CN106957315A - N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of medicine - Google Patents
N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of medicine Download PDFInfo
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Abstract
The present invention relates to a class N- replace benzenesulfonyl-azaindole oxybenzamide class compound, its crystal formation, 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).Experiment shows that it has higher inhibitory activity to Bcl-2 protein families anti-apoptotic members and HDAC, and show 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).Pointing out such compound has the medicine for preparing the disease related to Bcl-2 or HDAC activity, prepares antineoplastic, and prepares synergist and other antineoplastics or radiotherapy shares to treat the potential use of tumour.
Description
Technical field
The present invention relates to pharmaceutical technology field; more specifically; replace benzenesulfonyl-azaindole oxybenzamide class compound the present invention relates to a class N-, the invention further relates to the composition of such compound, preparation method and its purposes in antineoplastic and antitumor synergist is prepared.
Background technology
Apoptosis be cell by the programmed cell death carried out after certain signal stimulus, be a kind of basic biological phenomena of cell.Bcl-2 protein families play important adjustment effect in Apoptosis path, and it can be divided into anti-apoptotic member (such as Bcl-2, Bcl-xL, Mcl-1 etc.) and promote the class of apoptosis member two.Research shows that the overexpression of Bcl-2 protein families anti-apoptotic members can cause normal apoptosis path to be obstructed, generation to many diseases (such as tumour, autoimmune disease) is related, particularly tumour produces and occurred one of the major reason of resistance (Nature 2000,407,796-801；Nat Rev Cancer 2004,4,592-603.).
Research shows that Bcl-2 protein families anti-apoptotic members are over-expressed in many tumours, the expression difference (Oncogene 2003,22,8590-607 in different tumours and different tumors subtypes；Oncogene 2008,27,6398-406).By the Anti-G value for the anti-apoptotic members for suppressing to over-express in tumour cell, its normal apoptosis pathway can be recovered, increase its sensitiveness to chemotherapy radiotherapy, be the new strategy for treating tumour.Bcl-2 protein family anti-apoptotic members are to be combined and interacted with the Bcl-2 protein families conservative region (BH) 3 of rush apoptosis member by the hydrophobic groove on its surface, to adjust the normal Apoptosis of cell.Micromolecular inhibitor can disturb that rush apoptosis member BH3 regions are in combination to play a part of promoting Apoptosis (Nat Rev Cancer 2005,5,876-85 by being incorporated into anti-apoptotic member's surface hydrophobicity groove；Kelly,P.N.；Cell Death Differ 2011,18,1414-24.).The type small molecular inhibitor caused the broad interest of researcher in recent years, a series of micromolecular inhibitors are found that by different approaches, wherein having four (ABT-199, ABT-263, AT-101, GX15-07) enter clinical research as oral antineoplastic.Result of study shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitors show preferable antitumor action and the synergy to other antineoplastics or radiotherapy acts synergistically, with 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, which are internal two groups, has the enzyme of reverse functions; the effect of the histone acetylation state inside and outside many seed nucleus including histone can be adjusted, so as to play a variety of functions such as regulatory gene transcription, cell differentiation, cell cycle and Apoptosis.HDAC includes four subfamilies, Zn2+I types (HDAC1-3,8), IIA (HDAC4,5,7,9), IIB (HDAC6,10) and the IV (HDAC11) of dependence, and NAD+The type III (sirtuins 1-7) of dependence.HDAC is proved that the occurrence and development with the disease such as tumour, the nervous system disease and inflammation and infection have substantial connection.Thus HDAC wide spectrums and selective micromolecular inhibitor are used for treatment and research (the Nat Rev Drug Discov 2014,13,673-91 of the diseases such as tumour, the nervous system disease, inflammation and virus infection；Pharmacol Ther 2014,143,323-36.).
