CN102532150A - Alkoxyl dibenzoazepine compound, and preparation method and medical application thereof - Google Patents
Alkoxyl dibenzoazepine compound, and preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to an alkoxyl dibenzoazepine compound, and a preparation method and medical application thereof, discloses an alkoxyl dibenzoazepine compound capable of inhibiting activity of P-glycoprotein and reversing multidrug resistance of tumor and shown as a general formula I or pharmaceutically acceptable salt thereof, and a preparation method and medical application thereof, and belongs to the field of biomedicine. The preparation method for the compound is mild in reaction condition, simple in operation, high in yield and high in practicability and universality. The result of a pharmacological test shows that the compound has excellent effects of inhibiting activity of the P-glycoprotein and increasing sensitivity on chemotherapy and can serve as tumor multidrug resistance reversing agent for clinical application.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to one type of alkoxyl group dibenzazepines compounds.This compounds can be used for preparing P-glycoprotein inhibitors and multidrug resistance reversing agent.The drug regimen that the invention still further relates to the preparation method of this compounds and contain them.
Background technology
The major reason that causes chemotherapy of tumors failure be tumour cell multidrug resistance that medicine is produced (multidrug resistance, MDR).P-gp in the tumour cell (P-glycoprotein, over-expresses P-gp) be the major reason that causes MDR to produce (Chem.Rev.2009,109,2989-3011.).The substrate that to surpass 200 chemotherapeutics molecules in clinical are P-gp (Methods.Mol.Biol.2010,596,405-432.), these medicines in case with the P-gp combination, will be pumped out outside the tumour cell, thereby reduce intracellular drug level, cause the failure of chemotherapy.In addition, P-gp can stop apoptosis through suppressing the activation of casepases, cause cell produce the apoptosis tolerance (Cell Death.Differ.2004,11,1028-1037.).Research shows, suppresses P-gp and can improve chemotherapeutics in intracellular accumulation, improves the susceptibility of mdr cell to chemotherapeutics, inducing apoptosis of tumour cell, and then reversion MDR.Therefore, seek and medicine that research suppresses P-gp has become and overcomes one of MDR hot research fields.
Up to now, the research and development of P-gp suppressor factor experienced altogether four-stage (Methods Mol.Biol.2010,596,405-432.).First three for the problem that suppressor factor faces is: 1, suppressor factor is to the poor selectivity of P-gp; 2, suppressor factor suppresses active low to P-gp; 3, the toxicity of suppressor factor self; 4, suppressor factor influences the cancer therapy drug pharmacokinetic property, has increased the toxic side effect of medicine etc.In addition, P-gp expresses in healthy tissues equally, mainly is distributed in intestinal epithelial cells, renal proximal tubular cell, hepatic duct cytolemma; And epithelial cell (the Drug Metab.Dispos.2002 of blood brain, blood testis and placenta; 30,838-844.), and pass through process (the Expert Opin.Drug Metab.Toxicol.2008 that the outflow pump is participated in secretion exogenous material and toxic metabolites; 4,205-223.).After the normal function of P-gp was suppressed, anticarcinogen metabolism and drainage in vivo was affected, and the Plasma Concentration level improves, and has increased its toxicity to healthy tissues.Therefore, be badly in need of development of new P-gp suppressor factor efficiently.
Discover; Many natural products such as flavonoid, curcumin, deoxyschizandrin and third element etc. are in the peculiar advantage that shows aspect the inhibition P-gp activity; Like low toxicity, tolerance etc. preferably, make natural product and verivate thereof become new hope and the opportunity of suppressor factor exploitation.From natural product and verivate exploitation P-gp suppressor factor become the suppressor factor research and development of the 4th generation new direction and emphasis (Expert Opin.Drug Metab.Toxicol.2008,4,205-223.).
Biphenylylmethylcarbinol (DDB) is one type of alkoxyl group biphenyl compound that is derived from Wuweizisu C, be used to treat hepatitis clinically the enzyme medicine falls.Research shows that Biphenylylmethylcarbinol has anti-tumor activity, and can efflux through intake, the minimizing substrate of raising drug-resistant tumor cell to the P-gp substrate; Reduce the expression of P-gp simultaneously, produce activity (Invest.New Drugs.2007,25 of reverse multiple drug resistance of tumor; 95-105.); And DDB and anticarcinogen coupling do not influence the pharmacokinetic property of cancer therapy drug, so can not increase the toxic side effect of anticarcinogen.
In order to obtain the stronger P-gp suppressor factor of anti-MDR activity, we are guide's thing with DDB, develop the structure activity relationship of summing up over nearly 30 years according to the P-gp suppressor factor, design, synthesized a series of alkoxyl group dibenzazepines compounds.Biological activity test is the result show, this compounds has significant P-gp restraining effect, can be through the outer row function of inhibition P-gp, and reversion MDR, its activity significantly is better than positive control drug verapamil (VRP).
Summary of the invention
The invention discloses one type of alkoxyl group dibenzazepines compounds, its preparation method and medicinal use.Pharmacological evaluation proves that this compounds has good P-gp and suppresses active, can significantly improve the susceptibility of drug-resistant tumor to chemotherapeutic.Therefore, they can be used as multidrug resistance reversing agent clinically.
