CN1362409A - 2-phenoxy pyrimidine derivative and its use in treating disease - Google Patents
2-phenoxy pyrimidine derivative and its use in treating disease Download PDFInfo
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Abstract
The present invention discloses a kind of 2-phenoxypyrimidine derivative. Said compound is inhibitor of protein kinase and its modified form, which can be used for curing and preventing prolifierative diseases and drug-resistance diseases, such as cancers and inflammations, also can be used for curing neurodegeneration diseases, such as senile dementia, angiocardiopathy and viral infection, etc..
Description
Technical field
The present invention relates to a class 2-phenoxy pyrimidine derivates, its salt and medicinal precursor, this compounds has the active effect of arrestin kinases and modification thereof, can be used for treatment and prevention proliferative disease such as cancer and inflammation class disease, also can be used for treatment and prevention neural deterioration disease such as senile dementia, cardiovascular disorder, virus infection and fungal infection etc. simultaneously.
Background technology
Protein kinase is the enzyme of phosphorylation on the hydroxyl of tyrosine, Serine and the Threonine of a class in protein.This simple biochemical reaction relates to the comings and goings of cell, comprises growth, division and hyperplasia.In a sense, the activity influence of protein kinase each link in the cell cycle activity.Simultaneously, abnormal protein kinase activity and various types of disease (from common psoriasis to fatal meninx cancer) all have close contact.
Protein kinase is divided into tyrosine protein kinase and serine/threonine protein kitase two big classes usually.
In protein kinase, people generally believe that tyrosine protein kinase plays important effect in many cell functions, particularly participate in the transmission of cell signal.Though detailed and accurate mechanism of action is also uncertain, great deal of research results proof tyrosine protein kinase is being played the part of indispensable key player in proliferation of cells, canceration and fission process.
Tyrosine protein kinase is divided into acceptor class and non-acceptor class two big classifications again.Acceptor class tyrosine protein kinase is made up of three parts in extracellular, transmembrane and the cell usually, but not acceptor class tyrosine protein kinase is then fully in cell.
Acceptor class tyrosine protein kinase contains the acceptor with different bioactive a large amount of and different transmembranes.So far, according to the feature of acceptor portion, the acceptor class tyrosine protein kinase of existing about 20 families is found and differentiates.Wherein, the HER subtribe comprises EGFR, HER2, HER3 and HER4, comprises Urogastron, TGF-β, cell membrane nuclear mould matter, HB-EGF etc. with the aglucon of the receptors bind of this subtribe.Another subtribe is the tyrosine protein kinase relevant with insulin receptor, comprises INS-R, IGF-IR and IR-R.The PDGF subtribe then is made up of PDGFR α, PDGFR β, CSFIR, C-kit and FLK-II.Also have a class FLK subtribe, it comprises KDR, FLK-1, FLK-4 and Flt-1.Because the similarity on the 26S Proteasome Structure and Function, people return PDGF to draw with FLK two subtribes usually and are in the same place.Elaborating of relevant acceptor class tyrosine protein kinase can be consulted Madhani, and 2001, Cell; 106 (1): 9-11.
Non-acceptor class tyrosine protein kinase also has multiple subtribe, as Abl, Src, Frk, Btk, Csk, ZAP70, FES/FPS, Fak, Jak, Ark and LIMK.Each subtribe also can further be divided into different subtribes.For example, Src is one of maximum subtribe, and it comprises Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.This subtribe is extensively thought to form closely related with tumour.Elaborating of relevant non-acceptor class tyrosine protein kinase can be consulted Adjei, and 2001, Curr Pharm Des; 7 (16): 1581-1594.
No matter be that the acceptor class also is non-acceptor class, thereby these tyrosine protein kinase are through participating in the information exchanging process and multiple disease-relateds such as cancer, neural function decline, psoriasis and immunologic dysfunction of cell.
Bone marrow stem cell class disease such as chronic medullary cell type leukemia are directly related in the increased activity of tyrosine protein kinase such as Abl and the blood.
The formation of malignant tumour has close getting in touch in the active unusual and human body of tyrosine protein kinase such as c-erB-2, c-Src, EGF-R, PDGF-R and ZAP70 etc.For example, the EGF-R increased activity causes the incidence cancer, and the high reactivity of c-erB-2 is relevant with mammary cancer, ovarian cancer, carcinoma of the pancreas, nonsmall-cell lung cancer and colorectal carcinoma, or the like.Therefore, the inhibitor of tyrosine protein kinase can be used for treating above-mentioned tumor disease.
In addition, protein tyrosine kinase activity is unusually also relevant with other a series of diseases in the body, as psoriasis (Dvir et al, 1991, J Cell Biol; 113:857-865), narrow down (Buchdanger et al, 1992, Proc Natl Acad Sci USA of fibrosis, atherosclerosis and heart lobe; 92:2258-2262), rejection (Klausneret al, 1991, the Cell when autonomous Immunological diseases, allergy, asthma and organ transplantation; 64:875-878), inflammation (Berkois, 1992, Blood; 79 (9): 2246-2254), thrombosis (Salari et al, 1990, FEBS Lett; 263 (1): 104-108) and nervous system disorders (Ohmichi et al, 1992, Biochemistry; 31:4034-4039).
