CN109310686B - 可溶性C5aR拮抗剂 - Google Patents
可溶性C5aR拮抗剂 Download PDFInfo
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- CN109310686B CN109310686B CN201780022458.9A CN201780022458A CN109310686B CN 109310686 B CN109310686 B CN 109310686B CN 201780022458 A CN201780022458 A CN 201780022458A CN 109310686 B CN109310686 B CN 109310686B
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- Prior art keywords
- acid
- compound
- pharmaceutically acceptable
- methyl
- acceptable salt
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- 239000005557 antagonist Substances 0.000 title description 42
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- 101710098483 C5a anaphylatoxin chemotactic receptor 1 Proteins 0.000 title 1
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- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 102000005590 Anaphylatoxin C5a Receptor Human genes 0.000 claims abstract description 23
- 108010059426 Anaphylatoxin C5a Receptor Proteins 0.000 claims abstract description 23
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 30
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- 238000011282 treatment Methods 0.000 claims description 20
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- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
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- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 claims description 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
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Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
Description
相关申请的交叉引用
本申请是根据35 U.S.C.§119(e)要求2016年4月4日提交的美国临时申请 No.62/317,721的优先权,该申请通过引用整体并入本文。
关于对联邦政府资助的研究和开发的发明权利的声明
不适用。
提交在压缩磁盘上的“序列表”,“表格”或“计算机程序列表附录” 不适用。
背景技术
基于非肽的C5a受体拮抗剂已在文献中有描述(例如,Sumichika,H.等,J.Biol.Chem.(2002),277,49403-49407),并且据报道它可有效治疗大鼠的内毒素休 克(Stracham,A.J.等,J.of Immunol.(2000),164(12):6560-6565);在大鼠模型中用于 治疗IBD(Woodruff,T.M.等,J.of Immunol.,2003,171:5514-5520)。基于非肽的 C5a受体调节剂也已在Neurogen公司的专利文献(例如,WO 2004/043925,WO 2004/018460,WO 2005/007087,WO 03/082826,WO 03/08828,WO 02/49993, WO 03/084524);Dompe S.P.A.的专利文献(WO 02/029187);昆士兰大学的专利 文献(WO 2004/100975);和ChemoCentryx公司的专利文献(WO2010/075257和 WO2011/163640)中描述。
在文献中有相当多的实验证据表明C5a水平的增加与许多疾病和病症有关, 特别是在自身免疫和炎性疾病和病症。本领域需要新的小有机分子调节剂,例如 C5a受体(C5aR)的激动剂、部分激动剂和拮抗剂(优选),其可用于抑制与过敏毒素 活性水平升高相关的致病事件,例如趋化作用。
尽管如WO2010/075257和WO2011/163640中所述可获得C5aR拮抗剂化合 物,仍然需要具有溶解度曲线改善的相关化合物,其可以配制成适于静脉内递送 方式并且还提供了类似于WO2010/075257和WO2011/163640中的化合物的治疗 益处。
发明内容
在一个方面,本文提供了具有式(I)的化合物:
或其药学上可接受的盐,其中:
R1选自H、-O-CH2-O-P(O)ORaORb、-OC(O)-C1-6亚烷基-L2-X1、O-P(O)ORaORb、 和-OC(O)-A1-(C1-3亚烷基)n-C4-7杂环基,其中C4-7杂环基任选被1至6个Rc基团 取代;
A1选自C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,它们各自任选 被1至5个相同或不同的Rx取代;
n为0或1;
L2选自键、-O-C(O)-C1-6亚烷基-和-NRd-C(O)-C1-6亚烷基-;
X1独立地选自-NReRf、-P(O)ORaORb、-O-P(O)ORaORb和-CO2H;
R2选自H、-L3-C1-6亚烷基-L4-X2、-L3-(C1-6亚烷基)m-A2-X2、 -P(O)ORaOC(O)-C1-6烷基、-P(O)ORaNRgNRh和-P(O)ORaORb;
L3独立地选自-C(O)-O-和-C(O)-;
L4独立地选自键、-OC(O)-C2-6亚烯基-、-O-C(O)-C1-6亚烷基-和-NRd-C(O)-C1-6亚烷基-,其中-NRd-C(O)-C1-6亚烷基-和-OC(O)-C1-6亚烷基中的C1-6亚烷基任选被 NReRf取代;
X2独立地选自-NRkR1、-P(O)ORaORb、-O-P(O)ORaORb和-CO2H;
m为0或1;
A2选自C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,它们各自任选 被1至5个可以相同或不同Rx取代;
R3为H或-L5-P(O)ORaORb,其中L5独立地选自键和-CH2-O-;
每个Rx独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、CN、NRyRz、 SRy和ORy;
每个Rc独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、CN、NRyRz、 SRy和ORy;
每个Ra、Rb、Rd、Re、Rf、Rg、Rk、R1、Ry和Rz独立地选自H和C1-6烷基;
每个Rh独立地选自H和C1-6烷基,其中C1-6烷基任选被1-5个取代基取代, 所述取代基独立地选自CO2H、NRiRj、C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,其中每个Ri和Rj独立地为H或C1-6烷基;以及
其中R1、R2和R3中的两个是H,并且R1、R2和R3中的一个不是H。
除了本文提供的化合物,本发明还提供了含有一种或多种这些化合物的药物 组合物,以及这些化合物在治疗方法中的用途,主要用于治疗与C5a信号传导活 性有关的疾病。
附图的简要说明
图1是显示活性化合物1.543(来自WO2011/163640)从实施例22的化合物 (0.5mg/kg摩尔当量,AUC=137ng.hr/mL)中释放的图。
图2是显示活性化合物1.172(来自WO2010/075257)从实施例11的化合物 (0.5mg/kg摩尔当量,AUC=108ng.hr/mL)中释放的图。
具体实施方式
I.缩写和定义
如本文使用的术语“一个”、“一种”或“该”不仅包括具有一个成员的方 面,而且还包括具有多个成员的方面。例如,除非上下文另有明确规定,单数形 式“一个”、“一种”和“该”包括复数指示物。因此,例如,提及“一种细胞” 包括多个这样的细胞,并且提及“该药剂”包括本领域技术人员已知的一种或多 种药剂等。
术语“约”和“大约”通常是指考虑到测量的性质或精度,所测量的量的可 接受程度的误差。典型的,示例的误差程度在给定值或值范围的20%以内,优选 10%以内,更优选在5%以内。或者,特别是在生物***中,术语“约”和“大约” 可以表示在一个数量级内的数值,优选在给定值的5倍以内,更优选在给定值的 2倍以内。除非另有说明,此处给出的数值量是近似值,这意味着当没有明确说 明时可以推断术语“约”或“大约”。
除非另有说明,术语“烷基”本身或作为另一取代基的一部分,是指具有指 定碳原子数的直链或支链烃基(即C1-8表示一至八个碳)。烷基的实例包括甲基、 乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、 正庚基、正辛基等。在最广泛的意义上,术语“烷基”也意味着包括那些不饱和 基团,如烯基和炔基。术语“烯基”是指具有一个或多个双键的不饱和烷基。类 似地,术语“炔基”是指具有一个或多个三键的不饱和烷基。这种不饱和烷基的 实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、 3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基以及高级同系物和异构体。 术语“环烷基”是指具有指定数目的环原子(例如,C3-6环烷基)并且在环顶点之间 完全饱和或具有不超过一个双键的烃环。“环烷基”还意指双环和多环烃环,例 如,双环[2.2.1]庚烷、双环[2.2.2]辛烷等。术语“杂环烷基”或“杂环基”是指含 有一个至五个选自N、O和S的杂原子作为环顶的环烷基,其中,氮和硫原子任 选地被氧化,并且氮原子是任选地被季铵化。杂环烷基可以是单环、双环或多环 环系。杂环烷基的非限制性实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内 酰胺、咪唑烷酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二氧六环、 吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶 酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以 通过环碳或杂原子与分子的其余部分连接。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团, 例如-CH2CH2CH2CH2-。通常,烷基(或亚烷基)具有1至24个碳原子,本发明优选 具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链的 烷基或亚烷基,通常具有四个或更少的碳原子。类似地,“亚烯基”和“亚炔基” 分别指具有双键或三键的不饱和形式的“亚烷基”。
除非另有说明,术语“杂烷基”本身或与另一术语组合是指稳定的直链或支 链,或环烃基,或其组合,由所述碳原子数和一至三个选自O、N、Si和S的杂 原子组成,并且其中氮和硫原子可任选地被氧化,氮杂原子可任选地被季铵化。 杂原子O、N和S可以位于杂烷基的任何内部位置。杂原子Si可以位于杂烷基的 任何位置,包括烷基与分子其余部分连接的位置。实例包括-CH2-CH2-O-CH3、 -CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、 -S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、 -CH=CH-N(CH3)-CH3。最多两个杂原子可以是连续的,例如-CH2-NH-OCH3和 -CH2-O-Si(CH3)3。类似地,除非另有说明,术语“杂烯基”和“杂炔基”本身或 与另一术语组合分别表示含有所述碳原子数且具有一至三个选自O、N、Si和S 的杂原子的烯基或炔基,其中氮和硫原子可任选被氧化,氮杂原子可任选被季铵 化。杂原子O、N和S可以位于杂烷基的任何内部位置。
术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的饱和 或不饱和或多不饱和的二价基团,例如-CH2-CH2-S-CH2CH2-和 -CH2-S-CH2-CH2-NH-CH2-、-O-CH2-CH=CH-、-CH2-CH=C(H)CH2-O-CH2-和 -S-CH2-C≡C-。对于杂亚烷基,杂原子还可以占据链的任一个或两个末端(例如, 亚烷氧基、亚烷二氧基、亚烷基氨基、亚烷基二氨基等)。
术语“烷氧基”、“烷基氨基”和“烷硫基”(或硫代烷氧基)以其常规意义使 用,并且是指分别通过氧原子、氨基或硫原子与分子的其余部分连接的那些烷基。 另外,对于二烷基氨基,烷基部分可以是相同的或不同的,也可以与各自连接的 氮原子结合形成3-7元环。因此,表示为-NRa Rb的基团意在包括哌啶基、吡咯烷 基、吗啉基、氮杂环丁基等。
除非另有说明,术语“卤代”或“卤素”本身或作为另一取代基的一部分是 指氟、氯、溴或碘原子。另外,诸如“卤代烷基”的术语意在包括单卤代烷基和 多卤代烷基。例如,术语“C1-4卤代烷基”是指包括三氟甲基、2,2,2-三氟乙基、 4-氯丁基、3-溴丙基等。
