CN101899051A - 1-azaxanthone-3-formamide compounds as well as preparation method and antitumor application thereof - Google Patents
1-azaxanthone-3-formamide compounds as well as preparation method and antitumor application thereof Download PDFInfo
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Abstract
The invention discloses 1-azaxanthone-3-formamide compounds represented by the general formula (I) as well as a preparation method and an application thereof, relating to the field of medicine. The compounds have certain antitumor effect. In particular, the compounds show good selective toxicity toward ambulant breast cancer cells, and provide a basis for developing an antitumor drug with high effect, low toxicity and strong specificity.
Description
Technical field
The present invention relates to medical technical field, more specifically, the present invention relates to a class 1-azepine xanthone-3-Carbox amide, the invention still further relates to the preparation method and the application in the preparation antitumour drug thereof of this compounds.
Background technology
Malignant tumour is one of principal disease of serious threat human life and quality of life.According to 2007 data that the end of the year, the Ministry of Health announced, malignant tumour has become first cause of the death of China urban and rural residents.In recent years, chemotherapy of tumors has been obtained sizable progress, the tumour patient survival time obviously prolongs, particularly the treatment to leukemia, malignant lymphoma etc. has had than quantum jump, but treatment the most serious, that account for the solid tumor (comprise lung cancer, liver cancer, bladder cancer and colorectal carcinoma etc.) of malignant tumour more than 90% still fails to reach promising result to the harm humans life and health.
Along with the progress at full speed of life science, tumour mechanism is progressively illustrated, and has occurred the inhibition tumor growth factor in succession, intervenes the tumor signal conduction, has suppressed new direction such as tumor-blood-vessel growth and inducing apoptosis of tumour cell; But because the pathogenesis of malignant tumour is very complicated, clinical practice in recent years shows that they have only with the cell toxicity medicament combined utilization and just can obtain clinical efficacy preferably.Therefore, as the drug screening target, find that selectively acting is significant in the new type anticancer medicine of efficient, the low toxicity of specific target spot, high specificity with key enzyme relevant in the tumour cell with differentiation and proliferation.
Topoisomerase I (Top1) has become one of crucial target enzyme of design new type anticancer medicine in recent years.It is the indispensable enzyme of cells survival, the whole process of participate in dna replication dna, transcribing, recombinate, repairing; And in the kinds of tumor cells especially the content of Top1 such as lung cancer, cancer of the stomach, colorectal carcinoma, ovarian cancer apparently higher than normal cell.These all make Top1 inhibitor class medicine, and not only curative effect height, antitumor spectra are wide, and tumour cell is also had good selectivity, are now classified as one of six big series antineoplastic medicaments of primary study by the American National ICR.
In all kinds of Top1 inhibitor, the research of camptothecine (CPT) analog derivative is the most deep, also is the most classical specific inhibitor of Top1.In this compounds, Yi Nuo successfully goes on the market for health (CPT-11) and topotecan, is used to the treatment of metastatic colorectal cancer and obstinate ovarian cancer etc., has obtained good curative effect.Yet also there is following outstanding problem in this compounds: 1) internal metabolism instability, and active essential E cyclic lactone structure is hydrolyzed into carboxylate form too quickly in human body, and carboxylate form is not only invalid to Top1, and easilier combines with human serum albumin; 2) Top1 cutting mixture (Top1cc) time that need keep a fixed length just can be converted into dna damage, however camptothecine be easy to dissociate from Top1cc, must prolong quiet time when therefore using camptothecine clinically; 3) poorly water-soluble, the five rings conjugate planes structure of camptothecine uniqueness has stronger hydrophobicity, causes it water-soluble relatively poor; 4) there is certain toxic side effect in camptothecine, such as reduce from cell, feel sick, vomiting etc., limited safe dose and and then limited curative effect of medication; 5) resistance, the camptothecine tolerance mutant strain report of existing now several Top1, modal have an Asn722, and the sudden change of Arg364 etc. all can cause the chemical sproof generation of camptothecine.
Non-camptothecin Top1 inhibitor has become the focus of anticarcinogen research in recent years.The Indolocarbazole compounds is to study a comparatively deep class at present, J-107088 in this compounds (Edotecarin) has entered clinical study, yet there are some researches show that this compounds is not the specific inhibitor of Top1, also have the activity of arrestin kinase c or check point kinase c hk-1.In addition, LuotonineA, LamellarinD separate the Top1 inhibitor that obtains from nature in recent years, but mostly there are problems such as complex structure, poor specificity, toxic side effect are bigger in they, at present clinical widely use still have only camptothecin antineoplastic agents.
In order to find the Top1 inhibitor of brand new type, we have carried out the virtual high flux screening research of Top1 inhibitor in earlier stage, have found that successfully several quasi-medicated properties are good, the lead compound of no potential carinogenicity.Investigate based on activity, novelty and binding molecule graphics, our finally selected purchase obtains part of compounds and presses down enzyme and cytotoxic activity test, the result shows: we find that first 1-azepine xanthone-3-Carbox amide has the activity of very strong inhibition Top1, significantly be better than the marketed drug topotecan, the cytotoxic activity test result shows that logarithm kind tumour cell has shown certain anti-tumor activity.Molecular Docking Study shows that such lead compound can form two hydrogen bond actions with the crucial avtive spot residue A rg364 that we discern the Topo I target enzyme of discovery in earlier stage, amide group on the side chain can form optionally effect with the cytosine(Cyt) in DNA cleavage site downstream on the target enzyme+1, this makes this compounds compare with existing Top1 inhibitor to have greater advantages, is expected to overcome well the resistance problem of existing antitumor drug.
Need explanation, though this compounds compound can have been bought and obtains individually, the document the inside do not announce physico-chemical property, the preparation method of this compounds, and more this compounds can not be used for antineoplastic report.Therefore, our 1-azepine xanthone-3-Carbox amide of finding has first been represented the active compound for anti tumor of a class brand new.
