CN101511187B - 哌啶和哌嗪衍生物 - Google Patents
哌啶和哌嗪衍生物 Download PDFInfo
- Publication number
- CN101511187B CN101511187B CN2006800352343A CN200680035234A CN101511187B CN 101511187 B CN101511187 B CN 101511187B CN 2006800352343 A CN2006800352343 A CN 2006800352343A CN 200680035234 A CN200680035234 A CN 200680035234A CN 101511187 B CN101511187 B CN 101511187B
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- China
- Prior art keywords
- ethyl
- phenyl
- compound
- piperazine
- phenoxy
- 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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- 150000004885 piperazines Chemical class 0.000 title description 8
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 108010085082 sigma receptors Proteins 0.000 claims abstract description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 107
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 106
- -1 3-chloro-phenyl- Chemical group 0.000 claims description 42
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 24
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
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- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
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- 125000004429 atom Chemical group 0.000 claims description 8
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- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
Description
技术领域
本发明是关于新颖1,4-哌啶和哌嗪衍生物、关于制备所述新颖衍生物的方法、关于用于所述方法的新颖中间体、关于包含所述衍生物的医药组合物,以及关于所述衍生物在治疗中枢神经系统病症中的用途。
背景技术
已在科学文献中揭示某些中枢神经系统病症可利用σ受体功能调节剂来治疗。已知对σ配体具有亲和力的化合物包括一些哌啶及哌嗪衍生物。
WO 91/09594揭示对σ受体具有亲和力的化合物,其中一些是哌啶或哌嗪衍生物,并揭示所述化合物可用于治疗精神分裂症及其他精神病。
美国专利第5,736,546号揭示一些具有一个未经取代的苯基及另一个经两个烷氧基取代的苯基的1,4-(二苯基烷基)哌嗪。所揭示化合物之一为1-[2-(3,4-二甲氧基苯基)乙基]-4-(3-苯基丙基)哌嗪。在科学文献中其也称为SA 4503。据说,美国专利第5,736,546号的化合物可用于治疗痴呆症、抑郁症、精神分裂症、焦虑性神经症、伴随异常免疫应答的疾病、内分泌异常及消化性溃疡。
WO 2004/110387揭示σ配体(尤其SA 4503)也可用于治疗患者以在诸如缺血性中风、外伤性脑损伤或脊髓损伤等神经退化性疾病发作后促进神经再生。
美国专利第5,389,630号揭示一些具有脑保护作用的二胺化合物。实例50化合物是哌嗪衍生物,但是绝大多数所例示化合物是高哌嗪衍生物。并没有论述所述化合物的作用机理。
现已发现某些新颖1,4-哌啶及哌嗪衍生物对σ受体(尤其σ-1受体)具有高亲和力。
发明内容
根据一方面,本发明提供通式(I)化合物
(I),
其中:-
R1代表苯基,其未经取代或经一个、两个或三个独立选自以下的取代基取代:(1-2C)亚烷基二氧基、卤素原子、羟基、(1-4C)烷基、(3-6C)环烷基、卤代(1-4C)烷基、(1-4C)烷氧基、氰基、及卤代(1-4C)烷氧基;
m为2、3、4或5;
X为CH或N;
n为0、1、2、3、4或5,其限制条件为当X是N时,n为2、3、4或5;
Y为O、NR2或S;
R2为氢、(1-4C)烷基或苯基(1-4C)烷基,或如对R3所定义;且
R3代表茚满-1-基、茚满-2-基、1,2,3,4-四氢萘-1-基或1,2,3,4-四氢萘-2-基,每一者可在非芳香碳原子上具有羟基取代基;(3-6C)环烷基;或苯基,其未经取代或经一个、两个或三个独立选自以下的取代基取代:(1-2C)亚烷基二氧基、卤素原子、羟基、(1-4C)烷基、(3-6C)环烷基、氰基;苯基、咪唑基、卤代(1-4C)烷基、(1-4C)烷氧基及卤代(1-4C)烷氧基;
或其医药上可接受的盐。
已发现本发明化合物对σ受体(尤其σ-1受体)具有高亲和力。
除非另有说明,否则本文所用术语卤素原子包括氟、氯及溴。
术语(1-2C)亚烷基二氧基包括亚甲基二氧基及亚乙基二氧基。
(1-4C)烷基的实例为甲基。其他实例为乙基、丙基、2-丙基、丁基、2-丁基及叔丁基。
本文所用术语卤代(1-4C)烷基包括全氟(1-4C)烷基,例如三氟甲基。
(1-4C)烷氧基的实例为甲氧基。其他实例为乙氧基、丙氧基及2-丙氧基。
本文所用术语卤代(1-4C)烷氧基包括全氟(1-4C)烷氧基,例如三氟甲氧基。
(3-6C)环烷基的实例为环戊基及环己基。
提及式(I),R1特定涵义的实例为苯基、苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3-氯苯基、3-甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-异丙氧基苯基、3,4-二甲氧基苯基、2,3,4-三甲氧基苯基、3,4,5-三甲氧基苯基、2-氟-3,4-二甲氧基苯基、3-氯-4-甲氧基苯基、4-氯-3-甲氧基苯基、2-三氟甲氧基苯基、4-三氟甲氧基苯基及3-三氟甲氧基苯基。
R1涵义的特定实例为苯基、苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、3,4-二氟苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3,4-二甲氧基苯基及2-三氟甲氧基苯基。
尤其提及其中R1代表以下的式(I)化合物:3,4-二甲氧基苯基、4-甲氧基苯基、4-异丙氧基苯基、4-三氟甲氧基苯基、或3,4,5-三甲氧基苯基。
m值的实例为2及3。m特定值的实例为2。
n特定值的实例为2及3。n特定值的实例为2。
R2特定涵义的实例为氢。
Y特定涵义的实例为O及NH。
R3特定涵义的实例为苯基、苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、4-氟苯基、2,4-二氟苯基、4-三氟甲氧基苯基、2-氯苯基、4-氯苯基、3,4-二氯苯基、4-甲基苯基、4-异丙基苯基、4-叔丁基苯基、4-氰基苯基、2-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、4-甲氧基苯基、4-联苯基、4-(1-咪唑基)苯基、2-氟-4-甲氧基苯基、3-氟-4-甲氧基苯基、3-氯-4-甲氧基苯基、2-三氟甲氧基苯基、3,4,5-三甲氧基苯基、及4-三氟甲氧基苯基。
R3的特定实例为苯基、2-氟苯基、4-氟苯基、2-氯苯基、4-氯苯基、4-甲基苯基、4-异丙基苯基、4-氰基苯基、3,4,5-三甲氧基、及2-三氟甲基苯基。
尤其提及其中R3代表4-氟苯基的式(I)化合物。
应了解,一些式(I)化合物含有不对称中心。因此,这些化合物可以立体异构体形式存在及被分离。本发明提供呈任何立体异构体形式的式(I)化合物。
而且应了解,所述式(I)化合物或其医药上可接受的盐可以溶剂合物的形式被分离,并且因此任何所述溶剂合物皆包括于本发明范围内。
