CN109748917A - Ellipticine derivative, its pharmaceutical composition and its preparation method and application - Google Patents
Ellipticine derivative, its pharmaceutical composition and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to formula (I, II, III, IV) ellipticine derivative or its pharmaceutically acceptable salts, the derivative has excellent anti-tumor activity, Small side effects, toxicity is low and/or solubility is high in water, they can be used as antitumor agent and antivirotic, and the present invention relates to such compound and preparation method thereof, pharmaceutical composition and purposes.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a new class of ellipticine derivative contains their drug
Composition, and its preparing the purposes in antitumor and antiviral drugs.
Background technique
In the late three decades, it although the various diagnosing and treating levels of tumour have obvious progress, worldwide, swells
The morbidity and mortality of tumor are still constantly increasing.It is predicted according to the World Health Organization (WHO), arrives the year two thousand twenty, the hair of global tumour
Patient's number will increase to 20,000,000, and death toll is up to 12,000,000[1].2015, global 8,200,000 people died of cancer, wherein China
2800000.China has 7500 people to die of cancer daily now.China is because of number of cancer deaths, the first in the world.In China, cancer
Illness rate is 280/100000ths, and the trend of rapid growth year by year is presented[2].The main biological property of malignant tumour be invasion and
Transfer, is the Major Clinical cause of death of tumour patient, accounts for the 83% of tumor mortality number.Therefore, the prevention and treatment of tumour
One of great difficult problem as current disease treatment field.
In recent years, chemotherapy of tumors achieved comparable progress, and tumor patient life span is obviously prolonged, especially dialogue
The treatment of blood disease, malignant lymphoma etc. has a breakthrough, but to endanger human life and health most serious, account for malignant tumour 90% with
On solid tumor treatment fail to achieve the effect that it is satisfied[3].Pharmacy man and oncologist more and more profoundly recognize: mentioning
The curative effect of high oncotherapy, it is necessary to set about from the mechanism of tumor development, new breakthrough progress could be obtained.In recent years,
The development of molecular weight tumor, molecular pharmacology illustrates that tumour essence gradually；Extensive quickly screening, combinatorial chemistry, base
Because the invention and application of the advanced technologies such as engineering accelerate drug development process；The research and development of anti-tumor drug have entered one
A brand-new epoch.The development strategy of current anti-tumor drug has the following: 1. to account for the entity of 90% or more malignant tumour
Tumor is main attack object；2. finding active constituent from natural products；3. being directed to the mechanism of tumor development, new molecule is found
Act on (enzyme, receptor, gene) target spot；4. extensive quickly screening；5. the importing and application of new technology: combinatorial chemistry, structure are raw
Object, CAD, genetic engineering, DNA chip, pharmacogenomics (functional genomics is in conjunction with pharmacology)
Deng[4]。
For anti-tumor drug just from traditional cytotoxic drug, what is acted on to the too many levels for tumour mechanism is novel anti-swollen
Tumor medicine development, the novel targets for the antitumor action paid close attention to both at home and abroad at present and corresponding new antitumoral agent or means have: 1.
Using cellular signal transduction molecule as target spot: logical including kinases inhibitor, farnesyl transferase inhibitor, MAPK signal transduction
Road inhibitor, cell cycle regulating agent etc.；2. using new vessels as target spot: angiogensis inhibitor；3. reducing cancer cell
It falls off, adhere to and basement membrane degradation: medicine for treating tumor metastasis；4. using Telomerase as target spot: telomerase inhibitor；5. thin for tumour
Born of the same parents' drug resistance: reversal agent of drug resistance；6. malignant cell is promoted to break up to maturation: differentiating inducer；7. specific killing cancer cell:
(antibody or toxin) targeted therapy；8. enhancing the curative effect of radiation and chemotherapy: oncotherapy sensitizer；9. improving or adjusting body to exempt from
Epidemic disease function: biological response modifiers；10. the immunization therapy of tumour: monoclonal antibody drug PD-1 and PD- more popular at present
The treatment such as L1[5]。
In recent years, anti-cancer active compound is found from natural products has become the exploitation hot spot of anticancer drug, preceding 20
Nian Jian, the whole world release Medicine small molecule new chemical entities in, have 61% natural products can be traced.Natural products is certain
Therapy field occurrence rate is very high: 78% antimicrobial compound and 74% antitumoral compounds are all natural products, or from certain
A natural products is derived, in practice it has proved that, unique effect of the natural products in anticancer drug discovery causes height weight again
Depending on.There are resistance problems in the chemotherapeutics of traditional treatment tumour, especially tumor stem cell is more insensitive.Chinese herbal medicine for preventing is vast
Profound, high-efficiency low-toxicity is therefrom possible to filter out and efficiently kills tumor stem cell, to treat the drug of malignant tumour.
Ellipticine (Ellipticine, 1) is naturally present in apocynaceae plant ellipse roserush (Ochrosia
Elliptica Labill.) leaf, barlan roserush (O.balansae) and Mohs roserush (O.moorei) bark and leaf
In.The colleagues of American Studies person Goodwin and he[1]It takes the lead in separating and having determined the structure of ellipticine, the same year in nineteen fifty-nine
Woodward etc.[2]The fully synthetic of ellipticine is realized for the first time, and hereafter many researchers have carried out ellipticine and its derivative
Fully synthetic research work.Experiments have shown that ellipticine to many tumour cells for example leukaemia, melanoma, sarcoma, lymthoma,
The tumour cells such as colon cancer, lung cancer, breast cancer, brain tumor, osteosarcoma, neuroblastoma have growth inhibition effect, half
Inhibition concentration (IC50) 10-10To 10-6mol·L-1.Contain 3 coplanar hexatomic rings and one in the molecule of ellipticine
Five-membered ring is one of the simplest natural alkaloid of structure (Fig. 1).Clinical research was carried out in France for the first time from 1977, later
Europe, U.S.'s ellipticine derivative (9- hydroxy-n2Methyl ellipticine, NSC264-137,2, Fig. 1) it spouts and has gone repeatedly
Clinical I phase, II phase anticancer test.Drug of this medicine in France's registration as treatment breast cancer, most patients are weekly administration
100mg/m2, intravenous drip 1 hour or more, this dose was equivalent to weekly administration 2.5mg/kg.It is various to have 600 many cases in total
Malignant tumor patient receives the treatment of NSC264-137, preferable to breast cancer curative effect, and especially this medicine and adriamycin is without intersecting
Drug resistance can be used for the end-stage patients of other treatment failure.Afterwards because two patients continuous use 15 months and 18 months after because
Renal failure death in addition its with mutagenesis terminate clinical research[3-4]。
Chinese Patent Application No. 85107911 discloses the production method of a kind of ellipticine derivative；Chinese patent application
Numbers 94101690.0 report the purposes of a kind of 9- hydroxyl ellipticine ester derivant and the preparation method of these derivatives.
