CN101824029A - Tyrosine kinase irreversible inhibitor and medicine composition and application thereof - Google Patents
Tyrosine kinase irreversible inhibitor and medicine composition and application thereof Download PDFInfo
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- CN101824029A CN101824029A CN200910111213A CN200910111213A CN101824029A CN 101824029 A CN101824029 A CN 101824029A CN 200910111213 A CN200910111213 A CN 200910111213A CN 200910111213 A CN200910111213 A CN 200910111213A CN 101824029 A CN101824029 A CN 101824029A
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Abstract
The invention discloses a tyrosine kinase irreversible inhibitor shown in general formula (I), medicine composition thereof and application thereof in preparing medicine for treating or preventing cell proliferation turbulence.
Description
Technical field
The present invention relates to new compound, its medical composition and its use, relate to tyrosine kinase irreversible inhibitor, its pharmaceutical composition and the application in preparation treatment or prevention cell generation disorders medicine thereof especially.
Background technology
Cancer is a kind of disease of organizing improper growth that comes from, and certain cancers has the invasion local organization and is transferred to the tendency of organ at a distance.This disease can develop in many different organs, tissue and cell type.Therefore, this speech of cancer just is meant the summation of thousands of kinds of diseases of this class.
2002, have more than 440 ten thousand people to be diagnosed as mammary cancer, colorectal carcinoma, ovarian cancer, lung cancer or prostate cancer in the world, and more than 250 ten thousand people die from these diseases, only in the U.S., more than 125 ten thousand newly-increased cases are just arranged.These newly-increased cases mainly comprise colorectal carcinoma (～100,000 example), lung cancer (～170,000 example), mammary cancer (～210,000 example) and prostate cancer (～230,000 example).After following 10 years, the generation of cancer and popularly will increase by 15%, promptly average growth rate is 1.4% (American Cancer Society, the cancer fact and data, 2005).
According to the difference of therapeutic purpose, treatment for cancer can be divided into two big classes: cure and palliative treatment.Main curative therapy method is surgical operation and radiotherapy, the most general methods of treatment be with surgical operation and put, chemotherapy combined uses, these methods are only just effective when cancer is found in early days, in case disease progression is to late period or begin transfer, these methods of treatment just are difficult to obtain good effect, the purpose of treatment just becomes the life quality that is intended to relief of symptoms and obtains to get well, promptly in the palliative treatment.
In cancer therapy, cytotoxic drug is used for curative therapy or relief of symptoms prolongs life.Cytotoxic drug can be used as adjuvant therapy and (dwindles tumour with chemotherapy earlier with radiotherapy or/and surgical operation combines, so that local therapeutic approaches is more effective as operation and radiotherapy), perhaps as adjuvant chemotherapy (uniting use or use afterwards) with operation and/or topical therapeutic.It is more effective that different pharmaceutical is used in combination the independent medication of common ratio: they can improve the reactivity to some tumours, weaken the development of drug resistance and/or prolong lifetime.Just because of these reasons, cytotoxic drug unite use widespread usage in many treatment for cancer.
The cytotoxic drug of using utilizes different mechanism to block cell growth and cell death inducing at present, they can be divided into following a few class according to the mechanism of action difference: the polymerization of interference microtubule and the microtubule conditioning agent of depolymerization are (as docetaxel, paclitaxel, vinblastine, vinorelbine), metabolic antagonist, the blocker that comprises nucleoside analog and other key cells pathways metabolisms is (as capecitabine, gemcitabine, methotrexate), the anthracene nucleus class DNA intercalator that disturbs archaeal dna polymerase and type is (as doxorubicin, epirubicin) and the activity inhibitor of the type of non-anthracene nucleus class and I (as topotecan, irinotecan, and etoposide).Though the mechanism of action difference of differential cytotoxicity medicine, they can both cause temporary transient the dwindling of tumour.
Cytotoxic drug continues to play the part of important role in the weapon that the oncologist resists cancer.At present overwhelming majority's medicine of being in clinical II phase and the test of III phase all concentrates on the known mechanism of action (tubulin binding reagents, antimetabolic, DNA are synthetic) and concentrates in the improvement to the known drug classification (as taxanes or the camptothecins).At present, the medicine of minority based on new mechanism of action also appears.The mechanism of action of these cytotoxic drugs comprises: to the proteic inhibition (as histone deacetylase (HDAC)) of participation dna modification, to participating in albumen and the inhibition of cell generation cycle (as kinesins, aurora kinase) and the new apoptosis pathway elicitor (as bc1-2inhibitors) of microtubule based motor.
