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CN104177376B - 1-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof - Google Patents

1-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof Download PDF

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CN104177376B
CN104177376B CN201310189078.8A CN201310189078A CN104177376B CN 104177376 B CN104177376 B CN 104177376B CN 201310189078 A CN201310189078 A CN 201310189078A CN 104177376 B CN104177376 B CN 104177376B
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alkyl
unsubstituted
substituted
carboline
alkoxy
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CN104177376A (en
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武嘉林
王子厚
马芹
张国贤
郭亮
范文玺
尚靖
刘利
周凡
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Xinjiang Huashidan Pharmaceutical Research Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

Specifically, the bis β -carboline alkali compound and the medicinal salt thereof are shown in a general formula II, and the bis β -carboline alkali compound is prepared by two molecules of β -carboline-1-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 II, a pharmaceutically acceptable carrier and an 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

1-diamine β -carboline alkali compound, preparation method thereof, pharmaceutical composition thereof and application thereof
Technical Field
The invention relates to 1-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.
Figure BDA00003216980000011
Literature reports of 1-position bridge connected bis β -carboline base
Figure BDA00003216980000021
6-position bridge connected bis β -carboline base reported in literature
Figure BDA00003216980000022
2-position bridge connected bis β -carboline base reported in literature
Figure BDA00003216980000023
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 1-site 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 invention also provides the following technical scheme, namely the 1-site diamine is connected with the bi β -carboline alkali compound and the medicinal salt thereof, as shown in the general formula II,
Figure BDA00003216980000031
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.
f, h are independently selected from integers from 0 to 12; i.e., f, h are independently integers selected from 0,1,2,3,4,5,6,7,8,9,10,11, 12.
Preferably f, h are independently selected from integers from 0 to 10; i.e., f, h are independently integers selected from 0,1,2,3,4,5,6,7,8,9, 10.
More preferably f, h are independently selected from integers of 1 to 8; i.e., f, h are independently integers selected from 1,2,3,4,5,6,7, 8.
Most preferably f, h are independently selected from integers of 1 to 4; i.e., f, h are independently integers selected from 1,2,3, 4.
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
Figure BDA00003216980000041
Preferred six membered heterocyclic groups containing 1 to 4 heteroatoms selected from N, O or S are selected from:
Figure BDA00003216980000042
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 R91And R92Independently selected from substituted or unsubstituted C1-6 straight or branched chain alkyl, substituted or unsubstitutedSubstituted 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 II according to the present invention include, but are not limited to, those of formula II 1:
Figure BDA00003216980000051
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 II according to the present invention include, but are not limited to, those of formula II 2:
Figure BDA00003216980000061
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 preferably f, h are independently selected from integers from 0 to 6; i.e., f, h are independently integers selected from 0,1,2,3,4,5, 6.
More preferred R91’And R92’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.
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: hydroxyl, sulfhydryl, amino, aldehyde group, carboxyl, aminoFormyl, 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 II,
Figure BDA00003216980000091
wherein R is91、R92N is as defined above;
β -carboline-1-carbaldehyde represented by formula 3, β -carboline-1-carbaldehyde represented by formula 4, and diamine NH2(CH2)nNH2Firstly carrying out condensation reaction and then carrying out hydrogenation reaction to prepare the compound shown in the formula II.
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 NaBH3CN, stirring the mixture at room temperature for 4 to 6 hours, and tracking and detecting 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 NaBH3CN。
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
Figure BDA00003216980000121
General synthetic procedure for intermediates 12 a-d:
adding 1-methyl- β -carboline (3.64 g, 20 mmol), DMF (60 ml) and 60% NaH (1.2g, 30mmol) into a 250ml round bottom flask, mixing, stirring at room temperature for 10min, adding corresponding halogenated alkane (30 mmol), stirring at room temperature, TLC tracking detection (developing agent: acetone/petroleum ether ═ 1: 1), after the reaction is finished, pouring the reaction mixture into 100ml ice water, extracting with ethyl acetate (150 ml. times.3), combining organic phases, washing with water, washing with saturated saline, acidifying the organic phase with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, recrystallizing the residue with acetone, filtering to obtain a yellow solid, dissolving the yellow solid in water, alkalifying the saturated solution of sodium bicarbonate, extracting with ethyl acetate (150 ml. times.3), combining the organic phases, washing with water, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, carrying out silica gel column chromatography on the residue, and taking petroleum ether: acetone =4:1 as a mobile phase, thereby obtaining the intermediate 12a-d.
9-isopropyl-1-methyl- β -carboline (12a):
starting from 2-bromo-propane, a white solid was obtained (2.91g, 65%). Mp 135.3-138.1 deg.C ESI-MS M/z 224.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.31(d,J=5.1Hz,1H,ArH);8.12(d,J=7.8Hz,1H,ArH);7.82(d,J=5.1Hz,1H,ArH);7.70(d,J=8.4Hz,1H,ArH);7.51(t,J=8.4Hz,1H,ArH);7.29-7.22(m,1H,ArH);5.62-5.50(m,1H,NCH[CH3]2);3.06(s,3H,CH3);1.76(d,J=7.2Hz,6H,NCH[CH3]2).13C NMR(75MHz,CDCl3):δ141.2,140.0,137.8,135.9,129.1,127.6,122.8,121.8,119.5,113.4,113.0,48.4,25.2,21.7.
9-isobutyl-1-methyl- β -carboline (12b):
starting from 1-bromo-2-methylpropane, a white solid was obtained (3.76g, 79%). Mp 71.8-72.6 deg.C ESI-MSm/z 238.8[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.33(d,J=5.1Hz,1H,ArH);8.11(d,J=7.8Hz,1H,ArH);7.84(d,J=5.1Hz,1H,ArH);7.55(t,J=8.4Hz,1H,ArH);7.46(d,J=8.4Hz,1H,ArH);7.28-7.23(m,1H,ArH);4.36(d,J=7.5Hz,2H,NCH2CH[CH3]2);3.04(s,3H,CH3);2.35-2.20(m,1H,NCH2CH[CH3]2);0.94(d,J=6.6Hz,6H,NCH2CH[CH3]2).13C NMR(75MHz,CDCl3):δ142.1,141.5,138.2,135.5,129.1,128.0,121.5,119.6,113.0,110.6,52.0,31.0,24.2,20.5.
