CN104177377B

CN104177377B - 3-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof

Info

Publication number: CN104177377B
Application number: CN201310189080.5A
Authority: CN
Inventors: 王子厚; 武嘉林; 郭亮; 范文玺; 尚靖; 马芹; 刘利; 周凡
Original assignee: Xinjiang Huashidan Pharmaceutical Research Co ltd
Current assignee: Xinjiang Huashidan Pharmaceutical Research Co ltd
Priority date: 2013-05-20
Filing date: 2013-05-20
Publication date: 2020-04-10
Anticipated expiration: 2033-05-20
Also published as: CN104177377A

Abstract

The invention discloses a bi- β -carboline alkali compound connected with diamine at the 3-position, a preparation method thereof, a pharmaceutical composition thereof and application thereof, in particular to a bi- β -carboline alkali compound and a pharmaceutical salt thereof shown in a general formula I, wherein the bi- β -carboline alkali compound is prepared by two molecules of β -carboline-3-formaldehyde and one molecule of diamine NH₂(CH₂)nNH₂The invention also discloses a pharmaceutical composition which comprises an effective dose of the double β -carboline alkali compound shown in the formula I and a pharmaceutically acceptable carrier, and application of the double β -carboline alkali compound in preparing antitumor drugs, wherein the antitumor drugs comprise melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and colon cancer.

Description

3-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof

Technical Field

The invention relates to 3-diamine β -carboline alkali compounds and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition of the compounds and application thereof in preparing antitumor drugs, belonging to the technical field of medicines.

Background

Jiang et al (2002) reported the design and synthesis of bis-3, 4-dihydro- β -carboline and bis- β -carboline compounds linked by a methylene bridge at the 1-position, and found that such bis β -carboline bases are cytotoxic to the L1210 cell line.

Cook et al (2005, 2010) reported a synthetic method for 6-alkynyl bridge-linked bis β -carbolines, and subsequently demonstrated that this class of bis β -carboline bases has good affinity for benzodiazepine receptors (Bz) and gamma-aminobutyric acid (GABA) receptors.

Winckler et al (2010) designed bis-3, 4-dihydro- β -carboline and bis- β -carboline compounds with 2-methylene bridge connection and 9-methylene bridge connection and confirmed that the compounds have good acetylcholinesterase and butyrylcholinesterase inhibition activities.

ZHEN et al (2011) synthesized a 9-methylene bridge-linked and fused peptide according to the synthetic method of Winckler et al¹¹C-labeled bis-3, 4-dihydro- β -carboline and bis- β -carboline compounds, such bis β -carboline compounds were found to be useful as novel imaging agents for electropositive radiation tomography (POST) for imaging acetylcholinesterase in Alzheimer's Disease (AD) patients, but the antitumor effects of such compounds are not disclosed.

Literature reports of 1-position bridge connected bis β -carboline base

6-position bridge connected bis β -carboline base reported in literature

2-position bridge connected bis β -carboline base reported in literature

Literature report of 9-linked bis β -carboline base

Disclosure of Invention

The invention aims to solve the technical problem of providing a novel anti-tumor compound, namely a 3-diamine-linked bis β -carboline alkali compound.

The technical problem to be solved by the invention is to provide a preparation method of the compound.

The technical problem to be solved by the invention is to provide a pharmaceutical composition containing the compound.

The invention aims to solve the technical problem of providing the application of the compounds in preparing antitumor drugs.

The technical problem to be solved by the invention is that the invention provides the following technical scheme that 3-position diamine is connected with a bi β -carboline alkali compound and a medicinal salt thereof, as shown in a general formula I,

n is an integer from 2 to 14; i.e. n is an integer selected from 2,3,4,5,6,7,8,9,10,11,12,13, 14.

Preferably n is selected from an integer from 2 to 10; i.e. n is an integer selected from 2,3,4,5,6,7,8,9, 10.

More preferably n is selected from an integer from 3 to 8; i.e. n is an integer selected from 3,4,5,6,7, 8.

Most preferably n is selected from an integer from 3 to 6; i.e. n is an integer selected from 3,4,5, 6.

K, l are independently selected from integers of 0-12; i.e., K, l are independently integers selected from 0,1,2,3,4,5,6,7,8,9,10,11, 12.

Preferably K, l are independently selected from integers from 0 to 10; i.e., K, l are independently integers selected from 0,1,2,3,4,5,6,7,8,9, 10.

More preferably K, l are independently selected from integers of 1 to 8; i.e., K, l are independently integers selected from 1,2,3,4,5,6,7, 8.

Most preferably K, l are independently selected from integers of 1 to 4; i.e., K, l are independently integers selected from 1,2,3, 4.

i, j are independently selected integers from 0-12; i.e., i, j are independently integers selected from 0,1,2,3,4,5,6,7,8,9,10,11, 12.

Preferably i, j are independently selected from integers from 0 to 9; i.e., i, j are independently integers selected from 0,1,2,3,4,5,6,7,8, 9.

More preferably, i, j are independently selected from integers from 0 to 6; i.e., i, j are independently integers selected from 0,1,2,3,4,5, 6.

Most preferably, i, j are independently selected from integers of 0 to 3; i.e., i, j are independently integers selected from 0,1,2, 3.

R₁₁And R₁₂Independently selected from hydrogen, substituted or unsubstituted C1-10 straight chain or branched chain alkyl, hydroxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkoxy, sulfydryl, substituted or unsubstituted C1-10 straight chain or branched chain alkylthio, C1-10 alkoxy C1-10 alkyl, amino, substituted or unsubstituted C1-10 straight chain or branched chain alkylamino, wherein the alkyl comprises monoalkylamino and dialkylamino, aldehyde group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-10 straight chain or branched chain alkanoylamino, carbamoyl, C2-10 alkene, halogen, nitro, cyano, substituted or unsubstituted six-membered aryl, 539 2-10 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-10 straight chain or branched chain alkanoylamino, carbamoyl, C2-10 alkene, halogen, nitro, cyano, A substituted or unsubstituted six membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S;

R₉₁and R₉₂Independently selected from hydrogen, substituted or unsubstituted C1-10 straight chain or branched chain alkyl, hydroxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkoxy, sulfydryl, substituted or unsubstituted C1-10 straight chain or branched chain alkylthio, C1-10 alkoxy C1-10 alkyl, aldehyde group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-10 straight chain or branched chain alkanoylamino, carbamoyl, C2-10 alkene, halogen, nitro, cyano, substituted or unsubstituted six-membered aryl, substituted or unsubstituted six-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

the substituent on the substituted or unsubstituted five-six-membered aryl is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxy C1-6 alkyl, -CO-C1-6 alkyl, -COO-C1-6 alkyl, -O-CO-C1-6 alkyl;

the substituents on the substituted or unsubstituted five-six membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxy C1-6 alkyl, -CO-C1-6 alkyl, -COO-C1-6 alkyl, -O-CO-C1-6 alkyl;

the substituent on the substituted or unsubstituted C1-10 straight or branched chain alkyl group is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkoxy, C1-6 alkylamino, -CO-C1-6 alkyl, -COO-C1-6 alkyl, -O-CO-C1-6 alkyl.

Preferred six membered aryl groups are selected from

Preferred six membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O or S are selected from:

preferred R₁₁And R₁₂Independently selected from hydrogen, substituted or unsubstituted C1-6 straight chain or branched chain alkyl, hydroxyl, substituted or unsubstituted C1-6 straight chain or branched chain alkoxy, sulfydryl, substituted or unsubstituted C1-6 straight chain or branched chain alkylthio, C1-6 alkoxy C1-6 alkyl, amino, substituted or unsubstituted C1-6 straight chain or branched chain alkylamino, wherein the alkyl comprises monoalkylamino and dialkylamino, aldehyde group, substituted or unsubstituted C1-6 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-6 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-6 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-6 straight chain or branched chain alkanoyloxyC1-6 straight-chain or branched-chain alkanamide, carbamoyl, C2-6 olefin, halogen, nitro, cyano, substituted or unsubstituted six-membered aryl, substituted or unsubstituted six-membered heteroaryl containing 1-2 heteroatoms selected from N, O or S;

preferred R₉₁And R₉₂Independently selected from hydrogen, substituted or unsubstituted C1-6 straight chain or branched chain alkyl, hydroxyl, substituted or unsubstituted C1-6 straight chain or branched chain alkoxy, sulfydryl, substituted or unsubstituted C1-6 straight chain or branched chain alkylthio, C1-6 alkoxy C1-6 alkyl, aldehyde group, substituted or unsubstituted C1-6 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-6 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-6 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-6 straight chain or branched chain alkanoylamino, carbamoyl, C2-6 alkene, halogen, nitro, cyano, substituted or unsubstituted six-membered aryl, and substituted or unsubstituted six-membered heteroaryl containing 1-2 heteroatoms selected from N, O or S;

the substituent on the substituted or unsubstituted five-six-membered aryl is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

the substituents on the substituted or unsubstituted five-six membered heteroaryl group containing 1-2 heteroatoms selected from N, O or S are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

the substituent on the substituted or unsubstituted C1-6 straight or branched chain alkyl group is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

more preferred R₁₁And R₁₂Independently selected from substituted or unsubstituted C1-6 straight chain or branched chain alkyl, substituted or unsubstitutedSubstituted phenyl, substituted or unsubstituted pyridyl;

more preferred R₉₁And R₉₂Independently selected from substituted or unsubstituted C1-6 straight or branched chain alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl;

the substituents on the substituted or unsubstituted phenyl are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

the substituents on the substituted or unsubstituted pyridyl group are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

the substituent on the substituted or unsubstituted C1-6 straight or branched chain alkyl group is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl.

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I1:

more preferably n is selected from an integer from 3 to 8; i.e. n is an integer selected from 3,4,5,6,7, 8;

more preferred R₉₁And R₉₂Independently selected from substituted or unsubstituted C1-10 straight or branched chain alkyl;

the substituent on the substituted or unsubstituted C1-10 straight or branched chain alkyl group is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl.

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I2:

More preferred R_91’And R_92’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl and-O-CO-C1-4 alkyl.

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I3:

More preferred R₁₁And R₁₂Independently selected from substituted or unsubstituted C1-10 straight or branched chain alkyl;

the substituent on the substituted or unsubstituted C1-10 straight or branched chain alkyl group is selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I4:

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I5:

more preferred R_11’And R_12’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl and-O-CO-C1-4 alkyl.

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I6:

more preferably K, l are independently selected from integers of 1 to 8; i.e., K, l are independently an integer selected from 1,2,3,4,5,6,7, 8;

more preferably, i, j are independently selected from integers from 0 to 6; i, j are independently an integer selected from 0,1,2,3,4,5, 6;

more preferred R_91’And R_92’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

more preferred R_11’And R_12’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkylAn alkyl group.

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I7:

Preferred compounds of formula I according to the present invention include, but are not limited to, those of formula I8:

In the invention:

preferred substituents on the substituted or unsubstituted five-six membered aryl group are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

preferred substituents on substituted or unsubstituted five-to six-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O or S are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

preferred substituents on substituted or unsubstituted five-to six-membered heteroaryl groups containing 1 to 2 heteroatoms selected from N, O or S are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

preferred substituents on the substituted or unsubstituted C1-6 straight or branched chain alkyl group are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkoxy, C1-4 alkylamino, -CO-C1-4 alkyl, -COO-C1-4 alkyl.

C1-10 alkyl includes but is not limited to CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂N-pentyl, i-pentyl, C₆H₁₃、C₈H₁₇、C₉H₁₉、C₁₀H₂₁；

C1-6 alkyl includes but is not limited to CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂N-pentyl, i-pentyl, C₆H₁₃；

C1-4 alkyl includes but is not limited to CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂；

C1-4 alkoxy includes, but is not limited to OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂；

C1-4 alkylamino includes, but is not limited to, NCH₃、NC₂H₅、n-NC₃H₇、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂；

-CO-C1-4 alkyl includes but is not limited to-COCH₃、-COC₂H₅、n-COC₃H₇、-COCH(CH₃)₂、n-COC₄H₉、COCH₂CH(CH₃)₂；

the-COO-C1-4 alkyl group includes but is not limited to COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、n-COOC₄H₉、COOCH₂CH(CH₃)₂；

the-O-CO-C1-4 alkyl group includes, but is not limited to, -O-CO-CH₃、-O-CO-C₂H₅、n--O-CO-C₃H₇、-O-CO-CH(CH₃)₂、n--O-CO-C₄H₉、-O-CO-CH₂CH(CH₃)₂；

More preferred substituents on the substituted or unsubstituted five-to six-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S are selected from: hydroxy, mercapto, amino, aldehyde, carboxy, carbamoyl, fluoro, chloro, bromo, nitro, cyano, CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂、OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂、NCH₃、NC₂H₅、n-NC₃H₇、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂、-COCH₃、-COC₂H₅、n-COC₃H₇、-COCH(CH₃)₂、n-COC₄H₉、COCH₂CH(CH₃)₂、COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、n-COOC₄H₉、COOCH₂CH(CH₃)₂；

More preferred substituents on the substituted or unsubstituted five-six membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O or S are selected from: hydroxy, mercapto, amino, aldehyde, carboxy, carbamoyl, fluoro, chloro, bromo, nitro, cyano, CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂、OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂、NCH₃、NC₂H₅、n-NC₃H₇、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂、-COCH₃、-COC₂H₅、n-COC₃H₇、-COCH(CH₃)₂、n-COC₄H₉、COCH₂CH(CH₃)₂、COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、n-COOC₄H₉、COOCH₂CH(CH₃)₂；

More preferred substituents on the substituted or unsubstituted phenyl group are selected from: hydroxy, mercapto, amino, aldehyde, carboxy, carbamoyl, fluoro, chloro, bromo, nitro, cyano, CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂、OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂、NCH₃、NC₂H₅、n-NC₃H7、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂、-CO CH₃、-CO C₂H₅、n-CO C₃H₇、-COCH(CH₃)₂、n-COC₄H₉、COCH₂CH(CH₃)₂、COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、n-COOC₄H₉、COOCH₂CH(CH₃)₂；

More preferred substituents on the substituted or unsubstituted pyridyl group are selected from: hydroxy, mercapto, amino, aldehyde, carboxy, carbamoyl, fluoro, chloro, bromo, nitro, cyano, CH₃、C₂H₅、n-C₃H₇、CH(CH₃)₂、n-C₄H₉、CH₂CH(CH₃)₂、OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂、NCH₃、NC₂H₅、n-NC₃H₇、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂、-CO CH₃、-CO C₂H₅、n-CO C₃H₇、-COCH(CH₃)₂、n-COC₄H₉、COCH₂CH(CH₃)₂、COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、n-COOC₄H₉、COOCH₂CH(CH₃)₂；

More preferred substituents on the substituted or unsubstituted C1-6 straight or branched chain alkyl group are selected from: hydroxy, mercapto, amino, aldehyde, carboxyl, carbamoyl, fluoro, chloro, bromo, nitro, cyano, OCH₃、OC₂H₅、n-OC₃H₇、OCH(CH₃)₂、n-OC₄H₉、OCH₂CH(CH₃)₂、NCH₃、NC₂H₅、n-NC₃H₇、NCH(CH₃)₂、n-NC₄H₉、NCH₂CH(CH₃)₂、-COCH₃、-COC₂H₅、-CO-nC₃H₇、-COCH(CH₃)₂、-CO-n-C₄H₉、COCH₂CH(CH₃)₂、COOCH₃、COOC₂H₅、n-COOC₃H₇、COOCH(CH₃)₂、-COO-n-C₄H₉、COOCH₂CH(CH₃)₂。

20、

The invention also provides a preparation method of the compound shown in the formula I,

wherein R is₁₁、R₁₂、R₉₁、R₉₂I, j, K, l, n are as defined above;

β -carboline-3-carbaldehyde represented by formula 1, β -carboline-3-carbaldehyde represented by formula 2, and diamine NH₂(CH₂)nNH₂Firstly carrying out condensation reaction and then carrying out hydrogenation reaction to prepare the compound shown in the formula I.

And (3) performing condensation reaction, namely heating and refluxing the mixed solution for 1-3 hours, preferably 2 hours. After the reflux was stopped, methanol was distilled off under reduced pressure, and the absolute ethanol was taken with water twice. Dissolving the reaction residual liquid in anhydrous methanol, and then adding NaBH₄The reaction is stirred for 4 to 6 hours at room temperature and is followed by TLC. After the reaction is finished, concentrated hydrochloric acid is carefully added into the reaction solution to stop the reaction, the reaction solution is stirred at room temperature, then is alkalized by concentrated sodium hydroxide solution, is extracted twice by dichloromethane, organic phases are combined, washed by water, washed by saturated salt, and dried by anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to dryness.

Preferred condensation reactants are selected from anhydrous methanol, and preferred hydrogenation reactants are selected from NaBH₄。

The reaction product was purified by silica gel column chromatography, and the mobile phase was eluted sequentially with dichloromethane/ammonia =100:0.8, dichloromethane/methanol/ammonia =100:1:0.8, and dichloromethane/methanol/ammonia =50:1: 0.8.

