CN101193885A - 作为5-ht6-受体抑制剂的苯并呋喃基衍生物 - Google Patents
作为5-ht6-受体抑制剂的苯并呋喃基衍生物 Download PDFInfo
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Abstract
本发明涉及式(I)的化合物,其中R1和R2如说明书中所限定;涉及包含这些化合物的药物制剂,并且涉及所述化合物用于预防和治疗与肥胖症、II型糖尿病、和/或CNS疾病有关的医学病症,以实现体重和体重增加的减少。
Description
技术领域
本发明涉及取代的磺酰胺(sulphonamide)化合物,涉及包含这些化合物的药物制剂,并且涉及所述化合物用于预防和治疗与肥胖症、II型糖尿病、和/或中枢神经***(CNS)疾病有关的医学病症的用途,以实现体重和体重增加的减少,以及用于美容用途。
背景技术
肥胖是一种病症,其特征在于体脂肪含量的增加,产生超过公认标准的过量体重。肥胖在西方世界是最重要的营养性疾病并且代表全部工业化国家中的主要健康问题。由于诸如心血管疾病、消化***疾病、呼吸道疾病、癌症和II型糖尿病的疾病发生率增加,该疾病导致死亡率增加。搜寻减少体重的化合物已经进行了数十年。一个研究路线已经是含血清素体系的活化,或者通过5-羟色胺受体亚型的直接活化或者通过抑制5-羟色胺再摄取。然而精确的所需受体亚型分布不是已知的。
5-羟色胺(5-羟色胺或5-HT),一种周围神经***和中枢神经***的关键递质,调节广泛的生理的和病理的功能,包括焦虑、睡眠调节、攻击、进食和抑郁。已经鉴定并克隆了多个5-羟色胺受体亚型。这些中的一种,5-HT6受体,在1993由数个小组克隆(Ruat,M.等.(1993)Biochem.Biophys.Res.Commun.193:268-276;Sebben,M.等.(1994)NeuroReport 5:2553-2557)。该受体正向偶联至腺苷酸环化酶并且对于抗抑郁药诸如氯氮平显示亲和性。最近,已经报道了5-HT6拮抗剂和5-HT6反义寡核苷酸在大鼠中减少食物摄入的效果(Bentley,J.C.等.(1999)Br J Pharmac.Suppl.126,P66;Bentley,J.C.等.(1997)J.Psychopharmacol.Suppl.A64,255;Woolley M.L等.(2001)Neuropharmacology).
已经鉴定了对于5-HT6受体具有增强亲和性和选择性的化合物,例如在WO 00/34242和Isaac,M.等(2000)6-Bicyclopiperazinyl-1-arylsulfonylindoles and 6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel,potent and selective 5-HT6 receptorantagonists.Bioorganic & Medicinal Chemistry Letters 10:1719-1721(2000)。
WO 2004/000828和WO 02/100822,都以Biovitrum AB的名义,公开了结合至5-HT6受体并且可以用于治疗与肥胖症、II型糖尿病、和/或CNS疾病有关的医学病症的磺酰胺衍生物。
然而,以前还没有公开过根据本发明的磺酰胺衍生物。
附图简述
图1表示用实施例1的治疗对于体重的影响。
图2表示用实施例1的治疗对于食物消耗的影响。
发明内容
已经意外地发现,式(I)的化合物在低的纳摩尔范围作为拮抗剂对于5-HT6受体显示亲和性和选择性,与现有技术涉及的化合物相比,其亲和性和选择性出乎意料地高。根据本发明的化合物和它们的药用盐具有5-HT6受体拮抗剂、激动剂和部分激动剂活性,并且被认为在治疗或预防肥胖症和II型糖尿病中具有潜在用途,以实现体重和体重增加的减少,而且在治疗或预防中枢神经***疾病诸如焦虑,抑郁,焦虑发作,记忆障碍,认知障碍,睡眠障碍,偏头痛,厌食,贪食症、暴食症,强迫症,精神病,阿尔茨海默病,帕金森病,亨廷顿舞蹈病和/或精神***症,注意涣散多动症(ADHD),药物滥用中具有潜在用途。特别通过减少食物摄入而实现体重和体重增加的减少(例如治疗体重失调)。如本文所用,术语“体重失调”指由能量吸收和能量消耗之间的不平衡所引起失调,导致失常的身体(例如,过多的)重量。这种体重失调包括肥胖症。
