CN1457337A - 取代的联苯衍生物、制备它们的方法和含有它们的药物组合物 - Google Patents
取代的联苯衍生物、制备它们的方法和含有它们的药物组合物 Download PDFInfo
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- CN1457337A CN1457337A CN01815642A CN01815642A CN1457337A CN 1457337 A CN1457337 A CN 1457337A CN 01815642 A CN01815642 A CN 01815642A CN 01815642 A CN01815642 A CN 01815642A CN 1457337 A CN1457337 A CN 1457337A
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Abstract
本发明涉及式(I)化合物,其中:B代表氢原子、COOR基团、CONRR’基团或被COOR、CONRR’或OR基团取代的(C1-C6)烷基;G1代表-X’-(CH2)n-X-(CH2)m-X”-链,其中X、X’、X”、n和m如说明书所定义;Cy代表式(II)或(III)基团;G2代表如说明书所定义的亚烷基链;A代表NRCOR’、NRCSR’、CONRR’、CSNRR’、NRCONR’R”或NRCSNR’R”基团。
Description
本发明涉及新颖的取代的联苯化合物、它们的制备方法和含有它们的药物组合物。
从文献中已经知道吲哚型联苯化合物可用作金属蛋白酶抑制剂(WO96/15096)或特异性5HT-1B与5HT-1D受体配体(WO 95/01334)。
而且,苯并咪唑型联苯化合物在专利申请EP 468470中被描述为血管紧张素抑制剂。
由于它们新颖的结构,本发明的化合物是新的,并且它们表现出与褪黑激素能受体密切相关的药理性质。
在过去的十年里,大量研究表明褪黑激素(N-乙酰基-5-甲氧基色胺)在大量生理病理现象中和在昼夜节律的控制中扮演着重要角色,但是由于它被迅速代谢,因此褪黑激素具有相当短的半衰期。因此人们浓厚的兴趣在于使褪黑激素类似物可供临床医师利用的可能性,这些类似物在代谢上更稳定,具有激动剂或拮抗剂的特征,它们的治疗效果可以预期优于该激素本身。
除了它们在昼夜节律紊乱(J.Neurosurg.(神经外科学杂志),1985,第63期,第321-341页)和睡眠障碍(Psychopharmacology(心理药理学),1990,第100期,第222-226页)方面的有益作用以外,褪黑激素能系统的配体在中枢神经系统方面具有宝贵的药理性质,例如抗焦虑和抗精神病性质(Neuropharmacology of Pineal Secretions(松果体分泌物的神经药理学),1990,8(3-4),第264-272页)和止痛性质(Pharmacopsychiat.(药理精神病学),1987,第20期,第222-223页),还用于治疗帕金森氏病(J.Neurosurg.,1985,第63期,第321-341页)和阿尔茨海默氏病(Brain Research(脑研究),1990,第528页,第170-174页)。这类化合物在以下方面也表现出活性:某些癌症(Melatonin-Clinical Perspectives(《褪黑激素之临床前景》),牛津大学出版社,1988,第164-165页)、排卵(Science(科学),1987,第227期,第714-720页)、糖尿病(Clinical Endocrinology(临床内分泌学),1986,第24期,第359-364页)和肥胖的治疗(International Journal of EatingDisorders(国际饮食障碍杂志),1996,20(4),第443-446页)。
各种这些效果是以特异性褪黑激素受体为媒介发挥的。分子生物学研究表明存在大量能够结合该激素的受体亚型(Trends Pharmacol.Sci.(药理科学趋势),1995,第16期,第50页;WO 97.04094)。对于包括哺乳动物在内的不同物种,已经可以定位和鉴别这些受体中的一些。为了能够更好地理解这些受体的生理功能,人们对获得特异性配体具有浓厚的兴趣。而且,这类化合物通过选择性地相互作用于这些受体中的一种或另一种,可以成为优异的药物,供临床医师治疗与褪黑激素能系统有关的病变,它们中的一些已经在上文中提到过。
除了是新化合物以外,本发明的化合物对褪黑激素受体表现出非常强的亲合性和/或对褪黑激素能受体亚型中的一种或另一种表现出选择性。
更尤其地,本发明涉及式(I)化合物:其中:□B代表氢原子、COOR基团、CONRR’基团或被COOR、CONRR’或OR基团取代的直链或支链(C1-C6)烷基(其中R和R’可以相同或不同,各自代表氢原子、直链或支链(C1-C6)烷基、直链或支链(C2-C6)链烯基、直链或支链(C2-C6)炔基、芳基、其中烷基部分可以是直链或支链的芳基-(C1-C6)烷基、杂芳基、其中烷基部分可以是直链或支链的杂芳基-(C1-C6)烷基、其中烷基部分可以是直链或支链的全卤代-(C1-C6)烷基、(C3-C8)环烷基或其中烷基部分可以是直链或支链的(C3-C8)环烷基-(C1-C6)烷基,另外有可能的是R和R’与携带它们的氮原子一起构成吗啉基、哌啶基、哌嗪基或吡咯烷基),□G1代表-X’-(CH2)n-X-(CH2)m-X”-链,其中 ◆X代表氧原子或硫原子,或CH2或NR基团(其中R如上所定义),◆X’和X”可以相同或不同,各自代表氧原子或硫原子或NR基团(其中
R如上所定义),◆n和m可以相同或不同,各自代表0、1、2、3、4或5,应理解的是不可能具有两个连续的杂原子且所定义的链可以含有一个或多个不饱和度,□Cy代表式(II)基团其中D代表苯基或吡啶,W代表氧原子或硫原子,或CH2或NR基团(其中R如上所定义),R1代表卤原子或R、OR或COOR基团(其中R如上所定义),符号
