CN107266461A - A kind of alkoxy dibenzazepines class compound, its preparation method and medical usage - Google Patents
A kind of alkoxy dibenzazepines class compound, its preparation method and medical usage Download PDFInfo
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- methylene
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses a kind of alkoxy dibenzazepines class compound, its preparation method and medical usage, belong to biomedicine field, it is specially alkoxy dibenzazepines class compound or its pharmaceutically acceptable salt shown in formula I.The Pharmacological experiment result shows that, the compounds of this invention has excellent P glycoprotein inhibitory activity, tumor multi-drug resistance reversal activity and activity of resisting tumor metastasis, can clinically be used as tumor multi-drug resistance reversal agents and metastases inhibitor application.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to a class alkoxy dibenzazepines class
Compound.Such compound can be used for preparing P- glycoprotein inhibitors, tumor multi-drug resistance reversal agents and metastases inhibitor.This
Invention further relates to the preparation method of such compound and the drug regimen containing them.
Background technology
Tumor multi-medicine drug-resistant (multidrug resistance, MDR) is to cause the important original of chemotherapy of tumors Endodontic failure
Because of (Curr Med Chem.2012,19,1946-2025.).P- glycoprotein (P- in ATP convolutions (ABC) transport protein family
Glycoprotein, P-gp) overexpression be widest tumour MDR generation mechanisms (the Eur J Med studied at present
Chem.2016,118,219-229.).More than 200 chemotherapeutic drug molecules are P-gp substrate (Pharmacology in clinic
Therapeutics.2015,149,1-123.), these medicines will be pumped out outside tumour cell once being combined with P-gp, so that
The intracellular drug concentration of reduction, causes the failure of chemotherapy.In addition, P-gp can be prevented by suppressing casepases activation
Apoptosis, causes cell to produce apoptosis tolerance (Cell Death.Differ.2004,11,1028-1037.).Research shows,
The accumulation of chemotherapeutics in the cell can be improved by suppressing P-gp, improve mdr cell to the sensitiveness of chemotherapeutics, induced tumor
Apoptosis, and then reversion MDR.Therefore, the medicine for suppressing P-gp is found and studies as the research heat for overcoming MDR fields
One of point.
Up to now, the research and development of P-gp inhibitor experienced altogether four-stage (Biochem pharmacol.2014,92,
558-566.).First three is for inhibitor problems faced：1st, poor selectivity of the inhibitor to P-gp；2nd, inhibitor presses down to P-gp
System activity is low；3rd, the toxicity of inhibitor itself is high；4th, inhibitor influence cancer therapy drug pharmacokinetic property, adds medicine
Toxic side effect etc..In addition, P-gp is equally expressed in the normal tissue, be mainly distributed on enterocyte, renal proximal tubular cell,
Hepatic duct cell membrane, and blood brain, blood testis and placenta epithelial cell (ChemMedChem.2016,11,374-376), and lead to
Cross efflux pump and participate in secretion exogenous material and process (the Expert Opin.Drug of toxic metabolites
Metab.Toxicol.2008,4,205-223.).When P-gp normal function be suppressed after, the metabolism of anticarcinogen in vivo and
Excretion is affected, and blood levels improve, and add the toxicity of its normal tissue.Therefore, it is badly in need of exploitation new and effective
P-gp inhibitor.
Research finds that many natural products such as flavonoids, curcumin, schizandrin A and C prime etc. are suppressing P-gp work
Property the peculiar advantage that shows of aspect, such as low toxicity, preferable tolerance make natural products and its derivative be opened as inhibitor
The hope for sending out new and opportunity.P-gp inhibitor is developed from natural products and derivative has turned into the new of forth generation inhibitor research and development
Direction and emphasis.
DDB (Bifendate) is the alkoxy biphenyl compound that a class is derived from schisandrin C, is clinically
Drop enzyme medicine for treating hepatitis.Research shows that DDB has antitumor activity, and can be swollen by improving resistance
Oncocyte to the intakes of P-gp substrates, reduce and arranged outside substrate, while lowering P-gp expression, produce reverse multiple drug resistance of tumor
Activity (Invest.New Drugs.2007,25,95-105.), and Bifendate and anticarcinogen combination do not influence anticancer
The pharmacokinetic property of medicine, therefore the toxic side effect of anticarcinogen will not be increased.But as P-gp inhibitor,
Bifendate activity is relatively low.
In order to obtain the P-gp inhibitor that anti-MDR activity is stronger, we are using Bifendate as primer, according to first three generation
The structure-activity relationship of P-gp inhibitor, designs, has synthesized a series of alkoxy dibenzazepines class compounds.Biological activity test
As a result show, such compound has significant P-gp inhibitory action, can be by suppressing P-gp outer row function, reversion MDR,
Its activity is significantly stronger than positive control drug Verapamil (VRP).
In addition, it is contemplated that metastases be also cause chemotherapy failure major reason (Biochem Cell Biol.2015,
, and literature survey finds that alkoxy biphenyl compound such as deoxyschizandrin can be by suppression 67,1191-1023.)
Chrotoplast interstitial transdifferentiation (EMT) suppresses invasion and attack and the transfer (Biomed of mouse mastopathy cell
Pharmacother.2015,74,77-82.), and glue can be suppressed by suppressing PI3K/Akt-mTOR-MMP-9 signal paths
The transfer (Plos One.2012,7, e40480.) of matter oncocyte, based on this, this paper is used before scratch experiment preliminary examinations
The activity of resisting tumor metastasis for the preferable compound of P-gp inhibitory activity that phase finds, has antitumor MDR and turns to obtain a class
Move the compound of double activity.
The content of the invention
It is an object of the invention to provide a class alkoxy dibenzazepines class compound.Pharmacological evaluation proves that such is changed
Compound has good P-gp inhibitory activity, can significantly improve sensitiveness of the drug-resistant tumor to chemotherapeutic, such compound is also
With activity of resisting tumor metastasis.
It is a further object of the present invention to provide a kind of preparation method of alkoxy dibenzazepines class compound.
Third object of the present invention is to provide a kind of alkoxy dibenzazepines class compound and pressed down with P- glycoprotein
Application in function processed, reverse multidrug resistance and anti-tumor metastasis relevant pharmaceuticals industry and therapeutic field of tumor.
The purpose of the present invention can be reached by following measures：
Alkoxy dibenzazepines class compound or its pharmaceutically acceptable salt shown in formula I,
Wherein：
X representatives-N (H) C (O)-or-C (O) N (H)-；
R1Represent C1-C10Alkylidene；
R2Represent C1-C10Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma heterocycle or-(CH2)nR3；
R3Represent phenyl, substituted-phenyl, aromatic heterocycle or substituted aroma heterocycle；
N represents 1-5 integer；
R2Or R3In one or more of the substituent in following radicals：C1-C6Alkyl, C1-C6Haloalkyl, C1-C6
Alkoxy, hydroxyl or halogen.
In a kind of preferred scheme, R1Represent C1-C8Alkylidene.
In a kind of preferred scheme, R1Represent C1-C6Alkylidene.
In a kind of preferred scheme, R2Represent C1-C8Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma heterocycle or
(CH2)nR3。
In a kind of preferred scheme, R2Represent C1-C6Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma are miscellaneous
Ring or (CH2)nR3。
In a kind of preferred scheme, R2Or R3In aromatic heterocycle be thiophene, furans, pyrroles or pyridine.
In a kind of preferred scheme, R2Represent C1-C8Alkyl, phenyl, substituted-phenyl, thiophene, substituted thiophene, furans,
Substituted furan, pyrroles, substituted azole, pyridine, substituted pyridines or (CH2)nR3。
In a kind of preferred scheme, R3Represent phenyl, substituted-phenyl, thiophene, substituted thiophene, furans, substituted furan,
Pyrroles, substituted azole, pyridine or substituted pyridines.
In a kind of preferred scheme, R2Or R3In one or more of the substituent in following radicals：C1-C4
Alkyl, C1-C4Haloalkyl, C1-C4Alkoxy, hydroxyl or halogen.
Further, compound described in formula I preferably is selected from following compounds：
6- [6- (2- methoxyl groups) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2- methoxyl groups) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2- methoxyl groups) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (2- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4- dimethoxys) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4,5- trimethoxies) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- methyl) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- chlorine) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4- dichloros) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (2,4- dichloros) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
Specifically, compound described in formula I is further preferably from following compounds：
6- [6- (2- methoxyl groups) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (compound number：6a, similarly hereinafter)；
6- [6- (3,4- dimethoxys) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6b)；
6- [6- (3,4,5- trimethoxies) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6c)；
6- [6- (4- methyl) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6d)；
6- [6- (4- chlorine) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6e)；
6- [6- (3,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6f)；
6- [6- (2,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6g)；
6- [6- (thiophene-2-carboxamide derivatives base)]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6h)；
6- [6- (2- methoxyl groups) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6i)；
6- [6- (3,4- dimethoxys) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6j)；
6- [6- (3,4,5- trimethoxies) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6k)；
6- [6- (4- methyl) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6l)；
6- [N- (2- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (9a)；
6- [N- (4- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (9b)；
6- [N- (3,4- dimethoxys) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines (9c).
The invention discloses a kind of preparation method of compound shown in formula I, it is directly entered using formula III compound as raw material
Prepared by row, specific method is：
A) R is worked as1For C1-C6Straight-chain alkyl-sub, when X be-N (H) C (O)-when, the preparation method bag of compound shown in formula I
Include following steps：Aliphatic diamine reaction generation the intermediate product IV, intermediate product IV that formula III compound is protected with Boc take off Boc
With carboxylic acid R after reaction2COOH reaction generation compound of Formula I；Synthetic route is as follows：
B) R is worked as1For C1-C6Straight-chain alkyl-sub, when X be-C (O) N (H)-when, the preparation of compound shown in formula I include such as
Lower step：The amino acid and the compound R containing primary amine group of formula IV compound Boc protections2NH2Reaction generation intermediate product V,
Intermediate product V is taken off after Boc reactions with formula III compound through annulation generation compound of Formula I；Synthetic route is as follows：
Each substituent involved respectively is as defined above in this method wherein a) and b), works as R1For branched alkylen
It during base, can be synthesized, can also be prepared using other method using similarity method.
The present invention further discloses a kind of preparation method of compound shown in more specifically formula I：
C) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-N (H) C (O)-when, the preparation method of compound includes shown in formula I
Following steps：By DDB reduce be made Formula II shown in compound 4,4 '-dimethoxy -5,6,5 ', 6 '-two (methylenedioxy)s
Base -2,2 '-'-bis (hydroxymethyl) biphenyl, Formula II compound and mesyl chloride reaction production III compounds 4,4 '-dimethoxy -5,
6,5 ', 6 '-two methylene-dioxy -2,2 '-disulfonic acid carbomethoxy biphenyl, formula III compound is reacted with the aliphatic diamine that Boc is protected
Intermediate product IV is generated, with carboxylic acid R after the de- Boc reactions of intermediate product IV2COOH reaction generation compound of Formula I；Synthetic route
It is as follows：
D) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-C (O) N (H)-when, the preparation of compound shown in formula I include it is as follows
Step：DDB is reduced to methylol, Formula II compound 4,4 '-dimethoxy -5,6,5 ', 6 '-two (methylenedioxy)s are obtained
Base -2,2 '-'-bis (hydroxymethyl) biphenyl, compound II and mesyl chloride reaction production III compounds 4,4 '-dimethoxy -5,6,
5 ', 6 '-two -2,2 '-disulfonic acid carbomethoxy biphenyl of methylene-dioxy；The amino acid and the chemical combination containing primary amine group of Boc protections
Thing R2NH2After the de- Boc reactions of reaction generation intermediate product V, intermediate product V formula I is generated with formula III compound through annulation
Compound；Synthetic route is as follows：
Each substituent involved respectively is as defined above in this method wherein c) and d), works as R1For branched alkylen
It during base, can be synthesized, can also be prepared using other method using similarity method.
In the reaction for preparing compound of Formula I by compound III prepare compounds IV or by compound III, used
Solvent organic solvent be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), acetonitrile, tetrahydrofuran,
One or more in pyridine, dichloromethane, 1,2- dichloroethanes, chloroform, toluene or dioxane, it is preferred to use N, N- diformazan
Base formamide (DMF), DMAC N,N' dimethyl acetamide (DMA), acetonitrile or tetrahydrofuran；The reaction temperature used is 0 DEG C to backflow.
Compound of Formula I is being prepared or in compound IV prepares V reactions by compound V, the solvent used is selected from N,
Dinethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), acetonitrile, tetrahydrofuran, dichloromethane, the chloroethenes of 1,2- bis-
One or more in alkane, chloroform, preferentially using DMF (DMF)；The condensing agent used for HATU,
HBTU, HOBt, EDCI, DCC, preferentially using HATU；The reaction temperature used is room temperature.
In the reaction by compound IV prepare compounds V, the solvent used is selected from ethanol, Isosorbide-5-Nitrae-dioxane, second
Acetoacetic ester, dichloromethane, preferentially using ethanol；The acid used is concentrated hydrochloric acid, trifluoroacetic acid (TFA), preferentially using concentrated hydrochloric acid；Adopt
Reaction temperature is 0 DEG C to room temperature.
These intermediates or target compound can be purified according to conventional isolation techniques, and as needed by its turn
Turn to the addition salts with pharmaceutically acceptable acid.
Unless otherwise indicated, the following term used in the specification and in the claims has implication discussed below：
" pharmaceutically acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of property.This kind of salt
Including：
(1) obtained, inorganic acid bag by the reaction of the free alkali and inorganic acid or organic acid of parent compound into salt with acid
Include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid include acetic acid, trifluoroacetic acid,
Propionic acid, acrylic acid, caproic acid, pentamethylene propionic acid, glycolic, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid,
Ascorbic acid, camphoric acid, benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid,
Ethyl sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecane
Base sulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, butanedioic acid, glutaric acid or malonic acid etc..
(2) it is present in the acid proton in parent compound to be replaced or given birth to organic base ligand compound by metal ion
Into salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example monoethanolamine, diethanol amine,
Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE, quinine etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten
Agent compound, hydrate or prodrug and other chemical composition, such as pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition
Be to promote process of the administration to animal.
