CN101184754B - 麦角灵衍生物和其作为趋化因子受体配体的用途 - Google Patents
麦角灵衍生物和其作为趋化因子受体配体的用途 Download PDFInfo
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- CN101184754B CN101184754B CN2006800186451A CN200680018645A CN101184754B CN 101184754 B CN101184754 B CN 101184754B CN 2006800186451 A CN2006800186451 A CN 2006800186451A CN 200680018645 A CN200680018645 A CN 200680018645A CN 101184754 B CN101184754 B CN 101184754B
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Classifications
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Abstract
本发明公开了以游离形式或盐形式存在的式(I)麦角灵衍生物，其用于预防或治疗由趋化因子受体和其配体间的相互作用介导的病症或疾病，在式(I)中，R1和R2各自独立地为H、任选被R10和/或R11取代的苯基或苯基-C1-4烷基、任选被R10和/或R11取代的杂芳基或杂芳基-C1-4烷基、任选被R10和/或R11取代的杂芳基N-氧化物、任选被R10取代的C1-C8烷基、任选被R10取代的C2-C8烯基、任选被R10取代的C2-C8炔基、任选被R10取代的C3-C8环烷基或任选被R10取代的C4-C8环烯基；或者R1和R2同与其连接的氮原子一起形成任选被R10取代的3-8元环，所述环除上述氮原子外还含有至多2个独立选自N、O和S的杂原子；R3是H、OR1、CH2R1R2、(CH2)1-2NR1R2、CH2-CH2-OR1、CH2-CO-NR1R2或CO-CH2R1R2；R4是F、Cl、Br、I、OR1、NR1R2或具有R1的给定含义之一；并且R5具有R1的给定含义之一。
Description
技术领域
本发明涉及麦角灵衍生物、其制备方法、其作为药物的用途以及包含它们的药物组合物。
更具体来讲，本发明提供游离形式或盐形式的式I化合物，
其中，
R1和R2各自独立地为H、任选被R10和/或R11取代的苯基或苯基-C1-4烷基、任选被R10和/或R11取代的杂芳基或杂芳基-C1-4烷基、任选被R10和/或R11取代的杂芳基N-氧化物、任选被R10取代的C1-C8烷基、任选被R10取代的C2-C8烯基、任选被R10取代的C2-C8炔基、任选被R10取代的C3-C8环烷基或任选被R10取代的C4-C8环烯基；
或者R1和R2同与其连接的氮原子一起形成任选被R10取代的3-8元环，所述环除了含有上述氮原子外，还至多含有2个独立选自N、O和S的杂原子；
其中R10代表独立地选自以下基团的1至4个取代基：C1-C6烷基、C1-C6羟基烷基、C1-C6烷氧基烷基、C1-C6卤代烷基、C3-C6环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、苯基、杂芳基、杂芳基N-氧化物、F、Cl、Br、I、OH、OR9、OCOR9、OCOOR9、OCONHR9、OCONR9R9、OSO2R9、COR9、COOH、COOR9、CONH2、CONHR9、CONR9R9、CF3、CHF2、CH2F、C1-4烷基NH2、C1-4烷基NHR9、C1-4烷基NR9R9、CN、NO2、NH2、NHR9、NR9R9、NHCOR9、NR9COR9、NHCONHR9、NHCONH2、NR9CONHR9、NR9CONR9R9、NHCOOR9、NR9COOR9、NHSO2R9、N(SO2R9)2、NR9SO2R9、SR9、SOR9、SO2R9、SO2NH2、SO2NHR9、SO2NR9R9；或者
R10为连接于苯基或杂芳基的碳原子上的＝O，或者，如果S原子存在的话，R10可为连接于杂芳基的相同S原子的一个或两个＝O；
R11代表两个相邻的取代基，其形成4-7元非芳香环，所述非芳香环任选包含至多两个独立选自N、O和S的杂原子；
每个R9独立地为C1-C6烷基、羟基-C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、苯基、苄基、杂芳基、-CH2-杂芳基或CF3；或者两个R9和与其相连的N原子一起形成任选被R10取代的4-8元环，所述环除含有N原子外，还至多含有2个独立选自N、O和S的杂原子；
R3是H、OR1、CH2R1R2、(CH2)1-2NR1R2、CH2-CH2-OR1、CH2-CO-NR1R2或CO-CH2R1R2；
R4是F、Cl、Br、I、OR1、NR1R2或者具有R1的给定含义之一；并且
R5具有R1的给定含义之一。
任何烷基、烯基或炔基可为线性的或分支的。
杂芳基意指含有单、双或三环体系的芳香环体系，其含有至多4个独立选自N、O和S的杂原子，例如呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、
唑基、异
唑基、
二唑基、噻二唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基、吲哚基、苯并噻吩基(benzothiophenyl)、苯并呋喃基、苯并咪唑基、吲唑基、苯并三唑基、苯并噻唑基、苯并唑基、喹啉基、异喹啉基、2，3-二氮杂萘基、喹喔啉基、喹唑啉基、噌啉基或1，5-二氮杂萘基。
优选的由R11所代表的4-7元非芳香环是任选包含1或2个氧原子的5或6元非芳香环，并包括例如与2个相邻碳原子相连的-O-CH2-O-或-O-CH2-CH2-O-。
当R1、R2和/或R3包含任选取代的氨基基团或可以形成加成盐的杂环基团时，式I化合物可以游离形式或盐形式存在，所述盐形式例如为与如有机或无机酸(例如盐酸、乙酸)的加成盐。当式I化合物分子中具有一个或多个不对称中心时，例如当哌啶环被取代时，应当理解，本发明包括各种旋光异构体和外消旋物、非对映异构体及其混合物。
在式I化合物中，独立的或在任何亚组合中的以下含义是优选的：
1.R1和R2各自独立地为H、任选被R10取代的苯基、任选被R10取代的杂芳基、任选被R10取代的杂芳基N-氧化物、任选被R10取代的C1-C6烷基、任选被R10取代的C2-C6烯基，任选被R10取代的C2-C6炔基、任选被R10取代的C3-C8环烷基或任选被R10取代的C4-C8环烯基；
2.R1和R2同与其连接的氮原子一起形成任选被R10取代的3-6元环，所述环除含有上述氮原子外，还含有至多1个独立选自N、O和S的杂原子。优选，该任选被R10取代的3-6元环仅包含一个N原子或两个N原子或一个N原子和一个O原子；更优选地，其为非芳香性的。实例为例如由任选被R10取代的以下化合物衍生得到的环，所述化合物为氮杂环丁烷、吡咯啉、吡咯烷、哌啶、哌嗪、酮基哌嗪(keto-piperazine)、噻嗪、噻嗪-二氧化物、四氢吡啶、哌啶酮、吗啉代或氮杂
