CN101423513B - Amine pyrimidine derivates, and production method thereof, and medicament composition and use - Google Patents
Amine pyrimidine derivates, and production method thereof, and medicament composition and use Download PDFInfo
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- CN101423513B CN101423513B CN 200710176471 CN200710176471A CN101423513B CN 101423513 B CN101423513 B CN 101423513B CN 200710176471 CN200710176471 CN 200710176471 CN 200710176471 A CN200710176471 A CN 200710176471A CN 101423513 B CN101423513 B CN 101423513B
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- 0 *C(Nc1cc(N(*)c2nccc(*)n2)c(*)cc1)=O Chemical compound *C(Nc1cc(N(*)c2nccc(*)n2)c(*)cc1)=O 0.000 description 1
- KMFDWQPHZZVLOH-UHFFFAOYSA-N CC(C)(C)C(OCN(c1c(C)ccc(N)c1)c1nccc(-c2cccnc2)n1)=O Chemical compound CC(C)(C)C(OCN(c1c(C)ccc(N)c1)c1nccc(-c2cccnc2)n1)=O KMFDWQPHZZVLOH-UHFFFAOYSA-N 0.000 description 1
- JXHOVWIDBLKEBG-UHFFFAOYSA-N CC(N(c1c(C)ccc(N)c1)c1nccc(-c2cccnc2)n1)=O Chemical compound CC(N(c1c(C)ccc(N)c1)c1nccc(-c2cccnc2)n1)=O JXHOVWIDBLKEBG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses an aminopyrimidine derivative shown in general formula I, medicinal salt thereof, hydrate and solvate thereof, polycrystal and eutectic crystal thereof, a precursor or a derivative with the same biological function thereof, a preparation method thereof, a composition containing one or a plurality of the compounds, and application of the compound in treating diseases related to protein-tyrosine kinase, such as immunity imbalance and neoplastic diseases.
Description
Technical field
The present invention relates to the amine pyrimidine derivates shown in the general formula I, 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 the composition of one or more these compounds, with this compounds in the treatment disease relevant with protein tyrosine kinase such as the purposes aspect immune disorder and the tumor disease.
Background technology
Cancer is still one of the most fatal disease at present, and chemotherapy is to suppress tumor growth and cancer cells diffusion, makes the important means of tumor regression.Traditional chemotherapeutics majority is for directtissima DNA or suppress its cytotoxic drug synthetic and function, also kills and wounds normal cell in the time of kill cancer cell, and only effective to breeding fast tumour, and side effect is strong.In order to improve the selectivity to the cancer cells effect, people have not passed through another approach of the carcinostatic agent of inhibition DNA synthesis mechanism in research.
In recent years, because the Study on Molecular Mechanism of tumor development has obtained breakthrough, the specific molecular biosciences target spot (Science that the research steering of new drug works in the nosetiology of cancer and pathologic process, 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 again canceration reverse (Drugs, 2000,59 (4), 753) 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): such as the member (for example HER1 and HER2) of epidermal growth factor kinase family, outside Thr6 PDGF BB (PDGF) and the kinases (Tie-2 and KDR) that in vascularization, works, also comprise non-receptor tyrosine kinase c-Ab 1, Syk, the member of JAK and Src family (Sro for example, Fyn, Lyn, Lck and Blk), (FASEB J.1992 to see " the src family of the tyrosine protein kinase in the hematopoiesis signal transduction ", 6,3403-3409); " Role in Plant Signal Transduction with acceptor of tyrosine kinase activity " (Cell, 1990,61,203-212).
Chronic granulocytic leukemia (chronic myeloid leukemia, CML) is the malignant clone disease that a kind of pluripotential hemopoietic stem cell proliferative abnormality causes, accounts for 15% of adult leukemia.Research is found, has a kind of unusual minisome (22q-) in CML patient's hemopoietic stem cell of 95%, i.e. Ph karyomit(e) is to be t (9 by No. 9 and No. 22 chromosome reciprocal translocation; 22) (q34; Ql1) form, transposition causes No. 9 long-armed ends of karyomit(e) (9q34) c-Abl proto-oncogene at 5 end fractures of exon 2, and merges formation Bcr-Abl fusion gene with the c-Bcr gene 3 ends generation of No. 22 long-armed ends of karyomit(e) (22ql1).The Bcr-Abl fusion rotein of this fusion gene coding has the tyrosine kinase activity of abnormal activation, cause self tyrosine residues and many important substrate protein phosphorylations, thereby activate many barss pathway, make cell in the situation that do not rely on cytokine and vicious transformation, hyper-proliferative, differentiation and apoptosis occur suppressed.Therefore, can reach by the tyrosine kinase activity that suppresses excessive activation the control leukemia cell and grow, induce its apoptosis.The tyrosine kinase inhibitor imatinib (imatinib) that has gone on the market at present can optionally suppress the tyrosine kinase activity of chronic myelocytic leukemia (CML) patient B cr-Abl albumen, thereby block many barss pathway, reach the leukemic purpose for the treatment of.In addition, this medicine can also suppress the receptor type tyrosine kinases activity such as c-Kit, platelet-derived growth factor acceptor (PDGFR), ARG.
