CN103191120A - Application of pyrimidine derivative in preparation of drugs capable of prevention and/or treatment and/or adjuvant therapy of tumors - Google Patents

Application of pyrimidine derivative in preparation of drugs capable of prevention and/or treatment and/or adjuvant therapy of tumors Download PDF

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CN103191120A
CN103191120A CN2012105936288A CN201210593628A CN103191120A CN 103191120 A CN103191120 A CN 103191120A CN 2012105936288 A CN2012105936288 A CN 2012105936288A CN 201210593628 A CN201210593628 A CN 201210593628A CN 103191120 A CN103191120 A CN 103191120A
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pyrimidine compound
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刘强
龙梓洁
鲁桂
郑飞猛
罗羽
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Abstract

The invention discloses application of a pyrimidine derivative in preparation of drugs capable of prevention and/or treatment and/or adjuvant therapy of tumors. The pyrimidine derivative comprises a pyrimidine compound having a structural formula (I), a pharmaceutically acceptable salt thereof, a solvate, a polymorphic substance, a tautomer and a prodrug or a composition containing the pyrimidine compound. The structural formula (I) is described in the specification. According to the invention, the novel pyrimidine derivative with Aurora kinase inhibition activity is formed through different C-N couplings and introduction of different pharmacophores respectively at positions 2, 4 and 6 of a pyrimidine ring, and the pyrimidine derivative can be used for preparation of drugs capable of prevention and/or treatment and/or adjuvant therapy of tumors.

Description

A kind of pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes.
Background technology
The Aurora kinases is a class has the important regulating and controlling effect in cell growth cycle serine/threonine kinase, participates in regulating spindle formation, centrosome maturation, chromosome differentiation and cytokinesis process, has pivotal role to keeping genomic stability.Discover that the kinase whose overexpression of Aurora easily causes cell mitogen unusual, and is closely related with the formation of tumor.The overexpression in many cancerous cell (as pulmonary carcinoma, breast carcinoma, rectal cancer, thyroid carcinoma, cancer of pancreas) of Aurora kinases suppresses gathering, promotion apoptosis, blocking-up cell proliferation that the kinase whose activity of Aurora can cause the tumor cell polyploid.Be that the research and development that target spot carries out antitumor drug also more and more are subject to people's attention with the Aurora kinases.The Aurora inhibitors of kinases belongs to the targeting anti-tumor medicine, compares with other non-specific cell cytotoxic drug, will have bigger advantage.
According to the difference of aminoacid sequence, human Aurora kinases is divided into Aurora A, Aurora B and three kinds of hypotypes of Aurora C.These three kinds of hypotypes have very conservative C-end catalytic domain and N-end variable region, namely have the ATP-binding site (C-holds catalytic domain) of height homology, but in amino acid length and the sequence of N-end larger difference are arranged.
Wherein Aurora A is positioned at centrosome and the mitotic spindle two ends of copying, and regulates the maturation of centrosome, assembling and the mitotic start-up course of spindle.Aurora A can phosphorylation cell periodic protein B 1-Cdk1 regulatory factor Cdc25b, the start-up course of regulating cell mitogen behind the activation Cdc25b.AuroraA is also by participating in regulating three kinds of centrosome protein, be centrosome protein (centrosomin, CNN), transform acid coiled coil albumen (trans-formingacidic coiled-coil protein, TACC) and spindle deficiency albumen (spindle defective-2 SPD-2) guarantees the maturation of centrosome in the mitosis process.
After scientist in 1998 confirms that the generation of tumor and the kinase whose overexpression of Aurora have substantial connection, academia and pharmaceuticals industry circle have been caused with the research boom of Aurora kinases as the antitumor drug action target spot.Along with Aurora kinases crystal structure research deeply and the application of computer modeling technique, it is found that the synthetic Aurora inhibitors of kinases of great majority belongs to the ATP(adenosine triphosphate) competitive inhibitors of kinases, competition is in conjunction with kinase whose ATP-binding site, cut off the direct energy source of kinases, thereby suppress its activity.
Discover that the purine ring in the ATP structure can be incorporated into the hydrophobic pocket of Aurora kinases structure, and form hydrogen bond with the amino acid residue of bonding pad.The ATP binding pocket is made up of following zone: kinases hinge region, hydrophobic pocket land, phosphate ditch bury the district, solvent can and be distinguished and the ribose part.
Aurora kinases family ATP-binding site has very high homology, and this makes the selectivity of inhibitors of kinases become a very big challenge.The Aurora inhibitors of kinases of many reports still can embody good selectivity, one of them major reason is inhibitor except by ATP-binding site and the kinase interactions, also act near the zone of ATP binding pocket, the hydrophobic pocket that comprises the kinases rear portion, the difference of all these zone of action amino acid residues have determined optionally difference of inhibitors of kinases jointly.The basic structure characteristics of the inhibitors of kinases of having reported are: have the heterocyclic system on a plane to compete in conjunction with kinase whose ATP pocket and to simulate adenine and kinase whose interaction; Also can form " D-A-donor " binding mode by hydrogen bond action between inhibitor and the kinases hinge region; The functional group of inhibitor often can enter kinase phosphorylation salt binding zone or selective binding pocket.On structure, synthetic at present Aurora inhibitors of kinases is mainly pyrimidine lopps, pyrrolo-pyrazoles, indoles, quinazoline ditosylate salt, benzo nitrogen miazines and other structure compounds.
