CN1849330A - 具有抗炎活性的特异性糖皮质类固醇化合物 - Google Patents
具有抗炎活性的特异性糖皮质类固醇化合物 Download PDFInfo
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Abstract
式(I)化合物或其生理学上可接受的溶剂合物。
Description
本发明涉及一种雄甾烷类糖皮质激素受体激动剂化合物。本发明也涉及含有该化合物的药用制剂以及该化合物的治疗用途,特别是对炎性疾病和过敏性疾病的治疗。
糖皮质激素具有抗炎性质是众所周知的,且被广泛用于炎症性紊乱或炎症性疾病如哮喘和鼻炎的治疗。我们又鉴定了一种新的糖皮质激素。
在本发明的一个方面,提供了式(I)化合物:
或其生理学上可接受的溶剂合物。
溶剂合物的实例包括水合物。
在本发明中,以下文中提及本发明化合物时均包括式(I)化合物和其溶剂合物。
应该认识到,本发明在其范围内包括式(I)化合物的所有立体异构体和它们的混合物。
优选地,绝对立体化学应如式(I)化合物所示。
式(I)化合物命名为:6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-羧酸氰甲酯。
式(I)化合物有潜在的有益的抗炎或抗过敏作用(特别是用于局部给药),例如式(I)化合物对糖皮质激素受体具有结合的能力,并通过该受体引发反应证实了其作用。因此,式(I)化合物具有治疗炎性和/或过敏性疾病的潜在用途。
本发明化合物可以在如下疾病实例中应用:包括皮肤疾病如湿疹、牛皮癣、过敏性皮炎、神经皮质炎、搔痒症和超敏反应;鼻、喉或肺的炎症性疾病如哮喘(包括过敏原诱导的哮喘反应)、鼻炎(包括枯草热)、鼻息肉、慢性阻塞性肺病、间隙性肺病和纤维化;炎性肠疾病如溃疡性大肠炎和克罗恩氏病;以及自身免疫性疾病如风湿性关节炎。
本发明化合物也用于治疗结膜和结膜炎。
本领域技术人员将会认同,本文涉及的“治疗”可延伸为疾病的预防和已确定疾病的治疗。
如上所述,式(I)化合物可作为人类或畜类用药物,特别是作为抗炎和抗过敏剂。
本发明的再一方面提供式(I)化合物或其生理学上可接受的溶剂合物用作人类或畜类用药物,特别是用于患有炎症性和/或过敏性疾病的患者的治疗。
本发明的另一方面提供了式(I)化合物或其生理学上可接受的溶剂合物在制备用于治疗患有炎症性或过敏性疾病的患者的药物中的应用。
本发明的再一方面提供了一种治疗患有炎症性和/或过敏性疾病的人或动物的方法,该方法包括给予所述人或动物有效量的式(I)化合物或其生理学上可接受的溶剂合物。
本发明化合物可配制成任何便于给药的制剂。因此本发明在其范围内也包括含有式(I)化合物或其生理学上可接受的溶剂合物(且如果需要的话,可与一种或多种生理学上可接受的稀释剂或载体混合)的药用组合物。
本发明进一步提供制备这样的药用组合物的方法,该方法包括将各组分混合。
本发明化合物可(例如)配制成口服、口腔、舌下、非肠道、局部或直肠给药的制剂,特别是局部给药制剂。
本文所指的局部给药包括吹入和吸入给药。各种类型的局部给药制剂包括软膏、洗剂、乳膏、凝胶剂、泡沫剂、经透皮贴片传递的制剂、粉末剂、喷雾剂、气雾剂、用于吸入器、吹入器或滴剂的胶囊或药筒(cartridges)(如眼睛或鼻子滴剂)、用于喷入的溶液/悬浮液、栓剂、阴道栓剂、保留灌肠剂和可咀嚼或可吮吸的片剂或丸剂(如用于口腔溃疡的治疗),或脂质体或微胶囊制剂。
软膏、乳膏和凝胶剂例如可用水性或油性基质并添加适合的增稠剂和/或凝固剂和/或溶剂配制成。因此该基质可以(例如)包括水和/或油,如液体石蜡或植物油(如花生油或蓖麻油),或溶剂如聚乙二醇。根据基质的性质,可用的增稠剂和凝固剂包括软石蜡、硬脂酸铝、十八醇十六醇混合物、聚乙二醇、羊毛脂、蜂蜡、羧聚甲烯、纤维素衍生物,和/或甘油单硬脂酸酯和/或非离子性乳化剂。
洗剂可用水性或油性基质配制成,且通常也含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂或增稠剂。
外用粉剂可用适合的粉性基质如滑石粉、乳糖或淀粉配制成。滴剂可用水性或非水性基质配制成,该基质也含有一种或多种分散剂、增溶剂、悬浮剂或保护剂。
喷雾剂可以(例如)配制成水溶液或悬浮液,或是释放于增压包的气雾剂,如应用了适合的液态抛射剂的定量剂量吸入气雾剂。适于吸入给药的气雾剂组合物可以是悬浮液或是溶液,且通常含有式(I)化合物和适合的抛射剂如碳氟化合物、含氢碳氯氟化合物或是它们的混合物,特别是氢氟烷类,优选1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟正丙烷或它们的混合物。该气雾剂组合物可任选含有本领域熟知的其它配制制剂时所用的赋型剂如表面活性剂(如油酸或卵磷脂)以及共溶剂(如乙醇)。
有益的是本发明剂型可以通过加入适合的缓冲剂进行缓冲。
用于吸入或吹入给药的胶囊和药筒(如明胶剂)可以配制成含有适于吸入的粉末混合物的制剂,该粉末混合物包含本发明化合物和适合的粉性基质如乳糖或淀粉。单位胶囊或药筒可通常含有20μg-10mg的式(I)化合物。另外,可在没有赋形剂如乳糖的情况下含有本发明化合物。
本发明活性式(I)化合物在局部用组合物中的比例依所制备制剂的明确剂型而定,但通常在0.001%到10%(重量)的范围内。通常,对于绝大多数剂型所用的适宜比例是从0.005%到1%,优选是从0.01%到0.5%范围内。但吸入剂或吹入剂中的粉末所用比例是在0.1%到5%范围内。
气雾剂的剂量制定优选是使气雾剂的单位定量剂量或“喷入”剂量中含有20μg-2000μg,优选约20μg-500μg的式(I)化合物。可以是一天一次或一天数次(如2、3、4或8次)给药,每次给药为如1、2或3个单位剂量。气雾剂的日总剂量在100μg-10mg,优选200μg-2000μg的范围内。胶囊或药筒以吸入或吹入给药释放的日总剂量和定量剂量通常是二倍于气雾剂的剂量。
局部制剂可以每天一次或多次给药用于感染面积;在皮肤表面上最好使用封闭性敷剂。可以通过粘附储库系统来实现药物的持续或延长释放。
关于体内用药,本发明化合物可以例如配制成便于口服、非肠道或直肠给药的制剂。口服给药制剂包括糖浆剂、酏剂、散剂、颗粒剂、片剂和胶囊,如果需要,这些制剂通常含有常规的赋形剂如粘合剂、填充剂、润滑剂、崩解剂、润湿剂、助悬剂、乳化剂、防腐剂、缓冲盐、调味剂、着色剂和/或甜味剂。优选的计量单位剂型为如下所述。
体内给药的优选剂型是诸如片剂和胶囊的单位剂型。这样的单位剂型含有0.1mg到20mg,优选2.5mg到10mg的本发明化合物。
在其中系统肾上腺皮质治疗为适应症的情况下,本发明化合物通常可以体内给药。
通常对于体内给药来说,术语制剂依据涉及的制剂类型可以含有0.05%到10%的活性成分。日剂量依据被治疗的疾病以及所需的疗程,可以在0.1mg到60mg(如5mg-30mg)范围内变化。
缓释剂或肠衣制剂可能具有优势,特别是对炎性肠疾病。
本发明的化合物和药物制剂可以与一种或多种选自以下的其它治疗剂联合应用或是包含一种或多种这样的治疗剂:例如抗炎药、抗胆碱药(特别是M1/M2/M3受体拮抗剂)、β2-肾上腺受体激动剂、抗感染药(如抗生素、抗病毒药)或抗组胺剂。因此,本发明的再一方面提供一种包含式(I)化合物或其药学上可接受的盐、溶剂合物或具有生理学功效的衍生物和一种或多种选自以下的其它药用活性剂:例如抗炎药(如另一种皮质类固醇物是NSAID)、抗胆碱药、β2-肾上腺受体拮抗剂、抗感染药(如抗生素、抗病毒药)或抗组胺剂的组合。优选的组合包含式(I)化合物或其药学上可接受的盐、溶剂合物或其具有生理学功效的衍生物,以及β2-肾上腺受体拮抗剂,和/或抗胆碱药,和/或PDE-4抑制剂。优选的组合是含有一种或多种其它治疗剂的那些组合。
本领域技术人员应该清楚,适当时,可将其它治疗组分以盐(如碱金属盐或铵盐,或是酸加成盐)、或前体药物、或酯(如低级烷基酯)、或溶剂合物(如水合物)的形式使用,以使该治疗成分的活性,和/或稳定性,和/或物理性质(如溶解性)达到最优化。应该清楚,适当时,该治疗组分可以以光学纯的形式使用。
包含本发明化合物和β2-肾上腺受体激动剂的组合是特别优选的。
β2-肾上腺受体激动剂的实例包括沙关特罗(如其外消旋体、或单一的对映异构体如R-对映异构体)、舒喘宁、福莫特罗(formoterol)、沙丁胺醇、非诺特罗、特布他林和它们的盐(如沙美特罗的羟萘甲酸盐、沙美特罗硫酸盐或游离碱、以及福莫特罗的富马酸盐)。优选长效β2-肾上腺受体激动剂,特别是疗效期长于24小时的那些长效β2-肾上腺受体激动剂如沙美特罗或福莫特罗。优选的长效β2-肾上腺受体激动剂包括在专利WO02/066422、WO02/070490、WO02/076933、WO03/024439、WO03/072539、WO03/091204、WO04/016578、WO04/022547、WO04/037807、WO04/037773、WO04/037768、WO04/039762、WO04/039766、WO01/42193以及WO03/042160中所述的长效β2-肾上腺受体激动剂。
特别优选的长效β2-肾上腺受体激动剂包括式(XX)的化合物:
或其盐或溶剂合物,其中:
m是2到8的整数;
n是3到11的整数,
前提是m+n的值是5到19,
R21是-XSO2NR26R27,其中X是-(CH2)p-或C2-6亚链烯基;
R26和R27独立选自氢、C1-6烷基、C3-7环烷基、C(O)NR28R29、苯基和苯基(C1-4烷基)-,或R26、R27和它们连接的氮一起形成5-、6-或7-元含氮环,并且R26和R27各自任选被一个或两个选自以下的基团取代:即卤代、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基取代的C1-6烷氧基、-CO2R28、-SO2NR28R29、-CONR28R29、-NR28C(O)R29,或5-、6或7-元杂环;
