD3OD,300MHz)δ:7.51-7.70(m,4H),5.04(dd,J=9.1,3.3Hz,1H),4.05-4.21(m,2H),3.47(m,2H),1.99(s,3H),1.71-1.90(m,2H),1.63(m,1H),0.99(s,3H),0.97(s,3H)。
实施例6
化合物19
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸
在25℃下搅拌化合物1(368mg,0.83mmol)和8mL甲酸的溶液12小时。所得反应用水(10mL)淬灭,并且产物用EtOAc萃取。有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩。残余物用丙酮:己烷(1:99)冲洗4次以产生呈白色固体状的化合物19;1H NMR(CD3OD,300MHz)δ:8.26(s,1H),7.33-7.45(m,4H),5.06-5.17(m,1H),3.84-4.04(m,2H),1.74-1.90(m,2H),1.63-1.74(m,1H),0.99(s,3H),0.97(s,3H)。
以与实施例6中对于化合物19所述的程序类似的方式由相应酯衍生物制备化合物20、21、22、23、24、25和26。具体来说,化合物20由化合物2制备;化合物21由化合物3制备;化合物22由化合物9制备;化合物23由化合物10制备;化合物24由化合物11制备;化合物25由化合物12制备;并且化合物26由化合物13制备。化合物20、21、22、23、24、25和26以白色固体形式获得;它们的特征描述于以下表3中。
表3
实施例7
化合物27
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-{甲基[2-(磺氧基)乙基]氨基}-1-氧代戊-2-基酯
在25℃下在氩气下向化合物4(166mg,0.42mmol)和8mL无水THF的溶液中添加Et3N(0.12mL,0.84mmol)、DMAP(56mg,0.42mmol)和氯硫酸2,2,2-三氯乙酯(205mg,0.84mmol)。在25℃下搅拌所得混合物12小时。混合物用10%HCl(2mL)淬灭,并且产物用乙酸乙酯(20mL)萃取。分离各层,并且有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。通过中压液相色谱法,在硅胶上使用甲醇:二氯甲烷(15:85)纯化所得产物以产生呈灰白色固体状的化合物27;1H NMR(CD3OD,300MHz)δ:7.38(s,4H),5.32-5.44(m,1H),4.08-4.28(m,2H),3.39-3.67(m,2H),3.25(s,3H),1.71-1.96(m,2H),1.50-1.70(m,1H),1.00(d,J=5.0Hz,6H)。
实施例8
化合物28
({(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)甲磺酸
在25℃下向中间体4(750mg,2.35mmol)和10mL DMF的溶液中添加氨基甲磺酸(260mg,2.35mmol)、HATU(983mg,2.58mmol)和二异丙基乙胺(0.49mL,2.82mmol)。在100℃下搅拌所得混合物12小时。浓缩混合物并用水(4mL)淬灭,并且产物用乙酸乙酯(20mL)萃取。分离各层,并且有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。通过中压液相色谱法,在硅胶上使用甲醇:二氯甲烷(15:85)纯化残余物以产生呈白色固体状的化合物28;1H NMR(CD3OD,300MHz)δ:7.51-7.69(m,4H),5.18(dd,J=9.2,3.7Hz,1H),4.22-4.48(m,2H),1.68-1.91(m,3H),0.99(s,3H),0.98(s,3H)。
实施例9
中间体2a
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸叔丁酯
以与实施例1中对于中间体1所述的程序类似的方式由相应氨基酸制备中间体2a。中间体2a以澄清油形式获得;[α]D=-13.7,(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.16-7.45(m,8H),5.07(dd,J=7.3,5.6Hz,1H),3.09-3.17(m,2H),1.35-1.42(m,9H)。
中间体4a
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸
以与实施例2中对于中间体3所述的程序类似的方式由相应氨基甲酸酯衍生物制备中间体4a。中间体4a以白色固体形式获得;[α]D=-13.3,c=1.00,MeOH;1H NMR(CD3OD,300MHz)δ:7.15-7.42(m,8H),5.20(s,1H),3.19-3.30(m,1H),3.05-3.17(m,1H)。
以与实施例4中对于化合物9所述的程序类似的方式由相应氨基甲酸酯衍生物制备化合物29、30、31、32、33、34、35和36。具体来说,化合物29、30和32由中间体4获得;化合物31和33由中间体3获得;并且化合物34、35和36由中间体4a获得。以下描述如此获得的化合物的特征。
化合物29
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸叔丁酯
白色固体;[α]D=-18.6(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.49-7.69(m,4H),5.41(d,J=10.3Hz,1H),4.20(d,J=17.3Hz,1H),3.76(d,J=16.7Hz,1H),3.36-3.45(m,1H),1.83(m,3H),1.56(m,2H),1.45(s,9H),0.88-1.09(m,9H);1H NMR光谱显示存在旋转异构体(rotomer)。
化合物30
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸叔丁酯
