CN101878198A - 苯基吡咯烷化合物 - Google Patents
苯基吡咯烷化合物 Download PDFInfo
- Publication number
- CN101878198A CN101878198A CN2008801131031A CN200880113103A CN101878198A CN 101878198 A CN101878198 A CN 101878198A CN 2008801131031 A CN2008801131031 A CN 2008801131031A CN 200880113103 A CN200880113103 A CN 200880113103A CN 101878198 A CN101878198 A CN 101878198A
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- Prior art keywords
- tetramethyleneimine
- phenyl
- methoxyl group
- disease
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- 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
-
- A—HUMAN NECESSITIES
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Abstract
本发明提供新的苯基吡咯烷通式化合物(I),它们治疗或预防褪黑激素能障碍的用途,以及其药物组合物。
Description
技术领域
本发明属于具有褪黑激素受体活性的化合物领域,尤其是苯基吡咯烷,更具体地说,是酰化的1-(3-烷氧基-苯基-吡咯烷-3-基-胺。
背景技术
失眠是最常见的睡眠障碍,并且影响到20-40%的成年人,发病频率随着年龄的增长而增加。失眠有多种原因。其中之一是正常清醒-睡眠周期的中断。这种不同步可能导致病变。一种潜在的治疗手段是矫正所述的影响,包括通过调节褪黑激素能系统来重新同步清醒-睡眠周期(Li-Qiang Sun,Bioorganic &Medicinal Chemistry Letters 2005,15,1345-49)。
褪黑激素是一种由松果腺分泌的激素,负责光暗周期信息、控制哺乳动物的昼夜节律、以及视网膜生理调节。褪黑激素的合成和它的夜间分泌通过视交叉上核控制,与环境光线同步(Osamu Uchikawa et al.,J.Med.Chem.2002,45,4222-39;Pandi-Perumal et al.,Nature Clinical Practice 2007,3(4),221-228)。
人体内褪黑激素的分泌与夜间睡眠同时发生,并且褪黑激素水平的增加与夜间睡眠需求的增加相关。
在人类中,褪黑激素的临床应用范围从治疗延迟睡眠相位综合症到时差治疗,包括对夜班工人的治疗和催眠治疗。
基于药理特征,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受体分布于整个中枢神经系统和视网膜。MT1和MT2受体的存在在末梢水平已有描述。MT1和MT2受体与大量病症有关,其中最具代表性的是抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。最近认为MT3受体的特点是与醌还原酶-2(QR2)同源。MT1和MT2是G蛋白偶联受体(GPCR),其通过激动剂兴奋,导致腺苷酸环化酶活性降低和相应的细胞内cAMP的降低。
专利US4600723和US4665086主张使用褪黑激素以最小化由于从白天到夜间轮班的改变、或由于在飞机上快速通过几个时区(时差)而发生的昼夜节律变化。在专利文献EP848699B1、US5276051、US5308866、US5633276、US5708005、US6034239(雷美替胺)、US6143789、US6310074、US6583319、US6737431、US6908931、US7235550、WO8901472和WO2005062992中描述了几类具有褪黑激素能活性的化合物。
专利申请WO9608466描述了作为褪黑激素受体配体的茚满化合物,通式为:
其中取代基R1、R2、R3和R4以及变量A、m和n的含义具有其中描述的含义。
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,是第一个用于治疗的褪黑激素激动剂。它用于治疗失眠,它的作用机理是基于对MT1和MT2受体的激动作用。
雷美替胺是对MT1和MT2具有非选择性的化合物,对中枢和外周水平的其他受体具有选择性。它的Ki对MT1为0.014nM,对MT2为0.045nM。它能够再吸收,但会经历重要的首次通过代谢作用。它生物转化为四种代谢物,其中之一为M-II,具有活性并且具有重要的分布容积。雷美替胺的清除率为88%。
对新的能用于治疗失眠的褪黑激素激动剂的研究是基于基本的健康需要,因此证明需要继续研究性能更好的化合物。
因此,本发明的目的是一种新的酰化的1-(3-烷氧基-苯基)-吡咯烷-3-基-胺,其对褪黑激素受体具有活性,尤其是对MT1和MT2受体。因此,本发明化合物能用于治疗和预防所有由MT1和MT2受体调节的疾病。某些非限制的褪黑激素能(melatoninergic)障碍的例子是抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。
发明详述
本发明涉及通式I苯基吡咯烷化合物
其中:
R1为任选被卤原子、NHR3、(C3-C6)环烷基、CF3和OR4取代的直链或支链(C1-C6)烷基;
R2为直链或支链(C1-C6)烷基;