Albumen deacetylation increase is one of characteristic feature of many tumours caused by the expression of HDAC height or activity are improved, and HDAC expression increases (Cancer Lett 2009,280,168-76) all can be observed in a variety of hematological system tumors.Huppert's disease is also unequivocally established the common high expression of I types HDAC (particularly HDAC1), and with poor prognosis closely related (Epigenetics 2014,9,1511-20).Therefore, targeting HDAC is increasingly becoming one of study hotspot of oncotherapy (Lancet Oncol 2013,14,1038-9.).In recent years, the development of HDAC micromolecular inhibitors is very fast, mainly including hydroxamic acid, benzamides, cyclic peptide and short-chain fat acids etc..They show extensive antitumous effect (the Nat Rev Drug Discov 2014,13,673-91 for hematological system tumor, lung cancer and prostate cancer etc. in vivo and in vitro；J Med Chem 2008,51,1505-29.).Foreign countries' approved lists three such medicine Vorinostat (vorinostat at present, SAHA), romidepsin (romidepsin) (J Clin Invest 2014,124,30-9.) and his (belinostat of Baily department, 2014.07 batches) (Br J Haematol 2015,168,811-9.), one medicine chidamide (chidamide of domestic just approval listing, 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 show good anti-Huppert's disease effect in clinical test, and shared with other antineoplastics and can play notable synergistic effect, 2015.02 LBH589s (panobinostat) are shared for multiple myeloma (Lancet Oncol 2014 by FDA approvals and bortezomib and dexamethasone, 15,1195-206.).Further, since isoform selective inhibitors may have more preferable curative effect and lower side effect, research in recent years focus (Nat Rev Drug Discov 2014,13,673-91 are increasingly becoming；Curr Pharm Des 2015,21,1472-502.).Research confirms newly discovered HDAC6 selective depressants (such as rocilinostat, ACY-1215) protein degradation systems can be participated in by influenceing aggresomes formation, so as to which the inhibitor bortezomib with another proteasome pathway of the system plays a part of Synergistic treatment Huppert's disease, (Blood 2012 is come into clinical test at present, 119,2579-89；Br J Haematol.2015,169,423-34).HDAC6 selective depressants are also used for the research (Nat Rev Drug Discov 2014,13,673-91.) of the disease treatments such as the nervous system disease (nerve degenerative diseases, alzheimer's disease etc.) and inflammation.
As it was previously stated, hdac inhibitor and Bcl-2 anti-apoptotic proteins subfamily inhibitor are each proved there is synergy synergy to other antineoplastics or radiotherapy.The clinical test currently carried out is also more using the schemes with existing medicine drug combination.Research also shows that this two classes medicine also has Synergistic antitumor action (Mol Cell Biol 2009,29,6149-69 each other；Cell Death Dis 2013,4, e798), and recent studies have shown that they are combined the synergy synergy (Blood 2014,124,2687-97) that can preferably play to other antineoplastics.Research shows, for the disease that the mechanism such as tumour, central nervous system disease are complicated, Mutiple Targets medicine can act on multiple links in disease network system simultaneously, it is not likely to produce drug resistance, effect to each target spot produces cooperative effect, and attenuating target spot is xicity related, reaches more preferably therapeutic effect (Nat Rev Cancer 2010,10,130-7).And compared with two class drug combinations, double target drugs have more single pharmacokinetic property, in the absence of complicated drug drug interaction, be conducive to the complete performance of curative effect of medication, development cost can also be reduced, increase patient compliance (J Med Chem 2014,57,7874-87).Therefore, Bcl-2 anti-apoptotic proteins subfamily and the double target spot inhibitor of HDAC can play more preferable antitumor or synergistic effect by mutual cooperative effect.
In summary, research and development Bcl-2 protein families anti-apoptotic members or HDAC inhibitor, the double inhibitor of the two target spots can be especially acted on simultaneously, the treatment for diseases such as tumours is significant.
The content of the invention
It is an object of the invention to provide preparation method, purposes and the composition of the new N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds of a class and such compound.
Replace benzenesulfonyl-azaindole oxybenzamide class compound there is provided a kind of N- in the first aspect of the present invention, it is characterised in that shown in its general structure such as formula (I)：
Wherein,
R1Group isWherein, R2For C1~C5Straight chain, side chain or cyclic alkane base；
Z is N, O, S,
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base, aromatic monocyclic, aromatic condensed ring.
