技术领域Technical field
本发明属于药物化学及药物治疗学技术领域，具体涉及一种苯基哌嗪衍生物或其药物学上的盐、制备方法及其在制备治疗疼痛药物中的应用。The invention belongs to the technical fields of medicinal chemistry and drug therapy, and specifically relates to a phenylpiperazine derivative or its pharmacological salt, a preparation method and its application in preparing pain treatment drugs.
背景技术Background technique
疼痛是临床常见症状，每年大约有5亿人遭受着各种各样疼痛的困扰。目前，临床上应用最多的镇痛药主要分为两类：直接激活阿片受体的麻醉性镇痛药和以非甾体抗炎药(NSAIDs)为代表的解热镇痛药。这些药物虽然临床效果较好，但是也有明显的副作用，如阿片类药物的成瘾性，非甾体抗炎药的胃肠副反应等。此外，慢性及神经性疼痛使用现有药物也无法得到有效控制。Pain is a common clinical symptom, and approximately 500 million people suffer from various types of pain every year. Currently, the most commonly used analgesics in clinical practice are mainly divided into two categories: narcotic analgesics that directly activate opioid receptors and antipyretic analgesics represented by nonsteroidal anti-inflammatory drugs (NSAIDs). Although these drugs have good clinical effects, they also have obvious side effects, such as the addiction of opioids and the gastrointestinal side effects of nonsteroidal anti-inflammatory drugs. In addition, chronic and neuropathic pain cannot be effectively controlled using existing medications.
近年来，随着相关学科的发展及新技术的应用，对各种与疼痛传导相关的受体及其选择性配体的研究取得了一定进展。TRPV1在初级感觉神经元高度表达，是一种非特异性阳离子通道，能被氢离子(pH<5.5)、高温(>42℃)以及其他内源性和外源性配体等激活，在机体对温度和疼痛的感知中发挥重要作用。TRPV1激活后，引起钙离子内流，导致神经末梢释放P物质和降钙素基因相关肽等，从而引发疼痛。下调TRPV1表达或使用TRPV1拮抗剂可以有效阻止TRPV1激活，抑制疼痛信号从外周神经到中枢神经的传导，缓解多种神经损伤带来的疼痛。TRPV1拮抗剂的研究已经成为目前最有前景的镇痛药研究方向之一。部分TRPV1拮抗剂具有体温升高的副作用，限制了该类药物的临床进展。开发无体温升高副作用的新型TRPV1拮抗剂是本领域的研究热点。基于此，研发了本申请。In recent years, with the development of related disciplines and the application of new technologies, certain progress has been made in the research on various receptors related to pain transmission and their selective ligands. TRPV1 is highly expressed in primary sensory neurons. It is a non-specific cation channel that can be activated by hydrogen ions (pH<5.5), high temperature (>42℃) and other endogenous and exogenous ligands. Play an important role in the perception of temperature and pain. After TRPV1 is activated, it causes the influx of calcium ions, causing nerve terminals to release substance P and calcitonin gene-related peptide, etc., thus causing pain. Down-regulating TRPV1 expression or using TRPV1 antagonists can effectively prevent TRPV1 activation, inhibit the conduction of pain signals from peripheral nerves to the central nervous system, and relieve pain caused by various nerve injuries. Research on TRPV1 antagonists has become one of the most promising analgesic research directions. Some TRPV1 antagonists have the side effect of increasing body temperature, which limits the clinical progress of this class of drugs. The development of new TRPV1 antagonists without side effects of increasing body temperature is a research hotspot in this field. Based on this, this application was developed.
发明内容Contents of the invention
本发明目的在于克服现有技术存在的缺陷和不足，提供一种苯基哌嗪衍生物或其药物学上的盐。该苯基哌嗪化合物或其药物学上的盐，能抑制hTRPV1受体从而产生治疗疼痛的效果。The object of the present invention is to overcome the defects and shortcomings of the prior art and provide a phenylpiperazine derivative or a pharmaceutical salt thereof. The phenylpiperazine compound or its pharmaceutical salt can inhibit the hTRPV1 receptor to produce a pain treatment effect.
本发明还提供了上述苯基哌嗪衍生物或其药物学上的盐的制备方法及其在制备治疗疼痛药物中的应用。The present invention also provides a preparation method of the above-mentioned phenylpiperazine derivative or a pharmaceutical salt thereof and its application in preparing drugs for treating pain.
为实现上述目的，本发明采用如下技术方案：In order to achieve the above objects, the present invention adopts the following technical solutions:
一种苯基哌嗪衍生物或其药物学上的盐，其将所述苯基哌嗪衍生物定义为化合物I，化合物I的结构如下所示：A phenylpiperazine derivative or a pharmaceutical salt thereof, which defines the phenylpiperazine derivative as compound I. The structure of compound I is as follows:
其中，环A为环己基、芳基或杂芳基；Wherein, Ring A is cyclohexyl, aryl or heteroaryl;
R1为氢、卤素、烷基、腈基、炔基、烷氧基或环烷氧基；R1 is hydrogen, halogen, alkyl, nitrile, alkynyl, alkoxy or cycloalkoxy;
R2为氢、卤素、烷基、腈基、硝基、烷氧基或环烷氧基；R2 is hydrogen, halogen, alkyl, nitrile, nitro, alkoxy or cycloalkoxy;
R3为氢、卤素、烷基、腈基、硝基、烷氧基或环烷氧基；R3 is hydrogen, halogen, alkyl, nitrile, nitro, alkoxy or cycloalkoxy;
X为CONH、或CONHSO2。X is CONH or CONHSO2 .
具体的，可以是，所述R1中烷基的至少一个氢被卤素取代，烷氧基的至少一个氢被卤素取代，环烷氧基的至少一个氢被卤素取代；Specifically, it can be that at least one hydrogen of the alkyl group in R1 is substituted by a halogen, at least one hydrogen of the alkoxy group is substituted by a halogen, and at least one hydrogen of the cycloalkoxy group is substituted by a halogen;
所述R2中烷基的至少一个氢被卤素取代，烷氧基的至少一个氢被卤素取代，环烷氧基的至少一个氢被卤素取代；In R2 , at least one hydrogen of the alkyl group is substituted by halogen, at least one hydrogen of the alkoxy group is substituted by halogen, and at least one hydrogen of the cycloalkoxy group is substituted by halogen;
所述R3中烷基的至少一个氢被卤素取代，烷氧基的至少一个氢被卤素取代，环烷氧基的至少一个氢被卤素取代。In R3 , at least one hydrogen of the alkyl group is substituted by halogen, at least one hydrogen of the alkoxy group is substituted by halogen, and at least one hydrogen of the cycloalkoxy group is substituted by halogen.
进一步的，所述环A为环己基、苯环或吡啶环；Further, the ring A is a cyclohexyl ring, a benzene ring or a pyridine ring;
所述R1为氢、甲基、三氟甲基、乙炔基、叔丁基、腈基、甲氧基、氟、或氯；The R1 is hydrogen, methyl, trifluoromethyl, ethynyl, tert-butyl, nitrile, methoxy, fluorine, or chlorine;
所述R2为氢、甲基、三氟甲基、硝基、氟、或氯；The R2 is hydrogen, methyl, trifluoromethyl, nitro, fluorine, or chlorine;
所述R3为氢、甲基、三氟甲基、硝基、氟、或氯。The R3 is hydrogen, methyl, trifluoromethyl, nitro, fluorine, or chlorine.
