1. A β-carboline compound with a structure shown in the following formula Ic or formula Id



wherein,

R4 and R5 respectively represent hydrogen, C1-C10 alkyl, C3-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, or C1-C10 sulfur-containing heterocyclic ring, or R4 and R5 form a C6 aliphatic ring, or R4 is hydrogen and R5 is prop-2-enyl; and

R6 represents hydrogen, hydroxy, C1-C6 alkoxy, substituted phenyl ring, C1-C10 oxygen-containing heterocyclic ring, or C1-C10 sulfur-containing heterocyclic ring.

2. A β-carboline compound selected from the group consisting of:

(1S, 3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-1);

(1S, 3S)—N′-(4-tert-butyl benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-2);

(1S, 3S)—N′-(4-dimethyl amino benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-3);

(1S, 3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-4);

(1S, 3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-5);

(1S, 3S)—N′-(2, 4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-6);

(1S, 3S)—N′-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-7);

(1S, 3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-8);

(1S, 3S)—N′-(3-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-9);

(1S, 3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-10);

(1S, 3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-11);

(1S, 3S)—N′-((benzo [d] [1, 3] dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-12);

(1S, 3S)—N′-(2, 3-dihydrobenzo [b] [1, 4] dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-13);

(1S, 3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-14);

(1S, 3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-15);

(1S, 3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-16);

(1S, 3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-17);

(1S, 3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-18);

(1S, 3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-19);

(1S, 3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-20);

(1S, 3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-21);

(1S, 3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-22);

(1S, 3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-23);

(1S, 3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-24);

(1S, 3S)—N′-(cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-25);

(1S, 3S)—N′-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-26);

(1S, 3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-27);

(1S, 3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-28);

(1S, 3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-29);

N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-tricarboxylate) benzo [d] [1,2,3] thiadiazole-7-formylhydrazine (Id-i);

4-methyl-N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-triformyl)-1, 2, 3-thiadiazole-5-formylhydrazine (Id-2);

(1S, 3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-3);

(1S, 3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-4);

(1S, 3S)—N′-n-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-5);

(1S, 3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-G); and

(1S, 3S)—N′-(cyclopentyl formyl)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-7).

3. A method for preparing the β-carboline according to claim 2:

regarding Ic-1-Ic-29, the method comprising:

reacting hydrazide compound Ib-15 with fatty aldehyde or aromatic aldehyde to obtain corresponding acylhydrazone compound Ic-1-Ic-29:



regarding Id-1-Id-7, the method comprising:

reacting hydrazide compound Ib-15 with acyl chloride to obtain corresponding bishydrazide compound Id-1-Id-7:



4. A method of treating plant viruses comprising administering the β-carboline compound according to claim 1.

5. A method of treating plant viruses comprising administering a β-carboline compound selected from the group consisting of:

(1S, 3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-1);

(1S, 3S)—N′-(4-tert-butyl benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-2);

(1S, 3S)—N′-(4-dimethyl amino benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-3);

(1S, 3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-4);

(1S, 3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-5);

(1S, 3S)—N′-(2, 4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-6);

(1S, 3S)—N′-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-7);

(1S, 3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-8);

(1S, 3S)—N′-(3-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-9);

(1S, 3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-10);

(1S, 3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-11);

(1S, 3S)—N′-((benzo [d] [1, 3] dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-12);

(1S, 3S)—N′-(2, 3-dihydrobenzo [b] [1, 4] dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-13);

(1S, 3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-14);

(1S, 3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-15);

(1S, 3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-16);

(1S, 3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-17);

(1S, 3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-18);

(1S, 3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-19);

(1S, 3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-20);

(1S, 3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-21);

(1S, 3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-22);

(1S, 3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-23);

(1S, 3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-24);

(1S, 3S)—N′-(cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-25);

(1S, 3S)—N′-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-26);

(1S, 3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-27);

(1S, 3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-28);

(1S, 3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-29);

N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-tricarboxylate) benzo [d] [1,2,3] thiadiazole-7-formylhydrazine (Id-1);

4-methyl-N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-triformyl)-1, 2, 3-thiadiazole-5-formylhydrazine (Id-2);

(1S, 3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-3);

(1S, 3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-4);

(1S, 3S)—N′-n-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-5);

(1S, 3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-f ormylhydrazine (Id-6); and

(1S, 3S)—N′-(cyclopentyl formyl)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-7).

6. The method according to claim 4, wherein the compound effectively inhibits tobacco mosaic virus, chilli virus, rice virus, tomato virus, sweet potato virus, potato virus and cucurbits virus as well as maize dwarf mosaic virus;

the compound shows bactericidal activity against 14 kinds of pathogenic bacteria, which are cucumber fusarium wilt, Cercospora arachidicola, Macrophoma kawatsukai, Alternaria solani, Fusarium graminearumt, potato late blight, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Phytophthora capsici, Fusarium fujikuroi, Rhizoctonia cereali, Bipolaria maydis and Colletotrichum orbiculare;

the compound shows activity against armyworms, cotton bollworms, corn borers and culex pipiens.

