CN109748917B - Ellipticine derivatives, pharmaceutical compositions thereof, process for their preparation and their use - Google Patents
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Abstract
The present invention relates to ellipticine derivatives of formula (I, II, III, IV) or pharmaceutically acceptable salts thereof, which have excellent antitumor activity, little side effects, low toxicity and/or high solubility in water, and which are useful as antitumor and antiviral agents, to processes for their preparation, to pharmaceutical compositions and to their use.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel ellipticine derivatives, a pharmaceutical composition containing the ellipticine derivatives and application of the ellipticine derivatives in preparing antitumor and antiviral drugs.
Background
Over the last thirty years, despite various diagnoses and treatments of tumorsThe level is obviously improved, but the morbidity and mortality of tumors are continuously increased in the world. According to the prediction of the World Health Organization (WHO), the number of the worldwide tumor diseases is increased to 2000 ten thousand and the number of the worldwide tumor deaths is 1200 ten thousand by 2020[1]. In 2015, 820 ten thousand people died from cancer worldwide, 280 ten thousand of China. 7500 people die of cancer every day in China. China is the first to die due to cancer. In China, the prevalence rate of cancer is 280 parts per million, and the disease shows a rapid growth trend year by year[2]. The main biological characteristics of malignant tumor are invasion and metastasis, which are the main clinical death cause of tumor patients, accounting for 83% of tumor deaths. Therefore, the prevention and treatment of tumors is one of the major problems in the disease treatment field today.
In recent years, considerable progress is made in tumor chemotherapy, the survival time of tumor patients is obviously prolonged, and particularly, the treatment of leukemia, malignant lymphoma and the like is broken through, but the treatment of solid tumors which have the most serious harm to the life health of human beings and account for more than 90 percent of malignant tumors cannot achieve satisfactory effect[3]. Pharmacologists and oncologists are increasingly aware of: to improve the curative effect of tumor treatment, a new breakthrough progress must be made by starting from the mechanism of tumor occurrence and development. In recent years, the development of molecular oncology and molecular pharmacology has gradually clarified the nature of tumors; the invention and the application of the advanced technologies such as large-scale rapid screening, combinatorial chemistry, genetic engineering and the like accelerate the drug development process; research and development of anti-tumor drugs have entered a new era. The development of the current antitumor drugs has the following points: solid tumors which account for more than 90 percent of malignant tumors are taken as main attacking objects; searching active ingredients from natural products; thirdly, aiming at the mechanism of tumor occurrence and development, new molecular action (enzyme, receptor and gene) targets are searched; fourthly, large-scale rapid screening; introduction and application of a new technology: combinatorial chemistry, structural biology, computer-aided design, genetic engineering, DNA chips, pharmacogenomics (a combination of functional and pharmacological genomics), and the like[4]。
The antineoplastic drugs are aiming at the traditional cytotoxic drugsThe development of novel antitumor drugs with multi-link effects of tumor mechanisms, the current new target of antitumor effect and corresponding novel antitumor agents or means which are concerned at home and abroad are as follows: taking a cell signal transduction molecule as a target: including protein kinase inhibitors, farnesyl transferase inhibitors, MAPK signal transduction pathway inhibitors, cell cycle modulators, and the like; using the new blood vessel as a target: an angiogenesis inhibitor; ③ reduction of cancer cell shedding, adhesion and degradation of basement membrane: anti-tumor metastasis agents; fourthly, taking telomerase as a target: a telomerase inhibitor; fifthly, aiming at the drug resistance of the tumor cells: a drug resistance reversal agent; sixthly, promoting the malignant cell to mature and differentiate: a differentiation-inducing agent; and (c) specifically killing cancer cells: (antibody or toxin) directed therapy; enhancing the curative effects of radiotherapy and chemotherapy: a sensitizer for tumor therapy; ninthly, the immune function of the organism is improved or adjusted: a biological response modifier; immunotherapy of tumor in r: the existing relatively popular monoclonal antibody medicines for treating PD-1, PD-L1 and the like[5]。
In recent years, the search for anticancer active compounds from natural products has become a hot spot for developing anticancer drugs, and in the last 20 years, 61% of new chemical entities of drug small molecules launched worldwide can be traced back to natural products. Natural products are very high in occurrence in certain therapeutic areas: 78% of the antibacterial compound and 74% of the antitumor compound are natural products or are derived from a natural product, and the practice proves that the unique effect of the natural product in the discovery of the anticancer drugs draws high attention again. The traditional chemotherapy drugs for treating tumors have the problem of drug resistance, and particularly, the tumor stem cells are less sensitive. The anticancer Chinese medicine has powerful effect, high efficiency and low toxicity, and may be used in screening out efficient tumor killing stem cell to treat malignant tumor.