。优选地，此环被一个或两个OH、C1-4烷基、C1-4烷氧基、CO-C1-4烷基或氨基甲酰基取代；
3.R10代表独立地选自以下基团的1到3个取代基，所述基团为：C1-C3烷基、C1-C3羟基烷基、C1-C6烷氧基烷基、C1-C3卤代烷基、苯基、杂芳基、F、Cl、OH；
4.R3是H、OR1、-CH2-CH2-NR1R2、-CH2-CH2-OR1、-CH2-C(O)-NR1R2；
5.R4是F、Cl、Br、I、-OR1、-NR1R2或具有R1的给定含义之一；
6.R5具有R1的给定含义之一。
本发明还包括制备式I化合物的方法，所述方法包括：
a)为制备其中R3和R4各自为H的式I化合物，将式II化合物
其中R1和R2定义同上，
与脲形成剂(urea forming agent)反应；或
b)为制备其中R3和R4各自为H的式I化合物，将式III化合物或其官能衍生物酰胺化
其中R5如上定义；或
c)为制备其中R3和R4各自均不为H的式I化合物，将其中R3和R4各自为H的式I化合物进行转化；
并且，需要时，将以游离形式获得的式I化合物转化为所需的盐形式，或将以盐形式获得的式I化合物转化为所需的游离形式。
上述方法步骤a)中所用的脲形成剂例如可为光气、三光气或甲酸三氯甲酯，随后加入胺。当式II化合物与异氰酸酯反应时，也可形成脲。
上述方法步骤b)中的酰胺化可通过下面方法方便地进行：形成活化的羰基官能衍生物(例如酰氯、混合酸酐或对称酸酐)，随后与胺反应；或直接使例如甲酯与胺在加热或微波辐射条件下反应。
用作起始原料的式II化合物可按以下方法制备：
R1和R2定义同上。
用作起始原料的式III化合物可按以下方法制备：
其中R5定义同上且P为保护基团，例如甲基、乙基、叔丁基、三苯甲基、苄基、芴基、三甲基硅烷基乙基或烯丙基酯。
可根据本领域公知的方法或下文公开的方法进行上述反应。可通过酸或碱水解、氟化物处理或氢化脱除保护基团P。
在未对起始产物的制备进行特别说明的情况下，所述化合物是已知的或可用与本领域已知的或此后描述的方法类似的方法进行制备。
以下实施例为举例说明本发明，而非对本发明进行限制。
实施例1
(6aR，9R)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7，9-二甲酸9-二乙基酰胺7-苯基酰胺
将在丙酮(5ml)中的(6aR，9R)-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸二乙基酰胺的甲磺酸酯(122mg，0.30mmol)和异氰酸苯酯(36mg，0.30mmol)的混合物在25℃搅拌3小时。除去溶剂，将所得残留物用快速色谱(SiO2，环己烷/叔丁基甲基醚1∶0→2∶3)处理，得到标题化合物。MS/ES：429[M+H]+
根据相似的方法制备下式的化合物
其中R5具有表1中给出的含义。
表1
实施例13
(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
步骤1：(6aR，9R)-7-氰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯
向盛有麦角酸甲酯(1.0g，3.54mmol)的无水二氯甲烷(50ml)溶液的50ml圆底烧瓶中缓慢地加入溴化氰(2.02g，19.11mmol)，将所得的黑色反应混合物在室温下搅拌4小时，此时使用10％甲醇/二氯甲烷的TLC表明起始原料部分转化，得到两种展开速度快(fast-running)的产物。将反应混合物搅拌一个周末，TLC监测显示没有变化。然后在50℃将反应混合物搅拌4小时，然后用酒石酸溶液和二氯甲烷萃取。将水相用二氯甲烷(100ml)再次萃取，用盐水(200ml)洗涤合并的有机相，经MgSO4干燥，过滤，真空下浓缩，得到深褐色(焦油色)的油。通过正相快速柱层析(Biotage Flash40，90g柱)，使用40％乙酸乙酯/己烷进行纯化，将以浅黄色固体分离得到的展开速度快的产物分离。将该产物用叔丁基甲基醚结晶并缓慢蒸发。将所得结晶物质用泵过滤，得到浅黄色结晶。
步骤2：(6aR，9R)-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯
向盛有(6aR，9R)-7-氰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯(1.57g，5.35mmol)的乙酸(20ml)溶液的100ml圆底烧瓶中，加入水(4ml)和锌(1.5g)。使反应混合物在100℃回流3小时，此时使用20％甲醇/DCM的TLC显示起始原料转化，生成非对映体混合物形式的产物。将反应混合物过滤以除去锌，用水(200ml)和乙酸乙酯(200ml)充分洗涤滤纸。通过加入固体碳酸氢钠使水相呈碱性。然后对水相进行萃取，并进行分离。用乙酸乙酯(2×100ml)再次萃取水相，用盐水(200ml)洗涤合并的有机相，干燥(MgSO4)，用泵过滤并真空下浓缩，得到米黄色泡沫状物。通过正相快速柱层析(Biotage Flash 40，40g柱料)，使用10％甲醇/二氯甲烷进行纯化，以完成分离。分离得到产物，为米黄色泡沫状物。
步骤3：(6aR，9R)-7-苯基氨基甲酰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯
向盛有(6aR，9R)-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯(0.8g，2.98mmol)的二氯甲烷(20ml)溶液的100ml圆底烧瓶中，加入异氰酸苯酯(0.45ml，4.5mmol，1.5当量)。将反应混合物在室温下搅拌16小时，此时使用10％甲醇/DCM的TLC显示起始原料转化，生成为非对映体混合物的产物。真空下浓缩挥发物，直接使用正相快速柱层析(Biotage Flash 40，90g柱)，用30％乙酸乙酯/己烷纯化，以分离为1∶1非对映体混合物的产物。
步骤4：(6aR，9R)-7-苯基氨基甲酰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸
向盛有(6aR，9R)-7-苯基氨基甲酰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸甲酯(0.8g，2.06mmol)的100ml圆底烧瓶中，加入甲醇(12ml)、THF(24ml)和氢氧化锂(247mg)的水(12ml)溶液。将反应混合物在室温下搅拌20分钟，此时使用20％甲醇/二氯甲烷的TLC显示起始原料已完全转化。粗反应混合物的颜色从亮黄色变为紫红色。真空下除去挥发物(仅留下水)，加入1M HCl使水溶液呈酸性。用泵过滤所得的米黄色沉淀并用蒸馏水(50ml)洗涤滤饼。然后将滤饼在高真空烘箱中在50℃下干燥16小时，以提供产品。
步骤5：(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