Compound of the present invention is shown in general formula I:
Wherein:
R
1Represent Wasserstoffatoms, C
1-C
10Straight or branched alkyl or form carbonyl with the carbon atom that links to each other;
R
2Represent Wasserstoffatoms, C
1-C
10Straight or branched alkyl, (CH
2)
nNR
3R
4, (CH
2)
nR
5Or CHR
6COOR
7
R
3And R
4Can be identical or different, and independent Wasserstoffatoms, the C of representing
1-C
5Straight or branched alkyl or R
3And R
4The nitrogen-atoms that connects with them forms 5 to 7 yuan of aliphatic heterocycles, and described aliphatic heterocycle also comprises morpholine ring, piperazine ring or contains 4-methyl, the substituted piperazine ring of benzyl;
R
5Representation hydroxy, halogen, phenyl or substituted-phenyl, described substituted-phenyl can at random be replaced to five replacements by following identical or different substituting group list, and said substituting group is C
1-C
6Straight or branched alkyl, C
1-C
6Alkoxyl group, hydroxyl or halogen;
R
6Represent Wasserstoffatoms, C
1-C
5Straight or branched alkyl, phenyl or benzyl;
R
7Represent C
1-C
5The straight or branched alkyl;
Wherein, n represents the integer of 1-5.
Specifically, the said compound of general formula I or its pharmacy acceptable salt is characterized in that in the said general formula I:
R
1Represent hydrogen or form carbonyl with the carbon atom that links to each other;
R
2Represent C
1-C
4Straight chained alkyl, (CH
2)
2NR
3R
4, (CH
2)
2R
5Or CHR
6COOR
7
R
3And R
4Can be identical or different, and independent Wasserstoffatoms, the C of representing
1-C
4Alkyl, R
3And R
4Nitrogen-atoms with connecting with them forms 5 to 6 yuan of aliphatic heterocycles, morpholine ring, piperazine ring, 4-N-METHYL PIPERAZINE ring or 4-benzyl diethylenediamine ring;
R
5Representation hydroxy, halogen, phenyl or substituted-phenyl, this phenyl can be at random by following identical or different C
1-C
6The alkoxy substituent list replaces to five replacements;
R
6Represent Wasserstoffatoms, methyl, benzyl;
R
7Represent methylidene, ethyl.
Further, the said compound of general formula I is preferably from following compounds:
6-methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-n-propyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(2-phenyl) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-[2-(3,4-subunit dioxy base) phenyl] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-dimethylin) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-diethylin) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-di-n-propylamine base) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-pyrrolidyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-piperidyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-morpholinyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-[2-(4-methyl) piperazinyl-1-] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-[2-(4-benzyl) piperazinyl-1-] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone.
Specifically, the said compound of general formula I is further preferably from following compounds:
6-methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (compound number: I
1, down together);
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
2);
6-n-propyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
3);
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
4);
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
5);
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
6);
6-(2-phenyl) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
7);
6-[2-(3,4-subunit dioxy base) phenyl] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
8);
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
9);
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
10);
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
11);
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
12);
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
13);
Preferred compound of the present invention and constituted intact part of the present invention with the adduct of pharmaceutically acceptable acid; Hydrochloric acid is arranged, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, Hydrocerol A, xitix, methylsulfonic acid, dextrocamphoric acid, oxalic acid etc. in pharmaceutically acceptable acid.
Another object of the present invention is to provide the preparation method of the said compound of general formula I of the present invention, it is characterized by and be, comprise the steps:
A) work as R
1During for Wasserstoffatoms, the preparation method of compound shown in the general formula I comprises the steps:
(DDB) uses LiAlH with Biphenylylmethylcarbinol
4Reduction makes 4,4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl (II), II and methylsulfonyl chloride (MsCl) generate 4 in the presence of triethylamine (TEA); 4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-dichloromethyl biphenyl (III), III and primary amine (R under the basic cpd effect
2NH
2) or NH
3Reaction generates compound of Formula I; Synthetic route is following:
Wherein, R
2Definition as previously mentioned;
B) work as R
1During for carbonylic oxygen atom, the preparation of compound shown in the general formula I comprises the steps:
(DDB) uses LiAlH with Biphenylylmethylcarbinol
4Be reduced to methylol, obtain 4,4 '-dimethoxy-5,6; 5 ', 6 '-two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl (II), II and methylsulfonyl chloride (MsCl) generate 4 in the presence of triethylamine (TEA); 4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-dichloromethyl biphenyl (III), III and the various compound (R that contains primary amine group
2NH
2) in the organic solvent that contains mineral alkali or organic amine hybrid reaction 1-48 hour, the temperature of reaction of employing be 0 ℃ to refluxing, generate midbody (IV), IV generates title product (I) through the oxygenant oxidation; Synthetic route is following:
Wherein, R
2Definition as previously mentioned;
Prepare compound of Formula I or prepare IV by III and be characterised in that the basic cpd that is adopted is yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, 4-Dimethylamino pyridine, pyridine or triethylamine by III; The organic solvent that is adopted is selected from N; Dinethylformamide (DMF), N; N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, THF, pyridine, methylene dichloride, 1, one or more in 2-ethylene dichloride, chloroform, toluene or the dioxane preferentially adopt N; Dinethylformamide (DMF), DMAC N,N (DMA), acetonitrile or THF; The temperature of reaction that adopts is 0 ℃ and extremely refluxes.
