CN1179945C - 吲哚衍生物、其制备方法及用途 - Google Patents
吲哚衍生物、其制备方法及用途 Download PDFInfo
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- CN1179945C CN1179945C CNB018088422A CN01808842A CN1179945C CN 1179945 C CN1179945 C CN 1179945C CN B018088422 A CNB018088422 A CN B018088422A CN 01808842 A CN01808842 A CN 01808842A CN 1179945 C CN1179945 C CN 1179945C
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- methyl
- benzoyl
- chloroform
- methyl alcohol
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/02—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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
通式(I)代表的吲哚衍生物(式中各符号如说明书中所述)、其制备方法及含有该衍生物作为活性成分的DP受体拮抗剂。通式(I)的化合物结合到DP受体上,显示出拮抗作用,因此可用于预防和/或治疗过敏性疾病,例如过敏性鼻炎、过敏性结膜炎、特异性皮炎、支气管哮喘和食物过敏等;全身性肥大细胞症;全身性肥大细胞活化障碍;过敏性休克;气管收缩;荨麻疹;湿疹等;伴随痒的疾病,例如;特异性皮炎、荨麻疹等;伴随痒的行为(抓、打等)产生的二次疾病,例如白内障、视网膜脱落、炎症、感染、睡眠障碍等;炎症;慢性闭塞性肺病;缺血再灌注障碍;脑血管障碍;风湿性关节炎并发胸膜炎;和溃疡性大肠炎等疾病。
Description
技术领域
本发明涉及吲哚衍生物。
更具体说,本发明涉及通式(I)代表的吲哚衍生物、其制备方法及用途
式中,所有符号的含义与下述相同。
背景技术
前列腺素D(以下简称为(“PGD”)作为花生四烯酸级联过程中的代谢产物是已知的,且知道具有支气管收缩、血管扩张或收缩和血小板凝固抑制作用。PGD被认为是从肥大细胞产生的,并已知道全身性肥大细胞症患者中PGD浓度增加(New Eng.J.Med.,
303,1400-1404(1980))。此外,PGD被认为与神经活动,尤其与睡眠和激素分泌有关。另外,也有与血小板凝固、糖原代谢和有眼压调节有关的报告。
PGD通过与其受体DP受体结合而发挥作用。DP受体拮抗剂结合到其受体上,并产生拮抗作用,从而能抑制PGD的作用。因此,被认为可用于预防和/或治疗过敏性疾病,例如过敏性鼻炎、过敏性结膜炎、特异性皮炎、支气管哮喘和食物过敏等;全身性肥大细胞症;全身性肥大细胞活化障碍;过敏性休克;气管收缩;荨麻疹;湿疹;过敏性支气管肺曲霉病;副鼻窦炎;鼻息肉;过敏性脉管炎;嗜曙红细胞增多症;接触性皮炎;伴随痒的疾病,例如;特异性皮炎、荨麻疹、过敏性结膜炎、过敏性鼻炎、接触性皮炎等;伴随痒的行为(抓、打等)产生的二次疾病,例如白内障、视网膜脱落、炎症、感染、睡眠障碍等;炎症;慢性闭塞性肺病;缺血再灌注障碍;脑血管障碍;风湿性关节炎并发胸膜炎;和溃疡性大肠炎等疾病。此外,也被认为与睡眠和血小板凝固有关,且对这些疾病也是有用的。
到目前为止已知有一些DP受体拮抗剂,而且通式(A)代表的BW-A868C被认为是最具有选择性的。
此外,最近在WO 98/25915,WO 98/25919,WO 97/00853,WO 98/15502等文献中也公开了血栓烷衍生物类DP受体拮抗剂。
另一方面,作为与本发明化合物类似的化合物,已知有作为合成中间体的通式(B)代表的化合物(J.Heterocyclic Chem.,
19,1195(1982)).
发明内容
本发明者们为了寻找能特异结合到DP受体上并具有拮抗活性的化合物,进行了锐意的研究,结果发现通过通式(I)代表的吲哚衍生物可以达到本发明的目的,于是完成了本发明。
即,本发明涉及通式(I)代表的吲哚衍生物或其无毒盐:
式中:
R1代表羟基、C1-6烷氧基或式NR8R9,其中R8和R9各自独立地代表氢原子、C1-6烷基或SO2R13,其中R13代表C1-6烷基、C3-15饱和或不饱和碳环或含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;
R2代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、氨基、三卤甲基、氰基、羟基、苄基或4-甲氧基苄基;
R3代表氢原子、C1-6烷基、C1-6烷氧基、卤原子、三卤甲基、氰基或羟基;
R4和R5各自独立地代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、硝基、氨基、三卤甲基、氰基或羟基;
D代表单键、C1-6亚烷基、C2-6亚链烯基或C1-6氧亚烷基;
在-G-R6中:
1)G代表单键、可被1-2个氧原子和/或硫原子取代的C1-6亚烷基或可被1-2个氧原子和/或硫原子取代的C2-6亚链烯基(其中该亚烷基和亚链烯基可被羟基或C1-4烷氧基取代)、-C(O)NH-、-NHC(O)-、-SO2NH-、-NHSO2-或重氮基;
R6代表C3-15饱和或不饱和碳环或含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;其中该环可被1-5个选自下列的取代基取代:
C1-6烷基、C1-10烷氧基、C2-6烷氧基烷基、卤原子、羟基、三卤甲基、硝基、氨基、苯基、苯氧基、氧代、C2-6酰基、C1-6烷磺酰基和氰基;或
2)G和R6合在一起代表
(i)可被1-5个氧原子和/或硫原子取代的C1-15烷基;
(ii)可被1-5个氧原子和/或硫原子取代的C2-15链烯基;或
(iii)可被1-5个氧原子和/或硫原子取代的C2-15链炔基,
其中该烷基、链烯基和链炔基可被1-12个选自C1-6烷氧基、卤原子、羟基、氰基、氧代、和NR11R12这一组中的取代基取代,其中R11和R12各自独立地代表氢原子、C1-6烷基、C2-6链烯基、苯基、苯甲酰基、萘基、被C1-6烷基取代的苯基或被苯基或氰基取代的C1-6烷基;
n代表1-3;
m代表1-3;
i代表1-4;和
(2)其制备方法;
(3)含有该化合物作为活性成分的药剂;以及
(4)作为其新型合成中间体的2-甲基吲哚-4-乙酸。
通式(I)中,R2、R3、R4、R5、R6、R8、R9、R11、R12或R13代表的C1-6烷基包括甲基、乙基、丙基、丁基、戊基、己基及其异构体。
通式(I)中,R1、R2、R3、R4、或R5代表的C1-6烷氧基包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基及其异构体。
通式(I)中,R6代表的C1-10烷氧基包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、庚氧基、辛氧基、壬氧基、癸氧基及其异构体。
通式(I)中,G和R6合在一起代表的C1-15烷基包括甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一基、十二基、十三基、十四基、十五基及其异构体。
通式(I)中,G和R6合在一起代表的可被1-5个氧原子和/或硫原子取代的C1-15烷基代表上述烷基中任何1-5个碳原子被氧原子和/或硫原子取代了的烷基。
通式(I)中,G和R6合在一起代表的C2-15链烯基包括乙烯基、丙烯基、丁烯基、戊烯、己烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一碳烯基、十二碳烯基、十三碳烯基、十四碳烯基、十五碳烯基及其异构体。
通式(I)中,G和R6合在一起代表的可被1-5个氧原子和/或硫原子取代的C2-15链烯基代表上述链烯基中任何1-5个碳原子被氧原子和/或硫原子取代了的链烯基。
通式(I)中,G和R6合在一起代表的C2-15炔基包括乙炔基、丙炔基、丁炔基、戊炔、己炔基、庚炔基、辛炔基、壬炔基、癸炔基、十一碳炔基、十二碳炔基、十三碳炔基、十四碳炔基、十五碳炔基及其异构体。
通式(I)中,G和R6合在一起代表的可被1-5个氧原子和/或硫原子取代的C2-15链炔基代表上述链炔基中任何1-5个饱和碳原子被氧原子和/或硫原子取代了的链炔基。
通式(I)中,R2、R4、R5或R6代表的C2-6烷氧基烷基包括甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、丙氧基甲基、丙氧基乙基、丙氧基丙基、丁氧基甲基、丁氧基乙基、戊氧基甲基及其异构体。
通式(I)中,D或G代表的C1-6亚烷基包括亚甲基、亚乙基、三亚甲基、四亚甲基、五亚甲基、六亚甲基及其异构体。
通式(I)中,D代表的C2-6亚链烯基包括亚乙烯基、亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基及其异构体。
通式(I)中,D代表的C1-6氧亚烷基包括氧亚甲基、氧亚乙基、氧亚丁基、氧亚戊基、氧亚己基及其异构体。
通式(I)中,G代表的可被1-2个氧原子和/或硫原子取代的C1-6亚烷基包括上述C1-6亚烷基中任何碳原子被氧原子和/或硫原子取代了的亚烷基。
通式(I)中,G代表的可被1-2个氧原子和/或硫原子取代的C2-6亚链烯基包括上述C2-6亚链烯基中任何饱和碳原子被氧原子和/或硫原子取代了的亚链烯基。
通式(I)中,R11和R12代表的C2-6链烯基包括乙烯基、丙烯基、丁烯基、戊烯基、己烯基及其异构体。
通式(I)中,R2、R3、R4、R5或R6代表的卤原子包括氟、氯、溴、和碘。
通式(I)中,R2、R3、R4、R5或R6代表的三卤甲基包括三氟甲基、三氯甲基、三溴甲基和三碘甲基。
通式(I)中,R10代表的C1-10烷氧基包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、庚氧基、辛氧基、壬氧基、癸氧基及其异构体。
通式(I)中,R6代表的C2-6酰基包括乙酰基、丙酰基、丁酰基、戊酰基、己酰基及其异构体。
通式(I)中,R6代表的C1-6烷基磺酰基包括甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基、己磺酰基及其异构体。
通式(I)中,R6和R13代表的含3-15个环碳原子的C3-15碳环包括含3-15个环碳原子的单环、双环或三环的不饱和或饱和碳环。
含3-15个环碳原子的单环、双环或三环的不饱和或饱和碳环的例子包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环戊二烯、环己二烯、苯、并环戊烷、茚、萘、甘菊环、全氢化并环戊烷、全氢化茚、二氢化萘、四氢化萘、全氢化萘、全氢化甘菊环、庚搭烯、联苯、芴、菲、蒽、二氢化蒽、四氢化蒽、全氢化蒽、,芴、二氢化芴、四氢化芴、全氢化芴、降冰片烷、降蒎烷、降冰片烷、降冰片烯、降蒎烷、降蒎烯环等。
通式(I)中,R6和R13代表的含1-5个氮原子、硫原子和/或氧原子的4-15元杂环是饱和或不饱和的,其例子包括下列通式表示的杂环:
通式(I)中,R1优选是羟基、C1-6烷基或NR8R9,更优选羟基或C1-8烷基。
通式(I)中,R2优选是氢原子、C1-6烷基或C1-6烷氧基烷基,更优选氢原子、C1-2烷基或C1-2烷氧基烷基。
通式(I)中,R3优选是氢原子或C1-6烷基。
通式(I)中,R4优选是氢原子或C1-6烷基,更优选氢原子或C1-2烷基。
通式(I)中,R5优选是氢原子或C1-6烷基,更优选氢原子或C1-2烷基。
通式(I)中,D优选是单键或C1-6亚烷基,更优选单键或C1-2亚烷基。
通式(I)中,G优选是可被1或2个氧原子取代的C1-6亚烷基,更优选是可被1个氧原子取代的C1-2亚烷基。
通式(I)中,R6优选是任选地含有取代基的C5-10碳环或含1-3个氮原子、氧原子和/或硫原子的单环或双环式5-10元杂环,更优选是任选地含有取代基的含1-3个氮原子、氧原子和/或硫原子的双环式9-10元杂环。
此外,优选的是,G和R6合在一起代表可被1-4个氧原子和/或硫原子取代的C1-10烷基、可被1-4个氧原子和/或硫原子取代的C2-10链烯基或可被1-4个氧原子和/或硫原子取代的C2-10炔基。
除非另有指出,否则所有异构体都包含在本发明中。例如,烷基、链烯基和炔基基团以及亚烷基基团包括直链基团和支链基团。此外,双键、环、稠环中的异构体(E、Z、顺式、反式异构体),由于存在不对称碳原子而产生的异构体(R-、S-、α-、β-异构体、对映体、非对映体),具有旋光性的旋光异构体(D、L、d、l异构体),通过色谱分离的极性化合物(高极性化合物和底极性化合物),平衡化合物,这些化合物的任意比例的混合物以及外消旋混合物都包括在本发明中。
通式(I)表示的本发明的化合物中,优选的化合物是实施例中所示的化合物,下列各式表示的化合物:
通式(I-A1):
式中,当R6代表一个环时,R61代表该环的取代基,p是0或1至3的整数,其他符号的含义与上述相同;
通式(I-A2):
式中,所有符号的含义与上述相同;
通式(I-A3):
式中,所有符号的含义与上述相同;
通式(I-A4):
式中,所有符号的含义与上述相同;
通式(I-A5):
式中,所有符号的含义与上述相同;
通式(I-A6):
式中,所有符号的含义与上述相同;
通式(I-A7):
式中,所有符号的含义与上述相同;
通式(I-A8):
式中,所有符号的含义与上述相同;
通式(I-A9):
式中,所有符号的含义与上述相同;
通式(I-A10):
式中,所有符号的含义与上述相同;
通式(I-B1):
式中,所有符号的含义与上述相同;
通式(I-B2):
式中,所有符号的含义与上述相同;
通式(I-B3):
式中,所有符号的含义与上述相同;
通式(I-B4):
式中,所有符号的含义与上述相同;
通式(I-B5):
式中,所有符号的含义与上述相同;
通式(I-B6):
式中,所有符号的含义与上述相同;
通式(I-B7):
式中,所有符号的含义与上述相同;
通式(I-B8):
式中,所有符号的含义与上述相同;
通式(I-C1):
式中,所有符号的含义与上述相同;
通式(I-C2):
式中,所有符号的含义与上述相同;
通式(I-C3):
式中,所有符号的含义与上述相同;
通式(I-C4):
式中,所有符号的含义与上述相同;
通式(I-C5):
式中,所有符号的含义与上述相同;
通式(I-C6):
式中,所有符号的含义与上述相同;
通式(I-C7):
式中,所有符号的含义与上述相同;
通式(I-C8):
式中,所有符号的含义与上述相同;
通式(I-C9):
式中,所有符号的含义与上述相同;
通式(I-C10):
式中,所有符号的含义与上述相同;
通式(I-C11):
式中,所有符号的含义与上述相同;
通式(I-C12):
式中,所有符号的含义与上述相同;
通式(I-C13):
式中,所有符号的含义与上述相同;
通式(I-C14):
式中,所有符号的含义与上述相同;
通式(I-C15):
式中,所有符号的含义与上述相同;
通式(I-D1):
式中,所有符号的含义与上述相同;
通式(I-D2):
式中,所有符号的含义与上述相同;
通式(I-D3):
式中,所有符号的含义与上述相同;
通式(I-D4):
式中,所有符号的含义与上述相同;
通式(I-D5):
式中,所有符号的含义与上述相同;
通式(I-D6):
式中,所有符号的含义与上述相同;
通式(I-D7):
式中,所有符号的含义与上述相同;
通式(I-D8):
式中,所有符号的含义与上述相同;
通式(I-D9):
式中,所有符号的含义与上述相同;
通式(I-E1):
式中,所有符号的含义与上述相同;
通式(I-E2):
式中,所有符号的含义与上述相同;
通式(I-E3):
式中,所有符号的含义与上述相同;
通式(I-E4):
式中,所有符号的含义与上述相同;
通式(I-E5):
式中,所有符号的含义与上述相同;
通式(I-E6):
式中,所有符号的含义与上述相同;
通式(I-E7):
式中,所有符号的含义与上述相同;
通式(I-E8):
式中,所有符号的含义与上述相同;
通式(I-E9):
式中,所有符号的含义与上述相同;
通式(I-E10):
式中,所有符号的含义与上述相同;
通式(I-E11):
式中,所有符号的含义与上述相同;
通式(I-E12):
式中,所有符号的含义与上述相同;
通式(I-E13):
式中,所有符号的含义与上述相同;
通式(I-E14):
式中,所有符号的含义与上述相同;
通式(I-E15):
式中,所有符号的含义与上述相同;
通式(I-E16):
式中,所有符号的含义与上述相同;
通式(I-E17):
式中,所有符号的含义与上述相同;
通式(I-E18):
式中,所有符号的含义与上述相同;
通式(I-E19):
式中,所有符号的含义与上述相同;
通式(I-E20):
式中,所有符号的含义与上述相同;
通式(I-E21):
式中,所有符号的含义与上述相同;
通式(I-E22):
式中,所有符号的含义与上述相同;
通式(I-E23):
式中,所有符号的含义与上述相同;
通式(I-F1):
式中,所有符号的含义与上述相同;
通式(I-F2):
式中,所有符号的含义与上述相同;
通式(I-F3):
式中,所有符号的含义与上述相同;
通式(I-F4):
式中,所有符号的含义与上述相同;
通式(I-F5):
式中,所有符号的含义与上述相同;
通式(I-F6):
式中,所有符号的含义与上述相同;
通式(I-F7):
式中,所有符号的含义与上述相同;
通式(I-F8:
式中,所有符号的含义与上述相同;
通式(I-F9):
式中,所有符号的含义与上述相同;
通式(I-F10):
式中,所有符号的含义与上述相同;
通式(I-F11):
式中,所有符号的含义与上述相同;
通式(I-F12):
式中,所有符号的含义与上述相同;
通式(I-F13):
式中,所有符号的含义与上述相同;
通式(I-F14):
式中,所有符号的含义与上述相同;以及
下列表1至表5所示的化合物和这些化合物的无毒盐。
表1
-G-R6
表2
-G-R6
表3
-G-R6
表4
-G-R6
表5
-G-R6
盐:
通式(I)表示的本发明的化合物可用公知方法转变成相应的盐。该盐优选是无毒盐,且是水溶性盐。适合的盐包括碱金属(钾、钠等)盐、碱土金属(钙、镁等)盐、铵盐(四甲铵、四丁铵盐等),和药物上可接受的有机铵(三乙胺、甲胺、二甲胺、环戊胺、苄胺、苯乙胺、哌啶、一乙醇胺、二乙醇胺、三(羟基甲基)甲胺、赖氨酸、精氨酸、N-甲基-D-葡糖胺等)。
通式(I)表示的本发明的化合物或其盐可用公知方法转变成水合物。
本发明化合物的制备方法:
通式(I)表示的本发明的化合物可用下列方法或实施例所示方法制备。
(a)通式(I)表示的化合物中,R1是羟基的化合物,即通式(Ia)表示的化合物
(式中,所有符号的含义与上述相同)可通过使通式(IV)表示的化合物进行脱保护反应来制备,
式中,R20是烯丙基或苄基、其他符号的含义与上述相同。
烯丙酯或苄酯的脱保护反应是公知的,例如,该反应可在有机溶剂(例如,甲醇、乙醇、四氢呋喃、二噁烷和乙酸乙酯等)中在-10至90℃通过
1)用四(三苯基膦)钯和吗啉,或
2)用钯碳、钯、铂、海绵镍(商品名阮内镍)等在氢气氛围下进行。
(b)通式(I)表示的化合物中,R1是C1-6烷氧基(式中,所有符号的含义与上述相同)的化合物,即通式(Ib)表示的化合物
(式中,R10代表C1-6烷基,其他符号的含义与上述相同)可通过使通式(Ia)表示的化合物与通式(III)表示的化合物进行酯化反应来制备,
R10-OH (III)
(式中,所有符号的含义与上述相同),接着视需要进行脱保护反应。
酯化反应是公知的,例如,该反应可在惰性有机溶剂(例如四氢呋喃、二氯甲烷、苯、丙酮、乙腈或其混合物等)中,在叔胺(二甲基氨基吡啶、吡啶、三乙胺等)的存在或不存在下,用缩合剂(1,3-二环己基碳化二亚胺(DCC)、1-乙基-3-[3-(二甲基氨基)丙基]碳化二亚胺(EDC)等)或酰卤(草酰氯、亚硫酰氯、磷酰氯等)在0至50℃进行。
(c)通式(I)表示的化合物中,R1是-NR8R9(式中,所有符号的含义与上述相同)的化合物,即通式(Ic)表示的化合物,
(式中,所有符号的含义与上述相同)可通过使通式(Ia)表示的化合物与通式(II)表示的化合物进行酰胺化反应来制备,
HNR8R9 (II)
(式中,所有符号的含义与上述相同),接着视需要进行脱保护反应。
酰胺化反应是公知的,例如,该反应可在惰性有机溶剂(例如四氢呋喃、二氯甲烷、苯、丙酮、乙腈或其混合物等)中,在叔胺(二甲基氨基吡啶、吡啶、三乙胺等)的存在或不存在下,用缩合剂(1,3-二环己基碳化二亚胺(DCC)、1-乙基-3-[3-(二甲基氨基)丙基]碳化二亚胺(EDC)等)或酰卤(草酰氯、亚硫酰氯、磷酰氯等)在0至50℃进行。
通式(IV)表示的化合物可通过用通式(VI)表示的化合物将通式(V)表示的化合物进行酰胺化反应来制备,
(式中R21、R31和R41的含义分别与R2、R3和R4相同,当它们代表氨基或羟基时,它们用保护基保护,其他符号的含义与上述相同),
(式中R51的含义与R5相同,当它代表氨基或羟基时,它用保护基保护,G1和R61的含义分别与G和R6相同,当它们含有氨基或羟基时,用保护基保护),接着视需要进行脱保护反应。该酰胺化反应可按上述方法进行。
通式(II)、(III)、(V)和(VI)代表的化合物本身是已知的,或者可通过已知方法制备。
通式(Ia)表示的化合物中,其中D是亚烷基的化合物可通过使其中D是亚链烯基的通式(Ia)表示的化合物还原或通过增加D中的亚烷基部分的碳原子来制备。
在本说明书的各反应中,反应产物可通过常规的精制技术进行精制,例如通过常压蒸馏或减压蒸馏、用硅胶或硅酸镁进行的高效液相色谱、薄层色谱、或柱色谱、或者洗涤和重结晶等方法进行精制。精制可在各个反应之后或在某些反应之后进行。
本发明化合物的药理活性
通式(I)表示的本发明的化合物对DP受体具有强的结合作用,并具有拮抗活性。例如,在实验室实验中,通过用类前列腺素表达细胞进行的下列受体结合实验证实了上述效果。
(i)用类前列腺素DP受体表达细胞进行的受体结合实验
按照Hirata等人的方法(Proc.Natl.Acad.Sci.,