Though cytotoxic drug remains advanced solid tumor patient's first-line treatment medicine, usefulness that they are limited and narrow therapeutic index can cause significant side effects.In addition, the fundamental research of cancer excites the research of people to the littler treatment of toxicity, this research is based on the special mechanism of tumor proliferation, thereby produced a class and be called as the new medicine of agent that cell suppresses, this class medicine directly acts on tumour cell, little to normal cellulotoxic side effect, can improve the tumour patient life quality.The development of these medicines has benefited from determining that the particular inheritance relevant with cancer proliferation changes, and the proteinic understanding to being activated in the cancer, and this proteinoid has Tyrosylprotein kinase and serine/threonine kinases or the like.
Except the direct inhibition to the tumour target cell, cytostatics is just being developed into the medicine of blocking-up tumor-blood-vessel growth process.The process of tumor-blood-vessel growth can provide the nutrition of the existing and new blood vessel of tumour to support that it continues, and therefore helps to promote growth of tumor.Crucial tyrosine kinase receptor comprises that VEGFR2, FGFR1 and Tie2 have proved can regulate vasculogenesis, and becomes highly tempting drug target.
Some directly go through as treatment for cancer in 5 years in the past at the new drug of differing molecular target spot.Imatinib is the inhibitor of Ab1 Tyrosylprotein kinase, and is first small molecules Tyrosylprotein kinase that is approved for the CML treatment.Because Imatinib has another activity, promptly tyrosine kinase receptor c-the KIT that can suppress to be activated is approved for the treatment in late period as GIST thereupon.Erlotinib, a kind of small molecules EGFR inhibitor was approved for the treatment of nonsmall-cell lung cancer in 2004.Sorafenib is a kind of multiple kinases inhibitor of (comprising c-Raf and VEGFR2), and it is approved for the treatment of renal cell carcinoma in late period in December, 2005.At present, Sunitinib, Dasatinib and Lapatinib also are approved for the treatment of various cancers.The application note of these micromolecular inhibitors targeted therapy in the dissimilar cancer of treatment, be successful.
Summary of the invention
The object of the present invention is to provide a class to have the tyrosine kinase irreversible inhibitor of pharmaceutical use.
Another object of the present invention provides a kind of pharmaceutical composition that can be used for treating or preventing cell generation disorders.
A further object of the present invention provides a kind of above-claimed cpd and the purposes of composition in pharmacy.
In order to reach above-mentioned purpose, solution of the present invention is:
The tyrosine kinase irreversible inhibitor of general formula (I):
Or it is at available salt pharmaceutically, wherein,
X represents N or C-CN;
M represents 0,1 or 2;
N represents 1,2 or 3;
Q represents 0 or 1;
R
1Expression H, C
1-4Alkyl or halogen;
R
2From following group, filter out: H ,-CN, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl or C
2-4Alkynyl;
R
3From following group, select: H, halogen ,-CN, C
1-4Alkyl, ethynyl, propargyl or *-O (CH
2)
pAr, wherein p represents 0,1 or 2, and Ar represents phenyl, pyridyl, thiazolyl or pyrazinyl, and wherein Ar optionally carries 1～2 and is selected from halogen or C
1-4The substituting group of alkyl;
R
2And R
3Can combine, condensing together with the carbon atom that is connected them forms 5 yuan or 6 yuan the saturated or unsaturated ring that merges, and perhaps forms the heterocycle that merges, wherein bonded R
2And R
3Group is represented with following formula:
Wherein Ar ' and Ar " represent benzene, pyridyl, thiazolyl or pyrazinyl, wherein Ar and Ar independently of one another " optionally carry 1～2 and be selected from halogen or C
1-4The substituting group of alkyl;
R
4From following group, screen: H ,-CN, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl or C
2-4Alkynyl;
R
5Expression H or halogen;
R
6From following group, screen: H ,-CN, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group ,-O-C
1-6Cycloalkyne ,-O-C
1-6Heterocycle, wherein said alkoxyl group, cycloalkyne or heterocyclic group optionally carry 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
7From following group, screen: H or C
1-6Alkyl, wherein said alkyl optionally carries 1 or 2 hydroxyl, C
1-6Alkyl, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
8Expression halogen, hydroxyl or C
1-4Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkyl, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
Preferably, m is 0.
