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Numero di pubblicazioneCN104003983 B
Tipo di pubblicazioneConcessione
Numero domandaCN 201410234882
Data di pubblicazione17 ago 2016
Data di registrazione28 mag 2014
Data di priorità28 mag 2014
Pubblicato anche comeCN104003983A
Numero di pubblicazione201410234882.8, CN 104003983 B, CN 104003983B, CN 201410234882, CN-B-104003983, CN104003983 B, CN104003983B, CN201410234882, CN201410234882.8
Inventori王宇光, 吴中礼, 朱冰春, 李清思, 张海梁
Candidato浙江工业大学
Esporta citazioneBiBTeX, EndNote, RefMan
Link esterni:  SIPO, Espacenet
含苯硒基取代的双杂环化合物及其制备与应用 Double benzene heterocyclic compounds and their preparation and application of selenium-substituted tradotto da: Cinese
CN 104003983 B
Estratto  tradotto da: Cinese
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 double selenium substituted heterocyclic compounds and their preparation and application of benzene, the benzene structure selenium-substituted heterocyclic compounds such as bis formula (VI-1) or formula (VI-2) , the synthesis route 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。 Benzene selenium-substituted heterocyclic compound of the double has a good monoamine oxidase inhibitory activity and can be used to prepare the monoamine oxidase inhibitor.
Rivendicazioni(8)  tradotto da: Cinese
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 benzene substituted seleno Bis-heterocyclic compounds, such as the structure of formula (VI) below:
Figure CN104003983BC00021
其中,R选自式(VII)或式(VIII)所示的基团: Wherein, R is selected from the formula (VII) or formula (VIII) as shown in 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 with the group of one or more phenyl substituted: C1-C3 alkyl, halogen, C1-C3 alkoxy, trifluoromethyl; 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, phenyl substituted by halogen, a benzyl group; protection, 1 4,1 5,1 6 are each independently selected from (: 1-06 alkyl???.
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。 Benzene substituted seleno bis 2. The heterocyclic compound according to claim 1, characterized in that:? Jealous, 1 4,1 5,1 6 are each independently selected from C1-C4 alkyl??.
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。 Benzene seleno-substituted heterocyclic compound according to the double claim, wherein: said halogen is F, C1 or Br.
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 heterocyclic seleno compound according to claim 1, wherein: said dual-substituted benzene selenium heterocyclic compound is one of the following Xi:
Figure CN104003983BC00024
Figure CN104003983BC00031
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: 5.- kind of claim 1 for preparing benzene substituted seleno bis heterocyclic compound of claim method, the bis-substituted benzene selenium heterocyclic compounds, such as structural formula (VI-1) in the formula ( VI-1) in the same way as formula (VI) in the definition of R1 include: benzene seleno Preparation of intermediate (1) (m) as shown in:
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 B in the reaction vessel, of formula (II) shown a- phenylselenyl propionaldehyde and n of formula (VII) as shown paraben hydrazine, acetic acid was added and dissolved completely after, under nitrogen and then the reaction was refluxed for 1-3 hours, after the completion of the reaction were purified by formula (III) shown in benzene seleno intermediate product; B is selected from one of the following organic solvents: ethanol, tetrahydrofuran, acetonitrile; (2) (IV) shown oxadiazoles preparing a compound of benzene selenium group:
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: In a reaction vessel of formula (III) shown in the intermediate product benzene and acetic anhydride selenium group, after completion of the reaction obtained by separation and purification of the formula (IV) shown in benzene selenium group oxadiazole compound; (3 ) oxadiazole-based compound containing a terminal triple bond of formula (V) prepared as shown:
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: Added to the reaction vessel in the organic solvent C, Formula (IV) shown in benzene seleno oxadiazole compound, potassium carbonate, added slowly propargyl bromide, the reaction was refluxed under nitrogen for 3 to 5 hours, after completion of the reaction of formula (V) as shown by the separation and purification of the oxadiazole compound containing a terminal triple bond; the organic solvent C is selected from one of the following: acetone, N, N- dimethylformamide; (4 ) of formula (VI-1) shown in benzene seleno-substituted heterocyclic compound prepared double:
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)。 So that formula (X), oximes and N- chlorosuccinimide at room temperature for 4-5 hours in an organic solvent D, followed by the addition of formula (V) shown with terminal triple bond evil oxadiazole the organic solvent is one selected from the group D; and triethylamine to compound 5 to 8 hours. after completion of the reaction were purified by formula (VI-1) is a heterocyclic compound bis-substituted benzene selenium: dichloromethane, chloroform, tetrahydrofuran; of formula (X) in the definition of R1 in formula (VI-1).
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: 6.- Preparation as claimed in one kind seleno-substituted benzene compound biheterocyclic method of claim seleno-substituted benzene compound bis heterocyclic structures such as formula (VI-2) in the formula ( VI-2) in the same way as formula (VI) in the definition of R2 include: benzene seleno preparing intermediate product (a) of formula (m) as shown in:
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 B in the reaction vessel, of formula (II) shown a- phenylselenyl propionaldehyde and n of formula (VII) as shown paraben hydrazine, acetic acid was added and dissolved completely after, under nitrogen and then the reaction was refluxed for 1-3 hours, after the completion of the reaction were purified by formula (III) shown in the intermediate group of benzene selenium; B is selected from one of the following organic solvents: ethanol, tetrahydrofuran, acetonitrile; (b) the formula (IV) shown oxadiazoles preparing a compound of benzene selenium group:
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: In a reaction vessel of formula (III) shown in the intermediate product benzene and acetic anhydride selenium group, after completion of the reaction obtained by separation and purification of the formula (IV) shown in benzene selenium group oxadiazole compound; (c ) oxadiazole-based compound containing a terminal triple bond of formula (V) prepared as shown:
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: Added to the reaction vessel in the organic solvent C, Formula (IV) shown in benzene seleno oxadiazole compound, potassium carbonate, added slowly propargyl bromide, the reaction was refluxed under nitrogen for 3 to 5 hours, after completion of the reaction of formula (V) as shown by the separation and purification of the oxadiazole compound containing a terminal triple bond; the organic solvent C is selected from one of the following: acetone, N, N- dimethylformamide; (D ) of formula (VI-2) shown in benzene seleno-substituted heterocyclic compound prepared double:
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) shown oxadiazole compound containing terminal triple bond is dissolved in a solvent E, followed by adding copper sulfate pentahydrate and ascorbic acid, nitrogen compounds added after stirring to dissolve the formula (XI) as shown in the stack, stirred at room temperature the reaction for 6-8 hours, after the completion of the reaction were purified by formula (VI-2) shown in benzene seleno-substituted heterocyclic compound bis; E is selected from one of the following solvents: THF mixed solvent of water, dimethyl sulfoxide; formula (XI), the definition of R2 in formula (VI-2).
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. selenium benzene substituted heterocyclic compound according to double in the preparation of monoamine oxidase inhibitor claim.
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。 8. The use according to claim 7, characterized in that: said monoamine oxidase inhibitor is MAO-B inhibitors.
Descrizione  tradotto da: Cinese
含苯砸基取代的双杂环化合物及其制备与应用1、 Substituted benzene hit double-heterocyclic compounds and their preparation and application 1,

