CN101679400A - 新颖的氨基甲酰氧基芳基链烷芳基哌嗪化合物,含该化合物的药物组合物以及通过给予该化合物治疗疼痛、焦虑和抑郁的方法 - Google Patents
新颖的氨基甲酰氧基芳基链烷芳基哌嗪化合物,含该化合物的药物组合物以及通过给予该化合物治疗疼痛、焦虑和抑郁的方法 Download PDFInfo
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- CN101679400A CN101679400A CN200880016354A CN200880016354A CN101679400A CN 101679400 A CN101679400 A CN 101679400A CN 200880016354 A CN200880016354 A CN 200880016354A CN 200880016354 A CN200880016354 A CN 200880016354A CN 101679400 A CN101679400 A CN 101679400A
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- phenyl
- piperazine
- compound
- carboxylamine
- propyl ester
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- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
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- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
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- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
提供一种由通式1表示的外消旋或对映异构特性富集的新颖的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物,及其药学上可用的盐或水合物。还提供包含有效量的所述化合物的用于治疗疼痛(即,急性痛或慢性痛、神经性痛、炎性痛、糖尿病性疼痛、疱疹后神经痛等)、焦虑和抑郁的药物组合物,以及通过给予需要治疗的哺乳动物有效量的化合物来治疗哺乳动物的疼痛、焦虑或抑郁的方法。
Description
技术领域
本发明涉及新颖的氨基甲酰氧基芳基链烷芳基哌嗪化合物,包含该化合物的药物组合物,以及通过给予需要治疗的哺乳动物该化合物治疗疼痛、焦虑和抑郁的方法,所述疼痛包括:急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性神经痛、疱疹后神经痛、炎性疼痛、关节痛、偏头痛等。
背景技术
迄今已经证实芳基哌嗪化合物对中枢神经系统领域的各种适应症是有效的。具体地,美国专利第3002976号报道了以下噻吩-接枝的(engrafted)芳基哌嗪化合物介于治疗抑郁的药理学效应。在以下式中,R表示氢、甲基或卤素。
还已知丁螺环酮和其结构相关的化合物在治疗焦虑方面的效应是因为它们对由受体5-HT1A代表的5-羟色胺(5-羟基色胺:5HT)亚型受体的选择活性。具体地,美国专利第4988814号公开一类对5-HT1A受体具有亲和性的哌嗪衍生物,其特征是可用作治疗抑郁和焦虑的治疗剂。
式中,R1是有1-6个碳原子的烷基;R2和R3各自独立地是有1-6个碳原子的烷基,或者R2和R3一起形成具有2-12个碳原子的多亚甲基,或者形成碳原子与R2和R3基团相连的5-降冰片烯-2-基残基;X选自下组:-CO2-、-OCO-、-OCO2-、-N(R7)CO-、-NHNHCO-、-ON(R7)CO-、-CON(R7)-、-N(R7)CO2-、-OCON(R7)-和-N(R7)CON(R8)(其中,R7和R8各自独立地选自下组:氢;有1-6个碳原子的烷基;苯基;苄基;被卤素、有1-6个碳原子的烷基、有1-6个碳原子的烷氧基、氰基、硝基或者全卤甲基取代的取代的苯基或苄基);R4是氢或有1-6个碳原子的烷基;R5选自下组:氢;有1-8个碳原子的烷基;有1-3个碳原子的羟烷基;苯基;苄基;和被羟基、卤素、有1-6个碳原子的烷基、有1-6个碳原子的烷氧基、三氟甲基、硝基、氰基、有2-7个碳原子的烷氧羰基、羧酰胺基、氨基、有1-6个碳原子的烷基氨基或有1-12个碳原子的二烷基氨基取代的苯基或苄基;R6是苯基、苄基、2-、3-或4-吡啶基、2-嘧啶基或2-吡嗪基,它们可被至少一个选自下组的取代基取代:羟基、卤素、有1-6个碳原子的烷基、有1-6个碳原子的烷氧基、三氟甲基、硝基、氰基、有2-7个碳原子的烷氧羰基、羧酰胺基、氨基、有1-6个碳原子的烷基氨基和有1-12个碳原子的二烷基氨基;n是选自0,1,2,3,4和5的一个整数,前提是,当X是-CON(R7)-(其中,R7是烷基)时,R6不是2-嘧啶基,当X是CO2,R1、R2和R3是甲基,n为1时,R6不是3,5-二(三氟甲基)苯基。
本发明人确定芳基哌嗪结构与治疗疼痛以及焦虑和抑郁的效应相关,并对芳基哌嗪结构进行广泛研究后发现新颖的氨基甲酰氧基芳基链烷芳基哌嗪化合物对各种疼痛诱发的动物模型具有医疗效应。特别是,本发明人已经发现,新颖的氨基甲酰氧基芳基链烷芳基哌嗪化合物在治疗各种疼痛、焦虑和抑郁方面的治疗效应,所述疼痛包括:急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性神经痛、疱疹后神经痛、炎性疼痛、关节痛、偏头痛等。因此,基于上述事实完成了本发明。
发明内容
技术问题
本发明一个方面提供了新颖的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物及其药学上可利用的盐或水合物。
本发明另一个方面提供了可用于治疗疼痛、焦虑或抑郁组合物的药物组合物,该组合物包含有效量的所述化合物。
本发明又一方面提供了治疗哺乳动物疼痛、焦虑或抑郁的方法,该方法包括给予需要这种治疗的哺乳动物有效量的所述化合物。
技术方案
根据本发明的一个方面,提供由以下通式1表示的外消旋或对映异构特性富集的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物,及其药学上可利用的盐或水合物:
通式1
式中,---可选择性形成环;
R1和R2是氢,或者R1或R2可以与X1一起形成双环;
X1可以是能被选自下组的至少一个相同或不同的取代基取代的苯基:氢、有1-6个碳原子的直链或支链的烷基、卤素如F、Cl和Br、有1-6个碳原子的直链或支链的烷氧基、硝基、二甲基氨基和三氟甲基;双环系统包括萘基和亚甲基二氧苯基;
Z是氢或氟,或者可以与X1一起形成双环;
Ar选自下组:可被选自下组的至少一个相同或不同的取代基取代的苯基、吡啶、嘧啶:氢、有1-6个碳原子的直链或支链的烷基、羟基、卤素、有1-6个碳原子的直链或支链的烷氧基、硝基、乙酰基、叔丁基乙酰基、三氟甲基、三氟甲氧基、氨基、苄氧基、3,4-亚甲基二氧、3,4-亚乙基二氧、新戊酰氧基、碳酸乙酯、碳酸苯基酯、碳酸苄基酯、乙酸酯和环戊氧基;以及萘基、二氢苯并二氧杂环己烯基(dioxinyl)、亚甲基二氧苯基、二(氟苯基)甲基和喹喔啉;
Y1和Y2各自独立地是氢或甲基(CH3);
Y3是氢、苯基或羰基(=O);
Y4是氢或甲基(CH3);
n是1或2的整数;
m是0或1的整数。
根据本发明的另一个方面,提供了可用于治疗疼痛、焦虑或抑郁的药物组合物,该组合物包含有效量的外消旋或对映异构特性富集的化合物。
根据本发明的又一个方面,提供了治疗哺乳动物疼痛、焦虑或抑郁的方法,该方法包括予需要这种治疗的哺乳动物有效量的外消旋或对映异构特性富集的化合物。
有益效果
如上所述,根据本发明的新颖的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物及其盐和水合物能够有效用作治疗疼痛、焦虑和抑郁的治疗剂,所述疼痛包括:急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性疼痛、疱疹后神经痛、炎性疼痛、关节痛、偏头痛等。
实施本发明的最佳方式
下面,将详细描述本发明。
本发明涉及具有以下通式1表示的外消旋或对映异构特性富集的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物,及其药学上可利用的盐或水合物:
通式1
式中,---可选择性形成环;
R1和R2是氢,或者R1或R2可以与X1一起形成双环;
X1可以是能被选自下组的至少一个相同或不同的取代基取代的苯基:氢、有1-6个碳原子的直链或支链的烷基、卤素如F、Cl和Br、有1-6个碳原子的直链或支链的烷氧基、硝基、二甲基氨基和三氟甲基;双环系统包括萘基和亚甲基二氧苯基;
Z是氢或氟,或者可以与X1一起形成双环;
Ar选自下组:可被选自下组的至少一个相同或不同的取代基取代的苯基、吡啶、嘧啶:氢、有1-6个碳原子的直链或支链的烷基、羟基、卤素、有1-6个碳原子的直链或支链的烷氧基、硝基、乙酰基、叔丁基乙酰基、三氟甲基、三氟甲氧基、氨基、苄氧基、3,4-亚甲基二氧、3,4-亚乙基二氧、新戊酰氧基、碳酸乙酯、碳酸苯基酯、碳酸苄基酯、乙酸酯和环戊氧基;以及萘基、二氢苯并二氧杂环己烯基、亚甲基二氧苯基、二(氟苯基)甲基和喹喔啉;
Y1和Y2各自独立地是氢或甲基(CH3);
Y3是氢、苯基或羰基(=O);
Y4是氢或甲基(CH3);
n是1或2的整数;
m是0或1的整数。
根据本发明的一个示例实施方式的化合物可以按照以下方案1至方案3化学合成。但是,这些方案仅用于说明目的,本发明不受其限制。
在以下方案中,HX表示能与具有碱性氮的化合物形成药学上可利用的盐的酸。这些酸包括但不限于,例如,盐酸、硫酸、磷酸、乙酸、苯甲酸、柠檬酸、丙二酸、水杨酸、苹果酸、富马酸、草酸、琥珀酸、酒石酸、乳酸、葡糖酸、抗坏血酸、马来酸、天冬氨酸、苯磺酸、甲磺酸、羟甲基磺酸、羟乙基磺酸等。加成酸可参见文献[“药学上的盐(Pharmaceutical Salts)”J.Pharm.Sci.,1977;66(1):1-19]。本发明的化合物可以在反应介质中制备,所述反应介质例如有:醚类溶剂(四氢呋喃、乙醚、丙醚、异丙醚和丁醚),醇类溶剂(甲醇、乙醇和异丙醇),酯类溶剂(乙酸乙酯),卤化烃溶剂(二氯甲烷、氯仿)以及它们的混合物。
方案1
如方案1所示,可在被X1取代的的起始原料(1-1)和被X2取代的苯基哌嗪(1-2)存在下通过曼尼希反应合成化合物(1-3)。化合物(1-4)可通过用硼氢化钠(NaBH4)使化合物(1-3)还原制备,化合物(1-4)与1,1-羰基二咪唑(CDI)反应,然后与各种胺(NHR1R2)反应,获得化合物(1-5)及其盐(1-6)。
通过方案1制备的反应产物(1-5)或其盐(1-6)可以以外消旋化合物的形式获得。
方案2
如方案2所示,各种哌嗪衍生物(2-2)接枝的化合物(2-3)可由起始原料3-氯-1-苯基-1-丙醇(化合物(2-1),n=1)或者4-氯-1-苯基-1-丁醇(化合物(2-1),n=2)制备,该化合物与1,1-羰基二咪唑(CDI)反应,然后与胺(NHR1R2)反应获得化合物(2-4)和其盐(2-5)。
反应产物(2-4)和其盐(2-5)的立体化学取决于起始原料(2-1);即,只具有(S)-对映异构体的反应产物可由具有(S)-对映异构体的起始原料(2-1)获得,只具有(R)-对映异构体的反应产物可由具有(R)-对映异构体的起始原料(2-1)获得。
方案3
如方案3所示,化合物(3-3)可由苯基-1-丙烯基酮(3-1)和取代基接枝的苯基哌嗪(3-2)通过1,4-迈克尔加成合成。化合物(3-3)在硼氢化钠(NaBH4)存在下发生碱性还原反应,以获得化合物(3-4)作为醇中间体,化合物(3-4)与1,1-羰基二咪唑(CDI)反应,如前面所述,获得氨基甲酸酯接枝的化合物(3-5)和其盐(3-6)。
通过方案3获得的反应产物都可以是外消旋化合物的形式。
根据本发明,提供用于治疗疼痛、焦虑或抑郁的药物组合物,该组合物包含有效量的所述化合物。在此,药物组合物包含在本申请中列出的化合物中的至少一种化合物作为活性组分,根据本发明的组合物可包含本发明化合物的任意组合。
本发明的药物组合物可以特别配制成能够通过各种形式,例如合适的给药途径给予。在此,合适的给药途径可包括例如,口服,直肠,鼻,肺,局部,经皮,脑池内,腹膜内,阴道和胃肠外(包括皮下、肌肉、鞘内、静脉和经皮途径)途径。本发明的药物组合物优选通过口途径给予。当然,优选的给药途径可依据各种因素而变化,包括一般性症状和进行治疗的对象的年龄,进行治疗的症状严重程度和选定的活性组分等。