The kinases inhibitor of participate in regulating and slowing down above-mentioned morbid state is being represented the fresh approach and the trend for the treatment of these diseases.The example of the kinases inhibitor of at present existing many therepic use below is some examples wherein.(1) suppresses Src, Raf and CDK and be used for the treatment of cancer (Martin, 2001, Nature Rev Mol Cell Biol; 2 (6): 467-475; Rowinsky et al, 1999, J ClinOncol; 17 (11): 3631-3652; Malumbres et al, 2000, Biol Chem 381 (9-10): 827-838); (2) suppress CDK-2 or RDGF-R and be used for the treatment of heart lobe narrow down (Buchdanger et al, 1995, Clin Cancer Res; 1 (8): 813-821); (3) suppress CDK-5 and GSK-3 and be used for the treatment of senile dementia (Aplin et al, 1996, J Neurochem; 67 (2): 699-707); (4) suppress c-Src and be used for the treatment of osteoporosis (Schmidt et al, 1996, Proc Natl Acad Sci USA; 93 (7): 3068-3073); (5) suppress GSK-3 and be used for the treatment of type ii diabetes (Frame et al, 2001, Mol Cell; 7 (6): 1321-1327); (6) suppress P38 and be used for the treatment of inflammation (Wang et al, 2000, J Immunol; 166 (11): 6877-6884); (7) suppress VEGFR-1-3 and TIE-1,2 are used for the treatment of revascularization disease (Hattori et al, 2001, J Exp Med; 193 (9): 1005-1014); (8) suppress uL97 and be used for the treatment of virus infection (Mendez et al, 1999, Transplantation; 67 (5): 755-757); (9) suppress CSF-1R and be used for the treatment of sclerotin disease (Hajiwaro et al, 2001, Int J Hematol; 73 (1): 100-107); (10) suppress Lck and be used for the treatment of autonomous immunological disease (Kanner et al, 1995, J Immunol; 154 (6): 2996-3005) suppress Abl and be used for the treatment of chronic medullary cell type leukemia (Zimmermann et al, 1997, Bioorg Med Chem Lett with (11); 7 (2): 187-192), yet bring unexpected resistance (Gorre et al, 2001, Science simultaneously; 293 (5531): 876-880).
United States Patent (USP) 5,302,739, people (Jojima et al, 1966, Agr Biol Chem such as United States Patent (USP) 4,770,691, United States Patent (USP) 4,427,437 and Jojima; 30 (9): 896-905) disclose a series of 2-phenoxy pyrimidine compounds with the effect of cutting weeds.Recently, people such as Boehm (Boehm et al, 2001, Bioorg Med Chem Lett; 11 (21): 1123-1126) also delivered a class and had the phenoxy pyrimidine derivates that suppresses the P38 alpha active.But the main chemical structure characteristic of these compounds of coming into the open and their effect and purposes and the present invention are irrelevant.
2-phenoxy pyrimidine derivates involved in the present invention is to have optionally effective inhibitor of tyrosine protein kinase, their main effect is to bring into play by the activity that suppresses tyrosine protein kinase, thereby optionally eliminates or reduce specific diseased tissue.The main tyrosine protein kinase that this compounds suppressed has Abl, P38 β, PDGF-R, C-kit etc.Certainly, can not get rid of the possibility that this compounds suppresses the protein kinase of other and disease-related.
Summary of the invention
One of purpose of the present invention provides a class special, efficient and oral administration or drug administration by injection compounds effective, and the activity of the tyrosine protein kinase that they can be by suppressing to participate in the transmission of cell information is treated blood of human body class disease, solid kind malignancy disease and other cell hyperplastic disease.
Another object of the present invention provides a class novel cpd and is used for the treatment of existing medicine is produced chemical sproof disease such as chronic medullary cell type leukemia, gi tract adhesive tumour and meninx cancer, they can by suppress or stop tyrosine protein kinase modification and to anti-drug resistance.
Blood of human body class disease described in the foregoing invention purpose is the neoplastic hematologic disorder of lymphocytic type and medullary cell type, and they comprise acute lymphoblastic type leukemia, acute original lymphocytic leukemia, type B cell lymphoma, T type cell lymphoma, He Jiejin lymphomas, non_hodgkin lymphoma, trichoblast lymphoma, Burkett lymphomas, acute medullary cell type leukemia, chronic medullary cell type leukemia, hypoplastic bone marrow disease and promyelocyte type leukemia;
The happening part of described solid kind malignancy disease is that one or more exist simultaneously, and they are positions such as mammary gland, ovary, colon, lung, brain, bone, respiratory tract, stomach, pancreas, prostate gland, liver, courage, throat, bladder, uterus, skin;
Described other cell hyperplastic disease comprises that vascular proliferative disease such as sacroiliitis and heart lobe narrow down, the rejection when fibroproliferative disease such as liver cirrhosis and atherosclerosis and messangial cell proliferative disease such as glomerulonephritis, glycosuria nephritis, chronic renal sclerosis and organ transplantation.These compounds can be used for also treating that metabolic disease such as psoriasis, chronic wounds fester, inflammation and neural deterioration disease such as senile dementia.