向盛有(6aR，9R)-7-苯基氨基甲酰基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸(0.2g，0.54mmol)、PYBOP(0.307g)、二氯甲烷(10ml)的混悬液的50ml圆底烧瓶中，加入吡咯烷(0.054ml，0.64mmol，1.2当量)和Hünigs碱(0.187ml，1.07mmol，2当量)。将反应混合物在室温下搅拌3小时。通过正相快速柱层析(Biotage Flash 40，40g柱料)，用50％乙酸乙酯/己烷作为溶剂进行纯化。分离得到(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺，为米黄色固体。MS/ES：427(M+H)+
用类似的方法和适当的胺制备下式化合物
其中R1和R2具有表2给出的含义。
表2
实施例45
(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸
(2-甲氧基-苯基)-酰胺
步骤1：((6aR，9R)-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基)-吡咯烷-1-基-甲酮
将30g(111.80mmol)麦角酸溶于400ml二氯甲烷中并冷却至0℃-5℃，加入31.16ml(223.61，2当量)三乙胺和18.66ml(223.61mmol，2当量)吡咯烷，在15分钟内加入1.5当量的丙烷膦酸酐(50％的乙酸乙酯溶液)。将反应混合物在室温下搅拌1小时，然后将其倒在冰上并用二氯甲烷萃取，用Na2SO4干燥有机层，蒸发，通过二氧化硅层析用二氯甲烷∶甲醇9∶1洗脱，纯化残留物(28.6g)，得到((6aR，9R)-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基)-吡咯烷-1-基-甲酮。
步骤2：(6aR，9R)-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基-吡咯烷-1-基-甲酮
在0℃，将6g(18.67mmol)步骤1的产物溶于180ml二氯甲烷中，并加入5.522g(22.40mmol，1.2当量)70％的间氯过苯甲酸。10分钟后中间体N-氧化物已经形成，加入在12ml甲醇中的2.594g(9.33mmol，0.5当量)FeSO4.7H2O，除去冷却并将混合物在室温下搅拌。1小时25分钟后用0.1M EDTA溶液(事先调节pH为9)萃取反应混合物，用Na2SO4干燥，蒸发，通过硅胶层析，用二氯甲烷∶甲醇∶氨水93∶6∶1洗脱进行纯化，得到(6aR，9R)-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基-吡咯烷-1-基-甲酮。
步骤3：(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸(2-甲氧基-苯基)-酰胺
将5.087g(16.54mmol)步骤2的产物溶于80ml四氢呋喃，加入1.79ml(16.5mmol)1-异氰酸根合-2-甲氧基-苯并在室温下搅拌。为捕获过量的异氰酸酯，加入0.3当量的3-氨基-1，2-丙二醇并搅拌2.5小时。然后用饱和碳酸氢钠溶液和盐水洗涤反应混合物，用Na2SO4干燥，并部分蒸发，结晶得到(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸(2-甲氧基-苯基)-酰胺。MS/ES：457(M+H)+
根据类似的方法制备下式的化合物
其中R5具有表3给出的含义。
表3
实施例56
5-甲基-9-(哌啶-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
按照类似于实施例45描述的方法，在步骤1中使用2-甲基-麦角酸(代替麦角酸)和哌啶(代替吡咯烷)并在步骤3中使用异氰酸苯酯，制备5-甲基-9-(哌啶-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS：455(M+H)+
实施例57
9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸(3-氟-苯基)-酰胺
将62 mg(0.20mmol)实施例45的步骤2中的产物溶于3 ml二氯甲烷中，加入0.14ml(10当量)三乙胺，以及在2ml二氯甲烷中的0.042ml氯甲酸三氯甲酯。30分钟后在室温下加入0.14ml三乙胺(10当量)和0.040ml(2当量)2-氟苯胺。在室温下搅拌22小时后，将反应混合物用100ml二氯甲烷和饱和碳酸氢钠溶液分离。将有机层用Na2SO4干燥并蒸发。将粗产品通过硅胶层析，用乙酸乙酯/环己烷3∶1洗脱进行纯化，得到(6aR，9R)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸(3-氟-苯基)-甲酰胺。MS/ES：445(M+H)+
按照类似的方法，使用适当的胺试剂制备下式化合物
其中R5具有表4给出的含义。
表4
实施例72
(6aR，9R)-5-氯-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将64mg实施例13(0.15mmol)溶于1ml DMF中，加入36mg(0.27mmol，1.8当量)N-氯代琥珀酰亚胺并在室温下搅拌。55分钟后通过二氧化硅层析，用乙酸乙酯洗脱，纯化反应混合物，得到(6aR，9R)-5-氯-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS：461(M+H)+
实施例73
(6aR，9R)-5-碘-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg喹啉-7-甲酸苯基酰胺
按照如实施例72所述的类似方法，使用N-碘代琥珀酰亚胺代替N-氯代琥珀酰亚胺，制备(6aR，9R)-5-碘-9-吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS：553(M+H)+
实施例74
(6aR，9R)-5-溴-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
步骤1：(6aR，9R)-5-溴-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸将麦角酸(8.05g，30mmol)混悬于二
烷中，并滴加加入TFA(放热)进行处理。滴加加入溶于氯仿的溴(1.54ml，30mmol，1.0当量)。将反应物冷却至5℃，使产品结晶。通过过滤分离得到(6aR，9R)-5-溴-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸，并用乙醚重结晶。Rf＝0.5，10％MeOH：DCM，M+H+＝346，348，m.p.＞245(分解)。
步骤2：(6aR，9R)-5-溴-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg喹啉-9-基)-吡咯烷-1-基-甲酮