It is used as the preference of the present invention：
R1Group isWherein, R2For C1~C5Straight chain, side chain or cyclic alkane base；
Z is N, O, S；
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base.
It is used as another preference of the present invention：
R1Group is
Z is N, O, S；
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base.
It is used as another preference of the present invention：
R1Group is
Z is N；
Y is C1~C10Linear paraffin base.
As a kind of preferred embodiment of the present invention, the N- substitutions benzenesulfonyl-azaindole oxybenzamide class compound is any one in following compounds：
1) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrophenylsulfonyls) benzamide
2) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrophenylsulfonyls) benzamide
3) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrophenylsulfonyls) benzamide
4) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the own amino of 5- (hydroxyl amino) -5- oxos) -3- nitrophenylsulfonyls) benzamide
5) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the own amino of 4- (hydroxyl amino) -4- oxos) -3- nitrophenylsulfonyls) benzamide
6) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the own amino of 3- (hydroxyl amino) -3- oxos) -3- nitrophenylsulfonyls) benzamide
7) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (2- (hydroxyl amino) -2- oxos ethylamino) -3- nitrophenylsulfonyls) benzamide.
In the second aspect of the present invention, there is provided the crystal formation of described N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
In the third aspect of the present invention; there is provided a kind of pharmaceutical composition; described pharmaceutical composition contains pharmaceutically acceptable excipient or carrier, and described N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds or the crystal formation of described N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
As a kind of embodiment of the present invention, described pharmaceutical composition also contains other drugs active component.
As the preference of the present invention, described other drugs active component is bortezomib.
It is highly preferred that the molar ratio of the N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds and bortezomib described in the pharmaceutical composition is 20-3000.
In the fourth aspect of the present invention; replace benzenesulfonyl-azaindole oxybenzamide class compound there is provided described N-; or described N- replaces the purposes of the crystal formation, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug of benzenesulfonyl-azaindole oxybenzamide class compound in medicine is prepared, described medicine is used for：
A) disease or symptom related to Bcl-2 or HDAC activity is treated,
B) it is antitumor, or
C) as antineoplastic or the synergist of radiotherapy.
As a kind of embodiment of the present invention, described tumour is myeloma, leukaemia, oophoroma, breast cancer, melanoma or lung cancer.
In the fifth aspect of the present invention there is provided the preparation method that described N- replaces benzenesulfonyl-azaindole oxybenzamide class compound, comprise the following steps：Under conditions of condensing agent presence, the azaindole p-methoxybenzoic acid of difference substitution occurs the different substituted N- of condensation generation from different substituted sulfonamide and replaces benzenesulfonyl benzamide compound.
Herein, " prodrug " refers to that a reagent is converted into prototype medicine in vivo.Prodrug is typically useful, because under certain conditions, they may administration easier than prototype medicine.Prodrug is typically the precursor of medicine, and ensuing administration and absorption are converted into active material, or are changed into the stronger species of activity by some processes, are such as converted by metabolic pathway.The chemical group that some prodrugs have makes its activity relatively low and/or the dissolubility or some other properties of contrast prototype medicine are changed.Once the chemical group of prodrug is removed and/or it is modified, active drug is obtained.
Described pharmaceutically acceptable inorganic acid salt may be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrobromate, nitrate；Described pharmaceutically acceptable acylate may be selected from acetate, maleate, fumarate, tartrate, succinate, lactate, tosilate, salicylate, oxalates.
