CN113891884A - 1-磷酸鞘氨醇受体调节剂 - Google Patents
1-磷酸鞘氨醇受体调节剂 Download PDFInfo
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- CN113891884A CN113891884A CN202080026688.4A CN202080026688A CN113891884A CN 113891884 A CN113891884 A CN 113891884A CN 202080026688 A CN202080026688 A CN 202080026688A CN 113891884 A CN113891884 A CN 113891884A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
背景
技术领域
提供了1-磷酸鞘氨醇受体的调节剂,其用于治疗医学上表明其活化的病症。
相关技术的描述
S1P1/EDG1受体是G-蛋白偶联受体(GPCR),并且是内皮细胞分化基因(EDG)受体家族的成员。EDG受体的内源性配体包括溶血磷脂,例如1-磷酸鞘氨醇(S1P)。同所有的GPCR一样,受体的连接(ligation)经由G-蛋白(α、β和γ)的激活而传递第二信使信号。小分子S1P1激动剂和拮抗剂的开发已经提供了对于S1P1/S1P-受体信号传导系统的一些生理作用的了解。为此,S1P受体被分成五种亚型(即,S1P1、S1P2、S1P3、S1P4和S1P5),这些亚型在多种组织中表达并表现出不同的细胞特异性。S1P1受体的激动干扰淋巴细胞转运(lymphocytetrafficking),将它们隔离(sequestering)在淋巴结和其它次级淋巴组织中。这导致快速且可逆的淋巴细胞减少症,并且这可能是因为淋巴内皮细胞和淋巴细胞本身的受体连接(Rosen et al,Immunol.Rev.,195:160-177,2003)。
简要概述
简而言之,提供了1-磷酸鞘氨醇受体的调节剂,其用于治疗医学上表明其活化的病症。在一个实施方案中,提供了具有式(I)的结构的化合物:
或其药学上可接受的盐、同系物、水合物或溶剂化物,其中Rb1和Rb2如下文所定义。
公开内容的详细描述
如在说明书和所附的权利要求书中所使用的,单数形式“一个”、“一种”和“该/所述”包括复数指示物,除非上下文另有明确规定。此外,词语“包含”、“包括”和“具有”是本文所使用的开放式术语,并且不排除另外要素或组分的存在。
本发明涉及调节S1P受体的化合物,以及相关产物及其制备方法和使用方法。S1P受体被分为五种亚型(即,S1P1、S1P2、S1P3、S1P4和S1P5),这些亚型在多种组织中表达并表现出不同的细胞特异性。本文公开的化合物调节这些亚型中的一种或多种。在一个实施方案中,化合物是“S1P1”调节剂,因为它们调节1-磷酸鞘氨醇受体的亚型1。在另一个实施方案中,所述化合物调节亚型1和另一种亚型,例如亚型5。如本文所用,“S1P1调节剂”应理解为包括单独调节S1P1亚型或调节S1P1亚型以及一种或多种其它亚型的化合物。在一个实施方案中,S1P1调节剂调节S1P1亚型和S1P5亚型两者。
如本文所用的,S1P1受体的“调节剂”是这样的化合物,当将其施用于个体时,通过直接作用于受体的化合物本身或通过作用于受体的化合物的代谢物的方式,提供所需的与靶受体的相互作用。在施用于个体时,本发明的化合物通过活化受体以进行信号转导来调节S1P1受体。此类化合物在本文中也称为“激动剂”或“S1P1激动剂”。此类S1P1激动剂可选择性地作用于S1P1。例如,选择性作用于S1P1的化合物以比作用于S1P受体家族的其它亚型更低的浓度作用于S1P1。
受体激动剂可以被分类为正构(orthosteric)或变构(allosteric),并且本发明的S1P1激动剂包括这两种分类,通过所述化合物或通过所述化合物的代谢物作用于所述受体。在某些实施方案中,本发明的化合物是正构激动剂。正构激动剂结合受体中的与天然配体的结合显著重叠的位点,并复制天然配体与受体的关键相互作用。正构激动剂将通过类似于天然配体的分子机制活化受体,将与天然配体竞争,并且将被作为天然配体的竞争性拮抗剂的药理学试剂竞争性地拮抗。
在某些其它实施方案中,本发明的化合物是变构激动剂。变构激动剂结合受体中的产生与天然配体部分或完全不重叠的一些显著相互作用的位点。变构激动剂是真正的激动剂而不是变构增效剂。因此,它们单独激活受体信号传导,并且不需要次于最大浓度的天然配体。当已知的与正构配体竞争的拮抗剂显示非竞争性拮抗作用时,可以鉴定为变构激动剂。变构激动剂位点也可以通过受体诱变来定位。
在一个实施方案中,提供了具有式(I)的结构的化合物:
或其药学上可接受的盐、同系物、水合物或溶剂化物,其中Rb1和Rb2独立地为:
氢、烃基或取代的烃基;
或者Rb1和Rb2与和它们所连接的氮一起形成杂环基或取代的杂环基。
代表性的式(I)化合物列于表1中。
表1
如在式(I)中使用的,以下术语具有下文给出的含义。
“烃二基”是指通过除去两个氢原子而衍生自烃基的二价基团,例如亚甲基(-CH2-)。因此,如本文所定义的任何烃基通过除去两个氢原子以提供二价基团来构成烃二基。