向盛有(6aR，9R)-5-溴-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸(5.0g，13.38mmol)的DMF(20ml)溶液的50ml圆底烧瓶中，加入HATU(6.10g，16.06mmol，1.2当量)并将反应混合物在室温下搅拌1小时。加入吡咯烷(2.24ml，26.78 mmol，2.0当量)，将反应混合物在室温下再搅拌2小时。使用10％甲醇/DCM的TLC显示起始原料已完全转化(用氯仿/TBDM试剂和UV使其可视化)。向反应混合物加入4M HCl(150ml)和水(150ml)，并加入乙酸乙酯(200ml)。萃取后，将水相用乙酸乙酯(2×200ml)再次萃取并用饱和碳酸氢盐(2×200ml)、水(200ml)、饱和盐水(200ml)洗涤合并的萃取物，泵过滤，干燥(MgSO4)，真空下浓缩得到深褐色油状物。通过正相快速柱层析(Biotage Flash 40，90g柱料)进行纯化，纯化中用20％乙酸乙酯/己烷逐渐过渡到100％乙酸乙酯然后到5％甲醇/乙酸乙酯，洗脱剂总共超过5升。合并相关流份，真空下浓缩并在50℃下置于高真空烘箱中3小时，以得到(6aR，9R)-5-溴-7-甲基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-甲酸和非对映体的混合物。
步骤3：((R)-5-溴-7-甲基-7-氧基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基)-吡咯烷-1-基-甲酮
利用超声发生器将1.1g(2.75mmol)步骤2的产物溶于THF(40ml)中，然后使用丙酮/干冰浴将所述溶液冷却至-40℃。分次加入(超过30分钟)m-CPBA(0.640g，3.75mmol，1.35当量)，使所得的深褐色反应混合物回温至0℃，期间恒速搅拌(约1.5小时)。在0℃下将氯化亚铁(II)(0.174g，1.37mmol，0.5当量)的水(10ml)溶液滴加到反应混合物中。1小时后使反应混合物缓慢回温至室温，然后继续搅拌2小时。使用20％甲醇/DCM的TLC显示N-氧化物中间体已完全耗尽。向反应混合物中加入亚硫酸氢钠(1g)的水(5ml)溶液，然后真空下除去挥发物，得到黑色泡沫状物。使2％甲醇/DCM以每升溶剂增加2％的幅度逐渐过渡到8％甲醇/DCM，通过BiotageFlash 40系统纯化所述黑色泡沫状物，得到((R)-5-溴-7-甲基-7-氧基-4，6，6a，7，8，9-六氢-吲哚并[4，3-fg]喹啉-9-基)-吡咯烷-1-基-甲酮。
步骤4：(6aR，9R)-5-溴-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将步骤3的产物(0.504g，1.32mmol)溶于无水二氯甲烷(20ml)中，用冰-盐浴将溶液冷却至0℃。然后加入Hünigs碱(0.940ml，0.21mmol)和异氰酸苯酯(0.388ml，3.9mmol)，使反应混合物回温到室温。继续搅拌16小时。使用20％甲醇/DCM的TLC显示起始原料已完全耗尽。通过正相快速柱层析(Biotage Flash 40，40g柱料)，使用梯度系统进行纯化，所述梯度系统从20％乙酸乙酯/己烷(1升)开始，并逐渐过渡到30％乙酸乙酯/己烷(1升)，然后过渡到50％乙酸乙酯/己烷(1升)，最终为60％乙酸乙酯/己烷(1升)。合并相关流份，真空下浓缩并置于50℃高真空烘箱中3小时。分离得到为无色固体的(6aR，9R)-5-溴-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺β。MS/ES：505(M+H)+
实施例75
(6aR，9R)-5-苯基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
向盛有在DME(1ml)中的实施例74的产物(0.05g，0.27mmol)的微波反应瓶中加入苯基硼酸(46mg，0.37mmol，1.4当量)和2M碳酸钠(1.50ml)。将反应混合物以氮气吹洗5分钟同时搅拌，然后加入催化剂(30mg)。用经氮气冲洗的乙醇(0.75ml)洗涤瓶壁，再用氮气吹洗反应混合物5分钟。将瓶用瓶帽密封并将反应混合物置于100℃微波下300秒(固定持续时间)。使用10％甲醇/DCM的TLC显示起始原料已全部耗尽(用氯/TBDM试剂和UV使其可视化)。将反应混合物在饱和碳酸氢盐(20ml)和二氯甲烷(20ml)中分配。将有机相直接应用于快速柱上，并通过正相快速柱层析(BiotageFlash 40，40g柱料)，使用30％乙酸乙酯/己烷(1升)逐步过渡到40％乙酸乙酯/己烷(1升)作为溶剂进行纯化。合并相关流份，真空下浓缩并置于50℃高真空烘箱中3小时，分离出产物。MS：503(M+H)+
根据类似的方法制备下式的化合物
其中R4具有表5中的含义。
表5
实施例78
(6aR，9R)-5-(3-羟基-丙-1-炔)-(9-吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸
将实施例74的化合物(50mg，0.1mmol)、三苯基膦(3mg，0.001mmol，0.1当量)、碘化亚铜(1mg，0.005mmol，0.05当量)、三乙胺(1ml)、吡啶(1ml)的溶液置于5ml微波反应瓶中，然后加入炔丙醇(0.007ml，0.12mmol，1.2当量)，将反应混合物用氮气吹洗5分钟同时搅拌。加入二氯双(三苯基膦)钯催化剂(7mg，0.01mmol，0.1当量)并再将反应物置于氮气吹洗下5分钟。将瓶用瓶帽密封并将反应混合物置于100℃微波下300秒(固定持续时间)。LC-MS显示一些转化为产物。将催化剂(7mg，0.01 mmol，0.1当量)、炔丙醇(7μl，0.12mmol，1.2当量)和碘化亚铜(I)(1mg，0.005mmol，0.05当量)加入反应混合物中并在100℃微波下再反应300秒。LC-MS显示转化进行到起始原料∶产物约为1∶1的程度。将反应混合物置于100℃下再反应600秒，其后LC-MS显示起始原料基本消耗，转变为产物。通过正相快速柱层析(Biotage Flash 40，40g柱料)，用50％乙酸乙酯/己烷(2升)进行纯化。合并相关流份，真空下浓缩并在50℃高真空烘箱中干燥3小时，分离所得产物。MS/ES：481(M+H)+
实施例79
[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙酸异丙酯
将5g(11.72mmol)实施例13的化合物溶于100ml二氯甲烷中。室温下加入30ml 40％的氢氧化钠水溶液和400mg苄基三乙基-氯化铵。将反应混合物冷却至0-5℃，加入6.23ml(46.89mmol，4当量)溴代乙酸异丙酯并搅拌1小时。将反应混合物倾倒在冰上并用CH2Cl2萃取，用水洗涤有机层，用Na2SO4干燥，并蒸发。残留物通过二氧化硅层析纯化，用叔丁基甲基醚洗脱，得到[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙酸异丙酯。MS/ES：527(M+H)+
实施例80
[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙酸
作为合成实施例79产物的副产物，分离得到[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙酸。MS/ES：485(M+H)+
根据类似实施例79的方法制备下式化合物
其中R3具有表6中的含义。
表6
根据类似实施例79的方法，以实施例1化合物代替实施例13化合物作为起始原料并使用适当的卤代烷，制备下式化合物
其中R3具有表7给出的含义。
表7
实施例87
(6aR，9R)-4-(2-羟基-乙基)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将3.99g(7.57mmol)实施例79的化合物溶于100ml四氢呋喃中，并在0-5℃下加入989mg(45.43mmol，4当量)硼氢化锂。将反应混合物在室温下搅拌4.5小时。然后将反应混合物倾倒在冰/乙酸混合物上(剧烈释放CO2)并用二氯甲烷萃取。用水洗涤有机层，用Na2SO4干燥并蒸发。将残留物通过二氧化硅层析，用二氯甲烷∶甲醇95∶5洗脱进行纯化，得到所期的(6aR，9R)-4-(2-羟基-乙基)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺的β-异构体。MS/ES：471(M+H)+
实施例88
(6aR，9R)-4-(2-吗啉-4-基-乙基)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
步骤1：甲苯-4-磺酸2-[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙基酯
将1.12g(2.38mmol)实施例87的化合物溶于40ml二氯甲烷中，在室温下加入437mg(3.58mmol，1.5当量)二甲基氨基吡啶并将混合物冷却至0-5℃。加入683mg(3.589mmol，1.5当量)4-甲基-苯磺酰氯，并将反应混合物在室温下搅拌3.5小时。将反应混合物倾倒在冰和一些6N的硫酸上并用二氯甲烷萃取。将有机层用Na2SO4干燥并蒸发。将残留物用二氧化硅层析纯化，得到甲苯-4-磺酸2-[(6aR，9R)-7-苯基氨基甲酰基-9-(吡咯烷-1-羰基)-6a，7，8，9-四氢-6H-吲哚并[4，3-fg]喹啉-4-基]-乙基酯。
步骤2：(6aR，9R)-4-(2-吗啉-4-基-乙基)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将80mg(0.128mmol)步骤1的产物和1ml吗啉在室温下搅拌16小时。通过硅胶层析，用丙酮∶环己烷6∶4洗脱，纯化反应混合物，得到(6aR，9R)-4-(2-吗啉-4-基-乙基)-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3fg]喹啉-7-甲酸苯基酰胺。MS/ES：540(M+H)+
根据与实施例88步骤2的类似方法制备下式化合物
其中R3具有表8给出的含义。
表8
实施例97
(6aR，9R)-4-乙酰基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将80mg实施例13的化合物(0.18mmol)和69mg(0.56mmol，3当量)二甲基氨基嘧啶溶于3ml二氯乙烷中，加入0.036ml(0.37mmol，2当量)乙酸酐。将反应混合物在65℃搅拌4小时。在二氯甲烷和饱和碳酸氢盐水溶液间分离反应混合物。将有机层用Na2SO4干燥并蒸发。将粗产物通过二氧化硅层析，用二氯甲烷∶甲醇97∶3洗脱，进行纯化，得到(6aR，9R)-4-乙酰基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS/ES：469(M+H)+
实施例98
(6aR，9R)-4-羟基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
步骤1：(5aS，6aR，9R)-9-(吡咯烷-1-羰基)-5，5a，6，6a，8，9-六氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将351mg(0.82mmol)实施例13的化合物溶于6ml三氟乙酸中并加入0.407ml(2.47mmol，3当量)三乙基硅烷。将反应混合物在室温下搅拌1小时10分钟。然后用乙酸乙酯和饱和碳酸氢盐水溶液分离反应混合物，用盐水洗涤有机层，用Na2SO4干燥并蒸发，用叔丁基甲基醚结晶，得到(5aS，6aR，9R)-9-(吡咯烷-1-羰基)-5，5a，6，6a，8，9-六氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。
步骤2：(6aR，9R)-4-羟基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将212mg(0.49mmol)步骤1的产物溶于12ml甲醇中，并加入41mg(0.12mmol，0.25当量)在几滴水中的钨酸钠脱水物。然后在0℃加入670μl30％H2O2(10当量)并在室温下搅拌50分钟。用二氯甲烷和饱和碳酸氢盐水溶液分离反应混合物，用盐水洗涤有机层，用Na2SO4干燥并蒸发，并通过二氧化硅层析，用叔丁基甲基醚∶环己烷9∶1洗脱，进行纯化，得到(6aR，9R)-4-羟基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS/ES：441(M+H)+
实施例99
(6aR，9R)-4-甲氧基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺
将17mg(0.038mmol)实施例98的化合物溶于2ml甲醇和二氯甲烷(1∶1)中，将新制重氮甲烷溶液蒸馏通入反应混合物中10分钟，直到黄色持续存在。将反应混合物蒸发并通过二氧化硅层析，使用叔丁基甲基醚∶环己烷9∶1作为洗脱剂进行纯化。通过蒸发使产物结晶，得到(6aR，9R)-4-甲氧基-9-(吡咯烷-1-羰基)-6，6a，8，9-四氢-4H-吲哚并[4，3-fg]喹啉-7-甲酸苯基酰胺。MS/ES：458(M+H)+
以游离形式或药学上可接受的盐形式存在的式I化合物具有有价值的药理学性质，例如作为CXCR3拮抗剂，例如在体外试验中所表明的，并因此可用于治疗。
a)CXCR3膜结合试验
配体结合试验是用来识别与CXCR3表达膜结合的I-TAC抑制剂的。由用人CXCR3转染的CHO细胞制备细胞膜。使用闪烁接近测定(Scintillation Proximity Assay)(SPA)技术(Amersham Pharmacia Biotech)评价125I标记的CXCR3配体(例如I-TAC(CXCL11))与CXCR3的结合。将缓冲液或化合物的系列稀释物与标记的CXCR3配体(例如I-TAC)、CXCR3表达膜和WGA包被的PVT珠在室温下孵育2小时。然后将板离心并在Topcount(Packard)仪器中计数。报告达到50％的125I配体结合抑制所需的化合物浓度的数据。在此试验中，式I化合物具有1μM-1nM的IC50值。例如，实施例18、23、43、59和79的化合物分别具有54、61、23、43和145 nM的IC50。