7. The method according to claim 5, wherein the compound effectively inhibits tobacco mosaic virus, chilli virus, rice virus, tomato virus, sweet potato virus, potato virus and cucurbits virus as well as maize dwarf mosaic virus;

the compound shows bactericidal activity against 14 kinds of pathogenic bacteria, which are cucumber fusarium wilt, Cercospora arachidicola, Macrophoma kawatsukai, Alternaria solani, Fusarium graminearumt, potato late blight, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Phytophthora capsici, Fusarium fujikuroi, Rhizoctonia cereali, Bipolaria maydis and Colletotrichum orbiculare;

the compound shows activity against armyworms, cotton bollworms, corn borers and culex pipiens.

8. The method according to claim 3, wherein the method for preparing Ib-15 comprises the steps of:

reacting methyl ester Ib-7 with hydrazine hydrate (80%) to obtain compound Ib-15:



9. The method according to claim 8, wherein the method for preparing Ib-7 comprises the steps of:

reacting L-tryptophan with an acetaldehyde aqueous solution to obtain cyclization product Ib-1, which is then further esterified by one step to obtain compound Ib-7,

CROSS REFERENCE TO RELATED APPLICATIONS

[0001]This application is a 35 USC § 371 national stage application of PCT/CN2014/094847, which was filed Dec. 24, 2014 and claims priority to Chinese Patent Application No. 201310752240.2, filed Dec. 30, 2013, entitled “β-Carboline, Dihydro-β-Carboline and Tetrahydro-β-Carboline Alkaloid Derivatives and Preparation Methods Same and Use in Aspects of Preventing and Treating Plant Viruses, Fungicides and Insecticides,” both of which are incorporated specifically and entirely herein by reference as if fully set forth.

FIELD OF THE INVENTION

[0002]The present invention relates to β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives and their preparation methods and use in the preventing and treating plant viruses fungicides and insecticides and pertains to the technical field of pesticides.

BACKGROUND OF THE INVENTION

[0003]The skeleton structures of β-carboline, dihydro-β-carboline and tetrahydro-β-carboline widely exist in natural products and drug molecules. Harmine and tetrahydroharmine belong to β-carboline and tetrahydro-β-carboline alkaloids respectively and are representative compounds of harmala alkaloids. Harmine was first separated from P. harmala L. This alkaloid shows cytotoxicity to leukemia cell lines HL60 and K562. Tetrahydroharmine is a fluorescent molecule separated from Malpighiacease plant Banisteriopsis caapi. This compound has weak inhibition to the re-uptake of 5-hydroxytryptamine. Harmaline is an agonist of the central nervous system and a reversible inhibitor of monoamine oxidase (MAO-A).

[0004]

[0005]Currently, the research on β-carboline, dihydro-β-carboline and tetrahydro-β-carboline and substances similar to them focuses on anti-tumor, killing of human parasites and monoamine oxidase inhibitors. However, as far as we know, no document reports the activity of β-carboline, dihydro-β-carboline and tetrahydro-β-carboline and substances similar to them against plant viruses, and little was reported on their bactericidal activity and insecticidal activity. In the aspect of bactericidal activity: Fu Haibo et al from Gansu Agricultural University researched and found in 2007 that the extracting solutions of P. harmala L. in different solvents all have certain inhibiting effect to spore germination of four kinds of pathogenic bacteria, including Botrytis cinerea, Fusarium oxysporum, Alternaria solani and Cladosporium cucumerinum Ellis et Arthur, and their EC50 is 0.060, 0.199, 0.105 and 0.223 g/mL respectively (Fu Haibo, Ding Defang, Zhao Hongmei, Yang Shunyi, Grassland and Lawn, 2008, 1, 44-48); in 2007, Wen Ren et al from Fudan University reported derivatives with a structure of 1-(3-indol)-1,2,3,4-tetrahydro-β-carboline and researched the in vitro activity of these derivatives against Pyricularia oryzae (CN101020688); in 2011, Zhang Yaomou et al from South China Agricultural University reported compounds with a structure of β-carboline-3-oxime ester and meanwhile studied the inhibitory activity of these compounds against Colletotrichum musae, Colletotrichum gloeosporioides and tomato late plight (Lu Shaoying, Zhang Yaomou, Synthetic Chemistry, 2011, 19 (6), 769-772); in 2012, this research group again reported compounds with a structure of 1-p-trifluoromethylphenyl-β-carboline-3-carbonyl bishydrazide, but the quantity of the compounds was small and their bacteriostatic activity against Rhizoctorzia solani was tested only (Cai Ying, Huang Jianfeng, Zhang Meidan, Zeng Yong, Zhang Yaomo, Synthetic Chemistry, 2012, 20(6), 736-739.). In the aspect of insecticidal activity: in 2005, Zhao Xiaomeng et al from Beijing University of Agriculture reported the contact activity of the ethanol extract, chloroform extract and water extract of the overground part of P. harmala L. in the growing period against Myzus persicae, Macrosiphum rosivorum and Tetranychus cinnabarinus. The result is that their contact activity against spider mites is all above 95% at concentration of 10 mg/mL, and that against two kinds of aphids is above 70% at concentration of 10 mg/mL (Zhao Xiaomeng, Zeng Zhaohai, Chinese Agricultural Science Bulletin, 2005, 21(4), 278-279); in 2010, Zhong Guohua et al from South China Agricultural University reported the insecticidal activity of 1,3-disubstituted β-carboline and tetrahydro-β-carboline derivatives against culex pipiens larvae and Lipaphis erysimi. To be specific, the LC50 of the compounds with a structure of 1-phenyl substituted β-carboline and tetrahydro-β-carboline-3-methyl ester against culex pipiens larvae is 20.82 mg/L and 23.98 mg/L respectively, and the LC50 against Lipaphis erysimi is 53.16 mg/L and 68.05 mg/L respectively (Zeng, Y; Zhang, Y M.; Weng, Q. F.; Hu, M. Y.; Zhong G H. Molecules 2010, 15, 7775-7791).