表示该键是单键或双键,应理解的是遵守原子的化合价,或式(III)基团其中R1和符号
如上所定义,□G2代表含有1至6个碳原子的链,它可选地被一个或多个选自R、OR、COR、COOR(其中R如上所定义)和卤原子的基团取代,□A代表基团NRCOR’、NRCSR’、CONRR’、CSNRR’、NRCONR’R”或NRCSNR’R”(其中R和R’如上所定义,R”可以具有与R和R’相同的含义),其中:●“芳基”应理解为指苯基或萘基,它是未取代的或者被一个或多个相同或不同的基团取代,取代基选自R、OR、COR、COOR、NRR’(其中R和R’如上所定义)、硝基、氰基和卤原子,●“杂芳基”应理解为指任意单-或二环基团,它具有5至10个环成员, 并且可以含有1至3个选自氧、硫和氮的杂原子,该基团是未取代的或者被一个或多个相同或不同的基团取代,取代基选自R、OR、COR、COOR、NRR’(其中R和R’如上所定义)、硝基、氰基和卤原子,还涉及它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐。
在药学上可接受的酸中,可以以非限制性实例提到盐酸、氢溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、甲磺酸、樟脑酸等。
在药学上可接受的碱中,可以以非限制性实例提到氢氧化钠、氢氧化钾、三乙胺、叔丁胺等。
优选的本发明化合物是这样的式(I)化合物,其中B代表:-COOR基团,其中R优选为氢原子或直链或支链(C1-C6)烷基,例如甲基,-或直链或支链(C1-C6)烷基,它被COOR或OR基团,更尤其被COOH、烷氧羰基、OH或烷氧基取代。
本发明化合物的优选G1基团是基团-O-(CH2)p-O-,其中p是整数,满足0<p<6,例如-O-(CH2)4-O-。
本发明更尤其地涉及这样的式(I)化合物,其中Cy代表萘、四氢化萘、苯并噻吩、苯并呋喃、吲哚、茚或吖吲哚基团。
G2优选地代表-(CH2)2-或-(CH2)3-基团。
A的优选含义是基团NRCOR’和CONRR’,更尤其为基团NHCOR’和CONHR。
进而更尤其地,本发明涉及下列式(I)化合物:-4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯,-4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸,-N-{2-[7-(4-{[4’-(羟甲基)-[1,1’-联苯]-4-基]氧基}丁氧基)-1-萘基]乙基}乙酰胺,-N-(2-{7-[4-([1,1’-联苯]-4-基氧基)丁氧基]-1-萘基}乙基)乙酰胺,-N-(2-{7-[4-([1,1’-联苯]-3-基氧基)丁氧基]-1-萘基}乙基)乙酰胺。
优选的本发明化合物的对映体、非对映体以及与药学上可接受的酸或碱的加成盐构成该整个本发明。
本发明还涉及式(I)化合物的制备方法,该方法的特征在于使用下式化合物作为原料:
MeO-Cy-G2-A (IV)其中A、G2和Cy如式(I)中所定义,利用常规试剂如HBr、AlCl3、AlBr3、BBr3或路易斯酸/亲核试剂二元体系如AlCl3/PhCH2SH或BBr3/Me2S将其进行脱甲基化,例如得到式(V)化合物:
HO-Cy-G2-A (V)其中A、G2和Cy如上所定义,式(V)化合物再按照常规方式,
-例如通过N,N-二甲基硫代氨基甲酸钠的作用,转化为对应的式(VI)硫
醇:
HS-Cy-G2-A (VI)
其中A、G2和Cy如上所定义,
-或者转化为对应的式(VII)胺化合物:
RNH-Cy-G2-A (VII)
其中A、G2、Cy和R如上所定义,式(V)、(VI)和(VII)化合物表示成式(VIII)化合物:
HX”-Cy-G2-A (VIII)其中Cy、G2、X”和A如上所定义,将式(VIII)化合物与式(IX)化合物缩合:其中Hal代表溴、氯或碘原子,X、n和m如式(I)中所定义(应理解的是不可能具有两个连续的杂原子且所定义的链可以含有一个或多个不饱和度),得到式(X)化合物:
HO-(CH2)n-X-(CH2)m-X”-Cy-G2-A (X)其中A、G2、Cy、X、X”、n和m如上所定义(应理解的是在HO-(CH2)n-X-(CH2)m-X”-链中不可能具有两个连续的杂原子且所定义的链可以含有一个或多个不饱和度),式(X)化合物的羟基官能团按照常规方式转化为离去基团,例如甲磺酸酯、甲苯磺酸酯或卤代化合物,得到式(X’)化合物:
E-(CH2)n-X-(CH2)m-X”-Cy-G2-A (X’)其中A、G2、Cy、X、X”、n和m如上所定义,E代表甲磺酰基、甲苯磺酰基或卤原子,将式(X’)化合物在碱性介质中与式(XI)化合物反应:
B’-Ph-Ph-X’H (XI)其中X’如式(I)中所定义,B’可以具有与为式(I)所定义的B相同的含义,但基团COOH和被COOH基团取代的烷基除外,得到式(I/a)化合物,其为式(I)化合物的特例:
B’-Ph-Ph-G1-Cy-G2-A (I/a)其中A、G2、G1、Cy和B’如上所定义,当B’代表COOR1’基团或被COOR1’基团取代的烷基(其中R1’可以具有任意如上所定义的R的含义,但氢原子除外)时,将式(I/a)化合物进行水解,得到式(I/b)化合物,其为式(I)化合物的特例:
B”-Ph-Ph-G1-Cy-G2-A (I/b)其中A、G2、G1和Cy如上所定义,B”代表COOH基团或被COOH基团取代的烷基,全部化合物(I/a)和(I/b)构成式(I)化合物,如果需要的话,它们可以通过常规纯化技术纯化,可选地按照常规分离技术分离为它们的异构体,如果需要的话,转化为与药学上可接受的酸或碱的加成盐。
按照文献所述方法,本领域熟练技术人员可容易得到式(IV)化合物。
本发明的化合物和含有它们的药物组合物已证实可用于治疗褪黑激素能系统的障碍。