“烃基”是指饱和或不饱和的直链、支链或环状烃基(环烃基),其具有1至约20个碳原子(C1-20烃基),并且在环烃基的情况下具有3至20个碳原子。烃基通常为1至12个碳(C1-12烃基),或在一些实施方案中为1至8个碳原子(C1-8烃基),或在一些实施方案中为1至4个碳原子(C1-4烃基),或在一些实施方案中为1至3个碳原子(C1-3烃基)。直链烷基的实例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链烷基的实例包括但不限于异丙基、异丁基、仲丁基、叔丁基、新戊基、异戊基和2,2-二甲基丙基。不饱和烃基的实例包括烯基和炔基。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在一些实施方案中,环烃基具有3至8个环成员,而在其它实施方案中,环碳原子的数目为3至5、3至6或3至7。环烃基基团还包括多环的环烃基基团,例如但不限于降冰片基、金刚烷基、冰片基、莰烯基、异莰烯基和蒈烯基基团,以及稠合环,例如但不限于十氢萘基等。
“烯基”是指如上文所定义的直链、支链或环状烃基,其中至少一个双键存在于两个碳原子之间。因此,烯基基团具有2至约20个碳原子,并且通常具有2至12个碳原子,或者在一些实施方案中具有2至8个碳原子。实例包括但不限于CH=CH(CH3)、CH=C(CH3)2、C(CH3)=CH2、C(CH3)=CH(CH3)、C(CH2CH3)=CH2、乙烯基、环己烯基、环戊烯基、环己二烯基、丁二烯基、戊二烯基和己二烯基等。
“炔基”是指如上文所定义的直链、支链或环状烃基,其中至少一个叁键存在于两个碳原子之间。因此,炔基基团具有2至约20个碳原子,并且通常具有2至12个碳原子,或者在一些实施方案中具有2至8个碳原子。实例包括但不限于–C≡CH、-C≡C(CH3)、-C≡C(CH2CH3)、CH2C≡CH、CH2C≡C(CH3)和CH2C≡C(CH2CH3)等。
“芳基”是指不含有杂原子(“杂原子”是指能够与碳形成共价键的非碳和非氢原子,并且通常是N、O、S和P)的环状芳香烃。芳基包括但不限于苯基、薁基(azulenyl)、庚搭烯基(heptalenyl)、联苯基、引达省基(indacenyl)、芴基、菲基、苯并菲基(triphenylenyl)、芘基、并四苯基(naphthacenyl)、基、亚联苯基、蒽基和萘基。在一些实施方案中,芳基在基团的环部分中含有6-14个碳。芳基还包括稠环,例如稠合的芳香族-脂肪族环系统(例如,茚满基、四氢萘基等)。
“芳基烃基”是指其中烃基的氢或碳键被与如上文所定义的芳基的键替代的如上文所定义的烃基。芳基烃基包括例如苄基(即,-CH2-苯基)。
“杂环基”是指含有3个或更多个环成员的芳香族(杂芳基)和非芳香族环化合物,其中一个或多个环成员是杂原子。在一些实施方案中,杂环基包括3至20个环成员,而其它这样的基团具有3至15个环成员。至少一个环含有杂原子,但多环系统中不需要每个环含有杂原子。例如,二氧戊环基环和苯并二氧戊环基环系统(亚甲二氧基苯基环系统)都是本文含义内的杂环基。命名为C2-杂环基的杂环基可以是具有两个碳原子和三个杂原子的5元环,具有两个碳原子和四个杂原子的6元环等。同样,C4-杂环基可以是具有一个杂原子的5元环,具有两个杂原子的6元环等。碳原子数加上杂原子数的总和等于环原子的总数。饱和杂环是指不含有不饱和碳原子的杂环。杂环包括稠环类,包括具有稠合的芳香族和非芳香族基团的那些。它们还包括含有杂原子的多环环系,例如但不限于奎宁环基(quinuclidyl)。
代表性的杂环基包括但不限于吡咯烷基、呋喃基、四氢呋喃基、二氧戊环基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、二氢苯并呋喃基、吲哚基、二氢吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基(thianaphthalenyl)、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。
“杂环基烃基”是指其中烃基的氢或碳键被与如上文所定义的杂环基的键替代的如上文所定义的烃基。
“杂芳基”意指含有5个或更多个环成员的芳香族杂环基,其中一个或多个环成员是杂原子。命名为C2-杂芳基的杂芳基可以是具有两个碳原子和三个杂原子的5元环,具有两个碳原子和四个杂原子的6元环等。同样,C4-杂芳基可以是具有一个杂原子的5元环,具有两个杂原子的6元环等。碳原子数加上杂原子数的总和等于环原子的总数。
代表性杂芳基包括但不限于吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、喹喔啉基和喹唑啉基。杂芳基还包括稠环化合物,例如当至少一个环,但不一定所有环是芳香族环时,包括四氢喹啉基、四氢异喹啉基、吲哚基和2,3-二氢吲哚基。
“杂芳基烃基”是指其中烃基的氢或碳键被与如上文所定义的杂芳基的键替代的如上文所定义的烃基。