进一步优选的，所述苯基哌嗪衍生物或其药物学上的盐可以为下述任意一种化合物：Further preferably, the phenylpiperazine derivative or its pharmaceutical salt can be any one of the following compounds:
N-环己基-4-苯基哌嗪-1-甲酰胺(I-1)；N-cyclohexyl-4-phenylpiperazine-1-carboxamide (I-1);
4-苯基-N-(对甲苯基)哌嗪-1-甲酰胺(I-2)；4-phenyl-N-(p-tolyl)piperazine-1-carboxamide (I-2);
4-苯基-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-3)；4-phenyl-N-(phenylsulfonyl)piperazine-1-carboxamide (I-3);
N-(4-(叔丁基)苯基)-4苯基哌嗪-1-甲酰胺(I-4)；N-(4-(tert-butyl)phenyl)-4phenylpiperazine-1-carboxamide (I-4);
N-(4-甲氧基吡啶-2-基)-4-苯基哌嗪-1-甲酰胺(I-5)；N-(4-methoxypyridin-2-yl)-4-phenylpiperazine-1-carboxamide (I-5);
N-(3-乙炔基苯基)-4-苯基哌嗪-1-甲酰胺(I-6)；N-(3-ethynylphenyl)-4-phenylpiperazine-1-carboxamide (I-6);
4-苯基-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-7)；4-phenyl-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-7);
N-(4-氯苯基)-4苯基哌嗪-1-甲酰胺(I-8)；N-(4-chlorophenyl)-4phenylpiperazine-1-carboxamide (I-8);
4-(4-氯苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-9)；4-(4-chlorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-9);
N-(苯基磺酰基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-10)；N-(phenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-10);
4-(4-氯苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-11)；4-(4-chlorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-11);
4-(4-氯苯基)-N-环己基哌嗪-1-羧酰胺(I-12)；4-(4-chlorophenyl)-N-cyclohexylpiperazine-1-carboxamide (I-12);
N-环己基-4-(4-硝基苯基)哌嗪-1-甲酰胺(I-13)；N-cyclohexyl-4-(4-nitrophenyl)piperazine-1-carboxamide (I-13);
4-(4-硝基苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-14)；4-(4-nitrophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-14);
4-(4-硝基苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-15)；4-(4-nitrophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-15);
4-(4-硝基苯基)-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-16)；4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-16);
N-(3-乙炔基苯基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-17)；N-(3-ethynylphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-17);
4-(2-氟苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-18)；4-(2-fluorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-18);
N-环己基-4-(2-氟苯基)哌嗪-1-甲酰胺(I-19)；N-cyclohexyl-4-(2-fluorophenyl)piperazine-1-carboxamide (I-19);
4-(2-氟苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-20)；4-(2-fluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-20);
4-(2,4-二氟苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-21)；4-(2,4-difluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-21);
N-环己基-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-22)；N-cyclohexyl-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-22);
N-(对甲苯基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-23)。N-(p-tolyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-23).
本发明公开了一种上述苯基哌嗪衍生物或药物学上的盐在制备镇痛药物或治疗疼痛药物中的应用。The invention discloses the use of the above-mentioned phenylpiperazine derivative or pharmaceutical salt in the preparation of analgesic drugs or drugs for treating pain.
具体的，上述的应用，其通过抑制hTRPV1受体，从而产生治疗镇痛或疼痛效果。所述的疼痛指糖尿病神经性疼痛、牙痛、骨关节炎疼痛或者疱疹后疼痛等。Specifically, the above-mentioned application produces therapeutic analgesic or pain effects by inhibiting hTRPV1 receptors. The pain refers to diabetic neuropathic pain, toothache, osteoarthritis pain or post-herpetic pain, etc.
本发明还公开了一种药物组合物，其含有治疗有效量的所述苯基哌嗪衍生物或其药物学上的盐，以及药学上可接受的载体、稀释剂或赋形剂等。载体、稀释剂或赋形剂等采用本领域常规技术即可。The present invention also discloses a pharmaceutical composition, which contains a therapeutically effective amount of the phenylpiperazine derivative or a pharmaceutical salt thereof, as well as a pharmaceutically acceptable carrier, diluent or excipient. The carrier, diluent or excipient can be prepared using conventional techniques in the art.
本发明还公开了上述药物组合物在制备镇痛药物或治疗疼痛药物中的应用。The invention also discloses the use of the above pharmaceutical composition in preparing analgesic drugs or drugs for treating pain.
除非另有说明，否则下列用在说明书和权利要求书中的术语具有下述含义。Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
“烷基”指饱和的脂肪族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，较优选含有1至6个碳原子的烷基，更优选含有1至3个碳原子的烷基，最优选为甲基。非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的基团所取代。"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 10 carbon atoms are preferred, alkyl groups containing 1 to 6 carbon atoms are more preferred, alkyl groups containing 1 to 3 carbon atoms are more preferred, and methyl is most preferred. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and Various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxyl, cyano , nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl groups substituted.
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably the cycloalkyl ring contains 3 to 10 carbon atoms. carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl, cyclooctyl, etc.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
“取代”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本发明所述化合物或其可药用的盐，或其前药与其他化学组分的混合物，其他化学组分例如可药用的载体、稀释剂或赋形剂等。药物组合物的目的是促进生物体对活性成分的吸收，利于活性成分在生物体内发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds of the present invention or pharmaceutically acceptable salts thereof, or prodrugs thereof and other chemical components, such as pharmaceutically acceptable carriers and diluents. Or excipients, etc. The purpose of the pharmaceutical composition is to promote the absorption of active ingredients by the living body and facilitate the active ingredients to exert biological activity in the living body.
和现有技术相比，本发明的有益效果如下：Compared with the prior art, the beneficial effects of the present invention are as follows:
本发明发现了一类新型的苯基哌嗪衍生物，并研究给出了其制备方法，其合成过程简单易操作，原料低廉易得，适合规模化生产。本发明还提供了以该类化合物为活性成分的药物组合物，以及它们在制备镇痛药物或治疗疼痛药物中的应用。试验验证：本发明苯基哌嗪衍生物对TRPV1具有较好的抑制活性，具有较好的镇痛效果，且无体温升高副作用，可用作镇痛药物或治疗疼痛药物。The present invention discovers a new type of phenylpiperazine derivatives, and studies and provides its preparation method. The synthesis process is simple and easy to operate, the raw materials are cheap and easy to obtain, and it is suitable for large-scale production. The present invention also provides pharmaceutical compositions using such compounds as active ingredients, and their use in preparing analgesic drugs or drugs for treating pain. Experimental verification: the phenylpiperazine derivative of the present invention has good inhibitory activity against TRPV1, has good analgesic effect, and has no side effects of increasing body temperature, and can be used as an analgesic drug or a pain treatment drug.
附图说明Description of drawings
图1为部分化合物对小鼠体温的影响。Figure 1 shows the effects of some compounds on the body temperature of mice.
具体实施方式Detailed ways
以下结合实施例对本发明的技术方案作进一步地详细介绍，但本发明的保护范围并不局限于此。The technical solution of the present invention will be described in further detail below with reference to the examples, but the protection scope of the present invention is not limited thereto.
下述实施例中，如无特殊说明，所用原料均为可以直接购买的普通市售产品或者可以采用本领域常规方法制备获得。室温指代25±5℃。In the following examples, unless otherwise specified, the raw materials used are common commercial products that can be purchased directly or can be prepared by conventional methods in the art. Room temperature refers to 25±5℃.
实施例1、N-环己基-4-苯基哌嗪-1-甲酰胺(I-1)Example 1, N-cyclohexyl-4-phenylpiperazine-1-carboxamide (I-1)
环己基异氰酸酯II-2(0.367g,2.94mmol)溶于20ml无水二氯甲烷中，冰浴下缓慢滴加苯基哌嗪II-1(0.5g,3.08mmol)的10ml无水二氯甲烷溶液，冰浴下反应2小时。反应结束后，减压蒸除溶剂，残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化，得0.77g白色固体I-1，产率90.8％。图谱数据如下。Cyclohexyl isocyanate II-2 (0.367g, 2.94mmol) was dissolved in 20ml of anhydrous dichloromethane, and phenylpiperazine II-1 (0.5g, 3.08mmol) in 10ml of anhydrous dichloromethane was slowly added dropwise in an ice bath. solution and reacted in an ice bath for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain 0.77g of white solid I-1 with a yield of 90.8%. The spectral data are as follows.
1H NMR(400MHz,Chloroform-d)δ7.40-7.19(m,2H),6.90(dd,J＝17.9,7.8Hz,3H),4.41(t,J＝7.5Hz,1H),3.67(m,1H),3.51(dd,J＝6.3,4.1Hz,4H),3.27-3.10(m,4H),2.08-1.86(m,2H),1.70(m,2H),1.62(m,1H),1.48-1.28(m,2H),1.13(m,3H).13C NMR(101MHz,Chloroform-d)δ157.02,151.07,129.21,120.24,116.44,49.51,49.15,43.75,34.00,25.70,25.11.ESI-MS m/z:288.4[M+H]+；元素分析计算值：For C17H25N3O:C,71.04；H,8.77；实测值：C,71.07；H,8.74。1 H NMR (400MHz, Chloroform-d) δ7.40-7.19(m,2H),6.90(dd,J＝17.9,7.8Hz,3H),4.41(t,J＝7.5Hz,1H),3.67(m ,1H),3.51(dd,J＝6.3,4.1Hz,4H),3.27-3.10(m,4H),2.08-1.86(m,2H),1.70(m,2H),1.62(m,1H), 1.48-1.28(m,2H),1.13(m,3H).13 C NMR(101MHz,Chloroform-d)δ157.02,151.07,129.21,120.24,116.44,49.51,49.15,43.75,34.00,25.70,25.11.ESI- MS m/z:288.4[M+H]+ ; Elemental analysis calculated value: For C17 H25 N3 O: C, 71.04; H, 8.77; Measured value: C, 71.07; H, 8.74.
