CN102459305A - 具有糖皮质激素活性的甾类[3,2-c]吡唑化合物的新衍生物 - Google Patents
具有糖皮质激素活性的甾类[3,2-c]吡唑化合物的新衍生物 Download PDFInfo
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- CN102459305A CN102459305A CN2010800245808A CN201080024580A CN102459305A CN 102459305 A CN102459305 A CN 102459305A CN 2010800245808 A CN2010800245808 A CN 2010800245808A CN 201080024580 A CN201080024580 A CN 201080024580A CN 102459305 A CN102459305 A CN 102459305A
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- naphtho
- indazole
- hydroxyl
- carbonyl
- sulfenyl
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Abstract
本发明披露式(I)的化合物以及含它们的药物组合物和它们的治疗用途。
Description
本发明涉及具有糖皮质激素受体激动剂活性的化合物、含它们的药物组合物和它们的治疗用途,特别是用于治疗炎性和变应性病症。
具有抗炎性的糖皮质激素(GCs)是公知的并且广泛用于治疗疾病,如炎性关节炎(例如类风湿性关节炎、强直性脊柱炎和牛皮癣性关节病),其它类风湿病如全身性红斑狼疮,硬皮病,包括颞动脉炎和结节性多动脉炎在内的脉管炎,炎性肠病如克罗恩病和溃疡性结肠炎,肺疾病如哮喘和慢性阻塞性气道疾病,以及很多其它病症如风湿性多发性肌痛(polymyalgia rheumatica)。GCs还因其免疫抑制性而广泛地用于预防和治疗移植排斥。最后,GCs因其抗肿瘤作用而用于治疗多种恶性肿瘤。
GCs通过作为细胞核受体亚家族之成员的特异性糖皮质激素受体(GR)发挥作用。配体结合促进受体二聚体形成,DNA结合,及转录激活。GC作用的该机制可很好地在体外确定,并且对下列事件而言是关键的:下丘脑-垂体-肾上腺轴的调节,葡萄糖异生,及抗炎基因如细胞分裂素活化蛋白激酶磷酸酶-1(mitogen-activated protein kinase phosphatase-1,MKP-1)和促分泌的白细胞蛋白酶抑制剂(SLPI)在体内的转录。与配体结合的受体还能通过干扰转录因子如AP-1和NFkB(它们均关键性地牵涉到炎性反应)的活性而以不依赖二聚体形成(dimerisation-independent manner)的方式来抑制基因转录。
配体结合之后,GR从细胞的细胞质转移至细胞核并与靶基因之调节物区域(regulator region)的糖皮质激素应答成分(glucocorticoid response element)结合。然后,活化的GR募集辅助因子,包括糖皮质激素受体相互作用蛋白1(GRIP-1)和甾类受体辅激活因子1(SRC1)。这些辅助蛋白结合到受体上,并使GR与一般性转录机(transcription machinery)相连以推动靶基因的转录。
糖皮质激素对转录的影响,既受活化的GR与靶DNA的直接结合和辅激活因子的同源二聚体形成和募集(称作“转录激活”)的介导,还受GR干扰的包括AP-1和NFkB在内的其它转录因子的功能的介导,后者是通过GR与这些其它转录因子结合并阻止它们与其靶基因结合,进而阻抑正常情况下受AP-1或NFkB正调节的基因(称作“转录阻抑”)来实现的。这两种受体活动方式是可以分离的,并且在缺少转录激活的情况下可以保持对NFkB活性的负影响。转录阻抑似乎是主要负责介导GR的治疗上所需要的抗炎活性。令人感兴趣的是,抑制AP-1或NFkB的IC50(0.04nM)低于活化靶基因的EC50(5nM),而治疗炎性疾病患者又经常需要高剂量的GCs。一种解释是,在炎症位点表达的细胞因子会例如通过活化AP 1或NFkB而引起相对的糖皮质激素抵抗。这是重要的,因为很多炎症前细胞因子信号借助于NFkB的活化产生,并且认为GCs的主要抗炎作用是通过对抗NFkB的作用介导的。
已公布的日本专利申请60067495描述了某些作为抗炎药的孕烯并吡唑(pregnenopyrazoles)。
我们的共同未决的国际专利申请PCT/GB2008/050890涉及式(I)化合物或其可药用盐,
其中
X1、X2、X3、X4和X5各自独立地表示CH或氮原子,条件是:X1、X2、X3、X4和X5中的不超过两个可同时表示氮原子;
n和p各自独立地表示0或1;
R1表示卤素原子或者甲基或甲氧基;
R2表示卤素原子、-C(O)OCH3、-C(O)-S-CH2CN、-C(O)-S-CH3、-C(O)-杂环基、-SO2CH3、C2-C6烯基,或甲基,所述基团任选被卤素、羟基、甲氧基、-OCH2CH=CH2或-NR7R8取代;
R3a表示氢原子或甲基以及R3b表示氢或氟原子;
R4表示-C(O)-S-C(O)N(CH3)2、-C(O)CH2Cl、-C(O)-Y-CH(R11)-R9或-C(O)-CH(R11)-Y-R9;
R5表示羟基、-OCH2SCH3、-O-C(O)-R10、-O-C(O)-NH-R10、-O-C(O)-O-R10或-O-C(O)-S-R10;
Rb表示氢或卤素原子或甲基,以及当R5不为羟基时,Rb还可表示羟基;
R7和R8各自独立地表示氢原子或C1-C3烷基或C1-C3羟基烷基,或者
R7和R8与它们连接的氮原子一起形成3元至8元的饱和或部分饱和的任选含有选自氮、S(O)m和氧的其它环杂基团(heterogroup)的杂环,所述杂环任选被选自以下的至少一个取代基取代羟基、C1-C3烷基和C1-C3羟基烷基;
M为0、1或2;
Y表示氧或硫原子或基团=NH;
R9表示氢、卤素、氰基、-S-CN、-C(O)N(R12)2、C1-C6烷氧基羰基、C1-C6烷基羰基(任选被-OC(O)CH3取代)、C1-C6烷基羰基氧基、C1-C6烷氧基、C1-C6烷基硫基、-C(O)-S-C1-C6烷基、-C(=CH2)-O-CH2OCH3、C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C7环烷基,所述C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C7环烷基任选被独立选自以下的一个或多个取代基取代:卤素、羟基、氰基、羟基甲基、C1-C4烷氧基和C1-C4烷基羰基氧基;
R10表示C1-C6烷基(任选被卤素、C1-C4烷氧基、C1-C4烷基羰基氧基或C3-C7环烷基取代)或3元至10元的饱和或不饱和的碳环或杂环的环系,所述环系可任选被选自以下的至少一个取代基取代:卤素、羧基、羟基、氧代、硝基、氰基、巯基、C1-C6烷基、C2-C6烯基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基硫基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C1-C6烷基羰基、C1-C6烷基羰基氧基、C1-C6烷氧基羰基、氨基(-NH2)、羧酰氨基(-CONH2)、(单)C1-C6烷基氨基、(二)C1-C6烷基氨基和苯基;
R11表示氢原子或甲基;以及
每个R12独立地表示氢原子或甲基;
条件是:当R4表示-C(O)CH2OH、-C(O)CH2OC(O)C2H5或-C(O)CH2Cl,X1、X2、X3、X4和X5各自表示CH以及R5表示-O-C(O)-R10(其中R10表示C1-C6烷基)时,存在R1和R2中的至少一个。
本发明提供这样的化合物,这些化合物落在上面提及的我们的共同未决的国际专利申请PCT/GB2008/050890的式(I)范围内,但是在上面提及的我们的共同未决的国际专利申请PCT/GB2008/050890中未具体披露。
因此,本发明提供选自以下的如上定义的式(I)化合物:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其任何一种的可药用盐。
应注意的是,上面所列的每个化合物均表示本发明的具体和独立的方面。
上面提及的式(I)化合物和本发明化合物可形成可药用盐,例如,酸加成盐如盐酸盐、氢溴酸盐、三氟乙酸盐、硫酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、乳酸盐、柠檬酸盐、丙酮酸盐、琥珀酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。
应理解的是,本发明化合物及其可药用盐可按溶剂化(例如水合)形式以及非溶剂化形式存在,以及本发明涵盖所有这些溶剂化形式。互变异构体及其混合物也形成本发明的方面。
本发明化合物及它们的可药用盐具有药物活性,特别是作为糖皮质激素受体活性调节剂的活性,因而可以用于治疗以下疾病:
1.呼吸道:气道阻塞性疾病,包括哮喘,包括支气管哮喘、变应性哮喘、内源性哮喘、外源性哮喘、运动诱发性哮喘、药物诱发性(包括阿司匹林和NSAID诱发的)哮喘和粉尘诱发性哮喘,既包括间歇性的又包括持续性的,以及各种严重度的哮喘,及其它原因引起的气道高反应性;慢性阻塞性肺病(COPD);支气管炎,包括传染性支气管炎和嗜酸性支气管炎;肺气肿;支气管扩张;囊性纤维化;结节病;农民肺及相关疾病;超敏感性肺炎;肺纤维化,包括隐原性纤维化肺泡炎、特发性间质性肺炎、抗肿瘤治疗和慢性感染(包括结核病和曲霉病及其它真菌感染)并发的纤维化;肺移植的并发症;肺血管的血管炎和血栓形成疾病及肺动脉高压;镇咳活性,包括治疗与气道炎症和分泌情况相关的慢性咳嗽及医源性咳嗽;急性鼻炎和慢性鼻炎,包括药物性鼻炎及血管运动性鼻炎;常年性(perennial)和季节性变应性鼻炎,包括神经性鼻炎(花粉症);鼻息肉病;急性病毒感染,包括普通感冒和由呼吸道合胞病毒、流行性感冒、冠状病毒(包括SARS)和腺病毒引起的感染;
2.皮肤:牛皮癣、特应性皮炎、接触性皮炎或其它湿疹性皮肤病及迟发型超敏反应;植物性和光照性皮炎;脂溢性皮炎、疱疹样皮炎、扁平苔癣、萎缩性硬化性苔癣、坏疽性脓皮症、皮肤结节病、盘状红斑狼疮、天疱疮、类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、中毒性红斑(toxicerythemas)、皮肤嗜酸粒细胞增多、斑秃、男性型脱发、斯威特综合征(Sweet’ssyndrome)、韦-克综合征(Weber-Christian syndrome)、多形性红斑;蜂窝组织炎,包括传染性和非传染性蜂窝组织炎;脂膜炎;皮肤淋巴瘤、非黑素瘤皮肤癌和其它发育不良性损伤;药物诱发的疾病,包括固定性药疹;
3.眼:睑炎;结膜炎,包括常年性(perennial)变应性结膜炎或春季变应性结膜炎;虹膜炎;前色素层炎和后色素层炎;脉络膜炎;自身免疫;影响视网膜的变性或炎性疾病;眼炎,包括交感性眼炎;结节病;感染,包括病毒、真菌和细菌感染;
4.生殖泌尿系统:肾炎,包括间质性肾炎和肾小球性肾炎;肾病综合征;膀胱炎,包括急性和慢性(间质性)膀胱炎和杭纳溃疡(Hunner’s ulcer);急性和慢性尿道炎、前列腺炎、附睾炎、卵巢炎和输卵管炎;女阴阴道炎;佩伦涅病(Peyronie’s disease);勃起机能障碍(男性和女性);
5.同种异体移植物排斥:在例如肾脏、心脏、肝、肺、骨髓、皮肤或角膜移植后或在输血后出现的急性和慢性同种异体移植物排斥;或慢性移植物抗宿主病;
6.其它自身免疫和变态反应性疾病:包括类风湿性关节炎、肠易激综合征、全身性红斑狼疮、多发性硬化症、桥本甲状腺炎(Hashimoto’s thyroiditis)、格雷夫斯病(Graves’disease)、阿狄森病(Addison’s disease)、糖尿病、特发性血小板减少性紫癜、嗜酸细胞性筋膜炎、高IgE综合征、抗磷脂综合征,及塞扎里综合征(Sazary syndrome);
7.肿瘤:对一般癌症的治疗,包括前列腺、乳腺、肺、卵巢、胰腺、肠和结肠、胃、皮肤和脑肿瘤及影响骨髓(包括白血病)和淋巴增生系统(例如何杰金(Hodgkin’s)和非何杰金淋巴瘤)的恶性肿瘤;包括对转移性疾病和肿瘤复发及瘤外综合征的预防和治疗;及
8.感染性疾病:病毒病如生殖器疣、人乳头瘤病毒、足底疣、乙型肝炎、丙型肝炎、单纯疱疹病毒、传染性软疣(molluscum contagiosum)、天花、人免疫缺陷症病毒(HIV)、人疣病毒(HPV)、巨细胞病毒(CMV)、水痘-带状疱疹病毒(VZV)、鼻病毒、腺病毒、冠形病毒、流行性感冒、副流行性感冒(para-influenza);细菌病如结核病和鸟分枝杆菌病、麻风病;其它传染病、如真菌病、衣原体病、念珠菌属病、曲霉病、隐球菌性脑膜炎、卡氏肺囊虫病、隐孢子虫病、组织胞浆菌病、弓形体病、锥虫感染和利什曼病。
因此,本发明提供选自以下的如上定义的式(I)化合物:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其可药用盐,用于治疗用途。
在另一方面,本发明提供选自以下的如上定义的式(I)化合物在制备用于治疗的药物中的用途:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其可药用盐。
在本说明书的上下文中,术语″治疗″还包括″预防″,除非有相反的说明。术语″治疗的″和″治疗上地″应当作相应的解释。
预期预防与以下患者的治疗特别相关:患有先前发作的所讨论的疾病或病症的人,或被视为面临所讨论的疾病或病症增加的风险的人。面临感染具体疾病或病症风险的人通常包括有所述疾病或病症家族史的人,或经遗传试验或筛选已经确定为对感染所述疾病或病症特别敏感的人。
具体地,本发明的化合物(包括可药用盐)可用于治疗哮喘{如支气管哮喘、变应性哮喘、内源性哮喘、外源性哮喘或粉尘性哮喘,特别是慢性或长期形成的哮喘(例如迟发哮喘或气道高反应性)},慢性阻塞性肺病(COPD),或者变应性鼻炎。
本发明还提供治疗阻塞性气道疾病或病症(例如哮喘或COPD)的方法,或者降低阻塞性气道疾病或病症(例如哮喘或COPD)危险的方法,其包括给予有此需要的患者治疗有效量的选自以下的如上定义的式(I)化合物:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯(R)/(S),
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其可药用盐。
对于上述治疗用途,给药剂量当然会随所采用的化合物、给药方式、需要的治疗和所显示的病症而变化。例如,如果吸入,则本发明的化合物的日剂量可以为0.05微克每千克体重(μg/kg)至100微克每千克体重(μg/kg)。可供选择地,如果化合物口服给药,则本发明的化合物的日剂量可以为0.01微克每千克体重(μg/kg)至100毫克每千克体重(mg/kg)。
本发明化合物及其可药用盐可以单独使用,但是通常以其中所述化合物/盐(活性成分)与可药用辅料、稀释剂或载体结合的药物组合物的形式给药。选择和制备适宜的药物制剂的常规方法可参见,例如″Pharmaceuticals-TheScience of Dosage Form Designs″,M.E.Aulton,Churchill Livingstone,1988。
依据给药方式,药物组合物优选包含0.05~99%w(重量百分数),更优选0.05~80%w,还优选0.10~70%w,甚至更优选0.10~50%w的活性成分,所有重量百分数均基于全部组合物。
本发明还提供药物组合物,其包含选自下列的如上定义的式(I)化合物:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其可药用盐,以及可药用辅剂、稀释剂或载体。
本发明还提供制备本发明药物组合物的方法,其包括使本发明化合物或其可药用盐与可药用辅剂、稀释剂或载体混合。
药物组合物可以例如乳膏、溶液、悬浮液、七氟烷烃(HFA)气雾剂和干粉制剂(例如置于已知为的吸入装置中的制剂)形式局部地给药(例如给药于皮肤或者给药于肺和/或气道);或所述化合物全身给药,如通过口服给药,例如采用如下形式:片剂、胶囊剂、糖浆剂、粉末剂或颗粒剂;或所述化合物可通过非经肠给药(包括腹膜内、静脉内、皮下、肌内、血管内注射或输注),例如以无菌注射用溶液剂、混悬剂或乳剂的形式来给药;或所述化合物可通过直肠给药,例如以栓剂的形式来给药。
本发明化合物及其可药用盐的干粉制剂和加压的HFA气雾剂可经口服或鼻吸入来给药。对于吸入给药,化合物/盐理想地为经微细分散的。经微细分散的化合物/盐优选具有小于10微米(μm)的质量中位直径(mass mediandiameter),并可在分散剂辅助下悬浮于抛射剂混合物中,所述的分散剂诸如C8-C20脂肪酸或其盐(例如,油酸)、胆汁酸盐、磷脂、烷基糖、全氟化的表面活性剂或聚乙氧基化的表面活性剂,或其它可药用分散剂。
本发明化合物及其可药用盐还可借助于干粉吸入器给药。吸入器可为单剂量或多剂量吸入器,并可为呼吸启动(breath actuated)的干粉吸入器。
一种可能性为混合微细分散的化合物/盐与载体物质,所述的载体物质例如单糖、二糖或多糖、糖醇或其它多元醇。适合的载体为糖,例如,乳糖、葡萄糖、棉子糖(raffinose)、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇;以及淀粉。可供选择地,微细分散的化合物/盐可用另一物质包衣。粉末混合物还可分配于硬明胶胶囊中,每个胶囊含有期望剂量的活性成分。
另一可能性为将微细分散的粉末加工成会在吸入操作过程中分解的球。可将该球状粉末装入多剂量吸入器(例如,已知为的吸入器,其中剂量单位量取被患者吸入的期望的剂量)的药物贮器中。有了该系统,将含有或不含载体物质的活性化合物递送至患者。
对于口服给药,可将本发明的化合物(或其可药用盐)与辅料或载体混合,然后压制成片剂,所述辅料或载体例如乳糖、蔗糖、山梨醇、甘露醇;淀粉,例如马铃薯淀粉、玉米淀粉或支链淀粉;纤维素衍生物;粘合剂,例如明胶或聚乙烯吡咯烷酮;和/或润滑剂,例如硬脂酸镁、硬脂酸钙、聚乙二醇、蜡、石蜡等等。若需要包衣片,可将如上描述制备的核心用浓的糖溶液包衣,所述的浓的糖溶液可含有,例如阿拉伯胶、明胶、滑石、二氧化钛。可供选择地,可将片剂用溶于易挥发有机溶剂中的适合的聚合物包衣。
对于制备软明胶胶囊而言,可将本发明的化合物(或其可药用盐)与例如植物油或聚乙二醇混合。硬明胶胶囊可含有使用了以上提及的用于片剂的赋形剂的化合物/盐颗粒。还可将本发明化合物的液态和半固态制剂装入硬明胶胶囊中。
用于口服的液体制剂可以如下形式存在:糖浆剂或混悬剂,例如含有本发明化合物的溶液剂,该溶液剂的其它成分为糖以及乙醇、水、甘油和丙二醇的混合物。所述液态制剂可任选含有着色剂、调味剂和/或作为增稠剂的羧甲基纤维素或本领域技术人员已知的其它赋形剂。
本发明的化合物及其可药用盐也可以与用于治疗上述疾病的其它化合物一起给药。
因此,本发明还涉及组合治疗,其中本发明的化合物或其可药用盐或者包含本发明的化合物或其可药用盐的药物组合物或剂型与一种或多种其它治疗剂同时、相继或者以组合制剂的形式给药,用于治疗一种或多种所列举的疾病。
具体地,为了治疗炎性疾病如(但不限于)类风湿性关节炎、骨关节炎、哮喘、变应性鼻炎、慢性阻塞性肺病(COPD)、牛皮癣和炎性肠病,本发明的化合物和它们的可药用盐可与下列药剂组合:非甾类抗炎药(在下文中为NSAIDs),包括无论局部应用还是全身应用的非选择性环氧化酶COX-1/COX-2抑制剂(例如吡罗昔康、双氯芬酸;丙酸类,例如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬;芬那酸类,例如甲芬那酸、吲哚美辛、舒林酸、阿扎丙宗(azapropazone);吡唑酮类,例如保泰松;水杨酸盐(酯),例如阿司匹林);选择性COX-2抑制剂(例如美洛昔康、塞来考昔、罗非考昔、伐地考昔、鲁马考昔(lumarocoxib)、帕瑞考昔和艾托考昔);抑制环氧化酶的一氧化氮供体(CINODs);糖皮质激素(无论通过局部、口服、肌内、静脉内途径还是通过关节内途径来给药);甲氨蝶呤;来氟米特;羟氯喹;d-青霉胺;金诺芬或其它非经肠或口服金制剂;镇痛药;双醋瑞因(diacerein);关节内治疗剂,例如透明质酸衍生物;和营养补剂,例如氨基葡萄糖。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:细胞因子或细胞因子功能的激动剂或拮抗剂(包括作用于细胞因子信号传导路径的药物,例如SOCS系统的调节剂),包括α-、β-和γ-干扰素;I型胰岛素样生长因子(IGF-1);白介素(IL),包括IL1至17和白介素拮抗剂或抑制剂(例如阿那白滞素);α肿瘤坏死因子(TNF-α)抑制剂,例如抗TNF单克隆抗体(例如英夫利昔单抗(infliximab)、阿达木单抗(adalimumab)和CDP-870)和TNF受体拮抗剂(包括免疫球蛋白分子(例如依那西普)和低分子量药物(例如己酮可可碱(pentoxyfylline)))。
另外,本发明涉及本发明化合物或其可药用盐与以下物质的组合:靶向于B淋巴细胞的单克隆抗体(例如CD20(利妥昔单抗(rituximab))、MRA-aIL16R)和靶向于T淋巴细胞的单克隆抗体(CTLA4-Ig、HuMax I1-15)。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:趋化因子受体功能调节剂,例如CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11(C-C家族)的拮抗剂;CXCR1、CXCR2、CXCR3、CXCR4和CXCR5(C-X-C家族)的拮抗剂;和CX3CR1(C-X3-C家族)的拮抗剂。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:基质金属蛋白酶(MMPs)即溶基质蛋白酶(stromelysin)、胶原酶和明胶酶及蛋白聚糖酶(aggrecanase)(尤其是胶原酶-1(MMP-1)、胶原酶-2(MMP-8)、胶原酶-3(MMP-13)、溶基质蛋白酶-1(MMP-3)、溶基质蛋白酶-2(MMP-10)和溶基质蛋白酶-3(MMP-11)及MMP-9和MMP-12)的抑制剂,包括药物,例如多西环素。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:白三烯生物合成抑制剂、5-脂肪氧化酶(5-LO)抑制剂或5-脂肪氧化酶活化蛋白(FLAP)拮抗剂,例如齐留通;ABT-761;芬留顿;替泊沙林;Abbott-79175;Abbott-85761;N-(5-取代的)-噻吩-2-烷基磺酰胺;2,6-二-叔丁基苯酚腙;甲氧基四氢吡喃,例如Zeneca ZD-2138;化合物SB-210661;吡啶基取代的2-氰基萘化合物,例如L-739,010;2-氰基喹啉化合物,例如L-746,530;或吲哚或喹啉化合物,例如MK-591、MK-886和BAY×1005。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:白三烯(LT)B4、LTC4、LTD4和LTE4的受体拮抗剂,选自吩噻嗪-3-基化合物,例如L-651,392;脒基化合物,例如CGS-25019c;苯并胺(benzoxalamine),例如昂唑司特;苯甲脒(benzenecarboximidamide),例如BIIL 284/260;和化合物,例如扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG-12525、Ro-245913、伊拉司特(CGP 45715A)和BAY×7195。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:磷酸二酯酶(PDE)抑制剂,例如甲基黄嘌呤(methylxanthanine),包括荼碱和氨荼碱;选择性PDE同工酶抑制剂,包括PDE4抑制剂或同工型PDE4D抑制剂,或PDE5抑制剂。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:组胺1型受体拮抗剂,例如西替利嗪、氯雷他定、地氯雷他定、非索非那定、阿伐斯汀、特非那定、阿司咪唑、氮斯汀、左卡巴斯汀、氯苯那敏、异丙嗪、赛克力嗪(cyclizine)或咪唑斯汀;口服、局部或非经肠给药。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:质子泵抑制剂(例如奥美拉唑)或胃保护性组胺2型受体拮抗剂。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:组胺4型受体拮抗剂。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:α1/α2肾上腺素能受体激动剂、血管收缩药、拟交感神经药,例如丙己君(propylhexedrine)、苯福林、苯丙醇胺、麻黄碱、伪麻黄碱、盐酸萘甲唑啉、盐酸羟甲唑啉、盐酸四氢唑啉、盐酸木甲唑啉、盐酸曲马唑啉或盐酸乙基去甲肾上腺素。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:抗胆碱能药,包括毒蕈碱受体(M1、M2和M3)拮抗剂,例如阿托品、东莨菪碱、格隆铵(glycopyrrrolate)、异丙托溴铵(ipratropium bromide)、噻托溴铵(tiotropiumbromide)、氧托溴铵(oxitropium bromide)、哌仑西平(pirenzepine)或替仑西平(telenzepine)。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:β-肾上腺素能受体激动剂(包括β受体亚型1-4),例如异丙去甲肾上腺素(isoprenaline)、沙丁胺醇(salbutamol)、福莫特罗(formoterol)、沙美特罗(salmeterol)、特布他林(terbutaline)、奥西那林(orciprenaline)、甲磺酸比托特罗(bitolterol mesylate)或吡布特罗(pirbuterol)或其手性对映异构体。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:色原酮,例如色甘酸钠或奈多罗米钠。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:调节细胞核激素受体(例如PPARs)的药物。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:免疫球蛋白(Ig)或Ig制品;或调节Ig功能的拮抗剂或抗体,例如抗IgE(例如奥马珠单抗(omalizumab))。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:另一种全身或局部应用的抗炎药,例如沙利度胺(thalidomide)或其衍生物、类维生素A(retinoid)、地蒽酚(dithranol)或卡泊三醇(calcipotriol)。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:氨基水杨酸盐(酯)和磺胺吡啶(例如柳氮磺吡啶、美沙拉嗪、巴柳氮和奥沙拉嗪)的组合;和免疫调节药,例如硫代嘌呤(thiopurine)。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:抗菌药,例如青霉素衍生物、四环素、大环内酯、β-内酰胺、氟喹诺酮、甲硝唑、吸入性氨基糖苷;抗病毒药,包括阿昔洛韦、泛昔洛韦、伐昔洛韦、更昔洛韦、西多福韦、金刚烷胺、金刚乙胺、利巴韦林、扎那米韦(zanamavir)和奥塞米韦(oseltamavir);蛋白酶抑制剂,例如茚地那韦、奈非那韦、利托那韦和沙奎那韦;核苷逆转录酶抑制剂,例如去羟肌苷、拉米夫定、司他夫定(stavudine)、扎西他宾或齐多夫定;或非核苷逆转录酶抑制剂,例如奈韦拉平(nevirapine)或依法韦仑(efavirenz)。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:心血管药,例如钙通道阻断剂、β-肾上腺素能受体阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素2受体拮抗剂;降脂药,例如他汀类或贝特类;血细胞形态学调节剂,例如己酮可可碱(pentoxyfylline);溶栓药或抗凝药,例如血小板聚集抑制剂。
本发明还涉及本发明化合物或其可药用盐与下列物质的组合:CNS药剂,如抗抑郁剂(如舍曲林),抗帕金森病的药物(如司来吉兰、左旋多巴、罗匹尼罗、普拉克索,MAOB抑制剂如司来吉兰和雷沙吉兰、comp抑制剂如托卡朋、A-2抑制剂、多巴胺再摄取抑制剂、NMDA拮抗剂、烟碱激动剂、多巴胺激动剂或者神经元一氧化氮合酶抑制剂),或者抗阿尔茨海默病的药物如多奈哌齐、利凡斯的明、他克林、COX-2抑制剂、丙戊荼碱或美曲磷酯。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:用于治疗急性或慢性疼痛的药物,例如在中枢或外周发挥作用的止痛药(例如阿片样物质或其衍生物)、卡马西平、苯妥英、丙戊酸钠、阿米替林(amitryptiline)或其它抗抑郁药、对乙酰氨基酚或非甾类抗炎药。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:非经肠或局部应用的(包括吸入的)局麻药,例如利诺卡因或其衍生物。
本发明的化合物或其可药用盐也可与以下物质联用:抗骨质疏松药,包括激素药物(例如雷洛昔芬(raloxifene))或二膦酸盐(例如阿伦膦酸盐(alendronate))。
本发明还涉及本发明化合物或其可药用盐与以下物质的组合:(i)类胰蛋白酶(tryptase)抑制剂;(ii)血小板活化因子(PAF)拮抗剂;(iii)白介素转化酶(ICE)抑制剂;(iv)IMPDH抑制剂;(v)粘附分子抑制剂,包括VLA-4拮抗剂;(vi)组织蛋白酶;(vii)激酶抑制剂,例如酪氨酸激酶(例如Btk、Itk、Jak3或MAP)抑制剂(例如吉非替尼(gefitinib)或甲磺酸伊马替尼(imatinib))、丝氨酸/苏氨酸激酶抑制剂(例如MAP激酶(例如p38,JNK,蛋白激酶A、B或C,或IKK)抑制剂)或在细胞周期调节中牵涉的激酶(例如细胞周期蛋白依赖性激酶)的抑制剂;(viii)葡萄糖-6磷酸脱氢酶抑制剂;(ix)激肽B1受体或激肽B2受体拮抗剂;(x)抗痛风药,例如秋水仙碱;(xi)黄嘌呤氧化酶抑制剂,例如别嘌醇;(xii)排尿酸药,例如丙磺舒、磺吡酮或苯溴马隆;(xiii)生长激素促分泌剂;(xiv)转化生长因子(TGFβ);(xv)血小板源性生长因子(PDGF);(xvi)成纤维细胞生长因子,例如基本的成纤维细胞生长因子(bFGF);(xvii)粒细胞巨噬细胞集落刺激因子(GM-CSF);(xviii)辣椒素油(capsaicin cream);(xix)速激肽NK1受体或速激肽NK3受体拮抗剂,例如NKP-608C、SB-233412(他奈坦(talnetant))或D-4418;(xx)弹性酶抑制剂,例如UT-77或ZD-0892;(xxi)TNF-α转化酶抑制剂(TACE);(xxii)诱导的一氧化氮合酶(iNOS)抑制剂;(xxiii)TH2细胞上表达的化学引诱物受体同源分子(例如CRTH2拮抗剂);(xxiv)P38的抑制剂;(xxv)调节Toll样受体(TLR)功能的药物;(xxvi)调节嘌呤能受体活性的药物,例如P2X7;(xxvii)转录因子活化抑制剂,例如NFkB、API或STATS;或(xxviii)糖皮质激素受体激动剂。
在又一方面,本发明提供前文定义的本发明化合物或者其可药用盐、一种或多种选自下列的药剂和任选的一种或多种可药用赋形剂的(固定剂量)组合(例如用于治疗COPD、哮喘或者变应性鼻炎):
●选择性β2肾上腺素能受体激动剂(如间羟异丙肾上腺素(metaproterenol)、异丙去甲肾上腺素(isoproterenol)、异丙肾上腺素(isoprenaline)、舒喘灵(albuterol)、沙丁胺醇、福莫特罗、沙美特罗、特布他林、奥西那林、甲磺酸比托特罗、吡布特罗或茚达特罗);
●磷酸二酯酶抑制剂(如PDE4抑制剂);
●蛋白酶抑制剂(如中性白细胞弹性蛋白酶或基质金属蛋白酶MMP-12抑制剂);
●抗胆碱能药物;
●趋化因子受体功能调节剂(如CCR1受体拮抗剂);及