Pyrimidines is the Aurora inhibitors of kinases of reporting the earliest, U.S.'s Vertex Standard (Vertex) company (US7361492B2, WO03092607A2) reported first in 2003 AuroraA kinases and pyrimidine compound N-(3-cyclopropyl-1H-pyrazoles-5-yl)-2-phenylquinazoline-4-amine compound crystal structure.Point out in the patent that two N atoms on this complex pyrazoles ring and kinase whose hinge region form hydrogen bond action, at kinase whose glycine rich region, have π-π to interact between the phenyl ring of kinases and this complex.The achievement in research of Vertex company is that follow-up appropriate design Aurora inhibitors of kinases is laid a good foundation.Structural formula of compound is as follows among the patent WO03092607A2:
Figure BDA00002695813100021
Vertex company and Merck (Merck) company has developed jointly first Aurora inhibitors of kinases VX-680(and has had another name called MK-0457) (WO2004000833A1).This molecular structure is the Y shape, and the pyrimidine ring at center is positioned at kinase whose hydrophobic region, and between the kinases amino acid residue hydrophobic interaction is arranged; The arm that contains amino-pyrazol stretches into kinase whose hinge area, and the nitrogen-atoms of pyrazoles ring and hinge region amino acid residue have hydrogen bond action; The arm that contains phenyl stretches in the pocket of kinase activity site, and the kinase whose F275 residue of the cyclopropyl of phenyl end and Aurora A has hydrophobic interaction; The piperazine side chain then by the active region of enzyme be stretched over enzyme solvent can and the district.Discover that the AuroraA of VX-680, B and C have good restraining effect, IC 50Value is respectively 0.6,18 and 4.6nM, can suppress the propagation of numerous tumor cells such as colorectal carcinoma, breast carcinoma, carcinoma of prostate, cancer of pancreas, melanoma, tumor colli, leukemia.2006, VX-680 entered the clinical II phase and has studied, and was mainly used in treating obstinate chronic lymphocytic leukemia and acute lymphatic leukemia.Discovering that this medicine can cause prolongs risk by patient's QTc (QTc is the T ripple proofreaied and correct on the electrocardiogram and the time difference between the Q ripple, the QTc prolongation causes arrhythmia easily), in November, 2007, Merck stopped II clinical trial phase (the Expert Opin.Investing Drugs.2009 of VX-680,18,379).
Figure BDA00002695813100022
Though exist in the prior art some be similar to VX-680 to the inhibited chemical compound of Aurora kinases, but still need further to study the chemical compound of the Aurora of having kinase inhibitory activities more, be suitable for prevent and/or treat and/or the needs of the medicine of adjuvant therapy of tumors so that produce more.
Summary of the invention
The object of the invention be to provide a kind of pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes, in order to a kind of pyrimidine derivatives with new construction is made be used to preventing and/or treating and/or the medicine of adjuvant therapy of tumors.
For this reason, in one aspect of the invention, provide a kind of pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes, this pyrimidine derivatives comprises have structural formula pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, the prodrug of (I), the compositions that perhaps contains pyrimidine compound, (I) is as follows for structural formula:
Figure BDA00002695813100031
Preferably, in such use, synthetic method with pyrimidine compound of structural formula (I) may further comprise the steps: compd A and the 1-methyl piperazine that will have structural formula (1) are dissolved into 1 according to mol ratio 1:8～12, in the 4-dioxane, 160～200 ℃, microwave reaction 30～60 minutes, reaction gained mixture is spin-dried for solvent, namely get the pyrimidine compound with structural formula (I), wherein, X is halogen in the formula (1).
Figure BDA00002695813100032
Preferably, in such use, be spin-dried for the step that further comprises after the solvent processing with the silicagel column purification in the method for synthetic pyrimidine compound with structural formula (I), be to be that dichloromethane and the methanol mixed solvent of 100:1～60:1 carries out eluting with volume ratio with the step of silicagel column purification, collect the pyrimidine compound with structural formula (I) of purification.
Preferably, in such use, the method of synthetic compound A is as follows: compd B and paranitroanilinum, the p-methyl benzenesulfonic acid that will have structural formula (2) are dissolved in the n-butyl alcohol according to mol ratio 1:1～1.2:0.8～1,130～150 ℃ of following back flow reaction 12～16h, be cooled to room temperature after the reaction, add saturated NaHCO 3Solution is regulated pH to 7～8, uses ethyl acetate extraction 3～5 times, and organic layer is used anhydrous Na again with saturated common salt water washing 3～5 times 2SO 4Drying is spin-dried for solvent and namely gets compd A, and wherein, X is halogen in the formula (2).
Figure BDA00002695813100041
Preferably, in such use, be spin-dried in the method for synthetic compound A and further comprise after the solvent processing with methanol and grinding, namely get compd A behind the sucking filtration.
Preferably, in such use, the method for synthetic compound B is as follows: with 2,4,6-three halogenated pyrimidines and 3-amino-5-methylpyrazole are dissolved in the dehydrated alcohol according to mol ratio 1:1～2, add triethylamine, 0 ℃ of stirring reaction 8～16h is after reaction stops, in reaction system, add water, separate out sucking filtration behind the white solid, adopt frozen water and ice methanol wash successively, obtain compd B after the drying.
