CN101591357A - One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL - Google Patents
One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL Download PDFInfo
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- CN101591357A CN101591357A CNA200810160750XA CN200810160750A CN101591357A CN 101591357 A CN101591357 A CN 101591357A CN A200810160750X A CNA200810160750X A CN A200810160750XA CN 200810160750 A CN200810160750 A CN 200810160750A CN 101591357 A CN101591357 A CN 101591357A
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Abstract
The present invention relates to one group and suppress the kinase whose phosphate/phosphate ester compounds of BCR-ABL, by regulation and control kinase activity treatment tumour and/or other diseases.This group compound has following common configuration, as shown at right, as compound 1, compound 2, compound 3, compound 4 the invention still further relates to the salt that above-claimed cpd is pharmaceutically approved, and prepares oral, injection, externally applied medicine according to any drug regimen.
Description
Technical field
The present invention relates to one group of kinase inhibitor.The present invention comprises that also relevant compound and intermediate make medicine and be used for the treatment of diseases related.
Background technology
Kinases is a kind of enzyme that changes the proteolytic enzyme structure by phosphorylated.Phosphorylation can make the function of proteolytic enzyme usually, the site of cell and change with other proteic combinations.30% proteic function is by kinases control, and kinase regulatory proteic passage, the signal transmission between the cell.Human genome contains more than 500 kind of kinase gene, accounts for 2% of all genes.
Protein kinase is a proteolytic enzyme relevant on one group of structure, and they can transfer to the Serine of enzyme to phosphoryl from Triphosaden, on Threonine and the tyrosine.The function of many cells as dna replication dna, energy metabolism, cell growth etc., is all regulated and control by phosphorylated by kinases.Special needs to be pointed out is that the generation of numerous disease (comprising cancer) is also regulated and control by protein kinase.
In the common oncogene of known kind more than 100, tenuigenin Tyrosylprotein kinase or be suppressed, or activated [Blume-Jensen and Hunter, Nature, 411:355-365, (2001)] greatly.Naturally, protein kinase promptly becomes the target of drug research, existing tens kinds of kinase inhibition agent medicines get the Green Light [reviewed in Fischer, Curr.Med.Chem., 11:1563 (2004); Dancey andSausville, Nature Rev.Drug Disc.2:296 (2003)].
Kinase whose action principle is seen Fig. 1.
The growth factor receptors that protein-tyrosine activates enzyme claims receptor tyrosine to activate the enzyme factor again.They have a variety of, are regulating and control the various kinds of cell activity.These factors are formed by having different bioactive cell-membrane receptors in a large number.Known have 19 kinds of these Class Activation enzymes at least, comprising: vascular endothelial growth factor receptor 1 (VEGFR-1), vascular endothelial growth factor receptor 2 (VEGFR-2), III receptor Tyrosylprotein kinase (FLT-3) and platelet-derived growth factor acceptor (PDGFR).
Chronic myeloid leukemia (CML) is a kind of stem cell disease, is because the cell that contains the BCR-ABL enzyme is bred in the hemocyte tissue causes.BCR-ABL oncogene is the product of Philadelphia karyomit(e) (Ph) 22q.It is decoded and reaches a carat BCR-ABL protein, makes it that ABL tyrosine-kinase activity be arranged, and this also is the cause of disease of chronic myeloid leukemia (CML).Although chronic myeloid leukemia philtrum 210kDaBCR-ABL proteolytic enzyme activates fully, show that the proteolytic enzyme of a 190kDaBCR-ABL of leukemia philtrum of the Ph positive (Ph+) also is activated.
