CN101265274B - Pyrimidinthiazolamine derivatives, and preparation method, medicament composition and use thereof - Google Patents
Pyrimidinthiazolamine derivatives, and preparation method, medicament composition and use thereof Download PDFInfo
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- CN101265274B CN101265274B CN2008100081963A CN200810008196A CN101265274B CN 101265274 B CN101265274 B CN 101265274B CN 2008100081963 A CN2008100081963 A CN 2008100081963A CN 200810008196 A CN200810008196 A CN 200810008196A CN 101265274 B CN101265274 B CN 101265274B
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- MRZQTKRHXQMTQI-UHFFFAOYSA-N CCOP(CCN(CC1)CCN1c1nc(C)nc(Nc2ncc(C(Nc3c(C)cccc3Cl)=O)[s]2)c1)(OCC)=O Chemical compound CCOP(CCN(CC1)CCN1c1nc(C)nc(Nc2ncc(C(Nc3c(C)cccc3Cl)=O)[s]2)c1)(OCC)=O MRZQTKRHXQMTQI-UHFFFAOYSA-N 0.000 description 1
- MBFCVHIBSGYVLG-UHFFFAOYSA-N O=P(N1CCNCC1)(OCc1ccccc1)OCc1ccccc1 Chemical compound O=P(N1CCNCC1)(OCc1ccccc1)OCc1ccccc1 MBFCVHIBSGYVLG-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to aminothiazolopyrimidine derivatives shown in formula I, pharmaceutical salts, hydrate and solvates thereof, polycrystals and eutectic crystals thereof, precursors or derivatives with the same biological function thereof, preparation method thereof, compositions containing one or more compounds, and application thereof in the treatment of the disease related to protein tyrosine kinase such as immune disorder and tumor disease.
Description
Invention field
The present invention relates to shown in the general formula I pyrimidine thiazole sulfonamide derivatives, its pharmacologically acceptable salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or derivative, and preparation method thereof, contain one or more these compound compositions and this compounds purposes aspect treatment and protein tyrosine kinase diseases associated such as immune disorder and tumor disease.
Background of invention
In recent years, because the Study on Molecular Mechanism of tumor development has obtained breakthrough, the specific molecular biosciences target spot that the research steering of new drug works in the nosetiology of cancer and pathologic process (Science, 1993,260 (5110), 918-919).(Science，1995，267(5205)，1782-1787)。Studies show that, oncogene more than 80% and proto-oncogene are present in people's the cancer proteins encoded Tyrosylprotein kinase (PTK), the generation of human various cancers is relevant with the abnormal cells signal conduction that comes from protein tyrosine kinase with development, an increase that principal feature is tyrosine kinase activity of malignant cell.In addition, the overexpression of normal former carcinogenic Tyrosylprotein kinase also can cause proliferative disease.Verified in the laboratory: by undue expression or the various receptor tyrosine kinases that make a variation, increase its activity, normal cell can be converted to cancer cells, and the degree of pernicious transformation is closely related with tyrosine kinase activity; And the antibody by utilizing acceptor or special kinase inhibitor reduce that kinase activity can make canceration reverse (Drugs, 2000,59 (4): 753) again in the acceptor.Therefore, suppress tyrosine kinase activity, the signal conducting path of blocking its activation becomes the new way of control tumour.
Protein tyrosine kinase (PTK) is a kind of enzyme, except comprising receptor tyrosine kinase (RPTK): as EGF-R ELISA (EGFR) kinases family, vascular endothelial growth factor receptor (VEGFR) family, platelet derived growth factor receptor (PDGFR) family, fibroblast growth factor acceptor (FGFR) family, outside hepatocyte growth factor receptor (HGFR) family and the Tie kinases family (Tie-2 and KDR) of in vascularization, working, also comprise nonreceptor tyrosine kinase family: as SRC, ABL, JAK, CSK, FAK, FES, FRK, TEC, SYK family etc.They play an important role at signal transduction pathway, find that recently 32 intracytoplasmic protein tyrosine kinases nearly half and human cancer are closely related.
The activity of PTK not only all demonstrates enhancing in many pernicious and non-neoplasm diseases, and PTK plays a crucial role in immune cell regulate and control.Therefore, ptk inhibitor can be influential to many kinds of tumours and amynologic disease.Can be by optionally suppressing certain acceptor or non-acceptor PTK, for example Lck perhaps owing to the homology between all kinds of PTK, utilizes inhibitor to suppress more than one PTK, thereby these illnesss is eased.
A kind of PTK of particularly important is the Lck that finds in the T cell, and it is relevant with the phosphorylation of key protein substrate in the T cell. it is that the conduction of productivity antigen receptor signal and cell activation are needed.When not having Lck active, TXi Baoshouti (TCR) zeta chain is not by phosphorylation, and kinases ZAP-70 is not activated, and can not take place for the activation of the vital Ca particle of T cell activation passage, therefore, the inhibitor of Lck can be used for treating the cell-mediated disease of T.For example, the chronic disease that the T cell plays an important role, the acute disease that plays an important role therein as rheumatoid arthritis, multiple sclerosis disease and lupus and known T cell, for example acute transplant rejection and delayed hypersensitivity.
Though it has been found that many small molecules tyrosine kinase inhibitors, as WO9903854, WO2004005281, WO0062778, WO2005013983 has made this area very big contribution, but for improving anticancer and immune disorder medicine, research is still being continued in this area.
Summary of the invention
The object of the present invention is to provide a kind of new pyrimidine thiazole sulfonamide derivatives, its pharmacologically acceptable salt, its solvate, its prodrug, its polycrystalline or eutectic.
Another object of the present invention is to provide a kind of method for preparing this class pyrimidine thiazole sulfonamide derivatives.
A further object of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds.
Another purpose of the present invention be to provide a kind of this compounds anticancer and immune and with the medicine of Tyrosylprotein kinase diseases related in purposes.