Preferably, in such use, in the method for synthetic compd B with structural formula (2) 2,4,6-three halogenated pyrimidines are 2,4,6-trichloropyrimidine.
Preferably, in such use, the tumor of tumor for causing because of the kinase whose unconventionality expression of Aurora.
Preferably, in such use, tumor is nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
Simultaneously, the present invention also provides a kind of purposes of pyrimidine derivatives extracorporeal suppression tumor cell growth, pyrimidine derivatives comprises have structural formula pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, the prodrug of (I), perhaps contains the compositions of pyrimidine compound.
Pass through at 2,4 of pyrimidine ring the 6-position in the present invention, carry out different C-N couplings respectively, introduce different pharmacophore, form the new pyrimidine derivatives with Aurora kinase inhibiting activity, this pyrimidine derivatives can be made into and can prevent and/or treat and/or the medicine of adjuvant therapy of tumors.
Except purpose described above, feature and advantage, the present invention also has other purpose, feature and advantage.With reference to figure, the present invention is further detailed explanation below.
Description of drawings
Accompanying drawing constitute this description a part, be used for further understanding the present invention, accompanying drawing shows the preferred embodiments of the present invention, and is used for illustrating principle of the present invention with description.Among the figure:
Fig. 1 shows the proton nmr spectra spectrogram that has the pyrimidine compound of structural formula (I) according to the present invention;
Fig. 2 shows the carbon-13 nmr spectra spectrogram that has the pyrimidine compound of structural formula (I) according to the present invention;
Fig. 3 a shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to AuroraA kinase inhibition result of the test figure among the breast cancer cell SUM149;
Fig. 3 b shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to AuroraA kinase inhibition result of the test figure among the breast cancer cell BT549;
Fig. 4 a shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of leukaemia HL-60;
Fig. 4 b shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell BT549;
Fig. 4 c shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell MCF-7;
Fig. 4 d shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of the breast carcinoma MCF-7 cell (MCF-7-Epi) of epirubicin drug resistance;
Fig. 4 e shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell MDA-MB-231;
Fig. 4 f shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell MDA-MB-453;
Fig. 4 g shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell MDA-MB-468;
Fig. 4 h shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell Sk-br-3;
Fig. 4 i shows the pyrimidine compound that has structural formula (I) according to the present invention (AKI603) of variable concentrations to the drug dose effect figure of breast cancer cell SUM149;
The pyrimidine compound that has structural formula (I) according to the present invention (AKI603) that Fig. 5 a shows variable concentrations is to the Cycle Arrest of leukaemia HL-60 figure as a result;
The pyrimidine compound that has structural formula (I) according to the present invention (AKI603) that Fig. 5 b shows variable concentrations is to the Cycle Arrest of breast cancer cell SUM149 figure as a result;
The pyrimidine compound that has structural formula (I) according to the present invention (AKI603) that Fig. 5 c shows variable concentrations is to the Cycle Arrest of breast cancer cell BT549 figure as a result;
Fig. 6 shows the figure as a result that the pyrimidine compound (AKI603) that has structural formula (I) according to the present invention suppresses breast cancer cell BT549 and SUM149 clone formation;
Fig. 7 a shows breast cancer cell MCF-7 and the cells survival rate comparison diagram of breast cancer cell MCF-7-Epi under the epirubicin effect;
Fig. 7 b shows breast cancer cell MCF-7 and breast cancer cell MCF-7-Epi detects CD24-CD44+ expression difference figure through flow cytometer;
Fig. 7 c shows that CD24-CD44+ expresses the figure as a result that changes among the breast cancer cell MCF-7-Epi after the pyrimidine compound (AKI603) that the present invention has structural formula (I) is handled; And
CD24-CD44+ expresses the cartogram that changes among the breast cancer cell MCF-7-Epi that Fig. 7 d shows pyrimidine compound that the present invention has structural formula (I) after handling.
The specific embodiment
Below in conjunction with the accompanying drawing in the embodiment of the invention, technical scheme in the embodiments of the invention is described in detail, but following embodiment and accompanying drawing only are in order to understand the present invention, and can not limit the present invention, the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
In one embodiment of the invention, provide a kind of pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes, this pyrimidine derivatives comprises have structural formula pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, the prodrug of (I), the compositions that perhaps contains described pyrimidine compound, (I) is as follows for described structural formula:
Figure BDA00002695813100061
The pyrimidine compound that the present invention has structural formula (I) is N 4-(5-methyl isophthalic acid H-pyrazole-3-yl)-6-(4-methyl piperazine-1-yl)-N 2-(4-nitrobenzophenone) pyrimidine-2,4-diamidogen, its chemical formula are C 19H 23N 9O 2Relative molecular weight is 409.2g/mol, this chemical compound is by at 2 of pyrimidine ring, 4, the 6-position is carried out different C-N couplings respectively, introduces different pharmacophore, form the new pyrimidine derivatives with Aurora kinase inhibiting activity, this pyrimidine derivatives can be made into and can prevent and/or treat and/or the medicine of adjuvant therapy of tumors.
