CN106957315B - N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of drug - Google Patents
N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of drug Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of N- replace benzenesulfonyl-azaindole oxybenzamide class compound, crystal form, pharmaceutically acceptable salt class, hydrate, solvate or prodrug, and preparation method thereof and pharmaceutical applications.Shown in the general structure of the compound such as formula (I).Experiments have shown that it is to Bcl-2 protein family anti-apoptotic members and HDAC inhibitory activity with higher, and it shows to combine selectivity, while such compound shows broad-spectrum anti-tumor activity to human blood tumour (myeloma, leukaemia) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer).It prompts such compound that there is the therapeutic agent for preparing disease relevant to Bcl-2 or HDAC activity, prepares anti-tumor drug, and prepare synergist and share with other anti-tumor drugs or radiotherapy to treat the potential use of tumour.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly it relates to which one kind N- replaces benzenesulfonyl-azepine Yin
Diindyl oxybenzamide class compound resists swollen the invention further relates to the composition of such compound, preparation method and its in preparation
Purposes in tumor medicine and antitumor synergist.
Background technique
Apoptosis is cell by the programmed cell death carried out after certain signal stimulus, is a kind of substantially biological of cell
Learn phenomenon.Bcl-2 protein family plays important adjustment effect in Apoptosis access, it can be divided into anti-apoptotic member (such as
Bcl-2、Bcl-xL, Mcl-1 etc.) and promote two class of apoptosis member.Research shows that Bcl-2 protein family anti-apoptotic members are excessive
Expression can lead to normal apoptosis access and be obstructed, related to the generation of many diseases (such as tumour, autoimmune disease),
Especially tumour generates and occurs drug resistant one of the major reasons (Nature 2000,407,796-801；Nat Rev Cancer
2004,4,592-603.)。
Research shows that Bcl-2 protein family anti-apoptotic members over-express in many tumours, different tumours with
And expression difference (the Oncogene 2003,22,8590-607 in different tumors subtypes；Oncogene 2008,27,
6398-406).By inhibiting the Anti-G value of the anti-apoptotic members over-expressed in tumour cell, it can restored just
Normal apoptosis pathway increases its sensibility to chemotherapy radiotherapy, is the new strategy for treating tumour.Bcl-2 protein family anti-cell
Apoptosis member is to be combined by the hydrophobic groove on its surface with the Bcl-2 protein family conservative region (BH) 3 for promoting apoptosis member
It interacts, to adjust the normal Apoptosis of cell.Micromolecular inhibitor is dredged by being incorporated into anti-apoptotic member surface
Water groove can interfere the rush region apoptosis member BH3 is in combination to play the role of promoting Apoptosis (Nat Rev Cancer
2005,5,876-85；Kelly,P.N.；Cell Death Differ 2011,18,1414-24.).The micromolecular in recent years
Inhibitor causes the broad interest of researcher, has found a series of micromolecular inhibitors by different approaches, wherein there are four
(ABT-199, ABT-263, AT-101, GX15-07) enters clinical research as oral anti-tumor drug.Result of study shows
Bcl-2 protein family anti-apoptotic members micromolecular inhibitor shows preferable antitumor action and to other antineoplastics
The synergy of object or radiotherapy acts synergistically, and has good development prospect (Nat Rev Drug Discov 2008,7,989-
100；Chinese Journal of New Drugs 2008,17,2008-2013.；Pharmacy progress 2004,28,97-103；Clin Cancer Res
2012,18,1-7；J Thorac Oncol 2011,6,1757-1760；Lung Cancer 2011,74,481-485).
HDAC and acetylation of histone enzyme are the internal two groups enzymes with reverse functions, adjustable including histone
A variety of cores inside and outside histone acetylation state effect, adjust genetic transcription, cell differentiation, cell cycle and cell to play
The multiple functions such as apoptosis.HDAC includes four subfamilies, Zn2+The I type (HDAC1-3,8) of dependence, IIA (HDAC4,5,7,9),
IIB (HDAC6,10) and IV (HDAC11) and NAD+The type III (sirtuins 1-7) of dependence.HDAC is proved and tumour, mind
Occurrence and development through the diseases such as systemic disease and inflammation and infection have substantial connection.Thus HDAC wide spectrum and selective small molecule
Inhibitor is used for treatment and research (the Nat Rev Drug of the diseases such as tumour, the nervous system disease, inflammation and virus infection
Discov 2014,13,673-91；Pharmacol Ther 2014,143,323-36.).