Ellipticine (Ellipticine, 1) occurs naturally in the leaves of the oleander family plant Elliptica (Ochrosia eliptica Labill.), in the bark and leaves of the Balanophora rosea (O.balansae) and in the bark and leaves of the Murray rosea (O.moorei). American researcher Goodwin and his colleagues[1]The structure of ellipticine was first isolated and determined in 1959, same year Woodward et al[2]The first time the total synthesis of ellipticine is achieved, and thereafter manyResearchers have conducted research on the total synthesis of ellipticine and its derivatives. The experiment shows that ellipticine has growth inhibiting effect on many tumor cells such as leukemia, melanoma, sarcoma, lymphoma, colon cancer, lung cancer, breast cancer, brain tumor, osteosarcoma, neuroblastoma, etc., and half Inhibitory Concentration (IC)50) At 10-10To 10-6mol·L-1. Ellipticine contains 3 coplanar six-membered and one five-membered rings in the molecule, and is one of the simplest natural alkaloids (FIG. 1). Since 1977 clinical studies in France were first conducted, followed by the use of ellipticine derivatives (9-hydroxy-N) in Europe, the United states2-methyl ellipticine, NSC264-137, 2, fig. 1) underwent multiple clinical phase I and phase II anticancer trials. The medicine is registered in France as medicine for treating breast cancer, and is administered at a dose of 100mg/m for most patients2The intravenous drip is more than 1 hour, and the dosage is equivalent to 2.5mg/kg of the medicine which is administrated every week. In total, more than 600 cases of various malignant tumor patients have been treated by NSC264-137, the curative effect on breast cancer is better, and particularly, the drug has no cross resistance with adriamycin and can be used for other late-stage patients with failed treatment. Clinical study was terminated in two patients with death from renal failure after 15 and 18 months of continuous use and with mutagenic effect[3-4]。
Chinese patent application No. 85107911 discloses a method for producing a class of ellipticine derivatives; chinese patent application No. 94101690.0 reports the use of a class of 9-hydroxy ellipticine ester derivatives and the preparation of these derivatives.
The following points are the main concern for the mechanism of action of ellipticine against tumors: (1) the DNA is inserted into a complementary double-helix structure of DNA as a structural analogue to inhibit the DNA replication and transcription process; (2) inhibiting the activity of DNA topoisomerase II; (3) inhibiting oxidation of cytochrome P450 enzyme. A number of studies have been made on this, Vann et al[22]Synthesizing 5-demethyl-6-N-methyl roseEllipticine, which is found to have significant topoisomerase II alpha inhibitory activity; kotrbova[23]The mechanism of anti-tumor is thought to be ellipticine in cytochrome P450 and cytochrome b5Forms oxidation products, particularly 13-hydroxy ellipticine, which binds to DNA to form ellipticine-DNA adducts and damages DNA. Amrita[24]Ellipticine was found to bind histidine in nuclear chromatin, thereby acting as an intramolecular target for achieving antitumor activity.
Disclosure of Invention
The invention aims to provide new ellipticine derivatives and pharmaceutically acceptable salts thereof, a preparation method of the derivatives and application of pharmaceutical compositions thereof in antitumor and antiviral drugs.