The activity of PTK not only all demonstrates enhancing in many pernicious and non-malignant proliferative 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, φt cell receptor (TCR) zeta chain is not phosphorylated, and kinases ZAP-70 is not activated, and can not occur 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 such as rheumatoid arthritis, multiple sclerosis and lupus and known T cell, for example acute transplant rejection and delayed hypersensitivity.
Although it has been found that many small molecule tyrosine kinase inhibitors, very large contribution has been made in this area, for improving cancer therapy drug, research is still being continued in this area.
Summary of the invention
The object of the present invention is to provide a kind of novel 2-anilino-pyrimidine derivative, 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 of the 2-of preparation anilino-pyrimidine derivative.
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.
In order to finish the present invention's purpose, can adopt following technical scheme:
The present invention relates to have the novel 2-anilino-pyrimidine derivative of following general formula I:
In addition, particularly preferred the compounds of this invention is general formula I pyrimidine derivatives or its pharmacologically acceptable salt.
In the formula,
R1 is selected from :-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.Wherein, " alkane " base is selected from C
1-12Straight or branched, 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, aryl, oxo.
" virtue " base is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace, such as phenyl ring, and naphthalene nucleus, quinoline ring, the isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene 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.
R1 is more preferably :-COOM (M=potassium, sodium, calcium, magnesium);-PO
3M
2,-CH
2OR5 (R5=hydrogen, the ethanoyl valeryl, isobutyryl, benzoyl, the benzoyl of replacement, the C1-C18 alkoxyl formyl replaces or does not replace aromatic ring or fragrant heterocycle oxygen formyl radical); (the R6=C1-C18 alkyl replaces or does not replace aromatic ring or aromatic heterocyclic, C to-COR6
1-18The alkyloyloxyethyl methoxyl group replaces or does not replace aromatic ring or fragrant heterocycle acyl-oxygen methoxyl group).
R1 is particularly preferably :-COOM (M=potassium, sodium);-CH
2OR5 (R5=hydrogen, ethanoyl, valeryl, isobutyryl, benzoyl, the benzoyl of replacement, methoxycarbonyl base, isobutyl oxygen formyl radical, uncle's fourth oxygen formyl radical, fluorobenzene formyl radical, pyridine formyl radical);-COR6 (the R6=methyl, the carboxylic propyl group, uncle's fourth oxygen formyl ethyl, salicyl,
Uncle's 2-fourth oxygen formylphenyl, 2-acetyl Oxymethylene phenyl, 2-pivalyl Oxymethylene phenyl, uncle's fourth oxygen methanoyl methylene radical oxygen base, pivalyl Oxymethylene oxygen base, fluorobenzene methanoyl methylene radical oxygen base).
R1 most preferably is :-COOM (M=potassium, sodium);-CH
2OR5 (R5=hydrogen, valeryl, the methoxycarbonyl base, uncle's fourth oxygen formyl radical);-COR6 (R6=methyl, uncle's fourth oxygen formyl ethyl, uncle's 2-fourth oxygen formylphenyl, 2-pivalyl Oxymethylene phenyl, uncle's fourth oxygen methanoyl methylene radical oxygen base, pivalyl Oxymethylene oxygen base, fluorobenzene methanoyl methylene radical oxygen base).
R2 is selected from hydrogen, alkyl, and (wherein, alkyl is selected from C to aryl
1-12Straight or branched, 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 that replaces, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino, " virtue " base, oxo.Wherein, " virtue " base is selected from aromatic ring and the fragrant heterocycle that replaces or do not replace, such as phenyl ring, and naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, imidazole ring.Substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, itrate group, amino, the amino of replacement, amido, the amino azo-group that replaces, 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: C
