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CN104003983B - Benzene bis heterocyclic compounds, preparation and application of substituted seleno - Google Patents

Benzene bis heterocyclic compounds, preparation and application of substituted seleno Download PDF

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CN104003983B
CN104003983B CN 201410234882 CN201410234882A CN104003983B CN 104003983 B CN104003983 B CN 104003983B CN 201410234882 CN201410234882 CN 201410234882 CN 201410234882 A CN201410234882 A CN 201410234882A CN 104003983 B CN104003983 B CN 104003983B
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CN 201410234882
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CN104003983A (en )
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王宇光
吴中礼
朱冰春
李清思
张海梁
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浙江工业大学
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Abstract

本发明公开了一种含苯硒基取代的双杂环化合物及其制备与应用,所述含苯硒基取代的双杂环化合物的结构如式(VI‑1)或式(VI‑2)所示,其合成路线如下所示。 The present invention discloses a bis-substituted heterocyclic selenium compounds and their preparation and application benzene, a substituted benzene structure selenium bis heterocyclic compound of formula (VI-1) or Formula (VI-2) , the synthesis route is shown below. 所述的含苯硒基取代的双杂环化合物具有良好的单胺氧化酶抑制活性,可用于制备单胺氧化酶抑制剂。 The bis-substituted benzene selenium heterocyclic compound having excellent monoamine oxidase inhibitory activity, useful for preparing monoamine oxidase inhibitor.

Description

含苯砸基取代的双杂环化合物及其制备与应用1、 Bis-substituted benzene drop heterocyclic compounds and their preparation and application 1,

技术领域 FIELD

[0001] 本发明设及一种含苯砸基取代的双杂环化合物及其制备与应用,尤其是其在制备单胺氧化酶抑制剂中的应用。 [0001] The present invention is provided a two-heterocyclic compound and its preparation and application to drop-substituted benzene, in particular their use in the preparation of monoamine oxidase inhibitors. 2、 2,

背景技术 Background technique

[0002] 单胺氧化酶(monoamine oxidase ,MA0,ECl. 4.3.4)全名为单胺氧化还原酶,在19 世纪30年代由Balschko发现,是对神经递质代谢起重要作用的一种酶。 [0002] monoamine oxidase (monoamine oxidase, MA0, ECl. 4.3.4) full name of monoamine oxidase-reductase, discovered by Balschko in the 1830s, is an enzyme for the metabolism of neurotransmitters play an important role. 它在大脑和周围神经组织中催化一些生物体产生的胺,氧化脱氨产生过氧化氨。 It catalyzes the amine number of organisms in the brain and peripheral nervous tissues, oxidative deamination peroxide generating ammonia. 1968年,Johnston根据单胺氧化酶对其不可逆抑制剂Clorgyline(氯吉兰)的敏感度将其分成A和B两个亚类,单胺氧化酶A对clorgy line敏感,而单胺氧化酶B不敏感。 In 1968, Johnston according to their monoamine oxidase inhibitor, clorgyline irreversible susceptibility (clorgyline) will be divided into two subgroups A and B, monoamine oxidase A clorgy line sensitive to, and monoamine oxidase B insensitive. 进一步研究表明单胺氧化酶A对底物血清素(5-肌)、去甲肾上腺素(肥)、多己胺(DA)和抑制剂Clorgyline具有高亲和性;而单胺氧化酶B则对苯乙基胺(PEA)、苯甲胺和抑制剂d邱renyl(丙烘苯丙胺)具有高亲和性化uwahara T, 等,Agric.Biol .Qiem. , 1990,54,253-257.)。 Further studies have shown that monoamine oxidase A on the substrate, a serotonin (5-muscle), norepinephrine (fat), multi-hexylamine (DA) and inhibitors Clorgyline with high affinity; and monoamine oxidase B of the amine by-phenylethyl ( PEA), benzylamine and inhibitors d Qiu renyl (prop-bake amphetamine) has a high affinity of uwahara T, etc., Agric.Biol .Qiem., 1990,54,253-257.).

[0003] 研究表明单胺氧化酶在代谢多己胺的过程中,伴随产生自由基和过氧化氨等内源性物质,其表达量的异常与帕金森病,抑郁症和攻击性行为有着极其密切的关系。 [0003] Studies have shown that monoamine oxidase in the metabolic process of the multi-hexylamine, accompanied by endogenous substances such as free radicals and peroxide, ammonia, and its abnormal expression of Parkinson's disease, depression and aggressive behavior has a very close relationship . 随着人们生活节奏的逐渐加快,精神压力不断增加,抑郁症的发病率正迅速攀升,预计至2020年,将成为世界上仅次于冠屯、病的第二大疾病。 With the gradually accelerating pace of life, mental stress increasing incidence of depression is rapidly rising, is expected to 2020, will be the crown after village in the world, the second largest disease disease. 运一疾病的引发可能与单胺氧化酶(MAO)的异常有关,而单胺氧化酶抑制剂(MAOI)是一类特异性抑制体内MAO活性的药物,曾在50年代首个被用来治疗抑郁症。 Transport a disease initiator may monoamine oxidase (MAO) abnormalities, and monoamine oxidase inhibitors (MAOI) are a class of specific inhibition of in vivo MAO activity of the drug, was in the 1950s the first to be used to treat depression. 其机理是通过抑制MO,减少中枢神经系统内单胺类神经递质的降解, 相对增加中枢单胺类递质的浓度,提高情绪,产生抗抑郁作用。 The mechanism by inhibiting MO, reduce the degradation of the central nervous system neurotransmitter monoamine, a relative increase in the concentration of the Central Nervous System, improving mood, antidepressant effect. 临床用过的单氨氧化酶抑制剂有阱类的苯乙阱(Phenel Zine )、异烟阱(Isoni COtiny 1 hydrazide)、异丙烟阱(Iproniazid)、尼亚拉胺(Nialamide,)等,非阱类W反苯环丙胺(Tranylcypromine)为代表化algutkar,AS化em.Res.Toxicol. ,2001,14(9) ,1139-1162.)。 Clinical used monoamine oxidase inhibitors are well phenethyl trap class (Phenel Zine), isonicotinate well (Isoni COtiny 1 hydrazide), isopropyl smoke trap (Iproniazid), Nyala amine (Nialamide,) and the like, non-type well W tranylcypromine (tranylcypromine) represented of algutkar, aS of em.Res.Toxicol., 2001,14 (9), 1139-1162.). 由于运些药物大部分毒副作用较大,且对单胺氧化酶的作用效果单一,所W寻求低毒,效果良好的MAOI成为当今研究的新目标。 The arrival of these drugs most toxic side effects, and the single role of monoamine oxidase effect, the W seeking low toxicity, good results MAOI become the new target of today's research.

[0004] 含氮杂环化合物都表现出尤为不错的单胺氧化酶抑制活性,特别是Mazouz,F.等报道不同取代基的1,3,4-嗯二挫酬类化合物衍生物具有单胺氧化酶抑制活性(Mazouz,F. 等,J Med Chem.,1993,36,6394-63981157-1167)。 A nitrogen-containing heterocyclic compounds [0004] exhibit particularly good monoamine oxidase inhibitory activity, especially Mazouz, F. Et al reported two different setback 1,3,4 ah pay compound derivative having a substituent monoamine oxidase inhibitory activity (Mazouz , F. et, J Med Chem., 1993,36,6394-63981157-1167). 异嗯挫类化合物存在于众多的天然产物骨架中,是一类具有很好的生物活性或潜在生物活性的物质,已渐渐成为重要的医药中间体及先导化合物。 Iso ah setback compounds present in the backbone of many natural product, is a class of substances with good biological activity or potential biological activity, has gradually become an important pharmaceutical intermediates and lead compounds. 例如,异嗯挫类化合物具有很好的抗菌、抗炎、抗肿瘤等生物学活性(贺红武等.农药.,2000,39(8),4-7)。 For example, compounds having different ah setback biologically active form antibacterial, anti-inflammatory, anti-tumor (He Hongwu etc. pesticides., 2000, 39 (8), 4-7). 异嗯挫化合物还被报道具有单胺氧化酶抑制活性,例如,兼有异嗯挫和酷阱运两种活性基团的化合物异卡波阱是第一代单胺氧化酶抑制剂;刘冰妮报道含有异嗯挫环的化合物表现出一定的单胺氧化酶抑制活性巧IJ冰妮等,合成化学.,2011, 19(6) ,734-736.)。 Iso ah setback compound is also reported to have monoamine oxidase inhibitory activity, e.g., compounds both iso ah setback and cool the well operation of the two active groups isocarboxazid well is a first generation monoamine oxidase inhibitor; Liu ni reported to contain heterologous ah setback ring compounds show some monoamine oxidase inhibitory activity ice Ni IJ Qiao et al., synthetic Chemistry, 2011, 19 (6), 734-736.). 本发明将异嗯挫环或S挫环引入到嗯二挫环,合成了一系列新型含苯砸基取代的双杂环化合物,它们具有很好的单胺氧化酶抑制活性,是一类很好的单胺氧化酶抑剂(MAOIs )。 The present invention iso ah setback ring or S setback ring into ah two frustrated ring, series of novel benzene drop-substituted bis heterocyclic compounds, which have excellent monoamine oxidase inhibitory activity, is a kind of good monoamine oxidase inhibitors (MAOIs). 3、发明内容 3. SUMMARY OF THE INVENTION

[0005] 本发明的第一个目的是提供一种具有良好的单胺氧化酶抑制活性的含苯砸基取代的双杂环化合物。 [0005] A first object of the present invention is to provide an excellent monoamine oxidase inhibitory activity heterocyclic compound bis-substituted benzene drop.

[0006] 本发明的第二个目的是提供一种制备所述含苯砸基取代的杂环化合物的方法。 [0006] A second object of the present invention is to provide a process for preparing the benzene-containing group substituted hit heterocyclic compound.

[0007] 本发明的第=个目的是提供所述含苯砸基取代的双杂环化合物在制备单胺氧化酶抑制剂中的应用。 [0007] The first object of the present invention = is to provide the application hit benzene substituted heterocyclic compound in the preparation of bis monoamine oxidase inhibitors.

[0008] 下面对为实现本发明目的而采用的技术方案做具体说明。 [0008] What follows is a detailed description of the technical solution to achieve the object of the present invention is employed.