R28和R29独立选自氢、C1-6烷基、C3-6环烷基、苯基和苯基(C1-4烷基)-;
且
p是0到6,优选是0到4的整数;
R22和R23独立选自氢、C1-6烷基、C1-6烷氧基、卤素、苯基和C1-6卤代烷基;和
R24和R25独立选自氢和C1-4烷基,前提是R24和R25中的碳原子总数不多于4。
最优选的长效β2-肾上腺受体激动剂是:
1 3-(4-{[6-({(2R)-2-羟基-2-[4-羟基-3-(羟甲基)苯基]乙基}氨基)己基]氧基}丁基)苯磺酰胺;
2 3-(3-{[7-({(2R)-2-羟基-2-[4-羟基-3-(羟甲基)苯基]乙基}氨基)庚基]氧基}丙基)苯磺酰胺;
3 4-{(1R)-2-[(6-{2-[(2,6-二氯苄基)氧基]乙氧基}己基)氨基]-1-羟乙基}-2-(羟甲基)苯酚;
4 4-{(1R)-2-[(6-{4-[3-(环戊基磺酰基)苯基]丁氧基}己基)氨基]-1-羟乙基}-2-(羟甲基)苯酚;
5 N-[2-羟基-5-[(1R)-1-羟基-2-[[2-4-[[(2R)-2-羟基-2-苯乙基]氨基]苯基]乙基]氨基]乙基]苯基]甲酰胺,和
6 N-2{2-[4-(3-苯基-4-甲氧基苯基)氨基苯基]乙基}-2-羟基-2-(8-羟基-2(1H)-喹啉酮-5-基)乙胺。
适合的抗炎药包括皮质类固醇。可与本发明化合物联合应用的适合皮质类固醇是口服或吸入给药的皮质类固醇以及它们的具有抗炎作用的前体药物。实例包括甲基强的松龙、强的松、地塞米松、丙酸氟替卡松、6α,9α-二氟-11β-羟基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-氧代-雄甾-1,4-二烯-17β-硫代羧酸S-氟代甲酯、6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-硫代羧酸S-氟代甲酯、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基-雄甾-1,4-二烯-17β-硫代羧酸S-(2-氧代-四氢-呋喃-3S-基)酯、倍氯米松酯(如17-丙酸酯或17,21-二丙酸酯)、布地奈德、氟尼缩松、莫美他松酯(如糠醛酯)、曲安奈德、罗氟奈德、环索奈德(16α,17-[[(R)-环己基亚甲基]双(氧基)]-11β,21-二羟基-孕甾-1,4-二烯-3,20-二酮]、丙酸布替可特、RPR-106541和ST-126。优选的皮质类固醇包括丙酸氟替卡松、6α,9α-二氟-11β-羟基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-氧代-雄甾-1,4-二烯-17β-硫代羧酸S-氟代甲酯、6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-硫代羧酸S-氟代甲酯;更优选是6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-硫代羧酸S-氟代甲酯。
可具有反式抑制超过反式激活的选择性的,并可用于联合治疗的具有糖皮质激素样作用的非甾体化合物包括以下专利中所覆盖的化合物:WO03/082827、WO01/10143、WO98/54159、WO04/005229、WO04/009016、WO04/009017、WO04/018429、WO03/104195、WO03/082787、WO03/082280、WO03/059899、WO03/101932、WO02/02565、WO01/16128、WO00/66590、WO03/086294、WO04/026248、WO03/061651、WO03/08277。
适合的抗炎药包括非甾体抗炎药(NSAID’s)。
适合的NSAID’s包括色甘酸钠、奈多罗米钠、磷酸二酯酶(PDE)抑制剂(如荼碱、PDE4抑制剂或混合PDE3/PDE4抑制剂)、白三烯拮抗剂、白三烯合成抑制剂(如孟鲁司特)、iNOS抑制剂、胰蛋白酶和弹性蛋白酶抑制剂、β-2整联蛋白拮抗剂、腺苷受体激动剂或拮抗剂(如腺苷2a激动剂)、细胞因子拮抗剂(如化学因子抑制剂如CCR3拮抗剂)或细胞因子合成抑制剂、以及5-脂氧化酶抑制剂。适合的其它β2-肾上腺受体激动剂包括沙美特罗(如其羟萘甲酸盐)、沙丁胺醇(如其硫酸盐或游离碱)、福莫特罗(如其富马酸盐)、非诺特罗、特布他林以及它们的盐。iNOS抑制剂(诱导型一氧化氮合酶抑制剂)优选口服给药。适合的iNOS抑制剂包括专利WO93/13055、WO98/30537、WO02/50021、WO95/34534及WO99/62875中公开的iNOS抑制剂。适合的CCR3抑制剂包括专利WO02/26722中公开的CCR3抑制剂。
式(I)化合物与磷酸二酯酶4(PDE4)抑制剂联合应用尤为有益,特别是在适于吸入的制剂的情况下。用于本发明该方面的PDE4-特异性抑制剂可以是熟知的抑制PDE4酶的任何化合物或已发现的用作PDE4抑制剂的化合物,且仅是PDE4抑制剂,而非抑制PDE家族其它成员如PDE3、PDE5及PDE4的化合物。
重要的化合物包括:顺式-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)环己烷-1-羧酸、2-甲酯基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-酮和顺式-[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己烷-1-醇]。也包括1996年9月3日授权的美国专利5,552,438中描述的顺式-4-氰基-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷-1-羧酸(也称西洛司特)及其盐、酯、前体药物或物理学形式。该专利和其所公开的化合物通过引用完整地结合在本文中。
Elbion的AWD-12-281(Hofgen,N.
et al.15th EFMC Iht Symp MedChem(Sept 6-10,Edinburgh)1998,Abst P.98;CAS参考编号247584020-9);一种命名为NCS-613(INSERM)的9-苄基腺嘌呤衍生物;一种确定为CI-1018(PD-168787),属Pfizer的苯并二氮杂PDE4抑制剂;Kyowa Hakko在WO99/16766中公开的苯并间二氧杂环戊烯衍生物;Kyowa Hakko的K-34;Napp的V-11294A(Landells,L.J.etal.Eur Resp J[Annu Cong Eur Resp Soc(Sept 19-23,Geneva)1998]1998,12(Suppl.28):Abst P2393);Byk-Gulden的罗氟司特(CAS参考编号162401-32-3)和一种pthalazinone(WO99/47505,该专利公开内容通过引用结合到本文);Byk-Gulden(现为Altana)制备并公开的混合PDE3/PDE4抑制剂普马芬群,(-)-p-[(4aR*,10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氢-8-甲氧基-2-甲基苯并[c][1,6]萘啶-6-基]-N,N-二异丙基苯甲酰胺;Almirall-Prodesfarma正开发的阿罗茶碱;Vernalis的VM554/UM565;以及T-440(Tanabe Seiyaku;Fuji,K.et al.J PharmacolExp Ther,1998,284(1):162)和T2585。
更重要的化合物公开于发表的国际专利申请WO04/024728(Glaxo Group Ltd)、PCT/EP2003/014867(Glaxo Group Ltd)及PCT/EP2004/005494(Glaxo Group Ltd)中。
适合的抗胆碱能药是用作蕈毒碱受体拮抗剂的化合物,特别是M1或M3受体拮抗剂、M1/M3或M2/M3的双重拮抗剂、M1/M2/M3受体全拮抗剂。吸入给药的典型化合物包括异丙托品(如异丙托溴铵,CAS 22254-24-6,商品名为定喘乐)、氧托品(如氧托溴铵,CAS30286-75-0)和噻托品(如噻托溴铵,CAS136310-93-5,商品名为Spiriva)。还包括瑞伐托酯(如氢溴酸瑞伐托酯,CAS262586-79-8)和WO01/04118公开的LAS-34273。口服给药的典型化合物包括哌仑西平(CAS28797-61-7)、达非那新(CAS133099-04-4或氢溴酸达非那新,CAS133099-07-7,商品名为Enablex)、奥昔布宁(CAS5633-20-5,商品名为Ditropan)、特罗地林(CAS15793-40-5),托特罗定(CAS124937-51-5或酒石酸托特罗定,CAS编号124937-52-6,商品名Detrol)、otilonium(如奥替溴铵,CAS26095-59-0,商品名斯巴敏)、曲司氯铵(CAS10405-02-4)以及solifenacin(CAS242478-37-1或其称为YM-905的琥珀酸盐,CAS242478-38-2,商品名为Vesicare)。
其它适合的抗胆碱能药包括美国专利申请60/487981公开的式(XXI)化合物:
其中,连接在莨菪烷(tropane)环上的烷基链优选取向是内型的;
