CN1906189A - 用于治疗呼吸系统疾病的1-乙酸-吲哚、-吲唑和-苯并咪唑衍生物 - Google Patents
用于治疗呼吸系统疾病的1-乙酸-吲哚、-吲唑和-苯并咪唑衍生物 Download PDFInfo
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- CN1906189A CN1906189A CNA2004800409412A CN200480040941A CN1906189A CN 1906189 A CN1906189 A CN 1906189A CN A2004800409412 A CNA2004800409412 A CN A2004800409412A CN 200480040941 A CN200480040941 A CN 200480040941A CN 1906189 A CN1906189 A CN 1906189A
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- Prior art keywords
- acetate
- compound
- alkyl
- phenyl
- methyl
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- 125000003118 aryl group Chemical group 0.000 claims description 27
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 22
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- JBIBXDFXFBUZTB-UHFFFAOYSA-N 2-(2h-pyridin-1-yl)acetic acid Chemical compound OC(=O)CN1CC=CC=C1 JBIBXDFXFBUZTB-UHFFFAOYSA-N 0.000 claims description 18
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及用作治疗呼吸系统疾病的药物化合物的通式(I)的取代的吲哚类。
Description
本发明涉及用作治疗呼吸系统疾病的药物化合物的取代的杂环、含有它们的药物组合物及其制备方法。
EPA 1 170 594公开了鉴定用于治疗由孤独受体CRTH2的配体前列腺素D2介导的疾病状态的化合物的方法。GB 1356834公开了据说具有抗炎、止痛和解热活性的一系列化合物。目前令人意外地发现某些吲唑乙酸类对CRTH2受体具有活性并且因此预计可能用于治疗各种呼吸系统疾病,包括哮喘和COPD。
本发明由此在第一个方面中提供了通式(I)的化合物或其药物上可接受的盐:
其中:
每个A、B、D和E独立地为C-R1或N;
Y=C-R2、N或C=O;
Z为氧、硫、C1-6亚烷基链或键;
R1独立地选自氢、卤素、CN、硝基、S(O)xR6、OR6、SO2NR4R5、CONR4R5,NR4R5、NR7SO2R7、NR7C(O)xR7、C2-C6链烯基、C2-C6炔基、C1-6烷基、芳基或杂芳基,后5个基团任选地被一个或多个独立地选自1-3个卤原子、-OR7和-NR4R5、S(O)xR8、C(O)NR4R5的取代基取代,其中x为0、1或2;
R2为任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
R3为芳基或杂芳基,它们各自任选地被一个或多个取代基取代,所述的取代基独立地选自卤素、CN、硝基、S(O)xR6、OR7、SO2NR4R5、CONR4R5、NR4R5、NR7SO2R3、NR7C(O)xR6、C2-C6链烯基、C2-C6炔基、C1-6烷基,后3个基团任选地被一个或多个独立地选自卤原子、-OR6和-NR4R5的取代基取代,其中x=0、1或2;
R4和R5独立地表示氢原子、C1-6烷基或芳基,它们中的后两个基团任选地被一个或多个独立地选自卤原子、芳基、-OR12和-NR13R14、-CONR13R14、-NR13COR14、-SO2NR13R14、NR13SO2R14的取代基取代;或
R4和R5与它们所连接的氮原子一起可以形成3-8员饱和杂环,该杂环任选地含有一个或多个选自O、S、NR15的原子并且其自身任选地被C1-3烷基、卤素取代;
R6表示任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
每个R7、R8、R9、R10、R11、R12、R13、R14独立地表示氢原子、C1-C6烷基、芳基或杂芳基,它们任选地被一个或多个卤原子、OH、O-C1-C6烷基取代;且
R15为氢、C1-4烷基、-COC1-C4烷基、-COQC1-C4烷基,Q=O或NR6;
条件是:
-当Y为CR2时,环ABDE内的氮原子数为1或2;且
-当Y为C=O且X为氮时,R3不能为苯基。
在本说明书的上下文中,除非另有说明,烷基或链烯基或烷基或链烯基部分可以为直链、支链或环状的。
芳基为苯基和萘基。将杂芳基定义为5-7员芳族环或可以为6,6-或6,5-稠合双环,每个环含有一个或多个选自N、S和O的杂原子。实例包括吡啶、嘧啶、噻唑、唑、吡唑、咪唑、呋喃、异唑、吡咯、异噻唑和甘菊环、萘基、茚、喹啉、异喹啉、吲哚、中氮茚、苯并[b]呋喃、苯并[b]噻吩、1H-吲唑、苯并咪唑、苯并噻唑、苯并唑、嘌呤、4H-喹嗪、噌啉、酞嗪、喹唑啉、喹喔啉、1,8-二氮杂萘、蝶啶、喹诺酮。
对R4和R5定义的杂环指的是饱和杂环,实例包括吗啉、硫代吗啉、氮杂环丁烷、咪唑烷、吡咯烷、哌啶和哌嗪。
通式(I)的某些化合物能够以立体异构体形式存在。当然本发明包括通式(I)化合物的所有几何和旋光异构体及其混合物,包括外消旋物。其互变体和混合物也形成本发明的一个方面。
可以将上述通式(I)的化合物转化成其药物上可接受的盐或溶剂合物,优选碱加成的盐,诸如钠、钾、钙、铝、锂、镁、锌、苄星(benzathine)、氯普鲁卡因、胆碱、二乙醇胺、乙醇胺、乙二胺、葡甲胺、氨丁三醇或普鲁卡因盐;或酸加成的盐,诸如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。优选的盐包括钠盐。
术语烷基无论是单独还是作为另一个基团的组成部分均包括直链、支链和环状烷基。
优选当Y为氮或C-R2时,Z为键或硫且R3为芳基或杂芳基。
优选R1为氢、烷基、取代的烷基、卤素或腈、NR7SO2经R7、NR7C(O)xR7。
更优选R1为氢、苯基、CF3、CN、烷基或卤素,最优选氢、苯基、CF3、CN、甲基、碘或氯。
取代基R1可以存在于环ABDE的任何位置上,更优选C-R1基团存在于D和(或)E位上。
优选当环ABDE含有氮原子时,其可以存在于ABDE四个位置的任何位置上,更优选N原子存在于A、D或E位置上。
优选当Y为CR2时,环ABDE中的氮原子数为1-2,更优选当Y为CR2时,氮原子数为1。
优选当Y为N或C=O时,环ABDE内的氮原子数为0-2。更优选当Y为N或C=O时,环内的氮原子数为1,即A或D或E为N。
更优选当Y为N或C=O时,环ABDE中包含的氮原子数为0。
优选当Y为C=O时,X为氮且Z为键。
优选当Y为氮或C-R2时,X为碳,Z可以为氧、硫、亚甲基或键,优选硫、亚甲基或键。优选R2为烷基,更优选甲基。
式(I)一般结构的实例为:-
合适的R3为芳基或杂芳基。合适的杂芳基包括任选地含有1-3个选自氮、氧或硫的杂原子的6,6-或6,5-稠合双环芳族环或含有1-3个选自氮、氧或硫的杂原子的5-7-元杂环。
6,6-或6,5-稠合双环芳族环的实例包括萘基、茚、喹啉、异喹啉、吲哚、中氮茚、苯并[b]呋喃、苯并[b]噻吩、1H-吲唑、苯并咪唑、苯并噻唑、嘌呤、4H-喹嗪、噌啉、酞嗪、喹唑啉、喹喔啉、1,8-二氮杂萘、蝶啶、喹诺酮。
5-7-元杂环的实例包括吡啶、嘧啶、噻唑、唑、异唑、吡唑、咪唑、呋喃、噻吩、吡咯、异噻唑和甘菊环。
优选R3为喹啉或苯基,它们均任选地如上所述被取代。取代基可以存在于R3基团的任何合适的位置上,包括存在的氮原子上。优选的R3基团的取代基包括卤素、S(O)xR6,更优选氟、氯或SO2Me。
本发明优选的化合物包括:
5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸;
4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-[(4-氯苯基)硫基]-5-碘-1H-吲唑-1-乙酸;
3-(7-氯-4-喹啉基)-2-甲基-1H-吡咯并[2,3-b]吡啶-1-乙酸,钠盐;
3-[(4-氯-2,4-环己二烯-1-基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)-2,4-环己二烯-1-基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
4-氯-2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-c]吡啶-1-乙酸;
