阅读说明：本技术 N-2-吡啶基-2,3-二叠氮吲哚啉类化合物及其制备与应用 (Two nitrine indoline-like compound of N-2- pyridyl group -2,3- and its preparation and application ) 是由 朱勍 刘江 刘鑫 于 2019-08-02 设计创作，主要内容包括：本发明公开了一种N-2-吡啶基-2,3-二叠氮吲哚啉类化合物,及其制备方法与应用,所述化合物的结构如式(I)所示。本发明的有益效果主要体现在：(1)本发明通过N-2-嘧啶吲哚类化合物与三甲基硅烷类化合物发生分子内自由基加成反应,一步高收率地制备了一类新的N-2-吡啶基-2,3-二叠氮吲哚啉类化合物；(2)本发明提供了一种新的N-2-吡啶基-2,3-二叠氮吲哚啉类化合物,该类化合物是一种具有显著抑制单胺氧化酶活性的抑制剂药物,为抗抑郁、抗帕金森等新药筛选提供了研究基础；(3)本发明所述的化合物,合成工艺简单,收率高,易于产业化。<Image he="458" wi="585" file="DDA0002154335560000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a kind of bis- nitrine indoline-like compound of N-2- pyridyl group -2,3-, and the preparation method and application thereof, shown in the structure of the compound such as formula (I).The beneficial effects are mainly reflected as follows: (1) by N-2- pyrimidine Benzazole compounds and trimethyl silicane alkanes compound intramolecular Radical Addition occurs for the present invention, one step is prepared for a new class of bis- nitrine indoline-like compound of N-2- pyridyl group -2,3- in high yield；(2) the present invention provides a kind of new N-2- pyridyl groups -2, bis- nitrine indoline-like compound of 3-, such compound is a kind of with the inhibitor medicaments for significantly inhibiting activity of monoamine oxidase, provides Research foundation for new medicament screens such as antidepression, anti-Parkinsons；(3) compound of the present invention, synthesis technology is simple, and high income is easy to industrialization.)

1. a kind of N-2- pyridyl group 2, bis- nitrine indoline-like compound of 3-, shown in structure such as formula (I):

R in formula (I)₁、R₂、R₃、R₄、R₅Respectively stand alone as the alkyl or methoxyl group of H, halogen, nitro, cyano, C1-C3.

2. N-2- pyridyl group 2 as described in claim 1, bis- nitrine indoline-like compound of 3-, it is characterised in that R in formula (I)₁、 R₂、R₃、R₄、R₅Respectively stand alone as H, Cl, F, nitro, cyano or methyl.

3. N-2- pyridyl group 2 as described in claim 1, bis- nitrine indoline-like compound of 3-, it is characterised in that the chemical combination Object is one of following:

4. the method for preparing compound described in claim 1, which comprises with trimethyl silane nitrine shown in formula (II) It is raw material with N-2- pyridyl group indoles shown in formula (III), under the action of catalyst and oxidant, in organic solvent, 0~ 1~3h is reacted under the conditions of 50 DEG C, reaction solution is through isolating and purifying to obtain the N-2- pyridyl group 2, bis- nitrine of 3- after reaction Indoline-like compound；

The organic solvent is one of following: acetone, tetrahydrofuran, methylene chloride, acetonitrile, dimethyl sulfoxide, N, N- dimethyl Formamide；

The catalyst is one of following: copper acetate, copper oxide, cupric iodide, copper bromide, copper chloride；

The oxidant is one of following: diethyl acyl-oxygen iodobenzene, two chloroiodobenzones, two (trifluoroacetyl oxygen) iodobenzenes, iodosobenzene；

R in formula (I)₁、R₂、R₃、R₄、R₅Respectively stand alone as the alkyl or methoxyl group of H, halogen, nitro, cyano, C1-C3.

5. method as claimed in claim 3, it is characterised in that: substituent indole compound shown in formula (III), formula (II) institute The ratio between amount for the substance that feeds intake of the trimethyl silane nitrine, catalyst, oxidant that show be 1:2.0~4.0:0.1~1.0:2.0~ 4.0。

6. method as claimed in claim 3, it is characterised in that the isolation and purification method is as follows: after reaction, reaction solution It is extracted with ethyl acetate and saturated sodium-chloride, organic phase is taken to wash, then is dry with anhydrous magnesium sulfate, concentration obtains crude product with volume Petroleum ether and ethyl acetate mixtures than 30:1 are that solvent carries out thin-layer chromatography, obtain the N-2- pyridyl group 2,3- bis- Nitrine indoline-like compound.

