CN104402861A - Benzene sulfonamide derivatives, preparation method, and treatment application - Google Patents

Benzene sulfonamide derivatives, preparation method, and treatment application Download PDF

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CN104402861A
CN104402861A CN201410621004.1A CN201410621004A CN104402861A CN 104402861 A CN104402861 A CN 104402861A CN 201410621004 A CN201410621004 A CN 201410621004A CN 104402861 A CN104402861 A CN 104402861A
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base
group
compound
alkynes
quinoline
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朱驹
宋云龙
陈颖
杨超
张懿
田巍
王重庆
蒋骏航
刘婷
章玲
周有骏
吕加国
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The invention relates to the technical field of medicine, and specifically relates to benzene sulfonamide derivatives in different substitution types, wherein the derivatives are represented by the formula (A), and the definitions of each group are listed in the description. The derivatives have an excellent performance on inhibiting the activity of PI3K kinase, and moreover have high antitumor activities on tumors such as human lung cancer, human colon cancer, human liver cancer, human breast cancer, and the like. So the derivatives can be used to prepare target antitumor drugs having the advantages of high efficiency, low toxicity, and strong specificity, and thus the derivatives have very good development values. The invention further relates to a composition composed of the derivatives, a preparation method thereof, and applications of the composition in preparation of antitumor drugs.

Description

Benzenesulfonamide derivatives, preparation method and therepic use
Technical field
The present invention relates to medical art, relate to benzenesulfonamide derivatives, preparation method, the composition of the various dissimilar replacement of a class.The invention still further relates to the purposes of this compounds in the medicine for the preparation of one or more diseases following: autoimmune disorder, inflammatory diseases, cardiovascular disorder, neurodegenerative disease, transformation reactions, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, motility of sperm, transplant rejection, transplant rejection and injury of lung, particularly cancer.This compounds all shows good wide spectrum inhibit activities to kinds of tumor cells such as people's lung cancer, colorectal carcinoma, mammary cancer, liver cancer.
Background technology
In recent years, malignant tumour has become the first cause of the death of urban and rural residents of China, and mortality ratio shows a rising trend, and chemotherapeutics is the main method for the treatment of tumour.And traditional cell toxicant series antineoplastic medicament to there is selectivity low, the shortcoming that the large grade of side effect is serious, targeted inhibition agent can act on tumour cell, is expected to reduce above-mentioned shortcoming.
Phosphatidylinositol3 3 kinase be fat kinase families member, in mammalian cell, PI3K can mainly be divided into three types according to its structure and biological function.I type is 4,5-bisphosphate phosphatidylinositols [PtdIns (4, the 5) P2] kinases of receptor modulators, can be divided into IA and IB two hypotypes.IA hypotype by the heterodimer regulating subunit p85 and catalytic subunit p110 to form.IB hypotype namely , be by the heterodimer that catalytic subunit and p101 regulate subunit to form.
PI3K-AKT-mTOR signal path can be activated by number of ways, comprises tyrosine kinase receptor as EGF-R ELISA (EGFR), IGF-1 (IGFR), g protein coupled receptor (GPCRs) etc.The phosphorylation of PI3K catalysis inositol in D3 position after activation, the product 3 of phosphorylation, 4,5-triphosphoric acid phosphatidylinositols [PtdIns (3,4,5) P3, PIP3] be directly combined with the PH structural domain of protein kinase B (AKT) under the effect of phosphatidylinositols dependant kinase (PDK-1), promote the phosphorylation of the Thr308 of AKT, Mammals rapamycin target protein mixture 2(mTORC2) Ser473 phosphorylation can be made, the phosphorylation of Thr308 and Ser473 is the prerequisite of AKT activation.Mammals rapamycin target protein (Mammalian target of rapamycin, mTOR) is one of important substrate of AKT, has serine/threonine (Ser/Thr) protein kinase activity.AKT activates mTOR by Direct Phosphorylation mTOR, or the nodositas mixture 2(Tuberous sclerosis complex 2, TSC2 formed after making AKT phosphorylation) inactivation, reach the activation of mTOR.Downstream effect mainly rrna p70S6 kinase protein (S6K1, Ribosomal p70S61 kinase) and the Translational repression factor 4EBP1 of mTORC1, has Function protein matter to translate and improves the effect of cell proliferation, survival and Angiogensis.
PI3K path is regulated by the negative regulatory factor phosphoprotein phosphatase (Phosphatase and tensin homologue deleted on chromosome, PTEN) of PI3K and is suppressed PIP2 to the conversion of PIP3.In malignant tumour, the disappearance of common PTEN or sudden change make cell reduce the dependence of somatomedin, and apoptosis is slack-off, promote the invasion and attack of tumour cell.To encode gene PIK3CA process LAN in more than the solid tumor of 15% of p110 α subunit simultaneously.In addition, nearly all I type PI3Ks can be activated because p85 regulates the sudden change of subunit.
The abnormal activation of PI3K path can cause a series of reaction, comprises the growth of cell, propagation or transfer, epithelial cell to the generation of mesenchymal transformation and blood vessel.Thus, the suppression of PI3K path becomes the very promising therapeutic strategy of therapeutic field of tumor in recent years.
Compared with mTOR inhibitors, the double inhibitor of PI3K-mTOR can be suppressed by the multiple spot on this signal path, the increase of the signal simultaneously preventing AKT from mediating, and reaches the effect that antitumous effect strengthens.In addition, the structural similarity between the p110 subunit of PI3K and the catalyst structure domain of mTOR has promoted the development of such double inhibitor greatly.
Wortmannin (wortmannin) and LY294002 are first-generation PI3K inhibitor, and these two kinds of inhibitor are to PI3K non-selectivity, and thus toxicity is larger.The compound of many target PI3K has entered clinical, and wherein major part is PI3K/ mTOR double inhibitor, shows good treatment potentiality.
Summary of the invention
The present invention first relate to a class such as formula ( a) shown in the benzenesulfonamide derivatives of various dissimilar replacement or its solvate, salt, prodrug or polymorphic form pharmaceutically:
Wherein:
R 1group can separately be selected from: hydrogen, halogen, itrile group, nitro, hydroxyl, carboxyl, substituted or unsubstituted C1-8 acyl group, substituted or unsubstituted amino, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxyl group, can be single, double or polysubstituted;
R 2group can separately be selected from: hydrogen, substituted or unsubstituted C1-8 alkoxyl group, halogen;
R 3group is selected from following groups:
; Wherein, R 4, R 5hydrogen, the straight chain of substituted or unsubstituted C1-8, side chain or cycloalkyl can be selected from respectively; R 6be selected from hydrogen, the straight or branched alkyl of substituted or unsubstituted C1-8, the alkyl sulphonyl of C1-8, the straight or branched carbonyl of C1-8, the alkoxy carbonyl of C1-8; R 7, R 8the straight or branched alkyl of hydrogen, substituted or unsubstituted C1-8 can be selected from respectively;
Described replacement to refer to replace by following one or more substituting group: C1-5 alkyl, C2-5 thiazolinyl, C2-5 alkynyl, C1-5 alkoxyl group, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, oxo.
Preferably, the compound shown in formula (I), wherein R 1group is the single, double or polysubstituted of halogen.More preferably, R 1group is that 2,4-difluoro or 4-fluorine replace.
Preferably, the compound shown in formula (I), wherein R 2group is methoxyl group or halogen.
Preferably, the compound shown in formula (I), is characterized in that, R 3group is
。
Present invention also offers a kind of such as formula ( iII)the preparation method of described compound, comprises the steps:
(1) prepare compound ( iI)
The bromo-4-chloroquinoline of 6-is dissolved in dioxane, adds connection pinacol borate and potassium acetate and palladium catalyst, and under argon shield condition, reflux a few hours are detected raw material point to TLC and disappear, stopped reaction; Add in mixed system bromo aromatic compound ( i) and palladium catalyst and K 2cO 3solution, under nitrogen protection condition reflux a few hours obtain intermediate ( iI).
(2) prepare target product ( iII)
Intermediate ( iI) be dissolved in DMF, add dinaphthalene hexichol phosphorus and K 2cO 3and palladium acetate catalyst, under nitrogen protection condition, add dissimilar propargylamine compounds, 100 DEG C of heating a few hours are detected raw material point to TLC and disappear, stopped reaction, after column chromatography target product ( iII).
More specifically, the present invention relates to compound as follows:
(1) N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(2) N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide;
The fluoro-N-of (3) 2,4-bis-(2-methoxyl group-5-(4-(3-(4-(sulfonyloxy methyl) piperazine-1-base) the third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
(4) N-(5-(4-(3-(diethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(5) 2, the fluoro-N-of 4-bis-(5-(4-(3-((2-hydroxyethyl) (methyl) is amino) the third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(6) N-(5-(4-(3-(dicyclohexyl is amino) the third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
The fluoro-N-of (7) 2,4-bis-(2-methoxyl group-5-(4-(3-(piperidin-1-yl) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (8) 2,4-bis-(2-methoxyl group-5-(4-(3-(4-methyl piperidine-1-base) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (9) 2,4-bis-(2-methoxyl group-5-(4-(3-(pipecoline-1-base) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (10) 2,4-bis-(2-methoxyl group-5-(4-(3-morpholino third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
(11) 4-(3-(6-(5-(2,4 difluorobenzene sulphonamide)-6-methoxypyridine-3-base) quinolyl-4) the third-2-alkynes-1-base) piperazine-1-carboxylic acid, ethyl ester.
Part of compounds chemical structure of the present invention and 1h-NMR data are in Table 1, mass spectrum, melting point data are in Table 2.
。
The invention still further relates to a kind of medicinal compositions, containing, for example the compound described in upper any one and pharmaceutically acceptable carrier.Can be solid form or liquid form, described pharmaceutical dosage form can be tablet, capsule, powder agent, granule, suspensoid or injection.When the compounds of this invention is used for such use, can with one or more pharmaceutically acceptable carrier or mixed with excipients, as solvent, thinner etc., and can with following form oral administration: tablet, pill, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% is sugared according to appointment), with elixir (containing 20-50% ethanol of having an appointment), or with the administration of external application mode: ointment, gel, pastille adhesive plaster etc., or carry out parenteral routes with sterile injectable solution or form of suspension (containing 0.05-5% suspension agent of having an appointment in isotonic medium).Such as, these pharmaceutical preparations containing the about 0.01-99% mixed with carrier, can more preferably be about the activeconstituents of 0.1%-90% (weight).
The invention still further relates to a kind of pharmaceutical composition, comprise compound as above described in any one and at least one is selected from following antineoplastic compound: anti-microtubule agent, platinum coordination complex, alkylating agent, microbiotic, Topoisomerase II inhibitors, antimetabolite, topoisomerase I inhibitor, hormone and hormone analogs, signal transduction pathway inhibitor, nonreceptor tyrosine kinase angiogenesis inhibitor, immunosuppressor, short apoptosis inhibitor and cell cycle signals transduction inhibitor.Preferably, described antineoplastic compound is at present for clinical antitumor drug.
Compound due to pharmaceutical activity of the present invention has the activity as PI3K inhibitor, particularly regulates/suppresses compound be used for the treatment of cancer.Because pharmaceutical active compounds of the present invention is also right one or more there is activity, therefore they treatment following disease in show therapeutic value: autoimmune disorder, inflammatory diseases, cardiovascular disorder, neurodegenerative disease, transformation reactions, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, motility of sperm, transplant rejection, graft get rid of and injury of lung.
The invention still further relates to compound described in any one for the preparation of the application in the kinase whose medicine of inhibition of phosphatidylinositol3 3.Preferably, described medicine is antitumor drug or immunosuppressive drug.More preferably, described tumour behaviour lung cancer, colorectal carcinoma, mammary cancer, liver cancer.
Formula of the present invention (1) compound effective dose can change with the severity of the pattern of compound used, administration and disease to be treated.But, usually when compound of the present invention gives with the dosage of about 0.25-1000mg/kg the weight of animals every day, gratifying effect can be obtained, preferably give with the dosage that 2-4 time is separated every day, or with sustained release forms administration.For most of large mammal, the total dose of every day is about 1-100mg/kg, is preferably about 2-80mg/kg.Be applicable to the dosage form taken orally, comprise the active compound with the intimately mixed about 0.25-500mg of solid-state or liquid pharmaceutically acceptable carrier.This dosage adjustable is replied to provide optimal treatment.Such as, by an urgent demand for the treatment of situation, the dosage that several times separate can be given every day, or dosage is reduced pari passu.
These active compounds by oral and knurl, intravenously, intramuscular or the administration such as subcutaneous.Solid-state carrier comprises: starch, lactose, Si Liaodengji dicalcium phosphate feed grade, Microcrystalline Cellulose, sucrose and white bole, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be applicable to the characteristic of activeconstituents and required specific administration mode.In pharmaceutical compositions, normally used adjuvant also can advantageously be included, and such as seasonings, pigment, sanitas and antioxidant are as vitamin-E, vitamins C, BHT and BHA.
From the position being easy to preparation and administration, preferred pharmaceutical composition is solid-state composition, especially the capsule of tablet and solid-filling or liquid filling.The knurl of compound is interior is preferred with oral administration.
These active compounds also can parenteral or intraperitoneal administration.Also solution or the suspension of these active compounds (as free alkali or pharmacy acceptable salt) can be prepared in the water being suitably mixed with tensio-active agent (as hydroxypropylcellulose, polyvinylpyrrolidone).Also can prepare dispersion liquid in glycerine, liquid, polyoxyethylene glycol and the mixture in oil thereof.Under conventional storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.
The medicament forms being adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (for extemporaneous preparation of sterile injection solution or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is to be easy to syringe displacement fluids.Must be stable under conditions of manufacture and storage, and must can prevent the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, wherein containing, for example water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
" safe and effective amount " refers to: the amount of compound is enough to improve the state of an illness, and is unlikely to produce severe side effect.Safe and effective amount was determined according to the age, the state of an illness, the course for the treatment of etc. for the treatment of target.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and their are applicable to people and use, and must have enough purity and enough low toxicity." consistency " herein means generation be in composition each component energy and compound of the present invention and they between mutually admix, and the curative effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has sugar (as glucose, sucrose, lactose etc.), starch is (as W-Gum, yam starch etc.), cellulose and its derivates is (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum powder, solid lubricant is (as sodium stearate, Magnesium Stearate), calcium sulfate, vegetables oil is (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol is (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as Tweens), wetting agent (as sodium laurylsulfonate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Accompanying drawing explanation
Figure 1be compound of the present invention general structure ( a), specification sheets text is shown in illustrating of each group.
Figure 2it is compound of the present invention 3at its of national cancer institute test to people 9 large class tumour, the growth inhibitory activity result of totally 60 kinds of tumor cell lines.
Figure 3it is compound 3when qf oral administration dosage 30mg/kg, to the interior curative effect of the model in nude mice of liver cancer cell BEL7404.
Figure 4it is compound 10when qf oral administration dosage 50mg/kg, to the interior curative effect of the model in nude mice of liver cancer cell BEL7404.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number are weight percent and parts by weight.Test reagent used all from the analytical reagent of market sale.
Embodiment 1:
N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (III, the compound number in table 1) preparation
A) preparation of N-(5-(4-chloroquinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (II)
Bromo-for 6-4-chloroquinoline (2g, 8.25mmol) is dissolved in dioxane (30 mL), adds connection pinacol borate (2.30 g, 9.07 mmol) and potassium acetate (1.62 g, 16.50 mmol) and palladium catalyst PdCl 2(dppf) CH 2cl 2(0.21g, 0.25mmol), 100 DEG C of reflux 3h under nitrogen protection condition, detect raw material point and disappear, stopped reaction.The palladium catalyst PdCl of N-(5-bromo-2-methoxypyridine-3 base)-2,4 difluorobenzene sulphonamide (I) (3.4g, 9.08mmol) and another part is added in mixed system 2(dppf) CH 2cl 2the K of (0.21 g, 0.25 mmol) and 2M 2cO 3solution (10mL), 110 DEG C of reflux 16h stopped reaction under nitrogen protection condition.Solvent evaporated, adds water (50 mL), and with methylene dichloride (4 × 15 mL) extraction, merge organic layer, salt solution (15 mL) washs, with anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent.Product 1.11g is obtained, yield 29.13% with silica gel chromatography column purification (eluent: petrol ether/ethyl acetate=3:1). 1H NMR (300 MHz, CDCl 3) δ 8.82 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.93 (m, 2H), 7.58 (d, J = 4.8 Hz, 1H), 7.32 (s, 1H), 6.98 (m, 2H), 4.00 (s, 3H)，MS（ESI）m/z : 462.56 (M+H +)。
A) N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide (III, the compound number in table 1) preparation
Take N-(5-(4-chloroquinoline-6-base)-2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (0.30g, 0.65mmol) in 25mL three-necked bottle, add (±)-2,2 '-bis--(diphenyl phosphine)-1,1 '-dinaphthalene (40.47mg, 0.065mmol), palladium (8mg, 0.033mmol), K 2cO 3(0.18g, 1.30mmol), at N 2under protective condition, add DMF(10mL), 1-dimethyl amine-2-propine (65mg, 0.78mmol), 100 DEG C of heated and stirred 24 hours, detect raw material point and disappear, stopped reaction.Diatomite filtration, filtrate joins in water (100mL), and with ethyl acetate (4 × 50 mL) extraction, merge organic layer, salt solution (15 mL) washs, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent.Product 0.16g is obtained, yield 48.4% with silica gel chromatography column purification (eluent: methylene chloride/methanol=20:1).