芳基和杂芳基的其它实例包括但不限于苯基、联苯基、茚基、萘基(1-萘基、2-萘基)、N-羟基四唑基、N-羟基三唑基、N-羟基咪唑基、蒽基(1-蒽基、2-蒽基、3-蒽基)、噻吩基(2-噻吩基、3-噻吩基)、呋喃基(2-呋喃基、3-呋喃基)、吲哚基、噁二唑基、异噁唑基、喹唑啉基、芴基、呫吨基、异茚满基、二苯甲基、吖啶基、噻唑基、吡咯基(2-吡咯基)、吡唑基(3-吡唑基)、咪唑基(1-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、三唑基(1,2,3-三唑-1-基、1,2,3-三唑-2-基、1,2,3-三唑-4-基、1,2,4-三唑-3-基)、噁唑基(2-噁唑基、4-噁唑基、5-噁唑基)、噻唑基(2-噻唑基、4-噻唑基、5-噻唑基)、吡啶基(2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(2-嘧啶基、4-嘧啶基、5-嘧啶基、6-嘧啶基)、吡嗪基、哒嗪基(3-哒嗪基、4-哒嗪基、5-哒嗪基)、喹啉基(2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基)、异喹啉基(1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基、8-异喹啉基)、苯并[b]呋喃基(2-苯并[b]呋喃基、3-苯并[b]呋喃基、4-苯并[b]呋喃基、5-苯并[b]呋喃基、6-苯并[b]呋喃基、7-苯并[b]呋喃基)、2,3-二氢-苯并[b]呋喃基(2-(2,3-二氢-苯并[b]呋喃基)、3-(2,3-二氢-苯并[b]呋喃基)、4-(2,3-二氢-苯并[b]呋喃基)、5-(2,3-二氢-苯并[b]呋喃基)、6-(2,3-二氢-苯并[b]呋喃基)、7-(2,3-二氢-苯并[b]呋喃基)、苯并[b]噻吩基(2-苯并[b]噻吩基、3-苯并[b]噻吩基、4-苯并[b]噻吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基、7-苯并[b]噻吩基)、2,3-二氢-苯并[b]噻吩基、(2-(2,3-二氢-苯并[b]噻吩基)、3-(2,3-二氢-苯并[b]噻吩基)、4-(2,3-二氢-苯并[b]噻吩基)、5-(2,3-二氢-苯并[b]噻吩基)、6-(2,3-二氢-苯并[b]噻吩基)、7-(2,3-二氢-苯并[b]噻吩基)、吲哚基(1-吲哚基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-吲哚基、7-吲哚基)、吲唑(1-吲唑基、3-吲唑基、4-吲唑基、5-吲唑基、6-吲唑基、7-吲唑基)、苯并咪唑基(1-苯并咪唑基、2-苯并咪唑基、4-苯并咪唑基、5-苯并咪唑基、6-苯并咪唑基、7-苯并咪唑基、8-苯并咪唑基)、苯并噁唑基(1-苯并噁唑基、2-苯并噁唑基)、苯并噻唑基(1-苯并噻唑基、2-苯并噻唑基、4-苯并噻唑基、5-苯并噻唑基、6-苯并噻唑基、7-苯并噻唑基)、咔唑基(1-咔唑基、2-咔唑基、3-咔唑基、4-咔唑基)、5H-二苯并[b,f]氮杂(5H-二苯并[b,f]氮杂-1-基、5H-二苯并[b,f]氮杂-2-基、5H-二苯并[b,f]氮杂-3-基、5H-二苯并[b,f]氮杂-4-基、5H-二苯并[b,f]氮杂-5-基)、10,11-二氢-5H-二苯并[b,f]氮杂(10,11-二氢-5H-二苯并[b,f]氮杂-1-基、10,11-二氢-5H-二苯并[b,f]氮杂-2-基、10,11-二氢-5H-二苯并[b,f]氮杂-3-基、10,11-二氢-5H-二苯并[b,f]氮杂-4-基、10,11-二氢-5H-二苯并[b,f]氮杂-5-基),等等。
在式(I)的一些实施方案中,烃基、芳基、芳基烃基、杂环基和/或杂环基烃基是取代的。在本文中,“取代的”是指烃基、芳基、芳基烃基、杂环基和/或杂环基烃基,其中与氢原子的一个或多个键被与非氢原子的一个或多个键替代。烃基、芳基、芳基烃基、杂环基和/或杂环基烃基可以是单取代的,或被取代一次以上,例如二取代的,三取代的或更高取代的。在这方面,代表性的取代基包括但不限于卤素(F、Cl、Br或I);在基团如羟基、烷氧基、芳氧基、芳烷基氧基、氧代(羰基)、羧基(包括羧酸、羧酸盐和羧酸酯)中的氧原子;在基团如硫醇基、烃基和芳基硫化物基团、亚砜基团、砜基团、磺酰基和磺酰胺基团中的硫原子;在基团如胺、羟胺、腈、硝基、N-氧化物、酰肼、叠氮化物和烯胺中的氮原子;以及在各种其它基团中的其它杂原子。可以键合到取代的碳(或其它)原子上的取代基的非限制性实例包括F、Cl、Br、I、OR'、OC(O)N(R')2、CN、CF3、OCF3、R'、O、S、C(O)、S(O)、亚甲二氧基、亚乙二氧基、N(R')2、SR'、SOR'、SO2R'、SO2N(R')2、SO3R'、C(O)R'、C(O)C(O)R'、C(O)CH2C(O)R'、C(S)R'、C(O)OR'、OC(O)R'、C(O)N(R')2、OC(O)N(R')2、C(S)N(R')2、(CH2)0-2NHC(O)R'、(CH2)0-2N(R')N(R')2、N(R')N(R')C(O)R'、N(R')N(R')C(O)OR'、N(R')N(R')CON(R')2、N(R')SO2R'、N(R')SO2N(R')2、N(R')C(O)OR'、N(R')C(O)R'、N(R')C(S)R'、N(R')C(O)N(R')2、N(R')C(S)N(R')2、N(COR')COR'、N(OR')R'、C(=NH)N(R')2、C(O)N(OR')R'或C(=NOR')R',其中每次出现的R'为氢或C1-4烷基。在更具体的实施方案中,代表性的取代基包括-CN、-OH、-OCH3、-SH、-SCH3、-NH2、CH3、-CH2CH3、-CH2CH2CH3、-N+(C1-4烷基)3、-C(=O)OH、-C(=O)NH2、-NHC(=NH)NH2、-OP(=O)(OH)2和-OS(=O)2OH。
在式(I)的其它实施方案中,取代的烃基是指其中烃基的与氢原子的一个或多个键被与芳基或杂环基的一个或多个键替代的烃基,其中所述芳基或杂环基可进一步被如前段中所定义的取代基取代。