按照本发明配制的药物制剂可以任何给药形式通过口服给药,所述给药形式例如是片剂、胶囊、粉剂、颗粒、团粒、含片、糖衣丸、药丸或锭剂,在水性液体或非水性液体中的溶液或混悬液,或者水包油或油包水乳剂,酏剂,糖浆剂等,或者以注射形式胃肠外给予。可通过胃肠外给予的其他药物组合物包括分散剂、混悬剂和乳剂,以及在使用之前包含在无菌注射溶液或分散体中的无菌粉末。长效注射制剂也被认为包括在本发明的范围之内。其他合适的给药形式包括栓剂,喷雾剂,软膏,乳剂,凝胶,吸入剂,皮肤贴片等。根据本发明的组合物可以按照本领域已知的各种方法配制。在此可使用本领域中普遍使用的药学上可用的载体、稀释剂、赋形剂或其他添加剂。
载体通常是配制中使用的那些载体,包括但不具体限于:乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯基吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。本发明的组合物还包含防腐剂、稳定改进性化合物、粘度改进/调节性化合物、溶解改进性化合物、甜味剂、染料、味觉增强化合物、用来改变渗透压的盐、缓冲剂、抗氧化剂等。
上述化合物在显示所需的治疗疼痛、焦虑或抑郁的效力时,化合物可以溶剂合物、酯、立体异构体等形式,包括游离化合物、药学上可用的盐和水合物形式使用。并且,上述化合物也包括在本发明的范围之内。
根据本发明,药学上可用的盐包括药学上可用的酸加成盐。药学上可用的酸加成盐可由以下的酸获得:无机酸,例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸和亚磷酸;无毒的有机酸,例如脂族单羧酸酯和二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯和链烷二酸酯(alkandioate)、芳族酸、脂族磺酸和芳族磺酸等。药学上可用的盐的具体例子包括但不限于:硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、重亚硫酸盐、硝酸盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙酸盐、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、己烷-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、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。特别优选盐酸和甲磺酸盐。
本发明提供一种治疗哺乳动物的疼痛、焦虑或抑郁的方法,其特征在于,给予需要这种治疗的哺乳动物有效量的所述化合物。
可以使用本发明的化合物进行治疗的疼痛包括广泛范围内的各种疼痛,例如,急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性疼痛、疱疹后神经痛、炎性疼痛、关节痛、偏头痛等。
一般而言,本发明的药物组合物可以作为约20-500毫克单位剂量的活性组分给予。本发明的活性化合物通常给予的总的日剂量在约10-7000毫克范围,优选20-3500毫克。但是,在对患者的症状进行常规研究,并还考虑了给予的药剂的活性后,所述活性化合物也可以该剂量范围之外的用量给药。在这种情况下,这类药剂对特定症状的最佳剂量应通过常规试验来确定。
本发明的化合物可以按每天一次或多次的剂量给予,本发明化合物优选分成每天一次、两次和三次的剂量。本发明的化合物可以单独给予或者与药学上可用的载体或赋形剂组合给予。根据本发明的药物组合物可以在药学可用的载体或稀释剂,以及本领域公知的添加物和赋形剂中配制。为方便起见,制剂可以通过采用药学领域已知的方法以适用于这种给药方式的剂型存在。
本发明的方式
下面,详细描述本发明的示例实施方式。但是,应理解,在此提供的描述内容只是用于说明目的的优选实施例,并不意图限制本发明的范围。
1.氨基甲酰氧基芳基链烷芳基哌嗪化合物的合成
实施例1:氨基甲酸1-苯基-3-(4-苯基-哌嗪-1-基)-丙酯
将苯乙酮(4.67毫摩尔)和苯基哌嗪(5.61毫摩尔)溶解于乙醇(30毫升),通过滴加浓盐酸将形成的混合物pH调节至2-3。在该混合物中加入多聚甲醛(46.7毫摩尔),使形成的混合物回流24小时。产生的反应混合物在减压下蒸馏,用1标准(normal)氯化钠水溶液中和,用水稀释,然后用乙酸乙酯萃取几次。产生的有机相用硫酸镁干燥,过滤,在减压条件下浓缩形成滤液,通过柱色谱进行分离和纯化(己烷∶乙酸乙酯=1∶1至1∶10)。将分离的化合物(3.5毫摩尔)溶解于甲醇(20毫升),冷却至0℃,向混合物中缓慢加入硼氢化钠(5毫摩尔)。室温下搅拌形成的混合物2小时,在减压下浓缩。然后,形成的黄色颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1)获得醇类中间体。将制备的中间体(10毫摩尔)溶解于四氢呋喃(15毫升),在该中间体混合物中加入1,1′-羰基二咪唑(20毫摩尔)。室温下搅拌形成的中间体混合物1小时,在该中间体混合物中加入过量的氢氧化铵,室温下再次搅拌形成的混合物2小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。形成的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1至己烷∶乙酸乙酯=0∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.21(m,1H),2.41(m,2H),2.60(m,4H),3.10(m,4H),4.92(br,2H),5.75(t,1H),6.89(m,4H),7.11(m,5H)
按照与实施例1相同的方式制备实施例2-84的化合物,除了在实施例2-84中使用标题的起始原料。
实施例2:氨基甲酸1-(4-氯-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氯苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,1H),2.16(m,1H),2.33(m,2H),2.45(m,4H),3.01(m,4H),4.57(br,2H),5.51(t,1H),6.80(m,2H),7.19(m,2H),7.28(m,5H)
实施例3:氨基甲酸1-(4-二甲基氨基-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-二甲基氨基苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.62(m,3H),2.71(m,1H),2.82(m,2H),2.94(dd,6H),3.25(m,4H),4.87(dd,1H),5.8(br,2H),6.71(d,2H),6.9(m,3H),7.26(m,5H)
实施例4:氨基甲酸1-(3-硝基苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-硝基氨基苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.58(m,2H),2.66(m,2H),2.95(m,4H),3.36(m,4H),4.86(br,2H),5.80(t,1H),6.89-6.97(m,3H),7.29(m,2H),7.54(t,1H),7.75(d,1H),8.15(q,1H),8.29(d,1H)
实施例5:氨基甲酸1-(4-叔丁基-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
1H NMR(200MHz,CDCl3)d:1.32(s,9H),3.27(m,6H),3.41(m,4H),3.88(m,4H),4.90(br,2H),5.66(t,1H),6.81(m,1H),7.01(m,3H),7.42(m,5H)
实施例6:氨基甲酸1-(4-氟-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.88(m,2H),2.76(m,6H),3.27(m,2H),4.57(br,2H),5.51(t,1H),6.89(m,4H),7.32(m,5H)
实施例7:氨基甲酸1-(3-氯-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-氯苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHZ,CDCl3)d:1.85(m,2H),2.61-2.84(m,6H),3.27(m,4H),4.83(br,2H),5.79(t,1H),6.89(m,3H),7.21-7.40(m,6H)
实施例8:氨基甲酸1-(4-甲氧基-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-甲氧基苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.56(m,2H),2.65(m,4H),2.93(m,2H),3.25(m,4H),3.81(s,3H),4.77(t,1H),5.02(br,2H),6.91(m,5H),7.29(m,4H)
实施例9:氨基甲酸1-(4-硝基苯基)-3-(4-苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-硝基苯乙酮和苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.22(m,2H),3.23(m,6H),3.68(m,2H),3.91(m,2H),5.10(br,2H),5.81(t,1H),6.91(m,2H),7.02(m,2H),7.40(m,2H),7.62(m,2H),8.23(m,2H)
实施例10:氨基甲酸3-(4-苯基-哌嗪-1-基)-1-对甲苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-甲基苯乙酮和苯基哌嗪作为起始原料。
1H NMR(500MHz,DMSO)d:2.11(s,1H),2.31(s,3H),2.50(s,1H),3.20(m,6H),3.51(m,2H),5.55(t,1H),6.80(br,2H),6.89(m,1H),7.01(m,2H),7.24(m,4H),7.29(m,4H)
实施例11:氨基甲酸3-[4-(2,3-二氢-苯并[1,4]二氧杂环己烯-6-基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和1-(2,3-二氢-苯并[1,4]二氧杂环己烯-6-基-1)-哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.03(m,1H),2.21(m,1H),2.42(m,2H),2.55(m,4H),3.05(m,4H),4.20(m,4H),4.80(br,2H),5.82(t,1H),6.45(m,2H),6.84(m,1H),7.32(m,5H)
实施例12:氨基甲酸1-苯基-3-[4-(4-三氟甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-三氟甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.12(m,2H),2.41(m,2H),2.56(m,4H),3.17(m,4H),4.65(br,2H),5.90(t,1H),6.86(m,2H),7.11(m,2H),7.31(m,5H)
实施例13:氨基甲酸3-[4-(2,4-二甲基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2,4-二甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.97-2.10(m,1H),2.13-2.24(m,1H),2.29(s,3H),2.30(s,3H),2.43-2.51(m,2H),2.61-2.82(m,4H),2.91-2.95(m,4H),4.84(br,2H),5.76(t,1H),6.94-7.03(m,3H),7.28-7.38(m,5H)
实施例14:氨基甲酸1-苯基-3-[4-(2-三氟甲基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-三氟甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.07(m,2H),2.35(m,2H),2.45(m,4H),2.76(m,4H),5.78(t,1H),6.01(br,2H),7.34(m,5H),7.57(m,4H)