In order to solve the technical problem, the invention provides the following technical scheme:
in a first aspect of the present invention, there are provided ellipticine derivatives represented by the following general formula (I, II, III, IV) and pharmaceutically acceptable salts thereof:
wherein:
r is hydrogen or C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, benzyloxy, halogen, and the like;
R1is hydrogen, C1-4Alkyl, aryl;
R2is hydrogen, OH, OCH3Formyl, nitro, halogen.
Further: c1-4Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, C1-4The alkoxy is selected from methoxy, ethoxy and benzyloxy, the aryl is selected from benzene ring, and the halogen is selected from fluorine, chlorine, bromine and iodine.
Said 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:
of the ellipticine derivatives of the formula (I, II, III, IV) described above
Preferably, R is hydrogen, R1Is methyl.
Preferably, the ellipticine derivative is:
preferably, R2Hydrogen or formyl, nitro, hydroxyl and methoxy.
The pharmaceutically acceptable salts as described above include inorganic acid salts such as hydrochloride, hydrobromide, sulfate or bisulfate, nitrate, phosphate or biphosphate and the like, and organic acid salts such as formate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like.
In a second aspect of the present invention there is provided a process for the preparation of ellipticine derivatives of formula (I, II, III, IV) as follows:
the synthesis method of the general formula I:
a synthetic method of formula II:
a synthetic method of formula III:
a method of synthesis of formula IV:
the compounds of the present invention contain basic groups in the molecule and can be converted into pharmaceutically acceptable salts by acid treatment, as is recognized in the art. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate or bisulfate, nitrate, phosphate or bisulfate, and the like, and organic acid salts such as formate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like.
The invention provides the use of ellipticine derivatives of formula (I, II, III, IV) and pharmaceutically acceptable salts thereof in medicaments for the treatment of cancer, preferably non-small cell lung cancer, colon cancer, gastric cancer, leukaemia, lymphoma, brain glioma, liver cancer and the like, but not limited to the above-mentioned tumours.
A third aspect of the present invention provides a pharmaceutical composition comprising an ellipticine derivative of formula (I, II, III, IV) as defined above, characterized in that the pharmaceutical composition comprises an ellipticine derivative of formula (I, II, III, IV) and pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier or excipient.
When used as a medicament, the compounds of the present invention may be used as such or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the invention, and the balance pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers and/or excipients for humans and animals or in combination with other anti-cancer drugs. The pharmaceutical composition can be prepared into injections, tablets, capsules, pills, powder and the like.
The pharmaceutical composition of the invention can be a controlled release administration form, a sustained release administration form and various microparticle administration systems.
The compounds of the present invention may be administered orally, for example, in the form of capsules, tablets, powders, granules, syrups or the like, or parenterally by injection, ointment, suppository or the like. Such pharmaceutical preparations may be produced in a conventional manner by using auxiliary agents well known in the art, such as binders, excipients, stabilizers, disintegrants, flavoring agents, lubricants and the like, and although the dosage varies depending on the symptoms and age of the patient, the nature and severity of the disease or disorder and the route and manner of administration, in the case of oral administration to adult patients, the compound of the present invention is normally administered in a total dose of 1 to 1000mg, preferably 5 to 200mg, per day, in a single dose, or in a divided dose form; e.g., twice or three times daily; in the case of intravenous injection, a dose of 0.1 to 100mg, preferably 0.5 to 50mg, may be administered in one to three times a day.
In a fourth aspect of the present invention, there is provided the use of the ellipticine derivative and pharmaceutically acceptable salts thereof as described above in the preparation of anti-tumour or anti-viral medicaments.
The tumor of the invention is preferably non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, brain glioma and the like, but is not limited to the tumors.
The viral diseases of the present invention are preferably infectious diseases such as influenza virus, dengue virus, hand-foot-and-mouth virus, hepatitis virus, but are not limited to the above-mentioned diseases.