Summary of the invention
The present invention seeks to for a class 1-azepine xanthone-3-Carbox amide is provided, or its pharmacy acceptable salt.The present invention discloses preparation method, medical use and the composition of this compounds.
The present invention is according to our guide's thing structure of obtaining of virtual high flux screening in early stage, further designed, synthesized the derivative of this compounds, active testing to kinds of tumor cells shows, this compounds has certain anti-tumor activity, it is worthy of note especially, this compounds has shown good selective toxicity to metastatic breast cancer cell, and the antitumor drug of, low toxicity efficient for being developed as, high specificity is laid a good foundation.
1-azepine xanthone of the present invention-3-Carbox amide structure is shown in logical formula I:
Or its pharmacy acceptable salt, wherein, R
1The position of substitution can be positioned at 6 to 9, can be single, double or polysubstituted, R
1Be the arbitrary class in the following groups: a) hydrogen; B) the straight or branched alkoxyl group of C1-8; C) the straight or branched alkyl of C1-8; D) halogen; M) methylene-dioxy;
R
2, R
3Represent following groups independently: the alkyl of the straight or branched of hydrogen, C1-8, replacement or unsubstituted aryl methylene, alkoxyl group, nitro, amino, the hydroxyl of the straight or branched of the described alkyl that is substituted by the straight or branched of hydrogen, halogen, C1-8, C1-8; Or R
2, R
3Form together by 3 to 7 CH
2The chain that the unit connects to form;
R
4Straight or branched alkyl for hydrogen, C1-8.
In the further preferred embodiment of the present invention, above-mentioned 1-azepine xanthone-3-Carbox amide is worked as R
1Replace and 7 when being fluorine, chlorine R for single
2And R
3Combination can not be diethyl, the tertiary butyl, benzyl, p-chlorobenzyl; Work as R
1Replace and 7 when being hydrogen R for single
2And R
3Combination can not be benzyl, p-chlorobenzyl; Work as R
1Replace and 7 when being methyl R for single
2And R
3Combination can not be the tertiary butyl, benzyl, p-chlorobenzyl.
Further, above-mentioned 1-azepine xanthone-3-Carbox amide, R
1Be substituted by single replacement, be preferably 7 single replacements.
In the preferred embodiment of the present invention, above-mentioned 1-azepine xanthone-3-Carbox amide, R
2And R
3Be combined as and replace or unsubstituted aryl methylene, alkoxyl group, nitro, amino, the hydroxyl of the straight or branched of the described alkyl that is substituted by the straight or branched of hydrogen, halogen, C1-8, C1-8; Or R
2, R
3Form together by 3 to 7 CH
2The chain that the unit connects to form.Described aryl methylene is preferably benzyl, and further the replacement on the aryl methylene is preferably hydrogen or halogen.
In the preferred embodiment of the present invention, described 1-azepine xanthone-3-Carbox amide, R
4Be preferably methyl.
Aryl of the present invention is that remaining atomic group is called aryl after removing a hydrogen atom in the aromatic hydrocarbon molecule.Aromatic hydrocarbon is the compound that a class has aromaticity, its chemical property is stable, be difficult for addition, be difficult for oxidation, replace easily and the unusual stable properties of carbocyclic ring, be different from the character of general saturated compound, comprising: 1) mononuclear aromatics, only contain a phenyl ring in the molecule, as benzene, toluene, ethylbenzene, vinylbenzene etc.; 2) polycyclic aromatic hydrocarbons contains the phenyl ring more than 2 or 2 in the molecule, as biphenyl, naphthalene, anthracene, phenanthrene etc.; 3) non-benzene aromatic hydrocarbons does not contain phenyl ring in the molecule, but contains structure and the character aromatic hydrocarbons similar to phenyl ring, and has the characteristic of aromatics, as cyclopentadienide anion etc.
Described substituted aryl is meant that the hydrogen atom on the aryl is replaced the group that obtains by other substituting group.
In an embodiment of the present invention, described 1-azepine xanthone-3-Carbox amide, each substituted radical make up to comprise and are not limited to following table:
Another object of the present invention has provided the preparation method of above-mentioned 1-azepine xanthone-3-benzamide type, comprises the following steps:
(1) preparation 3-cyano group-4-benzopyrone (II)
Earlier DMF and phosphorus oxychloride are reacted half an hour at 0 ℃, add the hydroxy acetophenone (I) that replaces again, add oxammonium hydrochloride again behind the stirring at room reaction 4h and continue to react 6h, generate 3-cyano group-4-benzopyrone (II);
(2) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III)
3-cyano group-4-benzopyrone (II), methyl aceto acetate and piperidines are refluxed in ethanol, generate 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III);
(3) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV)
With 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III) are at 50%H
2Reflux in the SO4-AcOH mixing acid, generate 2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV);
(4) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxamides (V)
With 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV) are dissolved among the DMF, add the dichloromethane solution of DCC and HOBt under 0 ℃ respectively, add amine after the stirred for several minute, stirring at room reaction 24h generates 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxamides (V).
Some 1-azepine xanthone-3-Carbox amide of the present invention can be prepared as the form of the salt of its pharmacy acceptance according to ordinary method.Comprise its inorganic acid salt and organic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc.; Organic acid includes, but is not limited to acetate, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
Compound of the present invention has good antineoplastic activity, they can be used for the treatment of tumour, comprise the cancer that positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system take place, and thyroid carcinoma, leukemia, Huo Jiejinshi disease, lymphoma and myelomatosis etc.Preferably, the tumour of being treated is a mammary cancer, more preferably, is metastatic mammary cancer.
The pharmacologically active of 1-azepine xanthone of the present invention-3-Carbox amide makes it can be used to prepare antitumor, antimycotic and antiviral, therefore the present invention also comprises with these compounds or its pharmacologically acceptable salts pharmaceutical composition as activeconstituents, also contain the carrier of pharmaceutically accepting in this pharmaceutical composition, can be solid form or liquid form, described pharmaceutical dosage form can be tablet, capsule, powder agent, granule, suspensoid or injection.