The invention also provides a pharmaceutical composition comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or the mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and the mannitol, glucose and the like can be added as a propping agent when preparing freeze-dried powder injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The compound can be used for preparing antitumor drugs. The tumor includes but is not limited to melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, and bladder cancer. The gastric cancer comprises gastric adenocarcinoma; the lung cancer comprises lung adenocarcinoma; the colon cancer comprises colon adenocarcinoma; the ovarian cancer comprises ovarian adenocarcinoma; the renal cancer comprises renal clear cell adenocarcinoma.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

Detailed Description

The various aspects and features of the present invention are described in more detail below by way of preferred examples of the synthesis of bis β -carboline base compounds it will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

In addition, it should be noted that, unless otherwise specified, various materials and reagents used in the following examples are those commonly used in the art and are commercially available in a usual manner; the intermediates used may be obtained by conventional commercial routes or prepared by well-known methods; the methods used are all conventional methods known to the person skilled in the art.

Preparation example: preparation of intermediates

Preparation example 1

Preparation of 1-substituted-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylic acid 2 a-h:

1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 a):

l-tryptophan (102g,0.5mol) and NaOH (20g,0.5mol) were mixed, 800ml of water was added, and magnetic stirring was carried out. After the solution was clear, 37-40% formaldehyde (37.5ml,0.54mol) was added and the gauge rinsed with about 100ml of water. The reaction was carried out at room temperature for 3.5h, and then heated under reflux for 2.5 h. After the reaction was complete, it was cooled, adjusted to about pH6 with concentrated HCl, and placed in a refrigerator overnight. Filtration and washing of the solid with water several times and finally with a small amount of acetone once. Drying to obtain white solid with the yield of 98.5 percent.

1-methyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 b):

L-Tryptophan (0.4mol) and 600ml H₂O and then 7.5ml of H are added₂SO₄(0.5mol/L), stirring for 10 minutes, adding 40% acetaldehyde (150ml,1.15mol), stirring for 10 hours at room temperature, tracking the reaction process by TLC, filtering after the reaction is completed, washing with water for several times, and drying to obtain a white product, wherein the yield is 98%, and the general synthesis process of 1-substituted-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylic acid derivatives 2c-h comprises the following steps:

mixing L-tryptophan (200mol), corresponding aldehyde (205 mol) and glacial acetic acid 250ml, heating and refluxing for 3h, pouring the reaction solution into ice water, adjusting the pH value to 5-6 by sodium hydroxide to precipitate a light yellow solid, filtering, washing with water, and drying to obtain a solid.

1- (4-methoxyphenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2c) as a yellow solid in 84% yield EI-MSm/z 323(M +1)⁺。

1-isopropyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 d) as white solid in 92% yield EI-MS M/z:258(M +1)⁺。

1- (4-chlorophenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 e) as a yellow solid in 84% yield EI-MS M/z 327(M +1)⁺。

1- (2-chlorophenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 f) as a yellow solid in 82% yield EI-MS M/z 327(M +1)⁺。

1-phenyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 g) as a white solid in 89% yield EI-MS M/z 293(M +1)⁺。

1- (3-pyridyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (2 h) yellow solid, yield 75%. EI-MS M/z 294(M +1)⁺。

Preparing ethyl 1-substituted-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylate 3 a-h:

mixing the corresponding carboxylic acid 2a-h (50mmol), absolute ethyl alcohol 1L and thionyl chloride (25 ml), heating and refluxing for 6 hours, evaporating to remove ethanol under reduced pressure, dissolving residues in cold water, alkalifying with sodium bicarbonate, extracting with ethyl acetate, washing with organic phase water, washing with saturated saline, drying with anhydrous sodium sulfate, decoloring with activated carbon, filtering, concentrating under reduced pressure to obtain yellow oily matter, recrystallizing with ethyl acetate to separate out white crystals, filtering, washing with diethyl ether, and drying to obtain white solid.

Ethyl 1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 a) white solid in 82% yield EI-MS M/z 245(M +1)⁺。

Ethyl 1-methyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 b) as a white solid in 91% yield EI-MS M/z 259(M +1)⁺。

Ethyl 1- (4-methoxyphenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 c) as a white solid in 83% yield EI-MS M/z 351(M +1)⁺。

Ethyl 1-isopropyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 d) white solid, yield 95%. EI-MSm/z 287(M +1)⁺。

Ethyl 1- (4-chlorophenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 e) as a white solid in 87% yield EI-MSm/z 355(M +1)⁺。

Ethyl 1- (2-chlorophenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 f) as a white solid in 79% yield EI-MSm/z 355(M +1)⁺。

Ethyl 1-phenyl-1, 2,3, 4-tetrahydro- β -carboline-3-carboxylate (3 g) as a white solid in 82% yield EI-MS M/z 321(M +1)⁺。

Ethyl 1- (3-pyridyl) -1,2,3, 4-tetrahydro-β -carboline-3-carboxylic ester (3 h) brown solid, 65% yield EI-MS M/z 322(M +1)⁺。

Preparing ethyl 1-substituted- β -carboline-3-carboxylic ester 4 a-h:

mixing the intermediate 3a-h (100 mmol), sulfur (16 g, 500 mmol) and xylene (250ml), heating and refluxing for 10h, cooling, separating out yellow crystals, filtering, washing with cold xylene, fully washing with petroleum ether, drying, completely dissolving ethyl acetate, decolorizing with activated carbon, filtering, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain white solid.

Ethyl β -carboline-3-carboxylate (4 a) as a white solid in 77% yield EI-MS M/z241 (M +1)⁺。

Ethyl 1-methyl- β -carboline-3-carboxylate (4 b) as a white solid in 81% yield EI-MS M/z255 (M +1)⁺。

Ethyl 1- (4-methoxyphenyl) - β -carboline-3-carboxylate (4 c) as a white solid in 65% yield EI-MS M/z 347(M +1)⁺。

Ethyl 1-isopropyl- β -carboline-3-carboxylate (4 d) as a white solid in 84% yield EI-MS M/z283 (M +1)⁺。

Ethyl 1- (4-chlorophenyl) - β -carboline-3-carboxylate (4 e) as a white solid in 62% yield EI-MS M/z 351(M +1)⁺。

Ethyl 1- (2-chlorophenyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (4 f) as a white solid in 60% yield EI-MSm/z 351(M +1)⁺。

Ethyl 1-phenyl- β -carboline-3-carboxylate (4 g) as a white solid in 71% yield EI-MS M/z 317(M +1)⁺Ethyl 1- (3-pyridyl) - β -carboline-3-carboxylate (4 h) brown solid, yield 55%. EI-MS M/z 318(M +1)⁺。

Preparing tetra-ethyl 1, 9-disubstituted- β -carboline-3-carboxylic ester 5 a-m:

putting ethyl 1-substituted- β -carboline-3-carboxylate (10mmol) into a 100ml round-bottom flask, adding 60 ml DMF, shaking to dissolve the DMF as far as possible, adding alkyl halide (15mmol), adding NaH (15mmol), magnetically stirring, monitoring the reaction process by TLC, measuring once every 30 minutes, stopping the reaction after the raw materials completely react, pouring the reaction solution into a proper amount of water, extracting with ethyl acetate, washing the extract with saturated sodium chloride solution for 2 times to remove emulsification, adding a proper amount of ethanol and concentrated hydrochloric acid, standing, concentrating to dryness, adding a proper amount of acetone for crystallization, cooling to separate out crystals, filtering to obtain a solid, dissolving with water, alkalifying with sodium bicarbonate, adding ethyl acetate for extraction, drying the extract with anhydrous sodium sulfate, decolorizing with activated carbon, standing for about 5 hours to remove impurities, concentrating until a small amount of crystals are separated out, refrigerating, standing, filtering, washing, and drying to obtain the product.

Ethyl 9- (3-chlorobenzyl) - β -carboline-3-carboxylate (5 a) from ethyl β -carboline-3-carboxylate and 3-chlorobenzyl bromide to obtain white crystal with yield of 70.2%, m.p.128-129 deg.C, EI-MS M/z:364(M +1)⁺。¹H-NMR(DMSO-d₆,400MHz):δ8.90(2H,d,J=8.0Hz);8.25(1H,d,J=8.0Hz);7.62(1H,m);7.47(1H,d,J=8.0Hz);7.39-7.43(1H,m);7.24-7.27(1H,m);7.21-7.23(1H,m);7.15-7.16(1H,s);6.99(1H,d,J=6.4Hz);5.60(2H,m);4.55-4.60(2H,m);1.47-1.49(3H,t,J=8.0Hz).

Ethyl 1-methyl-9- (3-chlorobenzyl) - β -carboline-3-carboxylate (5 b), which is prepared from ethyl 1-methyl- β -carboline-3-carboxylate and 3-chlorobenzyl bromide, to obtain white crystal with yield of 82%, EI-MS M/z:379(M +1)⁺。

Ethyl 1- (4-methoxyphenyl) -9-hexyl- β -carboline-3-carboxylate (5 c) taking 1- (4-methoxyphenyl) - β -carboline-3-carboxylic acid ethyl ester and iodo-n-hexane as raw materials to obtain white crystals with the yield of 86 percent and EI-MS M/z of 445(M +1) +.

Ethyl 1-isopropyl-9-benzyl- β -carboline-3-carboxylate (5 d) ethyl 1-isopropyl- β -carboline-3-carboxylate and benzyl bromide are used as raw materials to obtain white crystals with a yield of 46%, EI-MS M/z:373(M +1)⁺。

Ethyl 1-isopropyl-9-butyl- β -carboline-3-carboxylate (5 e) ethyl 1-isopropyl- β -carboline-3-carboxylate and n-butyl iodide as raw materials to obtain white crystals with a yield of 47%, EI-MS M/z:341(M +1)⁺。

Ethyl 1- (4-chlorophenyl) -9-butyl- β -carboline-3-Carboxylic acid ester (5 f) Ethyl 1- (4-chlorophenyl) - β -carboline-3-carboxylic acid ester and n-butyl iodide as raw materials to obtain white crystal with yield of 81%, EI-MS M/z:407(M +1)⁺。

Ethyl 1- (4-chlorophenyl) -9-benzyl- β -carboline-3-carboxylate (5 g) Ethyl 1- (4-chlorophenyl) - β -carboline-3-carboxylate and benzyl bromide as raw materials to obtain white crystal with yield of 77%, m.p.135-137 deg.C, EI-MS M/z:441(M +1)⁺。

Ethyl 1- (2-chlorophenyl) -9-butyl- β -carboline-3-carboxylate (5 h) ethyl 1- (2-chlorophenyl) - β -carboline-3-carboxylate and n-butyl iodide as raw materials to obtain white crystal with yield of 87%, EI-MS M/z:407(M +1)⁺。

Ethyl 1- (2-chlorophenyl) -9- (3-chlorobenzyl) - β -carboline-3-carboxylate (5 i) ethyl 1- (2-chlorophenyl) - β -carboline-3-carboxylate and 3-chlorobenzyl bromide are used as raw materials to obtain white crystals with a yield of 81%, EI-MS M/z:476(M +1)⁺。

Ethyl 1-phenyl-9-methyl- β -carboline-3-carboxylate (5 j), which is prepared from ethyl 1-phenyl- β -carboline-3-carboxylate and methyl iodide, and has yield of 71%, EI-MS M/z:331(M +1)⁺。

Ethyl 1-phenyl-9-benzyl- β -carboline-3-carboxylate (5 k) is prepared from ethyl 1-phenyl- β -carboline-3-carboxylate and benzyl bromide by mixing to obtain white crystal with yield of 74% and EI-MS M/z:407(M +1)⁺。

Ethyl 1- (3-pyridyl) -9-butyl- β -carboline-3-carboxylate (5 l) ethyl 1- (3-pyridyl) - β -carboline-3-carboxylate and n-butyl iodide as raw materials to obtain yellow crystal with yield of 52%, EI-MS M/z:374(M +1)⁺。

Ethyl 1- (3-pyridyl) -9-benzyl- β -carboline-3-carboxylate (5M) ethyl 1- (3-pyridyl) - β -carboline-3-carboxylate and benzyl bromide are used as raw materials to obtain white crystals with the yield of 62%, EI-MS M/z:408(M +1)⁺。

The general preparation process of the penta, 3-hydroxymethyl-9-alkyl- β -carboline 6a-o comprises the following steps:

9-alkyl- β -carboline-3-carboxylic acid ethyl ester 4c, 4d and 5a-m (10mmol), THF (200ml), LiBH₄(30mmol) of the mixture was mixed,stirring and reacting for 12h at room temperature, tracking and detecting by TLC (petroleum ether/acetone-1/1), after the reaction is finished, slowly pouring the reaction mixed solution into 200ml of ice water, stirring and reacting for 10min, dropwise adding concentrated hydrochloric acid to the pH value of 2-3, stirring for 2h at room temperature, cooling the mixture by ice water, adjusting the pH value to 9-10 by using sodium hydroxide solution, extracting by using ethyl acetate, washing by using water, washing by using saturated salt water, drying by using anhydrous sodium sulfate, decoloring by using activated carbon, filtering, concentrating to be dry, and recrystallizing by using acetone to obtain a white or off-white solid, namely the target compound 6 a-o.

3-hydroxymethyl-9- (3-chlorobenzyl) - β -carboline (6a):

using ethyl 9- (3-chlorobenzyl) - β -carboline-3-carboxylate as raw material to obtain white solid with yield of 75% EI-MSm/z:324(M +1)⁺。¹H NMR(400MHz,CDCl₃):δ8.75(1H,s),8.19(1H,d,J=8.0Hz),8.02(1H,s),7.60-7.64(1H,m),7.44(1H,d,J=8.4Hz),7.33-7.37(1H,m),7.19-7.25(2H,m),7.14(1H,s),7.00(1H,d,J=7.2Hz),5.55(2H,s),4.98(2H,s).

3-hydroxymethyl-9- (3-chlorobenzyl) -1-methyl- β -carboline (6 b):

ethyl 9- (3-chlorobenzyl) -1-methyl- β -carboline-3-carboxylate is used as raw material to obtain white solid with yield of 72%, EI-MS M/z:338(M +1)⁺。¹H NMR(400MHz,CDCl₃):δ8.15(1H,d,J=8.0Hz),7.86(1H,s),7.54-7.58(1H,m),7.30-7.34(2H,m),7.18-7.25(2H,m),7.03(1H,s),6.80-6.83(1H,m),5.74(2H,s),4.91(2H,s),2.88(s,3H).

1- (4-methoxyphenyl) -3-hydroxymethyl-9-hexyl- β -carboline (6c):

ethyl 1- (4-methoxyphenyl) -9-hexyl- β -carboline-3-carboxylate as raw material to obtain white solid with yield of 75% and EI-MS M/z of 390(M +1)⁺。¹H NMR(400MHz,CDCl₃):δ8.17(1H,d,J=8.0Hz),7.93(1H,s),7.55-7.62(3H,m),7.44(1H,d,J=8.4Hz),7.28-7.32(1H,m),7.04-7.07(2H,m),4.97(2H,s),3.98(2H,t,J=8.0Hz),3.90(3H,s),1.32-1.36(2H,m),1.08-1.12(2H,m),0.96-1.01(2H,m),0.84-0.87(2H,m),0.77(3H,t,J=7.2Hz).

1- (4-methoxyphenyl) -3-hydroxymethyl- β -carboline (6d):

ethyl 1- (4-methoxyphenyl) - β -carboline-3-carboxylic ester is used as raw material to obtain white solidYield 72%, EI-MSm/z 306(M +1)⁺。¹H NMR(400MHz,DMSO):δ8.25(1H,d,J=8.0Hz),8.10(1H,s),7.97-8.01(2H,m),7.62(1H,d,J=8.0Hz),7.50-7.54(1H,m),7.21-7.25(1H,m),7.14-7.18(2H,m),5.37(1H,t,J=5.6Hz),4.77(2H,d,J=6.0Hz),3.87(3H,s).

1-isopropyl-3-hydroxymethyl-9-benzyl- β -carboline (6e):

ethyl 1-isopropyl-9-benzyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with a yield of 83%, and EI-MSm/z:331(M + 1).¹H NMR(400MHz,CDCl₃):δ8.14(1H,d,J=8.0Hz),7.75(1H,s),7.52-7.56(1H,m),7.37(1H,d,J=8.0Hz),7.22-7.30(4H,m),7.01(1H,d,J=7.6Hz),6.99-7.01(2H,d,J=8.0Hz),5.76(2H,s),4.91(2H,s),3.58-3.62(1H,m),1.29(6H,d,J=6.8Hz).