Further preferably, n is 1.
Still more preferably, q is 0.
In some particular cases, R
1Be H or fluorine; R
2Can be hydrogen, cyano group, halogen, C
1-4Alkyl or C
2-4Alkynyl; R
3Can be hydrogen, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen atom replaces; R
4Can be hydrogen, cyano group or halogen; R
5Be H; R
6Can be hydrogen, cyano group, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group ,-O-C
1-6Cycloalkyl or-O-C
1-6The heteroatomic ring alkyl, wherein said alkoxyl group, cycloalkyl or heteroatomic ring alkyl optionally carry 1 or 2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2R
7Can be hydrogen or C
1-6Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
In some particular cases, R
1Be H; R
2Can be hydrogen, halogen or ethynyl; R
3Can be hydrogen, cyano group, halogen, methyl or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar can be phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces; R
4Can be hydrogen, halogen or C
1-4Alkyl; R
5Be H; R
6Can be hydrogen, cyano group, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, O-C
1-6Cycloalkyl or O-C
1-6The heteroatomic ring alkyl, wherein said alkoxyl group, cycloalkyl or heteroatomic ring alkyl optionally carry 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2R
7Can be H or C
1-6Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
In some particular cases, R
2It is halogen; R
3Can be hydrogen, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces.
In some particular cases, R
3It is halogen.
In some particular cases, R
2It is ethynyl; R
3Can be hydrogen atom, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces; R
4Be H.
As the preferred compound of general formula (I) institute, can be listed below:
R wherein
6Group be methoxyl group, oxyethyl group,
Or
When compound of the present invention imposes on the human and animal as medicine, they can self or the hydrated form that is fit to as the mode administration of drug component.The invention provides the pharmaceutical composition that is used for the treatment of or prevents cell generation disorders, comprise the above-mentioned tyrosine kinase irreversible inhibitor for the treatment of significant quantity and available carrier pharmaceutically, its formulation can be said any formulation on the pharmaceutics, includes but not limited to oral preparation, solution, inhalation, sustained release preparation or controlled release preparation.
It is 0.1%～99.5% tyrosine kinase irreversible inhibitor that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5%～90% tyrosine kinase irreversible inhibitor.
Tyrosine kinase irreversible inhibitor of the present invention can be used for preparation treatment or prevention cell generation disorders medicine.
Tyrosine kinase irreversible inhibitor of the present invention can be used for preparation treatment or preventing cancer medicine.
Effective antiproliferative dosage is gone up in the pharmaceutically effective antiproliferative dosage of The compounds of this invention or prevention can be at an easy rate by experienced doctor or animal doctor's decision, perhaps the result who observes under the similar environment with currently known methods decides, and dosage can be according to the clinician to the difference of the judgement of patients ' demand, the seriousness of being treated situation and used different compounds and different.On the decision medicine in antiproliferative effective dose and the prevention during antiproliferative effective dose, the clinician will consider many factors, it is unusual to include but are not limited to the cell proliferation that relates to, the drug effect characteristic and the route of administration of specific drugs, required treatment time, mammiferous kind, size, age and healthy state roughly, related special disease, the degree of disease and seriousness, mode of administration, bioavailability, dosage, the methods of treatment of Shi Yonging (interacting) and other correlation circumstances simultaneously as the common therapy of using of medicine of the present invention and other.Treatment initially can be adopted and is lower than the suitableeest dosage of compound, and escalated dose a little afterwards is up to optimum response occurring.
The amount of application of tyrosine kinase irreversible inhibitor provided by the invention can adjust accordingly according to route of administration, patient age, body weight, the disease type of being treated and severity, its per daily dose can be 0.01～10mg/kg body weight, preferred 0.1～5mg/kg body weight, for simplicity, daylong dosage can be divided into distinct portions and apply, and adopts once-a-day or administering mode administration repeatedly on the one.
Under some particular case, compound of the present invention can be in conjunction with traditional cancer treatment method such as chemotherapy or radiotherapy combination therapy.
The preparation of compound can be undertaken by following scheme among the present invention:
1, the synthetic schemes the first step:
2, second step of synthetic schemes:
Need to prove that the starting material of synthetic compound are that commercial method ready-made or available existing standard prepares, these methods comprise but are not limited only to listed method for transformation here.
If do not point out in addition, reaction is carried out in the organic solvent of non-activity usually, these organic solvents can not change under reaction conditions, comprise that ether is (as ether, 1,4-dioxane or tetrahydrofuran (THF)), halohydrocarbon is (as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, trichloroethane or tetrachloroethane), hydro carbons (as benzene,toluene,xylene, hexane, hexanaphthene or petroleum fractions), alcohols (as methyl alcohol, ethanol or Virahol), Nitromethane 99Min., diformamide or acetonitrile, also available mixed solvent.
These reactions are carried out in 0 ℃～150 ℃ scopes usually, preferably carry out in 0 ℃～70 ℃ scopes.Reaction can be carried out in atmosphere, perhaps carries out (as 0.5～5bar), carrying out in the atmosphere that is lower than an atmospheric rare gas element (as nitrogen) usually in being higher or lower than an atmospheric pressure.
Unless otherwise indicated, the definition of following technical term runs through this specification sheets and statement all the time.
Salt: the salt in the expression The compounds of this invention is meant pharmaceutically available salt.Can be with reference to S.M.Berge, et al. " Pharmaceutical Salts, " J.Pharm.Sci.1977,66,1-19.
Pharmaceutically available salt comprises the acid-salt of following several acid: mineral acid, carboxylic acid or sulfonic acid, and such as the salt of following several acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthene sulfonic acid, acetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid (FUMARIC ACID TECH GRADE), toxilic acid (maleic acid) or phenylformic acid.
Pharmaceutically available salt also comprises the salt of common group, such as an alkali metal salt (as sodium salt, sylvite, calcium salt or magnesium salts), ammonia salt or organic amine salt, wherein said organic amine has 1～16 carbon atom, such as ethamine, diethylamine, triethylamine, diisopropyl ethyl amine, thanomin, diethanolamine, trolamine, dicyclohexylamine, diethylaminoethanol, PROCAINE HCL, PHARMA GRADE, company's benzyl amine, N-methylmorpholine, dihydro abietyl amine, arginine, Methionin, quadrol or methyl piperidine.
C
1-6Alkyl and C
1-4Alkyl is represented the straight or branched alkyl group, as methyl, ethyl, n-propyl, sec.-propyl, the tertiary butyl, n-pentyl or n-hexyl etc.
Alkylamino, the amino of 1 or 2 alkyl substituent is carried in expression, as methylamino-, ethylamino, n-propylamine base, isopropylamino, uncle's fourth amino, pentylamine base, just own amino, N, N-dimethylamino, N, N-diethylin, N-ethyl-N-methylamino-, N-methyl-N-n-propylamine base, N-sec.-propyl-N-n-propylamine base, the N-tertiary butyl-N-methylamino-, N-ethyl-N-pentylamine base or N-n-hexyl-N-methylamino-.NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2The expression alkylamino has 1 or 2 C
1-4Alkyl substituent.
Halogen is represented fluorine, chlorine, bromine or iodine.
* represent bonded site in the molecule.
Pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, include but not limited to weighting agent, disintegrating agent, tackiness agent, wetting agent, lubricant, solvent, solubilizing agent, solubility promoter, emulsifying agent and pH regulator agent, described weighting agent comprises starch, dextrin, lactose, sucrose, Icing Sugar, Microcrystalline Cellulose, glucose, meglumine, glucosamine, N.F,USP MANNITOL, calcium sulfate, calcium bisulfate; Disintegrating agent comprises hydroxypropylcellulose, sodium starch glycolate, polyvinylpolypyrrolidone, croscarmellose sodium, crosslinked HPMC; Tackiness agent comprises HPMC sodium, polyvidone; Wetting agent comprises water, ethanol; Lubricant comprises Magnesium Stearate, talcum powder; Described solvent comprises water, glycerine, ethanol, polyoxyethylene glycol, fatty oil, whiteruss; Solubilizing agent comprises the polyvinyl ether Viscotrol C, tween, pluronic F-68; Solubility promoter comprises arginine, Methionin, meglumine, glucosamine, diethylamine, quadrol, urea, carnitine, Ligustrazine, niacinamide, proline(Pro), glucose, Citric Acid and sodium salt thereof; Isotonic regulator comprises glucose, sodium-chlor; The pH regulator agent comprises arginine, Methionin, meglumine, glucosamine, diethylamine, quadrol, and various mineral acids, alkali and organic acid, alkali and damping fluid thereof.