91,11192-11196(1994))制备表达小鼠DP受体的CHO细胞,并用作膜标本。
含有制备的膜标本(30-166μg)和3H-PGD2的反应溶液(200μL)在室温下孵育20分钟。用冰冷的缓冲液(1mL)使反应停止,在减压下立即抽吸过滤,将结合的3H-PGD2截留在玻璃过滤器(GF/B)上,然后用液体闪烁器测定其结合放射性。
从Scatchard曲线图上求出Kd值和Bmax值(Ann.N.Y.Acad.Sci.,51,660(1949))。在过量(10μmol/L)的非标记PGD2的存在下求出非特异结合作为结合放射性。添加3H-PGD2(2.5nmol/L)和各种浓度的本发明的化合物以测定由于本发明化合物产生的3H-PGD2结合抑制作用。要说明的是,反应中使用了下列缓冲液。
孵育缓冲液
HEPES-NaOH(25mmol/L,pH7.4)
EDTA(1mmol/L)
MgCl2(5mmol/L)
MnCl2(10mmol/L)
洗涤缓冲液
Tris-HCl(10mmol/L,pH7.5)
NaCl(0.1mol/L)
牛血清清蛋白(0.01%)
用下式求出个化合物的离解常数Ki(μmol/L)
Ki=IC50/(1+([L]*/Kd))
[L*]:放射性配体的浓度
结果示于下表6:
表6
实施例号 | DP Ki(μM) |
1(3)1(4) | 0.00180.0043 |
上述结果表明本发明的化合物对DP受体具有强的结合作用。
(ii)用类前列腺素DP受体表达细胞进行的DP拮抗活性测定试验
按照Nishigaki等人的方法制备表达小鼠DP受体的CHO细胞(FEBSlett.,
364,339-341(1995)),以105细胞/孔播种在24孔微试验板上,接着培养2天,用于试验。各孔用500μL MEM(最小基本培养基)洗涤,加入450μL测试培养基(含1mmol/L IBMX和0.1或1%BSA的MEM),接着在37℃孵育10分钟。然后往其中加入含有PGD2单独或PGD2与试验化合物一起的测试培养基(50μL)以启动反应,在37℃反应10分钟,然后往其中加入500μL冰冷的三氯乙酸(TCA)(10%w/v)使反应停止。将反应液冷冻(-80℃)一次,熔解后用刮刀剥离细胞,接着以13,000rpm速度离心3分钟。用所得上清液和cAMP测试试制盒(Amersham公司制造)测定cAMP的浓度。即,[125I]-cAMP测试试制盒缓冲液加入到125μL上清液中,得到总量500μL,所得混合物与1mL浓度为0.5mol/L的三正辛胺的氯仿溶液混合。将三氯乙酸(TCA)萃取到氯仿层中,从而除去,然后用水层作为样品按照[125I]cAMP测试试制盒中所述方法测定样品中cAMP的量。
要说明的是,试验化合物的拮抗活性(IC50值),作为相对于表示PGD2单独造成的第二最大cAMP产生作用浓度100nM的反应的抑制率算出,求出IC50值。
表7
实施例号 | DP拮抗活性IC50(μM) |
1(3) | 0.12 |
上述结果表明本发明的化合物对DP受体具有拮抗活性。
毒性
通式(I)表示的本发明化合物的毒性非常低,所以可以确认该化合物作为药物使用是安全的。
产业上利用的可能性
应用于药物
由于通式(I)表示的本发明化合物能结合到DP受体上,并产生拮抗作用,因此,被认为可用于预防和/或治疗过敏性疾病,例如过敏性鼻炎、过敏性结膜炎、特异性皮炎、支气管哮喘和食物过敏等;全身性肥大细胞症;全身性肥大细胞活化障碍;过敏性休克;气管收缩;荨麻疹;湿疹;过敏性支气管肺曲霉病;副鼻窦炎;鼻息肉;过敏性脉管炎;嗜曙红细胞增多症;接触性皮炎;伴随痒的疾病,例如;特异性皮炎、荨麻疹、过敏性结膜炎、过敏性鼻炎、接触性皮炎等;伴随痒的行为(抓、打等)产生的二次疾病,例如白内障、视网膜脱落、炎症、感染、睡眠障碍等;炎症;慢性闭塞性肺病;缺血再灌注障碍;脑血管障碍;风湿性关节炎并发胸膜炎;和溃疡性大肠炎等疾病。此外,也被认为与睡眠和血小板凝固有关,且对这些疾病也是有用的。
在通式(I)表示的本发明的化合物中,对DP受体以外的化合物具有弱结合活性的化合物由于不显示其他活性所以可用作副作用少的药物。
当通式(I)表示的本发明的化合物、其无毒盐或其环糊精包合物用于上述目的时,通常是全身或局部给药,并通过口服或非经肠给药。
剂量依年龄、体重、症状、治疗效果、给药方法、治疗时间等而异。通常,成年人每天1μg至100mg,一天一次至数次,口服给药,或者成年人每天0.1μg至10mg,一天一次至数次,非经肠给药,(优选经静脉给药),或者一天1至24小时连续经静脉给药。
如上所述,由于剂量依各种条件而变化,因此必要时可以使用高于或低于上述范围的剂量。
本发明的化合物给药时,口服给药可用固体组合物、液体组合物、或其它组合物,非经肠给药可用注射剂、外用剂或栓剂等。
用于口服给药的固体组合物包括片剂、丸剂、胶囊剂、粉剂、粒剂等。
胶囊剂包括硬胶囊和软胶囊。
在这种固体组合物中,一种或多种活性化合物与至少一种惰性稀释剂,例如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯基吡咯烷酮或铝硅酸镁混合。
按照通常的方法,该组合物还可包含除稀释剂以外添加剂,例如,润滑剂如硬酯酸镁,崩解剂如纤维素钙乙醇酸酯,以及溶解助剂如谷氨酸和天冬氨酸。如希望的话,片剂和丸剂可以用胃溶性或肠溶性物质如蔗糖、明胶、羟丙基纤维素或羟丙基纤维素邻苯二甲酸酯的薄膜包覆,或者包覆2层或多层薄膜。此外,还可包含可吸收物质如明胶胶囊。
口服给药的液体组合物包括药物上可接受的乳液、溶液、糖浆和酏剂。在这种液体组合物中,一种或多种活性物质被包含在常用的惰性稀释剂(例如精制水、乙醇)中。此外,这种组合物除惰性稀释剂外还可包含润湿剂、悬浮剂等助剂、甜味剂、风味剂、香味剂和防腐剂。
用于口服给药的其他组合物包括本身可用公知方法制备的包含一种或多种活性物质的喷雾剂。这种组合物除惰性稀释剂外还可包含亚硫酸氢钠等稳定剂和提供等渗性的稳定剂,氯化钠、柠檬酸钠或柠檬酸之类的等渗溶液。喷雾剂的制备方法详细记载于美国专利2,868,691和3,095,355中。
按照本发明,用于非经肠给药的注射剂包含无菌的水或非水溶液、悬浮液、和乳液。作为水溶液或悬浮液包括例如注射用蒸馏水和生理食盐水。作为非水溶液或悬浮液包括例如丙二醇、聚乙二醇、植物油如橄榄油、醇如乙醇和吐温(YSORBATE80,注册商标)等。
这样的组合物还可包含防腐剂、润湿剂、乳化剂、分散剂、稳定剂和溶解助剂(例如谷氨酸和天冬氨酸)等助剂。这种组合物可通过细菌截留过滤器过滤、加入杀菌剂或进行照射来达到无菌化。这种组合物也可制成无菌的固体组合物形式,在使用前溶解在无菌的注射用蒸馏水或其他溶剂中。
用于非经肠给药的其他组合物包括可按常规方法制备的、含有一种或一种以上的活性物质的外用液剂、软膏、涂布剂、供直肠给药的栓剂以及供阴道内给药的阴道栓剂。
实施发明的最佳方式
以下通过参考例和实施例详细说明本发明,但本发明不限于这些例子。
以下的化学式中,Tf代表三氟甲磺酰基,Boc代表叔丁氧羰基,TMS代表三甲基甲硅烷基,Bn代表苄基。
在色谱分离或TLC中,括号内的溶剂表示所使用的洗脱溶剂或展开溶剂,比例表示体积比。
NMR中括号内的溶剂表示测定用的溶剂。
参考例1
2-甲基-4-三氟甲磺酰基吲哚
2-甲基-4-羟基吲哚(10g)的二氯甲烷(100ml)溶液在0℃搅拌,往其中加入卢剔啶(10.28ml)和三氟甲磺酸酐(13.72ml),在同一温度下搅拌1小时。往混合液中加水,用乙酸乙酯萃取。水层用乙酸乙酯萃取。合并的有机层依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,减压浓缩后得到具有下列物性数据的标题化合物。该化合物未经精制用下一步反应。
TLC:Rf 0.57(己烷∶乙酸乙酯=7∶3)。
参考例2
1-叔丁氧羰基-2-甲基-4-三氟甲磺酰基吲哚
往2-甲基-4-三氟甲磺酰基吲哚(1g,参考例1合成的)和连二碳酸二叔丁酯(1ml)的乙腈(12ml)溶液中加入二甲基氨基吡啶(催化量),在室温下搅拌过夜。往反应溶液中加水和乙酸乙酯,分离各层。有机层依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,减压浓缩后得到具有下列物性数据的标题化合物(1.38g)。
TLC:Rf 0.50(己烷∶乙酸乙酯=1∶1)。
参考例3
1-叔丁氧羰基-2-甲基-4-(2-三甲基甲硅烷基乙炔基)吲哚
往1-叔丁氧羰基-2-甲基-4-三氟甲磺酰基吲哚(17.9g;参考例2合成的)、二氯二(三苯基膦)钯(1.6g),碘化铜(0.88g)和碘化四丁铵(3.4g)的N,N-二甲基甲酰胺(180ml)溶液中加入三甲基甲硅烷基乙炔(11ml),混合物在65℃搅拌2小时。往反应混合物中加入0.5N盐酸-乙酸乙酯,然后通过Celite(注册商标)过滤除去不溶物。有机层依次用水(2次)和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(己烷∶乙酸乙酯=10∶1)精制,得到具有下列物性数据的标题化合物(15.0g)。
NMR(CDCl3):δ8.09-8.05(d,J=8.5Hz,1H),7.32-7.29(m,1H),7.17-7.08(m,1H),6.49(s,1H),2.61(s,3H),0.29(s,9H)。
参考例4
1-叔丁氧羰基-2-甲基吲哚-4-乙酸
环己烷(16.1ml)的四氢呋喃(160ml)溶液冷却到-10℃,然后往混合物中滴加硼烷-四氢呋喃配合物(1M,80ml),在0℃搅拌1小时。往该溶液中滴加1-叔丁氧羰基-2-甲基-4-(2-三甲基甲硅烷基乙炔基)吲哚(13.1g;参考例3合成的)的四氢呋喃(60ml)溶液,在室温下搅拌1小时。往反应溶液中依次滴加3N氢氧化钠水溶液(40ml)和30%过氧化氢水(45ml),然后搅拌12小时。反应混合物用水-乙醚萃取,水层用盐酸调至酸性,用乙酸乙酯萃取。萃取液依次用水和饱和食盐水洗涤,经干燥,减压浓缩后得到标题化合物(10.4g,粗产物)。
参考例5
2-甲基吲哚-4-乙酸
在室温下往1-叔丁氧羰基-2-甲基吲哚-4-乙酸(96.3g)的甲醇(200ml)-水(100ml)混合溶液中滴加5N氢氧化钠水溶液(200ml),在50℃搅拌3小时,在室温下搅拌12小时。反应液用己烷-乙醚萃取。水层用盐酸调至酸性,用乙酸乙酯萃取。萃取液依次用水和饱和食盐水洗涤,经干燥,减压浓缩后得到标题化合物(53.9g,粗产物)。
要说明的是,该中间体化合物是文献中没有记载过的新化合物。
参考例6
2-甲基吲哚-4-乙酸烯丙酯
往2-甲基吲哚-4-乙酸(53g)的N,N-二甲基甲酰胺(500ml)溶液中滴加烯丙基溴(31ml)和无水碳酸钾(59g)然后在50℃搅拌1小时。冷却至室温后将反应液倒入2N盐酸-乙酸乙酯混合溶液中,用乙酸乙酯萃取。萃取液依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(正己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(43.5g)。
TLC:Rf 0.50(己烷∶乙酸乙酯=1∶2);
NMR(CDCl3):δ7.92(brs,1H),7.19(d,J=7.0Hz,1H),7.06(t,J=1H),6.96(dd,J=7.0,1.2Hz,1H),6.27(m,1H),5.90(ddt,J=17.2,10.4,5.4Hz,1H),5.25(d,J=17.2Hz,1H),5.18(d,J=10.4Hz,1H),4.59(m,2H),3.88(s,2H),2.43(s,3H)。
参考例7
4-(2-丙基氧乙氧基)苯甲酸
往4-羟基苯甲酸(3.04g)和无水碳酸钾(5.52g)的N,N-二甲基甲酰胺(20ml)溶液中加入2-丙氧基乙基氯(2.94g),混合物在室温下搅拌-夜,在80℃搅拌8小时。往反应液中加水,用乙酸乙酯萃取。有机层依次用水和饱和食盐水洗涤,干燥,减压浓缩后得到具有下列物性数据的标题化合物(5.21g粗产物)。
TLC:Rf 0.47(己烷∶乙酸乙酯=2∶1)。
参考例8
1-(4-(2-丙基氧乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸烯丙酯
往4-(2-丙基氧乙氧基)苯甲酸(448mg;参考例7合成的)的甲苯(5ml)溶液中加入N,N-二甲基甲酰胺(催化量)和草酰氯(350μl),在室温下搅拌30分钟,然后浓缩。把残留物的二氯甲烷(2ml)溶液加入到2-甲基吲哚-4-乙酸烯丙酯(230mg;参考例6合成的)、氢氧化钠(200mg)和氯化四丁铵(15mg)的二氯甲烷(8ml)溶液中,然后在室温下搅拌30分钟。往反应液中加入1N盐酸-乙酸乙酯,有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(正己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(276mg)。
TLC:Rf 0.39(己烷∶乙酸乙酯=2∶1)。
实施例1
1-(4-(2-丙基氧乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
往1-(4-(2-丙基氧乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸烯丙酯(276mg;参考例8合成的)和吗啉(275μl)的四氢呋喃(3ml)溶液中加入四(三苯基膦)钯(35mg),在室温下搅拌2小时。往反应液中加入1N盐酸-乙酸乙酯,有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。将残留物溶解在己烷-乙酸乙酯(1/2)中,过滤除去不溶物,加入环己胺(70mg),然后在室温下搅拌30分钟。将反应液过滤,往所得结晶中加入1N盐酸-乙酸乙酯。有机层依次用水和饱和食盐水洗涤,经干燥减压浓缩后得到具有下列物性数据的本发明化合物(204mg)。
TLC:Rf 0.20(乙酸乙酯);
NMR(CDCl3):δ7.71-7.69(m,2H),7.04-6.92(m,5H),6.48(s,1H),4.23-4.19(m,2H),3.86(s,2H),3.86-3.81(m,2H),3.51(t,J=7.0Hz,2H),2.44(s,3H),1.65(tq,J=7.0,7.5Hz,2H),0.94(t,J=7.5Hz,3H)。
实施例1(1) to 1(75)
通过与参考例1、2、3、4、5、6、7、8和实施例1相同的操作得到具有下列物性数据的各化合物。在实施例1(8)、1(51)、1(67)、1(68)和1(69)中羟基或氨基通过保护基保护,该保护基在相应于实施例1的反应之前除去。
实施例1(1)
1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.46(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.08-6.90(m,5H),6.49(s,1H),4.05(t,J=6.6Hz,2H),3.87(s,2H),2.45(s,3H),1.88-1.74(m,2H),1.80-1.40(br,1H),1.60-1.45(m,2H),1.00(t,J=7.5Hz,3H).
实施例1(2)
1-(4-丙氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.74-7.69(m,2H),7.12-6.90(m,5H),6.49(s,1H),4.01(t,J=6.6Hz,2H),3.87(s,2H),2.45(s,3H),1.86(dt,J=7.5,6.6Hz,2H),1.07(t,J=7.5Hz,3H).
实施例1(3)
1-(4-(2-苯氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.60(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.72-7.66(m,2H),7.38-7.23(m,5H),7.07-6.92(m,5H),6.49(s,1H),4.26(t,J=6.9Hz,2H),3.86(s,2H),3.14(t,J=6.9Hz,2H),2.44(s,3H).
实施例1(4)
1-(4-戊氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.64(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.73-7.66(m,2H),7.07-6.92(m,5H),6.49(s,1H),4.04(t,J=6.6Hz,2H),3.87(s,2H),2.44(s,3H),1.86-1.23(m,6H),0.95(t,J=6.9Hz,3H).
实施例1(5)
1-(4-戊氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.73-7.67(m,2H),7.06-6.91(m,5H),6.48(s,1H),4.07(t,J=6.6Hz,2H),3.86(s,2H),2.45(s,3H),1.84(m,1H),1.72(m,2H),0.98(d,J=6.4Hz,6H).
实施例1(6)
1-(4-(2-乙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.08-6.92(m,5H),6.49(s,1H),4.21(t,J=4.8Hz,2H),3.87-3.81(m,4H),3.62(q,J=7.5Hz,2H),2.45(s,3H),1.26(t,J=7.5Hz,3H).
实施例1(7)
1-(4-苄氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.65-7.33(d,J=8.8Hz,2H),7.45-7.36(m,5H),7.05-6.90(m,5H),6.48(s,1H),5.14(s,2H),3.85(s,2H),2.43(d,J=1.0Hz,3H).
实施例1(8)
1-(4-(2-(4-羟基苯基)乙氧基))苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.30(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.68(d,J=8.6Hz,2H),7.14(d,J=8.2Hz,2H),7.08-6.89(m,5H),6.78(d,J=8.0Hz,2H),6.48(s,1H),4.20(t,J=7.0Hz,2H),3.85(s,2H),3.05(t,J=7.0Hz,2H),2.43(s,3H).
实施例1(9)
1-(4-丁氧基苯甲酰基)吲哚-4-乙酸
TLC:Rf 0.25(己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):δ8.26(d,J=8.2Hz,1H),7.72-7.68(m,2H),7.38-7.16(m,3H),7.00-6.96(m,2H),6.65(d,J=3.6Hz,1H),4.05(t,J=6.4Hz,2H),3.87(s,2H),1.82(m,2H),1.52(m,2H),1.00(t,J=7.2Hz,3H).
实施例1(10)
1-(4-(3-苯基丙基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.61(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.64(d,J=8.0Hz,2H),7.38-7.16(m,7H),7.08-6.93(m,3H),6.49(s,1H),3.85(s,2H),2.82-2.60(m,4H),2.42(s,3H),2.05(m,2H).
实施例1(11)
1-(4-(2-(4-甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.72-7.65(m,2H),7.23-7.17(m,2H),7.06-6.84(m,7H),6.47(s,1H),4.21(t,J=7.0Hz,2H),3.85(s,2H),3.80(s,3H),3.08(t,J=7.0Hz,2H),2.43(s,3H).
实施例1(12)
1-(4-(2-(2-吡啶基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.59(d,J=5.2Hz,1H),7.68-6.88(m,10H),6.52(s,1H),4.39(t,J=6.6Hz,2H),3.86(s,2H),3.31(t,J=6.6Hz,2H),2.43(s,3H).
实施例1(13)
1-(4-(2-环丙基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(乙酸乙酯);
NMR(CDCl3):δ7.73-7.69(m,2H),7.08-6.94(m,5H),6.49(s,1H),4.12(t,J=6.5Hz,2H),3.87(s,2H),2.45(s,3H),1.72(q,J=6.5Hz,2H),0.96-0.80(m,1H),0.56-0.47(m,2H),0.18-0.13(m,2H).
实施例1(14)
1-(4-(2-异丙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(乙酸乙酯);
NMR(CDCl3):δ7.72-7.67(m,2H),7.04-6.90(m,5H),6.48(s,1H),4.22-4.17(m,2H),3.86(s,2H),3.84-3.80(m,2H),3.78-3.62(m,1H),2.44(s,3H),1.21(d,J=6.0Hz,6H).
实施例1(15)
1-(4-(4-甲氧基苄氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(乙酸乙酯);
NMR(CDCl3):δ7.74-7.69(m,2H),7.40-7.35(m,2H),7.08-6.92(m,7H),6.49(s,1H),5.07(s,2H),3.87(s,2H),3.83(s,3H),2.45(s,3H).