1-isopropyl-3-hydroxymethyl-9-butyl- β -carboline (6f):

ethyl 1-isopropyl-9-butyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with a yield of 86 percent and EI-MSm/z:297(M + 1).¹H NMR(400MHz,CDCl₃):δ8.11(1H,d,J=8.0Hz),7.70(1H,s),7.55-7.59(1H,m),7.46(1H,d,J=8.0Hz),7.23-7.27(1H,m),4.90(2H,s),4.48(2H,t,J=8.0Hz),3.74-3.77(1H,m),1.78-1.86(2H,m),1.43-1.50(9H,m),0.88(3H,t,J=7.2Hz).

1- (4-chlorophenyl) -3-hydroxymethyl-9-butyl- β -carboline (6 g):

ethyl 1- (4-chlorphenyl) -9-butyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with the yield of 79 percent, and EI-MS M/z is 365(M + 1).¹H NMR(400MHz,CDCl₃):δ8.17(1H,d,J=8.0Hz),7.95(1H,s),7.55-7.62(3H,m),7.49-7.52(2H,m),7.44(1H,d,J=8.4Hz),7.28-7.32(1H,m),4.95(2H,s),3.97(2H,t,J=8.0Hz),1.28-1.36(2H,m),0.85-0.91(2H,m),0.66(3H,t,J=7.2Hz).

1- (4-chlorophenyl) -3-hydroxymethyl-9-benzyl- β -carboline (6 h):

ethyl 1- (4-chlorphenyl) -9-benzyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with a yield of 72 percent and EI-MS M/z of 399(M + 1).¹H NMR(400MHz,CDCl₃):δ8.21(1H,d,J=8.0Hz),7.99(1H,s),7.52-7.57(1H,m),7.23-7.34(6H,m),7.09-7.16(3H,m),6.57(2H,d,J=8.0Hz),5.21(2H,s),4.94(2H,s).

1-isopropyl-3-hydroxymethyl- β -carboline (6i):

ethyl 1-isopropyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid, the yield is 84%, and EI-MS M/z is 241(M + 1).¹H NMR(400MHz,CDCl₃):δ8.09(1H,d,J=8.0Hz),7.71(1H,s),7.52-7.57(2H,m),7.26-7.30(1H,m),4.92(2H,s),3.50-3.53(1H,m),1.50(6H,d,J=6.4Hz).

1- (2-chlorophenyl) -3-hydroxymethyl-9-butyl- β -carboline (6 j):

ethyl 1- (2-chlorphenyl) -9-butyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with the yield of 79 percent and EI-MS M/z of 366(M + 1).¹H NMR(400MHz,CDCl₃):δ8.19(1H,d,J=8.0Hz),8.02(1H,s),7.54-7.63(3H,m),7.41-7.50(3H,m),7.29-7.33(1H,m),4.99(2H,d,J=2.4Hz),3.75-3.98(2H,m),1.30-1.47(2H,m),0.80-0.94(2H,m),0.68(3H,t,J=7.2Hz).

1- (2-chlorophenyl) -3-hydroxymethyl-9- (3-chlorobenzyl) - β -carboline (6 k):

ethyl 1- (2-chlorphenyl) -9- (3-chlorobenzyl) - β -carboline-3-carboxylate is used as raw material to obtain white solid with yield of 82%, EI-MS M/z 434(M + 1).¹H NMR(400MHz,CDCl₃):δ8.27(1H,d,J=8.0Hz),8.10(1H,s),7.60-7.64(1H,m),7.36-7.47(4H,m),7.10-7.18(3H,m),6.98(1H,t,J=8.0Hz),6.43(1H,s),6.34(1H,d,J=7.6Hz),5.30(2H,dd,J=79.2,17.6Hz),4.99(2H,d,J=2.4Hz).

1-phenyl-3-hydroxymethyl-9-methyl- β -carboline (6 l):

ethyl 1-phenyl-9-methyl- β -carboline-3-carboxylate is used as raw material to obtain white solid with yield of 73.5%, EI-MSm/z:289(M + 1).¹H NMR(400MHz,CDCl₃):δ8.17(1H,d,J=8.0Hz),7.94(1H,s),7.59-7.66(3H,m),7.50-7.55(3H,m),7.42(1H,d,J=8.4Hz),7.29-7.33(1H,m),4.97(2H,s),3.46(3H,s).

1-phenyl-3-hydroxymethyl-9-benzyl- β -carboline (6 m):

ethyl 1-phenyl-9-benzyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with a yield of 83%, and EI-MS M/z is 365(M + 1).¹H NMR(400MHz,CDCl₃):δ8.21(1H,d,J=8.0Hz),7.99(1H,s),7.53-7.56(1H,m),7.25-7.40(7H,m),7.07-7.14(3H,m),6.54(2H,d,J=6.8Hz,),5.20(2H,s),4.96(2H,s).

1- (3-pyridyl) -3-hydroxymethyl-9-butyl- β -carboline (6 n):

ethyl 1- (3-pyridyl) -9-butyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with the yield of 61 percent, and EI-MS M/z is 331(M + 1).¹H-NMR(400MHz,CDCl₃):δ8.84(1H,d,J=8.0Hz),8.72(1H,s),8.61(1H,d,J=8.0Hz),8.22(1H,d,J=7.2Hz),7.92-7.94(1H,m),7.62-7.64(1H,m),7.45-7.51(2H,m),4.93(2H,s),3.96(2H,t,J=7.2Hz),1.42-1.47(2H,m);0.91-1.01(2H,m);0.77(3H,t,J=7.2Hz).

1- (3-pyridyl) -3-hydroxymethyl-9-benzyl- β -carboline (6):

ethyl 1- (3-pyridyl) -9-benzyl- β -carboline-3-carboxylate is used as a raw material to obtain a white solid with a yield of 77 percent, and EI-MS M/z is 365(M + 1).¹H-NMR(400MHz,CDCl₃):δ8.64(1H,d,J=8.0Hz),8.58(1H,s),8.52(1H,d,J=8.0Hz),8.24(1H,d,J=7.2Hz),7.88-7.91(2H,m),7.74-7.81(2H,m),7.46-7.50(3H,m),7.02-7.18(3H,m),6.07(2H,s);4.99(2H,s).

The general preparation process of hexa and 3-aldehyde-9-alkyl- β -carboline 7a-o comprises the following steps:

3-hydroxymethyl-9-alkyl- β -carboline 6a-o (10mmol), acetonitrile (250ml), active MnO₂(50mmol) were mixed, heated to reflux for 5h and checked by TLC. Immediately filtering to remove MnO after the reaction is finished₂And concentrating under reduced pressure to dryness to obtain a yellow solid. Dissolving the solid in ethyl acetate, decoloring by using activated carbon, passing through silica gel, concentrating under reduced pressure, and recrystallizing by using acetone/petroleum ether to obtain white or off-white solid, namely the target compound 7a-7 o.

9- (3-chlorobenzyl) - β -carboline-3-carbaldehyde (7a):

taking 3-hydroxymethyl-9- (3-chlorobenzyl) - β -carboline as a raw material to obtain white crystals with the yield of 74 percent, and EI-MS M/z:322(M + 1).¹H NMR(400MHz,CDCl₃):δ10.47(1H,s),9.01(1H,s),8.87(1H,s),8.33(1H,d,J=8.0Hz),7.73-7.77(1H,s),7.49-7.58(2H,m),7.24-7.31(2H,m),7.14(1H,s),7.02(1H,d,J=6.8Hz),5.69(2H,s).

9-octyl- β -carboline-3-carbaldehyde (2c):

3-hydroxymethyl-9-octyl- β -carboline is used as a raw material to obtain white crystals with the yield of 71 percent,¹H NMR(400MHz,CDCl₃):δ10.27(1H,s),8.99(1H,s),8.75(1H,s),8.24(1H,d,J=8.0Hz),7.66-7.70(1H,m),7.55(1H,d,J=8.0Hz),7.40(1H,t,J=7.2Hz),4.46(2H,t,J=7.2Hz),1.91-1.96(2H,m),1.23-1.41(10H,m),0.85(3H,t,J=6.8Hz).

1- (4-methoxyphenyl) -9-hexyl- β -carboline-3-carbaldehyde (7 c):

1- (4-methoxyphenyl) -3-hydroxymethyl-9-hexyl- β -carboline is used as a raw material to obtain yellow solid, the yield is 71%, and EI-MS M/z is 388(M + 1).¹H NMR(400MHz,CDCl₃):δ10.30(1H,s),8.75(1H,s),8.26(1H,d,J=8.0Hz),7.63-7.67(1H,m),7.56-7.59(2H,m),7.51(1H,d,J=8.4Hz),7.40(1H,t,J=7.6Hz),7.08(2H,d,J=8.0Hz),4.03(2H,t,J=8.0Hz),3.92(3H,s),1.40-1.44(2H,m),1.12-1.17(2H,m),0.98-1.06(2H,m),0.87-0.91(2H,m),0.80(3H,t,J=7.2Hz).

1- (4-methoxyphenyl) - β -carboline-3-carbaldehyde (7 d):

1- (4-methoxyphenyl) -3-hydroxymethyl- β -carboline is used as a raw material to obtain white solid with the yield of 84.5 percent, and EI-MSm/z is 304(M + 1).¹H NMR(400MHz,CDCl₃):δ10.30(1H,s),8.86(1H,s),8.68(1H,s),8.22(1H,d,J=8.0Hz),7.93-7.98(2H,m),7.54-7.63(2H,m),7.37-7.41(1H,m),7.15(2H,d,J=8.0Hz),3.91(3H,s).

1- (4-methoxyphenyl) -9-methyl- β -carboline-3-carbaldehyde:

1- (4-methoxyphenyl) -3-hydroxymethyl-9-methyl- β -carboline is used as a raw material to obtain yellow crystals, the yield is 74%, and EI-MS M/z is 318(M + 1).¹H NMR(400MHz,CDCl₃):δ10.32(1H,s),8.75(1H,s),8.26(1H,d,J=8.0Hz),7.59-7.70(3H,m),7.51(1H,d,J=8.0Hz),7.41(1H,t,J=7.2Hz),7.09(2H,d,J=8.0Hz),3.92(3H,s),3.57(3H,s).

1-isopropyl-9-benzyl- β -carboline-3-carbaldehyde (7 e):

1-isopropyl-3-hydroxymethyl-9-benzyl- β -carboline is used as a raw material to obtain a white solid with a yield of 86 percent and EI-MSm/z:329(M + 1).¹H NMR(400MHz,CDCl₃):δ10.24(1H,s),8.64(1H,s),8.23(1H,d,J=8.0Hz),7.56-7.60(1H,m),7.36-7.43(2H,m),7.27-7.32(3H,m),7.01(2H,d,J=8.0Hz),5.83(2H,s),3.63-3.66(1H,m),1.36(6H,d,J=6.4Hz).

1-isopropyl-9-butyl- β -carboline-3-carbaldehyde (7 f):

1-isopropyl-3-hydroxymethyl-9-butyl- β -carboline is used as a raw material to obtain a white solid with a yield of 74 percent and an EI-MSm/z ratio of 295(M + 1).¹H NMR(400MHz,CDCl₃):δ10.22(1H,s),8.58(1H,s),8.18(1H,d,J=8.0Hz),7.61-7.65(1H,m),7.51(1H,d,J=8.0Hz),7.33-7.37(1H,m),4.45(2H,t,J=8.0Hz),3.74-3.81(1H,m),1.83-1.91(2H,m),1.43-1.54(8H,m),1.01(3H,t,J=7.2Hz).

1- (4-chlorophenyl) -9-butyl- β -carboline-3-carbaldehyde (7 g):

1- (4-chlorphenyl) -3-hydroxymethyl-9-butyl- β -carboline is used as a raw material to obtain a white solid with the yield of 89 percent, and EI-MSm/z is 363(M + 1).¹H NMR(400MHz,CDCl₃):δ10.33(1H,s),8.79(1H,s),8.26(1H,d,J=8.0Hz),7.66-7.70(1H,m),7.50-7.63(5H,m),7.40-7.44(1H,m),4.04(2H,t,J=8.0Hz),1.37-1.43(2H,m),0.90-0.96(2H,m),0.70(3H,t,J=7.2Hz).

1- (4-chlorophenyl) -9-benzyl- β -carboline-3-carbaldehyde (7 h):

1- (4-chlorphenyl) -3-hydroxymethyl-9-benzyl- β -carboline is used as a raw material to obtain a white solid with the yield of 72 percent, and EI-MSm/z is 397(M + 1).¹H NMR(400MHz,CDCl₃):δ10.24(1H,s),8.80(1H,s),8.30(1H,d,J=8.0Hz),7.58-7.62(1H,m),7.38-7.45(2H,m),7.27-7.33(4H,m),7.12-7.18(3H,m),6.58(2H,d,J=8.0Hz),5.28(2H,s).

1- (2-chlorophenyl) -9-butyl- β -carboline-3-carbaldehyde (7 j):

taking 1- (2-chlorphenyl) -3-hydroxymethyl-9-butyl- β -carboline as a raw material to obtain white solid with the yield of 72.5 percent and EI-MS M/z of 364(M + 1).¹H NMR(400MHz,CDCl₃):δ10.33(1H,s),8.83(1H,s),8.29(1H,d,J=8.0Hz),7.59-7.70(3H,m),7.48-7.56(3H,m),7.40-7.44(1H,m),3.82-4.04(2H,m),1.35-1.58(2H,m),0.87-1.01(2H,m),0.73(3H,t,J=7.2Hz).

1- (2-chlorophenyl) -9- (3-chlorobenzyl) - β -carboline-3-carbaldehyde (7 k):

1- (2-chlorphenyl) -3-hydroxymethyl-9- (3-chlorobenzyl) - β -carboline is used as a raw material to obtain a white solid with the yield of 89.5 percent and EI-MS M/z of 432(M + 1).¹H NMR(400MHz,CDCl₃):δ10.25(1H,s),8.85(1H,s),8.32(1H,d,J=8.0Hz),7.64-7.67(1H,m),7.41-7.49(4H,m),7.12-7.21(3H,m),7.00(1H,t,J=8.0Hz),6.45(1H,s),6.35(1H,d,J=7.6Hz),5.30(2H,dd,J=79.2,17.6Hz).

1-phenyl-9-methyl- β -carboline-3-carbaldehyde (7 l):

1-phenyl-3-hydroxymethyl-9-methyl- β -carboline is used as a raw material to obtain a white solid with a yield of 79 percent, and EI-MS M/z is 287(M + 1).¹H NMR(400MHz,CDCl₃):δ10.29(1H,s),8.75(1H,s),8.26(1H,d,J=8.0Hz),7.65-7.69(3H,m),7.54-7.60(3H,m),7.39-7.50(2H,m),3.52(3H,s).

1-phenyl-9-benzyl- β -carboline-3-carbaldehyde (7 m):

1-phenyl-3-hydroxymethyl-9-benzyl- β -carboline is used as a raw material to obtain a white solid with the yield of 87 percent, and EI-MS M/z is 363(M + 1).¹H NMR(400MHz,CDCl₃):δ10.28(1H,s),8.80(1H,s),8.27(1H,d,J=8.0Hz),7.56-7.60(1H,m),7.30-7.56(7H,m),7.09-7.17(3H,m),6.53-6.56(2H,m),5.24(2H,s).

1- (3-pyridyl) -9-butyl- β -carboline-3-carbaldehyde (7 n):

1- (3-pyridyl) -3-hydroxymethyl-9-butyl- β -carboline is used as a raw material to obtain a white solid with the yield of 52 percent, and EI-MSm/z is 329(M + 1).¹H-NMR(400MHz,CDCl₃):δ10.21(1H,s),8.77(1H,s),8.71(1H,d,J=8.0Hz),8.58(1H,d,J=8.0Hz),7.84-7.94(2H,m),7.66-7.71(1H,m),7.36-7.49(3H,m),3.99(2H,t,J=8.0Hz),1.38-1.44(2H,m);0.90-0.98(2H,m);0.78(3H,t,J=7.2Hz).

1- (3-pyridyl) -9-benzyl- β -carboline-3-carbaldehyde (7):

1- (3-pyridyl) -3-hydroxymethyl-9-benzyl- β -carboline is used as a raw material to obtain a white solid with the yield of 49 percent, and EI-MSm/z is 363(M + 1).¹H-NMR(400MHz,CDCl₃):δ10.29(1H,s),8.80(1H,s),8.48(1H,d,J=8.0Hz),8.22-8.27(1H,m),7.58-7.64(2H,m),7.44-7.53(3H,m),7.27-7.40(2H,m),7.01-7.22(2H,m),6.62(2H,d,J=8.0Hz),5.32(2H,s).