7. compound described in claim 1 is preparing the application in activity of monoamine oxidase inhibition.

8. application as claimed in claim 6, it is characterised in that the compound is compound (I-1), compound (I-2), changes Close object (I-3), compound (I-4), compound (I-5), compound (I-6), compound (I-7) or compound (I-8).

(1) technical field

The present invention relates to bis- nitrine indoline-like compound of one kind -2- pyridyl group -2,3-, and the preparation method and application thereof.

(2) background technique

Monoamine oxidase (monoamine oxidase, MAO) is naturally occurring a kind of enzyme in human body, is catalyzed monoamine The enzyme of substance oxidative deamination.Human body is included there are two types of monoamine oxidase: monoamine oxidase A and monoamine oxidase B.Monoamine oxygen Changing enzyme inhibitor then can be by inhibiting the oxidation activity to Monoamines of monoamine oxidase, to reach mitigation or disappear Except the reduction of the Monoamines as caused by a variety of causes or the excessively high caused disease of activity of monoamine oxidase.

Monoamine oxidase inhibitors is broadly divided into three kinds, the first, non-selective monoamine oxidase inhibitor can be simultaneously Monoamine oxidase A and monoamine oxidase B, this class drug is inhibited mainly to have Pheniprazine, nardil, Isocarboxazid and anti-phenyl ring third Amine etc., wherein Pheniprazine is tried out in patients with depression and is succeeded in nineteen fifty-seven as the 1st anti-depression drug.The Two kinds, monoamine oxidase A inhibitor, the inhibitor only has inhibitory effect to monoamine oxidase A, and does not press down to monoamine oxidase Effect processed is unobvious, and it is a kind of anti-suppression in France's listing in 1985 that oxazolidinones MAO-A, which inhibits drug Toloxatone, Strongly fragrant drug is strong and reversible to the inhibiting effect of MAO-A.The third, the inhibitor of monoamine oxidase B, the inhibitor just in Monoamine oxidase B plays inhibiting effect.

But the most yield of these methods is low, condition requires harsh, device complexity, and non-corresponding body is selectively low.

(3) summary of the invention

It is an object of the present invention to provide a kind of bis- nitrine indoline-like compound of N-2- pyridyl group -2,3- and preparation method thereof, And application of such compound in monoamine oxidase (MAO) inhibitor medicaments, such compound have monoamine oxidase Significant inhibiting effect, such compound synthesis technology is simple, is easy to industrialization.

The technical solution adopted by the present invention is that:

A kind of N-2- pyridyl group 2, bis- nitrine indoline-like compound of 3-, shown in structure such as formula (I):

R in formula (I)₁、R₂、R₃、R₄、R₅Respectively stand alone as the alkyl or methoxyl group of H, halogen, nitro, cyano, C1-C3.It is excellent Choosing, R₁、R₂、R₃、R₄、R₅Respectively stand alone as H, Cl, F, nitro, cyano or methyl.

The present invention is anti-by the N-2- pyridine indoles copper of trimethyl silicon substrate nitrine and different substituents catalysis free radical addition Single step reaction is answered to be prepared for a new class of bis- nitrine indoline-like compound of N-2- pyridyl group -2,3- with high selectivity in high yield, Such compound is a kind of with the inhibitor class compound for significantly inhibiting activity of monoamine oxidase, is antidepression, anti-Parkinson Class drug screening provides Research foundation.

Preferably, the compound is one of following:

The invention further relates to the methods for preparing the compound, which comprises with trimethyl silicane shown in formula (II) N-2- pyridyl group indoles shown in alkane nitrine and formula (III) is raw material, under the action of catalyst and oxidant, in organic solvent In, 1~3h is reacted under the conditions of 0~50 DEG C, reaction solution is through isolating and purifying to obtain the N-2- pyridyl group 2,3- after reaction Two nitrine indoline-like compounds；

The organic solvent is one of following: acetone, tetrahydrofuran, methylene chloride, acetonitrile, dimethyl sulfoxide, N, N- bis- Methylformamide；

The catalyst is one of following: copper acetate, copper oxide, cupric iodide, copper bromide, copper chloride；

The oxidant is one of following: diethyl acyl-oxygen iodobenzene (PIDC), two chloroiodobenzones (PIDA), two (trifluoroacetyls Oxygen) iodobenzene (PIFA), iodosobenzene (PhIO)；

R in formula (I)₁、R₂、R₃、R₄、R₅Respectively stand alone as the alkyl or methoxyl group of H, halogen, nitro, cyano, C1-C3.

