CN101878200A - 二氢吲哚化合物 - Google Patents
二氢吲哚化合物 Download PDFInfo
- Publication number
- CN101878200A CN101878200A CN200880118151XA CN200880118151A CN101878200A CN 101878200 A CN101878200 A CN 101878200A CN 200880118151X A CN200880118151X A CN 200880118151XA CN 200880118151 A CN200880118151 A CN 200880118151A CN 101878200 A CN101878200 A CN 101878200A
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- CN
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- Prior art keywords
- indoles
- dihydro
- ethyl
- ethanamide
- methoxyl group
- Prior art date
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Classifications
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- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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Abstract
本发明提供新的2,3-二氢-吲哚化合物,它们在治疗或预防褪黑激素能障碍中的应用及它的组合物。
Description
技术领域
本发明属于对褪黑激素受体有活性的化合物的领域,具体是指二氢吲哚类(2,3-二氢-1H-吲哚类),更具体是指酰化的6-(烷氧基或苯基烷氧基)-2,3-二氢-吲哚-1-基-烷基胺。
背景技术
失眠是最常见的睡眠障碍,困扰着20-40%的成年人,其频率随着年龄而增加。失眠有很多原因。其中之一是正常的觉醒-睡眠循环被间断。这种不同步性会产生病理变化。能够改正所述困扰的可能的治疗包括通过调节褪黑激素系统使觉醒-睡眠循环重新同步(Li-QiangSun,Bioorganic & Medicinal Chemistry Letters 2005,15,1345-49)。
褪黑激素是一种分离自松果腺的激素,负责亮-暗循环的信息,控制哺乳动物的生理节律并调节视网膜的生理学。褪黑激素的合成及其夜间分泌是由视交叉上核控制的,并由环境的光线同步化(OsamuUchikawa等人,J.Med.Chem.2002,45,4222-39;Pandi-Perumal等人,Nature Clinical Practice 2007,3(4),221-228)。
人体内褪黑激素的分泌是与夜间睡眠同时发生的,褪黑激素水平的升高与晚间对睡眠的需要增加相关。
在人体中,褪黑激素的临床应用范围包括治疗睡眠时相延迟综合征乃至时差综合征的治疗,包括用于夜班工人的治疗以及作为安眠药治疗。
根据药理学性质,褪黑激素受体分类为MT1、MT2和MT3。MT1受体位于下丘脑中枢神经系统,而MT2受体遍布整个中枢神经系统和视网膜。在末梢水平也已经描述了MT1和MT2受体的存在。MT1和MT2受体与大量的病理有关,其中最有代表性的是抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。近来,已经将MT3受体表征为醌还原酶-2(QR2)酶的同系物。MT1和MT2是G蛋白偶联受体(GPCR),通过激动剂使其兴奋可以导致腺嘌呤核苷酸环化酶活性降低,并由此导致细胞内cAMP减少。
专利US 4600723和US 4665086提出了褪黑激素在减小生理节律变化中的应用,其中所述变化是由于从白天到夜晚的工作转变或乘飞机快速通过几个时区(时差综合征)的转换而发生的。在专利文献EP848699B1,US 5276051,US 5308866,US 5708005,US 6034239(ramelteon),US 6143789,US 6310074,US 6583319,US 6737431,US 6908931,US 7235550,WO 8901472和WO 2005062992中描述了几族具有褪黑激素能活性的化合物。
专利US 5633276描述了治疗褪黑激素能系统变化的化合物,其属于下式:
其中取代基R1和R2以及变量n具有如其中所述的含义,优选的化合物是实施例7的那种(R1=H,R2=(CH2)2-NHCOCH3,n=2)。
雷美替胺,N-[2-[(8S)-1,6,7,8-四氢-2H-茚并[5,4-b]呋喃-8-基)乙基]丙酰胺,是第一种在治疗中引入的褪黑激素激动剂。它用于失眠,其作用机制是基于对MT1和MT2受体的激动作用。
在中枢和末梢水平下,雷美替胺是一种对MT1和MT2的非选择性化合物,而对其他受体具有选择性。其对MT1的Ki是0.014nM,对MT2则为0.045nM。它显示了良好的吸收,但是会发生严重的首过代谢效应。它经生物转化为四种代谢产物,其中之一为M-II,具有活性并且有重要的分布容积。雷美替胺清除率是88%。
对可以用于治疗失眠的新褪黑激素激动剂的研究满足了基本的健康需要,因此证明了需要继续研究性质改善的化合物。