3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
及其药物上可接受的盐。
通式(I)的某些化合物能够以立体异构体形式存在。当然本发明包括通式(I)化合物的所有几何和旋光异构体及其混合物,包括外消旋物。其互变体和混合物也构成本发明的一个方面。
可以将上述通式(I)的化合物转化成其药物上可接受的盐或溶剂合物,优选碱加成的盐,诸如钠、钾、钙、铝、锂、镁、锌、苄星、氯普鲁卡因、胆碱、二乙醇胺、乙醇胺、乙二胺、葡甲胺、氨丁三醇或普鲁卡因盐;或酸加成的盐,诸如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。优选的盐包括钠盐。
可以理解某些官能基可能需要使用一般保护基保护。官能基的保护和脱保护基例如描述在J.W.F.McOmie编辑的‘Protective Groups in OrganicChemistry’,Plenum Press(1973),和‘Protective Groups in Organic Synthesis’,3rd edition,T.W.Greene & P.G.M.Wuts,Wiley-Interscience(1999)中。
可以通过下列方法制备通式(I)的化合物:使通式(II)的化合物或其被保护的衍生物:
其中A、B、D、E、Y、Z和R3如(I)中所定义;与通式(III)的化合物在有碱存在下反应:
L-CH2CO2R16
其中R16为烷基且L为离去基;且
此后任选地按照如下任何顺序进行:
●除去保护基;
●将酯基R11水解成相应的酸;
●形成药物上可接受的盐。
该反应可以使用碱,诸如氢化钠等在合适的溶剂,诸如THF中进行。合适的基团R16包括C1-6烷基,诸如甲基、乙基或叔丁基。合适的L为离去基,诸如卤素,特别是溴。优选通式(III)的化合物为溴乙酸甲酯、溴乙酸乙酯或溴乙酸叔丁酯。
可以使用常规方法,例如通过与氢氧化钠水溶液或三氟乙酸一起搅拌对酯基R16进行水解。
可以通过使通式(IV)的化合物反应制备其中Y为N的通式(II)化合物。
可以通过使通式(V)的化合物与肼反应并且在100℃下加热制备通式(IV)的化合物。
可以通过氧化通式(V)的化合物制备通式(IV)的化合物。合适的氧化条件为Swern或Dess-martin条件。
可以通过使通式(VI)的化合物与通式(VII)的化合物反应制备通式(V)的化合物。
其中R3在通式(II)中定义。
通式(VII)和(VIII)的化合物为商购的或可以使用本领域众所周知的标准化学方法制备。
通过使用WO 01/07436中所述的方法使通式(IX)的化合物与通式(XI)的化合物反应制备通其中Y=C-R2的通式(II)化合物。
当Z为硫时,在有诸如叔丁醇钾这类碱存在下的合适溶剂,诸如DMF或叔丁醇中用二硫化物(IXa)处理通式(II)的化合物并且加热。
R3-S-S-R3(IXa)
当Z为CH2时,用格利雅试剂,诸如溴化乙基镁和BrCH2R3处理通式(II)的化合物。
由通式(XII)的化合物通过在三乙胺和合适的溶剂,诸如DMF中用叠氮化磷酸二苯酯处理合成通式(II)的化合物,其中Y=C=O且X=N。
(XII) (II)
可以通过使通式(XII)和(XIII)的化合物反应制备通式(XIV)的化合物。
认为通式(II)、(V)和(IV)的某些化合物或其被保护的衍生物是新的并且构成本发明的另一个方面。
本领域技术人员可以理解在本发明的方法中,原料试剂或中间体化合物上的某些官能基可能需要被保护基保护。因此,制备通式(I)的化合物可以在适当阶段包括除去一个或多个保护基。官能基的保护和脱保护基完整地描述在J.W.F.McOmie编辑的‘Protective Groups in Organic Chemistry’,PlenumPress(1973)和‘Protective Groups in Organic Synthesis’,3rd edition,T.W.Greene & P.G.M.Wuts,Wiley-Interscience(1999)中。
本发明在另一个方面中提供了通式(I)的化合物、其药物上可接受的盐或溶剂合物在治疗中的用途。
通式(I)的化合物具有作为药物,特别是作为CRTh2受体活性调节剂的活性,并且可以用于治疗(治疗或预防)人和非人的动物中的病症/疾病,这些病症/疾病因PGD2及其代谢物过度或不加调节的产生而引起或加重。这类病症/疾病实例包括:
本发明在另一个方面中提供了通式(I)的化合物、其前体药物、药物上可接受的盐或溶剂合物在治疗中的用途。
通式(I)的化合物具有作为药物,特别是作为CRTh2受体活性调节剂的活性,并且可以用于治疗(治疗或预防)人和非人的动物中的病症/疾病,这些病症/疾病因PGD2及其代谢物过度或不加调节的产生而引起或加剧。这类病症/疾病实例包括:
本发明的化合物或其药物上可接受的盐可以用于治疗:
(1)(呼吸道)-气道阻塞性疾病,包括:哮喘,包括支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、运动诱发哮喘、药物-诱发的(包括阿司匹林和NSAID-诱发的)和粉尘-诱发的哮喘,间歇性的和持续性的,所有都是严重度的;和其它原因的气道高反应性;慢性阻塞性肺病(COPD);支气管炎,包括传染性和嗜酸性支气管炎;肺气肿;支气管扩张;囊性纤维化;结节病;农民肺和相关疾病;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、并发抗肿瘤治疗和慢性感染的纤维化,包括结核病和喂鸽者病和其它真菌感染;肺移植并发症;肺脉管系统血管炎和血栓形成疾病;和肺动脉高压;镇咳活性,包括治疗与气道炎症和分泌情况相关的久嗽和医源性咳嗽;急性和慢性鼻炎,包括药物性鼻炎和血管舒缩性鼻炎;全年性鼻炎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,包括感冒和因呼吸道合胞病毒、流行性感冒、冠形病毒(包括SARS)和腺病毒引起的感染。
(2)(骨和关节)与骨关节炎/骨关节病相关或包括它们的关节炎,既包括原发性的又包括继发性的例如先天性髋关节发育不良;颈和腰脊椎炎和腰部和颈痛;类风湿性关节炎和斯蒂尔病;血清阴性脊柱关节病,包括强直性脊柱炎、牛皮癣性关节炎、反应性关节炎和未分化脊柱关节病(undifferentiatedspondarthropathy);脓毒性关节炎和其它与感染相关的关节病(arthopathies)和骨疾病,诸如结核病,包括波特病和蓬塞综合症;急性和慢性晶体诱发的滑膜炎,包括尿酸盐贮积病、焦磷酸钙沉积病与钙磷灰石相关的腱、粘液囊和滑液炎症;贝切特病;原发性和继发性斯耶格伦综合征;全身性硬化和局限性硬皮病;系统性红斑狼疮、混合型结缔组织病和未分化结缔组织病;炎性肌病,包括皮肌炎和多肌炎;风湿性多肌病;少年关节炎,包括无论何种关节分布的原发性炎性关节炎和相关综合征以及风湿热及其全身并发症;脉管炎,包括巨细胞性动脉炎、高安动脉炎、丘-施综合征、结节性多动脉炎、微观多动脉炎,和与病毒感染、超敏反应、冷球蛋白和异蛋白相关的血管炎;腰背痛;家族性地中海热、穆-韦综合征和家族性爱尔兰热、菊池病(kikuchi);药物诱发的关节痛、腱炎(tendonititides)和肌病。
(3)(皮肤)银屑病、特应性皮炎、接触性皮炎或其它湿疹性皮肤病和迟发型超敏反应;植物性皮炎和光照性皮炎;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、脉管炎、中毒性红斑、表皮嗜曙红细胞增多、斑秃、男性型秃发症、斯成特综合征、韦-克综合征、多形性红斑;蜂窝组织炎,包括传染性的和非传染性的;脂膜炎;皮肤淋巴细胞瘤;非黑素瘤皮肤癌和其它发育不良性损害;药物诱发的疾病,包括固定性药疹。
(4)(眼)睑炎;结膜炎,包括多年性和春季变应性结膜炎;虹膜炎;前色素层炎和后色素层炎;脉络膜炎;自身免疫病;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。
(5)(胃肠道)舌炎、龈炎、牙周炎;食管炎,包括返流;嗜酸细胞性胃肠炎、肥大细胞增多症、克罗恩病、结肠炎,包括溃疡性结肠炎、直肠炎、肛门瘙痒;腹部疾病、过敏性肠综合征和可以具有远离肠的作用的与食物相关的变态反应(例如偏头痛、鼻炎或湿疹)。
(6)(腹部)肝炎,包括自身免疫性、酒精性和病毒性肝炎;肝纤维变性和肝硬变;胆囊炎;胰腺炎,包括急性和慢性的。
(7)(生殖泌尿系统)肾炎,包括间质性和肾小球肾炎;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;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;佩罗尼病;勃起机能障碍(男性和女性)。
(8)(同种异体移植物排斥),例如肾、心脏、肝、肺、骨髓、皮肤或角膜移植后或输血后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。