Described pharmaceutical composition can be solid form or liquid form, and its formulation can be tablet, dispersible tablet, lozenge, oral disintegrating tablet, sustained release tablets, capsule, soft capsule, dripping pill, granule, injection, powder-injection or aerosol etc..When the compounds of this invention is used for such use, it can be mixed with one or more pharmaceutically acceptable carriers or excipient, such as solvent, diluent, and can be administered orally with following form：Tablet, pill, capsule, dispersible powder, particle or suspension (containing such as from about 0.05-5% suspending agents), syrup (containing such as from about 10-50% sugar) and elixir (containing about 20-50% ethanol), or be administered in external application mode：Ointment, gel, pastille adhesive plaster etc., or parenteral routes are carried out with sterile injectable solution or form of suspension (containing about 0.05-5% suspending agents in isotonic medium).For example, these pharmaceutical preparations can contain the about 0.01-99% mixed with carrier, more preferably about 0.1-90% (weight) active component.Suitable method of administration include but is not limited to orally, intravenous injection, rectum, aerosol, parenterai administration, dosing eyes, pulmonary administration, percutaneous dosing, vagina administration, duct administration, nasal-cavity administration and local administration.
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or gelatinous mass, they are adapted to people and used 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 partial example has sugared (such as glucose, sucrose, lactose etc.), starch (such as cornstarch, farina etc.), cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum powder, kollag (such as odium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite etc.), emulsifying agent (such as Tweens), wetting agent (such as dodecyl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water etc..
Described " synergist " refers to a class with certain class compatibility of drugs in use, strengthening the medicine of such pharmaceutical activity with specific mechanism, plays synergy., can be with other drugs drug combination as synergist, " administering drug combinations " refer to several selected medicines to patient's medication, with identical or different administering mode in identical or different time administration.Term " collaboration ", " synergy " or " synergy ", as used herein, original Drug inhibition HDAC activity can be strengthened when sharing another medicine in the presence of suppression Bcl-2 activity or suppression HDAC activity or anti-tumor drug to script or suppress the effect of HDAC activity or antitumous effect by referring to.
The invention has the advantages that：
1st, N- of the invention substitution benzenesulfonyl-azaindole oxybenzamide class compound shows the inhibitory activity higher to Bcl-2 protein family anti-apoptotic members; particularly part of compounds shows good inhibitory activity to HDAC simultaneously, and shows to combine selectivity.Therefore these compounds, which have, prepares antineoplastic, and prepares synergist and share to treat the potential use of tumour with other antineoplastics or radiotherapy.
2nd, N- of the invention substitution benzenesulfonyl-azaindole oxybenzamide class compound shows wide spectrum and significant antitumor activity to human blood tumour (myeloma, leukaemia) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer).And show preferable synergistic effect with existing drug combination.Therefore, compound of the invention is expected have good DEVELOPMENT PROSPECT.
It should be understood that, in within the scope of the present invention, it can be combined with each other between above-mentioned each technical characteristic of the present invention and each technical characteristic specifically described in below (eg embodiment), so as to constitute new or preferred technical scheme, it can be combined with each other between each substituted radical of the invention, its particular compound constituted is the part of the present invention.As space is limited, no longer tire out one by one herein and state.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only illustrative of the invention and is not intended to limit the scope of the invention.The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are percentage by weight and parts by weight.
Embodiment 1
(1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrophenylsulfonyls) benzamide (compound 1 in table 1) preparation：
Synthetic route is：
Concretely comprise the following steps：
1) ((((1H- pyrroles [2 by 2- by N- by 4- by 8-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases) benzoyl) sulfuryl amino) -2- nitro-phenylaminos) and ethyl caprilate preparation：
By ((1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4; 4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases) benzoic acid 100mg (0.175mmol); 8- (2- nitro -4- sulphonylaminophenyls amino) ethyl caprilate 68mg (0.175mmol); 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) 167mg (0.875mmol); DMAP 25.6mg (0.21mmol); using anhydrous DCM as solvent, normal-temperature reaction 24h.After reaction terminates, successively with 1M hydrochloric acid, saturated sodium bicarbonate, saturated common salt washing, aqueous phase is extracted with EA, merges organic phase, is concentrated to give solid 160mg, column chromatography purifying, yield 85%.