因此,本发明的目的是新的酰化6-(烷氧基或苯基烷氧基)-2,3-二氢-吲哚-1-基-烷基胺,其对于褪黑激素受体,特别是对MT1和MT2受体具有活性。结果,本发明的化合物可以用于治疗和预防所有由MT1和MT2受体介导的疾病。褪黑激素能障碍的一些非限制性的例子是抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。
发明详述
本发明涉及通式I的二氢吲哚化合物:
其中:
R1是选自直链或支链(C1-C6)烷基、(C3-C6)环烷基和CF3的基团;
R2是氢或直链或支链(C1-C6)烷基;
R3是氢或直链或支链(C1-C6)烷基;
R4是选自氢、卤素原子、苯基和吡啶基的基团;
R5是选自直链或支链烷基(C1-C6)和(CH2)n-Ph的基团;和n是1-6的整数;及其药学可接受的盐和水合物。
药学可接受的盐是可以施用于患者,例如哺乳动物的那些盐(例如,对于给定的给药方案,具有哺乳动物可接受的安全性的盐)。这些盐可以由药学可接受的无机和有机碱,和药学可接受的无机和有机酸获得。由药学可接受的无机碱获得的盐包括铵、钙、铜、三价铁和亚铁盐,锂、镁、锰和亚锰盐,钾、钠、锌盐等等。特别优选的是铵、钙、镁、钾和钠盐。由药学可接受的有机碱获得的盐包括伯、仲和叔胺盐,包括取代的胺类、环胺类、天然胺类等等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N′-二苄基乙二胺、二乙胺、2-二乙胺乙醇、2-二甲胺乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、海巴胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤类、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。由药学可接受的酸获得的盐包括乙酸、抗坏血酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、edisylic、延胡索酸、龙胆酸、葡糖酸、葡糖醛酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、乳酸、乳糖醛酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸、烟酸、硝酸、乳清酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸、xinafoic等的盐。特别优选的是柠檬酸、氢溴酸、盐酸、羟乙磺酸、马来酸、萘-1,5-二磺酸、磷酸、硫酸和酒石酸的盐。
式I的具体化合物选自下组:
1)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
2)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-丙酰胺;
3)[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-环丙羧酰胺;
4)2,2,2-三氟-N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
5)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-丙基]-乙酰胺;
6)N-[2-(6-甲氧基-3-甲基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
7)N-[2-(5-溴-6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
8)N-[2-(6-甲氧基-5-吡啶-4-基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
9)N-[2-(6-甲氧基-5-苯基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
10)N-[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
11)[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-环丙羧酰胺;
12)N-[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-丙酰胺;
13)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺;
14)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-丁酰胺;
15)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-丙酰胺;
16){2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-环丙羧酰胺;
17)2,2,2-三氟-N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺;和
18)N-{2-[6-(4-苯基-丁氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺.
