CN101759668A - Cinnamamide derivative and application as cerebral nerve protective agent - Google Patents
Cinnamamide derivative and application as cerebral nerve protective agent Download PDFInfo
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- CN101759668A CN101759668A CN200910264122A CN200910264122A CN101759668A CN 101759668 A CN101759668 A CN 101759668A CN 200910264122 A CN200910264122 A CN 200910264122A CN 200910264122 A CN200910264122 A CN 200910264122A CN 101759668 A CN101759668 A CN 101759668A
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- 239000003223 protective agent Substances 0.000 title claims 2
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title description 3
- 230000002490 cerebral effect Effects 0.000 title description 2
- 210000005036 nerve Anatomy 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 210000004556 brain Anatomy 0.000 claims abstract description 18
- 208000032382 Ischaemic stroke Diseases 0.000 claims abstract description 9
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical class NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- -1 nitro, amino Chemical group 0.000 claims description 14
- 150000002430 hydrocarbons Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 210000002569 neuron Anatomy 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000006038 hexenyl group Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 9
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 9
- 206010008118 cerebral infarction Diseases 0.000 abstract description 9
- 241001465754 Metazoa Species 0.000 abstract description 8
- 239000004090 neuroprotective agent Substances 0.000 abstract description 4
- 230000001681 protective effect Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 210000003792 cranial nerve Anatomy 0.000 abstract 2
- 230000001012 protector Effects 0.000 abstract 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- 241000700159 Rattus Species 0.000 description 11
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- 206010008089 Cerebral artery occlusion Diseases 0.000 description 7
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Abstract
本发明公开了一类取代的肉桂酰胺衍生物及其作为脑神经保护剂在制药中的应用。本发明涉及的取代的肉桂酰胺衍生物是具有的结构为通式(I)化合物的游离碱和盐。本发明的化合物在动物实验中显示出对动物脑缺血模型具有治疗作用。本发明的化合物对缺血性脑卒中后的脑神经有保护作用，可用于制备缺血性脑卒中后的脑神经保护剂，用于治疗缺血性脑卒中。
Description
技术领域technical field
本发明属于制药领域，涉及一种新的取代的肉桂酰胺衍生物，以及该衍生物作为脑神经保护剂的用途。The invention belongs to the field of pharmacy, and relates to a new substituted cinnamic amide derivative and the use of the derivative as a brain neuroprotective agent.
背景技术Background technique
脑卒中是当今致死率和致残率最高的疾病之一，其中近80％的脑卒中属于缺血性脑卒中。脑卒中发生后脑细胞的存亡取决于神经元细胞受损害的程度，也就是取决于为细胞提供氧气和营养的大脑血流量减少的程度。缺血性脑卒中发生时，缺血核心部位的脑血流严重减少，在60-90min后脑组织发生不可逆损伤；而核心部位外围的局部缺血性半影，大脑血流量相对减少，但细胞代谢异常增高，在缺血发生后的数小时内，缺血区域内异常电活动和代谢紊乱形成一个链式反应，称之为“缺血瀑布”，瀑布效应的结局是缺血核心不断扩展、半影逐渐消失，这个过程就是脑卒中治疗的时间窗。Stroke is one of the diseases with the highest mortality and disability rate today, and nearly 80% of strokes are ischemic strokes. The survival of brain cells after a stroke depends on how much neurons are damaged, that is, how much blood flow to the brain that supplies cells with oxygen and nutrients is reduced. When ischemic stroke occurs, the cerebral blood flow in the ischemic core is severely reduced, and irreversible damage occurs to the brain tissue after 60-90 minutes; while the cerebral blood flow in the peripheral ischemic penumbra of the core is relatively reduced, but the cell metabolism Within a few hours after the occurrence of ischemia, the abnormal electrical activity and metabolic disorder in the ischemic area form a chain reaction, which is called "ischemic waterfall". The shadow gradually disappears, and this process is the time window for stroke treatment.
国外从二十世纪九十年代开始提出缺血性脑卒中的神经保护治疗，在随后的十年里有了迅猛的发展。神经保护的目标是干预缺血性半影发生的病理生化级联反应，挽救尚具活力的脑组织，防止或延迟细胞死亡。目前神经保护剂种类和作用机制繁多，如电压依赖性钙通道阻滞剂、谷氨酸受体拮抗剂、抗氧化剂、自由基清除剂、一氧化氮合酶抑制剂等药物，已经成为脑卒中治疗的研究热点。The neuroprotective treatment of ischemic stroke has been proposed abroad since the 1990s, and has developed rapidly in the following ten years. The goal of neuroprotection is to intervene in the pathobiochemical cascades that occur in the ischemic penumbra, to salvage viable brain tissue, and to prevent or delay cell death. At present, there are many types and mechanisms of action of neuroprotective agents, such as voltage-dependent calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, nitric oxide synthase inhibitors and other drugs, which have Research hotspots in treatment.
发明内容Contents of the invention
本发明需要解决的技术问题之一是公开一种新的具有具有医用价值的取代的肉桂酰胺衍生物，以克服现有技术存在的诱发出血、难以透过血脑屏障、口服生物利用度差、选择性低和神经行为毒性大等缺陷。One of the technical problems to be solved in the present invention is to disclose a new substituted cinnamic amide derivative with medical value, so as to overcome the existing problems of the prior art, such as induced hemorrhage, difficulty in penetrating the blood-brain barrier, poor oral bioavailability, Defects such as low selectivity and high neurobehavioral toxicity.
本发明需要解决的技术问题之二是公开上述取代的肉桂酰胺衍生物作为脑神经保护剂在缺血性脑卒中治疗中的应用。The second technical problem to be solved by the present invention is to disclose the application of the above-mentioned substituted cinnamic amide derivatives as brain neuroprotective agents in the treatment of ischemic stroke.
为解决上述问题，提供如下技术方案：In order to solve the above problems, the following technical solutions are provided:
本发明涉及的取代的肉桂酰胺衍生物是具有的结构为通式(I)化合物的游离碱和盐：The substituted cinnamic amide derivatives involved in the present invention are free bases and salts of compounds of general formula (I):
所说的盐为盐酸盐、氢溴酸盐、硫酸盐、三氟乙酸盐或甲磺酸盐中的一种。Said salt is one of hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate.