技术领域 TECHNICAL 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 and hit one kind of benzene-substituted heterocyclic compounds and double preparation and application, in particular its application in the manufacture of monoamine oxidase inhibitor. 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) The full name of monoamine oxidase-reductase in the 1830s by the Balschko found, is an enzyme 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。 Some organisms that catalyzes the amine in the brain and peripheral nervous tissue, oxidative deamination to produce peroxide 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。 1968, Johnston monoamine oxidase according to their sensitivity to the irreversible inhibitors Clorgyline (chlorine Gilan) will be divided into two sub-categories A and B, monoamine oxidase A pair clorgy line sensitive, 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 showed that monoamine oxidase A on the substrate of serotonin (5-muscle), norepinephrine (fertilizer), multi-hexylamine (DA) and inhibitors Clorgyline with high affinity; and monoamine oxidase B is for phenethylamine ( 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 multi-hexylamine, accompanied by generation of free radicals and peroxide, ammonia and other endogenous substances, their abnormal expression and 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。 As people gradually accelerated pace of life, mental stress, increasing the incidence of depression is rapidly rising, is expected by 2020, it will be second only to the highest 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。 Transported a disease caused by possible with monoamine oxidase (MAO) abnormalities, and monoamine oxidase inhibitor (MAOI) are a class-specific in vivo inhibition of MAO activity of drugs, who in the 1950s 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。 Its mechanism is by inhibiting MO, reducing the CNS monoamine neurotransmitter degradation, the relative increase in the concentration of monoamine neurotransmitters, improve mood, produces antidepressant effects. 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 trap class phenethyl trap (Phenel Zine), isonicotinoyl well (Isoni COtiny 1 hydrazide), isopropyl smoke trap (Iproniazid), Nyala amine (Nialamide,) etc. non-type well W tranylcypromine (tranylcypromine) as a representative 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 role of monoamine oxidase single effect, the W seeking low toxicity, good results MAOI become the new target of today's study.