Preparing compound of Formula I by IV is characterised in that; The solvent that adopts is selected from methylene dichloride, 1; In 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or the acetone one or more preferentially adopt methylene dichloride, 1,2-ethylene dichloride, chloroform or acetone; The oxygenant that adopts is 2-iodoxy phenylformic acid (IBX), potassium permanganate, Manganse Dioxide or chromated oxide; The phase-transfer catalyst that is adopted is benzyl triethyl ammonium bromide, Tetrabutyl amonium bromide, ethyl brometo de amonio or cetyl trimethylammonium bromide; The temperature of reaction that adopts is 0 ℃ and extremely refluxes.
These midbodys or target compound all can be according to conventional stripping technique purifying in addition, and are translated into the additive salt with pharmaceutically acceptable acid as required.
Further purpose of the present invention is to provide a kind of compound of Formula I of significant quantity and pharmaceutical composition of pharmacy acceptable salt and carrier thereof of containing.
A purpose more of the present invention provides the application of representation compound of the present invention in preparation P-gp suppressor factor and multidrug resistance reversing agent.
The compounds of this invention can with other antitumor drugs for example alkylating agent (like endoxan or cis-platinum), antimetabolite (like 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (like NSC 94600), mitotic inhibitor (like taxol or vinealeucoblastine(VLB)), DNA intercalating agent (like Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.Through with the antitumor drug combination therapy, strengthen the susceptibility of drug-resistant tumor cell, thereby help to improve result of treatment cancer therapy drug.
Be the part pharmacological testing and the result of representation compound of the present invention below:
1, external P-gp suppresses experiment
Utilization Flow Cytometry research compound is to K562 and the intracellular influence of accumulating and effluxing of drug-fast K562/A02 in sensitivity of P-gp substrate rhodamine 123 (Rh123) and anti-anticarcinogen Zorubicin (ADR).
1.1 the influence that compound is accumulated in mdr cell K562/A02 and responsive K562 cell the P-gp substrate
With 10 μ M compound (I
1-13) and after Rh123 and K562/ADR cell educate certain hour altogether, with fluorescence intensity in the cells were tested by flow cytometry cell.Experimental result is seen Fig. 1.
Fig. 1 result shows that this patent compound significantly increases Rh123 accumulating in the mdr cell K562/A02 of high expression level P-gp.Compound I
6-8Activity be better than classical P-gp suppressor factor verapamil (VRP).
Fig. 2 result shows, compound I
6-8The function of specific inhibition P-gp presents dose-dependent effects under 10,3.3 and 0.3 μ M concentration, and does not influence intracellular the accumulating of K562 that Rh123 expresses at no P-gp, and the restraining effect of P-gp is better than positive control drug VRP equally.
Fig. 3 result shows, compound I
8Increase antitumour drug Zorubicin (ADR) accumulating in the mdr cell K562/A02 of high expression level P-gp; And do not influence its accumulating in the sensitive cells K562 that no P-gp expresses; Further proved conclusively the effect of compound inhibition P-gp, and effect is better than positive control drug VRP.
1.2 compound suppresses the outer row function of P-gp
Compound I with 5,2.5 or 0.25 μ M
8After educating certain hour with the Rh of 0.5 μ M 123 altogether with the K562/A02 cell, places after 60 minutes, detect the residual quantity of Rh123 in the cell, the size of the effect that effluxes of judgement compound inhibition P-gp with copolymerization Jiao and flow cytometry.The P-gp suppressor factor VRP that selects same concentration is as positive control drug.The result sees Figure 4 and 5.
Fig. 4 shows that the sensitive cells K562 that does not express P-gp has kept most of Rh123 (Fig. 4 A1), and the P-gp of high expression level has effluxed all Rh123 (Fig. 4 A2) among the mdr cell K562/A02.Active compound I
8Significantly suppress the outer row function of P-gp, and present dose-dependently (Fig. 4 B1-3).Restraining effect significantly is better than the positive VRP (Fig. 4 C1-3) with isoconcentration.
Fig. 5 shows that compound almost completely suppresses the outer row function of P-gp under 2.5 μ M, and restraining effect significantly is better than the positive control drug VRP of 5 μ M concentration.
2, MTS experiment
The vitro cytotoxicity of MTS experimental study compound.Experimental technique is following: get and be in one bottle in cell in good condition exponential phase of growth, process every milliliter and contain 5 * 10
4～7 * 10
4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 160 μ L put constant temperature CO
2Cultivated 24 hours in the incubator.Change liquid, add the test-compound 40 μ L (compound dilutes with nutrient solution with DMSO dissolving back) of different concns, continue to cultivate 72 hours.MTS is added in 96 orifice plates, and reaction is 3 hours in the incubator.Use enzyme-linked immunosorbent assay instrument in the optical density of wavelength, calculate cell inhibitory rate as the every hole of mensuration, 490nm place.Select anticarcinogen Zorubicin (ADR) as positive control.Experimental result is as shown in table 1.
Cell inhibitory rate=(negative control group OD value one is tried thing group OD value)/negative control group OD value * 100%.