实施例2、4-苯基-N-(对甲苯基)哌嗪-1-甲酰胺(I-2)Example 2, 4-phenyl-N-(p-tolyl)piperazine-1-carboxamide (I-2)
合成方法参照实施例1，不同之处在于：将起始原料II-2替换为对甲苯异氰酸酯，得白色固体0.38g,产率92.5％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-2 was replaced with p-toluene isocyanate, and 0.38 g of white solid was obtained with a yield of 92.5%. The spectral data are as follows.
1H NMR(400MHz,Chloroform-d)δ7.36-7.18(m,4H),7.09(d,J＝8.1Hz,2H),7.00-6.87(m,3H),6.49(s,1H),3.72-3.54(m,4H),3.24-3.09(m,4H),2.29(s,3H).13C NMR(101MHz,Chloroform-d)δ155.28,150.95,136.27,132.90,129.44,129.26,120.44,120.41,116.51,49.20,44.05,20.79.ESI-MS m/z:296.4[M+H]+；元素分析计算值：ForC18H21N3O:C,73.19；H,7.17；实测值：C,73.17；H,7.14。1 H NMR (400MHz, Chloroform-d) δ7.36-7.18 (m, 4H), 7.09 (d, J = 8.1Hz, 2H), 7.00-6.87 (m, 3H), 6.49 (s, 1H), 3.72 -3.54(m,4H),3.24-3.09(m,4H),2.29(s,3H).13 C NMR(101MHz,Chloroform-d)δ155.28,150.95,136.27,132.90,129.44,129.26,120.44,120.41, 116.51,49.20,44.05,20.79.ESI-MS m/z:296.4[M+H]+ ;Elemental analysis calculated value:ForC18 H21 N3 O:C,73.19;H,7.17;Measured value:C,73.17 ;H,7.14.
实施例3、4-苯基-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-3)Example 3, 4-phenyl-N-(phenylsulfonyl)piperazine-1-carboxamide (I-3)
合成方法参照实施例1，不同之处在于：将起始原料II-2替换为异氰酸苯磺酰酯，得白色固体0.38g,产率92.5％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-2 was replaced with benzenesulfonyl isocyanate to obtain 0.38 g of white solid with a yield of 92.5%. The spectral data are as follows.
1H NMR(400MHz,Chloroform-d)δ8.17-8.00(m,2H),7.58(t,J＝8.7Hz,1H),7.50(t,J＝8.5Hz,2H),7.27-7.14(m,2H),6.84(m,3H),3.55(t,J＝5.1Hz,4H),3.07(t,J＝5.1Hz,4H).13C NMR(101MHz,Chloroform-d)δ151.38,151.35,150.70,139.68,133.53,132.71,129.45,129.26,129.19,128.99,128.12,126.32,120.54,117.04,116.60,49.02,46.78.ESI-MS m/z:346.4[M+H]+；元素分析计算值：For C17H19N3O3S:C,59.11；H,5.54；实测值：C,59.13；H,5.54。1 H NMR (400MHz, Chloroform-d) δ8.17-8.00(m,2H),7.58(t,J＝8.7Hz,1H),7.50(t,J＝8.5Hz,2H),7.27-7.14(m ,2H),6.84(m,3H),3.55(t,J＝5.1Hz,4H),3.07(t,J＝5.1Hz,4H).13 C NMR(101MHz,Chloroform-d)δ151.38,151.35,150.70 ,139.68,133.53,132.71,129.45,129.26,129.19,128.99,128.12,126.32,120.54,117.04,116.60,49.02,46.78.ESI-MS m/z:346.4[M+H]+ ;Elemental analysis calculated value: For C17 H19 N3 O3 S: C, 59.11; H, 5.54; found value: C, 59.13; H, 5.54.
实施例4、N-(4-(叔丁基)苯基)-4苯基哌嗪-1-甲酰胺(I-4)Example 4, N-(4-(tert-butyl)phenyl)-4phenylpiperazine-1-carboxamide (I-4)
合成方法参照实施例1，不同之处在于：将起始原料II-2替换为对叔丁基苯异氰酸酯，得白色固体0.34g,产率91.5％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-2 was replaced with p-tert-butylbenzene isocyanate to obtain 0.34g of white solid with a yield of 91.5%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝10.3Hz,1H),7.42-7.32(m,2H),7.31-7.20(m,4H),6.99(d,J＝7.1,1.1Hz,2H),6.81(t,J＝7.2Hz,1H),4.09(q,J＝5.3Hz,1H),3.58(t,J＝5.1Hz,3H),3.16(t,J＝4.9Hz,4H),1.26(d,J＝2.3Hz,9H).13C NMR(101MHz,DMSO-d6)δ155.63,151.45,144.51,138.29,137.62,129.44,125.83,125.37,119.97,119.71,118.45,116.30,49.08,48.86,44.13,34.33,31.75.ESI-MS m/z:338.5[M+H]+；元素分析计算值：For C21H27N3O:C,74.74；H,8.06；实测值：C,74.73；H,8.04。1 H NMR (400MHz, DMSO-d6 ) δ8.52 (d, J = 10.3 Hz, 1H), 7.42-7.32 (m, 2H), 7.31-7.20 (m, 4H), 6.99 (d, J = 7.1 ,1.1Hz,2H),6.81(t,J＝7.2Hz,1H),4.09(q,J＝5.3Hz,1H),3.58(t,J＝5.1Hz,3H),3.16(t,J＝4.9 Hz, 4H), 1.26 (d, J = 2.3Hz, 9H).13 C NMR (101MHz, DMSO-d6 ) δ 155.63, 151.45, 144.51, 138.29, 137.62, 129.44, 125.83, 125.37, 119.97, 119.71, 118.45, 116.30,49.08,48.86,44.13,34.33,31.75.ESI-MS m/z:338.5[M+H]+ ;Elemental analysis calculated value:For C21 H27 N3 O:C,74.74; H,8.06; Measured Values: C, 74.73; H, 8.04.
实施例5、N-(4-甲氧基吡啶-2-基)-4-苯基哌嗪-1-甲酰胺(I-5)Example 5, N-(4-methoxypyridin-2-yl)-4-phenylpiperazine-1-carboxamide (I-5)
采用一锅煮的方法合成I-5,氮气保护下，将2-氨基-4-甲氧基吡啶II-3(0.2g,1.61mmol)的无水二氯甲烷(20ml)溶液缓慢滴加到三光气II-4(0.16g,0.54mmol)的二氯甲烷(20ml)溶液中，加入4-二甲氨基吡啶DMAP(0.59g,4.83mmol)，室温下搅拌30分钟，加入II-1的二氯甲烷(20ml)溶液，室温下继续反应6小时后，减压蒸除溶剂，残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化，得0.32g白色固体I-5，产率63.6％。图谱数据如下。I-5 was synthesized by a one-pot method. Under nitrogen protection, a solution of 2-amino-4-methoxypyridine II-3 (0.2 g, 1.61 mmol) in anhydrous dichloromethane (20 ml) was slowly added dropwise to a solution of triphosgene II-4 (0.16 g, 0.54 mmol) in dichloromethane (20 ml), 4-dimethylaminopyridine DMAP (0.59 g, 4.83 mmol) was added, stirred at room temperature for 30 minutes, a solution of II-1 in dichloromethane (20 ml) was added, and the reaction was continued at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain 0.32 g of white solid I-5 with a yield of 63.6%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.27-8.08(m,2H),7.22(m,2H),7.07-6.93(m,1H),6.93-6.76(m,3H),3.48-3.34(m,2H),3.16(d,J＝5.9Hz,3H),3.09(s,6H).13C NMR(101MHz,DMSO-d6)δ156.55,150.51,141.90,129.53,120.28,116.40,107.33,49.00,45.77,42.86.ESI-MS m/z:313.5[M+H]+；元素分析计算值：For C17H20N4O2:C,65.37；H,6.45；实测值：C,65.36；H,6.44。1 H NMR (400MHz, DMSO-d6 ) δ8.27-8.08(m,2H),7.22(m,2H),7.07-6.93(m,1H),6.93-6.76(m,3H),3.48-3.34 (m, 2H), 3.16 (d, J = 5.9Hz, 3H), 3.09 (s, 6H).13 C NMR (101MHz, DMSO-d6 ) δ 156.55, 150.51, 141.90, 129.53, 120.28, 116.40, 107.33, 49.00,45.77,42.86.ESI-MS m/z:313.5[M+H]+ ;Elemental analysis calculated value: For C17 H20 N4 O2 :C,65.37; H,6.45; Measured value: C,65.36 ;H,6.44.