In one embodiment of the invention, provide a kind of synthetic above-mentioned method with pyrimidine compound of structural formula (I) may further comprise the steps: compd A and the 1-methyl piperazine that will have structural formula (1) are dissolved into 1 according to mol ratio 1:8～12, in the 4-dioxane, 160～200 ℃, microwave reaction 30～60 minutes, reaction gained mixture is spin-dried for solvent, namely gets described pyrimidine compound with structural formula (I), wherein, X is halogen in the formula (1).
Figure BDA00002695813100062
Preferably, be spin-dried for the step that further comprises after the solvent processing with the silicagel column purification in the method for synthetic above-mentioned pyrimidine compound with structural formula (I), be to be that dichloromethane and the methanol mixed solvent of 100:1～60:1 carries out eluting with volume ratio with the step of silicagel column purification, collect the described pyrimidine compound with structural formula (I) of purification.Increased the step with the silicagel column purification in the method, the increase of this step is conducive to improve the purity of the pyrimidine compound with structural formula (I) that is synthesized, and is conducive to the later stage pharmaceutical applications.
In one embodiment of the invention, synthetic described method with the compd A in the structural formula (1) comprises that compd B and paranitroanilinum, the p-methyl benzenesulfonic acid that will have structural formula (2) are dissolved in the n-butyl alcohol according to mol ratio 1:1～1.2:0.8～1,130～150 ℃ of following back flow reaction 12～16h, be cooled to room temperature after the reaction, add saturated NaHCO 3Solution is regulated pH to 7～8, uses ethyl acetate extraction 3～5 times, and organic layer is used anhydrous Na again with saturated common salt water washing 3～5 times 2SO 4Drying is spin-dried for solvent and namely gets the compd A with structural formula (1), and wherein, X is halogen in the formula (2).
Figure BDA00002695813100071
Preferably, be spin-dried in the method for synthetic compd A with structural formula (1) and further comprise with methanol after the solvent processing and grinding, namely get described compd A with structural formula (1) behind the sucking filtration.Increased the step that methanol grinds in the method, the increase of this step is conducive to obtain the higher compd A of purity, and then the by-product when being conducive to reduce follow-up synthetic pyrimidine compound with structural formula (I), and then improve the purity of the pyrimidine compound with structural formula (I), be conducive to the later stage pharmaceutical applications.
In one embodiment of the invention, synthetic described method with compd B of structural formula (2) comprises 2,4,6-, three halogenated pyrimidines and 3-amino-5-methylpyrazole are dissolved in the dehydrated alcohol according to mol ratio 1:1～2, add triethylamine, 0 ℃ of stirring reaction 8～16h, after reaction stops, in reaction system, adding water, separate out sucking filtration behind the white solid, adopt frozen water and ice methanol wash successively, obtain having the compd B of structural formula (2) after the drying.Wherein, 2,4,6-, three halogenated pyrimidines are preferably 2,4,6-trichloropyrimidine.
The tumor of tumor for excessively causing because Aurora is kinase whose in one embodiment of the present invention.Be preferably nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
Simultaneously, in one embodiment of the invention, a kind of purposes of pyrimidine derivatives extracorporeal suppression tumor cell growth is provided, this pyrimidine derivatives comprises pyrimidine compound with said structure formula (I), its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, perhaps contains the compositions of described pyrimidine compound.
To describe exemplary of the present invention in detail below.Yet these embodiments are not intended to limit the scope of the invention only for the purpose of illustration.
As used herein, if for concrete restriction is provided, term of the present invention has following implication.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" treatment effective dose " refers to when needing the mammal of such treatment, is enough to the effectively amount of the general formula compound for the treatment of.The treatment effective dose will depend on the existence of given activity, patient's age, physiological situation, other morbid state of used healing potion and nutriture and change.In addition, the other medicines treatment that may just accept of patient will influence treatment effective dose definite of the healing potion that will give.
Chemical compound of the present invention also comprises all isotopic atoms, no matter is at intermediate or last chemical compound.Isotopic atom comprises having identical atomic number, but the different quality number.For example, the isotope of hydrogen comprises tritium and deuterium.
Chemical compound of the present invention also comprises pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to the form of the conversion of the basic group in parent compound salify.Pharmaceutically acceptable salt include but not limited to, and basic group is the inorganic or organic acid salt of amine (ammonia) base for example.Pharmaceutically acceptable salt of the present invention can be synthetic by parent compound, i.e. the acid of the basic group in the parent compound and 1-4 equivalent is reacted in a solvent system.Suitable salt is set forth in Remington ' s Pharmaceutical Sciences, 17th ed., and Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, in 66,2 (1977).
Pharmaceutically-acceptable acid addition can be by inorganic and organic acid preparation.Mineral acid by the derived acids addition salts comprises hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.Organic acid by the derived acids addition salts comprises acetic acid, propanoic acid, glycolic, acetone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, benzenesulfonic acid etc.The mineral acid of derived acids addition salts and organic acid especially are selected from hydrochloric acid, phosphoric acid, sulphuric acid, nitric acid, perchloric acid, hydrobromic acid, acetic acid, benzoic acid and p-methyl benzenesulfonic acid.
As used herein, " pharmaceutically acceptable carrier " comprise any and whole solvents, disperse medium, coating, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are used for pharmaceutically active substances and are well known in the art.Unless any conventional media or medicament and active component are incompatible, its application in therapeutic combination is expected.Supplementary active ingredients also can be incorporated in the compositions.