(9)(CNS)阿尔茨海默病和其它痴呆疾病,包括CJD和nvCJD;淀粉样变性病;多发性硬化和其它脱髓鞘综合征;脑动脉粥样硬化和脉管炎;颞动脉炎;重症肌无力;急性和慢性痛(急性、间歇性或持续性的,无论是来源于中枢的还是外周的),包括内脏痛、头痛、偏头痛、三叉神经痛、不典型面痛、关节和骨痛、因癌症和肿瘤侵入引起的疼痛、神经性疼痛综合征,包括糖尿病、疱疹后和与HIV-相关的神经病变;神经类肉瘤病;恶性、感染性和自身免疫过程的中枢和外周神经系统并发症。
(10)其它自身免疫病和变态反应性疾病,包括桥本甲状腺炎、格雷夫斯病、阿狄森病、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。
(11)其它具有炎性或免疫性成分的疾病,包括获得性免疫缺陷综合征(AIDS)、麻风病、恶性皮肤网状细胞增多综合征和瘤外综合征。
(12)(心血管)动脉粥样硬化、影响冠状动脉和外周循环的心包炎;心肌炎、炎性和自身免疫性心肌病,包括心肌结节病;局部缺血性再灌注损伤;心内膜炎、心瓣炎和主动脉炎,包括传染性的(例如梅毒性的);脉管炎;近静脉和外周静脉疾病,包括静脉炎和血栓形成,包括深部静脉血栓形成和静脉曲张并发症。
(13)(肿瘤)治疗常见癌症,包括前列腺、乳腺、肺、卵巢、胰腺、肠和结肠、胃、皮肤和脑肿瘤和侵害骨髓(包括白血病)和淋巴组织增生系统的恶性肿瘤,诸如何杰金淋巴瘤和非何杰金淋巴瘤;包括预防和治疗转移性疾病和肿瘤复发以及瘤外综合征。
(14)与PGD2或其代谢物水平升高相关的疾病。
因此,本发明提供了如上所述的用于治疗的通式(I)的化合物或其药物上可接受的盐或溶剂合物。
本发明的化合物优选用于治疗趋化因子受体属于CRTh2受体亚族的疾病。
可以用本发明化合物治疗的具体疾病为哮喘、鼻炎和其它PGD2或其代谢物水平升高相关的疾病。优选本发明的化合物用于治疗哮喘。
本发明在另一个方面中提供了如上所述的通式(I)的化合物或其药物上可接受的盐或溶剂合物在制备用于治疗的药物中的用途。
本发明进一步涉及联合治疗,其中将通式(1)的化合物或其药物上可接受的盐、溶剂合物或体内可水解的酯或包括通式(1)化合物的药物组合物或制剂与用于治疗哮喘、过敏性鼻炎、癌症、COPD、类风湿性关节炎、银屑病、炎症性肠病、骨关节炎或骨质疏松的治疗和/或药剂同时或依次给药。
特别地,为了治疗炎性疾病类风湿性关节炎、银屑病、炎症性肠病、COPD、哮喘和过敏性鼻炎,可以将本发明的化合物与如下药剂联用(combine):诸如TNF-α抑制剂、诸如抗-TNF单克隆抗体(诸如Remicade、CDP-870和D.sub2.E.sub7.)和TNF受体免疫球蛋白分子(诸如Enbrel.reg.);非选择性COX-1/COX-2抑制剂(诸如吡罗昔康;双氯芬酸;丙酸类,诸如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬;灭酸酯类,诸如甲芬那酸、吲哚美辛、舒林酸、阿扎丙宗;吡唑酮类,诸如保泰松;水杨酸酯类,诸如阿司匹林);COX-2抑制剂(诸如美洛昔康、塞来考昔、罗非考昔、伐地考昔和艾托考昔);低剂量氨甲蝶呤、耒氟米特;环索奈德;羟氯喹、d-青霉胺、金诺芬或非肠道或口服金。
本发明进一步涉及本发明化合物与如下药剂的联用药(combination):白细胞三烯生物合成抑制剂、5-脂氧合酶(5-LO)抑制剂或5-脂氧合酶活化蛋白(FLAP)拮抗剂,诸如齐留通;ABT-761;芬留顿;替泊沙林;Abbott-79175;Abbott-85761;N-(5-取代的)-噻吩-2-烷基磺酰胺类;2,6-二-叔丁基苯酚腙类;甲氧基四氢吡喃类,诸如Zeneca ZD-2138;化合物SB-210661;吡啶基-取代的2-氰基萘化合物,诸如L-739,010;2-氰基喹啉化合物,诸如L-746,530;吲哚和喹啉化合物诸如MK-591、MK-886和BAY x 1005。
本发明进一步涉及本发明化合物与白细胞三烯LTB.sub4.、LTC.sub4.、LTD.sub4.和LTE.sub4.的受体拮抗剂的联用药,所述受体拮抗剂选自下列化合物组成的组:吩噻嗪-3-酮类诸如L-651,392;脒基化合物,诸如CGS-25019c;benzoxalamines,诸如昂唑司特;benzenecarboximidamides,诸如BIIL 284/260;和化合物,诸如扎鲁司特、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 x 7195。
本发明进一步涉及本发明化合物与PDE4抑制剂,包括同种型PDE4D抑制剂的联用药。
本发明进一步涉及本发明化合物与抗组胺H.sub1.受体拮抗剂的联用药,所述受体拮抗剂诸如西替利嗪、氯雷他定、地氯雷他定、非索非那定、阿司咪唑、氮卓斯汀和氯苯那敏。
本发明进一步涉及本发明化合物与胃保护性H.sub2.受体拮抗剂的联用药。
本发明进一步涉及本发明化合物与α.sub1.和α.sub2.肾上腺素受体激动剂血管收缩药拟交感神经药的联用药,所述药物诸如丙己君、去氧肾上腺素、苯丙醇胺、伪麻黄碱、盐酸萘甲唑啉、盐酸氧甲唑啉、盐酸四氢唑啉、盐酸木甲唑啉和盐酸乙基去甲肾上腺素。
本发明进一步涉及本发明化合物与抗胆碱能药的联用药,所述胆碱能药诸如:异丙托溴铵;噻托溴铵;氧托溴铵;哌仑西平;和替仑西平。
本发明进一步涉及本发明化合物与β.sub1.-β.sub4.肾上腺素受体激动剂的联用药,所述受体激动剂诸如:间羟异丙贤上腺素、异丙肾上腺素、异丙肾上腺素、沙丁胺醇、沙丁胺醇、福莫特罗、沙美特罗、特布他林、奥西那林、双甲苯喘定甲磺酸盐和吡布特罗;或甲基黄嘌呤,包括茶碱和氨茶碱;色甘酸钠;或毒蕈碱受体(M1、M2和M3)拮抗剂。
本发明进一步涉及本发明化合物与胰岛素样生长因子I型(IGF-1)模拟物的联用药。
本发明进一步涉及本发明化合物与具有全身副作用降低的吸入糖皮质激素的联用药,所述糖皮质激素诸如泼尼松、泼尼松龙、氟尼缩松、曲安奈德、二丙酸倍氯米松、布地奈德、丙酸氟替卡松和糠酸莫米松。
本发明进一步涉及本发明化合物与如下药剂的联用药:基质金属蛋白酶(MMPs)抑制剂,即溶基质素,胶原酶,和明胶酶,以及聚集蛋白聚糖酶;尤其是胶原酶-1(MMP-1)、胶原酶-2(MMP-8)、胶原酶-3(MMP-13)、溶基质素-1(MMP-3)、溶基质素-2(MMP-10)和溶基质素-3(MMP-11)和MMP-12。
本发明进一步涉及本发明化合物与其它趋化因子受体功能调节剂的联用药,所述调节剂诸如:CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11(就C-C族而言);CXCR1、CXCR3、CXCR4和CXCR5(就C-X-C族而言);和CX3CR1(就C-X3-C族而言)。
本发明进一步涉及本发明化合物与抗病毒药的联用药,所述抗病毒药诸如:奈非那韦、AZT、阿昔洛韦和泛昔洛韦;和防腐化合物,诸如Valant。
本发明进一步涉及本发明化合物与心血管药剂的联用药,所述药剂诸如:钙通道阻滞剂,降脂药,诸如斯特汀类、贝特类、β-阻滞剂、Ace抑制剂、血管紧张素-2受体拮抗剂和血小板聚集抑制剂。
本发明进一步涉及本发明化合物与CNS药剂的联用药,所述药剂诸如抗抑郁药(诸如舍曲林)、抗帕金森症药(诸如司来吉兰;L-多巴;Requip;Mirapex;MAOB抑制剂,诸如selegine和雷沙吉兰;comP抑制剂,诸如Tasmar;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;和神经元-氧化氮合酶抑制剂);和抗阿尔茨海默病药,诸如多奈哌齐、他克林、COX-2抑制剂、丙戊茶碱或metryfonate。
本发明进一步涉及本发明化合物与如下药剂的联用药:(i)类胰蛋白酶抑制剂;(ii)血小板活化因子(PAF)拮抗剂;(iii)白细胞介素转化酶(ICE)抑制剂;(iv)IMPDH抑制剂;(v)粘着分子抑制剂,包括VLA-4拮抗剂;(vi)组织蛋白酶;(vii)MAP激酶抑制剂;(viii)葡糖-6磷酸脱氢酶抑制剂;(ix)激肽-B.sub1.-和B.sub2.-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)促尿酸排除剂,例如丙磺舒、磺吡酮和苯溴马隆;(xiii)生长激素促分泌素;(xiv)转化生长因子(TGFβ);(xv)血小板衍生生长因子(PDGF);(xvi)成纤维细胞生长因子,例如碱性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)辣椒碱霜;(xix)选自NKP-608C、SB-233412(他奈坦)和D-4418组成的组的速激肽NK.sub1.和NK.sub3.受体拮抗剂;(xx)选自UT-77和ZD-0892组成的组的弹性酶抑制剂;(xxi)TNF 转化酶抑制剂(TACE);(xxii)诱导的一氧化氮合酶抑制剂(iNOS)或(xxiii)在TH2细胞上表达的化学引诱物受体-同源分子(CRTH2拮抗剂)。
本发明化合物还可以与如下骨质疏松药剂联用,诸如雷洛昔芬(roloxifene)、屈洛昔芬、拉索昔芬或fosomax;和免疫抑制剂,诸如FK-506、雷帕霉素、环孢菌素、硫唑嘌呤和甲氨蝶呤。