[0009] 本发明提供了一种含苯砸基取代的双杂环化合物,其结构如式(VI)所示: [0009] The present invention provides a heterocyclic compound of the bis-substituted benzene hit, such as the structure of formula (VI) below:

Figure CN104003983BD00071

[OOU] 式(VIII)中,Ri为芳基;[0014] 式(K)中,R2选自下列基团之一: In [OOU] of formula (VIII), Ri is an aryl group; in the [0014] Formula (K), R2 is selected from one of the following groups:

[0010] [0010]

[001U 的基团: [001U groups:

[0012] [0012]

[00巧] [00 clever]

Figure CN104003983BD00072

芳基,苄基; An aryl group, a benzyl group;

[0016]所述芳基未被取代或被下列基团中的一种或几种取代:C1-C3的烷基、面素、C1-C3 的烷氧基、=氣甲基; [0016] The aryl group unsubstituted or substituted with one kind of the following groups or several substituents: C1-C3 alkyl group, the surface element, C1-C3 alkoxy, gas = methyl;

[0017]护、於、1?5、护各自独立选自(:1-〔6的烷基。 [0017] protection at, 15, is independently selected guard (:? 1- [6 alkyl.

[0018] 具体的,本发巧所沐的含龙砸基取代的双杂环化合物可分为W下两类: [0018] Specifically, the present invention Qiao Mu bis-containing heterocyclic compound group substituted Long drop W can be divided into the categories:

[0019 [0019

Figure CN104003983BD00073

[0020] 进一步,Ri为未被取代或被下列基团中的一种或几种取代的苯基:C1-C3的烷基、 面素、C1-C3的烷氧基、=氣甲基。 [0020] Further, Ri of which is unsubstituted or one or more of the group consisting of substituted phenyl: C1-C3 alkyl group, the surface element, C1-C3 alkoxy, = methyl gas.

[0021] 进一步,R2选自下列基团之一: [0021] Further, R2 is selected from one of the following groups:

[0022] [0022]

Figure CN104003983BD00074

苯基,面素取代的苯基,苄基。 Phenyl, substituted phenyl prime face, a benzyl group.

[0023] 更进一步,R3、R4、r5、R6各自独立选自C1-C4的烷基。 [0023] Still further, R3, R4, r5, R6 are each independently selected from C1-C4 alkyl group.

[0024] 更进一步,R2选自下列基团之一: [0024] Still further, R2 is selected from one of the following groups:

[00巧] [00 clever]

Figure CN104003983BD00081

苯基,面素取代的苯基,苄基。 Phenyl, substituted phenyl prime face, a benzyl group.

[00%]更进一步,所述的面素为F、C1或化。 [00%] Furthermore, the surface element is F, C1 or chemical.

[0027]再更进一步,所述的含苯砸基取代的双杂环化合物为下列之一: [002引 [0027] Still further again, said bis-substituted benzene hit one of the following heterocyclic compounds: [002 primer

[0( [0 (

Figure CN104003983BD00082

[0030] 本发明还提供了一种制备式(VI-I)所示的含苯砸基取代的双杂环化合物的方法, 所述方法包括: [0030] The present invention also provides a method drop benzene bis-substituted heterocyclic compound of formula a (VI-I) shown, the method comprising:

[0031] (1)式(虹)所示的含苯砸基的中间产物的制备: [0031] The intermediate product benzene drop group (1) of formula (Hong) prepared as shown:

[00391 [00391

Figure CN104003983BD00091

[0033] 在反应容器中加入有机溶剂B、式(II)所示的a-苯砸基正丙醒和式(VII)所示的对径基苯阱,使之完全溶解后加入醋酸,然后在氮气保护下回流反应1-3小时,反应完全后经分离纯化得到式(III)所示的含苯砸基的中间产物; [0033] adding an organic solvent in the reaction vessel B, A- benzene of formula (II) shown in hit-n-propyl and wake of formula (VII) shown on the benzene diameter wells, and dissolved completely after the addition of acetic acid, and then intermediate hit benzene group refluxed under nitrogen for 1-3 hours, after the completion of the reaction of formula (III) was purified by shown;

[0034] (2)式(IV)所示的含苯砸基的嗯二挫类化合物的制备: [0034] Preparation of compounds setback ah two benzene (2) of formula (IV) shown hit groups:

[003J [003J

Figure CN104003983BD00092

[0036] 在反应容器中加入式(III)所示的含苯砸基的中间产物和乙酸酢,反应完毕后经分离纯化得到式(IV)所示的含苯砸基的嗯二挫类化合物; [0036] added to the formula (III) shown in the reaction vessel to drop benzene group intermediates and Health acetate, obtained after the completion of the reaction was purified by formula (IV) shown in benzene drop ah two groups setback compound ;

[0037] (3)式(V)所示的含末端S键的嗯二挫类化合物的制备: [0037] Preparation of compound ah two setback S bond-containing end (3) of formula (V) shown below:

[0038 [0038

Figure CN104003983BD00093

[0039] 在反应容器中加入有机溶剂C、式(IV)所示的含苯砸基的嗯二挫类化合物、碳酸钟,揽拌下缓慢加入烘丙基漠,在氮气保护下回流反应3~5小时,反应完毕后经分离纯化得到式(V)所示的含末端=键的嗯二挫类化合物; [0039] C is added an organic solvent in the reaction vessel, benzene of formula (IV) shown hit ah two groups fell compound, carbonate minutes, the mix was slowly added to embrace bake propyl desert, the reaction was refluxed under nitrogen for 3 to 5 hours, to give the formula (V) after completion of the reaction was shown with terminal purification ah = bond fell two compounds;

[0040] (4)式(VI-I)所示的含苯砸基取代的双杂环化合物的制备: [0040] Preparation of benzene (4) of formula (VI-I) represented by the double drop-substituted heterocyclic compound:

Figure CN104003983BD00094

LUU4Z」 '1义;tVAA;尸矢'忙百''物与JlN-录W~J ^邸:业妝化巧f化銜•化IUT全湿•仅雌4- 5小时,然后加入式(V)所示的含末端=键的嗯二挫类化合物和=乙胺反应5~8小时,反应完全后经分离纯化得到式(VI-I)所示的含苯砸基取代的双杂环化合物; LUU4Z " '1 sense; tVAA; dead vector' busy one hundred 'was recorded with JlN- W ~ J ^ Di: f industry makeup of coincidence of the title • • IUT all wet estrogen only 4-5 hours, then the formula ( benzene V) containing terminal keys ah = setback two compounds represented by the reaction of diethylamine and 5 to 8 hours, after the completion of the reaction formula (VI-I) was purified by FIG hit bis-substituted heterocycle compound;

[0043]式(X)中,Ri的定义同式(VI-1)。 In [0043] formula (X), Ri is defined with the formula (VI-1).

[0044] 进一步,步骤(1)中,有机溶剂B选自下列之一:乙醇、四氨巧喃、乙腊。 [0044] Further, the step (1), the organic solvent B is selected from one of the following: ethanol, tetraammine clever furans, acetate wax.

[0045] 进一步,步骤(1)中,a-苯砸基正丙醒、式(VII)所示的对径基酷阱、醋酸的投料摩尔比为1:1:10~15。 [0045] Further, the step (1), A- phenyl-n-propyl wake drop, of formula (VII) as shown in the group cool diameter wells, acetic acid feed molar ratio of 1: 1: 10 to 15.

[0046] 进一步,步骤(2)中,乙酸酢的加入体积量W式(III)所示的含苯砸基的中间产物的摩尔数计为(4~6)mL/mmol。 [0046] Further, the step (2), the intermediate product of the number of moles of benzene was added acetic acid by volume vinegar amount W of formula (III) is shown in terms of hit-yl (4 ~ 6) mL / mmol.

[0047] 进一步,步骤(2)中,反应时间在3~4小时。 [0047] Further, the step (2), the reaction time is 3 to 4 hours.

[004引进一步,步骤(3)中,有机溶剂C选自下列之一:丙酬、N,N-二甲基甲酯胺。 [004 one of the following primers Further, step (3), the organic solvent C is selected from: propyl pay, N, N- dimethyl ester amine.

[0049] 进一步,步骤(3)中,式(IV)所示的含苯砸基的嗯二挫类化合物与碳酸钟、烘丙基漠的投料摩尔比为1:1~1.3:1.2~1.5。 [0049] Further, step (3), and ah two setback carbonate compound bell, the drying desert feed propyl benzene of formula (IV) shown hit group molar ratio of 1: 1 to 1.3: 1.2 to 1.5 .

[0050] 进一步,步骤(4)中,有机溶剂D选自下列之一:二氯甲烧、=氯甲烧、四氨巧喃。 [0050] Further, the step (4), the organic solvent D is selected from one of the following: dichloromethane burn, burn A = chloro, tetraammine clever furans.

[0051] 进一步,步骤(4)中,式(V)所示的含末端=键的嗯二挫类化合物、式(X)所示的月亏类化合物、N-氯代下二酷亚胺、S乙胺的投料摩尔比为1:1.5~2:1.5~2:2~3。 [0051] Further, the step (4), two months ah = fell compound containing a terminal bond of formula (V) represented by the formula (X) compound represented by the loss, the cool two-chloro-N- imine , S molar feed ratio of amine is 1: 1.5 to 2: 1.5 to 2: 2 to 3.

[0052] 本发明还提供了一种制备式(VI-2)所示的含苯砸基取代的双杂环化合物的方法, 所述方法包括: [0052] The present invention further provides a method of preparing the one shown in benzene of formula (VI-2) double hit substituted heterocyclic compound, said method comprising:

[0053] (a)式(虹)所示的含苯砸基的中间产物的制备: [0053] The intermediate product benzene drop group (a) of formula (Hong) prepared as shown:

[0化4] [0 of 4]

Figure CN104003983BD00101

[0055] 在反应容器中加入有机溶剂B、式(II)所示的a-苯砸基正丙醒和式(VII)所示的对径基苯阱,使之完全溶解后加入醋酸,然后在氮气保护下回流反应1-3小时,反应完全后经分离纯化得到式(III)所示的含苯砸基的中间产物; [0055] adding an organic solvent in the reaction vessel B, A- benzene of formula (II) shown in hit-n-propyl and wake of formula (VII) shown on the benzene diameter wells, and dissolved completely after the addition of acetic acid, and then intermediate hit benzene group refluxed under nitrogen for 1-3 hours, after the completion of the reaction of formula (III) was purified by shown;

[0056] (b)式(IV)所示的含苯砸基的嗯二挫类化合物的制备: [0056] Preparation of compounds setback ah two benzene (b) of formula (IV) shown hit groups:

[005 III [005 III

Figure CN104003983BD00102

王, king,

[0058] 在反应容器中加入式(III)所示的含苯砸基的中间产物和乙酸酢,反应完毕后经分离纯化得到式(IV)所示的含苯砸基的嗯二挫类化合物; [0058] added to the formula (III) shown in the reaction vessel to drop benzene group intermediates and Health acetate, obtained after the completion of the reaction was purified by formula (IV) shown in benzene drop ah two groups setback compound ;