除非另有说明,术语“芳基”是指多不饱和的、通常为芳族的烃基,其可以 是单环或多环(最多三个环),其稠合在一起或共价连接。术语“杂芳基”是指含有 一至五个选自N、O和S的杂原子的芳基(或环),其中氮和硫原子任选被氧化,并 且氮原子任选被季铵化。杂芳基可以通过杂原子与分子的其余部分连接。芳基的 非限制性实例包括苯基、萘基和联苯基,而杂芳基的非限制性实例包括吡啶基、 哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞 嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并***基、苯并异噁 唑基、异苯并呋喃基、异吲哚基、中氮茚基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、苯并噻唑基、苯并呋喃基、苯并噻吩 基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、 ***基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻 吩基等。上述每个芳基和杂芳基环***的取代基选自下述可接受的取代基。
为简洁起见,术语“芳基”,当与其他术语(例如芳氧基,芳硫基氧基,芳基 烷基)组合使用时,包括如上定义的芳基和杂芳基环。因此,术语“芳基烷基”意 指包括其中芳基与烷基连接的那些基团(例如苄基,苯乙基,吡啶基甲基等)。
在一些实施方案中,上述术语(例如,“烷基”、“芳基”和“杂芳基”)将包 括所示基团的取代和未取代形式。下面提供了每种类型基团的优选取代基。为简 洁起见,术语芳基和杂芳基是指如下提供的取代或未取代的形式,而除非指明被 取代,术语“烷基”和相关的脂族基团是指未取代的形式。
烷基的取代基(包括通常称为亚烷基、烯基、炔基和环烷基的那些基团)可以是 选自以下的各种基团:-卤素、-OR'、-NR'R”、-SR'、-SiR'R”R'”、-OC(O)R'、-C(O)R'、 -CO2R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)2R'、 -NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、 -S(O)2NR'R”、-NR'S(O)2R”、-CN和-NO2,数量范围从零到(2m'+1),其中m'是这 种基团中碳原子的总数。R'、R”和R”'各自独立地表示氢、未取代的C1-8烷基、未 取代的杂烷基、未取代的芳基、被1-3个卤素取代的芳基、未取代的C1-8烷基、 C1-8烷氧基或C1-8硫代烷氧基、或未取代的芳基-C1-4烷基。当R'和R”与相同的氮 原子连接时,它们可与氮原子结合形成3-、4-、5-、6-或7-元环。例如,-NR'R” 意指包括1-吡咯烷基和4-吗啉基。术语“酰基”本身或作为另一基团的一部分是 指烷基,其中最接近连接点的碳上的两个取代基被取代基=O取代(例如, -C(O)CH3,-C(O)CH2CH2OR'等。
类似地,芳基和杂芳基的取代基是变化的,通常选自:-卤素、-OR'、-OC(O)R'、 -NR'R”、-SR'、-R'、-CN、-NO2、-CO2R'、-CORR'R”、-C(O)R'、-OC(O)NR'R”、 -NR”C(O)R'、-NR”C(O)2R'、-NR'-C(O)NR”R”'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、 -NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R”、-NR'S(O)2R”、-N3、全氟(C1-C4) 烷氧基和全氟(C1-C4)烷基,数量范围从零到芳环***上的开放化合价总数;其中 R',R”和R”'独立地选自氢、C1-8烷基、C3-6环烷基、C2-8烯基、C2-8炔基、未取代 的芳基和杂芳基、(未取代的芳基)-C1-4烷基和未取代的芳氧基-C1-4烷基。其它合 适的取代基包括通过1-4个碳原子的亚烷基系连接环原子的上述芳基的每个取代 基。
芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-取代基取代,其中T和U独立地为-NH-、-O-、-CH2-或单键,q是0-2的整数。 或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-Rb-取 代基取代,其中A和B独立地是-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2 NR'-或单键,r是1至3的整数。如此形成的新环的单键之一可任选地用双键代替。 或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t- 取代基取代,其中s和t独立地为0至3的整数,X是-O-、-NR'-、-S-、-S(O)-、 -S(O)2-或-S(O)2NR'-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”意指包括氧(O)、氮(N)、硫(S)和硅(Si)。
术语“药学上可接受的盐”意指包括用相对无毒的酸或碱制备的活性化合物 的盐,这取决于本文所述化合物上发现的特定取代基。当本发明的化合物含有相 对酸性的官能团时,碱加成盐可以通过将中性形式的这些化合物与足量的所需碱 (无溶剂的或在合适的惰性溶剂中)接触而获得。衍生自药学上可接受的无机碱的盐 的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰、亚锰、钾、钠、锌等。衍 生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,包括取代的胺、环 胺、天然存在的胺等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、 二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N- 乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴明、异丙胺、赖氨酸、甲葡糖胺、 吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三 丙胺、氨丁三醇等。当本发明的化合物含有相对碱性的官能团时,酸加成盐可以 通过将中性形式的这些化合物与足量的所需酸(无溶剂的或在合适的惰性溶剂中) 接触而获得。药学上可接受的酸加成盐的实例包括衍生自无机酸的那些,如盐酸、 氢溴酸、硝酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷酸、硫酸、单氢硫酸、 氢碘酸或亚磷酸等,以及衍生自相对无毒的有机酸的盐,如乙酸、丙酸、异丁酸、 丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸的盐,如精氨酸盐等,以 及有机酸的盐,如葡糖醛酸或半乳糖醛酸等(参见,例如,Berge,S.M.等,“药用 盐”,药学杂志,1977,66,1-19)。本发明的某些具体化合物含有碱性和酸性官能团, 其允许化合物转化成碱或酸加成盐。本发明某些具体化合物包含多于一个酸性官 能度或多于一个碱性官能度。在那些情况下,术语“或其药学上可接受的盐”意 指包括多盐化合物,例如二钠盐,二盐酸盐。
通过使盐与碱或酸接触并以常规方式分离母体化合物,可以再生化合物的中 性形式。该化合物的母体形式在某些物理性质上不同于各种盐形式,例如在极性 溶剂中的溶解度,但是为了本发明目的,盐与化合物的母体形式等同。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水化形式。 溶剂化形式通常与非溶剂化形式等同,应包括在本发明范围内。本发明的某些化 合物可以多晶型或无定形形式存在。通常,就本发明所考虑的应用而言,所有物 理形式是等同的,应包括在本发明范围内。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明 范围内。当显示有立体化学描述(例如,虚线或楔形键)时,其意指其中存在一种异 构体并且基本上不含另一种异构体的化合物。“基本上不含”另一种异构体表示 两种异构体的比例至少为80/20,更优选为90/10,或95/5或更高。在一些实施方 案中,异构体之一的存在量为至少99%。
本发明的化合物还可以在构成这些化合物的一个或多个原子上含有非天然比 例的原子同位素。例如,化合物可以用放射性同位素放射性标记,例如氚(3H),碘 -125(125I)或碳-14(14C)。无论是否具有放射性,本公开化合物的所有同位素变体都 包括在本发明的范围内。例如,可以制备化合物,使得任何数量的氢原子被氘(2H) 同位素取代。本发明的化合物还可以在构成这些化合物的一个或多个原子上含有 非天然比例的原子同位素。非天然比例的同位素可以定义为从自然界中发现的量 到由所讨论的原子的100%组成的量。例如,化合物可以掺入放射性同位素,例如 氚(3H),碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。 这种同位素变体可以为本申请中其他地方描述的那些提供额外的用途。例如,本 公开化合物的同位素变体可以发现另外的用途,包括但不限于,作为诊断和/或成 像试剂,或作为细胞毒性/放射性毒性治疗剂。另外,本公开化合物的同位素变体 可具有不同的药代动力学和药效学特征,其可有助于在治疗期间增强安全性、耐受性或功效。无论是否具有放射性,本公开化合物的所有同位素变体都包括在本 发明的范围内。
II.化合物
在一个方面,本发明提供了具有式(I)的化合物:
或其药学上可接受的盐,其中:
R1选自H、-O-CH2-OP(O)ORaORb、-OC(O)-C1-6亚烷基-L2-X1、O-P(O)ORaORb、 和-OC(O)-A1-(C1-3亚烷基)n-C4-7杂环基,其中C4-7杂环基任选被1至6个Rc基团 取代;
A1选自C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,它们各自任选 被1至5个可以相同或不同的Rx取代;
n为0或1;
L2选自键、-O-C(O)-C1-6亚烷基-和-NRd-C(O)-C1-6亚烷基-;
X1独立地选自-NReRf、-P(O)ORaORb、-OP(O)ORaORb和-CO2H;
R2选自H、-L3-C1-6亚烷基-L4-X2、-L3-(C1-6亚烷基)m-A2-X2、 -P(O)ORaOC(O)-C1-6烷基、-P(O)ORaNRgRh和-P(O)ORaRb;
L3独立地选自-C(O)-O-和-C(O)-;
L4独立地选自键、-OC(O)-C2-6亚烯基-、-O-C(O)-C1-6亚烷基-和-NRd-C(O)-C1-6亚烷基-,其中,-NRd-C(O)-C1-6亚烷基-和-OC(O)-C1-6亚烷基中的C1-6亚烷基可任 选地被NReRf取代;
X2独立地选自-NRkR1、-P(O)ORaORb、-O-P(O)ORaORb和-CO2H;
m为0或1;
A2选自C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,它们各自任选 被1至5个可以相同或不同的Rx取代;
R3为H或-L5-P(O)ORaORb,其中L5独立地选自键和-CH2-O-;
每个Rx独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、CN、NRyRz、 SRy和ORy;
每个Rc独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、CN、NRyRz、 SRy和ORy;
每个Ra、Rb、Rd、Re、Rf、Rg、Rk、R1、Ry和Rz独立地选自H和C1-6烷基;
每个Rh独立地选自H和C1-6烷基,其中C1-6烷基任选被1-5个取代基取代, 所述取代基独立地选自CO2H、NR Rj、C6-10芳基、C3-10环烷基、C5-10杂芳基和C5-10杂环基,其中每个Ri和Rj独立地为H或C1-6烷基;以及
其中R1、R2和R3中的两个是H,并且R1、R2和R3中的一个不是H。
在一组实施方案中,提供了式(I)化合物或其药学上可接受的盐,其中R1选自 O-(CO)-C1-6亚烷基-NReRf、O-(CO)-C1-6亚烷基-NRd(CO)-C1-6亚烷基-NReRf、 O-P(O)ORaORb、O-CH2-O-P(O)ORaORb和O-(CO)-C6-10亚芳基-C1-3亚烷基-C4-7杂 环基,其中C4-7杂环基选自哌啶基、哌嗪基、吡咯烷基、吗啉基和氮杂环丁基, 并且其中哌啶基、哌嗪基、吡咯烷基、吗啉基和氮杂环丁基任选被1至6个Rc基 团取代。
在另一组实施方案中,提供了式(I)化合物或其药学上可接受的盐,其中R1选 自:
在其他实施方案中,提供了式(I)化合物或其药学上可接受的盐,其中R3选自 -CH2-O-P(O)ORaORb和-P(O)ORaORb。
在其他实施方案中,提供了式(I)化合物或其药学上可接受的盐,其中R2选自 -(CO)-C1-6亚烷基-NRkR1、-(CO)-O-C1-6亚烷基-OP(O)ORaORb、-P(O)ORaO(CO)-C1-6烷基、-P(O)ORaNRgRh、-(CO)-O-C1-6亚烷基-O-(CO)-C2-6亚烯基-CO2H、-(CO)-C1-6亚烷基-NRd(CO)-C1-6-亚烷基-NRkR1,其中C1-6亚烷基-NRkR1可任选地被NReRf、 -(CO)-O-C1-6亚烷基-O-(CO)-C1-6亚烷基-NRkR1和-(CO)-O-C1-6亚烷基-C6-10芳基 -O-P(O)ORaORb取代,其中C6-10芳基任选被1至5个可以相同或不同的Rx取代。
在某些选定的实施方案中,R2选自:
在选定的实施方案中,提供了选自下组的化合物:
或其药学上可接受的盐。
除了上面提供的化合物外,还提供了那些化合物的药学上可接受的盐。在一 些实施方案中,药学上可接受的盐选自铵、钙、镁、钾、钠、锌、精氨酸、甜菜 碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基 氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组 氨酸、海巴明、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、普鲁卡因、嘌 呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇、盐酸、碳酸、单氢碳酸、磷 酸、单氢磷酸、二氢磷酸、乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛 二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、 甲磺酸、精氨酸、葡萄糖醛酸和半乳糖酸。在一些实施方案中,药学上可接受的 盐选自铵、钙、镁、钾、钠、盐酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷 酸、乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、 邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、精氨酸、葡糖醛 酸和半乳糖醛酸。在一些实施方案中,药学上可接受的盐是钠盐或盐酸盐。