SUMMARY OF THE INVENTION

[0006]The object of the present invention is to provide β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives and their preparation methods and use in the preventing and treating plant viruses and killing of bacteria and insects. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives described in the present invention show very good activity against plant viruses and also show bactericidal activity and insecticidal activity. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives described in the present invention are compounds with a structure shown in the following general formula (I):

[0007]

[0008]The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) described in the present invention are compounds with structures shown in the following four general formulas (Ia, Ib, Ic, Id):

[0009]

[0010]The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) described in the present invention further comprise natural compounds with structures shown in the following formulae:

[0011]

[0012]The dihydro-β-carboline alkaloid described in the present invention may be prepared by the following method (Path 1): firstly introducing aldehyde group to indol 3-site to obtain compound 1, the compound 1 then reacts with nitromethane and ammonium acetate to obtain intermediate 2, the intermediate 2 is reduced to obtain tryptamine 3, and then the tryptamine 3 is acylated and cyclized to obtain dihydro-β-carboline alkaloid harmalan.

[0013]Path 1:

[0014]

[0015]The β-carboline and tetrahydro-β-carboline alkaloid described in the present invention may be prepared by the following method (Path 2): firstly, reacting tryptamine 3 with an acetaldehyde aqueous solution under the catalysis of sulfuric acid to obtain tetrahydro-β-carboline alkaloid tetrahydroharmane, which is then further dehydrogenated by one step and oxidized to obtain β-carboline alkaloid harmane.

[0016]Path 2:

[0017]

[0018]The tetrahydro-β-carboline alkaloid described in the present invention may be prepared by the following method (Path 3): firstly, reacting harmine with benzyl bromide to obtain quaternary ammonium salt 4, which is then reduced to obtain compound 5; lastly, the compound 5 is hydrogenated under the catalysis of Pd/C to obtain tetrahydro-β-carboline alkaloid tetrahydroharmine.

[0019]Path 3:

[0020]

[0021]The β-carboline alkaloid described in the present invention may be prepared by the following method (Path 4): Harmine is demethylated under acidic condition to obtain β-carboline alkaloid harmol.

[0022]Path 4:

[0023]

[0024]The β-carboline alkaloid derivatives (Ia) described in the present invention may be prepared by the following method (Path 5): reacting Harmane with bromosuccinimide under acidic condition to obtain compounds Ia-1 and Ia-2, and reacting the obtained compounds with sodium nitrate under acidic condition to obtain compounds Ia-3 and Ia-4 containing substituted nitro on phenyl ring.

[0025]Path 5:

[0026]

[0027]The β-carboline alkaloid derivatives (I) described in the present invention may be prepared by the following method (Path 6): reacting Harmol with isocyanate to obtain compound Ia-5, reacting Harmol with acyl chloride to obtain compound Ia-6-Ia-8, and reacting Harmol with amino acid in presence of a condensation agent to obtain compound Ia-9.

[0028]Path 6:

[0029]

[0030]The β-carboline and tetrahydro-β-carboline alkaloid derivatives (Ia and Ib) described in the present invention may be prepared by the following method (Path 7): firstly, reacting L-tryptophan with an acetaldehyde aqueous solution to obtain cyclization product Ib-1, which is then further esterified by one step to obtain compound Ib-13. Compound Ib-13 is dehydrogenated and oxidized to obtain compound Ia-10. Compound Ia-10 is hydrolyzed under alkaline condition to obtain compound Ia-11. Compound Ia-10 is reduced by lithium aluminum hydride to obtain compound Ia-12. The compound is oxidized to obtain aldehyde Ia-13. Compound Ia-13 reacts with malonic acid to obtain acrylic acid Ia-14. By a same path, compound Ia-15-Ia-16 can be synthesized.

[0031]Path 7:

[0032]

[0033]The tetrahydro-β-carboline alkaloid derivatives (Ib) described in the present invention may be prepared by the following method (Path 8): L/D-tryptophan takes Pictet-spengler reaction with fatty aldehyde or aromatic aldehyde under acidic or alkaline condition to obtain acids Ib-1-Ib-6, and acids Ib-1-Ib-6 are further esterified to obtain ester Ib-7-Ib-12.