2) (1H- pyrroles [2 by 2-; 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrophenylsulfonyls) benzamide preparation：
By 8-, ((((1H- pyrroles [2 by 2- by N- by 4-, 3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4, 4- dimethylcyclohexenes -1- alkenyls) methyl) piperazine -1- bases) benzoyl) sulfuryl amino) -2- nitro-phenylaminos) ethyl caprilate 160mg (0.170mmol) is dissolved in the methanol solution of the azanol of the 8ml of existing system 1.12mol/L potassium hydroxide, 3h is stirred at room temperature, TLC detection reactions are complete, solution is spin-dried for, pH is adjusted with diluted acid, constantly there is solid precipitation, filtering, collect filter residue, obtain solid, column chromatography is purified, yield 90%.
Embodiment 2-7
Embodiment 1 is repeated, difference is：Using different raw materials, so that compound 2-7 in table 1 is made.It is specific as follows：Use 7- (2- nitro -4- sulphonylaminophenyls amino) cognac oil, 6- (2- nitro -4- sulphonylaminophenyls amino) ethyl hexanoate, 5- (2- nitro -4- sulphonylaminophenyls amino) ethyl hexanoate, 4- (2- nitro -4- sulphonylaminophenyls amino) ethyl hexanoate, 3- (2- nitro -4- sulphonylaminophenyls amino) ethyl hexanoates and 2- (2- nitro -4- sulphonylaminophenyls amino) ethyl acetate replace raw material 8- (2- nitro -4- sulphonylaminophenyls amino) ethyl caprilate in embodiment 1, compound 2-7 is made respectively.
The chemical constitution of target product is shown in Table 1 in the logical formula (I) of above example 1-7 synthesis, and nucleus magnetic hydrogen spectrum and mass spectrometer system characterize the chemical constitution of target product, and its specific data is 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)
Bcl-2 the and Mcl-1 protein affinities of embodiment 8 are tested
With reference to previous work and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44；ChemMedChem 2011,6,904-21), using gossypol acetate (AT-101) and ABT-199 as comparison medicine, investigate target compound Competitive assays Bcl-2 and Mcl-1 albumen with the ability of pro apoptotic protein Bim or Bid BH3 peptide fragments (fluorescein mark) combination to evaluate its affinity with target protein using fluorescence polarization (FP) method.Fluorescence polarization signal is detected by sepectrophotofluorometer under conditions of excitation wavelength 485nm and wavelength of transmitted light are 535nm.After series concentration target compound is cultivated 20 minutes at room temperature with fluorescein-labeled Bim or Bid BH3 peptide fragments together with Bcl-2 or Mcl-1 albumen, its fluorescence polarization signal is detected, the IC of the compound is calculated50Value.And total protein concentration according to used in measurement, the total concentration of fluorescent polypeptide, the IC of the dissociation constant of albumen-polypeptide complex and detection compound50Value, calculates the Reverse transcriptase constant K of detection compoundi.Positive control drug 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 affinities in formula (I)
As a result show, compound 1-7 is shown and the good binding ability of Bcl-2 albumen in table 1, hence it is evident that suitable with ABT-199 better than positive drug AT-101, and with higher combination selectivity.Result above shows that N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds of the present invention have the medicine for preparing the disease related to the high expression of Bcl-2 protein families anti-apoptotic members; antineoplastic is prepared, and prepares synergist and shares to treat the potential use of tumour with other antineoplastics or radiotherapy.
The HDAC inhibitory activity of embodiment 9 is tested
Inhibitory action of the target compound to HDAC families is investigated using fluorescence method, its general principle is to make its deacetylation with substrate of the HDAC catalysis containing acylated chains, then with hydrolysate of the substrate generation with fluorescence of trypsin hydrolysis deacetylation.By series concentration target compound and the buffer solution containing substrate and trypsase, and the HDAC solution mixing prepared is incubated detection fluorescence signal (excitation wavelength 355nm, launch wavelength 460nm) after a period of time at room temperature.The change of fluorescence light absorption value can reflect HDAC suppressed situation, and the suppression IC of compound is calculated using its numerical value change50Value.Positive control drug 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)
As a result show, compound 1-2 is in addition to preferable Bcl-2 protein affinities in table 1, it also show and the preferable inhibitory activity of HDAC, the activity of compound 1 better than two positive drugs ACY-1215 and SAHA, it also shows good selective inhibitory activity to HDAC1, HDAC2, HDAC3 and HDAC6.Compound 3-7 concrete outcome is not shown in table 1, but equally shows the inhibitory activity to HDAC.Result above shows that N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds of the present invention have the medicine for preparing the disease related to HDAC activity; antineoplastic is prepared, and synergist shares to treat the potential use of tumour with other antineoplastics or radiotherapy.