Substituent indole compound shown in formula (III), trimethyl silane nitrine, catalyst, oxidation shown in formula (II) The ratio between amount for the substance that feeds intake of agent is 1:2.0~4.0:0.1~1.0:2.0~4.0.The volumetric usage of the organic solvent with Formula (III) compound represented quality is calculated as 10~50mL/g.

The isolation and purification method is as follows: after reaction, reaction solution ethyl acetate and saturated sodium-chloride extraction have taken Machine Xiang Shuixi, then it is dry with anhydrous magnesium sulfate, concentration, obtain crude product with the petroleum ether of volume ratio 30:1 is with ethyl acetate mixtures Solvent carries out thin-layer chromatography, obtains the N-2- pyridyl group 2, bis- nitrine indoline-like compound of 3-.

The invention further relates to the compounds to prepare the application in activity of monoamine oxidase inhibition.Preferably, described Compound is compound (I-1), compound (I-2), compound (I-3), compound (I-4), compound (I-5), compound (I- 6), compound (I-7) or compound (I-8).

The beneficial effects are mainly reflected as follows: (1) present invention pass through N-2- pyrimidine Benzazole compounds and trimethyl Intramolecular Radical Addition occurs for silane compound, and a step is prepared for a new class of pyridyl group -2 N-2- in high yield, Bis- nitrine indoline-like compound of 3-；(2) the present invention provides a kind of new two nitrine indoline-likes of N-2- pyridyl group -2,3- Object is closed, it is antidepression, anti-Parkinson that such compound, which is a kind of with the inhibitor medicaments for significantly inhibiting activity of monoamine oxidase, Equal new medicament screens provide Research foundation；(3) compound of the present invention, synthesis technology is simple, and high income is easy to industry Change.

(4) Detailed description of the invention

Fig. 1 is the nucleus magnetic hydrogen spectrum for the compound (I-1) that in the present invention prepared by embodiment 1.

Fig. 2 is the nuclear-magnetism carbon spectrum for the compound (I-1) that in the present invention prepared by embodiment 1.

Fig. 3 is the nucleus magnetic hydrogen spectrum for the compound (I-2) that in the present invention prepared by embodiment 2.

Fig. 4 is the nuclear-magnetism carbon spectrum for the compound (I-2) that in the present invention prepared by embodiment 2.

Fig. 5 is the nucleus magnetic hydrogen spectrum for the compound (I-3) that in the present invention prepared by embodiment 3.

Fig. 6 is the nuclear-magnetism carbon spectrum for the compound (I-3) that in the present invention prepared by embodiment 3.

Fig. 7 is the nucleus magnetic hydrogen spectrum for the compound (I-4) that in the present invention prepared by embodiment 4.

Fig. 8 is the nuclear-magnetism carbon spectrum for the compound (I-4) that in the present invention prepared by embodiment 4.

Fig. 9 is the nucleus magnetic hydrogen spectrum for the compound (I-5) that in the present invention prepared by embodiment 5.

Figure 10 is the nuclear-magnetism carbon spectrum for the compound (I-5) that in the present invention prepared by embodiment 5.

Figure 11 is the nucleus magnetic hydrogen spectrum for the compound (I-6) that in the present invention prepared by embodiment 6.

Figure 12 is the nuclear-magnetism carbon spectrum for the compound (I-6) that in the present invention prepared by embodiment 6.

Figure 13 is the nucleus magnetic hydrogen spectrum for the compound (I-7) that in the present invention prepared by embodiment 7.

Figure 14 is the nuclear-magnetism carbon spectrum for the compound (I-7) that in the present invention prepared by embodiment 7.

Figure 15 is the nucleus magnetic hydrogen spectrum for the compound (I-8) that in the present invention prepared by embodiment 8.

Figure 16 is the nuclear-magnetism carbon spectrum for the compound (I-8) that in the present invention prepared by embodiment 8.

(5) specific embodiment

The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in This: