CN1227241C - 具有5-羟色胺1a受体活性的芳基哌嗪类化合物 - Google Patents
具有5-羟色胺1a受体活性的芳基哌嗪类化合物 Download PDFInfo
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- CN1227241C CN1227241C CNB988135191A CN98813519A CN1227241C CN 1227241 C CN1227241 C CN 1227241C CN B988135191 A CNB988135191 A CN B988135191A CN 98813519 A CN98813519 A CN 98813519A CN 1227241 C CN1227241 C CN 1227241C
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- phenyl
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一系列芳基哌嗪化合物为用于治疗涉及或由所述5-羟色胺1A受体影响的疾病的有效的药物;所述化合物为特别有效的该受体的拮抗剂,并且特别是用于缓解尼古丁和烟草戒断的症状。
Description
本申请要求1997年12月16日递交的U.S.临时申请第60/069,772号、1997年12月16日递交的第60/069,791号和1998年6月17日递交的第60/089,589号的权益。
本发明属于药理学和药物化学领域,并且提供了新的用于治疗由5-羟色胺影响的神经系统障碍引起或影响的疾病的药物,尤其是那些涉及所述1A受体的紊乱引起或影响的疾病的药物。
近年来,药学研究已经发现含有单胺的大脑神经元在大量的生理过程中是极其重要的,其非常强烈地影响许多心理以及影响个性过程。尤其是已经发现血清素(5-羟色胺;5-HT)对许多影响生理和心理功能是很关键的。影响大脑中5-羟色胺功能的药物相应地也是非常重要的,并且目前可用于令人惊奇地大量不同的疗法。
从机制和治疗的观点考虑,早期那几代影响5-羟色胺的药物试图具有多种不同的生理功能。最近,在体内或离体单独受体上研究所述药物的功能已是可能的,并且也已认识到具有单一作用机理的治疗药物对患者经常是有利的。因此目前研究的目的是发现不仅仅仅影响5-羟色胺功能的药物,而且要发现在单一的可确定的受体上仅影响5-羟色胺的单一功能的药物。
本发明提供作为所述5-羟色胺1A受体的拮抗剂具有高选择性活性的化合物。
本发明提供一系列新芳基哌嗪化合物、使用它们用于药用目的的方法和由此所述化合物可便利给药的药用组合物。
本发明也提供拮抗所述5HT-1A受体的方法和涉及它们在所述5HT-1A受体上作用的治疗方法。这样的治疗方法尤其包括缓解由烟草或尼古丁使用的戒断或部分戒断引起的症状的方法,该方法包括给予需要此治疗的患者式I化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物:
其中:
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、(C1-C6)烷基卤代、(C3-C8)环烷基、(C3-C8)环烯基或卤代的取代基取代的单-或双-环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、(C1-C6)烷基卤代、(C3-C8)环烷基、(C3-C8)环烯基或卤代的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、(C1-C6)烷基卤代、(C3-C8)环烷基、(C3-C8)环烯基或卤代;
X为-C(=O)-、-CHOH-或-CH2-。
另外,这样的治疗方法包括治疗焦虑、抑郁、高血压、识别障碍、精神病、睡眠障碍、胃动力障碍、性机能紊乱、大脑损伤、记忆丧失、饮食障碍和肥胖症、物质滥用、强迫观念与行为疾病、惊恐障碍和偏头痛的方法。
由本发明提供的另一个治疗方法是用于增强5-羟色胺重摄取抑制剂的作用的方法,该方法包括给予患者与所述5-羟色胺重摄取抑制剂联合的有效量的式I化合物。
更详细地讲,本发明提供式Ia化合物或者它们的药学上可接受的盐:
式Ia
所述式Ia化合物包括在所述式I化合物的范围内,并由此用于在此描述的有关式I的化合物的方法中。例如,本发明提供拮抗所述5HT-1A受体的方法和涉及它们对所述5HT-1A受体作用的治疗方法。这样的治疗方法包括尤其是缓解由烟草或尼古丁使用的戒断或部分戒断引起的症状的方法,该方法包括给予需要此治疗的患者有效量的式Ia化合物。另外,这样的治疗方法包括治疗焦虑、抑郁、高血压、识别障碍、精神病、睡眠障碍、胃动力障碍、性机能紊乱、大脑损伤、记忆丧失、饮食障碍和肥胖症、物质滥用、强迫观念与行为疾病、惊恐障碍和偏头痛的方法。
此外,本发明提供了用于增强5-羟色胺重摄取抑制剂的作用的方法,该方法包括给予患者与所述5-羟色胺重摄取抑制剂联合的有效量的式Ia化合物。
本发明还提供了帮助患者在停止或减少烟草或尼古丁使用的方法,该方法包括包括给予患者有效量的式I或式Ia化合物。
本发明也包括式I和式Ia化合物的新的合成方法、新中间体的合成方法,并且进一步包括本身为新的中间体。
优选实施方案的描述
在本文件中,所有浓度、量、比率等的描述将以重量单位表示,除非另外指出。所有温度以摄氏度表示。
化合物
人们认为对技术人员读者而言,以上所述化合物的一般描述足以解释它们的性质;也鼓励对以下所述实施例加以注意。将提供一些另外的描述以确保不发生误解。
在一般描述中,所述一般化学术语全部以它们正常和习惯的含义来使用。例如,依基团大小而定,小的烷基和烷氧基如(C1-C6)烷基和(C1-C6)烷氧基包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、戊基、3-甲基丁基、己基和分支己基和如同可被单独命名的基团允许的那样的相应的烷氧基。在一个基团上允许存在多个可能的取代基,如在Ar基团上允许有一至三个烷基、烷氧基或卤代基团,读者可以理解仅使用电子上和立体上可行的取代基。
在此使用的术语“链烯基”表示不饱和的分支的或线性的具有至少一个双键的基团。这样基团的实例包括基团如乙烯基、烯丙基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基以及直链和支链的二烯和三烯。
术语“炔基”意指这样的基团如乙炔基、丙炔基、丁炔基、戊炔基、己炔基以及二-和三-炔基。
术语“(C1-C6)烷硫基”定义为通过一个硫原子连接于该分子剩余部分的直形和分支的具有一至六个碳原子的烷基链。一般的(C1-C6)烷硫基基团包括甲硫基、乙硫基、丙硫基、丁硫基、戊硫基、己硫基等。
术语“(C1-C6)烷基卤代”指的是具有一个或多个独立选自连接在一个或多个可行的碳原子的卤原子的烷基取代基。这些术语包括氯甲基、溴乙基、三氟乙基、三氟甲基、3-溴丙基、2-溴丙基、3-氯丁基、2,3-二氯丁基、3-氯-2-溴-丁基、三氯甲基、二氯乙基、1,4-二氯丁基、3-溴戊基、1,3-二氯丁基、1,1-二氯丙基等。更优选的(C1-C6)烷基卤代为三氯甲基、三氯乙基和三氟甲基。最优选的(C1-C6)烷基卤代为三氟甲基。
术语“(C3-C8)环烷基”包括基团如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。术语“(C3-C8)环烷基”包括(C3-C6)环烷基。
术语“(C3-C8)环烯基”表示具有3至8个碳原子的烯键式不饱和环,其包括基团如环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基和环辛烯基等。术语“(C3-C8)环烯基”包括(C3-C6)环烯基。
术语“芳基”表示苯基或萘基。
术语“双环”表示不饱和的或饱和的稳定的7-至12-元桥或稠和的双环碳环。该双环可连接在任何可得到稳定结构的碳原子上。所述术语包括(但不局限于)萘基、二环己基、二环己烯基等。
术语“单或双环杂芳基”意指衍生自具有5至14个环原子并含有1至3个选自氮、氧或硫的杂原子的单环或多环芳环基团。典型的杂环基为吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、中氮茚基、异喹啉基、苯并噻吩基、异中氮茚基、噁唑基、吲哚基、咔唑基、降哈尔满基(norharmanyl)、氮杂吲哚基、二苯并呋喃基、硫茚基、二苯并噻吩基、吲唑基、咪唑并(1.2-A)吡啶基、anthranilyl、嘌呤基、吡啶基、苯基吡啶基、嘧啶基、吡嗪基、喹啉基。
用于上式的术语“卤”或“卤代物”指的是氟代、氯代、溴代或碘代。
术语“非质子溶剂”意指其不含有酸性氢的具有中等高度的介电常数的极性溶剂。普通非质子溶剂的实例为二甲基亚砜(DMSO)、二甲基甲酰胺、环丁砜、四氢呋喃、乙醚、甲基叔丁基醚或1,2-二甲氧基乙烷。
术语“质子溶剂”意指其含有连接于氧的氢并且由此具有明显酸性的溶剂。普通质子溶剂包括这样的溶剂如水、甲醇、乙醇、2-丙醇和1-丁醇。
术语“惰性气氛”意指反应条件,其中所述混合物以例如氮气或氩气的惰性气体层覆盖。
如在此使用的术语“Me”意指-CH3基团,术语“Et”意指-CH2CH3基团,术语“Pr”意指-CH2CH2CH3基团。
如在此使用的术语“立体异构体”意指通过相同键键合相同的原子所组成的但是具有不可互变的不同的三维结构的化合物。所述三维结构称作构型。如在此使用的术语“对映体”意指其分子为彼此不能重叠的镜像的两个立体异构体。如在此使用的术语“旋光异构体”等价于术语“对映体”。术语“外消旋体”、“外消旋混合物”或“外消旋形式”意指等份对映体的混合物。术语“手性中心”意指连接有四个不同基团的碳原子。
如在此使用的术语“对映体富集”意指一种对映体相对于另一种对映体的量的增加。表示所取得的所述对映体富集的方便方法属于对映体过量即“ee”的概念,发现该概念可使用以下等式:
其中E1为第一个对映体的量而E2为第二个对映体的量。因此,如果两种对映体的起始比例为50∶50,例如以外消旋混合物的形式存在,并且如果得到足以产生最后比例为50∶30的对映体富集,则相应于第一个对映体的ee为25%。然而,如果最后比例为90∶10,则相应于第一个对映体的ee为80%。大于90%的ee为优选的。大于95%的ee为最优选的,并且大于99%的ee为最特别优选的。本领域普通技术人员使用标准的技术和方法例如采用手性柱的气相或高效液相色谱法易于测定对映体富集。所述适宜的手性柱、洗脱液和必要的进行对映体对分离的条件是处于本领域普通技术人员的知识范围内。另外,可通过本领域普通技术人员使用本领域普通熟知的标准技术拆分式I或Ia化合物的对映体,例如由J.Jacques等在“对映体、外消旋体和拆分”,John Wiley和Sons,Inc.,1981中描述的那些方法。拆分的实例包括重结晶技术或手性层析法。
作为一类的式I和Ia化合物是高活性的、重要的,特别可用于本发明的治疗方法中,但是所述化合物的某些种类是优选的。以下段落描述了这样优选的种类。可以理解的是所述优选种类对于本发明的治疗方法和新化合物是适用的。
读者可以理解所述优选类别的化合物可结合形成另外更宽或更窄类别的优选化合物。
a)Ar1为苯基或吡啶基;
b)Ar1为萘基;
c)Ar1为吡嗪基、嘧啶基、吡咯基、呋喃基、噻吩基、吲哚基、嘌呤基、咪唑基、吡唑基、中氮茚基、苯并呋喃基、异喹啉基、喹啉基、苯并噻吩基或异中氮茚基;
d)Ar1任选以(C1-C6)烷基、(C1-C6)烷氧基、卤代、(C2-C6)链烯基或(C2-C6)炔基取代;
e)Ar1任选以(C1-C4)烷基、(C1-C4)烷氧基或卤代取代;
f)R1为氢;
g)R1为(C1-C6)烷基或(C1-C6)烷氧基;
h)R1为(C1-C2)烷基或(C1-C2)烷氧基;
i)R2为苯基;
j)R2为(C3-C8)环烷基;
k)R2为(C3-C6)环烷基
l)R2为环己基;