R31和R32独立选自以下基团:含优选为1到6个碳原子的直链或支链低级烷基基团、含5到6个碳原子的环烷基基团、含6到10个碳原子的环烷基-烷基、2-噻吩基、2-吡啶基、苯基、不多于4个碳原子的烷基取代的苯基,以及不多于4个碳原子的烷氧基取代的苯基;X-表示与N原子正电荷结合的阴离子,X-可以(但不限于)是氯、溴、碘、硫酸根、苯磺酸根和甲苯磺酸根,
如包括:
1 溴化(3-内桥)-3-(2,2-二-2-噻吩基乙烯基)-8,8-二甲基-8-氮双环[3.2.1]辛烷;
2 溴化(3-内桥)-3-(2,2-二苯基乙烯基)-8,8-二甲基-8-氮双环[3.2.1]辛烷;
3 (3-内桥)-3-(2,2-二苯基乙烯基)-8,8-二甲基-8-氮双环[3.2.1]辛烷4-甲基苯磺酸;
4 溴化(3-内桥)-8,8-二甲基-3-[2-苯基-2-(2-噻吩基)乙烯基]-8-氮双环[3.2.1]辛烷;
5 溴化(3-内桥)-8,8-二甲基-3-[2-苯基-2-(2-吡啶基)乙烯基]-8-氮双环[3.2.1]辛烷;
其它适合的抗胆碱药包括美国专利申请60/511009公开的式
(XXII)或(XXIII)的化合物:
其中:
所指出的H原子处于外型位置;
R41表示与N原子正电荷结合的阴离子,R41可以(但不限于)是氯、溴、碘、硫酸根、苯磺酸根和甲苯磺酸根;
R42和R43独立选自直链或支链低级烷基基团(优选1到6个碳原子)、环烷基基团(含5到6个碳原子)、环烷基-烷基(含6到10个碳原子)、含(5到6个碳原子)及作为杂原子的N或O的杂环烷基、含(6到、10个碳原子)及作为杂原子的N或O的杂环烷基-烷基、芳基、任选取代的芳基、杂芳基和任选取代的杂芳基;
R44选自(C1-C6)烷基、(C3-C12)环烷基、(C3-C7)杂环烷基、(C1-C6)烷基(C3-C12)环烷基、(C1-C6)烷基(C3-C7)杂环烷基、芳基、杂芳基、(C1-C6)烷基-芳基、(C1-C6)烷基-杂芳基、-OR45、-CH2OR45、-CH2OH、-CN,-CF3、-CH2O(CO)R46、-CO2R47、-CH2NH2、-CH2N(R47)SO2R45、-SO2N(R47)(R48)、-CON(R47)(R48)、-CH2N(R48)CO(R46)、-CH2N(R48)SO2(R46)、-CH2N(R48)CO2(R45)、-CH2N(R48)CONH(R47);
R45选自(C1-C6)烷基、(C1-C6)烷基(C3-C12)环烷基、(C1-C6)烷基(C3-C7)杂环烷基、(C1-C6)烷基-芳基、(C1-C6)烷基-杂芳基;
R46选自(C1-C6)烷基、(C3-C12)环烷基、(C3-C7)杂环烷基、(C1-C6)烷基(C3-C12)环烷基、(C1-C6)烷基(C3-C7)杂环烷基、芳基、杂芳基、(C1-C6)烷基-芳基、(C1-C6)烷基-杂芳基;
R47和R48独立选自H、(C1-C6)烷基、(C3-C12)环烷基、(C3-C7)杂环烷基、(C1-C6)烷基(C3-C12)环烷基、(C1-C6)烷基(C3-C7)杂环烷基、(C1-C6)烷基-芳基,和(C1-C6)烷基-杂芳基,例如包括:
1 碘化(内桥)-3-(2-甲氧基-2,2-二噻吩-2-基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
2 3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙腈;
3 (内桥)-8-甲基-3-(2,2,2-三苯基-乙基)-8-氮杂-双环[3.2.1]辛烷;
4 3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙酰胺;
5 3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙酸;
6 碘化(内桥)-3-(2-氰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
7 溴化(内桥)-3-(2-氰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
8 3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙-1-醇;
9 N-苄基-3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙酰胺;
10 碘化(内桥)-3-(2-氨基甲酰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
11 1-苄基-3-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二甲基-丙基]-脲;
12 1-乙基-3-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-脲;
13 N-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-乙酰胺;
14 N-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-苯甲酰胺;
15 3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二噻吩-2-基-丙腈;
16 碘化(内桥)-3-(2-氰基-2,2-二噻吩-2-基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
17 N-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-苯磺酰胺;
18 [3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-脲;
19 N-[3-((内桥)-8-甲基-8-氮杂-双环[3.2.1]辛-3-基)-2,2-二苯基-丙基]-甲烷磺酰胺;和/或
20 溴化(内桥)-3-{2,2-二苯基-3-[(1-苯基-甲酰氧基)-氨基]-丙基}-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
本发明应用的更优选化合物包括:
1 碘化(内桥)-3-(2-甲氧基-2,2-二噻吩-2-基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
2 碘化(内桥)-3-(2-氰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
3 溴化(内桥)-3-(2-氰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
4 碘化(内桥)-3-(2-氨基甲酰基-2,2-二苯基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;
5 碘化(内桥)-3-(2-氰基-2,2-二噻吩-2-基-乙基)-8,8-二甲基-8-氮-双环[3.2.1]辛烷;和/或
6 (内桥)-3-{2,2-二苯基-3-[(1-苯基-甲酰氧基)-氨基]-丙基}-8,8-二甲基-8-氮-双环[3.2.1]溴辛烷。
适合的抗组胺剂(也称为H1-受体拮抗剂)包括任何一种或多种已知的、可供人类安全使用的大量的抑制H1-受体的拮抗剂。第一代拮抗剂包括乙醇胺、乙烯二胺及烷基胺的衍生物(如二苯醇胺、吡拉明、氯马斯汀)。第二代拮抗剂(非镇静性)包括氯雷他定、地氯雷他定、特非那定、阿司咪唑、阿伐司汀、氮斯汀、左西替利嗪、非索非那定以及西替利嗪。
优选抗组胺药的实例包括氯雷他定、地氯雷他定、非索非那定以及西替利嗪。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或其具有生理功效的衍生物和PDE4抑制剂的组合。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或其具有生理功效的衍生物和β2-肾上腺受体激动剂的组合。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或其具有生理功效的衍生物和抗胆碱能药的组合。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或其具有生理功效的衍生物和抗组胺药的组合。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或其具有生理功效的衍生物,以及PDE4抑制剂和β2-肾上腺受体激动剂的组合。
本发明的再一方面提供了一种包含式(I)化合物、其药学上可接受的溶剂合物或具有生理功效的衍生物,以及抗胆碱能药和PDE4抑制剂的组合。
上述组合可以方便地以药物制剂的形式使用,因此包含上所述组合物以及药学上可接受的稀释剂或载体的药物制剂代表本发明的另一个方面。
此类组合中的各单个化合物可按单独的剂型或组合剂型或者顺序给药或者同时给药。优选地,此类组合中的各单个化合物可以以联合的药物组合同时给药。已知治疗剂的适合剂量对本领域技术人员是熟知的。
非生理学上可接受的式(I)化合物的溶剂合物可以用作制备式(I)化合物或其生理学上可接受的溶剂合物的中间体。
式(I)化合物或其溶剂合物对糖皮质激素受体显示出激动作用。
可预知的药动学和药效学行为可证实式(I)化合物或其溶剂合物有好的抗炎特性。该化合物可能有吸引人的负作用,这一点可通过(例如)提高了对糖皮质激素受体的选择性超过了对黄酮受体的选择性,和提高了对糖皮质激素受体介导的反式抑制超过了反式激活的选择性得到证实,并可能适合于人类患者的方便疗法。