Table 1 representation compound of the present invention is to resistance and the active (IC of responsive tumor cell proliferation inhibition
50, μ mol/L)
The result shows that antitumour drug ADR is stronger to sensitive strain K562 cytotoxicity, IC
50Be 0.43 μ M, and mdr cell K562/A02 obviously produces resistance to substrate A DR, the resistance multiple is 108.Opposite with ADR, no matter be that sensitive cells K562 or mdr cell K562/A02 are all insensitive to compound, show that this compounds self toxicity is little.
3, the chemotherapy sensitizing effect of compound
ADR perhaps educates with K562/A02 cell or K562 cell with 5,2.5 or 1.25 μ M compounds separately together altogether, uses MTS method detection anticarcinogen ADR or unites the influence of use back to resistance K562/A02 cell and responsive K562 cell proliferation with compound.The result sees Fig. 6.
Fig. 6 shows that the ADR of 3.5 μ M acts on mdr cell K562/A02 or 0.05 μ M ADR acts on responsive K562 cell, does not influence the propagation of cell, and the cells survival rate is respectively 91.4% and 85.0%.Test-compound does not influence the propagation of K562/A02 or K562 cell equally under high density (5 μ M); But with after the ADR coupling; Significantly increased the cytotoxicity of ADR; Reduced the survival rate of mdr cell K562/A02, and do not influenced the inhibited proliferation of Zorubicin the sensitive cells of no P-gp expression.
This experiment further specifies the function of this compounds through inhibition P-gp, the purpose of reversion MDR, and effect is better than positive control VRP.
4, compound is to the influence of P-gp albumen and genetic expression
5 μ M test-compound I
6-8After educating 72 hours altogether with K562/A02, use RT-PCR and Western blot method to detect its influence to the P-gp expression at mRNS and protein level.The result sees Fig. 7.
Fig. 7 shows, active compound I
6-8Do not influence P-gp gene and proteic expression.Therefore, this compounds is functional to the inhibition of P-gp, and non-genomic property is the suppressor factor of one type of safety.
Above pharmacology data shows that The compounds of this invention has excellent P-gp restraining effect, can significantly reverse the MDR of P-gp mediation.Wherein, compound I
6-8Restraining effect and chemotherapy sensitizing effect to P-gp all significantly are better than positive control drug VRP, and the effect that this compounds suppresses P-gp is functional and non-genomic property, are the P-gp suppressor factor of one type of safety therefore.
5, description of drawings
Fig. 1 representation compound of the present invention increases the focusing experiment of substrate Rh123 in mdr cell K562/A02
Fig. 2 representation compound of the present invention increases substrate Rh123 accumulative dose-dependently experiment in resistance and sensitive cells
Fig. 3 representation compound of the present invention increases the focusing experiment of anticarcinogen Zorubicin in resistance and sensitive cells
Fig. 4 representation compound of the present invention suppresses P-gp and effluxes functional experiment (A1 is the K562 cell, and other are the K562/A02 cell)
Fig. 5 representation compound of the present invention suppresses P-gp and effluxes functional experiment
Fig. 6 representation compound of the present invention strengthens the susceptibility experiment of mdr cell K562/A02 to chemotherapeutic
The influence experiment that Fig. 7 representation compound of the present invention is expressed P-gp among the mdr cell K562/A02
Embodiment:
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl
(4g 9.56mmol) is dissolved in the 50mL anhydrous tetrahydro furan Biphenylylmethylcarbinol, and ice bath is cooled to 0 ℃, carefully adds Lithium Aluminium Hydride (1.09g in batches; 28.68mmol), after 4 hours, ice bath is cooled to 0 ℃ to mixture in the stirring at room reaction, slowly adds zero(ppm) water till no hydrogen produces along the bottle wall; Filtering-depositing, solid are filtrated with after adding water-dispersion with washed with dichloromethane for several times; Dichloromethane extraction, organic layer with the saturated common salt water washing after, use anhydrous sodium sulfate drying.Filter, decompression gets white solid (2.9g, 85%) after removing solvent.This compound is a known compound.
m.p.170-171℃(Eur.J.Med.Chem.1992，27，353-358.172-173℃)；
ESI-MS：m/z?385[M+Na]+.
4,4 '-dimethoxy-5,6,5 ', 6 '-two methylene-dioxies-2,2 '-dichloromethyl biphenyl
4,4 '-dimethoxy-5,6,5 ', 6 ' two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl (2g 5.5mmol) is dissolved in the 20mL methylene dichloride, add triethylamine (2.33mL, 16.5mmol), dropwise add then methylsulfonyl chloride (1.28mL, 16.5mmol).Room temperature reaction 6 hours, wherein TLC follows the tracks of reaction, adds water-dispersion after the end, dichloromethane extraction, organic layer with the saturated common salt water washing after, use anhydrous sodium sulfate drying.Filter, concentrate, and rapid column chromatography (petrol ether/ethyl acetate: 4/1, V/V) obtain white title compound (2g, 91%).
m.p.134-135℃；
ESI-MS：m/z?399[M+H]+；
1H-NMR(CDCl
3，300MHz，δppm)：3.96(s，6H，2×OCH
3)，4.37(s，4H，2×CH
2Cl)，5.97(s，4H，2×OCH
2O)，6.78(s，2H，2×Ar-H).
