CN104045632B - Antineoplastic benzodihydropyran (thiapyran) amides compound and pharmaceutically acceptable salt thereof and preparation method and application - Google Patents
Antineoplastic benzodihydropyran (thiapyran) amides compound and pharmaceutically acceptable salt thereof and preparation method and application Download PDFInfo
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Abstract
The present invention relates to formula is new compound benzodihydropyran (thiapyran) amides compound shown in I, or this compounds pharmaceutically acceptable salt, as a kind of antineoplastic.Present invention also offers the preparation method of this compounds, and the pharmaceutical composition containing them, with antitumor action result of study, antineoplastic benzodihydropyran (thiapyran) amides compound that the present invention obtains, antitumor activity, anti-drug resistance and the security more excellent than having with a line anti-tumor medicine imatinib, can be in the application in treating the tumours such as leukaemia, gastrointestinal stromal tumor, lung cancer, liver cancer, colon cancer, oophoroma and kidney, thus treatment window width, so it is to have very much using value as antitumor agent in field of medicaments.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to suppress growth of tumour cell, benzodihydropyran (thiapyran) amides compound playing antitumous effect and its pharmaceutically acceptable salt and Preparation method and use.
Background technology
Imatinib Reverse transcriptase atriphos (ATP) and the binding site of thymidine kinase (TK) acceptor such as KIT, retardance TK phosphorylation, thus suppress signal to conduct, and the KIT relevant to kinase activity can be suppressed to suddenly change (causing KIT receptor activation) and the KIT of wild type.Its target site mainly has 3 kinds: Abelson (ABL) albumen, KIT albumen and platelet derived growth factor (PDGF) acceptor.Imatinib can cause, by gain-of-function KIT sudden change, the activation being independent of stem cell factor, reduces the tyrosine phosphorylation of clone (GIST882) from GIST, when concentration reaches 1 μm ol/L, can completely inhibit tyrosine phosphorylation.
Imatinib, is used for treating chronic myelocytic leukemia (CML) by FDA approval, within 2003, is used for treating gastrointestinal stromal tumor (GIST) by FDA approval May calendar year 2001.
Its structure is:
Imatinib has obvious bad reaction, and most of patients there will be some bad reactions during taking, but the overwhelming majority belongs to mild to moderate.
During the clinical testing of CML, the bad reaction relevant because of medicine and drug withdrawal person, the chronic phase patient that alpha-interferon therapy is failed only accounts for 1%, accelerated period accounts for 2%, CML-BC accounts for 5%.
In GIST clinical testing, the adverse events relevant because of medicine and drug withdrawal person accounts for 3.4%.
The bad reaction that CML with GIST patient occurs is similar, only two kinds exceptions: patient GIST occurs bone marrow suppression less, and tumor hemorrhage is only observed in patient GIST.In CML and GIST patient, the adverse events relevant to drug therapy of most common report have mild nausea (50～60%), vomit, suffer from diarrhoea, suffer from abdominal pain, weak, myalgia, muscle spasmus and erythema, these adverse events are all easily processed.
In all researchs, all reports have edema and water retention, and incidence is respectively 47～59% and 7～13%, and wherein severe patient is respectively 1～3% and 1～2%.The edema of Most patients shows as socket of the eye week and edema of lower extremity.Once there were indivedual reports of glaucoma, relevant with water retention.Also there is the report that hydrothorax, ascites, pulmonary edema and body weight increase sharply.These events generally can use time-out to use Imatinib, use diuretics or give other supportive treatment and alleviated.But few patients's situation is serious, even life-threatening.There is 1 example CML-BC patient dead because of the complex clinical situation of concurrent hydrothorax, congestive heart failure and renal failure.