[0059] (C)式(V)所示的含末端S键的嗯二挫类化合物的制备: [0059] Preparation of compound ah two setback S bond-containing end (C) of formula (V) shown below:

[0060] [0060]

Figure CN104003983BD00103

[0061]在反应容器中加入有机溶剂C、式(IV)所示的含苯砸基的嗯二挫类化合物、碳酸钟,揽拌下缓慢加入烘丙基漠,在氮气保护下回流反应3~5小时,反应完毕后经分离纯化得到式(V)所示的含末端=键的嗯二挫类化合物; [0061] C is added an organic solvent in the reaction vessel, benzene of formula (IV) shown hit ah two groups fell compound, carbonate minutes, the mix was slowly added to embrace bake propyl desert, the reaction was refluxed under nitrogen for 3 to 5 hours, to give the formula (V) after completion of the reaction was shown with terminal purification ah = bond fell two compounds;

[0062] (d)式(VI-2)所示的含苯砸基取代的双杂环化合物的制备: 「r\r\'o 1 Preparation of Benzene [0062] (d) represented by formula (VI-2) double hit substituted heterocyclic compound: "r \ r \ 'o 1

Figure CN104003983BD00111

[0064]使式(V)所示的含末端=键的嗯二挫类化合物溶于溶剂E中,依次加入五水硫酸铜和抗坏血酸,揽拌溶解后加入式(XI)所示的叠氮化合物,室溫揽拌反应6-8小时,反应完全后经分离纯化得到式(VI-2)所示的含苯砸基取代的双杂环化合物; [0064] formula (V) shown containing two terminal ah = bond setback compound E is dissolved in a solvent, were added copper sulfate pentahydrate and ascorbic acid, azide was added to dissolve rear embrace mixed (XI) shown in FIG. compound, reaction was stirred for 6-8 hours at room temperature embrace, after completion of the reaction was purified by formula shown in (VI-2) a benzene-containing bis-substituted heterocyclic compound hit;

[00化]式(XI)中,r2的定义同式(VI-2)。 In [of 00] of formula (XI), r2 defined for formula (VI-2).

[0066] 步骤(a)-步骤(C)即上述步骤(1)-步骤(3),其制备细节在此不再寶述。 [0066] Step (A) - Step (C) i.e. the above step (1) - Step (3), which details the preparation of which is not described treasure.

[0067] 步骤(d)中,溶剂E选自下列之一:THF和水的混合溶剂、二甲亚讽。 [0067] step (d), the solvent is E is selected from one of the following: a mixed solvent of THF and water, dimethylsulfoxide ridicule.

[0068] 步骤(d)中,式(V)所示的含末端=键的嗯二挫类化合物、五水硫酸铜、抗坏血酸、 叠氮化合物的投料摩尔比为1:0.05~0.1:0.15~0.25:1.3~1.6。 [0068] step (d), a compound containing ah two end setback = bond of formula (V) as shown in, copper sulfate pentahydrate, ascorbic acid, azide feed molar ratio of 1: 0.05 to 0.1: 0.15 0.25: 1.3 to 1.6.

[0069] 本发明使用的原料式(II)所示的a-苯砸基正丙醒可按照现有文献报道的方法通过如下方程式制备: [0069] The starting material used in the present invention of formula (II) a- phenyl-n-propoxy shown hit wake prepared according to the following equation can be obtained by conventional methods reported in the literature:

[0070] [0070]

Figure CN104003983BD00112

[0071] 本发明所述的含苯砸基取代的双杂环化合物具有良好的单胺氧化酶抑制活性,尤其是MO-B抑制活性,故可用于制备单胺氧化酶(尤其是MO-B)抑制剂。 [0071] bis heterocyclic compound drop-substituted benzene according to the present invention has excellent monoamine oxidase inhibitory activity, especially MO-B inhibitory activity, it can be used for the preparation of monoamine oxidase (especially MO-B) inhibitors.

[0072] 本发明的有益效果在于提供了一类新的具有良好的的单胺氧化酶抑制活性的含苯砸基取代的双杂环化合物。 [0072] Advantageous effects of the present invention is to provide a new class of excellent monoamine oxidase inhibitory activity of the bis-substituted benzene drop heterocyclic compound. 4、具体实施方式 4. DETAILED DESCRIPTION

[0073] 下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此: [0073] The following embodiments in conjunction with specific embodiments of the present invention is further described, although the scope of the present invention is not limited thereto:

[0074] 实施例1含异嗯挫的嗯二挫类化合物衍生物VI-1-1.的合成[007; [0074] Example 1 containing two different ah ah setback of the setback-based compound derivative VI-1-1 Synthesis of [007.;

Figure CN104003983BD00113

[0076] 1)将等当量的日-苯砸基丙醒(0.213旨,1111111〇1)与对径基苯阱(1111111〇1,0.152旨)加入含有20ml乙醇的圆底烧瓶中,揽拌使之完全溶解,再加入S(K)化醋酸,在氮气保护下回流反应化。 [0076] 1) The equivalent daily - phenyl propan-yl wake drop (0.213 purpose, 1111111〇1) benzene and diameter of the well (1111111〇1,0.152 purpose) was added to a round bottom flask containing 20ml ethanol, mixed with olive completely dissolved, then added to S (K) of acetic acid, at reflux of the reaction under nitrogen. TLC检测反应完全后,抽干乙醇,添加20血C也Ch,用饱和Na2〇)3溶液(3 X 20血)水溶液洗涂,无水Na2S〇4干燥,浓缩,得到含苯砸基的中间产物(虹)粗产物。 After completion of the reaction by TLC, drained of ethanol, the blood was added 20 C also Ch, Na2〇 with saturated) aqueous solution (3 X-20 blood) wash-coated, dried over anhydrous Na2S〇4, and concentrated to give an intermediate benzene drop group The product (Hong) of crude product.

[0077] 2)将得到的产物(In)(Immol)加入到5mL的醋酸酢中,在氮气保护下加热回流反应3h,溶液颜色变为枯红色并有悬浮物生成。 [0077] 2) The product obtained in (In) (Immol) was added to 5mL of acetic acid in the vinegar, the reaction was heated to reflux under nitrogen for 3h, the solution color changes to red and dry suspended solids generated. TLC检测反应完全后,抽干乙酸酢,添加20mLC此Cl2,用饱和化2〇)3溶液(3 X 20mL)水溶液洗涂来除去未抽干的乙酸酢,再用无水Na2S〇4干燥,浓缩,经薄板层析分离得到产物(IV),产率75 %。 After completion of the reaction by TLC, drained of Health acetate, this added 20mLC Cl2, washed with saturated of 2〇) 3 solution (3 X 20mL) solution to remove the non-washcoated drain of Health acetate, and then dried over anhydrous Na2S〇4, concentrated and purified by chromatography to give the sheet product (IV), 75% yield.

[007引3)将Immol(0.390g)化合物IV溶于20mL丙酬中,再加入(1.5mmol,0.207g)碳酸钟, 揽拌下缓慢加入(1.2mmol,0.143g)烘丙基漠,在氮气保护下回流反应化。 [007 primer 3) Immol (0.390g) was dissolved in 20mL Compound IV propan paid, then add (1.5mmol, 0.207g) carbonate clock, embrace stirred slowly added (1.2mmol, 0.143g) propyl desert drying, in of reflux under nitrogen. TLC检测反应完全后,抽干丙酬,添加20mLC此C12,用饱和化20)3溶液(3 X 20mL)水溶液洗涂,无水化2S化干燥, 浓缩,经薄板层析后得到化合物V。 After completion of the reaction by TLC, propyl drained paid, this added 20mLC C12, washed with saturated coating of 20) 3 solution (3 X 20mL) solution, dried over anhydrous technology of 2S, concentrated and purified by TLC to give the compound V.

[0079] 4)先将对甲基苯目亏(2mmol,0.272g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应4h,再加入化合物¥(1111111〇1,0.388旨)并滴加入^乙胺(2111111〇1, 0.28mL)反应6个小时,TLC检测大部分反应完全后,加入饱和氯化钢分层,有机相饱和氯化钢水洗(30mL X 3),有机相无水硫酸儀干燥,浓缩,薄板层析得VI-1-1.,产率82.5 %。 [0079] 4) Methylphenyl first head loss (2mmol, 0.272g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 for 4h at room temperature, was added the compound ¥ (1111111〇1,0.388 purpose) was added dropwise and ^ ethylamine (2111111〇1, 0.28 mL) 6 hours of reaction, the reaction TLC detect most complete, saturated steel chloride layers were separated and the organic phase washed with saturated steel chloride (30mL X 3), The organic phase was dried over anhydrous sulfate meter, and concentrated to thin layer chromatography to give VI-1-1., yield 82.5%. 产物表征方法:Ir醒R由化址er Avance核磁共振仪测定,I3C醒R由化址er Avance核磁共振仪测定,用CDC13作溶剂,TMS作内标。 Product characterization: Ir measured by the wake of the R address er Avance NMR spectrometer, I3C R wake of the measurement site er Avance NMR spectrometer, using CDC13 as solvent, TMS as internal standard. FT-IR由化址er Tensor27型红外光谱仪测定,固体采用邸r 压片法,液体采用液膜法。 FT-IR er address of the Tensor27 infrared spectrometer, using Di r tableting solid, liquid using liquid membrane. 结果如下: The results are as follows:

[0080] Ih NMR(400MHz,CDC13)S1h NMR(400MHz,CDCl3)S7.70(d,J = 7.9Hz,2H),7.62(d,J = 7.8Hz,2H),7.52-7.48(m,4H),7.37-7.17(m,5H),6.92(d,J = 8.5Hz,lH),6.35(s,lH), 4.10(dd,J = 49.1,14.1Hz,lH),2.46(s,2H),2.40(s,3H),1.62(s,3H),1.25(d,J = 4.細z, 3H).IRv"ax(cm"^) :3375,2971,1767,1665,1599,1562,1508,1493,1432,1397,1210,1193, 1122,1087,927,891,789,690,525,480.MS化SI)m/z562.1(M+H) +. [0080] Ih NMR (400MHz, CDC13) S1h NMR (400MHz, CDCl3) S7.70 (d, J = 7.9Hz, 2H), 7.62 (d, J = 7.8Hz, 2H), 7.52-7.48 (m, 4H ), 7.37-7.17 (m, 5H), 6.92 (d, J = 8.5Hz, lH), 6.35 (s, lH), 4.10 (dd, J = 49.1,14.1Hz, lH), 2.46 (s, 2H) , 2.40 (s, 3H), 1.62 (s, 3H), 1.25 (d, J = 4. thin z, 3H) .IRv "ax (cm" ^): 3375,2971,1767,1665,1599,1562, 1508,1493,1432,1397,1210,1193, 1122,1087,927,891,789,690,525,480.MS of SI) m / z562.1 (m + H) +.