实施例6、N-(3-乙炔基苯基)-4-苯基哌嗪-1-甲酰胺(I-6)Example 6, N-(3-ethynylphenyl)-4-phenylpiperazine-1-carboxamide (I-6)
合成方法参照实施例5，不同之处在于：将起始原料II-3替换为间氨基苯乙炔，得到白色固体0.35g，产率68.3％。图谱数据如下。The synthesis method was as in Example 5, except that the starting material II-3 was replaced with m-aminophenylacetylene to obtain 0.35 g of white solid with a yield of 68.3%. The spectral data are as follows.
1H NMR(300MHz,DMSO-d6)δ7.67(t,J＝1.9Hz,1H),7.52(d,J＝8.3Hz,1H),7.33-7.19(m,3H),7.08-6.95(m,3H),6.90-6.73(m,1H),3.61(t,J＝6.1Hz,4H),3.16(t,J＝6.1Hz,4H).13C NMR(75MHz,DMSO-d6)δ155.23,151.37,141.21,129.44,129.25,125.44,122.78,122.08,120.54,119.74,116.31,84.16,80.55,48.82,44.10.ESI-MS m/z:306.4[M+H]+；元素分析计算值：For C19H19N3O:C,74.73；H,6.27；实测值：C,74.76；H,6.24。1 H NMR (300MHz, DMSO-d6 ) δ7.67 (t, J = 1.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33-7.19 (m, 3H), 7.08-6.95 ( m,3H),6.90-6.73(m,1H),3.61(t,J＝6.1Hz,4H),3.16(t,J＝6.1Hz,4H).13 C NMR (75MHz, DMSO-d6 )δ155 .23,151.37,141.21,129.44,129.25,125.44,122.78,122.08,120.54,119.74,116.31,84.16,80.55,48.82,44.10.ESI-MS m/z:306.4[M+H]+ ; Calculated value of elemental analysis :For C19 H19 N3 O: C, 74.73; H, 6.27; found value: C, 74.76; H, 6.24.
实施例7、4-苯基-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-7)Example 7, 4-phenyl-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-7)
合成方法参照实施例5，不同之处在于：将起始原料II-3替换为对三氟甲基苯胺，得到白色固体0.27g，产率65.2％。图谱数据如下。The synthesis method was as in Example 5, except that the starting material II-3 was replaced with p-trifluoromethylaniline to obtain 0.27 g of white solid with a yield of 65.2%. The spectral data are as follows.
1H NMR(300MHz,DMSO-d6)δ9.03(s,1H),7.81-7.49(m,5H),7.32-7.13(m,2H),7.09-6.93(m,2H),6.82(td,J＝7.2,1.1Hz,1H),3.73-3.51(m,4H),3.18(dd,J＝6.2,3.9Hz,4H).13CNMR(75MHz,DMSO-d6)δ154.98,151.35,144.85,129.43,126.89,126.10,126.05,123.30,122.27,121.84,119.76,119.35,118.57,116.31,107.15,48.82,44.14.ESI-MS m/z:350.4[M+H]+；元素分析计算值：For C18H13F3N3O:C,61.88；H,5.19；实测值：C,61.86；H,5.22。1 H NMR (300MHz, DMSO-d6 ) δ9.03 (s, 1H), 7.81-7.49 (m, 5H), 7.32-7.13 (m, 2H), 7.09-6.93 (m, 2H), 6.82 (td ,J＝7.2,1.1Hz,1H),3.73-3.51(m,4H),3.18(dd,J＝6.2,3.9Hz,4H).13 CNMR(75MHz,DMSO-d6 )δ154.98,151.35,144.85, 129.43,126.89,126.10,126.05,123.30,122.27,121.84,119.76,119.35,118.57,116.31,107.15,48.82,44.14.ESI-MS m/z:350.4[M+H]+ ;Elemental analysis calculated value: For C18 H13 F3 N3 O: C, 61.88; H, 5.19; found value: C, 61.86; H, 5.22.
实施例8、N-(4-氯苯基)-4苯基哌嗪-1-甲酰胺(I-8)Example 8, N-(4-chlorophenyl)-4phenylpiperazine-1-carboxamide (I-8)
合成方法参照实施例5，不同之处在于：将起始原料II-3替换为对氯苯胺，得到白色固体0.31g，产率61.2％。图谱数据如下。The synthesis method was as in Example 5, except that the starting material II-3 was replaced with p-chloroaniline to obtain 0.31 g of white solid with a yield of 61.2%. The spectral data are as follows.
1H NMR(300MHz,DMSO-d6)δ8.76(s,1H),7.63-7.50(m,2H),7.38-7.19(m,4H),7.08-6.93(m,2H),6.91-6.69(m,1H),3.60(t,J＝5.1Hz,4H),3.16(dd,J＝6.3,3.9Hz,4H).13C NMR(75MHz,DMSO-d6)δ155.23,151.37,139.98,129.44,129.10,128.64,125.77,121.44,119.75,116.31,48.82,44.08.ESI-MS m/z:316.8[M+H]+；元素分析计算值：ForC17H18ClN3O:C,64.66；H,5.75；实测值：C,64.68；H,5.77。1 H NMR (300MHz, DMSO-d6 ) δ8.76 (s, 1H), 7.63-7.50 (m, 2H), 7.38-7.19 (m, 4H), 7.08-6.93 (m, 2H), 6.91-6.69 (m, 1H), 3.60 (t, J = 5.1Hz, 4H), 3.16 (dd, J = 6.3, 3.9Hz, 4H).13 C NMR (75MHz, DMSO-d6 ) δ 155.23, 151.37, 139.98, 129.44 ,129.10,128.64,125.77,121.44,119.75,116.31,48.82,44.08.ESI-MS m/z:316.8[M+H]+ ;Elemental analysis calculated value:ForC17 H18 ClN3 O:C,64.66;H ,5.75; measured value: C,64.68; H,5.77.
实施例9、4-(4-氯苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-9)Example 9, 4-(4-chlorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-9)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-氯苯基)哌嗪，将起始原料II-2替换为对甲苯异氰酸酯，得白色固体0.18g，产率91.8％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced with 1-(4-chlorophenyl)piperazine, and the starting material II-2 is replaced with p-toluene isocyanate, to obtain a white solid 0.18 g, yield 91.8%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.42-7.29(m,2H),7.29-7.16(m,2H),7.14-6.99(m,3H),6.99-6.88(m,1H),3.58(t,J＝6.5Hz,4H),3.15(t,J＝6.2Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ155.54,150.94,150.20,138.30,131.02,129.18,129.11,129.00,123.15,122.49,120.27,117.67,117.12,49.63,48.58,45.97,43.95,20.82.ESI-MS m/z:330.8[M+H]+；元素分析计算值：For C18H20ClN3O:C,65.55；H,6.11；实测值：C,65.58；H,6.13。1 H NMR (400MHz, DMSO-d6 ) δ8.54(s,1H),7.42-7.29(m,2H),7.29-7.16(m,2H),7.14-6.99(m,3H),6.99-6.88 (m, 1H), 3.58 (t, J = 6.5Hz, 4H), 3.15 (t, J = 6.2Hz, 4H), 2.23 (s, 3H).13 C NMR (101MHz, DMSO-d6 ) δ155. 54,150.94,150.20,138.30,131.02,129.18,129.11,129.00,123.15,122.49,120.27,117.67,117.12,49.63,48.58,45.97,43.95,20.82.ESI-MS m/ z:330.8[M+H]+ ; element Analytical calculated value: For C18 H20 ClN3 O:C, 65.55; H, 6.11; found value: C, 65.58; H, 6.13.