Albumen deacetylation increase is one of the characteristic feature of many tumours caused by HDAC high expression or activity improve,
HDAC expression all can be observed in a variety of hematological system tumors and increase (Cancer Lett 2009,280,168-76).It is multiple
Property myeloma be also unequivocally established the common high expression of I type HDAC (especially HDAC1), and it is closely related with poor prognosis
(Epigenetics 2014,9,1511-20).Therefore, targeting HDAC is increasingly becoming one of research hotspot of oncotherapy
(Lancet Oncol 2013,14,1038-9.).In recent years, the development of HDAC micromolecular inhibitor is very fast, mainly includes different
Hydroximic acid, benzamides, cyclic peptide and short-chain fat acids etc..They show swollen for hematological system in vivo and in vitro
Extensive antitumous effect (the Nat Rev Drug Discov 2014,13,673-91 of tumor, lung cancer and prostate cancer etc.；J Med
Chem 2008,51,1505-29.).Three such drug Vorinostats of current foreign countries' approved listing (vorinostat,
SAHA), romidepsin (romidepsin) (J Clin Invest 2014,124,30-9.) and Baily department he
(belinostat, 2014.07 crowdes) (Br J Haematol 2015,168,811-9.), domestic just approval one drug of listing
Chidamide (chidamide, 2015.01 approvals) (Cancer Chemother Pharmacol 2012,69,1413-22.),
It is approved for the treatment of skin or lymphoma peripheral T cell.And multiple hdac inhibitors are shown very in clinical test
Good anti-Huppert's disease effect, and shared with other anti-tumor drugs and can play significant synergistic effect, 2015.02 pas are than department
His (panobinostat) is shared with bortezomib and dexamethasone for multiple myeloma (Lancet by FDA approval
Oncol 2014,15,1195-206.).In addition, since isoform selective inhibitors may have better curative effect and lower
Side effect is increasingly becoming research in recent years hot spot (Nat Rev Drug Discov 2014,13,673-91；Curr Pharm Des
2015,21,1472-502.).Research confirms newly discovered HDAC6 selective depressant (such as rocilinostat, ACY-
1215) protein degradation systems can be participated in by influencing aggresomes formation, thus with another proteasome pathway of the system
Inhibitor bortezomib play the role of synergistic treatment Huppert's disease, come into clinical test at present
(Blood 2012,119,2579-89；Br J Haematol.2015,169,423-34).HDAC6 selective depressant also by
Research (Nat Rev for disease treatments such as the nervous system disease (neurodegenerative disease, alzheimer's disease etc.) and inflammation
Drug Discov 2014,13,673-91.)。
It swells as previously mentioned, hdac inhibitor and Bcl-2 anti-apoptotic proteins subfamily inhibitor are respectively proved to resist other
Tumor medicine or radiotherapy act synergistically with synergy.The clinical test currently carried out also mostly uses and existing therapeutic agent
The scheme of drug combination.Research, which also shows these two types of drugs between each other, also has synergistic antitumor action (Mol Cell
Biol 2009,29,6149-69；Cell Death Dis 2013,4, e798), and it is more preferable to recent studies have shown that they are combined energy
Play to other anti-tumor drugs synergy synergistic effect (Blood 2014,124,2687-97).Studies have shown that for swollen
The disease of the mechanism such as tumor, central nervous system disease complexity, multiple target point drug can act on more in disease network system simultaneously
A link, is not likely to produce drug resistance, generates synergistic effect to the effect of each target spot, attenuating target spot is xicity related, reaches and more preferably controls
Therapeutic effect (Nat Rev Cancer 2010,10,130-7).And compared with two class drug combinations, double target drugs have more
Add single pharmacokinetic property, there is no complicated drug drug interactions, are conducive to the complete performance of curative effect of medication, can also
To reduce development cost, increase patient compliance (J Med Chem 2014,57,7874-87).Therefore, Bcl-2 anti-apoptotic egg
White subfamily and the bis- target spot inhibitor of HDAC can play better antitumor or synergistic effect by mutual synergistic effect.