The present invention relates to have the pyrimidine thiazole sulfonamide derivatives of following general formula I:
(I)
In the formula,
R1 is selected from alkyl amine group, and (wherein, alkyl is selected from the straight or branched of C1-C12 to arylamine group, can comprise carbocyclic ring or heterocycle (contain aerobic, nitrogen, sulfur heteroatom 1-3), the alkyl that replaces or do not replace, wherein substituting group comprises halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, itrate group, cyano group, amino, the amino of replacement, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino.Wherein aryl is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace, (as phenyl ring, naphthalene nucleus, the quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, imidazole ring), its substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, itrate group, amino, the amino that replaces, amido, the amino azo-group of replacement, carboxyl, ester group, alkoxyl group, alkanoyloxy, imidazoles, the imidazoles that alkyl replaces, the heterocycle or the aromatic heterocyclic that replace or do not replace, the heterocycle or the fragrant Heterocyclylalkyl that replace or do not replace).
R2 is selected from: hydrogen ,-COOM (M=hydrogen, potassium, sodium, lithium, calcium, magnesium) ,-PO
3M
2,-CH
2OR5 (R5=hydrogen, alkyl, alkane (virtue) acyl group, alkane (virtue) oxygen formyl radical) ,-COR6 (R6=alkane (virtue) base, alkane (virtue) oxygen base, alkane (virtue) acyl-oxygen methoxyl group).
R3, R4 is selected from hydrogen, metal (as: potassium, sodium, lithium, calcium, magnesium), alkyl, aralkyl, aryl, alkaryl.
Wherein, " alkane " base is selected from the straight or branched of C1-C12, can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace, wherein substituting group comprises halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, itrate group, cyano group, amino, the amino that replaces, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino, " virtue " base, oxo." virtue " base is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace, as phenyl ring, and naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, thiazole ring, imidazole ring, substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, itrate group, amino, the amino of replacement, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy.
R5 is selected from hydrogen, alkyl, alkylamino, arylalkylamino." alkane " base is selected from the straight or branched of C1-C12, can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace." virtue " base is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace.
X is selected from singly-bound, CH
2, O, NR or NAr, NH, S, and contain the heteroatom group that can link to each other with pyrimidine ring, and as: 1,4-piperazinyl, Alkylpiperidine base etc.
Y is selected from singly-bound, alkyl, aryl, alkaryl, aralkyl, alkoxyl group, alkylamino, aryloxy, aryl amine.Wherein, " alkane " base is selected from the straight or branched of C1-C12, can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace, wherein substituting group comprises halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, itrate group, cyano group, amino, the amino that replaces, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino, " virtue " base, oxo." virtue " base is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace, as phenyl ring, and pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, thiazole ring, imidazole ring etc., substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, itrate group, amino, the ammonia sulfo group, the amino of replacement, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy.
Z is selected from O, S.
R1 is more preferably: include carbocyclic ring or heterocycle (contain aerobic, nitrogen, sulfur heteroatom 1-3), and the alkylamino that replaces or do not replace, wherein the substitution in ring base comprises halogen (fluorine, chlorine, bromine, iodine), methyl, hydroxyl, nitro, amino, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino.Include the aromatic ring and the fragrant heterocycle that replace or do not replace, (as phenyl ring, naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, imidazole ring), its substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, amino, the amino of replacement, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, imidazoles, the imidazoles that alkyl replaces, the heterocycle or the aromatic heterocyclic that replace or do not replace, the heterocycle or the fragrant Heterocyclylalkyl that replace or do not replace).
R2 is more preferably: hydrogen ,-COOM (M=hydrogen, potassium, sodium, lithium, calcium, magnesium) ,-COR6 (R6=alkane (virtue) base, alkane (virtue) oxygen base, alkane (virtue) acyl-oxygen methoxyl group.
R3, R4 be more preferably: hydrogen, potassium, sodium, lithium, calcium, magnesium, alkyl, aralkyl, aryl, alkaryl.
R5 is more preferably: hydrogen, methyl, trifluoromethyl.
X is more preferably: O, and NR or NAr, NH, S, and contain the heteroatomic group that can link to each other with pyrimidine ring, and as: 1,4-piperazinyl, Alkylpiperidine base etc.
Y is more preferably: singly-bound, and the straight or branched of C1-C12 can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace, alkoxyl group, alkylamino; The aromatic ring that replaces or do not replace, alkaryl, aralkyl, fragrant heterocycle, aryloxy, aryl amine.
Z is more preferably: O, S.
R1 is preferably especially: the arylamino of the aromatic ring that replaces or do not replace and fragrant heterocycle (as phenyl ring,, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, imidazole ring), its substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, amino.
R2 is preferably especially: hydrogen ,-COR6 (R6=alkane (virtue) base, alkane (virtue) oxygen base, alkane (virtue) acyl-oxygen methoxyl group.
R3, R4 is preferably especially: hydrogen, potassium, sodium, calcium, alkyl, aralkyl.
R5 is preferably especially: methyl, trifluoromethyl.
X is preferably especially: O, and NH, and contain the heteroatomic group that can link to each other with pyrimidine ring, and as: 1,4-piperazinyl.
Y is preferably especially: singly-bound, and the straight or branched of C1-C12 can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace, alkoxyl group, alkylamino; The aromatic ring that replaces or do not replace, alkaryl, aralkyl, aromatic heterocyclic, aryloxy, aryl amine.
Z is more preferably: O, S.
R1 most preferably is: have amino aromatic ring or a fragrant heterocycle (as phenyl ring, pyridine ring, pyrimidine ring) that replaces at least, its substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, amino.
R2 most preferably is: hydrogen, COR6 (R6=alkane (virtue) oxygen base, alkane (virtue) acyl-oxygen methoxyl group).
R3, R4 most preferably is: hydrogen, potassium, sodium, calcium, alkyl, benzyl.
R5 most preferably is: methyl.
X most preferably is: NH, and contain the heteroatomic group that can link to each other with pyrimidine ring, and as: 1,4-piperazinyl.
Y most preferably is: singly-bound, the straight or branched of C1-C12 can comprise carbocyclic ring or heterocycle (containing 1-3 oxygen or nitrogen or sulphur atom), the alkyl that replaces or do not replace, alkaryl, aralkyl, alkoxyl group, alkylamino.
Z most preferably is: O.
Most preferably
R1 is selected from: oxyethyl group, and hydroxyl, 2-chloro-6-toluidine,
R2 is selected from: hydrogen,
R3 is selected from: ethyl, and hydrogen,
R4 is selected from: ethyl, hydrogen
R5 is selected from: methyl,
X is selected from: piperazine
Y is selected from: singly-bound, and ethylidene, methylene radical,
Z is selected from: oxygen.