Imatinib (Imatinib), Chinese name Gleevec, it is the anticarcinogen with molecular targeted tumour generting machanism of first man work synthesis, is used for treating Ph chromatin-positive CML.Its mechanism is combined with the catalytic center of EGFR-TK for suppression bcr/abl signal transduction system, Reverse transcriptase substrate or ATP, stops tyrosine kinase activation, Selective depression P210bcr/abl, thus plays targeted therapy effect, is CML chronic phase drug of first choice.But Imatinib is easier to resistance at treatment stage, causes the main cause of resistance to be the district's point mutation of bcr/abl kinases or P210 tyrosine kinase activity that gene expression increase causes increases, blocking drugs and P210 protein combination.Once produce resistance, Second line Drug treatment, the problem that drug resistance has occurred in current Second line Drug need to be carried out.
Summary of the invention
For solving problem above, it is an object of the invention to provide, than Imatinib, there is more excellent antitumor activity, more drug resistance and security, and treat antineoplastic benzodihydropyran (thiapyran) amides compound and its pharmaceutically acceptable salt of window width.
It is a further object of the present invention to provide the preparation method and applications of antineoplastic benzodihydropyran (thiapyran) amides compound and its pharmaceutically acceptable salt.
In the present invention, for changing the above-mentioned weakness of Imatinib, we carry out structural modification to it, synthesize multiple benzodihydropyran (thiapyran) amides compound and its pharmaceutically acceptable salt, its antitumor activity and drug resistance are studied, found that the compound represented with following formula [I], [II] and [III] has the most excellent antitumor activity and drug resistance, and there is stability and security.
The compound represented with formula [I] and pharmaceutically acceptable salt thereof:
In formula:
R is a saturated cyclic amino；Described saturated cyclic amino is selected from piperidyl, piperazinyl, imidazolidinyl, pyrrolidinyl, heterocyclic butane group, morpholinyl or N-methyl piperazinyl；
D is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, thiazolyl, isothiazolyl, imidazole radicals, oxazolyl, isoxazolyl, triazolyl or pyrazolyl, or each group is alternatively by 1,2 or 3 R2Replaced, described R2It is independently selected from halogen, cyano group, amino, C1-6Alkyl, C1-6Hydroxyalkyl, C1-6Haloalkyl or C1-6Cyanogen substituted alkyl；
E is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, thiazolyl, isothiazolyl, imidazole radicals, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, nitrogen oxazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, pyrazolopyrimidine base, quinolyl, isoquinolyl, quinazolyl, piperazinyl or morpholinyl；
X is selected from oxygen or sulphur.
Above-mentioned compound and pharmaceutically acceptable salt thereof, it is preferred that D is pyrimidine radicals, E is pyridine radicals, and R is N-methyl piperazinyl, and X is selected from oxygen or sulphur, has a structure of formula [II]:
Above-mentioned compound and pharmaceutically acceptable salt thereof, it is preferred that D is pyrimidine radicals, E is pyrimidine radicals, and R is N-methyl piperazinyl, and X is selected from oxygen or sulphur, has a structure of formula [III]:
Above-mentioned compound and pharmaceutically acceptable salt thereof, it is furthermore preferred that D is pyrimidine radicals, E is pyridine radicals, and R is N-methyl piperazinyl, and X is selected from oxygen, has a structure of [IV]:
Above-mentioned compound and pharmaceutically acceptable salt thereof, it is furthermore preferred that D is pyrimidine radicals, E is pyridine radicals, and R is N-methyl piperazinyl, and X is selected from sulphur, has a structure of [V]:
Above-mentioned compound and pharmaceutically acceptable salt thereof, described pharmaceutically acceptable salt, can be prepared by inorganic acid or organic acid.Its inorganic acid can include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid etc..Organic acid can include but are not limited to acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, benzene sulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid or salicylic acid etc..
Above-mentioned compound and pharmaceutically acceptable salt thereof are in the application prepared on antineoplastic, and it is right that its antitumor application includes: leukaemia, gastrointestinal stromal tumor, lung cancer, liver cancer, colon cancer, neural cancer, melanoma, oophoroma, kidney prostate cancer and breast cancer and the treatment etc. of above drug-resistant cancer.