Said composition preferably is formulated into unit dosage forms.Term " unit dosage forms " refers to and is suitable for use as the physics discrete unit that gives human experimenter and other mammiferous single doses, and per unit contains and calculates in order to produce the predetermined amount of the effective active substance of needed treatment and relevant suitable pharmaceutical excipient (as tablet, capsule, ampoule).The chemical compound of general formula (I) is the active drug amount that effectively and usually gives in dosage range widely.Preferably, for oral administration, each dosage unit comprises general formula (I) chemical compound of 10mg to 2g, and more preferably 10 to 700mg, and for parenteral, is preferably 10 to 700mg general formula (I) chemical compound, and more preferably from about 50 to 200mg.Yet, should understand, the amount of the actual general formula that gives (I) chemical compound will be determined according to relevant situation by the doctor, comprise the disease that to treat, the route of administration of selecting, the pragmatize compound that gives with and relative activity, each patient's age, body weight and reaction, the seriousness of patient's symptom etc.
In order to prepare solid composite such as tablet, main active component is mixed to form solid preformulation composition with drug excipient (or carrier), it comprises the homogeneous mixture of chemical compound of the present invention.When claiming that these preformulation composition are uniform, it refers to that active component is dispersed in the whole compositions, so that compositions can easily be subdivided into identical effective unit dosage forms such as tablet, pill and capsule.
Tablet of the present invention or pill can be applied or otherwise by compound so that a kind of dosage form with prolongation effect advantage to be provided, or protection tablet or pill are avoided the effect of acid condition in the stomach.For example, dosage and external dose composition in tablet or pill can comprise, the latter has the form of the crust on the former.Can separate two kinds of compositions with enteric layer, wherein enteric layer is used for stoping disintegrate under one's belt and allows interior complete components to enter duodenum or be delayed release.Various materials can be used for such enteric layer or coating, and above-mentioned material comprises many polymer acids and polymer acid and such material such as the mixture of Lac, hexadecanol and cellulose acetate.
The compositions that is used for inhalation or insufflation is included in solution and the suspension of pharmaceutically acceptable aqueous solvent or organic solvent or its mixture and powder.The liquid or solid compositions can comprise suitable pharmaceutical excipient as indicated above.Preferably, give these compositionss to obtain part or systemic effect by oral or nasal respiration approach.Can be by using atomize compositions in preferred pharmacy acceptable solvent of noble gas.Can directly suck atomized soln from atomising device, or atomising device can be connected in face shield account shape thing or intermittent positive pressure breathing machine.Can be by the device of sending dosage form in a suitable manner, preferred oral or nose approach give solution, suspensoid or powder composite.
Chemical compound of the present invention and pharmaceutically acceptable salt also comprise the form of solvate or hydrate.In general, the form form of solvate or hydrate and non-solventization or non-hydrated is equal to, and contains within the scope of the invention.Some chemical compound among the present invention might exist polycrystal or unbodied form.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
The present invention also comprises the prodrug of described chemical compound.Prodrug is a pharmacology material (medicine), is derived by parent drug.In case enter in the body, prodrug just is transformed into parent drug by metabolism.Prodrug can replace by the one or more functional groups to parent drug and prepare, and its substituted radical will be degraded in vivo and discharge parent compound.The preparation of prodrug and use can be at T.Higuchi and V. Stella, " Pro-drugs as Novel Delivery Systems; " Vol.14of the A.C.S.Symposium Series, with Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press finds in 1987.
The present invention also provides the pharmaceutical composition that comprises general formula (I) chemical compound or the acceptable salt of its pharmacy or its prodrug and at least a pharmaceutically acceptable carrier.Pharmaceutical composition of the present invention can be oral, injection injection, and spraying sucks, the skin external, rectum usefulness, nasal cavity usefulness, vagina usefulness, abdominal cavity usefulness, or use by implanting approach such as reservoir or transdermal patch.
Further prove beneficial effect of the present invention below with reference to specific embodiment.
Embodiment 1
Synthetic compound B:
(1.83g, 10mmol), (0.97g 10mmol) is dissolved in the 100mL dehydrated alcohol 3-amino-5-methylpyrazole, adds the 1.4mL triethylamine, 0 ℃ of following stirring reaction 12h to take by weighing 2,4,6-trichloropyrimidine.Behind the stopped reaction, in reaction solution, add 150mL water, separate out a large amount of white solids immediately, sucking filtration, and successively with 50mL frozen water and 20mL ice methanol wash, obtain white solid B(1.82g after the drying, 75%).
Product analysis: the nuclear magnetic data of resulting white solid B is 1H NMR (400MHz, DMSO-d 6) δ: 12.21 (s, 1H), 10.63 (s, 1H), 7.74and6.76 (m, 1H), 6.38,5.78 (m, 1H), 2.21 (s, 3H); 13C NMR (100MHz, DMSO-d 6) δ: 161.1,159.7,158.4,147.1,139.0,102.6,95.2,10.4ppm.This shows that resulting white solid B has structure in the structural formula (2).