式(I)的化合物
本发明的一个目的是式(I)的化合物:
或其药用盐,其中:
R1是甲氧基并且R2是甲基;或
R1是甲氧基并且R2是羟甲基;或
R1是羟基并且R2是甲基。
式(I)的化合物可以照原样使用,在适当情况下,作为其药用盐(酸或碱加成盐)使用。如上所述的药用盐意味着包含所述化合物能形成的治疗活性的无毒的酸和碱加成盐形式。通过用适当的酸处理碱形式,具有碱性性质的化合物可以转变成它们的药用酸加成盐。例举性的酸包括无机酸,诸如氯化氢、溴化氢、碘化氢、硫酸、磷酸;和有机酸诸如乙酸、丙酸、羟基乙酸(hydroxyacetic acid)、乳酸、丙酮酸、乙醇酸(glycolic acid)、马来酸、丙二酸、草酸、苯磺酸、甲苯磺酸、甲烷磺酸、三氟乙酸、延胡索酸、琥珀酸、苹果酸、酒石酸、柠檬酸、水杨酸、对-氨基水杨酸、双羟萘酸(pamoicacid)、苯甲酸、抗坏血酸等。例举性的碱加成盐形式是钠、钾、钙盐,和含有药物上可接受的胺的盐,所述胺诸如,例如,氨、烷基胺、N,N′-双苄基乙撑二胺(benzathine),和氨基酸,诸如,例如精氨酸和赖氨酸。如本文所用的术语加成盐也包含所述化合物和其盐能形成的溶剂合物,诸如,例如水合物、醇化物等。
对于临床用途,将本发明的化合物配制成用于口服的、直肠的、胃肠外的或其它方式给药的药物制剂。通常通过将活性物质或其药用盐与常规的药物赋形剂混合而制备药物制剂。可以另外通过已知的方法诸如造粒、压缩、微囊化、喷涂等制备所述制剂。可以通过常规方法将所述制剂制备成片剂、胶囊、颗粒剂、散剂、糖浆剂、混悬剂、栓剂或注射剂的剂型。可以通过将活性物质溶解或悬浮在水中或其它适合载体中而制备液体制剂。片剂和颗粒剂可以以常规方式涂敷。
本发明的另一个目的是用于治疗的以上化合物。
本发明的另一个目的是以上化合物在治疗或预防5-HT6受体相关的疾病中的用途,所述疾病诸如肥胖症、II型糖尿病、和/或CNS疾病,以实现体重和体重增加的减少。
本发明的另一个目的是包含作为活性成分的以上化合物与药用稀释剂或载体的药物制剂。
本发明的另一个目的是包含以上化合物的药物制剂在治疗或预防5-HT6受体相关的疾病中的用途,所述疾病诸如肥胖症、II型糖尿病、和/或中枢神经***疾病,以实现体重和体重增加的减少。
本发明的另一个目的是用于治疗或预防5-HT6受体相关的疾病的方法,所述疾病诸如肥胖症、II型糖尿病、和/或中枢神经***疾病,以实现体重和体重增加的减少,所述方法包含将有效量的以上化合物施用至需要这种治疗的受试者。
本发明的另一个目的是用于调节5-HT6受体活性的方法,所述方法包含将有效量的以上化合物施用至需要其的受试者。
本发明的另一个目的是以上化合物用于制备在治疗或预防5-HT6受体相关的疾病中使用的药物的用途,所述疾病诸如肥胖症、II型糖尿病、和/或中枢神经***疾病,以实现体重和体重增加的减少。
中枢神经***疾病的实例是认知障碍包括阿尔茨海默病和与精神***症有关的认知损伤。
在本文叙述的方法还可以包括识别需要治疗肥胖症、II型糖尿病、或中枢神经***疾病,或需要减少体重和体重增加的受试者的步骤。
本发明进一步涉及本文描述的任何式的一种或多种化合物的用于引起体重下降的美容用途,,而且涉及含有所述化合物的美容制剂。
更进一步,本发明涉及用于改善哺乳动物包括人的身体外观的非治疗方法,其中所述方法包含将本文描述的任何式的一种或多种化合物口服施用至所述哺乳动物。
“有效量”指将治疗效果赋予被治疗的受试者的化合物的量。所述治疗效果可以是客观的(即,通过一些测试或标记物可测量的)或主观的(即,受试者给出效果的指示或感受到效果)。
对于临床用途,将本发明的化合物配制成用于口服的、直肠的、胃肠外的或其它方式给药的药物制剂。通常,活性化合物的量在所述制剂的0.1-95重量%之间,对于胃肠外用途优选在制剂的0.2-20重量%之间,并且对于口服优选在制剂的1和50重量%之间。
活性物质的典型日剂量在宽范围之内改变并且将取决于多种因素诸如,例如每个患者的单独需要和给药途径。通常,口服的和胃肠外的剂量将在每天50至300mg活性物质的范围之内,优选每天50至150mg。