In conclusion the inhibitor of research and development Bcl-2 protein family anti-apoptotic members or HDAC, can especially make simultaneously
For the double inhibitor of the two target spots, it is of great significance for the treatment of the diseases such as tumour.
Summary of the invention
The object of the present invention is to provide a kind of novel N- to replace benzenesulfonyl-azaindole oxybenzamide class chemical combination
The preparation method of object and such compound, purposes and composition.
In the first aspect of the present invention, a kind of N- substitution benzenesulfonyl-azaindole oxybenzamide class is provided
Close object, which is characterized in that shown in its general structure such as formula (I):
Wherein,
R1Group isWherein,
R2For C1~C5Straight chain, branch or cyclic alkane base；
Z is N, O, S,
Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic olefin base, aromatic monocyclic,
Aromatic condensed ring.
As a preference of the invention:
R1Group isWherein, R2For C1~C5Straight chain, branch or ring-type
Alkyl；
Z is N, O, S；
Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic olefin base.
As another preference of the invention:
R1Group is
Z is N, O, S；
Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic olefin base.
As another preference of the invention:
R1Group is
Z is N；
Y is C1~C10Linear paraffin base.
As a kind of preferred embodiment of the invention, the N- replaces benzenesulfonyl-azaindole oxybenzamide
Class compound is any of following compounds:
1) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxo) -3- nitrophenylsulfonyl)
Benzamide
2) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (7- (hydroxyl amino) -7- oxo amino in heptan) -3- nitrophenylsulfonyl)
Benzamide
3) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxo) -3- nitrophenylsulfonyl)
Benzamide
4) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 5- (hydroxyl amino) -5- oxo) -3- nitrophenylsulfonyl)
Benzamide
5) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 4- (hydroxyl amino) -4- oxo) -3- nitrophenylsulfonyl)
Benzamide
6) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 3- (hydroxyl amino) -3- oxo) -3- nitrophenylsulfonyl)
Benzamide
7) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (2- (hydroxyl amino) -2- oxo ethylamino) -3- nitrophenylsulfonyl)
Benzamide.
In the second aspect of the present invention, provides the N- and replace benzenesulfonyl-azaindole oxybenzamide class
The crystal form of compound, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
In the third aspect of the present invention, a kind of pharmaceutical composition is provided, the pharmaceutical composition, which contains, pharmaceutically may be used
The excipient or carrier of receiving and the N- replace benzenesulfonyl-azaindole oxybenzamide class compound or institute
The N- stated replaces benzenesulfonyl-azaindole oxybenzamide class compound crystal form, pharmaceutically acceptable inorganic acid salt
Or acylate, hydrate, solvate or prodrug.
As a kind of specific embodiment of the invention, the pharmaceutical composition also contains other drugs active constituent.
As a preference of the invention, the other drugs active constituent is bortezomib.
It is highly preferred that N- described in the pharmaceutical composition replaces benzenesulfonyl-azaindole oxybenzamide class
The molar ratio for closing object and bortezomib is 20-3000.
In the fourth aspect of the present invention, provides the N- and replace benzenesulfonyl-azaindole oxybenzamide class
Compound or the N- replace benzenesulfonyl-azaindole oxybenzamide class compound crystal form, pharmaceutically acceptable
Inorganic acid salt or acylate, hydrate, solvate or prodrug purposes in medicine preparation, the drug is used for:
A) disease relevant to Bcl-2 or HDAC activity or symptom are treated,
B) antitumor, or
C) as antineoplastic or the synergist of radiotherapy.
As a kind of specific embodiment of the invention, the tumour be myeloma, leukaemia, oophoroma, breast cancer,
Melanoma or lung cancer.