[0034]Path 8:

[0035]

[0036]The dihydro-β-carboline alkaloid derivatives (Ib) described in the present invention may be prepared by the following method (Path 9): reacting L-tryptophan with ethanol to obtain ethyl ester 6, which is acylated and then reacting with phosphorus oxychloride to obtain dihydro-β-carboline alkaloid derivative Ib-14.

[0037]Path 9:

[0038]

[0039]The tetrahydro-β-carboline alkaloid derivatives (Ib) described in the present invention may be prepared by the following method (Path 10): reacting methyl ester Ib-7 with hydrazine hydrate (80%) to obtain compound Ib-15, and reacting compound Ib-7 with amine to obtain amides Ib-16 and Ib-18.

[0040]Path 10:

[0041]

[0042]The tetrahydro-β-carboline alkaloid derivatives (Ib) described in the present invention may be prepared by the following method (Path 11): reacting acid Ib-1 with amine in presence of a condensation agent to obtain amides Ib-17, Ib-19-Ib-20.

[0043]Path 11:

[0044]

[0045]The tetrahydro-β-carboline alkaloid derivatives (Ic) described in the present invention may be prepared by the following method (Path 12): reacting hydrazide compound Ib-15 with fatty aldehyde or aromatic aldehyde to obtain corresponding acylhydrazone type compound Ic-1-Ic-29.

[0046]Path 12:

[0047]

[0048]The tetrahydro-β-carboline alkaloid derivatives (Id) described in the present invention may be prepared by the following method (Path 13): reacting hydrazide compound Ib-15 with acyl chloride to obtain corresponding bishydrazide type compound Id-1-Id-7.

[0049]Path 13:

[0050]

[0051]In the above general formulas,

[0052]R represents hydrogen, 1˜4 halogen atoms, 1˜4 nitro groups, 1˜4 cyano groups, 1˜4 C1-C6 alkoxy groups, 1˜4 hydroxy groups, 1˜4 ester groups, 1˜2OCH2O, 1-2OCH2CH2O, 1˜4 C0-C10 amino groups, 1˜4 C1-C6 alkyl carbonyl groups, 1˜4 C1-C10 alkoxy carbonyl groups, 1˜4 C1-C10 alkyl amino carbonyl groups, 1˜4 C1-C6 alkoxy carbonyloxy groups, 1˜4 C1-C6 alkyl amino carbonyloxy groups, 1˜4 C1-C10 α-amino alkyl carbonyloxy groups:

[0053]R1 respectively represents hydrogen, hydroxy, halogen atom, cyano group, ester group, amido group, C1-C10 hydrocarbyl, C1-C6 alkoxy, C1-C4 alkyl carbonyloxy, C1-C4 alkoxy carbonyloxy, C1-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10 sulfur-containing heterocyclic ring, as well as stereomers of the foregoing compounds;

[0054]R2 respectively represents hydrogen, hydroxy, C1-C6 alkoxy, amino, C1-C10 amino, halogen atom, cyano group, aldehyde group, C1-C6 alkyl carbonyl, C1-C10 alkoxy carbonyl, C1-C10 alkyl amino carbonyl, C1-C6 alkoxy carbonyloxy, C1-C6 alkyl amino carbonyloxy;

[0055]X respectively represents hydrogen, oxygen, sulfur, nitrogen, carbon;

[0056]R3 respectively represents hydrogen, hydroxy, halogen atom, cyano group, ester group, amido group, C1-C10 hydrocarbyl, C1-C6 alkoxy, C1-C4 alkyl carbonyloxy, C1-C4 alkoxy carbonyloxy, C1-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10 sulfur-containing heterocyclic ring;

[0057]R4 and R5 respectively represents hydrogen, C1-C10 hydrocarbyl, C1-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10 sulfur-containing heterocyclic ring; R4 and R5 are C1-C10 aliphatic ring, C1-C10 unsaturated carbon ring, C1-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-10 sulfur-containing heterocyclic ring;

[0058]R6 respectively represents hydrogen, hydroxy, amino, C1-C10 hydrocarbyl, C1-C6 alkoxy, C1-C10 amino group, substituted phenyl ring, C1-C10 nitrogen-containing heterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10 sulfur-containing heterocyclic ring.