本发明的化合物还可以与现有的治疗骨关节炎的治疗剂联用。用于联用药中的合适的药剂包括标准的非类固醇类消炎药(下文中的NSAID′s),诸如吡罗昔康;双氯芬酸;丙酸类,诸如萘普生、氟比洛芬、非诺洛芬、布洛芬;灭酸类,诸如甲芬那酸、吲哚美辛、舒林酸、阿扎丙宗;吡唑酮类,诸如保泰松;水杨酸类,诸如阿司匹林;COX-2抑制剂,诸如塞来考昔、伐地考昔、罗非考昔和艾托考昔;止痛药和关节内治疗,诸如皮质类固醇和透明质酸类,诸如透明蛋白原和synvisc和P2X7受体拮抗剂。
本发明的化合物还可以与现有的治疗癌症的治疗剂联用。联用的合适的药剂包括:
(i)医学肿瘤学中使用的抗增殖药/抗肿瘤药及其联用药,诸如烷基化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安和亚硝基脲类);抗代谢药(例如抗叶酸剂,诸如氟嘧啶类,如5-氟尿嘧啶和替加氟,雷替曲塞、甲氨蝶呤、阿糖胞苷、羟基脲、吉西他滨和紫杉醇(Taxol);抗肿瘤抗生素(例如蒽环类抗肿瘤抗生素,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、放线菌素D和普卡霉素);抗有丝分裂剂(例如长春花生物碱,如长春新碱、长春碱、长春地辛和长春瑞滨和紫杉类,如紫杉醇和泰索替尔);和拓扑异构酶抑制剂(例如鬼臼乙叉甙,如依托泊苷和替尼泊苷、安吖啶、托泊替康和喜树碱);
(ii)细胞抑制剂,诸如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、雌激素受体负调节物(例如氟维司群)、抗雄激素(例如比卡鲁胺、氟他胺、尼鲁米特和环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素类(例如醋酸甲地孕酮)、芳香酶抑制剂(例如为阿那曲唑、来曲唑、vorazole和依西美坦)和5α-还原酶抑制剂,诸如非那雄胺;
(iii)抑制癌细胞侵入的药剂(例如金属蛋白酶抑制剂,如马立马司他,和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,这类抑制剂包括生长因子抗体、生长因子受体抗体(例如抗-erbb2抗体曲妥单抗[HerceptinTM]和抗-erbb1抗体西妥昔单抗[C225])、法尼基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子族抑制剂(例如EGFR族酪氨酸激酶抑制剂,诸如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(gefitinib,AZD 1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,OSI-774)和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)),例如血小板衍生的生长因子族抑制剂和例如肝细胞生长因子族抑制剂;
(v)抗血管生成剂,诸如那些抑制血管内皮生长因子作用的药剂(例如抗血管内皮细胞生长因子抗体贝伐单抗[AvastinTM];诸如那些在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的化合物)和通过其它机制起作用的化合物(例如利诺胺,整联蛋白αvβ3功能和血管生长抑素);
(vi)血管损害剂,诸如考布他汀A4和在国际专利申请WO99/02166、WO00/40529、WO00/41669、WO01/92224、WO02/04434和WO02/08213中公开的化合物;
(vii)反义治疗,例如那些定向于上述靶的治疗,诸如ISIS 2503,即抗-ras反义治疗;
(viii)基因治疗手段,包括:例如取代异常基因,诸如异常p53或异常BRCA1或BRCA2的手段;GDEPT(定向于基因的酶前体药物治疗)手段,诸如那些使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的手段和增加患者对化疗或放疗耐受性的手段,诸如多药物抗性基因治疗;和
(ix)免疫治疗手段,包括:例如增加患者肿瘤细胞免疫原性的体外和体内手段,诸如用细胞因子转染,所述的细胞因子诸如白细胞介素2,白细胞介素4或粒细胞巨噬细胞集落刺激因子;减少T-细胞无反应性的手段;使用转染的免疫细胞,诸如细胞因子转染的树突细胞的手段;使用细胞因子转染的肿瘤细胞系的手段和使用抗独特型抗体的手段。
本发明在另一个方面中提供了如上文所定义的通式(I)的化合物或其药物上可接受的盐或溶剂合物在制备用于治疗调节CRTh2受体活性有益的人疾病或病症的药物中的用途。
在本说明书的上下文中,除非有相反的具体说明,术语″治疗″还包括″预防″。术语″治疗(therapeutic)″和″治疗上(therapeutically)″应如此解释。
本发明进一步提供了治疗由PGD2或其代谢物介导的疾病的方法,其中前列腺素类结合其受体(尤其是CRTh2受体),该方法包括对患者给药治疗有效量的如上文所定义的通式(I)的化合物或其药物上可接受的盐、溶剂合物或前体药物。
本发明还提供了治疗患有炎性疾病,尤其是银屑病或有患所述疾病危险的患者的所述疾病的方法,该方法包括对该患者给药治疗有效量的如上文所定义的通式(I)的化合物或其药物上可接受的盐、溶剂合物或前体药物。
就上述治疗用途而言,给药剂量当然随所用化合物、给药方式、所需的治疗和显示出的疾病的不同而改变。
就上述治疗用途而言,给药剂量当然随所用化合物、给药方式、所需的治疗和显示出的疾病的不同而改变。
通式(I)的化合物、其前体药物及其药物上可接受的盐和溶剂合物可以以其自身的形式使用,但一般以药物组合物形式给药,其中将通式(I)的化合物/盐/溶剂合物(活性组分)与药物上可接受的佐剂、稀释剂或载体混合。随给药方式的不同,该药物组合物优选包括0.05-99%w(重量百分比),更优选0.05-80%w,更优选0.10-70%w,且最优选0.10-50%w的活性组分,所有重量百分比均以总组合物为基准。
本发明还提供了药物组合物,包括如上文所定义的通式(I)的化合物或其药物上可接受的盐或溶剂合物与药物上可接受的佐剂、稀释剂或载体。
可以将所述的药物组合物以溶液、混悬液、七氟烷气溶胶和干粉制剂的形式经局部给药(例如给药于肺和/或气道或给药于皮肤);或经全身给药,例如通过以片剂、胶囊、糖浆、粉剂或颗粒形式经口给药或通过以溶液或混悬液形式非肠道给药或通过皮下给药或通过以栓剂形式直肠给药或通过透皮给药。优选口服给药本发明的化合物。
本发明还提供了药物组合物,包括如上文所定义的通式(I)的化合物或其药物上可接受的盐或溶剂合物与药物上可接受的佐剂、稀释剂或载体。
现在通过下列非限制性实施例解释本发明,除非另有说明,其中:
i)使用来自Advanced Chemical Development Inc,Canada的ACDlabs/name程序(6.0版)命名实施例和方法的标题和小标题化合物;
ii)除非另有说明,使用Symmetry,NovaPak或Ex-Terra反相硅胶柱进行反相制备型HPLC;
iii)快速柱色谱法指的是正相硅胶色谱法;
iv)用MgSO4或Na2SO4干燥溶剂;
v)通过在真空中旋转蒸发进行蒸发并且在通过过滤除去残余固体,诸如干燥剂后进行处理操作;
vi)除非另有说明,在环境温度,即18-25℃下和惰性气体,诸如氩气或氮气环境中进行操作;
vii)给出的收率仅用于解释并且不一定为可达到的最大值;
viii)通式(1)化合物的终产物的结构通过核(一般为质子)磁共振(NMR)和质谱技术证实;以δ标度测定质子磁共振化学位移值并且如下表示峰的多样性:s,单峰;d,双峰;t,三重峰;m,多重峰;br,宽峰;q,四重峰,quin,五重峰;
ix)一般并不完全表征中间体并且通过薄层色谱法、高效液相色谱法(HPLC)、质谱法(MS)、红外(IR)或NMR分析确定纯度;
x)质谱(MS):在给出时,一般仅报导表示母体质量的离子,以δ值(δ)的形式提供用于主要特征质子的1H NMR数据,以与作为内标的四甲基硅烷(TMS)相比为百万分之几(ppm)的形式给出;
xi)使用下列缩写:
EtOAc 乙酸乙酯
DMF N,N-二甲基甲酰胺
NMP N-甲基吡咯烷
THF 四氢呋喃
RT 室温
TFA 三氟乙酸
实施例1
5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸
a)-(2-氟-5-甲基苯基)-4-喹啉甲醇
在-78℃下将n-BuLi(2.5M己烷溶液,5.1ml)滴加到在THF(100ml)中的3-溴-4-氟甲苯(2g)中。将该反应混合物搅拌10分钟且然后滴加在THF(10ml)中的4-喹啉甲醛(1.7g)并且搅拌40分钟。使该反应混合物猝灭(水),使其达到RT且然后萃取(EtOAc),干燥(MgSO4)并且在真空中浓缩。通过色谱法纯化残余物(硅胶(silica),洗脱EtOAc∶己烷;6∶4)而得到小标题的化合物,为白色固体(1.15g)。
MS ESI+267[M+1]
b)(2-氟-5-甲基苯基)-4-喹啉基-甲酮