下面的非限制性实施例描述了本发明:
实施例
概述
应用购自Varian的预包装Bond Elut硅胶管,或是通过预包装Biotage硅胶柱快速色谱来进行色谱纯化。这些硅胶管在使用前用二氯甲烷预处理。LCMS采用Supelcosil的LCABZ+PLUS柱(3.3cm×4.6mm ID)进行,用0.1%HCO2H、0.01M醋酸铵的水溶液(溶剂A);0.05%HCO2H、5%水的乙腈溶液(溶剂B),洗脱剃度为0-0.7min0%B;0.7-4.2min100%B;4.2-5.3min0%B;5.3-5.5min0%B,以3ml/min的流速进行洗脱。质谱采用电喷雾正负模式(ES+ve和ES-ve),在FisonsVG Platform光谱仪上记录。1H NMR谱用Bruker DPX400光谱仪,在400.13MHz和9.4Tesla条件下,在CDCl3中测试,并以7.25ppm的残留质子溶剂的信号为内标。
中间体
中间体1:氯化
2,3-二甲基-1-[(2,2,3,3-四甲基环丙基)羰基]-IH-咪唑-3-
在34℃下,将草酰氯(360ml,4.1mol)经65min加入到2,2,3,3-四甲基环丙烷羧酸(600g,4.2mol)的二氯甲烷(3.6L)搅拌液中,将该溶液加热回流30min后冷却至5℃,再经45min加入1,2-二甲基咪唑(490g,5.1mol)的二氯甲烷(1.2L)溶液,并保持内部温度约5℃。然后将得到的悬液加热到18℃,再经45分钟加入丙酮(4.8L),并保持内部温度约18℃。将该浆液经30分钟冷却至5℃,再在5℃下搅拌30分钟,然后过滤。经过滤收集产物,并用丙酮∶二氯甲烷(3∶1,3×1.2L)洗涤,吸干后在25-30℃的真空箱中干燥10小时,得到
中间体1为白色固体(890g)。1Hnmr:δH(CDCI3,400MHz)8.45(d,J 2.4Hz,1H),8.11(d,J2.4Hz,1H),4.21(s,3H),2.96(s,3H),2.21(s,1H),1.43(s,6H),1.33(s,6H)。
实施例
实施例1:6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基
环丙基羰基)氧基-雄甾-1,4-二烯-17β-羧酸氰甲酯
方法A
通氮气下,将溴乙腈(0.229ml,3.29mmol)加入到6α,9α-二氟-11β-羟基-16α-甲基-3-氧杂-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-羧酸(按WO2003/3072592中所述制备)(634mg,1.22mmol)和碳酸钠(1.29g,12.2mmol)的DMF(15ml)的搅拌和冷却(冰)溶液中,并在室温下搅拌混合液2h,再加入碳酸钠(258mg),继续搅拌混合液18h。在混合液中滴入2MHCl(20ml)后,加入水(25ml),然后用乙酸乙酯(2×50ml)萃取。合并的有机相依次用碳酸氢钠水溶液(50ml)和盐水(50ml)洗涤,用疏水玻璃漏斗干燥,并蒸发至干。起始用环己烷、最后用环己烷∶乙酸乙酯3∶1在Bond Elut硅胶管上进行纯化,得到为白色固体的
标题化合物(485mg):LCMS保留时间3.79min,m/z 560MH+。
方法B
将6α,9α-二氟-11β,17α-二羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β羧酸(G.H.Phillipps et al.,(1994)Journal of Medicinal Chemistry,37,3717-3729)(490g,1.2mol)和中间体1(790g,3.1mol)混悬在3-戊酮(7.3L)中,经10min加入1,2-二甲基咪唑(120g,1.2mol)的水(730ml)溶液到该搅拌悬液中,并保持内部温度约19℃。35min后,经10min加入1-甲基哌嗪(230ml,2.1mol)并保持内部温度约19℃。搅拌混合液30min,然后依次用2M HCl(290ml)和水(290ml)洗涤。依次将二异丙基乙胺(430ml,2.5mol)和溴乙腈(120ml,1.7mol)加入到该溶液中,并加热到53℃持续13小时。将溶液冷却到34℃,加入1-甲基哌嗪(105ml),在约34℃下,再搅拌混合液一小时,冷却至25℃,然后依次用2M HCl(290ml)、水(290ml)、2%的碳酸钾溶液(290ml)和水(290ml)洗涤。常压蒸馏浓缩有机溶液至3.9L,冷却至75℃,并用
实 施例1的结晶作晶种。在75℃下,经3小时加入2,2,4-三甲基戊烷(6.83L),经2小时将浆液冷却至10℃,再搅拌30min,然后过滤。用3-戊酮∶2,2,4-三甲基戊烷(1∶3,3×1L)洗涤产物,吸干,最后在50℃的真空箱中干燥12小时,得到与用方法A获得的物质相同的产物
实 施例1,为白色固体(640g)。
药理活性
药理活性可以采用糖皮质激素激动剂活性的功能
体外试验进行评价。
依据K.P.Ray等(BiochemJ.(1997),328,707-715)描述的功能试验,给出一种糖皮质激素激动剂的反式抑制活性测试方法。在37℃下,用适当剂量的受试化合物处理稳定转染有报告基因的A549细胞1小时,该报告基因含来自ELAM启动子连接sPAP(分泌性磷酸脂酶)基因的响应NF-κB元件。然后用肿瘤坏死因子(TNF,10ng/ml)刺激该细胞16小时,并用标准的比色法测试此时产生的碱性磷酸酶含量。构建剂量响应曲线,并可通过曲线估算EC50值。
实施例1的EC50值小于0.1nM。
依据R.J.H.Austin等(Eur Resp J.(2002),20,1386-1392)描述的功能试验,测试化合物直接反式激活基因表达的能力。在37℃下,用适当剂量的受试化合物处理稳定转染有报告基因的A549细胞6个小时,该报告基因含小鼠乳腺瘤病毒长末端重复系列(MMTV-LTR)的糖皮质激素响应区连接renilla荧光素酶基因。通过将细胞酶与适合的底物一起孵育后,通过测量所发出的光来测定荧光素酶活性。构建剂量响应曲线,并通过曲线估算EC50值,其中最大响应值是相对于地塞米松值(100%)来计算的。
实施例1化合物在该试验中的最大响应值小于5%。
孕酮受体活性试验
已报道人乳腺癌细胞T47D会上调内源性碱性磷酸酶对孕激素的响应(Di Lorenzo
et al.,Cancer Research(1991)51,4470-4475)。将T47D细胞以每孔1×105细胞的密度接种于96孔板中,在37℃下生长过夜。将皮质类固醇化合物溶解在DMSO中,加入到细胞中(DMSO终浓度为0.7%),并在37℃下孵育24小时。然后用PBS洗涤细胞,再用RIPA缓冲液(含1%IGEPAL、0.5%去氧胆酸钠及0.1%SDS的磷酸缓冲盐溶液)将细胞裂解。用溶解在0.28M NaCl、0.5mM MgCl2的1M二乙醇胺中的磷酸对硝基苯酯(1.5mg/ml)作底物,采用分光光度法在405nm处测试碱性磷酸酶活性。构建剂量响应曲线,并通过曲线估算EC50值。
实施例1化合物在该试验中的EC50值大于100nM。
在说明书和权利要求书全文中,除非在文字中另外要求,词语“包含”及其词性变化形式“含有”、“含”均应理解为是指包含所述整体或整体的某步骤或某部分内容,而非排除任何其它整体或整体的某步骤或某部分的内容。
本申请的说明书和权利要求书形式部分可以作为后续申请的优先权的基础。这样的后续申请的权利要求书可以指本发明所述的任一特征或所述特征的组合。这些后续申请可以采用产品、组合物、方法或是用途权利要求的形式,且可包括例如(但不限于)以下的权利要求:
本申请中描述的专利和专利申请通过引用结合到本文中。
Claims (8)
2.一种权利要求1的式(I)化合物或其生理学上可接受的溶剂合物,它用作畜药或人用药。
3.权利要求1的式(I)化合物或其生理学上可接受的溶剂合物在制备治疗炎性疾病和/或过敏性疾病的药物中的用途。
4.一种药用组合物,它包含权利要求1的式(I)化合物或其生理学上可接受的溶剂合物,以及需要时,与之混合的一种或多种生理学上可接受的稀释剂或载体。
5.一种药用气雾剂,它包含权利要求1的式(I)化合物或其生理学上可接受的溶剂合物,以及作为抛射剂的碳氟化合物或含氢碳氯氟化合物,任选与表面活性剂和/或共溶剂混合。
6.一种权利要求5的药用组合物,它还包含另一种治疗活性剂。
7.一种权利要求6的药用组合物,其中所述另一种治疗活性剂是β2-肾上腺受体激动剂。
8.一种治疗患有炎性疾病和/或过敏性疾病的人或动物患者的方法,该方法包括给予所述人或动物患者有效量的权利要求1的式(I)化合物或其生理学上可接受的溶剂合物。
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Families Citing this family (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0125259D0 (en) * | 2001-10-20 | 2001-12-12 | Glaxo Group Ltd | Novel compounds |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
GB0316290D0 (en) * | 2003-07-11 | 2003-08-13 | Glaxo Group Ltd | Novel compounds |
GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