白色固体;[α]D=-22.3(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.51-7.67(m,4H),5.49(d,J=10.0Hz,1H),4.20-4.35(m,1H),3.89-4.05(m,1H),3.69-3.80(m,1H),1.77-1.98(m,2H),1.54-1.68(m,1H),1.44(s,9H),1.21-1.35(m,6H),0.91-1.06(m,6H);1HNMR光谱显示存在旋转异构体。
化合物31
(4-溴苯基)氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯
白色固体;[α]D=-12.6(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.27-7.47(m,4H),5.34(m,1H),5.00(d,J=15.8Hz,1H),4.70(d,J=15.8Hz,1H),3.54-3.71(m,2H),1.72-1.96(m,2H),1.54(m,1H),1.35(t,J=7.2Hz,3H),0.90-1.07(m,6H);1H NMR光谱显示存在旋转异构体。
化合物32
[4-(三氟甲基)苯基]氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯
白色固体;[α]D=-9.1(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.51-7.69(m,4H),7.43(s,NH),5.28-5.44(m,1H),5.08(d,J=14.9Hz,1H),4.56-4.69(m,1H),3.48-3.64(m,1H),1.70-1.98(m,2H),1.58(m,1H),1.23-1.42(m,3H),0.93-1.07(m,6H);1H NMR光谱显示存在旋转异构体。
化合物33
(4-溴苯基)氨基甲酸(1S)-1-[({2-[(叔丁氧基羰基)氨基]乙基}氨基)羰基]-3-甲基丁酯
白色固体;[α]D=-12.4(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.40(s,4H),4.94-5.06(m,1H),3.24-3.31(m,2H),3.17(m,2H),1.79(m,2H),1.55-1.69(m,2H),1.40(s,9H),0.97(d,J=6.4Hz,6H)。
化合物34
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸叔丁酯
白色固体;[α]D=-23.0(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.15-7.43(m,8H),5.27(s,1H),3.84(d,J=7.6Hz,2H),3.02-3.29(m,2H),1.46(s,9H)。
化合物35
(4-溴苯基)氨基甲酸(1S)-1-苯甲基-2-氧代-2-[(1H-四唑-5-基甲基)氨基]乙酯
灰白色固体;1H NMR(CD3OD,300MHz)δ:7.18-7.41(m,9H),5.22(m.,1H),4.66-4.85(m,2H),3.15-3.26(m,2H)。
化合物36
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸叔丁酯
白色固体;[α]D=-18.3(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.20-7.45(m,9H),5.57(dd,J=8.4,5.4Hz,1H),4.02-4.15(m,2H),3.18(m,2H),3.16(S,3H),1.40-1.53(m,9H)。
以与实施例6中对于化合物19所述的程序类似的方式由相应酯衍生物制备化合物37、38、39、40和41。具体来说,化合物37由化合物29获得;化合物38由化合物30获得;化合物39由化合物33获得;化合物40由化合物34获得;并且化合物41由化合物36获得。以下描述如此获得的化合物的特征。
化合物37
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸
白色固体;[α]D=-10.3(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.49-7.68(m,4H),5.42(d,J=10.8Hz,1H),4.34(d,J=17.3Hz,1H),3.81(d,J=17.3Hz,1H),3.36-3.57(m,1H),1.62–1.98(m,3H),1.61-1.48(m,2H),0.81-1.08(m,9H);1H NMR光谱显示存在旋转异构体。
化合物38
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸
白色固体;[α]D=-9.5(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.47-7.68(m,4H),5.50(d,J=9.7Hz,1H),4.20-4.41(m,1H),3.96-4.17(m,1H),3.82(d,J=17.3Hz,1H),1.73-2.03(m,2H),1.61(m,1H),1.29(m,6H),0.83-1.16(m,6H);1H NMR光谱显示存在旋转异构体。
化合物39
(4-溴苯基)氨基甲酸(1S)-1-{[(2-氨基乙基)氨基]羰基}-3-甲基丁酯
白色固体;[α]D=-9.8(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.32-7.47(m,4H),4.94-5.03(m,1H),3.48(m,2H),2.99-3.10(m,2H),1.54-1.90(m,3H),0.94-1.02(m,6H)。
化合物40
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸
白色固体;[α]D=-13.1(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.15-7.43(m,8H),5.30(dd,J=8.6,4.2Hz,1H),3.84-4.02(m,2H),3.01-3.29(m,2H)。