This vocabulary of cell generation disorders shows not to be wished to have or out of contior cell generation disorders, this disorder comprises but is not limited only to tumour or cancer, (as brains, lung (minicell or non-small cell)), ovarian cancer, prostate cancer, mammary cancer, colorectal cancer or other cancers or sarcoma (as leukemia and lymphoma).Under some particular cases, cell generation disorders is exactly a cancer.
Embodiment
The tumor cell proliferation testing apparatus that is used for measuring The compounds of this invention comprises a Cell that is called by the exploitation of Promega company
The reading device of Luminescent Cell Viability Assay, it can measure the restraining effect of on cell proliferation.The generation of fluorescent signal is relevant with the amount of ATP, and ATP directly indicates the quantity of viable cell.
Embodiment 1
Embodiment 1 has investigated the tumor cell in vitro proliferation test of A431 and N87 clone.
A431 (people's epithelial cancer, ATCC#HTB-20 cross expression HER1) and N87 (people's cancer of the stomach, ATCC#CRL-1555 cross expression HER2 and HER1) are with 2.5x10
3The density of individual cells/well is seeded in the 96 hole tissue culturing plates, cultivates down at 37 ℃ with the RPMI substratum that contains 10%FBS.After 24 hours, testing drug adds with the final concentration of 100 μ M-64pM, and add-on depends on the activity (DMSO final concentration be 0.1%) of tested medicine in serial solvent.After the dosing cell at 37 ℃ down with complete culture medium culturing 72 hours.After 72 hours the drug treating, culture plate is placed on the about 30min of balance under the room temperature, handle with the Promega test kit then, in every hole, add dissolving damping fluid, the fluorescein mixture that contains 100 μ L luciferases and its substrate, culture plate mixes 2min on vibrator so that cytolysis is at room temperature hatched 10min so that fluorescent signal is stable.Sample is read on VICTOR2 with the method for fluorescence, analyzes IC with Analyze5 software then
50Value.
The result shows that testing drug shows IC in A431 or N87 clone
50The antiproliferative activity of≤50 μ M.
Embodiment 2
Present embodiment has been investigated the test of H1975 cells in vitro tumor cell proliferation.
H1975 cell (human non-small cell lung cancer, ATCC#CRL-5908, the HER1 that expresses sudden change) is with 3x10
3The density of individual cells/well is seeded in the 96 hole tissue culturing plates, cultivates down at 37 ℃ with the RPMI substratum that contains 10%FBS.After 24 hours, testing drug adds with the final concentration of 100 μ M-64pM, and add-on depends on the activity (DMSO final concentration be 0.1%) of tested medicine in serial solvent.After the dosing cell at 37 ℃ down with complete culture medium culturing 72 hours.After 72 hours the drug treating, culture plate is placed on the about 30min of balance under the room temperature, handle with the Promega test kit then, in every hole, add dissolving damping fluid, the fluorescein mixture that contains 100 μ L luciferases and its substrate, culture plate mixes 2min on vibrator so that cytolysis is at room temperature hatched 10min so that fluorescent signal is stable.Sample is read on VICTOR2 with the method for fluorescence, analyzes IC with Analyze5 software then
50Value.