Embodiment 2-11:
Table 1middle compound 2-11can by corresponding raw material, reference preparation embodiment 1the general method of compound prepares.
Embodiment 12: the Inhibiting enzyme activity of this series compound measures:
To the test result of above-claimed cpd Inhibiting enzyme activity in Table 3, test takes altogether three kinds of methods:
Utilize the method for Lance Ultra Assay, test the IC to mTOR 50value.
Utilize the method for ADP-Glo Luminescent Kinase Assay, test the IC to PI3K β and PI3K γ 50value.
Utilize the method for Kinase-Glo Luminescent Kinase Assay, test the IC to PI3K α and PI3K δ 50value.
table 3 part of compounds is to the IC of PI3K α 50 (nM)
From table 3in can find out, synthesized compound all has good inhibit activities to PI3K α, and wherein best is compound 3, be 2.0 nM.On this basis, preferably active good two compounds, test its inhibit activities to mTOR and PI3K different subtype, demonstrate and all have inhibit activities (table to each hypotype and mTOR 4).
table 4 part of compounds is to the activity research result of mTOR and PI3K different subtype
Embodiment 13: the anti tumor activity in vitro research of this series compound
(1) test method:
1. sample preparation: with DMSO(Merck) dissolve after, add PBS (-) and be made into solution or uniform suspension, then dilute with the PBS (-) containing DMSO.Positive control drug adopts Zorubicin (DOX).
1. cell strain
1) A549(human lung carcinoma cell)
2) HCT116(human colon cancer cell)
3) MDA-MB-231(human breast cancer cell)
4) BEL7404(human liver cancer cell)
3. nutrient solution
DMEM+5-10%FBS+ is dual anti-
4. other materials
Full-automatic microplate reader:
Model: WellscanMK-2 production firm: Labsystems
Import 96 well culture plate etc.
5. test method
Mtt assay.The 96 every holes of orifice plate add concentration and are cell suspension , put 37 DEG C, 5% CO 2in incubator.After 24h, add sample liquid, if, duplicate hole, 37 DEG C, 5% CO 2effect 72h.Every hole adds the MTT solution of 5mg/ml , add lysate after effect 4h, , put in incubator, after dissolving, survey 570nm OD value by the full-automatic microplate reader of MK-2.
(1) test-results: (see table 5)
table 5 part of compounds is to the in-vitro multiplication restraining effect of human body four kinds of tumour cells
From table 5known, compound of the present invention all shows good anti-tumor activity to liver cancer cell BEL7404, breast cancer cell MDA-MB-231.Specific value obtain it is noted that part of compounds as 1, 3, 10show higher in-vitro multiplication restraining effect, wherein, compound 3to the IC of liver cancer cell BEL7404 50value is 20nM, to the IC of breast cancer cell MDA-MB-231 50be 1.44 μMs, compound 3for the compound of cytoactive optimum in this series compound.This is efficient for exploitation, the antitumor drug of low toxicity, high specificity is laid a good foundation, and has good Development volue.
Embodiment 14: compound 3to national cancer institute people 60plant the cytotoxic activity test of tumor cell line
Compound 3it is tested to people 9 large class tumour, the cytotoxic activity of totally 60 kinds of tumor cell lines at national cancer institute.Figure 2for compound 3active testing result.Compound 3show good broad-spectrum anti-tumor activity, to the average half growth inhibitory concentration (GI of wherein 4 kinds of tumor cell lines 50) be less than 10 nM, be 65nM to the average GI50 of 60 kinds of tumour cells.Wherein, strong growth-inhibiting effect is had to kinds of tumor cells.
table 6 compound 3 is to the inhibit activities result of study (GI50 value: nM) of external 7 kinds of tumour cells
From table 6in can find out, compound 3outstanding growth inhibitory activity is demonstrated, wherein to the GI of lung carcinoma cell HOP-62, ovarian cancer cell IGROV1, breast cancer cell MCF7 to human body multiple kinds of tumor cell 50value is all less than 10nM.It is to the GI of colon cancer cell COLO 205, central nerve neuroma SNB-75, kidney TK-10, prostate cancer PC-3 50value is respectively 42,10,12 and 63nM.Compound 3as anti-tumor drugs targeting, there is broad-spectrum anti-tumor activity, have good drug development prospect.
Embodiment 15compound 3and compound 10to drug efficacy study in the body of human hepatocellular BEL7404 transplanted tumor in nude mice
(1) test method:
1. sample preparation:
Compound 3and compound 10and positive control drug toluenesulphonic acids BAY 43-9006 is with after tween-80 hydrotropy, distilled water diluting is to desired concn.
2. experimental animal
Strain: BALB/C nude mice (SPF level), source: Shanghai Slac Experimental Animal Co., Ltd., production licence number: SCXK(Shanghai) 2012-0002, occupancy permit number: SYXK(Shanghai) 2009-0068, sex: male, body weight: 18-20g, every treated animal number: 6.
3. test method
Get well-grown BEL7404 solid tumor, under aseptic condition, cut into the even fritter of about 2mm size, with the right armpit subcutaneous vaccination of trochar every mouse one piece, be divided into 4 groups at random, often organize processing mode and be respectively:
1) Control(physiological saline), gavage, dosage 25ml/kg, 14 days;
2) compound toluene sulfonic acid BAY 43-9006, gavage, dosage 50mg/kg, 14 days;
3) compound 3, gavage, dosage 30mg/kg, 14 days;
4) compound 10, gavage, dosage 50mg/kg, 14 days
Inoculate latter 13 days again to divide into groups according to tumor size, eliminate the animal that tumour is excessive and too small, often organize tumor average volume basically identical, start by above administration, administration volume is 0.5ml/20g body weight.Survey major diameter (a), the minor axis (b) of knurl block with digimatic calipers 2 times weekly, gross tumor volume (tumor volume, TV) calculation formula is: , relative tumour volume (relative tumor volume, RTV) calculation formula is: , Vo measures gained gross tumor volume for (d1) during point cage, and Vt is gross tumor volume when measuring each time.The evaluation index of anti-tumor activity is Relative tumor proliferation rate , or Relative tumor proliferation inhibition rate (%): 100%.And carry out T inspection.Inoculate latter 30 days and put to death animal, solution takes knurl block, claims knurl weight.
(2) test-results:
drug effect in the body of table 7 compound 3 and compound 10 pairs of human hepatocellular BEL7404 transplanted tumor in nude mice
Compound 3continuous per os gavage 14 times is 52.33% at the tumour inhibiting rate of dosage 30mg/kg to human hepatocellular BEL7404 nude mice model.(see figure 3), and not remarkable on the weight of animals impact.
Compound 10continuous per os gavage 14 days is 50.22% at the tumour inhibiting rate of dosage 50mg/kg to human hepatocellular BEL7404 nude mice model, but it has the decline of statistically significant to affect on the weight of animals, points out it may there is certain toxicity (see figure 4).
The continuous per os gavage of positive drug toluenesulphonic acids BAY 43-9006 14 days is 43.81% at the tumour inhibiting rate of dosage 50mg/kg to human hepatocellular BEL7404 nude mice model, not remarkable on the weight of animals impact.