●激酶(如激酶p38或IKK)功能的抑制剂。
本发明还提供一种药物产品(pharmaceutical product),其包含第一活性成分,即如上所定义的本发明化合物或其药用盐的制剂,和下列的第二活性成分的制剂:
●选择性β2肾上腺素能受体激动剂;
●磷酸二酯酶抑制剂;
●蛋白酶抑制剂;
●抗胆碱能药物;
●趋化因子受体功能调节剂;或者
●激酶功能抑制剂
其中将所述制剂同时、先后或分开给药于有此需要的患者。
在另一方面,本发明提供试剂盒,该试剂盒包含第一活性成分,即如上所定义的本发明化合物或其药用盐,与下列的第二活性成分的制剂以及说明书,用于将所述制剂同时、先后或分开给予有有此需要的患者:
●选择性β2肾上腺素能受体激动剂;
●磷酸二酯酶抑制剂;
●蛋白酶抑制剂;
●抗胆碱能药物;
●趋化因子受体功能调节剂;或者
●激酶功能抑制剂。
本发明的化合物或其可药用盐还可以与现有的用于治疗癌症的治疗药剂组合使用,例如适宜的药剂包括:
(i)在医用肿瘤学中使用的抗增殖/抗肿瘤药或其组合,例如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安或亚硝基脲);抗代谢剂(例如抗叶酸剂,例如氟嘧啶样5-氟尿嘧啶或替加氟、雷替曲塞、甲氨蝶呤、阿糖胞苷、羟基脲、吉西他滨或紫杉醇);抗肿瘤抗生素(例如蒽环类抗生素,例如阿霉素、博来霉素、多柔比星、柔红霉素、表柔比星、伊达比星、丝裂霉素C、更生霉素或光辉霉素);抗有丝分裂剂(例如长春花属生物碱,例如长春新碱、长春碱、长春地辛或长春瑞滨;或紫杉烷,例如泰素(taxol)或泰索帝(taxotere));或拓扑同工酶抑制剂(例如表鬼臼毒素,例如依托泊苷、替尼泊苷、安沙可林、托泊替康或喜树碱);
(ii)细胞生长抑制药,例如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬或iodoxyfene);雌激素受体下调剂(例如氟维司群);抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特或乙酸环丙孕酮);LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林或布舍瑞林);孕激素(例如乙酸甲地孕酮);芳构酶(aromatase)抑制剂(例如为阿那曲唑、来曲唑、伏氯唑(vorazole)或依西美坦);或5α-还原酶抑制剂(例如非那雄胺);
(iii)抑制癌细胞侵入的药物(例如金属蛋白酶抑制剂(例如马立马司他)或尿激酶纤维蛋白溶酶原激活剂受体功能抑制剂);
(iv)生长因子功能抑制剂,例如:生长因子抗体(例如抗erb b2抗体曲妥单抗或抗erb b1抗体西妥昔单抗[C225]);法尼基转移酶抑制剂;酪氨酸激酶抑制剂或丝氨酸/苏氨酸激酶抑制剂;表皮生长因子家族抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,AZD1839)、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(埃罗替尼(erlotinib),OSI-774)或6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033));血小板源性生长因子家族抑制剂;或肝细胞生长因子家族抑制剂;
(v)抗血管生成药,例如抑制血管内皮生长因子作用的抗血管生成药(例如抗血管内皮细胞生长因子抗体贝伐单抗、在WO 97/22596、WO 97/30035、WO 97/32856或WO 98/13354中披露的化合物);或通过另一种机制发挥作用的化合物(例如利诺胺、整联蛋白αvβ3功能抑制剂或血管生长抑素);
(vi)血管损伤剂,例如考布他汀A4或在WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434或WO 02/08213中披露的化合物;
(vii)在反义治疗中使用的药物,例如指向以上所列靶标之一的反义治疗药物,例如ISIS 2503、抗ras反义物;
(viii)在例如以下基因治疗方法中使用的药物:置换异常基因(例如异常的p53或异常的BRCA1或BRCA2)的方法;GDEPT(基因介导的酶前药治疗)方法,例如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的GDEPT方法;和提高患者化疗或放疗耐受的方法,例如多种药物抵抗基因治疗;或
(ix)在例如以下免疫治疗方法中使用的药物:提高患者肿瘤细胞免疫原性的离体和在体方法,例如用细胞因子(例如白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子)转染;降低T细胞无反应性的方法;使用转染的免疫细胞(例如细胞因子转染的树突细胞)的方法;使用细胞因子转染的肿瘤细胞系的方法;和使用抗个体基因型抗体的方法。
具体实施方式
现将参照下面示例性实施例进一步说明本发明,其中使用下列缩写:
一般方法
NMR光谱记录在Varian Mercury-VX 300MHz仪器或者Varian Inova400MHz仪器上。使用氯仿-d(H 7.26ppm)、丙酮-d6(H 2.05ppm)、乙腈-d3(δH1.94ppm)或者DMSO-d6(H 2.50ppm)的中心峰作为内标。
下列方法用于LC/MS分析:
仪器Agilent 1100;色谱柱Waters Symmetry 2.1×30mm;质谱APCI;流速0.7mL/min;波长254nm;溶剂A:水+0.1%TFA;溶剂B:乙腈+0.1%TFA;梯度15-95%/B 2.7分钟,95%B 0.3分钟。
柱色谱法采用硅胶(0.040-0.063mm,Merck)进行。
对于制备性HPLC,或者使用KR-100-5-C18色谱柱(250×20mm,Akzo Nobel)和流速为10ml/分钟的乙腈/水混合物(0.1%TFA),或者使用Prep MS C18OBDTM色谱柱,5μm,19×50mm(乙腈/水/0.1%NH3),流速为20ml/分钟。使用UV=254nm或220nm进行检测。
除非另外说明,原料可以商购。所有溶剂和商业试剂均为实验室级并原样使用。
中间体1
(8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羟基-17-(2-羟基乙酰基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊并[a]菲-3(2H)-酮
在1000mL圆底烧瓶中,将地塞米松(10g,25.48mmol)悬浮在EtOAc(400mL)和乙醇(100mL)中,并使用磁力搅拌子添加三(三苯基膦)氯化铑(I)(Wilkinson′s催化剂,2.5g,2.70mmol)。将混合物在氢气气氛(1atm)中在室温剧烈搅拌1周并添加另外1.0g催化剂。使反应再进行一周并真空浓缩所得混合物,得到固体,将所述固体悬浮在DCM(100ml)中并过滤悬浮液。将所得固体用3份DCM(50ml)洗涤并在烧结漏斗(sinter)上在空气中干燥,得到9.6g目标化合物,为灰白色固体。APCI-MS m/z:395[MH+].
中间体2
(8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羟基-10,13,16-三甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
在500mL圆底烧瓶中,将中间体1(9.5g,24.08mmol)溶解在THF(200mL)中并在室温添加原高碘酸(10.98g,48.17mmol)在80ml水中的溶液。将所得混合物在相同温度搅拌2小时,真空除去有机溶剂,并用水(100ml)稀释所得湿浆料。将所得固体过滤,在滤器上用水洗涤并在烧结漏斗上在空气流中干燥,得到9.0g目标产物,为灰白色固体。APCI-MS m/z:381[MH+].
中间体3
(8S,9R,10S,11S,13S,14S,16R,17R,Z)-9-氟-11,17-二羟基-2-(羟基亚甲基)-10,13,16-三甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
在1000mL配有磁力搅拌子和回流冷凝器的圆底烧瓶中,添加氢化钠(60%,在矿物油中,10.32g,236.56mmol)和无水THF(150mL),得到白色悬浮液,在氩气气氛中在室温搅拌所述白色悬浮液。添加中间体2(9g,23.66mmol),接着添加甲酸乙酯(96mL,1182.81mmol),并将所得混合物在相同温度搅拌约2小时。通过小心地添加2M NaOH(50ml)淬灭反应,将所得混合物搅拌5分钟,随后转移至分液漏斗,在分液漏斗中分离各相。收集水相,并用另外40ml 2M NaOH萃取有机相。将合并的水相用水(50ml)稀释,用Et2O(50ml)洗涤并用4M HCl(90ml)酸化。用EtOAc(2x150ml)萃取产物,将合并的有机相用盐水(100ml)洗涤并用Na2SO4干燥。过滤并真空蒸发有机溶液,得到7.2g目标产物,为橙色泡沫状物,所述橙色泡沫状物不经任何进一步纯化就用于后续步骤。APCI-MS m/z:409[MH+].
中间体4
(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-1,11-二羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
在500mL圆底烧瓶中,将中间体3(7.2g,17.63mmol)溶解在乙酸(100mL)中并将溶液用氮气N2脱气。在室温添加2-氟-5-肼基吡啶(2.465g,19.39mmol),并将混合物用磁力搅拌器搅拌30分钟。将溶液冻干过夜,得到8.7g目标产物,为橙色固体。APCI-MS m/z:500[MH+].
中间体5
(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-1,11-二羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸(carbothioic S-acid)
在100mL圆底烧瓶中,将中间体4(8.7g,17.62mmol)溶解在DMF(20mL)中并在室温添加二(1H-咪唑-1-基)甲酮(CDI,5.71g,35.23mmol)。在气体逸出停止后,将混合物在密封烧瓶中搅拌过夜。随后使硫化氢(H2S)鼓泡通过溶液,历时10分钟,并将所得溶液再搅拌10分钟。将溶液添加至分液漏斗中的200ml 1M HCl,并用EtOAc(2x150ml)萃取混合物。将合并的有机相用0.5MHCl(3x100ml)和盐水(40ml)洗涤,随后用Na2SO4干燥,过滤并真空蒸发有机溶剂,得到9.0g目标产物,为橙色泡沫状物,其不经任何进一步纯化就用于后续步骤。APCI-MS m/z:516[MH+].