The result shows that testing drug shows antiproliferative activity in H1975 clone.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. the tyrosine kinase irreversible inhibitor of general formula (I):
Or it is at available salt pharmaceutically, wherein,
X represents N or C-CN;
M represents 0,1 or 2;
N represents 1,2 or 3;
Q represents 0 or 1;
R
1Expression H, C
1-4Alkyl or halogen;
R
2From following group, filter out: H ,-CN, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl or C
2-4Alkynyl;
R
3From following group, select: H, halogen ,-CN, C
1-4Alkyl, ethynyl, propargyl or *-O (CH
2)
pAr, wherein p represents 0,1 or 2, and Ar represents phenyl, pyridyl, thiazolyl or pyrazinyl, and wherein Ar optionally carries 1～2 and is selected from halogen or C
1-4The substituting group of alkyl;
R
2And R
3Can combine, condensing together with the carbon atom that is connected them forms 5 yuan or 6 yuan the saturated or unsaturated ring that merges, and perhaps forms the heterocycle that merges, wherein bonded R
2And R
3Group is represented with following formula:
Wherein Ar ' and Ar " represent benzene, pyridyl, thiazolyl or pyrazinyl, wherein Ar and Ar independently of one another " optionally carry 1～2 and be selected from halogen or C
1-4The substituting group of alkyl;
R
4From following group, screen: H ,-CN, halogen, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl or C
2-4Alkynyl;
R
5Expression H or halogen;
R
6From following group, screen: H ,-CN, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group ,-O-C
1-6Cycloalkyne ,-O-C
1-6Heterocycle, wherein said alkoxyl group, cycloalkyne or heterocyclic group optionally carry 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
7From following group, screen: H or C
1-6Alkyl, wherein said alkyl optionally carries 1 or 2 hydroxyl, C
1-6Alkyl, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
8Expression halogen, hydroxyl or C
1-4Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkyl, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
2. according to the tyrosine kinase irreversible inhibitor described in the claim 1, it is characterized in that: m is 0, and n is 1, and q is 0.
3. according to the tyrosine kinase irreversible inhibitor described in the claim 1, it is characterized in that:
R
1Be H or fluorine;
R
2Be hydrogen, cyano group, halogen, C
1-4Alkyl or C
2-4Alkynyl;
R
3Be hydrogen, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen atom replaces;
R
4Be hydrogen, cyano group or halogen;
R
5Be H;
R
6Be hydrogen, cyano group, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group ,-O-C
1-6Cycloalkyl or-O-C
1-6The heteroatomic ring alkyl, wherein said alkoxyl group, cycloalkyl or heteroatomic ring alkyl optionally carry 1 or 2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
7Be hydrogen or C
1-6Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
4. according to the tyrosine kinase irreversible inhibitor described in the claim 1, it is characterized in that:
R
1Be H;
R
2Be hydrogen, halogen or ethynyl;
R
3Be hydrogen, cyano group, halogen, methyl or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces;
R
4Be hydrogen, halogen or C
1-4Alkyl;
R
5Be H;
R
6Be hydrogen, cyano group, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, O-C
1-6Cycloalkyl or O-C
1-6The heteroatomic ring alkyl, wherein said alkoxyl group, cycloalkyl or heteroatomic ring alkyl optionally carry 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
R
7Be H or C
1-6Alkyl, wherein said alkyl optionally carries 1～2 hydroxyl, C
1-6Alkoxyl group, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
5. according to the tyrosine kinase irreversible inhibitor described in the claim 1, it is characterized in that:
R
2It is halogen;
R
3From following group, select: hydrogen, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces.
6. according to the tyrosine kinase irreversible inhibitor described in the claim 4, it is characterized in that:
R
2It is ethynyl;
R
3From following group, select: hydrogen atom, halogen or *-O (CH
2)
pAr, wherein p is 0 or 1, Ar is phenyl, pyridyl, pyrazinyl or 1～2 phenyl, pyridyl or pyrazinyl that halogen replaces;
R
4Be H.
7. according to the tyrosine kinase irreversible inhibitor described in the claim 1, this compound is selected from following component:
R wherein
6Group be methoxyl group, oxyethyl group,
Or
8. be used for the treatment of or prevent the pharmaceutical composition of cell generation disorders, comprise claim 1 tyrosine kinase irreversible inhibitor for the treatment of significant quantity and available carrier pharmaceutically.
9. any one tyrosine kinase irreversible inhibitor application in preparation treatment or prevention cell generation disorders medicine in the claim 1～7.
10. any one tyrosine kinase irreversible inhibitor application in preparation treatment or preventing cancer medicine in the claim 1～7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910111213A CN101824029A (en) | 2009-03-05 | 2009-03-05 | Tyrosine kinase irreversible inhibitor and medicine composition and application thereof |
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