DE102004025985A1 (de) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estriol- und Estetrol-Prodrugs |
DE102004025966A1 (de) * | 2004-05-21 | 2005-12-15 | Schering Ag | Estradiol-Prodrugs |
US20090124588A1 (en) * | 2005-01-10 | 2009-05-14 | Glaxo Group Limited | Androstane 17-Alpha-Carbonate for Use in the Treatment of Inflammatory and Allergic Conditions |
EP1841780B1 (en) * | 2005-01-10 | 2011-07-27 | Glaxo Group Limited | Androstane 17-alpha-carbonate derivatives for use in the treatment of allergic and inflammatory conditions |
MX2007012084A (es) * | 2005-03-30 | 2007-11-21 | Schering Corp | Medicamentos y metodos que combinan un anticolinergico, un corticosteroide y un agonista beta de accion prolongada. |
CN106075449A (zh) | 2005-07-14 | 2016-11-09 | 尼奥塞蒂克斯公司 | 用于局部脂肪组织治疗的持续释放的增强性脂肪分解性制剂 |
GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
AU2007242851A1 (en) | 2006-04-20 | 2007-11-01 | Glaxo Group Limited | Novel compounds |
GB0611587D0 (en) | 2006-06-12 | 2006-07-19 | Glaxo Group Ltd | Novel compounds |
GB0615108D0 (en) * | 2006-07-28 | 2006-09-06 | Glaxo Group Ltd | Novel formulations |
PL2077830T3 (pl) * | 2006-10-17 | 2013-04-30 | Lithera Inc | Sposoby, kompozycje i formulacje do leczenia orbitopatii tarczycowej |
PE20081889A1 (es) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | Indol carboxamidas como inhibidores de ikk2 |
KR20160129109A (ko) | 2008-05-23 | 2016-11-08 | 아미라 파마슈티칼스 인코포레이티드 | 5-리폭시게나아제 활성화 단백질 억제제 |
US8163743B2 (en) | 2008-06-05 | 2012-04-24 | GlaxoGroupLimited | 4-carboxamide indazole derivatives useful as inhibitors of PI3-kinases |
WO2010071865A1 (en) | 2008-12-19 | 2010-06-24 | Nuon Therapeutics, Inc. | Pharmaceutical compositions and methods for treating hyperuricemia and related disorders |
US20100160351A1 (en) * | 2008-12-19 | 2010-06-24 | Nuon Therapeutics, Inc. | Pharmaceutical compositions and methods for treating hyperuricemia and related disorders |
JP5656880B2 (ja) | 2009-03-09 | 2015-01-21 | グラクソ グループ リミテッドGlaxo Group Limited | Pi3キナーゼの阻害剤としての4−オキサジアゾール−2−イル−インダゾール |
US8354539B2 (en) | 2009-03-10 | 2013-01-15 | Glaxo Group Limited | Indole derivatives as IKK2 inhibitors |
JP2012520845A (ja) | 2009-03-17 | 2012-09-10 | グラクソ グループ リミテッド | Itk阻害剤として使用されるピリミジン誘導体 |
US20120029054A1 (en) | 2009-03-19 | 2012-02-02 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of GATA Binding Protein 3 (GATA3) Gene Expression Using Short Intefering Nucleic Acid (siNA) |
AU2010226604A1 (en) | 2009-03-19 | 2011-10-13 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach 1) gene expression using short interfering nucleic acid (siNA) sequence listing |
EP2408916A2 (en) | 2009-03-19 | 2012-01-25 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CONNECTIVE TISSUE GROWTH FACTOR (CTGF) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2010107958A1 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 (STAT6) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20120004282A1 (en) | 2009-03-27 | 2012-01-05 | Merck Sharp & Dohme Corp, | RNA Interference Mediated Inhibition of the Intercellular Adhesion Molecule 1 (ICAM-1) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
WO2010111490A2 (en) | 2009-03-27 | 2010-09-30 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20120004281A1 (en) | 2009-03-27 | 2012-01-05 | Merck Sharp & Dohme Corp | RNA Interference Mediated Inhibition of the Nerve Growth Factor Beta Chain (NGFB) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
JP2012521763A (ja) | 2009-03-27 | 2012-09-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 低分子干渉核酸(siNA)を用いたシグナル伝達性転写因子1(STAT1)遺伝子発現のRNA干渉媒介性阻害 |
EP2411516A1 (en) | 2009-03-27 | 2012-02-01 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP2421834A1 (en) | 2009-04-24 | 2012-02-29 | Glaxo Group Limited | Pyrazole and triazole carboxamides as crac channel inhibitors |
US8399436B2 (en) | 2009-04-24 | 2013-03-19 | Glaxo Group Limited | N-pyrazolyl carboxamides as CRAC channel inhibitors |
KR101771193B1 (ko) | 2009-04-30 | 2017-09-05 | 글락소 그룹 리미티드 | Pi3키나아제 억제제로서 옥사졸 치환된 인다졸 |
US9132084B2 (en) | 2009-05-27 | 2015-09-15 | Neothetics, Inc. | Methods for administration and formulations for the treatment of regional adipose tissue |