For achieving the above object, the technical solution used in the present invention is: a kind of 2-phenoxy pyrimidine derivates, it is to contain the compound of following chemical structure of general formula or its salt, can be used for the treatment of and prevents various human body proliferative diseases and other disease by the kinase whose activity of arrestin
Wherein,
X be oxygen, sulphur, secondary amino (NH-) or carbonyl
Y is a carbonyl
, oxygen, sulphur or secondary amino (NH-);
R
1, R
2, R
3, R
5, R
6, R
7, R
8Be hydrogen, halogen, alkyl, aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, the assorted alkyl of ring-type or the assorted alkanisation alkyl of ring-type;
R
4Be hydrogen, halogen, hydroxyl, alkoxyl group or the alkyl that contains 1-6 carbon atom;
R
9Be selected from hydrogen, oxygen, sulphur, methyne (CH
2-), secondary amino (NH-), alkyl or-Z-R
10
Wherein Z represents oxygen, sulphur, methyne (CH
2-), secondary amino (NH-) or alkyl;
R
10Be aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, hydrogen or halogen, alkyl, the assorted alkyl of ring-type, the assorted alkanisation alkyl of ring-type.
In the technique scheme, the heteroatoms that has free bond valence all is by the hydrogen atom combination, and " heteroatoms " wherein refers to oxygen (O), nitrogen (N) and sulphur (S) atom;
Described " halogen " is meant fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) atom;
Described alkyl is meant the unit price alkane that contains 1-12 carbon atom, can be straight chain, bifurcated or ring-type, comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, octyl group etc.;
Described " cycloalkyl " is meant a class ring-type and contains 3-15 carbon atom but do not have the alkyl of conjugated double bond, they can contain 1-4 ring, the example of unsubstituted has cyclopropane base, tetramethylene base, pentamethylene base, cyclohexane base etc., and substituting group then refers to contain one or more following groups: halogen, alkyl, alkoxyl group, hydroxyl, amino, nitro, cyano group, sulfenyl etc.;
Described " aryl " is meant the aromatic nucleus of monocycle or dicyclo, as phenyl, the group that substituent phenyl and thick shape are arranged such as naphthyl, phenanthryl etc., aryl contains at least one six-ring, and may be that 1-5 six-ring is connected, have between carbon and carbon atom between the ring that links to each other or form between carbon and heteroatoms conjugated double bond, in addition, may there be substituted radicals such as halogen, alkyl, alkoxyl group, hydroxyl, amino, nitro, carboxyl, acyl group, cyano group, sulfenyl on the aryl;
Described " fragrant heterocyclic radical " is meant in the dicyclo of five yuan or the single aromatic nucleus of hexavalent or 8 yuan or 10 yuan and contains at least one heteroatoms, wherein, nitrogen-atoms can a plurality ofly coexist, also may and deposit with oxygen or sulphur atom, the example of fragrant heterocyclic radical has thienyl, furyl, pyridyl, pyrryl, imidazolyl, piperidyl, thiazolyl, pyrazolyl, triazolyl isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidyl, triazine azepine base, indyl, pseudoindoyl, quinolyl, isoquinolyl etc., also may there be different substituting groups on these rings, as halogen, alkyl, alkoxyl group, hydroxyl, cycloalkyl, nitro, amino, sulfenyl etc.;
Described " ring-type mix alkyl " is 1-3 carbon atom in the finger ring cyclic alkyl after by the heteroatoms displacement, piperazinyl etc. for example, also may exist on the ring as substituted radicals such as halogen, alkyl, alkoxyl group, hydroxyl, cycloalkyl, nitro, amino, sulfenyls, in addition, when heteroatoms is sulphur, may be sulfone or sulfoxide, when being nitrogen as if heteroatoms, might be quaternary nitrogen.
In the technique scheme, compound commonly used is described R
2, R
3, R
5, R
6, R
7Be hydrogen; Described R
9For-Z-R
10, wherein Z represents oxygen, sulphur, methyne (CH
2-), secondary amino (NH-) or alkyl; R
10Be aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, hydrogen or halogen, alkyl, the assorted alkyl of ring-type, the assorted alkanisation alkyl of ring-type.
Except that the compound that the present invention directly describes, also in protection scope of the present invention, the medicinal salt that the present invention relates to compound comprises and mineral acid, organic acid or mineral alkali, the formed various salt of organic bases the medicinal salt of these compounds.
The example of acid-salt has acetate, adipic acid salt, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, the camphor iodate, cyclopentyl propionate, two gluconates, dodecane sulfonate, metilsulfate, ethyl sulfonate, formate, fumarate, gluceptate, glycerophosphate, glycollate,-sulfinate, enanthate, caproate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyethyl sulfonate, lactic acid salt, malate, malonate, naphthalenesulfonate, the Nicotine hydrochlorate, nitrate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, isopropyl acid salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecane hydrochlorate; The example of basic salt then has basic metal (as sodium, potassium) salt, alkaline divalent metal (as magnesium) salt, ammonia salt and contains the alkylamine salt of 1-4 carbon atom.