制备方法
在进一步的方面中,本发明涉及制备本文的任何式的化合物的方法,所述方法包含本文叙述的式的任何一种或多种化合物起反应,包括本文叙述的任何方法。以上式的化合物可以通过或类似于常规方法,并且特别是根据或类似于下列方法制备。
用于上述合成路线的化学品可以包括,例如,溶剂、试剂、催化剂、保护基和去保护基试剂。上述方法也可以另外包括本文具体描述的步骤之前或之后添加或除去适合的保护基的步骤以便最终可以合成上述任何式的化合物、它们的盐形式、或包括所述化合物或它们的盐形式的制剂。另外,可以以备选顺序进行多种合成步骤以便产生所需化合物。在合成可应用的化合物中有用的合成化学转化和保护基方法学(保护和去保护)在本领域是已知的并且包括,例如,在R.Larock,Comprehensive OrganicTransformations,VCH Publishers(1989);T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,2ndEd.,John Wiley and Sons(1991);L.Fieser and M.Fieser,Fieser and Fieser′s Reagents for Organic Synthesis,John Wiley and Sons(1994);and L.Paquette,ed.,Encyclopedia of Reagentsfor Organic Synthesis,John Wiley and Sons(1995)及其后来的版本中描述的那些。
无论以任何方式,公开内容的其余部分在下面的具体实例将仅仅解释为说明性的,而不是限制性的。在不进一步详细描述的情况下,相信本领域技术人员可以基于本文的描述将本发明利用至它的最充分程度。在本文引用的全部出版物全部结合于此作为参考。
实施例1
N-[7-(4-哌啶基)氧基-1-苯并呋喃-5-基]-2-甲氧基-5-甲基苯磺酰胺
实施例1制备如下:
7-碘-N-(2-甲氧基-5-甲基苯基)-1-苯并呋喃-5-磺酰胺是从2,3-二氢苯并呋喃(2,3-dihydrobensofuran)开始产生的。用氯磺酸的处理给出相应的磺酰氯,将其利用一氯化碘碘化。利用NBS进行芳构化,在用3-氨基对甲苯甲醚处理后产生7-碘-N-(2-甲氧基-5-甲基苯基)-1-苯并呋喃-5-磺酰胺。
利用铜作为催化剂的7-碘-N-(2-甲氧基-5-甲基苯基)-1-苯并呋喃-5-磺酰胺在碱性溶液中的水解产生7-羟基-N-(2-甲氧基-5-甲基苯基)-1-苯并呋喃-5-磺酰胺。与4-羟基哌啶的氨基甲酸甲酯保护的甲磺酸盐(mesylate)的反应产生4-[(5-{[(2-甲氧基-5-甲基苯基)氨基]磺酰基}-1-苯并呋喃-7-基)氧基]哌啶-1-羧酸甲酯,其在碱性溶液中水解得到标题化合物。
实施例2(实施例1的代谢物)
N-[7-(4-哌啶基)氧基-1-苯并呋喃-5-基]-5-羟甲基-2-甲氧基苯磺酰胺
实施例3(实施例1的代谢物)
N-[7-(4-哌啶基)氧基-1-苯并呋喃-5-基]-2-羟基-5-甲基苯磺酰胺
生物学测试
根据本发明的化合物结合5-HT6受体的能力,和在药用上有效性,可以利用本领域已知的体内和体外测定而确定。
(a)5-HT6结合测定
根据由Boess F.G等.Neuropharmacology vol.36(4/5)713-720,1997描述的一般方法,在用5-HT6受体转染的HEK293细胞中利用(3H)-LSD作为标记配体进行5-HT6受体的结合亲和性实验。
材料
细胞培养
将用5-HT6受体转染的HEK-293细胞系培养在含有5%透析的胎牛血清,(Gibco BRL 10106-169),0.5mM丙酮酸钠和400μg/ml的遗传霉素(G-418)(Gibco BRL 10131-019)的Dulbeccos改进的Eagles培养基中。将细胞1∶10传代,每周两次。
化学品
将从Amersham Pharmacia Biotech,(Buckinghamshire,英国)获得的放射性配体[3H]LSD 60-240 Ci/mmol在乙醇中并储存在-20℃。将所述化合物溶解在100%DMSO中并用结合缓冲液稀释。
处理