Synthetic compound A:
(244mg, 1.0mmol), (166mg, 1.2mmol), (152mg 0.8mmol), is dissolved in the 10mL n-butyl alcohol 140 ℃ of following back flow reaction 12h to a hydration p-methyl benzenesulfonic acid to paranitroanilinum to take by weighing compd B.Add the saturated NaHCO of 2.5mL after being cooled to room temperature 3Solution is neutralized to pH=7-8, uses dichloromethane extraction (20mL * 3), the organic layer anhydrous Na 2SO 4After the drying, be spin-dried for solvent, grind with methanol, sucking filtration gets yellow solid A(130mg, 36.8%).
Product analysis: the nuclear magnetic data of resulting yellow solid A is 1H NMR (400MHz, DMSO-d 6) δ: 11.86 (s, 1H), 10.26 (s, 2H), 8.16 (d, 2H), 8.04 (s, 2H), 6.26 (s, 2H), 2.22 (t, 3H).This shows that resulting yellow solid A has structure in the structural formula (2).
Synthetic pyrimidine compound with structural formula (I):
(100mg, 0.29mmol), (0.32mL 2.9mmol) is dissolved in 1 of 2mL to the 1-methyl piperazine, and in the 4-dioxane, 180 ℃ of following microwave reactions 45 minutes are spin-dried for solvent, uses silicagel column purification (CH to take by weighing compd A 2Cl 2: MeOH=100:1-60:1), obtain yellow solid (57mg, 48%).
Product analysis: the nuclear magnetic data of resulting yellow solid is 1H NMR (400MHz, DMSO-d 6) δ: 11.88 (s, 1H), 9.55 (s, 1H), 9.04 (s, 1H), 8.11 (s, 2H), 8.04 (s, 2H), 6.24 (s, 1H), 6.07 (s, 1H), 3.50 (s, 4H), 2.39 (s, 4H), 2.21 (s, 6H). 13C NMR (100MHz, DMSO-d 6) the resulting yellow solid high resolution mass spectrum of δ: 163.2,160.5,157.9,148.2,139.4,124.8,117.2,95.0,78.2,54.1,45.6,43.7,10.7ppm. data are HRMS (ESI-TOF): m/z calcd for C 19H 23N 9O 2, [M+H] +: 410.2047, found:410.2050.This shows resultant pyrimidine compound with structure formula I.
Embodiment 2
Synthetic compound B:
(1.83g, 10mmol), (1.94g 20mmol) is dissolved in the 100mL dehydrated alcohol 3-amino-5-methylpyrazole, adds the 1.4mL triethylamine, 0 ℃ of following stirring reaction 16h to take by weighing 2,4,6-trichloropyrimidine.Behind the stopped reaction, in reaction solution, add 150mL water, separate out a large amount of white solids immediately, sucking filtration, and successively with 50mL frozen water and 20mL ice methanol wash, obtain white solid B(1.82g after the drying, 70%).
Synthetic compound A:
(244mg, 1.0mmol), (138mg, 1mmol), (190mg 1mmol), is dissolved in the 10mL n-butyl alcohol 150 ℃ of following back flow reaction 10h to a hydration p-methyl benzenesulfonic acid to paranitroanilinum to take by weighing compd B.Add the saturated NaHCO of 2.5mL after being cooled to room temperature 3Solution is neutralized to pH=7-8, uses dichloromethane extraction (20mL * 3), the organic layer anhydrous Na 2SO 4After the drying, be spin-dried for solvent, grind with methanol, sucking filtration gets yellow solid A(117mg, 33%).
Synthetic pyrimidine compound with structural formula (I)
(100mg, 0.29mmol), (0.348mL 3.48mmol) is dissolved in 1 of 2mL to the 1-methyl piperazine, and in the 4-dioxane, 160 ℃ of following microwave reactions 60 minutes are spin-dried for solvent, uses silicagel column purification (CH to take by weighing compd A 2Cl 2: MeOH=100:1-60:1), obtain yellow solid (53mg, 45%).This yellow solid detects through nuclear-magnetism and analyzes to having the pyrimidine compound of structural formula (I).
Can both obtain the pyrimidine compound that the application has structural formula (I) by method among embodiment 1 and the embodiment 2, wherein adopt the productive rate of the pyrimidine compound with structural formula (I) that method obtains among the embodiment 1 higher.
One, the synthetic pyrimidine compound with structural formula (I) (AKI603) of embodiment 1 is to the kinase whose inhibition activity experiment of Aurora-A in the cell.
Experiment object: breast cancer cell SUM149 and BT549.
Experimental technique: the pyrimidine compound with structural formula (I) that embodiment is synthesized is dissolved in DMSO(100mM) as storage liquid, dilute with PBS during experiment, be added in the culture fluid.Adopt the pyrimidine compound solution with structural formula (I) of variable concentrations that breast cancer cell is handled, collecting cell lysate after 48 hours, adopt Western blot method to detect the expression (T288) of phosphorylation Aurora-A in the cell lysate, as confidential reference items, the result is shown in Fig. 3 a and Fig. 3 b with GAPDH.
Experimental result: in breast cancer cell SUM149 and BT549, have the reduction Aurora-A kinase activity (T288 site) of the pyrimidine compound energy dose dependent of structural formula (I), show the targeting specific of this inhibitor.
Fig. 3 a is for to have the pyrimidine compound of structural formula (I) to the inhibitory action figure of phosphorylation Aurora-A among the breast cancer cell SUM149.The pyrimidine compound that is had structural formula (I) by Fig. 3 a as can be known can suppress the kinase whose activity of AuroraA among the breast cancer cell SUM149.