正如本领域所公知的,“盐”包括有机化合物,例如,以离子形式与抗衡离子组合的羧酸、磺酸或胺。例如,以其阴离子形式的酸可以与阳离子例如,金属阳离子,如钠、钾等;与铵盐,如NH4 +或各种胺的阳离子,包括四烷基铵盐如四甲基铵和烷基铵盐如氨丁三醇盐;或其它阳离子,如三甲基锍等形成盐。“药学上可接受的”或“药理学上可接受的”盐是由已经批准用于人类消费的并且通常是无毒的离子形成的盐,例如,氯盐或钠盐。“两性离子”为内盐,例如可以在具有至少两个可离子化的基团(一个形成阴离子而另一个形成阳离子,其用于彼此平衡)的分子内形成的内盐。例如,氨基酸(如甘氨酸)可以以两性离子形式存在。“两性离子”属于本文含义内的盐。本公开的化合物可以采取盐的形式。术语“盐”包括作为本公开的化合物的游离酸或游离碱的加成盐。盐可以为“药学上可接受的盐”。术语“药学上可接受的盐”是指具有在药物应用中提供效用的范围内的毒性特性的盐。但是,药学上不可接受的盐可以具有例如高结晶度的性质,其在本公开的实践中是有效用的,例如,如在本公开的化合物的合成、纯化或配制过程中的效用。
合适的药学上可接受的酸加成盐可以由无机酸或有机酸制备。无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸可以选自脂肪族、脂环族、芳香族、芳脂族(araliphatic)、杂环、羧酸和磺酸类的有机酸,其实例包括甲酸、乙酸、丙酸、丁二酸、羟基乙酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天门冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、亚甲基双羟萘酸(扑酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、磺胺酸、环己基氨基磺酸、硬脂酸、海藻酸、β-羟基丁酸、水杨酸、半乳糖二酸和半乳糖醛酸。药学上不可接受的酸加成盐的实例包括,例如,高氯酸盐和四氟硼酸盐。
本公开的化合物的合适的药学上可接受的碱加成盐包括,例如,金属盐,包括碱金属盐、碱土金属盐和过渡金属盐,例如,如钙盐、镁盐、钾盐、钠盐和锌盐。药学上可接受的碱加成盐还包括由碱性胺制备的有机盐,例如,如N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因。药学上不可接受的碱加成盐的实例包括锂盐和氰酸盐。尽管药学上不可接受的盐通常不用作药物,但是这样的盐可以用作,例如,化合物合成过程中的中间体,例如,在通过重结晶的其纯化过程中。所有这些盐可以通过使例如合适的酸或碱与相应的化合物反应而通过常规的方式由该化合物制备。术语“药学上可接受的盐”是指无毒的无机或有机酸和/或碱加成盐,参见例如Gould et al.,SaltSelection for Basic Drugs(1986),Int J.Pharm.,33,201-217,其通过引用的方式并入到本文中。
本公开的潜在盐的非限制性实例包括,但不限于,盐酸盐、柠檬酸盐、羟乙酸盐、延胡索酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、肉桂酸盐、羟乙基磺酸盐、硫酸盐、磷酸盐、磷酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、丁二酸盐、甲酸盐、乙酸盐、二氯乙酸盐、乳酸盐、对甲苯磺酸盐、棕榈酸盐、吡酮酸盐(pidolate)、扑酸盐、水杨酸盐、4-氨基水杨酸盐、苯甲酸盐、4-乙酰氨基苯甲酸盐、谷氨酸盐、天冬氨酸盐、羟乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、苯磺酸盐、樟脑酸盐、樟脑磺酸盐、右旋樟脑磺酸盐、癸酸盐、己酸盐、环己烷氨基磺酸盐、十二烷基硫酸盐、乙二磺酸盐、龙胆酸盐、半乳糖二酸盐、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸盐、酮戊二酸盐、马尿酸盐、乳糖醛酸盐、丙二酸盐、马来酸盐、扁桃酸盐、萘磺酸盐、萘二磺酸盐、草酸盐、油酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、硫氰酸盐、十一碳烯酸盐和昔萘酸盐。
本公开的化合物的“同系物”是该化合物的一个或多个原子被该原子的同位素替代的化合物。例如,同系物包括用氘替代化合物中的一个或多个氢原子的化合物,例如,其中式I-R和式I-S的异丙氧基部分的甲基全部或部分被氘代(例如,(D3C)2CHO-)的本公开的化合物。可以在本公开的同系物的形成中进行的同位素取代包括非放射性的(稳定的)原子,例如,氘和碳13,以及放射性的(不稳定的)原子,例如,氚、碳14、碘123、碘125等。
“水合物”是以与水分子的组合物存在的化合物。该组合物可以包括化学计量的量的水,例如一水合物或二水合物,或者可以包括任意量的水。在本文中使用的术语“水合物”指的是固体形式,即,在水溶液中的化合物虽然其可以为水合的,但是它不是如本文中使用的术语的水合物。
除了使用水以外的溶剂代替水之外,“溶剂化物”为类似的组合物。例如,甲醇或乙醇可以形成“醇化物”,其也可以为化学计量的或非化学计量的。在本文中使用的术语“溶剂化物”指的是固体形式,即,在溶剂的溶液中的化合物虽然其可以为溶剂化的,但是它不是如本文中使用的术语的溶剂化物。
本文公开的化合物可以通过本领域技术人员已知的技术以及通过以下实施例中公开的程序制备。
实施例
通用合成方法