" pharmaceutical carrier " or " pharmaceutically acceptable carrier " refers to not causing organism obvious excitant and not
The non-active ingredient in the bioactivity of compound and the pharmaceutical composition of property is given in interference, such as, but not limited to：Carbonic acid
Calcium, calcium phosphate, various sugared (such as lactose, mannitol), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic acid
Polymer or methacrylate polymer, gel, water, polyethylene glycol, propane diols, ethylene glycol, castor oil or rilanit special or
Many ethoxy aluminium castor oil, sesame oil, corn oil, peanut oil etc..
"-N (H) C (O)-" represent NHCO groups orGroup.
"-C (O) N (H)-" represent CONH groups orGroup.
" alkyl " represents that the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group (are carried in this specification
The digital scope arrived, such as " 1-20 ", refer to the group, are now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3
Carbon atom etc., until including 20 carbon atoms).It is further preferred that alkyl is the medium sized alkyl for having 1-10 carbon atom,
Such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group, the tert-butyl group, amyl group.Preferably, alkyl is to have 1-8 or 1-6
The low alkyl group of individual carbon atom, such as methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group or the tert-butyl group.Alkyl can be with
It is substituted or unsubstituted.When being the alkyl of substitution, the substituent is preferably one or more, more preferably 1-3, most preferably
1 or 2 substituent.
" alkylidene " represents the aliphatic group of the saturation for 1-20 carbon atom being connected with two groups, including straight chain and branch
(digital scope mentioned in this specification, such as " 1-20 ", refer to the group to chain group, are now alkylidene, can contain 1
Carbon atom, 2 carbon atoms, 3 carbon atoms etc., until including 20 carbon atoms).It is further preferred that alkylidene is that have 1-10
The medium sized alkylidene of carbon atom, such as methylene, ethylidene, propylidene, Asia 2- propyl group, sub- normal-butyl, the sub- tert-butyl group,
Amyl group etc..Preferably, alkyl is the low-grade alkylidene for having 1-8 or 1-6 carbon atom.Alkylidene can be substitution or unsubstituted
's.When being the alkylidene of substitution, the substituent is preferably one or more, more preferably 1-3, most preferably 1 or 2 substituent.
" aromatic heterocycle " or " heteroaryl " represent 5 to 12 annular atoms monocyclic or fused ring group, containing one, two
Individual, three or four ring hetero atoms for being selected from N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated.
Unsubstituted heteroaryl base non-limiting examples have pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyridine, pyrimidine, quinoline
Quinoline, isoquinolin, purine, tetrazolium, triazine and carbazole.Heteroaryl can be substituted or unsubstituted.When substituted, substituent
It is preferably one or more, more preferably one, two or three, and then be more highly preferred to one or two, independently selected from
Following group, including：Low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyanogen
Base, acyl group, Thioacyl, O- carbamoyls, N- carbamoyls, O- thiocarbamoyls, N- thiocarbamoyls,
C- acylamino-s, N- acylamino-s, nitro, N- sulfonamidos, S- sulfonamidos.It is preferred that heteroaryl alternatively taken by one or two
For base substitution, substituent is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N- acylamino-s, Dan Huo
Dialkyl amino, carboxyl or N- sulfonamidos.
" hydroxyl " expression-OH groups.
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl).Representative example is included but not
It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine or chlorine.
" haloalkyl " represents the alkyl of halogen substitution, the low alkyl group of halogen substitution preferably as defined above, its quilt
One or more identical or different halogen atom substitutions, such as-CH2Cl ,-CF3 ,-CH2CF3 ,-CH2CCl3.
" optional " or " alternatively " mean event described later or environment can with but need not occur, the explanation includes
The occasion that the event or environment occur and do not occurred.For example, " heteroaryl is alternatively replaced by one or two substituent " is meaned
Heteroaryl substituent can with but need not be one, the explanation includes the situation and heteroaryl that heteroaryl is replaced by a substituent
The situation that base is replaced by two substituents.
The present invention further provide a kind of pharmaceutical composition, it with compound of the present invention or its pharmaceutically may be used
The salt of receiving is active component or main active, is aided with pharmaceutically acceptable carrier.The compounds of this invention can be with it
His antineoplastic such as alkylating agent (such as endoxan or cis-platinum), antimetabolite (such as 5 FU 5 fluorouracil or hydroxycarbamide), topology
Isomerase inhibitors (such as camptothecine), mitotic inhibitor (such as taxol or vincaleukoblastinum), DNA inserting agents (such as adriamycin) connection
Close application, it can in addition contain with radiotherapy use in conjunction.By with antineoplastic therapeutic alliance, strengthen cells of resistant tumors
To the sensitiveness of cancer therapy drug, so as to help to improve therapeutic effect.
The compound or its pharmaceutically acceptable salt of the present invention can be applied suppresses function medicine in preparation and P- glycoprotein
In terms of thing and reverse multidrug resistance medicine, medicine for anti transfer of tumor or antineoplastic.
Here is the part pharmacological testing and result of the representation compound of the present invention：
1st, external P-gp Inhibition tests
Compound is studied to P-gp substrate Rhodamines 123 (Rh123) in sensitive K562 and resistance to Flow Cytometry
The accumulation intracellular K562/A02 of medicine and the influence of outer row.
10 μM of compounds (6a-l) and Rh123 are educated after certain time altogether with K562/A02 cells, surveyed with flow cytometer
Determine intensity of cellular fluorescence.Experimental result is shown in Fig. 1.
Fig. 1 results show that this patent compound dramatically increases mdr cell K562/A02s of the Rh123 in high expression P-gp
In accumulation.Compared with DDB, target compound can dramatically increase the intracellular Rh123 levels of K562/A02, especially
It is compound 6j, 6k and 9c.Wherein, compound 9c effect becomes apparent from, and higher than positive control drug VRP.
Fig. 2 results show, the specific suppression P-gp of compound 6j, 6k and 9c function, 10,3.3 and 0.3 μM it is dense
Degree is lower to be presented dose-dependent effects, and does not influence Rh123 in the accumulation intracellular K562 expressed without P-gp, P-gp suppression
Make of being equally better than positive control drug VRP.
2nd, MTT experiment
The vitro cytotoxicity of MTT experiment research compound.Experimental method is as follows：Take in good condition in exponential phase of growth
One bottle of cell, be made every milliliter contain 5 × 104~7 × 104The suspension of individual cell.Cell suspension inoculation is taken on 96 orifice plates, often
The μ L of hole 160, put constant temperature CO2Cultivated 24 hours in incubator.Liquid is changed, the μ L (compounds of test-compound 40 of various concentrations are added
Diluted after being dissolved with DMSO with nutrient solution), continue to cultivate 72 hours.MTT is added in 96 orifice plates, reacted 4 hours in incubator.
With enzyme-linked immunosorbent assay instrument in the trap that wavelength is the every hole of measure at 490nm, cell inhibitory rate is calculated.Select anticarcinogen Ah mould
Plain (ADR) is used as positive control.Experimental result is as shown in table 1.
Cell inhibitory rate=(negative control group OD values-tested material group OD values)/negative control group OD value × 100%.