实施例15:氨基甲酸1-苯基-3-[4-(2-氯-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-氯-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:1.99(m,2H),2.21(m,2H),2.36(m,4H),2.77(m,4H),5.89(t,1H),6.10(br,2H),7.30(m,5H),7.48(m,4H)
实施例16:氨基甲酸1-苯基-3-[4-(4-硝基苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-硝基苯基-哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.11(m,2H),2.26(m,2H),2.51(m,4H),2.59(m,4H),4.81(br,2H),5.81(t,1H),6.48(m,4H),7.28(2H),7.42(m,2H)
实施例17:氨基甲酸3-[4-(2,4-二甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2,4-二甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.06(m,1H),2.18(m,1H),2.45(m,3H),2.64(m,4H),3.03(m,4H),3.79(s,3H),3.84(s,3H),3.84(s,3H),4.73(br,2H),5.87(t,1H),6.48(m,2H),6.86(d,1H),7.28-7.37(m,5H)
实施例18:氨基甲酸3-[4-(4-氯-3-三氟甲基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-三氟甲基-4-氯苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.03(m,1H),2.18(m,1H),2.44(m,2H),2.60(m,4H),3.23(m,4H),4.71(br,2H),5.78(t,1H),6.96(m,1H),7.28-7.32(m,7H)
实施例19:氨基甲酸3-[4-(2,6-二甲基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2,6-二甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.05(m,1H),2.18(m,1H),2.27(s,6H),2.41(m,2H),2.55(m,4H),3.13(m,4H),4.70(br,2H),5.77(t,1H),6.97-6.99(m,3H),7.28-7.39(m,5H)
实施例20:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.12(m,1H),2.27(m,1H),2.42(m,2H),2.65(m,4H),3.13(m,4H),3.79(s,3H),4.87(br,2H),5.79(t,1H),6.89(m,4H),7.33(m,5H)
实施例21:氨基甲酸3-[4-(4-氟-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-氟-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.11(m,1H),2.21(m,1H),2.29(m,2H),2.61(m,4H),3.14(m,4H),4.83(br,2H),5.75(t,1H),6.93(m,4H),7.33(m,5H)
实施例22:氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-氯-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.21(m,1H),2.43(m,2H),2.60(m,4H),3.18(m,4H),4.67(br,2H),5.76(t,1H),6.85(m,2H),7.24(m,2H),7.37(m,5H)
实施例23:氨基甲酸3-[4-(2-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-羟基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.05(m,2H),2.40(m,2H),2.62(m,4H),2.90(m,4H),4.63(br,2H),5.71(t,1H),6.96(m,3H),7.14(m,2H),7.35(m,3H)
实施例24:氨基甲酸1-苯基-3-(4-间甲苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.07(m,2H),2.28(s,3H),2.39(m,2H),2.55(m,4H),3.17(m,4H),5.81(t,1H),6.61(br,2H),6.78(m,2H),7.10(t,1H),7.31-7.40(m,5H)
实施例25:氨基甲酸1-苯基-3-(4-吡啶-2-基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-吡啶基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.19(m,2H),2.32(m,2H),2.48(m,4H),2.67(m,4H),4.84(br,2H),5.79(t,1H),6.89(m,1H),7.19(m,1H),7.34(m,3H),7.56(m,3H),8.11(m,1H)
实施例26:氨基甲酸3-[4-(3-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.97(m,2H),2.39(m,2H),2.55(m,4H),3.18(m,4H),3.77(s,3H),5.76(t,1H),6.1(br,2H),6.43(m,1H),6.53(m,1H),7.12(t,1H),7.30-7.43(m,5H)
实施例27:氨基甲酸3-[4-(2-甲氧基-苯基)-哌嗪-1-基]1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.88(m,2H),2.29(m,2H),2.46(m,4H),3.09(m,4H),3.82(s,3H),5.66(t,1H),5.90(br,2H),6.82(m,4H),7.29(m,5H)
实施例28:氨基甲酸3-[4-(3-氯-吡啶-2-基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和1-(3-氯-吡啶-2-基)-哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:1.58(m,2H),1.89(m,2H),2.42(m,2H),2.54(m,4H),3.32(m,4H),5.69(t,1H),6.07(br,2H),6.95(m,1H),7.27-7.39(m,5H),7.71(m,1H),8.21(m,1H)
实施例29:氨基甲酸3-[4-(3,4-二甲基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3,4-二甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.01(m,2H),2.17(s,3H),2.21(s,3H),2.40(m,2H),2.57(m,4H),3.13(m,4H),4.78(br,2H),5.82(t,1H),6.82(m,2H),7.01(m,1H),7.33(m,5H)
实施例30:氨基甲酸3-(4-苯并[1,3]间二氧杂环戊烯-5-基-哌嗪-1-基)-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3,4-亚甲基二氧-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,1H),2.12(m,1H),2.36(m,2H),2.54(m,4H),3.05(m,4H),4.77(br,2H),5.72(t,1H),5.90(s,2H),6.32(dd,1H),6.55(m,1H),6.72(d,1H),7.33(m,5H)
实施例31:氨基甲酸3-[4-(3,4-二氯-苯基)-哌嗪-1-基]1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3,4-二氯-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.10(m,2H),2.39(m,2H),2.54(m,4H),3.15(m,4H),4.62(br,2H),5.85(t,1H),6.81(dd,1H),6.99(m,1H),7.34(m,6H)
实施例32:氨基甲酸3-[4-(5-氯-2-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和5-氯-2-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.04(m,2H),2.41(m,2H),2.61(m,4H),3.06(m,4H),3.82(s,3H),4.62(br,2H),5.82(t,1H),6.71(d,1H),6.99(m,2H),7.34(m,5H)
实施例33:氨基甲酸3-[4-(3,5-二甲氧基-苯基)-哌嗪-1-基]1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3,5-二甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,2H),2.21(m,1H),2.49(m,2H),2.58(m,4H),3.20(m,4H),3.80(s,3H),4.89(br,2H),5.89(t,1H),6.11(m,1H),6.12(m,2H),7.37(m,5H)
实施例34:氨基甲酸1-苯基-3-(4-嘧啶-2-基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-哌嗪-1-基-嘧啶作为起始原料。
1H NMR(200MHz,CDCl3)d:2.00(m,2H),2.44(m,6H),3.83(m,4H),4.79(br,2H),5.45(t,1H),6.49(t,1H),7.31(m,5H),8.31(m,2H)
实施例35:氨基甲酸3-[4-(2-硝基-4-三氟甲基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-硝基4-三氟甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.10(m,2H),2.21(m,2H),2.59(m,4H),3.19(m,4H),4.62(br,2H),5.81(t,1H),7.36(m,5H),7.41(m,1H),7.62(m,1H),8.09(s,1H)
实施例36:氨基甲酸3-[4-(3-氯-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-氯-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.11(m,1H),2.21(m,1H),2.29(m,2H),2.61(m,4H),3.14(m,4H),4.83(br,2H),5.75(t,1H),6.93(m,4H),7.33(m,5H)
实施例37:氨基甲酸1-苯基-3-(4-邻甲苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.05(m,2H),2.19(s,3H),2.37(m,2H),2.58(m,4H),2.89(m,4H),5.78(t,1H),6.2(br,2H),6.92(t,1H),7.19(m,3H),7.31-7.40(m,5H)
实施例38:氨基甲酸1-苯基-3-(4-对甲苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.08(m,2H),2.10(s,3H),2.29(m,2H),2.55(m,4H),3.13(m,4H),5.76(t,1H),6.01(br,2H),6.85(m,2H),7.03(m,5H),7.31-7.40(m,5H)
实施例39:氨基甲酸1-苯基-3-[4-(3-三氟甲基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-三氟甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.03(m,2H),2.42(m,2H),2.58(m,4H),3.29(m,4H),5.78(t,1H),6.01(br,2H),7.09(m,1H),7.23(m,2H),7.30-7.43(m,6H)
实施例40:氨基甲酸1-苯基-3-[4-(4-三氟甲基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-三氟甲基-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.41(m,2H),2.57(m,4H),2.83(m,2H),3.34(m,4H),5.77(t,1H),5.97(br,2H),7.09(m,2H),7.36(m,5H),7.52(m,2H)
实施例41:氨基甲酸3-[4-(2-氟-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-氟-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.05(m,2H),2.38(m,2H),2.58(m,4H),3.09(m,4H),,5.77(t,1H),5.89(br,2H),7.06(m,4H),7.30-7.40(m,5H)
实施例42:氨基甲酸3-[4-(3-氟-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和3-氟-苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.08(m,2H),2.39(m,2H),2.56(m,4H),3.22(m,4H),5.80(t,1H),6.17(br,2H),6.62(m,1H),6.78(m,2H),7.20-7.45(m,6H)
实施例43:氨基甲酸3-[4-(2-硝基苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和2-硝基苯基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.05(m,2H),2.40(m,2H),2.44-2.62(m,4H),3.07(m,4H),5.77(t,1H),5.98(br,2H),7.32(m,1H),7.57-7.76(m,2H)
实施例44:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]1-(4-硝基苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-硝基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.95(m,1H),2.17(m,1H),2.43(m,2H),2.60(m,4H),3.10(m,4H),3.78(s,3H),4.91(br,2H),5.83(t,1H),6.88(m,4H),7.53(d,2H),8.23(d,2H)
实施例45:氨基甲酸1-(3-氯-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-氯苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.20(m,1H),2.43(m,2H),2.61(m,4H),3.11(m,4H),3.79(s,3H),4.75(br,2H),5.73(t,1H),6.89(m,4H),7.32(m,4H)
实施例46:氨基甲酸1-(2-氟-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-氟苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.88-2.00(m,2H),2.32(m,2H),2.58(m,4H),3.09(m,4H),3.81(s,3H),4.89(br,2H),5.81(t,1H),6.92(m,4H),7.28(m,5H)
实施例47:氨基甲酸1-(4-甲氧基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-甲氧基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.97(m,1H),2.17(m,1H),2.41(m,2H),2.60(m,4H),3.10(m,4H),3.78(s,3H),3.81(s,3H),4.87(br,2H),5.69(t,1H),6.88(m,6H),7.30(m,2H)
实施例48:氨基甲酸1-(4-叔丁基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-叔丁基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.32(s,9H),1.94(m,2H),2.68(m,3H),2.80(m,3H),3.27(m,4H),3.78(s,3H),4.95(t,1H),5.82(br,2H),6.90(m,3H),7.24-7.38(m,6H)
实施例49:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]1-萘-2-基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-萘乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.08(m,1H),2.43(m,1H),2.47(m,2H),2.55(m,4H),3.12(m,4H),3.79(s,3H),4.7(br,2H),5.93(t,1H),6.89(m,4H),7.51(m,3H),7.86(m,4H)
实施例50:氨基甲酸1-(2-氯-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-氯苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.08(m,2H),2.58(m,6H),3.10(m,4H),3.78(s,3H),4.85(br,2H),6.12(t,1H),6.82-6.94(m,4H),7.21-7.45(m,4H)
实施例51:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]1-(2-三氟甲基-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-三氟甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.04(m,2H),2.63(m,6H),3.11(m,4H),3.79(s,3H),4.78(br,2H),6.12(t,1H),6.83-6.95(m,4H),7.37-7.69(m,4H)
实施例52:氨基甲酸1-(3,4-二氟-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′,4′-二氟甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.21(m,1H),2.41(m,2H),2.60(m,4H),3.10(m,4H),3.80(s,3H),4.92(br,2H),5.75(t,1H),6.89(m,4H),7.11(m,3H)
实施例53:氨基甲酸1-(3-氟-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-氟苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,1H),2.19(m,1H),2.43(m,2H),2.60(m,4H),3.11(m,4H),3.78(s,3H),4.88(br,2H),5.74(t,1H),6.91(m,4H),7.10(m,3H),7.33(m,1H)
实施例54:氨基甲酸1-(3-甲氧基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-甲氧基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.14(m,1H),2.44(m,2H),2.61(m,4H),3.11(m,4H),3.78(s,3H),3.82(s,3H),4.86(br,2H),5.72(t,1H),6.83(m,7H),7.28(m,1H)
实施例55:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-萘-1-基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用1’-萘乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.26(m,2H),2.55(m,2H),2.63(m,4H),3.12(m,4H),3.80(s,3H),4.71(br,2H),6.59(t,1H),6.92(m,4H),7.45-7.58(m,4H),7.62-7.92(m,2H),8.25(d,1H)
实施例56:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-对甲苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.17(m,2H),2.36(s,3H),2.42(m,2H),2.64(m,4H),3.12(m,4H),3.78(s,3H),4.78(br,2H),5.87(t,1H),6.88(m,4H),7.23(m,4H)
实施例57:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-间甲苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.01(m,1H),2.178(m,1H),2.37(s,3H),2.42(m,2H),2.61(m,4H),3.11(m,4H),3.79(s,3H),4.86(br,2H),5.72(t,1),6.89(m,4H),7.18(m,4H)
实施例58:氨基甲酸1-(2,4-二氯-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′,4′-二氯苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.06(m,2H),2.50(m,2H),2.6(m,2H),3.1(m,4H),3.78(s,3H),4.76(br,2H),6.07(t,1H),6.88(m,4H),7.32(m,3H)
实施例59:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-邻甲苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.95-2.03(m,1H),2.06-2.13(m,1H),2.45(s,3H),2.5-2.63(m,4H),3.08-3.13(m,4H),3.79(s,3H),4.66(br,2H),6.00(t,1H),6.83-6.95(m,4H),7.18-7.40(m,4H)
实施例60:氨基甲酸1-(2,4-二甲基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′,4′-二甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.94-2.04(m,2H),2.10-2.21(m,2H),2.32(s,3H),2.41(s,3H),2.60-2.63(m,4H),3.08-3.13(m,4H),3.79(s,3H),4.65(br,2H),5.96(t,1H),6.87-7.06(m,6H),7.27(d,1H)
实施例61:氨基甲酸1-(3,4-二甲基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′,4′-二甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.01(m,1H),2.11(m,1H),2.32(s,3H),2.41(s,3H),2.44(m,2H),2.62(m,4H),3.12(m,4H),3.80(s,3H),4.65(br,2H),5.69(t,1H),6.91(m,4H),7.14(m,3H)
实施例62:氨基甲酸1-(2,5-二甲基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′,5′-二甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,2H),2.09(m,2H),2.54(m,3H),3.10(m,4H),3.80(s,3H),4.75(br,2H),5.96(t,1H),6.88(m,4H),7.03(dd,2H),7.18(s,1H)
实施例63:氨基甲酸1-(4-氯-3-三氟甲基-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氯-3′-三氟甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.93(m,1H),2.22(m,1H),2.39(m,2H),2.63(m,4H),3.11(m,4H),3.79(s,3H),4.89(br,2H),5.77(t,1H),6.89(m,4H),7.52(m,4H)
实施例64:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-(2-硝基苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-硝基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.07(m,2H),2.62(m,6H),3.09(m,4H),3.78(s,3H),4.80(br,2H),6.27(t,1H),6.88(m,4H),7.45(m,1H),7.64(d,2H),7.98(d,1H)
实施例65:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-(3-硝基苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-硝基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,2H),2.42-2.65(m,6H),3.11(m,4H),3.80(s,3H),5.01(br,2H),6.22(t,1H),6.78(m,4H),7.37(m,1H),7.8(d,2H),7.98(d,1H)
实施例66:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-(4-三氟甲基-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-三氟甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.97(m,1H),2.20(m,1H),2.44(m,2H),2.61(m,4H),3.15(m,4H),3.79(s,3H),4.73(br,2H),5.80(t,1H),6.89(m,4H),7.42(d,2H),7.64(d,2H)
实施例67:氨基甲酸1-苯并[1,3]间二氧杂环戊烯-5-基-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′,4′-亚甲基二氧苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.19(m,1H),2.19(m,1H),2.39(m,2H),2.60(m,4H),3.11(m,4H),3.78(s,3H),4.75(br,2H),5.65(t,1H),5.97(s,2H),6.76-6.94(m,7H)
实施例68:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]1-(3-三氟甲基-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′-三氟甲基苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,1H),2.22(m,1H),2.39(m,2H),2.61(m,4H),3.11(m,4H),3.79(s,3H),4.77(br,2H)5.82(t,1H),6.89(m,4H),7.56(m,4H)
实施例69:氨基甲酸1-(2-氟-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用2′-氟苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.14(m,2H),2.49(m,2H),2.61(m,4H),3.09(m,4H),3.79(s,3H),4.91(br,2H),6.02(t,1H),6.91(m,4H),7.14(m,2H),7.36(m,2H)
实施例70:氨基甲酸1-(3,4-二氯-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′,4′-二氯苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.11(m,2H),2.17(m,2H),2.68(m,4H),3.15(m,4H),3.72(s,3H),4.81(br,2H),5.90(t,1H),6.92(m,4H),7.12(m,1H),7.28(m,2H)
实施例71:氨基甲酸1-(4-氯-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-二氯苯乙酮和4-甲氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.17(m,1H),2.42(m,2H),2.61(m,4H),3.11(m,4H),3.80(s,3H),4.83(br,2H),5.87(t,1H),6.89(m,4H),7.32(m,4H)
实施例72:氨基甲酸1-(4-氯-3-三氟甲基-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氯-3′-三氟甲基苯乙酮和4-羟基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.01(m,1H),2.21(m,1H),2.53(m,2H),2.71(m,4H),4.92(br,2H),5.82(t,1H),6.80(m,4H),7.49(m,2H),7.70(s,1H)
实施例73:氨基甲酸1-(3,4-二氯-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用3′,4′-二氯苯乙酮和4-羟基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.08(m,2H),2.16(m,2H),2.65(m,4H),3.11(m,4H),4.75(br,2H),5.83(t,1H),6.82(m,4H),7.29(m,1H),7.43(m,2H)
实施例74:氨基甲酸3-[4-(2-乙氧基-苯基)-哌嗪-1-基]-1-(4-氟-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和2-乙氧基-苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.43(m,3H),2.18(m,2H),2.55-3.05(m,10H),4.11(m,2H),5.76(t,1H),5.99(br,2H),7.08(m,3H),7.13(m,3H),7.44(m,2H)
实施例75:氨基甲酸3-[4-(5-氯-2-甲氧基-苯基)-哌嗪-1-基]-1-(4-氟-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和5-氯-2-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.38(m,2H),2.54(m,6H),3.04(m,4H),3.86(s,3H),5.73(t,1H),5.93(br,2H),6.93(m,4H),7.16(m,2H),7.51(m,1H)
实施例76:氨基甲酸3-[4-(3,4-二氯-苯基)-哌嗪-1-基]1-(4-氟-苯基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和3,4-二氯苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.22(m,1H),2.48(m,3H),2.54(m,6H),3.24(m,2H),5.72(t,1H),5.97(br,2H),6.91(m,1H),7.08(m,3H),7.45(m,3H)
实施例77:氨基甲酸1-(4-氟-苯基)-3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和4-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.89(m,1H),2.15(m,1H),2.42(m,2H),2.58(m,4H),3.07(m,4H),3.76(s,3H),4.93(br,2H),5.82(t,1H),6.86(m,4H),7.02(m,2H),7.39(m,2H)
实施例78:氨基甲酸1-(4-氟-苯基)-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和2-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,1H),2.20(m,1H),2.43(m,2H),2.97(m,4H),3.11(m,4H),3.87(s,3H),4.62(br,2H),5.87(t,1H),6.89-7.09(m,6H),7.35(m,2H)
实施例79:氨基甲酸1-(4-氟-苯基)-3-[4-(4-硝基苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和4-硝基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.07(m,1H),2.17(m,1H),2.65(m,4H),3.49(m,4H),4.65(br,2H),5.75(t,1H),6.83(m,2H),6.98(m,2H),7.35(m,2H),8.18(m,2H)
实施例80:氨基甲酸1-(4-氟-苯基)-3-(4-邻甲苯基-哌嗪-1-基)-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和2-甲基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.01(m,2H),2.17(m,2H),2.31(s,3H),2.43(m,2H),2.63(m,4H),2.69(m,4H),4.77(br,2H),5.76(t,1H),7.09(m,4H),7.23(m,2H),7.36(m,3H)
实施例81:氨基甲酸1-(4-氟-苯基)-3-[4-(4-氟-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和4-氟苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.89(m,1H),2.21(m,1H),2.39(m,2H),2.59(m,4H),3.14(m,4H),4.82(br,2H),5.80(t,1H),6.89-7.09(m,5H),7.24(m,3H)
实施例82:氨基甲酸2-[4-(4-甲氧基-苯基)-哌嗪-1-基甲基]-1,2,3,4-四氢-萘-1-基酯
按照与实施例1相同的方式制备标题化合物,除了使用α-四氢萘酮和4-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.91(m,3H),2.52(m,2H),2.67(m,4H),2.80(m,2H),3.15(m,4H),3.78(s,3H),4.66(br,2H),6.05(t,1H),6.90(m,4H),7.28(m,4H)
实施例83:氨基甲酸1-(4-氯-苯基)-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氯苯乙酮和2-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.28(m,2H),2.39(m,2H),3.09(m,4H),3.23(m,4H),3.70(s,3H),4.99(br,2H),5.88(t,1H),7.11(m,4H),7.31(m,4H)
实施例84:氨基甲酸3-[4-(4-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用苯乙酮和4-羟基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,2H),2.14(m,2H),2.58(m,4H),3.12(m,4H),5.12(br,2H),5.78(t,1H),6.99(m,4H),7.21(m,5H)
实施例85:氨基甲酸3-[4-(4-苄氧基苯基)-哌嗪-1-基]-1-苯基-丙酯
将实施例84中制备的化合物-氨基甲酸3-[4-(4-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯(2毫摩尔)溶解于四氢呋喃(25毫升)中,向其中加入碳酸钾(K2CO3,2.4毫摩尔)和苄基溴(2.4毫摩尔),于70℃搅拌形成的混合物10小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制成的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:2.05(m,1H),2.17(m,1H),2.37(m,2H),2.65(m,4H),3.14(m,4H),4.65(br,2H),5.04(s,2H),5.87(t,1H),7.29-7.43(m,9H)
实施例86:乙酸4-[4-(3-氨基甲酰氧基-3-苯基-丙基)-哌嗪-1-基]-苯基酯
将实施例84中制得的化合物氨基甲酸3-[4-(4-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯(2毫摩尔)溶解于四氢呋喃(25毫升)中,向其中加入三乙胺(2.4毫摩尔)和乙酰氯(2.4毫摩尔),室温下搅拌形成的混合物5小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:2.04(m,1H),2.17(m,1H),2.29(s,3H),2.43(m,2H),2.61(m,4H),3.19(m,4H),4.74(br,2H),5.75(t,1H),6.95(m,4H),7.33(m,5H)
实施例87:氨基甲酸3-[4-(4-环戊氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
将实施例84中制得的化合物氨基甲酸3-[4-(4-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯(2毫摩尔)溶解于四氢呋喃(25毫升)中,向其中加入三乙胺(2.4毫摩尔)和溴戊基(2.4毫摩尔),于80℃搅拌形成的混合物10小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩,制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:1.61(m,3H),1.85(m,8H),2.11(m,1H),2.27(m,1H),2.62(m,4H),3.11(m,4H),4.76(br,2H),5.78(t,1H),6.85(m,4H),7.34(m,5H)
实施例88:氨基甲酸1-(4-氟-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯
按照与实施例1相同的方式制备标题化合物,除了使用4′-氟苯乙酮和4-羟基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.97(m,1H),2.12(m,1H),2.40(m,2H),2.62(m,4H),3.08(m,4H),4.78(br,2H),5.82(t,1H),7.07(m,5H),7.23(m,3H)
实施例89:1-(4-氟苯基)-3-(4-(4-(新戊酰氧基)苯基)哌嗪-1-基)丙基氨基甲酸酯
将实施例88中制得的化合物氨基甲酸1-(4-氟-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯(2毫摩尔)溶解于丙酮(15毫升)中,向其中加入三乙胺(2.4毫摩尔,滴加三甲基乙酰氯(2.4毫摩尔),室温下搅拌形成的混合物5小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:1.35(m,9H),1.97(m,1H),2.21(m,1H),2.42(m,2H),2.64(m,4H),3.17(m,4H),4.90(br,2H),5.75(t,1H),6.94(m,4H),7.08-7038(m,4H)
实施例90:碳酸4-{4-[3-氨基甲酰氧基-3-(4-氟-苯基)-丙基]-哌嗪-1-基}-苯基乙酯
将实施例88中制得的化合物氨基甲酸1-(4-氟-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯(0.93毫摩尔)溶解于丙酮(15毫升)中,向其中加入三乙胺(1.86毫摩尔),并滴加氯甲酸乙酯(2.4毫摩尔),室温下搅拌形成的混合物5小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩.制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHZ,CDCl3)d:1.40(m,3H),2.04(m,1H),2.21(m,1H),2.43(m,2H),2.63(m,4H),3.19(m,4H),4.30(m,2H),4.79(br,2H),5.72(t,1H),6.88(m,2H),7.06(m,4H),7.34(m,4H)
实施例91:碳酸苄基酯4-{4-[3-氨基甲酰氧基-3-(4-氟-苯基)-丙基]-哌嗪-1-基}-苯基酯
将实施例88中制得的化合物氨基甲酸1-(4-氟-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯(1毫摩尔)溶解于丙酮(20毫升),向其中加入三乙胺(2毫摩尔),并滴加氯甲酸苄酯(2.4毫摩尔),室温下搅拌形成的混合物5小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩.制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:1.99(m,2H),2.12(m,2H),2.66(m,4H),3.12(m,4H),3.52(s,2H),4.90(br,2H),5.81(t,1H),6.89(m,4H),7.33(m,9H)
实施例92:乙酸4-{4-[3-氨基甲酰氧基-3-(4-氟-苯基)-丙基]-哌嗪-1-基}-苯基酯
将实施例88中制得的化合物氨基甲酸1-(4-氟-苯基)-3-[4-(4-羟基-苯基)-哌嗪-1-基]-丙酯(0.6毫摩尔)溶解于丙酮(15毫升)中,向其中加入三乙胺(1.2毫摩尔),并滴加乙酰氯(2.4毫摩尔)。室温下搅拌形成的混合物5小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:2.02(m,1H),2.17(m,1H),2.38(s,3H),2.42(m,2H),2.60(m,4H),3.18(m,4H),4.82(br,2H),5.75(t,1H),6.88-7.09(m,6H),7.33(m,2H)
实施例93:氨基甲酸3-{4-[二-(4-氟-苯基)-甲基]-哌嗪-1-基}-1-苯基-丙酯
将3-氯苯丙酮(4毫摩尔)和4,4′-二氟苯基哌嗪(5.2毫摩尔)溶解于乙腈(50毫升)中,向其中滴加三乙胺(5.2毫摩尔),于80℃搅拌形成的混合物24小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次。产生的有机相用硫酸镁干燥,过滤,在减压条件下浓缩形成的滤液,通过柱色谱进行分离和纯化(己烷∶乙酸乙酯=1∶1)。将产生的化合物(3.5毫摩尔)溶解于甲醇(20毫升),冷却至0℃,向该混合物中缓慢加入硼氢化钠(5毫摩尔)。室温下搅拌形成的混合物2小时,在减压下浓缩,获得黄色颗粒。然后,将制得的黄色颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得粗化合物。
将制得的粗化合物(2毫摩尔)溶解于四氢呋喃(10毫升)中,向其中加入1,1′-碳二咪唑(carbodiimidazole)(4毫摩尔),室温下搅拌形成的混合物1小时。然后,向化合物中加入过量的氢氧化铵,室温下搅拌形成的混合物1小时。反应混合物用水稀释,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,丙酮)d:2.34(m,10H),2.84(m,2H),4.35(s,1H),5.7(t,1H),5.99(br,2H),7.07(m,4H),7.31(m,5H),7.50(m,4H)
实施例94:氨基甲酸1-苯基-4-(4-苯基-哌嗪-1-基)-丁酯
按照于实施例93相同的方式制备标题化合物,除了使用4-溴苯丁酮和苯基哌嗪作为起始原料。
1H NMR(500MHz,DMSO)d 1.82(m,2H),2.78(m,3H),3.08(m,4H),3.21(m,4H),3.52(m,2H),5.51(br,2H),5.78(t,1H),7.01(m,5H),7.23(m,5H)
实施例95:氨基甲酸4-[4-(2-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照于实施例93相同的方式制备标题化合物,除了使用4-溴苯丁酮和2-甲氧基苯基哌嗪作为起始原料。
1H NMR(500MHz,DMSO)d 1.88(m,4H),3.10-3.30(m,6H),3.52(m,4H),3.80(s,3H),5.42(br,2H),5.51(t,1H),6.91(m,1H),7.01(m,2H),7.09(m,1H),7.33(m,5H)
实施例96:氨基甲酸1-苯基-4-(4-吡啶-2-基-哌嗪-1-基)-丁酯
按照于实施例93相同的方式制备标题化合物,除了使用4-溴苯丁酮和2-吡啶基哌嗪作为起始原料。
1H NMR(500MHz,DMSO)d 3.12(m,6H),3.44(m,4H),3.64(m,4H),4.52(m,4H),5.55(t,1H),6.51-6.91(br,2H),7.01(m,2H),7.30-7.40(m,5H),8.01((m,2H)
实施例97:氨基甲酸4-[4-(3-氯-吡啶-2-基)-哌嗪-1-基]-1-苯基-丁酯
按照于实施例93相同的方式制备标题化合物,除了使用4-溴苯丁酮和1-(3-氯-吡啶-2-基)-哌嗪作为起始原料。
1H NMR(500MHz,DMSO)d:1.78(m,5H),3.80(m,3H),3.52(m,3H),3.41(m,3H),5.02(br,2H),5.50(t,1H),7.10(m,1H),7.41(m,5H),7.91(m,1H),8.31((m,1H)
实施例98:氨基甲酸3-(4-苯并[1,3]间二氧杂环戊烯-5-基甲基-哌嗪-1-基)-1-苯基-丙酯
按照于实施例93相同的方式制备标题化合物,除了使用3-氯苯丙酮和3,4-亚甲基二氧苄基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:1.99(m,2H),2.35(m,10H),3.40(d,2H),5.78(t,1H),5.97(br,4H),6.78(d,2H),6.87(s,1H),7.36(m,5H)
实施例99:氨基甲酸3-(4-苯甲酰基-哌嗪-1-基)-1-苯基-丙酯
按照于实施例93相同的方式制备标题化合物,除了使用3-氯苯丙酮和苯甲酰哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.9-2.3(m,8H),3.2-3.8(br,4H),4.95(br,2H),5.82(t,1H),7.32-7.39(m,10H)