[0059]The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) described in the present invention are preferably the following compounds:[0060](E)-3-(1-methyl-pyridino [3,4-b] indol-3)-acrylic acid (Ia-14);[0061](E)-3-(1-(thiophene-2)-pyridino [3,4-b] indol-3)-acrylic acid (Ia-15);[0062](E)-3-(1-(pyridine-3)-pyridino [3,4-b] indol-3)-acrylic acid (Ia-16);[0063](1S, 3S)—N-butyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b] indol-3-formamide (Ib-16);[0064](1S, 3S)—N-cyclohexyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b] indol-3-formamide (Ib-17);[0065](1S, 3S)—N-(2-ethoxyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b] indol-3-formamide (Ib-18);[0066](1S, 3S)—N-(dimethyl amino methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b] indol-3-formamide (Ib-19);[0067](1S, 3S)—N-((tetrahydrofuran-2)-methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b] indol-3-formamide (Ib-20);[0068](1S, 3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine[0069](1S, 3S)—N′-(4-tert-butyl benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-2);[0070](1S, 3S)—N′-(4-dimethyl amino benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-3);[0071](1S, 3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-4);[0072](1S, 3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-5);[0073](1S, 3S)—N′-(2, 4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-6);[0074](1S, 3S)—N′-(4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-7);[0075](1S, 3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-8);[0076](1S, 3S)—N′-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-9);[0077](1S, 3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-10);[0078](1S, 3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-11);[0079](1S, 3S)—N′-((benzo [d] [1, 3] dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-12);[0080](1S, 3S)—N-((2, 3-dihydrobenzo [b] [1, 4] dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-13);[0081](1S, 3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-14);[0082](1S, 3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-15);[0083](1S, 3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-16);[0084](1S, 3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-17);[0085](1S, 3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-18);[0086](1S, 3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-19);[0087](1S, 3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-20);[0088](1S, 3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-21);[0089](1S, 3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-22);[0090](1S, 3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-23);[0091](1S, 3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-24);[0092](1S, 3S)—N′-cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-25);[0093](1S, 3S)—N-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-26);[0094](1S, 3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-27);[0095](1S, 3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-28);[0096](1S, 3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Ic-29);[0097]N′—((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-tricarboxylate)benzo [d] [1,2,3] thiadiazole-7-formylhydrazine (Id-1);[0098]4-methyl-N′-((1S, 3S)methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-triformyl)-1,2,3-thiadiazole-5-formylhydrazine (Id-2);[0099](1S, 3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-3);[0100](1S, 3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-4);[0101](1S, 3S)—N′—N-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-5);[0102](1S, 3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-6);[0103](1S, 3S)—N′-(cyclopentylformyl)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formylhydrazine (Id-7).

[0104]The compounds shown in general formula (I) of the present invention have excellent activity against plant viruses, can satisfactorily inhibit tobacco mosaic virus, chilli virus, rice virus, tomato virus, sweet potato virus, potato virus and cucurbits virus and maize dwarf mosaic virus, may effectively prevent and control virus diseases of tobacco, chilli, paddy, tomato, cucurbitaceous vegetable, grain, vegetable, bean and other crops, and is particularly applicable to the prevention and treating of tobacco mosaic. β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives shown in general formula (I) have very high in vitro activity against TMV and also show very good in vivo activity against tobacco mosaic virus (TMV), and the in vivo activity of some of β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives against tobacco mosaic virus is obviously better than that of commercial variety virazole. Particularly, the activity of compounds Harmalan, Tetrahydroharmane, Harmane, Tetrahydroharmine, Ia-1, Ib-13, Ib-15, Ic-1-Ic-9, Ic-12, Ic-19, Ic-20, Ic-24-Ic-26, Ic-28, Id-1, Id-6 and Id-7 against tobacco mosaic virus at concentration of 100 μg/mL is equivalent to the activity of commercial variety ningnanmycin at concentration of 100 μg/mL. As far as we know, it is also the first time to report β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid and their derivatives have activity against plant viruses.

[0105]The compounds shown in general formula (I) of the present invention can be used as inhibitors of plant viruses directly, or used by adding an agriculturally acceptable vector, or used by forming interactive compositions with other agents against plant viruses, such as: diazosulfide (BTH), tiadinil (TDL), 4-methyl-1,2,3-thiadiazole-5-formic acid (TDLA), DL-p-aminobutyric acid (BABA), virazole, ningnanmycin, phenanthroindolizidine alkaloid Antofine, linked triazole compounds XY-13 and XY-30, virus A, salicylic acid, polyhydroxy dinaphthaldehyde and amino oligosaccharin. Some of these compositions show a synergistic effect and some show an additive effect.

[0106]The compounds shown in general formula (I) of the present invention have the activity of killing armyworms, cotton bollworms and corn borers as well as culex pipiens.

[0107]The compounds shown in general formula (I) of the present invention show bactericidal activity against the following 14 kinds of pathogenic bacteria: cucumber fusarium wilt, Cercospora arachidicola, Macrophoma kawatsukai, Alternaria solani, Fusarium graminearumt, potato late blight, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Phytophthora capsici, Fusarium fujikuroi, Rhizoctonia cereali, Bipolaria maydis and Colletotrichum orbiculare.

[0108]The compounds shown in general formula (I) of the present invention can be used as insecticides and bactericides directly, or used by adding an agriculturally acceptable vector, or used in combination with other insecticides, miticides and bactericides, such as: tebufenpyrad, chlorfenapyr, etoxazole and fenpyroximate etc. Some of these compositions show a synergistic effect and some show an additive effect.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0109]The following embodiments and bioassay results are intended to further illustrate but not to limit the present invention.