In addition, particularly preferred The compounds of this invention is general formula I pyrimidine thiazole sulfonamide derivatives or its pharmacologically acceptable salt.
In order to prepare the described compound of general formula I of the present invention, preparation method of the present invention utilizes pyrimidine derivatives to link to each other with phosphate derivative earlier, and then links to each other with thiazole derivative, finally obtains the described compound of general formula I.
In pyrimidine derivatives, A represents leavings group, as halogen; B represents leavings group, as halogen, or represents amino; A can equal B.In thiazole derivative, the blocking group of CO for leaving away, as alkoxyl group or aralkoxy, but D represents amino or leavings group, as halogen.When B was halogen, D represented amino; When B was amino, D represented halogen.
Intermediate thiazole derivative 4, pyrimidine derivatives 1 and phosphate derivative 2 can synthesize according to the synthetic method of the analogue of having reported usually.
Intermediate 3 synthetic can by 1 and 2 directly or in solvent direct heating synthetic, or synthetic under base catalysis, comprise organic bases, as diisopropyl ethamine, triethylamine, pyridine etc., or mineral alkali, as sodium hydride, Anhydrous potassium carbonate etc.
The synthetic of intermediate 5 can become the N negative ion by first amino (D represents amino) with 4 in anhydrous aprotic solvent, react with 3 (when B is halogen) again; Or earlier 3 amino (B represent amino) is become the N negative ion, react with 4 (when D is halogen) again; Also can mix in anhydrous aprotic solvent 3 and 4 earlier, add alkali then, as sodium hydride, LDA etc., reaction be taken place.
Intermediate 5 can be directly and nucleophilic reagent R1 reaction; Also can become carboxyl with 5 by saponification, acidifying (when CO is alkoxyl group) or hydrogenolysis (when CO is benzyloxy or substituted benzyloxy) earlier, react with HR1 again, can add dewatering agent such as DCC, P205, add condensing agent such as diethyl phosphorocyanidate (DECP), triphenylphosphine-NBS etc.; Also carboxyl can be become carboxylic acid halides or acid anhydrides, again with R1 or HR1 reaction, but Jia Ru Tied acid agent such as triethylamine, pyridine etc. and catalyzer such as zinc powder etc.
In addition, starting raw material and intermediate in the above-mentioned reaction obtain easily, or can be easy to the ordinary method in the organic synthesis synthesize to those skilled in the art.The described pyrimidine thiazole of general formula I sulfonamide derivatives can solvate or the form of non-solvent compound exist, utilize different solvents to carry out crystallization and may obtain different solvates.The described pharmacy acceptable salt of general formula I comprises different acid salt, as following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid, tartrate, fumaric acid, citric acid, lactic acid.The described pharmacy acceptable salt of general formula I also comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt (calcium, magnesium salts) and ammonium salt and the salt of physiologically acceptable cationic organic bases can be provided, as methylamine, dimethylamine, Trimethylamine 99, piperidines, the salt of morpholine and three (2-hydroxyethyl) amine.All these salt within the scope of the present invention all can adopt the ordinary method preparation.In the preparation process of described pyrimidine thiazole sulfonamide derivatives and solvate and its salt, polycrystalline or eutectic may appear in different crystallization conditions.
The invention still further relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, making any formulation that is suitable for human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in the administration unit, the effective constituent The compounds of this invention can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also the effective constituent The compounds of this invention particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.The capsule that also can be used for preparing The compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of The compounds of this invention tablet.
For The compounds of this invention is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of The compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
The compounds of this invention is tyrosine kinase inhibitor or its precursor, not only suppresses non-receptor protein tyrosine kinase, as the Src family kinase, and is used for kinds of tumors and amynologic disease; And the inhibition receptor protein tyrosine kinase, as HER1 and HER2, therefore can be used for treating proliferative disease, as psoriasis and cancer.These compounds suppress the ability of HER1 and other receptor kinase, also make it can be used as anti-angiogenic formation agent and are used for the treatment of such as illnesss such as cancer and diabetic retinopathies.In addition, the activation of T cell has been blocked in the inhibition of Lck in the Src family, and this compounds can be used for the cell-mediated disease of T.Because this compounds can block the activation of epidermic cell PTK, thereby limit the surface expression of the adhesion molecule that brings out the neutrophilia combination, and suppressed neutrophilia and activate necessary PTK, thereby be used for the treatment of ischemic disorders and reperfusion injury.With vascular smooth muscle cells migration and increment diseases associated therapeutic action is arranged in addition, especially anti-tumor activity is obvious.The compounds of this invention can be used for treating hypersensitivity disease, psoriasis, Hashimoto's struma, guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis, asthma, ischemia and the reperfusion injury of nonshrink main sick, the T cell modulation of transplant rejection effect, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, enteritis, lupus, graft and has with PTK or irrelevant atopic dermatitis etc.The compounds of this invention has high bioavailability, can be used for the treatment of multiple human malignancies, comprises leukemia, neurospongioma, incidence cancer, non-small cell cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma etc.
Embodiment
Be described further below with reference to the invention of embodiment, but do not limit the scope of the invention.
Determining instrument: NMR (Nuclear Magnetic Resonance) spectrum Vaariaan Mercury 300 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment 1.4-[2-(diethoxy phosphoryl) ethyl]-piperazine-1-benzyl carboxylate
Restrain (0.1536 mole) piperazine hexahydrates and 150 ml waters and 185 milliliters of trimethyl carbinols with 30.16 and place ice bath; drip 24.4 milliliters of 2.5N sodium hydroxide when being chilled to 5 ℃; slowly drip 13.5 gram (0.061 mole) two uncle's fourth oxygen formic anhydrides then; and keep 5-6 ℃ to stir one hour; stirred overnight at room temperature; the pressure reducing and steaming trimethyl carbinol; remove by filter two protection solids (molten some 162-163 ℃); filtrate is used dichloromethane extraction three times, washing, and salt is washed; anhydrous magnesium sulfate drying; filter by anhydrous sodium sulphate, concentrating under reduced pressure, crystallisation by cooling filters and obtains white solid product piperazine-1-carboxylic acid tert-butyl ester (molten some 47-49 ℃) in the frozen water.