[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)。 [0004] The nitrogen-containing heterocyclic compounds have shown particularly good monoamine oxidase inhibitory activity, particularly Mazouz, F. Et al reported different substituents 1,3,4-ah two setback pay compound derivatives have 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 many natural products skeleton, are a class of very good biological activity or potential biological active substances, it 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, different ah setback compounds have good anti-bacterial, anti-inflammatory and anti-tumor biological activity (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 was also reported to have monoamine oxidase inhibitory activity, for example, the compounds of both iso ah frustration and cool well run two active groups isocarboxazid well is the first generation of monoamine oxidase inhibitor; Liu Ni reported to contain different ah setback ring compounds show some monoamine oxidase inhibiting activity Qiao IJ ice-ni, etc. 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 will vary ah setback ring or S setback ring introduced into ah two frustrated ring, synthesized a series of novel benzene hit substituted double heterocyclic compounds, which have excellent monoamine oxidase inhibitory activity is a kind of good monoamine oxidase suppression agent (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 of substituted benzene hit double heterocyclic compounds.

[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 substituted benzene 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] = first object of the present invention is to provide the benzene hit substituted heterocyclic compound in the manufacture of dual monoamine oxidase inhibitor.

[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] Next, the technical solution to achieve the object of the present invention and used to make a specific description.

[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 substituted benzene hit double-heterocyclic compounds, such as the structure of formula (VI) as follows:

Figure CN104003983BD00071

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

[0010] [0010]

[001U 的基团: [001U groups:

[0012] [0012]

[00巧] [00 Qiao]

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 the following groups substituted with one or more of: C1-C3 alkyl, plain face, C1-C3 alkoxy, gas = methyl;

[0017]护、於、1?5、护各自独立选自(:1-〔6的烷基。 [0017] conservation, in, 15, nursing each independently selected from (:? 1- [6 alkyl group.

[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 dragon drop-substituted heterocyclic compound containing a double coincidence of the Mu can be divided into W under two 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, of Ri is unsubstituted or substituted with the group of one or more phenyl substituted: C1-C3 alkyl group, pigment surface, C1-C3 alkoxy, gas = methyl.

[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, face-substituted phenyl, benzyl.

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

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

[00巧] [00 Qiao]

Figure CN104003983BD00081

苯基,面素取代的苯基,苄基。 Phenyl, face-substituted phenyl, benzyl.

[00%]更进一步,所述的面素为F、C1或化。 [00%] Furthermore, the surface of the pigment 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] and then further, said substituted benzene hit double heterocyclic compound is one of: [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 process for preparing a benzene of formula (VI-I) shown double hit-substituted heterocyclic compounds, said method comprising:

[0031] (1)式(虹)所示的含苯砸基的中间产物的制备: [0031] benzene smashing group of intermediate (1) (Rainbow) 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; Acetic acid [0033] The organic solvent B was added to the reaction vessel, the formula (II) shown a- phenyl-n-propyl wake up and hit the formula (VII) as shown on the benzene diameter wells, make it completely dissolved, then reflux under nitrogen for 1-3 hours after the reaction was complete separation and purification of formula (III) shown in the intermediate benzene hit group;