而且已发现与σ-2受体相比一些式(I)化合物对σ-1受体具有较好选择性。这尤其令人期望,因为已显示σ-2受体在大鼠σ受体调介的颈张力障碍中起重要作用(松本(Matsumoto RR)等人,药理学、生物化学及行为(Pharmacol.Biochem.Behav.)36,151-155,1996)。例如,微注射DTG(1,3-二-2-甲苯基-胍,σ-1及σ-2受体激动剂)诱导大鼠颈张力障碍,而注射SA-4503(选择性σ1激动剂)无影响(中泽(NakazawaM)等人,药理学、生物化学及行为,62,123-126,1999)。此外,σ-2受体与细胞增殖调节有关。细胞毒性效应与σ-2受体配体相关(维尔纳(Vilner)及鲍恩(Bowen),欧洲药理学及分子药理学部分期刊(Eur.J.Pharmacol Mol Pharmacol Sect)244,199-201,1993)。σ-2选择性药物可通过可能涉及细胞凋亡及细胞内钙释放的机理抑制肿瘤细胞增殖(艾达尔(Aydar E)等人,癌症研究(Cancer Research)64,5029-5035,2004)。因此这些化合物尤其佳。
因此,根据另一方面,本发明提供选自以下的化合物:
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氟苯氧基)乙基)哌啶;
1-(4-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌啶;
4-(2-(2-氟苯氧基)乙基)-1-(3,4-二甲氧基苯乙基)哌啶;
1-(3,4-二甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(3-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(4-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)-4-(2-苯氧基乙基)哌嗪;
1-(3,4-二氟苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-苯乙基-4-(2-苯氧基乙基)哌嗪;
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌嗪;
4-(2-(4-(3,4-二甲氧基苯乙基)哌嗪-1-基)乙基氧基)苄腈;
及其医药上可接受的盐。
已发现这些化合物均对σ-1具有优于σ-2受体的较好选择性。
通式(I)化合物可通过习用方法制备。
因此,根据另一方面,本发明提供制备通式(I)化合物或其医药上可接受的盐的方法,其包含:
a)用还原剂还原通式(II)化合物
(II);
b)对于其中X为N的式(I)化合物,使通式(III)化合物
(III)
其中Z1及Z2各自独立地代表离去原子或基团,与通式(IV)化合物
R1-(CH2)m-NH2
(IV)
或对应化合物反应,其中R1上的一个或两个取代基经过保护;或
c)对于其中X为N的式(I)化合物,使通式(V)化合物
(V)
与通式(VI)化合物反应
Z3-(CH2)n-Y-R3
(VI),
其中Z3代表离去原子或基团;
随后去除任何保护基团并且视情况形成医药上可接受的盐。
提及方法步骤a),所述还原剂可方便地为硼烷(BH3)、硼氢化物还原剂(例如硼氢化钠)、或碱金属铝氢化物(例如氢化铝锂)。所述还原反应可方便地在诸如醚(例如四氢呋喃)等溶剂存在下实施。实施所述还原反应的温度可方便地介于-25至100℃范围内,例如-10至40℃。
通式(II)化合物可通过使通式(VII)化合物
(VII)
其中Z4代表离去原子或基团,例如对甲苯磺酰基氧基,
与通式(VIII)化合物反应制备
H-Y-R3
(VIII)。
通式(VII)化合物可自对应通式(IX)化合物制备,
(IX)
例如通过与磺酰基卤化物(例如对甲苯磺酰氯)反应。
通式(IX)化合物可通过使用标准酰胺键偶合条件使通式(X)化合物
与通式(XI)化合物
R1-(CH2)m-1COOH
(XI)
或其反应衍生物反应制备。
或者,通式(II)化合物可通过使用标准酰胺键偶合条件使通式(XII)化合物
(XII)
与通式(XI)化合物或其反应衍生物反应制备。
通式(XII)化合物可通过对通式(XIII)化合物实施去保护制备
(XIII),
其中P1代表氨基保护基团,例如叔丁氧基羰基。
通式(XIII)化合物可遵循自通式(IX)化合物制备通式(II)化合物的程序自对应通式(XIV)化合物制备
(XIV)。
提及方法步骤b),Z1及Z2所代表的离去原子或基团可为(例如)烃基磺酰基氧基(例如甲烷磺酰基氧基或对甲苯磺酰基氧基)或卤素原子(例如氯原子)。
所述反应可方便地在介于0至100℃范围内(例如50至90℃)的温度下实施。适合溶剂包括诸如酰胺(例如二甲基甲酰胺)等有机溶剂。所述反应可方便地在诸如碱金属碳酸盐(例如碳酸钾)等碱存在下实施。所述反应可在诸如碘化钠等催化剂存在下实施。
通式(III)化合物可自对应通式(XV)化合物
(XV)
(例如)通过与亚硫酰氯反应制备以提供其中Z1及Z2代表氯原子的式(III)化合物。
通式(XV)化合物可通过使通式(XVI)化合物
(XVI)
与通式(XVII)化合物反应制备
Z5-(CH2)n-Y-R3
(XVII),
其中Z5代表离去原子或基团,例如诸如溴原子等卤素原子。
提及方法步骤c),Z3所代表的离去原子或基团可为(例如)烃基磺酰基氧基,例如对甲苯磺酰基氧基。适合溶剂包括酮(例如丙酮)。所述反应可方便地在介于0至100℃范围内的温度下实施。
医药上可接受的盐可通过习用方法形成,例如通过使式(I)化合物与医药上可接受的酸(例如盐酸)反应。
某些中间体(例如式(II)化合物)可能为新颖化合物。本发明也提供本文所揭示的全部新颖中间体。
本发明化合物可通过任何方便途径投与,例如,经胃肠道(例如经直肠或口服)、经鼻、经肺、经肌肉组织或脉管系统或经皮。所述化合物可以任何方便投与形式投与,例如片剂、粉剂、胶囊、溶液、分散液、悬浮液、糖浆、喷雾剂、栓剂、凝胶剂、乳液、贴剂等。所述组合物可含有医药制剂中的习用组份,例如稀释剂、载剂、pH改良剂、甜味剂、膨胀剂、及其他活性剂。如果希望非经肠投与,则所述组合物将为无菌的并且呈适于注射或输注的溶液或悬浮液形式。所述组合物构成本发明的又一方面。
根据另一方面,本发明提供医药组合物,其包含如上文所定义的式(I)化合物或其医药上可接受的盐、与医药上可接受的稀释剂或载剂。
根据另一方面,本发明提供用于治疗的式(I)化合物或其医药上可接受的盐。
根据另一方面,本发明提供式(I)化合物或其医药上可接受的盐的用途,其用以制造用于治疗对σ受体功能调节剂有响应的病症的药剂。
根据另一方面,本发明提供在需要治疗的患者中治疗对σ受体功能调节剂有响应的病状的方法,其包含向所述患者投与有效量的式(I)化合物或其医药上可接受的盐。
个体可为人类或非人类动物,例如诸如猫、狗、马、牛或羊等非人类哺乳动物。
对σ受体调节剂有响应的病症可例如为中枢神经系统病症,例如已与σ受体相关联的神经障碍或精神异常。神经障碍的实例包括心脏搭桥手术和移植术之后的脑损伤、脑缺血症(例如与中风或心脏停搏有关);脊髓外伤;头部外伤;多发性硬化、阿兹海默氏症(Alzheimer′s Disease);亨庭顿氏舞蹈症(Huntington′s Chorea);肌萎缩侧索硬化;艾滋病(AIDS)诱导的痴呆症;肌肉痉挛;惊厥;药物耐受性、戒断和成瘾(即阿片(opiate)、苯二氮卓(benzodiazepine)、尼古丁(nicotine)、可卡因(cocaine)、或酒精);眼部损伤及视网膜病变;认知障碍;特发性及药物诱导的帕金森氏病(Parkinson′sDisease);疼痛;及诸如迟发性运动障碍等运动障碍。用式I化合物治疗的精神异常的实例包括精神分裂症、焦虑症及相关病症(例如惊恐发作及压力相关病症)、抑郁症、双相情感障碍、精神病、及强迫性神经症。
本发明化合物尤其适合用作神经保护剂和用于治疗患者以在神经退化性疾病(尤其缺血性中风、外伤性脑损伤、脊髓损伤及多发性硬化)发作后促进神经再生及功能恢复。
式(I)化合物的剂量应根据所治疗病状的性质及严重程度、投与途径及个体的个头及物种而定。一般来说,将投与介于0.01至100mg/kg体重范围内的量。
本文所用术语“治疗”包括预防性使用。术语“有效量”指可有效减轻或抑制所治疗病症症状发展的式(I)化合物的量。
本发明化合物可单独投与或与具有不同作用模式的另一治疗剂组合投与。
可通过一个或多个以下测试来证实化合物与σ受体结合的能力。
σ-1(σ1)及σ-2(σ2)受体结合分析在来自HEK-293(人胚肾(Human EmbryonicKidney))细胞的膜中实施。
膜制备:
将融合HEK-293细胞收集在PBS/5mM EDTA中。将其在2000rpm下离心5min并随后在PBS中洗涤两次。将细胞在含有5mM EDTA、0.5mM PMSF及0.5μg/ml亮抑蛋白酶肽(leupeptin)的20mM Tris-HCL(pH=7.5)中使用杜恩斯(Dounce)均浆器均浆并超声处理5分钟。
核碎片和完整细胞通过在3000rpm下于4℃下离心10分钟去除。将上清液在12000rpm下离心30分钟并将所得小颗粒重悬浮在含有0.5mM PMSF、2mM AEBSF、1mM EDTA、130μM苯丁抑制素(bestatin)、14μM E-64、1μM亮抑蛋白酶肽及0.3mM抑肽酶(aprotinin)的25mM Tris-HCL(pH=7.5)、25mM Mg2Cl、10%蔗糖中。
使用伯乐蛋白质分析染料试剂(Bio Rad Protein Assay Dye Reagent)来测定蛋白质并对所述膜进行等分并冷冻于-80℃下。
σ1受体结合分析
在96孔板中实施结合分析。
利用σ1选择性探针(+)-[3H]喷他佐辛(Pentazocine)对σ1受体进行标记(鲍恩(Bowen WD)等人,分子神经药理学(Mol Neuropharmacol)3,117-126,1993)。