本发明化合物的药理研究事实上已表明它们是无毒的,对褪黑激素受体具有高亲合性,在中枢神经系统和微循环方面具有显著的活性,因此能够确立本发明的产物可用于治疗精神紧张、睡眠障碍、焦虑、季节性情感障碍、心血管病变、消化系统病变、由飞行时差反应引起的失眠与疲劳、精神分裂症、恐慌发作、精神忧郁症、食欲紊乱、肥胖、失眠、疼痛、精神病、癫痫、糖尿病、帕金森氏病、老年性痴呆、与正常或病理性衰老有关的各种障碍、偏头痛、记忆丧失、阿尔茨海默氏病和脑循环障碍。在活性的另一个领域,似乎本发明的产物可用于治疗性功能障碍,它们具有排卵抑制性质和免疫调节性质,以及它们能够用于治疗癌症。
化合物将优选地用于治疗季节性情感障碍、睡眠障碍、心血管病变、由飞行时差反应引起的失眠与疲劳、食欲紊乱和肥胖。
例如,化合物将用于治疗季节性情感障碍和睡眠障碍。
本发明还涉及药物组合物,包含单独的至少一种式(I)化合物或者与一种或多种药学上可接受的赋形剂的组合。
在本发明的药物组合物中,可以更尤其地提到适合于口服、肠胃外、鼻、经皮或透皮、直肠、经舌、眼或呼吸给药的那些,尤其是片剂或糖锭剂、舌下片、袋装药、paquet、明胶胶囊剂、glossette、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶剂和可饮用或可注射的安瓿剂。
剂量因患者的性别、年龄与体重、给药途径、治疗适应症的属性或可能联用的治疗而异,从每24小时0.01mg至1g不等,分一次或多次给药。
下列实施例阐述本发明,但是不以任何方式限制之。下列制备例得到本发明化合物或得到可用于本发明制备过程中的合成中间体。制备例1:N-[2-(7-羟基-1-萘基)乙基]乙酰胺
在惰性气氛下,将27.5mmol三溴化硼/二甲基硫配合物溶于100ml二氯甲烷中,在室温下搅拌15分钟。加入13.7mmol N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的50ml二氯甲烷溶液,将反应混合物加热回流30小时。冷却后,小心地水解反应混合物,蒸发除去二氯甲烷。然后用乙酸乙酯萃取混合物,合并有机相,用1M碳酸氢钾水溶液洗涤。有机相经硫酸镁干燥,浓缩,得到标题化合物,为白色固体。熔点:125-126℃
按制备例1进行操作,使用适当的反应物作为原料,得到制备例2至14:制备例2:N-[2-(5-羟基-1-苯并呋喃-3-基)乙基]乙酰胺制备例3:N-[2-(5-羟基-1-苯并呋喃-3-基)乙基]环丙烷甲酰胺制备例4:N-[2-(5-羟基-1-苯并呋喃-3-基)乙基]-2-糠酰胺制备例5:N-[2-(7-羟基-1-萘基)乙基]丁酰胺制备例6:N-[2-(5-羟基-1-苯并噻吩-3-基)乙基]乙酰胺制备例7:N-[2-(5-羟基-1H-吡咯并[2,3-b]吡啶-3-基)乙基]环丙烷甲酰胺制备例8:N-[2-(5-羟基-1H-吲哚-3-基)乙基]乙酰胺制备例9:N-[2-(5-羟基-1H-吡咯并[2,3-b]吡啶-3-基)乙基]乙酰胺制备例10:N-[2-(7-羟基-1-萘基)乙基]环丁烷甲酰胺制备例11:2,2,2-三氟-N-[2-(7-羟基-1-萘基)乙基]乙酰胺制备例12:N-[2-(7-羟基-1-萘基)乙基]-2-糠酰胺制备例13:N-[2-(2-苄基-5-羟基-1H-吡咯并[2,3-b]吡啶-3-基)乙基]乙酰胺制备例14:N-[2-(5-羟基-1H-茚-3-基)乙基]戊酰胺制备例15:N-[2-(5-巯基-1-苯并呋喃-3-基)乙基]乙酰胺
在搅拌下,向氢氧化钾(10mmol)的15ml水与16ml四氢呋喃的溶液中,加入制备例2所得产物(9mmol)。将溶液用冰/盐浴冷却,在搅拌下滴加二甲基硫代氨基甲酰氯(9mmol)的四氢呋喃(15ml)溶液。搅拌半小时,同时保持冷却,将反应混合物用氯仿萃取。合并有机相,经硫酸镁干燥,过滤,然后在减压下浓缩。将残余物溶于二苯醚(10ml)中,在氮气氛下加热回流一小时。在减压下蒸发除去二苯醚,直至得到大约2ml溶液。将该2ml蒸馏物趁热小心地倒入50ml己烷中,冷却后,过滤得到固体。向氢氧化钾(380mg)的水/甲醇(1ml/10ml)溶液中加入所得固体。将溶液加热回流12小时,然后冷却,在减压下浓缩。将残余物溶于20ml氯仿中,用水萃取3次。有机相经硫酸镁干燥,过滤,在减压下浓缩。残余物经过硅胶色谱纯化,得到标题产物。制备例16:N-[2-(5-氨基-1-苯并呋喃-3-基)乙基]乙酰胺步骤A:N-[2-(5-溴-1-苯并呋喃-3-基)乙基]乙酰胺将三苯膦(10mmol)和乙腈(70ml)倒入150ml三颈烧瓶内,该烧瓶配有滴液漏斗、冷凝器和机械搅拌器,冷凝器的顶部装有充满氯化钙的试管。将溶液用冰浴冷却,同时保持搅拌,加入溴(10mmol)。当加入完毕时,除去冰浴,然后加入制备例2所得产物(8mmol)。将反应混合物在60-70℃下搅拌,直至原料消失。在反应结束时,过滤混合物,然后在减压下浓缩滤液。将残余物溶于乙酸乙酯中,用水洗涤,再用饱和碳酸氢钾溶液洗涤,再用水洗涤一次,然后经硫酸镁干燥,在减压下浓缩。残余物经过硅胶过滤,得到标题产物。步骤B:N-[2-(5-碘-1-苯并呋喃-3-基)乙基]乙酰胺
在氮气氛和搅拌下,将步骤A所得产物(2mmol)、碘化钾(30mmol)与碘化铜(I)(10mmol)在六甲基磷酰胺(6ml)中的混合物在150-160℃下加热,直至达到90%的转化率。然后依次加入稀盐酸和乙醚,然后过滤混合物,除去不溶的铜(I)盐。分离有机相,用亚硫酸钠溶液和水洗涤,经硫酸镁干燥,蒸发,得到残余物,经过硅胶色谱纯化,得到标题产物。步骤C:N-[2-(5-乙烯基-1-苯并呋喃-3-基)乙基]乙酰胺
在30ml N-甲基吡咯烷酮中,在搅拌下将15mmol步骤B所得产物、16mmol乙烯基三丁基锡和0.43mmol四(三苯膦)钯在110℃下加热3小时。蒸发除去溶剂后,将残余物溶于20ml二氯甲烷中,用10%氟化钾水溶液处理。萃取,在减压下浓缩和硅胶色谱纯化,得到纯的标题产物。步骤D:N-[2-(5-甲酰基-1-苯并呋喃-3-基)乙基]乙酰胺