在氘代氯仿(CDCl3)、氘代甲醇(CD3OD)或二甲亚砜-D6(DMSO)的溶液中获得1H NMR(400MHz)和13C NMR(100MHz)。使用Mestrec 5.3.0和6.0.1处理NMR图谱。括号内的13C NMR峰是相同碳的两种旋转异构体(rotomer)。质谱(LCMS)是使用Agilent 1100/6110HPLC系统获得的,所述系统配备有Thompson ODS-A,100A,5μ(50X 4.6mm)柱,使用含有0.1%甲酸的水作为流动相A,以及使用含有0.1%甲酸的乙腈作为流动相B。梯度是在2.5min内使用20-100%的流动相B,然后保持在100%,持续2.5min。流速为1mL/min。对于疏水性更强的化合物,使用下述梯度,如方法1所示:在0.5min内40-95%,保持在95%持续8.5min,然后在2min内返回到40%,流速为1mL/min。最终的化合物使用方法2检验纯度:5%持续1min,在9min内5-95%,然后保持在95%持续5min,流速为1mL/min。通过在Chiralpak AD-H,250x 4.6mm柱,5μm粒度上分离的峰的积分确定对映体过量。流速为1mL/min和等度流动相。除非另外指出,提供的手性数据使用该方法。或者,在下面的条件下进行手性分离,如在手性方法1中所示:Chiralpak AY-H,250x 4.6mm柱,5μm粒度。流速为1mL/min和等度流动相。手性方法2:Chiralcel OZ-3,250x 4.6,3μm粒度,流速:0.75mL/min。在该程序中使用的吡啶、二氯甲烷(DCM)、四氢呋喃(THF)和甲苯都是来自保持在氮气(N2)下的Aldrich Sure-Seal瓶。所有的反应都在磁力搅拌下,且温度为外部反应温度。使用配备有Redisep(Teledyne Isco)硅胶(SiO2)柱的Combiflash Rf快速纯化系统(Teledyne Isco)进行色谱分析。制备型HPLC纯化是在Varian ProStar/PrepStar系统上进行的,使用含有0.05%三氟乙酸的水作为流动相A,以及含有0.05%三氟乙酸的乙腈作为流动相B。梯度为在12min内10-80%的流动相B,保持在80%持续2min,然后在2min内返回至10%,流速为22mL/min。可以使用与此类似的其它方法。使用Varian Prostar级分收集器收集级分,并使用Savant SpeedVac Plus真空泵进行蒸发。使用配备有Biotage微波容器的Biotage Initiator微波反应器进行微波加热。使用了如下缩写:乙醇(EtOH)、羰基二咪唑(CDI)、异丙醇(IPA)和4-二甲基氨基吡啶(DMAP)。
实施例1
化合物编号1的合成
步骤1—3-乙氧基-1H-茚-7-甲腈((Int 2)的合成:
将无水EtOH(20mL)中的1-氧代-2,3-二氢-1H-茚-4-甲腈(Int 1)(20.0g,98wt%,测定18.6g,124.8mmol)、原甲酸三乙酯(80mL,481mmol)和甲磺酸(0.88mL,12.5mmol)在甲苯(80mL)中的搅拌混合物在43-47℃下加热。在1h后,GC分析显示原甲酸酯被消耗并且剩余12.8面积%的Int 1。进一步加入原甲酸三乙酯(20mL,120.2mmol),并在45分钟后GC分析显示1.5面积%的Int 1。将批料冷却至环境温度,然后在剧烈搅拌下倒入1M aq.K2HPO4(200mL)中,同时保持淬灭温度<15℃。将两相混合物剧烈搅拌10min。相分离,将水相(pH11)用甲苯(100mL)反萃取。合并有机相并在大气压下蒸馏以除去340mL馏出物。加入甲苯(500mL)并在大气压下蒸馏以除去500mL馏出物。总蒸馏时间3小时,温度范围80-120℃。此时,将批料在<5℃下储存过夜。通过在减压下用乙酸乙酯(100mL)追赶来除去过量的原甲酸酯,直至停止蒸馏。加入另一体积的乙酸乙酯(100mL),然后在减压下浓缩直至停止蒸馏。加入第三体积的乙酸乙酯(100mL),然后在减压下浓缩直至停止蒸馏,之后GC分析确认没有剩余原甲酸酯。然后将粗产物在110℃下搅拌1h,以将中间体缩酮转化为3-乙氧基-1H-茚-7-甲腈(Int 2)。冷却后,通过1H NMR使用均三甲苯作为内标物来对Int 2测定粗产物(流动油,21.34g)。在78.1wt%测定所述油,产物=16.73测定g,90.0mmol=72.1%测定收率。然后通过硅胶塞过滤来纯化粗品油,用15%EtOAc/己烷洗脱。合并纯的级分并用于下一步骤。1H NMR(400MHz,d6-DMSO)δ7.78(d,J=8.4,1H),7.63(m,1H),7.49(m,1H),5.60(m,1H),1.38(t,J=6.8Hz,1H),1.19(t,J=6.8Hz,1H);LRMS:计算值:C12H12NO+[M+H]:186.2;实测值:186.2。
步骤2—Int 3的合成:
将3-乙氧基-1H-茚-7-甲腈(Int 2)的EtOAc/己烷溶液(650mL)在减压下浓缩至~17mL,并加入异丙醇(IPA,40mL)。将溶液浓缩至~17mL,并加入第二体积的IPA(34mL)。向搅拌的溶液中加入羟胺水溶液(50%,30mL,455mmol)。然后将批料在35-40℃下温热5小时,然后在环境温度下搅拌过夜。将批料冷却至0℃,接种(50mg),并搅拌30分钟以使种晶床发展。然后在~1.5小时内滴加水(250mL)。将批料在0-20℃搅拌1h。通过过滤分离产物,用水(100mL)洗涤滤饼,并在真空和氮气气氛下在过滤器上干燥,得到3-乙氧基-N-羟基-1H-茚-7-甲脒carboximidamide(Int 3)(20.8g,90%收率)。1H NMR(400MHz,d6-DMSO)δ9.61(s,1H),7.43(m,1H),7.32(m,2H),5.77(s,1H),5.41(s,1H),4.08(q,J=6.8Hz,2H),3.45(s,2H),1.39(t,J=6.8Hz,3H);LRMS:计算值C12H15N2O2 +[M+H]:219.2;实测值:219.1。