9-hexyl-1-methyl- β -carboline (12c):
starting from 1-bromo-hexane, a white solid was obtained (4.36g, 82%). Mp49.2-52.3 ℃ ESI-MS M/z 266.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.31(d,J=5.1Hz,1H,ArH);8.11(d,J=7.8Hz,1H,ArH);7.83(d,J=5.1Hz,1H,ArH);7.57(t,J=8.4Hz,1H,ArH);7.45(d,J=8.4Hz,1H,ArH);7.29-7.25(m,1H,ArH);4.52(t,J=8.1Hz,2H,NCH2[CH2]4CH3);3.06(s,3H,CH3);1.91-1.77(m,2H,NCH2CH2[CH2]3CH3);1.50-1.23(m,6H,NCH2CH2[CH2]3CH3);0.90(t,J=6.6Hz,3H,NCH2[CH2]4CH3).13C NMR(75MHz,CDCl3):δ141.4,141.2,137.9,135.1,129.0,128.1,121.5,121.3,119.6,113.0,109.7,45.0,31.8,31.0,26.9,23.8,22.9,14.3.
9-octyl-1-methyl- β -carboline (12d):
1-iodo-octane was used as the starting material to give a colorless oil (4.76g,81%), ESI-MS M/z:294.8[ M + H ]]+.1HNMR(300MHz,CDCl3):δ8.31(d,J=5.1Hz,1H,ArH);8.10(d,J=7.8Hz,1H,ArH);7.82(d,J=5.1Hz,1H,ArH);7.57(t,J=8.4Hz,1H,ArH);7.44(d,J=8.4Hz,1H,ArH);7.29-7.22(m,1H,ArH);4.50(t,J=7.8Hz,2H,NCH2[CH2]6CH3);3.05(s,3H,CH3);1.90-1.77(m,2H,NCH2CH2[CH2]5CH3);1.48-1.23(m,10H,NCH2CH2[CH2]5CH3);0.89(t,J=6.6Hz,3H,NCH2[CH2]6CH3).13CNMR(75MHz,CDCl3):δ141.6,141.4,138.1,135.3,129.2,128.2,121.6,121.5,119.7,113.1,109.9,45.2,32.1,31.1,29.6,29.5,27.3,23.9,22.9,14.4.
Preparation example 2
Figure BDA00003216980000141
General synthesis of intermediates 13 a-f:
adding corresponding 1-methyl- β -carboline (15mmol) and 1, 4-dioxane (100ml) into a 250ml round bottom flask, heating and stirring until the mixture is clear, then adding sublimed selenium dioxide (40 mmol), heating and refluxing, tracking and detecting by TLC, immediately filtering to remove the selenium dioxide after the reaction is finished, decompressing and concentrating the filtrate until the filtrate is dry, and carrying out silica gel column chromatography on the residue (ethyl acetate/petroleum ether is 1: 5) to obtain the intermediate 13 a-f.
β -carboline-1-carbaldehyde (13a):
1-methyl- β -carboline is used as a raw material to obtain yellow solid (1.09g, 31%). Mp197.5-199.3 ℃, ESI-MS M/z 294.8[ M + H ]]+.1H NMR(300MHz,CDCl3):δ 10.35(s,1H,CHO);10.06(s,1H,NH);8.64(d,J=5.1Hz,1H,ArH);8.20-8.14(m,2H,ArH);7.67-7.57(m,2H,ArH);7.37(t,J=6.3Hz,1H,ArH).13C NMR(75MHz,CDCl3):δ195.7,141.4,139.7,136.1,135.3,131.7,129.7,122.0,121.3,120.6,119.4,112.2.
9-methyl- β -carboline-1-carbaldehyde (13b):
1, 9-dimethyl- β -carboline is taken as a raw material to obtain yellow solid (1.63g, 52%). Mp130.4-132.4 ℃ ESI-MS M/z 196.8[ M + H ]]+.1H NMR(300MHz,CDCl3):δ10.31(s,1H,CHO);8.62(d,J=4.8Hz,1H,ArH);8.17-8.12(m,2H,ArH);7.67(t,J=8.4Hz,1H,ArH);7.52(d,J=8.4Hz,1H,ArH);4.24(s,3H,NCH3).13C NMR(75MHz,CDCl3):δ193.6,143.1,138.3,137.6,135.9,132.2,129.4,121.3,120.8,120.5,118.5,110.2,34.6.
9-ethyl- β -carboline-1-carbaldehyde (13c):
using 9-ethyl-1-methyl- β -carboline as raw material to obtain yellow solid (1.71g, 51%). Mp58.3-59.9 deg.C, ESI-MS M/z:224.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ10.33(s,1H,CHO);8.64(d,J=4.8Hz,1H,ArH);8.20-8.14(m,2H,ArH);7.67(t,J=7.2Hz,1H,ArH);7.56(d,J=8.1Hz,1H,ArH);7.36(t,J=7.2Hz,1H,ArH);4.98-4.88(m,2H,NCH2CH3);1.43(t,J=6.9Hz,1H,NCH2CH3).13C NMR(75MHz,CDCl3):δ193.9,142.0,138.2,137.5,134.8,132.4,129.4,121.4,120.8,120.8,118.6,110.3,41.9,15.2.