m)R3为(C1-C6)烷基、(C1-C6)烷氧基或卤代
n)R3为(C1-C4)烷基、(C1-C4)烷氧基或卤代;
o)X为-C=O;
p)X为-CHOH;和
q)X为-CH2;
r)式Ia
s)其中在甲醇中的[α]D 20为(+)的式Ia的对映体。
因为本发明的化合物在性质上是碱性的,所以它们相应可与多种无机和有机酸中的任何一种反应形成药学上可接受的酸加成盐。所述单-和双-盐包括在本发明范围中。通常用于形成这样盐的酸为无机酸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等和有机酸如对-甲苯磺酸、甲磺酸、草酸、对-溴苯磺酸、碳酸、琥珀酸、枸橼酸、苯甲酸、乙酸等。因此,这样的药学上可接受的盐的实例为硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、枸橼酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。优选的药学上可接受的盐为单盐酸盐、二盐酸盐、单氢溴酸盐、二氢溴酸盐、式I/琥珀酸盐(1∶1)、式Ia/琥珀酸盐(1∶1)、式I/琥珀酸盐2∶1、式Ia/琥珀酸盐2∶1、磷酸盐、d-酒石酸盐、l-酒石酸盐或马来酸盐。本领域普通技术人员可以理解所述游离碱或药学上可接受的盐的水合物被包括在本发明的范围内。
许多包括式Ia的式I化合物为旋光异构体。例如,所述化合物在连接R1和X的碳原子上具有不对称中心(或者手性中心)。然而,当未指明不对称形式而命名本发明化合物时,则包括任何所有可能的不对称形式。本发明不限制于任何特殊的异构体,而是包括所以可能的单一异构体和外消旋物
通过常规技术如使用硅胶层析法的纯化方法或者结晶离析的重结晶方法可分离和纯化所述中间体和最终产物。
技术人员易于意识到未被描述的原料或者是由市售得到或者通过已知技术由市售原料容易地制备得到。用于制备本发明化合物的所有其它反应物是市售的。
按照以下流程通常可制备本发明化合物。
流程I
以优选为叔丁醇钾的碱处理原料(1),随后通过以2-溴甲基-1,3-二氧戊环进行烷基化。其它适宜的碱包括氢化钠、氢氧化钠、氢氧化钾、碳酸钾、碳酸铯等。
所述反应优选在15℃至回流的温度下、于溶剂如二甲基亚砜中进行,45-55℃的温度是最优选的,并且在1至24小时内基本上完成制备中间体(2)。
在适当的有机溶剂中,以酸如盐酸或对-甲苯磺酸处理(2),得到醛(3)。所述反应一般在质子溶剂如酸的水溶液和丙酮的混合物中、于大约5至75℃下,优选在室温下进行。
醛(3)与所需的芳基哌啶(4)经还原胺化偶合,得到(5)。在三乙酰氧基硼氢化钠存在下,所述反应优选在室温下、于非反应性溶剂如二氯乙烷或二氯甲烷中进行,并且在1至24小时内基本上完成。参见例如A.F.Abdel-Magid等,J.Org.Chem.,
61,3849(1996)。
使用还原剂如硼氢化钠或者优选二异丁基氢化铝,可容易地完成(5)的还原,制备所述羟基化合物(6)。所述反应优选在大约-20℃至0℃的温度下、于有机溶剂如二氯甲烷中进行。
在非质子溶剂如四氢呋喃中,于室温下,通过以还原剂如三乙基硅烷或三氟化硼(当R2为苯基或取代苯基时)处理,或者通过以酸如盐酸或三氟乙酸处理形成双键,随后经例如以氢和披钯炭进行氢化,可使(6)进一步还原得到产物(7)。
原料(1)可为市售或如同在以下流程II中描述的那样经过偶合(8)[参见Nahm和Weinreb,Tetrahedron.Lett.,
22,3815(1981)]和(9)进行制备。
流程II
M为金属盐,例如锂或镁的卤化物。在室温下,该反应优选在惰性气氛优选为氮下、于非质子溶剂如四氢呋喃中进行。
更详细的说,按照在流程III中描述的方法,能制备所述式Ia化合物。除非另外指出,所有取代基如前述定义。对本领域普通技术人员而言所述试剂和原料易于得到。
流程III
在流程III步骤A中,在本领域熟知的标准条件下,以苄基氯化镁或苄基溴化镁处理结构(10)的酯,得到结构(11)的酮。例如,在惰性气氛下,将大约1.05至大约1.1当量的适宜的胺如二甲胺溶于适宜的有机溶剂如四氢呋喃(冷却至大约-5℃)中。将该溶液温热至室温,在搅拌下加入1.0当量的所述酯(10)。然后,将大约1.0至大约1.05当量的苄基氯化镁缓慢加入到该溶液中,加入期间以冷却浴维持该温度在大约15-20℃。加入完全后,将该反应在室温下搅拌大约1至2小时,然后冷却至低于0℃,随后小心以适宜的酸如HCl骤冷。然后以适宜的有机溶剂如叔丁基甲基醚(在下文意指为MTBE)提取该骤冷的反应物。合并有机层,经无水硫酸镁干燥,过滤并浓缩,得到酮(11)。通过本领域熟知的技术,例如硅胶快速层析,用适宜的洗脱剂如乙酸乙酯/己烷洗脱来纯化酮(11),得到纯的物质。或者,将粗品的酮(11)用于步骤B。
在流程III步骤B中,在本领域熟知的标准条件下,以溴乙醛二乙缩醛、然后以碘甲烷将酮(11)烷基化,得到结构(12)的化合物。例如,将酮(11)溶于适宜的有机溶剂如二甲基亚砜中,并以大约1.05至大约1.1当量的适宜的碱如叔丁醇钾处理。将所述反应物搅拌大约15至30分钟,并将大约1.0至大约1.05当量的溴乙醛二乙缩醛滴加到所述反应物中。本领域普通技术人员易于理解溴乙醛二甲缩醛、溴乙醛亚乙缩醛等可用来替代相应的二乙缩醛。然后将所述反应混合物加热至大约50℃大约2至2.5小时。然后以冰/水浴冷却所述反应混合物,加入大约2.2当量的适宜的碱如叔丁醇钾。继续冷却下,将该反应物搅拌大约15至30分钟,然后将大约1.5至大约1.8当量的碘甲烷滴加到所述反应混合物中,维持该混合物温度低于41℃,优选低于21℃。加入完全后,将该反应温热至室温并搅拌大约1至4小时。然后在水和适宜的有机溶剂如MTBE之间分配该反应混合物。分离这些层并以水、盐水洗涤该有机相,经无水硫酸镁干燥,过滤并真空浓缩,得到化合物(12)。
在流程III步骤C中,以类似于在流程I中所描述的方法,在酸性条件下,将化合物(12)水解,得到醛(13)。更详细的说,例如,将化合物(12)溶于适宜的有机溶剂如丙酮中,并以适宜的酸如盐酸处理。在室温下将所述反应混合物搅拌大约1至3小时。然后以适宜的有机溶剂例如乙酸乙酯或二氯甲烷提取所述反应混合物,合并该有机提取液,以盐水洗涤,经无水硫酸镁干燥,过滤并真空浓缩,得到醛(13)。通过本领域熟知的技术,例如用适宜的洗脱剂如乙酸乙酯/己烷进行硅胶快速层析可以纯化醛(13)。或者,将粗品的醛(13)直接用于步骤D。
在流程III步骤D中,在本领域熟知的标准条件下,以类似于在流程I中所描述的方法,以哌嗪(14)将醛(13)还原胺化,得到式Ia化合物。更详细的说,例如,将醛(13)溶于适宜的有机溶剂如二氯甲烷中。向该溶液中加入大约1.1当量的哌嗪(14)。可任选加入乙酸以帮助所述哌嗪(14)溶解。然后,加入大约1.2至1.3当量的三乙酰氧基硼氢化钠,并将所述反应物在室温下搅拌大约3至5小时。然后通过加入适宜的碱如氢氧化钠水溶液骤冷该反应物,以使得pH为大约10至大约12。随后以适宜的有机溶剂如二氯甲烷提取所述骤冷的反应物。合并该有机提取液,以盐水洗涤,经无水硫酸镁干燥,过滤并真空浓缩,得到式Ia化合物。然后通过本领域熟知的技术,例如硅胶快速层析法,用适宜的洗脱剂如乙酸乙酯/己烷可以纯化该物质。
在本领域熟知的标准条件下,将式Ia的游离碱转化为相应的药学上可接受的盐。例如,将所述式Ia的游离碱溶于适宜的有机溶剂如甲醇中,以例如1当量的马来酸或草酸或两当量的盐酸处理,然后真空浓缩,得到相应的药学上可接受的盐。经从适宜的有机溶剂或有机溶剂的混合物例如甲醇/乙醚中重结晶,可以纯化所述残余物。
在流程III步骤E中,使用本领域熟知的技术和方法,例如由J.Jacques等在“对映体、外消旋体和拆分”,John Wiley和Sons,Inc.,1981中描述的那些方法,可以将所述式Ia的(+)对映体与(-)对映体分离开来。例如,使用适宜的有机溶剂如乙醇/乙腈和Chiralpak AD填充物(20微米)的手性层析法也可用于进行分离所述对映体。
在流程III步骤F中,以类似于以上步骤D结束时描述的方法,将所述式Ia的(+)对映体转化为其药学上可接受的盐,例如单盐酸盐、二盐酸盐、单氢溴酸盐、二氢溴酸盐、式Ia/琥珀酸盐(1∶1)、式Ia/琥珀酸盐2∶1、磷酸盐、d-酒石酸盐、l-酒石酸盐或马来酸盐。
或者,按照在流程IV中描述的方法制备结构(5)的化合物。除非另外指出,所有取代基如前定义。对本领域技术人员而言试剂和原料易于得到。
流程IV
在流程IV步骤A中,在本领域熟知的条件下,使醛(15)与适宜的有机金属试剂(16)化合,得到醇(17)。适宜的有机金属试剂的实例包括格氏试剂、烷基锂试剂、烷基锌试剂等。格氏试剂为优选的有机金属试剂。典型的格氏试剂和反应条件的实例参见J.March“高等有机化学:反应、机理和结构”,第2版,McGraw-Hill,第836-841页(1977)。更详细的说,将醛(15)溶于适宜的有机溶剂如四氢呋喃或甲苯中,冷却至大约-5℃,并以大约1.1至1.2当量的其中M为MgCl或MgBr的式(16)的格氏试剂处理。将所述反应物搅拌大约0.5至2小时,然后骤冷,并且分离醇(17)。例如,将所述反应混合物倾入到冰冷的1N HCl中,以适宜的有机溶剂如甲苯提取所述骤冷的混合物,共沸或经适宜的干燥剂如无水硫酸镁来干燥所述有机提取液,过滤并真空浓缩,得到醇(17)。
在流程IV步骤B中,在本领域熟知的标准条件下,如以J.March在“高等有机化学:反应、机理和结构”,第2版,McGraw-Hill,第1082-1084页(1977)中描述那些方法氧化醇(17),得到酮(1)。[酮(1)为用于以上流程I中的原料]。
例如,将醇(17)溶于适宜的有机溶剂如二氯甲烷中,用湿的冰-丙酮浴冷却所述溶液,并以2.5至3.0当量的二甲基亚砜处理。搅拌大约30分钟后,然后以大约1.8当量的P2O5处理该反应。然后将该反应物搅拌大约3小时,并优选在30分钟内、以大约3.5当量的适宜的胺如三乙胺处理。然后撤除冷却浴,并使所述反应物搅拌大约8至16小时。然后通过本领域熟知的标准提取技术分离所述酮(1)。使用本领域普通技术人员熟知的标准Swern氧化条件也能进行以上氧化反应。
在流程IV步骤C中,以适宜的碱、随后加入其中X为适宜的离去基团的烯烃(18)处理酮(1),得到化合物(19)。例如,在适宜的有机溶剂如四氢呋喃中将酮(1)与过量烯烃(18)化合,并且以湿的冰-丙酮浴冷却。适宜的离去基团的实例为Cl、Br、I、甲苯磺酸根、甲磺酸根等。优选的离去基团为Cl和Br。加入大约1.1当量的适宜的碱,并将所述反应物在室温下搅拌大约2小时。适宜的碱的实例为叔丁醇钾、氢化钠、NaN(Si(CH3)3)2、LDA、KN(Si(CH3)3)2、NaNH2、乙醇钠、甲醇钠等。叔丁醇钾为优选的适宜的碱。然后以酸的水溶液骤冷所述反应物并以适宜的有机溶剂如庚烷提取分离化合物(19)。以碳酸氢钠洗涤所述庚烷提取液,经无水硫酸镁干燥,过滤并真空浓缩,得到化合物(19)。
在流程IV步骤D中,以适宜的氧化剂处理化合物(19),得到醛(3)[醛(3)也以流程I制备]。适宜的氧化剂的实例为臭氧、NaIO4/锇催化剂等。臭氧为优选的氧化剂。适宜氧化剂的实例和条件由J.March在“高等有机化学:反应、机理和结构”,第2版,McGraw-Hill,第1090-1096页(1977)中描述。
例如,将化合物(19)溶于适宜的有机溶剂如甲醇中,加入少量的苏丹III,并将所述溶液冷却至大约-20℃。向所述溶液中通入臭氧约4小时,直到粉红色转变为浅黄色。然后将所述Me2S加入到所述反应混合物中并撤除冷却浴。真空下浓缩所述反应混合物,得到中间体醛(3)的二甲缩醛。在标准酸性条件下,该二甲缩醛易于水解,得到醛(3)。或者,直接酸化处理该粗品反应混合物得到醛(3)。或者,在非缩醛形成溶剂如二氯甲烷中通过将(19)臭氧化能够直接得到醛(3)。
在流程IV步骤E中,在类似于上述流程III步骤D中描述的那些方法的条件下,还原胺化醛(3),得到化合物(5)。[化合物(5)也以流程I制备]。