Embodiment 1: Synthesis of Dihydro-β-Carboline Alkaloid Harmalan

[0110]

Synthesis of Indol-3-Formaldehyde

[0111]Add 140 mL of DMF to a 500 mL single-necked flask, add 27 mL of POCl3 at 0° C., then add 50 mL of DMF solution containing 25 g (214 mmol) of indole and stir them overnight. Add 50 mL of water and 150 mL of 20% NaOH aqueous solution in turn and heat and reflux them for 6 h. Pour the reaction solution into water and conduct suction filtration to obtain 20.6 g of brown solid. The yield is 66% and the melting point is 190-192° C. (literature value: 190-192° C.);

[0112]1H NMR (400 MHz, CDCl3)

[0113]δ 10.08 (s, 1H, CHO), 8.80 (s, 1H, NH), 8.32-8.34 (m, 1H, Ar—H), 7.86 (d, 3JHH=2.8 Hz, 1H, Ar—H), 7.44-7.62 (m, 1H, Ar—H), 7.31-7.36 (m, 2H, Ar—H).

Synthesis of (E)-3-(Nitrovinyl) Indole

[0114]Add 20 g (138 mmol) of indol-3-formaldehyde, 5.3 g (69 mmol) of ammonium acetate and 200 mL of nitromethane to a 500 mL single-necked flask, and heat and reflux them for 8 h. Add 200 mL of water and 150 mL of ethyl acetate and separate the liquid. Wash the organic phase with water, dry it and evaporate the solvent under a reduced pressure. Use dichloromethane for column chromatography under normal pressure to obtain 19.1 g of yellow solid. The yield is 74% and the melting point is 170-171° C.;

[0115]1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H, NH), 8.30 (d, 3JHH=13.6 Hz, 1H, CH), 7.79-7.83 (m, 2H, CH and Ar—H), 7.69 (d, 3JHH=2.8 Hz, 1H, Ar—H), 7.48-7.50 (m, 1H, Ar—H), 7.33-7.38 (m, 2H, Ar—H).

Synthesis of Tryptamine

[0116]Add 500 mL of tetrahydrofuran to a 1000 mL single-necked flask, and add 11.4 g (300 mmol) of lithium aluminum hydride and 9.4 g (50 mmol) of (E)-3-(nitrovinyl) indole. Heat and reflux them for 7 h. Use water to quench lithium aluminum hydride not fully reacted. Conduct suction filtration, remove the solvent in the filtrate and add ethyl acetate and water to separate liquid. Wash the organic phase with a saturated saline solution, dry it with anhydrous sodium sulfate, remove solvent to obtain a red viscous substance, and dry it naturally to obtain 8.9 g of brown solid. The yield is 89% and the melting point is 115-117° C.;

[0117]1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H, NH), 7.62 (d, 3JHH=7.6 Hz, 1H, Ar—H), 7.36 (d, 3JHH=8.0 Hz, 1H, Ar—H), 7.20 (t, 3JHH=7.6 Hz, 1H, Ar—H), 7.12 (t, 3JHH=7.3 Hz, 1H, Ar—H), 7.02 (s, 1H, Ar—H), 3.04 (t, 3JHH=6.4 Hz, 2H, CH2), 2.91 (t, 3JHH=6.8 Hz, 2H, CH2), 1.47 (s, 2H, NH2).

Synthesis of Harmalan

[0118]Add 0.5 g (3.13 mmol) of tryptamine, 40 mL of dichloromethane and 2 mL of triethylamine to a 100 mL single-necked flask. Add 5 mL of dichloromethane solution containing 0.27 g (3.44 mmol) of acetylchloride and react at room temperature for 5 h. Wash the reaction solution with a saturated sodium bicarbonate aqueous solution, dry it with anhydrous sodium sulfate and remove the solvent. Add 20 mL of toluene, 20 mL of chloroform and 3 mL of phosphorus oxychloride without the need of purification. Heat and reflux them for 7 h. Add sodium carbonate to regulate the reaction solution to be alkaline. Extract the reaction solution with dichloromethane, and wash the organic phase with a saturated saline solution, dry it with anhydrous sodium sulfate and remove the solvent. Use dichloromethane/methanol (10:1) for column chromatography under normal pressure to obtain 0.35 g of brownish yellow solid. The yield is 60% and the melting point is 110-113° C.;

[0119]1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H, NH), 7.60 (d, 3JHH=8.0 Hz, 1H, Ar—H), 7.48 (d, 3JHH=8.4 Hz, 1H, Ar—H), 7.31 (t, 3JHH=8.0 Hz, 1H, Ar—H), 7.16 (t, 3JHH=8.0 Hz, 1H, Ar—H), 3.88 (t, 3JHH=8.4 Hz, 2H, CH2), 2.95 (t, 3JHH=8.8 Hz, 2H, CH2), 2.53 (s, 3H, CH3), HRMS (ESI) calcd for C32H13N2(M+H)+ 185.1073. found 185.1077.