在室温下,向10mmol步骤C所得产物的50ml二噁烷与25ml水的溶液中,依次加入1.10g四氧化锇的2-甲基-2-丙醇溶液和8.70g高碘酸钠。在室温下搅拌一夜后,过滤该悬浮液,在减压下浓缩滤液。将所得残余物溶于二氯甲烷中。将有机相用水洗涤,干燥,蒸发。残余物经过硅胶色谱纯化,得到标题产物。步骤E:3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-甲酸
在室温下,向6.88mmol步骤D所得产物的30ml丙酮溶液中加入2.7g高锰酸钾的50ml丙酮/水(50/50)溶液。将溶液在室温下搅拌2小时,然后过滤。在减压下浓缩滤液,经过硅胶色谱纯化,得到标题产物。步骤F:3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-甲酰氯
将5mmol步骤E所得产物溶于40ml亚硫酰氯中。在惰性气氛下搅拌1小时后,在减压下蒸发除去亚硫酰氯,得到标题产物。步骤G:N-[2-(5-氨基-1-苯并呋喃-3-基)乙基]乙酰胺
将步骤F所得产物(20mmol)在含有溴化四丁基铵(20mg)的二氯甲烷(30ml)中的溶液在冰浴中冷却。在加入叠氮化钠(25mmol)的5ml水溶液后,将溶液在0℃下剧烈搅拌2小时。分离有机相,用水洗涤(2×5ml),经硫酸镁干燥。过滤后,加入三氟乙酸(30mmol),将溶液在回流下搅拌60小时。冷却后,将有机相用饱和碳酸氢钠溶液洗涤(2×5ml),在减压下浓缩。然后将残余物溶于甲醇(20ml)中,依次加入水(80ml)和碳酸钾(30mmol)。在室温下搅拌20小时后,将反应混合物在减压下浓缩至体积约60ml,然后用乙醚萃取3次(3×50ml)。经硫酸钠干燥后,过滤有机相,然后在减压下蒸发。残余物经过硅胶色谱纯化,得到标题产物。制备例17:N-[2-(5-氨基-1-苯并呋喃-3-基)乙基]-2-糠酰胺
工艺同制备例16,但从制备例4所得化合物开始。制备例18:N-[2-(5-羟基-1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)乙基]乙酰胺
工艺同制备例1。制备例19:N-[2-(7-羟基-1,2,3,4-四氢-1-萘基)乙基]乙酰胺
工艺同制备例1。制备例20:N-[2-(5-羟基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-基)乙基]乙酰胺
工艺同制备例1。实施例1:4’-[2-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯步骤A:N-{2-[7-(2-溴乙氧基)萘-1-基]乙基}乙酰胺
将制备例1所得化合物(0.009mol)溶于20ml二甲基亚砜(6ml)与丁酮(14ml)的混合物中。加入0.027mol碳酸钾和0.036mol二溴乙烷,将混合物加热回流48小时。然后将反应混合物冷却,倒入水中。含水相用Et2O萃取,然后将有机相用水洗涤,直至洗涤的水呈中性,随后经硫酸镁干燥,在减压下蒸发。所得残余物经过硅胶色谱纯化(洗脱剂:丙酮/环己烷(2/8)),重结晶,得到白色固体。熔点:110-111℃元素微量分析:
% C H N
计算值: 57.15 5.40 4.17
实测值: 57.28 5.38 3.91步骤B:4’-[2-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
在100ml圆底烧瓶内,将0.003mol 4’-羟基[1,1’-联苯]-4-甲酸甲酯和0.003mol步骤A所得化合物溶于3ml 甲基亚砜与20ml丁酮的混合物中。加入0.009mol碳酸钾和一粒碘化钾晶体,然后将混合物加热回流12小时。然后将反应混合物冷却,倒入100ml水中。吸出所生成的沉淀,重结晶,得到标题产物。实施例2:4’-[2-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸
在100ml圆底烧瓶内,将19mmol实施例1所得化合物悬浮在25mlTHF中,然后加入15ml甲醇、15ml水和38mmol氢氧化钠。将反应混合物在室温下搅拌10小时。随后将溶液浓缩,倒入水中,然后用12M HCl酸化。滤出所得沉淀,用水洗涤,重结晶,得到标题产物。实施例3:4’-[2-({3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例2所得化合物代替制备例1所得化合物。实施例4:4’-{2-[(3-{2-[(环丙基羰基)氨基]乙基}-1-苯并呋喃-5-基)氧基]乙氧基}-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例3所得化合物代替制备例1所得化合物。实施例5:4’-[2-({3-[2-(2-呋喃甲酰氨基)乙基]-1-苯并呋喃-5-基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例4所得化合物代替制备例1所得化合物。实施例6:4’-[2-({3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-基}氨基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例16所得化合物代替制备例1所得化合物。实施例7:4’-[2-({8-[2-(丁酰氨基)乙基]-2-萘基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例5所得化合物代替制备例1所得化合物。实施例8:4’-[2-({3-[2-(乙酰氨基)乙基]-1-苯并噻吩-5-基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例6所得化合物代替制备例1所得化合物。实施例9:4’-{2-[(3-{2-[{环丙基羰基)氨基]乙基}-1H-吡咯并[2,3-b]吡啶-5-基)氧基]乙氧基}-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例7所得化合物代替制备例1所得化合物。实施例10:N-{2-[7-(2-{[4’-(羟甲基)-[1,1’-联苯]-4-基]氧基}乙氧基)-1-萘基]乙基}乙酰胺