6-methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
1)
4,4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-(100mg 0.25mmol) is dissolved in the 15mL acetonitrile dichloromethyl biphenyl; (145 μ L 1.0mmol), add methylamine hydrochloride (67.52mg to add triethylamine; 1.0mmol) in 40 ℃ of reactions 6-8 hour, reaction added water-dispersion, ethyl acetate extraction after finishing.Organic layer with the saturated common salt water washing after, use anhydrous sodium sulfate drying.Filter, concentrate, (methylene chloride: 0-9% V/V) obtains white title compound (76mg, 85%) to rapid column chromatography.
m.p.180-182℃；
ESI-MS：m/z?358[M+H]
+；
1H?NMR(CDCl
3，300MHz，δppm)：2.45(s，3H，CH
3)，3.28(d，2H，NCH
2，J＝12.3Hz)，3.46(d，2H，NCH
2，J＝12.3Hz)，3.95(s，6H，2×OCH
3)，6.00(s，2H，OCH
2O)，6.10(s，2H，OCH
2O)，6.60(s，2H，2×Ar-H).
Embodiment 4
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
2)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (81.54mg, 1.0mmol) reaction obtains white title compound (81mg, 87%) to ethylamine hydrochloride.
m.p.151-153℃.
ESI-MS：m/z?372[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：1.06(t，3H，CH
3，J＝7.2Hz)，2.67-2.85(m，2H，NCH
2)，3.33(d，2H，NCH
2，J＝12.6Hz)，3.73(d，2H，NCH
2，J＝12.6Hz)，3.96(s，6H，2×OCH
3)，6.01(s，2H，OCH
2O)，6.10(s，2H，OCH
2O)，6.64(s，2H，2×Ar-H).
Embodiment 5
6-n-propyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
3)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (59.1mg, 1.0mmol) reaction obtains white title compound (76mg, 79%) to Tri N-Propyl Amine.
m.p.138-140℃；
ESI-MS：m/z?386[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：0.97(t，3H，CH
3，J＝7.2Hz)，1.57-1.65(m，2H，CH
3CH
2)，2.42-2.59(m，2H，NCH
2)，3.20(d，2H，NCH
2，J＝12.6Hz)，3.54(d，2H，NCH
2，J＝12.6Hz)，3.95(s，6H，2×OCH
3)，5.99(s，2H，OCH
2O)，6.09(s，2H，OCH
2O)，6.57(s，2H，2×Ar-H).
Embodiment 6
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
4)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (73.1mg, 1.0mmol) reaction obtains white title compound (86mg, 86%) to n-Butyl Amine 99.
m.p.144-146℃；
ESI-MS：m/z?400[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：0.96(t，3H，CH
3，J＝7.2Hz)，1.32-1.45(m，2H，CH
2)，1.53-1.59(m，2H，CH
2)，2.38-2.60(m，2H，NCH
2)，3.18(d，2H，NCH
2，J＝12.5Hz)，3.53(d，2H，NCH
2，J＝12.5Hz)，3.95(s，6H，2×OCH
3)，5.99(s，2H，OCH
2O)，6.09(s，2H，OCH
2O)，6.56(s，2H，2×Ar-H).
Embodiment 7
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
5)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (61.08mg, 1.0mmol) reaction obtains white title compound (82mg, 84%) to thanomin.
m.p.100-101℃；
ESI-MS：m/z?388[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：2.68-2.77(m，1H，NH
2)，2.95-3.03(m，1H，NH
2)，3.37(d，2H，NCH
2，J＝12.6Hz)，3.69(d，2H，NCH
2，J＝12.6Hz)，3.83(t，2H，OCH
2，J＝5.1Hz)，3.96(s，6H，2×OCH
3)，6.01(s，2H，OCH
2O)，6.10(s，2H，OCH
2O)，6.63(s，2H，2×Ar-H).
Embodiment 8
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
6)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (107.1mg, 1.0mmol) reaction obtains white title compound (88mg, 81%) to benzylamine.
m.p.178-179℃；
ESI-MS：m/z?434[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：3.21(d，2H，NCH
2，J＝12.5Hz)，3.47(d，2H，NCH
2，J＝12.5Hz)，3.59-3.71(m，2H，NCH
2)，3.94(s，6H，2×OCH
3)，5.99(s，2H，OCH
2O)，6.09(s，2H，OCH
2O)，6.53(s，2H，2×Ar-H)，7.19-7.44(m，5H，5×Ar-H).
Embodiment 9
6-(2-phenyl) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
7)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (121.1mg, 1.0mmol) reaction obtains white title compound (92mg, 82%) to the 2-phenylethylamine.
m.p.138-140℃；
ESI-MS：m/z?448[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：2.65-2.85(m，2H，NCH
2CH
2)，2.86-2.93(m，2H，NCH
2CH
2)，3.26(d，2H，NCH
2，J＝12.5Hz)，3.60(d，2H，NCH
2，J＝12.5Hz)，3.93(s，6H，2×OCH
3)，5.93(s，2H，OCH
2O)，5.99(s，2H，OCH
2O)，6.09(s，2H，OCH
2O)，6.55(s，2H，2×Ar-H)，7.19-7.33(m，5H，5×Ar-H).