其中，R1、R2、R3、R4和R5相同或不同，各自独立地代表H、卤素、硝基、氨基、腈基、羟基、烷氧基、烃基、芳烃基、杂环基、芳基、取代烃基、取代芳烃基、取代杂环、取代芳基；Among them, R 1 , R 2 , R 3 , R 4 and R 5 are the same or different, each independently representing H, halogen, nitro, amino, nitrile, hydroxyl, alkoxy, hydrocarbon group, aromatic hydrocarbon group, heterocyclic group , aryl, substituted hydrocarbon group, substituted aromatic hydrocarbon group, substituted heterocycle, substituted aryl group;
R6和R7相同或不同，各自独立地代表H、卤素、烃基、卤素取代的烃基、硝基、氨基、腈基、羟基、烷氧基、芳烷氧基、杂环烷氧基。R 6 and R 7 are the same or different, and each independently represents H, halogen, hydrocarbyl, halogen-substituted hydrocarbyl, nitro, amino, nitrile, hydroxyl, alkoxy, aralkoxy, heterocycloalkoxy.
所述通式(I)化合物，其特征在于：R1、R2、R3、R4、R5、R6或R7代表的芳基、芳烃基或芳烷氧基中的芳基，为苯、联苯或萘，或者为F、Cl、Br、I、C1～10烷基、C1～10烷氧基、硝基或氨基取代的苯、联苯或萘。The compound of the general formula (I) is characterized in that: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 represent the aryl group, the aryl group or the aryl group in the aralkoxy group, Benzene, biphenyl or naphthalene, or benzene, biphenyl or naphthalene substituted by F, Cl, Br, I, C 1-10 alkyl, C 1-10 alkoxy, nitro or amino.
所述通式(I)化合物，其特征在于：R1、R2、R3、R4、R5、R6或R7代表的烃基、芳烃基中的烃基，指具有1-10个碳原子的直链或支链的烷基，或2-10个碳原子的直链或支链的烯基，或3-10个碳原子的直链或支链的环烷基；烷氧基或芳烷氧基或杂环烷氧基中的烷基指具有1-10个碳原子的直链或支链的烷基。其中烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、己基、庚基、辛基、壬基、癸基；烯基是乙烯基、丙烯基、烯丙基、丁烯基、异丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基、癸烯基；环烷基是环丙基、环丁基、环己基、环庚基、环辛基、环壬基、环癸基。The compound of general formula (I) is characterized in that: the hydrocarbon group represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 , and the hydrocarbon group in the aromatic hydrocarbon group refer to the hydrocarbon group with 1-10 carbons straight-chain or branched-chain alkyl, or straight-chain or branched-chain alkenyl of 2-10 carbon atoms, or straight-chain or branched-chain cycloalkyl of 3-10 carbon atoms; alkoxy or The alkyl group in aralkoxy or heterocycloalkoxy refers to a straight-chain or branched-chain alkyl group having 1 to 10 carbon atoms. Wherein alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, Decyl; alkenyl is vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl; cycloalkyl is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl.
所述通式(I)化合物，其特征在于：R1、R2、R3、R4、R5、R6或R7代表的杂环基、取代杂环或杂环烷氧基中的杂环基指含有从氧、氮、硫原子中任选的一个或一个以上的杂原子的饱和杂环或芳香杂环。The compound of the general formula (I) is characterized in that: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 represent heterocyclyl, substituted heterocycle or heterocycloalkoxy The heterocyclic group refers to a saturated or aromatic heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur atoms.
所述通式(I)化合物，其特征在于：R1、R2、R3、R4、R5、F6或R7代表的卤素为F、Cl、Br或I。The compound of general formula (I) is characterized in that the halogen represented by R 1 , R 2 , R 3 , R 4 , R 5 , F 6 or R 7 is F, Cl, Br or I.
所述通式(I)化合物，其特征在于：R1、R2、R3、R4、R5、R6或R7中取代的烃基、芳烃基、杂环基、芳基，其取代基是卤素、硝基、氨基、羟基、醚基、羧基、酯基和酰胺基。The compound of the general formula (I) is characterized in that: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are substituted hydrocarbon groups, aromatic hydrocarbon groups, heterocyclic groups, aryl groups, and the substituted The radicals are halogen, nitro, amino, hydroxyl, ether, carboxyl, ester and amide.
所述通式(I)化合物，其特征在于：氨基为NH2、R8NH、R9R10N；其中R8、R9或R10为权利要求3所述的烃基，或者R9R10N为含氮原子的三元～八元杂环。The compound of general formula (I) is characterized in that: the amino group is NH 2 , R 8 NH, R 9 R 10 N; wherein R 8 , R 9 or R 10 is the hydrocarbon group described in claim 3, or R 9 R 10 N is a three- to eight-membered heterocyclic ring containing a nitrogen atom.
本发明用各种取代的苯甲醛为起始原料，按常规方法与丙二酸缩合制备相应的苯环取代的肉桂酸衍生物；取代的二苯甲酮按常规方法还原、卤代、取代制备相应的取代的二苯甲基哌嗪，然后取代的肉桂酸衍生物与氯化亚砜反应制备相应的酰氯，与取代的二苯甲基哌嗪反应，制备了一系列新的取代的肉桂酰胺衍生物，这些化合物具有较好的神经元保护作用和脑中风治疗活性。The present invention uses various substituted benzaldehydes as starting materials to condense with malonic acid to prepare corresponding benzene ring-substituted cinnamic acid derivatives according to conventional methods; substituted benzophenones are prepared by reduction, halogenation and substitution in conventional methods The corresponding substituted benzhydrylpiperazines, and then the substituted cinnamic acid derivatives were reacted with thionyl chloride to prepare the corresponding acid chlorides, which reacted with substituted benzhydrylpiperazines to prepare a series of new substituted cinnamic amides Derivatives, these compounds have good neuron protection and cerebral apoplexy therapeutic activity.
通式(I)化合物的制备方法包括以下步骤：The preparation method of general formula (I) compound comprises the following steps:
a.取代的苯甲醛(II)与丙二酸(III)缩合得到取代的肉桂酸衍生物(IV)；a. Substituted benzaldehyde (II) and malonic acid (III) are condensed to obtain substituted cinnamic acid derivatives (IV);
b.取代的二苯甲酮(V)经还原、卤代、取代得到取代的二苯甲基哌嗪(VI)；b. Substituted benzophenone (V) is reduced, halogenated and substituted to obtain substituted benzhydrylpiperazine (VI);
c.将取代的肉桂酸衍生物(IV)与氯化亚砜反应制备相应的酰氯，与取代的二苯甲基哌嗪(VI)缩合；得通式(I)化合物；c. reacting the substituted cinnamic acid derivative (IV) with thionyl chloride to prepare the corresponding acid chloride, and condensing with the substituted benzhydrylpiperazine (VI); the compound of general formula (I) is obtained;
(II) (III) (IV) (V) (VI)(II) (III) (IV) (V) (VI)
(注：化合物II、III、IV、V、VI中的R1、R2、R3、R4、R5、R6与R7代表的取代基与在化合物I中上述限定相同)。(Note: the substituents represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 in compounds II, III, IV, V, and VI are the same as those defined above in compound I).