实施例100:氨基甲酸3-(4-苄基-哌嗪-1-基)-1-苯基-丙酯
按照于实施例93相同的方式制备标题化合物,除了使用3-氯苯丙酮和苄基哌嗪作为起始原料。
1H NMR(200MHz,丙酮)d:2.07(m,2H),2.41(m,10H),3.53(s,2H),4.90(br,2H),5.70(t,1H),7.31(m,10H)
实施例101:氨基甲酸(R)-3-[4-(4-甲氧基-苯基)-2,6-二甲基-哌嗪-1-基]-1-苯基-丙酯
将(R)-3-氯-1-苯基-1-丙醇(10毫摩尔)溶解于乙腈(100毫升),向形成的混合物中加入2,6-二甲基-4-甲氧基苯基哌嗪(12毫摩尔)和三乙胺(12毫摩尔)。于80℃搅拌制得的混合物24小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次。用氯化钠水溶液洗涤萃取的有机相,用硫酸镁干燥,然后减压下浓缩,获得颗粒物。将制得的颗粒(8.2毫摩尔)溶解于四氢呋喃(50毫升),向其中加入1,1′-羰基二咪唑(16.5毫摩尔),室温下搅拌形成的混合物1小时。向混合物中加入过量的氢氧化铵,搅拌形成的混合物2小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次,获得有机相。然后,制得的有机相用硫酸镁干燥,在减压下浓缩.形成的黄色颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得标题化合物。
1H NMR(200MHz,CDCl3)d:1.05(dd,6H),1.99(m,2H),2.45(m,2H),2.78(m,4H),3.27(m,2H),3.78(s,3H),4.71(br,2H),5.66(t,1H),6.85(m,4H),7.3(m,5H)
实施例102:(R)-氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例101相同的方式制备标题化合物,除了使用(R)-3-氯-1-苯基-1-丙醇和4-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.12(m,1H),2.27(m,1H),2.42(m,2H),2.65(m,4H),3.13(m,4H),3.79(s,3H),4.87(br,2H),5.79(t,1H),6.89(m,4H),7.33(m,5H)
实施例103:(R)-氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]1-苯基-丙酯
按照与实施例101相同的方式制备标题化合物,除了使用(R)-3-氯-1-苯基-1-丙醇和4-氯苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.98(m,1H),2.21(m,1H),2.43(m,2H),2.60(m,4H),3.18(m,4H),4.67(br,2H),5.76(t,1H),6.85(m,2H),7.24(m,2H),7.37(m,5H)
实施例104:(R)-氨基甲酸3-[4-(4-氟-苯基)-哌嗪-1-基]1-苯基-丙酯
按照与实施例101相同的方式制备标题化合物,除了使用(R)-3-氯-1-苯基-1-丙醇和4-氟苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.11(m,1H),2.21(m,1H),2.29(m,2H),2.61(m,4H),3.14(m,4H),4.83(br,2H),5.75(t,1H),6.93(m,4H),7.33(m,5H)
实施例105:(R)-氨基甲酸3-[4-(4-羟基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例101相同的方式制备标题化合物,除了使用(R)-3-氯-1-苯基-1-丙醇和4-羟基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.99(m,2H),2.14(m,2H),2.58(m,4H),3.12(m,4H),5.12(br,2H),5.78(t,1H),6.99(m,4H),7.21(m,5H)
实施例106:(S)-氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯
按照与实施例101相同的方式制备标题化合物,除了使用(S)-3-氯-1-苯基-1-丙醇和4-甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:2.12(m,1H),2.27(m,1H),2.42(m,2H),2.65(m,4H),3.13(m,4H),3.79(s,3H),4.87(br,2H),5.79(t,1H),6.89(m,4H),7.33(m,5H)
实施例107:4-{2-[4-(4-甲氧基-苯基)-哌嗪-1-基]-乙基}-1,4-二氢-苯并[d][1,3]噁嗪-2-酮
将2′-硝基苯乙酮(4.67毫摩尔)和4-甲氧基苯基哌嗪(5.61毫摩尔)溶解于乙醇(30毫升),通过滴加浓盐酸将形成的混合物的pH调节至2-3。向该混合物中加入多聚甲醛(37.36毫摩尔),形成的混合物回流24小时。在减压下蒸馏产生的反应混合物,用1标准氯化钠水溶液中和,用水稀释,然后用乙酸乙酯萃取几次。产生的有机相用硫酸镁干燥,过滤,在减压条件下浓缩形成滤液,通过柱色谱进行分离和纯化(己烷∶乙酸乙酯=1∶1),获得粗化合物。将分离的粗化合物(3.65毫摩尔)溶解于甲醇(30毫升),冷却至0℃,在该混合物中缓慢加入硼氢化钠(NaBH4,7毫摩尔)。室温下搅拌形成的混合物2小时,在减压下浓缩。然后,产生的橙色颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1)。将纯化后的化合物(3.1毫摩尔)溶解于甲醇,在铂催化剂存在下进行加氢反应,获得具有还原的硝基的氨基化合物。将制得的化合物(1.21毫摩尔)溶解于四氢呋喃(20毫升)中,加入三乙胺(3毫摩尔),在该混合物中缓慢加入光气(2.4M甲苯溶液,1.21毫摩尔)。在这种情况,小心控制反应产物的温度,保持在不大于10℃的范围。室温下搅拌反应产物16小时,用氢氧化铵稀释,然后用乙酸乙酯萃取几次。产生的有机相用硫酸镁干燥,过滤,在减压条件下浓缩形成滤液,用乙酸乙酯重结晶,制得最终化合物。
1H NMR(200MHz,CDCl3)d:2.07(m,4H),2.61(m,4H),3.12(m,4H),3.78(s,3H),5.58(t,1H),6.85(m,5H),7.16(m,1H),7.22(m,3H),9.14(s,1H)
实施例108:氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯
将苯基-1-丙烯基-酮(4.1毫摩尔)和4-甲氧基苯基哌嗪(4.9毫摩尔)溶解于乙醇(30毫升),于72℃搅拌形成的混合物48小时。减压下蒸馏该混合物,用水稀释,然后用乙酸乙酯萃取。产生的有机相在减压下蒸馏,用硫酸镁干燥,过滤,在减压条件下浓缩形成滤液,用柱色谱纯化(己烷∶乙酸乙酯=4∶1),获得粗化合物。将制得的粗化合物(2.9毫摩尔)溶解于甲醇(20毫升),向该混合物中缓慢加入NaBH4(3.8毫摩尔)。室温下搅拌形成的混合物2小时,在减压下浓缩,获得黄色颗粒。制得的黄色颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1)。将纯化后的化合物(2毫摩尔)溶解于四氢呋喃(15毫升),向其中加入1,1′-碳二咪唑(4毫摩尔)。室温下搅拌形成的混合物1小时,向混合物中加入过量的氢氧化铵,室温下再搅拌形成的混合物2小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,在减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶1),获得最终化合物。
1H NMR(200MHz,CDCl3)d 1.81(m,1H),2.32(m,1H),2.5(m,3H),2.8(m,2H),3.14(m,4H),3.80(s,3H),4.80(br,2H),6.02(t,1H),6.92(m,4H),7.36(m,5H)
实施例109:氨基甲酸3-[4-(4-氯-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和4-氯苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.82(m,2H),2.31(m,1H),2.74-2.55(m,8H),3.18(m,3H),4.69(br,2H),5.90(t,1H),6.87(m,2H),7.22(m,2H),7.32(m,5H)
实施例110:氨基甲酸3-[4-(4-硝基苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和4-硝基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.81(m,2H),1.91(m,1H),2.20-2.90(m,8H),3.45(m,3H),4.75(br,2H),5.92(t,1H),6.84(m,2H),7.35(m,5H),8.13(m,2H)
实施例111:氨基甲酸3-[4-(3,4-二甲基-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和3,4-二甲基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.72(m,2H),2.20(s,3H),2.52(s,3H),2.52(m,4H),2.80(m,3H),3.17(m,5H),5.01(br,2H),5.82(t,1H),6.90(m,2H),7.05(m,1H),7.37(m,5H)
实施例112:氨基甲酸3-[4-(4-喹喔啉-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和2-哌嗪-1-基-喹喔啉作为起始原料。
1H NMR(200MHz,CDCl3)d:1.71(m,2H),2.21(m,2H),2.48-2.78(m,7H),3.83(m,3H),4.69(br,2H),5.87(t,1H),7.38(m,5H),7.61(m,3H),7.86(m,1H),8.59(d,1H)
实施例113:氨基甲酸3-[4-(3,4-二甲氧基-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和3,4-二甲氧基苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.32(m,1H),2.21(m,1H),2.42(m,4H),2.72(m,4H),3.10(m,5H),3.80(s,3H),3.83(s,3H),5.01(br,2H),5.89(t,1H),6.42(d,1H),6.80(d,1H),6.89(d,1H),7.33(m,5H)
实施例114:氨基甲酸3-[4-(3,5-二氯-吡啶-2-基-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和3,5-二氯吡啶基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.68(m,1H)2.21(m,2H),2.54(m,4H),2.71(m,2H),3.36(m,5H),5.01(br,2H),5.91(t,1H),7.2-7.4(m,5H),7.60(m,1H),8.10(m,1H)
实施例115:氨基甲酸3-[4-(3,4-二氯-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和3,4-二氯苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.62(m,2H),1.96(m,2H),2.20-2.60(m,5H),2.75(m,2H),3.16(m,3H),4.96(br,2H),5.91(t,1H),6.77(m,1H),7.00(m,1H),7.36(m,6H)
实施例116:氨基甲酸3-[4-(2,4-二氟-苯基)-哌嗪-1-基]-1-苯基-丁酯
按照与实施例104相同的方式制备标题化合物,除了使用苯基-1-丙烯基-酮和2,4-二氟苯基哌嗪作为起始原料。