在-78℃下将DMSO(1.26ml)滴加到草酰氯(1.12ml)在二氯甲烷(40ml)中的溶液中。将该溶液搅拌30分钟且然后滴加在二氯甲烷(10ml)中的来自步骤a的产物(1.11g)。使该反应混合物在2小时内达到0℃。加入三乙胺(1.25ml),保持温度在(0-10℃)并且搅拌5分钟。使该反应混合物猝灭(水),分离两层。然后用二氯甲烷再萃取。干燥合并的有机萃取液(MgSO4)并且在真空中浓缩。通过色谱法纯化残余物(硅胶,洗脱EtOAc∶己烷;1∶1)而得到小标题的化合物,为黄色固体(1.2g)。
MS ESI+265[M+1]
c)4-(5-甲基-1H-吲唑-3-基)-喹啉
将肼一水合物(0.48ml)加入到在甲苯(6ml)中的步骤b)的产物(0.52g)中并且在110℃下加热3天。在真空中浓缩该反应混合物并且通过色谱法纯化残余物(硅胶,洗脱EtOAc∶己烷4∶6)而得到小标题的化合物(0.25g)。
MS ESI+260[M+1]
d)5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸乙酯
在氮气环境中将NaH(60%在矿物油中的分散体,50mg)加入到在THF(8ml)中的来自步骤c的产物(245mg)中。将该反应混合物搅拌10分钟且然后滴加溴乙酸乙酯(0.11ml)并且将该混合物再搅拌1小时。用水使反应混合物猝灭,萃取(EtOAc)。干燥有机相(MgSO4)并且在真空中浓缩。通过色谱法纯化残余物(硅胶,洗脱EtOAc∶己烷,3∶7)而得到小标题的化合物(100mg)。
MS ESI+346[M+1]
e)5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸
用NaOH(2M,0.2ml)、THF(1ml)和甲醇(1ml)处理来自步骤b的产物(70mg)。将所得溶液在室温下搅拌3小时。在真空中浓缩该反应混合物,然后通过反相HPLC纯化(用氨和乙腈洗脱)而得到标题化合物,为淡黄色固体(15mg)。
1H NMR(DMSO)δ2.43(s,3H),5.38(s,2H),7.35(d,1H),7.5-7.83(m,5H),8.12(d,1H),8.53(d,1H),9.03(d,1H)。
MS APCI+318[M+1]
实施例2
5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸
a)4-氟-3-(羟基-4-喹啉基甲基)-苄腈
使用2-氟-4-氰基溴苯和喹啉-4-醛,通过实施例1部分a的方法制备小标题化合物。
1H NMR(CDCl3)δ2.84(d,1H),6.85(d,1H),7.18-7.22(m,1H),7.52-7.89(m,5H),7.92(d,1H),8.08(d,1H)和8.97(d,1H)。
b)4-氟-3-(4-喹啉基羰基)-苄腈
使用步骤a)的产物,通过实施例1部分b的方法制备小标题化合物。
1H NMR(CDCl3)δ7.23-7.31(m,1H),7.39(d,1H),7.62(t,1H),7.82(t,1H),7.84-7.98(m,1H),8.13-8.18(m,2H),8.2-8.25(d,1H),9.05(d,1H)。
c)3-(4-喹啉基)-1H-吲唑-5-腈
使用步骤b)的产物,通过实施例1部分c的方法制备小标题化合物。
MS APCI+279[M+1]
d)5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸乙酯
使用步骤c)的产物,通过实施例1部分d的方法制备小标题化合物。
1H NMR(CDCl3)δ0.83(t,3H),4.31(q,2H),5.34(s,2H),7.54-7.76(m,4H),7.8-7.84(m,1H),8.14(s,1H),8.27-8.31(m,2H),9.08(d,1H)。
e)5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸
使用步骤d)的产物,通过实施例1部分e的方法制备小标题化合物。
1H NMR(DMSO)δ5.16(s,2H),7.6-7.7(m,1H),7.78-7.96(m,4H),8.15-8.19(d,1H),8.42(s,1H),8.78(d,1H)和9.05(d,1H)。
实施例3
3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸
a)7-氟-α-[2-氟-6-(三氟甲基)苯基]-1-萘甲醇
使用2-溴-1-氟-3-(三氟甲基)-苯和6-氟喹啉,通过实施例1步骤a的方法制备。
MS ESI+340[M+1]
b)(6-氟-4-喹啉基)[2-氟-6-(三氟甲基)苯基]-甲酮
将Dess-martin periodinone(1.06g)加入到在二氯甲烷(25ml)中的步骤a的产物(0.85g)中。得到的该溶液搅拌2小时且然后用硫代硫酸钠、碳酸氢钠和盐水洗涤。干燥(MgSO4)有机相且然后在真空中浓缩。通过色谱法纯化残余物(硅胶,洗脱EtOAc∶己烷3∶7)而得到小标题的化合物(420mg)。
MS ESI+338[M+1]
C)6-氟-4-[4-(三氟甲基)-1H-吲唑-3-基]-喹啉
使用步骤c)的产物,通过实施例1步骤c)的方法制备小标题化合物。
MS ESI+314[M+1]
d)3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸,乙酯
在氮气环境中将NaH(60%在矿物油中的分散体,22mg)加入到在THF(8ml)中的来自步骤c的产物(245mg)中。将该反应混合物搅拌1O分钟且然后滴加溴乙酸乙酯(O.11ml)并且将该混合物再搅拌1小时。用水使反应混合物猝灭,萃取(EtOAc)。干燥有机相(MgSO4)并且在真空中浓缩。通过色谱法纯化残余物(硅胶,洗脱EtOAc∶己烷,3∶7)而得到小标题的化合物(100mg)。
MS ESI+346[M+1]
e)3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸
使用步骤d)的产物,通过实施例1步骤e)的方法制备标题化合物。
1H NMR(DMSO)δ5.1(s,2H),7.14(dd,1H),7.57-7.62(m,3H),7.62-7.75(m,1H),8.051(d,1H),8.18-8.22(m,1H)和9.01(d,1H)。
实施例4
4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸
a)-(2-氟-6-碘苯基)-4-喹啉甲醇
在0℃下和氮气环境中将n-BuLi(2.5M)滴加到搅拌的二异丙基胺在THF(80ml)中的溶液中。将该反应混合物冷却至-78℃并且滴加1-碘-3-氟苯(10g)。将该反应混合物在该温度下搅拌1.5小时并且用喹啉-4-醛(7.1g)在THF(30ml)中的溶液处理且搅拌10分钟,此后用氯化铵溶液猝灭并且使该反应混合物达到室温。用水和乙酸乙酯稀释该混合物。干燥有机相(MgSO4)并且在真空中浓缩。在用乙醚研制后得到小标题的化合物,为白色固体(6.65g)。
1H NMR(CDCl3)δ2.97-3(m,1H),6.76(d,1H),7-7.5(m,1H),7.42(m,1H),7.52-7.58(m,1H),7.64-7.79(m,2H),8.02(d,1H)和8.18(d,1H)。
b)4-(4-碘-1H-吲唑-3-基)-喹啉
使用步骤a)的产物,通过实施例3部分b和c的方法制备。
MS ESI+372[M+1]
c)4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸,1,1-二甲基乙酯
使用步骤b)的产物(0.82g)和溴乙酸叔丁酯(0.5ml),通过实施例1部分d的方法制备小标题的化合物。将该产物不经任何进一步纯化用于下一步。
d)4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸
将步骤c)的产物(0.2g)溶于二氯甲烷(4ml)并且用TFA(1ml)处理,在室温下搅拌过夜并且在真空中浓缩。通过反相HPLC进一步纯化小标题的化合物而得到为黄色固体的小标题化合物(93mg)。
1H NMR(DMSO)δ5.4(s,2H),7.2-7.23(m,1H),7.42-7.9(m,5H),8.16(d,1H)和9.07(d,1H)。
实施例5
3-[(4-氯苯基)硫基]-5-碘-1H-吲唑-1-乙酸
a)3-[(4-氯苯基)硫基]-5-碘-1H-吲唑
用叔丁醇钾溶液(1.5ml,1M THF溶液)和双(4-氯苯基)二硫化物处理在DMF(8ml)中的5-碘吲唑(0.3g)并且在65℃下加热4天,此后用水使反应猝灭并且用乙酸乙酯萃取,干燥有机层(MgSO4)且然后在真空中浓缩。通过硅胶色谱法纯化而得到为白色固体的产物。
MS ES+387[M+1]
b)3-[(4-氯苯基)硫基]-5-碘-1H-吲唑-1-乙酸
使用步骤a)的产物,通过实施例1部分d)和实施例1部分e)的方法制备小标题的化合物。
1H NMR(CDCl3)δ4.98(s,2H),7.17(dd,2H),7.36(dd,2H),7.51(d,1H),7.63(dd,1H)和7.87(s,1H)。
实施例6
3-(7-氯-4-喹啉基)-2-甲基-1H-吡咯并[2,3-b]吡啶-1-乙酸,钠盐