9-isopropyl- β -carboline-1-carbaldehyde (13d):
using 9-isopropyl-1-methyl- β -carboline as raw material to obtain yellow solid (1.89g, 53%). Mp43.3-46.7 deg.C, ESI-MS M/z:238.8[ M + H ]]+.1H NMR(300MHz,CDCl3):δ10.31(s,1H,CHO);8.62(d,J=4.8Hz,1H,ArH);8.18-8.12(m,2H,ArH);7.79(t,J=8.4Hz,1H,ArH);7.60(d,J=7.2Hz,1H,ArH);7.33(t,J=7.2Hz,1H,ArH);5.88-5.72(m,1H,NCH[CH3]2);1.74(d,J=6.9Hz,6H,NCH[CH3]2).13C NMR(75MHz,CDCl3):δ194.1,140.9,138.4,137.8,136.3,132.3,128.7,122.6,121.8,120.6,118.5,114.1,51.4,21.4.
9-hexyl- β -carboline-1-carbaldehyde (13e):
using 9-hexyl-1-methyl- β -carboline as raw material to obtain yellow solid (2.56g, 61%). Mp39.1-42.5 deg.C, ESI-MS M/z 280.9[ M + H ],]+.1H NMR(300MHz,CDCl3):δ10.32(s,1H,CHO);8.63(d,J=4.8Hz,1H,ArH);8.20-8.13(m,2H,ArH);7.66(t,J=8.4Hz,1H,ArH);7.54(d,J=8.4Hz,1H,ArH);7.35(t,J=7.5Hz,1H,ArH);4.86(t,J=7.5Hz,2H,NCH2[CH2]4CH3);1.83-1.71(m,2H,NCH2CH2[CH2]3CH3);1.43-1.21(m,6H,NCH2CH2[CH2]3CH3);0.87(t,J=6.6Hz,3H,NCH2[CH2]4CH3).13C NMR(75MHz,CDCl3):δ193.9,142.5,138.3,137.8,135.2,132.6,129.4,121.5,120.9,120.8,118.7,110.7,47.1,31.8,30.0,26.7,22.9,14.3.
9-octyl- β -carboline-1-carbaldehyde (13f):
using 9-octyl-1-methyl- β -carboline as raw material to obtain yellow solid (2.72g, 59%). Mp45.5-47.4 deg.C, ESI-MS M/z 308.8[ M + H ]]+。1H NMR(300MHz,CDCl3):δ10.32(s,1H,CHO);8.64(d,J=5.1Hz,1H,ArH);8.20-8.14(m,2H,ArH);7.66(t,J=8.4Hz,1H,ArH);7.54(d,J=8.4Hz,1H,ArH);7.36(t,J=7.2Hz,1H,ArH);4.87(t,J=7.5Hz,2H,NCH2[CH2]6CH3);1.83-1.71(m,2H,NCH2CH2[CH2]5CH3);1.43-1.21(m,10H,NCH2CH2[CH2]5CH3);0.87(t,J=6.6Hz,3H,NCH2[CH2]6CH3).13C NMR(75MHz,CDCl3):δ193.9,142.5,138.3,137.8,135.2,132.6,129.4,121.5,120.9,120.8,118.7,110.7,47.1,32.1,30.0,29.7,29.5,27.0,23.0,14.5.
Examples
Example 1
Figure BDA00003216980000161
General synthesis process of 1-position alkylamino bridge connected bis β -carboline base (66-95)
Adding corresponding β -carboline-1-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 reaction residue in anhydrous methanol (30ml), then adding NaBH3CN (5mmol), stirred at room temperature for 4-6 hours, and detected by TLC. After the reaction was completed, concentrated hydrochloric acid (10ml) was carefully added to the reaction solution, and stirred at room temperature for 15 minutes, followed by basification with concentrated sodium hydroxide solution, extraction with methylene chloride (100ml) twice, combination of organic phases, washing with water, washing with saturated saline, and drying with 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 [ (β -carbolin-1-yl) methyl ] butane-1, 4-diamine (66):
β -carboline-1-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily substance (A)0.33g,74.5%),ESI-MS m/z:449.1[M+H]+.1H NMR(300MHz,CDCl3):δ10.25(s,2H),8.31(d,J=6.0Hz,2H),8.09(d,J=7.8Hz,2H,ArH,7.84(d,J=5.4Hz,2H),7.52-7.45(m,4H),7.27-7.22(m,2H),4.35(s,2H),2.77-2.59(m,4H),1.68-1.54(m,4H);13C NMR(75MHz,CDCl3):δ143.51,140.47,137.96,135.07,129.05,128.38,121.87,121.56,119.84,113.96,111.96,54.75,49.86,27.98.
N, N-bis [ (β -carbolin-1-yl) methyl ] pentane-1, 5-diamine (67):
β -carboline-1-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain yellow oily substance (0.36g,77.6%), ESI-MS M/z is 462.9[ M + H ]]+.1H NMR(300MHz,CDCl3)：δ10.37(s,2H),8.32(d,J=5.4Hz,2H),8.07(d,J=7.8Hz,2H),7.82(d,J=5.1Hz,2H),7.52-7.41(m,4H),7.26-7.18(m,2H),4.33(s,2H),2.57(t,J=6.6Hz,4H),1.50-1.38(m,4H),1.33-1.20(m,2H).13C NMR(75MHz,CDCl3)：δ143.59,140.45,137.97,135.09,129.05,128.37,121.86,121.56,119.82,113.93,111.94,54.89,50.00,30.07,25.27.
N, N-bis [ (9-methyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (68):
9-methyl- β -carboline-1-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.30g,65.2%), ESI-MS M/z is 476.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.30(d,J=5.1Hz,2H),8.08(d,J=7.8Hz,2H),7.84(d,J=5.1Hz,2H),7.58(t,J=7.2Hz,2H),7.42(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.38(s,4H),4.18(s,4H),2.88-2.78(m,4H),1.74-1.66(m,4H).13C NMR(75MHz,CDCl3):δ142.86,142.17,137.67,135.63,129.42,128.29,121.38,121.13,119.64,113.91,109.61,54.33,50.30,32.08,28.44.