1H NMR(200MHz,CDCl3)d:1.86(m,2H),2.12(m,2H),2.52(m,4H),2.75(m,3H),3.06(m,3H),4.98(br,2H),5.81(t,1H),6.79(m,3H),7.36(m,5H)
实施例117:氨基甲酸2-氟-1-苯基-3-(4-苯基-哌嗪-1-基)-丙酯
将3-氯苯丙酮(14.77毫摩尔)和苯基哌嗪(17.7毫摩尔)溶解于乙腈(50毫升),向其中加入三乙胺(17.7毫摩尔),于80℃搅拌形成的混合物24小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次。收集萃取的有机相,用水和饱和氯化钠水溶液洗涤,用硫酸镁干燥,然后减压下浓缩,获得颗粒物。将制得的颗粒(1.75毫摩尔)溶解于四氢呋喃(20毫升),滴加1.5摩尔环己烷锂二酰亚胺(1.92毫摩尔)溶液,同时保持形成的混合物的温度为-78℃。然后,于-78℃搅拌形成的混合物10分钟,然后于0℃搅拌30分钟。再次冷却形成的混合物并且保持温度为-78℃,向该混合物中加入N-氟苯磺酰亚胺(2.27毫摩尔),室温下搅拌形成的混合物2小时。通过加入饱和氯化铵溶液来稀释产生的反应混合物,稀释后的反应混合物用乙酸乙酯萃取几次。产生的有机相用硫酸镁干燥,在减压下浓缩。在这种情况下,制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶4),获得粗化合物。将制得的粗化合物(1.5毫摩尔)溶解于甲醇(20毫升),向混合物中缓慢加入NaBH4(3.0毫摩尔)。室温搅拌形成的混合物1小时,在减压下浓缩以除去溶剂。然后制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶2),获得粗化合物。将制得的粗化合物(1毫摩尔)溶解于四氢呋喃(20毫升),向其中加入1,1′-碳二咪唑(2毫摩尔),室温下搅拌形成的混合物2小时。然后,向混合物中加入过量的氢氧化铵,室温下再搅拌形成的混合物2小时。用水稀释产生的反应混合物,用乙酸乙酯萃取几次,获得有机相。制得的有机相用硫酸镁干燥,然后减压下浓缩。制得的颗粒通过柱色谱纯化(己烷∶乙酸乙酯=1∶4),获得最终化合物。
1H NMR(200MHz,CDCl3)d:2.59(m,6H),3.19(m,4H),4.92(m,1H,J=48Hz),5.52(br,2H),5.92(m,1H,J=I 8Hz),6.90(m,3H),7.34(m,7H)
采用以下动物模型测试上面列举的化合物的镇痛作用。
2.对小鼠的乙酸诱发的扭体试验
乙酸诱发的扭体试验是测量药物镇痛作用的模型之一。将溶解于适当载剂中的测试物质以10毫克/千克的剂量,通过口服给予体重为30-35克的雄性ICR小鼠。口服给药1小时后,将10毫克/毫升的0.8%乙酸水溶液通过腹膜内注射到雄性ICR小鼠内,以诱发雄性ICR小鼠腹痛。在给予乙酸后立刻将雄性ICR小鼠投入空的笼中,统计小鼠在10分钟内的扭体次数。术语“扭体”表示小鼠因为腹痛而通过伸展其后腿来展开其腹部的反射动作。测试物质的镇痛作用由疼痛响应的抑制比{[(给予载剂组的扭体次数-给予测试物质组的扭体次数)/(给予载剂组的扭体次数)]×100%}表示,或者测试物质的50%有效量(ED50(中值有效剂量);抑制50%疼痛行为所需的测试物质量)表示。ED50(中值有效剂量)可采用计算至少三种剂量的测试物质对疼痛的抑制比并进行线性回归来确定。由这些结果观察到,镇痛作用越高显示的疼痛响应抑制比(%)越高,而ED50值越小。
3.小鼠的晚期甲醛溶液测试
甲醛溶液试验是测量药物镇痛作用的另一种模型。当将甲醛溶液通过皮下给予小鼠后肢的足底面时,小鼠显示特有的疼痛行为,例如立刻举起和放下,退缩和舔小鼠的左足。这些疼痛行为具有双阶段模式,因此可将这些行为划分为在给予甲醛溶液后10秒内的早期行为;以及在最多10-60分钟的晚期行为。在甲醛溶液测试晚期观察到的药用作用表明测试物质在炎性疼痛模型中的镇痛作用,并也成为一种预测神经性疼痛模型中的药用作用的测量方式(Vissers K等,2003)。将测试物质口服给予体重30-35克的雄性ICR小鼠。口服给药1小时后,将20微升2.5%甲醛溶液通过皮下给予小鼠后肢的足底面以诱发疼痛。给予甲醛溶液20分钟后,在15分钟内记录小鼠显示疼痛行为(退缩,舔足等)的时间并量化。测试物质的镇痛作用由疼痛响应的抑制比{[(给予载剂组的疼痛响应时间-给予测试物质组的疼痛响应时间)/(给予载剂组的疼痛响应时间)]×100%}表示,或者测试物质的50%有效量(ED50;抑制50%疼痛行为所需的测试物质量)表示。ED50(中值有效剂量)可采用计算至少三种剂量的测试物质对疼痛响应的抑制比并进行线性回归来确定。由这些结果观察到镇痛作用越高显示的疼痛响应抑制比(%)越高,而ED50值越小。
[表1]
对小鼠的乙酸-诱发的扭体测试和晚期甲醛溶液测试的结果
已知5-羟色胺(5-HT)受体的作用与各种精神病学病症,例如抑郁、焦虑、精神分裂症、恐怖症、强迫症、偏头痛、急性焦虑症等的诱发密切相关。5-羟色胺受体分为亚型,包括5-HT1,5-HT2,5HT3,5-HT4,5-HT6,5-HT7等。具体地,5-HT1受体可分为以下亚型:5-HT1A,5-HT1B,5-HT1E,5-HT1F等。由临床前电生理学试验发现,突触后神经元的5-HT1A受体与抗抑郁作用相关。还发现,刺激突触后5-HT1A受体可增加焦虑,而激活突触前5-HT1A受体则可降低焦虑。正常人体中,5-HT2A受体从青春期至中年急剧下降,而在中年之后缓慢下降。患有抑郁的老年患者中的5-HT2A受体水平比正常人低得多,因此,发现在大脑广泛区域内5-羟色胺的缺乏是老年人中抑郁症的原因之一。通过使上述化合物与5-HT1A受体和5-HT2A受体结合测试这些化合物对抑郁症的药学作用。
与5-HT1A受体结合
将10只6周龄的Sprague-Dawley(SD)大鼠在醚容器中麻醉5分钟,分离大鼠的大脑,然后从大鼠大脑分离皮质区。将大鼠皮质区置于Tris-HCl缓冲溶液(50mM,pH7.4)中匀浆化,于4℃以50,000g转速将该匀浆离心两次,获得沉淀物(膜蛋白)。将该沉淀物放入缓冲溶液中,匀浆化,稍后用作蛋白质源。使用2nM[3H]-8-OH-DPAT作为放射性同位素,并使用10uM 5-羟色胺除去非特异结合。将25微升化合物、100微升放射性同位素水溶液和100微升蛋白质源放在一起并在25℃保持1小时。当96孔板反应完成时,在96孔收集器中用膜滤器过滤形成的混合物。化合物与[3H]-8-OH-DPAT的竞争性通过取下膜滤器并在闪烁计数器中测量该膜滤器的放射性进行确定,IC50值可通过测量浓度增加的化合物进行确定。该化合物的特异性反应大于或等于90%。按照Middlemiss等的方法(1984,Eur.J.Pharmacol.)进行常规试验。
与5-HT2A受体的结合
将10只6周龄的Sprague-Dawley(SD)大鼠在醚容器中麻醉5分钟,分离大鼠大脑,然后从大鼠大脑分离皮质区。将大鼠皮质区放入Tris-HCl缓冲溶液(50mM,pH7.7)中匀浆化,于4℃以50,000g转速将该匀浆离心两次,获得沉淀物(膜蛋白)。将该沉淀物放入缓冲溶液中,匀浆化,稍后用作蛋白质源。使用0.5nM[3H]-酮色林(Ketanserin)作为放射性同位素,并使用10uM 5-羟色胺去除非特异结合。将25微升化合物、100微升放射性同位素水溶液和100微升蛋白质源放在一起并在25℃保持1小时。当96孔板反应完成时,在96孔收集器中用膜滤器过滤形成的混合物。化合物与[3H]-酮色林的竞争性通过取下膜滤器并在闪烁计数器中测量该膜滤器的放射性进行确定,IC50值可通过测量浓度增加的化合物进行确定。该化合物的特异性反应大于或等于90%。按照Leysen等的方法(1982,Eur.J.Pharmacol)进行常规试验。
表2
5-HT1A和5-HT2A受体结合的测试结果
为治疗各种疾病例如各种疼痛(包括急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性神经痛、疱疹后神经痛、炎性疼痛、关节痛、偏头痛等,焦虑和抑郁)、焦虑和抑郁,将本发明的化合物单独或者与药学上可用的载体组合给予患者。给予的化合物的精确剂量可以根据患者的症状、患者状况的严重性和化合物的活性来确定。在特定情况下,给予的化合物的最佳剂量基本上应按照临床方式确定,但应在本发明的范围之内。
对本发明化合物的应用,所述化合物优选通过口服给药,因为化合物易于口服吸收,但是本发明并不具体限于这种方式。对于口服给药,通式1表示的化合物优选与药学上的载体组合使用。限制载体与本发明化合物的剂量比以使化合物对患者有效,并且可以根据组合物是填充在胶囊中还是配制成片剂进行变化。在片剂的情况,可以使用可食用的药学载体或它们的混合物。合适载体的例子包括但不限于:乳糖、磷酸氢钙和/或玉米淀粉,以及它们的混合物等。还可以加入其他药学上可用的化合物,包括润滑剂例如硬脂酸镁。
Claims (13)
1.一种由以下通式1表示的外消旋或对映异构特性富集的氨基甲酰氧基芳基链烷芳基哌嗪衍生物化合物,及其药学上可利用的盐或水合物:
通式1
式中:---可以选择性地成环;
R1和R2是氢,或者R1或R2可与X1一起形成双环;
X1可以是能被选自下组的至少一个相同或不同的取代基取代的苯基:氢、有1-6个碳原子的直链或支链烷基、卤素如F、Cl和Br、有1-6个碳原子的直链或支链烷氧基、硝基、二甲基氨基和三氟甲基;以及包括萘基和亚甲基二氧苯基的双环系统;
Z是氢或氟,或者与X1一起形成双环;
Ar选自下组:可被选自下组的至少一个相同或不同的取代基取代的苯基、吡啶和嘧啶:氢、有1-6个碳原子的直链或支链烷基、羟基、卤素、有1-6个碳原子的直链或支链烷氧基、硝基、乙酰基、叔丁基乙酰基、三氟甲基、三氟甲氧基、氨基、苄氧基、3,4-亚甲基二氧、3,4-亚乙基二氧、新戊酰氧基、碳酸乙酯、碳酸苯酯、碳酸苄基酯、乙酸酯和环戊氧基;以及萘基、二氢苯并二氧杂环己烯基、亚甲基二氧苯基、二(氟苯基)甲基和喹喔啉;
Y1和Y2各自独立地是氢或甲基(CH3);
Y3是氢、苯基或羰基(=O);
Y4是氢或甲基(CH3);
n是1或2的整数;和
m是0或1的整数。
2.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸1-(4-氯-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯。
3.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸1-(4-氟-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯。
4.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸1-(4-硝基-苯基)-3-(4-苯基-哌嗪-1-基)-丙酯。
5.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸1-苯基-3-[4-(4-硝基-苯基)-哌嗪-1-基]-丙酯。
6.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯。
7.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括氨基甲酸3-[4-(4-氟-苯基)-哌嗪-1-基]-1-苯基-丙酯。
8.如权利要求1的化合物及其药学上可用的盐或水合物,其特征在于,所述化合物包括(R)-氨基甲酸3-[4-(4-甲氧基-苯基)-哌嗪-1-基]-1-苯基-丙酯。
9.一种用于治疗焦虑或抑郁的药物组合物,该组合物包含有效量的如权利要求1-8中任一项所述的外消旋或对映异构特性富集的化合物。
10.一种用于治疗疼痛的药物组合物,该组合物包含有效量的如权利要求1-8中任一项所述的外消旋或对映异构特性富集的化合物。
11.如权利要求10所述的药物组合物,其特征在于,所述疼痛选自下组:急性痛、慢性痛、神经性痛、术后神经性痛、糖尿病性疼痛、疱疹后神经痛、炎性疼痛、关节痛和偏头痛。
12.一种治疗哺乳动物的疼痛、焦虑或抑郁的方法,该方法包括给予需要这种治疗的哺乳动物有效量的如权利要求1-8中任一项所述的外消旋或对映异构特性富集的化合物。
13.如权利要求12所述的方法,其特征在于,以包含20-500毫克总的活性组分的单位剂量,并以每天10-7000毫克的日剂量给予有效量的所述化合物。
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KR101810975B1 (ko) * | 2010-07-08 | 2017-12-20 | 에스케이바이오팜 주식회사 | 카바모일옥시 아릴알칸노일 아릴피페라진계 화합물을 포함하는 약학적 조성물 |
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