a)7-氯-4-(2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-喹啉
将2-甲基-1H-吡咯并[2,3-b]吡啶(0.4g)、4-氯喹啉(0.6g)和N-甲基吡咯烷(1ml)在100℃下搅拌2天。将该反应混合物用乙醚研制并且过滤而得到固体,将其通过硅胶色谱法进一步纯化,使用乙酸乙酯∶异己烷(3∶7)洗脱而得到小标题的化合物(31mg)。
MS ES+293[M+1]
b)3-(7-氯-4-喹啉基)-1H-吡咯并[23-b]吡啶-1-乙酸,乙酯通过实施例1部分d)的方法由步骤a)的产物制备小标题的化合物。
MS ES+380[M+1]
c)3-(7-氯-4-喹啉基)-2-甲基-1H-吡咯并[2,3-b]吡啶-1-乙酸,钠盐
将部分b)的产物(30mg,0.09mmol)、氢氧化钠(0.09ml)、甲醇(0.2ml)和THF(0.2ml)在室温下搅拌过夜。在真空中浓缩该溶液且然后用乙醚研制而得到标题化合物,为白色固体(20mg)。
1H NMR(DMSO)δ2.3(s,3H),4.62(d,2H),7.01-7.06(M,1H),7.5-7.6(m,3H),7.8(d,1H),8.15-8.22(m,2H)和8.98(d,1H)。
实施例7
3-[(4-氯-2,4-环己二烯-1-基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸
a)3-[(4-氯苯基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶
将2,5-二甲基-1H-吡咯并[3,2-b]吡啶(0.5g)和叔丁醇钾(3.7ml,1M叔丁醇溶液)在叔丁醇(5ml)中的混合物在回流下加热20分钟,然后加热双(4-氯苯基)二硫化物(1.44g)。在进一步加热1小时后,冷却该混合物并且加入水(100ml)。过滤出沉淀,用水、乙醚洗涤并且干燥至得到标题化合物(930mg)。
MS ESI+289[M+1]
b)3-[(4-氯苯基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸乙酯
使用步骤a)的产物,通过实施例1部分d的方法制备小标题的化合物。
MS ESI+375[M+1]
c)3-[(4-氯-2,4-环己二烯-1-基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸
用NaOH水溶液(1M,0.95ml)、THF(15ml)和水(2ml)处理来自步骤b的产物(355mg)。将所得溶液在室温下搅拌5小时,然后在减压下蒸发。将残余物用乙醚研制,过滤并且干燥至得到标题化合物(0.302g)
δH(DMSO)2.39(s,3H),2.47(s,3H),4.46(s,2H),6.69-7.25(m,5H),7.65(d,1H)。
MS APCI-345[M-1]
实施例8
2,5-二甲基-3-[[4-(甲基磺酰基)-2,4-环己二烯-1-基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸
a)2,5-二甲基-3-[[4-(甲基磺酰基)苯基]甲基]-1H-吡咯并[3,2-b]吡啶在RT下将溴化乙基镁(1.2ml,3M乙醚溶液)加入到搅拌的2,5-二甲基-1H-吡咯并[3,2-b]吡啶(0.44g)在THF(20ml)中的溶液中。30分钟后,加入对-甲基磺酰基苄基溴(0.7g)并且将该混合物在回流下加热2小时。加入DMF(5ml),将该混合物在回流下加热4小时,冷却并且使其在乙酸乙酯与水之间分配。分离有机层,用水洗涤,干燥并且在减压下蒸发。通过硅胶色谱法纯化残余物,用5%甲醇/DCM洗脱而得到标题化合物(0.121g)。
MS ESI+315[M+1]
b)2,5-二甲基-3-[[4-(甲基磺酰基)苯基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸,乙酯
将在DMF(5ml)中的来自步骤a)的产物(0.115g)、碳酸钾(0.2g)和溴乙酸乙酯(0.05ml)在50℃下加热5小时。加入溴乙酸乙酯(0.1ml)并且将该混合物在80℃下再加热4小时,冷却,然后使其在乙醚与水之间分配。分离有机层,用水洗涤,干燥并且在减压下蒸发。通过硅胶色谱法纯化残余物,用2-3%甲醇/DCM洗脱而得到小标题的化合物(73mg)。
MS ESI+401[M+1]
c)2,5-二甲基-3-[[4-(甲基磺酰基)-2,4-环己二烯-1-基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸
用NaOH水溶液(1M,0.3ml)、THF(5ml)和水(3ml)处理来自步骤b)的产物(72mg)。将所得溶液在室温下搅拌3小时,然后加入2M HCl(3ml)。用乙酸乙酯萃取水层,然后在减压下蒸发。使残余物从水中重结晶而得到小标题的化合物(40mg)。
1H NMR(DMSO)δ2.40(s,3H),2.81(s,3H),3.17(s,3H),4.52(s,2H),5.27(s,2H),7.45(d,1H),7.49(d,2H),7.82(d,2H),8.57(d,1H),15.74(s,1H)。
MS APCI-371[M-1]
实施例9
2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸
a)2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶
将2,5-二甲基-1H-吡咯并[3,2-b]吡啶(0.4g)、碳酸钾(0.7g)和双(4-甲基磺酰基苯基)二硫化物(1.2g)在DMF(15ml)中的混合物在RT下搅拌4天,然后在50℃下加热6小时。使该混合物在乙酸乙酯与水之间分配,分离有机层,用水洗涤,干燥并且在减压下蒸发。将残余物用乙酸乙酯研制并且过滤而得到小标题的化合物(0.3g)。
MS ESI+333[M+1]
b)2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸,1,1-二甲基乙酯
将在DMF(8ml)中的来自步骤a)的产物(0.3g)、碳酸钾(0.3g)和溴乙酸叔丁酯(0.13ml)在RT下搅拌18小时。使该混合物在乙酸乙酯与水之间分配,分离有机层,用水洗涤,干燥并且在减压下蒸发。将残余物用乙酸乙酯/异己烷研制而得到小标题的化合物(0.175g)。
MS ESI+447[M+1]
c)2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸
将来自步骤b)的产物(0.175g)、三氟乙酸(5ml)和DCM(10ml)在RT下搅拌16小时。将残余物用乙醚研制而得到标题的化合物(125mg)。
1H NMR(DMSO)δ2.71(s,3H),3.16(s,3H),5.34(s,2H),7.21(d,2H),7.43(brd,1H),7.75(d,2H),8.46(brs,1H)。
MS APCI-389[M-1]
实施例10
4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸
a)[2-氯-3-(1-丙炔基)-4-吡啶基]-氨基甲酸,1,1-二甲基乙酯
将(2-氯-3-碘-吡啶-4-基)-氨基甲酸叔丁酯(3.4g)、碘化亚铜(I)(0.09g)、三乙胺(2.8ml)、丙炔(约1g)和二氯(双三苯膦)合钯(0.2g)在DMF(30ml)中的混合物在50℃下加热5小时。使该混合物在乙醚与水之间分配,分离有机层,用水洗涤,干燥并且在减压下蒸发。通过硅胶色谱法纯化残余物,用10%乙酸乙酯/异己烷洗脱而得到小标题的化合物(2.14g)。
MS ESI-265/7[M-1]
b)4-氯-2-甲基-1H-吡咯并[3,2-c]吡啶
将在DMF(50ml)中的来自步骤a)的产物(2.1g)和碘化亚铜(I)(0.035g)在90℃下加热6小时,冷却并且在乙酸乙酯与盐水之间分配。分离有机层,用盐水洗涤,干燥并且在减压下蒸发。通过硅胶色谱法纯化残余物,用40%乙酸乙酯/异己烷洗脱而得到小标题的化合物(0.785g)。
1H NMR(DMSO)δ2.42(s,3H),6.24(s,1H),7.29(d,1H),7.87(d,1H),11.76(s,1H)。
c)4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶
使用步骤b)的产物,通过实施例9部分a)的方法制备小标题的化合物。
MS ESI+309/11[M+1]
d)4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸,1,1-二甲基乙酯
使用步骤c)的产物,通过实施例9部分b)的方法制备小标题的化合物。
MS ESI+423/5[M+1]
e)4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸
使用步骤d)的产物,通过实施例9部分c)的方法制备标题化合物。