Preparation example 2

General preparation procedure for intermediates 9 a-e:

β -carboline-3-carboxylic acid ethyl ester 8a or 8b (10mmol) and 30ml of DMF are respectively added into a 100ml round bottom flask, the mixture is stirred at room temperature until the solution is clear, then 60% NaH (0.8 g,20 mmol) is added, the mixture is stirred at room temperature for 15 minutes, then alkyl halide (30mmol) is added, the mixture is stirred at room temperature, TLC tracking detection is carried out, after the reaction is finished, the reaction solution is poured into ice water, ethyl acetate is extracted (100ml multiplied by 3), organic phases are combined, washed by water, washed by saturated salt water, dried, filtered, concentrated under reduced pressure until the mixture is dry, subjected to silica gel column chromatography, eluted by ethyl acetate petroleum ether =1:2, the target product is collected, and concentrated under reduced pressure until the target product.

Ethyl 9-isopropyl- β -carboline-3-carboxylate (9 a)

β -carboline-3-carboxylic acid ethyl ester and 2-bromopropane are used as raw materials to obtain white solid (1.8 g, 64%). FAB-MS M/z283[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ9.09(1H,s,ArH),8.56(1H,s,ArH),8.20(1H,d,J=7.8Hz),7.59-7.61(2H,m,ArH),7.30-7.35(2H,m,ArH),5.03-5.13(1H,m,CH[CH₃]₂),4.53(2H,q,J=7.2Hz,OCH₂CH₃),1.76(6H,d,J=6.9Hz,CH[CH₃]₂),1.49(3H,t,J=7.2Hz,OCH₂CH₃).¹³C NMR(75MHz,CDCl₃):δ166.3,141.0,137.4,137.1,133.0,129.1,128.8,122.2,121.9,120.6,117.8,111.2,61.8,47.9,21.6(2C),14.9.

Ethyl 9-isopropyl-1-methyl- β -carboline-3-carboxylate (9 b)

1-methyl- β -carboline-3-carboxylic acid ethyl ester and 2-bromopropane are used as raw materials to obtain white solid (2.1 g, 71%). FAB-MS M/z 297[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.72(1H,s,ArH),8.18(1H,d,J=7.8Hz),7.73(1H,d,J=8.4Hz),7.51-7.57(1H,m,ArH),7.29-7.33(1H,m,ArH),5.57-5.67(1H,m,CH[CH₃]₂),4.51(2H,q,J=7.2Hz,OCH₂CH₃),3.13(3H,s,CH₃),1.77(6H,d,J=6.9Hz,CH[CH₃]₂),1.49(3H,t,J=7.2Hz,OCH₂CH₃).¹³C NMR(75MHz,CDCl₃):δ166.3,141.3,140.3,137.3,136.8,128.9,128.0,123.1,122.0,120.4,116.2,113.8,61.8,48.9,25.8,21.8(2C),14.9.

Ethyl 9-isobutyl- β -carboline-3-carboxylate (9 c)

β -carboline-3-carboxylic acid ethyl ester and 1-bromo-2-methyl-propane are used as raw materials to obtain a white solid (2.2 g, 78%). FAB-MSm/z 297[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.93(1H,s,ArH),8.88(1H,s,ArH),8.20(1H,d,J=7.8Hz),7.60-7.65(1H,m,ArH),7.49-7.51(1H,m,ArH),7.32-7.38(1H,m,ArH),4.54(2H,q,J=7.2Hz,OCH₂CH₃),4.21(2H,d,J=7.5Hz,CH₂CH[CH₃]₂),2.31-2.45(1H,m,CH₂CH[CH₃]₂),1.51(3H,t,J=7.2Hz,OCH₂CH₃),1.00(6H,d,J=6.6Hz,CH₂CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ166.3,142.0,138.3,137.7,132.2,128.9,128.4,122.2,121.5,120.8,117.9,110.5,61.9,51.5,29.4,20.9,14.9.

Ethyl 9-isobutyl-1-methyl- β -carboline-3-carboxylate (9 d)

1-methyl- β -carboline-3-carboxylic acid ethyl ester and 1-bromo-2-methyl-propane are used as raw materials to obtain a white solid (2.4 g, 77%). FAB-MS M/z 311[ M + H ],]⁺。¹H NMR(300MHz,CDCl₃):δ8.75(1H,s,ArH),8.18(1H,d,J=7.8Hz),7.57-7.62(1H,m,ArH),7.49-7.51(1H,m,ArH),7.30-7.35(1H,m,ArH),4.52(2H,q,J=7.2Hz,OCH₂CH₃),4.21(2H,d,J=7.5Hz,CH₂CH[CH₃]₂),3.12(3H,s,CH₃),2.21-2.34(1H,m,CH₂CH[CH₃]₂),1.50(3H,t,J=7.2Hz,OCH₂CH₃),0.94(6H,d,J=6.6Hz,CH₂CH[CH₃]₂).

ethyl 9- (3-chlorobenzyl) -1-methyl- β -carboline-3-carboxylate (9 e)

1-methyl- β -carboline-3-carboxylic acid ethyl ester and 3-chloro benzyl bromide are used as raw materials to obtain white solid (2.8 g, 74%). FAB-MS M/z 379[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.90(1H,s,ArH),8.23(1H,d,J=5.4Hz),7.55-7.65(1H,m,ArH),7.35-7.47(2H,m,ArH),7.15-7.24(3H,m,ArH),6.99(1H,s,ArH,),5.81(2H,NCH₂Ph[3-Cl]),3.72(2H,q,J=6.9Hz,OCH₂CH₃),2.96(3H,s,CH₃),1.50(3H,t,J=7.2Hz,OCH₂CH₃).

General synthesis of intermediates 10 a-e:

ethyl 9-substituted- β -carboline-3-carboxylate 9a-e (10mmol), THF (100ml), LiBH₄(30mmol), stirring at room temperature for reaction, tracking and detecting by TLC (petroleum ether: acetone is 1: 1), after the reaction is finished, slowly pouring the reaction mixed solution into 200ml of ice water, stirring for reaction for 1 minute, adjusting the pH to 2.0 by concentrated hydrochloric acid, stirring for 20 minutes at room temperature, adjusting the pH to 9.0 by 10% sodium hydroxide solution, extracting the mixed solution by ethyl acetate, combining organic phases, washing by water, washing by saturated salt solution, drying by anhydrous sodium sulfate, decoloring by activated carbon, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, dissolving the residue by acetone, and recrystallizing by a refrigerator to obtain a white solid.

3-hydroxymethyl-9-isopropyl- β -carboline (10a)

Ethyl 9-isopropyl- β -carboline-3-carboxylate is used as raw material to obtain white solid (1.6 g, 67%). FAB-MS M/z241[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.13(1H,d,J=7.8Hz,ArH),7.95(1H,s,ArH),7.67(1H,d,J=8.4Hz,ArH),7.48-7.53(1H,m,ArH),7.21(1H,d,J=7.8Hz,ArH),5.43-5.57(1H,m,CH[CH₃]₂),4.89(2H,s,CH₂OH),3.03(3H,s,CH₃),1.73(2H,d,J=7.2Hz,CH[CH₃]₂).

3-hydroxymethyl-9-isopropyl-1-methyl- β -carboline (10 b)

Ethyl 9-isopropyl-1-methyl- β -carboline-3-carboxylate is used as raw material to obtain white solid (1.6 g, 63%). FAB-MS M/z255[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.09(1H,d,J=7.8MHz,ArH),7.78(1H,s,ArH),7.53-7.61(2H,m,ArH),7.24-7.29(2H,m,ArH),4.99-5.08(1H,m,CH[CH₃]₂),4.94(2H,s,CH₂OH),1.75(2H,d,J=6.9Hz,CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ147.6,140.5,140.2,135.2,130.2,127.7,122.8,121.9,119.5,113.4,109.9,65.0,48.5,24.9,21.7.

3-hydroxymethyl-9-isobutyl- β -carboline (10c)

With ethyl 9-isobutyl- β -carboLin-3-Carboxylic acid ester as starting material gave a white solid (1.8 g, 71%). FAB-MS M/z255[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.90(1H,s,ArH),8.23(1H,d,J=7.2Hz,ArH),8.12(1H,s,ArH),7.66(1H,d,J=8.4Hz,ArH),7.53-7.59(1H,m,ArH),7.22(1H,d,J=7.8Hz,ArH),4.69(2H,s,CH₂OH),4.26(2H,d,J=7.5Hz,CH₂CH[CH₃]₂),2.22-2.31(1H,m,CH₂CH[CH₃]₂),0.87(6H,d,J=6.6Hz,CH₂CH[CH₃]₂).

3-hydroxymethyl-9-isobutyl-1-methyl- β -carboline (10d)

Ethyl 9-isobutyl-1-methyl- β -carboline-3-carboxylate was used as a starting material to obtain a white solid (2.0 g, 75%). FAB-MS M/z 269[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.08(1H,d,J=7.8Hz,ArH),7.78(1H,s,ArH),7.53-7.58(1H,m,ArH),7.44(1H,d,J=8.4Hz,ArH),7.22-7.27(1H,m,ArH),4.89(2H,s,CH₂OH),4.32(2H,d,J=7.5Hz,CH₂CH[CH₃]₂),3.02(3H,s,CH₃),2.18-2.32(1H,m,CH₂CH[CH₃]₂),0.93(6H,d,J=6.6Hz,CH₂CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ147.4,142.7,140.5,134.9,130.3,128.2,121.6,119.7,112.3,110.7,109.9,65.0,52.1,31.0,23.8,20.5.

3-hydroxymethyl-9- (3-chlorobenzyl) -1-methyl- β -carboline (10e)

Ethyl 9- (3-chlorobenzyl) -1-methyl- β -carboline-3-carboxylate is used as raw material to obtain white solid (2.3 g, 68%). FAB-MS M/z 337[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.13(1H,d,J=7.8Hz,ArH),7.83(1H,s,ArH),7.51-7.56(1H,m,ArH),7.18-7.36(4H,m,ArH),7.02(1H,s,ArH),6.80(1H,d,J=6.9Hz,ArH),5.71(2H,s,NCH₂Ph[3-Cl]),4.89(2H,s,CH₂OH),2.85(3H,s,CH₃).

General synthesis of intermediates 11 a-e:

3-hydroxymethyl-9-alkyl- β -carboline 10a-e (10mmol), acetonitrile (150ml), active MnO₂(50mmol) are mixed, heated and refluxed, TLC tracking detection is carried out, MnO is removed by filtering immediately after the reaction is finished₂Decrease, decreaseConcentrating under pressure to dryness to obtain yellow solid. Dissolving the solid in ethyl acetate, decoloring by using activated carbon, passing through silica gel, concentrating under reduced pressure to be dry, and carrying out silica gel column chromatography on residues, wherein the weight ratio of ethyl acetate: petroleum ether =1:2 as mobile phase, collecting target product, and concentrating under reduced pressure to dryness to obtain white crystal.

9-isopropyl- β -carboline-3-carbaldehyde (11a)

3-hydroxymethyl-9-isopropyl- β -carboline as raw material to obtain white solid (1.8 g, 76%). FAB-MS M/z239[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ10.22(1H,s,CHO),9.12(1H,s,ArH),8.73(1H,s,ArH),8.22(1H,d,J=7.2Hz,ArH),7.59-7.65(2H,m,ArH),7.34-7.40(1H,m,ArH),5.06-5.20(1H,m,CH[CH₃]₂),1.80(2H,d,J=6.9Hz,CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ193.1,143.7,141.1,137.9,133.2,129.1,122.4,122.2,120.9,114.8,111.4,110.0,48.2,21.6.

9-isopropyl-1-methyl- β -carboline-3-carbaldehyde (11b)

3-hydroxymethyl-9-isopropyl-1-methyl- β -carboline as raw material to obtain white solid (1.7 g, 67%). FAB-MSm/z253[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ10.15(1H,s,CHO),8.58(1H,s,ArH),8.19(1H,d,J=7.8Hz,ArH),7.76(1H,d,J=8.4Hz,ArH),7.55-7.60(1H,m,ArH),7.31-7.36(1H,m,ArH),5.58-5.72(1H,m,CH[CH₃]₂),3.14(3H,s,CH₃),1.80(2H,d,J=6.9Hz,CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ193.0,142.9,141.5,140.2,138.0,128.8,128.3,123.2,122.0,120.8,113.9,113.5,49.0,25.6,21.8.

9-isobutyl- β -carboline-3-carbaldehyde (11c)

3-hydroxymethyl-9-isobutyl- β -carboline is used as a raw material to obtain a white solid (1.8 g, 71%). FAB-MS M/z253[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ10.22(1H,s,CHO),8.97(1H,s,ArH),8.73(1H,s,ArH),8.21(1H,d,J=7.8Hz,ArH),7.62-7.68(1H,m,ArH),7.53(1H,d,J=8.4Hz,ArH)，7.36-7.41(1H,m,ArH),4.25(2H,d,J=6.9Hz,CH₂CH[CH₃]₂),2.38-2.47(1H,m,CH₂CH[CH₃]₂),1.03(2H,d,J=6.9Hz,CH₂CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ193.1,144.0,142.2,139.1,132.5,129.2,128.4,122.3,121.7,121.1,114.9,110.7,51.8,29.5,20.9.

9-isobutyl-1-methyl- β -carboline-3-carbaldehyde (11d)

3-hydroxymethyl-9-isobutyl-1-methyl- β -carboline as raw material to obtain white solid (1.8 g, 68%). FAB-MSm/z 267[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ10.17(1H,s,CHO),8.60(1H,s,ArH),8.17(1H,d,J=7.8Hz,ArH),7.59-7.65(1H,m,ArH),7.51(1H,d,J=8.4Hz,ArH)，7.32-7.38(1H,m,ArH),4.43(2H,d,J=6.9Hz,CH₂CH[CH₃]₂),3.12(3H,s,CH₃),2.23-2.37(1H,m,CH₂CH[CH₃]₂),0.97(2H,d,J=6.9Hz,CH₂CH[CH₃]₂).¹³C NMR(75MHz,CDCl₃):δ193.0,143.2,142.4,141.7,137.7,129.0,128.8,121.7,121.0,113.5,111.2,52.1,31.0,24.3,20.5.

9- (3-chlorobenzyl) -1-methyl- β -carboline-3-carbaldehyde (11e)

Using 3-hydroxymethyl-9- (3-chlorobenzyl) -1-methyl- β -carboline as raw material to obtain white solid (2.4 g, 72%). FAB-MS M/z 335[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃):δ10.17(1H,s,CHO),8.64(1H,s,ArH),8.22(1H,d,J=7.8Hz,ArH),7.57-7.62(1H,m,ArH),7.37-7.42(2H,m,ArH),7.18-7.27(2H,m,ArH),7.03(1H,s,ArH),6.81-6.84(1H,m,ArH),5.83(2H,s,CH₂Ph[3-Cl]).

Examples

Synthesis process of 3-amino alkyl chain connected bis β -carboline alkali derivative

Example 1

General preparation process for connecting 3-amino alkyl chain with bis β -carboline alkali 1-39

Adding corresponding β -carboline-3-formaldehyde (2mmol) and anhydrous methanol (30ml) into a 100ml round bottom flask, stirring for 10 minutes at room temperature, then adding corresponding diamine (1mmol), heating and refluxing the reaction mixture for 2 hours, stopping refluxing, evaporating the methanol under reduced pressure, adding water in the anhydrous ethanol twice, dissolving the reaction residue in the anhydrous methanol (30ml), then adding sodium borohydride (5mmol), stirring for 4-6 hours at room temperature, detecting by TLC tracking, after the reaction is finished, adding concentrated hydrochloric acid (10ml) into the reaction solution carefully, stirring for 15 minutes at room temperature, basifying with concentrated sodium hydroxide solution, extracting with dichloromethane (100ml) twice, combining organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating to dryness under reduced pressure, purifying the residue by silica gel column chromatography, sequentially eluting with mobile phase dichloromethane/ammonia water =100:0.8, dichloromethane/methanol/ammonia water =50:1:0.8, collecting the target product, and concentrating to dryness under reduced pressure.

N, N-bis [ (9-methyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (1):

9-methyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain white solid with the yield of 57 percent, ESI-MS M/z is 504 (M +1)]⁺。¹H NMR(400MHz,CDCl₃):δ8.80(2H,d,J=0.8Hz),8.11(2H,d,J=7.8Hz),7.96(2H,s),7.56-7.61(2H,m),7.41(2H,d,J=8.4Hz,),7.24-7.28(2H,m),4.09(4H,s),3.89(6H,s),2.70-2.74(3H,m),1.58-1.61(4H,m),1.36-1.39(4H,m)；¹³C NMR(100MHz,CDCl₃)：δ148.6,142.1,136.1,131.1,129.0,128.3,121.9,121.0,119.4,113.1,109.1,55.6,49.5,31.9,30.0,29.5,27.2.