步骤3—N-((3-氰基-4-异丙氧基苯甲酰基)氧基)-3-乙氧基-1H-茚-7-甲脒(Int
4)的合成:
将CDI(16.64g,102.6mmol)和3-氰基-4-异丙氧基苯甲酸(21.06g 102.6mmol)在DMF(83mL)中的混合物在20℃下搅拌1小时。通过加料漏斗在~5分钟内加入3-乙氧基-N-羟基-1H-茚-7-甲脒(Int 3)(20.8g,93.3mmol)DMF(40mL)溶液。在~30分钟后,批料变粘稠,加入另外体积的DMF(40mL)以帮助搅拌。此时,HPLC分析表明反应完成。用水(1.5L)稀释所得浆液,冷却至0℃,并通过过滤分离。将滤饼用水(1.5L)洗涤,并将产物在氮气流下在过滤器上干燥,得到N-((3-氰基-4-异丙氧基苯甲酰基)氧基)-3-乙氧基-1H-茚-7-甲脒(Int4),为灰白色固体(34.8g,90%收率)。1H NMR(400MHz,d6-DMSO)δ8.70(s,1H),8.33(d,J=6.8Hz,1H),7.45(m,4H),7.10(m,2H),5.49(s,1H),4.94(m,1H),4.10(q,J=6.8Hz,2H),3.55(s,2H),1.38(m,9H);LRMS:计算值:C23H24N3O4 +[M+H]:406.4;实测值:406.2。
步骤4—5-(3-(3-乙氧基-1H-茚-7-基)-1,2,4-噁二唑-5-基)-2-异丙氧基苄腈
(Int 5)的合成
将N-((3-氰基-4-异丙氧基苯甲酰基)氧基)-3-乙氧基-1H-茚-7-甲脒(Int 4)(34.8g,83.97mmol)悬浮于甲苯(590mL)中,用Dean-Stark装置加热回流18小时。收集~2mL(理论值1.5mL)。将批料冷却至环境温度,通过硅藻土过滤,并在真空下浓缩。粗品固体5-(3-(3-乙氧基-1H-茚-7-基)-1,2,4-噁二唑-5-基)-2-异丙氧基苄腈(Int 5)(30g,90%收率)直接用于下一步骤。LRMS:计算值:C23H22N3O3 +[M+H]:388.4;实测值:388.3。
步骤5—2-异丙氧基-5-(3-(1-氧代-2,3-二氢-1H-茚-4-基)-1,2,4-噁二唑-5-
基)苄腈(化合物编号1)的合成:
将Int 5(30g,75.57mmol)悬浮在4:1IPA/H2O(300mL)中。加入催化剂H2SO4(0.1mL,0.19mmol),并将所得混合物加热回流12h。将浆液冷却至环境温度并搅拌1小时。通过过滤分离产物并用4:1IPA/H2O(100mL)洗涤。在真空下在过滤器上干燥1h后,将湿滤饼装回到反应器中并悬浮于EtOAc(300mL)中。将混合物加热回流3小时,然后冷却至环境温度并搅拌1小时。将浆液过滤,用EtOAc(100mL)洗涤,并在氮气下在过滤器上干燥,得到2-异丙氧基-5-(3-(1-氧代-2,3-二氢-1H-茚-4-基)-1,2,4-噁二唑-5-基)苄腈(化合物编号1)(22g,80%收率),为灰白色固体。1H NMR(400MHz,d6-DMSO)δ8.55(d,J=2.0Hz,1H),8.44(m,2H),7.88(d,J=7.6Hz,1H),7.69(t,J=7.6Hz,1H),7.57(d,J=9.2Hz,1H),4.99(h,J=12.4Hz,1H),3.46(dd,J 1=5.6,J2=11.2Hz,2H),2.76(dd,J1=5.6,J2=11.2Hz,2H),1.45(d,J=12.4Hz,6H);13C NMR(100MHz,d6-DMSO)δ205.9,173.4,167.4,162.6,154.2,138.1,134.7,134.2,133.9,128.2,125.9,124.5,115.8,115.3,114.9,102.5,72.6,35.9,27.3,21.5;LRMS:计算值:C21H18N3O3 +[M+H]:360.1;实测值:360.2;C,H,N分析:实测值:%C:70.25,%H:4.69;%N:11.71;理论值:%C:70.18;%H:4.77;%N:11.69。
实施例2
式(I)化合物的通用合成
式(I)化合物可以由化合物1(实施例1)通过用强碱处理然后用氨基甲酰氯捕获相应的烯醇化物来合成。
实施例3
化合物3-1的合成
(7-(5-(3-氰基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)-1H-茚-3-基二甲基氨基
甲酸酯)
将NaH(13.4mg,0.339mmol)加入到无水DMSO(5mL)中,并在50℃下搅拌2小时。在15分钟内加入在DMSO(1mL)中的化合物1(100mg,0.278mmol),并搅拌15分钟。在15分钟内加入在DMSO(1mL)中的二甲基氨基甲酰氯(36mg,0.339mmol)。LCMS显示2小时后30%转化。将反应混合物用EtOAc稀释并用H2O洗涤。将有机相用Na2SO4干燥,过滤并浓缩。通过硅胶色谱法纯化,用EtOAc/hex洗脱,得到所需产物:7-(5-(3-氰基-4-异丙氧基苯基)-1,2,4-噁二唑-3-基)-1H-茚-3-基二甲基氨基甲酸酯(18mg,0.042mmol,15%);1H NMR(400MHz,CHLOROFORM-d)δppm 1.48(d,J=8Hz,6H),3.06(s,3H),3.35(s,3H),3.83(s,2H),4.81(m,1H),6.43(t,J=4Hz,1H),7.12(d,J=8Hz,1H),7.49(m,2H),8.12(d,J=8Hz,1H),8.35(d,J=8Hz,1H),8.46(s,1H);ESIMS对于C24H22N4O4的实测值:m/z 431.4(M+1)。