将化合物在Costar 96孔V-底聚丙烯板(Coming Inc.Costar,NY,美国)中稀释。将样品温育在Packard Optiplate(Packard Instruments B.V.Groningen,荷兰)。在Packard 24-孔Barex板(Packard Instruments B.V.,Groningen,荷兰)中在MicroscintTM 20闪烁流体(Packard Bioscience,Meriden,CT,USA)存在下测量添加的放射性配体的总量。
缓冲液
结合缓冲液由20mM HEPES,150mM NaCl,10mM MgCl2,和1mM,EDTA,pH7.4组成。
方法
膜制备
将细胞在24.5×24.5NUNC培养皿上培养到大约90%汇合。将培养基吸出,并且在用冰冷的PBS漂洗以后,利用25ml的Tris缓冲液(50mM的Tris-HCl,1mM的EDTA,1mM的EGTA,pH7.4)和窗状刮板刮取细胞。然后将细胞用Polytron匀浆器破碎,并且用1000×g,5min的低速离心除去残留的颗粒物质。最终,用高速离心(20000×g)收集所述膜,将其悬浮在结合缓冲液中,并且以等分部分冷冻在-70℃。
放射性配体结合
将冷冻的细胞膜解冻,立即用Polytron匀浆器再匀浆,并且在管的连续振动下用30min偶联至SPA小麦胚芽凝集素珠(Amersham LifeSciences,加的夫,英国)。在偶联以后,将所述珠在1000g离心10分钟,并且随后悬浮在20ml/96-孔板的结合缓冲液中。然后通过将放射性配体和测试化合物添加至珠-膜混悬液而启动结合反应。在室温下温育以后,将所述测定板进行闪烁计数。
接着是原始的SPA法,不同之处在于,从表达人5-HT6受体的HEK293细胞代替海拉细胞(Dinh DM,Zaworski PG,Gill GS,Schlachter SK,LawsonCF,Smith MW.Validation of human 5-HT6 receptors expressed in HeLa cellmembranes:saturation binding studies,pharmacological profiles of standardCNS agents and SPA development.The Upjohn Company Technical Report7295-95-064 1995年12月27日)制备膜。[3H]LSD的特异性结合是可饱和的,而非特异性结合随着添加的放射性配体的浓度而线性增加。[3H]LSD以高亲和性结合至5-HT6受体。基于四个单独的实验,Kd值估计是2.6±0.2nM。
总的结合在3nM的[3H]LSD,用于竞争性实验的放射性配体浓度,典型地是6000dpm,并且特异性结合大于70%。当针对两个不同的膜制剂测试时,5-HT引起浓度依赖性的[3H]LSD结合的抑制,其中总的平均Ki值为236nM。经过三个实验的内部测定可变性显示CV为10%,平均Ki值为173nM(SD 30)和Hill系数为0.94(SD 0.09)。内部测定变化是3%(n=4)。实施例1的Ki值表示在表3中。即使在不同的效应,全部未标记的配体以浓度依赖性的方式取代[3H]LSD的特异性结合。所述化合物效应的等级次序是美赛西平(2nM)>米安舍林(190nM)≈5-HT(236nM)>二甲麦角新碱(482nM)>mesulergide(1970nM)。
蛋白质测定
用BioRad蛋白质测定法确定蛋白质浓度(Bradford MM.A rapid andsensitive method for the quantitation of microgram quantities of proteinutilizing the principle of protein-dye binding.Anal Biochem 1976;72:248-54)。将牛血清白蛋白用作标准。
闪烁计数
在Packard TopCountTM闪烁计数器(Packard Instruments,Meriden,CT,美国)中以大约20%的计数效率确定放射性。在单独实验组中确定计数效率。
饱和实验