1-18The alkyl that replaces or do not replace comprises the carbocyclic ring that replaces or do not replace or heterocycle (contain aerobic, nitrogen, sulfur heteroatom 1-3), and wherein substituting group comprises halogen, hydroxyl, nitro, itrate group, cyano group, amino, the amino of replacement, amido, carboxyl, ester group, alkoxyl group, alkanoyloxy, alkylamino; The aromatic ring and the fragrant heterocycle that replace or do not replace, such as phenyl ring, naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, pyrrole ring, pyridine ring, pyrimidine ring, furan nucleus, thiphene ring, imidazole ring, substituting group is selected from halogen, methyl, trifluoromethyl, hydroxyl, nitro, itrate group, amino, the amino of replacement, amido, the amino azo-group that replaces, 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 particularly preferably: methyl, the 2-methoxy ethyl, the 3-methoxy-propyl, 4-methoxyl group butyl, the 2-ethoxyethyl group, the 3-ethoxycarbonyl propyl, N-methyl piperidine methyl, 4-oxyethyl group butyl, trifluoromethyl, 2,2, the 2-trifluoroethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 2-(N, the N-dimethylamino) ethyl, 3-(N, the N-dimethylamino) propyl group, 4-N, the N-dimethylamino) butyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, 5-morpholino amyl group, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, 5-piperidino-(1-position only) amyl group, 2-(piperazine-1-yl) ethyl, 3-(piperazine-1-yl) propyl group, 4-(piperazine-1-yl) butyl, 2-(4-methylpiperazine-1-yl) ethyl, 3-(4-methylpiperazine-1-yl) propyl group, 4-(4-methylpiperazine-1-yl) butyl, 2-(2-methylsulfonyl oxyethyl group) ethyl, 2-(2-methylsulfonyl ethylamino-) ethyl, 2-(2-methylsulfonyl second sulfydryl) ethyl, 2-pyrrolidino ethyl, 3-pyrrolidino propyl group, 4-pyrrolidino butyl, 2-(2-oxo-pyrrolidine subbase) ethyl, 3-(2-oxo-pyrrolidine subbase) propyl group, 4-(2-oxo-pyrrolidine subbase) butyl, 2-(imidazoles-1-yl)-ethyl, 3-(imidazoles-1-yl)-propyl group, 4-(imidazoles-1-yl)-butyl, 2-(dialkylamino) ethyl, 3-(dialkylamino) propyl group, 4-(dialkylamino) butyl, 2-(substituted benzoyl amido) ethyl, 3-(substituted benzoyl amido) propyl group, 4-(substituted benzoyl amido) butyl, 2-methanesulfonamido ethyl, 3-methanesulfonamido propyl group, 4-methanesulfonamido butyl, 2-phenylsulfonamido ethyl, 3-phenylsulfonamido propyl group, 4-phenylsulfonamido butyl, 2-sulfamyl ethyl, 3-sulfamyl propyl group, 4-sulfamyl butyl; 3-trifluoromethyl-5-acetylamino phenyl; 3-trifluoromethyl-5-ethylamino phenyl; 3-trifluoromethyl-5-(N-morpholinyl) phenyl; 3-trifluoromethyl-5-(4-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-5-(2-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-5-(TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(4-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(2-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(2; 4-dimethyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(4-methylpiperazine-1-yl) methylene radical phenyl; 3-bromo-4-(4-methylpiperazine-1-yl) methylene radical phenyl; 4-(N-methyl hydroxyethylamine) azo-group phenyl; 4-dimethylin azo-group phenyl; 4-(4-methylpiperazine-1-yl) methylene radical phenyl .R2 most preferably is: 4-N; the N-dimethylamino) butyl; 5-morpholino amyl group; 2-piperidino-(1-position only) ethyl; 4-piperidino-(1-position only) butyl; 4-(piperazine-1-yl) butyl; 4-(4-methylpiperazine-1-yl) butyl; 2-(2-methylsulfonyl oxyethyl group) ethyl; 4-(2-oxo-pyrrolidine subbase) butyl; 4-methanesulfonamido butyl; 4-sulfamyl butyl; 3-trifluoromethyl-5-acetylamino phenyl; 3-trifluoromethyl-5-ethylamino phenyl; 3-trifluoromethyl-5-(N-morpholinyl) phenyl; 3-trifluoromethyl-5-(4-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-5-(2-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-5-(TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(4-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(2-methyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(2; 4-dimethyl-TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(TMSIM N imidazole base) phenyl; 3-trifluoromethyl-4-(4-methylpiperazine-1-yl methylene radical) phenyl; 3-bromo-4-(4-methylpiperazine-1-yl methylene radical) phenyl; 4-(N-methyl hydroxyethylamine azo-group) phenyl; 4-dimethylin azo-group phenyl, 4-(4-methylpiperazine-1-yl methylene radical) phenyl.
R3 is selected from, the heterocycle or the aromatic heterocyclic that replace or do not replace.
R3 is more preferably: the phenyl ring that replaces or do not replace, pyridine ring, pyrimidine ring.
R3 is particularly preferably: 3-pyridine-1-base, 3,5-pyrimidine-1-base, 3-bromo-5-pyridine-1-base.
R3 most preferably is: 3-pyridine-1-base, 3,5-pyrimidine-1-base.
R4 is selected from hydrogen, methyl, trifluoromethyl, halogen.
R4 is more preferably: hydrogen, methyl, trifluoromethyl.
R4 is particularly preferably: hydrogen, methyl, trifluoromethyl.
R4 most preferably is: methyl, trifluoromethyl.
Most preferred compound is selected from:
R1 is selected from hydrogen, methyl, tert.-butoxy.
R2 is more preferably: hydrogen, methyl, trifluoromethyl.
R3 most preferably is: 3-pyridine-1-base, 3,5-pyrimidine-1-base.
R4 most preferably is: methyl.