6-[2-(3,4-subunit dioxy base) phenyl] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
8)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L, 1.0mmol), 3,4-methylenedioxybenzenes ethylamine hydrochloride (201.6mg; 1.0mmol) reaction obtains white title compound (100mg, 81%).
m.p.149-150℃；
ESI-MS：m/z?492[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：2.60-2.70(m，2H，NCH
2CH
2)，2.73-2.86(m，2H，NCH
2CH
2)，?3.24(d，2H，NCH
2，J＝12.5Hz)，3.58(d，2H，NCH
2，J＝12.5Hz)，3.94(s，6H，2×OCH
3)，5.93(s，2H，OCH
2O)，5.99(s，2H，OCH
2O)，6.09(s，2H，OCH
2O)，6.55(s，2H，2×Ar-H)，6.64-6.78(m，3H，2×Ar-H).
Embodiment 11
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines (I
9)
Press the similar approach of embodiment 3, use 100mg (0.25mmol) 4,4 '-dimethoxy-5; 6,5 ', 6 '-two methylene-dioxies-2; 2 ' xenyl dimethyl chloride, triethylamine (145 μ L; 1.0mmol), (125.5mg, 1.0mmol) reaction obtains white title compound (80mg, 77%) to glycine methyl ester hydrochloride.
m.p.156-158℃；
ESI-MS：m/z?416[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：3.25(d，1H，NCH
2，J＝16.2Hz)，3.30(d，2H，NCH
2，J＝12.6Hz)，3.45(d，1H，NCH
2，J＝16.2Hz)，3.57(d，2H，NCH
2，J＝12.6Hz)，3.79(s，3H，OCH
3)，3.94(s，6H，2×OCH
3)，5.96(s，2H，OCH
2O)，6.10(s，2H，OCH
2O)，6.58(s，2H，2×Ar-H).
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
10)
I
2(100mg 0.27mmol) is dissolved in the methylene dichloride, and adding phase-transfer catalyst cetyl trimethylammonium bromide (98mg, 0.27mmol), potassium permanganate (170mg, 1.08mmol) back flow reaction 0.5-1 hour.Reaction finishes postcooling to room temperature, adds saturated aqueous solution of sodium bisulfite vigorous stirring, and reaction solution becomes white.Dichloromethane extraction, organic layer with the saturated common salt water washing after, use anhydrous sodium sulfate drying.Filter, concentrate, and rapid column chromatography (dichloromethane/ethyl acetate: 5/1, V/V) obtain white title compound (45mg, 43%).
m.p.125-127℃；
ESI-MS：m/z?386[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：1.21(t，3H，CH
3，J＝7.2Hz)，3.29-3.41(m，1H，NCH
2)，3.72-3.87(m，1H，NCH
2)，3.83(d，1H，NCH
2，J＝14.6Hz)，3.96(s，3H，OCH
3)，3.97(s，3H，OCH
3)，4.30(d，1H，NCH
2，J＝14.6Hz)，5.95-6.13(m，4H，2×OCH
2O)，6.52(s，1H，Ar-H)，7.20(s，1H，Ar-H).
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
11)
Press the similar approach of embodiment 13, use I
4(100mg, 0.25mmol), cetyl trimethylammonium bromide (91mg, 0.25mmol), (157mg, 1.0mmol) back flow reaction obtains white title compound (47mg, 45%) to potassium permanganate.
m.p.162-163℃；
ESI-MS：m/z?414[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：0.93(t，3H，CH
3，J＝7.2Hz)，1.23-1.35(m，2H，CH
2)，1.53-1.65(m，2H，CH
2)，3.26-3.36(m，1H，NCH
2)，3.66-3.75(m，1H，NCH
2)，3.81(d，2H，NCH
2，J＝14.4Hz)，3.95(s，3H，OCH
3)，3.97(s，3H，OCH
3)，4.30(d，2H，NCH
2，J＝14.4Hz)，5.94-6.12(m，4H，2×OCH
2O)，6.52(s，1H，Ar-H)，7.23(s，1H，Ar-H).
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
12)
Press the similar approach of embodiment 13, use I
6(100mg, 0.23mmol), cetyl trimethylammonium bromide (84mg, 0.23mmol), (144mg, 0.92mmol) back flow reaction obtains white title compound (46mg, 41%) to potassium permanganate.
m.p.170-171℃；
ESI-MS：m/z?448[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：3.75-3.86(m，1H，PhCH
2)，3.81(s，3H，OCH
3)，3.99(s，3H，OCH
3)，4.26(d，1H，PhCH
2，J＝14.5Hz)，4.59(d，1H，NCH
2，J＝14.8Hz)，4.93(d，1H，NCH
2，J＝14.8Hz)，5.96-6.10(m，4H，2×OCH
2O)，6.14(s，1H，Ar-H)，7.26(s，1H，Ar-H)，7.28-7.35(m，5H，5×Ar-H).