For the Anticancer Effect and Mechanism of ellipticine, what is received significant attention mainly has the following: (1) being used as structure
Analog is inserted into DNA complementation double-spiral structure, inhibits DNA replication dna transcription；(2) inhibit the activity of DNA topoisomerase II；
(3) inhibit the oxidation of cytochrome P 450 enzymes.Many people have made correlative study, Vann etc. to this[22]It has synthesized 5- and has gone first
Base -6-N- methyl ellipticine finds that the analog derivative has significant topoisomerase II α inhibitory activity；Kotrbova[23]Recognize
It is ellipticine in Cytochrome P450 and cytochrome b for its antitumor mechanism5Oxidation under to form oxidation product special
It is not 13- hydroxyl ellipticine, the ellipticine-DNA adduct formed in conjunction with DNA and damage dna.Amrita[24]It was found that
Ellipticine can realize anti-tumor activity in this, as intramolecular target in conjunction with the histidine in nuclear chromatin.
Summary of the invention
The technical problem to be solved by the present invention is to provide new class ellipticine derivative and its pharmaceutically acceptable salts, spread out
The preparation method of biology, purposes of the pharmaceutical composition in antitumor and antiviral drugs.
To solve technical problem of the invention, the invention provides the following technical scheme:
There is provided ellipticines shown in general formula (I, II, III, IV) to spread out for the first aspect of technical solution of the present invention
Biology and its pharmaceutically acceptable salt:
Wherein:
R is hydrogen or C1-4Alkyl, C substituted or unsubstituted1-4Alkoxy, benzyloxy, halogen etc.；
R1For hydrogen, C1-4Alkyl, aryl；
R2For hydrogen, OH, OCH3, formoxyl, nitro, halogen.
It is further: C1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, fluoroform
Base, C1-4Alkoxy selects methoxyl group, ethyoxyl, benzyloxy, and aryl is selected from phenyl ring, and halogen is selected from fluorine, chlorine, bromine, iodine.
The compound is further selected from:
Structural formula 1:
Structural formula 2:
Structural formula 3:
Structural formula 4:
Structural formula 5:
Structural formula 6:
Structural formula 7:
Structural formula 8:
Structural formula 9:
Structural formula 10:
Structural formula 11:
Structural formula 12:
Structural formula 13:
Structural formula 14:
Structural formula 15:
Structural formula 16:
Structural formula 17:
Structural formula 18:
Structural formula 19:
Structural formula 20:
Structural formula 21:
Structural formula 22:
Structural formula 23:
Structural formula 24:
In the ellipticine derivative of formula (I, II, III, IV) described above
Preferably, R is hydrogen, R1For methyl.
Preferably, ellipticine derivative are as follows:
Preferably, R2For hydrogen or formoxyl, nitro, hydroxyl and methoxyl group.
Above-described pharmaceutically acceptable salt includes inorganic acid salt such as hydrochloride, hydrobromate, sulfate or sulfuric acid
Hydrogen salt, nitrate, phosphate or hydrophosphate etc. and acylate for example formates, acetate, benzoate, succinate,
Fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, mesylate, benzene sulfonic acid
Salt, tosilate etc..
There is provided the preparation sides of formula (I, II, III, IV) ellipticine derivative for the second aspect of technical solution of the present invention
Method is as follows:
General formula I synthetic method:
General formula II synthetic method:
The synthetic method of general formula III:
The synthetic method of general formula IV:
Contain basic group in the compound of the present invention molecule, peracid treatment, conversion can be led to as this profession is generally acknowledged
At pharmaceutically acceptable salt.This kind of example at salt includes inorganic acid salt such as hydrochloride, hydrobromate, sulfate or hydrogen sulfate
Salt, nitrate, phosphate or hydrophosphate etc. and acylate such as formates, acetate, benzoate, succinate, richness
Horse hydrochlorate, maleate, lactate, citrate, tartrate, succinate, gluconate, mesylate, benzene sulfonate,
Tosilate etc..
The present invention provides the ellipticine derivatives of formula (I, II, III, IV) and its pharmaceutically acceptable salt to treat
Purposes in cancer drug, cancer therein are preferably non-small cell lung cancer, colon cancer, gastric cancer, leukaemia, lymthoma, brain glue
Matter tumor, liver cancer etc., but it is not limited to above-mentioned tumour.
The third aspect of technical solution of the present invention includes that above-mentioned formula (I, II, III, IV) ellipticine spreads out there is provided one kind
The pharmaceutical composition of biology, which is characterized in that the pharmaceutical composition includes that the ellipticine of formula (I, II, III, IV) is derivative
Object and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
When the compounds of this invention is used as drug, can directly it use, or used with pharmaceutical compositions.The medicine group
Close object and contain 0.1-99%, the preferably the compounds of this invention of 0.5-90%, remaining for it is pharmaceutically acceptable, to people and dynamic
The nontoxic and inert pharmaceutical acceptable carrier of object and/or excipient or with other Anticancer drug combinations.Pharmaceutical composition of the invention
Object can be prepared into injection, tablet, capsule, pill, powder etc..
Pharmaceutical composition of the invention can be controlled release drug administration dosage form, sustained-release administration dosage form, various particulate delivery systems.
The compound of the present invention can such as capsule, tablet, pulvis, granula, syrup or similar dosage form take orally to
Medicine, or pass through injection, ointment, suppository or similar dosage form parenteral routes.These pharmaceutical preparations can by using it is well known that
Adjuvant, such as adhesive, excipient, stabilizer, disintegrating agent, corrigent, lubricant etc. is generated with commonsense method, although agent
It measures the age with symptom and patient, the property and seriousness of disease or imbalance and approach and the mode of administration and becomes, but to adult
For the case where patient is administered orally, it is daily accumulated dose 1 to 1000mg that the compounds of this invention, which normally be administered, preferably 5 to
200mg with for single dose, or is divided doses；Such as twice a day or three times；The case where for being injected intravenously, daily
It can divide one to three times to 0.1 to 100mg, preferably 0.5 to 50mg dosage.