总结合通过用总体积为200μl的10nM(+)-[3H]-喷他佐辛(珀金埃尔默公司(Perkin-Elmer),35Ci/mmol)及分析缓冲液(50mM Tris-HCl,pH=8.3)培育50μgHEK-293细胞膜来测定。非特异性结合在10μM未经标记的喷他佐辛存在下测定。对于竞争实验,以8种不同浓度添加50μl替代化合物。培育在37℃下实施120min。通过用冰冷10mM Tris-HCl,pH=8.3稀释并且使用来自美国分子仪器公司(MolecularDevices)的斯卡顿(Skatron)细胞收集器通过玻璃纤维真空过滤终止分析。将过滤器洗涤三次并在微贝他(Microbeta)闪烁计数器中测定膜结合放射性。
将过滤器在使用前于0.5%聚乙烯亚胺中浸泡1小时。
特异性结合通过自总结合中减去非特异性结合确定。IC50值(50%抑制[3H]-喷他佐辛结合所需要的竞争配体浓度)通过使用GraphPad Prism软件进行非线性回归拟合来分析。
σ2受体结合分析
在96孔板中实施结合分析。
σ2受体使用[3H]DTG(二邻甲苯基胍)在σ1受体用σ1选择性化合物喷他佐辛遮蔽的条件下进行标记(赫勒韦尔(Hellewell SB)等人,欧洲药理学杂志(Eur.J.Pharmacol),268,9-18,1994)。
总结合通过用10nM[3H]-DTG(珀金埃尔默公司(Perkin-Elmer),58 Ci/mmol)在总体积为200μl的10μM喷他佐辛及分析缓冲液(50mM Tris-HCl,pH=8.3)存在下培育50μg HEK-293细胞膜来测定。非特异性结合在10μM未经标记的DTG存在下测定。对于竞争实验,以8种不同浓度添加50μl替代化合物。培育在37℃下实施120min。通过用冰冷10mM Tris-HCl,pH=8.3稀释并且使用来自美国分子仪器公司(MolecularDevices)的斯卡顿(Skatron)细胞收集器通过玻璃纤维真空过滤终止分析。将过滤器洗涤三次并在微贝他(Microbeta)闪烁计数器中测定膜结合放射性。
将过滤器在使用前于0.5%聚乙烯亚胺中浸泡1小时。
特异性结合通过自总结合中减去非特异性结合确定。IC50值(50%抑制[3H]-DTG结合所需要的竞争配体浓度)通过使用GraphPad Prism软件非线性回归拟合进行分析。
已发现,在σ1受体结合分析中本文所例示的化合物全部具有小于700nM的IC50值。
附图说明
具体实施方式
以下实例用于阐释本发明。
实例1
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌啶
步骤1:2-(3,4-二甲氧基苯基)-1-[4-(2-羟基乙基)哌啶-1-基]乙酮(A)
向3,4-二甲氧基苯乙酸(7.60g,38.7mmol)、N,N-二甲基氨基吡啶(DMAP;11.4g,93mmol)、及4-哌啶乙醇(5g,39mmol)于无水二氯甲烷(DCM;80mL)中的冰冷溶液中一次性添加N-(3-二甲基氨基丙基)-n’-乙基碳化二亚胺盐酸盐(EDAC·HCl;9.65g,50.3mmol)。去除冷却浴并使反应升温至室温。在5小时后,HPLC分析显示3,4-二甲氧基苯乙酸被耗尽。将反应混合物用1 N HCl(aq)(90mL)洗涤一次并在真空中浓缩。将残留物用色谱法分离以获得粘性油状标题化合物(A;10.67g,90%产率)。
1H NMR(400 MHz,CDCl3)0.91(br m,1H),1.04(br m,1H),1.44(q,J=6.6Hz,2H),1.64(m,3H),1.73(br s,2H),2.56(br m,1H),2.92(br m,1H),3.64(m,4H),3.84(s,3H),3.84(s,3H),4.59(br m,1H),6.73(dd,J=2.0,8.2Hz,1H),6.78(d,J=2.0Hz,1H),6.79(d,J=8.2Hz,1H)。
m/z 308[M+1]+。
步骤2:甲苯-4-磺酸2-{1-[2-(3,4-二甲氧基苯基)-乙酰基]哌啶-4-基}-乙基酯(B)
A B
向A(10.67g,34.7mmol)于无水DCM(100mL)中的溶液中添加三乙胺(Et3N;7.5mL,53.8mmol)。将反应混合物冷却至0℃。一次性添加对甲苯磺酰氯(10.0g,52.4mmol),并将所述混合物搅拌5分钟。去除冷却浴并使反应混合物升温至室温同时将其搅拌12h。TLC分析显示所述反应几乎完成。将反应混合物用1 N HCl(aq)(100mL)洗涤一次,在真空中浓缩,并通过色谱法纯化以获得油状标题化合物(B,14.2g,88%产率)。m/z 462[M+1]+。
步骤3:1-{4-[2-(4-氯苯氧基)乙基]哌啶-1-基}-2-(3,4-二甲氧基苯基)-乙酮(C)
B C
在配备有磁力搅拌棒的20-mL反应容器中,将B(1.4g,3.0mmol)、无水N,N-二甲基甲酰胺(DMF;11mL)、碳酸钾(K2CO3;1.26g,9.1mmol)及4-氯酚(0.78g,6.1mmol)在75℃下加热15h。通过LC分析起始材料消耗情况。通过在氮气流中加热来浓缩反应混合物。将残留物溶解于DCM(10mL)中并用水(10mL)洗涤。通过在氮气流中加热来浓缩有机层,并将残留物用色谱法分离以获得油状标题化合物(C,1.22g,96%产率)。m/z 418[M+1]+。
步骤4:1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌啶
C 实例1
在配备有磁力搅拌棒的20-mL反应容器中,在搅拌下将C(1.22g,2.9mmol)溶解于无水四氢呋喃(THF;6.7mL)中。将溶液冷却至0℃,并缓慢添加1.0M于THF(8.8mL,8.8mmol)中的硼烷(BH3)溶液。在10分钟后去除冷却浴,并将反应混合物在室温下搅拌12h。LC分析显示C完全耗尽。缓慢添加甲醇直至气体逸出停止(3-6mL)。通过在氮气流中加热来浓缩反应混合物。将残留物用色谱法分离以提供标题化合物(0.17g,15%)。
1H NMR(400MHz,DMSO-d6):δ1.5-1.9(m,7H),2.6-3.0(m,8H),3.71(s,3H),3.74(s,3H),4.01(m,2H),6.75(m,1H),6.81(d,1H),6.88(d,1H),6.96(m,2H),7.30(m,2H)。
m/z 404[M+1]+。
利用与实例1中所述相同的方法制备以下化合物。
实例2
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氟苯氧基)乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.47-1.7(m,8H),2.7-3.1(m,7H),3.72(s,3H),3.75(t,s,3H),3.97(t,2H),6.76(m,1H),6.82(s,1H),6.86(d,1H),6.94(m,2H),7.09(t,2H)。
m/z 388[M+1]+。
实例3
1-(3,4-二甲氧基苯乙基)-4-(2-(对甲苯基氧基)乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.4-1.9(m,7H),2.20(s,3H),2.6-3.0(m,8H),3.69(s,3H),3.72(s,3H),3.95(m,2H),6.73(m,1H),6.78(m,3H),6.85(d,1H),7.04(d,2H)。
m/z 384[M+1]+。
实例4
1-(3,4-二甲氧基苯乙基)-4-(2-(4-异丙基苯氧基)乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.13(d,6H),1.5-1.9(m,8H),2.6-3.0(m,8H),3.69(s,3H),3.73(s,3H),3.94(m,2H),6.72(m,H),4.06(m,2H),6.72(m,1H),6.80(s,1H),6.85(d,1H),6.90(m,1H),6.09(t,1H),7.16(m,2H)。
m/z 388[M+1]+。
实例5
4-(2-(2-氟苯氧基)乙基)-1-(3,4-二甲氧基苯乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.4-1.9(m,8H),2.6-3.0(m,7H),3.69(s,3H),3.72(s,3H),4.06(m,2H),6.72(m,1H),6.80(s,1H),6.85(d,1H),6.90(m,1H),6.09(t,1H),7.16(m,2H)。
m/z 388[M+1]+。
实例6
4-(2-(2-氯苯氧基)乙基)-1-(3,4-二甲氧基苯乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.54-1.89(m,7H),2.58-2.66(t,1H),2.80-3.03(m,6H),3.71(s,3H),3.74(s,3H),4.09-4.13(m,2H),6.72(m,1H),6.82-6.90(m,2H),6.93(t,1H),7.12(d,1H),7.27(t,1H),7.38(d,1H)。
m/z 404[M+1]+。
实例7