In the fifth aspect of the invention, it provides the N- and replaces benzenesulfonyl-azaindole oxybenzamide class
The preparation method of compound, including the following steps: under the conditions of existing for the condensing agent, azaindole oxygroup benzene first that difference replaces
It is sour that the different substituted N- substitution benzenesulfonyl benzamide compounds of condensation generation occur from different substituted sulfonamide.
Herein, " prodrug " refers to that a reagent is converted into prototype medicine in vivo.Prodrug is usually useful, because at certain
In the case of kind, they may administration easier than prototype medicine.Prodrug is usually the precursor of medicine, and next administration and absorption are converted
For active material, or by some processes become the stronger type of activity, such as passes through metabolic pathway conversion.What some prodrugs had
Chemical group changes its dissolubility that is active lower and/or comparing prototype medicine or some other properties.Once prodrug
Chemical group is removed and/or modifies it, obtains active drug.
The pharmaceutically acceptable inorganic acid salt can be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrogen bromine
Hydrochlorate, nitrate；The pharmaceutically acceptable acylate can be selected from acetate, maleate, fumarate, tartaric acid
Salt, succinate, lactate, tosilate, salicylate, oxalates.
Described pharmaceutical composition can be solid form or liquid form, and dosage form can be tablet, dispersible tablet, contain
Piece, oral disintegrating tablet, sustained release tablets, capsule, soft capsule, dripping pill, granule, injection, powder-injection or aerosol etc..Work as the present invention
It when compound is used for such use, can be mixed with one or more pharmaceutically acceptable carriers or excipient, such as solvent, dilution
Agent etc., and can be administered orally with following form: tablet, pill, capsule, dispersible powder, particle or suspension (contain
Such as from about 0.05-5% suspending agent), syrup (containing such as from about 10-50% sugar) and elixir (contain about 20-50% ethyl alcohol), or in addition
It is administered with mode: ointment, gel, drug containing adhesive plaster etc., or with sterile injectable solution or suspension form (in isotonic medium
In contain about 0.05-5% suspending agent) carry out parenteral routes.For example, these pharmaceutical preparations contain the pact mixed with carrier
The active constituent of 0.01-99%, more preferably about 0.1-90% (weight).Suitable administration route include but is not limited to it is oral,
Intravenous injection, rectum, aerosol, parenterai administration, ophthalmic administration, pulmonary administration, percutaneous dosing, vagina administration, ear canal administration,
Nasal-cavity administration and local administration.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass,
They are suitble to people to use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein means generation be in composition
Each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the curative effect of compound.Pharmaceutically
Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch),
Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum powder, Gu
Body lubricant (such as odium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil) are more
First alcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as Tweens), wetting agent (such as dodecyl sodium sulfonate
Sodium), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
" synergist " refers to a kind of and certain class compatibility of drugs and lives in use, enhancing such drug with specific mechanism
Property drug, play synergistic effect., can be with other drugs drug combination as synergist, " administering drug combinations " refer to will be several
Therapeutic agent selected by kind gives patient's medication, with identical or different administration mode in identical or different time administration.
Term " collaboration ", " synergistic effect " or " synergy " refers to script as used herein and there is inhibition Bcl-2 activity or inhibit HDAC
Activity or anti-tumor drug can enhance original Drug inhibition HDAC activity when sharing another drug or inhibit HDAC
The effect of activity or antitumous effect.
The invention has the advantages that:
1, N- of the invention replaces benzenesulfonyl-azaindole oxybenzamide class compound to show to Bcl-2 egg
The white higher inhibitory activity of family's anti-apoptotic members, especially part of compounds show good inhibition to HDAC simultaneously
Activity, and show to combine selectivity.Therefore these compounds have prepares anti-tumor drug, and prepare synergist with it is other
Anti-tumor drug or radiotherapy are shared to treat the potential use of tumour.
2, N- of the invention replaces benzenesulfonyl-azaindole oxybenzamide class compound to human blood tumour (bone
Myeloma, leukaemia) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer) show wide spectrum and significant antitumor work
Property.And preferable synergistic effect is shown with existing drug combination.Therefore, the compound of the present invention is expected have good exploitation
Prospect.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, it is to form a new or preferred technical solution, i.e., of the invention
It can be combined with each other between each substituent group, the particular compound constituted is a part of the invention.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight
Number.