1H NMR(DMSO)δ2.46(s,3H),5.23(s,2H),6.98(d,2H),7.29(d,2H),7.69(d,1H),8.05(d,1H)。
MS APCI-365/7[M-1]
实施例11
4-氯-2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-c]吡啶-1-乙酸
通过实施例10的方法制备标题化合物。
1H NMR(DMSO)δ2.71(s,3H),3.16(s,3H),5.34(s,2H),7.21(d,2H),7.43(brd,1H),7.75(d,2H),8.46(brs,1H)。
MS APCI-389[M-1]
实施例12
3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸
a)4-氯-2-甲基-1H-吡咯并[3,2-c]吡啶-1-甲酸,1,1-二甲基乙酯
将在DCM(20ml)中的来自实施例10部分b)的产物(0.5g)、二碳酸二叔丁酯(0.655g)和4-二甲氨基吡啶(0.05g)在RT下搅拌72小时,然后使其在乙醚与水之间分配。分离有机层,用水洗涤,干燥并且在减压下蒸发而得到小标题的化合物(0.8g)。
MS ESI+267/9[M+1]
b)2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-甲酸,1,1-二甲基乙酯
将在二烷(20ml)中的来自步骤a)的产物(0.6g)、氟化铯(0.87g)、苯基硼酸(0.45g)和四(三苯膦)合钯(0)(0.1g)在100℃下加热5小时,冷却并且使其在乙醚与水之间分配。分离有机层,用水洗涤,干燥并且在减压下蒸发。通过硅胶色谱法纯化残余物,用20%乙酸乙酯/异己烷洗脱而得到小标题的化合物(0.627g)。
MS ESI+309[M+1]
c)2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶,三氟乙酸盐
将来自步骤b)的产物(0.62g)、三氟乙酸(5ml)和DCM(15ml)在RT下搅拌24小时,然后在减压下蒸发。粗产物在下一步中使用。
d)3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶
使用步骤c的产物,通过实施例9部分a)的方法制备小标题的化合物。
MS ESI+351/3[M+1]
e)3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸,1,1-二甲基乙酯
使用步骤d)的产物,通过实施例9部分b)的方法制备小标题的化合物。
MS ESI+465/7[M+1]
f)3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸
使用步骤e)的产物,通过实施例9部分c)的方法制备标题化合物。
1H NMR(DMSO)δ2.53(s,3H),5.47(s,2H),6.58(d,2H),7.14(d,2H),7.35-7.56(m,5H),8.28(d,1H),8.55(d,1H)。
MS APCI-407/9[M-1]
实施例13
2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸
通过实施例11的方法制备标题化合物。
1H NMR(DMSO)δ2.53(s,3H),3.15(s,3H),5.49(s,2H),6.80(d,2H),7.29-7.51(m,5H),7.57(d,2H),8.30(d,1H),8.57(d,1H)。
MS APCI-451[M-1]
实施例14
3-(7-氯-4-喹啉基)-2,3-二氢-5-甲基-2-氧代-1H-苯并咪唑-1-乙酸
a)2-[(7-氯-4-喹啉基)氨基]-4-甲基-苯甲酸
将2-氨基-4-甲基苯甲酸(2g)和4,7-二氯喹啉(2.62g)在NMP中的溶液在140℃下搅拌4小时。将该反应混合物冷却至室温并且加入到盐水中而得到沉淀,将其过滤,用水洗涤并且干燥而得到小标题的化合物(4.04g)。
MS ES+313[M+1]
b)1-(7-氯-4-喹啉基)-1,3-二氢-6-甲基-2H-苯并咪唑-2-酮
用三乙胺(0.9ml)处理部分a)的产物(2g)在干DMF中的混悬液并且搅拌30分钟。加入叠氮化磷酸二苯酯(1.38ml)并且将该反应体系再搅拌2小时,然后在60℃下搅拌4小时。将该反应体系冷却至室温并且加入到盐水中且用乙酸乙酯萃取该混悬液。干燥合并的有机萃取液(MgSO4)并且在真空中浓缩。研制所得固体并且干燥而得到小标题的化合物(1.06g)。
3-(7-氯-4-喹啉基)-2,3-二氢-5-甲基-2-氧代-1H-苯并咪唑-1-乙酸
通过实施例1部分d)和e)的方法制备小标题的化合物。
1H NMR(DMSO)δ2.23(s,3H),4.74(d,2H),6.54(s,1H),7.07(d,1H),7.25(d,1H),7.64(m,2H),7.77(d,1H),8.28(s,1H),9.15(d,1H)和13.22(s,1H)。
MS APCI+369[M+1]
药理学数据
配体结合测定
具有比活性100-210Ci/mmol的[3H]PGD2购自Perkin Elmer LifeSciences。所有其它化学品均为分析级。
通常将表达rhCRTh2/Gα16的HEK细胞维持在含有10%胎牛血清(HyClone)、1mg/ml遗传霉素、2mM L-谷氨酰胺和1%非必需氨基酸的DMEM中。为了制备膜,使粘附转染的HEK细胞在两层组织培养工厂(factory)(Fisher,目录号TKT-170-070E)内生长至铺满(confluence)。在最后18小时培养中通过添加500mM丁酸钠诱导最高水平的受体表达。用磷酸盐缓冲盐水将贴附细胞洗涤一次(PBS,50ml/细胞工厂)并且通过每个细胞工厂添加50ml冰冷膜匀化缓冲液[20mM HEPES(pH 7.4)、0.1mM二硫苏糖醇、1mM EDTA、0.1mM苯甲基磺酰氟和100μg/ml杆菌肽]使脱附。通过在4℃下以220xg离心10分钟沉淀细胞,重新悬浮于一半原始体积的新鲜膜匀化缓冲液中并且使用Polytron匀化器进行2×20秒爆发破碎,始终使管保持在冰中。通过在4℃下以220xg离心10分钟除去未破碎的细胞并且通过在4℃下以90000xg离心30分钟沉淀膜部分。将最终的沉淀重新悬浮于使用的每个细胞工厂4ml膜匀化缓冲液中并且测定蛋白质含量。将膜以合适的等分试样储存在-80℃下。
在底部透明的白色corning 96-孔NBS平板(Fisher)中进行所有测定。在测定前,将含有CRTh2的HEK细胞膜包被在SPA PVT WGA珠(Amersham)上。为了进行包被,将膜与一般在25μg膜蛋白/mg珠下的珠一起在4℃在恒定搅拌下保温过夜。(对每批膜测定最佳包被浓度)。通过离心(在4℃下以800xg进行7分钟)沉淀珠,用试验缓冲液(含有5mM氯化镁的pH 7.4的50mM HEPES)洗涤一次并且最终以10mg/ml的珠浓度重新悬浮于试验缓冲液中。
每次测定含有20μl 6.25nM[3H]PGD2、20μl膜饱和的在试验缓冲液中的SPA珠和10μl化合物溶液或13,14-二氢-15-酮基前列腺素D2(DK-PGD2,为了测定非特异性结合,Cayman chemical company)。
将化合物和DK-PGD2溶于DMSO并且用相同溶剂稀释至100x所需终浓度。加入试验缓冲液至得到10%DMSO的终浓度(目前的化合物浓度为10x所需终浓度)并且它是加入到测定平板中的溶液。将该测定平板在室温下保温2小时并且在Wallac Microbeta液体闪烁计数器上进行计数(1分钟/孔)。
通式(I)的化合物的IC50值低于(<)10μM。
Claims (15)
1.通式(I)的化合物或其药物上可接受的盐:
其中:
每个A、B、D和E独立地为C-R1或N;
Y=C-R2、N或C=O;
Z为氧、硫、C1-6亚烷基链或键;
R1独立地选自氢、卤素、CN、硝基、S(O)xR6、OR6、SO2NR4R5、CONR4R5,NR4R5、NR7SO2R7、NR7C(O)xR7、C2-C6链烯基、C2-C6炔基、C1-6烷基、芳基或杂芳基,后5个基团任选地被一个或多个独立地选自1-3个卤原子、-OR7和-NR4R5、S(O)xR8、C(O)NR4R5的取代基取代,其中x为0、1或2;
R2为任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
R3为芳基或杂芳基,它们各自任选地被一个或多个取代基取代,所述的取代基独立地选自卤素、CN、硝基、S(O)xR6、OR7、SO2NR4R5、CONR4R5、NR4R5、NR7SO2R3、NR7C(O)xR6、C2-C6链烯基、C2-C6炔基、C1-6烷基,后3个基团任选地被一个或多个独立地选自卤原子、-OR6和-NR4R5的取代基取代,其中x=0、1或2;
R4和R5独立地表示氢原子、C1-6烷基或芳基,它们中的后两个基团任选地被一个或多个独立地选自卤原子、芳基、-OR12和-NR13R14、-CONR13R14、-NR13COR14、-SO2NR13R14、NR13SO2R14的取代基取代;或