至少6个一式两份浓度的放射性配体(0.1-20nM的[3H]LSD)用于饱和实验。将特异性结合计算为总结合和非特异性结合之间的差异,在5μM麦角乙脲存在下将其确定为放射性配体的结合。利用方程1从非线性回归分析确定Bmax和解离常数,Kd。Lu是放射性配体的未结合浓度,并且y是结合的量。
竞争实验
放射性配体的总特异性结合和非特异性结合以各自八个重复测定而限定。含有测试化合物的样品以11个浓度一式两份运行。在室温下将温育进行3小时。用非线性回归分析确定IC50值,即测试化合物抑制50%的放射性配体的特异性结合的浓度,并且利用方程2的方法[Cheng Y.C.Biochem.Pharmacol.22,3099-3108,1973S]计算Ki值。
(方程2)
L=放射性配体的浓度
Kd=放射性配体的亲和性
(b)5-HT6内在活性测定
通过测量5-HT诱导的cAMP在表达人5-HT6受体的HEK 293细胞中的增加的抑制表征5-HT6受体的拮抗剂(见Boess等(1997)Neuropharmacology 36:713-720)。简要地,将HEK 293/5-HT6细胞以25,000/孔的密度接种在聚赖氨酸包被的96-孔板中并且在37℃在5%CO2的培养箱中在含有5%透析的胎牛血清的DMEM(Dulbecco′s改进的Eagle培养基)(没有酚红)中生长48h。然后吸出培养基并用0.1ml测定培养基(含有20mM HEPES、1.5mM异丁基甲基黄嘌呤和1mg/ml牛血清白蛋白的Hanks平衡盐溶液)替换。在添加50μl溶解在测定培养基中的测试物质以后,将细胞在37℃在5%CO2培养箱中温育10min。将所述培养基再次吸出并利用放射性cAMP试剂盒(Amersham Pharmacia Biotech,BIOTRAKRPA 559)确定cAMP的含量。利用式IC50,corr=IC50/(1+[5HT]/EC50),通过确定引起5-HT(在[5-HT]=8倍EC50)50%抑制的浓度而定量拮抗药的效能,所述抑制因cAMP增加而引起。
实施例1具有对于5-HT6受体的选择性亲和力,Ki和IC50,corr值在0.5nM和5μM之间或者在50 nM显示[3H]LSD的%抑制≥20%并且在5-HT6是拮抗剂、激动剂或部分激动剂。实施例1在5-HT1a、5-HT2a、5-HT2a、5-HT2b、和5-HT2c上显示良好选择性(对于数值见表3)。
将另外的测定用于实施例1,见表1
表1-用于实施例1的另外的测定
测定 | 来源 | 参比化合物 | 参考文献 |
β1 | 人重组细胞(HEK-293细胞) | 阿替洛尔 | Levin等.(2002) |
β2 | 人重组体(Sf9细胞) | ICI 118551 | Smith和Teitler(1999) |
κ(KOP) | 豚鼠小脑 | U50488 | Kinouchi和Pasternak(1991) |
5-HT3 | 人重组体(HEK-293细胞) | MDL 72222 | Hope等.(1996) |
表1中的参考文献
LEVIN,M.C.,MARULLO,S.,MUNTANER,O.,ANDERSON,B.and MAGNUSSON,Y.(2002)The myocardium-protective Gly-49 variant ofthe beta 1-adrenergic receptor exhibits constitutive activity and increaseddesensitization and down regulation.J.BioLChem.277:30429-30435
SMITH,C.and TEITLER,M.(1999)Beta-blocker selectivity at clonedhuman beta1-and beta2-adrenergic receptors.Cardiovasc.Drugs Ther.,13:123-126.
KINOUCHI,K.and PASTERNAK,G.W.(1991)Evidence for κ1opioid receptor multiplicity in the guinea pig cerebellum.Eur.J.Pharmacol,207:135-141.