N, N-bis [ (9-methyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (69):
using 9-methyl- β -carboline-1-formaldehyde and 1, 6-hexanediamine as raw materials to obtain yellow oily substance (0.33g,66.1%), ESI-MS M/z:506.1[ M + H ]]+.1H NMR(300MHz,CDCl3)δ8.31(d,J=5.1Hz,2H),8.06(d,J=7.8Hz,2H),7.83(d,J=5.1Hz,2H),7.56(t,J=8.1Hz,2H),7.40(d,J=8.4Hz,2H),7.27-7.20(m,2H),4.35(s,4H),4.16(s,4H),2.78(t,J=6.9Hz,4H),1.64-1.52(m,4H)，1.43-1.35(m,4H);13CNMR(75MHz,CDCl3)：δ143.10,142.16,137.65,135.65,129.39,128.26,121.38,121.13,119.61,113.90,109.57,54.46,50.45,32.05,30.55,27.72.
N, N-bis [ (9-ethyl- β -carbolin-1-yl) methyl ] propane-1, 3-diamine (70):
9-ethyl- β -carboline-1-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain yellow oily matter (0.28g,56.3%), ESI-MS M/z is 491.1[ M + H [ ]]+.1H NMR(300MHz,CDCl3):δ8.27(d,J=5.4Hz,2H),8.05(d,J=7.5Hz,2H),7.81(d,J=5.1Hz,2H),7.53(t,J=7.5Hz,2H),7.37(d,J=8.4Hz,2H),7.26-7.18(m,2H),4.65-4.52(m,4H),4.37(s,4H),2.97(t,J=6.6Hz,4H),1.97-1.86(m,2H),1.41(t,J=7.2Hz,6H);13C NMR(75MHz,CDCl3):δ141.65,141.36,137.62,134.62,129.92,128.49,121.61,121.53,119.85,114.13,109.81,53.84,48.96,40.00,29.98,16.10.
N, N-bis [ (9-ethyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (71):
9-ethyl- β -carboline-1-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.28g,55.1%), ESI-MS M/z is 504.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.29(d,J=5.4Hz,2H),8.03(d,J=7.5Hz,2H),7.78(d,J=5.4Hz,2H),7.53(t,J=7.8Hz,2H),7.39(d,J=8.1Hz,2H),7.27-7.18(m,2H),4.68-4.53(m,4H),4.32(s,4H),2.88-2.80(m,4H),1.75-1.66(m,4H),1.41(t,J=6.9Hz,6H);13C NMR(75MHz,CDCl3)δ142.14,141.33,137.65,134.67,129.84,128.42,121.56,119.78,114.04,109.78,54.20,50.30,39.95,28.42,16.10.
N, N-bis [ (9-isopropyl- β -carbolin-1-yl) methyl ] propane-1, 3-diamine (72):
9-isopropyl- β -carboline-1-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain yellow oily matter (0.28g,53.1%), ESI-MS M/z is 518.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.26(d,J=5.1Hz,2H),8.12(d,J=7.8Hz,2H),7.87(d,J=5.1Hz,2H),7.63(d,J=8.4Hz,2H),7.48(t,J=8.4Hz,2H),7.25-7.20(m,2H),5.68-5.57(m,2H),4.04(s,4H),2.75-2.66(m,4H),1.80-1.70(m,2H),1.52(d,J=7.2Hz,12H);13C NMR(75MHz,CDCl3):δ141.47,139.94,137.05,136.36,129.71,127.61,122.72,121.60,119.34,114.07,113.48,61.73,52.57,48.44,23.94,21.60.
N, N-bis [ (9-isopropyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (73):
9-isopropyl- β -carboline-1-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain yellow oily matter (0.50g,89.2%), ESI-MS M/z is 560.9[ M + H [ ]]+.1H NMR(300MHz,CDCl3)：δ8.31(d,J=5.4Hz,2H),8.12(d,J=7.8Hz,2H),7.86(d,J=5.1Hz,2H),7.70(d,J=8.7Hz,2H),7.51(t,J=8.4Hz,2H),7.28-7.20(m,2H),5.74-5.62(m,2H),4.31(s,4H),2.78(t,J=6.9Hz,2H),1.73(d,J=6.9Hz,12H),1.63-1.52(m,4H),1.45-1.38(m,4H);13CNMR(75MHz,CDCl3):δ142.74,140.06,137.50,135.80,129.63,127.61,122.91,121.67,119.42,113.79,113.48,55.94,50.46,48.81,30.60,27.78,21.78.
N, N-bis [ (9-butyl- β -carbolin-1-yl) methyl ] propane-1, 3-diamine (74):
using 9-butyl- β -carboline-1-formaldehyde and 1, 3-propane diamine as raw materials to obtain yellow oily substance (0.26g,48.2%), ESI-MS M/z:546.9[ M + H ])]+.1H NMR(300MHz,CDCl3):δ8.31(d,J=5.1Hz,2H),8.10(d,J=7.8Hz,2H),7.87(d,J=5.1Hz,2H),7.55(t,J=7.8Hz,2H),7.47(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.56(t,J=7.8Hz,2H),4.33(s,4H),2.92(t,J=6.6Hz,4H),1.90-1.78(m,6H),1.51-1.37(m,4H),0.97(t,J=7.2Hz,6H);13C NMR(75MHz,CDCl3):δ142.57,141.72,137.70,134.93,129.75,128.31,121.54,121.43,119.70,114.05,109.99,54.73,49.05,45.08,33.29,30.97,20.77,14.38.
N, N-bis [ (9-butyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (75):
using 9-butyl- β -carboline-1-formaldehyde and 1, 4-butanediamine as raw materials to obtain yellow oily substance (0.33g,59.3%), ESI-MS M/z:560.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.29(d,J=5.1Hz,2H),8.07(d,J=7.8Hz,2H),7.82(d,J=5.1Hz,2H),7.56(t,J=7.2Hz,2H),7.44(d,J=8.4Hz,2H),7.26-7.21(m,2H),4.56(t,J=7.2Hz,2H),4.34(s,4H),2.90-2.82(m,4H),1.87-1.78(m,4H),1.77-1.67(m,4H),1.52-1.37(m,4H),0.98(t,J=6.9Hz,6H).13C NMR(75MHz,CDCl3):δ141.99,141.68,137.59,134.75,129.70,128.30,121.45,121.35,119.69,113.95,109.94,54.11,50.31,45.07,33.18,28.47,20.67,14.31.