There is provided above-mentioned ellipticine derivatives and its pharmaceutically acceptable for the fourth aspect of technical solution of the present invention
Salt preparing the application in antitumor or antiviral drugs.
The preferred non-small cell lung cancer of tumour of the present invention, colon cancer, gastric cancer, leukaemia, lymthoma, glioma
Deng, but it is not limited to above-mentioned tumour.
The preferred influenza virus of viral disease of the present invention, dengue fever virus, hand-foot-and-mouth disease poison, hepatitis virus etc. pass
Infectious diseases, but it is not limited to above-mentioned disease.
Advantageous effects
Emphasis of the present invention, which provides, has ellipticine derivative shown in general formula (I, II, III, IV), essentially consists in rose
Aryl is introduced on 1,2 of tree alkali and ring forms six ring derivatives.Shown by preliminary screening active ingredients, this analog derivative with
The anti-tumor activity having the same of ellipticine, but toxicity significantly reduces, and prompts this analog derivative to have preferable antitumor
Application prospect.
Detailed description of the invention
Fig. 1 ellipticine derivative is to rat liver cancer H22Growth inhibition effect
Specific embodiment
Abbreviation:
DMF:N, dinethylformamide
DMAP:4- dimethylamino naphthyridine
EDCI:1- ethyl-(3- dimethylamino-propyl) phosphinylidyne diimmonium salt hydrochlorate
THF: tetrahydrofuran
DCM: methylene chloride
Bn: benzyl
Ph: phenyl
CTX: cyclophosphamide
The invention discloses a kind of ellipticine derivatives and preparation method thereof, contain their salt, solvate, prodrug
With the application of pharmaceutical composition, those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.Especially need
It is noted that all similar substitutions and modifications are it will be apparent that they are considered as wrapping to those skilled in the art
It includes in the present invention.Method of the invention and application are described by preferred embodiment, and related personnel obviously can be
Do not depart from the content of present invention, in spirit and scope to method described herein and application is modified or appropriate changes and combinations,
Carry out implementation and application the technology of the present invention.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1.
9,15-Dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]
carbazol-5(10H)-one
9,15- dimethyl -15b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5 (10H) -one
Ellipticine 25mg (0.1mmol) and 27mg (0.2mmol) 2- aminobenzoic acid are dissolved in the anhydrous N of 3ml, N- diformazan
In base formamide, 38mg (0.2mmol) 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) is added,
It is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring display reaction carries out complete.Concentration, residue methylene chloride
It extracts (20mL × 3), merges organic interdependent secondary organic with the washing of saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution
Phase, anhydrous sodium sulfate are dried overnight.After steaming vibrating dichloromethane, obtained yellow solid is handled with dehydrated alcohol, and it is solid to obtain yellow
Body product 20mg, yield 54.8%.1H NMR(400MHz,DMSO-d6): δ 11.24 (s, 1H, N-H), 8.11 (d, J=7.7Hz,
1H, Ar-H), 7.76 (d, J=7.6Hz, 1H, Ar-H), 7.48 (d, J=7.8Hz, 1H, Ar-H)), 7.36 (dt, J=18.7,
7.4Hz, 2H, Ar-H)), 7.20-7.04 (m, 3H, Ar-H)), 6.96 (d, J=8.0Hz, 1H, Ar-H)) and, 6.84 (t, J=
7.3Hz, 1H, Ar-H)), 6.43 (s, 1H, N-H), 6.02 (d, J=8.1Hz, 1H, Ar-H)), 2.71 (s, 3H, CH3),2.48
(s,3H,CH3).
Embodiment 2
3,9,15-Trimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]
carbazol-5(10H)-on e
3,9,15- trimethyl -15b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5 (10H) -
Ketone
It is anhydrous that ellipticine 25mg (0.1mmol) and 30mg (0.2mmol) 2- amino -5- methyl benzoic acid is dissolved in 3ml
In n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC prison
Display reaction is surveyed to carry out completely.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturated carbon
Sour hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.Steaming vibrating dichloromethane
Afterwards, the yellow solid obtained is handled with dehydrated alcohol, obtains yellow solid product 24mg, yield 63.3%.1H NMR
(500MHz,DMSO-d6) δ 11.30 (s, 1H, N-H), 8.18 (d, J=7.7Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H),
7.55 (d, J=7.9Hz, 1H, Ar-H), 7.40 (t, J=7.3Hz, 1H, Ar-H), 7.29 (d, J=7.9Hz, 1H, Ar-H),
7.20 (t, J=7.3Hz, 1H, Ar-H), 7.15 (d, J=8.1Hz, 1H, Ar-H), 7.00 (s, 1H, R3), C-H 6.95 (d, J=
8.1Hz, 1H ,=C-H), 6.45 (s, 1H, N-H), 6.08 (d, J=8.1Hz, 1H ,=C-H), 2.77 (s, 3H, CH3),2.54
(s,3H,CH3),2.30(s,3H,CH3).HRMS(ESI)m/z calcd.For C25H22N3O[M+H]+380.17629,found
380.17230.
Embodiment 3
4,9,15-Trimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]
carbazol-5(10H)-one
4,9,15- trimethyl -15b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5 (10H) -
Ketone
It is anhydrous that ellipticine 25mg (0.1mmol) and 30mg (0.2mmol) 2- amino -6- methyl benzoic acid is dissolved in 3ml
In n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC prison
Display reaction is surveyed to carry out completely.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturated carbon
Sour hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.Steaming vibrating dichloromethane
Afterwards, the yellow solid obtained is handled with dehydrated alcohol, obtains yellow solid product 17mg, yield 44.9%.1H NMR
(500MHz,DMSO-d6) δ 11.27 (s, 1H, N-H), 8.17 (d, J=8.0Hz, 1H, Ar-H), 7.75 (d, J=7.4Hz, 1H,
), Ar-H 7.29 (dt, J=16.2,7.9Hz, 2H, Ar-H), 7.22-7.12 (m, 3H, Ar-H), 6.88 (d, J=8.1Hz, 1H,
=C-H), 6.70 (d, J=7.4Hz, 1H ,=C-H), 6.33 (s, 1H, N-H), 6.10 (d, J=8.3Hz, 1H), 2.74 (s,
3H,CH3),2.64(s,3H,CH3),2.55(s,3H,CH3).HRMS(ESI)m/z calcd.For C25H22N3O[M+H]+
380.17629,found 380.17331.