Embodiment 1
2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -
1- alkenyl) methyl) piperazine -1- base)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxo) -3- nitrophenylsulfonyl) benzene first
The preparation of amide (compound 1 in table 1):
Synthetic route are as follows:
Specific steps are as follows:
1) 8- (4- (N- (2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- two
Methylcyclohexene -1- alkenyl) methyl) piperazine -1- base) benzoyl) sulfuryl amino) -2- nitro-phenylamino) ethyl caprilate
Preparation:
By (2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base) benzoic acid 100mg (0.175mmol), 8- (2- nitro -4- sulphonylaminophenyl ammonia
Base) ethyl caprilate 68mg (0.175mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) 167mg
(0.875mmol), 4-dimethylaminopyridine 25.6mg (0.21mmol), using anhydrous DCM as solvent, normal-temperature reaction is for 24 hours.Reaction knot
Shu Hou successively uses the hydrochloric acid of 1M, saturated sodium bicarbonate, and saturated common salt is washed, and water phase is extracted with EA, merges organic phase, is concentrated to give
To solid 160mg, column chromatographic purifying, yield 85%.
2) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane
Alkene -1- alkenyl) methyl) piperazine -1- base)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxo) -3- nitrophenylsulfonyl)
The preparation of benzamide:
By 8- (4- (N- (2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- two
Methylcyclohexene -1- alkenyl) methyl) piperazine -1- base) benzoyl) sulfuryl amino) -2- nitro-phenylamino) ethyl caprilate
160mg (0.170mmol) is dissolved in the methanol solution of the azanol of the potassium hydroxide of the 1.12mol/L of the 8ml of existing system, is stirred at room temperature
3h, TLC detect fully reacting, and solution is spin-dried for, with diluted acid tune pH, constantly there is solid precipitation, filter, and collect filter residue, consolidate
Body, column chromatographic purifying, yield 90%.
Embodiment 2-7
Embodiment 1 is repeated, difference is: using different raw materials, so that compound 2-7 in table 1 be made.Specifically such as
Under: use 7- (2- nitro -4- sulphonylaminophenyl amino) cognac oil, 6- (2- nitro -4- sulphonylaminophenyl ammonia
Base) ethyl hexanoate, 5- (2- nitro -4- sulphonylaminophenyl amino) ethyl hexanoate, 4- (2- nitro -4- sulfuryl amino benzene
Base amino) ethyl hexanoate, 3- (2- nitro -4- sulphonylaminophenyl amino) ethyl hexanoate and 2- (2- nitro -4- Herbicidal sulphonylamino
Base phenyl amino) ethyl acetate replace embodiment 1 in raw material 8- (2- nitro -4- sulphonylaminophenyl amino) ethyl caprilate,
Compound 2-7 is made respectively.
The chemical structure of target product is shown in Table 1 in the logical formula (I) of above embodiments 1-7 synthesis, nucleus magnetic hydrogen spectrum and mass spectrum system
System characterizes the chemical structure of target product, and specific data are shown in Table 2.
Table 1 leads to target compound structure in formula (I)
Table 2 leads to the hydrogen spectrum and mass spectrometric data of target compound in formula (I)
The test of 8 Bcl-2 and Mcl-1 protein affinity of embodiment
With reference to previous work and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44；ChemMedChem
2011,6,904-21) it, using gossypol acetate (AT-101) and ABT-199 as comparison medicine, is investigated using fluorescence polarization (FP) method
The BH3 peptide fragment (fluorescein label) of target compound Competitive assays Bcl-2 and Mcl-1 albumen and pro apoptotic protein Bim or Bid are tied
The ability of conjunction evaluates its affinity with target protein.Fluorescence polarization signal is by sepectrophotofluorometer in excitation wavelength
485nm and wavelength of transmitted light detect under conditions of being 535nm.By series of concentrations target compound and fluorescein-labeled Bim or
The BH3 peptide fragment of Bid is cultivated after twenty minutes at room temperature together with Bcl-2 or Mcl-1 albumen, detects its fluorescence polarization signal, meter
Calculate the IC of the compound50Value.And the total concentration of the total protein concentration according to used in measurement, fluorescent polypeptide, albumen-polypeptide are multiple
Close the dissociation constant of object and the IC of detection compound50Value, calculates the Reverse transcriptase constant K of detection compoundi.Positive control
Medicine is AT-101 and ABT-199 (Abbott's exploitation).Experimental result is shown in Table 3.