[0034] (2)式(IV)所示的含苯砸基的嗯二挫类化合物的制备: [0034] benzene (2) of formula (IV) shown smashing ah two groups fell compound was prepared:

[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] In a reaction vessel of formula (III) shown intermediates and benzene acetic acid vinegar hit group, after completion of the reaction obtained by separation and purification of the formula (IV) shown in ah two benzene compounds setback hit group ;

[0037] (3)式(V)所示的含末端S键的嗯二挫类化合物的制备: [0037] (3) of formula (V) shown with terminal S bonds fell ah two compounds was prepared:

[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; Ah two setback compounds [0039] In a reaction vessel in the organic solvent C, benzene of formula (IV) shown in smashing group of carbonate, bell, olive mix was added slowly bake propyl desert, under nitrogen reflux 3 ~ 5 hours after completion of the reaction by the separation and purification of formula (V) shown in ah two compounds containing terminal setback = key;

[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] benzene (4) of formula (VI-I) shown double hit-substituted heterocyclic compound was prepared:

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 '' a meaning; tVAA; corpse vector 'busy one hundred' 'was recorded with JlN- W ~ J ^ Di: f clever makeup of industry awards • IUT of all wet • Only female 4-5 hours, then the formula ( V) ah two compounds containing terminal setback = key = amine reaction shown and 5 to 8 hours, the reaction was complete separation and purification by formula (VI-I) shown smashing benzene substituted heterocyclic bis compound;

[0043]式(X)中,Ri的定义同式(VI-1)。 [0043] Formula (X), the definition of Ri with 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, tetraamine Qiao Nan, B 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 smashing wake of formula (VII) as shown on the diameter of the base cool well, acetic acid molar ratio of 1: 1: 10-15.

[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 number of moles of benzene acetic acid vinegar added volume of W formula (III) shown in smashing group of intermediate product in terms of (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 cited Further, the step (3), the organic solvent C is selected from one of the following: propylene paid, 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, the step (3), a benzene of formula (IV) shown smashing ah two groups fell compound and the carbonic acid bell, baked desert propyl 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: methylene burn, burn = chloroformate, tetraamine 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), the month fell ah two compounds containing terminal = bond of formula (V) shown in the formula (X) shown in deficit-based compound, N- chlorodifluoromethane under cool imine , S ethylamine molar ratio of 1: 1.5 to 2: 1.5 to 2: 2-3.

[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 also provides a method for preparing a benzene of formula (VI-2) shown 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] benzene hit group intermediate product (a) of formula (rainbow) 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; Acetic acid [0055] The organic solvent B was added to the reaction vessel, the formula (II) shown a- phenyl-n-propyl wake up and hit the formula (VII) as shown on the benzene diameter wells, make it completely dissolved, then reflux under nitrogen for 1-3 hours after the reaction was complete separation and purification of formula (III) shown in the intermediate benzene hit group;

[0056] (b)式(IV)所示的含苯砸基的嗯二挫类化合物的制备: [0056] benzene (b) of formula (IV) shown smashing ah two groups fell compound was prepared:

[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] In a reaction vessel of formula (III) shown intermediates and benzene acetic acid vinegar hit group, after completion of the reaction obtained by separation and purification of the formula (IV) shown in ah two benzene compounds setback hit group ;

[0059] (C)式(V)所示的含末端S键的嗯二挫类化合物的制备: [0059] (C) of formula (V) shown with terminal S bonds fell ah two compounds was prepared:

[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; Ah two setback compounds [0061] In a reaction vessel in the organic solvent C, benzene of formula (IV) shown in smashing group of carbonate, bell, olive mix was added slowly bake propyl desert, under nitrogen reflux 3 ~ 5 hours after completion of the reaction by the separation and purification of formula (V) shown in ah two compounds containing terminal setback = key;

[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 bis heterocyclic compounds benzene [0062] (d) of formula (VI-2) shown smashing substituted: "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 in ah two setback compounds containing terminal E = bond dissolved in a solvent, and successively added copper sulfate pentahydrate and ascorbic acid, azide was added after dissolving embrace mix formula (XI) as shown compound, the reaction stirred for 6-8 hours at room temperature embrace, isolated and purified after completion of the reaction formula (VI-2) shown substituted benzene hit double heterocyclic compound;

[00化]式(XI)中,r2的定义同式(VI-2)。 [00 of] the formula (XI), the definition of r2 with the 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) That the above step (1) - Step (3), this is no longer prepared details Po said.