Embodiment 4
2,3-Dimethoxy-15-methyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
2,3- dimethoxy -15- methyl-15 b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -
5 (10H) -one
Ellipticine 25mg (0.1mmol) and 39mg (0.2mmol) 2- amino -4,5- dimethoxybenzoic acid is dissolved in
In the anhydrous n,N-Dimethylformamide of 3ml, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid analysis
Out, TLC monitoring display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time
Organic phase is washed with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, anhydrous sodium sulfate is dried overnight.Boil off two
After chloromethanes, obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 17mg, yield 35.6%.1H NMR
(500MHz,DMSO-d6) δ 11.21 (s, 1H, N-H), 8.12 (d, J=7.5Hz, 1H, Ar-H), 7.49 (d, J=7.7Hz, 1H,
), Ar-H 7.34 (t, J=7.1Hz, 1H, Ar-H), 7.21 (s, 1H, Ar-H), 7.14 (t, J=7.0Hz, 1H, Ar-H), 7.07
(d, J=7.9Hz, 1H ,=C-H), 6.81 (s, 1H, R3C-H),6.55(s,1H,Ar-H),6.38(s,1H,N-H),5.97(d,
J=7.9Hz, 1H ,=C-H), 3.76 (s, 3H, CH3),3.73(s,3H,CH3),3.24(s,3H,CH3),2.73(s,3H,
CH3).HRMS(ESI)m/z calcd.For C26H24N3O3[M+H]+426.18177,found426.17966.
Embodiment 5
1,3-Dichloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido
[4,3-b]carbazol-5(10H)-one
Chloro- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 1,3- bis- simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -
5 (10H) -one
By ellipticine 25mg (0.1mmol) and 41mg (0.2mmol) 2- amino -3,5- dichlorobenzoic acid be dissolved in 3ml without
In water n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC
Monitoring display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturation
Sodium bicarbonate solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.Steaming vibrating dichloromethane
Afterwards, the yellow solid obtained is handled with dehydrated alcohol, obtains yellow solid product 32mg, yield 74.7%.1H NMR
(400MHz,DMSO-d6) δ 11.27 (s, 1H, N-H), 8.11 (d, J=7.9Hz, 1H, Ar-H), 7.73 (s, 2H, Ar-H),
7.48 (d, J=8.0Hz, 1H, Ar-H), 7.35 (d, J=7.4Hz, 1H, Ar-H), 7.11 (dd, J=17.5,7.9Hz, 2H,
), Ar-H 7.03 (d, J=4.5Hz, 1H ,=C-H), 6.53 (d, J=4.7Hz, 1H ,=C-H), 6.11 (d, J=8.2Hz, 1H,
N-H),2.73(s,3H,CH3),2.48(s,3H,CH3).
Embodiment 6
2-Chloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
Chloro- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 2- simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 34mg (0.2mmol) 2- amino -4- chlorobenzoic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 10mg, yield 25.0%.1H NMR(400MHz,
DMSO-d6) δ 11.26 (s, 1H, N-H), 8.12 (d, J=7.6Hz, 1H, Ar-H), 7.77 (d, J=8.2Hz, 1H, Ar-H),
7.47 (d, J=7.7Hz, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.33 (t, J=7.2Hz, 1H, Ar-H), 7.17-7.02
(m, 2H, Ar-H), 6.98 (s, 1H, NC-H), 6.85 (d, J=8.0Hz, 1H ,=C-H), 6.48 (s, 1H, N-H), 6.03 (d, J
=8.0Hz, 1H ,=C-H), 2.69 (s, 3H, CH3),2.46(s,3H,CH3).
Embodiment 7
3-Chloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
Chloro- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 3- simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 34mg (0.2mmol) 2- amino -5- chlorobenzoic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 36mg, yield 86.3%.1H NMR(400MHz,
DMSO-d6) δ 11.25 (s, 1H, N-H), 8.12 (d, J=7.2Hz, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.49 (d, J=
6.8Hz, 3H, Ar-H), 7.37 (s, 2H, Ar-H), 7.08 (d, J=7.6Hz, 1H ,=C-H), 7.04-6.96 (m, 1H, NC-
), H 6.44 (s, 1H, N-H), 6.06 (d, J=7.9Hz, 1H ,=C-H), 2.70 (s, 3H, CH3),2.48(s,3H,CH3).
Embodiment 8
1-Fluoro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
Fluoro- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 1- simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 31mg (0.2mmol) 2- amino -3- fluobenzoic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 18mg, yield 47.0%.1H NMR(400MHz,
DMSO-d6) δ 11.23 (s, 1H, N-H), 8.13 (d, J=8.0Hz, 1H, Ar-H), 7.65 (d, J=7.7Hz, 1H, Ar-H),
7.49 (d, J=8.0Hz, 1H, Ar-H), 7.40-7.30 (m, 2H, Ar-H), 7.17-7.08 (m, 3H, Ar-H, NH), 6.88 (t,
J=4.7Hz, 1H ,=C-H), 6.52 (d, J=4.1Hz, 1H ,=C-H), 6.08 (d, J=8.2Hz, 1H, NC-H), 2.73 (s,
3H,CH3),2.49(s,3H,CH3).
Embodiment 9
4-Fluoro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
Fluoro- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 4- simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 31mg (0.2mmol) 2- amino -6- fluobenzoic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg is added, and (0.2mmol EDCI react 5 hours under room temperature, there is yellow solid precipitation, and TLC is monitored
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 29mg, yield 75.7%.1H NMR(400MHz,
DMSO-d6) δ 11.23 (s, 1H, N-H), 8.13 (d, J=8.0Hz, 1H, Ar-H), 7.65 (d, J=7.7Hz, 1H, Ar-H),
7.49 (d, J=8.0Hz, 1H, Ar-H), 7.34 (d, J=7.8Hz, 2H, Ar-H), 7.15 (m, 2H, Ar-H), 7.11 (s, 1H,
), N-H 6.89 (d, J=4.7Hz, 1H ,=C-H), 6.53 (d, J=4.1Hz, 1H ,=C-H), 6.09 (d, J=8.2Hz, 1H,
NC-H),2.74(s,3H,CH3),2.50(s,3H,CH3).