EP2435462A1 (en) | 2009-05-29 | 2012-04-04 | Pfizer Limited | Novel glucocorticoid receptor agonists |
WO2011032175A1 (en) | 2009-09-14 | 2011-03-17 | Nuon Therapeutics, Inc. | Combination formulations of tranilast and allopurinol and methods related thereto |
EP2507231A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Indazole derivatives as pi 3 - kinase inhibitors |
US20120238559A1 (en) | 2009-12-03 | 2012-09-20 | Glaxo Group Limited | Novel compounds |
EP2507223A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Benzpyrazole derivatives as inhibitors of p13 kinases |
EP2523667A4 (en) * | 2010-01-15 | 2014-04-02 | Lithera Inc | PREPARATIONS FOR LYOPHILIZED CAKES |
WO2011110575A1 (en) | 2010-03-11 | 2011-09-15 | Glaxo Group Limited | Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases |
GB201007203D0 (en) | 2010-04-29 | 2010-06-16 | Glaxo Group Ltd | Novel compounds |
JP5876051B2 (ja) | 2010-09-08 | 2016-03-02 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | インフルエンザウィルス感染の治療に使用するためのインダゾール誘導体 |
PL2614058T3 (pl) | 2010-09-08 | 2015-12-31 | Glaxosmithkline Ip Dev Ltd | Polimorfy i sole n-[5-[4-(5-{[(2r,6s)-2,6-dimetylo-4-morfolinylo]-metylo}-1,3-oksazol-2-ilo)-1h-indazol-6-ilo]-2-(metyloksy)-3-pirydynylo]metanosulfonamidu |
WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
UY33597A (es) | 2010-09-09 | 2012-04-30 | Irm Llc | Compuestos y composiciones como inhibidores de la trk |
WO2012035055A1 (en) | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
ES2532213T3 (es) | 2010-10-21 | 2015-03-25 | Glaxo Group Limited | Compuestos de pirazol que actúan contra afecciones alérgicas, inmunitarias e inflamatorias |
EP2630127A1 (en) | 2010-10-21 | 2013-08-28 | Glaxo Group Limited | Pyrazole compounds acting against allergic, inflammatory and immune disorders |
GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
EP2646012A4 (en) | 2010-11-24 | 2014-12-10 | Neothetics Inc | MONOTHERAPEUTIC FORMULATIONS OF SELECTIVE, LIPOPHILIC AND PROLONGED BETA AGONISTS AND METHODS OF COSMETIC TREATMENT OF SILHOUETTE ADPOSITY AND REINFORCEMENT |
JP5959541B2 (ja) | 2011-02-25 | 2016-08-02 | ノバルティス アーゲー | Trk阻害剤としてのピラゾロ[1,5−a]ピリジン |
JP2014507458A (ja) | 2011-03-11 | 2014-03-27 | グラクソ グループ リミテッド | Sykインヒビターとしてのピリド[3,4−B]ピラジン誘導体 |
GB201104153D0 (en) | 2011-03-11 | 2011-04-27 | Glaxo Group Ltd | Novel compounds |
US10155001B2 (en) | 2013-06-14 | 2018-12-18 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | RAC1 inhibitors for inducing bronchodilation |
EP3057587A1 (en) | 2013-10-17 | 2016-08-24 | GlaxoSmithKline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
EP3057588A1 (en) | 2013-10-17 | 2016-08-24 | GlaxoSmithKline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
WO2015173701A2 (en) | 2014-05-12 | 2015-11-19 | Glaxosmithkline Intellectual Property (No. 2) Limited | Pharmaceutical compositions for treating infectious diseases |
GB201602527D0 (en) | 2016-02-12 | 2016-03-30 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
JP2019524792A (ja) | 2016-08-08 | 2019-09-05 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | 化合物 |
GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
GB201712081D0 (en) | 2017-07-27 | 2017-09-13 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
US11759472B2 (en) * | 2017-11-21 | 2023-09-19 | Cs Pharmaceuticals Limited | Compositions and methods of use for treating aberrant inflammation in peri-ocular secretory glands or at the ocular surface |
AU2018372185B2 (en) * | 2017-11-21 | 2024-05-16 | Axerovision, Inc. | Compositions and methods of use for treating aberrant inflammation in peri-ocular secretory glands or at the ocular surface |
BR112022019245A2 (pt) | 2020-03-26 | 2022-11-16 | Glaxosmithkline Ip Dev Ltd | Inibidores de catepsina para prevenir ou tratar infecções virais |
Family Cites Families (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3943124A (en) * | 1970-12-17 | 1976-03-09 | Gordon Hanley Phillipps | Chemical compounds |
GB1384372A (en) * | 1971-01-20 | 1975-02-19 | Glaxo Lab Ltd | Dereivatives of 17alpha-hydroxyandrost-4-ene-17beta-carboxylic acids |