Embodiment
Below in conjunction with embodiment the present invention is done specific descriptions, but the following example should not regarded limitation of the scope of the invention as.
The preparation of embodiment 1:3-cyano group-4-benzopyrone (II)
In flask at the bottom of the garden, add DMF (20mL) and POCl
3(12mL, 0125mol), at 0 ℃ of following stirring reaction 0.5h.Adding o-hydroxyacetophenone under 0 ℃ (4.25g, 0.031mol), room temperature reaction 4h.Reaction adds CH after finishing
2Cl
2The 45mL dilution is chilled to 0 ℃, adds DMF solution (the 6.5g H of oxammonium hydrochloride again
2NOHHCl is dissolved among the 20mL DMF), stirring at room reaction 24h.Add water 35mL dilution after reaction finishes, (3 * 25mL), organic layer is used 10%NaHCO more successively with dichloromethane extraction
3Solution and saturated nacl aqueous solution washing.Anhydrous Na
2SO
4Drying is filtered, and the filtrate evaporate to dryness gets yellow solid.Recrystallizing methanol gets the brilliant 3.2g of colourless needle-like, yield 60.4.
1H-NMR(300MHz，CDCl
3)δ：7.53(1H，t，6-H)，7.55(1H，d，8-H)，7.78(1H，t，7-H)，8.25(1H，d，5-H)，8.40(1H，s，2-H)；ESI-MS(m/z)：210(M
++H+Na)；IR(KBr)cm
-1：2241，1662；m.p.176-178℃(lit.177-178℃)。
Embodiment 2:2-methyl-5-oxygen-5H-[1] preparation of chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III)
Get 3-cyano group-4-benzopyrone (II) (3.42g, 0.02mol), (2.60g's methyl aceto acetate 0.02mol) and piperidines 4mL, refluxes in 80mL ethanol.Stop to reflux after the reaction end, cooling adds water 250mL dilution, filters the solid of separating out, and is washed to neutrality, drains, and gets red crude product.(the eluent: sherwood oil: ethyl acetate=20: 1), get white crystal 2.65g, yield 46.8% of purifying on silica gel chromatographic column.
1H-NMR(300MHz，CDCl
3)δ：1.45(3H，t，2’-CH
3)，2.91(3H，s，2-CH
3)，4.42(2H，q，1’-CH
2-)，7.52(1H，t，7-H)，7.65(1H，d，9-H)，7.85(1H，t，8-H)，8.28(1H，d，6-H)，9.16(1H，s，4-H)。ESI-MS(m/z)：282(M
++Na-K)；IR(KBr)cm
-1：1715，1655；m.p.151-152℃
Embodiment 3:2-methyl-5-oxygen-5H-[1] preparation of chromene [2,3-b] pyridine-3-carboxylic acids (IV)
With 2-methyl-5-oxygen-5H-[1] (1.5g 0.0053mol) adds 50%H to chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III)
2SO
4-AcOH (1: 2) mixing acid 27mL, 130 ℃ of stirring 3h that reflux.Reaction solution is poured in the 200mL water, separated out solid, filter, washing is drained and is obtained pale solid, uses DMF-H
2The O recrystallization gets white solid 1.21g, yield 91.3%.
1H-NMR(300MHz，d
6-DMSO)δ：2.85(3H，s，2-CH
3)，7.51(1H，t，7-H)，7.71(1H，d，9-H)，7.90(1H，t，8-H)，8.15(1H，d，6-H)，8.90(1H，s，4-H)，13.56(1H，br，-COOH)。ESI-MS(m/z)：256(M+H
+)；IR(KBr)cm
-1：3103，3066，1732，1644；m.p.290-295℃。
Embodiment 4:2-methyl-5-oxygen-5H-[1] preparation of chromene [2,3-b] pyridine-3-benzyl acid amides (V)
With 2-methyl-5-oxygen-5H-[1] (1g 0.004mol) is dissolved among the 20mL DMF chromene [2,3-b] pyridine-3-carboxylic acids (IV), and frozen water is cooled to 0 ℃.Other take by weighing DCC (0.87g, 0.0042mol) and HOBt (0.57g 0.0042mol) is dissolved in 50mLCH respectively
2Cl
2In, under 0 ℃, add successively in the reaction solution, stir.Adding benzylamine under 0 ℃ (0.5mL, 0.004mol), stirred overnight at room temperature.Reaction solution is used 5% citric acid, saturated NaHCO successively
3And water washing, the organic layer anhydrous Na
2SO
4Drying is filtered, and is concentrated into dried.Use ethyl alcohol recrystallization, get white crystal 0.72g, yield 53.1%.
1H-NMR (300MHz, CDCl
3) δ: 2.85 (3H, s, 2-CH
3), 4.70 (2H, d, 2 '-CH
2-), 6.50 (1H, br ,-NH-), 7.34～7.46 (6H, m, 3 '
And 7-H), 7.64 (1H, d, 9-H), 7.80 (1H, t, 8-H), 8.24 (1H, d, 6-H), 8.65 (1H, s, 4-H).ESI-MS(m/z)：345(M+H
+)，711(2M+Na
+)；IR(KBr)cm
-1：3270，1673，1638；m.p.215-216℃
Remaining target compound is raw material with the o-hydroxyacetophenone that different groups replace with different amine respectively, repeats the step among the embodiment 1,2,3,4, obtains different 2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-amides.Agents useful for same is commercially available analytical pure among the embodiment.
Partly the chemical structure and the characterization data of synthetic compound are as follows in the present invention.
Table 1 part is the structure of synthetic compound
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-methyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-methyl-3-amide
1H?NMR(300MHz，CDCl
3)δ2.83(3H，s，2-CH
3)，3.09(3H，d，2’-CH
3)，6.21(1H，br，-NH-)，7.45(1H，t，7-H)，7.60(1H，d，9-H)，7.80(1H，t，8-H)，8.25(1H，d，6-H)，8.62(1H，s，4-H)；ESI-MS(m/z)：269(M+H
+)；IR(KBr)cm
-1：3275，1673，1642；m.p.277-278℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-ethyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-ethyl-3-amide
1H?NMR(300MHz，CDCl3)δ：1.32(3H，t，3’-CH
3)，2.84(3H，s，2-CH
3)，3.55(2H，m，2’-CH
2)，6.05(1H，br，-NH-)，7.46(1H，t，7-H)，7.63(1H，d，9-H)，7.82(1H，t，8-H)，8.30(1H，d，6-H)，8.65(1H，s，4-H).ESI-MS(m/z)：283(M+H
+)；IR(KBr)cm
-1：3274，1670，1637；m.p.252-254℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-n-propyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-propyl-3-amide
1H?NMR(300MHz，CDCl3)δ1.04(3H，t，4’-CH
3)，1.68(2H，m，3’-CH
2)，2.80(3H，s，2-CH
3)，3.48(2H，m，2’-CH
2)，6.22(1H，br，-NH-)，7.48(1H，t，7-H)，7.61(1H，d，9-H)，7.81(1H，t，8-H)，?8.25(1H，d，6-H)，8.61(1H，s，4-H).ESI-MS(m/z)：295(M-H+)；IR(KBr)cm-1：3281，1671，1634；m.p.211-212℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-sec.-propyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-isopropyl-3-amide
1H?NMR(300MHz，CDCl3)δ：1.29(6H，dd，3’-CH
3×2)，2.84(3H，s，2-CH
3)，4.33(1H，m，2’-CH)，5.85(1H，br，-NH-)，7.47(1H，t，7-H)，7.64(1H，d，9-H)，7.82(1H，t，8-H)，8.32(1H，d，6-H)，8.63(1H，s，4-H)；ESI-MS(m/z)：297(M+H
+)；IR(KBr)cm-1：3274，1671，1636；m.p.240-241℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-normal-butyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-butyl-3-amide
1H?NMR(300MHz，CDCl
3)δ1.01(3H，t，5’-CH
3)，1.48(2H，m，4’-CH
2-)，1.66(2H，m，3’-CH
2-)，2.83(3H，s，2-CH
3)，3.52(2H，q，2’-CH
2-)，6.10(1H，br，-NH-)，7.46(1H，t，7-H)，7.63(1H，d，9-H)，7.81(1H，t，8-H)，8.28(1H，d，6-H)，8.63(1H，s，4-H)；ESI-MS(m/z)：311(M+H
+)；IR(KBr)cm
-1：3285，1671，1634；m.p.193-195℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-benzyl-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-benzyl-3-amide
1H?NMR(300MHz，CDCl
3)δ2.85(3H，s，2-CH
3)，4.70(2H，d，2’-CH
2-)，6.50(1H，br，-NH-)，7.34～7.46(6H，m，Ar-H)，7.64(1H，d，9-H)，7.80(1H，t，8-H)，8.24(1H，d，6-H)，8.65(1H，s，4-H)；ESI-MS(m/z)：345(M+H)
+，711(2M+Na)
+；IR(KBr)cm
-1：3270，1673，1638.m.p.215-216℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-benzyl chloride base)-3-acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-chlorobenzyl)-3-amide
1H-NMR(300MHz，CDCl
3)δ2.84(3H，s，2-CH
3)，4.65(2H，d，2’-CH
2-)，6.49(1H，br，-NH-)，7.34(4H，m，Ar-H)，7.45(1H，t，7-H)，7.61(1H，d，9-H)，7.80(1H，t，8-H)，8.24(1H，d，6-H)，8.64(1H，s，4-H)；ESI-MS(m/z)：379(M+H)
+，779(2M+Na)
+；IR(KBr)cm
-1：3308，1672，1637；m.p.240-241℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-piperidyl amide
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-3-piperidyl?amide
1H?NMR(300MHz，CDCl
3)δ1.55(2H，m，4’-CH
2-)，1.73(4H，m，3’，5’-CH
2-×2)，2.71(3H，s，2-CH
3)，3.26(2H，t，6’-CH
2-)，3.81(2H，t，2’-CH
2-)，7.46(1H，t，7-H)7.62(1H，d，9-H)，7.81(1H，t，8-H)，8.32(1H，d，6-H)，8.50(1H，s，4-H)；ESI-MS(m/z)：323(M+H)
+；IR(KBr)cm
-1：1651，1635；m.p.194-195℃
2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-pyrryl acid amides
2-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-3-pyrrolidinyl?amide
1H?NMR(300MHz，CDCl
3)δ1.99(4H，m，3’，4’-CH
2-×2)，2.72(3H，s，2-CH
3)，3.28(2H，t，2’-CH
2-)，3.72(2H，t，5’-CH
2-)，7.48(1H，t，7-H)，7.62(1H，d，9-H)，7.80(1H，t，8-H)，8.30(1H，d，6-H)，8.56(1H，s，4-H)；ESI-MS(m/z)：309(M+H
+)，348(M+K)
+，639(2M+Na
+)；IR(KBr)cm
-1：1664，1629；m.p.159-160℃
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-methyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-methyl-3-amide
1H?NMR(300MHz，CDCl
3)δ2.50(3H，s，7-CH
3)，2.84(3H，s，2-CH
3)，3.08(3H，d，2’-CH
3)，6.11(1H，br，-NH-)，7.52(1H，d，9-H)，7.60(1H，d，8-H)，8.07(1H，s，6-H)，8.65(1H，s，4-H)；ESI-MS(m/z)：283(M+H)
+；IR(KBr)cm
-1：3277，1664，1643；m.p.279-281℃.
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-ethyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-ethyl-3-amide
1H-MR(300MHz，CDCl
3)δ：1.32(3H，t，CH
3)，2.50(3H，s，CH
3)，2.83(3H，s，CH
3)，3.55(2H，q，CH
2)，6.04(1H，br，NH)，7.52(1H，d，Ar-H)，7.61(1H，d，Ar-H)，8.08(1H，s，Ar-H)，8.64(1H，s，4-H)；ESI-MS(m/z)：297.46(M+H)
+；IR(KBr)cm
-13274，1672，1637；m.p.258-260℃
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-n-propyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-propyl-3-amide
1H?NMR(300MHz，CDCl
3)δ：1.05(3H，t，4’-CH
3)，1.71(2H，m，3’-CH
2)，2.50(3H，s，7-CH
3)，2.82(3H，s，2-CH
3)，3.49(2H，m，2’-CH
2)，6.11(1H，br，-NH-)，7.51(1H，d，9-H)，7.61(1H，d，8-H)，8.07(1H，s，6-H)，8.63(1H，s，4-H)；EI-MS(m/z)：351(M+K
+)，311(M+H
+)；IR(KBr)cm
-1：3284，1669，1635；m.p.221-222℃
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-sec.-propyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-isopropyl-3-amide
1H?NMR(300MHz，CDCl
3)δ1.33(6H，d，3’-CH
3×2)，2.51(3H，s，7-CH
3)，2.83(3H，s，2-CH
3)，4.32(1H，m，2’-CH)，5.85(1H，br，-NH-)，7.52(1H，d，9-H)，7.61(1H，d，8-H)，8.09(1H，s，6-H)，8.61(1H，s，4-H).ESI-MS(m/z)：311(M+H
+).IR(KBr)cm
-1：3298，1674，1633.m.p.254-256℃.
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-normal-butyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-butyl-3-amide
1H?NMR(300MHz，CDCl
3)δ1.01(3H，t，5’-CH
3)，1.48(2H，m，4’-CH
2-)，1.69(2H，m，3’-CH
2-)，2.49(3H，s，7-CH
3)，2.77(3H，s，2-CH
3)，3.51(2H，q，2’-CH
2-)，6.32(1H，br，-NH-)，7.48(1H，d，9-H)，7.60(1H，d，8-H)，8.01(1H，s，6-H)，8.57(1H，s，4-H).ESI-MS(m/z)：365(M+2H
++K
+).IR(KBr)cm
-1：3298，1674，1633.m.p.220-221℃.
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-benzyl-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-benzyl-3-amide
1H?NMR(300MHz，CDCl
3)δ2.47(3H，s，7-CH
3)，2.83(3H，s，2-CH
3)，4.69(2H，d，2’-CH
2)，6.51(1H，br，-NH-)，7.32～7.41(5H，m，Ar-H)，7.51(1H，d，9-H)，7.61(1H，d，8-H)，8.01(1H，s，6-H)，8.64(1H，s，4-H).ESI-MS(m/z)：739(2M+Na
+)，399(M+K
+)，359(M+H
+).IR(KBr)cm
-1：3270，1673，1633.m.p.248-249℃.
2-methyl-7-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-benzyl chloride base)-3-acid amides
2-methyl-7-methyl-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-chlorobenzyl)-3-amide
1H?NMR(300MHz，CDCl
3)δ2.49(3H，s，7-CH
3)，2.84(3H，s，2-CH
3)，4.65(2H，d，2’-CH
2)，6.53(1H，br，NH)，7.35(4H，d，Ar-H)，7.51(1H，d，9-H)，7.61(1H，d，8-H)，8.01(1H，s，6-H)，8.65(1H，s，4-H).ESI-MS(m/z)：393(M+H
+).IR(KBr)cm
-1：3277，1671，1635.m.p.245-246℃
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-n-propyl-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-propyl-3-amide
1H-NMR(300MHz，DMSO-d
6)δ0.93(t，3H，CH
3)，1.56(sext，2H，CH
2)，2.66(s，3H，CH
3)，3.24(m，2H，CH
2)，7.77(d，1H，J＝9.0Hz，Ar-H)，7.94(dd，1H，J
1＝8.7Hz，J
2＝2.4Hz，Ar-H)，8.07(s，1H，Ar-H)，8.46(s，1H，Ar-H)，8.71(br，1H，J＝5.4Hz，NH).ESI-MS(m/z)：329.63(M-H
-).IR(KBr)cm
-1：3283，1635，1671；m.p.256-258℃
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-sec.-propyl-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-isopropyl-3-amide
1H?NMR(300MHz，CDCl
3)δ1.33(6H，d，2CH
3)，2.85(3H，s，2-CH
3)，4.32(1H，m，CH)，5.80(1H，br，NH)，7.60(1H，d，9-H)，7.76(1H，d，8-H)，8.28(1H，s，6-H)，8.62(1H，s，4-H).ESI-MS(m/z)：331(M+H
+).IR(KBr)cm
-1：3282，1672，1637.m.p.280-281℃.
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-normal-butyl-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-n-butyl-3-amide
1H?NMR(300MHz，DMSO-d
6)δ0.92(t，3H，CH
3)，1.36(m，2H，CH
2)，1.51(m，2H，CH
2)，2.67(s，3H，CH
3)，3.27(m，2H，CH
2)，7.81(d，1H，J＝9.0Hz，Ar-H)，8.11(d，1H，J＝2.4Hz，Ar-H)，8.48(s，1H，Ar-H)，8.70(br，1H，J＝5.4Hz，NH).IR(KBr)cm
-1：3279，1698，1673.m.p.242-244℃.
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-hydroxyethyl-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-hydroxylethyl-3-amide
1H?NMR(300MHz，DMSO-d
6)δ1.24(m，2H，CH
2)，2.67(s，3H，CH
3)，3.54(m，2H，J＝5.7Hz，CH
2)，4.84(t，1H，J＝5.7Hz，OH)，7.81(d，1H，J＝9.0Hz，Ar-H)，7.99(dd，1H，J
1＝9.0Hz，J
2＝2.7Hz，Ar-H)，8.11(d，1H，J＝2.7Hz，Ar-H)，8.56(s，1H，Ar-H)，8.72(br，1H，J＝5.4Hz，NH).ESI-MS(m/z)：333.27(M+H
+).IR(KBr)cm
-1：3274，1681，1636.m.p.249-251℃.
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-benzyl-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-benzyl-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.68(s，3H，CH
3)，4.45(d，2H，J＝5.7Hz，CH
2)，7.28(dd，1H，J1＝8.4Hz，J
2＝4.2Hz，Ar-H)，7.37(d，4H，J＝5.2Hz，Ar-H)，7.78(d，1H，J＝9.0Hz，Ar-H)，7.94(dd，1H，J
1＝9.0Hz，J
2＝2.7Hz，Ar-H)，8.07(d，1H，J＝2.7Hz，Ar-H)，8.54(s，1H，Ar-H)，9.27(t，1H，J＝5.7Hz，NH).ESI-MS(m/z)：377.35(M-H)
-.IR(KBr)cm
-1：3269，1675，1634.m.p.268-270℃.
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-luorobenzyl)-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-flurobenzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.68(s，3H，CH
3)，4.48(d，2H，J
2＝6.0Hz，CH
2)，7.16-7.22(m，2H，Ar-H)，7.39-7.44(m，2H，Ar-H)，7.80(d，1H，J＝9.0Hz，Ar-H)，7.96(dd，1H，J
1＝9.0Hz，J
2＝2.7Hz，Ar-H)，8.10(d，1H，J＝2.4Hz，Ar-H)，8.56(s，1H，Ar-H)，9.25(t，1H，J＝6.0Hz，NH).ESI-MS(m/z)：395.62(M-H)
-.IR(KBr)cm
-1：3270，1677，1635.m.p.269℃(dec).
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-benzyl chloride base)-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-chlorobenzyl)-3-amide
1H?NMR(300MHz，CDCl
3)δ2.86(s，3H，CH
3)，4.64(d，2H，J＝5.7Hz，CH
2)，6.28(br，1H，NH)，7.32-7.39(m，4H，Ar-H)，7.59(d，1H，J＝8.7Hz，Ar-H)，7.75(dd，1H，J
1＝9.0Hz，J
2＝2.4Hz，Ar-H)，8.25(d，1H，J＝2.7Hz，Ar-H)，8.65(s，1H，Ar-H).ESI-MS(m/z)：411.64(M-H)
-.IR(KBr)cm
-1：3273，1674，1634.m.p.248℃(dec).
2-methyl-7-chloro-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-methyl-benzyl)-3-acid amides
2-methyl-7-chloro-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-methylbenzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.29(s，3H，CH
3)，2.68(s，3H，CH
3)，4.44(d，2H，J＝5.7Hz，CH
2)，7.17(d，2H，J＝8.1Hz，Ar-H)，7.26(d，2H，J＝8.1Hz，Ar-H)，7.81(d，1H，J＝9.0Hz，Ar-H)，7.97(dd，1H，J
1＝9.0Hz，J
2＝2.7Hz，Ar-H)，8.11(d，1H，J＝2.7Hz，Ar-H)，8.54(s，1H，Ar-H)，9.23(br，1H，NH).ESI-MS(m/z)：391.74(M-H)
-.IR(KBr)cm
-1：3277，1675，1635.m.p.261℃(dec).
2-methyl-7-methoxyl group-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-normal-butyl)-3-acid amides
2-methyl-7-methoxy-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-n-butyl)-3-amide
1H?NMR(300MHz，CDCl
3)δ0.92(t，3H，CH
3)，1.40(m，2H，CH
2)，1.52(m，2H，CH
2)，2.67(s，3H，CH
3)，3.26(m，2H，CH
2)，3.95(s，3H，OCH
3)，7.10(dd，1H，J
1＝8.7Hz，J
2＝2.4Hz，Ar-H)，7.26(d，1H，J＝2.4Hz，Ar-H)，8.09(d，1H，J＝9.0Hz，Ar-H)，8.45(s，1H，Ar-H)，8.68(br，1H，J＝5.4Hz，NH).ESI-MS(m/z)：341.66(M+H)
+.IR(KBr)cm
-1：3280，1694，1634.m.p.248-250℃.
2-methyl-7-methoxyl group-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-benzyl-3-acid amides
2-methyl-7-methoxy-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-benzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.68(s，3H，CH
3)，3.94(s，3H，OCH
3)，4.50(d，2H，J＝5.7Hz，CH
2)，7.09(dd，1H，J
1＝9.0Hz，J
2＝2.4Hz，Ar-H)，7.24(d，1H，J＝2.4Hz，Ar-H)，7.28(d，1H，J＝4.5Hz，Ar-H)，7.37(d，4H，J＝4.5Hz，Ar-H)，8.08(d，1H，J＝9.0Hz，Ar-H)，8.53(s，1H，Ar-H)，9.23(br，1H，NH).ESI-MS(m/z)：373.72(M-H)
-.IR(KBr)cm
-1：3270，1663，1634.m.p.268-270℃.
2-methyl-7-methoxyl group-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-luorobenzyl)-3-acid amides
2-methyl-7-methoxy-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-flurobenzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.67(s，3H，CH
3)，3.95(s，3H，OCH
3)，4.47(d，2H，J＝6.0Hz，CH
2)，7.08-7.26(m，4H，Ar-H)，7.39-7.43(m，2H，Ar-H)，8.09(d，1H，J＝9.0Hz，Ar-H)，8.53(s，1H，Ar-H)，9.23(br，1H，J＝6.0Hz，NH).EI-MS(m/z)：393.72(M+H)
+.IR(KBr)cm
-1：3292，1716，?1662.m.p.295-297℃.