Embodiment 10
2-(benzyloxy)-3-methoxy-9,15-dimethyl-15b,16-dihydroquinazolino[3',
2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
2- benzyloxy -3- methoxyl group -9,15- dimethyl -15b, 16- dihydroquinazoline simultaneously [3', 2':1,2] pyrido [4,
3-b] carbazole -5 (10H) -one
By ellipticine 25mg (0.1mmol) and 57mg (0.2mmol) 2- amino -4- benzyloxy -5- methoxy benzoic acid
It is dissolved in the anhydrous n,N-Dimethylformamide of 3ml, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, have yellow solid
Body is precipitated, and TLC monitoring display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic phase
Organic phase is successively washed with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, anhydrous sodium sulfate is dried overnight.It steams
After removing methylene chloride, obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 25mg, yield 48.5%.1H
NMR(400MHz,DMSO-d6) δ 11.22 (s, 1H, N-H), 8.13 (d, J=7.8Hz, 1H, Ar-H), 7.47 (dd, J=16.0,
7.5Hz, 3H, Ar-H), 7.37 (m, 4H, Ar-H), 7.24 (s, 1H, Ar-H), 7.15 (s, 1H, N-H), 7.08 (d, J=
8.1Hz, 1H ,=C-H), 6.83 (s, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 6.39 (s, 1H, NC-H), 5.98 (d, J=
8.1Hz, 1H ,=C-H), 5.08 (d, J=20.0Hz, 2H, CH2Ar),3.74(s,3H,OCH3),2.73(s,3H,CH3),2.48
(s,3H,CH3).
Embodiment 11
9,15,16-Trimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]
carbazol-5(10H)-one
9,15,16- trimethyl -15b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 30mg (0.2mmol) N- methyl anthranilic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, obtains yellow solid product 20mg, yield 52.8%.1H NMR(400MHz,
DMSO-d6) δ 11.26 (s, 1H, N-H), 8.11 (d, J=8.0Hz, 1H, Ar-H), 7.93-7.85 (m, 2H, Ar-H), 7.59-
7.52 (m, 1H, Ar-H), 7.49 (d, J=8.0Hz, 1H, Ar-H), 7.35 (t, J=7.6Hz, 1H, Ar-H), 7.18-7.08
(m, 4H, Ar-H), 6.58 (s, 1H, NC-H), 6.08 (d, J=8.2Hz, 1H ,=C-H), 2.85 (s, 3H, CH3),2.69(s,
3H,CH3),2.65(s,3H,CH3).
Embodiment 12
8,14-Dimethyl-14b,15-dihydrothieno[3”,2”:4',5']pyrimido[1',2':1,2]
pyrido[4,3-b]carbazol-4(9H)-One
8,14- dimethyl -14b, 15- dihydro-thiophene simultaneously [3 ", 2 ": 4 ', 5 '] pyrido [4,3-b] carbazole -4 (9H) -one
Ellipticine 25mg (0.1mmol) and 28mg (0.2mmol) 3- amino -2- thiophenic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with ethyl acetate, and suction filtration obtains yellow solid product 28mg, yield 75.5%.1H NMR
(400MHz,DMSO-d6) δ 11.21 (s, 1H, N-H), 8.12 (d, J=7.6Hz, 1H, Ar-H), 7.89 (d, J=4.1Hz, 1H,
), Ar-H 7.70 (s, 1H, Ar-H), 7.48 (d, J=7.7Hz, 1H, Ar-H), 7.34 (t, J=7.1Hz, 1H, Ar-H), 7.13
(t, J=7.0Hz, 1H, Ar-H), 7.01 (d, J=7.9Hz, 1H ,=C-H), 6.68 (d, J=4.1Hz, 1H, R3C-H),6.43
(s, 1H, N-H), 5.96 (d, J=7.9Hz, 1H ,=C-H), 2.74 (s, 3H, CH3),2.48(s,3H,CH3).
Embodiment 13
9,15-Dimethyl-16-phenyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,
3-b]carbazol-5(10H)-one
9,15- dimethyl -16- phenyl -15b, 16- dihydroquinazoline simultaneously [3 ', 2 ': 1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and 43mg (0.2mmol) N- phenylanthranilic acid are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring
Display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with unsaturated carbonate
Hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane,
Obtained yellow solid is handled with dehydrated alcohol, and suction filtration obtains yellow solid product 23mg, yield 52.2%.1H NMR
(400MHz,DMSO-d6) δ 11.15 (s, 1H), 8.12 (d, J=7.9Hz, 1H, Ar-H), 7.99 (d, J=7.4Hz, 1H, Ar-
), H 7.53 (t, J=7.4Hz, 1H, Ar-H), 7.46 (d, J=7.5Hz, 1H, Ar-H), 7.24 (t, J=7.3Hz, 1H, Ar-
), H 7.12 (d, J=7.6Hz, 2H, Ar-H), 7.07 (d, J=7.9Hz, 1H ,=C-H), 7.03 (s, 1H, R3C-H),6.97
(t, J=7.3Hz, 2H, Ar-H), 6.91 (d, J=6.3Hz, 1H, Ar-H), 6.72 (d, J=7.5Hz, 2H, Ar-H), 5.96
(d, J=7.9Hz, 1H ,=C-H), 2.86 (s, 3H, CH3),2.35(s,3H,CH3).