实施例1(16)
1-(4-(2--乙硫基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.71(d,J=9.0Hz,2H),7.05-6.93(m,5H),6.48(s,1H),4.22(t,J=6.8Hz,2H),3.86(s,2H),2.95(t,J=6.8Hz,2H),2.67(q,J=7.4Hz,2H),2.44(s,3H),1.31(t,J=7.4Hz,3H).
实施例1(17)
1-(4-(3,3-二甲基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.68(d,J=8.8Hz,2H),7.08-6.86(m,5H),6.47(s,1H),4.09(t,J=7.2Hz,2H),3.83(s,2H),2.43(s,3H),1.76(t,J=7.2Hz,2H),1.00(s,9H).
实施例1(18)
1-(4-苄氧基甲基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.72(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.39-7.31(m,4H),7.06-6.96(m,4H),6.50(s,1H),4.66(s,2H),4.63(s,2H),3.86(s,2H),2.42(s,3H).
实施例1(19)
1-(4-(3-乙氧基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.22(乙酸乙酯∶己烷=3∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.10-6.86(m,5H),6.49(s,1H),4.16(t,J=6.4Hz,2H),3.86(s,2H),3.62(t,J=6.4Hz,2H),3.51(q,J=6.8Hz,2H),2.45(s,3H),2.09(m,2H),1.21(t,J=6.8Hz,3H).
实施例1(20)
1-(4-(4-甲基戊氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.43(乙酸乙酯∶己烷=3∶1);
NMR(CDCl3):δ7.70(d,J=8.6Hz,2H),7.07-6.88(m,5H),6.48(s,1H),4.03(t,J=6.8Hz,2H),3.86(s,2H),2.45(s,3H),1.92-1.73(m,2H),1.73-1.52(m,1H),1.43-1.11(m,2H),0.94(d,J=6.8Hz,6H).
实施例1(21)
1-(4-(2-(3-氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.35-7.20(m,2H),7.09-6.85(m,7H),6.47(s,1H),4.25(t,J=6.6Hz,2H),3.84(s,2H),3.12(t,J=6.6Hz,2H),2.42(s,3H).
实施例1(22)
1-(4-(2-(3-甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(乙酸乙酯);
NMR(CDCl3):δ7.72-7.68(m,2H),7.44-7.36(m,1H),7.28-7.22(m,2H),7.06-6.88(m,6H),6.48(s,1H),4.24(t,J=7.0Hz,2H),3.86(s,5H),3.15(t,J=7.0Hz,2H),2.44(s,3H).
实施例1(23)
1-(4-(2-(2-噻吩基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=8.6Hz,2H),7.18(m,1H),7.02-6.90(m,7H),6.47(s,1H),4.26(t,J=6.8Hz,2H),3.84(s,2H),3.35(t,J=6.8Hz,2H),2.43(s,3H).
实施例1(24)
1-(4-(2-(2-甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.23-6.91(m,9H),6.48(s,1H),4.23(t,J=7.2Hz,2H),3.86(s,2H),3.16(t,J=7.2Hz,2H),2.44(s,3H),2.39(s,3H).
实施例1(25)
1-(4-(2-(3-甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.19-6.92(m,9H),6.48(s,1H),4.24(t,J=7.2Hz,2H),3.86(s,2H),3.10(t,J=7.2Hz,2H),2.44(s,3H),2.36(s,3H).
实施例1(26)
1-(4-(2-(4-甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.18-6.92(m,9H),6.49(s,1H),4.23(t,J=6.6Hz,2H),3.87(s,2H),3.10(t,J=6.6Hz,2H),2.44(s,3H),2.34(s,3H).
实施例1(27)
1-(4-(2-环己基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=8.8Hz,2H),7.06-6.91(m,5H),6.48(s,1H),4.08(t,J=6.8Hz,2H),3.86(s,2H),2.44(s,3H),1.81-0.95(m,13H).
实施例1(28)
1-(4-(2-(4-二甲基氨基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.69(d,J=8.6Hz,2H),7.17(d,J=8.6Hz,2H),7.06-6.92(m,5H),6.73(d,J=8.6Hz,2H),6.48(s,1H),4.20(t,J=7.4Hz,2H),3.86(s,2H),3.04(t,J=7.4Hz,2H),2.93(s,6H),2.44(s,3H).
实施例1(29)
1-(4-(2-(3-噻吩基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.30(dd,J=4.0,3.0Hz,1H),7.11(m,1H),7.06-7.01(m,2H),6.96-6.92(m,4H),6.48(s,1H),4.25(t,J=6.6Hz,2H),3.85(s,2H),3.17(t,J=6.6Hz,2H),2.43(s,3H).
实施例1(30)
1-(4-(2-(4-氯苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=8.4Hz,2H),7.33-7.20(m,5H),7.04-6.82(m,4H),6.49(s,1H),4.23(t,J=6.6Hz,2H),3.86(s,2H),3.11(t,J=6.6Hz,2H),2.44(s,3H).
实施例1(31)
1-(4-(2-(2-氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.68(d,J=8.8Hz,2H),7.40-7.08(m,4H),7.05-6.90(m,5H),6.47(s,1H),4.26(t,J=6.8Hz,2H),3.84(s,2H),3.18(t,J=6.8Hz,2H),2.43(s,3H).
实施例1(32)
1-(4-(2-(4-氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.30-7.21(m,2H),7.06-6.90(m,7H),6.48(s,1H),4.23(t,J=6.6Hz,2H),3.85(s,2H),3.11(t,J=6.6Hz,2H),2.43(s,3H).
实施例1(33)
1-(4-(2-(2-萘基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.86-6.90(m,14H),6.49(s,1H),4.35(t,J=7.2Hz,2H),3.86(s,2H),3.31(t,J=7.2Hz,2H),2.43(s,3H).
实施例1(34)
1-(4-(2-(4-氰基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=8.8Hz,2H),7.63(d,J=8.2Hz,2H),7.42(d,J=8.2Hz,2H),7.03-6.90(m,5H),6.48(s,1H),4.28(t,J=6.4Hz,2H),3.85(s,2H),3.20(t,J=6.4Hz,2H),2.43(s,3H).
实施例1(35)
1-(4-(2-叔丁氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.04-6.94(m,5H),6.48(s,1H),4.17(t,J=5.2Hz,2H),3.86(s,2H),3.76(t,J=5.2Hz,2H),2.44(s,3H),1.25(s,9H).
实施例1(36)
1-(4-(2-(2-甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.22(d,J=7.2Hz,2H),7.04-6.93(m,7H),6.47(s,1H),4.24(t,J=7.4Hz,2H),3.85(s,2H),3.85(s,3H),3.14(t,J=7.4Hz,2H),2.43(s,3H).
实施例1(37)
1-(3-丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.40-6.99(m,7H),6.48(s,1H),3.94(t,J=6.6Hz,2H),3.85(s,2H),2.41(s,3H),1.81(m,2H),1.03(t,J=7.4Hz,3H).
实施例1(38)
1-(4-(2-(3-吡啶基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.30(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.61(s,1H),8.54(dd,J=3.0Hz,1H),7.71-7.67(m,3H),7.34-7.31(m,1H),7.05-6.89(m,5H),6.52(s,1H),4.25(t,J=6.4Hz,2H),3.87(s,2H),3.14(t,J=6.4Hz,2H),2.42(s,3H).
实施例1(39)
1-(4-(2-(4-吡啶基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.30(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.57(d,J=6.2Hz,2H),7.70(d,J=8.8Hz,2H),7.29(m,2H),7.04-6.89(m,5H),6.52(s,1H),4.28(t,J=6.4Hz,2H),3.86(s,2H),3.15(t,J=6.4Hz,2H),2.42(s,3H).
实施例1(40)
1-(4-(2-(1-萘基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.13-8.08(m,1H),7.92-7.87(m,1H),7.83-7.75(m,1H),7.69(d,J=8.7Hz,2H),7.61-7.47(m,2H),7.48-7.41(m,2H),7.07-6.90(m,5H),6.48(s,1H),4.39(t,J=7.5Hz,2H),3.87(s,2H),3.63(t,J=7.5Hz,2H),2.43(s,3H).
实施例1(41)
1-(4-(3-乙氧基丙氧基)-3-甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.34(d,J=1.8Hz,1H),7.27(dd,J=8.4,1.8Hz,1H),7.10-6.93(m,3H),6.89(d,J=8.4Hz,1H),6.48(s,1H),4.19(t,J=6.4Hz,2H),3.85(s,3H),3.83(s,2H),3.62(t,J=5.8Hz,2H),3.50(q,J=6.8Hz,2H),2.44(s,3H),2.13(m,2H),1.19(t,J=6.8Hz,3H).
实施例1(42)
1-(4-己氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(乙酸乙酯);
NMR(CDCl3):δ7.72-7.69(m,2H),7.06-6.93(m,5H),6.49(s,1H),4.04(t,J=6.5Hz,2H),3.87(s,2H),2.45(s,3H),1.9-1.8(m,2H),3.87(s,2H),2.45(s,3H),1.9-1.8(m,2H),1.6-1.4(m,2H),1.4-1.3(m,4H),1.0-0.9(m,3H).
实施例1(43)
1-(4-丁氧基苯甲酰基)-3-(4-甲氧基苄基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.43(乙酸乙酯);
NMR(CDCl3):δ7.75-7.72(m,2H),7.11-6.92(m,7H),6.82-6.79(m,2H),4.15(s,2H),4.05(t,J=6.5Hz,2H),3.76(s,3H),3.72(s,2H),2.35(s,3H),1.9-1.7(m,2H),1.6-1.4(m,2H),1.00(t,J=7.0Hz,3H).
实施例1(44)
1-(4-(2-(2-甲氧基乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.20(乙酸乙酯);
NMR(CDCl3):δ7.71-7.68(m,2H),7.06-6.91(m,5H),6.48(s,1H),4.24-4.21(m,2H),3.92-3.89(m,2H),3.85(s,2H),3.76-3.73(m,2H),3.61-3.58(m,2H),3.40(s,3H),2.44(s,3H).
实施例1(45)
1-(4-(3-甲氧基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.12(乙酸乙酯);
NMR(CDCl3):δ7.72-7.69(m,2H),7.08-6.94(m,5H),6.48(s,1H),4.15(t,J=6.5Hz,2H),3.86(s,2H),3.58(t,J=6.0Hz,2H),3.37(s,3H),2.44(s,3H),2.13-2.05(m,2H).
实施例1(46)
1-(4-甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.41(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.08-6.92(m,5H),6.50(s,1H),3.90(s,3H),3.88(s,2H),2.45(s,3H).
实施例1(47)
1-(4-(5-甲基呋喃-2-基)甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.72(d,J=8.6Hz,2H),7.07-6.95(m,5H),6.49(s,1H),6.36(d,J=3.2Hz,1H),5.99(d,J=3.2Hz,1H),5.02(s,2H),3.86(s,2H),2.44(s,3H),2.32(s,3H).
实施例1(48)
1-(4-(2--甲氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.70(d,J=8.8Hz,2H),7.03-6.93(m,5H),6.48(s,1H),4.21(t,J=5.0Hz,2H),3.85(s,2H),3.79(t,J=5.0Hz,2H),3.47(s,3H),2.44(s,3H).
实施例1(49)
1-(4-(2-(3-硝基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.22-8.16(m,1H),8.16-8.10(m,1H),7.74-7.62(m,3H),7.52(t,J=8.1Hz,1H),7.08-6.90(m,5H),6.49(s,1H),4.31(t,J=6.3Hz,2H),3.87(s,2H),3.26(t.J=6.3Hz,2H),2.43(s,3H).
实施例1(50)
1-(4-(3-苯基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.41(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=9.3Hz,2H),7.34-7.16(m,5H),7.08-6.88(m,5H),6.50(s,1H),4.05(t,J=6.3Hz,2H),3.88(s,2H),2.84(t,J=6.3Hz,2H),2.45(s,3H),2.20-2.10(m,2H).
实施例1(51)
(±)-1-(4-(3-苯氧基-2-羟基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=8.8Hz,2H),7.33-7.2 3(m,2H),7.06-6.90(m,8H),6.47(s,1H),4.43(m,1H),4.24-4.15(m,4H),3.83(s,2H),2.42(s,3H).
实施例1(52)
1-(4-环己氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.25(乙酸乙酯);
NMR(CDCl3):δ7.71-7.68(m,2H),7.08-6.91(m,5H),6.49(s,1H),4.42-4.32(m,1H),3.86(s,2H),2.45(s,3H),2.08-1.96(m,2H),1.88-1.78(m,2H),1.64-1.32(m,6H).
实施例1(53)
1-(4-乙氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.21(乙酸乙酯);
NMR(CDCl3):δ7.72-7.69(m,2H),7.08-6.93(m,5H),6.49(s,1H),4.10(q,J=7.0Hz,2H),3.86(s,2H),2.45(s,3H),1.46(t,J=7.0Hz,3H).
实施例1(54)
1-(4-(3-丁烯氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.28(乙酸乙酯);
NMR(CDCl3):δ7.72-7.69(m,2H),7.08-6.94(m,5H),6.49(s,1H),5.98-5.85(m,1H),5.23-5.13(m,2H),4.10(t,J=6.5Hz,2H),3.86(s,2H),2.64-2.56(m,2H),2.45(s,3H).
实施例1(55)
1-(4-(2-(2,6-二甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.26(乙酸乙酯);
NMR(CDCl3):δ7.71-7.68(m,2H),7.20(t,J=8.5Hz,1H),7.07-6.98(m,5H),6.57(d,J=8.5Hz,2H),6.48(s,1H),4.17-4.11(m,2H),3.87(s,2H),3.84(s,6H),3.2 3-3.18(m,2H),2.45(s,3H).
实施例1(56)
1-(4-丁氧基苯甲酰基)-2,3-二甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.72-7.65(m,2H),7.07-6.90(m,5H),4.07(s,2H),4.04 (t,J=6.4Hz,2H),2.39(s,3H),2.30(s,3H),1.87-1.74(m,2H),1.60-1.41(m,2H),0.99(t,J=7.4Hz,3H).
实施例1(57)
1-(3-丁氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.36(m,1H),7.24-6.99(m,6H),6.48(d,J=1.2Hz,1H),3.98(t,J=6.4Hz,2H),3.85(s,2H),2.41(d,J=1.2Hz,3H),1.84-1.70(m,2H),1.58-1.38(m,2H),0.96(t,J=7.2Hz,3H).
实施例1(58)
1-(3-戊氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.35(m,1H),7.24-6.99(m,6H),6.48(d,J=1.0Hz,1H),3.97(t,J=6.4Hz,2H),3.85(s,2H),2.41(d,J=1.0Hz,3H),1.84-1.72(m,2H),1.50-1.32(m,4H),0.92(t,J=7.0Hz,3H).
实施例1(59)
1-(3-己氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.46(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.35(m,1H),7.24-6.98(m,6H),6.48(d,J=1.0Hz,1H),3.97(t,J=6.6Hz,2H),3.85(s,2H),2.41(d,J=1.0Hz,3H),1.85-1.69(m,2H),1.53-1.28(m,6H),0.90(m,3H).
实施例1(60)
1-(3-苄氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.46(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.44-7.18(m,9H),7.10-6.99(m,3H),6.48(d,J=1.0Hz,1H),5.08(s,2H),3.85(s,2H),2.36(d,J=1.0Hz,3H).
实施例1(61)
1-(3-苯基乙氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.46(氯仿∶甲醇=10∶1);
NMR(CDC13):δ7.39-6.97(m,12H),6.48(d,J=1.2Hz,1H),4.20(t,J=7.0Hz,2H),3.85(s,2H),3.09(t,J=7.0Hz,2H),2.40(d,J=1.2Hz,3H).
实施例1(62)
1-(3-(3-苯基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.40-6.98(m,12H),6.48(d,J=1.0Hz,1H),3.98(t,J=6.2Hz,2H),3.85(s,2H),2.80(t,J=7.2Hz,2H),2.41(d,J=1.0Hz,3H),2.17-2.03(m,2H).
实施例1(63)
1-(4-(2-(2-三氟甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.46(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.73-7.65(m,3H),7.56-7.45(m,2H),7.42-7.33(m,1H),7.08-6.90(m,5H),6.49(s,1H),4.27(t,J=6.6Hz,2H),3.87(s,2H),3.34(t,J=6.6Hz,2H),2.44(s,3H).
实施例1(64)
1-(4-(2-(2-三氟甲基苯基)乙氧基)苯甲酰基)-2-甲基-3-甲氧基甲基吲哚-4-乙酸
TLC:Rf 0.56(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.74-7.65(m,3H),7.57-7.45(m,2H),7.42-7.30(m,1H),7.14-7.10(m,1H),7.05-6.80(m,1H),6.98-6.90(m,3H),4.71(s,2H),4.27(t,J=6.6Hz,2H),4.09(s,2H),3.47(s,3H),3.34(t,J=6.6Hz,2H),2.46(s,3H).
实施例1(65)
1-(4-(2-(3-硝基苯基)乙氧基)苯甲酰基)-2-甲基-3-甲氧基甲基吲哚-4-乙酸
TLC:Rf 0.54(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.22-8.18(m,1H),8.16-8.11(m,1H),7.71(d,J=8.7Hz,2H),7.68-7.60(m,1H),7.52(t,J=7.8Hz,1H),7.14-7.09(m,1H),7.00(t,J=8.1Hz,1H),6.97-6.90(m,3H),4.70(s,2H),4.32(t,J=6.3Hz,2H),4.09(s,2H),3.46(s,3H),3.26(t,J=6.3Hz,2H),2.45(s,3H).
实施例1(66)
1-(4-(2-苯氧基乙基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.64(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),7.24(d,J=8.0Hz,2H),7.03-6.85(m,6H),6.47(s,1H),4.20(t,J=6.6Hz,2H),3.81(s,2H),3.15(t,J=6.6Hz,2H),2.39(s,3H).
实施例1(67)
(±)-1-(4-(2-苯基-2-羟基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.57(d,J=8.2Hz,2H),7.32(s,5H),6.99(m,1H),6.93-6.86(m,4H),6.44(s,1H),5.34(dd,J=8.0,3.6Hz,1H),3.97(dd,J=12.2,8.0Hz,1H),3.86(dd,J=12.2,3.6Hz,1H),3.81(s,2H),2.37(s,3H).
实施例1(68)
1-(4-(2-(3-氨基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.16-6.90(m,6H),6.72-6.67(m,1H),6.65-6.56(m,2H),6.49(s,1H),4.23(t,J=7.2Hz,2H),3.87(s,2H),3.05(t,J=7.2Hz,2H),2.45(s,3H).
实施例1(69)
1-(4-(2-(3-氨基苯基)乙氧基)苯甲酰基)-2-甲基-3-甲氧基甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.16-7.08(m,2H),7.01(t,J=8.4Hz,1H),6.97-6.90(m,3H),6.71-6.66(m,1H),6.64-6.56(m,2H),4.70(s,2H),4.23(t,J=7.2Hz,2H),4.09(s,2H),3.46(s,3H),3.05(t,J=7.2Hz,2H),2.46(s,3H).
实施例1(70)
1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.71(d,J=8.7Hz,2H),7.07-6.86(m,5H),6.53(s,1H),4.05(t,J=6.3Hz,2H),3.89(s,2H),2.87(q,J=7.5Hz,2H),1.90-1.35(m,4H),1.24(t,J=7.5Hz,3H),0.97(t,J=7.5Hz,3H).
实施例1(71)
1-(4-(2-苯氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.32(t,J=7.8Hz,2H),7.08-6.92(m,8H),6.49(s,1H),4.46-4.34(m,4H),3.87(s,2H),2.45(s,3H).
实施例1(72)
(±)-1-(4-(2-甲氧基-2-苯基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.59(d,J=9.0Hz,2H),7.38-7.30(m,5H),7.04-6.80(m,5H),6.44(s,1H),5.44(dd,J=8.0,4.0Hz,1H),3.84(dd,J=10.8,8.0Hz,1H),3.83(brs,2H),3.65(dd,J=10.8,4.0Hz,1H),3.47(s,3H),2.39(s,3H).
实施例1(73)
1-(4-苯基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.84-7.78(m,2H),7.74-7.66(m,4H),7.52-7.38(m,3H),7.10-6.98(m,3H),6.52(s,1H),3.87(s,2H),2.46(s,3H).
实施例1(74)
1-(4-苯基重氮基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ8.04-7.96(m,4H),7.90-7.86(m,2H),7.60-7.52(m,3H),7.10-7.00(m,3H),6.53(s,1H),3.87(s,2H),2.46(s,3H).
实施例1(75)
1-(4-丁氧基苯甲酰基)-2,5-二甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.68(d,J=9.3Hz,2H),6.93(d,J=9.3Hz,2H),6.85(d,J=9.0Hz,1H),6.82(d,J=9.0Hz,1H),6.44(s,1H),4.04(t,J=6.6Hz,2H),3.86(s,2H),2.43(s,3H),2.37(s,3H),1.80(m,2H),1.53(m,2H),0.99(t,J=7.5Hz,3H).
参考例9
2-甲基吲哚-4-羧酸甲酯
往2-甲基-4-三氟甲磺酰基吲哚(6.32g;参考例1合成的)的甲醇(33.43ml)-N,N-二甲基甲酰胺(200ml)溶液中加入三乙胺(6.3ml)和四(三苯基膦)钯(2.6g)。容器内部用一氧化碳置换,然后在60℃搅拌过夜。反应后加入水和乙酸乙酯,进行萃取。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(正己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(4.29g)。
TLC:Rf 0.18(甲苯)。
参考例10
2-甲基吲哚-4-羧酸
往2-甲基吲哚-4-羧酸甲酯(4.3g;参考例9合成的)的甲醇-二噁烷(10ml+10ml)溶液中加入5N氢氧化钠水溶液(10ml),混合物在60℃搅拌过夜。往反应溶液中加入2N盐酸,用乙酸乙酯萃取。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(氯仿-甲醇)精制,得到具有下列物性数据的标题化合物(1.6g)。
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.14-8.04(br,1H),7.93(dd,1H),7.52(m,1H),7.18(dd,1H),6.94(m,1H),3.71(s,3H).