表1显示了各化合物取代基的含义:
表1
实施例 | R1 | R2 | R3 | R4 | R5 |
1 | Me | H | H | H | Me |
2 | Et | H | H | H | Me |
3 | cPr | H | H | H | Me |
4 | CF3 | H | H | H | Me |
5 | Me | Me | H | H | Me |
6 | Me | H | Me | H | Me |
7 | Me | H | H | Br | Me |
实施例 | R1 | R2 | R3 | R4 | R5 |
8 | Me | H | H | 4-吡啶基 | Me |
9 | Me | H | H | pH | Me |
10 | Me | H | H | H | Ph-(CH2)2 |
11 | cPr | H | H | H | Ph-(CH2)2 |
12 | Et | H | H | H | Ph-(CH2)2 |
13 | Me | H | H | H | Ph-(CH2)3 |
14 | Pr | H | H | H | Ph-(CH2)3 |
15 | Et | H | H | H | Ph-(CH2)3 |
16 | cPr | H | H | H | Ph-(CH2)3 |
17 | CF3 | H | H | H | Ph-(CH2)3 |
18 | Me | H | H | H | Ph-(CH2)4 |
本发明的另一个方面提供表1的具体化合物在制备治疗或预防褪黑激素能障碍的医药产品中的应用。所述褪黑激素能障碍选自抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。
本发明的另一个方面提供药物组合物,其包含表1的具体化合物和一种或多种药学可接受的赋形剂。
本发明的另一个方面提供所述药物组合物在制备治疗或预防褪黑激素能障碍的医药产品中的应用。所述褪黑激素能障碍选自抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。
在下图中描述了如何得到通式I的化合物,其中取代基R1、R2、R3、R4、R5和R6如上所述。
图1描述的合成策略,对应的是引入取代基R1,如所示R2=R3=R4=H和R5=Me。
首先,通过在四氢呋喃(THF)中使用硼烷,由市售的吲哚II得到二氢吲哚III。在碳酸钾的乙腈(ACN)液中,用Boc保护的2-溴乙胺将所述二氢吲哚烷基化。在得到受保护的化合物IV后,通过在二氯甲烷(DCM)中与三氟乙酸(TFA)反应,得到相应的中间体胺V。最后,最后一步包括胺V与酰基氯之间的普通偶合,得到化合物I。
使用取代的溴乙腈对于侧链中引入R2取代基是必要的。图2显示了相应的合成路径,如所示R3=R4=H和R5=Me。
与上图1的不同在于烷基化步骤。在本情况中,烷化剂是取代的溴乙腈。在R2是甲基的情况中,所述衍生物是市售的。在获得VI后,通过用氢化锂铝和铝还原,产生胺VII。所述胺如图1所述进行相同的偶合过程。
当R3不是氢时,必须进行图3所述的合成路径。该路径描述了当R2=R4=H和R3=R5=Me时的特定情况。
起始的吲哚VIII是市售的。对于不是甲基的R3基团,很可能相应的吲哚也是市售的。此外,可以用强碱例如氢化钠,与相应的卤化衍生物进行吲哚II的3位的选择性烷基化。
引入不是氢的R4取代基如图4所详述,如所示R1=R5=Me和R2=R3=H。
可以观察到,在二氢吲哚环的5位选择性溴化的化合物是通过起始二氢吲哚(R4氢)与吡啶过溴化物在二氯甲烷中反应来获得。所述溴化衍生物,通过使用相应的硼酸进行Suzuki反应,可以得到5位取代的二氢吲哚I。
最后,图5显示了制备在R5上O-取代的二氢吲哚的合成路径,如所示R2=R3=R4=H。
上图1-3所述的合成方法的唯一差异就在于第一步。我们必须从6-羟基吲哚XII开始,通过氧原子上的选择性Williamson烷基化,得到烷氧基吲哚XIII。在得到烷氧基吲哚XIII后,可以根据如上所述的化学得到二氢吲哚I,即,还原成二氢吲哚,N-烷基化以引入侧链,脱保护,然后与酰基氯偶合。
包含本发明的化合物的药物组合物包括适合口服、直肠和胃肠外给药(包括皮下、肌内和静脉途径)的那些,尽管最适当的途径取决于所要治疗的病理学性质和严重度。本发明的化合物的优选给药途径通常是口服途径。
根据常规的药物配制制剂技术,活性成分可以与一种或多种药物赋形剂混合。根据所要制备的药物形式,可以使用数种赋形剂。口服液体组合物(例如,混悬液、溶液、乳剂、气雾剂和漱口剂)可以使用例如,水、二醇类、油类、醇类、增甜剂、防腐剂、着色剂等。口服固体组合物可以使用,例如,淀粉类、糖类(例如,乳糖、蔗糖和山梨糖醇)、纤维素类(例如,羟丙基纤维素、羧甲基纤维素、乙基纤维素和微晶纤维素)、滑石、硬脂酸、硬脂酸镁、磷酸二钙、橡胶类、聚维酮、表面活性剂例如去水山梨糖醇单油酸酯和聚乙二醇、金属氧化物(例如,二氧化钛和氧化铁)及其他药物稀释剂例如水。这样,可以形成包含本发明的化合物的均匀预配制剂。
在预配制剂的情况下,组合物是均匀的,以使得活性成分均匀地分散在该组合物中,因此它可以分成相同的单位剂量例如片剂、包衣片剂、粉末剂和胶囊剂。