The inhibitory activity that the representation compound of the present invention of table 1 is bred to resistance and Sensitive Tumor Cells
As a result show, antineoplastic ADR is stronger to sensitive strain K562 cytotoxicities, IC50For 0.39 μM, and mdr cell
K562/A02 substantially produces drug resistance to substrate A DR, and resistance multiple is 64.Most of target compounds are shown slightly in vitro
(IC50=26.24~72.93 μM) inherent cytotoxicity, wherein, compound 6d, 6e and 6f relatively strong (IC of cytotoxicity50=
11.47~23.31 μM).
3rd, the tumour MDR reversal experiments of compound
ADR is independent or is educated altogether with K562/A02 cells together with 2 μM of compounds, uses mtt assay reactive compound
ADR selects VRP and ZG1142 (6- [2- (3,4- methylenes two to the cytotoxicity of K562/A02 cells in the presence of 6j, 6k and 9c
Epoxide) phenyl] ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxy -6,7- dihydro -5H- hexichol
And [c, e] azepines, the preferable compound of P-gp inhibitory activity that this seminar early stage is found) it is positive control drug.Experiment knot
Fruit is as shown in table 2.
Cytotoxicities of the ADR to K562/A02 cells in the presence of the representation compound of the present invention of table 2
Test result indicates that compound 6j, 6k, 9c and VRP compound can increase sensitivity of the K562/A02 cells to ADR
Degree.Wherein, compound 9c effect is the most notable, IC50It is worth for 4.24, reversal index (RF) is 5.76, hence it is evident that higher than the positive
Compare VRP (RF=1.82) and ZG1142.
4th, compound is to P-gp albumen and the influence of gene expression
2 μM of test-compounds 6j, 6k and 9c and K562/A02 educated after 72 hours altogether, using Western blot methods in egg
White level detects its influence expressed P-gp.As a result Fig. 3 is seen.
Fig. 3 shows that reactive compound 6j, 6k and 9c do not influence the expression of P-gp albumen.Therefore, such compound is to P-
Gp suppression is functional, rather than gene traits, is the inhibitor of class safety.
5th, anti-tumor metastasis ability of the compound to breast cancer cell MDA-MB-231 cells
It is also to cause the major reason of chemotherapy of tumors failure in view of metastases, we detect activity using scratch experiment
Anti-tumor metastasis abilities of the compound 6k and 9c in human breast carcinoma MDA-MB-231 cells, compound concentration is 2 μM.Experiment knot
Fruit sees Fig. 4.
Fig. 4 shows that compound 6k and 9c can suppress the migration of tumour cell.
Above pharmacology data shows that the compounds of this invention has excellent P-gp inhibitory action, can significantly reverse P-gp
The MDR of mediation.Wherein, compound 6j, 6k and 9c is significantly stronger than positive control drug VRP, and such to P-gp inhibitory action
The effect that compound suppresses P-gp is feature rather than gene traits, therefore is the P-gp inhibitor of class safety.In addition, this hair
Bright compound has the activity of preferable anti-tumor metastasis.
Brief description of the drawings
Focusing experiments of Fig. 1 representation compound increase substrate Rh123 of the present invention in mdr cell K562/A02；
The dose dependent that Fig. 2 representation compound increase substrate Rh123 of the present invention assemble in resistance and sensitive cells is real
Test；
Fig. 3 representation compounds of the present invention are tested to the influence that P-gp in mdr cell K562/A02 is expressed；
Activity of resisting tumor metastasis of Fig. 4 representation compounds of the present invention to MDA-MB-231 cells.
Embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it
Only be used for the present invention specific descriptions, be not construed as limitation of the present invention.
Embodiment 1
4,4 '-dimethoxy -5,6,5 ', 6 '-two -2,2 '-'-bis (hydroxymethyl) biphenyls of methylene-dioxy
DDB (4g, 9.56mmol) is dissolved in 50mL anhydrous tetrahydro furans, and ice bath is cooled to 0 DEG C, in batches careful to add
Enter Lithium Aluminium Hydride (1.09g, 28.68mmol), after reaction is stirred at room temperature 4 hours in mixture, ice bath is cooled to 0 DEG C, along bottle
Wall is slowly added to distilled water untill no hydrogen is produced, filtering precipitation, and solid washs for several times with dichloromethane, and filtrate is with adding water
After scattered, dichloromethane extraction, organic layer uses anhydrous sodium sulfate drying with after saturated common salt water washing.Filtering, decompression removes molten
White solid (2.9g, 85%) is obtained after agent.The compound is known compound.
m.p.170-171℃(Eur.J.Med.Chem.1992,27,353-358.172-173℃)；
ESI-MS:m/z 385[M+Na]+.
Embodiment 2
4,4 '-dimethoxy -5,6,5 ', the methyl mesylate base biphenyl of 6 '-two methylene-dioxy -2,2 '-two
4,4 '-dimethoxy -5,6,5 ', 6 '-two -2,2 '-'-bis (hydroxymethyl) biphenyls of methylene-dioxy (2g, 5.5mmol) are molten
In 20mL dichloromethane, add triethylamine (2.33mL, 16.5mmol), be then added dropwise mesyl chloride (1.28mL,
16.5 mmol).Room temperature reaction 6 hours, wherein TLC tracking reactions, is added water scattered after terminating, and dichloromethane extraction, organic layer is used
After saturated common salt water washing, anhydrous sodium sulfate drying is used.Filtering, concentration, rapid column chromatography (petrol ether/ethyl acetate： 4/1,
V/V white title compound (2g, 91%)) is obtained.
m.p.134-135℃；
ESI-MS:m/z 399[M+H]+；
1H-NMR(CDCl3,300MHz,δppm):3.96(s,6H,2×-OCH3),4.37(s,4H,2×-CH2-),5.97
(s, 4H,2×-OCH2O-),6.78(s,2H,2×Ar-H).
Embodiment 3
6- [6- (N-Boc) amino]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines
4,4 '-dimethoxy -5,6,5 ', the methyl mesylate base biphenyl of 6 '-two methylene-dioxy -2,2 '-two (2.4g,
4.6mmol) it is dissolved in 30mL acetonitriles, the hexamethylene diamine (2g, 9.2mmol) of Boc protections is scattered in 20mL acetonitriles and is placed in constant pressure drop
In liquid funnel, it is slowly dropped in above-mentioned reaction solution, triethylamine (3.3mL, 23mmol) is added dropwise, is heated to 40 DEG C of reaction 6-8 small
When, reaction terminate after be concentrated under reduced pressure, residue add water it is scattered, ethyl acetate extraction.Organic layer uses distilled water, unsaturated carbonate successively
After hydrogen sodium solution, saturated common salt water washing, anhydrous sodium sulfate drying is used.Filtering, concentration, rapid column chromatography (dichloromethane:Acetone
=2:1, V/V) off-white color title compound (2.4g, 92%) is obtained.
m.p.134-135℃；
ESI-MS:m/z 543[M+H]+；
1H NMR(CDCl3,400MHz,δppm):1.36-1.42(m,4H),1.44(s,9H,3×-CH3),1.48-1.53
(m, 2H),1.92-2.07(m,2H),2.84-3.03(m,2H),3.09-3.14(m,2H),352-3.68(m,1H),3.98
(s,6H,3×-OCH3), 4.57-4.67 (m, 1H), 6.03 (d, J=1.3Hz, 2H ,-OCH2O-), 6.13 (d, J=1.3 Hz,
2H,-OCH2O-),6.78(s,2H,2×Ar-H).
Embodiment 4
6- [6- (2- methoxyl groups) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6a)
6- [6- (N-Boc) amino]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines (2.3g, 4.24mmol) are dissolved in 50mL ethanol, and ice bath cooling is slowly added dropwise dense
Hydrochloric acid/ethanol solution (15mL, V:V=1:4), completion of dropping, warms naturally to room temperature reaction 12 hours.Reaction terminates rear ice
Bath cooling, saturated sodium bicarbonate solution adjusts pH to alkalescent, and ethyl acetate extraction, organic layer uses distilled water, saturated common salt successively
After water washing, anhydrous sodium sulfate drying is used.Filtering, concentration, obtains intermediate product V, directly carries out next step reaction.O-methoxy benzene
Formic acid (37.9mg, 0.25mmol) is dissolved in 5mL DMF, plus HATU (104mg, 0.28mmol), and stirring is added dropwise 1 after 15 minutes and dripped
Triethylamine, continues after stirring 10 minutes plus intermediate product V (100mg, 0.23mmol), reacts at room temperature 8 hours.Reaction is anti-after terminating
Liquid is answered to add water scattered, ethyl acetate extraction, organic layer successively use after distilled water, saturated common salt water washing successively by organic layer, with nothing
Aqueous sodium persulfate is dried.Filtering, concentration, rapid column chromatography (dichloromethane:Acetone=3:1, V/V) yellow title compound is obtained
(84mg, 63.2%).
m.p.120.3-122.7℃；
ESI-MS:m/z 577.2[M+H]+；
1H NMR(CDCl3,400MHz,δppm):1.42-1.59(m,4H),1.60-1.72(m,2H),1.85-2.00(m,
2H),3.03-3.33(m,2H),3.39-3.52(m,2H),3.93(s,6H,2×Ar-OCH3),3.98(s,3H, Ar-OCH3),
4.09-4.24 (m, 2H), 6.05 (d, J=1.4Hz, 2H ,-OCH2), O- 6.14 (d, J=1.4Hz, 2H ,-OCH2O-),6.85
(s,2H,2×Ar-H),6.95-7.01(m,2H,2×Ar-H),7.41-7.46(m,1H,Ar-H), 7.91-7.93(m,1H,
Ar-H),8.05-8.11(m,1H,-NH-)；
Embodiment 5
6- [6- (3,4- dimethoxys) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6b)
By the similar approach of embodiment 4,3,4- dimethoxybenzoic acids (45.3mg, 0.25mmol), HATU (104 are used
Mg, 0.28mmol), 1 drop triethylamine, intermediate product V (100mg, 0.23mmol) reaction obtain yellow title compound (83mg,
60.4%).
m.p.129.8-131.6℃；
ESI-MS:m/z 607.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.37-1.44(m,4H),1.57-1.64(m,2H),1.70-1.90(m,
2H),2.86-3.11(m,2H),3.36-3.54(m,4H),3.87(s,3H,Ar-OCH3),3.89(s,3H,Ar-OCH3),
3.91(s,6H,2×Ar-OCH3), 3.94-4.00 (m, 2H), 6.02 (d, J=1.2Hz, 2H ,-OCH2), O- 6.12 (d, J=
1.2Hz,2H,-OCH2O-), 6.74 (s, 2H, 2 × Ar-H), 6.83 (d, J=8.0Hz, 1H, Ar-H), 7.29-7.35 (m,
2H,2×Ar-H).
Embodiment 6
6- [6- (3,4,5- trimethoxies) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6c)
By the similar approach of embodiment 4,3,4,5- trimethoxybenzoic acids (52.8mg, 0.25mmol), HATU are used
(104 mg, 0.28mmol), 1 drop triethylamine, intermediate product V (100mg, 0.23mmol) reactions obtain yellow title compound
(89mg, 61.6%).
m.p.134.2-136.1℃；
ESI-MS:m/z 637.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.35-1.50(m,4H),1.55-1.69(m,2H),1.71-1.98(m,
2H),2.17-2.37(m,1H),3.00-3.13(m,1H),3.20-3.48(m,4H),3.81(s,9H,3×Ar-OCH3),
3.84(s,3H,Ar-OCH3),3.97(s,3H,Ar-OCH3),4.00-4.05(m,1H),4.29-4.33(m,1H),6.03-
6.14(m,4H,2×-OCH2), O- 6.81 (d, J=4.4Hz, 2H, 2 × Ar-H), 7.01 (s, 2H, 2 × Ar-H), 8.71-
8.80(m,1H,-NH-).
Embodiment 7
6- [6- (4- methyl) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6d)
By the similar approach of embodiment 4,4- methyl benzoic acids (33.9mg, 0.25mmol), HATU (104mg, 0.28 are used
Mmol), 1 drop triethylamine, intermediate product V (100mg, 0.23mmol) reaction obtain yellow title compound (64mg,
50.2%).
m.p.101.6-103.2℃；
ESI-MS:m/z 561.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.36-1.48(m,4H),1.56-1.62(m,4H),2.37(s,3H, -
CH3), 2.44-2.66 (m, 2H), 3.20 (d, J=12.4Hz, 2H), 3.41-3.46 (m, 2H), 3.57 (d, J=12.8Hz,
2H),3.92(s,6H,2×Ar-OCH3), 5.97 (d, J=1.2Hz, 2H ,-OCH2O-), 6.08 (d, J=1.2Hz, 2H-
OCH2), O- 6.56 (s, 2H, 2 × Ar-H), 7.20 (d, J=8.0Hz, 2H, 2 × Ar-H), 7.64 (d, J=8.0Hz, 2H, 2
×Ar-H).
Embodiment 8
6- [6- (4- chlorine) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6e)
By the similar approach of embodiment 4,4- chlorobenzoic acids (77.9mg, 0.5mmol), HATU (208mg, 0.56 are used
Mmol), 1 drop triethylamine, intermediate product V (200mg, 0.46mmol) reaction obtain white title compound (137mg,
52.3%).
m.p.75.5-76.8℃；
ESI-MS:m/z 581.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.39-1.45(m,4H),1.59-1.76(m,4H),2.50-2.74(m,
2H), 3.28 (d, J=12.4Hz, 2H), 3.39-3.51 (m, 2H), 3.62 (d, J=12.4Hz, 2H), 3.93 (s, 6H, 2 ×
Ar-OCH3), 5.99 (d, J=1.2Hz, 2H ,-OCH2), O- 6.09 (d, J=1.4Hz, 2H ,-OCH2O-),6.59(s,2H, 2
×Ar-H),7.36-7.41(m,2H,2×Ar-H),7.70-7.76(m,2H,2×Ar-H).