R4和R5与它们所连接的氮原子一起可以形成3-8员饱和杂环,该杂环任选地含有一个或多个选自O、S、NR15的原子并且其自身任选地被C1-3烷基、卤素取代;
R6表示任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
每个R7、R8、R9、R10、R11、R12、R13、R14独立地表示氢原子、C1-C6烷基、芳基或杂芳基,它们任选地被一个或多个卤原子、OH、O-C1-C6烷基取代;且
R15为氢、C1-4烷基、-COC1-C4烷基、-COQC1-C4烷基,Q=O或NR6;
条件是:
当Y为CR2时,环ABDE内的氮原子数为1或2;且
当Y为C=O且X为氮时,R3不能为苯基。
2.根据权利要求1的化合物,其中A、B、D和E均为C-R1。
3.根据权利要求1的化合物,其中A、D或E之一为N且D和其它为C-R1,其中R1为氢、苯基、CF3、CN、烷基或卤素。
4.根据权利要求1-3中任何一项的化合物,其中Y为C=O且X为N。
5.根据权利要求4的化合物,其中Z为键。
6.根据权利要求1-3中任何一项的化合物,其中Y为氮或C-R2,其中R2为甲基。
7.根据权利要求6的化合物,其中X为碳。
8.根据权利要求6或7的化合物,其中Z为硫、亚甲基或键。
9.根据权利要求1的化合物,选自:
5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸;
4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-[(4-氯苯基)硫基]-5-碘-1H-吲唑-1-乙酸;
3-(7-氯-4-喹啉基)-2-甲基-1H-吡咯并[2,3-b]吡啶-1-乙酸,钠盐;
3-[(4-氯-2,4-环己二烯-1-基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)-2,4-环己二烯-1-基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
4-氯-2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-c]吡啶-1-乙酸;
3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
及其药物上可接受的盐。
10.根据权利要求1-9中任何一项的通式(I)的化合物在治疗中的用途。
11.治疗由前列腺素D2介导的疾病的方法,包括对患者给药治疗有效量的如权利要求1-9中所限定的通式(I)的化合物或其药物上可接受的盐。
12.根据权利要求11的治疗方法,其中所述的疾病为哮喘或鼻炎。
13.通式(I)的化合物或其药物上可接受的盐在制备用于治疗由前列腺素D2介导的疾病的药物中的用途:
其中:
每个A、B、D和E独立地为C-R1或N;
Y=C-R2、N或C=O;
Z为氧、硫、C1-6亚烷基链或键;
R1独立地选自氢、卤素、CN、硝基、S(O)xR6、OR6、SO2NR4R5、CONR4R5,NR4R5、NR7SO2R7、NR7C(O)xR7、C2-C6链烯基、C2-C6炔基、C1-6烷基、芳基或杂芳基,后5个基团任选地被一个或多个独立地选自1-3个卤原子、-OR7和-NR4R5、S(O)xR8、C(O)NR4R5的取代基取代,其中x为0、1或2;
R2为任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
R3为芳基或杂芳基,它们各自任选地被一个或多个取代基取代,所述的取代基独立地选自卤素、CN、硝基、S(O)xR6、OR7、SO2NR4R5、CONR4R5、NR4R5、NR7SO2R3、NR7C(O)xR6、C2-C6链烯基、C2-C6炔基、C1-6烷基,后3个基团任选地被一个或多个独立地选自卤原子、-OR6和-NR4R5的取代基取代,其中x=0、1或2;
R4和R5独立地表示氢原子、C1-6烷基或芳基,它们中的后两个基团任选地被一个或多个独立地选自卤原子、芳基、-OR12和-NR13R14、-CONR13R14、-NR13COR14、-SO2NR13R14、NR13SO2R14的取代基取代;或
R4和R5与它们所连接的氮原子一起可以形成3-8员饱和杂环,该杂环任选地含有一个或多个选自O、S、NR15的原子并且其自身任选地被C1-3烷基、卤素取代;
R6表示任选地被一个或多个独立地选自卤原子、芳基、-OR9和-NR10R11的取代基取代的C1-6烷基;
每个R7、R8、R9、R10、R11、R12、R13、R14独立地表示氢原子、C1-C6烷基、芳基或杂芳基,它们任选地被一个或多个卤原子、OH、O-C1-C6烷基取代;且
R15为氢、C1-4烷基、-COC1-C4烷基、-COQC1-C4烷基,Q=O或NR6;
条件是:
当Y为CR2时,环ABDE内的氮原子数为1或2;且
当Y为C=O且X为氮时,R3不能为苯基。
14.根据权利要求13的用途,其中所述的疾病为哮喘或鼻炎。
15.根据权利要求13或14的用途,其中所述的化合物选自:
5-甲基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
5-氰基-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-(6-氟-4-喹啉基)-4-(三氟甲基)-1H-吲唑-1-乙酸;
4-碘-3-(4-喹啉基)-1H-吲唑-1-乙酸;
3-[(4-氯苯基)硫基]-5-碘-1H-吲唑-1-乙酸;
3-(7-氯-4-喹啉基)-2-甲基-1H-吡咯并[2,3-b]吡啶-1-乙酸,钠盐;
3-[(4-氯-2,4-环己二烯-1-基)硫基]-2,5-二甲基-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)-2,4-环己二烯-1-基]甲基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
2,5-二甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-b]吡啶-1-乙酸;
4-氯-3-[(4-氯苯基)硫基]-2-甲基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
4-氯-2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-1H-吡咯并[3,2-c]吡啶-1-乙酸;
3-[(4-氯苯基)硫基]-2-甲基-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
2-甲基-3-[[4-(甲基磺酰基)苯基]硫基]-4-苯基-1H-吡咯并[3,2-c]吡啶-1-乙酸;
及其药物上可接受的盐。
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- 2004-11-24 JP JP2006540603A patent/JP2007512299A/ja active Pending
- 2004-11-24 EP EP04798644A patent/EP1699781A1/en not_active Withdrawn
- 2004-11-24 WO PCT/GB2004/004937 patent/WO2005054232A1/en active Application Filing
- 2004-11-24 US US10/580,576 patent/US20080027092A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102892288A (zh) * | 2010-02-11 | 2013-01-23 | 范德比尔特大学 | 作为亲代谢性谷氨酸受体4(mGLuR4)变构增效剂的吡唑并吡啶化合物、吡唑并吡嗪化合物、吡唑并吡嘧啶化合物、吡唑并噻吩化合物和吡唑并噻唑化合物,组合物,以及其治疗神经学上的功能失调的方法 |
CN102892288B (zh) * | 2010-02-11 | 2016-02-24 | 范德比尔特大学 | 作为亲代谢性谷氨酸受体4(mGLuR4)变构增效剂的吡唑并吡啶化合物、吡唑并吡嗪化合物、吡唑并吡嘧啶化合物、吡唑并噻吩化合物和吡唑并噻唑化合物,组合物,以及其治疗神经学上的功能失调的方法 |
Also Published As
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EP1699781A1 (en) | 2006-09-13 |
WO2005054232A1 (en) | 2005-06-16 |
SE0303180D0 (sv) | 2003-11-26 |
JP2007512299A (ja) | 2007-05-17 |
US20080027092A1 (en) | 2008-01-31 |
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