US3686978A (en) | 1971-04-09 | 1972-08-29 | Fairfied Mfg Co Inc | Plantetary reduction wheel hub |
GB1438940A (en) | 1972-07-19 | 1976-06-09 | Glaxo Lab Ltd | 17beta-haloalkoxycarbonyl-17alpha-oxysteroids |
US4093721A (en) * | 1974-08-30 | 1978-06-06 | Glaxo Laboratories Limited | Pharmaceutical compositions of 6α,9α-difluoro-androst-4-ene-17β-carboxylates and derivatives thereof |
GB1514476A (en) * | 1974-08-30 | 1978-06-14 | Glaxo Lab Ltd | Alkyl and haloalkyl androst-4-ene and androsta-1,4-diene-17beta-carboxylates |
GB2137206B (en) | 1980-02-15 | 1985-04-03 | Glaxo Group Ltd | Androstane 17-carbothioc acid derivatives |
SE449106B (sv) * | 1980-07-10 | 1987-04-06 | Otsuka Pharma Co Ltd | Steroid med anti-inflammatorisk verkan samt komposition innehallande denna |
US4996335A (en) * | 1980-07-10 | 1991-02-26 | Nicholas S. Bodor | Soft steroids having anti-inflammatory activity |
EP0334853B1 (en) * | 1987-10-13 | 1993-06-09 | BODOR, Nicholas S. | Soft steroids having anti-inflammatory activity |
US5990099A (en) | 1988-10-31 | 1999-11-23 | Alcon Laboratories, Inc. | Angiostatic agents and methods and compositions for controlling ocular hypertension |
GB9127376D0 (en) | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
AU677776B2 (en) | 1992-04-02 | 1997-05-08 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
CN1070849C (zh) | 1994-06-15 | 2001-09-12 | 惠尔康基金会集团公司 | 酶抑制剂 |
US6172054B1 (en) * | 1995-06-15 | 2001-01-09 | Alcon Laboratories, Inc. | Combination therapy for lowering and controlling intraocular pressure |
AU1970197A (en) | 1996-05-09 | 1997-11-26 | Alcon Laboratories, Inc. | Use of steroid compounds to prevent non-cancerous tissue growth |
MY117948A (en) | 1997-01-13 | 2004-08-30 | Glaxo Group Ltd | Nitride oxide synthase inhibitors. |
US6245804B1 (en) * | 1997-05-30 | 2001-06-12 | Schering Aktiengesellschaft | Nonsteroidal gestagens |
DE19723722A1 (de) | 1997-05-30 | 1998-12-10 | Schering Ag | Nichtsteroidale Gestagene |
AU9281298A (en) | 1997-10-01 | 1999-04-23 | Kyowa Hakko Kogyo Co. Ltd. | Benzodioxole derivatives |
DE69813605T2 (de) | 1997-10-01 | 2004-02-12 | Kyowa Hakko Kogyo Co., Ltd. | Benzofuranderivate |
US6506766B1 (en) | 1998-02-13 | 2003-01-14 | Abbott Laboratories | Glucocortiocoid-selective antinflammatory agents |
SI1070056T1 (en) | 1998-03-14 | 2004-12-31 | Altana Pharma Ag | Phthalazinone pde iii/iv inhibitors |
GB9811599D0 (en) | 1998-05-30 | 1998-07-29 | Glaxo Group Ltd | Nitric oxide synthase inhibitors |
AU4501800A (en) | 1999-05-04 | 2000-11-17 | American Home Products Corporation | Tetracyclic progesterone receptor modulator compounds and methods |
ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
US6263209B1 (en) | 1999-07-28 | 2001-07-17 | Motorola, Inc. | Method and apparatus in a wireless communication system for creating a learning function |
CO5180649A1 (es) | 1999-09-01 | 2002-07-30 | Abbott Lab | Antagonistas de los receptores de los glucocorticoides para el tratamiento de la diabetes para el tratamiento de la diabetes |
OA11558A (en) | 1999-12-08 | 2004-06-03 | Advanced Medicine Inc | Beta 2-adrenergic receptor agonists. |
GB0015876D0 (en) | 2000-06-28 | 2000-08-23 | Novartis Ag | Organic compounds |
OA12394A (en) * | 2000-08-05 | 2004-07-09 | Glaxo Group Ltd | 6.Alpha-,9.alpha.-difluoro-17.alpha.-'(2-furanylcarboxyl)oxyl-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4,-diene-17-carbothioic acid s-fuoromethyl ester as an anti-inflammatory agent. |
KR20030031198A (ko) | 2000-09-29 | 2003-04-18 | 글락소 그룹 리미티드 | 염증 질환 치료용 모르폴린-아세트아미드 유도체 |
WO2002040030A1 (en) | 2000-11-16 | 2002-05-23 | Alcon Manufacturing, Ltd. | Combination therapy for lowering and controlling intraocular pressure |
GB0031179D0 (en) | 2000-12-21 | 2001-01-31 | Glaxo Group Ltd | Nitric oxide synthase inhibitors |
US6484903B2 (en) | 2001-01-09 | 2002-11-26 | Riverwood International Corporation | Carton with an improved dispensing feature in combination with a unique handle |
GB0103630D0 (en) | 2001-02-14 | 2001-03-28 | Glaxo Group Ltd | Chemical compounds |
US7144908B2 (en) | 2001-03-08 | 2006-12-05 | Glaxo Group Limited | Agonists of beta-adrenoceptors |