III.药物组合物
除了上面提供的化合物之外,用于调节人和动物中C5aR活性的组合物通常 含有药物载体或稀释剂。
如本文所用,术语“组合物”旨在涵盖包含特定量的特定成分的产品,以及 直接或间接由特定量的特定成分的组合产生的任何产品。“药学上可接受的”是 指载体、稀释剂或赋形剂必须与制剂的其他成分相容并且对其接受者无害。
用于施用本公开化合物的药物组合物可以方便地以单位剂型存在,并且可以 通过药学和药物递送领域中熟知的任何方法制备。所有方法包括使活性成分与构 成一种或多种辅助成分的载体结合的步骤。通常,药物组合物通过将活性成分与 液体载体或细碎的固体载体或两者均匀且紧密地结合在一起制备,然后,如果需 要,将产品成型为所需的制剂。在药物组合物中,活性目标化合物的含量足以对 疾病的过程或病症产生所需的效果。
含有活性成分的药物组合物可以是适于口服使用的形式,例如如美国专利申 请2002-0012680中所述的片剂、锭剂、含片、水性或油性悬浮液、可分散的粉末 或颗粒、乳液和自乳化剂,硬或软胶囊,糖浆,酏剂,溶液,口腔贴剂,口服凝 胶,口香糖,咀嚼片,泡腾粉和泡腾片。用于口服的组合物可以根据本领域已知 的任何制备药物组合物的方法制备,并且这种组合物可以含有一种或多种选自甜 味剂、调味剂、着色剂、抗氧化剂和防腐剂的试剂,以提供药学上精致和可口的 制剂。片剂含有活性成分与适合制备片剂的无毒的药学上可接受的赋形剂的混合 物。这些赋形剂可以是,例如,惰性稀释剂,如纤维素、二氧化硅、氧化铝、碳 酸钙、碳酸钠、葡萄糖、甘露醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;制粒和崩 解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP,纤维素,PEG,淀粉,明胶 或***胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的, 或者可以通过已知技术以包衣、肠溶或其他方式,以延迟在胃肠道中的崩解和吸 收,从而提供更长时间的持续作用。例如,可以使用延时材料,例如单硬脂酸甘 油酯或二硬脂酸甘油酯。它们也可以通过美国专利号4,256,108、4,166,452和 4,265,874中描述的技术进行包衣,以形成用于控制释放的渗透性治疗片剂。
口服使用的制剂也可以作为硬明胶胶囊提供,其中活性成分与惰性固体稀释 剂(例如碳酸钙、磷酸钙或高岭土、各种平均大小的聚乙二醇(PEG),例如PEG400、 PEG4000)和某些表面活性剂(如氢化蓖麻油或聚乙二醇硬脂酸酯(solutol))混合,或 作为软明胶胶囊提供,其中活性成分与水或油介质(例如花生油,液体石蜡或橄榄 油)混合。另外,乳液可以用非水混溶性成分如油制备,并用表面活性剂,如甘油 单酯或甘油二酯、PEG酯等来稳定。
水性悬浮液含有与适于制备水性悬浮液的赋形剂混合的活性物质。这些赋形 剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、 聚乙烯吡咯烷酮、黄蓍胶和***树胶;分散剂或润湿剂可以是天然存在的磷脂 (例如卵磷脂),或环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),或环氧乙 烷与长链脂族醇的缩合产物(例如十七烷乙氧基十六烷醇),或环氧乙烷与衍生自脂 肪酸和己糖醇的偏酯的缩合产物(如聚氧乙烯山梨糖醇单油酸酯),或环氧乙烷与衍 生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚乙烯脱水山梨糖醇单油酸酯)。水 性悬浮液还可含有一种或多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正 丙酯)、一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂,例如蔗糖或 糖精。
油性悬浮液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油 或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可含有增稠剂(例如蜂 蜡、硬石蜡或鲸蜡醇)。可加入如上所述的甜味剂和调味剂以提供适口的口服制剂。 这些组合物可以通过加入抗氧化剂如抗坏血酸来保存。
适于通过加入水制备水性悬浮液的可分散粉末和颗粒提供活性成分与分散剂 或润湿剂、悬浮剂和一种或多种防腐剂的混合物。合适的分散剂或润湿剂和悬浮 剂的例子如上所述。还可以存在另外的赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物还可以是水包油乳液的形式。油相可以是植物油,例如 橄榄油或花生油,或矿物油,例如液体石蜡或这些的混合物。合适的乳化剂可以 是天然存在的树胶,例如***树胶或黄蓍胶,天然存在的磷脂,例如大豆,卵 磷脂,以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯, 和所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液 还可含有甜味剂和调味剂。
糖浆和酏剂可以用甜味剂,例如甘油、丙二醇、山梨糖醇或蔗糖配制。此类 制剂还可含有缓和剂、防腐剂和调味剂和着色剂。口服溶液可以与例如环糊精、 PEG和表面活性剂组合制备。
药物组合物可以是无菌可注射水性或油性悬浮液的形式。该悬浮液可以根据 已知技术使用上面提到的那些合适的分散剂或润湿剂和悬浮剂配制。无菌可注射 制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮 液,例如在1,3-丁二醇中的溶液。可以使用的可接受的载体和溶剂包括水、林格 氏溶液和等渗氯化钠溶液。另外,无菌的固定油通常用作溶剂或悬浮介质。为此 目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,脂 肪酸,如油酸可用于制备注射剂。
本发明化合物还可以以栓剂的形式施用,用于直肠给药。这些组合物可以通 过将药物与合适的无刺激性赋形剂混合来制备,所述赋形剂在常温下是固体但在 直肠温度下是液体,因此在直肠中融化以释放药物。这些材料包括可可脂和聚乙 二醇。另外,化合物可以通过溶液或软膏通过眼部递送给药。此外,本发明化合 物的透皮递送可以通过离子电渗疗法贴剂等实现。对于局部使用,使用含有本公 开化合物的霜剂、软膏、凝胶、溶液或悬浮液等。如本文所用,局部施用还意在 包括使用漱口水和漱口剂。
本发明化合物还可以偶联到为作为靶向药物载体的合适聚合物的载体上。所 述聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺-苯酚、 聚羟基乙基-天冬酰胺-苯酚、或用棕榈酰残基取代的聚环氧乙烷-聚赖氨酸。此外, 本发明的化合物可以偶联到载体上,所述载体是用于实现药物的控制释放的一类 生物可降解聚合物,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε 己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝 胶的交联或两性嵌段共聚物。聚合物和半透性聚合物基质可以制成成形制品,例 如瓣膜、支架、管道、假体等。在本发明的一个实施例中,本发明化合物偶联到 形成为支架或支架植入物装置的聚合物或半透性聚合物基质上。
提供了包含本公开化合物或其药学上可接受的盐和药学上可接受的赋形剂的 药物组合物。
在一些实施方案中,药物组合物配制成用于静脉内给药。
在一些实施方案中,药物组合物包含一种或多种另外的治疗剂。
在一些实施方案中,所述一种或多种另外的治疗剂选自皮质类固醇、类固醇、 免疫抑制剂、免疫球蛋白G激动剂、二肽基肽酶IV抑制剂、淋巴细胞功能抗原-3 受体拮抗剂、白介素-2配体、白介素-1β受体注射剂、IL-2受体α亚基抑制剂、 HGF基因刺激物、IL-6拮抗剂、IL-5拮抗剂、α1抗胰蛋白酶刺激剂、***素受 体拮抗剂、组蛋白去乙酰化酶抑制剂、AKT蛋白激酶抑制剂、CD20抑制剂、Abl 酪氨酸激酶抑制剂、JAK酪氨酸激酶抑制剂、TNFα配体抑制剂、血红蛋白调节 剂、TNF拮抗剂、蛋白酶体抑制剂、CD3调节剂、Hsp70家族抑制剂、免疫球蛋 白激动剂、CD30拮抗剂、微管蛋白拮抗剂、鞘氨醇-1-磷酸受体-1激动剂、结缔 组织生长因子配体抑制剂、半胱天冬酶抑制剂、促肾上腺皮质激素配体、Btk酪氨 酸激酶抑制剂、补体C1s亚组分抑制剂、***受体激动剂、B-淋巴细 胞刺激物配体抑制剂、细胞周期蛋白依赖性激酶-2抑制剂、P-选择素糖蛋白配体 -1刺激剂、mTOR抑制剂、延长因子2抑制剂、细胞粘附分子抑制剂、因子XIII 激动剂、钙调神经磷酸酶抑制剂、免疫球蛋白G1激动剂、肌苷单磷酸脱氢酶抑制 剂、补体C1s亚组分抑制剂、胸苷激酶调节剂、细胞毒性T淋巴细胞蛋白-4调节 剂、血管紧张素II受体拮抗剂、血管紧张素II受体调节剂、TNF超家族受体12A 拮抗剂、CD52拮抗剂、腺苷脱氨酶抑制剂、T细胞分化抗原CD6抑制剂、FGF-7 配体、二氢乳清酸脱氢酶抑制剂、CCR5趋化因子拮抗剂、CCR2趋化因子拮抗剂、 Syk酪氨酸激酶抑制剂、干扰素I型受体拮抗剂、干扰素α配体抑制剂、巨噬细胞 移动抑制剂因子抑制剂、整合素α-V/β-6拮抗剂、半胱氨酸蛋白酶刺激剂、p38 MAP激酶抑制剂、TP53基因抑制剂、志贺(Shiga)样毒素I抑制剂、岩藻糖转移酶 6刺激剂、白介素22配体、CXCR1趋化因子拮抗剂、CXCR4趋化因子拮抗剂、 IRS1基因抑制剂、蛋白激酶C刺激剂、蛋白激酶Cα抑制剂、CD74拮抗剂、免 疫球蛋白γFc受体IIB拮抗剂、T细胞抗原CD7抑制剂、CD95拮抗剂、N乙酰 甘露糖胺激酶刺激剂、心肌营养素-1配体、白细胞弹性蛋白酶抑制剂、CD40配体 受体拮抗剂、CD40配体调节剂、IL-17拮抗剂、TLR-2拮抗剂、甘露聚糖结合凝 集素丝氨酸蛋白酶-2(MASP-2)抑制剂、因子B抑制剂、因子D抑制剂和T细胞受 体拮抗剂,及其组合。
在一些实施方案中,所述一种或多种另外的治疗剂选自CTLA-4(CD152)、 PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、 BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、 A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)的 抑制剂,以及OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂。
在一些实施方案中,一种或多种另外的治疗剂选自CCR1、CCR2、CCR3、 CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、 CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1和ChemR23的调节剂。
在一些实施方案中,一种或多种另外的治疗剂选自皮质类固醇、类固醇、 CD20抑制剂和免疫抑制剂。在一些实施方案中,一种或多种另外的治疗剂是免疫 抑制剂。在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇。 在一些实施方案中,一种或多种另外的治疗剂是CD20抑制剂。在一些实施方案 中,一种或多种另外的治疗剂是皮质类固醇或类固醇和免疫抑制剂或CD20抑制 剂。在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇和免疫 抑制剂。在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇和 CD20抑制剂。
在一些实施方案中,所述一种或多种另外的治疗剂选自:奥滨尤妥珠单抗(obinutuzumab)、利妥昔单抗、欧克雷立珠单抗(ocrelizumab)、环磷酰胺、***、 氢化可的松、醋酸氢化可的松、醋酸可的松、新戊酸替可的松、强的松龙、甲基 强的松龙、曲安奈德、曲安奈德醇、莫米松、安西奈德、布***、***、氟 轻松、醋酸氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、***、地塞米 松磷酸钠、氟可龙、氢化可的松-17-戊酸酯、卤米松、二丙酸阿氯米松、倍氯米松、 倍他米松戊酸酯、倍他米松二丙酸酯、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍他索 -17-丙酸酯、氟可龙己酸酯、氟可龙新戊酸酯、氟泼尼定乙酸酯、氢化可的松-17- 丁酸酯、氢化可的松-17-乙丙酸酯、氢化可的松-17-丁烯酸酯、环索奈德、泼尼卡 酯、GB-0998、衣麦格抗体(immuglo)、倍格罗单抗(begelomab)、阿来塞普(alefacept)、 阿地白介素、格瓦珠单抗(gevokizumab)、达利珠单抗、巴利昔单抗、伊诺莫单抗、 倍普米诺基因质粒(beperminogene perplasmid)、司如库单抗(sirukumab)、托珠单抗、 克拉扎单抗(clazakizumab)、美泊利单抗、芬戈莫德(fingolimod)、帕比司他、曲西 立滨、尼洛替尼、伊马替尼、托法替尼、莫美替尼(momelotinib)、培西替尼 (peficitinib)、伊他替尼(itacitinib)、英夫利昔单抗、PEG-bHb-CO、依那西普 (etanercept)、伊克昔佐米、硼替佐米、莫罗单抗、奥立昔单抗(otelixizumab)、胍立 莫司(gusperinmus)、维本妥昔单抗(brentuximab vedotin)、泼尼司莫(Ponesimod)、 KRP-203、FG-3019、恩利卡生、促肾上腺皮质激素、依鲁替尼、辛吕泽(cinryze)、 康萘司他(conestat)、甲氧基聚乙二醇-依泊亭β、贝利木单抗、比利司莫 (blisibimod)、阿塞西普、赛立西立(seliciclib)、内胡立珠单抗(neihulizumab)、依维 