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) ethanamide
4N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) uncle's fourth oxygen methane amide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-nitro aniline
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide
2N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-amino aniline
5N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide
N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
3N-[3-(N-pivalyl Oxymethylene-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
6N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-methylpiperazine-1-yl methylene radical) benzamide
7N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-trifluoromethyl-5-(4-methylimidazole-1-yl) benzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-niacinamide
N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-cyano group benzoylamino) benzamide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-(indoles-3-propionamido) phenyl) uncle's fourth oxygen methane amide
N-[3-(uncle's N-fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
The described pyrimidine derivatives of general formula I can solvate or the form of non-solvent compound exist, utilize different solvents to carry out crystallization and may obtain different solvates.The salt of the pyrimidine derivatives of the described pharmaceutically acceptable alkalescence of general formula I comprises different acid salt, such 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 salt of the quinazoline derivant of the described pharmaceutically acceptable acidity of general formula I comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt (calcium, magnesium salts) and ammonium salt, with the salt that physiologically acceptable cationic organic bases can be provided, such 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 derivatives and solvate and its salt, polycrystalline or eutectic may appear in different crystallization conditions.
The present invention also relates to the method for preparing compound of Formula I of the present invention on the other hand.Preparation method of the present invention is that the anilino-pyrimidine that replaces of nitro provides the anilino-pyrimidine that N-R1 replaces with halides or carboxylic acid halides or ester or acid anhydride effect first between utilizing; be amino again with nitroreduction; then make the amido acidylate with carboxylic acid or ester or carboxylic acid halides or acid anhydride or isocyanate reaction, finally obtain the described compound of general formula I.
In addition, starting raw material and intermediate in the above-mentioned reaction easily obtain, or can be easy to the ordinary method in the organic synthesis synthesize to those skilled in the art.
Further aspect of the present invention also 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 the 0.1-95 % by 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, such 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 widely used 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 can with effective constituent the compounds of this invention elder generation and thinner, tamanori, disintegrating agent granulation or micropill, place again hard capsule or soft capsule.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, such as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
The compounds of this invention is tyrosine kinase inhibitor or its precursor, and to kinds of tumors and amynologic disease, the disease relevant with increment with vascular smooth muscle cells migration has therapeutic action, and especially anti-tumor activity is obvious.The compounds of this invention has higher bioavailability, can be used for the treatment of multiple human malignancies, comprises leukemia, neurospongioma, incidence cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma etc.
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 0.1-100mg/Kg body weight, and more preferably the 1-60mg/Kg body weight most preferably is the 2-30mg/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 according to practical situation its dosage.
Embodiment
Below with reference to embodiment invention is described further, but does not limit the scope of the invention.
Determining instrument: fusing point Yanaco micro-meldometer, NMR (Nuclear Magnetic Resonance) spectrum Vaariaan Mercury 300 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment 1.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) ethanamide
307mg 4-(pyridin-3-yl)-2-(2-methyl-5-nitro anilino) pyrimidine is placed 50 ml flasks, add 30 milliliters of acetic anhydrides and 100 milligrams of sodium acetate, anhydrouss, being heated to 70oC stirs after 5 hours decompression and takes out acetic anhydride, add 20 ml waters and use ethyl acetate extraction, washing, saturated sodium-chloride water solution is washed, and anhydrous sodium sulfate drying spends the night, and revolves desolventizing and obtains N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) ethanamide.
1H?NMR(300M，CDCl
3)，δ(ppm)9.12(S，1H，ArH)，8.65(d，1H，ArH)，8.62(d，1H，ArH)，8.17(m，1H，ArH)，8.10(dd，1H，ArH)，8.02(d，1H，ArH)，7.47(d，1H，ArH)，7.43(d，1H，ArH)，7.38(dd，1H，ArH)，2.61(S，3H，-COCH
3)，2.25(S，3H，-CH
3).FABMS：(M+H)
+＝350。
Embodiment 2.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide
349 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) ethanamide is placed 100 ml flasks, add 50 ml methanol and 35 milligrams of 10%Pd/C, normal pressure hydrogenation filtered after 5 hours, revolve desolventizing, obtain N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide.
1H?NMR(300M，DMSO-d)，δ(ppm)9.27(S，1H，ArH)，8.82(d，1H，ArH)，8.72(S，1H，ArH)，8.46(d，1H，ArH)，7.97(d，1H，ArH)，7.58(m，1H，ArH)，6.95(d，1H，ArH)，6.47(d，1H，ArH)，6.39(dd，1H，ArH)，2.32(S，3H，-COCH
3)，1.98(S，3H，-CH
3).FABMS：(M+H)
+＝320。
Embodiment 3.N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
319 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide and 197 milligrams of 3-kharophen Benzoyl chlorides are dissolved in 20 milliliters of anhydrous pyridines; after the stirring at room 12 hours; solvent is removed in decompression; add acetic acid ethyl dissolution; the saturated sodium bicarbonate solution washing; washing; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night; revolve desolventizing; column chromatography for separation obtains N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide.