Advantageous technical effects
The invention provides ellipticine derivatives having general formula (I, II, III, IV), mainly characterized in that the 1,2 position of ellipticine is introduced with aryl and forms six-ring derivatives. Preliminary activity screening shows that the derivatives have the same antitumor activity as ellipticine, but the toxicity is obviously reduced, and the derivatives have better antitumor application prospect.
Drawings
FIG. 1 ellipticine derivatives against mouse liver cancer H22Growth inhibition of
Detailed Description
Abbreviations:
DMF: n, N-dimethylformamide
DMAP: 4-dimethylaminopyridine
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
THF: tetrahydrofuran (THF)
DCM: methylene dichloride
Bn: benzyl radical
Ph: phenyl radical
CTX cyclophosphamide
The invention discloses ellipticine derivatives, a preparation method thereof, and application of salts, solvates, prodrugs and pharmaceutical compositions containing the ellipticine derivatives, and can be realized by appropriately modifying process parameters by taking the contents into consideration by the technical personnel in the field. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The invention is further illustrated by the following examples:
example 1.
9,15-Dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 27mg (0.2mmol) of 2-aminobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, and 38mg (0.2mmol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDCI) were added and reacted at room temperature for 5 hours, with the precipitation of a yellow solid, which was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20 mL. times.3), combining the organic phases with saturated sodium bicarbonate solution, purified waterThe organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate overnight. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 20mg in 54.8% yield.1H NMR(400MHz,DMSO-d6)：δ11.24(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)),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).
Example 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-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 30mg (0.2mmol) of 2-amino-5-methylbenzoic acid are dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI are added, and the reaction is carried out at room temperature for 5 hours, whereupon a yellow solid precipitates, which is monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 24mg in a yield of 63.3%.1H NMR(500MHz,DMSO-d6)δ11.30(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,R3C-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.
Example 3
4,9,15-Trimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
4,9, 15-trimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 30mg (0.2mmol) of 2-amino-6-methylbenzoic acid are dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI are added, and the reaction is carried out at room temperature for 5 hours, whereupon a yellow solid precipitates, which is monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 17mg in 44.9% yield.1H NMR(500MHz,DMSO-d6)δ11.27(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.
Example 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-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
Ellipticine 25mg (0.1mmol) and 39mg (0.2mmol) 2-amino-4, 5-dimethoxybenzoic acid were dissolved in 3ml anhydrous N, N-dimethylformamide, 38mg (0.2mmol) EDCI were added and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain 17mg of a yellow solid product with a yield of 35.6%.1H NMR(500MHz,DMSO-d6)δ11.21(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.
Example 5
1,3-Dichloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
1, 3-dichloro-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 41mg (0.2mmol) of 2-amino-3, 5-dichlorobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and the reaction was complete as monitored by TLC. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After evaporating off the dichloromethaneThe obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 32mg with a yield of 74.7%.1H NMR(400MHz,DMSO-d6)δ11.27(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).
Example 6
2-Chloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
2-chloro-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 34mg (0.2mmol) of 2-amino-4-chlorobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 10mg in a yield of 25.0%.1H NMR(400MHz,DMSO-d6)δ11.26(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).
Example 7
3-Chloro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
3-chloro-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 34mg (0.2mmol) of 2-amino-5-chlorobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 36mg in 86.3% yield.1H NMR(400MHz,DMSO-d6)δ11.25(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).
Example 8
1-Fluoro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
1-fluoro-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 31mg (0.2mmol) of 2-amino-3-fluorobenzoic acid are dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI are added, the reaction is carried out at room temperature for 5 hours, a yellow solid precipitates, and the reaction is complete by TLC monitoring. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After evaporating off the dichloromethaneThe obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product 18mg in 47.0% yield.1H NMR(400MHz,DMSO-d6)δ11.23(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).