HOPE,A.G.,PETERS,J.A.,BROWN,A.M.,LAMBERT,J.J.andBLACKBURN,T.P.(1996)Characterization of a human5-hydroxytryptamine3 receptor type A(h5-HT3R-As)subunit stably expressedin HEK 293 cells.Brit.J.Pharmacol,118:1237-1245.
(c)对于体重和对于食物摄入的影响
材料和方法
测试化合物
将实施例1溶解在5%(重量/体积)PEG 400,0.2%吐温80+10mM乙酸钠缓冲液(pH6)中。将相应的溶液用作载体。在储存14天后检验溶液的稳定性。将溶液每周配制两次并储存在冰箱中。分析所述溶液的实际浓度并且发现所述溶液在两种情况之间是类似的。
动物
将一百(100)只雄性Sprague-Dawley大鼠在Scanbur BKAB(Sollentuna,瑞典)在高脂肪饮食上饲养,当它们到达Biovitrum动物饲养设施时称重约为700g(17周龄)。在它们到达以后将所述大鼠适应并称重大约三周。在恒定的室内条件(温度22±1℃,湿度40-60%,12h光/暗循环,在10am关灯)期间,将大鼠单独置于标准笼中。所述大鼠接受与它们在Scanbur所接受的相同的高脂肪饮食(45kcal%脂肪,4.7kcal/g;D12451)。所述饮食购自Research Diets,Inc.,新泽西,美国,由小丸组成并储存在干冷条件下。
实验期间
选择得到最高重量的高脂肪喂养动物。该群称重为799±60g。将选择的四十八(48)只大鼠随机分配并且分成五个处理组以便获得尽可能根据体重的同类组。每个处理组由12只大鼠组成:组1-载体,组2-实施例1-5mg/kg(11μmol/kg),组3-实施例1-15mg/kg(33μmol/kg),组4-实施例1-30mg/kg(66μmol/kg)。分配另外九(9)只大鼠用于在第7天和第29天平行测量每个剂量组的化合物暴露和药物动力学。通过基线测量将所述研究启动五天以便使所述大鼠***均为2ml/(800g)大鼠的体积一天一次经口施用测试化合物。每天连同注射(injections)将小丸和身体称重。将水瓶一周称重一次。用计算机辅助的Mettler Toledo PR 5002天平进行称重。将全部数据传输到Excel模块中。
在第28天,将躯干血液取样用于测定血清葡萄糖、胰岛素、瘦蛋白、游离脂肪酸、甘油三酸酯、胆固醇、HDL、LDL、ALAT、ASAT和脲。还测定了血细胞比容。将附睾白色脂肪组织、肝和腓肠肌肌肉解剖,并称重。
药物动力学
将如上所述用于血浆暴露的试验动物(satellite animal)(3只动物/剂量)用5、15和30mg/kg/天-实施例1口服处理。在预剂量的时间点,服药后的10min、30min、1h、2h、3h、4h、6h、8h、och 24h,从尾静脉取第7天的血样。在第28天在相对于第7天的相应时间点从15mg/kg/天的处理组中的动物取新的血样。将血样(约150μL)取样在肝素化的管中并放置在冰上直到离心(4000rpm,5min,+4℃)。将血浆储存在-20℃直到分析。用HPLC和电喷射离子化串联质谱测定法分析血样。
统计
食品和水摄入、和体重数据以克和基础的%计算并且将其表示为平均值+/-SD和/或+/-SEM。在治疗开始前一天(第0天)的基础值被认为是代表性的,因为在全部预处理天数上平均所述值不改变结果。
通过用反复测量(处理x时刻)的双向单变量ANOVA,接着是用于在选定时间点在处理组之间比较的单向ANOVA,在统计上分析体重和食物摄入的数据。通过单向ANOVA接着是用于处理组比载体对照的显著性检验的Dunnetts t-检验,分析临床化学测量。如果P<0.05,则认为两个组之间的差异是显著的。利用Windows用的SPSS进行统计学评价。
结果
对体重的影响
长期研究的目的是研究延长处理时期达四周是否可以导致持续的体重减少并且还能够确定最小有效剂量。基于用实施例1的较早的急性和长期研究选择剂量。在全部处理期间,体重被实施例1显著地降低(重复的ANOVA组F(3,42)=12.6;P<0.001)(图1)。对于剂量5、15和15mg/kg,体重减少分别是3.9、3.7和6.9%(对于全部组对比载体,Dunnetts t-检验P<0.001)(见表2)。