N, N-bis [ (9-butyl- β -carbolin-1-yl) methyl ] pentane-1, 5-diamine (76):
9-butyl- β -carboline-1-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain yellow oily substance (0.37g,64.2%), ESI-MS M/z is 575.1[ M + H [ ]]+.1H NMR(300MHz,CDCl3)：δ8.34(d,J=5.1Hz,2H),8.10(d,J=7.8Hz,2H),7.88(d,J=5.1Hz,2H),7.57(t,J=7.5Hz,2H),7.44(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.60(t,J=8.1Hz,4H),4.33(s,4H),2.81(t,J=6.9Hz,4H),1.91-1.79(m,4H),1.70-1.56(m,4H),1.54-1.40(m,6H),1.00(t,J=7.2Hz,6H);13C NMR(75MHz,CDCl3):δ142.64,141.80,137.72,134.97,129.83,128.31,121.52,119.70,114.00,109.98,54.54,50.52,45.15,33.26,30.52,25.66,20.74,14.32.
N, N-bis [ (9-butyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (77):
9-butyl- β -carboline-1-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain yellow oily matter (0.40g,67.8%), ESI-MS M/z is 590.2[ M + H [ ]]+.1H NMR(300MHz,CDCl3)：δ8.34(d,J=5.1Hz,2H),8.11(d,J=7.8Hz,2H),7.88(d,J=5.1Hz,2H),7.57(t,J=7.5Hz,2H),7.46(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.61(t,J=7.5Hz,4H),4.32(s,4H),2.79(t,J=6.9Hz,4H),1.90-1.79(m,4H),1.66-1.54(m,4H),1.54-1.37(m,8H),1.00(t,J=7.5Hz,6H);13C NMR(75MHz,CDCl3):δ142.75,141.73,137.71,134.96,129.75,128.28,121.51,121.46,119.67,113.99,109.95,54.71,50.60,45.11,33.27,30.64,27.80,20.76,14.37.
N, N-bis [ (9-isobutyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (78):
using 9-isobutyl- β -carboline-1-formaldehyde and 1, 4-butanediamine as raw materials to obtain yellow oily substance (0.42g,74.3%), ESI-MS M/z:562.1[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.32(d,J=5.1Hz,2H),8.08(d,J=7.8Hz,2H),7.86(d,J=4.8Hz,2H),7.53(t,J=7.2Hz,2H),7.46(d,J=8.4Hz,2H),7.28-7.20(m,2H),4.39(d,J=7.5Hz,2H),4.33(s,4H),2.86-2.79(m,4H),2.32-2.17(m,2H),1.30-1.24(m,4H),0.93(d,J=6.6Hz,12H);13C NMR(75MHz,CDCl3):δ142.43,142.24,137.72,135.01,129.80,128.12,121.36,121.21,119.62,113.89,110.71,54.22,52.09,50.30,30.99,28.47,20.68.
N, N-bis [ (9-isobutyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (79):
using 9-isobutyl- β -carboline-1-formaldehyde and 1, 6-hexamethylene diamine as raw materials to obtain yellow oily matter (0.46g,77.8%), ESI-MS M/z:588.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.36(d,J=5.4Hz,2H),8.10(d,J=7.8Hz,2H),7.89(d,J=5.1Hz,2H),7.55(t,J=7.8Hz,2H),7.47(d,J=8.4Hz,2H),7.28-7.22(m,2H),4.42(d,J=7.5Hz,2H),4.33(s,4H),2.78(t,J=6.9Hz,4H),2.34-2.22(m,2H),1.66-1.53(m,4H),1.46-1.36(m,4H),0.95(d,J=6.6Hz,12H);13C NMR(75MHz,CDCl3):δ142.23,141.32,137.59,134.88,129.88,128.22,121.36,121.11,119.70,114.01,110.69,53.51,52.10,50.11,30.93,29.88,27.41,20.63.
N, N-bis [ (9-hexyl- β -carbolin-1-yl) methyl ] propane-1, 3-diamine (80):
using 9-hexyl- β -carboline-1-formaldehyde and 1, 3-propane diamine as raw materials to obtain yellow oily substance (0.43g,71.5%), ESI-MS M/z:603.0[ M + H ]]+.1H NMR(300MHz,CDCl3)δ8.31(d,J=5.1Hz,2H),8.10(d,J=7.8Hz,2H),7.86(d,J=5.4Hz,2H),7.56(t,J=7.5Hz,2H),7.40(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.54(t,J=7.8Hz,4H),4.32(s,4H),2.92(t,J=6.9Hz,4H),1.92-1.76(m,6H),1.48-1.21(m,12H),0.87(t,J=6.6Hz,6H);13C NMR(75MHz,CDCl3):δ137.89,137.01,132.96,130.21,125.05,123.56,116.79,114.95,109.26,105.24,49.94,44.25,40.61,27.19,26.40,26.26,22.38,18.21,9.64.
N, N-bis [ (9-hexyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (81):
9-hexyl- β -carboline-1-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.46g,74.7%), ESI-MS M/z is 616.9[ M + H]+.1H NMR(300MHz,CDCl3):δ8.33(d,J=5.4Hz,2H),8.10(d,J=7.8Hz,2H),7.87(d,J=5.1Hz,2H),7.55(t,J=7.2Hz,2H),7.43(d,J=8.4Hz,2H),7.28-7.22(m,2H),4.57(t,J=8.1Hz,4H),4.32(s,4H),2.88-2.79(m,4H),1.91-1.78(m,4H),1.73-1.63(m,4H),1.51-1.24(m,12H),0.89(t,J=6.6Hz,6H);13C NMR(75MHz,CDCl3):δ142.65,141.71,137.71,134.94,129.76,128.31,121.54,121.45,119.69,114.04,109.96,54.66,50.54,45.35,31.95,31.17,28.58,27.14,23.00,14.45.