由于易于给药,片剂和胶囊剂是最有利的口服形式。如果需要,可以用水性或非水性常规技术将片剂包衣。可以使用很多种类的物质来形成包衣。这些物质包括大量的聚合酸和它们与其他组分例如虫胶、十六烷醇和乙酸纤维素的混合物。
其中可以掺入本发明的化合物用于口服或注射给药的液体形式包括水溶液、用液体或凝胶填充的胶囊、含增甜剂的糖浆、在油中的水性混悬液以及用食用油(例如棉籽油、芝麻油、椰子油或花生油)增甜的乳剂,以及漱口剂和类似的药物载体。制备水性混悬液的适当分散或悬浮剂包括合成和天然胶例如黄芪胶、阿拉伯胶、海藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙二醇、聚乙烯吡咯烷酮或明胶。
所使用的适当剂量范围为每日总剂量约0.1-500mg,更优选1mg-100mg,单次给药或者如果必要分剂量给药。
本发明的实施方案
通过下列实施例进一步解释本发明,但并非是用于限制其范围。
药理学评价的实施例1
对MT1受体的激动活性的测定
为筛选作用于MT1受体的化合物,所使用的细胞株特征在于,在细胞株中稳定地过度表达重组人MT1受体,然后共表达线粒体apoaequorin和Gα16亚单元。
Gα16亚单元属于G蛋白家族,由GPCR形成,其中通过磷酸酯酶(PLC)发生细胞内信号的传导。PLC激活使得肌醇-三磷酸水平升高,导致细胞内的钙增加。因此,Gα16过度表达使得细胞内钙水平升高,这是独立的并且与所研究受体的自我信号传导途径相容。
Apoaequorin是发光蛋白的非活化形式,是一种磷蛋白,需要疏水性辅基,即腔肠素来产生活化形式。在它与钙结合后,发光蛋白将腔肠素氧化成腔肠酰胺,这是一种释放CO2和光的反应。
筛选可能的激动剂的试验方案包括收集细胞,在腔肠素存在下将它们在混悬液中保持过夜以重建发光蛋白。第二天,将细胞注射到板上,在板上稀释要筛选的化合物,立即对所释放的发光读数。当要研究相同化合物可能的拮抗作用时,在首次注射后15-30分钟后向相同的孔中加入参照的激动剂化合物,并评价所释放的冷光。
激动活性计算为相对于在对应于EC100的浓度下参照激动剂的活性百分比。拮抗活性表示为对对应于EC80的浓度下参照激动剂活性的抑制百分比。
药理学评价实施例2
对MT2受体的激动活性的测定
为了研究对MT2受体的激动作用,我们使用重组细胞株,其表达这些受体并如MT1筛选所使用的模型,共表达线粒体apoaequorin和Gα16亚单元。本发明的化合物在该模型中显示出,它们对MT2受体也有激动作用。
表2显示了对MT1受体激动作用的结果,对比标准品N-[2-(2,3,7,8-四氢-1H-呋喃并[2,3-g]吲哚-1-基)-乙基]-乙酰胺(US 5633276,实施例7)。
表2
简言之,本发明提供的新化合物,尽管与现有技术状态的化合物有某种结构类似性,但是,令人意外地显示了对MT1受体更大的激动活性,这意味着它有优良的治疗性质。
参照实施例1
得到二氢吲哚III的一般方法
在0℃下,将3g(20mmol)的6-甲氧基吲哚II溶于30mL的1MTHF的硼烷溶液(30mmol)中。用氮气氛清洁,并在0℃下搅拌30分钟。加入30mL的TFA,并在0℃下搅拌30分钟。在搅拌结束后,加入6MNaOH直至达到碱性pH来完成该反应。用DCM萃取粗产物。得到呈淡黄色油状的2.90g(收率=100%)的二氢吲哚III。
HPLC-MS:纯度99.9%,M+1=150
参照实施例2
得到二氢吲哚IV的一般方法
将0.67g(4.99mmol)的二氢吲哚III溶于15mL的乙腈。加入2.01g(8.98mmol)的溴衍生物和1.86g(13.47mmol)的碳酸钾。将它在80℃下加热12小时。使其冷却并低压除去溶剂。加入50mL的水和50mL的DCM,萃取有机相。用无水硫酸镁干燥有机相并过滤。蒸发,得到呈淡黄色油状的629mg(收率=43%)的二氢吲哚IV。
HPLC-MS:纯度99.9%,M+1=293
参照实施例3
得到脱保护的二氢吲哚V的一般方法
将0.25g(0.85mmol)的二氢吲哚IV溶于5mL的DCM。加入0.69mL(8.5mmol)的TFA。将其在室温下搅拌2小时。低压除去溶剂。将由此得到的残渣悬浮在DCM中,并用碳酸钠的饱和溶液洗涤。用无水硫酸镁干燥有机相并过滤。蒸发,得到呈淡黄色油状的160mg(收率=100%)的胺V。
HPLC-MS:纯度99.9%,M+1=193
参照实施例4
得到二氢吲哚I的一般方法
将160mg的胺V(0.85mmol)溶于20mL的无水DCM。缓慢加入0.339mL的三乙胺(TEA)(2.436mmol),然后同样缓慢加入0.93mmol的相应的酰基氯。在室温下搅拌2小时30分钟。加入5mL的1N HCl,并搅拌10分钟。分离有机相并干燥。蒸发至干燥,得到相应的酰胺I。
R1=CF3的实施例:得到220mg(收率=90%)
HPLC-MS:纯度94%,M+1=289
由此得到的化合物在下表3中详述。
表3
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
1 | Me | H | H | H | Me | 96 | 235 |
2 | Et | H | H | H | Me | 92 | 249 |
3 | cPr | H | H | H | Me | 100 | 261 |
4 | CF3 | H | H | H | Me | 94 | 289 |