莫司、西罗莫司、地尼白介素-白喉毒素融合蛋白(denileukindiftitox)、LMB-2、那 他珠单抗、卡曲得考(catridecacog)、环孢素、他克莫司、瓦克孢菌素(voclosporin)、 瓦克孢菌素、康纳单抗、麦考酚酯、咪唑立宾、CE-1145、TK-DLI、阿巴西普、贝拉西普、奥美沙坦酯、司巴森坦(sparsentan)、TXA-127、BIIB-023、阿仑单抗、 喷司他丁、伊妥立珠单抗(itolizumab)、帕利夫明、来氟米特、PRO-140、塞尼克 立瓦洛克(cenicriviroc)、氟司塔替尼(fostamatinib)、安尼鲁单抗(anifrolumab)、司伐 立单抗(sifalimumab)、BAX-069、BG-00011、罗斯麻匹莫德(losmapimod)、QPI-1002、 志贺单抗(Shigam Ab)、TZ-101、F-652、雷帕瑞辛(reparixin)、拉达瑞辛(ladarixin)、 PTX-9908、阿加尼尔森(aganirsen)、APH-703、索塔司塔瑞(sotrastaurin)、索塔司 塔瑞、米拉珠单抗(milatuzumab)、SM-101、T-Guard、APG-101、DEX-M74、心肌 营养素-1、替匹抑素(tiprelestat)、ASKP-1240、BMS-986004、HPH-116、KD-025、 OPN-305、TOL-101、去纤苷酸(defibrotide)、泊马度胺、胸腺球蛋白、拉喹莫德、 雷美司特西尔-L(remestemcel-L)、马类抗胸腺细胞免疫球蛋白、司特姆培西尔 (Stempeucel)、LIV-γ、奥克塔干(Octagam)10%、t2c-001、99mTc-赛司他米比 (sestamibi)、克莱依格(Clairyg)、普洛索巴(Prosorba)、泊马度胺、拉喹莫德、特普 立珠单抗(teplizumab)、FCRx、索那替德(solnatide)、弗拉单抗(foralumab)、 ATIR-101、BPX-501、ACP-01、ALLO-ASC-DFU、厄贝沙坦+丙帕锗、ApoCell、 ***二酚、RGI-2001、乳清酸(saratin)、抗CD3二价抗体-白喉毒素偶连物、NOX-100 和LT-1951。
在一些实施方案中,所述一种或多种另外的治疗剂选自OMS721、ALN-CC5、 ACH-4471、AMY-101、Acthar凝胶、CCX354、CCX9588、CCX140、CCX872、 CCX598、CCX6239、CCX9664、CCX2553、CCX 2991、CCX282、CCX025、CCX507、 CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、派姆单抗、纳武单 抗、IBI-308、mDX-400、BGB-108、MEDI-0680、SHR-1210、PF-06801591、PDR-001、 GB-226、STI-1110、度伐鲁单抗、阿特朱单抗、阿立库单抗(avelumab)、BMS-936559、ALN-PDL、TSR-042、KD-033、CA-170、STI-1014、KY-1003、CA-327 和CD4+CD25+调节T细胞及其组合。
在一些实施方案中,所述一种或多种另外的治疗剂选自下组:奥滨尤妥珠单 抗(obinutuzumab)、利妥昔单抗、欧克雷立珠单抗(ocrelizumab)、环磷酰胺、泼尼 松、氢化可的松、醋酸氢化可的松、醋酸可的松、新戊酸替可的松、强的松龙、 甲基强的松龙、曲安奈德、曲安奈德醇、莫米松、安西奈德、布***、***、 氟轻松、醋酸氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、***、地塞 米松磷酸钠、氟可龙、氢化可的松-17-戊酸酯、卤米松、二丙酸阿氯米松、倍氯米 松、倍他米松戊酸酯、倍他米松二丙酸酯、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍 他索-17-丙酸酯、氟可龙己酸酯、氟可龙新戊酸酯、氟泼尼定乙酸酯、氢化可的松 -17-丁酸酯、氢化可的松-17-乙丙酸酯、氢化可的松-17-丁烯酸酯、环索奈德和泼 尼卡酯。
在一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗或环磷酰胺。在 一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗。在一些实施方案中, 一种或多种另外的治疗剂是环磷酰胺。在一些实施方案中,一种或多种另外的治 疗剂是***。在一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗或环 磷酰胺和***。
IV.治疗由C5A调节的疾病和病症的方法
本发明化合物可用于在体内产生活性代谢物,为C5a受体的激动剂、(优选) 拮抗剂、部分激动剂、反向激动剂。在一个实施方案中,本发明的化合物可用于 产生活性代谢物,为C5aR拮抗剂,以在体内抑制C5a受体配体(例如,C5a)与C5a 受体的结合。
优选地,由本发明化合物与受体接触产生的C5a受体调节剂的量应足以抑制 C5a与C5a受体的结合。
在另一实施方案中,本发明化合物还可用于治疗患有对C5a受体调节有响应 的病症的患者。如本文所用,术语“治疗”或“疗法”包括疾病改善治疗和对症 治疗两者,其中任一种都可以是预防性的(即,在症状发作之前,为了预防、延迟 或减轻症状的严重程度)或治疗性的(即,在症状出现后,为了减轻症状的严重程度 和/或持续时间)。如本文所用,如果C5a受体活性的调节导致C5a受体不适当激 活的减少,则认为病症是“对C5a受体调节有响应的”。如本文所用,术语“患 者”包括灵长类动物(尤其是人类)、驯养的伴侣动物(例如狗、猫、马等)和家畜(例 如牛、猪、绵羊等),剂量如本文所述。
可通过C5a调节治疗的病症:
自身免疫性疾病-例如,类风湿性关节炎、***性红斑狼疮、格林-巴利综合征、 胰腺炎、狼疮性肾炎、狼疮肾小球肾炎、牛皮癣、克罗恩病、血管炎、肠易激综 合征、皮肌炎、多发性硬化、支气管哮喘、天疱疮、类天疱疮、硬皮病、重症肌 无力、自身免疫性溶血和血小板减少状态、aHUS(非典型溶血性***综合征)、 古德巴氏德氏(Goodpasture)综合征(及相关的肾小球肾炎和肺出血)、免疫性血管 炎、组织移植物排斥反应、移植器官的超急性排斥反应等等。
炎症性疾病和相关疾病-例如,嗜中性白细胞减少症、败血症、脓毒性休克、 阿尔茨海默病、多发性硬化症、中风、炎症性肠病(IBD)、年龄相关性黄斑变性 (AMD、湿性和干性形式)、与重度烧伤相关的炎症、肺损伤、缺血-再灌注损伤、 骨关节炎、以及急性(成人)呼吸窘迫综合征(ARDS)、慢性肺阻塞性疾病(COPD)、 全身炎症反应综合征(SIRS)、特应性皮炎、牛皮癣、慢性荨麻疹和多器官功能障 碍综合征(MODS)。还包括与胰岛素依赖性糖尿病相关的病理性后遗症(包括糖尿 病性视网膜病变)、狼疮肾病、海曼(Heyman)肾炎、膜性肾炎和其他形式的肾小球 肾炎、IGA肾病、接触敏感性反应以及血液与可以引起补体活化的接触人工表面 引起的炎症,例如,在血液的体外循环期间(例如,在血液透析期间或通过心肺机, 例如与冠状动脉旁路移植术或心脏瓣膜置换术等血管手术相关),或者与其他人造血管或容器表面接触相关的炎症(例如,心室辅助装置、人造心脏机器、输血管、 血液储存袋、血浆去除术、血小板分离术等)。还包括与缺血/再灌注损伤相关的疾 病,例如由移植引起的疾病,包括实体器官移植,和诸如缺血性再灌注损伤、缺 血性结肠炎和心肌缺血的综合征。本发明化合物还可用于治疗年龄相关性黄斑变 性(Hageman等,P.N.A.S.102:7227-7232,2005)。
心血管和脑血管疾病-例如,心肌梗塞、冠状动脉血栓形成、血管闭塞、术后 血管再闭塞、动脉粥样硬化、创伤性中枢神经***损伤和缺血性心脏病。在一个 实施方案中,可将有效量的本发明化合物给予有心肌梗塞或血栓形成风险的患者 (即,具有一种或多种公认的心肌梗塞或血栓形成风险因子的患者,例如但不限于, 肥胖、吸烟、高血压、高胆固醇血症、心肌梗塞或血栓形成的既往史或遗传史), 以降低心肌梗塞或血栓形成的风险。
血管炎性疾病-血管炎性疾病的特征在于血管的炎症。白细胞的浸润导致血管 壁的破坏,并且认为补体途径在引发白细胞迁移以及在炎症部位表现的所造成的 损伤中起主要作用(血管炎(Vasculitis),第二版,由波尔和布瑞基编辑,牛津大学 出版社,第47-53页,2008)。本发明提供的化合物可用于治疗ANCA血管炎(抗 中性粒细胞胞浆自身抗体血管炎)。本发明提供的化合物可用于治疗白细胞性血管 炎、荨麻疹性血管炎、韦格纳肉芽肿病、显微镜下多血管炎、丘-施氏综合征 (Churg-Strauss syndrome)、亨-舍氏紫癜(Henoch-Schonlein purpura)、结节性多动脉 炎、快速进展肾小球肾炎(RPGN)、冷球蛋白血症、巨细胞动脉炎(GCA)、白塞氏 病和高安氏动脉炎(TAK)。
HIV感染和AIDS—本文提供的C5a受体调节剂可用于抑制HIV感染,延迟 AIDS进展或降低症状或HIV感染和AIDS的严重性。
神经变性疾病和相关疾病--在其他方面,本文提供的C5a拮抗剂可用于治疗 阿尔茨海默氏病、多发性硬化和与心肺分流手术和相关程序相关的认知功能衰退。
癌症-本文提供的C5a拮抗剂还可用于治疗受试者的癌症和癌前病症。可以 治疗的具体癌症包括但不限于黑素瘤、肺癌、淋巴瘤、肉瘤、癌和混合肿瘤。可 根据本发明内容治疗的示例性病症包括纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉 瘤、血管肉瘤、***肉瘤、滑膜瘤、间皮瘤、脑膜瘤、白血病、淋巴瘤、平滑 肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基底细胞癌、腺癌、***状癌、囊腺癌、支 气管癌、黑色素瘤、肾细胞癌、肝细胞癌、移行细胞癌、绒毛膜癌、***瘤、 胚胎癌、威尔姆氏肿瘤、多形性腺瘤、肝细胞***状瘤、肾小管腺瘤、囊腺瘤、 ***状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、***瘤、骨瘤、软骨瘤、脂 肪瘤和纤维瘤。在一些实施方案中、所述疾病或病症选自成胶质细胞瘤、食道瘤、 鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性淋巴瘤、原发性中枢神经***淋 巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、原发性纵隔大B细胞淋巴瘤、前 列腺癌、去势耐药性***癌、慢性髓细胞白血病、卡波西肉瘤纤维肉瘤、脂肪 肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、***肉瘤、滑膜瘤、脑膜瘤、平滑肌 肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、败血症、胆道肿瘤、基底细胞癌、胸腺 肿瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、肝脏感染、梅克尔(Merkel) 细胞癌、神经肿瘤、卵泡中心淋巴瘤、结肠癌、霍奇金氏疾病、非霍奇金淋巴瘤、 白血病、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓性白血病、急性淋 巴细胞白血病、慢性淋巴细胞白血病)、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常 综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳 腺癌、鳞状非小细胞肺癌(SCLC))、非鳞状NSCLC、结直肠癌、卵巢癌、胃癌、 肝细胞癌、胰腺癌、胰腺癌、胰腺导管腺癌、头颈部鳞状细胞癌、头颈癌、胃肠 道癌、胃癌、骨癌、皮肤癌、直肠癌、***癌、睾丸癌、输卵管癌、子宫内膜癌、 ***、***癌、外阴癌、食道癌、小肠癌、内分泌***癌、尿道癌、***癌、 膀胱癌、肾癌、输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、肿瘤血管生成、脊 髓轴(spinal axis)肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、石棉肺和癌。
在另一实施方案中,本发明化合物可用于治疗顺铂引起的肾毒性。在该实施 方案中,化合物治疗可以减轻由恶性肿瘤的顺铂化学疗法引起的肾毒性(Hao Pan 等,Am JPhysiol Renal Physiol,296,F496-504,2009)。
在本发明的一个实施方案中,本发明的化合物可用于治疗选自脓毒症(和相关 病症)、COPD、类风湿性关节炎、狼疮性肾炎和多发性硬化症的疾病。
本文提供了一种治疗患有或易患涉及C5a受体病理性活化的疾病或病症的人 的方法,包括给予哺乳动物治疗有效量的本发明化合物或其药物组合物。
本文提供了一种抑制C5a受体介导的细胞趋化性的方法,包括使哺乳动物白 细胞与C5a受体调节量的本发明化合物的活性代谢物接触。
在一些实施方案中,所述疾病或病症是炎性疾病或病症、心血管或脑血管病 症、自身免疫疾病或肿瘤疾病或病症。
在一些实施方案中,所述疾病或病症选自嗜中性白细胞减少症、中性白细胞 增多症、C3-肾小球病、C3-肾小球肾炎、致密性沉积病、膜增生性肾小球肾炎、 川崎病、败血症、败血性休克、溶血性***综合征、非典型溶血性***综合 征(aHUS)、阿尔茨海默病、多发性硬化症、中风、炎症性肠病、慢性阻塞性肺病、 烧伤引起的炎症、肺损伤、骨关节炎、特应性皮炎、慢性荨麻疹、缺血再灌注损 伤、急性呼吸窘迫综合征、全身炎症反应综合征、多器官功能障碍综合征、葡萄 膜炎、组织移植排斥反应、移植器官超急性排斥反应、心肌梗死、冠状动脉血栓 形成、血管闭塞、术后血管再闭塞、动脉粥样硬化、息肉状脉络膜血管病变、创 伤性中枢神经***损伤、缺血性心脏病、类风湿性关节炎、***性红斑狼疮、格 林-巴利综合征、胰腺炎、狼疮性肾炎、狼疮肾小球肾炎、牛皮癣、克罗恩病、血 管炎、ANCA血管炎、肠易激综合征、皮肌炎、多发性硬化、支气管哮喘、天疱 疮、类天疱疮、硬皮病、重症肌无力、自身免疫性溶血和血小板减少症、古德巴 氏德氏综合征、免疫性血管炎、移植物抗宿主病、阵发性睡眠性血红蛋白尿、休 格连氏(Sjoegrens)综合征、胰岛素依赖型糖尿病、糖尿病、狼疮性肾病、海曼肾炎、 膜性肾炎、肾小球肾炎、IGA肾病、膜增生性肾小球肾炎、抗磷脂综合征、年龄 相关性黄斑变性、干性年龄相关性黄斑变性、湿性年龄相关性黄斑变性、运动神 经元疾病、接触敏感性反应和血液与人工表面接触引起的炎症。