其中，乙酰氧基取代的通式(IV)化合物是将相应的羟基化合物乙酰化得到的。Wherein, the compound of general formula (IV) substituted with acetoxy group is obtained by acetylating the corresponding hydroxyl compound.
本发明涉及的通式(I)取代的肉桂酸衍生物与二苯甲基哌嗪类化合物缩合成取代的肉桂酰胺衍生物的制备方法可由合成示意图1～3表示：The preparation method of the substituted cinnamic acid derivatives of general formula (I) involved in the present invention and the condensation of benzhydrylpiperazine compounds into substituted cinnamic acid amide derivatives can be represented by synthesis schematic diagrams 1 to 3:
a.取代的苯甲醛与丙二酸缩合得到取代的肉桂酸衍生物(见合成示意图1)；a. Substituted benzaldehyde and malonic acid are condensed to obtain substituted cinnamic acid derivatives (see synthesis scheme 1);
b.取代的二苯甲酮经还原、卤代、取代得到取代的二苯甲基哌嗪(见合成示意图2)；b. Substituted benzophenones are reduced, halogenated, and substituted to obtain substituted benzhydrylpiperazines (see synthesis scheme 2);
c.将取代的肉桂酸衍生物与氯化亚砜反应制备相应的酰氯，与取代的二苯甲基哌嗪缩合(见合成示意图3)；c. react the substituted cinnamic acid derivative with thionyl chloride to prepare the corresponding acid chloride, and condense with the substituted benzhydrylpiperazine (see synthesis scheme 3);
d.将缩合所得产物用无水乙醇重结晶，得目标化合物。d. Recrystallize the condensation product from absolute ethanol to obtain the target compound.
合成示意图1：Synthesis schematic 1:
合成示意图2：Synthesis schematic 2:
合成示意图3：Synthesis schematic 3:
本发明的有益效果：Beneficial effects of the present invention:
目前，脑神经保护活性的筛选动物实验按常规方法是采用颈内动脉线栓法制备大鼠大脑中动脉阻塞(MCAO)局灶性脑缺血模型评价抗脑缺血药物的药效。实验数据(详见实施例21)表明：预防性给予本发明部分化合物，大鼠脑指数明显降低，梗死面积明显减少，神经功能评分值降低，病理检查表明脑水肿及坏死症状明显改善，说明这些化合物对MCAO局灶性脑缺血具有较好的保护作用。At present, the conventional method for screening animal experiments of brain neuroprotective activity is to use internal carotid artery suture embolization method to prepare rat middle cerebral artery occlusion (MCAO) focal cerebral ischemia model to evaluate the efficacy of anti-ischemic drugs. Experimental data (see Example 21 for details) shows: prophylactic administration of some compounds of the present invention, rat brain index significantly reduced, infarct size significantly reduced, neurological score value decreased, pathological examination showed that cerebral edema and necrosis symptoms were significantly improved, illustrating that these The compound has better protective effect on MCAO focal cerebral ischemia.
具体实施方式Detailed ways
下面的实施例可使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。The following examples can enable those skilled in the art to understand the present invention more fully, but do not limit the present invention in any way.
实施例1Example 1
(E)-3-(3，4-二乙酰氧基苯基)丙烯酸(E)-3-(3,4-diacetoxyphenyl)acrylic acid
向装有回流冷凝管的250ml的圆底烧瓶中加入3，4-二羟基苯甲醛(13.8g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应3小时。冷却，减压蒸除溶剂，残余物倒入浓盐酸(68ml)和冰(150ml)的混合液中，搅拌，析出类白色固体。过滤，无水乙醇重结晶，得类白色粉末咖啡酸6.4g，收率35.2％，mp205.9-209.5℃。Add 3,4-dihydroxybenzaldehyde (13.8g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine ( 1.8ml), heated to 95°C for 3 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was poured into a mixture of concentrated hydrochloric acid (68ml) and ice (150ml) and stirred to precipitate an off-white solid. Filtration and recrystallization from absolute ethanol yielded 6.4 g of off-white powder caffeic acid, yield 35.2%, mp 205.9-209.5°C.
咖啡酸(5.2g，0.029mol)，乙酸酐(24ml)，吡啶(20ml)加到反应瓶中，室温搅拌过夜。减压蒸除溶剂，残余物倒入冰水中，得淡黄色固体，无水乙醇重结晶，得白色固体6.5g，收率85.9％，mp197.1-199.7℃。Add caffeic acid (5.2g, 0.029mol), acetic anhydride (24ml), and pyridine (20ml) into the reaction flask, and stir overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was poured into ice water to obtain a pale yellow solid, which was recrystallized from absolute ethanol to obtain 6.5 g of a white solid, yield 85.9%, mp 197.1-199.7°C.
实施例2Example 2
(E)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸(E)-3-(3-methoxy-4-acetoxyphenyl)acrylic acid
制备方法同实施例1，香兰素(15.2g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得阿魏酸9.2g，收率47.4％，mp170.7-172.4℃。The preparation method is the same as in Example 1. Vanillin (15.2g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), and hexahydropyridine (1.8ml) are heated to 95°C for reaction to obtain A Ferulic acid 9.2g, yield 47.4%, mp170.7-172.4°C.
阿魏酸(5.6g，0.029mol)，乙酸酐(12ml)，吡啶(20ml)室温反应，得白色固体6.1g，收率89.1％，mp168.5-169.9℃。Ferulic acid (5.6g, 0.029mol), acetic anhydride (12ml), and pyridine (20ml) were reacted at room temperature to obtain 6.1g of white solid, yield 89.1%, mp 168.5-169.9°C.
实施例3Example 3
(E)-3-(4-氟苯基)丙烯酸(E)-3-(4-fluorophenyl)acrylic acid
制备方法同实施例1，4-氟苯甲醛(12.4g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体13g，收率78.3％，mp209.1-210.8℃。The preparation method is the same as in Example 1, 4-fluorobenzaldehyde (12.4g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction, 13 g of white solid was obtained, yield 78.3%, mp 209.1-210.8°C.
实施例4Example 4
(E)-3-(4-甲基苯基)丙烯酸(E)-3-(4-methylphenyl)acrylic acid
制备方法同实施例1，4-甲基苯甲醛(12.0g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体12.3g，收率75.9％，mp195.1-196℃。The preparation method is the same as in Example 1, 4-methylbenzaldehyde (12.0g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction , 12.3 g of white solid was obtained, yield 75.9%, mp 195.1-196°C.