工艺同实施例1,但在步骤B中用4’-(羟甲基)-[1,1’-联苯]-4-醇代替4’-羟基[1,1’-联苯]-4-甲酸甲酯。实施例11:4’-[2-({3-[2-(乙酰氨基)乙基]-1H-吲哚-5-基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1,但在步骤A中用制备例8所得化合物代替制备例1所得化合物。实施例12:4’-[2-({3-[2-(乙酰氨基)乙基]-1H-吲哚-5-基}氧基)乙氧基]-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例11所得化合物开始。实施例13:4’-[3-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丙氧基]-[1,1’-联苯]-4-甲酸甲酯步骤A:N-{2-[7-(3-羟基丙氧基)萘-1-基]乙基}乙酰胺
在100ml圆底烧瓶内,将0.022mol制备例1所得化合物溶于30ml二甲基甲酰胺中。加入0.066mol碳酸钾和0.033mol 3-溴丙-1-醇,然后将混合物在80℃下加热4小时。将反应混合物冷却,倒入100ml 1M HCl溶液中。含水相用Et2O萃取3次,然后将有机相经MgSO4干燥,在减压下蒸发。重结晶,得到标题产物,为白色固体。熔点:141-142℃步骤B:甲磺酸3-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丙基酯
在250ml圆底烧瓶内,将步骤A所得醇溶于50ml二氯甲烷中,加入0.012mol三乙胺。将混合物在-10℃的冰/盐浴中冷却,然后在磁搅拌下滴加0.012mol甲磺酰氯。将反应混合物在室温下搅拌4小时。然后加入100ml水,然后用CH2Cl2萃取。将有机相用水洗涤,经MgSO4干燥,在减压下蒸发。所得油通过硅胶色谱纯化(洗脱剂:丙酮/环己烷(2/8))。步骤C:4’-[3-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丙氧基]-[1,1’-联苯]-4-甲酸甲酯
在含有30ml甲醇的100ml圆底烧瓶内,分小批量加入0.06g钠。当钠被完全耗尽时,加入0.0033mol 4’-羟基[1,1’-联苯]-4-甲酸甲酯,将混合物搅拌20分钟。在减压下蒸发除去甲醇,将残余物溶于15ml DMF中,然后加入0.0027mol步骤B所得化合物。然后将反应混合物加热回流12小时,随后冷却,倒入100ml水与10ml 3M HCl中。用乙酸乙酯萃取后,将有机相依次用10%氢氧化钠溶液和水洗涤。经MgSO4干燥后,在减压下蒸发除去溶剂,经过硅胶色谱纯化得到标题化合物。实施例14:4’-{3-[(8-{2-[(环丁基羰基)氨基]乙基}-2-萘基)氧基]丙氧基}-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例13,但从制备例10所得化合物开始。实施例15:4’-[3-({3-[2-(2-呋喃甲酰氧基)乙基]-1-苯并呋喃-5-基}氨基)丙氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例13,但从制备例17所得化合物开始。实施例16:4’-[3-({3-[2-(2-呋喃甲酰氨基)乙基l-1-苯并呋喃-5-基}氨基丙氧基)-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例15所得化合物开始。实施例17:4’-{3-[(8-{2-[(三氟乙酰基)氨基]乙基}-2-萘基)氧基]丙氧基}-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例13,但用制备例11化合物代替制备例1化合物。实施例18:4’-{3-[(8-{2-[(三氟乙酰基)氨基]乙基}-2-萘基)氧基]丙氧基}-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例17所得化合物开始。实施例19:4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯步骤A:N-{2-[7-(4-溴丁氧基)-1-萘基]乙基}乙酰胺
工艺同实施例1步骤A,但用1,4-二溴丁烷代替二溴乙烷。步骤B:4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例1步骤B。
白色固体。熔点:166-168℃元素微量分析:
% C H N
计算值: 74.61 6.45 2.72
实测值: 74.62 6.48 2.81实施例20:4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例19所得化合物开始。
白色固体。熔点:223-225℃元素微量分析:
% C H N
计算值: 70.83 5.94 2.66
实测值: 71.16 6.05 2.69实施例21:N-{2-[7-(4-{[4’-(羟甲基)-[1,1’-联苯]-4-基]氧基}丁氧基)-1-萘基]乙基}乙酰胺
工艺同实施例19,但在步骤B中用4’-(羟甲基)-[1,1’-联苯]-4-醇代替4’-羟基[1,1’-联苯]-4-甲酸甲酯。
米色固体。熔点:172-173℃元素微量分析:
% C H N
计算值: 76.99 6.88 2.90