参考例11
2-甲基吲哚-4-羧酸苄酯
在室温下往2-甲基吲哚-4-羧酸(690mg;参考例10合成的)的N,N-二甲基甲酰胺(10ml)溶液中加入无水碳酸钾(815mg)和苄基溴(0.7ml),在80℃搅拌2小时。往反应液中加入水和乙酸乙酯,进行萃取。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(610mg)。
TLC:Rf 0.44(己烷∶乙酸乙酯=8∶2);
NMR(CDCl3):δ8.05(brs,1H),7.91(d,1H),7.54-7.24(m,7H),6.88(m,1H),5.44(s,2H),2.48(s,3H).
参考例12
1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-羧酸苄酯
在0℃往2-甲基吲哚-4-羧酸苄酯(690mg;参考例11合成的)的N,N-二甲基甲酰胺(8ml)溶液中加入氢化钠(114mg;60%),在同一温度下搅拌30分钟。往反应混合物中加入4-丁氧基苯甲酰氯(0.54ml),然后在室温下搅拌过夜。往反应混合物中加入水和乙酸乙酯,分离各层。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(1.02g)。
TLC:Rf 0.61(己烷∶乙酸乙酯=8∶2);
NMR(CDCl3):δ8.10-6.90(m,13H),5.45(s,2H),4.05(t,2H),2.44(s,3H),1.86-1.74(m,2H),1.60-1.45(m,2H),,0.99(t,3H).
实施例2
(1)1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-羧酸和(2)1-(4-丁氧基苯甲酰基)-2-甲基-2,3-二氢吲哚-4-羧酸
往1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-羧酸苄酯(1.02g;参考例12合成的)的甲醇(10ml)-乙酸乙酯(5ml)混合溶液中加入钯碳(100mg)。容器内部用氢气置换,反应液在室温下搅拌过夜。反应混合物用Celite(注册商标)过滤,将滤液和氯仿洗涤液合并,然后减压浓缩。残留物用硅胶柱色谱(氯仿-甲醇)精制,得到具有下列物性数据的标题化合物。
(1)吲哚
TLC:Rf 0.59(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.99(d,J=8.1Hz,1H),7.70(d,J=9.0Hz,2H),7.36(d,J=8.1Hz,1H),7.21(brs,1H),7.13(t,J=8.1Hz,1H),6.97(d,J=9.0Hz,2H),4.06 t,J=6.6Hz,2H),2.48(s,3H),1.88-1.76(m,2H),1.60-1.46(m,2H),1.00(t,J=7.5Hz,3H).
(2)二氢吲哚
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.74(dd,1H),7.64-7.46(br,1H),7.50(d,2H),7.19(t,1H),6.93(d,2H),4.84-4.70(m,1H),4.02(t,2H),3.65(dd,1H),3.22(dd,1H),1.86-1.76(m,2H),1.60-1.45(m,2H),1.24(d,3H),1.00(t,3H).
参考例13
2-甲基吲哚-4-基氧乙酸甲酯
在室温下往2-甲基-4-羟基吲哚(5g)的N,N-二甲基甲酰胺(50ml)溶液中加入无水碳酸钾(11.7g)和溴乙酸甲酯(3.54ml),在80℃搅拌2小时。往反应液中加入冰水,得到具有下列物性数据的标题化合物(5.4g)。
TLC:Rf 0.75(苯∶乙酸乙酯=4∶1);
NMR(CDCl3):δ8.00-7.84(br,1H),7.04-6.94(m,2H),6.45-5.36(m,2H),4.77(s,2H),3.80(s,3H),2.43(s,3H).
参考例14
2-甲基吲哚-4-基氧乙酸
往2-甲基吲哚-4-基氧乙酸甲酯(5.4g)的甲醇(18ml)-二噁烷(36ml)混合溶液中加入5N氢氧化钠水溶液(15ml),混合物在室温下搅拌1小时。往反应溶液中加入2N盐酸,得到具有下列物性数据的标题化合物(3.5g)。
TLC:Rf 0.20(氯仿∶甲醇=9∶1)。
参考例15
2-甲基吲哚-4-基氧乙酸烯丙酯
往2-甲基吲哚-4-基氧乙酸(2g)的N,N-二甲基甲酰胺(20ml)溶液中加入无水碳酸钾(2.02g)和烯丙基溴(1.27ml),在80℃搅拌2小时。往反应液中加入水和乙酸乙酯,分离各层。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(正己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(1.88g)。
TLC:Rf 0.50(正己烷∶乙酸乙酯=7∶3)。
参考例16
1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸烯丙酯
在0℃往2-甲基吲哚-4-基氧乙酸烯丙酯(900mg)的N,N-二甲基甲酰胺(10ml)溶液中加入氢化钠(147mg;60%),在同一温度下搅拌30分钟。往该反应混合物中加入4-丁氧基苯甲酰氯(0.70ml),然后在室温下搅拌过夜。往反应混合物中加入水和乙酸乙酯,分离各层。水层用乙酸乙酯洗涤,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(正己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(800mg)。
TLC:Rf 0.63(正己烷∶乙酸乙酯=7∶3);
NMR(CDCl3):δ7.69(d,2H),7.00-6.85(m,3H),6.68(d,1H),6.67(s,1H),6.47(d,1H),6.00-5.87(m,1H),5.40-5.30(m,1H),5.30-5.24(m,1H),4.78(s,2H),4.75-4.68(m,2H),4.05(t,2H),2.42(s,3H),1.87-1.75(m,2H),1.60-1.45(m,2H),1.00(t,3H).
实施例3
1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸
通过与实施例1相同的操作,用参考例16合成的化合物制得了具有下列物性数据的本发明化合物。
TLC:Rf 0.38(氯仿∶甲醇∶乙酸=90∶9∶1);
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),6.98-6.89(m,3H),6.71(d,J=8.4Hz,1H),6.6 0-6.57(m,1H),6.51(d,J=8.4Hz,1H),4.84(s,2H),4.05(t,J=6.6Hz,2H),2.43(s,3H),1.87-1.75(m,2H),1.59-1.44(m,2H),1.00(t,J=7.5Hz,3H).
实施例3(1)至3(6)
通过与参考例13、14、15、16和实施例3相同的操作,制得了具有下列物性数据的各化合物。
实施例3(1)
1-(4-(2-乙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.19(二氯甲烷∶甲醇=9∶1);
NMR(CDCl3):δ7.68(d,J=8.5Hz,2H),6.97(d,J=8.5Hz,2H),6.91(m,1H),6.66(d,J=8.5Hz,1H),6.58(s,1H),6.49(d,J=8.0Hz,1H),4.77(s,2H),4.20(t,J=5.0Hz,2H),3.83(t,J=5.0Hz,2H),3.62(q,J=7.0Hz,2H),2.41(s,3H),1.26(t,J=7.0Hz,3H).
实施例3(2)
1-(4-丙氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.39(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.73-7.67(m,2H),6.97-6.90(m,3H),6.72(d,J=8.4Hz,1H),6.59(s,1H),6.52(d,J=7.5Hz,1H),4.80(s,2H),4.01(t,J=6.6Hz,2H),2.43(s,3H),1.86(dt,J=7.5,6.6Hz,2H),1.07(t,J=7.5Hz,3H).
实施例3(3)
1-(4-苯乙氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.35(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.71-7.67(m,2H),7.37-7.25(m,5H),6.97-6.89(m,3H),6.70(d,J=8.4Hz,1H),6.58(s,1H),6.52(d,J=8.1Hz,1H),4.80(s,2H),4.26(t,J=6.9Hz,2H),3.14(t,J=6.9Hz,2H),2.43(s,3H).
实施例3(4)
1-(4-苄氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(DMSO-d6):δ7.65(d,J=8.8Hz,2H),7.51-7.33(m,5H),7.17(d,J=8.8Hz,2H),6.93(t,J=8.2Hz,1H),6.59-6.52(m,3H),5.21(s,2H),4.77(s,2H),2.32(s,3H).
实施例3(5)
1-(4-(3-甲基丁氧基)苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.46(氯仿∶甲醇=5∶1);
NMR(CDCl3):δ7.64(d,J=8.6Hz,2H),6.92-6.84(m,3H),6.70-6.45(m,3H),4.72(s,2H),4.05(t,J=6.6Hz,2H), 2.37(s,3H),1.83(m,1H),1.72(m,2H),0.97(d,J=6.4Hz,6H).
实施例3(6)
1-(4-戊氧基苯甲酰基)-2-甲基吲哚-4-基氧乙酸
TLC:Rf 0.26(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),6.98-6.90(m,3H),6.72(d,J=8.7Hz,1H),6.58(brs,1H),6.52(d,J=8.1Hz,1H),4.80(s,2H),4.04(t,J=6.6Hz,2H),2.43(s,3H),2.10-1.30(m,7H),0.95(t,J=6.9Hz,3H).
参考例17
3-(2-甲基吲哚-4-基)丙烯酸甲酯
往2-甲基-4-三氟甲磺酰基吲哚(3.2g;参考例2合成的)的N,N-二甲基甲酰胺(50mL)溶液中加入丙烯酸甲酯(2.24ml)、二异丙基乙胺(5.9ml)和二(三苯基膦)二氯化钯(238mg),混合物在95℃搅拌2天。往反应液中加入水和乙酸乙酯,分离各层。水层用乙酸乙酯萃取,合并的有机层依次用水和饱和食盐水洗涤,干燥后减压浓缩。残留物用硅胶柱色谱(己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(950mg)。
TLC:Rf 0.50(己烷∶乙酸乙酯=8∶2)。
参考例18
3-(2-甲基吲哚-4-基)丙烯酸
通过与参考例14相同的操作,用3-(2-甲基吲哚-4-基)丙烯酸甲酯(950mg;参考例17合成的)制得了具有下列物性数据的标题化合物(700mg)。
TLC:Rf 0.54((氯仿∶甲醇=9∶1).
参考例19
3-(2-甲基吲哚-4-基)丙烯酸烯丙酯
通过与参考例15相同的操作,用3-(2-甲基吲哚-4-基)丙烯酸(300mg;参考例18合成的)制得了具有下列物性数据的标题化合物(240mg)。
TLC:Rf 0.43(己烷∶乙酸乙酯=8∶2).
参考例20
3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丙烯酸烯丙酯
通过与参考例16相同的操作,用3-(2-甲基吲哚-4-基)丙烯酸烯丙酯(240mg;参考例19合成的)制得了具有下列物性数据的标题化合物(545mg)。
TLC:Rf 0.59(己烷∶乙酸乙酯=8∶2);
NMR(CDCl3):δ8.10-8.00(m,1H),7.70(d,2H),7.39(d,1H),7.10-6.90(m,4H),6.72(s,1H),6.58(d,1H),6.10-5.95(m,1H),5.95-5.85(m,1H9,5.82-5.75(m,1H),4.80-4.70(m,2H),4.10-4.00(m,2H),2.47(s,3H),1.90-1.70(m,2H),1.70-1.40(m,2H),1.10-0.95(m,3H).
实施例4
3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丙烯酸
通过与实施例1相同的操作,用3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丙烯酸烯丙酯(413mg;参考例20合成的)制得了具有下列物性数据的标题化合物(374mg)。
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.16(d,J=16.2Hz,1H),7.70(d,J=9.0Hz,2H),7.43(brd,J=7.2Hz,1H),7.15-7.03(m,2H),6.96(d,J=9.0Hz,2H),6.74(brs,1H),6.59(d,J=16.2Hz,1H),4.06(t,J=6.3Hz,2H),2.48(s,3H),1.88-1.76(m,2H),1.60-1.46(m,2H),1.00(t,J=7.2Hz,3H).
实施例4(1)至4(7)
通过与参考例17、18、19、20和实施例4相同的操作,制得了具有下列物性数据的各化合物。
实施例4(1)
3-(1-(4-苄氧基苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
NMR(DMSO-d6):δ7.90(d,J=16Hz,1H),7.65(d,J=8.6Hz,2H),7.60-7.30(m,6H),7.17(d,J=8.6Hz,2H),7.16-7.05(m,2H),6.90(s,1H),6.60(d,J=16Hz,1H),5.21(s,2H),2.36(s,3H).
实施例4(2)
3-(1-(4-戊氧基苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.31(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.15(d,J=15.9Hz,1H),7.70(d,J=9.0Hz,2H),7.43(d,J=7.2Hz,1H),7.15-7.02(m,2H),6.96(d,J=9.0Hz,2H),6.74(s,1H),6.58(d,J=15.9Hz,1H),4.05(t,J=6.3Hz,2H),2.48(s,3H),2.00-1.30(m,7H),0.95(t,J=7.2Hz,3H).
实施例4(3)
3-(1-(4-苯乙氧基苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ 8.16(d,J=16Hz,1H),7.68(d,J=9.0Hz,2H),7.44-7.26(m,6H),7.09(m,2H),6.96(d,J=9.0Hz,2H),6.74(s,1H),6.58(d,J=16Hz,1H),4.27(t,J=7.0Hz,2H),3.15(t,J=7.0Hz,2H),2.47(s,3H).
实施例4(4)
3-(1-(4-(3-甲基丁氧基)苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.60(氯仿∶甲醇=10∶1);
NMR(DMSO-d6):δ12.4(brs,1H),7.90(d,J=16Hz,1H),7.66-7.60(m,2H),7.52(brd,J=6.4Hz,2H),7.11-7.05(m,4H),6.90(s,1H),6.59(d,J=16Hz,1H),4.09(t,J=6.4Hz,2H),2.36(s,3H),1.90-1.50(m,3H),0.92(dd,J=6.4,2.0Hz,6H).
实施例4(5)
3-(1-(4-(2-乙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.60(乙酸乙酯);
NMR(CDCl3):δ8.15(d,J=15.9Hz,1H),7.70(d,J=9.0Hz,2H),7.42(m,1H),7.09-6.98(m,4H),6.74(s,1H),6.58(d,J=15.9Hz,1H),4.22(t,J=4.6Hz,2H),3.84(t,J=4.6Hz,2H),3.63(q,J=7.0Hz,2H),2.48(d,J=1.0Hz,3H),1.27(t,J=7.0Hz,3H).
实施例4(6)
3-(1-(4-丙氧基苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.15(d,J=15.9Hz,1H),7.71(d,J=8.7Hz,2H),7.43(brd,J=7.2Hz,1H),7.15-7.03(m,2H),6.97(d,J=8.7Hz,2H),6.74(s,1H),6.58(d,J=15.9Hz,1H),4.02(t,J=6.6Hz,2H),2.48(s,3H),1.95-1.80(m,2H),1.07(t,J=7.5Hz,3H).
实施例4(7)
3-(1-(4-(2-(吡啶-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸
TLC:Rf 0.40(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ8.61(d,J=5.0Hz,1H),8.13(d,J=16.0Hz,1H),7.71-6.95(m,10H),6.72(s,1H),6.58(d,J=16.0Hz,1H),4.19(t,J=6.8Hz,2H),3.34(t,J=6.8Hz,2H),2.45(s,3H).
实施例5
3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丙酸
在室温下往3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)-2-丙烯酸(300mg;实施例4合成的)的甲醇-乙酸乙酯(5ml+5ml)混合溶液中加入钯碳(40mg),容器内部用氢气置换。反应混合物在室温下搅拌2小时。混合物用Celite(注册商标)过滤。将氯仿洗涤液合并于滤液中,然后减压浓缩。残留物用硅胶柱色谱(氯仿-甲醇)精制,得到具有下列物性数据的标题化合物(25mg)。
TLC:Rf 0.58(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.70(d,J=9.3Hz,2H),7.00-6.86(m,5H),6.48(s,1H),4.05(t,J=6.6Hz,2H),3.75-3.65(br,1H),3.19(t,J=8.4Hz,2H),2.79(t,J=8.4Hz,2H),2.45(s,3H),1.87-1.72(m,2H),1.60-1.40(m,2H),1.00(t,J=7.5Hz,3H).
参考例21
4-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丁酸苄酯
(1)在室温下往3-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丙酸(1.77g;实施例5合成的)的甲苯(20ml)溶液中加入草酰氯(0.64ml)和N,N-二甲基甲酰胺(数滴),在室温下搅拌1小时,然后将混合物减压浓缩。
(2)在0℃往(1)中合成的酰氯的四氢呋喃-乙腈(4ml+4ml)混合溶液中加入三甲基甲硅烷基重氮甲烷(4.67ml;2M),在同一温度下搅拌1小时,然后减压浓缩。往残留物中加入苄醇(4ml)和2,4,6-可力丁(4ml),然后在180℃搅拌30分钟。冷却至室温后反应物用硅胶柱色谱(己烷-乙酸乙酯)精制,得到具有下列物性数据的标题化合物(460mg)TLC:Rf 0.51(己烷∶乙酸乙酯=8∶2).
实施例6
4-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丁酸
通过与实施例2相同的操作,用4-(1-(4-丁氧基苯甲酰基)-2-甲基吲哚-4-基)丁酸苄酯(460mg,参考例21合成的)制得了具有下列物性数据的标题化合物(170mg)。
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.71(d,J=9.0Hz,2H),7.00-6.86(m,5H),6.48(s,1H),4.05(t,J=6.6Hz,2H),2.90(t,J=7.2Hz,2H),2.48-2.38(m,5H),2.14-2.00(m,2H),2.00-1.40(m,5H),1.00(t,J=7.5Hz,3H).
实施例7至实施例7(228)
按照参考例7→参考例8→实施例1所示的方法,用相应的化合物制得了具有下列物性数据的本发明化合物。在实施例7(37)和7(151)中羟基或氨基用保护基保护,在相应于实施例1的反应之前将保护基除去。
实施例7
1-(4-丁氧基苯甲酰基)-5-甲氧基-2-甲基吲哚-4-乙酸
TLC:Rf 0.48((氯仿∶甲醇=10∶1);
MS(MALDI,正):434(M+K)+,418(M+Na)+,396(M+H)+;
NMR(CDCl3):δ7.70-7.67(m,2H),6.98-6.93(m,3H),6.70(d,J=9.3Hz,1H),6.41(s,1H),4.05(t,J=6.5Hz,2H),3.90(s,2H),3.86(s,3H),2.41(s,3H),1.82(m,2H),1.54(m,2H),1.00(t,J=7.5Hz,3H).
实施例7(1)
1-(4-(2-甲基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇1=10∶1);
MS(MALDI,正):418(M+K)+,402(M+Na)+.
实施例7(2)
1-(4-环戊氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):376(M-H)-.
实施例7(3)
1-(4-(1-乙基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):378(M-H)-.
实施例7(4)
1-(4-(四氢呋喃-3-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):378(M-H)-.
实施例7(5)
1-(4-(1,2-二甲基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):418(M+K)+,402(M+Na)+.
实施例7(6)
1-(4-环丁氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):402(M+K)+,386(M+Na)+.
实施例7(7)
1-(4-(1-甲基环丙基甲基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):416(M+K)+,400(M+Na)+.
实施例7(8)
1-(4-环丁基甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):416(M+K)+,400(M+Na)+.
实施例7(9)
1-(4-(2-苄氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):442(M-H)-.
实施例7(10)
1-(4--环丙基甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):402(M+K)+,386(M+Na)+.
实施例7(11)
1-(4-(3,7-二甲基-6-辛烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(MALDI,正):486(M+K)+,470(M+Na)+.
实施例7(12)
1-(4-(3-(3,4-二甲氧基苯基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(MALDI,正):526(M+K)+,510(M+Na)+.
实施例7(13)
1-(4-(4-(4-甲氧基苯基)丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(MALDI,正):510(M+K)+,494(M+Na)+.
实施例7(14)
1-(4-(2,3,5,6-四氢吡喃-4-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(MALDI,正):432(M+K)+,416(M+Na)+,393(M)+.
实施例7(15)
1-(4-(1-甲基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(MALDI,正):365(M)+.
实施例7(16)
1-(4-(5-氯戊氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.28(氯仿∶甲醇=10∶1);
MS(MALDI,正):436(M+Na)+,413(M)+.
实施例7(17)
1-(4-(2,3,4,5-四氢呋喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.27(氯仿∶甲醇=10∶1);
MS(MALDI,正):432(M+K)+,416(M+Na)+,394(M+H)+,393(M)
实施例7(18)
1-(4-(2-(N,N-二乙基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.08(氯仿∶甲醇=2∶1);
MS(MALDI,正):409(M+H)+.
实施例7(19)
1-(4-(2-(哌啶-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.16(氯仿∶甲醇=2∶1);
MS(MALDI,正):443(M+Na)+,421(M+H)+.
实施例7(20)
1-(4-(2-环戊基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(MALDI,正):428(M+Na)+,406(M+H)+.
实施例7(21)
1-(4-(3-甲氧基-3-甲基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(MALDI,正):448(M+Na)+,432(M+H)+.
实施例7(22)
1-(4-(2-(3,5-二甲基吡唑-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(APCI,负):430(M-H)-.
实施例7(23)
1-(4-(2-(N,N-二烯丙基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.31(氯仿∶甲醇=10∶1);
MS(APCI,负):431(M-H)-.
实施例7(24)
1-(4-(6-(N,N-二甲基氨基)己氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):435(M-H)-.
实施例7(25)
1-(4-(3-丁炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):360(M-H)-.
实施例7(26)
1-(4-环己基甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):444(M+K)+,428(M+Na)+.
实施例7(27)
1-(4-(2-(吡咯-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇c=10∶1);
MS(MALDI,正):441(M+K)+,425(M+Na)+.
实施例7(28)
1-(4-(2-(3,4-二甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):512(M+K)+,496(M+Na)+.