[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 E is selected from one of the following: a mixed solvent of THF and water, dimethyl sulfoxide satirical.

[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), the two fell ah = compounds containing terminal bond of formula (V) shown, five water copper sulfate, ascorbic acid, azide 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] material of formula (II) used in the present invention is shown smashing a- benzene-n-propyl wake accordance with existing methods reported in the literature prepared by the following equation:

[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] drop-substituted bis heterocyclic compound benzene of the present invention have excellent monoamine oxidase inhibitory activity, in particular MO-B inhibitory activity, it can be used in 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] the beneficial effects of the present invention is to provide a new class of excellent monoamine oxidase inhibitory activity of substituted benzene hit double heterocyclic compounds. 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 with reference to specific embodiments of the present invention will be further described, but the scope of the present invention is not limited to:

[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 setback of 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 of day - benzene hit propionic awake (0.213 purpose, 1111111〇1) and Radial benzene trap (1111111〇1,0.152 purpose) added to a round bottom flask containing 20ml of ethanol, mixing football completely dissolved, then add S (K) of acetic acid, under reflux of 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, the ethanol drained, the blood C is also added 20 Ch, washed with saturated Na2〇) 3 solution (3 X-20 blood) coating aqueous solution, dried over anhydrous Na2S〇4 sulfate, and concentrated to give the intermediate benzene drop group The product (rainbow) 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) (Immol) was added to the acetic acid in vinegar 5mL, under nitrogen heated to reflux reaction 3h, dry red color of the solution changed and 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) aqueous solution to remove non-coated acetic Health drained, and then dried over anhydrous Na2S〇4, concentrated and the product was isolated by TLC (IV of), in 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) will Immol (0.390g) was dissolved in 20mL compound IV prop paid, then add (1.5mmol, 0.207g) carbonate bell, embrace mix slowly added (1.2mmol, 0.143g) propyl baked desert, in under nitrogen at reflux of the reaction. 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, drained propionate pay, add 20mLC this C12, saturated for 20) 3 solution (3 X 20mL) aqueous solution coating, anhydrous of 2S of dried and concentrated, after thin layer chromatography to give 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) on the first head loss methylbenzene (2mmol, 0.272g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved at room temperature in 20mLCH2Cl2 4h, then was added compound ¥ (1111111〇1,0.388 purpose) was added dropwise and ^ ethylamine (2111111〇1, 0.28mL) 6 hours the reaction, most of the detecting TLC the reaction was complete, saturated layered steel chloride, the organic phase was washed with saturated steel chloride (30mL X 3), The organic phase was dried over anhydrous sulfate instrument concentrated TLC was VI-1-1., a yield of 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。 The product characterization: Ir R wake of the address er Avance NMR measurement, I3C R wake of the address er Avance NMR spectrometer measured 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 of the address er Tensor27 infrared spectrometer, using solid Di r tablet, liquid using the liquid film method. 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. fine 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 [0081] Example 2 Synthesis of Iso ah ah two setback setback compound derivative VI-1-2. The

[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%。 123 451) for exploration as well buy in Example 1, Step 122) Operating as in Example 1, step 233) Operating as in Example 1, step 344) for the first methoxybenzene head loss (2mmol, 0.288g) dissolved with an equivalent of NCS (2mmol, 0.268g) in 20mLCH2Cl2 for 3h at room temperature, was added the compound ¥ (1111111〇1,0.388 purpose) was added dropwise and ^ ethylamine (2111111〇1, 0.28mL) reaction 6 hours, TLC detect most reaction was complete, the subsequent processing as in Example 1, step 4, by TLC was 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)+. The product characterization was 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 choose duck duck two banks of River compounds pray cow was VI-1-3. Synthesis of [0089