b)CXCR3功能试验-Ca2+动员
在CXCR3转染的L1.2细胞(小鼠前B细胞系)中评价CXCR3配体诱导的Ca2+动员。为此，将细胞载荷Ca2+敏感的荧光物Fluo-4(分子探针)。洗涤后，将细胞与低分子量抑制剂在室温下预孵育2小时。在加入CXCR3配体(例如I-TAC)后，在荧光成像读板仪(FLIPR)中监测细胞内的Ca2+的瞬时增加。在CXCR3拮抗剂存在下，以IC50值报告CXCR3配体诱导的Ca2+动员抑制作用，即将最大Ca2+响应降至50％的化合物浓度。在本试验中，式I化合物具有1μM-1nM的IC50值。例如，实施例18、23、43、59和79的化合物分别具有18、8、16、20和53nM的IC50。
c)CXCR3功能试验-趋化性
使用带有聚碳酸酯膜(具有5μm直径的孔)的96孔一次性趋化性测定仪(Multiscreen MIC，Costar)，评价由CXCR3配体(例如I-TAC)诱导的定向细胞迁移。将趋化因子(例如I-TAC)置于腔室的底孔中并将细胞(例如CXCR3转染的L-1.2细胞)置于趋化性测定仪的顶部隔室中。使跨越多孔膜的细胞迁移在37℃下进行4小时。通过流式细胞仪对从顶部隔室迁移到底部隔室的细胞进行定量。当测试低分子量抑制剂时，以同样的浓度向两个隔室中加入化合物。测试化合物的系列稀释物，以评价其对CXCR3依赖的细胞迁移的抑制作用。以IC50报告导致迁移的细胞减少50％的低分子量CXCR3抑制剂的浓度。在此试验中，式I化合物具有1μM-1nM的IC50值。例如，实施例18和43的化合物分别具有74和75 nM的IC50。
d)在鼠科动物模型中进行的实验表明在缺少功能性CXCR3的情况下，实验性损伤(例如由同种异体移植诱发)后的脉管壁重塑显著减少。
因此，式I化合物可用于预防和/或治疗由趋化因子受体(例如CXCR3)和其配体间相互作用介导的疾病或病症。所述疾病或病症例如自身免疫性疾病，例如类风湿性关节炎、系统性红斑狼疮、桥本(Hashimoto)氏甲状腺炎、多发性硬化、重症肌无力、I型或II型糖尿病及其并发症、血管炎、恶性贫血、Sjoegren氏综合征、葡萄膜炎、银屑病、斑秃等；过敏性疾病例如过敏性哮喘、特应性皮炎、过敏性鼻炎/结膜炎、过敏性接触性皮炎；任选与潜在异常反应有关的炎性疾病，例如炎性肠病、克罗恩(Crohn)氏病或溃疡性结肠炎、内源性哮喘、炎性肺损伤、炎性肝损伤、炎性肾小球损伤、动脉粥样硬化、骨关节炎、刺激性接触性皮炎，另外还包括湿疹性皮炎、脂溢性皮炎、免疫介导疾病的皮肤表现、炎性眼病、角膜结膜炎、心肌炎或肝炎；缺血/再灌注损伤，例如心肌梗塞、中风、肠缺血、肾衰竭或出血性休克、创伤性休克等；癌症，例如实体瘤或淋巴癌，例如T细胞淋巴瘤或T细胞白血病、转移或血管生成；感染性疾病，例如中毒性休克(例如由超抗原诱发的)、脓毒性休克、成人型呼吸窘迫综合征；或移植，比如急性或慢性器官、组织或细胞同种或异种移植排斥或移植物功能延迟恢复。移植意为例如细胞、组织或实体器官(例如胰岛、干细胞、骨髓、角膜组织、神经元组织、心脏、肺、心和肺、肾、肝、肠、胰腺、气管或食道)的同种或异种移植。慢性排斥也称为移植血管性疾病。
对于以上用途而言，所需剂量当然可根据给药模式、被治疗的具体病症和所期效果而变化。总体而言，每日约0.01到10mg/kg体重剂量，可得到系统性令人满意的结果。对大型哺乳动物(例如人)而言，推荐的日剂量为约0.5mg到约1000mg，该剂量可以方便地给药，例如以至多每日4次分剂量给药或以缓释形式给药。适当的用于口服给药的单位剂型包含约1-500mg的活性成分。
式I化合物可通过任何常规途径给药，尤其是肠内给药，例如口服，例如以片剂或胶囊形式；或胃肠外给药，例如以可注射溶液或混悬液的形式；局部给药，例如以洗剂、凝胶剂、膏剂或乳膏剂的形式；或以鼻内或栓剂的形式给药。可以用常规方法通过与药学上可接受的载体或稀释剂混合而生产药物组合物，该药物组合物包含游离形式或药学上可接受的盐形式的式I化合物和至少一种药学上可接受的载体或稀释剂。
式I化合物可以以游离形式或药学上可接受的盐形式(例如上面指出的)给药。这些盐可以用常规方法制备，并具有与游离化合物相同级别的活性。
根据前述内容，本发明还提供：
1.1预防或治疗需要此治疗的患者中的由趋化因子受体和其配体相互作用介导的病症或疾病(例如上述指出的)的方法，该方法包括将有效量的式I化合物或其药学上可接受的盐给药至所述患者；
1.2预防或治疗需要此治疗的患者中的炎性或自身免疫性疾病(如上面所指出的)的方法，该方法包括将有效量的式I化合物或其药学上可接受的盐给药至所述患者；
2.用作例如上述1.1或1.2下指出的任何方法中的药物的式I化合物或其药学上可接受的盐。
3.药物组合物，例如用于如上述1.1或1.2中的任何方法中的药物组合物，该药物组合物包含式I化合物或其药学上可接受的盐以及其药学上可接受的稀释剂或载体。
4.用于制备上述1.1或1.2中的任何方法中使用的药物组合物的式I化合物或其药学上可接受的盐。
式I化合物可单独作为活性成分给药或例如作为佐剂与其它药物一起给药，所述其它药物为：例如免疫抑制或免疫调节方案中的药物或其它抗炎药，它们是例如用于治疗或预防同种或异种移植的急性或慢性排斥或炎性或自身免疫性病症的药物；化疗药或抗感染药，例如抗病毒药，例如抗逆转录病毒药或抗生素。例如，式I化合物可与以下药物组合使用：钙依赖磷酸酶抑制剂，例如环孢菌素A或FK 506；mTOR抑制剂，例如雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、CCI779、ABT578或雷帕霉素类似物(rapalog)，例如AP23573、AP23464、AP23675、AP23841、TAFA-93、biolimus 7或biolimus 9；具有免疫抑制性质的子囊霉素，例如ABT-281、ASM981等；皮质类固醇；环磷酰胺；硫唑嘌呤；甲氨蝶呤；来氟米特；咪唑立宾；霉酚酸；吗替麦考酚酸酯；15-去氧精胍霉素(15-deoxyspergualine)或其免疫抑制剂同系物、类似物或衍生物；S1P受体激动剂或调节剂，例如FTY720或其类似物；PKC抑制剂，例如在WO 02/38561或WO 03/82859中公开的，例如实施例56或70的化合物；白细胞受体的单克隆抗体，例如MHC、CD2、CD3、CD4、CD7、CD8、CD11a/CD18、CD25、CD27、CD28、CD40、CD45、CD52、CD58、CD80、CD86、CD137、ICOS、CD150(SLAM)、OX40、4-1BB或其配体的单克隆抗体，例如CD154，或其拮抗剂；其它的免疫调节化合物，例如至少具有CTLA4胞外域的一部分的重组结合分子或其突变体，例如与非CTLA4蛋白序列结合的CTLA4的至少胞外域部分或其突变体，例如CTLA4Ig(例如ATCC 68629)或其突变体，例如LEA29Y；粘附分子抑制剂，例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂；或抗趋化因子抗体，例如抗MCP-1抗体或趋化因子受体抗体或低分子量趋化因子受体拮抗剂。
在式I化合物与其它免疫抑制/免疫调节、抗炎或化疗药物联合给药时，共同给药的免疫抑制剂、免疫调节剂、抗炎药或化疗药物的剂量当然可根据共同给药的药物类型(例如其为甾族化合物还是钙依赖磷酸酶抑制剂)、给药的具体药物、被治疗的病症等而变化。