1H?NMR(300M，DMSO-D6)，δ(ppm)10.25(S，1H，N-H)，10.12(S，1H，N-H)，9.30(d，1H，ArH)，8.84(d，1H，ArH)，8.76(dd，1H，ArH)，8.50(d，1H，ArH)，8.02(m，2H，ArH)，7.68(m，2H，ArH)，7.59(m，2H，ArH)，7.41(t，1H，ArH)，7.32(d，1H，ArH)，7.80(dd，1H，ArH)，2.50(S，3H，-CH
3)，2.12(S，3H，-CH
3)，2.06(S，3H，-CH
3).FABMS：(M+H)
+＝481。
Embodiment 4.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-nitro aniline
With 307mg 4-(pyridin-3-yl)-2-(2-methyl-5-nitro anilino) pyrimidine and 150 milligram 2,2-neopentanoic acid chloromethyl ester places 100 ml flasks, add 50 milliliters of anhydrous THF dissolvings, under the stirring at room, add 48 milligrams of sodium hydrides (60%), stir after 3 hours, add again 150 milligram 2,2-neopentanoic acid chloromethyl ester and 48 milligrams of sodium hydrides (60%) are stirred to and react completely, most of solvent is removed in decompression, add saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying revolves the desolventizing column chromatography for separation and obtains N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-nitro aniline.
1H?NMR(300M，DMSO-d6)，δ(ppm)9.25(S，1H，ArH)，8.72(d，1H，ArH)，8.22(m，1H，ArH)，8.58(S，1H，ArH)，8.42(S，1H，ArH)，8.19(m，1H，ArH)，7.68(m，2H，ArH)，7.56(m，1H，ArH)，6.19(d，1H，N-CH
2-O)，5.98(d，1H，N-CH
2-O)，2.26(S，3H，-CH
3)，1.09(S，9H，-CH
3).FABMS：(M+H)
+＝422。
Embodiment 5.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-amino aniline
421 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-nitro aniline is placed 100 ml flasks, add 50 ml methanol and 35 milligrams of 10%Pd/C, normal pressure hydrogenation filtered after 5 hours, revolve desolventizing, obtain N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-amino aniline.
1H?NMR(300M，DMSO-d6)，δ(ppm)9.25(S，1H，ArH)，8.69(d，1H，ArH)，8.49(m，2H，ArH)，7.55(m，1H，ArH)，7.46(d，1H，ArH)，6.95(d，1H，ArH)，6.49(m，2H，ArH)，5.05(m，2H，N-CH
2-O)，1.89(S，3H，-CH
3)，1.09(S，9H，-CH
3).FABMS：(M+H)
+＝392。
Embodiment 6.N-[3-(N-pivalyl Oxymethylene-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
391 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-amino aniline and 179 milligrams of 3-acetylamino benzoic acids are dissolved in 20 milliliters of dry DMF, add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP, be heated to 70oC, stir and be chilled to room temperature after 20 hours, in the impouring sodium bicarbonate frozen water solution, add ethyl acetate extraction three times, merge organic layer, wash 3 times, the saturated common salt water washing, anhydrous sodium sulfate drying spends the night, revolve desolventizing, column chromatography for separation obtains N-[3-(N-pivalyl Oxymethylene-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
1HNMR (300M, CD
3COCD
3), δ (ppm) 9.56 (S, 1H, N-H), 9.32 (S, 1H, N-H), 8.66 (S, 1H, ArH), 8.48 (S, 1H, ArH), 8.26 (m, 1H, ArH), 8.14 (m, 2H, ArH), 7.90 (m, 2H, ArH), 7.80 (m, 2H, ArH) 7.66 (m, 2H, ArH), 7.40 (m, 2H, ArH), (7.30 m, 1H, ArH) 5.68 (d, 1H ,-CH
2-), 5.22 (d, 1H ,-CH
2-), 2.12 (S, 3H ,-CH
3), 2.09 (S, 3H ,-CH
3), 1.22 (s, 9H ,-CH
3) .FABMS:(M+H)
+=553.
Embodiment 7.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) uncle's fourth oxygen methane amide
307mg 4-(pyridin-3-yl)-2-(2-methyl-5-nitro anilino) pyrimidine is placed 100 ml flasks, add 50 milliliters of anhydrous THF dissolvings, add 48 milligrams of sodium hydrides (60%) under the stirring at room in batches, stir after 0.5 hour, add 260 milligrams of uncle's fourth oxygen formic anhydrides, stirring at room 24 hours, revolve most of solvent, add saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying revolves desolventizing and obtains N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) uncle's fourth oxygen methane amide.
1HNMR(400M，CDCl3)，δ(ppm)9.19(S，1H，ArH)，8.73(d，1H，ArH)，8.69(d，1H，ArH)，8.28(d，1H，ArH)，7.42(d，2H，ArH)，7.07(d，1H，ArH)，6.66(m，2H，ArH)，2.15(S，3H，-CH
3)，1.47(S，9H，-CH
3)，FABMS：(M+H)
+＝408。
Embodiment 8.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide
407 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) uncle's fourth oxygen methane amide is placed 100 ml flasks, add 50 ml methanol and 35 milligrams of 10%Pd/C, normal pressure hydrogenation filtered after 5 hours, revolve desolventizing, obtain N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide.