Gleevec is a kind of ABL albumen activating enzyme inhibitor, also suppresses growth factor receptors PDGFR and KIT simultaneously, thus the anticancer growth.Its application has greatly changed cancer therapy.This targeted therapeutics not only provides effective therapy for chronic myeloid leukemia people, has also changed the history of cancer therapy.Some patient can develop immunity to drugs to Gleevec.This is owing to BCR-ABL protein enzyme generation allosteric, thereby insensitive to Gleevec.Overcoming the drug-fast method of Gleevec has: select to suppress the one-piece construction or the stability of BCR-ABL protein enzyme, suppress the signal transduction system of BCR-ABL protein enzyme.It is clearer that a lot of biochemical structure researchs make people resist the understanding of the property of medicine, thereby design new medicine to avoid the resistance of human body.Many new compounds are having drug-fast chronic myeloid leukemia patient to carry out first phase or the second stage of clinical experiment to Gleevec, two s-generation medicines demonstrate significant curative effect.
Modal patient's resistance is the site mutation owing to the BCR-ABL gene, thereby makes activating enzyme one or several amino acid change at catalytic domain, and kinase inhibitor just can't combine with kinases like this, and cancer cells is grown as usual.The resistance principle is seen Fig. 2.
Dasatanib is a s-generation BCR-ABL kinase inhibitor.It is the patient who Gleevec is developed immunity to drugs at.But its transformation period is less than 4 hours, pharmacokinetic show it in vivo major part be decomposed (Christopher et al, Drug Metablism and Disposition, 36,7,1357-1364.).
Summary of the invention
The invention provides kinase inhibitor compounds, particularly suppress the BCR-ABL kinases.They can combine with activating enzyme and suppress its activity, thus the treatment cancer.
Kinase inhibitor compounds provided by the invention can be used for pharmaceutical composition, is used to suppress the kinase pathway of people, animal, bird, is used for the treatment of tumour and/or other diseases.Therefore, The compounds of this invention can be treated malignant tumour (as chronic myeloid leukemia, lung cancer, carcinoma of the pancreas, bladder cancer, colorectal carcinoma etc.).
Compound shown in the present has following common configuration.
1.R1 R2 and R3 can be:
(1) hydrogen or hydroxyl
(2) OR4, SR4 or R4
1) R4 can be:
Alkyl, thiazolinyl, alkynyl, cycloalkyl, alkyl naphthene, cycloalkenyl group, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl etc., the wherein Z1 that does not replace or replace.
2) Z1 can be:
Hydrogen or thiazolinyl, alkynyl, cycloalkyl, alkyl naphthene, cycloalkenyl group, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, hydroxyl, halogen, cyano group, nitro, SH, OR, SR, NHR, NRR '.
3) R and R ' can be:
Hydrogen or thiazolinyl, alkynyl, cycloalkyl, alkyl naphthene, cycloalkenyl group, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl.
2.A can be:
1)R4；
2)S，SO，SO2。
The invention still further relates to the salt that above-claimed cpd is pharmaceutically approved.Suitable pharmaceutically approval and also those skilled in the art were familiar with, comprise mineral acid and organic acid subsalt: example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate, lactic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, oxalic acid, fumaric acid, succsinic acid, toxilic acid, Whitfield's ointment, phenylformic acid, toluylic acid, amygdalic acid etc.; In addition, also comprise the acid salt of mineral alkali, as contain the salt of alkali metal cation, alkaline earth metal cation and ammonium cation, and the acid salt of organic bases, comprise by aliphatics and the ammonium of aromatic series replacement and the salt of quaternary ammonium cation.
The compounds of this invention can be prepared from by commercially available chemical feedstocks with known chemical reaction and process.The preparation method implements part at experiment embodiment and provides specific embodiment.
The compounds of this invention can give or with the administration of unit formulation formulation by oral, local, injection, suction, spraying or rectum, per os, skin, parenteral." drug administration by injection " comprises intravenous injection, intramuscular injection, and subcutaneous injection and parenteral injection, and use infusion techn.