根据前述内容，另一方面，本发明还提供：
5.上述定义的方法，该方法包括将治疗有效量的式I化合物和至少另一种药物共同给药(例如同时或依次)，所述另一种药物例如为免疫抑制剂、免疫调节剂、抗炎药、抗感染药或化学治疗药(例如上述指出的)。
6.药物组合产品，例如药盒(kit)，该药物组合产品包含a)第一种药物，其为CXCR3拮抗剂，例如本文中所公开的游离形式或药学上可接受的盐形式的式I化合物，和b)至少一种共同给药药物，例如免疫抑制剂、免疫调节剂、抗炎药、抗感染药或化疗药。所述药盒可以包括其给药说明书。
本文中使用的术语“共同给药”或“组合给药”或类似术语意在包括将所选择的治疗药物给药至单个患者，并包括治疗方案，其中所述治疗药物并非必须通过同样的给药途径或在同时给药。
本文中使用的术语“药物组合产品”意指由混合或组合多种活性成分而得到的产品，且其包含活性成分的固定和非固定组合。术语“固定组合”意指将活性成分(例如式I化合物和共同给药药物)同时以单一实体或剂型给药至患者。术语“非固定组合”意指将活性成分(例如式I化合物和共同给药药物)作为独立的实体同时、并存地或依次(没有特定时间限制地)给药至患者，其中这类给药向患者体内提供治疗有效水平的两种化合物。后者也用于鸡尾酒(cocktail)疗法，即给予3种或更多种的活性成分。
Claims (5)
1.游离形式或盐形式的式I化合物：
其中
R1和R2各自独立地为H、任选被R10和/或R11取代的苯基或苯基-C1-4烷基、任选被R10和/或R11取代的杂芳基或杂芳基-C1-4烷基、任选被R10和/或R11取代的杂芳基N-氧化物、任选被R10取代的C1-C8烷基、任选被R10取代的C2-C8烯基、任选被R10取代的C2-C8炔基、任选被R10取代的C3-C8环烷基或任选被R10取代的C4-C8环烯基；
或者R1和R2同与其连接的氮原子一起形成任选被R10取代的3-8元环，所述环除上述氮原子外还含有至多2个独立选自N、O和S的杂原子；
其中R10代表独立选自以下基团的1至4个取代基：C1-C6烷基、C1-C6羟基烷基、C1-C6烷氧基烷基、C1-C6卤代烷基、C3-C6环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、苯基、杂芳基、杂芳基N-氧化物、F、Cl、Br、I、OH、OR9、OCOR9、OCOOR9、OCONHR9、OCONR9R9、OSO2R9、COR9、COOH、COOR9、CONH2、CONHR9、CONR9R9、CF3、CHF2、CH2F、C1-4烷基NH2、C1-4烷基NHR9、C1-4烷基NR9R9、CN、NO2、NH2、NHR9、NR9R9、NHCOR9、NR9COR9、NHCONHR9、NHCONH2、NR9CONHR9、NR9CONR9R9、NHCOOR9、NR9COOR9、NHSO2R9、N(SO2R9)2、NR9SO2R9、SR9、SOR9、SO2R9、SO2NH2、SO2NHR9、SO2NR9R9；或者
R10为连接于苯基或杂芳基的碳原子上的＝O，或者，如果S原子存在的话，R10可为连接于杂芳基的相同S原子的一个或两个＝O；
R11代表两个相邻的取代基，其形成4-7元非芳香环，该环任选包含至多两个独立选自N、O和S的杂原子；
每个R9独立地为C1-C6烷基、羟基-C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、苯基、苄基、杂芳基、-CH2-杂芳基或CF3；或者两个R9与其相连的N原子一起形成任选被R10取代的4-8元环，该环除了上述N原子以外还含有至多2个独立选自N、O和S的杂原子；
R3是H、OR1、CH2R1R2、(CH2)1-2NR1R2、CH2-CH2-OR1、CH2-CO-NR1R2或CO-CH2R1R2；
R4是F、Cl、Br、I、OR1、NR1R2或者具有R1的给定含义之一；并且
R5具有R1的给定含义之一，
前提是不包括下式的化合物：
2.制备根据权利要求1的式I化合物的方法，该方法包括：
a)为制备其中R3和R4各自为H的式I化合物，使式II化合物
其中R1和R2定义同上，与脲形成剂反应；或
b)为制备其中R3和R4各自为H的式I化合物，使式III化合物或其官能衍生物酰胺化
其中R5如上所定义；或
c)为制备其中R3和R4各自均不为H的式I化合物，将其中R3和R4各自均为H的式I化合物进行转化；
并且如果需要的话，将所得的游离形式的式I化合物转化为所需的盐形式的式I化合物，或将所得的盐形式的式I化合物转化为所需的游离形式的式I化合物。
3.根据权利要求1的式I化合物或其药学上可接受的盐，其用作药物。
4.药物组合物，该药物组合物包含根据权利要求1的式I化合物或其药学上可接受的盐以及一种或多种其药学上可接受的稀释剂或载体。
5.根据权利要求1的式I化合物或其药学上可接受的盐在制备预防或治疗由趋化因子受体和其配体间的相互作用介导的病症或疾病的药物中的用途。
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| GBGB0511060.6A GB0511060D0 (en) | 2005-05-31 | 2005-05-31 | Organic compounds |
| GB0511060.6 | 2005-05-31 | ||
| PCT/EP2006/005106 WO2006128658A1 (en) | 2005-05-31 | 2006-05-29 | Ergoline derivatives and their use as chemokine receptor ligands |
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| JP (1) | JP5121703B2 (zh) |
| KR (1) | KR20080013971A (zh) |
| CN (1) | CN101184754B (zh) |
| AU (1) | AU2006254395B2 (zh) |
| BR (1) | BRPI0611489A2 (zh) |
| CA (1) | CA2608702C (zh) |
| GB (1) | GB0511060D0 (zh) |
| MX (1) | MX2007015084A (zh) |
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| WO (1) | WO2006128658A1 (zh) |
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| EP2515654A4 (en) * | 2009-12-23 | 2013-04-24 | Map Pharmaceuticals Inc | NEW ERGOLINANALOGA |
| JP5874124B2 (ja) | 2010-06-28 | 2016-03-02 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 緑内障の処置に使用するための薬学的組成物 |