实施例4
体内生物测定
大鼠中的绝对口服生物利用度的测定
在非禁食的雄性Sprague-Dawely大鼠(Simonsen Laboratories or HarlanLaboratories)中进行药代动力学研究。将大鼠饲养在ALAAC认证机构中且该研究得到了机构实验动物管理与使用委员会(IACUC)批准。实验开始以前将动物在实验室中至少适应48小时。
将化合物用5%DMSO/5%Tween20和90%纯化水(静脉输注)或5%DMSO/5%Tween20和90%0.1N HCL(经口强饲)配制。给药溶液的浓度通过HPLC-UV来确认。对于静脉内给药,将化合物通过输注泵在一分钟以内向人工限制动物的颈静脉中给药(n=4只大鼠/化合物)。经口给药是用标准的不锈钢灌胃针通过强饲进行(n=2-4只大鼠/化合物)。对于这两种给药途径,给药之后在八个时间点采集血液,最后的样本在给药后24小时采集。将血液样本的等分试样转移到聚丙烯96孔板中并在-20℃下冷冻直到分析。
将血液样本在室温下解冻后,向每个孔中加入5μL的DMSO。通过加入含有200nM内标物(4-羟基-3-(α-亚氨基苯甲基)-1-甲基-6-苯基吡啶-2-(1H)-酮)和0.1%甲酸的150μL乙腈沉淀蛋白质。在平板振荡器上将板混合1分钟以促进蛋白质沉淀,然后以3,000rpm离心10分钟使蛋白质成团。在LC/MS/MS分析之前,将上清液转移至清洁的平板中并以3,000rpm离心10分钟以使任何剩余的固体物质成团。通过将5μL的化合物的DMSO储备液掺入新鲜采集的EDTA大鼠血液中来制成校正曲线标准。各轮生物-分析包括跨越5nM至10,000nM范围的八点标准曲线。标准品与大鼠药代动力学样本同样地处理。
大鼠药代动力学样本中的浓度是使用标准化的HPLC-LC/MS/MS法相对于八点标准曲线来测定的。所述系统由Leap CTC Pal注射器、具有与Applied Biosystems 3200QTrap偶联的二元泵的Agilent 1200HPLC组成。化合物在具有安全保护的Phenomenex SynergyFusion RP 20x2mm 2um Mercury Cartridge上进行色谱分析。梯度方法使用由含0.1%甲酸的水组成的流动相A和由含0.1%甲酸的乙腈组成的流动相B,0.7mL/min至0.8mL/min变化的流速。使用电喷雾电离(ESI)接口以正离子模式产生离子。开发针对各化合物的多反应监测(MRM)方法。加热的雾化器设置在325℃,具有4.8μA的雾化器电流。用于产生子离子的碰撞能量范围为29V至39V。从各化合物特定的质量转变的MRM得到的峰面积比被用来定量。本方法的定量极限通常为5nM。用Analyst软件版本1.4.2来采集和分析数据。
用非房室法(WinNonlin版本5.2;用于口服给药的模型200以及用于静脉输注的模型202)来分析血液浓度对时间的数据。使用如下表达式计算绝对口服生物利用度(%):(口服AUC×IV剂量)/(IV AUC×口服剂量)×100。
淋巴细胞减少
在小鼠中:将雌性C57BL6小鼠(Simonsen Laboratories,Gilroy CA)饲养在ALAAC认证机构中并且该研究得到了机构实验动物管理与使用委员会(IACUC)批准。实验开始以前将动物在实验室中适应至少5天。通过用由5%DMSO/5%Tween 20和90%0.1N HCl组成的媒介物中配制的1-30mg/kg化合物经口强饲来向小鼠给药(n=3/化合物/时间点)。对照小鼠用媒介物PO给药。从异氟烷麻醉的小鼠中通过心脏穿刺采集终末全血样本至EDTA中。用大鼠抗小鼠CD16/CD32(Mouse BD Fc Block,#553141)、PE-大鼠抗小鼠CD45R/B220(BD#553089)、APC-Cy7-大鼠抗小鼠CD8a(BD#557654)以及Alexa Fluor647-大鼠抗小鼠CD4(BD#557681)在冰上孵育全血30min。用BD Pharm Lyse Lysing缓冲液(#555899)溶解红细胞并通过FACS分析白细胞。淋巴细胞减少表示为作为CD4或CD8阳性T细胞的白细胞的百分比。通过用线性梯形法则计算效应曲线下面积(AUEC)来评价24小时内的整体淋巴细胞减少响应。
在大鼠中:将雄性大鼠(Simonsen Laboratories,Gilroy CA)饲养在ALAAC认证机构中并且该研究得到了机构实验动物管理与使用委员会(IACUC)批准。实验开始以前将动物在实验室中适应至少5天。通过用由5%DMSO/5%Tween 20和90%0.1N HCL组成的媒介物中配制的1-30mg/kg化合物经口强饲来向大鼠给药(n=3/化合物/时间点)。对照大鼠用媒介物PO给药。从异氟烷麻醉的大鼠中通过眶后窦采集全血并且通过心脏穿刺采集终末样本至EDTA中。用小鼠抗大鼠CD32(BD#550271)、PE-小鼠抗大鼠CD45R/B220(BD#554881)、PECy5-小鼠抗大鼠CD4(BD#554839)和APC-小鼠抗大鼠CD8a(eBioscience#17-0084)在冰上孵育全血30分钟。使用BD Pharm Lyse Lysing缓冲液(#555899)溶解红细胞并通过BDFACSArray分析白细胞。淋巴细胞减少表示为作为CD4或CD8阳性T细胞的白细胞的百分比。通过用线性梯形法则计算效应曲线下面积(AUEC)来评价24小时内的整体淋巴细胞减少响应。