在一些实施方案中,所述疾病或病症选自嗜中性白细胞减少症、中性白细胞 增多症、C3-肾小球病、C3-肾小球肾炎、致密沉积病、膜增生性肾小球肾炎、川 崎病、溶血性***综合征、非典型溶血性***综合征(aHUS)、组织移植排斥 反应、移植器官超急性排斥反应、类风湿性关节炎、***性红斑狼疮、狼疮性肾 炎、狼疮肾小球肾炎、血管炎、ANCA血管炎、自身免疫性溶血和血小板减少症、 免疫性血管炎、移植物抗宿主病、狼疮肾病、海曼肾炎、膜性肾炎、肾小球肾炎、 IGA肾病、膜增生性和肾小球肾炎。
在一些实施方案中,所述疾病或病症选自黑素瘤、肺癌、淋巴瘤、肉瘤、癌、 纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、***肉瘤、滑膜瘤、 间皮瘤、脑膜瘤、白血病、淋巴瘤、平滑肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基 底细胞癌、腺癌、***状癌、囊腺癌、支气管肺癌、肾细胞癌、肝细胞癌、移行 细胞癌、绒毛膜癌、***瘤、胚胎癌、威尔姆氏瘤、多形性腺瘤、肝细胞乳 头状瘤、肾小管腺瘤、囊腺瘤、***状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、 ***瘤、骨瘤、软骨瘤、脂肪瘤和纤维瘤。在一些实施方案中,所述疾病或病症选自成胶质细胞瘤、食道瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性 淋巴瘤、原发性中枢神经***淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、 原发性纵隔大B细胞淋巴瘤、***癌、去势耐药性***癌、慢性髓细胞白血 病、卡波西肉瘤纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、*** 肉瘤、滑膜瘤、脑膜瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、败血症、 胆道肿瘤、基底细胞癌、胸腺肿瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、 肝脏感染、梅克尔细胞癌、神经肿瘤、卵泡中心淋巴瘤、结肠癌、霍奇金氏疾病、 非霍奇金淋巴瘤、白血病、慢性或急性白血病(包括急性骨髓性白血病、慢性骨髓 性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病)、多发性骨髓瘤、卵巢肿 瘤、骨髓增生异常综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、 肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SCLC))、非鳞状NSCLC、结直肠癌、 卵巢癌、胃癌、肝细胞癌、胰腺癌、胰腺癌、胰腺导管腺癌、头颈部鳞状细胞癌、 头颈癌、胃肠道癌、胃癌、骨癌、皮肤癌、直肠癌、***癌、睾丸癌、输卵管癌、 子宫内膜癌、***、***癌、外阴癌、食道癌、小肠癌、内分泌***癌、尿道 癌、***癌、肾癌、输尿管癌、癌肾盂、中枢神经***肿瘤(CNS)、肿瘤血管生成、 脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、石棉肺和癌。
在一些实施方案中,治疗方法还包括向人施用治疗有效量的一种或多种另外 的治疗剂。在一些实施方案中,所述一种或多种另外的治疗剂选自皮质类固醇、 类固醇、免疫抑制剂、免疫球蛋白G激动剂、二肽基肽酶IV抑制剂、淋巴细胞 功能抗原-3受体拮抗剂、白介素-2配体、白介素-1β受体注射剂、IL-2受体α亚 基抑制剂、HGF基因刺激物、IL-6拮抗剂、IL-5拮抗剂、α1抗胰蛋白酶刺激剂、 ***素受体拮抗剂、组蛋白去乙酰化酶抑制剂、AKT蛋白激酶抑制剂、CD20抑 制剂、Abl酪氨酸激酶抑制剂、JAK酪氨酸激酶抑制剂、TNFα配体抑制剂、血红 蛋白调节剂、TNF拮抗剂、蛋白酶体抑制剂、CD3调节剂、Hsp70家族抑制剂、 免疫球蛋白激动剂、CD30拮抗剂、微管蛋白拮抗剂、鞘氨醇-1-磷酸受体-1激动 剂、***生长因子配体抑制剂、半胱天冬酶抑制剂、促肾上腺皮质激素配体、 Btk酪氨酸激酶抑制剂、补体C1s亚组分抑制剂、***受体激动剂、 B-淋巴细胞刺激物配体抑制剂、细胞周期蛋白依赖性激酶-2抑制剂、P-选择素糖 蛋白配体-1刺激剂、mTOR抑制剂、延长因子2抑制剂、细胞粘附分子抑制剂、 因子XIII激动剂、钙调神经磷酸酶抑制剂、免疫球蛋白G1激动剂、肌苷单磷酸 脱氢酶抑制剂、补体C1s亚组分抑制剂、胸苷激酶调节剂、细胞毒性T淋巴细胞 蛋白-4调节剂、血管紧张素II受体拮抗剂、血管紧张素II受体调节剂、TNF超家 族受体12A拮抗剂、CD52拮抗剂、腺苷脱氨酶抑制剂、T细胞分化抗原CD6抑 制剂、FGF-7配体、二氢乳清酸脱氢酶抑制剂、CCR5趋化因子拮抗剂、CCR2趋 化因子拮抗剂、Syk酪氨酸激酶抑制剂、干扰素I型受体拮抗剂、干扰素α配体抑 制剂、巨噬细胞移动抑制剂因子抑制剂、整合素α-V/β-6拮抗剂、半胱氨酸蛋白 酶刺激剂、p38MAP激酶抑制剂、TP53基因抑制剂、志贺样毒素I抑制剂、岩藻 糖转移酶6刺激剂、白介素22配体、CXCR1趋化因子拮抗剂、CXCR4趋化因子拮抗剂、IRS1基因抑制剂、蛋白激酶C刺激剂、蛋白激酶Cα抑制剂、CD74拮 抗剂、免疫球蛋白γFc受体IIB拮抗剂、T细胞抗原CD7抑制剂、CD95拮抗剂、 N乙酰甘露糖胺激酶刺激剂、心肌营养素-1配体、白细胞弹性蛋白酶抑制剂、CD40 配体受体拮抗剂、CD40配体调节剂、IL-17拮抗剂、TLR-2拮抗剂和T细胞受体 拮抗剂,及其组合。在一些实施方案中,所述一种或多种另外的治疗剂选自甘露 聚糖结合凝集素丝氨酸蛋白酶-2(MASP-2)抑制剂、因子B抑制剂、因子D抑制剂。
在一些实施方案中,所述一种或多种另外的治疗剂选自CTLA-4(CD152)、 PD-1(CD279)、PDL-1(CD274)、TIM-3、LAG-3(CD223)、VISTA、KIR、NKG2A、 BTLA、PD-1H、TIGIT、CD96、4-1BB(CD137)、4-1BBL(CD137L)、GARP、CSF-1R、 A2AR、CD73、CD47、色氨酸2,3-双加氧酶(TDO)或吲哚胺2,3双加氧酶(IDO)的 抑制剂,以及OX40、GITR、4-1BB、ICOS、STING或CD40的激动剂。
在一些实施方案中,一种或多种另外的治疗剂选自CCR1、CCR2、CCR3、 CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、 CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1和ChemR23的调节剂。
在一些实施方案中,一种或多种另外的治疗剂选自皮质类固醇、类固醇、CD20 抑制剂和免疫抑制剂。在一些实施方案中,一种或多种另外的治疗剂是免疫抑制 剂。在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇。在一 些实施方案中,一种或多种另外的治疗剂是CD20抑制剂。在一些实施方案中, 一种或多种另外的治疗剂是皮质类固醇或类固醇和免疫抑制剂或CD20抑制剂。 在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇和免疫抑制 剂。在一些实施方案中,一种或多种另外的治疗剂是皮质类固醇或类固醇和CD20 抑制剂。
在一些实施方案中,所述一种或多种另外的治疗剂选自下组:奥滨尤妥珠单 抗(obinutuzumab)、利妥昔单抗、欧克雷立珠单抗(ocrelizumab)、环磷酰胺、泼尼 松、氢化可的松、醋酸氢化可的松、醋酸可的松、新戊酸替可的松、强的松龙、 甲基强的松龙、曲安奈德、曲安奈德醇、莫米松、安西奈德、布***、***、 氟轻松、醋酸氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、***、地塞 米松磷酸钠、氟可龙、氢化可的松-17-戊酸酯、卤米松、二丙酸阿氯米松、倍氯米 松、倍他米松戊酸酯、倍他米松二丙酸酯、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍 他索-17-丙酸酯、氟可龙己酸酯、氟可龙新戊酸酯、氟泼尼定乙酸酯、氢化可的松 -17-丁酸酯、氢化可的松-17-乙丙酸酯、氢化可的松-17-丁烯酸酯、环索奈德和泼 尼卡酯、GB-0998、衣麦格抗体(immuglo)、倍格罗单抗(begelomab)、阿来塞普(alefacept)、阿地白介素、格瓦珠单抗(gevokizumab)、达利珠单抗、巴利昔单抗、 伊诺莫单抗、倍普米诺基因质粒(beperminogene perplasmid)、司如库单抗 (sirukumab)、托珠单抗、克拉扎单抗(clazakizumab)、美泊利单抗、芬戈莫德 (fingolimod)、帕比司他、曲西立滨、尼洛替尼、伊马替尼、托法替尼、莫美替尼 (momelotinib)、培西替尼(peficitinib)、伊他替尼(itacitinib)、英夫利昔单抗、 PEG-bHb-CO、依那西普(etanercept)、伊克昔佐米、硼替佐米、莫罗单抗、奥立昔 单抗(otelixizumab)、胍立莫司(gusperinmus)、维本妥昔单抗(brentuximab vedotin)、 泼尼司莫(Ponesimod)、KRP-203、FG-3019、恩利卡生、促肾上腺皮质激素、依鲁 替尼、辛吕泽(cinryze)、康萘司他(conestat)、甲氧基聚乙二醇-依泊亭β、贝利木 单抗、比利司莫(blisibimod)、阿塞西普、赛立西立(seliciclib)、内胡立珠单抗(neihulizumab)、依维莫司、西罗莫司、地尼白介素-白喉毒素融合蛋白(denileukindiftitox)、LMB-2、那他珠单抗、卡曲得考(catridecacog)、环孢素、他克莫司、瓦 克孢菌素(voclosporin)、瓦克孢菌素、康纳单抗、麦考酚酯、咪唑立宾、CE-1145、 TK-DLI、阿巴西普、贝拉西普、奥美沙坦酯、司巴森坦(sparsentan)、TXA-127、 BIIB-023、阿仑单抗、喷司他丁、伊妥立珠单抗(itolizumab)、帕利夫明、来氟米 特、PRO-140、塞尼克立瓦洛克(cenicriviroc)、氟司塔替尼(fostamatinib)、安尼鲁 单抗(anifrolumab)、司伐立单抗(sifalimumab)、BAX-069、BG-00011、罗斯麻匹莫 德(losmapimod)、QPI-1002、志贺单抗(Shigam Ab)、TZ-101、F-652、雷帕瑞辛 (reparixin)、拉达瑞辛(ladarixin)、PTX-9908、阿加尼尔森(aganirsen)、APH-703、 索塔司塔瑞(sotrastaurin)、索塔司塔瑞、米拉珠单抗(milatuzumab)、SM-101、 T-Guard、APG-101、DEX-M74、心肌营养素-1、替匹抑素(tiprelestat)、ASKP-1240、 BMS-986004、HPH-116、KD-025、OPN-305、TOL-101、去纤苷酸(defibrotide)、 泊马度胺、胸腺球蛋白、拉喹莫德、雷美司特西尔-L(remestemcel-L)、马类抗胸腺 细胞免疫球蛋白、司特姆培西尔(Stempeucel)、LIV-γ、奥克塔干(Octagam)10%、 t2c-001、99mTc-赛司他米比(sestamibi)、克莱依格(Clairyg)、普洛索巴(Prosorba)、 泊马度胺、拉喹莫德、特普立珠单抗(teplizumab)、FCRx、索那替德(solnatide)、 弗拉单抗(foralumab)、ATIR-101、BPX-501、ACP-01、ALLO-ASC-DFU、厄贝沙坦+丙帕锗、ApoCell、***二酚、RGI-2001、乳清酸(saratin)、抗CD3二价抗体- 白喉毒素偶连物、NOX-100和LT-1951。在一些实施方案中,所述一种或多种另 外的治疗剂选自OMS721、ALN-CC5、ACH-4471、AMY-101、Acthar凝胶、CCX354、 CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX 2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、 CCX650、CCX832、派姆单抗、纳武单抗、IBI-308、mDX-400、BGB-108、MEDI-0680、SHR-1210、PF-06801591、PDR-001、GB-226、STI-1110、度伐鲁单抗、阿特朱 单抗、阿立库单抗(avelumab)、BMS-936559、ALN-PDL、TSR-042、KD-033、CA-170、 STI-1014、KY-1003、CA-327和CD4+CD25+调节T细胞及其组合。
在一些实施方案中,所述一种或多种另外的治疗剂选自下组:奥滨尤妥珠单 抗(obinutuzumab)、利妥昔单抗、欧克雷立珠单抗(ocrelizumab)、环磷酰胺、泼尼 松、氢化可的松、醋酸氢化可的松、醋酸可的松、新戊酸替可的松、强的松龙、 甲基强的松龙、曲安奈德、曲安奈德醇、莫米松、安西奈德、布***、***、 氟轻松、醋酸氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、***、地塞 米松磷酸钠、氟可龙、氢化可的松-17-戊酸酯、卤米松、二丙酸阿氯米松、倍氯米 松、倍他米松戊酸酯、倍他米松二丙酸酯、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍 他索-17-丙酸酯、氟可龙己酸酯、氟可龙新戊酸酯、氟泼尼定乙酸酯、氢化可的松 -17-丁酸酯、氢化可的松-17-乙丙酸酯、氢化可的松-17-丁烯酸酯、环索奈德和泼 尼卡酯。
在一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗或环磷酰胺。在 一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗。在一些实施方案中, 一种或多种另外的治疗剂是环磷酰胺。在一些实施方案中,一种或多种另外的治 疗剂是***。在一些实施方案中,一种或多种另外的治疗剂是利妥昔单抗或环 磷酰胺和***。
本文提供的治疗方法通常包括向患者施用有效量的一种或多种本文提供的化 合物。合适的患者包括患有或易患(即,预防性治疗)本文鉴定的病症或疾病的那些 患者。如本文所述的用于治疗的典型患者包括哺乳动物,特别是灵长类动物,尤 其是人。其他合适的患者包括驯养的伴侣动物,例如狗、猫、马等,或家畜动物, 例如牛、猪、绵羊等。