Embodiment 14
6,18-Dimethyl-17,17a-dihydrobenzo[6',7']quinazolino[3',2':1,2]pyrido
[4,3-b]carbazol-10(5H)-one
6,18- dimethyl -17,17a- dihydrobenzo [6 ', 7 '] quinazo [3', 2':1,2] pyrido [4,3-b] click
Azoles -5 (10H) -one
Ellipticine 25mg (0.1mmol) and 37mg (0.2mmol) adjacent amino -2- naphthoic acid is dissolved in the anhydrous N of 3ml, N- bis-
In methylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC monitoring display
Reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturated sodium bicarbonate
Solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane, it obtains
Yellow solid handled with dehydrated alcohol, suction filtration obtain yellow solid product 29mg, yield 69.9%.1H NMR(400MHz,
DMSO-d6) δ 11.24 (s, 1H, N-H), 8.48 (s, 1H, Ar-H), 8.11 (d, J=8.0Hz, 1H, Ar-H), 7.93 (d, J=
8.2Hz, 1H ,=C-H), 7.68 (d, J=8.3Hz, 1H, Ar-H), 7.51-7.40 (m, 2H, Ar-H), 7.34 (t, J=
7.6Hz,1H,Ar-H),7.30(s,1H,Ar-H),7.29–7.21(m,1H,Ar-H),7.21–7.11(m,2H,Ar-H),6.99
(s,1H,N-H),6.54(s,1H,R3), C-H 6.09 (d, J=8.2Hz, 1H ,=C-H), 2.73 (s, 3H, CH3),2.44(s,
3H,CH3).
Embodiment 15
9,15-dimethyl-3-(trifluoromethyl)-15b,16-dihydroquinazolino[3',2':1,
2]pyrido[4,3-b]carbazol-5(10H)-one
9,15- dimethyl -3- (trifluoromethyl) -15b, 16- dihydroquinazoline simultaneously [3', 2':1,2] pyrido [4,3-b]
Carbazole -5 (10H) -one
Ellipticine 25mg (0.1mmol) and 41mg (0.2mmol) 5- trifluoromethyl -2- aminobenzoic acid are dissolved in 3ml
In anhydrous n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, reacts under room temperature overnight, TLC monitoring display react into
Row is complete.Concentration, residue is extracted with dichloromethane (20mL × 3), merges organic interdependent time with saturated sodium bicarbonate solution, pure
Change water and saturated sodium chloride solution washs organic phase, anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane, obtained yellow
Solid is handled with ethyl acetate, and suction filtration obtains yellow solid product 10mg, yield 23.1%.1H NMR(400MHz,CF3COOD)δ
9.55 (s, 1H, Ar-H), 8.74 (d, J=8.9Hz, 1H, Ar-H), 8.52 (s, 1H, Ar-H) 8.11 (d, J=8.0Hz, 1H,
), Ar-H 7.95 (d, J=8.9Hz, 1H ,=C-H), 7.53 (s, 2H, Ar-H), 7.36 (s, 1H, Ar-H), 3.26 (s, 3H,
CH3),2.80(s,3H,CH3)
Embodiment 16
3-bromo-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-
b]carbazol-5(10H)-one
Bromo- 9,15- dimethyl -15b, the 16- dihydroquinazoline of 3- simultaneously [3', 2':1,2] pyrido [4,3-b] carbazole -5
(10H) -one
Ellipticine 25mg (0.1mmol) and the bromo- 2- aminobenzoic acid of 43mg (0.2mmol) 5- are dissolved in the anhydrous N of 3ml,
In dinethylformamide, 38mg (0.2mmol) EDCI is added, is reacted under room temperature overnight, TLC monitoring display reaction has carried out
Entirely.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturated sodium bicarbonate solution, purified water
Organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dried overnight.After steaming vibrating dichloromethane, obtained yellow solid
It is handled with dehydrated alcohol, suction filtration obtains yellow solid product 8mg, yield 18.1%.1H NMR(400MHz,CF3COOH-d)δ
8.89 (s, 1H, N-H), 8.72 (s, 1H, Ar-H), 8.46-8.39 (m, 1H, Ar-H), 8.23 (d, J=8.8Hz, 1H ,=C-
), H 8.06 (s, 1H), 7.84 (d, J=9.6Hz, Ar-H), 7.68 (s, 2H, Ar-H), 7.50 (s, 1H, Ar-H), 3.75 (s,
3H,CH3),2.92(s,3H,CH3).
Embodiment 17
1,8,14-Dimethyl-14b,15-dihydrothieno[3”,2”:4',5']pyrimido[1',2':1,2]
pyrido[4,3-b]carbazol-4(9H)-One
1,8,14- dimethyl -14b, 15- dihydro-thiophene simultaneously [3 ", 2 ": 4 ', 5 '] pyrido [4,3-b] carbazole -4 (9H) -
Ketone
Ellipticine 25mg (0.1mmol) and -4 methyl-2-thiophenecarboxylic acid of 30mg (0.2mmol) 3- amino are dissolved in 3ml
In anhydrous n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation,
TLC monitoring display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with full
Organic phase is washed with sodium bicarbonate solution, purified water and saturated sodium chloride solution, anhydrous sodium sulfate is dried overnight.Boil off dichloromethane
After alkane, obtained yellow solid is handled with ethyl acetate, and suction filtration obtains yellow solid product 12mg, yield 31.1%.1H NMR
(400MHz,CF3COOH-d) δ 9.01 (d, J=9.3Hz, 1H, Ar-H), 8.46 (d, J=8.1Hz, 1H, Ar-H), 8.19 (d, J
=8.0Hz, Ar-H), 8.09 (s, 1H), 7.70 (s, 2H, Ar-H), 7.51 (d, J=6.3Hz, 1H, Ar-H), 3.84 (s, 3H,
CH3),2.95(s,3H,CH3),2.72(s,3H,CH3).