Embodiment 9
6- [6- (3,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6f)
By the similar approach of embodiment 4, using 3,4- dichlorobenzoic acids (95.1mg, 0.5mmol), HATU (208mg,
0.56mmol), 1 drop triethylamine, intermediate product V (200mg, 0.46mmol) reaction obtain yellow title compound (148.7 mg,
53.4%).
m.p.85.5-88.3℃；
ESI-MS:m/z 615.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.40-1.53(m,4H),1.62-1.74(m,2H),1.77-1.97(m,
2H), 2.77-2.96 (m, 2H), 3.41-3.52 (m, 4H), 3.88 (d, J=12.8Hz, 2H), 3.96 (s, 6H, 2 × Ar-
OCH3), 6.03 (d, J=1.2Hz, 2H ,-OCH2), O- 6.13 (d, J=1.2Hz, 2H ,-OCH2O-),6.72(s,2H, 2×
), Ar-H 7.49 (d, J=8.4Hz, 1H, Ar-H), 7.75-7.78 (m, 1H, Ar-H), 8.04 (d, J=2.0Hz, 1H, Ar-
H).
Embodiment 10
6- [6- (2,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6g)
By the similar approach of embodiment 4, using 2,4- dichlorobenzoic acids (95.1mg, 0.5mmol), HATU (208mg,
0.56mmol), 1 drop triethylamine, intermediate product V (200mg, 0.46mmol) reaction obtain yellow title compound (136.5 mg,
49.0%).
m.p.70.2-72.3℃；
ESI-MS:m/z 615.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.39-1.52(m,4H),1.61-1.67(m,2H),1.82-1.98(m,
2H),2.86-3.01(m,2H),3.41-3.46(m,4H),3.90(s,6H,2×Ar-OCH3),4.00-4.08(m,2H),
6.01 (d, J=1.6Hz, 2H ,-OCH2), O- 6.11 (d, J=1.2Hz, 2H ,-OCH2O-),6.68(s,1H,Ar-H),7.13 -
(s, 1H, the Ar-H) of 7.18 (m, 1H, Ar-H), 7.38 (d, J=2.0Hz, 1H, Ar-H), 7.54 (s, 1H, Ar-H), 7.56
Embodiment 11
6- [6- (thiophene-2-carboxamide derivatives base)]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6h)
By the similar approach of embodiment 4, thiophene -2-carboxylic acid (63.8mg, 0.5mmol), HATU (208mg, 0.56 are used
Mmol), 1 drop triethylamine, intermediate product V (200mg, 0.46mmol) reaction obtain yellow title compound (164.5 mg,
65.8%).
m.p.84.7-86.4℃；
ESI-MS:m/z 553.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):1.33-1.46(m,4H),1.52-1.67(m,4H),2.40-2.59(m,
2H), 3.17 (d, J=12.4Hz, 2H), 3.39-3.44 (m, 2H), 3.51 (d, J=12.4Hz, 2H), 3.92 (s, 6H, 2 ×
Ar-OCH3), 5.96 (d, J=1.4Hz, 2H ,-OCH2), O- 6.07 (d, J=1.4Hz, 2H ,-OCH2O-),6.54(s,2H, 2
×Ar-H),7.03-7.05(m,1H),7.42-7.44(m,1H),7.48-7.50(m,1H).
Embodiment 12
6- [6- (2- methoxyl groups) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines (6i)
4,4 '-dimethoxy -5,6,5 ', the methyl mesylate base biphenyl of 6 '-two methylene-dioxy -2,2 '-two (4g,
7.7mmol) it is dissolved in 50 mL acetonitriles, the ethylenediamine (2.5g, 15.6mmol) of Boc protections is scattered in 30mL acetonitriles and is placed in perseverance
Press in dropping funel, be slowly dropped in above-mentioned reaction solution, triethylamine (5.6mL, 39mmol) is added dropwise, be heated to 40 DEG C of reaction 6-
8 hours, reaction terminate after be concentrated under reduced pressure, residue add water it is scattered, ethyl acetate extraction.Organic layer uses distilled water, saturation successively
After sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate drying is used.Filtering, concentration, rapid column chromatography (dichloromethane:
Acetone=2:1, V/V) off-white color compound IV (3.2g, 84.4%) is obtained.
Compound IV (3g, 6.2mmol) is dissolved in 50mL ethanol, and concentrated hydrochloric acid/ethanol solution is slowly added dropwise in ice bath cooling
(25mL,V:V=1:4), completion of dropping, warms naturally to room temperature reaction 12 hours.Reaction terminates rear ice bath cooling, unsaturated carbonate
Hydrogen sodium solution adjusts pH to alkalescent, and ethyl acetate extraction, organic layer is used after distilled water, saturated common salt water washing successively, with anhydrous
Sodium sulphate is dried.Filtering, concentration, obtains intermediate product V, directly carries out next step reaction.O-methoxybenzoic acid (43.3mg,
0.28mmol) it is dissolved in 5mL DMF, plus HATU (119mg, 0.31mmol), it is added dropwise 1 after stirring 15 minutes and drips triethylamine, continues
Stirring adds intermediate product V (100mg, 0.26mmol) after 10 minutes, reacts at room temperature 8 hours.Reaction terminates rear reaction solution and added water point
Dissipate, ethyl acetate extraction, organic layer successively use after distilled water, saturated common salt water washing successively by organic layer, dry with anhydrous sodium sulfate
It is dry.Filtering, concentration, rapid column chromatography (dichloromethane:Acetone=5:1, V/V) obtain white title compound (80mg,
59.3%).
m.p.74.9-76.3℃；
ESI-MS:m/z 416[M+H]+；
1H-NMR(DMSO-d6,400MHz,δppm):2.49-2.51(m,2H),3.14-3.22(m,2H),3.29-3.41
(m,2H),3.64-3.83(m,2H),3.90(s,3H,Ar-OCH3),3.92(s,6H,2×Ar-OCH3), 6.09 (d, J=
0.8Hz,2H,-OCH2), O- 6.13 (d, J=0.8Hz, 2H ,-OCH2O-),6.96-7.02(m,1H,Ar-H),7.05- 7.09
(m,1H,Ar-H),7.17-7.21(m,1H,Ar-H),7.49-7.55(m,1H,Ar-H),7.84-7.88(m,1H, Ar-H),
8.54-8.57(m,1H,Ar-H).
Embodiment 13
6- [6- (3,4- dimethoxys) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6j)
By the similar approach of embodiment 13,3,4- dimethoxybenzoic acids (51.8mg, 0.28mmol), HATU (119 are used
Mg, 0.31mmol), 1 drop triethylamine, intermediate product V (100mg, 0.26mmol) reaction obtain yellow title compound (80mg,
56.1%).
m.p.90.6-92.4℃；
ESI-MS:m/z 551.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.64-2.96(m,2H),3.22-3.33(m,2H),3.51-3.60(m,
2H),3.61-3.70(m,2H),3.95(s,12H,4×Ar-OCH3),6.00(s,2H,-OCH2O-),6.10(s,2H, -
OCH2), O- 6.57 (s, 2H, 2 × Ar-H), 6.88 (d, J=7.6Hz, 1H, Ar-H), 6.97-7.01 (m, 1H, Ar-H),
7.49(s,1H,Ar-H).