N, N-bis [ (9-ethyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (2):

9-ethyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are taken as raw materials to obtain light yellow solid with the yield of 24 percent and ESI-MSm/z of 505 (M +1)]⁺。¹H NMR(400MHz,CDCl₃):δ8.78(2H,d,J=0.8Hz),8.12(2H,d,J=7.8Hz),7.96(2H,s),7.54-7.62(2H,m),7.43(2H,d,J=8.4Hz,),7.22-7.30(2H,m),4.38(4H,q,J=7.2Hz),4.10(4H,s),2.75-2.79(4H,m),1.67-1.69(4H,m),1.43-1.46(6H,t,J=7.2Hz)；¹³CNMR(100MHz,CDCl₃)：δ148.2,141.0,135.1,131.1,129.1,128.2,122.0,121.1,119.4,113.2,109.1,55.4,49.4,37.9,28.0,14.0.

N, N-bis [ (9-ethyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (3):

9-ethyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain brown solid with the yield of 17 percent, ESI-MS M/z is 532[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.78(2H,d,J=0.8Hz),8.12(2H,d,J=7.8Hz),7.96(2H,s),7.54-7.62(2H,m),7.43(2H,d,J=8.4Hz,),7.22-7.30(2H,m),4.38(4H,q,J=7.2Hz),4.10(4H,s),2.75-2.79(4H,m),1.67-1.69(4H,m),1.43-1.46(6H,t,J=7.2Hz).¹³CNMR(100MHz,CDCl₃)：δ148.6,141.4,138.4,135.2,131.6,127.2,123.9,122.3,118.8,116.2,108.7,55.1,49.3,38.9,28.7,27.1,13.8.

N, N-bis [ (9-octyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (4):

9-octyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain milk white solid with the yield of 38 percent, ESI-MSm/z 673[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.74(2H,d,J=1.0Hz),8.10(2H,d,J=7.8Hz),7.95(2H,d,J=1.0Hz),7.55-7.58(2H,m),7.40(2H,d,J=8.4Hz),7.21-7.29(2H,m),4.25(4H,t,J=7.2Hz),4.11(4H,s),2.80(4H,t,J=6.4Hz),1.79-1.90(4H,m),1.72(4H,s),1.22-1.28(20H,m),0.85(6H,t,J=6.8Hz).¹³C NMR(100MHz,CDCl₃)：δ148.2,141.4,135.6,131.3,129.0,128.1,121.9,121.0,119.3,113.1,109.4,55.5,49.5,43.3,31.7,30.5,29.7,29.2,28.1,27.2,22.5,19.1,14.0.

N, N-bis [ (9-octyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (5):

9-octyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow oily matter, the yield is 13%, ESI-MSm/z is 687[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.78(2H,d,J=1.0Hz),8.10(2H,d,J=7.8Hz),7.96(2H,d,J=1.0Hz),7.56-7.58(2H,m),7.43(2H,d,J=8.4Hz),7.23-7.29(2H,m),4.31(4H,t,J=7.2Hz),4.10(4H,s),2.76(4H,t,J=6.8Hz),1.82-1.92(4H,m),1.58-1.71(4H,m),1.47(4H,d,J=6.8Hz),1.15-1.40(18H,m),0.85(6H,t,J=6.8Hz).¹³C NMR(100MHz,CDCl₃)：δ148.7,141.5,135.6,131.3,129.0,128.1,121.9,121.0,119.3,113.0,109.3,55.7,49.6,43.4,31.7,29.9,29.3,27.2,25.2,22.5,14.0.

N, N-bis [ (9- (3-chlorobenzyl) - β -carbolin-3-yl) methyl ] butane-1, 4-diamine (6):

9- (3-chlorobenzyl) - β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain white solid with the yield of 43 percent, ESI-MS M/z is 697[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.68(2H,d,J=0.8Hz),8.13(2H,d,J=8.0Hz),8.00(2H,s),7.54-7.57(2H,m),7.35(2H,d,J=8.4Hz),7.26-7.32(2H,m),7.10-7.23(6H,m),6.95(2H,d,J=7.4Hz),5.44(4H,s),4.08(4H,s),2.77(4H,t,J=7.2Hz),1.69(4H,m).¹³C NMR(100MHz,CDCl₃)：δ148.9,141.5,138.5,135.6,134.8,131.3,130.2,129.4,128.6,128.1,126.5,124.5,122.1,121.3,120.1,113.2,109.4,55.3,49.4,46.3,28.0.

N, N-bis [ (9- (3-chlorobenzyl) - β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (7):

9- (3-chlorobenzyl) - β -carboline-3-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain milk white solid with the yield of 29 percent, ESI-MS M/z 711[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.70(2H,d,J=0.8Hz),8.16(2H,d,J=8.0Hz),8.02(2H,s),7.52-7.61(2H,m),7.36(2H,d,J=8.4Hz),7.27-7.33(2H,m),7.16-7.25(6H,m),6.96(2H,d,J=7.4Hz),5.44(4H,s),4.12(4H,s),2.79(4H,t,J=7.2Hz),1.60-1.73(4H,m),1.45-1.54(2H,m).¹³CNMR(100MHz,CDCl3):δ144.8,141.3,140.9,138.4,135.7,134.8,131.3,130.2,129.4,128.6,128.1,126.5,124.5,122.1,121.3,120.1,113.5,109.4,54.9,49.1,46.3,29.1,26.9.

N, N-bis [ (9- (3-chlorobenzyl) - β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (8):

9- (3-chlorobenzyl) - β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain yellow solid with the yield of 22 percent, ESI-MS M/z is 725[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.77(2H,d,J=1.0Hz),8.16(2H,d,J=8.0Hz),8.05(2H,s),7.55-7.59(2H,m),7.36(2H,d,J=8.4Hz),7.29-7.33(2H,m),7.13-7.23(6H,m),6.97-7.00(2H,m),5.48(4H,s),4.18(4H,s),2.82(4H,t,J=7.2Hz),1.67-1.69(4H,m),1.42-1.46(4H,m).¹³C NMR(100MHz,CDCl₃):δ163.4,161.0,148.9,141.5,135.6,132.1,131.1,129.4,128.5,128.2,128.1,122.0,121.3,119.9,115.9,115.7,113.2,109.5,55.4,49.5,46.2,29.7,25.0.

N, N-bis [ (9- (4-fluorobenzyl) - β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (9):

9- (4-fluorobenzyl) - β -carboline-3-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain light gray solid with the yield of 27%, ESI-MS M/z 679[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.68(2H,d,J=1.0Hz),8.16(2H,d,J=8.0Hz),8.05(2H,s),7.55-7.58(2H,m),7.35(2H,d,J=8.0Hz),7.27-7.31(2H,m),7.05-7.08(4H,m),6.90-6.95(4H,m),5.37(4H,s),4.17(4H,s),2.85(4H,t,J=7.2Hz),1.70-1.75(4H,m),1.31-1.34(2H,m).¹³C NMR(100MHz,CDCl₃):δ163.4,161.0,148.9,141.5,135.6,132.1,132.1,131.4,129.4,128.5,128.2,128.1,122.0,121.3,119.9,115.9,115.7,113.2,109.5,55.4,49.5,46.2,29.6.

N, N-bis [ (9- (4-fluorobenzyl) - β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (10):

9- (4-fluorobenzyl) - β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain milk white solid with the yield of 23%, ESI-MS M/z:693[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.76(2H,d,J=1.0Hz),8.16(2H,d,J=8.0Hz),8.02(2H,s),7.54-7.58(2H,m),7.38-7.40(2H,d,J=8.0Hz),7.27-7.31(2H,m),7.09-7.13(4H,m),6.92-6.97(4H,m),5.49(4H,s),4.13(4H,s),2.77(4H,t,J=7.2Hz),1.62-1.68(4H,m),1.34-1.41(4H,m).¹³C NMR(100MHz,CDCl3):δ167.7,163.4,161.0,149.1,141.5,135.6,132.3,132.2,132.1,131.4,130.9,129.4,128.8,128.8,128.5,128.2,128.1,122.0,119.9,,115.7,113.2,109.5,65.5,55.6,49.6,46.3,29.7.

N, N-bis [ (9-phenylpropyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (11):

9-phenylpropyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain a white solid, the yield is 19%, ESI-MSm/z is 685[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.61(2H,d,J=1.0Hz),8.08(2H,d,J=8.0Hz),7.93(2H,s),7.52-7.56(2H,m),7.18-7.30(10H,m),7.12-7.14(4H,m),4.20(4H,t,J=7.2Hz),4.11(4H,s),2.81-2.83(4H,m),2.66(4H,t,J=7.2Hz),2.14-2.18(4H,m),1.73-1.77(4H,m).¹³C NMR(100MHz,CDCl₃)：δ148.5,141.4,140.6,135.5,131.2,129.1,128.5,128.2,128.2,126.2,121.9,121.1,119.4,113.1,109.3,55.5,49.5,42.7,33.1,30.2,28.1.

N, N-bis [ (9-phenylpropyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (12):

9-phenylpropyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain light yellow solid with the yield of 52 percent, ESI-MS M/z is 713[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.79(2H,d,J=1.0Hz),8.12(2H,d,J=8.0Hz),8.00(2H,s),7.54-7.58(2H,m),7.20-7.34(10H,m),7.14-7.16(4H,m),4.35(6H,t,J=7.2Hz),4.20(4H,s),2.81-2.85(4H,m),2.70(4H,t,J=7.2Hz),2.19-2.26(4H,m),1.70-1.73(4H,m),1.41-1.45(4H,m).¹³C NMR(100MHz,CDCl3)：δ148.2,141.4,140.6,135.6,131.2,129.1,128.5,128.2,126.2,121.9,121.1,119.5,113.2,109.4,60.3,55.4,49.4,42.7,33.1,30.2,29.8,27.2.

N, N-bis [ (1-isopropyl-9-benzyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (13):

1-isopropyl-9-benzyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain a white solid with the yield of 32%, ESI-MS M/z:701[ M +1 ]]⁺。¹H NMR(400MHz,DMSO)：δ8.50(2H,s),8.32(2H,d,J=7.6Hz),7.80(2H,d,J=8.0Hz),7.68(2H,t,J=7.2Hz),7.40(2H,t,J=7.2Hz),7.21-7.31(6H,m),6.93(4H,d,J=6.8Hz),5.96(4H,s),4.54(4H,s),3.71-3.76(2H,m),3.19-3.22(4H,t,J=7.6Hz),2.25-2.29(2H,m),1.24(12H,d,J=6.8Hz).¹³C NMR(100MHz,DMSO)：δ149.4,143.2,138.5,137.7,132.3,128.7,127.2,125.2,121.8,120.8,119.9,110.8,48.0,43.8,30.1,30.0,22.2,22.0.

N, N-bis [ (1-isopropyl-9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (14):

1-isopropyl-9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain white solid with the yield of 43 percent, ESI-MS M/z is 741[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃)：δ9.19(2H,s),8.45(2H,d,J=7.6Hz),7.79(2H,d,J=8.0Hz),7.56(2H,t,J=7.2Hz),7.48(2H,t,J=7.2Hz),7.31-7.35(6H,m),7.01(4H,d,J=6.8Hz),5.84(4H,s),5.01(4H,s),3.89(2H,m),3.31-3.35(4H,m),2.58(4H,m),1.96-1.98(4H,m),1.59(12H,d,J=6.8Hz).¹³C NMR(100MHz,DMSO)：δ148.9,143.7,137.9,136.2,132.6,127.9,127.1,125.8,122.1,120.4,119.3,111.3,55.4,48.3,42.7,33.4,31.2,28.1,22.7.

N, N-bis [ (1-isopropyl-9-butyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (15):

1-isopropyl-9-butyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain light yellow solid with the yield of 26 percent, ESI-MS M/z is 645 (M +1)]⁺。¹H NMR(400MHz,CDCl₃):δ9.21(2H,s),8.10(2H,d,J=8.0Hz),7.95(2H,s),7.55(2H,d,J=8.4Hz),7.43(2H,d,J=7.4Hz),5.08(4H,s),4.48(4H,t,J=6.4Hz),3.72-3.76(2H,m),2.95-2.98(4H,t,J=7.6Hz),1.98-2.02(4H,m),1.79-1.83(4H,m),1.41-1.46(16H,m),0.96-0.99(6H,t,J=7.6Hz).¹³C NMR(100MHz,CDCl₃)：δ150.1,142.2,139.0,133.1,130.7,128.3,121.6,121.1,119.7,112.4,109.6,51.6,46.9,45.1,32.4,31.4,28.7,26.7,24.2,22.7,20.2,13.8.

N, N-bis [ (1-isopropyl-9-butyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (16):

1-isopropyl-9-butyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain yellow solid with the yield of 32%, ESI-MS M/z 659[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ9.19(2H,s),8.41(2H,d,J=8.0Hz),7.78(2H,t,J=7.6Hz),7.56(2H,d,J=8.4Hz),7.42(2H,t,J=7.4Hz),5.11(4H,s),4.54(4H,t,J=6.4Hz),3.99-4.06(2H,m),3.41(4H,s),2.12-2.15(4H,m),1.85-1.90(16H,m),1.47-1.55(4H,m),1.02(6H,t,J=7.2Hz).¹³C NMR(100MHz,CDCl₃)：δ147.6,145.3,135.3,133.6,132.6,131.9,124.1,122.6,120.0,119.8,110.3,47.1,46.7,46.2,32.5,29.9,22.7,21.9,20.1,13.7.

N, N-bis [ (1- (2-chlorophenyl) -9- (3-chlorobenzyl) - β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (17):

1- (2-chlorphenyl) -9- (3-chlorobenzyl) - β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow solid with the yield of 42 percent, ESI-MS M/z is 933[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.21(2H,d,J=7.6Hz),8.16(2H,s),7.59-7.63(2H,m),7.28-7.41(10H,m),7.06-7.13(4H,m),6.91-6.99(4H,m),6.57(2H,s),5.03-5.27(4H,m),4.18(4H,s),2.76(4H,t,J=7.6Hz),1.64-1.68(4H,m),1.27-1.33(2H,m).¹³C NMR(100MHz,CDCl₃):δ147.1,142.4,140.9,138.7,137.3,134.2,133.9,133.3,131.8,130.1,129.2,129.0,128.7,128.2,127.2,126.7,125.2,124.1,121.4,120.7,120.2,113.9,109.4,55.2,49.4,44.7,29.6,24.2.

N, N-bis [ (1- (2-chlorophenyl) -9- (3-chlorobenzyl) - β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (18):

1- (2-chlorphenyl) -9- (3-chlorobenzyl) - β -carboline-3-formaldehyde and 1, 6-hexanediamine are taken as raw materials to obtain off-white solid with the yield of 18 percent, ESI-MS M/z 948[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.23-8.25(2H,d,J=7.6Hz),8.15(2H,s),7.54-7.58(2H,m),7.31-7.41(8H,m),7.06-7.13(6H,m),6.94-6.98(2H,m),6.43(2H,s),6.32(2H,d,J=7.6Hz),5.01-5.24(4H,dd,J=76.0,17.6Hz),4.15(4H,s),2.72(4H,t,J=7.2Hz),1.55-1.59(4H,m),1.27-1.33(4H,m).¹³C NMR(100MHz,CDCl₃):δ146.6,142.6,140.6,139.1,137.7,134.2,134.1,133.5,131.5,131.3,129.9,129.6,129.2,129.0,127.3,126.5,125.6,123.4,121.9,121.2,120.4,113.3,109.7,54.4,49.0,46.9,29.0,26.8.

N, N-bis [ (1- (2-chlorophenyl) -9-butyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (19):

1- (2-chlorphenyl) -9-butyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow solid with the yield of 23 percent, ESI-MS M/z is 795[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ9.39(2H,d,J=3.2Hz),8.49(2H,d,J=8.0Hz),7.93(2H,d,J=7.2Hz),7.78(2H,t,J=8.0Hz),7.62-7.64(4H,m),7.54-7.60(2H,m),7.52(2H,d,J=8.0Hz),7.45(2H,t,J=8.0Hz),4.95(4H,s),3.81-4.02(4H,m),3.26-3.29(4H,m),1.90-1.97(4H,m),1.48-1.52(2H,m),1.37-1.47(4H,m),0.86-0.98(4H,m),0.68(6H,t,J=7.2Hz).¹³C NMR(100MHz,CDCl₃):δ145.0,135.5,134.9,134.4,133.3,133.1,132.9,132.7,132.3,129.8,128.3,127.5,124.4,122.7,120.7,120.1,110.5,47.1,46.8,44.7,31.3,24.4,19.9,13.3.

N, N-bis [ (1- (2-chlorophenyl) -9-butyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (20):

1- (2-chlorphenyl) -9-butyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain white solid with the yield of 29%, ESI-MS M/z 809[ M +1 ]]⁺。¹H NMR(400MHz,CD₃OD):δ9.05(2H,s),8.54(2H,d,J=8.0Hz),8.00(2H,t,J=6.8Hz),7.86-7.95(2H,m),7.75-7.86(6H,m),7.68-7.70(2H,m),7.52(2H,t,J=8.0Hz),4.88(4H,s),4.74-4.78(4H,m),3.91-4.20(4H,m),3.27-3.31(4H,m),1.86-1.89(4H,m),1.55-1.61(4H,m),1.40-1.51(2H,m),0.92-0.98(4H,m),0.71(6H,t,J=7.2Hz).¹³CNMR(100MHz,CD₃OD):δ145.3,136.2,135.3,134.3,133.8,133.4,133.2,132.7,132.6,130.4,130.1,129.9,127.8,123.2,122.5,120.0,118.5,111.3,47.4,46.3,44.5,31.3,25.6,25.5,19.7,12.5.