10 gram (54 mmole) piperazine-1-carboxylic acid tert-butyl esters and 8.2 milliliters of triethylamines are dissolved in 120 milliliters of methylene dichloride, be chilled to 0 ℃, drip the solution of 9.2 gram (54 mmole) carbobenzoxy chlorides and 100 milliliters of methylene dichloride, stirring at room to raw material disappears, concentrating under reduced pressure, add ethyl acetate, washing, sodium bicarbonate is washed, salt is washed, anhydrous sodium sulfate drying revolves desolventizing, and the short column separation obtains product piperazine-1-carboxylic acid tert-butyl ester-4-benzyl carboxylate.
4.14 gram (12.9 mmole) piperazine-1-carboxylic acid tert-butyl ester-4-benzyl carboxylates are dissolved in 30 milliliters of methylene dichloride, be chilled to 0 ℃, add 10 milliliters of trifluoroacetic acids, stirring at room to raw material disappears, concentrating under reduced pressure adds 150 milliliters of neutralizations of 1N sodium hydroxide, uses twice of dichloromethane extraction, anhydrous magnesium sulfate drying revolves desolventizing and obtains product piperazine-1-benzyl carboxylate.
20 milliliters of ethylene dibromides and 4 milliliters of triethyl-phosphites are placed 50 milliliters of single port bottles; reflux two days; the remaining ethylene dibromide of pressure reducing and steaming obtains the bromotrifluoromethane diethyl phosphoric acid. 2.45 gram (10 mmole) bromotrifluoromethane diethyl phosphoric acids and 2.2 gram (10 mmole) piperazine-1-benzyl carboxylates is dissolved in 30 milliliters of benzene; add triethylamine 1.1 grams and a small amount of sodium iodide; reflux two days; cooling; boil off benzene; add acetic acid ethyl dissolution; washing, salt is washed, anhydrous sodium sulfate drying; revolve desolventizing, the short column separation obtains product 4-[2-(diethoxy phosphoryl) ethyl]-piperazine-1-benzyl carboxylate.
1H?NMR(300MHz，D-acetone)，δ(ppm)：7.36(m，5H，ArH)，5.09(s，2H，ArH)，4.04(q，4H，2OCH
2)，3.44(t，4H，2NCH
2)，2.40(t，4H，2NCH
2)，2.57(m，2H，CH
2)，1.91(m，2H，CH
2)，1.25(t，6H，2CH
3).FABMS：(M+1)
+＝385.
Embodiment 2. 2-(piperazine-1-yl) ethyl phosphonic acid diethyl ester
With 384 milligrams of (1 mmole) 4-[2-(diethoxy phosphoryl) ethyl]-piperazine-1-benzyl carboxylate is dissolved in 25 milliliters of tetrahydrofuran (THF)/ethanol (1: 1) mixed solvent; add palladium carbon (10%; 180 milligrams); 40-50 ℃ of normal pressure hydrogenation spends the night; the complete after-filtration of hydrogenation revolves desolventizing and obtains product 2-(piperazine-1-yl) ethyl phosphonic acid diethyl ester.
1HNMR (300MHz, D-acetone), δ (ppm): 4.04 (m, 4H, 2OCH
2), 2.84 (t, 4H, 2NCH
2), 2.44 (t, 4H, 2NCH
2), 2.54 (m, 2H, CH
2), 1.91 (m, 2H, CH
2), 1.26 (t, 6H, 2CH
3) .FABMS:(M+1)
+=251.
Embodiment 3.2-[4-(6-chloro-2-methylpyrimidine-4-yl)-piperazine-1-yl]-the ethyl phosphonic acid diethyl ester
With 250 milligrams of (1 mmole) 2-(piperazine-1-yl) ethyl phosphonic acid diethyl esters and 243 milligrams of (1.5 Bo mole) 2-methyl-4,6 dichloro pyrimidines are dissolved in 20 milliliters anhydrous 1, in the 4-dioxane, add 130 milligrams of (1 mmole) diisopropyl ethamine, reflux is stirred to raw material and disappears, revolve desolventizing, add acetic acid ethyl dissolution, the sodium hydrogen carbonate solution washing, washing, anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product liquid 2-[4-(6-chloro-2 methylpyrimidines-4-yl)-piperazine-1-yl]-the ethyl phosphonic acid diethyl ester.
1H NMR (300MHz, CDCl
3), δ (ppm) 6.31 (s, 1H, ArH), 4.11 (q, 4H, 2OCH
2), 3.64 (t, 4H, 2NCH
2), 2.51 (t, 4H, 2NCH
2), 2.70 (m, 2H, CH
2), 2.45 (s, 3H, CH
3), 1.99 (m, 2H, CH
2), 1.31 (t, 6H, 2CH
3) .FABMS:(M+1)
+=377.
Embodiment 4.2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester
With 376 milligrams of (1 mmole) 2-[4-(6-chloro-2-methylpyrimidine-4-yl)-piperazine-1-yl]-ethyl phosphonic acid diethyl ester and 172 milligrams of (1 mmole) 2-amino-5-ethoxycarbonyl thiazoles are dissolved in 20 milliliters of dry DMF; stir and add 100 milligrams of (2.5 mmole) sodium hydrides (60%) down; stirring at room to raw material disappears; in the ice-cold sodium hydrogen carbonate solution of cooling back impouring; ethyl acetate extraction; washing; salt is washed; anhydrous sodium sulfate drying, the separation of desolventizing short column obtains product 2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester.
1H NMR (300MHz, D-acetone), δ (ppm) 7.95 (S, 1H, ArH), 6.17 (s, 1H, ArH), 4.30 (q, 2H, OCH
2), 4.07 (m, 4H, 2OCH
2), 3.62 (t, 4H, 2NCH
2), 2.53 (m, 4H, 2NCH
2), 3.41 (m, 2H, CH
2), 2.45 (s, 3H, CH
3), 1.95 (m, 2H, CH
2), 1.29 (t, 9H, 3CH
3).
FABMS：(M+1)
+＝513
Embodiment 5.2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine 4-amino }-thiazole-5-carboxylic acid
With 512 milligrams of (1 mmole) 2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester is dissolved in 10 ml methanol; add 10 milliliters in 2.5N sodium hydroxide; stirring at room to raw material disappears; methyl alcohol is revolved in decompression; ethyl acetate extraction; the water layer ice-water bath drips concentrated hydrochloric acid and is neutralized to a large amount of precipitations of generation; leave standstill suction filtration after half an hour; the washing solid, drying obtains product 2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid.