实施例7(29)
1-(4-(3-戊炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):414(M+K)+,398(M+Na)+.
实施例7(30)
1-(4-苯基丁氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
MS(MALDI,正):480(M+K)+,464(M+Na)+.
实施例7(31)
1-(4-(4-甲硫基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):450(M+K)+,434(M+Na)+.
实施例7(32)
1-(4-(4-戊炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):414(M+K)+,398(M+Na)+.
实施例7(33)
1-(4-(2-苯硫基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):484(M+K)+,468(M+Na)+.
实施例7(34)
1-(4-(4-戊烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):416(M+K)+,400(M+Na)+.
实施例7(35)
1-(4-(5-己烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):430(M+K)+,414(M+Na)+.
实施例7(36)
1-(4-(2-苄硫基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(MALDI,正):498(M+K)+,482(M+Na)+.
实施例7(37)
1-(4-(6-羟基己氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
MS(MALDI,正):508(M+K)+,492(M+Na)+.
实施例7(38)
1-(4-(2-(4-乙氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(MALDI,正):496(M+K)+,480(M+Na)+.
实施例7(39)
1-(4-(2-丁氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):408(M-H)-.
实施例7(40)
1-(4-(3-甲基氧杂环丁-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):392(M-H)-.
实施例7(41)
1-(4-(2-(N-乙基-N-(3-甲基苯基)氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
MS(MALDI,正):471(M+H)+.
实施例7(42)
1-(4-(2-(N-甲基-N-苯基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
MS(MALDI,正):481(M+K)+,465(M+Na)+,443(M+H)+.
实施例7(43)
1-(4-(3-(4-甲氧基苯基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):496(M+K)+,480(M+Na)+.
实施例7(44)
1-(4-(3-壬炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(MALDI,正):470(M+K)+,454(M+Na)+.
实施例7(45)
1-(4-(2-(4-氯苯硫基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(MALDI,正):518(M+K)+,502(M+Na)+.
实施例7(46)
1-(4-(2-苯基氨基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
MS(APCI,负):427(M-H)-.
实施例7(47)
1-(4-(3-(吡啶-3-基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.57(氯仿∶甲醇=10∶1);
MS(MALDI,正):467(M+K)+,451(M+Na)+.
实施例7(48)
1-(4-(2-(3-三氟甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.60(氯仿∶甲醇=10∶1);
MS(MALDI,正):520(M+K)+,504(M+Na)+.
实施例7(49)
1-(4-(2-(2-氯苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.61(氯访∶甲醇=10∶1);
MS(MALDI,正):504(M+K)+,488(M+Na)+.
实施例7(50)
1-(4-(2-(3-甲基苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.65(氯仿∶甲醇=10∶1);
MS(MALDI,正):482(M+K)+,466(M+Na)+.
实施例7(51)
1-(4-丁氧基苯甲酰基)-6-甲氧基-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=10∶1);
MS(MALDI,正):434(M+K)+,418(M+Na)+,395(M)+;
NMR(CDCl3):δ7.70(m,2H),6.95(m,2H),6.73(d,J=2.1Hz,1H),6.68(d,J=2.1Hz,1H),6.38(s,1H),4.04(t,J=6.6Hz,2H),3.81(s,2H),3.65(s,3H),2.34(s,3H),1.81(m,2H),1.51(m,2H),0.99(t,J=7.5Hz,3H).
实施例7(52)
1-(4-(噻吩-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):404(M-H)-.
实施例7(53)
1-(4-(2-(2-氯乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):414(M-H)-.
实施例7(54)
1-(4-(2-(吗啉-4-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(APCI,负):421(M-H)-.
实施例7(55)
1-(4-(5-己炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):388(M-H)-.
实施例7(56)
1-(4-(4-甲基-3-戊烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):390(M-H)-.
实施例7(57)
1-(4-(2-(5-甲基呋喃-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):416(M-H)-.
实施例7(58)
1-(4-(2-(呋喃-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):402(M-H)-.
实施例7(59)
1-(4-(2-环丁氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):406(M-H)-.
实施例7(60)
1-(4-(2-(2,4-二氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):448(M-H)-.
实施例7(61)
1-(4-(2-(2,5-二氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯访∶甲醇=10∶1);
MS(APCI,负):448(M-H)-.
实施例7(62)
1-(4-(2-(2-乙氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):456(M-H)-.
实施例7(63)
1-(4-(2-(2-甲基丙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):408(M-H)-.
实施例7(64)
1-(4-(4-甲氧基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):394(M-H)-.
实施例7(65)
1-(4-(2-(2,5-二甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):440(M-H)-.
实施例7(66)
1-(4-(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=10∶1);
MS(APCI,负):4 54(M-H)-.
实施例7(67)
1-(4-(2-(2,4-二甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯访∶甲醇=10∶1);
MS(APCI,负):472(M-H)-.
实施例7(68)
1-(4-(2-(2,3-二氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯访∶甲醇=10∶1);
MS(APCI,负):448(M-H)-.
实施例7(69)
1-(4-(1-苯基环丙基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯访∶甲醇=10∶1);
MS(APCI,负):438(M-H)-.
实施例7(70)
1-(4-(2-(3-甲氧基甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯访∶甲醇=10∶1);
MS(APCI,负):456(M-H)-.
实施例7(71)
1-(4-(呋喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯访∶甲醇=10∶1);
MS(APCI,负):388(M-H)-.
实施例7(72)
1-(4-(2-(N-苄基-N-甲基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯访∶甲醇=10∶1);
MS(APCI,负):455(M-H)-.
实施例7(73)
1-(4-(2-(2-丁氧基乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯访∶甲醇=10∶1);
MS(APCI,负):452(M-H)-.
实施例7(74)
1-(4-(2-甲氧基-3-苯氧基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯访∶甲醇=10∶1);
MS(APCI,负):472(M-H)-.
实施例7(75)
1-(4-(2-(4-甲基苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯访∶甲醇=10∶1);
MS(APCI,负):442(M-H)-.
实施例7(76)
1-(4-(2-(2-(2-乙氧基乙氧基)乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.36(氯访∶甲醇=10∶1);
MS(APCI,负):468(M-H)-.
实施例7(77)
1-(4-(2-(萘-1-基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯访∶甲醇=10∶1);
MS(APCI,负):477(M-H)-.
实施例7(78)
1-(4-(2-(萘奈-1-基氧)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(氯访∶甲醇=10∶1);
MS(APCI,负):478(M-H)-.
实施例7(79)
1-(4-(2-(吡唑-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.32(氯访∶甲醇=10∶1);
MS(APCI,负):402(M-H)-.
实施例7(80)
1-(4-(2-(2-丙烯-1-基氧)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯访∶甲醇=10∶1);
MS(APCI,负):392(M-H)-.
实施例7(81)
1-(4-(4,4,4-三氟丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯访∶甲醇=10∶1);
MS(APCI,负):418(M-H)-.
实施例7(82)
1-(4-(2,3-二氢化茚-2-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.36(氯访∶甲醇=10∶1);
MS(APCI,负):424(M-H)-.
实施例7(83)
1-(4-(2-(2-甲基苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯访∶甲醇=10∶1);
MS(APCI,负):442(M-H)-.
实施例7(84)
1-(4-(1,4-苯并二噁烷-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯访∶甲醇=10∶1);
MS(FAB,正):458(M+H)+;
NMR(CDCl3):δ7.71(d,J=8.8Hz,2H),7.09-6.82(m,9H),6.48(s,1H),4.61(m,2H),4.42(dd,J=11.8,2.6Hz,1H),4.38-4.18(m,3H),3.84(s,2),2.43(s,3H).
实施例7(85)
1-(4-(2-(2-氯苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf0.39(氯访∶甲醇=10∶1);
MS(APCI,负):446(M-H)-.
实施例7(86)
1-(4-(2-(2-乙氧基乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(氯访∶甲醇=10∶1);
MS(APCI,负):424(M-H)-.
实施例7(87)
1-(4-(5-乙氧基戊氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯访∶甲醇=10∶1);
MS(APCI,负):422(M-H)-.
实施例7(88)
1-(4-(5-甲氧基戊氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯访∶甲醇=10∶1);
MS(APCI,负):408(M-H)-.
实施例7(89)
1-(4-((3E)-4-苯基-3-丁烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.29(氯访∶甲醇=10∶1);
MS(APCI,负):438(M-H)-.
实施例7(90)
1-(4-(2-(N-苯甲酰基-N-甲基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.30(氯访∶甲醇=10∶1);
MS(APCI,负):469(M-H)-.
实施例7(91)
1-(4-(4-乙氧基丁氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯访∶甲醇=10∶1);
MS(APCI,负):408(M-H)-.
实施例7(92)
1-(4-(3-(吡咯-1-基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.43(氯访∶甲醇=10∶1);
MS(APCI,负):415(M-H)-.
实施例7(93)
1-(4-(2-萘-2-基氧)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯访∶甲醇=10∶1);
MS(APCI,负):478(M-H)-.
实施例7(94)
1-(4-(2-(2,4,6-三甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯访∶甲醇=10∶1);
MS(APCI,负):454(M-H)-.
实施例7(95)
1-(4-(3-苄氧基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.41(氯访∶甲醇=10∶1);
MS(APCI,负):456(M-H)-.
实施例7(96)
1-(4-(3,3,4,4,5,5,6,6,6-九氟己氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.42(氯访∶甲醇=10∶1);
MS(APCI,负):554(M-H)-.
实施例7(97)
1-(4-(3-苯氧基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯访∶甲醇=10∶1);
MS(APCI,负):442(M-H)-.
实施例7(98)
1-(4-(3-(2-氟乙氧基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯访∶甲醇=10∶1);
MS(APCI,负):412(M-H)-.
实施例7(99)
1-(4-(2-环戊氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.36(氯访∶甲醇=10∶1);
MS(APCI,负):420(M-H)-.
实施例7(100)
1-(4-(3-(2,2,2-三氟乙氧基)丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.41(氯访∶甲醇=10∶1);
MS(APCI,负):448(M-H)-.
实施例7(101)
1-(4-(2-环丙基甲氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯访∶甲醇=10∶1);
MS(APCI,负):406(M-H)-.
实施例7(102)
1-(4-(2-(3,3,3-三氟丙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.39(氯访∶甲醇=10∶1);
MS(APCI,负):448(M-H)-.
实施例7(103)
1-(4-(2-(2,2,2-三氟乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.39(氯访∶甲醇=10∶1);
MS(APCI,负):434(M-H)-.
实施例7(104)
1-(4-(2-(2-氟乙氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯访∶甲醇=10∶1);
MS(APCI,负):398(M-H)-.
实施例7(105)
1-(4-(2-(2,4-二氯苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯访∶甲醇=10∶1);
MS(APCI,负):480(M-H)-.
实施例7(106)
1-(4-(2-(2,3,4,5,6-五甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):482(M-H)-.
实施例7(107)
1-(4-(3,3,3-三氟丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.32(氯仿∶甲醇=10∶1);
MS(APCI,负):404(M-H)-.
实施例7(108)
1-(4-(2-(4-甲基-1,3-噻唑-5-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.28(氯仿∶甲醇=10∶1);
MS(APCI,负):433(M-H)-.
实施例7(109)
1-(4-(2-(咪唑-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=2∶1);
MS(FAB,正):404(M+H)+.
实施例7(110)
1-(4-(2-(2-甲基咪唑-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.28(氯仿∶甲醇=2∶1);
MS(APCI,负):416(M-H)-.
实施例7(111)
1-(4-(1,3-二氧杂-2,3-二氢化茚-4-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
MS(APCI,负):442(M-H)-.
实施例7(112)
1-(4-(萘-1-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.43(氯仿∶甲醇=9∶1);
MS(APCI,负):448(M-H)-.
实施例7(113)
1-(4-(3-(2-吡咯烷酮-1-基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=9∶1);
MS(APCI,负20V):433(M-H)-.
实施例7(114)
1-(4-(吡啶-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.42(氯仿∶甲醇=9∶1);
MS(APCI,负):399(M-H)-.
实施例7(115)
1-(4-(1-苄基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
MS(APCI,负):426(M-H)-.
实施例7(116)
-(4-((3Z)-3-辛烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):418(M-H)-.
实施例7(117)
1-(4-(2-苯基丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(APCI,负):426(M-H)-.
实施例7(118)
1-(4-(萘-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
MS(APCI,负:448(M-H)-.
实施例7(119)
1-(4-(3-氯丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.43(氯仿∶甲醇=9∶1);
MS(APCI,负):384(M-H)-.
实施例7(120)
1-(4-(2-(2,3-二甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
MS(APCI,负):44 0(M-H)-;
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.12-6.90(m,8H),6.49(s,1H),4.21(t,J=7.5Hz,2H),3.87(s,2H),3.19(t,J=7.5Hz,2H),2.45(s,3H),2.31(s,3H),2.30(s,3H).
实施例7(121)
1-(4-(2-(4-甲氧基甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.34-7.24(m,3H),7.10-6.85(m,6H),6.48(s,1H),4.45(s,2H),4.24(t,J=6.9Hz,2H),3.86(s,2H),3.40(s,3H),3.13(t,J=6.9Hz,2H),2.44(s,3H).
实施例7(122)
1-(4-(2,2,3,3,3-五氟丙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(APCI,负):440(M-H)-;
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.08-6.92(m,5H),6.49(s,1H),3.90(s,2H),3.86(s,2H),2.45(s,3H).
实施例7(123)
1-(4-(2-(2,6-二氟苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(APCI,负):448(M-H)-;
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.08-6.85(m,8H),6.49(s,1H),4.25(t,J=6.6Hz,2H),3.87(s,2H),3.26-3.16(m,2H),2.44(s,3H).
实施例7(124)
1-(4-(3-苯氧基苄氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.55(氯仿∶甲醇=9∶1);
MS(APCI,负):490(M-H)-;
NMR(CDCl3):δ7.71(d,J=8.7Hz,2H),7.40-6.85(m,14H),6.49(s,1H),5.12(s,2H),3.87(s,2H),2.44(s,3H).
实施例7(125)
1-(4-甲氧基甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
MS(APCI,负):352(M-H)-;
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.09(d,J=9.0Hz,2H),7.08-6.97(m,3H),6.48(s,1H),5.26(s,2H),3.85(s,2H),3.51(s,3H),2.43(s,3H).
实施例7(126)
1-(4-(2-(2,5-二甲基噁唑-4-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=9∶1);
MS(APCI,负):431(M-H)-;
NMR(CDCl3):δ7.67(d,J=8.7Hz,2H),7.08-6.86(m,5H),6.50(s,1H),4.22(t,J=6.6Hz,2H),3.86(s,2H),2.90(t,J=6.6Hz,2H),2.44(s,3H),2.39(s,3H),2.26(s,3H).
实施例7(127)
1-(4-(2-(4-甲氧基-3-甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.58(氯仿∶甲醇=9∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.69(d,J=9.3Hz,2H),7.11-6.87(m,7H),6.79(d,J=8.1Hz,1H),6.48(s,1H),4.21(t,J=7.2Hz,2H),3.86(s,2H),3.82(s,3H),3.05(t,J=7.2Hz,2H),2.44(s,3H),2.22(s,3H)。
实施例7(128)
1-(4-(2-(3-乙氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.56(氯仿∶甲醇=9∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.26-7.20(m,1H),7.08-6.76(m,8H),6.49(s,1H),4.25(t,J=7.2Hz,2H),4.04(q,J=7.2Hz,2H),3.87(s,2H),3.11(t,J=7.2Hz,2H),2.45(s,3H),1.42(t,J=7.2Hz,3H).
实施例7(129)
1-(4-(2-(1,3-二氢苯并[c]呋喃-5-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
MS(APCI,负):454(M-H)-;
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.22-7.15(m,2H),7.07-6.86(m,6H),6.49(s,1H),5.11(s,4H),4.25(t,J=6.9Hz,2H),3.87(s,2H),3.16(t,J=6.9Hz,2H),2.44(s,3H).
实施例7(130)
1-(4-(2-丁烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸(EZ体的混合物)
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
MS(APCI,负):362(M-H)-;
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.10-6.90(m,5H),6.49(s,1H),6.00-5.83(m,1H),5.80-5.70(m,1H),4.55(d,J=6.0Hz,2H),3.87(s,2H),2.45(s,3H),1.78(d,J=7.8Hz,3H).
实施例7(131)
1-(4-(2-(6-甲基吡啶-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.31(氯仿∶甲醇=10∶1);
MS(EI,正):428 (M)+;
NMR(CDCl3):δ7.68-7.63(m,2H),7.55(dd,J=6.6,6.6Hz,1H),7.11-7.04(m,3H),6.98-6.87(m,4H),6.51(s,1H),4.33(t,J=6.6Hz,2H),3.86(s,2H),3.26(t,J=6.6Hz,2H),2.56(s,3H),2.43(s,3H).
实施例7(132)
1-(4-(2-(3-甲基吡啶-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.32(氯仿∶甲醇=10∶1);
MS(EI,正):428(M)+;
NMR(CDCl3):δ8.43(dd,J=5.1,1.2Hz,1H),7.66-7.61(m,2H),7.51(dd,J=7.5,1.2Hz,1H),7.13(dd,J=7.5,5.1Hz,1H),7.06(dd,J=7.2,1.2Hz,1H),6.95(dd,J=8.1,7.2Hz,1H),6.91-6.86(m,3H),6.52(s,1H),4.40(t,J=6.6Hz,2H),3.86(s,2H),3.32(t,J=6.6Hz,2H),2.42(s,3H),2.41(s,3H).
实施例7(133)
1-(4-(2-氯乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
MS(APCI,负):370(M-H)-;
NMR(CDCl3):δ7.72(d,J=9.3Hz,2H),7.08-6.88(m,5H),6.50(s,1H),4.32(t,J=6.0Hz,2H),3.90-3.84(m,4H),2.45(s,3H).
实施例7(134)
1-(4-(2-(苯并[b]噻吩-3-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):468(M-H)-;
NMR(CDCl3):δ7.91-7.80(m,2H),7.70(d,J=8.7Hz,2H),7.46-7.30(m,2H),7.30-7.24(m,1H),7.08-6.88(m,5H),6.48(s,1H),4.38(t,J=6.9Hz,2H),3.87(8,2H),3.40(t,J=6.9Hz,2H),2.44(s,3H).
实施例7(135)
1-(4-乙氧基甲氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
MS(APCI,负):366(M-H)-;
NMR(CDCl3):δ7.63(d,J=8.8Hz,2H),7.05-6.90(m,5H),6.41(d,J=0.8Hz,1H),5.24(s,2H),3.79(s,2H),3.67(q,J=7.2Hz,2H),2.36(d,J=0.8Hz,3H),1.16(t,J=7.2Hz,3H).
实施例7(136)
1-(4-乙酰氧基苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
MS(APCI,负):350(M-H)-;
NMR(CDCl3):δ7.77(d,J=8.7Hz,2H),7.28-7.17(m,2H),7.10-6.94(m,3H),6.51(s,1H),3.87(s,2H),2.43(s,3H),2.35(s,3H).
实施例7(137)
1-(4-(2-丙炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.59(氯仿∶甲醇=9∶1);
MS(APCI,负):346(M-H)-;
NMR(CDCl3):δ7.73(d,J=9.0Hz,2H),7.09-6.90(m,5H),6.50(s,1H),4.79(d,J=2.4Hz,2H),3.87(s,2H),2.58(t,J=2.4Hz,1H),2.45(s,3H).
实施例7(138)
1-(4-(2-丙烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
MS(APCI,负):348(M-H)-;
NMR(CDCl3):δ7.71(d,J=8.7Hz,2H),7.10-6.90(m,5H),6.49(s,1H),6.15-6.00(m,1H),5.50-5.40(m,1H),5.40-5.30(m,1H),4.65-4.60(m,2H),3.87(s,2H),2.45(s,3H).
实施例7(139)
1-(4-(2-丁炔-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):360(M-H)-;
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.08-6.92(m,5H),6.49(s,1H),4.78-4.7 (m,2H),3.87(s,2H),2.45(s,3H),1.88(t,J=2.4Hz,3H).
实施例7(140)
1-(4-(3-戊烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):376(M-H)-;
NMR(CDC13):δ7.70(dd,J=6.9,2.4Hz,2H),7.05-6.92(m,5H),6.48(d,J=0.6Hz,1H),5.70-5.40(m,2H),4.05(t,J=6.6Hz,2H),3.86(s,2H),2.52(m,2H),2.44(d,J=0.6Hz,3H),1.69(m,3H).
实施例7(141)
1-(4-(2-(1-甲基吲哚-3-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):465(M-H)-;
NMR(CDCl3):δ7.70-7.63(m,3H),7.35-7.20(m,2H),7.14(m,1H),7.03(m,1H),7.05-6.93(m,5H),6.47(d,J=1.2Hz,1H),4.29(t,J=6.9Hz,2H),3.85(s,2H),3.77(s,3H),3.28(t,J=6.9Hz,2H),2.43(d,J=1.2Hz,3H).
实施例7(142)
1-(4-(2-(1,2,3,4-四氢化萘-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.53(氯仿∶甲醇=10∶1);
MS(APCI,负):452(M-H)-;
NMR(CDCl3):δ7.72(dd,J=6.9,1.8Hz,2H),7.12-7.10(m,4H),7.04(m,1H),7.03-6.95(m,4H),6.49(s,1H),4.02(d,J=6.3Hz,2H),3.87(s,2H),3.01(dd,J=14,4.2Hz,1H),2.92-2.87(m,2H),2.68(dd,J=14,10.5Hz,1H),2.45(s,3H),2.35(m,1H),2.10(m,1H),1.65(m,1H).