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone (I
13)
Press the similar approach of embodiment 13, use I
9(100mg, 0.24mmol), cetyl trimethylammonium bromide (88mg, 0.24mmol), (150mg, 0.96mmol) back flow reaction obtains white title compound (43mg, 40%) to potassium permanganate.
m.p.187-189℃；
ESI-MS：m/z?430[M+H]
+；
1H-NMR(CDCl
3，300MHz，δppm)：3.75(s，3H，OCH
3)，3.78-3.89(m，2H，NCH
2)，3.95(s，3H，OCH
3)，3.97(s，3H，OCH
3)，4.52(d，1H，NCH
2，J＝15.0Hz)，4.75(d，1H，NCH
2，J＝15.0Hz)，5.95-6.14(m，4H，2×OCH
2O)，6.48(s，H，Ar-H)，7.26(s，H，Ar-H)。
Claims (10)
1. a kind of alkoxyl group dibenzazepines compounds or its pharmacy acceptable salt shown in the general formula I:
Wherein:
R
1Represent Wasserstoffatoms, C
1-C
10Straight or branched alkyl or form carbonyl with the carbon atom that links to each other;
R
2Represent Wasserstoffatoms, C
1-C
10Straight or branched alkyl, (CH
2)
nNR
3R
4, (CH
2)
nR
5Or CHR
6COOR
7
R
3And R
4Can be identical or different, and independent Wasserstoffatoms, the C of representing
1-C
5Straight or branched alkyl or R
3And R
4The nitrogen-atoms that connects with them forms 5 to 7 yuan of aliphatic heterocycles, and described aliphatic heterocycle also comprises morpholine ring, piperazine ring or contains 4-methyl, the substituted piperazine ring of benzyl;
R
5Representation hydroxy, halogen, phenyl or substituted-phenyl, described substituted-phenyl can at random be replaced to five replacements by following identical or different substituting group list, and said substituting group is C
1-C
6Straight or branched alkyl, C
1-C
6Alkoxyl group, hydroxyl or halogen;
R
6Represent Wasserstoffatoms, C
1-C
5Straight or branched alkyl, phenyl or benzyl;
R
7Represent C
1-C
5The straight or branched alkyl;
Wherein, n represents the integer of 1-5.
2. compound of Formula I as claimed in claim 1 or its pharmacy acceptable salt is characterized in that said compound of Formula I is:
R
1Represent hydrogen, C
1-C
3Straight or branched alkyl or form carbonyl with the carbon atom that links to each other;
R
2Represent C
1-C
6Straight or branched alkyl, (CH
2)
nNR
3R
4, (CH
2)
nR
5Or CHR
6COOR
7
R
3And R
4Can be identical or different, and independent Wasserstoffatoms, the C of representing
1-C
4Alkyl, R
3And R
4Nitrogen-atoms with connecting with them forms 5 to 7 yuan of aliphatic heterocycles, and described aliphatic heterocycle also comprises morpholine ring, piperazine ring or contains 4-methyl, the substituted piperazine ring of benzyl;
R
5Representation hydroxy, halogen, phenyl or substituted-phenyl, this phenyl can be at random by following identical or different C
1-C
6The alkoxy substituent list replaces to five replacements;
R
6Represent Wasserstoffatoms, C
1-C
3The straight or branched alkyl;
R
7Represent C
1-C
5Straight chained alkyl;
Wherein, n represents the integer of 1-3.
3. compound of Formula I as claimed in claim 1 or its pharmacy acceptable salt is characterized in that said compound of Formula I is:
R
1Represent hydrogen or form carbonyl with the carbon atom that links to each other;
R
2Represent C
1-C
4Straight chained alkyl, (CH
2)
2NR
3R
4, (CH
2)
2R
5Or CHR
6COOR
7
R
3And R
4Can be identical or different, and independent Wasserstoffatoms, the C of representing
1-C
4Alkyl, R
3And R
4Nitrogen-atoms with connecting with them forms 5 to 6 yuan of aliphatic heterocycles, morpholine ring, piperazine ring, 4-N-METHYL PIPERAZINE ring or 4-benzyl diethylenediamine ring;
R
5Representation hydroxy, halogen, phenyl or substituted-phenyl, this phenyl can be at random by following identical or different C
1-C
6The alkoxy substituent list replaces to five replacements;
R
6Represent Wasserstoffatoms, methyl, benzyl;
R
7Represent methylidene, ethyl.
4. compound of Formula I according to claim 1 is characterized in that, said compound is selected from:
6-methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-n-propyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(2-phenyl) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-[2-(3,4-subunit dioxy base) phenyl] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-dimethylin) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-diethylin) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(2-di-n-propylamine base) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-pyrrolidyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-piperidyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(ethyl-3 of 2-morpholinyl-1-), 9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-[2-(4-methyl) piperazinyl-1-] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-[2-(4-benzyl) piperazinyl-1-] ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone.
5. compound of Formula I according to claim 1 is characterized in that, said compound is further certainly preferred:
6-methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-n-propyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-hydroxyethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(2-phenyl) ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-[2-(3,4-subunit dioxy base) phenyl] ethyl-3,9-methoxyl group-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-5H-dibenzo [c, e] azepines;
6-ethyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-normal-butyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-benzyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone;
6-(methoxycarbonyl) methyl-3,9-dimethoxy-1,2-methylene-dioxy-10,11-methylene-dioxy-6,7-dihydro-dibenzo [c, e] azepines-5-ketone.