实测值: 76.74 6.70 3.12实施例22:N-(2-{7-[4-(1,1’-联苯]-4-基氧基)丁氧基]-1-萘基}乙基)乙酰胺
工艺同实施例19,但在步骤B中用[1,1’-联苯]-4-醇代替4’-羟基[1,1’-联苯]-4-甲酸甲酯。
白色固体。熔点:138-140℃元素微量分析:
% C H N
计算值: 79.44 6.89 3.10
实测值: 79.19 6.93 3.24实施例23:N-(2-{7-[4-({1,1’-联苯]-3-基氧基)丁氧基]-1-萘基}乙基)乙酰胺
工艺同实施例19,但在步骤B中用[1,1’-联苯]-3-醇代替4’-羟基[1,1’-联苯]-4-甲酸甲酯。
白色固体。熔点:111-112℃元素微量分析:
% C H N
计算值: 79.44 6.89 3.10
实测值: 79.23 6.79 3.21实施例24:4’-[4-({3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例2所得化合物开始。实施例25:4’-[4-({3-[2-(乙酰氨基)乙基]-1-苯并噻吩-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例6所得化合物开始。实施例26:4’-[4-({3-[2-(乙酰氨基)乙基]-1H-吡咯并[2,3-b]吡啶-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例9所得化合物开始。实施例27:4’-[4-({3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例24所得化合物开始。实施例28:4’-[4-({3-[2-(乙酰氨基)乙基]-1-苯并噻吩-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例25所得化合物开始。实施例29:4’-[4-({3-[2-(乙酰氨基)乙基]-1H-吡咯并[2,3-b]吡啶-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸
工艺同实施例2,但从实施例26所得化合物开始。实施例30:4’-[4-({3-[2-(乙酰氨基)乙基]-2-苄基-1H-吡咯并[2,3-b]吡啶-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例13所得化合物开始。实施例31:4’-[4-({8-[2-(2-呋喃甲酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例12所得化合物开始。实施例32:4’-[4-({3-[2-(戊酰氨基)乙基]-1H-茚-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例14所得化合物开始。实施例33:4’-[4-({3-[2-(乙酰氨基)乙基]-1-苯并呋喃-5-基}硫基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例15所得化合物开始。实施例34:4’-[4-({3-[2-(乙酰氨基)乙基]-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯
工艺同实施例19,但从制备例18所得化合物开始。实施例35:3’-[4-({8-[2-(乙酰氨基)乙基]-5,6,7,8-四氢-2-萘基}氧基)丁氧基]-[1,1’-联苯]-3-甲酸甲酯
工艺同实施例19,但从制备例19所得化合物开始。实施例36:3’-[4-({8-[2-(乙酰氨基)乙基]-5,6,7,8-四氢-2-萘基}氧基)丁氧基]-[1,1’-联苯]-3-甲酸
工艺同实施例2,但从实施例35所得化合物开始。实施例37:4’-[4-({3-[2-(乙酰氨基)乙基]-1-甲基-1H-吡咯并[3,2-b]吡啶-5-基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸乙酯
工艺同实施例19,但从制备例20所得化合物和4’-羟基[1,1’-联苯]-4-甲酸乙酯开始。熔点:145-146℃元素微量分析:
% C H N
计算值: 70.30 6.66 7.93
实测值: 69.84 6.67 7.94
药理研究 实施例A:急性毒性研究
每8只小鼠(26±2克)为一组,口服给药后评价急性毒性。在第一天中按规则间隔观察这些动物,在处理后两周内每天对其观察。评价LD50(导致50%动物死亡的剂量),表明本发明化合物的低毒性。实施例B:针对绵羊结节部(Pars tuberalis)细胞的褪黑激素受体结合研究
按照常规技术,针对绵羊的结节部细胞进行本发明化合物的褪黑激素结合研究。腺垂体的结节部事实上在哺乳动物中以高密度褪黑激素受体为特征(Journal of Neuroendocrinology(神经内分泌学杂志)第1期,第1-4页,1989)。方案
1)准备绵羊结节部膜,在饱和实验中用作靶组织,以测定对2-[125I]-碘褪黑激素的结合能力和亲合性。
2)将绵羊结节部膜在竞争性结合实验中用作靶组织,对各种供试化合物与褪黑激素进行比较。
每项实验重复进行三次,试验每种化合物的不同浓度范围。经统计学处理后,结果能够确定供试化合物的结合亲合性。结果
本发明化合物对褪黑激素受体显示出强亲合性。实施例C:褪黑激素MT1和MT2受体结合研究
使用2-[125I]-碘褪黑激素作为参照放射性配体,进行MT1或MT2受体结合实验。利用液体闪烁计数器测定所保留的放射性。
然后使用各种供试化合物进行竞争性结合实验,重复三次。试验每种化合物的不同浓度范围。结果能够确定供试化合物的结合亲合性(IC50)。
因而,本发明化合物的IC50值显示结合MT1和MT2受体亚型的一种或另一种,这些值≤10μM。实施例D:本发明化合物对大鼠运动的昼夜节律的作用