实施例7(143)
1-(4-(2-(1,2,3,4-四氢喹啉-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):467(M-H)-;
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.15-6.90(m,7H),6.65-6.55(m,2H),6.47(s,1H),4.22(t,J=5.7Hz,2H),3.84(s,2H),3.73(t,J=5.7Hz,2H),3.44(t,J=5.7Hz,2H),2.76(t,J=5.7Hz,2H),2.43(s,3H),2.00-1.90(m,2H).
实施例7(144)
1-(4-(2-羟基-(1-羟甲基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.12(氯仿∶甲醇=9∶1);
MS(APCI,负):382(M-H)-;
NMR(CDCl3):δ7.70(d,J=8.7Hz,2H),7.10-6.90(m,5H),6.52(s,1H),4.58-4.48(m,1H),3.90(d,J=6.0Hz,4H),3.83(s,2H),2.44(s,3H).
实施例7(145)
1-(4-(2-(2-乙基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯仿∶甲醇=10∶1);
MS(APCI,负):440(M-H)-;
NMR(CDCl3):δ7.72-7.67(m,2H),7.26-7.15(m,3H),7.06-6.90(m,6H),6.49(d,J=0.9Hz,1H),4.23(t,J=7.5Hz,2H),3.87(s,2H),3.18(t,J=7.5Hz,2H),2.74(q,J=7.5Hz,2H),2.44(d,J=0.9Hz,3H),1.27(t,J=7.5Hz,3H).
实施例7(146)
1-(4-(2-(2-甲氧基甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(FAB,正):458(M+H)+;
NMR(CDCl3):δ7.71-7.67(m,2H),7.37-7.23(m,3H),7.06-6.93(m,6H),6.48(s,1H),4.54(s,2H),4.27(t,J=7.5Hz,2H),3.86(s,2H),3.41(s,3H),3.21(t,J=7.5Hz,2H),2.44(d,J=0.6Hz,3H).
实施例7(147)
1-(4-(3,4-二氢-2H-苯并[b]吡喃-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(APCI,负):4 54(M-H)-;
NMR(CDCl3):δ7.72-7.43(m,5H),7.15-6.82(m,6H),6.49(s,1H),4.36(m,1H),4.17(m,1H),4.08(d,J=6.9Hz,2H),3.87(s,2H),3.04(dd,J=16.5,6.0Hz,1H),2.78(dd,J=16.5,7.2Hz,1H),2.63(m,1H),2.44(d,J=1.2Hz,3H).
实施例7(148)
1-(4-(2,3-二氢化茚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯仿∶甲醇=10∶1);
MS(FAB,正):440(M+H)+;
NMR(CDCl3):δ7.7 3-7.68(m,2H),7.26-6.93(m,9H),6.49(s,1H),4.04(d,J=6.9Hz,2H),3.87(s,2H),3.19(dd,J=16.5,7.5Hz,2H),3.02(m,1H),2.89(dd,J=16.5,6.0Hz,2H),2.44(d,J=1.2Hz,3H).
实施例7(149)
1-(4-(2-(1,4-苯并二噁烷-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=9∶1);
MS(APCI,负):470(M-H)-;
NMR(CDCl3):δ7.71(d,J=8.7Hz,2H),7.10-6.80(m,9H),6.49(s,1H),4.50-4.40(m,1H),4.38-4.17(m,3H),4.01(dd,J=11.4,7.2Hz,1H),3.86(s,2H),2.44(s,3H),2.17(q,J=6.0Hz,2H).
实施例7(150)
1-(4-(3,4-二氢-2H-苯并[b]吡喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.49(氯仿∶甲醇=10∶1);
MS(APCI,负):454(M-H)-;
NMR(CDCl3):δ7.74-7.67(m,2H),7.06-6.87(m,9H),6.49(s,1H),4.45(m,1H),4.38-4.15(m,2H),3.86(s,2H),3.00-2.80(m,2H),2.44(s,3H),2.30-1.90(m,2H).
实施例7(151)
1-(4-(3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.25(氯仿∶甲醇=10∶1);
MS(APCI,负):455(M-H)-;
NMR(CDCl3):δ7.76-7.40(m,3H),7.10-6.89(m,4H),6.89-6.60(m,4H),6.49(s,1H),4.60(m,1H),4.31(dd,J=9.8,5.0Hz,1H),4.24(dd,J=9.8,6.2Hz,1H),3.86(s,2H),3.58(dd,J=11.8,3.0Hz,1H),3.42(dd,J=11.8,6.6Hz,1H),2.44(s,3H).
实施例7(152)
1-(4-(4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.26(氯仿∶甲醇=10∶1);
MS(APCI,负):469(M-H)-;
NMR(CDCl3):δ7.78-7.40(m,3H),7.10-6.78(m,6H),6.73(d,J=8.0Hz,2H),6.49(s,1H),4.68(m,1H),4.31(dd,J=10.0,5.2Hz,1H),4.20(dd,J=10.0,6.4Hz,1H),3.86(s,2H),3.41(dd,J=11.6,2.8Hz,1H),3.27(dd,J=11.6,6.6Hz,1H),2.92(s,3H),2.44(s,3H).
实施例7(153)
1-(4-(1,3-二氧杂-2,3-二氢化茚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=10∶1);
MS(FAB,正):444(M+H)+;
NMR(CDCl3):δ7.74-7.69(m,2H),7.06-6.85(m,9H),6.50-6.47(m,2H),4.35(d,J=4.2Hz,2H),3.85(s,2H),2.43(d,J=0.9Hz,3H).
实施例7(154)
1-(4-(苯并[b]呋喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=10∶1);
MS(FAB,正):440(M+H)+;
NMR(CDCl3):δ7.76-7.71(m,2H),7.59(m,1H),7.51(m,1H),7.32(m,1H),7.25(m,1H),7.11-6.92(m,5H),6.84(d,J=0.6Hz,1H),6.49(m,1H),5.26(s,2H),3.87(s,2H),2.45(d,J=1.2Hz,3H).
实施例7(155)
1-(4-(2,3-二氢-苯并[b]呋喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(EI,正):441(M)+;
NMR(CDCl3):δ7.73-7.69(m,2H),7.23-7.12(m,2H),7.06-6.82(m,7H),6.49(d,J=1.2Hz,1H),5.20(m,1H),4.29(dd,J=9.9,6.3Hz,1H),4.20(dd,J=9.9,4.2Hz,1H),3.86(s,2H),3.42(dd,J=15.9,9.6Hz,1H),3.17(dd,J=15.9,8.4Hz,1H),2.44(d,J=1.2Hz,3H).
实施例7(156)
1-(4-(2-(2,5-二甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(FAB,正):474(M+H)+;
NMR(CDCl3):δ7.69(m,2H),7.08-6.92(m,5H),6.86-6.72(m,3H),6.48(s,1H),4.24(t,J=6.8Hz,2H),3.86(s,2H),3.81(s,3H),3.77(s,3H),3.12(t,J=6.8Hz,2H),2.44(s,3H).
实施例7(157)
1-(4-(2,3-二氢苯并[b]呋喃-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
MS(FAB,正):442(M+H)+;
NMR(CDCl3):δ7.70(m,2H),7.31(d,J=7.4Hz,1H),7.21(m,1H),7.10-6.82(m,7H),6.49(s,1H),4.73(t,J=9.6Hz,1H),4.55(dd,J=9.6,4.6Hz,1H),4.29-3.88(m,3H),3.86(s,2H),2.44(s,3H).
实施例7(158)
1-(4-(2-环丙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.42(氯仿∶甲醇=10∶1);
MS(FAB,正):394(M+H)+;
NMR(CDCl3):δ7.71(m,2H),7.12-6.88(m,5H),6.49(s,1H),4.19(t,J=4.6Hz,2H),3.97-3.82(m,4H),3.42(m,1H),2.44(s,3H),0.72-0.58(m,2H),0.58-0.46(m,2H).
实施例7(159)
1-(4-(2-(2,4-二甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):440(M-H)-;
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.12(d,J=7.5Hz,1H),7.08-6.90(m,7H),6.49(s,1H),4.20(t,J=7.5Hz,2H),3.87(s,2H),3.12(t,J=7.5Hz,2H),2.45(s,3H),2.36(s,3H),2.31(s,3H).
实施例7(160)
1-(4-(2-(2,6-二甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.59(氯仿∶甲醇=9∶1);
MS(APCI,负):440(M-H)-;
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.09-6.90(m,8H),6.49(s,1H),4.13(t,J=7.2Hz,2H),3.88(s,2H),3.22(t,J=7.2Hz,2H),2.45(s,3H),2.41(s,6H).
实施例7(161)
1-(4-(2-(苯并[b]噻吩2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.61(氯仿∶甲醇=9∶1);
MS(APCI,负):468(M-H)-;
NMR(CDCl3):δ7.82-7.76(m,1H),7.75-7.68(m,3H),7.37-7.24(m,2H),7.16(s,1H),7.08-6.92(m,5H),6.49(s,1H),4.36(t,J=6.3Hz,2H),3.87(s,2H),3.43(t,J=6.3Hz,2H),2.44(s,3H).
实施例7(162)
1-(4-(2-(2-甲氧基苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):458(M-H)-;
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.03-6.92(m,9H),6.48(d,J=0.9Hz,1H),4.42(s,4H),3.85(s,3H),3.84(s,2H),2.44(d,J=0.9Hz,3H).
实施例7(163)
1-(4-(2-(N-乙基-N-苯基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸乙酸盐
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):455(M-H)-;
NMR(CDCl3):δ7.67(d,J=9.0Hz,2H),7.26-7.20(m,2H),7.04-6.88(m,5H),6.76-6.66(m,3H),6.45(d,J=0.9Hz,1H),4.17(d,J=6.8Hz,2H),3.83(s,2H),3.74(t,J=6.8Hz,2H),3.47(q,J=7.2Hz,2H),2.42(d,J=0.9Hz,3H),2.06(s,3H),1.19(t,J=7.2Hz,3H).
实施例7(164)
1-(4-(2-(吲哚-1-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):451(M-H)-;
NMR(CDCl3):δ7.68-7.63(m,3H),7.41(d,J=8.0Hz,1H),7.26-7.21(m,2H),7.14-6.86(m,8H),6.54(dd,J=3.0,0.6Hz,1H),6.48(s,1H),4.58(t,J=5.4Hz,2H),4.36(t,J=5.4Hz,2H),3.86(s,2H),2.42(s,3H).
实施例7(165)
1-(4-(2-(3-甲基吡啶-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=10∶1);
MS(APCI,负):427(M-H)-;
NMR(CDCl3):δ8.43(m,1H),7.64(d,J=6.9Hz,2H),7.49(m,1H),7.21(d,J=8.1Hz,1H),7.05(d,J=8.1Hz,1H),7.00-6.85(m,4H),6.53(d,J=0.9Hz,1H),4.33(t,J=6.6Hz,2H),3.85(s,2H),3.26(t,J=6.6Hz,2H),2.41(d,J=0.9Hz,3H),2.31(s,3H).
实施例7(166)
1-(4-(2-(苯并[b]呋喃-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):452(M-H)-;
NMR(CDCl3):δ7.76-7.42(m,4H),7.30-7.17(m,2H),7.10-6.90(m,5H),6.57(s,1H),6.49(s,1H),4.42(t,J=6.6Hz,2H),3.87(s,2H),3.32(t,J=6.6Hz,2H),2.44(s,3H).
实施例7(167)
1-(4-(4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(氯仿∶甲醇=10∶1);
MS(APCI,负):469(M-H)-;
NMR(CDCl3):δ7.72-7.67(m,2H),7.06-6.81(m,7H),6.69-6.62(m,2H),6.49(m,1H),4.48(dd,J=11.1,1.8Hz,1H),4.14(d,J=7.5Hz,2H),4.13(dd,J=11.1,2.4Hz,1H),3.86(s,2H),3.74(m,1H),3.08(s,3H),2.44(d,J=1.2Hz,3H).
实施例7(168)
1-(4-(2-(2,4-二甲氧基苯氧基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):488(M-H)-;
NMR(CDCl3):δ7.72-7.62(m,3H),7.58-7.50(m,1H),7.49-7.41(m,1H),7.06-6.85(m,4H),6.53-6.48(m,2H),6.39(dd,J=8.7,2.7Hz,1H),4.45-4.30(m,4H),3.85(s,2H),3.83(s,3H),3.78(s,3H),2.44(d,J=0.9Hz,3H).
实施例7(169)
1-(4-(2-(4-甲基吡啶-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=10∶1);
MS(APCI,负):427(M-H)-;
NMR(CDCl3):δ8.44(d,J=6.6Hz,1H),7.64(d,J=8.7Hz,2H),7.13-6.86(m,7H),6.52(d,J=0.8Hz,1H),4.34(t,J=6.2Hz,2H),3.85(s,2H),3.26(t,J=6.2Hz,2H),2.41(d,J=0.8Hz,3H),2.31(s,3H).
实施例7(170)
1-(4-(4-乙基-3,4-二氢-2H-1,4-苯并噁嗪-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.28(氯仿∶甲醇=10∶1);
MS(APCI,负):483(M-H)-;
NMR(CDCl3):δ7.80-7.57(m,2H),7.10-6.79(m,7H),6.79-6.56(m,2H),6.49(s,1H),4.68-4.50(m,1H),4.31(dd,J=9.6,5.2Hz,1H),4.21(dd,J=9.6,6.2Hz,1H),3.86(s,2H),3.57-3.20(m,4H),2.44(s,3H),1.17(t,J=7.4Hz,3H).
实施例7(171)
1-(4-(2-(N-甲基-N-(3-甲基苯基)氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.27(氯仿∶甲醇=10∶1);
MS(APCI,负):455(M-H)-;
NMR(CDCl3):δ7.68(d,J=8.8Hz,2H),7.21-6.87(m,6H),6.63-6.52(m,3H),6.48(s,1H),4.22(t,J=6.0Hz,2H),3.85(s,2H),3.79(t,J=6.0Hz,2H),3.06(s,3H),2.43(s,3H),2.32(s,3H).
实施例7(172)
1-(4-(3,4-二氢-2H-1,5-苯并二氧杂环庚烯-3-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.54(氯仿∶甲醇=9∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.78-7.42(m,6H),7.10-6.90(m,5H),6.50(s,1H),5.08-4.96(m,1H),4.57(dd,J=12.6,4.2Hz,2H),4.47(dd,J=12.6,4.2Hz,2H),3.87(s,2H),2.45(s,3H).
实施例7(173)
1-(4-(3,4-二氢-2H-1,5-苯并二氧杂环庚烯-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):470(M-H)-;
NMR(CDCl3):δ7.78-7.42(m,5H),7.10-6.90(m,6H),6.50(s,1H),4.40-4.28(m,4H),4.26(d,J=6.9Hz,2H),3.87(s,2H),2.80-2.70(m,1H),2.45(s,3H).
实施例7(174)
1-(4-(1,4-苯并二噁烷-6-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(EI,正):457(M)+;
NMR(CDCl3):δ7.73-7.68(m,2H),7.07-6.90(m,8H),6.49(s,1H),5.03(s,2H),4.27(s,4H),3.87(s,2H),2.45(d,J=0.9Hz,3H).
实施例7(175)
1-(4-(2-(4-甲氧基-2-甲基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.37(氯仿∶甲醇=10∶1);
MS(EI,正):457(M)+;
NMR(CDCl3):δ7.72-7.67(m,2H),7.15(d,J=8.1Hz,1H),7.06-6.91(m,5H),6.76-6.71(m,2H),6.49(s,1H),4.18(t,J=7.2Hz,2H),3.86(s,2H),3.79(s,3H),3.09(t,J=7.2Hz,2H),2.44(d,J=0.9Hz,3H) 2.37(s,3H).
实施例7(176)
1-(4-(1-甲基-1,2,3,4-四氢喹啉-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.39(氯仿∶甲醇=10∶1);
MS(EI,正):468(M)+;
NMR(CDCl3):δ7.72-7.67(m,2H),7.12(m,1H),7.06-6.91(m,6H),6.68-6.58(m,2H),6.49(m,1H),4.13(dd,J=9.3,5.7Hz,1H),4.00(dd,J=9.3,7.5Hz,1H),3.86(s,2H),3.79(m,1H),3.07(s,3H),2.89-2.70(m,2H),2.44(d,J=0.9Hz,3H)2.19(m,1H),2.02(m,1H).
实施例7(177)
1-(4-(2-(2,3-二氢苯并[b]呋喃-2-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):454(M-H)-;
NMR(CDCl3):δ7.72(d,J=8.7Hz,2H),7.22-6.76(m,9H),6.50(s,1H),5.10-5.00(m,1H),4.40-4.20(m,2H),3.88(s,2H),3.41(dd,J=15.6,8.4Hz,1H),2.97(dd,J=15.6,7.5Hz,1H),2.46(s,3H),2.35-2.15(m,2H).
实施例7(178)
1-(4-(4,7-二甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
MS(APCI,负):483(M-H)-;
NMR(CDCl3):δ7.69(dd,J=8.8,2.2Hz,2H),7.04-6.90(m,6H),6.70-6.63(m,2H),6.48(s,1H),4.65(m,1H),4.28(dd,J=7.2,5.1Hz,1H),4.23(dd,J=7.2,2.5Hz,1H),3.85(s,2H),3.32(dd,J=12.4,2.6Hz,1H),3.20(dd,J=12.4,6.6Hz,1H),2.87(s,3H),2.44(s,3H),2.23(s,3H).
实施例7(179)
1-(4-(4,6-二甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
MS(APCI,负):483(M-H)-;
NMR(CDCl3):δ7.69(m,2H),7.04-6.90(m,6H),6.73(d,J=8.0Hz,1H),6.53(s,1H),6.48(s,1H),4.65(m,1H),4.28(dd,J=7.2,5.1Hz,1H),4.22(dd,J=7.2,2.5Hz,1H),3.85(s,2H),3.35(dd,J=12.2,3.0Hz,1H),3.25(dd,J=12.2,6.2Hz,1H),2.90(s,3H),2.44(s,3H),2.27(s,3H).
实施例7(180)
1-(4-(1-甲基二氢吲哚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.49(氯仿∶甲醇=9∶1);
MS(APCI,负):453(M-H)-;
NMR(CDCl3):δ7.76-7.66(m,2H),7.20-6.46(m,10H),5.00-2.80(m,5H),3.87(s,2H),2.94 and 2.91(each s,total 3H),2.45(s,3H).
实施例7(181)
1-(4-(4,5-二甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=9∶1);
MS(APCI,负):483(M-H)-;
NMR(CDCl3):δ7.74(d,J=9.0Hz,2H),7.08-6.84(m,6H),6.82-6.75(m,2H),6.50(s,1H),4.55-4.45(m,1H),4.36(dd,J=9.9,4.5Hz,1H),4.22(dd,J=9.9,4.5Hz,1H),3.87(s,2H),3.27(dd,J=13.8,2.4Hz,1H),3.08(dd,J=13.8,9.9Hz,1H),2.78(s,3H),2.45(s,3H),2.33(s,3H).
实施例7(182)
1-(4-(4-乙酰基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):497(M-H)-;
NMR(CDCl3):δ7.75-7.62(m,4H),7.15-6.90(m,7H),6.49(s,1H),4.64(brs,2H),4.25(m,2H),3.86(s,2H),3.60(brs 1H),2.44(s,3H),2.35(s,3H).
实施例7(183)
1-(4-(3-乙酰基-2,3-二氢-1,3-苯并噁唑-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(FAB,正):485(M+H)+;
NMR(CDCl3):δ7.67(d,J=9.3Hz,2H),7.10-6.90(m,9H),6.66(brs,1H),6.48(s,1H),4.40(brs,2H),3.86(s,2H),2.43(s,3H),2.43(d,J=0.9Hz,3H).
实施例7(184)
1-(4-(4,6,8-三甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.36(氯仿∶甲醇=10∶1);
MS(APCI,负):497(M-H)-;
NMR(CDCl3):δ7.74-7.69(m,2H),7.07-6.93(m,5H),6.49(s,1H),6.40(s,1H),6.40(s,1H),4.65(m,1H),4.31(dd,J=9.9,4.8Hz,1H),4.21(dd,J=9.9,6.3Hz,1H),3.87(s,2H),3.39(dd,J=11.7,2.7Hz,1H),3.24(dd,J=11.7,6.0Hz,1H),2.89(s,3H),2.45(d,J=0.6Hz,3H),2.24(s,3H),2.14(s,3H).
实施例7(185)
1-(4-((3Z)-3-己烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):390(M-H)-;
NMR(CDCl3):δ7.70(dd,J=6.9,2.1Hz,2H),7.06-6.92(m,5H),6.48(d,J=0.9Hz,1H),5.56(m,1H),5.40(m,1H),4.05(t,J=6.9Hz,2H),3.86(s,2H),2.57(m,2H),2.44(d,J=0.9Hz,3H),2.11(m,2H),1.00(t,J=7.2Hz,3H).
实施例7(186)
1-(4-(4-甲基-1,3-二氧杂-2,3-二氢化茚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.71(dd,J=6.9,2.1Hz,2H),7.04-6.95(m,5H),6.80-6.67(m,2H),6.48-6.44(m,2H),4.35(d,J=4.2Hz,2H),3.85(s,2H),2.44(d,J=0.9Hz,3H),2.23(s,3H).
实施例7(187)
1-(4-(5-甲基-1,3-二氧杂-2,3-二氢化茚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):456(M-H)-;
NMR(CDCl3):δ7.71(m,2H),7.06-6.92(m,6H),6.75-6.65(m,2H),6.49-6.44(m,2H),4.32(d,J=4.2Hz,2H),3.86(s,2H),2.44(d,J=0.9Hz,3H),2.29(s,3H).