Table 3 leads to target compound and Bcl-2 and Mcl-1 protein affinity in formula (I)
The result shows that compound 1-7 is shown and the good binding ability of Bcl-2 albumen in table 1, hence it is evident that be better than positive drug
AT-101, it is suitable with ABT-199, and combination with higher selectivity.The above result shows that N- of the invention replaces benzene sulfonyl
There is base-azaindole oxybenzamide class compound preparation to express phase with Bcl-2 protein family anti-apoptotic members height
The therapeutic agent of the disease of pass prepares anti-tumor drug, and prepares synergist and other anti-tumor drugs or radiotherapy conjunction
To treat the potential use of tumour.
The test of 9 HDAC inhibitory activity of embodiment
Target compound is investigated to the inhibiting effect of HDAC family using fluorescence method, the basic principle is that being contained with HDAC catalysis
There is the substrate of acylated chains to make its deacetylation, then being generated with the substrate of trypsin hydrolysis deacetylation has fluorescence
Hydrolysate.Series of concentrations target compound and the buffer containing substrate and trypsase and prepared HDAC is molten
Liquid mixing detects fluorescence signal (excitation wavelength 355nm, launch wavelength 460nm) after being incubated at room temperature a period of time.Fluorescence
The variation of light absorption value is able to reflect the suppressed situation of HDAC, and the inhibition IC of compound is calculated using its numerical value change50Value.It is positive
Comparison medicine is ACY-1215 and SAHA.Experimental result is shown in Table 4.
Table 4 leads to the HDAC inhibitory activity of target compound in formula (I)
The result shows that in table 1 compound 1-2 other than with preferable Bcl-2 protein affinity, also show with
The preferable inhibitory activity of HDAC, the activity of compound 1 are better than two positive drugs ACY-1215 and SAHA, it also to HDAC1, HDAC2,
HDAC3 and HDAC6 shows good selective inhibitory activity.The concrete outcome of compound 3-7 is not shown in table 1, but same
Show the inhibitory activity to HDAC.The above result shows that N- of the invention replaces benzenesulfonyl-azaindole oxygroup benzoyl
Aminated compounds has the therapeutic agent for preparing relevant to HDAC activity disease, prepare anti-tumor drug and synergist and
Other anti-tumor drugs or radiotherapy are shared to treat the potential use of tumour.
The test of 10 anti tumor activity in vitro of embodiment
1, experimental tumor strain
This experiment uses tumour cell strain to be respectively as follows:, and RPMI-8226 (human myeloma cell), (human leukemia is thin by HL-60
Born of the same parents), U266 (human myeloma cell), SKOV3 (Proliferation of Human Ovarian Cell), MCF-7 (human breast cancer cell), A375 (human melanin
Oncocyte) and NCI-H23 (human lung carcinoma cell), it is purchased from Shanghai Institute of Pharmaceutical Industry.
2, sample preparation
After DMSO (Merck) dissolution, solution or uniform suspension that PBS (-) is made into 1000 μ g/mL is added, then
With PBS (-) dilution containing DMSO.Positive control drug is ABT-199 (Abbott's exploitation), ACY-1215 and SAHA.
3, test method
According to experiment detection and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44；
Nature.2005,437,677-681), using mtt assay.It is 4~5 × 10 that concentration, which is added, in the every hole of 96 orifice plates4The cell of a/mL is outstanding
100 μ L of liquid, sets 37 DEG C, 5%CO2In incubator.After for 24 hours, addition sample liquid, 10 holes μ L/, if duplicate hole, 37 DEG C, 5%CO2Make
Use 72h.The 20 μ L of MTT solution of 5mg/mL is added in every hole, and lysate is added after acting on 4h, and 100 holes μ L/ are set in incubator, dissolution
570nm OD value is surveyed with the full-automatic microplate reader of MK-2 afterwards.Test result is shown in Table 5.