通常,本文提供的治疗方法包括向患者施用有效量的本文提供的化合物一种 或多种化合物。在一些实施方案中,将本发明的化合物静脉内、口服或局部施用 于患者(例如人)。在优选的实施方案中,本发明化合物优选静脉内施用于患者(例 如人)。有效量可以是足以调节C5a受体活性的量和/或足以减轻或缓解患者所呈 现的症状的量。优选地,施用的量足以产生足够高的活性代谢物血浆浓度以在体 外可检测地抑制白细胞(例如,嗜中性粒细胞)趋化性。治疗方案可根据使用的化合 物和待治疗的具体病症而变化;对于大多数病症的治疗,优选每日4次或更少的 给药频率。通常,更优选每日2次的剂量方案,特别优选每天给药一次。然而, 应理解,任何特定患者的具体剂量水平和治疗方案将取决于多种因素,包括所用 特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药 途径、***速率、药物组合(即给予患者的其他药物)和接受治疗的具体疾病的严重 程度以及处方医师的判断。通常,优选使用足以提供有效治疗的最小剂量。通常 可以使用适合于治疗或预防的病症的医学或兽医标准来监测患者的治疗效果。
每天每千克体重约0.1mg至约140mg的剂量水平可用于治疗或预防涉及致病 性C5a活性的病症(每人每天约0.5mg至约7g)。可以与载体材料组合以产生单一 剂型的本发明化合物的量,将根据所治疗的宿主和特定的给药方式而变化。剂量 单位形式通常含有约1mg至约500mg活性成分。对于口服、经皮、静脉内、肌内 或皮下给药的化合物,优选给予足够量的化合物以达到血清浓度为5ng(纳克)/ mL-10μg(微克)/mL血清,更优选应给予足够的化合物以达到血清浓度为20ng-1 μg/ml血清,最优选给予足够的化合物以达到血清浓度为50ng/ml-200ng/ml血清。 对于直接注射到滑膜中(用于治疗关节炎),应给予足够的化合物以达到约1微摩尔 的局部浓度。
剂量频率也可根据所用化合物和所治疗的特定疾病而变化。然而,对于大多 数病症的治疗,优选每日4次,每日3次或更少的剂量方案,特别优选每日一次 或每日2次的剂量方案。然而,应理解,任何特定患者的具体剂量水平将取决于 多种因素,包括所用特定化合物的活性、年龄、体重、一般健康状况、性别、饮 食、给药时间、给药途径、给药速度、药物组合(即给予患者的其他药物)、接受治 疗的特定疾病的严重程度、以及其他因素,包括处方医生的判断。
试剂盒和包装
术语“试剂盒”和“药物试剂盒”是指商业试剂盒或包装,其在一个或多个 合适的容器中包含一种或多种药物组合物及其使用说明书。在一个实施方案中, 提供了包含本发明化合物或其药学上可接受的盐以及其给药说明书的试剂盒。在 一个实施方案中,试剂盒包含本发明化合物或其药学上可接受的盐,以及一种或 多种(例如,一种、两种、三种、一种或两种、或一种至三种)另外的治疗剂和它们 的给药说明书。
在一个实施方案中,将本发明的化合物配制成给药单元,其包装在单个包装 中。单个包装包括但不限于瓶、儿童防护瓶、安瓿和管。在一个实施方案中,将 本发明化合物和任选的另外的治疗剂配制成给药单元,并且每个单独的给药单元 单独包装在单个包装中。这种单独包装的单元可含有任何形式的药物组合物,包 括但不限于液体形式、固体形式、粉末形式、颗粒形式、泡腾粉末或片剂,硬或 软胶囊、乳液、悬浮液、糖浆、栓剂、片剂、锭剂、含片、溶液、口腔贴剂、薄 膜、口服凝胶、咀嚼片、口香糖和一次性注射器。这种单独包装的单元可以组合 在一个包装中,该包装由纸、卡纸板、纸板、金属箔和塑料箔中的一种或多种制 成的包装中,例如泡罩包装。一个或多个给药单元可以是每天施用一次或数次。 一个或多个给药单位可以一天施用三次。一个或多个给药单位可以每天施用两次。 可以在第一天施用一个或多个给药单位,并且可以在随后的日子施用一个或多个 给药单位。
V.实施例
提供以下实施例来说明而非限制要求保护的发明。
下面使用的试剂和溶剂可以从商业来源获得,例如阿德里奇化学公司 (AldrichChemical Co.,密尔沃基,威斯康星州,USA)。在Varian Mercury 400MHz NMR光谱仪上记录1H-NMR光谱。提供相对于TMS显著的峰,并按以下顺序制 表:多重性(s,单重态;d,双重态;t,三重态;q,四重态;m,多重态)和质子 数。质谱结果报告为质量与电荷的比率,然后是每个离子的相对丰度(括号内)。在 实施例中,单个m/e值用于报告含有最常见原子同位素的M+H(或,如所指出的, M-H)离子。在所有情况下,同位素模式对应于预期的公式。电喷雾电离(ESI)质谱 分析在Hewlett-Packrd MSD电喷雾质谱仪上使用HP1100HPLC进行送样。通常, 将分析物以0.1mg/mL溶解在甲醇中,并将1微升与送样溶剂输入质谱仪,从100 扫描至1500道尔顿。可以使用含有1%甲酸的乙腈/水作为送样溶剂,以正ESI模 式分析所有化合物。下面提供的化合物也可以在负ESI模式下分析,使用含有2mM NH4OAc的乙腈/水作为递送***。
以下缩写用于实施例和整个说明书中:
EtOH:乙醇
EtONa:乙醇钠
THF:四氢呋喃
TLC:薄层色谱
MeOH:甲醇
使用本领域技术人员已知的各种反应,可以如下所述合成本发明范围内的化 合物。本领域技术人员还将认识到,可以采用替代方法来合成本发明的目标化合 物,并且本文件正文中描述的方法并非穷尽的,但确实为目标化合物提供了广泛 适用和实用的途径。
在该专利中要求保护的某些分子可以以不同的对映体和非对映体形式存在, 并且要求保护这些化合物的所有这些变体。
在本文中用于合成关键化合物的实验程序的详细描述是指通过识别其物理数 据以及与其相关的结构描述来描述的分子。
本领域技术人员还将认识到,在有机化学中的标准后处理过程中,经常使用 酸和碱。在本专利中描述的实验程序中,如果母体化合物具有必要的内在酸性或 碱性,则有时会产生它们的盐。
实施例1:(2R,3S)-2-[4-[环戊基-[2-(二甲基氨基)乙酰基]氨基]苯基]-1-(2-氟-6- 甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺的合成
步骤a:在室温下,向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(100mg,0.17mmol)的无水二 氯甲烷(5mL)溶液中加入吡啶(0.2mL,0.26mmol)和2-氯乙酰氯(100μL, 0.34mmol)。将混合物在室温下搅拌1小时。反应完成后,将反应混合物用CH2Cl2稀释,用1N HCl洗涤,然后用饱和NaHCO3水溶液洗涤,用Na2SO4干燥并真空 浓缩。粗产物不经任何进一步纯化直接用于下一步。
步骤b:将来自上述反应的粗产物溶于四氢呋喃(5mL)和H2O(1mL)中,然后 加入K2CO3(50mg,0.36mmol)和1M二甲胺的THF溶液(0.6mL,0.6mmol)。然后 将混合物在室温下搅拌过夜,然后在60℃下搅拌2小时。反应完成后,用EtOAc 稀释,用水洗涤,用Na2SO4干燥,真空浓缩。通过硅胶色谱法(先用10-100%乙 酸乙酯/己烷,然后0-15%MeOH/EtOAc)纯化粗化合物,得到(2R,3S)-2-[4-[环戊基 -[2-(二甲氨基)乙酰基]氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲 基)苯基]哌啶-3-甲酰胺。C37H42F4N4O3[M+H]+的MS:(ES)m/z计算值667.3,实测 值667.8。
实施例2:(2R,3S)-2-[4-[(2-氨基乙酰基)-环戊基-氨基]苯基]-1-(2-氟-6-甲基-苯 甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺的合成
除了在步骤b中使用NH4OH代替二甲胺之外,采用与实施例1相同的步骤。 通过硅胶色谱法(首先10-100%乙酸乙酯/己烷,然后0-15%MeOH/EtOAc)纯化粗化 合物,得到(2R,3S)-2-[4-[(2-氨基乙酰基)-环戊基]-氨基]-1-(2-氟-6-甲基-苯甲酰 基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺。C35H38F4N4O3[M+H]+的MS: (ES)m/z计算值638.3,实测值638.8。
实施例3:2-[[[N-环戊基-4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三 氟甲基)]苯基]氨基甲酰基]-2-哌啶基]苯胺基]-羟基-磷酰基]氨基]-3-(1H-咪唑-4-基) 丙酸的合成
步骤a:在0℃下,向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(1.0g,1.78mmol)的三乙胺(3.0mL)溶液中加入POCl3(2.61g,17.8mmol)。将反应混合物在0℃下搅拌2小时, 然后温热至室温并搅拌36小时。在反应完成后,将其在0℃下用冰淬灭,搅拌1 小时并过滤。通过硅胶色谱法(5-60%乙酸乙酯/己烷)纯化粗化合物,得到 (2R,3S)-2-[4-[环戊基(二氯磷酰基)-氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基 -3-(三氟甲基)苯基]-哌啶-3-甲酰胺,为所需产物。C33H34Cl2F4N3O3P[M+H]+的MS: (ES)m/z计算值698.1,实测值698.6。
步骤b:向搅拌的(2R,3S)-2-[4-[环戊基(二氯磷酰基)氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.36mmol)的无 水THF(4mL)溶液中加入(2S)-2-氨基-3-(1H-咪唑-4-基)丙酸甲酯(216mg,0.89mmol) 和N,N-二异丙基乙胺(231mg,1.79mmol)。混合物在室温下搅拌过夜。反应完成 后,加入水(2mL)并搅拌2小时。然后反应混合物用EtOAc萃取,用盐水洗涤, 用Na2SO4干燥并真空浓缩。通过硅胶色谱法(0-100%EtOAc/己烷)纯化粗产物,得 到游离酸,然后用1N NaOH(1当量)处理并冻干,得到2-[[[N-环戊基-4-[(2R, 3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基] 苯胺基]-羟基-磷酰基]氨基]-3-(1H-咪唑-4-基)丙酸。C39H43F4N6O6P[M+H]+的MS: (ES)m/z计算值799.3,实测值799.7。
实施例4:N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3(三 氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]-(2-甲基丙酰氧基)膦酰胺酸的合成
向搅拌的(2R,3S)-2-[4-[环戊基(二氯磷酰基)氨基]苯基]-1-(2-氟-6-甲基-苯甲酰 基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(200mg,0.28mmol,参见实施例3)的乙酸乙酯(4mL)溶液中加入异丁酸的钠盐(85mg,0.72mmol)。反应混合物在室温 下搅拌过夜。反应完成后,加入饱和NH4Cl水溶液,用EtOAc萃取,真空浓缩。 通过硅胶色谱法(0-20%MeOH/CH2Cl2)纯化粗产物,得到N-环戊基 -N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3(三氟甲基)苯基]氨基甲酰 基]-2-哌啶基]苯基]-(2-甲基丙酰氧基)膦酰胺酸。C37H42F4N3O6P[M+H]+的MS: (ES)m/z计算值732.3,实测值732.3。
实施例5:(2R,3S)-2-[4-[[2-[(2-氨基乙酰基)氨基]乙酰基]-环戊基-氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基))-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺的合成
(2R,3S)-2-[4-[(2-氨基乙酰基)-环戊基-氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(200mg,0.31mmol),2-(叔丁氧基 羰基氨基)乙酸(82mg,0.46mmol),EDCI(118mg,0.62mmol),HOBT(71mg,0.46mmol) 和DIPEA(99mg,0.77mmol)加入到含有DMF(2mL)的小瓶中。反应混合物在室温 下搅拌24小时。反应完成后,反应混合物用EtOAc稀释,用饱和NaHCO3水溶 液和水洗涤,用Na2SO4干燥并真空浓缩。通过硅胶色谱法(10-100%EtOAc/己烷) 纯化粗产物。然后将所需物质溶解在CH2Cl2(3mL)中并在室温下用含有2N HCl的 二氧六环溶液(2mL)处理2小时。反应完成后,除去溶剂,残余物用CH2Cl2稀释, 用饱和NaHCO3水溶液和水洗涤,用Na2SO4干燥,真空浓缩。通过硅胶色谱法 (0-20%MeOH/CH2Cl2)纯化粗产物,得到(2R,3S)-2-[4-[[2-[(2-氨基乙酰基)氨基]乙 酰基]-环戊基-氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基] 哌啶-3-甲酰胺。C37H41F4N5O4[M+H]+的MS:(ES)m/z计算值696.3,实测值696.7。
实施例6:(2R,3S)-2-[4-[环戊基-[2-[[(2S)-2,5-二氨基戊酰基]氨基]乙酰基]氨基] 苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺二盐 酸盐的合成
(2R,3S)-2-[4-[(2-氨基乙酰基)-环戊基-氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.39mmol),(2S)-2,5-双(叔丁氧基羰基氨基)戊酸(309mg,0.59mmol),EDCI(150mg,0.78mmol),HOBT(将 90mg,0.59mmol)和DIPEA(151mg,1.17mmol)加入到含有DMF(3.0mL)的小瓶中。 反应在室温下搅拌24小时。反应完成后,用EtOAc稀释,用水洗涤,用Na2SO4干燥并真空浓缩。通过硅胶色谱法(首先10-100%EtOAc/己烷,然后 0-20%MeOH/CH2Cl2)纯化粗产物。然后将产物溶解在CH2Cl2(3mL)中并在室温下 用含有2N HCl的二氧六环溶液(2mL)处理2小时。反应完成后,除去溶剂,残余 物用CH3CN研磨,得到(2R,3S)-2-[4-[环戊基-[2-[[(2S)-2,5-二氨基戊酰基]氨基]乙 酰基]氨基]苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲 酰胺二盐酸盐。C40H48F4N6O4[M+H]+的MS:(ES)m/z计算值752.4,实测值752.4。