Above-mentioned 2-phenoxy pyrimidine derivates of the present invention, its salt or medicinal precursor can with can be as medicinal carrier combinations patent medicine preparation.
Described 2-phenoxy pyrimidine derivates, its salt or medicinal precursor can act on protein kinase and modification thereof, the catalysis of regulation and control and change protein kinase and modification thereof.
Wherein protein kinase that is acted on and modification thereof can be tyrosine protein kinase and modification thereof, comprise acceptor class tyrosine protein kinase and modification thereof and non-acceptor class tyrosine protein kinase and modification thereof.The tyrosine protein kinase of acceptor class and modification thereof comprise PDGFR α, PDGFR β, EGF, HER2, HER3, HER4, IR, IGF-IR, IRR, CSFIR, C-kit, C-fms, Flk-IR, Flk-4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R; Non-acceptor class tyrosine protein kinase and modification thereof comprise Abl, Src, Frk, Btk, Csk, MAP, P38, ZAP70, Fes/Fps, Fak, Jak, ArkYes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
Described protein kinase and modification thereof can be serine/threonine protein kitase and modification thereof also, comprise CDK2, MAP, P38, Raf and PKC.
Give the above-mentioned compound of human body effective dose, can be used for treating the disease relevant with protein kinase and modification thereof with prevention.
The compound that the present invention relates to can be via the carrier of medicinal to the human body administration, and these pharmaceutical carriers comprise ion exchange resin; aluminum oxide; aluminum stearate; Yelkin TTS; serum protein (as the human serum albumin); cushion is (as phosphoric acid salt; glycine; Sorbic Acid; potassium sorbate etc.); the glyceride of fractional saturation vegetables oil; the mixture of water and salt or ionogen are (as protamine sulfate; Sodium phosphate dibasic; potassium hydrogen phosphate; sodium-chlor etc.); zinc salt; colloidal silica gel; the trimerization Magnesium Silicate q-agent; polyvinylpyrrolidone; cellulose family; the polyethylene glyceryl alcohol; the carboxylic acid methyl sodium cellulosate; poly-acylate; wax class and lanolin etc.
The compound that the present invention relates to can be by different approaches to the human body administration, and that concrete route of administration comprises is oral, parenteral administration, oral cavity suction, administration through skin, rectal administration, intranasal administration, sublingual administration, cheek administration, vagina administration and by the administration of the property implanted container; That parenteral administration is included in again is subcutaneous, in the intravenously, intramuscular, intraarticular, synovial membrane chamber, in the breastbone, in the sheath, in the liver, in the damage location and intracranial injection or infiltration.
The compound that the present invention relates to can be made into different formulations and is used for the human body administration, concrete formulation has aqueous solution injection, oily suspension injection, oral capsule, oral tablet, oral aqueous solution, oral administration mixed suspension, rectal suppository, eye drop, eye ointment, skin with sprays, oral spray, oral cavity aerosol, nasal mist and nasal aerosol etc., also to comprise the sustained release dosage of these different dosage forms and the preparation of sustained release speed and dosage with ointment, dermatological cream, skin simultaneously.
The compound that the present invention relates to is when being used for human body and treating with preventing disease, used dosage is subjected to influence of various factors, these factors comprise age, body weight, healthy state, sex, race, food habits, administration time, the frequency of urinating reach whether use other medicines, or the like.
The compound that the present invention relates to has special pharmacologically active, and particularly tyrosine protein kinase acid and modification thereof work their activity by the arrestin kinases.In background technology one joint, all kinds of diseases relevant have been set forth with the activity of protein kinase, the present invention is by the activity of arrestin kinases and modification thereof, effective especially for proliferative disease, can also solve the existing resistance problem of present clinical use medicine simultaneously.
Compound of the present invention thus is specially adapted to treatment and prevents following various diseases:
Occur in the solid malignant tumour of following position and tissue: mammary gland, ovary, colon, liver, courage, lung, stomach, prostate gland, pancreas, throat, bladder, brain, skin etc.;
Lymphocytic type blood class tumour: acute lymphoblastic type blood disease, acute lymphoblast type leukemia, B cellular type leukemia, T cellular type leukemia, He Jiejin lymphomas, non_hodgkin lymphoma, trichoblast lymphoma and Burkett lymphomas;
Medullary cell type blood class tumour: acute medullary cell type leukemia, chronic medullary cell type leukemia, hypoplastic bone marrow disease and promyelocyte type leukemia;
Other also comprises and occurs in unify tumour in the peripheral nervous system of central nervous system;
Because the regulation and control of tyrosine protein kinase cellular function and proliferation of cells and breeding play important effect, compound of the present invention may have treatment and prophylactic effect to any disease that influences cell function regulation and control and hyperplasia, and these diseases comprise inflammation, neural deterioration disease, virus infection and fungal infection etc.
Compound of the present invention can prepare by (but being not limited to) following synthetic route:
Said synthesis route is that example proposes with the little compounds among the present invention, and other compound can prepare in a similar manner; Also can be by other synthetic route preparation.