The compounds of this invention can be made the known suitable pharmaceutical methods in field according to any drug regimen and prepare oral pharmaceutical.Can contain the auxiliary material of one or more screenings in the above-claimed cpd, comprise thinner, sweeting agent, seasonings, tinting material and sanitas.Contain activeconstituents in the tablet, they mix with pharmacy non-toxic excipients approval, that be suitable for tablet manufacturing.Described vehicle is an inert diluent, as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent (as W-Gum or alginic acid), tamanori (as Magnesium Stearate, stearic acid or talcum powder).Tablet can not have dressing, can carry out dressing by known technology yet, to postpone its disintegration and absorption in gi tract, so that secular lasting drug effect is provided.For example, can adopt as slow-release materials such as glyceryl monostearate or distearins.These compounds also can be made fast release solid formulation.
The compounds of this invention can be made different dosage form, as tablet, capsule, and suspensoid, powder, granule, non-aqueous liquid preparation and O/w emulsion.
Should be noted that, the concrete dosage level that particular patient needs is had nothing in common with each other, this depends on multiple factor, comprises the severity of activity, patient age, body weight, healthy state, sex, food habits, daily schedule, the mental status, the medicine velocity of discharge, drug regimen and the treatment disease of used particular compound.
The compounds of this invention can be by general preparation method's preparation of known compound, and following examples as an illustration.
Embodiment
Except as otherwise noted, all reactions all in the glassware of flame drying or oven drying, are carried out with magnetic agitation under the drying nitrogen environment.Sensitive liquid and solution add reaction vessel with injection or conduit by rubber skin plug.
All temperature of report be uncorrected degree centigrade (℃).Except that other have indicate, all shares and per-cent are all calculated by weight.
The commercial reagent and the solvent that use do not carry out secondarily purified.
Use prefabricated Whatman silica gel 60A GF254 thin layer of glass plate (250 μ m) to carry out thin-layer chromatography (TLC).Thin layer plate is inspected and can be adopted following a kind of or few techniques: 1) uviolizing, 2) put in the iodine vapor 3) spray is with 10% phospho-molybdic acid ethanol liquid, heating develops the color, and 4) spray with cerous sulfate solution the heating colour developing.Column chromatography uses 230-400 purpose EM Science silica gel G.
Fusing point (mp) measure to use Thomas-Hoover (the fusing point instrument of thomas-Hu Fo).Proton (1H) nucleus magnetic resonance (NMR) spectrum can adopt Varian 400 (400HZ) nuclear magnetic resonance analyser, detects for standard with Me4Si (δ 0.00ppm) or remaining protonic solvent (CHCl3, δ 7.2 δ ppm, MeOH δ 3.30ppm, DMSO δ 2.49ppm).Carbon (13C) nucleus magnetic resonance (NMR) spectrum can adopt Varian 400 (400Hz) nuclear magnetic resonance analyser, and (CDCl3 δ 77.0, MeOD δ 49.0, DMSO δ 39.5) detects as standard with solvent.Can obtain low resolution mass spectrum (MS) and high resolution mass spec (HRMS) with electron impact (EI) or fast atom bombardment MS (FAB).
The structure of all compounds is all passed through nuclear magnetic resonance spectrum (NMR), and mass spectrum (MS) is proved conclusively.
Above-claimed cpd is synthetic according to following reaction scheme.
Synthesis route is as follows:
(1) preparation of compound 2
The 200ml dichloromethane solution that will be dissolved with 2-chloro-6-monomethylaniline 25g (176.6mmol) is cooled to subzero 10 ℃, adds 28.6ml (353mmol) pyridine, adds 21.1ml (265mmol) chloroacetyl chloride (3a) after 10 minutes.Reaction mixture was raised to room temperature in 2 hours, add 1NHCl 500ml again, stirred 10 minutes.Tell organic phase, water dichloromethane extraction 2 times, each 300ml.Merge organic phase, use 1NHCl 400ml, water 400ml and salt solution 400ml washing.Sal epsom dehydrates, and filters, and concentrating under reduced pressure obtains the white solid (37.8g, yield 98%) of compound 2.