N, N-bis [ (9-hexyl- β -carbolin-1-yl) methyl ] pentane-1, 5-diamine (82):
using 9-hexyl- β -carboline-1-formaldehyde and 1, 5-pentanediamine as raw materials to obtain yellow oily substance (0.40,70.5%), ESI-MS M/z:632.3[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.1Hz,2H),8.11(d,J=7.8Hz,2H),7.88(d,J=5.4Hz,2H),7.57(t,J=7.2Hz,2H),7.44(d,J=8.4Hz,2H),7.28-7.24(m,2H),4.59(t,J=7.8Hz,4H),4.32(s,4H),2.81(t,J=6.6Hz,4H),1.92-1.79(m,4H),1.68-1.55(m,4H),1.53-1.25(m,14H),0.90(t,J=6.6Hz,6H);13C NMR(75MHz,CDCl3):δ142.69,141.68,137.69,134.92,129.72,128.28,121.51,121.44,119.66,113.99,109.91,54.68,50.60,45.33,31.94,31.13,30.63,27.13,25.73,23.00,14.46.
N, N-bis [ (9-hexyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (83):
9-hexyl- β -carboline-1-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain yellow oily matter (0.53g,81.6 percent), ESI-MS M/z is 645.3[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.4Hz,2H),8.10(d,J=7.8Hz,2H),7.87(d,J=5.4Hz,2H),7.57(t,J=7.8Hz,2H),7.45(d,J=8.1Hz,2H),7.2-7.22(m,2H),4.60(t,J=8.4Hz,4H),4.32(s,4H),2.80(t,J=6.9Hz,4H),1.92-1.80(m,4H),1.66-1.54(m,4H),1.53-1.28(m,16H),0.90(t,J=6.9Hz,6H)；13C NMR(75MHz,CDCl3)：δ141.65,137.54,134.74,129.76,128.34,121.47,121.32,119.72,114.04,109.90,53.91,50.33,45.33,31.87,31.07,30.16,27.59,27.04,22.93,14.39.
N, N-bis [ (9-octyl- β -carbolin-1-yl) methyl ] butane-1, 4-diamine (84):
9-octyl- β -carboline-1-formaldehyde and 1, 4-butanediamine are taken as raw materials to obtain yellow oily matter (0.41g,61.3 percent), ESI-MS M/z is 672.9[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.33(d,J=5.1Hz,2H),8.07(d,J=7.8Hz,2H),7.84(d,J=5.1Hz,2H),7.55(t,J=7.8Hz,2H),7.41(d,J=8.4Hz,2H),7.26-7.20(m,2H),4.55(t,J=7.8Hz,4H),4.33(s,4H),2.89-2.81(m,4H),1.90-1.77(m,4H),1.74-1.65(m,4H),1.48-1.20(m,10H),0.88(t,J=5.4Hz);13C NMR(75MHz,CDCl3):δ142.49,141.68,137.66,134.88,129.71,128.26,121.47,119.66,113.94,109.91,54.50,50.48,45.31,32.13,31.15,29.73,29.58,28.55,27.43,23.00,14.53.
N, N-bis [ (9-octyl- β -carbolin-1-yl) methyl ] pentane-1, 5-diamine (85):
9-octyl- β -carboline-1-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain yellow oily matter (0.46g,66.4%), ESI-MS M/z is 686.9[ M + H [ ]]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.1Hz,2H),8.10(d,J=7.8Hz,2H),7.88(d,J=5.1Hz,2H),7.57(t,J=8.1Hz,2H),7.44(d,J=8.4Hz,2H),7.29-7.22(m,2H),4.59(t,J=7.8Hz,4H),4.33(s,4H),2.81(t,J=6.9Hz,4H),1.92-1.80(m,4H),1.68-1.55(m,4H),1.54-1.20(m,22H),0.88(t,J=6.0Hz,6H);13C NMR(75MHz,CDCl3):δ142.68,141.78,137.73,134.98,129.80,128.29,121.51,119.68,113.96,109.96,54.61,50.54,45.39,32.13,31.17,30.57,29.75,29.57,27.47,25.69,22.97,14.44.
N, N-bis [ (9-benzyl- β -carbolin-1-yl) methyl ] propane-1, 3-diamine (86):
9-benzyl- β -carboline-1-formaldehyde and 1, 3-propane diamine are used as raw materials to obtain yellow oily matter (0.30g,49.2%), ESI-MS M/z is 614.9[ M + H]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.1Hz,2H),8.16(d,J=7.8Hz,2H),7.93(d,J=5.1Hz,2H),7.52(t,J=7.5Hz,2H),7.36-7.14(m,10H),6.94(d,J=6.0Hz,4H),5.94(s,4H),4.07(s,4H),2.74(t,J=6.6Hz,4H),1.74-1.62(m,2H);13C NMR(75MHz,CDCl3):δ143.02,142.23,138.83,138.18,135.83,129.15,128.71,127.43,125.39,121.61,120.21,114.25,110.17,54.61,48.77,48.49,30.75.
N, N-bis [ (9-benzyl- β -carbolin-1-yl) methyl ] hexane-1, 6-diamine (87):
9-benzyl- β -carboline-1-formaldehyde and 1, 6-hexamethylene diamine are used as raw materials to obtain yellow oily matter (0.49g,75.4%), ESI-MS M/z is 656.8[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.38(d,J=5.1Hz,2H),8.16(d,J=7.8Hz,2H),7.94(d,J=5.1Hz,2H),7.53(t,J=8.1Hz,2H),7.38-7.19(m,10H),6.98(d,J=6.6Hz,4H),6.00(s,4H),4.08(s,4H),2.66(t,J=6.9Hz,4H),1.54-1.43(m,4H),1.37-1.30(m,4H);13C NMR(75MHz,CDCl3):δ143.17,142.26,138.90,138.24,135.87,129.96,129.18,128.72,127.46,125.44,121.63,120.24,114.23,110.16,54.54,50.37,48.58,30.53,27.74.