Figure CN104003983BD00131

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

[0091] 2)操作如实施例1步骤2 [0091] 2) Operating as in Example 1, Step 2

[0092] 3)操作如实施例1步骤3 [0092] 3) Operating as 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) on the first head loss chlorobenzene (2mmol, 0.313g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved at room temperature in 20mLCH2Cl2 3h, then was added compound V (lmmol, 0.388g) and S was added dropwise triethylamine (2mmol, 0.28mL) 6 hours the reaction, most of the detecting TLC the reaction was complete, the subsequent processing as in step 4 of Example 1, obtained by TLC VI-1-3., 71% yield. 产物表征结果如下: The product characterization results are 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 4 containing two different ah ah setback setback of compound derivative [OOM] Examples Synthesis of VI-1-4.

[0096 [0096

Figure CN104003983BD00132

[0097] 1)操作如实施例1步骤1 [0097] 1) Operating as in Example 1, step 1

[0098] 2)操作如实施例1步骤2 [0098] 2) Operating as in Example 1, Step 2

[0099] 3)操作如实施例1步骤3 [0099] 3) Operating as 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 rotten benzene (2mmol, 0.280g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved at room temperature in 20mLCH2Cl2 3h, then was added compound V (lmmol, 0.388g) dropwise and S was added triethylamine (2mmol, 0.28mL) 6 hours the reaction, most of the detecting TLC the reaction was complete, the subsequent processing as in step 4 of Example 1, obtained by TLC VI-I-4., yield 78%. 产物表征结果如下: The product characterization results are 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 5 containing two different ah ah setback setback of compound derivative VI-1-5. Synthesis of [0103 [0102] Example

Figure CN104003983BD00141

[0104」 U探化观头她例i巧耀i [0104 "U Concept Exploration of her head Yao Qiao cases i i

[0105] 2)操作如实施例1步骤2 [0105] 2) Operating as in Example 1, Step 2

[0106] 3)操作如实施例1步骤3 [0106] 3) Operating as 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) S of the first gas-methylbenzene head loss (2mmol, 0.380g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved at room temperature in 20mLCH2Cl2 3h, then was added compound V (Immol, 0.388 g) was added dropwise S and triethylamine (2mmol, 0.28mL) 6 hours the reaction, most of the detecting TLC the reaction was complete, the subsequent treatment as Example 1, step 4, by TLC give VI-I-5., yield 72%. 产物表征结果如下: The product characterization results are 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 6 containing two different ah ah setback setback of compound derivative [0109] Synthesis Example [0110 VI-1-6's.

Figure CN104003983BD00142

[0111] 1)操作如实施例1步骤1 [0111] 1) Operating as in Example 1, step 1

[0112] 2)操作如实施例1步骤2 [0112] 2) Operating as in Example 1, Step 2

[0113] 3)操作如实施例1步骤3 [0113] 3) Operating as 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) the first inter-desert benzene mesh deficit (2mmol, 0.402g) with an equivalent amount of NCS (2mmol, 0.268g) was dissolved in 20mLCH2Cl2 at room temperature 3h, then add compound ¥ (1111111〇1,0.388 purpose) was added dropwise and ^ ethylamine (2111111〇1, 0.28mL) 6 hours the reaction, most of the detecting TLC the reaction was complete, the subsequent processing as in step 4 of Example 1, obtained by TLC VI-I-6., yield 76%. 产物表征结果如下: The product characterization results are 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 7 [0116] Example 2: Preparation = nitrogen-containing ring ah setback setback two classes of compounds VI-2-1

[0117 [0117

[011引1)操作如实施例1步骤1 [011 primer 1) Operating as in Example 1, step 1

[0119] 2)操作如实施例1步骤2 [0119] 2) Operating as in Example 1, Step 2

[0120] 3)操作如实施例1步骤3 [0120] 3) Operating as 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%。 [01 respectively] 4) Compound V (Immol) was dissolved IOmL THF: 0 This two 1: 1 (volume ratio), followed by adding this CuS〇4.5 0 (0.05mmol) and ascorbic acid (Vc, 0.15mmol), football added 1-azido-propionic acid ethyl ester (1.5mmol) was dissolved after mixing, at room temperature the reaction mix of football, the process of tracing the reaction by detection of C, cooled after completion of the reaction the solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic after repeated washing with anhydrous MgS drying, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give = nitrogen-containing ring ah two setback setback compound VI-2-1., yield 86%. 产物表征结果如下: The product characterization results are 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 candied Example 8: Preparation of nitrous River clever duck two banks of compounds containing VT-2-2 [0124