1H NMR (300MHz, CD
3OD), δ (ppm) 7.93 (S, 1H, ArH), 5.93 (s, 1H, ArH), 4.28 (m, 4H, 2OCH
2), 3.61 (m, 6H, 3NCH
2), 2.56 (m, 4H, 2NCH
2), 2.41 (s, 3H, CH
3), 2.74 (m, 2H, CH
2), 1.28 (t, 6H, 2CH
3) .FABMS:(M+1)
+=485.
Embodiment 6.2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1]-the ethyl phosphonic acid diethyl ester
With 484 milligrams of (1 mmole) 2-{6-[4-(2-diethoxy phosphoryl ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid and 126 milligrams of (1 mmole) 2-chloro-6-methyl phenylaminos and 152 milligrams of (1.5 mmole) triethylamines are dissolved in 15 milliliters of dry DMF; stir and drip 326 milligrams of (2 mmole) diethyl phosphorocyanidates (DECP) down; be heated to 60-70 ℃ gradually; the stirring raw material disappears; after revolving desolventizing; add dehydrated alcohol; separate out white solid, filter and obtain product 2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1]-the ethyl phosphonic acid diethyl ester.
1H NMR (300MHz, DMSO-D6), δ (ppm) 11.46 (S, 1H, NH), 9.87 (S, 1H, NH), 8.21 (S, 1H, ArH), 7.38 (m, 1H, ArH), 7.27 (m, 2H, ArH), 6.05 (S, 1H, ArH), 4.01 (m, 4H, 2OCH
2), 3.69 (m, 4H, 2NCH
2), 2.45 (m, 6H, 3NCH
2), 2.40 (s, 3H, CH
3), 2.23 (s, 3H, CH
3), 2.10 (m, 2H, PCH
2), 1.22 (t, 6H, 2CH
3) .FABMS:(M+1)
+=608.
Embodiment 7. (piperazine-1-yl) phosphate dibenzyl ester
1.01 gram (10 mmole) triethylamines are dissolved in 5 milliliters of tetracol phenixin; ice-water bath stirs the solution that adds 2.62 gram (10 mmole) dibenzyl phosphites and 7.5 milliliters of tetracol phenixin down; after the reflux 3 minutes; drip the solution of 1.86 gram (10 mmole) uncle's fourth oxygen formyl piperazines and 5 milliliters of tetracol phenixin; backflow is stirred to and reacts completely; cold filtration; filtrate water is washed; saturated sodium bicarbonate is washed, and salt is washed, anhydrous sodium sulfate drying; revolve the separation of desolventizing short column and obtain product uncle 4-fourth oxygen formyl piperazine-1-base phosphate dibenzyl ester. it is dissolved in 10 milliliters of methylene dichloride; be chilled to 0 ℃, add 5 milliliters of trifluoroacetic acids, stirring at room to raw material disappears; concentrating under reduced pressure; add 1N sodium hydroxide and be neutralized to PH=11, with 10%THF/ dichloromethane extraction twice, 10% ethanol/methylene extraction 2 times.Anhydrous magnesium sulfate drying revolves desolventizing short column separation (ethyl acetate) and obtains product piperazine-1-base phosphate dibenzyl ester.
1H NMR (300MHz, DMSO-d), δ (ppm): 7.27-7.38 (m, 10H, ArH), 4.98 (d, 4H, 2OCH
2), 3.19 (m, 4H, 2NCH
2), 2.89 (m, 4H, 2NCH
2) .FABMS:(M+1)
+=347.
Embodiment 8.2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1] phosphate dibenzyl ester
According to embodiment 3,4,5,6 similar experimentations can obtain title compound 2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1] phosphate dibenzyl ester.
1HNMR(300MHz，DMSO-D6)，δ(ppm)11.49(S，1H，NH)，9.87(S，1H，NH)，8.21(S，1H，ArH)，7.20-7.40(m，13H，ArH)，6.02(S，1H，ArH)，4.99(d，4H，2OCH
2)，3.44(m，4H，2NCH
2)，3.09(m，4H，2NCH
2)，2.39(s，3H，CH
3)，2.22(s，3H，CH
3).FABMS：(M+1)
+704.
Embodiment 9. (piperazine-1-yl) methylene radical phosphate dibenzyl ester
Place 250 ml flasks reflux to reacting completely for 120 milliliters 1 milliliter in formaldehyde and the benzene of 1.86 gram (10 mmole) uncle's fourth oxygen formyl piperazines and 2.62 gram (10 mmole) dibenzyl phosphites and 37%; cooling; revolve desolventizing; add acetic acid ethyl dissolution; the sodium hydrogen carbonate solution washing; washing; salt is washed; anhydrous sodium sulfate drying revolves desolventizing, and the short column separation obtains uncle's fourth oxygen formyl piperazine-1-methylene radical phosphate dibenzyl ester. it is dissolved in 10 milliliters of methylene dichloride; be chilled to 0 ℃; add 4 milliliters of trifluoroacetic acids, stirring at room to raw material disappears, concentrating under reduced pressure; add the neutralization of 1N sodium hydroxide; with dichloromethane extraction twice, anhydrous magnesium sulfate drying, revolve desolventizing and obtain product (piperazine-1-yl) methylene radical phosphate dibenzyl ester.
1H NMR (300MHz, CDCl3), δ (ppm): 7.25-7.35 (m, 10H, ArH), 5.01-5.14 (m, 4H, 2OCH
2), 2.82 (d, 2H, NCH
2), 2.65 (m, 4H, 2NCH
2), 2.46 (m, 4H, 2NCH
2) .FABMS:(M+1)
+=361.
Embodiment 10.2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1] the methylene radical phosphate dibenzyl ester
According to embodiment 3,4,5,6 similar experimentations can obtain title compound 2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1] the methylene radical phosphate dibenzyl ester.
1HNMR(300MHz，DMSO-D6)，δ(ppm)11.47(S，1H，NH)，9.87(S，1H，NH)，8.20(S，1H，ArH)，7.21-7.39(m，13H，ArH)，6.03(S，1H，ArH)，5.05(m，4H，2OCH
2)，2.95(d，2H，OCH2)，3.47(m，4H，2NCH
2)，2.62(m，4H，2NCH
2)，2.39(s，3H，CH
3)，2.22(s，3H，CH
3).FABMS：(M+1)
+＝718.