The biological activity of The compounds of this invention can be assessed by the restraining effect of measuring their enzyme propylhomoserin protein kinases, and its restraining effect is used half-inhibition concentration (IC usually
50) represent, in embodiment 20, provided the half-inhibition concentration experimental value of part of compounds.
Embodiment
Below in conjunction with embodiment the present invention is further described, these embodiment do not limit any technology and purposes involved in the present invention just with helping understand the present invention:
Embodiment one: preparation intermediate 4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-aniline
With 3-acetylpyridine (121 gram, 1 mole) and N, N-dimethyl aldehyde acid amides dimethyl half alditol (119 grams, 1 mole) was dissolved in 500 milliliters of anhydrous dimethyl formamides, 110 ℃ of back flow reaction 3 hours.Behind the solvent evaporate to dryness, add ether and make product precipitation and crystallization, obtain 182 gram white crystals after separation and the drying.
(18.4g 0.8mol) is dissolved in the 500ml straight alcohol, and (76.1g, 2mol) with the above white crystals of 176g, heating reflux reaction is 6 hours then to add the sulphur guanidine with sodium Metal 99.5 earlier.After reaction finishes, add 1000ml distilled water, transfer to acidity with glacial acetic acid again, the powerful stirring also is heated to boiling, determine that with the pH test paper solution presents acidity after, be cooled to 30 ℃ of also filtering precipitates rapidly, obtain the 138.6g white solid after the drying precipitate.
The above white solid of 94 grams is dissolved in 500 milliliters of 1N sodium hydroxide solutions, and (70.5g, 1mol), at room temperature stirring reaction is 3 hours to add methyl iodide.Transfer to neutrality with glacial acetic acid behind the reacting liquid filtering and separate out white precipitate.This throw out obtains 85.3 gram white crystals behind the recrystallization in ethanol.
The above white crystals of 61 grams is dissolved in 300 ml methanol-water (7: 3) mixed solution, adds the inclined to one side two potassium sulfite (KHSO of 50 grams
5).At room temperature stirring reaction is 3 hours, then with the solvent evaporate to dryness, dewaters with anhydrous magnesium sulfate after washing product again with water, obtains 57.8 gram white solids after the drying.
(44.7g 0.2mol) is dissolved in the 150ml dimethyl formamide respectively the above white solid of 47 grams to be dissolved in 75ml dimethyl formamide and 3-hydroxy-4-methyl-carbaniloyl tert-butyl ester.After two kinds of solution mixing, slowly the solution of Dropwise 35 ml suspendible 14.4g sodium hydride in dimethyl formamide added about 15 minutes.At room temperature stirring reaction transferred to acidity with citric acid after 18 hours, poured in the 2000ml frozen water and separated out precipitation.Throw out filters back water flushing.Then, when humidity, be dissolved in the methylene dichloride.Boil off solvent after dewatering with anhydrous magnesium sulfate, obtain oily matter.Behind this oily matter of ether dissolution, add 200 milliliters of 1N sodium hydroxide solution extraction products, obtain aqueous phase solution after the separation, produce crystalline precipitate with in 200 milliliters of 1N hydrochloric acid and back again.Obtain the little yellow crystal of 73.4 grams after sedimentation and filtration and the drying.
The above little yellow crystal of 70 grams is dissolved in 250 milliliters of methylene dichloride that contain 25% trifluoroacetic acid, and at room temperature stirring reaction is 8 hours.After reaction finishes, add 200 ml distilled waters and separate and obtain organic phase solution.After dewatering with anhydrous magnesium sulfate, the steaming vibrating dichloromethane solvent obtains 56.4 gram title compounds.
This product is little yellow solid, fusing point: 145-147 ℃.MS(ESI)m/z?278。
1HNMR(400MHz，CDCl
3)δ9.57(s，1H)，8.74(d，J＝4.9Hz，1H)，8.66(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.20(dd，J＝4.9，8.2Hz，1H)，7.09(d，J＝8.2Hz，1H)，6.52(s，1H)，6.35(d，J＝8.2Hz，1H)，4.82(s，2H)，2.40(s，3H)。
Embodiment two: 4-(4-methyl-piperazinyl-1-methyl)-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2 oxygen)-phenyl]-benzamide
Title compound (2.78g with gained among the embodiment one, 0.2ml) and 4-(4-methyl-piperazinyl-1-methyl) phenylformic acid (2.33g, 0.2mol) be dissolved in 50 milliliters of methylene dichloride, add N, N-two cyclohexyl carbodiimide (1.94ml, 0.2mol) after stirring reaction 3 hours at room temperature.After reaction is finished, wash reaction solution with water and separate again and obtain organic phase solution, boil off solvent after dewatering with sal epsom, obtain 3.88 gram title compounds after the drying.
This product is a white solid, fusing point: 209-214 ℃.MS(ESI)m/z?510。
1HNMR(400MHz，CDCl
3)δ9.57(s，1H)，8.74(d，J＝4.9Hz，1H)，8.66(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.74-7.76(m，3H)，7.23-7.24(m，2H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.03(d，J＝8.4Hz，1H)，3.57(s，2H)，2.37-2.58(m，11H)，2.30(s，3H)。
Embodiment three: N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.14 gram title compounds with phenylformic acid.