Figure CN104003983BD00151

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

[0126] 2)操作如实施例1步骤2; [0126] 2) Operating 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) Compound eight Immol) was dissolved IOmL THF: This 0 = 1: 1 (volume ratio), followed by adding this CuS〇4.5 0 (0.1 Ommo 1) and ascorbic acid (Vc, 0.25mmo 1), football was added 4-azido-acetic acid methyl ester (1.6mmo 1) after the mix is dissolved, at room temperature the reaction mix of football, the process of tracing the reaction by detection of C, cooled after completion of the reaction the solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic after repeated washing with anhydrous MgS drying, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give = nitrogen-containing ring ah two setback setback compound VI-2-2., a yield of 82.5%. 产物表征结果如下: The product characterization results are 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: ah two setbacks compounds containing nitrogen = setback ring VI-2-3 Preparation

[0131: [0131:

[0132] 操作如实施例1步骤I; [0132] Operating as described in Example 1, Step I;

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

[0134] 2)操作如实施例1步骤3; [0134] 2) Operating 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 IOmL THF: This 0 = 1: 1 (volume ratio), followed by adding this CuS04.5 0 (0.05mmol) and ascorbic acid (Vc, 0.15mmol), olive mix dissolved was added 4-azido-propionic acid methyl ester (1.5mmol), stirred the reaction at room temperature embrace 8h, the reaction of C with track detection, is cooled after completion of the reaction the solvent was concentrated, and extracted with CHsCb (3 X 20mL), the combined organic phases after washing several times anhydrous MgS drying, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give = nitrogen-containing ring ah two setback setback compound VI-2-3, a yield of 81.8%. 产物表征结果如下: The product characterization results are 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 10 [0137] Example: ah two setbacks compounds containing nitrogen = setback ring of Preparation VI-2-4

[0138] [0138]

Figure CN104003983BD00161

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

[0140] 2)操作如实施例1步骤2; [0140] 2) Operating 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) Compound V (Immol) was dissolved IOmL THF: This 0 = 1: 1 (volume ratio), followed by adding this CuS〇4.5 0 (0.05mmol) and ascorbic acid (Vc, 0.15mmol), olive mix after dissolution azide was added benzene (1.5mmol), stirred at room temperature embrace of the reaction, the reaction by TLC tracking process, completion of the reaction. after cooling the solvent was concentrated, the Cl2 and extracted with C (3 X 20mL), the combined organic phase washed with water several times drying anhydrous MgS, 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-2-4., a yield of 86.9%. 产物表征结果如下: The product characterization results are 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 Preparation ah setback two compounds containing nitrogen = setback ring of 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) Operating 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 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) Compound V (Immol) was dissolved IOmL THF: This 0 = 1: 1 (volume ratio), followed by adding this CuS〇4.5 0 (0.05mmol) and ascorbic acid (Vc, 0.15mmol), olive mix was added 4-azido-chlorobenzene (1.5mmol) dissolved, and the reaction stirred at room temperature embrace of the reaction process of tracking by detecting C, after completion of the reaction the solvent was concentrated cooling by the C Cl2 and extracted (3 X 20mL), the combined organic phases after washing several times anhydrous MgS drying, 30 ° C and concentrated by evaporation, after isolated and purified by thin layer chromatography to give = nitrogen-containing ring ah two setback setback compound VI-2-5., yield 87%. 产物表征结果如下: The product characterization results are 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 frustration ah two nitrogen compounds VI-2-6 setback ring containing =

[0152: [0152:

Figure CN104003983BD00171

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

[0154] 2)操作如实施例1步骤2; [0154] 2) Operating 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) Compound V (Immol) was dissolved IOmL THF: This 0 = 1: 1 (volume ratio), followed by adding this CuS〇4.5 0 (0.1 Ommol) and ascorbic acid (Vc, 0.25mmol), olive mix toluene was added and dissolved azide (1.5mmol), stirred at room temperature embrace of the reaction, the reaction by TLC tracking, after completion of the reaction the solvent was concentrated cooling by the C Cl2 and extracted (3 X 20mL), the combined organic phase washed with water several times plus drying over anhydrous MgS, 30 ° C and concentrated by evaporation, after thin layer chromatography to give ah two frustrated frustration nitrogen-containing compound S ring VI-2-6, a yield of 86.1%. 产物表征结果如下: The product characterization results are 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] Examples 1 to 12 Preparation of the implementation of ~ (VI-12) was dissolved in dimethyl sulfoxide satirical (DMSO), and were dubbed 10,50,75,100,150111111〇1 / a concentration gradient of the liquid sample, denoted 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) substituted benzene hit double-heterocyclic compound (VI) -A monoamine oxidase inhibitory activity detection method

[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。 [0162] to 12 parts containing, respectively, 38 of the L Shed acid buffer (pH = 8.4) of the EP tube was added 10 of (the concentration of 5mg / mL) monoamine oxidase -A (MAO-A) and 4 step (1) preparation samples 1 to 12, mixed, and the mixture in a water bath at 38 ° C in the reaction vessel, followed by addition of L 2 Button formula (XII), respectively, again to 12 parts of the above-mentioned probe shown in EP tube 7- (3-amino propoxy) -4-methyl-coumarin (20mmol / ml) and 2.5 of the bovine serum albumin (BSA, the concentration of 60mg / mL), and EP tube in a water bath at 38 ° C to continue the reaction of. 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。 Simultaneously with the enzymatic activity to be detected not added inhibitor, namely the shed containing 38 L of acid buffer (pH = 8.4) was added to the EP tube 10 monoamine oxidase -A (MAO-A), at 38 ° C bath for well-being, then added 2.5 of a probe (20mmol / ml) and L 2 of the same BSA are 38 ° C water bath of 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] Finally, remove the I (K) of a 96 well plate and with a full-featured clever light spectrophotometer (AexAem = 365 / 460nm) (spectraMax M, USA Molecular Devices EP in each tube (trace from Tuen tube) company) test samples. 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。 The samples ICso 1 ~ 12, the compound (VI-I) ~ (VI-12) based on the measured values clever light of monoamine oxidase -A activity inhibition test results 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 compound IC50 (ICso) to represent. 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" was half inhibitory concentration inhibitor compound to inhibit the stronger, the lower the value.

[0166] ICso可W用W下方法计算: [0166] ICso can be calculated under the W by 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) detect and calculate only the probe enzyme buffer Qiao average light intensity (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) contains an average calculated clever light intensity of each component of 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) linear regression relationship between light intensity and clever (F) of the light intensity of each component according to Qiao different concentrations of enzyme inhibitors, establishing give equation: F = aC + b (determined by linear regression equation coefficients a 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, find F = inhibitor concentration corresponds to 1 / 2FM under inhibitory concentration can be calculated Ij trial inhibition rate of 50%, is the 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) substituted benzene hit double-heterocyclic compound (VI) of the monoamine oxidase inhibitory activity test -B

[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 replace MA0-B, with 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 [0173] Table 1 Examples 1 to 12 Preparation of bis hit substituted heterocyclic compound (VI) 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: inhibitory activity with ICso said each sample to do three parallel group, take five concentration gradient;

[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: selective enzyme expressed by 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 primer from Table 1, the compounds (vi-1-1) ~ (VI-1-5) and (VI-2-1) ~ (VI-2-6) of monoamine oxidase A inhibitory activity, wherein the compound (VI-1-1) ~ (VI-1-5) has a stronger inhibitory activity; compound (VI-1-1) ~ (VI-I-6) and (VI-2-1) ~ ( VI-2-6) of monoamine oxidase B inhibitory activity, wherein the compound (VI-1-1) ~ (VI-1-6) and (VI-2-2) ~ (VI-2-6) has a strong inhibitory activity, especially the compound (VI-1-1) ~ (VI-1-5) have a strong inhibitory activity.

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