Example 9
4-Fluoro-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
4-fluoro-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 31mg (0.2mmol) of 2-amino-6-fluorobenzoic acid are dissolved in 3mL of anhydrous N, N-dimethylformamide, 38mg (0.2mmol of EDCI) are added, the reaction is carried out for 5 hours at room temperature, a yellow solid precipitates, and TLC monitoring shows that the reaction is complete, concentration, extraction of the residue with dichloromethane (20 mL. times.3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, drying over anhydrous sodium sulfate overnight, evaporation of dichloromethane, and treatment of the resulting yellow solid with anhydrous ethanol gives 29mg of the product as a yellow solid, in 75.7% yield.1H NMR(400MHz,DMSO-d6)δ11.23(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).
Example 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-methoxy-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
Ellipticine 25mg (0.1mmol) and 57mg (0.2mmol) 2-amino-4-benzyloxy-5-methoxybenzoic acid are dissolved in 3ml anhydrous N, N-dimethylformamide, 38mg (0.2mmol) EDCI are added and the reaction is allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitates and TLC monitoring shows that the reaction is complete. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a yellow solid product of 25mg in a yield of 48.5%.1H NMR(400MHz,DMSO-d6)δ11.22(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).
Example 11
9,15,16-Trimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
9,15, 16-trimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 30mg (0.2mmol) of N-methylanthranilic acid are dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI are added and the reaction is carried out for 5 hours at ambient temperature, a yellow solid precipitates and TLC monitoring shows that the reaction is complete. Concentrated, the residue extracted with dichloromethane (20 mL. times.3), and the organic phases combinedThe organic phase was washed with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution and dried over anhydrous sodium sulfate overnight. After methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol to obtain a product as a yellow solid in an amount of 20mg in a yield of 52.8%.1H NMR(400MHz,DMSO-d6)δ11.26(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).
Example 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-14 b, 15-dihydrothieno [3 ", 2": 4',5' ] pyrido [4,3-b ] carbazol-4 (9H) -one
25mg (0.1mmol) of ellipticine and 28mg (0.2mmol) of 3-amino-2-thiophenecarboxylic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI was added, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and the reaction was complete by TLC monitoring. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After the methylene chloride was distilled off, the resulting yellow solid was treated with ethyl acetate and filtered by suction to give 28mg of a yellow solid product in a yield of 75.5%.1H NMR(400MHz,DMSO-d6)δ11.21(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).
Example 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-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 43mg (0.2mmol) of N-phenylanthranilic acid are dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI are added and the reaction is carried out for 5 hours at ambient temperature, a yellow solid precipitates and TLC monitoring shows that the reaction is complete. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After the dichloromethane was distilled off, the obtained yellow solid was treated with absolute ethanol, and the product was suction filtered to obtain 23mg of a yellow solid with a yield of 52.2%.1H NMR(400MHz,DMSO-d6)δ11.15(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).
Example 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, 17 a-dihydrobenzo [6 ', 7' ] quinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 37mg (0.2mmol) of o-amino-2-naphthoic acid are dissolved in 3ml of anhydrousTo water, N-dimethylformamide was added 38mg (0.2mmol) of EDCI, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After the methylene chloride was distilled off, the obtained yellow solid was treated with anhydrous ethanol, and suction filtration was carried out to obtain 29mg of a yellow solid product with a yield of 69.9%.1H NMR(400MHz,DMSO-d6)δ11.24(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,R3C-H),6.09(d,J＝8.2Hz,1H,＝C-H),2.73(s,3H,CH3),2.44(s,3H,CH3).
Example 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-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 41mg (0.2mmol) of 5-trifluoromethyl-2-aminobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added and the reaction was allowed to proceed overnight at room temperature, as monitored by TLC. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After the methylene chloride was distilled off, the resulting yellow solid was treated with ethyl acetate, and suction filtration was carried out to obtain 10mg of a yellow solid product with a yield of 23.1%.1H NMR(400MHz,CF3COOD)δ9.55(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)
Example 16
3-bromo-9,15-dimethyl-15b,16-dihydroquinazolino[3',2':1,2]pyrido[4,3-b]carbazol-5(10H)-one
3-bromo-9, 15-dimethyl-15 b, 16-dihydroquinazolino [3',2':1,2] pyrido [4,3-b ] carbazol-5 (10H) -one
25mg (0.1mmol) of ellipticine and 43mg (0.2mmol) of 5-bromo-2-aminobenzoic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added, the reaction was allowed to proceed overnight at room temperature, and TLC monitoring showed that the reaction was complete. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After the dichloromethane was distilled off, the obtained yellow solid was treated with absolute ethanol, and the product was suction filtered to obtain 8mg of a yellow solid, with a yield of 18.1%.1H NMR(400MHz,CF3COOH-d)δ8.89(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).
Example 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-14 b, 15-dihydrothieno [3 ", 2": 4',5' ] pyrido [4,3-b ] carbazol-4 (9H) -one
Dissolving ellipticine 25mg (0.1mmol) and 30mg (0.2mmol) 3-amino-4-methyl-2-thiophenecarboxylic acid in 3ml anhydrous N, N-dimethylformamide, adding 38mg (0.2mmol) EDCI reacted for 5 hours at room temperature, a yellow solid precipitated, and TLC monitoring indicated that the reaction was complete. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the resulting yellow solid was treated with ethyl acetate, and suction filtration was carried out to obtain 12mg of a yellow solid product in a yield of 31.1%.1H NMR(400MHz,CF3COOH-d)δ9.01(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).
Example 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-14 b, 15-dihydrothieno [2 ", 3": 4',5' ] pyrimido [1',2':1,2] pyrido [4,3-b ] carbazol-4 (9H) -one
Ellipticine 25mg (0.1mmol) and 34mg (0.2mmol) 3-amino-4, 5-dimethyl-2-thiophenecarboxylic acid were dissolved in 3ml anhydrous N, N-dimethylformamide, and 38mg (0.2mmol) EDCI was added to react at room temperature for 5 hours, whereupon a yellow solid precipitated and TLC monitoring indicated that the reaction was complete. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After evaporation of the dichloromethane, the resulting yellow solid was treated with ethyl acetate and filtered by suction to give the product as a yellow solid, 7mg, in 17.5% yield.1H NMR(400MHz,CF3COOH-d)δ9.02(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)。
Example 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-tetrahydroisoquinolo [3',2':1,2] pyrido [4,3-b ] carbazole-13-carbaldehyde
27mg (0.1mmol) of 9-formyl ellipticine and 27mg (0.2mmol) of 2-carbamic acid were dissolved in 3ml of anhydrous N, N-dimethylformamide, 38mg (0.2mmol) of EDCI were added, and the reaction was allowed to proceed at room temperature for 5 hours, whereupon a yellow solid precipitated and was monitored by TLC to show completion of the reaction. Concentration, extraction of the residue with dichloromethane (20mL × 3), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution, purified water and saturated sodium chloride solution, and drying over night over anhydrous sodium sulfate. After methylene chloride was distilled off, the resulting yellow solid was treated with ethyl acetate, and suction filtration was carried out to obtain 12mg of a yellow solid product with a yield of 30.5%.1H NMR(400MHz,DMSO-d6)δ11.84(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 experiments
Experimental example 1 in vitro antitumor assay of ellipticine derivatives
Determination of tumor cell survival rate by MTT method
Cells in logarithmic phase are digested with pancreatin to prepare single cell suspension with certain concentration, and according to the difference of cell growth speed, 3000 cells are inoculated into a 96-well plate at 1500-. The next day, fresh medium containing different concentrations of drug and corresponding solvent control was added, 100. mu.l per well (DMSO final concentration)<0.1%), 4 dose groups (0.05, 0.5, 5, 50 μ) per test compoundmol/L) three parallel holes are arranged in each group. After further incubation for 96h at 37 ℃ with 5% CO2, the supernatant was discarded and 200. mu.L of freshly prepared serum-free medium containing 0.5mg/mL MTT was added to each well. Continuously culturing for 4h, removing supernatant, adding 200 μ L DMSO into each well to dissolve MTT formazan precipitate, shaking with a micro-oscillator, mixing, measuring Optical Density (OD) with an enzyme-labeling instrument at detection wavelength of 570nm, using solvent control-treated tumor cells as control group, calculating the inhibition rate of the drug on the tumor cells according to the following formula, and calculating IC according to the middle effect equation50：
The in vitro anti-tumor screening results of the derivatives are shown in Table 1
TABLE 1 ellipticine derivatives MTT screening results
HCT 116: a human colon cancer cell line; MGC 803: human gastric cancer cell lines; HT 29: a human colon cancer cell line;
MCF-7: a human breast cancer cell line; MCF-7/Taxol: human breast cancer cell strain with drug resistance to paclitaxel.