实施例10、N-(苯基磺酰基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-10)Example 10, N-(phenylsulfonyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-10)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-三氟甲基苯基)哌嗪，将起始原料II-2替换为异氰酸苯磺酰酯，得白色固体0.35g，产率90.6％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced by 1-(4-trifluoromethylphenyl)piperazine, and the starting material II-2 is replaced by benzene isocyanate. Acyl ester, 0.35g of white solid was obtained, with a yield of 90.6%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ7.97-7.91(m,2H),7.86(d,J＝1.6Hz,1H),7.63(d,J＝6.4Hz,1H),7.59(m,3H),7.51(d,J＝8.6Hz,2H),7.38(s,1H),7.06(d,J＝8.6Hz,1H),3.48(d,J＝5.4Hz,4H),3.26(d,J＝5.4Hz,4H).13C NMR(101MHz,DMSO-d6)δ153.44,152.82,144.59,142.41,132.63,132.24,129.38,129.27,129.01,127.74,127.66,126.80,126.76,126.67,126.64,126.61,126.57,126.04,124.07,118.70,118.39,115.39,115.30,114.83,47.25,44.79,43.00.ESI-MS m/z:414.4[M+H]+；元素分析计算值：For C18H18F3N3O3S:C,52.31；H,4.39；实测值：C,52.28；H,4.36。1 H NMR (400MHz, DMSO-d6 ) δ7.97-7.91 (m, 2H), 7.86 (d, J = 1.6Hz, 1H), 7.63 (d, J = 6.4Hz, 1H), 7.59 (m, 3H),7.51(d,J＝8.6Hz,2H),7.38(s,1H),7.06(d,J＝8.6Hz,1H),3.48(d,J＝5.4Hz,4H),3.26(d, J=5.4Hz, 4H).13 C NMR (101MHz, DMSO-d6 ) δ 153.44, 152.82, 144.59, 142.41, 132.63, 132.24, 129.38, 129.27, 129.01, 127.74, 127.66, 126.80, 126.76, 12 6.67,126.64,126.61 ,126.57,126.04,124.07,118.70,118.39,115.39,115.30,114.83,47.25,44.79,43.00.ESI-MS m/z:414.4[M+H]+ ;Elemental analysis calculated value:For C18 H18 F3 N3 O3 S: C, 52.31; H, 4.39; measured value: C, 52.28; H, 4.36.
实施例11、4-(4-氯苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-11)Example 11, 4-(4-chlorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-11)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-氯苯基)哌嗪，将起始原料II-2替换为异氰酸苯磺酰酯，得白色固体0.30g，产率89.3％。图谱数据如下。The synthesis method is as described in Example 1, except that the starting material II-1 is replaced by 1-(4-chlorophenyl)piperazine, and the starting material II-2 is replaced by benzene sulfonyl isocyanate, 0.30g of white solid was obtained, with a yield of 89.3%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ7.95-7.89(m,2H),7.87-7.79(m,1H),7.57(d,J＝3.8Hz,1H),7.38(s,1H),7.29-7.19(m,2H),6.99-6.82(m,2H),3.46(d,J＝5.2Hz,4H),3.07(t,J＝5.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ154.11,150.08,149.30,144.59,142.44,141.49,133.04,132.61,132.25,129.39,129.28,129.24,129.10,129.01,127.71,127.64,126.03,124.06,123.20,118.01,117.72,55.38,52.78,49.08,48.50,45.83,43.15.ESI-MSm/z:380.9[M+H]+；元素分析计算值：For C17H18ClN3O3S:C,53.75；H,4.78；实测值：C,53.78；H,4.76。1 H NMR (400MHz, DMSO-d6 ) δ7.95-7.89 (m, 2H), 7.87-7.79 (m, 1H), 7.57 (d, J = 3.8Hz, 1H), 7.38 (s, 1H), 7.29-7.19(m,2H),6.99-6.82(m,2H),3.46(d,J＝5.2Hz,4H),3.07(t,J＝5.2Hz,4H).13 C NMR(101MHz,DMSO- d6 )δ154.11,150.08,149.30,144.59,142.44,141.49,133.04,132.61,132.25,129.39,129.28,129.24,129.10,129.01,127.71,127.64,126.03 ,124.06,123.20,118.01,117.72,55.38,52.78,49.08 ,48.50,45.83,43.15.ESI-MSm/z:380.9[M+H]+ ;Elemental analysis calculated value: For C17 H18 ClN3 O3 S:C,53.75; H,4.78; Measured value: C, 53.78;H,4.76.
实施例12、4-(4-氯苯基)-N-环己基哌嗪-1-羧酰胺(I-12)Example 12, 4-(4-chlorophenyl)-N-cyclohexylpiperazine-1-carboxamide (I-12)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-氯苯基)哌嗪，得白色固体0.23g，产率92.3％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-1 was replaced with 1-(4-chlorophenyl)piperazine to obtain 0.23 g of white solid with a yield of 92.3%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ7.34-7.14(m,2H),7.04-6.92(m,2H),6.30(d,J＝7.7Hz,1H),3.46-3.40(m,4H),3.07(m,4H),1.84-1.62(m,4H),1.57(m,1H),1.21(m,4H),1.07(m,2H).13C NMR(101MHz,DMSO-d6)δ157.24,150.27,129.06,123.07,117.61,49.63,48.51,43.71,33.59,25.86,25.59.ESI-MS m/z:322.9[M+H]+；元素分析计算值：ForC17H24ClN3O:C,63.44；H,7.52；实测值：C,63.46；H,7.53。1 H NMR (400MHz, DMSO-d6 ) δ7.34-7.14 (m, 2H), 7.04-6.92 (m, 2H), 6.30 (d, J = 7.7Hz, 1H), 3.46-3.40 (m, 4H ),3.07(m,4H),1.84-1.62(m,4H),1.57(m,1H),1.21(m,4H),1.07(m,2H).13 C NMR(101MHz,DMSO-d6 ) δ157.24,150.27,129.06,123.07,117.61,49.63,48.51,43.71,33.59,25.86,25.59.ESI-MS m/z:322.9[M+H]+ ;Elemental analysis calculated value:ForC17 H24 ClN3 O: C, 63.44; H, 7.52; actual measured value: C, 63.46; H, 7.53.
实施例13、N-环己基-4-(4-硝基苯基)哌嗪-1-甲酰胺(I-13)Example 13, N-cyclohexyl-4-(4-nitrophenyl)piperazine-1-carboxamide (I-13)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-硝基苯基)哌嗪，得黄色固体0.26g，产率91.1％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-1 was replaced with 1-(4-nitrophenyl)piperazine to obtain 0.26 g of yellow solid with a yield of 91.1%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.17-7.99(m,2H),7.10-6.88(m,2H),6.30(d,J＝7.7Hz,1H),3.45(s,8H),1.72(m,4H),1.57(d,J＝12.8Hz,1H),1.30-0.96(m,6H).13C NMR(101MHz,DMSO-d6)δ157.13,155.06,137.30,126.16,113.00,49.66,46.42,43.22,33.82,33.58,25.84,25.57,24.93.ESI-MS m/z:322.9[M+H]+；元素分析计算值：For C17H24ClN3O:C,63.44；H,7.52；实测值：C,63.46；H,7.53。1 H NMR (400MHz, DMSO-d6 ) δ8.17-7.99 (m, 2H), 7.10-6.88 (m, 2H), 6.30 (d, J = 7.7Hz, 1H), 3.45 (s, 8H), 1.72 (m, 4H), 1.57 (d, J = 12.8Hz, 1H), 1.30-0.96 (m, 6H).13 C NMR (101MHz, DMSO-d6 ) δ 157.13, 155.06, 137.30, 126.16, 113.00, 49.66 ,46.42,43.22,33.82,33.58,25.84,25.57,24.93.ESI-MS m/z:322.9[M+H]+ ;Elemental analysis calculated value: For C17 H24 ClN3 O:C,63.44;H, 7.52; measured value: C, 63.46; H, 7.53.
实施例14、4-(4-硝基苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-14)Example 14, 4-(4-nitrophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-14)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-硝基苯基)哌嗪，将起始原料II-2替换为对甲苯异氰酸酯，得黄色固体0.21g，产率92.5％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced with 1-(4-nitrophenyl)piperazine, and the starting material II-2 is replaced with p-toluene isocyanate to obtain a yellow solid 0.21g, yield 92.5%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.15-8.01(m,1H),7.35(dd,J＝8.4,6.5Hz,2H),7.05(dd,J＝8.7,4.8Hz,3H),3.84-3.35(m,7H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ155.48,155.00,153.31,138.23,138.02,137.36,131.10,130.62,129.53,129.19,126.18,120.32,118.49,113.03,46.46,43.47,20.81.ESI-MS m/z:341.4[M+H]+；元素分析计算值：For C18H20N4O3:C,63.52；H,5.92；实测值：C,63.54；H,5.93。1 H NMR (400MHz, DMSO-d6 ) δ8.56 (s, 1H), 8.15-8.01 (m, 1H), 7.35 (dd, J = 8.4, 6.5Hz, 2H), 7.05 (dd, J = 8.7 ,4.8Hz,3H),3.84-3.35(m,7H),2.23(s,3H).13 C NMR(101MHz,DMSO-d6 )δ155.48,155.00,153.31,138.23,138.02,137.36,131.10,130.62, 129.53,129.19,126.18,120.32,118.49,113.03,46.46,43.47,20.81.ESI-MS m/z:341.4[M+H]+ ;Elemental analysis calculated value:For C18 H20 N4 O3 :C, 63.52; H, 5.92; measured value: C, 63.54; H, 5.93.