化合物41
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸
白色固体;[α]D=-16.1(c=1.00,MeOH);1H NMR(CD3OD,300MHz)δ:7.21-7.40(m,9H),5.58(dd,J=8.5,5.3Hz,1H),4.28(d,J=17.3Hz,1H),3.91(d,J=17.3Hz,1H),3.03-3.21(m,5H)。
化合物42
(4-溴苯基)氨基甲酸(1S)-1-{[(2-{[(二甲基氨基)磺酰基]氨基}乙基)氨基]羰基}-3-甲基丁酯
在25℃下搅拌于14mL无水THF中的化合物39(78mg,0.19mmol)、N,N-二甲基氨磺酰氯(33mg,0.23mmol)和14mL Et3N(48mg,0.48mmol)的溶液12小时。混合物用水(2mL)淬灭,用乙酸乙酯(10mL)萃取。有机层用水、盐水洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩滤液。通过中压液相色谱法,在硅胶上使用乙酸乙酯:己烷(8:2)纯化所得产物以产生呈白色固体状的化合物42;1H NMR(CD3OD,600MHz)δ:7.32-7.47(m,4H),4.97-5.07(m,1H),3.32(m,2H),3.07-3.19(m,2H),1.73-1.89(m,2H),1.64(m,1H),0.97(d,J=6.2Hz,6H)。
生物数据
根据式I的化合物的生物活性阐述于下表4中。在(F12、10%FBS、1%PSA、400μg/ml遗传霉素和50μg/ml潮霉素)中培养稳定表达FPR2的CHO-Gα16细胞,并且在(高葡萄糖DMEM、10%FBS、1%PSA、400μg/ml遗传霉素和50μg/ml潮霉素)中培养稳定表达FPR1的HEK-Gqi5细胞。一般来说,在实验前一天,将每孔18,000个细胞铺板于384-孔透明底部聚-D-赖氨酸涂布的板中。次日在FLIPRTetra上测定筛选化合物诱导的钙活性。在384-孔微板中使用EP3和MultiPROBE自动液体处理系统(MultiPROBE robotic liquid handling system)制备药板。在0.61至10,000nM范围内的浓度下测试化合物。结果表示为EC50(nM)和功效%值。
表4
Claims (16)
1.一种由式I表示的化合物:
其中:
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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、-S(O)mR13、–C(O)R14或–OR15;
R2是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R3是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R4是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R5是H、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C6-10芳基、任选取代的C3-8环烯基、卤素、NR11R12、氟化C1-8烷基、全氟化C1-8烷基、–S(O)mR13–C(O)R14或–OR15;
R6是H、任选取代的C1-8烷基、任选取代的杂环、-(CH2)pCOOH、-(CH2)p-NH2、-(CH2)p-OH、-(CH2)p-SH、-(CH2)p-CONH2、-(CH2)p-CONH2、-CH(OH)CH3、-(CH2)pSCH3、-(CH2)pNH-C(=NH)(NH2)或-CH2C6-10芳基,其中所述-C6-10芳基任选被取代;
R6a是H或任选取代的C1-8烷基;
R7是H或任选取代的C1-8烷基;
R8是H;
R9是H;
R10是–(CH2)nOR16、–(CH2)nS(O)2OH、–(CH2)nC(O)R17、–(CH2)nOS(O)2OH、-(CH2)nNR18R19、-(CH2)nP(O)(OC1-6烷基)2、-(CH2)nP(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R11是H、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C6-10芳基或任选取代的C3-8环烯基;
R12是H、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C6-10芳基或任选取代的C3-8环烯基;
R13是H、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C6-10芳基、OH或任选取代的C3-8环烯基;
R14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C6-10芳基、任选取代的C3-8环烯基或–OR15;
R15是H或任选取代的C1-8烷基;
R16是H、-C(O)(C1-8烷基)或任选取代的C1-8烷基;
R17是OH、-OC1-8烷基或C1-8烷基;
R18选自由以下组成的组:H、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C6-10芳基、任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
R19选自由以下组成的组:H、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C6-10芳基、或任选取代的C3-8环烯基、-C(O)R17和-S(O)2N(C1-8烷基)2;
p是1、2或3;
n是0、1、2、3、4、5、6、7或8;并且
m是0、1或2;
其中
各C1-8烷基取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、C3-8环烷基、氨基、杂环、C6-10芳基、羧酸、膦酸、磺酸、磷酸、硝基、酰胺、磺酰胺、羧酸酯;