[0081 ] 实施例2含异嗯挫的嗯二挫类化合物衍生物VI-1-2.的合成 2 Synthesis of Iso ah ah two setback setback compound derivative VI-1-2. In [0081] Example

[0082] [0082]

Figure CN104003983BD00121

12345 1)探作如买施例1步骤1 2 2)操作如实施例1步骤2 3 3)操作如实施例1步骤3 4 4)先将对甲氧基苯目亏(2mmol,0.288g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应3h,再加入化合物¥(1111111〇1,0.388旨)并滴加入^乙胺(2111111〇1, 0.28mL)反应6个小时,TLC检测大部分反应完全后,后续处理如实施例1步骤4,经薄板层析得VI-I-2.,产率85%。 123451) as a probe as in Example 1, Step Buy 122) operating as described in Example 1, step 233) operating as described in Example 1, step 344) for first-methoxybenzene head loss (2mmol, 0.288g) with an equivalent of NCS (2mmol, 0.268g) was dissolved at room temperature for 3h 20mLCH2Cl2, ¥ compound was added (1111111〇1,0.388 purpose) was added dropwise ethylamine ^ (2111111〇1, 0.28mL) reaction 6 h, TLC detect most after completion of the reaction, subsequent treatment as in Example 1, step 4, by thin layer chromatography to give VI-I-2., yield 85%. 产物表征结果如下: 5 Ih NMR(400MHz,CDCl3)S7.75-7.72(m,4H),7.68-7.64(m,4H),7.30(d,J = 3.5Hz, 2H),7.12-7.10(m,3H),6.99(d,J = 8.細z,lH),6.62(s,lH),5.24(s,2H),3.94-3.62(m, 1H),3.85(s,3H),2.31 (s,3H),1.34(d,J = 7.2Hz,3H); IRv^knfi) :3120,2976,2920,2820, 1665,1607,1580,1562,1504,1455,1409,1234,1210,1167,1122,1098,1026,927,803,708, 690,503,414,338.MS(ESI)m/z578.1(M+H)+. Results product was characterized as follows: 5 Ih NMR (400MHz, CDCl3) S7.75-7.72 (m, 4H), 7.68-7.64 (m, 4H), 7.30 (d, J = 3.5Hz, 2H), 7.12-7.10 (m , 3H), 6.99 (d, J = 8. fine z, lH), 6.62 (s, lH), 5.24 (s, 2H), 3.94-3.62 (m, 1H), 3.85 (s, 3H), 2.31 ( s, 3H), 1.34 (d, J = 7.2Hz, 3H); IRv ^ knfi): 3120,2976,2920,2820, 1665,1607,1580,1562,1504,1455,1409,1234,1210,1167, 1122,1098,1026,927,803,708, 690,503,414,338.MS (ESI) m / z578.1 (m + H) +.

[0088] 连施例3含择鴨畔的鴨二畔类化合物祈牛物VI-1-3.的合成[0089 [0088] Example 3 containing even duck duck Optional banks of two banks compound was imperative bovine VI-1-3. Synthesis of [0089

Figure CN104003983BD00131

[0090 J 1)操作如实施例1步骤1 Example 1 Step [0090 J 1) Operating as in Example 1

[0091] 2)操作如实施例1步骤2 Step 1 Example [0091] 2) The operation of Example 2

[0092] 3)操作如实施例1步骤3 [0092] 3) Operating as described in Example 1 Step 3

[OOW] 4)先将对氯苯目亏(2mmol,0.313g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应3h,再加入化合物V (lmmol,0.388g)并滴加入S乙胺(2mmol, 0.28mL)反应6个小时,TLC检测大部分反应完全后,后续处理如实施例1步骤4,经薄板层析得VI-1-3.,产率71 %。 [OOW] 4) p-chlorophenyl first head loss (2mmol, 0.313g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 reaction at room temperature for 3h, then was added compound V (lmmol, 0.388g) and S was added dropwise triethylamine (2mmol, 0.28mL) 6 hours of reaction, the reaction mostly complete after detecting TLC, subsequent treatment as in Example 1, step 4, by thin layer chromatography to give VI-1-3., yield 71%. 产物表征结果如下: Product was characterized as follows:

[0094] Ih NMR(400MHz,CDCl3)S7.68-7.60(m,4H),7.52(d,J = 8.5Hz,2H),7.37-7.17(m, 7H),6.92(d J = 8.甜z,lH),6.35(s,lH),4.10(ddJ = 49.1,14.1Hz,lH),2.47(s,2H),2.40 (s,3H),I. 25(d,J = 4.6Hz,3H); IRvmax(cm-i) :3031,2922,2867,1884,1760,1618,1578, 1551,1487,1445,1398,1376,1206,1175,1109,1088,1038,1014,938,802,739,630,483, 376.MS(ESI )m/z582.1 (M+H) +,584.1 (M+化H) +. [0094] Ih NMR (400MHz, CDCl3) S7.68-7.60 (m, 4H), 7.52 (d, J = 8.5Hz, 2H), 7.37-7.17 (m, 7H), 6.92 (d J = 8. Sweet z, lH), 6.35 (s, lH), 4.10 (ddJ = 49.1,14.1Hz, lH), 2.47 (s, 2H), 2.40 (s, 3H), I. 25 (d, J = 4.6Hz, 3H ); IRvmax (cm-i): 3031,2922,2867,1884,1760,1618,1578, 1551,1487,1445,1398,1376,1206,1175,1109,1088,1038,1014,938,802,739,630,483, 376.MS (ESI) m / z582.1 (m + H) +, 584.1 (m + of H) +.

[OOM] 实施例4含异嗯挫的嗯二挫类化合物衍生物VI-1-4.的合成 VI-1-4. Synthesis of the compound setback derivatives containing different ah ah setback [the OOM] Example 4

[0096 [0096

Figure CN104003983BD00132

[0097] 1)操作如实施例1步骤1 Step 1 Example [0097] 1) The operation of Example 1

[0098] 2)操作如实施例1步骤2 Step 1 Example [0098] 2) The operation of Example 2

[0099] 3)操作如实施例1步骤3 [0099] 3) Operating as described in Example 1 Step 3

[0100] 4)先将对氣苯朽(2mmol,0.280g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应3h,再加入化合物V(lmmol,0.388g)并滴加入S乙胺(2mmol, 0.28mL)反应6个小时,TLC检测大部分反应完全后,后续处理如实施例1步骤4,经薄板层析得VI-I-4.,产率78%。 [0100] 4) of the first gas benzene mortal (2mmol, 0.280g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 reaction at room temperature for 3h, then was added compound V (lmmol, 0.388g) dropwise and S was added triethylamine (2mmol, 0.28mL) 6 hours of reaction, TLC detect most complete reaction, subsequent treatment as in Example 1, step 4, by thin layer chromatography to give VI-I-4., yield 78%. 产物表征结果如下: Product was characterized as follows:

[0101] Ih NMR(400MHz,CDCl3)S7.75(d,J = 9.0Hz,2H),7.68-7.64(m,4H),7.33-7.28(m, 4H),7.16(d,J=1.7Hz,2H),7.13-7.10(m,lH),6.92(d,J = 8.7Hz,lH),6.63(s,lH),4.10 (dd,J = 49.1,14.1Hz,lH),2.46(s,2H),2.32(s,3H),1.37-1.35(m,3H);IRvmax(cm-i) :3042, 2927,1708,1613,1601,1551,1507,1454,1409,1223,1158,1114,1026,1019,842,814,730, 678,501,452,422..MS化SI)m/z566.1(M+H) +. [0101] Ih NMR (400MHz, CDCl3) S7.75 (d, J = 9.0Hz, 2H), 7.68-7.64 (m, 4H), 7.33-7.28 (m, 4H), 7.16 (d, J = 1.7Hz , 2H), 7.13-7.10 (m, lH), 6.92 (d, J = 8.7Hz, lH), 6.63 (s, lH), 4.10 (dd, J = 49.1,14.1Hz, lH), 2.46 (s, 2H), 2.32 (s, 3H), 1.37-1.35 (m, 3H); IRvmax (cm-i): 3042, 2927,1708,1613,1601,1551,1507,1454,1409,1223,1158,1114, 1026,1019,842,814,730, 678,501,452,422..MS of SI) m / z566.1 (m + H) +.

[0102] 实施例5含异嗯挫的嗯二挫类化合物衍生物VI-1-5.的合成[0103 Synthesis of 5 [0103 containing two different ah ah setback of the setback-based compound derivative VI-1-5. In [0102] Example

Figure CN104003983BD00141

[0104」 U探化观头她例i巧耀i [0104 "U exploration of the concept of her head cases Yao Qiao i i

[0105] 2)操作如实施例1步骤2 Step 1 Example [0105] 2) The operation of Example 2

[0106] 3)操作如实施例1步骤3 [0106] 3) Operating as described in Example 1 Step 3

[0107] 4)先将对S氣甲基苯目亏(2mmol,0.380g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应3h,再加入化合物V (Immol,0.388g)并滴加入S乙胺(2mmol, 0.28mL)反应6个小时,TLC检测大部分反应完全后,后续处理如实施例1步骤4,经薄板层析得VI-I-5.,产率72%。 [0107] 4) of the first S-methylbenzene gas losses mesh (2mmol, 0.380g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 reaction at room temperature for 3h, then was added compound V (Immol, 0.388 g) and triethylamine was added dropwise S (2mmol, 0.28mL) 6 hours of reaction, the reaction mostly complete after detecting TLC, subsequent treatment as in Example 1, step 4, by thin layer chromatography to give VI-I-5., yield 72%. 产物表征结果如下: Product was characterized as follows:

[010引Ih NMR(400MHz,CDCl3)S7.75-7.56(m,4H),7.28-7.25(m,4H),7.16-7.13(m,2H), 7.10-7.03(m,3H),6.69-6.68(m,lH),6.64(s,lH),5.27(s,2H),3.86(dd,J=14.1,9.8Hz, IH),2.31 (S,3H),I. :M(d J = 7.2Hz,3H); IRvmax(cm-I): 3475,3390,2971,1767,1665,1626, 1551,1524,1444,1324,1210,1184,I157,1110,1063,1010,927,830,691,599,505,428.MS 化SI)m/z616.1(M+H)+. [010 cited Ih NMR (400MHz, CDCl3) S7.75-7.56 (m, 4H), 7.28-7.25 (m, 4H), 7.16-7.13 (m, 2H), 7.10-7.03 (m, 3H), 6.69- 6.68 (m, lH), 6.64 (s, lH), 5.27 (s, 2H), 3.86 (dd, J = 14.1,9.8Hz, IH), 2.31 (S, 3H), I:. m (d J = 7.2Hz, 3H); IRvmax (cm-I): 3475,3390,2971,1767,1665,1626, 1551,1524,1444,1324,1210,1184, I157,1110,1063,1010,927,830,691,599,505,428.MS of SI ) m / z616.1 (m + H) +.