Embodiment 18
2,3,8,14-tetramethyl-14b,15-dihydrothieno[2”,3”:4',5']pyrimido[1',2':
1,2]pyrido[4,3-b]carbazol-4(9H)-one
2,3,8,14- tetramethyl -14b, 15- dihydro-thiophene simultaneously [2 ", 3 ": 4', 5'] pyrimido [1', 2':1,2] pyrido
[4,3-b] carbazole -4 (9H) -one
Ellipticine 25mg (0.1mmol) and 34mg (0.2mmol) 3- amino -4,5- dimethyl -2- thiophenic acid is molten
In the anhydrous n,N-Dimethylformamide of 3ml, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid
It is precipitated, TLC monitoring display reaction carries out complete.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent
Secondary to wash organic phase with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, anhydrous sodium sulfate is dried overnight.It boils off
After methylene chloride, obtained yellow solid is handled with ethyl acetate, and suction filtration obtains yellow solid product 7mg, yield 17.5%.1H
NMR(400MHz,CF3COOH-d) δ 9.02 (d, J=9.3Hz, 1H, Ar-H), 8.48 (d, J=8.1Hz, 1H, Ar-H), 8.20
(d, J=8.0Hz, Ar-H), 8.09 (s, 1H), 7.71 (s, 2H, Ar-H), 7.52 (d, J=6.3Hz, 1H, Ar-H), 3.83 (s,
3H,CH3),2.94(s,3H,CH3),2.71(s,3H,CH3), 2.65 (s, 3H, CH3)。
Embodiment 19
9,15-dimethyl-5-oxo-5,10,15b,16-tetrahydroquinazolino[3',2':1,2]
pyrido[4,3-b]carbazole-13-carbaldehyde
9,15- dimethyl -5- oxo -5,10,15b, 16- tetrahydroisoquinoline simultaneously [3', 2':1,2] pyrido [4,3-b] click
Azoles -13- formaldehyde
It is anhydrous that 9- formoxyl ellipticine 27mg (0.1mmol) and 27mg (0.2mmol) 2- amino this formic acid is dissolved in 3ml
In n,N-Dimethylformamide, 38mg (0.2mmol) EDCI is added, is reacted 5 hours under room temperature, there is yellow solid precipitation, TLC prison
Display reaction is surveyed to carry out completely.Concentration, residue are extracted with dichloromethane (20mL × 3), merge organic interdependent time with saturated carbon
Sour hydrogen sodium solution, purified water and saturated sodium chloride solution wash organic phase, and anhydrous sodium sulfate is dried overnight.Steaming vibrating dichloromethane
Afterwards, the yellow solid obtained is handled with ethyl acetate, and suction filtration obtains yellow solid product 12mg, yield 30.5%.1H NMR
(400MHz,DMSO-d6) δ 11.84 (s, 1H, N-H), 10.03 (s, 1H, CHO), 8.67 (s, 1H, Ar-H), 7.89 (d, J=
8.4Hz, 2H, Ar-H), 7.76 (d, J=7.7Hz, 1H, Ar-H), 7.63 (dd, J=23.3,9.5Hz, 2H, Ar-H), 7.42-
7.36 (m, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 7.11 (d, J=8.1Hz, 1H ,=C-H), 6.95 (d, J=8.1Hz, 1H,
=C-H), 6.85 (t, J=7.2Hz, 1H, Ar-H), 6.47 (s, 1H, N-H), 6.02 (d, J=8.2Hz, 1H, Ar-H), 2.77
(s,3H,CH3),2.49(s,3H,CH3).
Pharmacological evaluation
The detection of 1 ellipticine derivative extracorporeal anti-tumor of experimental example
Mtt assay measures tumor cell survival
After the cell of logarithmic growth phase is digested with pancreatin, it is configured to certain density single cell suspension, it is raw according to cell
The difference of long speed is inoculated in 96 orifice plates by 1500-3000/hole, and 100 μ l of cell suspension is added in every hole.Next day is added containing not
With the fresh culture that acute drug and coordinative solvent compare, every hole adds 100 μ l (DMSO final concentration < 0.1%), every kind of testedization
Conjunction object sets every group of 4 dosage groups (0.05,0.5,5,50 μm of ol/L) and sets three parallel holes.In 37 DEG C, 5%CO2 continues to cultivate 96h
After abandon supernatant, the serum free medium of the MTT containing 0.5mg/mL of 200 μ L Fresh is added in every hole.Continue to cultivate 4h, in abandoning
Clearly, 200 μ L DMSO dissolution MTT first hairpin precipitating is added in every hole, and after microoscillator oscillation mixes, microplate reader is in Detection wavelength
OD value (OD) is measured under the conditions of 570nm, medicine is calculated according to the following formula as control group in the tumour cell handled using solvent control
Object presses middle effect equation calculation IC to the inhibiting rate of tumour cell50:
Derivatives anti-tumor i n vitro test the results are shown in Table 1
1 ellipticine derivative MTT the selection result of table
HCT116: human colon cancer cell strain；MGC803: human stomach cancer cell line；HT29: human colon cancer cell strain；
MCF-7: Breast cancer lines；MCF-7/Taxol: to the Breast cancer lines of taxol resistance.
Antitumous effect in 2 ellipticine derivative body of experimental example
Murine transplanted hepatocarcinoma H22 experiment
KM mouse (16~18g), male, 7d, well-grown ascites cell after taking passage to be inoculated under aseptic condition,
It is diluted with sterile saline, adjusts cell density to 5 × 107/ml, take 0.2ml to be inoculated in mouse armpit subcutaneous.Next day with
Machine is grouped and is administered, the daily oral administration gavage distilled water of control group；Reagent group is configured to 4.5mg/ml and 4.4375mg/ml respectively
0.4ml, by daily single, successive administration 9 days is administered in the medical fluid of concentration, every 20g intragastric administration on mice.Mouse is taken off at the end of experiment
Mortar is put to death, and is then removed tumour, is weighed and take pictures.Finally calculate tumor control rate.
Internal anti-tumor activity effect is shown in Table 2 and Fig. 1
2 compound of table is to rat liver cancer H22Growth inhibition effect
* p < 0.001 p < 0.05, * * p < 0.01, * * *, compared with solvent control group.
Claims (15)
1. formula (I) ellipticine derivative and its pharmaceutically acceptable salt:
Wherein
R is hydrogen, C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, halogen；Substituent group is selected from halogen, benzyl；R represents 1,2,
3,4 substitutions；
R1It is hydrogen, C1-4Alkyl, aryl；
R2It is hydrogen, hydroxyl, methoxyl group, formoxyl, nitro, halogen；R2Represent 1,2,3,4 substitution.
2. ellipticine derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that the halogen
Selected from F, Cl, Br, I；The C1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl；It is described
C1-4Alkoxy is selected from methoxyl group, ethyoxyl, benzyloxy；The aryl is selected from phenyl ring.
3. formula (II) ellipticine derivative and its pharmaceutically acceptable salt:
Wherein
R is hydrogen, C1-4Alkyl, C1-4Alkoxy, halogen, phenyl ring；R represents 1,2 substitution；
R2It is hydrogen, hydroxyl, methoxyl group, formoxyl, nitro, halogen；R2Represent 1,2,3,4 substitution.