Embodiment 11.2-{6-[4-(2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester
(1.4-diethoxy phosphinylidyne oxygen ethyl)-piperazine-1-benzyl carboxylate
9.1 gram (70 mmole) hydroxyethyl piperazines are dissolved in 210 milliliters of dehydrated alcohols, drip 11.9 gram (70 mmole) carbobenzoxy chlorides under the ice-water bath, stir and drip 7 gram triethylamines after 1 hour, stirring at normal temperature to raw material disappears. and desolventizing is revolved in decompression, adds ethyl acetate, washing, salt is washed, anhydrous sodium sulfate drying revolves desolventizing, and the short column separation obtains product liquid 4-(hydroxyethyl)-piperazine-1-benzyl carboxylate.
2.64 gram (10 mmole) 4-(hydroxyethyl)-piperazine-1-benzyl carboxylates are dissolved among 60 milliliters of anhydrous THF, 60 milliliters of dichloromethane solutions that add the iodate diethyl phosphoric acid (1 mmole/5 milliliter) of equivalent, add 480 milligrams of (60%) sodium hydrides under the stirring at room in batches, stirring at room is to reacting completely. removal of solvent under reduced pressure, add acetic acid ethyl dissolution, the saturated sodium bicarbonate washing, washing, salt is washed, anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product liquid 4-(diethoxy phosphinylidyne oxygen ethyl)-piperazine-1-benzyl carboxylate.
1HNMR (300M, D3CCOCD3), δ ppm 7.33 (m, 5H, ArH), 5.10 (S, 2H ,-OCH2-), 4.08 (m, 6H, OCH2), 3.45 (t, 4H, J=5.1, CONCH2), 2.64 (t, 2H, J=5.7, NCH2), 2.47 (t, 4H, J=5.1, NCH2)-, (1.30 t, 6H, J=6.9, CH3) .FABMS:(M+1)
+=401.
(2.2-piperazine-1)-oxyethyl group diethyl phosphoric acid
4 gram (10 Bo mole) 4-(diethoxy phosphinylidyne oxygen ethyl)-piperazine-1-benzyl carboxylates are dissolved in 180 milliliters of dehydrated alcohols, add 2 gram 10% palladium/carbon, 40-50 ℃ of following normal pressure hydrogenation 16 hours filters, and revolves desolventizing and obtains product liquid 2-(piperazine-1)-oxyethyl group diethyl phosphoric acid.
1H NMR (300M, CDCl
3), δ ppm 4.08 (m, 6H, 3OCH
2), 3.06 (t, 4H, 2NCH
2), 2.69 (m, 6H, 3NCH
2), 1.30 (m, 6H, 2CH
3) .FABMS:(M+1)
+=267.
3. phosphoric acid 2[4-(6-chloro-2-methylpyrimidine-4-yl)-piperazine-1]-the ethyl ester diethyl ester
2.66 gram (10 mmole) 2-(piperazine-1)-oxyethyl group diethyl phosphoric acids are dissolved in 60 milliliters anhydrous 1, in the 4-dioxane, add 2,5 gram (15 mmole) 2-methyl 4,6-dichloro pyrimidine and 10 mmole diisopropyl ethamine, 60-70 ℃ of heated and stirred to raw material disappears, and removal of solvent under reduced pressure adds acetic acid ethyl dissolution, washing, salt is washed, and anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product phosphoric acid 2-[4-(6-chloro-2-methylpyrimidine-4-yl)-piperazine-1]-the ethyl ester diethyl ester.
1H NMR (300M, CDCl
3), δ ppm 6.30 (s, 1H, ArH), 4.09 (m, 6H, 3OCH
2), 3.63 (t, 4H, J=4.8,2NCH
2), 2.71 (t, 2H, J=5.7, NCH2), 2.57 (t, 4H, J=5.1,2NCH2), 2.45 (s, 3H, CH
3), 1.30 (t, 6H, J=6.9, CH
3) .FABMS:(M+1)
+=393.
(4.2-{6-[4-2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester
With 392 milligrams of (1 mmole) phosphoric acid 2-[4-(6-chloro-2-methylpyrimidine-4-yl)-piperazine-1]-ethyl ester diethyl ester and 172 milligrams of (1 mmole) 2-amino-5-ethoxycarbonyl thiazoles are dissolved in 20 milliliters of dry DMF; add 100 milligram (2; 5 mmoles) sodium hydride (60%); stirring at room is to reacting completely; in the impouring saturated solution of sodium bicarbonate; ethyl acetate extraction; washing; salt is washed; anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product 2-{6-[4-(2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4 amino }-thiazole-5-carboxylic acid ethyl ester.
1H NMR (300MHz, D-acetone), δ (ppm) 7.95 (S, 1H, ArH), 6.2 1 (s, 1H, ArH), 4.29 (q, 2H, J=7.2, OCH
2), 4.08 (m, 6H, 3OCH
2), 3.66 (t, 4H, J=5.1,2NCH
2), 2.67 (t, 4H, J=4.8,2NCH
2), 2.77 (t, 2H, J=5.4, CH
2), 2.44 (s, 3H, CH
3), 1.25 (m, 9H, 3CH
3) .FABMS:(M+1)
+=529.
Embodiment 12.2-{6-[4-(2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid
With 528 milligrams of (1 mmole) 2-{6-[4-(2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid ethyl ester is dissolved in 20 ml methanol, stir and drip 20 milliliters of 2.5N sodium hydroxide solutions down, stirring at room to raw material point disappears, methanol solvate is removed in decompression, resistates extracts with amount of ethyl acetate, water layer is placed ice bath, stir and drip concentrated hydrochloric acid or 6N hydrochloric acid down to PH=5-6, a large amount of precipitations appear, leave standstill half an hour, suction filtration obtains solid product 2-{6-[4-(2-diethoxy phosphorus acyloxy ethyl) piperazine-1]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid.
1H NMR (300MHz, DMSO-d6), δ (ppm) 11.74 (s, 1H, OH), 7.97 (S, 1H, ArH), 6.19 (s, 1H, ArH), 4.40 (br, 2H, OCH
2), 4.08 (q, 4H, J=7.5,2OCH
2), 3.0-3.7 (br, 10H, 5NCH
2), 2.44 (s, 3H, CH
3), 1.27 (t, 6H, J=7.2,2CH
3).