[0109]实施例6含异嗯挫的嗯二挫类化合物衍生物VI-1-6.的合成[0110 Setback two different compounds containing derivatives ah ah setback [0109] Example 6 VI-1-6. Synthesis of [0110

Figure CN104003983BD00142

[0111] 1)操作如实施例1步骤1 Step 1 Example [0111] 1) The operation of Example 1

[0112] 2)操作如实施例1步骤2 Step 1 Example [0112] 2) The operation of Example 2

[0113] 3)操作如实施例1步骤3 [0113] 3) Operating as described in Example 1 Step 3

[0114] 4)先将对间漠苯目亏(2mmol,0.402g)与等当量的NCS(2mmol,0.268g)溶解于20mLCH2Cl2在室溫下反应3h,再加入化合物¥(1111111〇1,0.388旨)并滴加入^乙胺(2111111〇1, 0.28mL)反应6个小时,TLC检测大部分反应完全后,后续处理如实施例1步骤4,经薄板层析得VI-I-6.,产率76%。 [0114] 4) of the first head loss between desert benzene (2mmol, 0.402g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 reaction at room temperature for 3h, then was added compound ¥ (1111111〇1,0.388 purpose) was added dropwise and ^ ethylamine (2111111〇1, 0.28 mL) 6 hours of reaction, TLC detect most reaction was completed, the subsequent treatment as in Example 1, step 4, by thin layer chromatography to give VI-I-6., yield 76%. 产物表征结果如下: Product was characterized as follows:

[0115] Ih 醒R(400MHz,CDCl3)S7.99-7.93(m,4H),7.75(d,J = 7.8Hz,2H),7.68(d,J = 4.6Hz,2H),7.36-7.32(m,2H),7.26-7.23(m,3H),6.87-6.82(m,lH),6.58(s,lH),5.21(s, 2H),3.97-3.92(m, IH),2.34(S,3H),1.36(d,J = 8.細Z,3H); IRv^knfi): 3058,2917,1708, 1629,1601,1568,1587,1473,1411,1214,1162,1115,1073,997,870,8:M ,772,679,664, 452,426.MS(ESI)m/z626.0(M+H) +,628.0(M+化H) +. [0115] Ih awake R (400MHz, CDCl3) S7.99-7.93 (m, 4H), 7.75 (d, J = 7.8Hz, 2H), 7.68 (d, J = 4.6Hz, 2H), 7.36-7.32 ( m, 2H), 7.26-7.23 (m, 3H), 6.87-6.82 (m, lH), 6.58 (s, lH), 5.21 (s, 2H), 3.97-3.92 (m, IH), 2.34 (S, 3H), 1.36 (d, J = 8. fine Z, 3H); IRv ^ knfi): 3058,2917,1708, 1629,1601,1568,1587,1473,1411,1214,1162,1115,1073,997,870, 8: m, 772,679,664, 452,426.MS (ESI) m / z626.0 (m + H) +, 628.0 (m + of H) +.

[0116] 实施例7:含=氮挫环的嗯二挫类化合物VI-2-1的制备 Preparation ah two setback compound VI-2-1 = nitrogen-containing ring setback: [0116] Example 7

[0117 [0117

[011引1)操作如实施例1步骤1 [011 Primer 1) Operating as described in Example 1 Step 1

[0119] 2)操作如实施例1步骤2 Step 1 Example [0119] 2) The operation of Example 2

[0120] 3)操作如实施例1步骤3 [0120] 3) Operating as described in Example 1 Step 3

[01別]4)将化合物V( Immol)溶于IOmL THF:此0二1:1 (体积比)中,依次加入CuS〇4.5此0 (0.05mmol)和抗坏血酸(Vc,0.15mmol),揽拌溶解后加入1-叠氮基丙酸乙醋(1.5mmol),常溫揽拌反应化,反应过程用化C检测追踪,反应完毕冷却后浓缩溶剂,用CHsCb萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含=氮挫环的嗯二挫化合物VI-2-1.,产率86%。 [Do 01] 4) Compound V (Immol) was dissolved in IOmL THF: This binary 0 is 1: (volume ratio) 1, were added to this CuS〇4.5 0 (0.05 mmol) and ascorbic acid (Vc, 0.15mmol), football added 1-azido-propionic acid ethyl ester (1.5 mmol) was dissolved after mixing, the reaction stirred at room temperature embrace of the reaction process using the tracking detection of C, after completion of cooling the reaction solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic after repeated washing with anhydrous MgS of sulfate, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give the nitrogen-containing setback = ah two ring setback compound VI-2-1., yield 86%. 产物表征结果如下: Product was characterized as follows:

[0122] Ih NMR(400MHz,CDCl3)S7.81-7.58(m,2H),7.61(t,J = 7.7Hz,lH),7.50-7.32(m, 3H),7.34-7.21(m,3H),7.03(s,lH),6.49-6.48(m,lH),5.42-5.26(m,2H),5.16(dd J = 20.4,2.4Hz,lH),4.31-4.21(m,4H),2.38-2.20(m,2H),1.94(s,3H),1.87(d,J=11.5Hz, 3H),0.94(t,J = 20.1 Hz,3H);IRvmaxkm-i):3:347,3155,2965,1708,1551,1530,1494,1454, 1379,1309,1255,1132,1114,1082,970,896,788,764,724,660,452,440.MS化SI)m/z572.I (M+H)+. [0122] Ih NMR (400MHz, CDCl3) S7.81-7.58 (m, 2H), 7.61 (t, J = 7.7Hz, lH), 7.50-7.32 (m, 3H), 7.34-7.21 (m, 3H) , 7.03 (s, lH), 6.49-6.48 (m, lH), 5.42-5.26 (m, 2H), 5.16 (dd J = 20.4,2.4Hz, lH), 4.31-4.21 (m, 4H), 2.38- 2.20 (m, 2H), 1.94 (s, 3H), 1.87 (d, J = 11.5Hz, 3H), 0.94 (t, J = 20.1 Hz, 3H); IRvmaxkm-i): 3: 347,3155,2965 , 1708,1551,1530,1494,1454, 1379,1309,1255,1132,1114,1082,970,896,788,764,724,660,452,440.MS of SI) m / z572.I (m + H) +.

[0123] 连脯例8:含二氮畔巧的鴨二畔类化合物VT-2-2的制备[0124 [0123] Even preserved Example 8: Preparation of skillful banks nitrous duck two banks VT-2-2 compound containing [0124

Figure CN104003983BD00151

[0125] 1)操作如实施例1步骤1; [0125] 1) as described in Example 1 Step 1;

[0126] 2)操作如实施例1步骤2; [0126] 2) as described in Example 1 Step 2;

[0127] 3)操作如实施例1步骤3; [0127] 3) Operating as described in Example 1 Step 3;

[0128] 4)将化合物八Immol)溶于IOmL THF:此0 = 1:1 (体积比)中,依次加入CuS〇4.5此0 (0.1 Ommo 1)和抗坏血酸(Vc,0.25mmo 1),揽拌溶解后加入4-叠氮基乙酸甲醋(1.6mmo 1),常溫揽拌反应化,反应过程用化C检测追踪,反应完毕冷却后浓缩溶剂,用CHsCb萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含=氮挫环的嗯二挫化合物VI-2-2.,产率82.5%。 [0128] 4) The compound of eight Immol) was dissolved in IOmL THF: This 1 = 0: (volume ratio) 1, were added to this CuS〇4.5 0 (0.1 Ommo 1) and ascorbic acid (Vc, 0.25mmo 1), Lan was added 4-azido-acetic acid methyl ester (1.6mmo 1) mixed after dissolved, the reaction stirred at room temperature embrace of the reaction process using the tracking detection of C, after completion of cooling the reaction solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic after repeated washing with anhydrous MgS of sulfate, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give compound containing setback two ah = VI-2-2 ring nitrogen frustration., a yield of 82.5%. 产物表征结果如下: Product was characterized as follows:

[0129] Ih NMR(400MHz,CDCl3)S7.96-7.74(m,2H),7.76-7.60(m,2H),7.65-7.50(m,2H), 7.52-7.29(m,3H),7.32-7.18(m,lH),6.59(d,J = 6.Wz,lH),5.22(s,2H),4.82(dd,J = 10.8,5.3Hz,lH),2.07(s,3H),1.45-1.43(m,2H),1.76(d,J=7.0Hz,3H),0.97(s,3H);IR Vmax(CHfi) :3639,3147,2922,1738,1511,1466,1436,1394,1364,1319,1252,12:34,1123, 1058,973,922,890,871,796,769,722,622,450,420.MS化SI)m/z544.1(M+H) +. [0129] Ih NMR (400MHz, CDCl3) S7.96-7.74 (m, 2H), 7.76-7.60 (m, 2H), 7.65-7.50 (m, 2H), 7.52-7.29 (m, 3H), 7.32- 7.18 (m, lH), 6.59 (d, J = 6.Wz, lH), 5.22 (s, 2H), 4.82 (dd, J = 10.8,5.3Hz, lH), 2.07 (s, 3H), 1.45- 1.43 (m, 2H), 1.76 (d, J = 7.0Hz, 3H), 0.97 (s, 3H); IR Vmax (CHfi): 3639,3147,2922,1738,1511,1466,1436,1394,1364, 1319,1252,12: 34,1123, 1058,973,922,890,871,796,769,722,622,450,420.MS of SI) m / z544.1 (m + H) +.