2-methyl-7-methoxyl group-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-benzyl chloride base)-3-acid amides
2-methyl-7-methoxy-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-chlorobenzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.67(s，3H，CH
3)，3.95(s，3H，OCH
3)，4.48(d，2H，J＝6.0Hz，CH
2)，7.10(dd，1H，J
1＝9.0Hz，J
2＝2.4Hz，Ar-H)，7.25(d，1H，J＝2.4Hz，Ar-H)，7.38-7.45(m，4H，Ar-H)，8.09(d，1H，J＝8.7Hz，Ar-H)，8.54(s，1H，Ar-H)，9.24(br，1H，J＝6.0Hz，NH).ESI-MS(m/z)：407.56M-H)
-.IR(KBr)cm
-1：3294，1716，1662.m.p.270℃(dec).
2-methyl-7-methoxyl group-5-oxygen-5H-[1] chromene [2,3-b] pyridine-N-(4-methyl-benzyl)-3-acid amides
2-methyl-7-methoxy-5-oxo-5H-[1]benzopyrano[2，3-b]pyridine-N-(4-methylbenzyl)-3-amide
1H?NMR(300MHz，DMSO-d
6)δ2.29(s，3H，CH
3)，2.67(s，3H，CH
3)，3.95(s，3H，OCH
3)，4.44(d，2H，J＝5.7Hz，CH
2)，7.10(dd，1H，J
1＝9.0Hz，J
2＝2.4Hz，Ar-H)，7.17(d，2H，J＝7.8Hz，Ar-H)，7.25(d，2H，J＝3.9Hz，Ar-H)，7.26(d，1H，J＝3.9Hz，Ar-H)，8.09(d，1H，J＝9.0Hz，Ar-H)，8.50(s，1H，Ar-H)，9.19(br，1H，NH).EI-MS(m/z)：389.61(M+H)
+.IR(KBr)cm
-1：3257，1662，1637.m.p.275-277℃.
Embodiment 5: the cytotoxicity of compound of the present invention
(1) experiment material and method:
1. experiment material
(1) experimental strain
This experiment has adopted 3 kinds of human cancer cell strains as the screening object, and this JEG-3 provides by Shanghai Institute of Pharmaceutical Industry's Pharmacology Lab.
1) human lung cancer cell A549
2) human colon cancer cell Colo205
3) human breast cancer cell MDA-MB-435
(2) nutrient solution is that RPMI1640+15%NBS+ is two anti-.Used full-automatic microplate reader model is: WellscanMK-2, production firm: Labsystems.Import 96 well culture plates etc.
2. experimental technique
The extracorporeal anti-tumor tumor activity adopts mtt assay.
Sample preparation: after DMSO (Merck) dissolving, add solution or uniform suspension that PBS (-) is made into 1000 μ g/ml, then with PBS (-) dilution that contains DMSO.
Nutrient solution: RPMI640+15%NBS+ is two anti-
Positive control medicine: hydroxycamptothecine
Experimental procedure is as follows:
Every hole adding concentration is 4～5 * 10 in 96 well culture plates
4The cell suspension 1000 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5m g/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and the 570nmOD value is surveyed with the full-automatic microplate reader of MK-2 in the dissolving back.
(2) experimental result
Table 2.29 compound is to the in-vitro multiplication restraining effect of human body tumour cell
Example 6: topoisomerase I suppresses activity test
Utilization literature method (Kingsbury WD, Boehm JC, Jakas DR, et al.J Med Chem, 1991,34,98-107), part of compounds has been carried out topoisomerase I suppressed activity test, found that they have the activity of good inhibition Top1 in the 0.01-100uM scope.
To sum up, The compounds of this invention has certain antitumor action, it is worthy of note especially, this compounds has shown good selective toxicity to metastatic breast cancer cell, the antitumor drug of, low toxicity efficient for being developed as, high specificity is laid a good foundation, and has good exploitation and is worth.1-azepine xanthone of the present invention-3-Carbox amide is being represented the compound with anti-tumor activity of a class brand new, and this is for furtheing investigate and developing new antitumor drug and opened up new approach and direction.
Claims (13)
1. the 1-azepine xanthone-3-Carbox amide of a class shown in general formula (I):
Or its pharmacy acceptable salt, wherein, R
1The position of substitution can be positioned at 6 to 9, can be single, double or polysubstituted, R
1Be the arbitrary class in the following groups: a) hydrogen; B) the straight or branched alkoxyl group of C1-8; C) the straight or branched alkyl of C1-8; D) halogen; M) methylene-dioxy;
R
2, R
3Represent following groups independently: the alkyl of the straight or branched of hydrogen, C1-8, replacement or unsubstituted aryl methylene, alkoxyl group, nitro, amino, the hydroxyl of the straight or branched of the described alkyl that is substituted by the straight or branched of hydrogen, halogen, C1-8, C1-8; Or R
2, R
3Form together by 3 to 7 CH
2The chain that the unit connects to form;
R
4Straight or branched alkyl for hydrogen, C1-8.
2. by the described 1-azepine xanthone of claim 1-3-Carbox amide, it is characterized in that,
Work as R
1Replace and 7 when being fluorine, chlorine R for single
2And R
3Combination can not be diethyl, the tertiary butyl, benzyl, p-chlorobenzyl;
Work as R
1Replace and 7 when being hydrogen R for single
2And R
3Combination can not be benzyl, p-chlorobenzyl;
Work as R
1Replace and 7 when being methyl R for single
2And R
3Combination can not be the tertiary butyl, benzyl, p-chlorobenzyl.
3. by the described 1-azepine xanthone of claim 1 to 2-3-Carbox amide, it is characterized in that R
1Be substituted by single replacement.