Table 5 leads in formula (I) target compound to the in-vitro multiplication inhibiting effect of human body tumour cell
As known from Table 5, compound 1-3,7 pairs of human blood tumours and solid tumor show broad-spectrum anti-tumor activity in table 1,
In, compound 1-3 in table 1,7 for Huppert's disease inhibiting effect better than three positive drugs ABT-199, ACY-1215 and
SAHA, compound 1 is better than three positive drugs for the inhibiting effect of melanoma in table 1, and compound 2 is for breast cancer in table 1
Inhibiting effect be better than three positive drugs.The concrete outcome of compound 4-6 is not shown in table 1, but it is anti-swollen equally to show wide spectrum
Tumor activity.The above result shows that N- of the invention replaces benzenesulfonyl-azaindole oxybenzamide class compound to have extensively
Anti-tumor activity is composed, and part of compounds exhibits improvements over three positive drugs in Huppert's disease, oophoroma and breast cancer
Activity, shown the potential advantages of the relatively single target spot inhibitor of double inhibitor, also implied that the compound of the present invention can
Prestige has good development prospect.
Embodiment 11 tests existing anti-tumor drug synergistic activity
Target compound is investigated on multiple myeloma cells sensitive or drug resistant to existing therapeutic agent to existing anti-
The synergistic activity of tumour medicine.Target compound carries out growth of tumour cell inhibitory activity using mtt assay.Multiple marrow
Tumor cell strain uses H929 cell.The H929R cell of bortezomib drug resistant can be by being gradually increased bortezomib concentration (initially
0.5nM, using 0.2nM as gradient be incremented by, be eventually increased to 15nM) culture medium in continuously culture to obtain.By tumour cell point
Enter in 96 orifice plates, target compound or the combination of various concentration is added, with culture medium culture 72 hours containing serum.It is added later
MTT is thin by evaluating it compared with blank control with the trap of microplate reader detection solution after cultivating 4 hours at 37 DEG C
Born of the same parents' Proliferation Ability situation.Based on target compound under various concentration and bortezomib independent medication to the inhibiting rate of tumour cell,
With to the inhibiting rate of tumour cell, cooperateing with for target compound and bortezomib is calculated using CalcuSyn 2.1 when drug combination
Index (combination index, CI), CI < 0.9 shows with synergistic effect.Test result is shown in Table 6.
It is living to the synergy of bortezomib in drug resistance and non-drug resistance H929 cell that table 6 leads to partial target compound in formula (I)
Property
As known from Table 6, compound 1 is either in non-drug resistance still on mdr cell in table 1, to existing anti-tumor drug
All there is synergistic effect, and under a variety of concentration ratios (compound 1 and bortezomib concentration ratio are 7.5 μM in such as table 1:
40nM, 7.5 μM: 320nM, 15 μM: 320nM, 60 μM: 640nM, 60 μM: 320nM) its synergistic effect is highly significant.Change in table 1
The concrete outcome for closing object 2-7 is not shown, but experimental data again shows that it all has synergistic effect to existing anti-tumor drug.With
Above the result shows that having synergistic effect between the compound of the present invention and existing anti-tumor drug, it is expected to before having good exploitation
Scape.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, under the premise of not departing from the method for the present invention, can also make several improvement and supplement, these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (8)
1. a kind of N- replaces benzenesulfonyl-azaindole oxybenzamide class compound, which is characterized in that its general structure is such as
Shown in formula (I):
Wherein,
R1Group is
Z is N, O, S；
Y is C1~C10Straight chain, branch or cyclic alkane base, C1~C10Straight chain, branch or cyclic olefin base.
2. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound, feature exists
In,
R1Group is
Z is N；
Y is C1~C10Linear paraffin base.
3. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound, feature exists
In the N- replaces benzenesulfonyl-azaindole oxybenzamide class compound to be any of following compounds:
1) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxo) -3- nitrophenylsulfonyl) benzoyl
Amine
2) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (7- (hydroxyl amino) -7- oxo amino in heptan) -3- nitrophenylsulfonyl) benzoyl
Amine
3) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxo) -3- nitrophenylsulfonyl) benzoyl
Amine
4) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 5- (hydroxyl amino) -5- oxo) -3- nitrophenylsulfonyl) benzoyl
Amine
5) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 4- (hydroxyl amino) -4- oxo) -3- nitrophenylsulfonyl) benzoyl
Amine
6) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (the own amino of 3- (hydroxyl amino) -3- oxo) -3- nitrophenylsulfonyl) benzoyl
Amine
7) 2- (1H- pyrroles [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethylcyclohexenes -1-
Alkenyl) methyl) piperazine -1- base)-N- (4- (2- (hydroxyl amino) -2- oxo ethylamino) -3- nitrophenylsulfonyl) benzoyl
Amine.
4. N- described in claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound that can pharmaceutically connect
The inorganic acid salt or acylate received.
5. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition contains pharmaceutically acceptable excipient or load
Body and N- described in claim 1 replace benzenesulfonyl-azaindole oxybenzamide class compound or claim 4
The N- replaces the pharmaceutically acceptable inorganic acid salt of benzenesulfonyl-azaindole oxybenzamide class compound or has
Machine hydrochlorate.
6. N- described in claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound or claim 4
The N- replaces the pharmaceutically acceptable inorganic acid salt of benzenesulfonyl-azaindole oxybenzamide class compound or has
The purposes of machine hydrochlorate in medicine preparation, which is characterized in that the drug is used for:
A) disease relevant to Bcl-2 or HDAC activity or symptom are treated,
B) antitumor, or
C) as antineoplastic or the synergist of radiotherapy.
7. purposes according to claim 6, which is characterized in that the tumour is myeloma, leukaemia, oophoroma, cream
Gland cancer, melanoma or lung cancer.
8. N- described in claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound preparation method,
Be characterized in that, including the following steps: under the conditions of existing for the condensing agent, azaindole p-methoxybenzoic acids that difference replaces from it is different
Substituted sulfonamide occurs condensation and generates different substituted N- substitution benzenesulfonyl benzamide compounds.
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| CN111801320A (en) | 2018-01-10 | 2020-10-20 | 里科瑞尔姆Ip控股有限责任公司 | Benzamide compounds |
| CN110054625B (en) * | 2018-01-18 | 2022-01-07 | 山东大学 | N-acylbenzenesulfonamide hydroxamic acid Bcl-2 and HDAC double-target inhibitor, and preparation method and application thereof |
| CN114588269B (en) * | 2022-04-06 | 2023-06-27 | 宁波大学附属人民医院 | Bcl-2 inhibitor and HDAC inhibitor composition and application thereof |
| CN115057856B (en) * | 2022-06-08 | 2024-04-02 | 澳门科技大学 | 3, 5-disubstituted-7-azaindole derivative and synthetic method and application thereof |
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| CN101898985A (en) * | 2010-05-20 | 2010-12-01 | 中国人民解放军第二军医大学 | N-substituted benzenesulfonyl-substituted benzamides small molecular inhibitor of Bcl-2 protein and application thereof |
| CN102947285A (en) * | 2009-12-04 | 2013-02-27 | 雅培制药有限公司 | Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
| CN103282025A (en) * | 2010-10-29 | 2013-09-04 | Abbvie公司 | Melt-extruded solid dispersions containing an apoptosis-nducing agent |
| CN104961771A (en) * | 2010-05-26 | 2015-10-07 | Abbvie公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102947285A (en) * | 2009-12-04 | 2013-02-27 | 雅培制药有限公司 | Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
| CN101898985A (en) * | 2010-05-20 | 2010-12-01 | 中国人民解放军第二军医大学 | N-substituted benzenesulfonyl-substituted benzamides small molecular inhibitor of Bcl-2 protein and application thereof |
| CN104961771A (en) * | 2010-05-26 | 2015-10-07 | Abbvie公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| CN103282025A (en) * | 2010-10-29 | 2013-09-04 | Abbvie公司 | Melt-extruded solid dispersions containing an apoptosis-nducing agent |
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