褪黑激素通过昼/夜交替参与影响大部分生理、生化与行为的昼夜节律,这有可能建立用于研究褪黑激素能配体的药理模型。
试验化合物对大量参数,尤其是对运动的昼夜节律的效果,该节律是内在昼夜节律钟活动的可靠指标。
在本研究中,评价这类化合物对特定实验模型,即处于暂时隔离(持久性黑暗)的大鼠的效果。实验方案
当一月龄雄性大鼠一运到实验室,立即对其进行这样的光照循环:每24小时光照12小时(LD 12:12)。
2至3周的适应期后,将它们置于笼子内,该笼子安装有与记录系统连接的轮子,目的是检测运动时相,从而监测明暗(nychthemeral)节律(LD)或昼夜节律(DD)。
一旦所记录的节律显示在光照周期LD 12:12中达到稳定方式,将大鼠置于永久性黑暗(DD)中。
二至三周后,当明显建立起自由过程(反映内在昼夜节律钟的节律)时,每天将供试化合物对大鼠给药。
通过活动节律的形象化进行观察:-光照节律对活动节律的影响,-在永久性黑暗中对节律的影响的消失,-通过将化合物每日给药所产生的影响;临时或持久的效果。
软件包可以:-测量动物在自由过程中和处理期间的活动持续时间和强度、节律的时期,-可选地通过光谱分析表明昼夜与非昼夜(例如次昼夜)成分的存在。结果
本发明的化合物明显显示出经由褪黑激素能系统对昼夜节律具有强大的作用。实施例E:亮/暗笼子试验
针对行为模型,即亮/暗笼子试验,试验本发明的化合物,这能够揭示这类化合物的抗焦虑活性。
装置具有两个用有机玻璃覆盖的聚乙烯盒子。一个盒子处于黑暗中。在另一个盒子上方放置一盏灯,使盒子中央的光强为大约4000勒克斯。不透明的塑料通道将明亮的盒子和暗盒子分隔开。将动物单独试验5分钟。在每次试验期之间清洁每个盒子的地面。在每次试验开始时,将小鼠置于通道内,面向暗盒子。在第一次进入暗盒子之后记录小鼠花在照明盒子内的时间和通过通道的次数。
在试验开始前30分钟将化合物给药后,本发明的化合物显著增加花在照明盒子内的时间和通过通道的次数,这表明本发明化合物的抗焦虑活性。实施例F:本发明化合物对大鼠尾动脉的活性
针对大鼠的尾动脉体外试验本发明的化合物。褪黑激素能受体存在这些血管中,因而提供相关的药理模型,用于研究褪黑激素能配体活性。刺激受体可诱导血管收缩或扩张,这取决于所研究的动脉片段。方案
使一月龄大鼠习惯12h/12h的亮/黑周期,为时2至3周。
处死后,分离尾动脉,供养在高度充氧的介质中。然后在动脉两端插套管,垂直悬挂在适合介质中的器官腔内,经由近端灌注。灌注流的压力变化能够评价化合物的血管收缩效果或血管扩张效果。
评价化合物对预先已被脱羟肾上腺素(1μM)收缩的片段的活性。向预先收缩的片段加入一定浓度的供试化合物,非累积地测定浓度/响应曲线。当所观察到的效果达到平衡时,更换介质,间隔20分钟,再加入相同浓度的脱羟肾上腺素和另外浓度的供试化合物。结果
本发明的化合物显著改变预先被脱羟肾上腺素收缩的尾动脉的直径。实施例G:药物组合物:片剂
1000片,每片含有5mg 4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸(实施例20)………………………………………5g小麦淀粉……………………………………………………………………………20g玉米淀粉……………………………………………………………………………20g乳糖…………………………………………………………………………………30g硬脂酸镁……………………………………………………………………………2g硅石…………………………………………………………………………………1g羟丙基纤维素………………………………………………………………………2g
Claims (17)
1、式(I)化合物:其中:□B代表氢原子、COOR基团、CONRR’基团或被COOR、CONRR’或OR基团取代的直链或支链(C1-C6)烷基,其中R和R’可以相同或不同,各自代表氢原子、直链或支链(C1-C6)烷基、直链或支链(C2-C6)链烯基、直链或支链(C2-C6)炔基、芳基、其中烷基部分可以是直链或支链的芳基-(C1-C6)烷基、杂芳基、其中烷基部分可以是直链或支链的杂芳基-(C1-C6)烷基、其中烷基部分可以是直链或支链的全卤代-(C1-C6)烷基、(C3-C8)环烷基或其中烷基部分可以是直链或支链的(C3-C8)环烷基-(C1-C6)烷基,另外有可能的是R和R’与携带它们的氮原子一起构成吗啉基、哌啶基、哌嗪基或吡咯烷基,□G1代表-X’-(CH2)n-X-(CH2)m-X”-链,其中◆X代表氧原子或硫原子,或CH2或NR基团,其中R如上所定义,◆X’和X”可以相同或不同,各自代表氧原子或硫原子或NR基团,其中
R如上所定义,◆n和m可以相同或不同,各自代表0、1、2、3、4或5,
应理解的是不可能具有两个连续的杂原子且所定义的链可以含有一个
或多个不饱和度,□Cy代表式(II)基团其中D代表苯基或吡啶,W代表氧原子或硫原子或CH2或NR基团,其中R如上所定义,R1代表卤原子或R、OR或COOR基团,其中R如上所定义,符号
表示该键是单键或双键,应理解的是遵守原子的化合价,或式(III)基团其中R1和符号
如上所定义,□G2代表含有1至6个碳原子的链,它可选地被一个或多个选自R、OR、COR、COOR和卤原子的基团取代,其中R如上所定义,□A代表基团NRCOR’、NRCSR’、CONRR’、CSNRR’、NRCONR’R”或NRCSNR’R”,其中R和R’如上所定义,R”可以具有与R和R’相同的含义,其中:●“芳基”应理解为指苯基或萘基,它是未取代的或者被一个或多个相同或不同的基团取代,取代基选自R、OR、COR、COOR、NRR’、硝基、氰基和卤原子,其中R和R’如上所定义,●“杂芳基”应理解为指任意单-或二环基团,它具有5至10个环成员,能够含有1至3个选自氧、硫和氮的杂原子,该基团是未取代的或者被一个或多个相同或不同的基团取代,取代基选自R、OR、COR、COOR、NRR’、硝基、氰基和卤原子,其中R和R’如上所定义,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐。