淋巴细胞减少
在小鼠中:将雌性C57BL6小鼠(Simonsen Laboratories,Gilroy CA)饲养在ALAAC认证机构中并且该研究得到了机构实验动物管理与使用委员会(IACUC)批准。实验开始以前将动物在实验室中适应至少5天。通过用由5%DMSO/5%Tween 20和90%0.1N HCl组成的媒介物中配制的1mg/kg化合物经口强饲来向小鼠给药(n=3/化合物/时间点)。对照小鼠用媒介物PO给药。从异氟烷麻醉的小鼠中通过心脏穿刺采集终末全血样本至EDTA中。用大鼠抗小鼠CD16/CD32(Mouse BD Fc Block,#553141)、PE-大鼠抗小鼠CD45R/B220(BD#553089)、APC-Cy7-大鼠抗小鼠CD8a(BD#557654)和Alexa Fluor647-大鼠抗小鼠CD4(BD#557681)在冰上孵育全血30min。用BD Pharm Lyse Lysing缓冲液(#555899)溶解红细胞并通过FACS分析白细胞。淋巴细胞减少表示为作为CD4或CD8阳性T细胞的白细胞的百分比。通过用线性梯形法则计算效应曲线下面积(AUEC)来评价24小时内的整体淋巴细胞减少响应。
在大鼠中:将雌性大鼠(Simonsen Laboratories,Gilroy CA)饲养在ALAAC认证机构中并且该研究得到了机构实验动物管理与使用委员会(IACUC)批准。实验开始以前将动物在实验室中适应至少5天。通过用由5%DMSO/5%Tween 20和90%0.1N HCL组成的媒介物中配制的1mg/kg化合物经口强饲来向大鼠给药(n=3/化合物/时间点)。对照大鼠用媒介物PO给药。从异氟烷麻醉的大鼠中通过眶后窦采集全血并且通过心脏穿刺采集终末样本至EDTA中。用小鼠抗大鼠CD32(BD#550271)、PE-小鼠抗大鼠CD45R/B220(BD#554881)、PECy5-小鼠抗大鼠CD4(BD#554839)和APC-小鼠抗大鼠CD8a(eBioscience#17-0084)在冰上孵育全血30分钟。使用BD Pharm Lyse Lysing缓冲液(#555899)溶解红细胞并通过BD FACSArray分析白细胞。淋巴细胞减少表示为作为CD4或CD8阳性T细胞的白细胞的百分比。通过用线性梯形法则计算效应曲线下面积(AUEC)来评价24小时内的整体淋巴细胞减少响应。
可以组合上述的各种实施方案以提供进一步的实施方案。本说明书中提到的和/或在申请数据表中列出的所有美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请和非专利公开均通过引用以其整体并入本文。如果需要,可以修改实施方案的各方面,以采用各种专利、申请和出版物的概念来提供另外的实施方案。根据上文详细描述,可以对实施方案进行这些和其它改变。通常,在以下权利要求中,所使用的术语不应被解释为将权利要求限制到说明书和权利要求中所公开的具体实施方案,而应被解释为包括所有可能的实施方案以及这些权利要求所授权的全部的等同范围。2019年3月29日提交的美国临时申请62/826,778通过引用以其整体并入本文中。
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WO2016164180A1 (en) * | 2015-04-06 | 2016-10-13 | Auspex Pharmaceuticals, Inc. | Deuterium-substituted oxadiazoles |
WO2018208855A1 (en) * | 2017-05-08 | 2018-11-15 | Celgene International Ii Sarl | Sphingosine 1 phosphate receptor agonists for neuroprotection |
US20180369212A1 (en) * | 2017-06-23 | 2018-12-27 | Enzo Biochem, Inc. | Sphingosine pathway modulating compounds for the treatment of cancers |
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WO2016164180A1 (en) * | 2015-04-06 | 2016-10-13 | Auspex Pharmaceuticals, Inc. | Deuterium-substituted oxadiazoles |
WO2018208855A1 (en) * | 2017-05-08 | 2018-11-15 | Celgene International Ii Sarl | Sphingosine 1 phosphate receptor agonists for neuroprotection |
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