4. ellipticine derivative according to claim 3 and its pharmaceutically acceptable salt, which is characterized in that the halogen
Selected from F, Cl, Br, I；The C1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl；It is described
C1-4Alkoxy is selected from methoxyl group, ethyoxyl, benzyloxy.
5. formula (III) ellipticine derivative and its pharmaceutically acceptable salt:
Wherein
R is hydrogen, C1-4Alkyl, halogen, substituted benzene ring；Substituent group is selected from halogen, C1-4Alkoxy；
R represents 1,2 substitution；
R2It is hydrogen, hydroxyl, methoxyl group, formoxyl, nitro, halogen；R2Represent 1,2,3,4 substitution.
6. ellipticine derivative according to claim 5 and its pharmaceutically acceptable salt, which is characterized in that the halogen
Selected from F, Cl, Br, I；The C1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl；It is described
C1-4Alkoxy is selected from methoxyl group, ethyoxyl, benzyloxy.
7. formula (IV) ellipticine derivative and its pharmaceutically acceptable salt:
Wherein
R is hydrogen, C1-4Alkyl, halogen；R represents 1,2 substitution；
R2It is hydrogen, hydroxyl, methoxyl group, formoxyl, nitro, halogen；R2Represent 1,2,3,4 substitution.
8. ellipticine derivative according to claim 7 and its pharmaceutically acceptable salt, which is characterized in that the halogen
Selected from F, Cl, Br, I；The C1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl；It is described
C1-4Alkoxy is selected from methoxyl group, ethyoxyl, benzyloxy.
9. any one of -8 ellipticine derivative and its pharmaceutically acceptable salt according to claim 1, the compound
It is selected from:
Structural formula 1:
Structural formula 2:
Structural formula 3:
Structural formula 4:
Structural formula 5:
Structural formula 6:
Structural formula 7:
Structural formula 8:
Structural formula 9:
Structural formula 10:
Structural formula 11:
Structural formula 12:
Structural formula 13:
Structural formula 14:
Structural formula 15:
Structural formula 16:
Structural formula 17:
Structural formula 18:
Structural formula 19:
Structural formula 20:
Structural formula 21:
Structural formula 22:
Structural formula 23:
Structural formula 24:
10. the preparation side of -9 described in any item ellipticine derivatives and its pharmaceutically acceptable salt according to claim 1
Method, which is characterized in that the compound of invention the preparation method is as follows:
General formula I synthetic method:
General formula II synthetic method:
The synthetic method of general formula III:
The synthetic method of general formula IV:
11. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes the rose of any one of claim 1-9
Set alkali derivant and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
12. pharmaceutical composition according to claim 11, which is characterized in that the pharmaceutical composition be selected from injection, tablet,
Capsule, pill, powder.
13. pharmaceutical composition according to claim 11, which is characterized in that the pharmaceutical composition is selected from controlled release drug administration agent
Type, sustained-release administration dosage form, various particulate delivery systems.
14. as the described in any item ellipticine derivatives of claim 1-9 and its pharmaceutically acceptable salt are anti-swollen in preparation
Application in tumor or antiviral drugs.
15. application according to claim 12, which is characterized in that the tumour is selected from non-small cell lung cancer, colon cancer, stomach
Cancer, leukaemia, lymthoma, glioma etc.；The virus is selected from hand-foot-and-mouth disease poison, influenza virus, retrovirus, Dengue
Fever virus, hepatitis virus, herpesviral.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4434290A (en) * | 1978-09-21 | 1984-02-28 | Agence Nationale De Valorisation De La Recherche | Pyrido (4,3-B) carbazoles substituted in the 1 position by a polyamine chain |
| EP0257701A1 (en) * | 1986-08-15 | 1988-03-02 | Cedona Pharmaceuticals B.V. | A process for preparing hydroxyl derivatives of compounds containing a carbazole, dibenzofurane or dibenzothiophene group |
| US5441941A (en) * | 1992-10-02 | 1995-08-15 | The United States Of America As Represented By The Secretary Of Dhhs | 1,2-dihydroellipticines with activity against CNS specific cancer |
| WO1998040104A2 (en) * | 1997-03-12 | 1998-09-17 | Yale University | Covalent conjugates of topoisomerase i and topoisomerase ii inhibitors |
| CN101472592A (en) * | 2006-05-22 | 2009-07-01 | 生物联合制药公司 | Reversion of malignant phenotype with 9-hydroxy ellipticine derivatives |
| WO2015179218A1 (en) * | 2014-05-17 | 2015-11-26 | Musc Foundation For Research Development | Aza-ellipticine analogs, methods of synthesis and methods of treatment |
| CN107365309A (en) * | 2017-07-14 | 2017-11-21 | 浙江大学 | The synthetic method of the methyl ellipticine of natural products derivative 6 |
-
2018
- 2018-10-29 CN CN201811267005.5A patent/CN109748917B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4434290A (en) * | 1978-09-21 | 1984-02-28 | Agence Nationale De Valorisation De La Recherche | Pyrido (4,3-B) carbazoles substituted in the 1 position by a polyamine chain |
| EP0257701A1 (en) * | 1986-08-15 | 1988-03-02 | Cedona Pharmaceuticals B.V. | A process for preparing hydroxyl derivatives of compounds containing a carbazole, dibenzofurane or dibenzothiophene group |
| US5441941A (en) * | 1992-10-02 | 1995-08-15 | The United States Of America As Represented By The Secretary Of Dhhs | 1,2-dihydroellipticines with activity against CNS specific cancer |
| WO1998040104A2 (en) * | 1997-03-12 | 1998-09-17 | Yale University | Covalent conjugates of topoisomerase i and topoisomerase ii inhibitors |
| CN101472592A (en) * | 2006-05-22 | 2009-07-01 | 生物联合制药公司 | Reversion of malignant phenotype with 9-hydroxy ellipticine derivatives |
| WO2015179218A1 (en) * | 2014-05-17 | 2015-11-26 | Musc Foundation For Research Development | Aza-ellipticine analogs, methods of synthesis and methods of treatment |
| CN107365309A (en) * | 2017-07-14 | 2017-11-21 | 浙江大学 | The synthetic method of the methyl ellipticine of natural products derivative 6 |
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