4-(2-(2-(三氟甲基)苯氧基)乙基)-1-(3,4-二甲氧基苯乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.4-1.9(m,8H),2.6-3.0(m,7H),3.69(s,3H),3.72(s,3H),4.14(t,2H),6.73(d,1H),6.83(m,2H),7.06(t,1H),7.24(d,1H),7.59(m,2H)。
m/z 438[M+1]+。
实例8
1-(3,4-二甲氧基苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.4-1.9(m,8H),2.6-3.0(m,7H),3.69(s,3H),3.72(s,3H),3.99(m,2H),6.71(t,1H),6.80(s,1H),6.84-6.92(m,4H),7.26(m,2H)。
m/z 370[M+1]+。
实例9
1-(2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)-4-(2-苯氧基乙基)哌啶
利用与实例1中所述类似的合成途径,但是自亚甲基二氧基苯乙酸而非3,4-二甲氧基苯乙酸开始制备标题化合物。
1H NMR(400MHz,CDCl3):δ1.5-1.99(m,8H),2.7-3.0(m,7H),3.98(m,2H),5.95(s,2H),6.66(m,1H),6.79-6.81(m,2H),6.91(m,3H),7.25(t,2H)
m/z 354[M+1]+。
以下化合物可利用与实例1中所述相同的程序制备:
4-[2-(4-氯-苯氧基)乙基]-1-[2-(3,4-二甲氧基苯基)乙基]哌啶
4-(2-{1-[2-(3,4-二甲氧基苯基)-乙基]哌啶-4-基}乙氧基)苄腈
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-甲氧基苯氧基)乙基]哌啶
4-[2-(联苯基-4-基氧基)乙基]-1-[2-(3,4-二甲氧基苯基)乙基]哌啶
4-[2-(苯并[1,3]二氧杂环戊烯-5-基氧基)乙基]-1-[2-(3,4-二甲氧基苯基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-三氟甲基苯氧基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-咪唑-1-基苯氧基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-三氟甲氧基苯氧基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(2-甲氧基苯氧基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(2-三氟甲氧基苯氧基)乙基]哌啶
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(3-氟-4-甲氧基苯氧基)乙基]哌啶
4-[2-(3-氯-4-甲氧基苯氧基)乙基]-1-[2-(3,4-二甲氧基苯基)乙基]哌啶及
4-[2-(3,4-二氯苯氧基)乙基]-1-[2-(3,4-二甲氧基苯基)乙基]哌啶。
实例10
N-(2-(1-(3,4-二甲氧基苯乙基)哌啶-4-基)乙基)苯胺(benzenamine)
利用与实例1中所述相同的程序通过在步骤3中用苯胺(aniline)代替4-氯酚制备标题化合物:
1H NMR(400MHz,CDCl3):δ1.4-1.9(m,8H),2.6-3.0(m,9H),3.69(s,3H),3.72(s,3H),5.35(m,1H),6.47(t,1H),6.51(d,2H),6.73 9(m,1H),6.80(s,1H),6.85(d,1H),7.03(m,2H)。
m/z 369[M+1]+。
以下化合物可利用与实例10中所述相同的程序制备:
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-氟苯基)胺
(4-氯苯基)-(2-{1-[2-(3,4-二甲氧基苯基)-乙基]-哌啶-4-基}乙基)胺
4-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基氨基)苄腈
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-甲氧基苯基)胺
联苯基-4-基-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)胺
苯并[1,3]二氧杂环戊烯-5-基-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-三氟甲基苯基)-胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-对-甲苯基胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-异丙基苯基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-咪唑-1-基-苯基)-胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(4-三氟甲氧基-苯基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(2-氟苯基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]-哌啶-4-基}乙基)-(2-甲氧基苯基)胺
(2-氯-苯基)-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]-哌啶-4-基}乙基)-(2-三氟甲基苯基)-胺
(2-{1-[2-(3,4-二甲氧基-苯基)乙基]-哌啶-4-基}乙基)-(2-三氟甲氧基-苯基)胺
(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)-(2-氟-4-甲氧基-苯基)胺
(2-{1-[2-(3,4-二甲氧基-苯基)乙基]哌啶-4-基}乙基)-(3-氟-4-甲氧基-苯基)胺
(3-氯-4-甲氧基苯基)-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}-乙基)胺及
(3,4-二氯-苯基)-(2-{1-[2-(3,4-二甲氧基苯基)乙基]哌啶-4-基}乙基)胺。
实例11
1-(2-甲氧基苯乙基)-4-(2-苯氧基乙基)哌啶
步骤1:4-[2-(甲苯-4-磺酰基氧基)乙基]哌啶-1-甲酸叔丁基酯(D)
D
向N-Boc-4-哌啶-乙醇(5.0g,21.8mmol)及Et3N(4.6mL,33.0mmol)于无水DCM(10mL)中的冰冷溶液中缓慢添加对甲苯磺酰氯(6.25g,32.8mmol)。在添加时,将反应升温至室温并搅拌20h。将反应混合物用水(40mL)、10%(wt/v)柠檬酸(aq)(40mL)、及饱和NaHCO3(aq)(40mL)洗涤。用MgSO4干燥DCM层,过滤并在真空中浓缩以得到浅黄色油状物,将其用色谱法分离以得到澄清且无色油状标题化合物(7.47g,89%产率)。
1H NMR(400MHz,CDCl3)1.02(m,2H),1.43(s,9H),1.50-1.57(m,5H),2.44(s,3H),2.60(br t,2H),4.02(br d,2H),4.06(t,2H),7.34(d,2H),7.78(d,2H)。
步骤2:4-(2-苯氧基-乙基)-哌啶-1-甲酸叔丁基酯(E)
D E
向D(8.24g,21.5mmol)于无水DMF(85mL)中的溶液中添加碳酸钾(K2CO3;8.9g,64mmol)及苯酚(4.0g,42.5mmol)。将反应混合物加热至70-75℃保持4h,冷却至室温,并倾倒入水(300mL)中。用乙酸乙酯(3×100mL)萃取混合物。合并乙酸乙酯萃取物,用0.25M K2CO3(aq)(100mL)及饱和氯化钠(100mL)洗涤,经MgSO4干燥,并在真空中浓缩。使所得油状物通过二氧化硅塞以去除非常极性物质,由此分离出标题化合物与苯酚的混合物(7.95g)。此物质未经进一步纯化即转至下一步骤。m/z 205[M-CO2C(CH3)3]+。
步骤3:4-(2-苯氧基乙基)-哌啶,盐酸盐(F)
E F
向E与苯酚(7.95g,理论上21.5mmol E)于DCM(80mL)中的溶液中以缓慢流添加三氟乙酸(20mL),并将混合物在室温下搅拌过夜。通过TLC分析起始材料消耗情况。用水(110mL)洗涤反应混合物,并用DCM(25mL)反萃取水性相。用饱和NaHCO3(aq)(100mL)洗涤合并的DCM层,经MgSO4干燥,并浓缩成油状物(7.32g)。将一部分所述油状物(6.60g)溶解于EtOAc(100mL)中。在搅拌下逐滴添加2 M于Et2O中的HCl(奥尔德里奇(Aldrich);13.5mL)。将所述混合物搅拌1.5h,过滤,用EtOAc洗涤,并在真空中干燥以得到白色固体状F(4.0g,85%产率)。
1H NMR(400MHz,DMSO-d6)1.39(m,2H),1.67(q,J=6.4Hz,2H),1.76(m,1H),1.84(br d,2H),2.83(br q,J=11.3Hz,2H),3.22(br d,J=12.9Hz,2H),4.00(t,J=6.3Hz,2H),6.90-6.93(m,3H),7.28(m,2H),8.73(br s,1H),8.96(br s,1H)。