’H?NMR(500MHz，CDCl?3)62.28(s，3H)，4.25(s，2H)，7.14-7.18(m，2H)，7.26-7.31(m，IH)，8.02(bs，IH)。
(2) preparation of compound 3 (N-(2-chlorine 6-tolyl)-2-(three phenylaminos) thiazole-5-methane amide)
1.09g compound 2 (5mmol) and 1.87g compound 2a (5mmol) reflux 6 hours in 25ml ethanol.The mass spectrum proof forms compound 3.
(3) preparation of compound 4
Add 96% formic acid 5ml in last step reaction solution, backflow is spent the night.Add ethyl acetate 50ml, water 50ml, separate organic phase, concentrating under reduced pressure.Enriched material obtains 0.94g compound 4 (yield 70%) through column chromatography (20%-80% ethyl acetate/normal hexane).
(4) preparation of compound 5:(2-(6-chloro-2-methylpyrimidine-4-amino)-N-(2-chloro-6-tolyl) thiazole-5-methane amide
4.0g compound 4 (10.14mmol) and 4,6-two chloro-2-methylpyrimidine 3.65g (22.4mmol) are dissolved in the 65ml tetrahydrofuran (THF), and (21.1g, 65.36mmol), temperature remains on 10-20 ℃ slowly to add 30% sodium tert-butoxide tetrahydrofuran solution.Stirring reaction is 1.5 hours under the room temperature.Be cooled to 0-5 ℃; Slowly add 2N hydrochloric acid 21.5ml again, 0-5 ℃ was stirred 1.75 hours down.Filter, gained solid water 15ml washing, drying gets compound 5 (6.63g).
(5) preparation of compound 6
Compound 5 (0.2g, 0.51mmol) and piperazine (4.0 equivalent) be dissolved in the 2ml propyl carbinol, add diisopropyl ethyl amine (DIPEA, 2 equivalents), mixture is cooled to room temperature 120 ℃ of stirring reactions 5 hours, filters, and obtains compound 6 (0.2g).
(6) preparation of compound 7
444mg compound 6 (1.0mmol) and compound 7a (1 equivalent) are dissolved in the 5ml dimethyl sulfoxide (DMSO), react with triethylamine (1.2 equivalent) under the room temperature.Add ethyl acetate 50ml after 3 hours, enriched material obtains white solid compound 7 through silica gel column chromatography (methylene chloride/water).
(7) preparation of compound 8
444mg (1.0mmol) compound 6 and compound 8a (1.0 equivalent) are dissolved in the 5ml dimethyl sulfoxide (DMSO), react with triethylamine (1.2 equivalent) under the room temperature.Add ethyl acetate 50ml, water 10ml after 3 hours, standing demix, the organic phase enriched material obtains compound 8 through column chromatography purification.
(8) preparation of compound 9
Operation steps similar compound 7. compounds 6 (444mg) and 1 equivalent compound 9a are dissolved in the 5ml dimethyl sulfoxide (DMSO), in the 1.2 equivalent triethylamines reaction of room temperature and adding.Add ethyl acetate 50ml after 3 hours, the organic phase enriched material obtains compound 9 through column chromatography purification.
(9) preparation of compound 10
Operation steps similar compound 8.Compound 6 (444mg) and 1.0 equivalent compound 10a are dissolved in the 5ml dimethyl sulfoxide (DMSO), react with the 1.2 equivalent triethylamines that add under the room temperature.Add ethyl acetate 50ml, water 10ml after 3 hours, standing demix, the organic phase enriched material obtains compound 10 through column chromatography purification.
(10) preparation of compound 2a
The synthetic route of compound 2a is as follows:
1) preparation of compound 1a
In the 5000ml round-bottomed flask that has stirring and nitrogen charging device, add N-trityl ammonia 159g and 1600ml trichloromethane.Mixture is cooled to-2 ℃, slowly adds PhC (O) NCS 82.6ml.Mixture rose to room temperature gradually 0-5 ℃ of reaction 45 minutes after 3.5 hours.Concentrating under reduced pressure obtains the 1a crude product of yellow solid, 3 ℃ of standing over night, is used for the next step.