FABMS：(M+1)
+＝501.
Embodiment 13. phosphoric acid 2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1]-the ethyl ester diethyl ester
2-{6-[4-(the 2-diethoxy phosphorus acyloxy ethyl) piperazine-1 that 500 milligrams (1 Bo mole) is dry]-2-methylpyrimidine-4-amino }-thiazole-5-carboxylic acid places the single port flask; DMF and 152 milligrams of (1.5 mmole) triethylamines of adding 15 milliliters of dryings; drip 326 milligrams of (2 mmole) diethyl phosphorocyanidates (DECP) after the stirring and dissolving; be heated to 60-70 ℃ gradually; the stirring raw material disappears; after revolving desolventizing; add dehydrated alcohol; separate out white solid, filter and obtain product phosphoric acid 2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1]-the ethyl ester diethyl ester.
1H NMR (300MHz, DMSO-D6), δ (ppm) 11.47 (S, 1H, NH), 9.87 (S, 1H, NH), 8.21 (S, 1H, ArH), 7.38 (m, 1H, ArH), 7.26 (m, 2H, ArH), 6.04 (S, 1H, ArH), 4.02 (m, 6H, 3OCH
2), 3.50 (m, 4H, 2NCH
2), 2.62-2.49 (m, 6H, 3NCH
2), 2.40 (s, 3H, CH
3), 2.22 (s, 3H, CH
3), 1.24 (t, 6H, 2CH
3) .FABMS:(M+1)
+=624.
Embodiment 14.3-{6-[5-(2-chloro-6-methylaniline formyl) thiazole-2-amino]-2-methylpyrimidine-4} propyl group diethyl phosphoric acid
1.66 gram (10 Bo mole) triethyl-phosphites and 12.12 gram (60 mmole) 1.3-dibromopropanes are placed 50 milliliters of single port bottles, reflux to triethyl-phosphite disappears, the remaining 1.3-dibromopropane of pressure reducing and steaming, obtain 3-bromopropyl diethyl phosphoric acid (85 ℃, 2mmHg).
4.3 gram (16.6 mmole) 3-bromopropyl diethyl phosphoric acids are dissolved in 40 milliliters of dry DMF, add phthalimide-based potassium 4.61 grams (24.9 mmole), stirred 10 hours down at 100 ℃, be down to room temperature, filter, collect filtrate, concentrating under reduced pressure adds 100 milliliters of chloroforms, washing, anhydrous sodium sulfate drying revolves desolventizing and obtains colourless liquid 3-phthalimide-based propyl group diethyl phosphoric acid.
3.5 gram (10.2 mmole) 3-phthalimide-based propyl group diethyl phosphoric acids are dissolved in 50 milliliters of dehydrated alcohols, splash into 0.7 milliliter of one hydrazine hydrate under stirring, stirring at room refluxed one hour after 5 hours, and removal of solvent under reduced pressure, column chromatography for separation obtain product 3-aminopropyl diethyl phosphoric acid.
1.95 gram (10 mmole) 3-aminopropyl diethyl phosphoric acids are dissolved among 60 milliliters of anhydrous THF, add 2,5 gram (15 mmole) 2-methyl 4,6-dichloro pyrimidine and 10 mmole diisopropyl ethamine, 40-50 ℃ of heated and stirred to raw material disappears, removal of solvent under reduced pressure, add acetic acid ethyl dissolution, washing, salt is washed, anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product 3-(6-chloro-2-methylpyrimidine-4-yl) propyl group diethyl phosphoric acid.
321 milligrams of (1 mmole) 3-(6-chloro-2-methylpyrimidine-4-yl) propyl group diethyl phosphoric acid and 172 milligrams of (1 mmole) 2-amino-5-ethoxycarbonyl thiazoles are dissolved in 20 milliliters of dry DMF; add 100 milligrams of (2.5 mmole) sodium hydrides (60%); stirring at room is to reacting completely; in the impouring saturated solution of sodium bicarbonate; ethyl acetate extraction; washing; salt is washed; anhydrous sodium sulfate drying revolves the separation of desolventizing short column and obtains product 2-[6-(3-diethoxy phosphinylidyne propyl group) amino-2-methyl pyrimidine-4] amino-thiazolyl--5-carboxylic acid, ethyl ester.
With 457 milligrams of (1 mmole) 2-[6-(3-diethoxy phosphinylidyne propyl group) amino-2-methyl pyrimidine-4] amino-thiazolyl--5-carboxylic acid, ethyl ester is dissolved in 20 ml methanol, stir and drip 20 milliliters of 2.5N sodium hydroxide solutions down, stirring at room to raw material point disappears, methanol solvate is removed in decompression, resistates extracts with amount of ethyl acetate, water layer is placed ice bath, stir and drip concentrated hydrochloric acid or 6N hydrochloric acid down to PH=5-6, a large amount of precipitations appear, leave standstill half an hour, suction filtration obtains solid product 2-[6-(3-diethoxy phosphinylidyne propyl group) amino-2-methyl pyrimidine-4] amino-thiazolyl--5-carboxylic acid.
With 429 milligrams of (1 mmole) 2-[6-(3-diethoxy phosphinylidyne propyl group) amino-2-methyl pyrimidine-4] amino-thiazolyl--5-carboxylic acid and 126 milligrams of (1 mmole) 2-chloro-6-methyl phenylaminos and 152 milligrams of (1.5 mmole) triethylamines are dissolved in 15 milliliters of dry DMF; stir and drip 326 milligrams of (2 mmole) diethyl phosphorocyanidates (DECP) down; be heated to 60-70 ℃ gradually; the stirring raw material disappears; after revolving desolventizing; add dehydrated alcohol; separate out white solid, filter and obtain product 3-{6-[5-(2-chloro-6-methylaniline formyl) thiazole-2-amino]-2-methylpyrimidine-4} propyl group diethyl phosphoric acid.
1H NMR (500MHz, DMSO-D6), δ (ppm) 10.02 (S, 1H, NH), 8.31 (S, 1H, ArH), 7.39 (m, 1H, ArH), 7.28 (m, 2H, ArH), 6.95 (S, 1H, ArH), 3.97 (m, 4H, 2OCH
2), 2.83 (m, 2H, NCH
2), 2.58 (s, 3H, CH
3), 2.23 (s, 3H, CH
3), 1.72 (m, 4H, 2CH
2), 1.21 (t, 6H, 2CH
3) .FABMS:(M+1)
+=553.