步骤4:2-(2-甲氧基-苯基)-1-[4-(2-苯氧基-乙基)哌啶-1-基]乙酮(G)
向F(0.32g,1.3mmol)、(2-甲氧基苯基)乙酸(0.26g,1.6mmol)、及DMAP(0.55g,4.5mmol)于DCM(6.5mL)中的溶液中添加EDAC·HCl(0.36g,1.9mmol)。将反应在室温下搅拌过夜。HPLC分析显示F完全耗尽。用1 N HCl(aq)(2×5mL)洗涤反应混合物,经MgSO4干燥,并通过在氮气流中加热来浓缩以提供标题化合物,将其不经进一步纯化即转至下一步骤。m/z 354[M+1]+。
步骤5:1-[2-(2-甲氧基苯基)乙基]-4-(2-苯氧基乙基)哌啶盐酸盐
G 实例11
向粗制残留物G(理论上1.3mmol)于无水THF(3mL)中的冰冷溶液中逐滴添加1.0M于THF中的BH3(奥尔德里奇(Aldrich);4.1mL,4.1mmol)。在添加时,将反应混合物升温至室温并继续搅拌19h。HPLC分析显示G完全耗尽。缓慢添加甲醇直至气体逸出停止(1-3mL)。通过在氮气流中加热来浓缩反应混合物。将残留物用色谱法分离以提供标题化合物(0.35g,从步骤4产率为79%)。
1H NMR(400MHz,DMSO-d6):δ1.5-1.7(m,8H),2.8-3.0(m,7H),3.77(s,3H),3.98(m,2H),6.84-6.95(m,5H),7.13-7.27(m,4H)。
m/z 340[M+1]+。
使用与实例11中所述相同的方法制备以下化合物。
实例12
1-(3-甲氧基苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.40-1.80(m,7H),2.10-2.40(m,1H),2.48(t,1H),2.89-3.18(m,6H),3.81(s,3H),4.02(m,2H),6.76-6.97(m,6H),7.21-7.31(m,3H)。
m/z 340[M+1]+。
实例13
1-(4-甲氧基苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.40-1.90(m,9H),2.70-3.10(m,6H),3.70(s,3H),3.98(m,2H),6.84(d,2H),6.90(d,3H),7.13(t,2H),7.23(m,2H)。
m/z 340[M+1]+。
实例14
1-苯乙基-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.5-1.9(m,9H),2.8-3.1(m,6H),4.01(m,2H),6.91(m,3H),7.2-7.3(m,7H)。
m/z 310[M+1]+。
实例15
1-(3-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.4-1.9(m,8H),2.6-3.7(m,7H),3.97(m,2H),6.90(m,3H),7.24(m,2H),7.51-7.61(m,4H)。
m/z 378[M+1]+。
实例16
1-(4-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,DMSO-d6):δ1.4-1.7(m,8H),2.6-3.1(m,7H),3.97(m,2H),6.90(m,3H),7.25(m,2H),7.47(t,2H),7.64(t,2H)。
m/z 378[M+1]+。
实例17
1-(2-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌啶
1H NMR(400MHz,CDCl3):δ1.4-1.7(m,8H),2.7-3.2(m,7H),3.97(t,2H),6.91(m,3H),7.25(m,2H),7.44(t,1H),7.49(d,1H),7.63(t,1H),7.68(d,1H)。
m/z 378[M+11]+。
以下化合物可利用与实例11相同的程序制备:
1-[2-(2-氟-3,4-二甲氧基苯基)乙基]-4-(2-苯氧基-乙基)哌啶
4-(2-苯氧基乙基)-1-[2-(2,3,4-三甲氧基苯基)乙基]哌啶
1-[2-(2-氟苯基)乙基]-4-(2-苯氧基乙基)哌啶
1-[2-(3-氟苯基)乙基]-4-(2-苯氧基乙基)哌啶
1-[2-(4-氟苯基)乙基]-4-(2-苯氧基乙基)哌啶
1-[2-(3,4-二氟苯基)乙基]-4-(2-苯氧基乙基)哌啶
4-(2-苯氧基乙基)-1-(2-间-甲苯基乙基)哌啶
1-[2-(3-氯苯基)乙基]-4-(2-苯氧基乙基)哌啶
1-[2-(4-氯-3-甲氧基苯基)乙基]-4-(2-苯氧基乙基)哌啶
4-(2-苯氧基乙基)-1-[2-(4-三氟甲氧基苯基)乙基]哌啶
4-[2-(4-氟苯氧基)乙基]-1-[2-(4-甲氧基苯基)乙基]哌啶
4-[2-(4-氟苯氧基)乙基]-1-[2-(4-三氟甲氧基-苯基)乙基]哌啶
4-[2-(2-氟苯氧基)乙基]-1-[2-(4-甲氧基苯基)乙基]哌啶
4-[2-(2-氟苯氧基)乙基]-1-[2-(4-三氟甲氧基苯基)乙基]哌啶
1-(2-苯并[1,3]二氧杂环戊烯-5-基乙基)-4-[2-(4-氟苯氧基)乙基]哌啶及
1-(2-苯并[1,3]二氧杂环戊烯-5-基乙基)-4-[2-(2-氟苯氧基)乙基]哌啶。
实例18
1-(3,4-二甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
步骤1:2-[(2-羟基-乙基)-(2-苯氧基-乙基)-氨基]-乙醇(H)
H
将2-(2-羟基-乙基氨基)乙醇(32g,310mmol)、1-(2-溴乙氧基)苯(51g,256mmol)、及碳酸钾(70g,512mmol)于乙醇(200mL)中的反应混合物回流过夜,浓缩,并分配在水与乙酸乙酯之间。用盐水洗涤有机层,经无水硫酸钠干燥,并浓缩。将残留物通过管柱色谱法纯化以提供标题化合物(45g,78%)。
步骤2:双-(2-氯乙基)-(2-苯氧基乙基)胺盐酸盐(I)
向2-[(2-羟基乙基)-(2-苯氧基乙基)-氨基]乙醇(H;43.9g,194mmol)于氯仿(140mL)中的冰冷溶液中逐滴添加亚硫酰氯(SOCl2;114.8g,965mmol)。随后将反应混合物回流1.5h并浓缩。随后将残留物悬浮在乙酸乙酯与异丙基酯的混合物中。过滤出沉淀并在真空烘箱中干燥以定量提供浅褐色晶体状标题化合物。随后未经进一步纯化即使用此产物。
步骤3:1-(3,4-二甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
将双-(2-氯乙基)-(2-苯氧基乙基)胺(0.895g,3mmol)、2-(3,4-二甲氧基苯基)乙胺(0.548g,3mmol)、碳酸钾(K2CO3;1.277g,9mmol)、及碘化钠(NaI;0.899g,6mmol)于DMF(6mL)中的反应混合物在70-80℃下搅拌5h,用水骤冷,并用乙酸乙酯萃取。经无水硫酸钠干燥有机层并浓缩。将残留物悬浮在6N HClaq(pH=3-4)中并过滤。随后用乙酸乙酯及乙醇洗涤滤饼并干燥以提供灰白色固体状标题化合物(330mg,23%)。
1H NMR(400MHz,CD3OD):δ3.08(m,2H),3.50(m,2H),3.74-3.84(m,16H),4.44(t,2H),6.85-7.05(m,6H),7.32(m,2H)。
m/z 371[M-2HC1+1]+。
使用与实例18中所述相同的方法制备以下化合物。
实例19
1-(2-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.13(m,2H),3.46(m,2H),3.5-3.9(m,13H),4.45(t,2H),6.90-7.06(m,5H),7.24-7.35(m,4H)。
m/z 341[M-2HCl+1]+。
实例20
1-(3-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.12(m,2H),3.52(m,2H),3.65-3.95(m,13),4.44(t,2H),6.83-6.91(m,3H),7.01-7.05(m,3H),7.23-7.35(m,3H)。
m/z 341[M-2HC1+1]+。
实例21
1-(4-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.08(m,2H),3.48(m,2H),3.6-3.0(m,13H),4.45(t,2H),6.90(m,2H),7.03(m,3H),7.23(m,2H),7.32(m,2H)。
m/z 341[M-2HC1+1]+。
实例22
1-(2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.05(m,2H),3.46(m,2H),3.6-3.9(m,10H),4.42(t,2H),5.93(s,2H),6.38(s,2H),6.84(s,1H),7.01-7.04(m,3H),7.32(dd,2H)。
m/z 355[M-2HCl+1]+。
实例23