实施例15、4-(4-硝基苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-15)Example 15, 4-(4-nitrophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-15)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-硝基苯基)哌嗪，将起始原料II-2替换为异氰酸苯磺酰酯，得黄色固体0.24g，产率88.5％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced with 1-(4-nitrophenyl)piperazine, and the starting material II-2 is replaced with benzene sulfonyl isocyanate. , 0.24g of yellow solid was obtained, with a yield of 88.5%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.15-8.01(m,1H),7.93-7.87(m,1H),7.86-7.80(m,1H),7.70-7.49(m,4H),7.37(s,1H),7.14-6.91(m,1H),3.71-3.47(m,4H),3.47-3.30(m,4H).13C NMR(101MHz,DMSO-d6)δ154.93,154.47,144.58,138.41,137.31,132.26,132.00,129.39,129.11,128.80,127.57,126.17,126.10,126.03,113.88,112.99,46.47,44.10,42.90.ESI-MS m/z:391.4[M+H]+；元素分析计算值：For C17H18N4O5S:C,52.30；H,4.65；实测值：C,52.31；H,4.63。1 H NMR (400MHz, DMSO-d6 ) δ8.15-8.01(m,1H),7.93-7.87(m,1H),7.86-7.80(m,1H),7.70-7.49(m,4H),7.37 (s,1H),7.14-6.91(m,1H),3.71-3.47(m,4H),3.47-3.30(m,4H).13 C NMR (101MHz, DMSO-d6 )δ154.93,154.47,144.58, 138.41,137.31,132.26,132.00,129.39,129.11,128.80,127.57,126.17,126.10,126.03,113.88,112.99,46.47,44.10,42.90.ESI-MS m/z:391.4[ M+H]+ ;Elemental analysis calculation Value: For C17 H18 N4 O5 S: C, 52.30; H, 4.65; measured value: C, 52.31; H, 4.63.
实施例16、4-(4-硝基苯基)-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-16)Example 16, 4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-16)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(4-硝基苯基)哌嗪，将起始原料II-2替换为4-三氟甲基苯异氰酸酯，得黄色固体0.22g，产率83.5％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced with 1-(4-nitrophenyl)piperazine, and the starting material II-2 is replaced with 4-trifluoromethylbenzene. Isocyanate, 0.22g of yellow solid was obtained, with a yield of 83.5%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.20-8.02(m,2H),7.71(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),7.14-6.95(m,2H),3.66(t,J＝6.8Hz,4H),3.57(t,J＝6.8Hz,4H).13CNMR(101MHz,DMSO-d6)δ154.94,144.72,137.41,126.42,126.20,126.12,126.08,123.72,122.31,122.00,119.43,118.58,113.04,46.38,43.50.ESI-MS m/z:391.4[M+H]+；元素分析计算值：For C18H17F3N4O3:C,54.85；H,4.35；实测值：C,54.83；H,4.33。1 H NMR (400MHz, DMSO-d6 ) δ9.02 (s, 1H), 8.20-8.02 (m, 2H), 7.71 (d, J = 8.6Hz, 2H), 7.60 (d, J = 8.6Hz, 2H),7.14-6.95(m,2H),3.66(t,J＝6.8Hz,4H),3.57(t,J＝6.8Hz,4H).13 CNMR(101MHz,DMSO-d6 )δ154.94,144.72, 137.41,126.42,126.20,126.12,126.08,123.72,122.31,122.00,119.43,118.58,113.04,46.38,43.50.ESI-MS m/z:391.4[M+H]+ ;Elemental analysis calculated value: For C18 H17 F3 N4 O3 :C, 54.85; H, 4.35; measured value: C, 54.83; H, 4.33.
实施例17、N-(3-乙炔基苯基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-17)Example 17, N-(3-ethynylphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (I-17)
合成方法参照实施例5，不同之处在于：将起始原料II-1替换为1-(4-三氟甲基苯基)哌嗪，将起始原料II-3替换为间氨基苯乙炔，得白色固体0.26g，产率85.5％。图谱数据如下。The synthesis method is as in Example 5, except that the starting material II-1 is replaced by 1-(4-trifluoromethylphenyl)piperazine, and the starting material II-3 is replaced by m-aminophenylacetylene. 0.26g of white solid was obtained, with a yield of 85.5%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ7.67(dt,J＝4.4,2.0Hz,1H),7.53(m,2H),7.41(m,1H),7.32-7.24(m,1H),7.08(m,3H),4.17(s,1H),3.61(t,J＝6.6Hz,4H),3.35(t,J＝5.1Hz,4H).13CNMR(101MHz,DMSO-d6)δ155.21,153.54,152.89,141.14,140.25,129.69,129.25,126.78,126.67,126.63,126.59,125.72,125.49,124.09,122.82,122.52,122.08,121.55,120.57,119.49,118.69,118.37,114.83,114.69,84.14,84.01,80.87,80.54,79.81,47.31,47.01,43.74.ESI-MS m/z:374.4[M+H]+；元素分析计算值：For C20H18F3N3O:C,64.34；H,4.86；实测值：C,64.33；H,4.89。1 H NMR (400MHz, DMSO-d6 ) δ7.67 (dt, J = 4.4, 2.0 Hz, 1H), 7.53 (m, 2H), 7.41 (m, 1H), 7.32-7.24 (m, 1H), 7.08(m,3H),4.17(s,1H),3.61(t,J＝6.6Hz,4H),3.35(t,J＝5.1Hz,4H).13 CNMR(101MHz,DMSO-d6 )δ155. 21,153.54,152.89,141.14,140.25,129.69,129.25,126.78,126.67,126.63,126.59,125.72,125.49,124.09,122.82,122.52,122.08,121.55,1 20.57,119.49,118.69,118.37,114.83,114.69,84.14,84.01, 80.87,80.54,79.81,47.31,47.01,43.74.ESI-MS m/z:374.4[M+H]+ ;Elemental analysis calculated value:For C20 H18 F3 N3 O:C,64.34;H,4.86 ; Actual measured value: C, 64.33; H, 4.89.
实施例18、4-(2-氟苯基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-18)Example 18, 4-(2-fluorophenyl)-N-(p-tolyl)piperazine-1-carboxamide (I-18)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(2-氟苯基)哌嗪，将起始原料II-2替换为对苯甲基异氰酸酯，得白色固体0.15g，产率84.6％。图谱数据如下。The synthesis method is as in Example 1. The difference is that the starting material II-1 is replaced with 1-(2-fluorophenyl)piperazine, and the starting material II-2 is replaced with p-benzyl isocyanate to obtain white color. Solid 0.15g, yield 84.6%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.43-7.30(m,2H),7.24-6.92(m,6H),3.60(t,J＝5.0Hz,4H),3.02(t,J＝5.0Hz,4H),2.23(s,3H).13C NMR(101MHz,DMSO-d6)δ156.69,155.53,154.26,140.20,140.12,138.28,131.05,129.19,125.35,125.32,123.22,123.14,120.28,120.03,120.00,116.54,116.34,50.68,50.65,44.27,20.81.ESI-MS m/z:314.4[M+H]+；元素分析计算值：For C18H20FN3O:C,68.99；H,6.43；实测值：C,68.97；H,6.44。1 H NMR (400MHz, DMSO-d6 ) δ8.51 (s, 1H), 7.43-7.30 (m, 2H), 7.24-6.92 (m, 6H), 3.60 (t, J = 5.0Hz, 4H), 3.02 (t, J=5.0Hz, 4H), 2.23 (s, 3H).13 C NMR (101MHz, DMSO-d6 ) δ 156.69, 155.53, 154.26, 140.20, 140.12, 138.28, 131.05, 129.19, 125.35, 125.32, 123.22,123.14,120.28,120.03,120.00,116.54,116.34,50.68,50.65,44.27,20.81.ESI-MS m/z:314.4[M+H]+ ;Elemental analysis calculated value:For C18 H20 FN3 O : C, 68.99; H, 6.43; actual measured value: C, 68.97; H, 6.44.