Embodiment 2: Synthesis of Tetrahydroharmane and Harmane

[0120]

Synthesis of Tetrahydroharmane

[0121]Add 8.1 mL (43.75 mmol) of 40% acetaldehyde aqueous solution, 250 mL of water and 5 drops of concentrated sulfuric acid to a 500 mL single-necked flask. Stir them at room temperature for 0.5 h, add 3.50 g (21.88 mmol) of tryptamine and heat and reflux them for 7 h. Add NaOH to regulate pH value to around 10, extract the solution with dichloromethane, wash the organic phase with a saturated saline solution, dry it with anhydrous sodium sulfate, remove the solvent, and use dichloromethane/methanol (5:1) for column chromatography under normal pressure to obtain 2.53 g of brown solid. The yield is 62% and the melting point is 173-175° C.;

[0122]1H NMR (400 MHz, d6-DMSO) δ 10.68 (s, 1H, NH), 7.35 (d, 3JHH=8.0 Hz, 1H, Ar—H), 7.27 (d, 3JHH=8.0 Hz, 1H, Ar—H), 6.98-7.02 (m, 1H, Ar—H), 6.97-6.95 (m, 1H, Ar—H), 3.99-4.04 (m, 1H, CHNH), 3.33 (s, 1H, CHNH), 3.14-3.19 (m, 1H, CH2NH), 2.81-2.87 (m, 1H, CH2NH), 2.51-2.62 (m, 2H, CH2CH2), 1.36 (d, 3JHH=6.8 Hz, 3H, CH2CH), HRMS (ESI) calcd for C12H12N2(M+H)+ 187.1230. found 187.1231.

Synthesis of Harmane

[0123]Add 0.85 g (4.57 mmol) of tetrahydrocarboline, 0.53 g (4.57 mmol) of maleic acid, 120 mL of water and 0.85 g of Pd/C to a 250 mL single-necked flask. Heat and reflux them for 8 h, conduct suction filtration, wash with water and regulate pH value of the filtrate with NaOH to 9-10 to obtain a large amount of white solid. Conduct suction filtration to obtain 0.5 g of white solid. The yield is 60% and the melting point is 244-245° C.;

[0124]1H NMR (400 Mhz, CDCl3) δ 8.41 (s, 1H, NH), 8.37 (d, 3JHH=5.2 Hz, 1H, Ar—H), 8.12 (d, 3JHH=8.0 Hz, 1H, Ar—H), 7.83 (d, 3JHH=5.2 Hz, 1H, Ar—H), 7.52-7.57 (m, 2H, Ar—H), 7.26-7.32 (m, 1H, Ar—H), 2.84 (s, 3H, CH3), HRMS (ESI) calcd for C12H11N2(M+H)+ 183.0917. found 183.0915.

Embodiment 3: Synthesis of Tetrahydroharmine

[0125]

Synthesis of Quaternary Ammonium Salt

[0126]Add 0.5 g (2.36 mmol) of harmine, 120 mL of ethyl acetate and 0.48 g (2.83 mmol) of benzyl bromide to a 250 mL single-necked flask. Heat and reflux them for 12 h. Conduct suction filtration to obtain 0.67 g of light yellow solid. The yield is 74% and the melting point is above 300° C.;

[0127]1H NMR (400 Mhz, d6-DMSO) δ 12.78 (s, 1H, NH), 8.74 (d, 3JHH=6.4 Hz, 1H, Ar—H), 8.58 (d, 3JHH=6.8 Hz, 1H, Ar—H), 8.37 (d, 3JHH=8.8 Hz, 1H, Ar—H), 7.35-7.44 (m, 3H, Ar—H), 7.23 (d, 3JHH=7.2 Hz, 2H, Ar—H), 7.12 (d, 3JHH=1.0 Hz, 1H, Ar—H), 7.08 (dd, 3JHH=8.8 Hz, 3JHH=1.0 Hz, 1H, Ar—H), 5.98 (s, 2H, CH2), 3.95 (s, 3H, OCH3), 2.98 (s, 3H, CH3).

Synthesis of N-Benzyl Tetrahydroharmine

[0128]Add 0.67 g (1.75 mmol) of quaternary ammonium salt and 150 mL of methanol to a 250 mL single-necked flask, and add 30 mL of methanol solution containing 0.53 g (14.0 mmol) of sodium borohydride. Heat and reflux them for 15 h. Remove the solvent and add dichloromethane and water to separate liquid. Wash the organic phase with a saturated saline solution, dry it with anhydrous sodium sulfate, remove the solvent, and use dichloromethane/methanol (20:1) for column chromatography under normal pressure to obtain 0.47 g of brown solid. The yield is 88% and the melting point is 147-149° C.;

[0129]1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H, NH), 7.50-7.52 (m, 2H, Ar—H), 7.43-7.47 (m, 3H, Ar—H), 7.36-7.40 (m, 1H, Ar—H), 6.90 (dd, 3JHH=8.8 Hz, 3JHH=2.4 Hz, 1H, Ar—H), 6.83 (d, 3JHH=2.4 Hz, 1H, Ar—H), 3.97 (d, 3JHH=13.6 Hz, 1H, CH2C6H5), 3.81 (q, 3JHH=6.8 Hz, 1H, CHCH3), 3.77 (d, 2JHH=13.6 Hz, 1H, CH2C6H5), 3.22-3.29 (m, 1H, CH2CH2), 2.85-2.95 (m, 2H, CH2CH2), 2.68-2.74 (m, 1H, CH2CH2), 1.61 (d, 3JHH=6.8 Hz, 1H, CHCH3).