中间体6
(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1-(丙酰氧基)-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
在50mL圆底烧瓶中,将中间体5(0.1g,0.19mmol)和三乙胺(0.067mL,0.48mmol)溶解在DCM(10mL)中并在室温添加丙酰氯(0.038g,0.41mmol)。继续搅拌10分钟。添加N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(0.091mL,0.58mmol)并将混合物再在相同温度搅拌10分钟。将反应混合物用DCM稀释至25ml的总体积,并将所得混合物用1M HCl(2x20ml)和盐水(10ml)洗涤。用Na2SO4干燥有机相,过滤干燥剂并真空蒸发有机溶剂,得到99mg目标化合物,为黄色半固体。APCI-MS m/z:572[MH+].
中间体7
(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1-[(1,3-噁唑-4-基羰基)氧基]-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的描述从中间体5开始制备。APCI-MS m/z:611[MH+].
中间体8
(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(4-氟苯基)-1,11-二羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据与对中间体5所述的操作相同的操作制备。APCI-MSm/z:515[MH+].
中间体9
(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-(2-羟基乙酰基)-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊并[a]菲-3(2H)-酮
在250mL圆底烧瓶中,将(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-(2-羟基乙酰基)-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊并[a]菲-3-酮(6α-甲基泼尼松龙,4.3g,11.48mmol)悬浮在EtOAc(80mL)中,并用乙醇(20.0mL)稀释反应混合物。使用磁力搅拌子添加三(三苯基膦)氯化铑(I)(Wilkinson′s催化剂,1g,1.08mmol),并将烧瓶在氢气气氛(1atm)中在室温剧烈搅拌1周。通过玻璃过滤漏斗过滤反应混合物并真空浓缩滤液,得到4.07g目标化合物,为浅棕色固体,其不经任何进一步纯化就用于后续步骤。APCI-MS m/z:377[MH+].
中间体10
(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-6,10,13-三甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
所述化合物根据对中间体2所述的操作从中间体9开始制备。APCI-MSm/z:363[MH+].
中间体11
(6S,8S,9S,10R,11S,13S,14S,17R,Z)-11,17-二羟基-2-(羟基亚甲基)-6,10,13-三甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
所述化合物根据中间体3的描述从中间体10开始制备。APCI-MS m/z:391[MH+].
中间体12
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-1,11-二羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
所述化合物根据对中间体4所述的操作从中间体11开始制备。APCI-MSm/z:482[MH+].
中间体13
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-1,11-二羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体5的描述从中间体12开始制备。APCI-MS m/z:498[MH+].
中间体14
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1-(丙酰氧基)-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的描述从中间体13开始制备。APCI-MS m/z:554[MH+].
中间体15
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-11-羟基-1-[(甲氧基乙酰基)氧基]-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的描述从中间体13开始制备。APCI-MS m/z:570[MH+].
中间体16
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1-[(1,3-噁唑-4-基羰基)氧基]-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的描述从中间体13开始制备。APCI-MS m/z:593[MH+].
中间体17
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-[(环丙基羰基)氧基]-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的描述从中间体13开始制备。APCI-MS m/z:566[MH+].
中间体18
(8S,9R,10S,11S,13S,14S,17R)-9-氟-11,17-二羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
在1000mL圆底烧瓶中,将乙酸2-((8S,9R,10S,11S,13S,14S,17R)-9-氟-11,17-二羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基)-2-氧代乙酯(氟氢可的松-21-乙酸酯(Fludrocortisone-21-acetate),22.8g,53.97mmol)悬浮在MeOH(200mL)中并将悬浮液用氮气脱气。将2M氢氧化钠(40.5mL,80.95mmol)添加至溶液并将混合物搅拌10分钟。向溶液添加4M HCl(20ml,80mmol)并真空除去MeOH。将所得残留物溶解在THF(200ml)中,在室温添加原高碘酸(15.99g,70.16mmol)在水(40ml)中的溶液,并将所得混合物搅拌1小时。添加100ml水并真空除去有机溶剂。将另外100ml水添加至含水残留物,将所得固体通过过滤收集,用水(2x200ml)洗涤并在烧结漏斗上空气干燥,然后真空干燥,得到20g目标化合物,为灰白色固体。APCI-MS m/z:367[MH+].
中间体19
(8S,9R,10S,11S,13S,14S,17R,Z)-9-氟-11,17-二羟基-2-(羟基亚甲基)-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
向氢化钠(6.55g,272.91mmol)(10.9g,60%悬浮液,在矿物油中)在THF(130mL)中的搅拌着的悬浮液分2-3份添加中间体18(10g,27.29mmol),然后添加甲酸乙酯(111mL,1364.54mmol)。将混合物在氩气气氛中在室温搅拌约2小时。通过小心地添加2M NaOH(50ml)淬灭反应并分离各相。用另外2x20ml 2M NaOH萃取有机相。将合并的水溶液用水(15ml)稀释,用Et2O(40ml)洗涤并通过添加4M HCl酸化。用EtOAc(3x100ml)萃取产物,将合并的有机相用盐水(30ml)洗涤,用Na2SO4干燥,过滤并真空蒸发,得到8.6g目标产物,为橙色半固体,其不经任何进一步纯化直接用于后续步骤。APCI-MS m/z:395[MH+].
中间体20
(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-1,11-二羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
在500mL圆底烧瓶中,将中间体19(10g,25.35mmol)溶解在乙酸(100mL)中,并将溶液用氮气脱气5次。在室温添加2-氟-5-肼基吡啶(3.22g,25.35mmol),并将所得混合物搅拌15分钟。将所得溶液冻干过夜,然后将所得物质悬浮在EtOAc(40ml)中并再在室温搅拌10分钟。将所得固体通过过滤分离,用EtOAc(10ml)洗涤并最后在玻璃过滤漏斗上在空气流中干燥,得到6.9g目标产物,为固体。APCI-MS m/z:486[MH+].
中间体21
(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-1,11-二羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体5的描述从中间体20开始制备。APCI-MS m/z:502[MH+].
中间体22
(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1-{[(2R)-四氢呋喃-2-基羰基]氧基}-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
将中间体21(0.3g,0.6mmol)溶解在DCM(10ml)中并在室温添加三乙胺(0.165ml,1.2mmol)。将混合物搅拌3分钟,然后逐份添加在DCM(1ml)中的(R)-四氢呋喃-2-甲酰氯(J.Chem.Soc,Perkin Trans.1,2002,571-576)(0.15g,1.2mmol),并将混合物搅拌15分钟。添加N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(0.305ml,2.04mmol),并将混合物再搅拌20分钟。将混合物用DCM(20ml)稀释,用2N HCl(2×20ml)、盐水洗涤并用硫酸钠干燥。过滤并在减压下蒸发溶剂,得到0.4g粗产物,其不经任何进一步纯化按原样使用。APCI-MS m/z:600[MH+].
中间体23
(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1-[(四氢呋喃-3-基羰基)氧基]-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体22的操作从中间体21开始制备。APCI-MS m/z:600[MH+].
中间体24
(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1-{[(2S)-四氢呋喃-2-基羰基]氧基}-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体22的操作从中间体21开始制备。APCI-MS m/z:600[MH+].
中间体25
(8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
在1000mL圆底烧瓶中,将(8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-(2-羟基乙酰基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊并[a]菲-3(2H)-酮(10.4g,28.69mmol)悬浮在MeOH(200mL)中并添加原高碘酸(9.81g,43.04mmol)在水(200mL)中的溶液,得到无色溶液。将混合物搅拌45分钟,然后添加另外3g原高碘酸并再继续搅拌1小时。真空除去MeOH,并用200ml水稀释残留的含水混合物。将所得固体通过过滤分离并在烧结漏斗上空气干燥,得到8.1g目标化合物,为白色固体。APCI-MS m/z:349[MH+].
中间体26
(8S,9S,10R,11S,13S,14S,17R)-2-甲酰基-11,17-二羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-羧酸
在氩气下,向氢化钠(5.73g,143.5mmol,60%悬浮液,在矿物油中)在THF(100ml)中的搅拌着的悬浮液分小份添加中间体25(5.00g,14.35mmol)。在5分钟后,添加甲酸乙酯(58.4ml,717.5mmol)并继续在室温搅拌过夜。用甲酸淬灭混合物,得到稠悬浮液,并添加NaOH水溶液(2M,50ml)。将混合物在室温搅拌10分钟,分离各层并丢弃有机层。将水层用浓HCl水溶液酸化并用乙酸乙酯(3×50ml)萃取。将合并的有机相用硫酸钠干燥,过滤并在减压下蒸发溶剂,得到目标化合物,为黄色固体(5.65g)。APCI-MS m/z:377[MH+].
中间体27
(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-1,11-二羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
将中间体26(4.2g,11.16mmol)溶解在乙酸(30mL)中并依次添加(4-氟苯基)肼盐酸盐(2.177g,13.39mmol)和乙酸钠(0.783mL,14.50mmol),然后用水(8ml)稀释。在室温搅拌2小时,然后真空浓缩混合物并将液体残留物倒入EtOAc(200ml)和水(150ml)中。除去水相并用2M NaOH(3x90ml)洗涤有机相,然后将合并的水相酸化并用EtOAc(3×100ml)萃取。将合并的有机相用盐水(100ml)洗涤,用Na2SO4干燥并真空浓缩,得到4.2g目标化合物,为浅棕色泡沫状物。APCI-MS m/z:467[MH+].
中间体28
(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-1,11-二羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
在25ml圆底烧瓶中,将中间体27(0.2g,0.43mmol)溶解在DMF(3ml)中并添加1,1-羰基二咪唑(0.139g,0.86mmol)。将所得溶液在室温搅拌过夜。使H2S(气体)鼓泡通过溶液,历时5分钟,并将混合物再搅拌30分钟。将反应混合物倒入1M HCl(15ml)中,将形成的固体通过过滤分离,用水洗涤并干燥,得到0.2g粗目标化合物,其不经任何进一步纯化按原样使用。APCI-MS m/z:483[MH+].
中间体29
(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-10a,12a-二甲基-1-[(四氢呋喃-2-基羰基)氧基]-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体22的操作从中间体28和四氢呋喃-2-甲酰氯(J.Chem.Soc,Perkin Trans.1,2002,571-576)制备。APCI-MS m/z:581[MH+].