流程V提供了制备化合物(5)的另一个合成方法。除非另外指出,所有取代基如前定义。对本领域普通技术人员而言所述试剂和原料易于得到。
流程V
在流程V步骤A中,在本领域熟知的标准条件下,使醛(3)与哌啶(4)缩合,得到所述烯胺(20)。例如,将溶于适宜的有机溶剂如乙酸异丙酯或异丙醇中的大约1.05当量的醛(3)加入到纯品哌嗪(4)游离碱中。再加入有机溶剂以产生浆化物,并且将所述反应物搅拌大约1至2小时。然后通过标准技术例如通过过滤收集分离烯胺(20)。
在流程V步骤B中,所述烯胺(20)在本领域普通技术人员熟知的条件下氢化,得到化合物(5)。例如,将烯胺(20)与适宜的有机溶剂如异丙醇和催化量的5%披钯炭于帕尔瓶中化合。将所述混合物置于50psi的氢气压下并在室温下振摇大约两天。然后将该浆化物过滤除去催化剂并浓缩滤液,得到化合物(5)。
以下实施例表示如上所述的式I和式Ia化合物的典型合成方法。这些实施例仅作为举例说明并且不打算以任何方式限制本发明。对本领域普通技术人员而言试剂和原料易于得到。如在此使用,以下术语具有指定的含义:“aq”意指水溶液;“eq”意指当量;“g”意指克;“mg”意指毫克;“L”意指升;“mL”意指毫升;“μL”意指微升;“mol”意指摩尔;“mmol”意指毫摩尔;“psi”意指每平方英寸磅;“min”意指分钟;“h”意指小时;“℃”意指摄氏度;“TLC”意指薄层层析法;“HPLC”意指高效液相色谱法;“Rf”意指保留因子;“Rt”意指保留时间;“δ”意指由四甲基硅烷向低场移动的百万份数;“THF”意指四氢呋喃;“DMF”意指N,N-二甲基甲酰胺;“IPA”意指异丙醇;“iPrOAc”意指乙酸异丙酯;“AcOH”意指乙酸;“HRMS”意指高分辨质谱;“Et3N”意指三乙胺;“LDA”意指二异丙基氨化锂;“RT”意指室温;“SRI”意指5-羟色胺重摄取抑制剂;“aq”意指水溶液和“MTBE”意指叔丁基甲基醚。
实施例1
1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丙基]哌嗪草酸盐
A.制备2-(2’-苯甲酰基-2’-苯基)乙基-1,3-二氧戊环:
在0℃下,于氮气氛中向搅拌着的氢化钠(61.25mmol)在150mL二甲基甲酰胺中的悬浮液中滴加入脱氧苯偶姻(50.96mmol)在150mL四氢呋喃中的溶液中。在0℃下,将该混合物搅拌1小时并在室温下搅拌1小时。向所述混合物加入2-溴甲基-1,3-二氧戊环(60.55mmol)和催化剂碘化钾(6.0mmol)。将所述混合物加热回流13小时。冷却后,加入乙醚(300mL)和水(300mL)。分离有机层并以水(150mL×2)洗涤。使用己烷和乙酸乙酯洗脱,经快速层析法纯化,得到2-(2’-苯甲酰基-2’-苯基)乙基-1,3-二氧戊环(8.18g;57%)。
B.制备3-苯甲酰基-3-苯基丙醛:
向100mL丙酮中加入2-(2’-苯甲酰基-2’-苯基)乙基-1,3-二氧戊环(8.85mmol)和100mL的2N盐酸溶液。室温下将该混合物搅拌7小时后,加入2N氢氧化钠100mL。蒸发丙酮并以乙醚和己烷(1∶1,100mL×3)提取残余物。干燥(硫酸钠)合并的有机层,过滤并浓缩。发现残余物是相当纯的物质3-苯甲酰基-3-苯基丙醛,并由此用于下一步反应。
C.制备1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丙基]哌嗪
将从以上步骤B得到的3-苯甲酰基-3-苯基丙醛残余物(~8.85mmol)溶于110mL二氯甲烷中。向该溶液中加入2-甲氧基苯基哌嗪(10.61mmol)和三乙酰氧基硼氢化钠NaBH(OAc)3(10.61mmol)。在室温下将该混合物搅拌3小时。水处理后经快速层析,得到上两个步骤为95%收率的纯的产物1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丙基]哌嗪(3.48g)。向溶于甲醇的游离碱中加入1当量的草酸。蒸发溶剂并真空干燥所述产物,以形成所述草酸盐。
m.p.=161-163℃;
MS(m/e):414(M+)。
实施例2
1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪草酸盐
A.制备环己基苄基酮:
在0℃下,于氮气氛中向搅拌着的N-甲基-N-甲氧基环己烷甲酰胺(7.42mmol)在30mL四氢呋喃中的溶液中加入苄基氯化镁的溶液(2.0M在四氢呋喃中,4.5mL,9.0mmol)。在0℃下,将该混合物搅拌30分钟并在室温下搅拌1小时。加入乙醚(50mL)和水(20mL)。分离有机层,干燥,过滤,浓缩。使用己烷和乙酸乙酯洗脱,经快速层析法纯化该残余物,得到收率为70%的油状物环己基苄基酮(1.05g)。
B.制备2-(2’-环己烷羰基-2’-苯基)乙基-1,3-二氧戊环
按照实施例1步骤A中描述的方法,在氢化钠(5.60mmol)存在下,使环己基苄基酮(5.09mmol)与2-溴甲基-1,3-二氧戊环(7.63mmol)反应,得到收率为59%的2-(2’-环己烷羰基-2’-苯基)乙基-1,3-二氧戊环(0.86g)。
C.制备3-环己烷羰基-3-苯基丙醛
按照在所述实施例1步骤B中描述的方法,使2-(2’-环己烷羰基-2’-苯基)乙基-1,3-二氧戊环(2.98mmol)与1N盐酸反应,得到收率100%的粗品产物3-环己烷羰基-3-苯基丙醛。
D.制备1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪
按照在所述实施例1步骤C中描述的方法,使3-环己烷羰基-3-苯基丙醛(1.39mmol)和2-甲氧基苯基哌嗪(1.39mmol)与三乙酰氧基硼氢化钠(1.80mmol)反应,得到收率79%的纯的产物1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪(464mg)。如上描述那样制备所述草酸盐。
m.p.=149-151℃;
MS(m/e):420(M+)。
实施例3
1-(2-吡啶基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪草酸盐
按照在所述实施例1步骤C中描述的方法,使3-环己烷羰基-3-苯基丙醛(1.55mmol)和1-(2-吡啶基)哌嗪(1.55mmol)与三乙酰氧基硼氢化钠(2.0mmol)反应,得到收率78%的纯的产物1-(2-吡啶基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪(475mg)。如同以上描述的那样,制备所述草酸盐。
m.p.=185-187℃;
MS(m/e):391(M+)。
实施例4
1-(2-乙氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪二盐酸盐
按照在所述实施例1步骤C中描述的方法,使3-环己烷羰基-3-苯基丙醛(1.02mmol)和1-(2-乙氧基苯基)哌嗪(1.13mmol)与三乙酰氧基硼氢化钠(1.33mmol)反应,得到收率52%的纯的产物1-(2-乙氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪(270mg)。向游离碱在甲醇中的溶液中加入所需量的盐酸在乙醚中的溶液。减压除去溶剂,并在真空干燥产物,得到二盐酸盐。
m.p.=180-183℃;
MS(m/e):434(M+)。
实施例5
1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丁基]哌嗪草酸盐
A.制备2-(2’-苯甲酰基-2’-苯基)丙基-1,3-二氧戊环
按照在所述实施例1步骤A中描述的方法,在氢化钠(4.25mmol)存在下,使2-(2’-苯甲酰基-2’-苯基)乙基-1,3-二氧戊环(3.54mmol)和碘甲烷(10.62mmol)反应,得到2-(2’-苯甲酰基-2’-苯基)丙基-1,3-二氧戊环(0.60g)。
B.制备3-苯甲酰基-3-苯基丁醛
按照在所述实施例1步骤B中描述的方法,使2-(2’-苯甲酰基-2’-苯基)丙基-1,3-二氧戊环(0.60g)与3N盐酸反应,得到为粗品的3-苯甲酰基-3-苯基丁醛(0.32g)。
C.制备1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丁基]哌嗪
按照在所述实施例1步骤C中描述的方法,使3-苯甲酰基-3-苯基丁醛(0.32g)和1-(2-甲氧基苯基)哌嗪(0.23g)与三乙酰氧基硼氢化钠(0.33g)反应,得到纯的产物1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丁基]哌嗪(0.12g)。如上所述制备所述草酸盐。
m.p.=192-193℃;
MS(m/e):428(M+)。
实施例6
1-(2-甲氧基苯基)-4-[3-(环庚烷羰基)-3-(苯基)丙基]哌嗪二盐酸盐
按照在所述实施例1步骤C中描述的方法,使3-环庚烷羰基-3-苯基丙醛(2.52mmol)和1-(2-甲氧基苯基)哌嗪(2.52mmol)与三乙酰氧基硼氢化钠(3.28mmol)反应,得到收率70%的纯的产物1-(2-甲氧基苯基)-4-[3-(环庚烷羰基)-3-(苯基)丙基]哌嗪(770mg)。如上所述制备二盐酸盐。
m.p.=193-194℃;
MS(m/e):434(M+)。
实施例7
1-(2-甲氧基苯基)-4-[3-(环戊烷羰基)-3-(苯基)丙基]哌嗪二盐酸盐
按照在所述实施例1步骤C中描述的方法,使3-环戊烷羰基-3-苯基丙醛(1.36mmol)和1-(2-甲氧基苯基)哌嗪(1.49mmol)与三乙酰氧基硼氢化钠(1.77mmol)反应,得到收率67%的纯的产物1-(2-甲氧基苯基)-4-[3-(环戊烷羰基)-3-(苯基)丙基]哌嗪(370mg)。如上所述制备二盐酸盐。
m.p.=210-212℃;
MS(m/e):406(M+)。
实施例8
1-(2-甲氧基苯基)-4-[4-(环己基)-4-(羟基)-3-(苯基)丁基]哌嗪草酸盐
在-78℃下,于氮气氛中向搅拌着的1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪(0.11g,0.20mmol)在二氯甲烷(10mL)中的溶液加入Dibal-HTM溶液(0.89mmol)。在-78℃下,将该混合物搅拌1小时,然后缓慢温热至室温搅拌16小时。处理后经快速层析法纯化,得到收率为78%的纯品1-(2-甲氧基苯基)-4-[4-(环己基)-4-(羟基)-3-(苯基)丁基]哌嗪(0.086g)。如上所述制备草酸盐。
m.p.=100-102℃;
MS(m/e):422(M+)。
实施例9
1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪
制备2-苯基-1-环己烷-乙-1-酮
流程III,步骤A:在氮气氛下,向5L反应容器中加入四氢呋喃(1.05L)。以丙酮/冰浴将所述溶液冷却至大约-5℃。然后通过聚四氟乙烯加料管加入液体二甲胺(115.9g,2.57mol)。撤除冷却浴并使所述溶液温热至大约15-20℃。然后加入环己烷甲酸甲酯(341.7g,2.40mol),生成茶色溶液。然后,缓慢加入苄基氯化镁(在THF中2.0M溶液,2.52L,246mol),控制其滴速在大约1.8至大约2.2小时内完成加入。加入期间,应用冷却浴维持所述反应混合物的温度在大约15-20℃。加入所述苄基氯化镁溶液后,在室温下,将生成的浆状物搅拌大约1-2小时。然后使所述反应混合物冷却至低于0℃。将浓HCl(709.7g,7.2mol)与水(3.08L)混合并将该溶液冷却至低于5℃。伴随冰浴应用到所述容器,将该稀酸混合物加入到22L反应容器中。然后在搅拌下将上述冷却的反应混合物缓慢倾入到冷却的稀酸溶液中。发生极度放热(使用小心)。所述反应混合物加入速率应该控制在维持骤冷的溶液的温度在45℃以下。将所述反应混合物加入到稀酸溶液中后,将所述骤冷的反应混合物冷却至室温,并且以足够量的浓HCl调节pH到大约6.5至7.5。以MTBE(1.71L)提取所述骤冷的反应混合物。分离各层并以水/MTBE混合物(1.03L/1.37L)洗涤有机层,随后以水/MTBE混合物(1.03L/1.03L)第二次洗涤。合并有机层,以盐水(683mL)洗涤,经无水硫酸镁(167g)干燥,过滤,真空浓缩。在室内真空下干燥该粗品油状物5-16小时,得到粗品2-苯基-1-环己烷-乙-1-酮(522.3g)。无须进一步纯化该粗品物质,将其用于下一步反应。