1-(2-氟苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.21(m,2H),3.50(m,2H),3.6-3.9(m,10H),4.39(m,2H),6.98-7.21(m,5H),7.30-7.40(m,4H)。
m/z 329[M-2HCl+1]+。
实例24
1-(3,4-二氟苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.14(m,2H),3.51 9m,2H),3.6-3.9(m,10H),4.43(t,2H),6.98-7.05(m,3H),7.06-7.35(m,5H)。
m/z 347[M-2HC1+1]+。
实例25
1-(3-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.25(m,2H),3.54(m,2H),3.7-3.9(m,10H),4.45(m,2H),7.02(m,3H),7.34(m,2H),7.55-7.69(m,4H)。
m/z 379[M-2HCl+1]+。
实例26
1-(2-(三氟甲氧基)苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD+CDCl3):δ3.22(m,2H),3.42(m,2H),3.6-3.8(m,10H),4.43(t,2H),6.99(m,3H),7.27-7.39(m,5H),7.47(d,1H)。
m/z 395[M-2HCl+1]+。
实例27
1-苯乙基-4-(2-苯氧基乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD+CDCl3):δ3.15(m,2H),3.48(m,2H),3.7-4.0(m,10H),4.43(t,2H),6.99(m,3H),7.25-7.34(m,7H)。
m/z 311[M-2HCl+1]+。
以下化合物可利用与实例18中所述相同的程序制备:
1-[2-(2-氟-3,4-二甲氧基苯基)乙基]-4-(2-苯氧基乙基)哌嗪
1-(2-苯氧基乙基)-4-[2-(2,3,4-三甲氧基苯基)乙基]哌嗪
1-[2-(3-氟苯基)乙基]-4-(2-苯氧基乙基)哌嗪
1-[2-(4-氟苯基)-乙基]-4-(2-苯氧基乙基)哌嗪
1-(2-苯氧基乙基)-4-(2-间-甲苯基乙基)哌嗪
1-(2-苯氧基乙基)-4-[2-(2-三氟甲基-苯基)乙基]哌嗪
1-(2-苯氧基乙基)-4-[2-(4-三氟甲基苯基)乙基]哌嗪
1-(2-苯氧基乙基)-4-[2-(3-三氟甲氧基苯基)乙基]哌嗪
1-[2-(3-氯-苯基)乙基]-4-(2-苯氧基乙基)哌嗪及
1-[2-(3-氯-4-甲氧基苯基)乙基]-4-(2-苯氧基乙基)哌嗪。
实例28
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌嗪二盐酸盐
步骤1:4-甲基苯磺酸2-(4-氯苯氧基)乙酯(J)
J
向2-(4-氯苯氧基)乙醇(2.0g,11.6mmol)于DCM(10mL)中的溶液中顺序添加Et3N(5mL)及4-甲基苯-1-磺酰氯(TsCl;2.43g,12.8mmol)。将反应混合物在室温下搅拌过夜并分配在水与乙酸乙酯之间。用水、5%碳酸氢钠(NaHCO3)、及盐水洗涤有机层并浓缩。用己烷洗涤所得残留物以定量提供标题化合物。
步骤2:1-(3,4-二甲氧基苯乙基)哌嗪二盐酸盐(L)
K L
将2-(3,4-二甲氧基苯基)乙醇(6.0g,32.8mmol)与亚硫酰氯(19g,164mmol)于氯仿(20mL)中的反应混合物在回流下搅拌4h,浓缩,并分配在水与乙酸乙酯之间。用NaHCO3及盐水洗涤有机层,经无水硫酸钠干燥,并浓缩以定量提供4-(2-氯乙基)-1,2-二甲氧基苯(K)(6.6g)。
将4-(2-氯乙基)-1,2-二甲氧基苯(3.6g,17.9mmol)、哌嗪-1-甲酸叔丁基酯(4.0g,21.5mmol)、K2CO3(4.97g,36mmol)、及NaI(2.7g,18mmol)于DMF(20mL)中的反应混合物在80℃下搅拌3h,冷却至室温,并分配在水与乙酸乙酯之间。用水和盐水洗涤有机层,经无水硫酸钠干燥,并浓缩。将残留物通过管柱色谱法纯化以提供4-[2-(3,4-二甲氧基-苯基)-乙基]-哌嗪-1-甲酸叔丁基酯(4.8g,76%),将其溶解在于二氧杂环己烷中的4N HCl中。将此溶液在室温下搅拌4h,浓缩,并在高真空烘箱中干燥以定量得到标题化合物。
步骤3:1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌嗪二盐酸盐
L J 实例28
向1-(3,4-二甲氧基苯乙基)哌嗪二盐酸盐(502mg,1.55mmol)及4-甲基苯磺酸2-(4-氯苯氧基)乙酯(460mg,1.4mmol)于丙酮(20mL)中的溶液中添加NaI(465mg,3.1mmol)及K2CO3(1.1g,7.0mmol)。随后将反应混合物回流过夜并浓缩。将残留物分配在乙酸乙酯与水之间。用水和盐水洗涤有机层,经无水硫酸钠干燥,并浓缩。将所得残留物通过管柱色谱法纯化以提供1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌嗪,将其悬浮在6N HClaq.(pH=3)中。过滤出沉淀,用冷乙醇洗涤,并干燥以提供标题化合物(350mg,52%)。
1H NMR(400MHz,DMSO-d6):δ2.96(m,2H),3.4(m,12H),3.70(s,3H),3.74(s,3H),4.36(b,2H),6.76(d,1H),6.89(m,2H),7.03(m,2H),7.34(m,2H)。
m/z 405[M-2HCl+1]+。
实例29
1-(2-(2-氯苯氧基)乙基)-4-(3,4-二甲氧基苯乙基)哌嗪二盐酸盐
利用与实例28中所述相同的程序通过在步骤1中用4-甲基苯磺酸2-(2-氯苯氧基)乙酯代替4-甲基苯磺酸2-(4-氯苯氧基)乙酯制备标题化合物。
1H NMR(400MHz,DMSO-d6):δ2.96(b,2H),3.4(m,12H),3.70(s,3H),3.72(s,3H),4.44(b,2H),6.76(d,1H),6.89(m,2H),6.98(m,1H),7.20(d,1H),7.33(m,1H),7.46(d,1H)。
m/z 405[M-2HCl+1]+。
实例30
4-(2-(4-(3,4-二甲氧基苯乙基)哌嗪-1-基)乙基氧基)苄腈二盐酸盐
步骤1:4-(2-溴乙氧基)苄腈(M)
M
将4-羟基苄腈(1.19g,10mmol)、1,2-二溴乙烷(9.39g,50mmol)、及K2CO3(4.14g,30mmol)于DMF(20mL)中的反应混合物在100℃下搅拌5h并冷却至室温。向所述反应混合物中添加乙酸乙酯及水。用盐水洗涤有机层,经无水硫酸钠干燥,并浓缩。将残留物通过管柱色谱法纯化以提供4-(2-溴乙氧基)苄腈(1.2g,53%)。
步骤2:4-(2-(4-(3,4-二甲氧基苯乙基)哌嗪-1-基)乙基氧基)苄腈二盐酸盐
L M 实例30
利用与实例28中所述相同的程序(步骤3)通过用4-(2-溴乙氧基)苄腈代替4-甲基苯磺酸2-(4-氯苯氧基)乙酯制备标题化合物。
1H NMR(400MHz,DMSO-d6):δ2.95-3.00(m,3H),3.20-3.60(m,11H),3.70(s,3H),7.73(s,3H),4.46(b,2H),6.77(d,1H),6.88(d,2H),7.17(d,2H),7.79(d,2H)。
m/z 396[M-2HCl+1]+。
利用与实例30中所述相同的程序通过用对应经取代苯酚代替4-羟基苄腈制备以下化合物。
实例31
1-(3,4-二甲氧基苯乙基)-4-(2-(4-异丙基苯氧基)乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ1.20(d,6H),2.69(s,1H),2.85(m,1H),3.09(m,2H),3.51(m,2H),3.73-3.80(m,15H),4.14(m,2H),6.85-6.97(m,5H),7.18(q,2H)。
m/z 413[M-2HCl+1]+。
实例32
1-(2-(2-(三氟甲基)苯氧基)乙基)-4-(3,4-二甲氧基苯乙基)哌嗪二盐酸盐
1H NMR(400MHz,CD3OD):δ3.09(m,2H),3.51(m,2H),3.6-4.0(m,16H),4.62(t,2H),6.85-6.96(m,3H),7.16(t,1H),7.26(d,1H),7.63(m,2H)。
m/z 439[M-2HCl+1]+。
以下化合物可利用与实例28及30中所述相同的程序制备:
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-氟-苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基苯基)乙基]-4-[2-(4-甲氧基苯氧基)乙基]哌嗪
1-[2-(联苯基-4-基氧基)乙基]-4-[2-(3,4-二甲氧基苯基)乙基]哌嗪