Synthesis of Tetrahydroharmine

[0130]Add 0.70 g (2.29 mmol) of N-benzyl-protected tetrahydroharmine, 120 mL of trifluoroethanol and 0.70 g of Pd/C to a 250 mL single-necked flask, input hydrogen and stir them overnight. Remove the solvent, and use dichloromethane/methanol (10:1) for column chromatography under normal pressure to obtain 0.37 g of light yellow viscous substance. The yield is 80% and the melting point is 195-197° C.;

[0131]1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H, NH), 7.35 (d, 3JHH=8.8 Hz, 1H, Ar—H), 6.85 (d, 3JHH=2.0 Hz, 1H, Ar—H), 6.77 (dd, 3JHH=8.4 Hz, 3JHH=2.4 Hz, 1H, Ar—H), 4.14-4.19 (m, 1H, CHCH3), 3.84 (s, 3H, OCH3), 3.33-3.39 (m, 1H, CH2CH2), 3.01-3.07 (m, 1H, CH2CH2), 2.66-2.78 (m, 2H, CH2CH2), 1.65 (s, 1H, NH), 1.44 (d, 3JHH=6.8 Hz, 3H, CH3), HRMS (ESI) calcd for C33H37N2O (M+H)+ 217.1335. found 217.1337.

Embodiment 4: Synthesis of Harmol

[0132]

[0133]Add 0.5 g (2.36 mmol) of harmine, 18 mL of glacial acetic acid and 18 mL of 40% hydrobromic acid aqueous solution to a 100 mL single-necked flask, and heat and reflux them for 10 h. Use saturated sodium bicarbonate to regulate pH value to around 8 and generate precipitate. Conduct suction filtration to obtain 0.46 g of yellow green solid. The yield is 98% and the melting point is above 300° C.;

[0134]1H NMR (400 MHz, d6-DMSO) δ 11.24 (s, 1H, NH), 9.72 (s, 1H, OH), 8.11 (d, 3JHH=5.2 Hz, 1H, Ar—H), 7.94 (d, 3JHH=8.0 Hz, 1H, Ar—H), 7.75 (d, 3JHH=5.2 Hz, 1H, Ar—H), 6.90 (d, 4JHH=1.2 Hz, 1H, Ar—H), 6.69 (dd, 3JHH=8.4 Hz, 4JHH=1.6 Hz, 1H, Ar—H), 2.69 (s, 3H, CH3), HRMS (ESI) calcd for C12H11N2O (M+H)+ 199.0866. found 199.0867.

Embodiment 5: Synthesis of Bromo and Nitro-Substituted Harmane

Synthesis of Bromo-Harmane (Ia-1 and Ia-2)

[0135]

[0136]Add of 0.2 g (1.10 mmol) of harman and 10 mL of glacial acetic acid to a 25 mL single-necked flask, add 0.2 g (1.10 mmol) of NB S, and react at room temperature for 6 h. Remove the solvent, wash with saturated sodium bicarbonate, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, remove the solvent and use dichloromethane/methanol (40:1→20:1) in turn for column chromatography under normal pressure to obtain two kinds of white solid: solid Ia-1 0.05 g, yield 17%; 1H NMR (400 MHz, CDCl3) δ 8.36-8.49 (m, 2H, NH and Ar—H), 8.04 (d, 3JHH=6.4 Hz, 1H, Ar—H), 7.77-7.84 (m, 1H, Ar—H), 7.70 (d, 3JHH=6.4 Hz, 1H, Ar—H), 7.18 (t, 3JHH=6.4 Hz, 1H, Ar—H), 2.88 (s, 3H, CH3). Solid Ia-2 0.24 g, yield 83%, melting point 256-257° C.;

[0137]1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H, NH), 8.39 (d, 3JHH=5.6 Hz, 1H, Ar—H), 8.24 (d, 4JHH=2.0 Hz, 1H, Ar—H), 7.78 (d, 3JHH=5.6 Hz, 1H, Ar—H), 7.63 (dd, 3JHH=8.4 Hz, 4JHH=2.0 Hz, 1H, Ar—H), 7.42 (d, 3JHH=8.8 Hz, 1H, Ar—H), 2.83 (s, 3H, CH3), HRMS (ESI) calcd for C12H13BrN2(M+H)+ 261.0022. found 261.0026.

Synthesis of Nitro-Substituted Harmane (Ic-3 and Ia-4)

[0138]

[0139]Add 0.4 g (2.20 mmol) of harman and 0.93 g (10.99 mmol) of sodium nitrate to a 50 mL single-necked flask, add 20 mL of trifluoroacetic acid, and stir them at room temperature for 6 h. Add a saturated sodium bicarbonate aqueous solution to the reaction solution to regulate pH value to 10-11 and generate yellow precipitate, and conduct suction filtration to obtain 0.06 g of yellow solid Ia-3. The yield is 12% and the melting point is 207-210° C.

[0140]1H N