实施例19、N-环己基-4-(2-氟苯基)哌嗪-1-甲酰胺(I-19)Example 19, N-cyclohexyl-4-(2-fluorophenyl)piperazine-1-carboxamide (I-19)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(2-氟苯基)哌嗪，得白色固体0.18g，产率88.6％。图谱数据如下。The synthesis method was as in Example 1, except that the starting material II-1 was replaced with 1-(2-fluorophenyl)piperazine to obtain 0.18 g of white solid with a yield of 88.6%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ7.17-6.95(m,4H),6.25(d,J＝7.7Hz,1H),3.43(t,J＝5.0Hz,4H),2.93(dd,J＝6.0,3.9Hz,4H),1.81-1.62(m,4H),1.62-1.44(m,1H),1.31-1.13(m,4H),1.08(m,2H).13C NMR(101MHz,Chloroform-d)δ157.05,156.94,154.49,139.86,139.77,124.54,124.51,122.95,122.87,119.11,119.09,116.28,116.08,50.40,50.36,49.51,43.93,33.96,25.68,25.12.ESI-MS m/z:306.4[M+H]+；元素分析计算值：ForC17H24FN3O:C,66.86；H,7.92；实测值：C,66.87；H,7.94。1 H NMR (400MHz, DMSO-d6 ) δ7.17-6.95 (m, 4H), 6.25 (d, J = 7.7Hz, 1H), 3.43 (t, J = 5.0Hz, 4H), 2.93 (dd, J＝6.0,3.9Hz,4H),1.81-1.62(m,4H),1.62-1.44(m,1H),1.31-1.13(m,4H),1.08(m,2H).13 C NMR(101MHz, Chloroform-d)δ157.05,156.94,154.49,139.86,139.77,124.54,124.51,122.95,122.87,119.11,119.09,116.28,116.08,50.40,50.36,49.51,43.93,3 3.96,25.68,25.12.ESI-MS m/z :306.4[M+H]+ ; Elemental analysis calculated value: ForC17 H24 FN3 O: C, 66.86; H, 7.92; Measured value: C, 66.87; H, 7.94.
实施例20、4-(2-氟苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-20)Example 20, 4-(2-fluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-20)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(2-氟苯基)哌嗪，将起始原料II-2替换为异氰酸苯磺酰酯，得白色固体0.21g，产率84.3％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced by 1-(2-fluorophenyl)piperazine, and the starting material II-2 is replaced by benzene sulfonyl isocyanate, 0.21g of white solid was obtained, with a yield of 84.3%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.00-7.88(m,2H),7.70-7.49(m,3H),7.17-7.06(m,2H),7.06-6.91(m,2H),3.48(t,J＝4.8Hz,4H),2.93(t,J＝5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ156.64,154.21,152.81,144.59,142.01,140.05,139.97,139.18,132.85,132.25,129.39,129.09,127.81,126.03,125.47,125.43,125.34,125.30,123.95,123.87,123.28,123.20,120.08,120.03,120.00,116.73,116.53,116.32,50.52,50.49,47.62,47.59,43.57.ESI-MS m/z:364.4[M+H]+；元素分析计算值：For C17H18FN3O3S:C,56.19；H,4.99；实测值：C,56.17；H,4.97。1 H NMR (400MHz, DMSO-d6 ) δ8.00-7.88(m,2H),7.70-7.49(m,3H),7.17-7.06(m,2H),7.06-6.91(m,2H),3.48 (t, J＝4.8Hz, 4H), 2.93 (t, J＝5.0Hz, 4H).13 C NMR (101MHz, DMSO-d6 ) δ156.64,154.21,152.81,144.59,142.01,140.05,139.97,139.18, 132.85,132.25,129.39,129.09,127.81,126.03,125.47,125.43,125.34,125.30,123.95,123.87,123.28,123.20,120.08,120.03,120.00,116. 73,116.53,116.32,50.52,50.49,47.62,47.59,43.57. ESI-MS m/z:364.4[M+H]+ ; Elemental analysis calculated value: For C17 H18 FN3 O3 S: C, 56.19; H, 4.99; measured value: C, 56.17; H, 4.97.
实施例21、4-(2,4-二氟苯基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-21)Example 21, 4-(2,4-difluorophenyl)-N-(phenylsulfonyl)piperazine-1-carboxamide (I-21)
合成方法参照实施例1，不同之处在于：将起始原料II-1替换为1-(2,4-二氟苯基)哌嗪，将起始原料II-2替换为异氰酸苯磺酰酯，得白色固体0.21g，产率84.3％。图谱数据如下。The synthesis method is as in Example 1, except that the starting material II-1 is replaced by 1-(2,4-difluorophenyl)piperazine, and the starting material II-2 is replaced by benzene sulfonate isocyanate. Acyl ester, 0.21g of white solid was obtained, with a yield of 84.3%. The spectral data are as follows.
1H NMR(400MHz,DMSO-d6)δ8.01-7.87(m,2H),7.70-7.51(m,3H),7.28-7.12(m,1H),7.12-6.90(m,2H),3.48(t,J＝4.8Hz,4H),2.88(t,J＝5.0Hz,4H).13C NMR(101MHz,Chloroform-d)δ159.55,157.13,154.51,151.71,139.83,136.04,133.38,132.79,129.18,128.01,126.35,120.00,110.97,105.09,50.57,47.85,44.13.ESI-MS m/z:382.4[M+H]+；元素分析计算值：For C17H17F2N3O3S:C,53.54；H,4.49；实测值：C,53.57；H,4.47。1 H NMR (400MHz, DMSO-d6 ) δ8.01-7.87(m,2H),7.70-7.51(m,3H),7.28-7.12(m,1H),7.12-6.90(m,2H),3.48 (t, J＝4.8Hz, 4H), 2.88 (t, J＝5.0Hz, 4H).13 C NMR (101MHz, Chloroform-d) δ 159.55, 157.13, 154.51, 151.71, 139.83, 136.04, 133.38, 132.79, 129.18 ,128.01,126.35,120.00,110.97,105.09,50.57,47.85,44.13.ESI-MS m/z:382.4[M+H]+ ;Elemental analysis calculated value: For C17 H17 F2 N3 O3 S: C, 53.54; H, 4.49; measured value: C, 53.57; H, 4.47.
本发明中化合物的TRPV1抑制活性及体内镇痛活性可以通过使用如下所述的测定系统测定。以下生物学测试实施例描述解释本发明。The TRPV1 inhibitory activity and in vivo analgesic activity of the compounds of the present invention can be measured by using the assay system described below. The following description of biological test examples illustrates the invention.
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常用试剂。The experimental method for the specific conditions in the test examples of the present invention is usually based on conventional conditions or conditions recommended by the product manufacturer. Reagents whose specific sources are not indicated are commonly used reagents purchased in the market.
测试例1本发明化合物对hTRPV1-HEK293稳转细胞的激动活性Test Example 1 Agonistic activity of compounds of the present invention on hTRPV1-HEK293 stably transfected cells
本发明使用以下方法测定本发明化合物的hTRPV1抑制活性：The present invention uses the following method to determine the hTRPV1 inhibitory activity of the compounds of the present invention:
hTRPV1-HEK293稳转细胞以2.5×104/孔的密度接种至96孔板上，置于37℃、5％CO2的细胞培养箱中过夜培养；在室温下装载Fluo-3AM钙离子荧光探针，首先配制2mM钙离子荧光探针Fluro-3AM的DMSO母液，用HBSS(Hank’s平衡盐溶液)稀释Fluo-3AM溶液，制备5μM的Fluo-3AM工作液，将上述工作液加入细胞板中，每孔10μL，37℃培养30分钟。每孔加入50μL含有1％胎牛血清的HBSS，继续培养40分钟。用台氏液(Tyrode’s solution)洗涤细胞4次，每孔加入40μL浓度为100nM的化合物溶液，每个样品浓度设置3个复孔，阳性对照组加入等量的N-(4-(叔丁基)苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺(BCTC)，阴性对照组加入台氏液(英文全称Tyrode's solution)。37℃孵育30分钟后给予辣椒碱刺激(50nM)，随后检测辣椒碱刺激前后λex＝488nm和λex＝540nm吸光度值来表征胞浆钙离子浓度，结果见表1。hTRPV1-HEK293 stably transfected cells were seeded on a 96-well plate at a density of 2.5×104 /well and cultured overnight in a cell culture incubator at 37°C and 5%CO2 ; Fluo-3AM calcium ion fluorescence probe was loaded at room temperature. Needle, first prepare a DMSO stock solution of 2mM calcium ion fluorescent probe Fluro-3AM, dilute the Fluo-3AM solution with HBSS (Hank's balanced salt solution), prepare a 5μM Fluo-3AM working solution, add the above working solution to the cell plate, and 10 μL in each well and incubate at 37°C for 30 minutes. Add 50 μL of HBSS containing 1% fetal calf serum to each well and continue culturing for 40 minutes. Wash the cells 4 times with Tyrode's solution, add 40 μL of compound solution with a concentration of 100 nM to each well, set 3 duplicate wells for each sample concentration, and add an equal amount of N-(4-(tert-butyl) to the positive control group. )Phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC), and Tyrode's solution (English full name: Tyrode's solution) was added to the negative control group. After incubation at 37°C for 30 minutes, capsaicin stimulation (50nM) was given, and then the absorbance values of λex=488nm and λex=540nm before and after capsaicin stimulation were measured to characterize the cytoplasmic calcium ion concentration. The results are shown in Table 1.