2) preparation of compound 2a
The 1a yellow solid is suspended in the mixing solutions of the 1600ml methyl alcohol that contains 248gNaOH (7.1mol) and 233ml water.Suspension stirred 2 hours 60 ℃ of reactions, concentrated, and obtained white solid; Add water 1500ml under the room temperature and stirred 35 minutes, suction filtration, the flushing of filter cake water, vacuum-drying obtains 193.8g white solid (yield in two steps is 99%).
Get 150g (471mmol) and place the 5000ml round-bottomed flask that has stirring and nitrogen charging device, add methyl alcohol 3000ml, dimethylformamide dimethyl acetal [(OMe)
2CHNMe
2] 80ml (600mmol), mixture stirring and refluxing 2 hours is cooled to room temperature.Suction filtration, the filter cake washed with methanol, drying obtains compound 2a white solid (157.9g, yield 90%).
Description of drawings
Accompanying drawing 1 is kinase whose inhibitor action principle.
Accompanying drawing 2 is resistance principles.
Accompanying drawing 3 is one group of synthesis technique figure that suppress the kinase whose phosphoric acid/phosphate compound of BCR-ABL.
Claims (3)
1, one group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL, and the compound shown in the invention of this group has following common configuration:
As: compound 1:
Compound 2:
Compound 3:
Compound 4:
2, the kinase whose phosphate/phosphate ester compounds of inhibition BCR-ABL according to claim 1, it is characterized in that also relating to the salt that this compound is pharmaceutically approved, comprise mineral acid and organic acid subsalt, described acid comprises: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate, lactic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, oxalic acid; In addition, also comprise the acid salt of mineral alkali, as contain the salt of alkali metal cation, alkaline earth metal cation and ammonium cation, and the acid salt of organic bases, comprise by aliphatics and the ammonium of aromatic series replacement and the salt of quaternary ammonium cation.
3, according to claim 1, the kinase whose phosphate/phosphate ester compounds of 2 described inhibition BCR-ABL, it is characterized in that this compound according to any drug regimen as oral, the injection of preparation treatment cancer and/or other diseases, the application of externally applied medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967142A (en) * | 2010-05-17 | 2011-02-09 | 苏州波锐生物医药科技有限公司 | Thiazoleamide compound and medical application thereof in treating malignant tumor |
| CN104151321A (en) * | 2013-05-15 | 2014-11-19 | 复旦大学 | N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
-
2008
- 2008-11-20 CN CNA200810160750XA patent/CN101591357A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967142A (en) * | 2010-05-17 | 2011-02-09 | 苏州波锐生物医药科技有限公司 | Thiazoleamide compound and medical application thereof in treating malignant tumor |
| CN101973989A (en) * | 2010-05-17 | 2011-02-16 | 苏州波锐生物医药科技有限公司 | Thiazole amide compound and medicinal application thereof for treating malignancy |
| CN101967142B (en) * | 2010-05-17 | 2012-05-30 | 苏州波锐生物医药科技有限公司 | Thiazoleamide compound and medical application thereof in treating malignant tumor |
| CN101973989B (en) * | 2010-05-17 | 2012-07-18 | 苏州波锐生物医药科技有限公司 | Thiazole amide compound and medicinal application thereof for treating malignancy |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN104151321A (en) * | 2013-05-15 | 2014-11-19 | 复旦大学 | N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof |
| CN104151321B (en) * | 2013-05-15 | 2016-09-07 | 复旦大学 | N-(2-chloro-6-aminomethyl phenyl)-2 [(2-methylpyrimidine-4-base) amino] thiazole-5-methanamide compound and its production and use |
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Open date: 20091202 |