6. the preparation method of the described compound of Formula I of claim 1 is characterized in that:
A) work as R
1During for Wasserstoffatoms, the preparation method of compound shown in the general formula I comprises the steps:
(DDB) uses LiAlH with Biphenylylmethylcarbinol
4Reduction makes 4,4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl (II), II and methylsulfonyl chloride (MsCl) generate 4 in the presence of triethylamine (TEA); 4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-dichloromethyl biphenyl (III), III and primary amine (R under the basic cpd effect
2NH
2) or NH
3Reaction generates compound of Formula I; Synthetic route is following:
Wherein, R
2Definition as previously mentioned;
B) work as R
1During for carbonylic oxygen atom, the preparation of compound shown in the general formula I comprises the steps:
(DDB) uses LiAlH with Biphenylylmethylcarbinol
4Be reduced to methylol, obtain 4,4 '-dimethoxy-5,6; 5 ', 6 '-two methylene-dioxies-2,2 '-'-bis (hydroxymethyl) biphenyl (II), II and methylsulfonyl chloride (MsCl) generate 4 in the presence of triethylamine (TEA); 4 '-dimethoxy-5,6,5 '; 6 '-two methylene-dioxies-2,2 '-dichloromethyl biphenyl (III), III and the various compound (R that contains primary amine group
2NH
2) in the organic solvent that contains mineral alkali or organic amine hybrid reaction 1-48 hour, the temperature of reaction of employing be 0 ℃ to refluxing, generate midbody (IV), IV generates title product (I) through the oxygenant oxidation; Synthetic route is following:
Wherein, R
2Definition as previously mentioned.
7. method according to claim 6 is prepared compound of Formula I or is prepared IV by III by III and is characterised in that the basic cpd that is adopted is yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, 4-Dimethylamino pyridine, pyridine or triethylamine; The organic solvent that is adopted is selected from N; Dinethylformamide (DMF), N; N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, THF, pyridine, methylene dichloride, 1, one or more in 2-ethylene dichloride, chloroform, toluene or the dioxane preferentially adopt N; Dinethylformamide (DMF), DMAC N,N (DMA), acetonitrile or THF; The temperature of reaction that adopts is 0 ℃ and extremely refluxes.
8. method according to claim 6; Preparing compound of Formula I by IV is characterised in that; The solvent that adopts is selected from methylene dichloride, 1; In 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or the acetone one or more preferentially adopt methylene dichloride, 1,2-ethylene dichloride, chloroform or acetone; The oxygenant that adopts is 2-iodoxy phenylformic acid (IBX), potassium permanganate, Manganse Dioxide or chromated oxide; The phase-transfer catalyst that is adopted is benzyl triethyl ammonium bromide, Tetrabutyl amonium bromide, ethyl brometo de amonio or cetyl trimethylammonium bromide; The temperature of reaction that adopts is 0 ℃ and extremely refluxes.
9. a pharmaceutical composition wherein contains the described compound of Formula I of the claim 1 of treating significant quantity or its pharmacy acceptable salt and carrier.
The compound of claim 1-5 or its pharmacy acceptable salt with P-gp inhibit feature with reverse relevant pharmaceutical industry and the oncotherapy Application for Field of multidrug resistance.
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Cited By (7)
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| CN102924462A (en) * | 2012-10-24 | 2013-02-13 | 华东师范大学 | Method for synthesis of 1,2,3,4,5,9-substituted benzazepine compound |
| CN107266461A (en) * | 2017-06-20 | 2017-10-20 | 徐州医科大学 | A kind of alkoxy dibenzazepines class compound, its preparation method and medical usage |
| CN107880046A (en) * | 2017-12-01 | 2018-04-06 | 青岛农业大学 | A kind of preparation method of dibenzo [b, e] azepines compound |
| CN108586425A (en) * | 2018-06-01 | 2018-09-28 | 徐州医科大学 | A kind of alkoxy biphenyl α, beta-unsaturated acyl aminated compounds, preparation method and medical usage |
| CN110627801A (en) * | 2019-10-17 | 2019-12-31 | 安徽中医药大学 | HDAC inhibitor and application thereof |
| CN113754627A (en) * | 2021-09-03 | 2021-12-07 | 西北师范大学白银师科创新研究院 | Preparation method of biphenylol acid |
| CN114805375A (en) * | 2022-04-12 | 2022-07-29 | 徐州医科大学 | N-phenyl alkoxy dibenzoazepine compound, preparation method and medical application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924462A (en) * | 2012-10-24 | 2013-02-13 | 华东师范大学 | Method for synthesis of 1,2,3,4,5,9-substituted benzazepine compound |
| CN107266461A (en) * | 2017-06-20 | 2017-10-20 | 徐州医科大学 | A kind of alkoxy dibenzazepines class compound, its preparation method and medical usage |
| CN107880046A (en) * | 2017-12-01 | 2018-04-06 | 青岛农业大学 | A kind of preparation method of dibenzo [b, e] azepines compound |
| CN108586425A (en) * | 2018-06-01 | 2018-09-28 | 徐州医科大学 | A kind of alkoxy biphenyl α, beta-unsaturated acyl aminated compounds, preparation method and medical usage |
| CN110627801A (en) * | 2019-10-17 | 2019-12-31 | 安徽中医药大学 | HDAC inhibitor and application thereof |
| CN113754627A (en) * | 2021-09-03 | 2021-12-07 | 西北师范大学白银师科创新研究院 | Preparation method of biphenylol acid |
| CN114805375A (en) * | 2022-04-12 | 2022-07-29 | 徐州医科大学 | N-phenyl alkoxy dibenzoazepine compound, preparation method and medical application thereof |
| CN114805375B (en) * | 2022-04-12 | 2023-07-25 | 徐州医科大学 | N-phenylalkoxy dibenzoazepine compound, preparation method and medical application thereof |
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