参照实施例5
得到二氢吲哚VI的一般方法
将0.51g(3.4mmol)的二氢吲哚III溶于10mL的乙腈。加入0.59mL(16.8mmol)的溴衍生物和1.41g(10mmol)的碳酸钾。将其在80℃下加热12小时。使其冷却,低压除去溶剂。加入50mL的水和50mL的DCM,并萃取有机相。用无水硫酸镁干燥有机相并过滤。通过柱色谱精制由此得到的残渣,使用己烷/乙酸乙酯作为洗脱液。得到呈淡黄色油状的0.27mg(收率=39%)的二氢吲哚VI。
HPLC-MS:纯度99.9%,M+1=203
参照实施例6
得到二氢吲哚VII的一般方法
在氮气氛和冰浴中,将76mg(2mmol)的氢化锂铝溶于5mL的无水THF中。将0.27g(1.33mmol)的二氢吲哚VI的溶液滴加至5mL的THF中。将其在0℃下搅拌1小时,移去冰浴,在室温下再搅拌1小时。加入水和1N NaOH,直至达到碱性pH。在Celite上过滤所形成的氧化铝。用DCM萃取滤液。用无水硫酸镁干燥有机相并过滤。得到呈淡黄色油状的0.21mg(收率=78%)的二氢吲哚。
HPLC-MS:纯度99.9%,M+1=207
合成的最后一步对应的是如上所述的与酰基氯偶合。因此,我们得到了该亚族的化合物的实施例,对应的是其中R2是甲基的具体情况。详情如表4所示。
表4
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
5 | Me | Me | H | H | Me | 94 | 249 |
当R3不是氢时,方法是一样的(表5)。
表5
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
6 | Me | H | Me | H | Me | 95 | 249 |
参照实施例7
得到溴化二氢吲哚I的一般方法
将70mg(0.30mmol)的起始化合物I溶于10mL的DCM,加入96mg(0.30mmol)的全溴代吡啶。将其在室温下搅拌1小时。蒸发反应粗品,并通过快速色谱法精制,使用DCM/MeOH作为洗脱液。得到80mg(收率=85%)的黄色油状物,经鉴定为I(R5=Br)。
HPLC-MS:纯度96%,M+1=314
参照实施例8
得到化合物I的一般方法
将0.15g(0.48mmol)的溴化酰胺I溶于20mL的二甲氧基乙烷,用惰性氩气清洁。加入一药铲尖的钯-二氯-二(三苯基膦),并加入在1mL水中的0.86mmol的相应硼酸和0.86mmol碳酸钠的0.43mL溶液。在75℃下搅拌3小时。使其冷却并加入100mL的水。用50mL的DCM萃取。干燥,过滤并蒸发有机相。通过反相制备色谱精制由此得到的残渣,使用乙腈/水作为洗脱液。由此得到淡黄色油状形式的I型产物。
由此得到的化合物在下表6中详述。
表6
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
7 | Me | H | H | Br | Me | 96 | 314 |
8 | Me | H | H | 4-吡啶基 | Me | 92 | 312 |
9 | Me | H | H | pH | Me | 100 | 311 |
参照实施例9
得到O-烷基化的二氢吲哚XIII的一般方法
将6-羟基吲哚XII(2.85g,21mmol)溶于50mL的DMF。加入7.67g(23mmol)的碳酸铯和23mmol的相应卤化衍生物。将其在80℃下加热2小时。使其冷却并过滤反应粗品。低压蒸发至干燥再溶于DCM中。用1N NaOH洗涤。分离有机相,过滤并蒸发。由此得到固体形式的XIII衍生物。
当R6=PhCH2CH2CH2时的实施例:得到3.10g(收率:59%)。
HPLC-MS:纯度99.9%,M+1=251
由此点开始,根据图1所述的反应制备XIII型化合物。
由此得到的化合物在下表7中详述。
表7
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
10 | Me | H | H | H | Ph-(CH2)2 | 325 | 93 |
11 | cPr | H | H | H | Ph-(CH2)2 | 351 | 100 |
12 | Et | H | H | H | Ph-(CH2)2 | 339 | 100 |
13 | Me | H | H | H | Ph-(CH2)3 | 339 | 95 |
实施例 | R1 | R2 | R3 | R4 | R5 | LCMS纯度(%) | M+1 |
14 | Pr | H | H | H | Ph-(CH2)3 | 368 | 91 |
15 | Et | H | H | H | Ph-(CH2)3 | 353 | 92 |
16 | cPr | H | H | H | Ph-(CH2)3 | 365 | 91 |
17 | CF3 | H | H | H | Ph-(CH2)3 | 393 | 98 |
18 | Me | H | H | H | Ph-(CH2)4 | 353 | 98 |
Claims (7)
1.二氢吲哚化合物,其选自下组:
1)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