实施例7:[环戊基-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲 基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酰基]氧甲基(2S)-2-氨基-3-甲基-丁酸 酯的合成
步骤a:在0℃下,向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(3.0g,5.15mmol)的无水二 氯甲烷(25mL)溶液中加入DIPEA(997mg,7072mmol)和氯甲基氯甲酸酯(791mg, 6.02mmol)。混合物搅拌2小时。反应完成后,反应用水淬灭,用CH2Cl2萃取, 得到粗产物氯甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基 -3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯(3.5g,收率:100%)。 C35H36ClF4N3O4[M+H]+的MS:(ES)m/z计算值674.2,实测值674.5。
步骤b:在室温下,向搅拌的氯甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯(450mg,0.67mmol)的无水THF(5.0mL)溶液中加入由(2S)-2-(苄氧基羰基氨基)-3- 甲基-丁酸(251mg,1mmol)和四丁基氢氧化铵(260mg,1mmol)混合并冻干得到的 加成物。反应在室温下搅拌48小时。反应完成后,混合物用水淬灭,用EtOAc 萃取,并通过硅胶色谱法(10-50%乙酸乙酯/己烷)纯化,得到所需中间体。然后使 用钯碳作为催化剂在甲醇中氢化,得到所需产物,[环戊基-[4-[(2R,3S)-1-(2-氟-6- 甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲 酰基]氧甲基(2S)-2-氨基-3-甲基-丁酸酯。C40H46F4N4O6[M+H]+的MS:(ES)m/z计 算值755.3,实测值755.5。
实施例8:(4-膦酰氧基苯基)甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲 酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯的合成
步骤a:在室温下,向搅拌的[4-(羟甲基)苯基]磷酸二乙酯(0.3g,1.14mmol)的 无水二氯甲烷(4mL)溶液中加入三光气(0.67g,2.29mmol)并搅拌4小时。然后除去 溶剂并在真空下干燥30分钟。所得残余物直接用于下一步骤。
步骤b:将上述残余物加入到(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基- 苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(0.66g,1.13mmol)和N,N-二异丙基乙胺(598mg,4.63mmol)的二氯甲烷(5mL)溶液中。将反应混合物在室温 下搅拌过夜。反应完成后,用水洗涤后处理,用CH2Cl2萃取。通过硅胶色谱法 (20-100%乙酸乙酯/己烷)纯化粗产物,得到所需中间体。然后将该中间体(80mg) 溶解在CH2Cl2(1mL)中并在室温下用溴代三甲基硅烷(84mg,0.55mmol)处理过夜。 反应完成后,反应混合物浓缩至干并通过制备型HPLC(含有0.1%TFA的乙腈-水) 纯化,得到(4-膦酰氧基苯基)甲基N-环戊基-N-[4-[(2R,3S))-1-(2-氟-6-甲基-苯甲酰 基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯。 C41H42F4N3O8P[M+H]+的MS:(ES)m/z计算值812.3,实测值812.4。
实施例9:膦酰氧基甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰 基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯的二钠 盐的合成
步骤a:在0℃下,向搅拌的二苄氧基磷酰氧基甲基氯甲酸酯(526mg,(~60% 纯度,1.05g,如WO 2014/193696中所述制备),1.42mmol)的无水二氯甲烷(10mL) 溶液中加入DIPEA(1.3mL,7.1mmol)。然后在0℃下加入(2R,3S)-2-[4-(环戊基氨基) 苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺 (826mg,1.42mmol)的无水二氯甲烷(5mL)溶液。混合物搅拌2小时。反应完成后, 反应用水淬灭,用CH2Cl2萃取,经Mg2SO4干燥并真空浓缩。通过硅胶色谱法 (20-100%EtOAc/己烷)纯化粗产物,得到所需产物,二苄氧基磷酰氧基甲基N-环 戊基-N-[4-[(2R,3S)-1-(2-氟-6-)甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基 甲酰基]-2-哌啶基]苯基]氨基甲酸酯。C49H50F4N3O8P[M+H]+的MS:(ES)m/z计算 值916.6,实测值916.6。
步骤b:向二苄氧基磷酰氧基甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯(690mg,0.75mmol)的乙酸乙酯(15mL)溶液中加入钯碳(2g,10重量%),在60psi 下氢化20分钟,通过硅藻土过滤,用1:1的EtOAc/MeOH(15mL)冲洗,浓缩至 干。将残余物溶于MeOH中,并用1M NaOMe(1.57mL,1.57mmol)处理。混合物 真空浓缩至干,加入溶剂***,过滤,用溶剂***冲洗,得到膦酰氧基甲基N-环 戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲 酰基]-2-哌啶基]苯基]氨基甲酸酯)二钠盐,C35H38F4N3O8P[M+H]+MS:(ES)m/z计 算值>736.6,发现736.6。
实施例10:(E)-4-[[环戊基-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基 -3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酰基]氧基甲氧基]-4-氧代-丁-2-烯酸的钠盐的合成
步骤a:在0℃下,向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(1g,1.72mmol)的无水 THF(10mL)溶液中加入氯甲酸氯甲酯(155μL,1.72mmol)和N,N-二异丙基乙胺 (392μL,2.58mmol),并反应1小时。反应完成后,除去溶剂,得到氯甲基N-环 戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基]-3-(三氟甲基)苯基]氨基 甲酰基]-2-哌啶基]苯基]氨基甲酸酯。
步骤b:在室温下,向氯甲基N-环戊基-N-[4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰基]-2-哌啶基]苯基]氨基甲酸酯(200mg,0.297mmol)和富马酸四丁基铵盐(106mg,0.297mmol)的THF(5mL)溶液中加入含四 丁基碘化铵(22mg,0.06mmol)的DMF溶液。混合物搅拌过夜,然后用EtOAc稀 释,用0.1M HCl洗涤,用Na2SO4干燥并真空浓缩。通过硅胶色谱法 5-10%MeOH/CH2Cl2纯化粗产物。通过用CH3CN(0.6mL)/H2O(0.4mL)稀释并加入 0.1M NaOH(213μL,1当量)将收集的产物转化为钠盐。冻干并获得的(E)-4-[[环戊 基4-[(2R,3S)-1-(2-氟-6-甲基-苯甲酰基)-3-[[4-甲基-3-(三氟甲基)苯基]氨基甲酰 基]-2-哌啶基]苯基]氨基甲酰基]氧基甲氧基]-4-氧代-丁-2-烯酸钠盐。 C39H38F4N3O8[M+H]+MS:(ES)m/z计算值754.2,实测值754.7。
实施例11:[N-[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶 -3-羰基]-4-甲基-3-(三氟甲基)苯胺基]甲基二氢磷酸酯的二钠盐的合成
向(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-甲基-3-(三 氟甲基)苯基]哌啶-3-甲酰胺(1.99g,3.42mmol)和多聚甲醛(308mg,10.26mmol)的二氧六环(10mL)悬浮液中加入三甲基氯硅烷(20mL,157.58mmol),并升温至70 ℃。反应搅拌9小时,然后真空浓缩。残余物溶于THF(10mL)中并加入四丁基 磷酸二氢铵(3.7g,10.9mmol)。混合物在40℃下搅拌1小时,然后用氢氧化铵(5mL), 水(20mL)和CH2Cl2(30mL)处理。有机层真空浓缩,并首先通过硅胶色谱法 (3-60%(MeOH:NH4OH 4:1/体积)/CH2Cl2)进行纯化。然后通过制备型HPLC(含 有0.1%NH4HCO3/ACN的乙腈-水)纯化。收集所需的级分并真空浓缩。然后将残 余物用2mL H2O,1mL CH3CN和1N NaOH(137μL,2当量)处理,冻干并获得 [N-[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]-4-甲基 -3-(三氟甲基)苯胺基]甲基二氢磷酸酯的二钠盐,C34H38F4N3O6P[M+H]+的MS: (ES)m/z计算值692.2,实测值692.6。
实施例12:[N-[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶 -3-羰基]-4-甲基-3-(三氟甲基)苯胺]膦酸的合成
在-78℃下,向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰 基)-N-[4-甲基-3-(三氟甲基)苯基]哌啶-3-甲酰胺(291mg,0.50mmol)的THF(3mL) 溶液中加入LHMDS(72μL,0.55mmol)。混合物搅拌5分钟。加入1-[氯(乙氧基) 磷酰基]氧乙烷(72μL,0.50mmol)并缓慢升温至室温。在反应完成时,用EtOAc 稀释,用饱和NaHCO3溶液洗涤,并用EtOAc萃取。通过硅胶色谱法(0-100%EtOAc /己烷)纯化粗产物,得到60mg所需中间体。将该中间体溶解在CH2Cl2(1mL)中并 在0℃下加入TMSBr(0.2mL)。混合物温热至室温并搅拌2小时。然后将其真空浓 缩,并通过制备型HPLC(含有0.1%TFA的乙腈-水)纯化,得到[N-[(2R,3S)-2-[4-(环 戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]-4-甲基-3-(三氟甲基)苯胺] 膦酸。C33H36F4N3O5P[M+H]+的MS:(ES)m/z计算值662.3,实测值662.3。
实施例13:([4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-[(2-氨基乙酰基)氨基]乙酸酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(220mg,0.37mmol),2-[[2-(叔丁氧基羰基氨 基)乙酰基]氨基]乙酸(213mg,0.92mmol),HATU(210mg,0.55mmol)和 DIPEA(95mg,0.74mmol)加入到含有DMF(2mL)的小瓶中。反应在55℃下搅拌24 小时。反应完成后,反应混合物用EtOAc稀释,用饱和NaHCO3水溶液和水洗涤, 用Na2SO4干燥并真空浓缩。然后将残余物溶解在CH2Cl2(3mL)中并在室温下用含 2N HCl的二氧六环(2mL)处理2小时。反应完成后,除去溶剂,残余物用CH2Cl2稀释,用饱和NaHCO3水溶液和水洗涤,用Na2SO4干燥,真空浓缩。通过硅胶色 谱法(0-20%MeOH/CH2Cl2)纯化粗产物,得到([4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-[(2-氨基乙酰基)氨基]乙酸酯。C37H41F4N5O5[M+H]+的MS:(ES)m/z计算值712.3,实测 值712.7。
实施例14:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-[[(2S)-2-氨基-3-甲基-丁酰基]氨基]乙酸 酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(200mg,0.33mmol),2-[[(2S)-2-(叔丁氧基羰 基氨基)-3-甲基-丁酰基]将氨基]乙酸(138mg,0.50mmol),HATU(190mg,0.50mmol) 和DIPEA(108mg,0.84mmol)加入到含有DMF(2.0mL)的小瓶中。按照与实施例1 相同的方法得到产物[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基) 哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-[[(2S)-2-氨基-3-甲基-丁酰基]氨基]乙 酸酯。C40H47F4N5O5[M+H]+MS:(ES)m/z计算值754.3,实测值754.8。