1H?NMR(400M，CDCl3)，δ(ppm)9.17(d，1H，ArH)，8.73(d，1H，ArH)，8.70(d，1H，ArH)，8.35(d，1H，ArH)，7.46(dd，1H，ArH)，7.42(d，1H，ArH)，7.35(m，1H，ArH)，7.20(d，1H，-ArH)，6.42(S，1H，-ArH)，2.20(S，3H，-CH
3)，1.46(d，9H，-CH
3).FABMS：(M+H)
+＝378。
Embodiment 9.N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-methylpiperazine-1-yl methylene radical) benzamide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 234 milligrams of 4-(4-methylpiperazine-1-yl methylene radical) phenylformic acid are dissolved in 20 milliliters of dry DMF; add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP; be heated to 70oC; stir and be chilled to room temperature after 20 hours; in the impouring sodium bicarbonate frozen water solution; add ethyl acetate extraction three times; merge organic layer; wash 3 times; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night; revolve desolventizing; column chromatography for separation obtains N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-methylpiperazine-1-yl methylene radical) benzamide.
1H?NMR(400M，D
2O)，δ(ppm)9.38(S，1H，ArH)，9.13(d，1H，ArH)，8.95(d，1H，ArH)，8.85(d，1H，ArH)，8.21(dd，1H，ArH)，7.97(m，3H，ArH)，7.67(m，3H，ArH)，7.50(S，2H，ArH)，4.48(S，2H，-ArCH
2N)，3.62(br，8H，-CH
2-)，3.04(S，3H，N-CH
3)，2.24(S，3H，-CH
3)，1.52(S，9H，-CH
3).FABMS：(M+H)
+＝594。
Embodiment 10.N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
With 377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 250 milligram 3; the 5-di-tert-butyl-4-hydroxybenzoic acid is dissolved in 20 milliliters of dry DMF; add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP; be heated to 70oC; stir and be chilled to room temperature after 20 hours; in the impouring sodium bicarbonate frozen water solution; add ethyl acetate extraction three times; merge organic layer; wash 3 times; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night, and revolves desolventizing, column chromatography for separation; obtain N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide.
1HNMR(300M，CD
3COCD
3)，δ(ppm)9.39(br，1H，N-H)，9.33(S，1H，ArH)，8.72(m，2H，ArH)，8.49(m，1H，ArH)，7.82(m，3H，ArH)，7.70(m，2H，ArH)，7.51(m，1H，ArH)，7.25(d，1H，ArH)，6.53(S，1H，OH)，2.25(S，3H，-CH
3)，1.47(S，9H，-CH
3)，1.44(S，18H，-CH
3).FABMS：(M+H)
+＝610。
Embodiment 11.N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-trifluoromethyl-5-(4-methylimidazole-1-yl) benzamide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 270 milligrams of 3-trifluoromethyl-5-(4-methylimidazole-1-yl) phenylformic acid are dissolved in 20 milliliters of dry DMF; add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP; be heated to 70oC; stir and be chilled to room temperature after 20 hours; in the impouring sodium bicarbonate frozen water solution; add ethyl acetate extraction three times; merge organic layer; wash 3 times; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night; revolve desolventizing; column chromatography for separation obtains N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-trifluoromethyl-5-(4-methylimidazole-1-yl) benzamide.
1H?NMR(300M，DMSO-d)，δ(ppm)10.45(S，1H，N-H)，9.31(d，1H，ArH)，8.80(d，1H，ArH)，8.73(d，1H，ArH)，8.48(m，1H，ArH)，8.41(S，1H，ArH)，8.37(d，1H，ArH)，8.21(S，1H，ArH)，8.12(S，1H，ArH)，7.96(d，1H，ArH)，7.72(dd，1H，ArH)，7.68(S，1H，ArH)，7.62(d，1H，ArH)，7.58(dd，1H，ArH)，7.35(d，1H，ArH)，2.20(S，3H，-CH
3)，2.16(S，3H，-CH
3)，1.43(S，9H，-CH
3).FABMS：(M+H)
+＝630。
Embodiment 12.N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-niacinamide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 123 milligrams of nicotinic acid are dissolved in 20 milliliters of dry DMF; add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP; be heated to 70oC; stir and be chilled to room temperature after 20 hours; in the impouring sodium bicarbonate frozen water solution; add ethyl acetate extraction three times; merge organic layer; wash 3 times; the saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and revolves desolventizing; column chromatography for separation obtains N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-niacinamide.
1H?NMR(300M，CD
3COCD
3)，δ(ppm)9.55(br，1H，N-H)9.32(S，1H，ArH)，9.22(S，1H，ArH)，8.73(m，3H，ArH)，8.50(m，1H，ArH)，8.29(m，1H，ArH)，7.83(d，1H，ArH)，7.80(s，1H，ArH)，7.73(m，1H，ArH)，7.50(m，2H，ArH)，7.31(m，1H，ArH)2.26(S，3H，-CH
3)，1.48(S，9H，-CH
3).FABMS：(M+H)
+＝483。
Embodiment 13.N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
With 319 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide and 268 milligram 3; 5-di-t-butyl-4-hydroxybenzoyl chloride is dissolved in 20 milliliters of anhydrous pyridines; after the stirring at room 12 hours; solvent is removed in decompression; add acetic acid ethyl dissolution; the saturated sodium bicarbonate solution washing; washing; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night, and revolves desolventizing, column chromatography for separation; obtain N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide.