2)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-丙酰胺;
3)[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-环丙羧酰胺;
4)2,2,2-三氟-N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
5)N-[2-(6-甲氧基-2,3-二氢-吲哚-1-基)-丙基]-乙酰胺;
6)N-[2-(6-甲氧基-3-甲基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
7)N-[2-(5-溴-6-甲氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
8)N-[2-(6-甲氧基-5-吡啶-4-基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
9)N-[2-(6-甲氧基-5-苯基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
10)N-[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-乙酰胺;
11)[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-环丙羧酰胺;
12)N-[2-(6-苯乙氧基-2,3-二氢-吲哚-1-基)-乙基]-丙酰胺;
13)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺;
14)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-丁酰胺;
15)N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-丙酰胺;
16){2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-环丙羧酰胺;
17)2,2,2-三氟-N-{2-[6-(3-苯基-丙氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺;和
18)N-{2-[6-(4-苯基-丁氧基)-2,3-二氢-吲哚-1-基]-乙基}-乙酰胺;
及其药学可接受的盐和水合物。
2.权利要求1的化合物在制备治疗或预防褪黑激素能障碍的医药产品中的应用。
3.权利要求2的应用,其中所述褪黑激素能障碍选自抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。
4.药物组合物,其包含权利要求1的化合物和一种或多种药学可接受的赋形剂。
5.权利要求4的药物组合物在制备治疗或预防褪黑激素能障碍的医药产品中的应用。
6.权利要求5的应用,其中所述褪黑激素能障碍选自抑郁、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病理、消化系统病理、由时差综合征导致的失眠或疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲障碍、肥胖、失眠、精神病、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性衰老有关的障碍、偏头痛、记忆丧失、阿尔茨海默病和脑循环障碍。
7.一种治疗或预防褪黑激素能障碍的方法,该方法包括给患者施用有效量的一种或多种权利要求1的化合物。
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CN109071435A (zh) * | 2016-01-21 | 2018-12-21 | 耶路撒冷希伯来大学伊森姆研究发展公司 | 吲哚啉衍生物、包含它们的组合物及其用途 |
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CN102942516B (zh) * | 2012-11-05 | 2015-02-25 | 宁波大学 | 一种生物碱类化合物及其制备方法和应用 |
CN103044310B (zh) * | 2013-01-18 | 2015-02-04 | 贵阳医学院 | 二氢吲哚-3-乙酸衍生物、其制备方法以及在药物中的应用 |
AR121842A1 (es) * | 2020-04-15 | 2022-07-13 | Ache Laboratorios Farmaceuticos Sa | Compuesto de benzimidazol para el tratamiento de trastornos metabólicos |
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FR2680366B1 (fr) * | 1991-08-13 | 1995-01-20 | Adir | Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