Inhibition test result in body, compound 3and compound 10there is tumour inhibiting rate in the body higher than toluenesulphonic acids BAY 43-9006, compound 10under effective dose, there is statistically significant to affect (* P<0.05) on the weight of animals, demonstrate certain toxicity.Compound 3under effective dose, the body weight of animal is not made significant difference, prompting compound 3security compare compound 10better.
Meanwhile, compound 3reach at comparatively low dosage (30mg/kg) and compare compound 10(50mg/kg) tumour inhibiting rate in higher body, shows compound 3body in validity be better than compound 10.
In sum, compound 3active good, and security is better, is expected to be developed as new drug further.
Embodiment 16capsule composition
For administration oral dosage form of the present invention, by using table 8shown in composition be filled in capsulae vacuus with shown ratio and prepare.
each component concentration in table 8 capsule
embodiment 17injectable parenteral composition
By by 1.5 %(weight percents for administration injection liquid of the present invention) the compound of example I in 10 %(volume percent) propylene glycol the aqueous solution in stir preparation.
Embodiment 18tablet composition
By following table 9shown in sucrose, calcium sulfate dihydrate and PI3K inhibitor mix with shown ratio and use 10% gelating soln granulate.Wet granular is sieved, dry, mix with starch, talcum and stearic acid, sieve and be pressed into tablet.
each component concentration in table 9 tablet composition
Although describe the preferred embodiments of the invention to previous exemplary; but should be appreciated that the present invention is not limited to disclosed herein clearly stating; for those skilled in the art; under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.

Claims (10)

1. one kind such as formula ( a) shown in benzenesulfonamide derivatives or its solvate, salt, prodrug or polymorphic form pharmaceutically:
Wherein:
R 1group can separately be selected from: hydrogen, halogen, itrile group, nitro, hydroxyl, carboxyl, substituted or unsubstituted C1-8 acyl group, substituted or unsubstituted amino, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 alkoxyl group, can be single, double or polysubstituted;
R 2group can separately be selected from: hydrogen, substituted or unsubstituted C1-8 alkoxyl group, halogen;
R 3group is selected from following groups:
; Wherein, R 4, R 5hydrogen, the straight chain of substituted or unsubstituted C1-8, side chain or cycloalkyl can be selected from respectively; R 6be selected from hydrogen, the straight or branched alkyl of substituted or unsubstituted C1-8, the alkyl sulphonyl of C1-8, the straight or branched carbonyl of C1-8, the alkoxy carbonyl of C1-8; R 7, R 8the straight or branched alkyl of hydrogen, substituted or unsubstituted C1-8 can be selected from respectively;
Described replacement to refer to replace by following one or more substituting group: C1-5 alkyl, C2-5 thiazolinyl, C2-5 alkynyl, C1-5 alkoxyl group, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, oxo.
2. compound according to claim 1, is characterized in that, R 1group is the single, double or polysubstituted of halogen.
3. compound according to claim 2, is characterized in that, R 1group is that 2,4-difluoro, 4-fluorine or 2-fluorine replace.
4. compound according to claim 1, is characterized in that, R 2group is methoxyl group or halogen.
5. compound according to claim 1, is characterized in that, R 3group is , , , , or .
6. compound according to claim 1, is selected from:
(1) N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(2) N-(5-(4-(3-(dimethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide;
The fluoro-N-of (3) 2,4-bis-(2-methoxyl group-5-(4-(3-(4-(sulfonyloxy methyl) piperazine-1-base) the third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
(4) N-(5-(4-(3-(diethylamino) third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(5) 2, the fluoro-N-of 4-bis-(5-(4-(3-((2-hydroxyethyl) (methyl) is amino) the third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
(6) N-(5-(4-(3-(dicyclohexyl is amino) the third-1-alkynes-1-base) quinoline-6-base)-2-methoxypyridine-3-base)-2,4 difluorobenzene sulphonamide;
The fluoro-N-of (7) 2,4-bis-(2-methoxyl group-5-(4-(3-(piperidin-1-yl) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (8) 2,4-bis-(2-methoxyl group-5-(4-(3-(4-methyl piperidine-1-base) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (9) 2,4-bis-(2-methoxyl group-5-(4-(3-(pipecoline-1-base) third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
The fluoro-N-of (10) 2,4-bis-(2-methoxyl group-5-(4-(3-morpholino third-1-alkynes-1-base) quinoline-6-base) pyridin-3-yl) benzsulfamide;
(11) 4-(3-(6-(5-(2,4 difluorobenzene sulphonamide)-6-methoxypyridine-3-base) quinolyl-4) the third-2-alkynes-1-base) piperazine-1-carboxylic acid, ethyl ester.