[0130] 实施例9:含=氮挫环的嗯二挫类化合物VI-2-3的制备 9 [0130] Example: Preparation of N = setback ring containing two ah setback of compound VI-2-3

[0131: [0131:

[0132] 操作如实施例1步骤I; Example 1, Step I [0132] The operation of embodiment;

[0133] 1)操作如实施例1步骤2; [0133] 1) as described in Example 1 Step 2;

[0134] 2)操作如实施例1步骤3; [0134] 2) as described in Example 1 Step 3;

[01对4)将化合物V(Immol)溶于IOmL THF:此0=1:1(体积比)中,依次加入CuS04.5此0 (0.05mmol)和抗坏血酸(Vc,0.15mmol),揽拌溶解后加入4-叠氮基丙酸甲醋(1.5mmol),常溫揽拌反应8h,反应过程用化C检测追踪,反应完毕冷却后浓缩溶剂,用CHsCb萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含=氮挫环的嗯二挫化合物VI-2-3,产率81.8%。 [01 pairs 4) Compound V (Immol) was dissolved in IOmL THF: This 1 = 0: (volume ratio) 1, were added to this CuS04.5 0 (0.05 mmol) and ascorbic acid (Vc, 0.15mmol), stirred embrace after dissolution was added 4-azido-propionic acid methyl ester (1.5 mmol), stirred the reaction at room temperature embrace 8h, the reaction of C with a tracking detector, after completion of cooling the reaction solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic phases after washing with water several times and dried anhydrous MgS of, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give the nitrogen-containing setback = ah two ring setback compound VI-2-3, a yield of 81.8%. 产物表征结果如下: Product was characterized as follows:

[0136] Ih NMR(400MHz,CDCl3)S8.22(d,J=1.9Hz,2H),7.94(d,J = 8.0Hz,2H),7.63-7.58 (m,2H),7.58-7.53(m,3H),7.10-7.06(m,lH),6.52-6.50(m,lH),5.25-5.21(m,2H),5.65 (s,2H),4.68(dd,J=12.6,8.4Hz,lH),2.28(s,3H),1.76(s,2H),1.34-1.32(m,3H),1.01-0.98(m,3H); IRvmax(cm-I):3287,2981,1768,1741,1500,1455,1384,1316,1271,I化0,1189, 1144,1098,1055,1020,976,879,806,754,722,618,520,480.MS化SI)m/z558.I(M+H)+. [0136] Ih NMR (400MHz, CDCl3) S8.22 (d, J = 1.9Hz, 2H), 7.94 (d, J = 8.0Hz, 2H), 7.63-7.58 (m, 2H), 7.58-7.53 (m , 3H), 7.10-7.06 (m, lH), 6.52-6.50 (m, lH), 5.25-5.21 (m, 2H), 5.65 (s, 2H), 4.68 (dd, J = 12.6,8.4Hz, lH ), 2.28 (s, 3H), 1.76 (s, 2H), 1.34-1.32 (m, 3H), 1.01-0.98 (m, 3H); IRvmax (cm-I): 3287,2981,1768,1741,1500 , 1455,1384,1316,1271, I of 0,1189, 1144,1098,1055,1020,976,879,806,754,722,618,520,480.MS of SI) m / z558.I (m + H) +.

[0137] 实施例10:含=氮挫环的嗯二挫类化合物VI-2-4的制备 Preparation VI-2-4 setback nitrogen-containing ring ah = setback two compounds: [0137] Example 10

[0138] [0138]

Figure CN104003983BD00161

[0139] 1)操作如实施例1步骤1; [0139] 1) as described in Example 1 Step 1;

[0140] 2)操作如实施例1步骤2; [0140] 2) as described in Example 1 Step 2;

[0141] 3)操作如实施例1步骤3; [0141] 3) Operating as described in Example 1 Step 3;

[0142] 4)将化合物V(Immol)溶于IOmL THF:此0=1:1(体积比)中,依次加入CuS〇4.5此0 (0.05mmol)和抗坏血酸(Vc,0.15mmol),揽拌溶解后加入叠氮基苯(1.5mmol),常溫揽拌反应化,反应过程用TLC检测追踪,反应完毕冷却后浓缩溶剂,用C出Cl2萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含S氮挫环的嗯二挫化合物VI-2-4.,产率86.9%。 [0142] 4) The compound V (Immol) was dissolved in IOmL THF: This 1 = 0: (volume ratio) 1, were added to this CuS〇4.5 0 (0.05 mmol) and ascorbic acid (Vc, 0.15mmol), stirred embrace after dissolution was added phenyl azide (1.5 mmol), stirred at room temperature embrace of the reaction, the reaction by TLC tracking, after completion of the reaction was cooled the solvent was concentrated, and extracted with Cl2 C out (3 X 20mL), the combined organic phases were washed with water several times of anhydrous MgS sulfate, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give two ah setback S-containing compound VI-2-4 ring nitrogen frustration., a yield of 86.9%. 产物表征结果如下: Product was characterized as follows:

[014;3] Ih NMR(400MHz,CDCl3)S8.22-7.93(m,4H),7.70-7.67(m,4H),7.58(d,J = 7.9Hz, 2H),7.43-7.38(m,4H),7.09(s,lH),5.81-5.80(m,lH),5.43(s,2H),3.98(dd,J=18.6, 9.8Hz,IH),2.48(S,3H),1.48(d,J = 6.8Hz,3H); IRvmaxknfi): 3059,2953,2925,1787,1707, 1552,1546,1493,1438,1405,1:M9,1210,1188,1012,987,865,745,695,626,525,420.MS (ESI)m/z548.1(M+H)+. [014; 3] Ih NMR (400MHz, CDCl3) S8.22-7.93 (m, 4H), 7.70-7.67 (m, 4H), 7.58 (d, J = 7.9Hz, 2H), 7.43-7.38 (m, 4H), 7.09 (s, lH), 5.81-5.80 (m, lH), 5.43 (s, 2H), 3.98 (dd, J = 18.6, 9.8Hz, IH), 2.48 (S, 3H), 1.48 (d , J = 6.8Hz, 3H); IRvmaxknfi): 3059,2953,2925,1787,1707, 1552,1546,1493,1438,1405,1: M9,1210,1188,1012,987,865,745,695,626,525,420.MS (ESI) m / z548.1 (M + H) +.

[0144] 实施例11:含=氮挫环的嗯二挫类化合物VI-2-5的制备 = Setback prepared containing a nitrogen ring ah two setback of compound VI-2-5: [0144] Example 11

[0145: [0145:

[0146] I)操作如实施例1步骤I; [0146] I) operating as described in Example 1, Step I;

[0147] 2)操作如实施例1步骤2; [0147] 2) as described in Example 1 Step 2;

[014引3)操作如实施例1步骤3; [014 primer 3) Operating as described in Example 1 Step 3;

[0149] 4)将化合物V(Immol)溶于IOmL THF:此0=1:1(体积比)中,依次加入CuS〇4.5此0 (0.05mmol)和抗坏血酸(Vc ,0.15mmol),揽拌溶解后加入4-叠氮基氯苯(1.5mmol),常溫揽拌反应化,反应过程用化C检测追踪,反应完毕冷却后浓缩溶剂,用C出Cl2萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含=氮挫环的嗯二挫化合物VI-2-5.,产率87%。 [0149] 4) The compound V (Immol) was dissolved in IOmL THF: This 1 = 0: (volume ratio) 1, were added to this CuS〇4.5 0 (0.05 mmol) and ascorbic acid (Vc, 0.15mmol), stirred embrace was added 4-azido-chlorobenzene (1.5 mmol) dissolved, at room temperature the reaction mix of football, the reaction of C with a tracking detector, after cooling the reaction was completed the solvent was concentrated, and extracted with Cl2 C out (3 X 20mL), the combined organic phases after washing with water several times and dried anhydrous MgS of, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give the nitrogen-containing setback = ah two ring setback compound VI-2-5., yield 87%. 产物表征结果如下: Product was characterized as follows:

[0150] Ih NMR(400MHz,CDCl3)S8.12(s,lH),7.90(d,J = 8.5Hz,2H),7.49-7.35(m,5H), 7.24(m,3H),7.07(d,J = 7.7Hz,2H),6.98(s,lH),5.71(d,J = 4.1Hz,lH),5.42(s,2H),4.38 (dd,J=16.2,8.6Hz,lH),2.82(s,3H),1.49-1.45(m,3H);IRvmax(cm-i):3061,2951,1738, 1707,1566,1545,1492,1438,1409,1352,1218,1114,1070,937,862,737,693,674,525, 468.MS(ESI)m/z582.1(M+H) +,584.1(M+H) +. [0150] Ih NMR (400MHz, CDCl3) S8.12 (s, lH), 7.90 (d, J = 8.5Hz, 2H), 7.49-7.35 (m, 5H), 7.24 (m, 3H), 7.07 (d , J = 7.7Hz, 2H), 6.98 (s, lH), 5.71 (d, J = 4.1Hz, lH), 5.42 (s, 2H), 4.38 (dd, J = 16.2,8.6Hz, lH), 2.82 (s, 3H), 1.49-1.45 (m, 3H); IRvmax (cm-i): 3061,2951,1738, 1707,1566,1545,1492,1438,1409,1352,1218,1114,1070,937,862,737,693,674,525, 468.MS (ESI) m / z582.1 (m + H) +, 584.1 (m + H) +.

[0151] 实施例12:含=氮挫环的嗯二挫类化合物VI-2-6的制备 [0151] Example 12: Preparation of compound ah two setback setback ring nitrogen-containing VI-2-6 =

[0152: [0152:

Figure CN104003983BD00171

[0153] 1)操作如实施例1步骤1; [0153] 1) as described in Example 1 Step 1;

[0154] 2)操作如实施例1步骤2; [0154] 2) as described in Example 1 Step 2;

[0155] 3)操作如实施例1步骤3; [0155] 3) Operating as described in Example 1 Step 3;

[0156] 4)将化合物V(Immol)溶于IOmL THF:此0=1:1(体积比)中,依次加入CuS〇4.5此0 (0.1 Ommol)和抗坏血酸(Vc,0.25mmol),揽拌溶解后加入叠氮甲苯(1.5mmol),常溫揽拌反应化,反应过程用TLC检测追踪,反应完毕冷却后浓缩溶剂,用C出Cl2萃取(3 X 20mL),合并有机相多次水洗后加无水MgS化干燥,30°C蒸发浓缩,经薄层层析分离纯化后得到含S氮挫环的嗯二挫化合物VI-2-6,产率86.1 %。 [0156] 4) The compound V (Immol) was dissolved in IOmL THF: This 1 = 0: (volume ratio) 1, were added to this CuS〇4.5 0 (0.1 Ommol) and ascorbic acid (Vc, 0.25mmol), stirred embrace azide was added dissolved in toluene (1.5 mmol), stirred at room temperature embrace of the reaction, the reaction by TLC tracking after completion of cooling the reaction solvent was concentrated, and extracted with Cl2 C out (3 X 20mL), the combined organic phase washed with water several times after adding dried over anhydrous MgS of, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give S-containing ring ah two nitrogen setback setback compound VI-2-6, 86.1% yield. 产物表征结果如下: Product was characterized as follows:

[0157] Ih NMR(400MHz,CDCl3)S8.24(d,J = 7.9Hz,lH),7.95(d,J = 8.3Hz,2H),7.73-7.68 (m,lH),7.63(s,lH),7.59(d,J=8.3Hz,2H),7.45-7.42(m,2H),7.32-7.38(m,5H),7.23-7.19(m,lH),5.64-5.62(m,lH),5.42(s,2H),4.99-4.96(m,2H),3.98(dd,J = 21.4,12.細z, IH),2.81(s,3H). 1.28-1.21(m,3H);IRvmax(cm-i):3066,2950,2941,1787,1708,1551,1540, 1444,1405,1:349,1218,1116,1009,927,865,715,695,653,586,480.MS(ESI)m/z562.I(M+ H) + . [0157] Ih NMR (400MHz, CDCl3) S8.24 (d, J = 7.9Hz, lH), 7.95 (d, J = 8.3Hz, 2H), 7.73-7.68 (m, lH), 7.63 (s, lH ), 7.59 (d, J = 8.3Hz, 2H), 7.45-7.42 (m, 2H), 7.32-7.38 (m, 5H), 7.23-7.19 (m, lH), 5.64-5.62 (m, lH), 5.42 (s, 2H), 4.99-4.96 (m, 2H), 3.98 (. dd, J = 21.4,12 fine z, IH), 2.81 (s, 3H) 1.28-1.21 (m, 3H);. IRvmax ( cm-i): 3066,2950,2941,1787,1708,1551,1540, 1444,1405,1: 349,1218,1116,1009,927,865,715,695,653,586,480.MS (ESI) m / z562.I (m + H) +.