R3为直链或支链(C1-C6)烷基;
R4为直链或支链(C1-C6)烷基;以及药学上可接受的盐及其水合物。
药学上可接受的盐是那些可向病人,例如哺乳动物给药的药学上可接受的盐(例如对于一个给定的给药方案,对哺乳动物安全的可接受的盐)。该盐可由药学上可接受的无机或有机碱,和由药学上可接受的无机或有机酸获得。由药学上可接受的无机碱获得的盐包括铵、钙、铜、铁和亚铁盐、锂、镁、锰和亚锰盐、钾、钠、锌盐等。尤其优选铵、钙、镁、钾和钠盐。由药学上可接受的有机碱获得的盐包括伯、仲和叔胺盐、包括取代胺、环胺、天然胺等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-2-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴明、异丙胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、聚氨酯、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。由药学上可接受的酸获得的盐包括乙酸、抗坏血酸、苯磺酸、苯甲酸、龙脑磺酸、柠檬酸、乙磺酸、乙二磺酸、富马酸、灰胆酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、马尿酸、氢溴酸、氢氯酸、羟乙基磺酸、乳酸、乳糖酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘液酸、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、昔萘酸(sinafoic)等。尤其优选柠檬酸、氢溴酸、氢氯酸、羟乙基磺酸、马来酸、萘-1,5-二磺酸、磷酸、硫酸和酒石酸。
通式I的具体化合物选自下述化合物:
1)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-2,2-二甲基-丙酰胺;
2)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-异丁酰胺;
3)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丙酰胺;
4)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3基]-乙酰胺;
5)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-环丙甲酰胺;
6)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丁酰胺;
7)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丁酰胺;
8)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-3-甲基-丁酰胺;
9)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-氨基甲酸甲酯;
10)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-氨基甲酸乙酯;
11)(S)-2,2,2-三氟-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-乙酰胺;
12)(S)-2-氟-N-[3-(3-甲氧基-苯基)-吡咯烷-3-基]-丙酰胺;以及
13)(S)-3-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-1-乙基脲。
表1显示每个化合物的取代基含义:
表1
实施例 | R1 | R2 |
1 | tBu | Me |
2 | iPr | Me |
3 | Et | Me |
4 | Me | Me |
实施例 | R1 | R2 |
5 | cPr | Me |
6 | Pr | Me |
7 | Bu | Me |
8 | iBu | Me |
9 | OMe | Me |
10 | OEt | Me |
11 | CF3 | Me |
12 | MeCHF | Me |
13 | EtNH | Me |
本发明另一方面在于提供表1中一种具体化合物用于制备治疗或预防褪黑激素能障碍的药物的用途。所述的褪黑激素能障碍选自抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。
本发明另一方面在于提供包含表1中一种具体化合物和一种或多种药学上可接受赋形剂的药物组合物。
本发明另一方面在于提供所述药物组合物用于制备治疗或预防褪黑激素能障碍的药物的用途。所述的褪黑激素能障碍选自抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。
获得通式I化合物的途径描述于下面的流程式1,其中取代基R1和R2如前所述,其中R2=Me。
流程式1
第一步为使3-甲氧基苯酚II中的羟基活化。所述羟基与三氟甲磺酸酐在吡啶和二氯甲烷中反应,获得相应的三氟甲磺酸酯III。接下来的合成步骤为在预先活化的苯酚III与被保护的氨基吡咯烷IV之间发生布赫瓦尔德反应,被保护的氨基吡咯烷IV可以市售获得。所述反应通过取代三氟甲磺基得到苯基吡咯烷V。在酸性介质条件下,V中Boc基团发生去保护反应得到产物VI。最后,最后一步为胺VI与酰氯之间的普通偶合反应,得到化合物I。同样地,当终产物I为脲类或氨基甲酸酯类时,相应地,偶合试剂分别为适合的异氰酸酯或氯甲酸酯。
包含本发明化合物的药物细合物包括那些适合口服、直肠和肠外给药(包括皮下、肌肉注射和静脉注射)的药物组合物,虽然最适合的途径依赖于被治疗的病理的性质和严重程度。本发明化合物优选的给药途径通常为口服途径。