1H?NMR(300M，CD
3COCD
3)，δ(ppm)9.40(S，1H，N-H)，9.30(d，1H，ArH)8.67(m，1H，ArH)，8.60(m，1H，ArH)，8.50(d，1H，ArH)，8.43(m，1H，ArH)，7.85(s，2H，ArH)，7.45(m，3H，ArH)，7.19(d，1H，ArH)，6.54(s，1H，O-H)，2.33(S，3H，-CH
3)，2.25(S，3H，-CH
3)，1.46(S，18H，-CH
3).FABMS：(M+H)
+＝552。
Embodiment 14.N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-cyano group benzoylamino) benzamide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 284 milligrams of 4-(4-cyano group benzoylamino) Benzoyl chloride are dissolved in 20 milliliters of anhydrous pyridines; after the stirring at room 12 hours; solvent is removed in decompression; add acetic acid ethyl dissolution; the saturated sodium bicarbonate solution washing; washing; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night; revolve desolventizing; column chromatography for separation obtains N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-cyano group benzoylamino) benzamide.
1H?NMR(300M，DMSO-D6)，δ(ppm)10.73(S，1H，NH)，10.16(S，1H，NH)，9.32(d，1H，ArH)，8.81(d，1H，ArH)，8.75(d，1H，ArH)，8.50(m，1H，ArH)，8.13(d，2H，ArH)，8.05(d，2H，ArH)，7.98(S，1H，ArH)，7.97(d，2H，ArH)，7.91(d，2H，ArH)，7.69(m，2H，ArH)7.60(m，1H，ArH)，7.30(m，1H，ArH)，2.19(S，3H，-CH
3)，1.44(S，9H，-CH
3).FABMS：(M+H)
+＝626。
Embodiment 15.N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-(indoles-3-propionamido) phenyl) uncle's fourth oxygen methane amide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 207 milligrams of indole-3-monoprops are dissolved among 20 milliliters of anhydrous THF, add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP, stirring at room is after 20 hours in the impouring sodium bicarbonate frozen water solution, add ethyl acetate extraction three times, merge organic layer, wash 3 times, the saturated common salt water washing, anhydrous sodium sulfate drying spends the night, revolve desolventizing, column chromatography for separation obtains N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-(indoles-3-propionamido) phenyl) uncle's fourth oxygen methane amide.
1H?NMR(300M，CD
3COCD
3)，δ(ppm)9.97(S，1H，NH)，9.31(S，1H，ArH)，9.12(S，1H，NH)，8.72(d，2H，ArH)，8.47(m，1H，ArH)，7.81(d，1H，ArH)，7.67(m，1H，ArH)，7.45-7.60(m，3H，ArH)，7.32(d，1H，ArH)，7.21(d，1H，ArH)，7.12-6.92(m，3H，ArH)，3.10(t，2H，-CH
2)，2.70(t，2H，-CH
2-)，2.21(S，3H，CH
3)，1.46(S，9H，CH
3).FABMS：(M+H)
+＝549。
Embodiment 16.N-[3-(uncle's N-fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
377 milligrams of N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide and 179 milligrams of 3-acetylamino benzoic acids are dissolved in 20 milliliters of dry DMF; add 202 milligrams of anhydrous triethylamines and 0.6 milliliter of DECP; be heated to 70oC; stir and be chilled to room temperature after 20 hours; in the impouring sodium bicarbonate frozen water solution; add ethyl acetate extraction three times; merge organic layer; wash 3 times; the saturated common salt water washing; anhydrous sodium sulfate drying spends the night; revolve desolventizing; column chromatography for separation obtains N-[3-(uncle's N-fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
1H NMR (300M, DMSO-D6), δ (ppm) 10.23 (S, 1H, N-H), (10.15 S, 1H, N-H), 9.31 (d, 1H, ArH), 8.80 (d, 1H, ArH), 8.75 (dd, 1H, ArH), 8.48 (m, 1H, ArH), (8.05 m, 1H, ArH), 7.97 (d, 1H, ArH) 7.80 (m, 1H, ArH), 7.69 (m, 1H, ArH), 7.67 (s, 1H, ArH), (7.59 m, 2H, ArH), 7.41 (d, 1H, ArH), 7.30 (d, 1H, ArH), 2.18 (S, 3H ,-CH
3), 2.07 (S, 3H ,-CH
3), 1.44 (s, 9H ,-CH
3) .FABMS:(M+H)
+=539.
Activity rating
1. external evaluating drug effect (mtt assay)
Be mixed with the cell suspension that concentration is 1 * 105 cell/ml behind the cell centrifugation with logarithmic phase, be inoculated in 96 orifice plates by 1000/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, continue to cultivate 4 hours, centrifugal, abandon supernatant, every hole adds 200 μ l DMSO dissolving MTT first hairpin precipitation, with the microoscillator mixing that vibrates,, detect under the wavelength 570nm condition and measure optical density value (OD) at reference wavelength 450nm with MK3 type microplate reader, the tumour cell of processing take solvent control is as control group, with the inhibiting rate of following formula calculating medicine to tumour cell.