各C3-8环烷基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、硝基、-OC1-8烷基、-SC1-8烷基、-C1-8烷基、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
各杂环取代基独立地选自由以下组成的组:卤素、羟基、-OC1-8烷基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-SC1-8烷基、-C1-8烷基、烷基氨基、氨基、C6-10芳基和C3-8环烷基;其中“杂环”是指3至10元环,其含有打断碳环结构的至少一个选自氧、氮、硫的杂原子或其至少两者的组合;
各C6-10芳基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、磺酰胺、羧酸、羧酸C1-8烷基酯、酰胺、硝基、-OC1-6烷基、-SC1-8烷基、-C1-8烷基、烷基氨基、氨基和C3-8环烷基;并且
各C3-8环烯基取代基独立地选自由以下组成的组:卤素、羟基、磺酰基C1-8烷基、亚砜C1-8烷基、硝基、-OC1-6烷基、-SC1-6烷基、-C1-6烷基、烷基氨基、氨基、C6-10芳基和C3-8环烷基;
或上述各物中任一个的药学上可接受的盐。
2.根据权利要求1所述的化合物,其中:
R1选自卤素、氟化C1-8烷基和全氟化C1-8烷基。
3.根据权利要求1所述的化合物,其中:
R2、R3、R4和R5各自是H。
4.根据权利要求1所述的化合物,其中:
R6是H、任选取代的C1-8烷基或-CH2C6-10芳基,其中所述C1-6芳基任选被取代;
R6a是H;并且
R7是H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
5.根据权利要求1所述的化合物,其中:
n是0或1;
R9是H;
R10是-(CH2)nOR16、-(CH2)nC(O)R17、-(CH2)nS(O)2OH、-(CH2)nNR18R19、-(CH2)n-P(O)(OC1-6烷基)2、-(CH2)n-P(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R16是H或-C(O)(C1-8烷基);
R17是OH或-OC1-8烷基;
R18是H;并且
R19选自由以下组成的组:H、-C(O)R17和-S(O)2N(C1-8烷基)2。
6.根据权利要求1所述的化合物,其中:
R1选自卤素、氟化C1-8烷基和全氟化C1-8烷基;
R2、R3、R4和R5各自是H;
R6是H、任选取代的C1-8烷基或-CH2C6-10芳基,其中所述C6-10芳基任选被取代;
R6a是H;
R9是H;
R10是-(CH2)nOR16、-(CH2)nC(O)R17、-(CH2)n-S(O)2OH、-(CH2)nNR18R19、-(CH2)n-P(O)(OC1-6烷基)2、-(CH2)n-P(O)(OC1-6烷基)OH、-(CH2)n-P(O)(OH)2或任选取代的杂环;
R16是H或-C(O)(C1-8烷基);
R17是OH或-OC1-8烷基;
R18是H;并且
R19选自由以下组成的组:H、-C(O)R17和-S(O)2N(C1-8烷基)2。
7.根据权利要求6所述的化合物,其中:
各C1-8烷基独立地选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基;并且
R7是H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
8.根据权利要求1所述的化合物,其选自:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸叔丁酯;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)(甲基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}甲基)膦酸二乙酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}甲基)膦酸二乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸叔丁酯;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
乙酸2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-{甲基[2-(磺氧基)乙基]氨基}-1-氧代戊-2-基酯;
({(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)甲磺酸;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸叔丁酯;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
[4-(三氟甲基)苯基]氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
(4-溴苯基)氨基甲酸(1S)-1-[({2-[(叔丁氧基羰基)氨基]乙基}氨基)羰基]-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-苯甲基-2-氧代-2-[(1H-四唑-5-基甲基)氨基]乙酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸叔丁酯;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸;
(4-溴苯基)氨基甲酸(1S)-1-{[(2-氨基乙基)氨基]羰基}-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸;和
(4-溴苯基)氨基甲酸(1S)-1-{[(2-{[(二甲基氨基)磺酰基]氨基}乙基)氨基]羰基}-3-甲基丁酯。
9.一种化合物,其选自由以下组成的组:
(S)-2-(((4-溴苯基)氨基甲酰基)氧基)-4-甲基戊酸叔丁酯;