This product is a white solid, fusing point: 181-183 ℃.MS(ESI)m/z?382。
1HNMR(400MHz，CDCl
3)?δ9.57(s，1H)，8.74(d，J＝4.9Hz，1H)，8.66(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.86(d，J＝7.7Hz，2H)，7.74(s，1H)，7.56(s，3H)，7.25(d，J＝8.4Hz，1H)，7.20(dd，J＝4.9，8.2Hz，1H)，7.03(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment four: 4-methyl-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.38 gram title compounds with the 4-tolyl acid.
This product is a white solid, fusing point: 106-110 ℃.MS(ESI)m/z?396。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.73(s，1H)，7.15-7.26(m，6H)，7.02(d，J＝8.4Hz，1H)，2.41(s，3H)，2.33(s，3H)。
Embodiment five: 3-methyl-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.05 gram title compounds with the 3-tolyl acid.
This product is a white solid, fusing point: 116-117 ℃.MS(ESI)m/z?396。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.75(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.69(d，J＝7.7Hz，1H)，7.48(dd，J＝7.7Hz，1H)，7.38(s，1H)，7.24(s，1H)，7.18-7.20(m，2H)，7.04(d，J＝8.4Hz，1H)，2.41(s，3H)，2.24(s，3H)。
Embodiment six: 4-methoxyl group-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.27 gram title compounds with the 4-methoxybenzoic acid.
This product is a white solid, fusing point: 96-98 ℃.MS(ESI)m/z?412。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.90(d，J＝8.4Hz，1H)，7.74(s，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，3.74(s，3H)，2.41(s，3H)。
Embodiment seven: 3-methoxyl group-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.93 gram title compounds with the 3-methoxybenzoic acid.
This product is a white solid, fusing point: 102-104 ℃.MS(ESI)m/z?412。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.74(s，1H)，7.59(dd，J＝7.9Hz，1H)，7.52(d，J＝7.9Hz，1H)，7.32(d，J＝7.8Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.14(s，1H)，7.04(d，J＝8.4Hz，1H)，3.79(s，3H)，2.40(s，3H)。
Embodiment eight: 4-fluoro-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.60 gram title compounds with the 4-fluorobenzoic acid.
This product is a white solid, fusing point: 193-196 ℃.MS(ESI)m/z?400。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.54(d，J＝8.8Hz，2H)，7.30(m，2H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment nine: 3-fluoro-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.32 gram title compounds with the 3-fluorobenzoic acid.
This product is a white solid, fusing point: 187-189 ℃.MS(ESI)m/z?400。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.62(d，J＝7.7Hz，1H)，7.58(s，1H)，7.48(dd，J＝7.7，8.3Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.16(d，J＝8.3Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment ten: 4-amino-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen) phenyl]-benzamide
Press embodiment two described methods, prepare 3.01 gram title compounds with the 4-benzaminic acid.
This product is little yellow solid, fusing point: 165-167 ℃.MS(ESI)m/z?397。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.79(d，J＝8.6Hz，1H)，7.74(s，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.91(s，2H)，6.89(m，2H)，2.40(s，3H)。
Embodiment 11: 3-amino-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.64 gram title compounds with the 3-benzaminic acid.
This product is little yellow solid, fusing point: 171-174 ℃.MS(ESI)m/z?397。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.50(d，J＝8.1Hz，1H)，7.36(d，J＝8.1Hz，1H)，7.29(s，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.28(s，2H)，2.40(s，3H)。
Embodiment 12: 4-hydroxy-n-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.14 gram title compounds with the 4-hydroxy-benzoic acid.
This product is a white solid, fusing point: 203-206 ℃.MS(ESI)m/z?398。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(m，2H)，7.24(d，J＝8.2Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.09(m，2H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 13: 3-hydroxy-n-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.87 gram title compounds with the 3-hydroxy-benzoic acid.
This product is a white solid, fusing point: 208-210 ℃.MS(ESI)m/z?398。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.56(dd，J＝7.9，8.0Hz，1H)，7.49(d，J＝7.9Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.13(s，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 14: N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-the isonicotine acid amides
Press embodiment two described methods, prepare 2.95 gram title compounds with isonicotine acid.
This product is a white solid, fusing point: 168-169 ℃.MS(ESI)m/z?383。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.81(m，2H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.73(m，2H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 15: N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-the Nicotine acid amides
Press embodiment two described methods, prepare 3.13 gram title compounds with Nicotinicum Acidum.
This product is a white solid, fusing point: 176-178 ℃.MS(ESI)m/z?383。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，9.03(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，8.21(d，J＝7.2Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.83(s，1H)，7.50(dd，J＝4.7，7.2Hz，1H)，7.32(d，J＝8.4Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 16: 6-(4-methyl-piperazinyl-1-methyl)-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-the Nicotine acid amides
Press embodiment two described methods, prepare 3.86 gram title compounds with 6-(4-methyl-piperazinyl-1-methyl) Nicotinicum Acidum.