实施例15:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2S)-2-[(2-氨基乙酰基)氨基]-3-甲基-丁酸 酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.42mmol),(2S)-2-[[2-(叔丁氧基羰 基氨基)乙酰基]氨基]-3-甲基-丁酸(172mg,0.62mmol),EDCI(160mg,0.83mmol), HOBT(96mg,062mmol)和DIPEA(108mg,0.83mmol)加入到含有DMF(2.5mL)的 小瓶中。反应在室温下搅拌24小时。反应完成后,用EtOAc稀释,用水洗涤, 用Na2SO4干燥并真空浓缩。通过硅胶色谱法(首先10-100%EtOAc/己烷,然后 0-20%MeOH/CH2Cl2)纯化粗产物。然后将产物溶解在CH2Cl2(3mL)中并在室温下 用含2N HCl的二氧六环(2mL)处理2小时。反应完成后,反应混合物用CH2Cl2稀释,用饱和NaHCO3和水洗涤,用Na2SO4干燥并真空浓缩。通过硅胶色谱法 (0-20%MeOH/CH2Cl2)纯化粗产物,得到产物[4-[[(2R,3S)-2-[4-(环戊基氨基)苯 基]-1-(2-氟代-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基 (2S)-2-[(2-氨基乙酰基)氨基]-3-甲基-丁酸酯。C40H47F4N5O5[M+H]+MS:(ES)m/z 计算值754.3,实测值754.8。
实施例16:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2S)-2-[[(2S)-2-氨基-3-甲基-丁酰基]氨基]-3-甲基-丁酸酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.42mmol),(2S)-2-[[(2S)-2-(叔丁氧 基羰基氨基)-3-甲基-丁酰基]氨基]-3-甲基-丁酸(196mg,0.62mmol),EDCI(160mg,0.83mmol),HOBT(96mg,0.62mmol)和DIPEA(108mg,0.83mmol)装入含 DMF(2.0mL)的小瓶中。按照与实施例3相同的方法得到产物[4-[[(2R,3S)-2-[4-(环 戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲 基(2S)-2-[[(2S)-2-氨基-3-甲基-丁酰基]氨基]-3-甲基-丁酸酯。C43H53F4N5O5MS: (ES)m/z计算值[M+H]+796.4,实测值796.8。
实施例17:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2R)-2-氨基-3-甲基-丁酸酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.42mmol),(2S)-2-(叔丁氧基羰基 氨基)-3-甲基-丁酸(180mg,0.83mmol),EDCI(160mg,0.83mmol),HOBT(96mg, 0.62mmol)和DIPEA(108mg,0.83mmol)加入到含有DMF(4mL)的小瓶中。按照与 实施例3相同的方法得到产物[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基- 苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2S)-2-氨基-3-甲基-丁酸酯。 C38H44F4N4O4[M+H]+MS:(ES)m/z计算值697.4,实测值697.7。
实施例18:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2S)-2-氨基丙酸酯的合成
(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(250mg,0.42mmol),(2S)-2-(叔丁氧基羰基氨 基)丙酸(118mg,0.62mmol),EDCI(119mg,0.83mmol),HOBT(96mg,0.62mmol) 和DIPEA(134mg,1.04mmol)加入到含有DMF(4.0mL)的小瓶中。按照与实施例3 相同的方法,得到产物[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰 基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基(2S)-2-氨基丙酸酯。 C36H40F4N4O4[M+H]+MS:(ES)m/z计算值669.3,实测值669.7。
实施例19:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-(二甲基氨基)乙酸酯的合成
向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟 甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(70mg,0.12mmol)和2-(二甲基氨基)乙酸盐酸盐(49mg,0.35mmol)的DMF(2.5mL)溶液中加入HATU(135mg,0.36mmol)和三 乙胺(82μL,0.59mmol)。混合物温热至70℃并搅拌2小时。然后冷却至室温,用 EtOAc稀释,用饱和NaHCO3水溶液和水洗涤,并真空浓缩。通过硅胶色谱法 (0-100%EtOAc/己烷)纯化粗产物,得到[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2- 氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-(二甲基氨基)乙 酸酯,C37H42F4N4O4[M+H]+MS:(ES)m/z计算值683.3,实测值683.3。
实施例20:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2-氨基乙酸酯的合成
向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟 甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(100mg,0.17mmol)和2-(叔丁氧基羰基氨基) 乙酸(88mg,0.50mmol)的DMF(2.5mL)溶液中加入HATU(190mg,0.50mmol)和三 乙胺(129μL,0.92mmol)。混合物温热至60℃并搅拌1小时。然后将其冷却至室 温,用EtOAc稀释,用饱和NaHCO3水溶液和水洗涤,并真空浓缩。通过硅胶色 谱法(0-90%EtOAc/己烷)纯化粗产物,得到110mg所需中间体。该中间体溶解在 CH2Cl2(2mL)中并在室温下用含4M HCl的二氧六环(2mL)处理45分钟。然后将其 冷却至室温,用EtOAc稀释,用饱和NaHCO3溶液和水洗涤,并用EtOAc萃取。 通过硅胶色谱法(0-20%MeOH/EtOAc)纯化粗产物,得到[4-[[(2R,3S)-2-[4-(环戊基 氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基2- 氨基乙酸酯,C35H38F4N4O4[M+H]+MS:(ES)m/z计算值655.3,实测值655.3。
实施例21:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基二氢磷酸酯的合成
向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟 甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(100mg,0.17mmol)和磷酸(100mg,1mmol)混合物中加入2,2,2-三氯乙腈(720mg,5mmol)和三乙胺(280μL,2mmol)。将混合 物在室温下搅拌2小时。然后用1%TFA/H2O淬灭,并用iPrOH/CHCl3(1:3)萃取。 通过硅胶色谱法使用0-60%(10%HOAc/MeOH)/CH2Cl2的梯度纯化粗产物,得到 [4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨 基]-2-(三氟甲基)苯基]甲基二氢磷酸酯,C33H36F4N3O6P[M+H]+MS:(ES)m/z计算 值678.3,发现678.3。
实施例22:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲氧基甲基二氢磷酸酯的二钠盐的合成
向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟 甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(598mg,1.0mmol)和多聚甲醛(120mg,4.0mmol)的二氧六环(8mL)悬浮液中加入三甲基氯硅烷(8mL)和磷酸(1.0g, 10.0mmol)。反应搅拌9小时,然后真空浓缩。残余物溶于CH3CN(5mL)中并在室 温下加入到85%H3PO4水溶液(1.2mL),含DIPEA(5.2mL)的CH3CN(15mL)中。在 室温下搅拌30分钟后,将反应混合物真空浓缩。向该粗残余物中加入水(30mL) 并在室温下搅拌30分钟。过滤得到的固体,用水(10mL)洗涤并在高真空下干燥。 然后用1:1EtOAc-Et2O(20mL)洗涤固体以除去非极性杂质。获得的粗产物通过制 备型HPLC(含有0.1%Et3N的乙腈-水)纯化,得到产物,为二甲基胺盐,用0.1M NaOH(11.7mL)和CH3CN(12mL)处理,冻干,得到[4-[[(2R,3S)-2-[4-(环戊基氨基) 苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲氧基甲基 二氢磷酸酯的二钠盐,C34H38F4N3O7P[M+H]+MS:(ES)m/z计算值708.2,实测值 708.2。
实施例23:[4-[[(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌 啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲基3-[(4-甲基哌嗪-1-基)甲基]苯甲酸酯的合成
向搅拌的(2R,3S)-2-[4-(环戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)-N-[4-(羟 甲基)-3-(三氟甲基)苯基]哌啶-3-甲酰胺(511mg,0.85mmol)和3-[(4-甲基哌嗪-1-基) 甲基]苯甲酸(200mg,0.85mmol)的DMF(5mL)溶液中加入HATU(485mg,1.27mmol) 和N,N-二异丙基乙胺(443μL,2.55mmol)。将混合物温热至70℃并搅拌2小时。 然后将其冷却至室温,用EtOAc稀释,用饱和NaHCO3溶液和水洗涤,并真空浓 缩。通过硅胶色谱法(0-20%MeOH/CH2Cl2)纯化粗产物,得到[4-[[(2R,3S)-2-[4-(环 戊基氨基)苯基]-1-(2-氟-6-甲基-苯甲酰基)哌啶-3-羰基]氨基]-2-(三氟甲基)苯基]甲 基3-[(4-甲基哌嗪-1-基)甲基]苯甲酸酯。C46H51F4N5O4[M+H]+MS:(ES)m/z计算值 814.3,实测值814.8。
实施例24:化合物的溶解度:
通过在室温下在1mL Milli-Q水中分散指定的任意量化合物并在彻底摇动小 瓶后用肉眼检查,获得下面化合物的溶解度。肉眼没有可见颗粒的实验组被认为 是清晰的溶液。重要的是要注意,报告的溶解度信息不是化合物在水中的最大溶 解度。
使用以下方案测定第一化合物在下表中的溶解度。将化合物在pH7缓冲液中 的饱和溶液在室温(25℃)下放置过夜,然后将它们离心。取出上清液并定量。溶解 度:0.053μg/mL。
使用以下方案测定第二化合物在下表中的溶解度。通过加入1mL D.I.水至 0.8mg化合物粉末中新鲜制备化合物的饱和溶液。在室温下振荡3小时后,将样 品在14000rpm下离心15分钟两次。小心取出上清液并通过LC-MS定量。溶解度: 1.2±0.2μg/mL(重复四次的平均值)。
实施例25:大鼠静脉内注射
重量为0.22至0.25kg的雄性大鼠购自查尔斯河实验室(Charles RiverLaboratories)(霍利斯特,CA)并在使用前适应环境。所有化合物均配制成溶液制剂, 并通过静脉内给药给予动物。在无菌水中配制实施例11的化合物,每只动物接受 1mL/kg。在0.9%生理盐水中配制实施例22的化合物,每只动物接受1mL/kg。分 别在静脉给药前和给药2分钟、5分钟、5分钟、15分钟和30分钟,1小时、2 小时、4小时、6小时和8小时后,通过颈静脉或心脏穿刺(仅用于终点)取血(0.2mL)。 将血液样品收集到含有EDTA钠作为抗凝血剂的冷冻聚丙烯管中,并通过在4℃ 下以10,000rpm离心(Eppendorf离心机5417R)6分钟收集血浆并储存在-20℃下, 直至分析。
血浆样品(50μL)用150μL含有内标的乙腈在线性振荡器上提取10分钟,然 后在4℃下以3700g离心10分钟(Allegra X-15R离心机,贝克曼库尔特公司,富 勒顿,CA)。将100μL所得上清液转移到新板中并与100μL0.1%甲酸水溶液混 合,用于LC-MS/MS分析。如图1和2所示,在雄性大鼠中静脉注射两种化合物 后释放出大量的活性药物。
Claims (19)
15.如权利要求1所述的化合物,所述化合物为药学上可接受的盐的形式。
16.如权利要求15所述的化合物,其中,所述药学上可接受的盐选自铵、钙、镁、钾、钠、锌、精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴明、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇、盐酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷酸、乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、精氨酸、葡萄糖醛酸和半乳糖酸。
17.一种药物组合物,其包含如权利要求1至16中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂。
18.如权利要求17所述的药物组合物,被配制成静脉、经皮或皮下给药。
19.如权利要求1至16中任一项所述的化合物或权利要求17至18任一项所述的药物组合物在制备治疗涉及C5a受体病理性活化的疾病或病症的药物中的用途;
其中,所述疾病或病症选自下组:ANCA血管炎和C3-肾小球病。
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