| MX2013015373A (es) | 2011-06-23 | 2014-02-11 | Map Pharmaceuticals Inc | Nuevos analogos de fluoroergolina. |
| SG11201403434YA (en) | 2011-12-19 | 2014-09-26 | Map Pharmaceuticals Inc | Novel iso-ergoline derivatives |
| SG10201506202RA (en) | 2011-12-21 | 2015-09-29 | Map Pharmaceuticals Inc | Novel neuromodulatory compounds |
| US9012640B2 (en) | 2012-06-22 | 2015-04-21 | Map Pharmaceuticals, Inc. | Cabergoline derivatives |
| BR112014031945A2 (pt) * | 2012-06-22 | 2017-06-27 | Map Pharmaceuticals Inc | derivados de cabergolina |
| BR112017015487A2 (pt) * | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | Composto; composição; método de tratamento e/ou prevenção de enxaqueca, als, doença de alzheimer, doença de parkinson, distúrbios extrapirimidais, depressão, náusea, êmese, síndrome das pernas inquietas, insônia, agressão, doença de huntington, doença cardiopulmonar, fibrogênese, hipertensão arterial pulmonar, ansiedade, dependências a drogas, distonia, parassonia ou hiperlactinemia em um indivíduo; métodos de agonização dos receptores d2, 5-ht1d, 5-ht1a e 5-ht2c, em um indivíduo; método de antagonização do receptor d3 em um indivíduo; métodos de agonização seletiva dos receptores 5 -ht1d, e 5-ht2c, método de fornecimento de atividade de antagonista funcional no receptor 5 -ht2b ou no receptor 5-ht7, ou em ambos, em um indivíduo; método de fornecimento de atividade de antagonista funcional nos receptores adrenérgicos em um indivíduo |
| JP2018502889A (ja) | 2015-01-20 | 2018-02-01 | エックスオーシー ファーマシューティカルズ インコーポレイテッドＸｏｃ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ | イソエルゴリン化合物およびその使用 |
| WO2018223065A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
| GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
| WO2020212948A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Methods of treating neurocognitive disorders, chronic pain and reducing inflammation |
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| WO2000042071A2 (en) * | 1999-01-12 | 2000-07-20 | Cambridge University Technical Services Ltd. | Compounds and methods to inhibit or augment an inflammatory response |
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| PE20040079A1 (es) | 2002-04-03 | 2004-04-19 | Novartis Ag | Derivados de indolilmaleimida |
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| Publication number | Publication date |
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| CA2608702C (en) | 2013-10-15 |
| CA2608702A1 (en) | 2006-12-07 |
| US7666877B2 (en) | 2010-02-23 |
| EP1893611A1 (en) | 2008-03-05 |
| RU2007147597A (ru) | 2009-07-20 |
| US20090018127A1 (en) | 2009-01-15 |
| RU2416613C2 (ru) | 2011-04-20 |
| BRPI0611489A2 (pt) | 2010-11-23 |
| GB0511060D0 (en) | 2005-07-06 |
| MX2007015084A (es) | 2008-01-17 |
| JP5121703B2 (ja) | 2013-01-16 |
| JP2008545725A (ja) | 2008-12-18 |
| CN101184754A (zh) | 2008-05-21 |
| AU2006254395A1 (en) | 2006-12-07 |
| KR20080013971A (ko) | 2008-02-13 |
| WO2006128658A1 (en) | 2006-12-07 |
| AU2006254395B2 (en) | 2010-09-09 |
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