As Fig. 3 b for to have the pyrimidine compound of structural formula (I) to the inhibitory action figure of Aurora-A among the breast cancer cell BT549.The pyrimidine compound that is had structural formula (I) by Fig. 3 b as can be known can suppress the kinase whose activity of AuroraA among the breast cancer cell BT549.
Two, the synthetic pyrimidine compound with structural formula (I) (AKI603) of embodiment 1 is to suppressing the growth experiment of tumor cell in the cell.
The experiment object: leukaemia HL-60, breast cancer cell BT549, MCF-7, and the MCF-7(MCF-7-Epi of epirubicin drug resistance), MDA-MB-231, MDA-MB-453, MDA-MB-468, Sk-br-3 and SUM149.
Experimental technique: the MCF-7-EPi of leukaemia HL-60 and each breast cancer cell and epirubicin drug resistance is incubated at respectively in 96 orifice plates, adopt the embodiment 1 synthetic pyrimidine compound with structural formula (I) of variable concentrations to handle each tumor cell 24 or add MTT after 48 hours respectively, 37 ° of C cultivated 4 hours, detect the OD value with 490nm, the result is shown in Fig. 4 a to 4i, abscissa is compound concentrations among each figure, and vertical coordinate is the cell relative survival rate.
Experimental result:
Shown in Fig. 4 a, the pyrimidine compound (concentration is 0 μ M, 0.1 μ M, 0.2 μ M, 0.5 μ M, 1 μ M, 2 μ M, 5 μ M, 10 μ M, 20 μ M) with structural formula (I) has dosage and dependent inhibitory action of time to the growth of HL-60 cell;
Shown in Fig. 4 b, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of BT549 cell;
Shown in Fig. 4 c, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of MCF-7 cell;
Shown in Fig. 4 d, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of MCF-7-Epi cell;
Shown in Fig. 4 e, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-231 cell;
Shown in Fig. 4 f, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-453 cell;
Shown in Fig. 4 g, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-468 cell;
Shown in Fig. 4 h, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of Sk-br-3 cell;
Shown in Fig. 4 i, the pyrimidine compound (concentration is 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M) with structural formula (I) has the inhibitory action of dose dependent to the growth of SUM149 cell.
Three, the embodiment 1 synthetic pyrimidine compound with structural formula (I) (AKI603) cell cycle retardation is tested.
Experiment object: leukaemia HL-60, breast cancer cell BT549 and SUM149.
Test method: the pyrimidine compound with structural formula (I) of getting concentration respectively and be 0,0.1,0.5 and 5 μ M is handled leukaemia HL-60, collecting cell after 24 hours, or concentration is that the pyrimidine compound with structural formula (I) of 0,0.3125,0.625,1.25,2.5 and 5 μ M is handled breast cancer cell BT549 and SUM149, collecting cell after 48 hours, dye with 50 μ g/ml PI in the fixing back of 70% ethanol, adopt flow cytometer to carry out cell cycle and apoptosis (sub-G1) detection, testing result is shown in Fig. 5 a, 5b, 5c.
Experimental result:
Shown in Fig. 5 a, 5b, 5c, in leukaemia HL-60 and breast cancer cell SUM149, BT549, the pyrimidine compound with structural formula (I) that is synthesized shown in all can obviously cause the G2/M cell cycle arrest in the concentration range, and the polyploid phenomenon appears, show to have structural formula the pyrimidine compound of (I) exerts an influence by suppressing Aurora-A and then cell cycle.
Shown in Fig. 5 a, 5b, 5c, in leukaemia HL-60 and breast cancer cell SUM149, BT549, the pyrimidine compound with structural formula (I) that is synthesized shown in can promote apoptosis in the concentration range, show as the increase of Sub-G1 peak ratio.This chemical compound all can cause the obvious apoptosis phenomenon in above-mentioned cell when concentration 5 μ M.
Four, the synthetic pyrimidine compound with structural formula (I) (AKI603) of embodiment 1 experiment that the clone who suppresses tumor cell in the cell is formed.
Experiment object: breast cancer cell BT549 and SUM149.
Test method: each breast cancer cell BT549 and SUM149 are incubated at 6 orifice plates with the density in 103/ hole, be that the synthetic pyrimidine compound with structural formula (I) of embodiment 1 of 0 μ M, 0.625 μ M, 1.25 μ M is handled each tumor cell with concentration respectively behind the cell attachment, observe clone's number after 6 days with violet staining, observed result as shown in Figure 6.
Experimental result: as shown in Figure 6, in breast cancer cell SUM149 and BT549, the clonality of the dose-dependent inhibition tumor cell of pyrimidine compound energy with structure formula I of variable concentrations, the result shows that further this chemical compound has the effect that suppresses tumor growth.
The flow cytometer of the cell after five, the embodiment 1 synthetic pyrimidine compound with structural formula (I) (AKI603) is handled detects the CD24-CD44+ change of Expression.
Experiment object: breast cancer cell MCF-7 and MCF-7-Epi.