N, N-bis [ [9- (4-fluorobenzyl) - β -carbolin-1-yl ] methyl ] propane-1, 3-diamine (88):
using 9- (4-fluorobenzyl) - β -carboline-1-formaldehyde and 1, 3-propane diamine as raw materials to obtain yellow oily substance (0.35g,53.1%), ESI-MS M/z:650.9[ M + H ]/[]+.1H NMR(300MHz,CDCl3):δ8.29(d,J=5.1Hz,2H),8.14(d,J=7.8Hz,2H),7.90(d,J=5.1Hz,2H),7.52(t,J=7.2Hz,2H),7.31-7.25(m,4H),6.97-6.87(m,8H),5.87(s,4H),4.11(s,4H),2.79(t,J=6.3Hz,4H),1.79-1.67(m,2H);13C NMR(75MHz,CDCl3):δ163.66,160.41,142.90,142.01,138.28,135.66,134.51,129.97,128.74,127.07,126.97,121.62,120.31,116.19,115.90,114.21,110.01,54.53,48.08,47.92,40.67,33.96.
N, N-bis [ [9- (4-fluorobenzyl) - β -carbolin-1-yl ] methyl ] butane-1, 4-diamine (89):
using 9- (4-fluorobenzyl) - β -carboline-1-formaldehyde and 1, 4-butanediamine as raw materials to obtain yellow oily substance (0.42g,62.9%), ESI-MS M/z:665.9[ M + H ])]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.1Hz,2H),8.14(d,J=7.8Hz,2H),7.91(d,J=5.1Hz,2H),7.53(t,J=7.2Hz,2H),7.34-7.25(m,4H),6.92(d,J=7.2Hz,8H),5.92(s,4H),4.07(s,4H),2.72-2.66(m,4H),1.60-1.54(m,4H);.13C NMR(75MHz,CDCl3):δ163.71,160.46,142.56,142.07,138.29,135.61,134.44,130.06,128.82,127.10,127.00,126.78,121.67,121.57,120.37,120.20,116.23,115.95,114.28,110.04,54.25,50.18,47.96,28.40.
N, N-bis [ [9- (3-chlorobenzyl) - β -carbolin-1-yl ] methyl ] propane-1, 3-diamine (90):
using 9- (3-chlorobenzyl) - β -carboline-1-formaldehyde and 1, 3-propane diamine as raw materials to obtain yellow oily substance (0.35g,51.1%), ESI-MS M/z:684.6[ M + H ]/[]+.1H NMR(300MHz,CDCl3):δ8.34(d,J=5.1Hz,2H),8.13(d,J=7.8Hz,2H),7.91(d,J=5.1Hz,2H),7.51(t,J=8.1Hz,2H),7.32-7.24(m,4H),7.19-7.06(m,4H),7.00(s,2H),6.87(d,J=7.5Hz,2H),5.92(s,4H),4.07(s,4H),2.77(t,J=6.6Hz,4H),1.74-1.64(m,2H);13C NMR(75MHz,CDCl3):δ142.75,142.05,141.17,138.35,135.78,135.14,130.50,130.10,128.88,127.73,125.67,123.68,121.72,121.62,120.48,114.36,110.03,54.54,48.76,48.17,30.54.
N, N-bis [ [9- (3-chlorobenzyl) - β -carbolin-1-yl ] methyl ] pentane-1, 5-diamine (91):
using 9- (3-chlorobenzyl) - β -carboline-1-formaldehyde and 1, 5-pentanediamine as raw materials to obtain yellow oil (0.37g,52.6%), ESI-MS M/z:710.5[ M + H ]]+.1H NMR(300MHz,CDCl3):δ8.38(d,J=5.1Hz,2H),8.16(d,J=7.8Hz,2H),7.95(d,J=5.1Hz,2H),7.50(t,J=7.2Hz,2H),7.34-7.24(m,4H),7.20-7.13(m,4H),7.03(s,2H),6.84(d,J=6.3Hz,2H),6.00(s,4H),4.05(s,4H),2.67(t,J=6.6Hz,4H),1.55-1.25(m,6H);13C NMR(75MHz,CDCl3)：δ143.08,142.09,141.21,138.44,135.19,130.46,130.12,128.81,127.72,125.69,123.64,121.69,120.43,114.27,110.00,54.76,50.33,48.25,30.47,25.61.
N, N-bis [ [9- (3-phenylpropyl) - β -carbolin-1-yl ] methyl ] propane-1, 3-diamine (92):
9- (3-phenylpropyl) - β -carboline-1-formaldehyde and 1, 3-propanediamine are used as raw materials to obtain yellow oily matter (0.33g,49.7 percent), ESI-MS M/z is 670.7[ M + H ])]+.1H NMR(300MHz,CDCl3):δ8.30(d,J=5.1Hz,2H),8.09(d,J=7.5Hz,2H),7.85(d,J=5.1Hz,2H),7.52(t,J=8.1Hz,2H),7.30-7.12(m,14H),4.57(t,J=8.1Hz,4H),4.19(s,4H),2.78-2.67(m,8H),2.20-2.08(m,4H),1.83-1.68(m,2H);13C NMR(75MHz,CDCl3):δ142.77,141.68,140.98,137.81,134.99,129.85,128.77,128.60,128.36,126.48,121.58,119.81,114.05,109.97,54.81,48.77,44.74,33.62,32.31,31.03.