表2.用实施例1的28天处理对于DIO大鼠体重影响的总结
单独的p.o.mg/kg | n | 体重平均值(g)初始的 | SD | 体重平均值(g)第28天 | SD | 体重增加平均值(g) | 减少克数 | 基础平均值(%)第28天 | SD | P | 载体的减少% | |
载体 | 12 | 807 | 47 | 867 | 42 | 60 | 107.5 | 2.1 | ||||
实施例1 | 5 | 12 | 816 | 76 | 845 | 82 | 29 | -31 | 103.5 | 2.1 | P<0.001 | 3.9 |
实施例1 | 15 | 12 | 804 | 60 | 834 | 65 | 30 | -30 | 103.7 | 1.9 | P<0.001 | 3.7 |
实施例1 | 30 | 10 | 806 | 85 | 810 | 76 | 4 | -57 | 100.6 | 3.2 | P<0.001 | 6.9 |
将体重增加计算为第28天-初始的;减少指的是在第28天对比载体的克数或%减少。利用Dunnetts t-检验,P值基于基本值(%)。
对食物摄入的影响
如图2中所示,在最初七天期间,实施例1显著地降低食物摄入(重复的ANOVA组F(3,42)=9.887;P<0.001)。Dunnets t-检验显示,剂量15和30mg/kg显著不同于载体(P<0.001),而5mg/kg的剂量则不是显著不同于载体。因而,最小有效剂量是15mg/kg。在第8至14天期间,对于食物摄入的影响衰减,但是在剩下的处理期间保持降低,尽管不是统计学上有意义的(组F(3,42)=2.459;P<0.076)。在15至28天内的平均减少是7-12%,但是仅最高剂量是统计学上有意义的(P<0.035)。
表3-实施例1的生物学数据
在人5-HT6受体的体外结合
测定 | 靶标 | 结果 |
结合(Ki) | 5-HT6 | 1.2nM |
功能的(cAMP活化受5-HT的抑制)(fKi) | 5-HT6 | 2.1nM |
选择性结合(Ki) | 5-HT1a | >1000nM(1400nM) |
5-HT1b | >1000nM(3600nM) | |
5-HT2a | >1000nM(5600nM) | |
5-HT2b | 440nM | |
5-HT2c | >1000nM(2300nM) | |
结合%抑制1μM | β1 | 26,26 |
β2 | 62,39 | |
κ(KOP) | 46,61(Ki=120nM,EC50=3780nM) | |
5-HT3 | 61,71(Ki190nM) |
在表4-6中,表3中对于实施例1给出的一些值是对于由现有技术所包括的化合物给出的。
表4-对于WO 02/100822中的实施例148(N-(7-哌嗪-1-基-苯并呋喃-5-基)-1-萘基磺酰胺,盐酸盐)给出的值。对于实施例148,磺胺基团的NH-部分结合至苯并呋喃环。
靶标 | 实施例148 |
5-HT6-Ki | 0.18nM |
5-HT6-fKi | 6nM |
5-HT2a-Ki | 412nM |
5-HT2b-Ki | 19.7nM |
5-HT2c-Ki | 158nM |
表4显示,与WO 02/100822中公开的实施例148相比,实施例1对于5-HT6具有优于5-HT2a、5-HT2b和5-HT2c的选择性。
为了对于5-HT6获得好于5-HT2a、5-HT2b和5-HT2c的选择性,对于后者受体的Ki-结合对比5-HT6结合应当至少是100倍。
表5-对于WO 2004/000828中没有具体公开的所包括的化合物A(5-氯噻吩-2-磺酸,[7-(哌啶-4-基氧基)-苯并呋喃-5-基]酰胺,盐酸盐)和化合物B(N-[7-(4-哌啶氧基)-1-苯并呋喃-5-基]-2-三氟甲基苯磺酰胺)所给出的值。对于化合物A和B两者,磺酰胺基团的NH-部分结合至苯并呋喃环。
靶标 | 化合物A | 化合物B |
5-HT6-Ki | 9nM | 4nM |