7. present invention also offers a kind of such as formula ( iII)the preparation method of described compound, comprises the steps:
(1) prepare compound ( iI)
The bromo-4-chloroquinoline of 6-is dissolved in dioxane, adds connection pinacol borate and potassium acetate and palladium catalyst, and under argon shield condition, reflux a few hours are detected raw material point to TLC and disappear, stopped reaction; Add in mixed system bromo aromatic compound ( i) and palladium catalyst and K 2cO 3solution, under nitrogen protection condition reflux a few hours obtain intermediate ( iI);
(2) prepare target product ( iII)
Intermediate ( iI) be dissolved in DMF, add dinaphthalene hexichol phosphorus and K 2cO 3and palladium acetate catalyst, under nitrogen protection condition, add dissimilar propargylamine compounds, 100 DEG C of heating a few hours are detected raw material point to TLC and disappear, stopped reaction, after column chromatography target product ( iII).
8. a medicinal compositions, containing arbitrary described compound and pharmaceutically acceptable carrier in claim 1.
9. a medicinal compositions, is selected from following antineoplastic compound containing described compound arbitrary in claim 1 and at least one: anti-microtubule agent, platinum coordination complex, alkylating agent, microbiotic, Topoisomerase II inhibitors, antimetabolite, topoisomerase I inhibitor, hormone and hormone analogs, signal transduction pathway inhibitor, nonreceptor tyrosine kinase angiogenesis inhibitor, immunosuppressor, short apoptosis inhibitor and cell cycle signals transduction inhibitor.
10. one kind if the compound as described in arbitrary in claim 1 is for the preparation of the application in antitumor and immunosuppressive drug.
CN201410621004.1A 2014-11-07 2014-11-07 Benzene sulfonamide derivatives, preparation method, and treatment application Pending CN104402861A (en)

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Publication number Priority date Publication date Assignee Title
CN105130954A (en) * 2015-06-18 2015-12-09 浙江大学 3,4-disubstituted-6-pyridylquinoline compound as well as preparation and application thereof
CN107513056A (en) * 2017-10-12 2017-12-26 淮北师范大学 A kind of synthetic method of the quinolines of the group containing tetrahydrofuran
CN108884046A (en) * 2016-02-12 2018-11-23 葛兰素史克知识产权开发有限公司 The chemical compound of inhibitor as kinase activity

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WO2013141586A1 (en) * 2012-03-19 2013-09-26 The Asan Foundation Novelpyridopyrimidine derivatives and use thereof
WO2014022128A1 (en) * 2012-07-29 2014-02-06 Calitor Sciences, Llc Pi3 kinase modulators and methods of use
CN104093407A (en) * 2012-02-06 2014-10-08 葛兰素史克知识产权第二有限公司 Pi3k inhibitors for treating cough

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WO2012037108A1 (en) * 2010-09-13 2012-03-22 Glaxosmithkline Llc Aminoquinoline derivatives as antiviral agents
CN104093407A (en) * 2012-02-06 2014-10-08 葛兰素史克知识产权第二有限公司 Pi3k inhibitors for treating cough
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105130954A (en) * 2015-06-18 2015-12-09 浙江大学 3,4-disubstituted-6-pyridylquinoline compound as well as preparation and application thereof
CN108884046A (en) * 2016-02-12 2018-11-23 葛兰素史克知识产权开发有限公司 The chemical compound of inhibitor as kinase activity
CN108884046B (en) * 2016-02-12 2021-11-09 葛兰素史克知识产权开发有限公司 Chemical compounds as inhibitors of kinase activity
CN107513056A (en) * 2017-10-12 2017-12-26 淮北师范大学 A kind of synthetic method of the quinolines of the group containing tetrahydrofuran
CN107513056B (en) * 2017-10-12 2019-07-12 淮北师范大学 A kind of synthetic method of the quinolines of the group containing tetrahydrofuran

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