制备1,1-二乙氧基-3-苯基-3-环己烷羰基-丁烷
流程III,步骤B:在配备有磁力搅拌棒、热电偶数字温度计和加料漏斗的250mL的三口圆底烧瓶中,将2-苯基-1-环己烷-乙-1-酮(8.26g,40.8mmol)和DMSO(45mL)混合。向该搅拌着的溶液中加入叔丁醇钾(5.04g,44.9mmol)。观察到16℃下的放热并且该黄色溶液变为深棕色。在加入完成后,将所述反应混合物再搅拌15分钟,然后用大约10分钟,借助加料漏斗滴加溴乙醛二乙缩醛(8.26g,41.9mmol)。然后在50℃下将所述反应混合物加热2至2.5小时,此间该反应混合物变成黄色。然后,以冰/水浴将所述反应混合物冷却至大约9.5℃,加入叔丁醇钾(10.07g,89.7mmol),产生放热反应并且颜色由黄色变成棕色。仍然保持冷却浴下,将所述反应混合物再搅拌15分钟随后滴加碘甲烷(10.26g,72.3mmol,纯品)。所述反应混合物的温度维持在21℃或以下。在加入碘甲烷期间,任何放热应维持在41-43℃以下,其为碘甲烷的沸点。在加入完成后,在室温下将所述反应混合物搅拌1至4小时。在MTBE(100mL)和水(100mL)之间分配所述反应混合物。以水(3×50mL)、盐水(50mL)洗涤有机相,经无水硫酸镁干燥,抽滤并真空浓缩,得到为黄色油状物的粗品1,1-二乙氧基-3-苯基-3-环己烷羰基-丁烷(13.6g)。无须进一步纯化该粗品物质,将其用于下一步反应。
制备1-环己基-2-苯基-丁-1-酮-4-醛
流程III,步骤C:将1,1-二乙氧基-3-苯基-3-环己烷羰基-丁烷(74.4g,224mmol)溶于丙酮(800mL)中随后加入3.0N的HCl(800mL)。在室温下,将该反应混合物搅拌一小时。然后将其真空浓缩至低于1/2原来的体积,然后以二氯甲烷(800mL)提取。然后以盐水(300mL)洗涤有机提取液,经无水硫酸镁干燥,抽滤并真空浓缩,得到粗品3-苯基-3-环己烷羰基-丁-1-醛(57.8g)。或者,所述干燥和过滤后的二氯甲烷溶液不经浓缩直接用于下一步反应。
制备最终标题化合物1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪
流程III,步骤D:将3-苯基-3-环己烷羰基-丁-1-醛(57.8g,224mmol)溶于二氯甲烷(1650mL)中,随后加入1-(2-甲氧基苯基)哌嗪盐酸盐(56.3g,246mmol)。任选加入乙酸(41mL)以将於浆变为溶液。向搅拌着的溶液中缓慢加入三乙酰氧基硼氢化钠(60.3g,284mmol)。导致轻微放热并生成浆状物。在室温下,将所述反应混合物再搅拌3小时。然后通过加入2.0N氢氧化钠(1050mL)使该反应物骤冷,生成pH大约为10的骤冷的反应混合物。然后以二氯甲烷(2次,1L和300mL)提取该混合物。合并有机提取液,以1.0N的HCl(600mL)、1.0N的氢氧化钠(600mL)、盐水(600mL)依次洗涤,经无水硫酸镁干燥,过滤并真空浓缩,得到为粘稠油状物的最终标题化合物;
UV(MeOH):λmax=243nm,ε243=7110;λmax=281nm,ε281=3200
IR(CDCl3,cm-1)2937,2856,2836,1698,1499,1451,1377,1316,1242,1029
1H NMR(300MHz,DMSO)δ7.75(2H,m),7.55(2H,m),6.93(3H,m),6.85(2H,m),3.75(3H,s),2.90(4H,m),2.43(4H,m),2.08(5H,m),1.5(10H,m),1.05(3H,m)
13C NMR(300MHz,DMSO)δ214.18,151.94,141.25,141.23,128.45,126.85,126.74,122.22,120.79,117.81,111.97,55.28,54.54,53.67,53.13,50.01,45.30,33.75,30.44,30.12,25.21,24.98,24.93,19.94。
C28H38N2O2分析计算值:C,77.38;H,8.81;N,6.45。实测值:C,76.44;H,8.89;N,6.01。
制备1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪马来酸盐
将1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪(以上制备)溶于温的甲醇(50mL)中,随后加入马来酸(26.8g)和MTBE(200mL)。将该混合物浓缩为糊状物,然后通过加入甲醇(大约15mL)和MTBE(200mL)再次溶解。向该混合物中种晶,一旦开始结晶即再加入MTBE(300mL)。将该混合物抽滤,并以MTBE漂洗所述固体,在40℃下真空干燥5小时,得到所述标题化合物(122g)。
此外,以类似于上述过程的方法,如同在流程V中一般描述的那样,本领域技术人员能从3-环己烷羰基-3-苯基-丁醛和1-(2-甲氧基苯基)哌嗪来制备标题化合物1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪。
制备1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪二盐酸盐
以类似于上述制备马来酸盐的方法,本领域技术人员能由所述游离碱和盐酸来制备标题化合物,得到白色固体;mp(DSC)=192.81℃。
制备(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪和(-)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪
流程III,步骤E:
材料:
Chiralpak AD松散填充物,20微米
乙腈
3A乙醇
Prochrom 8cm柱
Prochrom LC-80系统/收集系统
柱的制备:使用在丙醇(1L)中大约500g的Chiralpak AD(ChiralTechnologies,730 Springdale Drive,Exton,PA 19341),浆化填充具有8×19cm Prochrom柱的ProChem LC-80自动系统(ProChem,5622西第73大街,印地安纳波利斯,IN46278)。制备在乙腈中含有大约5%的3A乙醇的洗脱液。柱的流速为155mL/min,检测器设置在280nm。将外消旋的1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-甲基-3-(苯基)丙基]哌嗪(25g)溶于乙腈(50mL)中。将重大约3g的溶液称入到烧瓶中,并以乙腈(50mL)稀释。将该溶液泵入柱中开始分离1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪的(+)和(-)对映体。然后收集组分,首先洗脱出(-)对映体。总循环时间大约为15分钟。
在以下条件下测定所述两种分离的异构体的对映体过量:
柱:46×15cm Chiralcel OH-H
洗脱剂:含有0.2%二甲胺的在庚烷中的3%乙醇
流速:0.6mL/min
温度:室温
UV:280nm
对所述(-)对映体的%ee为96.4%
对所述(+)对映体的%ee为96.6%
制备(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪二盐酸盐
流程III,步骤F:以甲醇(40mL)稀释(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪(15.0g,34.5mmol,以上制备的)。向该溶液加入HCl(26.3%在甲醇中的溶液9.58g,69.0mmol)。所述混合物开始形成凝胶样结晶并在几分钟内成为固体。剧烈搅拌下向该混合物中加入乙醚(100mL)。通过抽滤收集白色固体,然后在45℃下真空干燥两天,得到白色固体的标题化合物(13.4g,76%);mp(DSC)=195.58℃。
IR(CDCl3,cm-1)2976,2939,1700,1502,1462,1451,1267,1243,1021;
1H NMR(300MHz,DMSO)δ7.40(2H,m),73.1(3H,m),7.03(3H,m),6.90(1H,m),3.78(3H,s),3.49(4H,m),3.16(5H,m),2.64(1H,m),2.40(3H,m),1.56(3H,s),1.46(4H,m),1.11(5H,m),0.86(1H,m);
13C NMR(300MHz,DMSO)δ213.46,151.84,139.56,138.12,128.72,127.37,126.86,124.29,120.85,118.71,112.29,55.48,54.06,52.20,50.78,50.57,46.93,45.14,30.31,30.16,25.15,24.91,24.89,19.15;
C28H39N2O2(MH+)的HRMS计算值:435.3012,实测值:435.3018。[α]25 D=+76.53°(c=1,MeOH),ee99.3%(Chiral HPLC)
制备(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪单盐酸盐
流程III,步骤F:以MTBE(120mL)稀释(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪(6.05g,13.9mmol),随后加入HCl(2.2M在异丙醇中的溶液,6.3mL,13.9mmol,由在10mL异丙醇中0.80g的HCl气体制备)。所述混合物形成油/固体混合物,其进一步搅拌得到不均匀结晶物质。对所述混合物进行抽滤,以MTBE漂洗,在45℃下真空干燥得到的白色固体(5.74g,96.2%ee)。
以类似于上述的方法,由1当量的浓HCl水溶液替代气态HCl,可以制备(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪单盐酸盐。
1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪的另外一种制备方法
制备1-环己基-2-苯基丙醇
流程IV,步骤A:在-5℃下,向环己基氯化镁(50mmol)在25mL的Et2O和40mL的THF中的溶液中加入2-苯基丙醛(5.36g,40mmol)在10mL的THF中的溶液。所述反应混合物放热至5℃。在室温下搅拌75分钟后,将该溶液倾入到冰冷的1N的HCl上,以甲苯提取,经MgSO4干燥并浓缩,得到无色油状的标题化合物(6.15g,70%):1HNMR(d6-DMSO):δ7.23-7.30(m,2H,苯基C
H),7.15-7.22(m,3H,苯基C
H),4.17-4.51(brs,1H,-OH),3.23-3.33(m,1H,R2CHOH),2.78(dq,J=7.0Hz,J=7.1Hz,1H,-CH(CH)3Ph),1.23-1.83(m,6H,环己基C
H),1.20(d,J=6.9Hz,3H,-CH(CH3)Ph),0.88-1.18(m,5H,环己基C