The anti tumor activity in vitro of embodiment 10 is tested
1st, experimental tumor strain
This experiment is respectively using tumour cell strain：RPMI-8226 (human myeloma cell), HL-60 (human leukemia cell), U266 (human myeloma cell), SKOV3 (Proliferation of Human Ovarian Cell), MCF-7 (human breast cancer cell), A375 (human melanoma cell) and NCI-H23 (human lung carcinoma cell), are purchased from Shanghai Institute of Pharmaceutical Industry.
2nd, sample preparation
After being dissolved with DMSO (Merck), solution or uniform suspension that PBS (-) is made into 1000 μ g/mL are added, then with PBS (-) dilution containing DMSO.Positive control drug is ABT-199 (Abbott's exploitation), ACY-1215 and SAHA.
3rd, 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 96 orifice plates, which add concentration per hole,4Individual/mL μ the L of cell suspension 100, put 37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO2Act on 72h.Lysate is added after the 5mg/mL μ L of MTT solution 20, effect 4h are added per hole, 100 μ L/ holes are put in incubator, 570nm OD values are surveyed with the full-automatic ELIASAs of MK-2 after dissolving.Test result is shown in Table 5.
Table 5 leads to in-vitro multiplication inhibitory action of the target compound to human body tumour cell in formula (I)
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, wherein, compound 1-3 in table 1,7 for Huppert's disease inhibitory action better than three positive drugs ABT-199, ACY-1215 and SAHA, compound 1 is better than better than three positive drugs of inhibitory action of compound 2 for breast cancer in three positive drugs, table 1 for the inhibitory action of melanoma in table 1.Compound 4-6 concrete outcome is not shown in table 1, but equally shows broad-spectrum anti-tumor activity.Result above shows that N- substitutions benzenesulfonyl-azaindole oxybenzamide class compound of the present invention has broad-spectrum anti-tumor activity; and part of compounds exhibits improvements over the activity of three positive drugs in Huppert's disease, oophoroma and breast cancer; the potential advantages of the relatively single target spot inhibitor of double inhibitor have been shown, also imply that the compound of the present invention is expected have good DEVELOPMENT PROSPECT.
Embodiment 11 is tested existing antineoplastic synergistic activity
Investigate synergistic activity of the target compound to existing antineoplastic in the multiple myeloma cells to existing medicine sensitivity or resistance.Target compound is carried out to growth of tumour cell inhibitory activity using mtt assay.Multiple myeloma cell line uses H929 cells.The H929R cells of bortezomib drug resistant can be cultivated to obtain by continuous in the culture medium for gradually stepping up bortezomib concentration (initial 0.5nM is incremented by by gradient of 0.2nM, is eventually increased to 15nM).Tumour cell is divided into 96 orifice plates, target compound or the combination of various concentrations is added, with the medium culture 72 hours containing serum.MTT is added afterwards, detects the trap of solution after being cultivated 4 hours at 37 DEG C with ELIASA, its cell inhibitory effect situation is evaluated by being compared with blank control.Based on the inhibiting rate of target compound under various concentrations and bortezomib independent medication to tumour cell, to the inhibiting rate of tumour cell during with drug combination, the index of cooperation (combination index, CI) of target compound and bortezomib, CI are calculated using CalcuSyn 2.1<0.9 shows with synergistic effect.Test result is shown in Table 6.