Embodiment 14
6- [6- (3,4,5- trimethoxies) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,
11- methylene-dioxies -6,7- dihydro -5H- dibenzo [c, e] azepines (6k)
By the similar approach of embodiment 13,3,4,5- trimethoxybenzoic acids (60.4mg, 0.28mmol), HATU are used
(119 mg, 0.31mmol), 1 drop triethylamine, intermediate product V (100mg, 0.26mmol) reactions obtain white title compound
(80mg, 53.2%).
m.p.122.1-123.8℃；
ESI-MS:m/z 581.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.88-3.13 (m, 2H), 3.44 (d, J=12.8Hz, 2H), 3.73-
3.82 (m,4H),3.89(s,3H,Ar-OCH3),3.94(s,6H,2×Ar-OCH3),3.96(s,6H,2×Ar-OCH3),
6.02(s, 2H,-OCH2O-),6.12(s,2H,-OCH2O-),6.65(s,2H,2×Ar-H),7.22(s,2H,2×Ar-H).
Embodiment 15
6- [6- (4- methyl) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (6l)
By the similar approach of embodiment 13, using 4- methyl benzoic acids (38.8mg, 0.28mmol), HATU (119mg,
0.31mmol), 1 drop triethylamine, intermediate product V (100mg, 0.26mmol) reaction obtain yellow title compound (68 mg,
52.4%).
m.p.94.7-96.6℃；
ESI-MS:m/z 505.2[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.40(s,3H,Ar-CH3),2.62-2.73(m,1H),2.86-2.93
(m, 1H),3.23-3.29(m,2H),3.51-3.58(m,2H),3.62-3.69(m,2H),3.95(s,6H,2×Ar-
OCH3), 6.00 (d, J=1.6Hz, 2H ,-OCH2), O- 6.10 (d, J=1.6Hz, 2H ,-OCH2O-),6.57(s,2H,2×
Ar-H), 7.23-7.26(m,2H,2×Ar-H),7.71-7.75(m,2H,2×Ar-H).
Embodiment 16
6- [N- (2- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (9a)
Boc protection Beta-alanines (200mg, 1.1mmol) are dissolved in 3mL DMF, plus HATU (442mg, 1.2mmol), room temperature
Stirring is added dropwise 3 and drips triethylamine after 10 minutes, o-aminoanisole (119 μ L, 1.1mmol) is added dropwise after 20 minutes in stirring, and room temperature is anti-
Answer 6-8 hours.After reaction terminates, reaction solution adds water scattered, ethyl acetate extraction, and organic layer saturated common salt water washing is anhydrous
Sodium sulphate is dried, filtering, is concentrated under reduced pressure, rapid column chromatography (petroleum ether:Ethyl acetate=2:1, V/V) faint yellow compound is obtained
V.Compound V (100mg, 0.34mmol) is dissolved in 2mL dichloromethane, and 0.5mL trifluoroacetic acids, room temperature reaction is added dropwise in ice bath cooling
4 hours.Reaction is directly concentrated under reduced pressure after terminating, and carries out next step reaction.4,4 '-dimethoxy -5,6,5 ', 6 '-two methylenes two
Epoxide -2,2 '-two methyl mesylate base biphenyl (100mg, 0.19mmol), compound obtained by upper step is dissolved in 10mL acetonitriles, is added dropwise
0.5mL triethylamines, are heated to 40 DEG C and react 6-8 hours.Reaction is concentrated under reduced pressure after terminating, and residue adds water scattered, ethyl acetate
Extraction, organic layer is washed with saturated sodium bicarbonate solution, distilled water, saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, mistake
Filter, is concentrated under reduced pressure, through flash column chromatography (dichloromethane：Ethyl acetate=1:1) white title compound, is obtained
(55.3mg, 55.1%).
m.p.190.2-191.8℃；
ESI-MS:m/z 521.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.65-3.04 (m, 4H), 3.33 (d, J=11.2Hz, 2H), 3.61 (s,
5H),3.94(s,6H,2×Ar-OCH3),6.02(s,2H,-OCH2O-),6.12(s,2H,-OCH2O-),6.58(s,2H,2 ×
Ar-H),6.81-6.89(m,1H,Ar-H),6.97-7.03(m,2H,2×Ar-H),8.38-8.48(m,1H,Ar-H),
11.00-11.21(m,1H,-NH-).
Embodiment 17
6- [N- (4- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines (9b)
By the similar approach of embodiment 16, Beta-alanine (200mg, 1.1mmol) is protected using Boc, HATU (442 mg,
1.2mmol), 3 drop triethylamine, 4- aminoanisoles (119 μ L, 1.1mmol), 0.5mL trifluoroacetic acids, 4,4 '-dimethoxy-
The reaction of the methyl mesylate base biphenyl (100mg, 0.19mmol) of 5,6,5 ', 6 '-two methylene-dioxy -2,2 '-two obtains white mark
Inscribe compound (149mg, 70.8%).
m.p.77.6-78.5℃；
ESI-MS:m/z 521.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.52-2.68 (m, 2H), 2.77-3.05 (m, 2H), 3.30 (d, J=
12.4 Hz, 2H), 3.59 (d, J=12.4Hz, 2H), 3.80 (s, 3H, Ar-OCH3),3.95(s,6H,2×Ar-OCH3),6.02
(d, J=0.8Hz, 2H ,-OCH2), O- 6.12 (d, J=1.2Hz, 2H ,-OCH2O-),6.56(s,2H,2×Ar-H),6.85
(d, J=8.8Hz, 2H, 2 × Ar-H), 7.47 (d, J=8.8Hz, 2H, 2 × Ar-H), 11.03-11.14 (m, 1H ,-NH-)
Embodiment 18
6- [N- (3,4- dimethoxys) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines (9c)
By the similar approach of embodiment 16, Beta-alanine (200mg, 1.1mmol) is protected using Boc, HATU (442 mg,
1.2mmol), 3 drop triethylamine, 0.5mL trifluoroacetic acids, 3,4- dimethoxybenzoic acids (162mg, 1.1mmol), 4,4 '-diformazan
Epoxide -5,6,5 ', the reaction of the methyl mesylate base biphenyl (100mg, 0.19mmol) of 6 '-two methylene-dioxy -2,2 '-two obtains white
Color title compound (55.3mg, 55.1%).
m.p.166.8-168.6℃；
ESI-MS:m/z 551.1[M+H]+；
1H-NMR(CDCl3,400MHz,δppm):2.57-2.72 (m, 2H), 2.79-3.10 (m, 2H), 3.35 (d, J=
12.4 Hz, 2H), 3.63 (d, J=12.4Hz, 2H), 3.87 (s, 3H, Ar-OCH3),3.89(s,3H,Ar-OCH3),3.96(s,
6H, 2×Ar-OCH3), 6.02 (d, J=1.4Hz, 2H ,-OCH2), O- 6.12 (d, J=1.4Hz, 2H ,-OCH2O-),6.59
(d, J=2.4Hz, 2H, 2 × Ar-H), 6.76-6.81 (m, 1H, Ar-H), 6.85-6.88 (m, 1H, Ar-H), 7.48 (d, J=
2.4Hz,1H,Ar-H),10.97-11.06(m,1H,-NH-)。
Claims (10)
1. alkoxy dibenzazepines class compound or its pharmaceutically acceptable salt shown in formula I,
Wherein：
X representatives-N (H) C (O)-or-C (O) N (H)-；
R1Represent C1-C10Alkylidene；
R2Represent C1-C10Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma heterocycle or-(CH2)nR3；
R3Represent phenyl, substituted-phenyl, aromatic heterocycle or substituted aroma heterocycle；
N represents 1-5 integer；
R2Or R3In one or more of the substituent in following radicals：C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Alcoxyl
Base, hydroxyl or halogen.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R1Represent C1-C8Alkylidene；R2Generation
Table C1-C8Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma heterocycle or (CH2)nR3。
3. compound according to claim 2 or its pharmaceutically acceptable salt, wherein R1Represent C1-C6Alkylidene；R2Generation
Table C1-C6Alkyl, phenyl, substituted-phenyl, aromatic heterocycle, substituted aroma heterocycle or (CH2)nR3。
4. compound or its pharmaceutically acceptable salt according to claim 1,2 or 3, wherein described aromatic heterocycle is
Thiophene, furans, pyrroles or pyridine；R2Or R3In one or more of the substituent in following radicals：C1-C4Alkyl, C1-C4
Haloalkyl, C1-C4Alkoxy, hydroxyl or halogen.