1-[2-(苯并[1,3]二氧杂环戊烯-5-基氧基)乙基]-4-[2-(3,4-二甲氧基苯基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(4-三氟甲基-苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-(2-对-甲苯基氧基乙基)哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(4-咪唑-1-基苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(4-三氟甲氧基苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(2-氟苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(2-甲氧基苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(2-三氟甲氧基苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(2-氟-4-甲氧基苯氧基)乙基]哌嗪
1-[2-(3,4-二甲氧基-苯基)乙基]-4-[2-(3-氟-4-甲氧基苯氧基)乙基]哌嗪
1-[2-(3-氯-4-甲氧基-苯氧基)乙基]-4-[2-(3,4-二甲氧基苯基)乙基]哌嗪
1-[2-(3,4-二氯-苯氧基)乙基]-4-[2-(3,4-二甲氧基苯基)乙基]哌嗪
1-[2-(4-异丙氧基-苯基)乙基]-4-(2-苯氧基-乙基)哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[2-(4-异丙氧基-苯基)乙基]哌嗪
1-[2-(2-氟-苯氧基)乙基]-4-[2-(4-异丙氧基-苯基)乙基]哌嗪
1-[2-(2-氟-苯氧基)乙基]-4-[2-(3,4,5-三甲氧基-苯基)乙基]哌嗪
1-[2-(2-氟-苯氧基)乙基]-4-[2-(4-甲氧基-苯基)乙基]哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[2-(4-甲氧基-苯基)乙基]哌嗪
1-(2-苯并[1,3]二氧杂环戊烯-5-基乙基)-4-[2-(4-氟-苯氧基)乙基]哌嗪
1-(2-苯氧基乙基)-4-[2-(4-三氟甲氧基苯基)乙基]哌嗪
4-(2-{4-[2-(4-三氟甲氧基苯基)乙基]哌嗪-1-基}乙氧基)苄腈
1-[2-(4-氟-苯氧基)乙基]-4-[2-(4-三氟甲氧基-苯基)乙基]哌嗪
1-[3-(3,4-二甲氧基-苯基)丙基]-4-(2-苯氧基乙基)哌嗪
1-[3-(3,4-二甲氧基-苯基)丙基]-4-[2-(4-氟苯氧基)乙基]哌嗪
1-(3-苯并[1,3]二氧杂环戊烯-5-基丙基)-4-(2-苯氧基乙基)哌嗪
1-(3-苯并[1,3]二氧杂环戊烯-5-基丙基)-4-[2-(4-氟苯氧基)乙基]哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-甲氧基苯基)丙基]哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-异丙氧基苯基)丙基]哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-三氟甲氧基苯基)丙基]哌嗪
1-[2-(4-氟-苯氧基)乙基]-4-[3-(3,4,5-三甲氧基苯基)丙基]哌嗪及
1-[2-(4-叔丁基-苯氧基)乙基]-4-[2-(3,4-二甲氧基苯基)乙基]哌嗪。
Claims (18)
1.一种通式(I)化合物
其中:
R1代表苯基,其经一个、两个或三个选自由下列组成的群组的取代基取代:(1-2C)亚烷基二氧基、卤素原子、羟基、氰基、(1-4C)烷基、(3-6C)环烷基、卤代(1-4C)烷基、(1-4C)烷氧基和卤代(1-4C)烷氧基;
m为2、3、4或5;
X为N;
n为2、3或4;
Y为O或NR2;
R2为氢、(1-4C)烷基或苯基(1-4C)烷基,或如对R3所定义;且
R3代表茚满-1-基、茚满-2-基、1,2,3,4-四氢萘-1-基或1,2,3,4-四氢萘-2-基,每一者可在非芳香碳原子上具有羟基取代基;(3-6C)环烷基;或苯基,其未经取代或经一个、两个或三个选自由下列组成的群组的取代基取代:(1-2C)亚烷基二氧基、卤素原子、羟基、(1-4C)烷基、(3-6C)环烷基、氰基;苯基、咪唑基、卤代(1-4C)烷基、(1-4C)烷氧基和卤代(1-4C)烷氧基;
或其医药上可接受的盐。
2.如权利要求1所述的化合物,其中R1代表苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3-氯苯基、3-甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-异丙氧基苯基、3,4-二甲氧基苯基、2,3,4-三甲氧基苯基、3,4,5-三甲氧基苯基、2-氟-3,4-二甲氧基苯基、3-氯-4-甲氧基苯基、4-氯-3-甲氧基苯基、2-三氟甲氧基苯基、4-三氟甲氧基苯基、或3-三氟甲氧基苯基。
3.如权利要求1所述的化合物,其中R1代表苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、3,4-二氟苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3,4-二甲氧基苯基或2-三氟甲氧基苯基。
4.如权利要求1所述的化合物,其中R1代表3,4-二甲氧基苯基、3,4,5-三甲氧基苯基、4-甲氧基苯基、4-异丙氧基苯基、或4-三氟甲氧基苯基。
5.如权利要求1至4中任一权利要求所述的化合物,其中R3代表苯基、苯并[1,3]二氧杂环戊烯-5-基、2-氟苯基、4-氟苯基、2,4-二氟苯基、4-三氟甲氧基苯基、2-氯苯基、4-氯苯基、3,4-二氯苯基、4-甲基苯基、4-异丙基苯基、4-叔丁基苯基、4-氰基苯基、2-三氟甲基苯基、4-三氟甲基苯基、2-甲氧基苯基、4-甲氧基苯基、4-联苯基、4-(1-咪唑基)苯基、2-氟-4-甲氧基苯基、3-氟-4-甲氧基苯基、3-氯-4-甲氧基苯基、2-三氟甲氧基苯基或4-三氟甲氧基苯基。
6.如权利要求1至4中任一权利要求所述的化合物,其中R3代表苯基、2-氟苯基、4-氟苯基、2-氯苯基、4-氯苯基、4-甲基苯基、4-异丙基苯基、4-氰基苯基或2-三氟甲基苯基。
7.如权利要求1至4中任一权利要求所述的化合物,其中R3代表4-氟苯基。
8.如权利要求1至4中任一权利要求所述的化合物,其中m或n为2,或m及n二者均为2。
9.如权利要求1-4中任一权利要求所述的化合物,其中Y为O或NH。
10.如权利要求1所述的化合物,其选自:
1-(3,4-二甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(3-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(4-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)-4-(2-苯氧基乙基)哌嗪;
1-(3,4-二氟苯乙基)-4-(2-苯氧基乙基)哌嗪;
1-(3,4-二甲氧基苯乙基)-4-(2-(4-氯苯氧基)乙基)哌嗪;
4-(2-(4-(3,4-二甲氧基苯乙基)哌嗪-1-基)乙基氧基)苄腈;
及其医药上可接受的盐。
11.如权利要求1所述的化合物,其选自:1-(4-甲氧基苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐和1-(3-(三氟甲基)苯乙基)-4-(2-苯氧基乙基)哌嗪二盐酸盐。
12.如权利要求1所述的化合物,其是1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-三氟甲氧基苯基)丙基]哌嗪或其医药上可接受的盐。
13.如权利要求1所述的化合物,其选自:
1-[3-(3,4-二甲氧基-苯基)丙基]-4-(2-苯氧基乙基)哌嗪;
1-[3-(3,4-二甲氧基-苯基)丙基]-4-[2-(4-氟苯氧基)乙基]哌嗪;
1-(3-苯并[1,3]二氧杂环戊烯-5-基丙基)-4-(2-苯氧基乙基)哌嗪;
1-(3-苯并[1,3]二氧杂环戊烯-5-基丙基)-4-[2-(4-氟苯氧基)乙基]哌嗪;
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-甲氧基苯基)丙基]哌嗪;
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-异丙氧基苯基)丙基]哌嗪;
1-[2-(4-氟-苯氧基)乙基]-4-[3-(4-三氟甲氧基苯基)丙基]哌嗪;
1-[2-(4-氟-苯氧基)乙基]-4-[3-(3,4,5-三甲氧基苯基)丙基]哌嗪;
或其医药上可接受的盐。
14.如权利要求1所述的化合物,其中m为3。
17.一种医药组合物,其包含如权利要求1至14中任一权利要求所述的化合物和医药上可接受的稀释剂或载剂。
18.一种如权利要求1至14中任一权利要求所述的化合物的用途,其用于制造治疗对σ受体功能调节剂有响应的病状的药剂。
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UY34585A (es) | 2012-01-24 | 2013-09-02 | Aicuris Gmbh & Co Kg | Compuestos b-lactámicos sustituidos con amidina, su preparación y uso |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5109002A (en) * | 1989-09-08 | 1992-04-28 | Du Pont Merck Pharmaceutical Company | Antipsychotic 1-cycloalkylpiperidines |