H)。
制备环己基1-苯基乙基酮
流程IV,步骤B:将DMSO(118mL,1.6674mol)滴加到126.42g(0.579mol)的1-环己基-2-苯基丙醇在1737mL的CH2Cl2(在湿冰丙酮浴中冷却)溶液中。29分钟后,加入147.93g(1.0422mol)的P2O5。11分钟后,撤除冷却浴。以Et3N骤冷一份显示室温下在3小时内反应完全。将该反应混合物在湿冰丙酮浴中冷却。用30分钟将Et3N(282mL,2.0265mol)滴加到该冷却的反应混合物中。撤除冷却浴并将所述混合物在室温下搅拌过夜。通过滴加500mL的3N HCl(水溶液)(pH=0)骤冷该反应混合物。在分液漏斗中振摇后,移去水相。以500mL的3N HCl(水溶液)(pH=0)洗涤有机相,以1L的10%K2CO3(水溶液)(pH=12;12)洗涤两次,以500mL的NaOCl(水溶液)洗涤三次,以1L水洗涤,以1L的25%NaCl(水溶液)洗涤,经MgSO4干燥,重力过滤并用干冰阱真空浓缩以收集Me2S。得到琥珀色油状的标题化合物(107.01g,85.437%);
1H NMR(d6-DMSO):δ7.30-7.37(m,2H,苯基C
H),7.21-7.28(m,3H,苯基C
H),4.08(q,J=6.9Hz,1H,-CH(CH3)Ph),2.40-2.49(m,1H,环己基C
H),1.82-1.84(m,1H,环己基-CH2),1.67-1.69(m,1H,环己基-CH2),1.52-1.63(m,1H,环己基-CH2),1.34-1.43(m,1H,环己基-CH2),1.26(d,J=6.9Hz,3H,-CH(CH3)Ph),1.01-1.24(m,4H,环己基-CH2)。
制备2-苯基-2-甲基-4-戊烯酰基环己烷
流程IV,步骤C:将31.39g(0.2797mol)的t-BuOK在100mL的THF中的溶液滴加到55.00g(0.2543mol)的环己基1-苯基乙基酮和26.4mL(0.3052mol)烯丙基溴在136mL的THF中的溶液(在湿冰丙酮浴中冷却)中。将THF洗涤液(16mL)加入到所述反应混合物中。加入后撤除冷却浴。在反应完全(2小时)后,以300mL的1N HCl(pH=0)骤冷所述反应混合物并以300mL庚烷提取。以10%的NaHCO3(水溶液)(pH=9)洗涤庚烷提取液,经MgSO4干燥,重力过滤并真空浓缩,得到59.70g(91.58%)琥珀色油状的标题化合物:1H NMR(d6-DMSO):δ7.32-7.42(m,2H,苯基C
H),7.24-7.31(m,3H,苯基C
H),5.34-5.47(m,1H,-CH=CH2),5.02(dd,J=17.1Hz,J=2.1Hz,1H,-CH=CH-H(反式)),4.97(ddd,J=10.2Hz,J=2.2Hz,J=1.0Hz,1H,-CH=CH-H(顺式,W-偶合)),2.66(ddd,J=14.2Hz,J=6.9Hz,J=1.0Hz,1H,-CH2CH=CH2),2.59(ddd,J=14.2Hz,J=7.3Hz,J=1.0Hz,1H,-CH2CH=CH2),2.38-2.49(m,1H,环己基C
H),1.48-1.69(m,4H,环己基-C
H 2),1.46(s,3H,-CH(CH3)Ph),1.36-1.44(m,1H,环己基-C
H 2),0.82-1.36(m,5H,环己基-C
H 2)。
制备4-环己基-3-甲基-4-氧代-3-苯基丁醛
流程IV,步骤D:将臭氧鼓入到56.50g(0.2204mol)2-苯基-2-甲基-4-戊烯酰基环己烷和少量(~10mg)苏丹III在220mL甲醇中的混浊混合物(在-20℃干冰丙酮浴上)中反应4小时,直到粉红色转变为浅黄色。在所有的烯烃消耗完全之后,将Me2S(50mL)加入到反应混合物中。撤除冷却浴。放热后温度升至38℃并在冷却浴中冷却该混合物直到不再放热。然后,撤除冷却浴并将该混合物搅拌过夜。以干冰阱真空浓缩所述反应溶液,收集过量的Me2S,得到粉红色油状的粗品4-环己基-3-甲基-4-氧代-3-苯基丁醛二甲缩醛(83.65g):
1H NMR(d6-DMSO):δ7.34-7.39(m,2H,苯基C
H),7.24-7.30(m,3H,苯基C
H),3.99(dd,J=4.2Hz,J=5.9Hz,1H,CH(OCH3)2),3.14(s,3H,CH(OCH3)2),3.06(s,3H,CH(OCH3)2),2.34-2.43(m,1H,环己基C
H),2.10-2.20(m,2H,-CH2CH(OCH3)2),1.55-1.67(m,1H,环己基-C
H 2),1.53(s,3H,R2C(CH3)Ph),0.80-1.52(m,9H,环己基-C
H 2)。
于室温下,向82.65g(66.29g,0.2177mol)的4-环己基-3-甲基-4-氧代-3-苯基丁醛二甲缩醛在539mL丙酮中的溶液中加入539mL的3N HCl(水溶液)。反应完全(2小时)后,将该混合物浓缩至426.5g(或者1/3体积)的残余物(RT-40℃)。所述残余物含有大部分水(pH=0),以300mL的MTBE提取两次。所述MTBE提取液以300mL的25%NaCl(水溶液)洗涤,经MgSO4干燥,重力过滤并浓缩,得到54.92g(97.65%)粉红色油状的标题化合物:1H NMR(d6-DMSO):δ9.54(t,J=2.0Hz,1H,-CHO),7.36-7.45(m,2H,苯基C
H),7.28-7.35(m,3H,苯基C
H),2.95(dd,J=16.6Hz,J=1.9Hz,1H,CH2CHO),2.85(dd,J=16.6Hz,J=1.7Hz,1H,CH2CHO),2.41-2.49(m,1H,环己基C
H),1.72(s,3H,R2C(CH3)Ph),0.85-1.66(m,10H,环己基C
H 2)。
制备最终标题化合物1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪
流程IV,步骤E:向13.72g(0.05310mol)的4-环己基-3-甲基-4-氧代-3-苯基丁醛和11.57g(0.05058mol)的1-(2’-甲氧基苯基)哌嗪盐酸盐在391mL CH2Cl2中的於浆中加入9.7mL的AcOH,使所述反应混合物均匀。向该反应溶液中缓慢加入14.63g(0.06904mol)的NaBH(OAc)3。搅拌4天(反应应在2-5小时内完成)后,向反应混合物中加入200mL的1N HCl(水溶液)(pH=1)以骤冷。以200mL的CH2Cl2提取所述化合物。以200mL的1N HCl(水溶液)(pH=1)再次洗涤CH2Cl2提取液。合并两份HCl(水溶液)的洗涤液并保存。以200mL的1N NaOH(水溶液)(pH=14)洗涤所述有机提取液。形成乳浊液并加入100mL水和100mL的MTBE打破。以200mL的1N NaOH(水溶液)(pH=14)再次洗涤有机相,并以200mL的25%的NaCl(水溶液)洗涤,经MgSO4干燥,重力过滤并浓缩,得到琥珀色油状的粗品标题化合物22.74g。经与纯标准品的HPLC分析比较显示,粗品产物油具有13.66g(61.71%)的标题化合物。
向所合并的HCl洗涤液中加入28.44g的NaOH(s)以使得混合物呈碱性(pH=14)。以100mL的CH2Cl2将所述混浊的混合物提取两次。合并所述CH2Cl2提取液,以25%的NaCl(水溶液)洗涤,经MgSO4干燥,重力过滤并浓缩,得到1.86g琥珀色油状残余物,其含有0.096g(总产率=62.15%)的标题化合物和1.05g(10.8%回收率)的1-(2’-甲氧基苯基)哌嗪。
1H NMR(d6-DMSO):δ7.35-7.43(m,2H,苯基C
H),7.26-7.32(m,3H,苯基C
H),6.89-6.96(m,2H,苯基C
H),6.83-6.88(m,2H,苯基C
H),3.76(s,3H,OCH3),2.80-3.03(m,4H,哌嗪C
H 2),2.34-2.49(m,4H,哌嗪C
H 2),1.91-2.24(m,4H),1.52-1.62(m,2H,环己基C
H 2),1.51(s,3H,R2C(CH3)Ph),1.34-1.48(m,2H,环己基-C
H 2),1.13-1.27(m,4H,环己基-C
H 2),1.00-1.10(m,2H,环己基-C
H 2),0.83-1.00(m,1H,环己基-C
H 2)。
最终标题化合物的另一种制备方法
制备烯胺
流程V,步骤A:向25.00g(0.1093mol)的1-(2’-甲氧基苯基)哌嗪盐酸盐在42mL水中的溶液中加入14.5mL(0.109mol)的浓(29.4%)NH4OH(水溶液)(pH=9)。以250mL的1∶1(v/v)的THF∶甲苯提取所述混合物两次。合并有机提取液。经MgSO4干燥,重力过滤并浓缩,得到淡绿色油状的1-(2’-甲氧基苯基)哌嗪20.17g(96.00%):1HNMR(d6-DMSO):d6.90-6.97(m,2H,苯基C
H),6.83-6.90(m,3H,苯基C
H),3.77(s,3H,OCH3),2.77-2.91(m,8H,哌嗪,CH2),2.49-2.53(m,1H,NH)。将9.55g(0.0370mol)的4-环己基-3-甲基-4-氧代-3-苯基丁醛在10mL的iPrOAc中的溶液加入到6.77g(0.0352mol)纯的1-(2’-甲氧基苯基)哌嗪中。该混合物变得混浊,然后当加入10mL的iPrOAc时转变为固体块状物。以45mL的iPrOAc使该固体浆化。1.5小时后,反应完全。真空过滤所述固体,并以10mL的iPrOAc洗涤,空气干燥,得到为灰白色粉末的9.81g(64.4%)的纯的烯胺。浓缩滤液,得到6.40g粗品烯胺;
1H NMR(d6-DMSO):δ7.31-7.43(m,2H,苯基C
H),7.20-7.31(m,3H,苯基C
H),6.82-7.04(m,4H,苯基C
H),6.06(d,J=14.2Hz,1H,CR3CH=CHNR2(反式)),4.98(d,J=14.2Hz,1H,CR3CH=CHNR2(反式)),3.80(s,3H,OCH3),2.93-3.15(m,8H,哌嗪,CH2),2.38-2.49(m,1H,环己基C
H),1.59-1.72(m,2H,环己基C
H 2),1.47-1.59(m,2H,环己基-C
H 2),1.40(s,3H,R2C(CH3)Ph),1.21-1.34(m,3H,环己基-C
H 2),1.03-1.21(m,2H,环己基-C
H 2),0.83-1.03(m,1H,环己基-C
H 2)。
制备最终标题化合物
流程V,步骤B:向在冰浴中冷却的500mL帕尔瓶中的5.35g(0.00101mol)的5%Pd/C中加入8.68g(0.0201mol)的上述形成的烯胺。向该固体混合物中加入在冰箱(-22℃)中冷却的40mL IPA。在50psi下导入H2并在室温下将混合物振摇2天以完成反应。真空过滤黑色浆状物并浓缩,得到8.70g无色的油状物。在搅拌下以50mL IPA洗涤所述Pd/C催化剂。真空过滤黑色浆状物。将滤液与8.70g残余物合并并浓缩,得到无色油状的最终标题化合物10.03g。
本领域普通技术人员可通过以类似于以上描述的方法制备的包括在本发明范围内的另外的化合物如下:
10)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪二氢溴酸盐;
11)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪单氢溴酸盐;
12)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪琥珀酸盐,1∶1;
13)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪琥珀酸盐,2∶1;