US7045658B2 (en) | 2001-03-22 | 2006-05-16 | Glaxo Group Limited | Formailide derivatives as beta2-adrenoreceptor agonists |
EP2039700A2 (en) * | 2001-04-30 | 2009-03-25 | Glaxo Group Limited | Novel anti-inflammatory androstane derivatives |
PT1425001E (pt) | 2001-09-14 | 2009-02-18 | Glaxo Group Ltd | Derivados de fenetanolamina para o tratamento de doenças respiratórias |
GB0125259D0 (en) * | 2001-10-20 | 2001-12-12 | Glaxo Group Ltd | Novel compounds |
WO2003042160A1 (en) | 2001-11-13 | 2003-05-22 | Theravance, Inc. | Aryl aniline beta-2 adrenergic receptor agonists |
DE60309829T2 (de) | 2002-01-14 | 2007-09-13 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Glucocorticoidmimetika, verfahren zu ihrer herstellung, diese enthaltende pharmazeutische formulierungen und ihre verwendungen |
WO2003072592A1 (en) * | 2002-01-15 | 2003-09-04 | Glaxo Group Limited | 17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents |
JP4745609B2 (ja) | 2002-01-22 | 2011-08-10 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | グルココルチコイドレセプターのための非ステロイド性リガンド、その組成物および使用 |
GB0204719D0 (en) | 2002-02-28 | 2002-04-17 | Glaxo Group Ltd | Medicinal compounds |
MXPA04009329A (es) | 2002-03-26 | 2005-01-25 | Boehringer Ingelheim Pharma | Mimeticos de glucocorticoides, metodos para su preparacion, composiciones farmaceuticas y usos de los mismos. |
US7268152B2 (en) | 2002-03-26 | 2007-09-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
DE10215316C1 (de) | 2002-04-02 | 2003-12-18 | Schering Ag | Chinolin- und Isochinolin-Derivate, ein pharmazeutisches Mittel und ihre Verwendung als Entzündungshemmer |
US6897224B2 (en) | 2002-04-02 | 2005-05-24 | Schering Ag | Quinoline and isoquinoline derivatives, a process for their production and their use as inflammation inhibitors |
DE60335869D1 (de) | 2002-04-11 | 2011-03-10 | Merck Sharp & Dohme | 1h-benzo(f)indazol-5-yl-derivate als selektive glucocorticoid-rezeptor-modulatoren |
US7271197B2 (en) | 2002-04-25 | 2007-09-18 | Glaxo Group Limited | Phenethanolamine derivatives |
US7186864B2 (en) | 2002-05-29 | 2007-03-06 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
US7074806B2 (en) | 2002-06-06 | 2006-07-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
WO2004005229A1 (en) | 2002-07-08 | 2004-01-15 | Pfizer Products Inc. | Modulators of the glucocorticoid receptor |
AU2003251969A1 (en) | 2002-07-18 | 2004-02-09 | Bristol-Myers Squibb Company | Compositions and methods involving nuclear hormone receptor site ii |
WO2004009017A2 (en) | 2002-07-18 | 2004-01-29 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
GB0217225D0 (en) | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicinal compounds |
AU2003259747A1 (en) | 2002-08-21 | 2004-03-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted hihydroquinolines as glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
GB0220730D0 (en) | 2002-09-06 | 2002-10-16 | Glaxo Group Ltd | Medicinal compounds |
PL375993A1 (en) | 2002-09-16 | 2005-12-12 | Glaxo Group Limited | Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors |
GB0230045D0 (en) | 2002-12-23 | 2003-01-29 | Glaxo Group Ltd | Compounds |
JP4520309B2 (ja) | 2002-09-20 | 2010-08-04 | メルク・シャープ・エンド・ドーム・コーポレイション | 選択的糖質コルチコイド受容体調節剤としてのオクタヒドロ−2−H−ナフト[1,2−f]インドール−4−カルボキサミド誘導体 |
EP1554264B1 (en) | 2002-10-22 | 2007-08-08 | Glaxo Group Limited | Medicinal arylethanolamine compounds |
AU2003286143A1 (en) | 2002-10-28 | 2004-05-13 | Glaxo Group Limited | Phenethanolamine derivative for the treatment of respiratory diseases |
GB0225030D0 (en) | 2002-10-28 | 2002-12-04 | Glaxo Group Ltd | Medicinal compounds |
GB0225535D0 (en) | 2002-11-01 | 2002-12-11 | Glaxo Group Ltd | Medicinal compounds |
GB0225540D0 (en) | 2002-11-01 | 2002-12-11 | Glaxo Group Ltd | Medicinal compounds |
TWI328009B (en) | 2003-05-21 | 2010-08-01 | Glaxo Group Ltd | Quinoline derivatives as phosphodiesterase inhibitors |
GB0316290D0 (en) * | 2003-07-11 | 2003-08-13 | Glaxo Group Ltd | Novel compounds |
-
2003
- 2003-07-11 GB GBGB0316290.6A patent/GB0316290D0/en not_active Ceased
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