And by middle efficacious prescriptions journey calculating IC50.
The MTT the selection result
2. evaluating drug effect (tubular fibre method) in the body
Experimental procedure:
The PVDF tubular fibre immerses and to be full of among the RPMI1640 that contains 20% foetal calf serum, and 37 ℃ of balances at least 12 hours are cooled off the segment of fiber handled well in ice-cold containing among 20% the RPMI1640; Collect K562 and K562/R cell under the aseptic condition, adjust cell concn to 1 * 10 with serum free medium
7Individual/ml, the cell suspension that has prepared is injected tubular fibre by 1ml syringe (No. 4 syringe needles), then seal with the tack needle holder, first segment of fiber is divided into some segments with the needle holder after the heating subsequently, every section is about 1-2cm, after cutting off each segment is put into the plate that fills perfect medium, 37 ℃, 5%CO
2, overnight incubation.Be inoculated in nude mice by subcutaneous with ready fiber next day.In inoculating rear second day to the nude mice gastric infusion, once a day, continuous 7 days.After 7 days, take out fiber, place the substratum balance 30 minutes of 37 ℃ of preheatings, with being placed on 1mg/mlMTT (substratum preparation, and in 37 ℃ of preheatings), 37 ℃, 4 hours.After blotting substratum, the segment of fiber normal saline flushing twice that contains 2.5% protamine sulfate (protamine sulfate), and in 4 ℃ of overnight incubation.Take out segment of fiber, place 24 orifice plates, every Kong Yigen, and it is truncated into two sections, dried overnight.The 2nd day, every hole added 250 μ lDMSO and extracts the first hairpin, horizontal shaking table upper 4 hour, then got 150 μ l in 96 orifice plates under the room temperature, and 570nm surveys absorbancy.
FAB107 and imatinib be antitumor action in vivo
Claims (6)
1. the 2-anilino-pyrimidine compound shown in general formula (I), its pharmacologically acceptable salt;
It is characterized in that, described compound has following structure
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) ethanamide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) ethanamide
N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-nitro aniline
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-pivalyl Oxymethylene-2-methyl-5-amino aniline
N-[3-(N-pivalyl Oxymethylene-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-nitrophenyl) uncle's fourth oxygen methane amide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-aminophenyl) uncle's fourth oxygen methane amide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-methylpiperazine-1-yl methylene radical) benzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-trifluoromethyl-5-(4-methylimidazole-1-yl) benzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-niacinamide
N-[3-(ethanoyl-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3,5-di-t-butyl-4-hydroxybenzamide
N-[3-(uncle's fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-4-(4-cyano group benzoylamino) benzamide
N-(4-(pyridin-3-yl) pyrimidine-2-base)-N-(2-methyl-5-(indoles-3-propionamido) phenyl) uncle's fourth oxygen methane amide
N-[3-(uncle's N-fourth oxygen formyl radical-(4-pyridin-3-yl-pyrimidine-2-base) amido)-4-aminomethyl phenyl]-3-kharophen benzamide.
2. the method for preparing the described compound of claim 1, it is characterized in that, comprise the steps: to utilize anilino-pyrimidine that a nitro replaces to provide the anilino-pyrimidine that N-R1 replaces with halides or carboxylic acid halides or ester or acid anhydride effect first, be amino again with nitroreduction, then make the amido acidylate with carboxylic acid or ester or carboxylic acid halides or acid anhydride or isocyanate reaction, finally obtain the described compound of general formula I;
The definition of R1, R2, R3 and R4 such as claim 1 definition;
3. pharmaceutical composition is characterized in that containing the arbitrary compound or pharmaceutically acceptable salt thereof of claim 1 of pharmacy effective dose and pharmaceutically acceptable carrier or vehicle.
4. the arbitrary compound or pharmaceutically acceptable salt thereof of claim 1 is bred the application of the medicine of relevant disease for the preparation of prevention or treatment.
5. use according to claim 4, it is characterized in that, the relevant disease of described propagation is selected from tumour.
6. use according to claim 5, it is characterized in that, described tumour is selected from leukemia, neurospongioma, incidence cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, colorectal cancer, cancer of the stomach, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma.
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| CN109928922A (en) * | 2017-12-18 | 2019-06-25 | 成都华健未来科技有限公司 | A kind of cyclohexanes compound |
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| WO2004043389A2 (en) * | 2002-11-13 | 2004-05-27 | Chiron Corporation | Methods of treating cancer and related methods |
| WO2005007628A1 (en) * | 2003-07-11 | 2005-01-27 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
| WO2006124413A2 (en) * | 2005-05-13 | 2006-11-23 | Novartis Ag | Methods for treating drug resistant cancer |
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| WO2005007628A1 (en) * | 2003-07-11 | 2005-01-27 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives as cannabinoid receptor modulators |
| WO2006124413A2 (en) * | 2005-05-13 | 2006-11-23 | Novartis Ag | Methods for treating drug resistant cancer |
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