14)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪磷酸盐;
15)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪d-酒石酸盐;
16)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪l-酒石酸盐;
17)(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪马来酸盐;
5-羟色胺1A受体活性
本发明化合物为所述5-羟色胺1A受体的选择性拮抗剂。先前已知的具有1A受体活性的化合物一般也具有其它中枢神经系统活性的缺点。目前,药理学家和医师熟知,具有单一生理活性的药物或在所需的活性上比在它们的其它活性具有大得多的活性的药物对疗法而言,比在大约相同剂量下具有多种活性的化合物(例如吲哚洛尔)是更合乎需要的。
许多其它已知的5-羟色胺1A受体拮抗剂一般也具有α-肾上腺素能、β-肾上腺素能或者多巴胺-2活性,并因此对1A活性是非选择性的。
本发明化合物的所述5-HT1A受体结合效力已经通过由Taylor等(J.Pharmacol.Exp.Ther.,
236,118-125,1986);和Wong等(Pharm.Biochem.Behav.,46,173-77(1993))中描述的改进的结合试验来测定。所述结合试验的膜由雄性Sprague-Dawley大鼠(150-250g)制备。通过断头处死动物,迅速冷冻大脑并解剖以得到海马回。或者当天制备来自海马回的膜,或者冷冻贮存(-70℃)所述海马回直到制备的那一天。使用匀浆器,通过在40体积的冰冷的Tris-盐酸缓冲液(50mM,22℃下pH7.4)中,将该组织匀浆15秒来制备所述膜,并将所述匀浆在39800xg下离心10分钟。然后将生成的沉淀物再次悬浮于相同的悬浮液中,并将离心和再悬浮过程再重复三次以洗涤该膜。在第二次和第三次洗涤之间,将所述再悬浮的膜在37℃下孵育10分钟,以便于除去内源性的配体。将最终的沉淀物再悬浮于67mM Tris-盐酸(pH7.4)中至浓度为每200μl中含有2mg湿重的原组织。将匀浆物冷冻贮存(-70℃)直到进行结合试验。用于结合试验的每只试管的最终体积为800μl,并且含有以下物质:Tris-盐酸(50mM)、帕吉林(10μM)、CaCl2(3mM)、[3H]8-OH-DPAT(1.0nM)、目的药物的适当的稀释液和相当于湿重的原组织2mg的膜悬浮液,最终pH为7.4。在37℃下,将试验试管孵育10分钟或15分钟。然后通过GF/B滤膜(用0.5%氮丙啶预处理)快速过滤所述内容物,随后以冰冷的缓冲液洗涤四次,每次1ml。经滤膜捕获的放射活性通过液体闪烁光谱仪定量,特异性结合于所述5-HT1A位点的[3H]8-OH-DPAT被定义为在10μM的5-HT存在或缺乏下所结合的[3H]8-OH-DPAT之间的差异。
使用非线性回归法(SYSTAT,SYSTAT公司,Evanston,Il),从12-点竞争曲线来测定IC50值即抑制50%的结合所需的浓度。使用Cheng-Prusoff方程(Biochem.Pharmacol.,
22,3099-3108(1973))将IC50值转变为Ki值。所有实验以一式三份进行。
通过试验方法,对本发明化合物进行了一些其它的结合试验,该方法使用表达所述5-HT1A受体的克隆的细胞系而不是所述海马回膜。这样的克隆的细胞系已经被Fargin等在J.Bio.Chem.,
264,14848-14852(1989)、Aune等在J.Immunology,
151,1175-1183(1993)和Raymond等在Naunyn-Schmiedeberg’s Arch.Pharmacol.,
346,127-137(1992)中描述。来自所述细胞系试验的结果基本上与所述海马回膜试验的结果相一致。
5HT1a拮抗剂体内试验
a)5HT1a拮抗作用皮下试验
在皮下剂量范围内,试验化合物阻断8-OH-DPAT诱导的行为和低温的活性。在雄性Sprague-Dawley大鼠(来自Harlan Sprague Dawley~250克)上记录下唇收缩(LLR)和扁平体姿(flat body posture)(FBP)。在0-3级范围内测量LLR和FBP(Wolff,1997)。在所述LLR行为试验中,“0”表明正常的唇位置;“1”表明所述唇稍微分开;“2”表明伴随一些牙齿可见的唇分开;“3”表明所述唇充分开启,所有前排牙齿暴露。在所述FBP试验中,“0”级表明正常体姿;“1”表明胃部在地板上,而背部在其正常成圆形(rounded)的位置;“2”表明胃部在地板上,而背部伸直并从肩部抬起至臀部;“3”表明胃部压在地板上,并且所述背部与肩部和甚至臀部成平面。在行为测量后,通过立即将直肠探头插入5.0cm,记录体核温度。记分前35分钟将化合物(在0、0.3、1.0和3.0mg/kg剂量下)皮下注射给予大鼠并且在记分前20分钟注射8-OH-DPAT(0.1mg/kg皮下给药)。
b)5HT1a激动剂皮下试验
在单独皮下给药的10mg/kg高剂量下,也对所述化合物进行试验以观察是否诱导5-HT1A激动剂样的低温。
本发明化合物的有效的5-羟色胺1A受体活性使它们具有多种药物和治疗应用。这些应用之一为帮助那些依赖烟草或尼古丁使用的人们去掉此习惯的方法。
烟草或尼古丁戒断
人们熟知慢性给予尼古丁导致耐受性,并且最终产生依赖性。在所有的国家烟草的使用变得极为广泛,尽管已经熟知使用所有形式的烟草的副作用。因此,人们清楚如果不成瘾的话,使用烟草极易形成习惯,并且其使用对使用者提供愉快的并受到欢迎的感觉,即使使用者充分意识到其使用的剧烈的长期不良作用。
最近,已经发生了反对使用烟草的激烈运动,并且停止吸烟带来许多不愉快的戒断症状是普通的常识,这些症状包括易怒、焦虑、坐立不安、注意力缺乏、头晕目眩、失眠、震颤、饥饿感和体重增加,并且当然具有烟瘾。
目前,可能是最广泛使用的帮助停止使用烟草的疗法是尼古丁替代疗法,方法是通过使用尼古丁口香糖或经皮提供尼古丁的贴剂。然而,人们广泛了解到,如果不进行改变习惯的心理治疗和训练,那么尼古丁替代疗法是不那么有效的。
本发明方法广泛用于帮助打算要停止或减少他们的烟草或尼古丁使用的人们。更经常地,使用烟草的形式是吸烟,最经常地是吸香烟。然而,在帮助人们改掉所有类型的吸服烟草以及嗅、吞服烟草等习惯方面,本发明也是有帮助的。本发明方法对那些以使用尼古丁替代疗法替代或部分替代他们对烟草的使用的人们也是有帮助的。因此,能够帮助这样的患者以减少并甚至完全消除他们对各种形式的尼古丁的依赖。
人们可以理解本发明对于阻止或缓解试图消除或减少他们对烟草或尼古丁的使用的苦恼的患者的戒断症状是有用的。这类人们的常见戒断症状至少包括易怒、焦虑、坐立不安、注意力缺乏、失眠、神经性震颤、饥饿感和体重增加,轻微的头晕,并且对烟草或尼古丁渴求。当这些戒断症状由于戒断或减少患者对烟草或尼古丁的使用而引起时,或者与停止或减少患者对烟草或尼古丁的使用同时发生时,阻止或缓解这样的戒断症状为本发明所要求的结果并且是它的一个重要方面。
通过给予需要或进行减少或停止对烟草或尼古丁的使用的患者有效量的式I或式Ia化合物来进行本发明。
在此使用的术语“患者”意指温血动物例如哺乳动物。包括在术语“患者”范围内的有人、狗、大鼠、小鼠等。应该理解优选的患者是人。
式I或式Ia化合物的有效量为提供在诊断或治疗下的患者所需作用的化合物的量或剂量。所给予的式I或式Ia化合物的剂量在广泛的剂量范围内是有效的,一般而言,它是在大约1至大约200mg/天;通常,日剂量可以单一剂量或以分剂量给药,这依负责该病例的医师的判断而定。剂量的更优选范围是大约5至大约100mg/天;在特定环境下可优选的其它剂量范围是大约10至大约50mg/天;大约5至大约50mg/天;大约10至大约25mg/天;并且特别优选的范围是大约20至大约25mg/天;可以理解对于给定患者而言,剂量总是由主治医师的判断来确定,并且该剂量应根据患者的体积、患者的瘦或胖的性质、所选择的具体化合物的特性、所述患者的烟草习惯的强度、所述患者戒断症状的强度和影响患者的生理反应的心理因素而定。
通过大鼠听觉吃惊试验,评价所述化合物缓解尼古丁戒断症状的作用,该方法如下进行。
尼古丁戒断研究方法
动物:雄性Long Evans大鼠在12小时光-暗循环下单独居住在控制的环境中,并且随意进食(Purina Rodent Chow)和饮水。所有治疗组包括8-10只大鼠。
慢性尼古丁治疗:以氟烷麻醉大鼠并且皮下植入AlzetTM微型渗透泵(Alza公司,Palo Alto,CA,型号2ML2)。将尼古丁二酒石酸盐溶于生理盐水。以尼古丁二酒石酸盐(6mg/kg base/天)或者生理盐水充入泵中。植入泵后12天,以氟烷麻醉大鼠并取出所述泵。
听觉吃惊反应:使用San Diego Instruments吃惊室(San Diego,CA),记录单个大鼠的感觉运动反应[听觉吃惊反应(峰幅度Vmax)]。在背景声音为70±3dBA的水平下,听觉吃惊反应包含5分钟的适应期、随后立即进行以8-秒间隔提供的25个听觉刺激(120±2dBA噪音,50ms持续时间)。然后使对每一段时间的所有25个刺激的峰吃惊幅度平均化。在尼古丁戒断后第1-4天时,以24小时间隔每天评价听觉吃惊反应。
与重摄取抑制剂的联合
式I或式Ia化合物的另一个应用是它们与5-羟色胺重摄取抑制剂的联合,通过增加被给予所述药物联合的患者大脑中的5-羟色胺以及去甲肾上腺素和多巴胺的利用度进一步增强这些药物的作用。典型的和适宜的5-羟色胺重摄取抑制剂(SRI)为氟西汀、度洛西汀、文拉法辛、米那普仑、西酞普兰、氟伏沙明和帕罗西汀。相应地,本发明提供了在增加大脑中的5-羟色胺以及去甲肾上腺素和多巴胺的利用度时,使5-羟色胺重摄取抑制剂尤其是选自氟西汀、度洛西汀、文拉法辛、米那普仑、西酞普兰、氟伏沙明和帕罗西汀的药物作用增强的方法,该方法包括给予与式I或式Ia化合物联合的所述5-羟色胺重摄取抑制剂。本发明也提供了包括与式I或式Ia化合物联合的5-羟色胺重摄取抑制剂的药用组合物和治疗病症的方法,这些病症由5-羟色胺、多巴胺或去甲肾上腺素的利用度减少而产生或依赖于它们,该方法包括给予需要此治疗的患者相同的辅助疗法。
氟西汀即N-甲基-3-(对-三氟甲基苯氧基)-3-苯基丙胺以盐酸盐的形式并作为其两种对映体的外消旋混合物上市。U.S.专利4,314,081为有关该化合物的早期参考文献。Robertson等在J.Med.Chem.,31,1412(1988)中提出氟西汀的R和S对映体的分离,并显示它们作为5-羟色胺重摄取抑制剂的活性是彼此相似的。在这篇文件中,术语“氟西汀”将用于意指任何酸加成盐或其游离碱并且包括外消旋混合物或者所述R和S对映体。
度洛西汀即N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺一般作为盐酸盐给药且为(+)对映体。首先由U.S.专利4,956,388提出该药,该文献显示其高度效力。术语“度洛西汀”将用于意指所述分子的任何酸加成盐或其游离碱。
文拉法辛在本文献中是已知的,并且由U.S.专利4,761,501提出了其合成方法和其作为5-羟色胺重摄取抑制剂的活性。在该专利中文拉法辛定义为化合物A。
米那普仑即(N,N-二乙基-2-氨基甲基-1-苯基环丙烷甲酰胺),其由U.S.专利4,478,836提出,在该专利实施例4中制备了米那普仑。在该专利中将其描述为抗抑郁药化合物。Moret等在Neuropharmacology
24,1211-19(1985)中描述了其药理活性。
西酞普兰即1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃甲腈,该药作为5-羟色胺重摄取抑制剂在U.S.专利4,136,193中公开。其药理学由Christensen等在Eur.J.Pharmacol.