实施例5Example 5
(E)-3-(4-乙酰氧基苯基)丙烯酸(E)-3-(4-Acetoxyphenyl)acrylic acid
制备方法同实施例1，4-羟基苯甲醛(12.2g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得(E)-3-(4-羟基苯基)丙烯酸6.4g，收率39％，mp210-213℃。The preparation method is the same as in Example 1, 4-hydroxybenzaldehyde (12.2g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction, 6.4 g of (E)-3-(4-hydroxyphenyl)acrylic acid was obtained, the yield was 39%, and the mp was 210-213°C.
(E)-3-(4-羟基苯基)丙烯酸(4.74g，0.029mol)，乙酸酐(12ml)，吡啶(20ml)室温反应，得白色固体5.4g，收率90.7％，mp157.3-158.5℃。(E)-3-(4-hydroxyphenyl)acrylic acid (4.74g, 0.029mol), acetic anhydride (12ml), pyridine (20ml) were reacted at room temperature to obtain 5.4g of white solid, yield 90.7%, mp157.3- 158.5°C.
实施例6Example 6
(E)-3-(4-甲氧基苯基)丙烯酸(E)-3-(4-methoxyphenyl)acrylic acid
制备方法同实施例1，4-甲氧基苯甲醛(13.6g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体12.6g，收率70.8％，mp173.2-174.4℃。The preparation method is the same as in Example 1, 4-methoxybenzaldehyde (13.6g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C After the reaction, 12.6 g of white solid was obtained, the yield was 70.8%, and the mp was 173.2-174.4°C.
实施例7Example 7
(E)-3-(苯并[d][1，3]二氧杂环戊烯-5-基)丙烯酸(E)-3-(Benzo[d][1,3]dioxol-5-yl)acrylic acid
制备方法同实施例1，胡椒醛(15.0g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体13.1g，收率68.2％，mp241.5-244.4℃。The preparation method is the same as in Example 1, piperonal (15.0g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction to obtain a white solid 13.1g, yield 68.2%, mp241.5-244.4°C.
实施例8Example 8
(E)-3-(4-氯苯基)丙烯酸(E)-3-(4-Chlorophenyl)acrylic acid
制备方法同实施例1，4-氯苯甲醛(14.5g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体13.2g，收率72.3％，mp238.3-240.5℃。The preparation method is the same as in Example 1, 4-chlorobenzaldehyde (14.5g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction, 13.2 g of white solid was obtained, yield 72.3%, mp 238.3-240.5°C.
实施例9Example 9
(E)-3-(4-溴苯基)丙烯酸(E)-3-(4-bromophenyl)acrylic acid
制备方法同实施例1，4-溴苯甲醛(18.4g，0.1mol)，丙二酸(15.6g，0.15mol)，吡啶(68ml)，六氢吡啶(1.8ml)，加热至95℃反应，得白色固体15.9g，收率70％，mp246.3-248.3℃。The preparation method is the same as in Example 1, 4-bromobenzaldehyde (18.4g, 0.1mol), malonic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml), heated to 95°C for reaction, 15.9 g of white solid was obtained, yield 70%, mp 246.3-248.3°C.
实施例10Example 10
1-[二-(4-甲氧基苯基)甲基]哌嗪1-[Di-(4-methoxyphenyl)methyl]piperazine
向装有回流冷凝管的500ml的圆底烧瓶中加入氢氧化钾(52.5g)，二-(4-甲氧基苯基)甲酮(84g，0.347mol)，锌粉(70g)，95％乙醇(350ml)，回流搅拌反应3小时。趁热过滤，滤液冷却，得白色固体。用无水乙醇重结晶，得白色针状晶体二-(4-甲氧基苯基)甲醇66.8g，收率78.9％，mp68.9-69.8℃。Add potassium hydroxide (52.5g), two-(4-methoxyphenyl) ketone (84g, 0.347mol), zinc powder (70g), 95% Ethanol (350ml), reflux and stir for 3 hours. Filtrate while hot, and the filtrate is cooled to obtain a white solid. Recrystallized from absolute ethanol to obtain 66.8 g of white needle-like bis-(4-methoxyphenyl)methanol, yield 78.9%, mp 68.9-69.8°C.
将二-(4-甲氧基苯基)甲醇(10g，0.041mol)，二氯甲烷(120ml)，氯化亚砜(4ml)加入反应瓶中，室温搅拌3小时。减压浓缩，得淡红色油状物二-(4-甲氧基苯基)氯甲烷。Add bis-(4-methoxyphenyl)methanol (10 g, 0.041 mol), dichloromethane (120 ml), and thionyl chloride (4 ml) into the reaction flask, and stir at room temperature for 3 hours. Concentration under reduced pressure gave bis-(4-methoxyphenyl)chloromethane as a light red oil.
向上述油状液中加入环己烷(160ml)，无水哌嗪(10.8g，0.125mol)，搅拌回流16h。减压浓缩得淡黄色固体，加入二氯甲烷(120ml)搅拌溶解，滤去不溶物。滤液中加入1MNaOH溶液(100ml)，搅拌，分液，浓缩有机层，得白色蜡状固体，用乙腈重结晶，得白色针状晶体8.6g，收率67.3％，mp130-132℃。Cyclohexane (160ml) and anhydrous piperazine (10.8g, 0.125mol) were added to the above oily liquid, and the mixture was stirred and refluxed for 16h. Concentrate under reduced pressure to obtain a light yellow solid, add dichloromethane (120ml) and stir to dissolve, and filter off the insoluble matter. 1M NaOH solution (100ml) was added to the filtrate, stirred, liquid-separated, and the organic layer was concentrated to obtain a white waxy solid, which was recrystallized with acetonitrile to obtain 8.6 g of white needle-shaped crystals, yield 67.3%, mp 130-132°C.