实施例7(188)
1-(4-((4E)-4-己烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(APCI,负):390(M-H)-;
NMR(CDCl3):δ7.72-7.67(m,2H),7.05-6.92(m,5H),6.48(s,1H),5.56-5.40(m,2H),4.04(t,J=6.6Hz,2H),3.85(s,2H),2.44(d,J=0.9Hz,3H),2.22-2.14(m,2H),1.92-1.83(m,2H),1.67-1.65(m,3H).
实施例7(189)
1-(4-((3E)-3-己烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=10∶1);
MS(APCI,负):390(M-H)-;
NMR(CDCl3):δ7.72-7.68(m,2H),7.06-6.93(m,5H),6.48(s,1H),5.64(dt,J=15.3,6.0Hz,H),5.48(dt,J=15.3,6.6Hz,1H),4.05(t,J=6.9Hz,2H),3.86(s,2H),2.52(dt,J=6.6,6.9Hz,2H),2.44(d,J=0.9Hz,3H),2.05(dq,J=6.0,7.5Hz,2H),0.99(t,J=7.5Hz,3H).
实施例7(190)
1-(4-(3-(N-甲基-N-苯基氨基)丙氧基苯甲酰基)-5-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=9∶1):
MS(APCI,负):455(M-H)-;
NMR(CDCl3):δ7.71(d,J=9.0Hz,2H),7.26-7.16(m,2H),7.08-6.92(m,5H),6.79-6.66(m,3H),6.49(s,1H),4.09(t,J=5.7Hz,2H),3.87(s,2H),3.57(t,J=6.9Hz,2H),2.60(s,3H),2.45(s,3H),2.20-2.00(m,2H).
实施例7(191)
1-(4-(4-甲磺酰基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,负):533(M-H)-;
NMR(CDCl3):δ7.72(m,3H),7.12-6.91(m,8H),6.50(s,1H),4.56(brs,1H),4.46-4.26(m,3H),3.88(s,2H),3.57(dd,J=13.8,9.3Hz,1H),3.02(s,3H)2.45(s,3H).
实施例7(192)
1-(4-(4-甲基-7-甲氧基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(APCI,负):499(M-H)-;
NMR(CDC13):δ7.75-7.62(m,4H),7.04-6.90(m,4H),6.66(d,J=9.0Hz,1H),6.49(s,1H),6.48(d,J=9.0Hz,1H),4.70(m,1H),4.30(dd,J=12.0,5.4Hz,1H),4.24(m,1H),3.87(s,2H),3.74(s,3H),3.33(dd,J=11.4,2.7Hz,1H),3.18(dd,J=11.7,6.6,1H),2.86(s,3H),2.45(s,3H).
实施例7(193)
1-(4-(2,2-二甲基-1,3-二氧戊环-4-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=10∶1);
NMR(FAB,正):424(M+H)+;
NMR(CDCl3):δ7.73-7.68(m,2H),7.06-6.92(m,5H),6.48(s,1H),4.52(m,1H),4.20(dd,J=8.4,6.6Hz,1H),4.13(dd,J=9.6,5.7Hz,1H),4.04(dd,J=9.6,5.7Hz,1H),3.94(dd,J=8.4,5.7Hz,1H),3.86(s,2H),2.44(s,3H),1.48(s,3H),1.42(s,3H).
实施例7(194)
1-(4-(6-氟-4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,正):489(M+H)+;
NMR(CDCl3):δ7.72(d,J=8.7Hz,2H),7.08-6.90(m,5H),6.74(dd,J=8.7,5.4Hz,1H),6.50(s,1H),6.35(m,2H),4.60(m,1H),4.30(dd,J=9.9,5.1Hz,1H),4.19(dd,J=9.9,6.3Hz,1H),3.87(s,2H),3.41(dd,J=11.7,3.6Hz,1H),3.30(dd,J=11.7,6.6Hz,1H),2.91(s,3H),2.45(s,3H).
实施例7(195)
1-(4-(4,5-二甲基-1,3-二氧戊环-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯仿∶甲醇=10∶1);
MS(EI,正):423(M)+;
NMR(CDCl3):δ7.72-7.67(m,2H),7.05-6.90(m,5H),6.48(s,1H),5.54 and 5.44 and 5.27(each t,J=4.2Hz,total 1H),4.36-4.31 and4.28-4.23 and 3.74-3.69(each m,total 2H),4.14 and 4.09 and 4.03(each d,J=4.2Hz,total 2H),3.85(s,2H),2.44(d,J=0.6Hz,3H),1.38-1.17(m,6H).
实施例7(196)
1-(4-((3Z)-3-戊烯-1-基氧)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):376(M-H)-;
NMR(CDCl3):δ7.69(m,2H),7.08-6.93(m,5H),6.49(d,J=1.2Hz,1H),5.64-5.40(m,2H),4.06(t,J=7.0Hz,2H),3.86(s,2H),2.60(m,2H),2.44(d,J=1.2Hz,3H),1.70(m,3H).
实施例7(197)
1-(4-(1,3-苯并氧硫杂环戊烷-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.51(氯仿∶甲醇=10∶1);
MS(APCI,负):458(M-H)-;
NMR(CDCl3):δ7.70(m,2H),7.25-7.20(m,2H),7.19-7.10(m,1H),7.08-6.82(m,6H),6.48(s,1H),6.36(dd,J=6.9,4.5Hz,1/5H),6.13(dd,J=4.2,2.1Hz,4/5H),4.45(dd,J=10.5,6.9Hz,1/5H),4.17(dd,J=10.5,4.5Hz,1/5H),3.84(s,2H),3.34(dd,J=13.2,2.1Hz,4/5H),3.23(dd,J=13.2,4.2Hz,4/5H),2.43(s,3H).
实施例7(198)
1-(4-(1,4-苯并二噁烷-5-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
MS(APCI,正):471(M+H)+;
NMR(CDCl3):δ7.69(d,J=8.7Hz,2H),7.10-6.90(m,5H),6.80(s,J=8.7,3H),6.48(s,1H),4.34-4.18(m,6H),3.86(s,2H),3.12(t,J=7.2Hz,2H),2.44(s,3H).
实施例7(199)
1-(4-(1,4-苯并氧硫杂环己烷-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.25(氯仿∶甲醇=10∶1);
MS(FAB,正):474(M+H)+;
NMR(CDCl3):δ7.73(d,J=8.7Hz,2H),7.12-6.83(m,9H),6.49(s,1H),4.68(m,1H),4.37(dd,J=9.6,4.8Hz,1H),4.26(dd,J=9.6,6.3Hz,1H),3.86(s,2H),3.26-3.15(m,2H),2.45(s,3H).
实施例7(200)
1-(4-(1,4-苯并氧硫杂环己烷-S,S-二氧化物-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.15(氯仿∶甲醇=10∶1);
MS(FAB,正):506(M+H)+;
NMR(CDCl3):δ7.88-7.60(m,4H),7.60-7.40(m,3H),7.23-7.10(m,1H),7.10-6.85(m,3H),6.50(s,1H),5.25(m,1H),4.48(dd,J=10.2,4.2Hz,1H),4.40(dd,J=10.2,4.2Hz,1H),3.86(s,2H),3.76(dd,J=13.8,12.0Hz,1H),3.58(dd,J=13.8,1.5Hz,1H),2.45(s,3H).
实施例7(201)
1-(4-(吡嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
MS(APCI,负):400(M-H)-;
NMR(CDCl3):δ8.86(s,1H),8.65-8.55(m,2H),7.74(d,J=8.7Hz,2H),7.13-6.90(m,5H),6.50(s,1H),5.33(s,2H),3.87(s,2H),2.45(s,3H).
实施例7(202)
1-(4-(2,3-二氢-1-乙基吲哚-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
MS(APCI,负):467(M-H)-;
NMR(CDCl3):δ7.76-7.68(m,2H),7.16-6.44(m,10H),5.00-2.80(m,7H),3.87(s,2H),2.45(s,3H),1.20-1.10(m,3H).
实施例7(203)
1-(4-(2,3,4,5-四氢呋喃-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=9∶1);
MS(MAL二,正):393(M+H)+,416(M+Na)+;
NMR(CDCl3):δ7.71(d,J=8.7Hz,2H),7.08-6.98(m,3H),6.95(d,J=8.7Hz,2H),6.49(s,1H),4.05-3.70(m,8H),2.85-2.72(m,1H),2.44(s,3H),2.22-2.08(m,1H),1.82-1.70(m,1H).
实施例7(204)
1-(4-(2-(2-苯基-5-甲基噁唑-4-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
MS(FAB,正):495(M+H)+.
实施例7(205)
1-(4-(2-(2,3-二甲氧基苯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.5(氯仿∶甲醇=10∶1);
MS(APCI,正):474(M+H)+;
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.08-6.92(m,6H),6.86(m,2H),6.48(s,1H),4.25(t,J=7.5Hz,2H),3.88(s,6H),3.84(s,2H),3.15(t,J=7.5Hz,2H),2.44(s,3H).
实施例7(206)
1-(4-(4-甲基-6-三氟甲基苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.5(氯仿∶甲醇=10∶1);
MS(APCI,正):539(M+H)+;
NMR(CDCl3):δ7.73(d,J=9.0Hz,2H),7.06-6.86(m,8H),6.50(s,1H),4.70(m,1H),4.31(dd,J=9.9,4.8Hz,1H),4.21(dd,J=9.9,6.3Hz,1H),3.87(s,2H),3.45(dd,J=11.7,2.7Hz,1H),3.33(dd,J=11.7,6.6Hz,1H),2.96(s,3H),2.45(s,3H).
实施例7(207)
1-(4-(2-(1,2,3,4-四氢化萘-5-基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.4(氯仿∶甲醇=10∶1);
MS(APCI,正):468(M+H)+;
NMR(CDCl3):δ7.69(d,J=9.0Hz,2H),7.10-6.92(m,8H),6.49(s,1H),4.22(t,J=7.5Hz,2H),3.86(s,2H),3.12(t,J=7.5Hz,2H),2.79(m,4H),2.44(s,3H),1.89-1.77(m,4H).
实施例7(208)
1-(4-(喹喔啉-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=9∶1);
MS(APCI,负):450(M-H)-;
NMR(CDCl3):δ9.12(s,1H),8.20-8.08(m,2H),7.88-7.78(m,2H),7.75(d,J=9.0Hz,2H),7.13(d,J=9.0Hz,2H),7.10-6.90(m,3H),6.50(s,1H),5.51(s,2H),3.88(s,2H),2.45(s,3H).
实施例7(209)
1-(4-(6-氯-4-甲基苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.38(氯仿∶甲醇=9∶1);
MS(APCI,负):503(M-H)-;
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.08-6.90(m,5H),6.74(dd,J=7.8,0.9Hz,1H),6.68-6.60(m,2H),6.49(t,J=0.9Hz,1H),4.68-4.56(m,1H),4.29(dd,J=9.9,4.8Hz,1H),4.19(dd,J=9.9,6.0Hz,1H),3.87(s,2H),3.41(dd,J=11.7,2.7Hz,1H),3.29(dd,J=11.7,6.6Hz,1H),2.91(s,3H),2.45(s,3H).
实施例7(210)
1-(4-(2-(6,6-二甲基[3.1.1]二环庚-2-烯基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):456(M-H)-.
实施例7(211)
1-(4-([2.2.1]二环庚烷-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):416(M-H)-.
实施例7(212)
1-(4-(氧杂环丁烷-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
MS(APCI,负):378(M-H)-.
实施例7(213)
1-(4-(4-甲基吡嗪并[2,3-b]噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
MS(FAB,正):473(M+H)+;
NMR(CDCl3):δ7.75-7.71(m,3H),7.43(d,J=3.3Hz,1H),7.07-6.92(m,5H),6.50(s,1H),4.80(m,1H),4.40(dd,J=9.9,4.5Hz,1H),4.26(dd,J=9.9,6.6Hz,1H),3.87(s,2H),3.65(dd,J=12.3,3.3Hz,1H),3.59(dd,J=12.3,6.9Hz,1H),3.17(s,3H),2.45(d,J=0.9Hz,3H).
实施例7(214)
1-(4-(四氢吡喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.44(氯仿∶甲醇=9∶1);
MS(FAB,正):407(M+H)+.
实施例7(215)
1-(4-(2-(N-(2-氰基乙基)-N-苯基氨基)乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=9∶1);
MS(FAB,甘油+m-NBA):482(M+H)+.
实施例7(216)
1-(4-(1,4-二甲基-1,2,3,4-四氢喹喔啉-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(APCI,负):482(M-H)-;
NMR(CDCl3):δ7.70(d,J=9.0Hz,2H),7.08-6.92(m,5H),6.80-6.66(m,2H),6.62-6.48(m,3H),4.27-4.07(m,2H),3.87(s,2H),3.83-3.73(m,1H),3.36-3.20(m,2H),3.05(s,3H),2.88(s,3H),2.45(s,3H).
实施例7(217)
1-(4-(5-氟-4-甲基-3,4-二氢-2H-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
MS::(正):488(M)+;
NMR(CDCl3):δ7.72(d,J=9.0Hz,2H),7.08-6.90(m,5H),6.83-6.73(m,1H),6.58-6.45(m,3H),4.76-4.66(m,1H),4.37(dd,J=9.9,5.1HZ,1H),4.24(dd,J=9.9,6.6Hz,1H),3.87(s,2H),3.46(dd,J=12.0,2.7Hz,1H),3.34(dd,J=12.0,6.6Hz,1H),2.94(s,3H),2.45(s,3H).
实施例7(218)
1-(4-(4,8-二甲基-3,4-二氢-2H-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
MS(负):483(M-H)-;
NMR(CDCl3):δ7.76-7.66(m,2H),7.08-6.90(m,6H),6.82-6.74(m,1H),6.58(d,J=7.5Hz,1H),6.49(s,1H),4.74-4.64(m,1H),4.33(dd,J=9.9,5.4Hz,1H),4.23(dd,J=9.9,6.3Hz,1H),3.87(s,2H),3.41(dd,J=11.4,2.7Hz,1H),3.26(dd,J=11.4,6.3Hz,1H),2.91(s,3H),2.45(s,3H),2.18(s,3H).
实施例7(219)
1-(4-(4-甲基-3,4-二氢-2H-苯并噻嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
MS(APCI,负):485(M-H)-;
NMR(CDCl3):δ7.68(d,J=8.7Hz,2H),7.22-6.92(m,7H),6.70-6.65(m,2H),6.47(s,1H),4.27(dd,J=9.6,9.3Hz,1H),4.16(dd,J=9.3,5.1Hz,1H),3.83(s,2H),3.67(m,1H),3.57(m,2H),2.91(s,3H),2.42(s,3H).
实施例7(220)
1-(4-(4-甲基-3,4-二氢-2H-吡啶并[3,2-b]噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.35(氯仿∶甲醇=9∶1);
MS(FAB,正):472(M+H)+;
NMR(CDCl3):δ7.81(dd,J=5.1,1.8Hz,1H),7.73(d,J=8.7Hz,2H),7.10-6.90(m,6H),6.56(dd,J=7.8,5.1Hz,1H),6.50(s,1H),4.67-4.58(m,1H),4.31(dd,J=9.9,5.1HZ,1H),4.20(dd,J=9.9,6.0Hz,1H),3.87(s,2H),3.58(dd,J=12.0,3.0Hz,1H),3.49(dd,J=12.0,6.9Hz,1H),3.15(s,3H),2.45(s,3H).
实施例7(221)
1-(4-(4-甲基-3,4-二氢-2H-吡啶并[2,3-b]噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(FAB,正):472(M+H)+;
NMR(CDCl3):δ7.74-7.69(m,2H),7.67(dd,J=5.1,1.5Hz,1H),7.05-6.85(m,7H),6.51(s,1H),4.82(m,1H),4.37(dd,J=9.6,4.2Hz,1H),4.23(dd,J=9.6,6.9Hz,1H),3.87(s,2H),3.45(dd,J=12.0,3.3Hz,1H),3.31(dd,J=12.0,7.0Hz,1H),2.92(s,3H),2.44(d,J=0.9Hz,3H).
实施例7(222)
1-(4-(7-氟-4-甲基-3,4-二氢-2H-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.33(氯仿∶甲醇=9∶1);
MS(MAR二,正):488(M+;
NMR(CDCl3):δ7.77-7.61(m,2H),7.59-7.41(m,2H),7.08-6.90(m,4H),6.60(d,J=8.1Hz,2H),6.50(s,1H),4.75-4.65(m,1H),4.34-4.18(m,2H),3.86(s,2H),3.40-3.18(m,2H),2.87(s,3H),2.44(s,3H).
实施例7(223)
1-(4-(7-氰基-4-甲基-3,4-二氢-2H-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.31(氯仿∶甲醇=9∶1);
MS(APCI,正):495(M)+,518(M+Na)+;
NMR(CDCl3):δ7.72(d,J=8.7Hz,2H),7.09-6.82(m,8H),6.50(s,1H),4.78-4.67(m,1H),4.35-4.18(m,2H),3.87(s,2H),3.49-3.30(m,2H),2.95(s,3H),2.45(s,3H).
实施例7(224)
1-(4-(4-甲基-6-甲氧基-3,4-二氢-2H-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(APCI,正):501(M+H)+;
NMR(CDCl3):δ7.72(d,J=8.7Hz,2H),7.08-6.90(m,5H),6.75(d,J=8.7Hz,1H),6.49(s,1H),6.29(d,J=2.7Hz,1H),6.23(dd,J=8.7,2.7Hz,1H),4.61(m,1H),4.30(dd,J=9.9,4.8Hz,1H),4.18(m,1H),3.87(s,2H),3.76(s,3H),3.40(dd,J=11.4,9.0Hz,1H),3.28(dd,J=11.4,6.6Hz,1H),2.91(s,3H),2.44(s,3H).
实施例7(225)
1-(4-(1-甲基二氢吲哚-3-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
MS(APCI,负):453(M-H)-;
NMR(CDCl3):δ7.74-7.68(m,3H),7.22-7.10(m,2H),7.08-6.90(m,4H),6.72(t,J=6.6Hz,1H),6.53(d,J=8.1Hz,1H),6.49(s,1H),4.24-4.06(m,2H),3.87(s,2H),3.78-3.70(m,1H),3.49(t,J=8.1Hz,1H),3.38(dd,J=9.0,5.1Hz,1H),2.79(s,3H),2.45(s,3H).
实施例7(226)
1-(4-(4-甲基-3,4-二氢-2H-苯并噁嗪-2-基)羰基氨基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:0.48(氯仿∶甲醇=10∶1);
MS(APCI,负):482(M-H)-;
NMR(CDCl3):δ8.53(s,1H),7.72(s,4H),7.20-6.90(m,5H),6.80-6.70(m,2H),6.49(s,1H),4.89(dd,J=6.9,3.3Hz,1H),3.85(s,2H),3.57(dd,J=12.0,3.3Hz,1H),3.44(dd,J=12.0,6.9Hz,1H),2.92(s,3H),2.49(s,3H).
实施例7(227)
1-(4-N-甲基-N-(4-甲基-3,4-二氢-2H-苯并噁嗪-2-基羰基)氨基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.77(d,J=8.7Hz,2H),7.43(d,J=8.7Hz,2H),7.05(d,J=6.3Hz,1H),6.90-6.75(m,3H),6.70-6.55(m,3H),6.49(s,1H),4.77(brd,J=6.3Hz,1H),3.84(s,2H),3.53(dd,J=12.0,7.8Hz,1H),3.40(s,3H),3.30(dd,J=12.0,2.4Hz,1H),2.86(s,3H),2.41(s,3H).
实施例7(228)
1-(4-(5-甲基-2,3,4,5-四氢呋喃-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
TLC:Rf 0.52(氯仿∶甲醇=10∶1);
NMR(CDCl3):δ7.69(d,J=9.3Hz,2H),7.07-6.88(m,5H),6.48(s,1H),4.50-4.30(m,1H),4.1 7-3.95(m,2H),3.85(s,2H),3.42(dd,J=16.5,8.1Hz,1H),2.50-2.20(m) and 2.44(s) total 5H,2.09-1.94(m) and 1.79-1.67(m) total 1H,1.50-1.22(m,1H),1.15-1.05(m,3H).
次外,实施例7(224)制备的化合物也可通过以下参考例22→参考例23→参考例24→参考例25→参考例26→参考例27→参考例28→实施例8所示的方法制造。
参考例22
2-乙氧羰基-6-甲氧基-3,4-二氢-2H-苯并噁嗪
在氩气氛围下往2-氨基-4-甲氧基苯酚(5.5g)的丙酮(200ml)溶液中加入碳酸钾(5g),混合物在40℃搅拌。往混合物中滴加1,2-二溴丙酸乙酯和碳酸钾(15g),然后回流15小时。让混合物冷却至室温,然后过滤。将滤液倒入水中,用乙酸乙酯萃取三次。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,然后减压浓缩。残留物用硅胶柱色谱(正己烷∶乙酸乙酯=10∶1)精制,得到具有下列物性数椐的标题化合物(1.65g)。
TLC:Rf 0.44(正己烷∶乙酸乙酯=2∶1)。
参考例23
2-羟甲基-6-甲氧基-3,4-二氢-2H-苯并噁嗪
在氩气氛围下往氢化铝锂(560mg)的四氢呋喃(50ml)溶液中滴加上述参考例制备的化合物(1.65g)的四氢呋喃(30ml)溶液,搅拌15分钟。往反应混合物中加入饱和食盐水,用乙酸乙酯萃取三次。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,然后减压浓缩。残留物用硅胶柱色谱(正己烷∶乙酸乙酯=4∶1)精制,得到具有下列物性数椐的标题化合物(1.3g)。
TLC:Rf 0.17(正己烷∶乙酸乙酯=2∶1).