US5281598A (en) * | 1992-04-13 | 1994-01-25 | Akzo N.V. | Piperazine derivatives |
EP0711763A1 (en) * | 1993-07-28 | 1996-05-15 | Santen Pharmaceutical Co., Ltd. | Novel 1,4-di(phenylalkyl)piperazine derivative |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3686187A (en) | 1970-05-25 | 1972-08-22 | Abbott Lab | 4-anilino-1-(4-p-fluorophenyl-1-butyl) piperidine compounds |
DE2125037C3 (de) | 1971-05-19 | 1980-04-24 | Sumitomo Chemical Co., Ltd., Osaka (Japan) | 4-(o-Methoxyphenyl)-piperazinderivate und deren Salze |
US4219559A (en) | 1979-01-10 | 1980-08-26 | Janssen Pharmaceutica N.V. | N-Heterocyclyl-4-piperidinamines |
JPS59112984A (ja) | 1982-12-21 | 1984-06-29 | Shionogi & Co Ltd | 1,4−ベンゾジアゼピン誘導体 |
DE3410070A1 (de) | 1984-03-20 | 1985-10-03 | Hoechst Ag, 6230 Frankfurt | 1-(2-aryl-1,3-dioxolan-2-ylmethyl)-azole, ihre salze, verfahren zu ihrer herstellung, sie enthaltende zubereitungen und ihre verwendung |
US4584303A (en) | 1984-04-09 | 1986-04-22 | The Boc Group, Inc. | N-aryl-N-(4-piperidinyl)amides and pharmaceutical compositions and method employing such compounds |
IE912759A1 (en) * | 1990-08-06 | 1992-02-12 | Smith Kline French Lab | Compounds |
AU6971794A (en) | 1993-05-26 | 1994-12-20 | Smithkline Beecham Laboratoires Pharmaceutiques | Novel compounds |
ZA9610745B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
TWI242011B (en) | 1997-03-31 | 2005-10-21 | Eisai Co Ltd | 1,4-substituted cyclic amine derivatives |
KR20020002501A (ko) | 1999-05-13 | 2002-01-09 | 시오노 요시히코 | 당뇨병의 예방 또는 치료약 |
DE10000739A1 (de) | 2000-01-11 | 2001-07-12 | Merck Patent Gmbh | Piperidin- und Piperazinderivate |
DE60126785T2 (de) | 2000-08-08 | 2007-10-25 | Ortho-Mcneil Pharmaceutical, Inc. | Nicht-imidazol aryloxypiperidine als h3 rezeptor liganden |
DE10132746A1 (de) | 2001-07-05 | 2003-02-06 | Gruenenthal Gmbh | Substituierte 1-Phenethylpiperidinverbindungen |
WO2003062224A1 (en) | 2002-01-17 | 2003-07-31 | Eli Lilly And Company | Aza-cyclic compounds as modulators of acetylcholine receptors |
-
2006
- 2006-09-18 WO PCT/IB2006/004324 patent/WO2008096189A2/en active Application Filing
- 2006-09-18 AU AU2005339865A patent/AU2005339865B2/en not_active Ceased
- 2006-09-18 NZ NZ567629A patent/NZ567629A/en unknown
- 2006-09-18 AT AT06851953T patent/ATE532514T1/de active
- 2006-09-18 CN CN2006800352343A patent/CN101511187B/zh not_active Expired - Fee Related
- 2006-09-18 PL PL06851953T patent/PL1978959T3/pl unknown
- 2006-09-18 JP JP2008543809A patent/JP2009528976A/ja not_active Withdrawn
- 2006-09-18 CA CA002631096A patent/CA2631096A1/en not_active Abandoned
- 2006-09-18 EP EP06851953A patent/EP1978959B1/en not_active Not-in-force
- 2006-09-18 ES ES06851953T patent/ES2374307T3/es active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5109002A (en) * | 1989-09-08 | 1992-04-28 | Du Pont Merck Pharmaceutical Company | Antipsychotic 1-cycloalkylpiperidines |
US5281598A (en) * | 1992-04-13 | 1994-01-25 | Akzo N.V. | Piperazine derivatives |
EP0711763A1 (en) * | 1993-07-28 | 1996-05-15 | Santen Pharmaceutical Co., Ltd. | Novel 1,4-di(phenylalkyl)piperazine derivative |
Non-Patent Citations (1)
Title |
---|
Salvino,Joseph M 等.The solid-phase Synthesis and Use of N-monosubstituted Piperazines in Chemical Library Synthesis.《Journal of Combinatorial Chemistry》.2003,第5卷(第3期),260-266. * |
Also Published As
Publication number | Publication date |
---|---|
EP1978959A2 (en) | 2008-10-15 |
AU2005339865B2 (en) | 2011-09-08 |
CN101511187A (zh) | 2009-08-19 |
WO2008096189A2 (en) | 2008-08-14 |
ES2374307T3 (es) | 2012-02-15 |
PL1978959T3 (pl) | 2012-04-30 |
ATE532514T1 (de) | 2011-11-15 |
CA2631096A1 (en) | 2007-03-23 |
AU2005339865A1 (en) | 2008-08-14 |
EP1978959A4 (en) | 2009-09-02 |
JP2009528976A (ja) | 2009-08-13 |
NZ567629A (en) | 2011-08-26 |
WO2008096189A3 (en) | 2009-04-16 |
EP1978959B1 (en) | 2011-11-09 |
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