依据传统的药学配制技术,活性成分可以与一种或多种药用赋形剂混合。根据制备的剂型可以加入几种赋形剂。液体口服组合物(例如,混悬液、溶液、乳液、气雾剂和漱口水)可以使用例如,水、二醇类、油、醇、增味剂、防腐剂、着色剂等。固体口服组合物使用例如,淀粉、糖(例如,乳糖、蔗糖和山梨醇)、纤维素(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)、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙、橡胶、共聚维酮(copovidone)、表面活性剂,例如脱水山梨醇单油酸酯和聚乙二醇、金属氧化物(例如,二氧化钛和三氧化二铁)和其他药用稀释剂,例如水。由此形成包含本发明化合物的均匀预制剂。
在预制剂中,组合物是均匀的,使得活性成分均匀分散在组合物中,该组合物能因此被分成等单位剂量,例如片剂、包衣片剂、粉末和胶囊。
因为其便于给药,因此片剂和胶囊是最优选的口服形式。如果需要,片剂可用水性或非水性的传统技术包衣。种类繁多的材料能用于形成包衣。该材料包括多种多元酸,和它们与其他组分,例如,虫胶、十六醇和纤维素乙酸酯的混合物。
本发明化合物可并入用于口服或注射给药的液体形式包括水溶液、以液体或凝胶填充的胶囊、加入增味剂的糖浆、油中的水混悬液和以食用油,例如,棉籽油、芝麻油、椰子油或花生油调味的乳液、以及漱口水和类似药用载体。适合的用于制备水混悬液的分散或悬浮剂包括合成和天然树胶,如黄蓍胶、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。
无论是单次服用还是按需要多次服用,所使用的适合的剂量是每日总剂量为约0.1-500mg,更优选1mg-100mg。
发明实施方案
本发明另外通过以下实施例加以说明,但并不试图限制其保护范围。
药理评估实施例1
对MT1受体激动剂活性的测定
为了筛选用于MT1受体的化合物,使用一种细胞系,其特点是在细胞系中重组的人类MT1受体能稳定地高效表达,并依次共同表达了线粒体原水母发光蛋白(apoaequorin)和Gα16亚单位。
Gα16亚单位属于G蛋白质家族,由GPCR形成,其中细胞内信号的传导通过磷脂酶(PLC)发生。PLC激活使得三磷酸肌醇水平提高,进而导致细胞内钙的增加。因而,Gα16的高效表达使得细胞内钙水平提高,其是独立的并且与研究的受体自身信号传导路径相适应。
原水母发光蛋白是非活化形式的水母发光蛋白,是一种需要疏水修复基团Coelenterazine以生产活化形式的磷酸蛋白。随着其与钙的结合,水母发光蛋白氧化coelenterazine成为coelenteramide,这是一种释放出二氧化碳和光的反应。
用于筛选可能的激动剂的试验方案包括采集细胞,在Coelenterazine的存在下使它们保持悬浮过夜以重构水母发光蛋白。第二天,将细胞注入盘中,在其中稀释需要筛选的化合物,立刻读取释放的荧光。当希望研究相同化合物可能的对抗作用时,在第一次注入15-30分钟后将参考激动剂化合物加入到相同的孔中,并且评阶释放的荧光。
激动剂活性以活性百分率计算,基于参考激动剂在相应于它的EC100的浓度。拮抗活性以抑制百分率表示,基于参考激动剂活性在相应于它的EC80的浓度。
药理评估实施例2
对MT2受体激动剂活性的测定
为了研究对MT2受体的激动作用,我们使用了一种重组的细胞系来表达这些受体和共同表达线粒体原水母发光蛋白以及Gα16亚单位,如在MT1筛选的模型中所使用的那样。在这一模型中,本发明化合物显示出它们对MT2受体同样具有激动作用。
表2显示了与雷美替胺、褪黑激素和(1S)-N-[2-(6-甲氧基-茚满-1-基)-乙基]-丙酰胺标准(WO9608466和O.Uchikawa et al.,J.Med.Chem,2002,45,4222-4239;化合物60)相对比,作用于MT1受体的激动作用的结果,证明本发明化合物显示出与所述参考化合物可比的活性。
表2
此外,本发明化合物有利地提供了相关的药代动力学的改进。因此,通过在1μM浓度下,在人微粒体中孵化120分钟而对由待测化合物消失决定的代谢稳定性的研究,和对服用1mg/Kg待测化合物15分钟后大鼠血浆水平(ng/mL)的研究表明实施例8的化合物具有高代谢稳定性(包括在71%和100%之间),血浆水平为15.1ng/ml和脑/血浆比为1,就作为对比而言,(1S)-N-[2-(6-甲氧基-茚满-1-基)-乙基]-丙酰胺显示出低代谢稳定性(少于30%)、血浆水平为10.1ng/mL,以及脑/血浆比接近于0。所以,尽管与参考化合物具有某种结构上的相似性,但由于其更好的代谢稳定性、更高的血浆水平和更高的脑/血浆比率,实施例8的化合物显示出出乎意料的更高的药代动力学性质。
简而言之,本发明提供了新的化合物,尽管与现有技术化合物具有某些相似的结构,却惊奇地显示出低生物转化性和在脑和血浆中的更高水平,因而提供更持久的睡眠。
参考实施例1
获得三氟甲磺酸酯III的一般过程
流程式2
将吡啶(28.7mL,354mmol)加入到3-甲氧基苯酚II(17.68mL,161mmol)的二氯甲烷(DCM)(250mL)溶液中。冰水浴冷却。缓慢加入三氟甲磺酸酐(Tf20,29.8mL,177mmol),耗时30分钟。在该加入过程中,始终保持温度在10℃以下。在0℃条件下搅拌30分钟,使温度升至室温3小时30分钟。收集溶液,以饱和偏亚硫酸氢盐水溶液和水洗涤。有机层用无水硫酸钠干燥,过滤,减压蒸馏溶剂。得到45g油状物III,直接用于下面的合成步骤。
参考实施例2
获得化合物V的一般过程
流程式3