41,153(1977)中公开,并且其在抑郁中的临床有效性的报道见Dufour等,Int.Clin.Psychopharmacol,
2,225(1987)和Timmerman等,同上,239。
氟伏沙明即5-甲氧基-1-[4-(三氟甲基)苯基]丙基-1-戊酮O-(2-氨基乙基)肟在U.S.专利4,085,225中提出。由Claassen等在Brit.J.Pharmacol.,
60,505(1977);和De Wilde等在J.Affective Disord.,
4,249(1982);和Benfield等在Drugs,
32,313(1986)公开有关该药的科学文献。
帕罗西汀即反式-(-)-3-[(1,3-苯并间二氧杂环戊烯-5-基氧)甲基]-4-(4-氟苯基)哌啶可在U.S.专利3,912,743和4,007,196中发现。该药的活性报道见Lassen,Eur.J.Pharmacol.,
47,351(1978);Hassan等,Brit.J.Clin.Pharmacol.,
19,705(1985);Laursen等,Acta Psychiat.Scand.,
71,249(1985);和Battegay等,Neuropsychobiology,
13,31(1985)。
以上提及的与本发明所使用的化合物相联系的所有U.S.专利通过引用结合到本文中。
通常,使用氟西汀或者度洛西汀作为SRI的联合和治疗方法是优选的。
技术读者可以理解用于本发明的所有化合物能够形成盐,并且通常使用药物的盐形式,经常是因为它们比所述游离碱更易于结晶和纯化。在所有的情况下,上述作为盐的药物的用途也包括于在此的描述中,并且经常是优选的,并且所有化合物的药学上可接受的盐包括在其中。
在最后的分析中,用于本联合的所述药物的剂量必须由负责该病例的医生根据药物的知识、在临床试验中测定的联合的药物的性质和患者的特性,包括疾病而不是所述医师正在治疗患者的情况来决定。提供所述剂量的总体概况和一些优选的剂量。对于一些药物的剂量准则将首先分别给出;为了确立用于任何所需联合的准则,医师应对这些药物成分的每一个选择一个准则。
氟西汀:大约1至大约80mg,一次/天;优选大约10至大约40mg,一次/天;优选用于食欲过盛和强迫观念与行为疾病时为大约20至大约80mg,一次/天;
度洛西汀:大约1至大约30mg,一次/天;优选大约5至大约20mg,一次/天;
文拉法辛:大约10至大约150mg,三次/天;优选大约25至大约125mg,三次/天;
米那普仑:大约10至大约100mg,一至两次/天;优选大约25至大约50mg,两次/天;
西酞普兰:大约5至大约50mg,一次/天;优选大约10至大约30mg,一次/天;
氟伏沙明:大约20至大约500mg,一次/天;优选大约50至大约300mg,一次/天;
帕罗西汀:大约5至大约100mg,一次/天;优选大约50至大约300mg,一次/天。
在更通常意义上,按照以上准则的精神,通过选择SRI的剂量可以确立本发明的联合,并且在以上所提出的范围内选择式I或式Ia化合物的剂量。
通过以任何方式给予与式I或式Ia化合物一起的SRI来实施本发明的辅助疗法,该方式可提供相同时间内两种化合物在体内的有效水平。所有有关的化合物均可以口服并且正常口服给药,且如此口服给药的辅助联合是优选的。它们可以单一剂型一起给药,或者可分别给药。
然而,口服给药并非仅有的途径或者甚至是仅有的优选途径。例如,对采用口服药物健忘的或性急的患者而言,经皮给药可为合乎要求的。所述药物之一可通过一种途径例如口服给药,而另一种可通过经皮、透皮、静脉、肌内、鼻内或直肠内途径给药,尤其是在特殊环境下。给药途径可以任何方式变化,由所述药物的物理性质和患者和caregiver的便利性来限制。
然而,对辅助联合而言特别优选地是作为单一药用组合物给药,并且此类包括有SRI和式I或式Ia化合物的药用组合物为本发明的重要的实施方案。这样的组合物可采用任何为药学上可接受的物理形式,但是口服用途的药用组合物为特别优选的。这样的辅助药用组合物含有有效量的化合物中的每一个,其有效量与所给予的化合物的日剂量有关。每一个辅助剂量单位可含有两个化合物的日剂量,或者可含有日剂量的一部分如三分之一的剂量。
或者每个剂量单位可含有所述化合物之一的全部剂量和另一化合物剂量的一部分。在这样的情况下,患者将每天服用一个联合剂量单位和仅含有另一个化合物的一个或多个单位。在每一个剂量单位中含有的每一个药物的量依所述疗法的所选择的药物和其它的因素如所给予的辅助疗法的适应症而定。
如上所述,辅助疗法的有利之处就是其具有增强由所述SRI引起的5-羟色胺、去甲肾上腺素和多巴胺的利用度增加的能力,在治疗以下详细描述的多种疾病中导致活性的改善。5-羟色胺利用度的增加是特别重要的并且为本发明优选的方面。另外,本发明提供比以SRI单独使用治疗通常所提供的作用更迅速起效。
本发明辅助方法所治疗的优选的病症包括抑郁、食欲过盛、强迫观念与行为疾病和肥胖症。对优选包括氟西汀而且包括文拉法辛和米那普仑的联合更特别的另一个优选的疾病为尿失禁。
最近,对大众而言,以许多变化形式存在的抑郁症已经变得比以前更加可见。其现在已经被认为是极度损害性的疾病,并且为使令人惊奇的一大部分人苦恼的疾病。自杀是抑郁症最极端的症状,但是数百万的人并不相当如此被剧烈苦恼,生活在痛苦中并且部分或完全无用,并且他们的苦恼也困扰他们的家庭。在治疗抑郁症中氟西汀的出现是突破性的,并且目前抑郁症仅比它们在十年前诊断和治疗可能的多。度洛西汀在临床试验中用于治疗抑郁症。
抑郁症经常与其它的疾病和病症有关,或者由这样的其它的疾病引起。例如,它与帕金森病、HIV、阿尔滋海默氏病、促蛋白合成甾类滥用有关。抑郁症也与某些物质滥用有关,或者可与头部损害、精神发育迟缓或中风联合导致或发生的行为问题有关。以其所有变化形式存在的抑郁症为用本发明辅助疗法和组合物治疗的优选目标。
强迫观念与行为疾病以各种程度和症状出现,一般通过所述患者的未控制的强烈要求来进行不需要仪式性的行动。超出任何合理的需要或理性,获得、命令、净化等行为是所述疾病的外在特征。严重困扰的患者可能不能做任何事情而是进行由这种疾病所要求的仪式。在美国和其他的国家,氟西汀被批准用于治疗强迫观念与行为疾病并已经发现是有效的。
肥胖症在美国人口中是频繁发生的病症。已发现氟西汀能使肥胖患者体重下降,从而对患者的循环和心脏状况以及总体健康和能量产生好处。
尿失禁通常分类为压迫性失禁或冲动性失禁,依其根本原因是否为所述保持控制的括约肌无力或者所述膀胱肌活动过度而定。度洛西汀控制两种类型的失禁或者同时控制两种类型,并且由此对患有这种窘迫和无力障碍的许多人是重要的。
本发明联合也用于治疗许多其它的疾病、障碍和病症,如下所列出。在许多情况下,在此所提及的所述疾病在国际疾病分类学第9版(ICD)或在精神疾病的诊断和统计手册中(第3次修订版,由美国精神病协会出版(DSM))分类。在这样的情况下,所述ICD或DSM编号提供如下以方便读者使用。
抑郁,ICD 296.2和296.3,DSM 296,294.80,293.81,293.82,293.83,310.10,318.00,317.00
偏头痛
疼痛,特别是神经性疼痛
食欲过盛,ICD 307.51,DSM 307.51
经期前综合征或迟发性黄体相综合征,DSM 307.90
酒精中毒,ICD 305.0,DSM 305.00和303.90
烟草滥用,ICD 305.1,DSM 305.10和292.00
惊恐障碍,ICD 300.01,DSM 300.01和300.21
焦虑,ICD 300.02,DSM 300.00
创伤后综合征,DSM 309.89
记忆丧失,DSM 294.00
老年性痴呆,ICD 290
社会恐怖症,ICD 300.23,DSM 300.23
注意力缺乏机能亢进障碍,ICD 314.0
破坏行为障碍,ICD 312
冲动控制障碍,ICD 312,DSM 312.39和312.34
不明确个性障碍,ICD 301.83,DSM 301.83
慢性疲劳综合征
早泄,DSM 302.75
勃起困难,DSM 302.72
神经性厌食,ICD 307.1,DSM 307.10
睡眠障碍,ICD 307.4
孤独症
缄默症
拔毛发癖
此外,当与5-羟色胺重摄取抑制剂联合给药时,式I或式Ia化合物尤其可用于缓解停止吸烟或尼古丁戒断的症状。用于这种治疗方法的SRI’s和给药方法和制剂如上所述。将本发明化合物与SRI’s用于力求停止使用烟草或尼古丁的患者中提供令人惊奇的完全缓解这样的患者的通常疼痛和损害症状,这些症状包括神经过敏、易怒、嗜欲、食欲过盛、焦虑、多种形式的抑郁、注意力不能集中等。
治疗应用
式I或式Ia化合物可用于其它重要的治疗目的以及与SRIs的联合并用于尼古丁戒断或停止吸烟的情况。所述化合物尤其可用于拮抗所述5-羟色胺1A受体,并且相应地可用于治疗或阻止由该受体过度活性引起或影响的疾病。
更详细的说,式I或式Ia化合物可用于治疗焦虑、抑郁、高血压、识别障碍、精神病、睡眠障碍、胃动力障碍、性机能紊乱、大脑损伤、记忆丧失、饮食障碍和肥胖症、物质滥用、强迫观念与行为疾病、惊恐障碍和偏头痛。
谈到本发明化合物时,可特别提及焦虑及其伴随的惊恐障碍。该主题由美国精神病协会出版的“精神障碍的诊断和统计手册”作认真解释,其中将焦虑分类在它的目录第300.02号下。另一种特别提到的障碍为抑郁症和一组与抑郁相关的障碍,其在以上与SRIs的辅助疗法的讨论中得到讨论。
药用组合物
配制用于给药的药物以提供控制剂量和产品在运输及贮存中的稳定性是惯例,并且该制剂的一般方法完全适用于式I或式Ia化合物。包括至少一种药学上可接受的载体的这样的组合物是有价值的并且是新的,因为其中存在式I或式Ia化合物。虽然药物化学家清楚意识到配制药剂的许多有效方法,这些技术也适用于本发明的化合物,但是为方便读者我们仍将给出有关该主题的讨论。
可使用用于药剂学的制剂的通用方法和组合物的通用类型,包括片剂、可咀嚼片剂、胶囊剂、溶液、非肠道溶液剂、鼻内喷雾剂或散剂、锭剂、栓剂、经皮贴剂和混悬剂。组合物一般含有大约0.5%至50%总量的化合物,依所需的剂量和所使用的组合物的类型而定。然而,式I或式Ia化合物的量最佳定义为有效量,即提供给需要此治疗的患者所需剂量的化合物的量。所述化合物的活性不依组合物的性质而定,所以选择该组合物并且为方便和经济起见单独配制。任何化合物可配制成任何所需形式的组合物。按照一些典型的制剂,将提供对不同组合物的讨论。
通过使所述化合物与适宜的稀释剂混合并且将适当量的混合物填充于胶囊中来制备胶囊剂。通常的稀释剂包括惰性粉状物质如多个不同种类的淀粉、粉状纤维素特别是结晶和微晶纤维素、糖类如果糖、甘露糖醇和蔗糖、粒状面粉和类似的食用粉末。
通过直接压制、湿法制粒或干法制粒制备片剂。它们的制剂通常包括稀释剂、粘合剂、润滑剂和崩解剂以及所述化合物。一般的稀释剂包括例如各种类型的淀粉、乳糖、甘露糖醇、高岭土、磷酸钙或硫酸钙、无机盐类如氯化钠和粉状糖。粉状纤维素衍生物也是有用的。一般的片剂粘合剂为像淀粉、明胶和糖类如乳糖、果糖、葡萄糖等物质。天然和合成的明胶也是便利的,包括阿拉伯胶、藻酸盐、甲基纤维素、聚乙烯吡咯烷酮等。聚乙二醇、乙基纤维素和蜡也能用作粘合剂。
在片剂配制中,润滑剂是必要的以阻止片剂和冲头粘结于模上。所述润滑剂选自滑动的固体如滑石粉、硬脂酸镁和硬脂酸钙、硬脂酸和氢化植物油。
片剂崩解剂为当被润湿以分解片剂并释放所述化合物时可膨胀的物质。它们包括淀粉、粘土、纤维素、藻胶和树胶。更详细地说,可使用例如玉米和马铃薯淀粉、甲基纤维素、琼脂、膨润土、木质纤维素、粉状天然海绵、阴离子交换树脂、藻酸、瓜尔豆胶、橘浆和羧甲基纤维素以及十二烷基硫酸钠。
包囊制剂经常用于保护活性成分免于胃内的强酸内容物破坏。通过采用在酸性环境中不溶解而在碱性环境中溶解的聚合物膜将固体制剂包衣来产生这样的制剂。示例性膜为乙酸邻苯二甲酸纤维素、聚乙烯乙酸酯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸酯琥珀酸酯。
片剂通常以作为矫味剂和密封材料的糖来包衣,或者以改善所述片剂溶出性质的薄膜形成保护试剂来包衣。通过在制剂中使用大量的良好味觉的物质如甘露糖醇,也可将所述化合物配制成可咀嚼的片剂,为目前充分确立的实践。快速溶解片剂类制剂目前也可经常使用以确保患者消费该剂型,并且避免了困扰一些患者的吞服固体物时的困难。
当需要作为栓剂给予所述联合时,可使用通常的基质。可可脂是传统的栓剂基质,该基质可通过加入蜡来改性以稍微提高其熔点。包括尤其是各种分子量的聚乙二醇的水可混溶的栓剂基质也被广泛使用。
经皮贴剂最近已变得大众化。通常它们包含其中所述药物将溶解或部分溶解的树脂组合物,该组合物通过保护所述组合物的膜保持与皮肤接触。最近在该领域已经出现了许多专利。另外,更复杂的贴剂组合物也在使用中,尤其是那些具有以无数的孔刺破的膜的组合物,所述药物通过这些孔经渗透作用泵出。