N, N-bis [ [9- (3-phenylpropyl) - β -carbolin-1-yl ] methyl ] butane-1, 4-diamine (93):
9- (3-phenylpropyl) - β -carboline-1-formaldehyde and 1, 4-butanediamine are used as raw materials to obtain yellow oily matter (0.38g,56.2%), ESI-MS M/z:685.1[ M + H ])]+.1H NMR(300MHz,CDCl3):δ8.70(s,2H),8.11(d,J=7.8Hz,2H),7.95(s,2H),7.52(t,J=6.9Hz,2H),7.36-7.12(m,14H),4.34(t,J=7.2Hz,4H),4.08(s,4H),2.79-2.67(m,8H),2.29-2.17(m,4H),1.70-1.64(m,4H);13C NMR(75MHz,CDCl3):δ149.04,141.60,140.78,135.70,131.49,131.39,129.34,128.75,128.41,126.44,122.17,121.36,119.66,113.29,109.60,56.01,49.96,43.02,33.53,30.59,28.50.
N, N-bis [ [9- (3-phenylpropyl) - β -carbolin-1-yl ] methyl ] pentane-1, 5-diamine (94):
9- (3-phenylpropyl) - β -carboline-1-formaldehyde and 1, 5-pentanediamine are used as raw materials to obtain yellow oily matter (0.40g,57.1 percent), ESI-MS M/z is 698.7[ M + H ]/z]+.1H NMR(300MHz,CDCl3):δ8.33(d,J=5.1Hz,2H),8.09(d,J=7.8Hz,2H),7.87(d,J=5.4Hz,2H),7.54(t,J=7.2Hz,2H),7.34-7.17(m,14H),4.62(t,J=8.1Hz,4H),4.21(s,4H),2.78(t,J=7.5Hz,4H),2.67(t,J=6.9Hz,4H),2.25-2.12(m,4H),1.62-1.50(m,4H),1.47-1.38(m,2H);13CNMR(75MHz,CDCl3):δ142.76,141.75,140.96,137.82,135.01,129.92,128.75,128.56,128.34,126.46,121.54,119.80,113.98,109.93,54.59,50.31,44.82,33.63,32.28,30.52,25.60.
N, N-bis [ [9- (3-phenylpropyl) - β -carbolin-1-yl ] methyl ] hexane-1, 6-diamine (95):
9- (3-phenylpropyl) - β -carboline-1-formaldehyde and 1, 6-hexanediamine are used as raw materials to obtain yellow oily matter (0.47g,65.6%), ESI-MS M/z:712.7[ M + H ])]+.1H NMR(300MHz,CDCl3):δ8.33(d,J=5.1Hz,2H),8.09(d,J=7.8Hz,2H),7.86(d,J=5.1Hz,2H),7.54(t,J=8.1Hz,2H),7.36-7.16(m,14H),4.63(t,J=8.1Hz,4H),4.21(s,4H),2.79(t,J=7.2Hz,4H),2.67(t,J=6.9Hz,4H),2.26-2.13(m,4H),1.58-1.48(m,4H),1.42-1.33(m,4H);13CNMR(75MHz,CDCl3):δ142.68,141.72,140.97,137.80,134.99,129.90,128.78,128.59,128.38,126.49,121.58,119.83,114.04,109.95,54.60,50.39,44.82,33.65,32.32,30.58,27.78.
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 concentration of one/ml, placing at 37 deg.C and containing 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
Figure BDA00003216980000261
Figure BDA00003216980000271
Experimental example 2 acute toxicity test in mice
Kunming mice (provided by Xinjiang experimental animal research center, the qualification number is SCXK 2011-one 0001, the weight is 19-20g, half of each mouse is female and male, each 10 mice form a 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-grade 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 assistance in the experiment, and then the drugs are gradually addedGradually adding 0.5% CMC-Na solution to the required concentration. The experimental volume was 0.5ml/20g mouse. A single intraperitoneal administration is adopted. The Kunming mice are taken and randomly grouped according to sex, each group is respectively administrated in the abdominal cavity according to the dosage setting, and the instant reaction of the mice after administration is observed. Dead animals were observed dissectively, surviving animals were observed for two additional weeks, and animal deaths were recorded for two weeks. After two weeks, the surviving animals were dissected and the parenchymal organ was observed for pathological 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
Figure BDA00003216980000281

Claims (11)

1. A bi β -carboline alkali compound shown in a general formula II and a medicinal salt thereof,
Figure FDA0002293638270000011
n is an integer from 2 to 14;
f, h are independently selected from integers from 0 to 12;
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 five-six-membered aryl, and substituted or unsubstituted five-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 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
Figure FDA0002293638270000021
The six-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S is selected from:
Figure FDA0002293638270000022
3. the compound of claim 1 and pharmaceutically acceptable salts thereof, wherein said compound is selected from the group consisting of compounds represented by formula II 2:
Figure FDA0002293638270000023
n is an integer from 3 to 8;
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.
4. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein said compound is selected from the group consisting of compounds represented by formula II 2:
Figure FDA0002293638270000024
n is an integer from 3 to 8;
f, h are independently selected from integers from 0 to 6;
R91’and R92’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 according to any one of claims 1 to 4, characterized in that it is selected from the group consisting of:
Figure FDA0002293638270000031
Figure FDA0002293638270000041
Figure FDA0002293638270000051
Figure FDA0002293638270000061
Figure FDA0002293638270000071
6. a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-5 and a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 5 for the preparation of an anti-neoplastic medicament.
8. The use according to claim 7, 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.
9. A process for the preparation of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof, comprising the steps of:
Figure FDA0002293638270000072
Figure FDA0002293638270000081
wherein R is91、R92N, f, h are as defined in any one of claims 1 to 5;
β -carboline-1-carbaldehyde represented by formula 3, β -carboline-1-carbaldehyde represented by formula 4, and diamine NH2(CH2)nNH2Firstly carrying out condensation reaction and then carrying out hydrogenation reaction to prepare the compound shown in the formula II.
10. The process according to claim 9, wherein the condensation reagent is selected from the group consisting of absolute methanol and the hydrogenation reagent is selected from the group consisting of NaBH3CN。
11. The process according to claim 9, 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.
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