[0158] 实施例13:单胺氧化酶抑制活性检测 [0158] Example 13: Monoamine oxidase inhibitory activity detected

[0159] (1)样品配制 [0159] (1) Sample preparation

[0160] 将实施例1~12制备的化合物(VI-I)~(VI-12)溶于二甲基亚讽(DMSO)中,分别配成10、50、75、100、150111111〇1/1浓度梯度的样品液,记为样品1~12。 Compound (VI-I) [0160] Example 1 - Preparation of embodiment 12 ~ (VI-12) was dissolved in dimethyl sulfoxide Bitterness dimethylsulfoxide (DMSO), were formulated 10,50,75,100,150111111〇1 / a concentration gradient of the liquid sample, referred to as samples 1 to 12.

[0161] (2)含苯砸基取代的双杂环化合物(VI)对单胺氧化酶-A抑制活性检测方法 [0161] (2) bis heterocyclic benzene compound (VI) drop-substituted monoamine oxidase inhibitory activity detection method -A

[0162] 分别向12份装有38化L棚酸缓冲液(pH=8.4)的EP管中加入10化(浓度5mg/mL)单胺氧化酶-A(MAO-A)和4化步骤(1)配制的样品1~12,混合,再将混合物在38°C水浴中反应池,然后分别再次向上述12份EP管中加入2.扣L式(XII)所示的探针7-(3-氨基丙氧基)-4-甲基香豆素(20mmol/ml)和2.5化的牛血清蛋白(BSA,浓度60mg/mL),并将EP管放在38°C水浴中继续反应化。 10 of (a concentration of 5mg / mL) monoamine oxidase -A (MAO-A) and 4 step (1) EP tube [0162] respectively, charged with 38 of L shelf acid buffer (pH = 8.4) to 12 parts was added formulation samples 1 to 12, mixed, and the mixture in the reaction vessel in a water bath at 38 ° C, and then were added to 12 parts of the above-described EP tube 2. the buckle L again formula (XII) shown probes 7- (3-amino propoxy) -4-methyl coumarin (20mmol / ml) and 2.5 of bovine serum albumin (BSA, a concentration of 60mg / mL), and EP tube placed in a water bath at 38 ° C of the reaction was continued. 与其同时需检测未加抑制剂的酶的酶活,即向装有38化L棚酸缓冲液(pH =8.4)的EP管中加入10化单胺氧化酶-A(MAO-A),在38°C水浴中反应祉,再加入2.5化探针(20mmol/ml)和2.化L的BSA同样也在38°C水浴中反应化。 10 monoamine oxidase enzyme activity to be detected simultaneously with the inhibitor is not added, namely the shed with 38 L of acid buffer (pH = 8.4) was added to the tube, EP -A (MAO-A), at 38 ° C the reaction Edwin water bath, was added 2.5 probes (20mmol / ml) of BSA and 2 L of the same water bath are 38 ° C of the reaction.

[0163] [0163]

Figure CN104003983BD00181

[0164] 最后在每个EP管(微量离屯、管)中取出I(K)化加入96孔板中并用全功能巧光分光光度计(AexAem = 365/460nm)(spectraMax M,美国分子仪器公司)检测样品。 [0164] Remove the last I (K) in each of the EP tube (Tun microcentrifuge tube) was added to 96-well plates and treated with full function Qiao spectrophotometer (AexAem = 365 / 460nm) (spectraMax M, Molecular Devices USA company) test sample. 根据所测的巧光值计算样品1~12的ICso,化合物(VI-I)~(VI-12)对单胺氧化酶-A活性抑制测试结果见表1。 ICso calculated Samples 1 to 12, the compound (VI-I) ~ (VI-12) According to the measured values ​​of the optical Qiao inhibition test results -A monoamine oxidase activity in Table 1.

[0165] 化合物的抑制效果用半数抑制浓度(ICso)来表示。 Inhibitory effect [0165] with a half-maximum inhibition concentration (ICSO) is represented. ICso是指"反应"被抑制一半时抑制剂的浓度,化合物抑制能力越强,该数值越低。 ICso refers to the "response" is inhibited half the concentration of inhibitor compound inhibits the ability, the lower the value.

[0166] ICso可W用W下方法计算: [0166] ICso W can be calculated by the method of W:

[0167] 1)检测并计算只加酶与探针缓冲液的平均巧光强度(Fm); [0167] 1) added only detect and calculate the average light intensity Qiao enzyme probe buffer (Fm);

[0168] 2)计算含有不同浓度梯度抑制剂的各组分酶的平均巧光强度(要扣除背景值); [0168] 2) comprises calculating an average intensity of each component light Qiao different concentrations of enzyme inhibitors (to subtract background value);

[0169] 3)根据不同浓度梯度抑制剂的各组分酶的巧光强度做抑制剂的浓度(C)与巧光强度(F)之间关系的直线回归,建立得到方程:F = aC+b(通过回归直线确定方程系数a和截踞b); [0169] 3) do inhibitor concentration (C) and linear relationships between light intensity Qiao (F) according to the light intensity of each component Qiao different concentrations of enzyme inhibitors, to establish the equation to give: F = aC + B (determined by a regression line equation coefficients and cut squat B);

[0170] 4)根据方程,求F = 1/2FM下的对应的抑制剂浓度,即可求出抑制率为50 %时的抑审Ij剂浓度,即为ICso。 [0170] 4) According to the equation, the concentration of inhibitor required F = 1 / 2FM under corresponding to obtain suppression Laid concentration Ij suppression rate of 50%, namely ICso.

[0171] (3)含苯砸基取代的双杂环化合物(VI)对单胺氧化酶-B抑制活性测试 [0171] (3) bis-substituted benzene drop heterocyclic compound (VI) -B inhibitory activity on monoamine oxidase test

[0172] 将MAO-A换成MA0-B,其他操作同步骤(2),结果见表1。 [0172] MAO-A will be replaced by MA0-B, with the other operations in step (2), the results shown in Table 1.

[0173] 表1实施例1~12制备的含苯砸基取代的双杂环化合物(VI)对单胺氧化酶A和B的抑制活性 Benzene-containing heterocyclic compound prepared in double Examples 1 to 12 of the embodiment [0173] Table 1 drop substituted group (VI) of inhibition of monoamine oxidase A and B activity

[01741 [01741

[0175] a:抑制活性用ICso表示,每个样品做3个平行组,取5个浓度梯度; [0175] a: inhibiting activity represented by ICSO, each sample was subjected to three parallel groups, take 5 concentration gradients;

[0176] b:对酶的选择性用SI表示,SI: selectivity index = IC日o(MA〇-A)/IC日O(MAO-B) [0176] b: selectivity enzyme expressed in SI, SI: selectivity index = IC day o (MA〇-A) / IC day O (MAO-B)

[0177] C:ND: too large that were not detectedOl.OmM). [0177] C: ND: too large that were not detectedOl.OmM).

[017引从表1可W看出,化合物(vi-1-1)~(VI-1-5)和(VI-2-1)~(VI-2-6)对单胺氧化酶A有抑制活性,其中化合物(VI-1-1)~(VI-1-5)有较强的抑制活性;化合物(VI-1-1)~ (VI-I-6)和(VI-2-1)~(VI-2-6)对单胺氧化酶B有抑制活性,其中化合物(VI-1-1)~(VI-1-6)和(VI-2-2)~(VI-2-6)有较强的抑制活性,特别是化合物(VI-1-1)~(VI-1-5)有极强的抑制活性。 [017 W can be cited seen from Table 1, Compound (vi-1-1) ~ (VI-1-5), and (VI-2-1) ~ (VI-2-6) inhibitory activity of monoamine oxidase A, wherein the compound (VI-1-1) ~ (VI-1-5) has strong inhibitory activity; compound (VI-1-1) ~ (VI-I-6) and (VI-2-1) ~ ( VI-2-6) inhibitory activity of monoamine oxidase B, where the compound (VI-1-1) ~ (VI-1-6), and (VI-2-2) ~ (VI-2-6) has a strong inhibiting activity, particularly compound (VI-1-1) ~ (VI-1-5) have a strong inhibitory activity.