(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酸;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸叔丁酯;
(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酸;
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸叔丁酯;和
(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酸;
以及前述各物的盐。
10.一种药物组合物,其包含作为活性成分的治疗有效量的根据权利要求1所述的化合物,以及药学上可接受的佐剂、稀释剂或载体。
11.根据权利要求10所述的药物组合物,其中所述化合物选自:
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸叔丁酯;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)(甲基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}甲基)膦酸二乙酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-1-[(2-羟乙基)氨基]-4-甲基-1-氧代戊-2-基酯;
({[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}甲基)膦酸二乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸叔丁酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸叔丁酯;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-氧代-1-[(1H-四唑-5-基甲基)氨基]戊-2-基酯;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
[4-(三氟甲基)苯基]氨基甲酸(2S)-4-甲基-1-[甲基(1H-四唑-5-基甲基)氨基]-1-氧代戊-2-基酯;
乙酸2-{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酯;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基]氨基}乙酸;
{[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](甲基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](丙-2-基)氨基}乙酸;
{[(2S)-2-{[(4-溴苯基)氨基甲酰基]氧基}-4-甲基戊酰基](乙基)氨基}乙酸;
{甲基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
{乙基[(2S)-4-甲基-2-({[4-(三氟甲基)苯基]氨基甲酰基}氧基)戊酰基]氨基}乙酸;
(4-溴苯基)氨基甲酸(2S)-4-甲基-1-{甲基[2-(磺氧基)乙基]氨基}-1-氧代戊-2-基酯;
({(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)甲磺酸;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸叔丁酯;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
[4-(三氟甲基)苯基]氨基甲酸(1S)-1-{[乙基(1H-四唑-5-基甲基)氨基]羰基}-3-甲基丁酯;
(4-溴苯基)氨基甲酸(1S)-1-[({2-[(叔丁氧基羰基)氨基]乙基}氨基)羰基]-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸叔丁酯;
(4-溴苯基)氨基甲酸(1S)-1-苯甲基-2-氧代-2-[(1H-四唑-5-基甲基)氨基]乙酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸叔丁酯;
[{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}(丙基)氨基]乙酸;
(异丙基{(2S)-4-甲基-2-[({[4-(三氟甲基)苯基]氨基}羰基)氧基]戊酰基}氨基)乙酸;
(4-溴苯基)氨基甲酸(1S)-1-{[(2-氨基乙基)氨基]羰基}-3-甲基丁酯;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基]氨基}乙酸;
{[(2S)-2-({[(4-溴苯基)氨基]羰基}氧基)-3-苯基丙酰基](甲基)氨基}乙酸;和
(4-溴苯基)氨基甲酸(1S)-1-{[(2-{[(二甲基氨基)磺酰基]氨基}乙基)氨基]羰基}-3-甲基丁酯。
12.根据权利要求1所述的化合物在制备用于治疗需要所述治疗的受试者的眼部炎性疾病或病状的药物中的用途。
13.如权利要求12所述的用途,其中所述眼部炎性疾病或病状选自:葡萄膜炎、干眼症、角膜炎、过敏性眼病、角膜血管生成、淋巴管生成、视网膜炎、脉络膜炎、急性多灶性鳞状色素上皮病变、贝切特氏病、手术后角膜伤口愈合、白内障手术后炎症、湿性和干性年龄相关性黄斑变性(ARMD)。
14.如权利要求12所述的用途,其中所述眼部炎性疾病或病状选自:传染性角膜炎和疱疹性角膜炎。
15.根据权利要求1所述的化合物在制备用于治疗需要所述治疗的受试者的皮肤炎症或皮肤疾病的药物中的用途。
16.如权利要求15所述的用途,其中所述皮肤炎症或疾病选自:皮肤伤口愈合、肥厚性瘢痕、疤痕疙瘩、烧伤、红斑痤疮、异位性皮炎、粉刺、牛皮癣、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、炎性后色素沉着过度、色素沉着病症、结疤性脱发和非结疤性脱发。
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