Test method:
Be that the epirubicin of 0 μ M, 0.049 μ M, 0.097 μ M, 0.195 μ M, 0.39 μ M, 0.78 μ M, 1.56 μ M, 3.13 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M is handled each breast cancer cell with concentration, add MTT after 48 hours, 37 ° of C cultivated 4 hours, detect the OD value with 490nm, test result is shown in Fig. 7 a;
Collect each breast cancer cell, with CD24 and CD44 antibody staining, the CD24-CD44+ change of Expression that adopts flow cytometer to detect, test result is shown in Fig. 7 b;
Employing concentration is that the embodiment 1 synthetic pyrimidine compound with structural formula (I) of 0.625 μ M is handled breast cancer cell MCF-7-EPi, difference 0 day, 6 days and 9 days collecting cells, with CD24 and CD44 antibody staining, the CD24-CD44+ change of Expression that adopts flow cytometer to detect, test result is shown in Fig. 7 c; The CD24-CD44+ of this breast cancer cell MCF-7-Epi after the pyrimidine compound that the present invention has a structural formula (I) is handled expresses the statistical result that changes shown in Fig. 7 d, L1 is contrast statistics line among the 7d, and L2 is for having the pyrimidine compound statistics line of structural formula (I).
Experimental result: shown in 7a, breast cancer cell MCF-7-Epi shows as tangible epirubicin drug resistance, and shown in Fig. 7 b, CD24-CD44+ breast carcinoma stem cell ratio obviously rises.As Fig. 7 c and 7d adopt have a pyrimidine compound effect of structural formula (I) after, observe the ratio of breast carcinoma stem cell respectively 0 day, 6 days and 9 days, found that the have structural formula pyrimidine compound of (I) obviously suppresses the ratio of CD24-CD44+ breast carcinoma stem cell, illustrate that this chemical compound can target killing tumor cell, also can the target killing tumor stem cell, have superiority than traditional chemotherapeutics.
Be the preferred embodiments of the present invention only below, be not limited to the present invention, for a person skilled in the art, the present invention can have various changes and variation.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (10)

  1. A pyrimidine derivatives preparation prevent and/or treat and/or the medicine of adjuvant therapy of tumors in purposes, it is characterized in that, described pyrimidine derivatives comprises have structural formula pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, the prodrug of (I), the compositions that perhaps contains described pyrimidine compound
    (I) is as follows for described structural formula:
    Figure FDA00002695813000011
  2. 2. purposes according to claim 1 is characterized in that, synthetic described method with pyrimidine compound of structural formula (I) may further comprise the steps:
    Compd A and the 1-methyl piperazine that will have structural formula (1) are dissolved in 1, the 4-dioxane 160～200 ℃ according to mol ratio 1:8～12, microwave reaction 30～60 minutes, reaction gained mixture is spin-dried for solvent, namely gets described pyrimidine compound with structural formula (I)
    Figure FDA00002695813000012
    Wherein, X is halogen in the formula (1).
  3. 3. purposes according to claim 2, it is characterized in that, be spin-dried for the step that further comprises after the solvent processing with the silicagel column purification in the method for synthetic described pyrimidine compound with structural formula (I), be to be that dichloromethane and the methanol mixed solvent of 100:1～60:1 carries out eluting with volume ratio with the step of silicagel column purification, collect the described pyrimidine compound with structural formula (I) of purification.
  4. 4. purposes according to claim 2 is characterized in that, the method for synthetic described compd A is as follows:
    To have compd B and the paranitroanilinum of structural formula (2), p-methyl benzenesulfonic acid is dissolved in the n-butyl alcohol according to mol ratio 1:1～1.2:0.8～1, and 130～150 ℃ of following back flow reaction 12～16h are cooled to room temperature after the reaction, add saturated NaHCO 3Solution is regulated pH to 7～8, uses ethyl acetate extraction 3～5 times, and organic layer is used anhydrous Na again with saturated common salt water washing 3～5 times 2SO 4Drying is spin-dried for solvent and namely gets compd A,
    Figure FDA00002695813000021
    Wherein, X is halogen in the formula (2).
  5. 5. purposes according to claim 4 is characterized in that, is spin-dried in the method for synthetic described compd A further to comprise with methanol after the solvent processing and grinding, and namely gets described compd A behind the sucking filtration.
  6. 6. purposes according to claim 4 is characterized in that, the method for synthetic described compd B is as follows:
    With 2,4,6-three halogenated pyrimidines and 3-amino-5-methylpyrazole are dissolved in the dehydrated alcohol according to mol ratio 1:1～2, add triethylamine, 0 ℃ of stirring reaction 8～16h is after reaction stops, in reaction system, add water, separate out sucking filtration behind the white solid, adopt frozen water and ice methanol wash successively, obtain described compd B after the drying.
  7. 7. purposes according to claim 6 is characterized in that, described in the method for synthetic described compd B with structural formula (2) 2,4,6-three halogenated pyrimidines are 2,4,6-trichloropyrimidine.
  8. 8. according to the purposes described in each in the claim 1 to 7, it is characterized in that the tumor of described tumor for causing because of the kinase whose unconventionality expression of Aurora.
  9. 9. purposes according to claim 8 is characterized in that, described tumor is nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
  10. 10. the purposes of pyrimidine derivatives extracorporeal suppression tumor cell growth, it is characterized in that, described pyrimidine derivatives comprises have structural formula pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, the prodrug of (I), the compositions that perhaps contains described pyrimidine compound
    (I) is as follows for described structural formula:
    Figure FDA00002695813000022
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