N, N-bis [ (1- (4-methoxyphenyl) -9-benzyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (21):

1- (4-methoxyphenyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain a white solid with the yield of 31 percent, ESI-MS M/z 856[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ9.24(2H,s),8.43(2H,d,J=8.0Hz),7.69(2H,t,J=7.6Hz),7.38-7.51(8H,m),7.12-7.21(6H,m),6.85(4H,d,J=8.4Hz),6.58(4H,d,J=6.8Hz),5.26(4H,s),4.97(4H,s),3.78(6H,s),3.27-2.30(4H,m),1.91-1.94(4H,m),1.67-1.70(2H,m).¹³C NMR(100MHz,CDCl₃):δ161.9,145.5,140.0,135.3,135.1,134.0,133.4,132.4,131.7,128.8,127.8,125.3,124.0,122.8,120.4,119.8,114.1,111.2,55.5,48.5,47.3,46.9,29.7,24.1.

N, N-bis [ (1- (4-methoxyphenyl) -9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (22):

1- (4-methoxyphenyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain yellow solid with the yield of 37 percent, ESI-MS M/z is 869[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.79(2H,s),8.40(2H,d,J=8.0Hz),7.69-7.78(4H,m),7.53(4H,d,J=8.4Hz),7.45(2H,t,J=7.2Hz),7.06-7.12(6H,m),7.02(4H,d,J=8.4Hz),6.51(4H,d,J=6.8Hz),5.42(4H,s),4.55(4H,s),3.84(6H,s),2.88-3.02(4H,m),1.73-1.76(4H,m),1.33-1.36(4H,m).¹³C NMR(100MHz,DMSO):δ160.2,143.7,136.6,133.0,131.2,130.4,128.2,127.1,125.4,122.2,121.3,120.0,113.4,111.6,55.3,47.3,46.6,33.9,25.4,25.0.

N, N-bis [ (1- (4-methoxyphenyl) -9-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (23):

1- (4-methoxyphenyl) -9-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materialsStarting material, yellow solid was obtained with a yield of 19%. ESI-MS M/z 689[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.07(2H,d,J=7.6Hz),7.84(2H,s),7.48-7.58(2H,m),7.34-7.37(6H,m),7.24-7.28(2H,m),6.94(4H,d,J=8.4Hz),4.08(4H,s),3.84(6H,s),3.31(6H,s),2.86-2.88(4H,m),1.76-1.78(4H,m).¹³C NMR(100MHz,CDCl₃):δ159.7,147.1,143.2,134.2,132.3,130.7,128.3,121.6,121.1,119.6,113.5,111.8,109.6,65.8,55.1,53.4,49.2,32.7,28.0,15.2.

N, N-bis [ (1- (4-methoxyphenyl) -9-methyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (24):

1- (4-methoxyphenyl) -9-methyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow solid with the yield of 28 percent, ESI-MS M/z:703 (M +1)]⁺。¹H NMR(400MHz,CDCl₃):δ8.12(2H,d,J=7.6Hz);8.01(2H,s),7.49-7.58(2H,m),7.47-7.51（4H,m）,7.35（2H，d，J=8.4Hz）,7.24-7.28（2H，m），6.98（4H,d,J=8.4Hz）,4.20(4H,s),3.86(6H,s),3.40(6H,s),2.84(4H,t,J=6.8Hz),1.68-1.74(4H,m),1.44-1.45(2H,m).¹³C NMR(100MHz,CDCl₃):δ159.8,143.3,134.5,131.8,130.9,130.9,121.8,121.0,119.9,113.6,112.7,109.7,32.8,31.9,29.7,26.9,23.8,22.7.

N, N-bis [ (1- (4-methoxyphenyl) -9-hexyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (25):

1- (4-methoxyphenyl) -9-hexyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain white solid with the yield of 33 percent, ESI-MS M/z 857[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.14(2H,d,J=7.6Hz),7.99(2H,s),7.47-7.57(6H,m),7.47-7.51(4H,m),7.38-7.41(2H,d,J=8.4Hz),7.24-7.28(2H,m),7.00-7.03(4H,d,J=8.4Hz),4.12(4H,s),3.90(4H,t,J=8.0Hz),3.87(6H,s),2.72(4H,t,J=7.2Hz),1.58-1.61(4H,m),1.25-1.36(8H,m),1.09-1.14(4H,m),0.94-1.02(4H,m),0.82-0.88(4H,m),0.75(6H,t,J=7.2Hz).¹³C NMR(100MHz,CDCl₃)：δ159.8,146.1,143.4,142.5,133.5,132.4,131.1,130.5,128.2,121.5,121.3,119.6,113.6,112.1,110.1,55.4,54.7,49.2,44.4,31.1,26.2,22.4.

N, N-bis [ (1- (4-chlorophenyl) -9-butyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (26):

1- (4-chlorphenyl) -9-butyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain yellow solid with the yield of 42 percent, ESI-MS M/z is 768[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.61(2H,d,J=7.6Hz),8.32(2H,s),7.66-7.79(12H,m),7.37-7.40(2H,t,J=7.2Hz),4.49(4H,s),4.05(4H,t,J=8.0Hz),3.16(4H,t,J=6.0Hz),2.23-2.26(2H,m),1.21-1.25(4H,m),0.81-0.83(4H,m),0.57(6H,t,J=7.2Hz).¹³C NMR(100MHz,DMSO):δ142.7,140.9,138.4,133.9,132.8,131.5,131.3,129.6,128.1,121.8,120.6,119.9,115.3,111.2,49.7,43.9,43.7,30.3,22.0,19.0,13.1.

N, N-bis [ (1- (4-chlorophenyl) -9-butyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (27):

1- (4-chlorphenyl) -9-butyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain brown solid with the yield of 18 percent, ESI-MS M/z:781[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.13(2H,d,J=7.6Hz),7.99(2H,s),7.39-7.59(12H,m),7.25-7.28(2H,t,J=7.2Hz),4.08(4H,s),3.87(4H,t,J=8.0Hz),2.76(4H,t,J=6.0Hz),1.67-1.69(4H,m),1.27-1.31(4H,m),0.83-0.89(4H,m),0.63(6H,t,J=7.2Hz).¹³C NMR(100MHz,CDCl₃)：δ142.5,142.0,138.6,134.4,133.2,131.4,130.7,128.3,121.7,121.3，119.8,112.4,110.1,65.8,54.9,49.3,44.3,30.8,28.0,19.8,13.5.

N, N-bis [ (1- (4-chlorophenyl) -9-benzyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (28):

1- (4-chlorphenyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow solid with the yield of 24 percent, ESI-MS M/z is 863[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.62(2H,s),8.37(2H,d,J=7.6Hz),7.74(2H,d,J=8.4Hz),7.67(2H,t,J=7.7Hz),7.33-7.59(12H,m),7.01-7.16(8H,m),6.45(4H,d,J=6.6Hz),4.47(4H,s),2.97(4H,t,J=6.0Hz),1.68-1.72(4H,m),1.36-1.40(2H,m).¹³C NMR(100MHz,DMSO)：δ143.1,141.2,139.4,136.7,133.7,133.1,131.5,131.3,129.7,128.2,127.8,127.0,125.2,121.8,120.9,120.2,115.0,111.3,47.3,46.4,33.9,24.6,22.9.

N, N-bis [ (1- (4-chlorophenyl) -9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (29):

1- (4-chlorphenyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain brown solid, the yield is 23%, ESI-MS M/z is 878[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.56(2H,s),8.41(2H,d,J=7.6Hz),7.62(2H,d,J=8.4Hz),7.57(2H,t,J=7.7Hz),7.36-7.51(10H,m),6.92-7.13(10H,m),6.36(4H,d,J=6.4Hz),4.22(4H,s),2.68(4H,t,J=6.0Hz),1.45-1.53(4H,m),1.12-1.21(4H,m).¹³C NMR(100MHz,DMSO)：δ145.4,141.9,140.1,136.7,135.6,133.8,133.2,131.2,129.7,128.3,127.9,125.6,123.3,122.7,121.1,119.1,115.3,111.2,52.4,51.5,47.4,26.1,22.4.

N, N-bis [ (1-phenyl-9-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (30):

1-phenyl-9-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain yellow solid with the yield of 42 percent, ESI-MS M/z is 629[ M +1 ]]⁺。¹H NMR(400MHz,D₂O):δ8.85(2H,s),8.60(2H,d,J=8.0Hz),7.85-8.11(14H,m),7.74(2H,t,J=7.6Hz),5.02(4H,s),3.64(6H,s),3.54(4H,t,J=6.0Hz),2.20-2.24(4H,m).¹³C NMR(100MHz,D₂O)：δ146.3,142.0,134.8,134.7,133.6,132.9,132.6,132.1,130.9,129.9,123.6,122.9,120.4,118.1,112.0,49.4,47.8,33.4,23.7.

N, N-bis [ (1-phenyl-9-methyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (31):

1-phenyl-9-methyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain white solid with the yield of 27%, ESI-MS M/z:656[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.74(2H,s),8.37(2H,d,J=8.0Hz),7.75-7.81(8H,m),7.60-7.66(6H,m),7.43(2H,t,J=7.6Hz),4.55(4H,s),3.50(6H,s),3.02(4H,t,J=6.0Hz),1.71-1.75(4H,m),1.33-1.38(4H,m).¹³C NMR(100MHz,D₂O)：δ148.1,142.3,138.4,134.2,133.6,132.2,130.5,129.3,126.8,123.9,122.4,121.7,119.2,117.8,111.0,51.4,49.2,33.8,26.1,24.4.

N, N-bis [ (1-phenyl-9-benzyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (32):

1-phenyl-9-benzyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are taken as raw materials to obtain yellow solid with the yield of 32%/z:767[M+1]⁺。¹H NMR(400MHz,CDCl₃):δ8.19(2H,s),8.11(2H,d,J=8.0Hz),7.47-7.51(2H,m),7.29-7.33(2H,m),7.07-7.25(18H,m),6.54(4H,d,J=8.0Hz),5.05(4H,s),4.19(4H,s),3.08(4H,t,J=6.0Hz),2.25-2.28(2H,m).¹³C NMR(100MHz,CDCl₃):δ143.9,143.2,142.9,139.2,136.8,133.9,131.3,129.1,128.8,128.4,128.0,127.0,125.6,121.8,121.2,120.4,113.4,110.5,52.7,48.9,47.9,24.1.

N, N-bis [ (1-phenyl-9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (33):

1-phenyl-9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain yellow solid with the yield of 29%, ESI-MS M/z 809[ M +1 ]]⁺。¹H NMR(400MHz,DMSO)δ8.92(2H,s),8.43(2H,d,J=8.0Hz),7.74-7.76(4H,m),7.56-7.60(6H,m),7.44-7.49(6H,m),7.06-7.12(6H,m),6.47(4H,d,J=8.0Hz),5.37(4H,s),4.58(4H,s),3.02-3.05(4H,t,J=6.0Hz),1.71-1.74(4H,m),1.36-1.42(4H,m),1.05(2H,t,J=7.0Hz).¹³C NMR(100MHz,CDCl₃)δ145.0,135.5,134.9,134.4,133.3,133.1,132.9,132.7,132.6,129.9,128.3,127.5,124.4,122.7,120.7,120.1,110.5,47.1,46.8,44.7,31.3,24.4,19.9,13.3.

N, N-bis [ (1- (4-methoxyphenyl) - β -carbolin-3-yl) methyl ] butane-1, 4-diamine (34):

1- (4-methoxyphenyl) - β -carboline-3-and 1, 4-butanediamine are used as raw materials to obtain yellow solid with the yield of 44%, ESI-MS M/z is 661[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃):δ8.44(2H,s),7.98(2H,d,J=8.0Hz),7.76(4H,d,J=8.4Hz),7.66(2H,s),7.40-7.51(4H,m),7.43(2H,d,J=8.1Hz),7.20-7.25(2H,m),6.99(4H,t,J=8.8Hz),4.02(4H,s),3.83(6H,s),2.82(4H,t,J=6.0Hz),1.73-1.76(4H,m).¹³C NMR(100MHz,CDCl₃):δ160.0,141.7,140.6,132.3,130.9,130.3,129.3,128.2,121.8,120.0,114.4,111.6,111.3,111.1,55.3,54.3,49.0,27.9.

N, N-bis [ (1-isopropyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (35):

1-isopropyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain yellow solid with the yield of 27%, ESI-MSm/z:547[ M +1 ]]⁺。¹H NMR(400MHz,DMSO):δ8.16(2H,d,J=8.0Hz),8.03(2H,s),7.61(2H,d,J=8.0Hz),7.52-7.56(2H,m),7.22-7.26(2H,m),4.24(4H,s),3.64-3.68(2H,m),2.90(4H,t,J=6.0Hz),1.64-1.68(4H,m),1.37-1.39(14H,m).¹³C NMR(100MHz,DMSO):δ149.8,140.6,132.4,127.97,127.93,121.3,120.7,119.2,111.9,111.8,51.7,46.8,30.8,26.0,23.4,21.3.

N, N-bis [ (1- (3-pyridyl) -9-butyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (36):

1- (3-pyridyl) -9-butyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain yellow solid with the yield of 36 percent, ESI-MS M/z 715[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃)：δ8.73(2H,d,J=8.0Hz),8.12(2H,s),8.04(2H,d,J=8.0Hz),7.86-7.92(2H,m),7.76-7.79(4H,m),7.42-7.53(4H,m),7.07(2H,d,J=7.2Hz),4.14(4H,s),3.92(4H,t,J=8.0Hz),2.66(4H,t,J=6.0Hz),1.68-1.71(4H,m),1.32-1.41(4H,m),0.93-0.98(4H,m),0.73(6H,t,J=7.2Hz).¹³C NMR(100MHz,CDCl₃):δ142.7,138.6,134.7,134.2,131.3,129.7,128.2,122.2,121.1，119.6,112.3,109.1,64.8,52.9,47.6,42.4,31.2,19.6,14.4.

N, N-bis [ (1- (3-pyridyl) -9-butyl- β -carbolin-3-yl) methyl ] pentane-1, 5-diamine (37):

1- (3-pyridyl) -9-butyl- β -carboline-3-formaldehyde and 1, 5-pentanediamine are taken as raw materials to obtain brown solid with the yield of 19 percent, ESI-MS M/z:729[ M +1 ]]⁺。¹H NMR(400MHz,CDCl₃)：δ8.23(2H,d,J=8.0Hz),8.16(2H,s),8.02(2H,d,J=8.0Hz),7.79-7.83(2H,m),7.28-7.51(8H,m),7.06-7.13(2H,m),4.18(4H,s),3.94(4H,t,J=8.0Hz),2.76(4H,t,J=7.6Hz),1.70-1.73(4H,m),1.64-1.68(4H,m),1.27-1.39(6H,m),0.68(6H,t,J=7.2Hz).¹³CNMR(100MHz,CDCl₃)：δ142.4,140.6,138.2,137.1,134.7,133.5,133.1,131.2,129.1,128.7,128.2,127.6,127.2,126.9,126.1,125.4,124.1,122.4,121.7,119.2,113.4,109.4,64.2,55.6,47.3,41.7,35.4,19.2,15.5,13.5.

N, N-bis [ (1- (3-pyridyl) -9-benzyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (38):

1- (3-pyridyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow solid with the yield of 36 percent.ESI-MS m/z:783[M+1]⁺。¹H NMR(400MHz,CDCl₃)：δ8.21(2H,d,J=8.0Hz),8.11(2H,s),8.01(2H,d,J=8.0Hz),7.69-7.73(2H,m),7.37-7.55(12H,m),7.02-7.13(4H,m),6.93-6.99(4H,m),5.26(4H,s),4.21(4H,s),3.11(4H,t,J=6.0Hz),2.25-2.28(4H,m).¹³C NMR(100MHz,CDCl₃)：δ143.6,143.1,142.7,140.2,137.2,132.9,131.5,129.2,128.6,127.9,127.2,126.4,125.6,121.6,120.8,120.1,112.8,111.0,54.6,45.9,29.7,13.7.