参考例24
2-羟甲基-6-甲氧基-4-甲基-3,4-二氢-2H-苯并噁嗪
将上述参考例制备的化合物(1.3g)溶解在丙酮(50ml)-N,N-二甲基甲酰胺(10ml)的混合溶液中,加入碳酸钾(10g)和碘甲烷(3ml),混合物在58℃搅拌2小时。往反应混合物中加入碘甲烷(3ml),然后搅拌12小时。将反应混合物倒入水中,用乙酸乙酯萃取三次。有机层用饱和食盐水洗涤,然后减压浓缩。残留物用硅胶柱色谱(正己烷∶乙酸乙酯=2∶1)精制,得到具有下列物性数椐的标题化合物(140mg)。
TLC:Rf 0.25(正己烷∶乙酸乙酯=2∶1).
参考例25
2-甲基吲哚-4-乙酸苄酯
在氩气氛围下往参考例5制备的化合物(55.0g)的N,N-二甲基甲酰胺(500ml)溶液中加入碳酸钾(109g),同时激烈搅拌。往反应混合物中加入苄基溴(34.6ml),然后在室温下搅拌2小时。将反应液倒入水(2000ml)中,用甲苯萃取。有机层依次用碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸镁干燥,然后过滤。将滤液减压浓缩。残留物用硅胶柱色谱(正己烷∶乙酸乙酯=5∶1)精制,得到具有下列物性数椐的标题化合物(70.3g)。
TLC:Rf 0.85(正己烷∶乙酸乙酯=1∶1).
参考例26
1-(4-乙酰氧基苯甲酰基)-2-甲基吲哚-4-乙酸苄酯
在氩气氛围下将4-乙酰氧基苯甲酸(516mg)和草酰氯(0.5ml)的混合物搅拌30分钟。混合物减压浓缩后得到4-乙酰氧基苯甲酰氯。
在室温下,在搅拌下往参考例25制备的化合物(400mg)的二氯甲烷(7ml)溶液中加入氢氧化钠(286mg)和氯化四丁胺(20mg)。往混合物中加入上述制备的4-乙酰氧基苯甲酰氯的二氯甲烷(3ml)溶液,然后在室温下搅拌过液。将反应混合物过滤,滤液浓缩,残留物用硅胶柱色谱(正己烷∶乙酸乙酯=7∶3)精制,得到具有下列物性数椐的标题化合物(500mg)。
TLC:Rf 0.34(正己烷∶乙酸乙酯=7∶3);
NMR(CDCl3):δ7.76(d,J=8.7Hz,2H),7.40-7.20(m,7H),7.08-6.92(m,3H),6.47(s,1H),5.15(s,2H),3.88(s,2H),2.40(s,3H),2.35(s,3H).
参考例27
1-(4-羟基苯甲酰基)-2-甲基吲哚-4-乙酸苄酯
将参考例26制备的化合物(500mg)溶解在5%哌啶/二氯甲烷溶液(5ml)中,然后将该混合物搅拌1小时。将反应混合物浓缩,残留物用硅胶柱色谱(氯仿∶甲醇=19∶1)精制,得到具有下列物性数椐的标题化合物(450mg)。
TLC:Rf 0.61(氯仿∶甲醇=9∶1);
NMR(CDCl3):δ7.72(m,2H),7.44-7.26(m,5H),7.08-6.84(m,5H),6.45(s,1H),5.83(brs,1H),5.15(s,2H),3.88(s,2H),2.42(s,3H).
参考例28
1-(4-(6-甲氧基-4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸苄酯
在氩气氛围下往参考例24制备的化合物(60mg)的二氯甲烷(10ml)溶液中依次加入三苯膦(76mg)、参考例27制备的化合物(95mg)和偶氮二甲酸二乙酯(126mg),搅拌3小时。将混合物倒入水中,用乙酸乙酯萃取三次。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,然后减压浓缩。残留物用硅胶柱色谱(正己烷∶乙酸乙酯=4∶1)精制,得到具有下列物性数椐的标题化合物(85mg)。
TLC:Rf 0.57(正己烷∶乙酸乙酯=1∶1);
NMR(CDCl3):7.71(d,J=9.0Hz,2H),7.32(m,5H),7.08-6.90(m,5H),6.75(d,J=8.4Hz,1H),6.46(s,1H),6.28(d,J=2.7Hz,1H),6.23(dd,J=8.7,2.7Hz,1H),5.15(s,2H),4.60(m,1H),4.27(dd,J=9.9,6.6Hz,1H),4.18(dd,J=9.9,6.3Hz,1H),3.88(s,2H),3.76(s,3H),3.39(dd,J=11.7,2.7Hz,1H),3.27(dd,J=11.7,6.6Hz,1H),2.90(s,3H),2.42(s,3H).
实施例8(与实施例7(224)相同的化合物)
1-(4-(6-甲氧基-4-甲基-3,4-二氢-2H-1,4-苯并噁嗪-2-基甲氧基)苯甲酰基)-2-甲基吲哚-4-乙酸
在氩气氛围下将上述实施例制备的化合物(50mg)、乙酸乙酯(5ml)和氢氧化钯(100mg)混合。在氢气氛围下将混合物搅拌2小时。将反应混合物过滤,滤液减压浓缩。残留物用硅胶柱色谱(氯仿∶甲醇=10∶1)精制,得到具有下列物性数椐的本发明化合物。
TLC:Rf 0.40(氯仿∶甲醇=10∶1);
MS(APCI,正):501(M+H)+;
NMR(CDCl3):δ7.72(d,J=8.7Hz,2H),7.08-6.90(m,5H),6.75(d,J=8.7Hz,1H),6.49(s,1H),6.29(d,J=2.7Hz,1H),6.23(dd,J=8.7,2.7Hz,1H),4.61(m,1H),4.30(dd,J=9.9,4.8Hz,1H),4.18(m,1H),3.87(s,2H),3.76(s,3H),3.40(dd,J=11.4,9.0Hz,1H),3.28(dd,J=11.4,6.6Hz,1H),2.91(s,3H),2.44(s,3H).
除实施例7(224)的化合物以外,按参考例28→实施例8所示方法,用相应的化合物可以制备实施例1至实施例1(75)、实施例7至实施例7(223)、(225)和(228)的化合物。
通过用保护基保护羟基或氨基,然后在相当于实施例9的反应之前除去该保护基,可以制备实施例1(8)、1(51)、1(67)、1(68)、(69)、实施例7(37)和7(151)的化合物。
制剂例1
将下列各成分按常规方法混合,然后压片,得到每片含5mg活性成分的片剂100片。
1-(4-(2-丙氧基乙氧基)苯甲酰基)-2-甲基吲哚-4-乙酸……500mg
羧甲基纤维素钙 ……200mg
硬酯酸镁 ……100mg
微晶纤维素 ……9.2g
Claims (8)
1.通式(I)代表的吲哚衍生物或其无毒盐:
式中:
R1代表羟基、C1-6烷氧基或式NR8R9,其中R8和R9各自独立地代表氢原子、C1-6烷基或SO2R13,其中R13代表C1-6烷基、C3-15饱和或不饱和碳环或含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;
R2代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、氨基、三卤甲基、氰基、羟基、苄基或4-甲氧基苄基;
R3代表氢原子、C1-6烷基、C1-6烷氧基、卤原子、三卤甲基、氰基或羟基;
R4和R5各自独立地代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、硝基、氨基、三卤甲基、氰基或羟基;
D代表单键、C1-6亚烷基、C2-6亚链烯基或C1-6氧亚烷基;
在-G-R6中:
G代表单键、可被1-2个氧原子和/或硫原子取代的C1-6亚烷基或可被1-2个氧原子和/或硫原子取代的C2-6亚链烯基(其中该亚烷基和亚链烯基可被羟基或C1-4烷氧基取代)、-C(O)NH-、-NHC(O)-、-SO2NH-、-NHSO2-或重氮基;
R6代表C3-15饱和或不饱和碳环,其中该环可被1-5个选自下列的取代基取代:C1-6烷基、C1-10烷氧基、C2-6烷氧基烷基、卤原子、羟基、三卤甲基、硝基、氨基、苯基、苯氧基、氧代、C2-6酰基、C1-6烷磺酰基和氰基;
n代表1-3;
m代表1-3;
i代表1-4;和
2.通式(I)代表的吲哚衍生物或其无毒盐:
式中:
R1代表羟基、C1-6烷氧基或式NR8R9,其中R8和R9各自独立地代表氢原子、C1-6烷基或SO2R13,其中R13代表C1-6烷基、C3-15饱和或不饱和碳环或含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;
R2代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、氨基、三卤甲基、氰基、羟基、苄基或4-甲氧基苄基;
R3代表氢原子、C1-6烷基、C1-6烷氧基、卤原子、三卤甲基、氰基或羟基;
R4和R5各自独立地代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、硝基、氨基、三卤甲基、氰基或羟基;
D代表单键、C1-6亚烷基、C2-6亚链烯基或C1-6氧亚烷基;
在-G-R6中:
G代表单键、可被1-2个氧原子和/或硫原子取代的C1-6亚烷基或可被1-2个氧原子和/或硫原子取代的C2-6亚链烯基(其中该亚烷基和亚链烯基可被羟基或C1-4烷氧基取代)、-C(O)NH-、-NHC(O)-、-SO2NH-、-NHSO2-或重氮基;
R6代表含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;其中该环可被1-5个选自下列的取代基取代:C1-6烷基、C1-10烷氧基、C2-6烷氧基烷基、卤原子、羟基、三卤甲基、硝基、氨基、苯基、苯氧基、氧代、C2-6酰基、C1-6烷磺酰基和氰基;
n代表1-3;
m代表1-3;
i代表1-4;和
3.通式(I)代表的吲哚衍生物或其无毒盐:
式中:
R1代表羟基、C1-6烷氧基或式NR8R9,其中R8和R9各自独立地代表氢原子、C1-6烷基或SO2R13,其中R13代表C1-6烷基、C3-15饱和或不饱和碳环或含1-5个氮原子、硫原子和/或氧原子的4-15元杂环;
R2代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、氨基、三卤甲基、氰基、羟基、苄基或4-甲氧基苄基;
R3代表氢原子、C1-6烷基、C1-6烷氧基、卤原子、三卤甲基、氰基或羟基;
R4和R5各自独立地代表氢原子、C1-6烷基、C1-6烷氧基、C2-6烷氧基烷基、卤原子、硝基、氨基、三卤甲基、氰基或羟基;
D代表C1-6亚烷基、C2-6亚链烯基或C1-6氧亚烷基;
在-G-R6中:
G和R6合在一起代表
(i)可被1-5个氧原子和/或硫原子取代的C1-15烷基;
(ii)可被1-5个氧原子和/或硫原子取代的C2-15链烯基;或
(iii)可被1-5个氧原子和/或硫原子取代的C2-15链炔基,
其中该烷基、链烯基和链炔基可被1-12个选自C1-6烷氧基、卤原子、羟基、氰基、氧代、和NR11R12这一组中的取代基取代,其中R11和R12各自独立地代表氢原子、C1-6烷基、C2-6链烯基、苯基、苯甲酰基、萘基、被C1-6烷基取代的苯基或被苯基或氰基取代的C1-6烷基;
n代表1-3;
m代表1-3;
i状表1-4:和
代表单键或双键。
7.一种DP受体拮抗剂,其中包含权利要求1记载的通式(I)代表的吲哚衍生物或其无毒盐作为活性成分。
8.2-甲基吲哚-4-乙酸。
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7135495B2 (en) * | 2000-03-09 | 2006-11-14 | Ono Pharmaceutical Co., Ltd. | Indole derivatives |
HUP0400606A2 (hu) * | 2001-03-01 | 2004-12-28 | Ono Pharmaceutical Co., Ltd. | 2-Metil-indol-4-ecetsav és intermedierei és eljárás előállításukra |
CA2459515A1 (en) * | 2001-09-07 | 2003-03-20 | Kazuhiko Torisu | Indole derivatives |
JP4292402B2 (ja) * | 2001-09-07 | 2009-07-08 | 小野薬品工業株式会社 | インドール誘導体化合物、それらの製造方法およびそれらを有効成分として含有する薬剤 |
ES2319886T3 (es) * | 2002-02-20 | 2009-05-14 | Abbott Laboratories | Compuestos azabiciclicos condensados que inhiben el sutipo 1 del receptor valinoide (vr1). |
ATE516277T1 (de) | 2002-03-19 | 2011-07-15 | Ono Pharmaceutical Co | Carbonsäureverbindungen und arzneimittel, die diese verbindungen als wirkstoffe enthalten |
AU2003231509A1 (en) | 2002-05-16 | 2003-12-02 | Shionogi And Co., Ltd. | Compound exhibiting pgd 2 receptor antagonism |
JP2004010601A (ja) * | 2002-06-11 | 2004-01-15 | Nippon Steel Chem Co Ltd | インドール誘導体の製造方法及びそのための有用な中間体 |
CA2496246A1 (en) * | 2002-08-23 | 2004-03-04 | Chiron Corporation | Pyrrole based inhibitors of glycogen synthase kinase 3 |
WO2004030674A1 (ja) * | 2002-09-30 | 2004-04-15 | Shionogi & Co., Ltd. | プロスタグランジンd2、プロスタグランジンd2アゴニストおよびプロスタグランジンd2アンタゴニストの新規用途 |
GB0224557D0 (en) | 2002-10-22 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
US6933311B2 (en) * | 2003-02-11 | 2005-08-23 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
JPWO2004078719A1 (ja) * | 2003-03-06 | 2006-06-08 | 小野薬品工業株式会社 | インドール誘導体化合物およびその化合物を有効成分とする薬剤 |
AR041089A1 (es) | 2003-05-15 | 2005-05-04 | Merck & Co Inc | Procedimiento y composiciones farmaceutiicas para tratar aterosclerosis, dislipidemias y afecciones relacionadas |
PT1666473E (pt) | 2003-09-17 | 2013-02-15 | Ono Pharmaceutical Co | Compostos ácido carboxílico e composições medicinais que os contêm como ingrediente activo |
US7268159B2 (en) * | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
PE20050483A1 (es) | 2003-10-31 | 2005-08-25 | Arena Pharm Inc | Derivados de tetrazol de formula (i), sus composiciones farmaceuticas y procesos para producir composiciones farmaceuticas |
US20070244107A1 (en) * | 2004-08-25 | 2007-10-18 | Waters M Gerard | Method of Treating Atherosclerosis, Dyslipidemias and Related Conditions |
CA2586156A1 (en) * | 2004-11-04 | 2006-05-18 | Merck & Co., Inc. | Niacin receptor agonists, compositions containing such compounds and methods of treatment |
AU2005309737A1 (en) * | 2004-11-23 | 2006-06-01 | Merck Sharp & Dohme Corp. | Niacin receptor agonists, compositions containing such compounds and methods of treatment |
PE20060949A1 (es) | 2004-12-23 | 2006-10-11 | Arena Pharm Inc | Derivados fusionados de pirazol como agonistas del receptor de niacina |
WO2006068162A1 (ja) * | 2004-12-24 | 2006-06-29 | Shionogi & Co., Ltd. | 慢性閉塞性肺疾患の治療剤 |
WO2006089309A2 (en) * | 2005-02-17 | 2006-08-24 | Merck & Co., Inc. | Method of treating atherosclerosis, dyslipidemias and related conditions |
AU2006287528A1 (en) * | 2005-09-07 | 2007-03-15 | Plexxikon, Inc. | 1 , 4 and 1 , 5-disubstituted indole derivatives for use as PPAR active compounds |
US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
US8399666B2 (en) | 2005-11-04 | 2013-03-19 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
GB2431927B (en) | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
PL3327016T3 (pl) * | 2006-04-07 | 2021-10-04 | Vertex Pharmaceuticals Incorporated | Wytwarzanie modulatorów transporterów posiadających kasetę wiążącą ATP |
DK2037967T3 (en) | 2006-06-16 | 2017-03-13 | Univ Pennsylvania | PROSTAGLANDIN-D2 RECEPTOR ANTAGONISTS FOR TREATMENT OF ANDROGENETIC ALOPECI |
JPWO2008001959A1 (ja) * | 2006-06-28 | 2009-12-03 | 株式会社三和化学研究所 | 新規6−5系二環式複素環誘導体及びその医薬用途 |
TW200824687A (en) * | 2006-08-25 | 2008-06-16 | Abbott Lab | Compounds that inhibit TRPV1 and uses thereof |
CA2679175C (en) | 2007-02-26 | 2015-01-13 | Merck Frosst Canada Ltd. | Indole and indoline cyclopropyl amide derivatives as ep4 receptor antagonists |
TWI410410B (zh) | 2007-08-10 | 2013-10-01 | Ono Pharmaceutical Co | Phenylacetic acid compounds |
KR20160129109A (ko) | 2008-05-23 | 2016-11-08 | 아미라 파마슈티칼스 인코포레이티드 | 5-리폭시게나아제 활성화 단백질 억제제 |
WO2010030360A1 (en) | 2008-09-11 | 2010-03-18 | Arena Pharmaceuticals, Inc. | 3H-IMIDAZO[4,5-b]PYRIDIN-5-OL DERIVATIVES USEFUL IN THE TREATMENT OF GPR81 RECEPTOR DISORDERS |
WO2010070021A1 (en) * | 2008-12-18 | 2010-06-24 | Glaxo Group Limited | Novel compounds |
US8367660B2 (en) * | 2008-12-30 | 2013-02-05 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
CN109081804B (zh) * | 2010-03-25 | 2021-12-10 | 弗特克斯药品有限公司 | 环丙烷甲酰胺的固体形式 |
US9198898B2 (en) | 2013-06-24 | 2015-12-01 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
US8906951B1 (en) | 2013-06-24 | 2014-12-09 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
CN107922396B (zh) * | 2015-07-20 | 2022-08-05 | 建新公司 | 集落刺激因子-1受体(csf-1r)抑制剂 |
EP4267573A1 (en) | 2020-12-23 | 2023-11-01 | Genzyme Corporation | Deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT290523B (de) * | 1962-01-05 | 1971-06-11 | Merck & Co Inc | Verfahren zur Herstellung neuer α-(3-Indolyl)-carbonsäuren |
GB8704158D0 (en) | 1987-02-23 | 1987-04-01 | Wellcome Found | Substituted hydantoin compounds |
GB9011589D0 (en) * | 1990-05-24 | 1990-07-11 | Wellcome Found | Amino bicyclic compounds |
JPH0764841B2 (ja) * | 1990-10-03 | 1995-07-12 | ファイザー製薬株式会社 | インドール誘導体およびその用途 |
EP0837052B1 (en) | 1995-06-21 | 2006-08-23 | Shionogi & Co., Ltd. | Bicyclic amino derivatives and pgd 2 antagonist containing the same |
JPH09176162A (ja) | 1995-12-22 | 1997-07-08 | Toubishi Yakuhin Kogyo Kk | チアゾリジンジオン誘導体及びその製造法並びにそれを含む医薬組成物 |
DE19641681A1 (de) | 1996-10-10 | 1998-07-23 | Peter Dr Bracher | Verfahren zur Abwasserreinigung in Kleinkläranlagen |
AU5409698A (en) | 1996-12-12 | 1998-07-03 | Shionogi & Co., Ltd. | Fused heterocyclic benzenecarboxylic acid amide derivatives and pgd2 antagonists containing the same |
ID22753A (id) | 1996-12-13 | 1999-12-09 | Shionogi & Co | Turunan-turunan benzotiofenkarboksamida dan antagonis pgd2 yang mengandung turunan benzotiofenkarboksamida tersebut |
-
2001
- 2001-03-08 RU RU2002123882/04A patent/RU2259998C2/ru not_active IP Right Cessation
- 2001-03-08 CN CNB018088422A patent/CN1179945C/zh not_active Expired - Fee Related
- 2001-03-08 US US10/220,806 patent/US6743793B2/en not_active Expired - Fee Related
- 2001-03-08 CA CA002402174A patent/CA2402174A1/en not_active Abandoned
- 2001-03-08 AU AU2001241068A patent/AU2001241068A1/en not_active Abandoned
- 2001-03-08 BR BR0109050-0A patent/BR0109050A/pt not_active IP Right Cessation
- 2001-03-08 EP EP01912193A patent/EP1262475A4/en not_active Withdrawn
- 2001-03-08 NZ NZ521192A patent/NZ521192A/en unknown
- 2001-03-08 MX MXPA02008801A patent/MXPA02008801A/es not_active Application Discontinuation
- 2001-03-08 HU HU0301493A patent/HUP0301493A2/hu unknown
- 2001-03-08 JP JP2001565338A patent/JP4292742B2/ja not_active Expired - Fee Related
- 2001-03-08 WO PCT/JP2001/001817 patent/WO2001066520A1/ja not_active Application Discontinuation
- 2001-03-08 KR KR1020027011769A patent/KR20030010589A/ko not_active Application Discontinuation
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2002
- 2002-09-06 NO NO20024281A patent/NO20024281L/no not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
RU2259998C2 (ru) | 2005-09-10 |
KR20030010589A (ko) | 2003-02-05 |
NO20024281L (no) | 2002-11-08 |
MXPA02008801A (es) | 2003-07-07 |
US20030176400A1 (en) | 2003-09-18 |
BR0109050A (pt) | 2004-04-27 |
NZ521192A (en) | 2005-01-28 |
US7098234B2 (en) | 2006-08-29 |
RU2002123882A (ru) | 2004-03-20 |
CA2402174A1 (en) | 2001-09-13 |
US6743793B2 (en) | 2004-06-01 |
JP4292742B2 (ja) | 2009-07-08 |
EP1262475A4 (en) | 2005-01-05 |
CN1427824A (zh) | 2003-07-02 |
WO2001066520A1 (fr) | 2001-09-13 |
AU2001241068A1 (en) | 2001-09-17 |
NO20024281D0 (no) | 2002-09-06 |
EP1262475A1 (en) | 2002-12-04 |
US20040180885A1 (en) | 2004-09-16 |
HUP0301493A2 (hu) | 2003-08-28 |
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