4. by the described 1-azepine xanthone of claim 1 to 3-3-Carbox amide, it is characterized in that R
1Replace and be positioned at 7.
5. by the described 1-azepine xanthone of claim 1 to 4-3-Carbox amide, it is characterized in that described aryl methylene is a benzyl.
6. by the described 1-azepine xanthone of claim 1 to 5-3-Carbox amide, it is characterized in that described R
2, R
3During for replacement or unsubstituted aryl methylene, the described hydrogen or halogen that is substituted by.
7. by the described 1-azepine xanthone of claim 1 to 6-3-Carbox amide, it is characterized in that R
4Be methyl.
8. by the described 1-azepine xanthone of claim 1-3-Carbox amide, comprise:
9. the preparation method of the 1-azepine xanthone-3-Carbox amide described in the claim 1 to 8 may further comprise the steps:
(1) preparation 3-cyano group-4-benzopyrone (II)
Earlier DMF and phosphorus oxychloride are reacted half an hour at 0 ℃, add the hydroxy acetophenone (I) that replaces again, add oxammonium hydrochloride again behind the stirring at room reaction 4h and continue to react 6h, generate 3-cyano group-4-benzopyrone (II);
(2) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III)
3-cyano group-4-benzopyrone (II), methyl aceto acetate and piperidines are refluxed in ethanol, generate 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III);
(3) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV)
With 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acid ethyl esters (III) are at 50%H
2Reflux in the SO4-AcOH mixing acid, generate 2-methyl-5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV);
(4) preparation 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxamides (V)
With 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxylic acids (IV) are dissolved among the DMF, add the dichloromethane solution of DCC and HOBt under 0 ℃ respectively, add amine after the stirred for several minute, stirring at room reaction 24h generates 5-oxygen-5H-[1] chromene [2,3-b] pyridine-3-carboxamides (V).
10. according to the application of the described 1-azepine xanthone of claim 1 to 8-3-Carbox amide in the preparation antitumor drug.
11., it is characterized in that tumour is a mammary cancer according to of the application of described this compounds of claim 1 to 8 at the preparation antitumor drug.
12., it is characterized in that tumour is a metastatic breast cancer according to of the application of described this compounds of claim 1 to 8 at the preparation antitumor drug.
13. a composition, the carrier that contains the described arbitrary 1-azepine xanthone of claim 1-8-3-Carbox amide or its pharmacy acceptable salt and pharmaceutically accept.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610219A (en) * | 2015-01-14 | 2015-05-13 | 云南民族大学 | Xanthone compound with isopentene oxide group as well as preparation method and application of xanthone compound |
| CN111961046A (en) * | 2020-08-12 | 2020-11-20 | 上海诺精生物科技有限公司 | Compound for improving sensitivity of PCa drug-resistant cells to antagonist and application thereof |
| CN112010852A (en) * | 2020-08-12 | 2020-12-01 | 上海诺精生物科技有限公司 | Compound for inhibiting PCa cell transfer and application |
| CN113200989A (en) * | 2021-05-18 | 2021-08-03 | 云南民族大学 | Preparation method and application of chromone alkaloid compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0102175A1 (en) * | 1982-08-20 | 1984-03-07 | Takeda Chemical Industries, Ltd. | 5-Oxo-5H-(1)benzopyrano(2,3-b)pyridine derivatives, their production and use |
| WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
| WO2008020269A2 (en) * | 2005-12-13 | 2008-02-21 | Supratek Pharma, Inc. | A method of treating tumors with azaxanthones |
-
2010
- 2010-05-17 CN CN 201010176290 patent/CN101899051B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0102175A1 (en) * | 1982-08-20 | 1984-03-07 | Takeda Chemical Industries, Ltd. | 5-Oxo-5H-(1)benzopyrano(2,3-b)pyridine derivatives, their production and use |
| WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
| WO2008020269A2 (en) * | 2005-12-13 | 2008-02-21 | Supratek Pharma, Inc. | A method of treating tumors with azaxanthones |
Non-Patent Citations (2)
| Title |
|---|
| 《STN Registry》 20010626 ACS RN 338778-93-1,343375-47-3,343375-46-2,338778-91-9, 338778-31-7,338778-29-3，338778-25-9, 338778-23-7, 338751-41-0, 338751-39-6,338417-62-2，338417-61-1,338417-60-0 1,3-4,6-7 , * |
| 《Tetrahedron Letters》 20040119 G.Jagath Reddy et.al. A mild, one-pot synthesis of 3-cyano-4-benzopyrones from 2-hydroxyacetophenones 第847-848页 9 第45卷, 第4期 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610219A (en) * | 2015-01-14 | 2015-05-13 | 云南民族大学 | Xanthone compound with isopentene oxide group as well as preparation method and application of xanthone compound |
| CN104610219B (en) * | 2015-01-14 | 2016-08-24 | 云南民族大学 | A kind of xanthones compound with oxidation isopentene group and its preparation method and application |
| CN111961046A (en) * | 2020-08-12 | 2020-11-20 | 上海诺精生物科技有限公司 | Compound for improving sensitivity of PCa drug-resistant cells to antagonist and application thereof |
| CN112010852A (en) * | 2020-08-12 | 2020-12-01 | 上海诺精生物科技有限公司 | Compound for inhibiting PCa cell transfer and application |
| CN112010852B (en) * | 2020-08-12 | 2021-09-07 | 上海诺精生物科技有限公司 | Compound for inhibiting PCa cell transfer and application |
| CN111961046B (en) * | 2020-08-12 | 2021-09-07 | 上海诺精生物科技有限公司 | Compound for improving sensitivity of PCa drug-resistant cells to antagonist and application thereof |
| CN113200989A (en) * | 2021-05-18 | 2021-08-03 | 云南民族大学 | Preparation method and application of chromone alkaloid compound |
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| Publication number | Publication date |
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| CN101899051B (en) | 2013-03-20 |
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