N, N-bis [ (1- (3-pyridyl) -9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (39):

1- (3-pyridyl) -9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexanediamine are used as raw materials to obtain yellow solid with the yield of 36 percent, ESI-MS M/z 812 (M +1)]⁺。¹H NMR(400MHz,CDCl₃)：δ8.23(2H,d,J=8.0Hz),8.15(2H,s),8.04(2H,d,J=8.0Hz),7.66-7.70(2H,m),7.31-7.41(10H,m),7.03-7.14(6H,m),6.94-6.98(4H,m),5.24(4H,s),4.22(4H,s),2.73(4H,t,J=7.2Hz),1.57-1.61(4H,m),1.23-1.29(4H,m).¹³C NMR(100MHz,CDCl₃)：δ142.9,142.6,141.7,137.7,134.2,133.5,131.7,131.2,129.6,129.2,128.4,127.3,126.5,125.7,123.4,121.9,120.8,120.4,113.1,109.9,54.9,46.4,29.0,19.8,14.1.

Example 2

General preparation process for connecting 3-amino alkyl chain with bis β -carboline alkali 40-65

Adding corresponding β -carboline-3-formaldehyde (2mmol) and anhydrous methanol (30ml) into a 100ml round bottom flask, stirring for 10 minutes at room temperature, then adding corresponding diamine (1mmol), heating and refluxing the reaction mixture for 2 hours, stopping refluxing, evaporating the methanol under reduced pressure, adding anhydrous ethanol with water twice, dissolving the residue in anhydrous methanol (30ml), then adding NaBH₄(5mmol), the reaction was stirred at room temperature for 6 hours and checked by TLC. After the reaction, concentrated hydrochloric acid (10ml) was carefully added to the reaction solution, stirred at room temperature for 15 minutes, then basified with concentrated sodium hydroxide solution, extracted twice with dichloromethane (100ml), the organic phases were combined, washed with water,washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to dryness, purifying the residue by silica gel column chromatography, eluting with mobile phase dichloromethane/ammonia water =100:0.8, dichloromethane/methanol/ammonia water =100:1:0.8, and dichloromethane/methanol/ammonia water =50:1:0.8, collecting the target product, and concentrating under reduced pressure to dryness.

N, N-bis [ (1, 9-dimethyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (40)

1, 9-dimethyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain white solid with the yield of 68 percent, EI-MSm/z is 505.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.04(2H,d,J=7.8Hz),7.75(2H,s),7.52-7.58(2H,m),7.35(2H,d,J=7.8Hz),7.20-7.23(2H,m),4.02(4H,s),3.96(6H,s),2.99(6H,s),2.81(4H,t,J=6.3Hz),1.71-1.75(4H,m).¹³C NMR(75MHz,CDCl₃):δ147.4,142.4,141.1,134.9,129.4,128.1,121.6,121.2,119.5,111.2,109.4,55.5,49.8,32.3,28.4,23.8.

N, N-bis [ (1, 9-dimethyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (41)

1, 9-dimethyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain white solid with the yield of 60 percent, EI-MSm/z is 533.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.07(2H,d,J=7.5Hz),7.80(2H,s),7.53-7.58(2H,m),7.40(2H,d,J=8.1Hz),7.21-7.23(2H,m),4.11(4H,s),4.02(6H,s),3.06(6H,s),2.71(4H,t,J=7.2Hz),1.55-1.64(4H,m),1.37-1.41(4H,m).¹³C NMR(75MHz,CDCl₃):δ148.1,142.6,141.2,135.1,129.6,128.1,121.6,121.4,119.6,111.3,109.5,55.9,50.0,32.5,30.6,27.8,24.0.

N, N-bis [ (9-isopropyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (42):

9-isopropyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.34g, 64%). EI-MS M/z:533.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.93(2H,s),8.12(2H,d,J=7.8Hz),7.96(2H,s),7.53-7.55(4H,m),7.21-7.25(2H,m),4.96-5.06(2H,m),4.07(4H,s),2.75(4H,t,J=6.3Hz),1.74(6H,s),1.72(6H,s),1.65-1.69(4H,m).¹³C NMR(75MHz,CDCl₃):δ147.9,140.9,134.9,132.6,129.9,128.3,122.1,121.5,119.4,113.5,110.7,55.6,49.6,47.5,28.3,21.5.

N, N-bis [ (9-isopropyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (43):

9-isopropyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain yellow oily matter (0.38g, 67%). EI-MSm/z:561.1[ M + H ]/]⁺。¹H NMR(300MHz,CDCl₃):δ8.94(2H,s),8.12(2H,d,J=7.8Hz),7.97(2H,s),7.49-7.56(4H,m),7.21-7.25(2H,m),4.95-5.04(2H,m),4.07(4H,s),2.71(4H,t,J=6.3Hz),1.73(6H,s),1.70(6H,s),1.53-1.63(4H,m),1.34-1.40(4H,m).¹³C NMR(75MHz,CDCl₃):δ147.9,140.9,134.9,132.6,129.9,128.3,122.1,121.5,119.4,113.5,110.7,55.6,49.6,47.5,28.3,21.5.

N, N-bis [ (9-isopropyl-1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (44):

9-isopropyl-1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.39g, 70%). EI-MS M/z:561.1[ M + H ]/]⁺。¹H NMR(300MHz,CDCl₃):δ8.09(2H,d,J=7.8Hz),7.80(2H,s),7.66(2H,d,J=8.7Hz),7.43-7.51(2H,m),7.18-7.24(2H,m),4.46-5.55(2H,m),4.02(4H,s),3.02(4H,s),2.76(4H,t,J=6.0Hz),1.74(6H,s),1.72(6H,s),1.65-1.70(4H,m).¹³CNMR(75MHz,CDCl₃):δ147.3,140.7,140.3,135.0,129.8,127.5,122.9,121.9,119.4,113.3,111.3,55.5,49.8,48.5,28.4,25.3,21.8.

N, N-bis [ (9-N-butyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (45):

9-n-butyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain yellow oily matter with the yield of 66%, EI-MSm/z is 547.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.69(2H,s),8.09(2H,s),8.02(2H,d,J=7.8Hz),7.46-7.51(2H,m),7.33(2H,d,J=7.8Hz),7.13-7.18(2H,m),4.18(4H,t,J=7.2Hz),3.95(4H,s),2.74(4H,t,J=6.3Hz),1.70-1.83(6H,m),1.23-1.35(4H,m),0.86(6H,t,J=7.2Hz).¹³C NMR(75MHz,CDCl₃):δ146.7,141.7,135.8,131.0,129.3,128.3,122.3,121.2,119.6,114.5,109.5,61.3,52.8,43.4,31.5,23.4,20.8,14.1.

N, N-bis [ (9-N-butyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (46):

9-n-butyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain a light yellow solid with a yield of 64 percent, EI-MSm/z is 561.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.69(2H,s),8.08(2H,d,J=7.5Hz)，7.92(2H,s),7.52-7.57(2H,m),7.37(2H,d,J=8.1Hz),7.20-7.23(2H,m),4.21(4H,t,J=6.6Hz),4.10(4H,s),2.81(4H,t,J=6.3Hz),1.78-1.89(4H,m),1.72-1.76(4H,m),1.30-1.40(4H,m),0.91(6H,t,J=7.2Hz).¹³C NMR(75MHz,CDCl₃):δ148.5,141.6,135.7,131.4,129.2,128.3,122.1,121.2,119.5,113.2,109.6,55.8,49.8,43.4,31.6,28.4,20.8,14.2.

N, N-bis [ (9-N-butyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (47):

using 9-n-butyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine as raw materials to obtain white solid with the yield of 61%, EI-MSm/z:589.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.80(2H,s),8.12(2H,d,J=7.8Hz),7.96(2H,s),7.53-7.59(2H,m),7.43(2H,d,J=7.8Hz),7.22-7.27(2H,m),4.35(4H,t,J=6.6Hz),4.08(4H,s),2.72(4H,t,J=7.2Hz),1.83-1.93(4H,m),1.57-1.62(4H,m),1.33-1.45(8H,m),0.95(6H,t,J=7.2Hz).¹³C NMR(75MHz,CDCl₃):δ148.9,141.7,135.8,131.5,129.2,128.3,122.1,121.3,119.5,113.3,109.6,56.0,50.0,43.5,31.6,30.6,27.8,20.9,14.2.

N, N-bis [ (9-isobutyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (48):

using 9-isobutyl- β -carboline-3-formaldehyde and 1, 4-butanediamine as raw materials to obtain a white solid (0.31 g, 54%). EI-MS M/z:561.1[ M + H ],]⁺。¹H NMR(300MHz,CDCl₃):δ8.77(2H,s),8.10(2H,d,J=7.8Hz),7.94(2H,s),7.51-7.56(2H,m),7.40(2H,d,J=8.4Hz),7.20-7.23(2H,m),4.10(4H,d,J=7.5Hz),4.07(4H,s),2.75(4H,t,J=6.3Hz),2.31-2.42(2H,m),1.64-1.68(4H,m),0.98(6H,s),0.96(6H,s).¹³C NMR(75MHz,CDCl₃):δ148.7,142.0,136.2,131.8,129.2,128.3,122.1,121.2,119.6,113.3,110.0,55.9,51.3,49.9,29.4,28.4,21.0.

n, N-bis [ (9-isobutyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (49):

9-isobutyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain a light yellow oily substance (0.34g, 58%). EI-MSm/z is 589.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.79(2H,s),8.12(2H,d,J=7.8Hz),7.96(2H,s),7.53-7.59(2H,m),7.43(2H,d,J=8.1Hz),7.22-7.27(2H,m),4.14(4H,d,J=7.5Hz),4.07(4H,s),2.71(4H,t,J=7.2Hz),2.31-2.45(2H,m),1.56-1.61(4H,m),1.37-1.40(4H,m),1.00(6H,s),0.98(6H,s).¹³C NMR(75MHz,CDCl₃):δ148.8,142.0,136.2,131.8,129.2,128.3,122.1,121.2,119.6,113.3,110.0,56.0,51.4,50.0,30.6,29.4,27.8,21.0.

N, N-bis [ (9-N-butyl-1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (50):

using 9-n-butyl-1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine as raw materials to obtain white solid with the yield of 25 percent, EI-MSm/z of 589.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.07(2H,d,J=7.8Hz),7.80(2H,s),7.51-7.56(2H,m),7.41(2H,d,J=7.8Hz),7.19-7.22(2H,m),4.47(4H,t,J=6.6Hz),4.02(4H,s),3.01(6H,s),2.76(4H,t,J=6.3Hz),1.75-1.85(4H,m),1.65-1.70(4H,m),1.37-1.49(4H,m),0.97(6H,t,J=7.2Hz).¹³C NMR(75MHz,CDCl₃):δ147.8,141.9,140.7,134.2,129.8,128.0,121.6,121.5,119.5,111.2,109.8,55.8,49.9,44.8,33.1,28.4,23.8,20.5,14.2.

N, N-bis [ (9-N-butyl-1-methyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (51):

using 9-n-butyl-1-methyl- β -carboline-3-formaldehyde and 1, 6-hexanediamine as raw materials to obtain light yellow oily substance with yield of 32%, EI-MS M/z:617.3[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.07(2H,d,J=7.8Hz),7.81(2H,s),7.50-7.56(2H,m),7.41(2H,d,J=7.8Hz),7.19-7.22(2H,m),4.47(4H,t,J=7.5Hz),4.02(4H,s),3.01(4H,s),2.73(4H,t,J=7.2Hz),1.75-1.85(4H,m),1.58-1.62(4H,m),1.37-1.47(8H,m),0.97(6H,t,J=7.2Hz).¹³C NMR(75MHz,CDCl₃):δ147.6,141.9,140.7,134.2,129.8,128.0,121.6,121.4,119.5,111.3,109.8,55.7,49.9,44.8,33.1,30.4,27.7,23.8,20.5,14.2.

N, N-bis [ (9-isobutyl-1-methyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (52):

9-isobutyl-1-methyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are taken as raw materials to obtain light yellow oily substance with the yield of 45 percent, EI-MS M/z is 575.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ7.93(2H,d,J=7.8Hz),7.83(2H,s),7.46-7.51(2H,m),7.35(2H,d,J=7.8Hz),7.09-7.14(2H,m),4.13(4H,s),4.09(4H,d,J=7.5Hz),3.11(4H,t,J=5.4Hz),2.82(6H,s),2.03-2.17(4H,m),0.85(6H,s),0.83(6H,s).¹³CNMR(75MHz,CDCl₃):δ143.5,142.3,141.1,134.7,129.8,128.1,121.6,121.0,119.7,112.3,110.6,53.7,51.8,49.2,31.0,25.6,23.9,20.5.

N, N-bis [ (9-isobutyl-1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (53):

9-isobutyl-1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain a light yellow oily substance with the yield of 40 percent, EI-MS M/z is 589.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.06(2H,d,J=7.8Hz),7.82(2H,s),7.48-7.53(2H,m),7.40(2H,d,J=7.8Hz),7.18-7.23(2H,m),4.28(4H,d,J=7.5Hz),4.02(4H,s),2.99(6H,s),2.77(4H,t,J=6.0Hz),2.19-2.28(2H,m),1.65-1.70(2H,m),0.92(6H,s),0.90(6H,s).¹³C NMR(75MHz,CDCl₃):δ147.9,142.4,140.8,134.5,129.9,127.9,121.6,121.3,119.4,111.3,110.5,55.8,51.9,50.0,30.9,28.4,24.1,20.5.

N, N-bis [ (9-isobutyl-1-methyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (54):

using 9-isobutyl-1-methyl- β -carboline-3-formaldehyde and 1, 6-hexanediamine as raw materials to obtain light yellow oily substance with yield% EI-MS M/z of 617.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.08(2H,d,J=7.8Hz),7.82(2H,s),7.49-7.54(2H,m),7.42(2H,d,J=7.8Hz),7.19-7.24(2H,m),4.31(4H,d,J=7.5Hz),4.03(4H,s),3.00(6H,s),2.74(4H,t,J=7.2Hz),2.17-2.29(2H,m),1.56-1.66(2H,m),1.37-1.41(2H,m),0.93(6H,s),0.91(6H,s).¹³C NMR(75MHz,CDCl₃):δ147.4,142.5,140.9,134.6,130.0,128.0,121.6,121.3,119.5,111.4,110.6,55.5,52.0,49.9,31.0,30.3,27.7,24.2,20.6.

N, N-bis [ (9-benzyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (55):

9-benzyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain a light yellow oily substance with a yield of 62%, EI-MS M/z is 615.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.71(2H,s),8.10(2H,d,J=7.8Hz),7.98(2H,s),7.49-7.53(2H,m),7.37-7.40(2H,m),7.23-7.26(8H,m),7.10-7.14(4H,m),5.50(4H,s),4.10(4H,s),2.83-2.88(4H,m),1.85-1.90(2H,m).¹³C NMR(75MHz,CDCl₃):δ149.3,141.9,136.6,136.0,131.7,129.6,129.1,128.6,128.0,126.7,122.2,121.5,120.0,113.3,109.9,55.9,48.4,47.3,30.7.

N, N-bis [ (9-benzyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (56):

9-benzyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain white solid with the yield of 58 percent, EI-MS M/z is 657.5[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.75(2H,s),8.15(2H,d,J=7.8Hz),7.99(2H,s),7.51-7.56(2H,m),7.41(2H,d,J=8.4Hz),7.23-7.30(8H,m),7.12-7.15(4H,m),5.55(4H,s),4.06(4H,s),2.71(4H,t,J=7.2Hz),1.53-1.61(4H,m),1.37-1.40(4H,m).¹³C NMR(75MHz,CDCl₃):δ149.5,141.9,136.7,135.9,131.8,129.5,129.1,128.6,128.0,126.7,122.2,121.5,120.0,113.3,109.9,56.1,50.1,47.2,30.6,27.8.

N, N-bis [ (9-benzyl-1-methyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (57):

9-benzyl-1-methyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain a light yellow oily substance (0.37g, 58%). EI-MS M/z:643.4[ M + H ]/]⁺。¹H NMR(300MHz,CDCl₃):δ8.08(2H,d,J=7.8Hz),7.87(2H,s),7.46-7.51(2H,m),7.31(2H,d,J=8.4Hz),7.20-7.24(8H,m),6.94-6.98(4H,m),5.71(4H,s),4.05(4H,s),2.88(4H,t,J=6.9Hz),2.82(6H,s),1.85-1.94(2H,m).¹³C NMR(75MHz,CDCl₃):δ148.1,142.4,141.2,138.2,134.7,130.0,129.1,128.5,127.6,125.6,121.8,121.6,120.1,111.6,110.0,55.8,48.6,48.4,30.5,23.5.