This product is a white solid, fusing point: 216-219 ℃.MS(ESI)m/z?495。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，9.14(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，8.18(d，J＝8.1Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.83(s，1H)，7.43(d，J＝8.1Hz，1H)，7.32(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，3.73(s，2H)，2.59(m，4H)，2.51(m，4H)，2.40(s，3H)，2.26(s，3H)。
Embodiment 17: 4-nitro-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 3.11 gram title compounds with the 4-nitrobenzoic acid.
This product is a faint yellow solid, fusing point: 213-216 ℃.MS(ESI)m/z?427。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)，8.65(d，J＝5.4Hz，1H)，8.61(d，J＝8.2Hz，1H)，8.27(m，2H)，8.05(d，J＝9.0Hz，1H)，7.97(d，J＝5.4Hz，1H)，7.74(s，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 18: 3-nitro-N-[4-methyl-3-(4-pyridyl-3-pyrimidyl-2-oxygen)-phenyl]-benzamide
Press embodiment two described methods, prepare 2.85 gram title compounds with the 3-nitrobenzoic acid.
This product is a faint yellow solid, fusing point: 215-218 ℃.MS(ESI)m/z?427。
1HNMR(400MHz，CDCl
3)δ9.56(s，1H)，8.74(d，J＝4.9Hz，1H)， 8.61-8.65(m，3H)，8.34(d，J＝8.5Hz，1H)，8.17(d，J＝8.0Hz，1H)，7.98(d，J＝5.4Hz，1H)，7.74(s，1H)，7.68(dd，J＝8.0，8.5Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.19(dd，J＝4.9，8.2Hz，1H)，7.04(d，J＝8.4Hz，1H)，2.40(s，3H)。
Embodiment 19: the mensuration of Abl protein tyrosine kinase activity
Enzyme reaction solution comprise 50mM Tris-HCL damping fluid (pH7.5), 10mM magnesium chloride, 1mM EDTA, 10 μ M γ-
32The ATP of P mark (3000-5000cpm/pmol), 0.2mM ATP and 10 μ g Abl peptide class substrate EAIYAAPFAKKK (1mg/ml, from New England Biolabs, MA, USA buys, catalog number is P6051).This reaction solution volume is 40 μ l.With this reaction solution be dissolved in after test compounds in the dimethyl sulfoxide (DMSO) mixes, (10000 units/ml are from Cell Signaling Technology to add 10 μ l Abl tyrosine protein kinase, MA, USA buys, and catalog number is 6150), thus the beginning enzyme reaction.
After 10 minutes, add 40 μ l, 10% trichoroacetic acid(TCA) solution termination reaction, centrifugal 2 minutes (10000rpm) 30 ℃ of reactions.Draw 35 μ l supernatant liquors and drop on the P81 ion-exchange filter paper (Whatman), behind 6% glacial acetic acid flushing filter paper three times, seasoning at room temperature.Then dried filter paper is placed in the radioactive rays counting bottle, on the beta-rays calculating instrument, measures exit dose.The activity of Abl tyrosine protein kinase is calculated by the exit dose on the filter paper.
Compound involved in the present invention is to the compound concentration (IC of restraining effect to cause 50% enzymic activity to suppress of Abl tyrosine protein kinase
50) represent.
Embodiment 20: The compounds of this invention is to the restraining effect of Abl tyrosine protein kinase
Compound of the present invention has obviously and very strong restraining effect the Abl tyrosine protein kinase, their half-inhibition concentration (IC
50) in the scope of 0.025-2.0 μ M.
Following table has provided the end value (compound is represented with corresponding embodiment title) that the compound among the embodiment two to 18 is tested.
Table 1 The compounds of this invention is to restraining effect (compound is with the title representative of embodiment) the compounds in side chain group IC of Abl
50(μ M)
Embodiment two
0.031
Embodiment three
0.078
Embodiment four
0.025
Embodiment five
0.027
Embodiment six
0.058
Embodiment seven
0.062
Embodiment eight
0.183
Embodiment nine
0.215
Embodiment ten
0.45 embodiment 11
0.60 embodiment 12
0.55 embodiment 13
0.82 embodiment 14
0.15 embodiment 15
0.18 embodiment 16
0.026 embodiment 17
1.45 embodiment 18
1.70
Claims (10)
1, a kind of 2-phenoxy pyrimidine derivates is characterized in that: it is to contain the compound of following chemical structure of general formula or its salt,
Wherein,
X be oxygen, sulphur, secondary amino (NH-) or carbonyl
Y is a carbonyl
Oxygen, sulphur or secondary amino are (NH-);
R
1, R
2, R
3, R
5, R
6, R
7, R
8Be hydrogen, halogen, alkyl, aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, the assorted alkyl of ring-type or the assorted alkanisation alkyl of ring-type;
R
4Be hydrogen, halogen, hydroxyl, alkoxyl group or the alkyl that contains 1-6 carbon atom;
R
9Be selected from hydrogen, oxygen, sulphur, methyne (CH
2-), secondary amino (NH-), alkyl or-Z-R
10
Wherein Z represents oxygen, sulphur, methyne (CH
2-), secondary amino (NH-) or alkyl;
R
10Be aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, hydrogen or halogen, alkyl, the assorted alkyl of ring-type, the assorted alkanisation alkyl of ring-type.