External activity is estimated:
1. to the restraining effect of growth of tumour cell
1). cell cultures
Test the K562 cell of used K562 cell and anti-Imatinib in containing 5%CO
237 ℃ of incubators in cultivate and go down to posterity, cultivate with the RPMI RPMI-1640 that contains 10% foetal calf serum and 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates, go down to posterity weekly twice.
2) the .MTT method is measured the tumour cell survival rate
Being mixed with concentration behind the cell centrifugation with logarithmic phase is 1 * 10
5The cell suspension of cell/ml, be inoculated in 96 orifice plates by 10000/hole, every hole adds 100 μ l, add the fresh culture that contains different concns medicine and coordinative solvent contrast, every hole adds 100 μ l (DMSO final concentration＜0.1%), establish three parallel holes for every group, in 37 ℃ cultivate 3 days after, every hole adds the serum free medium of the freshly prepared 5mg/ml of the containing MTT of 20 μ l, continues to cultivate 4 hours, and is centrifugal, abandon supernatant, every hole adds 200 μ l DMSO dissolving MTT first hairpin precipitation, with the microoscillator mixing that vibrates, with MK3 type microplate reader at reference wavelength 450nm, detect under the wavelength 570nm condition and measure optical density value (OD), the tumour cell of handling with solvent control is control group, calculates medicine to the inhibiting rate of tumour cell with following formula, and calculates IC50 by middle efficacious prescriptions journey:
3). experimental result:
Table 1. embodiment 6 is in external influence to tumor growth
The ND representative is not surveyed
Activity in vivo is estimated:
1. the foundation of leukemia mouse model
The SCID mouse, female, age in 6-8 week, body weight 20-25g, Chinese Academy of Medical Sciences's zooscopy provides.Continuous 2 days of abdominal cavity injection endoxan (CTX) 2mg/ only, inject once every day, the vegetative period K562 cell of taking the logarithm in the 3rd day is used for transplanting, with the disposable injection 1 * 10 of tail vein
7Individual/mouse, the SCID mouse number of each tail vein injection is identical.
2. animal grouping
The injection cell is after 20 days, and animal skin is wrinkling, and is dispirited few moving, loses weight.At this moment begin oral administration.Be divided into five groups, 4 every group, control group, the oral equivalent physiological saline of leukemia model mice.The Dasatinib group is pressed the 30mg/kg body weight, and embodiment 6 presses 18mg/kg, 36mg/kg body weight oral administration, successive administration 20 days, the lifetime of then observing mouse.
The influence of 6 couples of human chronic myelogenous leukemia K562 of embodiment cell NOD/SCID heteroplastic transplantation model mice spleen index
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with the normal control group; #P＜0.05, ##＜0.01, ###＜0.001 is compared with model group
6 pairs of white blood of people's chronic granulocyte of embodiment. the influence of sick K562 cell NOD/SCID heteroplastic transplantation model mice peripheral white blood cell
*P＜0.05,
*P＜0.01,
* *P＜0.001 is compared with the normal control group; #P＜0.05, ##P＜0.01, ###P＜0.001 is compared with model group
Claims (4)
1. pyrimidine thiazole sulfonamide derivatives and the pharmacologically acceptable salt thereof shown in the following formula
2-[4-{6-[5-(2-chloro-6-methylaniline formyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1]-the ethyl phosphonic acid diethyl ester
2. a pharmaceutical composition is characterized in that, contains compound as claimed in claim 1 and the pharmaceutical carrier of medicine effective dose.
3. compound according to claim 1 prevents and/or treats application in the tumour medicine in preparation.
4. according to the application of claim 3, it is characterized in that described tumour comprises leukemia, neurospongioma, incidence cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer, mammary cancer, ovarian cancer, squamous cell carcinoma.
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| CN101265274B (en) * | 2007-02-16 | 2013-09-04 | 中国医学科学院药物研究所 | Pyrimidinthiazolamine derivatives, and preparation method, medicament composition and use thereof |
| CN101812060B (en) * | 2010-02-02 | 2011-08-17 | 南京卡文迪许生物工程技术有限公司 | Simple novel method for preparing high-purity Sprycel, and intermediate compound |
| CN102786517B (en) * | 2011-05-18 | 2017-06-06 | 中国医学科学院药物研究所 | The pyrimidine thiazole amines derivative of GK and PPAR double excitation activity |
| CN103130740A (en) * | 2011-11-29 | 2013-06-05 | 长江大学 | Amino acid derivatives of seedvax and application for being used as bactericides thereof |
| CN115590852A (en) * | 2014-12-09 | 2023-01-13 | 正大天晴药业集团股份有限公司（Cn） | Quinoline derivatives for treating non-small cell lung cancer |
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| CN101265275A (en) * | 2007-02-16 | 2008-09-17 | 中国医学科学院药物研究所 | Diethyl 4-{6-[5-(2-chloro-6-methylanilinoformacyl)-thiazolyl-2-amino]-2-methylpyrimidin-4}-piperazin-1-phosphate |
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| CN101481359A (en) * | 1999-04-15 | 2009-07-15 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| GB0126902D0 (en) * | 2001-11-08 | 2002-01-02 | Novartis Ag | Organic compounds |
| US20050009891A1 (en) * | 2003-07-09 | 2005-01-13 | Lee Francis Y. | Combination of SRC Kinase inhibitors and chemotherapeutic agents for the treatment of proliferative diseases |
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| CN101265275A (en) * | 2007-02-16 | 2008-09-17 | 中国医学科学院药物研究所 | Diethyl 4-{6-[5-(2-chloro-6-methylanilinoformacyl)-thiazolyl-2-amino]-2-methylpyrimidin-4}-piperazin-1-phosphate |
| CN101323629A (en) * | 2007-02-16 | 2008-12-17 | 中国医学科学院药物研究所 | 4-{6-[5-(2-chlorinde-6- methylaniline formyl)-thiazole-2-amido]-2-methyl pyrimidine-4}-piperazine-1- diethyl methylphosphate |
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| CN101265274A (en) | 2008-09-17 |
| CN101323629A (en) | 2008-12-17 |
| CN101323629B (en) | 2011-08-17 |
| CN101265275B (en) | 2012-09-05 |
| CN101265275A (en) | 2008-09-17 |
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