2、根据权利要求1的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中B代表COOR基团。
3、根据权利要求2的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中B代表COOR基团,其中R代表氢原子。
4、根据权利要求2的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中B代表COOR基团,其中R代表直链或支链(C1-C6)烷基。
5、根据权利要求1的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中B代表被COOR基团取代的直链或支链(C1-C6)烷基。
6、根据权利要求1的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中B代表被OR基团取代的直链或支链(C1-C6)烷基。
7、根据权利要求1的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中G1代表-O-(CH2)p-O-基团,其中p是整数,满足0<p<6。
8、根据权利要求1的式(I)化合物,它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中Cy代表萘基。
9、根据权利要求1的式(I)化合物、它们的对映体和非对映体,及其与药学上可接受的酸或碱的加成盐,其中A代表NHCOR基团。
10、根据权利要求1的式(I)化合物,它是4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸甲酯,及其与药学上可接受的酸或碱的加成盐。
11、根据权利要求1的式(I)化合物,它是4’-[4-({8-[2-(乙酰氨基)乙基]-2-萘基}氧基)丁氧基]-[1,1’-联苯]-4-甲酸,及其与药学上可接受的酸或碱的加成盐。
12、根据权利要求1的式(I)化合物,它是N-{2-[7-(4-{[4’-(羟甲基)-[1,1’-联苯]-4-基]氧基}丁氧基)-1-萘基]乙基}乙酰胺,及其与药学上可接受的酸或碱的加成盐。
13、根据权利要求1的式(I)化合物,它是N-(2-{7-[4-([1,1’-联苯]-4-基氧基)丁氧基]-1-萘基}乙基)乙酰胺,及其与药学上可接受的酸或碱的加成盐。
14、根据权利要求1的式(I)化合物,它是N-(2-{7-[4-([1,1’-联苯]-3-基氧基)丁氧基]-1-萘基}乙基)乙酰胺,及其与药学上可接受的酸或碱的加成盐。
15、制备根据权利要求1的式(I)化合物的方法,其特征在于使用下式(IV)化合物作为原料:
MeO-Cy-G2-A (IV)其中A、G2和Cy如式(I)中所定义,利用常规试剂如HBr、AlCl3、AlBr3、BBr3或路易斯酸/亲核试剂二元体系如AlCl3/PhCH2SH或BBr3/Me2S将其进行脱甲基化,例如得到式(V)化合物:
HO-Cy-G2-A (V)其中A、G2和Cy如上所定义,式(V)化合物再按照常规方式,-例如通过N,N-二甲基硫代氨基甲酸钠的作用,转化为对应的式(VI)硫醇:
HS-Cy-G2-A (VI)其中A、G2和Cy如上所定义,-或者转化为对应的式(VII)胺化合物:
RNH-Cy-G2-A (VII)其中A、G2、Cy和R如上所定义,式(V)、(VI)和(VII)化合物表示成式(VIII)化合物:
HX”-Cy-G2-A (VIII)其中Cy、G2、X”和A如上所定义,将式(VIII)化合物与式(IX)化合物缩合:其中Hal代表溴、氯或碘原子,X、n和m如式(I)中所定义,应理解的是不可能具有两个连续的杂原子且所定义的链可以含有一个或多个不饱和度,得到式(X)化合物:
HO-(CH2)n-X-(CH2)m-X”-Cy-G2-A (X)其中A、G2、Cy、X、X”、n和m如上所定义,应理解的是在HO-(CH2)n-X-(CH2)m-X”-链中不可能具有两个连续的杂原子且所定义的链可以含有一个或多个不饱和度,式(X)化合物的羟基官能团按照常规方式转化为离去基团,例如甲磺酸酯、甲苯磺酸酯或卤代化合物,得到式(X’)化合物:
E-(CH2)n-X-(CH2)m-X”-Cy-G2-A (X’)其中A、G2、Cy、X、X”、n和m如上所定义,E代表甲磺酰基、甲苯磺酰基或卤原子,将式(X’)化合物在碱性介质中与式(XI)化合物反应:
B’-Ph-Ph-X’H (XI)其中X’如式(I)中所定义,B’可以具有与为式(I)所定义的B相同的含义,但基团COOH和被COOH基团取代的烷基除外,得到式(I/a)化合物,其为式(I)化合物的特例:
B’-Ph-Ph-G1-Cy-G2-A (I/a)其中A、G2、G1、Cy和B’如上所定义,当B’代表COOR1’基团或被COOR1’基团取代的烷基,其中R1’可以具有任意如上所定义的R的含义,但氢原子除外时,将式(I/a)化合物进行水解,得到式(I/b)化合物,其为式(I)化合物的特例:
B”-Ph-Ph-G1-Cy-G2-A (I/b)其中A、G2、G1和Cy如上所定义,B”代表COOH基团或被COOH基团取代的烷基,全部化合物(I/a)和(I/b)构成式(I)化合物,如果需要的话,它们可以通过常规纯化技术纯化,可选地按照常规分离技术分离为它们的异构体,如果需要的话,转化为与药学上可接受的酸或碱的加成盐。
16、药物组合物,包含作为活性成分的至少一种根据权利要求1至14任意一项的式(I)化合物或其与酸或碱的药学上可接受的加成盐与一种或多种药学上可接受的赋形剂的组合。
17、根据权利要求16的药物组合物,用于制备用于治疗与褪黑激素能系统有关的障碍的药物。
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