为药剂学家提供以下典型配方的重要信息。
制剂1
使用以下成分,制备硬明胶胶囊:
用量
(mg/胶囊)
实施例1 20mg
干燥淀粉 200mg
硬脂酸镁
10mg
合计 230mg
制剂2
使用以下成分,制备片剂:
用量
(mg/胶囊)
实施例2 10mg
微晶纤维素 400mg
热解法二氧化硅 10mg
硬脂酸
5mg
合计 425mg
粘合所述各组分并压制,形成每片重425mg的片剂。
制剂3
如下制备每片含有10mg活性成分的片剂:
实施例3 10mg
淀粉 45mg
微晶纤维素 35mg
聚乙烯吡咯烷酮 4mg
(10%的在水中的溶液)
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石粉
1mg
合计 100mg
将活性成分、淀粉和纤维素通过第45号U.S.筛并彻底混合。将含有聚乙烯吡咯烷酮的水溶液与所述生成的粉末混合,然后将该混合物通过第14号U.S.筛。在50℃下干燥如此生成的颗粒,将该颗粒通过第18号U.S.筛。预先将羧甲基淀粉钠、硬脂酸镁和滑石粉通过第60号U.S.筛,然后将其加入到所述颗粒中,混合后,在压片机上压制,得到每片重100mg的片剂。
制剂4
如下制备每胶囊含有30mg活性成分的胶囊剂:
实施例4 30mg
淀粉 59mg
微晶纤维素 59mg
硬脂酸镁
2mg
合计 150mg
将所述活性成分、纤维素、淀粉和硬脂酸镁混合,通过第45号U.S.筛,并以150mg的量填充到硬明胶胶囊中。
制剂5
如下制备每只含有5mg活性成分的栓剂:
实施例5 5mg
饱和脂肪酸甘油酯
2,000mg
合计 2005mg
将所述活性成分通过第60号U.S.筛,并在预先用最小量热熔化的饱和脂肪酸甘油酯中悬浮。然后将混合物倾入标示容量2g的栓剂模具中并使之冷却。
制剂6
如下制备每5ml含有10mg活性成分的剂量的栓剂:
实施例6 10mg
羧甲基纤维素钠 50mg
糖浆 1.25ml
苯甲酸溶液 0.10ml
矫味剂 适量
着色剂 适量
纯净水加至 5ml
将所述活性成分通过第45号U.S.筛,并与羧甲基纤维素钠和糖浆混合,形成均匀糊状物。以一部分水稀释苯甲酸溶液、矫味剂和着色剂并在搅拌下加入。然后加入足够的水以得到所需要的体积。
制剂7
如下可制备静脉制剂:
实施例7 10mg
等渗盐水 1,000ml
制剂8
使用以下成分,以类似于制剂1的方法制备硬明胶胶囊剂:
用量
(mg/胶囊)
(+)-1-(2-甲氧基苯基)-4-[3-(环己 20mg
烷羰基)-3-(苯基)丁基]哌嗪HCl
干燥淀粉 200mg
硬脂酸镁
10mg
合计 230mg
制剂9
使用以下成分,制备片剂:
用量
(mg/胶囊)
(+)-1-(2-甲氧基苯基)-4-[3-(环己 20mg
烷羰基)-3-(苯基)丁基]哌嗪HCl
微晶纤维素 400mg
热解法二氧化硅 10mg
硬脂酸
5mg
合计 425mg
以类似于制剂2的方法,使所述成分混合并压制成为每片重425mg的片剂。
制剂10
如下制备每片含有10mg所述活性成分的片剂:
(+)-1-(2-甲氧基苯基)-4-[3-(环己 10mg
烷羰基)-3-(苯基)丁基]哌嗪HCl
淀粉 45mg
微晶纤维素 35mg
聚乙烯吡咯烷酮 4mg
(10%的在水中的溶液)
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石粉
1mg
合计 100mg
将所述活性成分、淀粉和纤维素通过第45号U.S.筛并彻底混合。将含有聚乙烯吡咯烷酮的水溶液与所述生成的粉末混合,然后将该混合物通过第14号U.S.筛。在50℃下干燥如此生成的颗粒并将该颗粒通过第18号U.S.筛。将羧甲基淀粉钠、硬脂酸镁和滑石粉预先通过第60号U.S.筛,然后将其加入到所述颗粒中,混合后,在压片机上压制,得到每片含有重100mg的片剂。
制剂11
以类似于制剂4的方法,如下制备每胶囊含有30mg活性成分的胶囊剂:
(+)-1-(2-甲氧基苯基)-4-[3-(环己 30mg
烷羰基)-3-(苯基)丁基]哌嗪HCl
淀粉 59mg
微晶纤维素 59mg
硬脂酸镁
2mg
合计 150mg
Claims (43)
1.下式化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物:
其中:
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
2.权利要求1的化合物,其中Ar1为苯基或吡啶。
3.权利要求2的化合物,其中Ar1为由(C1-C6)烷氧基取代的苯基。
4.权利要求3的化合物,其中R2为苯基或(C3-C12)环烷基。
5.权利要求4的化合物,其中R1为氢。
6.权利要求5的化合物,其中X为-C=O。
8.权利要求1的化合物,其中该化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪和它的药学上可接受的盐。
9.权利要求8的化合物,其中所述药学上可接受的盐为二盐酸盐。
10.权利要求8的化合物,其中所述药学上可接受的盐为草酸盐。
11.权利要求8的化合物,其中所述药学上可接受的盐为马来酸盐。
12.权利要求8的化合物,其中所述药学上可接受的盐为磷酸盐。
13.权利要求1的化合物,其中该化合物为(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪一盐酸盐。
14.将权利要求1的化合物或它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备拮抗5-羟色胺1H受体的药物。
15.权利要求14的应用,其中所应用的化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
16.将下式(I)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备缓解由烟草或尼古丁使用的戒断或部分戒断引起的症状的药物
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
17.权利要求15的应用,其中所应用的化合物为1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丙基]哌嗪、1-(2-吡啶基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪、1-(2-乙氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丙基]哌嗪盐酸盐、1-(2-甲氧基苯基)-4-[3-(苯甲酰基)-3-(苯基)丁基]哌嗪草酸盐、1-(2-甲氧基苯基)-4-[3-(环庚烷羰基)-3-(苯基)丙基]哌嗪盐酸盐、1-(2-甲氧基苯基)-4-[3-(环戊烷羰基)-3-(苯基)丙基]哌嗪盐酸盐和1-(2-甲氧基苯基)-4-[4-(环己基)-4-(羟基)-3-(苯基)丁基]哌嗪草酸盐。
18.权利要求15的应用,其中在所制备的药物是可以与有效治疗量的5-羟色胺重摄取抑制剂联合施用的药物。
19.权利要求18的应用,其中所述5-羟色胺重摄取抑制剂为氟西汀、度洛西汀、文拉法辛、米那普仑、西酞普兰、氟伏沙明或帕罗西汀。
21.权利要求16的应用其中所应用的化合物(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
22.将下式(I)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备治疗焦滤症的药物
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
23.权利要求22的应用的化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
24.将下式(I)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备治疗抑郁、高血压、识别障碍、精神病、睡眠障碍、胃动力障碍、性机能紊乱、大脑损伤、记忆丧失、饮食障碍、肥胖症、物质滥用、强迫观念与行为疾病、惊恐障碍或偏头痛的药物
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
25.权利要求24的应用,其中所应用的化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
26.将下式(I)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备能与5-羟色胺重摄取抑制剂联合使用,而使5-羟色胺重摄取抑制剂在增加大脑中5-羟色胺、去甲肾上腺素和多巴胺的利用度中的作用增强的药物
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
28.权利要求26的应用,其中所应用的化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
29.权利要求26的应用,其中所述的5-羟色胺重摄取抑制剂为氟西汀。
30.将下式(I)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物应用于制备能帮助患者停止或减少他们使用烟草或尼古丁的药物
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素;
X为-(C=O)-、-CHOH-或-CH2-。
31.权利要求30的应用,其中所应用的化合物是下式的化合物或它们药学上可接受的盐:
32.权利要求30的应用,其中所应用的化合物是(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
33.制备以下所示的式II化合物的方法:
式II
其中R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素,该方法包括将其中R1、R2和R3如上所述的式III化合物
式III
用适宜的碱和其中X为适宜的离去基团的式IV化合物处理:
式IV
,得到所述式V化合物:
式V
,并且用适宜的氧化剂氧化该式V化合物,得到所述式II化合物。
34.权利要求33的方法,其中
R1为CH3;
R2为环己基;和
R3为氢。
35.权利要求34的方法,其中X为Br或Cl。
36.权利要求35的方法,其中所述适宜的氧化剂为臭氧。
37.权利要求36的方法,其中所述适宜的碱为叔丁醇钾。
38.一种药用组合物,该组合物包括药学上可接受的载体和权利要求1的式(I)化合物。
39.权利要求38的药用组合物,该组合物包括药学上可接受的载体和(+)-1-(2-甲氧基苯基)-4-[3-(环己烷羰基)-3-(苯基)丁基]哌嗪或其药学上可接受的盐。
41.权利要求40的化合物,其中
R1为CH3;
R2为环己基;和
R3为氢。
42.下式(20)的化合物或者它们的药学上可接受的盐、外消旋体、旋光异构体或溶剂合物:
其中
Ar1为由一至三个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的单或双环芳基或杂芳基;
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R2为由一或两个选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素的取代基取代的苯基、萘基或(C3-C12)环烷基;
R3选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C2-C6)链烯基、(C2-C6)炔基、卤代(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烯基或卤素。
43.权利要求42的式(20)化合物,其中
Ar1为
R1为甲基;
R2为环己基;和
R3为氢。
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US6979197P | 1997-12-16 | 1997-12-16 | |
US6972297P | 1997-12-16 | 1997-12-16 | |
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US60/069,791 | 1997-12-16 | ||
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