GB9326192D0 (en) | 1993-12-22 | 1994-02-23 | Glaxo Group Ltd | Chemical compounds |
CA2186412A1 (en) * | 1995-10-31 | 1997-05-01 | Katherine S. Takaki | Ethylamino carbazole melatonergic agents |
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2007
- 2007-10-25 ES ES200702798A patent/ES2331274B1/es not_active Withdrawn - After Issue
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2008
- 2008-10-23 BR BRPI0818850A patent/BRPI0818850A2/pt not_active IP Right Cessation
- 2008-10-23 KR KR1020107008669A patent/KR20100075518A/ko not_active Application Discontinuation
- 2008-10-23 AR ARP080104617A patent/AR069003A1/es not_active Application Discontinuation
- 2008-10-23 CA CA2703453A patent/CA2703453A1/en not_active Abandoned
- 2008-10-23 EP EP08842562A patent/EP2203423A1/en not_active Withdrawn
- 2008-10-23 JP JP2010530462A patent/JP2011500763A/ja not_active Abandoned
- 2008-10-23 CN CN200880118151XA patent/CN101878200A/zh active Pending
- 2008-10-23 RU RU2010120847/04A patent/RU2010120847A/ru not_active Application Discontinuation
- 2008-10-23 US US12/739,666 patent/US20110112148A1/en not_active Abandoned
- 2008-10-23 WO PCT/EP2008/064389 patent/WO2009053440A1/en active Application Filing
- 2008-10-23 MX MX2010004463A patent/MX2010004463A/es active IP Right Grant
- 2008-10-23 AU AU2008316472A patent/AU2008316472A1/en not_active Abandoned
- 2008-10-24 TW TW097140812A patent/TW200934760A/zh unknown
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Cited By (1)
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CN109071435A (zh) * | 2016-01-21 | 2018-12-21 | 耶路撒冷希伯来大学伊森姆研究发展公司 | 吲哚啉衍生物、包含它们的组合物及其用途 |
Also Published As
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AR069003A1 (es) | 2009-12-23 |
TW200934760A (en) | 2009-08-16 |
CL2008003139A1 (es) | 2009-03-06 |
WO2009053440A1 (en) | 2009-04-30 |
RU2010120847A (ru) | 2011-11-27 |
KR20100075518A (ko) | 2010-07-02 |
EP2203423A1 (en) | 2010-07-07 |
MX2010004463A (es) | 2010-05-03 |
BRPI0818850A2 (pt) | 2019-09-24 |
JP2011500763A (ja) | 2011-01-06 |
ES2331274B1 (es) | 2010-10-21 |
ES2331274A1 (es) | 2009-12-28 |
AU2008316472A1 (en) | 2009-04-30 |
UY31423A1 (es) | 2009-04-30 |
US20110112148A1 (en) | 2011-05-12 |
CA2703453A1 (en) | 2009-04-30 |
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