5-HT6-fKi | 6nM | 3nM |
5-HT1a-Ki | 1515nM | >1000nM |
5-HT1b-Ki | 1474nM | 1294nM |
5-HT2a-Ki | >1000nM | >1000nM |
5-HT2b-Ki | 356nM | 545nM |
5-HT2c-Ki | >1000nM | >1000nM |
β1 | 80% | 82% |
β2 | 89% | 82% |
κ(KOP) | 71% | 83% |
S-HT3 | 90% | 91% |
表5显示实施例1对于5-HT6具有优于5-HT1a、5-HT1b、5-HT2a、5-HT2b和5-HT2c的选择性,并且与WO 2004/000828包括的化合物A和B相比,具有优越的β1、β2、κ(KOP)和5-HT3抑制值。
为了实现对于5-HT6对β1、β2、κ(KOP)和5-HT3的良好选择性,在1μM对于后者的%抑制应当是≤70%。
表6-对于WO 2004/000828中没有具体公开的所包括的化合物C(N-[7-(4-哌啶基)氧基-1-苯并呋喃-5-基]-2-甲氧基-6-甲基苯磺酰胺)和化合物D(N-[7-(3-哌啶基)氧基-1-苯并呋喃-5-基]-2-甲氧基-5-甲基苯磺酰胺)所给出的值。对于化合物C和D二者,磺酰胺基团的SO2-部分结合至苯并呋喃环。
靶标 | 化合物C | 化合物D |
5-HT6-Ki | 26nM | 14nM |
5-HT6-fKi | 51nM | 37nM |
5-HT2a-Ki | 1000nM | 917nM |
5-HT2b-Ki | 600nM | 1450nM |
5-HT2c-Ki | 1250nM | 1370nM |
表4显示,与WO 2004/000828中包括的化合物A和B相比,实施例1对于5-HT6具有优于5-HT2a、5-HT2b和5-HT2c的选择性。
Claims (16)
2.用于治疗的根据权利要求1的化合物。
3.根据权利要求1的化合物,所述化合物用于治疗或预防5-HT6受体相关的疾病,诸如肥胖症、II型糖尿病,以实现体重和体重增加的减少。
4.根据权利要求1的化合物,所述化合物用于治疗或预防选自中枢神经***疾病的5-HT6受体相关的疾病。
5.根据权利要求4的化合物,其中所述中枢神经***的疾病是包括阿尔茨海默病的认知障碍和与精神***症有关的认知损伤。
6.一种药物制剂,所述药物制剂包含作为活性成分的根据权利要求1的化合物,和药用稀释剂或载体。
7.一种包含根据权利要求1的化合物的药物制剂,所述药物制剂用于治疗或预防5-HT6受体相关的疾病,诸如肥胖症、II型糖尿病,以实现体重和体重增加的减少。
8.一种包含根据权利要求1的化合物的药物制剂,其用于治疗或预防选自中枢神经***疾病的5-HT6受体相关的疾病。
9.根据权利要求8的药物制剂,其中所述中枢神经***的疾病是包括阿尔茨海默病的认知障碍和与精神***症有关的认知损伤。
10.用于治疗或预防5-HT6受体相关疾病的方法,所述疾病诸如肥胖症、II型糖尿病,以实现体重和体重增加的减少,所述方法包含将有效量的根据权利要求1的化合物施用至需要这种治疗的受试者。
11.用于治疗或预防选自中枢神经***疾病的5-HT6受体相关疾病的方法,所述方法包含将有效量的根据权利要求1的化合物施用至需要这种治疗的受试者。
12.根据权利要求11的方法,其中所述中枢神经***的疾病是包括阿尔茨海默病的认知障碍和与精神***症有关的认知损伤。
13.一种用于调节5-HT6受体活性的方法,所述方法包含将有效量的根据权利要求1的化合物施用至需要其的受试者。
14.根据权利要求1的化合物用于制备药物的用途,所述药物用于治疗或预防5-HT6受体相关的疾病诸如肥胖症、II型糖尿病,以实现体重和体重增加的减少。
15.根据权利要求1的化合物用于制备药物的用途,所述药物用于治疗或预防选自中枢神经***疾病的5-HT6受体相关的疾病。
16.根据权利要求15的用途,其中所述中枢神经***的疾病是包括阿尔茨海默病的认知障碍和与精神***症有关的认知损伤。
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