A kind of pharmaceutical composition, including compound and the pharmaceutically acceptable salt thereof of any of the above-described, and at least one pharmaceutically acceptable carrier.
Detailed description of the invention
Hereinafter enumerate embodiment, specifically describe the present invention further, but the present invention is not restricted by the embodiments.
The exemplary of the present invention is described more fully below.But, these embodiments are only for illustration purpose, it is no intended to limit the scope of the present invention.
The compounds of this invention also includes pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to the basic group in parent compound to be converted into the form of salt.Pharmaceutically acceptable salt includes, but not limited to the inorganic or acylate of basic group such as amine (ammonia) base.
Pharmaceutically acceptable salt can be prepared by inorganic or organic acid, and inorganic acid can include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..Organic acid can include but are not limited to acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, benzene sulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..
" pharmaceutically acceptable carrier " used herein include any and whole solvent pharmaceutically, decentralized medium, coating, etc. blend absorption delaying agent etc., such medium and medicament are for pharmaceutically active substances, it is well known in the art, unless any conventional media or medicament are incompatible with active component, its application in therapeutic combination it is expected to, and the active component supplemented can also be incorporated in composition.
The pharmaceutical composition of the present invention is orally available, inject, suction of spraying, external preparation for skin, rectum with, nasal cavity, vagina with, abdominal cavity with or use by implanting the purposes such as reservoir or transdermal patch.
Importance of the present invention is that the present invention can be used for treatment and relates to tumor disease, including: leukaemia, gastrointestinal stromal tumor, lung cancer, liver cancer, colon cancer, neural cancer, melanoma, oophoroma, kidney prostate cancer and breast cancer and the treatment etc. of above drug-resistant cancer.
The synthesis (CYBEN) of embodiment 1. compound (N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-4-(4-methylpiperazin-1-yl) chroman-7-carboxamide)
The synthesis of step A. compound 1 (3-chloro-1-(2,4-dihydroxyphenyl) propan-1-one)
Experimental procedure: take the eggplant shaped reaction bottle of 500mL, adds 3-chloropropionic acid 21.7g, resorcinol 21.8g, TFMS 63mL, adds magnetic stirring bar, heats up 80 DEG C, and reaction starts, and reacts complete, be cooled to room temperature after 0.5h.Reactant liquor adds the CH of 200mL after being down to room temperature2Cl2Dissolve, and by CH2Cl2Solution is poured slowly in 200mL frozen water, separates CH2Cl2Concentrate the most afterwards, separate out substantial amounts of orange/yellow solid.Obtaining product 12.9g, productivity is: 32.58%, is directly used in the next step.
IR(KBr,cm-1):3434,1633,1462,1384,1244,1207,1129,822,701,609。
The synthesis of step B. compound 2 (7-hydroxychroman-4-one)
Experimental procedure: take the eggplant shaped reaction bottle of 250mL, adds raw material 10g compound 1, adds magnetic stirring bar, adds the NaOH100mL of 2M under conditions of 5-10 DEG C, is warming up to room temperature, stops reaction, by reactant liquor PH H after stirring 2h2SO4It is adjusted to acidity (PH=2～4), has solid to separate out, filter, wash with water, dried product 7.6g, productivity: 92.7%.
IR(KBr,cm-1):3419,3272,1597,1582,1479,1383,1349,1243,1164,1128,1035,846,541,4741H NMR (DMSO) δ 10.52 (s, 1H), 7.60 (d, J=9Hz, 1H), 6.47 (dd, J1=2.4Hz, J2=9Hz, 1H), 6.29 (d, J=2.4Hz, 1H), 4.44 (t, J=6.6Hz, 2H), 2.64 (t, J=6.6Hz, 2H).
The synthesis of step C. compound 3 (4-oxochroman-7-yl trifluoromethanesulfonate)
Experimental procedure: take the eggplant shaped reaction bottle of 250mL, adds raw material 4g compound 2, CH2Cl250mL, now raw material is less soluble, dissolves, add magnetic stirring bar, drip the CH of trifluoromethanesulfanhydride anhydride under room temperature after adding the pyridine of 2 equivalents2Cl2Solution, is swift in response, and stirs 0.5h, react complete after dropping.Reactant liquor is added HCl (2N) be adjusted in PH=3 and pyridine, separate CH2Cl2Phase, adds 5%NaHCO3Solution 50mL, separates CH after extraction2Cl2Phase, Na2SO4Being dried, filter, after decompression screws out solution, obtaining product is liquid, about 7g, and productivity is 97%.It is directly used in the next step.
IR(KBr,cm-1):3466,1702,1614,1584,1482,1383,1323,1280,1141,1111,1036,912,842,637,5041H NMR(DMSO)δ7.99(dd,J1=3Hz, J2=6.6Hz, 1H), 6.94 (m, 2H), 4.60 (t, J=6.6Hz, 2H), 2.85 (t, J=6.6Hz, 2H).
The synthesis of step D. compound 4 (methyl4-oxochroman-7-carboxylate)
Experimental procedure: take the eggplant shaped reaction bottle of 250mL, adds magnetic stirring bar, raw material 6.2g compound 3, DPPP0.86g, Pd (OAc)20.47g, methyl alcohol 13.4g, Et3The lower 70 DEG C of stirring reactions of N4.23g, DMF40mL, CO, react about 15h.After reaction terminates, after reactant liquor decompression is screwed out MeOH, add dilute HCl/water solution and adjust PH=4, add the extraction of 50mL water, and respectively with 50mL, the ethyl acetate of 25mL aqueous phase extracted again, combined ethyl acetate mutually after, then with saturated salt solution 50mL, 50mL, 25mL extracts three times, separates ethyl acetate phase, uses anhydrous Na SO4Being dried, filter, filtrate decompression is spin-dried for.The MeOH adding 100mL dissolves, and adds the activated carbon of 3% and reflux under conditions of 70 DEG C 1h, and suction filtration is spin-dried for, crystallizes in ether, and precipitation product 1.2g, surplus products obtain the sterling of 0.8g after column chromatography for separation, and productivity is 49.8%.
IR(KBr,cm-1):3422,1720,1686,1569,1474,1436,1390,1334,1285,1212,1182,983,765,605,5331H NMR(DMSO)δ7.95(dd,J1=1.8Hz, J2=6.6Hz, 1H), 7.64 (dd, J1=1.8Hz, J2=7.2Hz, 2H), 4.57 (t, J=6.6Hz, 2H), 3.935 (s, 3H), 2.85 (t, J=6.6Hz, 2H).
The synthesis of step E. compound 5 (methyl4-hydroxychroman-7-carboxylate)
Experimental procedure: take the eggplant shaped reaction bottle of 250mL, adds magnetic stirring bar, raw material 2g compound 4, dissolves with the methyl alcohol of 30mL, add NaBH while stirring40.38g, airtight, to react under room temperature, 0.5h reaction is complete.After reaction terminates, by the HCl furnishing PH=6 of reactant liquor 1N, decompression screws out methyl alcohol, extracts with each 30mL of ethyl acetate and water, separate to obtain ethyl acetate phase, use anhydrous Na SO4Being dried, filter, after filtrate mixes sample, column chromatography (ethyl acetate: n-hexane=1:5) separates, and obtains colourless transparent liquid 2g, and productivity is 99%.
IR(KBr,cm-1):3270,2951,1721,1575,1427,1299,1217,1093,1062,1015,892,869,751
1H NMR(DMSO)δ7.54(dd,J1=1.8Hz, J2=7.8Hz, 1H), 7.47 (d, J=1.8Hz, 1H), 7.37 (d, J=7.8Hz, 1H), 4.80 (t, J=4.2Hz, 1H), 4.29 (m, 2H), 3.89 (s, 3H), 2.24 (s, 1H), 2.14 (m, 1H), 2.06 (m, 1H).
The synthesis of step F. compound 6 (methyl4-chlorochroman-7-carboxylate)
Experimental procedure: take the eggplant shaped reaction bottle of 125mL, adds magnetic stirring bar, adds raw material 2g compound 5, dissolves with 20mL toluene, under room temperature (20 DEG C), adds SOCl2(1.495g) toluene solution 5mL, after reacting 2.5h under stirring condition, raw material still has residue, adds SOCl2(0.72g) toluene solution 4mL continues reaction.After reaction terminates, add the NaHCO of 2%3Aqueous solution extraction reactant liquor, the ethyl acetate of aqueous phase 10mL is associated with cabinet after extracting one time, with saturated saline solution extraction (twice) organic phase, Na2SO4Being dried, decompression is spin-dried for, and obtains product 2.1g, and productivity is 96.2%, is directly used in next step reaction.
IR(KBr,cm-1):3481,2952,1723,1576,1436,1427,1284,1248,1211,1059,1046,1019,895,799,755,646,5281H NMR(DMSO)δ7.56(dd,J1=1.2Hz, J2=8.4Hz, 1H), 7.50 (d, J=1.2Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 5.21 (t, J=3.3Hz, 1H), 4.46 (td, J1=2.4Hz, J2=12Hz, 1H), 4.36 (m, 1H), 3.89 (d, J=7.2Hz, 1H), 2.48 (m, 1H), 2.33 (t, 1H).
The synthesis of step G. compound 7 (methyl4-(4-methylpiperazin-1-yl) chroman-7-carboxylate)
Experimental procedure: take the eggplant shaped reaction bottle of 250mL, adds magnetic stirring bar, raw material 2.1g compound 6, N methyl piperazine 1.12g, K2CO3After reacting 6h at 2.58g, KI1.5g, DMF30mL, 60 DEG C, 70 DEG C of reaction 2h.Reactant liquor adds the ethyl acetate of 50mL, and the water of 50mL extracts, separate ethyl acetate mutually after, add 2N HCl and adjust PH=1, extraction, separate ethyl acetate phase, detection product extracts an aqueous phase again at aqueous phase, the ethyl acetate adding 30mL, separates aqueous phase, add NaOH aqueous solution regulation PH=8～9, extraction, separate ethyl acetate phase, after saturated aqueous common salt extraction once, it is dried ethyl acetate phase, is dried, screw out ethyl acetate.Obtaining product 2.35g, productivity is 91.4%.
IR(KBr,cm-1):3445,2943,2790,1717,1631,1435,1421,1384,1282,1103,1054,7691H NMR (DMSO) δ 7.57 (d, J=7.8Hz, 1H), 7.53 (dd, J1=1.8Hz, J2=7.8Hz, 1H), 7.44 (d, J=1.2Hz, 1H), 4.38 (m, 1H), 4.14 (m, 1H), 3.89 (t, J=6Hz, 4H), 2.65 (s, 2H), 2.52 (d, J=41.4Hz, 5H), 2.29 (d, J=8.4Hz, 3H), 2.10 (m, 1H), 1.98 (m, 1H).
The synthesis (CYBEN) of step H. compound 8 (N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-4-(4-methylpiperazin-1-yl) chroman-7-carboxamide)
Experimental procedure: take 125mL eggplant shaped reaction bottle, adds Imatinib amine 2.45g, toluene 30mL, adds trimethyl aluminium 4.5mL by injection, and stirring added after half an hour reacts at raw material 1.6g compound 7,100 DEG C.After reaction stops, it is down to room temperature, adds the aqueous sodium potassium tartrate of 5%, with the water saturated extracting n-butyl alcohol of 50mL, separate the n-butanol phase containing toluene, when being threaded to remain a small amount of solution, stop operation, place and make it naturally separate out.Obtaining product 2.5g, productivity is 84.7%.
1H NMR (DMSO) δ 9.25 (d, J=1.8Hz, 1H), 8.946 (s, 1H), 8.67 (dd, J1=1.2Hz, J2=4.8Hz, 1H), 8.49 (d, J=5.4Hz, 1H), 8.46 (dt, J1=1.8Hz, J2=7.8Hz, 1H), 8.30 (s, 1H), 8.05 (d, J=1.8Hz, 1H), 7.51 (m, 2H), 7.46 (dd, J1=1.8Hz, J2=7.8Hz, 1H), 7.43 (dd, J1=1.8Hz, J2=8.4Hz, 1H), 7.40 (d, J=5.4Hz, 1H), 7.30 (d, J=1.8Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 4.33 (m, 1H), 4.15 (m, 1H), 3.90 (m, 1H), 3.16 (s, 1H), 2.49 (m, 2H), 2.43 (s, 2H), 2.37 (d, J=1.8Hz, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.96 (m, 2H).
The synthesis of embodiment 2. compound 9N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-(4-methylpiperazin-1-yl) chroman-7-carboxamide
Experimental procedure: take 125mL eggplant shaped reaction bottle, add N1-([4,5'-bipyrimidin]-2-yl)-6-methylbenzene-1,3-diamine2.45g, toluene 30mL, adding trimethyl aluminium 4.5mL by injection, stirring added after half an hour reacts at raw material 1.5g compound 7,100 DEG C.After reaction stops, it is down to room temperature, adds the aqueous sodium potassium tartrate of 5%, with the water saturated extracting n-butyl alcohol of 50mL, separate the n-butanol phase containing toluene, when being threaded to remain a small amount of solution, stop operation, place and make it naturally separate out.Obtaining product 2.4g, productivity is 82.7%.
MS (M+1)=537.27.
1H NMR (DMSO) δ 9.21 (d, J=1.8Hz, 1H), 8.93 (s, 1H), 8.66 (dd, J1=1.8Hz, J2=4.8Hz, 1H), 8.52 (d, J=5.4Hz, 1H), 8.44 (dt, J1=1.8Hz, J2=8.0Hz, 1H), 8.27 (s, 1H), 8.06 (d, J=1.8Hz, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 7.37 (d, J=5.4Hz, 1H), 7.29 (d, J=1.8Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 3.91 (m, 1H), 3.07 (m, 2H), 2.48-2.44 (m, 4H), 2.36 (m, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 1.96 (m, 2H).
The synthesis of embodiment 3. compound 10N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-4-(4-methylpiperazin-1-yl) thiochroman-7-carboxamide
Experimental procedure: take 125mL eggplant shaped reaction bottle, add methyl4-(4-methylpiperazin-1-yl) thiochroman-7-carboxylate2.6g, toluene 30mL, trimethyl aluminium 4.5mL is added by injection, stirring adds raw material 1.6g compound methyl4-(4-methylpiperazin-1-yl) thiochroman-7-carboxylate after half an hour, reacts at 100 DEG C.After reaction stops, it is down to room temperature, adds the aqueous sodium potassium tartrate of 5%, with the water saturated extracting n-butyl alcohol of 50mL, separate the n-butanol phase containing toluene, when being threaded to remain a small amount of solution, stop operation, place and make it naturally separate out.Obtaining product 2.4g, productivity is 84.7%.
MS (M+1)=552.25.
1H NMR(DMSO)δ9.47(s,1H),9.36(s,1H),9.27(s,1H),9.25(s,1H),8.98(s,1H),8.67(dd,J1=1.8Hz, J2=5.0Hz, 1H), 8.30 (s, 1H), 8.08 (d, J=1.8Hz, 1H), 7.52 (m, 2H), 7.45 (dd, J1=1.8Hz, J2=7.8Hz, 1H), 7.41 (dd, J1=1.8Hz, J2=8.4Hz, 1H), 7.31 (d, J=1.8Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 4.32 (m, 1H), 4.17 (m, 1H), 3.79 (m, 1H), 3.18 (s, 1H), 2.50 (m, 2H), 2.43 (s, 2H), 2.38-2.14 (m, 8H), 1.96 (m, 2H).
The synthesis (OB1209) of the tartrate of embodiment 4. compound 8 (N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-4-(4-methylpiperazin-1-yl) chroman-7-carboxamide)
Experimental procedure: take the eggplant shaped reaction bottle of 25mL, adds 200mg compound 8, and the ethanol adding 5mL dissolves, and adds tartaric acid and the magnetic stirring bar of 72.9mg, is warming up to 78 DEG C of backflow 0.5h.After reaction terminates, being cooled to room temperature, when solvent is threaded to surplus 1～2mL, have solid to separate out, filter, ether washs, and obtains product 227mg, and productivity is 88.67%.
The synthesis (OB1204) of the citrate of embodiment 5. compound 8 (N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl)-4-(4-methylpiperazin-1-yl) chroman-7-carboxamide)
Experimental procedure: take the eggplant shaped reaction bottle of 25mL, adds 200mg compound 8, and the ethanol adding 5mL dissolves, and adds citric acid and the magnetic stirring bar of 93.38mg, is warming up to 78 DEG C of backflow 0.5h.After reaction terminates, being cooled to room temperature, when solvent is threaded to surplus 1～2mL, have solid to separate out, filter, ether washs, and obtains product 240mg, and productivity is 88.56%.
The pharmacodynamics test of embodiment 6 compound CYBEN, OB1204 and OB1209
With embodiment 1, embodiment 4 and embodiment 5 provide CYBEN, OB1209 and OB1204 as given the test agent, illustrate the excellent antitumor action as shown in following pharmacodynamics test.
(1) method:
Select different types of Abl kinases, use Z'-Lay spy's enzyme assay (Z '-Lyte assay.) of maturation to measure.With the inhibitor [Imatinib (Imtinib), nilotinib (Nilotinib) and Dasatinib (Dasatinib)] of the Bcr-Abl of three FDA approvals as positive control, to verify screening conditions.
3 kinds of inhibitor have carried out direct comparative measurements, and as shown in table 1, under same experimental conditions, Imatinib effectively suppresses Bcr-Abl kinase activity to be 110.03nM, these data and the IC reporting data.However50It is worth close, it was demonstrated that experiment sieving condition is suitable for the mensuration of sample.
Compound CYBEN, OB1204 and OB1209 all demonstrate the activity to Bcr-Abl wild type and drug-resistant type, but OB1204 activity is more preferably, the wherein compound CYBEN IC to T315I saltant type50Value is 1.25nM；The compound OB1204 IC to T315I saltant type50Value is 0.43nM；The compound OB1209 IC to T315I saltant type50Value is that 1.77nM. is all better than 3 comparison medicines.
(2) result of the test
Abl1inhibition(IC50,nM)
Table 1
The kinase inhibitory activities were determined using the FRET-based Z′-Lyte assay.The data represent the mean values of three independent experiments.
As above-mentioned pharmacological tests shows, the compounds of this invention shows excellent antitumor action, and as antitumor agent, for prevention, treatment disease, it is effective for particularly disposing drug-resistant tumor.When the compound of the present invention is used for such purposes, can be made into the effective dose containing the compounds of this invention and carrier that pharmacy is allowed or the preparation of excipient.
Equally, done pharmacodynamic experiment as above with the compound that embodiment 2 and embodiment 3 synthesize, also showed that excellent antitumor action.
The administration form of the compounds of this invention is used as antitumor agent, optional various forms, such as, can enumerate the aqueous non-peroral formulations of the peroral formulations of tablet, capsule, pulvis, granule or liquor etc. or the sterilization of such as solution or suspension etc., injection, suppository, ointment etc..
The preparation of solid can directly manufacture with the form of tablet, capsule, granule or powder, but is used as suitable additive manufacture.As such additive, such as can enumerate the carbohydrate of lactose or glucose etc., such as corn, the starch of wheat or rice etc., the aliphatic acid of such as stearic acid etc., the such as inorganic salts of metasilicic acid magnesium aluminate or anhydrous calcium phosphate etc., the synthesis macromolecule of such as polyvinylpyrrolidone or PAG etc., the soap of such as calcium stearate or hard magnesium etc., the alcohols of such as octadecanol or benzylalcohol etc., such as methylcellulose, carboxymethylcellulose calcium, the synthetic cellulose derivative of ethyl cellulose or hydroxypropyl methyl cellulose etc., other, gelatin, talcum, vegetable oil, the usual spendable additive such as gum arabic.
The solid preparation of these tablets, capsule, granule and powder etc., generally can be containing 0.1～99% (w/w), preferably 0.1～the active ingredient of 50% (w/w).
Aqueous preparation, can use and conventionally used be properly added thing, with form manufactures such as suspension, syrup, injection, some drops in the aqueous preparation of the vegetable oil such as water, alcohols or such as soybean oil, peanut oil, sesame oil.
Especially as appropriate solvent when being administered with para-oral intramuscular injection, intravenous injection or hypodermic form, such as can enumerate distilled water for injection, normal saline solution, D/W, ethanol, polyethylene glycol, liquid for intravenous injection (aqueous solution of such as citric acid and sodium citrate etc.) or electrolyte solution (drop intravenous injection and used for intravenous injection) etc., or these mixed solution.
In addition to the injection that these dissolve in advance, it is possible to be made the form dissolved in use added with powder or suitable additive.These parenteral solutions generally can be containing 0.1～30% (w/w), preferably 0.5～the active ingredient of 10% (w/w).
It addition, the formulation of the suspending agent of oral administration, syrup etc., 0.5～the active ingredient of 10% (w/w) generally can be contained.
The preferred dosage of the compounds of this invention, can according to the kind of compound used, the composition kind of cooperation, be suitable for the kind etc. of frequency and the privileged site that should treat, the weight of the state of an illness, the age of patient, the diagnosis of doctor, tumour and change, but as substantially target, such as every day every 1 adult dosage, when oral administration, can be in the range of 1～800mg, additionally, when non-oral administration, when intravenous injection, preferably every day is in the range of 1～400mg.It addition, administration number of times, different according to medication and symptom, but within 1 day, be 1～3 time.It addition, be administered the next day of being used as, every medications such as administrations on the two etc. are administered intermittently.
Claims (8)
1. the compound represented with formula [I] and pharmaceutically acceptable salt thereof:
In formula:
R is N-methyl piperazinyl；
D is pyrimidine radicals；
E is pyridine radicals or pyrimidine radicals；
X is selected from oxygen or sulphur.
Compound the most according to claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that D is pyrimidine radicals, E is phonetic
Piperidinyl, R is N-methyl piperazinyl, and X is oxygen, has a structure of [III]:
Compound the most according to claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that D is pyrimidine radicals, E is pyrrole
Piperidinyl, R is N-methyl piperazinyl, and X is oxygen, has a structure of [IV]:
Compound the most according to claim 1 and pharmaceutically acceptable salt thereof, it is characterised in that D is pyrimidine radicals, E is pyrrole
Piperidinyl, R is N-methyl piperazinyl, and X is sulphur, has a structure of [V]:
5. according to the compound described in claim 1,2,3 or 4 and pharmaceutically acceptable salt thereof, it is characterised in that described
Pharmaceutically acceptable salt, is prepared by inorganic acid or organic acid, and described inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
Or phosphoric acid；Described organic acid includes acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, amber
Acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, benzene sulfonic acid, second sulphur
Acid, p-methyl benzenesulfonic acid or salicylic acid.
6. arbitrary compound described in claim 1-5 and pharmaceutically acceptable salt thereof are in the application prepared on antineoplastic.
Application the most according to claim 6, it is characterised in that: described tumour includes leukaemia, gastrointestinal stromal tumor, lung
Cancer, liver cancer, colon cancer, neural cancer, melanoma, oophoroma, kidney prostate cancer or breast cancer.
8. a pharmaceutical composition, it is characterised in that: include the arbitrary described compound of claim 1-5 and pharmaceutically acceptable
Salt, and at least one pharmaceutically acceptable carrier.
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