中间体30
(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-[(环丙基羰基)氧基]-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
将中间体20(0.1g,0.21mmol)溶解在DCM(4mL)中,添加三乙胺(0.09ml,0.65mmol)并将混合物搅拌5分钟,然后在室温添加在DCM(1ml)中的环丙烷甲酰氯(0.035ml,0.39mmol),并将混合物搅拌30分钟。添加N1,N1,N2-三甲基乙烷-1,2-二胺(0.12ml,0.94mmol),并将混合物再在相同温度搅拌25分钟。将反应混合物用DCM(10ml)稀释并用1M HCl(2x10ml)和盐水(20ml)洗涤。将有机相用Na2SO4干燥,过滤并真空蒸发,得到110mg目标化合物。APCI-MS m/z:554[MH+].
中间体31
(1R,3aS,3bS,10aR,10bS,11S,12aS)-1-[(环丙基羰基)氧基]-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-羧酸
所述化合物根据中间体27和中间体30的操作从中间体26和环丙烷甲酰氯开始制备。APCI-MS m/z:536[MH+].
中间体32
(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-1-[(呋喃-2-基羰基)氧基]-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸
所述化合物根据中间体6的操作从中间体13开始制备。APCI-MS m/z:592[MH+].
实施例1
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
在250mL圆底烧瓶中,将中间体5(8.8g,17.07mmol)溶解在DCM(80mL)中并添加三乙胺(5.91mL,42.67mmol)。向搅拌着的混合物添加2-甲氧基乙酰氯(3.89g,35.84mmol),同时在水浴中冷却,并将混合物搅拌10分钟。添加N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(3.48mL,22.19mmol),并将混合物再搅拌10分钟。添加60%溴氟甲烷(4.82g,25.60mmol)在DMF中的溶液,接着添加三乙胺(2ml)并将反应混合物再搅拌30分钟。将所得混合物真空浓缩并在EtOAc(150ml)和1M HCl(150ml)之间分配。用EtOAc(150ml)萃取水相,并将合并的有机相用0.5M HCl(2x100ml)、水(100ml)和盐水(50ml)洗涤。用Na2SO4干燥,然后过滤并真空蒸发,得到粗产物,为泡沫状物,其在硅胶上纯化(庚烷∶EtOAc 3∶1-2∶1),得到2.9g目标化合物,为淡黄色的固体。
在制备性HPLC柱(Kromasil C18,CH3CN/水)上纯化这种物质的小样(0.35g),冻干含化合物的级份,得到0.26g目标化合物,为无色固体。将固体悬浮在Et2O(10ml)中并将悬浮液在室温搅拌2小时。通过过滤分离固体,得到0.23g目标化合物,为白色结晶固体。APCI-MS m/z:620[MH+].
1H NMR(400MHz,CDCl3)δ8.36(1H,s),7.99(1H,m),7.51(1H,s),7.07(1H,dd),6.18(1H,s),6.01-5.76(2H,m),4.45(1H,bs),4.12(2H,s),3.45(3H,s),3.45-3.40(1H,m),3.32(1H,d),2.80(1H,d),2.61(1H,t),2.49-2.19(4H,m),1.96-1.82(2H,m),1.76-1.66(1H,m),1.65-1.51(1H,m),1.41(3H,s),1.41-1.33(1H,m),1.28(1H,bs),1.12(3H,s),1.04(3H,d).
实施例2
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
在瓶中,将中间体6(0.05g,0.09mmol)和N,N-二异丙基乙胺(0.043mL,0.26mmol)溶解在二噁烷(3mL)中并在室温添加溴氟甲烷(0.033g,0.17mmol)在DMF中的60%溶液。将混合物搅拌60分钟,然后将所得粗混合物真空浓缩,溶解在CH3CN/水(3ml/0.5ml)中并注射到制备性HPLC柱上。冻干含产物的级份,得到15mg目标化合物,为无色固体。APCI-MS m/z:604[MH+].
1H NMR(400MHz,CDCl3)δ8.36(1H,s),7.99(1H,m),7.50(1H,s),7.07(1H,m),6.18(1H,s),6.03-5.75(2H,m),4.45(1H,bs),3.41(1H,bs),3.33(1H,d),2.81(1H,d),2.61(1H,t),2.52-2.32(5H,m),2.32-2.21(1H,m),1.96-1.80(2H,m),1.77-1.66(1H,m),1.65-1.51(1H,m),1.41(3H,s),1.41-1.32(1H,m),1.29(1H,bs),1.17(3H,t),1.10(3H,s),1.01(3H,d).
实施例3
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
在瓶中,将中间体6(0.05g,0.09mmol)和N,N-二异丙基乙胺(0.020mL,0.12mmol)溶解在二噁烷(3mL)中并在室温添加2-溴代乙腈(6.99μL,0.10mmol)。将混合物搅拌10分钟,真空除去挥发物并将残留物悬浮在CH3CN(3ml)和水(1ml)中。过滤所得悬浮液并将溶液注射到制备性HPLC柱上。将含产物的级份合并并且冻干,得到8mg目标化合物,为无色固体。APCI-MS m/z:611[MH+].
1H NMR(400MHz,CDCl3)δ8.36(1H,s),7.99(1H,m),7.51(1H,s),7.07(1H,dd),6.18(1H,s),4.46(1H,bs),3.72(2H,s),3.41-3.28(2H,m),2.81(1H,d),2.61(1H,t),2.48-2.31(5H,m),2.31-2.18(1H,m),1.94-1.80(2H,m),1.77-1.66(1H,m),1.65-1.51(1H,m),1.44(1H,bs),1.41(3H,s),1.41-1.32(1H,m),1.16(3H,t),1.12(3H,s),1.02(3H,d).
实施例4
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体7开始制备。APCI-MS m/z:643[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.25(1H,s),7.99(1H,m),7.95(1H,s),7.51(1H,s),7.08(1H,dd),6.19(1H,s),6.05-5.74(2H,m),4.51(1H,bs),3.57-3.45(1H,m),3.37(1H,d),2.82(1H,d),2.69-2.51(2H,m),2.46-2.23(3H,m),2.03-1.85(2H,m),1.81-1.70(1H,m),1.66-1.56(1H,m),1.43(3H,s),1.42-1.32(2H,m),1.17(3H,s),1.08(3H,d).
实施例5
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
在50mL圆底烧瓶中,将中间体8(0.09g,0.17mmol)和三乙胺(0.061mL,0.44mmol)溶解在DCM(10mL)中,并在室温添加丙酰氯(0.034g,0.37mmol)。将混合物搅拌10分钟并添加N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(0.082mL,0.52mmol),然后将混合物再搅拌10分钟。将反应混合物用DCM稀释至25ml的总体积,并将所得混合物用1M HCl(2x20ml)和盐水(10ml)洗涤。将有机相用Na2SO4干燥,过滤并蒸发,得到90mg(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1-(丙酰氧基)-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸,为黄色固体。APCI-MS m/z:571[MH+].
将所得硫代羟酸(0.045g,0.08mmol)和N,N-二异丙基乙胺(0.039mL,0.24mmol)溶解在二噁烷(3mL)中并添加溴氟甲烷(0.030g,0.16mmol)在DMF中的60%溶液。将混合物搅拌60分钟,随后真空除去挥发物。将残留物悬浮在CH3CN(3ml)和水(1ml)的混合物中,并过滤所得悬浮液,并将溶液注射到制备性HPLC柱上。将含产物的级份合并并且冻干,得到15mg目标化合物,为无色固体。APCI-MS m/z:603[MH+].
1H NMR(400MHz,CDCl3)δ7.50-7.42(3H,m),7.16(2H,t),6.18(1H,s),6.02-5.75(2H,m),4.45(1H,bs),3.41(1H,bs),3.32(1H,d),2.79(1H,d),2.59(1H,t),2.51-2.38(3H,m),2.38-2.18(3H,m),1.97-1.79(2H,m),1.75-1.65(1H,m),1.63-1.51(1H,m),1.40(3H,s),1.39-1.32(1H,m),1.32-1.27(1H,m),1.17(3H,t),1.10(3H,s),1.01(3H,d).
实施例6
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
在50mL圆底烧瓶中,将中间体8(0.09g,0.17mmol)和三乙胺(0.061mL,0.44mmol)溶解在DCM(10mL)中并在室温添加2-甲氧基乙酰氯(0.040g,0.37mmol)。将混合物搅拌10分钟,添加N1-乙基-N2,N2-二甲基乙烷-1,2-二胺(0.082mL,0.52mmol),并将所得混合物再搅拌10分钟。将反应混合物用DCM稀释至25ml的总体积,并用1M HCl(2x20ml)和盐水(10ml)洗涤。将有机相用Na2SO4干燥,过滤并蒸发,得到105mg(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-7-(6-氟吡啶-3-基)-11-羟基-1-[(甲氧基乙酰基)氧基]-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-硫代羟酸,为黄色固体。APCI-MS m/z:587[MH+].
将所得硫代羟酸(0.05g,0.09mmol)和N,N-二异丙基乙胺(0.042mL,0.26mmol)溶解在二噁烷(3mL)中,并在室温添加溴氟甲烷(0.032g,0.17mmol)在DMF中的60%溶液。将所得混合物搅拌60分钟,真空除去挥发物,将残留物悬浮在CH3CN(3ml)中并添加水(1ml)。过滤悬浮液,并将溶液注射到制备性HPLC柱上。将含产物的级份合并并且冻干,得到12mg目标化合物,为白色固体。APCI-MS m/z:619[MH+].
1H NMR(400MHz,CDCl3)δ7.50-7.42(3H,m),7.16(2H,t),6.17(1H,s),6.01-5.76(2H,m),4.45(1H,bs),4.12(2H,s),3.46(3H,s),3.50-3.38(1H,m),3.31(1H,d),2.78(1H,d),2.59(1H,t),2.47-2.18(4H,m),1.95-1.81(2H,m),1.75-1.64(1H,m),1.63-1.51(1H,m),1.40(3H,s),1.39-1.29(2H,m),1.11(3H,s),1.04(3H,d).
实施例7
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体14开始制备。APCI-MS m/z:586[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.49(1H,s),7.09(1H,dd),6.12(1H,s),6.06-5.61(2H,m),4.57(1H,bs),3.06-2.95(2H,m),2.77(1H,d),2.54(1H,bs),2.37(2H,m),2.18-2.06(2H,m),2.04-1.91(3H,m),1.87-1.76(1H,m),1.68-1.58(1H,m),1.54-1.41(1H,m),1.34(3H,s),1.26(1H,d),1.20-1.08(7H,m),1.01(3H,s),0.87(1H,q).
实施例8
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体15开始制备。APCI-MS m/z:602[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.49(1H,s),7.09(1H,dd),6.12(1H,s),6.05-5.63(2H,m),4.57(1H,bs),4.06(2H,s),3.46(3H,s),3.10-2.96(2H,m),2.77(1H,d),2.54(1H,bs),2.19-1.91(5H,m),1.90-1.77(1H,m),1.67-1.42(2H,m),1.34(3H,s),1.26(1H,d),1.15-1.09(4H,m),1.01(3H,s),0.86(1H,q).
实施例9
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体16开始制备。APCI-MS m/z:625[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.31(1H,s),8.01(1H,m),7.96(1H,s),7.50(1H,s),7.09(1H,dd),6.12(1H,s),6.07-5.60(2H,m),4.64(1H,bs),3.17-3.06(1H,m),3.03(1H,d),2.81(1H,d),2.55(1H,bs),2.28(1H,d),2.22-2.05(3H,m),1.96(1H,m),1.92-1.80(1H,m),1.80-1.69(1H,m),1.59-1.47(1H,m),1.36(3H,s),1.34(1H,s),1.15(1H,d),1.11(3H,d),1.06(3H,s),0.90(1H,q).
实施例10
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例3中的描述从中间体16开始制备。APCI-MS m/z:632[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.31(1H,s),8.01(1H,m),7.96(1H,s),7.50(1H,s),7.09(1H,dd),6.12(1H,s),4.64(1H,bs),3.80(1H,d,AB),3.56(1H,d,AB),3.14-2.99(2H,m),2.81(1H,d),2.55(1H,bs),2.26(1H,d),2.22-2.10(2H,m),2.06(1H,d),1.96(1H,m),1.92-1.80(1H,m),1.79-1.67(1H,m),1.61-1.48(1H,m),1.36(3H,s),1.33(1H,s),1.22(1H,s),1.11(3H,d),1.07(3H,s),0.89(1H,q).
实施例11
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例3中的描述从中间体17开始制备。APCI-MS m/z:605[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.50(1H,s),7.09(1H,dd),6.12(1H,s),4.58(1H,bs),3.78(1H,d,AB),3.56(1H,d,AB),3.02(1H,d),2.96(1H,m),2.77(1H,d),2.54(1H,bs),2.19-2.06(2H,m),2.03-1.91(3H,m),1.90-1.78(1H,m),1.71-1.60(2H,m),1.54-1.41(1H,m),1.35(3H,s),1.27(1H,d),1.16(1H,d),1.12(3H,d),1.08-0.98(5H,m),0.97-0.83(3H,m).
实施例12
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
将中间体22(0.04g,0.07mmol)溶解在二噁烷(1mL)中,得到黄色溶液。添加N-乙基-N-异丙基丙-2-胺(0.03mL,0.18mmol)和2-溴代乙腈(20μL,0.03mmol),并将混合物搅拌过夜。用CH3CN(1ml)和水(1ml)稀释溶液,然后注射到制备性HPLC柱(CH3CN/水)中。将含产物的级份冻干,得到10mg目标化合物,为白色固体。APCI-MS m/z:634[MH+].
1H NMR(400MHz,DMSO)δ8.40(d,1H),8.17(t,1H),7.57(s,1H),7.35(d,1H),6.25(s,1H),5.34(s,1H),4.53-4.40(m,1H),4.31(s,1H),4.03(dd,2H),3.80(m,2H),3.13(d,1H),2.81(m,1H),2.42-2.13(m,2H),2.10-1.77(m,6H),1.70(m,2H),1.48-1.29(m,5H),0.98(s,3H).
实施例13
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体22和溴氟甲烷开始制备。APCI-MS m/z:632[MH+].
1H NMR(400MHz,DMSO)δ8.40(d,1H),8.15(s,1H),7.62(s,1H),7.36(dd,1H),6.28(s,1H),6.03-5.93(m,1H),5.90-5.80(m,1H),5.30(s,1H),4.47(dd,1H),4.31(s,1H),3.86-3.74(m,2H),3.14(d,1H),2.81(d,2H),2.41-2.13(m,5H),2.11-1.77(m,7H),1.77-1.62(m,1H),1.48-1.27(m,4H),0.95(s,3H).
实施例14
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体22和2-溴代乙醇开始制备。APCI-MS m/z:644[MH+].
1H NMR(400MHz,DMSO)δ8.40(d,1H),8.15(d,1H),7.57(s,1H),7.35(dd,1H),6.24(1,1H),5.17(s,1H),4.43(dd,1H),4.28(m,2H),3.87-3.70(m,4H),3.14(d,1H),2.99-2.72(m,4H),2.40-1.95(m,6H),1.94-1.60(m,7H),1.46-1.24(m,4H),0.95(s,3H).
实施例15
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体23和2-溴代乙腈开始制备。APCI-MS m/z:639[MH+].
1H NMR(400MHz,DMSO)δ8.40(s,1H),8.15(dd,1H),7.61(s,1H),7.36(dd,1H),6.29(s,1H),5.29(d,1H),4.32(s,1H),4.03(dd,2H),3.89-3.63(m,4H),3.25-3.08(m,2H),2.88-2.71(m,2H),2.42-2.14(m,4H),2.13-1.61(m,7H),1.50-1.28(m,5H),0.92(s,3H).
得到异构体混合物并在chiralpak IA柱(异己烷/EtOH=1∶1)上分离异构体,分析出两个峰。
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)
硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基
-1,2,3,3a,3b,4,5,7,10,l0a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-
基酯
上面的化合物为chiralpak IA柱(异己烷/EtOH=1∶1)上的第一洗脱异构体。APCI-MS m/z:639[MH+].
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)
硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基
-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-
基酯
上面的化合物为chiralpak IA柱(异己烷/EtOH=1∶1)上的第二洗脱异构体。APCI-MS m/z:639[MH+].
实施例16
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体23和溴氟甲烷开始制备。APCI-MS m/z:632[MH+].
1H NMR(400MHz,DMSO)δ8.40(d,1H),8.15(t,1H),7.63(s,1H),7.36(d,1H),6.32(s,1H),6.02-5.94(m,1H),5.89-5.81(m,1H),5.24(d,1H),4.31(s,1H),3.62-3.90(m,4H),3.08-3.26(m,2H),2.71-2.88(m,3H),2.29-2.41(m,2H),1.97-2.14(m,6H),1.78-1.96(m,2H),1.61-1.77(m,1H),1.29-1.48(m,4H),0.90(s,3H).
得到异构体混合物并在chiralpak IA柱(异己烷/EtOH=1∶1)上分离异构体,分析出两个峰。
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟
-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基
-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-
基酯
上面的化合物为chiralpak IA柱(异己烷/EtOH=1∶1)上的第一洗脱异构体。APCI-MS m/z:632[MH+].
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟
甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基
-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-
基酯
上面的化合物为chiralpak IA柱(异己烷/EtOH=1∶1)上的第二洗脱异构体。APCI-MS m/z:632[MH+].
实施例17
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体24和2-溴代乙腈开始制备。APCI-MS m/z:639[MH+].
1H NMR(400MHz,DMSO)δ8.45(s,1H),8.15(dd,1H),7.66(s,1H),7.36(dd,1H),6.30(s,1H),5.33(s,1H),4.48(dd,1H),4.30(s,1H),4.03(dd,2H),3.83(t,2H),3.14(d,1H),2.82(dd,2H),2.40-2.09(m,6H),2.10-1.61(m,7H),1.50-1.21(m,5H),0.77(s,3H).
实施例18
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯
基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基
-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-
基酯
所述化合物根据实施例12中描述的操作从中间体29和2-溴代乙醇制备。所得异构体为Kromasil C18HPLC柱上的第二洗脱物。APCI-MS m/z:625[MH+].
1H NMR(400MHz,DMSO-d6)δ7.52(m,2H),7.49(s,1H),7.35(m,2H),6.15(s,1H),4.46(m,2H),4.36(d,1H),3.79(m,2H),3.43(m,2H),2.93(m,3H),2.79(m,1H),2.64(m,1H),2.42(m,1H),2.29(m,1H),2.14(m,3H),2.00-1.70(m,7H),1.58(m,1H),1.34(m,1H),1.22(s,3H),1.11(m,1H)1.00(m,1H),0.86(s,3H).APCI-MS m/z:625[MH+].
实施例19
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体30和2-溴代乙腈开始制备。APCI-MS m/z:554[MH+].
1H NMR(400MHz,DMSO)δ8.40(d,1H),8.15(d,1H),7.57(s,1H),7.36(dd,1H),6.25(s,1H),5.24(s,1H),5.02(dd,2H),4.25(d,1H),3.14(d,1H),2.88-2.64(m,2H),2.41-1.99(m,5H),1.82-1.57(m,5H),1.50-1.36(m,2H),1.33(s,3H),0.95(s,3H),0.88-0.75(m,4H).
实施例20
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例12的操作从中间体31和2-溴代乙腈开始制备。APCI-MS m/z:575[MH+].
1H NMR(400MHz,DMSO)δ8.39(d,1H),8.13(d,,1H),7.54(s,1H),7.35(dd,1H),6.17(s,1H),5.00(dd,2H),4.42(s,1H),4.35(d,1H),2.97(d,1H),2.85-2.58(m,2H),2.46-2.25(m,2H),1.98-1.81(m,3H),1.81-1.56(m,5H),1.49-1.31(m,1H),1.23(s,3H),1.19-0.98(m,2H),0.96-0.76(m,7H).
实施例21
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体32开始制备。APCI-MS m/z:624[MH+].
1H NMR(400MHz,CDCl3)δ8.38(1H,s),8.01(1H,m),7.62(1H,s),7.51(1H,s),7.23(1H,m),7.09(1H,dd),6.55(1H,m),6.13(1H,s),6.09-5.58(2H,m),4.64(1H,bs),3.16-3.00(2H,m),2.82(1H,d),2.55(1H,bs),2.28(1H,d),2.21-2.05(3H,m),1.97(1H,m),1.92-1.80(1H,m),1.80-1.68(1H,m),1.60-1.46(1H,m),1.37(3H,s),1.33(1H,d),1.17-1.13(1H,m),1.12(3H,d),1.06(3H,s),0.90(1H,q).
实施例22
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例3中的描述从中间体32开始制备。APCI-MS m/z:631[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.63(1H,s),7.51(1H,s),7.23(1H,m),7.09(1H,dd),6.55(1H,m),6.12(1H,s),4.64(1H,bs),3.82(1H,d,AB),3.55(1H,d,AB),3.13-3.01(2H,m),2.82(1H,d),2.56(1H,bs),2.25(1H,d),2.21-2.10(2H,m),2.06(1H,d),1.97(1H,m),1.92-1.80(1H,m),1.80-1.67(1H,m),1.59-1.48(1H,m),1.36(3H,s),1.32(1H,d),1.23-1.19(1H,m),1.12(3H,d),1.07(3H,s),0.89(1H,q).
实施例23
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例3中的描述从中间体14开始制备。APCI-MS m/z:593[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.50(1H,s),7.09(1H,dd),6.12(1H,s),4.57(1H,bs),3.79(1H,d,AB),3.56(1H,d,AB),3.06-2.92(2H,m),2.77(1H,d),2.54(1H,bs),2.37(2H,q),2.18-2.06(2H,m),2.03-1.91(3H,m),1.89-1.76(1H,m),1.67-1.55(1H,m),1.54-1.41(1H,m),1.34(3H,s),1.26(1H,d),1.20-1.09(7H,m),1.01(3H,s),0.86(1H,q).
实施例24
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例3中的描述从中间体15开始制备。APCI-MS m/z:609[MH+].
1H NMR(400MHz,CDCl3)δ8.36(1H,s),8.01(1H,m),7.49(1H,s),7.09(1H,dd),6.12(1H,s),4.57(1H,bs),4.06(2H,s),3.79(1H,d,AB),3.58(1H,d,AB),3.46(3H,s),3.07-2.95(2H,m),2.77(1H,d),2.54(1H,bs),2.19-2.00(3H,m),2.00-1.91(2H,m),1.88-1.77(1H,m),1.67-1.43(2H,m),1.34(3H,s),1.25(1H,d),1.17(1H,d),1.12(3H,d),1.02(3H,s),0.86(1H,q).
实施例25
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例2中的描述从中间体17开始制备。APCI-MS m/z:598[MH+].
1H NMR(400MHz,CDCl3)δ8.37(1H,s),8.01(1H,m),7.49(1H,s),7.09(1H,dd),6.12(1H,s),6.05-5.60(2H,m),4.58(1H,bs),3.07-2.93(2H,m),2.77(1H,d),2.54(1H,bs),2.19-2.06(2H,m),2.05-1.90(3H,m),1.90-1.78(1H,m),1.72-1.60(2H,m),1.52-1.40(1H,m),1.34(3H,s),1.27(1H,d),1.16-1.09(4H,m),1.08-0.98(5H,m),0.96-0.83(3H,m).
实施例26
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例5中描述的制备从中间体8制备。APCI-MS m/z:610[MH+].
1H NMR(400MHz,CDCl3)δ7.50-7.43(3H,m),7.16(2H,t),6.17(1H,s),4.45(1H,bs),3.72(2H,s),3.40-3.26(2H,m),2.79(1H,d),2.59(1H,t),2.49-2.38(3H,m),2.38-2.18(3H,m),1.94-1.81(2H,m),1.75-1.64(1H,m),1.63-1.51(1H,m),1.40(3H,s),1.38-1.33(2H,m),1.16(3H,t),1.12(3H,s),1.01(3H,d).
实施例27
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例6中描述的操作从中间体8制备。APCI-MS m/z:626[MH+].
1H NMR(400MHz,CDCl3)δ7.50-7.42(3H,m),7.16(2H,t),6.18(1H,s),4.46(1H,bs),4.12(2H,s),3.73(2H,s),3.45(3H,s),3.42-3.26(2H,m),2.79(1H,d),2.59(1H,t),2.45-2.18(4H,m),1.95-1.81(2H,m),1.75-1.64(1H,m),1.63-1.51(1H,m),1.40(3H,s),1.39-1.32(2H,m),1.13(3H,s),1.05(3H,d).
实施例28
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例6中描述的操作从中间体8制备。APCI-MS m/z:642[MH+].
1H NMR(400MHz,CDCl3)δ8.25(1H,s),7.94(1H,s),7.50-7.43(3H,m),7.17(2H,t),6.19(1H,s),6.04-5.76(2H,m),4.51(1H,bs),3.56-3.44(1H,m),3.37(1H,d),2.81(1H,d),2.68-2.50(2H,m),2.46-2.25(3H,m),2.01-1.85(2H,m),1.80-1.68(1H,m),1.63-1.51(1H,m),1.42(3H,s),1.39(1H,m),1.33(1H,bs),1.17(3H,s),1.09(3H,d).
实施例29
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例6中描述的操作从中间体8制备。APCI-MS m/z:649[MH+].
实施例30
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯
所述化合物根据实施例1中描述的操作从中间体5制备。APCI-MS m/z:627[MH+].
1H NMR(400MHz,CDCl3)δ8.36(1H,s),7.99(1H,m),7.51(1H,s),7.07(1H,dd),6.18(1H,s),4.45(1H,bs),4.12(2H,s),3.73(2H,s),3.45(3H,s),3.42-3.27(2H,m),2.81(1H,d),2.61(1H,t),2.44-2.32(2H,m),2.31-2.18(2H,m),1.96-1.82(2H,m),1.75-1.66(1H,m),1.65-1.51(1H,m),1.41(3H,s),1.40-1.34(2H,m),1.13(3H,s),1.05(3H,d).
人糖皮质激素受体(GR)测定
该测定基于得自Panvera/Invitrogen(部件号P2893)商购试剂盒。该测定技术为荧光偏振。该试剂盒利用重组人GR(Panvera,部件号P2812),FluoromoneTM标记的示踪剂(GS Red,Panvera,部件号P2894),及稳定化肽10X(Panvera,部件号P2815)。GR和稳定化肽试剂贮存在-70℃,而GS Red贮存在-20℃。试剂盒中还包括1M DTT(Panvera,部件号P2325,贮存在-20℃)和GR筛选缓冲液10X(Panvera,部件号P2814,开始时贮存在-70℃,一旦解冻则贮存在室温)。所有试剂均避免反复冷冻/解冻。GR筛选缓冲液10X包含100mM磷酸钾,200mM钼酸钠,1mM EDTA,及20%的DMSO。
将于100%DMSO中的试验化合物(1μL)和对照(1μL)加到黑色聚苯乙烯384-孔板(Greiner小体积黑色平底,部件号784076)中。0%对照为100%的DMSO,100%对照为10μM的地塞米松。将背景溶液(background solution)(8μL;测定缓冲液10X,稳定化肽,DTT,及冰冷的MQ水)加到背景孔中。GS Red溶液(7μL;测定缓冲液10X,稳定化肽,DTT,GS Red,及冰冷的水)加到除背景孔之外的所有孔中。GR溶液(7μL;测定缓冲液10X,稳定化肽,DTT,GR,及冰冷的水)加到所有孔中。将培养板密封并在暗处和室温下培养2小时。在Analyst板读数器(LJL Biosystems/Molecular DevicesCorporation)或其它能够记录荧光偏振的类似板读数器中对板进行读数(激发波长530nm,发射波长590nm,分色镜在561nm)。利用Xlfit模型205计算IC50值,并示于表1中。
表1
Claims (8)
1.选自以下的化合物:
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2R)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(R)/(S)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-3-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(2S)-四氢呋喃-2-羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
(S)/(R)四氢呋喃-2-羧酸(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-氟苯基)-11-羟基-1-{[(2-羟基乙基)硫基]羰基}-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-10b-氟-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,10aS,10bR,11S,12aS)-1-{[氰基甲基氧基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-10a,12a-二甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
呋喃-2-羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
环丙烷羧酸(1R,3aS,3bS,5S,10aR,10bS,11S,12aS)-1-{[(氟甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-5,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
丙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氟甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
1,3-噁唑-4-羧酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(4-氟苯基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,和
甲氧基乙酸(1R,2R,3aS,3bS,10aS,10bR,11S,12aS)-10b-氟-1-{[(氰基甲基)硫基]羰基}-7-(6-氟吡啶-3-基)-11-羟基-2,10a,12a-三甲基-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-十四氢环戊并[5,6]萘并[1,2-f]吲唑-1-基酯,
或其可药用盐。
2.药物组合物,其包含权利要求1的化合物或其可药用盐以及可药用辅剂、稀释剂或载体。
3.权利要求1的化合物或其可药用盐,其用于治疗哮喘、慢性阻塞性肺病或变应性鼻炎。
4.权利要求1的化合物或其可药用盐在制备用于治疗哮喘、慢性阻塞性肺病或变应性鼻炎的药物中的用途。
5.治疗阻塞性气道疾病或病症或降低患有阻塞性气道疾病或病症的危险的方法,其包括给予有此需要的患者治疗有效量的权利要求1的化合物或其可药用盐。
6.权利要求5的方法,其中所述疾病或病症为哮喘或慢性阻塞性肺病。
7.药物组合,其包含权利要求1的化合物或其可药用盐和独立选自以下的一种或多种药物:
●选择性β2肾上腺素能受体激动剂;
●磷酸二酯酶抑制剂;
●蛋白酶抑制剂;
●抗胆碱能药;
●趋化因子受体功能调节剂;和
●激酶功能抑制剂;
以及任选的一种或多种可药用赋形剂。
8.试剂盒,其包含第一活性成分的制剂和第二活性成分的制剂,所述第一活性成分为权利要求1的化合物或其可药用盐,所述第二活性成分为
●选择性β2肾上腺素能受体激动剂;
●磷酸二酯酶抑制剂;
●蛋白酶抑制剂;
●抗胆碱能药;
●趋化因子受体功能调节剂;或
●激酶功能抑制剂;
以及将所述制剂同时、顺序或分开给予有此需要的患者的说明书。
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CN104402964A (zh) * | 2014-12-10 | 2015-03-11 | 南京大学 | 闭花木酮的o-(咪唑基)乙基衍生物、制备方法及其用途 |
CN104402964B (zh) * | 2014-12-10 | 2016-06-15 | 南京大学 | 闭花木酮的o-(咪唑基)乙基衍生物、制备方法及其用途 |
CN104744556A (zh) * | 2015-04-15 | 2015-07-01 | 南京大学 | 闭花木酮的o-(1h-四氮唑基)乙基衍生物、制备方法及其用途 |
CN104744556B (zh) * | 2015-04-15 | 2016-06-29 | 马修尧 | 闭花木酮的o-(1h-四氮唑基)乙基衍生物、制备方法及其用途 |
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