Claims (8)

  1. 1. 一种含苯硒基取代的双杂环化合物,其结构如式(VI)所示: A bis-substituted benzene selenium heterocyclic compounds, such as the structure shown in formula (VI):
    Figure CN104003983BC00021
    其中,R选自式(VII)或式(VIII)所示的基团: Wherein, R is selected from formula (VII) or formula (VIII) represented by the group:
    Figure CN104003983BC00022
    式(VII)中,R1为未被取代或被下列基团中的一种或几种取代的苯基:C1-C3的烷基、卤素、C1-C3的烷氧基、三氟甲基; 式(VIII)中,R2选自下列基团之一: Of formula (VII), R1 is unsubstituted or substituted one kind of the following groups or substituted phenyl several: C1-C3 alkyl, halogen, C1-C3 alkoxy, trifluoromethyl; in the formula (VIII), R2 is selected from one of the following groups:
    Figure CN104003983BC00023
    苯基,卤素取代的苯基,苄基; 护、1?4、1?5、1?6各自独立选自(:1-06的烷基。 Phenyl, halogen substituted phenyl, benzyl; nursing, 1 4,1 5,1 6 are each independently selected from (: 1-06 alkyl???.
  2. 2. 如权利要求1所述的含苯硒基取代的双杂环化合物,其特征在于:妒、1?4、1?5、1? 6各自独立选自C1-C4的烷基。 Bis-substituted benzene selenium heterocyclic compound as claimed in claim 1, wherein:? Jealous, 1 4,1 5,1 6 are each independently selected from C1-C4 alkyl??.
  3. 3. 如权利要求1所述的含苯硒基取代的双杂环化合物,其特征在于:所述的卤素为F、C1 或Br。 Bis benzene substituted heterocyclic seleno compound according to claim 1, wherein: said halogen is F, C1 or Br.
  4. 4. 如权利要求1所述的含苯硒基取代的双杂环化合物,其特征在于:所述的含苯硒基取代的双杂环化合物为下列夕一: 4. The bis-substituted benzene selenium heterocyclic compound according to claim 1, wherein: the seleno-substituted benzene bis heterocyclic compound is a following Xi:
    Figure CN104003983BC00024
    Figure CN104003983BC00031
  5. 5.-种制备如权利要求1所述含苯硒基取代的双杂环化合物的方法,所述含苯硒基取代的双杂环化合物的结构如式(VI-1)所示,式(VI-1)中,R1的定义同式(VI),所述方法包括: (1)式(m)所示的含苯硒基的中间产物的制备: The method of preparing seed structure 5.- seleno-substituted benzene bis heterocyclic compound according to claim 1, said bis-substituted benzene selenium heterocyclic compound of formula (VI-1) in the formula ( VI-1) in the definition of R1, the same method of formula (VI) comprising: preparing intermediates benzene selenium group (1) formula (m) as shown:
    Figure CN104003983BC00032
    在反应容器中加入有机溶剂B、式(II)所示的a-苯硒基正丙醛和式(VII)所示的对羟基苯肼,使之完全溶解后加入醋酸,然后在氮气保护下回流反应1-3小时,反应完全后经分离纯化得到式(III)所示的含苯硒基的中间产物;所述有机溶剂B选自下列之一:乙醇、四氢呋喃、乙腈; (2) 式(IV)所示的含苯硒基的噁二唑类化合物的制备: Adding an organic solvent in the reaction vessel B, A- phenyl selenium group of formula (II) n-propanal represented by formula (VII) as shown paraben hydrazine, and dissolved completely after the addition of acetic acid, and then under nitrogen at the reaction was refluxed for 1-3 hours, after the completion of the reaction obtained was purified by formula (III) shown selenium intermediate benzene group; B is selected from the organic solvent of the following: ethanol, tetrahydrofuran, acetonitrile; (2) preparation oxadiazoles benzene compound selenium group (IV) shown below:
    Figure CN104003983BC00041
    在反应容器中加入式(III)所示的含苯硒基的中间产物和乙酸酐,反应完毕后经分离纯化得到式(IV)所示的含苯硒基的噁二唑类化合物; (3) 式(V )所示的含末端三键的噁二唑类化合物的制备: Add the formula (III) shown in the reaction vessel and acetic anhydride intermediate benzene selenium group, obtained after the completion of the reaction was purified by formula (IV) shown in benzene seleno oxadiazole compound; (3 ) preparation of oxadiazole-based compound containing a terminal triple bond of the formula (V) shown below:
    Figure CN104003983BC00042
    在反应容器中加入有机溶剂C、式(IV)所示的含苯硒基的噁二唑类化合物、碳酸钾,搅拌下缓慢加入炔丙基溴,在氮气保护下回流反应3~5小时,反应完毕后经分离纯化得到式(V)所示的含末端三键的噁二唑类化合物;所述有机溶剂C选自下列之一:丙酮、N,N-二甲基甲酰胺; (4) 式(VI-1)所示的含苯硒基取代的双杂环化合物的制备: Adding an organic solvent C, Formula (IV) shown in the reaction vessel benzene seleno oxadiazole-based compound, potassium carbonate, was added slowly with stirring propargyl bromide, the reaction was refluxed under nitrogen for 3 to 5 hours, of formula (V) after completion of the reaction shown was purified by containing a terminal triple bond oxadiazole compound; the organic solvent C is selected from one of the following: acetone, N, N- dimethylformamide; (4 ) preparation of seleno benzene of formula (VI-1) represented by bis-substituted heterocyclic compound:
    Figure CN104003983BC00043
    使式(X)所示的肟类化合物与N-氯代丁二酰亚胺在有机溶剂D中室温反应4-5小时,然后加入式(V)所示的含末端三键的噁二唑类化合物和三乙胺反应5~8小时,反应完全后经分离纯化得到式(VI-1)所示的含苯硒基取代的双杂环化合物;所述有机溶剂D选自下列之一:二氯甲烷、三氯甲烷、四氢呋喃; 式(X)中,R1的定义同式(VI-1)。 Represented by formula (X), oximes reaction with N- chlorosuccinimide in an organic solvent D 4-5 hours at room temperature, followed by addition of the formula (V) shown evil terminal triple bond-containing oxadiazole compound and triethylamine 5-8 hours. after completion of the reaction was purified by formula shown in (VI-1) a bis-substituted benzene selenium heterocyclic compound; the organic solvent D is selected from one of the following: dichloromethane, chloroform, tetrahydrofuran; in formula (X-), R1 is as defined for formula (VI-1).
  6. 6.-种制备如权利要求1所述含苯硒基取代的双杂环化合物的方法,所述含苯硒基取代的双杂环化合物的结构如式(VI-2)所示,式(VI-2)中,R2的定义同式(VI ),所述方法包括: (a)式(m)所示的含苯硒基的中间产物的制备: The method of preparing seed structures 6.- seleno-substituted benzene bis heterocyclic compound according to claim 1, said bis-substituted benzene selenium heterocyclic compound of formula (VI-2), the formula ( VI-2) in, the definition of R2, with the process of formula (VI) comprising: preparing intermediates benzene selenium group (a) of formula (m) as shown:
    Figure CN104003983BC00044
    在反应容器中加入有机溶剂B、式(II)所示的a-苯硒基正丙醛和式(VII)所示的对羟基苯肼,使之完全溶解后加入醋酸,然后在氮气保护下回流反应1-3小时,反应完全后经分离纯化得到式(III)所示的含苯硒基的中间产物;所述有机溶剂B选自下列之一:乙醇、四氢呋喃、乙腈; (b) 式(IV)所示的含苯硒基的噁二唑类化合物的制备: Adding an organic solvent in the reaction vessel B, A- phenyl selenium group of formula (II) n-propanal represented by formula (VII) as shown paraben hydrazine, and dissolved completely after the addition of acetic acid, and then under nitrogen at the reaction was refluxed for 1-3 hours, after the completion of the reaction obtained was purified by formula (III) shown selenium intermediate benzene group; B is selected from the organic solvent of the following: ethanol, tetrahydrofuran, acetonitrile; (b) the formula preparation oxadiazoles benzene compound selenium group (IV) shown below:
    Figure CN104003983BC00051
    在反应容器中加入式(III)所示的含苯硒基的中间产物和乙酸酐,反应完毕后经分离纯化得到式(IV)所示的含苯硒基的噁二唑类化合物; (c) 式(V)所示的含末端三键的噁二唑类化合物的制备: Add the formula (III) shown in the reaction vessel and acetic anhydride intermediate benzene selenium group, obtained after the completion of the reaction was purified by formula (IV) shown in benzene seleno oxadiazole compound; (c ) preparation of oxadiazole-based compound containing a terminal triple bond of the formula (V) shown below:
    Figure CN104003983BC00052
    在反应容器中加入有机溶剂C、式(IV)所示的含苯硒基的噁二唑类化合物、碳酸钾,搅拌下缓慢加入炔丙基溴,在氮气保护下回流反应3~5小时,反应完毕后经分离纯化得到式(V)所示的含末端三键的噁二唑类化合物;所述有机溶剂C选自下列之一:丙酮、N,N-二甲基甲酰胺; (d) 式(VI-2)所示的含苯硒基取代的双杂环化合物的制备: Adding an organic solvent C, Formula (IV) shown in the reaction vessel benzene seleno oxadiazole-based compound, potassium carbonate, was added slowly with stirring propargyl bromide, the reaction was refluxed under nitrogen for 3 to 5 hours, of formula (V) after completion of the reaction shown was purified by containing a terminal triple bond oxadiazole compound; the organic solvent C is selected from one of the following: acetone, N, N- dimethylformamide; (D ) preparation of seleno benzene of formula (VI-2) represented by bis-substituted heterocyclic compound:
    Figure CN104003983BC00053
    使式(V)所示的含末端三键的噁二唑类化合物溶于溶剂E中,依次加入五水硫酸铜和抗坏血酸,搅拌溶解后加入式(XI)所示的叠氮化合物,室温搅拌反应6-8小时,反应完全后经分离纯化得到式(VI-2)所示的含苯硒基取代的双杂环化合物;所述溶剂E选自下列之一: THF和水的混合溶剂、二甲亚砜; 式(XI)中,R2的定义同式(VI-2)。 Of formula (V) containing a terminal triple bond represented oxadiazole compound E is dissolved in a solvent, were added copper sulfate pentahydrate and ascorbic acid, a nitrogen compound is added and stirred to dissolve formula (XI) as shown in stacked, stirred at room temperature the reaction for 6-8 hours, after the completion of the reaction obtained was purified by formula (VI-2) a bis-substituted benzene selenium heterocyclic compound; E the solvent is selected from one of the following: THF mixed solvent of water, dimethyl sulfoxide; in formula (XI), R2 is as defined in formula (VI-2).
  7. 7. 如权利要求1所述的含苯硒基取代的双杂环化合物在制备单胺氧化酶抑制剂中的应用。 7. The use of bis-substituted benzene-containing heterocyclic selenium compound of claim 1 in the manufacture of a monoamine oxidase inhibitor as claimed in claim.
  8. 8. 如权利要求7所述的应用,其特征在于:所述的单胺氧化酶抑制剂是MAO-B抑制剂。 The use as claimed in claim 7, wherein: said monoamine oxidase inhibitor is MAO-B inhibitors.
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CN102250048A (en) * 2011-06-03 2011-11-23 浙江工业大学 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof
WO2012030165A2 (en) * 2010-08-31 2012-03-08 서울대학교산학협력단 Use of the fetal reprogramming of a ppar δ agonist

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* Cited by examiner, † Cited by third party
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WO2012030165A2 (en) * 2010-08-31 2012-03-08 서울대학교산학협력단 Use of the fetal reprogramming of a ppar δ agonist
CN102250048A (en) * 2011-06-03 2011-11-23 浙江工业大学 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof

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