Experimental example 2 in vivo antitumor Effect of ellipticine derivative
Mouse liver cancer transplantation tumor H22 experiment
KM mice (16-18 g) are male, ascites tumor cells which grow well after 7 days of subculture are taken under aseptic condition, diluted by aseptic normal saline, the cell density is adjusted to 5 multiplied by 107 cells/ml, and 0.2ml is taken and inoculated under the axillary subcutaneous of the mice. Randomly grouping and administering the medicines the next day, and orally administering the stomach-irrigation distilled water to a control group every day; the tested medicine components are respectively prepared into liquid medicines with the concentration of 4.5mg/ml and 4.4375mg/ml, 0.4ml is administrated by intragastric administration to mice of 20g, the administration is carried out once a day, and the continuous administration is carried out for 9 days. At the end of the experiment, mice were sacrificed by dislocation, then the tumors were detached, weighed and photographed. And finally calculating the tumor inhibition rate.
The in vivo antitumor activity effect is shown in Table 2 and FIG. 1
TABLE 2 Compound on mouse liver cancer H22Growth inhibition of
P <0.05, p <0.01, p <0.001, compared to the solvent control group.
Claims (10)
1. Ellipticine derivatives of formula (I) and pharmaceutically acceptable salts thereof:
wherein
R is hydrogen, C1-4Alkyl, substituted or unsubstituted C1-4Alkoxy, halogen; the substituent is selected from halogen and benzyl; r represents 1 or 2 substitutions;
R1is hydrogen, C1-4An alkyl group;
R2is hydrogen.
2. The ellipticine derivative according to claim 1 and pharmaceutically acceptable salts thereof, wherein the halogen is selected from the group consisting of F, Cl, Br, I; said C1-4The alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl; said C1-4The alkoxy is selected from methoxy and ethoxy.
3. Ellipticine derivatives of formula (II):
wherein
R is hydrogen; r represents 1 or 2 substitutions;
R2is hydrogen.
4. The ellipticine derivative according to any of claims 1 to 3, and pharmaceutically acceptable salts thereof, which is selected from the group consisting of:
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 15:
structural formula 16:
structural formula 19:
structural formula 20:
structural formula 23:
5. the process for the preparation of the ellipticine derivative according to any of claims 1 to 4, or pharmaceutically acceptable salts thereof, wherein the compound is prepared by:
the synthesis method of the general formula I:
a synthetic method of formula II:
r is as defined in any one of claims 1 to 4.
6. A pharmaceutical composition, characterized in that it comprises the ellipticine derivative according to any of claims 1 to 5, and pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients.
7. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is selected from the group consisting of an injection, a tablet, a capsule, a pill, and a powder.
8. The pharmaceutical composition of claim 6, wherein said pharmaceutical composition is selected from the group consisting of controlled release dosage forms, sustained release dosage forms, and various microparticle delivery systems.
9. Use of the ellipticine derivative according to any of claims 1 to 4, and pharmaceutically acceptable salts thereof for the preparation of anti-tumour or anti-viral medicaments.
10. The use according to claim 9, wherein said tumor is selected from the group consisting of non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma or brain glioma; the virus is selected from hand-foot-and-mouth virus, influenza virus, retrovirus, dengue virus, hepatitis virus or herpes virus.
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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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