实施例11Example 11
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(3，4-二乙酰氧基苯基)-丙-2-烯-1-酮(WB-501)(E)-[4-[Di-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(3,4-diacetoxyphenyl)-prop-2-ene -1-keto (WB-501)
向装有直型干燥管的50ml圆底烧瓶中加入(E)-3-(3，4-二乙酰氧基苯基)丙烯酸(1.056g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，室温搅拌3.5小时。减压蒸除溶剂，残余物加无水丙酮(15ml)溶解，将所得溶液缓慢滴入装有1-[二-(4-甲氧基苯基)甲基]哌嗪(1.87g，6mmol)，丙酮(15ml)，三乙胺(5ml)的50ml圆底烧瓶中，搅拌过夜。过滤，所得滤液减压浓缩，残余物用无水乙醇重结晶，得淡黄色固体1.0g，收率44.8％，mp193.2-195.1℃。ESI-MS(m/z)：559.2(M+H)+；1HNMR(δ，ppm，CDCl3)：2.39-2.42(m，4H，N(CH2)2)；2.81(s，6H，CH3COO*2)；3.63-3.71(m，4H，CON(CH2)2)；3.77(s，6H，CH3O*2)；4.18(s，1H，CH(Ph)2)；6.64-6.69(d，1H，＝CHCO)；6.78-7.31(m，11H，Ph)；7.56-7.61(d，1H，Ph-CH＝)。Add (E)-3-(3,4-diacetoxyphenyl)acrylic acid (1.056g, 4mmol), dichloromethane (15ml), chlorinated Sulfone (1.5ml), pyridine (1 drop), stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in anhydrous acetone (15ml), and the resulting solution was slowly dropped into , acetone (15ml), triethylamine (5ml) in a 50ml round bottom flask, stirred overnight. After filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was recrystallized from absolute ethanol to obtain 1.0 g of a light yellow solid, yield 44.8%, mp 193.2-195.1°C. ESI-MS (m/z): 559.2 (M+H) + ; 1 H NMR (δ, ppm, CDCl 3 ): 2.39-2.42 (m, 4H, N(CH 2 ) 2 ); 2.81 (s, 6H, CH 3 COO*2); 3.63-3.71(m, 4H, CON(CH 2 ) 2 ); 3.77(s, 6H, CH 3 O*2); 4.18(s, 1H, CH(Ph) 2 ); 6.64 -6.69 (d, 1H, =CHCO); 6.78-7.31 (m, 11H, Ph); 7.56-7.61 (d, 1H, Ph-CH=).
实施例12Example 12
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-[(3-甲氧基-4-乙酰氧基)苯基]-丙-2-烯-1-酮(WB-502)(E)-[4-[two-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-[(3-methoxy-4-acetoxy)phenyl]- Prop-2-en-1-one (WB-502)
(E)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸(0.944g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.3g，收率61.3％，mp185.0-186.2℃。ESI-MS(m/z)：531.2(M+H)+；1HNMR(δ，ppm，CDCl3)：2.30(s，3H，CH3COO)；2.40-2.42(m，4H，N(CH2)2)；3.62-3.72(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；3.84(s，3H，CH3O)；4.19(s，1H，CH(Ph)2)；6.74-6.77(d，1H，＝CHCO)；6.81-7.31(m，11H，Ph)；7.57-7.60(d，1H，Ph-CH＝)。(E)-3-(3-methoxy-4-acetoxyphenyl)acrylic acid (0.944g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop) , other operations are the same as in Example 12. 1.3 g of a light yellow solid was obtained, the yield was 61.3%, and the mp was 185.0-186.2°C. ESI-MS (m/z): 531.2 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.30 (s, 3H, CH 3 COO); 2.40-2.42 (m, 4H, N(CH 2 ) 2 ); 3.62-3.72(m, 4H, CON(CH 2 ) 2 ); 3.76(s, 6H, CH 3 O*2); 3.84(s, 3H, CH 3 O); 4.19(s, 1H , CH(Ph) 2 ); 6.74-6.77 (d, 1H, =CHCO); 6.81-7.31 (m, 11H, Ph); 7.57-7.60 (d, 1H, Ph-CH=).
实施例13Example 13
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-氟苯基)-丙-2-烯-1-酮(WB-503)(E)-[4-[two-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-fluorophenyl)-prop-2-en-1-one ( WB-503)
(E)-3-(4-氟苯基)丙烯酸(0.664g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.2g，收率65.2％，mp148.1-150.4℃。ESI-MS(m/z)：461.2(M+H)+；1HNMR(δ，ppm，CDCl3)：2.43-2.45(m，4H，N(CH2)2)；3.65-3.76(m，4H，CON(CH2)2)；3.79(s，6H，CH3O*2)；4.22(s，1H，CH(Ph)2)；6.76-6.79(d，1H，＝CHCO)；6.84-7.51(m，12H，Ph)；7.62-7.65(d，1H，Ph-CH＝)。(E)-3-(4-fluorophenyl)acrylic acid (0.664g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), and other operations were the same as in Example 12. 1.2 g of a light yellow solid was obtained, the yield was 65.2%, and the mp was 148.1-150.4°C. ESI-MS (m/z): 461.2 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.43-2.45 (m, 4H, N(CH 2 ) 2 ); 3.65-3.76 (m, 4H, CON(CH 2 ) 2 ); 3.79 (s, 6H, CH 3 O*2); 4.22 (s, 1H, CH(Ph) 2 ); 6.76-6.79 (d, 1H, =CHCO); 6.84- 7.51 (m, 12H, Ph); 7.62-7.65 (d, 1H, Ph-CH=).
实施例14Example 14
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-甲基苯基)-丙-2-烯-1-酮(WB-504)(E)-[4-[Di-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-methylphenyl)-prop-2-en-1-one (WB-504)
(E)-3-(4-甲基苯基)丙烯酸(0.648g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.3g，收率71.3％，mp105.6-107.1℃。ESI-MS(m/z)：457.3(M+H)+；1HNMR(δ，ppm，CDCl3)：2.35(s，3H，CH3)；2.39-2.42(m，4H，N(CH2)2)；3.64-3.73(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；4.18(s，1H，CH(Ph)2)；6.76-6.80(d，1H，＝CHCO)；6.81-7.39(m，12H，Ph)；7.59-7.64(d，1H，Ph-CH＝)。(E)-3-(4-methylphenyl)acrylic acid (0.648g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), other operations are the same as in Example 12 . 1.3 g of light yellow solid was obtained, yield 71.3%, mp 105.6-107.1°C. ESI-MS (m/z): 457.3 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.35 (s, 3H, CH 3 ); 2.39-2.42 (m, 4H, N (CH 2 ) 2 ); 3.64-3.73(m, 4H, CON(CH 2 ) 2 ); 3.76(s, 6H, CH 3 O*2); 4.18(s, 1H, CH(Ph) 2 ); 6.76-6.80( d, 1H, =CHCO); 6.81-7.39 (m, 12H, Ph); 7.59-7.64 (d, 1H, Ph-CH=).
实施例15Example 15
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-乙酰氧基苯基)-丙-2-烯-1-酮(WB-505)(E)-[4-[Di-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-acetoxyphenyl)-prop-2-ene-1- Ketone (WB-505)
(E)-3-(4-乙酰氧基苯基)丙烯酸(0.824g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体0.9g，收率45.0％，mp171.2-173.1℃。ESI-MS(m/z)：501.3(M+H)+；1HNMR(δ，ppm，CDCl3)：2.31(s，3H，CH3COO)；2.39-2.42(m，4H，N(CH2)2)；3.64-3.74(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；4.18(s，1H，CH(Ph)2)；6.76-6.79(d，1H，＝CHCO)；6.87-7.41(m，12H，Ph)；7.61-7.64(d，1H，Ph-CH＝)。(E)-3-(4-acetoxyphenyl)acrylic acid (0.824g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), other operations are the same as the examples 12. Obtained 0.9 g of light yellow solid, yield 45.0%, mp 171.2-173.1°C. ESI-MS (m/z): 501.3 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.31 (s, 3H, CH 3 COO); 2.39-2.42 (m, 4H, N(CH 2 ) 2 ); 3.64-3.74 (m, 4H, CON(CH 2 ) 2 ); 3.76 (s, 6H, CH 3 O*2); 4.18 (s, 1H, CH(Ph) 2 ); 6.76-6.79 (d, 1H, =CHCO); 6.87-7.41 (m, 12H, Ph); 7.61-7.64 (d, 1H, Ph-CH=).
实施例16Example 16
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-甲氧基苯基)-丙-2-烯-1-酮(WB-506)(E)-[4-[two-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-methoxyphenyl)-prop-2-ene-1- Ketone (WB-506)
(E)-3-(4-甲氧基苯基)丙烯酸(0.712g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体0.9g，收率47.7％，mp146.1-148.3℃。ESI-MS(m/z)：473.2(M+H)+；1HNMR(δ，ppm，CDCl3)：2.39-2.42(m，4H，N(CH2)2)；3.65-3.73(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；3.84(s，3H，CH3O)；4.18(s，1H，CH(Ph)2)；6.67-6.72(d，1H，＝CHCO)；6.75-7.46(m，12H，Ph)；7.58-7.63(d，1H，Ph-CH＝)。(E)-3-(4-methoxyphenyl)acrylic acid (0.712g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), other operations are the same as the examples 12. Obtained 0.9 g of light yellow solid, yield 47.7%, mp 146.1-148.3°C. ESI-MS (m/z): 473.2 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.39-2.42 (m, 4H, N(CH 2 ) 2 ); 3.65-3.73 (m, 4H, CON(CH 2 ) 2 ); 3.76 (s, 6H, CH 3 O*2); 3.84 (s, 3H, CH 3 O); 4.18 (s, 1H, CH(Ph) 2 ); 6.67-6.72 (d, 1H, =CHCO); 6.75-7.46 (m, 12H, Ph); 7.58-7.63 (d, 1H, Ph-CH=).
实施例17Example 17
(E)-3-(苯并[d][1，3]二氧杂环戊烯-5-基)-1-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-丙-2-烯-1-酮(WB-507)(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-[4-[di-(4-methoxyphenyl)methyl]piperene Azin-1-yl]-prop-2-en-1-one (WB-507)
(E)-3-(苯并[d][1，3]二氧杂环戊烯-5-基)丙烯酸(0.768g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.1g，收率56.6％，mp145.1-146.0℃。ESI-MS(m/z)：487.3(M+H)+；1HNMR(δ，ppm，CDCl3)：2.38-2.42(m，4H，N(CH2)2)；3.62-3.74(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；4.18(s，1H，CH(Ph)2)；5.97(s，2H，OCH2O)；6.63-6.68(d，1H，＝CHCO)；6.77-7.32(m，11H，Ph)；7.53-7.59(d，1H，Ph-CH＝)。(E)-3-(Benzo[d][1,3]dioxol-5-yl)acrylic acid (0.768g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml ), pyridine (1 drop), and other operations are the same as in Example 12. 1.1 g of light yellow solid was obtained, yield 56.6%, mp 145.1-146.0°C. ESI-MS (m/z): 487.3 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.38-2.42 (m, 4H, N(CH 2 ) 2 ); 3.62-3.74 (m, 4H, CON(CH 2 ) 2 ); 3.76 (s, 6H, CH 3 O*2); 4.18 (s, 1H, CH(Ph) 2 ); 5.97 (s, 2H, OCH 2 O); 6.63-6.68 (d, 1H, =CHCO); 6.77-7.32 (m, 11H, Ph); 7.53-7.59 (d, 1H, Ph-CH=).
实施例18Example 18
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-氯苯基)-丙-2-烯-1-酮(WB-508)(E)-[4-[two-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-chlorophenyl)-prop-2-en-1-one ( WB-508)
(E)-3-(4-氯苯基)丙烯酸(0.73g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.3g，收率68.2％，mp114.2-116.0℃。ESI-MS(m/z)：477.3(M+H)+；1HNMR(δ，ppm，CDCl3)：2.39-2.43(m，4H，N(CH2)2)；3.52-3.73(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；4.18(s，1H，CH(Ph)2)；6.77-6.82(d，1H，＝CHCO)；6.78-7.43(m，12H，Ph)；7.56-7.61(d，1H，Ph-CH＝)。(E)-3-(4-Chlorophenyl)acrylic acid (0.73g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), and other operations were the same as in Example 12. 1.3 g of light yellow solid was obtained, yield 68.2%, mp 114.2-116.0°C. ESI-MS (m/z): 477.3 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.39-2.43 (m, 4H, N(CH 2 ) 2 ); 3.52-3.73 (m, 4H, CON(CH 2 ) 2 ); 3.76 (s, 6H, CH 3 O*2); 4.18 (s, 1H, CH(Ph) 2 ); 6.77-6.82 (d, 1H, =CHCO); 6.78- 7.43 (m, 12H, Ph); 7.56-7.61 (d, 1H, Ph-CH=).
实施例19Example 19
(E)-[4-[二-(4-甲氧基苯基)甲基]哌嗪-1-基]-3-(4-溴苯基)-丙-2-烯-1-酮(WB-509)(E)-[4-[two-(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(4-bromophenyl)-prop-2-en-1-one ( WB-509)
(E)-3-(4-溴苯基)丙烯酸(0.908g，4mmol)，二氯甲烷(15ml)，氯化亚砜(1.5ml)，吡啶(1滴)，其他操作同实施例12。得淡黄色固体1.0g，收率48.0％，mp122.4-124.0℃。ESI-MS(m/z)：521.1(M+H)+；1HNMR(δ，ppm，CDCl3)：2.39-2.43(m，4H，N(CH2)2)；3.62-3.73(m，4H，CON(CH2)2)；3.76(s，6H，CH3O*2)；4.19(s，1H，CH(Ph)2)；6.79-6.84(d，1H，＝CHCO)；6.80-7.54(m，12H，Ph)；7.54-7.59(d，1H，Ph-CH＝)。(E)-3-(4-bromophenyl)acrylic acid (0.908g, 4mmol), dichloromethane (15ml), thionyl chloride (1.5ml), pyridine (1 drop), and other operations were the same as in Example 12. 1.0 g of light yellow solid was obtained, yield 48.0%, mp 122.4-124.0°C. ESI-MS (m/z): 521.1 (M+H) + ; 1 HNMR (δ, ppm, CDCl 3 ): 2.39-2.43 (m, 4H, N(CH 2 ) 2 ); 3.62-3.73 (m, 4H, CON(CH 2 ) 2 ); 3.76 (s, 6H, CH 3 O*2); 4.19 (s, 1H, CH(Ph) 2 ); 6.79-6.84 (d, 1H, =CHCO); 6.80- 7.54 (m, 12H, Ph); 7.54-7.59 (d, 1H, Ph-CH=).
实施例20Example 20
实施例中目标化合物对急性脑缺血小鼠生存时间的影响。In the examples, the effect of the target compound on the survival time of mice with acute cerebral ischemia.
目标化合物及阳性对照药尼莫地平临用前用0.5％羧甲基纤维素钠配成所需浓度的混悬液；试验动物为ICR小鼠，体重19-25g，雌雄各半。将小鼠按性别随机分组，每组10只，雌雄各半。分别灌胃给予受试药物0.2ml/10g，空白对照组给予等容量NS，阳性对照组给予等容量尼莫地平80mg/Kg，给药后1小时乙醚麻醉，固定后颈部正中切开，分离两侧颈总动脉及迷走神经并结扎，记录小鼠存活时间(每分钟呼吸次数小于或等于5次，即认为小鼠死亡)。The target compound and the positive control drug nimodipine were mixed with 0.5% sodium carboxymethylcellulose to form a suspension at the required concentration before use; the test animals were ICR mice with a body weight of 19-25 g, half male and half male. Mice were randomly divided into groups according to gender, 10 in each group, half male and half male. The test drugs were given 0.2ml/10g by intragastric administration, the blank control group was given the same volume of NS, and the positive control group was given the same volume of nimodipine 80mg/Kg, ether anesthetized 1 hour after the administration, the neck was fixed, and the neck was cut in the middle and separated. The common carotid arteries and vagus nerves on both sides were ligated, and the survival time of the mice was recorded (the number of breaths per minute was less than or equal to 5, that is, the mice were considered dead).
与NS组比较，*P＜0.05Compared with NS group, *P<0.05
上述试验结果表明，化合物WB-502、WB-503、WB-508、WB-509可明显延长急性脑缺血小鼠的的生存时间，可能具有一定的抗脑缺血作用，其中化合物WB-502、WB-503作用较强。The above test results show that compounds WB-502, WB-503, WB-508, and WB-509 can significantly prolong the survival time of mice with acute cerebral ischemia, and may have certain anti-ischemic effects. Among them, compound WB-502 , WB-503 has a strong effect.
实施例21Example 21
实施例中目标化合物对大脑中动脉阻断脑缺血(MCAO)大鼠的影响。In the examples, the effect of the target compound on middle cerebral artery occlusion cerebral ischemia (MCAO) rats.
取SD大鼠60只，按性别体重随机分为6组，每组10只，雌雄各半。试验前3天及试验后1天分别灌胃给予目标化合物36、12、4mg/Kg及尼莫地平6mg/Kg，给药容积均为2ml/Kg。Sixty SD rats were randomly divided into 6 groups according to sex and body weight, 10 in each group, half male and half male. 3 days before the test and 1 day after the test, 36, 12, 4 mg/Kg of the target compound and 6 mg/Kg of nimodipine were administered by intragastric administration respectively, and the administration volume was 2 ml/Kg.
按上述方法进行分组给药，末次给药后1小时，10％水合氯醛0.5g/Kg ip(即0.5ml/100g)麻醉，仰卧位固定，分离右侧颈总动脉、颈外动脉及颈内动脉，结扎颈总动脉近心端，在颈总动脉与颈外动脉的分支处作一切口，用4-0号尼龙线(头端烧成圆形，外端约为0.2mm)由颈外动脉插入沿颈内动脉进入大脑中动脉，线栓总长约2cm。脑缺血2小时后，去除线栓，结扎动脉，缝合切口。假手术组大鼠只进行手术而不进行线栓。Dosing in groups according to the above method, 1 hour after the last administration, anesthetized with 10% chloral hydrate 0.5g/Kg ip (0.5ml/100g), fixed in supine position, and separated the right common carotid artery, external carotid artery and carotid artery For the internal artery, the proximal end of the common carotid artery was ligated, an incision was made at the branch of the common carotid artery and the external carotid artery, and a 4-0 nylon thread (the head end was burnt into a circle, and the outer end was about 0.2mm) was inserted from the carotid The external artery was inserted into the middle cerebral artery along the internal carotid artery, and the total length of the thread plug was about 2cm. After 2 hours of cerebral ischemia, the thread plug was removed, the artery was ligated, and the incision was sutured. Rats in the sham operation group were operated only without suture.
造模后4、8、24观察大鼠行为改变，进行神经症状评分，评分标准如下：(1)提鼠尾观察前肢屈曲情况，如双前肢对称伸向地面，计为0分，如手术对侧前肢出现腕曲、肘屈曲、肩内旋、既有肘屈曲又有肩内旋者，分别计为1、2、3、4分。(2)将动物置于平地面上，分别推双肩向对侧移动，检查阻力，如双侧阻力对等且有力者计为0分，如向手术的对侧推动时阻力下降者，根据下降程度不同分为轻、中、重度，分别计为1、2、3分。(3)将动物双前肢置于一金属网上，观察双前肢的肌张力。双前肢肌张力对等且有力者计为0分，同样根据手术对侧肌张力下降程度不同分别计为1、2、3分。(4)动物有不停向一侧转圈者，计为1分。根据评分标准，满分为11分，分数越高，动物行为障碍越严重。The behavioral changes of the rats were observed on 4, 8, and 24 days after modeling, and the neurological symptoms were scored. The scoring criteria were as follows: (1) Lift the tail of the rat to observe the flexion of the forelimbs. Those with wrist flexion, elbow flexion, shoulder internal rotation, and both elbow flexion and shoulder internal rotation in the lateral forelimb are scored as 1, 2, 3, and 4 points, respectively. (2) Place the animal on a flat ground, push both shoulders to move to the opposite side respectively, and check the resistance. If the resistance on both sides is equal and strong, it will be scored as 0 points. Different degrees are divided into mild, moderate and severe, respectively counting as 1, 2 and 3 points. (3) Place the animal's forelimbs on a metal net, and observe the muscle tension of the two forelimbs. If the muscle tone of the two forelimbs is equal and strong, it is scored as 0 points, and it is also scored as 1, 2, and 3 points according to the degree of muscle tone decrease on the contralateral side after surgery. (4) If the animal continuously circles to one side, it is counted as 1 point. According to the scoring standard, the full score is 11 points, the higher the score, the more serious the animal behavior disorder.
造模后24小时后再给药1次，给药后1小时将大鼠以10％水合氯醛0.5g/Kg ip(即0.5ml/100g)麻醉后断头处死取出脑组织，去掉嗅球、小脑和低位脑干后称重，计算脑指数(脑指数＝g脑重量/100g体重)。将大脑放入冰冷盐水中20min，切成5片冠状脑片，第一刀在脑前极与视交叉连线中点处，第二刀在视交叉部位，第三刀在漏斗柄部位，第四刀在漏斗柄与叶尾极之间，置于2％TTC溶液中，37℃光孵育30min。梗塞区呈现白色，非梗塞区呈红色。拍摄数码照片后用图像分析软件计算梗塞面积及脑片面积，计算梗塞面积百分率(梗塞面积百分率＝梗塞面积/脑片面积×100％)。取第三脑片用4％多聚甲醛固定后，用石蜡包埋，HE染色，在光学显微镜下观察神经细胞的病理改变。After 24 hours of modeling, the rats were given another administration. One hour after the administration, the rats were anesthetized with 10% chloral hydrate 0.5g/Kg ip (ie 0.5ml/100g) and killed by decapitation. The brain tissue was removed, and the olfactory bulb, The cerebellum and lower brainstem were weighed, and the brain index was calculated (brain index=g brain weight/100g body weight). Put the brain in ice-cold saline for 20 minutes, cut into 5 coronal brain slices, the first cut was at the midpoint of the line between the anterior pole of the brain and the optic chiasm, the second cut was at the optic chiasm, the third cut was at the funnel handle, and the second cut was at the funnel handle. Put four knifes between the funnel stalk and the caudal pole of the leaf, place in 2% TTC solution, and incubate at 37°C for 30min. The infarcted area appears white, and the non-infarcted area appears red. After digital photos were taken, the infarct area and brain slice area were calculated with image analysis software, and the percentage of infarct area was calculated (percentage of infarct area=infarct area/brain slice area×100%). The third brain slice was fixed with 4% paraformaldehyde, embedded in paraffin, stained with HE, and the pathological changes of nerve cells were observed under an optical microscope.
脑指数及梗塞面积以均数±标准差表示，用SPSS统计学软件进行统计学分析，各组数据使用ANOVA分析，用SNK检验进行组间均数的比较，以P≤0.05为差异有显著性统计学意义。神经症状分级组间整体平均秩和检验用Kruskal-Wallis法检验，组间两两比较采用重复测量资料的广义估计方程完成，以P≤0.05为差异有显著性统计学意义。The brain index and infarction area are expressed as mean ± standard deviation, and SPSS statistical software is used for statistical analysis. The data of each group is analyzed using ANOVA, and the SNK test is used to compare the means between groups. The difference is significant when P≤0.05 Statistical significance. The Kruskal-Wallis method was used to test the overall average rank sum test between the neurological symptom classification groups, and the generalized estimating equation for repeated measurement data was used to complete the comparison between groups. P≤0.05 was considered statistically significant.
*P＜0.05与MACO组比较，##P＜0.01与假手术组比较*P＜0.05 compared with MACO group, ## P＜0.01 compared with sham group
线栓法复制大鼠大脑中动脉阻断脑缺血(MCAO)模型被广泛用于评价抗脑缺血药物的药效，预防性给予WB-502、WB-503大鼠脑指数明显降低，梗死面积明显减少，神经功能评分值降低，病理检查表明脑水肿及坏死症状明显改善，说明化合物WB-502、WB-503对MCAO局灶性脑缺血具有较好的保护作用。The middle cerebral artery occluded cerebral ischemia (MCAO) model in rats was reproduced by suture method, which is widely used to evaluate the efficacy of anti-ischemic drugs. Prophylactic administration of WB-502 and WB-503 to rats significantly decreased the brain index, infarction The area was significantly reduced, the neurological function score value was reduced, and the pathological examination showed that the symptoms of cerebral edema and necrosis were significantly improved, indicating that compounds WB-502 and WB-503 have a better protective effect on MCAO focal cerebral ischemia.
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| CN102757336A (en) * | 2012-07-17 | 2012-10-31 | 湖北远成药业有限公司 | Preparation method of caffeic acid |
| CN102942538A (en) * | 2012-11-07 | 2013-02-27 | 南京医科大学 | Substituted benzhydryl piperazine derivative and preparation method and application thereof |
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| CN102757336A (en) * | 2012-07-17 | 2012-10-31 | 湖北远成药业有限公司 | Preparation method of caffeic acid |
| CN102757336B (en) * | 2012-07-17 | 2014-11-05 | 湖北远成赛创科技有限公司 | Preparation method of caffeic acid |
| CN102942538A (en) * | 2012-11-07 | 2013-02-27 | 南京医科大学 | Substituted benzhydryl piperazine derivative and preparation method and application thereof |
| CN102942538B (en) * | 2012-11-07 | 2014-11-05 | 南京医科大学 | Substituted benzhydryl piperazine derivative and preparation method and application thereof |
| CN108658843A (en) * | 2017-03-30 | 2018-10-16 | 上海医药工业研究院 | Acetobenzylamide piperidine amides analog derivative and its application as neuroprotection agent |
| CN108658843B (en) * | 2017-03-30 | 2021-06-04 | 上海医药工业研究院 | Acetylbenzylamine piperidine amide derivative and application thereof as cerebral nerve protective agent |
| CN109651253A (en) * | 2017-10-12 | 2019-04-19 | 上海医药工业研究院 | Cinnamic acid ester derivant and its application as nerve protection medicine |
| CN109651253B (en) * | 2017-10-12 | 2022-03-25 | 上海医药工业研究院 | Phenylacrylate derivatives and their application as neuroprotective drugs |
| CN110128369A (en) * | 2019-05-27 | 2019-08-16 | 东南大学 | Benzo[d]isothiazol-3(2H)-one derivatives and their preparation methods and applications |
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Application publication date: 20100630 |