通过强Ar起泡过程对100mL甲苯进行脱气10分钟。加入2.51g(4.03mmol)[1,1’-联萘]-2,2’-双[二苯基膦](BINAP)和0.61g(2.68mmol)乙酸钯。在室温下搅拌15分钟。加入14.52g(44.6mmol)碳酸铯和5g(26.8mmol)氨基吡咯烷IV。最后,加入10mL甲苯中的5.78g(22.5mmol)三氟甲磺酸酯III。在回流下加热16小时。冷却,过滤反应粗产物。用DCM/水洗涤固体。干燥有机层,过滤。所得物用柱色谱纯化,以乙酸乙酯/己烷作混合洗脱液。得到3.3g(产率为42%)黄色油状被保护的胺V。
HPLC-MS:纯度100%,M+1=293
参考实施例3
获得胺VI的一般过程
流程式4
取3.3g(11.29mmol)被保护的胺V,加入56.4mL(226mmol)4N的HCl的二烷溶液。随着原料的溶解出现一种新的固体。在室温下继续搅拌1小时。减压蒸馏二烷,将所得固体悬浮于DCM中。以50mL、3N的氢氧化钠洗涤三次。分离有机层,无水硫酸镁干燥。过滤溶剂,并蒸馏。得2.09g(产率为96%)无色油状物VI。
HPLC-MS:纯度98%,M+1=I 93
参考实施例4
获得化合物I的一般过程
流程式5
将300mg胺V(1.56mmol)溶解于15mL无水DCM中。缓慢加口入0.395mL的TEA(三乙胺)(2.84mmol),然后再缓慢加入1.42mmol相应的酰氯。在室温下搅拌1小时30分钟。加入10mL1N的HCl,搅拌15分钟。分离有机层,并干燥。蒸干。所得物用柱色谱纯化,以乙酸乙酯/己烷作洗脱液。由此得到白色固体化合物I。
R1为Me的实施例:获得产物199.8mg(产率为60%)。
HPLC-MS:纯度98%,M+1=235
所获得的化合物列于下面的表3。
表3
实施例 | R1 | R2 | LCMS纯度(%) | M+1 |
1 | tBu | Me | 98 | 277 |
2 | iPr | Me | 97 | 263 |
3 | Et | Me | 96 | 249 |
4 | Me | Me | 98 | 235 |
5 | cfr | Me | 97 | 261 |
6 | Pr | Me | 97 | 263 |
7 | Bu | Me | 99 | 277 |
8 | iBu | Me | 97 | 277 |
9 | OMe | Me | 100 | 251 |
10 | OEt | Me | 97 | 265 |
11 | CF3 | Me | 98 | 289 |
12 | MeCHF | Me | 100 | 267 |
实施例 | R1 | R2 | LCMS纯度(%) | M+1 |
13 | EtNH | Me | 99 | 264 |
Claims (7)
1.苯基吡咯烷化合物,选自下述化合物组成的组:
1)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-2,2-二甲基-丙酰胺;
2)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-异丁酰胺;
3)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丙酰胺;
4)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3基]-乙酰胺;
5)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-环丙甲酰胺;
6)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丁酰胺;
7)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丁酰胺;
8)(S)-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-3-甲基-丁酰胺;
9)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-氨基甲酸甲酯;
10)(S)-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-氨基甲酸乙酯;
11)(S)-2,2,2-三氟-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-乙酰胺;
12)(S)-2-氟-N-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-丙酰胺;以及
13)(S)-3-[1-(3-甲氧基-苯基)-吡咯烷-3-基]-1-乙基脲;
以及药学上可接受的盐及其水合物。
2.权利要求1化合物用于制备治疗或预防褪黑激素能障碍的药物的用途。
3.权利要求2的用途,其中所述的褪黑激素能障碍选自抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。
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上可接受的赋形剂。
5.权利要求4的药物组合物用于制备治疗或预防褪黑激素能障碍的药物的用途。
6.权利要求5的用途,其中所述的褪黑激素能障碍选自抑郁症、应激、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、时差导致的失眠或疲劳、精神分裂症、恐慌、忧郁症、食欲紊乱、肥胖、失眠、精神疾病、癫痫、糖尿病、帕金森氏症、老年痴呆症、与正常或病理老化相关的疾病、偏头痛、记忆丧失、阿尔兹海默氏症以及脑循环障碍。
7.治疗或预防褪黑激素能障碍的方法,包括给病人服用有效量的一种或多种权利要求1的化合物。
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