N, N-bis [ (9-benzyl-1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (58):

9-benzyl-1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain a light yellow oily substance (0.36g,60％)。EI-MS m/z:658.2[M+H]⁺。¹H NMR(300MHz,CDCl₃):δ8.12(2H,d,J=7.8Hz),7.86(2H,s),7.48-7.53(2H,m),7.31(2H,d,J=8.4Hz),7.22-7.26(8H,m),6.94-6.97(4H,m),5.71(4H,s),4.04(4H,s),2.82(6H,s),2.77(4H,t,J=6.0Hz),1.68-1.72(4H,m).¹³C NMR(75MHz,CDCl₃):δ148.0,142.4,141.2,138.2,134.8,130.0,129.2,128.5,127.7,125.6,121.8,121.6,120.1,111.6,110.0,55.6,49.9,48.4,28.4,23.5.

n, N-bis [ (9-benzyl 1-methyl- β -carbolin-3-yl) methyl ] hexane-1, 6-diamine (59):

9-benzyl-1-methyl- β -carboline-3-formaldehyde and 1, 6-hexamethylene diamine are taken as raw materials to obtain a light yellow oily substance (0.28g, 48%). EI-MS M/z:684.9[ M + H ]/]⁺。¹H NMR(300MHz,CDCl₃):δ8.13(2H,d,J=7.8Hz),7.87(2H,s),7.47-7.52(2H,m),7.23-7.34(10H,m),6.96-6.99(4H,m),5.76(4H,s),4.03(4H,s),2.85(6H,s),2.74(4H,t,J=7.2Hz),1.54-1.65(4H,m),1.39-1.42(4H,m).¹³C NMR(75MHz,CDCl₃):δ148.3,142.4,141.2,138.2,134.7,130.0,129.2,128.5,127.6,125.6,121.8,121.6,120.1,111.5,110.0,55.9,50.1,48.4,30.5,27.8,23.5.

N, N-bis [ (9- (3-chlorobenzyl) -1-methyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (60):

using 9- (3-chlorobenzyl) -1-methyl- β -carboline-3-formaldehyde and 1, 3-propane diamine as raw materials to obtain white solid with the yield of 58 percent, EI-MS M/z:711.0[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃):δ8.07(2H,d,J=7.8Hz),7.87(2H,s),7.46-7.51(2H,m),7.13-7.26(8H,m),7.00(2H,s),6.76(2H,d,J=7.5Hz),5.63(4H,s),4.06(4H,s),2.89(4H,t,J=6.9Hz),2.79(6H,s),1.85-1.92(2H,m).¹³C NMR(75MHz,CDCl₃):δ148.5,142.2,141.0,140.4,135.1,134.6,130.5,130.1,128.6,128.0,125.8,123.8,121.8,121.7,120.3,111.5,109.8,55.7,48.6,47.9,30.5,23.5.

N, N-bis [ (9- (3-chlorobenzyl) -1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (61):

9- (3-chlorobenzyl) -1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain yellow oily matter with the yield of 58 percent, EI-MS M/z is 726.7[ M + H []⁺。¹H NMR(300MHz,CDCl₃):δ8.12(2H,d,J=7.8Hz),7.87(2H,s),7.49-7.54(2H,m),7.13-7.30(8H,m),7.01(2H,s),6.78(2H,d,J=6.9Hz),5.66(4H,s),4.04(4H,s),2.82(6H,s),2.80(4H,t,J=6.0Hz),1.68-1.72(4H,m).¹³C NMR(75MHz,CDCl₃):δ148.3,142.1,141.0,140.4,135.1,134.5,130.5,130.1,128.6,127.9,125.7,123.8,121.9,121.6,120.3,111.5,109.8,55.7,50.0,47.9,28.5,23.5.

N, N-bis [ (9- (3-phenylpropyl) -1-methyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (62):

9- (3-phenylpropyl) -1-methyl- β -carboline-3-formaldehyde and 1, 3-propanediamine are used as raw materials to obtain a light yellow oily substance (0.20g, 38%). EI-MS M/z:698.8[ M + H ],]⁺。¹H NMR(300MHz,CDCl₃):δ8.02(2H,d,J=7.5Hz),7.80(2H,s),7.46-7.52(2H,m),7.15-7.31(14H,m),4.46(4H,t,J=8.1Hz),4.03(4H,s),2.86(6H,s),2.85(4H,t,J=6.6Hz),2.73(4H,t,J=7.5Hz),2.07-2.15(4H,m),1.83-1.89(2H,m).¹³C NMR(75MHz,CDCl₃):δ147.7,141.9,140.8,134.2,129.9,128.8,128.6,128.2,126.5,121.7,121.6,119.7,111.5,109.8,55.7,48.5,44.4,33.4,32.3,30.5,23.6.

n, N-bis [ (9- (3-phenylpropyl) -1-methyl- β -carbolin-3-yl) methyl ] butane-1, 4-diamine (63):

9- (3-phenylpropyl) -1-methyl- β -carboline-3-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain a light yellow oily substance (0.24g, 44%). EI-MS M/z:712.8[ M + H ]/]⁺。¹H NMR(300MHz,CDCl₃):δ8.06(2H,d,J=7.5Hz),7.79(2H,s),7.48-7.53(2H,m),7.16-7.30(14H,m),4.48(4H,t,J=7.8Hz),4.01(4H,s),2.87(6H,s),2.71-2.76(8H,m),2.09-2.19(4H,m),1.65-1.69(4H,m).¹³C NMR(75MHz,CDCl₃):δ147.8,141.9,140.8,134.3,130.0,128.8,128.6,128.2,126.5,121.7,121.6,119.7,111.4,109.8,55.7,49.9,44.5,33.4,32.3,28.4,23.6.

N, N-bis [ (1- (3,4, 5-trimethoxyphenyl) -9-ethyl- β -carbolin-3-yl) methyl ] propane-1, 3-diamine (64):

1- (3,4, 5-trimethoxy) phenyl-9-ethyl- β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain a white oily substance (0.20, 21%). EI-MS M/z:822.8[ M + H ],]⁺。¹H NMR(300MHz,CDCl₃):δ8.10(2H,d,J=7.5Hz),8.01(2H,s),7.53-7.59(2H,m),7.40(2H,d,J=8.4Hz),7.20-7.24(2H,m),6.78(4H,s),4.11(4H,s),3.99(4H,q,J=7.2Hz),3.90(6H,s),3.86(12H,s),2.90(4H,t,J=6.9Hz),1.85-1.94(2H,m),1.03(6H,t,J=6.9Hz).¹³C NMR(75MHz,CDCl₃):δ153.2,147.5,143.4,142.2,138.2,135.8,133.1,131.3,128.6,121.9,121.6,119.6,112.6,110.2,106.5,61.2,56.5,55.7,48.7,39.4,30.2,14.7.

n, N-bis [ (1- (3,4, 5-trimethoxyphenyl) -9- (3-phenylpropyl) - β -carbolin-3-yl) methyl ] propane-1, 3-diamine (65):

1- (3,4, 5-trimethoxy) phenyl-9- (3-phenylpropyl) - β -carboline-3-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain a light yellow oily substance with the yield of 76 percent, EI-MS M/z is 1045.3M + H]⁺。¹H NMR(300MHz,CDCl₃):δ8.15(2H,d,J=7.8Hz),8.04(2H,s),7.51-7.56(2H,m),7.30(2H,d,J=8.7Hz),7.12-7.26(8H,m),6.96(4H,d,J=6.9Hz),6.81(4H,s),4.13(4H,s),3.97(4H,t,J=7.8Hz),3.94(6H,s),3.86(12H,s),2.77(4H,t,J=7.2Hz),2.23(4H,t,J=7.8Hz),1.70-1.81(4H,m),1.58-1.63(4H,m),1.33-1.41(4H,m).¹³CNMR(75MHz,CDCl₃):δ153.3,147.1,143.4,142.5,140.8,138.4,135.7,133.4,131.4,128.6,128.1,126.2,122.0,121.6,120.1,112.8,110.2,106.9,61.3,56.6,55.4,49.8,44.6,33.3,31.2,30.0,27.6.

Pharmacological experiments

Experimental example 1 in vitro anticancer screening test

769-P (human kidney cancer, urinary system), BGC-823 (human stomach cancer, digestive system), A375 (human melanoma), HT-29 (human colon cancer, digestive system), HepG2 (human liver cancer, digestive system), MCF-7 (human breast cancer, reproductive system), LLC (mouse Lewis lung cancer, respiratory system), Eca-109 (human esophageal cancer, digestive system), SK-OV-3 (human ovarian cancer, reproductive system) and 22RV1 (human prostate cancer, reproductive system) are selected respectively, and MTT method is adopted for testing. Cisplatin was used as a positive control.

The specific method comprises respectively growing cell lines in logarithmic growth phase at a ratio of 1 × 10⁴Inoculating to 96-well plate at a concentration of one/ml, and placingAt 37 deg.C, 5% CO₂Culturing for 24 hours in the incubator, discarding the old solution, replacing the fresh culture solution, adding the sterilized compound to be detected, continuing culturing for 48 hours, discarding the culture solution, adding 20ul of RPMI 1640 culture solution containing 5mg/ml MTT into each well, continuing culturing for 4 hours, carefully removing the supernatant, adding 100 mul of DMSO into each well, shaking for about 10min to dissolve the precipitate, and detecting the OD value with a microplate reader with the wavelength of 490 nm. Cell viability was determined for each sample concentration using the following formula:

percent survival%

Plotting cell viability against log drug concentration and determining IC for each sample by plotting₅₀The value is obtained.

The test results are shown in Table 1.

TABLE 1 in vitro antitumor Activity of bis β -carboline base derivatives

Experimental example 2 acute toxicity test in mice

Kunming mice (provided by Xinjiang experimental animal research center, the qualification number: SCXK 2011 + 0001, the weight is 19-20g, each half of the male and female mice is one group, the solvent adopts physiological saline and 0.5% CMC-Na solution, according to the pre-test result, each drug to be tested is designed into five-level dose, the dose interval is 0.8 times, after each drug to be tested is weighed, a small amount of Tween 80 is added for wetting and dissolving assisting in the experiment, then 0.5% CMC-Na solution is gradually added to the required concentration, the experiment volume is 0.5ml/20g mice, single intraperitoneal administration is adopted, Kunming mice are taken and randomly grouped according to the sex, each group is respectively provided with intraperitoneal administration according to the dose, the immediate reaction after the administration of the mice is observed, dead animals are dissected and observed, the living animals continue to observe for two weeks, the death condition of the animals in two weeks is recorded, the living animals are dissected after two weeks, observing the pathological changes of parenchymal organs, treating the parenchymal organsAnd (6) physical examination. Based on the number of deaths in each group of animals, the half-Lethal Dose (LD) of the drug was calculated by the Bliss method₅₀Value).

The results of the tests are shown in Table 2 below.

EXAMPLE 3 in vivo anticancer test

BABL/C mice and C₅₇BL/6 mice (provided by the research center of experimental animals in Xinjiang, the qualification number: SCXK (New) 2011-. Anti-tumor experiment BABL/C mice and C₅₇One group of 8-10 BL/6 mice, and two groups of negative controls; the tumor source adopts mouse Lewis lung cancer and H22 liver cancer (maintained by pharmacologic laboratory passage of Xinjiang Huashi Dan medicine research Limited liability company); the solvent adopts physiological saline and 0.5 percent CMC-Na solution; the tested drugs are respectively administered to LD in abdominal cavity of the drug by a single administration₅₀1/5 for the value is benchmark; weighing each sample to be tested, adding a small amount of Tween-80 for wetting and dissolving aid during experiment, and gradually adding 0.5% CMC-Na solution to the required concentration. The experimental volume was 0.5ml/20g mouse. The preparation is administered to abdominal cavity 1 time per day for 10 days, and 10 times. The negative control was given an equal volume of the corresponding solvent, and the dosing regimen was all intraperitoneal, 1 time per day for 10 consecutive days. Positive control Cyclophosphamide (CTX) was administered once daily for 7 consecutive days at a dose of 30 mg/kg. Adopting an in vivo anti-tumor axillary subcutaneous inoculation model: taking tumor source with vigorous growth under aseptic condition, homogenizing to obtain about 1 × 10⁷0.2 ml/mouse is inoculated to the axilla of the corresponding host subcutaneously, the administration is carried out according to the experimental design scheme on the next day, each group of animals is killed in about three weeks, the tumor is dissected and weighed, and the tumor inhibition rate is calculated according to the following formula:

percent tumor inhibition is [ (average tumor weight in negative control group-average tumor weight in administration group)/average tumor weight in negative control group ] × 100%

The results of the tests are shown in Table 2 below.

TABLE 2 test results of acute toxicity and antitumor activity of mouse using bis β -carboline compounds

Claims

1. Bis β -carboline alkali compounds shown in the general formula I and medicinal salts thereof,

n is an integer from 2 to 14;

k, l are independently selected from integers from 0 to 12;

i, j are independently selected integers from 0-12;

R₁₁and R₁₂Independently selected from hydrogen, substituted or unsubstituted C1-10 linear or branched alkyl, hydroxyl, substituted or unsubstituted C1-10 linear or branched alkoxy, sulfydryl, substituted or unsubstituted C1-10 linear or branched alkylthio, amino, substituted or unsubstituted C1-10 linear or branched alkylamino: wherein the compound comprises monoalkylamino and bialkylamino, aldehyde group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-10 straight chain or branched chain alkanoylamino, carbamoyl, C2-10 alkene, halogen, nitro, cyano, substituted or unsubstituted five-six-membered aryl, and substituted or unsubstituted five-six-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

R₉₁and R₉₂Independently selected from hydrogen, substituted or unsubstituted C1-10 straight chain or branched chain alkyl, hydroxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkoxy, sulfydryl, substituted or unsubstituted C1-10 straight chain or branched chain alkylthio, aldehyde, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyl, carboxyl, substituted or unsubstituted C1-10 straight chain or branched chain alkyl-ester group, substituted or unsubstituted C1-10 straight chain or branched chain alkanoyloxy, substituted or unsubstituted C1-10 straight chain or branched chain alkanoylamino, carbamoyl, C2-10 alkene, halogen, nitro, cyano, substituted or unsubstituted six-membered aryl, and substituted or unsubstituted six-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

the substituents on the above substituted or unsubstituted five-to six-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkoxy C1-6 alkyl, -CO-C1-6 alkyl, -COO-C1-6 alkyl, -O-CO-C1-6 alkyl;

all substituents on the substituted or unsubstituted C1-10 straight or branched chain alkyl groups in the above definitions are selected from: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkoxy, C1-6 alkylamino, -CO-C1-6 alkyl, -COO-C1-6 alkyl, -O-CO-C1-6 alkyl.

2. The compound according to claim 1, characterized in that,

the six-membered aryl is selected from

The six-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S is selected from:

3. the compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I1:

n is an integer from 3 to 8;

R₉₁and R₉₂Independently selected from substituted or unsubstituted C1-10 straight or branched chain alkyl;

4. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I2:

n is an integer from 3 to 8;

k, l are independently selected from integers of 1-8;

R_91’and R_92’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl and-O-CO-C1-4 alkyl.

5. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I3:

n is an integer from 3 to 8;

R₁₁and R₁₂Independently selected from substituted or unsubstituted C1-10 straight or branched chain alkyl;

6. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I4:

n is an integer from 3 to 8;

k, l are independently selected from integers of 1-8;

7. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I5:

n is an integer from 3 to 8;

i, j are independently selected integers from 0-6;

R_11’and R_12’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl and-O-CO-C1-4 alkyl.

8. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I6:

n is an integer from 3 to 8;

k, l are independently selected from integers of 1-8;

i, j are independently selected integers from 0-6;

R_91’and R_92’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

R_11’and R_12’Independently selected from hydroxyl, sulfydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy, C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl.

9. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I7:

n is an integer from 3 to 8;

i, j are independently selected integers from 0-6;

10. The compound of claim 1, wherein said compound is selected from the group consisting of compounds represented by formula I8:

n is an integer from 3 to 8;

k, l are independently selected from integers of 1-8;

i, j are independently selected integers from 0-6;

R_91’and R_92’Independently selected from hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, carbamoyl, halogen, nitro, cyano,C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkoxy C1-4 alkyl, -CO-C1-4 alkyl, -COO-C1-4 alkyl, -O-CO-C1-4 alkyl;

11. A compound according to any one of claims 1 to 10, and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:

12. a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-11 and a pharmaceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11 for the preparation of an anti-neoplastic medicament.

14. The use according to claim 13, wherein said tumor is selected from the group consisting of melanoma, oral epidermoid carcinoma, esophageal carcinoma, gastric carcinoma, lung carcinoma, breast carcinoma, renal carcinoma, liver carcinoma, cervical carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, colon carcinoma, and bladder carcinoma.

15. A process for the preparation of a compound according to any one of claims 1 to 11, and pharmaceutically acceptable salts thereof, characterized in that it comprises the steps of:

wherein R is₁₁、R₁₂、R₉₁、R₉₂I, j, K, l, n are as defined in any one of claims 1 to 11;

16. The method of claim 15, wherein the method comprisesThe condensation reaction reagent is selected from absolute methanol, and the hydrogenation reaction reagent is selected from NaBH₄。

17. The process according to claim 15, wherein the reaction product is purified by silica gel column chromatography, and the mobile phase is eluted sequentially with dichloromethane/ammonia water 100:0.8, dichloromethane/methanol/ammonia water 100:1:0.8, and dichloromethane/methanol/ammonia water 50:1: 0.8.