抑制率＝(空白组差值-实验组差值)/空白组差值(差值＝给辣椒碱前后荧光值的差)Inhibition rate = (difference in blank group - difference in experimental group)/difference in blank group (difference = difference in fluorescence values before and after capsaicin administration)
表1：hTRPV1受体抑制活性Table 1: hTRPV1 receptor inhibitory activity
表1中化合物代号对应的化学结构同实施例。The chemical structures corresponding to the compound codes in Table 1 are the same as those in the Examples.
测试结果表明，本发明所有化合物在不同浓度下对TRPV1具有明显的抑制活性，其中化合物I-17、I-19、I-20与I-21具有较强的抑制活性，与阳性对照BCTC相当。The test results show that all compounds of the present invention have obvious inhibitory activity against TRPV1 at different concentrations. Among them, compounds I-17, I-19, I-20 and I-21 have strong inhibitory activity, which is equivalent to the positive control BCTC.
测试例2本发明化合物的体内镇痛活性可以通过使用如下所述的两种小鼠疼痛模型测定系统测定：Test Example 2 The in vivo analgesic activity of the compounds of the present invention can be measured by using two mouse pain model assay systems as follows:
(1)醋酸诱导扭体实验(1) Acetic acid-induced writhing experiment
10周龄昆明种清洁级小鼠，体重22～25g，雄性，实验前12h禁食，按照体重随机分组，每组6只。测试前30min灌胃给药本发明化合物，剂量均为30mg/kg，空白对照组给予等体积的0.5％的羧甲基纤维素钠溶液。测试时小鼠腹腔注射0.6％醋酸溶液，记录小鼠15min内出现扭体反应(腹部内凹、伸展后肢、臀部抬高)的次数。10-week-old Kunming clean-grade mice, weighing 22-25g, male, fasted for 12 hours before the experiment, were randomly divided into groups according to body weight, with 6 mice in each group. The compounds of the present invention were administered intragastrically 30 minutes before the test at a dose of 30 mg/kg. The blank control group was administered an equal volume of 0.5% carboxymethyl cellulose sodium solution. During the test, the mice were intraperitoneally injected with 0.6% acetic acid solution, and the number of writhing reactions (abdominal indentation, hind limb extension, buttock elevation) in the mice was recorded within 15 minutes.
(2)辣椒碱诱导小鼠舔足实验(2) Capsaicin-induced foot licking experiment in mice
10周龄昆明种清洁级小鼠，体重22～25g，雄性，实验前12h禁食，按照体重随机分组，每组6只。测试前30min灌胃给药本发明化合物，剂量均为30mg/kg，空白对照组给予等体积的0.5％的羧甲基纤维素钠溶液。测试时使用微量注射器将20μl辣椒碱溶剂(1.6μg/20μl)注射到小鼠右后足背侧皮下。观察并记录辣椒碱注射后5min内小鼠舔足的累积时间。10-week-old Kunming clean-grade mice, weighing 22-25g, male, fasted for 12 hours before the experiment, were randomly divided into groups according to body weight, with 6 mice in each group. The compounds of the present invention were administered intragastrically 30 minutes before the test at a dose of 30 mg/kg. The blank control group was administered an equal volume of 0.5% carboxymethyl cellulose sodium solution. During the test, 20 μl of capsaicin solvent (1.6 μg/20 μl) was injected subcutaneously into the dorsal side of the right hind foot of the mouse using a microsyringe. Observe and record the cumulative paw licking time of mice within 5 minutes after capsaicin injection.
(3)热水浴诱导小鼠缩尾实验(3) Hot water bath induced tail shrinking experiment in mice
10周龄昆明种清洁级小鼠，体重22～25g，雄性，实验前12h禁食，按照体重随机分组，每组6只。测试前30min灌胃给药本发明化合物，剂量均为30mg/kg，空白对照组给予等体积的0.5％的羧甲基纤维素钠溶液。测试时将小鼠尾部三分之一浸入52℃的水浴中，分别观察并记录给药前和给药后30min小鼠缩尾的响应时间，小鼠抗热伤害反应用maximalpossible effect百分比(MPE％)来表示，MPE％＝(给到后的响应时间－基础响应时间)/(截止时间－基础响应时间)100％(其中截止时间为12s，用以避免小鼠组织损伤)。10-week-old Kunming clean-grade mice, weighing 22-25g, male, fasted for 12 hours before the experiment, were randomly divided into groups according to body weight, with 6 mice in each group. The compounds of the present invention were administered intragastrically 30 minutes before the test at a dose of 30 mg/kg. The blank control group was administered an equal volume of 0.5% carboxymethyl cellulose sodium solution. During the test, one-third of the mouse's tail was immersed in a water bath at 52°C. The response time of the mouse's tail flinching before administration and 30 minutes after administration was observed and recorded. The mouse's thermal injury response was measured by the maximum possible effect percentage (MPE%). ) to express, MPE% = (response time after administration - basic response time) / (cutoff time - basic response time) 100% (the cutoff time is 12s to avoid mouse tissue damage).
上述实验结果见表2。表2可以看出：本发明中所述优选化合物在三种疼痛模型中均有较高的镇痛效果，与阳性对照BCTC产生的镇痛效果相当。The above experimental results are shown in Table 2. It can be seen from Table 2 that the preferred compounds described in the present invention have high analgesic effects in the three pain models, which are equivalent to the analgesic effects produced by the positive control BCTC.
表2部分化合物在三种小鼠疼痛模型中的镇痛活性Table 2 Analgesic activity of some compounds in three mouse pain models
测试例3本发明部分化合物对小鼠体温的影响可以通过使用如下所述的两种小鼠疼痛模型测定系统测定：Test Example 3 The effect of some compounds of the present invention on the body temperature of mice can be measured by using two mouse pain model measurement systems as follows:
10周龄昆明种清洁级小鼠，体重22～25g，雄性，实验前12h禁食，按照体重随机分组，每组6只。测试化合物组以及阳性对照BCTC组以30mg/kg剂量灌胃给药，空白组(control)给予等容积的0.5％ CMC-Na，分别测试所有小鼠给药前、给药后30分钟、60分钟、90分钟和120分钟的小鼠体温。测试结果如图1所示。10-week-old Kunming clean-grade mice, weighing 22-25g, male, fasted for 12 hours before the experiment, were randomly divided into groups according to body weight, with 6 mice in each group. The test compound group and the positive control BCTC group were administered intragastrically at a dose of 30 mg/kg, and the blank group (control) was administered an equal volume of 0.5% CMC-Na. All mice were tested before administration, 30 minutes, and 60 minutes after administration. , 90 minutes and 120 minutes of mouse body temperature. The test results are shown in Figure 1.
由图1可以看出：阳性对照BCTC组小鼠体温明显升高，而本发明中所述化合物没有体温升高的副作用，具有更高的安全性。It can be seen from Figure 1 that the body temperature of the mice in the positive control BCTC group increased significantly, while the compound described in the present invention has no side effects of increased body temperature and has higher safety.
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| CN119613401A (en)* | 2024-11-04 | 2025-03-14 | 兰州大学第二医院 | Phenyl piperazinyl beta-carboline derivative and preparation method and application thereof |
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| US20020132853A1 (en)* | 2000-07-20 | 2002-09-19 | Rajagopal Bakthavatchalam | Capsaicin receptor ligands |
| JP2003192673A (en)* | 2001-12-27 | 2003-07-09 | Bayer Ag | Piperazinecarboxamide derivative |
| CN1863777A (en)* | 2003-02-11 | 2006-11-15 | 艾博特公司 | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
| WO2007076055A2 (en)* | 2005-12-22 | 2007-07-05 | Entremed, Inc. | Compositions and methods comprising proteinase activated receptor antagonists |
| CN113292485A (en)* | 2021-06-08 | 2021-08-24 | 河南大学 | Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target-point medicine, preparation method and application |
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020132853A1 (en)* | 2000-07-20 | 2002-09-19 | Rajagopal Bakthavatchalam | Capsaicin receptor ligands |
| JP2003192673A (en)* | 2001-12-27 | 2003-07-09 | Bayer Ag | Piperazinecarboxamide derivative |
| CN1863777A (en)* | 2003-02-11 | 2006-11-15 | 艾博特公司 | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
| WO2007076055A2 (en)* | 2005-12-22 | 2007-07-05 | Entremed, Inc. | Compositions and methods comprising proteinase activated receptor antagonists |
| CN113292485A (en)* | 2021-06-08 | 2021-08-24 | 河南大学 | Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target-point medicine, preparation method and application |
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| CN119613401A (en)* | 2024-11-04 | 2025-03-14 | 兰州大学第二医院 | Phenyl piperazinyl beta-carboline derivative and preparation method and application thereof |
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