2,2-phenoxy pyrimidine derivates as claimed in claim 1 is characterized in that: described R
2, R
3, R
5, R
6, R
7Be hydrogen.
3,2-phenoxy pyrimidine derivates as claimed in claim 1 or 2 is characterized in that: described R
9For-Z-R
10, wherein Z represents oxygen, sulphur, methyne (CH
2-), secondary amino (NH-) or alkyl; R
10Be aryl, aralkyl, aralkyl heterocyclic radical, cycloalkyl, hydrogen or halogen, alkyl, the assorted alkyl of ring-type, the assorted alkanisation alkyl of ring-type.
4, a kind of therepic use of 2-phenoxy pyrimidine derivates is characterized in that: adopt as 2-phenoxy pyrimidine derivates, its salt or the medicinal precursor described in 1 to 3 and with can be as medicinal carrier combinations patent medicine preparation.
5, the therepic use of 2-phenoxy pyrimidine derivates as claimed in claim 4, it is characterized in that: described 2-phenoxy pyrimidine derivates, its salt or medicinal precursor can act on protein kinase and modification thereof, the catalysis of regulation and control and change protein kinase and modification thereof.
6, the therepic use of 2-phenoxy pyrimidine derivates as claimed in claim 5 is characterized in that: described protein kinase and modification thereof are tyrosine protein kinase and modification thereof.
7, the therepic use of 2-phenoxy pyrimidine derivates as claimed in claim 6 is characterized in that: described tyrosine protein kinase and modification thereof comprise acceptor class tyrosine protein kinase and modification and non-acceptor class tyrosine protein kinase and modification thereof.
8, the therepic use of 2-phenoxy pyrimidine derivates as claimed in claim 5 is characterized in that: described protein kinase and modification thereof are serine/threonine protein kitase and modification thereof.
9, a kind of therepic use of 2-phenoxy pyrimidine derivates is characterized in that: give the compound as claimed in claim 1 of human body effective dose, can be used for treating the disease relevant with protein kinase and modification thereof with prevention.
10, the therepic use of 2-phenoxy pyrimidine derivates as claimed in claim 9 is characterized in that: the described disease relevant with protein kinase and modification thereof comprises the disease of being correlated with acceptor class tyrosine protein kinase and modification thereof, the disease of being correlated with non-acceptor class tyrosine protein kinase and modification thereof and the disease of being correlated with serine/threonine protein kitase and modification thereof.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010057418A1 (en) * | 2008-11-21 | 2010-05-27 | Chen Yijun | A phenoxypyrimidine derivative, its preparation method and the use thereof |
| CN101528715B (en) * | 2006-10-25 | 2011-08-24 | 埃科特莱茵药品有限公司 | 2-phenyl-6-aminocarbonyl-pyrimidine derivatives |
| CN103360366A (en) * | 2013-07-26 | 2013-10-23 | 天津禾盛医药技术开发有限公司 | Preparation methods of N-(2-methylpyridyl-5-nitro-3-)-4-(3-pyridinyl)pyrimidin-2-amine and intermediate thereof |
| CN103893182A (en) * | 2014-03-27 | 2014-07-02 | 中国药科大学 | SET protein small-molecule inhibitor and application thereof |
| CN105153123A (en) * | 2015-09-29 | 2015-12-16 | 合肥师范学院 | Method for synthesizing 4-pyrazinyl pyrimidine-2-sodium sulfonate |
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2001
- 2001-12-28 CN CNB011380705A patent/CN1181062C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101528715B (en) * | 2006-10-25 | 2011-08-24 | 埃科特莱茵药品有限公司 | 2-phenyl-6-aminocarbonyl-pyrimidine derivatives |
| WO2010057418A1 (en) * | 2008-11-21 | 2010-05-27 | Chen Yijun | A phenoxypyrimidine derivative, its preparation method and the use thereof |
| CN101417995B (en) * | 2008-11-21 | 2012-06-06 | 陈依军 | Phenoxy pyrimidine derivates and preparation method and use thereof |
| CN103360366A (en) * | 2013-07-26 | 2013-10-23 | 天津禾盛医药技术开发有限公司 | Preparation methods of N-(2-methylpyridyl-5-nitro-3-)-4-(3-pyridinyl)pyrimidin-2-amine and intermediate thereof |
| CN103360366B (en) * | 2013-07-26 | 2015-04-01 | 天津禾盛医药技术开发有限公司 | Preparation methods of N-(2-methylpyridyl-5-nitro-3-)-4-(3-pyridinyl)pyrimidin-2-amine and intermediate thereof |
| CN103893182A (en) * | 2014-03-27 | 2014-07-02 | 中国药科大学 | SET protein small-molecule inhibitor and application thereof |
| CN105153123A (en) * | 2015-09-29 | 2015-12-16 | 合肥师范学院 | Method for synthesizing 4-pyrazinyl pyrimidine-2-sodium sulfonate |
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