5. compound or its pharmaceutically acceptable salt according to claim 1,2 or 3, wherein the compound is selected from：
6- [6- (2- methoxyl groups) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2- methoxyl groups) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-butyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2- methoxyl groups) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (2- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4- dimethoxys) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4,5- trimethoxies) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- methyl) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- chlorine) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxy -6,
7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4- dichloros) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (2,4- dichloros) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines.
6. compound or its pharmaceutically acceptable salt according to claim 1,2 or 3, wherein the compound is selected from：
6- [6- (2- methoxyl groups) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- chlorine) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylene-dioxies -
6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2,4- dichloros) benzamido]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (thiophene-2-carboxamide derivatives base)]-hexyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (2- methoxyl groups) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes two
Epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4- dimethoxys) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11- is sub-
Methylenedioxy group -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (3,4,5- trimethoxies) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxies -10,11-
Methylene-dioxy -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [6- (4- methyl) benzamido]-ethyl -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (2- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (4- methoxyl groups) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- (methylenedioxy)s
Base -6,7- dihydro -5H- dibenzo [c, e] azepines；
6- [N- (3,4- dimethoxys) phenyl]-propionamido- -3,9- dimethoxy -1,2- methylene-dioxy -10,11- methylenes
Two epoxide -6,7- dihydro -5H- dibenzo [c, e] azepines.
7. a kind of preparation method of the compound described in claim 1, it is characterised in that
A) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-N (H) C (O)-when, the preparation method of compound shown in formula I include it is as follows
Step：Formula III compound and Boc are protected aliphatic diamine reaction generation intermediate product IV, intermediate product IV take off after Boc reactions with
Carboxylic acid R2COOH reaction generation compound of Formula I；Synthetic route is as follows：
B) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-C (O) N (H)-when, the preparation of compound shown in formula I comprises the following steps：
The amino acid and the compound R containing primary amine group of formula IV compound Boc protections2NH2Reaction generation intermediate product V, intermediate product
V is taken off after Boc reactions with formula III compound through annulation generation compound of Formula I；Synthetic route is as follows：
8. a kind of preparation method of the compound described in claim 1, it is characterised in that
C) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-N (H) C (O)-when, the preparation method of compound shown in formula I include it is as follows
Step：By DDB reduce be made Formula II shown in compound 4,4 '-dimethoxy -5,6,5 ', 6 '-two methylene-dioxies -
2,2 '-'-bis (hydroxymethyl) biphenyl, Formula II compound and mesyl chloride reaction production III compounds 4,4 '-dimethoxy -5,6,
5 ', 6 '-two methylene-dioxy -2,2 '-disulfonic acid carbomethoxy biphenyl, the aliphatic diamine reaction that formula III compound is protected with Boc is given birth to
Into intermediate product IV, with carboxylic acid R after the de- Boc reactions of intermediate product IV2COOH reaction generation compound of Formula I；Synthetic route is such as
Under：
D) R is worked as1For C1-C6Straight-chain alkyl-sub, X be-C (O) N (H)-when, the preparation of compound shown in formula I comprises the following steps：
DDB is reduced to methylol, Formula II compound 4 is obtained, 4 '-dimethoxy -5,6,5 ', 6 '-two methylene-dioxy -2,
2 '-'-bis (hydroxymethyl) biphenyl, compound II and mesyl chloride reaction production III compounds 4,4 '-dimethoxy -5,6,5 ', 6 ' -
Two -2,2 '-disulfonic acid carbomethoxy biphenyl of methylene-dioxy；The amino acid and the compound R containing primary amine group of Boc protections2NH2
After the de- Boc reactions of reaction generation intermediate product V, intermediate product V compound of Formula I is generated with formula III compound through annulation；
Synthetic route is as follows：
9. a kind of pharmaceutical composition, it is using the compound described in claim 1 or its pharmaceutically acceptable salt as active component
Or main active, it is aided with pharmaceutically acceptable carrier.
10. the compound or its pharmaceutically acceptable salt described in claim 1,2 or 3 suppress function in preparation and P- glycoprotein
Application in terms of medicine and reverse multidrug resistance medicine, medicine for anti transfer of tumor or antineoplastic.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04202153A (en) * | 1990-11-29 | 1992-07-22 | Tokyo Tanabe Co Ltd | New tricyclic composition having treating action on hepatic disease |
| CN102532150A (en) * | 2012-02-27 | 2012-07-04 | 中国药科大学 | Alkoxyl dibenzoazepine compound, and preparation method and medical application thereof |
| CN106187986A (en) * | 2015-04-30 | 2016-12-07 | 嘉兴汉纯生物科技有限公司 | There is after film forming the naked axial chirality biphenyl derivatives regarding 3D effect and preparation thereof and application |
-
2017
- 2017-06-20 CN CN201710471416.5A patent/CN107266461B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04202153A (en) * | 1990-11-29 | 1992-07-22 | Tokyo Tanabe Co Ltd | New tricyclic composition having treating action on hepatic disease |
| CN102532150A (en) * | 2012-02-27 | 2012-07-04 | 中国药科大学 | Alkoxyl dibenzoazepine compound, and preparation method and medical application thereof |
| CN106187986A (en) * | 2015-04-30 | 2016-12-07 | 嘉兴汉纯生物科技有限公司 | There is after film forming the naked axial chirality biphenyl derivatives regarding 3D effect and preparation thereof and application |
Non-Patent Citations (5)
| Title |
|---|
| XIAOBO TANG ET AL.: "Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P-glycoprotein-mediated multidrug resistance reversal agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XIAOKE GU ET AL.: "Discovery of alkoxyl biphenyl derivatives bearing dibenzo[c,e]azepine scaffold as potential dual inhibitors of P-glycoprotein and breast cancer resistance protein", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XIAOKE GU ET AL.: "Synthesis and biological evaluation of novel bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potent P-glycoprotein inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 尤启冬主编: "《药物化学》", 31 January 2004, 化学工业出版社 * |
| 谷小珂等: "一氧化氮供体型烷氧基联苯化合物的合成及抗肿瘤活性", 《中国药科大学学报》 * |
Cited By (6)
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| 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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