Table 6 leads to synergistic activity of the partial target compound in resistance and non-resistance H929 cells to bortezomib in formula (I)
As known from Table 6, in table 1 compound 1 either in non-resistance still on mdr cell, all there is synergistic effect to existing antineoplastic, and (compound 1 and bortezomib concentration ratio are 7.5 μM in such as table 1 under a variety of concentration ratios:40nM、7.5μM:320nM、15μM:320nM、60μM:640nM、60μM:320nM) its synergistic effect highly significant.Compound 2-7 concrete outcome is not shown in table 1, but experimental data again shows that it all has synergistic effect to existing antineoplastic.Result above shows possess synergy between the compound and existing antineoplastic of the present invention, it is expected to have good DEVELOPMENT PROSPECT.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, on the premise of the inventive method is not departed from; some improvement and supplement can also be made, these are improved and supplement also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of N- replaces benzenesulfonyl-azaindole oxybenzamide class compound, it is characterised in that
Shown in its general structure such as formula (I)：
Wherein,
R1Group isWherein,
R2For C1~C5Straight chain, side chain or cyclic alkane base；
Z is N, O, S,
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base,
Aromatic monocyclic, aromatic condensed ring.
2. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class chemical combination
Thing, it is characterised in that
R1Group isWherein, R2For C1~C5Straight chain, side chain
Or cyclic alkane base；
Z is N, O, S；
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base.
3. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class chemical combination
Thing, it is characterised in that
R1Group is
Z is N, O, S；
Y is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or cyclic olefin base.
4. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class chemical combination
Thing, it is characterised in that
R1Group is
Z is N；
Y is C1~C10Linear paraffin base.
5. N- according to claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class chemical combination
Thing, it is characterised in that described N- substitutions benzenesulfonyl-azaindole oxybenzamide class compound is
Any one in following compounds：
1) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (the pungent amino of 8- (hydroxyl amino) -8- oxos) -3- nitrophenylsulfonyls)
Benzamide
2) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (7- (hydroxyl amino) -7- oxos amino in heptan) -3- nitrophenylsulfonyls)
Benzamide
3) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (the own amino of 6- (hydroxyl amino) -6- oxos) -3- nitrophenylsulfonyls)
Benzamide
4) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (the own amino of 5- (hydroxyl amino) -5- oxos) -3- nitrophenylsulfonyls)
Benzamide
5) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (the own amino of 4- (hydroxyl amino) -4- oxos) -3- nitrophenylsulfonyls)
Benzamide
6) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (the own amino of 3- (hydroxyl amino) -3- oxos) -3- nitrophenylsulfonyls)
Benzamide
7) 2- (1H- pyrroles [2,3-b] pyridine -5- bases epoxide) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethylcyclohexenes -1- alkene
Base) methyl) piperazine -1- bases)-N- (4- (2- (hydroxyl amino) -2- oxos ethylamino) -3- nitrophenylsulfonyls)
Benzamide.
6. the N- described in claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound
Crystal formation, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
7. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition contains pharmaceutically acceptable
Excipient or carrier, and N- substitution benzenesulfonyl-azaindole epoxide benzoyls described in claim 1
N- substitution benzenesulfonyl-azaindole oxybenzamide classes described in aminated compounds or claim 6
The crystal formation of compound, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
8. N- substitution benzenesulfonyl-azaindole oxybenzamide class compounds described in claim 1,
Or the N- described in claim 6 replaces the crystalline substance of benzenesulfonyl-azaindole oxybenzamide class compound
Type, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug are preparing medicine
Purposes in thing, it is characterised in that described medicine is used for：
A) disease or symptom related to Bcl-2 or HDAC activity is treated,
B) it is antitumor, or
C) as antineoplastic or the synergist of radiotherapy.
9. purposes according to claim 8, it is characterised in that described tumour is myeloma, white blood
Disease, oophoroma, breast cancer, melanoma or lung cancer.
10. the N- described in claim 1 replaces benzenesulfonyl-azaindole oxybenzamide class compound
Preparation method, it is characterised in that comprise the following steps：Under conditions of condensing agent presence, difference substitution
From different substituted sulfonamide the different substituted N- substituted benzenes of condensation generation occur for azaindole p-methoxybenzoic acid
Sulfonyl benzamide compound.
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